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700 | 12,385,856 | 1,631 | A conformation analysis device and analysis method with which discrimination can be achieved even if there is a subtle difference in a conformational structure, a given molecule can be processed in a unified manner, and large-scale computer processing can be performed, and a conformational notation device and notation method with which even in the case where a conformation cannot be uniquely determined if a rule in accordance with the IUPAC Nomenclature is followed, the conformation can be uniquely notated, a given molecule can be processed in a unified manner, and large-scale computer processing can be performed, are provided. In one embodiment of the invention, a processing section receives an input of a chemical structural formula of a compound to be analyzed, puts a predetermined code indicating a dihedral angle to each chemical binding site based on the received chemical structural formula, extracts an encoded conformational notation of interest with respect to a structure capable of uniquely determining a conformation with one conformational notation, and stores the extracted encoded conformational notation in a storage section. Then, the processing section creates a molecular model based on the extracted encoded conformational notation, performs geometry optimization and frequency calculation for the created molecular model, determines a geometry optimized structure and a physical property value of the geometry optimized structure, extracts the encoded conformational notation from the storage section, and performs a homology analysis based on the notation. | 1. A conformation analysis method characterized in that:
a processing section receives an input of a chemical structural formula of a compound to be analyzed; the processing section puts a predetermined code indicating a dihedral angle to each chemical binding site based on the received chemical structural formula, extracts an encoded conformational notation of interest with respect to a structure capable of uniquely determining a conformation with one conformational notation and stores the extracted encoded conformational notation in a storage section; the processing section creates a molecular model based on the extracted encoded conformational notation; the processing section performs geometry optimization and frequency calculation for the created molecular model and determines a geometry optimized structure and a physical property value of the geometry optimized structure; and the processing section extracts the encoded conformational notation from the storage section and performs a homology analysis based on the notation. 2. The conformation analysis method according to claim 1, characterized in that the compound to be analyzed is an optically active molecule and a conformational structure of the optically active molecule in a liquid phase is verified by comparing an observed vibrational circular dichroism spectrum with a predicted spectrum obtained from candidate conformations. 3. The conformation analysis method according to claim 1, characterized in that as a method for indicating the dihedral angle, a rule in accordance with the IUPAC Notation is included. 4. A conformation analysis device characterized by comprising:
a unit which receives an input of a chemical structural formula of a compound to be analyzed; a unit which puts a predetermined code indicating a dihedral angle to each chemical binding site based on the received chemical structural formula, extracts an encoded conformational notation of interest with respect to a structure capable of uniquely determining a conformation with one conformational notation and stores the extracted encoded conformational notation in a storage unit; a unit which creates a molecular model based on the extracted encoded conformational notation; a unit which performs geometry optimization and frequency calculation for the created molecular model and determines a geometry optimized structure and a physical property value of the geometry optimized structure; and a unit which extracts the encoded conformational notation from the storage unit and performs a homology analysis based on the notation. 5. The conformation analysis device according to claim 4, characterized in that in the case where the compound to be analyzed is an optically active molecule, the device further comprises a unit which compares an observed vibrational circular dichroism spectrum with a predicted spectrum obtained from candidate conformations and verifies a conformational structure of the optically active molecule in a liquid phase. 6. The conformation analysis device according to claim 4, characterized in that as a method for indicating the dihedral angle, a rule in accordance with the IUPAC Notation is included. 7. A conformational notation method characterized in that:
a processing section receives an input of a molecular model of a compound to be analyzed; with respect to a structure capable of uniquely determining a conformation with one conformational notation (hereinafter, referred to as an encoded conformational notation) expressed in a notation using two types of codes determined by dividing 360 degrees into six segments, putting predetermined codes to the respective divided segments, further dividing the respective divided segments into two segments and putting other predetermined codes to the respective further divided segments by expressing each chemical binding site in the encoded conformational notation based on the received molecular model, the processing section extracts an encoded conformational notation which is required for the conformational notation and is obtained by leaving a notation of a chemical bond of interest and omitting an unnecessary notation from the molecular model and stores the extracted encoded conformational notation in a storage section; the processing section stores physical property values including an observed measured value and a calculated predicted value which are in a correspondence relation with the compound to be analyzed in the storage section; and the processing section extracts the encoded conformational notation and the physical property values which are in a correspondence relation with the compound to be analyzed from the storage section. 8. The conformational notation method according to claim 7, characterized in that in the case where a plurality of molecular models correspond to one encoded conformational notation, the conformation can be uniquely determined by putting a new code. 9. The conformational notation method according to claim 7, characterized in that in the case where one molecular model can be expressed in a plurality of the encoded conformational notations, the conformation can be uniquely determined by following a predetermined priority rule and selecting the encoded conformational notation. 10. The conformational notation method according to claim 8, characterized in that in the case where one molecular model can be expressed in a plurality of the encoded conformational notations, the conformation can be uniquely determined by following a predetermined priority rule and selecting the encoded conformational notation. 11. A conformational notation device characterized in that:
a processing section receives an input of a molecular model of a compound to be analyzed; with respect to a structure capable of uniquely determining a conformation with one conformational notation (hereinafter, referred to as an encoded conformational notation) expressed in a notation using two types of codes determined by dividing 360 degrees into six segments, putting predetermined codes to the respective divided segments, further dividing the respective divided segments into two segments and putting other predetermined codes to the respective further divided segments by expressing each chemical binding site in the encoded conformational notation based on the received molecular model, the processing section extracts an encoded conformational notation which is required for the conformational notation and is obtained by leaving a notation of a chemical bond of interest and omitting an unnecessary notation from the molecular model and stores the extracted encoded conformational notation in a storage section; the processing section stores physical property values including an observed measured value and a calculated predicted value which are in a correspondence relation with the compound to be analyzed in the storage section; and the processing section extracts the encoded conformational notation and the physical property values which are in a correspondence relation with the compound to be analyzed from the storage section. 12. The conformational notation device according to claim 11, characterized in that in the case where a plurality of molecular models correspond to one encoded conformational notation, the conformation can be uniquely determined by putting a new code. 13. The conformational notation device according to claim 11, characterized in that in the case where one molecular model can be expressed in a plurality of the encoded conformational notations, the conformation can be uniquely determined by following a predetermined priority rule and selecting the encoded conformational notation. 14. The conformational notation device according to claim 12, characterized in that in the case where one molecular model can be expressed in a plurality of the encoded conformational notations, the conformation can be uniquely determined by following a predetermined priority rule and selecting the encoded conformational notation. 15. The conformation analysis method according to claim 2, characterized in that as a method for indicating the dihedral angle, a rule in accordance with the IUPAC Notation is included. 16. The conformation analysis device according to claim 5, characterized in that as a method for indicating the dihedral angle, a rule in accordance with the IUPAC Notation is included. | A conformation analysis device and analysis method with which discrimination can be achieved even if there is a subtle difference in a conformational structure, a given molecule can be processed in a unified manner, and large-scale computer processing can be performed, and a conformational notation device and notation method with which even in the case where a conformation cannot be uniquely determined if a rule in accordance with the IUPAC Nomenclature is followed, the conformation can be uniquely notated, a given molecule can be processed in a unified manner, and large-scale computer processing can be performed, are provided. In one embodiment of the invention, a processing section receives an input of a chemical structural formula of a compound to be analyzed, puts a predetermined code indicating a dihedral angle to each chemical binding site based on the received chemical structural formula, extracts an encoded conformational notation of interest with respect to a structure capable of uniquely determining a conformation with one conformational notation, and stores the extracted encoded conformational notation in a storage section. Then, the processing section creates a molecular model based on the extracted encoded conformational notation, performs geometry optimization and frequency calculation for the created molecular model, determines a geometry optimized structure and a physical property value of the geometry optimized structure, extracts the encoded conformational notation from the storage section, and performs a homology analysis based on the notation.1. A conformation analysis method characterized in that:
a processing section receives an input of a chemical structural formula of a compound to be analyzed; the processing section puts a predetermined code indicating a dihedral angle to each chemical binding site based on the received chemical structural formula, extracts an encoded conformational notation of interest with respect to a structure capable of uniquely determining a conformation with one conformational notation and stores the extracted encoded conformational notation in a storage section; the processing section creates a molecular model based on the extracted encoded conformational notation; the processing section performs geometry optimization and frequency calculation for the created molecular model and determines a geometry optimized structure and a physical property value of the geometry optimized structure; and the processing section extracts the encoded conformational notation from the storage section and performs a homology analysis based on the notation. 2. The conformation analysis method according to claim 1, characterized in that the compound to be analyzed is an optically active molecule and a conformational structure of the optically active molecule in a liquid phase is verified by comparing an observed vibrational circular dichroism spectrum with a predicted spectrum obtained from candidate conformations. 3. The conformation analysis method according to claim 1, characterized in that as a method for indicating the dihedral angle, a rule in accordance with the IUPAC Notation is included. 4. A conformation analysis device characterized by comprising:
a unit which receives an input of a chemical structural formula of a compound to be analyzed; a unit which puts a predetermined code indicating a dihedral angle to each chemical binding site based on the received chemical structural formula, extracts an encoded conformational notation of interest with respect to a structure capable of uniquely determining a conformation with one conformational notation and stores the extracted encoded conformational notation in a storage unit; a unit which creates a molecular model based on the extracted encoded conformational notation; a unit which performs geometry optimization and frequency calculation for the created molecular model and determines a geometry optimized structure and a physical property value of the geometry optimized structure; and a unit which extracts the encoded conformational notation from the storage unit and performs a homology analysis based on the notation. 5. The conformation analysis device according to claim 4, characterized in that in the case where the compound to be analyzed is an optically active molecule, the device further comprises a unit which compares an observed vibrational circular dichroism spectrum with a predicted spectrum obtained from candidate conformations and verifies a conformational structure of the optically active molecule in a liquid phase. 6. The conformation analysis device according to claim 4, characterized in that as a method for indicating the dihedral angle, a rule in accordance with the IUPAC Notation is included. 7. A conformational notation method characterized in that:
a processing section receives an input of a molecular model of a compound to be analyzed; with respect to a structure capable of uniquely determining a conformation with one conformational notation (hereinafter, referred to as an encoded conformational notation) expressed in a notation using two types of codes determined by dividing 360 degrees into six segments, putting predetermined codes to the respective divided segments, further dividing the respective divided segments into two segments and putting other predetermined codes to the respective further divided segments by expressing each chemical binding site in the encoded conformational notation based on the received molecular model, the processing section extracts an encoded conformational notation which is required for the conformational notation and is obtained by leaving a notation of a chemical bond of interest and omitting an unnecessary notation from the molecular model and stores the extracted encoded conformational notation in a storage section; the processing section stores physical property values including an observed measured value and a calculated predicted value which are in a correspondence relation with the compound to be analyzed in the storage section; and the processing section extracts the encoded conformational notation and the physical property values which are in a correspondence relation with the compound to be analyzed from the storage section. 8. The conformational notation method according to claim 7, characterized in that in the case where a plurality of molecular models correspond to one encoded conformational notation, the conformation can be uniquely determined by putting a new code. 9. The conformational notation method according to claim 7, characterized in that in the case where one molecular model can be expressed in a plurality of the encoded conformational notations, the conformation can be uniquely determined by following a predetermined priority rule and selecting the encoded conformational notation. 10. The conformational notation method according to claim 8, characterized in that in the case where one molecular model can be expressed in a plurality of the encoded conformational notations, the conformation can be uniquely determined by following a predetermined priority rule and selecting the encoded conformational notation. 11. A conformational notation device characterized in that:
a processing section receives an input of a molecular model of a compound to be analyzed; with respect to a structure capable of uniquely determining a conformation with one conformational notation (hereinafter, referred to as an encoded conformational notation) expressed in a notation using two types of codes determined by dividing 360 degrees into six segments, putting predetermined codes to the respective divided segments, further dividing the respective divided segments into two segments and putting other predetermined codes to the respective further divided segments by expressing each chemical binding site in the encoded conformational notation based on the received molecular model, the processing section extracts an encoded conformational notation which is required for the conformational notation and is obtained by leaving a notation of a chemical bond of interest and omitting an unnecessary notation from the molecular model and stores the extracted encoded conformational notation in a storage section; the processing section stores physical property values including an observed measured value and a calculated predicted value which are in a correspondence relation with the compound to be analyzed in the storage section; and the processing section extracts the encoded conformational notation and the physical property values which are in a correspondence relation with the compound to be analyzed from the storage section. 12. The conformational notation device according to claim 11, characterized in that in the case where a plurality of molecular models correspond to one encoded conformational notation, the conformation can be uniquely determined by putting a new code. 13. The conformational notation device according to claim 11, characterized in that in the case where one molecular model can be expressed in a plurality of the encoded conformational notations, the conformation can be uniquely determined by following a predetermined priority rule and selecting the encoded conformational notation. 14. The conformational notation device according to claim 12, characterized in that in the case where one molecular model can be expressed in a plurality of the encoded conformational notations, the conformation can be uniquely determined by following a predetermined priority rule and selecting the encoded conformational notation. 15. The conformation analysis method according to claim 2, characterized in that as a method for indicating the dihedral angle, a rule in accordance with the IUPAC Notation is included. 16. The conformation analysis device according to claim 5, characterized in that as a method for indicating the dihedral angle, a rule in accordance with the IUPAC Notation is included. | 1,600 |
701 | 14,749,966 | 1,628 | The present invention provides a triazolopyridine compound having a prolyl hydroxylase inhibitory action and an erythropoietin production-inducing ability. The present invention relates to a compound represented by the following formula [I]:
wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof, or a solvate thereof, as well as a prolyl hydroxylase inhibitor or erythropoietin production-inducing agent containing the compound. The compound of the present invention shows a prolyl hydroxylase inhibitory action and an erythropoietin production-inducing ability and is useful as a prophylactic or therapeutic agent for various diseases and pathologies (disorders) caused by decreased production of erythropoietin. | 1. A compound represented by the following formula [I], or a pharmaceutically acceptable salt thereof, or a solvate thereof:
wherein
the partial structural formula:
is a group represented by any of the following formulas:
R1 is
(1) a hydrogen atom,
(2) a C1-6 alkyl group,
(3) a C6-14 aryl group,
(4) a C3-8 cycloalkyl group,
(5) a C6-14 aryl-C1-6 alkyl group, or
(6) a C3-8 cycloalkyl-C1-6 alkyl group;
R2 is
(1) a hydrogen atom,
(2) a C1-10 alkyl group,
(3) a C6-14 aryl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(4) a C3-8 cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(5) a C3-8 cycloalkenyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(6) a heteroaryl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B (wherein the heteroaryl has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom),
(7) a C6-14 aryl-C1-6 alkyl group (wherein C6-14 aryl is optionally substituted by the same or different 1 to 5 substituents selected from the following group B), or
(8) a C3-8 cycloalkyl-C1-6 alkyl group (wherein C3-8 cycloalkyl is optionally substituted by the same or different 1 to 5 substituents selected from the following group B);
R3 is
(1) a hydrogen atom,
(2) a halogen atom,
(3) a C1-6 alkyl group,
(4) a C6-14 aryl group,
(5) a C3-8 cycloalkyl group, or
(6) a C6-14 aryl-C1-6 alkyl group; and
R4 and R5 are each independently
(1) a hydrogen atom, or
(2) a C1-6 alkyl group,
group B:
(a) a halogen atom,
(b) a C1-6 alkyl group,
(c) a C3-8 cycloalkyl group,
(d) a cyano group, and
(e) a halo-C1-6 alkyl group. 2. The compound according to claim 1 wherein the partial structural formula:
is a group represented by the following formula
or a pharmaceutically acceptable salt thereof, or a solvate thereof. 3. The compound according to claim 1, wherein the partial structural formula:
is a group represented by the following formula
or a pharmaceutically acceptable salt thereof, or a solvate thereof. 4. The compound according to claim 1, wherein the partial structural formula:
is a group represented by the following formula
or a pharmaceutically acceptable salt thereof, or a solvate thereof. 5. The compound according to claim 1, wherein the partial structural formula:
is a group represented by the following formula
or a pharmaceutically acceptable salt thereof, or a solvate thereof. 6. The compound according to claim 1, wherein both R4 and R5 are hydrogen atoms, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 7. The compound according to claim 1, wherein R3 is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 8. The compound according to claim 1, wherein R1 is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 9. The compound according to claim 1, wherein R2 is
(1) a C1-10 alkyl group, (2) a C6-14 aryl group optionally substituted by the same or different 1 to 5 substituents selected from the above-mentioned group B, (3) a C6-14 aryl-C1-6 alkyl group (wherein C6-14 aryl is optionally substituted by the same or different 1 to 5 substituents selected from the above-mentioned group B), or (4) a C3-8 cycloalkyl-C1-6 alkyl group (wherein C3-8 cycloalkyl is optionally substituted by the same or different 1 to 5 substituents selected from the above-mentioned group B), or a pharmaceutically acceptable salt thereof, or a solvate thereof. 10. The compound according to claim 2, wherein both R4 and R5 are hydrogen atoms, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 11. The compound according to claim 10, wherein R3 is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 12. The compound according to claim 11, wherein R1 is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 13. The compound according to claim 12, wherein R2 is
(1) a C1-10 alkyl group, or (2) a C6-14 aryl-C1-6 alkyl group (wherein C6-14 aryl is optionally substituted by the same or different 1 to 5 substituents selected from the above-mentioned group B), or a pharmaceutically acceptable salt thereof, or a solvate thereof. 14. A compound represented by the following formula [I-1] or a pharmaceutically acceptable salt thereof, or a solvate thereof:
wherein the partial structural formula:
is a group represented by:
R11 is
(1) a hydrogen atom,
(2) a C1-6 alkyl group,
(3) a phenyl group,
(4) a C3-8 cycloalkyl group,
(5) a phenyl-C1-6 alkyl group, or
(6) a C3-8 cycloalkyl-C1-6 alkyl group;
R21 is
(1) a hydrogen atom,
(2) a C1-10 alkyl group,
(3) a phenyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(4) a C3-8 cycloalkyl group,
(5) a C3-8 cycloalkenyl group,
(6) a thienyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(7) a phenyl-C1-6 alkyl group (wherein phenyl is optionally substituted by the same or different 1 to 5 substituents selected from the following group B), or
(8) a C3-8 cycloalkyl-C1-6 alkyl group;
R31 is
(1) a hydrogen atom,
(2) a halogen atom,
(3) a C1-6 alkyl group,
(4) a phenyl group,
(5) a C3-8 cycloalkyl group, or
(6) a phenyl-C1-6 alkyl group; and
R41 and R51 are each independently
(1) a hydrogen atom, or
(2) a C1-6 alkyl group
group B:
(a) a halogen atom,
(b) a C1-6 alkyl group,
(c) a C3-8 cycloalkyl group,
(d) a cyano group, and
(e) a halo-C1-6 alkyl group. 15.-25. (canceled) 26. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier. 27.-34. (canceled) 35. A method of inhibiting prolyl hydroxylase, comprising administering an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof to a mammal. 36. A method of inducing erythropoietin production, comprising administering an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof to a mammal. 37. A method of treating anemia, comprising administering an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof to a mammal. 38. A method of treating renal anemia, comprising administering an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof to a mammal. 39. A commercial package comprising the pharmaceutical composition according to claim 26 and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for the treatment or prophylaxis of a disease selected from anemia and renal anemia. 40. A kit comprising the pharmaceutical composition according to claim 26 and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for the treatment or prophylaxis of a disease selected from anemia and renal anemia. | The present invention provides a triazolopyridine compound having a prolyl hydroxylase inhibitory action and an erythropoietin production-inducing ability. The present invention relates to a compound represented by the following formula [I]:
wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof, or a solvate thereof, as well as a prolyl hydroxylase inhibitor or erythropoietin production-inducing agent containing the compound. The compound of the present invention shows a prolyl hydroxylase inhibitory action and an erythropoietin production-inducing ability and is useful as a prophylactic or therapeutic agent for various diseases and pathologies (disorders) caused by decreased production of erythropoietin.1. A compound represented by the following formula [I], or a pharmaceutically acceptable salt thereof, or a solvate thereof:
wherein
the partial structural formula:
is a group represented by any of the following formulas:
R1 is
(1) a hydrogen atom,
(2) a C1-6 alkyl group,
(3) a C6-14 aryl group,
(4) a C3-8 cycloalkyl group,
(5) a C6-14 aryl-C1-6 alkyl group, or
(6) a C3-8 cycloalkyl-C1-6 alkyl group;
R2 is
(1) a hydrogen atom,
(2) a C1-10 alkyl group,
(3) a C6-14 aryl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(4) a C3-8 cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(5) a C3-8 cycloalkenyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(6) a heteroaryl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B (wherein the heteroaryl has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom),
(7) a C6-14 aryl-C1-6 alkyl group (wherein C6-14 aryl is optionally substituted by the same or different 1 to 5 substituents selected from the following group B), or
(8) a C3-8 cycloalkyl-C1-6 alkyl group (wherein C3-8 cycloalkyl is optionally substituted by the same or different 1 to 5 substituents selected from the following group B);
R3 is
(1) a hydrogen atom,
(2) a halogen atom,
(3) a C1-6 alkyl group,
(4) a C6-14 aryl group,
(5) a C3-8 cycloalkyl group, or
(6) a C6-14 aryl-C1-6 alkyl group; and
R4 and R5 are each independently
(1) a hydrogen atom, or
(2) a C1-6 alkyl group,
group B:
(a) a halogen atom,
(b) a C1-6 alkyl group,
(c) a C3-8 cycloalkyl group,
(d) a cyano group, and
(e) a halo-C1-6 alkyl group. 2. The compound according to claim 1 wherein the partial structural formula:
is a group represented by the following formula
or a pharmaceutically acceptable salt thereof, or a solvate thereof. 3. The compound according to claim 1, wherein the partial structural formula:
is a group represented by the following formula
or a pharmaceutically acceptable salt thereof, or a solvate thereof. 4. The compound according to claim 1, wherein the partial structural formula:
is a group represented by the following formula
or a pharmaceutically acceptable salt thereof, or a solvate thereof. 5. The compound according to claim 1, wherein the partial structural formula:
is a group represented by the following formula
or a pharmaceutically acceptable salt thereof, or a solvate thereof. 6. The compound according to claim 1, wherein both R4 and R5 are hydrogen atoms, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 7. The compound according to claim 1, wherein R3 is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 8. The compound according to claim 1, wherein R1 is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 9. The compound according to claim 1, wherein R2 is
(1) a C1-10 alkyl group, (2) a C6-14 aryl group optionally substituted by the same or different 1 to 5 substituents selected from the above-mentioned group B, (3) a C6-14 aryl-C1-6 alkyl group (wherein C6-14 aryl is optionally substituted by the same or different 1 to 5 substituents selected from the above-mentioned group B), or (4) a C3-8 cycloalkyl-C1-6 alkyl group (wherein C3-8 cycloalkyl is optionally substituted by the same or different 1 to 5 substituents selected from the above-mentioned group B), or a pharmaceutically acceptable salt thereof, or a solvate thereof. 10. The compound according to claim 2, wherein both R4 and R5 are hydrogen atoms, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 11. The compound according to claim 10, wherein R3 is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 12. The compound according to claim 11, wherein R1 is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof. 13. The compound according to claim 12, wherein R2 is
(1) a C1-10 alkyl group, or (2) a C6-14 aryl-C1-6 alkyl group (wherein C6-14 aryl is optionally substituted by the same or different 1 to 5 substituents selected from the above-mentioned group B), or a pharmaceutically acceptable salt thereof, or a solvate thereof. 14. A compound represented by the following formula [I-1] or a pharmaceutically acceptable salt thereof, or a solvate thereof:
wherein the partial structural formula:
is a group represented by:
R11 is
(1) a hydrogen atom,
(2) a C1-6 alkyl group,
(3) a phenyl group,
(4) a C3-8 cycloalkyl group,
(5) a phenyl-C1-6 alkyl group, or
(6) a C3-8 cycloalkyl-C1-6 alkyl group;
R21 is
(1) a hydrogen atom,
(2) a C1-10 alkyl group,
(3) a phenyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(4) a C3-8 cycloalkyl group,
(5) a C3-8 cycloalkenyl group,
(6) a thienyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B,
(7) a phenyl-C1-6 alkyl group (wherein phenyl is optionally substituted by the same or different 1 to 5 substituents selected from the following group B), or
(8) a C3-8 cycloalkyl-C1-6 alkyl group;
R31 is
(1) a hydrogen atom,
(2) a halogen atom,
(3) a C1-6 alkyl group,
(4) a phenyl group,
(5) a C3-8 cycloalkyl group, or
(6) a phenyl-C1-6 alkyl group; and
R41 and R51 are each independently
(1) a hydrogen atom, or
(2) a C1-6 alkyl group
group B:
(a) a halogen atom,
(b) a C1-6 alkyl group,
(c) a C3-8 cycloalkyl group,
(d) a cyano group, and
(e) a halo-C1-6 alkyl group. 15.-25. (canceled) 26. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier. 27.-34. (canceled) 35. A method of inhibiting prolyl hydroxylase, comprising administering an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof to a mammal. 36. A method of inducing erythropoietin production, comprising administering an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof to a mammal. 37. A method of treating anemia, comprising administering an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof to a mammal. 38. A method of treating renal anemia, comprising administering an effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof to a mammal. 39. A commercial package comprising the pharmaceutical composition according to claim 26 and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for the treatment or prophylaxis of a disease selected from anemia and renal anemia. 40. A kit comprising the pharmaceutical composition according to claim 26 and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for the treatment or prophylaxis of a disease selected from anemia and renal anemia. | 1,600 |
702 | 15,102,511 | 1,618 | The present invention relates to the field of radiopharmaceuticals for in vivo imaging, in particular to a method of purifying a radiotracer which comprises 18 F-labelled aminoxy-functionalised biological targeting moiety. The invention provides radioprotectant-containing radiopharmaceutical compositions of the tracers, as well as associated automated methods and cassettes. | 1. A method of purification of a radiotracer which comprises the following steps:
(a) provision of a radiotracer which comprises an 18F-labelled aminoxy-functionalised biological targeting moiety; (b) adding a radioprotectant to said radiotracer to give a radiotracer solution which comprises said radiotracer in one or more aqueous water-miscible organic solvent(s) of 5 to 25% v/v organic solvent content; (c) passing the radiotracer solution from step (b) through a reverse phase SPE cartridge, wherein the radiotracer is retained on said SPE cartridge; (d) washing the SPE cartridge from step (c) one or more times with a wash solution which comprises an aqueous water-miscible organic solvent(s) solution of a radioprotectant of 15 to 25% v/v organic solvent content; (e) washing the SPE cartridge from step (d) one or more times with water or aqueous buffer solution; (f) eluting the washed SPE cartridge of step (d) or (e) with an elution solvent which comprises a radioprotectant in an aqueous ethanol solution having an ethanol content of 35 to 80% v/v, wherein the eluent comprises purified radiotracer in said elution solvent;
wherein each radioprotectant independently comprises one or more of: ascorbic acid; para-aminobenzoic acid; and gentisic acid, and salts thereof with a biocompatible cation. 2. The method of claim 1, where the water-miscible organic solvent of the radiotracer solution comprises acetonitrile. 3. The method of claim 2, where the radiotracer solution of step (b) comprises 0.5 to 5% v/v ethanol. 4. The method of claim 1, wherein the SPE cartridge is a C18 SPE cartridge. 5. The method of claim 1 wherein the elution solvent of step (f) comprises 35 to 70% v/v aqueous ethanol. 6. (canceled) 7. (canceled) 8. The method of claim 1, where the radioprotectant comprises 4-aminobenzoic acid, or a salt thereof with a biocompatible cation. 9. The method of claim 8, where the BTM comprises a single amino acid, a 3-100 mer peptide, an enzyme substrate, an enzyme antagonist an enzyme agonist, an enzyme inhibitor or a receptor-binding compound. 10. The method of claim 9, where the BTM comprises an Affibody™. 11. The method of claim 9, where the BTM comprises a 3-100 mer peptide which is chosen from Peptide A, Peptide B, Peptide C and Peptide D as defined below:
(i) Peptide A=an Arg-Gly-Asp peptide; (ii) Peptide B=an Arg-Gly-Asp peptide which comprises the fragment
(iii) Peptide C=a c-Met binding cyclic peptide which comprises the amino acid sequence:
-Cysa-X1-Cysc-X2-Gly-Pro-Pro-X3-Phe-Glu-Cysd-Trp-
Cysb-Tyr-X4-X5-X6-
wherein X1 is Asn, His or Tyr;
X2 is Gly, Ser, Thr or Asn;
X3 is Thr or Arg;
X4 is Ala, Asp, Glu, Gly or Ser;
X5 is Ser or Thr;
X6 is Asp or Glu;
and Cysa-d are each cysteine residues such that residues a and b as well as c and d are cyclised to form two separate disulfide bonds;
(iv) Peptide D=a lantibiotic peptide of formula:
Cysa-Xaa-Gln-Serb-Cysc-Serd-Phe-Gly-Pro-Phe-Thrc-
Phe-Val-Cysb-(HO-Asp)-Gly-Asn-Thra-Lysd
wherein Xaa is Arg or Lys;
Cysa-Thra, Serb-Cysb and Cysc-Thrc are covalently linked via thioether bonds;
Serd-Lysd are covalently linked via a lysinoalanine bond;
HO-Asp is β-hydroxyaspartic acid. 12. A method of preparation of a radiopharmaceutical composition, said composition comprising:
(i) the radiotracer as defined in claim 1; (ii) at least one radioprotectant; (iii) a biocompatible carrier which comprises aqueous ethanol having an ethanol content of 0.1 to 10% v/v;
in a form suitable for mammalian administration;
where said method of preparation comprises:
carrying out the radiotracer purification method of steps (a)-(f);
(g) optionally diluting the purified [18F]-radiotracer from step (f) with a biocompatible carrier;
(h) aseptic filtration of the optionally diluted solution from step (g) to give said [18F] radiopharmaceutical composition. 13. (canceled) 14. The method of claim 12, wherein at least one of steps (b)-(f) or (b)-(h) is automated and where the automation is carried out using an automated synthesizer apparatus. 15. The method of claim 14, where said automated synthesizer apparatus comprises a single use cassette. 16. The method of claim 15, where the single use cassette comprises:
(i) a vessel containing the [18F]-radiotracer solution to be purified; (ii) one or more reverse phase SPE cartridges; (iii) a supply of the wash solution; (iv) a supply of the elution solvent. 17. (canceled) 18. A single use cassette for carrying out the automated method according to claim 15, which comprises:
(i) a vessel suitable for containing the [18F]-radiotracer solution to be purified; (ii) one or more reverse phase SPE cartridges; (iii) a supply of the wash solution; (iv) a supply of the elution solvent. 19. Use of the automated synthesizer apparatus as defined in claim 16, to carry out the method of purification or the method of preparation. | The present invention relates to the field of radiopharmaceuticals for in vivo imaging, in particular to a method of purifying a radiotracer which comprises 18 F-labelled aminoxy-functionalised biological targeting moiety. The invention provides radioprotectant-containing radiopharmaceutical compositions of the tracers, as well as associated automated methods and cassettes.1. A method of purification of a radiotracer which comprises the following steps:
(a) provision of a radiotracer which comprises an 18F-labelled aminoxy-functionalised biological targeting moiety; (b) adding a radioprotectant to said radiotracer to give a radiotracer solution which comprises said radiotracer in one or more aqueous water-miscible organic solvent(s) of 5 to 25% v/v organic solvent content; (c) passing the radiotracer solution from step (b) through a reverse phase SPE cartridge, wherein the radiotracer is retained on said SPE cartridge; (d) washing the SPE cartridge from step (c) one or more times with a wash solution which comprises an aqueous water-miscible organic solvent(s) solution of a radioprotectant of 15 to 25% v/v organic solvent content; (e) washing the SPE cartridge from step (d) one or more times with water or aqueous buffer solution; (f) eluting the washed SPE cartridge of step (d) or (e) with an elution solvent which comprises a radioprotectant in an aqueous ethanol solution having an ethanol content of 35 to 80% v/v, wherein the eluent comprises purified radiotracer in said elution solvent;
wherein each radioprotectant independently comprises one or more of: ascorbic acid; para-aminobenzoic acid; and gentisic acid, and salts thereof with a biocompatible cation. 2. The method of claim 1, where the water-miscible organic solvent of the radiotracer solution comprises acetonitrile. 3. The method of claim 2, where the radiotracer solution of step (b) comprises 0.5 to 5% v/v ethanol. 4. The method of claim 1, wherein the SPE cartridge is a C18 SPE cartridge. 5. The method of claim 1 wherein the elution solvent of step (f) comprises 35 to 70% v/v aqueous ethanol. 6. (canceled) 7. (canceled) 8. The method of claim 1, where the radioprotectant comprises 4-aminobenzoic acid, or a salt thereof with a biocompatible cation. 9. The method of claim 8, where the BTM comprises a single amino acid, a 3-100 mer peptide, an enzyme substrate, an enzyme antagonist an enzyme agonist, an enzyme inhibitor or a receptor-binding compound. 10. The method of claim 9, where the BTM comprises an Affibody™. 11. The method of claim 9, where the BTM comprises a 3-100 mer peptide which is chosen from Peptide A, Peptide B, Peptide C and Peptide D as defined below:
(i) Peptide A=an Arg-Gly-Asp peptide; (ii) Peptide B=an Arg-Gly-Asp peptide which comprises the fragment
(iii) Peptide C=a c-Met binding cyclic peptide which comprises the amino acid sequence:
-Cysa-X1-Cysc-X2-Gly-Pro-Pro-X3-Phe-Glu-Cysd-Trp-
Cysb-Tyr-X4-X5-X6-
wherein X1 is Asn, His or Tyr;
X2 is Gly, Ser, Thr or Asn;
X3 is Thr or Arg;
X4 is Ala, Asp, Glu, Gly or Ser;
X5 is Ser or Thr;
X6 is Asp or Glu;
and Cysa-d are each cysteine residues such that residues a and b as well as c and d are cyclised to form two separate disulfide bonds;
(iv) Peptide D=a lantibiotic peptide of formula:
Cysa-Xaa-Gln-Serb-Cysc-Serd-Phe-Gly-Pro-Phe-Thrc-
Phe-Val-Cysb-(HO-Asp)-Gly-Asn-Thra-Lysd
wherein Xaa is Arg or Lys;
Cysa-Thra, Serb-Cysb and Cysc-Thrc are covalently linked via thioether bonds;
Serd-Lysd are covalently linked via a lysinoalanine bond;
HO-Asp is β-hydroxyaspartic acid. 12. A method of preparation of a radiopharmaceutical composition, said composition comprising:
(i) the radiotracer as defined in claim 1; (ii) at least one radioprotectant; (iii) a biocompatible carrier which comprises aqueous ethanol having an ethanol content of 0.1 to 10% v/v;
in a form suitable for mammalian administration;
where said method of preparation comprises:
carrying out the radiotracer purification method of steps (a)-(f);
(g) optionally diluting the purified [18F]-radiotracer from step (f) with a biocompatible carrier;
(h) aseptic filtration of the optionally diluted solution from step (g) to give said [18F] radiopharmaceutical composition. 13. (canceled) 14. The method of claim 12, wherein at least one of steps (b)-(f) or (b)-(h) is automated and where the automation is carried out using an automated synthesizer apparatus. 15. The method of claim 14, where said automated synthesizer apparatus comprises a single use cassette. 16. The method of claim 15, where the single use cassette comprises:
(i) a vessel containing the [18F]-radiotracer solution to be purified; (ii) one or more reverse phase SPE cartridges; (iii) a supply of the wash solution; (iv) a supply of the elution solvent. 17. (canceled) 18. A single use cassette for carrying out the automated method according to claim 15, which comprises:
(i) a vessel suitable for containing the [18F]-radiotracer solution to be purified; (ii) one or more reverse phase SPE cartridges; (iii) a supply of the wash solution; (iv) a supply of the elution solvent. 19. Use of the automated synthesizer apparatus as defined in claim 16, to carry out the method of purification or the method of preparation. | 1,600 |
703 | 15,634,114 | 1,626 | A dibenzo[f,h]quinoxaline derivative in which impurities are reduced and a novel method of synthesizing the dibenzo[f,h]quinoxaline derivative in which impurities are reduced are provided. In addition, a light-emitting element, a light-emitting device, an electronic appliance, or a lighting device with high emission efficiency and high reliability in which the dibenzo[f,h]quinoxaline derivative is used as an EL material is provided. In the synthesis method, a 2-(chloroaryl)dibenzo[f,h]quinoxaline derivative is used as a synthetic intermediate in a synthetic pathway so that an impurity contained in a final product can be removed easily by purification by sublimation. | 1. A light-emitting element comprising:
a pair of electrodes; and an EL layer between the pair of electrodes, wherein the EL layer contains a dibenzo[f,h]quinoxaline derivative, wherein the dibenzo[f,h]quinoxaline derivative includes hydrogen at a 3-position and an aryl group at a 2-position of a dibenzo[f,h]quinoxaline skeleton, wherein the aryl group includes at least one aryl group or heteroaryl group as a substituent, and wherein the dibenzo[f,h]quinoxaline derivative contains 10 ppm or less of chlorine. 2. A light-emitting element comprising:
a pair of electrodes; and an EL layer between the pair of electrodes, wherein the EL layer contains a light-emitting layer, wherein the light-emitting layer contains a dibenzo[f,h]quinoxaline derivative, wherein the dibenzo[f,h]quinoxaline derivative includes hydrogen at a 3-position and an aryl group at a 2-position of a dibenzo[f,h]quinoxaline skeleton, wherein the aryl group includes at least one aryl group or heteroaryl group as a substituent, and wherein the light-emitting layer contains 10 ppm or less of chlorine. 3. A light-emitting element comprising:
a pair of electrodes; and an EL layer between the pair of electrodes, wherein the EL layer contains a light-emitting layer, wherein the light-emitting layer contains a dibenzo[f,h]quinoxaline derivative, wherein the dibenzo[f,h]quinoxaline derivative includes hydrogen at a 3-position and an aryl group at a 2-position of a dibenzo[f,h]quinoxaline skeleton, wherein the aryl group includes at least one aryl group or heteroaryl group as a substituent, and wherein the dibenzo[f,h]quinoxaline derivative contains 10 ppm or less of chlorine. 4. The light-emitting element according to claim 1,
wherein the dibenzo[f,h]quinozaline derivative represented by General Formula (G1),
wherein Ar1 represents a substituted or unsubstituted arylene group having 6 to 13 carbon atoms, Ar2 represents a substituted or unsubstituted aryl group having 6 to 40 carbon atoms or a substituted or unsubstituted heteroaryl group having 6 to 40 carbon atoms, R1 to R8 separately represent hydrogen, an alkyl group having 1 to 6 carbon atoms, a phenyl group, or a phenyl group having an alkyl group having 1 to 6 carbon atoms as a substituent, and n is any of 1 to 3. 5. The light-emitting element according to claim 2,
wherein the dibenzo[f,h]quinozaline derivative represented by General Formula (G1),
wherein Ar1 represents a substituted or unsubstituted arylene group having 6 to 13 carbon atoms, Ar2 represents a substituted or unsubstituted aryl group having 6 to 40 carbon atoms or a substituted or unsubstituted heteroaryl group having 6 to 40 carbon atoms, R1 to R8 separately represent hydrogen, an alkyl group having 1 to 6 carbon atoms, a phenyl group, or a phenyl group having an alkyl group having 1 to 6 carbon atoms as a substituent, and n is any of 1 to 3. 6. The light-emitting element according to claim 3,
wherein the dibenzo[f,h]quinozaline derivative represented by General Formula (G1),
wherein Ar1 represents a substituted or unsubstituted arylene group having 6 to 13 carbon atoms, Ar2 represents a substituted or unsubstituted aryl group having 6 to 40 carbon atoms or a substituted or unsubstituted heteroaryl group having 6 to 40 carbon atoms, R1 to R8 separately represent hydrogen, an alkyl group having 1 to 6 carbon atoms, a phenyl group, or a phenyl group having an alkyl group having 1 to 6 carbon atoms as a substituent, and n is any of 1 to 3. 7. The light-emitting element according to claim 4,
wherein the heteroaryl group contains one of a carbazole skeleton, a dibenzothiophene skeleton and a dibenzofuran skeleton. 8. The light-emitting element according to claim 5,
wherein the heteroaryl group contains one of a carbazole skeleton, a dibenzothiophene skeleton and a dibenzofuran skeleton. 9. The light-emitting element according to claim 6,
wherein the heteroaryl group contains one of a carbazole skeleton, a dibenzothiophene skeleton and a dibenzofuran skeleton. 10. The light-emitting element according to claim 1,
wherein the dibenzo[f,h]quinozaline derivative represented by Formula (200). 11. The light-emitting element according to claim 2,
wherein the dibenzo[f,h]quinozaline derivative represented by Formula (200). 12. The light-emitting element according to claim 3,
wherein the dibenzo[f,h]quinozaline derivative represented by Formula (200). 13. The light-emitting element according to claim 1,
wherein the light-emitting element keeps 90% or more of an initial luminance after 200 hours under a current with a density of 10 mA/cm2. 14. The light-emitting element according to claim 2,
wherein the light-emitting element keeps 90% or more of an initial luminance after 200 hours under a current with a density of 10 mA/cm2. 15. The light-emitting element according to claim 3,
wherein the light-emitting element keeps 90% or more of an initial luminance after 200 hours under a current with a density of 10 mA/cm2. | A dibenzo[f,h]quinoxaline derivative in which impurities are reduced and a novel method of synthesizing the dibenzo[f,h]quinoxaline derivative in which impurities are reduced are provided. In addition, a light-emitting element, a light-emitting device, an electronic appliance, or a lighting device with high emission efficiency and high reliability in which the dibenzo[f,h]quinoxaline derivative is used as an EL material is provided. In the synthesis method, a 2-(chloroaryl)dibenzo[f,h]quinoxaline derivative is used as a synthetic intermediate in a synthetic pathway so that an impurity contained in a final product can be removed easily by purification by sublimation.1. A light-emitting element comprising:
a pair of electrodes; and an EL layer between the pair of electrodes, wherein the EL layer contains a dibenzo[f,h]quinoxaline derivative, wherein the dibenzo[f,h]quinoxaline derivative includes hydrogen at a 3-position and an aryl group at a 2-position of a dibenzo[f,h]quinoxaline skeleton, wherein the aryl group includes at least one aryl group or heteroaryl group as a substituent, and wherein the dibenzo[f,h]quinoxaline derivative contains 10 ppm or less of chlorine. 2. A light-emitting element comprising:
a pair of electrodes; and an EL layer between the pair of electrodes, wherein the EL layer contains a light-emitting layer, wherein the light-emitting layer contains a dibenzo[f,h]quinoxaline derivative, wherein the dibenzo[f,h]quinoxaline derivative includes hydrogen at a 3-position and an aryl group at a 2-position of a dibenzo[f,h]quinoxaline skeleton, wherein the aryl group includes at least one aryl group or heteroaryl group as a substituent, and wherein the light-emitting layer contains 10 ppm or less of chlorine. 3. A light-emitting element comprising:
a pair of electrodes; and an EL layer between the pair of electrodes, wherein the EL layer contains a light-emitting layer, wherein the light-emitting layer contains a dibenzo[f,h]quinoxaline derivative, wherein the dibenzo[f,h]quinoxaline derivative includes hydrogen at a 3-position and an aryl group at a 2-position of a dibenzo[f,h]quinoxaline skeleton, wherein the aryl group includes at least one aryl group or heteroaryl group as a substituent, and wherein the dibenzo[f,h]quinoxaline derivative contains 10 ppm or less of chlorine. 4. The light-emitting element according to claim 1,
wherein the dibenzo[f,h]quinozaline derivative represented by General Formula (G1),
wherein Ar1 represents a substituted or unsubstituted arylene group having 6 to 13 carbon atoms, Ar2 represents a substituted or unsubstituted aryl group having 6 to 40 carbon atoms or a substituted or unsubstituted heteroaryl group having 6 to 40 carbon atoms, R1 to R8 separately represent hydrogen, an alkyl group having 1 to 6 carbon atoms, a phenyl group, or a phenyl group having an alkyl group having 1 to 6 carbon atoms as a substituent, and n is any of 1 to 3. 5. The light-emitting element according to claim 2,
wherein the dibenzo[f,h]quinozaline derivative represented by General Formula (G1),
wherein Ar1 represents a substituted or unsubstituted arylene group having 6 to 13 carbon atoms, Ar2 represents a substituted or unsubstituted aryl group having 6 to 40 carbon atoms or a substituted or unsubstituted heteroaryl group having 6 to 40 carbon atoms, R1 to R8 separately represent hydrogen, an alkyl group having 1 to 6 carbon atoms, a phenyl group, or a phenyl group having an alkyl group having 1 to 6 carbon atoms as a substituent, and n is any of 1 to 3. 6. The light-emitting element according to claim 3,
wherein the dibenzo[f,h]quinozaline derivative represented by General Formula (G1),
wherein Ar1 represents a substituted or unsubstituted arylene group having 6 to 13 carbon atoms, Ar2 represents a substituted or unsubstituted aryl group having 6 to 40 carbon atoms or a substituted or unsubstituted heteroaryl group having 6 to 40 carbon atoms, R1 to R8 separately represent hydrogen, an alkyl group having 1 to 6 carbon atoms, a phenyl group, or a phenyl group having an alkyl group having 1 to 6 carbon atoms as a substituent, and n is any of 1 to 3. 7. The light-emitting element according to claim 4,
wherein the heteroaryl group contains one of a carbazole skeleton, a dibenzothiophene skeleton and a dibenzofuran skeleton. 8. The light-emitting element according to claim 5,
wherein the heteroaryl group contains one of a carbazole skeleton, a dibenzothiophene skeleton and a dibenzofuran skeleton. 9. The light-emitting element according to claim 6,
wherein the heteroaryl group contains one of a carbazole skeleton, a dibenzothiophene skeleton and a dibenzofuran skeleton. 10. The light-emitting element according to claim 1,
wherein the dibenzo[f,h]quinozaline derivative represented by Formula (200). 11. The light-emitting element according to claim 2,
wherein the dibenzo[f,h]quinozaline derivative represented by Formula (200). 12. The light-emitting element according to claim 3,
wherein the dibenzo[f,h]quinozaline derivative represented by Formula (200). 13. The light-emitting element according to claim 1,
wherein the light-emitting element keeps 90% or more of an initial luminance after 200 hours under a current with a density of 10 mA/cm2. 14. The light-emitting element according to claim 2,
wherein the light-emitting element keeps 90% or more of an initial luminance after 200 hours under a current with a density of 10 mA/cm2. 15. The light-emitting element according to claim 3,
wherein the light-emitting element keeps 90% or more of an initial luminance after 200 hours under a current with a density of 10 mA/cm2. | 1,600 |
704 | 14,978,590 | 1,651 | Provided herein, inter alia, are compositions and kits comprising a bacterial cell and a tumor penetrating agent. Also provided are methods of treating cancer in a subject including the step of administering to the subject an effective amount of a bacterial cell and a tumor penetrating agent. Provided are methods of stimulating an immune system in a subject. The methods include administering to the subject an effective amount of a bacterial cell and a tumor penetrating agent. Also provided are methods of enhancing delivery of an anti-cancer agent to a tumor cell including the step of contacting the tumor cell with a bacterial cell, a tumor penetrating agent and an anti-cancer agent. | 1. A method of treating cancer in a subject comprising administering to the subject a combined effective amount of a bacterial cell and a tumor penetrating agent, wherein administration treats the cancer in the subject. 2. The method of claim 1, wherein the combined effective amount is a combined synergistic amount. 3. A method of stimulating an immune system in a subject comprising administering to the subject a combined effective amount of a bacterial cell and a tumor penetrating agent, wherein administration of the bacterial cell and the tumor penetrating agent stimulates the immune system of the subject. 4. The method of claim 3, wherein the immune response is an anti-cancer immune response. 5. The method of claim 1, further comprising administering to the subject an anti-cancer agent. 6. (canceled) 7. A method of enhancing delivery of an anti-cancer agent to a tumor cell comprising contacting the tumor cell with a bacterial cell, a tumor penetrating agent and an anti-cancer agent, wherein contacting the tumor cell with the bacterial cell and cell penetrating agent enhances delivery of the anti-cancer agent. 8. The method of 5 or 7, wherein the anti-cancer agent is selected from the group consisting of a small molecule, a nucleic acid, a polypeptide, and an antibody. 9. The method of claim 1 or 7, wherein the bacterial cell is a Salmonella bacterial cell. 10. (canceled) 11. The method of claim 9, wherein the Salmonella bacterial cell is selected from the group consisting of YS1646 (ATCC #202165), RE88, LH430, SL7207, χ8429, χ8431 an χ8468. 12. The method of claim 1 or 7, wherein the bacterial cell comprises an antisense nucleic acid. 13. (canceled) 14. The method of claim 12, wherein the antisense nucleic acid targets an immunosuppressive target. 15. The method of claim 14, wherein the immunosuppressive target is STAT3, IDO1, IDO2, Arginase 1, iNOS, CTLA-4, TGF-β, IL-10, pGE2 or VEGF. 16. (canceled) 17. (canceled) 18. The method of claim 12, wherein the antisense nucleic acid is selected from the group consisting of SEQ ID NO:3-31. 19. The method of claim 1 or 7, wherein the tumor penetrating agent is a hyaluronidase polypeptide. 20. (canceled) 21. (canceled) 22. (canceled) 23. (canceled) 24. A composition comprising a Salmonella bacterial cell and a hyaluronidase polypeptide. 25. (canceled) 26. The composition of claim 24, wherein the Salmonella bacterial cell is selected from the group consisting of YS1646 (ATCC #202165), RE88, LH430, SL7207, χ8429, χ8431 an χ8468. 27. The composition of claim 24, wherein the bacterial cell comprises an antisense nucleic acid. 28. (canceled) 29. The composition of claim 27, wherein the antisense nucleic acid targets an immunosuppressive target. 30. (canceled) 31. (canceled) 32. (canceled) 33. The composition of claim 27, wherein the antisense nucleic acid is selected from the group consisting of SEQ ID NO:3-31. 34. (canceled) 35. (canceled) 36. (canceled) 37. The composition of claim 24, further comprising an anti-cancer agent. 38.-41. (canceled) | Provided herein, inter alia, are compositions and kits comprising a bacterial cell and a tumor penetrating agent. Also provided are methods of treating cancer in a subject including the step of administering to the subject an effective amount of a bacterial cell and a tumor penetrating agent. Provided are methods of stimulating an immune system in a subject. The methods include administering to the subject an effective amount of a bacterial cell and a tumor penetrating agent. Also provided are methods of enhancing delivery of an anti-cancer agent to a tumor cell including the step of contacting the tumor cell with a bacterial cell, a tumor penetrating agent and an anti-cancer agent.1. A method of treating cancer in a subject comprising administering to the subject a combined effective amount of a bacterial cell and a tumor penetrating agent, wherein administration treats the cancer in the subject. 2. The method of claim 1, wherein the combined effective amount is a combined synergistic amount. 3. A method of stimulating an immune system in a subject comprising administering to the subject a combined effective amount of a bacterial cell and a tumor penetrating agent, wherein administration of the bacterial cell and the tumor penetrating agent stimulates the immune system of the subject. 4. The method of claim 3, wherein the immune response is an anti-cancer immune response. 5. The method of claim 1, further comprising administering to the subject an anti-cancer agent. 6. (canceled) 7. A method of enhancing delivery of an anti-cancer agent to a tumor cell comprising contacting the tumor cell with a bacterial cell, a tumor penetrating agent and an anti-cancer agent, wherein contacting the tumor cell with the bacterial cell and cell penetrating agent enhances delivery of the anti-cancer agent. 8. The method of 5 or 7, wherein the anti-cancer agent is selected from the group consisting of a small molecule, a nucleic acid, a polypeptide, and an antibody. 9. The method of claim 1 or 7, wherein the bacterial cell is a Salmonella bacterial cell. 10. (canceled) 11. The method of claim 9, wherein the Salmonella bacterial cell is selected from the group consisting of YS1646 (ATCC #202165), RE88, LH430, SL7207, χ8429, χ8431 an χ8468. 12. The method of claim 1 or 7, wherein the bacterial cell comprises an antisense nucleic acid. 13. (canceled) 14. The method of claim 12, wherein the antisense nucleic acid targets an immunosuppressive target. 15. The method of claim 14, wherein the immunosuppressive target is STAT3, IDO1, IDO2, Arginase 1, iNOS, CTLA-4, TGF-β, IL-10, pGE2 or VEGF. 16. (canceled) 17. (canceled) 18. The method of claim 12, wherein the antisense nucleic acid is selected from the group consisting of SEQ ID NO:3-31. 19. The method of claim 1 or 7, wherein the tumor penetrating agent is a hyaluronidase polypeptide. 20. (canceled) 21. (canceled) 22. (canceled) 23. (canceled) 24. A composition comprising a Salmonella bacterial cell and a hyaluronidase polypeptide. 25. (canceled) 26. The composition of claim 24, wherein the Salmonella bacterial cell is selected from the group consisting of YS1646 (ATCC #202165), RE88, LH430, SL7207, χ8429, χ8431 an χ8468. 27. The composition of claim 24, wherein the bacterial cell comprises an antisense nucleic acid. 28. (canceled) 29. The composition of claim 27, wherein the antisense nucleic acid targets an immunosuppressive target. 30. (canceled) 31. (canceled) 32. (canceled) 33. The composition of claim 27, wherein the antisense nucleic acid is selected from the group consisting of SEQ ID NO:3-31. 34. (canceled) 35. (canceled) 36. (canceled) 37. The composition of claim 24, further comprising an anti-cancer agent. 38.-41. (canceled) | 1,600 |
705 | 15,559,395 | 1,612 | The present disclosure related to a method of treating bladder cancer in a subject in need of treatment, by administering to the subject an amount of a prodrug of mitomycin C that yields a therapeutically effective amount of mitomycin C. In one embodiment, the prodrug of mitomycin C is a liposomal-prodrug of mitomycin C. In another embodiment, the liposomal-prodrug of mitomycin C is a folate-targeted liposomal-prodrug of mitomycin C. | 1. A method for treating bladder cancer, comprising:
administering to an individual with bladder cancer liposomes comprising a folate targeting moiety and a prodrug of mitomycin C, the liposomes administered in an amount that yields a therapeutically-effective amount of mitomycin C for the treatment of bladder cancer. 2. The method of claim 1, wherein the prodrug is a conjugate of mitomycin C releasably attached to a lipophilic moiety. 3. The method of claim 1, wherein administering comprises administering via intravesical instillation. 4. The method of claim 1, further comprising retaining the liposomes in the bladder for a period of between about 15 minutes and about 2 hours. 5. The method of claim 2, further comprising administering to the individual a reducing agent to initiate release of the prodrug conjugate of mitomycin C from the attached lipophilic moiety. 6. The method of claim 1, wherein the individual with bladder cancer is an individual with Stage 0 bladder cancer or with Stage I bladder cancer. 7. The method of claim 1, wherein the individual with bladder cancer is an individual with low-grade or high-grade bladder cancer. 8. The method of claim 3, wherein the liposomes are retained in the bladder for a period of between about 15 minutes and about 2 hours. 9. The method of claim 8, further comprising administering to the individual a reducing agent to initiate release of the prodrug conjugate of mitomycin C from the attached lipophilic moiety. 10. The method of claim 8, wherein the individual with bladder cancer is an individual with Stage 0 bladder cancer or with Stage I bladder cancer. 11. The method of claim 9, wherein the individual with bladder cancer is an individual with Stage 0 bladder cancer or with Stage I bladder cancer. | The present disclosure related to a method of treating bladder cancer in a subject in need of treatment, by administering to the subject an amount of a prodrug of mitomycin C that yields a therapeutically effective amount of mitomycin C. In one embodiment, the prodrug of mitomycin C is a liposomal-prodrug of mitomycin C. In another embodiment, the liposomal-prodrug of mitomycin C is a folate-targeted liposomal-prodrug of mitomycin C.1. A method for treating bladder cancer, comprising:
administering to an individual with bladder cancer liposomes comprising a folate targeting moiety and a prodrug of mitomycin C, the liposomes administered in an amount that yields a therapeutically-effective amount of mitomycin C for the treatment of bladder cancer. 2. The method of claim 1, wherein the prodrug is a conjugate of mitomycin C releasably attached to a lipophilic moiety. 3. The method of claim 1, wherein administering comprises administering via intravesical instillation. 4. The method of claim 1, further comprising retaining the liposomes in the bladder for a period of between about 15 minutes and about 2 hours. 5. The method of claim 2, further comprising administering to the individual a reducing agent to initiate release of the prodrug conjugate of mitomycin C from the attached lipophilic moiety. 6. The method of claim 1, wherein the individual with bladder cancer is an individual with Stage 0 bladder cancer or with Stage I bladder cancer. 7. The method of claim 1, wherein the individual with bladder cancer is an individual with low-grade or high-grade bladder cancer. 8. The method of claim 3, wherein the liposomes are retained in the bladder for a period of between about 15 minutes and about 2 hours. 9. The method of claim 8, further comprising administering to the individual a reducing agent to initiate release of the prodrug conjugate of mitomycin C from the attached lipophilic moiety. 10. The method of claim 8, wherein the individual with bladder cancer is an individual with Stage 0 bladder cancer or with Stage I bladder cancer. 11. The method of claim 9, wherein the individual with bladder cancer is an individual with Stage 0 bladder cancer or with Stage I bladder cancer. | 1,600 |
706 | 14,884,445 | 1,631 | A system and method are for analyzing fluorescence of fluorophors in an eye using a non-negative matrix factorization (NMF) method. The NMF method may be initialized with Gaussian mixture model fits and may optionally be constrained to provide identical abundance images for data obtained in response to two or more excitation wavelengths. | 1. A method for analyzing fluorescence of fluorophors in an eye, comprising:
obtaining, from a plurality of hyperspectral sensors, a first data matrix representative of a first electromagnetic emission spectrum from the fluorophors in response to an excitation signal; isolating a second data matrix from the first data matrix, the second data matrix being representative of a second electromagnetic emission spectrum from a retinal pigment epithelium (RPE) of the eye in response to the excitation signal; identifying one or more Gaussian functions, wherein each Gaussian function is an initial approximation representative of a spectral component of the second electromagnetic emission spectrum; and analyzing the second data matrix using non-negative matrix factorization initialized with the one or more Gaussian functions to generate one or more component matrices, wherein each component matrix is a second approximation representative of the corresponding spectral component of the second electromagnetic emission spectrum. 2. The method of claim 1, further comprising, generating a two-dimensional image from one of the component matrices, wherein the two-dimensional image approximately corresponds, in part, to a histological image of the eye. 3. The method of claim 1, wherein a composite of the one or more Gaussian functions approximates the second data matrix. 4. The method of claim 1, wherein the number of Gaussian functions corresponds to the number of peaks within the second electromagnetic emission spectrum. 5. The method of claim 1, wherein the fluorophors comprise lipofuscins endogenously generated in the RPE. 6. The method of claim 5, further comprising, quantifying the amount of lipofuscin present in the RPE based on an intensity of one of the spectral components represented by the corresponding component matrix. 7. A method for analyzing fluorescence of fluorophors in an eye, comprising:
obtaining, from a plurality of hyperspectral sensors, a first data cube representative of first electromagnetic emission spectra from the fluorophors in response to excitation signals having two or more different wavelengths; isolating a second data cube from the first data cube, the second data cube comprising a plurality of data matrices, each data matrix being representative of an individual emission spectrum from a retinal pigment epithelium (RPE) of the eye in response to the excitation signal at each of the different wavelengths; identifying one or more Gaussian functions for each data matrix, wherein each Gaussian function is an initial approximation representative of a spectral component of the corresponding individual emission spectrum; and analyzing the second data cube using non-negative tensor factorization initialized with the one or more Gaussian functions for each data matrix to generate one or more component matrix functions, wherein the component matrix functions are concatenated across the plurality of data matrices such that each component matrix function is a common approximation representative of each corresponding spectral component shared across each individual emission spectrum. 8. The method of claim 7, wherein the excitation signals have three or more different wavelengths. 9. The method of claim 7, further comprising, generating a two-dimensional image from one of the component matrix functions, wherein the two-dimensional image approximately corresponds, in part, to a histological image of the eye. 10. The method of claim 7, wherein a composite of the one or more Gaussian functions for each data matrix approximates the corresponding data matrix. 11. The method of claim 7, wherein the number of Gaussian functions for each data matrix corresponds to the number of peaks within each individual emission spectrum. 12. The method of claim 7, wherein the fluorophors comprise lipofuscins endogenously generated in the RPE. 13. The method of claim 12, further comprising, quantifying the amount of lipofuscin present in the RPE based on an intensity of one of the spectral components represented by the corresponding component matrix. 14. A hyperspectral imaging device for detecting fluorophors in an eye, comprising:
a light source configured to deliver an excitation signal to the eye; a hyperspectral sensor configured to collect hyperspectral data in a first data matrix representative of a first electromagnetic emission spectrum from the fluorophors in response to the excitation signal; a processing arrangement configured to isolate a second data matrix from the first data matrix, the second data matrix being representative of a second electromagnetic emission spectrum from a retinal pigment epithelium (RPE) of the eye in response to the excitation signal; and an analyzing arrangement configured to identify one or more Gaussian functions, wherein each Gaussian function is an initial approximation representative of a spectral component of the second electromagnetic emission spectrum, and analyze the second data matrix using non-negative matrix factorization initialized with the one or more Gaussian functions to generate one or more component matrices, wherein each component matrix is a second approximation representative of the corresponding spectral component of the second electromagnetic emission spectrum. 15. The hyperspectral imaging device of claim 14, wherein the hyperspectral sensor is included in a hyperspectral camera. 16. The hyperspectral imaging device of claim 15, wherein the hyperspectral camera is a scanning laser ophthalmoscope. 17. The hyperspectral imaging device of claim 15, where in the hyperspectral camera is a fundus camera. 18. The hyperspectral imaging device of claim 15, further comprising an imaging arrangement configured to generate a two-dimensional image from one of the component matrices, wherein the two-dimensional image approximately corresponds, in part, to a histological image of the eye. 19. A system, comprising one or more processor cores and a set of instructions executing on the one or more processor cores, the set of instructions being operable to perform steps of claim 1. 20. A non-transitory computer-readable storage medium including a set of instructions executable by a processor, the set of instructions, when executed by the processor, causing the processor to perform operations according to steps of claim 1. | A system and method are for analyzing fluorescence of fluorophors in an eye using a non-negative matrix factorization (NMF) method. The NMF method may be initialized with Gaussian mixture model fits and may optionally be constrained to provide identical abundance images for data obtained in response to two or more excitation wavelengths.1. A method for analyzing fluorescence of fluorophors in an eye, comprising:
obtaining, from a plurality of hyperspectral sensors, a first data matrix representative of a first electromagnetic emission spectrum from the fluorophors in response to an excitation signal; isolating a second data matrix from the first data matrix, the second data matrix being representative of a second electromagnetic emission spectrum from a retinal pigment epithelium (RPE) of the eye in response to the excitation signal; identifying one or more Gaussian functions, wherein each Gaussian function is an initial approximation representative of a spectral component of the second electromagnetic emission spectrum; and analyzing the second data matrix using non-negative matrix factorization initialized with the one or more Gaussian functions to generate one or more component matrices, wherein each component matrix is a second approximation representative of the corresponding spectral component of the second electromagnetic emission spectrum. 2. The method of claim 1, further comprising, generating a two-dimensional image from one of the component matrices, wherein the two-dimensional image approximately corresponds, in part, to a histological image of the eye. 3. The method of claim 1, wherein a composite of the one or more Gaussian functions approximates the second data matrix. 4. The method of claim 1, wherein the number of Gaussian functions corresponds to the number of peaks within the second electromagnetic emission spectrum. 5. The method of claim 1, wherein the fluorophors comprise lipofuscins endogenously generated in the RPE. 6. The method of claim 5, further comprising, quantifying the amount of lipofuscin present in the RPE based on an intensity of one of the spectral components represented by the corresponding component matrix. 7. A method for analyzing fluorescence of fluorophors in an eye, comprising:
obtaining, from a plurality of hyperspectral sensors, a first data cube representative of first electromagnetic emission spectra from the fluorophors in response to excitation signals having two or more different wavelengths; isolating a second data cube from the first data cube, the second data cube comprising a plurality of data matrices, each data matrix being representative of an individual emission spectrum from a retinal pigment epithelium (RPE) of the eye in response to the excitation signal at each of the different wavelengths; identifying one or more Gaussian functions for each data matrix, wherein each Gaussian function is an initial approximation representative of a spectral component of the corresponding individual emission spectrum; and analyzing the second data cube using non-negative tensor factorization initialized with the one or more Gaussian functions for each data matrix to generate one or more component matrix functions, wherein the component matrix functions are concatenated across the plurality of data matrices such that each component matrix function is a common approximation representative of each corresponding spectral component shared across each individual emission spectrum. 8. The method of claim 7, wherein the excitation signals have three or more different wavelengths. 9. The method of claim 7, further comprising, generating a two-dimensional image from one of the component matrix functions, wherein the two-dimensional image approximately corresponds, in part, to a histological image of the eye. 10. The method of claim 7, wherein a composite of the one or more Gaussian functions for each data matrix approximates the corresponding data matrix. 11. The method of claim 7, wherein the number of Gaussian functions for each data matrix corresponds to the number of peaks within each individual emission spectrum. 12. The method of claim 7, wherein the fluorophors comprise lipofuscins endogenously generated in the RPE. 13. The method of claim 12, further comprising, quantifying the amount of lipofuscin present in the RPE based on an intensity of one of the spectral components represented by the corresponding component matrix. 14. A hyperspectral imaging device for detecting fluorophors in an eye, comprising:
a light source configured to deliver an excitation signal to the eye; a hyperspectral sensor configured to collect hyperspectral data in a first data matrix representative of a first electromagnetic emission spectrum from the fluorophors in response to the excitation signal; a processing arrangement configured to isolate a second data matrix from the first data matrix, the second data matrix being representative of a second electromagnetic emission spectrum from a retinal pigment epithelium (RPE) of the eye in response to the excitation signal; and an analyzing arrangement configured to identify one or more Gaussian functions, wherein each Gaussian function is an initial approximation representative of a spectral component of the second electromagnetic emission spectrum, and analyze the second data matrix using non-negative matrix factorization initialized with the one or more Gaussian functions to generate one or more component matrices, wherein each component matrix is a second approximation representative of the corresponding spectral component of the second electromagnetic emission spectrum. 15. The hyperspectral imaging device of claim 14, wherein the hyperspectral sensor is included in a hyperspectral camera. 16. The hyperspectral imaging device of claim 15, wherein the hyperspectral camera is a scanning laser ophthalmoscope. 17. The hyperspectral imaging device of claim 15, where in the hyperspectral camera is a fundus camera. 18. The hyperspectral imaging device of claim 15, further comprising an imaging arrangement configured to generate a two-dimensional image from one of the component matrices, wherein the two-dimensional image approximately corresponds, in part, to a histological image of the eye. 19. A system, comprising one or more processor cores and a set of instructions executing on the one or more processor cores, the set of instructions being operable to perform steps of claim 1. 20. A non-transitory computer-readable storage medium including a set of instructions executable by a processor, the set of instructions, when executed by the processor, causing the processor to perform operations according to steps of claim 1. | 1,600 |
707 | 15,235,478 | 1,631 | A bioinformatics process which provides an improved means to detect NFkB cellular signaling pathway in a subject, such as a human, based on the expression levels of at least six unique target genes of the NFkB cellular signaling pathway measured in a sample. The invention includes an apparatus comprising a digital processor configured to perform such a method, a non-transitory storage medium storing instructions that are executable by a digital processing device to perform such a method, and a computer program comprising program code means for causing a digital processing device to perform such a method. Kits are also provided for measuring expression levels of unique sets of NFkB cellular signaling pathway target genes. | 1. A computer implemented method for determining the activity level of a NFkB cellular signaling pathway in a subject performed by a computerized device having a processor comprising:
a. calculating an activity level of NFkB transcription factor element in a sample isolated from the subject, wherein the activity level of NFkB transcription factor element in the sample is calculated by:
i. receiving data on the expression levels of at least six target genes derived from the sample, wherein the NFkB transcription factor element controls transcription of the at least six target genes, and wherein the at least six target genes are selected from BCL2L1, BIRC3, CCL2, CCL3, CCL4, CCL5, CCL20, CCL22, CX3CL1, CXCL1, CXCL2, CXCL3, ICAM1, IL1B, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, PTGS2, SELE, STAT5A, TNF, TNFAIP2, TNIP1, TRAF1, and VCAM1;
ii. calculating the activity level of the NFkB transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define an activity level of NFkB transcription factor element; and,
b. calculating the activity level of the NFkB cellular signaling pathway in the sample based on the calculated activity levels of NFkB transcription factor element in the sample. 2. The method of claim 1, further comprising assigning a NFkB cellular signaling pathway activity status to the calculated activity level of the NFkB cellular signaling in the sample, wherein the activity status is indicative of either an active NFkB cellular signaling pathway or a passive NFkB cellular signaling pathway. 3. The method of claim 2, further comprising displaying the NFkB cellular signaling pathway activity status. 4. The method of claim 1, wherein the at least six target genes are selected from BIRC3, CCL2, CCL5, CCL20, CXCL1, CXCL2, CXCL3, ICAM1, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, TNF, TNFAIP2, TRAF1, and VCAM1. 5. The method of claim 1, wherein the at least six target genes comprise at least three target genes selected from CCL2, CCL5, CCL20, CXCL1, CXCL2, CXCL3, ICAM1, IL6, IL8, MMP9, NFKB2, NFKBIA, and TNFAIP2. 6. The method of claim 5, wherein the at least three target genes are selected from CCL5, CXCL2, ICAM1, IL6, IL8, NFKBIA, and TNFAIP2. 7. The method of claim 1, wherein the calibrated pathway model is a probabilistic model incorporating conditional probabilistic relationships that compare the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define a level of NFkB transcription factor element to determine the activity level of NFkB transcription factor element in the sample. 8. The method of claim 1, wherein the calibrated pathway model is a linear model incorporating relationships that compare the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define a level of NFkB transcription factor element to determine the activity level of NFkB transcription factor element in the sample. 9. A computer program product for determining the activity level of a NFkB cellular signaling pathway in a subject comprising
a. a non-transitory computer readable storage medium having computer readable program code embodied therewith, the computer readable program code executable by at least one processor to:
i. calculate a level of NFkB transcription factor element in a sample isolated from a subject, wherein the level of the NFkB transcription factor element in the sample is calculated by:
1. receiving data on the expression levels of at least six target genes derived from the sample, wherein the at least six target genes are selected from BCL2L1, BIRC3, CCL2, CCL3, CCL4, CCL5, CCL20, CCL22, CX3CL1, CXCL1, CXCL2, CXCL3, ICAM1, IL1B, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, PTGS2, SELE, STAT5A, TNF, TNFAIP2, TNIP1, TRAF1, and VCAM1;
2. calculating the level of NFkB transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define an activity level of the NFkB transcription factor element; and,
ii. calculate the activity level of the NFkB cellular signaling pathway in the sample based on the calculated NFkB transcription factor element level in the sample. 10. The computer program product of claim 9, wherein the computer readable program code is executable by at least one processor to assign a NFkB cellular signaling pathway activity status to the calculated activity level of the NFkB cellular signaling in the sample, wherein the activity status is indicative of either an active NFkB cellular signaling pathway or a passive NFkB cellular signaling pathway. 11. The computer program product of claim 10, wherein the computer readable program code is executable by at least one processor to display the NFkB signaling pathway activity status. 12. The computer program product of claim 9, wherein the at least six target genes are selected from BIRC3, CCL2, CCL5, CCL20, CXCL1, CXCL2, CXCL3, ICAM1, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, TNF, TNFAIP2, TRAF1, and VCAM1. 13. The computer program product of claim 9, wherein the at least six target genes comprise at least three target genes selected from CCL2, CCL5, CCL20, CXCL1, CXCL2, CXCL3, ICAM1, IL6, IL8, MMP9, NFKB2, NFKBIA, and TNFAIP2. 14. The computer program product of claim 13, wherein the at least three target genes are selected from CCL5, CXCL2, ICAM1, IL6, IL8, NFKBIA, and TNFAIP2. 15. The computer program product of claim 9, wherein the calibrated pathway model is a probabilistic model incorporating conditional probabilistic relationships that compare the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define a level of NFkB transcription factor element to determine the activity level of the NFkB transcription factor element in the sample. 16. The computer program product of claim 9, wherein the calibrated pathway model is a linear model incorporating relationships that compare the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define a level of NFkB transcription factor element to determine the activity level of the NFkB transcription factor element in the sample. 17. A method of treating a subject suffering from a disease associated with an activated NFkB cellular signaling pathway comprising:
a. receiving information regarding the activity level of a NFkB cellular signaling pathway derived from a sample isolated from the subject, wherein the activity level of the NFkB cellular signaling pathway is determined by:
i. calculating an activity level of NFkB transcription factor element in a sample isolated from the subject, wherein the level of the NFkB transcription factor element in the sample is calculated by:
1. receiving data on the expression levels of at least six target genes derived from the sample, wherein the NFkB transcription factor element controls transcription of the at least six target genes, and wherein the at least six target genes are selected from BCL2L1, BIRC3, CCL2, CCL3, CCL4, CCL5, CCL20, CCL22, CX3CL1, CXCL1, CXCL2, CXCL3, ICAM1, IL1B, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, PTGS2, SELE, STAT5A, TNF, TNFAIP2, TNIP1, TRAF1, and VCAM1;
2. calculating the level of the NFkB transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define an activity level of NFkB transcription factor element; and,
ii. calculating the activity level of the NFkB cellular signaling pathway in the sample based on the calculated NFkB transcription factor element level in the sample; and,
b. administering to the subject a NFkB inhibitor if the information regarding the activity level of the NFkB cellular signaling pathway is indicative of an active NFkB cellular signaling pathway. 18. The method of claim 17, wherein the at least six target genes are selected from BIRC3, CCL2, CCL5, CCL20, CXCL1, CXCL2, CXCL3, ICAM1, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, TNF, TNFAIP2, TRAF1, and VCAM1. 19. The method of claim 17, wherein the at least six target genes comprise at least three target genes selected from CCL2, CCL5, CCL20, CXCL1, CXCL2, CXCL3, ICAM1, IL6, IL8, MMP9, NFKB2, NFKBIA, and TNFAIP2. 20. The method of claim 19, wherein the at least three target genes are selected from CCL5, CXCL2, ICAM1, IL6, IL8, NFKBIA, and TNFAIP2. 21. The method of claim 17, wherein the calibrated pathway model is a probabilistic model incorporating conditional probabilistic relationships that compare the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define a level of NFkB transcription factor element to determine the activity level of the NFkB transcription factor element in the sample. 22. The method of claim 17, wherein the calibrated pathway model is a linear model incorporating relationships that compare the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define a level of NFkB transcription factor element to determine the activity level of the NFkB transcription factor element in the human cancer sample. 23. The method of claim 17, wherein the NFkB inhibitor is DHMEQ, bindarit, Bortesomib or BU-32 (proteazome inhibitors), BMS-345541, or glucocorticoids. 24. The method of claim 17, wherein the disease is a cancer. 25. The method of claim 24, wherein the cancer is colon, breast, prostate, pancreatic, lung, brain, leukemia, lymphoma, or glioma. 26. The method of claim 25, wherein the cancer is breast cancer. 27. A kit for measuring expression levels of NFkB cellular signaling pathway target genes comprising:
a. a set of polymerase chain reaction primers directed to at least six NFkB cellular signaling pathway target genes from a sample isolated from a subject; and b. a set of probes directed to the at least six NFkB cellular signaling pathway target genes;
wherein the at least six NFkB cellular signaling pathway target genes are selected from BCL2L1, BIRC3, CCL2, CCL3, CCL4, CCL5, CCL20, CCL22, CX3CL1, CXCL1, CXCL2, CXCL3, ICAM1, IL1B, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, PTGS2, SELE, STAT5A, TNF, TNFAIP2, TNIP1, TRAF1, and VCAM1. 28. The kit of claim 27, wherein the at least six target genes are selected from BIRC3, CCL2, CCL5, CCL20, CXCL1, CXCL2, CXCL3, ICAM1, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, TNF, TNFAIP2, TRAF1, and VCAM1. 29. The kit of claim 27, wherein the at least six target genes comprise at least three target genes selected from CCL2, CCL5, CCL20, CXCL1, CXCL2, CXCL3, ICAM1, IL6, IL8, MMP9, NFKB2, NFKBIA, and TNFAIP2. 30. The kit of claim 29, wherein the at least three target genes are selected from CCL5, CXCL2, ICAM1, IL6, IL8, NFKBIA, and TNFAIP2. 31. The kit of claim 27, wherein the probes are labeled. 32. The kit of claim 27, wherein the set of probes includes at least one of SEQ. ID. NOS. 46, 49, 52, 55, and 58. 33. The kit of claim 27, wherein the set of primers include at least one of SEQ. ID. NOS. 44 and 45, 47 and 48, 50 and 51, 53 and 54, and 56 and 57. 34. The kit of claim 27, further comprising a computer program product for determining the activity level of a NFkB cellular signaling pathway in the subject comprising
a. a non-transitory computer readable storage medium having computer readable program code embodied therewith, the computer readable program code executable by at least one processor to:
i. calculate a level of NFkB transcription factor element in the sample, wherein the level of NFkB transcription factor element in the sample is associated with NFkB cellular signaling, and wherein the level of the NFkB transcription factor element in the sample is calculated by:
1. receiving data on the expression levels of the at least six target genes derived from the sample;
2. calculating the level of the NFkB transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define an activity level of the NFkB transcription factor element; and,
ii. calculate the activity level of the NFkB cellular signaling pathway in the sample based on the calculated NFkB transcription factor element level in the sample. 35. A kit for determining the activity level of a NFkB cellular signaling pathway in a subject comprising:
a. one or more components capable of identifying expression levels of at least six NFkB cellular signaling pathway target genes from a sample of the subject, wherein the at least six NFkB cellular signaling pathway target genes are selected from BCL2L1, BIRC3, CCL2, CCL3, CCL4, CCL5, CCL20, CCL22, CX3CL1, CXCL1, CXCL2, CXCL3, ICAM1, IL1B, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, PTGS2, SELE, STAT5A, TNF, TNFAIP2, TNIP1, TRAF1, and VCAM1; and, b. optionally, a non-transitory computer readable storage medium having computer readable program code embodied therewith, the computer readable program code executable by at least one processor to:
i. calculate a level of NFkB transcription factor element in the sample, wherein the level of the NFkB transcription factor element in the sample is associated with NFkB cellular signaling, and wherein the level of the NFkB transcription factor element in the sample is calculated by:
1. receiving data on the expression levels of the at least six target genes derived from the sample;
2. calculating the level of the NFkB transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define an activity level of NFkB transcription factor element; and,
ii. calculate the activity level of the NFkB cellular signaling pathway in the sample based on the calculated NFkB transcription factor element level in the sample. | A bioinformatics process which provides an improved means to detect NFkB cellular signaling pathway in a subject, such as a human, based on the expression levels of at least six unique target genes of the NFkB cellular signaling pathway measured in a sample. The invention includes an apparatus comprising a digital processor configured to perform such a method, a non-transitory storage medium storing instructions that are executable by a digital processing device to perform such a method, and a computer program comprising program code means for causing a digital processing device to perform such a method. Kits are also provided for measuring expression levels of unique sets of NFkB cellular signaling pathway target genes.1. A computer implemented method for determining the activity level of a NFkB cellular signaling pathway in a subject performed by a computerized device having a processor comprising:
a. calculating an activity level of NFkB transcription factor element in a sample isolated from the subject, wherein the activity level of NFkB transcription factor element in the sample is calculated by:
i. receiving data on the expression levels of at least six target genes derived from the sample, wherein the NFkB transcription factor element controls transcription of the at least six target genes, and wherein the at least six target genes are selected from BCL2L1, BIRC3, CCL2, CCL3, CCL4, CCL5, CCL20, CCL22, CX3CL1, CXCL1, CXCL2, CXCL3, ICAM1, IL1B, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, PTGS2, SELE, STAT5A, TNF, TNFAIP2, TNIP1, TRAF1, and VCAM1;
ii. calculating the activity level of the NFkB transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define an activity level of NFkB transcription factor element; and,
b. calculating the activity level of the NFkB cellular signaling pathway in the sample based on the calculated activity levels of NFkB transcription factor element in the sample. 2. The method of claim 1, further comprising assigning a NFkB cellular signaling pathway activity status to the calculated activity level of the NFkB cellular signaling in the sample, wherein the activity status is indicative of either an active NFkB cellular signaling pathway or a passive NFkB cellular signaling pathway. 3. The method of claim 2, further comprising displaying the NFkB cellular signaling pathway activity status. 4. The method of claim 1, wherein the at least six target genes are selected from BIRC3, CCL2, CCL5, CCL20, CXCL1, CXCL2, CXCL3, ICAM1, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, TNF, TNFAIP2, TRAF1, and VCAM1. 5. The method of claim 1, wherein the at least six target genes comprise at least three target genes selected from CCL2, CCL5, CCL20, CXCL1, CXCL2, CXCL3, ICAM1, IL6, IL8, MMP9, NFKB2, NFKBIA, and TNFAIP2. 6. The method of claim 5, wherein the at least three target genes are selected from CCL5, CXCL2, ICAM1, IL6, IL8, NFKBIA, and TNFAIP2. 7. The method of claim 1, wherein the calibrated pathway model is a probabilistic model incorporating conditional probabilistic relationships that compare the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define a level of NFkB transcription factor element to determine the activity level of NFkB transcription factor element in the sample. 8. The method of claim 1, wherein the calibrated pathway model is a linear model incorporating relationships that compare the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define a level of NFkB transcription factor element to determine the activity level of NFkB transcription factor element in the sample. 9. A computer program product for determining the activity level of a NFkB cellular signaling pathway in a subject comprising
a. a non-transitory computer readable storage medium having computer readable program code embodied therewith, the computer readable program code executable by at least one processor to:
i. calculate a level of NFkB transcription factor element in a sample isolated from a subject, wherein the level of the NFkB transcription factor element in the sample is calculated by:
1. receiving data on the expression levels of at least six target genes derived from the sample, wherein the at least six target genes are selected from BCL2L1, BIRC3, CCL2, CCL3, CCL4, CCL5, CCL20, CCL22, CX3CL1, CXCL1, CXCL2, CXCL3, ICAM1, IL1B, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, PTGS2, SELE, STAT5A, TNF, TNFAIP2, TNIP1, TRAF1, and VCAM1;
2. calculating the level of NFkB transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define an activity level of the NFkB transcription factor element; and,
ii. calculate the activity level of the NFkB cellular signaling pathway in the sample based on the calculated NFkB transcription factor element level in the sample. 10. The computer program product of claim 9, wherein the computer readable program code is executable by at least one processor to assign a NFkB cellular signaling pathway activity status to the calculated activity level of the NFkB cellular signaling in the sample, wherein the activity status is indicative of either an active NFkB cellular signaling pathway or a passive NFkB cellular signaling pathway. 11. The computer program product of claim 10, wherein the computer readable program code is executable by at least one processor to display the NFkB signaling pathway activity status. 12. The computer program product of claim 9, wherein the at least six target genes are selected from BIRC3, CCL2, CCL5, CCL20, CXCL1, CXCL2, CXCL3, ICAM1, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, TNF, TNFAIP2, TRAF1, and VCAM1. 13. The computer program product of claim 9, wherein the at least six target genes comprise at least three target genes selected from CCL2, CCL5, CCL20, CXCL1, CXCL2, CXCL3, ICAM1, IL6, IL8, MMP9, NFKB2, NFKBIA, and TNFAIP2. 14. The computer program product of claim 13, wherein the at least three target genes are selected from CCL5, CXCL2, ICAM1, IL6, IL8, NFKBIA, and TNFAIP2. 15. The computer program product of claim 9, wherein the calibrated pathway model is a probabilistic model incorporating conditional probabilistic relationships that compare the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define a level of NFkB transcription factor element to determine the activity level of the NFkB transcription factor element in the sample. 16. The computer program product of claim 9, wherein the calibrated pathway model is a linear model incorporating relationships that compare the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define a level of NFkB transcription factor element to determine the activity level of the NFkB transcription factor element in the sample. 17. A method of treating a subject suffering from a disease associated with an activated NFkB cellular signaling pathway comprising:
a. receiving information regarding the activity level of a NFkB cellular signaling pathway derived from a sample isolated from the subject, wherein the activity level of the NFkB cellular signaling pathway is determined by:
i. calculating an activity level of NFkB transcription factor element in a sample isolated from the subject, wherein the level of the NFkB transcription factor element in the sample is calculated by:
1. receiving data on the expression levels of at least six target genes derived from the sample, wherein the NFkB transcription factor element controls transcription of the at least six target genes, and wherein the at least six target genes are selected from BCL2L1, BIRC3, CCL2, CCL3, CCL4, CCL5, CCL20, CCL22, CX3CL1, CXCL1, CXCL2, CXCL3, ICAM1, IL1B, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, PTGS2, SELE, STAT5A, TNF, TNFAIP2, TNIP1, TRAF1, and VCAM1;
2. calculating the level of the NFkB transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define an activity level of NFkB transcription factor element; and,
ii. calculating the activity level of the NFkB cellular signaling pathway in the sample based on the calculated NFkB transcription factor element level in the sample; and,
b. administering to the subject a NFkB inhibitor if the information regarding the activity level of the NFkB cellular signaling pathway is indicative of an active NFkB cellular signaling pathway. 18. The method of claim 17, wherein the at least six target genes are selected from BIRC3, CCL2, CCL5, CCL20, CXCL1, CXCL2, CXCL3, ICAM1, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, TNF, TNFAIP2, TRAF1, and VCAM1. 19. The method of claim 17, wherein the at least six target genes comprise at least three target genes selected from CCL2, CCL5, CCL20, CXCL1, CXCL2, CXCL3, ICAM1, IL6, IL8, MMP9, NFKB2, NFKBIA, and TNFAIP2. 20. The method of claim 19, wherein the at least three target genes are selected from CCL5, CXCL2, ICAM1, IL6, IL8, NFKBIA, and TNFAIP2. 21. The method of claim 17, wherein the calibrated pathway model is a probabilistic model incorporating conditional probabilistic relationships that compare the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define a level of NFkB transcription factor element to determine the activity level of the NFkB transcription factor element in the sample. 22. The method of claim 17, wherein the calibrated pathway model is a linear model incorporating relationships that compare the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define a level of NFkB transcription factor element to determine the activity level of the NFkB transcription factor element in the human cancer sample. 23. The method of claim 17, wherein the NFkB inhibitor is DHMEQ, bindarit, Bortesomib or BU-32 (proteazome inhibitors), BMS-345541, or glucocorticoids. 24. The method of claim 17, wherein the disease is a cancer. 25. The method of claim 24, wherein the cancer is colon, breast, prostate, pancreatic, lung, brain, leukemia, lymphoma, or glioma. 26. The method of claim 25, wherein the cancer is breast cancer. 27. A kit for measuring expression levels of NFkB cellular signaling pathway target genes comprising:
a. a set of polymerase chain reaction primers directed to at least six NFkB cellular signaling pathway target genes from a sample isolated from a subject; and b. a set of probes directed to the at least six NFkB cellular signaling pathway target genes;
wherein the at least six NFkB cellular signaling pathway target genes are selected from BCL2L1, BIRC3, CCL2, CCL3, CCL4, CCL5, CCL20, CCL22, CX3CL1, CXCL1, CXCL2, CXCL3, ICAM1, IL1B, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, PTGS2, SELE, STAT5A, TNF, TNFAIP2, TNIP1, TRAF1, and VCAM1. 28. The kit of claim 27, wherein the at least six target genes are selected from BIRC3, CCL2, CCL5, CCL20, CXCL1, CXCL2, CXCL3, ICAM1, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, TNF, TNFAIP2, TRAF1, and VCAM1. 29. The kit of claim 27, wherein the at least six target genes comprise at least three target genes selected from CCL2, CCL5, CCL20, CXCL1, CXCL2, CXCL3, ICAM1, IL6, IL8, MMP9, NFKB2, NFKBIA, and TNFAIP2. 30. The kit of claim 29, wherein the at least three target genes are selected from CCL5, CXCL2, ICAM1, IL6, IL8, NFKBIA, and TNFAIP2. 31. The kit of claim 27, wherein the probes are labeled. 32. The kit of claim 27, wherein the set of probes includes at least one of SEQ. ID. NOS. 46, 49, 52, 55, and 58. 33. The kit of claim 27, wherein the set of primers include at least one of SEQ. ID. NOS. 44 and 45, 47 and 48, 50 and 51, 53 and 54, and 56 and 57. 34. The kit of claim 27, further comprising a computer program product for determining the activity level of a NFkB cellular signaling pathway in the subject comprising
a. a non-transitory computer readable storage medium having computer readable program code embodied therewith, the computer readable program code executable by at least one processor to:
i. calculate a level of NFkB transcription factor element in the sample, wherein the level of NFkB transcription factor element in the sample is associated with NFkB cellular signaling, and wherein the level of the NFkB transcription factor element in the sample is calculated by:
1. receiving data on the expression levels of the at least six target genes derived from the sample;
2. calculating the level of the NFkB transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define an activity level of the NFkB transcription factor element; and,
ii. calculate the activity level of the NFkB cellular signaling pathway in the sample based on the calculated NFkB transcription factor element level in the sample. 35. A kit for determining the activity level of a NFkB cellular signaling pathway in a subject comprising:
a. one or more components capable of identifying expression levels of at least six NFkB cellular signaling pathway target genes from a sample of the subject, wherein the at least six NFkB cellular signaling pathway target genes are selected from BCL2L1, BIRC3, CCL2, CCL3, CCL4, CCL5, CCL20, CCL22, CX3CL1, CXCL1, CXCL2, CXCL3, ICAM1, IL1B, IL6, IL8, IRF1, MMP9, NFKB2, NFKBIA, NFKBIE, PTGS2, SELE, STAT5A, TNF, TNFAIP2, TNIP1, TRAF1, and VCAM1; and, b. optionally, a non-transitory computer readable storage medium having computer readable program code embodied therewith, the computer readable program code executable by at least one processor to:
i. calculate a level of NFkB transcription factor element in the sample, wherein the level of the NFkB transcription factor element in the sample is associated with NFkB cellular signaling, and wherein the level of the NFkB transcription factor element in the sample is calculated by:
1. receiving data on the expression levels of the at least six target genes derived from the sample;
2. calculating the level of the NFkB transcription factor element in the sample using a calibrated pathway model, wherein the calibrated pathway model compares the expression levels of the at least six target genes in the sample with expression levels of the at least six target genes in the model which define an activity level of NFkB transcription factor element; and,
ii. calculate the activity level of the NFkB cellular signaling pathway in the sample based on the calculated NFkB transcription factor element level in the sample. | 1,600 |
708 | 12,175,716 | 1,627 | A process for obtaining an increase in the concentration and/or production of milk protein and/or improving reproductive performance. The process includes administering to a mammal a composition including at least one unsaturated fatty acid, or a derivative thereof, and at least one feed supplement, wherein the combination is administered in an amount such that the mammal absorbs 1 g to 95 g of the at least one unsaturated fatty acid, or the derivative thereof, per day. | 1. A process for obtaining an increase the concentration and/or production of milk protein characterized by the fact of feeding mammalians with one or more unsaturated fatty acids with 18 carbons molecule or its derivatives with metabolic modifying functions, associated or not with one or more vegetable or animal oils, in combination or not with one or more feedstuffs and/or feedstuffs supplements with varying metabolizable protein:energy ratio, optionally flavoring agents, coloring additives, vitamins, minerals, conditioners, stabilizers, and other additives known by the “homem da técnica” in amounts that makes it possible for the mammalian to absorb from 1 up to 95 grams of one or more fatty acids with 18 or 19 carbons per day and per animal. 2. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of when applied to confined cows that the animals receive the roughage and concentrate containing the fatty acids mixture as total mixed rations. 3. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of the process being possible to be utilized preferentially by cattle, goats, sheep or even human beings. 4. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of being possible to use as vegetable oil, palm oil. 5. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of the fatty acid mixture used with varying concentrations of the active ingredient being supplemented from 20 to 50 g/100 kg liveweight in the total diet or any specific portion of the diet. 6. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of the fatty acid mixture used with varying concentrations of the active ingredient being ingested in its protect form in amounts from 0.01 to 2.5 grams by day and by kilogram of liveweight, or 0.01 to 0.15 grams of active ingredient being absorbed by day and by kilogram of grazing animals, added to a concentrated or a multiple mixture supplement. 7. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of being possible to use as supplements for bypassing protein in the rumen, oilseed meals, animal byproducts, vegetable byproducts, and other known by the men of the field or yet mixture of them. 8. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of being possible to use fish meal, soybean meal, cottonseed meal, meat meal, feather meal, blood meal, wheat middlings, soybean hulls, yeast, corn grain, citrus pulp, sorghum grain, etc. or mixtures of them. 9. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 7 characterized by the fact of being possible to use fish meal, soybean meal, cottonseed meal, meat meal, feather meal, blood meal, wheat middlings, soybean hulls, yeast, corn grain, citrus pulp, sorghum grain, etc. or mixtures of them. 10. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of the fatty acid being in the conjugated form, including several combinations of positional and geometric (cis and/or trans) isomers, in different carbon positions. 11. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of using preferentially conjugated linoleic acid or not (CLA) preferentially as calcium salts. 12. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 10 characterized by the fact of using preferentially conjugated linoleic acid or not (CLA) preferentially as calcium salts. 13. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 11 characterized by the fact of being possible to use linoleic acid C18: cis 9, trans 11; C 18:2 trans 10, cis 12 and C 18:2 cis 8, trans 10 in several different concentrations as well as just one specific fatty acid as C 18:2 trans 10, cis 12 and C 18:2 cis 8, trans 10. 14. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of using about 0.5% to 90% in mass of the one or more unsaturated fatty acids with 18 carbons in the molecule (active ingredient) in relation of the total mass of the mixture of lipids added to the ration or diet. 15. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 11 characterized by the fact of using preferentially between 1% to 80% in mass of the active ingredient in relation of the total mass of the mixture of lipids added to the ration or diet. 16. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of possibility that the active ingredient can be used in the protected form that uses the formulation of calcium salts of fatty acids, or its mixtures with “amidas” or formaldehydes, or yet another processes of protection against biohydrogenation of fat without metabolic effects, known by the men of the field. 17. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of the unsaturated fatty acids being possible to be used in combination with several different ration ingredients, including sources of fermentable carbohydrates, proteins, additives, antibiotics, ingredients that can alter the digestive tract pH in a manner that it elicits the production in situ of the fatty acids with metabolic modifying capabilities, from fatty acids added to the diet that do not have the modifying effects before the here said conversion due to the characteristics of the ration's ingredients. 18. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact that the diet can be formulated in a manner to result in a surplus of 10 to 50% of metabolizable protein in mass. 19. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 10 characterized by the fact of the roughages of diet can be conserved, as hay and silages, forages directly grazed by the animals or other fibrous feedstuffs like sugarcane bagasse treated under steam and pressure in natura. | A process for obtaining an increase in the concentration and/or production of milk protein and/or improving reproductive performance. The process includes administering to a mammal a composition including at least one unsaturated fatty acid, or a derivative thereof, and at least one feed supplement, wherein the combination is administered in an amount such that the mammal absorbs 1 g to 95 g of the at least one unsaturated fatty acid, or the derivative thereof, per day.1. A process for obtaining an increase the concentration and/or production of milk protein characterized by the fact of feeding mammalians with one or more unsaturated fatty acids with 18 carbons molecule or its derivatives with metabolic modifying functions, associated or not with one or more vegetable or animal oils, in combination or not with one or more feedstuffs and/or feedstuffs supplements with varying metabolizable protein:energy ratio, optionally flavoring agents, coloring additives, vitamins, minerals, conditioners, stabilizers, and other additives known by the “homem da técnica” in amounts that makes it possible for the mammalian to absorb from 1 up to 95 grams of one or more fatty acids with 18 or 19 carbons per day and per animal. 2. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of when applied to confined cows that the animals receive the roughage and concentrate containing the fatty acids mixture as total mixed rations. 3. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of the process being possible to be utilized preferentially by cattle, goats, sheep or even human beings. 4. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of being possible to use as vegetable oil, palm oil. 5. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of the fatty acid mixture used with varying concentrations of the active ingredient being supplemented from 20 to 50 g/100 kg liveweight in the total diet or any specific portion of the diet. 6. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of the fatty acid mixture used with varying concentrations of the active ingredient being ingested in its protect form in amounts from 0.01 to 2.5 grams by day and by kilogram of liveweight, or 0.01 to 0.15 grams of active ingredient being absorbed by day and by kilogram of grazing animals, added to a concentrated or a multiple mixture supplement. 7. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of being possible to use as supplements for bypassing protein in the rumen, oilseed meals, animal byproducts, vegetable byproducts, and other known by the men of the field or yet mixture of them. 8. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of being possible to use fish meal, soybean meal, cottonseed meal, meat meal, feather meal, blood meal, wheat middlings, soybean hulls, yeast, corn grain, citrus pulp, sorghum grain, etc. or mixtures of them. 9. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 7 characterized by the fact of being possible to use fish meal, soybean meal, cottonseed meal, meat meal, feather meal, blood meal, wheat middlings, soybean hulls, yeast, corn grain, citrus pulp, sorghum grain, etc. or mixtures of them. 10. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of the fatty acid being in the conjugated form, including several combinations of positional and geometric (cis and/or trans) isomers, in different carbon positions. 11. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of using preferentially conjugated linoleic acid or not (CLA) preferentially as calcium salts. 12. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 10 characterized by the fact of using preferentially conjugated linoleic acid or not (CLA) preferentially as calcium salts. 13. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 11 characterized by the fact of being possible to use linoleic acid C18: cis 9, trans 11; C 18:2 trans 10, cis 12 and C 18:2 cis 8, trans 10 in several different concentrations as well as just one specific fatty acid as C 18:2 trans 10, cis 12 and C 18:2 cis 8, trans 10. 14. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of using about 0.5% to 90% in mass of the one or more unsaturated fatty acids with 18 carbons in the molecule (active ingredient) in relation of the total mass of the mixture of lipids added to the ration or diet. 15. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 11 characterized by the fact of using preferentially between 1% to 80% in mass of the active ingredient in relation of the total mass of the mixture of lipids added to the ration or diet. 16. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of possibility that the active ingredient can be used in the protected form that uses the formulation of calcium salts of fatty acids, or its mixtures with “amidas” or formaldehydes, or yet another processes of protection against biohydrogenation of fat without metabolic effects, known by the men of the field. 17. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact of the unsaturated fatty acids being possible to be used in combination with several different ration ingredients, including sources of fermentable carbohydrates, proteins, additives, antibiotics, ingredients that can alter the digestive tract pH in a manner that it elicits the production in situ of the fatty acids with metabolic modifying capabilities, from fatty acids added to the diet that do not have the modifying effects before the here said conversion due to the characteristics of the ration's ingredients. 18. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 1 characterized by the fact that the diet can be formulated in a manner to result in a surplus of 10 to 50% of metabolizable protein in mass. 19. A process for obtaining an increase in the concentration and/or production of milk protein as in claim 10 characterized by the fact of the roughages of diet can be conserved, as hay and silages, forages directly grazed by the animals or other fibrous feedstuffs like sugarcane bagasse treated under steam and pressure in natura. | 1,600 |
709 | 12,944,937 | 1,612 | Example embodiments of the present invention include methods, devices, and systems that provide effective dental treatments to all tooth surfaces of the entire dental arch. In particular, embodiments of the present invention include treatment devices and systems that are capable of treating the entire arch by covering and delivering active ingredients to the front, back, and top surfaces of each of the teeth of the full dental arch. Moreover, example embodiments of the present invention provide treatment devices and systems that are capable of treating the gingival margin and gums of an entire arch. | 1. A dental treatment system, comprising:
a front portion treatment strip that fully covers one or more teeth on a front portion of a user's dental arch; at least one back portion treatment strip that fully covers one or more teeth on a back portion of the user's dental arch. 2. The dental treatment system recited in claim 1, wherein the front portion treatment strip, and the at least one back portion treatment strip have correlated lengths that when applied to the teeth of the user, the entire dental arch of the user is covered by at least one of the front portion treatment strip and/or the at least one back portion treatment strip. 3. The dental treatment system recited in claim 2, wherein the front portion treatment strip, when applied to the user's teeth, overlaps a portion of the at least one back portion treatment strip. 4. The dental treatment system recited in claim 3, wherein the front portion treatment strip has a length greater than the length of the at least one back portion treatment strip. 5. The dental treatment system recited in claim 4, wherein the front portion treatment strip and the at least one back portion treatment strip have a width such that the treatment strips also cover the gingival margin and gums of the user's entire dental arch. 6. A dental treatment system, comprising:
a front portion treatment strip that fully covers one or more teeth on a front portion of a user's dental arch; at least one back portion treatment strip that fully covers one or more teeth on a back portion of the user's dental arch; wherein the front portion treatment strip and the at least one back portion treatment strip comprise:
an insoluble backing layer; and
a treatment composition layer formed on one side of the insoluble backing layer. 7. The dental treatment system recited in claim 6, wherein the treatment composition layer is temporally attached to a package for shipment of the dental treatment system. 8. The dental treatment system recited in claim 6, wherein the insoluble backing layer is made from a polymer. 9. The dental treatment system recited in claim 6, wherein the treatment composition layer comprises one or more active ingredients to treat one or more dental conditions. 10. The dental treatment system recited in claim 9, wherein the one or more active ingredients comprises one or more of the following: fluoride, anti-microbials, desensitizers, teeth whitening agents, re-mineralizers, and/or periodontal agents. 11. A dental treatment system, comprising:
a full arch dental strip device, wherein the full arch dental strip device is configured to treat the entire dental arch of a user, the full arch dental strip device, comprising:
a backing layer; and
a treatment composition layer formed on one side of the backing layer,
wherein the treatment composition layer contains one or more active ingredients that treats one or more dental conditions. 12. The dental treatment system recited in claim 11, wherein the full arch dental strip device further comprises a release liner to which the treatment composition is temporarily attached for shipment of the dental treatment system. 13. The dental treatment system recited in claim 12, wherein the one or more active ingredients of the treatment composition include one or more of the following: fluoride, anti-microbials, desensitizers, teeth whitening agents, re-mineralizers, and/or periodontal agents. 14. The dental treatment system recited in claim 13, wherein the full arch dental strip device comprises a single full coverage treatment strip. 15. The dental treatment system recited in claim 14, wherein the single full coverage treatment strip comprises one or more notches along an outer perimeter of the single full coverage treatment strip. 16. The dental treatment system recited in claim 13, wherein the full arch dental strip device comprises two full coverage treatment strips. 17. The dental treatment system recited in claim 16, wherein the two full coverage treatment strips have substantially the same dimensions and are dimensioned to overlap one another when applied to the teeth of a user. 18. The dental treatment system recited in claim 13, wherein the full arch dental strip device comprises three full coverage treatment strips. 19. The dental treatment system recited in claim 18, wherein the three full coverage treatment strips comprise:
a front portion treatment strip configured to treat a front portion of a user's dental arch; and at least one back portion treatment strip configured to treat a back portion of a user's dental arch. | Example embodiments of the present invention include methods, devices, and systems that provide effective dental treatments to all tooth surfaces of the entire dental arch. In particular, embodiments of the present invention include treatment devices and systems that are capable of treating the entire arch by covering and delivering active ingredients to the front, back, and top surfaces of each of the teeth of the full dental arch. Moreover, example embodiments of the present invention provide treatment devices and systems that are capable of treating the gingival margin and gums of an entire arch.1. A dental treatment system, comprising:
a front portion treatment strip that fully covers one or more teeth on a front portion of a user's dental arch; at least one back portion treatment strip that fully covers one or more teeth on a back portion of the user's dental arch. 2. The dental treatment system recited in claim 1, wherein the front portion treatment strip, and the at least one back portion treatment strip have correlated lengths that when applied to the teeth of the user, the entire dental arch of the user is covered by at least one of the front portion treatment strip and/or the at least one back portion treatment strip. 3. The dental treatment system recited in claim 2, wherein the front portion treatment strip, when applied to the user's teeth, overlaps a portion of the at least one back portion treatment strip. 4. The dental treatment system recited in claim 3, wherein the front portion treatment strip has a length greater than the length of the at least one back portion treatment strip. 5. The dental treatment system recited in claim 4, wherein the front portion treatment strip and the at least one back portion treatment strip have a width such that the treatment strips also cover the gingival margin and gums of the user's entire dental arch. 6. A dental treatment system, comprising:
a front portion treatment strip that fully covers one or more teeth on a front portion of a user's dental arch; at least one back portion treatment strip that fully covers one or more teeth on a back portion of the user's dental arch; wherein the front portion treatment strip and the at least one back portion treatment strip comprise:
an insoluble backing layer; and
a treatment composition layer formed on one side of the insoluble backing layer. 7. The dental treatment system recited in claim 6, wherein the treatment composition layer is temporally attached to a package for shipment of the dental treatment system. 8. The dental treatment system recited in claim 6, wherein the insoluble backing layer is made from a polymer. 9. The dental treatment system recited in claim 6, wherein the treatment composition layer comprises one or more active ingredients to treat one or more dental conditions. 10. The dental treatment system recited in claim 9, wherein the one or more active ingredients comprises one or more of the following: fluoride, anti-microbials, desensitizers, teeth whitening agents, re-mineralizers, and/or periodontal agents. 11. A dental treatment system, comprising:
a full arch dental strip device, wherein the full arch dental strip device is configured to treat the entire dental arch of a user, the full arch dental strip device, comprising:
a backing layer; and
a treatment composition layer formed on one side of the backing layer,
wherein the treatment composition layer contains one or more active ingredients that treats one or more dental conditions. 12. The dental treatment system recited in claim 11, wherein the full arch dental strip device further comprises a release liner to which the treatment composition is temporarily attached for shipment of the dental treatment system. 13. The dental treatment system recited in claim 12, wherein the one or more active ingredients of the treatment composition include one or more of the following: fluoride, anti-microbials, desensitizers, teeth whitening agents, re-mineralizers, and/or periodontal agents. 14. The dental treatment system recited in claim 13, wherein the full arch dental strip device comprises a single full coverage treatment strip. 15. The dental treatment system recited in claim 14, wherein the single full coverage treatment strip comprises one or more notches along an outer perimeter of the single full coverage treatment strip. 16. The dental treatment system recited in claim 13, wherein the full arch dental strip device comprises two full coverage treatment strips. 17. The dental treatment system recited in claim 16, wherein the two full coverage treatment strips have substantially the same dimensions and are dimensioned to overlap one another when applied to the teeth of a user. 18. The dental treatment system recited in claim 13, wherein the full arch dental strip device comprises three full coverage treatment strips. 19. The dental treatment system recited in claim 18, wherein the three full coverage treatment strips comprise:
a front portion treatment strip configured to treat a front portion of a user's dental arch; and at least one back portion treatment strip configured to treat a back portion of a user's dental arch. | 1,600 |
710 | 15,318,897 | 1,617 | The invention relates to a method for coating plant seed, to a seed coating composition, to a coated plant seed, to a use of one or more water-insoluble polymers with a T g of at least 35° C., to a method of preparing a seed coating composition, to a method of preparing coated seed, to coated seed, to a use of an abrasive material primer or plasma, and to an apparatus for coating of seed.
The method for coating plant seed comprises applying to the seed a seed coating composition comprising one or more water-insoluble polymers with a T g of at least 35° C. | 1. A method for coating plant seed, comprising applying to said seed a seed coating composition comprising one or more water-insoluble polymers with a Tg of at least 35° C. 2. A method according to claim 1, wherein the seed coating composition has a Minimum Film Forming Temperature (MFFT) at least 10° C. lower than the Tg of the one or more water-insoluble polymers with a Tg of at least 35° C. 3. A method according to claim 1, wherein said seed coating composition comprises at least 2.0 wt. % of acrylic water-insoluble polymers with a Tg of at least 60° C. 4. A method according to claim 1, wherein said seed coating composition comprises one or more additional polymers with a Tg of less than 10° C. 5. A method according to claim 4, wherein said seed coating composition comprises one or more water-insoluble acrylic polymers with a Tg of at least 60° C. and one or more additional acrylic polymers with a Tg of less than 10° C. and has a weight ratio of total water-insoluble acrylic polymers with a Tg of at least 60° C. to total additional acrylic polymers with a Tg of less than 10° C. in the range of 10:1 to 1:5. 6. A method according to claim 1, wherein said seed coating composition comprises a wax. 7. A method according to claim 6, wherein said seed coating composition has a weight ratio of wax to water-insoluble polymers with Tg of at least 35° C. in the range of 1:50 to 1:1. 8. A method according to claim 4, wherein said one or more water-insoluble polymers have a Tg of at least a temperature T1 and wherein said one or more additional polymers have a Tg of less than a temperature T2, wherein T1 is at least 10° C. higher than T2. 9. A method according to claim 1, wherein said one or more water-insoluble polymers have a Tg of at least 90° C. 10. A method according to claim 1, wherein said method comprises combining said seed coating composition with a liquid based formulation comprising a plant enhancing agent and one or more selected from the group consisting of a non-aqueous solvent, a surfactant and an anti-freeze agent. 11. A method according to claim 1, wherein said coating composition is applied to said seed at a temperature at least 10° C. lower than the Tg of the one or more water-insoluble polymers with a Tg of at least 35° C., or at a temperature in the range of −5° C. to 35° C. 12. Seed coating composition comprising one or more water-insoluble polymers with a Tg of at least 35° C. 13. Seed coating composition according to claim 12, wherein the composition comprises one or more water-insoluble acrylic polymers with a Tg of at least 60° C. and one or more additional acrylic polymers with a Tg of less than 10° C. and has a weight ratio of total water-insoluble acrylic polymers with a Tg of at least 60° C. to total additional acrylic polymers with a Tg of less than 10° C. in the range of 10:1 to 1:5. 14. Seed coating composition according to claim 12, further comprising a wax. 15. Coated plant seed having a coating layer comprising one or more water-insoluble polymers with a Tg of at least 35° C., in an amount of at least 0.10 g of said polymers per kg seed. 16. (canceled) 17. Method of preparing a seed coating composition according to claim 12, the method comprising providing a coating formulation (a) comprising one or more water-insoluble polymers with a Tg of at least 35° C., and, separately, at least one liquid based formulation (b) comprising at least one plant enhancing agent and one or more components selected from the group consisting of a non-aqueous solvent, a surfactant and an anti-freeze agent; and combining said coating formulation (a) and said formulation (b). 18. Method of preparing coated seed, comprising subjecting seed to a surface treatment, and applying a coating layer onto the treated surface of the seed, wherein said coating layer is applied by film coating with a liquid coating composition comprising a polymeric binder. 19. Method according to claim 18, wherein said surface treatment comprises one or more selected from the group of increasing the surface roughness of the seed, plasma treatment, applying a primer formulation, exposure to hot humid air, flame treatment, laser treatment and electron beam surface treatment. 20. Method according to claim 18, wherein said film coating comprises a binder selected from the group consisting of polyvinyl acetates, polyvinyl alcohols, hydroxypropyl methyl cellulose, polysaccharides, proteins, polyethylene glycol, polyvinyl pyrrolidones, and styrene acrylic polymer. 21. Method according to claim 18, wherein said surface treatment comprises contacting the seed with abrasive particles having a hardness higher than the hardness of the seed coat and having an average particle size (D50) of 30 to 750 μm. 22. Method according to claim 18, wherein said surface treatment comprises plasma treatment with a plasma of one or more selected from the group consisting of nitrogen, oxygen, carbon dioxide, carbon monoxide, hydrogen, helium, argon, and a noble gas. 23. Method according to claim 18, wherein said surface treatment comprises applying a primer formulation comprising: 10-80 wt. % binder, based on dry weight, selected from the group consisting of styrene acrylic, ethylene acrylic and/or acrylic, and 10-80 wt. % particulate material having a D50 particle size (by volume) of 1-10 μm, the method further comprising applying subsequently a coating layer formulation comprising plant protective products and a binder. 24. Method for preparing coated seed, according to claim 18, wherein the coating layer is applied from a seed coating composition comprising one or more water-insoluble polymers with a Tg of at least 35° C. 25. A coated seed according to claim 15, wherein said coating layer comprises one or more selected from the group consisting of biocides including fungicidal agents, bactericidal agents, insecticidal agents, nematicidal agents, molluscidal agents, pesticides, herbicides, acaricides and miticides; attracting agents, repellent agents, plant growth regulators nutrients, plant hormones, minerals, plant extracts, germination stimulants, pheromones, chitosan, and chitine-based preparations. 26. (canceled) 27. (canceled) 28. Apparatus for coating of seed, comprising a first chamber for surface-treatment of the seed comprising, an inlet for seed and an outlet for surface-treated seed, which can be the same or different, one or more surface treatment devices arranged for surface treatment of the seed, selected from a plasma generator, a flame generator, a laser, an electron beam, an abrasive blast injector, and abrasive parts in combination with an actuator for relative movement in said pre-treatment chamber of said abrasive material and seed in contact with each other; and a second chamber for contacting seed with coating composition, which second chamber is downstream of the first chamber, with respect to seed, and comprises an inlet for coating composition and an inlet for seed, an outlet for coated seed, which inlets and outlet of the second chamber can be the same or different. 29. A method according to claim 3, wherein said seed coating composition comprises at least 5.0 wt. % of acrylic water-insoluble polymers with a Tg of at least 60° C. 30. A method according to claim 5, wherein said seed coating comprising has a weight ratio of total water-insoluble acrylic polymers with a Tg of at least 60° C. to total additional acrylic polymers with a Tg of less than 10° C. in the range of 5:1 to 1:2. 31. Seed coating composition according to claim 13, wherein the composition has a weight ratio of total water-insoluble acrylic polymers with a Tg of at least 60° C. to total additional acrylic polymers with a Tg of less than 10° C. in the range of 5:1 to 1:2. 32. Coated plant seed according to claim 15 comprising one or more water-insoluble polymers with a Tg of at least 35° C., in an amount of at least 0.20 g of said polymers per kg seed. | The invention relates to a method for coating plant seed, to a seed coating composition, to a coated plant seed, to a use of one or more water-insoluble polymers with a T g of at least 35° C., to a method of preparing a seed coating composition, to a method of preparing coated seed, to coated seed, to a use of an abrasive material primer or plasma, and to an apparatus for coating of seed.
The method for coating plant seed comprises applying to the seed a seed coating composition comprising one or more water-insoluble polymers with a T g of at least 35° C.1. A method for coating plant seed, comprising applying to said seed a seed coating composition comprising one or more water-insoluble polymers with a Tg of at least 35° C. 2. A method according to claim 1, wherein the seed coating composition has a Minimum Film Forming Temperature (MFFT) at least 10° C. lower than the Tg of the one or more water-insoluble polymers with a Tg of at least 35° C. 3. A method according to claim 1, wherein said seed coating composition comprises at least 2.0 wt. % of acrylic water-insoluble polymers with a Tg of at least 60° C. 4. A method according to claim 1, wherein said seed coating composition comprises one or more additional polymers with a Tg of less than 10° C. 5. A method according to claim 4, wherein said seed coating composition comprises one or more water-insoluble acrylic polymers with a Tg of at least 60° C. and one or more additional acrylic polymers with a Tg of less than 10° C. and has a weight ratio of total water-insoluble acrylic polymers with a Tg of at least 60° C. to total additional acrylic polymers with a Tg of less than 10° C. in the range of 10:1 to 1:5. 6. A method according to claim 1, wherein said seed coating composition comprises a wax. 7. A method according to claim 6, wherein said seed coating composition has a weight ratio of wax to water-insoluble polymers with Tg of at least 35° C. in the range of 1:50 to 1:1. 8. A method according to claim 4, wherein said one or more water-insoluble polymers have a Tg of at least a temperature T1 and wherein said one or more additional polymers have a Tg of less than a temperature T2, wherein T1 is at least 10° C. higher than T2. 9. A method according to claim 1, wherein said one or more water-insoluble polymers have a Tg of at least 90° C. 10. A method according to claim 1, wherein said method comprises combining said seed coating composition with a liquid based formulation comprising a plant enhancing agent and one or more selected from the group consisting of a non-aqueous solvent, a surfactant and an anti-freeze agent. 11. A method according to claim 1, wherein said coating composition is applied to said seed at a temperature at least 10° C. lower than the Tg of the one or more water-insoluble polymers with a Tg of at least 35° C., or at a temperature in the range of −5° C. to 35° C. 12. Seed coating composition comprising one or more water-insoluble polymers with a Tg of at least 35° C. 13. Seed coating composition according to claim 12, wherein the composition comprises one or more water-insoluble acrylic polymers with a Tg of at least 60° C. and one or more additional acrylic polymers with a Tg of less than 10° C. and has a weight ratio of total water-insoluble acrylic polymers with a Tg of at least 60° C. to total additional acrylic polymers with a Tg of less than 10° C. in the range of 10:1 to 1:5. 14. Seed coating composition according to claim 12, further comprising a wax. 15. Coated plant seed having a coating layer comprising one or more water-insoluble polymers with a Tg of at least 35° C., in an amount of at least 0.10 g of said polymers per kg seed. 16. (canceled) 17. Method of preparing a seed coating composition according to claim 12, the method comprising providing a coating formulation (a) comprising one or more water-insoluble polymers with a Tg of at least 35° C., and, separately, at least one liquid based formulation (b) comprising at least one plant enhancing agent and one or more components selected from the group consisting of a non-aqueous solvent, a surfactant and an anti-freeze agent; and combining said coating formulation (a) and said formulation (b). 18. Method of preparing coated seed, comprising subjecting seed to a surface treatment, and applying a coating layer onto the treated surface of the seed, wherein said coating layer is applied by film coating with a liquid coating composition comprising a polymeric binder. 19. Method according to claim 18, wherein said surface treatment comprises one or more selected from the group of increasing the surface roughness of the seed, plasma treatment, applying a primer formulation, exposure to hot humid air, flame treatment, laser treatment and electron beam surface treatment. 20. Method according to claim 18, wherein said film coating comprises a binder selected from the group consisting of polyvinyl acetates, polyvinyl alcohols, hydroxypropyl methyl cellulose, polysaccharides, proteins, polyethylene glycol, polyvinyl pyrrolidones, and styrene acrylic polymer. 21. Method according to claim 18, wherein said surface treatment comprises contacting the seed with abrasive particles having a hardness higher than the hardness of the seed coat and having an average particle size (D50) of 30 to 750 μm. 22. Method according to claim 18, wherein said surface treatment comprises plasma treatment with a plasma of one or more selected from the group consisting of nitrogen, oxygen, carbon dioxide, carbon monoxide, hydrogen, helium, argon, and a noble gas. 23. Method according to claim 18, wherein said surface treatment comprises applying a primer formulation comprising: 10-80 wt. % binder, based on dry weight, selected from the group consisting of styrene acrylic, ethylene acrylic and/or acrylic, and 10-80 wt. % particulate material having a D50 particle size (by volume) of 1-10 μm, the method further comprising applying subsequently a coating layer formulation comprising plant protective products and a binder. 24. Method for preparing coated seed, according to claim 18, wherein the coating layer is applied from a seed coating composition comprising one or more water-insoluble polymers with a Tg of at least 35° C. 25. A coated seed according to claim 15, wherein said coating layer comprises one or more selected from the group consisting of biocides including fungicidal agents, bactericidal agents, insecticidal agents, nematicidal agents, molluscidal agents, pesticides, herbicides, acaricides and miticides; attracting agents, repellent agents, plant growth regulators nutrients, plant hormones, minerals, plant extracts, germination stimulants, pheromones, chitosan, and chitine-based preparations. 26. (canceled) 27. (canceled) 28. Apparatus for coating of seed, comprising a first chamber for surface-treatment of the seed comprising, an inlet for seed and an outlet for surface-treated seed, which can be the same or different, one or more surface treatment devices arranged for surface treatment of the seed, selected from a plasma generator, a flame generator, a laser, an electron beam, an abrasive blast injector, and abrasive parts in combination with an actuator for relative movement in said pre-treatment chamber of said abrasive material and seed in contact with each other; and a second chamber for contacting seed with coating composition, which second chamber is downstream of the first chamber, with respect to seed, and comprises an inlet for coating composition and an inlet for seed, an outlet for coated seed, which inlets and outlet of the second chamber can be the same or different. 29. A method according to claim 3, wherein said seed coating composition comprises at least 5.0 wt. % of acrylic water-insoluble polymers with a Tg of at least 60° C. 30. A method according to claim 5, wherein said seed coating comprising has a weight ratio of total water-insoluble acrylic polymers with a Tg of at least 60° C. to total additional acrylic polymers with a Tg of less than 10° C. in the range of 5:1 to 1:2. 31. Seed coating composition according to claim 13, wherein the composition has a weight ratio of total water-insoluble acrylic polymers with a Tg of at least 60° C. to total additional acrylic polymers with a Tg of less than 10° C. in the range of 5:1 to 1:2. 32. Coated plant seed according to claim 15 comprising one or more water-insoluble polymers with a Tg of at least 35° C., in an amount of at least 0.20 g of said polymers per kg seed. | 1,600 |
711 | 12,918,159 | 1,653 | A method for detecting at least one microorganism that may be present in a sample, comprising the steps of:
a) bringing into contact, in a container: a culture medium that enables the growth and/or detection of microorganisms, said sample and a sensitized solid support;
b) subjecting the whole to a temperature that promotes the growth and/or detection of microorganisms; and
c) observing, in real time, the appearance of an agglutination indicating the presence of the microorganism(s) or confirming said presence when said microorganisms are detected in said culture medium, when step b) has been completed, and
a method for detecting and identifying at least one target microorganism that may be present in a sample. | 1. A method for detecting at least one microorganism that may be present in a sample, comprising the steps of:
a) bringing into contact, in a container: a culture medium that enables the growth and/or detection of microorganisms, said sample and a sensitized solid support; b) subjecting the whole to a temperature that promotes the growth and/or detection of microorganisms; and c) observing, in real time, the appearance of an agglutination indicating the presence of the microorganism(s) or confirming said presence when said microorganisms are detected in said culture medium, when step b) has been completed. 2. A method for detecting and identifying at least one microorganism that may be present in a sample, comprising the steps of:
a) bringing into contact, in a container: a culture medium that enables the growth and/or identification of microorganisms, said sample and a sensitized solid support; b) subjecting the whole to a temperature that promotes the growth and/or identification of microorganisms; and c) observing, in real time, the appearance of an agglutination making it possible to identify the microorganism(s) or to confirm said identification, when said microorganism(s) is (are) identified in said culture medium, when step b) has been completed. 3. A method for detecting and identifying at least one microorganism that may be present in a sample, comprising the steps of:
a) bringing into contact, in a container: a culture medium that enables the growth and identification of microorganisms, said sample and a sensitized solid support; b) subjecting the whole to a temperature that promotes the growth and identification of microorganisms; and c) observing, in real time, the appearance of an agglutination making it possible to supplement the identification of the microorganism(s), made when step b) has been completed. 4. The method as claimed in claim 1, in which the detection or the identification in the culture medium uses the appearance or the disappearance of a coloration or of a fluorescence. 5. The method as claimed in claim 1, in which the agglutination is demonstrated by the appearance or the disappearance of a coloration or of a fluorescence. 6. The method as claimed in claim 1, in which the container is taken from the group constituted of microplates, microcupules, microtubes, capillaries or multiwell cards. 7. The method as claimed in claim 1, also comprising a step of counting the microorganisms. 8. The method as claimed in claim 1, in which the agglutination reaction implements an antigen-antibody reaction. 9. The method as claimed in claim 1, in which the agglutination reaction implements a phage-bacterial protein reaction. 10. The method as claimed in claim 1, in which the agglutination reaction implements a ligand/antiligand reaction. 11. A microbiological diagnostic kit for carrying out the method as claimed in claim 1, and comprising:
a container; a selective or nonselective culture medium, said culture medium optionally containing a substrate specific for the metabolism of the microbial genus or species to be detected; and a sensitized solid support. 12. The diagnostic kit as claimed in claim 11, in which the container is taken from the group constituted of microplates, microcupules, microtubes, capillaries or multiwell cards. 13. The diagnostic kit as claimed in claim 11, in which said sensitized support is a solid support-antigen complex or a solid support-antibody complex. 14. The diagnostic kit as claimed in claim 11, in which said sensitized support is a solid support-ligand complex or a solid support-antiligand complex. 15. The diagnostic kit as claimed in claim 14, in which the ligand comprises all or part of a bacteriophage. 16. The diagnostic kit as claimed in claim 11, also comprising at least one chromogenic or fluorescent compound. 17. A method for detecting and/or identifying at least one microorganism that may be present in a sample employing using the diagnostic kit as claimed in claim 11. | A method for detecting at least one microorganism that may be present in a sample, comprising the steps of:
a) bringing into contact, in a container: a culture medium that enables the growth and/or detection of microorganisms, said sample and a sensitized solid support;
b) subjecting the whole to a temperature that promotes the growth and/or detection of microorganisms; and
c) observing, in real time, the appearance of an agglutination indicating the presence of the microorganism(s) or confirming said presence when said microorganisms are detected in said culture medium, when step b) has been completed, and
a method for detecting and identifying at least one target microorganism that may be present in a sample.1. A method for detecting at least one microorganism that may be present in a sample, comprising the steps of:
a) bringing into contact, in a container: a culture medium that enables the growth and/or detection of microorganisms, said sample and a sensitized solid support; b) subjecting the whole to a temperature that promotes the growth and/or detection of microorganisms; and c) observing, in real time, the appearance of an agglutination indicating the presence of the microorganism(s) or confirming said presence when said microorganisms are detected in said culture medium, when step b) has been completed. 2. A method for detecting and identifying at least one microorganism that may be present in a sample, comprising the steps of:
a) bringing into contact, in a container: a culture medium that enables the growth and/or identification of microorganisms, said sample and a sensitized solid support; b) subjecting the whole to a temperature that promotes the growth and/or identification of microorganisms; and c) observing, in real time, the appearance of an agglutination making it possible to identify the microorganism(s) or to confirm said identification, when said microorganism(s) is (are) identified in said culture medium, when step b) has been completed. 3. A method for detecting and identifying at least one microorganism that may be present in a sample, comprising the steps of:
a) bringing into contact, in a container: a culture medium that enables the growth and identification of microorganisms, said sample and a sensitized solid support; b) subjecting the whole to a temperature that promotes the growth and identification of microorganisms; and c) observing, in real time, the appearance of an agglutination making it possible to supplement the identification of the microorganism(s), made when step b) has been completed. 4. The method as claimed in claim 1, in which the detection or the identification in the culture medium uses the appearance or the disappearance of a coloration or of a fluorescence. 5. The method as claimed in claim 1, in which the agglutination is demonstrated by the appearance or the disappearance of a coloration or of a fluorescence. 6. The method as claimed in claim 1, in which the container is taken from the group constituted of microplates, microcupules, microtubes, capillaries or multiwell cards. 7. The method as claimed in claim 1, also comprising a step of counting the microorganisms. 8. The method as claimed in claim 1, in which the agglutination reaction implements an antigen-antibody reaction. 9. The method as claimed in claim 1, in which the agglutination reaction implements a phage-bacterial protein reaction. 10. The method as claimed in claim 1, in which the agglutination reaction implements a ligand/antiligand reaction. 11. A microbiological diagnostic kit for carrying out the method as claimed in claim 1, and comprising:
a container; a selective or nonselective culture medium, said culture medium optionally containing a substrate specific for the metabolism of the microbial genus or species to be detected; and a sensitized solid support. 12. The diagnostic kit as claimed in claim 11, in which the container is taken from the group constituted of microplates, microcupules, microtubes, capillaries or multiwell cards. 13. The diagnostic kit as claimed in claim 11, in which said sensitized support is a solid support-antigen complex or a solid support-antibody complex. 14. The diagnostic kit as claimed in claim 11, in which said sensitized support is a solid support-ligand complex or a solid support-antiligand complex. 15. The diagnostic kit as claimed in claim 14, in which the ligand comprises all or part of a bacteriophage. 16. The diagnostic kit as claimed in claim 11, also comprising at least one chromogenic or fluorescent compound. 17. A method for detecting and/or identifying at least one microorganism that may be present in a sample employing using the diagnostic kit as claimed in claim 11. | 1,600 |
712 | 15,823,918 | 1,613 | A tamper-resistant pharmaceutical dosage form comprising a multitude of particles which comprise a pharmacologically active compound, a polyalkylene oxide, and a disintegrant; wherein the pharmacologically active compound is dispersed in a matrix comprising the polyalkylene oxide and the disintegrant; wherein the content of the disintegrant is more than 5.0 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles; wherein the content of the polyalkylene oxide is at least 25 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles; and wherein the dosage form provides under in vitro conditions immediate release of the pharmacologically active compound in accordance with Ph. Eur. | 1. A tamper-resistant pharmaceutical dosage form comprising a multitude of particles which comprise a pharmacologically active compound, a polyalkylene oxide, and a disintegrant;
wherein the pharmacologically active compound is a stimulant; wherein the pharmacologically active compound is dispersed in a matrix comprising the polyalkylene oxide and the disintegrant; wherein the content of the disintegrant is more than 5.0 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles; wherein the content of the polyalkylene oxide is at least 25 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles; and wherein the dosage form provides under in vitro conditions immediate release of the pharmacologically active compound in accordance with Ph. Eur. 2. The pharmaceutical dosage form according to claim 1, which has a breaking strength of at least 300 N. 3. The pharmaceutical dosage form according to claim 1, which exhibits resistance against solvent extraction such that when
(i) dispensing the pharmaceutical dosage form that is either intact or has been manually comminuted by means of two spoons in 5 ml of purified water, (ii) heating the liquid up to its boiling point, (iii) boiling the liquid in a covered vessel for 5 min without the addition of further purified water, (iv) drawing up the hot liquid into a syringe, and (v) determining the amount of the pharmacologically active compound contained in the liquid within the syringe,
the liquid part of the formulation that can be separated from the remainder by means of the syringe is not more than 10 wt.-% of the pharmacologically active compound originally contained in the dosage form. 4. The pharmaceutical dosage form according to claim 1, wherein the disintegrant is selected from the group consisting of polysaccharides, starches, starch derivatives, cellulose derivatives, acrylates, polyvinylpyrrolidones, gas releasing substances, proteins and protein derivatives. 5. The pharmaceutical dosage form according to claim 4, wherein the disintegrant is or comprises a polysaccharide; and/or the polysaccharide is a polysaccharide mixture obtained from soybeans or sodium alginate. 6. The pharmaceutical dosage form according to claim 4, wherein the disintegrant is or comprises a starch; and/or the starch is standard starch or pregelatinized starch. 7. The pharmaceutical dosage form according to claim 4, wherein the disintegrant is or comprises a starch derivative; and/or the starch derivative is sodium starch glycolate or sodium carboxymethyl starch. 8. The pharmaceutical dosage form according to claim 4, wherein the disintegrant is or comprises a cellulose derivative; and/or the cellulose derivative is croscarmellose sodium. 9. The pharmaceutical dosage form according to claim 4, wherein the disintegrant is or comprises an acrylate; and/or the acrylate is carbopol. 10. The pharmaceutical dosage form according to claim 4, wherein the disintegrant is or comprises a polyvinylpyrrolidone; and/or the polyvinylpyrrolidone is crospovidone. 11. The pharmaceutical dosage form according to claim 4, wherein the disintegrant is or comprises a gas releasing substance; and/or the gas releasing substance is sodium bicarbonate. 12. The pharmaceutical dosage form according to claim 4, wherein the disintegrant is or comprises a protein or protein derivative; and/or the protein or protein derivative is crosslinked casein. 13. The pharmaceutical dosage form according to claim 1, wherein the content of the disintegrant is at least 10 wt.-%, based on the total weight of the particles; or the content of the disintegrant is within the range of 15±5.0 wt.-%, based on the total weight of the particles; or the content of the disintegrant is within the range of 20±5.0 wt.-%, based on the total weight of the particles; or the content of the disintegrant is within the range of 25±5.0 wt.-%, based on the total weight of the particles. 14. The pharmaceutical dosage form according to claim 1, wherein the polyalkylene oxide has a weight average molecular weight of at least 500,000 g/mol; or the content of the polyalkylene oxide is at least 40 wt.-%, based on the total weight of the particles; or the content of the polyalkylene oxide is at least 45 wt.-%, based on the total weight of the particles; or the content of the polyalkylene oxide is at least 50 wt.-%, based on the total weight of the particles; or the total content of the polyalkylene oxide that is contained in the pharmaceutical dosage form is contained in the particles. 15. The pharmaceutical dosage form according to claim 1, which provides a release profile such that under in vitro conditions in 600 ml 0.1 M HCl (pH 1) at 75 rpm after 30 min at least 90 wt.-% of the pharmacologically active ingredient that was originally contained in the dosage form have been released. 16. The pharmaceutical dosage form according to claim 1, which additionally comprises a gelling agent. 17. The pharmaceutical dosage form according to claim 16, wherein the gelling agent is a polysaccharide; or the content of the gelling agent is at least 1.0 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles. 18. The pharmaceutical dosage form according to claim 1, wherein the stimulant is selected from the group consisting of amphetamine, dexamphetamine, methylphenidate, dexmethylphenidate, pseudoephedrine, and the physiologically acceptable salts thereof. 19. The pharmaceutical dosage form according to claim 1, wherein the content of the pharmacologically active compound is at least 5.0 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles. 20. The pharmaceutical dosage form according to claim 1, wherein the particles are hot melt-extruded. 21. The pharmaceutical dosage form according to claim 1, wherein the particles are film coated. 22. The pharmaceutical dosage form according to claim 1, which is a tablet or capsule. 23. A method of treating pain in a patient, said method comprising administering to said patient at least one dosage form according to claim 1 in a quantity and for a period of time effective to treat pain. | A tamper-resistant pharmaceutical dosage form comprising a multitude of particles which comprise a pharmacologically active compound, a polyalkylene oxide, and a disintegrant; wherein the pharmacologically active compound is dispersed in a matrix comprising the polyalkylene oxide and the disintegrant; wherein the content of the disintegrant is more than 5.0 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles; wherein the content of the polyalkylene oxide is at least 25 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles; and wherein the dosage form provides under in vitro conditions immediate release of the pharmacologically active compound in accordance with Ph. Eur.1. A tamper-resistant pharmaceutical dosage form comprising a multitude of particles which comprise a pharmacologically active compound, a polyalkylene oxide, and a disintegrant;
wherein the pharmacologically active compound is a stimulant; wherein the pharmacologically active compound is dispersed in a matrix comprising the polyalkylene oxide and the disintegrant; wherein the content of the disintegrant is more than 5.0 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles; wherein the content of the polyalkylene oxide is at least 25 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles; and wherein the dosage form provides under in vitro conditions immediate release of the pharmacologically active compound in accordance with Ph. Eur. 2. The pharmaceutical dosage form according to claim 1, which has a breaking strength of at least 300 N. 3. The pharmaceutical dosage form according to claim 1, which exhibits resistance against solvent extraction such that when
(i) dispensing the pharmaceutical dosage form that is either intact or has been manually comminuted by means of two spoons in 5 ml of purified water, (ii) heating the liquid up to its boiling point, (iii) boiling the liquid in a covered vessel for 5 min without the addition of further purified water, (iv) drawing up the hot liquid into a syringe, and (v) determining the amount of the pharmacologically active compound contained in the liquid within the syringe,
the liquid part of the formulation that can be separated from the remainder by means of the syringe is not more than 10 wt.-% of the pharmacologically active compound originally contained in the dosage form. 4. The pharmaceutical dosage form according to claim 1, wherein the disintegrant is selected from the group consisting of polysaccharides, starches, starch derivatives, cellulose derivatives, acrylates, polyvinylpyrrolidones, gas releasing substances, proteins and protein derivatives. 5. The pharmaceutical dosage form according to claim 4, wherein the disintegrant is or comprises a polysaccharide; and/or the polysaccharide is a polysaccharide mixture obtained from soybeans or sodium alginate. 6. The pharmaceutical dosage form according to claim 4, wherein the disintegrant is or comprises a starch; and/or the starch is standard starch or pregelatinized starch. 7. The pharmaceutical dosage form according to claim 4, wherein the disintegrant is or comprises a starch derivative; and/or the starch derivative is sodium starch glycolate or sodium carboxymethyl starch. 8. The pharmaceutical dosage form according to claim 4, wherein the disintegrant is or comprises a cellulose derivative; and/or the cellulose derivative is croscarmellose sodium. 9. The pharmaceutical dosage form according to claim 4, wherein the disintegrant is or comprises an acrylate; and/or the acrylate is carbopol. 10. The pharmaceutical dosage form according to claim 4, wherein the disintegrant is or comprises a polyvinylpyrrolidone; and/or the polyvinylpyrrolidone is crospovidone. 11. The pharmaceutical dosage form according to claim 4, wherein the disintegrant is or comprises a gas releasing substance; and/or the gas releasing substance is sodium bicarbonate. 12. The pharmaceutical dosage form according to claim 4, wherein the disintegrant is or comprises a protein or protein derivative; and/or the protein or protein derivative is crosslinked casein. 13. The pharmaceutical dosage form according to claim 1, wherein the content of the disintegrant is at least 10 wt.-%, based on the total weight of the particles; or the content of the disintegrant is within the range of 15±5.0 wt.-%, based on the total weight of the particles; or the content of the disintegrant is within the range of 20±5.0 wt.-%, based on the total weight of the particles; or the content of the disintegrant is within the range of 25±5.0 wt.-%, based on the total weight of the particles. 14. The pharmaceutical dosage form according to claim 1, wherein the polyalkylene oxide has a weight average molecular weight of at least 500,000 g/mol; or the content of the polyalkylene oxide is at least 40 wt.-%, based on the total weight of the particles; or the content of the polyalkylene oxide is at least 45 wt.-%, based on the total weight of the particles; or the content of the polyalkylene oxide is at least 50 wt.-%, based on the total weight of the particles; or the total content of the polyalkylene oxide that is contained in the pharmaceutical dosage form is contained in the particles. 15. The pharmaceutical dosage form according to claim 1, which provides a release profile such that under in vitro conditions in 600 ml 0.1 M HCl (pH 1) at 75 rpm after 30 min at least 90 wt.-% of the pharmacologically active ingredient that was originally contained in the dosage form have been released. 16. The pharmaceutical dosage form according to claim 1, which additionally comprises a gelling agent. 17. The pharmaceutical dosage form according to claim 16, wherein the gelling agent is a polysaccharide; or the content of the gelling agent is at least 1.0 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles. 18. The pharmaceutical dosage form according to claim 1, wherein the stimulant is selected from the group consisting of amphetamine, dexamphetamine, methylphenidate, dexmethylphenidate, pseudoephedrine, and the physiologically acceptable salts thereof. 19. The pharmaceutical dosage form according to claim 1, wherein the content of the pharmacologically active compound is at least 5.0 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles. 20. The pharmaceutical dosage form according to claim 1, wherein the particles are hot melt-extruded. 21. The pharmaceutical dosage form according to claim 1, wherein the particles are film coated. 22. The pharmaceutical dosage form according to claim 1, which is a tablet or capsule. 23. A method of treating pain in a patient, said method comprising administering to said patient at least one dosage form according to claim 1 in a quantity and for a period of time effective to treat pain. | 1,600 |
713 | 15,331,759 | 1,612 | Compositions comprised of a delivery vehicle or delivery system and an active agent dispersed within the delivery vehicle or system, wherein the delivery vehicle or system contains a polyorthoester polymer and a polar aprotic solvent. Also disclosed are low viscosity delivery systems for administration of active agents. The low viscosity delivery systems have a polyorthoester polymer, a polar aprotic solvent and a solvent containing a triglyceride viscosity reducing agent. Compositions described include an amide- or anilide-type local anesthetic of the “caine” classification, and a non-steroidal anti-inflammatory drug (NSAID), along with related methods, e.g., for treatment of post-operative pain or for prophylactic treatment of pain. The compositions are suitable for delivery via, e.g., direct application and instillation, intradermal injection, subcutaneous injection, and nerve block (perineural). | 1. A pharmaceutical composition comprising a delivery system, an amide-type local anesthetic, and meloxicam, wherein the amide-type local anesthetic and meloxicam are present in the composition at a ratio ranging from about 10:1 to 50:1. 2. The composition of claim 1, wherein the amide-type local anesthetic is bupivacaine. 3. The composition of claim 1, wherein the amide-type local anesthetic is ropivacaine. 4. The composition of claim 1, wherein the amide-type local anesthetic is present in the composition in an amount ranging from about 0.1 to 8.0 wt % and the meloxicam in present in the composition in an amount ranging from about 0.005% to 1%. 5. The composition of claim 1, wherein the delivery system is a sustained-release delivery system. 6. The composition of claim 1, wherein the delivery system is aqueous based. 7. The composition of claim 5, wherein the sustained-release delivery system is a polymeric formulation, a liposome, a microsphere, an implantable device or a non-polymeric formulation. 8. The composition of claim 5, wherein the sustained-release delivery system is a liposome selected from the group consisting of small unilamellar vesicles (SUV), large unilamellar vesicles (LUV), multi-lamellar vesicles (MLV) and multivesicular liposomes (MVL). 9. The composition of claim 8, wherein the amide-type local anesthetic and the meloxicam are entrapped in an aqueous space of the liposome or in a lipid layer of the liposome. 10. The composition of claim 5, wherein the sustained-release delivery system is a microsphere comprised of a bioerodible or biodegradable polymer. 11. The composition of claim 10, wherein the amide-type local anesthetic and the meloxicam are entrapped in the microsphere. 12. The composition of claim 7, wherein the implantable device is an osmotic pump with a reservoir comprising the amide-type local anesthetic and the meloxicam. 13. The composition of claim 5, wherein the sustained-release delivery system is a non-polymeric formulation comprising sucrose acetate isobutyrate. 14. The composition of claim 5, wherein the sustained-release delivery system is a polymeric formulation in the form of a semi-solid polymer formulation comprising a polymer, the amide-type local anesthetic and the meloxicam. 15. The composition of claim 14, wherein the polymer is a bioerodible or biodegradable polymer. 16. The composition of claim 14, wherein the polymer formulation forms an implant or depot in situ. 17. The composition of claim 14 wherein the polymer is selected from the group consisting of polylactides, polyglycolides, poly(lactic-co-glycolic acid) copolymers, polycaprolactones, poly-3-hydroxybutyrates, and polyorthoesters. 18. The composition of claim 14, wherein the polymer is a polyorthoester. 19. The composition of claim 17, wherein the polyorthoester in the composition is selected from the polyorthoesters represented by Formulas I, II, III and IV. 20. The composition of claim 17, wherein the polyorthoester is represented by Formula I. 21. The composition of claim 1, wherein the delivery system comprises the polyorthoester, a polar aprotic solvent and a triglyceride viscosity reducing agent, wherein the triglyceride viscosity reducing agent comprises three fatty acid groups each independently comprising between 1-7 carbon atoms, and wherein the amide-type local anesthetic and meloxicam are present in the delivery system at a ratio ranging from about 10:1 to 50:1. 22. The composition of claim 21, wherein the triglyceride viscosity reducing agent is selected from the group consisting of triacetin and tributyrin. 23. The composition of claim 21, wherein the polar aprotic solvent is selected from dimethylsulfoxide, N-methyl pyrrolidone and dimethyl acetamide. 24. The composition of claim 21, wherein the amide-type local anesthetic and meloxicam are soluble in the triglyceride viscosity reducing agent, the polar aprotic solvent, or a mixture thereof. 25. The composition of claim 21, wherein the amide-type local anesthetic is present in the delivery system at between about 0.01 wt % and about 7.5 wt % of the delivery system. 26. The composition of claim 25, wherein the meloxicam is present in the delivery system at between about 0.005 wt % to 0.25 wt % of the delivery system. 27. The composition of claim 1, wherein the delivery system comprises:
40 wt % to 75 wt % of a polyorthoester; 5 wt % to 12 wt % dimethyl sulfoxide; 20 wt % to 40 wt % triacetin; 1 wt % to 5 wt % bupivacaine or ropivacaine; and 0.005 wt % to 1 wt % meloxicam. 28. The composition of claim 27, wherein the delivery system further comprises 0.01 wt % to 0.30 wt % maleic acid. 29. The composition of claim 27, wherein the polyorthoester is represented by the structure shown as Formula I:
where
R* is C1-4 alkyl,
n ranges from 5 to 400, and
A is a diol. 30. The composition of claim 29, where
A is R1 or R3, where the fraction of A units that are of formula R1 is between 0 and 25 mole percent, R1 is
p and q are each independently integers ranging from between about 1 and 20 and the average number of p or the average sum of p and q is between about 1 and 7, and
R5 is H or methyl,
R6 is
where s is an integer ranging from 0 to 10, and
R3 is
where x is an integer ranging from 1 to 10. 31. The composition of claim 30, wherein s is 2 and x is 2. 32. The composition of claim 29, wherein R3 and R6 are both —(CH2—CH2—O)2—(CH2—CH2)—; R5 is H; and p is 1 or 2. 33. The composition of claim 29, wherein R5 is hydrogen. 34. The composition of claim 29, wherein
when A is R1, R1 is
R5 is H, and R6 is
where the resulting polyorthoester comprises the subunit
where the sum of p and q is, on average, 2 and s is 2, and
when A is R3, x is 2. 35. The composition of claim 29, wherein the fraction of A units that are of formula R1 is about 20 percent. 36. The composition of claim 27, wherein the polyorthoester has a weight average molecular weight between 2,500 daltons and 10,000 daltons. 37. The composition of claim 27, wherein the delivery system has a viscosity less than 10000 mPa-s when measured at 37° C. using a viscometer. 38. The composition of claim 27, wherein the bupivacaine or ropivacaine and the meloxicam are solubilized in a single phase. 39. The composition of claim 27, wherein the composition is an extended-release composition. 40. The composition of claim 5, wherein the local anesthetic is released from the composition over a time period of about 1 day to about 5 days. 41. A method for producing analgesia or pain relief in a subject in need thereof, comprising: administering to the subject the composition according to claim 1. 42. A method for managing pain in a subject in need thereof, comprising administering to the subject the composition according to claim 1. 43. A method for prophylactic treatment of pain in a subject, comprising administering to the subject the composition according to claim 1. 44. The method of claim 41, wherein the administering is intramuscular, subcutaneous, perineural or to a wound. 45. The method of claim 41, wherein the pain is acute pain or chronic pain. 46. The method of claim 41, wherein the composition or delivery system is administered to a surgical wound. 47. The method according to claim 46, wherein the pain is postsurgical pain. 48. The method of claim 41, wherein the composition produces pain relief for a time period of about 3 days to about 5 days following administration. 49. The method of claim 41, wherein the composition or delivery system is administered as a nerve block. 50. The method of claim 41, wherein the composition or delivery system is administered as a peripheral nerve block. 51. The method of claim 41, further comprising administering the composition to a person in need thereof, whereby said administering provides, as measured in an in vivo model for postsurgical pain, an initial decrease in pain relief between about 1 hours and 24 hours after administering and a period of increased pain relief between about 1-3 days after administering, wherein the initial decrease in pain relief is with respect to pain relief provided immediately after administering. 52. The method of claim 51, wherein the composition provides pain relief over days 2 to 5 following administration that is at least, on average, about 50% of the average pain relief provided by the composition 1-5 hours post-administration. 53. The method of claim 51, whereby the administering is effective to provide a measurable plasma concentration of the amide-type local anesthetic and of the NSAID for a period of at up to 5 days following administration. 54. The method of claim 51, wherein about 80% by weight or more of both the local anesthetic and the enolic-acid NSAID are released from the composition over a period of up to about 3 days when measured in an in vitro test at 37° C. | Compositions comprised of a delivery vehicle or delivery system and an active agent dispersed within the delivery vehicle or system, wherein the delivery vehicle or system contains a polyorthoester polymer and a polar aprotic solvent. Also disclosed are low viscosity delivery systems for administration of active agents. The low viscosity delivery systems have a polyorthoester polymer, a polar aprotic solvent and a solvent containing a triglyceride viscosity reducing agent. Compositions described include an amide- or anilide-type local anesthetic of the “caine” classification, and a non-steroidal anti-inflammatory drug (NSAID), along with related methods, e.g., for treatment of post-operative pain or for prophylactic treatment of pain. The compositions are suitable for delivery via, e.g., direct application and instillation, intradermal injection, subcutaneous injection, and nerve block (perineural).1. A pharmaceutical composition comprising a delivery system, an amide-type local anesthetic, and meloxicam, wherein the amide-type local anesthetic and meloxicam are present in the composition at a ratio ranging from about 10:1 to 50:1. 2. The composition of claim 1, wherein the amide-type local anesthetic is bupivacaine. 3. The composition of claim 1, wherein the amide-type local anesthetic is ropivacaine. 4. The composition of claim 1, wherein the amide-type local anesthetic is present in the composition in an amount ranging from about 0.1 to 8.0 wt % and the meloxicam in present in the composition in an amount ranging from about 0.005% to 1%. 5. The composition of claim 1, wherein the delivery system is a sustained-release delivery system. 6. The composition of claim 1, wherein the delivery system is aqueous based. 7. The composition of claim 5, wherein the sustained-release delivery system is a polymeric formulation, a liposome, a microsphere, an implantable device or a non-polymeric formulation. 8. The composition of claim 5, wherein the sustained-release delivery system is a liposome selected from the group consisting of small unilamellar vesicles (SUV), large unilamellar vesicles (LUV), multi-lamellar vesicles (MLV) and multivesicular liposomes (MVL). 9. The composition of claim 8, wherein the amide-type local anesthetic and the meloxicam are entrapped in an aqueous space of the liposome or in a lipid layer of the liposome. 10. The composition of claim 5, wherein the sustained-release delivery system is a microsphere comprised of a bioerodible or biodegradable polymer. 11. The composition of claim 10, wherein the amide-type local anesthetic and the meloxicam are entrapped in the microsphere. 12. The composition of claim 7, wherein the implantable device is an osmotic pump with a reservoir comprising the amide-type local anesthetic and the meloxicam. 13. The composition of claim 5, wherein the sustained-release delivery system is a non-polymeric formulation comprising sucrose acetate isobutyrate. 14. The composition of claim 5, wherein the sustained-release delivery system is a polymeric formulation in the form of a semi-solid polymer formulation comprising a polymer, the amide-type local anesthetic and the meloxicam. 15. The composition of claim 14, wherein the polymer is a bioerodible or biodegradable polymer. 16. The composition of claim 14, wherein the polymer formulation forms an implant or depot in situ. 17. The composition of claim 14 wherein the polymer is selected from the group consisting of polylactides, polyglycolides, poly(lactic-co-glycolic acid) copolymers, polycaprolactones, poly-3-hydroxybutyrates, and polyorthoesters. 18. The composition of claim 14, wherein the polymer is a polyorthoester. 19. The composition of claim 17, wherein the polyorthoester in the composition is selected from the polyorthoesters represented by Formulas I, II, III and IV. 20. The composition of claim 17, wherein the polyorthoester is represented by Formula I. 21. The composition of claim 1, wherein the delivery system comprises the polyorthoester, a polar aprotic solvent and a triglyceride viscosity reducing agent, wherein the triglyceride viscosity reducing agent comprises three fatty acid groups each independently comprising between 1-7 carbon atoms, and wherein the amide-type local anesthetic and meloxicam are present in the delivery system at a ratio ranging from about 10:1 to 50:1. 22. The composition of claim 21, wherein the triglyceride viscosity reducing agent is selected from the group consisting of triacetin and tributyrin. 23. The composition of claim 21, wherein the polar aprotic solvent is selected from dimethylsulfoxide, N-methyl pyrrolidone and dimethyl acetamide. 24. The composition of claim 21, wherein the amide-type local anesthetic and meloxicam are soluble in the triglyceride viscosity reducing agent, the polar aprotic solvent, or a mixture thereof. 25. The composition of claim 21, wherein the amide-type local anesthetic is present in the delivery system at between about 0.01 wt % and about 7.5 wt % of the delivery system. 26. The composition of claim 25, wherein the meloxicam is present in the delivery system at between about 0.005 wt % to 0.25 wt % of the delivery system. 27. The composition of claim 1, wherein the delivery system comprises:
40 wt % to 75 wt % of a polyorthoester; 5 wt % to 12 wt % dimethyl sulfoxide; 20 wt % to 40 wt % triacetin; 1 wt % to 5 wt % bupivacaine or ropivacaine; and 0.005 wt % to 1 wt % meloxicam. 28. The composition of claim 27, wherein the delivery system further comprises 0.01 wt % to 0.30 wt % maleic acid. 29. The composition of claim 27, wherein the polyorthoester is represented by the structure shown as Formula I:
where
R* is C1-4 alkyl,
n ranges from 5 to 400, and
A is a diol. 30. The composition of claim 29, where
A is R1 or R3, where the fraction of A units that are of formula R1 is between 0 and 25 mole percent, R1 is
p and q are each independently integers ranging from between about 1 and 20 and the average number of p or the average sum of p and q is between about 1 and 7, and
R5 is H or methyl,
R6 is
where s is an integer ranging from 0 to 10, and
R3 is
where x is an integer ranging from 1 to 10. 31. The composition of claim 30, wherein s is 2 and x is 2. 32. The composition of claim 29, wherein R3 and R6 are both —(CH2—CH2—O)2—(CH2—CH2)—; R5 is H; and p is 1 or 2. 33. The composition of claim 29, wherein R5 is hydrogen. 34. The composition of claim 29, wherein
when A is R1, R1 is
R5 is H, and R6 is
where the resulting polyorthoester comprises the subunit
where the sum of p and q is, on average, 2 and s is 2, and
when A is R3, x is 2. 35. The composition of claim 29, wherein the fraction of A units that are of formula R1 is about 20 percent. 36. The composition of claim 27, wherein the polyorthoester has a weight average molecular weight between 2,500 daltons and 10,000 daltons. 37. The composition of claim 27, wherein the delivery system has a viscosity less than 10000 mPa-s when measured at 37° C. using a viscometer. 38. The composition of claim 27, wherein the bupivacaine or ropivacaine and the meloxicam are solubilized in a single phase. 39. The composition of claim 27, wherein the composition is an extended-release composition. 40. The composition of claim 5, wherein the local anesthetic is released from the composition over a time period of about 1 day to about 5 days. 41. A method for producing analgesia or pain relief in a subject in need thereof, comprising: administering to the subject the composition according to claim 1. 42. A method for managing pain in a subject in need thereof, comprising administering to the subject the composition according to claim 1. 43. A method for prophylactic treatment of pain in a subject, comprising administering to the subject the composition according to claim 1. 44. The method of claim 41, wherein the administering is intramuscular, subcutaneous, perineural or to a wound. 45. The method of claim 41, wherein the pain is acute pain or chronic pain. 46. The method of claim 41, wherein the composition or delivery system is administered to a surgical wound. 47. The method according to claim 46, wherein the pain is postsurgical pain. 48. The method of claim 41, wherein the composition produces pain relief for a time period of about 3 days to about 5 days following administration. 49. The method of claim 41, wherein the composition or delivery system is administered as a nerve block. 50. The method of claim 41, wherein the composition or delivery system is administered as a peripheral nerve block. 51. The method of claim 41, further comprising administering the composition to a person in need thereof, whereby said administering provides, as measured in an in vivo model for postsurgical pain, an initial decrease in pain relief between about 1 hours and 24 hours after administering and a period of increased pain relief between about 1-3 days after administering, wherein the initial decrease in pain relief is with respect to pain relief provided immediately after administering. 52. The method of claim 51, wherein the composition provides pain relief over days 2 to 5 following administration that is at least, on average, about 50% of the average pain relief provided by the composition 1-5 hours post-administration. 53. The method of claim 51, whereby the administering is effective to provide a measurable plasma concentration of the amide-type local anesthetic and of the NSAID for a period of at up to 5 days following administration. 54. The method of claim 51, wherein about 80% by weight or more of both the local anesthetic and the enolic-acid NSAID are released from the composition over a period of up to about 3 days when measured in an in vitro test at 37° C. | 1,600 |
714 | 16,212,056 | 1,624 | The present invention is directed towards the hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid, preferably in substantially crystalline form, as well as pharmaceutical compositions and uses thereof in therapy, preferably chemotherapy. | 1-17. (canceled) 18. A method for the prevention of cancer or for controlling cancer comprising administering a hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid to a subject in need of such treatment. 19. A hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid, which is in a form readily administrable after quick dissolution of said active agent in a pharmaceutically acceptable carrier. 20. The use of a hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid according to claim 19 in medical treatment, like in chemotherapy. 21. A method according to claim 18, which is for preventing cancer. 22. A method for preventing rectal cancer according to claim 18, comprising administering the hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid in conjunction with a chemotherapeutic agent in an effective amount to a subject in need of such treatment. 23. The hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid according to claim 19, which is in a flavored drink. | The present invention is directed towards the hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid, preferably in substantially crystalline form, as well as pharmaceutical compositions and uses thereof in therapy, preferably chemotherapy.1-17. (canceled) 18. A method for the prevention of cancer or for controlling cancer comprising administering a hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid to a subject in need of such treatment. 19. A hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid, which is in a form readily administrable after quick dissolution of said active agent in a pharmaceutically acceptable carrier. 20. The use of a hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid according to claim 19 in medical treatment, like in chemotherapy. 21. A method according to claim 18, which is for preventing cancer. 22. A method for preventing rectal cancer according to claim 18, comprising administering the hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid in conjunction with a chemotherapeutic agent in an effective amount to a subject in need of such treatment. 23. The hemisulfate salt of 5,10-methylene-(6R)-tetrahydrofolic acid according to claim 19, which is in a flavored drink. | 1,600 |
715 | 15,702,697 | 1,612 | Compositions comprised of a delivery vehicle or delivery system and an active agent dispersed within the delivery vehicle or system, wherein the delivery vehicle or system contains a polyorthoester polymer and a polar aprotic solvent. Also disclosed are low viscosity delivery systems for administration of active agents. The low viscosity delivery systems have a polyorthoester polymer, a polar aprotic solvent and a solvent containing a triglyceride viscosity reducing agent. Compositions described include an amide- or anilide-type local anesthetic of the “caine” classification, and a non-steroidal anti-inflammatory drug (NSAID), along with related methods, e.g., for treatment of post-operative pain or for prophylactic treatment of pain. The compositions are suitable for delivery via, e.g., direct application and instillation, intradermal injection, subcutaneous injection, and nerve block (perineural). | 1. A composition, consisting essentially of: a delivery vehicle, an amide-type local anesthetic, and a non-steroidal anti-inflammatory drug (NSAID), wherein the ratio of the amide-type local anesthetic to the NSAID ranges from about 15:1 to 50:1, and wherein the NSAID is present in the composition in an amount between about 0.005-0.75 wt %. 2. The composition of claim 1, wherein the amide-type local anesthetic is present in the composition in an amount ranging from about 0.1 to 8.0 wt % and the NSAID is present in the composition in an amount ranging from about 0.01-0.5 wt %. 3. The composition of claim 1, wherein the delivery vehicle is a sustained-release delivery vehicle. 4. The composition of claim 1, wherein the delivery vehicle is aqueous based. 5. The composition of claim 3, wherein the sustained-release delivery vehicle is a bioerodible or biodegradable polymer. 6. The composition of claim 5, wherein the polymer is a polyorthoester represented by the structure shown as Formula I:
where:
R* is a C1-4 alkyl,
n is an integer ranging from 5 to 400, and
A is a diol, where A is R1 or R3, where the fraction of A units that are of formula R1 is between 0 and 25 mole percent, where
when A is R3, R3 is
where x is 2; and
when A is R1, R1 is
R5 is H, and R6 is
the sum of p and q is, on average, 2 and s is 2,
where the resulting component of the polyorthoester comprises the subunit 7. The composition of claim 6, wherein the delivery vehicle comprises the polyorthoester, a polar aprotic solvent and a triglyceride viscosity reducing agent. 8. The composition of claim 7, wherein the polar aprotic solvent is selected from dimethyl sulfoxide, N-methyl pyrrolidone and dimethyl acetamide. 9. The composition of claim 7, wherein the amide-type local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt % of the composition. 10. The composition of claim 9, wherein the NSAID is present in the composition at between about 0.005 wt % to 0.25 wt % of the composition. 11. The composition of claim 7, wherein the delivery vehicle comprises:
40 wt % to 75 wt % of the polyorthoester; 5 wt % to 12 wt % dimethyl sulfoxide; and 20 wt % to 40 wt % triacetin; and wherein the amide-type local anesthetic is present in an amount of between about 1 wt % to 5 wt %. 12. The composition of claim 11, wherein the delivery vehicle further comprises 0.01 wt % to 0.3 wt % maleic acid. 13. The composition of claim 1, wherein the NSAID is present in the composition in an amount ranging from about 0.005-0.25 wt %. 14. The composition of claim 1, wherein the NSAID is present in the composition in an amount ranging from about 0.005-0.125 wt %. 15. The composition of claim 1, wherein the NSAID is meloxicam. 16. The composition of claim 1, wherein the amide-type local anesthetic is bupivacaine. 17. A method for producing analgesia or pain relief in a subject in need thereof, comprising: administering to the subject the composition according to claim 1. 18. A method for managing pain or for prophylactic treatment of pain in a subject, comprising administering to the subject the composition according to claim 1. 19. The method of claim 17, wherein the composition is administered perineural or to a surgical wound. 20. The method of claim 18, wherein the pain is postsurgical pain. | Compositions comprised of a delivery vehicle or delivery system and an active agent dispersed within the delivery vehicle or system, wherein the delivery vehicle or system contains a polyorthoester polymer and a polar aprotic solvent. Also disclosed are low viscosity delivery systems for administration of active agents. The low viscosity delivery systems have a polyorthoester polymer, a polar aprotic solvent and a solvent containing a triglyceride viscosity reducing agent. Compositions described include an amide- or anilide-type local anesthetic of the “caine” classification, and a non-steroidal anti-inflammatory drug (NSAID), along with related methods, e.g., for treatment of post-operative pain or for prophylactic treatment of pain. The compositions are suitable for delivery via, e.g., direct application and instillation, intradermal injection, subcutaneous injection, and nerve block (perineural).1. A composition, consisting essentially of: a delivery vehicle, an amide-type local anesthetic, and a non-steroidal anti-inflammatory drug (NSAID), wherein the ratio of the amide-type local anesthetic to the NSAID ranges from about 15:1 to 50:1, and wherein the NSAID is present in the composition in an amount between about 0.005-0.75 wt %. 2. The composition of claim 1, wherein the amide-type local anesthetic is present in the composition in an amount ranging from about 0.1 to 8.0 wt % and the NSAID is present in the composition in an amount ranging from about 0.01-0.5 wt %. 3. The composition of claim 1, wherein the delivery vehicle is a sustained-release delivery vehicle. 4. The composition of claim 1, wherein the delivery vehicle is aqueous based. 5. The composition of claim 3, wherein the sustained-release delivery vehicle is a bioerodible or biodegradable polymer. 6. The composition of claim 5, wherein the polymer is a polyorthoester represented by the structure shown as Formula I:
where:
R* is a C1-4 alkyl,
n is an integer ranging from 5 to 400, and
A is a diol, where A is R1 or R3, where the fraction of A units that are of formula R1 is between 0 and 25 mole percent, where
when A is R3, R3 is
where x is 2; and
when A is R1, R1 is
R5 is H, and R6 is
the sum of p and q is, on average, 2 and s is 2,
where the resulting component of the polyorthoester comprises the subunit 7. The composition of claim 6, wherein the delivery vehicle comprises the polyorthoester, a polar aprotic solvent and a triglyceride viscosity reducing agent. 8. The composition of claim 7, wherein the polar aprotic solvent is selected from dimethyl sulfoxide, N-methyl pyrrolidone and dimethyl acetamide. 9. The composition of claim 7, wherein the amide-type local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt % of the composition. 10. The composition of claim 9, wherein the NSAID is present in the composition at between about 0.005 wt % to 0.25 wt % of the composition. 11. The composition of claim 7, wherein the delivery vehicle comprises:
40 wt % to 75 wt % of the polyorthoester; 5 wt % to 12 wt % dimethyl sulfoxide; and 20 wt % to 40 wt % triacetin; and wherein the amide-type local anesthetic is present in an amount of between about 1 wt % to 5 wt %. 12. The composition of claim 11, wherein the delivery vehicle further comprises 0.01 wt % to 0.3 wt % maleic acid. 13. The composition of claim 1, wherein the NSAID is present in the composition in an amount ranging from about 0.005-0.25 wt %. 14. The composition of claim 1, wherein the NSAID is present in the composition in an amount ranging from about 0.005-0.125 wt %. 15. The composition of claim 1, wherein the NSAID is meloxicam. 16. The composition of claim 1, wherein the amide-type local anesthetic is bupivacaine. 17. A method for producing analgesia or pain relief in a subject in need thereof, comprising: administering to the subject the composition according to claim 1. 18. A method for managing pain or for prophylactic treatment of pain in a subject, comprising administering to the subject the composition according to claim 1. 19. The method of claim 17, wherein the composition is administered perineural or to a surgical wound. 20. The method of claim 18, wherein the pain is postsurgical pain. | 1,600 |
716 | 15,577,522 | 1,649 | The invention relates to panels of biomarkers including proteins phosphatase 1 regulatory subunit 14A and/or 2′,3′-cyclic-nucleotide 3′-phosphodiesterase and/or phosphorylated tau or fragments thereof and methods using thereof for diagnosing, staging, treating and assessing the response of a treatment for a neurocognitive disorder characterised by tau toxicity, in particular for Alzheimer's disease. The present invention shows that the biomarkers disclosed herein are elevated in the brain of subjects with an advanced stage of a neurocognitive disorder (Braak stage V/VI) and/or are regulated in the CSF of AD subjects in comparison to cognitively affected non-AD controls; and/or regulated in response to two casein kinase 1 delta inhibitors. | 1-30. (canceled) 31. A kit comprising reagents for assaying and/or measuring in a sample one or more biomarkers of a panel comprising:
i) a protein phosphatase 1 regulatory subunit 14A comprising the amino acid sequence of SEQ ID NO:1 or an isoform, a variant or a fragment thereof; and/or ii) a 2′,3′-cyclic-nucleotide 3′-phosphodiesterase comprising the amino acid sequence of SEQ ID NO:2 or an isoform, a variant or a fragment thereof. 32-36. (canceled) 37. The kit according to claim 31, wherein the reagents comprise a set of reference peptides in an assay compatible format and each reference peptide is uniquely representative of a single biomarker in the panel. 38. The kit according to claim 37, wherein the set of reference peptides comprises at least two uniquely representative peptides for each biomarker in the panel, and wherein the uniquely representative peptides are provided in known amounts which reflect the amount or concentration of each biomarker in a sample of a healthy subject. 39. The kit according to claim 37, wherein the reference peptides are synthetic peptides. 40. The kit according to claim 37, wherein the reference peptides comprise one or more heavy isotopes of carbon, nitrogen, oxygen and/or hydrogen. 41. The kit according to claim 31, wherein the panel further comprises one or more biomarkers selected from Group A, which comprises Actin alpha cardiac muscle 1 comprising the amino acid sequence of SEQ ID NO:11, Antithrombin-III comprising the amino acid sequence of SEQ ID NO:12, BH3-interacting domain death agonist comprising the amino acid sequence of SEQ ID NO:3, cAMP-dependent protein kinase type I-beta regulatory subunit comprising the amino acid sequence of SEQ ID NO:24, Catenin delta-1 comprising the amino acid sequence of SEQ ID NO:4, Centrosomal protein of 170 kDa comprising the amino acid sequence of SEQ ID NO:23, Clathrin light chain B comprising the amino acid sequence of SEQ ID NO:5, Egl nine homolog 1 comprising the amino acid sequence of SEQ ID NO:13, Fibrinogen gamma chain comprising the amino acid sequence of SEQ ID NO:14, GMP reductase 1 comprising the amino acid sequence of SEQ ID NO:27, Guanine nucleotide-binding protein G(q) subunit alpha comprising the amino acid sequence of SEQ ID NO:6, Insulin-like growth factor-binding protein 6 comprising the amino acid sequence of SEQ ID NO:15, KxDL motif-containing protein 1 comprising the amino acid sequence of SEQ ID NO:28, Lambda-crystallin homolog comprising the amino acid sequence of SEQ ID NO:18, Myelin-associated oligodendrocyte basic protein comprising the amino acid sequence of SEQ ID NO:20, Neutral alpha-glucosidase AB comprising the amino acid sequence of SEQ ID NO:7, Nuclear pore complex protein Nup155 comprising the amino acid sequence of SEQ ID NO:19, OCIA domain-containing protein 1 comprising the amino acid sequence of SEQ ID NO:16, Protein KIAA1045 comprising the amino acid sequence of SEQ ID NO:25, Secernin-2 comprising the amino acid sequence of SEQ ID NO:8, Serum albumin comprising the amino acid sequence of SEQ ID NO:17, Short-chain specific acyl-CoA dehydrogenase comprising the amino acid sequence of SEQ ID NO:9, Synaptoporin comprising the amino acid sequence of SEQ ID NO:22, Syntaphilin comprising the amino acid sequence of SEQ ID NO:10, Transmembrane protein 119 comprising the amino acid sequence of SEQ ID NO: 21 and Tubulin alpha chain-like 3 comprising the amino acid sequence of SEQ ID NO:26. 42. The kit according to claim 41, wherein the biomarker panel further comprises one or more biomarkers selected from Groups B, C or D. 43. The kit according to claim 31, wherein the biomarker panel further comprises one or more of a tau protein or a fragment thereof, wherein the tau protein:
i) comprises the amino acid sequence of SEQ ID NO:29 and ii) comprises one or more phosphorylated amino acids selected from T39, S46, T50, T52, T56, S61, T63, S64, S68, T69, S113, T181, S184, S185, S191, S195, S198, S199, S202, S205, S208, S210, T212, S214, T217, T231, S235, S237, S238, S258, S262, S285, S289, S356, Y394, S396, S400, T403, S404, S409, S412, S413, T414/S416 or S422 of SEQ ID NO:29; wherein when the phosphorylated amino acid is T181, the panel further comprises a tau protein or a fragment thereof having at least one more phosphorylated amino acid. 44. The kit according to claim 31, wherein the biomarker panel further comprises one or more biomarkers selected from Tables 5, 6, 7, 8, 9, 10, 11, 12, 13, or a combination thereof. 45. The kit according to claim 31, wherein the reagents comprise one or more binding agents, wherein each binding agent binds specifically to one of the biomarkers of the panel. 46. The kit according to claim 31, wherein the sample is selected from cerebrospinal fluid (CSF), blood, plasma, serum, saliva, urine, tissue, or a combination thereof. 47. A method for measuring in a sample the concentration or amount of one or more biomarkers of a panel, comprising:
i) a protein phosphatase 1 regulatory subunit 14A comprising the amino acid sequence of SEQ ID NO:1 or an isoform, a variant or a fragment thereof; and/or ii) a 2′,3′-cyclic-nucleotide 3′-phosphodiesterase comprising the amino acid sequence of SEQ ID NO:2 or an isoform, a variant or a fragment thereof; said method comprising at least one of the following steps:
a) detecting in the sample by mass spectrometry each of the one or more biomarkers of the panel or fragments thereof;
b) contacting the sample with one or more binding agents to each of the biomarkers of the panel; and/or
c) detecting in the sample by 2D gel electrophoresis each of the biomarkers of the panel. 48. The method according to claim 47, wherein step a) and/or step b) comprises detecting one or more fragments of the biomarkers in the panel. 49. The method according to claim 47, wherein the sample is immobilized on a solid support. 50. The method according to claim 47, wherein the sample is selected from cerebrospinal fluid (CSF), blood, plasma, serum, saliva, urine, tissue or combinations thereof taken from a human subject. 51. The method according to claim 47, wherein the method is performed using the kit of claim 31. 52. The method according to claim 47, further comprising measuring in the sample the concentration or amount of one or more biomarkers selected from Group A, which comprises Actin alpha cardiac muscle 1 comprising the amino acid sequence of SEQ ID NO:11, Antithrombin-III comprising the amino acid sequence of SEQ ID NO:12, BH3-interacting domain death agonist comprising the amino acid sequence of SEQ ID NO:3, cAMP-dependent protein kinase type I-beta regulatory subunit comprising the amino acid sequence of SEQ ID NO:24, Catenin delta-1 comprising the amino acid sequence of SEQ ID NO:4, Centrosomal protein of 170 kDa comprising the amino acid sequence of SEQ ID NO:23, Clathrin light chain B comprising the amino acid sequence of SEQ ID NO:5, Egl nine homolog 1 comprising the amino acid sequence of SEQ ID NO:13, Fibrinogen gamma chain comprising the amino acid sequence of SEQ ID NO:14, GMP reductase 1 comprising the amino acid sequence of SEQ ID NO:27, Guanine nucleotide-binding protein G(q) subunit alpha comprising the amino acid sequence of SEQ ID NO:6, Insulin-like growth factor-binding protein 6 comprising the amino acid sequence of SEQ ID NO:15, KxDL motif-containing protein 1 comprising the amino acid sequence of SEQ ID NO:28, Lambda-crystallin homolog comprising the amino acid sequence of SEQ ID NO:18, Myelin-associated oligodendrocyte basic protein comprising the amino acid sequence of SEQ ID NO:20, Neutral alpha-glucosidase AB comprising the amino acid sequence of SEQ ID NO:7, Nuclear pore complex protein Nup155 comprising the amino acid sequence of SEQ ID NO:19, OCIA domain-containing protein 1 comprising the amino acid sequence of SEQ ID NO:16, Protein KIAA1045 comprising the amino acid sequence of SEQ ID NO:25, Secernin-2 comprising the amino acid sequence of SEQ ID NO:8, Serum albumin comprising the amino acid sequence of SEQ ID NO:17, Short-chain specific acyl-CoA dehydrogenase comprising the amino acid sequence of SEQ ID NO:9, Synaptoporin comprising the amino acid sequence of SEQ ID NO:22, Syntaphilin comprising the amino acid sequence of SEQ ID NO:10, Transmembrane protein 119 comprising the amino acid sequence of SEQ ID NO: 21 and Tubulin alpha chain-like 3 comprising the amino acid sequence of SEQ ID NO:26. 53. The method according to claim 47, further comprising measuring in the sample the concentration or amount of one or more biomarkers selected from Groups B, C or D. 54. The method according to claim 47, further comprising measuring in the sample the concentration or amount of:
a) a tau protein or a fragment thereof, wherein the tau protein:
i) comprises the amino acid sequence of SEQ ID NO:29 and
ii) comprises one or more phosphorylated amino acids selected from T39, S46, T50, T52, T56, S61, T63, S64, S68, T69, S113, T181, S184, S185, S191, S195, S198, S199, S202, S205, S208, S210, T212, S214, T217, T231, S235, S237, S238, S258, S262, S285, S289, S356, Y394, S396, S400, T403, S404, S409, S412, S413, T414/S416 or S422 of SEQ ID NO:29;
wherein when the phosphorylated amino acid is T181, the panel further comprises a tau protein or a fragment thereof having at least more phosphorylated amino acid; or b) one or more biomarkers selected from Tables 5, 6, 7, 8, 9, 10, 11, 12, 13, or combinations thereof. 55. A kit comprising reagents for assaying and/or measuring in a sample:
a) one or more biomarkers of a panel comprising a tau protein or a fragment thereof, wherein the tau protein:
i) comprises the amino acid sequence of SEQ ID NO:29 and
ii) comprises one or more, optionally two or more phosphorylated amino acids selected from T39, S46, T50, T52, T56, S61, T63, S64, S68, T69, S113, T181, S184, S185, S191, S195, S198, S199, S202, S205, S208, S210, T212, S214, T217, T231, S235, S237, S238, S258, S262, S285, S289, S356, Y394, S396, S400, T403, S404, S409, S412, S413, T414/S416 or S422 of SEQ ID NO:29;
wherein when the phosphorylated amino acid is T181, the panel further comprises a tau protein or a fragment thereof having at least one more phosphorylated amino acid; or b) one or more biomarkers selected from Tables 5, 6, 7, 8, 9, 10, 11, 12, 13 or combinations thereof. | The invention relates to panels of biomarkers including proteins phosphatase 1 regulatory subunit 14A and/or 2′,3′-cyclic-nucleotide 3′-phosphodiesterase and/or phosphorylated tau or fragments thereof and methods using thereof for diagnosing, staging, treating and assessing the response of a treatment for a neurocognitive disorder characterised by tau toxicity, in particular for Alzheimer's disease. The present invention shows that the biomarkers disclosed herein are elevated in the brain of subjects with an advanced stage of a neurocognitive disorder (Braak stage V/VI) and/or are regulated in the CSF of AD subjects in comparison to cognitively affected non-AD controls; and/or regulated in response to two casein kinase 1 delta inhibitors.1-30. (canceled) 31. A kit comprising reagents for assaying and/or measuring in a sample one or more biomarkers of a panel comprising:
i) a protein phosphatase 1 regulatory subunit 14A comprising the amino acid sequence of SEQ ID NO:1 or an isoform, a variant or a fragment thereof; and/or ii) a 2′,3′-cyclic-nucleotide 3′-phosphodiesterase comprising the amino acid sequence of SEQ ID NO:2 or an isoform, a variant or a fragment thereof. 32-36. (canceled) 37. The kit according to claim 31, wherein the reagents comprise a set of reference peptides in an assay compatible format and each reference peptide is uniquely representative of a single biomarker in the panel. 38. The kit according to claim 37, wherein the set of reference peptides comprises at least two uniquely representative peptides for each biomarker in the panel, and wherein the uniquely representative peptides are provided in known amounts which reflect the amount or concentration of each biomarker in a sample of a healthy subject. 39. The kit according to claim 37, wherein the reference peptides are synthetic peptides. 40. The kit according to claim 37, wherein the reference peptides comprise one or more heavy isotopes of carbon, nitrogen, oxygen and/or hydrogen. 41. The kit according to claim 31, wherein the panel further comprises one or more biomarkers selected from Group A, which comprises Actin alpha cardiac muscle 1 comprising the amino acid sequence of SEQ ID NO:11, Antithrombin-III comprising the amino acid sequence of SEQ ID NO:12, BH3-interacting domain death agonist comprising the amino acid sequence of SEQ ID NO:3, cAMP-dependent protein kinase type I-beta regulatory subunit comprising the amino acid sequence of SEQ ID NO:24, Catenin delta-1 comprising the amino acid sequence of SEQ ID NO:4, Centrosomal protein of 170 kDa comprising the amino acid sequence of SEQ ID NO:23, Clathrin light chain B comprising the amino acid sequence of SEQ ID NO:5, Egl nine homolog 1 comprising the amino acid sequence of SEQ ID NO:13, Fibrinogen gamma chain comprising the amino acid sequence of SEQ ID NO:14, GMP reductase 1 comprising the amino acid sequence of SEQ ID NO:27, Guanine nucleotide-binding protein G(q) subunit alpha comprising the amino acid sequence of SEQ ID NO:6, Insulin-like growth factor-binding protein 6 comprising the amino acid sequence of SEQ ID NO:15, KxDL motif-containing protein 1 comprising the amino acid sequence of SEQ ID NO:28, Lambda-crystallin homolog comprising the amino acid sequence of SEQ ID NO:18, Myelin-associated oligodendrocyte basic protein comprising the amino acid sequence of SEQ ID NO:20, Neutral alpha-glucosidase AB comprising the amino acid sequence of SEQ ID NO:7, Nuclear pore complex protein Nup155 comprising the amino acid sequence of SEQ ID NO:19, OCIA domain-containing protein 1 comprising the amino acid sequence of SEQ ID NO:16, Protein KIAA1045 comprising the amino acid sequence of SEQ ID NO:25, Secernin-2 comprising the amino acid sequence of SEQ ID NO:8, Serum albumin comprising the amino acid sequence of SEQ ID NO:17, Short-chain specific acyl-CoA dehydrogenase comprising the amino acid sequence of SEQ ID NO:9, Synaptoporin comprising the amino acid sequence of SEQ ID NO:22, Syntaphilin comprising the amino acid sequence of SEQ ID NO:10, Transmembrane protein 119 comprising the amino acid sequence of SEQ ID NO: 21 and Tubulin alpha chain-like 3 comprising the amino acid sequence of SEQ ID NO:26. 42. The kit according to claim 41, wherein the biomarker panel further comprises one or more biomarkers selected from Groups B, C or D. 43. The kit according to claim 31, wherein the biomarker panel further comprises one or more of a tau protein or a fragment thereof, wherein the tau protein:
i) comprises the amino acid sequence of SEQ ID NO:29 and ii) comprises one or more phosphorylated amino acids selected from T39, S46, T50, T52, T56, S61, T63, S64, S68, T69, S113, T181, S184, S185, S191, S195, S198, S199, S202, S205, S208, S210, T212, S214, T217, T231, S235, S237, S238, S258, S262, S285, S289, S356, Y394, S396, S400, T403, S404, S409, S412, S413, T414/S416 or S422 of SEQ ID NO:29; wherein when the phosphorylated amino acid is T181, the panel further comprises a tau protein or a fragment thereof having at least one more phosphorylated amino acid. 44. The kit according to claim 31, wherein the biomarker panel further comprises one or more biomarkers selected from Tables 5, 6, 7, 8, 9, 10, 11, 12, 13, or a combination thereof. 45. The kit according to claim 31, wherein the reagents comprise one or more binding agents, wherein each binding agent binds specifically to one of the biomarkers of the panel. 46. The kit according to claim 31, wherein the sample is selected from cerebrospinal fluid (CSF), blood, plasma, serum, saliva, urine, tissue, or a combination thereof. 47. A method for measuring in a sample the concentration or amount of one or more biomarkers of a panel, comprising:
i) a protein phosphatase 1 regulatory subunit 14A comprising the amino acid sequence of SEQ ID NO:1 or an isoform, a variant or a fragment thereof; and/or ii) a 2′,3′-cyclic-nucleotide 3′-phosphodiesterase comprising the amino acid sequence of SEQ ID NO:2 or an isoform, a variant or a fragment thereof; said method comprising at least one of the following steps:
a) detecting in the sample by mass spectrometry each of the one or more biomarkers of the panel or fragments thereof;
b) contacting the sample with one or more binding agents to each of the biomarkers of the panel; and/or
c) detecting in the sample by 2D gel electrophoresis each of the biomarkers of the panel. 48. The method according to claim 47, wherein step a) and/or step b) comprises detecting one or more fragments of the biomarkers in the panel. 49. The method according to claim 47, wherein the sample is immobilized on a solid support. 50. The method according to claim 47, wherein the sample is selected from cerebrospinal fluid (CSF), blood, plasma, serum, saliva, urine, tissue or combinations thereof taken from a human subject. 51. The method according to claim 47, wherein the method is performed using the kit of claim 31. 52. The method according to claim 47, further comprising measuring in the sample the concentration or amount of one or more biomarkers selected from Group A, which comprises Actin alpha cardiac muscle 1 comprising the amino acid sequence of SEQ ID NO:11, Antithrombin-III comprising the amino acid sequence of SEQ ID NO:12, BH3-interacting domain death agonist comprising the amino acid sequence of SEQ ID NO:3, cAMP-dependent protein kinase type I-beta regulatory subunit comprising the amino acid sequence of SEQ ID NO:24, Catenin delta-1 comprising the amino acid sequence of SEQ ID NO:4, Centrosomal protein of 170 kDa comprising the amino acid sequence of SEQ ID NO:23, Clathrin light chain B comprising the amino acid sequence of SEQ ID NO:5, Egl nine homolog 1 comprising the amino acid sequence of SEQ ID NO:13, Fibrinogen gamma chain comprising the amino acid sequence of SEQ ID NO:14, GMP reductase 1 comprising the amino acid sequence of SEQ ID NO:27, Guanine nucleotide-binding protein G(q) subunit alpha comprising the amino acid sequence of SEQ ID NO:6, Insulin-like growth factor-binding protein 6 comprising the amino acid sequence of SEQ ID NO:15, KxDL motif-containing protein 1 comprising the amino acid sequence of SEQ ID NO:28, Lambda-crystallin homolog comprising the amino acid sequence of SEQ ID NO:18, Myelin-associated oligodendrocyte basic protein comprising the amino acid sequence of SEQ ID NO:20, Neutral alpha-glucosidase AB comprising the amino acid sequence of SEQ ID NO:7, Nuclear pore complex protein Nup155 comprising the amino acid sequence of SEQ ID NO:19, OCIA domain-containing protein 1 comprising the amino acid sequence of SEQ ID NO:16, Protein KIAA1045 comprising the amino acid sequence of SEQ ID NO:25, Secernin-2 comprising the amino acid sequence of SEQ ID NO:8, Serum albumin comprising the amino acid sequence of SEQ ID NO:17, Short-chain specific acyl-CoA dehydrogenase comprising the amino acid sequence of SEQ ID NO:9, Synaptoporin comprising the amino acid sequence of SEQ ID NO:22, Syntaphilin comprising the amino acid sequence of SEQ ID NO:10, Transmembrane protein 119 comprising the amino acid sequence of SEQ ID NO: 21 and Tubulin alpha chain-like 3 comprising the amino acid sequence of SEQ ID NO:26. 53. The method according to claim 47, further comprising measuring in the sample the concentration or amount of one or more biomarkers selected from Groups B, C or D. 54. The method according to claim 47, further comprising measuring in the sample the concentration or amount of:
a) a tau protein or a fragment thereof, wherein the tau protein:
i) comprises the amino acid sequence of SEQ ID NO:29 and
ii) comprises one or more phosphorylated amino acids selected from T39, S46, T50, T52, T56, S61, T63, S64, S68, T69, S113, T181, S184, S185, S191, S195, S198, S199, S202, S205, S208, S210, T212, S214, T217, T231, S235, S237, S238, S258, S262, S285, S289, S356, Y394, S396, S400, T403, S404, S409, S412, S413, T414/S416 or S422 of SEQ ID NO:29;
wherein when the phosphorylated amino acid is T181, the panel further comprises a tau protein or a fragment thereof having at least more phosphorylated amino acid; or b) one or more biomarkers selected from Tables 5, 6, 7, 8, 9, 10, 11, 12, 13, or combinations thereof. 55. A kit comprising reagents for assaying and/or measuring in a sample:
a) one or more biomarkers of a panel comprising a tau protein or a fragment thereof, wherein the tau protein:
i) comprises the amino acid sequence of SEQ ID NO:29 and
ii) comprises one or more, optionally two or more phosphorylated amino acids selected from T39, S46, T50, T52, T56, S61, T63, S64, S68, T69, S113, T181, S184, S185, S191, S195, S198, S199, S202, S205, S208, S210, T212, S214, T217, T231, S235, S237, S238, S258, S262, S285, S289, S356, Y394, S396, S400, T403, S404, S409, S412, S413, T414/S416 or S422 of SEQ ID NO:29;
wherein when the phosphorylated amino acid is T181, the panel further comprises a tau protein or a fragment thereof having at least one more phosphorylated amino acid; or b) one or more biomarkers selected from Tables 5, 6, 7, 8, 9, 10, 11, 12, 13 or combinations thereof. | 1,600 |
717 | 14,858,164 | 1,619 | Foaming sunscreen compositions of the present invention include a continuous water phase containing from about 0.75% to about 6% of a superhydrophilic amphiphilic copolymer and a discontinuous oil phase dispersed in the water phase, which oil phase contains a UV-absorbing compound, and which foaming sunscreen compositions are essentially free of monomeric surfactants and substantially free of oil soluble polymers. | 1. A foaming sunscreen composition, comprising:
an oil-in-water emulsion, comprising
a continuous water phase comprising from about 0.75% to about 6% by weight of a superhydrophilic amphiphilic copolymer, based on total weight of the foaming sunscreen composition; and
a discontinuous oil phase dispersed in the water phase,
wherein the discontinuous oil phase comprises a UV absorbing compound and is substantially free of an oil soluble polymer, and wherein the foaming sunscreen composition is essentially free of monomeric surfactant. 2. The foaming sunscreen composition according to claim 1, wherein the superhydrophilic amphiphilic copolymer has a mole percent of amphiphilic unit that is between about 5% and about 10%, and a weight average molecular weight that is about 200,000 or less. 3. The foaming sunscreen composition according to claim 1, wherein the oil phase comprises less than 0.1% by weight of the oil soluble polymers, bases on total weight of the composition. 4. The foaming sunscreen composition according to claim 1, wherein the oil phase consists essentially of the UV absorbing compound. 5. The foaming sunscreen composition according to claim 1, wherein the oil phase comprises about 80% or more by weight of the UV absorbing compound. 6. The foaming sunscreen composition according to claim 1, wherein the oil phase comprises about 95% or more by weight of the UV absorbing compound. 7. The foaming composition of claim 1 wherein the composition is essentially free of a propellant gas. 8. The foaming sunscreen composition according to claim 1, wherein the UV absorbing compound is selected from the group consisting of a UV-A absorbing moiety and a UV-B absorbing moiety. 9. The foaming sunscreen composition of claim 8, wherein the UV-A absorbing moiety is selected from the group consisting of tertrahydroxybenzophenones; dicarboxydihydroxybenzophenones and alkane ester or acid halide derivatives thereof; dihydroxy-, dicarboxy-, and hydroxycarboxydibenzoylmethanes and alkane ester or acid halide derivatives thereof; dihydroxy-, dicarboxy-, and hydroxycarboxystilbenes and alkane ester or acid halide derivatives thereof bis(hydroxystyrenyl) benzenes, bis(carboxystyrenyl)benzenes and alkane ester or acid halide derivatives thereof dihydroxy-, dicarboxy, and hydroxycarboxycarotenes and alkane ester or acid halide derivatives thereof bis-ethylhexyloxyphenol methoxyphenyl triazine; and 2 cyano-3,3-diphenyl acrylic acid, 2-ethyl hexyl ester. 10. The foaming sunscreen composition of claim 8, wherein the UV-B absorbing moiety is selected from the group consisting of a 4-aminobenzoic acid and alkane esters thereof anthranilic acid and alkane esters thereof salicylic acid and alkane esters thereof hydroxycinnamic acid and alkane esters thereof dihydroxy-, dicarboxy-, and hydroxycarboxybenzophenones and alkane ester or acid halide derivatives thereof dihydroxy-, dicarboxy-, and hydroxycarboxychalcones and alkane ester or acid halide derivatives thereof bis-ethylhexyloxyphenol methoxyphenyl triazine; octyl salicylate;
homosalate; oxybenzone; octocrylene; and dihydroxy-, dicarboxy-, and hydroxycarboxycoumarins and alkane ester or acid halide derivatives thereof 11. The foaming composition of claim 1 wherein the UV absorbing compound is selected from the group consisting of octyl salicylate, homosalate, oxybenzone, octocrylene, avobenzone, and Bis-ethyhexylophenol methoxyphenyl triazine). 12. The foaming sunscreen composition according to claim 1, wherein a density of the oil phase is at least 0.995 g/ml. 13. The foaming sunscreen composition according to claim 1, comprising from about 10% to about 55% by weight of the oil phase. 14. The foaming sunscreen composition according to claim 1, comprising from about 20% to 40% by weight of the oil phase. 15. The foaming sunscreen composition according to claim 1, comprising from about 10% to about 40% by weight of the UV absorbing compound. 16. The foaming sunscreen composition according to claim 1, further comprising a polyol having a density of at least 1 g/ml. 17. The foaming sunscreen composition according to claim 16, wherein the polyol is glycerin. 18. The foaming sunscreen composition according to claim 17, comprising from about 1% to about 20% by weight of the glycerin. 19. The foaming sunscreen composition of claim 1, wherein the oil phase comprises about 3% or less by weight of the oil soluble polymer, based on total weight of the foaming sunscreen composition. 20. The foaming sunscreen composition according to claim 1 having a viscosity of about 2000 cps or less. 21. The foaming sunscreen composition according to claim 1 having a viscosity of about 1000 cps or less. 22. The foaming sunscreen composition according to claim 1 further comprising an emulsifier other than the superhydrophilic amphiphilic copolymer. 23. The foaming sunscreen composition of claim 22, wherein the emulsifier other than the superhydrophilic amphiphilic copolymer is polyglyceryl 10 laurate. 24. The foaming sunscreen composition of claim 1 which is free of an emulsifier other than the superhydrophilic amphiphilic copolymer. 25. The foaming sunscreen composition according to claim 1 further comprising a suspension comprising non-UV-absorbing light-scattering particles. 26. The foaming sunscreen composition of claim 25 comprising from about 1% to about 10% by weight of the non-UV-absorbing light-scattering particles. 27. The foaming sunscreen composition of claim 25 comprising from about 1% to about 5% by weight of the non-UV-absorbing light-scattering particles. 28. The foaming sunscreen composition according to claim 27, wherein the non-UV- absorbing light-scattering particles comprise a styrene/acrylate copolymer. 29. The foaming sunscreen composition according to claim 25 wherein the oil-in-water emulsion is phase-stable. 30. The foaming composition of claim 1 wherein the oil phase comprises about 3% or less by weight of an oil-soluble emollient. 31. The foaming sunscreen composition of claim 1 further comprising bis-PEG-18 methyl ether dimethyl silane. 32. The composition of claim 1 which is essentially free of an emollient. 33. The foaming sunscreen composition according to claim 13, comprising from about 90% to about 45% by weight of the water phase. 34. The foaming sunscreen composition according to claim 14, comprising from about 80% to about 60% by weight of the water phase. 35. A non-aerosol mechanical dispensing container comprising a foaming sunscreen composition contained therein, the foaming sunscreen composition comprising:
an oil-in-water emulsion, comprising a continuous water phase comprising from about 0.75% to about 6% by weight of a superhydrophilic amphiphilic copolymer, based on total weight of the foaming sunscreen composition; and a discontinuous oil phase dispersed in the water phase,
wherein the discontinuous oil phase comprises a UV absorbing compound and is substantially free of an oil soluble polymer, the foaming sunscreen composition is essentially free of monomeric surfactant , and the foaming sunscreen composition and the container are free of a propellant gas. | Foaming sunscreen compositions of the present invention include a continuous water phase containing from about 0.75% to about 6% of a superhydrophilic amphiphilic copolymer and a discontinuous oil phase dispersed in the water phase, which oil phase contains a UV-absorbing compound, and which foaming sunscreen compositions are essentially free of monomeric surfactants and substantially free of oil soluble polymers.1. A foaming sunscreen composition, comprising:
an oil-in-water emulsion, comprising
a continuous water phase comprising from about 0.75% to about 6% by weight of a superhydrophilic amphiphilic copolymer, based on total weight of the foaming sunscreen composition; and
a discontinuous oil phase dispersed in the water phase,
wherein the discontinuous oil phase comprises a UV absorbing compound and is substantially free of an oil soluble polymer, and wherein the foaming sunscreen composition is essentially free of monomeric surfactant. 2. The foaming sunscreen composition according to claim 1, wherein the superhydrophilic amphiphilic copolymer has a mole percent of amphiphilic unit that is between about 5% and about 10%, and a weight average molecular weight that is about 200,000 or less. 3. The foaming sunscreen composition according to claim 1, wherein the oil phase comprises less than 0.1% by weight of the oil soluble polymers, bases on total weight of the composition. 4. The foaming sunscreen composition according to claim 1, wherein the oil phase consists essentially of the UV absorbing compound. 5. The foaming sunscreen composition according to claim 1, wherein the oil phase comprises about 80% or more by weight of the UV absorbing compound. 6. The foaming sunscreen composition according to claim 1, wherein the oil phase comprises about 95% or more by weight of the UV absorbing compound. 7. The foaming composition of claim 1 wherein the composition is essentially free of a propellant gas. 8. The foaming sunscreen composition according to claim 1, wherein the UV absorbing compound is selected from the group consisting of a UV-A absorbing moiety and a UV-B absorbing moiety. 9. The foaming sunscreen composition of claim 8, wherein the UV-A absorbing moiety is selected from the group consisting of tertrahydroxybenzophenones; dicarboxydihydroxybenzophenones and alkane ester or acid halide derivatives thereof; dihydroxy-, dicarboxy-, and hydroxycarboxydibenzoylmethanes and alkane ester or acid halide derivatives thereof; dihydroxy-, dicarboxy-, and hydroxycarboxystilbenes and alkane ester or acid halide derivatives thereof bis(hydroxystyrenyl) benzenes, bis(carboxystyrenyl)benzenes and alkane ester or acid halide derivatives thereof dihydroxy-, dicarboxy, and hydroxycarboxycarotenes and alkane ester or acid halide derivatives thereof bis-ethylhexyloxyphenol methoxyphenyl triazine; and 2 cyano-3,3-diphenyl acrylic acid, 2-ethyl hexyl ester. 10. The foaming sunscreen composition of claim 8, wherein the UV-B absorbing moiety is selected from the group consisting of a 4-aminobenzoic acid and alkane esters thereof anthranilic acid and alkane esters thereof salicylic acid and alkane esters thereof hydroxycinnamic acid and alkane esters thereof dihydroxy-, dicarboxy-, and hydroxycarboxybenzophenones and alkane ester or acid halide derivatives thereof dihydroxy-, dicarboxy-, and hydroxycarboxychalcones and alkane ester or acid halide derivatives thereof bis-ethylhexyloxyphenol methoxyphenyl triazine; octyl salicylate;
homosalate; oxybenzone; octocrylene; and dihydroxy-, dicarboxy-, and hydroxycarboxycoumarins and alkane ester or acid halide derivatives thereof 11. The foaming composition of claim 1 wherein the UV absorbing compound is selected from the group consisting of octyl salicylate, homosalate, oxybenzone, octocrylene, avobenzone, and Bis-ethyhexylophenol methoxyphenyl triazine). 12. The foaming sunscreen composition according to claim 1, wherein a density of the oil phase is at least 0.995 g/ml. 13. The foaming sunscreen composition according to claim 1, comprising from about 10% to about 55% by weight of the oil phase. 14. The foaming sunscreen composition according to claim 1, comprising from about 20% to 40% by weight of the oil phase. 15. The foaming sunscreen composition according to claim 1, comprising from about 10% to about 40% by weight of the UV absorbing compound. 16. The foaming sunscreen composition according to claim 1, further comprising a polyol having a density of at least 1 g/ml. 17. The foaming sunscreen composition according to claim 16, wherein the polyol is glycerin. 18. The foaming sunscreen composition according to claim 17, comprising from about 1% to about 20% by weight of the glycerin. 19. The foaming sunscreen composition of claim 1, wherein the oil phase comprises about 3% or less by weight of the oil soluble polymer, based on total weight of the foaming sunscreen composition. 20. The foaming sunscreen composition according to claim 1 having a viscosity of about 2000 cps or less. 21. The foaming sunscreen composition according to claim 1 having a viscosity of about 1000 cps or less. 22. The foaming sunscreen composition according to claim 1 further comprising an emulsifier other than the superhydrophilic amphiphilic copolymer. 23. The foaming sunscreen composition of claim 22, wherein the emulsifier other than the superhydrophilic amphiphilic copolymer is polyglyceryl 10 laurate. 24. The foaming sunscreen composition of claim 1 which is free of an emulsifier other than the superhydrophilic amphiphilic copolymer. 25. The foaming sunscreen composition according to claim 1 further comprising a suspension comprising non-UV-absorbing light-scattering particles. 26. The foaming sunscreen composition of claim 25 comprising from about 1% to about 10% by weight of the non-UV-absorbing light-scattering particles. 27. The foaming sunscreen composition of claim 25 comprising from about 1% to about 5% by weight of the non-UV-absorbing light-scattering particles. 28. The foaming sunscreen composition according to claim 27, wherein the non-UV- absorbing light-scattering particles comprise a styrene/acrylate copolymer. 29. The foaming sunscreen composition according to claim 25 wherein the oil-in-water emulsion is phase-stable. 30. The foaming composition of claim 1 wherein the oil phase comprises about 3% or less by weight of an oil-soluble emollient. 31. The foaming sunscreen composition of claim 1 further comprising bis-PEG-18 methyl ether dimethyl silane. 32. The composition of claim 1 which is essentially free of an emollient. 33. The foaming sunscreen composition according to claim 13, comprising from about 90% to about 45% by weight of the water phase. 34. The foaming sunscreen composition according to claim 14, comprising from about 80% to about 60% by weight of the water phase. 35. A non-aerosol mechanical dispensing container comprising a foaming sunscreen composition contained therein, the foaming sunscreen composition comprising:
an oil-in-water emulsion, comprising a continuous water phase comprising from about 0.75% to about 6% by weight of a superhydrophilic amphiphilic copolymer, based on total weight of the foaming sunscreen composition; and a discontinuous oil phase dispersed in the water phase,
wherein the discontinuous oil phase comprises a UV absorbing compound and is substantially free of an oil soluble polymer, the foaming sunscreen composition is essentially free of monomeric surfactant , and the foaming sunscreen composition and the container are free of a propellant gas. | 1,600 |
718 | 15,314,414 | 1,618 | The concentration of an administered compound, such as a drug (D), in an organ or a bodily fluid, such as blood, is determined directly through detecting the drug (D) or its metabolites (DM) in sweat. The concentration may be determined indirectly by administering the drug (D) together with one or more tracer compounds (T, T 2 ) or metabolites thereof (TM, T 2 M) or by detecting concentrations and trends of other analytes present in the body that react to the presence of the drug (D). By determining tracer concentration in sweat, the concentration of the drug (D) in blood or an organ can be determined. The tracer (T, T 2 ) is a compound selected for ease of detection in sweat, known metabolic and solubility profiles that correspond to those of the drug (D), and safety of use. A smart transdermal delivery patch ( 300 ) is used to administer a dosage of drug to a wearer in coordination with at least one sweat sensor ( 324 ) reading conveying information about the wearer. | 1. A method of determining a concentration of a primary drug administered to a patient comprising:
administering to said patient a known amount of said primary drug; administering to said patient a known amount of at least one tracer compound; detecting a concentration of said at least one tracer compound or a metabolite of said at least one tracer compound in sweat; and determining a concentration of the primary drug in said patient's blood or an organ using the concentration of the tracer compound or the metabolite of said tracer compound in the sweat. 2. The method of claim 1, wherein detecting the concentration includes measuring said primary drug, at least one metabolite of said primary drug, or at least one analyte in the sweat. 3. The method of claim 2, wherein determining the concentration of said primary drug includes measuring a relationship among concentrations in sweat of at least two of: said primary drug, at least one metabolite of said primary drug, at least one tracer compound, at least one metabolite of said tracer compound, and said at least one analyte. 4. The method of claim 1, wherein at least one tracer compound is metabolized in a known rate correlated to said primary drug. 5. The method of claim 1, wherein detecting the concentration occurs more than once. 6. The method of claim 1, wherein detecting the concentration includes measuring the sweat using a sweat sensor. 7. The method of claim 1, wherein at least one of said tracer compounds is selected from the group consisting of R-ibuprofen, S-ibuprofen, indoprofen, diclofenac, naproxen, and sulindac. 8. A method of determining a concentration of a placebo administered to a patient comprising:
administering to said patient a placebo, said placebo being a tracer compound to be detected in sweat; detecting a concentration of said placebo or at least one metabolite of said placebo in sweat; and determining the concentration of said placebo in said patient's blood or an organ using the concentration of said placebo or at least one metabolite of said placebo in the sweat. 9. The method of claim 8, wherein detecting the concentration includes measuring said placebo, at least one metabolite of said placebo, or at least one analyte in the sweat. 10. The method of claim 9, wherein determining the concentration of said placebo includes measuring a relationship among concentrations in sweat of at least two of: said placebo, at least one metabolite of said placebo, at least one tracer compound, at least one metabolite of said tracer compound, and said at least one analyte. 11. The method of claim 8, wherein at least one tracer compound is metabolized in a known rate correlated to said placebo. 12. The method of claim 8, wherein detecting the concentration occurs more than once. 13. The method of claim 8, wherein detecting the concentration includes measuring the sweat using a sweat sensor. 14. The method of claim 8, wherein at least one of said tracer compounds is selected from the group consisting of R-ibuprofen, S-ibuprofen, indoprofen, diclofenac, naproxen, and sulindac. 15. A sweat sensing and drug delivery system including a sweat sensor and a smart transdermal delivery device capable of feedback control, the system comprising:
said smart transdermal delivery device comprising:
at least one reservoir containing a primary drug or a tracer compound that is available for transdermal delivery; and
a power source; said at least one sweat sensor; and a communication mechanism for allowing communication between said at least one sensor and said smart transdermal delivery device. 16. The system of claim 15, wherein said reservoir contains said primary drug and said tracer compound. 17. The system of claim 15, wherein said reservoir contains said tracer compound and said tracer compound is a placebo. 18. The system of claim 15, wherein the reservoir contains more than one tracer compound. 19. The system of claim 15, further comprising:
a feedback control mechanism for controlling the dosage of one or more substances into the body. 20. The system of claim 15, further comprising:
one or more electrodes for delivering said primary drug or said tracer compound to the skin. 21. The system of claim 20, wherein the one or more electrodes include at least one of an iontophoresis electrode or an electro-osmosis electrode. 22. The system of claim 20 wherein said device is configured to deliver said primary drug or said tracer compound by iontophoresis. 23. The system of claim 20, further comprising:
electronics for limiting an activating current or a total dosage of said primary drug or said tracer compound to prevent administration of a harmful or toxic dosage. 24. The system of claim 15, wherein said device is configured to deliver said primary drug or said tracer compound by diffusion. 25. The system of claim 15, further comprising:
one or more microfluidic components configured to control a flow of said primary drug or said tracer compound or sweat. 26. The system of claim 25, wherein said one or more microfluidic components includes at least two microfluidic gates for controlling the delivery of said primary drug or said tracer compound to the skin. 27. The system of claim 15, further comprising:
a strain sensor for detecting twitches in the skin or a muscle when said device is placed on the skin. 28. The system of claim 15, further comprising:
a delivery mechanism configured to control transdermal delivery, the delivery mechanism using one of electroporation and microneedle arrays. 29. The system of claim 15, further comprising:
a solvent reservoir containing a one or more solvents that are available for delivery to the skin, the one or more solvents for increasing skin permeability to control transdermal delivery of said primary drug or said tracer compound. 30. The system of claim 15, wherein said device is configured to control transdermal delivery by using heat to change skin capillary flow or swelling to control skin permeability or substance permeation rate. 31. The system of claim 15, wherein said at least one sweat sensor is a component of said smart transdermal delivery device. 32. The device of claim 15, wherein said at least one sweat sensor is configured to monitor a sweat rate. 33. A method of transdermally delivering a primary drug or a tracer compound using a smart transdermal delivery device on an individual's skin, the method comprising:
performing at least one measurement of sweat; and delivering a dosage of said primary drug or said tracer compound based on said at least one measurement using said smart transdermal delivery device. 34. The method of claim 33, wherein performing at least one measurement of sweat includes using a sensing and delivery system including said smart transdermal delivery device and at least one sweat sensor. 35. The method of claim 33, wherein performing at least one measurement includes measuring a sweat rate. 36. The method of claim 33, further comprising:
performing at least one measurement of a twitch of the skin or a muscle. 37. The method of claim 33, wherein performing at least one measurement includes measuring a concentration of at least one analyte in sweat, the method further comprising:
correlating the concentration of said analyte in sweat to a concentration of said primary drug or said tracer compound in the individual's blood. 38. The method of claim 33, wherein delivering a dosage of the solute includes delivering a dosage of a primary drug. 39. A method of delivering a primary drug and/or a tracer compound to an individual using a smart transdermal delivery device with feedback control, comprising:
performing at least one measurement of sweat; delivering a dosage of said primary drug or said tracer compound using said at least one measurement; performing at least one follow-up measurement; and delivering an additional dosage of said primary drug or said tracer compound using said at least one follow-up measurement. 40. The method of claim 39, wherein performing at least one measurement of sweat includes using a sensing and delivery system including said smart transdermal delivery device and at least one sweat sensor. 41. The method of claim 39, wherein delivering a dosage includes delivering a dosage of said primary drug and said tracer compound. 42. The method of claim 41, wherein delivering an additional dosage includes delivering an additional dosage of said primary drug and said tracer compound. 43. The method of claim 39, further comprising:
determining an initial concentration of said primary drug or said tracer compound in blood, plasma, or an organ of said individual using said at least one measurement; wherein delivering a dosage of said primary drug or said tracer compound includes using said initial concentration and a threshold concentration of said primary drug or said tracer compound. 44. The method of claim 39, wherein delivering a dosage of said primary drug or said tracer compound includes using a threshold concentration of said primary drug or said tracer compound. 45. The method of claim 44, further comprising:
determining said additional dosage of said primary drug or said tracer compound using said at least one follow-up measurement and said threshold concentration. 46. The method of claim 44, wherein said threshold concentration represents an optimally effective dose of said primary drug or said tracer compound. 47. The method of claim 44, wherein said threshold concentration represents a maximum safe dose of said primary drug or said tracer compound. | The concentration of an administered compound, such as a drug (D), in an organ or a bodily fluid, such as blood, is determined directly through detecting the drug (D) or its metabolites (DM) in sweat. The concentration may be determined indirectly by administering the drug (D) together with one or more tracer compounds (T, T 2 ) or metabolites thereof (TM, T 2 M) or by detecting concentrations and trends of other analytes present in the body that react to the presence of the drug (D). By determining tracer concentration in sweat, the concentration of the drug (D) in blood or an organ can be determined. The tracer (T, T 2 ) is a compound selected for ease of detection in sweat, known metabolic and solubility profiles that correspond to those of the drug (D), and safety of use. A smart transdermal delivery patch ( 300 ) is used to administer a dosage of drug to a wearer in coordination with at least one sweat sensor ( 324 ) reading conveying information about the wearer.1. A method of determining a concentration of a primary drug administered to a patient comprising:
administering to said patient a known amount of said primary drug; administering to said patient a known amount of at least one tracer compound; detecting a concentration of said at least one tracer compound or a metabolite of said at least one tracer compound in sweat; and determining a concentration of the primary drug in said patient's blood or an organ using the concentration of the tracer compound or the metabolite of said tracer compound in the sweat. 2. The method of claim 1, wherein detecting the concentration includes measuring said primary drug, at least one metabolite of said primary drug, or at least one analyte in the sweat. 3. The method of claim 2, wherein determining the concentration of said primary drug includes measuring a relationship among concentrations in sweat of at least two of: said primary drug, at least one metabolite of said primary drug, at least one tracer compound, at least one metabolite of said tracer compound, and said at least one analyte. 4. The method of claim 1, wherein at least one tracer compound is metabolized in a known rate correlated to said primary drug. 5. The method of claim 1, wherein detecting the concentration occurs more than once. 6. The method of claim 1, wherein detecting the concentration includes measuring the sweat using a sweat sensor. 7. The method of claim 1, wherein at least one of said tracer compounds is selected from the group consisting of R-ibuprofen, S-ibuprofen, indoprofen, diclofenac, naproxen, and sulindac. 8. A method of determining a concentration of a placebo administered to a patient comprising:
administering to said patient a placebo, said placebo being a tracer compound to be detected in sweat; detecting a concentration of said placebo or at least one metabolite of said placebo in sweat; and determining the concentration of said placebo in said patient's blood or an organ using the concentration of said placebo or at least one metabolite of said placebo in the sweat. 9. The method of claim 8, wherein detecting the concentration includes measuring said placebo, at least one metabolite of said placebo, or at least one analyte in the sweat. 10. The method of claim 9, wherein determining the concentration of said placebo includes measuring a relationship among concentrations in sweat of at least two of: said placebo, at least one metabolite of said placebo, at least one tracer compound, at least one metabolite of said tracer compound, and said at least one analyte. 11. The method of claim 8, wherein at least one tracer compound is metabolized in a known rate correlated to said placebo. 12. The method of claim 8, wherein detecting the concentration occurs more than once. 13. The method of claim 8, wherein detecting the concentration includes measuring the sweat using a sweat sensor. 14. The method of claim 8, wherein at least one of said tracer compounds is selected from the group consisting of R-ibuprofen, S-ibuprofen, indoprofen, diclofenac, naproxen, and sulindac. 15. A sweat sensing and drug delivery system including a sweat sensor and a smart transdermal delivery device capable of feedback control, the system comprising:
said smart transdermal delivery device comprising:
at least one reservoir containing a primary drug or a tracer compound that is available for transdermal delivery; and
a power source; said at least one sweat sensor; and a communication mechanism for allowing communication between said at least one sensor and said smart transdermal delivery device. 16. The system of claim 15, wherein said reservoir contains said primary drug and said tracer compound. 17. The system of claim 15, wherein said reservoir contains said tracer compound and said tracer compound is a placebo. 18. The system of claim 15, wherein the reservoir contains more than one tracer compound. 19. The system of claim 15, further comprising:
a feedback control mechanism for controlling the dosage of one or more substances into the body. 20. The system of claim 15, further comprising:
one or more electrodes for delivering said primary drug or said tracer compound to the skin. 21. The system of claim 20, wherein the one or more electrodes include at least one of an iontophoresis electrode or an electro-osmosis electrode. 22. The system of claim 20 wherein said device is configured to deliver said primary drug or said tracer compound by iontophoresis. 23. The system of claim 20, further comprising:
electronics for limiting an activating current or a total dosage of said primary drug or said tracer compound to prevent administration of a harmful or toxic dosage. 24. The system of claim 15, wherein said device is configured to deliver said primary drug or said tracer compound by diffusion. 25. The system of claim 15, further comprising:
one or more microfluidic components configured to control a flow of said primary drug or said tracer compound or sweat. 26. The system of claim 25, wherein said one or more microfluidic components includes at least two microfluidic gates for controlling the delivery of said primary drug or said tracer compound to the skin. 27. The system of claim 15, further comprising:
a strain sensor for detecting twitches in the skin or a muscle when said device is placed on the skin. 28. The system of claim 15, further comprising:
a delivery mechanism configured to control transdermal delivery, the delivery mechanism using one of electroporation and microneedle arrays. 29. The system of claim 15, further comprising:
a solvent reservoir containing a one or more solvents that are available for delivery to the skin, the one or more solvents for increasing skin permeability to control transdermal delivery of said primary drug or said tracer compound. 30. The system of claim 15, wherein said device is configured to control transdermal delivery by using heat to change skin capillary flow or swelling to control skin permeability or substance permeation rate. 31. The system of claim 15, wherein said at least one sweat sensor is a component of said smart transdermal delivery device. 32. The device of claim 15, wherein said at least one sweat sensor is configured to monitor a sweat rate. 33. A method of transdermally delivering a primary drug or a tracer compound using a smart transdermal delivery device on an individual's skin, the method comprising:
performing at least one measurement of sweat; and delivering a dosage of said primary drug or said tracer compound based on said at least one measurement using said smart transdermal delivery device. 34. The method of claim 33, wherein performing at least one measurement of sweat includes using a sensing and delivery system including said smart transdermal delivery device and at least one sweat sensor. 35. The method of claim 33, wherein performing at least one measurement includes measuring a sweat rate. 36. The method of claim 33, further comprising:
performing at least one measurement of a twitch of the skin or a muscle. 37. The method of claim 33, wherein performing at least one measurement includes measuring a concentration of at least one analyte in sweat, the method further comprising:
correlating the concentration of said analyte in sweat to a concentration of said primary drug or said tracer compound in the individual's blood. 38. The method of claim 33, wherein delivering a dosage of the solute includes delivering a dosage of a primary drug. 39. A method of delivering a primary drug and/or a tracer compound to an individual using a smart transdermal delivery device with feedback control, comprising:
performing at least one measurement of sweat; delivering a dosage of said primary drug or said tracer compound using said at least one measurement; performing at least one follow-up measurement; and delivering an additional dosage of said primary drug or said tracer compound using said at least one follow-up measurement. 40. The method of claim 39, wherein performing at least one measurement of sweat includes using a sensing and delivery system including said smart transdermal delivery device and at least one sweat sensor. 41. The method of claim 39, wherein delivering a dosage includes delivering a dosage of said primary drug and said tracer compound. 42. The method of claim 41, wherein delivering an additional dosage includes delivering an additional dosage of said primary drug and said tracer compound. 43. The method of claim 39, further comprising:
determining an initial concentration of said primary drug or said tracer compound in blood, plasma, or an organ of said individual using said at least one measurement; wherein delivering a dosage of said primary drug or said tracer compound includes using said initial concentration and a threshold concentration of said primary drug or said tracer compound. 44. The method of claim 39, wherein delivering a dosage of said primary drug or said tracer compound includes using a threshold concentration of said primary drug or said tracer compound. 45. The method of claim 44, further comprising:
determining said additional dosage of said primary drug or said tracer compound using said at least one follow-up measurement and said threshold concentration. 46. The method of claim 44, wherein said threshold concentration represents an optimally effective dose of said primary drug or said tracer compound. 47. The method of claim 44, wherein said threshold concentration represents a maximum safe dose of said primary drug or said tracer compound. | 1,600 |
719 | 14,245,276 | 1,613 | A hair care composition comprising from about 0.25% to about 80% of a pre-emulsified emulsion comprising from about 0.005% to about 80% of one or more materials selected from the group comprising metathesized unsaturated polyol esters, sucrose polyesters, fatty esters with a molecular weight greater than or equal to 1500 and mixtures thereof and mixtures thereof or, by weight of said hair care composition; wherein an emulsifier is selected from the group consisting of anionic, non-ionic, cationic, amphoteric and mixtures thereof wherein the average particle size of the pre-emulsified oil in water emulsion is from about 20 nanometers to 20 microns; and a cationic surfactant system wherein the composition is stable with respect to one of the following measures selected from emulsion particle size, viscosity or visual phase separation and mixtures thereof. | 1) A hair care composition comprising:
a. from about 0.25% to about 80% of a pre-emulsified emulsion comprising from about 0.005% to about 80% of one or more materials selected from the group comprising metathesized unsaturated polyol esters, sucrose polyesters, fatty esters with a molecular weight greater than or equal to 1500 and mixtures thereof and mixtures thereof or, by weight of said hair care composition; wherein an emulsifier is selected from the group consisting of anionic, non-ionic, cationic, amphoteric and mixtures thereof wherein the average particle size of the pre-emulsified oil in water emulsion is from about 20 nanometers to 20 microns; and b. a cationic surfactant system further wherein the composition is stable with respect to one of the following measures selected from emulsion particle size, viscosity or visual phase separation and mixtures thereof. 2). The hair care composition of claim 1 wherein the hair care composition further comprise
a. a gel matrix comprising:
i. from about 0.1% to about 20% of one or more high melting point fatty compounds, by weight of said hair care composition;
ii. from about 0.1% to about 10% a cationic surfactant system of, by weight of said hair care composition; and
at least about 20% of an aqueous carrier, by weight of said hair care composition. 3). The hair care composition of claim 1 wherein the pre-emulsified emulsion comprises one or more water-miscible solvents. 4). The hair care composition of claim 1 wherein the sucrose polyester is sefose. 5). The hair care composition of claim 1 wherein the average particle size of the pre-emulsified emulsion is from about 100 nm to 20 microns 6) The hair care composition of claim 1 wherein the average particle size of the metathesized unsaturated polyol esters, sucrose polyesters, or fatty esters in the hair care composition is from about 100 nm to 20 microns. 7). The hair care composition of claim 1 wherein the emulsifier is selected from the group consisting of anionic, non-ionic, cationic, amphoteric and mixtures thereof. 8) The hair care composition of claim 1, wherein said one or more oligomers is a triglyceride oligomer. 9) The hair care composition of claim 8, wherein said triglyceride oligomer is a soy oligomer. 10) The hair care composition of claim 9, wherein said soy oligomer is fully hydrogenated. 11) The hair care composition of claim 9, wherein said soy oligomer is about 80% hydrogenated or more. 12) The hair care composition of claim 9 wherein said soy oligomer is about 80% or more non-hydrogenated. 13) The hair care composition of claim 1, wherein said hair care composition further comprises one or more additional conditioning agents. 14) The hair care composition of claim 13, wherein said one or more additional conditioning agents is a silicone. 15). The hair care composition of claim 1, wherein said hair care composition further comprises a deposition polymer. 16). The hair care composition of claim 10, wherein said hair care compositions comprises from about 0.03% to about 8% of a deposition polymer which is a copolymer comprising: a vinyl monomer (A) with a carboxyl group in the structure; and a vinyl monomer (B) expressed by the following formula (1):
CH2═C(R1)—CO—X-(Q-O)r—R2 (1)
wherein: R1 represents a hydrogen atom or a methyl group; R2 represents a hydrogen atom or an alkyl group with from 1 to 5 carbon atoms, which may have a substitution group; Q represents an alkylene group with from 2 to 4 carbon atoms which may also have a substitution group; r represents an integer from 2 to 15; and X represents an oxygen atom or an NH group; and, in the following structure -(Q-O)r—R2, the number of atoms bonded in a straight chain is 70 or less; and wherein the vinyl monomer (A) is contained at a level of from about 10 mass % to about 50 mass %, and the vinyl monomer (B) is contained at level of from about 50 mass % to about 90 mass %. 17). The hair care composition of claim 16, wherein said hair care compositions comprises a weight ratio of (i) the deposition polymer to (ii) a sum of the mono-alkyl amine salt cationic surfactant, di-alkyl quaternized ammonium salt cationic surfactant, and high melting point fatty compound is from about 1:1 to about 1:160. 18) The hair care composition of claim 1, wherein said hair care composition further comprises one or more additional benefit agents. 19) The hair care composition of claim 18, wherein said one or more additional benefit agents is selected from the group consisting of anti-dandruff agents, vitamins, chelants, perfumes, brighteners, enzymes, sensates, attractants, anti-bacterial agents, dyes, pigments, bleaches, and mixtures thereof. 20) The hair care composition of claim 1, wherein said hair care composition is a leave-on product. 21) The hair care composition of claim 1, wherein said one or more oligomers is self-metathesized. 22) The hair care composition of claim 1, wherein said one or more oligomers is cross-metathesized. 23) The hair care composition of claim 1, wherein said hair care composition further comprises one or more non-metathesized unsaturated polyol esters. 24) The hair care composition of claim 23, wherein said one or more non-metathesized unsaturated polyol esters includes a soybean oil and other natural oils. 25) A method for conditioning hair comprising the step of applying an effective amount of the hair care composition of claim 1 to the hair. 26) The hair care composition of claim 1 wherein the composition provides improvement of wet/dry conditioning | A hair care composition comprising from about 0.25% to about 80% of a pre-emulsified emulsion comprising from about 0.005% to about 80% of one or more materials selected from the group comprising metathesized unsaturated polyol esters, sucrose polyesters, fatty esters with a molecular weight greater than or equal to 1500 and mixtures thereof and mixtures thereof or, by weight of said hair care composition; wherein an emulsifier is selected from the group consisting of anionic, non-ionic, cationic, amphoteric and mixtures thereof wherein the average particle size of the pre-emulsified oil in water emulsion is from about 20 nanometers to 20 microns; and a cationic surfactant system wherein the composition is stable with respect to one of the following measures selected from emulsion particle size, viscosity or visual phase separation and mixtures thereof.1) A hair care composition comprising:
a. from about 0.25% to about 80% of a pre-emulsified emulsion comprising from about 0.005% to about 80% of one or more materials selected from the group comprising metathesized unsaturated polyol esters, sucrose polyesters, fatty esters with a molecular weight greater than or equal to 1500 and mixtures thereof and mixtures thereof or, by weight of said hair care composition; wherein an emulsifier is selected from the group consisting of anionic, non-ionic, cationic, amphoteric and mixtures thereof wherein the average particle size of the pre-emulsified oil in water emulsion is from about 20 nanometers to 20 microns; and b. a cationic surfactant system further wherein the composition is stable with respect to one of the following measures selected from emulsion particle size, viscosity or visual phase separation and mixtures thereof. 2). The hair care composition of claim 1 wherein the hair care composition further comprise
a. a gel matrix comprising:
i. from about 0.1% to about 20% of one or more high melting point fatty compounds, by weight of said hair care composition;
ii. from about 0.1% to about 10% a cationic surfactant system of, by weight of said hair care composition; and
at least about 20% of an aqueous carrier, by weight of said hair care composition. 3). The hair care composition of claim 1 wherein the pre-emulsified emulsion comprises one or more water-miscible solvents. 4). The hair care composition of claim 1 wherein the sucrose polyester is sefose. 5). The hair care composition of claim 1 wherein the average particle size of the pre-emulsified emulsion is from about 100 nm to 20 microns 6) The hair care composition of claim 1 wherein the average particle size of the metathesized unsaturated polyol esters, sucrose polyesters, or fatty esters in the hair care composition is from about 100 nm to 20 microns. 7). The hair care composition of claim 1 wherein the emulsifier is selected from the group consisting of anionic, non-ionic, cationic, amphoteric and mixtures thereof. 8) The hair care composition of claim 1, wherein said one or more oligomers is a triglyceride oligomer. 9) The hair care composition of claim 8, wherein said triglyceride oligomer is a soy oligomer. 10) The hair care composition of claim 9, wherein said soy oligomer is fully hydrogenated. 11) The hair care composition of claim 9, wherein said soy oligomer is about 80% hydrogenated or more. 12) The hair care composition of claim 9 wherein said soy oligomer is about 80% or more non-hydrogenated. 13) The hair care composition of claim 1, wherein said hair care composition further comprises one or more additional conditioning agents. 14) The hair care composition of claim 13, wherein said one or more additional conditioning agents is a silicone. 15). The hair care composition of claim 1, wherein said hair care composition further comprises a deposition polymer. 16). The hair care composition of claim 10, wherein said hair care compositions comprises from about 0.03% to about 8% of a deposition polymer which is a copolymer comprising: a vinyl monomer (A) with a carboxyl group in the structure; and a vinyl monomer (B) expressed by the following formula (1):
CH2═C(R1)—CO—X-(Q-O)r—R2 (1)
wherein: R1 represents a hydrogen atom or a methyl group; R2 represents a hydrogen atom or an alkyl group with from 1 to 5 carbon atoms, which may have a substitution group; Q represents an alkylene group with from 2 to 4 carbon atoms which may also have a substitution group; r represents an integer from 2 to 15; and X represents an oxygen atom or an NH group; and, in the following structure -(Q-O)r—R2, the number of atoms bonded in a straight chain is 70 or less; and wherein the vinyl monomer (A) is contained at a level of from about 10 mass % to about 50 mass %, and the vinyl monomer (B) is contained at level of from about 50 mass % to about 90 mass %. 17). The hair care composition of claim 16, wherein said hair care compositions comprises a weight ratio of (i) the deposition polymer to (ii) a sum of the mono-alkyl amine salt cationic surfactant, di-alkyl quaternized ammonium salt cationic surfactant, and high melting point fatty compound is from about 1:1 to about 1:160. 18) The hair care composition of claim 1, wherein said hair care composition further comprises one or more additional benefit agents. 19) The hair care composition of claim 18, wherein said one or more additional benefit agents is selected from the group consisting of anti-dandruff agents, vitamins, chelants, perfumes, brighteners, enzymes, sensates, attractants, anti-bacterial agents, dyes, pigments, bleaches, and mixtures thereof. 20) The hair care composition of claim 1, wherein said hair care composition is a leave-on product. 21) The hair care composition of claim 1, wherein said one or more oligomers is self-metathesized. 22) The hair care composition of claim 1, wherein said one or more oligomers is cross-metathesized. 23) The hair care composition of claim 1, wherein said hair care composition further comprises one or more non-metathesized unsaturated polyol esters. 24) The hair care composition of claim 23, wherein said one or more non-metathesized unsaturated polyol esters includes a soybean oil and other natural oils. 25) A method for conditioning hair comprising the step of applying an effective amount of the hair care composition of claim 1 to the hair. 26) The hair care composition of claim 1 wherein the composition provides improvement of wet/dry conditioning | 1,600 |
720 | 15,793,340 | 1,624 | This invention relates to a process for the production of a high purity polyether carbonate polyol. The high purity polyether carbonate polyols prepared by the process herein contain a low level of catalyst residue. The process purifies polyether carbonate polyol through use of activated carbon, mixed into the polyether carbonate polyol and later removed. In addition, the activated carbon may be coated on the filter through which the polyether carbonate polyol is filtered to form the high purity polyether carbonate polyol. | 1. A process for producing a high purity polyether carbonate polyol which contains a low level of catalyst residue, comprising
(1) adding from 0.1% to 10% by weight, based on 100% by weight of polyether carbonate polyol, of activated carbon, to the polyether carbonate polyol; (2) mixing the composition formed in (1) for a time period of from 20 minutes to 5 hours at temperature in the range of from 20° C. to 150° C.; and (3) filtering the mixed composition from (2), thereby forming the high purity polyether carbonate polyol. 2. The process of claim 1, wherein 0.5% to 2.0% by weight, based on 100% by weight of polyether carbonate polyol, of activated carbon is added in (1). 3. The process of claim 2, wherein 0.75% to 1.5% by weight, based on 100% by weight of polyether carbonate polyol, of activated carbon is added in (1). 4. The process of claim 1, wherein the activated carbon is acid washed. 5. The process of claim 1, wherein the activated carbon is a powder. 6. The process of claim 1, wherein the composition in (2) is mixed for a time period of from 30 minutes to 120 minutes. 7. The process of claim 6, wherein the composition in (2) is mixed for a time period of from 45 minutes to 90 minutes. 8. The process of claim 1, wherein the composition in (2) is mixed at a temperature in the range of from 70° C. to 125° C. 9. The process of claim 1, wherein the filtering in (3) is done by a filter paper. 10. The process of claim 9, wherein the filter paper has a pore size of 10-30 μm. 11. The process of claim 1, wherein the polyether carbonate polyol is prepared with a double metal cyanide catalyst. 12. The process of claim 1, wherein at least 60% of one of cobalt or zinc is removed from the polyether carbonate polyol. 13. The process of claim 1, wherein the high purity polyether carbonate polyol contains no more than 6 ppm of cobalt residue. 14. The process of claim 1, wherein the filtering in step (3) is through a filter that has been pre-coated with activated carbon. 15. The process of claim 14, wherein the filter paper is pre-coated by the steps comprising: (a) dispersing activated carbon in a solvent to form a mixture, (b) passing the mixture of (a) through a filter paper, and (c) drying the mixture on the filter paper. 16. The process of claim 14, wherein the activated carbon substantially covers the area of filter through which the mixed composition will pass. 17. The process of claim 14, wherein the concentration of activated carbon on the filter is between about 0.05 g/cm2 and about 0.10 g/cm2. | This invention relates to a process for the production of a high purity polyether carbonate polyol. The high purity polyether carbonate polyols prepared by the process herein contain a low level of catalyst residue. The process purifies polyether carbonate polyol through use of activated carbon, mixed into the polyether carbonate polyol and later removed. In addition, the activated carbon may be coated on the filter through which the polyether carbonate polyol is filtered to form the high purity polyether carbonate polyol.1. A process for producing a high purity polyether carbonate polyol which contains a low level of catalyst residue, comprising
(1) adding from 0.1% to 10% by weight, based on 100% by weight of polyether carbonate polyol, of activated carbon, to the polyether carbonate polyol; (2) mixing the composition formed in (1) for a time period of from 20 minutes to 5 hours at temperature in the range of from 20° C. to 150° C.; and (3) filtering the mixed composition from (2), thereby forming the high purity polyether carbonate polyol. 2. The process of claim 1, wherein 0.5% to 2.0% by weight, based on 100% by weight of polyether carbonate polyol, of activated carbon is added in (1). 3. The process of claim 2, wherein 0.75% to 1.5% by weight, based on 100% by weight of polyether carbonate polyol, of activated carbon is added in (1). 4. The process of claim 1, wherein the activated carbon is acid washed. 5. The process of claim 1, wherein the activated carbon is a powder. 6. The process of claim 1, wherein the composition in (2) is mixed for a time period of from 30 minutes to 120 minutes. 7. The process of claim 6, wherein the composition in (2) is mixed for a time period of from 45 minutes to 90 minutes. 8. The process of claim 1, wherein the composition in (2) is mixed at a temperature in the range of from 70° C. to 125° C. 9. The process of claim 1, wherein the filtering in (3) is done by a filter paper. 10. The process of claim 9, wherein the filter paper has a pore size of 10-30 μm. 11. The process of claim 1, wherein the polyether carbonate polyol is prepared with a double metal cyanide catalyst. 12. The process of claim 1, wherein at least 60% of one of cobalt or zinc is removed from the polyether carbonate polyol. 13. The process of claim 1, wherein the high purity polyether carbonate polyol contains no more than 6 ppm of cobalt residue. 14. The process of claim 1, wherein the filtering in step (3) is through a filter that has been pre-coated with activated carbon. 15. The process of claim 14, wherein the filter paper is pre-coated by the steps comprising: (a) dispersing activated carbon in a solvent to form a mixture, (b) passing the mixture of (a) through a filter paper, and (c) drying the mixture on the filter paper. 16. The process of claim 14, wherein the activated carbon substantially covers the area of filter through which the mixed composition will pass. 17. The process of claim 14, wherein the concentration of activated carbon on the filter is between about 0.05 g/cm2 and about 0.10 g/cm2. | 1,600 |
721 | 13,803,716 | 1,627 | A drink product having as an active ingredient an inositol hexaphosphate and optionally additional inositol moieties. Hexaphosphates for use in the invention include myoinositol hexaphosphate and/or any of the other 8 optical isomers thereof. The optional additional inositols include myoinositol and/or any of the other 8 optical isomers thereof. Uses for prevention, treatment, and reduction in risk of developing or progression of a number of conditions are disclosed. | 1. An aqueous liquid formulation comprising:
(a) water and (b) myoinositol hexaphosphate and/or an optical isomer thereof, and/or an orally acceptable salt thereof, further optionally comprising one or more components selected from the group consisting of:
(1) myoinositol and/or an optical isomer;
(2) an orally acceptable free radical scavenger
(3) a nutritionally acceptable orally administrable electrolyte;
(4) a nutritionally acceptable orally administrable vitamin;
(5) a flavor;
(6) an orally administrable coloring agent;
(7) an orally administrable sweetener;
(8) an oral formulation acceptable thickener;
(9) an orally administrable, liquid formulation processing aid; and
(10) an orally administrable, liquid formulation auxiliary carrier other than water. 2. A method of reducing the risk of damage to cells or tissues due to reactive oxygen species free radicals in a subject in need thereof comprising orally administering the formulation of claim 1. 3. A method of preventing damage to cells or tissues due to reactive oxygen species free radicals in a subject in need thereof comprising orally administering the formulation of claim 1. 4. A method of treating damage to cells or tissues due to reactive oxygen species free radicals in a subject in need thereof comprising orally administering the formulation of claim 1. 5. A method of reducing the risk of developing a cancer selected from breast, pancreatic, ovarian, prostate, lung cancer, skin cancer, colon cancer liver, cervical, uterine, liver, blood, soft tissue, and muscular tumors in a subject in need thereof comprising orally administering the formulation of claim 1. 6. A method of preventing a cancer selected from breast, pancreatic, ovarian, prostate, lung cancer, skin cancer, colon cancer liver, cervical, uterine, liver, blood, soft tissue, and muscular tumors in a subject in need thereof comprising orally administering the formulation of claim 1. 7. A method of treating a cancer selected from breast, pancreatic, ovarian, prostate, lung cancer, skin cancer, colon cancer liver, cervical, uterine, liver, blood, soft tissue, and muscular tumors in a subject in need thereof comprising orally administering the formulation of claim 1. 8. A method of reducing adverse effects of diagnostic radiation treatments in a patient in need thereof comprising orally administering to such a patient, before, during, or after said diagnostic radiation treatment, the formulation of claim 1. 9. A method of reducing the risk of adverse effects of environmental radiation exposure to a human or animal in need thereof comprising administering to said human or said animal respectively, before, during, or after said environmental, radiation exposure, the composition of claim 1. 10. The method of claim 9 wherein said environmental radiation exposure is selected from the group consisting of:
a) extreme elevation above sea level;
b) flying;
c) going into planetary orbit or further into space; and
d) mining, purification, or handling of radioactive materials. 11. A method of reducing the risk of adverse effects of environmental exposure to at least one of air pollutants, cigarette smoke, and/or other free oxygen radical generating substances in a human or animal comprising administering to said human or said animal respectively, before, during, or after said exposure, the composition of claim 1. 12. The product of claim 1 which is a liquid nutritional supplement. 13. The product of claim 1 which is an orally administered product. | A drink product having as an active ingredient an inositol hexaphosphate and optionally additional inositol moieties. Hexaphosphates for use in the invention include myoinositol hexaphosphate and/or any of the other 8 optical isomers thereof. The optional additional inositols include myoinositol and/or any of the other 8 optical isomers thereof. Uses for prevention, treatment, and reduction in risk of developing or progression of a number of conditions are disclosed.1. An aqueous liquid formulation comprising:
(a) water and (b) myoinositol hexaphosphate and/or an optical isomer thereof, and/or an orally acceptable salt thereof, further optionally comprising one or more components selected from the group consisting of:
(1) myoinositol and/or an optical isomer;
(2) an orally acceptable free radical scavenger
(3) a nutritionally acceptable orally administrable electrolyte;
(4) a nutritionally acceptable orally administrable vitamin;
(5) a flavor;
(6) an orally administrable coloring agent;
(7) an orally administrable sweetener;
(8) an oral formulation acceptable thickener;
(9) an orally administrable, liquid formulation processing aid; and
(10) an orally administrable, liquid formulation auxiliary carrier other than water. 2. A method of reducing the risk of damage to cells or tissues due to reactive oxygen species free radicals in a subject in need thereof comprising orally administering the formulation of claim 1. 3. A method of preventing damage to cells or tissues due to reactive oxygen species free radicals in a subject in need thereof comprising orally administering the formulation of claim 1. 4. A method of treating damage to cells or tissues due to reactive oxygen species free radicals in a subject in need thereof comprising orally administering the formulation of claim 1. 5. A method of reducing the risk of developing a cancer selected from breast, pancreatic, ovarian, prostate, lung cancer, skin cancer, colon cancer liver, cervical, uterine, liver, blood, soft tissue, and muscular tumors in a subject in need thereof comprising orally administering the formulation of claim 1. 6. A method of preventing a cancer selected from breast, pancreatic, ovarian, prostate, lung cancer, skin cancer, colon cancer liver, cervical, uterine, liver, blood, soft tissue, and muscular tumors in a subject in need thereof comprising orally administering the formulation of claim 1. 7. A method of treating a cancer selected from breast, pancreatic, ovarian, prostate, lung cancer, skin cancer, colon cancer liver, cervical, uterine, liver, blood, soft tissue, and muscular tumors in a subject in need thereof comprising orally administering the formulation of claim 1. 8. A method of reducing adverse effects of diagnostic radiation treatments in a patient in need thereof comprising orally administering to such a patient, before, during, or after said diagnostic radiation treatment, the formulation of claim 1. 9. A method of reducing the risk of adverse effects of environmental radiation exposure to a human or animal in need thereof comprising administering to said human or said animal respectively, before, during, or after said environmental, radiation exposure, the composition of claim 1. 10. The method of claim 9 wherein said environmental radiation exposure is selected from the group consisting of:
a) extreme elevation above sea level;
b) flying;
c) going into planetary orbit or further into space; and
d) mining, purification, or handling of radioactive materials. 11. A method of reducing the risk of adverse effects of environmental exposure to at least one of air pollutants, cigarette smoke, and/or other free oxygen radical generating substances in a human or animal comprising administering to said human or said animal respectively, before, during, or after said exposure, the composition of claim 1. 12. The product of claim 1 which is a liquid nutritional supplement. 13. The product of claim 1 which is an orally administered product. | 1,600 |
722 | 14,431,534 | 1,627 | Provided is a method of treating and/or preventing Wolfram Syndrome (WS)-related neurodegeneration (i.e. of Wolfram Syndrome-Associated Neuronal Degeneration), by increasing the expression and/or functional activity of p21. A method of screening for pharmacological agents useful in treating and/or preventing such conditions is also provided. | 1. A compound capable of increasing the expression and/or functional activity of p21 for use in the treatment and/or prevention of Wolfram Syndrome (WS)-related neurodegeneration. 2. A compound for use according to claim 1, where the compound is capable of increasing the expression; increasing the binding; increasing the activation;
increasing the accumulation; and/or increasing the induction of p21. 3. A compound for use according to claim 1, selected from one or more of the compounds listed in Table 4. 4. A compound for use according to claim 1, selected from one or more of the group consisting of: Valproic acid or a salt thereof, Chloroquine diphosphate, Pioglitazone, 4-phenylbutyric acid or a salt thereof, Fusidic acid, Ciclopriox Olamine, Dapsone, Rifampicin, Loperamide hydrochloride, Rapamycin, Flurbiprofen and Dexrazoxane. 5. A compound for use according to claim 1, wherein the increased expression of p21 encompass one or both of:
(i) increased transcription of p21; and/or (ii) reduced degradation of p21 RNA and/or peptide and/or protein. 6. A compound for use according to claim 1, wherein the increased functional activity of p21 encompass one or both of:
(iii) enhanced activation of p21; (iv) enhanced nuclear translocation of p21. 7. A compound for use according to claim 1, wherein the compound acts to either increase the amount of p21 protein available and/or acts to maximise that any p21 protein is activated and has been delivered to the nucleus. 8. A compound for use according to claim 1, wherein the compound acts to increase expression of p21. 9. A compound for use according to claim 1, wherein the compound acts to increase p21 activation (without an increase in p21 expression). 10. A compound for use according to claim 1, wherein the compound relieves symptoms, or halts the progression, of the disease, or results in an improvement in overall CNS function. 11. A compound for use according to claim 1, wherein the compound is Rapamycin. 12. A compound for use according to claim 1, wherein the compound is Flurbiprofen. 13. A compound for use according to claim 1, wherein the compound is Dexrazoxane. 14. A method of treating and/or preventing Wolfram Syndrome (WS)-related neurodegeneration, comprising administering the compound of claim 1 to a patient in need thereof. 15. A method of screening for pharmacological agents useful in treating and/or preventing Wolfram Syndrome (WS)-related neurodegeneration in a particular patient, comprising:
(i) contacting a cell of the patient with a test agent; (ii) measuring the expression and/or functional activity of p21; (iii) measuring the expression and/or functional activity of p21 in a control cell not exposed to the agent; and (iv) comparing the measurements taken in steps (ii) and (iii).
wherein a difference the measurements taken in steps (ii) and (iii) indicates that the agent is suitable for use in a method of treating and/or preventing Wolfram Syndrome (WS)-related neurodegeneration in the patient. | Provided is a method of treating and/or preventing Wolfram Syndrome (WS)-related neurodegeneration (i.e. of Wolfram Syndrome-Associated Neuronal Degeneration), by increasing the expression and/or functional activity of p21. A method of screening for pharmacological agents useful in treating and/or preventing such conditions is also provided.1. A compound capable of increasing the expression and/or functional activity of p21 for use in the treatment and/or prevention of Wolfram Syndrome (WS)-related neurodegeneration. 2. A compound for use according to claim 1, where the compound is capable of increasing the expression; increasing the binding; increasing the activation;
increasing the accumulation; and/or increasing the induction of p21. 3. A compound for use according to claim 1, selected from one or more of the compounds listed in Table 4. 4. A compound for use according to claim 1, selected from one or more of the group consisting of: Valproic acid or a salt thereof, Chloroquine diphosphate, Pioglitazone, 4-phenylbutyric acid or a salt thereof, Fusidic acid, Ciclopriox Olamine, Dapsone, Rifampicin, Loperamide hydrochloride, Rapamycin, Flurbiprofen and Dexrazoxane. 5. A compound for use according to claim 1, wherein the increased expression of p21 encompass one or both of:
(i) increased transcription of p21; and/or (ii) reduced degradation of p21 RNA and/or peptide and/or protein. 6. A compound for use according to claim 1, wherein the increased functional activity of p21 encompass one or both of:
(iii) enhanced activation of p21; (iv) enhanced nuclear translocation of p21. 7. A compound for use according to claim 1, wherein the compound acts to either increase the amount of p21 protein available and/or acts to maximise that any p21 protein is activated and has been delivered to the nucleus. 8. A compound for use according to claim 1, wherein the compound acts to increase expression of p21. 9. A compound for use according to claim 1, wherein the compound acts to increase p21 activation (without an increase in p21 expression). 10. A compound for use according to claim 1, wherein the compound relieves symptoms, or halts the progression, of the disease, or results in an improvement in overall CNS function. 11. A compound for use according to claim 1, wherein the compound is Rapamycin. 12. A compound for use according to claim 1, wherein the compound is Flurbiprofen. 13. A compound for use according to claim 1, wherein the compound is Dexrazoxane. 14. A method of treating and/or preventing Wolfram Syndrome (WS)-related neurodegeneration, comprising administering the compound of claim 1 to a patient in need thereof. 15. A method of screening for pharmacological agents useful in treating and/or preventing Wolfram Syndrome (WS)-related neurodegeneration in a particular patient, comprising:
(i) contacting a cell of the patient with a test agent; (ii) measuring the expression and/or functional activity of p21; (iii) measuring the expression and/or functional activity of p21 in a control cell not exposed to the agent; and (iv) comparing the measurements taken in steps (ii) and (iii).
wherein a difference the measurements taken in steps (ii) and (iii) indicates that the agent is suitable for use in a method of treating and/or preventing Wolfram Syndrome (WS)-related neurodegeneration in the patient. | 1,600 |
723 | 12,798,027 | 1,647 | The invention relates to medicine. The inventive agent which exhibits immunoregulatory properties and accelerated clinical performance at a recrudescence stage and is mainly used for treating autoimmune diseases comprises trophoblastic β-1-glycoprotein and immunoglobulin (Ig) which is embodied in the form of a multivalent ligand G (Ig-G) or A (Ig-A) or M (Ig-M) immunoglobulin. According to the second invention, an agent for treating autoimmune diseases comprises β-1-glycoprotein and immunoglobulin (Ig-G), wherein the multivalent ligand G or A (Ig-A) is used in the form of an immunoglobulin and the β-1-glycoprotein and immunoglobulin (Ig-G) are taken in equal portions on in portions whose ratio is equal to 1:19, respectively. For treating autoimmune diseases, the agent containing β-1-glycoprotein and immunoglobulin (Ig) is parenterally administratable. | 1. An agent with the property to induce the suppressor activity and cytokine secretion of mononuclear cells that contains trophoblastic β-1-glycoprotein (TBG), distinctive in that it also contains immunoglobulin (Ig). 2. An agent per item 1, distinctive in that immunoglobulin class G (Ig-G), or class A (Ig-A), or class M (Ig-M) is used as immunoglobulin. 3. An agent per item 1, distinctive in that TBG and Ig are used in equal ratio. 4. An agent per item 1, distinctive in that TBG and Ig are used in the ratio of 1:19, respectively. 5. The use of an agent with the property to induce the suppressor activity and cytokine secretion of mononuclear cells that contains TBG and immunoglobulin (Ig) for treatment of autoimmune diseases. 6. The use of the agent per item 5, distinctive in that class G (Ig-G), or class A (Ig-A), or class M (Ig-M) immunoglobulin is used as immunoglobulin. 7. The use of an agent per item 5, distinctive in that it is administered parenterally. 8. The use of the agent per item 6, distinctive in that TBG and Ig are used in equal ratio. 9. The use of the agent per item 6, distinctive in that TBG and Ig are used in the ratio of 1:19, respectively. | The invention relates to medicine. The inventive agent which exhibits immunoregulatory properties and accelerated clinical performance at a recrudescence stage and is mainly used for treating autoimmune diseases comprises trophoblastic β-1-glycoprotein and immunoglobulin (Ig) which is embodied in the form of a multivalent ligand G (Ig-G) or A (Ig-A) or M (Ig-M) immunoglobulin. According to the second invention, an agent for treating autoimmune diseases comprises β-1-glycoprotein and immunoglobulin (Ig-G), wherein the multivalent ligand G or A (Ig-A) is used in the form of an immunoglobulin and the β-1-glycoprotein and immunoglobulin (Ig-G) are taken in equal portions on in portions whose ratio is equal to 1:19, respectively. For treating autoimmune diseases, the agent containing β-1-glycoprotein and immunoglobulin (Ig) is parenterally administratable.1. An agent with the property to induce the suppressor activity and cytokine secretion of mononuclear cells that contains trophoblastic β-1-glycoprotein (TBG), distinctive in that it also contains immunoglobulin (Ig). 2. An agent per item 1, distinctive in that immunoglobulin class G (Ig-G), or class A (Ig-A), or class M (Ig-M) is used as immunoglobulin. 3. An agent per item 1, distinctive in that TBG and Ig are used in equal ratio. 4. An agent per item 1, distinctive in that TBG and Ig are used in the ratio of 1:19, respectively. 5. The use of an agent with the property to induce the suppressor activity and cytokine secretion of mononuclear cells that contains TBG and immunoglobulin (Ig) for treatment of autoimmune diseases. 6. The use of the agent per item 5, distinctive in that class G (Ig-G), or class A (Ig-A), or class M (Ig-M) immunoglobulin is used as immunoglobulin. 7. The use of an agent per item 5, distinctive in that it is administered parenterally. 8. The use of the agent per item 6, distinctive in that TBG and Ig are used in equal ratio. 9. The use of the agent per item 6, distinctive in that TBG and Ig are used in the ratio of 1:19, respectively. | 1,600 |
724 | 14,701,248 | 1,631 | Systems, methods, and apparatuses are provided for determining a sequence of a heteropolymer molecule. For example, all or part of a chromosome or a protein can be determined using sequence data from a plurality of heteropolymer fragments corresponding to the heteropolymer molecule. As one example, a position in the sequence read of a DNA fragment can be identified where a single base call is not clear. A multiplet base call can then be used, where the multiplet base call includes two or more bases at the position, along with a score for each base. The scores can be carried through mapping and assembly procedures, where the scores can be used to determine a final base call for the position in a chromosome of a genome of an organism. Other examples can be used for other monomer units besides bases. | 1. A method comprising performing, by a computer system:
receiving sequence data from a sequencing of a plurality of heteropolymer fragments corresponding to a heteropolymer molecule of an organism, wherein the sequence data for each heteropolymer fragment of the plurality of heteropolymer fragments includes:
intensity values for a set of monomers at a plurality of positions of the heteropolymer fragment;
determining a first score of a first monomer at a first position of a first heteropolymer fragment based on a first intensity value of the first monomer measured at the first position, the first score providing a first likelihood of the first monomer being at the first position of the first heteropolymer fragment; determining a second score of a second monomer at the first position of the first heteropolymer fragment based on a second intensity value of the second monomer measured at the first position, the second score providing a second likelihood of the second monomer being at the first position of the first heteropolymer fragment; based on the first score and the second score, identifying the first position of the first heteropolymer fragment to correspond to a multiplet call that includes the first monomer and the second monomer; and using the first monomer and the second monomer in a mapping procedure and/or an assembly procedure to determine a final monomer call at a final position in a sequence of monomers corresponding to the heteropolymer molecule of the organism. 2. The method of claim 1, further comprising, by the computer system:
using the first score and the second score in the mapping procedure and/or the assembly procedure to determine the final monomer call at the final position in the sequence of monomers. 3. The method of claim 1, wherein identifying the first position of the first heteropolymer fragment to correspond to the multiplet call includes:
determining that the first score is a highest score of the set of monomers at the first position of the first heteropolymer fragment; comparing the first score to a first threshold; determining that the first score is below the first threshold; and identifying the first position as corresponding to the multiplet call based on the first score being below the first threshold. 4. The method of claim 3, further comprising, by the computer system:
determining that the first score is above a second threshold; and identifying the first position as corresponding to the multiplet call based on the first score being above the second threshold. 5. The method of claim 4, further comprising, by the computer system:
identifying a second position as a no-call when a highest score of the set of monomers at the second position is below the second threshold. 6. The method of claim 3, further comprising, by the computer system:
determining that the second score is a second highest score of the set of monomers at the first position of the first heteropolymer fragment; determining that the second score is above a second threshold; and identifying the first position as corresponding to the multiplet call based on the second score being above the second threshold. 7. The method of claim 1, further comprising, by the computer system:
determining a sequence read corresponding to the first heteropolymer fragment, the sequence read having a no-call at the first position; and mapping the sequence read to a location of a reference sequence, the location including the final position in the sequence of monomers, wherein the first score and the second score are used in the assembly procedure involving the sequence read at the final position, thereby determining the final monomer call at the final position in the sequence of monomers. 8. The method of claim 1, further comprising, by the computer system:
determining one or more first sequence reads corresponding to the first heteropolymer fragment, the one or more first sequence reads including the first monomer at the first position; determining one or more second sequence reads corresponding to the first heteropolymer fragment, the one or more second sequence reads including the second monomer at the first position; mapping the one or more first sequence reads to a reference sequence to obtain one or more first mapping scores based on the first score; mapping the one or more second sequence reads to the reference sequence to obtain one or more second mapping scores based on the second score; and using the one or more first mapping scores and the one or more second mapping scores to determine the final monomer call at the final position in the sequence of monomers corresponding to the heteropolymer molecule of the organism. 9. The method of claim 8, wherein the final position in the sequence of monomers corresponds to where the first position in at least one of the first and second sequence reads maps to the reference sequence. 10. The method of claim 8, wherein obtaining a first mapping score for a first sequence read based on the first score includes:
determining an initial mapping score that corresponds to an accuracy of mapping the first sequence read to the reference sequence; and using the initial mapping score and the first score to determine the first mapping score. 11. The method of claim 10, wherein determining the first score includes:
multiplying the first score and the initial mapping score. 12. The method of claim 1, further comprising, by the computer system:
using the first score and the second score in the assembly procedure to determine the final monomer call at the final position in the sequence of monomers. 13. The method of claim 12, further comprising, by the computer system:
identifying a set of sequence reads that align to the final position in the sequence of monomers and that have a score for a monomer at the final position, the set of sequence reads including:
sequence reads that respectively include the first monomer and the second monomer at the first position and that correspond to the first heteropolymer fragment; and
using the scores of the monomers of the set of sequence reads to determine the final monomer call at the final position. 14. The method of claim 13, wherein using the scores of the monomers of the set of sequence reads includes:
computing a sum of the scores for each monomer of the monomers of the set of sequence reads; and using the monomer having a highest sum as the final monomer call. 15. The method of claim 12, further comprising, by the computer system:
determining a first sequence read corresponding to the first heteropolymer fragment, the first sequence read including the first monomer at the first position; extracting a first plurality of Kmers from the first sequence read, the first plurality of Kmers including the first monomer at the first position; determining a second sequence read corresponding to the first heteropolymer fragment, the second sequence read including the second monomer at the first position; extracting a second plurality of Kmers from the second sequence read, the first plurality of Kmers including the second monomer at the first position; and creating a Kmer index including the first plurality of Kmers and the second plurality of Kmers. 16. The method of claim 15, wherein a first Kmer of the first plurality of Kmers is stored in the Kmer index in association with a first read score corresponding to the first heteropolymer fragment, the first read score being determined based on the first score, and
wherein a second Kmer of the second plurality of Kmers is stored in the Kmer index in association with a second read score corresponding to the first heteropolymer fragment, the second read score being determined based on the second score. 17. The method of claim 16, wherein the first read score is the first score. 18. The method of claim 16, further comprising:
extending a contig using Kmers in the Kmer index based on read scores associated with the Kmers in the Kmer index. 19. The method of claim 18, extending the contig includes:
identifying a set of Kmers that align to an end of the contig; for each Kmer of the set of Kmers:
computing a Kmer score based on the read scores associated with the Kmer; and
using the Kmer scores to determine which Kmer of the set of Kmers to use to extend the contig. 20. A computer product comprising a computer readable medium storing a plurality of instructions, that when executed on one or more processors of a computer system, perform:
receiving sequence data from a sequencing of a plurality of heteropolymer fragments corresponding to a heteropolymer molecule of an organism, wherein the sequence data for each heteropolymer fragment of the plurality of heteropolymer fragments includes:
intensity values for monomers at a plurality of positions of the heteropolymer fragment;
determining a first score of a first monomer at a first position of a first heteropolymer fragment based on a first intensity value of the first monomer measured at the first position, the first score providing a first likelihood of the first monomer being at the first position of the first heteropolymer fragment; determining a second score of a second monomer at the first position of the first heteropolymer fragment based on a second intensity value of the second monomer measured at the first position, the second score providing a second likelihood of the second monomer being at the first position of the first heteropolymer fragment; based on the first score and the second score, identifying the first position of the first heteropolymer fragment to correspond to a multiplet call that includes the first monomer and the second monomer; and using the first monomer and the second monomer in a mapping procedure and/or an assembly procedure to determine a final monomer call at a final position in a sequence of monomers corresponding to the heteropolymer molecule of the organism. | Systems, methods, and apparatuses are provided for determining a sequence of a heteropolymer molecule. For example, all or part of a chromosome or a protein can be determined using sequence data from a plurality of heteropolymer fragments corresponding to the heteropolymer molecule. As one example, a position in the sequence read of a DNA fragment can be identified where a single base call is not clear. A multiplet base call can then be used, where the multiplet base call includes two or more bases at the position, along with a score for each base. The scores can be carried through mapping and assembly procedures, where the scores can be used to determine a final base call for the position in a chromosome of a genome of an organism. Other examples can be used for other monomer units besides bases.1. A method comprising performing, by a computer system:
receiving sequence data from a sequencing of a plurality of heteropolymer fragments corresponding to a heteropolymer molecule of an organism, wherein the sequence data for each heteropolymer fragment of the plurality of heteropolymer fragments includes:
intensity values for a set of monomers at a plurality of positions of the heteropolymer fragment;
determining a first score of a first monomer at a first position of a first heteropolymer fragment based on a first intensity value of the first monomer measured at the first position, the first score providing a first likelihood of the first monomer being at the first position of the first heteropolymer fragment; determining a second score of a second monomer at the first position of the first heteropolymer fragment based on a second intensity value of the second monomer measured at the first position, the second score providing a second likelihood of the second monomer being at the first position of the first heteropolymer fragment; based on the first score and the second score, identifying the first position of the first heteropolymer fragment to correspond to a multiplet call that includes the first monomer and the second monomer; and using the first monomer and the second monomer in a mapping procedure and/or an assembly procedure to determine a final monomer call at a final position in a sequence of monomers corresponding to the heteropolymer molecule of the organism. 2. The method of claim 1, further comprising, by the computer system:
using the first score and the second score in the mapping procedure and/or the assembly procedure to determine the final monomer call at the final position in the sequence of monomers. 3. The method of claim 1, wherein identifying the first position of the first heteropolymer fragment to correspond to the multiplet call includes:
determining that the first score is a highest score of the set of monomers at the first position of the first heteropolymer fragment; comparing the first score to a first threshold; determining that the first score is below the first threshold; and identifying the first position as corresponding to the multiplet call based on the first score being below the first threshold. 4. The method of claim 3, further comprising, by the computer system:
determining that the first score is above a second threshold; and identifying the first position as corresponding to the multiplet call based on the first score being above the second threshold. 5. The method of claim 4, further comprising, by the computer system:
identifying a second position as a no-call when a highest score of the set of monomers at the second position is below the second threshold. 6. The method of claim 3, further comprising, by the computer system:
determining that the second score is a second highest score of the set of monomers at the first position of the first heteropolymer fragment; determining that the second score is above a second threshold; and identifying the first position as corresponding to the multiplet call based on the second score being above the second threshold. 7. The method of claim 1, further comprising, by the computer system:
determining a sequence read corresponding to the first heteropolymer fragment, the sequence read having a no-call at the first position; and mapping the sequence read to a location of a reference sequence, the location including the final position in the sequence of monomers, wherein the first score and the second score are used in the assembly procedure involving the sequence read at the final position, thereby determining the final monomer call at the final position in the sequence of monomers. 8. The method of claim 1, further comprising, by the computer system:
determining one or more first sequence reads corresponding to the first heteropolymer fragment, the one or more first sequence reads including the first monomer at the first position; determining one or more second sequence reads corresponding to the first heteropolymer fragment, the one or more second sequence reads including the second monomer at the first position; mapping the one or more first sequence reads to a reference sequence to obtain one or more first mapping scores based on the first score; mapping the one or more second sequence reads to the reference sequence to obtain one or more second mapping scores based on the second score; and using the one or more first mapping scores and the one or more second mapping scores to determine the final monomer call at the final position in the sequence of monomers corresponding to the heteropolymer molecule of the organism. 9. The method of claim 8, wherein the final position in the sequence of monomers corresponds to where the first position in at least one of the first and second sequence reads maps to the reference sequence. 10. The method of claim 8, wherein obtaining a first mapping score for a first sequence read based on the first score includes:
determining an initial mapping score that corresponds to an accuracy of mapping the first sequence read to the reference sequence; and using the initial mapping score and the first score to determine the first mapping score. 11. The method of claim 10, wherein determining the first score includes:
multiplying the first score and the initial mapping score. 12. The method of claim 1, further comprising, by the computer system:
using the first score and the second score in the assembly procedure to determine the final monomer call at the final position in the sequence of monomers. 13. The method of claim 12, further comprising, by the computer system:
identifying a set of sequence reads that align to the final position in the sequence of monomers and that have a score for a monomer at the final position, the set of sequence reads including:
sequence reads that respectively include the first monomer and the second monomer at the first position and that correspond to the first heteropolymer fragment; and
using the scores of the monomers of the set of sequence reads to determine the final monomer call at the final position. 14. The method of claim 13, wherein using the scores of the monomers of the set of sequence reads includes:
computing a sum of the scores for each monomer of the monomers of the set of sequence reads; and using the monomer having a highest sum as the final monomer call. 15. The method of claim 12, further comprising, by the computer system:
determining a first sequence read corresponding to the first heteropolymer fragment, the first sequence read including the first monomer at the first position; extracting a first plurality of Kmers from the first sequence read, the first plurality of Kmers including the first monomer at the first position; determining a second sequence read corresponding to the first heteropolymer fragment, the second sequence read including the second monomer at the first position; extracting a second plurality of Kmers from the second sequence read, the first plurality of Kmers including the second monomer at the first position; and creating a Kmer index including the first plurality of Kmers and the second plurality of Kmers. 16. The method of claim 15, wherein a first Kmer of the first plurality of Kmers is stored in the Kmer index in association with a first read score corresponding to the first heteropolymer fragment, the first read score being determined based on the first score, and
wherein a second Kmer of the second plurality of Kmers is stored in the Kmer index in association with a second read score corresponding to the first heteropolymer fragment, the second read score being determined based on the second score. 17. The method of claim 16, wherein the first read score is the first score. 18. The method of claim 16, further comprising:
extending a contig using Kmers in the Kmer index based on read scores associated with the Kmers in the Kmer index. 19. The method of claim 18, extending the contig includes:
identifying a set of Kmers that align to an end of the contig; for each Kmer of the set of Kmers:
computing a Kmer score based on the read scores associated with the Kmer; and
using the Kmer scores to determine which Kmer of the set of Kmers to use to extend the contig. 20. A computer product comprising a computer readable medium storing a plurality of instructions, that when executed on one or more processors of a computer system, perform:
receiving sequence data from a sequencing of a plurality of heteropolymer fragments corresponding to a heteropolymer molecule of an organism, wherein the sequence data for each heteropolymer fragment of the plurality of heteropolymer fragments includes:
intensity values for monomers at a plurality of positions of the heteropolymer fragment;
determining a first score of a first monomer at a first position of a first heteropolymer fragment based on a first intensity value of the first monomer measured at the first position, the first score providing a first likelihood of the first monomer being at the first position of the first heteropolymer fragment; determining a second score of a second monomer at the first position of the first heteropolymer fragment based on a second intensity value of the second monomer measured at the first position, the second score providing a second likelihood of the second monomer being at the first position of the first heteropolymer fragment; based on the first score and the second score, identifying the first position of the first heteropolymer fragment to correspond to a multiplet call that includes the first monomer and the second monomer; and using the first monomer and the second monomer in a mapping procedure and/or an assembly procedure to determine a final monomer call at a final position in a sequence of monomers corresponding to the heteropolymer molecule of the organism. | 1,600 |
725 | 13,972,274 | 1,627 | A drink product having as an active ingredient genistein and an inositol hexaphosphate and/or an unphosphorylated inositol and optionally additional inositol (unphosphorylated as well as hexaphosphorylated) moieties. Hexaphosphates for use in the invention include myoinositol hexaphosphate and/or any of the other 8 optical isomers thereof. The optional additional inositols include myoinositol and/or any of the other 8 optical isomers thereof. Uses for prevention, treatment, and reduction in risk of developing or progression of a number of conditions are disclosed. | 1. An aqueous liquid formulation comprising:
(a) water and (b) myoinositol hexaphosphate and/or an optical isomer thereof, and/or an orally acceptable salt thereof, (c) Genistein (d) further optionally comprising one or more components selected from the group consisting of:
(1) myoinositol and/or an optical isomer;
(2) an orally acceptable free radical scavenger other than Genistein
(3) a nutritionally acceptable orally administrable electrolyte;
(4) a nutritionally acceptable orally administrable vitamin;
(5) a flavor;
(6) an orally administrable coloring agent;
(7) an orally administrable sweetener;
(8) an oral formulation acceptable thickener;
(9) an orally administrable, liquid formulation processing aid; and (10) an orally administrable, liquid formulation auxiliary carrier other than water. 2. A method of reducing the risk of damage to cells or tissues due to reactive oxygen species free radicals in a subject in need thereof comprising orally administering the formulation of claim 1. 3. A method of preventing damage to cells or tissues due to reactive oxygen species free radicals in a subject in need thereof comprising orally administering the formulation of claim 1. 4. A method of treating damage to cells or tissues due to reactive oxygen species free radicals in a subject in need thereof comprising orally administering the formulation of claim 1. 5. A method of reducing the risk of developing HIV and/or AIDS and secondary cancers related to HIV and AIDS comprising orally administering the formulation of claim 1. 6. The method of claim 5 wherein said cancers related to HIV and AIDS is selected from Kaposi sarcoma and non-Hodgkin lymphoma, Hodgkin disease and cancers of the lung, mouth, skin, cervix, and digestive system, liver, blood, soft tissue, and muscular tumors. 7. A method of preventing a HIV/AIDS related cancer selected from breast, pancreatic, ovarian, prostate, lung cancer, skin cancer, colon cancer liver, cervical, uterine, liver, blood, soft tissue, and muscular tumors in a subject in need thereof comprising orally administering the formulation of claim 1. 8. A method of treating a cancer selected from Kaposi sarcoma and non-Hodgkin lymphoma, other AIDS-related cancers selected from Hodgkin disease and cancers of the lung, mouth, skin, cervix, and digestive system, liver, blood, soft tissue, and muscular tumors breast, pancreatic, ovarian, prostate, lung cancer, skin cancer, colon cancer liver, cervical, uterine, liver, blood, soft tissue, and muscular tumors in a subject in need thereof comprising orally administering the formulation of claim 1. 9. A method of increasing T cells and or inhibiting HIV related CD4 reduction comprising administering the composition of claim 1 to a subject in need thereof. 10. A method for blocking the communication between a HIV cell surface to internal cellular compartment comprising administering the composition of claim 1 to a subject in need thereof. 11. A method for preventing an HIV particle from entering the internal cellular compartments thereby preventing the spread of the infection comprising administering the composition of claim 1 to a subject in need thereof. 12. A method of reducing the risk of adverse effects of common and current drug toxicities' associated with current anti-viral therapies comprising administering the composition of claim 1 to a subject in need thereof. 13. A method of reducing drug resistance known to occur with current drugs because it's a plant based product comprising administering the composition of claim 1 to a subject in need thereof. 14. A method for both prevention HIV infection of resting CD4 T− cells, viral DNA synthesis, and/or viral nuclear migration comprising administering the composition of claim 1 to a subject in need thereof. 15. A method for preventing Gag-NA inositol does that interactions prior to membrane binding in HIV comprising administering the composition of claim 1 to a subject in need thereof. 16. A method for inhibiting the replication of HIV-1 comprising administering the composition of claim 1 to a subject in need thereof. 17. A method for AP3B1 regulation and HIV-1 Gag release comprising administering the composition of claim 1 to a subject in need thereof. 18. The product of claim 1 which is a liquid nutritional supplement. 19. The product of claim 1 which is an orally administered product. 20. A method of reducing the risk of damage to cells or tissues due to reactive oxygen species free radicals in a subject in need thereof comprising orally administering the formulation of claim 1. 21. A method of preventing damage to cells or tissues due to reactive oxygen species free radicals in a subject in need thereof comprising orally administering the formulation of claim 1. 22. A method of treating damage to cells or tissues due to reactive oxygen species free radicals in a subject in need thereof comprising orally administering the formulation of claim 1. 23. A method of reducing the risk of developing a cancer selected from breast, pancreatic, ovarian, prostate, lung cancer, skin cancer, colon cancer liver, cervical, uterine, liver, blood, soft tissue, and muscular tumors in a subject in need thereof comprising orally administering the formulation of claim 1. 24. A method of preventing a cancer selected from breast, pancreatic, ovarian, prostate, lung cancer, skin cancer, colon cancer liver, cervical, uterine, liver, blood, soft tissue, and muscular tumors in a subject in need thereof comprising orally administering the formulation of claim 1. 25. A method of treating a cancer selected from breast, pancreatic, ovarian, prostate, lung cancer, skin cancer, colon cancer liver, cervical, uterine, liver, blood, soft tissue, and muscular tumors in a subject in need thereof comprising orally administering the formulation of claim 1. 26. A method of reducing adverse effects of diagnostic radiation treatments in a patient in need thereof comprising orally administering to such a patient, before, during, or after said diagnostic radiation treatment, the formulation of claim 1. 27. A method of reducing the risk of adverse effects of environmental radiation exposure to a human or animal in need thereof comprising administering to said human or said animal respectively, before, during, or after said environmental, radiation exposure, the composition of claim 1. 28. The method of claim 27 wherein said environmental radiation exposure is selected from the group consisting of:
a) extreme elevation above sea level;
b) flying;
c) going into planetary orbit or further into space; and
d) mining, purification, or handling of radioactive materials. 29. A method of reducing the risk of adverse effects of environmental exposure to at least one of air pollutants, cigarette smoke, and/or other free oxygen radical generating substances in a human or animal comprising administering to said human or said animal respectively, before, during, or after said exposure, the composition of claim 1. 30. A method of prophylactic treatment of a subject to prevent or slow the progression of an HIV infection wherein said subject is known to be or suspected to be at risk of an HIV infection due to actual or suspected exposure to HIV virus or has been determined to have a detectable titer of HIV/AID virus or surrogate markers therefor and has not yet presented with clinical symptoms of HIV/AIDS comprising administering a composition of claim 1 to said subject. | A drink product having as an active ingredient genistein and an inositol hexaphosphate and/or an unphosphorylated inositol and optionally additional inositol (unphosphorylated as well as hexaphosphorylated) moieties. Hexaphosphates for use in the invention include myoinositol hexaphosphate and/or any of the other 8 optical isomers thereof. The optional additional inositols include myoinositol and/or any of the other 8 optical isomers thereof. Uses for prevention, treatment, and reduction in risk of developing or progression of a number of conditions are disclosed.1. An aqueous liquid formulation comprising:
(a) water and (b) myoinositol hexaphosphate and/or an optical isomer thereof, and/or an orally acceptable salt thereof, (c) Genistein (d) further optionally comprising one or more components selected from the group consisting of:
(1) myoinositol and/or an optical isomer;
(2) an orally acceptable free radical scavenger other than Genistein
(3) a nutritionally acceptable orally administrable electrolyte;
(4) a nutritionally acceptable orally administrable vitamin;
(5) a flavor;
(6) an orally administrable coloring agent;
(7) an orally administrable sweetener;
(8) an oral formulation acceptable thickener;
(9) an orally administrable, liquid formulation processing aid; and (10) an orally administrable, liquid formulation auxiliary carrier other than water. 2. A method of reducing the risk of damage to cells or tissues due to reactive oxygen species free radicals in a subject in need thereof comprising orally administering the formulation of claim 1. 3. A method of preventing damage to cells or tissues due to reactive oxygen species free radicals in a subject in need thereof comprising orally administering the formulation of claim 1. 4. A method of treating damage to cells or tissues due to reactive oxygen species free radicals in a subject in need thereof comprising orally administering the formulation of claim 1. 5. A method of reducing the risk of developing HIV and/or AIDS and secondary cancers related to HIV and AIDS comprising orally administering the formulation of claim 1. 6. The method of claim 5 wherein said cancers related to HIV and AIDS is selected from Kaposi sarcoma and non-Hodgkin lymphoma, Hodgkin disease and cancers of the lung, mouth, skin, cervix, and digestive system, liver, blood, soft tissue, and muscular tumors. 7. A method of preventing a HIV/AIDS related cancer selected from breast, pancreatic, ovarian, prostate, lung cancer, skin cancer, colon cancer liver, cervical, uterine, liver, blood, soft tissue, and muscular tumors in a subject in need thereof comprising orally administering the formulation of claim 1. 8. A method of treating a cancer selected from Kaposi sarcoma and non-Hodgkin lymphoma, other AIDS-related cancers selected from Hodgkin disease and cancers of the lung, mouth, skin, cervix, and digestive system, liver, blood, soft tissue, and muscular tumors breast, pancreatic, ovarian, prostate, lung cancer, skin cancer, colon cancer liver, cervical, uterine, liver, blood, soft tissue, and muscular tumors in a subject in need thereof comprising orally administering the formulation of claim 1. 9. A method of increasing T cells and or inhibiting HIV related CD4 reduction comprising administering the composition of claim 1 to a subject in need thereof. 10. A method for blocking the communication between a HIV cell surface to internal cellular compartment comprising administering the composition of claim 1 to a subject in need thereof. 11. A method for preventing an HIV particle from entering the internal cellular compartments thereby preventing the spread of the infection comprising administering the composition of claim 1 to a subject in need thereof. 12. A method of reducing the risk of adverse effects of common and current drug toxicities' associated with current anti-viral therapies comprising administering the composition of claim 1 to a subject in need thereof. 13. A method of reducing drug resistance known to occur with current drugs because it's a plant based product comprising administering the composition of claim 1 to a subject in need thereof. 14. A method for both prevention HIV infection of resting CD4 T− cells, viral DNA synthesis, and/or viral nuclear migration comprising administering the composition of claim 1 to a subject in need thereof. 15. A method for preventing Gag-NA inositol does that interactions prior to membrane binding in HIV comprising administering the composition of claim 1 to a subject in need thereof. 16. A method for inhibiting the replication of HIV-1 comprising administering the composition of claim 1 to a subject in need thereof. 17. A method for AP3B1 regulation and HIV-1 Gag release comprising administering the composition of claim 1 to a subject in need thereof. 18. The product of claim 1 which is a liquid nutritional supplement. 19. The product of claim 1 which is an orally administered product. 20. A method of reducing the risk of damage to cells or tissues due to reactive oxygen species free radicals in a subject in need thereof comprising orally administering the formulation of claim 1. 21. A method of preventing damage to cells or tissues due to reactive oxygen species free radicals in a subject in need thereof comprising orally administering the formulation of claim 1. 22. A method of treating damage to cells or tissues due to reactive oxygen species free radicals in a subject in need thereof comprising orally administering the formulation of claim 1. 23. A method of reducing the risk of developing a cancer selected from breast, pancreatic, ovarian, prostate, lung cancer, skin cancer, colon cancer liver, cervical, uterine, liver, blood, soft tissue, and muscular tumors in a subject in need thereof comprising orally administering the formulation of claim 1. 24. A method of preventing a cancer selected from breast, pancreatic, ovarian, prostate, lung cancer, skin cancer, colon cancer liver, cervical, uterine, liver, blood, soft tissue, and muscular tumors in a subject in need thereof comprising orally administering the formulation of claim 1. 25. A method of treating a cancer selected from breast, pancreatic, ovarian, prostate, lung cancer, skin cancer, colon cancer liver, cervical, uterine, liver, blood, soft tissue, and muscular tumors in a subject in need thereof comprising orally administering the formulation of claim 1. 26. A method of reducing adverse effects of diagnostic radiation treatments in a patient in need thereof comprising orally administering to such a patient, before, during, or after said diagnostic radiation treatment, the formulation of claim 1. 27. A method of reducing the risk of adverse effects of environmental radiation exposure to a human or animal in need thereof comprising administering to said human or said animal respectively, before, during, or after said environmental, radiation exposure, the composition of claim 1. 28. The method of claim 27 wherein said environmental radiation exposure is selected from the group consisting of:
a) extreme elevation above sea level;
b) flying;
c) going into planetary orbit or further into space; and
d) mining, purification, or handling of radioactive materials. 29. A method of reducing the risk of adverse effects of environmental exposure to at least one of air pollutants, cigarette smoke, and/or other free oxygen radical generating substances in a human or animal comprising administering to said human or said animal respectively, before, during, or after said exposure, the composition of claim 1. 30. A method of prophylactic treatment of a subject to prevent or slow the progression of an HIV infection wherein said subject is known to be or suspected to be at risk of an HIV infection due to actual or suspected exposure to HIV virus or has been determined to have a detectable titer of HIV/AID virus or surrogate markers therefor and has not yet presented with clinical symptoms of HIV/AIDS comprising administering a composition of claim 1 to said subject. | 1,600 |
726 | 15,498,728 | 1,646 | A polypeptide comprising the sequence of SEQ. ID NO. 2, 3, 4, 7 or 8. The polypeptide may have the sequence of an immunogenic fragment thereof comprising at least eight amino acids, wherein the immunogenic fragment is not one of SEQ. ID NOS. 6 or 11 to 16. The polypeptide may have a sequence having at least 80% sequence identity to the aforementioned polypeptide or immunogenic fragment. The polypeptide is less than 100 amino acids in length and does not comprise the sequence of any of SEQ. ID NOS. 10, 46, 56, 57 or 59 to 62 and does not consist of the sequence of SEQ ID NO. 58. The polypeptide is useful in the treatment or prophylaxis of cancer. | 1. A method of treatment or prophylaxis of cancer in a patient comprising administering to the patient at least one selected from the group consisting of:
a) a polypeptide comprising a sequence selected from the group consisting of:
i) SEQ, ID NOS. 2, 3, 4, 7 or 8;
ii) the sequence of an immunogenic fragment of i) comprising at least eight amino acids, wherein the immunogenic fragment is not one of SEQ. ID NOS. 6 or 11 to 16; or
iii) a sequence having at least 80% sequence identity to i) or ii),
wherein the polypeptide is less than 100 amino acids in length and wherein the polypeptide does not comprise the sequence of SEQ. ID NO. 10 and does not consist of the sequence of SEQ ID NO. 56; b) a nucleic acid molecule consisting of a nucleotide sequence encoding the polypeptide of part a); and c) a pharmaceutical composition comprising the polypeptide of part a) or the nucleic acid molecule of part b) and a pharmaceutically acceptable adjuvant, diluent or excipient. 2. The method according to claim 1, wherein the polypeptide comprises a sequence selected from the group consisting of:
i) SEQ. ID NO. 1; ii) the sequence of an immunogenic fragment of i) comprising at least eight amino acids, wherein the immunogenic fragment is not one of SEQ. ID NOS. 6, 11 to 16 or 56; and iii) a sequence having at least 80% sequence identity to i) or ii),
wherein the polypeptide is less than 100 amino acids in length. 3. The method according to claim 2, part ii), wherein the sequence of the immunogenic fragment, or a sequence having at least 80% identity thereto, comprises at least 20 amino acids. 4. The method according to claim 1, wherein the immunogenic fragment has the sequence of any one of SEQ. ID NOS. 17 to 40. 5. The method according to claim 4, wherein the immunogenic fragment consists of the sequence of any one of SEQ ID NOS: 18, 24, 36 or 37. 6. The method according to claim 1, wherein the polypeptide is less than or equal to 80, 50, 30, 20 or 11 amino acids in length. 7. The method according to claim 1, wherein the cancer is selected from breast cancer, prostate cancer, pancreatic cancer, colorectal cancer, lung cancer, malignant melanoma, a leukemia, a lymphoma, ovarian cancer, cervical cancer, or biliary tract carcinomas. 8. The method according to claim 1, part (a), wherein the polypeptide is linked to a substance selected from the group consisting of lipids, sugar and sugar chains, acetyl groups, at least one further polypeptide, natural polymers and synthetic polymers. 9. The method according to claim 8, wherein the polypeptide is in the form of a lipopeptide conjugate. 10. The method according to claim 1, part c), wherein the pharmaceutical composition comprises a further therapeutic ingredient. 11. The method according to claim 1, part c), wherein the pharmaceutical composition comprises the polypeptide or the nucleic acid molecule in a dose of between 1 and 500 μg. 12. A method of treatment or prophylaxis of cancer in a patient comprising administering to the patient at least one selected from the group consisting of:
a) a polypeptide comprising the sequence of SEQ ID NO: 1, wherein the polypeptide is less than 100 amino acids in length and wherein the polypeptide does not comprise the sequence of SEQ ID NO: 10; b) a nucleic acid molecule consisting of a nucleotide sequence encoding the polypeptide of part a); and c) a pharmaceutical composition comprising the polypeptide of part a) or the nucleic acid molecule of part b) and a pharmaceutically acceptable adjuvant, diluent or excipient. 13. The method according to claim 12, wherein the cancer is selected from breast cancer, prostate cancer, pancreatic cancer, colorectal cancer, lung cancer, malignant melanoma, a leukemia, a lymphoma, ovarian cancer, cervical cancer, or biliary tract carcinomas. 14. The method according to claim 12, part c), wherein the pharmaceutical composition comprises a further therapeutic ingredient. 15. The method according to claim 12, part c), wherein the pharmaceutical composition comprises the polypeptide or the nucleic acid molecule in a dose of between 1 and 500 μg. 16. A method of treatment or prophylaxis of cancer in a patient comprising administering to the patient at least one selected from the group consisting of:
a) a cocktail of polypeptides comprising at least two different polypeptides comprising sequences selected from the group consisting of:
i) SEQ. ID NOS. 2 to 7;
ii) the sequence of an immunogenic fragment of i) comprising at least eight amino acids; and
iii) a sequence having at least 80% sequence identity to i) or ii),
wherein each polypeptide is less than 100 amino acids in length; b) a cocktail of nucleic acid molecules comprising at least two different nucleic acid molecules, each consisting of a nucleotide sequence encoding a polypeptide of part a); and c) a pharmaceutical composition comprising the cocktail of polypeptides of part a) or the cocktail of nucleic acid molecules of part b) and a pharmaceutically acceptable adjuvant, diluent or excipient. 17. The method according to claim 16, wherein at least one polypeptide comprises a sequence selected from the group consisting of:
i) SEQ. ID NOS. 1, 7, 8, 9 or 10; ii) the sequence of an immunogenic fragment of i) comprising at least eight amino acids; and iii) a sequence having at least 80% sequence identity to i) or ii),
wherein the polypeptides are less than 100 amino acids in length. 18. The method according to claim 16, wherein the at least two different polypeptides comprise a cocktail of polypeptides selected from the group consisting of:
i) a cocktail of: a polypeptide comprising the sequence of SEQ. ID NO. 1 or a sequence having at least 80% sequence identity thereto or an immunogenic fragment thereof comprising at least eight amino acids; a polypeptide comprising the sequence of SEQ. ID NO. 7 or a sequence having at least 80% sequence identity thereto or an immunogenic fragment thereof comprising at least eight amino acids; and a polypeptide comprising the sequence of SEQ. ID NO. 9 or a sequence having at least 80% sequence identity thereto or an immunogenic fragment thereof comprising at least eight amino acids; ii) a cocktail of: a polypeptide comprising the sequence of SEQ. ID NO. 1 or a sequence having at least 80% sequence identity thereto or an immunogenic fragment thereof comprising at least eight amino acids; a polypeptide comprising the sequence of SEQ. ID NO. 8 or a sequence having at least 80% sequence identity thereto or an immunogenic fragment thereof comprising at least eight amino acids; and a polypeptide comprising the sequence of SEQ. ID NO. 9 or a sequence having at least 80% sequence identity thereto or an immunogenic fragment thereof comprising at least eight amino acids; and iii) a cocktail of: a polypeptide comprising the sequence of SEQ. ID NO. 1 or a sequence having at least 80% sequence identity thereto or an immunogenic fragment thereof comprising at least eight amino acids; a polypeptide comprising the sequence of SEQ. ID NO. 8 or a sequence having at least 80% sequence identity thereto or an immunogenic fragment thereof comprising at least eight amino acids; and a polypeptide comprising the sequence of SEQ. ID NO. 10 or a sequence having at least 80% sequence identity thereto or an immunogenic fragment thereof comprising at least eight amino acids, wherein each polypeptide is less than 100 amino acids in length. 19. The method according to claim 16, wherein the or each immunogenic fragment has a sequence of any one of SEQ. ID NOS. 17 to 40. 20. The method according to claim 16, wherein the cancer is selected from breast cancer, prostate cancer, pancreatic cancer, colorectal cancer, lung cancer, malignant melanoma, a leukemia, a lymphoma, ovarian cancer, cervical cancer, or biliary tract carcinomas. 21. The method according to claim 16, part (a), wherein the at least two different polypeptides are each linked to a substance selected from the group consisting of lipids, sugar and sugar chains, acetyl groups, at least one further polypeptide, natural polymers and synthetic polymers. 22. The method according to claim 21, wherein the at least two different polypeptides are each in the form of a lipopeptide conjugate. 23. The method according to claim 16, part c), wherein the pharmaceutical composition comprises a further therapeutic ingredient. 24. The method according to claim 16, part c), wherein the pharmaceutical composition comprises the cocktail of polypeptides or the cocktail of nucleic acid molecules in a dose of between 1 and 500 μg. | A polypeptide comprising the sequence of SEQ. ID NO. 2, 3, 4, 7 or 8. The polypeptide may have the sequence of an immunogenic fragment thereof comprising at least eight amino acids, wherein the immunogenic fragment is not one of SEQ. ID NOS. 6 or 11 to 16. The polypeptide may have a sequence having at least 80% sequence identity to the aforementioned polypeptide or immunogenic fragment. The polypeptide is less than 100 amino acids in length and does not comprise the sequence of any of SEQ. ID NOS. 10, 46, 56, 57 or 59 to 62 and does not consist of the sequence of SEQ ID NO. 58. The polypeptide is useful in the treatment or prophylaxis of cancer.1. A method of treatment or prophylaxis of cancer in a patient comprising administering to the patient at least one selected from the group consisting of:
a) a polypeptide comprising a sequence selected from the group consisting of:
i) SEQ, ID NOS. 2, 3, 4, 7 or 8;
ii) the sequence of an immunogenic fragment of i) comprising at least eight amino acids, wherein the immunogenic fragment is not one of SEQ. ID NOS. 6 or 11 to 16; or
iii) a sequence having at least 80% sequence identity to i) or ii),
wherein the polypeptide is less than 100 amino acids in length and wherein the polypeptide does not comprise the sequence of SEQ. ID NO. 10 and does not consist of the sequence of SEQ ID NO. 56; b) a nucleic acid molecule consisting of a nucleotide sequence encoding the polypeptide of part a); and c) a pharmaceutical composition comprising the polypeptide of part a) or the nucleic acid molecule of part b) and a pharmaceutically acceptable adjuvant, diluent or excipient. 2. The method according to claim 1, wherein the polypeptide comprises a sequence selected from the group consisting of:
i) SEQ. ID NO. 1; ii) the sequence of an immunogenic fragment of i) comprising at least eight amino acids, wherein the immunogenic fragment is not one of SEQ. ID NOS. 6, 11 to 16 or 56; and iii) a sequence having at least 80% sequence identity to i) or ii),
wherein the polypeptide is less than 100 amino acids in length. 3. The method according to claim 2, part ii), wherein the sequence of the immunogenic fragment, or a sequence having at least 80% identity thereto, comprises at least 20 amino acids. 4. The method according to claim 1, wherein the immunogenic fragment has the sequence of any one of SEQ. ID NOS. 17 to 40. 5. The method according to claim 4, wherein the immunogenic fragment consists of the sequence of any one of SEQ ID NOS: 18, 24, 36 or 37. 6. The method according to claim 1, wherein the polypeptide is less than or equal to 80, 50, 30, 20 or 11 amino acids in length. 7. The method according to claim 1, wherein the cancer is selected from breast cancer, prostate cancer, pancreatic cancer, colorectal cancer, lung cancer, malignant melanoma, a leukemia, a lymphoma, ovarian cancer, cervical cancer, or biliary tract carcinomas. 8. The method according to claim 1, part (a), wherein the polypeptide is linked to a substance selected from the group consisting of lipids, sugar and sugar chains, acetyl groups, at least one further polypeptide, natural polymers and synthetic polymers. 9. The method according to claim 8, wherein the polypeptide is in the form of a lipopeptide conjugate. 10. The method according to claim 1, part c), wherein the pharmaceutical composition comprises a further therapeutic ingredient. 11. The method according to claim 1, part c), wherein the pharmaceutical composition comprises the polypeptide or the nucleic acid molecule in a dose of between 1 and 500 μg. 12. A method of treatment or prophylaxis of cancer in a patient comprising administering to the patient at least one selected from the group consisting of:
a) a polypeptide comprising the sequence of SEQ ID NO: 1, wherein the polypeptide is less than 100 amino acids in length and wherein the polypeptide does not comprise the sequence of SEQ ID NO: 10; b) a nucleic acid molecule consisting of a nucleotide sequence encoding the polypeptide of part a); and c) a pharmaceutical composition comprising the polypeptide of part a) or the nucleic acid molecule of part b) and a pharmaceutically acceptable adjuvant, diluent or excipient. 13. The method according to claim 12, wherein the cancer is selected from breast cancer, prostate cancer, pancreatic cancer, colorectal cancer, lung cancer, malignant melanoma, a leukemia, a lymphoma, ovarian cancer, cervical cancer, or biliary tract carcinomas. 14. The method according to claim 12, part c), wherein the pharmaceutical composition comprises a further therapeutic ingredient. 15. The method according to claim 12, part c), wherein the pharmaceutical composition comprises the polypeptide or the nucleic acid molecule in a dose of between 1 and 500 μg. 16. A method of treatment or prophylaxis of cancer in a patient comprising administering to the patient at least one selected from the group consisting of:
a) a cocktail of polypeptides comprising at least two different polypeptides comprising sequences selected from the group consisting of:
i) SEQ. ID NOS. 2 to 7;
ii) the sequence of an immunogenic fragment of i) comprising at least eight amino acids; and
iii) a sequence having at least 80% sequence identity to i) or ii),
wherein each polypeptide is less than 100 amino acids in length; b) a cocktail of nucleic acid molecules comprising at least two different nucleic acid molecules, each consisting of a nucleotide sequence encoding a polypeptide of part a); and c) a pharmaceutical composition comprising the cocktail of polypeptides of part a) or the cocktail of nucleic acid molecules of part b) and a pharmaceutically acceptable adjuvant, diluent or excipient. 17. The method according to claim 16, wherein at least one polypeptide comprises a sequence selected from the group consisting of:
i) SEQ. ID NOS. 1, 7, 8, 9 or 10; ii) the sequence of an immunogenic fragment of i) comprising at least eight amino acids; and iii) a sequence having at least 80% sequence identity to i) or ii),
wherein the polypeptides are less than 100 amino acids in length. 18. The method according to claim 16, wherein the at least two different polypeptides comprise a cocktail of polypeptides selected from the group consisting of:
i) a cocktail of: a polypeptide comprising the sequence of SEQ. ID NO. 1 or a sequence having at least 80% sequence identity thereto or an immunogenic fragment thereof comprising at least eight amino acids; a polypeptide comprising the sequence of SEQ. ID NO. 7 or a sequence having at least 80% sequence identity thereto or an immunogenic fragment thereof comprising at least eight amino acids; and a polypeptide comprising the sequence of SEQ. ID NO. 9 or a sequence having at least 80% sequence identity thereto or an immunogenic fragment thereof comprising at least eight amino acids; ii) a cocktail of: a polypeptide comprising the sequence of SEQ. ID NO. 1 or a sequence having at least 80% sequence identity thereto or an immunogenic fragment thereof comprising at least eight amino acids; a polypeptide comprising the sequence of SEQ. ID NO. 8 or a sequence having at least 80% sequence identity thereto or an immunogenic fragment thereof comprising at least eight amino acids; and a polypeptide comprising the sequence of SEQ. ID NO. 9 or a sequence having at least 80% sequence identity thereto or an immunogenic fragment thereof comprising at least eight amino acids; and iii) a cocktail of: a polypeptide comprising the sequence of SEQ. ID NO. 1 or a sequence having at least 80% sequence identity thereto or an immunogenic fragment thereof comprising at least eight amino acids; a polypeptide comprising the sequence of SEQ. ID NO. 8 or a sequence having at least 80% sequence identity thereto or an immunogenic fragment thereof comprising at least eight amino acids; and a polypeptide comprising the sequence of SEQ. ID NO. 10 or a sequence having at least 80% sequence identity thereto or an immunogenic fragment thereof comprising at least eight amino acids, wherein each polypeptide is less than 100 amino acids in length. 19. The method according to claim 16, wherein the or each immunogenic fragment has a sequence of any one of SEQ. ID NOS. 17 to 40. 20. The method according to claim 16, wherein the cancer is selected from breast cancer, prostate cancer, pancreatic cancer, colorectal cancer, lung cancer, malignant melanoma, a leukemia, a lymphoma, ovarian cancer, cervical cancer, or biliary tract carcinomas. 21. The method according to claim 16, part (a), wherein the at least two different polypeptides are each linked to a substance selected from the group consisting of lipids, sugar and sugar chains, acetyl groups, at least one further polypeptide, natural polymers and synthetic polymers. 22. The method according to claim 21, wherein the at least two different polypeptides are each in the form of a lipopeptide conjugate. 23. The method according to claim 16, part c), wherein the pharmaceutical composition comprises a further therapeutic ingredient. 24. The method according to claim 16, part c), wherein the pharmaceutical composition comprises the cocktail of polypeptides or the cocktail of nucleic acid molecules in a dose of between 1 and 500 μg. | 1,600 |
727 | 16,120,120 | 1,612 | Compositions for upregulating defensin expression include oleic acid and linoleic acid. The compositions can be in a liposomal, nanoliposomal, or nanoemulsion form. The compositions are useful in preventing, treating and ameliorating defensin-related conditions, such as preventing and treating HIV infection. | 1. A pharmaceutical composition for upregulating defensin expression, comprising oleic acid and linoleic acid, the composition being in a form of a nanoliposome, wherein the nanoliposome has an average particle size of 150 nm. 2. (canceled) 3. The pharmaceutical composition according to claim 1, wherein the nanoliposome further includes phospholids and cholestrol. 4-5. (canceled) 6. The pharmaceutical composition according to claim 1, wherein a ratio of oleic acid to linoleic acid is 1:1. 7-15. (canceled) | Compositions for upregulating defensin expression include oleic acid and linoleic acid. The compositions can be in a liposomal, nanoliposomal, or nanoemulsion form. The compositions are useful in preventing, treating and ameliorating defensin-related conditions, such as preventing and treating HIV infection.1. A pharmaceutical composition for upregulating defensin expression, comprising oleic acid and linoleic acid, the composition being in a form of a nanoliposome, wherein the nanoliposome has an average particle size of 150 nm. 2. (canceled) 3. The pharmaceutical composition according to claim 1, wherein the nanoliposome further includes phospholids and cholestrol. 4-5. (canceled) 6. The pharmaceutical composition according to claim 1, wherein a ratio of oleic acid to linoleic acid is 1:1. 7-15. (canceled) | 1,600 |
728 | 15,241,260 | 1,661 | A watermelon plant that produces fruit having (i) ultra-firm flesh and/or liquid-retaining flesh and (ii) soluble solids of at least about 6 brix. | 1. A watermelon plant, or a part thereof, that produces a mature fruit having flesh that resists pressure of at least 3.5 pounds force (lbf) and has soluble solids of at least 6 brix. 2. (canceled) 3. The watermelon plant, or part thereof, of claim 1 wherein said flesh resists pressure of at least 4.0 lbf. 4. The watermelon plant, or part thereof, of claim 3 wherein said flesh resists pressure of at least 5.0 lbf. 5. The watermelon plant, or part thereof, of claim 4 wherein said flesh resists pressure of at least 6.0 lbf. 6. The watermelon plant, or part thereof, of claim 5 wherein said flesh resists pressure of at least 8.0 lbf. 7. The watermelon plant, or part thereof, of claim 1, wherein said soluble solids is at least 8 brix, at least 10 brix, or at least 11.5 brix. 8. (canceled) 9. The watermelon plant of claim 1, wherein the plant produces a fruit weighing at least about 1.5 kilograms (kg), at least 3.0 kg, at least 4.5 kg, or at least 6.0 kg. 10. The watermelon plant of claim 9, wherein the plant produces a fruit weighing between 3.0 kg and 6.0 kg. 11. (canceled) 12. (canceled) 13. The watermelon plant, or part thereof, of claim 1, wherein said fruit has red flesh, yellow flesh, or orange flesh. 14. (canceled) 15. (canceled) 16. The watermelon plant, or part thereof, of claim 1, wherein said plant is diploid. 17. The watermelon plant, or part thereof, of claim 1, wherein said plant is tetraploid or triploid. 18. (canceled) 19. (canceled) 20. The watermelon plant, or part thereof, of claim 1, wherein said part is a seed, a pollen or an ovule. 21. (canceled) 22. (canceled) 23. (canceled) 24. (canceled) 25. (canceled) 26. (canceled) 27. A method for producing a watermelon plant that produces a mature fruit having flesh that resists pressure of at least 3.5 pounds force (lbf) and soluble solids of at least 6 brix comprising:
a. crossing a first watermelon variety having soluble solids of not less than 8 brix with a second watermelon variety comprises mature fruit flesh that resists pressure of at least 3.5 pounds force (lbf); b. performing at least one backcross with said first watermelon variety or said second watermelon variety, and c. performing one or more cycles of self-pollination of products of the backcross of step (b) or one or more recurrent backcrosses with said first watermelon variety or said second watermelon variety, wherein the progeny of said crosses, backcrosses, or self-pollination are selected for soluble solids of not less than 8 brix, flesh that resists pressure of at least 3.5 lbf, or both. 28. The method of claim 27 wherein said second watermelon variety having mature fruit flesh that resists pressure of at least 3.5 pounds force (lbf) is from USDA Collection No. PI296341 or watermelon line 3347, wherein a representative sample of seed of said line 3347 has been deposited with the NCIMB under NCIMB Accession No. 41230. 29-49. (canceled) 50. The method of claim 27, wherein said second watermelon variety comprises flesh that resists pressure of at least 4.0 lbf, at least 5.0 lbf, at least 6.0 lbf, or at least 7.0 lbf. 51. The method of claim 50, wherein said progeny are selected for flesh that resists pressure of at least 4.0 lbf, at least 5.0 lbf, at least 6.0 lbf, at least 7.0 lbf, or at least 8.0 lbf, 52. The method of claim 27, wherein said first watermelon variety has soluble solids of at least 10 brix. 53. The method of claim 27, wherein said performing step c comprises self-pollination. 54. The method of claim 27, wherein said performing step c comprises recurrent backcrosses with said first watermelon variety. 55. The method of claim 27, wherein said performing step c comprises recurrent backcrosses with said first watermelon variety. 56. The method of claim 27, wherein said first watermelon variety is a commercial line. | A watermelon plant that produces fruit having (i) ultra-firm flesh and/or liquid-retaining flesh and (ii) soluble solids of at least about 6 brix.1. A watermelon plant, or a part thereof, that produces a mature fruit having flesh that resists pressure of at least 3.5 pounds force (lbf) and has soluble solids of at least 6 brix. 2. (canceled) 3. The watermelon plant, or part thereof, of claim 1 wherein said flesh resists pressure of at least 4.0 lbf. 4. The watermelon plant, or part thereof, of claim 3 wherein said flesh resists pressure of at least 5.0 lbf. 5. The watermelon plant, or part thereof, of claim 4 wherein said flesh resists pressure of at least 6.0 lbf. 6. The watermelon plant, or part thereof, of claim 5 wherein said flesh resists pressure of at least 8.0 lbf. 7. The watermelon plant, or part thereof, of claim 1, wherein said soluble solids is at least 8 brix, at least 10 brix, or at least 11.5 brix. 8. (canceled) 9. The watermelon plant of claim 1, wherein the plant produces a fruit weighing at least about 1.5 kilograms (kg), at least 3.0 kg, at least 4.5 kg, or at least 6.0 kg. 10. The watermelon plant of claim 9, wherein the plant produces a fruit weighing between 3.0 kg and 6.0 kg. 11. (canceled) 12. (canceled) 13. The watermelon plant, or part thereof, of claim 1, wherein said fruit has red flesh, yellow flesh, or orange flesh. 14. (canceled) 15. (canceled) 16. The watermelon plant, or part thereof, of claim 1, wherein said plant is diploid. 17. The watermelon plant, or part thereof, of claim 1, wherein said plant is tetraploid or triploid. 18. (canceled) 19. (canceled) 20. The watermelon plant, or part thereof, of claim 1, wherein said part is a seed, a pollen or an ovule. 21. (canceled) 22. (canceled) 23. (canceled) 24. (canceled) 25. (canceled) 26. (canceled) 27. A method for producing a watermelon plant that produces a mature fruit having flesh that resists pressure of at least 3.5 pounds force (lbf) and soluble solids of at least 6 brix comprising:
a. crossing a first watermelon variety having soluble solids of not less than 8 brix with a second watermelon variety comprises mature fruit flesh that resists pressure of at least 3.5 pounds force (lbf); b. performing at least one backcross with said first watermelon variety or said second watermelon variety, and c. performing one or more cycles of self-pollination of products of the backcross of step (b) or one or more recurrent backcrosses with said first watermelon variety or said second watermelon variety, wherein the progeny of said crosses, backcrosses, or self-pollination are selected for soluble solids of not less than 8 brix, flesh that resists pressure of at least 3.5 lbf, or both. 28. The method of claim 27 wherein said second watermelon variety having mature fruit flesh that resists pressure of at least 3.5 pounds force (lbf) is from USDA Collection No. PI296341 or watermelon line 3347, wherein a representative sample of seed of said line 3347 has been deposited with the NCIMB under NCIMB Accession No. 41230. 29-49. (canceled) 50. The method of claim 27, wherein said second watermelon variety comprises flesh that resists pressure of at least 4.0 lbf, at least 5.0 lbf, at least 6.0 lbf, or at least 7.0 lbf. 51. The method of claim 50, wherein said progeny are selected for flesh that resists pressure of at least 4.0 lbf, at least 5.0 lbf, at least 6.0 lbf, at least 7.0 lbf, or at least 8.0 lbf, 52. The method of claim 27, wherein said first watermelon variety has soluble solids of at least 10 brix. 53. The method of claim 27, wherein said performing step c comprises self-pollination. 54. The method of claim 27, wherein said performing step c comprises recurrent backcrosses with said first watermelon variety. 55. The method of claim 27, wherein said performing step c comprises recurrent backcrosses with said first watermelon variety. 56. The method of claim 27, wherein said first watermelon variety is a commercial line. | 1,600 |
729 | 15,558,700 | 1,653 | What is disclosed is a method of reducing undesirable concentrations of microorganisms without the use of man-made antibiotics, comprising the steps of: introducing a quantity of fermentable carbohydrate; sugar or cellulose to an aqueous system; introducing a quantity of desirable microorganism to the aqueous system; introducing at least one acid into the aqueous system, wherein the at least one acid is selected from the group consisting of hops acid, organic acid, or a combination of hops acid and organic acid; and introducing a compound comprised of Lauryl-L-arginine ethyl ester monohydrochloride (LAE) into the aqueous system. The use of LAE as a preservative of distiller's grains and solubles is also disclosed. | 1. A method of controlling undesirable microorganism concentration in an aqueous fluid solution employed in a fermentation process, the method comprising the steps of:
introducing a fermentable carbohydrate to the aqueous fluid solution; introducing at least one desirable microorganism that is capable of fermenting carbohydrate to the aqueous fluid solution; and introducing at least one LAE compound into the aqueous fluid solution. 2. The method of claim 1, further comprising the step of introducing at least one acid into the aqueous fluid solution,
wherein the at least one acid is selected from the group consisting of hops acid, organic acid, or a combination of hops acid and organic acid. 3. The method of claim 1, wherein the LAE compound is selected from the group consisting of LAEPro™, LAEPro™ S50, MIRENAT®-P/100, and MIRENAT®-GA. 4. The method of claim 1, wherein said at least one desirable microorganism is selected from the group consisting of a yeast, a fungi, a bacteria, and combination thereof. 5. The method of claim 1, wherein the steps are performed sequentially in the order provided in claim 1. 6. The method of claim 2, wherein the concentration of the at least one acid in said aqueous fluid solution is in the range of 1 ppm to 100 ppm. 7. The method of claim 2, wherein the concentration of the at least one acid in the aqueous fluid solution is in the range of 2 ppm to 70 ppm. 8. The method of claim 2, wherein the dosage of the at least one acid is at least 0.5 ppm. 9. The method of any of claims 1 through 8, wherein the LAE compound has a dosage of at least 0.5 ppm and less than or equal to 75 ppm. 10. The method of claim 9, wherein the LAE compound is LAEPro™, LAEPro™ S50, MIRENAT®-P/100, or MIRENAT®-GA, and the ratio of the at least one acid to LAE compound is from 1:10 to 1:6500. 11. A method of reducing residual byproduct of antibiotic in a fermentation process, the method comprising the steps of:
introducing a fermentable carbohydrate to an aqueous system; introducing at least one desirable microorganism to said aqueous system; and introducing at least one LAE compound into said aqueous system. 12. The method of claim 11, further comprising the step of introducing at least one acid into the aqueous fluid solution,
wherein the at least one acid is selected from the group consisting of hops acid, organic acid, or a combination of hops acid and organic acid. 13. The method of claim 11, wherein the LAE compound is selected from the group consisting of LAEPro™, LAEPro™ S50, MIRENAT®-P/100, and MIRENAT®-GA. 14. The method of claim 11, wherein said at least one desirable microorganism is selected from the group consisting of a yeast, a fungi, a bacteria, and combination thereof. 15. The method of claim 11, wherein the steps are performed sequentially in the order provided in claim 11. 16. The method of claim 12, wherein the concentration of the at least one acid in said aqueous fluid solution is in the range of 1 ppm to 100 ppm. 17. The method of claim 12, wherein the concentration of the at least one acid in the aqueous fluid solution is in the range of 2 ppm to 70 ppm. 18. The method of claim 12, wherein the dosage of the at least one acid is at least 0.5 ppm. 19. The method of any of claims 11 through 18, wherein the LAE compound has a dosage of at least 0.5 ppm and less than or equal to 35 ppm. 20. The method of claim 19, wherein the LAE compound is LAEPro™, LAEPro™ S50, MIRENAT®-P/100, or MIRENAT®-GA, and the ratio of the at least one acid to LAE compound is from 1:10 to 1:6500. 21. A system for controlling undesirable microorganism concentration in an aqueous fluid solution employed in a fermentation process, comprising:
a means for introducing a fermentable carbohydrate to the aqueous fluid solution; a means for introducing at least one desirable microorganism that is capable of fermenting carbohydrate to the aqueous fluid solution; and a means for introducing at least one LAE compound into the aqueous fluid solution. 22. The system of claim 21, further comprising a means for introducing at least one acid into the aqueous fluid solution,
wherein the at least one acid is selected from the group consisting of hops acid, organic acid, or a combination of hops acid and organic acid. 23. The system of claim 21, wherein the LAE compound is selected from the group consisting of LAEPro™, LAEPro™ S50, MIRENAT®-P/100, and MIRENAT®-GA. 24. The system of claim 21, wherein said at least one desirable microorganism is selected from the group consisting of a yeast, a fungi, a bacteria, and combination thereof. 25. The system of claim 22, wherein the concentration of the at least one acid in said aqueous fluid solution is in the range of 1 ppm to 100 ppm. 26. The system of claim 22, wherein the concentration of the at least one acid in the aqueous fluid solution is in the range of 2 ppm to 70 ppm. 27. The system of claim 22, wherein the dosage of the at least one acid is at least 0.5 ppm. 28. The system of any of claims 21 through 27, wherein the LAE compound has a dosage of at least 0.5 ppm and less than or equal to 35 ppm. 29. The system of claim 28, wherein the LAE compound is LAEPro™, LAEPro™ S50, MIRENAT®-P/100, or MIRENAT®-GA, and the ratio of the at least one acid to LAE compound is from 1:10 to 1:6500. 30. A composition for preserving distiller's grains, associated grain products, and/or other plant biomass, said distiller's grains, associated grain products, and/or other plant biomass having a total moisture content of >10% and water activity greater than 0.10 and less than 0.90, with initial levels of microbes and/or molds that cause spoilage of the grain product, comprising:
10% to 99.9% by weight of LAE, wherein said composition is applied to said distiller's grains, associated grain products, and/or other plant biomass at a concentration of 0.05% to 30.0% by weight in order to maintain or reduce the level of microbes in the grain product at or below the initial levels for a period of not less than seven days. 31. The composition of claim 30, further comprising one or more organic acids selected from the group consisting of propionic acid, sorbic acid, citric acid, ascorbic acid, benzoic acid, and phosphoric acid. 32. The composition of claim 31, wherein the concentration of said one or more organic acids is of 5% to 70% by weight. 33. The composition of any of claims 30 through 32, wherein the LAE compound is selected from the group consisting of LAEPro™, LAEPro™ S50, MIRENAT®-P/100, and MIRENAT®-GA. 34. A method of using a composition for preserving distiller's grains, associated grain products, and/or other plant biomass, said distiller's grains, associated grain products, and/or other plant biomass having a water activity greater than 0.10 and less than 0.90, with initial levels of microbes that cause spoilage of the grain product, comprising the steps of:
obtaining a composition for preserving distiller's grains and/or associated grain products, said distiller's grains and associated grain products having a water activity greater than 0.10 and less than 0.90, with initial levels of microbes that cause spoilage of the grain product, according to any of claims 30 through 33; and adding an effective amount of said preservative composition to a distiller's grain, an associated grain products, and/or other plant biomass. 35. The method of claim 34, wherein said distiller's grain, associated grain product, and/or other plant biomass to be preserved is selected from the group consisting of wet-corn gluten feed, wet distiller's grains with or without solubles, distiller's dried grains, fuzzy cottonseed, wet and dry brewer's grains, cottonseed meal, corn hominy feed, almond hulls, wet and dry sugar beet pulp, canola meal, citrus pulp, rice bran, safflower meal, soybean hulls, food processing waste, wheat-mill run, switch grass, corn stover, and forestry plants. 36. The method of claim 34, wherein said distiller's grain, associated grain product, and/or other plant biomass to be preserved is a cannabis-related biomass in jurisdictions where such operations are legally allowed. 37. The method of claim 34, wherein said effective amount of said preservative composition is in the range of 0.05 ppm to 50.0 ppm of LAE-based preservative. 38. The method of claim 35, wherein said effective amount of said preservative composition is in the range of 0.05 ppm to 50.0 ppm of LAE-based preservative. 39. The method of claim 36, wherein said effective amount of said preservative composition is in the range of 0.05 ppm to 50.0 ppm of LAE-based preservative. 40. The method of claim 34, wherein said effective amount of said preservative composition is applied at a rate of greater than or equal to 2 lbs. and less than or equal to 50 lbs. per ton of distiller's grains, associated grain products, and/or other plant biomass. 41. The method of claim 40, wherein said preservative composition incorporates organic acid(s) included at a rate of between greater than or equal to 0.0005% and less than or equal to 0.70% by weight. 42. The method of claim 35, wherein said effective amount of said preservative composition is applied at a rate of greater than or equal to 2 lbs. and less than or equal to 50 lbs. per ton of distiller's grains, associated grain products, and/or other plant biomass. 43. The method of claim 42, wherein said preservative composition incorporates organic acid(s) included at a rate of between greater than or equal to 0.0005% and less than or equal to 0.70% by weight. 44. The method of claim 36, wherein said effective amount of said preservative composition is applied at a rate of greater than or equal to 2 lbs. and less than or equal to 50 lbs. per ton of distiller's grains, associated grain products, and/or other plant biomass. 45. The method of claim 44, wherein said preservative composition incorporates organic acid(s) included at a rate of between greater than or equal to 0.0005% and less than or equal to 0.70% by weight. 46. An ethanol product-by-process that is substantially free of added man-made antibiotics and is substantially free of undesirable microorganisms, said ethanol product produced by a fermentation process comprising the steps of:
introducing a fermentable carbohydrate to the aqueous fluid solution; introducing at least one desirable microorganism to the aqueous fluid solution; and introducing at least one LAE compound into the aqueous fluid solution. 47. The product-by-process of claim 46, wherein said at least one desirable microorganism is selected from the group consisting of a yeast, a fungi, a bacteria, and combination thereof. 48. The product-by-process of claim 46, wherein the process used to produce said product further comprises the step of introducing at least one acid into the aqueous fluid solution,
wherein the at least one acid is selected from the group consisting of hops acid, organic acid, or a combination of hops acid and organic acid. 49. The product-by-process of claim 46, wherein said at least one LAE compound is selected from the group consisting of LAEPro™, LAEPro™ S50, MIRENAT®-P/100, and MIRENAT®-GA. 50. The product-by-process of claim 48, wherein the concentration of the at least one acid in said aqueous fluid solution is in the range of 1 ppm to 100 ppm. 51. The product-by-process of claim 48, wherein the concentration of the at least one acid in the aqueous fluid solution is in the range of 2 ppm to 70 ppm. 52. The product-by-process of claim 48, wherein the dosage of the at least one acid is at least 0.5 ppm. 53. The product-by-process of any of claims 46 through 52, wherein the LAE compound has a dosage of at least 0.5 ppm and less than or equal to 75 ppm. 54. The product-by-process of any of claims 46 through 52, wherein the process used to produce said product further comprises the steps of:
separating ethanol from whole stillage byproducts; and
storing said separated ethanol. 55. The product-by-process of claim 54, wherein the process used to produce said product further comprises the step of separating said whole-stillage byproducts into solid particulates and thin stillage. 56. The product-by-process of claim 55, wherein the process used to produce said product further comprises the steps of:
subjecting said thin stillage to evaporation processes to release condensed vapors; and transferring said evaporation-processed thin-stillage byproduct to storage. 57. The product-by-process of claim 55, wherein the process used to produce said product further comprises the step of transferring said separated solid particulates to said storage,
whereby said storage contains distiller's grains and solubles that are substantially man-made antibiotic-free. 58. The product-by-process of claim 57, wherein the process used to produce said product further comprises the steps of:
subjecting separated solid particulates to a drying process to create distiller's grains and solubles; and transferring said distiller's dried grains and solubles to storage; whereby said storage contains distiller's grains and solubles that are substantially man-made antibiotic-free. 59. The product-by-process of claim 56, wherein the process used to produce said product further comprises the step of:
adding an effective amount of a preservative composition to said stored whole stillage byproducts, said preservative composition comprising:
10% to 99.9% by weight of LAE,
wherein said composition is applied to said distiller's grains, associated grain products, and/or other plant biomass at a concentration of 0.05% to 30.0% by weight in order to maintain or reduce the level of microbes in the grain product at or below the initial levels for a period of not less than seven days. 60. The product-by-process of claim 59, further comprising one or more organic acids selected from the group consisting of propionic acid, sorbic acid, citric acid, ascorbic acid, benzoic acid, and phosphoric acid. 61. The product-by-process of claim 60, wherein the concentration of said one or more organic acids is of 5% to 70% by weight. 62. The product-by-process of any of claims 59 through 61, wherein the LAE compound is selected from the group consisting of LAEPro™, LAEPro™ S50, MIRENAT®-P/100, and MIRENAT®-GA. 63. The product-by-process of claim 57, wherein the process used to produce said product further comprises the step of:
adding an effective amount of a preservative composition to said stored whole stillage byproducts, said preservative composition comprising:
10% to 99.9% by weight of LAE,
wherein said composition is applied to said distiller's grains, associated grain products, and/or other plant biomass at a concentration of 0.05% to 30.0% by weight in order to maintain or reduce the level of microbes in the grain product at or below the initial levels for a period of not less than seven days. 64. The product-by-process of claim 63, further comprising one or more organic acids selected from the group consisting of propionic acid, sorbic acid, citric acid, ascorbic acid, benzoic acid, and phosphoric acid. 65. The product-by-process of claim 64, wherein the concentration of said one or more organic acids is of 5% to 70% by weight. 66. The product-by-process of any of claims 63 through 65, wherein the LAE compound is selected from the group consisting of LAEPro™, LAEPro™ S50, MIRENAT®-P/100, and MIRENAT®-GA. 67. The product-by-process of claim 58, wherein the process used to produce said product further comprises the step of:
adding an effective amount of a preservative composition to said stored whole stillage byproducts, said preservative composition comprising:
10% to 99.9% by weight of LAE,
wherein said composition is applied to said distiller's grains, associated grain products, and/or other plant biomass at a concentration of 0.05% to 30.0% by weight in order to maintain or reduce the level of microbes in the grain product at or below the initial levels for a period of not less than seven days. 68. The product-by-process of claim 67, further comprising one or more organic acids selected from the group consisting of propionic acid, sorbic acid, citric acid, ascorbic acid, benzoic acid, and phosphoric acid. 69. The product-by-process of claim 68, wherein the concentration of said one or more organic acids is of 5% to 70% by weight. 70. The product-by-process of any of claims 67 through 69, wherein the LAE compound is selected from the group consisting of LAEPro™, LAEPro™ S50, MIRENAT®-P/100, and MIRENAT®-GA. | What is disclosed is a method of reducing undesirable concentrations of microorganisms without the use of man-made antibiotics, comprising the steps of: introducing a quantity of fermentable carbohydrate; sugar or cellulose to an aqueous system; introducing a quantity of desirable microorganism to the aqueous system; introducing at least one acid into the aqueous system, wherein the at least one acid is selected from the group consisting of hops acid, organic acid, or a combination of hops acid and organic acid; and introducing a compound comprised of Lauryl-L-arginine ethyl ester monohydrochloride (LAE) into the aqueous system. The use of LAE as a preservative of distiller's grains and solubles is also disclosed.1. A method of controlling undesirable microorganism concentration in an aqueous fluid solution employed in a fermentation process, the method comprising the steps of:
introducing a fermentable carbohydrate to the aqueous fluid solution; introducing at least one desirable microorganism that is capable of fermenting carbohydrate to the aqueous fluid solution; and introducing at least one LAE compound into the aqueous fluid solution. 2. The method of claim 1, further comprising the step of introducing at least one acid into the aqueous fluid solution,
wherein the at least one acid is selected from the group consisting of hops acid, organic acid, or a combination of hops acid and organic acid. 3. The method of claim 1, wherein the LAE compound is selected from the group consisting of LAEPro™, LAEPro™ S50, MIRENAT®-P/100, and MIRENAT®-GA. 4. The method of claim 1, wherein said at least one desirable microorganism is selected from the group consisting of a yeast, a fungi, a bacteria, and combination thereof. 5. The method of claim 1, wherein the steps are performed sequentially in the order provided in claim 1. 6. The method of claim 2, wherein the concentration of the at least one acid in said aqueous fluid solution is in the range of 1 ppm to 100 ppm. 7. The method of claim 2, wherein the concentration of the at least one acid in the aqueous fluid solution is in the range of 2 ppm to 70 ppm. 8. The method of claim 2, wherein the dosage of the at least one acid is at least 0.5 ppm. 9. The method of any of claims 1 through 8, wherein the LAE compound has a dosage of at least 0.5 ppm and less than or equal to 75 ppm. 10. The method of claim 9, wherein the LAE compound is LAEPro™, LAEPro™ S50, MIRENAT®-P/100, or MIRENAT®-GA, and the ratio of the at least one acid to LAE compound is from 1:10 to 1:6500. 11. A method of reducing residual byproduct of antibiotic in a fermentation process, the method comprising the steps of:
introducing a fermentable carbohydrate to an aqueous system; introducing at least one desirable microorganism to said aqueous system; and introducing at least one LAE compound into said aqueous system. 12. The method of claim 11, further comprising the step of introducing at least one acid into the aqueous fluid solution,
wherein the at least one acid is selected from the group consisting of hops acid, organic acid, or a combination of hops acid and organic acid. 13. The method of claim 11, wherein the LAE compound is selected from the group consisting of LAEPro™, LAEPro™ S50, MIRENAT®-P/100, and MIRENAT®-GA. 14. The method of claim 11, wherein said at least one desirable microorganism is selected from the group consisting of a yeast, a fungi, a bacteria, and combination thereof. 15. The method of claim 11, wherein the steps are performed sequentially in the order provided in claim 11. 16. The method of claim 12, wherein the concentration of the at least one acid in said aqueous fluid solution is in the range of 1 ppm to 100 ppm. 17. The method of claim 12, wherein the concentration of the at least one acid in the aqueous fluid solution is in the range of 2 ppm to 70 ppm. 18. The method of claim 12, wherein the dosage of the at least one acid is at least 0.5 ppm. 19. The method of any of claims 11 through 18, wherein the LAE compound has a dosage of at least 0.5 ppm and less than or equal to 35 ppm. 20. The method of claim 19, wherein the LAE compound is LAEPro™, LAEPro™ S50, MIRENAT®-P/100, or MIRENAT®-GA, and the ratio of the at least one acid to LAE compound is from 1:10 to 1:6500. 21. A system for controlling undesirable microorganism concentration in an aqueous fluid solution employed in a fermentation process, comprising:
a means for introducing a fermentable carbohydrate to the aqueous fluid solution; a means for introducing at least one desirable microorganism that is capable of fermenting carbohydrate to the aqueous fluid solution; and a means for introducing at least one LAE compound into the aqueous fluid solution. 22. The system of claim 21, further comprising a means for introducing at least one acid into the aqueous fluid solution,
wherein the at least one acid is selected from the group consisting of hops acid, organic acid, or a combination of hops acid and organic acid. 23. The system of claim 21, wherein the LAE compound is selected from the group consisting of LAEPro™, LAEPro™ S50, MIRENAT®-P/100, and MIRENAT®-GA. 24. The system of claim 21, wherein said at least one desirable microorganism is selected from the group consisting of a yeast, a fungi, a bacteria, and combination thereof. 25. The system of claim 22, wherein the concentration of the at least one acid in said aqueous fluid solution is in the range of 1 ppm to 100 ppm. 26. The system of claim 22, wherein the concentration of the at least one acid in the aqueous fluid solution is in the range of 2 ppm to 70 ppm. 27. The system of claim 22, wherein the dosage of the at least one acid is at least 0.5 ppm. 28. The system of any of claims 21 through 27, wherein the LAE compound has a dosage of at least 0.5 ppm and less than or equal to 35 ppm. 29. The system of claim 28, wherein the LAE compound is LAEPro™, LAEPro™ S50, MIRENAT®-P/100, or MIRENAT®-GA, and the ratio of the at least one acid to LAE compound is from 1:10 to 1:6500. 30. A composition for preserving distiller's grains, associated grain products, and/or other plant biomass, said distiller's grains, associated grain products, and/or other plant biomass having a total moisture content of >10% and water activity greater than 0.10 and less than 0.90, with initial levels of microbes and/or molds that cause spoilage of the grain product, comprising:
10% to 99.9% by weight of LAE, wherein said composition is applied to said distiller's grains, associated grain products, and/or other plant biomass at a concentration of 0.05% to 30.0% by weight in order to maintain or reduce the level of microbes in the grain product at or below the initial levels for a period of not less than seven days. 31. The composition of claim 30, further comprising one or more organic acids selected from the group consisting of propionic acid, sorbic acid, citric acid, ascorbic acid, benzoic acid, and phosphoric acid. 32. The composition of claim 31, wherein the concentration of said one or more organic acids is of 5% to 70% by weight. 33. The composition of any of claims 30 through 32, wherein the LAE compound is selected from the group consisting of LAEPro™, LAEPro™ S50, MIRENAT®-P/100, and MIRENAT®-GA. 34. A method of using a composition for preserving distiller's grains, associated grain products, and/or other plant biomass, said distiller's grains, associated grain products, and/or other plant biomass having a water activity greater than 0.10 and less than 0.90, with initial levels of microbes that cause spoilage of the grain product, comprising the steps of:
obtaining a composition for preserving distiller's grains and/or associated grain products, said distiller's grains and associated grain products having a water activity greater than 0.10 and less than 0.90, with initial levels of microbes that cause spoilage of the grain product, according to any of claims 30 through 33; and adding an effective amount of said preservative composition to a distiller's grain, an associated grain products, and/or other plant biomass. 35. The method of claim 34, wherein said distiller's grain, associated grain product, and/or other plant biomass to be preserved is selected from the group consisting of wet-corn gluten feed, wet distiller's grains with or without solubles, distiller's dried grains, fuzzy cottonseed, wet and dry brewer's grains, cottonseed meal, corn hominy feed, almond hulls, wet and dry sugar beet pulp, canola meal, citrus pulp, rice bran, safflower meal, soybean hulls, food processing waste, wheat-mill run, switch grass, corn stover, and forestry plants. 36. The method of claim 34, wherein said distiller's grain, associated grain product, and/or other plant biomass to be preserved is a cannabis-related biomass in jurisdictions where such operations are legally allowed. 37. The method of claim 34, wherein said effective amount of said preservative composition is in the range of 0.05 ppm to 50.0 ppm of LAE-based preservative. 38. The method of claim 35, wherein said effective amount of said preservative composition is in the range of 0.05 ppm to 50.0 ppm of LAE-based preservative. 39. The method of claim 36, wherein said effective amount of said preservative composition is in the range of 0.05 ppm to 50.0 ppm of LAE-based preservative. 40. The method of claim 34, wherein said effective amount of said preservative composition is applied at a rate of greater than or equal to 2 lbs. and less than or equal to 50 lbs. per ton of distiller's grains, associated grain products, and/or other plant biomass. 41. The method of claim 40, wherein said preservative composition incorporates organic acid(s) included at a rate of between greater than or equal to 0.0005% and less than or equal to 0.70% by weight. 42. The method of claim 35, wherein said effective amount of said preservative composition is applied at a rate of greater than or equal to 2 lbs. and less than or equal to 50 lbs. per ton of distiller's grains, associated grain products, and/or other plant biomass. 43. The method of claim 42, wherein said preservative composition incorporates organic acid(s) included at a rate of between greater than or equal to 0.0005% and less than or equal to 0.70% by weight. 44. The method of claim 36, wherein said effective amount of said preservative composition is applied at a rate of greater than or equal to 2 lbs. and less than or equal to 50 lbs. per ton of distiller's grains, associated grain products, and/or other plant biomass. 45. The method of claim 44, wherein said preservative composition incorporates organic acid(s) included at a rate of between greater than or equal to 0.0005% and less than or equal to 0.70% by weight. 46. An ethanol product-by-process that is substantially free of added man-made antibiotics and is substantially free of undesirable microorganisms, said ethanol product produced by a fermentation process comprising the steps of:
introducing a fermentable carbohydrate to the aqueous fluid solution; introducing at least one desirable microorganism to the aqueous fluid solution; and introducing at least one LAE compound into the aqueous fluid solution. 47. The product-by-process of claim 46, wherein said at least one desirable microorganism is selected from the group consisting of a yeast, a fungi, a bacteria, and combination thereof. 48. The product-by-process of claim 46, wherein the process used to produce said product further comprises the step of introducing at least one acid into the aqueous fluid solution,
wherein the at least one acid is selected from the group consisting of hops acid, organic acid, or a combination of hops acid and organic acid. 49. The product-by-process of claim 46, wherein said at least one LAE compound is selected from the group consisting of LAEPro™, LAEPro™ S50, MIRENAT®-P/100, and MIRENAT®-GA. 50. The product-by-process of claim 48, wherein the concentration of the at least one acid in said aqueous fluid solution is in the range of 1 ppm to 100 ppm. 51. The product-by-process of claim 48, wherein the concentration of the at least one acid in the aqueous fluid solution is in the range of 2 ppm to 70 ppm. 52. The product-by-process of claim 48, wherein the dosage of the at least one acid is at least 0.5 ppm. 53. The product-by-process of any of claims 46 through 52, wherein the LAE compound has a dosage of at least 0.5 ppm and less than or equal to 75 ppm. 54. The product-by-process of any of claims 46 through 52, wherein the process used to produce said product further comprises the steps of:
separating ethanol from whole stillage byproducts; and
storing said separated ethanol. 55. The product-by-process of claim 54, wherein the process used to produce said product further comprises the step of separating said whole-stillage byproducts into solid particulates and thin stillage. 56. The product-by-process of claim 55, wherein the process used to produce said product further comprises the steps of:
subjecting said thin stillage to evaporation processes to release condensed vapors; and transferring said evaporation-processed thin-stillage byproduct to storage. 57. The product-by-process of claim 55, wherein the process used to produce said product further comprises the step of transferring said separated solid particulates to said storage,
whereby said storage contains distiller's grains and solubles that are substantially man-made antibiotic-free. 58. The product-by-process of claim 57, wherein the process used to produce said product further comprises the steps of:
subjecting separated solid particulates to a drying process to create distiller's grains and solubles; and transferring said distiller's dried grains and solubles to storage; whereby said storage contains distiller's grains and solubles that are substantially man-made antibiotic-free. 59. The product-by-process of claim 56, wherein the process used to produce said product further comprises the step of:
adding an effective amount of a preservative composition to said stored whole stillage byproducts, said preservative composition comprising:
10% to 99.9% by weight of LAE,
wherein said composition is applied to said distiller's grains, associated grain products, and/or other plant biomass at a concentration of 0.05% to 30.0% by weight in order to maintain or reduce the level of microbes in the grain product at or below the initial levels for a period of not less than seven days. 60. The product-by-process of claim 59, further comprising one or more organic acids selected from the group consisting of propionic acid, sorbic acid, citric acid, ascorbic acid, benzoic acid, and phosphoric acid. 61. The product-by-process of claim 60, wherein the concentration of said one or more organic acids is of 5% to 70% by weight. 62. The product-by-process of any of claims 59 through 61, wherein the LAE compound is selected from the group consisting of LAEPro™, LAEPro™ S50, MIRENAT®-P/100, and MIRENAT®-GA. 63. The product-by-process of claim 57, wherein the process used to produce said product further comprises the step of:
adding an effective amount of a preservative composition to said stored whole stillage byproducts, said preservative composition comprising:
10% to 99.9% by weight of LAE,
wherein said composition is applied to said distiller's grains, associated grain products, and/or other plant biomass at a concentration of 0.05% to 30.0% by weight in order to maintain or reduce the level of microbes in the grain product at or below the initial levels for a period of not less than seven days. 64. The product-by-process of claim 63, further comprising one or more organic acids selected from the group consisting of propionic acid, sorbic acid, citric acid, ascorbic acid, benzoic acid, and phosphoric acid. 65. The product-by-process of claim 64, wherein the concentration of said one or more organic acids is of 5% to 70% by weight. 66. The product-by-process of any of claims 63 through 65, wherein the LAE compound is selected from the group consisting of LAEPro™, LAEPro™ S50, MIRENAT®-P/100, and MIRENAT®-GA. 67. The product-by-process of claim 58, wherein the process used to produce said product further comprises the step of:
adding an effective amount of a preservative composition to said stored whole stillage byproducts, said preservative composition comprising:
10% to 99.9% by weight of LAE,
wherein said composition is applied to said distiller's grains, associated grain products, and/or other plant biomass at a concentration of 0.05% to 30.0% by weight in order to maintain or reduce the level of microbes in the grain product at or below the initial levels for a period of not less than seven days. 68. The product-by-process of claim 67, further comprising one or more organic acids selected from the group consisting of propionic acid, sorbic acid, citric acid, ascorbic acid, benzoic acid, and phosphoric acid. 69. The product-by-process of claim 68, wherein the concentration of said one or more organic acids is of 5% to 70% by weight. 70. The product-by-process of any of claims 67 through 69, wherein the LAE compound is selected from the group consisting of LAEPro™, LAEPro™ S50, MIRENAT®-P/100, and MIRENAT®-GA. | 1,600 |
730 | 15,518,080 | 1,699 | The present invention relates to a catalytic process for the ethynylation of specific poly-unsaturated aldehydes and ketones. | 1. A catalytic ethynylation of a compound of formula (I)
wherein
R1 signifies —H, —CH3 or —CH2CH3, and
R2 signifies —H, —CH3 or —CH2CH3, and
R3 signifies a moiety
with ethyne
in the presence of a catalyst of formula ROH, wherein
R signifies K or Cs, and
wherein NH3 is used as solvent. 2. Catalytic ethynylation according to claim 1, wherein
R1 signifies —H or —CH3, and R2 signifies —H or —CH3, preferably —H. 3. Catalytic ethynylation according to claim 1, wherein the compound of formula (I) is the compound of formula (Ia) 4. Catalytic ethynylation according to claim 1, wherein the compound of formula (I) compound of formula (Ib) 5. Catalytic ethynylation according to claim 1, wherein the compound of formula (I) compound of formula (Ic) 6. Catalytic ethynylation according to claim 1, wherein the catalyst is added to the reaction mixture as an aqueous solution. 7. Catalytic ethynylation according to claim 1, wherein R is K. 8. Catalytic ethynylation according to claim 1, wherein the catalytic ethynylation is carried out under pressure and wherein the pressure is in the range from 2 bar to 15 bar (preferably from 5 bar to 12 bar, more preferably from 6 bar to 10 bar). 9. Catalytic ethynylation according to claim 1, wherein the catalytic ethynylation is carried at a reaction temperature of between −40° C.-10° C. (preferably −30°-5° C.). | The present invention relates to a catalytic process for the ethynylation of specific poly-unsaturated aldehydes and ketones.1. A catalytic ethynylation of a compound of formula (I)
wherein
R1 signifies —H, —CH3 or —CH2CH3, and
R2 signifies —H, —CH3 or —CH2CH3, and
R3 signifies a moiety
with ethyne
in the presence of a catalyst of formula ROH, wherein
R signifies K or Cs, and
wherein NH3 is used as solvent. 2. Catalytic ethynylation according to claim 1, wherein
R1 signifies —H or —CH3, and R2 signifies —H or —CH3, preferably —H. 3. Catalytic ethynylation according to claim 1, wherein the compound of formula (I) is the compound of formula (Ia) 4. Catalytic ethynylation according to claim 1, wherein the compound of formula (I) compound of formula (Ib) 5. Catalytic ethynylation according to claim 1, wherein the compound of formula (I) compound of formula (Ic) 6. Catalytic ethynylation according to claim 1, wherein the catalyst is added to the reaction mixture as an aqueous solution. 7. Catalytic ethynylation according to claim 1, wherein R is K. 8. Catalytic ethynylation according to claim 1, wherein the catalytic ethynylation is carried out under pressure and wherein the pressure is in the range from 2 bar to 15 bar (preferably from 5 bar to 12 bar, more preferably from 6 bar to 10 bar). 9. Catalytic ethynylation according to claim 1, wherein the catalytic ethynylation is carried at a reaction temperature of between −40° C.-10° C. (preferably −30°-5° C.). | 1,600 |
731 | 15,509,438 | 1,629 | The invention provides therapeutic methods comprising the administration of thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof. The methods are useful for modulating muscle atrophy, performance, recovery, generation, or maintenance in animals. | 1. A method comprising modulating muscle atrophy, performance, recovery, generation, or maintenance in an animal in need thereof by administering thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof to the animal. 2. The method of claim 1 wherein the animal is a human. 3. The method of claim 1 wherein the animal is a food animal. 4. The method of claim 2 wherein the human is a chronically hospitalized patient. 5. The method of claim 2 wherein the human has been or will be immobilized for a period of several days or more. 6. The method of claim 2 wherein the human has cancer. 7. A method comprising restoring diaphragm endurance or strength to assist in extubation of a mechanically ventilated patient by administering thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof to the patient. 8. A method comprising enhancing muscular recovery in a rehabilitating patient in need thereof by administering thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof to the patient. 9. A method comprising increasing lean body mass, increasing metabolic rate, or promoting fat weight loss in an animal in need thereof by administering thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof to the animal. 10. A method comprising improving the effects of exercise on muscle endurance or muscle mass in an animal in need thereof by administering thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof to the animal. 11. A method comprising promoting weight loss in an animal in need thereof by administering thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof to the animal. 12. The method of claim 11 wherein the thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof is administered as an adjuvant to exercise and diet. 13. The method of claim 1 wherein muscle loss is reversed in the animal. 14. The method of claim 1 wherein muscle gain is enhanced in the animal. 15. A pharmaceutical composition comprising thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof, formulated for administration to modulate muscle atrophy, performance, recovery, generation, or maintenance in an animal. 16. The composition of claim 15 wherein the composition further comprises an agent that modulates muscle atrophy, performance, recovery, generation, or maintenance. 17. A kit comprising:
1) packaging material, 2) thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof, and 3) instructions for administering the thymol, carvacrol, pharmaceutically acceptable salt, or prodrug to an animal to modulate muscle atrophy, performance, recovery, generation, or maintenance. 18. The kit of claim 17 further comprising an agent that modulates muscle atrophy, performance, recovery, generation, or maintenance. 19-30. (canceled) 31. A method for treating a disease or condition in an animal wherein activation of the sarcoplasmic reticulum calcium release channel is indicated comprising administering thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof to the animal. 32. The method of claim 31 wherein the disease or condition is sarcopenia. 33. A method for activating a sarcoplasmic reticulum calcium release channel in an animal in need thereof comprising administering thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof to the animal. | The invention provides therapeutic methods comprising the administration of thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof. The methods are useful for modulating muscle atrophy, performance, recovery, generation, or maintenance in animals.1. A method comprising modulating muscle atrophy, performance, recovery, generation, or maintenance in an animal in need thereof by administering thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof to the animal. 2. The method of claim 1 wherein the animal is a human. 3. The method of claim 1 wherein the animal is a food animal. 4. The method of claim 2 wherein the human is a chronically hospitalized patient. 5. The method of claim 2 wherein the human has been or will be immobilized for a period of several days or more. 6. The method of claim 2 wherein the human has cancer. 7. A method comprising restoring diaphragm endurance or strength to assist in extubation of a mechanically ventilated patient by administering thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof to the patient. 8. A method comprising enhancing muscular recovery in a rehabilitating patient in need thereof by administering thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof to the patient. 9. A method comprising increasing lean body mass, increasing metabolic rate, or promoting fat weight loss in an animal in need thereof by administering thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof to the animal. 10. A method comprising improving the effects of exercise on muscle endurance or muscle mass in an animal in need thereof by administering thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof to the animal. 11. A method comprising promoting weight loss in an animal in need thereof by administering thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof to the animal. 12. The method of claim 11 wherein the thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof is administered as an adjuvant to exercise and diet. 13. The method of claim 1 wherein muscle loss is reversed in the animal. 14. The method of claim 1 wherein muscle gain is enhanced in the animal. 15. A pharmaceutical composition comprising thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof, formulated for administration to modulate muscle atrophy, performance, recovery, generation, or maintenance in an animal. 16. The composition of claim 15 wherein the composition further comprises an agent that modulates muscle atrophy, performance, recovery, generation, or maintenance. 17. A kit comprising:
1) packaging material, 2) thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof, and 3) instructions for administering the thymol, carvacrol, pharmaceutically acceptable salt, or prodrug to an animal to modulate muscle atrophy, performance, recovery, generation, or maintenance. 18. The kit of claim 17 further comprising an agent that modulates muscle atrophy, performance, recovery, generation, or maintenance. 19-30. (canceled) 31. A method for treating a disease or condition in an animal wherein activation of the sarcoplasmic reticulum calcium release channel is indicated comprising administering thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof to the animal. 32. The method of claim 31 wherein the disease or condition is sarcopenia. 33. A method for activating a sarcoplasmic reticulum calcium release channel in an animal in need thereof comprising administering thymol or carvacrol, or a pharmaceutically acceptable salt or prodrug thereof to the animal. | 1,600 |
732 | 14,773,497 | 1,644 | The disclosure relates generally to methods and compositions of treating or preventing diabetes mellitus by administering to a subject a composition comprising an amount of stem and/or progenitor cells and at least one antigen-specific therapy. | 1. A method of treating or preventing diabetes mellitus in a subject, the method comprising: administering to the subject a composition comprising an amount of one or more stem and/or progenitor cells and an amount of at least one antigen-specific therapy. 2. The method of claim 1, wherein the diabetes mellitus is type 1 diabetes. 3. The method of claim 1, wherein the subject is a mammal. 4. The method of claim 3, wherein the mammal is a human. 5. The method of claim 1, wherein the stem and/or progenitor cells are totipotent, pluripotent, multipotent or unipotent. 6. The method of claim 1, wherein the stem and/or progenitor cells are isolated from bone marrow. 7. The method of claim 6, wherein the stem and/or progenitor cells are purified bone marrow endothelial progenitor cells. 8. The method of claim 1, wherein the stem and/or progenitor cells are allogenic cells. 9. The method of claim 1, wherein the stem and/or progenitor cells are autologous cells. 10. The method of claim 1, wherein the at least one antigen-specific therapy is an immunoglobulin-polypeptide chimera. 11. The method of claim 10, wherein the immunoglobulin-polypeptide chimera is soluble. 12. The method of claim 10, wherein the immunoglobulin-polypeptide chimera is aggregated. 13. The method of claim 10, wherein the immunoglobulin-polypeptide chimera comprises an immunoglobulin having a CDR3 region, and wherein a diabetogenic epitope is inserted within the CDR3 region. 14. The method of claim 13, wherein the diabetogenic epitope comprises GAD2 (SEQ ID NO: 1), GAD1 (SEQ ID NO: 2) or INSβ (SEQ ID NO: 3). 15. A composition comprising an amount of one or more stem and/or progenitor cells and an amount of at least one antigen-specific therapy. 16. The composition of claim 15, wherein the stem and/or progenitor cells are totipotent, pluripotent, multipotent or unipotent. 17. The composition of claim 15, wherein the stem and/or progenitor cells are isolated from bone marrow. 18. The composition of claim 15, wherein the stem and/or progenitor cells are purified bone marrow endothelial progenitor cells. 19. The composition of claim 15, wherein the stem and/or progenitor cells are allogenic cells. 20. The composition of claim 15, wherein the stem and/or progenitor cells are autologous cells. 21. The composition of claim 15, wherein the at least one antigen-specific therapy is an immunoglobulin-polypeptide chimera. 22. The composition of claim 21, wherein the immunoglobulin-polypeptide chimera is soluble. 23. The composition of claim 21, wherein the immunoglobulin-polypeptide chimera is aggregated. 24. The composition of claim 21, wherein the immunoglobulin-polypeptide chimera comprises an immunoglobulin having a CDR3 region, and wherein a diabetogenic epitope is inserted within the CDR3 region. 25. The composition of claim 24, wherein the diabetogenic epitope comprises GAD2 (SEQ ID NO: 1), GAD1 (SEQ ID NO: 2) or INSβ (SEQ ID NO: 3). 26. A method of treating or preventing diabetes mellitus in a subject, the method comprising: administering to the subject a composition comprising an amount of purified bone marrow endothelial progenitor cells and the immunoglublin Ig-GAD2. 27. A method of treating or preventing diabetes mellitus in a subject, the method comprising: administering to the subject a composition comprising an amount of one or more stem and/or progenitor cells. 28. The method of claim 27 wherein the progenitor cells comprise an amount of purified bone marrow endothelial progenitor cells. 29. The method of claim 28 wherein the stem and/or progenitor cells are delivered directly to a pancreas of the subject. | The disclosure relates generally to methods and compositions of treating or preventing diabetes mellitus by administering to a subject a composition comprising an amount of stem and/or progenitor cells and at least one antigen-specific therapy.1. A method of treating or preventing diabetes mellitus in a subject, the method comprising: administering to the subject a composition comprising an amount of one or more stem and/or progenitor cells and an amount of at least one antigen-specific therapy. 2. The method of claim 1, wherein the diabetes mellitus is type 1 diabetes. 3. The method of claim 1, wherein the subject is a mammal. 4. The method of claim 3, wherein the mammal is a human. 5. The method of claim 1, wherein the stem and/or progenitor cells are totipotent, pluripotent, multipotent or unipotent. 6. The method of claim 1, wherein the stem and/or progenitor cells are isolated from bone marrow. 7. The method of claim 6, wherein the stem and/or progenitor cells are purified bone marrow endothelial progenitor cells. 8. The method of claim 1, wherein the stem and/or progenitor cells are allogenic cells. 9. The method of claim 1, wherein the stem and/or progenitor cells are autologous cells. 10. The method of claim 1, wherein the at least one antigen-specific therapy is an immunoglobulin-polypeptide chimera. 11. The method of claim 10, wherein the immunoglobulin-polypeptide chimera is soluble. 12. The method of claim 10, wherein the immunoglobulin-polypeptide chimera is aggregated. 13. The method of claim 10, wherein the immunoglobulin-polypeptide chimera comprises an immunoglobulin having a CDR3 region, and wherein a diabetogenic epitope is inserted within the CDR3 region. 14. The method of claim 13, wherein the diabetogenic epitope comprises GAD2 (SEQ ID NO: 1), GAD1 (SEQ ID NO: 2) or INSβ (SEQ ID NO: 3). 15. A composition comprising an amount of one or more stem and/or progenitor cells and an amount of at least one antigen-specific therapy. 16. The composition of claim 15, wherein the stem and/or progenitor cells are totipotent, pluripotent, multipotent or unipotent. 17. The composition of claim 15, wherein the stem and/or progenitor cells are isolated from bone marrow. 18. The composition of claim 15, wherein the stem and/or progenitor cells are purified bone marrow endothelial progenitor cells. 19. The composition of claim 15, wherein the stem and/or progenitor cells are allogenic cells. 20. The composition of claim 15, wherein the stem and/or progenitor cells are autologous cells. 21. The composition of claim 15, wherein the at least one antigen-specific therapy is an immunoglobulin-polypeptide chimera. 22. The composition of claim 21, wherein the immunoglobulin-polypeptide chimera is soluble. 23. The composition of claim 21, wherein the immunoglobulin-polypeptide chimera is aggregated. 24. The composition of claim 21, wherein the immunoglobulin-polypeptide chimera comprises an immunoglobulin having a CDR3 region, and wherein a diabetogenic epitope is inserted within the CDR3 region. 25. The composition of claim 24, wherein the diabetogenic epitope comprises GAD2 (SEQ ID NO: 1), GAD1 (SEQ ID NO: 2) or INSβ (SEQ ID NO: 3). 26. A method of treating or preventing diabetes mellitus in a subject, the method comprising: administering to the subject a composition comprising an amount of purified bone marrow endothelial progenitor cells and the immunoglublin Ig-GAD2. 27. A method of treating or preventing diabetes mellitus in a subject, the method comprising: administering to the subject a composition comprising an amount of one or more stem and/or progenitor cells. 28. The method of claim 27 wherein the progenitor cells comprise an amount of purified bone marrow endothelial progenitor cells. 29. The method of claim 28 wherein the stem and/or progenitor cells are delivered directly to a pancreas of the subject. | 1,600 |
733 | 15,111,328 | 1,642 | The present invention primarily relates to a method for stratification of a patient for assessing the suitability of a therapy. The invention also relates to a method for the prognosis of the outcome of a disease of a patient and a method for the prediction and/or detection of therapy resistance of a patient towards a therapy. Furthermore, the invention relates to a novel kit, and corresponding uses thereof. | 1. A method for stratification of a patient for assessing the suitability of a therapy for the patient suffering from an ER and/or PR positive and HER2 negative cancer, the therapy being directed towards a signaling pathway, comprising the following step:
(i) determining the activation status of an ER and/or PR signaling pathway by applying a Proximity Ligation Assay to detect in a tissue sample of the patient the presence of at least one member of the ER family, said at least one member being part of a transcription factor complex, and at least one protein selected from the group consisting of TAFs, TBP, POLII, TFII, p300, CREB, and CBP, wherein the at least one protein is part of the same transcription factor complex,
wherein the stratification is based on the activation status determined in step (i) and the suitability of the therapy is assessed based on the stratification,
wherein a signaling pathway of step (i) is determined to be active, if the at least one ER family member is located in the nucleus in close proximity to the at least one protein selected from the group consisting of either TAFs, TBP, POLII, TFII, p300, CREB, and CBP. 2. The method of claim 1, wherein the at least one member of the ER family is an ER dimer. 3. The method of claim 1, additionally comprising the following step:
(ii) determining the activation status of a signaling pathway, which is different from the signaling pathway assessed in step (i), by applying an in-situ staining assay to detect in the same or in a different tissue sample of the patient the presence of at least one member of the ER family and at least one protein selected from the group consisting of, c-Fos, c-Jun (AP1), SP1, CREB, GATA-transcription factor, NFkappaB family, c/EBP proteins, FOXO, SMAD transcription factor proteins,
wherein the stratification is further based on the activation status determined in step (ii). 4. The method of claim 1, additionally comprising the following step:
(iii) determining the phosphorylation status of at least one member of the ER family at serine 305 in the tissue sample of the patient,
wherein the stratification is further based on the phosphorylation status determined in step (iii). 5. The method of claim 1, additionally comprising the following step:
(iv) determining the activation status of one or more signaling pathways, which is/are different from the signaling pathway assessed in step (i) and is/are selected from the group consisting of PI3K pathway, Wnt pathway, hedgehog (HH) pathway, NFkappaB, Notch pathway, TGFbeta, FGF, VEGF, EMT, pathways, other nuclear receptor pathways, like the AR, RAR, PPAR, glucocorticoid, VitD pathways and growth factor pathways, like insulin GF and EGF, by applying an in-situ staining assay, wherein the same or a different tissue sample of the patient is used,
wherein the stratification is further based on the activation status determined in step (iv). 6. The method of claim 1, additionally comprising the following step:
(v) determining the activation status of the PI3K pathway by applying an in-situ-staining assay to detect in the same or in a different tissue sample of the patient an active PKB/Akt protein by measuring the phosphorylation status of PBK/Akt,
wherein the stratification is further based on the activation status determined in step (v). 7. The method of claim 1, additionally comprising the following step:
(vi) applying an in-situ staining assay to detect in the same or in a different tissue sample of the patient the presence of at least one member of the ER family and at least one component which is expected to be present at any ERE (Estrogen Response Element) half-site or any non ERE site and/or wherein the at least one component is selected from the group consisting of AP1, cAMP response element-binding protein/CREB, GATA transcription factor, NFkappaB, SP1, C/EBP, FOXO, and SMAD transcription factor proteins,
wherein the stratification is further based on the detection in step (vi). 8. A method for the prognosis of the outcome of a disease of a patient, the method comprising performing a method as detailed above in claim 1, wherein the prognosis is based on the determined activation status. 9. A method for the prediction and/or detection of therapy resistance of a patient towards a therapy, the method comprising performing a method as detailed above in claim 1, wherein the prediction and/or detection is based on the determined activation status. 10. A kit, comprising the following components:
a first antibody directed against the epitope of a member of the ER family, said member being part of a transcription factor complex, and a second antibody directed against the epitope of a protein being selected from the group consisting of TAFs, TBP, POLII, TFII, p300, CREB, and CBP, wherein the protein is part of the same transcription factor complex as the member of the ER family. 11. Use of a kit in a method according to claim 1, said kit comprising the following components:
a first antibody directed against the epitope of a transcription factor or, respectively, a transcription factor complex, or, respectively, a receptor being part of a transcription factor complex, and a second antibody directed against the epitope of a corresponding co activator protein, wherein, if applicable, the (co activator) protein is part of the same transcription factor complex. 12. Use of a kit in a method according to claim 8, said kit comprising the following components:
a first antibody directed against the epitope of a transcription factor or, respectively, a transcription factor complex, or, respectively, a receptor being part of a transcription factor complex, and a second antibody directed against the epitope of a corresponding co activator protein, wherein, if applicable, the (co activator) protein is part of the same transcription factor complex. 13. Use of a kit in a method according to claim 9, said kit comprising the following components:
a first antibody directed against the epitope of a transcription factor or, respectively, a transcription factor complex, or, respectively, a receptor being part of a transcription factor complex, and a second antibody directed against the epitope of a corresponding co activator protein, wherein, if applicable, the (co activator) protein is part of the same transcription factor complex. | The present invention primarily relates to a method for stratification of a patient for assessing the suitability of a therapy. The invention also relates to a method for the prognosis of the outcome of a disease of a patient and a method for the prediction and/or detection of therapy resistance of a patient towards a therapy. Furthermore, the invention relates to a novel kit, and corresponding uses thereof.1. A method for stratification of a patient for assessing the suitability of a therapy for the patient suffering from an ER and/or PR positive and HER2 negative cancer, the therapy being directed towards a signaling pathway, comprising the following step:
(i) determining the activation status of an ER and/or PR signaling pathway by applying a Proximity Ligation Assay to detect in a tissue sample of the patient the presence of at least one member of the ER family, said at least one member being part of a transcription factor complex, and at least one protein selected from the group consisting of TAFs, TBP, POLII, TFII, p300, CREB, and CBP, wherein the at least one protein is part of the same transcription factor complex,
wherein the stratification is based on the activation status determined in step (i) and the suitability of the therapy is assessed based on the stratification,
wherein a signaling pathway of step (i) is determined to be active, if the at least one ER family member is located in the nucleus in close proximity to the at least one protein selected from the group consisting of either TAFs, TBP, POLII, TFII, p300, CREB, and CBP. 2. The method of claim 1, wherein the at least one member of the ER family is an ER dimer. 3. The method of claim 1, additionally comprising the following step:
(ii) determining the activation status of a signaling pathway, which is different from the signaling pathway assessed in step (i), by applying an in-situ staining assay to detect in the same or in a different tissue sample of the patient the presence of at least one member of the ER family and at least one protein selected from the group consisting of, c-Fos, c-Jun (AP1), SP1, CREB, GATA-transcription factor, NFkappaB family, c/EBP proteins, FOXO, SMAD transcription factor proteins,
wherein the stratification is further based on the activation status determined in step (ii). 4. The method of claim 1, additionally comprising the following step:
(iii) determining the phosphorylation status of at least one member of the ER family at serine 305 in the tissue sample of the patient,
wherein the stratification is further based on the phosphorylation status determined in step (iii). 5. The method of claim 1, additionally comprising the following step:
(iv) determining the activation status of one or more signaling pathways, which is/are different from the signaling pathway assessed in step (i) and is/are selected from the group consisting of PI3K pathway, Wnt pathway, hedgehog (HH) pathway, NFkappaB, Notch pathway, TGFbeta, FGF, VEGF, EMT, pathways, other nuclear receptor pathways, like the AR, RAR, PPAR, glucocorticoid, VitD pathways and growth factor pathways, like insulin GF and EGF, by applying an in-situ staining assay, wherein the same or a different tissue sample of the patient is used,
wherein the stratification is further based on the activation status determined in step (iv). 6. The method of claim 1, additionally comprising the following step:
(v) determining the activation status of the PI3K pathway by applying an in-situ-staining assay to detect in the same or in a different tissue sample of the patient an active PKB/Akt protein by measuring the phosphorylation status of PBK/Akt,
wherein the stratification is further based on the activation status determined in step (v). 7. The method of claim 1, additionally comprising the following step:
(vi) applying an in-situ staining assay to detect in the same or in a different tissue sample of the patient the presence of at least one member of the ER family and at least one component which is expected to be present at any ERE (Estrogen Response Element) half-site or any non ERE site and/or wherein the at least one component is selected from the group consisting of AP1, cAMP response element-binding protein/CREB, GATA transcription factor, NFkappaB, SP1, C/EBP, FOXO, and SMAD transcription factor proteins,
wherein the stratification is further based on the detection in step (vi). 8. A method for the prognosis of the outcome of a disease of a patient, the method comprising performing a method as detailed above in claim 1, wherein the prognosis is based on the determined activation status. 9. A method for the prediction and/or detection of therapy resistance of a patient towards a therapy, the method comprising performing a method as detailed above in claim 1, wherein the prediction and/or detection is based on the determined activation status. 10. A kit, comprising the following components:
a first antibody directed against the epitope of a member of the ER family, said member being part of a transcription factor complex, and a second antibody directed against the epitope of a protein being selected from the group consisting of TAFs, TBP, POLII, TFII, p300, CREB, and CBP, wherein the protein is part of the same transcription factor complex as the member of the ER family. 11. Use of a kit in a method according to claim 1, said kit comprising the following components:
a first antibody directed against the epitope of a transcription factor or, respectively, a transcription factor complex, or, respectively, a receptor being part of a transcription factor complex, and a second antibody directed against the epitope of a corresponding co activator protein, wherein, if applicable, the (co activator) protein is part of the same transcription factor complex. 12. Use of a kit in a method according to claim 8, said kit comprising the following components:
a first antibody directed against the epitope of a transcription factor or, respectively, a transcription factor complex, or, respectively, a receptor being part of a transcription factor complex, and a second antibody directed against the epitope of a corresponding co activator protein, wherein, if applicable, the (co activator) protein is part of the same transcription factor complex. 13. Use of a kit in a method according to claim 9, said kit comprising the following components:
a first antibody directed against the epitope of a transcription factor or, respectively, a transcription factor complex, or, respectively, a receptor being part of a transcription factor complex, and a second antibody directed against the epitope of a corresponding co activator protein, wherein, if applicable, the (co activator) protein is part of the same transcription factor complex. | 1,600 |
734 | 15,677,809 | 1,626 | Disclosed are benzimidazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure
and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein R 1 , R 2 , R 3 , R 4 , Y and X are as described herein. In certain embodiments, a compound disclosed herein activates AMPK, and can be used to treat disease by activating the AMPK pathway. | 1. A compound having the structure of formula (I):
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
R1 and R2 together with the atoms to which they are attached form ring A, wherein ring A is a 5- or 6-membered Het optionally substituted with one or more RA groups that are each independently C3-8Cak(C0-6alkyl), Hca(C0-6alkyl), Ar(C0-6alkyl), Het(C0-6alkyl), —O—C0-6alkyl-C3-8Cak, —O—C0-6alkyl-Hca, —O—C0-6alkyl-Ar, —O—C0-6alkyl-Het, halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR) wherein each Ar, Het, Cak, Hca, alkyl, alkoxy and haloalkyl group is optionally substituted by one or two —RAx groups,
wherein each —RAx is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
or one of R1 and R2 is Ar or Het, wherein Ar and Het are optionally substituted with one or more independently selected RA groups, and the other is hydrogen, halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
R3 and R4 are independently hydrogen, halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
X is —O—, —S—, —NR— or —CF2—;
Y is selected from NR2, —CN, —C(O)ORY, —C(O)NHOH,
wherein RY is hydrogen or C1-6alkyl; and
each R is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl or cyano;
provided that the compound is not
5-((6-([1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
4-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)benzoic acid;
4-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)benzamide;
3-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)benzoic acid;
3-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)benzoate;
3-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-5-methylbenzoic acid;
5-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((5-([1,1′-biphenyl]-4-yl)-6-fluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((6-chloro-5-(2′-methyl-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
4-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-chlorobenzoic acid;
4-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-hydroxybenzoic acid;
3-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-5-hydroxybenzoic acid;
5-((6-chloro-5-(2-methyl-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
3-((6-chloro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-5-methylbenzoic acid;
5-((6-chloro-5-(4′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((6-chloro-5-(2′-chloro-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((6-chloro-5-(2′-fluoro-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-hydroxybenzoic acid;
5-((6-chloro-5-(4′-fluoro-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
2-(3-(2H-tetrazol-5-yl)phenoxy)-5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazole;
5-((6-chloro-5-(4′-cyano-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((6-chloro-5-(4′-methoxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((6-chloro-5-(3′-fluoro-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((6-chloro-5-(3′-chloro-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
3-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-4-fluorobenzoic acid;
3-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-4-chlorobenzoic acid;
5-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-ethylbenzoic acid;
5-((6-fluoro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
4′-(2-(3-carboxy-4-methylphenoxy)-6-chloro-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxylic acid;
4′-(2-(3-carboxy-4-methylphenoxy)-6-fluoro-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxylic acid;
4-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)phthalic acid;
5-((6-chloro-5-(3′-methoxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((5-(2′-amino-[1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
3-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-4-methoxybenzoic acid;
methyl 5-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate;
methyl 5-((5-([1,1′-biphenyl]-4-yl)-6-fluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate;
5-((6-chloro-5-(2′-methoxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((6-chloro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)isophthalic acid;
methyl 5-((6-chloro-5-(2′-methyl-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate;
methyl 4-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-hydroxybenzoate;
methyl 5-((6-chloro-5-(2′-fluoro-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate;
methyl 5-((6-chloro-5-(2′-chloro-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate;
methyl 5-((5-chloro-6-(3′-fluoro-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate;
methyl 5-((6-chloro-5-(2′-methoxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate;
5-((5-(9H-carbazol-2-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
dimethyl 4-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)phthalate;
ethyl 4′-(6-fluoro-2-(3-(methoxycarbonyl)-4-methylphenoxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxylate;
or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
R1 and R2 together with the atoms to which they are attached form ring A, wherein ring A is 5- or 6-membered Het optionally substituted with one or more RA groups that are each independently C3-8Cak(C0-6alkyl), Hca(C0-6alkyl), Ar(C0-6alkyl), Het(C0-6alkyl), —O—C0-6alkyl-C3-8Cak, —O—C0-6alkyl-Hca, —O—C0-6alkyl-Ar, —O—C0-6alkyl-Het, halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR), wherein each Ar, Het, Cak, Hca, alkyl, alkoxy and haloalkyl group is optionally substituted by one or two —RAx groups,
wherein each —RAx is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
or one of R1 and R2 is Ar or Het, wherein Ar and Het are substituted with one or more RA groups, and the other is hydrogen, halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR). 3. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
R1 and R2 together with the atoms to which they are attached form a 5- or 6-membered Het optionally substituted with one or more RA groups, or one of R1 and R2 is Ar. 4. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
R1 and R2 together with the atoms to which they are attached form a 5- or 6-membered Het optionally substituted with one or more RA groups. 5. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
R1 is Ar optionally substituted with one or more RA groups. 6. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
X is —O—. 7. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
each RA is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR), wherein each alkyl, alkoxy and haloalkyl group is optionally substituted by one or two —RAx groups,
wherein each —RAx is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR). 8. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
Y is selected from —NR2, —CN, —C(O)NHOH,
wherein RY is hydrogen or C1-6alkyl. 9. The compound of claim 1, wherein the compound is
5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-N-hydroxy-2-methylbenzamide; 5-((6-chloro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 5-((6-chloro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-N-hydroxy-2-methylbenzamide; 1-(5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one; 1-(5-((6-fluoro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one; 1-(5-((6-fluoro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one; 5-((6-fluoro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 1-(5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one; 5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylaniline; 4′-(6-fluoro-2-(4-methyl-3-(1H-tetrazol-1-yl)phenoxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-2-ol; 5-((6-fluoro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzonitrile; 4′-(6-fluoro-2-(4-methyl-3-(2H-tetrazol-5-yl)phenoxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-2-ol 1-(5-((6-fluoro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one;
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof. 10. The compound of claim 1, having the structure of formula (II):
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
ring A is a 5- or 6-membered Het; and
n is 1, 2, 3 or 4. 11. The compound of claim 10, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
ring A is a 5-membered Het. 12. The compound of claim 10, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
ring A is a 6-membered Het. 13. The compound of claim 10, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
ring A is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl or thiazolyl. 14. The compound of claim 11, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
ring A is pyrrolyl. 15. The compound of claim 11, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
ring A is N-methylpyrrolyl. 16. The compound of any of claims 10-15, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
each RA is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR), wherein each alkyl, alkoxy and haloalkyl group is optionally substituted by one or two —RAx groups,
wherein each —RAx is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR). 17. The compound of any of claims 10-16, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
X is —O—. 18. The compound of any of claims 10-17, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
each R is independently hydrogen, C1-C6alkyl or C1-C6haloalkyl. 19. The compound of claim 1, having the structure of formula (III):
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
each RA1 is independently hydrogen, C3-8Cak(C0-6alkyl), Hca(C0-6alkyl), Ar(C0-6alkyl), Het(C0-6alkyl), —O—C0-6alkyl-C3-8Cak, —O—C0-6alkyl-Hca, —O—C0-6alkyl-Ar, —O—C0-6alkyl-Het, cyano, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
each RA2 is independently hydrogen, C3-8Cak(C0-6alkyl), Hca(C0-6alkyl), Ar(C0-6alkyl), Het(C0-6alkyl), —O—C0-6alkyl-C3-8Cak, —O—C0-6alkyl-Hca, —O—C0-6alkyl-Ar, —O—C0-6alkyl-Het, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
RA3 is hydrogen, C3-8Cak(C0-6alkyl), Hca(C0-6alkyl), Ar(C0-6alkyl), Het(C0-6alkyl), —O—C0-6alkyl-C3-8Cak, —O—C0-6alkyl-Hca, —O—C0-6alkyl-Ar, —O—C0-6alkyl-Het, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —SR, —NR2, —C(O)R, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
wherein each Ar, Het, Cak, Hca, alkyl, alkoxy and haloalkyl group in each RA1, RA2 and RA3 is optionally substituted by one or two —RAx groups,
wherein each —RAx is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
R3 is hydrogen, halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
R4 is halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
X is —O—, —S—, —NR— or —CF2—;
Y is selected from —NR2, —CN, —C(O)ORY, —C(O)NHOH,
wherein RY is hydrogen or C1-6alkyl; and
each R is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl or cyano provided that
(a) at least one of RA1, RA2 or RA3 is not hydrogen;
(b) when RA1 or RA5 is hydroxyl, R3 is not fluoro; and
(c) when RA1 or RA5 is methoxy, R3 is not chloro. 20. The compound of claim 19, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
each RA1 is independently hydrogen, cyano, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR); each RA2 is independently hydrogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR); RA3 is hydrogen, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —SR, —NR2, —C(O)R, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR); wherein each alkyl, alkoxy and haloalkyl group in each RA1, RA2 and RA3 is optionally substituted by one or two —RAx groups. 21. The compound of claim 19 or 20, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
X is —O—. 22. The compound of any of claims 19-21, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
each R is independently hydrogen, C1-C6alkyl or C1-C6haloalkyl. 23. The compound of claim 1, having the structure of formula (IIIa):
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
RA1 is C3-8Cak(C0-6alkyl), Hca(C0-6alkyl), Ar(C0-6alkyl), Het(C0-6alkyl), —O—C0-6alkyl-C3-8Cak, —O—C0-6alkyl-Hca, —O—C0-6alkyl-Ar, —O—C0-6alkyl-Het, cyano, C1-6haloalkyl, —C1-C6alkoxy, —OH, —SR, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
each RA2 group is independently hydrogen, C3-8Cak(C0-6alkyl), Hca(C0-6alkyl), Ar (C0-6alkyl), Het(C0-6alkyl), —O—C0-6alkyl-C3-8Cak, —O—C0-6alkyl-Hca, —O—C0-6alkyl-Ar, —O—C0-6alkyl-Het, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
RA3 is hydrogen, C3-8Cak(C0-6alkyl), Hca(C0-6alkyl), Ar(C0-6alkyl), Het(C0-6alkyl), —O—C0-6alkyl-C3-8Cak, —O—C0-6alkyl-Hca, —O—C0-6alkyl-Ar, —O—C0-6alkyl-Het, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —SR, —NR2, —C(O)R, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
wherein each Ar, Het, Cak, Hca, alkyl, alkoxy and haloalkyl group in each RA1, RA2 and RA3 is optionally substituted by one or two —RAx groups,
wherein each —RAx is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
R3 is hydrogen, chloro, bromo, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
R4 is halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
X is —O—, —S—, —NR— or —CF2—;
Y is selected from —NR2, —CN, —C(O)OR, —C(O)NHOH,
wherein RY is hydrogen or C1-6alkyl; and
each R is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl or cyano. 24. The compound of claim 23, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
RA1 is cyano, C1-6haloalkyl, —C1-C6alkoxy, —OH, —SR, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR); each RA2 group is independently hydrogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR); RA3 is hydrogen, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —SR, —NR2, —C(O)R, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR); wherein each alkyl, alkoxy and haloalkyl group in each RA1, RA2 and RA3 is optionally substituted by one or two —RAx groups. 25. The compound of claim 23 or 24, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
X is —O—. 26. The compound of any of claims 23-25, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
each R is independently hydrogen, C1-C6alkyl or C1-C6haloalkyl. 27. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, and a pharmaceutically acceptable excipient, diluent, or carrier. 28. A method for activating the AMPK pathway in a cell, the method comprising contacting the cell with an effective amount of the compound of any of claims 1-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, or the pharmaceutical composition of claim 27. 29. A method for increasing fatty acid oxidation in a cell, the method comprising contacting the cell with an effective amount of a compound of any of claims 1-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, or the pharmaceutical composition of claim 27. 30. A method for decreasing glycogen concentration in a cell, the method comprising contacting the cell with an effective amount of a compound of any of claims 1-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, or the pharmaceutical composition of claim 27. 31. A method for increasing glucose uptake in a cell, the method comprising contacting the cell with an effective amount of a compound of any of claims 1-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, or the pharmaceutical composition of claim 27. 32. A method for reducing triglyceride levels in a subject, the method comprising administering to the subject an effective amount of a compound of any of claims 1-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, or the pharmaceutical composition of claim 27. 33. A method for treating type II diabetes in a subject with type II diabetes, the method comprising administering to the subject a therapeutically effective amount of a compound of any of claims 1-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, or the pharmaceutical composition of claim 27 to ameleoriate type II diabetes or at least one symptom thereof in the subject. 34. A method for treating atherosclerosis or cardiovascular disease in a subject with atherosclerosis or cardiovascular disease, the method comprising administering to the subject a therapeutically effective amount of a compound of any of claims 1-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, or the pharmaceutical composition of claim 27 to ameleoriate atherosclerosis, cardiovascular disease, or at least one symptom thereof in the subject. 35. A method for preventing atherosclerosis or cardiovascular disease in a subject, the method comprising administering to the subject an effective amount of a compound of any of claims 1-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, or the pharmaceutical composition of claim 27 to ameleoriate atherosclerosis, cardiovascular disease, or at least one symptom thereof in the subject. | Disclosed are benzimidazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure
and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein R 1 , R 2 , R 3 , R 4 , Y and X are as described herein. In certain embodiments, a compound disclosed herein activates AMPK, and can be used to treat disease by activating the AMPK pathway.1. A compound having the structure of formula (I):
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
R1 and R2 together with the atoms to which they are attached form ring A, wherein ring A is a 5- or 6-membered Het optionally substituted with one or more RA groups that are each independently C3-8Cak(C0-6alkyl), Hca(C0-6alkyl), Ar(C0-6alkyl), Het(C0-6alkyl), —O—C0-6alkyl-C3-8Cak, —O—C0-6alkyl-Hca, —O—C0-6alkyl-Ar, —O—C0-6alkyl-Het, halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR) wherein each Ar, Het, Cak, Hca, alkyl, alkoxy and haloalkyl group is optionally substituted by one or two —RAx groups,
wherein each —RAx is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
or one of R1 and R2 is Ar or Het, wherein Ar and Het are optionally substituted with one or more independently selected RA groups, and the other is hydrogen, halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
R3 and R4 are independently hydrogen, halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
X is —O—, —S—, —NR— or —CF2—;
Y is selected from NR2, —CN, —C(O)ORY, —C(O)NHOH,
wherein RY is hydrogen or C1-6alkyl; and
each R is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl or cyano;
provided that the compound is not
5-((6-([1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
4-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)benzoic acid;
4-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)benzamide;
3-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)benzoic acid;
3-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)benzoate;
3-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-5-methylbenzoic acid;
5-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((5-([1,1′-biphenyl]-4-yl)-6-fluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((6-chloro-5-(2′-methyl-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
4-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-chlorobenzoic acid;
4-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-hydroxybenzoic acid;
3-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-5-hydroxybenzoic acid;
5-((6-chloro-5-(2-methyl-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
3-((6-chloro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-5-methylbenzoic acid;
5-((6-chloro-5-(4′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((6-chloro-5-(2′-chloro-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((6-chloro-5-(2′-fluoro-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-hydroxybenzoic acid;
5-((6-chloro-5-(4′-fluoro-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
2-(3-(2H-tetrazol-5-yl)phenoxy)-5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazole;
5-((6-chloro-5-(4′-cyano-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((6-chloro-5-(4′-methoxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((6-chloro-5-(3′-fluoro-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((6-chloro-5-(3′-chloro-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
3-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-4-fluorobenzoic acid;
3-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-4-chlorobenzoic acid;
5-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-ethylbenzoic acid;
5-((6-fluoro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
4′-(2-(3-carboxy-4-methylphenoxy)-6-chloro-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxylic acid;
4′-(2-(3-carboxy-4-methylphenoxy)-6-fluoro-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxylic acid;
4-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)phthalic acid;
5-((6-chloro-5-(3′-methoxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((5-(2′-amino-[1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
3-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-4-methoxybenzoic acid;
methyl 5-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate;
methyl 5-((5-([1,1′-biphenyl]-4-yl)-6-fluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate;
5-((6-chloro-5-(2′-methoxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
5-((6-chloro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)isophthalic acid;
methyl 5-((6-chloro-5-(2′-methyl-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate;
methyl 4-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-hydroxybenzoate;
methyl 5-((6-chloro-5-(2′-fluoro-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate;
methyl 5-((6-chloro-5-(2′-chloro-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate;
methyl 5-((5-chloro-6-(3′-fluoro-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate;
methyl 5-((6-chloro-5-(2′-methoxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate;
5-((5-(9H-carbazol-2-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid;
dimethyl 4-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)phthalate;
ethyl 4′-(6-fluoro-2-(3-(methoxycarbonyl)-4-methylphenoxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxylate;
or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
R1 and R2 together with the atoms to which they are attached form ring A, wherein ring A is 5- or 6-membered Het optionally substituted with one or more RA groups that are each independently C3-8Cak(C0-6alkyl), Hca(C0-6alkyl), Ar(C0-6alkyl), Het(C0-6alkyl), —O—C0-6alkyl-C3-8Cak, —O—C0-6alkyl-Hca, —O—C0-6alkyl-Ar, —O—C0-6alkyl-Het, halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR), wherein each Ar, Het, Cak, Hca, alkyl, alkoxy and haloalkyl group is optionally substituted by one or two —RAx groups,
wherein each —RAx is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
or one of R1 and R2 is Ar or Het, wherein Ar and Het are substituted with one or more RA groups, and the other is hydrogen, halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR). 3. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
R1 and R2 together with the atoms to which they are attached form a 5- or 6-membered Het optionally substituted with one or more RA groups, or one of R1 and R2 is Ar. 4. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
R1 and R2 together with the atoms to which they are attached form a 5- or 6-membered Het optionally substituted with one or more RA groups. 5. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
R1 is Ar optionally substituted with one or more RA groups. 6. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
X is —O—. 7. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
each RA is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR), wherein each alkyl, alkoxy and haloalkyl group is optionally substituted by one or two —RAx groups,
wherein each —RAx is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR). 8. The compound of claim 1, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
Y is selected from —NR2, —CN, —C(O)NHOH,
wherein RY is hydrogen or C1-6alkyl. 9. The compound of claim 1, wherein the compound is
5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-N-hydroxy-2-methylbenzamide; 5-((6-chloro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 5-((6-chloro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-N-hydroxy-2-methylbenzamide; 1-(5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one; 1-(5-((6-fluoro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one; 1-(5-((6-fluoro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-1,4-dihydro-5H-tetrazol-5-one; 5-((6-fluoro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 1-(5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one; 5-((6-chloro-5-(1-methyl-1H-indol-5-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylaniline; 4′-(6-fluoro-2-(4-methyl-3-(1H-tetrazol-1-yl)phenoxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-2-ol; 5-((6-fluoro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzonitrile; 4′-(6-fluoro-2-(4-methyl-3-(2H-tetrazol-5-yl)phenoxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-2-ol 1-(5-((6-fluoro-5-(2′-hydroxy-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylphenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one;
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof. 10. The compound of claim 1, having the structure of formula (II):
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
ring A is a 5- or 6-membered Het; and
n is 1, 2, 3 or 4. 11. The compound of claim 10, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
ring A is a 5-membered Het. 12. The compound of claim 10, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
ring A is a 6-membered Het. 13. The compound of claim 10, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
ring A is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl or thiazolyl. 14. The compound of claim 11, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
ring A is pyrrolyl. 15. The compound of claim 11, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
ring A is N-methylpyrrolyl. 16. The compound of any of claims 10-15, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
each RA is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR), wherein each alkyl, alkoxy and haloalkyl group is optionally substituted by one or two —RAx groups,
wherein each —RAx is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR). 17. The compound of any of claims 10-16, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
X is —O—. 18. The compound of any of claims 10-17, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
each R is independently hydrogen, C1-C6alkyl or C1-C6haloalkyl. 19. The compound of claim 1, having the structure of formula (III):
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
each RA1 is independently hydrogen, C3-8Cak(C0-6alkyl), Hca(C0-6alkyl), Ar(C0-6alkyl), Het(C0-6alkyl), —O—C0-6alkyl-C3-8Cak, —O—C0-6alkyl-Hca, —O—C0-6alkyl-Ar, —O—C0-6alkyl-Het, cyano, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
each RA2 is independently hydrogen, C3-8Cak(C0-6alkyl), Hca(C0-6alkyl), Ar(C0-6alkyl), Het(C0-6alkyl), —O—C0-6alkyl-C3-8Cak, —O—C0-6alkyl-Hca, —O—C0-6alkyl-Ar, —O—C0-6alkyl-Het, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
RA3 is hydrogen, C3-8Cak(C0-6alkyl), Hca(C0-6alkyl), Ar(C0-6alkyl), Het(C0-6alkyl), —O—C0-6alkyl-C3-8Cak, —O—C0-6alkyl-Hca, —O—C0-6alkyl-Ar, —O—C0-6alkyl-Het, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —SR, —NR2, —C(O)R, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
wherein each Ar, Het, Cak, Hca, alkyl, alkoxy and haloalkyl group in each RA1, RA2 and RA3 is optionally substituted by one or two —RAx groups,
wherein each —RAx is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
R3 is hydrogen, halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
R4 is halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
X is —O—, —S—, —NR— or —CF2—;
Y is selected from —NR2, —CN, —C(O)ORY, —C(O)NHOH,
wherein RY is hydrogen or C1-6alkyl; and
each R is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl or cyano provided that
(a) at least one of RA1, RA2 or RA3 is not hydrogen;
(b) when RA1 or RA5 is hydroxyl, R3 is not fluoro; and
(c) when RA1 or RA5 is methoxy, R3 is not chloro. 20. The compound of claim 19, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
each RA1 is independently hydrogen, cyano, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR); each RA2 is independently hydrogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR); RA3 is hydrogen, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —SR, —NR2, —C(O)R, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR); wherein each alkyl, alkoxy and haloalkyl group in each RA1, RA2 and RA3 is optionally substituted by one or two —RAx groups. 21. The compound of claim 19 or 20, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
X is —O—. 22. The compound of any of claims 19-21, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
each R is independently hydrogen, C1-C6alkyl or C1-C6haloalkyl. 23. The compound of claim 1, having the structure of formula (IIIa):
or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
RA1 is C3-8Cak(C0-6alkyl), Hca(C0-6alkyl), Ar(C0-6alkyl), Het(C0-6alkyl), —O—C0-6alkyl-C3-8Cak, —O—C0-6alkyl-Hca, —O—C0-6alkyl-Ar, —O—C0-6alkyl-Het, cyano, C1-6haloalkyl, —C1-C6alkoxy, —OH, —SR, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
each RA2 group is independently hydrogen, C3-8Cak(C0-6alkyl), Hca(C0-6alkyl), Ar (C0-6alkyl), Het(C0-6alkyl), —O—C0-6alkyl-C3-8Cak, —O—C0-6alkyl-Hca, —O—C0-6alkyl-Ar, —O—C0-6alkyl-Het, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
RA3 is hydrogen, C3-8Cak(C0-6alkyl), Hca(C0-6alkyl), Ar(C0-6alkyl), Het(C0-6alkyl), —O—C0-6alkyl-C3-8Cak, —O—C0-6alkyl-Hca, —O—C0-6alkyl-Ar, —O—C0-6alkyl-Het, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —SR, —NR2, —C(O)R, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
wherein each Ar, Het, Cak, Hca, alkyl, alkoxy and haloalkyl group in each RA1, RA2 and RA3 is optionally substituted by one or two —RAx groups,
wherein each —RAx is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
R3 is hydrogen, chloro, bromo, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
R4 is halogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —OR, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR);
X is —O—, —S—, —NR— or —CF2—;
Y is selected from —NR2, —CN, —C(O)OR, —C(O)NHOH,
wherein RY is hydrogen or C1-6alkyl; and
each R is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, —(C0-C6alkyl)-Ar, —(C0-C6alkyl)-Het, —(C0-C6alkyl)-Cak, or —(C0-C6alkyl)-Hca, wherein Ar, Het, Cak, Hca, alkyl, and haloalkyl are optionally substituted with C1-C6alkyl, halogen, C1-C6haloalkyl or cyano. 24. The compound of claim 23, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
RA1 is cyano, C1-6haloalkyl, —C1-C6alkoxy, —OH, —SR, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR); each RA2 group is independently hydrogen, cyano, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —SR, —NR2, —C(O)R, —C(O)OR, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR); RA3 is hydrogen, C1-6alkyl, C1-6haloalkyl, —C1-C6alkoxy, —SR, —NR2, —C(O)R, —C(O)NR2, —S(O)2NR2, —S(O)2R, —OC(O)R, —N(R)C(O)R, —OC(O)OR, —OC(O)NR2, —N(R)C(O)OR, —N(R)C(O)NR2, —N(R)S(O)2R, —OP(O)(OR)2 or —CH2—OP(O)(OR); wherein each alkyl, alkoxy and haloalkyl group in each RA1, RA2 and RA3 is optionally substituted by one or two —RAx groups. 25. The compound of claim 23 or 24, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
X is —O—. 26. The compound of any of claims 23-25, or a pharmaceutically acceptable salt, prodrug or N-oxide thereof, or solvate or hydrate thereof, wherein
each R is independently hydrogen, C1-C6alkyl or C1-C6haloalkyl. 27. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, and a pharmaceutically acceptable excipient, diluent, or carrier. 28. A method for activating the AMPK pathway in a cell, the method comprising contacting the cell with an effective amount of the compound of any of claims 1-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, or the pharmaceutical composition of claim 27. 29. A method for increasing fatty acid oxidation in a cell, the method comprising contacting the cell with an effective amount of a compound of any of claims 1-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, or the pharmaceutical composition of claim 27. 30. A method for decreasing glycogen concentration in a cell, the method comprising contacting the cell with an effective amount of a compound of any of claims 1-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, or the pharmaceutical composition of claim 27. 31. A method for increasing glucose uptake in a cell, the method comprising contacting the cell with an effective amount of a compound of any of claims 1-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, or the pharmaceutical composition of claim 27. 32. A method for reducing triglyceride levels in a subject, the method comprising administering to the subject an effective amount of a compound of any of claims 1-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, or the pharmaceutical composition of claim 27. 33. A method for treating type II diabetes in a subject with type II diabetes, the method comprising administering to the subject a therapeutically effective amount of a compound of any of claims 1-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, or the pharmaceutical composition of claim 27 to ameleoriate type II diabetes or at least one symptom thereof in the subject. 34. A method for treating atherosclerosis or cardiovascular disease in a subject with atherosclerosis or cardiovascular disease, the method comprising administering to the subject a therapeutically effective amount of a compound of any of claims 1-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, or the pharmaceutical composition of claim 27 to ameleoriate atherosclerosis, cardiovascular disease, or at least one symptom thereof in the subject. 35. A method for preventing atherosclerosis or cardiovascular disease in a subject, the method comprising administering to the subject an effective amount of a compound of any of claims 1-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate or N-oxide thereof, or the pharmaceutical composition of claim 27 to ameleoriate atherosclerosis, cardiovascular disease, or at least one symptom thereof in the subject. | 1,600 |
735 | 13,129,544 | 1,639 | A process for removing by-products from N-vinylamide-rich product mixtures (crude N-vinylamide), which comprises performing an extraction of the crude N-vinylamide with an organic solvent as the extractant. | 1. A process for removing by-products from a N-vinylamide-rich product mixture, which comprises extracting the crude N-vinylamide with an organic solvent as the extractant. 2. The process according to claim 1, wherein the N-vinylamide comprises cyclic N-vinylamides (vinyllactams) or noncyclic N-vinylamides of the formula
in which R1 and R2 are each independently a hydrogen atom or a C1 to C10 alkyl group. 3. The process claim 1, wherein the noncyclic N-vinylamides of the formula I comprise N-vinylformamide, wherein (R1 and R2=H, or N-vinyl-N-methylacetamide, and VIMA, R1 and R2=methyl. 4. The process according to claim 1, wherein the cyclic N-vinylamide is N-vinylpiperidone, N-vinyl-caprolactam or N-vinylpyrrolidone or derivatives thereof. 5. The process according to claim 1, wherein the N-vinylamide is N-vinylpyrrolidone. 6. The process according to claim 1, wherein the crude N-vinylamide consists of the N-vinylamide to an extent of at least 50% by weight. 7. The process according to claim 1, wherein the crude N-vinylamide was obtained by a process comprising reacting starting materials with acetylene and optionally a subsequent workup. 8. The process according to claim 1, wherein the crude N-vinylamide is crude N-vinylpyrrolidone which was obtained by a process comprising reacting 2-pyrrolidone (gamma-butyrolactam) with acetylene and optionally a subsequent workup. 9. The process according to claim 1, wherein the extraction is preceded by distillation to remove the high boilers from the crude N-vinylamide. 10. The process according to claim 1, wherein the solvent is an aliphatic or cycloaliphatic solvent. 11. The process according to claim 1, wherein the extraction is effective with addition of water. 12. The process according to claim 1, wherein crude N-vinylpyrrolidone is extracted with methylcyclohexane with addition of water. 13. The process according to claim 1, wherein the extraction is performed within a temperature range from 20 to 100° C. 14. The process according to claim 1, wherein the extraction is performed continuously in one or more columns. 15. The process according to claim 1, wherein crude N-vinylpyrrolidone is extracted continuously with methylcyclohexane with addition of water in a column, water being supplied via a distributor in the upper part of the column, methylcyclohexane via a distributor in the lower part of the column and the crude N-vinylpyrrolidone in the middle part of the column. 16. The process according to claim 15, wherein a mixture of methylcyclohexane and removed by-products is withdrawn at the top of the column, and a mixture of purified crude N-vinylpyrrolidone and water at the bottom of the column. 17. The process according to claim 1, wherein the extraction removes fluorescent by-products from the crude N-vinylamide down to a content of less than 0.05 part by weight, based on 100 parts by weight of N-vinylpyrrolidone. 18. The process according to claim 1, wherein the cyclic N-vinylamide is at least one selected from the group consisting of N-vinylmethylpyrrolidone, N-vinyldimethylpyrrolidone and N-vinylethylpyrrolidone. | A process for removing by-products from N-vinylamide-rich product mixtures (crude N-vinylamide), which comprises performing an extraction of the crude N-vinylamide with an organic solvent as the extractant.1. A process for removing by-products from a N-vinylamide-rich product mixture, which comprises extracting the crude N-vinylamide with an organic solvent as the extractant. 2. The process according to claim 1, wherein the N-vinylamide comprises cyclic N-vinylamides (vinyllactams) or noncyclic N-vinylamides of the formula
in which R1 and R2 are each independently a hydrogen atom or a C1 to C10 alkyl group. 3. The process claim 1, wherein the noncyclic N-vinylamides of the formula I comprise N-vinylformamide, wherein (R1 and R2=H, or N-vinyl-N-methylacetamide, and VIMA, R1 and R2=methyl. 4. The process according to claim 1, wherein the cyclic N-vinylamide is N-vinylpiperidone, N-vinyl-caprolactam or N-vinylpyrrolidone or derivatives thereof. 5. The process according to claim 1, wherein the N-vinylamide is N-vinylpyrrolidone. 6. The process according to claim 1, wherein the crude N-vinylamide consists of the N-vinylamide to an extent of at least 50% by weight. 7. The process according to claim 1, wherein the crude N-vinylamide was obtained by a process comprising reacting starting materials with acetylene and optionally a subsequent workup. 8. The process according to claim 1, wherein the crude N-vinylamide is crude N-vinylpyrrolidone which was obtained by a process comprising reacting 2-pyrrolidone (gamma-butyrolactam) with acetylene and optionally a subsequent workup. 9. The process according to claim 1, wherein the extraction is preceded by distillation to remove the high boilers from the crude N-vinylamide. 10. The process according to claim 1, wherein the solvent is an aliphatic or cycloaliphatic solvent. 11. The process according to claim 1, wherein the extraction is effective with addition of water. 12. The process according to claim 1, wherein crude N-vinylpyrrolidone is extracted with methylcyclohexane with addition of water. 13. The process according to claim 1, wherein the extraction is performed within a temperature range from 20 to 100° C. 14. The process according to claim 1, wherein the extraction is performed continuously in one or more columns. 15. The process according to claim 1, wherein crude N-vinylpyrrolidone is extracted continuously with methylcyclohexane with addition of water in a column, water being supplied via a distributor in the upper part of the column, methylcyclohexane via a distributor in the lower part of the column and the crude N-vinylpyrrolidone in the middle part of the column. 16. The process according to claim 15, wherein a mixture of methylcyclohexane and removed by-products is withdrawn at the top of the column, and a mixture of purified crude N-vinylpyrrolidone and water at the bottom of the column. 17. The process according to claim 1, wherein the extraction removes fluorescent by-products from the crude N-vinylamide down to a content of less than 0.05 part by weight, based on 100 parts by weight of N-vinylpyrrolidone. 18. The process according to claim 1, wherein the cyclic N-vinylamide is at least one selected from the group consisting of N-vinylmethylpyrrolidone, N-vinyldimethylpyrrolidone and N-vinylethylpyrrolidone. | 1,600 |
736 | 14,209,056 | 1,616 | The invention relates to a method for the production of carrier pellets for pharmaceutical active substances. Likewise, the invention relates to such carrier pellets and also to pharmaceutical formulations containing these. The carrier pellets according to the invention are used for transporting and releasing pharmaceutical active substances, in particular in the human body. | 1. A method for the production of carrier pellets for a pharmaceutically active substance, the method comprising:
a) producing a liquid formulation by dissolving, dispersing, or a combination of dissolving and dispersing at least one physiologically well-tolerated pH regulator in at least one solvent or emulsifier; b) introducing the liquid formulation into a fluidized-bed or spouted-bed unit using at least one nozzle; c) forming essentially spherical carrier pellets by spray granulation in the unit wherein the solvent is evaporated by a drying gas flow; and d) discharging the carrier pellets from the unit. 2. The method according to claim 1;
wherein the at least one pH regulator has a regulating effect in physiological surroundings such that the pH value is lowered or increased and the bioavailability of the pharmaceutically active substance is made possible or increased. 3. The method according to claim 1;
wherein the at least one pH regulator comprises at least one organic acid selected from the group consisting of ascorbic acid, a C1-C18 monocarboxylic acid, a C1-C18 dicarboxylic acid, a C1-C18 tricarboxylic acid and mixtures thereof. 4. The method according to claim 3;
wherein the at least one organic acid is selected from the group consisting of citric acid, succinic acid, malic acid, fumaric acid, tartaric acid, sorbic acid, adipinic acid, salts thereof, and mixtures thereof. 5. The method according to claim 1;
wherein the at least one pH regulator comprises an acidic or basic salt. 6. The method according to claim 1;
wherein the pH regulator comprises a buffer system comprising an organic acid and salt of the organic acid or an organic base and salt of the organic base, wherein the buffer system stabilizes the pH. 7. The method according to claim 6;
wherein the buffer system comprises at least one combination selected from the group consisting of:
citric acid and a citrate; and
tartaric acid and a tartrate. 8. The method according to claim 1;
wherein the pH regulator acts in physiological surroundings as pH-increasing, pH-lowering, or pH-stabilising. 9. The method according to claim 1;
wherein the pH regulator comprises at least one organic base selected from the group consisting of a purine base, a pyrimidine base, and a mixture thereof. 10. The method according to claim 9;
wherein the purine base is selected from the group consisting of adenine, guanine, hypoxanthine, xanthine, and mixtures thereof. 11. The method according to claim 9;
wherein the pyrimidine base is selected from the group consisting of cytosine, uracil, thymine, and mixtures thereof. 12. The method according to claim 1;
wherein the pH regulator comprises at least one basic inorganic salt selected from the group consisting of NaHCO3, K2CO3, Na2CO3, KHCO3, Ca(OH)2, CaO, phosphates, and mixtures thereof. 13. The method according to claim 1;
wherein the liquid formulation further comprises at least one physiologically well-tolerated binder. 14. The method according to claim 13;
wherein the at least one binder is selected from the group consisting of methyl celluloses, hydroxymethyl celluloses, hydroxypropylmethyl celluloses, alginates, pectins, polyvinylpyrrolidones, xanthanes, hydrocolloids, and mixtures thereof. 15. The method according to claim 1;
wherein the at least one solvent or emulsifier is water or an organic solvent selected from the group consisting of ethyl alcohol, isopropanol, n-propanol, and mixtures thereof. 16. The method according to claim 13;
wherein the quantity ratio of pH regulator to binder in the liquid formulation is in the range of 50:50 to 99:1. 17. The method according to claim 13;
wherein the liquid formulation contains:
30 to 80% by weight of the at least one pH regulator;
0.5 to 5% by weight of the at least one binder; and
15 to 69.5% by weight of the at least one solvent. 18. The method according to claim 1;
wherein the temperature in the unit is in the range of 5 to 100° C. 19. The method according to claim 1;
wherein the drying gas flow has, at the entrance into the unit, a temperature in the range of 5 to 120°. 20. The method according to claim 1;
wherein the drying gas is air, nitrogen, or inert gas. 21. The method according to claim 1;
wherein the spray granulation is effected in a fluidized-bed unit into which the drying gas is supplied via a sieve plate and the liquid formulation is introduced by the at least one nozzle disposed above the sieve plate. 22. The method according to claim 1;
wherein the spray granulation is effected in a spouted-bed unit into which the drying gas is supplied via longitudinal gaps disposed in the lower half of the unit and the liquid formulation is introduced by the at least one nozzle disposed between the longitudinal gaps. 23. The method according to claim 22;
wherein the introduction of the liquid formulation is effected through the nozzle from below to above. 24. A carrier pellet for carrying a pharmaceutically active substance, the carrier pellet comprising at least one physiologically well-tolerated pH regulator, wherein the carrier pellets are produced by the method comprising:
a) producing a liquid formulation by dissolving, dispersing, or a combination of dissolving and dispersing at least one physiologically well-tolerated pH regulator in at least one solvent or emulsifier; b) introducing the liquid formulation into a fluidized-bed or spouted-bed unit using at least one nozzle; c) forming essentially spherical carrier pellets by spray granulation in the unit wherein the solvent is evaporated by a drying gas flow; and d) discharging the carrier pellets from the unit. 25. The carrier pellet according to claim 24;
wherein the carrier pellet has a diameter in the range of 50 μm to 1.5 mm. 26. The carrier pellet according to claim 24;
wherein the carrier pellet is essentially spherical. 27. The carrier pellet according to claim 26;
wherein the carrier pellet has a sphericity of 0.8 to 1.0. 28. The carrier pellet according to claim 24;
wherein the carrier pellet has a width-length ratio of 0.8 to 1.0. 29. The carrier pellet according to claim 24;
wherein the carrier pellet is a dense carrier pellet. 30. A combination of carrier pellets comprising:
at least two of the carrier pellets according claim 24; wherein at least two of the carrier pellets in the combination have essentially the same size. 31. A pharmaceutical formulation comprising:
one or more carrier pellets according to claim 24; and at least one pharmaceutically active substance. 32. A method of releasing a pharmaceutically active substance, the method comprising:
introducing one or more pharmaceutical formulations according to claim 31 into physiological surroundings, wherein the one or more carrier pellets releases the pharmaceutically active substance into the physiological surroundings. | The invention relates to a method for the production of carrier pellets for pharmaceutical active substances. Likewise, the invention relates to such carrier pellets and also to pharmaceutical formulations containing these. The carrier pellets according to the invention are used for transporting and releasing pharmaceutical active substances, in particular in the human body.1. A method for the production of carrier pellets for a pharmaceutically active substance, the method comprising:
a) producing a liquid formulation by dissolving, dispersing, or a combination of dissolving and dispersing at least one physiologically well-tolerated pH regulator in at least one solvent or emulsifier; b) introducing the liquid formulation into a fluidized-bed or spouted-bed unit using at least one nozzle; c) forming essentially spherical carrier pellets by spray granulation in the unit wherein the solvent is evaporated by a drying gas flow; and d) discharging the carrier pellets from the unit. 2. The method according to claim 1;
wherein the at least one pH regulator has a regulating effect in physiological surroundings such that the pH value is lowered or increased and the bioavailability of the pharmaceutically active substance is made possible or increased. 3. The method according to claim 1;
wherein the at least one pH regulator comprises at least one organic acid selected from the group consisting of ascorbic acid, a C1-C18 monocarboxylic acid, a C1-C18 dicarboxylic acid, a C1-C18 tricarboxylic acid and mixtures thereof. 4. The method according to claim 3;
wherein the at least one organic acid is selected from the group consisting of citric acid, succinic acid, malic acid, fumaric acid, tartaric acid, sorbic acid, adipinic acid, salts thereof, and mixtures thereof. 5. The method according to claim 1;
wherein the at least one pH regulator comprises an acidic or basic salt. 6. The method according to claim 1;
wherein the pH regulator comprises a buffer system comprising an organic acid and salt of the organic acid or an organic base and salt of the organic base, wherein the buffer system stabilizes the pH. 7. The method according to claim 6;
wherein the buffer system comprises at least one combination selected from the group consisting of:
citric acid and a citrate; and
tartaric acid and a tartrate. 8. The method according to claim 1;
wherein the pH regulator acts in physiological surroundings as pH-increasing, pH-lowering, or pH-stabilising. 9. The method according to claim 1;
wherein the pH regulator comprises at least one organic base selected from the group consisting of a purine base, a pyrimidine base, and a mixture thereof. 10. The method according to claim 9;
wherein the purine base is selected from the group consisting of adenine, guanine, hypoxanthine, xanthine, and mixtures thereof. 11. The method according to claim 9;
wherein the pyrimidine base is selected from the group consisting of cytosine, uracil, thymine, and mixtures thereof. 12. The method according to claim 1;
wherein the pH regulator comprises at least one basic inorganic salt selected from the group consisting of NaHCO3, K2CO3, Na2CO3, KHCO3, Ca(OH)2, CaO, phosphates, and mixtures thereof. 13. The method according to claim 1;
wherein the liquid formulation further comprises at least one physiologically well-tolerated binder. 14. The method according to claim 13;
wherein the at least one binder is selected from the group consisting of methyl celluloses, hydroxymethyl celluloses, hydroxypropylmethyl celluloses, alginates, pectins, polyvinylpyrrolidones, xanthanes, hydrocolloids, and mixtures thereof. 15. The method according to claim 1;
wherein the at least one solvent or emulsifier is water or an organic solvent selected from the group consisting of ethyl alcohol, isopropanol, n-propanol, and mixtures thereof. 16. The method according to claim 13;
wherein the quantity ratio of pH regulator to binder in the liquid formulation is in the range of 50:50 to 99:1. 17. The method according to claim 13;
wherein the liquid formulation contains:
30 to 80% by weight of the at least one pH regulator;
0.5 to 5% by weight of the at least one binder; and
15 to 69.5% by weight of the at least one solvent. 18. The method according to claim 1;
wherein the temperature in the unit is in the range of 5 to 100° C. 19. The method according to claim 1;
wherein the drying gas flow has, at the entrance into the unit, a temperature in the range of 5 to 120°. 20. The method according to claim 1;
wherein the drying gas is air, nitrogen, or inert gas. 21. The method according to claim 1;
wherein the spray granulation is effected in a fluidized-bed unit into which the drying gas is supplied via a sieve plate and the liquid formulation is introduced by the at least one nozzle disposed above the sieve plate. 22. The method according to claim 1;
wherein the spray granulation is effected in a spouted-bed unit into which the drying gas is supplied via longitudinal gaps disposed in the lower half of the unit and the liquid formulation is introduced by the at least one nozzle disposed between the longitudinal gaps. 23. The method according to claim 22;
wherein the introduction of the liquid formulation is effected through the nozzle from below to above. 24. A carrier pellet for carrying a pharmaceutically active substance, the carrier pellet comprising at least one physiologically well-tolerated pH regulator, wherein the carrier pellets are produced by the method comprising:
a) producing a liquid formulation by dissolving, dispersing, or a combination of dissolving and dispersing at least one physiologically well-tolerated pH regulator in at least one solvent or emulsifier; b) introducing the liquid formulation into a fluidized-bed or spouted-bed unit using at least one nozzle; c) forming essentially spherical carrier pellets by spray granulation in the unit wherein the solvent is evaporated by a drying gas flow; and d) discharging the carrier pellets from the unit. 25. The carrier pellet according to claim 24;
wherein the carrier pellet has a diameter in the range of 50 μm to 1.5 mm. 26. The carrier pellet according to claim 24;
wherein the carrier pellet is essentially spherical. 27. The carrier pellet according to claim 26;
wherein the carrier pellet has a sphericity of 0.8 to 1.0. 28. The carrier pellet according to claim 24;
wherein the carrier pellet has a width-length ratio of 0.8 to 1.0. 29. The carrier pellet according to claim 24;
wherein the carrier pellet is a dense carrier pellet. 30. A combination of carrier pellets comprising:
at least two of the carrier pellets according claim 24; wherein at least two of the carrier pellets in the combination have essentially the same size. 31. A pharmaceutical formulation comprising:
one or more carrier pellets according to claim 24; and at least one pharmaceutically active substance. 32. A method of releasing a pharmaceutically active substance, the method comprising:
introducing one or more pharmaceutical formulations according to claim 31 into physiological surroundings, wherein the one or more carrier pellets releases the pharmaceutically active substance into the physiological surroundings. | 1,600 |
737 | 15,800,407 | 1,645 | Administration of an antibody that specifically binds IL-1α is useful for reducing the chance or severity of a major adverse clinical event occurring in a mammalian subject having received or expected to receive surgical treatment for a stenosed blood vessel, and for reducing the change of restenosis occurring (or increasing the time until restenosis occurs) in a mammalian subject having received or expected to receive surgical treatment for a stenosed blood vessel. | 1. A method of reducing the chance of a major adverse clinical event occurring in a human subject having received or expected to receive surgical treatment for a stenosed blood vessel, the method comprising the step of repeatedly administering to the subject a 0.2 to 20 mg/kg dose of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-interleukin-1alpha (anti-IL-1α) antibody at least until the chance of a major adverse clinical event occurring in the subject is reduced. 2. The method of claim 1, wherein the anti-IL-1α antibody is a monoclonal antibody. 3. The method of claim 2, wherein the monoclonal antibody is an IgG1. 4. The method of claim 2, wherein the monoclonal antibody comprises a complementarity determining region of MABp1. 5. The method of claim 2, wherein the monoclonal antibody is MABp1. 6. The method of claim 1, wherein at least 4 doses are administered to the subject. 7. The method of claim 1, wherein the pharmaceutical composition is administered to the subject biweekly. 8. A method of reducing the chance of restenosis occurring in a human subject having received or expected to receive surgical treatment for a stenosed blood vessel, the method comprising the step of repeatedly administering to the subject a 0.2 to 20 mg/kg dose of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-IL-1α antibody at least until the chance that the vessel will become restenosed is reduced. 9. The method of claim 8, wherein the anti-IL-1α antibody is a monoclonal antibody. 10. The method of claim 9, wherein the monoclonal antibody is an IgG1. 11. The method of claim 9, wherein the monoclonal antibody comprises a complementarity determining region of MABp1. 12. The method of claim 9, wherein the monoclonal antibody is MABp1. 13. The method of claim 8, wherein at least 4 doses are administered to the subject. 14. The method of claim 8, wherein the pharmaceutical composition is administered to the subject biweekly. | Administration of an antibody that specifically binds IL-1α is useful for reducing the chance or severity of a major adverse clinical event occurring in a mammalian subject having received or expected to receive surgical treatment for a stenosed blood vessel, and for reducing the change of restenosis occurring (or increasing the time until restenosis occurs) in a mammalian subject having received or expected to receive surgical treatment for a stenosed blood vessel.1. A method of reducing the chance of a major adverse clinical event occurring in a human subject having received or expected to receive surgical treatment for a stenosed blood vessel, the method comprising the step of repeatedly administering to the subject a 0.2 to 20 mg/kg dose of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-interleukin-1alpha (anti-IL-1α) antibody at least until the chance of a major adverse clinical event occurring in the subject is reduced. 2. The method of claim 1, wherein the anti-IL-1α antibody is a monoclonal antibody. 3. The method of claim 2, wherein the monoclonal antibody is an IgG1. 4. The method of claim 2, wherein the monoclonal antibody comprises a complementarity determining region of MABp1. 5. The method of claim 2, wherein the monoclonal antibody is MABp1. 6. The method of claim 1, wherein at least 4 doses are administered to the subject. 7. The method of claim 1, wherein the pharmaceutical composition is administered to the subject biweekly. 8. A method of reducing the chance of restenosis occurring in a human subject having received or expected to receive surgical treatment for a stenosed blood vessel, the method comprising the step of repeatedly administering to the subject a 0.2 to 20 mg/kg dose of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an anti-IL-1α antibody at least until the chance that the vessel will become restenosed is reduced. 9. The method of claim 8, wherein the anti-IL-1α antibody is a monoclonal antibody. 10. The method of claim 9, wherein the monoclonal antibody is an IgG1. 11. The method of claim 9, wherein the monoclonal antibody comprises a complementarity determining region of MABp1. 12. The method of claim 9, wherein the monoclonal antibody is MABp1. 13. The method of claim 8, wherein at least 4 doses are administered to the subject. 14. The method of claim 8, wherein the pharmaceutical composition is administered to the subject biweekly. | 1,600 |
738 | 16,205,602 | 1,628 | Provided herein is a method for administering dichlorphenamide, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the subject is also being administered a therapeutically effective amount of a drug chosen from a P-gp substrate, BCRP substrate, OAT2 substrate, OAT4 substrate, OCT1 substrate, MATE1 substrate, MATE2-K substrate, and combinations thereof. The method comprises administering to the subject a therapeutically effective amount of dichlorphenamide, or a pharmaceutically acceptable salt thereof. The therapeutically effective amount of the drug is not adjusted relative to a subject who is not being administered dichlorphenamide. | 1. A method for administering dichlorphenamide, or a pharmaceutically acceptable salt thereof, to treat a disease chosen from primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants in a subject in need thereof, wherein the subject is also being administered a therapeutically effective amount of an OCT1 substrate to treat a disease or disorder, the method comprising:
administering to the subject a therapeutically effective amount of dichlorphenamide, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of the OCT1 substrate is not adjusted relative to a subject who is being administered the OCT 1 substrate and who is not being administered dichlorphenamide, or a pharmaceutically acceptable salt thereof. 2. A method for administering dichlorphenamide, or a pharmaceutically acceptable salt thereof, to treat a disease chosen from primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants in a subject in need thereof, the method comprising:
administering to the subject a therapeutically effective amount of dichlorphenamide, or a pharmaceutically acceptable salt thereof, subsequently determining that the subject is to begin treatment with a therapeutically effective amount of an OCT1 substrate to treat a disease or disorder, and continuing administration of the therapeutically effective amount of dichlorphenamide, or a pharmaceutically acceptable salt thereof and beginning administration of the OCT1 substrate, wherein the therapeutically effective amount of the OCT1 substrate is not adjusted relative to a subject who is being administered the OCT 1 substrate and who is not being administered dichlorphenamide, or a pharmaceutically acceptable salt thereof. 3. The method claim 1, further comprising informing the subject or a medical care worker that administering dichlorphenamide, or a pharmaceutically acceptable salt thereof, to a subject who is also taking an OCT1, results in no increase in drug exposure as compared with administering the OCT1 substrate to a patient who is not being administered dichlorphenamide, or a pharmaceutically acceptable salt thereof. 4. The method of claim 1, further comprising informing the patient or a medical care worker that administering dichlorphenamide, or a pharmaceutically acceptable salt thereof to a subject who is also taking an OCT1 substrate, may result in no increased risk of one or more exposure-related adverse reactions than administering the OCT1 substrate to a subject who is not being administered dichlorphenamide, or a pharmaceutically acceptable salt thereof. 5. (canceled) 6. (canceled) 7. (canceled) 8. (canceled) 9. (canceled) 10. (canceled) 11. (canceled) 12. (canceled) 13. (canceled) 14. The method of claim 1, wherein the OCT1 substrate is chosen from ganciclovir, acyclovir, choline, amantadine, verapamil, quinine, cimetidine, dexchlorpheniramine, choline salicylate, rocuronium, phenformin, metformin, thiamine, dopamine, dancuronium, epinephrine, imatinib, norepinephrine, acetylcholine, spermine, spermidine, tubocurarine, buformin, cytarabine, pramipexole, agmatine, lamivudine, nafamostat, and combinations thereof. 15. (canceled) 16. (canceled) 17. (canceled) 18. (canceled) 19. (canceled) 20. The method of claim 1, wherein the therapeutically effective amount of the dichlorphenamide, or a pharmaceutically acceptable salt thereof, is between 25 mg and 200 mg per day. 21. The method of claim 1, wherein the therapeutically effective amount of the dichlorphenamide, or a pharmaceutically acceptable salt thereof, is 50 mg twice daily. 22. The method of claim 1, wherein the dichlorphenamide, or a pharmaceutically acceptable salt thereof, is administered via a titration scheme that comprises the up-titration of the dichlorphenamide, or a pharmaceutically acceptable salt thereof, at weekly intervals until a modified dose is administered. 23. The method of claim 14, wherein the OCT1 substrate is verapamil. 24. The method of claim 2, wherein the OCT1 substrate is verapamil. | Provided herein is a method for administering dichlorphenamide, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the subject is also being administered a therapeutically effective amount of a drug chosen from a P-gp substrate, BCRP substrate, OAT2 substrate, OAT4 substrate, OCT1 substrate, MATE1 substrate, MATE2-K substrate, and combinations thereof. The method comprises administering to the subject a therapeutically effective amount of dichlorphenamide, or a pharmaceutically acceptable salt thereof. The therapeutically effective amount of the drug is not adjusted relative to a subject who is not being administered dichlorphenamide.1. A method for administering dichlorphenamide, or a pharmaceutically acceptable salt thereof, to treat a disease chosen from primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants in a subject in need thereof, wherein the subject is also being administered a therapeutically effective amount of an OCT1 substrate to treat a disease or disorder, the method comprising:
administering to the subject a therapeutically effective amount of dichlorphenamide, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of the OCT1 substrate is not adjusted relative to a subject who is being administered the OCT 1 substrate and who is not being administered dichlorphenamide, or a pharmaceutically acceptable salt thereof. 2. A method for administering dichlorphenamide, or a pharmaceutically acceptable salt thereof, to treat a disease chosen from primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants in a subject in need thereof, the method comprising:
administering to the subject a therapeutically effective amount of dichlorphenamide, or a pharmaceutically acceptable salt thereof, subsequently determining that the subject is to begin treatment with a therapeutically effective amount of an OCT1 substrate to treat a disease or disorder, and continuing administration of the therapeutically effective amount of dichlorphenamide, or a pharmaceutically acceptable salt thereof and beginning administration of the OCT1 substrate, wherein the therapeutically effective amount of the OCT1 substrate is not adjusted relative to a subject who is being administered the OCT 1 substrate and who is not being administered dichlorphenamide, or a pharmaceutically acceptable salt thereof. 3. The method claim 1, further comprising informing the subject or a medical care worker that administering dichlorphenamide, or a pharmaceutically acceptable salt thereof, to a subject who is also taking an OCT1, results in no increase in drug exposure as compared with administering the OCT1 substrate to a patient who is not being administered dichlorphenamide, or a pharmaceutically acceptable salt thereof. 4. The method of claim 1, further comprising informing the patient or a medical care worker that administering dichlorphenamide, or a pharmaceutically acceptable salt thereof to a subject who is also taking an OCT1 substrate, may result in no increased risk of one or more exposure-related adverse reactions than administering the OCT1 substrate to a subject who is not being administered dichlorphenamide, or a pharmaceutically acceptable salt thereof. 5. (canceled) 6. (canceled) 7. (canceled) 8. (canceled) 9. (canceled) 10. (canceled) 11. (canceled) 12. (canceled) 13. (canceled) 14. The method of claim 1, wherein the OCT1 substrate is chosen from ganciclovir, acyclovir, choline, amantadine, verapamil, quinine, cimetidine, dexchlorpheniramine, choline salicylate, rocuronium, phenformin, metformin, thiamine, dopamine, dancuronium, epinephrine, imatinib, norepinephrine, acetylcholine, spermine, spermidine, tubocurarine, buformin, cytarabine, pramipexole, agmatine, lamivudine, nafamostat, and combinations thereof. 15. (canceled) 16. (canceled) 17. (canceled) 18. (canceled) 19. (canceled) 20. The method of claim 1, wherein the therapeutically effective amount of the dichlorphenamide, or a pharmaceutically acceptable salt thereof, is between 25 mg and 200 mg per day. 21. The method of claim 1, wherein the therapeutically effective amount of the dichlorphenamide, or a pharmaceutically acceptable salt thereof, is 50 mg twice daily. 22. The method of claim 1, wherein the dichlorphenamide, or a pharmaceutically acceptable salt thereof, is administered via a titration scheme that comprises the up-titration of the dichlorphenamide, or a pharmaceutically acceptable salt thereof, at weekly intervals until a modified dose is administered. 23. The method of claim 14, wherein the OCT1 substrate is verapamil. 24. The method of claim 2, wherein the OCT1 substrate is verapamil. | 1,600 |
739 | 15,024,567 | 1,616 | An agrochemical formulation comprising an agricultural active and an adjuvant is disclosed. The adjuvant comprises a residue of sorbitan or sorbitan derivative having at least one active hydrogen atom replaced to form an ethyloxylated or propoxylated ester. The adjuvant and methods of treating crops with an agrochemical formulation comprising the adjuvant are also disclosed. | 1.-5. (canceled) 6. An agrochemical formulation comprising;
i) an adjuvant; and ii) at least one agrochemical active;
wherein said adjuvant has general structure (I):
Sorb.(AO1H)n1(AO2H)n3(AO3H)n3(AO4R1)n4 (I)
wherein:
Sorb represents a residue of a sorbitan or sorbitan derivative;
AO1, AO2, AO3, and AO4 each independently represents an oxyalkylene group formed from oxyethylene units, oxypropylene units, or a mixture thereof, wherein at least one of AO1, AO2, AO3, and AO4 comprises a mixture of oxyethylene and oxypropylene units;
the total sum of oxyethylene units and oxypropylene units is in the range from 5 to 38;
n1, n2, and n3 each independently represent an integer having a value of 0 or 1;
n4 represents a value of 1; and
R1 represents an alkanoyl group —C(O)R2 wherein R2 represents a C4 to C28 hydrocarbyl. 7. The agrochemical formulation according to claim 6, wherein the residue of a sorbitan or sorbitan derivative is selected from 1,4-anhydrosorbitol, 1,5-anhydrosorbitol, and 3,6-anhydrosorbitol. 8. The agrochemical formulation according to claim 6, wherein said alkanoyl group is a residue of a fatty acid. 9. The agrochemical formulation according to claim 8, where the fatty acid is selected from linear or branched, saturated or unsaturated, C8 to C28 fatty acids. 10. The agrochemical formulation according to claim 6, wherein each oxyalkylene group is copolymeric. 11. The agrochemical formulation according to claim 10, wherein the oxyalkylene group is a reverse copolymer. 12. The agrochemical formulation according to claim 10, wherein the molar proportion of oxyethylene units comprised in the oxyalkylene group may be in the range of between 20% and 90%. 13. The agrochemical formulation according to claim 6, wherein the number of moles of oxyethylene present in each oxyalkylene group is independently an integer in the range from 1 to 8. 14. The agrochemical formulation according to claim 6, wherein the moles of both oxyethylene and oxypropylene units present in each adjuvant molecule has an integer value in the range of from 5 to 38. 15. The agrochemical formulation according to claim 6, wherein the molecular weight (weight average) of the adjuvant is in the range from 450 to 2,700. 16. A concentrate formulation suitable for making an agrochemical formulation, said concentrate comprising;
i) an adjuvant, wherein said adjuvant wherein said adjuvant has general structure (I):
Sorb.(AO1H)n1(AO2H)n2(AO3H)n3(AO4R1)n4 (I)
wherein:
Sorb represents a residue of a sorbitan or sorbitan derivative;
AO1, AO2, AO3, and AO4 each independently represents an oxyalkylene group formed from oxyethylene units, oxypropylene units, or a mixture thereof, wherein at least one of AO1, AO2, AO3, and AO4 comprises a mixture of oxyethylene and oxypropylene units;
the total sum of oxyethylene units and oxypropylene units is in the range from 5 to 38;
n1, n2, and n3 each independently represent an integer having a value of Q or 1; n4 represents a value of 1;
R1 represents an alkanoyl group —C(O)R2 wherein R2 represents a C4 to C28 hydrocarbyl; and
ii) optionally, at least one agrochemical active. 17. A method of treating vegetation to control pests, the method comprising applying a formulation according to claim 6 either to said vegetation or to an immediate environment of said vegetation. 18. A compound having general structure (I):
Sorb.(AO1H)n1(AO2H)n2(AO3H)n3(AO4R1)n4 (I)
wherein:
Sorb represents a residue of a sorbitan or sorbitan derivative;
AO1, AO2, AO3, and AO4 each independently represents an oxyalkylene group formed from oxyethylene units, oxypropylene units, or a mixture thereof, wherein at least one of AO1, AO2, AO3, and AO4 comprises a mixture of oxyethylene and oxypropylene units;
the total sum of oxyethylene units and oxypropylene units is in the range from 5 to 38;
n1, n2, and n3 each independently represent an integer having a value of 0 or 1; n4 represents a value of 1; and
R1 represents an alkanoyl group —C(O)R2 wherein R2 represents a C4 to C28 hydrocarbyl;
suitable for use as an adjuvant in an agrochemical formulation. | An agrochemical formulation comprising an agricultural active and an adjuvant is disclosed. The adjuvant comprises a residue of sorbitan or sorbitan derivative having at least one active hydrogen atom replaced to form an ethyloxylated or propoxylated ester. The adjuvant and methods of treating crops with an agrochemical formulation comprising the adjuvant are also disclosed.1.-5. (canceled) 6. An agrochemical formulation comprising;
i) an adjuvant; and ii) at least one agrochemical active;
wherein said adjuvant has general structure (I):
Sorb.(AO1H)n1(AO2H)n3(AO3H)n3(AO4R1)n4 (I)
wherein:
Sorb represents a residue of a sorbitan or sorbitan derivative;
AO1, AO2, AO3, and AO4 each independently represents an oxyalkylene group formed from oxyethylene units, oxypropylene units, or a mixture thereof, wherein at least one of AO1, AO2, AO3, and AO4 comprises a mixture of oxyethylene and oxypropylene units;
the total sum of oxyethylene units and oxypropylene units is in the range from 5 to 38;
n1, n2, and n3 each independently represent an integer having a value of 0 or 1;
n4 represents a value of 1; and
R1 represents an alkanoyl group —C(O)R2 wherein R2 represents a C4 to C28 hydrocarbyl. 7. The agrochemical formulation according to claim 6, wherein the residue of a sorbitan or sorbitan derivative is selected from 1,4-anhydrosorbitol, 1,5-anhydrosorbitol, and 3,6-anhydrosorbitol. 8. The agrochemical formulation according to claim 6, wherein said alkanoyl group is a residue of a fatty acid. 9. The agrochemical formulation according to claim 8, where the fatty acid is selected from linear or branched, saturated or unsaturated, C8 to C28 fatty acids. 10. The agrochemical formulation according to claim 6, wherein each oxyalkylene group is copolymeric. 11. The agrochemical formulation according to claim 10, wherein the oxyalkylene group is a reverse copolymer. 12. The agrochemical formulation according to claim 10, wherein the molar proportion of oxyethylene units comprised in the oxyalkylene group may be in the range of between 20% and 90%. 13. The agrochemical formulation according to claim 6, wherein the number of moles of oxyethylene present in each oxyalkylene group is independently an integer in the range from 1 to 8. 14. The agrochemical formulation according to claim 6, wherein the moles of both oxyethylene and oxypropylene units present in each adjuvant molecule has an integer value in the range of from 5 to 38. 15. The agrochemical formulation according to claim 6, wherein the molecular weight (weight average) of the adjuvant is in the range from 450 to 2,700. 16. A concentrate formulation suitable for making an agrochemical formulation, said concentrate comprising;
i) an adjuvant, wherein said adjuvant wherein said adjuvant has general structure (I):
Sorb.(AO1H)n1(AO2H)n2(AO3H)n3(AO4R1)n4 (I)
wherein:
Sorb represents a residue of a sorbitan or sorbitan derivative;
AO1, AO2, AO3, and AO4 each independently represents an oxyalkylene group formed from oxyethylene units, oxypropylene units, or a mixture thereof, wherein at least one of AO1, AO2, AO3, and AO4 comprises a mixture of oxyethylene and oxypropylene units;
the total sum of oxyethylene units and oxypropylene units is in the range from 5 to 38;
n1, n2, and n3 each independently represent an integer having a value of Q or 1; n4 represents a value of 1;
R1 represents an alkanoyl group —C(O)R2 wherein R2 represents a C4 to C28 hydrocarbyl; and
ii) optionally, at least one agrochemical active. 17. A method of treating vegetation to control pests, the method comprising applying a formulation according to claim 6 either to said vegetation or to an immediate environment of said vegetation. 18. A compound having general structure (I):
Sorb.(AO1H)n1(AO2H)n2(AO3H)n3(AO4R1)n4 (I)
wherein:
Sorb represents a residue of a sorbitan or sorbitan derivative;
AO1, AO2, AO3, and AO4 each independently represents an oxyalkylene group formed from oxyethylene units, oxypropylene units, or a mixture thereof, wherein at least one of AO1, AO2, AO3, and AO4 comprises a mixture of oxyethylene and oxypropylene units;
the total sum of oxyethylene units and oxypropylene units is in the range from 5 to 38;
n1, n2, and n3 each independently represent an integer having a value of 0 or 1; n4 represents a value of 1; and
R1 represents an alkanoyl group —C(O)R2 wherein R2 represents a C4 to C28 hydrocarbyl;
suitable for use as an adjuvant in an agrochemical formulation. | 1,600 |
740 | 15,035,633 | 1,613 | A composition comprising:
(a) a hydrogen peroxide source (b) an acetyl source (c) a peracetic acid bleachable dye
wherein, in solution, colour generated by said peracetic acid bleachable dye is substantially discharged when a biocidally effective concentration of peracetic acid is achieved. | 1. A composition comprising:
(a) a hydrogen peroxide source (b) an acetyl source (c) a peracetic acid bleachable dye wherein, in solution, colour generated by said peracetic acid bleachable dye is substantially discharged when a biocidally effective concentration of peracetic acid is achieved. 2. A composition according to claim 1 comprising in addition a substantially bleach stable dye. 3. A composition according to claim 1 wherein the biocidally effective concentration is greater than 0.14% w/w of peracetic acid of the solution. 4. A composition according to claim 1 wherein the composition is in powder form. 5. A composition according to claim 1 wherein the solution comprises water as solvent. 6. A composition according to claim 1 wherein the peracetic acid bleachable dye is a 1-arylazo-2-hydroxynaphthyl dye. 7. A composition according to claim 6 wherein the peracetic acid bleachable dye is selected from the group consisting of Amaranth (C.I. 16185), Ponceau 4R (C.I. 16255), FD&C Yellow 6 (C.I. 15985), any other 1-arylazo-2-hydroxynaphthyl dye, and combinations thereof. 8. A composition according to claim 7 wherein the peracetic acid bleachable dye is Amaranth (C.I. 16185). 9. A composition according to claim 2 wherein the substantially bleach stable dye is selected from the group consisting of Acid Blue 182, Acid Blue 80, Direct Blue 86, Acid Green 25 (C.I. 61570) and combinations thereof. 10. A composition according to claim 9 wherein the substantially bleach stable dye is Acid Blue 182 (C.I. 61570) 11. A composition according to claim 1 wherein the hydrogen peroxide source is selected from the group consisting of sodium perborate, sodium percarbonate, urea peroxide, povidone-hydrogen peroxide, calcium peroxide, hydrogen peroxide solution, and combinations thereof. 12. A composition according to claim 11 wherein the hydrogen peroxide source is sodium percarbonate. 13. A composition according to claim 1 wherein the acetyl donor is selected from the group consisting of tetraacetylethylenediamine (TAED), N-acetyl caprolactam, N-acetyl succinimide, N-acetyl phthalimide, N-acetyl maleimide, pentaacetyl glucose, octaacetyl sucrose, acetylsalicylic acid, tetraacetyl glycouril, and combinations thereof. 14. A composition according to claim 13 wherein the acetyl donor is tetraacetylethylenediamine (TAED). 15. A composition according to claim 1 in addition comprising one or more of an acidifying agent, a wetting agent, a pH buffering agent, a sequestering agent, a flow modifier, a perfume, other additives, or combinations thereof. 16. A composition comprising a combination of:
(i) a first part comprising a hydrogen peroxide source; and (ii) a second part comprising a mixture of an acetyl source and a peracetic acid bleachable dye; wherein, in solution, colour generated by said peracetic acid bleachable dye is substantially discharged when a biocidally effective concentration of peracetic acid is achieved. 17. The composition of claim 1 wherein a powder blend of the hydrogen peroxide source, acetyl source and peracetic acid bleachable dye is not classifiable as a Dangerous Good. 18. The composition of claim 1 wherein a powder blend of the hydrogen peroxide source, acetyl source and peracetic acid bleachable dye is not classifiable as a self-reactive solid. 19. A process of preparing a solution having biocidal properties, which process comprises dissolving the composition of claim 1 in a solvent and waiting for the colour generated by said peracetic acid bleachable dye to substantially discharge. 20. A biocidal composition comprising a solution of a hydrogen peroxide source, an acetyl source and a peracetic acid bleachable dye, wherein colour generated by said peracetic acid bleachable dye has substantially discharged. 21. The use of a composition of claim 1 for disinfecting an object or surface requiring disinfection. 22. A method of disinfecting an object or surface requiring disinfection, which method comprises preparing a solution of the composition of claim 1 and applying the solution to said object or surface after the colour generated by said peracetic acid bleachable dye has substantially discharged. 23. A method of disinfecting an object or surface requiring disinfection, which method comprises applying to said object or surface the biocidal composition of claim 20. | A composition comprising:
(a) a hydrogen peroxide source (b) an acetyl source (c) a peracetic acid bleachable dye
wherein, in solution, colour generated by said peracetic acid bleachable dye is substantially discharged when a biocidally effective concentration of peracetic acid is achieved.1. A composition comprising:
(a) a hydrogen peroxide source (b) an acetyl source (c) a peracetic acid bleachable dye wherein, in solution, colour generated by said peracetic acid bleachable dye is substantially discharged when a biocidally effective concentration of peracetic acid is achieved. 2. A composition according to claim 1 comprising in addition a substantially bleach stable dye. 3. A composition according to claim 1 wherein the biocidally effective concentration is greater than 0.14% w/w of peracetic acid of the solution. 4. A composition according to claim 1 wherein the composition is in powder form. 5. A composition according to claim 1 wherein the solution comprises water as solvent. 6. A composition according to claim 1 wherein the peracetic acid bleachable dye is a 1-arylazo-2-hydroxynaphthyl dye. 7. A composition according to claim 6 wherein the peracetic acid bleachable dye is selected from the group consisting of Amaranth (C.I. 16185), Ponceau 4R (C.I. 16255), FD&C Yellow 6 (C.I. 15985), any other 1-arylazo-2-hydroxynaphthyl dye, and combinations thereof. 8. A composition according to claim 7 wherein the peracetic acid bleachable dye is Amaranth (C.I. 16185). 9. A composition according to claim 2 wherein the substantially bleach stable dye is selected from the group consisting of Acid Blue 182, Acid Blue 80, Direct Blue 86, Acid Green 25 (C.I. 61570) and combinations thereof. 10. A composition according to claim 9 wherein the substantially bleach stable dye is Acid Blue 182 (C.I. 61570) 11. A composition according to claim 1 wherein the hydrogen peroxide source is selected from the group consisting of sodium perborate, sodium percarbonate, urea peroxide, povidone-hydrogen peroxide, calcium peroxide, hydrogen peroxide solution, and combinations thereof. 12. A composition according to claim 11 wherein the hydrogen peroxide source is sodium percarbonate. 13. A composition according to claim 1 wherein the acetyl donor is selected from the group consisting of tetraacetylethylenediamine (TAED), N-acetyl caprolactam, N-acetyl succinimide, N-acetyl phthalimide, N-acetyl maleimide, pentaacetyl glucose, octaacetyl sucrose, acetylsalicylic acid, tetraacetyl glycouril, and combinations thereof. 14. A composition according to claim 13 wherein the acetyl donor is tetraacetylethylenediamine (TAED). 15. A composition according to claim 1 in addition comprising one or more of an acidifying agent, a wetting agent, a pH buffering agent, a sequestering agent, a flow modifier, a perfume, other additives, or combinations thereof. 16. A composition comprising a combination of:
(i) a first part comprising a hydrogen peroxide source; and (ii) a second part comprising a mixture of an acetyl source and a peracetic acid bleachable dye; wherein, in solution, colour generated by said peracetic acid bleachable dye is substantially discharged when a biocidally effective concentration of peracetic acid is achieved. 17. The composition of claim 1 wherein a powder blend of the hydrogen peroxide source, acetyl source and peracetic acid bleachable dye is not classifiable as a Dangerous Good. 18. The composition of claim 1 wherein a powder blend of the hydrogen peroxide source, acetyl source and peracetic acid bleachable dye is not classifiable as a self-reactive solid. 19. A process of preparing a solution having biocidal properties, which process comprises dissolving the composition of claim 1 in a solvent and waiting for the colour generated by said peracetic acid bleachable dye to substantially discharge. 20. A biocidal composition comprising a solution of a hydrogen peroxide source, an acetyl source and a peracetic acid bleachable dye, wherein colour generated by said peracetic acid bleachable dye has substantially discharged. 21. The use of a composition of claim 1 for disinfecting an object or surface requiring disinfection. 22. A method of disinfecting an object or surface requiring disinfection, which method comprises preparing a solution of the composition of claim 1 and applying the solution to said object or surface after the colour generated by said peracetic acid bleachable dye has substantially discharged. 23. A method of disinfecting an object or surface requiring disinfection, which method comprises applying to said object or surface the biocidal composition of claim 20. | 1,600 |
741 | 13,980,593 | 1,612 | This disclosure relates to compounds and compositions for forming bone and methods related thereto. In certain embodiments, the disclosure relates to methods of forming bone comprising implanting a bone graft composition comprising a growth factor such as BMP in a subject at a site of desired bone growth or enhancement in combination with a JAB1 blocker. | 1. A bone graft composition comprising a quinoline derivative, 4-(phenoxy)-quinoline derivative, N-phenylquinolin-4-amine derivative, N2-(phenyl)-N4-(phenyl)pyrimidine-2,4-diamine derivative, 3-(benzylidene)indolin-2-one derivative, 2-((phenylamino)methylene)malononitrile derivative, 2-benzylidenemalononitrile derivative, N′-benzylidene-2-naphthohydrazide derivative, 3-((indol-3-yl)methylene)indolin-2-one derivative, or salt thereof. 2. The bone graft composition of claim 1, wherein the quinoline derivative, 4-(phenoxy)-quinoline derivative, N-phenylquinolin-4-amine derivative, N2-(phenyl)-N4-(phenyl)pyrimidine-2,4-diamine derivative, 3-(benzylidene)indolin-2-one derivative, 2-((phenylamino)methylene)malononitrile derivative, 2-benzylidenemalononitrile derivative, N′-benzylidene-2-naphthohydrazide derivative, 3-((indol-3-yl)methylene)indolin-2-one derivative, or salt thereof is covalently linked to a graft matrix. 3. The graft of claim 1 further comprising a growth factor. 4. The graft of claim 3, wherein the growth factor is a bone morphogenetic protein. 5. The graft of claim 4, wherein the bone morphogenetic protein is BMP-2, BMP-7, BMP-6, or BMP-9. 6. The graft composition of claim 1 further comprising calcium phosphates. 7. The graft composition of claim 6, wherein said calcium phosphates are hydroxyapatite and tricalcium phosphate. 8. The graft composition of claim 1 further comprising a collagen or hydrogel matrix. 9. A kit comprising a quinoline derivative, 4-(phenoxy)-quinoline derivative, N-phenylquinolin-4-amine derivative, N2-(phenyl)-N4-(phenyl)pyrimidine-2,4-diamine derivative, 3-(benzylidene)indolin-2-one derivative, 2-((phenylamino)methylene)malononitrile derivative, 2-benzylidenemalononitrile derivative, N′-benzylidene-2-naphthohydrazide derivative, 3-((indol-3-yl)methylene)indolin-2-one derivative, or salt thereof and a bone graft composition and optionally a bone morphogenetic protein. 10. A method of forming bone comprising implanting a bone graft composition comprising a JAB1 blocker optionally comprising a growth factor in a subject at a site of desired bone growth. 11. The method of claims 10 wherein the JAB1 blocker is a quinoline derivative, 4-(phenoxy)-quinoline derivative, N-phenylquinolin-4-amine derivative, N2-(phenyl)-N4-(phenyl)pyrimidine-2,4-diamine derivative, 3-(benzylidene)indolin-2-one derivative, 2-((phenylamino)methylene)malononitrile derivative, 2-benzylidenemalononitrile derivative, N′-benzylidene-2-naphthohydrazide derivative, 3-((indol-3-yl)methylene)indolin-2-one derivative, or salt thereof. 12. The method of claim 11, wherein the 4-(phenoxy)-quinoline derivative is 4-(4-bromo-3-methylphenoxy)-6,7-dimethoxyquinoline or salt thereof. 13. The method of claim 11, wherein the N2-(phenyl)-N4-(phenyl)pyrimidine-2,4-diamine derivative is N2-(3,5-dimethoxyphenyl)-N4-(4-fluorophenyl)pyrimidine-2,4-diamine. 14. The method of claim 11, wherein the 3-(benzylidene)indolin-2-one derivative is 6-chloro-3-(2,4,6-trimethoxybenzylidene)indolin-2-one. 15. The method of claim 10, wherein the growth factor is a bone morphogenetic protein. 16. The method of claim 15, wherein the bone morphogenetic protein is BMP-2, BMP-7, BMP-6, or BMP-9. 17. A pharmaceutical composition comprising a quinoline derivative, 4-(phenoxy)-quinoline derivative, N-phenylquinolin-4-amine derivative, N2-(phenyl)-N4-(phenyl)pyrimidine-2,4-diamine derivative, 3-(benzylidene)indolin-2-one derivative, 2-((phenylamino)methylene)malononitrile derivative, 2-benzylidenemalononitrile derivative, N′-benzylidene-2-naphthohydrazide derivative, 3-((indol-3-yl)methylene)indolin-2-one derivative, or pharmaceutically acceptable salt thereof 18. A method of forming bone comprising
a) implanting a bone graft composition optionally comprising a JAB1 blocker and optionally comprising a growth factor in a subject at a site of desired bone growth and b) administering a pharmaceutical composition comprising a JAB1 blocker to the subject. | This disclosure relates to compounds and compositions for forming bone and methods related thereto. In certain embodiments, the disclosure relates to methods of forming bone comprising implanting a bone graft composition comprising a growth factor such as BMP in a subject at a site of desired bone growth or enhancement in combination with a JAB1 blocker.1. A bone graft composition comprising a quinoline derivative, 4-(phenoxy)-quinoline derivative, N-phenylquinolin-4-amine derivative, N2-(phenyl)-N4-(phenyl)pyrimidine-2,4-diamine derivative, 3-(benzylidene)indolin-2-one derivative, 2-((phenylamino)methylene)malononitrile derivative, 2-benzylidenemalononitrile derivative, N′-benzylidene-2-naphthohydrazide derivative, 3-((indol-3-yl)methylene)indolin-2-one derivative, or salt thereof. 2. The bone graft composition of claim 1, wherein the quinoline derivative, 4-(phenoxy)-quinoline derivative, N-phenylquinolin-4-amine derivative, N2-(phenyl)-N4-(phenyl)pyrimidine-2,4-diamine derivative, 3-(benzylidene)indolin-2-one derivative, 2-((phenylamino)methylene)malononitrile derivative, 2-benzylidenemalononitrile derivative, N′-benzylidene-2-naphthohydrazide derivative, 3-((indol-3-yl)methylene)indolin-2-one derivative, or salt thereof is covalently linked to a graft matrix. 3. The graft of claim 1 further comprising a growth factor. 4. The graft of claim 3, wherein the growth factor is a bone morphogenetic protein. 5. The graft of claim 4, wherein the bone morphogenetic protein is BMP-2, BMP-7, BMP-6, or BMP-9. 6. The graft composition of claim 1 further comprising calcium phosphates. 7. The graft composition of claim 6, wherein said calcium phosphates are hydroxyapatite and tricalcium phosphate. 8. The graft composition of claim 1 further comprising a collagen or hydrogel matrix. 9. A kit comprising a quinoline derivative, 4-(phenoxy)-quinoline derivative, N-phenylquinolin-4-amine derivative, N2-(phenyl)-N4-(phenyl)pyrimidine-2,4-diamine derivative, 3-(benzylidene)indolin-2-one derivative, 2-((phenylamino)methylene)malononitrile derivative, 2-benzylidenemalononitrile derivative, N′-benzylidene-2-naphthohydrazide derivative, 3-((indol-3-yl)methylene)indolin-2-one derivative, or salt thereof and a bone graft composition and optionally a bone morphogenetic protein. 10. A method of forming bone comprising implanting a bone graft composition comprising a JAB1 blocker optionally comprising a growth factor in a subject at a site of desired bone growth. 11. The method of claims 10 wherein the JAB1 blocker is a quinoline derivative, 4-(phenoxy)-quinoline derivative, N-phenylquinolin-4-amine derivative, N2-(phenyl)-N4-(phenyl)pyrimidine-2,4-diamine derivative, 3-(benzylidene)indolin-2-one derivative, 2-((phenylamino)methylene)malononitrile derivative, 2-benzylidenemalononitrile derivative, N′-benzylidene-2-naphthohydrazide derivative, 3-((indol-3-yl)methylene)indolin-2-one derivative, or salt thereof. 12. The method of claim 11, wherein the 4-(phenoxy)-quinoline derivative is 4-(4-bromo-3-methylphenoxy)-6,7-dimethoxyquinoline or salt thereof. 13. The method of claim 11, wherein the N2-(phenyl)-N4-(phenyl)pyrimidine-2,4-diamine derivative is N2-(3,5-dimethoxyphenyl)-N4-(4-fluorophenyl)pyrimidine-2,4-diamine. 14. The method of claim 11, wherein the 3-(benzylidene)indolin-2-one derivative is 6-chloro-3-(2,4,6-trimethoxybenzylidene)indolin-2-one. 15. The method of claim 10, wherein the growth factor is a bone morphogenetic protein. 16. The method of claim 15, wherein the bone morphogenetic protein is BMP-2, BMP-7, BMP-6, or BMP-9. 17. A pharmaceutical composition comprising a quinoline derivative, 4-(phenoxy)-quinoline derivative, N-phenylquinolin-4-amine derivative, N2-(phenyl)-N4-(phenyl)pyrimidine-2,4-diamine derivative, 3-(benzylidene)indolin-2-one derivative, 2-((phenylamino)methylene)malononitrile derivative, 2-benzylidenemalononitrile derivative, N′-benzylidene-2-naphthohydrazide derivative, 3-((indol-3-yl)methylene)indolin-2-one derivative, or pharmaceutically acceptable salt thereof 18. A method of forming bone comprising
a) implanting a bone graft composition optionally comprising a JAB1 blocker and optionally comprising a growth factor in a subject at a site of desired bone growth and b) administering a pharmaceutical composition comprising a JAB1 blocker to the subject. | 1,600 |
742 | 16,200,233 | 1,648 | The invention relates to an influenza vaccine composition for spray-administration to nasal mucosa, which comprises an inactivated whole influenza virion and a gel base material comprising carboxy vinyl polymer, which is characterized by not comprising an adjuvant. | 1-10. (canceled) 11. A method for preventing influenza in a human subject, comprising:
administering to the human subject an influenza vaccine composition comprising: (i) an inactivated whole influenza virion; and (ii) a gel base material comprising carboxy vinyl polymer
that is prepared by treating the gel base material by adding an outside shearing force with a high-speed spinning-type emulsifying device, a colloidal mill-type emulsifying device, a high-pressure emulsifying device, a roll mill-type emulsifying device, an ultrasonic-type emulsifying device or a membrane-type emulsifying device to add spray-performance, and then mixing the resulting gel base material with a virus stock solution comprising an inactivated whole influenza virion homogeneously without stress,
wherein the influenza vaccine composition does not comprise and adjutant,
by spraying the influenza vaccine composition from a spray device that can spray a viscous formulation from naris to intranasal mucosa of the human subject. 12. The method of claim 11, wherein the influenza vaccine composition contains the inactivated whole influenza virion in an amount of 1-500 μg HA/mL per type of vaccine virus strain. 13. The method of claim 11, wherein the influenza vaccine composition comprises 0.1 w/v % to 1.0 w/v % carboxy vinyl polymer. 14. The method of claim 11, wherein the gel base material comprises 0.5 w/v % to 2.0 w/v % carboxy vinyl polymer. 15. The method of claim 11, wherein
(1) a the particle-size-distribution of the sprayed composition has a mean particle size is in a range of 30 μm to 80 μm, and a particle distribution between 10 μm and 100 μm is 80% or more, (2) a spray density is uniform to form a homogeneous full-corn shape, and (3) a spray angle is in a range of 30° to 70°. 16. The method of claim 15, wherein
(1) the mean particle size is in a range of 40 μm to 70 μm, and the particle distribution between 10 μm and 100 μm is 90% or more, (2) the spray density is uniform to form a homogeneous full-corn shape, and (3) the spray angle is adjusted in a range of 40° to 60°. 17. The method of claim 11, wherein the spray device sprays the influenza vaccine composition without a pumping function. | The invention relates to an influenza vaccine composition for spray-administration to nasal mucosa, which comprises an inactivated whole influenza virion and a gel base material comprising carboxy vinyl polymer, which is characterized by not comprising an adjuvant.1-10. (canceled) 11. A method for preventing influenza in a human subject, comprising:
administering to the human subject an influenza vaccine composition comprising: (i) an inactivated whole influenza virion; and (ii) a gel base material comprising carboxy vinyl polymer
that is prepared by treating the gel base material by adding an outside shearing force with a high-speed spinning-type emulsifying device, a colloidal mill-type emulsifying device, a high-pressure emulsifying device, a roll mill-type emulsifying device, an ultrasonic-type emulsifying device or a membrane-type emulsifying device to add spray-performance, and then mixing the resulting gel base material with a virus stock solution comprising an inactivated whole influenza virion homogeneously without stress,
wherein the influenza vaccine composition does not comprise and adjutant,
by spraying the influenza vaccine composition from a spray device that can spray a viscous formulation from naris to intranasal mucosa of the human subject. 12. The method of claim 11, wherein the influenza vaccine composition contains the inactivated whole influenza virion in an amount of 1-500 μg HA/mL per type of vaccine virus strain. 13. The method of claim 11, wherein the influenza vaccine composition comprises 0.1 w/v % to 1.0 w/v % carboxy vinyl polymer. 14. The method of claim 11, wherein the gel base material comprises 0.5 w/v % to 2.0 w/v % carboxy vinyl polymer. 15. The method of claim 11, wherein
(1) a the particle-size-distribution of the sprayed composition has a mean particle size is in a range of 30 μm to 80 μm, and a particle distribution between 10 μm and 100 μm is 80% or more, (2) a spray density is uniform to form a homogeneous full-corn shape, and (3) a spray angle is in a range of 30° to 70°. 16. The method of claim 15, wherein
(1) the mean particle size is in a range of 40 μm to 70 μm, and the particle distribution between 10 μm and 100 μm is 90% or more, (2) the spray density is uniform to form a homogeneous full-corn shape, and (3) the spray angle is adjusted in a range of 40° to 60°. 17. The method of claim 11, wherein the spray device sprays the influenza vaccine composition without a pumping function. | 1,600 |
743 | 15,521,787 | 1,617 | The invention relates to an oil-based cleansing product which contains abrasive particles as exfoliating substances. In one particular embodiment, salt and sugar crystals are used as exfoliating substances. | 1.-20. (canceled) 21. A skin cleansing preparation, wherein the preparation has an abrasive effect, comprises less than 5% of water and comprises
(a) one or more lipids, (b) one or more polyols, (c) one or more oil-soluble surfactants, (d) one or more kinds of abrasive particles, and (e) one or more polymeric structurants, 22. The preparation of claim 21, wherein a weight ratio of (a) and (b) is from 4:1 to 1:4. 23. The preparation of claim 21, wherein a weight ratio of (a) plus (b) to surfactants is from 2:1 to 1:2. 24. The preparation of claim 21, wherein (c) comprises one or more non-ionic surfactants. 25. The preparation of claim 21, wherein the preparation comprises at least one non-ionic principal surfactant, 26. The preparation of claim 21, wherein the preparation comprises at least one cosurfactant. 27. The preparation of claim 26, wherein the cosurfactant is an amide of a C10-C16-fatty acid. 28. The preparation of claim 26, wherein the cosurfactant is an amide of a C10-C16-fatty acid which is different from a principal surfactant. 29. The preparation of claim 26, wherein the cosurfactant is selected from alkoxylated fatty alcohols having a chain length of from 8 to 16 and a degree of alkoxylation of from 2 to 10. 30. The preparation of claim 26, wherein the cosurfactant is selected from ethoxylated fatty alcohols. 31. The preparation of claim 26, wherein the cosurfactant comprises an amide of a C10-C16-fatty acid and an alkoxylated fatty alcohol having a chain length of from 8 to 16 and a degree of alkoxylation of from 2 to 10. 32. The preparation of claim 21, wherein (b) comprises at least one of propylene glycol and glycerol. 33. The preparation of claim 21, wherein (e) comprises one or more anionic polymers. 34. The preparation of claim 21, wherein (e) comprises one or more crosslinked acrylic acid copolymers. 35. The preparation of claim21, wherein (d) comprises one or more soluble kinds of particles. 36. The preparation of claim 35, wherein the one or more soluble kinds of particles comprise sugar and/or salt particles. 37. The preparation of claim 36, wherein (d) comprises sucrose. 38. The preparation of claim 21, wherein (d) comprises sodium chloride. 39. The preparation of claim 21, wherein (d) comprises particles of natural origin. 40. A method of deep cleansing dry and/or sensitive and/or aged skin, wherein the method comprises treating the dry and/or sensitive and/or aged skin with the preparation of claim 21. | The invention relates to an oil-based cleansing product which contains abrasive particles as exfoliating substances. In one particular embodiment, salt and sugar crystals are used as exfoliating substances.1.-20. (canceled) 21. A skin cleansing preparation, wherein the preparation has an abrasive effect, comprises less than 5% of water and comprises
(a) one or more lipids, (b) one or more polyols, (c) one or more oil-soluble surfactants, (d) one or more kinds of abrasive particles, and (e) one or more polymeric structurants, 22. The preparation of claim 21, wherein a weight ratio of (a) and (b) is from 4:1 to 1:4. 23. The preparation of claim 21, wherein a weight ratio of (a) plus (b) to surfactants is from 2:1 to 1:2. 24. The preparation of claim 21, wherein (c) comprises one or more non-ionic surfactants. 25. The preparation of claim 21, wherein the preparation comprises at least one non-ionic principal surfactant, 26. The preparation of claim 21, wherein the preparation comprises at least one cosurfactant. 27. The preparation of claim 26, wherein the cosurfactant is an amide of a C10-C16-fatty acid. 28. The preparation of claim 26, wherein the cosurfactant is an amide of a C10-C16-fatty acid which is different from a principal surfactant. 29. The preparation of claim 26, wherein the cosurfactant is selected from alkoxylated fatty alcohols having a chain length of from 8 to 16 and a degree of alkoxylation of from 2 to 10. 30. The preparation of claim 26, wherein the cosurfactant is selected from ethoxylated fatty alcohols. 31. The preparation of claim 26, wherein the cosurfactant comprises an amide of a C10-C16-fatty acid and an alkoxylated fatty alcohol having a chain length of from 8 to 16 and a degree of alkoxylation of from 2 to 10. 32. The preparation of claim 21, wherein (b) comprises at least one of propylene glycol and glycerol. 33. The preparation of claim 21, wherein (e) comprises one or more anionic polymers. 34. The preparation of claim 21, wherein (e) comprises one or more crosslinked acrylic acid copolymers. 35. The preparation of claim21, wherein (d) comprises one or more soluble kinds of particles. 36. The preparation of claim 35, wherein the one or more soluble kinds of particles comprise sugar and/or salt particles. 37. The preparation of claim 36, wherein (d) comprises sucrose. 38. The preparation of claim 21, wherein (d) comprises sodium chloride. 39. The preparation of claim 21, wherein (d) comprises particles of natural origin. 40. A method of deep cleansing dry and/or sensitive and/or aged skin, wherein the method comprises treating the dry and/or sensitive and/or aged skin with the preparation of claim 21. | 1,600 |
744 | 14,420,518 | 1,618 | Provided is an antimicrobial non-isotactic polymer based hard or semi-flexible surface in a thermoset and/or thermoplastic resin matrix wherein the active antimicrobial ingredient is copper oxide! Processes for preparing the same and applications thereof are also described. The invention is directed to polymeric solid panels and slab possessing and polymer resin treatments imparting antibacterial, antifungal, antiviral and sporicidal properties. | 1. A composite structural solid material comprising a polymeric resin and copper oxide particles substantially uniformly dispersed therein optionally further comprising a filler material, wherein said copper oxide is present at a concentration ranging from 10 to 50% w/w % and wherein a portion of said copper oxide particles are surface exposed. 2. The composite structural solid material of claim 1, wherein said polymeric resin comprises epoxy, acrylic or polyester resins or thermoset resins or a combination thereof. 3. (canceled) 4. The composite structural solid material of claim 1, wherein said composite structural solid material further comprises calcium carbonate, marble, granite, quartz, feldspar, marble and quartzite and mixtures thereof. 5. The composite structural solid material of claim 1, wherein said filler material comprises fumed silica, sand, clay, kaolin, fly ash, cement, broken ceramics, mica, silicate flakes, broken glass, glass beads, glass spheres, mirror fragments, steel grit, aluminum grit, carbides, plastic beads, pelletized rubber, ground polymer composites, wood chips, sawdust, paper laminates, pigments, colorants, and mixtures thereof. 6. The composite structural solid material of claim 1, wherein said filler material makes up to between 10% and 75% by weight of the total composition. 7. The composite structural solid material of claim 1, wherein said copper oxide particle have a size ranging from a preferred size of 5 to about 20 microns but can be of almost any size. 8. A finished product comprising the composite structural solid material of claim 1, wherein said finished product comprises a work top, tabletop, a countertop and backsplash, architectural facings and moldings, walkways, home finishing, patio furniture, hospital furniture, hospital bed fittings, handles, decorative stone, indoor and outdoor tile, flooring, mantles, wall facings both cladding sheets and decorative surfacing, bathroom fixtures, imitation stone structures cast and molded structures, and other related materials for which incorporation of the composite structural solid material there within is appropriate. 9. The composite structural solid material of claim 1, wherein said composite structural solid material is cast into a sheet or is cast using a compression molding process or is cast using an extrusion process or is cast using an injection molding process. 10-12. (canceled) 13. The composite structural liquid material of claim 1, wherein said composite structural liquid material is sprayed or painted on a surface or wherein said composite structural liquid material is used as a glue or binder for composite constructions and parts such as glass reinforced plastic, fiber glass composites, carbon fiber composites, Keval composites and the like. 14. (canceled) 15. A mixed batch process for the manufacture of a composite structural solid material comprising a polymeric resin and copper oxide particles substantially uniformly dispersed therein the process comprising the steps of:
mixing a polymeric resin, a filler and optionally a pigment; mixing a catalyst with a mixture of said polymeric resin, filler and optionally said pigment; simultaneously mixing copper oxide or a copper oxide containing composition with said catalyst to said mixture of said polymeric resin, filler and optionally said pigment or stepwise mixing copper oxide or a copper oxide containing composition with said mixture of said polymeric resin, filler and optionally said pigment and said catalyst to form a polymerizable composite structural material; distributing said polymerizable composite structural material in a mold; and providing conditions for polymerization of said polymerizable composite structural material, thereby preparing a composite structural solid material. 16. The process of claim 15, wherein said process further comprises adjusting a viscosity level of said mixture by altering the quantity of filler added to said mixture, by altering the concentration of catalyst added to said mixture or a combination thereof. 17. The process of claim 15, wherein said catalyst is methyl ethyl ketone. 18. The process of claim 15, wherein said polymeric resin comprises epoxy, acrylic or polyester resins or wherein said polymeric resin comprises thermoplastic resins, thermoset resins or a combination thereof. 19-20. (canceled) 21. The process of claim 15, wherein said filler comprises calcium carbonate, marble, granite, quartz, feldspar, marble and quartzite and mixtures thereof. 22. The process of claim 15, wherein said filler material comprises fumed silica, sand, clay, fly ash, cement, broken ceramics, mica, silicate flakes, broken glass, glass beads, glass spheres, mirror fragments, steel grit, aluminum grit, carbides, plastic beads, pelletized rubber, ground polymer composites, wood chips, sawdust, paper laminates, pigments, colorants, and mixtures thereof. 23. The process of claim 15, wherein said filler material makes up to between 10 and 30% by weight of the total composition. 24. The process of claim 15, wherein said copper oxide particle have a size ranging from about 5 to about 20 microns. 25. (canceled) 26. The process of claim 15, further comprising the step of preparing a finished product incorporating said composite structural solid material. 27. The process of claim 26, wherein said finished product comprises a tabletop, a countertop, architectural facings, walkways, home finishing, patio furniture, decorative stone, indoor and outdoor tile, flooring, mantles, wall facings, bathroom fixtures, and imitation stone structures tabletop, a countertop, architectural facings and moldings, walkways, home finishing, patio furniture, hospital furniture, hospital bed fittings, handles, decorative stone, indoor and outdoor tile, flooring, mantles, wall facings both cladding sheets and decorative surfacing (painting), bathroom fixtures, imitation stone structures cast and molded structures, and other related materials for which incorporation of the composite structural solid material there within is appropriate. 28. The process of claim 15, further comprising the step of casting said polymeric resin mixture containing copper oxide powder and catalyst into a sheet or further comprising the step of casting said polymeric resin mixture containing copper oxide powder and catalyst using a compression molding process or further comprising the step of casting said polymeric resin mixture containing copper oxide powder and catalyst using an extrusion process or further comprising the step of casting said polymeric resin mixture containing copper oxide powder and catalyst using an injection molding process. 29-31. (canceled) 32. A continuous pour process for the manufacture of a composite structural solid material comprising a polymeric resin and copper oxide particles substantially uniformly dispersed therein the process comprising the steps of:
mixing a polymeric resin or a filler with copper oxide until well blended to form a resin-copper oxide paste or filler-copper oxide blend; stepwise, subsequently mixing said resin-copper oxide paste or filler-copper oxide blend with a filler or resin, respectively and optionally a pigment to form a copper oxide containing blended composition; stepwise, subsequently mixing a catalyst with said copper oxide containing blended composition to form a polymerizable composite structural material; distributing said polymerizable composite structural material in a mold; and providing conditions for polymerization of said polymerizable composite structural material, thereby preparing a composite structural solid material. 33. The process of claim 32, wherein said process further comprises adjusting a viscosity level of said mixture by altering the quantity of filler added to said mixture, by altering the concentration of catalyst added to said mixture or a combination thereof. 34. The process of claim 32, wherein said resin-copper oxide paste or filler-copper oxide blend is mixed with a filler or resin, respectively and a second copper oxide containing composition and optionally a pigment. 35. The process of claim 32, wherein said catalyst is methyl ethyl ketone. 36. The process of claim 32, wherein said polymeric resin comprises epoxy, acrylic or polyester resins or said polymeric resin comprises thermoplastic resins, thermoset resins or a combination thereof. 37-38. (canceled) 39. The process of claim 32, wherein said filler comprises calcium carbonate, marble, granite, quartz, feldspar, marble and quartzite and mixtures thereof. 40. The process of claim 32, wherein said filler material comprises fumed silica, sand, clay, fly ash, cement, broken ceramics, mica, silicate flakes, broken glass, glass beads, glass spheres, mirror fragments, steel grit, aluminum grit, carbides, plastic beads, pelletized rubber, ground polymer composites, wood chips, sawdust, paper laminates, pigments, colorants, and mixtures thereof. 41. The process of claim 32, wherein said filler material makes up to between 10 and 30% by weight of the total composition. 42. The process of claim 32, wherein said copper oxide particle have a size ranging from about 5 to about 20 microns. 43. (canceled) 44. The process of claim 32, further comprising the step of preparing a finished product incorporating said composite structural solid material. 45. The process of claim 44, wherein said finished product comprises a tabletop, a countertop, architectural facings, walkways, home finishing, patio furniture, decorative stone, indoor and outdoor tile, flooring, mantles, wall facings, bathroom fixtures, and imitation stone structures tabletop, a countertop, architectural facings and moldings, walkways, home finishing, patio furniture, hospital furniture, hospital bed fittings, handles, decorative stone, indoor and outdoor tile, flooring, mantles, wall facings both cladding sheets and decorative surfacing (painting), bathroom fixtures, imitation stone structures cast and molded structures, and other related materials for which incorporation of the composite structural solid material there within is appropriate. 46. The process of claim 32, further comprising the step of casting said polymeric resin mixture containing copper oxide powder and catalyst into a sheet or further comprising the step of casting said polymeric resin mixture containing copper oxide powder and catalyst using a compression molding process or further comprising the step of casting said polymeric resin mixture containing copper oxide powder and catalyst using an extrusion process or further comprising the step of casting said polymeric resin mixture containing copper oxide powder and catalyst using an injection molding process. 47-49. (canceled) 50. A composite structural solid material prepared by the process of claim 32, further comprising said polymeric resin mixture containing copper oxide powder and catalyst using a spray or paint application process. 51. A method for imparting antimicrobial activity to a composite structural solid material, said method comprising preparing a composite structural solid material containing copper oxide dispersed therein, wherein said copper oxide is present at a concentration ranging from 10 to 50% w/w % and wherein a portion of said copper oxide particles are surface exposed. 52. The method of claim 51, wherein an exposed surface of said composite structural solid material has an antimicrobial reduction activity representing a 90% reduction of microbial units within 24 hours of sample incubation. 53. The method of claim 52, wherein an exposed surface of said composite structural solid material is characterized in its ability to be repeatedly exposed to organism challenge while maintaining said antimicrobial reduction activity during a period of time within said 24 hours of sample incubation. 54. The method of claim 51, wherein said antimicrobial activity represents bactericidal, sporicidal, or bacteriostatic activity. 55. The method of claim 51, wherein said antimicrobial activity represents fungicidal, viricidal, fungistatic or viristatic activity. | Provided is an antimicrobial non-isotactic polymer based hard or semi-flexible surface in a thermoset and/or thermoplastic resin matrix wherein the active antimicrobial ingredient is copper oxide! Processes for preparing the same and applications thereof are also described. The invention is directed to polymeric solid panels and slab possessing and polymer resin treatments imparting antibacterial, antifungal, antiviral and sporicidal properties.1. A composite structural solid material comprising a polymeric resin and copper oxide particles substantially uniformly dispersed therein optionally further comprising a filler material, wherein said copper oxide is present at a concentration ranging from 10 to 50% w/w % and wherein a portion of said copper oxide particles are surface exposed. 2. The composite structural solid material of claim 1, wherein said polymeric resin comprises epoxy, acrylic or polyester resins or thermoset resins or a combination thereof. 3. (canceled) 4. The composite structural solid material of claim 1, wherein said composite structural solid material further comprises calcium carbonate, marble, granite, quartz, feldspar, marble and quartzite and mixtures thereof. 5. The composite structural solid material of claim 1, wherein said filler material comprises fumed silica, sand, clay, kaolin, fly ash, cement, broken ceramics, mica, silicate flakes, broken glass, glass beads, glass spheres, mirror fragments, steel grit, aluminum grit, carbides, plastic beads, pelletized rubber, ground polymer composites, wood chips, sawdust, paper laminates, pigments, colorants, and mixtures thereof. 6. The composite structural solid material of claim 1, wherein said filler material makes up to between 10% and 75% by weight of the total composition. 7. The composite structural solid material of claim 1, wherein said copper oxide particle have a size ranging from a preferred size of 5 to about 20 microns but can be of almost any size. 8. A finished product comprising the composite structural solid material of claim 1, wherein said finished product comprises a work top, tabletop, a countertop and backsplash, architectural facings and moldings, walkways, home finishing, patio furniture, hospital furniture, hospital bed fittings, handles, decorative stone, indoor and outdoor tile, flooring, mantles, wall facings both cladding sheets and decorative surfacing, bathroom fixtures, imitation stone structures cast and molded structures, and other related materials for which incorporation of the composite structural solid material there within is appropriate. 9. The composite structural solid material of claim 1, wherein said composite structural solid material is cast into a sheet or is cast using a compression molding process or is cast using an extrusion process or is cast using an injection molding process. 10-12. (canceled) 13. The composite structural liquid material of claim 1, wherein said composite structural liquid material is sprayed or painted on a surface or wherein said composite structural liquid material is used as a glue or binder for composite constructions and parts such as glass reinforced plastic, fiber glass composites, carbon fiber composites, Keval composites and the like. 14. (canceled) 15. A mixed batch process for the manufacture of a composite structural solid material comprising a polymeric resin and copper oxide particles substantially uniformly dispersed therein the process comprising the steps of:
mixing a polymeric resin, a filler and optionally a pigment; mixing a catalyst with a mixture of said polymeric resin, filler and optionally said pigment; simultaneously mixing copper oxide or a copper oxide containing composition with said catalyst to said mixture of said polymeric resin, filler and optionally said pigment or stepwise mixing copper oxide or a copper oxide containing composition with said mixture of said polymeric resin, filler and optionally said pigment and said catalyst to form a polymerizable composite structural material; distributing said polymerizable composite structural material in a mold; and providing conditions for polymerization of said polymerizable composite structural material, thereby preparing a composite structural solid material. 16. The process of claim 15, wherein said process further comprises adjusting a viscosity level of said mixture by altering the quantity of filler added to said mixture, by altering the concentration of catalyst added to said mixture or a combination thereof. 17. The process of claim 15, wherein said catalyst is methyl ethyl ketone. 18. The process of claim 15, wherein said polymeric resin comprises epoxy, acrylic or polyester resins or wherein said polymeric resin comprises thermoplastic resins, thermoset resins or a combination thereof. 19-20. (canceled) 21. The process of claim 15, wherein said filler comprises calcium carbonate, marble, granite, quartz, feldspar, marble and quartzite and mixtures thereof. 22. The process of claim 15, wherein said filler material comprises fumed silica, sand, clay, fly ash, cement, broken ceramics, mica, silicate flakes, broken glass, glass beads, glass spheres, mirror fragments, steel grit, aluminum grit, carbides, plastic beads, pelletized rubber, ground polymer composites, wood chips, sawdust, paper laminates, pigments, colorants, and mixtures thereof. 23. The process of claim 15, wherein said filler material makes up to between 10 and 30% by weight of the total composition. 24. The process of claim 15, wherein said copper oxide particle have a size ranging from about 5 to about 20 microns. 25. (canceled) 26. The process of claim 15, further comprising the step of preparing a finished product incorporating said composite structural solid material. 27. The process of claim 26, wherein said finished product comprises a tabletop, a countertop, architectural facings, walkways, home finishing, patio furniture, decorative stone, indoor and outdoor tile, flooring, mantles, wall facings, bathroom fixtures, and imitation stone structures tabletop, a countertop, architectural facings and moldings, walkways, home finishing, patio furniture, hospital furniture, hospital bed fittings, handles, decorative stone, indoor and outdoor tile, flooring, mantles, wall facings both cladding sheets and decorative surfacing (painting), bathroom fixtures, imitation stone structures cast and molded structures, and other related materials for which incorporation of the composite structural solid material there within is appropriate. 28. The process of claim 15, further comprising the step of casting said polymeric resin mixture containing copper oxide powder and catalyst into a sheet or further comprising the step of casting said polymeric resin mixture containing copper oxide powder and catalyst using a compression molding process or further comprising the step of casting said polymeric resin mixture containing copper oxide powder and catalyst using an extrusion process or further comprising the step of casting said polymeric resin mixture containing copper oxide powder and catalyst using an injection molding process. 29-31. (canceled) 32. A continuous pour process for the manufacture of a composite structural solid material comprising a polymeric resin and copper oxide particles substantially uniformly dispersed therein the process comprising the steps of:
mixing a polymeric resin or a filler with copper oxide until well blended to form a resin-copper oxide paste or filler-copper oxide blend; stepwise, subsequently mixing said resin-copper oxide paste or filler-copper oxide blend with a filler or resin, respectively and optionally a pigment to form a copper oxide containing blended composition; stepwise, subsequently mixing a catalyst with said copper oxide containing blended composition to form a polymerizable composite structural material; distributing said polymerizable composite structural material in a mold; and providing conditions for polymerization of said polymerizable composite structural material, thereby preparing a composite structural solid material. 33. The process of claim 32, wherein said process further comprises adjusting a viscosity level of said mixture by altering the quantity of filler added to said mixture, by altering the concentration of catalyst added to said mixture or a combination thereof. 34. The process of claim 32, wherein said resin-copper oxide paste or filler-copper oxide blend is mixed with a filler or resin, respectively and a second copper oxide containing composition and optionally a pigment. 35. The process of claim 32, wherein said catalyst is methyl ethyl ketone. 36. The process of claim 32, wherein said polymeric resin comprises epoxy, acrylic or polyester resins or said polymeric resin comprises thermoplastic resins, thermoset resins or a combination thereof. 37-38. (canceled) 39. The process of claim 32, wherein said filler comprises calcium carbonate, marble, granite, quartz, feldspar, marble and quartzite and mixtures thereof. 40. The process of claim 32, wherein said filler material comprises fumed silica, sand, clay, fly ash, cement, broken ceramics, mica, silicate flakes, broken glass, glass beads, glass spheres, mirror fragments, steel grit, aluminum grit, carbides, plastic beads, pelletized rubber, ground polymer composites, wood chips, sawdust, paper laminates, pigments, colorants, and mixtures thereof. 41. The process of claim 32, wherein said filler material makes up to between 10 and 30% by weight of the total composition. 42. The process of claim 32, wherein said copper oxide particle have a size ranging from about 5 to about 20 microns. 43. (canceled) 44. The process of claim 32, further comprising the step of preparing a finished product incorporating said composite structural solid material. 45. The process of claim 44, wherein said finished product comprises a tabletop, a countertop, architectural facings, walkways, home finishing, patio furniture, decorative stone, indoor and outdoor tile, flooring, mantles, wall facings, bathroom fixtures, and imitation stone structures tabletop, a countertop, architectural facings and moldings, walkways, home finishing, patio furniture, hospital furniture, hospital bed fittings, handles, decorative stone, indoor and outdoor tile, flooring, mantles, wall facings both cladding sheets and decorative surfacing (painting), bathroom fixtures, imitation stone structures cast and molded structures, and other related materials for which incorporation of the composite structural solid material there within is appropriate. 46. The process of claim 32, further comprising the step of casting said polymeric resin mixture containing copper oxide powder and catalyst into a sheet or further comprising the step of casting said polymeric resin mixture containing copper oxide powder and catalyst using a compression molding process or further comprising the step of casting said polymeric resin mixture containing copper oxide powder and catalyst using an extrusion process or further comprising the step of casting said polymeric resin mixture containing copper oxide powder and catalyst using an injection molding process. 47-49. (canceled) 50. A composite structural solid material prepared by the process of claim 32, further comprising said polymeric resin mixture containing copper oxide powder and catalyst using a spray or paint application process. 51. A method for imparting antimicrobial activity to a composite structural solid material, said method comprising preparing a composite structural solid material containing copper oxide dispersed therein, wherein said copper oxide is present at a concentration ranging from 10 to 50% w/w % and wherein a portion of said copper oxide particles are surface exposed. 52. The method of claim 51, wherein an exposed surface of said composite structural solid material has an antimicrobial reduction activity representing a 90% reduction of microbial units within 24 hours of sample incubation. 53. The method of claim 52, wherein an exposed surface of said composite structural solid material is characterized in its ability to be repeatedly exposed to organism challenge while maintaining said antimicrobial reduction activity during a period of time within said 24 hours of sample incubation. 54. The method of claim 51, wherein said antimicrobial activity represents bactericidal, sporicidal, or bacteriostatic activity. 55. The method of claim 51, wherein said antimicrobial activity represents fungicidal, viricidal, fungistatic or viristatic activity. | 1,600 |
745 | 11,464,704 | 1,613 | A process for manufacturing and using pancreatin micropellet cores and pancreatin micropellets which are substantially free of synthetic oils. In one embodiment, a pharmaceutical composition is provided comprising a pancreatin micropellet with the enteric coating being designed to deliver pancreatin to the upper portion of the intestine of a mammal for release. | 1. A process for the manufacture of pancreatin micropellet cores, comprising the steps of:
a. preparing an extrudable mixture comprising:
i. about 10% to about 95% pancreatin;
ii. about 5% to about 90% of at least one pharmaceutically acceptable binding agent;
iii. 0% to about 10% of at least one pharmaceutically acceptable excipient; and
iv. one or more enzyme-friendly organic solvents in an amount sufficient to form an extrudable mixture;
wherein the percentages of components are weight to weight of the pancreatin micropellet cores; b. creating pancreatin micropellet cores from the extrudable mixture; c. forming the pancreatin micropellet cores into approximately spherical or approximately ellipsoidal shape in the presence of additional enzyme-friendly organic solvent; and d. removing the one or more enzyme-friendly organic solvents from the pancreatin micropellet cores such that the pancreatin micropellet cores are substantially free of the one or more enzyme-friendly organic solvents; wherein the pancreatin micropellet cores are substantially free of synthetic oils. 2. The process of claim 1 wherein the pancreatin is present between about 70% and about 90% weight to weight of the pancreatin micropellet cores. 3. The process of claim 1 wherein the binding agent is present between about 10% and about 30% weight to weight of the pancreatin micropellet cores. 4. The process of claim 1 wherein the pharmaceutically acceptable excipient is present between about 0% and about 5% weight to weight of the pancreatin micropellet cores. 5. The process of claim 1 wherein the binding agent is selected from the group consisting of: polyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, hydroxypropyl methylcellulose, polyoxyethylen, copolymers of polyoxyethylen-polyoxypropylen and mixtures of said organic polymers. 6. The process of claim 1 wherein the binding agent is polyethylene glycol 4000. 7. The process of claim 1 wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of: magnesium stearate, calcium stearate, stearic acid, talcum, starch, calcium phosphate, corn starch, dextrans, dextrin, hydrated silicon dioxide, microcrystalline cellulose, kaolin, lactose, mannitol, polyvinyl pyrrolidone, precipitated calcium carbonate, sorbitol, silicic acid, alginic acid, amylose, calcium alginate, calcium carbonate, formaldehyde gelatin, pectic carbonate, sago starch, sodium bicarbonate and glycerol. 8. The process of claim 1 wherein the one or more enzyme-friendly organic solvents are present between about 15% and about 35% by weight relative to the amount of pancreatin. 9. The process of claim 1 wherein the one or more enzyme-friendly organic solvents are present in an amount of less then about 5% weight to weight of the pancreatin micropellet cores after the one or more enzyme-friendly organic solvents have been removed from the pancreatin micropellet cores. 10. The process of claim 1 wherein the one or more enzyme-friendly organic solvents is selected from the group consisting of: acetone, chloroform, dichloromethane, methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, tert-butanol and mixtures of said solvents. 11. The process of claim 1 wherein the one or more enzyme-friendly organic solvents is 2-propanol. 12. The process of claim 1 wherein removing of the one or more enzyme-friendly organic solvents from the pancreatin micropellet cores is by drying at a temperature between about 30° C. and about 75° C. 13. The process of claim 1 wherein creating the pancreatin micropellet cores is by extrusion. 14. The process of claim 1 wherein forming of the pancreatin micropellet cores is performed in a rounding apparatus. 15. A process for the manufacture of pancreatin micropellets, comprising the steps of:
aa. providing pancreatin micropellet cores wherein the pancreatin micropellet cores are substantially free of synthetic oils; bb. providing an enteric-coating solution comprising
i. one or more film-forming agents;
ii. a plasticizer in an amount greater than about 1.5% by weight relative to the one or more film-forming agents film-forming agents; and
iii. optionally, at least one anti-sticking agent, and
iv. one or more enzyme-friendly organic solvent(s);
cc. coating the pancreatin micropellet cores with the enteric-coating solution wherein the temperature of the pancreatin micropellet cores during coating is kept at a temperature suitable for applying the enteric-coating solution; and dd. drying the coated pancreatin micropellet cores. 16. The process of claim 15 wherein the enteric coating is between about 20% and about 30% by weight of the pancreatin micropellets. 17. The process of claim 15 wherein the one or more film-forming agents is selected from the group consisting of: agar, carbomer polymers, carboxymethyl cellulose, carboxymethylethyl cellulose, carrageen, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimelliate, chitin, corn protein extract, ethyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropylmethyl acetate succinate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid-ethyl methacrylate-copolymer, methyl cellulose, pectin, polyvinyl acetate phthalate, polivinyl alcohol, shellac, sodium alginate, starch acetate phthalate, styrene/maleic acid copolymer and mixtures of said film-forming polymers. 18. The process of claim 15 wherein the plasticizer is selected from the group consisting of: saturated linear monohydric alcohols having 12 to 30 carbon atoms, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, arachic alcohol, behenyl alcohol, carnaubyl alcohol, ceryl alcohol, corianyl alcohol, melissyl alcohol, acetyl tributyl citrate, dibutyl sebacate, fatty acid esters of glycerol, glycerol, polyethylene glycol, propyleneglycol, sorbitan fatty acids, triacetin, triethyl citrate and mixtures of any of said plasticizers. 19. The process of claim 15 wherein the plasticizer is cetyl alcohol. 20. The process of claim 15 wherein the plasticizer is triethyl citrate present in an amount of between about 5% and about 20% by weight relative to the film-forming agent. 21. The process of claim 15 wherein the plasticizer is comprised of cetyl alcohol and triethyl citrate which are collectively present in an amount greater than about 3% by weight relative to the film-forming agent. 22. The process of claim 15 wherein the plasticizer is comprised of cetyl alcohol and triethyl citrate which are collectively present in an amount between about 4% and about 20% by weight relative to the film-forming agent. 23. The process of claim 22 wherein the ratio of cetyl alcohol to triethyl citrate is between about 0.05:1 and about 1:1 by weight. 24. The process of claim 15 wherein the anti-sticking agent is selected from the group consisting of: dimethicone and castor oil. 25. The process of claim 15 wherein the anti-sticking agent is present in an amount between about 1.5% and about 3% by weight relative to the film-forming agent. 26. The process of claim 15 wherein the one or more enzyme-friendly organic solvents is selected from the group consisting of: acetone, chloroform, dichloromethane, methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, tert-butanol and mixtures of said solvents. 27. A method of treating a medical condition in a mammalian subject, comprising the steps of:
a. providing pancreatin micropellet cores manufactured according to the process of claim 1 in a dosage form suitable for oral administration; and b. orally administering the dosage form to the subject to provide pancreatin in an amount sufficient to treat the medical condition; wherein the medical condition is selected from the group consisting of: pancreatic exocrine insufficiency, pancreatitis, cystic fibrosis, diabetes type I and diabetes type II. 28. A method of treating a medical condition in a mammalian subject, comprising the steps of:
a. providing pancreatin micropellets manufactured according to the process of claim 15 in a dosage form suitable for oral administration; and b. orally administering the dosage form to the subject to provide pancreatin in an amount sufficient to treat the medical condition; wherein the medical condition is selected from the group consisting of: pancreatic exocrine insufficiency, pancreatitis, cystic fibrosis, diabetes type I and diabetes type II. 29. A pharmaceutical composition, comprising
a. a pharmacologically effective amount of pancreatin wherein said pancreatin is in the form of pancreatin micropellet cores manufactured according to the process of claim 1; and b. a dosage form suitable for oral administration containing said pharmacologically effective amount of pancreatin. 30. A pharmaceutical composition, comprising
a. a pharmacologically effective amount of pancreatin wherein said pancreatin is in the form of pancreatin micropellets manufactured according to the process of claim 15; and b. a dosage form suitable for oral administration containing said pharmacologically effective amount of pancreatin. 31. A pharmaceutical composition, prepared by a process comprising the steps of:
a. preparing an extrudable mixture comprising:
i. about 10% to about 95% pancreatin;
ii. about 5% to about 90% of at least one pharmaceutically acceptable binding agent;
iii. 0% to about 10% of at least one pharmaceutically acceptable excipient; and
iv. one or more enzyme-friendly organic solvents in an amount sufficient to form an extrudable mixture;
wherein the percentages of components are weight to weight of the pancreatin micropellet cores;
b. creating pancreatin micropellet cores from the extrudable mixture; c. forming the pancreatin micropellet cores into approximately spherical or approximately ellipsoidal shape in the presence of additional enzyme-friendly organic solvent; d. removing the one or more enzyme-friendly organic solvents from the pancreatin micropellet cores such that the pancreatin micropellet cores are substantially free of the one or more enzyme-friendly organic solvents; wherein the pancreatin micropellet cores are substantially free of synthetic oils; e. coating the pancreatin micropellet cores with an enteric-coating solution wherein the temperature of the pancreatin micropellet cores during coating is is kept at a temperature suitable to apply the enteric-coating solution; f. drying the coated pancreatin micropellet cores; and g. placing the coated pancreatin micropellet cores in a dosage form suitable for oral administration. 32. The process of claim 31 wherein the pancreatin is present between about 70% and about 90% weight to weight of the pancreatin micropellet cores. 33. The process of claim 31 wherein the binding agent is present between about 10% and about 30% weight to weight of the pancreatin micropellet cores. 34. The process of claim 31 wherein the binding agent is selected from the group consisting of: polyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, hydroxypropyl methylcellulose, polyoxyethylen, copolymers of polyoxyethylen-polyoxypropylen and mixtures of said organic polymers. 35. The process of claim 31 wherein the binding agent is polyethylene glycol 4000. 36. The process of claim 31 wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of: magnesium stearate, calcium stearate, stearic acid, talcum, starch, calcium phosphate, corn starch, dextrans, dextrin, hydrated silicon dioxide, microcrystalline cellulose, kaolin, lactose, mannitol, polyvinyl pyrrolidone, precipitated calcium carbonate, sorbitol, silicic acid, alginic acid, amylose, calcium alginate, calcium carbonate, formaldehyde gelatin, pectic carbonate, sago starch, sodium bicarbonate and glycerol. 37. The process of claim 31 wherein the one or more enzyme-friendly organic solvents are present between about 15% and about 35% by weight relative to the amount of pancreatin. 38. The process of claim 31 wherein the one or more enzyme-friendly organic solvents is selected from the group consisting of: acetone, chloroform, dichloromethane, methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, tert-butanol and mixtures of said solvents. 39. The process of claim 31 wherein the one or more enzyme-friendly organic solvents is 2-propanol. 40. The process of claim 31 wherein removing the one or more enzyme-friendly organic solvents from the pancreatin micropellet cores is by drying at a temperature between about 30° C. and about 75° C. 41. A pharmaceutical composition, prepared by a process comprising the steps of:
a. providing pancreatin micropellet cores wherein the pancreatin micropellet cores are substantially free of synthetic oils; b. providing an enteric-coating solution comprising
i. at least one film-forming agent
ii. a plasticizer in an amount of greater than about 1.5% by weight relative to the one or more film-forming agents film-forming agents; and
iii. optionally at least one anti-sticking agent in one or more enzyme-friendly organic solvent;
c. coating the pancreatin micropellet cores with the enteric-coating solution wherein the temperature of the pancreatin micropellet cores during coating is kept at a temperature suitable to apply the enteric-coating solution ; and d. drying the coated pancreatin micropellet cores; and e. placing the coated pancreatin micropellet cores in a dosage form suitable for oral administration. 42. The composition of claim 41 wherein the enteric coating is between about 20% and about 30% by weight of the pancreatin micropellets. 43. The composition of claim 41 wherein the one or more film-forming agents is selected from the group consisting of: agar, carbomer polymers, carboxymethyl cellulose, carboxymethylethyl cellulose, carrageen, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimelliate, chitin, corn protein extract, ethyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropylmethyl acetate succinate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid-ethyl methacrylate-copolymer, methyl cellulose, pectin, polyvinyl acetate phthalate, polivinyl alcohol, shellac, sodium alginate, starch acetate phthalate, styrene/maleic acid copolymer and mixtures of said film-forming polymers. 44. The composition of claim 41 wherein the plasticizer is selected from the group consisting of: saturated linear monohydric alcohols having 12 to 30 carbon atoms, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, arachic alcohol, behenyl alcohol, carnaubyl alcohol, ceryl alcohol, corianyl alcohol, melissyl alcohol, acetyl tributyl citrate, dibutyl sebacate, fatty acid esters of glycerol, glycerol, polyethylene glycol, propyleneglycol, sorbitan fatty acids, triacetin, triethyl citrate and mixtures of any of said plasticizers. 45. The composition of claim 41 wherein the plasticizer is cetyl alcohol. 46. The composition of claim 41 wherein the plasticizer is triethyl citrate present in an amount of between about 5% and about 20% by weight relative to the film-forming agent. 47. The composition of claim 41 wherein the plasticizer is a mixture of cetyl alcohol and triethyl citrate which are collectively present in an amount of greater than about 3% by weight relative to the film-forming agent. 48. The composition of claim 47 wherein the ratio of cetyl alcohol to triethyl citrate is between about 0.05:1 and about 1:1 by weight. 49. The composition of claim 41 wherein the anti-sticking agent is selected from the group consisting of: dimethicone and castor oil. 50. The composition of claim 41 wherein the anti-sticking agent is present in an amount between about 1.5% and about 3% by weight relative to the film-forming agent. 51. The composition of claim 41 wherein the one or more enzyme-friendly organic solvents is selected from the group consisting of: acetone, chloroform, dichloromethane, methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, tert-butanol and mixtures of said solvents. 52. A pharmaceutical composition comprising:
pancreatin micropellets wherein the pancreatin micropellets are substantially free of synthetic oils and wherein said pancreatin micropellets have a gastric acid resistance of about 75% or more at about a pH 1. 53. A pharmaceutical composition comprising:
pancreatin micropellets wherein the pancreatin micropellets are substantially free of synthetic oils and wherein said pancreatin micropellets have a gastric acid resistance of about 75% or more at about a pH 5. 54. A pharmaceutical composition comprising:
a. pancreatin micropellet cores wherein the pancreatin micropellet cores are substantially free of synthetic oils; b. at least one film-forming agent; c. a plasticizer in an amount greater than about 1.5% by weight relative to the one or more film-forming agents; and d. optionally at least one anti-sticking agent in one or more enzyme-friendly organic solvent. | A process for manufacturing and using pancreatin micropellet cores and pancreatin micropellets which are substantially free of synthetic oils. In one embodiment, a pharmaceutical composition is provided comprising a pancreatin micropellet with the enteric coating being designed to deliver pancreatin to the upper portion of the intestine of a mammal for release.1. A process for the manufacture of pancreatin micropellet cores, comprising the steps of:
a. preparing an extrudable mixture comprising:
i. about 10% to about 95% pancreatin;
ii. about 5% to about 90% of at least one pharmaceutically acceptable binding agent;
iii. 0% to about 10% of at least one pharmaceutically acceptable excipient; and
iv. one or more enzyme-friendly organic solvents in an amount sufficient to form an extrudable mixture;
wherein the percentages of components are weight to weight of the pancreatin micropellet cores; b. creating pancreatin micropellet cores from the extrudable mixture; c. forming the pancreatin micropellet cores into approximately spherical or approximately ellipsoidal shape in the presence of additional enzyme-friendly organic solvent; and d. removing the one or more enzyme-friendly organic solvents from the pancreatin micropellet cores such that the pancreatin micropellet cores are substantially free of the one or more enzyme-friendly organic solvents; wherein the pancreatin micropellet cores are substantially free of synthetic oils. 2. The process of claim 1 wherein the pancreatin is present between about 70% and about 90% weight to weight of the pancreatin micropellet cores. 3. The process of claim 1 wherein the binding agent is present between about 10% and about 30% weight to weight of the pancreatin micropellet cores. 4. The process of claim 1 wherein the pharmaceutically acceptable excipient is present between about 0% and about 5% weight to weight of the pancreatin micropellet cores. 5. The process of claim 1 wherein the binding agent is selected from the group consisting of: polyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, hydroxypropyl methylcellulose, polyoxyethylen, copolymers of polyoxyethylen-polyoxypropylen and mixtures of said organic polymers. 6. The process of claim 1 wherein the binding agent is polyethylene glycol 4000. 7. The process of claim 1 wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of: magnesium stearate, calcium stearate, stearic acid, talcum, starch, calcium phosphate, corn starch, dextrans, dextrin, hydrated silicon dioxide, microcrystalline cellulose, kaolin, lactose, mannitol, polyvinyl pyrrolidone, precipitated calcium carbonate, sorbitol, silicic acid, alginic acid, amylose, calcium alginate, calcium carbonate, formaldehyde gelatin, pectic carbonate, sago starch, sodium bicarbonate and glycerol. 8. The process of claim 1 wherein the one or more enzyme-friendly organic solvents are present between about 15% and about 35% by weight relative to the amount of pancreatin. 9. The process of claim 1 wherein the one or more enzyme-friendly organic solvents are present in an amount of less then about 5% weight to weight of the pancreatin micropellet cores after the one or more enzyme-friendly organic solvents have been removed from the pancreatin micropellet cores. 10. The process of claim 1 wherein the one or more enzyme-friendly organic solvents is selected from the group consisting of: acetone, chloroform, dichloromethane, methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, tert-butanol and mixtures of said solvents. 11. The process of claim 1 wherein the one or more enzyme-friendly organic solvents is 2-propanol. 12. The process of claim 1 wherein removing of the one or more enzyme-friendly organic solvents from the pancreatin micropellet cores is by drying at a temperature between about 30° C. and about 75° C. 13. The process of claim 1 wherein creating the pancreatin micropellet cores is by extrusion. 14. The process of claim 1 wherein forming of the pancreatin micropellet cores is performed in a rounding apparatus. 15. A process for the manufacture of pancreatin micropellets, comprising the steps of:
aa. providing pancreatin micropellet cores wherein the pancreatin micropellet cores are substantially free of synthetic oils; bb. providing an enteric-coating solution comprising
i. one or more film-forming agents;
ii. a plasticizer in an amount greater than about 1.5% by weight relative to the one or more film-forming agents film-forming agents; and
iii. optionally, at least one anti-sticking agent, and
iv. one or more enzyme-friendly organic solvent(s);
cc. coating the pancreatin micropellet cores with the enteric-coating solution wherein the temperature of the pancreatin micropellet cores during coating is kept at a temperature suitable for applying the enteric-coating solution; and dd. drying the coated pancreatin micropellet cores. 16. The process of claim 15 wherein the enteric coating is between about 20% and about 30% by weight of the pancreatin micropellets. 17. The process of claim 15 wherein the one or more film-forming agents is selected from the group consisting of: agar, carbomer polymers, carboxymethyl cellulose, carboxymethylethyl cellulose, carrageen, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimelliate, chitin, corn protein extract, ethyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropylmethyl acetate succinate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid-ethyl methacrylate-copolymer, methyl cellulose, pectin, polyvinyl acetate phthalate, polivinyl alcohol, shellac, sodium alginate, starch acetate phthalate, styrene/maleic acid copolymer and mixtures of said film-forming polymers. 18. The process of claim 15 wherein the plasticizer is selected from the group consisting of: saturated linear monohydric alcohols having 12 to 30 carbon atoms, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, arachic alcohol, behenyl alcohol, carnaubyl alcohol, ceryl alcohol, corianyl alcohol, melissyl alcohol, acetyl tributyl citrate, dibutyl sebacate, fatty acid esters of glycerol, glycerol, polyethylene glycol, propyleneglycol, sorbitan fatty acids, triacetin, triethyl citrate and mixtures of any of said plasticizers. 19. The process of claim 15 wherein the plasticizer is cetyl alcohol. 20. The process of claim 15 wherein the plasticizer is triethyl citrate present in an amount of between about 5% and about 20% by weight relative to the film-forming agent. 21. The process of claim 15 wherein the plasticizer is comprised of cetyl alcohol and triethyl citrate which are collectively present in an amount greater than about 3% by weight relative to the film-forming agent. 22. The process of claim 15 wherein the plasticizer is comprised of cetyl alcohol and triethyl citrate which are collectively present in an amount between about 4% and about 20% by weight relative to the film-forming agent. 23. The process of claim 22 wherein the ratio of cetyl alcohol to triethyl citrate is between about 0.05:1 and about 1:1 by weight. 24. The process of claim 15 wherein the anti-sticking agent is selected from the group consisting of: dimethicone and castor oil. 25. The process of claim 15 wherein the anti-sticking agent is present in an amount between about 1.5% and about 3% by weight relative to the film-forming agent. 26. The process of claim 15 wherein the one or more enzyme-friendly organic solvents is selected from the group consisting of: acetone, chloroform, dichloromethane, methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, tert-butanol and mixtures of said solvents. 27. A method of treating a medical condition in a mammalian subject, comprising the steps of:
a. providing pancreatin micropellet cores manufactured according to the process of claim 1 in a dosage form suitable for oral administration; and b. orally administering the dosage form to the subject to provide pancreatin in an amount sufficient to treat the medical condition; wherein the medical condition is selected from the group consisting of: pancreatic exocrine insufficiency, pancreatitis, cystic fibrosis, diabetes type I and diabetes type II. 28. A method of treating a medical condition in a mammalian subject, comprising the steps of:
a. providing pancreatin micropellets manufactured according to the process of claim 15 in a dosage form suitable for oral administration; and b. orally administering the dosage form to the subject to provide pancreatin in an amount sufficient to treat the medical condition; wherein the medical condition is selected from the group consisting of: pancreatic exocrine insufficiency, pancreatitis, cystic fibrosis, diabetes type I and diabetes type II. 29. A pharmaceutical composition, comprising
a. a pharmacologically effective amount of pancreatin wherein said pancreatin is in the form of pancreatin micropellet cores manufactured according to the process of claim 1; and b. a dosage form suitable for oral administration containing said pharmacologically effective amount of pancreatin. 30. A pharmaceutical composition, comprising
a. a pharmacologically effective amount of pancreatin wherein said pancreatin is in the form of pancreatin micropellets manufactured according to the process of claim 15; and b. a dosage form suitable for oral administration containing said pharmacologically effective amount of pancreatin. 31. A pharmaceutical composition, prepared by a process comprising the steps of:
a. preparing an extrudable mixture comprising:
i. about 10% to about 95% pancreatin;
ii. about 5% to about 90% of at least one pharmaceutically acceptable binding agent;
iii. 0% to about 10% of at least one pharmaceutically acceptable excipient; and
iv. one or more enzyme-friendly organic solvents in an amount sufficient to form an extrudable mixture;
wherein the percentages of components are weight to weight of the pancreatin micropellet cores;
b. creating pancreatin micropellet cores from the extrudable mixture; c. forming the pancreatin micropellet cores into approximately spherical or approximately ellipsoidal shape in the presence of additional enzyme-friendly organic solvent; d. removing the one or more enzyme-friendly organic solvents from the pancreatin micropellet cores such that the pancreatin micropellet cores are substantially free of the one or more enzyme-friendly organic solvents; wherein the pancreatin micropellet cores are substantially free of synthetic oils; e. coating the pancreatin micropellet cores with an enteric-coating solution wherein the temperature of the pancreatin micropellet cores during coating is is kept at a temperature suitable to apply the enteric-coating solution; f. drying the coated pancreatin micropellet cores; and g. placing the coated pancreatin micropellet cores in a dosage form suitable for oral administration. 32. The process of claim 31 wherein the pancreatin is present between about 70% and about 90% weight to weight of the pancreatin micropellet cores. 33. The process of claim 31 wherein the binding agent is present between about 10% and about 30% weight to weight of the pancreatin micropellet cores. 34. The process of claim 31 wherein the binding agent is selected from the group consisting of: polyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, hydroxypropyl methylcellulose, polyoxyethylen, copolymers of polyoxyethylen-polyoxypropylen and mixtures of said organic polymers. 35. The process of claim 31 wherein the binding agent is polyethylene glycol 4000. 36. The process of claim 31 wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of: magnesium stearate, calcium stearate, stearic acid, talcum, starch, calcium phosphate, corn starch, dextrans, dextrin, hydrated silicon dioxide, microcrystalline cellulose, kaolin, lactose, mannitol, polyvinyl pyrrolidone, precipitated calcium carbonate, sorbitol, silicic acid, alginic acid, amylose, calcium alginate, calcium carbonate, formaldehyde gelatin, pectic carbonate, sago starch, sodium bicarbonate and glycerol. 37. The process of claim 31 wherein the one or more enzyme-friendly organic solvents are present between about 15% and about 35% by weight relative to the amount of pancreatin. 38. The process of claim 31 wherein the one or more enzyme-friendly organic solvents is selected from the group consisting of: acetone, chloroform, dichloromethane, methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, tert-butanol and mixtures of said solvents. 39. The process of claim 31 wherein the one or more enzyme-friendly organic solvents is 2-propanol. 40. The process of claim 31 wherein removing the one or more enzyme-friendly organic solvents from the pancreatin micropellet cores is by drying at a temperature between about 30° C. and about 75° C. 41. A pharmaceutical composition, prepared by a process comprising the steps of:
a. providing pancreatin micropellet cores wherein the pancreatin micropellet cores are substantially free of synthetic oils; b. providing an enteric-coating solution comprising
i. at least one film-forming agent
ii. a plasticizer in an amount of greater than about 1.5% by weight relative to the one or more film-forming agents film-forming agents; and
iii. optionally at least one anti-sticking agent in one or more enzyme-friendly organic solvent;
c. coating the pancreatin micropellet cores with the enteric-coating solution wherein the temperature of the pancreatin micropellet cores during coating is kept at a temperature suitable to apply the enteric-coating solution ; and d. drying the coated pancreatin micropellet cores; and e. placing the coated pancreatin micropellet cores in a dosage form suitable for oral administration. 42. The composition of claim 41 wherein the enteric coating is between about 20% and about 30% by weight of the pancreatin micropellets. 43. The composition of claim 41 wherein the one or more film-forming agents is selected from the group consisting of: agar, carbomer polymers, carboxymethyl cellulose, carboxymethylethyl cellulose, carrageen, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimelliate, chitin, corn protein extract, ethyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropylmethyl acetate succinate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, methacrylic acid-ethyl methacrylate-copolymer, methyl cellulose, pectin, polyvinyl acetate phthalate, polivinyl alcohol, shellac, sodium alginate, starch acetate phthalate, styrene/maleic acid copolymer and mixtures of said film-forming polymers. 44. The composition of claim 41 wherein the plasticizer is selected from the group consisting of: saturated linear monohydric alcohols having 12 to 30 carbon atoms, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, heptadecyl alcohol, stearyl alcohol, nonadecyl alcohol, arachic alcohol, behenyl alcohol, carnaubyl alcohol, ceryl alcohol, corianyl alcohol, melissyl alcohol, acetyl tributyl citrate, dibutyl sebacate, fatty acid esters of glycerol, glycerol, polyethylene glycol, propyleneglycol, sorbitan fatty acids, triacetin, triethyl citrate and mixtures of any of said plasticizers. 45. The composition of claim 41 wherein the plasticizer is cetyl alcohol. 46. The composition of claim 41 wherein the plasticizer is triethyl citrate present in an amount of between about 5% and about 20% by weight relative to the film-forming agent. 47. The composition of claim 41 wherein the plasticizer is a mixture of cetyl alcohol and triethyl citrate which are collectively present in an amount of greater than about 3% by weight relative to the film-forming agent. 48. The composition of claim 47 wherein the ratio of cetyl alcohol to triethyl citrate is between about 0.05:1 and about 1:1 by weight. 49. The composition of claim 41 wherein the anti-sticking agent is selected from the group consisting of: dimethicone and castor oil. 50. The composition of claim 41 wherein the anti-sticking agent is present in an amount between about 1.5% and about 3% by weight relative to the film-forming agent. 51. The composition of claim 41 wherein the one or more enzyme-friendly organic solvents is selected from the group consisting of: acetone, chloroform, dichloromethane, methanol, ethanol, 1-propanol, 2-propanol, 2-butanol, tert-butanol and mixtures of said solvents. 52. A pharmaceutical composition comprising:
pancreatin micropellets wherein the pancreatin micropellets are substantially free of synthetic oils and wherein said pancreatin micropellets have a gastric acid resistance of about 75% or more at about a pH 1. 53. A pharmaceutical composition comprising:
pancreatin micropellets wherein the pancreatin micropellets are substantially free of synthetic oils and wherein said pancreatin micropellets have a gastric acid resistance of about 75% or more at about a pH 5. 54. A pharmaceutical composition comprising:
a. pancreatin micropellet cores wherein the pancreatin micropellet cores are substantially free of synthetic oils; b. at least one film-forming agent; c. a plasticizer in an amount greater than about 1.5% by weight relative to the one or more film-forming agents; and d. optionally at least one anti-sticking agent in one or more enzyme-friendly organic solvent. | 1,600 |
746 | 10,940,892 | 1,631 | Efficient sequence specific gene silencing is possible through the use of siRNA technology. By selecting particular siRNAs by rational design, one can maximize the generation of an effective gene silencing reagent, as well as methods for silencing genes. Methods, compositions, and kits generated through rational design of siRNAs are disclosed. | 1. A kit for gene silencing, wherein said kit is comprised of a pool of at least two siRNA duplexes, each of which is comprised of a sequence that is complementary to a portion of the sequence of one or more target messenger RNA, and each of which is selected using selection criteria that are embodied in a formula comprising: selection criteria are embodied in a formula comprising:
(−8)*A1+(−1)*A2+(12)*A3+(7)*A4+(18)*A5+(12)*A6+(19)*A7+(6)*A8+(−4)*A9+(−5)*A10+(−2)*A11+(−5)*A12+(17)*A13+(−3)*A14+(4)*A15+(2)*A16+(8)*A17+(11)*A18+(30)*A19+(−13)*U1+(−10)*U2+(2)*U3+(−2)*U4+(−5)*U5+(5)*U6+(−2)*U7+(−10)*U8+(−5)*U9+(15)*U10+(−1)*U11+(0)*U12+(10)*U13+(−9)*U14+(−13)*U15+(−10)*U16+(3)*U17+(9)*U18+(9)*U19+(7)*C1+(3)*C2+(−21)*C3+(5)*C4+(−9)*C5+(−20)*C6+(−18)*C7+(−5)*C8+(5)*C9+(1)*C10+(2)*C11+(−5)*C12+(−3)*C13+(−6)*C14+(−2)*C15+(−5)*C16+(−3)*C17+(−12)*C18+(−18)*C19+(14)*G1+(8)*G2+(7)*G3+(−10)*G4+(−4)*G5+(2)*G6+(1)*G7+(9)*G8+(5)*G9+(−11)*G10+(1)*G11+(9)*G12+(−24)*G13+(18)*G14+(11)*G15+(13)*G16+(−7)*G17+(−9)*G18+(−22)*G19+6*(number of A+U in position 15-19)−3*(number of G+C in whole siRNA), Formula X
wherein position numbering begins at the 5′-most position of a sense strand, and
A1=1 if A is the base at position 1 of the sense strand, otherwise its value is 0;
A2=1 if A is the base at position 2 of the sense strand, otherwise its value is 0;
A3=1 if A is the base at position 3 of the sense strand, otherwise its value is 0;
A4=1 if A is the base at position 4 of the sense strand, otherwise its value is 0;
A5=1 if A is the base at position 5 of the sense strand, otherwise its value is 0;
A6=1 if A is the base at position 6 of the sense strand, otherwise its value is 0;
A7=1 if A is the base at position 7 of the sense strand, otherwise its value is 0;
A10=1 if A is the base at position 10 of the sense strand, otherwise its value is 0;
A11=1 if A is the base at position 11 of the sense strand, otherwise its value is 0;
A13=1 if A is the base at position 13 of the sense strand, otherwise its value is 0;
A19=1 if A is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
C3=1 if C is the base at position 3 of the sense strand, otherwise its value is 0;
C4=1 if C is the base at position 4 of the sense strand, otherwise its value is 0;
C5=1 if C is the base at position 5 of the sense strand, otherwise its value is 0;
C6=1 if C is the base at position 6 of the sense strand, otherwise its value is 0;
C7=1 if C is the base at position 7 of the sense strand, otherwise its value is 0;
C9=1 if C is the base at position 9 of the sense strand, otherwise its value is 0;
C17=1 if C is the base at position 17 of the sense strand, otherwise its value is 0;
C18=1 if C is the base at position 18 of the sense strand, otherwise its value is 0;
C19=1 if C is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
G1=1 if G is the base at position 1 on the sense strand, otherwise its value is 0;
G2=1 if G is the base at position 2 of the sense strand, otherwise its value is 0;
G8=1 if G is the base at position 8 on the sense strand, otherwise its value is 0;
G10=1 if G is the base at position 10 on the sense strand, otherwise its value is 0;
G13=1 if G is the base at position 13 on the sense strand, otherwise its value is 0;
G19=1 if G is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
U1=1 if U is the base at position 1 on the sense strand, otherwise its value is 0;
U2=1 if U is the base at position 2 on the sense strand, otherwise its value is 0;
U3=1 if U is the base at position 3 on the sense strand, otherwise its value is 0;
U4=1 if U is the base at position 4 on the sense strand, otherwise its value is 0;
U7=1 if U is the base at position 7 on the sense strand, otherwise its value is 0;
U9=1 if U is the base at position 9 on the sense strand, otherwise its value is 0;
U10=1 if U is the base at position 10 on the sense strand, otherwise its value is 0;
U15=1 if U is the base at position 15 on the sense strand, otherwise its value is 0;
U16=1 if U is the base at position 16 on the sense strand, otherwise its value is 0;
U17=1 if U is the base at position 17 on the sense strand, otherwise its value is 0;
U18=1 if U is the base at position 18 on the sense strand, otherwise its value is 0. 2. A method for selecting an siRNA, said method comprising:
applying selection criteria to a set of potential siRNA that comprise 18-30 base pairs; and determining the relative functionality of the at least two siRNAs, wherein said section criteria are non-target specific criteria, said set comprises at least two siRNAs and each of said at least two siRNAs contains a sequence that is at least substantially complementary to a target gene, and said selection criteria are embodied in a formula comprising: (−8)*A1+(−1)*A2+(12)*A3+(7)*A4+(18)*A5+(12)*A6+(19)*A7+(6)*A8+(−4)*A9+(−5)*A10+(−2)*A11+(−5)*A12+(17)*A13+(−3)*A14+(4)*A15+(2)*A16+(8)*A17+(11)*A18+(30)*A19+(−13)*U1+(−10)*U2+(2)*U3+(−2)*U4+(−5)*U5+(5)*U6+(−2)*U7+(−10)*U8+(−5)*U9+(15)*U10+(−1)*U11+(0)*U12+(10)*U13+(−9)*U14+(−13)*U15+(−10)*U16+(3)*U17+(9)*U18+(9)*U19+(7)*C1+(3)*C2+(−21)*C3+(5)*C4+(−9)*C5+(−20)*C6+(−18)*C7+(−5)*C8+(5)*C9+(1)*C10+(2)*C11+(−5)*C12+(−3)*C13+(−6)*C14+(−2)*C15+(−5)*C16+(−3)*C17+(−12)*C18+(−18)*C19+(14)*G1+(8)*G2+(7)*G3+(−10)*G4+(−4)*G5+(2)*G6+(1)*G7+(9)*G8+(5)*G9+(−11)*G10+(1)*G11+(9)*G12+(−24)*G13+(18)*G14+(11)*G15+(13)*G16+(−7)*G17+(−9)*G18+(−22)*G19+6*(number of A+U in position 15-19)−3*(number of G+C in whole siRNA), Formula X wherein position numbering begins at the 5′-most position of a sense strand, and A1=1 if A is the base at position 1 of the sense strand, otherwise its value is 0; A2=1 if A is the base at position 2 of the sense strand, otherwise its value is 0; A3=1 if A is the base at position 3 of the sense strand, otherwise its value is 0; A4=1 if A is the base at position 4 of the sense strand, otherwise its value is 0; A5=1 if A is the base at position 5 of the sense strand, otherwise its value is 0; A6=1 if A is the base at position 6 of the sense strand, otherwise its value is 0; A7=1 if A is the base at position 7 of the sense strand, otherwise its value is 0; A10=1 if A is the base at position 10 of the sense strand, otherwise its value is 0; A11=1 if A is the base at position 11 of the sense strand, otherwise its value is 0; A13=1 if A is the base at position 13 of the sense strand, otherwise its value is 0; A19=1 if A is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0; C3=1 if C is the base at position 3 of the sense strand, otherwise its value is 0; C4=1 if C is the base at position 4 of the sense strand, otherwise its value is 0; C5=1 if C is the base at position 5 of the sense strand, otherwise its value is 0; C6=1 if C is the base at position 6 of the sense strand, otherwise its value is 0; C7=1 if C is the base at position 7 of the sense strand, otherwise its value is 0; C9=1 if C is the base at position 9 of the sense strand, otherwise its value is 0; C17=1 if C is the base at position 17 of the sense strand, otherwise its value is 0; C18=1 if C is the base at position 18 of the sense strand, otherwise its value is 0; C19=1 if C is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0; G1=1 if G is the base at position 1 on the sense strand, otherwise its value is 0; G2=1 if G is the base at position 2 of the sense strand, otherwise its value is 0; G8=1 if G is the base at position 8 on the sense strand, otherwise its value is 0; G10=1 if G is the base at position 10 on the sense strand, otherwise its value is 0; G13=1 if G is the base at position 13 on the sense strand, otherwise its value is 0; G19=1 if G is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0; U1=1 if U is the base at position 1 on the sense strand, otherwise its value is 0; U2=1 if U is the base at position 2 on the sense strand, otherwise its value is 0; U3=1 if U is the base at position 3 on the sense strand, otherwise its value is 0; U4=1 if U is the base at position 4 on the sense strand, otherwise its value is 0; U7=1 if U is the base at position 7 on the sense strand, otherwise its value is 0; U9=1 if U is the base at position 9 on the sense strand, otherwise its value is 0; U10=1 if U is the base at position 10 on the sense strand, otherwise its value is 0; U15=1 if U is the base at position 15 on the sense strand, otherwise its value is 0; U16=1 if U is the base at position 16 on the sense strand, otherwise its value is 0; U17=1 if U is the base at position 17 on the sense strand, otherwise its value is 0; U18=1 if U is the base at position 18 on the sense strand, otherwise its value is 0. 3. A method according to claim 1, further comprising comparing the internal stability profiles of said at least two siRNAs. 4. A method according to claim 2, further comprising comparing the internal stability profiles of said at least two siRNAs. 5. A method according to claim 1, further comprising selecting either for or against sequences that contain motifs that induce cellular stress. 6. A method according to claim 2, further comprising selecting either for or against sequences that contain motifs that induce cellular stress. 7. A method according to claim 1, further comprising selecting either for or against sequences that comprise stability motifs. 8. A method according to claim 2, further comprising selecting either for or against sequences that comprise stability motifs. 9. A method of gene silencing, comprising introducing into a cell at least one siRNA selected according to a method of claim 1. 10. A method of gene silencing, comprising introducing into a cell at least one siRNA selected according to a method of claim 2. 11. A method according to claim 1, wherein said introducing is by allowing passive uptake of the at least one siRNA. 12. A method according to claim 2, wherein said introducing is by allowing passive uptake of the at least one siRNA. 13. A method according claim 9, wherein said introducing in through the use of a vector. 14. A method for developing an siRNA algorithm for selecting siRNA, said method comprising:
(a) selecting a set of siRNA; (b) measuring gene silencing ability of each siRNA from said set; (c) determining relative functionality of each siRNA; (d) determining improved functionality based on the following variables: the presence or absence of a particular nucleotide at a particular position, the total number of As and Us in positions 15-19, the number of times that the same nucleotide repeats within a given sequence, and the total number of Gs and Cs; and (e) developing an algorithm using the information of step (d). 15. A method of selecting an siRNA with improved functionality, said method comprising using the algorithm of claim 14. 16. A kit, wherein said kit is comprised of at least two siRNAs, wherein said at least two siRNAs comprise a first optimized siRNA and a second optimized siRNA, wherein said first optimized siRNA and said second optimized siRNA are optimized according a formula comprising:
(−8)*A1+(−1)*A2+(12)*A3+(7)*A4+(18)*A5+(12)*A6+(19)*A7+(6)*A8+(−4)*A9+(−5)*A10+(−2)*A11+(−5)*A12+(17)*A13+(−3)*A14+(4)*A15+(2)*A16+(8)*A17+(11)*A18+(30)*A19+(−13)*U1+(−10)*U2+(2)*U3+(−2)*U4+(−5)*U5+(5)*U6+(−2)*U7+(−10)*U8+(−5)*U9+(15)*U10+(−1)*U11+(0)*U12+(10)*U13+(−9)*U14+(−13)*U15+(−10)*U16+(3)*U17+(9)*U18+(9)*U19+(7)*C1+(3)*C2+(−21)*C3+(5)*C4+(−9)*C5+(−20)*C6+(−18)*C7+(−5)*C8+(5)*C9+(1)*C10+(2)*C11+(−5)*C12+(−3)*C13+(−6)*C14+(−2)*C15+(−5)*C16+(−3)*C17+(−12)*C18+(−18)*C19+(14)*G1+(8)*G2+(7)*G3+(−10)*G4+(−4)*G5+(2)*G6+(1)*G7+(9)*G8+(5)*G9+(−11)*G10+(1)*G11+(9)*G12+(−24)*G13+(18)*G14+(11)*G15+(13)*G16+(−7)*G17+(−9)*G18+(−22)*G19+6*(number of A+U in position 15-19)−3*(number of G+C in whole siRNA), Formula X
wherein position numbering begins at the 5′-most position of a sense strand, and
A1=1 if A is the base at position 1 of the sense strand, otherwise its value is 0;
A2=1 if A is the base at position 2 of the sense strand, otherwise its value is 0;
A3=1 if A is the base at position 3 of the sense strand, otherwise its value is 0;
A4=1 if A is the base at position 4 of the sense strand, otherwise its value is 0;
A5=1 if A is the base at position 5 of the sense strand, otherwise its value is 0;
A6=1 if A is the base at position 6 of the sense strand, otherwise its value is 0;
A7=1 if A is the base at position 7 of the sense strand, otherwise its value is 0;
A10=1 if A is the base at position 10 of the sense strand, otherwise its value is 0;
A11=1 if A is the base at position 11 of the sense strand, otherwise its value is 0;
A13=1 if A is the base at position 13 of the sense strand, otherwise its value is 0;
A19=1 if A is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
C3=1 if C is the base at position 3 of the sense strand, otherwise its value is 0;
C4=1 if C is the base at position 4 of the sense strand, otherwise its value is 0;
C5=1 if C is the base at position 5 of the sense strand, otherwise its value is 0;
C6=1 if C is the base at position 6 of the sense strand, otherwise its value is 0;
C7=1 if C is the base at position 7 of the sense strand, otherwise its value is 0;
C9=1 if C is the base at position 9 of the sense strand, otherwise its value is 0;
C17=1 if C is the base at position 17 of the sense strand, otherwise its value is 0;
C18=1 if C is the base at position 18 of the sense strand, otherwise its value is 0;
C19=1 if C is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
G1=1 if G is the base at position 1 on the sense strand, otherwise its value is 0;
G2=1 if G is the base at position 2 of the sense strand, otherwise its value is 0;
G8=1 if G is the base at position 8 on the sense strand, otherwise its value is 0;
G10=1 if G is the base at position 10 on the sense strand, otherwise its value is 0;
G13=1 if G is the base at position 13 on the sense strand, otherwise its value is 0;
G19=1 if G is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
U1=1 if U is the base at position 1 on the sense strand, otherwise its value is 0;
U2=1 if U is the base at position 2 on the sense strand, otherwise its value is 0;
U3=1 if U is the base at position 3 on the sense strand, otherwise its value is 0;
U4=1 if U is the base at position 4 on the sense strand, otherwise its value is 0;
U7=1 if U is the base at position 7 on the sense strand, otherwise its value is 0;
U9=1 if U is the base at position 9 on the sense strand, otherwise its value is 0;
U10=1 if U is the base at position 10 on the sense strand, otherwise its value is 0;
U15=1 if U is the base at position 15 on the sense strand, otherwise its value is 0;
U16=1 if U is the base at position 16 on the sense strand, otherwise its value is 0;
U17=1 if U is the base at position 17 on the sense strand, otherwise its value is 0;
U18=1 if U is the base at position 18 on the sense strand, otherwise its value is 0. 17. A method for identifying hyperfunctional siRNA, comprising:
applying selection criteria to a set of potential siRNA that comprise 18-30 base pairs, wherein said selection criteria are non-target specific criteria, and said set comprises at least two siRNAs and each of said at least two siRNAs contains a sequence that is at least substantially complementary to a target gene; and determining the relative functionality of the at least two siRNAs and assigning each of the at least two siRNAs a functionality score; and selecting siRNAs from the at least two siRNAs that have a functionality score that reflects greater than 80 percent silencing at a concentration in the picomolar range, wherein said greater than 80 percent silencing endures for greater than 120 hours. 18. A method according to claim 1, wherein said siRNA are unimolecular. 19. A method according to claim 2, wherein said siRNA are unimolecular. 20. A method according to claim 14, wherein said siRNA are unimolecular. 21. A method according to claim 16, wherein said siRNA are unimolecular. 22. A method according to claim 17, wherein said siRNA are unimolecular. 23. A method according to claim 1, wherein said siRNA are comprised of two separate polynucleotide strands. 24. A method according to claim 2, wherein said siRNA are comprised of two separate polynucleotide strands. 25. A method according to claim 14, wherein said siRNA are comprised of two separate polynucleotide strands. 26. A method according to claim 16, wherein said siRNA are comprised of two separate polynucleotide strands. 27. A method according to claim 17, wherein said siRNA are comprised of two separate polynucleotide strands. 28. A method according to claim 1, wherein said siRNA are expressed from one or more vectors. 29. A method according to claim 2, wherein said siRNA are expressed from one or more vectors. 30. A method according to claim 14, wherein said siRNA are expressed from one or more vectors. 31. A method according to claim 16, wherein said siRNA are expressed from one or more vectors. 32. A method according to claim 17, wherein said siRNA are expressed from one or more vectors. 33. A method according to claim 1, wherein two or more genes are silenced by a single administration of siRNA. 34. A method according to claim 2, wherein two or more genes are silenced by a single administration of siRNA. 35. A method according to claim 14, wherein two or more genes are silenced by a single administration of siRNA. 36. A method according to claim 16, wherein two or more genes are silenced by a single administration of siRNA. 37. A method according to claim 17, wherein two or more genes are silenced by a single administration of siRNA. 38. A kit according to claim 13, wherein one or more of said siRNA are unimolecular. 39. A kit according to claim 13, wherein one or more of said siRNA are comprised of two separate polynucleotide strands. 40. A kit according to claim 13, wherein one or more of said siRNA are capable of silencing the Bcl2 gene. 41. A method for developing an siRNA algorithm for selecting functional and hyperfunctional siRNAs for a given sequence, comprising:
(a) selecting a set of siRNAs; (b) measuring the gene silencing ability of each siRNA from said set; (c) determining the relative functionality of each siRNA; (d) determining the amount of improved functionality based on the following variables: the total GC content, melting temperature of the siRNA, GC content at positions 15-19, the presence or absence of a particular nucleotide at a particular position, relative thermodynamic stability at particular positions in a duplex, and the number of times that the same nucleotide repeats within a given sequence; and (e) developing an algorithm using the information of step (d). | Efficient sequence specific gene silencing is possible through the use of siRNA technology. By selecting particular siRNAs by rational design, one can maximize the generation of an effective gene silencing reagent, as well as methods for silencing genes. Methods, compositions, and kits generated through rational design of siRNAs are disclosed.1. A kit for gene silencing, wherein said kit is comprised of a pool of at least two siRNA duplexes, each of which is comprised of a sequence that is complementary to a portion of the sequence of one or more target messenger RNA, and each of which is selected using selection criteria that are embodied in a formula comprising: selection criteria are embodied in a formula comprising:
(−8)*A1+(−1)*A2+(12)*A3+(7)*A4+(18)*A5+(12)*A6+(19)*A7+(6)*A8+(−4)*A9+(−5)*A10+(−2)*A11+(−5)*A12+(17)*A13+(−3)*A14+(4)*A15+(2)*A16+(8)*A17+(11)*A18+(30)*A19+(−13)*U1+(−10)*U2+(2)*U3+(−2)*U4+(−5)*U5+(5)*U6+(−2)*U7+(−10)*U8+(−5)*U9+(15)*U10+(−1)*U11+(0)*U12+(10)*U13+(−9)*U14+(−13)*U15+(−10)*U16+(3)*U17+(9)*U18+(9)*U19+(7)*C1+(3)*C2+(−21)*C3+(5)*C4+(−9)*C5+(−20)*C6+(−18)*C7+(−5)*C8+(5)*C9+(1)*C10+(2)*C11+(−5)*C12+(−3)*C13+(−6)*C14+(−2)*C15+(−5)*C16+(−3)*C17+(−12)*C18+(−18)*C19+(14)*G1+(8)*G2+(7)*G3+(−10)*G4+(−4)*G5+(2)*G6+(1)*G7+(9)*G8+(5)*G9+(−11)*G10+(1)*G11+(9)*G12+(−24)*G13+(18)*G14+(11)*G15+(13)*G16+(−7)*G17+(−9)*G18+(−22)*G19+6*(number of A+U in position 15-19)−3*(number of G+C in whole siRNA), Formula X
wherein position numbering begins at the 5′-most position of a sense strand, and
A1=1 if A is the base at position 1 of the sense strand, otherwise its value is 0;
A2=1 if A is the base at position 2 of the sense strand, otherwise its value is 0;
A3=1 if A is the base at position 3 of the sense strand, otherwise its value is 0;
A4=1 if A is the base at position 4 of the sense strand, otherwise its value is 0;
A5=1 if A is the base at position 5 of the sense strand, otherwise its value is 0;
A6=1 if A is the base at position 6 of the sense strand, otherwise its value is 0;
A7=1 if A is the base at position 7 of the sense strand, otherwise its value is 0;
A10=1 if A is the base at position 10 of the sense strand, otherwise its value is 0;
A11=1 if A is the base at position 11 of the sense strand, otherwise its value is 0;
A13=1 if A is the base at position 13 of the sense strand, otherwise its value is 0;
A19=1 if A is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
C3=1 if C is the base at position 3 of the sense strand, otherwise its value is 0;
C4=1 if C is the base at position 4 of the sense strand, otherwise its value is 0;
C5=1 if C is the base at position 5 of the sense strand, otherwise its value is 0;
C6=1 if C is the base at position 6 of the sense strand, otherwise its value is 0;
C7=1 if C is the base at position 7 of the sense strand, otherwise its value is 0;
C9=1 if C is the base at position 9 of the sense strand, otherwise its value is 0;
C17=1 if C is the base at position 17 of the sense strand, otherwise its value is 0;
C18=1 if C is the base at position 18 of the sense strand, otherwise its value is 0;
C19=1 if C is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
G1=1 if G is the base at position 1 on the sense strand, otherwise its value is 0;
G2=1 if G is the base at position 2 of the sense strand, otherwise its value is 0;
G8=1 if G is the base at position 8 on the sense strand, otherwise its value is 0;
G10=1 if G is the base at position 10 on the sense strand, otherwise its value is 0;
G13=1 if G is the base at position 13 on the sense strand, otherwise its value is 0;
G19=1 if G is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
U1=1 if U is the base at position 1 on the sense strand, otherwise its value is 0;
U2=1 if U is the base at position 2 on the sense strand, otherwise its value is 0;
U3=1 if U is the base at position 3 on the sense strand, otherwise its value is 0;
U4=1 if U is the base at position 4 on the sense strand, otherwise its value is 0;
U7=1 if U is the base at position 7 on the sense strand, otherwise its value is 0;
U9=1 if U is the base at position 9 on the sense strand, otherwise its value is 0;
U10=1 if U is the base at position 10 on the sense strand, otherwise its value is 0;
U15=1 if U is the base at position 15 on the sense strand, otherwise its value is 0;
U16=1 if U is the base at position 16 on the sense strand, otherwise its value is 0;
U17=1 if U is the base at position 17 on the sense strand, otherwise its value is 0;
U18=1 if U is the base at position 18 on the sense strand, otherwise its value is 0. 2. A method for selecting an siRNA, said method comprising:
applying selection criteria to a set of potential siRNA that comprise 18-30 base pairs; and determining the relative functionality of the at least two siRNAs, wherein said section criteria are non-target specific criteria, said set comprises at least two siRNAs and each of said at least two siRNAs contains a sequence that is at least substantially complementary to a target gene, and said selection criteria are embodied in a formula comprising: (−8)*A1+(−1)*A2+(12)*A3+(7)*A4+(18)*A5+(12)*A6+(19)*A7+(6)*A8+(−4)*A9+(−5)*A10+(−2)*A11+(−5)*A12+(17)*A13+(−3)*A14+(4)*A15+(2)*A16+(8)*A17+(11)*A18+(30)*A19+(−13)*U1+(−10)*U2+(2)*U3+(−2)*U4+(−5)*U5+(5)*U6+(−2)*U7+(−10)*U8+(−5)*U9+(15)*U10+(−1)*U11+(0)*U12+(10)*U13+(−9)*U14+(−13)*U15+(−10)*U16+(3)*U17+(9)*U18+(9)*U19+(7)*C1+(3)*C2+(−21)*C3+(5)*C4+(−9)*C5+(−20)*C6+(−18)*C7+(−5)*C8+(5)*C9+(1)*C10+(2)*C11+(−5)*C12+(−3)*C13+(−6)*C14+(−2)*C15+(−5)*C16+(−3)*C17+(−12)*C18+(−18)*C19+(14)*G1+(8)*G2+(7)*G3+(−10)*G4+(−4)*G5+(2)*G6+(1)*G7+(9)*G8+(5)*G9+(−11)*G10+(1)*G11+(9)*G12+(−24)*G13+(18)*G14+(11)*G15+(13)*G16+(−7)*G17+(−9)*G18+(−22)*G19+6*(number of A+U in position 15-19)−3*(number of G+C in whole siRNA), Formula X wherein position numbering begins at the 5′-most position of a sense strand, and A1=1 if A is the base at position 1 of the sense strand, otherwise its value is 0; A2=1 if A is the base at position 2 of the sense strand, otherwise its value is 0; A3=1 if A is the base at position 3 of the sense strand, otherwise its value is 0; A4=1 if A is the base at position 4 of the sense strand, otherwise its value is 0; A5=1 if A is the base at position 5 of the sense strand, otherwise its value is 0; A6=1 if A is the base at position 6 of the sense strand, otherwise its value is 0; A7=1 if A is the base at position 7 of the sense strand, otherwise its value is 0; A10=1 if A is the base at position 10 of the sense strand, otherwise its value is 0; A11=1 if A is the base at position 11 of the sense strand, otherwise its value is 0; A13=1 if A is the base at position 13 of the sense strand, otherwise its value is 0; A19=1 if A is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0; C3=1 if C is the base at position 3 of the sense strand, otherwise its value is 0; C4=1 if C is the base at position 4 of the sense strand, otherwise its value is 0; C5=1 if C is the base at position 5 of the sense strand, otherwise its value is 0; C6=1 if C is the base at position 6 of the sense strand, otherwise its value is 0; C7=1 if C is the base at position 7 of the sense strand, otherwise its value is 0; C9=1 if C is the base at position 9 of the sense strand, otherwise its value is 0; C17=1 if C is the base at position 17 of the sense strand, otherwise its value is 0; C18=1 if C is the base at position 18 of the sense strand, otherwise its value is 0; C19=1 if C is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0; G1=1 if G is the base at position 1 on the sense strand, otherwise its value is 0; G2=1 if G is the base at position 2 of the sense strand, otherwise its value is 0; G8=1 if G is the base at position 8 on the sense strand, otherwise its value is 0; G10=1 if G is the base at position 10 on the sense strand, otherwise its value is 0; G13=1 if G is the base at position 13 on the sense strand, otherwise its value is 0; G19=1 if G is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0; U1=1 if U is the base at position 1 on the sense strand, otherwise its value is 0; U2=1 if U is the base at position 2 on the sense strand, otherwise its value is 0; U3=1 if U is the base at position 3 on the sense strand, otherwise its value is 0; U4=1 if U is the base at position 4 on the sense strand, otherwise its value is 0; U7=1 if U is the base at position 7 on the sense strand, otherwise its value is 0; U9=1 if U is the base at position 9 on the sense strand, otherwise its value is 0; U10=1 if U is the base at position 10 on the sense strand, otherwise its value is 0; U15=1 if U is the base at position 15 on the sense strand, otherwise its value is 0; U16=1 if U is the base at position 16 on the sense strand, otherwise its value is 0; U17=1 if U is the base at position 17 on the sense strand, otherwise its value is 0; U18=1 if U is the base at position 18 on the sense strand, otherwise its value is 0. 3. A method according to claim 1, further comprising comparing the internal stability profiles of said at least two siRNAs. 4. A method according to claim 2, further comprising comparing the internal stability profiles of said at least two siRNAs. 5. A method according to claim 1, further comprising selecting either for or against sequences that contain motifs that induce cellular stress. 6. A method according to claim 2, further comprising selecting either for or against sequences that contain motifs that induce cellular stress. 7. A method according to claim 1, further comprising selecting either for or against sequences that comprise stability motifs. 8. A method according to claim 2, further comprising selecting either for or against sequences that comprise stability motifs. 9. A method of gene silencing, comprising introducing into a cell at least one siRNA selected according to a method of claim 1. 10. A method of gene silencing, comprising introducing into a cell at least one siRNA selected according to a method of claim 2. 11. A method according to claim 1, wherein said introducing is by allowing passive uptake of the at least one siRNA. 12. A method according to claim 2, wherein said introducing is by allowing passive uptake of the at least one siRNA. 13. A method according claim 9, wherein said introducing in through the use of a vector. 14. A method for developing an siRNA algorithm for selecting siRNA, said method comprising:
(a) selecting a set of siRNA; (b) measuring gene silencing ability of each siRNA from said set; (c) determining relative functionality of each siRNA; (d) determining improved functionality based on the following variables: the presence or absence of a particular nucleotide at a particular position, the total number of As and Us in positions 15-19, the number of times that the same nucleotide repeats within a given sequence, and the total number of Gs and Cs; and (e) developing an algorithm using the information of step (d). 15. A method of selecting an siRNA with improved functionality, said method comprising using the algorithm of claim 14. 16. A kit, wherein said kit is comprised of at least two siRNAs, wherein said at least two siRNAs comprise a first optimized siRNA and a second optimized siRNA, wherein said first optimized siRNA and said second optimized siRNA are optimized according a formula comprising:
(−8)*A1+(−1)*A2+(12)*A3+(7)*A4+(18)*A5+(12)*A6+(19)*A7+(6)*A8+(−4)*A9+(−5)*A10+(−2)*A11+(−5)*A12+(17)*A13+(−3)*A14+(4)*A15+(2)*A16+(8)*A17+(11)*A18+(30)*A19+(−13)*U1+(−10)*U2+(2)*U3+(−2)*U4+(−5)*U5+(5)*U6+(−2)*U7+(−10)*U8+(−5)*U9+(15)*U10+(−1)*U11+(0)*U12+(10)*U13+(−9)*U14+(−13)*U15+(−10)*U16+(3)*U17+(9)*U18+(9)*U19+(7)*C1+(3)*C2+(−21)*C3+(5)*C4+(−9)*C5+(−20)*C6+(−18)*C7+(−5)*C8+(5)*C9+(1)*C10+(2)*C11+(−5)*C12+(−3)*C13+(−6)*C14+(−2)*C15+(−5)*C16+(−3)*C17+(−12)*C18+(−18)*C19+(14)*G1+(8)*G2+(7)*G3+(−10)*G4+(−4)*G5+(2)*G6+(1)*G7+(9)*G8+(5)*G9+(−11)*G10+(1)*G11+(9)*G12+(−24)*G13+(18)*G14+(11)*G15+(13)*G16+(−7)*G17+(−9)*G18+(−22)*G19+6*(number of A+U in position 15-19)−3*(number of G+C in whole siRNA), Formula X
wherein position numbering begins at the 5′-most position of a sense strand, and
A1=1 if A is the base at position 1 of the sense strand, otherwise its value is 0;
A2=1 if A is the base at position 2 of the sense strand, otherwise its value is 0;
A3=1 if A is the base at position 3 of the sense strand, otherwise its value is 0;
A4=1 if A is the base at position 4 of the sense strand, otherwise its value is 0;
A5=1 if A is the base at position 5 of the sense strand, otherwise its value is 0;
A6=1 if A is the base at position 6 of the sense strand, otherwise its value is 0;
A7=1 if A is the base at position 7 of the sense strand, otherwise its value is 0;
A10=1 if A is the base at position 10 of the sense strand, otherwise its value is 0;
A11=1 if A is the base at position 11 of the sense strand, otherwise its value is 0;
A13=1 if A is the base at position 13 of the sense strand, otherwise its value is 0;
A19=1 if A is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
C3=1 if C is the base at position 3 of the sense strand, otherwise its value is 0;
C4=1 if C is the base at position 4 of the sense strand, otherwise its value is 0;
C5=1 if C is the base at position 5 of the sense strand, otherwise its value is 0;
C6=1 if C is the base at position 6 of the sense strand, otherwise its value is 0;
C7=1 if C is the base at position 7 of the sense strand, otherwise its value is 0;
C9=1 if C is the base at position 9 of the sense strand, otherwise its value is 0;
C17=1 if C is the base at position 17 of the sense strand, otherwise its value is 0;
C18=1 if C is the base at position 18 of the sense strand, otherwise its value is 0;
C19=1 if C is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
G1=1 if G is the base at position 1 on the sense strand, otherwise its value is 0;
G2=1 if G is the base at position 2 of the sense strand, otherwise its value is 0;
G8=1 if G is the base at position 8 on the sense strand, otherwise its value is 0;
G10=1 if G is the base at position 10 on the sense strand, otherwise its value is 0;
G13=1 if G is the base at position 13 on the sense strand, otherwise its value is 0;
G19=1 if G is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
U1=1 if U is the base at position 1 on the sense strand, otherwise its value is 0;
U2=1 if U is the base at position 2 on the sense strand, otherwise its value is 0;
U3=1 if U is the base at position 3 on the sense strand, otherwise its value is 0;
U4=1 if U is the base at position 4 on the sense strand, otherwise its value is 0;
U7=1 if U is the base at position 7 on the sense strand, otherwise its value is 0;
U9=1 if U is the base at position 9 on the sense strand, otherwise its value is 0;
U10=1 if U is the base at position 10 on the sense strand, otherwise its value is 0;
U15=1 if U is the base at position 15 on the sense strand, otherwise its value is 0;
U16=1 if U is the base at position 16 on the sense strand, otherwise its value is 0;
U17=1 if U is the base at position 17 on the sense strand, otherwise its value is 0;
U18=1 if U is the base at position 18 on the sense strand, otherwise its value is 0. 17. A method for identifying hyperfunctional siRNA, comprising:
applying selection criteria to a set of potential siRNA that comprise 18-30 base pairs, wherein said selection criteria are non-target specific criteria, and said set comprises at least two siRNAs and each of said at least two siRNAs contains a sequence that is at least substantially complementary to a target gene; and determining the relative functionality of the at least two siRNAs and assigning each of the at least two siRNAs a functionality score; and selecting siRNAs from the at least two siRNAs that have a functionality score that reflects greater than 80 percent silencing at a concentration in the picomolar range, wherein said greater than 80 percent silencing endures for greater than 120 hours. 18. A method according to claim 1, wherein said siRNA are unimolecular. 19. A method according to claim 2, wherein said siRNA are unimolecular. 20. A method according to claim 14, wherein said siRNA are unimolecular. 21. A method according to claim 16, wherein said siRNA are unimolecular. 22. A method according to claim 17, wherein said siRNA are unimolecular. 23. A method according to claim 1, wherein said siRNA are comprised of two separate polynucleotide strands. 24. A method according to claim 2, wherein said siRNA are comprised of two separate polynucleotide strands. 25. A method according to claim 14, wherein said siRNA are comprised of two separate polynucleotide strands. 26. A method according to claim 16, wherein said siRNA are comprised of two separate polynucleotide strands. 27. A method according to claim 17, wherein said siRNA are comprised of two separate polynucleotide strands. 28. A method according to claim 1, wherein said siRNA are expressed from one or more vectors. 29. A method according to claim 2, wherein said siRNA are expressed from one or more vectors. 30. A method according to claim 14, wherein said siRNA are expressed from one or more vectors. 31. A method according to claim 16, wherein said siRNA are expressed from one or more vectors. 32. A method according to claim 17, wherein said siRNA are expressed from one or more vectors. 33. A method according to claim 1, wherein two or more genes are silenced by a single administration of siRNA. 34. A method according to claim 2, wherein two or more genes are silenced by a single administration of siRNA. 35. A method according to claim 14, wherein two or more genes are silenced by a single administration of siRNA. 36. A method according to claim 16, wherein two or more genes are silenced by a single administration of siRNA. 37. A method according to claim 17, wherein two or more genes are silenced by a single administration of siRNA. 38. A kit according to claim 13, wherein one or more of said siRNA are unimolecular. 39. A kit according to claim 13, wherein one or more of said siRNA are comprised of two separate polynucleotide strands. 40. A kit according to claim 13, wherein one or more of said siRNA are capable of silencing the Bcl2 gene. 41. A method for developing an siRNA algorithm for selecting functional and hyperfunctional siRNAs for a given sequence, comprising:
(a) selecting a set of siRNAs; (b) measuring the gene silencing ability of each siRNA from said set; (c) determining the relative functionality of each siRNA; (d) determining the amount of improved functionality based on the following variables: the total GC content, melting temperature of the siRNA, GC content at positions 15-19, the presence or absence of a particular nucleotide at a particular position, relative thermodynamic stability at particular positions in a duplex, and the number of times that the same nucleotide repeats within a given sequence; and (e) developing an algorithm using the information of step (d). | 1,600 |
747 | 13,867,308 | 1,611 | Tablets are prepared with friability reducing agents to yield tablets that are more resistant to breakage or crumbling, but with satisfactory hardness. The friability reducing agents include low molecular weight polyethylene glycol as well as similar agents exhibiting at least three percent (3%) hydroxide moieties and a water solubility of at least eighty percent (80%) (w/w %) in room temperature water. The tablets may comprise an active agent and excipient of almost any type, and about 0.1-about 0.5% by weight friability reducing agent. They exhibit a hardness of at least eighty percent (80%) of the same tablet prepared without the friability reducing agent. | 1. A tablet exhibiting reduced friability, comprising an active agent, an excipient compatible with said active agent, and an agent to reduce friability, wherein said agent to reduce friability is present in amounts of about 0.1%-about 5.0% by weight of the tablet, said friability reducing agent comprises a compound which exhibits a solubility in room temperature water of at least eighty percent (80%) (w/w %), wherein said friability reducing agent is comprised of at least three percent (3%) by weight —OH moieties and wherein said tablet comprising said friability reducing agent exhibits a hardness of at least eighty percent (80%) of the hardness exhibited by said tablet prepared in the absence of said friability reducing agent. 2. The tablet of claim 1, wherein said tablet comprises an effervescent couple which combine to release carbon dioxide when the tablet is moistened. 3. The tablet of claim 1 wherein said friability reducing agent is comprised of polyethylene glycol of about 200-1,000, polypropylene glycol of about 250-1,000, methoxypolyethylene glycol of about 350-1,000, polysorbate, glycerin and mixtures thereof. 4. The tablet of claim 3, wherein said friability reducing agent is comprised of polyethylene glycol of about 200-1,000. 5. The tablet of claim 4, wherein said friability reducing agent is comprised of polyethylene glycol 400. 6. The tablet of claim 1, wherein said active agent comprises a flavor, an aroma, a medication, a nutritional product, a bleach, a detergent, an herbicide, an insecticide or bactericide. 7. The tablet of claim 1, wherein said excipient is a stabilizer, lubricant, a binder, a disintegrant, or a coating. 8. The tablet of claim 1, wherein said tablet composition is compatible with its consumption by an animal or plant. 9. The tablet of claim 8, wherein said animal is a mammal 10. The tablet of claim 9, wherein sad mammal is a human. | Tablets are prepared with friability reducing agents to yield tablets that are more resistant to breakage or crumbling, but with satisfactory hardness. The friability reducing agents include low molecular weight polyethylene glycol as well as similar agents exhibiting at least three percent (3%) hydroxide moieties and a water solubility of at least eighty percent (80%) (w/w %) in room temperature water. The tablets may comprise an active agent and excipient of almost any type, and about 0.1-about 0.5% by weight friability reducing agent. They exhibit a hardness of at least eighty percent (80%) of the same tablet prepared without the friability reducing agent.1. A tablet exhibiting reduced friability, comprising an active agent, an excipient compatible with said active agent, and an agent to reduce friability, wherein said agent to reduce friability is present in amounts of about 0.1%-about 5.0% by weight of the tablet, said friability reducing agent comprises a compound which exhibits a solubility in room temperature water of at least eighty percent (80%) (w/w %), wherein said friability reducing agent is comprised of at least three percent (3%) by weight —OH moieties and wherein said tablet comprising said friability reducing agent exhibits a hardness of at least eighty percent (80%) of the hardness exhibited by said tablet prepared in the absence of said friability reducing agent. 2. The tablet of claim 1, wherein said tablet comprises an effervescent couple which combine to release carbon dioxide when the tablet is moistened. 3. The tablet of claim 1 wherein said friability reducing agent is comprised of polyethylene glycol of about 200-1,000, polypropylene glycol of about 250-1,000, methoxypolyethylene glycol of about 350-1,000, polysorbate, glycerin and mixtures thereof. 4. The tablet of claim 3, wherein said friability reducing agent is comprised of polyethylene glycol of about 200-1,000. 5. The tablet of claim 4, wherein said friability reducing agent is comprised of polyethylene glycol 400. 6. The tablet of claim 1, wherein said active agent comprises a flavor, an aroma, a medication, a nutritional product, a bleach, a detergent, an herbicide, an insecticide or bactericide. 7. The tablet of claim 1, wherein said excipient is a stabilizer, lubricant, a binder, a disintegrant, or a coating. 8. The tablet of claim 1, wherein said tablet composition is compatible with its consumption by an animal or plant. 9. The tablet of claim 8, wherein said animal is a mammal 10. The tablet of claim 9, wherein sad mammal is a human. | 1,600 |
748 | 15,315,777 | 1,653 | The invention concerns plant wax extracts and a method for extracting wax from plants, such as agricultural biowaste and in particular from cereal straw, including a first dry mechanical treatment step to separate a wax enriched fraction from a straw fraction low in wax and a second wet step including enzymatic treatment of the wax enriched fraction. | 1. A method for separating wax-containing plant material into a wax fraction and a fiber fraction partly depleted of wax, comprising:
a. mechanically treating plant material in a dry process at ambient temperature to provide comminuted plant material, b. separating the comminuted plant material into a fraction A comprising plant fines enriched in plant wax and a fraction B comprising plant fibers partly depleted of plant wax, c. adding an aqueous liquid to fraction A followed by mixing and agitation at an elevated temperature, d. adding one or more enzymes to the aqueous mixture, optionally accompanied by a mechanical treatment, such as wet-milling, e. heating the mixture to a temperature whereby the wax is liquefied and the enzymes are inactivated, f. separating from the heated mixture a wax-containing liquid fraction C and a fiber containing fraction D, g. separating the wax from fraction C. 2. A method for obtaining a sample enriched in wax from plants, comprising:
a. providing a sample of plant fines enriched in plant wax, b. adding an aqueous liquid to the sample followed by mixing and agitation at an elevated temperature, c. adding one or more enzymes to the mixture, d. heating the mixture to a temperature whereby the wax is liquefied, e. separating the wax from the mixture. 3. Method according to claim 2, wherein the sample of plant fines enriched in wax is resulting from fractionation of straw being mechanically dry-treated at ambient temperature. 4. Method according to any one of claims 1-3, wherein the mechanical treatment comprised cutting and crushing (chopping). 5. Method according to any one of claims 1-4, wherein the fractionation is by weight/size (e.g. sieving). 6. Method according to any one of claims 1-5, wherein the enzyme(s) is/are selected from the group of proteases. 7. Method according to any one of claims 1-6, wherein the plant is selected from cereals, grasses, sugar cane, palms, trees, etc. 8. Method according to claim 7, wherein the cereal is selected from wheat, rye, barley, oats, sorghum (durra), rice, etc. 9. Method according to any one of claims 1-8, wherein the sample of plant fines enriched in plant wax comprise wax particles and flakes liberated from the plant matter during the mechanical treatment. 10. Method according to any one of claims 1-9, wherein the aqueous liquid is water at a temperature adjusted for solubilizing water soluble components in the mixture and the water to plant matter ratio is at least 5:1 (by weight), such as 10:1. 11. Method according to any of claims 1-10, wherein the temperature and pH are adjusted to optimize the activity of the enzyme(s) added. 12. Method according to any one of claims 1-11, wherein the enzyme(s) is or are selected for degrading one or more proteins associated with the wax in the sample of plant fines. 13. Method according to claim 12, wherein the enzyme(s) is or are selected from endo- and/or exo-proteases. 14. Method according to any one of claims 1-13, wherein the enzyme-treated liquid mixture is mechanically treated, e.g. in a wet-mill, to liberate wax associated with the plant matter remains, such as proteins and fibers. 15. Method according to any one of claims 1-14, wherein the enzyme-treated mixture is heated to liquefy the wax. 16. Method according to claim 15, wherein the temperature is further selected to inactivate the enzyme(s). 17. Method according to any one of claims 1-16, wherein the remaining plant matters after enzyme treatment and heating are separated and removed from the liquid phase. 18. Method according to any one of claims 1-17, wherein the wax phase is separated from the aqueous phase of the liquid before or after removal of the remaining plant matters. 19. Method according to any one of claims 1-18, wherein the wax is purified by removing remaining impurities from the wax phase. 20. Method according to claim 17, wherein the solids in the remaining plant matter is pressed to pellets for use in a combustion process. 21. A plant wax obtained in a method according to any one of claims 1-19. 22. A product comprising a plant wax according to claim 21. 23. A product comprising a de-waxed plant material obtained as fraction B in the method according to any one of claims 1-8. 24. A combustible pellet obtained according to the method of claim 20. | The invention concerns plant wax extracts and a method for extracting wax from plants, such as agricultural biowaste and in particular from cereal straw, including a first dry mechanical treatment step to separate a wax enriched fraction from a straw fraction low in wax and a second wet step including enzymatic treatment of the wax enriched fraction.1. A method for separating wax-containing plant material into a wax fraction and a fiber fraction partly depleted of wax, comprising:
a. mechanically treating plant material in a dry process at ambient temperature to provide comminuted plant material, b. separating the comminuted plant material into a fraction A comprising plant fines enriched in plant wax and a fraction B comprising plant fibers partly depleted of plant wax, c. adding an aqueous liquid to fraction A followed by mixing and agitation at an elevated temperature, d. adding one or more enzymes to the aqueous mixture, optionally accompanied by a mechanical treatment, such as wet-milling, e. heating the mixture to a temperature whereby the wax is liquefied and the enzymes are inactivated, f. separating from the heated mixture a wax-containing liquid fraction C and a fiber containing fraction D, g. separating the wax from fraction C. 2. A method for obtaining a sample enriched in wax from plants, comprising:
a. providing a sample of plant fines enriched in plant wax, b. adding an aqueous liquid to the sample followed by mixing and agitation at an elevated temperature, c. adding one or more enzymes to the mixture, d. heating the mixture to a temperature whereby the wax is liquefied, e. separating the wax from the mixture. 3. Method according to claim 2, wherein the sample of plant fines enriched in wax is resulting from fractionation of straw being mechanically dry-treated at ambient temperature. 4. Method according to any one of claims 1-3, wherein the mechanical treatment comprised cutting and crushing (chopping). 5. Method according to any one of claims 1-4, wherein the fractionation is by weight/size (e.g. sieving). 6. Method according to any one of claims 1-5, wherein the enzyme(s) is/are selected from the group of proteases. 7. Method according to any one of claims 1-6, wherein the plant is selected from cereals, grasses, sugar cane, palms, trees, etc. 8. Method according to claim 7, wherein the cereal is selected from wheat, rye, barley, oats, sorghum (durra), rice, etc. 9. Method according to any one of claims 1-8, wherein the sample of plant fines enriched in plant wax comprise wax particles and flakes liberated from the plant matter during the mechanical treatment. 10. Method according to any one of claims 1-9, wherein the aqueous liquid is water at a temperature adjusted for solubilizing water soluble components in the mixture and the water to plant matter ratio is at least 5:1 (by weight), such as 10:1. 11. Method according to any of claims 1-10, wherein the temperature and pH are adjusted to optimize the activity of the enzyme(s) added. 12. Method according to any one of claims 1-11, wherein the enzyme(s) is or are selected for degrading one or more proteins associated with the wax in the sample of plant fines. 13. Method according to claim 12, wherein the enzyme(s) is or are selected from endo- and/or exo-proteases. 14. Method according to any one of claims 1-13, wherein the enzyme-treated liquid mixture is mechanically treated, e.g. in a wet-mill, to liberate wax associated with the plant matter remains, such as proteins and fibers. 15. Method according to any one of claims 1-14, wherein the enzyme-treated mixture is heated to liquefy the wax. 16. Method according to claim 15, wherein the temperature is further selected to inactivate the enzyme(s). 17. Method according to any one of claims 1-16, wherein the remaining plant matters after enzyme treatment and heating are separated and removed from the liquid phase. 18. Method according to any one of claims 1-17, wherein the wax phase is separated from the aqueous phase of the liquid before or after removal of the remaining plant matters. 19. Method according to any one of claims 1-18, wherein the wax is purified by removing remaining impurities from the wax phase. 20. Method according to claim 17, wherein the solids in the remaining plant matter is pressed to pellets for use in a combustion process. 21. A plant wax obtained in a method according to any one of claims 1-19. 22. A product comprising a plant wax according to claim 21. 23. A product comprising a de-waxed plant material obtained as fraction B in the method according to any one of claims 1-8. 24. A combustible pellet obtained according to the method of claim 20. | 1,600 |
749 | 15,593,586 | 1,612 | Provided herein are methods for preparing liposomes comprising increased concentration of hydrophobic therapeutic agents and improved stability, and uses thereof. In certain embodiments, liposomes are prepared without using heat, organic solvents, proteins, and/or inorganic salts. | 1. A method of incorporating a hydrophobic therapeutic agent into preformed liposomes, the method comprising the steps of:
(a) providing (i) a liposome suspension comprising a plurality of preformed liposomes suspended in an aqueous medium, the liposomes comprising lipid forming a lipid bilayer phase, and (ii) a solid form of a hydrophobic therapeutic agent; (b) adding the solid form of the hydrophobic therapeutic agent to the liposome suspension, thereby forming a liposome-drug suspension; and (c) homogenizing the liposome-drug suspension;
whereby the hydrophobic therapeutic agent is incorporated into the lipid bilayer phase; and
wherein step (c) is performed at a temperature at or below ambient temperature. 2. The method of claim 1, wherein steps (b) and/or (c) are performed in the absence of solvent. 3. The method of claim 1, wherein steps (b) and/or (c) are performed in the absence of surfactant. 4. The method of claim 1, wherein the hydrophobic therapeutic agent is a small molecule drug or an antibody. 5. The method of claim 1, wherein at least about 80% of the hydrophobic therapeutic agent is bound to the lipid bilayer phase after step (c). 6. The method of claim 1, wherein the molar ratio of therapeutic agent to liposomal lipid is at least about 1:10. 7. The method of claim 1, wherein homogenization of the liposome-drug suspension in step (c) is performed by microfluidization, sonication, extrusion, freeze-thaw, or a combination thereof. 8. The method of claim 1, wherein the therapeutic agent does not contact solvent during steps (b) and (c), and does not contact the liposomal lipid prior to the formation of the liposomes. 9. The method of claim 1, wherein the liposomes are essentially unilamellar after step (c). 10. The method of claim 1, wherein the liposomes have a diameter of about 100 nm or less after step (c). 11. The method of claim 1, wherein the liposomes have a diameter of about 50 nm or less after step (c). 12. The method of claim 1, wherein the liposome suspension provided in step (a) comprises an additional therapeutic agent present in the aqueous medium and/or the liposomes. 13. The method of claim 1, wherein the composition of the aqueous medium inside and outside the liposomes is identical in steps (a), (b), and (c). 14. The method of claim 1, wherein the liposomal lipid comprises not more than 20% saturated fatty acids. 15. The method of claim 1, wherein the liposomal lipid comprises L-α-phosphatidylcholine. 16. The method of claim 1, wherein the method further comprises, after step (c), performing sterile filtration, lyophilization, or lyophilization and reconstitution with an aqueous medium. 17. The method of claim 1, wherein the therapeutic agent remains bound to the lipid bilayer phase of the liposomes after step (c) for at least 2 months upon storage in the aqueous medium at about 4° C. 18. The method of claim 1, wherein the therapeutic agent remains associated with the lipid bilayer phase after step (c) followed by lyophilization and storage for at least 1 year at ambient temperature and reconstitution in an aqueous medium. 19. The method of claim 1, wherein average liposome size after step (c) remains less than about 100 nm for at least 2 months upon storage in the aqueous medium at about 4° C. 20. The method of claim 1, wherein after step (c) followed by lyophilization, storage for at least 1 year at ambient temperature, and reconstitution in an aqueous medium, the average liposome size remains less than about 100 nm. 21. The method of claim 1, wherein said temperature is from about 15° C. to about 35° C. 22. The method of claim 1, wherein the lipid bilayer phase is liquid crystalline at said temperature. 23. The method of claim 1, wherein the lipid concentration of the liposome-drug suspension in steps (b) and (c) is from about 1 to about 7% by weight. 24. The method of claim 1, wherein the solid hydrophobic therapeutic agent added in step (b) provides a total concentration of the agent in the liposome-drug suspension of from about 1 to about 20 mg/mL. 25. A method of incorporating a hydrophobic therapeutic agent into preformed liposomes, the method comprising the steps of:
(a) providing (i) a liposome suspension comprising a plurality of preformed liposomes suspended in an aqueous medium, the liposomes comprising lipid forming a lipid bilayer phase, and (ii) a therapeutic agent concentrate comprising a hydrophobic therapeutic agent dissolved in a liquid medium comprising or consisting of solvent; (b) adding the therapeutic agent concentrate to the liposome suspension to form a liposome-drug suspension, wherein the total concentration of solvent in the liposome-drug suspension is not more than 10 weight percent; and (c) homogenizing the liposome-drug suspension;
whereby the hydrophobic therapeutic agent is incorporated into the lipid bilayer phase; and
wherein step (c) is performed at a temperature at or below ambient temperature. 26. The method of claim 25, wherein the total concentration of solvent in the liposome-drug suspension in step (b) is not more than about 5 weight percent. 27. The method of claim 25, wherein the solvent is a water miscible organic solvent. 28. The method of claim 25, wherein the liquid medium further comprises water or an aqueous medium. 29. The method of claim 25, wherein the solvent is selected from the group consisting of alcohols, ketones, ethers, organic acids, organic bases, and mixtures thereof 30. The method of claim 25, wherein the solvent is selected from the group consisting of ethanol, propanol, isopropanol, butanol, isobutanol, and DMSO. 31. The method of claim 25, wherein the liquid medium is 100% ethanol. 32. The method of claim 25, wherein step (c) is performed without the use of surfactant. 33. The method of claim 25, wherein the hydrophobic therapeutic agent is a small molecule drug or an antibody. 34. The method of claim 25, wherein at least about 80% of the hydrophobic therapeutic agent is associated with the lipid bilayer phase after step (c). 35. The method of claim 25, wherein the molar ratio of therapeutic agent to lipid is at least about 1:10. 36. The method of claim 25, wherein homogenization of the liposome-drug suspension in step (c) is performed by microfluidization, sonication, extrusion, freeze-thaw, or a combination thereof. 37. The method of claim 25, wherein the therapeutic agent does not contact the liposomal lipid prior to the formation of the liposomes. 38. The method of claim 25, wherein the liposomes are essentially unilamellar after step (c). 39. The method of claim 25, wherein the liposomes have a diameter of about 100 nm or less after step (c). 40. The method of claim 25, wherein the liposomes have a diameter of about 50 nm or less after step (c). 41. The method of claim 25, wherein the liposome suspension provided in step (a) comprises an additional therapeutic agent present in the aqueous medium and/or the liposomes. 42. The method of claim 25, wherein the composition of the aqueous medium inside and outside the liposomes is identical in steps (a), (b), and (c). 43. The method of claim 25, wherein the liposomal lipid comprises not more than 20% saturated fatty acids. 44. The method of claim 25, wherein the liposomal lipid comprises L-α-phosphatidylcholine. 45. The method of claim 25, wherein the method further comprises, after step (c), performing sterile filtration, lyophilization, or lyophilization and reconstitution with an aqueous medium. 46. The method of claim 25, wherein the therapeutic agent remains bound to the lipid bilayer phase of the liposomes after step (c) for at least 2 months upon storage in the aqueous medium at about 4° C. 47. The method of claim 25, wherein the therapeutic agent remains associated with the lipid bilayer phase after step (c) followed by lyophilization and storage for at least 1 year at ambient temperature and reconstitution in an aqueous medium. 48. The method of claim 25, wherein average liposome size after step (c) remains less than about 100 nm for at least 2 months upon storage in the aqueous medium at about 4° C. 49. The method of claim 25, wherein after step (c) followed by lyophilization, storage for at least 1 year at ambient temperature, and reconstitution in an aqueous medium, the average liposome size remains less than about 100 nm. 50. The method of claim 25, wherein said temperature is from about 15° C. to about 35° C. 51. The method of claim 25, wherein the lipid bilayer phase is liquid crystalline at said temperature. 52. The method of claim 25, wherein the lipid concentration of the liposome-drug suspension in steps (b) and (c) is from about 1 to about 7% by weight. 53. The method of claim 25, wherein the solid hydrophobic therapeutic agent added in step (b) provides a total concentration of the agent in the liposome-drug suspension of from about 1 to about 20 mg/mL. 54. The method of claim 25, further comprising:
(d) lyophilizing the homogenized liposome suspension, whereby said solvent is removed. | Provided herein are methods for preparing liposomes comprising increased concentration of hydrophobic therapeutic agents and improved stability, and uses thereof. In certain embodiments, liposomes are prepared without using heat, organic solvents, proteins, and/or inorganic salts.1. A method of incorporating a hydrophobic therapeutic agent into preformed liposomes, the method comprising the steps of:
(a) providing (i) a liposome suspension comprising a plurality of preformed liposomes suspended in an aqueous medium, the liposomes comprising lipid forming a lipid bilayer phase, and (ii) a solid form of a hydrophobic therapeutic agent; (b) adding the solid form of the hydrophobic therapeutic agent to the liposome suspension, thereby forming a liposome-drug suspension; and (c) homogenizing the liposome-drug suspension;
whereby the hydrophobic therapeutic agent is incorporated into the lipid bilayer phase; and
wherein step (c) is performed at a temperature at or below ambient temperature. 2. The method of claim 1, wherein steps (b) and/or (c) are performed in the absence of solvent. 3. The method of claim 1, wherein steps (b) and/or (c) are performed in the absence of surfactant. 4. The method of claim 1, wherein the hydrophobic therapeutic agent is a small molecule drug or an antibody. 5. The method of claim 1, wherein at least about 80% of the hydrophobic therapeutic agent is bound to the lipid bilayer phase after step (c). 6. The method of claim 1, wherein the molar ratio of therapeutic agent to liposomal lipid is at least about 1:10. 7. The method of claim 1, wherein homogenization of the liposome-drug suspension in step (c) is performed by microfluidization, sonication, extrusion, freeze-thaw, or a combination thereof. 8. The method of claim 1, wherein the therapeutic agent does not contact solvent during steps (b) and (c), and does not contact the liposomal lipid prior to the formation of the liposomes. 9. The method of claim 1, wherein the liposomes are essentially unilamellar after step (c). 10. The method of claim 1, wherein the liposomes have a diameter of about 100 nm or less after step (c). 11. The method of claim 1, wherein the liposomes have a diameter of about 50 nm or less after step (c). 12. The method of claim 1, wherein the liposome suspension provided in step (a) comprises an additional therapeutic agent present in the aqueous medium and/or the liposomes. 13. The method of claim 1, wherein the composition of the aqueous medium inside and outside the liposomes is identical in steps (a), (b), and (c). 14. The method of claim 1, wherein the liposomal lipid comprises not more than 20% saturated fatty acids. 15. The method of claim 1, wherein the liposomal lipid comprises L-α-phosphatidylcholine. 16. The method of claim 1, wherein the method further comprises, after step (c), performing sterile filtration, lyophilization, or lyophilization and reconstitution with an aqueous medium. 17. The method of claim 1, wherein the therapeutic agent remains bound to the lipid bilayer phase of the liposomes after step (c) for at least 2 months upon storage in the aqueous medium at about 4° C. 18. The method of claim 1, wherein the therapeutic agent remains associated with the lipid bilayer phase after step (c) followed by lyophilization and storage for at least 1 year at ambient temperature and reconstitution in an aqueous medium. 19. The method of claim 1, wherein average liposome size after step (c) remains less than about 100 nm for at least 2 months upon storage in the aqueous medium at about 4° C. 20. The method of claim 1, wherein after step (c) followed by lyophilization, storage for at least 1 year at ambient temperature, and reconstitution in an aqueous medium, the average liposome size remains less than about 100 nm. 21. The method of claim 1, wherein said temperature is from about 15° C. to about 35° C. 22. The method of claim 1, wherein the lipid bilayer phase is liquid crystalline at said temperature. 23. The method of claim 1, wherein the lipid concentration of the liposome-drug suspension in steps (b) and (c) is from about 1 to about 7% by weight. 24. The method of claim 1, wherein the solid hydrophobic therapeutic agent added in step (b) provides a total concentration of the agent in the liposome-drug suspension of from about 1 to about 20 mg/mL. 25. A method of incorporating a hydrophobic therapeutic agent into preformed liposomes, the method comprising the steps of:
(a) providing (i) a liposome suspension comprising a plurality of preformed liposomes suspended in an aqueous medium, the liposomes comprising lipid forming a lipid bilayer phase, and (ii) a therapeutic agent concentrate comprising a hydrophobic therapeutic agent dissolved in a liquid medium comprising or consisting of solvent; (b) adding the therapeutic agent concentrate to the liposome suspension to form a liposome-drug suspension, wherein the total concentration of solvent in the liposome-drug suspension is not more than 10 weight percent; and (c) homogenizing the liposome-drug suspension;
whereby the hydrophobic therapeutic agent is incorporated into the lipid bilayer phase; and
wherein step (c) is performed at a temperature at or below ambient temperature. 26. The method of claim 25, wherein the total concentration of solvent in the liposome-drug suspension in step (b) is not more than about 5 weight percent. 27. The method of claim 25, wherein the solvent is a water miscible organic solvent. 28. The method of claim 25, wherein the liquid medium further comprises water or an aqueous medium. 29. The method of claim 25, wherein the solvent is selected from the group consisting of alcohols, ketones, ethers, organic acids, organic bases, and mixtures thereof 30. The method of claim 25, wherein the solvent is selected from the group consisting of ethanol, propanol, isopropanol, butanol, isobutanol, and DMSO. 31. The method of claim 25, wherein the liquid medium is 100% ethanol. 32. The method of claim 25, wherein step (c) is performed without the use of surfactant. 33. The method of claim 25, wherein the hydrophobic therapeutic agent is a small molecule drug or an antibody. 34. The method of claim 25, wherein at least about 80% of the hydrophobic therapeutic agent is associated with the lipid bilayer phase after step (c). 35. The method of claim 25, wherein the molar ratio of therapeutic agent to lipid is at least about 1:10. 36. The method of claim 25, wherein homogenization of the liposome-drug suspension in step (c) is performed by microfluidization, sonication, extrusion, freeze-thaw, or a combination thereof. 37. The method of claim 25, wherein the therapeutic agent does not contact the liposomal lipid prior to the formation of the liposomes. 38. The method of claim 25, wherein the liposomes are essentially unilamellar after step (c). 39. The method of claim 25, wherein the liposomes have a diameter of about 100 nm or less after step (c). 40. The method of claim 25, wherein the liposomes have a diameter of about 50 nm or less after step (c). 41. The method of claim 25, wherein the liposome suspension provided in step (a) comprises an additional therapeutic agent present in the aqueous medium and/or the liposomes. 42. The method of claim 25, wherein the composition of the aqueous medium inside and outside the liposomes is identical in steps (a), (b), and (c). 43. The method of claim 25, wherein the liposomal lipid comprises not more than 20% saturated fatty acids. 44. The method of claim 25, wherein the liposomal lipid comprises L-α-phosphatidylcholine. 45. The method of claim 25, wherein the method further comprises, after step (c), performing sterile filtration, lyophilization, or lyophilization and reconstitution with an aqueous medium. 46. The method of claim 25, wherein the therapeutic agent remains bound to the lipid bilayer phase of the liposomes after step (c) for at least 2 months upon storage in the aqueous medium at about 4° C. 47. The method of claim 25, wherein the therapeutic agent remains associated with the lipid bilayer phase after step (c) followed by lyophilization and storage for at least 1 year at ambient temperature and reconstitution in an aqueous medium. 48. The method of claim 25, wherein average liposome size after step (c) remains less than about 100 nm for at least 2 months upon storage in the aqueous medium at about 4° C. 49. The method of claim 25, wherein after step (c) followed by lyophilization, storage for at least 1 year at ambient temperature, and reconstitution in an aqueous medium, the average liposome size remains less than about 100 nm. 50. The method of claim 25, wherein said temperature is from about 15° C. to about 35° C. 51. The method of claim 25, wherein the lipid bilayer phase is liquid crystalline at said temperature. 52. The method of claim 25, wherein the lipid concentration of the liposome-drug suspension in steps (b) and (c) is from about 1 to about 7% by weight. 53. The method of claim 25, wherein the solid hydrophobic therapeutic agent added in step (b) provides a total concentration of the agent in the liposome-drug suspension of from about 1 to about 20 mg/mL. 54. The method of claim 25, further comprising:
(d) lyophilizing the homogenized liposome suspension, whereby said solvent is removed. | 1,600 |
750 | 15,308,445 | 1,646 | Excessive or repeated activation of inflammatory and pro-coagulant mechanisms at the site of tissue injury contributes to the development scar tissue that can lead to intimal hyperplasia and fibrotic disease. It has been established that inhibition of the LYST protein is associated with reduced inflammatory responses and reduced platelet activation at the site of tissue damage. Compositions and methods for inhibition of the expression and function of the LYST protein are described. The compositions and methods can be useful for the modulation of immune processes that contribute to formation of neointima and fibroproliferative disorders by altering macrophage, platelet and natural killer cell function to create a pro-regenerative immune response. | 1. A pharmaceutical composition comprising:
a) one or more inhibitors of LYST in an amount effective to reduce or prevent macrophage infiltration, natural killer cells and to reduce or prevent platelet activation in a subject in a subject; and b) a physiologically acceptable carrier, wherein the amount of one or more inhibitors of LYST does not prevent vascular neotissue formation in the subject. 2. The composition of claim 1 in a dosage formulation delivering one or more LYST inhibitors in an amount between 0.1 and 1000 mg/kg body weight of a human. 3. The composition of claim 1 in a dosage effective to reduce or prevent macrophage infiltration. 4. The composition of claim 1 in a dosage effective to reduce or prevent platelet activation. 5. The composition of claim 1 wherein one or more LYST inhibitors are antibodies, antibody fragments, or proteins having the binding specificity of an anti-LYST antibody. 6. The composition of claim 1 wherein one or more LYST inhibitors is a functional nucleic acid selected from the group consisting of an antisense molecule, siRNA, miRNA, aptamers, ribozymes, triplex forming molecules, RNAi, and external guide sequences. 7. The composition of claim 6 wherein one or more functional nucleic acids are expressed from an expression vector. 8. The composition of claim 1 further comprising a delivery vehicle selected from the group consisting of nanoparticles, microparticles, micelles, emulsions, synthetic lipoprotein particles, liposomes, carbon nanotubes, gels, or coatings. 9. The composition of claim 1 further comprising one or more additional therapeutic agents selected from the group consisting of other anti-neointima agents, chemotherapeutic agents, steroidal and non-steroidal anti-inflammatories, conventional immunotherapeutic agents, immune-suppressants, cytokines, chemokines, and growth factors. 10. A vascular graft or medical device comprising the composition of claim 1. 11. The vascular graft or medical device of claim 10 wherein the composition is coated onto or incorporated into the graft or device. 12. The medical device of claim 11 wherein the device is selected from the group consisting of stents, implants, needles, cannulas, catheters, shunts, balloons, and valves. 13. The medical device of claim 12 wherein the device is a stent. 14. The medical device of claim 13 wherein the stent is a drug eluting stent that elutes the composition. 15. The vascular graft of claim 10 wherein the graft is an autologous, preserved autologous, allogeneic, xenogenic or synthetic graft. 16. A method of reducing or preventing macrophage infiltration scar formation or stenosis in a subject, comprising administering to a subject in need thereof an effective amount of the composition of claim 1 optionally in combination with any of the compounds of claim 9,
to decrease scar formation, myocardial infarction, scarring adhesions, and liver fibrosis or to reduce or prevent platelet activation that could lead to arterial or venous thrombosis in a subject. 17. The method of reducing or preventing platelet activation that could lead to arterial or venous thrombosis in a subject of claim 16, comprising administering to a subject in need thereof the composition of claim 1. 18. The method of claim 16 wherein the subject is at risk of or has restenosis or other vascular proliferation disorder. 19. The method of claim 16 wherein the subject has undergone, is undergoing, or will undergo vascular trauma, angioplasty, vascular surgery, or transplantation arteriopathy. 20. The method of claim 16, wherein the composition or device is used to reduce or prevent the formation of scar tissue, promote healing, reduce or prevent the development of hypertrophic scarring, keloids, or adhesions, reduce or prevent fibrosis of the liver, fibrosis of the lungs, fibrosis of the heart or fibrosis of the kidneys, reduce or prevent neointima formation, stenosis or restenosis, reduce or prevent thrombosis, or any combination thereof in a subject relative to an untreated control subject. 21. The method of claim 16, wherein reducing or preventing the formation of scar tissue promotes integration but blocks encapsulation of one or more bio-prosthesis devices selected from the group consisting of pacemakers, nerve stimulators, replacement heart valves and artificial joints. 22. The method of claim 16, wherein reducing or preventing the formation of scar tissue is effective to treat or prevent neointima formation at a site of implantation of a vascular implant, a site of vascular injury, or a site of surgery in a subject, relative to an untreated control subject. 23. The method of claim 17, wherein the composition or device is used to reduce or prevent the expression of platelet derived growth factor, transforming growth factor beta, or any combination thereof in a subject relative to an untreated control subject. 24. A method of reducing stenosis or restenosis of a vascular graft comprising treating the graft ex vivo with the composition of claim 1 prior to implantation of the graft into a subject. | Excessive or repeated activation of inflammatory and pro-coagulant mechanisms at the site of tissue injury contributes to the development scar tissue that can lead to intimal hyperplasia and fibrotic disease. It has been established that inhibition of the LYST protein is associated with reduced inflammatory responses and reduced platelet activation at the site of tissue damage. Compositions and methods for inhibition of the expression and function of the LYST protein are described. The compositions and methods can be useful for the modulation of immune processes that contribute to formation of neointima and fibroproliferative disorders by altering macrophage, platelet and natural killer cell function to create a pro-regenerative immune response.1. A pharmaceutical composition comprising:
a) one or more inhibitors of LYST in an amount effective to reduce or prevent macrophage infiltration, natural killer cells and to reduce or prevent platelet activation in a subject in a subject; and b) a physiologically acceptable carrier, wherein the amount of one or more inhibitors of LYST does not prevent vascular neotissue formation in the subject. 2. The composition of claim 1 in a dosage formulation delivering one or more LYST inhibitors in an amount between 0.1 and 1000 mg/kg body weight of a human. 3. The composition of claim 1 in a dosage effective to reduce or prevent macrophage infiltration. 4. The composition of claim 1 in a dosage effective to reduce or prevent platelet activation. 5. The composition of claim 1 wherein one or more LYST inhibitors are antibodies, antibody fragments, or proteins having the binding specificity of an anti-LYST antibody. 6. The composition of claim 1 wherein one or more LYST inhibitors is a functional nucleic acid selected from the group consisting of an antisense molecule, siRNA, miRNA, aptamers, ribozymes, triplex forming molecules, RNAi, and external guide sequences. 7. The composition of claim 6 wherein one or more functional nucleic acids are expressed from an expression vector. 8. The composition of claim 1 further comprising a delivery vehicle selected from the group consisting of nanoparticles, microparticles, micelles, emulsions, synthetic lipoprotein particles, liposomes, carbon nanotubes, gels, or coatings. 9. The composition of claim 1 further comprising one or more additional therapeutic agents selected from the group consisting of other anti-neointima agents, chemotherapeutic agents, steroidal and non-steroidal anti-inflammatories, conventional immunotherapeutic agents, immune-suppressants, cytokines, chemokines, and growth factors. 10. A vascular graft or medical device comprising the composition of claim 1. 11. The vascular graft or medical device of claim 10 wherein the composition is coated onto or incorporated into the graft or device. 12. The medical device of claim 11 wherein the device is selected from the group consisting of stents, implants, needles, cannulas, catheters, shunts, balloons, and valves. 13. The medical device of claim 12 wherein the device is a stent. 14. The medical device of claim 13 wherein the stent is a drug eluting stent that elutes the composition. 15. The vascular graft of claim 10 wherein the graft is an autologous, preserved autologous, allogeneic, xenogenic or synthetic graft. 16. A method of reducing or preventing macrophage infiltration scar formation or stenosis in a subject, comprising administering to a subject in need thereof an effective amount of the composition of claim 1 optionally in combination with any of the compounds of claim 9,
to decrease scar formation, myocardial infarction, scarring adhesions, and liver fibrosis or to reduce or prevent platelet activation that could lead to arterial or venous thrombosis in a subject. 17. The method of reducing or preventing platelet activation that could lead to arterial or venous thrombosis in a subject of claim 16, comprising administering to a subject in need thereof the composition of claim 1. 18. The method of claim 16 wherein the subject is at risk of or has restenosis or other vascular proliferation disorder. 19. The method of claim 16 wherein the subject has undergone, is undergoing, or will undergo vascular trauma, angioplasty, vascular surgery, or transplantation arteriopathy. 20. The method of claim 16, wherein the composition or device is used to reduce or prevent the formation of scar tissue, promote healing, reduce or prevent the development of hypertrophic scarring, keloids, or adhesions, reduce or prevent fibrosis of the liver, fibrosis of the lungs, fibrosis of the heart or fibrosis of the kidneys, reduce or prevent neointima formation, stenosis or restenosis, reduce or prevent thrombosis, or any combination thereof in a subject relative to an untreated control subject. 21. The method of claim 16, wherein reducing or preventing the formation of scar tissue promotes integration but blocks encapsulation of one or more bio-prosthesis devices selected from the group consisting of pacemakers, nerve stimulators, replacement heart valves and artificial joints. 22. The method of claim 16, wherein reducing or preventing the formation of scar tissue is effective to treat or prevent neointima formation at a site of implantation of a vascular implant, a site of vascular injury, or a site of surgery in a subject, relative to an untreated control subject. 23. The method of claim 17, wherein the composition or device is used to reduce or prevent the expression of platelet derived growth factor, transforming growth factor beta, or any combination thereof in a subject relative to an untreated control subject. 24. A method of reducing stenosis or restenosis of a vascular graft comprising treating the graft ex vivo with the composition of claim 1 prior to implantation of the graft into a subject. | 1,600 |
751 | 15,683,210 | 1,612 | The present invention pertains to a pharmaceutical composition comprising the compound of the formula (I) in a high concentration and at least one pharmaceutically acceptable excipient, the use of the composition for the treatment of hyper-proliforative diseases, such as cancer, either as a sole agent, or in combination with other anti-cancer therapies, and the process for preparing of said composition. | 1. A pharmaceutical composition comprising 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide, its solvates, hydrates, pharmaceutically acceptable salts, or a combination thereof as active agent in a portion of at least 40% by weight of the composition and at least one pharmaceutically acceptable excipient. 2. The pharmaceutical composition of claim 1 comprising the active agent in a portion of at least 55% by weight of the composition. 3. The pharmaceutical composition of any of claim 2 wherein the active agent is the p-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide. 4. The pharmaceutical composition of claim 3 comprising the active agent in a portion of at least 55% by weight of the composition. 5. The pharmaceutical composition of claim 3 comprising the active agent in a portion of at least 75% by weight of the composition. 6. The pharmaceutical composition of claim 5 wherein the />-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide exists for at least 80% in the stable polymorph I. 7. The pharmaceutical composition of claim 1 comprising the active agent in a portion of at least 40%, a filler in a portion of from 0 to 60%, a disintegrant in a portion of from 0 to 15%, a binder in a portion of from 0 to 15%, a lubricant in a portion of from 0 to 2% and a surfactant in a portion of from 0 to 5% by weight of the composition. 8. The pharmaceutical composition of claim 7 comprising the ̂-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifiuoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide in a portion of at least 55%, microcrystalline cellulose as a filler in a portion of from 0 to 60%, croscarmellose sodium as a disintegrant in a portion of from 0 to 15%, hypromellose as a binder in a portion of from 0 to 15%, magnesium stearate as a lubricant in a portion of from 0 to 2% and sodium lauryl sulfate as a surfactant in a portion of from 0 to 5% by weight of the composition. 9. The pharmaceutical composition of claim 8 for oral administration. 10. The pharmaceutical composition of claim 9 is solid oral dosage form. 11. (canceled) 12. (canceled) 13. The pharmaceutical composition of claim 1 wherein the active agent is micronized. 14. The pharmaceutical composition of claim 13 comprising water in an amount of less than or equal to 6% by weight of the composition. 15. The pharmaceutical composition of claim 14 in combination with one or more cytotoxic agents, signal transduction inhibitors, or with other anti-cancer agents or therapies, as well as with admixtures and combinations thereof. 16. A process for manufacturing a pharmaceutical composition of claim 14 wherein the active agent is blended with at least one pharmaceutically acceptable excipient. 17. The process of claim 16 wherein:
a) the active agent and at least one pharmaceutically acceptable excipient are wet granulated,
b) the granulate is blended with the lubricant and optionally with one or more further pharmaceutically acceptable excipient,
c) the post blend granulate is subdivided into single units,
d) and the product of step c) is optionally coated with one or more further pharmaceutically acceptable excipients. 18. The process of claim 17 wherein the product of step c) is a tablet, capsule or sachet. 19. The process of claim 18 wherein the product of step c) is coated with one or more further pharmaceutically acceptable excipients 20. The process of claim 16 wherein the active agent and at least one pharmaceutically acceptable excipient are blended without granulation and directly compressed to tablets or filled into capsules or sachets. 21. The process of claim 16 wherein the active agent anlone or the active agent and at least one pharmaceutically acceptable excipient are treated by a dry granulation method and then compressed to tablets or filled into capsules or sachets. 22. Method for using the pharmaceutical composition of claim 1 to treat mammalian hyper-proliferative disorders, including cancer. | The present invention pertains to a pharmaceutical composition comprising the compound of the formula (I) in a high concentration and at least one pharmaceutically acceptable excipient, the use of the composition for the treatment of hyper-proliforative diseases, such as cancer, either as a sole agent, or in combination with other anti-cancer therapies, and the process for preparing of said composition.1. A pharmaceutical composition comprising 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide, its solvates, hydrates, pharmaceutically acceptable salts, or a combination thereof as active agent in a portion of at least 40% by weight of the composition and at least one pharmaceutically acceptable excipient. 2. The pharmaceutical composition of claim 1 comprising the active agent in a portion of at least 55% by weight of the composition. 3. The pharmaceutical composition of any of claim 2 wherein the active agent is the p-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide. 4. The pharmaceutical composition of claim 3 comprising the active agent in a portion of at least 55% by weight of the composition. 5. The pharmaceutical composition of claim 3 comprising the active agent in a portion of at least 75% by weight of the composition. 6. The pharmaceutical composition of claim 5 wherein the />-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifluoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide exists for at least 80% in the stable polymorph I. 7. The pharmaceutical composition of claim 1 comprising the active agent in a portion of at least 40%, a filler in a portion of from 0 to 60%, a disintegrant in a portion of from 0 to 15%, a binder in a portion of from 0 to 15%, a lubricant in a portion of from 0 to 2% and a surfactant in a portion of from 0 to 5% by weight of the composition. 8. The pharmaceutical composition of claim 7 comprising the ̂-toluenesulfonic acid salt of 4{4-[3-(4-chloro-3-trifiuoromethylphenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl amide in a portion of at least 55%, microcrystalline cellulose as a filler in a portion of from 0 to 60%, croscarmellose sodium as a disintegrant in a portion of from 0 to 15%, hypromellose as a binder in a portion of from 0 to 15%, magnesium stearate as a lubricant in a portion of from 0 to 2% and sodium lauryl sulfate as a surfactant in a portion of from 0 to 5% by weight of the composition. 9. The pharmaceutical composition of claim 8 for oral administration. 10. The pharmaceutical composition of claim 9 is solid oral dosage form. 11. (canceled) 12. (canceled) 13. The pharmaceutical composition of claim 1 wherein the active agent is micronized. 14. The pharmaceutical composition of claim 13 comprising water in an amount of less than or equal to 6% by weight of the composition. 15. The pharmaceutical composition of claim 14 in combination with one or more cytotoxic agents, signal transduction inhibitors, or with other anti-cancer agents or therapies, as well as with admixtures and combinations thereof. 16. A process for manufacturing a pharmaceutical composition of claim 14 wherein the active agent is blended with at least one pharmaceutically acceptable excipient. 17. The process of claim 16 wherein:
a) the active agent and at least one pharmaceutically acceptable excipient are wet granulated,
b) the granulate is blended with the lubricant and optionally with one or more further pharmaceutically acceptable excipient,
c) the post blend granulate is subdivided into single units,
d) and the product of step c) is optionally coated with one or more further pharmaceutically acceptable excipients. 18. The process of claim 17 wherein the product of step c) is a tablet, capsule or sachet. 19. The process of claim 18 wherein the product of step c) is coated with one or more further pharmaceutically acceptable excipients 20. The process of claim 16 wherein the active agent and at least one pharmaceutically acceptable excipient are blended without granulation and directly compressed to tablets or filled into capsules or sachets. 21. The process of claim 16 wherein the active agent anlone or the active agent and at least one pharmaceutically acceptable excipient are treated by a dry granulation method and then compressed to tablets or filled into capsules or sachets. 22. Method for using the pharmaceutical composition of claim 1 to treat mammalian hyper-proliferative disorders, including cancer. | 1,600 |
752 | 15,724,502 | 1,615 | A benzimidazole formulation which lacks an intermediate layer and yet which is stable both during storage and during the passage through the stomach, and which has low levels of residual volatile excipients, including but not limited to residual alkalinizing agents and/or residual solvents. | 1. A stable composition for a benzimidazole derivative, the composition comprising:
a substrate, said substrate comprising the benzimidazole derivative, and a single coating layer consisting essentially of one or more enteric polymers selected from the group consisting of cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate, cellulose acetate trimellitate, poly(methacrylic acid, methyl methacrylate (1:1)), poly(methacrylic acid, ethyl acrylate (1:1)), poly(methacrylic acid, methyl methacrylate (1:2)), hydroxypropyl methylcellulose acetate succinate (HPMCAS), sodium alginate, and alginic acid or mixtures thereof; the one or more enteric polymers being neutralized by at least two alkalizing agents comprising at least one volatile alkalizing agent prior to applying over the substrate to give a pH of at least 6.5; wherein the alkalizing agents are selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonium hydroxide, methanolamine, monoethanol amine, propanolamine, arginine, lysine, methylene diamine, ethylene diamine, and propylene diamine; wherein said composition comprises less than 500 parts per million of residual volatile alkalizing agents relative to composition weight; and wherein the pH of said coating layer after being applied to said substrate is in the range of from about 4.5 to about 6.5 as measured in 30 ml of distilled water at 20-25° C. 2. The composition of claim 1, wherein the pH of said coating layer after being applied to said substrate is in the range of from about 5 to about 6. 3. The composition of claim 2, wherein the pH is about 5. 4. The composition of claim 1, wherein said enteric polymer is dissolved in an organic solvent prior to application. 5. The composition of claim 4, comprising less than about 1000 parts per million of residual organic solvent. 6. The composition of claim 4, wherein said organic solvent is selected from the group consisting of acetone, ethanol, isopropanol and a mixture thereof. 7. The composition of claim 1, wherein said substrate is an active core containing the benzimidazole derivative. 8. The composition of claim 7, wherein said active core is selected from the group consisting of a pellet, a bead and a tablet. 9. The composition of claim 8, wherein said active core is a tablet formed by compression. 10. The composition of claim 1, wherein said substrate features:
(i) a neutral core; and (ii) an active coating containing the benzimidazole derivative, said active coating being layered over said neutral core; such that the composition is in a form of a pellet. 11. The composition of claim 1, wherein said substrate features a core containing the benzimidazole derivative with a suitable binding agent, said core being prepared by spheronisation and pelletization;
such that the composition is in a form of a pellet. 12. The composition of claim 1, wherein the benzimidazole derivative is selected from the group consisting of Omeprazole, Pantoprazole, Lansoprazole, Leminoprazole, Perprazole, Rabeprazole, and pharmaceutically acceptable salts thereof. 13. The composition of claim 1, wherein said substrate further comprises a filler. 14. The composition of claim 13, wherein said filler is selected from the group consisting of microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, starch, lactose, glucose, fructose, sucrose, dicalcium phosphate, sorbitol, mannitol, maltitol, lactitol, xylitol, isomalt, erythritol, and hydrogenated starch hydrolysates, or a mixture thereof. 15. The composition of claim 1, wherein said substrate further comprises a disintegrant. 16. The composition of claim 15, wherein said disintegrant is selected from the group consisting of low-substituted carboxymethyl cellulose sodium, cross-linked polyvinyl pyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, pregelatinized starch, microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, magnesium aluminum silicate, or a mixture thereof. 17. The composition of claim 1, wherein said substrate further comprises a lubricant. 18. The composition of claim 17, wherein said lubricant is selected from the group consisting of sodium stearyl fumarate, polyethylene glycol, silica colloidal anhydrous and magnesium stearate, or a mixture thereof. 19. The composition of claim 1, wherein said substrate further comprises an alkalizing agent. 20. The composition of claim 19, wherein said alkalizing agent is selected from the group consisting of sodium stearate, meglumine, disodium phosphate, and ammonia, or a mixture thereof. 21. The composition of claim 1, wherein said coating layer further comprises a plasticizer. 22. The composition of claim 21, wherein said plasticizer is selected from the group consisting of a citric acid ester and a phthalic acid ester. 23. The composition of claim 1, wherein said coating layer further comprises a surfactant. 24. The composition of claim 23, wherein said surfactant is selected from the group consisting of polysorbate 80 and sodium lauryl sulfate. 25. The composition of claim 1, wherein said coating layer further comprises a glidant. 26. The composition of claim 25, wherein said glidant is selected from the group consisting of talc and titanium dioxide. 27. The composition of claim 1, wherein said coating layer further comprises at least one of a coloring agent and a polishing agent. 28. The composition of claim 1, wherein said single coating layer being neutralized by at least two alkalizing agents to give a pH in the range of from about 7 to about 10. 29. The composition of claim 1, wherein said composition comprises between 6 to 500 parts per million of residual volatile alkalizing agents relative to composition weight. 30. The composition of claim 1, wherein said residual volatile alkalizing agent comprises an ammonia solution. 31. A stable composition for a benzimidazole derivative, the composition comprising:
a substrate, said substrate comprising the benzimidazole derivative; and a single coating layer consisting essentially of at least one neutralized enteric polymer comprising hydroxypropyl methylcellulose acetate succinate (HPMCAS), wherein said enteric polymer is neutralized to a pH of at least 6.5 by at least two alkalizing agents prior to applying to said substrate, wherein the two alkalizing agents are selected from the group consisting of ammonium hydroxide, methanolamine, monoethanol amine, propanolamine, methylene diamine, ethylene diamine, propylene diamine, arginine and lysine, said single coating layer being layered directly over said substrate, without an intermediate layer between said substrate and said enteric coating, wherein said composition comprises less than about 500 parts per million of residual volatile alkalizing agent relative to the total weight of the composition. 32. The composition of claim 31, wherein said alkalizing agents are ammonium hydroxide and monoethanol amine. | A benzimidazole formulation which lacks an intermediate layer and yet which is stable both during storage and during the passage through the stomach, and which has low levels of residual volatile excipients, including but not limited to residual alkalinizing agents and/or residual solvents.1. A stable composition for a benzimidazole derivative, the composition comprising:
a substrate, said substrate comprising the benzimidazole derivative, and a single coating layer consisting essentially of one or more enteric polymers selected from the group consisting of cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate, cellulose acetate trimellitate, poly(methacrylic acid, methyl methacrylate (1:1)), poly(methacrylic acid, ethyl acrylate (1:1)), poly(methacrylic acid, methyl methacrylate (1:2)), hydroxypropyl methylcellulose acetate succinate (HPMCAS), sodium alginate, and alginic acid or mixtures thereof; the one or more enteric polymers being neutralized by at least two alkalizing agents comprising at least one volatile alkalizing agent prior to applying over the substrate to give a pH of at least 6.5; wherein the alkalizing agents are selected from the group consisting of sodium hydroxide, potassium hydroxide, ammonium hydroxide, methanolamine, monoethanol amine, propanolamine, arginine, lysine, methylene diamine, ethylene diamine, and propylene diamine; wherein said composition comprises less than 500 parts per million of residual volatile alkalizing agents relative to composition weight; and wherein the pH of said coating layer after being applied to said substrate is in the range of from about 4.5 to about 6.5 as measured in 30 ml of distilled water at 20-25° C. 2. The composition of claim 1, wherein the pH of said coating layer after being applied to said substrate is in the range of from about 5 to about 6. 3. The composition of claim 2, wherein the pH is about 5. 4. The composition of claim 1, wherein said enteric polymer is dissolved in an organic solvent prior to application. 5. The composition of claim 4, comprising less than about 1000 parts per million of residual organic solvent. 6. The composition of claim 4, wherein said organic solvent is selected from the group consisting of acetone, ethanol, isopropanol and a mixture thereof. 7. The composition of claim 1, wherein said substrate is an active core containing the benzimidazole derivative. 8. The composition of claim 7, wherein said active core is selected from the group consisting of a pellet, a bead and a tablet. 9. The composition of claim 8, wherein said active core is a tablet formed by compression. 10. The composition of claim 1, wherein said substrate features:
(i) a neutral core; and (ii) an active coating containing the benzimidazole derivative, said active coating being layered over said neutral core; such that the composition is in a form of a pellet. 11. The composition of claim 1, wherein said substrate features a core containing the benzimidazole derivative with a suitable binding agent, said core being prepared by spheronisation and pelletization;
such that the composition is in a form of a pellet. 12. The composition of claim 1, wherein the benzimidazole derivative is selected from the group consisting of Omeprazole, Pantoprazole, Lansoprazole, Leminoprazole, Perprazole, Rabeprazole, and pharmaceutically acceptable salts thereof. 13. The composition of claim 1, wherein said substrate further comprises a filler. 14. The composition of claim 13, wherein said filler is selected from the group consisting of microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, starch, lactose, glucose, fructose, sucrose, dicalcium phosphate, sorbitol, mannitol, maltitol, lactitol, xylitol, isomalt, erythritol, and hydrogenated starch hydrolysates, or a mixture thereof. 15. The composition of claim 1, wherein said substrate further comprises a disintegrant. 16. The composition of claim 15, wherein said disintegrant is selected from the group consisting of low-substituted carboxymethyl cellulose sodium, cross-linked polyvinyl pyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, pregelatinized starch, microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, magnesium aluminum silicate, or a mixture thereof. 17. The composition of claim 1, wherein said substrate further comprises a lubricant. 18. The composition of claim 17, wherein said lubricant is selected from the group consisting of sodium stearyl fumarate, polyethylene glycol, silica colloidal anhydrous and magnesium stearate, or a mixture thereof. 19. The composition of claim 1, wherein said substrate further comprises an alkalizing agent. 20. The composition of claim 19, wherein said alkalizing agent is selected from the group consisting of sodium stearate, meglumine, disodium phosphate, and ammonia, or a mixture thereof. 21. The composition of claim 1, wherein said coating layer further comprises a plasticizer. 22. The composition of claim 21, wherein said plasticizer is selected from the group consisting of a citric acid ester and a phthalic acid ester. 23. The composition of claim 1, wherein said coating layer further comprises a surfactant. 24. The composition of claim 23, wherein said surfactant is selected from the group consisting of polysorbate 80 and sodium lauryl sulfate. 25. The composition of claim 1, wherein said coating layer further comprises a glidant. 26. The composition of claim 25, wherein said glidant is selected from the group consisting of talc and titanium dioxide. 27. The composition of claim 1, wherein said coating layer further comprises at least one of a coloring agent and a polishing agent. 28. The composition of claim 1, wherein said single coating layer being neutralized by at least two alkalizing agents to give a pH in the range of from about 7 to about 10. 29. The composition of claim 1, wherein said composition comprises between 6 to 500 parts per million of residual volatile alkalizing agents relative to composition weight. 30. The composition of claim 1, wherein said residual volatile alkalizing agent comprises an ammonia solution. 31. A stable composition for a benzimidazole derivative, the composition comprising:
a substrate, said substrate comprising the benzimidazole derivative; and a single coating layer consisting essentially of at least one neutralized enteric polymer comprising hydroxypropyl methylcellulose acetate succinate (HPMCAS), wherein said enteric polymer is neutralized to a pH of at least 6.5 by at least two alkalizing agents prior to applying to said substrate, wherein the two alkalizing agents are selected from the group consisting of ammonium hydroxide, methanolamine, monoethanol amine, propanolamine, methylene diamine, ethylene diamine, propylene diamine, arginine and lysine, said single coating layer being layered directly over said substrate, without an intermediate layer between said substrate and said enteric coating, wherein said composition comprises less than about 500 parts per million of residual volatile alkalizing agent relative to the total weight of the composition. 32. The composition of claim 31, wherein said alkalizing agents are ammonium hydroxide and monoethanol amine. | 1,600 |
753 | 15,418,412 | 1,663 | The invention relates to methods of producing a desired phenotype in a plant by manipulation of gene expression within the plant. The method relates to means which increase the level of expression of a MYB-subgroup14 polynucleotide or a MYB68 polypeptide. The method also relates to expression of a nucleic acid sequence encoding a MYB-subgroup14 or a MYB68 transcriptional factor. The methods are directed to elevating the levels of a MYB-subgroup14 or a MYB68 expression, wherein a desired phenotype such as reduced flower abortion and increased yield during heat stress is observed. The invention also relates to nucleic acid sequences useful in such methods. | 1. A method of producing a heat stress tolerant plant, comprising:
a) providing a nucleic acid encoding a MYB subgroup-14 polypeptide selected from the group consisting of MYB36, MYB37, MYB38, MYB68, MYB84, and MYB87; b) inserting said nucleic acid into a vector; c) transforming a plant, a tissue culture, or a plant cell with said vector to obtain a transformed plant, tissue culture, or plant cell with an increased expression of said MYB subgroup-14 polypeptide; d) growing said transformed plant or regenerating a plant from said transformed tissue culture or plant cell, wherein a heat stress tolerant plant is produced which has an increased heat stress tolerance as compared to a wild type plant. 2. The method according to claim 1, wherein said MYB subgroup-14 polypeptide is selected from the group consisting of MYB36, MYB68, and MYB84. 3. The method according to claim 1, wherein said MYB subgroup-14 polypeptide is MYB68. 4. The method according to claim 1, wherein said MYB subgroup-14 polypeptide is MYB36. 5. The method according to claim 1, wherein said MYB subgroup-14 polypeptide is MYB37. 6. The method according to claim 1, wherein said vector comprises a constitutive promoter or an inducible promoter. 7. A heat stress tolerant transgenic plant produced by the method of claim 1, wherein said transgenic plant contains a vector or an expression cassette comprising said nucleic acid encoding said MYB subgroup-14 polypeptide resulting in increased expression of said MYB subgroup-14 polypeptide, and has an increased tolerance to heat stress, and wherein said MYB subgroup-14 polypeptide is MYB68. 8. The transgenic plant of claim 7, wherein said transgenic plant has an increased seed yield relative to a wild type control. 9. A transgenic seed produced by the transgenic plant of claim 7, wherein said transgenic seed is transformed with said nucleic acid encoding MYB68 and produces a heat stress tolerant plant which expresses said nucleic acid encoding said MYB68 and has an increased heat stress tolerance. 10. A heat stress tolerant transgenic plant produced by the method of claim 1, wherein said transgenic plant contains a vector or an expression cassette comprising said nucleic acid encoding said MYB subgroup 14 polypeptide resulting in increased expression of said MYB subgroup-14 polypeptide, and has an increased tolerance to heat stress, and wherein said MYB subgroup 14 polypeptide is MYB36. 11. The transgenic plant of claim 10, wherein said transgenic plant has an increased seed yield relative to a wild type control. 12. A transgenic seed produced by the transgenic plant of claim 10, wherein said transgenic seed is transformed with said nucleic acid encoding MYB36 and produces a heat stress tolerant plant which expresses said nucleic acid encoding MYB36 and has an increased heat stress tolerance. | The invention relates to methods of producing a desired phenotype in a plant by manipulation of gene expression within the plant. The method relates to means which increase the level of expression of a MYB-subgroup14 polynucleotide or a MYB68 polypeptide. The method also relates to expression of a nucleic acid sequence encoding a MYB-subgroup14 or a MYB68 transcriptional factor. The methods are directed to elevating the levels of a MYB-subgroup14 or a MYB68 expression, wherein a desired phenotype such as reduced flower abortion and increased yield during heat stress is observed. The invention also relates to nucleic acid sequences useful in such methods.1. A method of producing a heat stress tolerant plant, comprising:
a) providing a nucleic acid encoding a MYB subgroup-14 polypeptide selected from the group consisting of MYB36, MYB37, MYB38, MYB68, MYB84, and MYB87; b) inserting said nucleic acid into a vector; c) transforming a plant, a tissue culture, or a plant cell with said vector to obtain a transformed plant, tissue culture, or plant cell with an increased expression of said MYB subgroup-14 polypeptide; d) growing said transformed plant or regenerating a plant from said transformed tissue culture or plant cell, wherein a heat stress tolerant plant is produced which has an increased heat stress tolerance as compared to a wild type plant. 2. The method according to claim 1, wherein said MYB subgroup-14 polypeptide is selected from the group consisting of MYB36, MYB68, and MYB84. 3. The method according to claim 1, wherein said MYB subgroup-14 polypeptide is MYB68. 4. The method according to claim 1, wherein said MYB subgroup-14 polypeptide is MYB36. 5. The method according to claim 1, wherein said MYB subgroup-14 polypeptide is MYB37. 6. The method according to claim 1, wherein said vector comprises a constitutive promoter or an inducible promoter. 7. A heat stress tolerant transgenic plant produced by the method of claim 1, wherein said transgenic plant contains a vector or an expression cassette comprising said nucleic acid encoding said MYB subgroup-14 polypeptide resulting in increased expression of said MYB subgroup-14 polypeptide, and has an increased tolerance to heat stress, and wherein said MYB subgroup-14 polypeptide is MYB68. 8. The transgenic plant of claim 7, wherein said transgenic plant has an increased seed yield relative to a wild type control. 9. A transgenic seed produced by the transgenic plant of claim 7, wherein said transgenic seed is transformed with said nucleic acid encoding MYB68 and produces a heat stress tolerant plant which expresses said nucleic acid encoding said MYB68 and has an increased heat stress tolerance. 10. A heat stress tolerant transgenic plant produced by the method of claim 1, wherein said transgenic plant contains a vector or an expression cassette comprising said nucleic acid encoding said MYB subgroup 14 polypeptide resulting in increased expression of said MYB subgroup-14 polypeptide, and has an increased tolerance to heat stress, and wherein said MYB subgroup 14 polypeptide is MYB36. 11. The transgenic plant of claim 10, wherein said transgenic plant has an increased seed yield relative to a wild type control. 12. A transgenic seed produced by the transgenic plant of claim 10, wherein said transgenic seed is transformed with said nucleic acid encoding MYB36 and produces a heat stress tolerant plant which expresses said nucleic acid encoding MYB36 and has an increased heat stress tolerance. | 1,600 |
754 | 15,188,239 | 1,653 | Methods are provided for detecting enzymatic activity of various lysosomal storage enzymes using substrates that include: a sugar moiety; a linker moiety allowing the conjugation of sugar moiety with the remaining structure of the substrate; and two or more fatty acid chains or derivatives thereof at least one of which is sufficiently structured to provide improved solubility in aqueous or organic solvent systems. Also provided are internal standards, and inhibitors for use in detecting or reducing enzymatic activity using the inventive substrates. | 1. A method for detecting enzymatic activity, comprising:
contacting a sample containing a target enzyme with a substrate, under conditions wherein the target enzyme is capable of acting on the substrate to produce an enzymatic product; and detecting said enzymatic product; the substrate having formula:
where A is a monosaccharide or a disaccharide linked to O by a glycosidic bond;
B1 is selected from the group consisting of: a C1-C20 alkyl; a heteroatom containing C1-C20 alkyl; C2-C20 alkenyl; a heteroatom containing C2-C20 alkenyl; and a substituted or unsubstituted C6-C20 aryl;
B2 is selected from the group consisting of: a C2-C7 urethane; a C2-C7 amido; a C2-C7 ester; a C2-C7 uriedo; a C2-C7 carbamato; a C2-C7 carbonyl; a C1-C7 alkyl; a heteroatom containing C1-C7 alkyl; a C1-C7 alkyl having a substituent of N, O, or S; a C2-C7 alkenyl; a heteroatom containing C2-C7 alkenyl; and a C2-C7 alkenyl having a substituent of N, O, or S; and
B3 is selected from the group consisting of: a C1-C20 alkyl; a heteroatom containing C1-C20 alkyl; C1-C20 alkyl having a substituent of N, O, or S; C4-C20 ether; C1-C20 ester, C1-C20 alkenyl; a heteroatom containing C1-C20 alkenyl; C2-C20 alkenyl having a substituent of N, O, or S; C1-C20 alkynl; a heteroatom containing C1-C20 alkynl; C2-C20 alkynl having a substituent of N, O, or S; C6-C20 aryl; and a C6-C20 heterocyclic containing a heteroatom of N, O or S. 2. The method of claim 1 wherein said target enzyme is acid β-glucocerebrosidase and said B2 is a C2-C7 amido, and said B3 is a C2-C20 alkenyl having a substituent of N, O, or S. 3. The method of claim 1 wherein said target enzyme is acid galactocerebroside β-galactosidase or acid-β-glucocerebrosidase and said wherein said B2 is a C2-C7 amido, and B3 is a C13-C20 having a substituent of O present as a hydroxyl. 4. The method of claim 1 wherein A is an aldohexose or a ketohexose. 5. The method of claim 1 wherein A is a D-glucose or a D-galactose. 6. The method of claim 1 wherein B1 is a methylene. 7. The method of claim 1 where B2 is a C2-C7 amido. 8. The method of claim 1 wherein B3 is a C2-C20 alkenyl having a substituent of N, O, or S. 9. The method of claim 1 wherein: A is a D-glucose or a D-galactose; B1 is a C1-C2 alkyl or a C6 aryl; and B2 is a C2-C7 amido. 10. The method of claim 9 wherein B3 is a C2-C20 alkenyl having a substituent of N, O, or S. 11. The method of claim 1 wherein the substrate comprises:
where: A is an aldohexose or ketohexose; R1 is a C1-C6 alkyl or a C2-C20 alkenyl; and R2 is a C1-C20 alkyl, a C1-C20 alkyl having a substituent of N, O, or S, a C1-C20 alkenyl, or a C1-C20 alkenyl having a substituent of N, O or S. 12. The method of claim 11 wherein A is a D-glucose or D-galactose, R1 is a C4-C6 alkyl, and R2 is a C13-C20 alkyl, a C13-C20 alkyl having a substituent of N, O, or S, a C13-C20 alkenyl, or a C13-C20 alkenyl having a substituent of N, O or S. 13. The method of claim 11 wherein R2 is a C13 alkyl. 14. A molecule having the formula:
where B1 is selected from the group consisting of: a C1-C20 alkyl; a heteroatom containing C1-C20 alkyl, C2-C20 alkenyl; a heteroatom containing C2-C20 alkenyl; a substituted or unsubstituted C6-C20 aryl;
B2 is selected from the group consisting of: a C2-C7 urethane; a C2-C7 amido; a C2-C7 ester; a C2-C7 uriedo; a C2-C7 carbamato; a C2-C7 carbonyl; a C1-C7 alkyl; a heteroatom containing C1-C7 alkyl; a C1-C7 alkyl having a substituent of N, O, or S; a C2-C7 alkenyl; a heteroatom containing C2-C7 alkenyl; a C2-C7 alkenyl having a substituent of N, O, or S; and
B3 is selected from the group consisting of: a C1-C20 alkyl; a heteroatom containing C1-C20 alkyl; C1-C20 alkyl having a substituent of N, O, or S; C4-C20 ether; C1-C20 ester, C1-C20 alkenyl; a heteroatom containing C1-C20 alkenyl; C2-C20 alkenyl having a substituent of N, O, or S; C1-C20 alkynl; a heteroatom containing C1-C20 alkynl; C2-C20 alkynl having a substituent of N, O, or S C6-C20 aryl; and C6-C20 heterocyclic containing a heteroatom of N, O or S;
the molecule further including a stable secondary prevalence isotope of an element. 15. The molecule of claim 14 wherein said stable secondary prevalence isotope in each occurrence is selected from the group consisting of 2H, 13C, 15N, 17O, 18O, 31P and 34S. 16. The molecule of claim 14 wherein B1 is a methylene. 17. The molecule of claim 14 where B2 is a C2-C7 amido. 18. The molecule of claim 14 wherein B3 is a C2-C20 alkenyl having a substituent of N, O, or S. | Methods are provided for detecting enzymatic activity of various lysosomal storage enzymes using substrates that include: a sugar moiety; a linker moiety allowing the conjugation of sugar moiety with the remaining structure of the substrate; and two or more fatty acid chains or derivatives thereof at least one of which is sufficiently structured to provide improved solubility in aqueous or organic solvent systems. Also provided are internal standards, and inhibitors for use in detecting or reducing enzymatic activity using the inventive substrates.1. A method for detecting enzymatic activity, comprising:
contacting a sample containing a target enzyme with a substrate, under conditions wherein the target enzyme is capable of acting on the substrate to produce an enzymatic product; and detecting said enzymatic product; the substrate having formula:
where A is a monosaccharide or a disaccharide linked to O by a glycosidic bond;
B1 is selected from the group consisting of: a C1-C20 alkyl; a heteroatom containing C1-C20 alkyl; C2-C20 alkenyl; a heteroatom containing C2-C20 alkenyl; and a substituted or unsubstituted C6-C20 aryl;
B2 is selected from the group consisting of: a C2-C7 urethane; a C2-C7 amido; a C2-C7 ester; a C2-C7 uriedo; a C2-C7 carbamato; a C2-C7 carbonyl; a C1-C7 alkyl; a heteroatom containing C1-C7 alkyl; a C1-C7 alkyl having a substituent of N, O, or S; a C2-C7 alkenyl; a heteroatom containing C2-C7 alkenyl; and a C2-C7 alkenyl having a substituent of N, O, or S; and
B3 is selected from the group consisting of: a C1-C20 alkyl; a heteroatom containing C1-C20 alkyl; C1-C20 alkyl having a substituent of N, O, or S; C4-C20 ether; C1-C20 ester, C1-C20 alkenyl; a heteroatom containing C1-C20 alkenyl; C2-C20 alkenyl having a substituent of N, O, or S; C1-C20 alkynl; a heteroatom containing C1-C20 alkynl; C2-C20 alkynl having a substituent of N, O, or S; C6-C20 aryl; and a C6-C20 heterocyclic containing a heteroatom of N, O or S. 2. The method of claim 1 wherein said target enzyme is acid β-glucocerebrosidase and said B2 is a C2-C7 amido, and said B3 is a C2-C20 alkenyl having a substituent of N, O, or S. 3. The method of claim 1 wherein said target enzyme is acid galactocerebroside β-galactosidase or acid-β-glucocerebrosidase and said wherein said B2 is a C2-C7 amido, and B3 is a C13-C20 having a substituent of O present as a hydroxyl. 4. The method of claim 1 wherein A is an aldohexose or a ketohexose. 5. The method of claim 1 wherein A is a D-glucose or a D-galactose. 6. The method of claim 1 wherein B1 is a methylene. 7. The method of claim 1 where B2 is a C2-C7 amido. 8. The method of claim 1 wherein B3 is a C2-C20 alkenyl having a substituent of N, O, or S. 9. The method of claim 1 wherein: A is a D-glucose or a D-galactose; B1 is a C1-C2 alkyl or a C6 aryl; and B2 is a C2-C7 amido. 10. The method of claim 9 wherein B3 is a C2-C20 alkenyl having a substituent of N, O, or S. 11. The method of claim 1 wherein the substrate comprises:
where: A is an aldohexose or ketohexose; R1 is a C1-C6 alkyl or a C2-C20 alkenyl; and R2 is a C1-C20 alkyl, a C1-C20 alkyl having a substituent of N, O, or S, a C1-C20 alkenyl, or a C1-C20 alkenyl having a substituent of N, O or S. 12. The method of claim 11 wherein A is a D-glucose or D-galactose, R1 is a C4-C6 alkyl, and R2 is a C13-C20 alkyl, a C13-C20 alkyl having a substituent of N, O, or S, a C13-C20 alkenyl, or a C13-C20 alkenyl having a substituent of N, O or S. 13. The method of claim 11 wherein R2 is a C13 alkyl. 14. A molecule having the formula:
where B1 is selected from the group consisting of: a C1-C20 alkyl; a heteroatom containing C1-C20 alkyl, C2-C20 alkenyl; a heteroatom containing C2-C20 alkenyl; a substituted or unsubstituted C6-C20 aryl;
B2 is selected from the group consisting of: a C2-C7 urethane; a C2-C7 amido; a C2-C7 ester; a C2-C7 uriedo; a C2-C7 carbamato; a C2-C7 carbonyl; a C1-C7 alkyl; a heteroatom containing C1-C7 alkyl; a C1-C7 alkyl having a substituent of N, O, or S; a C2-C7 alkenyl; a heteroatom containing C2-C7 alkenyl; a C2-C7 alkenyl having a substituent of N, O, or S; and
B3 is selected from the group consisting of: a C1-C20 alkyl; a heteroatom containing C1-C20 alkyl; C1-C20 alkyl having a substituent of N, O, or S; C4-C20 ether; C1-C20 ester, C1-C20 alkenyl; a heteroatom containing C1-C20 alkenyl; C2-C20 alkenyl having a substituent of N, O, or S; C1-C20 alkynl; a heteroatom containing C1-C20 alkynl; C2-C20 alkynl having a substituent of N, O, or S C6-C20 aryl; and C6-C20 heterocyclic containing a heteroatom of N, O or S;
the molecule further including a stable secondary prevalence isotope of an element. 15. The molecule of claim 14 wherein said stable secondary prevalence isotope in each occurrence is selected from the group consisting of 2H, 13C, 15N, 17O, 18O, 31P and 34S. 16. The molecule of claim 14 wherein B1 is a methylene. 17. The molecule of claim 14 where B2 is a C2-C7 amido. 18. The molecule of claim 14 wherein B3 is a C2-C20 alkenyl having a substituent of N, O, or S. | 1,600 |
755 | 15,664,146 | 1,626 | An additive composition comprises phosphate ester anions conforming to a specified structure, aromatic carboxylate anions, optionally cycloaliphatic dicarboxylate anions, aluminum (III) cations, sodium cations, optionally calcium cations, optionally lithium cations, and optionally zinc (II) cations. The anions are present in the additive composition in specified molar percentages. The cations are also present in the additive composition in specified molar percentages. | 1. An additive composition comprising:
(a) phosphate ester anions conforming to the structure of Formula (I)
wherein R1 and R2 are independently selected from the group consisting of hydrogen and C1-C18 alkyl groups, and R3 is an alkanediyl group;
(b) aromatic carboxylate anions;
(c) aluminum (III) cations;
(d) sodium cations;
(e) optionally, lithium cations; and
(f) optionally, zinc (II) cations,
wherein:
(i) the phosphate ester anions are present in the additive composition in an amount of about 2 mol. % to about 90 mol. % of the total amount of phosphate ester anions and aromatic carboxylate anions present in the additive composition;
(ii) the aromatic carboxylate anions are present in the additive composition in an amount of about 10 mol. % to about 98 mol. % of the total amount of phosphate ester anions and aromatic carboxylate anions present in the additive composition;
(iii) the aluminum (III) cations are present in the additive composition in an amount of about 1 mol. % to about 35 mol. % of the total amount of aluminum (III) cations, sodium cations, lithium cations, and zinc (II) cations present in the additive composition;
(iv) the sodium cations are present in the additive composition in an amount of about 10 mol. % to about 96 mol. % of the total amount of aluminum (III) cations, sodium cations, lithium cations, and zinc (II) cations present in the additive composition;
(v) the lithium cations, if present, are present in the additive composition in an amount of about 0 mol. % to about 60 mol. % of the total amount of aluminum (III) cations, sodium cations, lithium cations, and zinc (II) cations present in the additive composition;
(vi) the zinc (II) cations, if present, are present in the additive composition in an amount of about 0 mol. % to about 20 mol. % of the total amount of aluminum (III) cations, sodium cations, lithium cations, and zinc (II) cations present in the additive composition; and
(vii) the additive composition contains 5 wt. % or more fatty acid salts. 2. The additive composition of claim 1, wherein R1 and R2 are selected from the group consisting of hydrogen and C1-C4 alkyl groups. 3. The additive composition of claim 2, wherein R1 and R2 are tert-butyl groups. 4. The additive composition of claim 1, wherein R3 is a C1-C4 alkanediyl group. 5. The additive composition of claim 4, wherein R3 is a methanediyl group. 6. The additive composition of claim 1, wherein the aromatic carboxylate anions are benzoate anions. 7. The additive composition of claim 1, wherein the phosphate ester anions are present in the additive composition in an amount of about 15 mol. % to about 50 mol. % of the total amount of phosphate ester anions and aromatic carboxylate anions present in the additive composition. 8. The additive composition of claim 1, wherein the aromatic carboxylate anions are present in the additive composition in an amount of about 50 mol. % to about 85 mol. % of the total amount of phosphate ester anions and aromatic carboxylate anions present in the additive composition. 9. The additive composition of claim 1, wherein the aluminum (III) cations are present in the additive composition in an amount of about 5 mol. % to about 15 mol. % of the total amount of aluminum (III) cations, sodium cations, lithium cations, and zinc (II) cations present in the additive composition; 10. The additive composition of claim 1, wherein the sodium cations are present in the additive composition in an amount of about 45 mol. % to about 95 mol. % of the total amount of aluminum (III) cations, sodium cations, lithium cations, and zinc (II) cations present in the additive composition. 11. The additive composition of claim 1, wherein the additive composition comprises lithium cations, and the lithium cations are present in the additive composition in an amount of about 10 mol. % to about 40 mol. % of the total amount of aluminum (III) cations, sodium cations, lithium cations, and zinc (II) cations present in the additive composition. 12. The additive composition of claim 1, wherein the additive composition comprises zinc (II) cations, and the zinc (II) cations are present in the additive composition in an amount of about 0.1 mol. % to about 5 mol. % of the total amount of aluminum (III) cations, sodium cations, lithium cations, and zinc (II) cations present in the additive composition. 13. The additive composition of claim 1, wherein the additive composition contains about 20 wt. % to about 55 wt. % fatty acid salts. 14. An additive composition comprising:
(a) phosphate ester anions conforming to the structure of Formula (I)
wherein R1 and R2 are independently selected from the group consisting of hydrogen and C1-C18 alkyl groups, and R3 is an alkanediyl group;
(b) aromatic carboxylate anions;
(c) cycloaliphatic dicarboxylate anions;
(d) aluminum (III) cations;
(e) sodium cations;
(f) optionally, calcium cations;
(g) optionally, lithium cations; and
(h) optionally, zinc (II) cations,
wherein:
(i) the phosphate ester anions are present in the additive composition in an amount of about 1.5 mol. % to about 45 mol. % of the total amount of phosphate ester anions, aromatic carboxylate anions, and cycloaliphatic dicarboxylate anions present in the additive composition;
(ii) the aromatic carboxylate anions are present in the additive composition in an amount of about 5 mol. % to about 80 mol. % of the total amount of phosphate ester anions, aromatic carboxylate anions, and cycloaliphatic dicarboxylate anions present in the additive composition;
(iii) the cycloaliphatic dicarboxylate anions are present in the additive composition in an amount of about 3 mol. % to about 55 mol. % of the total amount of phosphate ester anions, aromatic carboxylate anions, and cycloaliphatic dicarboxylate anions present in the additive composition;
(iv) the aluminum (III) cations are present in the additive composition in an amount of about 0.5 mol. % to about 20 mol. % of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition;
(v) the sodium cations are present in the additive composition in an amount of about 30 mol. % to about 90 mol. % of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition;
(vi) the calcium cations, if present, are present in the additive composition in an amount of about 35 mol. % or less of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition;
(vii) the lithium cations, if present, are present in the additive composition in an amount of about 30 mol. % or less of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition;
(viii) the zinc (II) cations, if present, are present in the additive composition in an amount of about 15 mol. % or less of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition; and
(ix) the additive composition contains 5 wt. % or more fatty acid salts. 15. The additive composition of claim 14, wherein R1 and R2 are selected from the group consisting of hydrogen and C1-C4 alkyl groups. 16. The additive composition of claim 15, wherein R1 and R2 are tert-butyl groups. 17. The additive composition of claim 14, wherein R3 is a C1-C4 alkanediyl group. 18. The additive composition of claim 17, wherein R3 is a methanediyl group. 19. The additive composition of claim 14, wherein the aromatic carboxylate anions are benzoate anions. 20. The additive composition of claim 14, wherein the cycloaliphatic dicarboxylate anions conform to a structure selected from the group consisting of Formula (X) and Formula (XX) below:
wherein R10, R11, R12, R13, R14, R15, R16, R17, R18, and R19 are independently selected from the group consisting of hydrogen, halogens, C1-C9 alkyl groups, C1-C9 alkoxy groups, and C1-C9 alkylamine groups;
wherein R20, R21, R22, R23, R24, R25, R26, R27, R28, and R29 are independently selected from the group consisting of hydrogen, halogens, C1-C9 alkyl groups, C1-C9 alkoxy groups, and C1-C9 alkylamine groups. 21. The additive composition of claim 14, wherein the phosphate ester anions are present in the additive composition in an amount of about 20 mol. % to about 40 mol. % of the total amount of phosphate ester anions, aromatic carboxylate anions, and cycloaliphatic dicarboxylate anions present in the additive composition. 22. The additive composition of claim 14, wherein the aromatic carboxylate anions are present in the additive composition in an amount of about 20 mol. % to about 50 mol. % of the total amount of phosphate ester anions, aromatic carboxylate anions, and cycloaliphatic dicarboxylate anions present in the additive composition. 23. The additive composition of claim 14, wherein the cycloaliphatic dicarboxylate anions are present in the additive composition in an amount of about 5 mol. % to about 50 mol. % of the total amount of phosphate ester anions, aromatic carboxylate anions, and cycloaliphatic dicarboxylate anions present in the additive composition. 24. The additive composition of claim 14, wherein the aluminum (III) cations are present in the additive composition in an amount of about 5 mol. % to about 15 mol. % of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition. 25. The additive composition of claim 14, wherein the sodium cations are present in the additive composition in an amount of about 70 mol. % to about 90 mol. % of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition. 26. The additive composition of claim 14, wherein calcium cations are present in the additive composition in an amount of about 15 mol. % or less of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition. 27. The additive composition of claim 14, wherein the additive composition comprises lithium cations, and the lithium cations are present in the additive composition in an amount of about 3 mol. % to about 15 mol. % of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition. 28. The additive composition of claim 14, wherein the additive composition comprises zinc (II) cations, and the zinc (II) cations are present in the additive composition in an amount of about 1 mol. % to about 15 mol. % of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition. 29. The additive composition of claim 14, wherein the additive composition contains about 15 wt. % to about 45 wt. % fatty acid salts. | An additive composition comprises phosphate ester anions conforming to a specified structure, aromatic carboxylate anions, optionally cycloaliphatic dicarboxylate anions, aluminum (III) cations, sodium cations, optionally calcium cations, optionally lithium cations, and optionally zinc (II) cations. The anions are present in the additive composition in specified molar percentages. The cations are also present in the additive composition in specified molar percentages.1. An additive composition comprising:
(a) phosphate ester anions conforming to the structure of Formula (I)
wherein R1 and R2 are independently selected from the group consisting of hydrogen and C1-C18 alkyl groups, and R3 is an alkanediyl group;
(b) aromatic carboxylate anions;
(c) aluminum (III) cations;
(d) sodium cations;
(e) optionally, lithium cations; and
(f) optionally, zinc (II) cations,
wherein:
(i) the phosphate ester anions are present in the additive composition in an amount of about 2 mol. % to about 90 mol. % of the total amount of phosphate ester anions and aromatic carboxylate anions present in the additive composition;
(ii) the aromatic carboxylate anions are present in the additive composition in an amount of about 10 mol. % to about 98 mol. % of the total amount of phosphate ester anions and aromatic carboxylate anions present in the additive composition;
(iii) the aluminum (III) cations are present in the additive composition in an amount of about 1 mol. % to about 35 mol. % of the total amount of aluminum (III) cations, sodium cations, lithium cations, and zinc (II) cations present in the additive composition;
(iv) the sodium cations are present in the additive composition in an amount of about 10 mol. % to about 96 mol. % of the total amount of aluminum (III) cations, sodium cations, lithium cations, and zinc (II) cations present in the additive composition;
(v) the lithium cations, if present, are present in the additive composition in an amount of about 0 mol. % to about 60 mol. % of the total amount of aluminum (III) cations, sodium cations, lithium cations, and zinc (II) cations present in the additive composition;
(vi) the zinc (II) cations, if present, are present in the additive composition in an amount of about 0 mol. % to about 20 mol. % of the total amount of aluminum (III) cations, sodium cations, lithium cations, and zinc (II) cations present in the additive composition; and
(vii) the additive composition contains 5 wt. % or more fatty acid salts. 2. The additive composition of claim 1, wherein R1 and R2 are selected from the group consisting of hydrogen and C1-C4 alkyl groups. 3. The additive composition of claim 2, wherein R1 and R2 are tert-butyl groups. 4. The additive composition of claim 1, wherein R3 is a C1-C4 alkanediyl group. 5. The additive composition of claim 4, wherein R3 is a methanediyl group. 6. The additive composition of claim 1, wherein the aromatic carboxylate anions are benzoate anions. 7. The additive composition of claim 1, wherein the phosphate ester anions are present in the additive composition in an amount of about 15 mol. % to about 50 mol. % of the total amount of phosphate ester anions and aromatic carboxylate anions present in the additive composition. 8. The additive composition of claim 1, wherein the aromatic carboxylate anions are present in the additive composition in an amount of about 50 mol. % to about 85 mol. % of the total amount of phosphate ester anions and aromatic carboxylate anions present in the additive composition. 9. The additive composition of claim 1, wherein the aluminum (III) cations are present in the additive composition in an amount of about 5 mol. % to about 15 mol. % of the total amount of aluminum (III) cations, sodium cations, lithium cations, and zinc (II) cations present in the additive composition; 10. The additive composition of claim 1, wherein the sodium cations are present in the additive composition in an amount of about 45 mol. % to about 95 mol. % of the total amount of aluminum (III) cations, sodium cations, lithium cations, and zinc (II) cations present in the additive composition. 11. The additive composition of claim 1, wherein the additive composition comprises lithium cations, and the lithium cations are present in the additive composition in an amount of about 10 mol. % to about 40 mol. % of the total amount of aluminum (III) cations, sodium cations, lithium cations, and zinc (II) cations present in the additive composition. 12. The additive composition of claim 1, wherein the additive composition comprises zinc (II) cations, and the zinc (II) cations are present in the additive composition in an amount of about 0.1 mol. % to about 5 mol. % of the total amount of aluminum (III) cations, sodium cations, lithium cations, and zinc (II) cations present in the additive composition. 13. The additive composition of claim 1, wherein the additive composition contains about 20 wt. % to about 55 wt. % fatty acid salts. 14. An additive composition comprising:
(a) phosphate ester anions conforming to the structure of Formula (I)
wherein R1 and R2 are independently selected from the group consisting of hydrogen and C1-C18 alkyl groups, and R3 is an alkanediyl group;
(b) aromatic carboxylate anions;
(c) cycloaliphatic dicarboxylate anions;
(d) aluminum (III) cations;
(e) sodium cations;
(f) optionally, calcium cations;
(g) optionally, lithium cations; and
(h) optionally, zinc (II) cations,
wherein:
(i) the phosphate ester anions are present in the additive composition in an amount of about 1.5 mol. % to about 45 mol. % of the total amount of phosphate ester anions, aromatic carboxylate anions, and cycloaliphatic dicarboxylate anions present in the additive composition;
(ii) the aromatic carboxylate anions are present in the additive composition in an amount of about 5 mol. % to about 80 mol. % of the total amount of phosphate ester anions, aromatic carboxylate anions, and cycloaliphatic dicarboxylate anions present in the additive composition;
(iii) the cycloaliphatic dicarboxylate anions are present in the additive composition in an amount of about 3 mol. % to about 55 mol. % of the total amount of phosphate ester anions, aromatic carboxylate anions, and cycloaliphatic dicarboxylate anions present in the additive composition;
(iv) the aluminum (III) cations are present in the additive composition in an amount of about 0.5 mol. % to about 20 mol. % of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition;
(v) the sodium cations are present in the additive composition in an amount of about 30 mol. % to about 90 mol. % of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition;
(vi) the calcium cations, if present, are present in the additive composition in an amount of about 35 mol. % or less of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition;
(vii) the lithium cations, if present, are present in the additive composition in an amount of about 30 mol. % or less of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition;
(viii) the zinc (II) cations, if present, are present in the additive composition in an amount of about 15 mol. % or less of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition; and
(ix) the additive composition contains 5 wt. % or more fatty acid salts. 15. The additive composition of claim 14, wherein R1 and R2 are selected from the group consisting of hydrogen and C1-C4 alkyl groups. 16. The additive composition of claim 15, wherein R1 and R2 are tert-butyl groups. 17. The additive composition of claim 14, wherein R3 is a C1-C4 alkanediyl group. 18. The additive composition of claim 17, wherein R3 is a methanediyl group. 19. The additive composition of claim 14, wherein the aromatic carboxylate anions are benzoate anions. 20. The additive composition of claim 14, wherein the cycloaliphatic dicarboxylate anions conform to a structure selected from the group consisting of Formula (X) and Formula (XX) below:
wherein R10, R11, R12, R13, R14, R15, R16, R17, R18, and R19 are independently selected from the group consisting of hydrogen, halogens, C1-C9 alkyl groups, C1-C9 alkoxy groups, and C1-C9 alkylamine groups;
wherein R20, R21, R22, R23, R24, R25, R26, R27, R28, and R29 are independently selected from the group consisting of hydrogen, halogens, C1-C9 alkyl groups, C1-C9 alkoxy groups, and C1-C9 alkylamine groups. 21. The additive composition of claim 14, wherein the phosphate ester anions are present in the additive composition in an amount of about 20 mol. % to about 40 mol. % of the total amount of phosphate ester anions, aromatic carboxylate anions, and cycloaliphatic dicarboxylate anions present in the additive composition. 22. The additive composition of claim 14, wherein the aromatic carboxylate anions are present in the additive composition in an amount of about 20 mol. % to about 50 mol. % of the total amount of phosphate ester anions, aromatic carboxylate anions, and cycloaliphatic dicarboxylate anions present in the additive composition. 23. The additive composition of claim 14, wherein the cycloaliphatic dicarboxylate anions are present in the additive composition in an amount of about 5 mol. % to about 50 mol. % of the total amount of phosphate ester anions, aromatic carboxylate anions, and cycloaliphatic dicarboxylate anions present in the additive composition. 24. The additive composition of claim 14, wherein the aluminum (III) cations are present in the additive composition in an amount of about 5 mol. % to about 15 mol. % of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition. 25. The additive composition of claim 14, wherein the sodium cations are present in the additive composition in an amount of about 70 mol. % to about 90 mol. % of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition. 26. The additive composition of claim 14, wherein calcium cations are present in the additive composition in an amount of about 15 mol. % or less of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition. 27. The additive composition of claim 14, wherein the additive composition comprises lithium cations, and the lithium cations are present in the additive composition in an amount of about 3 mol. % to about 15 mol. % of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition. 28. The additive composition of claim 14, wherein the additive composition comprises zinc (II) cations, and the zinc (II) cations are present in the additive composition in an amount of about 1 mol. % to about 15 mol. % of the total amount of aluminum (III) cations, sodium cations, calcium cations, lithium cations, and zinc (II) cations present in the additive composition. 29. The additive composition of claim 14, wherein the additive composition contains about 15 wt. % to about 45 wt. % fatty acid salts. | 1,600 |
756 | 14,400,846 | 1,618 | Monolayer protected nanoclusters (MPCs) are described herein. The MPCs contain a cluster of atoms or molecules (e.g. core) having bound thereto a plurality of ligands (e.g., monolayer). The ligands can be bound covalently or semi-covalently bound to the cluster. The ligands are generally in the form of a monolayer or mixed monolayer. The monolayer or mixed monolayer contains a plurality of ligands. In one embodiment, the monolayer and/or mixed monolayer contains 1,4-dithiolate ligands. The MPCs described herein exhibit improved quantum efficiency allowing for single cluster emissions to be measured. Moreover, some embodiments of the MPCs described herein exhibit enhanced redox activity, including the ability to transfer a plurality of electrons, i.e., up to about 19 or up to about 30 electrons under controlled conditions, while displaying improved overall chemical stability. Such behavior can be utilized in catalysis and nanoelectronics applications. | 1. Water-soluble monolayer protected nanoclusters comprising clusters and a plurality of water-soluble ligands bound to the clusters, wherein the quantum efficiency of the near-IR luminescence is greater than 1%, preferably greater than 3%, single clusters can be imaged, or combinations thereof. 2. Organo-soluble monolayer protected clusters comprising clusters and a plurality of ligands bound to the clusters, wherein a plurality of the ligands comprises a 1,4-dithiolate moiety. 3. The clusters of claim 1, wherein the cluster comprises metal atoms or mixtures of metal atoms (alloys), metal oxides, metal atoms bridged by non-metallic elements, and combinations thereof. 4. The clusters of claim 3, wherein the cluster comprises metal atoms or mixtures of metal atoms. 5. The clusters of claim 3, wherein the cluster comprises metal oxides. 6. The clusters of claim 3, wherein the cluster comprises metal atoms bridged by non-metallic elements, and combinations thereof. 7. The clusters of claim 4, wherein the metal is selected from the group consisting of aluminum, tin, magnesium, gold, copper, nickel, iron, cobalt, magnesium, platinum, palladium, iridium, vanadium, silver, rhodium, ruthenium, and combinations thereof. 8. The clusters of claim 7, wherein the metal is gold. 9. The clusters of claim 4, wherein the mixture of metal atoms is an alloy of aluminum, tin, magnesium, gold, copper, nickel, iron, cobalt, magnesium, platinum, palladium, iridium, vanadium, silver, rhodium, ruthenium, or combinations thereof. 10. The clusters of claim 9, wherein the mixture of metal atoms contains gold and silver. 11. The clusters of claim 5, wherein the metal oxide is an early transition metal oxide. 12. The clusters of claim 6, wherein metals are bridged with oxygen, phosphorous, sulfur, or selenium. 13. The clusters of claim 1, wherein the largest dimension of the cluster is less than about or equal to 5 nm, 4 nm, 3 nm, 2.5 nm, 2.2 nm, 2.0 nm, 1.5 nm, or 1.0 nm. 14. The clusters of claim 2, wherein the 1,4-dithiolate moiety has the following formula:
wherein, R1-R8 are independently hydrogen; hydroxy (—OH), thiol (—SH), ether (e.g., —OR7), thioether (e.g., —SRS), primary amine (—NH2), secondary amine (e.g., —NHR7), tertiary amine (e.g., —NR7R7), primary amide (e.g., —CONH2), secondary amide (e.g., —NHCOR7), tertiary amide (e.g., —NR7COR7), secondary carbamate (e.g., —OCONHR7; —NHCOOR7), tertiary carbamate (e.g., —OCONR7R7; —NR7COOR7), urea (e.g., —NHCONHR7; —NR7CONHR7; —NHCONR7R7, —NR7CONR7R7), sulfinyl group (e.g., —SORA), sulfonyl group (e.g., —SOOR7) sulfino group, halogen, nitrile, or CF3; or an alkyl, cycloalkyl, heterocycloalkyl, alkylaryl, alkenyl, alkynyl, aryl, or heteroaryl group optionally substituted with between one and five substituents individually selected from alkyl, cyclopropyl, cyclobutyl ether, amine, halogen, hydroxyl, ether, nitrile, CF3, ester, amide, urea, carbamate, thioether, carboxylic acid, and aryl; or
R1-R4 taken together form a fused substituted or unsubstituted benzene ring. 15. The clusters of claim 14, wherein the R1-R4 together form a fused substituted or unsubstituted benzene ring and R5-R8 are hydrogen. 16. The clusters of claim 1, wherein the quantum efficiency is greater than 8%, 9%, 10%, or 11%. 17. The clusters of claim 1 wherein the ligands are selected from the group consisting of MSA, tiopronin, or combinations thereof. 18. The clusters of claim 17, wherein the ligands are covalently functionalized with polyethylene glycol. 19. The clusters of claim 1, further comprising a targeting moiety. 20. The clusters of claim 1, further comprising a fluorescent label. 21. A method for imaging a biological system in vivo, the method comprising contacting cells in vivo with the clusters of claim 1 and measuring the emission of the clusters. 22. The method of claim 21, wherein the cluster forms a conjugate with a target to be imaged. 23. The method of claim 21, wherein the emission shifts to shorter or longer wavelengths upon formation of the conjugate compared to the unconjugated cluster. 24. A method for imaging a biological system in vitro, the method comprising contacting in vitro the material to be imaged with the clusters of claim 1 and measuring the emission of the clusters. 25. The method of claim 24, wherein the cluster forms a conjugate with a target to be imaged. 26. The method of claim 25, wherein the emission shifts to shorter or longer wavelengths upon formation of the conjugate compared to the unconjugated cluster. 27. The method of claim 25, wherein the intensity of the emission decreases or increases upon formation of the conjugate compared to the unconjugated cluster. 28. A method of detecting a pollutant in a sample, the method comprising administering the clusters of claim 1 and detecting the emission of the clusters. 29. The method of claim 28, wherein the cluster forms a conjugate with the pollutant to be detected. 30. The method of claim 29, wherein the emission shifts to shorter or longer wavelengths upon formation of the conjugate compared to the unconjugated cluster. 31. The method of claim 29, wherein the intensity of the emission decreases or increases upon formation of the conjugate compared to the unconjugated cluster. 32. A method of making the clusters of claim 1, the method comprising contacting a cluster of metal atoms or mixed metal atoms with one or more ligands to form covalent or semi-covalent bonds between the cluster and the ligands. 33. The method of claim 32, further comprising annealing the clusters by stirring the clusters with an excess of free ligand(s). | Monolayer protected nanoclusters (MPCs) are described herein. The MPCs contain a cluster of atoms or molecules (e.g. core) having bound thereto a plurality of ligands (e.g., monolayer). The ligands can be bound covalently or semi-covalently bound to the cluster. The ligands are generally in the form of a monolayer or mixed monolayer. The monolayer or mixed monolayer contains a plurality of ligands. In one embodiment, the monolayer and/or mixed monolayer contains 1,4-dithiolate ligands. The MPCs described herein exhibit improved quantum efficiency allowing for single cluster emissions to be measured. Moreover, some embodiments of the MPCs described herein exhibit enhanced redox activity, including the ability to transfer a plurality of electrons, i.e., up to about 19 or up to about 30 electrons under controlled conditions, while displaying improved overall chemical stability. Such behavior can be utilized in catalysis and nanoelectronics applications.1. Water-soluble monolayer protected nanoclusters comprising clusters and a plurality of water-soluble ligands bound to the clusters, wherein the quantum efficiency of the near-IR luminescence is greater than 1%, preferably greater than 3%, single clusters can be imaged, or combinations thereof. 2. Organo-soluble monolayer protected clusters comprising clusters and a plurality of ligands bound to the clusters, wherein a plurality of the ligands comprises a 1,4-dithiolate moiety. 3. The clusters of claim 1, wherein the cluster comprises metal atoms or mixtures of metal atoms (alloys), metal oxides, metal atoms bridged by non-metallic elements, and combinations thereof. 4. The clusters of claim 3, wherein the cluster comprises metal atoms or mixtures of metal atoms. 5. The clusters of claim 3, wherein the cluster comprises metal oxides. 6. The clusters of claim 3, wherein the cluster comprises metal atoms bridged by non-metallic elements, and combinations thereof. 7. The clusters of claim 4, wherein the metal is selected from the group consisting of aluminum, tin, magnesium, gold, copper, nickel, iron, cobalt, magnesium, platinum, palladium, iridium, vanadium, silver, rhodium, ruthenium, and combinations thereof. 8. The clusters of claim 7, wherein the metal is gold. 9. The clusters of claim 4, wherein the mixture of metal atoms is an alloy of aluminum, tin, magnesium, gold, copper, nickel, iron, cobalt, magnesium, platinum, palladium, iridium, vanadium, silver, rhodium, ruthenium, or combinations thereof. 10. The clusters of claim 9, wherein the mixture of metal atoms contains gold and silver. 11. The clusters of claim 5, wherein the metal oxide is an early transition metal oxide. 12. The clusters of claim 6, wherein metals are bridged with oxygen, phosphorous, sulfur, or selenium. 13. The clusters of claim 1, wherein the largest dimension of the cluster is less than about or equal to 5 nm, 4 nm, 3 nm, 2.5 nm, 2.2 nm, 2.0 nm, 1.5 nm, or 1.0 nm. 14. The clusters of claim 2, wherein the 1,4-dithiolate moiety has the following formula:
wherein, R1-R8 are independently hydrogen; hydroxy (—OH), thiol (—SH), ether (e.g., —OR7), thioether (e.g., —SRS), primary amine (—NH2), secondary amine (e.g., —NHR7), tertiary amine (e.g., —NR7R7), primary amide (e.g., —CONH2), secondary amide (e.g., —NHCOR7), tertiary amide (e.g., —NR7COR7), secondary carbamate (e.g., —OCONHR7; —NHCOOR7), tertiary carbamate (e.g., —OCONR7R7; —NR7COOR7), urea (e.g., —NHCONHR7; —NR7CONHR7; —NHCONR7R7, —NR7CONR7R7), sulfinyl group (e.g., —SORA), sulfonyl group (e.g., —SOOR7) sulfino group, halogen, nitrile, or CF3; or an alkyl, cycloalkyl, heterocycloalkyl, alkylaryl, alkenyl, alkynyl, aryl, or heteroaryl group optionally substituted with between one and five substituents individually selected from alkyl, cyclopropyl, cyclobutyl ether, amine, halogen, hydroxyl, ether, nitrile, CF3, ester, amide, urea, carbamate, thioether, carboxylic acid, and aryl; or
R1-R4 taken together form a fused substituted or unsubstituted benzene ring. 15. The clusters of claim 14, wherein the R1-R4 together form a fused substituted or unsubstituted benzene ring and R5-R8 are hydrogen. 16. The clusters of claim 1, wherein the quantum efficiency is greater than 8%, 9%, 10%, or 11%. 17. The clusters of claim 1 wherein the ligands are selected from the group consisting of MSA, tiopronin, or combinations thereof. 18. The clusters of claim 17, wherein the ligands are covalently functionalized with polyethylene glycol. 19. The clusters of claim 1, further comprising a targeting moiety. 20. The clusters of claim 1, further comprising a fluorescent label. 21. A method for imaging a biological system in vivo, the method comprising contacting cells in vivo with the clusters of claim 1 and measuring the emission of the clusters. 22. The method of claim 21, wherein the cluster forms a conjugate with a target to be imaged. 23. The method of claim 21, wherein the emission shifts to shorter or longer wavelengths upon formation of the conjugate compared to the unconjugated cluster. 24. A method for imaging a biological system in vitro, the method comprising contacting in vitro the material to be imaged with the clusters of claim 1 and measuring the emission of the clusters. 25. The method of claim 24, wherein the cluster forms a conjugate with a target to be imaged. 26. The method of claim 25, wherein the emission shifts to shorter or longer wavelengths upon formation of the conjugate compared to the unconjugated cluster. 27. The method of claim 25, wherein the intensity of the emission decreases or increases upon formation of the conjugate compared to the unconjugated cluster. 28. A method of detecting a pollutant in a sample, the method comprising administering the clusters of claim 1 and detecting the emission of the clusters. 29. The method of claim 28, wherein the cluster forms a conjugate with the pollutant to be detected. 30. The method of claim 29, wherein the emission shifts to shorter or longer wavelengths upon formation of the conjugate compared to the unconjugated cluster. 31. The method of claim 29, wherein the intensity of the emission decreases or increases upon formation of the conjugate compared to the unconjugated cluster. 32. A method of making the clusters of claim 1, the method comprising contacting a cluster of metal atoms or mixed metal atoms with one or more ligands to form covalent or semi-covalent bonds between the cluster and the ligands. 33. The method of claim 32, further comprising annealing the clusters by stirring the clusters with an excess of free ligand(s). | 1,600 |
757 | 15,179,696 | 1,613 | Methods and compositions are provided that are utilized for treatment and/or prevention of intraventricular hemorrhage or progressive hemorrhagic necrosis (PHN), particularly following spinal cord injury. In particular, the methods and compositions are inhibitors of a particular NC Ca-ATP channel and include, for example, inhibitors of SUR1 and/or inhibitors of TRPM4. Kits for treatment and/or prevention of intraventricular hemorrhage or progressive hemorrhagic necrosis (PHN), particularly following spinal cord injury, are also provided. The present invention also concerns treatment and/or prevention of intraventricular hemorrhage in infants, including premature infants utilizing one or more inhibitors of the channel is provided to the infant, for example to brain cells of the infant. | 1.-48. (canceled) 49. A method of targeting a plasma level of glyburide in an individual, comprising the step of administering glyburide to the individual as follows:
(a) an intravenous loading dose of glyburide; and (b) a maintenance dose of glyburide, which is different than the loading dose. 50. The method of claim 49, wherein the loading dose of glyburide is 30-90 times the amount of the maintenance dose. 51. The method of claim 50, wherein the loading dose of glyburide is 40-80 times the amount of the maintenance dose. 52. The method of claim 50, wherein the loading dose of glyburide is 50-60 times the amount of the maintenance dose. 53. The method of claim 49, wherein the loading dose is 15.7 ug to 665 ug. 54. The method of claim 53, wherein the loading dose is 15.7 ug to 117 ug. 55. The method of claim 49, wherein the loading dose is 117 ug to 665 ug. 56. The method of claim 49, wherein the maintenance dose is 0.3 ug/min to 11.8 ug/min. 57. The method of claim 56, wherein the maintenance dose is 0.3 ug/min to 2.1 ug/min. 58. The method of claim 49, wherein the total daily dose is 432 ug/day to 17 mg/day. 59. The method of claim 58, wherein the total daily dose is 432 ug/day to 3 mg/day. 60. The method of claim 49, wherein the targeted plasma level of glyburide is from 4.07 ng/ml to 160.2 ng/ml. 61. The method of claim 60, wherein the targeted plasma level of glyburide is from 4.07 ng/ml to 28.3 ng/ml. 62. The method of claim 49, wherein the glyburide is administered to said individual for 3 days to 7 days. 63. The method of claim 62, wherein the glyburide is administered to said individual for 3 days to 5 days. | Methods and compositions are provided that are utilized for treatment and/or prevention of intraventricular hemorrhage or progressive hemorrhagic necrosis (PHN), particularly following spinal cord injury. In particular, the methods and compositions are inhibitors of a particular NC Ca-ATP channel and include, for example, inhibitors of SUR1 and/or inhibitors of TRPM4. Kits for treatment and/or prevention of intraventricular hemorrhage or progressive hemorrhagic necrosis (PHN), particularly following spinal cord injury, are also provided. The present invention also concerns treatment and/or prevention of intraventricular hemorrhage in infants, including premature infants utilizing one or more inhibitors of the channel is provided to the infant, for example to brain cells of the infant.1.-48. (canceled) 49. A method of targeting a plasma level of glyburide in an individual, comprising the step of administering glyburide to the individual as follows:
(a) an intravenous loading dose of glyburide; and (b) a maintenance dose of glyburide, which is different than the loading dose. 50. The method of claim 49, wherein the loading dose of glyburide is 30-90 times the amount of the maintenance dose. 51. The method of claim 50, wherein the loading dose of glyburide is 40-80 times the amount of the maintenance dose. 52. The method of claim 50, wherein the loading dose of glyburide is 50-60 times the amount of the maintenance dose. 53. The method of claim 49, wherein the loading dose is 15.7 ug to 665 ug. 54. The method of claim 53, wherein the loading dose is 15.7 ug to 117 ug. 55. The method of claim 49, wherein the loading dose is 117 ug to 665 ug. 56. The method of claim 49, wherein the maintenance dose is 0.3 ug/min to 11.8 ug/min. 57. The method of claim 56, wherein the maintenance dose is 0.3 ug/min to 2.1 ug/min. 58. The method of claim 49, wherein the total daily dose is 432 ug/day to 17 mg/day. 59. The method of claim 58, wherein the total daily dose is 432 ug/day to 3 mg/day. 60. The method of claim 49, wherein the targeted plasma level of glyburide is from 4.07 ng/ml to 160.2 ng/ml. 61. The method of claim 60, wherein the targeted plasma level of glyburide is from 4.07 ng/ml to 28.3 ng/ml. 62. The method of claim 49, wherein the glyburide is administered to said individual for 3 days to 7 days. 63. The method of claim 62, wherein the glyburide is administered to said individual for 3 days to 5 days. | 1,600 |
758 | 14,373,413 | 1,618 | The present invention relates to a method of labelling biological molecules with 18 F, via attachment to fluorine to a macrocyclic metal complex of a non-radioactive metal, where the metal complex is conjugated to the biological molecule. Also provided are pharmaceutical compositions, kits and methods of in vivo imaging. | 1. An imaging agent which comprises an 18F-labelled compound of Formula I:
where:
Y1 and Y2 are independently O or NR1,
X1, X2 and X3 are independently Br, Cl, 19F or 18F,
with the proviso that at least one of X1, X2 and X3 is 18F;
x, y and z are independently 0, 1 or 2;
M is Al3+, Ga3+, In3+, Sc3+, Y3+, Ho3+, Er3+, Tm3+, Yb3+ or Lu3+;
R1 is C1-3 alkyl or —CH2—Ar1, wherein Ar1 is C5-12 aryl or C3-12 heteroaryl;
R2 is R1 or Q;
Q is -L-[BTM], and may be present or absent; when present it is either R2 or is attached at one of the carbon atoms of the —(CH2)(CH2)x—, —(CH2)(CH2)y— or —(CH2)(CH2)z— groups;
L is a synthetic linker group of formula -(A)m- wherein each A is independently —CR2—, —CR═CR—, —C≡C—, —CR2CO2—, —CO2CR2—, —NRCO—, —CONR—, —CR═N—O—, —NR(C═O)NR—, —NR(C═S)NR—, —SO2NR—, —NRSO2—, —CR2OCR2—, —CR2SCR2—, —CR2NRCR2 −, a C4-8 cycloheteroalkylene group, a C4-8 cycloalkylene group, —Ar—, —NR—Ar—, —O—Ar—, —Ar—(CO)—, an amino acid, a sugar or a monodisperse polyethyleneglycol (PEG) building block,
wherein each R is independently chosen from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxyalkyl or C1-4 hydroxyalkyl;
m is an integer of value 1 to 20;
each Ar is independently a C5-12 arylene group, or a C3-12 heteroarylene group;
BTM is a biological targeting moiety. 2. The agent of claim 1, where Q is present. 3. The agent of claim 1, which is of Formula IA: 4. The agent of claim 1, where Y1=Y2=NR1. 5. The agent of claim 1, where x=y=z=1. 6. The agent of claim 1, which is of Formula IB: 7. The agent of claim 1, where M is Ga3+ or In3+. 8. The agent of claim 1, where X1, X2 and X3 are independently Cl, 19F or 18F. 9. The agent of claim 1, where the BTM is chosen from:
a single amino acid, a 3-100 mer peptide, an enzyme substrate, an enzyme antagonist an enzyme agonist, an enzyme inhibitor or a receptor-binding compound. 10. A method of preparation of the agent of claim 1, which comprises reaction of a precursor of Formula II with a supply of [18F]-fluoride or [18F]NaF, optionally in the presence of [19F]-fluoride, in a suitable solvent:
where M, Y1, Y2, x, y and z are as defined in claim 1;
Q may be present or absent and is as defined in claim 1; and
X1a, X2a and X3a are independently Br or Cl. 11. The method of claim 10, where the precursor is of Formula IIA: 12. The method of claim 10, where the precursor is of Formula IIB: 13. The method of claim 10, where X1a=X2a=X3a=Cl. 14. A precursor of Formula IIA or IIB:
where M, Y1, Y2, x, y and z are as defined in claim 1;
where Q comprises a BTM which is chosen from: a 3-100 mer peptide, an enzyme substrate, an enzyme antagonist an enzyme agonist, an enzyme inhibitor or a receptor-binding compound; and
X1a, X2a and X3a are independently Br or Cl. 15. A radiopharmaceutical composition which comprises the agent of claim 1, together with a biocompatible carrier, in a form suitable for mammalian administration. 16. A method, which comprises reaction of a precursor of Formula II with a supply of [18F]-fluoride or [18F]NaF, optionally in the presence of [19F]-fluoride, in a suitable solvent:
where M, Y1, Y2, x, y and z are as defined in claim 1;
Q may be present or absent and is as defined in claim 1; and
X1a, X2a and X3a are independently Br or Cl;
using an automated synthesizer apparatus. 17. The method of claim 16, where the automated synthesizer apparatus comprises a cassette which comprises the non-radioactive reagents necessary to carry out the method. 18. The method of claim 16, wherein the precursor is provided in sterile, lyophilized form. 19. A method of imaging the human or animal body which comprises generating an image of at least a part of said body to which the imaging agent of claim 1 has distributed using PET, wherein said agent has been previously administered to said body. 20. A method of imaging the human or animal body which comprises generating an image of at least a part of said body to which the composition of claim 15 has distributed using PET, wherein said composition has been previously administered to said body. | The present invention relates to a method of labelling biological molecules with 18 F, via attachment to fluorine to a macrocyclic metal complex of a non-radioactive metal, where the metal complex is conjugated to the biological molecule. Also provided are pharmaceutical compositions, kits and methods of in vivo imaging.1. An imaging agent which comprises an 18F-labelled compound of Formula I:
where:
Y1 and Y2 are independently O or NR1,
X1, X2 and X3 are independently Br, Cl, 19F or 18F,
with the proviso that at least one of X1, X2 and X3 is 18F;
x, y and z are independently 0, 1 or 2;
M is Al3+, Ga3+, In3+, Sc3+, Y3+, Ho3+, Er3+, Tm3+, Yb3+ or Lu3+;
R1 is C1-3 alkyl or —CH2—Ar1, wherein Ar1 is C5-12 aryl or C3-12 heteroaryl;
R2 is R1 or Q;
Q is -L-[BTM], and may be present or absent; when present it is either R2 or is attached at one of the carbon atoms of the —(CH2)(CH2)x—, —(CH2)(CH2)y— or —(CH2)(CH2)z— groups;
L is a synthetic linker group of formula -(A)m- wherein each A is independently —CR2—, —CR═CR—, —C≡C—, —CR2CO2—, —CO2CR2—, —NRCO—, —CONR—, —CR═N—O—, —NR(C═O)NR—, —NR(C═S)NR—, —SO2NR—, —NRSO2—, —CR2OCR2—, —CR2SCR2—, —CR2NRCR2 −, a C4-8 cycloheteroalkylene group, a C4-8 cycloalkylene group, —Ar—, —NR—Ar—, —O—Ar—, —Ar—(CO)—, an amino acid, a sugar or a monodisperse polyethyleneglycol (PEG) building block,
wherein each R is independently chosen from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxyalkyl or C1-4 hydroxyalkyl;
m is an integer of value 1 to 20;
each Ar is independently a C5-12 arylene group, or a C3-12 heteroarylene group;
BTM is a biological targeting moiety. 2. The agent of claim 1, where Q is present. 3. The agent of claim 1, which is of Formula IA: 4. The agent of claim 1, where Y1=Y2=NR1. 5. The agent of claim 1, where x=y=z=1. 6. The agent of claim 1, which is of Formula IB: 7. The agent of claim 1, where M is Ga3+ or In3+. 8. The agent of claim 1, where X1, X2 and X3 are independently Cl, 19F or 18F. 9. The agent of claim 1, where the BTM is chosen from:
a single amino acid, a 3-100 mer peptide, an enzyme substrate, an enzyme antagonist an enzyme agonist, an enzyme inhibitor or a receptor-binding compound. 10. A method of preparation of the agent of claim 1, which comprises reaction of a precursor of Formula II with a supply of [18F]-fluoride or [18F]NaF, optionally in the presence of [19F]-fluoride, in a suitable solvent:
where M, Y1, Y2, x, y and z are as defined in claim 1;
Q may be present or absent and is as defined in claim 1; and
X1a, X2a and X3a are independently Br or Cl. 11. The method of claim 10, where the precursor is of Formula IIA: 12. The method of claim 10, where the precursor is of Formula IIB: 13. The method of claim 10, where X1a=X2a=X3a=Cl. 14. A precursor of Formula IIA or IIB:
where M, Y1, Y2, x, y and z are as defined in claim 1;
where Q comprises a BTM which is chosen from: a 3-100 mer peptide, an enzyme substrate, an enzyme antagonist an enzyme agonist, an enzyme inhibitor or a receptor-binding compound; and
X1a, X2a and X3a are independently Br or Cl. 15. A radiopharmaceutical composition which comprises the agent of claim 1, together with a biocompatible carrier, in a form suitable for mammalian administration. 16. A method, which comprises reaction of a precursor of Formula II with a supply of [18F]-fluoride or [18F]NaF, optionally in the presence of [19F]-fluoride, in a suitable solvent:
where M, Y1, Y2, x, y and z are as defined in claim 1;
Q may be present or absent and is as defined in claim 1; and
X1a, X2a and X3a are independently Br or Cl;
using an automated synthesizer apparatus. 17. The method of claim 16, where the automated synthesizer apparatus comprises a cassette which comprises the non-radioactive reagents necessary to carry out the method. 18. The method of claim 16, wherein the precursor is provided in sterile, lyophilized form. 19. A method of imaging the human or animal body which comprises generating an image of at least a part of said body to which the imaging agent of claim 1 has distributed using PET, wherein said agent has been previously administered to said body. 20. A method of imaging the human or animal body which comprises generating an image of at least a part of said body to which the composition of claim 15 has distributed using PET, wherein said composition has been previously administered to said body. | 1,600 |
759 | 14,377,723 | 1,612 | The present invention relates to an effective formulation for the treatment or the prevention of irritable bowel syndrome, a method for treating irritable bowel syndrome, and processes for preparing such formulations. | 1. A composition for treatment and/or prevention of irritable bowel syndrome comprising resins and/or extracts thereof, polysaccharides and/or plant extracts comprising polysaccharides, antioxidants and/or plant extracts comprising antioxidants. 2. The composition according to claim 1 wherein said resins or extracts thereof are selected from the group incense and myrrh. 3. The composition according to claim 1 wherein said polysaccharides are selected from the group consisting of polysaccharides extracted from Aloe vera, chamomile, and althea; and wherein said plant extracts comprising polysaccharides are selected from the group consisting of extracts of aloe vera, chamomile, and althea. 4. The composition according to claim 1 wherein said antioxidants are selected from the group consisting of antioxidants extracted from chamomile and lemon-balm; and wherein said plant extracts comprising antioxidants are selected from the group consisting of extracts of chamomile and lemon-balm. 5. The composition according to claim 1, wherein said resins or extracts thereof are selected from the group consisting of incense and myrrh; wherein said polysaccharides are selected from the group consisting of polysaccharides extracted from aloe vera, chamomile, and althea; wherein said plant extracts comprising polysaccharides are selected from the group consisting of extracts of aloe vera, chamomile, and althea; wherein said antioxidants are selected from the group consisting of antioxidants extracted from chamomile and lemon-balm; and wherein said plant extracts comprising antioxidants are selected from the group consisting of extracts of chamomile and lemon-balm. 6. The composition according to claim 1 wherein said resins and/or extracts thereof are in a percentage from 30% to 60% by weight. 7. The composition according to claim 1 wherein said polysaccharides and/or plant extracts comprising polysaccharides are in a percentage from 12% to 22% by weight. 8. The composition according to claim 1 wherein said antioxidants and/or plant extracts comprising antioxidants are in a percentage from 35 to 65% weight. 9. The composition according to claim 1 wherein said resins and/or extracts thereof are in a percentage in weight from 30% to 60% by weight, wherein said polysaccharides and/or plant extracts comprising polysaccharides are in a percentage from 12% to 22% by weight, and wherein said antioxidants and/or plant extracts comprising antioxidants are in a percentage from 35% to 65% by weight. 10. The composition according to claim 1 further comprising natural and/or plant derived compounds with eminent, digestive, pro-kinetic, cholagogic, carminative, prebiotic, relaxing, excipient, preserving, and/or wetting activity. 11. The composition according to claim 10 wherein said natural and/or plant derived compounds are one or more selected from the group consisting of gentian root extract, boldo leaf extract, milk thistle fruit extract, artichoke leaves extract, dandelion root extract, anise fruit extract, rosemary leaf extract, mint leaf extract, marjoram leaf extract, cumin fruit extract, seed extract, coriander fruit extract, ginger root extract, fennel fruit extract, caraway fruit extract, plant charcoal, and inulin. 12. The composition according to claim 1 in the form of capsule, tablet, lozenge, granule, powder, syrup, elixir, hard gelatine, soft gelatine, suspension, emulsion, or solution. 13. The composition according to claim 1 wherein said composition is a pharmaceutical composition, is comprised in or consists of a medical device, is comprised in or consists of a dietary supplement, or is comprised in a medical food. 14. A medical device, medicament, medical food, or dietary supplement comprising a composition according to claim 1. 15. A method for preparation of a composition according to claim 1, comprising admixing together said resins and/or extracts thereof, said polysaccharides and/or plant extracts comprising polysaccharides, and said antioxidants and/or plant extracts comprising antioxidants; optionally together with further excipients and/or one or more of natural and/or plant derived compounds with eminent, digestive, pro-kinetic, cholagogic, carminative, prebiotic, relaxing, excipient, preserving, and/or wetting activity. 16. A method for treatment and/or prevention of irritable bowel syndrome, comprising administering a composition according to a claim 1 to an individual requiring it. | The present invention relates to an effective formulation for the treatment or the prevention of irritable bowel syndrome, a method for treating irritable bowel syndrome, and processes for preparing such formulations.1. A composition for treatment and/or prevention of irritable bowel syndrome comprising resins and/or extracts thereof, polysaccharides and/or plant extracts comprising polysaccharides, antioxidants and/or plant extracts comprising antioxidants. 2. The composition according to claim 1 wherein said resins or extracts thereof are selected from the group incense and myrrh. 3. The composition according to claim 1 wherein said polysaccharides are selected from the group consisting of polysaccharides extracted from Aloe vera, chamomile, and althea; and wherein said plant extracts comprising polysaccharides are selected from the group consisting of extracts of aloe vera, chamomile, and althea. 4. The composition according to claim 1 wherein said antioxidants are selected from the group consisting of antioxidants extracted from chamomile and lemon-balm; and wherein said plant extracts comprising antioxidants are selected from the group consisting of extracts of chamomile and lemon-balm. 5. The composition according to claim 1, wherein said resins or extracts thereof are selected from the group consisting of incense and myrrh; wherein said polysaccharides are selected from the group consisting of polysaccharides extracted from aloe vera, chamomile, and althea; wherein said plant extracts comprising polysaccharides are selected from the group consisting of extracts of aloe vera, chamomile, and althea; wherein said antioxidants are selected from the group consisting of antioxidants extracted from chamomile and lemon-balm; and wherein said plant extracts comprising antioxidants are selected from the group consisting of extracts of chamomile and lemon-balm. 6. The composition according to claim 1 wherein said resins and/or extracts thereof are in a percentage from 30% to 60% by weight. 7. The composition according to claim 1 wherein said polysaccharides and/or plant extracts comprising polysaccharides are in a percentage from 12% to 22% by weight. 8. The composition according to claim 1 wherein said antioxidants and/or plant extracts comprising antioxidants are in a percentage from 35 to 65% weight. 9. The composition according to claim 1 wherein said resins and/or extracts thereof are in a percentage in weight from 30% to 60% by weight, wherein said polysaccharides and/or plant extracts comprising polysaccharides are in a percentage from 12% to 22% by weight, and wherein said antioxidants and/or plant extracts comprising antioxidants are in a percentage from 35% to 65% by weight. 10. The composition according to claim 1 further comprising natural and/or plant derived compounds with eminent, digestive, pro-kinetic, cholagogic, carminative, prebiotic, relaxing, excipient, preserving, and/or wetting activity. 11. The composition according to claim 10 wherein said natural and/or plant derived compounds are one or more selected from the group consisting of gentian root extract, boldo leaf extract, milk thistle fruit extract, artichoke leaves extract, dandelion root extract, anise fruit extract, rosemary leaf extract, mint leaf extract, marjoram leaf extract, cumin fruit extract, seed extract, coriander fruit extract, ginger root extract, fennel fruit extract, caraway fruit extract, plant charcoal, and inulin. 12. The composition according to claim 1 in the form of capsule, tablet, lozenge, granule, powder, syrup, elixir, hard gelatine, soft gelatine, suspension, emulsion, or solution. 13. The composition according to claim 1 wherein said composition is a pharmaceutical composition, is comprised in or consists of a medical device, is comprised in or consists of a dietary supplement, or is comprised in a medical food. 14. A medical device, medicament, medical food, or dietary supplement comprising a composition according to claim 1. 15. A method for preparation of a composition according to claim 1, comprising admixing together said resins and/or extracts thereof, said polysaccharides and/or plant extracts comprising polysaccharides, and said antioxidants and/or plant extracts comprising antioxidants; optionally together with further excipients and/or one or more of natural and/or plant derived compounds with eminent, digestive, pro-kinetic, cholagogic, carminative, prebiotic, relaxing, excipient, preserving, and/or wetting activity. 16. A method for treatment and/or prevention of irritable bowel syndrome, comprising administering a composition according to a claim 1 to an individual requiring it. | 1,600 |
760 | 15,429,671 | 1,642 | The present invention relates to therapeutic ADCs comprising a drug attached to an anti-cancer antibody or antigen-binding antibody fragment. Preferably the drug is SN-38. More preferably the antibody or fragment thereof binds to Trop-2 and the therapy is used to treat a Trop-2 positive cancer. Most preferably the antibody is hRS7. The ADC is administered to a subject with a cancer in combination with an ABCG2 inhibitor. The combination therapy is effective to treat cancers that are resistant to drug alone and/or to ADC alone. | 1. A method of treating a Trop-2 positive cancer comprising:
a. administering to a human patient with a Trop-2 positive cancer an anti-Trop-2 antibody-drug conjugate (ADC) comprising an anti-cancer drug conjugated to an anti-Trop-2 antibody or antigen-binding fragment thereof; and b. administering to the patient an ABCG2 inhibitor. 2. The method of claim 1, wherein the ABCG2 inhibitor is selected from the group consisting of fumitremorgin C, Ko143, GF120918, YHO-13351, curcumin, CID44640177, CID1434724, CID46245505, CCT129202, artesunate, ST1481, dihydropyridine, dofequjidar fumarate, gefitinib, imatinib mesylate, lapatinib, WK-X-34 and YHO-13177. 3. The method of claim 2, wherein the ABCG2 inhibitor is fumitremorgin C, Ko143, or YHO-13351. 4. The method of claim 2, wherein the ABCG2 inhibitor is YHO-13351. 5. The method of claim 1, wherein the anti-cancer drug is selected from the group consisting of a camptothecin, an anthracycline, an anthracenedione, a taxane, a vinca alkaloid, an epipodophyllotoxin and a platinum compound. 6. The method of claim 6, wherein the anti-cancer drug is selected from the group consisting of SN-38, topotecan, doxorubicin, dauorubicin, mitoxantrone, paclitaxel, vincristine, vinblastine, etoposide, teniposide, and cisplatinum. 7. The method of claim 6, wherein the anti-cancer drug is SN-38. 8. The method of claim 1, wherein the anti-Trop-2 antibody is hRS7. 9. The method of claim 1, wherein the ADC is administered at a dosage of between 3 mg/kg and 18 mg/kg. 10. The method of claim 1, wherein the patient has relapsed from or failed to respond to therapy with a camptothecin, prior to administration of the ADC and ABCG2 inhibitor. 11. The method of claim 10, wherein the patient has relapsed from or failed to respond to therapy with irinotecan or SN-38, prior to administration of the ADC and ABCG2 inhibitor. 12. The method of claim 1, wherein the patient has relapsed from or failed to respond to therapy with a drug-conjugated antibody, prior to administration of the ADC and ABCG2 inhibitor. 13. The method of claim 1, further comprising: (i) screening cancer cells from the patient for sensitivity to the ADC; and (ii) selecting patients for therapy with the ADC and ABCG2 inhibitor whose cancer cells are resistant to therapy with the ADC alone. 14. The method of claim 1, wherein the cancer is selected from the group consisting of colorectal, lung, stomach, urinary bladder, renal, pancreatic, breast, ovarian, uterine, esophageal and prostatic cancer. 15. The method of claim 9, wherein the dosage is selected from the group consisting of 3 mg/kg, 4 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 16 mg/kg and 18 mg/kg. 16. The method of claim 1, wherein the treatment results in a reduction in tumor size of at least 15%, at least 20%, at least 30%, or at least 40%. 17. The method of claim 1, wherein the cancer is selected from the group consisting of triple-negative breast cancer, HER+, ER+, progesterone+ breast cancer, metastatic non-small-cell lung cancer, metastatic small-cell lung cancer, metastatic urothelial cancer and metastatic pancreatic cancer. 18. The method of claim 7, wherein the ADC comprises 4 or more molecules of SN-38 conjugated to the antibody or antigen-binding fragment thereof. 19. The method of claim 7, wherein the ADC comprises 6 to 8 molecules of SN-38 conjugated to the antibody or antigen-binding fragment thereof. 20. The method of claim 1, wherein the cancer is metastatic. 21. The method of claim 20, further comprising reducing in size or eliminating the metastases. 22. The method of claim 7, wherein there is a linker between the SN-38 and the antibody. 23. The method of claim 22, wherein the linker is CL2A and the structure of the ADC is MAb-CL2A-SN-38 24. The method of claim 23, wherein the 10-hydroxy position of SN-38 in MAb-CL2A-SN-38 is a 10-O-ester or 10-O-carbonate derivative using a ‘COR’ moiety, wherein “CO” is carbonyl and the “R” group is selected from (i) an N,N-disubstituted aminoalkyl group “N(CH3)2—(CH2)n—” wherein n is 1-10 and wherein the terminal amino group is optionally in the form of a quaternary salt; (ii) an alkyl residue “CH3—(CH2)n—” wherein n is 0-10; (iii) an alkoxy moiety “CH3—(CH2)n-O—” wherein n is 0-10; (iv) an “N(CH3)2—(CH2)n—O—” wherein n is 2-10; or (v) an “R1O—(CH2—CH2—O)n—CH2—CH2—O—” wherein R1 is ethyl or methyl and n is an integer with values of 0-10. 25. The method of claim 1, wherein the antibody binds to the same epitope as, or competes for binding to Trop-2 with, an anti-Trop-2 antibody comprising the light chain CDR sequences CDR1 (KASQDVSIAVA, SEQ ID NO: 14); CDR2 (SASYRYT, SEQ ID NO: 15); and CDR3 (QQHYITPLT, SEQ ID NO: 16) and the heavy chain CDR sequences CDR1 (NYGMN, SEQ ID NO: 17); CDR2 (WINTYTGEPTYTDDFKG, SEQ ID NO: 18) and CDR3 (GGFGSSYWYFDV, SEQ ID NO: 19). 26. The method of claim 1, wherein the antibody comprises the light chain CDR sequences CDR1 (KASQDVSIAVA, SEQ ID NO: 14); CDR2 (SASYRYT, SEQ ID NO: 15); and CDR3 (QQHYITPLT, SEQ ID NO: 16) and the heavy chain CDR sequences CDR1 (NYGMN, SEQ ID NO: 17); CDR2 (WINTYTGEPTYTDDFKG, SEQ ID NO: 18) and CDR3 (GGFGSSYWYFDV, SEQ ID NO: 19). 27. The method of claim 1, further comprising administering to the patient at least one other anti-cancer therapy selected from the group consisting of surgery, external radiation, radioimmunotherapy, immunotherapy, chemotherapy, antisense therapy, interference RNA therapy, treatment with a therapeutic agent and gene therapy. 28. The method of claim 27, wherein the therapeutic agent is a drug, toxin, immunomodulator, second antibody, antigen-binding fragment of a second antibody, pro-apoptotic agent, toxin, RNase, hormone, radionuclide, anti-angiogenic agent, siRNA, RNAi, chemotherapeutic agent, cytokine, chemokine, prodrug or enzyme. 29. The method of claim 28, wherein the drug is selected from the group consisting of 5-fluorouracil, afatinib, aplidin, azaribine, anastrozole, anthracyclines, axitinib, AVL-101, AVL-291, bendamustine, bleomycin, bortezomib, bosutinib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatinum, Cox-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dasatinib, dinaciclib, docetaxel, dactinomycin, daunorubicin, doxorubicin, 2-pyrrolinodoxorubicine (2P-DOX), cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, erlotinib, estramustine, epidophyllotoxin, erlotinib, entinostat, estrogen receptor binding agents, etoposide (VP16), etoposide glucuronide, etoposide phosphate, exemestane, fingolimod, floxuridine (FUdR), 3′,5′-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, farnesyl-protein transferase inhibitors, flavopiridol, fostamatinib, ganetespib, GDC-0834, GS-1101, gefitinib, gemcitabine, hydroxyurea, ibrutinib, idarubicin, idelalisib, ifosfamide, imatinib, L-asparaginase, lapatinib, lenolidamide, leucovorin, LFM-A13, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, navelbine, neratinib, nilotinib, nitrosurea, olaparib, plicomycin, procarbazine, paclitaxel, PCI-32765, pentostatin, PSI-341, raloxifene, semustine, sorafenib, streptozocin, SU11248, sunitinib, tamoxifen, temazolomide (an aqueous form of DTIC), transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vatalanib, vinorelbine, vinblastine, vincristine, vinca alkaloids and ZD1839. 30. The method of claim 28, wherein the wherein the immunomodulator is selected from the group consisting of cytokines, lymphokines, monokines, stem cell growth factors, lymphotoxins, hematopoietic factors, colony stimulating factors (CSF), interferons (IFN), parathyroid hormone, thyroxine, insulin, proinsulin, relaxin, prorelaxin, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), hepatic growth factor, prostaglandin, fibroblast growth factor, prolactin, placental lactogen, OB protein, transforming growth factor (TGF), TGF-α, TGF-β, insulin-like growth factor (IGF), erythropoietin, thrombopoietin, tumor necrosis factor (TNF), TNF-α, TNF-β, mullerian-inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, integrin, interleukin (IL), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-α, interferon-β, interferon-γ, S1 factor, IL-1, IL-1 cc, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18 IL-21, IL-23, IL-25, LIF, kit-ligand, FLT-3, angiostatin, thrombospondin and endostatin. 31. The method of claim 1, further comprising administering to the patient an inhibitor of ABCB1 or ABCC1. 32. The method of claim 1, further comprising administering to the patient a tyrosine kinase inhibitor. 33. A method of treating a cancer that is resistant to SN-38 or irinotecan comprising:
a. administering to a human patient with cancer that is resistant to SN-38 or irinotecan an ADC comprising SN-38 conjugated to an antibody or antigen-binding fragment thereof that binds to an antigen expressed by the cancer; and b. administering to the patient an ABCG2 inhibitor. 34. The method of claim 33, wherein the ABCG2 inhibitor is selected from the group consisting of fumitremorgin C, Ko143, GF120918, YHO-13351, curcumin, CID44640177, CID1434724, CID46245505, CCT129202, artesunate, ST1481, dihydropyridine, dofequjidar fumarate, gefitinib, imatinib mesylate, lapatinib, WK-X-34 and YHO-13177. 35. The method of claim 33, wherein the ABCG2 inhibitor is selected from the group consisting of fumitremorgin C, Ko143, GF120918 and YHO-13351. 36. The method of claim 33, wherein the ABCG2 inhibitor is YHO-13351. 37. The method of claim 33, wherein the antigen is selected from the group consisting of carbonic anhydrase IX, alpha-fetoprotein (AFP), α-actinin-4, A3, antigen specific for A33 antibody, ART-4, B7, Ba 733, BAGE, BrE3-antigen, CA125, CAMEL, CAP-1, CASP-8/m, CCL19, CCL21, CD1, CD1a, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD66a-e, CD67, CD70, CD70L, CD74, CD79a, CD80, CD83, CD95, CD126, CD132, CD133, CD138, CD147, CD154, CDC27, CDK-4/m, CDKN2A, CTLA-4, CXCR4, CXCR7, CXCL12, HIF-1α, colon-specific antigen-p (CSAp), CEA (CEACAM5), CEACAM6, c-Met, DAM, EGFR, EGFRvIII, EGP-1 (Trop-2), EGP-2, ELF2-M, Ep-CAM, fibroblast growth factor (FGF), Flt-1, Flt-3, folate receptor, G250 antigen, GAGE, gp100, GRO-β, HLA-DR, HM1.24, human chorionic gonadotropin (HCG) and its subunits, HER2/neu, HMGB-1, hypoxia inducible factor (HIF-1), HSP70-2M, HST-2, Ia, IGF-1R, IFN-γ, IFN-α, IFN-β, IFN-λ, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-2, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-23, IL-25, insulin-like growth factor-1 (IGF-1), KC4-antigen, KS-1-antigen, KS1-4, Le-Y, LDR/FUT, macrophage migration inhibitory factor (MIF), MAGE, MAGE-3, MART-1, MART-2, NY-ESO-1, TRAG-3, mCRP, MCP-1, MIP-1A, MIP-1B, MIF, MUC1, MUC2, MUC3, MUC4, MUC5ac, MUC13, MUC16, MUM-1/2, MUM-3, NCA66, NCA95, NCA90, PAM4 antigen, pancreatic cancer mucin, PD-1 receptor, placental growth factor, p53, PLAGL2, prostatic acid phosphatase, PSA, PRAME, PSMA, PlGF, ILGF, ILGF-1R, IL-6, IL-25, RS5, RANTES, T101, SAGE, 5100, survivin, survivin-2B, TAC, TAG-72, tenascin, TRAIL receptors, TNF-α, Tn antigen, Thomson-Friedenreich antigens, tumor necrosis antigens, VEGFR, ED-B fibronectin, WT-1, 17-1A-antigen, complement factors C3, C3a, C3b, C5a, C5, an angiogenesis marker, bcl-2, bcl-6, Kras, and an oncogene marker. 38. The method of claim 33, wherein the antigen is selected from the group consisting of Trop-2, CEACAM-5, CD74, CD22, CD20, MUC-5ac and HLA-DR. 39. The method of claim 33, wherein the antibody is selected from the group consisting of LL1 (anti-CD74), LL2 (anti-CD22), RFB4 (anti-CD22), veltuzumab (hA20, anti-CD20), rituxumab (anti-CD20), obinutuzumab (GA101, anti-CD20), lambrolizumab (anti-PD-1 receptor), nivolumab (anti-PD-1 receptor), ipilimumab (anti-CTLA-4), RS7 (anti-Trop-2), PAM4 (anti-MUC-5ac), KC4 (anti-mucin), MN-14 (anti-CEACAM5), MN-15 (anti-CEACAM6), MN-3 (anti-CEACAM6), Mu-9 (anti-CSAp), Immu 31 (anti-alpha-fetoprotein), R1 (anti-IGF-1R), A19 (anti-CD19), TAG-72 (anti-PSMA), Tn (anti-PSMA), J591 (anti-PSMA), HuJ591 (anti-PSMA), AB-PG1-XG1-026 (anti-PSMA dimer), D2/B (anti-PSMA), G250 (anti-carbonic anhydrase IX), L243 (anti-HLA-DR), alemtuzumab (anti-CD52), bevacizumab (anti-VEGF), cetuximab (anti-EGFR), gemtuzumab (anti-CD33), ibritumomab tiuxetan (anti-CD20), panitumumab (anti-EGFR), tositumomab (anti-CD20), and trastuzumab (anti-ErbB2). 40. The method of claim 33, wherein the antibody is selected from the group consisting of hRS7, hMN-13, hLL1, hLL2, hA20, hPAM4 and hL243. 41. The method of claim 33, wherein the cancer is selected from the group consisting of B-cell lymphoma, B-cell leukemia, Hodgkin's disease, T-cell leukemia, T-cell lymphoma, myeloma, colon cancer, stomach cancer, esophageal cancer, medullary thyroid cancer, kidney cancer, breast cancer, lung cancer, pancreatic cancer, urinary bladder cancer, ovarian cancer, uterine cancer, cervical cancer, testicular cancer, prostate cancer, liver cancer, skin cancer, bone cancer, brain cancer, rectal cancer, and melanoma. 42. The method of claim 41, wherein the B-cell leukemia or B-cell lymphoma is selected from the group consisting of indolent forms of B-cell lymphoma, aggressive forms of B-cell lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, hairy cell leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Burkitt lymphoma, follicular lymphoma, diffuse B-cell lymphoma, mantle cell lymphoma and multiple myeloma. 43. The method of claim 33, wherein the ADC comprises 6 to 8 molecules of SN-38 conjugated to the antibody or antigen-binding fragment thereof. 44. The method of claim 33, wherein the cancer is metastatic. 45. The method of claim 33, wherein there is a linker between the SN-38 and the antibody. 46. The method of claim 45, wherein the linker is CL2A and the structure of the ADC is MAb-CL2A-SN-38 47. The method of claim 33, wherein the ADC is administered at a dosage of between 8 mg/kg and 12 mg/kg. 48. The method of claim 33, wherein the ADC is administered at a dosage of between 8 mg/kg and 10 mg/kg. 49. The method of claim 33, further comprising administering to the patient at least one other anti-cancer therapy selected from the group consisting of surgery, external radiation, radioimmunotherapy, immunotherapy, chemotherapy, antisense therapy, interference RNA therapy, treatment with a therapeutic agent and gene therapy. | The present invention relates to therapeutic ADCs comprising a drug attached to an anti-cancer antibody or antigen-binding antibody fragment. Preferably the drug is SN-38. More preferably the antibody or fragment thereof binds to Trop-2 and the therapy is used to treat a Trop-2 positive cancer. Most preferably the antibody is hRS7. The ADC is administered to a subject with a cancer in combination with an ABCG2 inhibitor. The combination therapy is effective to treat cancers that are resistant to drug alone and/or to ADC alone.1. A method of treating a Trop-2 positive cancer comprising:
a. administering to a human patient with a Trop-2 positive cancer an anti-Trop-2 antibody-drug conjugate (ADC) comprising an anti-cancer drug conjugated to an anti-Trop-2 antibody or antigen-binding fragment thereof; and b. administering to the patient an ABCG2 inhibitor. 2. The method of claim 1, wherein the ABCG2 inhibitor is selected from the group consisting of fumitremorgin C, Ko143, GF120918, YHO-13351, curcumin, CID44640177, CID1434724, CID46245505, CCT129202, artesunate, ST1481, dihydropyridine, dofequjidar fumarate, gefitinib, imatinib mesylate, lapatinib, WK-X-34 and YHO-13177. 3. The method of claim 2, wherein the ABCG2 inhibitor is fumitremorgin C, Ko143, or YHO-13351. 4. The method of claim 2, wherein the ABCG2 inhibitor is YHO-13351. 5. The method of claim 1, wherein the anti-cancer drug is selected from the group consisting of a camptothecin, an anthracycline, an anthracenedione, a taxane, a vinca alkaloid, an epipodophyllotoxin and a platinum compound. 6. The method of claim 6, wherein the anti-cancer drug is selected from the group consisting of SN-38, topotecan, doxorubicin, dauorubicin, mitoxantrone, paclitaxel, vincristine, vinblastine, etoposide, teniposide, and cisplatinum. 7. The method of claim 6, wherein the anti-cancer drug is SN-38. 8. The method of claim 1, wherein the anti-Trop-2 antibody is hRS7. 9. The method of claim 1, wherein the ADC is administered at a dosage of between 3 mg/kg and 18 mg/kg. 10. The method of claim 1, wherein the patient has relapsed from or failed to respond to therapy with a camptothecin, prior to administration of the ADC and ABCG2 inhibitor. 11. The method of claim 10, wherein the patient has relapsed from or failed to respond to therapy with irinotecan or SN-38, prior to administration of the ADC and ABCG2 inhibitor. 12. The method of claim 1, wherein the patient has relapsed from or failed to respond to therapy with a drug-conjugated antibody, prior to administration of the ADC and ABCG2 inhibitor. 13. The method of claim 1, further comprising: (i) screening cancer cells from the patient for sensitivity to the ADC; and (ii) selecting patients for therapy with the ADC and ABCG2 inhibitor whose cancer cells are resistant to therapy with the ADC alone. 14. The method of claim 1, wherein the cancer is selected from the group consisting of colorectal, lung, stomach, urinary bladder, renal, pancreatic, breast, ovarian, uterine, esophageal and prostatic cancer. 15. The method of claim 9, wherein the dosage is selected from the group consisting of 3 mg/kg, 4 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 16 mg/kg and 18 mg/kg. 16. The method of claim 1, wherein the treatment results in a reduction in tumor size of at least 15%, at least 20%, at least 30%, or at least 40%. 17. The method of claim 1, wherein the cancer is selected from the group consisting of triple-negative breast cancer, HER+, ER+, progesterone+ breast cancer, metastatic non-small-cell lung cancer, metastatic small-cell lung cancer, metastatic urothelial cancer and metastatic pancreatic cancer. 18. The method of claim 7, wherein the ADC comprises 4 or more molecules of SN-38 conjugated to the antibody or antigen-binding fragment thereof. 19. The method of claim 7, wherein the ADC comprises 6 to 8 molecules of SN-38 conjugated to the antibody or antigen-binding fragment thereof. 20. The method of claim 1, wherein the cancer is metastatic. 21. The method of claim 20, further comprising reducing in size or eliminating the metastases. 22. The method of claim 7, wherein there is a linker between the SN-38 and the antibody. 23. The method of claim 22, wherein the linker is CL2A and the structure of the ADC is MAb-CL2A-SN-38 24. The method of claim 23, wherein the 10-hydroxy position of SN-38 in MAb-CL2A-SN-38 is a 10-O-ester or 10-O-carbonate derivative using a ‘COR’ moiety, wherein “CO” is carbonyl and the “R” group is selected from (i) an N,N-disubstituted aminoalkyl group “N(CH3)2—(CH2)n—” wherein n is 1-10 and wherein the terminal amino group is optionally in the form of a quaternary salt; (ii) an alkyl residue “CH3—(CH2)n—” wherein n is 0-10; (iii) an alkoxy moiety “CH3—(CH2)n-O—” wherein n is 0-10; (iv) an “N(CH3)2—(CH2)n—O—” wherein n is 2-10; or (v) an “R1O—(CH2—CH2—O)n—CH2—CH2—O—” wherein R1 is ethyl or methyl and n is an integer with values of 0-10. 25. The method of claim 1, wherein the antibody binds to the same epitope as, or competes for binding to Trop-2 with, an anti-Trop-2 antibody comprising the light chain CDR sequences CDR1 (KASQDVSIAVA, SEQ ID NO: 14); CDR2 (SASYRYT, SEQ ID NO: 15); and CDR3 (QQHYITPLT, SEQ ID NO: 16) and the heavy chain CDR sequences CDR1 (NYGMN, SEQ ID NO: 17); CDR2 (WINTYTGEPTYTDDFKG, SEQ ID NO: 18) and CDR3 (GGFGSSYWYFDV, SEQ ID NO: 19). 26. The method of claim 1, wherein the antibody comprises the light chain CDR sequences CDR1 (KASQDVSIAVA, SEQ ID NO: 14); CDR2 (SASYRYT, SEQ ID NO: 15); and CDR3 (QQHYITPLT, SEQ ID NO: 16) and the heavy chain CDR sequences CDR1 (NYGMN, SEQ ID NO: 17); CDR2 (WINTYTGEPTYTDDFKG, SEQ ID NO: 18) and CDR3 (GGFGSSYWYFDV, SEQ ID NO: 19). 27. The method of claim 1, further comprising administering to the patient at least one other anti-cancer therapy selected from the group consisting of surgery, external radiation, radioimmunotherapy, immunotherapy, chemotherapy, antisense therapy, interference RNA therapy, treatment with a therapeutic agent and gene therapy. 28. The method of claim 27, wherein the therapeutic agent is a drug, toxin, immunomodulator, second antibody, antigen-binding fragment of a second antibody, pro-apoptotic agent, toxin, RNase, hormone, radionuclide, anti-angiogenic agent, siRNA, RNAi, chemotherapeutic agent, cytokine, chemokine, prodrug or enzyme. 29. The method of claim 28, wherein the drug is selected from the group consisting of 5-fluorouracil, afatinib, aplidin, azaribine, anastrozole, anthracyclines, axitinib, AVL-101, AVL-291, bendamustine, bleomycin, bortezomib, bosutinib, bryostatin-1, busulfan, calicheamycin, camptothecin, carboplatin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatinum, Cox-2 inhibitors, irinotecan (CPT-11), SN-38, carboplatin, cladribine, camptothecans, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dasatinib, dinaciclib, docetaxel, dactinomycin, daunorubicin, doxorubicin, 2-pyrrolinodoxorubicine (2P-DOX), cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, erlotinib, estramustine, epidophyllotoxin, erlotinib, entinostat, estrogen receptor binding agents, etoposide (VP16), etoposide glucuronide, etoposide phosphate, exemestane, fingolimod, floxuridine (FUdR), 3′,5′-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, farnesyl-protein transferase inhibitors, flavopiridol, fostamatinib, ganetespib, GDC-0834, GS-1101, gefitinib, gemcitabine, hydroxyurea, ibrutinib, idarubicin, idelalisib, ifosfamide, imatinib, L-asparaginase, lapatinib, lenolidamide, leucovorin, LFM-A13, lomustine, mechlorethamine, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, navelbine, neratinib, nilotinib, nitrosurea, olaparib, plicomycin, procarbazine, paclitaxel, PCI-32765, pentostatin, PSI-341, raloxifene, semustine, sorafenib, streptozocin, SU11248, sunitinib, tamoxifen, temazolomide (an aqueous form of DTIC), transplatinum, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, vatalanib, vinorelbine, vinblastine, vincristine, vinca alkaloids and ZD1839. 30. The method of claim 28, wherein the wherein the immunomodulator is selected from the group consisting of cytokines, lymphokines, monokines, stem cell growth factors, lymphotoxins, hematopoietic factors, colony stimulating factors (CSF), interferons (IFN), parathyroid hormone, thyroxine, insulin, proinsulin, relaxin, prorelaxin, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), hepatic growth factor, prostaglandin, fibroblast growth factor, prolactin, placental lactogen, OB protein, transforming growth factor (TGF), TGF-α, TGF-β, insulin-like growth factor (IGF), erythropoietin, thrombopoietin, tumor necrosis factor (TNF), TNF-α, TNF-β, mullerian-inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, integrin, interleukin (IL), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-α, interferon-β, interferon-γ, S1 factor, IL-1, IL-1 cc, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18 IL-21, IL-23, IL-25, LIF, kit-ligand, FLT-3, angiostatin, thrombospondin and endostatin. 31. The method of claim 1, further comprising administering to the patient an inhibitor of ABCB1 or ABCC1. 32. The method of claim 1, further comprising administering to the patient a tyrosine kinase inhibitor. 33. A method of treating a cancer that is resistant to SN-38 or irinotecan comprising:
a. administering to a human patient with cancer that is resistant to SN-38 or irinotecan an ADC comprising SN-38 conjugated to an antibody or antigen-binding fragment thereof that binds to an antigen expressed by the cancer; and b. administering to the patient an ABCG2 inhibitor. 34. The method of claim 33, wherein the ABCG2 inhibitor is selected from the group consisting of fumitremorgin C, Ko143, GF120918, YHO-13351, curcumin, CID44640177, CID1434724, CID46245505, CCT129202, artesunate, ST1481, dihydropyridine, dofequjidar fumarate, gefitinib, imatinib mesylate, lapatinib, WK-X-34 and YHO-13177. 35. The method of claim 33, wherein the ABCG2 inhibitor is selected from the group consisting of fumitremorgin C, Ko143, GF120918 and YHO-13351. 36. The method of claim 33, wherein the ABCG2 inhibitor is YHO-13351. 37. The method of claim 33, wherein the antigen is selected from the group consisting of carbonic anhydrase IX, alpha-fetoprotein (AFP), α-actinin-4, A3, antigen specific for A33 antibody, ART-4, B7, Ba 733, BAGE, BrE3-antigen, CA125, CAMEL, CAP-1, CASP-8/m, CCL19, CCL21, CD1, CD1a, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD66a-e, CD67, CD70, CD70L, CD74, CD79a, CD80, CD83, CD95, CD126, CD132, CD133, CD138, CD147, CD154, CDC27, CDK-4/m, CDKN2A, CTLA-4, CXCR4, CXCR7, CXCL12, HIF-1α, colon-specific antigen-p (CSAp), CEA (CEACAM5), CEACAM6, c-Met, DAM, EGFR, EGFRvIII, EGP-1 (Trop-2), EGP-2, ELF2-M, Ep-CAM, fibroblast growth factor (FGF), Flt-1, Flt-3, folate receptor, G250 antigen, GAGE, gp100, GRO-β, HLA-DR, HM1.24, human chorionic gonadotropin (HCG) and its subunits, HER2/neu, HMGB-1, hypoxia inducible factor (HIF-1), HSP70-2M, HST-2, Ia, IGF-1R, IFN-γ, IFN-α, IFN-β, IFN-λ, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-2, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-23, IL-25, insulin-like growth factor-1 (IGF-1), KC4-antigen, KS-1-antigen, KS1-4, Le-Y, LDR/FUT, macrophage migration inhibitory factor (MIF), MAGE, MAGE-3, MART-1, MART-2, NY-ESO-1, TRAG-3, mCRP, MCP-1, MIP-1A, MIP-1B, MIF, MUC1, MUC2, MUC3, MUC4, MUC5ac, MUC13, MUC16, MUM-1/2, MUM-3, NCA66, NCA95, NCA90, PAM4 antigen, pancreatic cancer mucin, PD-1 receptor, placental growth factor, p53, PLAGL2, prostatic acid phosphatase, PSA, PRAME, PSMA, PlGF, ILGF, ILGF-1R, IL-6, IL-25, RS5, RANTES, T101, SAGE, 5100, survivin, survivin-2B, TAC, TAG-72, tenascin, TRAIL receptors, TNF-α, Tn antigen, Thomson-Friedenreich antigens, tumor necrosis antigens, VEGFR, ED-B fibronectin, WT-1, 17-1A-antigen, complement factors C3, C3a, C3b, C5a, C5, an angiogenesis marker, bcl-2, bcl-6, Kras, and an oncogene marker. 38. The method of claim 33, wherein the antigen is selected from the group consisting of Trop-2, CEACAM-5, CD74, CD22, CD20, MUC-5ac and HLA-DR. 39. The method of claim 33, wherein the antibody is selected from the group consisting of LL1 (anti-CD74), LL2 (anti-CD22), RFB4 (anti-CD22), veltuzumab (hA20, anti-CD20), rituxumab (anti-CD20), obinutuzumab (GA101, anti-CD20), lambrolizumab (anti-PD-1 receptor), nivolumab (anti-PD-1 receptor), ipilimumab (anti-CTLA-4), RS7 (anti-Trop-2), PAM4 (anti-MUC-5ac), KC4 (anti-mucin), MN-14 (anti-CEACAM5), MN-15 (anti-CEACAM6), MN-3 (anti-CEACAM6), Mu-9 (anti-CSAp), Immu 31 (anti-alpha-fetoprotein), R1 (anti-IGF-1R), A19 (anti-CD19), TAG-72 (anti-PSMA), Tn (anti-PSMA), J591 (anti-PSMA), HuJ591 (anti-PSMA), AB-PG1-XG1-026 (anti-PSMA dimer), D2/B (anti-PSMA), G250 (anti-carbonic anhydrase IX), L243 (anti-HLA-DR), alemtuzumab (anti-CD52), bevacizumab (anti-VEGF), cetuximab (anti-EGFR), gemtuzumab (anti-CD33), ibritumomab tiuxetan (anti-CD20), panitumumab (anti-EGFR), tositumomab (anti-CD20), and trastuzumab (anti-ErbB2). 40. The method of claim 33, wherein the antibody is selected from the group consisting of hRS7, hMN-13, hLL1, hLL2, hA20, hPAM4 and hL243. 41. The method of claim 33, wherein the cancer is selected from the group consisting of B-cell lymphoma, B-cell leukemia, Hodgkin's disease, T-cell leukemia, T-cell lymphoma, myeloma, colon cancer, stomach cancer, esophageal cancer, medullary thyroid cancer, kidney cancer, breast cancer, lung cancer, pancreatic cancer, urinary bladder cancer, ovarian cancer, uterine cancer, cervical cancer, testicular cancer, prostate cancer, liver cancer, skin cancer, bone cancer, brain cancer, rectal cancer, and melanoma. 42. The method of claim 41, wherein the B-cell leukemia or B-cell lymphoma is selected from the group consisting of indolent forms of B-cell lymphoma, aggressive forms of B-cell lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, hairy cell leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, Burkitt lymphoma, follicular lymphoma, diffuse B-cell lymphoma, mantle cell lymphoma and multiple myeloma. 43. The method of claim 33, wherein the ADC comprises 6 to 8 molecules of SN-38 conjugated to the antibody or antigen-binding fragment thereof. 44. The method of claim 33, wherein the cancer is metastatic. 45. The method of claim 33, wherein there is a linker between the SN-38 and the antibody. 46. The method of claim 45, wherein the linker is CL2A and the structure of the ADC is MAb-CL2A-SN-38 47. The method of claim 33, wherein the ADC is administered at a dosage of between 8 mg/kg and 12 mg/kg. 48. The method of claim 33, wherein the ADC is administered at a dosage of between 8 mg/kg and 10 mg/kg. 49. The method of claim 33, further comprising administering to the patient at least one other anti-cancer therapy selected from the group consisting of surgery, external radiation, radioimmunotherapy, immunotherapy, chemotherapy, antisense therapy, interference RNA therapy, treatment with a therapeutic agent and gene therapy. | 1,600 |
761 | 14,353,299 | 1,653 | The present invention relates to an anaerobic process for biogas upgrading and hydrogen utilization comprising the use of acidic waste as co-substrate. In this process, H 2 and CO 2 will be converted to CH 4 , which will result in lower CO 2 content in the biogas. The invention relates to both in situ and ex situ methods of biogas upgrading. The invention further relates to a bioreactor comprising hollow fibre membranes. | 1. A method of manufacturing an upgraded biogas, said method comprising the steps of:
a. initiating an anaerobic digestion process in a bioreactor comprising:
i. substrate,
ii. anaerobic inoculum comprising anaerobic hydrogenotrophic methanogenic organisms,
b. feeding the bioreactor with an acidic waste substrate to maintain the pH in the bioreactor between 7 and 8, c. feeding the bioreactor with biomass, d. injecting H2 containing gas into the bioreactor, and e. collecting the upgraded biogas thus produced, thereby manufacturing an upgraded biogas. 2. The method of claim 1, wherein the substrate of step a) i. is biomass. 3. The method of claim 1, wherein the biomass of step a) i. is protein-rich organic waste selected from the group consisting of manure, activated sludge from a wastewater treatment plant and fish processing residues. 4. The method of claim 1, wherein the biomass of step a) i. is manure. 5. The method of claim 1, wherein the acidic waste is a carbohydrate-rich waste selected from the group consisting of whey, stillage and fruit juice from potato processing industries. 6. The method of claim 1, wherein the acidic waste is whey. 7. The method of claim 1, wherein the acidic waste and biomass is fed to the bioreactor once or several times a day. 8. The method of claim 1, wherein the ratio of biomass to acidic waste fed to the reactor is 3 to 2. 9. The method of claim 1, wherein the ratio of biomass to acidic waste is 1 to 1. 10. The method of claim 1, wherein the upgraded biogas has a CH4 content of at least 90%. 11. The method of claim 1, wherein the H2 containing gas consists essentially of H2. 12. (canceled) 13. The method of claim 1, further comprising the steps of:
a. transferring the biogas produced in the bioreactor to a second bioreactor, wherein an anaerobic digestion process has been initiated with:
i. nutrients,
ii. anaerobic inoculum comprising anaerobic hydrogenotrophic methanogenic organisms,
b. feeding the second bioreactor with nutrients, c. injecting H2 containing gas into the second bioreactor, and d. collecting the upgraded biogas thus produced, thereby producing a further upgraded biogas. 14. The method of claim 12, wherein the H2 containing gas is co-injected into the second bioreactor together with the biogas. 15. The method of claim 13, wherein the nutrients are micro and macro nutrients necessary for microbial growth, such as a wastewater solution. 16. The method of claim 13, wherein the CH4 content of the biogas is at least 95%. 17. The method of claim 1, further comprising a step of separating CH4 from the other components of the upgraded biogas produced, thus producing a substantially pure CH4. 18. The method of claim 1, wherein the bioreactor comprises a gas injection system comprising hollow fibres. 19. The method of claim 1, wherein the hydrogenotrophic methanogenic organisms is hydrogenotrophic methanogenic archaea. 20. The method of claim 19, wherein the archaea comprise one or more species selected from the group consisting of Methanobacterium alcaliphilum, Methanobacterium bryantii, Methanobacterium congolense, Methanobacterium defluvii, Methanobacterium espanolae, Methanobacterium formicicum, Methanobacterium ivanovii, Methanobacterium palustre, Methanobacterium thermaggregans, Methanobacterium uliginosum, Methanobrevibacter acididurans, Methanobrevibacter arboriphilicus, Methanobrevibacter gottschalkii, Methanobrevibacter olleyae, Methanobrevibacter ruminantium, Methanobrevibacter smithii, Methanobrevibacter woesei, Methanobrevibacter wolinii, Methanothermobacter marburgensis, Methanothermobacter thermautotrophicum, Methanothermobacter thermoflexus, Methanothermobacter thermophilus, Methanothermobacter wolfeii, Methanothermus sociabilis, Methanocorpusculum bavaricum, Methanocoipusculum parvum, Methanoculleus chikuoensis, Methanoculleus submarinus, Methanogenium frigidum, Methanogenium liminatans, Methanogenium marinum, Methanosarcina acetivorans, Methanosarcina barkeri, Methanosarcina maei, Methanosarcina thermophila, Methanomicrobium mobile, Methanocaldococcus jannaschii, Methanococcus aeolicus, Methanococcus maripaludis, Methanococcus vannielii, Methanococcus voltaei, Methanothermococcus thermolithotrophicus, Methanopyrus kandleri, Methanothermobacter thermautotroiphicus, Methanocaldococcus fervens, Methanocaldococcus indices, Methanocaldococcus infernos, and Methanocaldococcus vulcanius. 21. The method of claim 1, wherein the hydrogenotrophic methanogenic organism is a substantially pure culture of one hydrogenotrophic methanogenic archaea species. 22. (canceled) 23. (canceled) | The present invention relates to an anaerobic process for biogas upgrading and hydrogen utilization comprising the use of acidic waste as co-substrate. In this process, H 2 and CO 2 will be converted to CH 4 , which will result in lower CO 2 content in the biogas. The invention relates to both in situ and ex situ methods of biogas upgrading. The invention further relates to a bioreactor comprising hollow fibre membranes.1. A method of manufacturing an upgraded biogas, said method comprising the steps of:
a. initiating an anaerobic digestion process in a bioreactor comprising:
i. substrate,
ii. anaerobic inoculum comprising anaerobic hydrogenotrophic methanogenic organisms,
b. feeding the bioreactor with an acidic waste substrate to maintain the pH in the bioreactor between 7 and 8, c. feeding the bioreactor with biomass, d. injecting H2 containing gas into the bioreactor, and e. collecting the upgraded biogas thus produced, thereby manufacturing an upgraded biogas. 2. The method of claim 1, wherein the substrate of step a) i. is biomass. 3. The method of claim 1, wherein the biomass of step a) i. is protein-rich organic waste selected from the group consisting of manure, activated sludge from a wastewater treatment plant and fish processing residues. 4. The method of claim 1, wherein the biomass of step a) i. is manure. 5. The method of claim 1, wherein the acidic waste is a carbohydrate-rich waste selected from the group consisting of whey, stillage and fruit juice from potato processing industries. 6. The method of claim 1, wherein the acidic waste is whey. 7. The method of claim 1, wherein the acidic waste and biomass is fed to the bioreactor once or several times a day. 8. The method of claim 1, wherein the ratio of biomass to acidic waste fed to the reactor is 3 to 2. 9. The method of claim 1, wherein the ratio of biomass to acidic waste is 1 to 1. 10. The method of claim 1, wherein the upgraded biogas has a CH4 content of at least 90%. 11. The method of claim 1, wherein the H2 containing gas consists essentially of H2. 12. (canceled) 13. The method of claim 1, further comprising the steps of:
a. transferring the biogas produced in the bioreactor to a second bioreactor, wherein an anaerobic digestion process has been initiated with:
i. nutrients,
ii. anaerobic inoculum comprising anaerobic hydrogenotrophic methanogenic organisms,
b. feeding the second bioreactor with nutrients, c. injecting H2 containing gas into the second bioreactor, and d. collecting the upgraded biogas thus produced, thereby producing a further upgraded biogas. 14. The method of claim 12, wherein the H2 containing gas is co-injected into the second bioreactor together with the biogas. 15. The method of claim 13, wherein the nutrients are micro and macro nutrients necessary for microbial growth, such as a wastewater solution. 16. The method of claim 13, wherein the CH4 content of the biogas is at least 95%. 17. The method of claim 1, further comprising a step of separating CH4 from the other components of the upgraded biogas produced, thus producing a substantially pure CH4. 18. The method of claim 1, wherein the bioreactor comprises a gas injection system comprising hollow fibres. 19. The method of claim 1, wherein the hydrogenotrophic methanogenic organisms is hydrogenotrophic methanogenic archaea. 20. The method of claim 19, wherein the archaea comprise one or more species selected from the group consisting of Methanobacterium alcaliphilum, Methanobacterium bryantii, Methanobacterium congolense, Methanobacterium defluvii, Methanobacterium espanolae, Methanobacterium formicicum, Methanobacterium ivanovii, Methanobacterium palustre, Methanobacterium thermaggregans, Methanobacterium uliginosum, Methanobrevibacter acididurans, Methanobrevibacter arboriphilicus, Methanobrevibacter gottschalkii, Methanobrevibacter olleyae, Methanobrevibacter ruminantium, Methanobrevibacter smithii, Methanobrevibacter woesei, Methanobrevibacter wolinii, Methanothermobacter marburgensis, Methanothermobacter thermautotrophicum, Methanothermobacter thermoflexus, Methanothermobacter thermophilus, Methanothermobacter wolfeii, Methanothermus sociabilis, Methanocorpusculum bavaricum, Methanocoipusculum parvum, Methanoculleus chikuoensis, Methanoculleus submarinus, Methanogenium frigidum, Methanogenium liminatans, Methanogenium marinum, Methanosarcina acetivorans, Methanosarcina barkeri, Methanosarcina maei, Methanosarcina thermophila, Methanomicrobium mobile, Methanocaldococcus jannaschii, Methanococcus aeolicus, Methanococcus maripaludis, Methanococcus vannielii, Methanococcus voltaei, Methanothermococcus thermolithotrophicus, Methanopyrus kandleri, Methanothermobacter thermautotroiphicus, Methanocaldococcus fervens, Methanocaldococcus indices, Methanocaldococcus infernos, and Methanocaldococcus vulcanius. 21. The method of claim 1, wherein the hydrogenotrophic methanogenic organism is a substantially pure culture of one hydrogenotrophic methanogenic archaea species. 22. (canceled) 23. (canceled) | 1,600 |
762 | 13,059,753 | 1,631 | A method of characterizing a population of antibodies to an antigen comprises contacting a sensor surface having the antigen immobilized thereto with a sample containing the antibody population to bind antibodies to the surface, and detecting dissociation of antibodies from the sensor surface during a dissociation phase when sample no longer contacts the surface. Based on the dissociation behaviour, the antibody population is characterized in terms of subpopulations of more and less stable antibodies, respectively. The method may be used to determine the immunogenicity of drug by monitoring the appearance of anti-drug antibodies in a patient over time, and determining any shift in proportions between more stable and less stable antibodies. | 1. A method of characterizing a population of antibodies to an antigen, which comprises providing a sensor surface having the antigen immobilized thereto, contacting the sensor surface with a sample containing the antibody population to bind antibodies to the surface, detecting dissociation of antibodies from the sensor surface during a dissociation phase when sample no longer contacts the surface, wherein the dissociation behaviour of the antibody population is characterized by analyzing a first subpopulation and a second subpopulation of said antibody population, and wherein antibodies in said first subpopulation form a more stable complex with the immobilized antigen than antibodies in said second subpopulation. 2. The method of claim 1, further comprising fitting dissociation phase detection data to a kinetic model which describes simultaneous dissociation from two independent monovalent sites, one with a faster dissociation phase, and one with a slower dissociation phase. 3. The method of claim 2, wherein the kinetic model is a two-component equation:
R=R 1 *e −k d1 (t−t 0 ) +R 2 *e −k d2 (t−t 0 )
where R is the detection response time at time t, R1 and R2 are the response contributions from the sites with the faster and slower dissociation phases, respectively, at the beginning of the dissociation at time t0, and kd1 and kd2 are the dissociation rate constants for the sites with the faster and slower dissociation phases, respectively. 4. The method of claim 3, wherein the dissociation rate constants determined by the fitting are converted to half-lives (t1/2) by the equation:
t
1
2
=
ln
2
k
d
where t1/2 is the time required for the amount of antibody-antigen complex to be reduced to 50% during dissociation. 5. The method of claim 4, wherein the results of the fitting are presented by four parameters: fraction fast, t1/2 fast, fraction slow, t1/2 slow. 6. The method of claim 1, further comprising contacting the sample with sensor surfaces or discrete areas of a sensor surface having different domains of the antigen immobilized thereto. 7. The method of claim 1, further comprising contacting the sample with sensor surfaces or discrete areas of a sensor surface having different densities of immobilized antigen or antigen domains. 8. The method of claim 1, wherein the antigen is a drug. 9. The method of claim 1, wherein the antigen is a vaccine. 10. A method of determining the immunogenicity of drug, comprising monitoring the appearance of anti-drug antibodies in a patient over time by the method of claim 1, and determining any shift in proportions between more stable and less stable antibodies. | A method of characterizing a population of antibodies to an antigen comprises contacting a sensor surface having the antigen immobilized thereto with a sample containing the antibody population to bind antibodies to the surface, and detecting dissociation of antibodies from the sensor surface during a dissociation phase when sample no longer contacts the surface. Based on the dissociation behaviour, the antibody population is characterized in terms of subpopulations of more and less stable antibodies, respectively. The method may be used to determine the immunogenicity of drug by monitoring the appearance of anti-drug antibodies in a patient over time, and determining any shift in proportions between more stable and less stable antibodies.1. A method of characterizing a population of antibodies to an antigen, which comprises providing a sensor surface having the antigen immobilized thereto, contacting the sensor surface with a sample containing the antibody population to bind antibodies to the surface, detecting dissociation of antibodies from the sensor surface during a dissociation phase when sample no longer contacts the surface, wherein the dissociation behaviour of the antibody population is characterized by analyzing a first subpopulation and a second subpopulation of said antibody population, and wherein antibodies in said first subpopulation form a more stable complex with the immobilized antigen than antibodies in said second subpopulation. 2. The method of claim 1, further comprising fitting dissociation phase detection data to a kinetic model which describes simultaneous dissociation from two independent monovalent sites, one with a faster dissociation phase, and one with a slower dissociation phase. 3. The method of claim 2, wherein the kinetic model is a two-component equation:
R=R 1 *e −k d1 (t−t 0 ) +R 2 *e −k d2 (t−t 0 )
where R is the detection response time at time t, R1 and R2 are the response contributions from the sites with the faster and slower dissociation phases, respectively, at the beginning of the dissociation at time t0, and kd1 and kd2 are the dissociation rate constants for the sites with the faster and slower dissociation phases, respectively. 4. The method of claim 3, wherein the dissociation rate constants determined by the fitting are converted to half-lives (t1/2) by the equation:
t
1
2
=
ln
2
k
d
where t1/2 is the time required for the amount of antibody-antigen complex to be reduced to 50% during dissociation. 5. The method of claim 4, wherein the results of the fitting are presented by four parameters: fraction fast, t1/2 fast, fraction slow, t1/2 slow. 6. The method of claim 1, further comprising contacting the sample with sensor surfaces or discrete areas of a sensor surface having different domains of the antigen immobilized thereto. 7. The method of claim 1, further comprising contacting the sample with sensor surfaces or discrete areas of a sensor surface having different densities of immobilized antigen or antigen domains. 8. The method of claim 1, wherein the antigen is a drug. 9. The method of claim 1, wherein the antigen is a vaccine. 10. A method of determining the immunogenicity of drug, comprising monitoring the appearance of anti-drug antibodies in a patient over time by the method of claim 1, and determining any shift in proportions between more stable and less stable antibodies. | 1,600 |
763 | 14,917,643 | 1,648 | A method for measuring influenza B virus by an immunoassay, which method enables specific detection of influenza B virus with a higher sensitivity than conventional methods, and a device or a kit therefor are disclosed. The method for measuring influenza B virus includes carrying out an immunoassay of influenza B virus by a sandwich method using two kinds of monoclonal antibodies each of which specifically reacts with the region of the 125th to 248th amino acids of matrix protein (M1) of influenza B virus, which two kinds of monoclonal antibodies are capable of binding to the region of the 125th to 248th amino acids of M1 at the same time, or antigen-binding fragments thereof. | 1. A method for measuring influenza B virus, said method comprising carrying out an immunoassay of influenza B virus by a sandwich method using two kinds of monoclonal antibodies each of which specifically reacts with the region of the 125th to 248th amino acids of matrix protein (M1) of influenza B virus, said two kinds of monoclonal antibodies being capable of binding to the region of the 125th to 248th amino acids of M1 at the same time, or antigen-binding fragments thereof. 2. The method according to claim 1, wherein said sandwich method is immunochromatography. 3. The method according to claim 1, wherein said sandwich method is an ELISA method. 4. An immunoassay device or a kit for measuring influenza B virus, comprising two kinds of monoclonal antibodies each of which specifically reacts with the region of the 125th to 248th amino acids of matrix protein (M1) of influenza B virus, said two kinds of monoclonal antibodies being capable of binding to the region of the 125th to 248th amino acids of M1 at the same time, or antigen-binding fragments thereof. 5. An immunochromatographic immunoassay device comprising: a detection area in which a first antibody as one of said monoclonal antibodies, or an antigen-binding fragment thereof, is immobilized on a support; a label area in which a second antibody as the other monoclonal antibody, or an antigen-binding fragment thereof, is supplied together with a sample; and a sample movement area. 6. The immunoassay device or the kit for measuring influenza B virus according to claim 4, comprising: a support on which a first antibody as one of said monoclonal antibodies, or an antigen-binding fragment thereof, is immobilized; and a second antibody as the other monoclonal antibody, or an antigen-binding fragment thereof. | A method for measuring influenza B virus by an immunoassay, which method enables specific detection of influenza B virus with a higher sensitivity than conventional methods, and a device or a kit therefor are disclosed. The method for measuring influenza B virus includes carrying out an immunoassay of influenza B virus by a sandwich method using two kinds of monoclonal antibodies each of which specifically reacts with the region of the 125th to 248th amino acids of matrix protein (M1) of influenza B virus, which two kinds of monoclonal antibodies are capable of binding to the region of the 125th to 248th amino acids of M1 at the same time, or antigen-binding fragments thereof.1. A method for measuring influenza B virus, said method comprising carrying out an immunoassay of influenza B virus by a sandwich method using two kinds of monoclonal antibodies each of which specifically reacts with the region of the 125th to 248th amino acids of matrix protein (M1) of influenza B virus, said two kinds of monoclonal antibodies being capable of binding to the region of the 125th to 248th amino acids of M1 at the same time, or antigen-binding fragments thereof. 2. The method according to claim 1, wherein said sandwich method is immunochromatography. 3. The method according to claim 1, wherein said sandwich method is an ELISA method. 4. An immunoassay device or a kit for measuring influenza B virus, comprising two kinds of monoclonal antibodies each of which specifically reacts with the region of the 125th to 248th amino acids of matrix protein (M1) of influenza B virus, said two kinds of monoclonal antibodies being capable of binding to the region of the 125th to 248th amino acids of M1 at the same time, or antigen-binding fragments thereof. 5. An immunochromatographic immunoassay device comprising: a detection area in which a first antibody as one of said monoclonal antibodies, or an antigen-binding fragment thereof, is immobilized on a support; a label area in which a second antibody as the other monoclonal antibody, or an antigen-binding fragment thereof, is supplied together with a sample; and a sample movement area. 6. The immunoassay device or the kit for measuring influenza B virus according to claim 4, comprising: a support on which a first antibody as one of said monoclonal antibodies, or an antigen-binding fragment thereof, is immobilized; and a second antibody as the other monoclonal antibody, or an antigen-binding fragment thereof. | 1,600 |
764 | 14,855,355 | 1,618 | Compositions, formulations and kits comprising chlorotoxin conjugate compounds are provided, including native and modified variants of chlorotoxin peptide conjugated to reporter molecules including fluorescent dyes. Methods of detecting and treating cancers and tumors with chlorotoxin conjugate compounds are also provided, including methods of imaging tumor tissues and cells. Dosing and pharmacokinetic profiles for therapeutic and diagnostic applications using chlorotoxin conjugate compounds are also provided. | 1. A compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof:
wherein:
R1, R2, R3, R4, R5, R6, R7, R8, R15, and R16 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkylene-COOH, sulfonate, —COOH, —SO2—NH2, or C1-C6 alkoxy;
R9 is hydrogen, sulfonate, or —COOH;
L1 is C3-C6 alkylene;
L2 is C1-C10 alkylene;
L3 is a bond, —O—, —NR10—, —NR10—C1-C6 alkylene-, —O—NR10—, —NR10—C1-C6 alkylene-(O—C1-C6 alkylene)n-, —NR10-L4-, —NR10—C1-C6 alkylene-NR11—(C(═O)—C1-C6 alkylene-O—)m—, or —NR10—C1-C6 alkylene-NR10—C1-C6 alkylene-NR10—C1-C6 alkylene-;
L4 is a bond, -heterocyclyl-, or -heterocyclyl-C1-C6 alkylene-;
R10 is hydrogen or C1-C6 alkyl;
R11 is hydrogen or C1-C6 alkyl;
R12 and R13 are independently selected from hydrogen, C1-C6 alkyl, or R12 and R13 are joined together along with the other atoms to which they are attached to form a 5-membered or 6-membered carbocyclic or heterocyclic ring;
R14 is hydrogen or C1-C6 alkylene, -(L5)-aryl, -(L5)-heteroaryl, —NR17R18, R14 and R19 are joined together along with the other atoms to which they are attached to form a 5-membered or 6-membered carbocyclic or heterocyclic ring, or R14 and R20 are joined together along with the other atoms to which they are attached to form a 5-membered or 6-membered carbocyclic or heterocyclic ring;
L5 is a bond, C1-C10 alkylene, —O—, —NR10—;
R17 and R18 are each independently hydrogen or aryl;
R19 and R20 are independently selected from hydrogen, C1-C6 alkyl, R14 and R19 are joined together along with the other atoms to which they are attached to form a 5-membered or 6-membered carbocyclic or heterocyclic ring, or R14 and R20 are joined together along with the other atoms to which they are attached to form a 5-membered or 6-membered carbocyclic or heterocyclic ring;
n is 0, 1, 2, or 3;
m is 0, 1, 2, or 3;
p is 0, 1, 2, or 3;
q is 0, 1, 2, or 3; and
A4 is a polypeptide having at least 90% sequence identity with MCMPCFTTDHQMARRCDDCCGGRGRGKCYGPQCLCR (SEQ ID NO: 9) or a fragment thereof. 2. The compound of claim 1, wherein:
R3, R4, R5, R6 are each independently methyl; R1, R2, R7, R8, R15, and R16 are each independently hydrogen; R9 is sulfonate; R10 is hydrogen; and R12, R13, R14, R19, and R20 are each independently hydrogen. 3. The compound of claim 1, wherein:
L1 is butylene; and L2 is pentylene. 4. The compound of claim 1 having the structure of any one of Formulas (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV): 5. The compound of claim 1, wherein the polypeptide comprises an isoelectric point of greater than 7.5 and three or four disulfide bonds. 6. The compound of claim 1, wherein the polypeptide contains no lysine amino acid residues. 7. The compound of claim 1, wherein the fragment of A4 has a length of at least 25 amino acid residues. 8. The compound of claim 1, wherein one or more methionine residues of the polypeptide are replaced with other amino acid residues. 9. The compound of claim 1, wherein the polypeptide comprises a lysine residue at the position corresponding to K-27 of native chlorotoxin, K-23 of native chlorotoxin, K-15 of native chlorotoxin, or a combination thereof. 10. The compound of claim 1, wherein L3 is attached to A4 at a lysine amino acid residue of the polypeptide. 11. The compound of claim 1, wherein the compound is conjugated to polyethylene glycol (PEG), hydroxyethyl starch, polyvinyl alcohol, a water soluble polymer, a zwitterionic water soluble polymer, a water soluble poly(amino acid), an albumin derivative, or a fatty acid. 12. The compound of claim 1, further comprising a therapeutic agent attached to A4. 13. The compound of claim 12, wherein the therapeutic agent is selected from a radioisotope, toxin, cytotoxic agent, enzyme, sensitizing drug, nucleic acid, interfering RNA, antibody, anti-angiogenic agent, cisplatin, anti-metabolite, mitotic inhibitor, growth factor inhibitor, paclitaxel, temozolomide, topotecan, fluorouracil, vincristine, vinblastine, procarbazine, dacarbazine, altretamine, methotrexate, mercaptopurine, thioguanine, fludarabine phosphate, cladribine, pentostatin, cytarabine, azacitidine, etoposide, teniposide, irinotecan, docetaxel, doxorubicin, daunorubicin, dactinomycin, idarubicin, plicamycin, mitomycin, bleomycin, tamoxifen, flutamide, leuprolide, goserelin, aminogluthimide, anastrozole, amsacrine, asparaginase, mitoxantrone, mitotane, amifostine or a combination thereof. 14. A method of treating a subject in need thereof, the method comprising administering to the subject the compound of claim 12 in an amount sufficient to treat cancer in the subject. 15. The method of claim 14, wherein the cancer is selected from glioma, astrocytoma, medulloblastoma, choroids plexus carcinoma, ependymoma, neuroblastoma, basal cell carcinoma, cutaneous squamous cell carcinoma, head and neck cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, intestinal cancer, pancreatic cancer, liver cancer, kidney cancer, sarcoma, osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma, gastrointestinal stromal tumors, melanoma, ovarian cancer, cervical cancer, lymphoma, thyroid cancer, anal cancer, colo-rectal cancer, endometrial cancer, laryngeal cancer, multiple myeloma, prostate cancer, retinoblastoma, gastric cancer, testicular cancer, or Wilm's tumor. 16. The method of claim 14, wherein the therapeutic agent is selected from a radioisotope, toxin, cytotoxic agent, enzyme, sensitizing drug, nucleic acid, interfering RNA, antibody, anti-angiogenic agent, cisplatin, anti-metabolite, mitotic inhibitor, growth factor inhibitor, paclitaxel, temozolomide, topotecan, fluorouracil, vincristine, vinblastine, procarbazine, dacarbazine, altretamine, methotrexate, mercaptopurine, thioguanine, fludarabine phosphate, cladribine, pentostatin, cytarabine, azacitidine, etoposide, teniposide, irinotecan, docetaxel, doxorubicin, daunorubicin, dactinomycin, idarubicin, plicamycin, mitomycin, bleomycin, tamoxifen, flutamide, leuprolide, goserelin, aminogluthimide, anastrozole, amsacrine, asparaginase, mitoxantrone, mitotane, amifostine or a combination thereof. 17. A method for detecting a cancerous tissue or cancer cell in a subject, the method comprising:
administering to the subject the compound of claim 1; and detecting the presence or absence of the compound in a tissue or cell, wherein the presence of the compound in the tissue or cell indicates the presence of a cancerous tissue or cancer cell. 18. The method of claim 17, wherein the detecting comprises visualizing. 19. The method of claim 17, wherein the detecting comprises ex vivo imaging. 20. The method of claim 17, further comprising surgically removing from the subject a cancerous tissue or cancer cell that is detected. 21. A method of administering the compound of claim 1 to a subject, the method comprising administering a therapeutically effective amount of the compound to the subject. 22. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. 23. The composition of claim 22, wherein the composition is formulated for intravenous administration, intravenous bolus administration, intravenous infusion administration, intramuscular administration, subcutaneous administration, intraperitoneal administration, oral administration, topical administration, transdermal administration, intralesional administration, or a combination thereof. 24. The composition of claim 22, wherein the composition comprises a pH from 6 to 7.5. 25. The composition of claim 22, wherein the ionic strength of the composition is less than 50 mM. 26. The composition of claim 22, further comprising a buffer, wherein the buffer is selected from histidine, tris, HEPES, ethylene diamine, or a combination thereof. 27. The composition of claim 22, further comprising a sugar alcohol. 28. The composition of claim 22, further comprising 10 mM to 100 mM histidine, 2% to 10% (wt/vol %) mannitol, and a pH from 6 to 7.5. 29. The composition of claim 22, wherein the composition is stored as a lyophilized solid. 30. A method of administering a composition to a human subject, the method comprising:
intravenously administering to the human subject a dose of from 1 mg to 30 mg of a compound comprising a polypeptide having at least 90% sequence identity with MCMPCFTTDHQMARRCDDCCGGRGRGKCYGPQCLCR (SEQ ID NO: 9) or a fragment thereof; and producing in the human subject an average maximum compound blood plasma concentration (average Cmax) of at least from 110 ng/mL to 240 ng/mL per each 1 mg dosage of the compound administered. | Compositions, formulations and kits comprising chlorotoxin conjugate compounds are provided, including native and modified variants of chlorotoxin peptide conjugated to reporter molecules including fluorescent dyes. Methods of detecting and treating cancers and tumors with chlorotoxin conjugate compounds are also provided, including methods of imaging tumor tissues and cells. Dosing and pharmacokinetic profiles for therapeutic and diagnostic applications using chlorotoxin conjugate compounds are also provided.1. A compound having the structure of Formula (III), or a pharmaceutically acceptable salt thereof:
wherein:
R1, R2, R3, R4, R5, R6, R7, R8, R15, and R16 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkylene-COOH, sulfonate, —COOH, —SO2—NH2, or C1-C6 alkoxy;
R9 is hydrogen, sulfonate, or —COOH;
L1 is C3-C6 alkylene;
L2 is C1-C10 alkylene;
L3 is a bond, —O—, —NR10—, —NR10—C1-C6 alkylene-, —O—NR10—, —NR10—C1-C6 alkylene-(O—C1-C6 alkylene)n-, —NR10-L4-, —NR10—C1-C6 alkylene-NR11—(C(═O)—C1-C6 alkylene-O—)m—, or —NR10—C1-C6 alkylene-NR10—C1-C6 alkylene-NR10—C1-C6 alkylene-;
L4 is a bond, -heterocyclyl-, or -heterocyclyl-C1-C6 alkylene-;
R10 is hydrogen or C1-C6 alkyl;
R11 is hydrogen or C1-C6 alkyl;
R12 and R13 are independently selected from hydrogen, C1-C6 alkyl, or R12 and R13 are joined together along with the other atoms to which they are attached to form a 5-membered or 6-membered carbocyclic or heterocyclic ring;
R14 is hydrogen or C1-C6 alkylene, -(L5)-aryl, -(L5)-heteroaryl, —NR17R18, R14 and R19 are joined together along with the other atoms to which they are attached to form a 5-membered or 6-membered carbocyclic or heterocyclic ring, or R14 and R20 are joined together along with the other atoms to which they are attached to form a 5-membered or 6-membered carbocyclic or heterocyclic ring;
L5 is a bond, C1-C10 alkylene, —O—, —NR10—;
R17 and R18 are each independently hydrogen or aryl;
R19 and R20 are independently selected from hydrogen, C1-C6 alkyl, R14 and R19 are joined together along with the other atoms to which they are attached to form a 5-membered or 6-membered carbocyclic or heterocyclic ring, or R14 and R20 are joined together along with the other atoms to which they are attached to form a 5-membered or 6-membered carbocyclic or heterocyclic ring;
n is 0, 1, 2, or 3;
m is 0, 1, 2, or 3;
p is 0, 1, 2, or 3;
q is 0, 1, 2, or 3; and
A4 is a polypeptide having at least 90% sequence identity with MCMPCFTTDHQMARRCDDCCGGRGRGKCYGPQCLCR (SEQ ID NO: 9) or a fragment thereof. 2. The compound of claim 1, wherein:
R3, R4, R5, R6 are each independently methyl; R1, R2, R7, R8, R15, and R16 are each independently hydrogen; R9 is sulfonate; R10 is hydrogen; and R12, R13, R14, R19, and R20 are each independently hydrogen. 3. The compound of claim 1, wherein:
L1 is butylene; and L2 is pentylene. 4. The compound of claim 1 having the structure of any one of Formulas (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV): 5. The compound of claim 1, wherein the polypeptide comprises an isoelectric point of greater than 7.5 and three or four disulfide bonds. 6. The compound of claim 1, wherein the polypeptide contains no lysine amino acid residues. 7. The compound of claim 1, wherein the fragment of A4 has a length of at least 25 amino acid residues. 8. The compound of claim 1, wherein one or more methionine residues of the polypeptide are replaced with other amino acid residues. 9. The compound of claim 1, wherein the polypeptide comprises a lysine residue at the position corresponding to K-27 of native chlorotoxin, K-23 of native chlorotoxin, K-15 of native chlorotoxin, or a combination thereof. 10. The compound of claim 1, wherein L3 is attached to A4 at a lysine amino acid residue of the polypeptide. 11. The compound of claim 1, wherein the compound is conjugated to polyethylene glycol (PEG), hydroxyethyl starch, polyvinyl alcohol, a water soluble polymer, a zwitterionic water soluble polymer, a water soluble poly(amino acid), an albumin derivative, or a fatty acid. 12. The compound of claim 1, further comprising a therapeutic agent attached to A4. 13. The compound of claim 12, wherein the therapeutic agent is selected from a radioisotope, toxin, cytotoxic agent, enzyme, sensitizing drug, nucleic acid, interfering RNA, antibody, anti-angiogenic agent, cisplatin, anti-metabolite, mitotic inhibitor, growth factor inhibitor, paclitaxel, temozolomide, topotecan, fluorouracil, vincristine, vinblastine, procarbazine, dacarbazine, altretamine, methotrexate, mercaptopurine, thioguanine, fludarabine phosphate, cladribine, pentostatin, cytarabine, azacitidine, etoposide, teniposide, irinotecan, docetaxel, doxorubicin, daunorubicin, dactinomycin, idarubicin, plicamycin, mitomycin, bleomycin, tamoxifen, flutamide, leuprolide, goserelin, aminogluthimide, anastrozole, amsacrine, asparaginase, mitoxantrone, mitotane, amifostine or a combination thereof. 14. A method of treating a subject in need thereof, the method comprising administering to the subject the compound of claim 12 in an amount sufficient to treat cancer in the subject. 15. The method of claim 14, wherein the cancer is selected from glioma, astrocytoma, medulloblastoma, choroids plexus carcinoma, ependymoma, neuroblastoma, basal cell carcinoma, cutaneous squamous cell carcinoma, head and neck cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, intestinal cancer, pancreatic cancer, liver cancer, kidney cancer, sarcoma, osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma, gastrointestinal stromal tumors, melanoma, ovarian cancer, cervical cancer, lymphoma, thyroid cancer, anal cancer, colo-rectal cancer, endometrial cancer, laryngeal cancer, multiple myeloma, prostate cancer, retinoblastoma, gastric cancer, testicular cancer, or Wilm's tumor. 16. The method of claim 14, wherein the therapeutic agent is selected from a radioisotope, toxin, cytotoxic agent, enzyme, sensitizing drug, nucleic acid, interfering RNA, antibody, anti-angiogenic agent, cisplatin, anti-metabolite, mitotic inhibitor, growth factor inhibitor, paclitaxel, temozolomide, topotecan, fluorouracil, vincristine, vinblastine, procarbazine, dacarbazine, altretamine, methotrexate, mercaptopurine, thioguanine, fludarabine phosphate, cladribine, pentostatin, cytarabine, azacitidine, etoposide, teniposide, irinotecan, docetaxel, doxorubicin, daunorubicin, dactinomycin, idarubicin, plicamycin, mitomycin, bleomycin, tamoxifen, flutamide, leuprolide, goserelin, aminogluthimide, anastrozole, amsacrine, asparaginase, mitoxantrone, mitotane, amifostine or a combination thereof. 17. A method for detecting a cancerous tissue or cancer cell in a subject, the method comprising:
administering to the subject the compound of claim 1; and detecting the presence or absence of the compound in a tissue or cell, wherein the presence of the compound in the tissue or cell indicates the presence of a cancerous tissue or cancer cell. 18. The method of claim 17, wherein the detecting comprises visualizing. 19. The method of claim 17, wherein the detecting comprises ex vivo imaging. 20. The method of claim 17, further comprising surgically removing from the subject a cancerous tissue or cancer cell that is detected. 21. A method of administering the compound of claim 1 to a subject, the method comprising administering a therapeutically effective amount of the compound to the subject. 22. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. 23. The composition of claim 22, wherein the composition is formulated for intravenous administration, intravenous bolus administration, intravenous infusion administration, intramuscular administration, subcutaneous administration, intraperitoneal administration, oral administration, topical administration, transdermal administration, intralesional administration, or a combination thereof. 24. The composition of claim 22, wherein the composition comprises a pH from 6 to 7.5. 25. The composition of claim 22, wherein the ionic strength of the composition is less than 50 mM. 26. The composition of claim 22, further comprising a buffer, wherein the buffer is selected from histidine, tris, HEPES, ethylene diamine, or a combination thereof. 27. The composition of claim 22, further comprising a sugar alcohol. 28. The composition of claim 22, further comprising 10 mM to 100 mM histidine, 2% to 10% (wt/vol %) mannitol, and a pH from 6 to 7.5. 29. The composition of claim 22, wherein the composition is stored as a lyophilized solid. 30. A method of administering a composition to a human subject, the method comprising:
intravenously administering to the human subject a dose of from 1 mg to 30 mg of a compound comprising a polypeptide having at least 90% sequence identity with MCMPCFTTDHQMARRCDDCCGGRGRGKCYGPQCLCR (SEQ ID NO: 9) or a fragment thereof; and producing in the human subject an average maximum compound blood plasma concentration (average Cmax) of at least from 110 ng/mL to 240 ng/mL per each 1 mg dosage of the compound administered. | 1,600 |
765 | 14,271,021 | 1,658 | A hair care composition having from about from about 0.025% to about 0.25% by weight of the composition of histidine. The hair care composition further includes a gel matrix phase. The gel matrix has from about 0.1% to about 20% of one or more high melting point fatty compounds, from about 0.1% to about 10% of a C22 cationic surfactant system, and at least about 20% of an aqueous carrier, by weight of said hair care composition. The present invention may further comprise a deposition polymer. | 1. A hair care composition comprising:
a. from about 0.025% to about 0.25% by weight of the composition of histidine; b. a gel matrix comprising:
i. from about 0.1% to about 20% of one or more high melting point fatty compounds, by weight of said hair care composition;
ii. from about 0.1% to about 10% a cationic surfactant system comprising cationic surfactant having single straight alkyl chain with 22 carbon atoms, by weight of said hair care composition; and
iii. at least about 20% of an aqueous carrier, by weight of said hair care composition. 2. The hair care composition of claim 1, wherein said hair care composition comprises from about 0.05% to about 0.25% of said histidine, by weight of said hair care composition. 3. The hair care composition of claim 1, wherein said hair care composition comprises from about 0.08% to about 0.15% of said histidine, by weight of said hair care composition. 4. The hair care composition of claim 1, wherein said hair care composition comprises from about 0.10% to about 0.15% of said histidine, by weight of said hair care composition. 5. The hair care composition of claim 1, wherein said hair care composition further comprises one or more additional conditioning agents. 6. The hair care composition of claim 8, wherein said one or more additional conditioning agents is a silicone. 7. The hair care composition of claim 1, wherein said hair care composition further comprises one or more additional benefit agents. 8. The hair care composition of claim 11, wherein said one or more additional benefit agents is selected from the group consisting of anti-dandruff agents, vitamins, chelants, perfumes, brighteners, enzymes, sensates, attractants, anti-bacterial agents, dyes, pigments, bleaches, and mixtures thereof. 9. A method for conditioning hair comprising the step of applying an effective amount of the hair care composition of claim 1 to the hair. 10. The hair care composition of claim 1, further comprising from about 0.01% to about 0.5% by weight of citric acid. | A hair care composition having from about from about 0.025% to about 0.25% by weight of the composition of histidine. The hair care composition further includes a gel matrix phase. The gel matrix has from about 0.1% to about 20% of one or more high melting point fatty compounds, from about 0.1% to about 10% of a C22 cationic surfactant system, and at least about 20% of an aqueous carrier, by weight of said hair care composition. The present invention may further comprise a deposition polymer.1. A hair care composition comprising:
a. from about 0.025% to about 0.25% by weight of the composition of histidine; b. a gel matrix comprising:
i. from about 0.1% to about 20% of one or more high melting point fatty compounds, by weight of said hair care composition;
ii. from about 0.1% to about 10% a cationic surfactant system comprising cationic surfactant having single straight alkyl chain with 22 carbon atoms, by weight of said hair care composition; and
iii. at least about 20% of an aqueous carrier, by weight of said hair care composition. 2. The hair care composition of claim 1, wherein said hair care composition comprises from about 0.05% to about 0.25% of said histidine, by weight of said hair care composition. 3. The hair care composition of claim 1, wherein said hair care composition comprises from about 0.08% to about 0.15% of said histidine, by weight of said hair care composition. 4. The hair care composition of claim 1, wherein said hair care composition comprises from about 0.10% to about 0.15% of said histidine, by weight of said hair care composition. 5. The hair care composition of claim 1, wherein said hair care composition further comprises one or more additional conditioning agents. 6. The hair care composition of claim 8, wherein said one or more additional conditioning agents is a silicone. 7. The hair care composition of claim 1, wherein said hair care composition further comprises one or more additional benefit agents. 8. The hair care composition of claim 11, wherein said one or more additional benefit agents is selected from the group consisting of anti-dandruff agents, vitamins, chelants, perfumes, brighteners, enzymes, sensates, attractants, anti-bacterial agents, dyes, pigments, bleaches, and mixtures thereof. 9. A method for conditioning hair comprising the step of applying an effective amount of the hair care composition of claim 1 to the hair. 10. The hair care composition of claim 1, further comprising from about 0.01% to about 0.5% by weight of citric acid. | 1,600 |
766 | 15,567,496 | 1,642 | An object of the present invention is to identify a cancer antigen protein specifically expressed on the surface of cancer cells and provide use of an antibody targeting the cancer antigen protein as a therapeutic and/or prophylactic agent for cancer. A pharmaceutical composition for treating and/or preventing cancer comprising an antibody or a fragment thereof having immunological reactivity with CSPG5 protein consisting of any one of amino acid sequences represented by SEQ ID NOs: 8, 4, 6, 10, and 12 and an amino acid sequence having an amino acid identity of 80% or more to the amino acid sequence, or a fragment thereof consisting of 7 or more consecutive amino acids, as an active ingredient. | 1. A pharmaceutical composition for treating and/or preventing cancer, comprising an antibody or a fragment thereof having immunological reactivity with CSPG5 protein or a fragment thereof consisting of at least 7 or more consecutive amino acid residues, as an active ingredient. 2. The pharmaceutical composition according to claim 1, wherein the CSPG5 protein consists of
any one of amino acid sequences represented by SEQ ID NOs: 8, 4, 6, 10 and 12, or an amino acid sequence having an amino acid identity of 80% or more to the amino acid sequence. 3. The pharmaceutical composition according to claim 1, wherein the cancer is leukemia or malignant lymphoma. 4. The pharmaceutical composition according to claim 1, wherein the antibody is a monoclonal antibody or a polyclonal antibody. 5. The pharmaceutical composition according to claim 1, wherein the antibody is a human antibody, a humanized antibody, a chimeric antibody, a single-chain antibody or a bispecific antibody. | An object of the present invention is to identify a cancer antigen protein specifically expressed on the surface of cancer cells and provide use of an antibody targeting the cancer antigen protein as a therapeutic and/or prophylactic agent for cancer. A pharmaceutical composition for treating and/or preventing cancer comprising an antibody or a fragment thereof having immunological reactivity with CSPG5 protein consisting of any one of amino acid sequences represented by SEQ ID NOs: 8, 4, 6, 10, and 12 and an amino acid sequence having an amino acid identity of 80% or more to the amino acid sequence, or a fragment thereof consisting of 7 or more consecutive amino acids, as an active ingredient.1. A pharmaceutical composition for treating and/or preventing cancer, comprising an antibody or a fragment thereof having immunological reactivity with CSPG5 protein or a fragment thereof consisting of at least 7 or more consecutive amino acid residues, as an active ingredient. 2. The pharmaceutical composition according to claim 1, wherein the CSPG5 protein consists of
any one of amino acid sequences represented by SEQ ID NOs: 8, 4, 6, 10 and 12, or an amino acid sequence having an amino acid identity of 80% or more to the amino acid sequence. 3. The pharmaceutical composition according to claim 1, wherein the cancer is leukemia or malignant lymphoma. 4. The pharmaceutical composition according to claim 1, wherein the antibody is a monoclonal antibody or a polyclonal antibody. 5. The pharmaceutical composition according to claim 1, wherein the antibody is a human antibody, a humanized antibody, a chimeric antibody, a single-chain antibody or a bispecific antibody. | 1,600 |
767 | 14,171,766 | 1,639 | System, including methods and apparatus, for spacing droplets from each other and for detection of spaced droplets. | 1. A particle singulator, comprising
a particle channel including a particle inlet configured to receive particles suspended in a carrier fluid; a shell surrounding at least a portion of the particle channel; and a plurality of dilution channels formed within the shell and configured to transport dilution fluid to the particle channel at a controlled rate. 2. The particle singulator of claim 1, further comprising a dilution fluid input channel formed in the shell and configured to receive dilution fluid from a dilution fluid source disposed outside the shell. 3. The particle singulator of claim 1, wherein the shell is cylindrical, further comprising a cylindrical frit disposed within the shell, the frit having porous walls and a central bore defining the portion of the droplet channel surrounded by the shell, and wherein the dilution channels are formed by the porous walls of the frit. 4. The particle singulator of claim 1, further comprising a porous inner cylinder disposed within the shell, the porous inner cylinder having porous walls forming the dilution channels and a central bore defining the portion of the particle channel surrounded by the shell. 5. The particle singulator of claim 4, wherein the inner cylinder is a capillary. 6. The particle singulator of claim 4, wherein the inner cylinder is a filter. 7. The particle singulator of claim 1, further comprising an inner filter disposed within the shell, the inner filter having a central bore defining the portion of the particle channel surrounded by the shell and a plurality of radial pathways extending between the central bore and an outer surface of the inner filter, and wherein the dilution channels are formed by the radial pathways. 8. The droplet singulator of claim 1, wherein the particle singulator is modular, wherein a first module of the particle singulator includes the shell, and wherein a second module of the particle singulator includes a microfluidic “T” fitting into which the shell is disposed. 9. A detection system for droplet-based assays, comprising
a droplet channel including a droplet inlet; a droplet input tip configured to inject droplets suspended in a carrier fluid into the droplet inlet and to cause the suspended droplets to move through the droplet channel; a shell surrounding a portion of the droplet channel; a plurality of dilution channels formed inside the shell and configured to transport dilution fluid into the droplet channel at a controlled rate such that an average distance between droplets disposed within the droplet channel is increased; a detection region disposed downstream from the dilution fluid input channel; and a detector configured to detect fluorescence radiation emitted by droplets passing through the detection region. 10. The system of claim 9, further comprising a dilution fluid input channel formed in the shell and configured to receive dilution fluid from a source disposed outside the shell. 11. The system of claim 9, further comprising a porous inner cylinder disposed within the shell, the porous inner cylinder having porous walls forming the dilution channels and a central bore defining a dilution region of the droplet channel. 12. The system of claim 11, wherein the inner cylinder includes a frit. 13. The system of claim 11, wherein the inner cylinder includes a capillary. 14. The system of claim 11, wherein the inner cylinder includes a filter. 15. The system of claim 9, further comprising an inner filter disposed within the shell, the inner filter having a plurality of radial bores forming the dilution channels and a central bore defining a dilution region of the droplet channel. 16. The system of claim 9, wherein the shell is configured to interface with a standard microfluidic “T” fitting. 17. A method of detecting radiation emitted by droplets in a droplet-based assay, the method comprising:
transporting droplets of a sample fluid suspended in a carrier fluid into a droplet channel; transporting the droplets through the droplet channel; transporting dilution fluid into a shell surrounding the droplet channel; transporting the dilution fluid from the shell into the droplet channel at a controlled rate through a plurality of dilution channels formed inside the shell, such that an average distance between droplets disposed within the droplet channel is increased; transporting the droplets to a detection region; and detecting fluorescence radiation emitted by droplets passing through the detection region. 18. The method of claim 17, wherein transporting the dilution fluid through a plurality of dilution channels into the droplet channel includes transporting the dilution fluid through porous walls of a frit disposed within the shell. 19. The method of claim 17, wherein transporting the dilution fluid through a plurality of dilution channels includes transporting the dilution fluid through porous walls of a capillary disposed within the shell. 20. The method of claim 17, wherein transporting the dilution fluid through a plurality of dilution channels includes transporting the dilution fluid through a plurality of radial bores formed in an inner cylinder disposed within the shell. | System, including methods and apparatus, for spacing droplets from each other and for detection of spaced droplets.1. A particle singulator, comprising
a particle channel including a particle inlet configured to receive particles suspended in a carrier fluid; a shell surrounding at least a portion of the particle channel; and a plurality of dilution channels formed within the shell and configured to transport dilution fluid to the particle channel at a controlled rate. 2. The particle singulator of claim 1, further comprising a dilution fluid input channel formed in the shell and configured to receive dilution fluid from a dilution fluid source disposed outside the shell. 3. The particle singulator of claim 1, wherein the shell is cylindrical, further comprising a cylindrical frit disposed within the shell, the frit having porous walls and a central bore defining the portion of the droplet channel surrounded by the shell, and wherein the dilution channels are formed by the porous walls of the frit. 4. The particle singulator of claim 1, further comprising a porous inner cylinder disposed within the shell, the porous inner cylinder having porous walls forming the dilution channels and a central bore defining the portion of the particle channel surrounded by the shell. 5. The particle singulator of claim 4, wherein the inner cylinder is a capillary. 6. The particle singulator of claim 4, wherein the inner cylinder is a filter. 7. The particle singulator of claim 1, further comprising an inner filter disposed within the shell, the inner filter having a central bore defining the portion of the particle channel surrounded by the shell and a plurality of radial pathways extending between the central bore and an outer surface of the inner filter, and wherein the dilution channels are formed by the radial pathways. 8. The droplet singulator of claim 1, wherein the particle singulator is modular, wherein a first module of the particle singulator includes the shell, and wherein a second module of the particle singulator includes a microfluidic “T” fitting into which the shell is disposed. 9. A detection system for droplet-based assays, comprising
a droplet channel including a droplet inlet; a droplet input tip configured to inject droplets suspended in a carrier fluid into the droplet inlet and to cause the suspended droplets to move through the droplet channel; a shell surrounding a portion of the droplet channel; a plurality of dilution channels formed inside the shell and configured to transport dilution fluid into the droplet channel at a controlled rate such that an average distance between droplets disposed within the droplet channel is increased; a detection region disposed downstream from the dilution fluid input channel; and a detector configured to detect fluorescence radiation emitted by droplets passing through the detection region. 10. The system of claim 9, further comprising a dilution fluid input channel formed in the shell and configured to receive dilution fluid from a source disposed outside the shell. 11. The system of claim 9, further comprising a porous inner cylinder disposed within the shell, the porous inner cylinder having porous walls forming the dilution channels and a central bore defining a dilution region of the droplet channel. 12. The system of claim 11, wherein the inner cylinder includes a frit. 13. The system of claim 11, wherein the inner cylinder includes a capillary. 14. The system of claim 11, wherein the inner cylinder includes a filter. 15. The system of claim 9, further comprising an inner filter disposed within the shell, the inner filter having a plurality of radial bores forming the dilution channels and a central bore defining a dilution region of the droplet channel. 16. The system of claim 9, wherein the shell is configured to interface with a standard microfluidic “T” fitting. 17. A method of detecting radiation emitted by droplets in a droplet-based assay, the method comprising:
transporting droplets of a sample fluid suspended in a carrier fluid into a droplet channel; transporting the droplets through the droplet channel; transporting dilution fluid into a shell surrounding the droplet channel; transporting the dilution fluid from the shell into the droplet channel at a controlled rate through a plurality of dilution channels formed inside the shell, such that an average distance between droplets disposed within the droplet channel is increased; transporting the droplets to a detection region; and detecting fluorescence radiation emitted by droplets passing through the detection region. 18. The method of claim 17, wherein transporting the dilution fluid through a plurality of dilution channels into the droplet channel includes transporting the dilution fluid through porous walls of a frit disposed within the shell. 19. The method of claim 17, wherein transporting the dilution fluid through a plurality of dilution channels includes transporting the dilution fluid through porous walls of a capillary disposed within the shell. 20. The method of claim 17, wherein transporting the dilution fluid through a plurality of dilution channels includes transporting the dilution fluid through a plurality of radial bores formed in an inner cylinder disposed within the shell. | 1,600 |
768 | 15,478,041 | 1,636 | A method of determining a beating parameter of cells that undergo excitation contraction coupling, the method including providing a cell analysis device having a substrate and a sensor that measures cell adhesion or attachment to the substrate in millisecond time resolution; adding excitable cells capable of undergoing excitation contraction coupling to the substrate; monitoring cell adhesion or attachment of the excitable cells to the substrate in millisecond time resolution; and calculating one or more beating parameters from the monitored adhesion. | 1. A method of determining a beating parameter of cells that undergo excitation contraction coupling, the method comprising:
a) providing a cell analysis device comprising a substrate and a sensor that measures cell adhesion or attachment to the substrate in millisecond time resolution; b) adding excitable cells capable of undergoing excitation contraction coupling to the substrate; c) monitoring cell adhesion or attachment of the excitable cells to the substrate in millisecond time resolution; and d) calculating one or more beating parameters from the monitored adhesion. 2. The method according to claim 1, wherein the cell analysis device is an impedance monitoring device that measures cell-substrate impedance. 3. The method according to claim 1, wherein the cells are cardiomyocytes. 4. The method according to claim 1, wherein the cells are stem cell derived cardiomyocytes. 5. The method according to claim 1, wherein the cells are induced pluripotent stem cell (iPS cell) derived cardiomyocytes. 6. The method according to claim 1, wherein the millisecond resolution is characterized as consecutive impedance measurements less than 40 milliseconds apart. 7. The method according to claim 6, wherein the millisecond resolution is characterized as consecutive impedance measurements less than 20 milliseconds apart. 8. The method according to claim 1, wherein the step of calculating one or more parameters comprises forming a beating curve from the monitored cell adhesion or attachment and deriving the one or more beating parameters from the beating curve. 9. The method according to claim 1, wherein the one or more beating parameters are selected from the group consisting of beating rate, beating amplitude, rising time, falling time, beating period, IBD10, IBD50, IBD90, rising slope and falling slope. 10. The method according to claim 1, wherein the one or more beating parameters are selected from the group consisting of normalized beating rate, normalized beating amplitude, beating pattern similarity and beating rhythm irregularity. 11. The method according to claim 1, wherein the one or more beating parameters comprises 5 beating parameters. 12. The method according to claim 1, wherein the one or more beating parameters are calculated while the device continues to monitor the cell adhesion or attachment. 13. The method according to claim 1, further comprising adding a test compound to the cells, wherein the step of monitoring cell adhesion or attachment of the excitable cells is performed after adding the test compound. 14. The method according to claim 13, wherein the step of monitoring cell adhesion or attachment of the excitable cells is performed before and after adding the test compound. 15. A method of determining a dose response for a test compound on a cell population, the method comprising:
a) determining a beating parameter for different doses of a test compound according to the method of claim 1, wherein the test compound is added at different doses to different populations of cells; and b) plotting the beating parameters for each dose to form a dose response curve. 16. The method according to claim 15, wherein the beating parameter for each dose is from a same time point. 17. The method according to claim 15, further comprising determining a IC50 or EC50 value from the dose response curve. 18. A method for identifying a compound having a potentially cardiotoxic effect, comprising:
a) providing a test compound suspected of having a cardiotoxic effect; b) performing the method according to claim 1 to obtain a beating parameter for the test compound, wherein the cells are cardiomyocytes and wherein the test compound is added to the cardiomyocytes; and c) comparing the beating parameter for the test compound to a control beating parameter to identify whether there is a difference between beating parameters and if so, concluding the test compound has the potentially cardiotoxic effect. 19. The method according to claim 18, wherein the beating parameter for the test compound comprises 2 beating parameters, which are compared to 2 control beating parameters, further wherein the test compound is concluded to have a cardiotoxic effect if at least one of the compared parameters is different. 20. The method according to claim 18, wherein the compound is suspected of being a pro-arrhythmic drug that may induce arrhythmia. 21. The method according to claim 18, wherein the step of monitoring the beating of cells is also performed before adding the test compound. 22. The method according to claim 18, wherein the test compound is added at different doses to the cells. | A method of determining a beating parameter of cells that undergo excitation contraction coupling, the method including providing a cell analysis device having a substrate and a sensor that measures cell adhesion or attachment to the substrate in millisecond time resolution; adding excitable cells capable of undergoing excitation contraction coupling to the substrate; monitoring cell adhesion or attachment of the excitable cells to the substrate in millisecond time resolution; and calculating one or more beating parameters from the monitored adhesion.1. A method of determining a beating parameter of cells that undergo excitation contraction coupling, the method comprising:
a) providing a cell analysis device comprising a substrate and a sensor that measures cell adhesion or attachment to the substrate in millisecond time resolution; b) adding excitable cells capable of undergoing excitation contraction coupling to the substrate; c) monitoring cell adhesion or attachment of the excitable cells to the substrate in millisecond time resolution; and d) calculating one or more beating parameters from the monitored adhesion. 2. The method according to claim 1, wherein the cell analysis device is an impedance monitoring device that measures cell-substrate impedance. 3. The method according to claim 1, wherein the cells are cardiomyocytes. 4. The method according to claim 1, wherein the cells are stem cell derived cardiomyocytes. 5. The method according to claim 1, wherein the cells are induced pluripotent stem cell (iPS cell) derived cardiomyocytes. 6. The method according to claim 1, wherein the millisecond resolution is characterized as consecutive impedance measurements less than 40 milliseconds apart. 7. The method according to claim 6, wherein the millisecond resolution is characterized as consecutive impedance measurements less than 20 milliseconds apart. 8. The method according to claim 1, wherein the step of calculating one or more parameters comprises forming a beating curve from the monitored cell adhesion or attachment and deriving the one or more beating parameters from the beating curve. 9. The method according to claim 1, wherein the one or more beating parameters are selected from the group consisting of beating rate, beating amplitude, rising time, falling time, beating period, IBD10, IBD50, IBD90, rising slope and falling slope. 10. The method according to claim 1, wherein the one or more beating parameters are selected from the group consisting of normalized beating rate, normalized beating amplitude, beating pattern similarity and beating rhythm irregularity. 11. The method according to claim 1, wherein the one or more beating parameters comprises 5 beating parameters. 12. The method according to claim 1, wherein the one or more beating parameters are calculated while the device continues to monitor the cell adhesion or attachment. 13. The method according to claim 1, further comprising adding a test compound to the cells, wherein the step of monitoring cell adhesion or attachment of the excitable cells is performed after adding the test compound. 14. The method according to claim 13, wherein the step of monitoring cell adhesion or attachment of the excitable cells is performed before and after adding the test compound. 15. A method of determining a dose response for a test compound on a cell population, the method comprising:
a) determining a beating parameter for different doses of a test compound according to the method of claim 1, wherein the test compound is added at different doses to different populations of cells; and b) plotting the beating parameters for each dose to form a dose response curve. 16. The method according to claim 15, wherein the beating parameter for each dose is from a same time point. 17. The method according to claim 15, further comprising determining a IC50 or EC50 value from the dose response curve. 18. A method for identifying a compound having a potentially cardiotoxic effect, comprising:
a) providing a test compound suspected of having a cardiotoxic effect; b) performing the method according to claim 1 to obtain a beating parameter for the test compound, wherein the cells are cardiomyocytes and wherein the test compound is added to the cardiomyocytes; and c) comparing the beating parameter for the test compound to a control beating parameter to identify whether there is a difference between beating parameters and if so, concluding the test compound has the potentially cardiotoxic effect. 19. The method according to claim 18, wherein the beating parameter for the test compound comprises 2 beating parameters, which are compared to 2 control beating parameters, further wherein the test compound is concluded to have a cardiotoxic effect if at least one of the compared parameters is different. 20. The method according to claim 18, wherein the compound is suspected of being a pro-arrhythmic drug that may induce arrhythmia. 21. The method according to claim 18, wherein the step of monitoring the beating of cells is also performed before adding the test compound. 22. The method according to claim 18, wherein the test compound is added at different doses to the cells. | 1,600 |
769 | 14,333,608 | 1,618 | The present invention relates to a pigment mixture based on spherical particles having a defined particle-size distribution, and to the use thereof in paints, coatings, printing inks, security printing inks, plastics, ceramic materials, glasses, in cosmetic formulations, as tracer, as filler and for the preparation of pigment preparations and dry preparations. | 1. A pigment mixture comprising at least two components A and B:
component A is spherical base particles having a particle-size distribution D90 of uncoated particles of 0.5-15 μm, said particles being coated on their surface firstly with TiO2 and subsequently with SiO2, and component B is spherical base particles having a particle-size distribution D90 of uncoated particles of 0.5-15 μm, said particles being coated on the surface firstly with TiO2 and subsequently with iron oxide or with a mixture of TiO2 and iron oxide. 2. The pigment mixture according to claim 1, wherein the spherical base particles are magnesium silicate, aluminium silicate, alkali-metal aluminium silicates, alkaline-earth metal aluminium silicates, SiO2 spheres, glass beads, hollow glass beads, nylon, aluminium oxide beads, polymeric beads comprising ethylene-acrylic acid copolymers, ethylene-methacrylate copolymers, HDI-trimethylol hexyl lactone copolymers, nylon, polyacrylates, polymethyl methacrylate copolymers, polyethylene, polymethylsilsesquioxanes or mixtures thereof. 3. The pigment mixture according to claim 1, wherein the spherical base particles of component A and/or B are SiO2. 4. The pigment mixture according to claim 1, wherein the spherical particles of component A and component B each consist of SiO2. 5. The pigment mixture according to claim 1, wherein the iron oxide of component B is Fe2O3. 6. The pigment mixture according to claim 1, wherein component A is coated on the surface with TiO2 in anatase modification. 7. The pigment mixture according to claim 1, wherein the TiO2 layer of component A has a layer thickness of 10-500 nm. 8. The pigment mixture according to claim 1, wherein the SiO2 layer of component A has a layer thickness of 10-500 nm. 9. The pigment mixture according to claim 1, wherein component B is coated on the surface with TiO2 in anatase modification. 10. The pigment mixture according to claim 1, wherein the TiO2 layer of component B has a layer thickness of 50-400 nm. 11. The pigment mixture according to claim 1, wherein the iron oxide layer of component B has a layer thickness of 5-300 nm. 12. The pigment mixture according to claim 1, wherein the mixture of TiO2 and iron oxide of component B has a layer thickness of 55-700 nm. 13. The pigment mixture according to claim 1, wherein components A and B are mixed in a weight ratio of 99:1 to 90:10. 14. The pigment mixture according to claim 1, wherein component A and/or component B additionally has an outer protective layer in increasing light, temperature or weather stability compared to pigment without said layer. 15. A process for the preparation of the pigment mixture according to claim 1, comprising covering the spherical particles of components A and B with one or more coatings by wet-chemical coating or by a CVD or PVD process, and component A and component B are subsequently mixed with one another. 16. In paints, coatings, printing inks, security printing inks, plastics, ceramic materials, glasses, in cosmetic formulations, tracers, fillers or dry preparations comprising a pigment, the improvement wherein the pigment comprises a pigment of claim 1. 17. A formulation comprising the pigment mixture according to claim 1, and at least one absorbent, astringent, antimicrobial substance, antioxidant, antiperspirant, antifoaming agent, antidandruff active compound, antistatic, binder, biological additive, bleach, chelating agent, deodorizer, emollient, emulsifier, emulsion stabilizers, dye, humectant, film former, filler, fragrance, flavor, insect repellent, preservative, anticorrosion agent, cosmetic oil, solvent, oxidant, vegetable constituent, buffer substance, reducing agent, surfactant, propellant gas, opacifier, UV filter, UV absorber, denaturing agent, viscosity regulator, perfume or vitamin. | The present invention relates to a pigment mixture based on spherical particles having a defined particle-size distribution, and to the use thereof in paints, coatings, printing inks, security printing inks, plastics, ceramic materials, glasses, in cosmetic formulations, as tracer, as filler and for the preparation of pigment preparations and dry preparations.1. A pigment mixture comprising at least two components A and B:
component A is spherical base particles having a particle-size distribution D90 of uncoated particles of 0.5-15 μm, said particles being coated on their surface firstly with TiO2 and subsequently with SiO2, and component B is spherical base particles having a particle-size distribution D90 of uncoated particles of 0.5-15 μm, said particles being coated on the surface firstly with TiO2 and subsequently with iron oxide or with a mixture of TiO2 and iron oxide. 2. The pigment mixture according to claim 1, wherein the spherical base particles are magnesium silicate, aluminium silicate, alkali-metal aluminium silicates, alkaline-earth metal aluminium silicates, SiO2 spheres, glass beads, hollow glass beads, nylon, aluminium oxide beads, polymeric beads comprising ethylene-acrylic acid copolymers, ethylene-methacrylate copolymers, HDI-trimethylol hexyl lactone copolymers, nylon, polyacrylates, polymethyl methacrylate copolymers, polyethylene, polymethylsilsesquioxanes or mixtures thereof. 3. The pigment mixture according to claim 1, wherein the spherical base particles of component A and/or B are SiO2. 4. The pigment mixture according to claim 1, wherein the spherical particles of component A and component B each consist of SiO2. 5. The pigment mixture according to claim 1, wherein the iron oxide of component B is Fe2O3. 6. The pigment mixture according to claim 1, wherein component A is coated on the surface with TiO2 in anatase modification. 7. The pigment mixture according to claim 1, wherein the TiO2 layer of component A has a layer thickness of 10-500 nm. 8. The pigment mixture according to claim 1, wherein the SiO2 layer of component A has a layer thickness of 10-500 nm. 9. The pigment mixture according to claim 1, wherein component B is coated on the surface with TiO2 in anatase modification. 10. The pigment mixture according to claim 1, wherein the TiO2 layer of component B has a layer thickness of 50-400 nm. 11. The pigment mixture according to claim 1, wherein the iron oxide layer of component B has a layer thickness of 5-300 nm. 12. The pigment mixture according to claim 1, wherein the mixture of TiO2 and iron oxide of component B has a layer thickness of 55-700 nm. 13. The pigment mixture according to claim 1, wherein components A and B are mixed in a weight ratio of 99:1 to 90:10. 14. The pigment mixture according to claim 1, wherein component A and/or component B additionally has an outer protective layer in increasing light, temperature or weather stability compared to pigment without said layer. 15. A process for the preparation of the pigment mixture according to claim 1, comprising covering the spherical particles of components A and B with one or more coatings by wet-chemical coating or by a CVD or PVD process, and component A and component B are subsequently mixed with one another. 16. In paints, coatings, printing inks, security printing inks, plastics, ceramic materials, glasses, in cosmetic formulations, tracers, fillers or dry preparations comprising a pigment, the improvement wherein the pigment comprises a pigment of claim 1. 17. A formulation comprising the pigment mixture according to claim 1, and at least one absorbent, astringent, antimicrobial substance, antioxidant, antiperspirant, antifoaming agent, antidandruff active compound, antistatic, binder, biological additive, bleach, chelating agent, deodorizer, emollient, emulsifier, emulsion stabilizers, dye, humectant, film former, filler, fragrance, flavor, insect repellent, preservative, anticorrosion agent, cosmetic oil, solvent, oxidant, vegetable constituent, buffer substance, reducing agent, surfactant, propellant gas, opacifier, UV filter, UV absorber, denaturing agent, viscosity regulator, perfume or vitamin. | 1,600 |
770 | 14,494,170 | 1,628 | The present invention relates to pharmaceutical compositions comprising a combination of a therapeutically-effective amount of the antiviral compound valaciclovir and a therapeutically-effective amount of the COX-2 inhibitor celecoxib. The invention is further related to methods of treating functional somatic syndromes by administering a therapeutically-effective combination of valaciclovir and celecoxib. | 1-21. (canceled) 22. A method to treat a subject susceptible to or afflicted with fibromyalgia, the method comprising administering to the subject a therapeutically-effective co-acting combination of valaciclovir and celecoxib, wherein each of valaciclovir and celecoxib is administered in an amount in combination effective to treat fibromyalgia. 23. The method of claim 22 wherein the amount of valaciclovir is administered in a unit dose in a range of about 750 mg to about 3000 mg, and wherein the amount of celecoxib is administered in a unit dose in a range of 100 mg to about 800 mg. 24. The method of claim 23, wherein the amount of valaciclovir is administered in a unit dose in a range of about 750 mg to about 1500 mg, and wherein the amount of celecoxib is administered in a unit dose in a range of about 100 mg to about 400 mg. 25. The method of claim 24, wherein the amount of valaciclovir is administered in a unit dose in a range of about 750 mg to about 1000 mg, and wherein the amount of celecoxib is administered in a unit dose in a range of about 100 mg to about 200 mg. 26. The method claim 23, wherein the amount of valaciclovir is administered in a unit dose of about 750 mg, about 1000 mg, about 1250 mg, or about 1500 mg, and wherein the amount of celecoxib is administered in a unit dose of about 100 or about 200 mg. 27. The method of claim 25, wherein a unit dose of valaciclovir is administered two or three times per day, and wherein a unit dose of celecoxib is administered two or three times per day. 28. A method to treat a subject susceptible to or afflicted with one or more functional somatic syndrome conditions selected from the group consisting of fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, chronic pain, chronic headache, chronic neck pain, chronic back pain, chronic depression, chronic clinical anxiety disorder, posttraumatic stress disorder (PTSD), brain fog, cognitive dysfunction and chronic interstitial cystitis, the method comprising administering to the subject a therapeutically-effective co-acting combination of valaciclovir and celecoxib, wherein each of valaciclovir and celecoxib is administered in an amount in combination effective to treat one or more functional somatic syndrome conditions. 29. The method of claim 28 wherein the amount of valaciclovir is administered in a unit dose in a range of about 750 mg to about 3000 mg, and wherein the amount of celecoxib is administered in a unit dose in a range of 100 mg to about 800 mg. 30. The method of claim 29, wherein the amount of valaciclovir is administered in a unit dose in a range of about 750 mg to about 1500 mg, and wherein the amount of celecoxib is administered in a unit dose in a range of about 100 mg to about 400 mg. 31. The method of claim 30, wherein the amount of valaciclovir is administered in a unit dose in a range of about 750 mg to about 1000 mg, and wherein the amount of celecoxib is administered in a unit dose in a range of about 100 mg to about 200 mg. 32. The method claim 29, wherein the amount of valaciclovir is administered in a unit dose of about 750 mg, about 1000 mg, about 1250 mg, or about 1500 mg, and wherein the amount of celecoxib is administered in a unit dose of about 100 or about 200 mg. 33. The method of claim 31, wherein a unit dose of valaciclovir is administered two or three times per day, and wherein a unit dose of celecoxib is administered two or three times per day. 34. The method of claim 28, wherein the functional somatic syndrome condition is a combination of fibromyalgia, irritable bowel syndrome, and chronic fatigue syndrome, coexistent in the subject. 35. The method of claim 28, wherein the functional somatic syndrome condition is a combination of fibromyalgia and irritable bowel syndrome, coexistent in the subject. 36. The method of claim 28, wherein the functional somatic syndrome condition is a combination of fibromyalgia and chronic fatigue syndrome, coexistent in the subject. 37. A method to treat a subject susceptible to or afflicted with irritable bowel syndrome or chronic fatigue syndrome, the method comprising administering to the subject a therapeutically-effective co-acting combination of valaciclovir and celecoxib, wherein each of valaciclovir and celecoxib is administered in an amount in combination effective to treat irritable bowel syndrome or chronic fatigue syndrome. 38. The method of claim 37 wherein the amount of valaciclovir is administered in a unit dose in a range of about 750 mg to about 3000 mg, and wherein the amount of celecoxib is administered in a unit dose in a range of 100 mg to about 800 mg. 39. The method of claim 38, wherein the amount of valaciclovir is administered in a unit dose in a range of about 750 mg to about 1500 mg, and wherein the amount of celecoxib is administered in a unit dose in a range of about 100 mg to about 400 mg. 40. The method of claim 39, wherein the amount of valaciclovir is administered in a unit dose in a range of about 750 mg to about 1000 mg, and wherein the amount of celecoxib is administered in a unit dose in a range of about 100 mg to about 200 mg. 41. The method claim 38, wherein the amount of valaciclovir is administered in a unit dose of about 750 mg, about 1000 mg, about 1250 mg, or about 1500 mg, and wherein the amount of celecoxib is administered in a unit dose of about 100 or about 200 mg. 42. The method of claim 40, wherein a unit dose of valaciclovir is administered two or three times per day, and wherein a unit dose of celecoxib is administered two or three times per day. 43. A drug-combination comprising valaciclovir and celecoxib, wherein valaciclovir and celecoxib are each present in a co-acting chronic-disease-treatment-effective amount. 44. The drug-combination of claim 43, wherein valaciclovir and celecoxib are each present in a co-acting functional-somatic-syndrome-condition-treatment-effective amount. 45. The drug-combination of claim 44, wherein valaciclovir and celecoxib are each present in a co-acting fibromyalgia-treatment-effective amount. 46. The drug-combination of claim 43, wherein valaciclovir is present in an amount in a range of about 750 mg to about 3000 mg, and wherein celecoxib is present in an amount in a range of about 100 mg to about 800 mg. 47. The drug-combination of claim 46, wherein valaciclovir is present in an amount in a range of about 750 mg to about 1500 mg, and wherein celecoxib is present in an amount in a range of about 100 mg to about 400 mg. 48. The drug-combination of claim 47, wherein valaciclovir is present in an amount in a range of about 750 mg to about 1000 mg, and wherein celecoxib is present in an amount in a range of about 100 mg to about 200 mg. 49. The drug-combination of claim 46, wherein valaciclovir is present in an amount of about 750 mg, about 1000 mg, about 1250 mg, or about 1500 mg, and wherein celecoxib is present in an amount of about 100 mg or about 200 mg. | The present invention relates to pharmaceutical compositions comprising a combination of a therapeutically-effective amount of the antiviral compound valaciclovir and a therapeutically-effective amount of the COX-2 inhibitor celecoxib. The invention is further related to methods of treating functional somatic syndromes by administering a therapeutically-effective combination of valaciclovir and celecoxib.1-21. (canceled) 22. A method to treat a subject susceptible to or afflicted with fibromyalgia, the method comprising administering to the subject a therapeutically-effective co-acting combination of valaciclovir and celecoxib, wherein each of valaciclovir and celecoxib is administered in an amount in combination effective to treat fibromyalgia. 23. The method of claim 22 wherein the amount of valaciclovir is administered in a unit dose in a range of about 750 mg to about 3000 mg, and wherein the amount of celecoxib is administered in a unit dose in a range of 100 mg to about 800 mg. 24. The method of claim 23, wherein the amount of valaciclovir is administered in a unit dose in a range of about 750 mg to about 1500 mg, and wherein the amount of celecoxib is administered in a unit dose in a range of about 100 mg to about 400 mg. 25. The method of claim 24, wherein the amount of valaciclovir is administered in a unit dose in a range of about 750 mg to about 1000 mg, and wherein the amount of celecoxib is administered in a unit dose in a range of about 100 mg to about 200 mg. 26. The method claim 23, wherein the amount of valaciclovir is administered in a unit dose of about 750 mg, about 1000 mg, about 1250 mg, or about 1500 mg, and wherein the amount of celecoxib is administered in a unit dose of about 100 or about 200 mg. 27. The method of claim 25, wherein a unit dose of valaciclovir is administered two or three times per day, and wherein a unit dose of celecoxib is administered two or three times per day. 28. A method to treat a subject susceptible to or afflicted with one or more functional somatic syndrome conditions selected from the group consisting of fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, chronic pain, chronic headache, chronic neck pain, chronic back pain, chronic depression, chronic clinical anxiety disorder, posttraumatic stress disorder (PTSD), brain fog, cognitive dysfunction and chronic interstitial cystitis, the method comprising administering to the subject a therapeutically-effective co-acting combination of valaciclovir and celecoxib, wherein each of valaciclovir and celecoxib is administered in an amount in combination effective to treat one or more functional somatic syndrome conditions. 29. The method of claim 28 wherein the amount of valaciclovir is administered in a unit dose in a range of about 750 mg to about 3000 mg, and wherein the amount of celecoxib is administered in a unit dose in a range of 100 mg to about 800 mg. 30. The method of claim 29, wherein the amount of valaciclovir is administered in a unit dose in a range of about 750 mg to about 1500 mg, and wherein the amount of celecoxib is administered in a unit dose in a range of about 100 mg to about 400 mg. 31. The method of claim 30, wherein the amount of valaciclovir is administered in a unit dose in a range of about 750 mg to about 1000 mg, and wherein the amount of celecoxib is administered in a unit dose in a range of about 100 mg to about 200 mg. 32. The method claim 29, wherein the amount of valaciclovir is administered in a unit dose of about 750 mg, about 1000 mg, about 1250 mg, or about 1500 mg, and wherein the amount of celecoxib is administered in a unit dose of about 100 or about 200 mg. 33. The method of claim 31, wherein a unit dose of valaciclovir is administered two or three times per day, and wherein a unit dose of celecoxib is administered two or three times per day. 34. The method of claim 28, wherein the functional somatic syndrome condition is a combination of fibromyalgia, irritable bowel syndrome, and chronic fatigue syndrome, coexistent in the subject. 35. The method of claim 28, wherein the functional somatic syndrome condition is a combination of fibromyalgia and irritable bowel syndrome, coexistent in the subject. 36. The method of claim 28, wherein the functional somatic syndrome condition is a combination of fibromyalgia and chronic fatigue syndrome, coexistent in the subject. 37. A method to treat a subject susceptible to or afflicted with irritable bowel syndrome or chronic fatigue syndrome, the method comprising administering to the subject a therapeutically-effective co-acting combination of valaciclovir and celecoxib, wherein each of valaciclovir and celecoxib is administered in an amount in combination effective to treat irritable bowel syndrome or chronic fatigue syndrome. 38. The method of claim 37 wherein the amount of valaciclovir is administered in a unit dose in a range of about 750 mg to about 3000 mg, and wherein the amount of celecoxib is administered in a unit dose in a range of 100 mg to about 800 mg. 39. The method of claim 38, wherein the amount of valaciclovir is administered in a unit dose in a range of about 750 mg to about 1500 mg, and wherein the amount of celecoxib is administered in a unit dose in a range of about 100 mg to about 400 mg. 40. The method of claim 39, wherein the amount of valaciclovir is administered in a unit dose in a range of about 750 mg to about 1000 mg, and wherein the amount of celecoxib is administered in a unit dose in a range of about 100 mg to about 200 mg. 41. The method claim 38, wherein the amount of valaciclovir is administered in a unit dose of about 750 mg, about 1000 mg, about 1250 mg, or about 1500 mg, and wherein the amount of celecoxib is administered in a unit dose of about 100 or about 200 mg. 42. The method of claim 40, wherein a unit dose of valaciclovir is administered two or three times per day, and wherein a unit dose of celecoxib is administered two or three times per day. 43. A drug-combination comprising valaciclovir and celecoxib, wherein valaciclovir and celecoxib are each present in a co-acting chronic-disease-treatment-effective amount. 44. The drug-combination of claim 43, wherein valaciclovir and celecoxib are each present in a co-acting functional-somatic-syndrome-condition-treatment-effective amount. 45. The drug-combination of claim 44, wherein valaciclovir and celecoxib are each present in a co-acting fibromyalgia-treatment-effective amount. 46. The drug-combination of claim 43, wherein valaciclovir is present in an amount in a range of about 750 mg to about 3000 mg, and wherein celecoxib is present in an amount in a range of about 100 mg to about 800 mg. 47. The drug-combination of claim 46, wherein valaciclovir is present in an amount in a range of about 750 mg to about 1500 mg, and wherein celecoxib is present in an amount in a range of about 100 mg to about 400 mg. 48. The drug-combination of claim 47, wherein valaciclovir is present in an amount in a range of about 750 mg to about 1000 mg, and wherein celecoxib is present in an amount in a range of about 100 mg to about 200 mg. 49. The drug-combination of claim 46, wherein valaciclovir is present in an amount of about 750 mg, about 1000 mg, about 1250 mg, or about 1500 mg, and wherein celecoxib is present in an amount of about 100 mg or about 200 mg. | 1,600 |
771 | 14,138,026 | 1,658 | The monofunctional branched poly(ethylene glycol) (PEG) has a general formula shown in formula (1), and the bio-related substance modified by the monofunctional branched PEG has a general fomula shown in formula (2), wherein X 1 and X 2 are each independently a hydrocarbon group having 1 to 20 carbon atoms, n 1 and n 2 are each independently an integer selected from 1 to 1000, n 3 is an integer selected from 11 to 1000, L 1 , L 2 are each independently a linking group, p is 0 or 1, q is 0 or 1, R 1 is a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms, D is a bio-related substance, Z is a linking group, and Z can react with the bio-related substance to form a residue group L 3 . The PEG-modified bio-related substance maintains good biological activity, and has better solubility and a longer half-life in vivo. | 1. A monofunctional branched poly(ethylene glycol) (PEG) represented by general formula (1):
wherein X1 and X2 are each independently an hydrocarbon group having 1 to 20 carbon atoms at a terminal end of the two branch chains, wherein n1 and n2 are each independently an integer selected from 1 to 1000, wherein n3 is an integer selected from 11 to 1000, wherein L1 and L2 are each independently a linking group stable under conditions of illumination, enzyme, acid or base, wherein p is selected from one of a group consisting of 0 and 1, wherein R1 is selected from one of a group consisting of a hydrogen atom and a hydrocarbon group having 1 to 20 carbon atoms, and wherein R is a functional group on a terminal of a main chain of the branched poly(ethylene glycol). 2. The monofunctional branched PEG according to claim 1, wherein X1 and X2 are each independently a group selected from the group consisting of a methyl, an ethyl, a propyl, a propenyl, a propinyl, an isopropyl, a butyl, a tertiary butyl, a pentyl, a heptyl, a 2-ethylhexyl, an octyl, a nonyl, a decyl, an undecyl, a dodecyl, a tridecyl, a tetradecyl, a pentadecyl, a hexadecyl, a heptadecyl, an octadecyl, a nonadecyl, an eicosyl, a benzyl and a butylphenyl, and wherein X1 and X2 are the same or different from each other in one molecule. 3. The monofunctional branched PEG according to claim 1, wherein L1 and L2 are each independently a divalent hydrocarbon group having 1 to 20 carbon atoms. 4. The monofunctional branched PEG according to claim 1, wherein L1 and L2 are each independently a divalent hydrocarbon group having 1 to 20 carbon atoms containing groups stable under conditions of illumination, enzyme, acid or base, wherein groups are selected from a group consisting of an ether bond, a thioether bond, an amide bond, a double bond, a triple bond, an amino group. 5. The monofunctional branched PEG according to claim 1, wherein R1 is selected from one of a group consisting of a hydrogen atom, a hydrocarbon group having 1 to 20 carbon atoms and a hydrocarbon group having 1 to 20 carbon atoms containing a group stable under anionic polymerization conditions. 6. The monofunctional branched PEG according to claim 5, wherein the group stable under anionic polymerization conditions is selected from one of a group consisting of an ester bond, a urethane bond, an amide bond, an ether bond, a double bond, a triple bond, a carbonate bond and a tertiary amine group. 7. The monofunctional branched PEG according to claim 1, wherein R is a functional group interreacting with a bio-related substance. 8. The monofunctional branched PEG according to claim 1, wherein R is selected from one of a group consisting of the following groups:
wherein Z is selected from one of a group consisting of an alkylidene group and an alkylidene group containing groups stable under conditions of illumination, enzyme, acid or base, wherein each group is selected from a group consisting of an ester bond, a urethane bond, an amide bond, an ether bond, a double bond, a triple bond, a carbonate bond, and a secondary amine group;
wherein q is selected from one of a group consisting of 0 and 1;
wherein Y is selected from one of a group consisting of a hydrocarbon group having 1 to 10 carbon atoms and a hydrocarbon group having 1 to 10 carbon atoms containing a fluorine atom;
wherein Q is selected from one of a group consisting of hydrogen and a group favoring one a group consisting of an inductive effect, a conjugative effect or both of electrons of unsaturated bond;
wherein M is selected from one of a group consisting of a carbon atom and a nitrogen atom on a ring; and
wherein W is a halogen atom. 9. The monofunctional branched PEG according to claim 1, wherein n3 is an integer selected from 11 to 200. 10. The production method of the monofunctional branched PEG according to claim 1, comprising the steps as follows:
(a) polymerizing, in a coinitiator system consisting of a small molecule initiator and a base, ethylene oxide to two geometrically symmetrical hydroxyl groups of the initiator to generate two branch chains, said two branch chains having terminal ends deprotonated to obtain a first intermediate; (b) alkyl-etherifying initiating active terminals of the two branch chains of said first intermediate to obtain a second intermediate; (c) deprotecting a terminal hydroxyl group on a symmetry axis of said second intermediate to obtain a third intermediate; (d) polymerizing ethylene oxide to the deprotected terminal hydroxyl group on a symmetry axis of said third intermediate to generate a main chain, said main chain being subsequently protonated to obtain a fourth intermediate with a terminal hydroxyl group; and (e) functionalizing a terminal of the main chain of said fourth intermediate, obtaining a monofunctional branched poly(ethylene glycol) of the general formula (1),
wherein PG represents a protective group of a hydroxyl group. 11. A PEG-modified bio-related substance having a chemical structure shown in the general formula (2):
wherein X1 and X2 are each independently a hydrocarbon group having 1 to 20 carbon atoms at a terminal end of two branch chains, wherein n1 and n2 are each independently an integer selected from 1 to 1000, wherein n3 is an integer selected from 11 to 1000, wherein L1 and L2 are each independently a linking group stable under the conditions of illumination, enzyme, acid or base, wherein p is selected from one of a group consisting of 0 and 1, wherein q is selected from one of a group consisting of 0 and 1, wherein R1 is selected from one of a group consisting of a hydrogen atom and a hydrocarbon group having 1 to 20 carbon atoms, wherein D is a bio-related substance, wherein Z is a linking group having a functional group reacting with the bio-related substance, said functional group being linked to a main chain of PEG, and wherein Z reacts with the bio-related substance to form a residue group L3. 12. The PEG-modified bio-related substance according to claim 11, wherein X1 and X2 are each independently a group selected from the group consisting of a methyl, an ethyl, a propyl, a propenyl, a propinyl, an isopropyl, a butyl, a tertiary butyl, a pentyl, a heptyl, a 2-ethylhexyl, an octyl, a nonyl, a decyl, an undecyl, a dodecyl, a tridecyl, a tetradecyl, a pentadecyl, a hexadecyl, a heptadecyl, an octadecyl, a nonadecyl, an eicosyl, a benzyl and a butylphenyl, and wherein X1 and X2 are the same or different from each other in one molecule. 13. The PEG-modified bio-related substance according to claim 11, wherein L1 and L2 are each independently a divalent hydrocarbon group having 1 to 20 carbon atoms. 14. The PEG-modified bio-related substance according to claim 11, wherein L1 and L2 are each independently a divalent hydrocarbon group containing groups stable under conditions of illumination, enzyme, acid or base, and wherein groups are selected from a group consisting of an ester bond, a urethane bond, an amide bond, an ether bond, a double bond, a triple bond, a carbonate bond and a secondary amine group. 15. The PEG-modified bio-related substance according to claim 11, wherein R1 is selected from one of a group consisting of a hydrogen atom, a hydrocarbon group having 1 to 20 carbon atoms and a hydrocarbon group having 1 to 20 carbon atoms containing groups stable under anionic polymerization conditions. 16. The PEG-modified bio-related substance according to claim 11, wherein D is selected from one of a group consisting of polypeptide, protein, enzyme, small molecule drug, dye, liposome, nucleoside, nucleotide, oligonucleotide, polynucleotide, nucleic acid, polysaccharose, steroid, lipid, phospholipid, glycolipid, glycoprotein, cell, virus and micelle. 17. The PEG-modified bio-related substance according to claim 11, wherein n1 and n2 are each independently an integer selected from 10 to 800. 18. The PEG-modified bio-related substance according to claim 11, wherein n3 is an integer selected from 11 to 500. | The monofunctional branched poly(ethylene glycol) (PEG) has a general formula shown in formula (1), and the bio-related substance modified by the monofunctional branched PEG has a general fomula shown in formula (2), wherein X 1 and X 2 are each independently a hydrocarbon group having 1 to 20 carbon atoms, n 1 and n 2 are each independently an integer selected from 1 to 1000, n 3 is an integer selected from 11 to 1000, L 1 , L 2 are each independently a linking group, p is 0 or 1, q is 0 or 1, R 1 is a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms, D is a bio-related substance, Z is a linking group, and Z can react with the bio-related substance to form a residue group L 3 . The PEG-modified bio-related substance maintains good biological activity, and has better solubility and a longer half-life in vivo.1. A monofunctional branched poly(ethylene glycol) (PEG) represented by general formula (1):
wherein X1 and X2 are each independently an hydrocarbon group having 1 to 20 carbon atoms at a terminal end of the two branch chains, wherein n1 and n2 are each independently an integer selected from 1 to 1000, wherein n3 is an integer selected from 11 to 1000, wherein L1 and L2 are each independently a linking group stable under conditions of illumination, enzyme, acid or base, wherein p is selected from one of a group consisting of 0 and 1, wherein R1 is selected from one of a group consisting of a hydrogen atom and a hydrocarbon group having 1 to 20 carbon atoms, and wherein R is a functional group on a terminal of a main chain of the branched poly(ethylene glycol). 2. The monofunctional branched PEG according to claim 1, wherein X1 and X2 are each independently a group selected from the group consisting of a methyl, an ethyl, a propyl, a propenyl, a propinyl, an isopropyl, a butyl, a tertiary butyl, a pentyl, a heptyl, a 2-ethylhexyl, an octyl, a nonyl, a decyl, an undecyl, a dodecyl, a tridecyl, a tetradecyl, a pentadecyl, a hexadecyl, a heptadecyl, an octadecyl, a nonadecyl, an eicosyl, a benzyl and a butylphenyl, and wherein X1 and X2 are the same or different from each other in one molecule. 3. The monofunctional branched PEG according to claim 1, wherein L1 and L2 are each independently a divalent hydrocarbon group having 1 to 20 carbon atoms. 4. The monofunctional branched PEG according to claim 1, wherein L1 and L2 are each independently a divalent hydrocarbon group having 1 to 20 carbon atoms containing groups stable under conditions of illumination, enzyme, acid or base, wherein groups are selected from a group consisting of an ether bond, a thioether bond, an amide bond, a double bond, a triple bond, an amino group. 5. The monofunctional branched PEG according to claim 1, wherein R1 is selected from one of a group consisting of a hydrogen atom, a hydrocarbon group having 1 to 20 carbon atoms and a hydrocarbon group having 1 to 20 carbon atoms containing a group stable under anionic polymerization conditions. 6. The monofunctional branched PEG according to claim 5, wherein the group stable under anionic polymerization conditions is selected from one of a group consisting of an ester bond, a urethane bond, an amide bond, an ether bond, a double bond, a triple bond, a carbonate bond and a tertiary amine group. 7. The monofunctional branched PEG according to claim 1, wherein R is a functional group interreacting with a bio-related substance. 8. The monofunctional branched PEG according to claim 1, wherein R is selected from one of a group consisting of the following groups:
wherein Z is selected from one of a group consisting of an alkylidene group and an alkylidene group containing groups stable under conditions of illumination, enzyme, acid or base, wherein each group is selected from a group consisting of an ester bond, a urethane bond, an amide bond, an ether bond, a double bond, a triple bond, a carbonate bond, and a secondary amine group;
wherein q is selected from one of a group consisting of 0 and 1;
wherein Y is selected from one of a group consisting of a hydrocarbon group having 1 to 10 carbon atoms and a hydrocarbon group having 1 to 10 carbon atoms containing a fluorine atom;
wherein Q is selected from one of a group consisting of hydrogen and a group favoring one a group consisting of an inductive effect, a conjugative effect or both of electrons of unsaturated bond;
wherein M is selected from one of a group consisting of a carbon atom and a nitrogen atom on a ring; and
wherein W is a halogen atom. 9. The monofunctional branched PEG according to claim 1, wherein n3 is an integer selected from 11 to 200. 10. The production method of the monofunctional branched PEG according to claim 1, comprising the steps as follows:
(a) polymerizing, in a coinitiator system consisting of a small molecule initiator and a base, ethylene oxide to two geometrically symmetrical hydroxyl groups of the initiator to generate two branch chains, said two branch chains having terminal ends deprotonated to obtain a first intermediate; (b) alkyl-etherifying initiating active terminals of the two branch chains of said first intermediate to obtain a second intermediate; (c) deprotecting a terminal hydroxyl group on a symmetry axis of said second intermediate to obtain a third intermediate; (d) polymerizing ethylene oxide to the deprotected terminal hydroxyl group on a symmetry axis of said third intermediate to generate a main chain, said main chain being subsequently protonated to obtain a fourth intermediate with a terminal hydroxyl group; and (e) functionalizing a terminal of the main chain of said fourth intermediate, obtaining a monofunctional branched poly(ethylene glycol) of the general formula (1),
wherein PG represents a protective group of a hydroxyl group. 11. A PEG-modified bio-related substance having a chemical structure shown in the general formula (2):
wherein X1 and X2 are each independently a hydrocarbon group having 1 to 20 carbon atoms at a terminal end of two branch chains, wherein n1 and n2 are each independently an integer selected from 1 to 1000, wherein n3 is an integer selected from 11 to 1000, wherein L1 and L2 are each independently a linking group stable under the conditions of illumination, enzyme, acid or base, wherein p is selected from one of a group consisting of 0 and 1, wherein q is selected from one of a group consisting of 0 and 1, wherein R1 is selected from one of a group consisting of a hydrogen atom and a hydrocarbon group having 1 to 20 carbon atoms, wherein D is a bio-related substance, wherein Z is a linking group having a functional group reacting with the bio-related substance, said functional group being linked to a main chain of PEG, and wherein Z reacts with the bio-related substance to form a residue group L3. 12. The PEG-modified bio-related substance according to claim 11, wherein X1 and X2 are each independently a group selected from the group consisting of a methyl, an ethyl, a propyl, a propenyl, a propinyl, an isopropyl, a butyl, a tertiary butyl, a pentyl, a heptyl, a 2-ethylhexyl, an octyl, a nonyl, a decyl, an undecyl, a dodecyl, a tridecyl, a tetradecyl, a pentadecyl, a hexadecyl, a heptadecyl, an octadecyl, a nonadecyl, an eicosyl, a benzyl and a butylphenyl, and wherein X1 and X2 are the same or different from each other in one molecule. 13. The PEG-modified bio-related substance according to claim 11, wherein L1 and L2 are each independently a divalent hydrocarbon group having 1 to 20 carbon atoms. 14. The PEG-modified bio-related substance according to claim 11, wherein L1 and L2 are each independently a divalent hydrocarbon group containing groups stable under conditions of illumination, enzyme, acid or base, and wherein groups are selected from a group consisting of an ester bond, a urethane bond, an amide bond, an ether bond, a double bond, a triple bond, a carbonate bond and a secondary amine group. 15. The PEG-modified bio-related substance according to claim 11, wherein R1 is selected from one of a group consisting of a hydrogen atom, a hydrocarbon group having 1 to 20 carbon atoms and a hydrocarbon group having 1 to 20 carbon atoms containing groups stable under anionic polymerization conditions. 16. The PEG-modified bio-related substance according to claim 11, wherein D is selected from one of a group consisting of polypeptide, protein, enzyme, small molecule drug, dye, liposome, nucleoside, nucleotide, oligonucleotide, polynucleotide, nucleic acid, polysaccharose, steroid, lipid, phospholipid, glycolipid, glycoprotein, cell, virus and micelle. 17. The PEG-modified bio-related substance according to claim 11, wherein n1 and n2 are each independently an integer selected from 10 to 800. 18. The PEG-modified bio-related substance according to claim 11, wherein n3 is an integer selected from 11 to 500. | 1,600 |
772 | 14,409,664 | 1,631 | Systems and methods are provided herein for generating a classifier for phenotypic prediction. A computational causal network model representing a biological system includes a plurality of nodes and a plurality of edges connecting pairs of nodes. A first set of data corresponding to activities of a first subset of biological entities obtained under a first set of conditions is received, and a second set of data corresponding to activities of the first subset of biological entities obtained under a second set of conditions is received. A set of activity measures representing a difference between the first and second sets of data for a first subset of nodes is calculated. A set of activity values for a second subset of nodes, which are unmeasured, is generated. A classifier is generated for the phenotypes based on the set of activity measures, the set of activity values, or both. | 1. A computerized method for identifying biological entities that are representative of a phenotype of interest, comprising the steps of:
(a) providing, at a processing device, a computational causal network model that represents a biological system that contributes to the phenotype and includes: a plurality of nodes that represent biological entities in the biological system; and a plurality of edges connecting pairs of nodes among the plurality of nodes and representing relationships between the biological entities represented by the nodes; wherein one or more edges is associated with a direction value that represents a causal activation or causal suppression relationship between the biological entities represented by the nodes, and wherein each node is connected by an edge to at least one other node; (b) receiving, at the processing device, (i) a first set of data corresponding to activities of a first subset of biological entities obtained under a first set of conditions; and (ii) a second set of data corresponding to activities of the first subset of biological entities obtained under a second set of conditions different from the first set of conditions, wherein the first and second sets of conditions relate to the phenotype; (c) calculating, with the processing device, a set of activity measures for a first subset of nodes corresponding to the first subset of biological entities, the activity measure representing a difference between the first set of data and the second set of data; (d) generating, with the processing device, a set of activity values for a second subset of nodes representing candidates of biological entities that contribute to the phenotype but whose activities are not measured, based on the computational causal network model and the set of activity measures; (e) generating, with the processing device using a machine learning technique, a classifier for the phenotypes based on the set of activity measures, the set of activity values, or both. 2. The computerized method of claim 1, wherein generating the classifier for the phenotypes at step (e) comprises:
(e1) generating an operator that translates information about the activity measures of the first subset of biological entities into information about the activity values for the second subset of nodes; (e2) using the operator to identify a subset of the second subset of nodes; and (e3) providing the identified subset as an input to the machine learning technique. 3. The computerized method of claim 1, wherein steps (c) and (d) are performed for a plurality of computational causal network models, and the sets of activity values corresponding to each of the computational causal network models are aggregated into the set of activity values used at step (e). 4. The computerized method of claim 1, wherein steps (c), (d) and (e) are performed for a plurality of computational causal network models, and further comprising:
(h1) for each classifier, identifying one or more biological entities of the second set of biological entities with classification performance statistics above a threshold; and (h2) aggregating all of the identified biological entities into a set of high performing entities; (h3) generating, with the processing device, a new classifier of biological conditions based on the activity values associated with the set of high performing entities using a machine learning technique; and (h4) outputting the new classifier. 5. The computerized method of claim 1, wherein the machine learning technique includes a support vector machine technique. 6. The computerized method of claim 1, wherein generating the set of activity values at step (d) comprises identifying, for each particular node in the second subset of nodes, an activity value that minimizes a difference statement that represents the difference between the activity value of the particular node and the activity value or activity measure of nodes to which the particular node is connected by an edge within the computational causal network model, wherein the difference statement depends on the activity values of each node in the second subset of nodes. 7. The computerized method of claim 6, wherein the difference statement further depends on the direction values of each node in the second subset of nodes. 8. The computerized method of claim 1, wherein each activity value in the set of activity values is a linear combination of activity measures in the set of activity measures. 9. The computerized method of claim 8, wherein the linear combination depends on edges between nodes in the first subset of nodes and nodes in the second subset of nodes, and also depends on edges between nodes in the second subset of nodes. 10. The computerized method of claim 8, wherein the linear combination does not depend on edges between nodes in the first subset of nodes. 11. The computerized method of claim 1, further comprising providing a variation estimate for each activity value of the set of activity values by forming a linear combination of variation estimates for each activity measure of the set of activity measures. 12. The computerized method of claim 1, wherein the activity measure of step (c) is a fold-change value, and the fold-change value for each node represents a logarithm of the difference between corresponding sets of treatment data for the biological entity represented by the respective node. 13. The computerized method of claim 1, wherein the first subset of biological entities includes a set of genes and the first set of data include expression levels of the set of genes. 14. A computer program product comprising computer-readable instructions that, when executed in a computerized system comprising at least one processor, cause the processor to carry out a method comprising:
(a) providing a computational causal network model that represents a biological system that contributes to the phenotype and includes: a plurality of nodes that represent biological entities in the biological system; and a plurality of edges connecting pairs of nodes among the plurality of nodes and representing relationships between the biological entities represented by the nodes; wherein one or more edges is associated with a direction value that represents a causal activation or causal suppression relationship between the biological entities represented by the nodes, and wherein each node is connected by an edge to at least one other node; (b) receiving (i) a first set of data corresponding to activities of a first subset of biological entities obtained under a first set of conditions; and (ii) a second set of data corresponding to activities of the first subset of biological entities obtained under a second set of conditions different from the first set of conditions, wherein the first and second sets of conditions relate to the phenotype; (c) calculating a set of activity measures for a first subset of nodes corresponding to the first subset of biological entities, the activity measure representing a difference between the first set of data and the second set of data; (d) generating a set of activity values for a second subset of nodes representing candidates of biological entities that contribute to the phenotype but whose activities are not measured, based on the computational causal network model and the set of activity measures; (e) generating, using a machine learning technique, a classifier for the phenotypes based on the set of activity measures, the set of activity values, or both. 15. A computerized system comprising a processing device configured with non-transitory computer-readable instructions that, when executed, cause the processing device to carry out a method comprising:
(a) providing a computational causal network model that represents a biological system that contributes to the phenotype and includes: a plurality of nodes that represent biological entities in the biological system; and a plurality of edges connecting pairs of nodes among the plurality of nodes and representing relationships between the biological entities represented by the nodes; wherein one or more edges is associated with a direction value that represents a causal activation or causal suppression relationship between the biological entities represented by the nodes, and wherein each node is connected by an edge to at least one other node; (b) receiving (i) a first set of data corresponding to activities of a first subset of biological entities obtained under a first set of conditions; and (ii) a second set of data corresponding to activities of the first subset of biological entities obtained under a second set of conditions different from the first set of conditions, wherein the first and second sets of conditions relate to the phenotype; (c) calculating a set of activity measures for a first subset of nodes corresponding to the first subset of biological entities, the activity measure representing a difference between the first set of data and the second set of data; (d) generating a set of activity values for a second subset of nodes representing candidates of biological entities that contribute to the phenotype but whose activities are not measured, based on the computational causal network model and the set of activity measures; (e) generating, using a machine learning technique, a classifier for the phenotypes based on the set of activity measures, the set of activity values, or both. | Systems and methods are provided herein for generating a classifier for phenotypic prediction. A computational causal network model representing a biological system includes a plurality of nodes and a plurality of edges connecting pairs of nodes. A first set of data corresponding to activities of a first subset of biological entities obtained under a first set of conditions is received, and a second set of data corresponding to activities of the first subset of biological entities obtained under a second set of conditions is received. A set of activity measures representing a difference between the first and second sets of data for a first subset of nodes is calculated. A set of activity values for a second subset of nodes, which are unmeasured, is generated. A classifier is generated for the phenotypes based on the set of activity measures, the set of activity values, or both.1. A computerized method for identifying biological entities that are representative of a phenotype of interest, comprising the steps of:
(a) providing, at a processing device, a computational causal network model that represents a biological system that contributes to the phenotype and includes: a plurality of nodes that represent biological entities in the biological system; and a plurality of edges connecting pairs of nodes among the plurality of nodes and representing relationships between the biological entities represented by the nodes; wherein one or more edges is associated with a direction value that represents a causal activation or causal suppression relationship between the biological entities represented by the nodes, and wherein each node is connected by an edge to at least one other node; (b) receiving, at the processing device, (i) a first set of data corresponding to activities of a first subset of biological entities obtained under a first set of conditions; and (ii) a second set of data corresponding to activities of the first subset of biological entities obtained under a second set of conditions different from the first set of conditions, wherein the first and second sets of conditions relate to the phenotype; (c) calculating, with the processing device, a set of activity measures for a first subset of nodes corresponding to the first subset of biological entities, the activity measure representing a difference between the first set of data and the second set of data; (d) generating, with the processing device, a set of activity values for a second subset of nodes representing candidates of biological entities that contribute to the phenotype but whose activities are not measured, based on the computational causal network model and the set of activity measures; (e) generating, with the processing device using a machine learning technique, a classifier for the phenotypes based on the set of activity measures, the set of activity values, or both. 2. The computerized method of claim 1, wherein generating the classifier for the phenotypes at step (e) comprises:
(e1) generating an operator that translates information about the activity measures of the first subset of biological entities into information about the activity values for the second subset of nodes; (e2) using the operator to identify a subset of the second subset of nodes; and (e3) providing the identified subset as an input to the machine learning technique. 3. The computerized method of claim 1, wherein steps (c) and (d) are performed for a plurality of computational causal network models, and the sets of activity values corresponding to each of the computational causal network models are aggregated into the set of activity values used at step (e). 4. The computerized method of claim 1, wherein steps (c), (d) and (e) are performed for a plurality of computational causal network models, and further comprising:
(h1) for each classifier, identifying one or more biological entities of the second set of biological entities with classification performance statistics above a threshold; and (h2) aggregating all of the identified biological entities into a set of high performing entities; (h3) generating, with the processing device, a new classifier of biological conditions based on the activity values associated with the set of high performing entities using a machine learning technique; and (h4) outputting the new classifier. 5. The computerized method of claim 1, wherein the machine learning technique includes a support vector machine technique. 6. The computerized method of claim 1, wherein generating the set of activity values at step (d) comprises identifying, for each particular node in the second subset of nodes, an activity value that minimizes a difference statement that represents the difference between the activity value of the particular node and the activity value or activity measure of nodes to which the particular node is connected by an edge within the computational causal network model, wherein the difference statement depends on the activity values of each node in the second subset of nodes. 7. The computerized method of claim 6, wherein the difference statement further depends on the direction values of each node in the second subset of nodes. 8. The computerized method of claim 1, wherein each activity value in the set of activity values is a linear combination of activity measures in the set of activity measures. 9. The computerized method of claim 8, wherein the linear combination depends on edges between nodes in the first subset of nodes and nodes in the second subset of nodes, and also depends on edges between nodes in the second subset of nodes. 10. The computerized method of claim 8, wherein the linear combination does not depend on edges between nodes in the first subset of nodes. 11. The computerized method of claim 1, further comprising providing a variation estimate for each activity value of the set of activity values by forming a linear combination of variation estimates for each activity measure of the set of activity measures. 12. The computerized method of claim 1, wherein the activity measure of step (c) is a fold-change value, and the fold-change value for each node represents a logarithm of the difference between corresponding sets of treatment data for the biological entity represented by the respective node. 13. The computerized method of claim 1, wherein the first subset of biological entities includes a set of genes and the first set of data include expression levels of the set of genes. 14. A computer program product comprising computer-readable instructions that, when executed in a computerized system comprising at least one processor, cause the processor to carry out a method comprising:
(a) providing a computational causal network model that represents a biological system that contributes to the phenotype and includes: a plurality of nodes that represent biological entities in the biological system; and a plurality of edges connecting pairs of nodes among the plurality of nodes and representing relationships between the biological entities represented by the nodes; wherein one or more edges is associated with a direction value that represents a causal activation or causal suppression relationship between the biological entities represented by the nodes, and wherein each node is connected by an edge to at least one other node; (b) receiving (i) a first set of data corresponding to activities of a first subset of biological entities obtained under a first set of conditions; and (ii) a second set of data corresponding to activities of the first subset of biological entities obtained under a second set of conditions different from the first set of conditions, wherein the first and second sets of conditions relate to the phenotype; (c) calculating a set of activity measures for a first subset of nodes corresponding to the first subset of biological entities, the activity measure representing a difference between the first set of data and the second set of data; (d) generating a set of activity values for a second subset of nodes representing candidates of biological entities that contribute to the phenotype but whose activities are not measured, based on the computational causal network model and the set of activity measures; (e) generating, using a machine learning technique, a classifier for the phenotypes based on the set of activity measures, the set of activity values, or both. 15. A computerized system comprising a processing device configured with non-transitory computer-readable instructions that, when executed, cause the processing device to carry out a method comprising:
(a) providing a computational causal network model that represents a biological system that contributes to the phenotype and includes: a plurality of nodes that represent biological entities in the biological system; and a plurality of edges connecting pairs of nodes among the plurality of nodes and representing relationships between the biological entities represented by the nodes; wherein one or more edges is associated with a direction value that represents a causal activation or causal suppression relationship between the biological entities represented by the nodes, and wherein each node is connected by an edge to at least one other node; (b) receiving (i) a first set of data corresponding to activities of a first subset of biological entities obtained under a first set of conditions; and (ii) a second set of data corresponding to activities of the first subset of biological entities obtained under a second set of conditions different from the first set of conditions, wherein the first and second sets of conditions relate to the phenotype; (c) calculating a set of activity measures for a first subset of nodes corresponding to the first subset of biological entities, the activity measure representing a difference between the first set of data and the second set of data; (d) generating a set of activity values for a second subset of nodes representing candidates of biological entities that contribute to the phenotype but whose activities are not measured, based on the computational causal network model and the set of activity measures; (e) generating, using a machine learning technique, a classifier for the phenotypes based on the set of activity measures, the set of activity values, or both. | 1,600 |
773 | 16,012,988 | 1,617 | Compositions of the present invention include sunscreen compositions containing a primary UV-absorbing agent in an amount effective to absorb ultraviolet (UV) and about 5% or less of a visible light radiation agent that includes a continuous silica-containing coating. | 1-10. (canceled) 11. A method of protecting skin against visible light radiation, which comprises topically applying to skin a sunscreen composition, comprising:
about 1.0% or more of disodium phenyldibenzimidazole tetrasulfonate; and about 0.5 to 2% of a visible light absorbing agent comprising titanium dioxide, wherein said visible light absorbing agent comprises a silica-containing film and wherein said silica-containing film is essentially free of alumina. 12. The method of claim 11, wherein the thickness of said film on said visible light absorbing agent is from about 0.1 to about 100 nm. 13. The method of claim 11, wherein said silica-containing coating is continuous. 14. The method of claim 11, wherein said composition further comprises a secondary UV-absorbing agent. 15. A method of protecting skin against visible light radiation, which comprises topically applying to skin a sunscreen composition, comprising:
about 1.5% of disodium phenyldibenzimidazole tetrasulfonate; about 1% of titanium dioxide comprising a silica-containing film wherein said silica-containing film is essentially free of alumina; about 2.5% of phenylbenzimidazole sulfonic acid; about 1.5% of bis-ethylhexyloxyphenol methoxyphenyl triazine; about 1.5% of butyl methoxydibenzoylmethane; about 2% of octocrylene; about 1.5% of methylene bis-benzotriazolyl betramethylbutylphenol; about 1.5% of ethylhexyl triazone; and about 1.5% of homosalate. | Compositions of the present invention include sunscreen compositions containing a primary UV-absorbing agent in an amount effective to absorb ultraviolet (UV) and about 5% or less of a visible light radiation agent that includes a continuous silica-containing coating.1-10. (canceled) 11. A method of protecting skin against visible light radiation, which comprises topically applying to skin a sunscreen composition, comprising:
about 1.0% or more of disodium phenyldibenzimidazole tetrasulfonate; and about 0.5 to 2% of a visible light absorbing agent comprising titanium dioxide, wherein said visible light absorbing agent comprises a silica-containing film and wherein said silica-containing film is essentially free of alumina. 12. The method of claim 11, wherein the thickness of said film on said visible light absorbing agent is from about 0.1 to about 100 nm. 13. The method of claim 11, wherein said silica-containing coating is continuous. 14. The method of claim 11, wherein said composition further comprises a secondary UV-absorbing agent. 15. A method of protecting skin against visible light radiation, which comprises topically applying to skin a sunscreen composition, comprising:
about 1.5% of disodium phenyldibenzimidazole tetrasulfonate; about 1% of titanium dioxide comprising a silica-containing film wherein said silica-containing film is essentially free of alumina; about 2.5% of phenylbenzimidazole sulfonic acid; about 1.5% of bis-ethylhexyloxyphenol methoxyphenyl triazine; about 1.5% of butyl methoxydibenzoylmethane; about 2% of octocrylene; about 1.5% of methylene bis-benzotriazolyl betramethylbutylphenol; about 1.5% of ethylhexyl triazone; and about 1.5% of homosalate. | 1,600 |
774 | 15,481,884 | 1,628 | Disclosed herein are cationic steroidal antimicrobials (“CSA compounds” or “ceragenins”) and methods of making the same. Particularly advantageous methods are identified for the synthesis of CSA compounds. CSA compounds may be formulated for treating subjects with ailments responsive to CSA compounds, including but not limited to treating bacterial infections. Accordingly, some embodiments include formulations and methods of administering CSA compounds. | 1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein
R1 is selected from the group consisting of an optionally substituted C11-22-alkylamino-Cx-alkyl; an optionally substituted C8-22-alkylester-Cx-alkyl; and optionally substituted Z1, Z2-amino-Cx-alkyl;
R2, R3, and R4, are independently selected from the group consisting of optionally substituted amino-Ca-alkyl and optionally substituted amino-Ca-alkylcarbonyl;
x is 1-5;
Z1 and Z2 are independently C6-22-alkyl; and
a is 2-5,
with the proviso that when R2, R3, and R4 are each unsubstituted amino-C3-alkyl, R1 is not unsubstituted C16-alkylamino-C3-alkyl,
with the proviso that when R2, R3, and R4 are each the same unsubstituted amino-C2-4-alkylcarbonyl, R1 is not unsubstituted C9-alkylcarboxylic ester-C2-alkyl, and
with the proviso that when R2, R3, and R4 are each unsubstituted amino-C3-alkyl, Z1 and Z2 are not both C8-alkyl. 2. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein R1 is an optionally substituted C11-22-alkylamino-Cx-alkyl. 3. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 2, wherein R1 is an optionally substituted C11-15-alkylamino-Cx-alkyl. 4. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 2, wherein R1 is an optionally substituted C16-alkylamino-Cx-alkyl, with the proviso that R2, R3, and R4 are not all unsubstituted amino-C3-alkyl. 5. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 2, wherein R1 is an optionally substituted C17-C22-alkylamino-Cx-alkyl. 6. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein R1 is an optionally substituted C8-22-alkylester-Cx-alkyl. 7. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 6, wherein R1 is an optionally substituted C8-alkylester-Cx-alkyl . 8. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 6, wherein R1 is an optionally substituted C9-alkylester-Cx-alkyl, with the proviso that when R1 is an unsubstituted C9-alkylcarboxylic ester-C2-alkyl, R2, R3, and R4 are not all the same unsubstituted amino-C2-4-alkylcarbonyl. 9. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 6, wherein R1 is an optionally substituted C10-alkylester-Cx-alkyl . 10. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 6, wherein R1 is an optionally substituted C11-alkylester-Cx-alkyl . 11. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 6, wherein R1 is an optionally substituted C12-22-alkylester-Cx-alkyl. 12. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 6, wherein the ester is a carboxlic ester selected from oxycarbonyl or carbonyloxy. 13. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein R1 is an optionally substituted Z1, Z2-amino-Cx-alkyl. 14. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 13, wherein Z1 and Z2 are the same. 15. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 13, wherein Z1 and Z2 are different. 16. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 13, wherein at least one or Z1 or Z2 is C6-7-alkyl. 17. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 13, wherein at least one of Z1 or Z2 is C8-alkyl, with the proviso that when R2, R3, and R4 are amino-C3-alkyl Z1 and Z2 are not both C8-alkyl. 18. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 13, wherein at least one or Z1 or Z2 is C9-22-alkyl. 19. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein x is 1. 20. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein x is 2. 21. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein x is 3. 22. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein x is 4. 23. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein x is 5. 24. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein two or three of R2, R3, and R4 are the same. 25. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein R2, R3, and R4 are all different. 26. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein a is 2. 27. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein a is 3. 28. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein a is 4. 29. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein a is 5. 30. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein R2, R3, and R4 are optionally substituted amino-Ca-alkyl. 31. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein R2, R3, and R4 are optionally substituted amino-Ca-alkylcarbonyl. 32. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein one or more of R1, R2, R3, and R4 is unsubstituted. 33. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein two or more of R1, R2, R3, and R4 are unsubstituted. 34. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein three or more of R1, R2, R3, and R4 are unsubstituted. 35. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein R1, R2, R3, and R4 are unsubstituted. 36. A pharmaceutical composition comprising at one compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1 and a pharmaceutically acceptable excipient. 37. A pharmaceutical composition as in claim 36, wherein the pharmaceutically acceptable excipient comprises a liquid. 38. A pharmaceutical composition as in claim 36, wherein the pharmaceutically acceptable excipient comprises a solid. 39. A composition of matter comprising at one compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1 and at least one carrier. 40. A composition of matter as in claim 39, wherein the carrier is a liquid. 41. A composition of matter as in claim 39, wherein the carrier is a solid. 42. A cationic steroidal antimicrobial (CSA) compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof 43. A cationic steroidal antimicrobial CSA compound as in claim 42, wherein the CSA compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof 44. A cationic steroidal antimicrobial CSA compound as in claim 42, wherein the CSA compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof 45. A cationic steroidal antimicrobial CSA compound as in claim 42, wherein the CSA compound is selected from the group consisting of:
pharmaceutically acceptable salts thereof | Disclosed herein are cationic steroidal antimicrobials (“CSA compounds” or “ceragenins”) and methods of making the same. Particularly advantageous methods are identified for the synthesis of CSA compounds. CSA compounds may be formulated for treating subjects with ailments responsive to CSA compounds, including but not limited to treating bacterial infections. Accordingly, some embodiments include formulations and methods of administering CSA compounds.1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein
R1 is selected from the group consisting of an optionally substituted C11-22-alkylamino-Cx-alkyl; an optionally substituted C8-22-alkylester-Cx-alkyl; and optionally substituted Z1, Z2-amino-Cx-alkyl;
R2, R3, and R4, are independently selected from the group consisting of optionally substituted amino-Ca-alkyl and optionally substituted amino-Ca-alkylcarbonyl;
x is 1-5;
Z1 and Z2 are independently C6-22-alkyl; and
a is 2-5,
with the proviso that when R2, R3, and R4 are each unsubstituted amino-C3-alkyl, R1 is not unsubstituted C16-alkylamino-C3-alkyl,
with the proviso that when R2, R3, and R4 are each the same unsubstituted amino-C2-4-alkylcarbonyl, R1 is not unsubstituted C9-alkylcarboxylic ester-C2-alkyl, and
with the proviso that when R2, R3, and R4 are each unsubstituted amino-C3-alkyl, Z1 and Z2 are not both C8-alkyl. 2. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein R1 is an optionally substituted C11-22-alkylamino-Cx-alkyl. 3. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 2, wherein R1 is an optionally substituted C11-15-alkylamino-Cx-alkyl. 4. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 2, wherein R1 is an optionally substituted C16-alkylamino-Cx-alkyl, with the proviso that R2, R3, and R4 are not all unsubstituted amino-C3-alkyl. 5. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 2, wherein R1 is an optionally substituted C17-C22-alkylamino-Cx-alkyl. 6. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein R1 is an optionally substituted C8-22-alkylester-Cx-alkyl. 7. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 6, wherein R1 is an optionally substituted C8-alkylester-Cx-alkyl . 8. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 6, wherein R1 is an optionally substituted C9-alkylester-Cx-alkyl, with the proviso that when R1 is an unsubstituted C9-alkylcarboxylic ester-C2-alkyl, R2, R3, and R4 are not all the same unsubstituted amino-C2-4-alkylcarbonyl. 9. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 6, wherein R1 is an optionally substituted C10-alkylester-Cx-alkyl . 10. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 6, wherein R1 is an optionally substituted C11-alkylester-Cx-alkyl . 11. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 6, wherein R1 is an optionally substituted C12-22-alkylester-Cx-alkyl. 12. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 6, wherein the ester is a carboxlic ester selected from oxycarbonyl or carbonyloxy. 13. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein R1 is an optionally substituted Z1, Z2-amino-Cx-alkyl. 14. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 13, wherein Z1 and Z2 are the same. 15. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 13, wherein Z1 and Z2 are different. 16. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 13, wherein at least one or Z1 or Z2 is C6-7-alkyl. 17. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 13, wherein at least one of Z1 or Z2 is C8-alkyl, with the proviso that when R2, R3, and R4 are amino-C3-alkyl Z1 and Z2 are not both C8-alkyl. 18. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 13, wherein at least one or Z1 or Z2 is C9-22-alkyl. 19. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein x is 1. 20. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein x is 2. 21. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein x is 3. 22. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein x is 4. 23. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein x is 5. 24. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein two or three of R2, R3, and R4 are the same. 25. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein R2, R3, and R4 are all different. 26. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein a is 2. 27. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein a is 3. 28. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein a is 4. 29. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein a is 5. 30. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein R2, R3, and R4 are optionally substituted amino-Ca-alkyl. 31. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein R2, R3, and R4 are optionally substituted amino-Ca-alkylcarbonyl. 32. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein one or more of R1, R2, R3, and R4 is unsubstituted. 33. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein two or more of R1, R2, R3, and R4 are unsubstituted. 34. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein three or more of R1, R2, R3, and R4 are unsubstituted. 35. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1, wherein R1, R2, R3, and R4 are unsubstituted. 36. A pharmaceutical composition comprising at one compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1 and a pharmaceutically acceptable excipient. 37. A pharmaceutical composition as in claim 36, wherein the pharmaceutically acceptable excipient comprises a liquid. 38. A pharmaceutical composition as in claim 36, wherein the pharmaceutically acceptable excipient comprises a solid. 39. A composition of matter comprising at one compound of Formula (I), or a pharmaceutically acceptable salt thereof, as in claim 1 and at least one carrier. 40. A composition of matter as in claim 39, wherein the carrier is a liquid. 41. A composition of matter as in claim 39, wherein the carrier is a solid. 42. A cationic steroidal antimicrobial (CSA) compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof 43. A cationic steroidal antimicrobial CSA compound as in claim 42, wherein the CSA compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof 44. A cationic steroidal antimicrobial CSA compound as in claim 42, wherein the CSA compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof 45. A cationic steroidal antimicrobial CSA compound as in claim 42, wherein the CSA compound is selected from the group consisting of:
pharmaceutically acceptable salts thereof | 1,600 |
775 | 14,506,209 | 1,619 | In an embodiment, the present invention is directed a method of achieving hair volume and combability comprising applying to hair a personal care composition comprising from about 0.25% to about 80% of a pre-emulsified emulsion comprising from about 0.005% to about 80% of one or more materials selected from the group comprising metathesized unsaturated polyol esters, sucrose polyesters, fatty esters with a molecular weight greater than or equal to 1500 and mixtures thereof or, by weight of said hair care composition; wherein an emulsifier is selected from the group consisting of anionic, non-ionic, cationic, amphoteric and mixtures thereof wherein the average particle size of the pre-emulsified emulsion is from about 20 nanometers to 20 microns; from about 5% to about 50% of one or more anionic surfactants, by weight of said hair care composition; from about 5% to about 40% of a gel matrix comprising:
(i) from 0.1% to 30% of one or more fatty alcohols, by weight of the gel matrix; (ii) from 0.1% to 15% of one or more surfactants, by weight of the gel matrix; and (iii) from 20% to 95% of an aqueous carrier, by weight of the gel matrix; d) at least about 20% of an aqueous carrier, by weight of said hair care composition; wherein the hair has a dry static friction index in the range of about 1.05-3 and a dry and wet combing index of larger than or equal to about 1.5. | 1. A method of achieving hair volume and combability comprising applying to hair a personal care composition comprising:
a) from about 0.25% to about 80% of a pre-emulsified emulsion comprising from about 0.005% to about 80% of one or more materials selected from the group comprising metathesized unsaturated polyol esters, sucrose polyesters, fatty esters with a molecular weight greater than or equal to 1500 and mixtures thereof or, by weight of said hair care composition; wherein an emulsifier is selected from the group consisting of anionic, non-ionic, cationic, amphoteric and mixtures thereof wherein the average particle size of the pre-emulsified emulsion is from about 20 nanometers to 20 microns; b) from about 5% to about 50% of one or more anionic surfactants, by weight of said hair care composition; c) from about 5% to about 40% of a gel matrix comprising:
(i) from 0.1% to 30% of one or more fatty alcohols, by weight of the gel matrix;
(ii) from 0.1% to 15% of one or more surfactants, by weight of the gel matrix; and
(iii) from 20% to 95% of an aqueous carrier, by weight of the gel matrix;
d) at least about 20% of an aqueous carrier, by weight of said hair care composition; wherein the hair has a dry static friction index in the range of about 1.05-3 and a dry and wet combing index of larger than or equal to about 1.5. 2. The method according to claim 1 wherein the average particle size of the pre-emulsified emulsion is from about 100 nm to 20 microns. 3. The method according to claim 1 wherein in the personal care composition the average particle size of the metathesized unsaturated polyol esters, sucrose polyesters, or fatty esters in the hair care composition is from about 100 nm to 15 microns. 4. The method according to claim 1 wherein the sucrose polyester is sefose. 5. The method according to claim 1 wherein the emulsifier is selected from the group consisting of anionic, non-ionic, cationic, amphoteric and mixtures thereof. 6. The method according to claim 1 wherein the aqueous carrier is a water-miscible solvent. 7. The method according to claim 1 wherein the preemulsion comprise 0.25% to 50% of a comprising metathesized unsaturated polyol esters, sucrose polyesters, sucrose ester, or fatty esters or mixtures therefore. 8. The method according to claim 1 wherein said one or more oligomers is a triglyceride oligomer. 9. The method according to claim 8 wherein said triglyceride oligomer is a soy oligomer. 10. The method according to claim 9 wherein said soy oligomer is fully hydrogenated. 11. The method according to claim 9 wherein said soy oligomer is about 80% hydrogenated or more. 12. The method according to claim 9 wherein said soy oligomer is about 80% non-hydrogenated or more. 13. The method according to claim 1 wherein said one or more anionic surfactants is sodium laureth sulfate. 14. The method according to claim 1 further comprising from about 0.02% to about 2% of a cationic polymer, by weight of said personal care composition. 15. The method according to claim 1 wherein said hair care composition further comprises one or more additional conditioning agents. 16. The method according to claim 15 wherein said one or more additional conditioning agents is a silicone. 17. The method according to claim 1 wherein said personal care composition further comprises one or more additional benefit agents. 18. The method according to claim 17 wherein said one or more additional benefit agents is selected from the group consisting of anti-dandruff agents, vitamins, chelants, perfumes, brighteners, enzymes, sensates, attractants, anti-bacterial agents, dyes, pigments, bleaches, and mixtures thereof. 19. The method according to claim 18 wherein the anti-dandruff agent is a polyvalent metal salt of pyrithione. 20. The method according to claim 19 wherein the anti-dandruff agent is zinc pyrithione. 21. The method according to claim 1 wherein said personal care composition further comprises a zinc-containing layered material. 22. The method according to claim 21 wherein the zinc-containing layered material is basic zinc carbonate. 23. The method according to claim 1 wherein said one or more oligomers are self-metathesized. 24. The method according to claim 1 wherein said one or more oligomers are cross-metathesized. 25. The method according to claim 1 wherein said hair care composition further comprises one or more non-metathesized unsaturated polyol esters. 26. The method according to claim 25 wherein said one or more non-metathesized unsaturated polyol esters includes a soy bean oil and other natural oils. 27. A method for cleansing hair comprising the step of applying an effective amount of the hair care composition of claim 1 to the hair. 28. The method according to claim 1 wherein there is an increase deposition of silicone when in combination with materials selected from the group comprising metathesized unsaturated polyol esters, sucrose polyesters, fatty esters of with a molecular weight greater than or equal to 1500 and mixtures thereof. 29. The method according to claim 1 wherein the personal care composition has increased stability. | In an embodiment, the present invention is directed a method of achieving hair volume and combability comprising applying to hair a personal care composition comprising from about 0.25% to about 80% of a pre-emulsified emulsion comprising from about 0.005% to about 80% of one or more materials selected from the group comprising metathesized unsaturated polyol esters, sucrose polyesters, fatty esters with a molecular weight greater than or equal to 1500 and mixtures thereof or, by weight of said hair care composition; wherein an emulsifier is selected from the group consisting of anionic, non-ionic, cationic, amphoteric and mixtures thereof wherein the average particle size of the pre-emulsified emulsion is from about 20 nanometers to 20 microns; from about 5% to about 50% of one or more anionic surfactants, by weight of said hair care composition; from about 5% to about 40% of a gel matrix comprising:
(i) from 0.1% to 30% of one or more fatty alcohols, by weight of the gel matrix; (ii) from 0.1% to 15% of one or more surfactants, by weight of the gel matrix; and (iii) from 20% to 95% of an aqueous carrier, by weight of the gel matrix; d) at least about 20% of an aqueous carrier, by weight of said hair care composition; wherein the hair has a dry static friction index in the range of about 1.05-3 and a dry and wet combing index of larger than or equal to about 1.5.1. A method of achieving hair volume and combability comprising applying to hair a personal care composition comprising:
a) from about 0.25% to about 80% of a pre-emulsified emulsion comprising from about 0.005% to about 80% of one or more materials selected from the group comprising metathesized unsaturated polyol esters, sucrose polyesters, fatty esters with a molecular weight greater than or equal to 1500 and mixtures thereof or, by weight of said hair care composition; wherein an emulsifier is selected from the group consisting of anionic, non-ionic, cationic, amphoteric and mixtures thereof wherein the average particle size of the pre-emulsified emulsion is from about 20 nanometers to 20 microns; b) from about 5% to about 50% of one or more anionic surfactants, by weight of said hair care composition; c) from about 5% to about 40% of a gel matrix comprising:
(i) from 0.1% to 30% of one or more fatty alcohols, by weight of the gel matrix;
(ii) from 0.1% to 15% of one or more surfactants, by weight of the gel matrix; and
(iii) from 20% to 95% of an aqueous carrier, by weight of the gel matrix;
d) at least about 20% of an aqueous carrier, by weight of said hair care composition; wherein the hair has a dry static friction index in the range of about 1.05-3 and a dry and wet combing index of larger than or equal to about 1.5. 2. The method according to claim 1 wherein the average particle size of the pre-emulsified emulsion is from about 100 nm to 20 microns. 3. The method according to claim 1 wherein in the personal care composition the average particle size of the metathesized unsaturated polyol esters, sucrose polyesters, or fatty esters in the hair care composition is from about 100 nm to 15 microns. 4. The method according to claim 1 wherein the sucrose polyester is sefose. 5. The method according to claim 1 wherein the emulsifier is selected from the group consisting of anionic, non-ionic, cationic, amphoteric and mixtures thereof. 6. The method according to claim 1 wherein the aqueous carrier is a water-miscible solvent. 7. The method according to claim 1 wherein the preemulsion comprise 0.25% to 50% of a comprising metathesized unsaturated polyol esters, sucrose polyesters, sucrose ester, or fatty esters or mixtures therefore. 8. The method according to claim 1 wherein said one or more oligomers is a triglyceride oligomer. 9. The method according to claim 8 wherein said triglyceride oligomer is a soy oligomer. 10. The method according to claim 9 wherein said soy oligomer is fully hydrogenated. 11. The method according to claim 9 wherein said soy oligomer is about 80% hydrogenated or more. 12. The method according to claim 9 wherein said soy oligomer is about 80% non-hydrogenated or more. 13. The method according to claim 1 wherein said one or more anionic surfactants is sodium laureth sulfate. 14. The method according to claim 1 further comprising from about 0.02% to about 2% of a cationic polymer, by weight of said personal care composition. 15. The method according to claim 1 wherein said hair care composition further comprises one or more additional conditioning agents. 16. The method according to claim 15 wherein said one or more additional conditioning agents is a silicone. 17. The method according to claim 1 wherein said personal care composition further comprises one or more additional benefit agents. 18. The method according to claim 17 wherein said one or more additional benefit agents is selected from the group consisting of anti-dandruff agents, vitamins, chelants, perfumes, brighteners, enzymes, sensates, attractants, anti-bacterial agents, dyes, pigments, bleaches, and mixtures thereof. 19. The method according to claim 18 wherein the anti-dandruff agent is a polyvalent metal salt of pyrithione. 20. The method according to claim 19 wherein the anti-dandruff agent is zinc pyrithione. 21. The method according to claim 1 wherein said personal care composition further comprises a zinc-containing layered material. 22. The method according to claim 21 wherein the zinc-containing layered material is basic zinc carbonate. 23. The method according to claim 1 wherein said one or more oligomers are self-metathesized. 24. The method according to claim 1 wherein said one or more oligomers are cross-metathesized. 25. The method according to claim 1 wherein said hair care composition further comprises one or more non-metathesized unsaturated polyol esters. 26. The method according to claim 25 wherein said one or more non-metathesized unsaturated polyol esters includes a soy bean oil and other natural oils. 27. A method for cleansing hair comprising the step of applying an effective amount of the hair care composition of claim 1 to the hair. 28. The method according to claim 1 wherein there is an increase deposition of silicone when in combination with materials selected from the group comprising metathesized unsaturated polyol esters, sucrose polyesters, fatty esters of with a molecular weight greater than or equal to 1500 and mixtures thereof. 29. The method according to claim 1 wherein the personal care composition has increased stability. | 1,600 |
776 | 13,832,394 | 1,619 | Phenylephrine particles suitable for solid, semi solid or liquid dosage forms are disclosed. | 1. A drug-resin complex comprising phenylephrine and a cation polystyrene sulfonate, wherein said cation polystyrene sulfonate comprises particle sizes of about 74 μm to about 177 μm prior to being combined with the phenylephrine. 2. The drug-resin complex of claim 1, wherein the cation is selected from the group consisting of sodium, copper, zinc, iron, calcium, strontium, magnesium and lithium. 3. The drug-resin complex of claim 2, wherein the cation is sodium. 4. An extended release particle, wherein said extended release particle comprises the drug-resin complex of claim 3 coated with a coating. 5. The extended release particle of claim 4, wherein the coating comprises a cellulose material. 6. The extended release particle of claim 5, wherein the cellulose material is selected from the group consisting of cellulose acetate and hydroxypropylcellulose. 7. A pharmaceutical formulation comprising the extended release particle of claim 6. 8. The pharmaceutical formulation of claim 7, further comprising an immediate release form of phenylephrine. 9. A method of forming a coated drug-resin complex, comprising coating the drug-resin complex of claim 1. 10. The drug-resin complex of claim 1, wherein at least about 50% of the particles have particle sizes of about 74 μm to about 177 μm. 11. The drug-resin complex of claim 10, wherein at least about 80% of the particles have a particle sizes of about 74 μm to about 177 μm. 12. The drug-resin complex of claim 11, wherein at least about 90% of the particles have a particle sizes of about 74 μm to about 177 μm. 13. The drug-resin complex of claim 1, wherein less than 15% of the particles have a particle size less than about 44 μm. | Phenylephrine particles suitable for solid, semi solid or liquid dosage forms are disclosed.1. A drug-resin complex comprising phenylephrine and a cation polystyrene sulfonate, wherein said cation polystyrene sulfonate comprises particle sizes of about 74 μm to about 177 μm prior to being combined with the phenylephrine. 2. The drug-resin complex of claim 1, wherein the cation is selected from the group consisting of sodium, copper, zinc, iron, calcium, strontium, magnesium and lithium. 3. The drug-resin complex of claim 2, wherein the cation is sodium. 4. An extended release particle, wherein said extended release particle comprises the drug-resin complex of claim 3 coated with a coating. 5. The extended release particle of claim 4, wherein the coating comprises a cellulose material. 6. The extended release particle of claim 5, wherein the cellulose material is selected from the group consisting of cellulose acetate and hydroxypropylcellulose. 7. A pharmaceutical formulation comprising the extended release particle of claim 6. 8. The pharmaceutical formulation of claim 7, further comprising an immediate release form of phenylephrine. 9. A method of forming a coated drug-resin complex, comprising coating the drug-resin complex of claim 1. 10. The drug-resin complex of claim 1, wherein at least about 50% of the particles have particle sizes of about 74 μm to about 177 μm. 11. The drug-resin complex of claim 10, wherein at least about 80% of the particles have a particle sizes of about 74 μm to about 177 μm. 12. The drug-resin complex of claim 11, wherein at least about 90% of the particles have a particle sizes of about 74 μm to about 177 μm. 13. The drug-resin complex of claim 1, wherein less than 15% of the particles have a particle size less than about 44 μm. | 1,600 |
777 | 15,099,737 | 1,617 | An aqueous skin cosmetic product exerting a high irregularity correction effect, providing a non-greasy and light feeling when applied and having an excellent sebum suppressing effect is provided. The skin cosmetic product of the present invention is characterized by comprising (A) 15 to 50% by mass of a powder formed of an (adipic acid/neopentyl glycol) crosspolymer and (B) 0.5 to 3% by mass of a hydrophobically modified polyurethane. (PEG-240/Decyltetradeceth-20/HDI) copolymer is preferable as the hydrophobically modified polyurethane, It is preferable that the skin cosmetic product is a gel having a viscosity of 15,000 mPa·s or more and 200,000 mPa·s or less. | 1. A skin cosmetic product comprising:
(A) 15 to 50% by mass of a powder formed of an (adipic acid/neopentyl glycol) crosspolymer, and (B) 0.5 to 3% by mass of a hydrophobically modified polyurethane. 2. The skin cosmetic product according to claim 1, wherein:
the hydrophobically modified polyurethane is (PEG-240/Decyltetradeceth-20/HDI) copolymer. 3. The skin cosmetic product according to claim 1, wherein:
the skin cosmetic product is a gel having a viscosity of 15,000 mPa·s or more and 200,000 mPa·s or less. 4. The skin cosmetic product according to claim 1, wherein:
the skin cosmetic is an aqueous cosmetic product having an oil content of at most 20% by mass or less. 5. The skin cosmetic product according to claim 3, wherein:
the skin cosmetic is an aqueous cosmetic product having an oil content of at most 20% by mass or less. | An aqueous skin cosmetic product exerting a high irregularity correction effect, providing a non-greasy and light feeling when applied and having an excellent sebum suppressing effect is provided. The skin cosmetic product of the present invention is characterized by comprising (A) 15 to 50% by mass of a powder formed of an (adipic acid/neopentyl glycol) crosspolymer and (B) 0.5 to 3% by mass of a hydrophobically modified polyurethane. (PEG-240/Decyltetradeceth-20/HDI) copolymer is preferable as the hydrophobically modified polyurethane, It is preferable that the skin cosmetic product is a gel having a viscosity of 15,000 mPa·s or more and 200,000 mPa·s or less.1. A skin cosmetic product comprising:
(A) 15 to 50% by mass of a powder formed of an (adipic acid/neopentyl glycol) crosspolymer, and (B) 0.5 to 3% by mass of a hydrophobically modified polyurethane. 2. The skin cosmetic product according to claim 1, wherein:
the hydrophobically modified polyurethane is (PEG-240/Decyltetradeceth-20/HDI) copolymer. 3. The skin cosmetic product according to claim 1, wherein:
the skin cosmetic product is a gel having a viscosity of 15,000 mPa·s or more and 200,000 mPa·s or less. 4. The skin cosmetic product according to claim 1, wherein:
the skin cosmetic is an aqueous cosmetic product having an oil content of at most 20% by mass or less. 5. The skin cosmetic product according to claim 3, wherein:
the skin cosmetic is an aqueous cosmetic product having an oil content of at most 20% by mass or less. | 1,600 |
778 | 14,657,523 | 1,623 | A method for digestion of a crude terephthalic slurry obtained from oxidation of para-xylene in a bubble column reactor oxidation process is provided. The method is conducted in one or more bubble column reactors having one or more segregrated zones defined by horizontal baffles and particle flow through the digestion system is controlled to maximize conversion of partial oxidation intermediates to terephthalic acid while minimizing formation of other contaminant products. Temperature, oxygen flow and content as well as other process and equipment variables are controlled throughout the process to support formation of terephthalic acid. Also provided are bubble column digestion systems structured to conduct the digestion method. | 1. A method for purification of crude terephthalic acid comprising:
a) obtaining a digester feed slurry of particles of crude terephthalic acid, comprising terephthalic acid, 4-carboxybenzaldehyde and p-toluic acid in a solvent liquid comprising aqueous acetic acid and a catalyst system comprising at least one heavy metal compound; b) feeding the crude terephthalic acid slurry to a first digestion zone of a bubble column system; c) heating the crude terephthalic acid slurry to a temperature of from about 150° C. to about 280° C. either before entry to the first digestion zone or when within the first digestion zone; d) supplying a gas comprising oxygen to the first digestion zone where the superficial velocity of the gas rising near the top of the first digestion zone is in a range of from about 0.1 cm/s to about 8 cm/s; e) at least partially dissolving particles of crude terephthalic acid in the acetic acid thereby releasing at least some 4-carboxybenzaldehyde and p-toluic acid from the particles and exposing the dissolved 4-carboxybenzaldehyde and p-toluic acid to the oxygen to effect oxidation to terephthalic acid, and to obtain a first stage digester slurry; f) passing the first stage digester slurry to a second digestion zone which is optionally located vertically beneath the first digestion zone; g) supplying a gas comprising oxygen to a lower portion of the second digestion zone; wherein a supply rate of the gas to the second digestion zone is less than the rate of supply to the first digestion zone; and h) dissolving and releasing additional 4-carboxybenzaldehyde and p-toluic acid from the particles and exposing the dissolved 4-carboxybenzaldehyde and p-toluic acid to the oxygen to effect additional oxidation to terephthalic acid, and to obtain a second stage digester slurry; i) optionally, moving the second stage digester slurry through one or more further digestion zones structured similar to the second digestion zone and optionally vertically beneath the second digestion zone; j) removing the resulting terephthalic acid crystal slurry from the last digestion zone; and k) isolating the obtained terephthalic acid crystal particles. 2. The method of claim 1, wherein the superficial velocity of the gas rising in the second digestion zone is less than 1 cm/sec. 3. The method of claim 1, wherein a mean particle size of the crude terephthalic acid is from 20 to 150 microns. 4. The method of claim 1, wherein a BET surface area of the crude terephthalic acid is from 0.6 to 4.0 m2/g. 5. The method of claim 1, wherein a retention time of the particles in the first digestion zone is from 10 to 60 minutes. 6. The method of claim 1, wherein a temperature of the CTA slurry within the first digestion zone is from 180 to 230° C. 7. The method of claim 1, wherein a temperature of at least one digestion zone is at least 10° C. higher than the temperature of the CTA slurry when obtained from a primary oxidation system. 8. The method of claim 1 wherein a total residence time of the terephthalic acid particles in the first and second digestion zones is from 60 to 120 minutes. 9. The method of claim 1 wherein an oxygen content of the exhaust gas is 6% by volume or less, according to dry basis measurement. 10. The method of claim 1, wherein a mean particle size of the terephthalic acid particle at the outlet of the digestion is from 60 to 100 microns. 11. The method of claim 1, wherein a gas mixing power summed for all zones of the digestion is less than about 0.2 Watt/kg of slurry. 12. The method of claim 11, wherein the gas mixing power summed for all zones of the digestion is less than about 0.05 Watt/kg of slurry. 13. The method of claim 1 wherein a maximum time-averaged, area averaged bubble hold-up within the bubble column is less than about 6 percent. 14. The method of claim 1, wherein a maximum time-averaged, area averaged bubble hold-up within at least one zone of the bubble column is less than about 2 percent. 15. The method of claim 1, wherein an overall digestion RTD for each of the solid, liquid, and combined slurry phases has a CMF(0.5) of less than about 0.35 and a CMF(1.5) of more than about 0.80. 16. The method of claim 1, wherein at least about 25 percent of the molecular oxygen supply for the first digestion zone is combined with the CTA slurry within about 8 minutes after the digester feed slurry is first heated at least about 10° C. above the temperature at the exit from initial oxidation. 17. The method of claim 1, wherein at least about 25 percent of the molecular oxygen supply for the first digestion zone is fed into the first digestion zone comingled with the digester feed slurry. 18. The method of claim 1, wherein the temperature of at least about 50% of digester feed slurry is increased by at least about 10° C. using at least one non-contacting heat exchanger apparatus situated external to the bubble column. 19. The method of claim 18, wherein at least about 25 percent of the molecular oxygen supply for the first digestion zone is mixed with the digester feed slurry before the exit of the external heat exchanger. 20. The method of claim 1 wherein the first digestion zone is substantially free of mechanical agitation. 21. The method of claim 1 wherein the second and optional one or more further digestion zones are free of mechanical agitation. 22. An oxidative digestion system, comprising:
a series of at least two oxidative digestion zones arranged vertically in one bubble column reactor; a reactant inlet located in a lower portion of the first uppermost digestion zone; oxygen gas supply inlets to the first uppermost digestion zone and at least one zone in series vertically beneath the first uppermost zone; at least one horizontal baffle located between the first uppermost zone and the second zone vertically beneath; at least one horizontal baffle located between each respective vertically adjacent zones when more than one zone is present beneath the first uppermost zone; a product slurry outlet at the bottom of the at least one bubble column. wherein each oxygen gas supply comprises a gas distributor unit which feeds the oxygen gas into the zone as a bubbly flow, and each horizontal baffle comprises a tray having multiple inverted shaped sloped surfaces with multiple open areas. 23. The oxidation system of claim 22, further comprising an exhaust gas outlet having an oxygen content monitoring system. 24. The oxidation system of claim 22, wherein a total height of the bubble column is from 16 to 40 meters. 25. The oxidation system of claim 22, wherein a diameter of all zones is the same and is from 1.0 meters to 8.0 meters. 26. The oxidation system of claim 22, comprising 3 to 5 zones arranged vertically below the first uppermost zone. 27. The oxidation system of claim 22, wherein a height to diameter ratio of the first uppermost zone is from 1/1 to 4/1. 28. The oxidation system of claim 22, wherein the horizontal baffle comprises a plurality of laterally-spaced baffle members. 29. The oxidation system of claim 28, wherein the laterally-spaced baffle members each comprise a substantially cylindrical exposed outer surface. 30. The oxidation system of claim 22, wherein the horizontal baffle comprises an inverted V-shaped upwardly-facing exposed outer surface. 31. The oxidation system of claim 22, wherein each horizontal baffle comprises open area of from 25 to 75% of the total horizontal area of the baffle. 32. The oxidation system of claim 22, wherein the system is free of mechanical agitation. 33. A bubble column digestion system, comprising:
a first BCR unit, structured for convection flow; and at least one BCR unit structured for plug-flow in series following the first BCR unit; wherein the first BCR unit comprises: a slurry inlet in a central vertical position of the column; an oxygen containing gas inlet below the slurry inlet; a slurry outlet at a bottom of the column; a gas exhaust outlet at a top of the column equipped with an oxygen content monitor; and optionally, a horizontal baffle between the gas inlet and the slurry outlet; and wherein the at least one second BCR unit comprises: from 1 to 5 horizontally segregated zones, each zone optionally equipped with an oxygen gas inlet; horizontal baffles between each zone; a slurry inlet in a highest zone; and a slurry outlet at a bottom of the BCR unit; wherein at least one zone is equipped with an oxygen gas inlet. | A method for digestion of a crude terephthalic slurry obtained from oxidation of para-xylene in a bubble column reactor oxidation process is provided. The method is conducted in one or more bubble column reactors having one or more segregrated zones defined by horizontal baffles and particle flow through the digestion system is controlled to maximize conversion of partial oxidation intermediates to terephthalic acid while minimizing formation of other contaminant products. Temperature, oxygen flow and content as well as other process and equipment variables are controlled throughout the process to support formation of terephthalic acid. Also provided are bubble column digestion systems structured to conduct the digestion method.1. A method for purification of crude terephthalic acid comprising:
a) obtaining a digester feed slurry of particles of crude terephthalic acid, comprising terephthalic acid, 4-carboxybenzaldehyde and p-toluic acid in a solvent liquid comprising aqueous acetic acid and a catalyst system comprising at least one heavy metal compound; b) feeding the crude terephthalic acid slurry to a first digestion zone of a bubble column system; c) heating the crude terephthalic acid slurry to a temperature of from about 150° C. to about 280° C. either before entry to the first digestion zone or when within the first digestion zone; d) supplying a gas comprising oxygen to the first digestion zone where the superficial velocity of the gas rising near the top of the first digestion zone is in a range of from about 0.1 cm/s to about 8 cm/s; e) at least partially dissolving particles of crude terephthalic acid in the acetic acid thereby releasing at least some 4-carboxybenzaldehyde and p-toluic acid from the particles and exposing the dissolved 4-carboxybenzaldehyde and p-toluic acid to the oxygen to effect oxidation to terephthalic acid, and to obtain a first stage digester slurry; f) passing the first stage digester slurry to a second digestion zone which is optionally located vertically beneath the first digestion zone; g) supplying a gas comprising oxygen to a lower portion of the second digestion zone; wherein a supply rate of the gas to the second digestion zone is less than the rate of supply to the first digestion zone; and h) dissolving and releasing additional 4-carboxybenzaldehyde and p-toluic acid from the particles and exposing the dissolved 4-carboxybenzaldehyde and p-toluic acid to the oxygen to effect additional oxidation to terephthalic acid, and to obtain a second stage digester slurry; i) optionally, moving the second stage digester slurry through one or more further digestion zones structured similar to the second digestion zone and optionally vertically beneath the second digestion zone; j) removing the resulting terephthalic acid crystal slurry from the last digestion zone; and k) isolating the obtained terephthalic acid crystal particles. 2. The method of claim 1, wherein the superficial velocity of the gas rising in the second digestion zone is less than 1 cm/sec. 3. The method of claim 1, wherein a mean particle size of the crude terephthalic acid is from 20 to 150 microns. 4. The method of claim 1, wherein a BET surface area of the crude terephthalic acid is from 0.6 to 4.0 m2/g. 5. The method of claim 1, wherein a retention time of the particles in the first digestion zone is from 10 to 60 minutes. 6. The method of claim 1, wherein a temperature of the CTA slurry within the first digestion zone is from 180 to 230° C. 7. The method of claim 1, wherein a temperature of at least one digestion zone is at least 10° C. higher than the temperature of the CTA slurry when obtained from a primary oxidation system. 8. The method of claim 1 wherein a total residence time of the terephthalic acid particles in the first and second digestion zones is from 60 to 120 minutes. 9. The method of claim 1 wherein an oxygen content of the exhaust gas is 6% by volume or less, according to dry basis measurement. 10. The method of claim 1, wherein a mean particle size of the terephthalic acid particle at the outlet of the digestion is from 60 to 100 microns. 11. The method of claim 1, wherein a gas mixing power summed for all zones of the digestion is less than about 0.2 Watt/kg of slurry. 12. The method of claim 11, wherein the gas mixing power summed for all zones of the digestion is less than about 0.05 Watt/kg of slurry. 13. The method of claim 1 wherein a maximum time-averaged, area averaged bubble hold-up within the bubble column is less than about 6 percent. 14. The method of claim 1, wherein a maximum time-averaged, area averaged bubble hold-up within at least one zone of the bubble column is less than about 2 percent. 15. The method of claim 1, wherein an overall digestion RTD for each of the solid, liquid, and combined slurry phases has a CMF(0.5) of less than about 0.35 and a CMF(1.5) of more than about 0.80. 16. The method of claim 1, wherein at least about 25 percent of the molecular oxygen supply for the first digestion zone is combined with the CTA slurry within about 8 minutes after the digester feed slurry is first heated at least about 10° C. above the temperature at the exit from initial oxidation. 17. The method of claim 1, wherein at least about 25 percent of the molecular oxygen supply for the first digestion zone is fed into the first digestion zone comingled with the digester feed slurry. 18. The method of claim 1, wherein the temperature of at least about 50% of digester feed slurry is increased by at least about 10° C. using at least one non-contacting heat exchanger apparatus situated external to the bubble column. 19. The method of claim 18, wherein at least about 25 percent of the molecular oxygen supply for the first digestion zone is mixed with the digester feed slurry before the exit of the external heat exchanger. 20. The method of claim 1 wherein the first digestion zone is substantially free of mechanical agitation. 21. The method of claim 1 wherein the second and optional one or more further digestion zones are free of mechanical agitation. 22. An oxidative digestion system, comprising:
a series of at least two oxidative digestion zones arranged vertically in one bubble column reactor; a reactant inlet located in a lower portion of the first uppermost digestion zone; oxygen gas supply inlets to the first uppermost digestion zone and at least one zone in series vertically beneath the first uppermost zone; at least one horizontal baffle located between the first uppermost zone and the second zone vertically beneath; at least one horizontal baffle located between each respective vertically adjacent zones when more than one zone is present beneath the first uppermost zone; a product slurry outlet at the bottom of the at least one bubble column. wherein each oxygen gas supply comprises a gas distributor unit which feeds the oxygen gas into the zone as a bubbly flow, and each horizontal baffle comprises a tray having multiple inverted shaped sloped surfaces with multiple open areas. 23. The oxidation system of claim 22, further comprising an exhaust gas outlet having an oxygen content monitoring system. 24. The oxidation system of claim 22, wherein a total height of the bubble column is from 16 to 40 meters. 25. The oxidation system of claim 22, wherein a diameter of all zones is the same and is from 1.0 meters to 8.0 meters. 26. The oxidation system of claim 22, comprising 3 to 5 zones arranged vertically below the first uppermost zone. 27. The oxidation system of claim 22, wherein a height to diameter ratio of the first uppermost zone is from 1/1 to 4/1. 28. The oxidation system of claim 22, wherein the horizontal baffle comprises a plurality of laterally-spaced baffle members. 29. The oxidation system of claim 28, wherein the laterally-spaced baffle members each comprise a substantially cylindrical exposed outer surface. 30. The oxidation system of claim 22, wherein the horizontal baffle comprises an inverted V-shaped upwardly-facing exposed outer surface. 31. The oxidation system of claim 22, wherein each horizontal baffle comprises open area of from 25 to 75% of the total horizontal area of the baffle. 32. The oxidation system of claim 22, wherein the system is free of mechanical agitation. 33. A bubble column digestion system, comprising:
a first BCR unit, structured for convection flow; and at least one BCR unit structured for plug-flow in series following the first BCR unit; wherein the first BCR unit comprises: a slurry inlet in a central vertical position of the column; an oxygen containing gas inlet below the slurry inlet; a slurry outlet at a bottom of the column; a gas exhaust outlet at a top of the column equipped with an oxygen content monitor; and optionally, a horizontal baffle between the gas inlet and the slurry outlet; and wherein the at least one second BCR unit comprises: from 1 to 5 horizontally segregated zones, each zone optionally equipped with an oxygen gas inlet; horizontal baffles between each zone; a slurry inlet in a highest zone; and a slurry outlet at a bottom of the BCR unit; wherein at least one zone is equipped with an oxygen gas inlet. | 1,600 |
779 | 15,823,272 | 1,644 | An anti-Ang2 antibody or an antigen-binding fragment thereof that specifically binds to an angiogenesis-inducing factor Angiopoietin-2 (Ang2) and complexes with a Tie2 receptor and Ang2, and related methods and compositions. | 1.-24. (canceled) 25. A method of activating Tie-2 receptor in a subject, comprising administering an anti-Ang2 antibody or an antigen-binding fragment thereof to the subject to form a complex comprising the anti-Ang2 antibody or the antigen-binding fragment thereof, Ang2, and a Tie2 receptor, while inducing Tie2 phosphorylation,
wherein the anti-Ang2 antibody or the antigen-binding fragment thereof comprises: heavy chain complementarity determining regions (CDRs) comprising a polypeptide (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 1, a polypeptide (CDR-H2) comprising the amino acid sequence of SEQ ID NO: 2, and a polypeptide (CDR-H3) comprising the amino acid sequence of SEQ ID NO: 3; and light chain complementarity determining regions comprising a polypeptide (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 4, a polypeptide (CDR-L2) comprising the amino acid sequence of SEQ ID NO: 5, and a polypeptide (CDR-L3) comprising the amino acid sequence of SEQ ID NO: 6. 26. The method of claim 25, wherein the anti-Ang2 antibody or the antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 9. 27. The method of claim 25, wherein the anti-Ang2 antibody is a monoclonal antibody. 28. The method of claim 27, wherein the anti-Ang2 antibody is obtained from a hybridoma deposited with accession number KCLRF-BP-00295. 29. The method of claim 25, further comprising administering Ang2 to the subject. 30. A hybridoma cell line of accession number KCLRF-BP-00295. | An anti-Ang2 antibody or an antigen-binding fragment thereof that specifically binds to an angiogenesis-inducing factor Angiopoietin-2 (Ang2) and complexes with a Tie2 receptor and Ang2, and related methods and compositions.1.-24. (canceled) 25. A method of activating Tie-2 receptor in a subject, comprising administering an anti-Ang2 antibody or an antigen-binding fragment thereof to the subject to form a complex comprising the anti-Ang2 antibody or the antigen-binding fragment thereof, Ang2, and a Tie2 receptor, while inducing Tie2 phosphorylation,
wherein the anti-Ang2 antibody or the antigen-binding fragment thereof comprises: heavy chain complementarity determining regions (CDRs) comprising a polypeptide (CDR-H1) comprising the amino acid sequence of SEQ ID NO: 1, a polypeptide (CDR-H2) comprising the amino acid sequence of SEQ ID NO: 2, and a polypeptide (CDR-H3) comprising the amino acid sequence of SEQ ID NO: 3; and light chain complementarity determining regions comprising a polypeptide (CDR-L1) comprising the amino acid sequence of SEQ ID NO: 4, a polypeptide (CDR-L2) comprising the amino acid sequence of SEQ ID NO: 5, and a polypeptide (CDR-L3) comprising the amino acid sequence of SEQ ID NO: 6. 26. The method of claim 25, wherein the anti-Ang2 antibody or the antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 9. 27. The method of claim 25, wherein the anti-Ang2 antibody is a monoclonal antibody. 28. The method of claim 27, wherein the anti-Ang2 antibody is obtained from a hybridoma deposited with accession number KCLRF-BP-00295. 29. The method of claim 25, further comprising administering Ang2 to the subject. 30. A hybridoma cell line of accession number KCLRF-BP-00295. | 1,600 |
780 | 13,419,045 | 1,656 | The present invention relates to improved decorin compositions and methods of their production. | 1. A fusion protein comprising a heterologous signal peptide operably linked to a sequence encoding decorin. 2. The fusion protein of claim 1, wherein said signal sequence is an alpha-lactalbumin signal sequence. 3. The fusion protein of claim 2, wherein said alpha lactalbumin sequence is a bovine alpha-lactalbumin signal sequence. 4. The fusion protein of claim 1, wherein said sequence encoding decorin encodes a decorin core protein. 5. The fusion protein of claim 4, wherein said decorin core protein comprises a mutation at position 4 of the mature decorin core protein. 6. The fusion protein of claim 5, wherein said mutation is a serine to alanine mutation. 7. The fusion protein of claim 4, wherein said decorin core protein lacks substantial modification by glycosaminoglycans molecules at position 4 of the mature decorin core protein. 8. A vector encoding the fusion protein of claim 1. 9. The vector of claim 8, wherein said vector comprises a nucleic acid sequence encoding an alpha-lactalbumin signal sequence operably linked to a sequence encoding a decorin core protein. 10. A host cell comprising the vector of claim 8. 11. A method of producing a non-gagylated decorin core protein comprising:
providing host cells expressing non-gagylated decorin core protein; culturing said host cell so that said non-gagylated decorin core protein is produced; and purifying said non-gagylated decorin core protein. 12. The method of claim 11, wherein said non-gagylated decorin core protein is secreted into medium used to culture said host cells. 13. The method of claim 12, wherein said purifying comprises contacting said culture medium with an ion exchange medium. 14. The method of claim 12, wherein said purifying comprises contacting said culture medium with a hydroxyapatite medium. 15. The method of claim 12, wherein said purifying comprises contacting said culture medium with at least one ion exchange medium and at least one hydroxyapatite medium in any order. 16. The method of claim 12, wherein said purifying comprises:
contacting said culture medium with a cation exchange medium; washing said cation exchange medium; eluting a first decorin-containing eluate from said cation exchange medium; contacting said first decorin-containing eluate with a hydroxyapatite medium; washing said hydroxyapatite medium; eluting a second decorin-containing eluate from said hydroxyapatite medium. 17. The method of claim 16, wherein said cation exchange medium is SP-Sepharose FF. 18. The method of claim 16, wherein said hydroxyapatite medium is ceramic hydroxyapatite type I. 19. The method of claim 16, further comprising further purification of said second decorin-containing eluate with an ion exchange membrane or column. 20. The method of claim 19, wherein said ion exchange membrane is a Q ion exchange membrane. 21. The method of claim 16, further comprising a viral inactivation step. 22. The method of claim 21, wherein said viral inaction step comprises treatment with a surfactant. 23. The method of claim 22, wherein said surfactant is Triton X-100. 24. The method of claim 16, further comprising a viral filtration step. 25. The method of claim 16, further comprising concentrating said decorin. 26. The method of claim 11, wherein said non-gagylated decorin core protein is produced by said host cells at a rate of about greater than 1, 5, or 10 pg/cell/day. 27. A method for purifying decorin from a decorin-containing medium comprising:
contacting said decorin-containing medium with a cation exchange medium; washing said cation exchange medium; eluting a first decorin-containing eluate from said cation exchange medium; contacting said at first decorin-containing eluate with a hydroxyapatite medium; washing said hydroxyapatite medium; eluting a second decorin-containing eluate from said hydroxyapatite medium; filtering said second decorin-containing eluate with an ion exchange membrane to provide a decorin-containing filtrate; treating said filtrate to remove viruses; concentrating decorin from said filtrate. 28. A composition comprising a purified decorin core protein comprising a mutation at position 4 of the mature decorin core protein so that said decorin protein is substantially non-gagylated, said composition comprising less than about 100 ng residual host cell protein/mg decorin core protein in said composition and less than about 20 pg residual host cell DNA/mg decorin core protein. 29. The composition of claim 28, said composition comprising less than about 5 ng residual host cell protein/mg decorin core protein in said composition and less than about 5 pg residual host cell DNA/mg decorin core protein. 30. The composition of claim 28, wherein said decorin is formulated as an aqueous solution. 31. The composition of claim 30, wherein said aqueous solution comprises a phosphate buffered solution with a pH of from about 6.5 to about 7.5. | The present invention relates to improved decorin compositions and methods of their production.1. A fusion protein comprising a heterologous signal peptide operably linked to a sequence encoding decorin. 2. The fusion protein of claim 1, wherein said signal sequence is an alpha-lactalbumin signal sequence. 3. The fusion protein of claim 2, wherein said alpha lactalbumin sequence is a bovine alpha-lactalbumin signal sequence. 4. The fusion protein of claim 1, wherein said sequence encoding decorin encodes a decorin core protein. 5. The fusion protein of claim 4, wherein said decorin core protein comprises a mutation at position 4 of the mature decorin core protein. 6. The fusion protein of claim 5, wherein said mutation is a serine to alanine mutation. 7. The fusion protein of claim 4, wherein said decorin core protein lacks substantial modification by glycosaminoglycans molecules at position 4 of the mature decorin core protein. 8. A vector encoding the fusion protein of claim 1. 9. The vector of claim 8, wherein said vector comprises a nucleic acid sequence encoding an alpha-lactalbumin signal sequence operably linked to a sequence encoding a decorin core protein. 10. A host cell comprising the vector of claim 8. 11. A method of producing a non-gagylated decorin core protein comprising:
providing host cells expressing non-gagylated decorin core protein; culturing said host cell so that said non-gagylated decorin core protein is produced; and purifying said non-gagylated decorin core protein. 12. The method of claim 11, wherein said non-gagylated decorin core protein is secreted into medium used to culture said host cells. 13. The method of claim 12, wherein said purifying comprises contacting said culture medium with an ion exchange medium. 14. The method of claim 12, wherein said purifying comprises contacting said culture medium with a hydroxyapatite medium. 15. The method of claim 12, wherein said purifying comprises contacting said culture medium with at least one ion exchange medium and at least one hydroxyapatite medium in any order. 16. The method of claim 12, wherein said purifying comprises:
contacting said culture medium with a cation exchange medium; washing said cation exchange medium; eluting a first decorin-containing eluate from said cation exchange medium; contacting said first decorin-containing eluate with a hydroxyapatite medium; washing said hydroxyapatite medium; eluting a second decorin-containing eluate from said hydroxyapatite medium. 17. The method of claim 16, wherein said cation exchange medium is SP-Sepharose FF. 18. The method of claim 16, wherein said hydroxyapatite medium is ceramic hydroxyapatite type I. 19. The method of claim 16, further comprising further purification of said second decorin-containing eluate with an ion exchange membrane or column. 20. The method of claim 19, wherein said ion exchange membrane is a Q ion exchange membrane. 21. The method of claim 16, further comprising a viral inactivation step. 22. The method of claim 21, wherein said viral inaction step comprises treatment with a surfactant. 23. The method of claim 22, wherein said surfactant is Triton X-100. 24. The method of claim 16, further comprising a viral filtration step. 25. The method of claim 16, further comprising concentrating said decorin. 26. The method of claim 11, wherein said non-gagylated decorin core protein is produced by said host cells at a rate of about greater than 1, 5, or 10 pg/cell/day. 27. A method for purifying decorin from a decorin-containing medium comprising:
contacting said decorin-containing medium with a cation exchange medium; washing said cation exchange medium; eluting a first decorin-containing eluate from said cation exchange medium; contacting said at first decorin-containing eluate with a hydroxyapatite medium; washing said hydroxyapatite medium; eluting a second decorin-containing eluate from said hydroxyapatite medium; filtering said second decorin-containing eluate with an ion exchange membrane to provide a decorin-containing filtrate; treating said filtrate to remove viruses; concentrating decorin from said filtrate. 28. A composition comprising a purified decorin core protein comprising a mutation at position 4 of the mature decorin core protein so that said decorin protein is substantially non-gagylated, said composition comprising less than about 100 ng residual host cell protein/mg decorin core protein in said composition and less than about 20 pg residual host cell DNA/mg decorin core protein. 29. The composition of claim 28, said composition comprising less than about 5 ng residual host cell protein/mg decorin core protein in said composition and less than about 5 pg residual host cell DNA/mg decorin core protein. 30. The composition of claim 28, wherein said decorin is formulated as an aqueous solution. 31. The composition of claim 30, wherein said aqueous solution comprises a phosphate buffered solution with a pH of from about 6.5 to about 7.5. | 1,600 |
781 | 11,315,969 | 1,632 | Cells derived from postpartum tissue and methods for their isolation and induction to differentiate to cells of a chondrogenic or osteogenic phenotype are provided by the invention. The invention further provides cultures and compositions of the postpartum-derived cells and products such as lysates related thereto. The postpartum-derived cells of the invention and products related thereto have a plethora of uses, including but not limited to research, diagnostic, and therapeutic applications, for example, in the treatment of bone and cartilage conditions such as osteoarthritis. | 1. A postpartum-derived cell comprising a cell derived from human postpartum tissue substantially free of blood, wherein said cell is capable of self-renewal and expansion in culture and has the potential to differentiate into a cell of an osteogenic or chondrogenic phenotype; wherein said cell requires L-valine for growth; wherein said cell is capable of growth in about 5% to about 20% oxygen; wherein said cell further comprises at least one of the following characteristics:
(a) production of at least one of granulocyte chemotactic protein 2 (GCP-2), reticulon 1, tissue factor, vimentin, and alpha-smooth muscle actin; (b) lack of production of at least one of GRO-alpha or oxidized low density lipoprotein receptor, as detected by flow cytometry; (c) production of at least one of CD10, CD13, CD44, CD73, CD90, PDGFr-alpha, PD-L2 and HLA-A,B,C; (d) lack of production of at least one of CD31, CD34, CD45, CD80, CD86, CD117, CD141, CD178, B7-H2, HLA-G, and HLA-DR,DP,DQ, as detected by flow cytometry; (e) expression, which relative to a human cell that is a fibroblast, a mesenchymal stem cell, or an ileac crest bone marrow cell, is increased for at least one of interleukin 8; reticulon 1; chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha); chemokine (C-X-C motif) ligand 6 (granulocyte chemotactic protein 2); chemokine (C-X-C motif) ligand 3; and tumor necrosis factor, alpha-induced protein 3 or expression, which relative to a human cell that is a fibroblast, a mesenchymal stem cell, or an ileac crest bone marrow cell, is increased for at least one of C-type lectin superfamily member A2, Wilms tumor 1, aldehyde dehydrogenase 1 family member A2, renin, oxidized low density lipoprotein receptor 1, protein kinase C zeta, clone IMAGE:4179671, hypothetical protein DKFZp564F013, downregulated in ovarian cancer 1, and clone DKFZp547K1113; (f) expression, which relative to a human cell that is a fibroblast, a mesenchymal stem cell, or an ileac crest bone marrow cell, is reduced for at least one of: short stature homeobox 2; heat shock 27 kDa protein 2; chemokine (C-X-C motif) ligand 12 (stromal cell-derived factor 1); elastin; cDNA DKFZp586M2022 (from clone DKFZp586M2022); mesenchyme homeobox 2; sine oculis homeobox homolog 1; crystallin, alpha B; dishevelled associated activator of morphogenesis 2; DKFZP586B2420 protein; similar to neuralin 1; tetranectin; src homology three (SH3) and cysteine rich domain; B-cell translocation gene 1, anti-proliferative; cholesterol 25-hydroxylase; runt-related transcription factor 3; hypothetical protein FLJ23191; interleukin 11 receptor, alpha; procollagen C-endopeptidase enhancer; frizzled homolog 7; hypothetical gene BC008967; collagen, type VIII, alpha 1; tenascin C; iroquois homeobox protein 5; hephaestin; integrin, beta 8; synaptic vesicle glycoprotein 2; cDNA FLJ12280 fis, clone MAMMA1001744; cytokine receptor-like factor 1; potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4; integrin, alpha 7; DKFZP586L151 protein; transcriptional co-activator with PDZ-binding motif (TAZ); sine oculis homeobox homolog 2; KIAA1034 protein; early growth response 3; distal-less homeobox 5; hypothetical protein FLJ20373; aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II); biglycan; fibronectin 1; proenkephalin; integrin, beta-like 1 (with EGF-like repeat domains); cDNA clone EUROIMAGE 1968422; EphA3; KIAA0367 protein; natriuretic peptide receptor C/guanylate cyclase C (atrionatriuretic peptide receptor C); hypothetical protein FLJ14054; cDNA DKFZp564B222 (from clone DKFZp564B222); vesicle-associated membrane protein 5; EGF-containing fibulin-like extracellular matrix protein 1; BCL2/adenovirus E1B 19 kDa interacting protein 3-like; AE binding protein 1; cytochrome c oxidase subunit VIIa polypeptide 1 (muscle); neuroblastoma, suppression of tumorigenicity 1; and insulin-like growth factor binding protein 2, 36 kDa; (g) secretion of at least one of monocyte chemotactic protein-1, interleukin(IL)-6, IL-8, granulocyte chemotactic protein-2, hepatocyte growth factor, keratinocyte growth factor, fibroblast growth factor, heparin binding-epidermal growth factor, brain derived neurotrophic factor, thrombopoietin, macrophage inflammatory protein (MIP)-1a, RANTES, and tissue inhibitor of matrix metalloprotease 1; (h) lack of secretion of at least one of transforming growth factor-beta2, angiopoetin-2, platelet derived growth factor-bb, MIP1b, I309, macrophage-derived chemokine, and vascular endothelial growth factor, as detected by ELISA; and (i) the ability to undergo at least 40 population doublings in culture. 2. A method of inducing differentiation of a postpartum-derived cell of claim 1 to a chondrogenic phenotype comprising exposing said cell to one or more chondrogenic differentiation-inducing agents. 3. The method of claim 2 wherein said chondrogenic differentiation-inducing agent comprises at least one of transforming growth factor-beta3 (TGFbeta3) and growth and differentiation factor-5 (GDF-5). 4. The method of claim 2 further comprising culturing the cell in chondrogenic medium. 5. The cell produced by the method of claim 2. 6. A method of inducing differentiation of a postpartum-derived cell of claim 1 to an osteogenic phenotype comprising exposing said cell to one or more osteogenic differentiation-inducing agents. 7. The method of claim 6 wherein said differentiation-inducing agent comprises at least one of bone morphogenic protein (BMP)-2, BMP-4, and transforming growth factor-beta1. 8. The method of claim 6 further comprising culturing said cell in osteogenic medium. 9. The cell produced according to the method of claim 6. 10. A cell population comprising the postpartum-derived cell of claim 1. 11. The cell population of claim 10 wherein said cell population is substantially homogeneous. 12. The cell population of claim 10 wherein said cell population is heterogeneous. 13. The cell population of claim 12 further comprising at least one cell type of bone marrow cells, chondrocytes, synoviocytes, chondroblasts, chondrocyte progenitor cells, perichondral cells, periosal cells, stem cells, or other pluripotent or multipotent cells. 14. A cell population comprising the postpartum-derived cell of claim 5. 15. A cell population comprising the postpartum-derived cell of claim 9. 16. A cell product prepared from the cell population of claim 10. 17. A cell product prepared from the cell population of claim 14. 18. A cell product prepared from the cell population of claim 15. 19. A composition comprising the cell population of claim 10 and one or more bioactive factors. 20. A composition comprising the cell population of claim 14 and one or more bioactive factors. 21. A composition comprising the cell population of claim 15 and one or more bioactive factors. 22. A composition comprising the cell population of claim 10 and at least one other cell type of bone marrow cells, chondrocytes, synoviocytes, chondroblasts, chondrocyte progenitor cells, perichondral cells, periosal cells, osteocytes, osteoblasts, osteoclasts, bone lining cells, stem cells, and other bone or cartilage cell progenitors or cells. 23. A composition comprising the cell population of claim 14 and at least one other cell type of bone marrow cells, chondrocytes, synoviocytes, chondroblasts, chondrocyte progenitor cells, perichondral cells, periosal cells, osteocytes, osteoblasts, osteoclasts, bone lining cells, stem cells, and other bone or cartilage cell progenitors or cells. 24. A composition comprising the cell population of claim 15 and at least one other cell type of bone marrow cells, chondrocytes, synoviocytes, chondroblasts, chondrocyte progenitor cells, perichondral cells, periosal cells, osteocytes, osteoblasts, osteoclasts, bone lining cells, stem cells, and other bone or cartilage cell progenitors or cells. 25. A composition comprising the cell product of claim 16 and one or more bioactive factors. 26. A composition comprising the cell product of claim 17 and one or more bioactive factors. 27. A composition comprising the cell product of claim 18 and one or more bioactive factors. 28. A pharmaceutical composition comprising a cell of claim 1 and a pharmaceutically acceptable carrier. 29. A pharmaceutical composition comprising a cell of claim 5 and a pharmaceutically acceptable carrier. 30. A pharmaceutical composition comprising a cell of claim 9 and a pharmaceutically acceptable carrier. 31. A pharmaceutical composition comprising the cell product of claim 16 and a pharmaceutically acceptable carrier. 32. A pharmaceutical composition comprising the cell product of claim 17 and a pharmaceutically acceptable carrier. 33. A pharmaceutical composition comprising the cell product of claim 18 and a pharmaceutically acceptable carrier. 34. A cell culture comprising at least one cell of claim 1 in a culture medium. 35. The cell culture of claim 34 wherein said culture medium comprises chondrogenic medium or osteogenic medium. 36. The cell culture of claim 34 further comprising at least one chondrogenic differentiation-inducing agent. 37. The cell culture of claim 34 further comprising at least one osteogenic differentiation-inducing agent. 38. A matrix comprising a cell population of claim 10. 39. A matrix comprising a cell population of claim 14. 40. A matrix comprising a cell population of claim 15. 41. A method of treating a bone or cartilage condition in a patient comprising administering to said patient one or more postpartum-derived cells of claim 1. 42. A method of treating a bone or cartilage condition in a patient comprising administering to said patient one or more postpartum-derived cells of claim 5. 43. A method of treating a bone or cartilage condition in a patient comprising administering to said patient one or more postpartum-derived cells of claim 9. 44. A method of treating a bone or cartilage condition in a patient comprising administering to said patient the cell product of claim 16. 45. A method of treating a bone or cartilage condition in a patient comprising administering to said patient the cell product of claim 17. 46. A method of treating a bone or cartilage condition in a patient comprising administering to said patient the cell product of claim 18. 47. A method of regenerating a tissue in a patient in need thereof comprising administering the cell population of claim 10 to said patient. 48. A method of regenerating a tissue in a patient in need thereof comprising administering the cell population of claim 14 to said patient. 49. A method of regenerating a tissue in a patient in need thereof comprising administering the cell population of claim 15 to said patient. 50. A method for identifying a compound that stimulates chondrogenesis of a postpartum-derived cell comprising contacting a cell of claim 1 with said compound and monitoring said cell for a marker of chondrogenesis. 51. A method for identifying a compound that stimulates osteogenesis of a postpartum-derived cell comprising contacting a cell of claim 1 with said compound and monitoring said cell for a marker of osteogenesis. 52. A method for identifying a compound that is toxic to a postpartum-derived cell of claim 1 comprising contacting said cell with said compound and monitoring survival of said cell. 53. A kit comprising at least one cell of claim 1 and at least one additional component of a matrix, a hydrating agent, a cell culture substrate, a differentiation-inducing agent, and cell culture media. 54. A kit comprising at least one cell of claim 5 and at least one additional component of a matrix, a hydrating agent, a cell culture substrate, a differentiation-inducing agent, and cell culture media. 55. A kit comprising at least one cell of claim 9 and at least one additional component of a matrix, a hydrating agent, a cell culture substrate, a differentiation-inducing agent, and cell culture media. | Cells derived from postpartum tissue and methods for their isolation and induction to differentiate to cells of a chondrogenic or osteogenic phenotype are provided by the invention. The invention further provides cultures and compositions of the postpartum-derived cells and products such as lysates related thereto. The postpartum-derived cells of the invention and products related thereto have a plethora of uses, including but not limited to research, diagnostic, and therapeutic applications, for example, in the treatment of bone and cartilage conditions such as osteoarthritis.1. A postpartum-derived cell comprising a cell derived from human postpartum tissue substantially free of blood, wherein said cell is capable of self-renewal and expansion in culture and has the potential to differentiate into a cell of an osteogenic or chondrogenic phenotype; wherein said cell requires L-valine for growth; wherein said cell is capable of growth in about 5% to about 20% oxygen; wherein said cell further comprises at least one of the following characteristics:
(a) production of at least one of granulocyte chemotactic protein 2 (GCP-2), reticulon 1, tissue factor, vimentin, and alpha-smooth muscle actin; (b) lack of production of at least one of GRO-alpha or oxidized low density lipoprotein receptor, as detected by flow cytometry; (c) production of at least one of CD10, CD13, CD44, CD73, CD90, PDGFr-alpha, PD-L2 and HLA-A,B,C; (d) lack of production of at least one of CD31, CD34, CD45, CD80, CD86, CD117, CD141, CD178, B7-H2, HLA-G, and HLA-DR,DP,DQ, as detected by flow cytometry; (e) expression, which relative to a human cell that is a fibroblast, a mesenchymal stem cell, or an ileac crest bone marrow cell, is increased for at least one of interleukin 8; reticulon 1; chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha); chemokine (C-X-C motif) ligand 6 (granulocyte chemotactic protein 2); chemokine (C-X-C motif) ligand 3; and tumor necrosis factor, alpha-induced protein 3 or expression, which relative to a human cell that is a fibroblast, a mesenchymal stem cell, or an ileac crest bone marrow cell, is increased for at least one of C-type lectin superfamily member A2, Wilms tumor 1, aldehyde dehydrogenase 1 family member A2, renin, oxidized low density lipoprotein receptor 1, protein kinase C zeta, clone IMAGE:4179671, hypothetical protein DKFZp564F013, downregulated in ovarian cancer 1, and clone DKFZp547K1113; (f) expression, which relative to a human cell that is a fibroblast, a mesenchymal stem cell, or an ileac crest bone marrow cell, is reduced for at least one of: short stature homeobox 2; heat shock 27 kDa protein 2; chemokine (C-X-C motif) ligand 12 (stromal cell-derived factor 1); elastin; cDNA DKFZp586M2022 (from clone DKFZp586M2022); mesenchyme homeobox 2; sine oculis homeobox homolog 1; crystallin, alpha B; dishevelled associated activator of morphogenesis 2; DKFZP586B2420 protein; similar to neuralin 1; tetranectin; src homology three (SH3) and cysteine rich domain; B-cell translocation gene 1, anti-proliferative; cholesterol 25-hydroxylase; runt-related transcription factor 3; hypothetical protein FLJ23191; interleukin 11 receptor, alpha; procollagen C-endopeptidase enhancer; frizzled homolog 7; hypothetical gene BC008967; collagen, type VIII, alpha 1; tenascin C; iroquois homeobox protein 5; hephaestin; integrin, beta 8; synaptic vesicle glycoprotein 2; cDNA FLJ12280 fis, clone MAMMA1001744; cytokine receptor-like factor 1; potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4; integrin, alpha 7; DKFZP586L151 protein; transcriptional co-activator with PDZ-binding motif (TAZ); sine oculis homeobox homolog 2; KIAA1034 protein; early growth response 3; distal-less homeobox 5; hypothetical protein FLJ20373; aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II); biglycan; fibronectin 1; proenkephalin; integrin, beta-like 1 (with EGF-like repeat domains); cDNA clone EUROIMAGE 1968422; EphA3; KIAA0367 protein; natriuretic peptide receptor C/guanylate cyclase C (atrionatriuretic peptide receptor C); hypothetical protein FLJ14054; cDNA DKFZp564B222 (from clone DKFZp564B222); vesicle-associated membrane protein 5; EGF-containing fibulin-like extracellular matrix protein 1; BCL2/adenovirus E1B 19 kDa interacting protein 3-like; AE binding protein 1; cytochrome c oxidase subunit VIIa polypeptide 1 (muscle); neuroblastoma, suppression of tumorigenicity 1; and insulin-like growth factor binding protein 2, 36 kDa; (g) secretion of at least one of monocyte chemotactic protein-1, interleukin(IL)-6, IL-8, granulocyte chemotactic protein-2, hepatocyte growth factor, keratinocyte growth factor, fibroblast growth factor, heparin binding-epidermal growth factor, brain derived neurotrophic factor, thrombopoietin, macrophage inflammatory protein (MIP)-1a, RANTES, and tissue inhibitor of matrix metalloprotease 1; (h) lack of secretion of at least one of transforming growth factor-beta2, angiopoetin-2, platelet derived growth factor-bb, MIP1b, I309, macrophage-derived chemokine, and vascular endothelial growth factor, as detected by ELISA; and (i) the ability to undergo at least 40 population doublings in culture. 2. A method of inducing differentiation of a postpartum-derived cell of claim 1 to a chondrogenic phenotype comprising exposing said cell to one or more chondrogenic differentiation-inducing agents. 3. The method of claim 2 wherein said chondrogenic differentiation-inducing agent comprises at least one of transforming growth factor-beta3 (TGFbeta3) and growth and differentiation factor-5 (GDF-5). 4. The method of claim 2 further comprising culturing the cell in chondrogenic medium. 5. The cell produced by the method of claim 2. 6. A method of inducing differentiation of a postpartum-derived cell of claim 1 to an osteogenic phenotype comprising exposing said cell to one or more osteogenic differentiation-inducing agents. 7. The method of claim 6 wherein said differentiation-inducing agent comprises at least one of bone morphogenic protein (BMP)-2, BMP-4, and transforming growth factor-beta1. 8. The method of claim 6 further comprising culturing said cell in osteogenic medium. 9. The cell produced according to the method of claim 6. 10. A cell population comprising the postpartum-derived cell of claim 1. 11. The cell population of claim 10 wherein said cell population is substantially homogeneous. 12. The cell population of claim 10 wherein said cell population is heterogeneous. 13. The cell population of claim 12 further comprising at least one cell type of bone marrow cells, chondrocytes, synoviocytes, chondroblasts, chondrocyte progenitor cells, perichondral cells, periosal cells, stem cells, or other pluripotent or multipotent cells. 14. A cell population comprising the postpartum-derived cell of claim 5. 15. A cell population comprising the postpartum-derived cell of claim 9. 16. A cell product prepared from the cell population of claim 10. 17. A cell product prepared from the cell population of claim 14. 18. A cell product prepared from the cell population of claim 15. 19. A composition comprising the cell population of claim 10 and one or more bioactive factors. 20. A composition comprising the cell population of claim 14 and one or more bioactive factors. 21. A composition comprising the cell population of claim 15 and one or more bioactive factors. 22. A composition comprising the cell population of claim 10 and at least one other cell type of bone marrow cells, chondrocytes, synoviocytes, chondroblasts, chondrocyte progenitor cells, perichondral cells, periosal cells, osteocytes, osteoblasts, osteoclasts, bone lining cells, stem cells, and other bone or cartilage cell progenitors or cells. 23. A composition comprising the cell population of claim 14 and at least one other cell type of bone marrow cells, chondrocytes, synoviocytes, chondroblasts, chondrocyte progenitor cells, perichondral cells, periosal cells, osteocytes, osteoblasts, osteoclasts, bone lining cells, stem cells, and other bone or cartilage cell progenitors or cells. 24. A composition comprising the cell population of claim 15 and at least one other cell type of bone marrow cells, chondrocytes, synoviocytes, chondroblasts, chondrocyte progenitor cells, perichondral cells, periosal cells, osteocytes, osteoblasts, osteoclasts, bone lining cells, stem cells, and other bone or cartilage cell progenitors or cells. 25. A composition comprising the cell product of claim 16 and one or more bioactive factors. 26. A composition comprising the cell product of claim 17 and one or more bioactive factors. 27. A composition comprising the cell product of claim 18 and one or more bioactive factors. 28. A pharmaceutical composition comprising a cell of claim 1 and a pharmaceutically acceptable carrier. 29. A pharmaceutical composition comprising a cell of claim 5 and a pharmaceutically acceptable carrier. 30. A pharmaceutical composition comprising a cell of claim 9 and a pharmaceutically acceptable carrier. 31. A pharmaceutical composition comprising the cell product of claim 16 and a pharmaceutically acceptable carrier. 32. A pharmaceutical composition comprising the cell product of claim 17 and a pharmaceutically acceptable carrier. 33. A pharmaceutical composition comprising the cell product of claim 18 and a pharmaceutically acceptable carrier. 34. A cell culture comprising at least one cell of claim 1 in a culture medium. 35. The cell culture of claim 34 wherein said culture medium comprises chondrogenic medium or osteogenic medium. 36. The cell culture of claim 34 further comprising at least one chondrogenic differentiation-inducing agent. 37. The cell culture of claim 34 further comprising at least one osteogenic differentiation-inducing agent. 38. A matrix comprising a cell population of claim 10. 39. A matrix comprising a cell population of claim 14. 40. A matrix comprising a cell population of claim 15. 41. A method of treating a bone or cartilage condition in a patient comprising administering to said patient one or more postpartum-derived cells of claim 1. 42. A method of treating a bone or cartilage condition in a patient comprising administering to said patient one or more postpartum-derived cells of claim 5. 43. A method of treating a bone or cartilage condition in a patient comprising administering to said patient one or more postpartum-derived cells of claim 9. 44. A method of treating a bone or cartilage condition in a patient comprising administering to said patient the cell product of claim 16. 45. A method of treating a bone or cartilage condition in a patient comprising administering to said patient the cell product of claim 17. 46. A method of treating a bone or cartilage condition in a patient comprising administering to said patient the cell product of claim 18. 47. A method of regenerating a tissue in a patient in need thereof comprising administering the cell population of claim 10 to said patient. 48. A method of regenerating a tissue in a patient in need thereof comprising administering the cell population of claim 14 to said patient. 49. A method of regenerating a tissue in a patient in need thereof comprising administering the cell population of claim 15 to said patient. 50. A method for identifying a compound that stimulates chondrogenesis of a postpartum-derived cell comprising contacting a cell of claim 1 with said compound and monitoring said cell for a marker of chondrogenesis. 51. A method for identifying a compound that stimulates osteogenesis of a postpartum-derived cell comprising contacting a cell of claim 1 with said compound and monitoring said cell for a marker of osteogenesis. 52. A method for identifying a compound that is toxic to a postpartum-derived cell of claim 1 comprising contacting said cell with said compound and monitoring survival of said cell. 53. A kit comprising at least one cell of claim 1 and at least one additional component of a matrix, a hydrating agent, a cell culture substrate, a differentiation-inducing agent, and cell culture media. 54. A kit comprising at least one cell of claim 5 and at least one additional component of a matrix, a hydrating agent, a cell culture substrate, a differentiation-inducing agent, and cell culture media. 55. A kit comprising at least one cell of claim 9 and at least one additional component of a matrix, a hydrating agent, a cell culture substrate, a differentiation-inducing agent, and cell culture media. | 1,600 |
782 | 14,742,864 | 1,627 | The present invention is directed to an improved effectiveness pharmaceutical carrier comprising anyone or a combination of edible or pharmaceutical acceptable fatty acids and anyone or a combination of non-ionic surfactants, which is capable of improving the bio-absorption of drugs with intermediate log P ranging from 2 to 4 (having poor solubility in both water and triglycerides) as well as those with high log P of more than 4. | 1. A pharmaceutical composition comprising:
an edible and pharmaceutically acceptable fatty acid; and a non-ionic surfactant,
wherein the pharmaceutical composition is a self-emulsifying drug delivery system. 2. The pharmaceutical composition of claim 1, further comprising:
a drug, wherein the drug has an intermediate log P (partition coefficient) of 4 or greater. 3. The pharmaceutical composition of claim 2 excluding a co-solvent. 4. The pharmaceutical composition of claim 1, further comprising:
a co-solvent; and a drug, wherein the drug has an intermediate log P (partition coefficient) of about 2 to 4. 5. The pharmaceutical composition of claim 1, wherein the fatty acid has a saturated or unsaturated C12-C22 carbon chain. 6. The pharmaceutical composition of claim 1, wherein the fatty acid includes anyone or a combination of oleic acid, eleostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, elaidic acid, linoleic acid, linolenic acid, and docosahexaenoic acid. 7. The pharmaceutical composition of claim 1, wherein the non-ionic surfactant includes, anyone or a combination of polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monostearate, glyceryl polyethylene glycol oxystearate (Cremophor® CO and RH grades), glycerol polyethylene glycol ricinoleate (Cremophor® EL, polyoxyl 35 hydrogenated castor oil), sucrose stearate, sucrose oleate, sucrose palmitate, sucrose myristate, sucrose laurate, decaglycerol lauric acid esters, decaglycerol myristic acid esters, decaglycerol stearic acid esters. 8. The pharmaceutical composition of claim 1, wherein the non-ionic surfactant has a hydrophile-lipophile balance (HLB) value ranging from 11 to 17. 9. The pharmaceutical composition of claim 1, wherein the fatty acid and non-ionic surfactant are mixed in a ratio ranging from 9.5:0.5 w/w to 1:1 w/w. 10. The pharmaceutical composition of claim 4:
wherein the drug has limited solubility in both water and triglycerides. 11. The pharmaceutical composition of claim 4, wherein the drug is selected from the group consisting of griseofluvin, pravastatin, carbamazepine, phenytoin, piroxicam, ketoprofen, naproxen, testosterone, progesterone, and ibuprofen. 12. The pharmaceutical composition of claim 2, wherein the drug is selected from the group consisting of lovastatin, indomethacin, ketoconazole, diclofenac, simvastatin, gemfibrozil, testosterone undecanoate, and ubiquonone. 13. The pharmaceutical composition of claim 1 excluding ethanol. 14. A method of increasing the bio-availability of a drug, comprising:
providing a self-emulsifying drug delivery system, comprising:
an edible and pharmaceutically acceptable fatty acid,
a non-ionic surfactant, and
a drug;
dissolving the drug in the self-emulsifying drug delivery system,
wherein the drug has a log P (partition coefficient) of 4 or greater. 15. The method of claim 15, wherein the fatty acid includes anyone or a combination of oleic acid, eleostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, elaidic acid, linoleic acid, linolenic acid, and docosahexaenoic acid. 16. The method of claim 15, wherein the non-ionic surfactant includes, anyone or a combination of polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monostearate, glyceryl polyethylene glycol oxystearate (Cremophor® CO and RH grades), glycerol polyethylene glycol ricinoleate (Cremophor® EL, polyoxyl 35 hydrogenated castor oil), sucrose stearate, sucrose oleate, sucrose palmitate, sucrose myristate, sucrose laurate, decaglycerol lauric acid esters, decaglycerol myristic acid esters, decaglycerol stearic acid esters. 17. The method of claim 15, further comprising:
providing a co-solvent. | The present invention is directed to an improved effectiveness pharmaceutical carrier comprising anyone or a combination of edible or pharmaceutical acceptable fatty acids and anyone or a combination of non-ionic surfactants, which is capable of improving the bio-absorption of drugs with intermediate log P ranging from 2 to 4 (having poor solubility in both water and triglycerides) as well as those with high log P of more than 4.1. A pharmaceutical composition comprising:
an edible and pharmaceutically acceptable fatty acid; and a non-ionic surfactant,
wherein the pharmaceutical composition is a self-emulsifying drug delivery system. 2. The pharmaceutical composition of claim 1, further comprising:
a drug, wherein the drug has an intermediate log P (partition coefficient) of 4 or greater. 3. The pharmaceutical composition of claim 2 excluding a co-solvent. 4. The pharmaceutical composition of claim 1, further comprising:
a co-solvent; and a drug, wherein the drug has an intermediate log P (partition coefficient) of about 2 to 4. 5. The pharmaceutical composition of claim 1, wherein the fatty acid has a saturated or unsaturated C12-C22 carbon chain. 6. The pharmaceutical composition of claim 1, wherein the fatty acid includes anyone or a combination of oleic acid, eleostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, elaidic acid, linoleic acid, linolenic acid, and docosahexaenoic acid. 7. The pharmaceutical composition of claim 1, wherein the non-ionic surfactant includes, anyone or a combination of polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monostearate, glyceryl polyethylene glycol oxystearate (Cremophor® CO and RH grades), glycerol polyethylene glycol ricinoleate (Cremophor® EL, polyoxyl 35 hydrogenated castor oil), sucrose stearate, sucrose oleate, sucrose palmitate, sucrose myristate, sucrose laurate, decaglycerol lauric acid esters, decaglycerol myristic acid esters, decaglycerol stearic acid esters. 8. The pharmaceutical composition of claim 1, wherein the non-ionic surfactant has a hydrophile-lipophile balance (HLB) value ranging from 11 to 17. 9. The pharmaceutical composition of claim 1, wherein the fatty acid and non-ionic surfactant are mixed in a ratio ranging from 9.5:0.5 w/w to 1:1 w/w. 10. The pharmaceutical composition of claim 4:
wherein the drug has limited solubility in both water and triglycerides. 11. The pharmaceutical composition of claim 4, wherein the drug is selected from the group consisting of griseofluvin, pravastatin, carbamazepine, phenytoin, piroxicam, ketoprofen, naproxen, testosterone, progesterone, and ibuprofen. 12. The pharmaceutical composition of claim 2, wherein the drug is selected from the group consisting of lovastatin, indomethacin, ketoconazole, diclofenac, simvastatin, gemfibrozil, testosterone undecanoate, and ubiquonone. 13. The pharmaceutical composition of claim 1 excluding ethanol. 14. A method of increasing the bio-availability of a drug, comprising:
providing a self-emulsifying drug delivery system, comprising:
an edible and pharmaceutically acceptable fatty acid,
a non-ionic surfactant, and
a drug;
dissolving the drug in the self-emulsifying drug delivery system,
wherein the drug has a log P (partition coefficient) of 4 or greater. 15. The method of claim 15, wherein the fatty acid includes anyone or a combination of oleic acid, eleostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, elaidic acid, linoleic acid, linolenic acid, and docosahexaenoic acid. 16. The method of claim 15, wherein the non-ionic surfactant includes, anyone or a combination of polyoxyethylene (20) sorbitan monooleate, polyoxyethylene (20) sorbitan monostearate, glyceryl polyethylene glycol oxystearate (Cremophor® CO and RH grades), glycerol polyethylene glycol ricinoleate (Cremophor® EL, polyoxyl 35 hydrogenated castor oil), sucrose stearate, sucrose oleate, sucrose palmitate, sucrose myristate, sucrose laurate, decaglycerol lauric acid esters, decaglycerol myristic acid esters, decaglycerol stearic acid esters. 17. The method of claim 15, further comprising:
providing a co-solvent. | 1,600 |
783 | 14,236,828 | 1,615 | The invention relates to a product, method of use, and/or method of preparing a capsule or capsular like product that comprises hydrophilic fluid-absorbing materials that bind, entrap, and/or absorb large quantities of fluid. The capsules or capsular like product may be capable of diverting the mode of fluid and waste elimination from the renal route to the gastrointestinal route. | 1-64. (canceled) 65. An orally consumable medical product comprising a substantially nitrogen-free capsule containing a water-insoluble fluid-absorbing material. 66. The product of claim 1, wherein the capsules are made from non-animal and/or non-protein based material, wherein the materials contain no protein. 67. The product of claim 1, wherein the substantially nitrogen-free capsule comprises a singular opening, preferably at the distal end of the capsule, sealed with a hydrogel plug, optionally made of polymethacrylates, hydropropylmethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, saturated polyglycolated glycerides, glyceryl monooleates, pectin, sodium polyacrylate, acrylate polymers, copolymers with an abundance of hydrophilic groups, agarose, methylcellulose, hyaluronan, and other naturally derived polymers, and preferably wherein the hydrogel plug swells, erodes, congeals, melts, enzymatically erodes, or a combination thereof. 68. The product of claim 1, wherein release of the water insoluble fluid-absorbing material from the substantially nitrogen-free capsule is pH dependent, preferably at a pH of about 1 to about 3, or preferably at a pH of about 5 to about 8. 69. The product of claim 1, wherein the substantially nitrogen-free capsule is a two piece capsule. 70. The product of claim 1, wherein the substantially nitrogen-free capsule is constructed of a natural vegetable-derived polysaccharide, a non-animal and/or non-protein based material, preferably being hypromellose, cellulose, alginate, or a biodegradable carbohydrate, weaken plastic, rubber, silicone rubber, gelatinous material, hypromellose, cellulose, alginate, biodegradable carbohydrates, weakened plastic, rubber, silicone rubber, gelatinous material, or a combination thereof; and optionally wherein the substantially nitrogen-free capsule is enterically coated. 71. The product of claim 1, wherein the fluid-absorbing material is a hydrophilic fiber, powder, gel, or grain; or wherein the fluid-absorbing material is an insoluble, cross-linked polysaccharide, preferably nitrogen-free in pH ranging from about 1 to about 8; or wherein the fluid-absorbing material is non-ionic and further comprises a high content of hydroxyl groups. 72. The product of claim 1, wherein the fluid-absorbing material is dextran, preferably a modified dextran, wherein the modified dextran is preferably cross linked with epichlorohydrin; modified starches; dextrin; cellulose; polyglucose; hydroxyl group containing uncharged derivatives; or product obtained by partial depolymerization; or combinations thereof. 73. The product of claim 1, wherein the fluid-absorbing material is a copolymer in the form of a gel grain comprising a three dimensional network of dextran substances, preferably a copolymer comprising α-1,6-glucosidically bonded glucose residues, preferably having general formula —R—O—Xn—O—R, wherein R is a dextran substance, X is an aliphatic radical with carbon, n is 3-10; and preferably wherein the α-1,6-glucosidically bonded glucose residues are linked by ether bridges. 74. The product of claim 1, wherein the fluid-absorbing material comprises a water regain in the range of about 1 to about 100 grams/dry gram of dry product, preferably 1 to about 85 grams/dry grams of dry product and optionally wherein the fluid-absorbing material is a particle size ranging from about 50 to about 200 mesh. 75. The product of claim 1, wherein the fluid-absorbing material is Sephadex, preferably G-50 Sephadex; Sephacryl; Superdex; Sephacel; Sepharose; or any derivative thereof. 76. An orally consumable medical product comprising a substantially nitrogen-free capsule containing a water-insoluble fluid-absorbing material for use in treating renal failure; treating obesity; inducing a sense of fullness; relieving constipation; reducing the frequency of dialysis; removing excess accumulation of serum toxins, wherein the toxins are preferably potassium, urea, ammonia, or combinations thereof; treating hyperkalemia; treating hyperammonemia; treating ureamia; reducing triglycerides; and/or treating non-insulin dependent diabetes in a human subject in need thereof. 77. A method of preparing an orally consumable medical product according to any one of claim 1, said method comprising encapsulating a fluid absorbing polymer comprising:
a. filling a substantially nitrogen-free capsule with a fluid absorbing material; and b. sealing or enclosing the substantially nitrogen-free capsule, whereby the substantially nitrogen-free capsule encapsulates the fluid absorbing material. | The invention relates to a product, method of use, and/or method of preparing a capsule or capsular like product that comprises hydrophilic fluid-absorbing materials that bind, entrap, and/or absorb large quantities of fluid. The capsules or capsular like product may be capable of diverting the mode of fluid and waste elimination from the renal route to the gastrointestinal route.1-64. (canceled) 65. An orally consumable medical product comprising a substantially nitrogen-free capsule containing a water-insoluble fluid-absorbing material. 66. The product of claim 1, wherein the capsules are made from non-animal and/or non-protein based material, wherein the materials contain no protein. 67. The product of claim 1, wherein the substantially nitrogen-free capsule comprises a singular opening, preferably at the distal end of the capsule, sealed with a hydrogel plug, optionally made of polymethacrylates, hydropropylmethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, saturated polyglycolated glycerides, glyceryl monooleates, pectin, sodium polyacrylate, acrylate polymers, copolymers with an abundance of hydrophilic groups, agarose, methylcellulose, hyaluronan, and other naturally derived polymers, and preferably wherein the hydrogel plug swells, erodes, congeals, melts, enzymatically erodes, or a combination thereof. 68. The product of claim 1, wherein release of the water insoluble fluid-absorbing material from the substantially nitrogen-free capsule is pH dependent, preferably at a pH of about 1 to about 3, or preferably at a pH of about 5 to about 8. 69. The product of claim 1, wherein the substantially nitrogen-free capsule is a two piece capsule. 70. The product of claim 1, wherein the substantially nitrogen-free capsule is constructed of a natural vegetable-derived polysaccharide, a non-animal and/or non-protein based material, preferably being hypromellose, cellulose, alginate, or a biodegradable carbohydrate, weaken plastic, rubber, silicone rubber, gelatinous material, hypromellose, cellulose, alginate, biodegradable carbohydrates, weakened plastic, rubber, silicone rubber, gelatinous material, or a combination thereof; and optionally wherein the substantially nitrogen-free capsule is enterically coated. 71. The product of claim 1, wherein the fluid-absorbing material is a hydrophilic fiber, powder, gel, or grain; or wherein the fluid-absorbing material is an insoluble, cross-linked polysaccharide, preferably nitrogen-free in pH ranging from about 1 to about 8; or wherein the fluid-absorbing material is non-ionic and further comprises a high content of hydroxyl groups. 72. The product of claim 1, wherein the fluid-absorbing material is dextran, preferably a modified dextran, wherein the modified dextran is preferably cross linked with epichlorohydrin; modified starches; dextrin; cellulose; polyglucose; hydroxyl group containing uncharged derivatives; or product obtained by partial depolymerization; or combinations thereof. 73. The product of claim 1, wherein the fluid-absorbing material is a copolymer in the form of a gel grain comprising a three dimensional network of dextran substances, preferably a copolymer comprising α-1,6-glucosidically bonded glucose residues, preferably having general formula —R—O—Xn—O—R, wherein R is a dextran substance, X is an aliphatic radical with carbon, n is 3-10; and preferably wherein the α-1,6-glucosidically bonded glucose residues are linked by ether bridges. 74. The product of claim 1, wherein the fluid-absorbing material comprises a water regain in the range of about 1 to about 100 grams/dry gram of dry product, preferably 1 to about 85 grams/dry grams of dry product and optionally wherein the fluid-absorbing material is a particle size ranging from about 50 to about 200 mesh. 75. The product of claim 1, wherein the fluid-absorbing material is Sephadex, preferably G-50 Sephadex; Sephacryl; Superdex; Sephacel; Sepharose; or any derivative thereof. 76. An orally consumable medical product comprising a substantially nitrogen-free capsule containing a water-insoluble fluid-absorbing material for use in treating renal failure; treating obesity; inducing a sense of fullness; relieving constipation; reducing the frequency of dialysis; removing excess accumulation of serum toxins, wherein the toxins are preferably potassium, urea, ammonia, or combinations thereof; treating hyperkalemia; treating hyperammonemia; treating ureamia; reducing triglycerides; and/or treating non-insulin dependent diabetes in a human subject in need thereof. 77. A method of preparing an orally consumable medical product according to any one of claim 1, said method comprising encapsulating a fluid absorbing polymer comprising:
a. filling a substantially nitrogen-free capsule with a fluid absorbing material; and b. sealing or enclosing the substantially nitrogen-free capsule, whereby the substantially nitrogen-free capsule encapsulates the fluid absorbing material. | 1,600 |
784 | 14,892,866 | 1,662 | Crop growth management system comprising a process of providing a plant with improved abiotic stress tolerance, comprising providing aerial parts of said plant with a suspension containing cells of an Agrobacterium strain comprising a nucleic acid molecule comprising a nucleic acid construct containing a nucleotide sequence of interest, said nucleotide sequence of interest providing said plant with increased abiotic stress tolerance upon expression in said plant. | 1. A process of providing a plant with improved abiotic stress tolerance, comprising providing aerial parts of said plant with a suspension containing cells of an Agrobacterium strain comprising a nucleic acid molecule comprising a nucleic acid construct containing a nucleotide sequence of interest, said nucleotide sequence of interest providing said plant with increased abiotic stress tolerance upon expression in said plant. 2. The process of providing a plant with improved abiotic stress tolerance according to claim 1, comprising
(i) growing said plant up to a desired growth state; and (ii) expressing, in said plant, said nucleotide sequence of interest providing said plant with increased abiotic stress tolerance, comprising providing aerial parts of said plant with said suspension containing cells of said Agrobacterium strain. 3. A process of providing a plurality of plants with improved abiotic stress tolerance, comprising
(a) growing said plurality of plants on a farm field; (b) determining whether an abiotic stress affects said plants; (c) providing aerial parts of said plants with said suspension containing cells of an Agrobacterium strain comprising a nucleic acid molecule comprising a nucleic acid construct containing a nucleotide sequence of interest, said nucleotide sequence of interest providing said plants with increased abiotic stress resistance upon expression in said plants. 4. The process according to any one of claims 1 to 3, wherein said abiotic stress is drought stress. 5. An agricultural process of producing plants or parts of said plants, comprising the following steps:
(A) growing a plurality of plants on a farm field; (B) determining whether drought stress affects said plants; (C) if it was determined in step (B) that drought stress affects or may affect said plants, providing aerial parts of said plants with a suspension containing cells of an Agrobacterium strain comprising a nucleic acid molecule comprising a nucleic acid construct containing a nucleotide sequence of interest, said nucleotide sequence of interest providing said plants with increased drought stress resistance upon expression in said plants; (D) harvesting said plants or desired parts thereof; and (E) if step (C) was performed, using the harvest of step (D) for a purpose for which having performed step (C) is acceptable; or, if step (C) was not performed, using the harvest of step (D) for a purpose for which having performed step (C) is not acceptable. 6. The process according to claim 4 or 5, wherein the presence or absence of drought stress affecting said plants is determined using one or more of the following criteria:
water status in the soil such as soil moisture content, water status in tissue of the plants such as relative water content, a plant water stress index, turgor pressure, or stromatal conduct, and water potential in soil or the plant. 7. The process according to any one of claims 1 to 6, wherein said nucleotide sequence of interest encodes a protein capable of providing said plant(s) with said increased abiotic stress tolerance. 8. The process according to claim 7, wherein said protein
i. has an amino acid sequence of any one of the amino acid sequences of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24; or ii. has an amino acid sequence having at least 80% sequence identity to the entire amino acid sequence of any one of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24; or iii. has an amino acid sequence of a length of at least 80%, preferably at least 90%, more preferably at least 95% of the number of amino acid residues of any one of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22, and a sequence identity of at least 90% to SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 respectively, over such length; or iv. has an amino acid sequence having from 1 to 20 amino acid additions, substitutions or deletions compared to the amino acid sequence of any one of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24. 9. The process according to any one of claim 7 or 8, wherein said protein is CspB from B. subtilis. 10. The process according to any one of claim 7 or 8, wherein said abiotic stress tolerance is drought tolerance, and said protein is plant transcription factor LAS of SEQ ID NO: 8 or GmRE222 of SEQ ID NO: 10 or a variant thereof as defined in items ii to iv of claim 8. 11. The process according to any one of claims 1 to 10, wherein said plant(s) is (are) dicot, preferably Solanaceae, more preferably tomato plants. 12. The process according to any one of claims 1 to 11, wherein said nucleic acid construct is present in T-DNA and flanked on both sides by T-DNA border sequences, said T-DNA not containing a selectable marker allowing selection of plant or plant cell containing said T-DNA. 13. The process according to any one of claims 1 to 12, wherein said nucleotide sequence of interest is operably linked to a promoter active in plant cells. 14. The process according to any one of claims 1 to 13, wherein said nucleic acid construct encodes a DNA or RNA replicon encoding said protein. 15. DNA molecule or vector for Agrobacterium-mediated transformation of plants, comprising in T-DNA a nucleic acid construct containing a DNA sequence of interest operably linked to a promoter; said DNA sequence of interest encoding a protein capable of providing a plant with increased abiotic stress tolerance; said T-DNA not containing a selectable marker allowing selection of plant cells containing said T-DNA. 16. DNA molecule or vector according to claim 15, wherein said protein is plant transcription factor LAS of SEQ ID NO: 8 or GmRE222 of SEQ ID NO: 10 or a variant thereof as defined in items ii to iv of claim 8. 17. Agrobacterium cell comprising the DNA molecule of claim 15 or 16. 18. Agrobacterium strain comprising a heterologous DNA molecule comprising in T-DNA a nucleic acid construct containing a heterologous DNA sequence of interest operably linked to a promoter; said heterologous DNA sequence of interest encoding a protein capable of providing a plant with increased drought resistance;
said T-DNA not containing a selectable marker allowing selection of plant cells containing said T-DNA. 19. A plant treated with a composition containing cells of an Agrobacterium strain comprising a nucleic acid molecule comprising a nucleic acid construct containing a nucleotide sequence of interest, said nucleotide sequence of interest providing said plant with increased abiotic stress resistance upon expression in said plant; said plant containing in cells thereof said nucleotide sequence of interest and expresses said nucleotide sequence of interest. 20. Method of conferring abiotic stress tolerance to a plant, comprising the following steps: preparing a suspension containing cells of an Agrobacterium strain comprising a nucleic acid molecule comprising a nucleic acid construct containing a nucleotide sequence of interest, said nucleotide sequence of interest providing said plant with increased abiotic stress resistance upon expression in said plant; and providing the suspension prepared in the previous step to aerial parts of said plant. | Crop growth management system comprising a process of providing a plant with improved abiotic stress tolerance, comprising providing aerial parts of said plant with a suspension containing cells of an Agrobacterium strain comprising a nucleic acid molecule comprising a nucleic acid construct containing a nucleotide sequence of interest, said nucleotide sequence of interest providing said plant with increased abiotic stress tolerance upon expression in said plant.1. A process of providing a plant with improved abiotic stress tolerance, comprising providing aerial parts of said plant with a suspension containing cells of an Agrobacterium strain comprising a nucleic acid molecule comprising a nucleic acid construct containing a nucleotide sequence of interest, said nucleotide sequence of interest providing said plant with increased abiotic stress tolerance upon expression in said plant. 2. The process of providing a plant with improved abiotic stress tolerance according to claim 1, comprising
(i) growing said plant up to a desired growth state; and (ii) expressing, in said plant, said nucleotide sequence of interest providing said plant with increased abiotic stress tolerance, comprising providing aerial parts of said plant with said suspension containing cells of said Agrobacterium strain. 3. A process of providing a plurality of plants with improved abiotic stress tolerance, comprising
(a) growing said plurality of plants on a farm field; (b) determining whether an abiotic stress affects said plants; (c) providing aerial parts of said plants with said suspension containing cells of an Agrobacterium strain comprising a nucleic acid molecule comprising a nucleic acid construct containing a nucleotide sequence of interest, said nucleotide sequence of interest providing said plants with increased abiotic stress resistance upon expression in said plants. 4. The process according to any one of claims 1 to 3, wherein said abiotic stress is drought stress. 5. An agricultural process of producing plants or parts of said plants, comprising the following steps:
(A) growing a plurality of plants on a farm field; (B) determining whether drought stress affects said plants; (C) if it was determined in step (B) that drought stress affects or may affect said plants, providing aerial parts of said plants with a suspension containing cells of an Agrobacterium strain comprising a nucleic acid molecule comprising a nucleic acid construct containing a nucleotide sequence of interest, said nucleotide sequence of interest providing said plants with increased drought stress resistance upon expression in said plants; (D) harvesting said plants or desired parts thereof; and (E) if step (C) was performed, using the harvest of step (D) for a purpose for which having performed step (C) is acceptable; or, if step (C) was not performed, using the harvest of step (D) for a purpose for which having performed step (C) is not acceptable. 6. The process according to claim 4 or 5, wherein the presence or absence of drought stress affecting said plants is determined using one or more of the following criteria:
water status in the soil such as soil moisture content, water status in tissue of the plants such as relative water content, a plant water stress index, turgor pressure, or stromatal conduct, and water potential in soil or the plant. 7. The process according to any one of claims 1 to 6, wherein said nucleotide sequence of interest encodes a protein capable of providing said plant(s) with said increased abiotic stress tolerance. 8. The process according to claim 7, wherein said protein
i. has an amino acid sequence of any one of the amino acid sequences of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24; or ii. has an amino acid sequence having at least 80% sequence identity to the entire amino acid sequence of any one of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24; or iii. has an amino acid sequence of a length of at least 80%, preferably at least 90%, more preferably at least 95% of the number of amino acid residues of any one of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 22, and a sequence identity of at least 90% to SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 respectively, over such length; or iv. has an amino acid sequence having from 1 to 20 amino acid additions, substitutions or deletions compared to the amino acid sequence of any one of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24. 9. The process according to any one of claim 7 or 8, wherein said protein is CspB from B. subtilis. 10. The process according to any one of claim 7 or 8, wherein said abiotic stress tolerance is drought tolerance, and said protein is plant transcription factor LAS of SEQ ID NO: 8 or GmRE222 of SEQ ID NO: 10 or a variant thereof as defined in items ii to iv of claim 8. 11. The process according to any one of claims 1 to 10, wherein said plant(s) is (are) dicot, preferably Solanaceae, more preferably tomato plants. 12. The process according to any one of claims 1 to 11, wherein said nucleic acid construct is present in T-DNA and flanked on both sides by T-DNA border sequences, said T-DNA not containing a selectable marker allowing selection of plant or plant cell containing said T-DNA. 13. The process according to any one of claims 1 to 12, wherein said nucleotide sequence of interest is operably linked to a promoter active in plant cells. 14. The process according to any one of claims 1 to 13, wherein said nucleic acid construct encodes a DNA or RNA replicon encoding said protein. 15. DNA molecule or vector for Agrobacterium-mediated transformation of plants, comprising in T-DNA a nucleic acid construct containing a DNA sequence of interest operably linked to a promoter; said DNA sequence of interest encoding a protein capable of providing a plant with increased abiotic stress tolerance; said T-DNA not containing a selectable marker allowing selection of plant cells containing said T-DNA. 16. DNA molecule or vector according to claim 15, wherein said protein is plant transcription factor LAS of SEQ ID NO: 8 or GmRE222 of SEQ ID NO: 10 or a variant thereof as defined in items ii to iv of claim 8. 17. Agrobacterium cell comprising the DNA molecule of claim 15 or 16. 18. Agrobacterium strain comprising a heterologous DNA molecule comprising in T-DNA a nucleic acid construct containing a heterologous DNA sequence of interest operably linked to a promoter; said heterologous DNA sequence of interest encoding a protein capable of providing a plant with increased drought resistance;
said T-DNA not containing a selectable marker allowing selection of plant cells containing said T-DNA. 19. A plant treated with a composition containing cells of an Agrobacterium strain comprising a nucleic acid molecule comprising a nucleic acid construct containing a nucleotide sequence of interest, said nucleotide sequence of interest providing said plant with increased abiotic stress resistance upon expression in said plant; said plant containing in cells thereof said nucleotide sequence of interest and expresses said nucleotide sequence of interest. 20. Method of conferring abiotic stress tolerance to a plant, comprising the following steps: preparing a suspension containing cells of an Agrobacterium strain comprising a nucleic acid molecule comprising a nucleic acid construct containing a nucleotide sequence of interest, said nucleotide sequence of interest providing said plant with increased abiotic stress resistance upon expression in said plant; and providing the suspension prepared in the previous step to aerial parts of said plant. | 1,600 |
785 | 14,905,394 | 1,663 | Provided are plants that express, or overexpress, type III Gγ protein AGG3. Such plants exhibit faster vegetative and reproductive growth, accompanied by an increase in photosynthetic efficiency. Constitutive or seed-specific expression of AGG3 in Camelina increases seed size, seed mass, and seed number per plant by 15-40%, effectively resulting in significantly higher oil yield per plant. AGG3-expressing Camelina plants also exhibit improved stress tolerance. Use of AGG3 is therefore an effective biotechnological tool to dramatically increase stress tolerance and plant yield, including oil, in agricultural and horticultural crops. | 1. A transgenic plant, other than a rice plant or Arabidopsis, with enhanced resistance to a redox stress comprising expressing in said transgenic plant a DNA construct comprising a promoter that functions in plants, operably linked to a DNA polynucleotide molecule selected from the group consisting of:
a. a DNA molecule encoding a polypeptide sequence at least 90% identical to SEQ ID NO:3; and b. a DNA molecule comprising the polynucleotide sequence of SEQ ID NO: 1 wherein said transgenic plant exhibits enhanced resistance to a redox stress compared to a plant of a same plant species not containing the DNA construct. 2. The transgenic plant of claim 1, wherein said DNA molecule is expressed in cells of said plant at a level effective to confer enhanced resistance to said redox stress. 3. The transgenic plant of claim 2, wherein said DNA molecule is expressed under the control of a heterologous plant promoter. 4. The transgenic plant of claim 1 wherein said redox stress is caused by an abiotic stress that disrupts the normal redox state of plants. 5. The transgenic plant of claim 4, wherein said abiotic stress is selected from the group consisting of cold, heat, drought, flood, ionizing or non-ionizing radiation, acid rain, an air pollutant, a water or soil pollutant, mineralized soil, a pesticide, and a herbicide. 6. The transgenic plant of claim 5, wherein said air pollutant is elevated carbon dioxide, ozone, or sulfur dioxide, and said water or soil pollutant is a salt or heavy metal. 7. The transgenic plant of claim 1, wherein said enhanced resistance to said redox stress is in the range from about 10% to about 15% greater than that exhibited by said otherwise identical control plant when both plants are grown under the same conditions. 8. The transgenic plant of claim 1, wherein said DNA molecule is expressed in cells of said plant to produce an enhanced amount of oil compared to the amount of oil produced by an otherwise identical control plant grown under the same conditions. 9. The transgenic plant of claim 1, wherein said plant is a crop plant. 10. The transgenic plant of claim 9, wherein said crop plant is selected from the group consisting of corn, soybean, rapeseed/canola, wheat, peanut, palm, coconut, safflower, sesame, cottonseed, sunflower, flax, olive, safflower, sugarcane, castor bean, Camelina, switchgrass, Miscanthus, and Jatropha. 11. The transgenic plant of claim 8, wherein said enhanced amount of oil accumulates in a part of said plant selected from the group consisting of an inflorescence, a flower, a seed, a fruit, a leaf, a stem, a root, a tuberous root, a rhizome, a tuber, a stolon, a corm, a bulb, and an offset, or in a cell of said plant in culture, a tissue of said plant in culture, an organ of said plant in culture, and a callus. 12. The transgenic plant of claim 1, wherein said polypeptide is an AGG3 protein. 13. The transgenic plant of claim 12, wherein said AGG3 protein comprises the amino acid sequence shown in SEQ ID NO:3. 14. A method of generating a transgenic plant, other than a rice plant or Arabidopsis, with enhanced resistance to a redox stress comprising expressing in said transgenic plant a DNA construct comprising a promoter that functions in plants, operably linked to a DNA polynucleotide molecule selected from the group consisting of:
a. a DNA molecule encoding a polypeptide sequence at least 90% identical to SEQ ID NO:3; and b. a DNA molecule comprising the polynucleotide sequence of SEQ ID NO:1 wherein said transgenic plant exhibits enhanced resistance to a redox stress compared to a plant of a same plant species not containing the DNA construct. 15. A method of obtaining oil from seeds of an oilseed crop plant, comprising:
expressing a heterologous nucleotide sequence that encodes a type III Gγ protein in said oilseed crop plant, and recovering oil from said seeds of said oilseed crop plant, wherein the amount of oil obtained from said oilseed crop plant is greater than that obtained from an otherwise identical control oilseed crop plant grown under the same conditions. | Provided are plants that express, or overexpress, type III Gγ protein AGG3. Such plants exhibit faster vegetative and reproductive growth, accompanied by an increase in photosynthetic efficiency. Constitutive or seed-specific expression of AGG3 in Camelina increases seed size, seed mass, and seed number per plant by 15-40%, effectively resulting in significantly higher oil yield per plant. AGG3-expressing Camelina plants also exhibit improved stress tolerance. Use of AGG3 is therefore an effective biotechnological tool to dramatically increase stress tolerance and plant yield, including oil, in agricultural and horticultural crops.1. A transgenic plant, other than a rice plant or Arabidopsis, with enhanced resistance to a redox stress comprising expressing in said transgenic plant a DNA construct comprising a promoter that functions in plants, operably linked to a DNA polynucleotide molecule selected from the group consisting of:
a. a DNA molecule encoding a polypeptide sequence at least 90% identical to SEQ ID NO:3; and b. a DNA molecule comprising the polynucleotide sequence of SEQ ID NO: 1 wherein said transgenic plant exhibits enhanced resistance to a redox stress compared to a plant of a same plant species not containing the DNA construct. 2. The transgenic plant of claim 1, wherein said DNA molecule is expressed in cells of said plant at a level effective to confer enhanced resistance to said redox stress. 3. The transgenic plant of claim 2, wherein said DNA molecule is expressed under the control of a heterologous plant promoter. 4. The transgenic plant of claim 1 wherein said redox stress is caused by an abiotic stress that disrupts the normal redox state of plants. 5. The transgenic plant of claim 4, wherein said abiotic stress is selected from the group consisting of cold, heat, drought, flood, ionizing or non-ionizing radiation, acid rain, an air pollutant, a water or soil pollutant, mineralized soil, a pesticide, and a herbicide. 6. The transgenic plant of claim 5, wherein said air pollutant is elevated carbon dioxide, ozone, or sulfur dioxide, and said water or soil pollutant is a salt or heavy metal. 7. The transgenic plant of claim 1, wherein said enhanced resistance to said redox stress is in the range from about 10% to about 15% greater than that exhibited by said otherwise identical control plant when both plants are grown under the same conditions. 8. The transgenic plant of claim 1, wherein said DNA molecule is expressed in cells of said plant to produce an enhanced amount of oil compared to the amount of oil produced by an otherwise identical control plant grown under the same conditions. 9. The transgenic plant of claim 1, wherein said plant is a crop plant. 10. The transgenic plant of claim 9, wherein said crop plant is selected from the group consisting of corn, soybean, rapeseed/canola, wheat, peanut, palm, coconut, safflower, sesame, cottonseed, sunflower, flax, olive, safflower, sugarcane, castor bean, Camelina, switchgrass, Miscanthus, and Jatropha. 11. The transgenic plant of claim 8, wherein said enhanced amount of oil accumulates in a part of said plant selected from the group consisting of an inflorescence, a flower, a seed, a fruit, a leaf, a stem, a root, a tuberous root, a rhizome, a tuber, a stolon, a corm, a bulb, and an offset, or in a cell of said plant in culture, a tissue of said plant in culture, an organ of said plant in culture, and a callus. 12. The transgenic plant of claim 1, wherein said polypeptide is an AGG3 protein. 13. The transgenic plant of claim 12, wherein said AGG3 protein comprises the amino acid sequence shown in SEQ ID NO:3. 14. A method of generating a transgenic plant, other than a rice plant or Arabidopsis, with enhanced resistance to a redox stress comprising expressing in said transgenic plant a DNA construct comprising a promoter that functions in plants, operably linked to a DNA polynucleotide molecule selected from the group consisting of:
a. a DNA molecule encoding a polypeptide sequence at least 90% identical to SEQ ID NO:3; and b. a DNA molecule comprising the polynucleotide sequence of SEQ ID NO:1 wherein said transgenic plant exhibits enhanced resistance to a redox stress compared to a plant of a same plant species not containing the DNA construct. 15. A method of obtaining oil from seeds of an oilseed crop plant, comprising:
expressing a heterologous nucleotide sequence that encodes a type III Gγ protein in said oilseed crop plant, and recovering oil from said seeds of said oilseed crop plant, wherein the amount of oil obtained from said oilseed crop plant is greater than that obtained from an otherwise identical control oilseed crop plant grown under the same conditions. | 1,600 |
786 | 13,714,243 | 1,637 | A Method for nucleic acid analysis involving the steps of receiving sample tubes which contain samples, receiving a test request for each sample (the test request specifying one or more assays to be conducted for said sample), obtaining one or more sample aliquots of each sample depending on if one or more assays are to be conducted, assigning each of the sample aliquots to one or more test classes according to the assay which is to be conducted for that sample aliquot and combining sample aliquots belonging to the same test class into the same batch, while the batch includes samples for which a first and samples for which a second assay is to be conducted. | 1. A method for nucleic add analysis involving the steps of
receiving sample tubes each containing a sample, receiving a test request for each sample, said test request specifying one or more assays to be conducted for said sample, obtaining one or more sample aliquots of each sample depending on if one or more assays are to be conducted, assigning each of the sample aliquots to one or more test classes according to the assay which is to be conducted for that sample aliquot combining sample aliquots belonging to the same test class into the same batch, said batch comprising samples for which a first and samples for which a second assay is to be conducted, simultaneous amplification of nucleic acids contained in said batch conducting an analysis of the sample aliquots to determine the presence and/or concentration of nucleic acids in said sample aliquots. 2. The method according to claim 1, wherein said assignment step involves the check of a lookup table which shows a corresponding test class for an assay to be conducted. 3. The method according to claim 1, wherein a first and a second sample aliquot are assigned to the same test class if
a) the sample processing steps are identical, or b) the same thermal profile for nucleic acid isolation is employed, or c) the same consumables are employed for the first and second sample aliquot. 4. The method according to claim 1, wherein a first and a second sample aliquot are belonging to the same batch while reagents employed for testing the first and the second sample aliquot are different. 5. The method according to claim 1, wherein said obtaining of sample aliquots is done by aspirating a volume of sample and discharging said volume or a portion thereof into a well. 6. The method according to claim 1, wherein said combining of sample aliquots into a batch is done by pipetting said sample aliquots into different wells of the same microwell plate. 7. The method according to claim 6, wherein said processing together of sample aliquots is performed by subjecting said microwell plate to a thermal profile such that all sample aliquots in said microwell plate are subjected to the same thermal profile. 8. The method according to claim 1, wherein the analysis involves the detection of fluorescence light from the sample aliquots. 9. A system for analyzing nucleic acid containing samples, comprising:
a sample reception unit in which sample tubes each containing a sample are received, a reader which reads identifications on the sample tubes, a data management unit which receives test requests for samples, said test requests are specifying assays to be conducted for the samples, the data management unit further receives sample tube identifications from the reader, the data management unit determines how many aliquots of a sample are necessary; assigns the sample aliquots to test classes and provides such assignment to a control unit, the control unit controls a pipettor to pipette sample aliquots having the same test class assigned thereto into the same batch of wells, the same or a further pipettor for pipetting reagents into the batch of wells, a thermal unit for subjecting the batch of wells to a thermal profile for amplifying nucleic acids, a detection unit which detects signals from the batch of wells, an evaluation unit which determines the presence and/or quantity of nucleic acids in the wells of the batch. 10. The system according to claim 9 further comprising a purification unit which purities nucleic acids contained in the wells. 11. The system according to claim 9, wherein the data management unit has stored therein a lookup table which assigns each type of assay to at least one test class. 12. The system according to claim 9, wherein the thermal unit has two or more segments which perform different thermal profiles. 13. The system according to claim 9, wherein the batch of wells is provided by a unitary microwell plate. 14. The system according to claim 9, wherein the detection system is a fluorescence detection system comprising an illumination unit for illuminating sample aliquots located in sample wells and further comprising a detector for detecting fluorescent light emitted from the sample wells. 15. The system according to claim 9, wherein the data management unit receives the sample orders from a laboratory information system (LIS). | A Method for nucleic acid analysis involving the steps of receiving sample tubes which contain samples, receiving a test request for each sample (the test request specifying one or more assays to be conducted for said sample), obtaining one or more sample aliquots of each sample depending on if one or more assays are to be conducted, assigning each of the sample aliquots to one or more test classes according to the assay which is to be conducted for that sample aliquot and combining sample aliquots belonging to the same test class into the same batch, while the batch includes samples for which a first and samples for which a second assay is to be conducted.1. A method for nucleic add analysis involving the steps of
receiving sample tubes each containing a sample, receiving a test request for each sample, said test request specifying one or more assays to be conducted for said sample, obtaining one or more sample aliquots of each sample depending on if one or more assays are to be conducted, assigning each of the sample aliquots to one or more test classes according to the assay which is to be conducted for that sample aliquot combining sample aliquots belonging to the same test class into the same batch, said batch comprising samples for which a first and samples for which a second assay is to be conducted, simultaneous amplification of nucleic acids contained in said batch conducting an analysis of the sample aliquots to determine the presence and/or concentration of nucleic acids in said sample aliquots. 2. The method according to claim 1, wherein said assignment step involves the check of a lookup table which shows a corresponding test class for an assay to be conducted. 3. The method according to claim 1, wherein a first and a second sample aliquot are assigned to the same test class if
a) the sample processing steps are identical, or b) the same thermal profile for nucleic acid isolation is employed, or c) the same consumables are employed for the first and second sample aliquot. 4. The method according to claim 1, wherein a first and a second sample aliquot are belonging to the same batch while reagents employed for testing the first and the second sample aliquot are different. 5. The method according to claim 1, wherein said obtaining of sample aliquots is done by aspirating a volume of sample and discharging said volume or a portion thereof into a well. 6. The method according to claim 1, wherein said combining of sample aliquots into a batch is done by pipetting said sample aliquots into different wells of the same microwell plate. 7. The method according to claim 6, wherein said processing together of sample aliquots is performed by subjecting said microwell plate to a thermal profile such that all sample aliquots in said microwell plate are subjected to the same thermal profile. 8. The method according to claim 1, wherein the analysis involves the detection of fluorescence light from the sample aliquots. 9. A system for analyzing nucleic acid containing samples, comprising:
a sample reception unit in which sample tubes each containing a sample are received, a reader which reads identifications on the sample tubes, a data management unit which receives test requests for samples, said test requests are specifying assays to be conducted for the samples, the data management unit further receives sample tube identifications from the reader, the data management unit determines how many aliquots of a sample are necessary; assigns the sample aliquots to test classes and provides such assignment to a control unit, the control unit controls a pipettor to pipette sample aliquots having the same test class assigned thereto into the same batch of wells, the same or a further pipettor for pipetting reagents into the batch of wells, a thermal unit for subjecting the batch of wells to a thermal profile for amplifying nucleic acids, a detection unit which detects signals from the batch of wells, an evaluation unit which determines the presence and/or quantity of nucleic acids in the wells of the batch. 10. The system according to claim 9 further comprising a purification unit which purities nucleic acids contained in the wells. 11. The system according to claim 9, wherein the data management unit has stored therein a lookup table which assigns each type of assay to at least one test class. 12. The system according to claim 9, wherein the thermal unit has two or more segments which perform different thermal profiles. 13. The system according to claim 9, wherein the batch of wells is provided by a unitary microwell plate. 14. The system according to claim 9, wherein the detection system is a fluorescence detection system comprising an illumination unit for illuminating sample aliquots located in sample wells and further comprising a detector for detecting fluorescent light emitted from the sample wells. 15. The system according to claim 9, wherein the data management unit receives the sample orders from a laboratory information system (LIS). | 1,600 |
787 | 14,197,339 | 1,619 | Novel mixtures of sugar amides or sugar amines are disclosed that have improved thermal properties over the individual components. New feedstocks based on both the surfactant tail as well as the sugar head group allow for improved physical properties of sugar amide surfactant mixtures and thus improved formulatability. Furthermore, new sources of unique methyl esters from both bioengineering and or co-metathesis of fats and oils provide novel and improved sugar amide surfactant mixtures. | 1. A mixture comprising a first chemical and a second chemical, wherein said first chemical has the chemical structure of Formula I and said second chemical has the chemical structure of Formula II:
wherein:
n1 is 2 to 4;
n2 is 1 to 3;
n1 is greater than n2
R1 and R3 are independently selected from hydrogen, C1-C16 alkyl, C1-C3 hydroxy- or methoxy-alkyl and;
R2 and R4 are independently selected from hydrogen, C1-C16 alkyl, C1-C3 hydroxy- or methoxy-alkyl, or a structure of Formula III
wherein: R5 is C7-C23 alkyl, mono-alkenyl, di-alkenyl, tri-alkenyl, hydroxyl-alkyl, or hydroxyl-alkenyl;
and mixtures thereof. 2. The mixture of claim 1, wherein n1 is 4. 3. The mixture of claim 1, wherein a portion of the molecule of Formula I is derived from glucose. 4. The mixture of claim 1, wherein n2 is 3. 5. The mixture of claim 1, wherein a portion of the molecule of Formula II is derived from xylose. 6. The mixture of claim 1, wherein n1 is 4 and n2 is 3. 7. The mixture of claim 1, wherein a portion of the molecule of Formula I is derived from glucose and a portion of the molecule of Formula II is derived from xylose. 8. The mixture of claim 7, wherein the glucose is derived from starch. 9. The mixture of claim 7, wherein the glucose is derived from a lignocellulosic material. 10. The mixture of claim 7, wherein the xylose is derived from xylans. 11. The mixture of claim 7, wherein the xylose is derived from a lignocellulosic material. 12. The mixture of claim 7, wherein the weight ratio of the chemical structure of Formula I to the chemical structure of Formula II is from 50:50 to 0.5:99.5. 13. The mixture of claim 12, wherein R1 and R3 are methyl groups, and R2 and R4 have the structure of Formula III and R5 is a mixture of C11 and C13, wherein the weight ratio of C11 to C13 is between 99:1 and 60:40. 14. The mixture of claim 1, wherein R1 is methyl. 15. The mixture of claim 1, wherein R3 is methyl. 16. The mixture of claim 1, wherein R5 is C7-C18 alkyl, and mixtures thereof. 17. The mixture of claim 1, wherein R2 and R4 are C1-C16 alkyl, and mixtures thereof. 18. The mixture of claim 1, wherein the ratio of the first chemical to the second chemical is from 99.5:0.5 to 0.5:99.5. 19. The mixture of claim 1, wherein said mixture further comprises a third chemical, said third chemical having the chemical structure of Formula IV:
wherein:
R5 is selected from hydrogen, C1-C16 alkyl, C1-C3 hydroxy- or methoxy-alkyl;
R6 is independently selected from C8-C22 alkyl, mono-alkenyl, di-alkenyl, or tri-alkenyl and mixtures thereof;
n3 is 2 to 4. 20. The mixture of claim 19, wherein n3 is 4. 21. The mixture of claim 19, wherein n3 is 3. 22. The mixture of claim 19, wherein a portion of the molecule of Formula IV is selected from the group consisting of fragments derived from arabinose, galactose, mannose and combinations thereof. 23. A composition comprising
(a) from about 0.001 wt % to about 99.999 wt % of the mixture of claim 1, and (b) from about 0.001 wt % to about 99.999 wt % of at least one additional component selected from the group consisting of cleaning components and personal care components. 24. A composition comprising
(a) from about 0.001 wt % to about 99.999 wt % of the mixture of claim 19, and (b) from about 0.001 wt % to about 99.999 wt % of at least one additional component selected from the group consisting of cleaning components and personal care components. 25. The composition of claim 23 or 24, wherein at least one cleaning component is selected from the group consisting of a surfactant, a carrier, an enzyme, a builder, an alkalinity system, an organic polymeric compound, a hueing dye, a bleaching compound, an alkanolamine, a soil suspension agent, an anti-redeposition agent, a corrosion inhibitor, and mixtures thereof. 26. The composition of claim 23 or 24, wherein the composition is selected from the group consisting of a granular detergent, a bar-form detergent, a liquid laundry detergent, a liquid hand dishwashing mixture, a hard surface cleaner, a tablet, a disinfectant, an industrial cleaner, a highly compact liquid, a powder, and a decontaminant. 27. A method of laundering soiled fabrics comprising the step of contacting said soiled fabrics with an effective amount of the composition of claim 23 or 24 in an aqueous solution. 28. The composition of claim 23 or 24, wherein the personal care component is selected from the group consisting of an oil, and emollient, a moisturizer, a carrier, an extract, a vitamin, a mineral, an anti-aging compound, a surfactant, a solvent, a polymer, a preservative, an antimicrobial, a wax, a particle, a colorant, a dye, a fragrance, and mixtures thereof. 29. The composition of claim 23 or 24, wherein the composition is selected from the group consisting of a shampoo, a hair conditioner, a hair treatment, a facial soap, a body wash, a body soap, a foam bath, a make-up remover, a skin care product, an acne control product, a deodorant, an antiperspirant, a shaving aid, a cosmetic, a depilatory, a fragrance, a lotion, and a mixtures thereof. 30. A method of treating, cleansing, or conditioning skin or hair comprising contacting the skin or hair with an effective amount of the composition of claim 23 or 24. | Novel mixtures of sugar amides or sugar amines are disclosed that have improved thermal properties over the individual components. New feedstocks based on both the surfactant tail as well as the sugar head group allow for improved physical properties of sugar amide surfactant mixtures and thus improved formulatability. Furthermore, new sources of unique methyl esters from both bioengineering and or co-metathesis of fats and oils provide novel and improved sugar amide surfactant mixtures.1. A mixture comprising a first chemical and a second chemical, wherein said first chemical has the chemical structure of Formula I and said second chemical has the chemical structure of Formula II:
wherein:
n1 is 2 to 4;
n2 is 1 to 3;
n1 is greater than n2
R1 and R3 are independently selected from hydrogen, C1-C16 alkyl, C1-C3 hydroxy- or methoxy-alkyl and;
R2 and R4 are independently selected from hydrogen, C1-C16 alkyl, C1-C3 hydroxy- or methoxy-alkyl, or a structure of Formula III
wherein: R5 is C7-C23 alkyl, mono-alkenyl, di-alkenyl, tri-alkenyl, hydroxyl-alkyl, or hydroxyl-alkenyl;
and mixtures thereof. 2. The mixture of claim 1, wherein n1 is 4. 3. The mixture of claim 1, wherein a portion of the molecule of Formula I is derived from glucose. 4. The mixture of claim 1, wherein n2 is 3. 5. The mixture of claim 1, wherein a portion of the molecule of Formula II is derived from xylose. 6. The mixture of claim 1, wherein n1 is 4 and n2 is 3. 7. The mixture of claim 1, wherein a portion of the molecule of Formula I is derived from glucose and a portion of the molecule of Formula II is derived from xylose. 8. The mixture of claim 7, wherein the glucose is derived from starch. 9. The mixture of claim 7, wherein the glucose is derived from a lignocellulosic material. 10. The mixture of claim 7, wherein the xylose is derived from xylans. 11. The mixture of claim 7, wherein the xylose is derived from a lignocellulosic material. 12. The mixture of claim 7, wherein the weight ratio of the chemical structure of Formula I to the chemical structure of Formula II is from 50:50 to 0.5:99.5. 13. The mixture of claim 12, wherein R1 and R3 are methyl groups, and R2 and R4 have the structure of Formula III and R5 is a mixture of C11 and C13, wherein the weight ratio of C11 to C13 is between 99:1 and 60:40. 14. The mixture of claim 1, wherein R1 is methyl. 15. The mixture of claim 1, wherein R3 is methyl. 16. The mixture of claim 1, wherein R5 is C7-C18 alkyl, and mixtures thereof. 17. The mixture of claim 1, wherein R2 and R4 are C1-C16 alkyl, and mixtures thereof. 18. The mixture of claim 1, wherein the ratio of the first chemical to the second chemical is from 99.5:0.5 to 0.5:99.5. 19. The mixture of claim 1, wherein said mixture further comprises a third chemical, said third chemical having the chemical structure of Formula IV:
wherein:
R5 is selected from hydrogen, C1-C16 alkyl, C1-C3 hydroxy- or methoxy-alkyl;
R6 is independently selected from C8-C22 alkyl, mono-alkenyl, di-alkenyl, or tri-alkenyl and mixtures thereof;
n3 is 2 to 4. 20. The mixture of claim 19, wherein n3 is 4. 21. The mixture of claim 19, wherein n3 is 3. 22. The mixture of claim 19, wherein a portion of the molecule of Formula IV is selected from the group consisting of fragments derived from arabinose, galactose, mannose and combinations thereof. 23. A composition comprising
(a) from about 0.001 wt % to about 99.999 wt % of the mixture of claim 1, and (b) from about 0.001 wt % to about 99.999 wt % of at least one additional component selected from the group consisting of cleaning components and personal care components. 24. A composition comprising
(a) from about 0.001 wt % to about 99.999 wt % of the mixture of claim 19, and (b) from about 0.001 wt % to about 99.999 wt % of at least one additional component selected from the group consisting of cleaning components and personal care components. 25. The composition of claim 23 or 24, wherein at least one cleaning component is selected from the group consisting of a surfactant, a carrier, an enzyme, a builder, an alkalinity system, an organic polymeric compound, a hueing dye, a bleaching compound, an alkanolamine, a soil suspension agent, an anti-redeposition agent, a corrosion inhibitor, and mixtures thereof. 26. The composition of claim 23 or 24, wherein the composition is selected from the group consisting of a granular detergent, a bar-form detergent, a liquid laundry detergent, a liquid hand dishwashing mixture, a hard surface cleaner, a tablet, a disinfectant, an industrial cleaner, a highly compact liquid, a powder, and a decontaminant. 27. A method of laundering soiled fabrics comprising the step of contacting said soiled fabrics with an effective amount of the composition of claim 23 or 24 in an aqueous solution. 28. The composition of claim 23 or 24, wherein the personal care component is selected from the group consisting of an oil, and emollient, a moisturizer, a carrier, an extract, a vitamin, a mineral, an anti-aging compound, a surfactant, a solvent, a polymer, a preservative, an antimicrobial, a wax, a particle, a colorant, a dye, a fragrance, and mixtures thereof. 29. The composition of claim 23 or 24, wherein the composition is selected from the group consisting of a shampoo, a hair conditioner, a hair treatment, a facial soap, a body wash, a body soap, a foam bath, a make-up remover, a skin care product, an acne control product, a deodorant, an antiperspirant, a shaving aid, a cosmetic, a depilatory, a fragrance, a lotion, and a mixtures thereof. 30. A method of treating, cleansing, or conditioning skin or hair comprising contacting the skin or hair with an effective amount of the composition of claim 23 or 24. | 1,600 |
788 | 15,518,256 | 1,615 | It is an object to provide a therapeutic material for a skin ulcer which has excellent therapeutic effects on intractable skin ulcers such as decubitus ulcers with pockets and huge decubitus ulcers. By applying the therapeutic material for decubitus ulcers consisting of a fibrous material holding an antibiotic and a cell proliferation accelerator therein which is formed into an approximately spherical shape to a site of decubitus in a state in which a defect extending to the dermis, subcutaneous tissue, muscle or bone occurs, it is possible to treat critical skin ulcers such as intractable decubitus ulcers with pockets and huge intractable decubitus ulcers, as well as to treat not only relatively mild decubitus classified as stage II according to the US National Pressure Ulcer Advisory Panel (NPUAP) staging system, i.e., decubitus having ulcers in a state in which a part of the dermis is deficient, but also severe decubitus that has progressed to stage III to IV according to the NPUAP staging system, particularly decubitus with intractable ulcers with pockets or decubitus with huge intractable ulcers. | 1. A method for treating a skin ulcer, comprising applying a therapeutic material for a skin ulcer consisting of a fibrous material holding an antibiotic and a cell proliferation accelerator therein which is formed into an approximately spherical shape to a site of a skin ulcer in a state in which a defect extending to the dermis, subcutaneous tissue, muscle or bone occurs. 2. The method according to claim 1, wherein the skin ulcer is a decubitus ulcer. 3. The method according to claim 1, wherein the fibrous material is cotton. 4. The method according to claim 1, wherein the cell proliferation accelerator has angiogenesis and/or granulation promoting actions. 5. The method according to claim 1, wherein the cell proliferation accelerator is trafermin. 6. The method according to claim 1, wherein the antibiotic is fradiomycin sulfate. 7. The method according to claim 2, wherein the decubitus is a decubitus classified as stage III to IV when the degree of progression of decubitus is classified according to the US National Pressure Ulcer Advisory Panel (NPUAP) staging system. 8. (canceled) 9. (canceled) 10. The method according to claim 2, wherein the fibrous material is cotton. 11. The method according to claim 2, wherein the cell proliferation accelerator has angiogenesis and/or granulation promoting actions. 12. The method according to claim 3, wherein the cell proliferation accelerator has angiogenesis and/or granulation promoting actions. 13. The method according to claim 10, wherein the cell proliferation accelerator has angiogenesis and/or granulation promoting actions. 14. The method according to claim 2, wherein the cell proliferation accelerator is trafermin. 15. The method according to claim 3, wherein the cell proliferation accelerator is trafermin. 16. The method according to claim 4, wherein the cell proliferation accelerator is trafermin. 17. The method according to claim 10, wherein the cell proliferation accelerator is trafermin. 18. The method according to claim 11, wherein the cell proliferation accelerator is trafermin. 19. The method according to claim 12, wherein the cell proliferation accelerator is trafermin. 20. The method according to claim 13, wherein the cell proliferation accelerator is trafermin. 21. The method according to claim 2, wherein the antibiotic is fradiomycin sulfate. 22. The method according to claim 3, wherein the antibiotic is fradiomycin sulfate. | It is an object to provide a therapeutic material for a skin ulcer which has excellent therapeutic effects on intractable skin ulcers such as decubitus ulcers with pockets and huge decubitus ulcers. By applying the therapeutic material for decubitus ulcers consisting of a fibrous material holding an antibiotic and a cell proliferation accelerator therein which is formed into an approximately spherical shape to a site of decubitus in a state in which a defect extending to the dermis, subcutaneous tissue, muscle or bone occurs, it is possible to treat critical skin ulcers such as intractable decubitus ulcers with pockets and huge intractable decubitus ulcers, as well as to treat not only relatively mild decubitus classified as stage II according to the US National Pressure Ulcer Advisory Panel (NPUAP) staging system, i.e., decubitus having ulcers in a state in which a part of the dermis is deficient, but also severe decubitus that has progressed to stage III to IV according to the NPUAP staging system, particularly decubitus with intractable ulcers with pockets or decubitus with huge intractable ulcers.1. A method for treating a skin ulcer, comprising applying a therapeutic material for a skin ulcer consisting of a fibrous material holding an antibiotic and a cell proliferation accelerator therein which is formed into an approximately spherical shape to a site of a skin ulcer in a state in which a defect extending to the dermis, subcutaneous tissue, muscle or bone occurs. 2. The method according to claim 1, wherein the skin ulcer is a decubitus ulcer. 3. The method according to claim 1, wherein the fibrous material is cotton. 4. The method according to claim 1, wherein the cell proliferation accelerator has angiogenesis and/or granulation promoting actions. 5. The method according to claim 1, wherein the cell proliferation accelerator is trafermin. 6. The method according to claim 1, wherein the antibiotic is fradiomycin sulfate. 7. The method according to claim 2, wherein the decubitus is a decubitus classified as stage III to IV when the degree of progression of decubitus is classified according to the US National Pressure Ulcer Advisory Panel (NPUAP) staging system. 8. (canceled) 9. (canceled) 10. The method according to claim 2, wherein the fibrous material is cotton. 11. The method according to claim 2, wherein the cell proliferation accelerator has angiogenesis and/or granulation promoting actions. 12. The method according to claim 3, wherein the cell proliferation accelerator has angiogenesis and/or granulation promoting actions. 13. The method according to claim 10, wherein the cell proliferation accelerator has angiogenesis and/or granulation promoting actions. 14. The method according to claim 2, wherein the cell proliferation accelerator is trafermin. 15. The method according to claim 3, wherein the cell proliferation accelerator is trafermin. 16. The method according to claim 4, wherein the cell proliferation accelerator is trafermin. 17. The method according to claim 10, wherein the cell proliferation accelerator is trafermin. 18. The method according to claim 11, wherein the cell proliferation accelerator is trafermin. 19. The method according to claim 12, wherein the cell proliferation accelerator is trafermin. 20. The method according to claim 13, wherein the cell proliferation accelerator is trafermin. 21. The method according to claim 2, wherein the antibiotic is fradiomycin sulfate. 22. The method according to claim 3, wherein the antibiotic is fradiomycin sulfate. | 1,600 |
789 | 14,891,763 | 1,629 | The invention relates to the use of additives in the preparation of crop protection composition spray mixtures, in particular as additives for tank mixtures of specific pesticides according to formula (I), pesticide mixtures and crop protection compositions comprising these pesticides. | 1. A pesticidal composition comprising a tetramic acid compound of the formula (I)
wherein
X, Y and Z independently of each other are C1-4alkyl, C3-6cycloalkyl, C1-4haloalkyl, C1-4alkoxy, halogen, phenyl or phenyl substituted by C1-4alkyl, C1-4haloalkyl, halogen or cyano;
m and n, independently of each other, are 0, 1, 2 or 3 and m+n is 0, 1, 2 or 3;
G is hydrogen, a metal, ammonium, sulfonium or a latentiating group selected from the groups C1-C8alkyl, C2-C8haloalkyl, phenylC1-C8alkyl (wherein the phenyl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano or by nitro), heteroarylC1-C8alkyl (wherein the heteroaryl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3 alkylsulfonyl, halogen, cyano or by nitro), C3-C8alkenyl, C3-C8haloalkenyl, C3-C8alkynyl, C(Xa)—Ra, C(X)—Xc—Rb, C(Xd)—N(Rc)—Rd, —SO2—Re, —P(Xe)(Rf)—Rg or CH2—Xf—Rh wherein Xa, Xb, Xc, Xd, Xe and Xf are independently of each other oxygen or sulfur;
Ra is H, C1-C18alkyl, C2-C18alkenyl, C2-C18alkynyl, C1-C10haloalkyl, C1-C10cyanoalkyl, C1-C10nitroalkyl, C1-C10aminoalkyl, C1-C5alkylaminoC1-C5alkyl, C2-C8dialkylaminoC1-C5alkyl, C3-C7cycloalkylC1-C5alkyl, C1-C5alkoxyC1-C5alkyl, C3-C5alkenyloxyC1-C5alkyl, C3-C5alkynylC1-C5oxyalkyl, C1-C5alkylthioC1-C5alkyl, C1-C5alkylsulfinylC1-C5alkyl, C1-C5alkylsulfonylC1-C5alkyl, C2-C8alkylideneaminoxyC1-C5alkyl, C1-C5alkylcarbonylC1-C5alkyl, C1-C5alkoxycarbonylC1-C5alkyl, aminocarbonylC1-C5alkyl, C1-C5alkylaminocarbonylC1-C5alkyl, C2-C8dialkylaminocarbonylC1-C5alkyl, C1-C5alkylcarbonylaminoC1-C5alkyl, N—C1-C5alkylcarbonyl-N—C1-C5alkylaminoC1-C5alkyl, C3-C8trialkylsilylC1-C5alkyl, phenylC1-C5alkyl (wherein the phenyl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), heteroarylC1-C5alkyl, (wherein the heteroaryl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), C2-C5haloalkenyl, C3-C8cycloalkyl, phenyl or phenyl substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, heteroaryl or heteroaryl substituted by C1-C3 alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro,
Rb is C1-C18alkyl, C3-C18alkenyl, C3-C18alkynyl, C2-C10haloalkyl, C1-C10cyanoalkyl, C1-C10nitroalkyl, C2-C10aminoalkyl, C1-C5alkylaminoC1-C5alkyl, C2-C8dialkylaminoC1-C5alkyl, C3-C7cycloalkylC1-C5alkyl, C1-C5alkoxyC1-C5alkyl, C3-C5alkenyloxyC1-C5alkyl, C3-C5alkynyloxyC1-C5alkyl, C1-C5alkylthioC1-C5alkyl, C1-C5alkylsulfinylC1-C5alkyl, C1-C5alkylsulfonylC1-C5alkyl, C2-C8alkylideneaminoxyC1-C5alkyl, C1-C5alkylcarbonylC1-C5alkyl, C1-C5alkoxycarbonylC1-C5alkyl, aminocarbonylC1-C5alkyl, C1-C5alkylaminocarbonylC1-C5alkyl, C2-C8dialkylaminocarbonylC1-C5alkyl, C1-C5alkylcarbonylaminoC1-C5alkyl, N—C1-C5alkylcarbonyl-N—C1-C5alkylaminoC1-C5alkyl, C3-C8trialkylsilylC1-C5alkyl, phenylC1-C5alkyl (wherein the phenyl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), heteroarylC1-C5alkyl, (wherein the heteroaryl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkyl-thio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), C3-C5haloalkenyl, C3-C8cycloalkyl, phenyl or phenyl substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3halo-alkoxy, halogen, cyano or nitro, heteroaryl or heteroaryl substituted by C1-C3 alkyl, C1-3 haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro,
Rc and Rd are each independently of each other hydrogen, C1-C10alkyl, C3-C10alkenyl, C3-C10alkynyl, C2-C10haloalkyl, C1-C10cyanoalkyl, C1-C10nitroalkyl, C1-C10aminoalkyl, C1-C5alkylaminoC1-C5alkyl, C2-C8dialkylaminoC1-C5alkyl, C3-C7cycloalkylC1-C5alkyl, C1-C5alkoxyC1-C5alkyl, C3-C5alkenyloxyC1-C5alkyl, C3-C5alkynyloxyC1-C5alkyl, C1-C5alkylthioC1-C5alkyl, C1-C5alkylsulfinylC1-C5alkyl, C1-C5alkylsulfonylC1-C5alkyl, C2-C8alkylideneaminoxyC1-C5alkyl, C1-C5alkylcarbonylC1-C5alkyl, C1-C5alkoxycarbonylC1-C5alkyl, aminocarbonylC1-C5alkyl, C1-C5alkylaminocarbonylC1-C5alkyl, C2-C8dialkylaminocarbonylC1-C5alkyl, C1-C5alkylcarbonylaminoC1-C5alkyl, N—C1-C5alkylcarbonyl-N—C2-C5alkylaminoalkyl, C3-C8trialkylsilylC1-C5alkyl, phenylC1-C5alkyl (wherein the phenyl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), heteroarylC1-C5alkyl, (wherein the heteroaryl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), C2-C5haloalkenyl, C3-C8cycloalkyl, phenyl or phenyl substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, heteroaryl or heteroaryl substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, heteroarylamino or heteroarylamino substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, diheteroarylamino or diheteroarylamino substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, phenylamino or phenylamino substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro, diphenylamino or diphenylamino substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro or C3-C7cycloalkylamino, di-C3-C7cycloalkylamino or C3-C7cycloalkoxy or Rc and Rd may join together to form a 3-7 membered ring, optionally containing one heteroatom selected from O or S,
Re is C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C1-C10haloalkyl, C1-C10cyanoalkyl, C1-C10nitroalkyl, C1-C10aminoalkyl, C1-C5alkylaminoC1-C5alkyl, C2-C8dialkylaminoC1-C5alkyl, C3-C7cycloalkylC1-C5alkyl, C1-C5alkoxyC1-C5alkyl, C3-C5alkenyloxyC1-C5alkyl, C3-C5alkynyloxyC1-C5alkyl, C1-C5alkylthioC1-C5alkyl, C1-C5alkylsulfinylC1-C5alkyl, C1-C5alkylsulfonylC1-C5alkyl, C2-C8alkylideneaminoxyC1-C5alkyl, C1-C5alkylcarbonylC1-C5alkyl, C1-C5alkoxycarbonylC1-C5alkyl, aminocarbonylC1-C5alkyl, C1-C5alkylaminocarbonylC1-C5alkyl, C2-C8dialkylaminocarbonylC1-C5alkyl, C1-C5alkylcarbonylaminoC1-C5alkyl, N—C1-C5alkylcarbonyl-N—C1-C5alkylaminoC1-C5alkyl, C3-C8trialkylsilylC1-C5alkyl, phenylC1-C5alkyl (wherein the phenyl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), heteroarylC1-C5alkyl (wherein the heteroaryl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), C2-C5haloalkenyl, C3-C8cycloalkyl, phenyl or phenyl substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, heteroaryl or heteroaryl substituted by C1-C3 alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro, heteroarylamino or heteroarylamino substituted by C1-C3 alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro, diheteroarylamino or diheteroarylamino substituted by C1-C3 alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, phenylamino or phenylamino substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, diphenylamino, or diphenylamino substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, or C3-C7cycloalkylamino, diC3-C7cycloalkylamino or C3-C7cycloalkoxy, C1-C10alkoxy, C1-C10haloalkoxy, C1-C5alkylamino or C2-C8dialkylamino
Rf and Rg are are each independently of each other C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C1-C10alkoxy, C1-C10haloalkyl, C1-C10cyanoalkyl, C1-C10nitroalkyl, C1-C10aminoalkyl, C1-C5alkylaminoC1-C5alkyl, C2-C8dialkylaminoC1-C5alkyl, C3-C7cycloalkylC1-C5alkyl, C1-C5alkoxyC1-C5alkyl, C3-C5alkenyloxyC1-C5alkyl, C3-C5alkynyloxyC1-C5alkyl, C1-C5alkylthioC1-C5alkyl, C1-C5alkylsulfinylC1-C5alkyl, C1-C5alkylsulfonylC1-C5alkyl, C2-C8alkylideneaminoxyC1-C5alkyl, C1-C5alkylcarbonylC1-C5alkyl, C1-C5alkoxycarbonylC1-C5alkyl, aminocarbonylC1-C5alkyl, C1-C5alkylaminocarbonylC1-C5alkyl, C2-C8dialkylaminocarbonylC1-C5alkyl, C1-C5alkylcarbonylaminoC1-C5alkyl, N—C1-C5alkylcarbonyl-N—C2-C5alkylaminoalkyl, C3-C8trialkylsilylC1-C5alkyl, phenylC1-C5alkyl (wherein the phenyl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), heteroarylC1-C5alkyl (wherein the heteroaryl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), C2-C5haloalkenyl, C3-C8cycloalkyl, phenyl or phenyl substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, heteroaryl or heteroaryl substituted by C1-C3 alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro, heteroarylamino or heteroarylamino substituted by C1-C3 alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro, diheteroarylamino or diheteroarylamino substituted by C1-C3 alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, phenylamino or phenylamino substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, diphenylamino, or diphenylamino substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, or C3-C7cycloalkylamino, diC3-C7cycloalkylamino or C3-C7cycloalkoxy, C1-C10haloalkoxy, C1-C5alkylamino or C2-C8dialkylamino, benzyloxy or phenoxy, wherein the benzyl and phenyl groups may in turn be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, and
Rh is C1-C10alkyl, C3-C10alkenyl, C3-C10alkynyl, C1-C10haloalkyl, C1-C10cyanoalkyl, C1-C10nitroalkyl, C2-C10aminoalkyl, C1-C5alkylaminoC1-C5alkyl, C2-C8dialkylaminoC1-C5alkyl, C3-C7cycloalkylC1-C5alkyl, C1-C5alkoxyC1-C5alkyl, C3-C5alkenyloxyC1-C5alkyl, C3-C5alkynyloxyC1-C5alkyl, C1-C5alkylthioC1-C5alkyl, C1-C5alkylsulfinylC1-C5alkyl, C1-C5alkylsulfonylC1-C5alkyl, C2-C8alkylideneaminoxyC1-C5alkyl, C1-C5alkylcarbonylC1-C5alkyl, C1-C5alkoxycarbonylC1-C5alkyl, aminocarbonylC1-C5alkyl, C1-C5alkylaminocarbonylC1-C5alkyl, C2-C8dialkylaminocarbonylC1-C5alkyl, C1-C5alkylcarbonylaminoC1-C5alkyl, N—C1-C5alkylcarbonyl-N—C1-C5alkylaminoC1-C5alkyl, C3-C8trialkylsilylC1-C5alkyl, phenylC1-C5alkyl (wherein wherein the phenyl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3 alkylsulfonyl, halogen, cyano or by nitro), heteroarylC1-C5alkyl (wherein the heteroaryl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3 alkylsulfonyl, halogen, cyano or by nitro), phenoxyC1-C5alkyl (wherein wherein the phenyl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3 alkylsulfonyl, halogen, cyano or by nitro), heteroaryloxyC1-C5alkyl (wherein the heteroaryl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3akylsulfinyl, C3 alkylsulfonyl, halogen, cyano or by nitro), C3-C5haloalkenyl, C3-C8cycloalkyl, phenyl or phenyl substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen or by nitro, or heteroaryl, or heteroaryl substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro;
R is hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6cyanoalkyl, benzyl, C1-4alkoxy(C1-4)alkyl, C1-4alkoxy(C1-4)alkoxy(C1-4)alkyl or a group selected from G; and
A is hydrogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6cycloalkyl(C1-4)alkyl, or C3-6cycloalkyl(C1-4)alkyl where in the cycloalkyl moiety a methylene group is replaced by O, S or NR0, where R0 is C1-6alkyl or C1-6alkoxy, or A is C2-6alkenyl, C2-6haloalkenyl, C3-6alkynyl, C1-6cyanoalkyl, benzyl, C1-4alkoxy(C1-4)alkyl, C1-4alkoxy(C1-4)alkoxy(C1-4)alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, C3-6cycloalkylcarbonyl, N-di(C1-6alkyl)carbamoyl, benzoyl, C1-6alkylsulfonyl, phenylsulfonyl, C1-4alkylthio(C1-4)alkyl, C1-4alkylsulfinyl(C1-4)alkyl or C1-4alkylsulfonyl(C1-4)alkyl;
Or A is O-A1 where A1 is selected from one of A, as defined above, or furanyl-(C1-4)alkyl, tetrahydro-thiofuranyl, tetrahydro-thiopyranyl or 1-(C1-4)alkoxy-piperidin-4-yl;
or an agrochemically acceptable salt or an N-oxide of formula (I);
and a polymeric adjuvant selected from the group consisting of terpene alcohol polymeric derivatives, pinolene polymeric derivatives, polymers comprising cyclohexene derivatives and mixtures thereof. 2. The composition according to claim 1 wherein the compound of formula (I) is selected from compounds wherein R is methyl, X is methyl or methoxy, Y and Z, independently of each other, are methyl, ethyl, methoxy, chloro or bromo, G is hydrogen, methoxycarbonyl or propenyloxycarbonyl or —(C═O)OCH2CH3, and A is hydrogen, methyl, ethyl, methoxy, ethoxy, methoxymethyl, tetrahydrofuran-2-yl or tetrahydrofuran-3-yl. 3. The composition according to claim 1 wherein the compound of formula (I) is selected from compounds wherein m is 1 and n is 1 and Y is in the ortho position and Z is in the para position. 4. The composition according to claim 1 wherein the compound of formula (I) is selected from one or more of
wherein G is
or H. 5. The composition according to claim 1 wherein the compound according to formula (I) is formulated as a suspension concentrate, emulsion concentrate, wettable powder, water dispersible granule, soluble liquid, emulsion in water, oil dispersion, soluble granule or soluble powder. 6. The composition according to claim 1 wherein the polymeric adjuvant is selected from pinolene polymeric derivatives. 7. A combination pack comprising a combination of a compound according to formula (I) as defined in claim 1 and a polymeric adjuvant selected from the group consisting of terpene alcohol polymeric derivatives, pinolene polymeric derivatives, polymers comprising cyclohexene derivatives and mixtures thereof.
wherein a first container contains the compound according to formula (I) and a second container contains the said adjuvant. 8. The combination pack according to claim 7 wherein the adjuvant is selected from pinolene polymeric derivatives. 9. (canceled) 10. (canceled) 11. (canceled) 12. A method of increasing the efficacy and reducing the phytoxicity of pesticidally active tetramic acid compounds according to formula (I) as defined in claim 1 in comparison to when said tetramic acid compound is used alone, by adding an adjuvant selected from the group consisting of terpene alcohol polymeric derivatives, pinolene polymeric derivatives, polymers comprising cyclohexene derivatives and mixtures thereof
to the tetramic acid compounds prior to applying the pesticidally active tetramic acid compounds to crops. 13. The method according to claim 12 wherein the polymeric adjuvant is selected from pinolene polymeric derivatives. 14. A method of combating and controlling pests which comprises applying to a pest, to a locus of a pest, or to a plant susceptible to attack by a pest a composition according to claim 1. 15. A method of combating and controlling pests which comprises the following steps:
a) Obtaining a polymeric adjuvant selected from the group consisting of terpene alcohol polymeric derivatives, pinolene polymeric derivatives, polymers comprising cyclohexene derivatives and mixtures thereof
and obtaining a formulated tetramic acid compound according to formula (I) as defined in claim 5;
b) Mixing the formulated tetramic acid compound according to formula (I) with the polymeric adjuvant to prepare a pesticidal composition for application on a crop c) Applying the resulting composition to a pest, to a locus of a pest, or to a plant susceptible to attack by a pest. 16. The method according to claim 15 wherein the polymeric adjuvant is selected from pinolene polymeric derivatives. | The invention relates to the use of additives in the preparation of crop protection composition spray mixtures, in particular as additives for tank mixtures of specific pesticides according to formula (I), pesticide mixtures and crop protection compositions comprising these pesticides.1. A pesticidal composition comprising a tetramic acid compound of the formula (I)
wherein
X, Y and Z independently of each other are C1-4alkyl, C3-6cycloalkyl, C1-4haloalkyl, C1-4alkoxy, halogen, phenyl or phenyl substituted by C1-4alkyl, C1-4haloalkyl, halogen or cyano;
m and n, independently of each other, are 0, 1, 2 or 3 and m+n is 0, 1, 2 or 3;
G is hydrogen, a metal, ammonium, sulfonium or a latentiating group selected from the groups C1-C8alkyl, C2-C8haloalkyl, phenylC1-C8alkyl (wherein the phenyl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano or by nitro), heteroarylC1-C8alkyl (wherein the heteroaryl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3 alkylsulfonyl, halogen, cyano or by nitro), C3-C8alkenyl, C3-C8haloalkenyl, C3-C8alkynyl, C(Xa)—Ra, C(X)—Xc—Rb, C(Xd)—N(Rc)—Rd, —SO2—Re, —P(Xe)(Rf)—Rg or CH2—Xf—Rh wherein Xa, Xb, Xc, Xd, Xe and Xf are independently of each other oxygen or sulfur;
Ra is H, C1-C18alkyl, C2-C18alkenyl, C2-C18alkynyl, C1-C10haloalkyl, C1-C10cyanoalkyl, C1-C10nitroalkyl, C1-C10aminoalkyl, C1-C5alkylaminoC1-C5alkyl, C2-C8dialkylaminoC1-C5alkyl, C3-C7cycloalkylC1-C5alkyl, C1-C5alkoxyC1-C5alkyl, C3-C5alkenyloxyC1-C5alkyl, C3-C5alkynylC1-C5oxyalkyl, C1-C5alkylthioC1-C5alkyl, C1-C5alkylsulfinylC1-C5alkyl, C1-C5alkylsulfonylC1-C5alkyl, C2-C8alkylideneaminoxyC1-C5alkyl, C1-C5alkylcarbonylC1-C5alkyl, C1-C5alkoxycarbonylC1-C5alkyl, aminocarbonylC1-C5alkyl, C1-C5alkylaminocarbonylC1-C5alkyl, C2-C8dialkylaminocarbonylC1-C5alkyl, C1-C5alkylcarbonylaminoC1-C5alkyl, N—C1-C5alkylcarbonyl-N—C1-C5alkylaminoC1-C5alkyl, C3-C8trialkylsilylC1-C5alkyl, phenylC1-C5alkyl (wherein the phenyl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), heteroarylC1-C5alkyl, (wherein the heteroaryl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), C2-C5haloalkenyl, C3-C8cycloalkyl, phenyl or phenyl substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, heteroaryl or heteroaryl substituted by C1-C3 alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro,
Rb is C1-C18alkyl, C3-C18alkenyl, C3-C18alkynyl, C2-C10haloalkyl, C1-C10cyanoalkyl, C1-C10nitroalkyl, C2-C10aminoalkyl, C1-C5alkylaminoC1-C5alkyl, C2-C8dialkylaminoC1-C5alkyl, C3-C7cycloalkylC1-C5alkyl, C1-C5alkoxyC1-C5alkyl, C3-C5alkenyloxyC1-C5alkyl, C3-C5alkynyloxyC1-C5alkyl, C1-C5alkylthioC1-C5alkyl, C1-C5alkylsulfinylC1-C5alkyl, C1-C5alkylsulfonylC1-C5alkyl, C2-C8alkylideneaminoxyC1-C5alkyl, C1-C5alkylcarbonylC1-C5alkyl, C1-C5alkoxycarbonylC1-C5alkyl, aminocarbonylC1-C5alkyl, C1-C5alkylaminocarbonylC1-C5alkyl, C2-C8dialkylaminocarbonylC1-C5alkyl, C1-C5alkylcarbonylaminoC1-C5alkyl, N—C1-C5alkylcarbonyl-N—C1-C5alkylaminoC1-C5alkyl, C3-C8trialkylsilylC1-C5alkyl, phenylC1-C5alkyl (wherein the phenyl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), heteroarylC1-C5alkyl, (wherein the heteroaryl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkyl-thio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), C3-C5haloalkenyl, C3-C8cycloalkyl, phenyl or phenyl substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3halo-alkoxy, halogen, cyano or nitro, heteroaryl or heteroaryl substituted by C1-C3 alkyl, C1-3 haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro,
Rc and Rd are each independently of each other hydrogen, C1-C10alkyl, C3-C10alkenyl, C3-C10alkynyl, C2-C10haloalkyl, C1-C10cyanoalkyl, C1-C10nitroalkyl, C1-C10aminoalkyl, C1-C5alkylaminoC1-C5alkyl, C2-C8dialkylaminoC1-C5alkyl, C3-C7cycloalkylC1-C5alkyl, C1-C5alkoxyC1-C5alkyl, C3-C5alkenyloxyC1-C5alkyl, C3-C5alkynyloxyC1-C5alkyl, C1-C5alkylthioC1-C5alkyl, C1-C5alkylsulfinylC1-C5alkyl, C1-C5alkylsulfonylC1-C5alkyl, C2-C8alkylideneaminoxyC1-C5alkyl, C1-C5alkylcarbonylC1-C5alkyl, C1-C5alkoxycarbonylC1-C5alkyl, aminocarbonylC1-C5alkyl, C1-C5alkylaminocarbonylC1-C5alkyl, C2-C8dialkylaminocarbonylC1-C5alkyl, C1-C5alkylcarbonylaminoC1-C5alkyl, N—C1-C5alkylcarbonyl-N—C2-C5alkylaminoalkyl, C3-C8trialkylsilylC1-C5alkyl, phenylC1-C5alkyl (wherein the phenyl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), heteroarylC1-C5alkyl, (wherein the heteroaryl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), C2-C5haloalkenyl, C3-C8cycloalkyl, phenyl or phenyl substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, heteroaryl or heteroaryl substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, heteroarylamino or heteroarylamino substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, diheteroarylamino or diheteroarylamino substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, phenylamino or phenylamino substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro, diphenylamino or diphenylamino substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro or C3-C7cycloalkylamino, di-C3-C7cycloalkylamino or C3-C7cycloalkoxy or Rc and Rd may join together to form a 3-7 membered ring, optionally containing one heteroatom selected from O or S,
Re is C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C1-C10haloalkyl, C1-C10cyanoalkyl, C1-C10nitroalkyl, C1-C10aminoalkyl, C1-C5alkylaminoC1-C5alkyl, C2-C8dialkylaminoC1-C5alkyl, C3-C7cycloalkylC1-C5alkyl, C1-C5alkoxyC1-C5alkyl, C3-C5alkenyloxyC1-C5alkyl, C3-C5alkynyloxyC1-C5alkyl, C1-C5alkylthioC1-C5alkyl, C1-C5alkylsulfinylC1-C5alkyl, C1-C5alkylsulfonylC1-C5alkyl, C2-C8alkylideneaminoxyC1-C5alkyl, C1-C5alkylcarbonylC1-C5alkyl, C1-C5alkoxycarbonylC1-C5alkyl, aminocarbonylC1-C5alkyl, C1-C5alkylaminocarbonylC1-C5alkyl, C2-C8dialkylaminocarbonylC1-C5alkyl, C1-C5alkylcarbonylaminoC1-C5alkyl, N—C1-C5alkylcarbonyl-N—C1-C5alkylaminoC1-C5alkyl, C3-C8trialkylsilylC1-C5alkyl, phenylC1-C5alkyl (wherein the phenyl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), heteroarylC1-C5alkyl (wherein the heteroaryl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), C2-C5haloalkenyl, C3-C8cycloalkyl, phenyl or phenyl substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, heteroaryl or heteroaryl substituted by C1-C3 alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro, heteroarylamino or heteroarylamino substituted by C1-C3 alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro, diheteroarylamino or diheteroarylamino substituted by C1-C3 alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, phenylamino or phenylamino substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, diphenylamino, or diphenylamino substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, or C3-C7cycloalkylamino, diC3-C7cycloalkylamino or C3-C7cycloalkoxy, C1-C10alkoxy, C1-C10haloalkoxy, C1-C5alkylamino or C2-C8dialkylamino
Rf and Rg are are each independently of each other C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C1-C10alkoxy, C1-C10haloalkyl, C1-C10cyanoalkyl, C1-C10nitroalkyl, C1-C10aminoalkyl, C1-C5alkylaminoC1-C5alkyl, C2-C8dialkylaminoC1-C5alkyl, C3-C7cycloalkylC1-C5alkyl, C1-C5alkoxyC1-C5alkyl, C3-C5alkenyloxyC1-C5alkyl, C3-C5alkynyloxyC1-C5alkyl, C1-C5alkylthioC1-C5alkyl, C1-C5alkylsulfinylC1-C5alkyl, C1-C5alkylsulfonylC1-C5alkyl, C2-C8alkylideneaminoxyC1-C5alkyl, C1-C5alkylcarbonylC1-C5alkyl, C1-C5alkoxycarbonylC1-C5alkyl, aminocarbonylC1-C5alkyl, C1-C5alkylaminocarbonylC1-C5alkyl, C2-C8dialkylaminocarbonylC1-C5alkyl, C1-C5alkylcarbonylaminoC1-C5alkyl, N—C1-C5alkylcarbonyl-N—C2-C5alkylaminoalkyl, C3-C8trialkylsilylC1-C5alkyl, phenylC1-C5alkyl (wherein the phenyl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), heteroarylC1-C5alkyl (wherein the heteroaryl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3alkylsulfonyl, halogen, cyano, or by nitro), C2-C5haloalkenyl, C3-C8cycloalkyl, phenyl or phenyl substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, heteroaryl or heteroaryl substituted by C1-C3 alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro, heteroarylamino or heteroarylamino substituted by C1-C3 alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro, diheteroarylamino or diheteroarylamino substituted by C1-C3 alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, phenylamino or phenylamino substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, diphenylamino, or diphenylamino substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, or C3-C7cycloalkylamino, diC3-C7cycloalkylamino or C3-C7cycloalkoxy, C1-C10haloalkoxy, C1-C5alkylamino or C2-C8dialkylamino, benzyloxy or phenoxy, wherein the benzyl and phenyl groups may in turn be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or nitro, and
Rh is C1-C10alkyl, C3-C10alkenyl, C3-C10alkynyl, C1-C10haloalkyl, C1-C10cyanoalkyl, C1-C10nitroalkyl, C2-C10aminoalkyl, C1-C5alkylaminoC1-C5alkyl, C2-C8dialkylaminoC1-C5alkyl, C3-C7cycloalkylC1-C5alkyl, C1-C5alkoxyC1-C5alkyl, C3-C5alkenyloxyC1-C5alkyl, C3-C5alkynyloxyC1-C5alkyl, C1-C5alkylthioC1-C5alkyl, C1-C5alkylsulfinylC1-C5alkyl, C1-C5alkylsulfonylC1-C5alkyl, C2-C8alkylideneaminoxyC1-C5alkyl, C1-C5alkylcarbonylC1-C5alkyl, C1-C5alkoxycarbonylC1-C5alkyl, aminocarbonylC1-C5alkyl, C1-C5alkylaminocarbonylC1-C5alkyl, C2-C8dialkylaminocarbonylC1-C5alkyl, C1-C5alkylcarbonylaminoC1-C5alkyl, N—C1-C5alkylcarbonyl-N—C1-C5alkylaminoC1-C5alkyl, C3-C8trialkylsilylC1-C5alkyl, phenylC1-C5alkyl (wherein wherein the phenyl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3 alkylsulfonyl, halogen, cyano or by nitro), heteroarylC1-C5alkyl (wherein the heteroaryl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3 alkylsulfonyl, halogen, cyano or by nitro), phenoxyC1-C5alkyl (wherein wherein the phenyl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3alkylsulfinyl, C1-C3 alkylsulfonyl, halogen, cyano or by nitro), heteroaryloxyC1-C5alkyl (wherein the heteroaryl may optionally be substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkylthio, C1-C3akylsulfinyl, C3 alkylsulfonyl, halogen, cyano or by nitro), C3-C5haloalkenyl, C3-C8cycloalkyl, phenyl or phenyl substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen or by nitro, or heteroaryl, or heteroaryl substituted by C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, halogen, cyano or by nitro;
R is hydrogen, C1-6alkyl, C1-6haloalkyl, C1-6cyanoalkyl, benzyl, C1-4alkoxy(C1-4)alkyl, C1-4alkoxy(C1-4)alkoxy(C1-4)alkyl or a group selected from G; and
A is hydrogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6cycloalkyl(C1-4)alkyl, or C3-6cycloalkyl(C1-4)alkyl where in the cycloalkyl moiety a methylene group is replaced by O, S or NR0, where R0 is C1-6alkyl or C1-6alkoxy, or A is C2-6alkenyl, C2-6haloalkenyl, C3-6alkynyl, C1-6cyanoalkyl, benzyl, C1-4alkoxy(C1-4)alkyl, C1-4alkoxy(C1-4)alkoxy(C1-4)alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, C3-6cycloalkylcarbonyl, N-di(C1-6alkyl)carbamoyl, benzoyl, C1-6alkylsulfonyl, phenylsulfonyl, C1-4alkylthio(C1-4)alkyl, C1-4alkylsulfinyl(C1-4)alkyl or C1-4alkylsulfonyl(C1-4)alkyl;
Or A is O-A1 where A1 is selected from one of A, as defined above, or furanyl-(C1-4)alkyl, tetrahydro-thiofuranyl, tetrahydro-thiopyranyl or 1-(C1-4)alkoxy-piperidin-4-yl;
or an agrochemically acceptable salt or an N-oxide of formula (I);
and a polymeric adjuvant selected from the group consisting of terpene alcohol polymeric derivatives, pinolene polymeric derivatives, polymers comprising cyclohexene derivatives and mixtures thereof. 2. The composition according to claim 1 wherein the compound of formula (I) is selected from compounds wherein R is methyl, X is methyl or methoxy, Y and Z, independently of each other, are methyl, ethyl, methoxy, chloro or bromo, G is hydrogen, methoxycarbonyl or propenyloxycarbonyl or —(C═O)OCH2CH3, and A is hydrogen, methyl, ethyl, methoxy, ethoxy, methoxymethyl, tetrahydrofuran-2-yl or tetrahydrofuran-3-yl. 3. The composition according to claim 1 wherein the compound of formula (I) is selected from compounds wherein m is 1 and n is 1 and Y is in the ortho position and Z is in the para position. 4. The composition according to claim 1 wherein the compound of formula (I) is selected from one or more of
wherein G is
or H. 5. The composition according to claim 1 wherein the compound according to formula (I) is formulated as a suspension concentrate, emulsion concentrate, wettable powder, water dispersible granule, soluble liquid, emulsion in water, oil dispersion, soluble granule or soluble powder. 6. The composition according to claim 1 wherein the polymeric adjuvant is selected from pinolene polymeric derivatives. 7. A combination pack comprising a combination of a compound according to formula (I) as defined in claim 1 and a polymeric adjuvant selected from the group consisting of terpene alcohol polymeric derivatives, pinolene polymeric derivatives, polymers comprising cyclohexene derivatives and mixtures thereof.
wherein a first container contains the compound according to formula (I) and a second container contains the said adjuvant. 8. The combination pack according to claim 7 wherein the adjuvant is selected from pinolene polymeric derivatives. 9. (canceled) 10. (canceled) 11. (canceled) 12. A method of increasing the efficacy and reducing the phytoxicity of pesticidally active tetramic acid compounds according to formula (I) as defined in claim 1 in comparison to when said tetramic acid compound is used alone, by adding an adjuvant selected from the group consisting of terpene alcohol polymeric derivatives, pinolene polymeric derivatives, polymers comprising cyclohexene derivatives and mixtures thereof
to the tetramic acid compounds prior to applying the pesticidally active tetramic acid compounds to crops. 13. The method according to claim 12 wherein the polymeric adjuvant is selected from pinolene polymeric derivatives. 14. A method of combating and controlling pests which comprises applying to a pest, to a locus of a pest, or to a plant susceptible to attack by a pest a composition according to claim 1. 15. A method of combating and controlling pests which comprises the following steps:
a) Obtaining a polymeric adjuvant selected from the group consisting of terpene alcohol polymeric derivatives, pinolene polymeric derivatives, polymers comprising cyclohexene derivatives and mixtures thereof
and obtaining a formulated tetramic acid compound according to formula (I) as defined in claim 5;
b) Mixing the formulated tetramic acid compound according to formula (I) with the polymeric adjuvant to prepare a pesticidal composition for application on a crop c) Applying the resulting composition to a pest, to a locus of a pest, or to a plant susceptible to attack by a pest. 16. The method according to claim 15 wherein the polymeric adjuvant is selected from pinolene polymeric derivatives. | 1,600 |
790 | 15,098,727 | 1,617 | A silicone composition, especially advantageous for incorporation in a personal care product, includes a silicone resin (a) and a silicone gum (b), the mixture of resin (a) and gum (b) having a softening point of 50° C. or greater and an elastic modulus at ambient temperature of 10 6 Pa or less. | 1-20. (canceled) 21. A composition which comprises:
a) a MT resin having a molecular weight higher than 10,000 and containing one or more M units of the formula R1 3SiO1/2, and T units of the formula R3SiO3/2 wherein the ratio of M to T units ranges from 1:1 to 1:7, and the softening point of the MT resin ranges from 50° C. to 110° C. wherein each R1 and R3 is independently a hydroxyl radical or monovalent hydrocarbon radical; and, b) silicone gum,
wherein the mixture of MT resin (a) and silicone gum (b) is non-crosslinked and has a softening point greater than 50° C. and an elastic modulus at ambient temperature of less than 106 Pa. 22. The composition of claim 21 wherein silicone gum (b) possesses a viscosity of from 300 to 200,000,000 centipoise at 25° C. 23. The composition of claim 21 wherein silicone gum (b) contains one or more M′ units of the formula R4 3SiO1/2 and one or more additional units selected from amongst D′ units of the formula R5 2SiO2/2, T′ units of the formula R6SiO3/2 and Q′ units of the formula SiO4/2, and mixtures thereof, wherein each R4, R5 and R6 is independently a hydroxyl radical or a monovalent hydrocarbon radical. 24. The composition of claim 21 wherein silicone gum (b) is selected from the group consisting of dimethiconol gum, dimethicone gum, polydimethysiloxane gum, amodimethicone, phenyl-modified silicone, silicone block copolymers containing amine groups or quat groups and alkyl-modified aminosilicone. 25. The composition of claim 21 wherein the weight ratio of silicone resin (a) to silicone gum (b) ranges from 0.4 to 6. 26. The composition of claim 21 wherein the softening point of the MT resin ranges from 60° C. to 110° C. 27. The composition of claim 21 wherein the softening point of the MT resin ranges from 70° C. to 110° C. 28. The composition of claim 21 which is cationic surfactant-free. 29. The composition of claim 21 further comprising a solvent for the mixture of silicone resin (a) and silicone gum (b). 30. The composition of claim 29 wherein the solvent is a volatile organic solvent or organosilicon-containing volatile solvent. 31. A personal care product which comprises:
a) a MT resin having a molecular weight higher than 10,000 and containing one or more M units of the formula R1 3SiO1/2, and T units of the formula R3SiO3/2 wherein the ratio of M to T units ranges from 1:1 to 1:7, and the softening point of the MT resin ranges from 50° C. to 110° C. wherein each R1 and R3 is independently a hydroxyl radical or monovalent hydrocarbon radical; and, b) silicone gum,
wherein the mixture of MT resin (a) and silicone gum (b) is non-crosslinked and has a softening point greater than 50° C. and an elastic modulus at ambient temperature of less than 106 Pa. 32. The personal care product of claim 31 wherein silicone gum (b) possesses a viscosity of from 300 to 200,000,000 centipoise at 25° C. 33. The personal care product of claim 31 wherein silicone gum (b) contains one or more M′ units of the formula R4 3SiO1/2 and one or more additional units selected from amongst D′ units of the formula R5 2SiO2/2, T′ units of the formula R6SiO3/2 and Q′ units of the formula SiO4/2, and mixtures thereof, wherein each R4, R5 and R6 is independently a hydroxyl radical or a monovalent hydrocarbon radical. 34. The personal care product of claim 31 wherein silicone gum (b) is selected from the group consisting of dimethiconol gum, dimethicone gum, polydimethysiloxane gum, amodimethicone, phenyl-modified silicone, silicone block copolymers containing amine groups or quat groups and alkyl-modified aminosilicone. 35. The personal care product of claim 31 wherein the weight ratio of silicone resin (a) to silicone gum (b) ranges from 0.4 to 6. 36. The personal care product of claim 31 wherein the softening point of the MT resin ranges from 60° C. to 110° C. 37. The personal care product of claim 31 wherein the softening point of the MT resin ranges from 70° C. to 110° C. 38. The personal care product of claim 31 wherein the personal care product is cationic surfactant-free. 39. The personal care product of claim 31 wherein the personal care product is a hair care product or a lip gloss. 40. The personal care product of claim 31 further comprising a solvent for the mixture of silicone resin (a) and silicone gum (b). 41. The personal care product of claim 40 wherein the solvent is a volatile organic solvent or organosilicon-containing volatile solvent. | A silicone composition, especially advantageous for incorporation in a personal care product, includes a silicone resin (a) and a silicone gum (b), the mixture of resin (a) and gum (b) having a softening point of 50° C. or greater and an elastic modulus at ambient temperature of 10 6 Pa or less.1-20. (canceled) 21. A composition which comprises:
a) a MT resin having a molecular weight higher than 10,000 and containing one or more M units of the formula R1 3SiO1/2, and T units of the formula R3SiO3/2 wherein the ratio of M to T units ranges from 1:1 to 1:7, and the softening point of the MT resin ranges from 50° C. to 110° C. wherein each R1 and R3 is independently a hydroxyl radical or monovalent hydrocarbon radical; and, b) silicone gum,
wherein the mixture of MT resin (a) and silicone gum (b) is non-crosslinked and has a softening point greater than 50° C. and an elastic modulus at ambient temperature of less than 106 Pa. 22. The composition of claim 21 wherein silicone gum (b) possesses a viscosity of from 300 to 200,000,000 centipoise at 25° C. 23. The composition of claim 21 wherein silicone gum (b) contains one or more M′ units of the formula R4 3SiO1/2 and one or more additional units selected from amongst D′ units of the formula R5 2SiO2/2, T′ units of the formula R6SiO3/2 and Q′ units of the formula SiO4/2, and mixtures thereof, wherein each R4, R5 and R6 is independently a hydroxyl radical or a monovalent hydrocarbon radical. 24. The composition of claim 21 wherein silicone gum (b) is selected from the group consisting of dimethiconol gum, dimethicone gum, polydimethysiloxane gum, amodimethicone, phenyl-modified silicone, silicone block copolymers containing amine groups or quat groups and alkyl-modified aminosilicone. 25. The composition of claim 21 wherein the weight ratio of silicone resin (a) to silicone gum (b) ranges from 0.4 to 6. 26. The composition of claim 21 wherein the softening point of the MT resin ranges from 60° C. to 110° C. 27. The composition of claim 21 wherein the softening point of the MT resin ranges from 70° C. to 110° C. 28. The composition of claim 21 which is cationic surfactant-free. 29. The composition of claim 21 further comprising a solvent for the mixture of silicone resin (a) and silicone gum (b). 30. The composition of claim 29 wherein the solvent is a volatile organic solvent or organosilicon-containing volatile solvent. 31. A personal care product which comprises:
a) a MT resin having a molecular weight higher than 10,000 and containing one or more M units of the formula R1 3SiO1/2, and T units of the formula R3SiO3/2 wherein the ratio of M to T units ranges from 1:1 to 1:7, and the softening point of the MT resin ranges from 50° C. to 110° C. wherein each R1 and R3 is independently a hydroxyl radical or monovalent hydrocarbon radical; and, b) silicone gum,
wherein the mixture of MT resin (a) and silicone gum (b) is non-crosslinked and has a softening point greater than 50° C. and an elastic modulus at ambient temperature of less than 106 Pa. 32. The personal care product of claim 31 wherein silicone gum (b) possesses a viscosity of from 300 to 200,000,000 centipoise at 25° C. 33. The personal care product of claim 31 wherein silicone gum (b) contains one or more M′ units of the formula R4 3SiO1/2 and one or more additional units selected from amongst D′ units of the formula R5 2SiO2/2, T′ units of the formula R6SiO3/2 and Q′ units of the formula SiO4/2, and mixtures thereof, wherein each R4, R5 and R6 is independently a hydroxyl radical or a monovalent hydrocarbon radical. 34. The personal care product of claim 31 wherein silicone gum (b) is selected from the group consisting of dimethiconol gum, dimethicone gum, polydimethysiloxane gum, amodimethicone, phenyl-modified silicone, silicone block copolymers containing amine groups or quat groups and alkyl-modified aminosilicone. 35. The personal care product of claim 31 wherein the weight ratio of silicone resin (a) to silicone gum (b) ranges from 0.4 to 6. 36. The personal care product of claim 31 wherein the softening point of the MT resin ranges from 60° C. to 110° C. 37. The personal care product of claim 31 wherein the softening point of the MT resin ranges from 70° C. to 110° C. 38. The personal care product of claim 31 wherein the personal care product is cationic surfactant-free. 39. The personal care product of claim 31 wherein the personal care product is a hair care product or a lip gloss. 40. The personal care product of claim 31 further comprising a solvent for the mixture of silicone resin (a) and silicone gum (b). 41. The personal care product of claim 40 wherein the solvent is a volatile organic solvent or organosilicon-containing volatile solvent. | 1,600 |
791 | 15,315,173 | 1,656 | Liquid cleaning agents and methods for cleaning are provided herein. In one embodiment, the liquid cleaning agent includes at least one liquid enzyme formulation which includes at least one protease and/or at least one amylase. The liquid cleaning agent further includes at least one solid enzyme formulation which includes at least one protease and/or at least one amylase, wherein the solid enzyme formulation is homogeneously suspended in the liquid cleaning agent. In another embodiment, the method includes the step of providing the liquid cleaning agent. The method further includes the step of dosing the liquid cleaning agent into the interior of the dishwasher. | 1. A liquid cleaning agent, comprising:
at least one liquid enzyme formulation which comprises at least one protease and/or at least one amylase; and at least one solid enzyme formulation which comprises at least one protease and/or at least one amylase, wherein the solid enzyme formulation is homogeneously suspended in the liquid cleaning agent. 2. The cleaning agent according to claim 1, wherein the cleaning agent comprises at least one first amylase and/or at least one second amylase, wherein:
the first amylase is contained in the solid enzyme formulation; and the second amylase is contained in the liquid enzyme formulation. 3. The cleaning agent according to claim 1, wherein:
the first amylase is an α-amylase of Bacillus sp. No. 707 or a functional fragment or a variant thereof; and/or the first amylase includes an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence stated in SEQ ID NO:1. 4. The cleaning agent according to claim 1, wherein:
the second amylase is an AA560 α-amylase of Bacillus sp. or a functional fragment or a variant thereof; and/or the second amylase includes an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence stated in SEQ ID NO:2. 5. The cleaning agent according to claim 1, wherein the cleaning agent comprises at least one first protease and/or at least one second protease, wherein:
the first protease is comprised in the solid enzyme formulation; and the second protease is comprised in the liquid enzyme formulation. 6. The cleaning agent according to claim 5, wherein the first protease comprises a protease of Bacillus alcalophilus PB92 or a functional fragment or a variant thereof, in particular a protease having an amino acid sequence which is at least 80%, identical over its entire length to the amino acid sequence stated in SEQ ID NO:4, and which has at least one amino acid substitution at one of the following positions: 32, 33, 48-54, 58-62, 94-107, 116, 123-133, 150, 152-156, 158-161, 164, 169, 175-186, 197, 198, 203-216 in the count according to SEQ ID NO:4. 7. The cleaning agent according to claim 5, wherein the second protease:
comprises a subtilisin 309 of Bacillus lentus or a functional fragment or a variant thereof, the subtilisin has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence stated in SEQ ID NO:3, and has at least one amino acid substitution at one of the positions 9, 15, 66, 212, and 239 in the count according to SEQ ID NO:3; comprises a subtilisin 309 of Bacillus lentus or a functional fragment or a variant thereof, the subtilisin has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence stated in SEQ ID NO:3, and has an amino acid substitution at position 99 and an insertion of an amino acid between the amino acids at positions 99 and 100 in the count according to SEQ ID NO:3; comprises an alkaline protease of Bacillus lentus DSM 5483 or a functional fragment or a variant thereof, the protease has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence stated in SEQ ID NO:5, and has at least one amino acid substitution at one, two, three, or four of the following positions: 3, 4, 99, and 199 in the count according to SEQ ID NO:5; or (d) has an amino acid sequence according to one of SEQ ID NOs:6-10. 8. The cleaning agent according to claim 1, wherein:
the solid enzyme formulation is comprised in a quantity of 0.01 to 5% by weight based on the total weight of the cleaning agent, wherein the solid enzyme formulation has an active enzyme content of 2 to 20% by weight; and/or the liquid enzyme formulation is comprised in a quantity of 0.01 to 8% by weight based on the total weight of the cleaning agent, wherein the liquid enzyme formulation in particular has an active enzyme content of 1 to 6% by weight. 9. The cleaning agent according to claim 1, wherein the cleaning agent comprises the liquid enzyme formulation and the solid enzyme formulation in a mass ratio of 10:1 to 1:10. 10. The cleaning agent according to claim 1, wherein the cleaning agent:
comprises at least one phosphate-containing builder component; comprises at least one polyhydric alcohol; and has a water content less than 50% by weight. 11. The cleaning agent according to claim 1, wherein the cleaning agent comprises at least one sulfopolymer. 12. (canceled) 13. The cleaning agent according to claim 1, wherein the cleaning agent is a machine dishwasher detergent and:
is present in preportioned form; and/or contains multiple compositions that are spatially separate from one another; and/or is present in a water-insoluble, water-soluble, or water-dispersible package. 14. (canceled) 15. A method for cleaning dishes in an automatic dishwasher, the method comprising the steps of:
providing a cleaning agent according to claim 1; and dosing the liquid cleaning agent into the interior of the dishwasher. 16. The cleaning agent according to claim 3, wherein the first amylase has at least one amino acid substitution at one of the positions 172, 202, 208, 255, and 261 in the count according to SEQ ID NO:1. 17. The cleaning agent according to claim 16, wherein the first amylase has at least one amino acid substitution selected from the group comprising M202L, M202V, M2025, M202T, M202I, M202Q, M202W, S255N, and R172Q. 18. The cleaning agent according to claim 4, wherein the second amylase has at least one amino acid substitution at one of the positions 9, 26, 30, 33, 82, 37, 106, 118, 128, 133, 149, 150, 160, 178, 182, 186, 193, 195, 202, 203, 214, 231, 256, 257, 258, 269, 270, 272, 283, 295, 296, 298, 299, 303, 304, 305, 311, 314, 315, 318, 319, 320, 323, 339, 345, 361, 378, 383, 419, 421, 437, 441, 444, 445, 446, 447, 450, 458, 461, 471, 482, and 484, and/or one of the deletions D183* and G184* in the count according to SEQ ID NO:2. 19. The cleaning agent according to claim 4, wherein the second amylase has amino acid substitutions at three or more of the positions 9, 26, 149, 182, 186, 202, 257, 295, 299, 323, 339, and 345 in the count according to SEQ ID NO:2. 20. The cleaning agent according to claim 19, wherein the second amylase has one or more of the substitutions and/or deletions at positions: 118, 183, 184, 195, 320, and 458 in the count according to SEQ ID NO:2. 21. The cleaning agent according to claim 20, wherein the second amylase has one or more of the following substitutions and/or deletions in the count according to SEQ ID NO:2: R118K, D183*, G184*, N195F, R320K, and/or R458K. 22. The cleaning agent according to claim 4, wherein the second amylase has the following amino acid substitutions and/or deletions in the count according to SEQ ID NO:2:
(i) M9L+M323T; (ii) M9L+M202L/T/V/I+M323T; (iii) M9L+N195F+M202L/T/V/I+M323T; (iv) M9L+R118K+D183*+G184*+R320K+M323T+R458K; (v) M9L+R118K+D183*+G184*+M202L/T/V/I+R320K+M323T+R458K; (vi) M9L+G149A+G182T+G186A+M202L+T257I+Y295F+N299Y+M323T+A339S+E345R; (vii) M9L+G149A+G182T+G186A+M202I+T257I+Y295F+N299Y+M323T+A339S+E345R; (viii) M9L+R118K+G149A+G182T+D183*+G184*+G186A+M202L+T257I+Y295F+N299Y+R320K+M323T+A339S+E345R+R458K; (ix) M9L+R118K+G149A+G182T+D183*+G184*+G186A+N195F+M202L+T257I+Y295F+N299Y+R320K+M323T+A339S+E345R+R458K; (x) M9L+R118K+G149A+G182T+D183*+G184*+G186A+M202I+T257I+Y295F+N299Y+R320K+M323T+A339S+E345R+R458K; (xi) M9L+R118K+D183*+D184*+N195F+M202L+R320K+M323T+R458K; (xii) M9L+R118K+D183*+D184*+N195F+M202T+R320K+M323T+R458K; (xiii) M9L+R118K+D183*+D184*+N195F+M202I+R320K+M323T+R458K; (xiv) M9L+R118K+D183*+D184*+N195F+M202V+R320K+M323T+R458K; (xv) M9L+R118K+N150H+D183*+D184*+N195F+M202L+V214T+R320K+M323T+R458K; or (xvi) M9L+R118K+D183*+D184*+N195F+M202L+V214T+R320K+M323T+E345N+R458K. | Liquid cleaning agents and methods for cleaning are provided herein. In one embodiment, the liquid cleaning agent includes at least one liquid enzyme formulation which includes at least one protease and/or at least one amylase. The liquid cleaning agent further includes at least one solid enzyme formulation which includes at least one protease and/or at least one amylase, wherein the solid enzyme formulation is homogeneously suspended in the liquid cleaning agent. In another embodiment, the method includes the step of providing the liquid cleaning agent. The method further includes the step of dosing the liquid cleaning agent into the interior of the dishwasher.1. A liquid cleaning agent, comprising:
at least one liquid enzyme formulation which comprises at least one protease and/or at least one amylase; and at least one solid enzyme formulation which comprises at least one protease and/or at least one amylase, wherein the solid enzyme formulation is homogeneously suspended in the liquid cleaning agent. 2. The cleaning agent according to claim 1, wherein the cleaning agent comprises at least one first amylase and/or at least one second amylase, wherein:
the first amylase is contained in the solid enzyme formulation; and the second amylase is contained in the liquid enzyme formulation. 3. The cleaning agent according to claim 1, wherein:
the first amylase is an α-amylase of Bacillus sp. No. 707 or a functional fragment or a variant thereof; and/or the first amylase includes an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence stated in SEQ ID NO:1. 4. The cleaning agent according to claim 1, wherein:
the second amylase is an AA560 α-amylase of Bacillus sp. or a functional fragment or a variant thereof; and/or the second amylase includes an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence stated in SEQ ID NO:2. 5. The cleaning agent according to claim 1, wherein the cleaning agent comprises at least one first protease and/or at least one second protease, wherein:
the first protease is comprised in the solid enzyme formulation; and the second protease is comprised in the liquid enzyme formulation. 6. The cleaning agent according to claim 5, wherein the first protease comprises a protease of Bacillus alcalophilus PB92 or a functional fragment or a variant thereof, in particular a protease having an amino acid sequence which is at least 80%, identical over its entire length to the amino acid sequence stated in SEQ ID NO:4, and which has at least one amino acid substitution at one of the following positions: 32, 33, 48-54, 58-62, 94-107, 116, 123-133, 150, 152-156, 158-161, 164, 169, 175-186, 197, 198, 203-216 in the count according to SEQ ID NO:4. 7. The cleaning agent according to claim 5, wherein the second protease:
comprises a subtilisin 309 of Bacillus lentus or a functional fragment or a variant thereof, the subtilisin has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence stated in SEQ ID NO:3, and has at least one amino acid substitution at one of the positions 9, 15, 66, 212, and 239 in the count according to SEQ ID NO:3; comprises a subtilisin 309 of Bacillus lentus or a functional fragment or a variant thereof, the subtilisin has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence stated in SEQ ID NO:3, and has an amino acid substitution at position 99 and an insertion of an amino acid between the amino acids at positions 99 and 100 in the count according to SEQ ID NO:3; comprises an alkaline protease of Bacillus lentus DSM 5483 or a functional fragment or a variant thereof, the protease has an amino acid sequence which is at least 80% identical over its entire length to the amino acid sequence stated in SEQ ID NO:5, and has at least one amino acid substitution at one, two, three, or four of the following positions: 3, 4, 99, and 199 in the count according to SEQ ID NO:5; or (d) has an amino acid sequence according to one of SEQ ID NOs:6-10. 8. The cleaning agent according to claim 1, wherein:
the solid enzyme formulation is comprised in a quantity of 0.01 to 5% by weight based on the total weight of the cleaning agent, wherein the solid enzyme formulation has an active enzyme content of 2 to 20% by weight; and/or the liquid enzyme formulation is comprised in a quantity of 0.01 to 8% by weight based on the total weight of the cleaning agent, wherein the liquid enzyme formulation in particular has an active enzyme content of 1 to 6% by weight. 9. The cleaning agent according to claim 1, wherein the cleaning agent comprises the liquid enzyme formulation and the solid enzyme formulation in a mass ratio of 10:1 to 1:10. 10. The cleaning agent according to claim 1, wherein the cleaning agent:
comprises at least one phosphate-containing builder component; comprises at least one polyhydric alcohol; and has a water content less than 50% by weight. 11. The cleaning agent according to claim 1, wherein the cleaning agent comprises at least one sulfopolymer. 12. (canceled) 13. The cleaning agent according to claim 1, wherein the cleaning agent is a machine dishwasher detergent and:
is present in preportioned form; and/or contains multiple compositions that are spatially separate from one another; and/or is present in a water-insoluble, water-soluble, or water-dispersible package. 14. (canceled) 15. A method for cleaning dishes in an automatic dishwasher, the method comprising the steps of:
providing a cleaning agent according to claim 1; and dosing the liquid cleaning agent into the interior of the dishwasher. 16. The cleaning agent according to claim 3, wherein the first amylase has at least one amino acid substitution at one of the positions 172, 202, 208, 255, and 261 in the count according to SEQ ID NO:1. 17. The cleaning agent according to claim 16, wherein the first amylase has at least one amino acid substitution selected from the group comprising M202L, M202V, M2025, M202T, M202I, M202Q, M202W, S255N, and R172Q. 18. The cleaning agent according to claim 4, wherein the second amylase has at least one amino acid substitution at one of the positions 9, 26, 30, 33, 82, 37, 106, 118, 128, 133, 149, 150, 160, 178, 182, 186, 193, 195, 202, 203, 214, 231, 256, 257, 258, 269, 270, 272, 283, 295, 296, 298, 299, 303, 304, 305, 311, 314, 315, 318, 319, 320, 323, 339, 345, 361, 378, 383, 419, 421, 437, 441, 444, 445, 446, 447, 450, 458, 461, 471, 482, and 484, and/or one of the deletions D183* and G184* in the count according to SEQ ID NO:2. 19. The cleaning agent according to claim 4, wherein the second amylase has amino acid substitutions at three or more of the positions 9, 26, 149, 182, 186, 202, 257, 295, 299, 323, 339, and 345 in the count according to SEQ ID NO:2. 20. The cleaning agent according to claim 19, wherein the second amylase has one or more of the substitutions and/or deletions at positions: 118, 183, 184, 195, 320, and 458 in the count according to SEQ ID NO:2. 21. The cleaning agent according to claim 20, wherein the second amylase has one or more of the following substitutions and/or deletions in the count according to SEQ ID NO:2: R118K, D183*, G184*, N195F, R320K, and/or R458K. 22. The cleaning agent according to claim 4, wherein the second amylase has the following amino acid substitutions and/or deletions in the count according to SEQ ID NO:2:
(i) M9L+M323T; (ii) M9L+M202L/T/V/I+M323T; (iii) M9L+N195F+M202L/T/V/I+M323T; (iv) M9L+R118K+D183*+G184*+R320K+M323T+R458K; (v) M9L+R118K+D183*+G184*+M202L/T/V/I+R320K+M323T+R458K; (vi) M9L+G149A+G182T+G186A+M202L+T257I+Y295F+N299Y+M323T+A339S+E345R; (vii) M9L+G149A+G182T+G186A+M202I+T257I+Y295F+N299Y+M323T+A339S+E345R; (viii) M9L+R118K+G149A+G182T+D183*+G184*+G186A+M202L+T257I+Y295F+N299Y+R320K+M323T+A339S+E345R+R458K; (ix) M9L+R118K+G149A+G182T+D183*+G184*+G186A+N195F+M202L+T257I+Y295F+N299Y+R320K+M323T+A339S+E345R+R458K; (x) M9L+R118K+G149A+G182T+D183*+G184*+G186A+M202I+T257I+Y295F+N299Y+R320K+M323T+A339S+E345R+R458K; (xi) M9L+R118K+D183*+D184*+N195F+M202L+R320K+M323T+R458K; (xii) M9L+R118K+D183*+D184*+N195F+M202T+R320K+M323T+R458K; (xiii) M9L+R118K+D183*+D184*+N195F+M202I+R320K+M323T+R458K; (xiv) M9L+R118K+D183*+D184*+N195F+M202V+R320K+M323T+R458K; (xv) M9L+R118K+N150H+D183*+D184*+N195F+M202L+V214T+R320K+M323T+R458K; or (xvi) M9L+R118K+D183*+D184*+N195F+M202L+V214T+R320K+M323T+E345N+R458K. | 1,600 |
792 | 13,546,757 | 1,651 | A flow cytometer system for sorting haploid cells, specifically sperm cells, may include an intermittingly punctuated radiation emitter, such as a pulsed laser. Embodiments include a beam manipulator and even split radiation beams directed to multiple nozzles. Differentiation of sperm characteristics with increased resolution may efficiently allow differentiated sperm cells to be separated at higher speeds and even into subpopulations having higher purity. | 1-231. (canceled) 232. A method of sorting sperm cells comprising the steps of:
producing a stream of stained sperm cells and sheath fluid; exciting the stained sperm cells within the stream with a pulsed laser; detecting an emitted fluorescence from each of the stained sperm cells; distinguishing between X chromosome bearing sperm and Y chromosome bearing sperm based on the emitted fluorescence in response to the pulsed laser; isolating sperm cells within droplets; charging the droplets based upon the emitted fluorescence of the sperm cells contained within each droplet; deflecting the charged droplets; and collecting the deflected droplets to form at least one sorted sperm population. 233. The method of claim 232 wherein the step of producing a stream of stained sperm cells and sheath fluid further comprises the step of injecting stained sperm cells in a sheath fluid within a nozzle. 234. The method of claim 232 wherein said step of detecting an amount of emitted fluorescence from each of the stained sperm cells comprises the step of detecting an amount of emitted fluorescence from each of the sperm cells with a detection system utilizing a photomultipler tube. 235. The method of claim 232 wherein the step of exciting stained sperm cells within the stream with a pulsed laser comprises subjecting the stained sperm cells to a laser pulse for a pulse duration between about 5 to about 20 picoseconds. 236. The method of claim 232 wherein the step of exciting stained sperm cells within the stream with a pulsed laser comprises providing a pulse resting period between about 0.5 to about 20 nanoseconds. 237. The method of claim 232 wherein the step of exciting stained sperm cells within the stream with a pulsed laser further comprises providing a repetition rate between 50-200 MHz. 238. The method of claim 232 wherein the step of exciting stained sperm cells within the stream with a pulsed laser comprises providing an average power radiation of less than 300 mW. 239. The method of claim 232 further comprising the step of staining the sperm cells with a reduced amount of fluorescent dye. 240. The method of claim 232 wherein the step of staining the sperm cells with a reduced amount of fluorescent dye comprises providing a percentage of stain selected from a group consisting of about 90%, about 80%, about 70% and about 60% of a maximum stain. 241. The method of claim 232 wherein the sperm cells are selected from a group consisting of non-human mammals, bovine sperm cells, equine sperm cells, porcine sperm cells, ovine sperm cells, camelid sperm cells, ruminant sperm cells, and canine sperm cells. 242. The method of claim 232 further comprising the step of utilizing at least one shared resource to sort the sperm cells. 243. The method of claim 242, wherein the step of utilizing at least one shared resource to sort the sperm cells comprises the steps of:
utilizing one pulsed laser; splitting the pulsed laser into at least two beams; and directing each of the beams to a different stream of stained sperm cells and sheath fluid. 244. The method of claim 232 further comprising the step of utilizing said collected sorted sperm for insemination of female non-human mammals. 245. A non-human mammal produced through use of a sorted sperm cells produced with a flow cytometer system according to claim 232. 246. A flow cytometry system for sorting sperm comprising:
a. a nozzle for producing a stream of stained sperm cells and sheath fluid; b. a pulsed laser for exciting stained sperm cells in the stream; c. a detection system for detecting the emitted fluorescence of stained sperm cells; d. a processing unit for differentiating X chromosome sperm from Y chromosome sperm; e. an oscillator to which the stream is responsive for forming droplets; f. a drop charge circuit to apply a charge to the droplets, wherein the charge applied to each droplet is based on the presence of an X-chromosome or Y chromosome as determined by the processing unit; g. a first and second deflection plate each disposed adjacent to a free fall area in which a droplet forms; and h. at least one collector to collect sorted sperm. 247. The flow cytometry system for sorting sperm as claimed in claim 246 further comprising a radiation beam manipulator selected from a group consisting mirrors, deflectors, beam splitters, prisms, refractive objects, lenses and filters. 248. The flow cytometry system for sorting sperm as claimed in claim 247 wherein the detection system comprises a photomultipler tube. 249. The flow cytometry system for sorting sperm as claimed in claim 246 wherein the stained sperm cells are stained with a fluorescent dye. 250. The flow cytometry system for sorting sperm as claimed in claim 246 wherein the fluorescent dye comprises Hoechst 33342. 251. The flow cytometry system for sorting sperm as claimed in claim 246 wherein the pulsed laser comprises an average power less than about 300 mW. 252. The flow cytometry system for sorting sperm as claimed in claim 246 further comprising a beam splitter. 253. The flow cytometry system for sorting sperm as claimed in claim 246 further comprising a high purity sorted population of said X chromosome bearing sperm and said Y chromosome bearing sperm. 254. The flow cytometry system for sorting sperm as claimed in claim 246 wherein said high purity is selected from a group consisting of:
greater than 85% purity;
greater than 90% purity;
greater than 95% purity;
greater than 96% purity; and
greater than 98% purity. 255. The flow cytometry system for sorting sperm as claimed in claim 246 wherein the pulsed laser comprises a pulse duration between about 5 to about 20 picoseconds. 256. The flow cytometry system for sorting sperm as claimed in claim 246 wherein the pulsed laser comprises a pulse resting period between about 0.5 to about 20 nanoseconds. 257. The flow cytometry system for sorting sperm as claimed in claim 246 the pulsed laser has a repetition rate comprises between about 50 to about 200 MHz. 258. The flow cytometry system for sorting sperm as claimed in claim 257 wherein the repetition rate comprises up to about 80 MHz. 259. The flow cytometry system for sorting sperm as claimed in claim 246 wherein the sperm cells are stained with a reduced amount of stain. 260. The flow cytometry system for sorting sperm as claimed in claim 259 wherein the reduced amount of stain comprises a percentage of stain selected from a group consisting of about 90%, about 80%, about 70% and about 60% of a maximum stain. 261. The flow cytometry system for sorting sperm as claimed in claim 246 further comprising at least one shared resource, wherein said shared resource comprises a pulsed laser and a beam splitter. | A flow cytometer system for sorting haploid cells, specifically sperm cells, may include an intermittingly punctuated radiation emitter, such as a pulsed laser. Embodiments include a beam manipulator and even split radiation beams directed to multiple nozzles. Differentiation of sperm characteristics with increased resolution may efficiently allow differentiated sperm cells to be separated at higher speeds and even into subpopulations having higher purity.1-231. (canceled) 232. A method of sorting sperm cells comprising the steps of:
producing a stream of stained sperm cells and sheath fluid; exciting the stained sperm cells within the stream with a pulsed laser; detecting an emitted fluorescence from each of the stained sperm cells; distinguishing between X chromosome bearing sperm and Y chromosome bearing sperm based on the emitted fluorescence in response to the pulsed laser; isolating sperm cells within droplets; charging the droplets based upon the emitted fluorescence of the sperm cells contained within each droplet; deflecting the charged droplets; and collecting the deflected droplets to form at least one sorted sperm population. 233. The method of claim 232 wherein the step of producing a stream of stained sperm cells and sheath fluid further comprises the step of injecting stained sperm cells in a sheath fluid within a nozzle. 234. The method of claim 232 wherein said step of detecting an amount of emitted fluorescence from each of the stained sperm cells comprises the step of detecting an amount of emitted fluorescence from each of the sperm cells with a detection system utilizing a photomultipler tube. 235. The method of claim 232 wherein the step of exciting stained sperm cells within the stream with a pulsed laser comprises subjecting the stained sperm cells to a laser pulse for a pulse duration between about 5 to about 20 picoseconds. 236. The method of claim 232 wherein the step of exciting stained sperm cells within the stream with a pulsed laser comprises providing a pulse resting period between about 0.5 to about 20 nanoseconds. 237. The method of claim 232 wherein the step of exciting stained sperm cells within the stream with a pulsed laser further comprises providing a repetition rate between 50-200 MHz. 238. The method of claim 232 wherein the step of exciting stained sperm cells within the stream with a pulsed laser comprises providing an average power radiation of less than 300 mW. 239. The method of claim 232 further comprising the step of staining the sperm cells with a reduced amount of fluorescent dye. 240. The method of claim 232 wherein the step of staining the sperm cells with a reduced amount of fluorescent dye comprises providing a percentage of stain selected from a group consisting of about 90%, about 80%, about 70% and about 60% of a maximum stain. 241. The method of claim 232 wherein the sperm cells are selected from a group consisting of non-human mammals, bovine sperm cells, equine sperm cells, porcine sperm cells, ovine sperm cells, camelid sperm cells, ruminant sperm cells, and canine sperm cells. 242. The method of claim 232 further comprising the step of utilizing at least one shared resource to sort the sperm cells. 243. The method of claim 242, wherein the step of utilizing at least one shared resource to sort the sperm cells comprises the steps of:
utilizing one pulsed laser; splitting the pulsed laser into at least two beams; and directing each of the beams to a different stream of stained sperm cells and sheath fluid. 244. The method of claim 232 further comprising the step of utilizing said collected sorted sperm for insemination of female non-human mammals. 245. A non-human mammal produced through use of a sorted sperm cells produced with a flow cytometer system according to claim 232. 246. A flow cytometry system for sorting sperm comprising:
a. a nozzle for producing a stream of stained sperm cells and sheath fluid; b. a pulsed laser for exciting stained sperm cells in the stream; c. a detection system for detecting the emitted fluorescence of stained sperm cells; d. a processing unit for differentiating X chromosome sperm from Y chromosome sperm; e. an oscillator to which the stream is responsive for forming droplets; f. a drop charge circuit to apply a charge to the droplets, wherein the charge applied to each droplet is based on the presence of an X-chromosome or Y chromosome as determined by the processing unit; g. a first and second deflection plate each disposed adjacent to a free fall area in which a droplet forms; and h. at least one collector to collect sorted sperm. 247. The flow cytometry system for sorting sperm as claimed in claim 246 further comprising a radiation beam manipulator selected from a group consisting mirrors, deflectors, beam splitters, prisms, refractive objects, lenses and filters. 248. The flow cytometry system for sorting sperm as claimed in claim 247 wherein the detection system comprises a photomultipler tube. 249. The flow cytometry system for sorting sperm as claimed in claim 246 wherein the stained sperm cells are stained with a fluorescent dye. 250. The flow cytometry system for sorting sperm as claimed in claim 246 wherein the fluorescent dye comprises Hoechst 33342. 251. The flow cytometry system for sorting sperm as claimed in claim 246 wherein the pulsed laser comprises an average power less than about 300 mW. 252. The flow cytometry system for sorting sperm as claimed in claim 246 further comprising a beam splitter. 253. The flow cytometry system for sorting sperm as claimed in claim 246 further comprising a high purity sorted population of said X chromosome bearing sperm and said Y chromosome bearing sperm. 254. The flow cytometry system for sorting sperm as claimed in claim 246 wherein said high purity is selected from a group consisting of:
greater than 85% purity;
greater than 90% purity;
greater than 95% purity;
greater than 96% purity; and
greater than 98% purity. 255. The flow cytometry system for sorting sperm as claimed in claim 246 wherein the pulsed laser comprises a pulse duration between about 5 to about 20 picoseconds. 256. The flow cytometry system for sorting sperm as claimed in claim 246 wherein the pulsed laser comprises a pulse resting period between about 0.5 to about 20 nanoseconds. 257. The flow cytometry system for sorting sperm as claimed in claim 246 the pulsed laser has a repetition rate comprises between about 50 to about 200 MHz. 258. The flow cytometry system for sorting sperm as claimed in claim 257 wherein the repetition rate comprises up to about 80 MHz. 259. The flow cytometry system for sorting sperm as claimed in claim 246 wherein the sperm cells are stained with a reduced amount of stain. 260. The flow cytometry system for sorting sperm as claimed in claim 259 wherein the reduced amount of stain comprises a percentage of stain selected from a group consisting of about 90%, about 80%, about 70% and about 60% of a maximum stain. 261. The flow cytometry system for sorting sperm as claimed in claim 246 further comprising at least one shared resource, wherein said shared resource comprises a pulsed laser and a beam splitter. | 1,600 |
793 | 12,727,824 | 1,634 | The invention generally relates to methods for detecting fetal nucleic acids and methods for diagnosing fetal abnormalities. In certain embodiments, the invention provides methods for determining whether fetal nucleic acid is present in a maternal sample including obtaining a maternal sample suspected to include fetal nucleic acids, and performing a sequencing reaction on the sample to determine presence of at least a portion of a Y chromosome in the sample, thereby determining that fetal nucleic acid is present in the sample. In other embodiments, the invention provides methods for quantitative or qualitative analysis to detect fetal nucleic acid in a maternal sample, regardless of the ability to detect the Y chromosome, particularly for samples including normal nucleic acids from a female fetus. | 1. A method for determining a fetal abnormality, the method comprising:
obtaining a maternal sample; sequencing at least a portion of nucleic acids in the sample; comparing obtained sequence information to a reference sequence; identifying fetal nucleic acid, if present, in the sample; optionally, if fetal nucleic acid is present, determining whether the fetus has an abnormality. 2. The method of claim 1, wherein said reference sequence is selected from a maternal reference sequence, a fetal reference sequence, or a consensus human genomic sequence. 3. The method of claim 2, wherein said maternal reference sequence is selected from a sequence obtained from a buccal sample, a saliva sample, a urine sample, a breast nipple aspirate sample, a sputum sample, a tear sample, and an amniotic fluid sample. 4. The method of claim 1, wherein the sequencing reaction is a single molecule sequencing reaction. 5. The method of claim 4, wherein the single molecule sequencing reaction comprises sequencing by synthesis and/or sequencing by nanopore detection. 6. The method according to claim 1, wherein the maternal sample is a tissue or body fluid. 7. The method according to claim 6, wherein the body fluid is maternal blood, blood plasma, or serum. 8. The method according to claim 1, wherein the fetal nucleic acid is cell free circulating fetal nucleic acid. 9. The method according to claim 1, wherein prior to the sequencing step, the method further comprises enriching for fetal nucleic acid in the sample. 10. The method of claim 1, wherein said identifying step comprises a technique selected from sparse allele calling, targeted gene sequencing, identification of Y chromosomal material, enumeration, copy number analysis, and breakpoint analysis. 11. A method for determining whether a fetus has an abnormality, the method comprising:
obtaining a maternal sample comprising both maternal and fetal nucleic acids; attaching a plurality of unique tags to nucleic acids in the sample, wherein each type of tag is associated with a different genomic region; performing a sequencing reaction on the tagged nucleic acids to obtain tagged sequences; and determining whether the fetus has an abnormality by quantifying the tagged sequences. 12. The method according to claim 11, wherein the different genomic region is at least a portion of a chromosome. 13. A method determining the presence of fetal nucleic acid, the method comprising:
obtaining a maternal sample; sequencing nucleic acids in the sample, wherein said sequencing has an associated error rate; determining whether fetal nucleic acid is present in the sample based at least in part on a quantitative measure of nucleic acid identified as fetal by said sequencing wherein the quantitative measure has a confidence level determined at least in part by the error rate. 14. A method for determining whether a fetus has an abnormality, the method comprising:
obtaining a maternal sample suspected to contain maternal and fetal nucleic acids; sequencing nucleic acids in the sample; comparing obtained sequence information to a reference sequence; identifying regions of sequence match or mismatch between the obtained sequence information and the reference sequence; confirming the presence of fetal nucleic acid in the sample; and optionally determining whether the fetus has an abnormality based upon the results of the identifying step. 15. A method for determining whether fetal nucleic acid is present in a maternal sample, the method comprising:
obtaining a maternal sample suspected to include fetal nucleic acids; and performing a sequencing reaction on the sample that is capable of detecting presence of at least a portion of a Y chromosome in the sample if such portion is present; and determining that fetal nucleic acid is present in the sample. 16. The method according to claim 15, wherein the sequencing reaction is a single molecule sequencing reaction. 17. The method according to claim 15, wherein the maternal sample is a tissue or body fluid. 18. The method according to claim 17, wherein the body fluid is maternal blood, blood plasma, or serum. 19. The method according to claim 15, further comprising: performing a quantitative analysis on the obtained sequences to detect presence of fetal nucleic acid if the Y chromosome is not detected in the sample. 20. A method for determining proper function of an assay used for detection of an abnormality in a fetus, the method comprising:
obtaining a maternal sample suspected to include fetal nucleic acids; determining whether at least a portion of a Y chromosome is present in the sample; and optionally performing a quantitative analysis on the obtained sequences to detect presence of nucleic acid from a normal female fetus if the Y chromosome is not detected in the sample, thereby determining that that the assay is functioning properly. 21. A method for determining whether a fetus has an abnormality, the method comprising:
obtaining a maternal sample comprising both maternal and fetal nucleic acids; performing a sequencing reaction on the sample to obtain sequence information on nucleic acids in the sample; comparing the obtained sequence information to sequence information from a reference genome, thereby determining whether the fetus has an abnormality; detecting presence of at least a portion of a Y chromosome in the sample; and distinguishing false negatives from true negatives if the Y chromosome is not detected in the sample. 22. The method according to claim 21, wherein distinguishing comprises: performing a quantitative analysis selected from the group consisting of copy number analysis; sparse allele calling; targeted resequencing; and inversion analysis. 23. A method for determining whether a fetus has an abnormality, the method comprising:
obtaining a maternal sample comprising both maternal and fetal nucleic acids; performing a sequencing reaction on the sample to obtain sequence information on nucleic acids in the sample; comparing the obtained sequence information to sequence information from a reference genome, thereby determining whether the fetus has an abnormality; and distinguishing false negatives from true negatives. 24. The method according to claim 23, wherein distinguishing comprises:
assaying the sample for presence of at least a portion of a Y chromosome; and optionally performing a quantitative analysis on the obtained sequences to detect presence of nucleic acid from a normal female fetus if the Y chromosome is not detected in the sample. 25. The method according to claim 24, wherein the quantitative analysis is accomplished by a technique selected from the group consisting of: copy number analysis; sparse allele calling; targeted resequencing; and breakpoint analysis. 26. The method according to claim 23, wherein the distinguishing comprises performing a quantitative analysis on the obtained sequences to detect presence of nucleic acid from a normal fetus. 27. The method according to claim 26, wherein the quantitative analysis is accomplished by a technique selected from the group consisting of copy number analysis; sparse allele calling; targeted resequencing; and breakpoint analysis. 28. The method according to claim 23, wherein prior to the performing step, the method further comprises enriching for the fetal nucleic acids in the sample. 29. The method according to claim 23, wherein the sequencing reaction is a single molecule sequencing by synthesis reaction. 30. The method according to claim 23, wherein the maternal sample is a tissue or body fluid. 31. The method according to claim 30, wherein the body fluid is maternal blood, blood plasma, or serum. 32. The method according to claim 23, wherein the abnormality results from a chromosomal aberration. 33. The method according to claim 23, wherein the abnormality results from fetal aneuploidy. 34. The method according to claim 23, wherein the abnormality is selected from the group consisting of Down syndrome (trisomy of chromosome 21), Edward syndrome (trisomy of chromosome 18), and Patau syndrome (trisomy of chromosome 13). 35. A method for determining whether a fetus has an abnormality, the method comprising:
obtaining a maternal sample comprising both maternal and fetal nucleic acids; performing a sequencing reaction on the sample to obtain sequence information on nucleic acids in the sample; comparing the obtained sequence information to sequence information from a reference genome, thereby determining whether the fetus has an abnormality; detecting presence of at least a portion of a Y chromosome in the sample; and distinguishing false negatives from true negatives if the Y chromosome is not detected in the sample. 36. The method according to claim 35, wherein prior to the performing step, the method further comprises enriching for the fetal nucleic acids in the sample. 37. The method according to claim 35, wherein distinguishing comprises: performing a quantitative analysis selected from the group consisting of: copy number analysis; sparse allele calling; targeted resequencing; and breakpoint analysis. 38. The method according to claim 35, wherein the comparing step comprises comparison of measured depth of sequencing coverage in a region of interest to expected depth of coverage in a diploid sample with the same total coverage. 39. The method according to claim 38, wherein the region of interest is an entire chromosome. 40. The method according to claim 38, wherein the region of interest is a part of a chromosome. 41. The method according to claim 38, wherein where the expected depth of coverage is determined by average coverage from a control population. 42. The method according to claim 38, wherein the expected depth of coverage is determined by comparison to majority of regions of the same sample. 43. The method according to claim 38, wherein the expected depth of coverage is determined by a model of the observed distribution of coverage values in the sample which partitions the space of coverage depth into ranges corresponding to different copy numbers. 44. A method for determining whether a fetus has an abnormality, the method comprising:
obtaining a maternal sample comprising both maternal and fetal nucleic acids; attaching unique tags to nucleic acids in the sample, wherein each tag is associated with a different chromosome; performing a sequencing reaction on the tagged nucleic acids to obtain tagged sequences; and optionally determining whether the fetus has an abnormality by quantifying the tagged sequences. 45. The method according to claim 44, wherein the tags comprise unique nucleic acid sequences. 46. A method for determining whether fetal nucleic acid is present in a maternal sample, the method comprising:
obtaining a maternal sample suspected to include fetal nucleic acids; selecting at least two unique k-mers for detection in the sample; and determining whether fetal nucleic acid is present in the maternal sample based on the ratio of the unique k-mers. 47. The method according to claim 46, further comprising diagnosing an abnormality in the fetus based on analysis of the detected sequence. 48. The method according to claim 46, wherein the unique sequences comprise one or more single nucleotide polymorphisms. 49. The method according to claim 46, further comprising the step of determining an amount of each of said unique k-mers. 50. The method according to claim 46, wherein said determining step comprises sequencing at least a portion of said nucleic acid. 51. The method according to claim 46, wherein the maternal sample is a tissue or body fluid. 52. The method according to claim 46, wherein the body fluid is maternal blood, blood plasma, or serum. 53. A method for identifying a fetal abnormality, the method comprising the steps of:
sequencing nucleic acid from a maternal sample; distinguishing fetal nucleic acid from maternal nucleic acid; confirming presence or absence of said fetal nucleic acid; and optionally identifying an abnormality based upon a sequence variant in said fetal nucleic acid. 54. The method of claim 53, wherein said confirming step comprises identifying false negative results in said distinguishing step. 55. The method of claim 53, wherein said confirming step comprises identifying false positive results in said distinguishing step. 56. The method of claim 53, wherein said confirming step comprises identification of nucleic acid associated with a Y chromosome. 57. The method of claim 53, wherein said distinguishing step comprises comparing obtained sequence to one or more reference sequence. 58. The method of claim 57, wherein said reference sequence is selected from a human genome consensus sequence, a maternal reference sequence, a paternal reference sequence, and a fetal reference sequence. 59. A method for analyzing nucleic acids in a sample, the method comprising:
sequencing a sample to obtain nucleic acid sequence information; determining an amount of GC bias in the sequence information; correcting the sequence information to account for the GC bias; and analyzing the corrected information. 60. The method according to claim 59, wherein determining comprises:
partitioning the sequence information into bins; and measuring a correlation between a number of chromosome counts in each bin and its GC content, wherein a statistically significant negative or positive correlation indicates existence of GC bias. 61. The method according to claim 59, wherein correcting comprises:
selecting a subset of bins within a given range such that average GC content per chromosome is equalized. 62. The method according to claim 59, wherein correcting comprises:
modeling a correlation between GC content and chromosome counts across a set of bins; and adjusting the effect of the GC bias by subtracting the GC-dependent component from the chromosome count in each bin based upon the modeling. 63. The method according to claim 59, wherein correcting comprises:
obtaining an average sequence coverage per bin over a number of controls; and dividing the obtained coverage in the sample by the mean of the controls. 64. The method according to claim 59, wherein the sample is a tissue or body fluid. 65. The method according to claim 64, wherein the sample is suspected to contain fetal nucleic acid. 66. The method according to claim 65, wherein the body fluid is maternal blood, blood plasma, or serum. 67. The method according to claim 59, wherein sequencing is single molecule sequencing and/or sequencing by nanopore detection. 68. The method according to claim 67, wherein single molecule sequencing is sequencing by synthesis and/or sequencing by nanopore detection. 69. A method for identifying a fetal abnormality, the method comprising:
obtaining a maternal sample; sequencing at least a portion of nucleic acids in the sample to obtain sequence information; determining an amount of GC bias in the sequence information; correcting the sequence information to account for the GC bias; comparing corrected sequence information to a reference sequence; identifying fetal nucleic acid, if present, in the sample; optionally, if fetal nucleic acid is present, determining whether the fetus has an abnormality. 70. The method according to claim 69, wherein the reference sequence is selected from a maternal reference sequence, a fetal reference sequence, or a consensus human genomic sequence. 71. The method according to claim 69, wherein said maternal reference sequence is selected from a sequence obtained from a buccal sample, a saliva sample, a urine sample, a breast nipple aspirate sample, a sputum sample, a tear sample, and an amniotic fluid sample. 72. The method according to claim 69, wherein sequencing is single molecule sequencing. 73. The method according to claim 72, wherein single molecule sequencing comprises sequencing by synthesis and/or sequencing by nanopore detection. 74. The method according to claim 69, wherein the maternal sample is a tissue or body fluid. 75. The method according to claim 74, wherein the body fluid is maternal blood, blood plasma, or serum. 76. The method according to claim 69, wherein the fetal nucleic acid is cell free circulating fetal nucleic acid. 77. The method according to claim 69, wherein prior to the sequencing step, the method further comprises enriching for fetal nucleic acid in the sample. 78. The method according to claim 69, wherein the identifying step comprises a technique selected from sparse allele calling, targeted gene sequencing, identification of Y chromosomal material, enumeration, copy number analysis, and inversion analysis. 79. The method according to claim 69, wherein determining comprises:
partitioning the sequence information into bins; and measuring a correlation between a number of chromosome counts in each bin and its GC content, wherein a statistically significant negative or positive correlation indicates existence of GC bias. 80. The method according to claim 69, wherein correcting comprises:
selecting a subset of bins within a given range such that average GC content per chromosome is equalized. 81. The method according to claim 69, wherein correcting comprises:
modeling a correlation between GC content and chromosome counts across a set of bins; and adjusting the effect of the GC bias by subtracting the GC-dependent component from the chromosome count in each bin based upon the modeling. 82. The method according to claim 69, wherein correcting comprises:
obtaining an average sequence coverage per bin over a number of controls and dividing the obtained coverage in the sample by the mean of the controls. 83. The method according to claim 69, wherein the determining comprises:
comparing measured depth of coverage in chromosome regions to a normal control that was processed with the sample. | The invention generally relates to methods for detecting fetal nucleic acids and methods for diagnosing fetal abnormalities. In certain embodiments, the invention provides methods for determining whether fetal nucleic acid is present in a maternal sample including obtaining a maternal sample suspected to include fetal nucleic acids, and performing a sequencing reaction on the sample to determine presence of at least a portion of a Y chromosome in the sample, thereby determining that fetal nucleic acid is present in the sample. In other embodiments, the invention provides methods for quantitative or qualitative analysis to detect fetal nucleic acid in a maternal sample, regardless of the ability to detect the Y chromosome, particularly for samples including normal nucleic acids from a female fetus.1. A method for determining a fetal abnormality, the method comprising:
obtaining a maternal sample; sequencing at least a portion of nucleic acids in the sample; comparing obtained sequence information to a reference sequence; identifying fetal nucleic acid, if present, in the sample; optionally, if fetal nucleic acid is present, determining whether the fetus has an abnormality. 2. The method of claim 1, wherein said reference sequence is selected from a maternal reference sequence, a fetal reference sequence, or a consensus human genomic sequence. 3. The method of claim 2, wherein said maternal reference sequence is selected from a sequence obtained from a buccal sample, a saliva sample, a urine sample, a breast nipple aspirate sample, a sputum sample, a tear sample, and an amniotic fluid sample. 4. The method of claim 1, wherein the sequencing reaction is a single molecule sequencing reaction. 5. The method of claim 4, wherein the single molecule sequencing reaction comprises sequencing by synthesis and/or sequencing by nanopore detection. 6. The method according to claim 1, wherein the maternal sample is a tissue or body fluid. 7. The method according to claim 6, wherein the body fluid is maternal blood, blood plasma, or serum. 8. The method according to claim 1, wherein the fetal nucleic acid is cell free circulating fetal nucleic acid. 9. The method according to claim 1, wherein prior to the sequencing step, the method further comprises enriching for fetal nucleic acid in the sample. 10. The method of claim 1, wherein said identifying step comprises a technique selected from sparse allele calling, targeted gene sequencing, identification of Y chromosomal material, enumeration, copy number analysis, and breakpoint analysis. 11. A method for determining whether a fetus has an abnormality, the method comprising:
obtaining a maternal sample comprising both maternal and fetal nucleic acids; attaching a plurality of unique tags to nucleic acids in the sample, wherein each type of tag is associated with a different genomic region; performing a sequencing reaction on the tagged nucleic acids to obtain tagged sequences; and determining whether the fetus has an abnormality by quantifying the tagged sequences. 12. The method according to claim 11, wherein the different genomic region is at least a portion of a chromosome. 13. A method determining the presence of fetal nucleic acid, the method comprising:
obtaining a maternal sample; sequencing nucleic acids in the sample, wherein said sequencing has an associated error rate; determining whether fetal nucleic acid is present in the sample based at least in part on a quantitative measure of nucleic acid identified as fetal by said sequencing wherein the quantitative measure has a confidence level determined at least in part by the error rate. 14. A method for determining whether a fetus has an abnormality, the method comprising:
obtaining a maternal sample suspected to contain maternal and fetal nucleic acids; sequencing nucleic acids in the sample; comparing obtained sequence information to a reference sequence; identifying regions of sequence match or mismatch between the obtained sequence information and the reference sequence; confirming the presence of fetal nucleic acid in the sample; and optionally determining whether the fetus has an abnormality based upon the results of the identifying step. 15. A method for determining whether fetal nucleic acid is present in a maternal sample, the method comprising:
obtaining a maternal sample suspected to include fetal nucleic acids; and performing a sequencing reaction on the sample that is capable of detecting presence of at least a portion of a Y chromosome in the sample if such portion is present; and determining that fetal nucleic acid is present in the sample. 16. The method according to claim 15, wherein the sequencing reaction is a single molecule sequencing reaction. 17. The method according to claim 15, wherein the maternal sample is a tissue or body fluid. 18. The method according to claim 17, wherein the body fluid is maternal blood, blood plasma, or serum. 19. The method according to claim 15, further comprising: performing a quantitative analysis on the obtained sequences to detect presence of fetal nucleic acid if the Y chromosome is not detected in the sample. 20. A method for determining proper function of an assay used for detection of an abnormality in a fetus, the method comprising:
obtaining a maternal sample suspected to include fetal nucleic acids; determining whether at least a portion of a Y chromosome is present in the sample; and optionally performing a quantitative analysis on the obtained sequences to detect presence of nucleic acid from a normal female fetus if the Y chromosome is not detected in the sample, thereby determining that that the assay is functioning properly. 21. A method for determining whether a fetus has an abnormality, the method comprising:
obtaining a maternal sample comprising both maternal and fetal nucleic acids; performing a sequencing reaction on the sample to obtain sequence information on nucleic acids in the sample; comparing the obtained sequence information to sequence information from a reference genome, thereby determining whether the fetus has an abnormality; detecting presence of at least a portion of a Y chromosome in the sample; and distinguishing false negatives from true negatives if the Y chromosome is not detected in the sample. 22. The method according to claim 21, wherein distinguishing comprises: performing a quantitative analysis selected from the group consisting of copy number analysis; sparse allele calling; targeted resequencing; and inversion analysis. 23. A method for determining whether a fetus has an abnormality, the method comprising:
obtaining a maternal sample comprising both maternal and fetal nucleic acids; performing a sequencing reaction on the sample to obtain sequence information on nucleic acids in the sample; comparing the obtained sequence information to sequence information from a reference genome, thereby determining whether the fetus has an abnormality; and distinguishing false negatives from true negatives. 24. The method according to claim 23, wherein distinguishing comprises:
assaying the sample for presence of at least a portion of a Y chromosome; and optionally performing a quantitative analysis on the obtained sequences to detect presence of nucleic acid from a normal female fetus if the Y chromosome is not detected in the sample. 25. The method according to claim 24, wherein the quantitative analysis is accomplished by a technique selected from the group consisting of: copy number analysis; sparse allele calling; targeted resequencing; and breakpoint analysis. 26. The method according to claim 23, wherein the distinguishing comprises performing a quantitative analysis on the obtained sequences to detect presence of nucleic acid from a normal fetus. 27. The method according to claim 26, wherein the quantitative analysis is accomplished by a technique selected from the group consisting of copy number analysis; sparse allele calling; targeted resequencing; and breakpoint analysis. 28. The method according to claim 23, wherein prior to the performing step, the method further comprises enriching for the fetal nucleic acids in the sample. 29. The method according to claim 23, wherein the sequencing reaction is a single molecule sequencing by synthesis reaction. 30. The method according to claim 23, wherein the maternal sample is a tissue or body fluid. 31. The method according to claim 30, wherein the body fluid is maternal blood, blood plasma, or serum. 32. The method according to claim 23, wherein the abnormality results from a chromosomal aberration. 33. The method according to claim 23, wherein the abnormality results from fetal aneuploidy. 34. The method according to claim 23, wherein the abnormality is selected from the group consisting of Down syndrome (trisomy of chromosome 21), Edward syndrome (trisomy of chromosome 18), and Patau syndrome (trisomy of chromosome 13). 35. A method for determining whether a fetus has an abnormality, the method comprising:
obtaining a maternal sample comprising both maternal and fetal nucleic acids; performing a sequencing reaction on the sample to obtain sequence information on nucleic acids in the sample; comparing the obtained sequence information to sequence information from a reference genome, thereby determining whether the fetus has an abnormality; detecting presence of at least a portion of a Y chromosome in the sample; and distinguishing false negatives from true negatives if the Y chromosome is not detected in the sample. 36. The method according to claim 35, wherein prior to the performing step, the method further comprises enriching for the fetal nucleic acids in the sample. 37. The method according to claim 35, wherein distinguishing comprises: performing a quantitative analysis selected from the group consisting of: copy number analysis; sparse allele calling; targeted resequencing; and breakpoint analysis. 38. The method according to claim 35, wherein the comparing step comprises comparison of measured depth of sequencing coverage in a region of interest to expected depth of coverage in a diploid sample with the same total coverage. 39. The method according to claim 38, wherein the region of interest is an entire chromosome. 40. The method according to claim 38, wherein the region of interest is a part of a chromosome. 41. The method according to claim 38, wherein where the expected depth of coverage is determined by average coverage from a control population. 42. The method according to claim 38, wherein the expected depth of coverage is determined by comparison to majority of regions of the same sample. 43. The method according to claim 38, wherein the expected depth of coverage is determined by a model of the observed distribution of coverage values in the sample which partitions the space of coverage depth into ranges corresponding to different copy numbers. 44. A method for determining whether a fetus has an abnormality, the method comprising:
obtaining a maternal sample comprising both maternal and fetal nucleic acids; attaching unique tags to nucleic acids in the sample, wherein each tag is associated with a different chromosome; performing a sequencing reaction on the tagged nucleic acids to obtain tagged sequences; and optionally determining whether the fetus has an abnormality by quantifying the tagged sequences. 45. The method according to claim 44, wherein the tags comprise unique nucleic acid sequences. 46. A method for determining whether fetal nucleic acid is present in a maternal sample, the method comprising:
obtaining a maternal sample suspected to include fetal nucleic acids; selecting at least two unique k-mers for detection in the sample; and determining whether fetal nucleic acid is present in the maternal sample based on the ratio of the unique k-mers. 47. The method according to claim 46, further comprising diagnosing an abnormality in the fetus based on analysis of the detected sequence. 48. The method according to claim 46, wherein the unique sequences comprise one or more single nucleotide polymorphisms. 49. The method according to claim 46, further comprising the step of determining an amount of each of said unique k-mers. 50. The method according to claim 46, wherein said determining step comprises sequencing at least a portion of said nucleic acid. 51. The method according to claim 46, wherein the maternal sample is a tissue or body fluid. 52. The method according to claim 46, wherein the body fluid is maternal blood, blood plasma, or serum. 53. A method for identifying a fetal abnormality, the method comprising the steps of:
sequencing nucleic acid from a maternal sample; distinguishing fetal nucleic acid from maternal nucleic acid; confirming presence or absence of said fetal nucleic acid; and optionally identifying an abnormality based upon a sequence variant in said fetal nucleic acid. 54. The method of claim 53, wherein said confirming step comprises identifying false negative results in said distinguishing step. 55. The method of claim 53, wherein said confirming step comprises identifying false positive results in said distinguishing step. 56. The method of claim 53, wherein said confirming step comprises identification of nucleic acid associated with a Y chromosome. 57. The method of claim 53, wherein said distinguishing step comprises comparing obtained sequence to one or more reference sequence. 58. The method of claim 57, wherein said reference sequence is selected from a human genome consensus sequence, a maternal reference sequence, a paternal reference sequence, and a fetal reference sequence. 59. A method for analyzing nucleic acids in a sample, the method comprising:
sequencing a sample to obtain nucleic acid sequence information; determining an amount of GC bias in the sequence information; correcting the sequence information to account for the GC bias; and analyzing the corrected information. 60. The method according to claim 59, wherein determining comprises:
partitioning the sequence information into bins; and measuring a correlation between a number of chromosome counts in each bin and its GC content, wherein a statistically significant negative or positive correlation indicates existence of GC bias. 61. The method according to claim 59, wherein correcting comprises:
selecting a subset of bins within a given range such that average GC content per chromosome is equalized. 62. The method according to claim 59, wherein correcting comprises:
modeling a correlation between GC content and chromosome counts across a set of bins; and adjusting the effect of the GC bias by subtracting the GC-dependent component from the chromosome count in each bin based upon the modeling. 63. The method according to claim 59, wherein correcting comprises:
obtaining an average sequence coverage per bin over a number of controls; and dividing the obtained coverage in the sample by the mean of the controls. 64. The method according to claim 59, wherein the sample is a tissue or body fluid. 65. The method according to claim 64, wherein the sample is suspected to contain fetal nucleic acid. 66. The method according to claim 65, wherein the body fluid is maternal blood, blood plasma, or serum. 67. The method according to claim 59, wherein sequencing is single molecule sequencing and/or sequencing by nanopore detection. 68. The method according to claim 67, wherein single molecule sequencing is sequencing by synthesis and/or sequencing by nanopore detection. 69. A method for identifying a fetal abnormality, the method comprising:
obtaining a maternal sample; sequencing at least a portion of nucleic acids in the sample to obtain sequence information; determining an amount of GC bias in the sequence information; correcting the sequence information to account for the GC bias; comparing corrected sequence information to a reference sequence; identifying fetal nucleic acid, if present, in the sample; optionally, if fetal nucleic acid is present, determining whether the fetus has an abnormality. 70. The method according to claim 69, wherein the reference sequence is selected from a maternal reference sequence, a fetal reference sequence, or a consensus human genomic sequence. 71. The method according to claim 69, wherein said maternal reference sequence is selected from a sequence obtained from a buccal sample, a saliva sample, a urine sample, a breast nipple aspirate sample, a sputum sample, a tear sample, and an amniotic fluid sample. 72. The method according to claim 69, wherein sequencing is single molecule sequencing. 73. The method according to claim 72, wherein single molecule sequencing comprises sequencing by synthesis and/or sequencing by nanopore detection. 74. The method according to claim 69, wherein the maternal sample is a tissue or body fluid. 75. The method according to claim 74, wherein the body fluid is maternal blood, blood plasma, or serum. 76. The method according to claim 69, wherein the fetal nucleic acid is cell free circulating fetal nucleic acid. 77. The method according to claim 69, wherein prior to the sequencing step, the method further comprises enriching for fetal nucleic acid in the sample. 78. The method according to claim 69, wherein the identifying step comprises a technique selected from sparse allele calling, targeted gene sequencing, identification of Y chromosomal material, enumeration, copy number analysis, and inversion analysis. 79. The method according to claim 69, wherein determining comprises:
partitioning the sequence information into bins; and measuring a correlation between a number of chromosome counts in each bin and its GC content, wherein a statistically significant negative or positive correlation indicates existence of GC bias. 80. The method according to claim 69, wherein correcting comprises:
selecting a subset of bins within a given range such that average GC content per chromosome is equalized. 81. The method according to claim 69, wherein correcting comprises:
modeling a correlation between GC content and chromosome counts across a set of bins; and adjusting the effect of the GC bias by subtracting the GC-dependent component from the chromosome count in each bin based upon the modeling. 82. The method according to claim 69, wherein correcting comprises:
obtaining an average sequence coverage per bin over a number of controls and dividing the obtained coverage in the sample by the mean of the controls. 83. The method according to claim 69, wherein the determining comprises:
comparing measured depth of coverage in chromosome regions to a normal control that was processed with the sample. | 1,600 |
794 | 15,150,373 | 1,633 | The present invention provides an expression vector for preventing or inhibiting HIV entry, fusion or replication in mammalian cells. In particular, the invention provides a recombinant retroviral vector that encodes an inhibitor of a HIV co-receptor, such as CCR5 or CXCR4, and a protein that inhibits HIV fusion to target cells and/or HIV replication. Pharmaceutical compositions comprising such constructs and methods of use thereof to prevent or treat HIV infection in a patient are also disclosed. | 1. (canceled) 2. A method of treating or preventing HIV infection in a patient comprising (i) transducing hematopoietic cells with an expression vector, the expression vector comprising a first nucleic acid sequence encoding an inhibitor of an HIV co-receptor and a second nucleic acid sequence encoding a protein that inhibits HIV fusion to a target cell or HIV replication, and (ii) transplanting said transduced hematopoietic cells in the patient, wherein said transduced hematopoietic cells are resistant to HIV infection. 3. The method of claim 2, wherein said hematopoietic cells are hematopoietic progenitor/stem cells (HPSC), CD4+ T lymphocytes, CD8+ T lymphocytes, monocyte/macrophages, or combinations thereof. 4. The method of claim 4, wherein said transplanted HPSC generate granulocytes, monocyte/macrophages, and lymphocytes that are resistant to HIV infection. 5. The method of claim 2, wherein said hematopoietic cells are autologous or allogeneic. 6. The method of claim 2, wherein said first nucleic acid sequence encodes a siRNA or shRNA having a double-stranded region, said double-stranded region comprising a sequence that is substantially identical and complementary to a sequence of CCR5. 7. The method of claim 6, wherein the shRNA has a sequence of SEQ ID NO: 1. 8. The method of claim 6, wherein said transduced hematopoietic cells express reduced levels of CCR5 protein as compared to non-transduced hematopoietic cells. 9. The method of claim 2, wherein said second nucleic acid sequence encodes a C46 protein. 10. (canceled) 11. (canceled) 12. The method of claim 4, wherein said granulocytes, monocyte/macrophages, and lymphocytes are resistant to infection by R5 and X4 tropic strains of HIV. 13. The method of claim 12, wherein said granulocytes, monocyte/macrophages, and lymphocytes are resistant to infection by HAART-resistant HIV strains. 14-17. (canceled) 18. A method of treating or preventing HIV infection in a patient comprising administering a pharmaceutical composition to patient, the pharmaceutical composition comprising (i) an expression vector comprising a first nucleic acid sequence encoding an inhibitor of an HIV co-receptor and a second nucleic acid sequence encoding a protein that inhibits HIV fusion to a target cell or HIV replication; and (ii) a pharmaceutically acceptable carrier. 19. The method of claim 18, wherein the patient is resistant to infection by R5 and X4 tropic strains of HIV following administration of the composition. 20. The method of claim 19, wherein the patient is resistant to infection by HAART-resistant HIV strains following administration of the composition. 21-24. (canceled) 25. A method of treating or preventing HIV infection in a patient comprising:
(i) transducing hematopoietic cells with an expression vector, the expression vector comprising a first nucleic acid sequence encoding a shRNA having a sequence of SEQ ID NO: 1, and a second nucleic acid sequence encoding a C46 protein, and (ii) transplanting said transduced hematopoietic cells in the patient, wherein said transduced hematopoietic cells are resistant to HIV infection. 26. The method of claim 25, wherein said first and second nucleic acid sequences are operably linked to a promoter. 27. The method of claim 25, wherein said hematopoietic cells are hematopoietic progenitor/stem cells (HPSC), CD4+ T lymphocytes, CD8+ T lymphocytes, monocyte/macrophages, or combinations thereof. 28. The method of claim 25, wherein said transplanted HPSC generate granulocytes, monocyte/macrophages, and lymphocytes that are resistant to HIV infection. 29. The method of claim 25, wherein said hematopoietic cells are autologous or allogeneic. 30. The method of claim 28, wherein said granulocytes, monocyte/macrophages, and lymphocytes are resistant to infection by R5 and X4 tropic strains of HIV. 31. The method of claim 28, wherein said granulocytes, monocyte/macrophages, and lymphocytes are resistant to infection by HAART-resistant HIV strains. | The present invention provides an expression vector for preventing or inhibiting HIV entry, fusion or replication in mammalian cells. In particular, the invention provides a recombinant retroviral vector that encodes an inhibitor of a HIV co-receptor, such as CCR5 or CXCR4, and a protein that inhibits HIV fusion to target cells and/or HIV replication. Pharmaceutical compositions comprising such constructs and methods of use thereof to prevent or treat HIV infection in a patient are also disclosed.1. (canceled) 2. A method of treating or preventing HIV infection in a patient comprising (i) transducing hematopoietic cells with an expression vector, the expression vector comprising a first nucleic acid sequence encoding an inhibitor of an HIV co-receptor and a second nucleic acid sequence encoding a protein that inhibits HIV fusion to a target cell or HIV replication, and (ii) transplanting said transduced hematopoietic cells in the patient, wherein said transduced hematopoietic cells are resistant to HIV infection. 3. The method of claim 2, wherein said hematopoietic cells are hematopoietic progenitor/stem cells (HPSC), CD4+ T lymphocytes, CD8+ T lymphocytes, monocyte/macrophages, or combinations thereof. 4. The method of claim 4, wherein said transplanted HPSC generate granulocytes, monocyte/macrophages, and lymphocytes that are resistant to HIV infection. 5. The method of claim 2, wherein said hematopoietic cells are autologous or allogeneic. 6. The method of claim 2, wherein said first nucleic acid sequence encodes a siRNA or shRNA having a double-stranded region, said double-stranded region comprising a sequence that is substantially identical and complementary to a sequence of CCR5. 7. The method of claim 6, wherein the shRNA has a sequence of SEQ ID NO: 1. 8. The method of claim 6, wherein said transduced hematopoietic cells express reduced levels of CCR5 protein as compared to non-transduced hematopoietic cells. 9. The method of claim 2, wherein said second nucleic acid sequence encodes a C46 protein. 10. (canceled) 11. (canceled) 12. The method of claim 4, wherein said granulocytes, monocyte/macrophages, and lymphocytes are resistant to infection by R5 and X4 tropic strains of HIV. 13. The method of claim 12, wherein said granulocytes, monocyte/macrophages, and lymphocytes are resistant to infection by HAART-resistant HIV strains. 14-17. (canceled) 18. A method of treating or preventing HIV infection in a patient comprising administering a pharmaceutical composition to patient, the pharmaceutical composition comprising (i) an expression vector comprising a first nucleic acid sequence encoding an inhibitor of an HIV co-receptor and a second nucleic acid sequence encoding a protein that inhibits HIV fusion to a target cell or HIV replication; and (ii) a pharmaceutically acceptable carrier. 19. The method of claim 18, wherein the patient is resistant to infection by R5 and X4 tropic strains of HIV following administration of the composition. 20. The method of claim 19, wherein the patient is resistant to infection by HAART-resistant HIV strains following administration of the composition. 21-24. (canceled) 25. A method of treating or preventing HIV infection in a patient comprising:
(i) transducing hematopoietic cells with an expression vector, the expression vector comprising a first nucleic acid sequence encoding a shRNA having a sequence of SEQ ID NO: 1, and a second nucleic acid sequence encoding a C46 protein, and (ii) transplanting said transduced hematopoietic cells in the patient, wherein said transduced hematopoietic cells are resistant to HIV infection. 26. The method of claim 25, wherein said first and second nucleic acid sequences are operably linked to a promoter. 27. The method of claim 25, wherein said hematopoietic cells are hematopoietic progenitor/stem cells (HPSC), CD4+ T lymphocytes, CD8+ T lymphocytes, monocyte/macrophages, or combinations thereof. 28. The method of claim 25, wherein said transplanted HPSC generate granulocytes, monocyte/macrophages, and lymphocytes that are resistant to HIV infection. 29. The method of claim 25, wherein said hematopoietic cells are autologous or allogeneic. 30. The method of claim 28, wherein said granulocytes, monocyte/macrophages, and lymphocytes are resistant to infection by R5 and X4 tropic strains of HIV. 31. The method of claim 28, wherein said granulocytes, monocyte/macrophages, and lymphocytes are resistant to infection by HAART-resistant HIV strains. | 1,600 |
795 | 14,906,089 | 1,627 | The invention relates to compounds of formula I or pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels: (I). The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders, including pain. | 1. A compound of formula I
or a pharmaceutically acceptable salt thereof,
wherein, independently for each occurrence:
R1 is H, Cl, CH3, CF3 or cyclopropyl;
R2 is H, F, Cl, CN, CH3, CF3 or CHF2;
R3 is H, F, Cl, CN, CF3, OCF3 or CF2CF3;
R4 is H;
R5 is H, F, Cl, CH3, OCH3, OCH2CH3, OCH2CH2CH3 or OCHF2;
R5′ is H, F, Cl, CH3, OCH3, OCH2CH3, OCH2CH2CH3 or OCHF2;
R6 is H, F or Cl;
R6′ is H, F or Cl; and
R7 is H, F, Cl, OCH3, OCF3, OCH2CH3, OCH(CH3)2 or OCHF2,
provided that R1, R2, and R3 are not simultaneously hydrogen; and
that R5, R5′, R6, R6′, and R7 are not simultaneously hydrogen. 2. The compound or salt according to claim 1, wherein R1 is H, CF3 or Cl. 3. The compound or salt according to claim 1 or 2, wherein R1 is H or CF3. 4. The compound or salt according to any one of claims 1 to 3, wherein R2 is H, CF3 or Cl. 5. The compound or salt according to claim 4, wherein R2 is H or CF3. 6. The compound or salt according to any one of claims 1 to 5, wherein R3 is H, CF3, Cl or OCF3. 7. The compound or salt according to claim 6, wherein R3 is H, CF3 or Cl. 8. The compound or salt according to any one of claims 1 to 7, wherein R5 is H. 9. The compound or salt according to any one of claims 1 to 8, wherein R6 or R6′ is H or F. 10. The compound or salt according to claim any one of claims 1 to 9, wherein R7 is F, Cl, OCH3 or OCF3. 11. The compound or salt according to claim 10, wherein R7 is F or OCH3. 12. The compound or salt according claim 1, wherein the compound has formula I-D:
wherein, independently for each occurrence:
R2 is F, Cl, CN, CH3, CF3 or CHF2;
R5 is F, Cl, CH3, OCH3, OCH2CH3, OCH2CH2CH3 or OCHF2; and
R7 is F, Cl, OCH3, OCF3, OCH2CH3, OCH(CH3)2 or OCHF2. 13. The compound or salt according to claim 12, wherein R2 is Cl or CF3. 14. The compound or salt according to claim 12 or 13, wherein R5 is F, Cl, CH3 or OCH3. 15. The compound or salt according to any one of claims 12 to 14, wherein R7 is F, Cl, OCH3 or OCF3. 16. The compound or salt according to claim 1, wherein the compound has formula I-E:
wherein, independently for each occurrence:
R3 is F, Cl, CN, CF3, OCF3 or CF2CF3;
R5 is F, Cl, CH3, OCH3, OCH2CH3, OCH2CH2CH3 or OCHF2; and
R7 is F, Cl, OCH3, OCF3, OCH2CH3, OCH(CH3)2 or OCHF2. 17. The compound or salt according to claim 16, wherein R3 is Cl, CF3 or OCF3. 18. The compound or salt according to claim 16 or 17, wherein R5 is F, Cl, CH3 or OCH3. 19. The compound or salt according to any one of claims 16 to 18, wherein R7 is F, Cl, OCH3 or OCF3. 20. The compound or salt of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof, is selected from Table 1. 21. A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 20 and one or more pharmaceutically acceptable carriers or vehicles. 22. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 20 or a pharmaceutical composition according to claim 21. 23. The method of claim 22, wherein the voltage-gated sodium channel is Nav1.8. 24. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 20 or a pharmaceutical composition of claim 21. 25. The method of claim 24, wherein the method comprises treating or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain. 26. The method of claim 24, wherein the method comprises treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia; post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia. 27. The method of claim 24, wherein the method comprises treating or lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain. 28. The method of claim 24, wherein the method comprises treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia. 29. The method of claim 24, wherein the method comprises treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain. 30. The method according to any one of claims 22 to 29, wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound, salt, or pharmaceutical composition. | The invention relates to compounds of formula I or pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels: (I). The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders, including pain.1. A compound of formula I
or a pharmaceutically acceptable salt thereof,
wherein, independently for each occurrence:
R1 is H, Cl, CH3, CF3 or cyclopropyl;
R2 is H, F, Cl, CN, CH3, CF3 or CHF2;
R3 is H, F, Cl, CN, CF3, OCF3 or CF2CF3;
R4 is H;
R5 is H, F, Cl, CH3, OCH3, OCH2CH3, OCH2CH2CH3 or OCHF2;
R5′ is H, F, Cl, CH3, OCH3, OCH2CH3, OCH2CH2CH3 or OCHF2;
R6 is H, F or Cl;
R6′ is H, F or Cl; and
R7 is H, F, Cl, OCH3, OCF3, OCH2CH3, OCH(CH3)2 or OCHF2,
provided that R1, R2, and R3 are not simultaneously hydrogen; and
that R5, R5′, R6, R6′, and R7 are not simultaneously hydrogen. 2. The compound or salt according to claim 1, wherein R1 is H, CF3 or Cl. 3. The compound or salt according to claim 1 or 2, wherein R1 is H or CF3. 4. The compound or salt according to any one of claims 1 to 3, wherein R2 is H, CF3 or Cl. 5. The compound or salt according to claim 4, wherein R2 is H or CF3. 6. The compound or salt according to any one of claims 1 to 5, wherein R3 is H, CF3, Cl or OCF3. 7. The compound or salt according to claim 6, wherein R3 is H, CF3 or Cl. 8. The compound or salt according to any one of claims 1 to 7, wherein R5 is H. 9. The compound or salt according to any one of claims 1 to 8, wherein R6 or R6′ is H or F. 10. The compound or salt according to claim any one of claims 1 to 9, wherein R7 is F, Cl, OCH3 or OCF3. 11. The compound or salt according to claim 10, wherein R7 is F or OCH3. 12. The compound or salt according claim 1, wherein the compound has formula I-D:
wherein, independently for each occurrence:
R2 is F, Cl, CN, CH3, CF3 or CHF2;
R5 is F, Cl, CH3, OCH3, OCH2CH3, OCH2CH2CH3 or OCHF2; and
R7 is F, Cl, OCH3, OCF3, OCH2CH3, OCH(CH3)2 or OCHF2. 13. The compound or salt according to claim 12, wherein R2 is Cl or CF3. 14. The compound or salt according to claim 12 or 13, wherein R5 is F, Cl, CH3 or OCH3. 15. The compound or salt according to any one of claims 12 to 14, wherein R7 is F, Cl, OCH3 or OCF3. 16. The compound or salt according to claim 1, wherein the compound has formula I-E:
wherein, independently for each occurrence:
R3 is F, Cl, CN, CF3, OCF3 or CF2CF3;
R5 is F, Cl, CH3, OCH3, OCH2CH3, OCH2CH2CH3 or OCHF2; and
R7 is F, Cl, OCH3, OCF3, OCH2CH3, OCH(CH3)2 or OCHF2. 17. The compound or salt according to claim 16, wherein R3 is Cl, CF3 or OCF3. 18. The compound or salt according to claim 16 or 17, wherein R5 is F, Cl, CH3 or OCH3. 19. The compound or salt according to any one of claims 16 to 18, wherein R7 is F, Cl, OCH3 or OCF3. 20. The compound or salt of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof, is selected from Table 1. 21. A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 20 and one or more pharmaceutically acceptable carriers or vehicles. 22. A method of inhibiting a voltage-gated sodium channel in a subject comprising administering to the subject a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 20 or a pharmaceutical composition according to claim 21. 23. The method of claim 22, wherein the voltage-gated sodium channel is Nav1.8. 24. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence or cardiac arrhythmia comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof of any one of claims 1 to 20 or a pharmaceutical composition of claim 21. 25. The method of claim 24, wherein the method comprises treating or lessening the severity in a subject of gut pain, wherein gut pain comprises inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain. 26. The method of claim 24, wherein the method comprises treating or lessening the severity in a subject of neuropathic pain, wherein neuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuroma; traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury, brachial plexus avulsion injury; complex regional pain syndrome, drug therapy induced neuralgia, cancer chemotherapy induced neuralgia, anti-retroviral therapy induced neuralgia; post spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy or trigeminal autonomic cephalalgia. 27. The method of claim 24, wherein the method comprises treating or lessening the severity in a subject of musculoskeletal pain, wherein musculoskeletal pain comprises osteoarthritis pain, back pain, cold pain, burn pain or dental pain. 28. The method of claim 24, wherein the method comprises treating or lessening the severity in a subject of inflammatory pain, wherein inflammatory pain comprises rheumatoid arthritis pain or vulvodynia. 29. The method of claim 24, wherein the method comprises treating or lessening the severity in a subject of idiopathic pain, wherein idiopathic pain comprises fibromyalgia pain. 30. The method according to any one of claims 22 to 29, wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound, salt, or pharmaceutical composition. | 1,600 |
796 | 14,986,904 | 1,619 | In some aspects, the present disclosure pertains to tissue bulking compositions that comprise: (a) solid particles comprising a pH-sensitive polymer that has a pH-dependent solubility such that the solid particles dissolve upon an increase or decrease in pH, (b) a crosslinking agent for the pH-sensitive polymer and (c) a pH modifying agent that generates acid or base in vivo, wherein when the tissue bulking composition comprises solid particles that dissolve upon a decrease in pH, the pH modifying agent generates acid in vivo and wherein when the tissue bulking composition comprises solid particles that dissolve upon an increase in pH, the pH modifying agent generates base in vivo. Other aspects of the present disclosure pertain to kits that comprise such compositions, to methods of forming injectable dispersions that comprise such compositions and to methods of treatment comprising injecting injectable dispersions that comprise such compositions into a subject. | 1. A tissue bulking composition comprising: (a) solid particles comprising a pH-sensitive polymer that has a pH-dependent solubility such that the solid particles dissolve upon an increase or decrease in pH, (b) a crosslinking agent for the pH-sensitive polymer and (c) a pH modifying agent that generates acid or base in vivo, wherein when the tissue bulking composition comprises solid particles that dissolve upon a decrease in pH, the pH modifying agent generates acid in vivo and wherein when the tissue bulking composition comprises solid particles that dissolve upon an increase in pH, the pH modifying agent generates base in vivo. 2. The tissue bulking composition of claim 1, wherein the solid particles are less than 100 microns (μm) in size. 3. The tissue bulking composition of claim 1, wherein the tissue bulking composition is in the form of a dry powder or wherein the tissue bulking composition is an injectable dispersion that further comprises an aqueous or non-aqueous liquid. 4. The tissue bulking composition of claim 1, wherein the solid particles comprise a pH-sensitive polymer that dissolves upon a decrease in pH. 5. The tissue bulking composition of claim 4, wherein the pH-sensitive polymer comprises amine groups. 6. The tissue bulking composition of claim 4, wherein the pH-sensitive polymer is a polysaccharide that comprises amine groups. 7. The tissue bulking composition of claim 4, wherein the pH-sensitive polymer is chitosan. 8. The tissue bulking composition of claim 4, wherein the pH modifying agent is a polyester or a cyclic ester. 9. The tissue bulking composition of claim 8, wherein the pH modifying agent is a cyclic ester which produces a hydroxyacid upon hydrolysis or which produces a diol and a dicarboxylic acid upon hydrolysis. 10. The tissue bulking composition of claim 5, wherein the crosslinking agent is an agent that crosslinks amine groups. 11. The tissue bulking composition of claim 5, wherein the crosslinking agent is genipin. 12. The tissue bulking composition of claim 1, wherein the solid particles comprise a pH-sensitive polymer that dissolves upon an increase in pH. 13. The tissue bulking composition of claim 1, further comprising inorganic filler particles. 14. A method comprising injecting an injectable dispersion into a subject, the injectable dispersion comprising: (a) solid particles comprising a pH-sensitive polymer that has a pH-dependent solubility such that the solid particles dissolve upon an increase or decrease in pH, (b) a crosslinking agent adapted to crosslink the pH-sensitive polymer upon dissolution and (c) a pH modifying agent that generates acid or base in vivo, wherein when the injectable dispersion comprises solid particles that dissolve upon a decrease in pH, the pH modifying agent generates acid in vivo and wherein when the injectable dispersion comprises solid particles that dissolve upon an increase in pH, the pH modifying agent generates base in vivo. 15. The method of claim 14, comprising admixing a powder comprising the solid particles, the pH modifying agent and the crosslinking agent with a liquid vehicle to form the injectable dispersion. 16. The method of claim 14, wherein the injectable dispersion is delivered via a catheter. 17. The method of claim 14, wherein the method comprises injecting the injectable dispersion into a ventricular wall of a heart. 18. A kit comprising: (a) tissue bulking composition comprising: (i) solid particles comprising a pH-sensitive polymer that has a pH-dependent solubility such that the solid particles dissolve upon an increase or decrease in pH, (ii) a crosslinking agent for the pH-sensitive polymer and (iii) a pH modifying agent that generates acid or base in vivo, wherein when the tissue bulking composition comprises solid particles that dissolve upon a decrease in pH, the pH modifying agent generates acid in vivo and wherein when the tissue bulking composition comprises solid particles that dissolve upon an increase in pH, the pH modifying agent generates base in vivo and (b) an injection device configured to inject an injectable dispersion comprising the tissue bulking composition into a subject. 19. The kit of claim 18, wherein the injection device is a needle injection catheter. 20. The kit of claim 18, wherein the tissue bulking composition is in the form of a dry powder that is disposed in a container having a needle-penetrable septum. | In some aspects, the present disclosure pertains to tissue bulking compositions that comprise: (a) solid particles comprising a pH-sensitive polymer that has a pH-dependent solubility such that the solid particles dissolve upon an increase or decrease in pH, (b) a crosslinking agent for the pH-sensitive polymer and (c) a pH modifying agent that generates acid or base in vivo, wherein when the tissue bulking composition comprises solid particles that dissolve upon a decrease in pH, the pH modifying agent generates acid in vivo and wherein when the tissue bulking composition comprises solid particles that dissolve upon an increase in pH, the pH modifying agent generates base in vivo. Other aspects of the present disclosure pertain to kits that comprise such compositions, to methods of forming injectable dispersions that comprise such compositions and to methods of treatment comprising injecting injectable dispersions that comprise such compositions into a subject.1. A tissue bulking composition comprising: (a) solid particles comprising a pH-sensitive polymer that has a pH-dependent solubility such that the solid particles dissolve upon an increase or decrease in pH, (b) a crosslinking agent for the pH-sensitive polymer and (c) a pH modifying agent that generates acid or base in vivo, wherein when the tissue bulking composition comprises solid particles that dissolve upon a decrease in pH, the pH modifying agent generates acid in vivo and wherein when the tissue bulking composition comprises solid particles that dissolve upon an increase in pH, the pH modifying agent generates base in vivo. 2. The tissue bulking composition of claim 1, wherein the solid particles are less than 100 microns (μm) in size. 3. The tissue bulking composition of claim 1, wherein the tissue bulking composition is in the form of a dry powder or wherein the tissue bulking composition is an injectable dispersion that further comprises an aqueous or non-aqueous liquid. 4. The tissue bulking composition of claim 1, wherein the solid particles comprise a pH-sensitive polymer that dissolves upon a decrease in pH. 5. The tissue bulking composition of claim 4, wherein the pH-sensitive polymer comprises amine groups. 6. The tissue bulking composition of claim 4, wherein the pH-sensitive polymer is a polysaccharide that comprises amine groups. 7. The tissue bulking composition of claim 4, wherein the pH-sensitive polymer is chitosan. 8. The tissue bulking composition of claim 4, wherein the pH modifying agent is a polyester or a cyclic ester. 9. The tissue bulking composition of claim 8, wherein the pH modifying agent is a cyclic ester which produces a hydroxyacid upon hydrolysis or which produces a diol and a dicarboxylic acid upon hydrolysis. 10. The tissue bulking composition of claim 5, wherein the crosslinking agent is an agent that crosslinks amine groups. 11. The tissue bulking composition of claim 5, wherein the crosslinking agent is genipin. 12. The tissue bulking composition of claim 1, wherein the solid particles comprise a pH-sensitive polymer that dissolves upon an increase in pH. 13. The tissue bulking composition of claim 1, further comprising inorganic filler particles. 14. A method comprising injecting an injectable dispersion into a subject, the injectable dispersion comprising: (a) solid particles comprising a pH-sensitive polymer that has a pH-dependent solubility such that the solid particles dissolve upon an increase or decrease in pH, (b) a crosslinking agent adapted to crosslink the pH-sensitive polymer upon dissolution and (c) a pH modifying agent that generates acid or base in vivo, wherein when the injectable dispersion comprises solid particles that dissolve upon a decrease in pH, the pH modifying agent generates acid in vivo and wherein when the injectable dispersion comprises solid particles that dissolve upon an increase in pH, the pH modifying agent generates base in vivo. 15. The method of claim 14, comprising admixing a powder comprising the solid particles, the pH modifying agent and the crosslinking agent with a liquid vehicle to form the injectable dispersion. 16. The method of claim 14, wherein the injectable dispersion is delivered via a catheter. 17. The method of claim 14, wherein the method comprises injecting the injectable dispersion into a ventricular wall of a heart. 18. A kit comprising: (a) tissue bulking composition comprising: (i) solid particles comprising a pH-sensitive polymer that has a pH-dependent solubility such that the solid particles dissolve upon an increase or decrease in pH, (ii) a crosslinking agent for the pH-sensitive polymer and (iii) a pH modifying agent that generates acid or base in vivo, wherein when the tissue bulking composition comprises solid particles that dissolve upon a decrease in pH, the pH modifying agent generates acid in vivo and wherein when the tissue bulking composition comprises solid particles that dissolve upon an increase in pH, the pH modifying agent generates base in vivo and (b) an injection device configured to inject an injectable dispersion comprising the tissue bulking composition into a subject. 19. The kit of claim 18, wherein the injection device is a needle injection catheter. 20. The kit of claim 18, wherein the tissue bulking composition is in the form of a dry powder that is disposed in a container having a needle-penetrable septum. | 1,600 |
797 | 10,876,998 | 1,632 | Cells derived from postpartum tissue and methods for their isolation and induction to differentiate to cells of a chondrogenic or osteogenic phenotype are provided by the invention. The invention further provides cultures and compositions of the postpartum-derived cells and products related thereto. The postpartum-derived cells of the invention and products related thereto have a plethora of uses, including but not limited to research, diagnostic, and therapeutic applications, for example, in the treatment of bone and cartilage conditions. | 1. A postpartum-derived cell comprising a cell derived from human postpartum tissue substantially free of blood, wherein said cell is capable of self-renewal and expansion in culture and has the potential to differentiate into a cell of an osteogenic or chondrogenic phenotype; wherein said cell requires L-valine for growth; wherein said cell is capable of growth in about 5% to about 20% oxygen; wherein said cell further comprises at least one of the following characteristics:
(a) production of at least one of granulocyte chemotactic protein 2 (GCP-2), reticulon 1, tissue factor, vimentin, and alpha-smooth muscle actin; (b) lack of production of at least one of GRO-alpha or oxidized low density lipoprotein receptor, as detected by flow cytometry; (c) production of at least one of CD10, CD13, CD44, CD73, CD90, PDGFr-alpha, PD-L2 and HLA-A,B,C; (d) lack of production of at least one of CD31, CD34, CD45, CD80, CD86, CD117, CD141, CD178, B7-H2, HLA-G, and HLA-DR,DP,DQ, as detected by flow cytometry; (e) expression, which relative to a human cell that is a fibroblast, a mesenchymal stem cell, or an ileac crest bone marrow cell, is increased for at least one of interleukin 8; reticulon 1; chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha); chemokine (C-X-C motif) ligand 6 (granulocyte chemotactic protein 2); chemokine (C-X-C motif) ligand 3; and tumor necrosis factor, alpha-induced protein 3 or expression, which relative to a human cell that is a fibroblast, a mesenchymal stem cell, or an ileac crest bone marrow cell, is increased for at least one of C-type lectin superfamily member A2, Wilms tumor 1, aldehyde dehydrogenase 1 family member A2, renin, oxidized low density lipoprotein receptor 1, protein kinase C zeta, clone IMAGE:4179671, hypothetical protein DKFZp564F013, downregulated in ovarian cancer 1, and clone DKFZp547K1113; (f) expression, which relative to a human cell that is a fibroblast, a mesenchymal stem cell, or an ileac crest bone marrow cell, is reduced for at least one of: short stature homeobox 2; heat shock 27 kDa protein 2; chemokine (C-X-C motif) ligand 12 (stromal cell-derived factor 1); elastin; cDNA DKFZp586M2022 (from clone DKFZp586M2022); mesenchyme homeobox 2; sine oculis homeobox homolog 1; crystallin, alpha B; dishevelled associated activator of morphogenesis 2; DKFZP586B2420 protein; similar to neuralin 1; tetranectin; src homology three (SH3) and cysteine rich domain; B-cell translocation gene 1, anti-proliferative; cholesterol 25-hydroxylase; runt-related transcription factor 3; hypothetical protein FLJ23191; interleukin 11 receptor, alpha; procollagen C-endopeptidase enhancer; frizzled homolog 7; hypothetical gene BC008967; collagen, type VIII, alpha 1; tenascin C; iroquois homeobox protein 5; hephaestin; integrin, beta 8; synaptic vesicle glycoprotein 2; cDNA FLJ12280 fis, clone MAMMA1001744; cytokine receptor-like factor 1; potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4; integrin, alpha 7; DKFZP586L151 protein; transcriptional co-activator with PDZ-binding motif (TAZ); sine oculis homeobox homolog 2; KIAA1034 protein; early growth response 3; distal-less homeobox 5; hypothetical protein FLJ20373; aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II); biglycan; fibronectin 1; proenkephalin; integrin, beta-like 1 (with EGF-like repeat domains); cDNA clone EUROIMAGE 1968422; EphA3; KIAA0367 protein; natriuretic peptide receptor C/guanylate cyclase C (atrionatriuretic peptide receptor C); hypothetical protein FLJ14054; cDNA DKFZp564B222 (from clone DKFZp564B222); vesicle-associated membrane protein 5; EGF-containing fibulin-like extracellular matrix protein 1; BCL2/adenovirus E1B 19 kDa interacting protein 3-like; AE binding protein 1; cytochrome c oxidase subunit VIIa polypeptide 1 (muscle); neuroblastoma, suppression of tumorigenicity 1; and insulin-like growth factor binding protein 2, 36 kDa; (g) secretion of at least one of monocyte chemotactic protein-1, interleukin (IL)-6, IL-8, granulocyte chemotactic protein-2, hepatocyte growth factor, keratinocyte growth factor, fibroblast growth factor, heparin binding-epidermal growth factor, brain derived neurotrophic factor, thrombopoietin, macrophage inflammatory protein (MIP)-1a, RANTES, and tissue inhibitor of matrix metalloprotease 1; (h) lack of secretion of at least one of transforming growth factor-beta2, angiopoetin-2, platelet derived growth factor-bb, MIP1b, 1309, macrophage-derived chemokine, and vascular endothelial growth factor, as detected by ELISA; and (i) the ability to undergo at least 40 population doublings in culture. 2. The cell of claim 1 which has been isolated from a post-partum placenta or fragment thereof by enzymatic dissociation with at least one of a matrix metalloprotease, a neutral protease, and a mucolytic enzyme that digests hyaluronic acid. 3. A method of inducing differentiation of a postpartum-derived cell of claim 1 to a chondrogenic phenotype comprising exposing said cell to one or more chondrogenic differentiation-inducing agents. 4. The method of claim 3 wherein said chondrogenic differentiation-inducing agent comprises at least one of transforming growth factor-beta3 (TGFbeta3) and growth and differentiation factor-5 (GDF-5). 5. The method of claim 3 further comprising culturing the cell in chondrogenic medium. 6. The method of claim 5 wherein said chondrogenic medium comprises Dulbecco's modified Eagle's medium, L-glutamine, sodium pyruvate, L-proline, dexamethasone, L-ascorbic acid, insulin, transferrin, selenium, and an antibiotic agent. 7. The method of claim 6 wherein said chondrogenic medium further comprises at least one of collagen and sodium hydroxide. 8. The method of claim 3 further comprising evaluating differentiation of said cell by a pellet culture assay. 9. The method of claim 3 further comprising evaluating differentiation of said cell by detecting the presence of a glycosaminoglycan or collagen. 10. The method of claim 9 wherein said step of evaluating comprises staining said cell with Safranin-O or hematoxylin/eosin. 11. The cell produced by the method of claim 3. 12. A method of inducing differentiation of a postpartum-derived cell of claim 1 to an osteogenic phenotype comprising exposing said cell to one or more osteogenic differentiation-inducing agents. 13. The method of claim 12 wherein said differentiation-inducing agent comprises at least one of bone morphogenic protein (BMP)-2, BMP-4, and transforming growth factor-beta1. 14. The method of claim 12 further comprising culturing said cell in osteogenic medium. 15. The method of claim 14 wherein said osteogenic medium comprises Dulbecco's modified Eagle's medium-low glucose, serum, beta-glycerophosphate, dexamethasone, ascorbic phosphate salt, and at least one antibiotic or antimycotic agent. 16. The method of claim 12 further comprising evaluating said differentiation by detecting an osteogenic lineage-specific marker. 17. The method of claim 16 wherein said marker is osteocalcin, bone sialoprotein, or alkaline phosphatase. 18. The method of claim 12 further comprising detecting said differentiation by measuring mineralization. 19. The method of claim 18 wherein said step of detecting comprises von Kossa staining. 20. The cell produced according to the method of claim 12. 21. A cell population comprising the postpartum-derived cell of claim 1. 22. The cell population of claim 21 wherein said cell population is substantially homogeneous. 23. The cell population of claim 21 wherein said cell population is heterogeneous. 24. The cell population of claim 23 further comprising at least one cell type of bone marrow cells, chondrocytes, chondroblasts, chondrocyte progenitor cells, or stem cells. 25. A cell population comprising the postpartum-derived cell of claim 12. 26. The cell population of claim 25 wherein said cell population is substantially homogeneous. 27. The cell population of claim 25 wherein said cell population is heterogeneous. 28. The cell population of claim 27 further comprising at least one cell type of bone marrow cells, chondrocytes, chondroblasts, chondrocyte progenitor cells, stem cells, or other pluripotent or multipotent cell. 29. A cell population comprising the postpartum-derived cell of claim 20. 30. The cell population of claim 29 wherein said cell population is substantially homogeneous. 31. The cell population of claim 29 wherein said cell population is heterogeneous. 32. The cell population of claim 31 further comprising at least one cell type of bone marrow cells, osteocytes, osteoblasts, osteoclasts, bone lining cells, stem cells or other pluripotent or multipotent cell. 33. A cell lysate prepared from the cell population of claim 21. 34. A soluble cell fraction prepared from the cell lysate of claim 33. 35. A cell lysate prepared from the cell population of claim 25. 36. A soluble cell fraction prepared from the cell lysate of claim 35. 37. A cell lysate prepared from the cell population of claim 29. 38. A soluble cell fraction prepared from the cell lysate of claim 37. 39. An extracellular matrix of the cell population of claim 21. 40. An extracellular matrix of the cell population of claim 25. 41. An extracellular matrix of the cell population of claim 29. 42. A composition comprising the cell population of claim 21 and one or more bioactive factors. 43. A composition comprising the cell population of claim 25 and one or more bioactive factors. 44. A composition comprising the cell population of claim 29 and one or more bioactive factors. 45. The composition of claim 42 wherein said bioactive factor is a chondrogenic differentiation-inducing factor. 46. The composition of claim 42 wherein said bioactive factor is an osteogenic differentiation-inducing factor. 47. A pharmaceutical composition comprising a cell of claim 1 and a pharmaceutically acceptable carrier. 48. A pharmaceutical composition comprising a cell of claim 11 and a pharmaceutically acceptable carrier. 49. A pharmaceutical composition comprising a cell of claim 20 and a pharmaceutically acceptable carrier. 50. A pharmaceutical composition comprising the extracellular matrix of claim 39 and a pharmaceutically acceptable carrier. 51. A pharmaceutical composition comprising the extracellular matrix of claim 40 and a pharmaceutically acceptable carrier. 52. A pharmaceutical composition comprising the extracellular matrix of claim 41 and a pharmaceutically acceptable carrier. 53. A pharmaceutical composition comprising the lysate of claim 33 and a pharmaceutically acceptable carrier. 54. A pharmaceutical composition comprising the lysate of claim 35 and a pharmaceutically acceptable carrier. 55. A pharmaceutical composition comprising the lysate of claim 37 and a pharmaceutically acceptable carrier. 56. A cell culture comprising at least one cell of claim 1 in a culture medium. 57. The cell culture of claim 56 wherein said culture medium comprises chondrogenic medium or osteogenic medium. 58. The cell culture of claim 56 further comprising at least one chondrogenic differentiation-inducing agent. 59. The cell culture of claim 58 wherein said chondrogenic differentiation-inducing agent is at least one of transforming growth factor-beta3 or growth and differentiation factor-5. 60. The cell culture of claim 56 further comprising at least one osteogenic differentiation-inducing agent. 61. The cell culture of claim 60 wherein said osteogenic differentiation-inducing agent is at least one of transforming growth factor-beta 1, bone morphogenic protein (BMP)-2, or BMP4. 62. A matrix comprising a cell population of claim 21. 63. A matrix comprising a cell population of claim 25. 64. A matrix comprising a cell population of claim 29. 65. The matrix of claim 62 wherein said matrix comprises a three-dimensional scaffold. 66. The matrix of claim 63 wherein said matrix comprises a three-dimensional scaffold. 67. The matrix of claim 64 wherein said matrix comprises a three-dimensional scaffold. 68. A method of treating a condition in a patient comprising administering to said patient one or more postpartum-derived cells of claim 1. 69. The method of claim 68 wherein said condition is a bone or cartilage condition. 70. The method of claim 69 wherein said bone or cartilage condition is a congenital bone or cartilage defect, meniscal injury or defect, bone/spinal deformation, osteosarcoma, myeloma, bone dysplasia or scoliosis, osteoporosis, periodontal disease, dental bone loss, osteomalacia, rickets, fibrous osteitis, renal bone dystrophy, spinal fusion, spinal disc reconstruction or removal, Paget's disease of bone, rheumatoid arthritis, osteoarthritis, or a traumatic or surgical injury. 71. The method of claim 68 wherein said postpartum-derived cells are administered with at least one other cell type. 72. The method of claim 71 wherein said at least one other cell type is bone marrow cells, chondrocytes, chondroblasts, chondrocyte progenitor cells, osteocytes, osteoblasts, osteoclasts, bone lining cells, stem cells, or other pluripotent or multipotent cell. 73. The method of claim 68 wherein said postpartum-derived cells are inoculated on a matrix. 74. The method of claim 73 wherein said matrix is implanted into said patient. 75. The method of claim 68 wherein said postpartum-derived cells are induced to differentiate to a chondrogenic or osteogenic phenotype prior to said step of administering. 76. The method of claim 68 wherein said postpartum-derived cells are co-administered with at least one bioactive factor. 77. The method of claim 68 wherein said cells are administered to a bone of said patient. 78. The method of claim 68 wherein said cells are administered to cartilage of said patient. 79. A method of regenerating a tissue in a patient in need thereof comprising administering the cell population of claim 21 to said patient. 80. The method of claim 79 wherein said tissue is bone or cartilage. 81. A method of regenerating a tissue in a patient in need thereof comprising administering the cell population of claim 25 to said patient. 82. The method of claim 81 wherein said tissue is bone or cartilage. 83. A method of regenerating a tissue in a patient in need thereof comprising administering the cell population of claim 29 to said patient. 84. The method of claim 83 wherein said tissue is bone or cartilage. 85. The method of claim 68 wherein said cells are implanted into said patient. 86. A conditioned medium generated by the growth of the culture of claim 56. 87. A method for identifying a compound that stimulates chondrogenesis of a postpartum-derived cell comprising contacting a cell of claim 1 with said compound and monitoring said cell for a marker of chondrogenesis. 88. A method for identifying a compound that stimulates osteogenesis of a postpartum-derived cell comprising contacting a cell of claim 1 with said compound and monitoring said cell for a marker of osteogenesis. 89. A method for identifying a compound that is toxic to a postpartum-derived cell of claim 1 comprising contacting said cell with said compound and monitoring survival of said cell. 90. A kit comprising at least one cell of claim 1 and at least one additional component of a matrix, a hydrating agent, a cell culture substrate, a differentiation-inducing agent, and cell culture media. 91. The kit of claim 90 wherein said matrix is a three-dimensional scaffold. 92. The kit of claim 91 wherein said cell is seeded on said scaffold. 93. The kit of claim 90 wherein said differentiation-inducing agent is an osteogenic differentiation-inducing agent or a chondrogenic differentiation-inducing agent. 94. A method of treating a patient having a bone or cartilage condition comprising administering to said patient the extracellular matrix of a cell of claim 1. 95. A method of treating a patient having a bone or cartilage condition comprising administering to said patient the cell lysate of claim 33. 96. A method of treating a patient having a bone or cartilage condition comprising administering to said patient the conditioned medium of claim 86. 97. The pharmaceutical composition of claim 47 wherein said composition comprises an effective amount of said cells to treat a bone or cartilage condition. 98. The pharmaceutical composition of claim 48 wherein said composition comprises an effective amount of said cells to treat a bone or cartilage condition. 99. The pharmaceutical composition of claim 49 wherein said composition comprises an effective amount of said cells to treat a bone or cartilage condition. 100. The pharmaceutical composition of claim 50 wherein said composition comprises an effective amount of said extracellular matrix to treat a bone or cartilage condition. 101. The pharmaceutical composition of claim 51 wherein said composition comprises an effective amount of said extracellular matrix to treat a bone or cartilage condition. 102. The pharmaceutical composition of claim 52 wherein said composition comprises an effective amount of said extracellular matrix to treat a bone or cartilage condition. 103. The pharmaceutical composition of claim 53 wherein said composition comprises an effective amount of said lysate to treat a bone or cartilage condition. 104. The pharmaceutical composition of claim 54 wherein said composition comprises an effective amount of said lysate to treat a bone or cartilage condition. 105. The pharmaceutical composition of claim 55 wherein said composition comprises an effective amount of said lysate to treat a bone or cartilage condition. 106. The pharmaceutical composition of claim 47 further comprising at least one other cell type of stem cells, bone marrow cells, chondrocytes, chondroblasts, osteocytes, osteoblasts, osteoclasts, bone lining cells, and other bone or cartilage progenitor cells. 107. The pharmaceutical composition of claim 48 further comprising at least one other cell type of stem cells, bone marrow cells, chondrocytes, chondroblasts, osteocytes, osteoblasts, osteoclasts, bone lining cells, and other bone or cartilage progenitor cells. 108. The pharmaceutical composition of claim 49 further comprising at least one other cell type of stem cells, bone marrow cells, chondrocytes, chondroblasts, osteocytes, osteoblasts, osteoclasts, bone lining cells, and other bone or cartilage progenitor cells. | Cells derived from postpartum tissue and methods for their isolation and induction to differentiate to cells of a chondrogenic or osteogenic phenotype are provided by the invention. The invention further provides cultures and compositions of the postpartum-derived cells and products related thereto. The postpartum-derived cells of the invention and products related thereto have a plethora of uses, including but not limited to research, diagnostic, and therapeutic applications, for example, in the treatment of bone and cartilage conditions.1. A postpartum-derived cell comprising a cell derived from human postpartum tissue substantially free of blood, wherein said cell is capable of self-renewal and expansion in culture and has the potential to differentiate into a cell of an osteogenic or chondrogenic phenotype; wherein said cell requires L-valine for growth; wherein said cell is capable of growth in about 5% to about 20% oxygen; wherein said cell further comprises at least one of the following characteristics:
(a) production of at least one of granulocyte chemotactic protein 2 (GCP-2), reticulon 1, tissue factor, vimentin, and alpha-smooth muscle actin; (b) lack of production of at least one of GRO-alpha or oxidized low density lipoprotein receptor, as detected by flow cytometry; (c) production of at least one of CD10, CD13, CD44, CD73, CD90, PDGFr-alpha, PD-L2 and HLA-A,B,C; (d) lack of production of at least one of CD31, CD34, CD45, CD80, CD86, CD117, CD141, CD178, B7-H2, HLA-G, and HLA-DR,DP,DQ, as detected by flow cytometry; (e) expression, which relative to a human cell that is a fibroblast, a mesenchymal stem cell, or an ileac crest bone marrow cell, is increased for at least one of interleukin 8; reticulon 1; chemokine (C-X-C motif) ligand 1 (melanoma growth stimulating activity, alpha); chemokine (C-X-C motif) ligand 6 (granulocyte chemotactic protein 2); chemokine (C-X-C motif) ligand 3; and tumor necrosis factor, alpha-induced protein 3 or expression, which relative to a human cell that is a fibroblast, a mesenchymal stem cell, or an ileac crest bone marrow cell, is increased for at least one of C-type lectin superfamily member A2, Wilms tumor 1, aldehyde dehydrogenase 1 family member A2, renin, oxidized low density lipoprotein receptor 1, protein kinase C zeta, clone IMAGE:4179671, hypothetical protein DKFZp564F013, downregulated in ovarian cancer 1, and clone DKFZp547K1113; (f) expression, which relative to a human cell that is a fibroblast, a mesenchymal stem cell, or an ileac crest bone marrow cell, is reduced for at least one of: short stature homeobox 2; heat shock 27 kDa protein 2; chemokine (C-X-C motif) ligand 12 (stromal cell-derived factor 1); elastin; cDNA DKFZp586M2022 (from clone DKFZp586M2022); mesenchyme homeobox 2; sine oculis homeobox homolog 1; crystallin, alpha B; dishevelled associated activator of morphogenesis 2; DKFZP586B2420 protein; similar to neuralin 1; tetranectin; src homology three (SH3) and cysteine rich domain; B-cell translocation gene 1, anti-proliferative; cholesterol 25-hydroxylase; runt-related transcription factor 3; hypothetical protein FLJ23191; interleukin 11 receptor, alpha; procollagen C-endopeptidase enhancer; frizzled homolog 7; hypothetical gene BC008967; collagen, type VIII, alpha 1; tenascin C; iroquois homeobox protein 5; hephaestin; integrin, beta 8; synaptic vesicle glycoprotein 2; cDNA FLJ12280 fis, clone MAMMA1001744; cytokine receptor-like factor 1; potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4; integrin, alpha 7; DKFZP586L151 protein; transcriptional co-activator with PDZ-binding motif (TAZ); sine oculis homeobox homolog 2; KIAA1034 protein; early growth response 3; distal-less homeobox 5; hypothetical protein FLJ20373; aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II); biglycan; fibronectin 1; proenkephalin; integrin, beta-like 1 (with EGF-like repeat domains); cDNA clone EUROIMAGE 1968422; EphA3; KIAA0367 protein; natriuretic peptide receptor C/guanylate cyclase C (atrionatriuretic peptide receptor C); hypothetical protein FLJ14054; cDNA DKFZp564B222 (from clone DKFZp564B222); vesicle-associated membrane protein 5; EGF-containing fibulin-like extracellular matrix protein 1; BCL2/adenovirus E1B 19 kDa interacting protein 3-like; AE binding protein 1; cytochrome c oxidase subunit VIIa polypeptide 1 (muscle); neuroblastoma, suppression of tumorigenicity 1; and insulin-like growth factor binding protein 2, 36 kDa; (g) secretion of at least one of monocyte chemotactic protein-1, interleukin (IL)-6, IL-8, granulocyte chemotactic protein-2, hepatocyte growth factor, keratinocyte growth factor, fibroblast growth factor, heparin binding-epidermal growth factor, brain derived neurotrophic factor, thrombopoietin, macrophage inflammatory protein (MIP)-1a, RANTES, and tissue inhibitor of matrix metalloprotease 1; (h) lack of secretion of at least one of transforming growth factor-beta2, angiopoetin-2, platelet derived growth factor-bb, MIP1b, 1309, macrophage-derived chemokine, and vascular endothelial growth factor, as detected by ELISA; and (i) the ability to undergo at least 40 population doublings in culture. 2. The cell of claim 1 which has been isolated from a post-partum placenta or fragment thereof by enzymatic dissociation with at least one of a matrix metalloprotease, a neutral protease, and a mucolytic enzyme that digests hyaluronic acid. 3. A method of inducing differentiation of a postpartum-derived cell of claim 1 to a chondrogenic phenotype comprising exposing said cell to one or more chondrogenic differentiation-inducing agents. 4. The method of claim 3 wherein said chondrogenic differentiation-inducing agent comprises at least one of transforming growth factor-beta3 (TGFbeta3) and growth and differentiation factor-5 (GDF-5). 5. The method of claim 3 further comprising culturing the cell in chondrogenic medium. 6. The method of claim 5 wherein said chondrogenic medium comprises Dulbecco's modified Eagle's medium, L-glutamine, sodium pyruvate, L-proline, dexamethasone, L-ascorbic acid, insulin, transferrin, selenium, and an antibiotic agent. 7. The method of claim 6 wherein said chondrogenic medium further comprises at least one of collagen and sodium hydroxide. 8. The method of claim 3 further comprising evaluating differentiation of said cell by a pellet culture assay. 9. The method of claim 3 further comprising evaluating differentiation of said cell by detecting the presence of a glycosaminoglycan or collagen. 10. The method of claim 9 wherein said step of evaluating comprises staining said cell with Safranin-O or hematoxylin/eosin. 11. The cell produced by the method of claim 3. 12. A method of inducing differentiation of a postpartum-derived cell of claim 1 to an osteogenic phenotype comprising exposing said cell to one or more osteogenic differentiation-inducing agents. 13. The method of claim 12 wherein said differentiation-inducing agent comprises at least one of bone morphogenic protein (BMP)-2, BMP-4, and transforming growth factor-beta1. 14. The method of claim 12 further comprising culturing said cell in osteogenic medium. 15. The method of claim 14 wherein said osteogenic medium comprises Dulbecco's modified Eagle's medium-low glucose, serum, beta-glycerophosphate, dexamethasone, ascorbic phosphate salt, and at least one antibiotic or antimycotic agent. 16. The method of claim 12 further comprising evaluating said differentiation by detecting an osteogenic lineage-specific marker. 17. The method of claim 16 wherein said marker is osteocalcin, bone sialoprotein, or alkaline phosphatase. 18. The method of claim 12 further comprising detecting said differentiation by measuring mineralization. 19. The method of claim 18 wherein said step of detecting comprises von Kossa staining. 20. The cell produced according to the method of claim 12. 21. A cell population comprising the postpartum-derived cell of claim 1. 22. The cell population of claim 21 wherein said cell population is substantially homogeneous. 23. The cell population of claim 21 wherein said cell population is heterogeneous. 24. The cell population of claim 23 further comprising at least one cell type of bone marrow cells, chondrocytes, chondroblasts, chondrocyte progenitor cells, or stem cells. 25. A cell population comprising the postpartum-derived cell of claim 12. 26. The cell population of claim 25 wherein said cell population is substantially homogeneous. 27. The cell population of claim 25 wherein said cell population is heterogeneous. 28. The cell population of claim 27 further comprising at least one cell type of bone marrow cells, chondrocytes, chondroblasts, chondrocyte progenitor cells, stem cells, or other pluripotent or multipotent cell. 29. A cell population comprising the postpartum-derived cell of claim 20. 30. The cell population of claim 29 wherein said cell population is substantially homogeneous. 31. The cell population of claim 29 wherein said cell population is heterogeneous. 32. The cell population of claim 31 further comprising at least one cell type of bone marrow cells, osteocytes, osteoblasts, osteoclasts, bone lining cells, stem cells or other pluripotent or multipotent cell. 33. A cell lysate prepared from the cell population of claim 21. 34. A soluble cell fraction prepared from the cell lysate of claim 33. 35. A cell lysate prepared from the cell population of claim 25. 36. A soluble cell fraction prepared from the cell lysate of claim 35. 37. A cell lysate prepared from the cell population of claim 29. 38. A soluble cell fraction prepared from the cell lysate of claim 37. 39. An extracellular matrix of the cell population of claim 21. 40. An extracellular matrix of the cell population of claim 25. 41. An extracellular matrix of the cell population of claim 29. 42. A composition comprising the cell population of claim 21 and one or more bioactive factors. 43. A composition comprising the cell population of claim 25 and one or more bioactive factors. 44. A composition comprising the cell population of claim 29 and one or more bioactive factors. 45. The composition of claim 42 wherein said bioactive factor is a chondrogenic differentiation-inducing factor. 46. The composition of claim 42 wherein said bioactive factor is an osteogenic differentiation-inducing factor. 47. A pharmaceutical composition comprising a cell of claim 1 and a pharmaceutically acceptable carrier. 48. A pharmaceutical composition comprising a cell of claim 11 and a pharmaceutically acceptable carrier. 49. A pharmaceutical composition comprising a cell of claim 20 and a pharmaceutically acceptable carrier. 50. A pharmaceutical composition comprising the extracellular matrix of claim 39 and a pharmaceutically acceptable carrier. 51. A pharmaceutical composition comprising the extracellular matrix of claim 40 and a pharmaceutically acceptable carrier. 52. A pharmaceutical composition comprising the extracellular matrix of claim 41 and a pharmaceutically acceptable carrier. 53. A pharmaceutical composition comprising the lysate of claim 33 and a pharmaceutically acceptable carrier. 54. A pharmaceutical composition comprising the lysate of claim 35 and a pharmaceutically acceptable carrier. 55. A pharmaceutical composition comprising the lysate of claim 37 and a pharmaceutically acceptable carrier. 56. A cell culture comprising at least one cell of claim 1 in a culture medium. 57. The cell culture of claim 56 wherein said culture medium comprises chondrogenic medium or osteogenic medium. 58. The cell culture of claim 56 further comprising at least one chondrogenic differentiation-inducing agent. 59. The cell culture of claim 58 wherein said chondrogenic differentiation-inducing agent is at least one of transforming growth factor-beta3 or growth and differentiation factor-5. 60. The cell culture of claim 56 further comprising at least one osteogenic differentiation-inducing agent. 61. The cell culture of claim 60 wherein said osteogenic differentiation-inducing agent is at least one of transforming growth factor-beta 1, bone morphogenic protein (BMP)-2, or BMP4. 62. A matrix comprising a cell population of claim 21. 63. A matrix comprising a cell population of claim 25. 64. A matrix comprising a cell population of claim 29. 65. The matrix of claim 62 wherein said matrix comprises a three-dimensional scaffold. 66. The matrix of claim 63 wherein said matrix comprises a three-dimensional scaffold. 67. The matrix of claim 64 wherein said matrix comprises a three-dimensional scaffold. 68. A method of treating a condition in a patient comprising administering to said patient one or more postpartum-derived cells of claim 1. 69. The method of claim 68 wherein said condition is a bone or cartilage condition. 70. The method of claim 69 wherein said bone or cartilage condition is a congenital bone or cartilage defect, meniscal injury or defect, bone/spinal deformation, osteosarcoma, myeloma, bone dysplasia or scoliosis, osteoporosis, periodontal disease, dental bone loss, osteomalacia, rickets, fibrous osteitis, renal bone dystrophy, spinal fusion, spinal disc reconstruction or removal, Paget's disease of bone, rheumatoid arthritis, osteoarthritis, or a traumatic or surgical injury. 71. The method of claim 68 wherein said postpartum-derived cells are administered with at least one other cell type. 72. The method of claim 71 wherein said at least one other cell type is bone marrow cells, chondrocytes, chondroblasts, chondrocyte progenitor cells, osteocytes, osteoblasts, osteoclasts, bone lining cells, stem cells, or other pluripotent or multipotent cell. 73. The method of claim 68 wherein said postpartum-derived cells are inoculated on a matrix. 74. The method of claim 73 wherein said matrix is implanted into said patient. 75. The method of claim 68 wherein said postpartum-derived cells are induced to differentiate to a chondrogenic or osteogenic phenotype prior to said step of administering. 76. The method of claim 68 wherein said postpartum-derived cells are co-administered with at least one bioactive factor. 77. The method of claim 68 wherein said cells are administered to a bone of said patient. 78. The method of claim 68 wherein said cells are administered to cartilage of said patient. 79. A method of regenerating a tissue in a patient in need thereof comprising administering the cell population of claim 21 to said patient. 80. The method of claim 79 wherein said tissue is bone or cartilage. 81. A method of regenerating a tissue in a patient in need thereof comprising administering the cell population of claim 25 to said patient. 82. The method of claim 81 wherein said tissue is bone or cartilage. 83. A method of regenerating a tissue in a patient in need thereof comprising administering the cell population of claim 29 to said patient. 84. The method of claim 83 wherein said tissue is bone or cartilage. 85. The method of claim 68 wherein said cells are implanted into said patient. 86. A conditioned medium generated by the growth of the culture of claim 56. 87. A method for identifying a compound that stimulates chondrogenesis of a postpartum-derived cell comprising contacting a cell of claim 1 with said compound and monitoring said cell for a marker of chondrogenesis. 88. A method for identifying a compound that stimulates osteogenesis of a postpartum-derived cell comprising contacting a cell of claim 1 with said compound and monitoring said cell for a marker of osteogenesis. 89. A method for identifying a compound that is toxic to a postpartum-derived cell of claim 1 comprising contacting said cell with said compound and monitoring survival of said cell. 90. A kit comprising at least one cell of claim 1 and at least one additional component of a matrix, a hydrating agent, a cell culture substrate, a differentiation-inducing agent, and cell culture media. 91. The kit of claim 90 wherein said matrix is a three-dimensional scaffold. 92. The kit of claim 91 wherein said cell is seeded on said scaffold. 93. The kit of claim 90 wherein said differentiation-inducing agent is an osteogenic differentiation-inducing agent or a chondrogenic differentiation-inducing agent. 94. A method of treating a patient having a bone or cartilage condition comprising administering to said patient the extracellular matrix of a cell of claim 1. 95. A method of treating a patient having a bone or cartilage condition comprising administering to said patient the cell lysate of claim 33. 96. A method of treating a patient having a bone or cartilage condition comprising administering to said patient the conditioned medium of claim 86. 97. The pharmaceutical composition of claim 47 wherein said composition comprises an effective amount of said cells to treat a bone or cartilage condition. 98. The pharmaceutical composition of claim 48 wherein said composition comprises an effective amount of said cells to treat a bone or cartilage condition. 99. The pharmaceutical composition of claim 49 wherein said composition comprises an effective amount of said cells to treat a bone or cartilage condition. 100. The pharmaceutical composition of claim 50 wherein said composition comprises an effective amount of said extracellular matrix to treat a bone or cartilage condition. 101. The pharmaceutical composition of claim 51 wherein said composition comprises an effective amount of said extracellular matrix to treat a bone or cartilage condition. 102. The pharmaceutical composition of claim 52 wherein said composition comprises an effective amount of said extracellular matrix to treat a bone or cartilage condition. 103. The pharmaceutical composition of claim 53 wherein said composition comprises an effective amount of said lysate to treat a bone or cartilage condition. 104. The pharmaceutical composition of claim 54 wherein said composition comprises an effective amount of said lysate to treat a bone or cartilage condition. 105. The pharmaceutical composition of claim 55 wherein said composition comprises an effective amount of said lysate to treat a bone or cartilage condition. 106. The pharmaceutical composition of claim 47 further comprising at least one other cell type of stem cells, bone marrow cells, chondrocytes, chondroblasts, osteocytes, osteoblasts, osteoclasts, bone lining cells, and other bone or cartilage progenitor cells. 107. The pharmaceutical composition of claim 48 further comprising at least one other cell type of stem cells, bone marrow cells, chondrocytes, chondroblasts, osteocytes, osteoblasts, osteoclasts, bone lining cells, and other bone or cartilage progenitor cells. 108. The pharmaceutical composition of claim 49 further comprising at least one other cell type of stem cells, bone marrow cells, chondrocytes, chondroblasts, osteocytes, osteoblasts, osteoclasts, bone lining cells, and other bone or cartilage progenitor cells. | 1,600 |
798 | 14,312,749 | 1,619 | The present invention provides an oral care composition, containing at least 0.5% by weight of silica agglomerates, wherein each of the silica agglomerates has: (i) an overall particle size from 200 μm to 2000 μm, and (ii) a crush strength from 0.1N to 5N. The silica particles that make up the silica agglomerate can have an average particle size from 1 μm to 50 μm. The composition can have a viscosity from 10 to 90 BKU. The present invention also provides a method of encouraging proper tooth cleaning by administering the oral care composition of the present invention to a subject's tooth surface. The present invention further provides the use of a silica agglomerate in manufacturing an oral care composition for encouraging proper tooth cleaning | 1. An oral care composition, comprising at least 0.5% by weight of silica agglomerates, wherein each of the silica agglomerates has: (i) an overall particle size from 200 μm to 2000 μm, and (ii) a crush strength from 0.1N to 5N; wherein silica particles that make up the silica agglomerates have an average particle size from 1 μm to 50 μm; and wherein the composition has a viscosity from 10 to 90 BKU. 2. The oral care composition according to claim 1, wherein said oral care composition has a viscosity from 15 to 70 BKU. 3. The oral care composition according to claim 1, wherein said silica particles that make up the silica agglomerates are selected from the group consisting of fumed silica, pyrogenic silica, precipitated silica, silica gel, and mixtures thereof. 4. The oral care composition according to claim 1, wherein said oral care composition comprises 1% to 30% by weight of said silica agglomerates. 5. The oral care composition according to claim 1, wherein said silica particles that make up the silica agglomerates have an average particle size from 2 μm to 45 μm. 6. The oral care composition according to claim 1, wherein each of said silica agglomerates has an overall particle size from 250 μm to 1500 μm. 7. The oral care composition according to claim 1, wherein each of said silica agglomerates has a crush strength from 0.5N to 4N. 8. The oral care composition according to claim 1, wherein each of said silica agglomerates has: (i) an overall particle size from 300 μm to 600 μm, and (ii) a crush strength from 1N to 3N. 9. The oral care composition according to claim 1, wherein said oral care composition further comprises a thickening agent selected from the group consisting of polysaccharides and derivatives thereof, carbomers, natural and synthetic gums, acrylamide polymers, acrylic acid polymers, vinyl polymers, polyamines, ethylene oxide polymers, mineral oils, petrolatums, clays and organomodified clays, and mixtures thereof. 10. The oral care composition according to claim 9, wherein the thickening agent is selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, carrageenan, xanthan gum, guar gum, tragacanth gum, alginate, acacia gum, gelatin, and mixtures thereof. 11. The oral care composition according to claim 9, wherein said thickening agent is present in an amount from 0.2% to 5% by weight of said oral care composition. 12. The oral care composition according to claim 11, wherein the thickening agent is present in said oral care composition in an amount from 0.4% to 1.5% by weight, and wherein the thickening agent is selected from the group consisting of hydroxyethylcellulose, carrageenan, sodium carboxymethylcellulose, and mixtures thereof. 13. The oral care composition according to claim 1, wherein said oral care composition comprises a surfactant selected from the group consisting of glycerin, sorbitol, xylitol, butylene glycol, polyethylene glycol, propylene glycol, and mixtures thereof. 14. The oral care composition according to claim 1, wherein each of said silica agglomerates further comprises one or more ingredients selected from the group consisting of an antibacterial agent, a colorant, a flavorant, and mixtures thereof. 15. The oral care composition according to claim 1, wherein said oral care composition is in a form selected from the group consisting of toothpaste, tooth powder, tooth gel, and mixtures thereof. 16. A method of encouraging proper tooth cleaning, comprising the steps of applying the oral care composition according to claim 1 onto a subject's tooth surface and brushing said tooth surface with said oral care composition. 17. Use of a silica agglomerate in manufacturing an oral care composition, wherein said silica agglomerate has: (i) a particle size from 200 μm to 2000 μm, and (ii) a crush strength from 0.1N to 5N; and wherein silica particles that make up the silica agglomerates have an average particle size from 1 μm to 50 μm. 18. The use according to claim 17, wherein said oral care composition has a viscosity from 10 to 90 BKU. 19. The use according to claim 17, wherein said oral care composition is in a form selected from the group consisting of toothpaste, tooth powder, tooth gel, and mixtures thereof. | The present invention provides an oral care composition, containing at least 0.5% by weight of silica agglomerates, wherein each of the silica agglomerates has: (i) an overall particle size from 200 μm to 2000 μm, and (ii) a crush strength from 0.1N to 5N. The silica particles that make up the silica agglomerate can have an average particle size from 1 μm to 50 μm. The composition can have a viscosity from 10 to 90 BKU. The present invention also provides a method of encouraging proper tooth cleaning by administering the oral care composition of the present invention to a subject's tooth surface. The present invention further provides the use of a silica agglomerate in manufacturing an oral care composition for encouraging proper tooth cleaning1. An oral care composition, comprising at least 0.5% by weight of silica agglomerates, wherein each of the silica agglomerates has: (i) an overall particle size from 200 μm to 2000 μm, and (ii) a crush strength from 0.1N to 5N; wherein silica particles that make up the silica agglomerates have an average particle size from 1 μm to 50 μm; and wherein the composition has a viscosity from 10 to 90 BKU. 2. The oral care composition according to claim 1, wherein said oral care composition has a viscosity from 15 to 70 BKU. 3. The oral care composition according to claim 1, wherein said silica particles that make up the silica agglomerates are selected from the group consisting of fumed silica, pyrogenic silica, precipitated silica, silica gel, and mixtures thereof. 4. The oral care composition according to claim 1, wherein said oral care composition comprises 1% to 30% by weight of said silica agglomerates. 5. The oral care composition according to claim 1, wherein said silica particles that make up the silica agglomerates have an average particle size from 2 μm to 45 μm. 6. The oral care composition according to claim 1, wherein each of said silica agglomerates has an overall particle size from 250 μm to 1500 μm. 7. The oral care composition according to claim 1, wherein each of said silica agglomerates has a crush strength from 0.5N to 4N. 8. The oral care composition according to claim 1, wherein each of said silica agglomerates has: (i) an overall particle size from 300 μm to 600 μm, and (ii) a crush strength from 1N to 3N. 9. The oral care composition according to claim 1, wherein said oral care composition further comprises a thickening agent selected from the group consisting of polysaccharides and derivatives thereof, carbomers, natural and synthetic gums, acrylamide polymers, acrylic acid polymers, vinyl polymers, polyamines, ethylene oxide polymers, mineral oils, petrolatums, clays and organomodified clays, and mixtures thereof. 10. The oral care composition according to claim 9, wherein the thickening agent is selected from the group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, carrageenan, xanthan gum, guar gum, tragacanth gum, alginate, acacia gum, gelatin, and mixtures thereof. 11. The oral care composition according to claim 9, wherein said thickening agent is present in an amount from 0.2% to 5% by weight of said oral care composition. 12. The oral care composition according to claim 11, wherein the thickening agent is present in said oral care composition in an amount from 0.4% to 1.5% by weight, and wherein the thickening agent is selected from the group consisting of hydroxyethylcellulose, carrageenan, sodium carboxymethylcellulose, and mixtures thereof. 13. The oral care composition according to claim 1, wherein said oral care composition comprises a surfactant selected from the group consisting of glycerin, sorbitol, xylitol, butylene glycol, polyethylene glycol, propylene glycol, and mixtures thereof. 14. The oral care composition according to claim 1, wherein each of said silica agglomerates further comprises one or more ingredients selected from the group consisting of an antibacterial agent, a colorant, a flavorant, and mixtures thereof. 15. The oral care composition according to claim 1, wherein said oral care composition is in a form selected from the group consisting of toothpaste, tooth powder, tooth gel, and mixtures thereof. 16. A method of encouraging proper tooth cleaning, comprising the steps of applying the oral care composition according to claim 1 onto a subject's tooth surface and brushing said tooth surface with said oral care composition. 17. Use of a silica agglomerate in manufacturing an oral care composition, wherein said silica agglomerate has: (i) a particle size from 200 μm to 2000 μm, and (ii) a crush strength from 0.1N to 5N; and wherein silica particles that make up the silica agglomerates have an average particle size from 1 μm to 50 μm. 18. The use according to claim 17, wherein said oral care composition has a viscosity from 10 to 90 BKU. 19. The use according to claim 17, wherein said oral care composition is in a form selected from the group consisting of toothpaste, tooth powder, tooth gel, and mixtures thereof. | 1,600 |
799 | 13,855,846 | 1,619 | Hard shell capsules filled with a pharmaceutical medicament and at least one modifier, selected to prevent abuse of the medicament are described. The modifier may have a high melting point, and therefore melt at a temperature too high to inject or be insoluble in liquid, having a density less than 1, to prevent “spiking” of drinks. The modifier may also be a waxy substance which cannot be crushed, a viscosity modifier, a dye or a taste modifier. | 1.-26. (canceled) 27. An abuse resistant capsule comprising a hard shell capsule filled with a composition comprising at least one pharmaceutical medicament, at least one waxy substance having melting point greater than about 50° C., present in an amount ranging from about 10% to about 98.8% w/w, and at least one water-soluble excipient capable of forming channels in the fill composition when said composition is exposed to an aqueous solution; and wherein the fill composition is in a solid or semi-solid state at room temperature and exhibits a melting point from about 35° C. to about 90° C. 28. The abuse resistant capsule according to claim 27, wherein the fill composition exhibits a melting point ranging from about 35° C. to about 70° C. 29. The abuse resistant capsule according to claim 27, wherein the at least one waxy substance is present in an amount ranging from about 59% to about 66% w/w. 30. The abuse resistant capsule according to claim 27, wherein the at least one waxy substance is insoluble in an aqueous solution, organic solvent, or ethanol. 31. The abuse resistant capsule according to claim 27, wherein the at least one waxy substance is insoluble in aqueous solvents. 32. The abuse resistant capsule according to claim 27, wherein the at least one waxy substance has a density of less than approximately 1 g/cm3. 33. The abuse resistant capsule according to claim 27, wherein the hard shell capsule comprises gelatin, hydroxypropyl methylcellulose (HPMC), pullulan, or mixtures thereof. 34. The abuse resistant capsule according to claim 27, wherein the at least one waxy substance is selected from the group consisting of macrogol glycerides, PEGs, glycerol monooleates, glycerol monostearates, hydrogenated or partially hydrogenated glycerides, hard fats, beeswax, poloxamer 188, Gelucires™, polyethylene 6000, glycerol monostearate, hydrogenated palm kernel oil, hydrogenated cottonseed oil, Softisan™ 138, Gelucire™ 40/01™, hexadecan-1-ol, and mixtures thereof. 35. The abuse resistant capsule according to claim 27, wherein the fill composition further comprises a thixotrope. 36. The abuse resistant capsule according to claim 35, wherein the thixotrope is selected from the group consisting of fumed silica, pulverized attapulgite, HPMC, and mixtures thereof. 37. The abuse resistant capsule according to claim 27, further comprising a viscosity modifier selected from the group consisting of hydroxylpropyl methylcellulose, gellan gum, fractionated coconut oil, soyabean oil, fumed silica, and mixtures thereof. 38. The abuse resistant capsule according to claim 27, wherein the at least one waxy substance comprises a digestible material. 39. The abuse resistant capsule according to claim 27, wherein the fill composition comprises a paste. 40. The abuse resistant capsule according to claim 27, wherein the fill composition comprises at least one additional modifier selected from the group consisting of a food or pharmaceutical dye, a viscous material, a taste modifier, a water insoluble, a density modifier, and mixtures thereof. 41. The abuse resistant capsule according to claim 27, wherein the fill composition comprises suspended solids. 42. The abuse resistant capsule according to claim 27, wherein the pharmaceutical medicament is incorporated in the fill composition as particles suspended in at least one modifier. 43. The abuse resistant capsule according to claim 42, wherein the particles exhibit a diameter ranging from about 100 microns to about 2000 microns. 44. The abuse resistant capsule according to claim 42, wherein the particles are coated. 45. A method for preparing an abuse resistant capsule according to claim 27 comprising
preparing a fill composition comprising a pharmaceutical medicament and modifiers;
heating the fill composition to a temperature greater than about 50° C. to bring the fill composition to a liquid state, and
filling a hard shell with the liquid fill composition. | Hard shell capsules filled with a pharmaceutical medicament and at least one modifier, selected to prevent abuse of the medicament are described. The modifier may have a high melting point, and therefore melt at a temperature too high to inject or be insoluble in liquid, having a density less than 1, to prevent “spiking” of drinks. The modifier may also be a waxy substance which cannot be crushed, a viscosity modifier, a dye or a taste modifier.1.-26. (canceled) 27. An abuse resistant capsule comprising a hard shell capsule filled with a composition comprising at least one pharmaceutical medicament, at least one waxy substance having melting point greater than about 50° C., present in an amount ranging from about 10% to about 98.8% w/w, and at least one water-soluble excipient capable of forming channels in the fill composition when said composition is exposed to an aqueous solution; and wherein the fill composition is in a solid or semi-solid state at room temperature and exhibits a melting point from about 35° C. to about 90° C. 28. The abuse resistant capsule according to claim 27, wherein the fill composition exhibits a melting point ranging from about 35° C. to about 70° C. 29. The abuse resistant capsule according to claim 27, wherein the at least one waxy substance is present in an amount ranging from about 59% to about 66% w/w. 30. The abuse resistant capsule according to claim 27, wherein the at least one waxy substance is insoluble in an aqueous solution, organic solvent, or ethanol. 31. The abuse resistant capsule according to claim 27, wherein the at least one waxy substance is insoluble in aqueous solvents. 32. The abuse resistant capsule according to claim 27, wherein the at least one waxy substance has a density of less than approximately 1 g/cm3. 33. The abuse resistant capsule according to claim 27, wherein the hard shell capsule comprises gelatin, hydroxypropyl methylcellulose (HPMC), pullulan, or mixtures thereof. 34. The abuse resistant capsule according to claim 27, wherein the at least one waxy substance is selected from the group consisting of macrogol glycerides, PEGs, glycerol monooleates, glycerol monostearates, hydrogenated or partially hydrogenated glycerides, hard fats, beeswax, poloxamer 188, Gelucires™, polyethylene 6000, glycerol monostearate, hydrogenated palm kernel oil, hydrogenated cottonseed oil, Softisan™ 138, Gelucire™ 40/01™, hexadecan-1-ol, and mixtures thereof. 35. The abuse resistant capsule according to claim 27, wherein the fill composition further comprises a thixotrope. 36. The abuse resistant capsule according to claim 35, wherein the thixotrope is selected from the group consisting of fumed silica, pulverized attapulgite, HPMC, and mixtures thereof. 37. The abuse resistant capsule according to claim 27, further comprising a viscosity modifier selected from the group consisting of hydroxylpropyl methylcellulose, gellan gum, fractionated coconut oil, soyabean oil, fumed silica, and mixtures thereof. 38. The abuse resistant capsule according to claim 27, wherein the at least one waxy substance comprises a digestible material. 39. The abuse resistant capsule according to claim 27, wherein the fill composition comprises a paste. 40. The abuse resistant capsule according to claim 27, wherein the fill composition comprises at least one additional modifier selected from the group consisting of a food or pharmaceutical dye, a viscous material, a taste modifier, a water insoluble, a density modifier, and mixtures thereof. 41. The abuse resistant capsule according to claim 27, wherein the fill composition comprises suspended solids. 42. The abuse resistant capsule according to claim 27, wherein the pharmaceutical medicament is incorporated in the fill composition as particles suspended in at least one modifier. 43. The abuse resistant capsule according to claim 42, wherein the particles exhibit a diameter ranging from about 100 microns to about 2000 microns. 44. The abuse resistant capsule according to claim 42, wherein the particles are coated. 45. A method for preparing an abuse resistant capsule according to claim 27 comprising
preparing a fill composition comprising a pharmaceutical medicament and modifiers;
heating the fill composition to a temperature greater than about 50° C. to bring the fill composition to a liquid state, and
filling a hard shell with the liquid fill composition. | 1,600 |
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