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400 | 15,709,029 | 1,612 | The present invention relates to a dry mouthwash comprising granules that reconstitute in an aqueous solution, such as water, to produce a solution that tastes and functions as a typical liquid mouthwash. | 1. A dry mouthwash granule for reconstitution in an aqueous medium, comprising:
an active component, an organic acid component and a carbonate salt component wherein said granule causes an effervescent reaction to occur upon being combined with said aqueous medium; wherein said granule has a particle size between 53 microns and 1190 microns, and has a density of from about 0.5-1.2 g/cc; and wherein said dry mouthwash granule is not a tablet. 2. The dry mouthwash granule as recited in claim 1, wherein said organic acid component comprises one or more acids selected from citric acid, malic acid, tartaric acid, ascorbic acid, fumaric acid, adipic acid, sodium hydrogen sulfate and mixtures thereof. 3. The dry mouthwash granule as recited in claim 2, wherein said organic acid comprises tartaric acid and citric acid. 4. The dry mouthwash granule as recited in claim 1, wherein said carbonate salt component is a carbonate salt selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate and mixtures thereof. 5. The dry mouthwash granule as recited in claim 4, wherein said carbonate salt is sodium bicarbonate. 6. The mouthwash granule as recited in claim 1, which substantially dissolves when placed in water of 60-150° F. in less than 30 seconds. 7. The dry mouthwash granule as recited in claim 1, wherein said granule has a particle size between 53 microns and 1000 microns. 8. The dry mouthwash granule as recited in claim 1, wherein said granule has a particle size between 74 microns and 1190 microns. 9. The dry mouthwash granule as recited in claim 1, further comprising a flavor component. 10. The dry mouthwash granule as recited in claim 9, wherein said flavor component is selected from peppermint flavor, spearmint flavor and orange flavor. 11. The dry mouthwash granule as recited in claim 1, wherein said active component is selected from an antimicrobial agent, remineralizing agent, anti-caries agent, anticalculus agent, moisturizing agent, breath freshening agent and desensitizing agents. 12. The dry mouthwash granule as recited in claim 11, wherein said active component is an antimicrobial agent. 13. The dry mouthwash granule as recited in claim 12, wherein said antimicrobial agent is cetylpyridinium chloride or a monohydrate thereof. 14. The dry mouthwash granule as recited in claim 1, further comprising a coloring agent. 15. The dry mouthwash granule as recited in claim 14, wherein said coloring agent is selected from FD&C Blue #1 Al Lake, FD&C Yellow #5 Al Lake, and FD&C Red #40 Al Lake. 16. The dry mouthwash granule as recited in claim 1, further comprising one or more sweetening agents. 17. The dry mouthwash granule as recited in claim 16, wherein said one or more sweetening agents are selected from mannitol, xylitol, and sucralose. 18. The dry mouthwash granule as recited in claim 1, further comprising a surfactant. 19. The dry mouthwash granule as recited in claim 18, wherein said surfactant is a poloxamer. 20. The dry mouthwash granule as recited in claim 19, wherein said poloxamer is poloxamer 188. 21. The dry mouthwash granule as recited in claim 1, further comprising a binder. 22. The dry mouthwash granule of claim 21, wherein said binder is hydroxypropyl cellulose. 23. The dry mouthwash granule of claim 1, which is non-hygroscopic. 24. A method of rinsing the mouth of a subject comprising the steps of:
a. combining the dry mouthwash granule of claim 1 with an aqueous medium in a container; b. allowing the dry mouthwash granule to fully dissolve in said aqueous medium to form a solution; and c. rinsing the mouth of said subject with said solution. | The present invention relates to a dry mouthwash comprising granules that reconstitute in an aqueous solution, such as water, to produce a solution that tastes and functions as a typical liquid mouthwash.1. A dry mouthwash granule for reconstitution in an aqueous medium, comprising:
an active component, an organic acid component and a carbonate salt component wherein said granule causes an effervescent reaction to occur upon being combined with said aqueous medium; wherein said granule has a particle size between 53 microns and 1190 microns, and has a density of from about 0.5-1.2 g/cc; and wherein said dry mouthwash granule is not a tablet. 2. The dry mouthwash granule as recited in claim 1, wherein said organic acid component comprises one or more acids selected from citric acid, malic acid, tartaric acid, ascorbic acid, fumaric acid, adipic acid, sodium hydrogen sulfate and mixtures thereof. 3. The dry mouthwash granule as recited in claim 2, wherein said organic acid comprises tartaric acid and citric acid. 4. The dry mouthwash granule as recited in claim 1, wherein said carbonate salt component is a carbonate salt selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate and mixtures thereof. 5. The dry mouthwash granule as recited in claim 4, wherein said carbonate salt is sodium bicarbonate. 6. The mouthwash granule as recited in claim 1, which substantially dissolves when placed in water of 60-150° F. in less than 30 seconds. 7. The dry mouthwash granule as recited in claim 1, wherein said granule has a particle size between 53 microns and 1000 microns. 8. The dry mouthwash granule as recited in claim 1, wherein said granule has a particle size between 74 microns and 1190 microns. 9. The dry mouthwash granule as recited in claim 1, further comprising a flavor component. 10. The dry mouthwash granule as recited in claim 9, wherein said flavor component is selected from peppermint flavor, spearmint flavor and orange flavor. 11. The dry mouthwash granule as recited in claim 1, wherein said active component is selected from an antimicrobial agent, remineralizing agent, anti-caries agent, anticalculus agent, moisturizing agent, breath freshening agent and desensitizing agents. 12. The dry mouthwash granule as recited in claim 11, wherein said active component is an antimicrobial agent. 13. The dry mouthwash granule as recited in claim 12, wherein said antimicrobial agent is cetylpyridinium chloride or a monohydrate thereof. 14. The dry mouthwash granule as recited in claim 1, further comprising a coloring agent. 15. The dry mouthwash granule as recited in claim 14, wherein said coloring agent is selected from FD&C Blue #1 Al Lake, FD&C Yellow #5 Al Lake, and FD&C Red #40 Al Lake. 16. The dry mouthwash granule as recited in claim 1, further comprising one or more sweetening agents. 17. The dry mouthwash granule as recited in claim 16, wherein said one or more sweetening agents are selected from mannitol, xylitol, and sucralose. 18. The dry mouthwash granule as recited in claim 1, further comprising a surfactant. 19. The dry mouthwash granule as recited in claim 18, wherein said surfactant is a poloxamer. 20. The dry mouthwash granule as recited in claim 19, wherein said poloxamer is poloxamer 188. 21. The dry mouthwash granule as recited in claim 1, further comprising a binder. 22. The dry mouthwash granule of claim 21, wherein said binder is hydroxypropyl cellulose. 23. The dry mouthwash granule of claim 1, which is non-hygroscopic. 24. A method of rinsing the mouth of a subject comprising the steps of:
a. combining the dry mouthwash granule of claim 1 with an aqueous medium in a container; b. allowing the dry mouthwash granule to fully dissolve in said aqueous medium to form a solution; and c. rinsing the mouth of said subject with said solution. | 1,600 |
401 | 14,966,276 | 1,631 | Chemical compositions may be selectively or preferentially excited by the application of scores comprising a series of energy inputs. | 1.-22. (canceled) 23. A method, comprising
identifying a naturally-occurring agent in a body; selecting a set of differing energy inputs specific to the agent, wherein the set of differing energy inputs selectively resonates a plurality of resonant structures in the agent; and directing the set of differing energy inputs towards the agent. 24. The method of claim 23, wherein the agent has a metabolic effect in the body. 25. The method of claim 24, wherein directing the set of differing energy inputs towards the agent modulates the metabolic effect in the body. 26.-28. (canceled) 29. The method of claim 24, wherein directing the set of differing energy inputs towards the agent destroys the agent. 30.-34. (canceled) 35. The method of claim 23, wherein the body is alive. 36. The method of claim 23, wherein the body is human. 37. The method of claim 23, wherein the agent is present in blood. 38. The method of claim 37, wherein directing the set of differing energy inputs towards the agent comprises directing the set of differing energy inputs into the body. 39. The method of claim 37, wherein directing the set of differing energy inputs towards the agent comprises treating the blood by directing the set of differing energy inputs into the blood external from the body, and the method further comprises introducing the treated blood into the body. 40. The method of claim 23, further comprising monitoring the body for activity of the agent. 41. The method of claim 23, further comprising monitoring the body for quantity of the agent. 42. (canceled) 43. The method of claim 23, further comprising modifying the agent in the body to add a functional group selected to be responsive to the set of differing energy inputs. 44. The method of claim 23, wherein the agent is selected from the group consisting of blood clotting factors, sugars, lipids, lipoproteins, vitamins, minerals, hormones, enzymes, antibodies, and proteins. 45. The method of claim 44, wherein the agent is a blood clotting factor selected from the group consisting of prekallikrein, high molecular weight kininogen, clotting factors I-XIII, von Willebrand factor, protein C, protein S, thrombomodulin, and antithrombin III. 46. The method of claim 44, wherein the agent is a sugar selected from the group consisting of glucose, fructose, sucrose, galactose, mannose, glycerol, and glucuronate. 47. The method of claim 44, wherein the agent is a lipid or lipoprotein selected from the group consisting of cholesterol, triglicerides, triacylglycerols, chylomicrons, very low density lipoproteins, low density lipoproteins, intermediate density lipoproteins, and high density lipoproteins. 48. The method of claim 44, wherein the agent is a hormone selected from the group consisting of adrenalin, adrenocorticotropic hormone, aldosteron, calcitonin, cortisol, insulin, gastrin, glucagon, glucocorticoids, thyroid hormone, gastrin, secretin, cholecystokinin, somatostatin, neuropeptide Y, other hormones of the gut, thyrotropin-releasing hormone, gonadotropin-releasing hormone, growth hormone-releasing hormone, ghrelin, corticotrophin-releasing hormone, somatostatin, dopamine, antidiuretic hormone, oxytocin, other hormones of the hypothalamus, renin, erythropoietin, calcitrol, other hormones of the kidney, insulin-like growth factor-1, angiotensinogen, thrombopoietin, other hormones of the liver, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, growth hormone, adrenocorticotropic hormone, antidiuretic hormone, other hormones of the pituitary, estrogen, testosterone, progesterone, anabolic steroids, other reproductive hormones, melanocyte-stimulating hormone, parathyroid hormone, melatonin, prolactin, and thyroid hormones. 49. The method of claim 44, wherein the agent is an enzyme selected from the group consisting of creatine kinase, lactate dehydrogenase, troponin, other cardiac enzymes, aspartate transaminase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyltranspeptidase, and other liver enzymes. 50. The method of claim 44, wherein the agent is an antibody to an autoimmune disorders selected from the group consisting of acute transverse myelitis, allergic (Henoch-Schönlein) purpura, alopecia areata, aplastic anemia, brachial neuritis, bullous pemphigoid, dermatitis herpetiformis, polymyositis, dermatomyositis, Eaton-Lambert syndrome, eosinophilic fasciitis, Goodpasture's syndrome, Guillain-Barré syndrome, hemolytic anemia, hepatitis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus, peripheral ulcerative keratitis, polyglandular deficiency syndrome, relapsing polychondritis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, and system lupus erythematosus, 51. The method of claim 44, wherein the agent is an antibody to a transplanted material. 52. The method of claim 51, wherein the transplanted material is selected from the group consisting of organs, stem cells, and device implants. 53. The method of claim 44, wherein the agent is a protein selected from the group consisting of albumins, globulins, fibrinogens, and hemoglobins. | Chemical compositions may be selectively or preferentially excited by the application of scores comprising a series of energy inputs.1.-22. (canceled) 23. A method, comprising
identifying a naturally-occurring agent in a body; selecting a set of differing energy inputs specific to the agent, wherein the set of differing energy inputs selectively resonates a plurality of resonant structures in the agent; and directing the set of differing energy inputs towards the agent. 24. The method of claim 23, wherein the agent has a metabolic effect in the body. 25. The method of claim 24, wherein directing the set of differing energy inputs towards the agent modulates the metabolic effect in the body. 26.-28. (canceled) 29. The method of claim 24, wherein directing the set of differing energy inputs towards the agent destroys the agent. 30.-34. (canceled) 35. The method of claim 23, wherein the body is alive. 36. The method of claim 23, wherein the body is human. 37. The method of claim 23, wherein the agent is present in blood. 38. The method of claim 37, wherein directing the set of differing energy inputs towards the agent comprises directing the set of differing energy inputs into the body. 39. The method of claim 37, wherein directing the set of differing energy inputs towards the agent comprises treating the blood by directing the set of differing energy inputs into the blood external from the body, and the method further comprises introducing the treated blood into the body. 40. The method of claim 23, further comprising monitoring the body for activity of the agent. 41. The method of claim 23, further comprising monitoring the body for quantity of the agent. 42. (canceled) 43. The method of claim 23, further comprising modifying the agent in the body to add a functional group selected to be responsive to the set of differing energy inputs. 44. The method of claim 23, wherein the agent is selected from the group consisting of blood clotting factors, sugars, lipids, lipoproteins, vitamins, minerals, hormones, enzymes, antibodies, and proteins. 45. The method of claim 44, wherein the agent is a blood clotting factor selected from the group consisting of prekallikrein, high molecular weight kininogen, clotting factors I-XIII, von Willebrand factor, protein C, protein S, thrombomodulin, and antithrombin III. 46. The method of claim 44, wherein the agent is a sugar selected from the group consisting of glucose, fructose, sucrose, galactose, mannose, glycerol, and glucuronate. 47. The method of claim 44, wherein the agent is a lipid or lipoprotein selected from the group consisting of cholesterol, triglicerides, triacylglycerols, chylomicrons, very low density lipoproteins, low density lipoproteins, intermediate density lipoproteins, and high density lipoproteins. 48. The method of claim 44, wherein the agent is a hormone selected from the group consisting of adrenalin, adrenocorticotropic hormone, aldosteron, calcitonin, cortisol, insulin, gastrin, glucagon, glucocorticoids, thyroid hormone, gastrin, secretin, cholecystokinin, somatostatin, neuropeptide Y, other hormones of the gut, thyrotropin-releasing hormone, gonadotropin-releasing hormone, growth hormone-releasing hormone, ghrelin, corticotrophin-releasing hormone, somatostatin, dopamine, antidiuretic hormone, oxytocin, other hormones of the hypothalamus, renin, erythropoietin, calcitrol, other hormones of the kidney, insulin-like growth factor-1, angiotensinogen, thrombopoietin, other hormones of the liver, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, growth hormone, adrenocorticotropic hormone, antidiuretic hormone, other hormones of the pituitary, estrogen, testosterone, progesterone, anabolic steroids, other reproductive hormones, melanocyte-stimulating hormone, parathyroid hormone, melatonin, prolactin, and thyroid hormones. 49. The method of claim 44, wherein the agent is an enzyme selected from the group consisting of creatine kinase, lactate dehydrogenase, troponin, other cardiac enzymes, aspartate transaminase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyltranspeptidase, and other liver enzymes. 50. The method of claim 44, wherein the agent is an antibody to an autoimmune disorders selected from the group consisting of acute transverse myelitis, allergic (Henoch-Schönlein) purpura, alopecia areata, aplastic anemia, brachial neuritis, bullous pemphigoid, dermatitis herpetiformis, polymyositis, dermatomyositis, Eaton-Lambert syndrome, eosinophilic fasciitis, Goodpasture's syndrome, Guillain-Barré syndrome, hemolytic anemia, hepatitis, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus, peripheral ulcerative keratitis, polyglandular deficiency syndrome, relapsing polychondritis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, and system lupus erythematosus, 51. The method of claim 44, wherein the agent is an antibody to a transplanted material. 52. The method of claim 51, wherein the transplanted material is selected from the group consisting of organs, stem cells, and device implants. 53. The method of claim 44, wherein the agent is a protein selected from the group consisting of albumins, globulins, fibrinogens, and hemoglobins. | 1,600 |
402 | 15,897,030 | 1,636 | This document provides methods and materials for treating diabetes. For example, methods and materials for using nucleic acid encoding human preproinsulin to treat diabetes (e.g., type I or type II diabetes) are provided. | 1. A method for treating diabetes, wherein said method comprises administering, to a mammal with diabetes, a vector comprising a nucleic acid construct comprising a nucleic acid encoding an insulin polypeptide and a nucleic acid encoding an inducible death switch polypeptide. 2. The method of claim 1, wherein said mammal comprises type I diabetes. 3. The method of claim 1, wherein said mammal comprises type II diabetes. 4. The method of claim 1, wherein said mammal experiences hypoglycemia, and said method comprises administering an inducing agent to said mammal. 5. The method of claim 4, wherein said inducible death switch polypeptide is an iCasp9 polypeptide, and said inducing agent is AP1903 or AP20187. 6. The method of claim 4, wherein said vector is administered intramuscularly, and wherein administration of said inducing agent safely reduces said hypoglycemia. 7. The method of claim 1, wherein said insulin polypeptide is a proinsulin polypeptide. 8. The method of claim 1, wherein said insulin polypeptide is a furin-activatable proinsulin polypeptide. 9. The method of claim 1, wherein said inducible death switch polypeptide is an iCasp9 polypeptide. 10. The method of claim 1, wherein said construct comprises an IRES located between said nucleic acid encoding said insulin polypeptide and said nucleic acid encoding an inducible death switch polypeptide. 11. The method of claim 1, wherein said vector is an AAV1 vector. | This document provides methods and materials for treating diabetes. For example, methods and materials for using nucleic acid encoding human preproinsulin to treat diabetes (e.g., type I or type II diabetes) are provided.1. A method for treating diabetes, wherein said method comprises administering, to a mammal with diabetes, a vector comprising a nucleic acid construct comprising a nucleic acid encoding an insulin polypeptide and a nucleic acid encoding an inducible death switch polypeptide. 2. The method of claim 1, wherein said mammal comprises type I diabetes. 3. The method of claim 1, wherein said mammal comprises type II diabetes. 4. The method of claim 1, wherein said mammal experiences hypoglycemia, and said method comprises administering an inducing agent to said mammal. 5. The method of claim 4, wherein said inducible death switch polypeptide is an iCasp9 polypeptide, and said inducing agent is AP1903 or AP20187. 6. The method of claim 4, wherein said vector is administered intramuscularly, and wherein administration of said inducing agent safely reduces said hypoglycemia. 7. The method of claim 1, wherein said insulin polypeptide is a proinsulin polypeptide. 8. The method of claim 1, wherein said insulin polypeptide is a furin-activatable proinsulin polypeptide. 9. The method of claim 1, wherein said inducible death switch polypeptide is an iCasp9 polypeptide. 10. The method of claim 1, wherein said construct comprises an IRES located between said nucleic acid encoding said insulin polypeptide and said nucleic acid encoding an inducible death switch polypeptide. 11. The method of claim 1, wherein said vector is an AAV1 vector. | 1,600 |
403 | 15,551,597 | 1,617 | Disclosed is a cosmetic product comprising a metal can which comprises a metal container (A) which has a rotary thread (A′) and contains a cosmetic preparation as well as a lid (D) having a thread (D′) and being of the same metal as the container. The lid can be screwed onto/unscrewed from the container by means of threads (D′) and (A′) via rotational movement. The cosmetic preparation comprises an emulsion of one or more hydrophilic phases and one or more lipophilic phases. The one or more lipophilic phases comprise at least one lipid having a spreading coefficient at 25° C. of no more than 700 mm 2 /10 minutes, at least one lipid having a dropping point of >30° C., and at least one monovalent and/or polyvalent alcohol in a total amount of at least 3 wt. %. | 1.-4. (canceled) 5. A cosmetic product, wherein the product comprises a metal can which comprises a metallic container (A) containing a cosmetic preparation (Z) and comprising a rotation thread (A′) and a lid (D) having a thread (D′) and being made of the same metal as the container (A), lid (D) being unscrewable and screwable onto container (A) in by thread (D′) and thread (A′) via rotational movement, and wherein the cosmetic preparation (Z) comprises an emulsion of one or more hydrophilic phases and one or more lipophilic phases, the one or more lipophilic phases comprising, in a total concentration of at least 3% by weight, based on a total weight of the preparation, (i) at least one lipid having a spreading value at 25° C. of at least 700 mm2/10 minutes, (ii) at least one lipid having a dropping point >30° C., and (iii) at least one monohydric and/or polyhydric alcohol. 6. The cosmetic product of claim 5, wherein the lipids (i) and (ii) are selected from palmitic acid, stearic acid, myristic acid, arachidonic acid, oleic acid, glyceryl stearate, cetyl alcohol, stearyl alcohol, hydrogenated coconut fatty acid glycerides, cera microcristallina, paraffinum liquidum, dimethicone. 7. The cosmetic product of claim 5, wherein the preparation comprises up to 20% by weight of lipophilic substances, based on a total weight of the preparation. 8. The cosmetic product of claim 7, wherein a weight ratio lipid (i) to lipid (ii) is from 20:80 to 50:50. 9. The cosmetic product of claim 7, wherein a weight ratio lipid (i) to lipid (ii) is from 30:70 to 45:55. 10. The cosmetic product of claim 5, wherein the preparation further comprises one or more UV filter substances. 11. The cosmetic product of claim 5, wherein the metal can consists of aluminum. 12. The cosmetic product of claim 11, wherein a protective lining is present on an inner side of the can. | Disclosed is a cosmetic product comprising a metal can which comprises a metal container (A) which has a rotary thread (A′) and contains a cosmetic preparation as well as a lid (D) having a thread (D′) and being of the same metal as the container. The lid can be screwed onto/unscrewed from the container by means of threads (D′) and (A′) via rotational movement. The cosmetic preparation comprises an emulsion of one or more hydrophilic phases and one or more lipophilic phases. The one or more lipophilic phases comprise at least one lipid having a spreading coefficient at 25° C. of no more than 700 mm 2 /10 minutes, at least one lipid having a dropping point of >30° C., and at least one monovalent and/or polyvalent alcohol in a total amount of at least 3 wt. %.1.-4. (canceled) 5. A cosmetic product, wherein the product comprises a metal can which comprises a metallic container (A) containing a cosmetic preparation (Z) and comprising a rotation thread (A′) and a lid (D) having a thread (D′) and being made of the same metal as the container (A), lid (D) being unscrewable and screwable onto container (A) in by thread (D′) and thread (A′) via rotational movement, and wherein the cosmetic preparation (Z) comprises an emulsion of one or more hydrophilic phases and one or more lipophilic phases, the one or more lipophilic phases comprising, in a total concentration of at least 3% by weight, based on a total weight of the preparation, (i) at least one lipid having a spreading value at 25° C. of at least 700 mm2/10 minutes, (ii) at least one lipid having a dropping point >30° C., and (iii) at least one monohydric and/or polyhydric alcohol. 6. The cosmetic product of claim 5, wherein the lipids (i) and (ii) are selected from palmitic acid, stearic acid, myristic acid, arachidonic acid, oleic acid, glyceryl stearate, cetyl alcohol, stearyl alcohol, hydrogenated coconut fatty acid glycerides, cera microcristallina, paraffinum liquidum, dimethicone. 7. The cosmetic product of claim 5, wherein the preparation comprises up to 20% by weight of lipophilic substances, based on a total weight of the preparation. 8. The cosmetic product of claim 7, wherein a weight ratio lipid (i) to lipid (ii) is from 20:80 to 50:50. 9. The cosmetic product of claim 7, wherein a weight ratio lipid (i) to lipid (ii) is from 30:70 to 45:55. 10. The cosmetic product of claim 5, wherein the preparation further comprises one or more UV filter substances. 11. The cosmetic product of claim 5, wherein the metal can consists of aluminum. 12. The cosmetic product of claim 11, wherein a protective lining is present on an inner side of the can. | 1,600 |
404 | 14,511,702 | 1,631 | Short fixed length source sub-sequences are extracted from a collection of source sequences derived from a sample for which the biological signature is to be determined. The extracted short fixed length source sub-sequences are compiled to determine the frequency of each within the collection. Overlaps between the short fixed length source sub-sequences are used to find a chain of overlaps from one or more sub-sequences equivalent to a pre-flanking reference marker sequence to one or more sub-sequences equivalent to a post-flanking reference marker sequence, wherein the reference marker sequences flank a region containing a repetitive sequence region. In response to the chain containing multiple instances of the one or more short fixed length source sub-sequences, thereby defining a cycle, the sequences from the collection derived from the sample are examined to find one or more sequences that span the cycle, and at least one of: (i) the lengths of the spanning sequences are used to determine the length of the cycle and; (ii) the number of repeat motif copies within each spanning sequence are counted. | 1-20. (canceled) 21. An article of manufacture comprising a computer readable storage medium for storing computer readable program code which, when executed, causes a computer node to perform the steps of:
extracting short fixed length source sub-sequences from a collection of source sequences derived from a sample for which the biological signature is to be determined; compiling the extracted short fixed length source sub-sequences to determine the frequency of each within the collection; using overlaps between the short fixed length source sub-sequences to find a chain of overlaps from one or more sub-sequences equivalent to a pre-flanking reference marker sequence to one or more sub-sequences equivalent to a post-flanking reference marker sequence, the reference marker sequences flanking a region containing a repetitive sequence region; and in response to the chain containing multiple instances of the one or more short fixed length source sub-sequences, thereby defining a cycle, examining the sequences from the collection derived from the sample to find one or more sequences that span the cycle, and at least one of: (i) using the lengths of the spanning sequences to determine the length of the cycle and; (ii) counting the number of repeat motif copies within each spanning sequence; wherein one or more of the above steps are performed in accordance with a processor and a memory. 22. The article of manufacture of claim 21, further comprising determining a length of the repetitive sequence region by taking into account the distance between the reference marker sequence equivalents, and the number of extra sequence letters between the reference marker sequence equivalents and the repetitive sequence region. 23. The article of manufacture of claim 21, further comprising using at least one of the frequency of the extracted short fixed length source sub-sequences and overlap relationships between the short fixed length source sub-sequences to eliminate short fixed length source sub-sequences that are due to measurement error. 24. The article of manufacture of claim 21, wherein the biological sequence data is classified as at least one of DNA, RNA, and proteins. 25. The article of manufacture of claim 21, wherein the repetitive sequence region comprises at least one of a tandem repeat, a tandem repeat motif region, and a micro-satellite. 26. The article of manufacture of claim 21, wherein the reference marker sequences comprise primers. 27. The article of manufacture of claim 21, wherein the short fixed length sub-sequences comprise k-mers. 28. The article of manufacture of claim 21, wherein the sample from which the source sub-sequences are derived comprises one of next-generation sequences, high-throughput sequences, whole-genome sequences, whole-exome sequences, transcriptomes, and metagenomes. 29. The article of manufacture of claim 21, wherein the chain of sub-sequence overlaps is represented in the form of a de Bruijn graph. 30. A system for determining a signature from biological sequence data, comprising:
a memory; and a processor operatively coupled to the memory and configured to: extract short fixed length source sub-sequences from a collection of source sequences derived from a sample for which the biological signature is to be determined; compile the extracted short fixed length source sub-sequences to determine the frequency of each within the collection; use overlaps between the short fixed length source sub-sequences to find a chain of overlaps from one or more sub-sequences equivalent to a pre-flanking reference marker sequence to one or more sub-sequences equivalent to a post-flanking reference marker sequence, the reference marker sequences flanking a region containing a repetitive sequence region; and in response to the chain containing multiple instances of the one or more short fixed length source sub-sequences, thereby defining a cycle, examine the sequences from the collection derived from the sample to find one or more sequences that span the cycle, and at least one of: (i) use the lengths of the spanning sequences to determine the length of the cycle and; (ii) count the number of repeat motif copies within each spanning sequence. 31. The system of claim 30, further configured to determine a length of the repetitive sequence region by taking into account the distance between the reference marker sequence equivalents, and the number of extra sequence letters between the reference marker sequence equivalents and the repetitive sequence region. 32. The system of claim 30, further configured to use at least one of the frequency of the extracted short fixed length source sub-sequences and overlap relationships between the short fixed length source sub-sequences to eliminate short fixed length source sub-sequences that are due to measurement error. 33. The system of claim 30, wherein the biological sequence data is classified as at least one of DNA, RNA, and proteins. 34. The system of claim 30, wherein the repetitive sequence region comprises at least one of a tandem repeat, a tandem repeat motif region, and a micro-satellite. 35. The system of claim 30, wherein the reference marker sequences comprise primers. 36. The system of claim 30, wherein the short fixed length sub-sequences comprise k-mers. 37. The system of claim 30, wherein the sample from which the source sub-sequences are derived comprises one of next-generation sequences, high-throughput sequences, whole-genome sequences, whole-exome sequences, transcriptomes, and metagenomes. 38. The system of claim 30, wherein the chain of sub-sequence overlaps is represented in the form of a de Bruijn graph. | Short fixed length source sub-sequences are extracted from a collection of source sequences derived from a sample for which the biological signature is to be determined. The extracted short fixed length source sub-sequences are compiled to determine the frequency of each within the collection. Overlaps between the short fixed length source sub-sequences are used to find a chain of overlaps from one or more sub-sequences equivalent to a pre-flanking reference marker sequence to one or more sub-sequences equivalent to a post-flanking reference marker sequence, wherein the reference marker sequences flank a region containing a repetitive sequence region. In response to the chain containing multiple instances of the one or more short fixed length source sub-sequences, thereby defining a cycle, the sequences from the collection derived from the sample are examined to find one or more sequences that span the cycle, and at least one of: (i) the lengths of the spanning sequences are used to determine the length of the cycle and; (ii) the number of repeat motif copies within each spanning sequence are counted.1-20. (canceled) 21. An article of manufacture comprising a computer readable storage medium for storing computer readable program code which, when executed, causes a computer node to perform the steps of:
extracting short fixed length source sub-sequences from a collection of source sequences derived from a sample for which the biological signature is to be determined; compiling the extracted short fixed length source sub-sequences to determine the frequency of each within the collection; using overlaps between the short fixed length source sub-sequences to find a chain of overlaps from one or more sub-sequences equivalent to a pre-flanking reference marker sequence to one or more sub-sequences equivalent to a post-flanking reference marker sequence, the reference marker sequences flanking a region containing a repetitive sequence region; and in response to the chain containing multiple instances of the one or more short fixed length source sub-sequences, thereby defining a cycle, examining the sequences from the collection derived from the sample to find one or more sequences that span the cycle, and at least one of: (i) using the lengths of the spanning sequences to determine the length of the cycle and; (ii) counting the number of repeat motif copies within each spanning sequence; wherein one or more of the above steps are performed in accordance with a processor and a memory. 22. The article of manufacture of claim 21, further comprising determining a length of the repetitive sequence region by taking into account the distance between the reference marker sequence equivalents, and the number of extra sequence letters between the reference marker sequence equivalents and the repetitive sequence region. 23. The article of manufacture of claim 21, further comprising using at least one of the frequency of the extracted short fixed length source sub-sequences and overlap relationships between the short fixed length source sub-sequences to eliminate short fixed length source sub-sequences that are due to measurement error. 24. The article of manufacture of claim 21, wherein the biological sequence data is classified as at least one of DNA, RNA, and proteins. 25. The article of manufacture of claim 21, wherein the repetitive sequence region comprises at least one of a tandem repeat, a tandem repeat motif region, and a micro-satellite. 26. The article of manufacture of claim 21, wherein the reference marker sequences comprise primers. 27. The article of manufacture of claim 21, wherein the short fixed length sub-sequences comprise k-mers. 28. The article of manufacture of claim 21, wherein the sample from which the source sub-sequences are derived comprises one of next-generation sequences, high-throughput sequences, whole-genome sequences, whole-exome sequences, transcriptomes, and metagenomes. 29. The article of manufacture of claim 21, wherein the chain of sub-sequence overlaps is represented in the form of a de Bruijn graph. 30. A system for determining a signature from biological sequence data, comprising:
a memory; and a processor operatively coupled to the memory and configured to: extract short fixed length source sub-sequences from a collection of source sequences derived from a sample for which the biological signature is to be determined; compile the extracted short fixed length source sub-sequences to determine the frequency of each within the collection; use overlaps between the short fixed length source sub-sequences to find a chain of overlaps from one or more sub-sequences equivalent to a pre-flanking reference marker sequence to one or more sub-sequences equivalent to a post-flanking reference marker sequence, the reference marker sequences flanking a region containing a repetitive sequence region; and in response to the chain containing multiple instances of the one or more short fixed length source sub-sequences, thereby defining a cycle, examine the sequences from the collection derived from the sample to find one or more sequences that span the cycle, and at least one of: (i) use the lengths of the spanning sequences to determine the length of the cycle and; (ii) count the number of repeat motif copies within each spanning sequence. 31. The system of claim 30, further configured to determine a length of the repetitive sequence region by taking into account the distance between the reference marker sequence equivalents, and the number of extra sequence letters between the reference marker sequence equivalents and the repetitive sequence region. 32. The system of claim 30, further configured to use at least one of the frequency of the extracted short fixed length source sub-sequences and overlap relationships between the short fixed length source sub-sequences to eliminate short fixed length source sub-sequences that are due to measurement error. 33. The system of claim 30, wherein the biological sequence data is classified as at least one of DNA, RNA, and proteins. 34. The system of claim 30, wherein the repetitive sequence region comprises at least one of a tandem repeat, a tandem repeat motif region, and a micro-satellite. 35. The system of claim 30, wherein the reference marker sequences comprise primers. 36. The system of claim 30, wherein the short fixed length sub-sequences comprise k-mers. 37. The system of claim 30, wherein the sample from which the source sub-sequences are derived comprises one of next-generation sequences, high-throughput sequences, whole-genome sequences, whole-exome sequences, transcriptomes, and metagenomes. 38. The system of claim 30, wherein the chain of sub-sequence overlaps is represented in the form of a de Bruijn graph. | 1,600 |
405 | 14,767,601 | 1,656 | Provided is a collagen sponge which has compressive strength (stress) equivalent to that of a tissue into which the collagen sponge is to be implanted, has no unevenness in structure and stress, and has a pore structure for allowing cells to infiltrate thereinto. The collagen sponge is obtained by subjecting a collagen dispersion, a collagen solution, or a mixture thereof having a collagen concentration of 50 mg/ml or more to freeze-drying and insolubilization treatment thereafter. The collagen sponge thus obtained has a stress of from 10 kPa to 30 kPa when loaded with 10% strain, has in its surface and inside a pore structure having a mean pore diameter ranging from 50 μm to 400 μm, and has a pore diameter standard deviation equal to or less than 80% of the mean pore diameter. | 1. A collagen sponge, which is obtained by subjecting a collagen dispersion, a collagen solution, or a mixture thereof having a collagen concentration of 50 mg/ml or more to freeze-drying and insolubilization treatment thereafter,
wherein the collagen sponge has a stress of from 10 kPa to 30 kPa when loaded with 10% strain, has in its surface and inside a pore structure having a mean pore diameter ranging from 50 μm to 400 μm, and has a pore diameter standard deviation equal to or less than 80% of the mean pore diameter. 2. A collagen sponge according to claim 1, wherein the collagen sponge is obtained by performing a centrifugation step at 700 G or more prior to the freeze-drying. 3. A collagen sponge according to claim 1, wherein the pore diameter standard deviation is equal to or less than 60% of the mean pore diameter. 4. A collagen sponge according to claim 1, wherein the pore diameter standard deviation is equal to or less than 40% of the mean pore diameter. | Provided is a collagen sponge which has compressive strength (stress) equivalent to that of a tissue into which the collagen sponge is to be implanted, has no unevenness in structure and stress, and has a pore structure for allowing cells to infiltrate thereinto. The collagen sponge is obtained by subjecting a collagen dispersion, a collagen solution, or a mixture thereof having a collagen concentration of 50 mg/ml or more to freeze-drying and insolubilization treatment thereafter. The collagen sponge thus obtained has a stress of from 10 kPa to 30 kPa when loaded with 10% strain, has in its surface and inside a pore structure having a mean pore diameter ranging from 50 μm to 400 μm, and has a pore diameter standard deviation equal to or less than 80% of the mean pore diameter.1. A collagen sponge, which is obtained by subjecting a collagen dispersion, a collagen solution, or a mixture thereof having a collagen concentration of 50 mg/ml or more to freeze-drying and insolubilization treatment thereafter,
wherein the collagen sponge has a stress of from 10 kPa to 30 kPa when loaded with 10% strain, has in its surface and inside a pore structure having a mean pore diameter ranging from 50 μm to 400 μm, and has a pore diameter standard deviation equal to or less than 80% of the mean pore diameter. 2. A collagen sponge according to claim 1, wherein the collagen sponge is obtained by performing a centrifugation step at 700 G or more prior to the freeze-drying. 3. A collagen sponge according to claim 1, wherein the pore diameter standard deviation is equal to or less than 60% of the mean pore diameter. 4. A collagen sponge according to claim 1, wherein the pore diameter standard deviation is equal to or less than 40% of the mean pore diameter. | 1,600 |
406 | 15,621,782 | 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, comprising: an amide-type local anesthetic, an enolic-acid non-steroidal anti-inflammatory drug (NSAID) and a delivery vehicle. 2. The composition of claim 1, wherein the amide-type local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, and tetracaine. 3. The composition of claim 1, wherein the enolic-acid NSAID is selected from the group consisting of meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam. 4. The composition of claim 1, wherein the amide-type local anesthetic is bupivacaine or ropivacaine and the enolic-acid NSAID is meloxicam. 5. The composition of claim 4, wherein the amide-type local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt %. 6. The composition of claim 1, wherein the enolic-acid NSAID is present in an amount above about 0.01 wt % of the composition. 7. The composition of claim 1, wherein the delivery vehicle is a sustained-release delivery vehicle. 8. The composition of claim 7, wherein the sustained-release delivery vehicle is a polymeric formulation, a liposome, a microsphere, an implantable device or a non-polymeric formulation. 9. The composition of claim 7, wherein the sustained-release delivery vehicle 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). 10. The composition of claim 9, wherein the amide-type local anesthetic and the enolic-acid NSAID are entrapped in an aqueous space of the liposome or in a lipid layer of the liposome. 11. The composition of claim 7, wherein the sustained-release delivery vehicle is a microsphere comprised of a bioerodible or biodegradable polymer. 12. The composition of claim 11, wherein the amide-type local anesthetic and the enolic-acid NSAID are entrapped in the microsphere. 13. The composition of claim 8, wherein the implantable device is an osmotic pump with a reservoir comprising the amide-type local anesthetic and the enolic-acid NSAID. 14. The composition of claim 7, wherein the sustained-release delivery vehicle is a non-polymeric formulation comprising sucrose acetate isobutyrate. 15. The composition of claim 7, wherein the sustained-release delivery vehicle is a polymeric formulation in the form of a semi-solid polymer formulation comprising a polymer, the amide-type local anesthetic and the enolic-acid NSAID. 16. The composition of claim 15, wherein the polymer is a bioerodible or biodegradable polymer. 17. The composition of claim 15, wherein the polymer formulation forms an implant or depot in situ. 18. The composition of claim 15, wherein the polymer is selected from the group consisting of polylactides, polyglycolides, poly(lactic-co-glycolic acid) copolymers, polycaprolactones, poly-3-hydroxybutyrates, and polyorthoesters. 19. The composition of claim 15, wherein the polymer is a polyorthoester. 20. The composition of claim 1, wherein the delivery vehicle is an aqueous solution. 21. A method for managing pain in a subject in need thereof, comprising: administering to the subject a composition according to claim 1. 22. A method for prophylactic treatment of pain in a subject, comprising: administering to the subject a composition according to claim 1. 23. The method of claim 21, wherein the administering is intramuscular, subcutaneous, perineural or to a wound. 24. The method of claim 23, wherein the pain is acute pain or chronic pain. 25. A semi-solid composition, comprising: a biodegradable polyorthoester, an amide-type local anesthetic, and an enolic-acid non-steroidal anti-inflammatory drug (NSAID). 26. The composition of claim 25, wherein the amide-type local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, and tetracaine. 27. The composition of claim 25, wherein amide-type local anesthetic is ropivacaine or bupivacaine. 28. The composition of claim 25, wherein the enolic-acid NSAID is selected from the group consisting of meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam. 29. The composition of claim 25, wherein the enolic-acid NSAID is meloxicam. 30. The composition of claim 25, wherein the amide-type local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt %. 31. The composition of claim 25, wherein the enolic-acid NSAID is present in an amount above about 0.01 wt % of the composition. 32. The composition of claim 25, wherein the polyorthoester comprised in the composition is selected from the polyorthoesters represented by Formulas I, II, III and IV. 33. The composition of claim 25, wherein the polyorthoester is represented by Formula I. 34. The composition of claim 25, further comprising a protic or an aprotic solvent. 35. The composition of claim 25, further comprising a triglyceride viscosity reducing agent, wherein the triglyceride viscosity reducing agent comprises three fatty acid groups each independently comprising between 1-7 carbon atoms. 36. A method for managing pain in a subject in need thereof, comprising: administering to the subject a composition of claim 25. 37. A method for prophylactic treatment of pain in a subject, comprising: administering to the subject a composition of claim 25. 38. The method of claim 36, wherein the administering is intramuscular, subcutaneous, perineural or to a wound. 39. The method of claim 38, wherein the pain is acute pain or chronic pain. 40. A composition, comprising: a first therapeutic agent and a delivery vehicle comprised of a 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. 41. The composition of claim 40, wherein the composition has a viscosity ranging from about 2500 mPa-s to 10000 mPa-s when measured at 25° C. using a viscometer. 42. The composition of claim 40, wherein the viscosity of the composition is 10 to 40-fold lower than the viscosity of a similar composition with no triglyceride viscosity reducing agent when measured at 25° C. using a viscometer. 43. The composition of claim 40, wherein the triglyceride viscosity reducing agent is selected from the group consisting of triacetin and tributyrin. 44. The composition of claim 40, wherein the polar aprotic solvent is selected from dimethylsulfoxide, N-methyl pyrrolidone and dimethyl acetamide. 45. The composition of claim 40, wherein the first therapeutic agent is soluble in the triglyceride viscosity reducing agent, the polar aprotic solvent, or a mixture thereof. 46. The composition of claim 40, wherein the first therapeutic agent is an anesthetic. 47. The composition of claim 40, wherein the first therapeutic agent is selected from the group consisting of bupivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and ropivacaine. 48. The composition of claim 40, wherein the first therapeutic agent is an anti-emetic. 49. The composition of claim 40, wherein the composition comprises a second therapeutic agent. 50. The composition of claim 49, wherein the first therapeutic agent is an amide-type local anesthetic and the second therapeutic agent is a non-steroidal anti-inflammatory drug (NSAID). 51. The composition of claim 50, wherein the first therapeutic agent is selected from the group consisting of bupivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and ropivacaine. 52. The composition of claim 50, wherein the NSAID is an enolic-acid NSAID. 53. The composition of claim 52, wherein the enolic-acid NSAID is selected from the group consisting of meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam. 54. The composition of claim 50, wherein the amide-type local anesthetic is bupivacaine or ropivacaine and the enolic-acid NSAID is meloxicam. 55. The composition of claim 54, wherein the amide-type local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt %. 56. The composition of claim 54, wherein the enolic-acid NSAID is present in an amount above about 0.01 wt % of the composition. 57. The composition of claim 40, wherein the polyorthoester is selected from the polyorthoesters represented by Formulas I, II, III and IV. 58. The composition of claim 40, wherein the polyorthoester is represented by Formula I. 59. The pharmaceutical composition of claim 40, wherein the first therapeutic agent is released from the composition over a time period of about 1 day to about 8 weeks. 60. A method of treatment, comprising: administering to a patient in need thereof the pharmaceutical composition according to claim 40. 61. The method according to claim 60, wherein the patient is experiencing pain or is in need of prophylactic treatment for pain and the first therapeutic agent provides pain relief. 62. The method of claim 61, wherein the pain is acute pain or chronic pain. 63. The method of claim 60, wherein the administering is intramuscular, subcutaneous, perineural or to a wound. 64. A method for prophylactic treatment of nausea, comprising: administering to a patient in need thereof the composition according to claim 60, wherein the first therapeutic agent is granisetron. 65. A method for extending duration of pain relief of a polyorthoester composition comprising an amide-type local anesthetic, comprising: incorporating in the composition an enolic acid-NSAID in an amount effective to extend the duration of pain relief provided by the composition when compared to a similar composition lacking the effective amount of the enolic acid-NSAID. 66. The method of claim 65, wherein the enolic acid-NSAID containing composition provides pain relief for a period of time of about 3 days to about 5 days following administration. 67. The method of claim 65, wherein the amide-type local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and ropivacaine. 68. The method of claim 65, wherein the enolic-acid NSAID is selected from the group consisting of meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam. 69. The method of claim 65, wherein the amide-type local anesthetic is bupivacaine or ropivacaine and the enolic-acid NSAID is meloxicam. 70. The method of claim 65, wherein the amide-type local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt %. 71. The method of claim 70, wherein the enolic-acid NSAID is present in an amount above about 0.01 wt % of the composition. 72. The method of claim 65, wherein the polyorthoester is selected from the polyorthoesters represented by Formulas I, II, III and IV. 73. The method of claim 65, wherein the polyorthoester is represented by Formula I. 74. The method of claim 65, further comprising administering the composition to a person in need thereof, whereby said administering provides, as measured in an in vivo model for post-operative 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. 75. The method of claim 74, wherein the composition provides pain relief over days 2-5 following administration that is at least, on average, about 50% of the average pain relief provided by the composition 1-5 hours post-administration. 76. The method of claim 65, 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 least 5 days following administration. 77. The method of claim 65, 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 5 days when measured in an in vitro test at 37° C. 78. The method of claim 65, wherein the administering is at a nerve, into the epidural space, intrathecal, or directly to a surgical site or wound. 79. A method for providing pain relief to a patient in need thereof, comprising:
providing a composition according to claim 1, and instructing that the composition be administered to the patient to provide pain relief for an extended period. 80. The method of claim 79, wherein the extended period is for at least 5 days. 81. The method of claim 79, wherein the extended period is for up to 5 days. 82. The method of claim 79, wherein the extended period is from about 1 day to at least about 5 days. 83. The method of claim 79, wherein the extended period is for about 3 days. 84. The method of claim 79, wherein the instructing that the composition be administered comprises instructing that the composition be administered subcutaneously at or near a wound site. 85. A method for providing pain relief to a patient in need thereof, comprising:
providing a composition according to claim 40, and instructing that the composition be administered to the patient to provide pain relief for an extended period. | 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, comprising: an amide-type local anesthetic, an enolic-acid non-steroidal anti-inflammatory drug (NSAID) and a delivery vehicle. 2. The composition of claim 1, wherein the amide-type local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, and tetracaine. 3. The composition of claim 1, wherein the enolic-acid NSAID is selected from the group consisting of meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam. 4. The composition of claim 1, wherein the amide-type local anesthetic is bupivacaine or ropivacaine and the enolic-acid NSAID is meloxicam. 5. The composition of claim 4, wherein the amide-type local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt %. 6. The composition of claim 1, wherein the enolic-acid NSAID is present in an amount above about 0.01 wt % of the composition. 7. The composition of claim 1, wherein the delivery vehicle is a sustained-release delivery vehicle. 8. The composition of claim 7, wherein the sustained-release delivery vehicle is a polymeric formulation, a liposome, a microsphere, an implantable device or a non-polymeric formulation. 9. The composition of claim 7, wherein the sustained-release delivery vehicle 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). 10. The composition of claim 9, wherein the amide-type local anesthetic and the enolic-acid NSAID are entrapped in an aqueous space of the liposome or in a lipid layer of the liposome. 11. The composition of claim 7, wherein the sustained-release delivery vehicle is a microsphere comprised of a bioerodible or biodegradable polymer. 12. The composition of claim 11, wherein the amide-type local anesthetic and the enolic-acid NSAID are entrapped in the microsphere. 13. The composition of claim 8, wherein the implantable device is an osmotic pump with a reservoir comprising the amide-type local anesthetic and the enolic-acid NSAID. 14. The composition of claim 7, wherein the sustained-release delivery vehicle is a non-polymeric formulation comprising sucrose acetate isobutyrate. 15. The composition of claim 7, wherein the sustained-release delivery vehicle is a polymeric formulation in the form of a semi-solid polymer formulation comprising a polymer, the amide-type local anesthetic and the enolic-acid NSAID. 16. The composition of claim 15, wherein the polymer is a bioerodible or biodegradable polymer. 17. The composition of claim 15, wherein the polymer formulation forms an implant or depot in situ. 18. The composition of claim 15, wherein the polymer is selected from the group consisting of polylactides, polyglycolides, poly(lactic-co-glycolic acid) copolymers, polycaprolactones, poly-3-hydroxybutyrates, and polyorthoesters. 19. The composition of claim 15, wherein the polymer is a polyorthoester. 20. The composition of claim 1, wherein the delivery vehicle is an aqueous solution. 21. A method for managing pain in a subject in need thereof, comprising: administering to the subject a composition according to claim 1. 22. A method for prophylactic treatment of pain in a subject, comprising: administering to the subject a composition according to claim 1. 23. The method of claim 21, wherein the administering is intramuscular, subcutaneous, perineural or to a wound. 24. The method of claim 23, wherein the pain is acute pain or chronic pain. 25. A semi-solid composition, comprising: a biodegradable polyorthoester, an amide-type local anesthetic, and an enolic-acid non-steroidal anti-inflammatory drug (NSAID). 26. The composition of claim 25, wherein the amide-type local anesthetic is selected from the group consisting of bupivacaine, ropivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, and tetracaine. 27. The composition of claim 25, wherein amide-type local anesthetic is ropivacaine or bupivacaine. 28. The composition of claim 25, wherein the enolic-acid NSAID is selected from the group consisting of meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam. 29. The composition of claim 25, wherein the enolic-acid NSAID is meloxicam. 30. The composition of claim 25, wherein the amide-type local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt %. 31. The composition of claim 25, wherein the enolic-acid NSAID is present in an amount above about 0.01 wt % of the composition. 32. The composition of claim 25, wherein the polyorthoester comprised in the composition is selected from the polyorthoesters represented by Formulas I, II, III and IV. 33. The composition of claim 25, wherein the polyorthoester is represented by Formula I. 34. The composition of claim 25, further comprising a protic or an aprotic solvent. 35. The composition of claim 25, further comprising a triglyceride viscosity reducing agent, wherein the triglyceride viscosity reducing agent comprises three fatty acid groups each independently comprising between 1-7 carbon atoms. 36. A method for managing pain in a subject in need thereof, comprising: administering to the subject a composition of claim 25. 37. A method for prophylactic treatment of pain in a subject, comprising: administering to the subject a composition of claim 25. 38. The method of claim 36, wherein the administering is intramuscular, subcutaneous, perineural or to a wound. 39. The method of claim 38, wherein the pain is acute pain or chronic pain. 40. A composition, comprising: a first therapeutic agent and a delivery vehicle comprised of a 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. 41. The composition of claim 40, wherein the composition has a viscosity ranging from about 2500 mPa-s to 10000 mPa-s when measured at 25° C. using a viscometer. 42. The composition of claim 40, wherein the viscosity of the composition is 10 to 40-fold lower than the viscosity of a similar composition with no triglyceride viscosity reducing agent when measured at 25° C. using a viscometer. 43. The composition of claim 40, wherein the triglyceride viscosity reducing agent is selected from the group consisting of triacetin and tributyrin. 44. The composition of claim 40, wherein the polar aprotic solvent is selected from dimethylsulfoxide, N-methyl pyrrolidone and dimethyl acetamide. 45. The composition of claim 40, wherein the first therapeutic agent is soluble in the triglyceride viscosity reducing agent, the polar aprotic solvent, or a mixture thereof. 46. The composition of claim 40, wherein the first therapeutic agent is an anesthetic. 47. The composition of claim 40, wherein the first therapeutic agent is selected from the group consisting of bupivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and ropivacaine. 48. The composition of claim 40, wherein the first therapeutic agent is an anti-emetic. 49. The composition of claim 40, wherein the composition comprises a second therapeutic agent. 50. The composition of claim 49, wherein the first therapeutic agent is an amide-type local anesthetic and the second therapeutic agent is a non-steroidal anti-inflammatory drug (NSAID). 51. The composition of claim 50, wherein the first therapeutic agent is selected from the group consisting of bupivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and ropivacaine. 52. The composition of claim 50, wherein the NSAID is an enolic-acid NSAID. 53. The composition of claim 52, wherein the enolic-acid NSAID is selected from the group consisting of meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam. 54. The composition of claim 50, wherein the amide-type local anesthetic is bupivacaine or ropivacaine and the enolic-acid NSAID is meloxicam. 55. The composition of claim 54, wherein the amide-type local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt %. 56. The composition of claim 54, wherein the enolic-acid NSAID is present in an amount above about 0.01 wt % of the composition. 57. The composition of claim 40, wherein the polyorthoester is selected from the polyorthoesters represented by Formulas I, II, III and IV. 58. The composition of claim 40, wherein the polyorthoester is represented by Formula I. 59. The pharmaceutical composition of claim 40, wherein the first therapeutic agent is released from the composition over a time period of about 1 day to about 8 weeks. 60. A method of treatment, comprising: administering to a patient in need thereof the pharmaceutical composition according to claim 40. 61. The method according to claim 60, wherein the patient is experiencing pain or is in need of prophylactic treatment for pain and the first therapeutic agent provides pain relief. 62. The method of claim 61, wherein the pain is acute pain or chronic pain. 63. The method of claim 60, wherein the administering is intramuscular, subcutaneous, perineural or to a wound. 64. A method for prophylactic treatment of nausea, comprising: administering to a patient in need thereof the composition according to claim 60, wherein the first therapeutic agent is granisetron. 65. A method for extending duration of pain relief of a polyorthoester composition comprising an amide-type local anesthetic, comprising: incorporating in the composition an enolic acid-NSAID in an amount effective to extend the duration of pain relief provided by the composition when compared to a similar composition lacking the effective amount of the enolic acid-NSAID. 66. The method of claim 65, wherein the enolic acid-NSAID containing composition provides pain relief for a period of time of about 3 days to about 5 days following administration. 67. The method of claim 65, wherein the amide-type local anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine, and ropivacaine. 68. The method of claim 65, wherein the enolic-acid NSAID is selected from the group consisting of meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, and isoxicam. 69. The method of claim 65, wherein the amide-type local anesthetic is bupivacaine or ropivacaine and the enolic-acid NSAID is meloxicam. 70. The method of claim 65, wherein the amide-type local anesthetic is present in the composition at between about 0.01 wt % and about 7.5 wt %. 71. The method of claim 70, wherein the enolic-acid NSAID is present in an amount above about 0.01 wt % of the composition. 72. The method of claim 65, wherein the polyorthoester is selected from the polyorthoesters represented by Formulas I, II, III and IV. 73. The method of claim 65, wherein the polyorthoester is represented by Formula I. 74. The method of claim 65, further comprising administering the composition to a person in need thereof, whereby said administering provides, as measured in an in vivo model for post-operative 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. 75. The method of claim 74, wherein the composition provides pain relief over days 2-5 following administration that is at least, on average, about 50% of the average pain relief provided by the composition 1-5 hours post-administration. 76. The method of claim 65, 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 least 5 days following administration. 77. The method of claim 65, 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 5 days when measured in an in vitro test at 37° C. 78. The method of claim 65, wherein the administering is at a nerve, into the epidural space, intrathecal, or directly to a surgical site or wound. 79. A method for providing pain relief to a patient in need thereof, comprising:
providing a composition according to claim 1, and instructing that the composition be administered to the patient to provide pain relief for an extended period. 80. The method of claim 79, wherein the extended period is for at least 5 days. 81. The method of claim 79, wherein the extended period is for up to 5 days. 82. The method of claim 79, wherein the extended period is from about 1 day to at least about 5 days. 83. The method of claim 79, wherein the extended period is for about 3 days. 84. The method of claim 79, wherein the instructing that the composition be administered comprises instructing that the composition be administered subcutaneously at or near a wound site. 85. A method for providing pain relief to a patient in need thereof, comprising:
providing a composition according to claim 40, and instructing that the composition be administered to the patient to provide pain relief for an extended period. | 1,600 |
407 | 15,711,316 | 1,618 | The present invention is directed towards new 18 F-folate radiopharmaceuticals, wherein fluorine-18 is covalently linked to the glutamate portion of a folate or derivative thereof, a method of their preparation, as well as their use in diagnosis and monitoring of therapy of cancer and inflammatory and autoimmune diseases. | 1. A compound of formula I,
wherein
P is a pteroyl group or derivative thereof,
Xa, Xb are independently of each other C, N, O, S,
Ra, Rb are independently of each other H or straight-chain or branched C1-C12 alkyl, C3-C6 cycloalkyl, C5-C14 aryl or C5-C14 heteroaryl, which independently of each other are unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —SO2—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl; and
Z1, Z2are independently of each other H or 18F, with the proviso that one of Z1 and Z2 is 18F. 2. A compound according to claim 1 having formula II
wherein
X1 to X5 are independently of each other C or N,
R1 and R2 are independently of each other H, Hal, —OR′, —NR′R′″, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, and (C1-C12 alkylamino)carbonyl, wherein R′ is H or C1-C6 alkyl, and wherein R′ and R′″ are independently of each other selected from H, formyl, straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl,
R3, R4 are independently of each other H, formyl, trifluoroacetyl, iminomethyl, nitroso, straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C 1-C6 alkyl, or R3 and R4 form together a C1 or C2-bridge between X3 and X5,
R5 is H, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, and (C1-C12 alkylamino)carbonyl,
m is 0 or 1,
P is 0, 1 or 2,
q has a value of 1 to 7
Xa, Xb are independently of each other C, N, O, S,
Ra, Rbare independently of each other H or straight-chain or branched C1-C12 alkyl, C3-C6 cycloalkyl, C5-C14 aryl or C5-C14 heteroaryl, which independently of each other are unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —SO2—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl; and
Z1, Z2 are independently of each other H or 18F, with the proviso that one of Z1 and Z2 is 18F. 3. A compound according to claim 1 having formulae IIIa, IIIb, IVa, or IVb,
wherein
X1 to X5 are independently of each other C or N,
R1 and R2 are independently of each other H, Hal, —OR′, —NR″R′″, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, and (C1-C12 alkylamino)carbonyl, wherein R′ is H or C1-C6 alkyl, and wherein R″ and R′″ are independently of each other selected from H, formyl, straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—,—CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl,
R3, R4 are independently of each other H, formyl, trifluoroacetyl, iminomethyl, nitroso, straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl, or R3 and R4 form together a C1 or C2-bridge between X3 and X5,
R5 is H, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, or (Ci-C12 alkylamino)carbonyl,
m is 0 or 1,
p is 0, 1 or 2,
q has a value of 1 to 7,
Xa, Xb are independently of each other C, N, O, S,
Ra, Rb are independently of each other H or straight-chain or branched C1-C12 alkyl, C3-C6 cycloalkyl, C5-C14 aryl or C5-C14 heteroaryl, which independently of each other are unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —SO2—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl. 4. A compound according to claim 1, wherein R1 and R2 are independently of each other H, alkyl, —OR′, —NHR′, wherein R′ represents H or C1-C6 alkyl. 5. A compound according to claim 1, wherein R3 is H, formyl, C1-C12 alkyl or C1-C12 alkanoyl. 6. A compound according to claim 1, wherein R3 is H, formyl, or methyl. 7. A compound according to claim 1, wherein R4 is H, formyl, nitroso, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 alkanoyl. 8. A compound according to claim 1, wherein R4 is H, formyl, or methyl. 9. A compound according to wherein R5 is H, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, (C1-C12 alkoxy)carbonyl, or (C1-C12 alkylamino)carbonyl. 10. A compound according to claim 1, wherein R5 is H. 11. A compound according to claim 1 having formulae Va, Vb, VIa or VIb,
wherein,
Xa, Xb are independently of each other C, N, O, S,
Ra, Rbare independently of each other H or straight-chain or branched C1-Cu alkyl, C3-C6 cycloalkyl, C5-C14 aryl or C5-C14 heteroaryl, which independently of each other are unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —SO2—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl;
Y1, Y2are independently of each other selected from H, formyl, straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl,
Y3is selected from H, formyl, trifluoroacetyl, nitroso, straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by—O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl. 12. A compound according to claim 1 having formulae VIIa, VIlb, VIIa or VIIIb,
wherein,
Xa, Xb are independently of each other C, N, O, S,
Ra, Rbare independently of each other H or straight-chain or branched C 1-C12 alkyl, C3-C6 cycloalkyl, C5-C14 aryl or C5-C14 heteroaryl, which independently of each other are unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —SO2—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl;
p is 0, 1 or 2,
Y1, Y2are independently of each other selected from H, formyl, straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl,
R3 is H, formyl, iminomethyl, nitroso, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, halosubstituted C1-C12 alkanoyl, and
Y3is selected from H, formyl, trifluoroacetyl, nitroso, straight chain or branched C 1-C 12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl, or
R3 and Y3 form together a C1 or C2-bridge between the two N-atoms to which they are attached to. 13. (canceled) 14. (canceled) 15. Method for diagnostic imaging of a cell or population of cells expressing a folate-receptor, said method comprising the steps of administering at least one compound according to claim 1, diagnostic imaging amount, and obtaining a diagnostic image of said cell or population of cells. 16. Method according to claim 15, wherein the diagnostic imaging is performed of a cell or population of cells expressing a folate-receptor in vitro or in vivo. 17. Method for in vitro detection of a cell expressing the folate receptor in a tissue sample which includes contacting said tissue sample with a compound according to claim 1 in effective amounts and for sufficient time and conditions to allow binding to occur and detecting such binding by PET imaging. 18. Method of diagnostic imaging or monitoring a subject comprising the steps of (i) administering at least one compound according to claim 1 in a diagnostic imaging amount, and (ii) performing diagnostic imaging using PET by detecting a signal from said at least one compound. 19. Method of monitoring therapy of cancer and inflammatory and autoimmune diseases in a subject comprising the steps of (i) administering to a subject in need thereof at least one compound according to claim 1 in a diagnostic imaging amount in combination with a therapeutically active, and (ii) performing diagnostic imaging using PET by detecting a signal from said at least one compound to follow the course of therapy of cancer and inflammatory and autoimmune diseases. 20. Method of claim 15 used in combination with any other methods of diagnosis or therapy of cancer and inflammatory and autoimmune diseases. | The present invention is directed towards new 18 F-folate radiopharmaceuticals, wherein fluorine-18 is covalently linked to the glutamate portion of a folate or derivative thereof, a method of their preparation, as well as their use in diagnosis and monitoring of therapy of cancer and inflammatory and autoimmune diseases.1. A compound of formula I,
wherein
P is a pteroyl group or derivative thereof,
Xa, Xb are independently of each other C, N, O, S,
Ra, Rb are independently of each other H or straight-chain or branched C1-C12 alkyl, C3-C6 cycloalkyl, C5-C14 aryl or C5-C14 heteroaryl, which independently of each other are unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —SO2—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl; and
Z1, Z2are independently of each other H or 18F, with the proviso that one of Z1 and Z2 is 18F. 2. A compound according to claim 1 having formula II
wherein
X1 to X5 are independently of each other C or N,
R1 and R2 are independently of each other H, Hal, —OR′, —NR′R′″, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, and (C1-C12 alkylamino)carbonyl, wherein R′ is H or C1-C6 alkyl, and wherein R′ and R′″ are independently of each other selected from H, formyl, straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl,
R3, R4 are independently of each other H, formyl, trifluoroacetyl, iminomethyl, nitroso, straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C 1-C6 alkyl, or R3 and R4 form together a C1 or C2-bridge between X3 and X5,
R5 is H, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, and (C1-C12 alkylamino)carbonyl,
m is 0 or 1,
P is 0, 1 or 2,
q has a value of 1 to 7
Xa, Xb are independently of each other C, N, O, S,
Ra, Rbare independently of each other H or straight-chain or branched C1-C12 alkyl, C3-C6 cycloalkyl, C5-C14 aryl or C5-C14 heteroaryl, which independently of each other are unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —SO2—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl; and
Z1, Z2 are independently of each other H or 18F, with the proviso that one of Z1 and Z2 is 18F. 3. A compound according to claim 1 having formulae IIIa, IIIb, IVa, or IVb,
wherein
X1 to X5 are independently of each other C or N,
R1 and R2 are independently of each other H, Hal, —OR′, —NR″R′″, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, and (C1-C12 alkylamino)carbonyl, wherein R′ is H or C1-C6 alkyl, and wherein R″ and R′″ are independently of each other selected from H, formyl, straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—,—CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl,
R3, R4 are independently of each other H, formyl, trifluoroacetyl, iminomethyl, nitroso, straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl, or R3 and R4 form together a C1 or C2-bridge between X3 and X5,
R5 is H, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, C2-C12 alkenyl, C2-C12 alkynyl, (C1-C12 alkoxy)carbonyl, or (Ci-C12 alkylamino)carbonyl,
m is 0 or 1,
p is 0, 1 or 2,
q has a value of 1 to 7,
Xa, Xb are independently of each other C, N, O, S,
Ra, Rb are independently of each other H or straight-chain or branched C1-C12 alkyl, C3-C6 cycloalkyl, C5-C14 aryl or C5-C14 heteroaryl, which independently of each other are unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —SO2—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl. 4. A compound according to claim 1, wherein R1 and R2 are independently of each other H, alkyl, —OR′, —NHR′, wherein R′ represents H or C1-C6 alkyl. 5. A compound according to claim 1, wherein R3 is H, formyl, C1-C12 alkyl or C1-C12 alkanoyl. 6. A compound according to claim 1, wherein R3 is H, formyl, or methyl. 7. A compound according to claim 1, wherein R4 is H, formyl, nitroso, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 alkanoyl. 8. A compound according to claim 1, wherein R4 is H, formyl, or methyl. 9. A compound according to wherein R5 is H, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, (C1-C12 alkoxy)carbonyl, or (C1-C12 alkylamino)carbonyl. 10. A compound according to claim 1, wherein R5 is H. 11. A compound according to claim 1 having formulae Va, Vb, VIa or VIb,
wherein,
Xa, Xb are independently of each other C, N, O, S,
Ra, Rbare independently of each other H or straight-chain or branched C1-Cu alkyl, C3-C6 cycloalkyl, C5-C14 aryl or C5-C14 heteroaryl, which independently of each other are unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —SO2—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl;
Y1, Y2are independently of each other selected from H, formyl, straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl,
Y3is selected from H, formyl, trifluoroacetyl, nitroso, straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by—O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl. 12. A compound according to claim 1 having formulae VIIa, VIlb, VIIa or VIIIb,
wherein,
Xa, Xb are independently of each other C, N, O, S,
Ra, Rbare independently of each other H or straight-chain or branched C 1-C12 alkyl, C3-C6 cycloalkyl, C5-C14 aryl or C5-C14 heteroaryl, which independently of each other are unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —SO2—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl;
p is 0, 1 or 2,
Y1, Y2are independently of each other selected from H, formyl, straight chain or branched C1-C12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl,
R3 is H, formyl, iminomethyl, nitroso, C1-C12 alkyl, C1-C12 alkoxy, C1-C12 alkanoyl, halosubstituted C1-C12 alkanoyl, and
Y3is selected from H, formyl, trifluoroacetyl, nitroso, straight chain or branched C 1-C 12 alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2, and wherein one or more of embedded, non-adjacent CH2 groups may independently be replaced by —O—, —CO—, —CO—O—, —CO—NR′—, —CH═CH—, —C≡C—, wherein R′ is H or C1-C6 alkyl, or
R3 and Y3 form together a C1 or C2-bridge between the two N-atoms to which they are attached to. 13. (canceled) 14. (canceled) 15. Method for diagnostic imaging of a cell or population of cells expressing a folate-receptor, said method comprising the steps of administering at least one compound according to claim 1, diagnostic imaging amount, and obtaining a diagnostic image of said cell or population of cells. 16. Method according to claim 15, wherein the diagnostic imaging is performed of a cell or population of cells expressing a folate-receptor in vitro or in vivo. 17. Method for in vitro detection of a cell expressing the folate receptor in a tissue sample which includes contacting said tissue sample with a compound according to claim 1 in effective amounts and for sufficient time and conditions to allow binding to occur and detecting such binding by PET imaging. 18. Method of diagnostic imaging or monitoring a subject comprising the steps of (i) administering at least one compound according to claim 1 in a diagnostic imaging amount, and (ii) performing diagnostic imaging using PET by detecting a signal from said at least one compound. 19. Method of monitoring therapy of cancer and inflammatory and autoimmune diseases in a subject comprising the steps of (i) administering to a subject in need thereof at least one compound according to claim 1 in a diagnostic imaging amount in combination with a therapeutically active, and (ii) performing diagnostic imaging using PET by detecting a signal from said at least one compound to follow the course of therapy of cancer and inflammatory and autoimmune diseases. 20. Method of claim 15 used in combination with any other methods of diagnosis or therapy of cancer and inflammatory and autoimmune diseases. | 1,600 |
408 | 10,564,012 | 1,653 | The present invention is concerned the labelling of biological compounds with stable isotopes such that the three-dimensional structure of the biological compounds may be analysed by e.g. NMR spectroscopy. The invention employs microorganisms that are grown on mineral media comprising carbon and nitrogen sources that contain stable isotopes to produce biomass that is uniformly labelled with stable isotopes. The biomass may be autolysed to produce an autolysate. The biomass may further be extracted with organic solvent to produce lipids. The (delipidised) biomass is hydrolysed to produce labelled amino acids and other nutrients, which are used together with the autolysate, extracted lipids and further components to compose a culture medium for a mammalian or insect host cells for the production of biological compounds that are uniformly labelled with stable isotopes. The biological compound preferably is a biological acromolecule, such as e.g. a mammalian membrane protein. Data supplied from the esp@cenet database—Worldwide | 1. A method for producing a nutrient medium for growing mammalian or insect cells in culture whereby for at least one of H, C or N, substantially all atoms in substrates that are used by the cells for synthesis of biomolecules in the nutrient medium are isotopically labelled, whereby the method comprising the steps of:
(a) growing an organism on a mineral medium which supports growth of the organism, whereby in the medium substantially all of the assimilable atoms, for at least one of H, C or N, are isotopically labelled, to produce labelled biomass; (b) autolysing the biomass of an organism grown as in (a) to produce an autolysate; and, (c) composing the nutrient medium by combining the autolysate as obtained in (b) with further components necessary for growth of the mammalian or insect cells. 2. A method according to claim 1, wherein the organism is a fungus, yeast or algae. 3. A method according to claim 2, wherein the organism is an organism that belongs to a genus selected from Saccharontyces, Pichia, Hansenula, Kluyveroznyces, Candida, Brettanonzyces, Debaryonzyces, Tolrulopsis, Yarrowia, Galdieria, Cyanidiunt, Porphyridiunz, Cystocloniunz, Audouinella, and Cyanidioschyzon. 4. A method according to claim 1, wherein the method further comprises the steps of:
(a) growing an organism on a mineral medium which supports growth of the organism, whereby in the medium substantially all of the assimilable atoms, for at least one of H, C or N, are isotopically labelled, to produce labelled biomass; (b) extracting biomass of an organism with an organic solvent to produce an extract comprising lipids, whereby the organism is grown as in (a) or is grown as in (a) on a medium without isotopic substitution; (c) hydrolysing biomass of an organism grown as in (a) at a non-alkaline pH to produce a hydrolysate comprising amino acids; (d) composing the nutrient medium by combining the autolysate as obtained in any one of claims 1-3 with amino acids as obtained in (c) and adding further components necessary for growth of the mammalian or insect cells. 5. A methods according to claim 4, wherein in step (d) the nutrient medium is composed by combining the autolysate with the amino acids and the lipids and adding further components necessary for growth of the mammalian or insect cells. 6. A method according to claim 1, whereby the nutrient medium is composed of autolysate, lipids and amino acids obtained from at least two different organisms. 7. A method according to claim 1, whereby, prior to hydrolysis in (c), lipids and pigments are extracted from the biomass using an organic solvent. 8. A method according to claim 1, whereby the organism from which the lipids are extracted, belongs to a genus selected from the group consisting of Rhodophyta, Cyanidiophyceae, Chlorophyta, Cyanophyta, Diatoms, Phaeophyceae, Dinoflagelate, Dinophyta and Galdieria. 9. A method according to claim 1, whereby the organism from which the hydrolysate comprising amino acids is produced, is an organism selected from the group consisting of algae, fungi, yeasts and methylotrophic bacteria. 10. A, method according to claim 9, whereby the organism belongs to a genus selected from the group consisting of Pichia, Saccharoinyces, Hansenula, Cvanidiunr, Ga/dienia, Porphynidiunr, Spirzdirra, and Merhvlobacilhis. 11. A method according to claim 1, whereby the further components necessary for growth of the mammalian or insect cells comprise one or more of:
(a) one or more of glucose, fructose, and sucrose; (b) one or more Krebs-cycles intermediates selected from the group consisting of citrate, succinate, fumarate, maleic acid, oxalate and malate; (c) pyruvate; and, (d) one or more vitamins selected from the group consisting of thiamin, riboflavin, niacin, vitamin B6, folic acid, vitamin B 12, biotin, pantothenic acid, choline, paraaminobenzoic acid and alpha-tocopherol. 12. A method according to claim 1, whereby substantially all atoms in substrates that are used by the mammalian or insect cells for synthesis of biomolecules in the nutrient medium are isotopically labelled with an isotope selected from 15N; 13C; 2H; 15N and 13C; 15N and 2H; 13C and 2H; or 15N, 13C and 2H. 13. A method for producing a biomolecule, whereby substantially all atoms in the biomolecule are isotopically labelled, the method comprising the steps of:
(a) growing a culture of mammalian or insect cells capable of producing the biomolecule under conditions conducive to the production of the biomolecule, in a nutrient medium produced in a method according to claim 1; and (b) recovery of the biomolecule. 14. A method according to claim 13, wherein the biomolecule is a soluble protein or a membrane protein. 15. A method according to claim 14, wherein the mammalian or insect cells capable of producing the protein comprise an expression vector comprising a nucleotide sequence coding for the protein. 16. A method according to claim 14, wherein the protein is a mammalian protein. 17. A method for obtaining structural information on a biomolecule, the method comprising the steps of:
(a) producing a biomolecule, whereby substantially all atoms in the biomolecule are isotopically labelled, in a method according to; (b) optionally, purifying the biomolecule; (c) subjecting the biomolecule to spectroscopic analysis to obtain information about its structure. 18. A method according to claim 17, wherein the spectroscopic analysis comprises NMR spectroscopy. 19. A method according to claim 17, wherein the structural information on a biomolecule is information about the three-dimensional structure of the biomolecule. 20. A method according to claim 17, wherein the biomolecule is a protein complexed to a second biomolecule. 21. A method according to claim 20, whereby 20-100% of the hydrogen atoms in the second biomolecule are uniformly substituted with the isotope 2H. 22. A method according to claim 21, wherein the second biomolecule is a protein. 23. A nutrient medium for the production of an isotopically labelled biomolecule from mammalian or insect cells, the medium supporting growth of a mammalian or insect cell culture under condition conducive to the production of the biomolecule, the medium comprising:
(a) a mixture of inorganic salts; (b) a source of amino acids; (c) a carbohydrate energy source; (d) a source of lipids; (e) optionally, a protective agent; (f) optionally, vitamins and/or organic compounds; (g) optionally, organic acids; and, (h) optionally, trace elements; whereby substantially all atoms in (a), (b), and (c), and, optionally in (d), (e), (f), (g) and (h) are isotopically labelled for at least one of H, C or N or whereby 20-100% of the hydrogen atoms in (a), (b), and (c), and, optionally in (d), (e), (f), (g) and (h) are uniformly substituted with the isotope 2H. 24. A nutrient medium according to claim 23, whereby the source of amino acids comprises an hydrolysate comprising amino acids that is produced from yeast biomass, whereby the hydrolysis of the biomass comprises autohydrolysis. 25. A nutrient medium according to claim 23, whereby the source of lipids comprises fatty acids, steroids, and lipid soluble vitamins. 26. A nutrient medium according to claim 23, whereby the carbohydrate energy source is one or more of glucose, fructose, and sucrose; the organic acids are one or more of pyruvate and the Krebs-cycles intermediates selected from the group consisting of citrate, succinate, fumarate, maleic acid, oxalate and malate; the vitamins are one or more vitamins selected from the group consisting of thiamin, riboflavin, niacin, vitamin B6, folic acid, vitamin B12, biotin, pantothenic acid, choline, para-aminobenzoic acid and alpha-tocopherol. 27. A nutrient medium according to claim 23, whereby substantially all atoms in (a), (b), and (c), and, optionally in (d), (e), (f), (g) and (h) are isotopically labelled with an isotope selected from 15N; 13C; 2H; 15N and 13C; 15N and 2H; 13C and 2H; or 15N, 13C and 2H. 28. A mammalian membrane protein whereby substantially all atoms in the protein are isotopically labelled with an isotope selected from 15N, 13C 2H 15N and 13C, ′5N and 2H, 13C, and 2H, or 13C and 2H. 29. A mammalian membrane protein whereby 20-100% of the hydrogen atoms in the protein are uniformly substituted with the isotope 2H. 30. A mammalian membrane protein according to claim 28, whereby the protein is a human protein. | The present invention is concerned the labelling of biological compounds with stable isotopes such that the three-dimensional structure of the biological compounds may be analysed by e.g. NMR spectroscopy. The invention employs microorganisms that are grown on mineral media comprising carbon and nitrogen sources that contain stable isotopes to produce biomass that is uniformly labelled with stable isotopes. The biomass may be autolysed to produce an autolysate. The biomass may further be extracted with organic solvent to produce lipids. The (delipidised) biomass is hydrolysed to produce labelled amino acids and other nutrients, which are used together with the autolysate, extracted lipids and further components to compose a culture medium for a mammalian or insect host cells for the production of biological compounds that are uniformly labelled with stable isotopes. The biological compound preferably is a biological acromolecule, such as e.g. a mammalian membrane protein. Data supplied from the esp@cenet database—Worldwide1. A method for producing a nutrient medium for growing mammalian or insect cells in culture whereby for at least one of H, C or N, substantially all atoms in substrates that are used by the cells for synthesis of biomolecules in the nutrient medium are isotopically labelled, whereby the method comprising the steps of:
(a) growing an organism on a mineral medium which supports growth of the organism, whereby in the medium substantially all of the assimilable atoms, for at least one of H, C or N, are isotopically labelled, to produce labelled biomass; (b) autolysing the biomass of an organism grown as in (a) to produce an autolysate; and, (c) composing the nutrient medium by combining the autolysate as obtained in (b) with further components necessary for growth of the mammalian or insect cells. 2. A method according to claim 1, wherein the organism is a fungus, yeast or algae. 3. A method according to claim 2, wherein the organism is an organism that belongs to a genus selected from Saccharontyces, Pichia, Hansenula, Kluyveroznyces, Candida, Brettanonzyces, Debaryonzyces, Tolrulopsis, Yarrowia, Galdieria, Cyanidiunt, Porphyridiunz, Cystocloniunz, Audouinella, and Cyanidioschyzon. 4. A method according to claim 1, wherein the method further comprises the steps of:
(a) growing an organism on a mineral medium which supports growth of the organism, whereby in the medium substantially all of the assimilable atoms, for at least one of H, C or N, are isotopically labelled, to produce labelled biomass; (b) extracting biomass of an organism with an organic solvent to produce an extract comprising lipids, whereby the organism is grown as in (a) or is grown as in (a) on a medium without isotopic substitution; (c) hydrolysing biomass of an organism grown as in (a) at a non-alkaline pH to produce a hydrolysate comprising amino acids; (d) composing the nutrient medium by combining the autolysate as obtained in any one of claims 1-3 with amino acids as obtained in (c) and adding further components necessary for growth of the mammalian or insect cells. 5. A methods according to claim 4, wherein in step (d) the nutrient medium is composed by combining the autolysate with the amino acids and the lipids and adding further components necessary for growth of the mammalian or insect cells. 6. A method according to claim 1, whereby the nutrient medium is composed of autolysate, lipids and amino acids obtained from at least two different organisms. 7. A method according to claim 1, whereby, prior to hydrolysis in (c), lipids and pigments are extracted from the biomass using an organic solvent. 8. A method according to claim 1, whereby the organism from which the lipids are extracted, belongs to a genus selected from the group consisting of Rhodophyta, Cyanidiophyceae, Chlorophyta, Cyanophyta, Diatoms, Phaeophyceae, Dinoflagelate, Dinophyta and Galdieria. 9. A method according to claim 1, whereby the organism from which the hydrolysate comprising amino acids is produced, is an organism selected from the group consisting of algae, fungi, yeasts and methylotrophic bacteria. 10. A, method according to claim 9, whereby the organism belongs to a genus selected from the group consisting of Pichia, Saccharoinyces, Hansenula, Cvanidiunr, Ga/dienia, Porphynidiunr, Spirzdirra, and Merhvlobacilhis. 11. A method according to claim 1, whereby the further components necessary for growth of the mammalian or insect cells comprise one or more of:
(a) one or more of glucose, fructose, and sucrose; (b) one or more Krebs-cycles intermediates selected from the group consisting of citrate, succinate, fumarate, maleic acid, oxalate and malate; (c) pyruvate; and, (d) one or more vitamins selected from the group consisting of thiamin, riboflavin, niacin, vitamin B6, folic acid, vitamin B 12, biotin, pantothenic acid, choline, paraaminobenzoic acid and alpha-tocopherol. 12. A method according to claim 1, whereby substantially all atoms in substrates that are used by the mammalian or insect cells for synthesis of biomolecules in the nutrient medium are isotopically labelled with an isotope selected from 15N; 13C; 2H; 15N and 13C; 15N and 2H; 13C and 2H; or 15N, 13C and 2H. 13. A method for producing a biomolecule, whereby substantially all atoms in the biomolecule are isotopically labelled, the method comprising the steps of:
(a) growing a culture of mammalian or insect cells capable of producing the biomolecule under conditions conducive to the production of the biomolecule, in a nutrient medium produced in a method according to claim 1; and (b) recovery of the biomolecule. 14. A method according to claim 13, wherein the biomolecule is a soluble protein or a membrane protein. 15. A method according to claim 14, wherein the mammalian or insect cells capable of producing the protein comprise an expression vector comprising a nucleotide sequence coding for the protein. 16. A method according to claim 14, wherein the protein is a mammalian protein. 17. A method for obtaining structural information on a biomolecule, the method comprising the steps of:
(a) producing a biomolecule, whereby substantially all atoms in the biomolecule are isotopically labelled, in a method according to; (b) optionally, purifying the biomolecule; (c) subjecting the biomolecule to spectroscopic analysis to obtain information about its structure. 18. A method according to claim 17, wherein the spectroscopic analysis comprises NMR spectroscopy. 19. A method according to claim 17, wherein the structural information on a biomolecule is information about the three-dimensional structure of the biomolecule. 20. A method according to claim 17, wherein the biomolecule is a protein complexed to a second biomolecule. 21. A method according to claim 20, whereby 20-100% of the hydrogen atoms in the second biomolecule are uniformly substituted with the isotope 2H. 22. A method according to claim 21, wherein the second biomolecule is a protein. 23. A nutrient medium for the production of an isotopically labelled biomolecule from mammalian or insect cells, the medium supporting growth of a mammalian or insect cell culture under condition conducive to the production of the biomolecule, the medium comprising:
(a) a mixture of inorganic salts; (b) a source of amino acids; (c) a carbohydrate energy source; (d) a source of lipids; (e) optionally, a protective agent; (f) optionally, vitamins and/or organic compounds; (g) optionally, organic acids; and, (h) optionally, trace elements; whereby substantially all atoms in (a), (b), and (c), and, optionally in (d), (e), (f), (g) and (h) are isotopically labelled for at least one of H, C or N or whereby 20-100% of the hydrogen atoms in (a), (b), and (c), and, optionally in (d), (e), (f), (g) and (h) are uniformly substituted with the isotope 2H. 24. A nutrient medium according to claim 23, whereby the source of amino acids comprises an hydrolysate comprising amino acids that is produced from yeast biomass, whereby the hydrolysis of the biomass comprises autohydrolysis. 25. A nutrient medium according to claim 23, whereby the source of lipids comprises fatty acids, steroids, and lipid soluble vitamins. 26. A nutrient medium according to claim 23, whereby the carbohydrate energy source is one or more of glucose, fructose, and sucrose; the organic acids are one or more of pyruvate and the Krebs-cycles intermediates selected from the group consisting of citrate, succinate, fumarate, maleic acid, oxalate and malate; the vitamins are one or more vitamins selected from the group consisting of thiamin, riboflavin, niacin, vitamin B6, folic acid, vitamin B12, biotin, pantothenic acid, choline, para-aminobenzoic acid and alpha-tocopherol. 27. A nutrient medium according to claim 23, whereby substantially all atoms in (a), (b), and (c), and, optionally in (d), (e), (f), (g) and (h) are isotopically labelled with an isotope selected from 15N; 13C; 2H; 15N and 13C; 15N and 2H; 13C and 2H; or 15N, 13C and 2H. 28. A mammalian membrane protein whereby substantially all atoms in the protein are isotopically labelled with an isotope selected from 15N, 13C 2H 15N and 13C, ′5N and 2H, 13C, and 2H, or 13C and 2H. 29. A mammalian membrane protein whereby 20-100% of the hydrogen atoms in the protein are uniformly substituted with the isotope 2H. 30. A mammalian membrane protein according to claim 28, whereby the protein is a human protein. | 1,600 |
409 | 15,565,983 | 1,613 | Emulsifiers for emulsions vaccine formulations and use in water-in-oil emulsion for vaccine formulations as an emulsifier. The emulsifier is an alkoxylated polyol or polyamine which is optionally acyl terminated. There is also provided a method of forming the vaccine formulation. The emulsifiers provide for emulsions which may require less emulsifier than known emulsifiers, and provide stable emulsions. | 1. A vaccine formulation comprising a water-in-oil emulsion and at least one vaccine antigen, oil, and water, where said emulsion comprises an emulsifier being an alkoxylated polyol or polyamine which is optionally acyl terminated. 2. The formulation according to claim 1, where the emulsifier has a general structure (I):
R1.[(AO)n—R2]m (I)
wherein R1 is the residue of a polyol or polyamine, each said polyol or polyamine having m active hydrogen atoms, where m is an integer of at least 2;
AO is an oxyalkylene group;
each n independently represents an integer in the range from 1 to 100;
each R2 independently represents hydrogen, or an acyl group represented by —C(O)R3 wherein each R3 independently represents a residue of polyhydroxyalkyl carboxylic acid, polyhydroxyalkenyl carboxylic acid, hydroxyalkyl carboxylic acid, hydroxyalkenyl carboxylic acid, oligomer of hydroxyalkyl carboxylic acid, or oligomer of hydroxyalkenyl carboxylic acid; and
wherein on average at least two R2 groups per molecule are alkanoyl groups as defined. 3. The formulation according to claim 2, wherein R1 is the residue of a group having at least 3 free hydroxyl and/or amino groups. 4. The formulation according to claim 2, wherein R1 is the residue of a sugar. 5. The formulation according to claim 1, where the emulsifier has a molecular weight of from 3,000 to 8,000. 6. The formulation according to claim 1, where the emulsifier has an HLB from 1.3 to 15. 7. The formulation according to claim 1, where the water-in-oil emulsion comprises 0.1 wt. % to 15 wt. % of the emulsifier. 8. The formulation according to claim 1, where the zero-shear viscosity of the emulsion at 0 days is less than 130 cP. 9. The formulation according to claim 1, where water particles present in emulsion have a D(v,0.5) value at 0 days in the range from 0.7 μm to 7.0 μm. 10. The formulation according to claim 1, where the emulsification efficiency value is greater than 15. 11. A method of forming a vaccine formulation which comprises mixing together:
(i) at least one emulsifier, said emulsifier being an alkoxylated polyol or polyamine which is optionally acyl terminated; (ii) at least one vaccine antigen; (iii) oil; and (iv) water. 12. (canceled) 13. A water-in-oil emulsion comprising an emulsifier being an alkoxylated polyol or polyamine which is optionally acyl terminated, said emulsifier being present in the emulsion in the range from 0.1 wt. % to 10 wt. %. 14. An oil phase comprising oil and an emulsifier being an alkoxylated polyol or polyamine which is optionally acyl terminated, said oil phase suitable for forming a vaccine formulation according to claim 1. 15. The formulation according to claim 4, wherein R1 is the residue of a monosaccharide. | Emulsifiers for emulsions vaccine formulations and use in water-in-oil emulsion for vaccine formulations as an emulsifier. The emulsifier is an alkoxylated polyol or polyamine which is optionally acyl terminated. There is also provided a method of forming the vaccine formulation. The emulsifiers provide for emulsions which may require less emulsifier than known emulsifiers, and provide stable emulsions.1. A vaccine formulation comprising a water-in-oil emulsion and at least one vaccine antigen, oil, and water, where said emulsion comprises an emulsifier being an alkoxylated polyol or polyamine which is optionally acyl terminated. 2. The formulation according to claim 1, where the emulsifier has a general structure (I):
R1.[(AO)n—R2]m (I)
wherein R1 is the residue of a polyol or polyamine, each said polyol or polyamine having m active hydrogen atoms, where m is an integer of at least 2;
AO is an oxyalkylene group;
each n independently represents an integer in the range from 1 to 100;
each R2 independently represents hydrogen, or an acyl group represented by —C(O)R3 wherein each R3 independently represents a residue of polyhydroxyalkyl carboxylic acid, polyhydroxyalkenyl carboxylic acid, hydroxyalkyl carboxylic acid, hydroxyalkenyl carboxylic acid, oligomer of hydroxyalkyl carboxylic acid, or oligomer of hydroxyalkenyl carboxylic acid; and
wherein on average at least two R2 groups per molecule are alkanoyl groups as defined. 3. The formulation according to claim 2, wherein R1 is the residue of a group having at least 3 free hydroxyl and/or amino groups. 4. The formulation according to claim 2, wherein R1 is the residue of a sugar. 5. The formulation according to claim 1, where the emulsifier has a molecular weight of from 3,000 to 8,000. 6. The formulation according to claim 1, where the emulsifier has an HLB from 1.3 to 15. 7. The formulation according to claim 1, where the water-in-oil emulsion comprises 0.1 wt. % to 15 wt. % of the emulsifier. 8. The formulation according to claim 1, where the zero-shear viscosity of the emulsion at 0 days is less than 130 cP. 9. The formulation according to claim 1, where water particles present in emulsion have a D(v,0.5) value at 0 days in the range from 0.7 μm to 7.0 μm. 10. The formulation according to claim 1, where the emulsification efficiency value is greater than 15. 11. A method of forming a vaccine formulation which comprises mixing together:
(i) at least one emulsifier, said emulsifier being an alkoxylated polyol or polyamine which is optionally acyl terminated; (ii) at least one vaccine antigen; (iii) oil; and (iv) water. 12. (canceled) 13. A water-in-oil emulsion comprising an emulsifier being an alkoxylated polyol or polyamine which is optionally acyl terminated, said emulsifier being present in the emulsion in the range from 0.1 wt. % to 10 wt. %. 14. An oil phase comprising oil and an emulsifier being an alkoxylated polyol or polyamine which is optionally acyl terminated, said oil phase suitable for forming a vaccine formulation according to claim 1. 15. The formulation according to claim 4, wherein R1 is the residue of a monosaccharide. | 1,600 |
410 | 15,346,189 | 1,617 | The invention is directed to an aqueous seed coating composition comprising one or more active ingredients, to a pre-blend and use thereof as a component of the seed coating composition, to a method for improving the bio-efficacy of an active ingredient in a seed coating, and to a coated seed.
The seed coating composition and/or pre-blend of the invention further comprise a wax, and at least one pigment. | 1. An aqueous seed coating composition comprising a wax, at least one pigment, an optional surface active agent and one or more biologically active ingredients. 2. The seed coating composition according to claim 1, wherein the wax is selected from the group consisting of polyethylene wax, Fischer-Tropsch wax, and carnauba wax. 3. The seed coating composition according to claim 1, comprising an effect pigment and a color pigment. 4. The seed coating composition according to claim 3, wherein the total amount of pigment is 11-15% based on the total weight of the composition. 5. The seed coating composition according to claim 1 wherein the amount of wax is 5-10% by weight based on the total weight of the composition. 6. The seed coating composition according to claim 1 comprising at least one hydrophobic and/or water insoluble biologically active ingredient. 7. The seed coating composition according to claim 1 wherein the biologically active ingredient comprises bacteria. 8. The seed coating composition according to claim 1 comprising substantially no polymeric binder other than wax. 9. A method of forming a seed coating composition which comprises combining (i) an aqueous pre-blend comprising a wax, at least one first pigment, and an optional surface active agent, (ii) one or more biologically active ingredients, (iii) a dye and/or second pigment different to the first pigment, and (iv) optionally water. 10. The method according to claim 9 wherein the wax in the pre-blend is selected from the group consisting of polyethylene wax, Fischer-Tropsch wax, and carnauba wax. 11. The method according to claim 9 wherein the first pigment is an effect pigment and the second pigment is a colored pigment. 12. The method according to claim 9 wherein (i) the amount of wax in the pre-blend is 40-85% by weight based on the total weight of solids in the pre-blend, (ii) the amount of pigment in the pre-blend is 15-60% by weight based on the total weight of solids in the pre-blend, and/or (iii) the ratio of wax to pigment in the pre-blend is 1.3-2.0:1 by weight. 13. The method according to claim 9 wherein the seed coating composition comprises at least one hydrophobic and/or water insoluble biologically active ingredient. 14. The method according to claim 9 wherein the amount of surface active agent in the pre-blend is 0.4-3.5% by weight based on the total weight of solids in the pre-blend. 15. The method according to claim 9 wherein the amount of wax in the seed coating composition is 4-12% by weight based on the total weight of the composition. 16. The method according to claim 9 wherein the amount of pre-blend in the seed coating composition is 5-30% by weight based on the total weight of the composition. 17. A seed with a coating comprising a wax, at least one pigment, an optional surface active agent and one or more biologically active ingredients. 18. The seed according to claim 17 wherein the coating is formed by applying a seed coating composition formed according to the method of claim 9. 19. An aqueous pre-blend comprising a wax, at least one pigment, and an optional surface active agent. 20. The pre-blend according to claim 19 wherein (i) the amount of wax in the pre-blend is 40-85% by weight based on the total weight of solids in the pre-blend, (ii) the amount of pigment in the pre-blend is 15-60% by weight based on the total weight of solids in the pre-blend, and/or (iii) the ratio of wax to pigment in the pre-blend is 1.3-2.0:1 by weight. 21. The pre-blend according to claim 19 comprising substantially no polymeric binder other than wax. 22. A method for improving the bio-efficacy and/or systemic uptake by plants of one or more active ingredients in a seed coating composition, comprising preparing a seed coating composition comprising a wax, at least one pigment, an optional surface active agent and one or more biologically active ingredients, and applying said seed coating composition to the seed. | The invention is directed to an aqueous seed coating composition comprising one or more active ingredients, to a pre-blend and use thereof as a component of the seed coating composition, to a method for improving the bio-efficacy of an active ingredient in a seed coating, and to a coated seed.
The seed coating composition and/or pre-blend of the invention further comprise a wax, and at least one pigment.1. An aqueous seed coating composition comprising a wax, at least one pigment, an optional surface active agent and one or more biologically active ingredients. 2. The seed coating composition according to claim 1, wherein the wax is selected from the group consisting of polyethylene wax, Fischer-Tropsch wax, and carnauba wax. 3. The seed coating composition according to claim 1, comprising an effect pigment and a color pigment. 4. The seed coating composition according to claim 3, wherein the total amount of pigment is 11-15% based on the total weight of the composition. 5. The seed coating composition according to claim 1 wherein the amount of wax is 5-10% by weight based on the total weight of the composition. 6. The seed coating composition according to claim 1 comprising at least one hydrophobic and/or water insoluble biologically active ingredient. 7. The seed coating composition according to claim 1 wherein the biologically active ingredient comprises bacteria. 8. The seed coating composition according to claim 1 comprising substantially no polymeric binder other than wax. 9. A method of forming a seed coating composition which comprises combining (i) an aqueous pre-blend comprising a wax, at least one first pigment, and an optional surface active agent, (ii) one or more biologically active ingredients, (iii) a dye and/or second pigment different to the first pigment, and (iv) optionally water. 10. The method according to claim 9 wherein the wax in the pre-blend is selected from the group consisting of polyethylene wax, Fischer-Tropsch wax, and carnauba wax. 11. The method according to claim 9 wherein the first pigment is an effect pigment and the second pigment is a colored pigment. 12. The method according to claim 9 wherein (i) the amount of wax in the pre-blend is 40-85% by weight based on the total weight of solids in the pre-blend, (ii) the amount of pigment in the pre-blend is 15-60% by weight based on the total weight of solids in the pre-blend, and/or (iii) the ratio of wax to pigment in the pre-blend is 1.3-2.0:1 by weight. 13. The method according to claim 9 wherein the seed coating composition comprises at least one hydrophobic and/or water insoluble biologically active ingredient. 14. The method according to claim 9 wherein the amount of surface active agent in the pre-blend is 0.4-3.5% by weight based on the total weight of solids in the pre-blend. 15. The method according to claim 9 wherein the amount of wax in the seed coating composition is 4-12% by weight based on the total weight of the composition. 16. The method according to claim 9 wherein the amount of pre-blend in the seed coating composition is 5-30% by weight based on the total weight of the composition. 17. A seed with a coating comprising a wax, at least one pigment, an optional surface active agent and one or more biologically active ingredients. 18. The seed according to claim 17 wherein the coating is formed by applying a seed coating composition formed according to the method of claim 9. 19. An aqueous pre-blend comprising a wax, at least one pigment, and an optional surface active agent. 20. The pre-blend according to claim 19 wherein (i) the amount of wax in the pre-blend is 40-85% by weight based on the total weight of solids in the pre-blend, (ii) the amount of pigment in the pre-blend is 15-60% by weight based on the total weight of solids in the pre-blend, and/or (iii) the ratio of wax to pigment in the pre-blend is 1.3-2.0:1 by weight. 21. The pre-blend according to claim 19 comprising substantially no polymeric binder other than wax. 22. A method for improving the bio-efficacy and/or systemic uptake by plants of one or more active ingredients in a seed coating composition, comprising preparing a seed coating composition comprising a wax, at least one pigment, an optional surface active agent and one or more biologically active ingredients, and applying said seed coating composition to the seed. | 1,600 |
411 | 14,663,533 | 1,699 | An ex vivo cell culture sustained release composition, including:
a mixture comprising:
a sustenant; and a non-biodegradable binder; and
a non-biodegradable and water insoluble encapsulant coat that encapsulates the mixture, as defined herein. Also disclosed is a method for sustainably providing a sustenant to a cell culture in aqueous media, including contacting a cell culture with the sustained release composition. | 1. An ex vivo cell culture sustained release composition, comprising:
a mixture comprising:
a sustenant in an amount of from 60 to 96 wt %; and
a non-biodegradable binder in an amount of from 1 to 20 wt %; and
a non-biodegradable and water insoluble encapsulant coat that encapsulates the mixture, in an amount of from 1 to 20 wt %, based on 100 wt % of the total composition. 2. The composition of claim 1 wherein the composition has a dosage form of at least one of a tablet, a pellet, a powder, a pill, or a combination thereof. 3. The composition of claim 1 wherein the sustenant has a water solubility of at least 0.01 to 10 wt % and comprises at least one sustenance ingredient selected from at least one o″: a nutrient, a protein, a vitamin, a growth factor, a performance enhancing molecule, an inhibitor, an amino acid, a metal ion, an organic acid, a reducing agent, a chelator, an anti-oxidant, or a combination thereof. 4. The composition of claim 1 wherein the sustenant is a sugar. 5. The composition of claim 1 wherein the sustenant is glucose. 6. The composition of claim 1 wherein the binder and the encapsulant are the same chemical entity and have the same or different molecular weight. 7. The composition of claim 1 wherein the binder, the encapsulant, or both, are not chemically crosslinked, and the binder further includes a plasticizer. 8. The composition of claim 1 wherein the sustained release composition is free of a hydrogel. 9. The composition of claim 1 wherein the sustained release composition has a release half-life of from 1 to 15 days. 10. A method for sustainably providing a sustenant to an ex vivo cell culture in aqueous media, comprising:
contacting the cell culture and the sustained release composition of claim 1. 11. The method of claim 10 wherein the cell culture comprises suspension cells, adherent cells, co-cultured cells, or a combination thereof, and basal media. 12. The method of claim 10 wherein the cell culture comprises mammalian suspension cells and basal media. 13. The method of claim 10 wherein the contacting comprises adding the sustained release composition as a solid dose form to the cell culture. 14. The method of claim 10 wherein the cell culture comprises adherent mammalian cells grown in suspension in basal media with a scaffold present. 15. The method of claim 14 wherein the scaffold is a microcarrier. 16. The method of claim 10 wherein the cell culture comprises adherent mammalian cells in basal media grown in a three-dimensional scaffold. 17. The method of claim 16 wherein the three-dimensional scaffold is at least one of: a gel matrix, a nanofiber, or a combination thereof. 18. The method of claim 10 wherein contacting the cell culture and the sustained release composition is accomplished by adding the sustained release composition to the cell culture, where the sustained release composition is present in an amount of from 0.001 to 5 wt % based on the total weight of the contacted cell culture. 19. The method of claim 10 wherein contacting the cell culture and the sustained release composition is accomplished at from cell inoculation (t=0) to 15 days. 20. The method of claim 10 wherein the sustenant is glucose and the glucose is sustainably delivered to the cells in the cell culture in an amount of from 0.1 to 5 grams per liter (g/L) over a period of from 1 hour to 240 hours. 21. The composition of claim 1 further comprising a pore former in from 0.001 to 10 wt % in the non-biodegradable and water insoluble encapsulant coat, the pore former wt % is based upon superaddition to 100 wt % of the encapsulant coat. | An ex vivo cell culture sustained release composition, including:
a mixture comprising:
a sustenant; and a non-biodegradable binder; and
a non-biodegradable and water insoluble encapsulant coat that encapsulates the mixture, as defined herein. Also disclosed is a method for sustainably providing a sustenant to a cell culture in aqueous media, including contacting a cell culture with the sustained release composition.1. An ex vivo cell culture sustained release composition, comprising:
a mixture comprising:
a sustenant in an amount of from 60 to 96 wt %; and
a non-biodegradable binder in an amount of from 1 to 20 wt %; and
a non-biodegradable and water insoluble encapsulant coat that encapsulates the mixture, in an amount of from 1 to 20 wt %, based on 100 wt % of the total composition. 2. The composition of claim 1 wherein the composition has a dosage form of at least one of a tablet, a pellet, a powder, a pill, or a combination thereof. 3. The composition of claim 1 wherein the sustenant has a water solubility of at least 0.01 to 10 wt % and comprises at least one sustenance ingredient selected from at least one o″: a nutrient, a protein, a vitamin, a growth factor, a performance enhancing molecule, an inhibitor, an amino acid, a metal ion, an organic acid, a reducing agent, a chelator, an anti-oxidant, or a combination thereof. 4. The composition of claim 1 wherein the sustenant is a sugar. 5. The composition of claim 1 wherein the sustenant is glucose. 6. The composition of claim 1 wherein the binder and the encapsulant are the same chemical entity and have the same or different molecular weight. 7. The composition of claim 1 wherein the binder, the encapsulant, or both, are not chemically crosslinked, and the binder further includes a plasticizer. 8. The composition of claim 1 wherein the sustained release composition is free of a hydrogel. 9. The composition of claim 1 wherein the sustained release composition has a release half-life of from 1 to 15 days. 10. A method for sustainably providing a sustenant to an ex vivo cell culture in aqueous media, comprising:
contacting the cell culture and the sustained release composition of claim 1. 11. The method of claim 10 wherein the cell culture comprises suspension cells, adherent cells, co-cultured cells, or a combination thereof, and basal media. 12. The method of claim 10 wherein the cell culture comprises mammalian suspension cells and basal media. 13. The method of claim 10 wherein the contacting comprises adding the sustained release composition as a solid dose form to the cell culture. 14. The method of claim 10 wherein the cell culture comprises adherent mammalian cells grown in suspension in basal media with a scaffold present. 15. The method of claim 14 wherein the scaffold is a microcarrier. 16. The method of claim 10 wherein the cell culture comprises adherent mammalian cells in basal media grown in a three-dimensional scaffold. 17. The method of claim 16 wherein the three-dimensional scaffold is at least one of: a gel matrix, a nanofiber, or a combination thereof. 18. The method of claim 10 wherein contacting the cell culture and the sustained release composition is accomplished by adding the sustained release composition to the cell culture, where the sustained release composition is present in an amount of from 0.001 to 5 wt % based on the total weight of the contacted cell culture. 19. The method of claim 10 wherein contacting the cell culture and the sustained release composition is accomplished at from cell inoculation (t=0) to 15 days. 20. The method of claim 10 wherein the sustenant is glucose and the glucose is sustainably delivered to the cells in the cell culture in an amount of from 0.1 to 5 grams per liter (g/L) over a period of from 1 hour to 240 hours. 21. The composition of claim 1 further comprising a pore former in from 0.001 to 10 wt % in the non-biodegradable and water insoluble encapsulant coat, the pore former wt % is based upon superaddition to 100 wt % of the encapsulant coat. | 1,600 |
412 | 12,161,445 | 1,627 | This invention relates to the use of a parenteral formulation comprising an anti-virally effective amount of TMC278 or a pharmaceutically acceptable acid-addition salt thereof, and a carrier, for the manufacture of a medicament for the treatment of a subject being infected with HIV, wherein the formulation is to be administered intermittently at a time interval of at least one week. | 1. The use of a parenteral formulation comprising an anti-virally effective amount of TMC278 or a pharmaceutically acceptable acid-addition salt thereof, and a carrier, for the manufacture of a medicament for the treatment of a subject infected with HIV, wherein the formulation is to be administered intermittently at a time interval that is in the range of one week to one year. 2. The use according to claim 1 wherein the formulation is to be administered at a time interval that is in the range of one week to one month. 3. The use according to claim 1 wherein the formulation is to be administered at a time interval that is in the range of one month to three months. 4. The use according to claim 1 wherein the formulation is to be administered at a time interval that is in the range of three months to six months. 5. The use according to claim 1 wherein the formulation is to be administered once every two weeks. 6. The use according to claim 1 wherein the formulation is to be administered once every month. 7. The use according to claim 1 wherein the effective amount of TMC278 in the parenteral formulation is selected such that the blood plasma concentration of TMC278 is kept during a prolonged period of time above a minimum blood plasma level that is the lowest blood plasma level that causes the HIV inhibitor to be effective in suppressing HIV. 8. The use according to claim 4 wherein the blood plasma level is kept at a level equal to or above about 20 ng/ml. 9. The use according to claim 1, wherein the formulation is to be administered subcutaneously or intramusculary. 10. A method of treating a subject infected with HIV, said method comprising the administration of a parenteral formulation comprising an anti-virally effective amount of TMC278 or a pharmaceutically acceptable acid-addition salt thereof, and a carrier, wherein the formulation is administered intermittently at a time interval of at least one week. | This invention relates to the use of a parenteral formulation comprising an anti-virally effective amount of TMC278 or a pharmaceutically acceptable acid-addition salt thereof, and a carrier, for the manufacture of a medicament for the treatment of a subject being infected with HIV, wherein the formulation is to be administered intermittently at a time interval of at least one week.1. The use of a parenteral formulation comprising an anti-virally effective amount of TMC278 or a pharmaceutically acceptable acid-addition salt thereof, and a carrier, for the manufacture of a medicament for the treatment of a subject infected with HIV, wherein the formulation is to be administered intermittently at a time interval that is in the range of one week to one year. 2. The use according to claim 1 wherein the formulation is to be administered at a time interval that is in the range of one week to one month. 3. The use according to claim 1 wherein the formulation is to be administered at a time interval that is in the range of one month to three months. 4. The use according to claim 1 wherein the formulation is to be administered at a time interval that is in the range of three months to six months. 5. The use according to claim 1 wherein the formulation is to be administered once every two weeks. 6. The use according to claim 1 wherein the formulation is to be administered once every month. 7. The use according to claim 1 wherein the effective amount of TMC278 in the parenteral formulation is selected such that the blood plasma concentration of TMC278 is kept during a prolonged period of time above a minimum blood plasma level that is the lowest blood plasma level that causes the HIV inhibitor to be effective in suppressing HIV. 8. The use according to claim 4 wherein the blood plasma level is kept at a level equal to or above about 20 ng/ml. 9. The use according to claim 1, wherein the formulation is to be administered subcutaneously or intramusculary. 10. A method of treating a subject infected with HIV, said method comprising the administration of a parenteral formulation comprising an anti-virally effective amount of TMC278 or a pharmaceutically acceptable acid-addition salt thereof, and a carrier, wherein the formulation is administered intermittently at a time interval of at least one week. | 1,600 |
413 | 14,358,274 | 1,649 | The present invention provides apoaequorin-based compositions and methods for preconditioning neurons in a subject to reduce neuronal injury due to brain ischemia. Methods include the step of administering apoaequorin to neurons in a subject, wherein the apoaequorin initiates a change in cytokine expression levels resulting in a reduction of neuronal injury due to brain ischemia as compared to neurons not administered the apoaequorin. Various formulations, including injectable dosages, are described. | 1. A method of preconditioning neurons to reduce neuronal injury due to brain ischemia in a subject, comprising administering apoaequorin to neurons in a subject, wherein the apoaequorin initiates a change in cytokine expression levels resulting in a reduction in neuronal injury due to brain ischemia in the subject, as compared to neurons not administered the apoaequorin. 2. The method of claim 1, wherein administration of the apoaequorin is by injection. 3. The method of claim 2, wherein the injection is an intra-hippocampal injection. 4. The method of claim 1, wherein the subject is human. 5. The method of claim 1, wherein the reduction in neuronal injury effect lasts at least 24 hours from the time of apoaequorin administration. 6. The method of claim 1, wherein the reduction in neuronal injury lasts at least 48 hours from the time of apoaequorin administration. 7. Use of apoaequorin for the manufacture of a medicament for preconditioning neurons in a subject to reduce neuronal injury due to brain ischemia. 8. Apoaequorin for use in preconditioning neurons in a subject to reduce neuronal injury due to brain ischemia. 9. A composition for preconditioning neurons in a subject to reduce neuronal injury due to brain ischemia, comprising:
(a) a therapeutically effective dosage of apoaequorin to precondition neurons in a subject to reduce neuronal injury due to brain ischemia; and (b) a pharmaceutically-acceptable carrier. 10. The composition of claim 9, wherein the composition is formulated as an injectable dosage. 11. A kit for preconditioning neurons in a subject to reduce neuronal injury due to brain ischemia, comprising:
(a) a therapeutically effective dosage of apoaequorin to precondition neurons in a subject to reduce neuronal injury due to brain ischemia; and (b) a delivery device configured to administer said amount of apoaequorin to the subject. | The present invention provides apoaequorin-based compositions and methods for preconditioning neurons in a subject to reduce neuronal injury due to brain ischemia. Methods include the step of administering apoaequorin to neurons in a subject, wherein the apoaequorin initiates a change in cytokine expression levels resulting in a reduction of neuronal injury due to brain ischemia as compared to neurons not administered the apoaequorin. Various formulations, including injectable dosages, are described.1. A method of preconditioning neurons to reduce neuronal injury due to brain ischemia in a subject, comprising administering apoaequorin to neurons in a subject, wherein the apoaequorin initiates a change in cytokine expression levels resulting in a reduction in neuronal injury due to brain ischemia in the subject, as compared to neurons not administered the apoaequorin. 2. The method of claim 1, wherein administration of the apoaequorin is by injection. 3. The method of claim 2, wherein the injection is an intra-hippocampal injection. 4. The method of claim 1, wherein the subject is human. 5. The method of claim 1, wherein the reduction in neuronal injury effect lasts at least 24 hours from the time of apoaequorin administration. 6. The method of claim 1, wherein the reduction in neuronal injury lasts at least 48 hours from the time of apoaequorin administration. 7. Use of apoaequorin for the manufacture of a medicament for preconditioning neurons in a subject to reduce neuronal injury due to brain ischemia. 8. Apoaequorin for use in preconditioning neurons in a subject to reduce neuronal injury due to brain ischemia. 9. A composition for preconditioning neurons in a subject to reduce neuronal injury due to brain ischemia, comprising:
(a) a therapeutically effective dosage of apoaequorin to precondition neurons in a subject to reduce neuronal injury due to brain ischemia; and (b) a pharmaceutically-acceptable carrier. 10. The composition of claim 9, wherein the composition is formulated as an injectable dosage. 11. A kit for preconditioning neurons in a subject to reduce neuronal injury due to brain ischemia, comprising:
(a) a therapeutically effective dosage of apoaequorin to precondition neurons in a subject to reduce neuronal injury due to brain ischemia; and (b) a delivery device configured to administer said amount of apoaequorin to the subject. | 1,600 |
414 | 15,366,327 | 1,612 | This application provides, among other things, novel aqueous oral care compositions useful for combining and delivering poorly compatible ingredients, for example to deliver effective levels of cationic antibacterial agents in combination with anionic polymers that protect against erosion and staining, by addition of a stabilizing amount of a polyamine, e.g., lysine, and methods for making and using the same. | 1. An oral care compositions comprising
a) an orally acceptable acidic polymer; b) an orally acceptable nonionic polymer; c) an effective amount of orally acceptable cationic active agent, in free or orally acceptable salt form; d) a stabilizing amount of a polyamine compound, in free or orally acceptable salt form; and e) water. 2. The composition of claim 1 wherein the orally acceptable acidic polymer is selected from one or more of synthetic anionic linear polycarboxylates, phosphate/acrylate co-polymers, and combinations thereof. 3. The composition of claim 2 wherein the orally acceptable acidic polymer is selected from a combination of
a) 1:4 to 4:1 copolymers of maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer, e.g., co-polymers of methyl vinyl ether/maleic anhydride, wherein some or all of the anhydride moieties are hydrolyzed to provide free carboxyl groups, and
b) co-polymerized products of a mixture of acrylic acid, methacrylic acid, and 2-hydroxyethyl methacrylate phosphates of Formula 1:
wherein n is 0, 1 or 2. 4. The composition of claim 1 wherein the orally acceptable nonionic polymer is selected from polyethylene glycols, polypropylene glycols, poloxamers and mixtures thereof. 5. The composition of claim 1 wherein the orally acceptable cationic active agent is selected from one or more of quaternary ammonium surfactants, bisguanides, cationic amino acids, metal cations, and combinations thereof. 6. The composition of claim 1 wherein the orally acceptable cationic active agent is provided by an orally acceptable salt selected from zinc salts, stannous salts, chlorhexidine digluconate, and cetyl pyridinium chloride. 7. The composition of claim 1 wherein the orally acceptable cationic active agent is chlorhexidine digluconate, at a concentration of 0.1%-0.2%. 8. The composition of claim 1 wherein the polyamine, in free or orally acceptable salt form, is lysine hydrochloride. 9. The composition of claim 1 wherein the composition comprises 70% to 95% water. 10. The composition of claim 1 wherein the composition comprises one or more of a thickener, a buffer, a humectant, a surfactant, an abrasive, a sweetener, a flavorant, a pigment, a dye, an anti-caries agent, an anti-bacterial agent, a whitening agent, a desensitizing agent, a preservative, or a mixture thereof. 11. The composition of claim 1 wherein the composition comprises an anionic surfactant. 12. The composition of claim 1 wherein the composition is a mouthwash. 13. The composition of claim 1 which is biphasic, wherein the solution comprises two distinct aqueous phases having different composition and density. 14. The composition of claim 1 which comprises less than 5% of hydrophobic ingredients. 15. The composition of claim 1 which is essentially oil-free, apart from flavoring agents. 16. The composition of claim 1 having a pH of 5.5 to 8.0. 17. The composition of claim 1 wherein there is no discernable precipitation or reaction between the orally acceptable acidic polymer and the orally acceptable cationic active agent after three months of storage at room temperature. 18. The composition of claim 1 wherein
a) the orally acceptable acidic polymer comprises a mixture of (a) a copolymer of maleic anhydride and methyl vinyl ether in an amount of 0.5 to 1.5% and (b) a phosphate/acrylate co-polymer, in an amount of 0.5 to 1.5%;
b) the orally acceptable nonionic polymer comprises polyethylene glycol having a molecular weight of 5 kD to 20 kD in an amount of 0 to 3% and poloxamer 407 in an amount of 0 to 1%, in a combined amount of 1 to 3%;
c) the effective amount of orally acceptable cationic active agent, in free or orally acceptable salt form, comprises chlorhexidine, in an amount of 0.1 to 0.2%
d) the polyamine compound, in free or orally acceptable salt form, is lysine in free or orally acceptable salt form, in an amount of 0.5 to 3%; and
e) the water is present in an amount of 70-95%;
wherein the composition optionally further comprises sodium lauryl sulfate in an amount of up to 1%; and
wherein all amounts are by weight of the total composition. | This application provides, among other things, novel aqueous oral care compositions useful for combining and delivering poorly compatible ingredients, for example to deliver effective levels of cationic antibacterial agents in combination with anionic polymers that protect against erosion and staining, by addition of a stabilizing amount of a polyamine, e.g., lysine, and methods for making and using the same.1. An oral care compositions comprising
a) an orally acceptable acidic polymer; b) an orally acceptable nonionic polymer; c) an effective amount of orally acceptable cationic active agent, in free or orally acceptable salt form; d) a stabilizing amount of a polyamine compound, in free or orally acceptable salt form; and e) water. 2. The composition of claim 1 wherein the orally acceptable acidic polymer is selected from one or more of synthetic anionic linear polycarboxylates, phosphate/acrylate co-polymers, and combinations thereof. 3. The composition of claim 2 wherein the orally acceptable acidic polymer is selected from a combination of
a) 1:4 to 4:1 copolymers of maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer, e.g., co-polymers of methyl vinyl ether/maleic anhydride, wherein some or all of the anhydride moieties are hydrolyzed to provide free carboxyl groups, and
b) co-polymerized products of a mixture of acrylic acid, methacrylic acid, and 2-hydroxyethyl methacrylate phosphates of Formula 1:
wherein n is 0, 1 or 2. 4. The composition of claim 1 wherein the orally acceptable nonionic polymer is selected from polyethylene glycols, polypropylene glycols, poloxamers and mixtures thereof. 5. The composition of claim 1 wherein the orally acceptable cationic active agent is selected from one or more of quaternary ammonium surfactants, bisguanides, cationic amino acids, metal cations, and combinations thereof. 6. The composition of claim 1 wherein the orally acceptable cationic active agent is provided by an orally acceptable salt selected from zinc salts, stannous salts, chlorhexidine digluconate, and cetyl pyridinium chloride. 7. The composition of claim 1 wherein the orally acceptable cationic active agent is chlorhexidine digluconate, at a concentration of 0.1%-0.2%. 8. The composition of claim 1 wherein the polyamine, in free or orally acceptable salt form, is lysine hydrochloride. 9. The composition of claim 1 wherein the composition comprises 70% to 95% water. 10. The composition of claim 1 wherein the composition comprises one or more of a thickener, a buffer, a humectant, a surfactant, an abrasive, a sweetener, a flavorant, a pigment, a dye, an anti-caries agent, an anti-bacterial agent, a whitening agent, a desensitizing agent, a preservative, or a mixture thereof. 11. The composition of claim 1 wherein the composition comprises an anionic surfactant. 12. The composition of claim 1 wherein the composition is a mouthwash. 13. The composition of claim 1 which is biphasic, wherein the solution comprises two distinct aqueous phases having different composition and density. 14. The composition of claim 1 which comprises less than 5% of hydrophobic ingredients. 15. The composition of claim 1 which is essentially oil-free, apart from flavoring agents. 16. The composition of claim 1 having a pH of 5.5 to 8.0. 17. The composition of claim 1 wherein there is no discernable precipitation or reaction between the orally acceptable acidic polymer and the orally acceptable cationic active agent after three months of storage at room temperature. 18. The composition of claim 1 wherein
a) the orally acceptable acidic polymer comprises a mixture of (a) a copolymer of maleic anhydride and methyl vinyl ether in an amount of 0.5 to 1.5% and (b) a phosphate/acrylate co-polymer, in an amount of 0.5 to 1.5%;
b) the orally acceptable nonionic polymer comprises polyethylene glycol having a molecular weight of 5 kD to 20 kD in an amount of 0 to 3% and poloxamer 407 in an amount of 0 to 1%, in a combined amount of 1 to 3%;
c) the effective amount of orally acceptable cationic active agent, in free or orally acceptable salt form, comprises chlorhexidine, in an amount of 0.1 to 0.2%
d) the polyamine compound, in free or orally acceptable salt form, is lysine in free or orally acceptable salt form, in an amount of 0.5 to 3%; and
e) the water is present in an amount of 70-95%;
wherein the composition optionally further comprises sodium lauryl sulfate in an amount of up to 1%; and
wherein all amounts are by weight of the total composition. | 1,600 |
415 | 14,423,751 | 1,646 | Provided is an antibody with a specificity to an epitope that is a region corresponding to amino acid positions 63-79 or 73-85 of the human protein S100A9. Provided is further an antibody with a specificity to an epitope that is a region corresponding to amino acid positions 55-71 of the human protein S100A8. Provided is further the use of such antibody in the treatment or diagnosis of an inflammatory disorder. Also provided is an in-vitro method of identifying a compound capable of inhibiting the formation of a complex between a peptide corresponding to one of the above epitopes of S100A9 or the above epitope of S100A8 and a TLR4 receptor, where a compound suspected to affect the complex formation is contacted with the peptide and the TLR4 receptor. Further provided is an in-vitro method of identifying a compound capable of increasing the stability of a complex between a S100A8 protein and a S100A9 protein, where the two proteins are contacted in the presence of a compound suspected to affect the complex formation. | 1. An immunoglobulin or proteinaceous binding partner having a binding specificity to an epitope of a vertebrate S100A9 protein, wherein the epitope has an amino acid sequence of a region corresponding to (i) the amino acid sequence ranging from amino acid position 63 to amino acid position 79 of the human protein S100A9 of Uniprot/Swissprot accession no. P06702 (SEQ ID NO: 77) or (ii) the amino acid sequence ranging from amino acid position 73 to amino acid position 85 of the human protein S100A9 of Uniprot/Swissprot accession no. P06702 (SEQ ID NO: 77). 2. The immunoglobulin or proteinaceous binding partner of claim 1, wherein the amino acid sequence is one of the sequences MEDLDTNADKQLSFEEF (SEQ ID NO: 1), MEDLDTNEDKQLSFEEF (SEQ ID NO: 14), MEDLDTNVDKQLSFEEF (SEQ ID NO: 15), MEDLDTNLDKQLSFEEF (SEQ ID NO: 16), MEDLDTNGDKQLNFEEF (SEQ ID NO: 17), LEDLDTNADKQLTFEEF (SEQ ID NO: 18), LEDLDTNVDKQLS FEEF (SEQ ID NO: 19), LEDLDTNEDKQLSFEEF (SEQ ID NO: 20), MEDLDTN GDKELNFEEF (SEQ ID NO: 21), MEDLDTNEDKELSFEEY (SEQ ID NO: 22), LEDLDTNGDKQLNFEEF (SEQ ID NO: 23), MEDLDTNQDNQLSFEEC (SEQ ID NO: 24), MEDLDTNLDQQLSFEEL (SEQ ID NO: 25), MQDLDTNQDQQLSFEEV (SEQ ID NO: 26), MEDLDTNQDKQLSFEEF (SEQ ID NO: 27), MQELDTNQ NGQVDFKEF (SEQ ID NO: 28), FEETDLNKDKELTFEEF (SEQ ID NO: 29), QLSFEEFIMLMAR (SEQ ID NO: 3), QLSFEEFIVLMAR (SEQ ID NO: 30), QLSFEEFIMLVAR (SEQ ID NO: 31), QLTFEEFIMLMGR (SEQ ID NO: 32), QLSFEEFIMLVIR (SEQ ID NO: 33), QLSFEEFIILVAR (SEQ ID NO: 34), QLSFEELTMLLAR (SEQ ID NO: 35), QLSFEEVIMLFAR (SEQ ID NO: 36), QLSFEEFSILMAK (SEQ ID NO: 37), QLSFEEFSMLVAK (SEQ ID NO: 38), QLSFEECMMLMAK (SEQ ID NO: 39), QLSFEECMMLMGK (SEQ ID NO: 40), ELSFEEYIVLVAK (SEQ ID NO: 41), QLSFEEFVILMAR (SEQ ID NO: 42), QLNFEEFSILVGR (SEQ ID NO: 43), and QVDFKEFSMMMAR (SEQ ID NO: 44). 3. An immunoglobulin or proteinaceous binding partner having a binding specificity to an epitope of a vertebrate S100A8 protein, wherein the epitope has an amino acid sequence of a region corresponding to the amino acid sequence ranging from amino acid position 55 to amino acid position 71 of the human protein S100A8 of Uniprot/Swissprot accession number P05109 (SEQ ID NO: 78). 4. The immunoglobulin or proteinaceous binding partner of claim 3, wherein the amino acid sequence is one of the sequences FKELDINTDGAVNFQEF (SEQ ID NO: 5), FKELDINTDGAINFQEF (SEQ ID NO: 45), FKELDINSDGAINFQEF (SEQ ID NO: 46), FKELDINEDGAVNFQEF (SEQ ID NO: 47), FKELDINKDGAVNFEEF (SEQ ID NO: 48), FKELDINSDGASNFQEF (SEQ ID NO: 49), FKELDVNSDGAINFEEF (SEQ ID NO: 50), FKQFDINEDGAVNFQEF (SEQ ID NO: 51), FRQLDINEDGAVNFQEF (SEQ ID NO: 52), FKELDINQDNAVNFEEF (SEQ ID NO: 53), FNELDINSDNAINFQEF (SEQ ID NO: 54), FKELDINQDGGINFEEF (SEQ ID NO: 55), FKELDVNSDSAINFEEF (SEQ ID NO: 56), FKELDVNSDNAINFEEF (SEQ ID NO: 57), FQELDVNSDGAINFEEF (SEQ ID NO: 58), FRELDINSDNAINFEEF (SEQ ID NO: 59), FKELDFTADGAINFEEF (SEQ ID NO: 60), FKELDINQDG GINLEEF (SEQ ID NO: 61), FKELDINQDGFINFEEF (SEQ ID NO: 62), and FKELDSNKDQQINFEEF (SEQ ID NO: 63). 5. (canceled) 6. The method of claim 11, wherein the condition is selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, immune reconstituation inflammatory syndrome (IRIS), sepsis, systemic inflammatory response syndrome (SIRS), pneumonia, osteomyelitis, autoinflammatory syndromes, hyperzincemia, systemic inflammation, atherosclerosis, acute coronary syndrome, myocardial infarction, diabetes, an inflammatory skin disease, psoriasis, inflammatory bowel disease, vasculitis, allograft rejection, glomerulonephritis, systemic lupus erythematosus, pancreatitis, a cancer, dermatomyositis and polymyositis, multiple sclerosis, allergies, infections, pulmonary inflammation, acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS). 7. A combination of one or more immunoglobulins or proteinaceous binding partners of claim 1 and the immunoglobulin or proteinaceous binding partner having a binding specificity to an epitope of a vertebrate S100A8 protein, wherein the epitope has an amino acid sequence of a region corresponding to the amino acid sequence ranging from amino acid position 55 to amino acid position 71 of the human protein S100A8 of Uniprot/Swissprot accession number P05109 (SEQ ID NO: 78). 8. The combination of claim 7, being comprised in a single immunoglobulin or proteinaceous binding partner, the immunoglobulin or proteinaceous binding partner having at least a dual binding specificity. 9. (canceled) 10. The method of claim 54, wherein the condition is selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, immune reconstituation inflammatory syndrome (IRIS), sepsis, systemic inflammatory response syndrome (SIRS), pneumonia, osteomyelitis, autoinflammatory syndromes, hyperzincemia, systemic inflammation, atherosclerosis, acute coronary syndrome, myocardial infarction, diabetes, an inflammatory skin disease, psoriasis, inflammatory bowel disease, vasculitis, allograft rejection, glomerulonephritis, systemic lupus erythematosus, pancreatitis, a cancer, dermatomyositis and polymyositis, multiple sclerosis, allergies, infections, pulmonary inflammation, acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS). 11. A method of treating a subject suffering from an inflammatory condition, the method comprising administering to the subject at least one of the immunoglobulin or proteinaceous binding partner of claim 1. 12. The method of claim 11, wherein the subject is a mammal. 13. An isolated peptide or peptidomimetic comprising the sequence of X3EX2X3X1X1X1 X1X1X1 X5X1X1X6X2X1X1 (SEQ ID NO: 6), wherein X1 represents any amino acid, X2 represents an amino acid with a side chain carrying a carboxylic acid group, X3 represents a non-polar amino acid, X5 represents D, N, E or Q, X6 represents an aromatic amino acid, wherein the peptide differs from a calcium binding protein. 14. The isolated peptide or peptidomimetic of claim 13, wherein the sequence of SEQ ID NO: 6 is (a) the sequence of MEX2X3DX1NX1DX1 QX1X1FEX2X1 (SEQ ID NO: 7), or a homolog thereof; or (b) the sequence of MEDX3DX3NX1DX1 QX3X1FEEX1 (SEQ ID NO: 8), or a homolog thereof. 15. The isolated peptide or peptidomimetic of claim 13, essentially consisting of the sequence of SEQ ID NO: 6. 16. An isolated peptide or peptidomimetic comprising the sequence of X5X1X1X6X2X1X1 X1X3X3 X3X3X1 (SEQ ID NO: 9), wherein X1 represents any amino acid, X2 represents an amino acid with a side chain carrying a carboxylic acid group, X3 represents a non-polar amino acid, X5 represents D, N, E or Q and X6 represents an aromatic amino acid, wherein the peptide differs from a calcium binding protein. 17. The isolated peptide or peptidomimetic of claim 16, (a) wherein the sequence of SEQ ID NO: 6 is the sequence of QX1X1FEX2X1X1X3X3X3X3X7 (SEQ ID NO: 10), or a homolog thereof, wherein X7 represents R or K, or (b) wherein the sequence of SEQ ID NO: 6 is the sequence of QX3X1FEEX1X1MLMX3X7 (SEQ ID NO: 11), or a homolog thereof or (c) essentially consisting of the sequence of SEQ ID NO: 9. 18. An isolated peptide or peptidomimetic comprising the sequence of X6X8X5X3X1X1X1X1X1X1 X1X1NX3X5X1X6 (SEQ ID NO: 12), or a homolog thereof, wherein X1 represents any amino acid, X3 represents a non-polar amino acid, X5 represents D, N, E or Q, X6 represents an aromatic amino acid, X8 represents a polar amino acid, wherein the peptide differs from a calcium binding protein. 19. The isolated peptide or peptidomimetic of claim 18, wherein the sequence of SEQ ID NO: 6 is the sequence of FX8EX3DX1NX1DX9X1X10NX11X5EF (SEQ ID NO: 13), wherein X9 represents a polar amino acid or G, wherein X10 represents I, V, S or L, X11 represents F or L, or a homolog thereof. 20. An isolated peptide or peptidomimetic comprising the sequence of SEQ ID NO: 5 or a homolog thereof, wherein the peptide differs from a calcium binding protein. 21. The isolated peptide or peptidomimetic of claim 20, essentially consisting of the sequence of SEQ ID NO: 1 or the homolog thereof. 22. A combination of an isolated peptide or peptidomimetic of claim 13 or an isolated peptide or peptidomimetic comprising the sequence of X5X1X1X6X2X1X1 X1X3X3 X3X3X1 (SEQ ID NO: 9), wherein X1 represents any amino acid, X2 represents an amino acid with a side chain carrying a carboxylic acid group, X3 represents a non-polar amino acid, X5 represents D, N, E or Q and X6 represents an aromatic amino acid, wherein the peptide differs from a calcium binding protein; and
an isolated peptide or peptidomimetic comprising the sequence of X6X8X5X3X1X1X1X1X1X1 X1X1NX3X5X1X6 (SEQ ID NO: 12), or a homolog thereof, wherein X1 represents any amino acid, X3 represents a non-polar amino acid, X5 represents D, N, E or Q, X6 represents an aromatic amino acid, X8 represents a polar amino acid, wherein the peptide differs from a calcium binding protein,
wherein the peptidomimetic comprising the sequence of SEQ ID NO: 6 or 9, and the peptidomimetic comprising the sequence of SEQ ID NO: 12 are comprised in a single chain. 23. The combination of claim 22, wherein the peptide comprising the sequence of SEQ ID NO: 6 or the sequence of SEQ ID NO: 9, and the peptide comprising the sequence of SEQ ID NO: 12, or the homolog thereof, are comprised in a single peptide chain. 24. An isolated nucleic acid molecule comprising one of (a) a sequence encoding a peptide of SEQ ID NO: 6, (b) a sequence encoding a peptide of SEQ ID NO: 9, and (c) a sequence encoding a peptide of SEQ ID NO: 12, or a homolog thereof, wherein the encoded peptide differs from the full-length sequence a calcium binding protein. 25. The isolated nucleic acid molecule of claim 24, essentially consisting of one of the sequence of SEQ ID NO: 6, the sequence encoding a peptide of SEQ ID NO: 9 and the sequence encoding a peptide of SEQ ID NO: 12, or the homolog thereof, and optionally an expression cassette. 26. The isolated nucleic acid molecule of claim 24, being comprised in a vector. 27. An in-vitro method of identifying a compound capable of decreasing or inhibiting the formation of a complex between a peptide comprising one of (i) the amino acid sequence of SEQ ID NO: 6 or 9 and (ii) the amino acid sequence of SEQ ID NO: 12 and a TLR4 receptor or a functional fragment thereof, the functional fragment of the TLR4 receptor comprising the binding site for SEQ ID NO: 1 and SEQ ID NO: 3, respectively, the method comprising
(a) allowing the peptide, the TLR4 receptor, or the functional fragment thereof, and a compound suspected to affect the said complex formation to contact each other, and (b) detecting the formation of a complex between the peptide and the TLR4 receptor, or the functional fragment thereof. 28. The method of claim 27, wherein the peptide comprising the amino acid sequence of SEQ ID NO: 6 or 9 is a S100A9 protein and/or the peptide comprising the amino acid sequence of SEQ ID NO: 12 is a S100A8 protein. 29. An in-vitro method of identifying a compound capable of increasing the stability of a complex between a S100A8 protein, or a functional fragment thereof, and a S100A9 protein, or functional fragments thereof, the method comprising
(a) allowing the S100A8 protein, or the functional fragment thereof, the S100A9 protein, or the functional fragment thereof, and a compound suspected to affect the said complex formation to contact each other, and (b) detecting the formation of a complex between the S100A8 protein, or the functional fragment thereof, and the S100A9 protein, or the functional fragment thereof. 30. The method of claim 29, wherein the functional fragment of the S100A8 protein and/or the functional fragment of the S100A9 protein comprises at least one of EF hand I and EF hand II. 31. The method of claim 29, wherein the S100A8 protein, or the functional fragment thereof, the S100A9 protein, or the functional fragment thereof, and the compound suspected to affect the said complex formation are allowed to contact each other in the presence of a salt of calcium, zinc or copper. 32. The method of claim 29, wherein the formation of a heterotetrameric complex between the S100A8 protein, or the functional fragment thereof, and the S100A9 protein, or the functional fragment thereof is detected, and wherein the method is a method of identifying a compound capable of increasing the stability of a heterotetrameric complex between a S100A8 protein, or a functional fragment thereof, and a S100A9 protein, or functional fragments thereof. 33. The method of claim 27, further comprising comparing the formation of the complex to a control measurement. 34. The method of claim 33, wherein the control measurement comprises detecting the formation of the complex between the protein S100A8, or the functional fragment thereof, and the protein S100A9, or the functional fragment thereof, in the absence of a compound suspected to affect the complex formation. 35. (canceled) 36. (canceled) 37. An in-vitro method of diagnosing the risk of occurrence, or the presence, of a condition associated with an inflammation in a subject, the method comprising detecting the amount of a complex between a S100A8 protein and a S100A9 protein in a sample from the subject, wherein a decreased amount of the complex relative to a threshold value, indicates an elevated risk of occurrence, or the presence, of a condition associated with an inflammation. 38. The method of claim 37, comprising contacting the sample with an immunoglobulin or proteinaceous binding partner having a binding specificity to (a) a region of a S100A9 protein that differs from the region toward which the immunoglobulin or proteinaceous binding partner according to claim 1 has a binding specificity, or (b) a region of a S100A8 protein that differs from the region toward which the immunoglobulin or proteinaceous binding partner according to claim 3 has a binding specificity, under non-denaturating conditions, and detecting the amount of the complex between protein S100A8 and the protein S100A9 bound, wherein an increased amount of S100A8 or S100A9 detected by binding to the respective immunoglobulin or proteinaceous binding partner, relative to a threshold value, indicates a decreased amount of a complex between a S100A8 protein and a S100A9 protein. 39. The method of claim 38, wherein detecting the amount of the complex between protein S100A8 and the protein S100A9 bound comprises one of immunoprecipitation, flow cytometry and mass spectrometry. 40. The method of claim 37, comprising contacting the sample with an immunoglobulin or proteinaceous binding partner according to claim 1 or according to claim 3 under non-denaturating conditions and detecting the amount of the S100A8 protein or the S100A9 protein, respectively, bound, wherein an increased amount of the S100A8 protein or the S100A9 protein detected, relative to a threshold value, indicates a decreased amount of a complex between a S100A8 protein and a S100A9 protein. 41. The method of claim 40, wherein the immunoglobulin or proteinaceous binding partner has a binding specificity to a peptide of the species to which the subject belongs. 42. The method of claim 41, wherein the immunoglobulin or proteinaceous binding partner has a binding specificity to a human peptide and wherein the subject is a human. 43. The method of claim 37, further comprising comparing the amount of the complex to a control measurement. 44. The method of claim 43, wherein the control measurement comprises detecting the amount of the complex between the S100A8 protein and the S100A9 protein in a sample from a subject known not to suffer from an inflammatory disorder. 45. The method of claim 37, comprising
(a) contacting a first sample from the subject with an immunoglobulin or proteinaceous binding partner having a binding specificity to (i) a region of a S100A9 protein that differs from the region toward which the immunoglobulin or proteinaceous binding partner according to claim 1 has a binding specificity, or (ii) a region of a S100A8 protein that differs from the region toward which the immunoglobulin or proteinaceous binding partner according to claim 3 has a binding specificity under non-denaturating conditions, (b) contacting a second sample from the subject with an immunoglobulin or proteinaceous binding partner (i) according to claim 1 or (ii) according to claim 3 under non-denaturating conditions, (c) detecting the amount of the protein S100A8 or the S100A9 protein, respectively, in the first sample and in the second sample, and (d) comparing the difference between the S100A8 protein or the S100A9 protein bound in the first sample and in the second sample to a threshold value, wherein a decreased difference between the protein bound in the first sample and in the second sample, relative to a threshold value, indicates an elevated risk of occurrence, or the presence, of a condition associated with an inflammation. 46. The method of claim 45, wherein the threshold value is based on the formation of a corresponding complex to a control measurement. 47. The method of claim 46, wherein the control measurement comprises determining the difference in the amount of the S100A8 protein or the S100A9 protein in a third and a fourth sample, the third and a fourth sample being from a subject known not to suffer from an inflammatory disorder. 48. The method of claim 45, wherein
(a) the immunoglobulin or proteinaceous binding partner contacted with the first sample has a binding specificity to a region of a S100A9 protein that differs from the region toward which the immunoglobulin or proteinaceous binding partner according to claim 1 has a binding specificity, and the immunoglobulin or proteinaceous binding partner contacted with the second sample is an immunoglobulin or proteinaceous binding partner according to claim 1, or (b) the immunoglobulin or proteinaceous binding partner contacted with the first sample has a binding specificity to a region of a S100A9 protein that differs from the region toward which the immunoglobulin or proteinaceous binding partner according to claim 3 has a binding specificity and the immunoglobulin or proteinaceous binding partner contacted with the second sample is an immunoglobulin or proteinaceous binding partner according to claim 3. 49. The method of claim 37, wherein the sample is one of a blood sample, a plasma sample and a serum sample. 50. A method of treating a subject suffering from an inflammatory disorder, the method comprising administering to the subject a compound obtained by the method of claim 29, thereby increasing the stability of a complex between a S100A8 protein and a S100A9 protein in a body fluid of the subject. 51. A method of treating a subject suffering from an inflammatory disorder, the method comprising administering to the subject a compound obtained by the method of claim 27, thereby decreasing or inhibiting the formation of a complex between the protein S100A8 or the protein S100A9 and a TLR4 receptor on cells of the subject. 52. A method of identifying a binding partner of the isolated peptide or peptidomimetic of claim 13, in an organism, the method comprising
(a) contacting the isolated peptide or peptidomimetic with a sample from the organism, thereby forming a reaction mixture, (b) allowing a complex to form between the isolated peptide or peptidomimetic and a binding partner in the reaction mixture, (c) isolating the peptide or peptidomimetic from the reaction mixture, wherein the peptide or peptidomimetic is comprised in a complex with the binding partner, and (d) analysing the binding partner. 53. The method of claim 52, wherein isolating the peptide or peptidomimetic from the reaction mixture comprises one of immunoprecipitation, chromatography and flow cytometry. 54. The method of claim 11 comprising administering to the subject an immunoglobulin or proteinaceous binding partner having a binding specificity to an epitope of a vertebrate S100A8 protein, wherein the epitope has an amino acid sequence of a region corresponding to the amino acid sequence ranging from amino acid position 55 to amino acid position 71 of the human protein S100A8 of Uniprot/Swissprot accession number P05109 (SEQ ID NO: 78). | Provided is an antibody with a specificity to an epitope that is a region corresponding to amino acid positions 63-79 or 73-85 of the human protein S100A9. Provided is further an antibody with a specificity to an epitope that is a region corresponding to amino acid positions 55-71 of the human protein S100A8. Provided is further the use of such antibody in the treatment or diagnosis of an inflammatory disorder. Also provided is an in-vitro method of identifying a compound capable of inhibiting the formation of a complex between a peptide corresponding to one of the above epitopes of S100A9 or the above epitope of S100A8 and a TLR4 receptor, where a compound suspected to affect the complex formation is contacted with the peptide and the TLR4 receptor. Further provided is an in-vitro method of identifying a compound capable of increasing the stability of a complex between a S100A8 protein and a S100A9 protein, where the two proteins are contacted in the presence of a compound suspected to affect the complex formation.1. An immunoglobulin or proteinaceous binding partner having a binding specificity to an epitope of a vertebrate S100A9 protein, wherein the epitope has an amino acid sequence of a region corresponding to (i) the amino acid sequence ranging from amino acid position 63 to amino acid position 79 of the human protein S100A9 of Uniprot/Swissprot accession no. P06702 (SEQ ID NO: 77) or (ii) the amino acid sequence ranging from amino acid position 73 to amino acid position 85 of the human protein S100A9 of Uniprot/Swissprot accession no. P06702 (SEQ ID NO: 77). 2. The immunoglobulin or proteinaceous binding partner of claim 1, wherein the amino acid sequence is one of the sequences MEDLDTNADKQLSFEEF (SEQ ID NO: 1), MEDLDTNEDKQLSFEEF (SEQ ID NO: 14), MEDLDTNVDKQLSFEEF (SEQ ID NO: 15), MEDLDTNLDKQLSFEEF (SEQ ID NO: 16), MEDLDTNGDKQLNFEEF (SEQ ID NO: 17), LEDLDTNADKQLTFEEF (SEQ ID NO: 18), LEDLDTNVDKQLS FEEF (SEQ ID NO: 19), LEDLDTNEDKQLSFEEF (SEQ ID NO: 20), MEDLDTN GDKELNFEEF (SEQ ID NO: 21), MEDLDTNEDKELSFEEY (SEQ ID NO: 22), LEDLDTNGDKQLNFEEF (SEQ ID NO: 23), MEDLDTNQDNQLSFEEC (SEQ ID NO: 24), MEDLDTNLDQQLSFEEL (SEQ ID NO: 25), MQDLDTNQDQQLSFEEV (SEQ ID NO: 26), MEDLDTNQDKQLSFEEF (SEQ ID NO: 27), MQELDTNQ NGQVDFKEF (SEQ ID NO: 28), FEETDLNKDKELTFEEF (SEQ ID NO: 29), QLSFEEFIMLMAR (SEQ ID NO: 3), QLSFEEFIVLMAR (SEQ ID NO: 30), QLSFEEFIMLVAR (SEQ ID NO: 31), QLTFEEFIMLMGR (SEQ ID NO: 32), QLSFEEFIMLVIR (SEQ ID NO: 33), QLSFEEFIILVAR (SEQ ID NO: 34), QLSFEELTMLLAR (SEQ ID NO: 35), QLSFEEVIMLFAR (SEQ ID NO: 36), QLSFEEFSILMAK (SEQ ID NO: 37), QLSFEEFSMLVAK (SEQ ID NO: 38), QLSFEECMMLMAK (SEQ ID NO: 39), QLSFEECMMLMGK (SEQ ID NO: 40), ELSFEEYIVLVAK (SEQ ID NO: 41), QLSFEEFVILMAR (SEQ ID NO: 42), QLNFEEFSILVGR (SEQ ID NO: 43), and QVDFKEFSMMMAR (SEQ ID NO: 44). 3. An immunoglobulin or proteinaceous binding partner having a binding specificity to an epitope of a vertebrate S100A8 protein, wherein the epitope has an amino acid sequence of a region corresponding to the amino acid sequence ranging from amino acid position 55 to amino acid position 71 of the human protein S100A8 of Uniprot/Swissprot accession number P05109 (SEQ ID NO: 78). 4. The immunoglobulin or proteinaceous binding partner of claim 3, wherein the amino acid sequence is one of the sequences FKELDINTDGAVNFQEF (SEQ ID NO: 5), FKELDINTDGAINFQEF (SEQ ID NO: 45), FKELDINSDGAINFQEF (SEQ ID NO: 46), FKELDINEDGAVNFQEF (SEQ ID NO: 47), FKELDINKDGAVNFEEF (SEQ ID NO: 48), FKELDINSDGASNFQEF (SEQ ID NO: 49), FKELDVNSDGAINFEEF (SEQ ID NO: 50), FKQFDINEDGAVNFQEF (SEQ ID NO: 51), FRQLDINEDGAVNFQEF (SEQ ID NO: 52), FKELDINQDNAVNFEEF (SEQ ID NO: 53), FNELDINSDNAINFQEF (SEQ ID NO: 54), FKELDINQDGGINFEEF (SEQ ID NO: 55), FKELDVNSDSAINFEEF (SEQ ID NO: 56), FKELDVNSDNAINFEEF (SEQ ID NO: 57), FQELDVNSDGAINFEEF (SEQ ID NO: 58), FRELDINSDNAINFEEF (SEQ ID NO: 59), FKELDFTADGAINFEEF (SEQ ID NO: 60), FKELDINQDG GINLEEF (SEQ ID NO: 61), FKELDINQDGFINFEEF (SEQ ID NO: 62), and FKELDSNKDQQINFEEF (SEQ ID NO: 63). 5. (canceled) 6. The method of claim 11, wherein the condition is selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, immune reconstituation inflammatory syndrome (IRIS), sepsis, systemic inflammatory response syndrome (SIRS), pneumonia, osteomyelitis, autoinflammatory syndromes, hyperzincemia, systemic inflammation, atherosclerosis, acute coronary syndrome, myocardial infarction, diabetes, an inflammatory skin disease, psoriasis, inflammatory bowel disease, vasculitis, allograft rejection, glomerulonephritis, systemic lupus erythematosus, pancreatitis, a cancer, dermatomyositis and polymyositis, multiple sclerosis, allergies, infections, pulmonary inflammation, acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS). 7. A combination of one or more immunoglobulins or proteinaceous binding partners of claim 1 and the immunoglobulin or proteinaceous binding partner having a binding specificity to an epitope of a vertebrate S100A8 protein, wherein the epitope has an amino acid sequence of a region corresponding to the amino acid sequence ranging from amino acid position 55 to amino acid position 71 of the human protein S100A8 of Uniprot/Swissprot accession number P05109 (SEQ ID NO: 78). 8. The combination of claim 7, being comprised in a single immunoglobulin or proteinaceous binding partner, the immunoglobulin or proteinaceous binding partner having at least a dual binding specificity. 9. (canceled) 10. The method of claim 54, wherein the condition is selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, immune reconstituation inflammatory syndrome (IRIS), sepsis, systemic inflammatory response syndrome (SIRS), pneumonia, osteomyelitis, autoinflammatory syndromes, hyperzincemia, systemic inflammation, atherosclerosis, acute coronary syndrome, myocardial infarction, diabetes, an inflammatory skin disease, psoriasis, inflammatory bowel disease, vasculitis, allograft rejection, glomerulonephritis, systemic lupus erythematosus, pancreatitis, a cancer, dermatomyositis and polymyositis, multiple sclerosis, allergies, infections, pulmonary inflammation, acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS). 11. A method of treating a subject suffering from an inflammatory condition, the method comprising administering to the subject at least one of the immunoglobulin or proteinaceous binding partner of claim 1. 12. The method of claim 11, wherein the subject is a mammal. 13. An isolated peptide or peptidomimetic comprising the sequence of X3EX2X3X1X1X1 X1X1X1 X5X1X1X6X2X1X1 (SEQ ID NO: 6), wherein X1 represents any amino acid, X2 represents an amino acid with a side chain carrying a carboxylic acid group, X3 represents a non-polar amino acid, X5 represents D, N, E or Q, X6 represents an aromatic amino acid, wherein the peptide differs from a calcium binding protein. 14. The isolated peptide or peptidomimetic of claim 13, wherein the sequence of SEQ ID NO: 6 is (a) the sequence of MEX2X3DX1NX1DX1 QX1X1FEX2X1 (SEQ ID NO: 7), or a homolog thereof; or (b) the sequence of MEDX3DX3NX1DX1 QX3X1FEEX1 (SEQ ID NO: 8), or a homolog thereof. 15. The isolated peptide or peptidomimetic of claim 13, essentially consisting of the sequence of SEQ ID NO: 6. 16. An isolated peptide or peptidomimetic comprising the sequence of X5X1X1X6X2X1X1 X1X3X3 X3X3X1 (SEQ ID NO: 9), wherein X1 represents any amino acid, X2 represents an amino acid with a side chain carrying a carboxylic acid group, X3 represents a non-polar amino acid, X5 represents D, N, E or Q and X6 represents an aromatic amino acid, wherein the peptide differs from a calcium binding protein. 17. The isolated peptide or peptidomimetic of claim 16, (a) wherein the sequence of SEQ ID NO: 6 is the sequence of QX1X1FEX2X1X1X3X3X3X3X7 (SEQ ID NO: 10), or a homolog thereof, wherein X7 represents R or K, or (b) wherein the sequence of SEQ ID NO: 6 is the sequence of QX3X1FEEX1X1MLMX3X7 (SEQ ID NO: 11), or a homolog thereof or (c) essentially consisting of the sequence of SEQ ID NO: 9. 18. An isolated peptide or peptidomimetic comprising the sequence of X6X8X5X3X1X1X1X1X1X1 X1X1NX3X5X1X6 (SEQ ID NO: 12), or a homolog thereof, wherein X1 represents any amino acid, X3 represents a non-polar amino acid, X5 represents D, N, E or Q, X6 represents an aromatic amino acid, X8 represents a polar amino acid, wherein the peptide differs from a calcium binding protein. 19. The isolated peptide or peptidomimetic of claim 18, wherein the sequence of SEQ ID NO: 6 is the sequence of FX8EX3DX1NX1DX9X1X10NX11X5EF (SEQ ID NO: 13), wherein X9 represents a polar amino acid or G, wherein X10 represents I, V, S or L, X11 represents F or L, or a homolog thereof. 20. An isolated peptide or peptidomimetic comprising the sequence of SEQ ID NO: 5 or a homolog thereof, wherein the peptide differs from a calcium binding protein. 21. The isolated peptide or peptidomimetic of claim 20, essentially consisting of the sequence of SEQ ID NO: 1 or the homolog thereof. 22. A combination of an isolated peptide or peptidomimetic of claim 13 or an isolated peptide or peptidomimetic comprising the sequence of X5X1X1X6X2X1X1 X1X3X3 X3X3X1 (SEQ ID NO: 9), wherein X1 represents any amino acid, X2 represents an amino acid with a side chain carrying a carboxylic acid group, X3 represents a non-polar amino acid, X5 represents D, N, E or Q and X6 represents an aromatic amino acid, wherein the peptide differs from a calcium binding protein; and
an isolated peptide or peptidomimetic comprising the sequence of X6X8X5X3X1X1X1X1X1X1 X1X1NX3X5X1X6 (SEQ ID NO: 12), or a homolog thereof, wherein X1 represents any amino acid, X3 represents a non-polar amino acid, X5 represents D, N, E or Q, X6 represents an aromatic amino acid, X8 represents a polar amino acid, wherein the peptide differs from a calcium binding protein,
wherein the peptidomimetic comprising the sequence of SEQ ID NO: 6 or 9, and the peptidomimetic comprising the sequence of SEQ ID NO: 12 are comprised in a single chain. 23. The combination of claim 22, wherein the peptide comprising the sequence of SEQ ID NO: 6 or the sequence of SEQ ID NO: 9, and the peptide comprising the sequence of SEQ ID NO: 12, or the homolog thereof, are comprised in a single peptide chain. 24. An isolated nucleic acid molecule comprising one of (a) a sequence encoding a peptide of SEQ ID NO: 6, (b) a sequence encoding a peptide of SEQ ID NO: 9, and (c) a sequence encoding a peptide of SEQ ID NO: 12, or a homolog thereof, wherein the encoded peptide differs from the full-length sequence a calcium binding protein. 25. The isolated nucleic acid molecule of claim 24, essentially consisting of one of the sequence of SEQ ID NO: 6, the sequence encoding a peptide of SEQ ID NO: 9 and the sequence encoding a peptide of SEQ ID NO: 12, or the homolog thereof, and optionally an expression cassette. 26. The isolated nucleic acid molecule of claim 24, being comprised in a vector. 27. An in-vitro method of identifying a compound capable of decreasing or inhibiting the formation of a complex between a peptide comprising one of (i) the amino acid sequence of SEQ ID NO: 6 or 9 and (ii) the amino acid sequence of SEQ ID NO: 12 and a TLR4 receptor or a functional fragment thereof, the functional fragment of the TLR4 receptor comprising the binding site for SEQ ID NO: 1 and SEQ ID NO: 3, respectively, the method comprising
(a) allowing the peptide, the TLR4 receptor, or the functional fragment thereof, and a compound suspected to affect the said complex formation to contact each other, and (b) detecting the formation of a complex between the peptide and the TLR4 receptor, or the functional fragment thereof. 28. The method of claim 27, wherein the peptide comprising the amino acid sequence of SEQ ID NO: 6 or 9 is a S100A9 protein and/or the peptide comprising the amino acid sequence of SEQ ID NO: 12 is a S100A8 protein. 29. An in-vitro method of identifying a compound capable of increasing the stability of a complex between a S100A8 protein, or a functional fragment thereof, and a S100A9 protein, or functional fragments thereof, the method comprising
(a) allowing the S100A8 protein, or the functional fragment thereof, the S100A9 protein, or the functional fragment thereof, and a compound suspected to affect the said complex formation to contact each other, and (b) detecting the formation of a complex between the S100A8 protein, or the functional fragment thereof, and the S100A9 protein, or the functional fragment thereof. 30. The method of claim 29, wherein the functional fragment of the S100A8 protein and/or the functional fragment of the S100A9 protein comprises at least one of EF hand I and EF hand II. 31. The method of claim 29, wherein the S100A8 protein, or the functional fragment thereof, the S100A9 protein, or the functional fragment thereof, and the compound suspected to affect the said complex formation are allowed to contact each other in the presence of a salt of calcium, zinc or copper. 32. The method of claim 29, wherein the formation of a heterotetrameric complex between the S100A8 protein, or the functional fragment thereof, and the S100A9 protein, or the functional fragment thereof is detected, and wherein the method is a method of identifying a compound capable of increasing the stability of a heterotetrameric complex between a S100A8 protein, or a functional fragment thereof, and a S100A9 protein, or functional fragments thereof. 33. The method of claim 27, further comprising comparing the formation of the complex to a control measurement. 34. The method of claim 33, wherein the control measurement comprises detecting the formation of the complex between the protein S100A8, or the functional fragment thereof, and the protein S100A9, or the functional fragment thereof, in the absence of a compound suspected to affect the complex formation. 35. (canceled) 36. (canceled) 37. An in-vitro method of diagnosing the risk of occurrence, or the presence, of a condition associated with an inflammation in a subject, the method comprising detecting the amount of a complex between a S100A8 protein and a S100A9 protein in a sample from the subject, wherein a decreased amount of the complex relative to a threshold value, indicates an elevated risk of occurrence, or the presence, of a condition associated with an inflammation. 38. The method of claim 37, comprising contacting the sample with an immunoglobulin or proteinaceous binding partner having a binding specificity to (a) a region of a S100A9 protein that differs from the region toward which the immunoglobulin or proteinaceous binding partner according to claim 1 has a binding specificity, or (b) a region of a S100A8 protein that differs from the region toward which the immunoglobulin or proteinaceous binding partner according to claim 3 has a binding specificity, under non-denaturating conditions, and detecting the amount of the complex between protein S100A8 and the protein S100A9 bound, wherein an increased amount of S100A8 or S100A9 detected by binding to the respective immunoglobulin or proteinaceous binding partner, relative to a threshold value, indicates a decreased amount of a complex between a S100A8 protein and a S100A9 protein. 39. The method of claim 38, wherein detecting the amount of the complex between protein S100A8 and the protein S100A9 bound comprises one of immunoprecipitation, flow cytometry and mass spectrometry. 40. The method of claim 37, comprising contacting the sample with an immunoglobulin or proteinaceous binding partner according to claim 1 or according to claim 3 under non-denaturating conditions and detecting the amount of the S100A8 protein or the S100A9 protein, respectively, bound, wherein an increased amount of the S100A8 protein or the S100A9 protein detected, relative to a threshold value, indicates a decreased amount of a complex between a S100A8 protein and a S100A9 protein. 41. The method of claim 40, wherein the immunoglobulin or proteinaceous binding partner has a binding specificity to a peptide of the species to which the subject belongs. 42. The method of claim 41, wherein the immunoglobulin or proteinaceous binding partner has a binding specificity to a human peptide and wherein the subject is a human. 43. The method of claim 37, further comprising comparing the amount of the complex to a control measurement. 44. The method of claim 43, wherein the control measurement comprises detecting the amount of the complex between the S100A8 protein and the S100A9 protein in a sample from a subject known not to suffer from an inflammatory disorder. 45. The method of claim 37, comprising
(a) contacting a first sample from the subject with an immunoglobulin or proteinaceous binding partner having a binding specificity to (i) a region of a S100A9 protein that differs from the region toward which the immunoglobulin or proteinaceous binding partner according to claim 1 has a binding specificity, or (ii) a region of a S100A8 protein that differs from the region toward which the immunoglobulin or proteinaceous binding partner according to claim 3 has a binding specificity under non-denaturating conditions, (b) contacting a second sample from the subject with an immunoglobulin or proteinaceous binding partner (i) according to claim 1 or (ii) according to claim 3 under non-denaturating conditions, (c) detecting the amount of the protein S100A8 or the S100A9 protein, respectively, in the first sample and in the second sample, and (d) comparing the difference between the S100A8 protein or the S100A9 protein bound in the first sample and in the second sample to a threshold value, wherein a decreased difference between the protein bound in the first sample and in the second sample, relative to a threshold value, indicates an elevated risk of occurrence, or the presence, of a condition associated with an inflammation. 46. The method of claim 45, wherein the threshold value is based on the formation of a corresponding complex to a control measurement. 47. The method of claim 46, wherein the control measurement comprises determining the difference in the amount of the S100A8 protein or the S100A9 protein in a third and a fourth sample, the third and a fourth sample being from a subject known not to suffer from an inflammatory disorder. 48. The method of claim 45, wherein
(a) the immunoglobulin or proteinaceous binding partner contacted with the first sample has a binding specificity to a region of a S100A9 protein that differs from the region toward which the immunoglobulin or proteinaceous binding partner according to claim 1 has a binding specificity, and the immunoglobulin or proteinaceous binding partner contacted with the second sample is an immunoglobulin or proteinaceous binding partner according to claim 1, or (b) the immunoglobulin or proteinaceous binding partner contacted with the first sample has a binding specificity to a region of a S100A9 protein that differs from the region toward which the immunoglobulin or proteinaceous binding partner according to claim 3 has a binding specificity and the immunoglobulin or proteinaceous binding partner contacted with the second sample is an immunoglobulin or proteinaceous binding partner according to claim 3. 49. The method of claim 37, wherein the sample is one of a blood sample, a plasma sample and a serum sample. 50. A method of treating a subject suffering from an inflammatory disorder, the method comprising administering to the subject a compound obtained by the method of claim 29, thereby increasing the stability of a complex between a S100A8 protein and a S100A9 protein in a body fluid of the subject. 51. A method of treating a subject suffering from an inflammatory disorder, the method comprising administering to the subject a compound obtained by the method of claim 27, thereby decreasing or inhibiting the formation of a complex between the protein S100A8 or the protein S100A9 and a TLR4 receptor on cells of the subject. 52. A method of identifying a binding partner of the isolated peptide or peptidomimetic of claim 13, in an organism, the method comprising
(a) contacting the isolated peptide or peptidomimetic with a sample from the organism, thereby forming a reaction mixture, (b) allowing a complex to form between the isolated peptide or peptidomimetic and a binding partner in the reaction mixture, (c) isolating the peptide or peptidomimetic from the reaction mixture, wherein the peptide or peptidomimetic is comprised in a complex with the binding partner, and (d) analysing the binding partner. 53. The method of claim 52, wherein isolating the peptide or peptidomimetic from the reaction mixture comprises one of immunoprecipitation, chromatography and flow cytometry. 54. The method of claim 11 comprising administering to the subject an immunoglobulin or proteinaceous binding partner having a binding specificity to an epitope of a vertebrate S100A8 protein, wherein the epitope has an amino acid sequence of a region corresponding to the amino acid sequence ranging from amino acid position 55 to amino acid position 71 of the human protein S100A8 of Uniprot/Swissprot accession number P05109 (SEQ ID NO: 78). | 1,600 |
416 | 15,332,572 | 1,645 | A method and a composition of matter formed in accordance with the method for anchoring and/or impregnation of a biological vehicle with a cargo molecule includes mixing the biological vehicle and the cargo molecule in suspension to create a cargo molecule and biological vehicle mixture, placing the cargo molecule and biological vehicle mixture inside a pressure vessel, subjecting the cargo molecule and biological vehicle mixture to subcritical or supercritical fluid, returning pressure and temperature within the pressure vessel to ambient conditions, and recovering a biological vehicle bound cargo molecule. | 1. A method for anchoring and/or impregnating a biological vehicle with a cargo molecule, comprising:
mixing the biological vehicle and the cargo molecule in suspension to create a cargo molecule and biological vehicle mixture; placing the cargo molecule and biological vehicle mixture inside a pressure vessel; subjecting the cargo molecule and biological vehicle mixture to subcritical or supercritical fluid; returning pressure and temperature within the pressure vessel to ambient conditions; and recovering a biological vehicle bound cargo molecule. 2. The method according to claim 1, wherein the biological vehicle is a spore, cell, virus, or cell-derived vesicle. 3. The method according to claim 1, wherein the biological vehicle is a bacterial spore, fungal spore, mammalian cell, bacterial cell, algal cell, plant cell, fungal cell, virus, exosome, microvesicle, or oncosome. 4. The method according to claim 1, wherein the cargo molecule is a small molecule or a biologic. 5. The method according to claim 1, wherein the cargo molecule is a drug, a prodrug, an imaging reagent, an ion, a natural compound, a synthetic compound, a polypeptide, a small peptide, a protein, an enzyme, an antigen, an antibody, a carbohydrate, a nucleic acid, DNA, RNA, or PNA. 6. The method according to claim 1, further separating the biological vehicle bound cargo molecule from excess cargo molecules. 7. The method according to claim 1, wherein the step of subjecting the cargo molecule and biological vehicle mixture to subcritical or supercritical fluid includes subjecting the cargo molecule and biological vehicle mixture to supercritical carbon dioxide above a critical temperature of 31.1° C. and critical pressure of 1,071 psi. 8. The method according to claim 1, wherein the step of subjecting the cargo molecule and biological vehicle mixture to subcritical or supercritical fluid includes subjecting the cargo molecule and biological vehicle mixture to subcritical carbon dioxide. 9. The method according to claim 1, wherein the step of mixing the biological vehicle and selected cargo molecule in suspension includes mixing the biological vehicle and cargo molecule in a buffer or solution. 10. The method according to claim 1, wherein the step of subjecting the cargo molecule and biological vehicle mixture to subcritical or supercritical fluid includes subjecting the cargo molecule and biological vehicle mixture to supercritical fluid. 11. The method according to claim 1, wherein the step of subjecting the cargo molecule and biological vehicle mixture to subcritical or supercritical fluid includes subjecting the cargo molecule and biological vehicle mixture to subcritical fluid. 12. The method according to claim 1, further including the step of adding a sterilant to the cargo molecule and biological vehicle mixture. 13. A composition of matter formed in accordance with the method for anchoring and/or impregnating a biological vehicle with a cargo molecule, comprising:
mixing the biological vehicle and the cargo molecule in suspension to create a cargo molecule and biological vehicle mixture; placing the cargo molecule and biological vehicle mixture inside a pressure vessel; subjecting the cargo molecule and biological vehicle mixture to subcritical or supercritical fluid; returning pressure and temperature within the pressure vessel to ambient conditions; and recovering a biological vehicle bound cargo molecule. 14. The composition of matter according to claim 13, wherein the biological vehicle is a bacterial spore, fungal spore, mammalian cell, bacterial cell, algal cell, plant cell, fungal cell, virus, exosome, microvesicle, or oncosome. 15. The composition of matter according to claim 13, wherein the cargo molecule is a drug, a prodrug, an imaging reagent, an ion, a natural compound, a synthetic compound, a polypeptide, a small peptide, a protein, an enzyme, an antigen, an antibody, a carbohydrate, a nucleic acid, DNA, RNA, or PNA. 16. The composition of matter according to claim 13, wherein the biological vehicle bound cargo molecule is the separated from excess cargo molecules. 17. The composition of matter according to claim 13, wherein the step of subjecting the cargo molecule and biological vehicle mixture to subcritical or supercritical fluid includes subjecting the cargo molecule and biological vehicle mixture to supercritical carbon dioxide above a critical temperature of 31.1° C. and critical pressure of 1,071 psi. 18. The composition of matter according to claim 13, wherein the step of subjecting the cargo molecule and biological vehicle mixture to subcritical or supercritical fluid includes subjecting the cargo molecule and biological vehicle mixture to subcritical carbon dioxide. 19. The composition of matter according to claim 13, wherein the step of mixing the biological vehicle and selected cargo molecule in suspension includes mixing the biological vehicle and cargo molecule in a buffer or solution. 20. The composition of matter according to claim 13, further including the step of adding a sterilant to the cargo molecule and biological vehicle mixture. | A method and a composition of matter formed in accordance with the method for anchoring and/or impregnation of a biological vehicle with a cargo molecule includes mixing the biological vehicle and the cargo molecule in suspension to create a cargo molecule and biological vehicle mixture, placing the cargo molecule and biological vehicle mixture inside a pressure vessel, subjecting the cargo molecule and biological vehicle mixture to subcritical or supercritical fluid, returning pressure and temperature within the pressure vessel to ambient conditions, and recovering a biological vehicle bound cargo molecule.1. A method for anchoring and/or impregnating a biological vehicle with a cargo molecule, comprising:
mixing the biological vehicle and the cargo molecule in suspension to create a cargo molecule and biological vehicle mixture; placing the cargo molecule and biological vehicle mixture inside a pressure vessel; subjecting the cargo molecule and biological vehicle mixture to subcritical or supercritical fluid; returning pressure and temperature within the pressure vessel to ambient conditions; and recovering a biological vehicle bound cargo molecule. 2. The method according to claim 1, wherein the biological vehicle is a spore, cell, virus, or cell-derived vesicle. 3. The method according to claim 1, wherein the biological vehicle is a bacterial spore, fungal spore, mammalian cell, bacterial cell, algal cell, plant cell, fungal cell, virus, exosome, microvesicle, or oncosome. 4. The method according to claim 1, wherein the cargo molecule is a small molecule or a biologic. 5. The method according to claim 1, wherein the cargo molecule is a drug, a prodrug, an imaging reagent, an ion, a natural compound, a synthetic compound, a polypeptide, a small peptide, a protein, an enzyme, an antigen, an antibody, a carbohydrate, a nucleic acid, DNA, RNA, or PNA. 6. The method according to claim 1, further separating the biological vehicle bound cargo molecule from excess cargo molecules. 7. The method according to claim 1, wherein the step of subjecting the cargo molecule and biological vehicle mixture to subcritical or supercritical fluid includes subjecting the cargo molecule and biological vehicle mixture to supercritical carbon dioxide above a critical temperature of 31.1° C. and critical pressure of 1,071 psi. 8. The method according to claim 1, wherein the step of subjecting the cargo molecule and biological vehicle mixture to subcritical or supercritical fluid includes subjecting the cargo molecule and biological vehicle mixture to subcritical carbon dioxide. 9. The method according to claim 1, wherein the step of mixing the biological vehicle and selected cargo molecule in suspension includes mixing the biological vehicle and cargo molecule in a buffer or solution. 10. The method according to claim 1, wherein the step of subjecting the cargo molecule and biological vehicle mixture to subcritical or supercritical fluid includes subjecting the cargo molecule and biological vehicle mixture to supercritical fluid. 11. The method according to claim 1, wherein the step of subjecting the cargo molecule and biological vehicle mixture to subcritical or supercritical fluid includes subjecting the cargo molecule and biological vehicle mixture to subcritical fluid. 12. The method according to claim 1, further including the step of adding a sterilant to the cargo molecule and biological vehicle mixture. 13. A composition of matter formed in accordance with the method for anchoring and/or impregnating a biological vehicle with a cargo molecule, comprising:
mixing the biological vehicle and the cargo molecule in suspension to create a cargo molecule and biological vehicle mixture; placing the cargo molecule and biological vehicle mixture inside a pressure vessel; subjecting the cargo molecule and biological vehicle mixture to subcritical or supercritical fluid; returning pressure and temperature within the pressure vessel to ambient conditions; and recovering a biological vehicle bound cargo molecule. 14. The composition of matter according to claim 13, wherein the biological vehicle is a bacterial spore, fungal spore, mammalian cell, bacterial cell, algal cell, plant cell, fungal cell, virus, exosome, microvesicle, or oncosome. 15. The composition of matter according to claim 13, wherein the cargo molecule is a drug, a prodrug, an imaging reagent, an ion, a natural compound, a synthetic compound, a polypeptide, a small peptide, a protein, an enzyme, an antigen, an antibody, a carbohydrate, a nucleic acid, DNA, RNA, or PNA. 16. The composition of matter according to claim 13, wherein the biological vehicle bound cargo molecule is the separated from excess cargo molecules. 17. The composition of matter according to claim 13, wherein the step of subjecting the cargo molecule and biological vehicle mixture to subcritical or supercritical fluid includes subjecting the cargo molecule and biological vehicle mixture to supercritical carbon dioxide above a critical temperature of 31.1° C. and critical pressure of 1,071 psi. 18. The composition of matter according to claim 13, wherein the step of subjecting the cargo molecule and biological vehicle mixture to subcritical or supercritical fluid includes subjecting the cargo molecule and biological vehicle mixture to subcritical carbon dioxide. 19. The composition of matter according to claim 13, wherein the step of mixing the biological vehicle and selected cargo molecule in suspension includes mixing the biological vehicle and cargo molecule in a buffer or solution. 20. The composition of matter according to claim 13, further including the step of adding a sterilant to the cargo molecule and biological vehicle mixture. | 1,600 |
417 | 14,767,936 | 1,642 | This invention relates to a method for detecting shed or circulating tumor cells in a biological fluid using labeled pituitary adenylate cyclase activating peptide or vasoactive intestinal peptide. | 1-4. (canceled) 5. A method for detecting shed or circulating tumor cells comprising:
(a) contacting a biological fluid from a subject with a labeled pituitary adenylate cyclase activating peptide (PACAP) having a label or labeled vasoactive intestinal peptide (VIP) having a label; and (b) determining binding of the labeled PACAP or labeled VIP to shed or circulating tumor cells in the biological fluid thereby detecting shed or circulating tumor cells. 6. The method of claim 5, wherein the biological fluid is blood, urine, cerebrospinal fluid, mucus, sputum, stool, a gastrointestinal secretion or a mammary gland secretion. 7. The method of claim 5, wherein shed or circulating tumor cells are detected with labeled PACAP and said method further comprises
(c) comparing binding of the labeled PACAP to shed or circulating tumor cells in the biological fluid to binding or lack of binding of labeled PACAP having a label or VIP binding in a control sample; and (d) diagnosing cancer in the subject, wherein the presence of binding of the labeled PACAP to shed or circulating tumor cells in the biological fluid is indicative of the subject either having, or being at risk for developing, cancer. 8. The method of claim 7, wherein the biological fluid is urine. 9. The method of claim 8, wherein the labeled PACAP includes the sequence of SEQ ID NO:7. 10. The method of claim 5, wherein the labeled PACAP includes the sequence of one of the following: SEQ ID NO:1; SEQ ID NO:2; or SEQ ID NO:7. 11. The method of claim 10, wherein the label includes a chromophore, fluorophore or protein. 12. The method of claim 10, wherein the label is luminescent or fluorescent. 13. The method of claim 5, wherein the labeled VIP includes the sequence of one of the following: SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:5; or SEQ ID NO:6. 14. The method of claim 5, further comprising visualizing the label of the labeled PACAP or labeled VIP to determine the binding. 15. The method of claim 5, comprising detecting the labeled PACAP or labeled VIP bound to a receptor that is overexpressed on cancerous cells. 16. The method of claim 15, comprising distinguishing cancerous cells bound with the labeled PACAP or labeled VIP from cells not bound with the labeled PACAP or labeled VIP. 17. The method of claim 15, comprising distinguishing cancerous cells bound with the labeled PACAP or labeled VIP from epithelial cells or white blood cells that are not bound with the labeled PACAP or labeled VIP. 18. The method of claim 5, comprising diagnosing the subject as having or being susceptible to prostate cancer, bladder cancer, or renal cancer when the biological sample is a urine sample. 19. The method of claim 5, comprising diagnosing the subject as having or being susceptible to breast cancer, lung cancer, or ovarian cancer when the biological sample is a blood sample. | This invention relates to a method for detecting shed or circulating tumor cells in a biological fluid using labeled pituitary adenylate cyclase activating peptide or vasoactive intestinal peptide.1-4. (canceled) 5. A method for detecting shed or circulating tumor cells comprising:
(a) contacting a biological fluid from a subject with a labeled pituitary adenylate cyclase activating peptide (PACAP) having a label or labeled vasoactive intestinal peptide (VIP) having a label; and (b) determining binding of the labeled PACAP or labeled VIP to shed or circulating tumor cells in the biological fluid thereby detecting shed or circulating tumor cells. 6. The method of claim 5, wherein the biological fluid is blood, urine, cerebrospinal fluid, mucus, sputum, stool, a gastrointestinal secretion or a mammary gland secretion. 7. The method of claim 5, wherein shed or circulating tumor cells are detected with labeled PACAP and said method further comprises
(c) comparing binding of the labeled PACAP to shed or circulating tumor cells in the biological fluid to binding or lack of binding of labeled PACAP having a label or VIP binding in a control sample; and (d) diagnosing cancer in the subject, wherein the presence of binding of the labeled PACAP to shed or circulating tumor cells in the biological fluid is indicative of the subject either having, or being at risk for developing, cancer. 8. The method of claim 7, wherein the biological fluid is urine. 9. The method of claim 8, wherein the labeled PACAP includes the sequence of SEQ ID NO:7. 10. The method of claim 5, wherein the labeled PACAP includes the sequence of one of the following: SEQ ID NO:1; SEQ ID NO:2; or SEQ ID NO:7. 11. The method of claim 10, wherein the label includes a chromophore, fluorophore or protein. 12. The method of claim 10, wherein the label is luminescent or fluorescent. 13. The method of claim 5, wherein the labeled VIP includes the sequence of one of the following: SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:5; or SEQ ID NO:6. 14. The method of claim 5, further comprising visualizing the label of the labeled PACAP or labeled VIP to determine the binding. 15. The method of claim 5, comprising detecting the labeled PACAP or labeled VIP bound to a receptor that is overexpressed on cancerous cells. 16. The method of claim 15, comprising distinguishing cancerous cells bound with the labeled PACAP or labeled VIP from cells not bound with the labeled PACAP or labeled VIP. 17. The method of claim 15, comprising distinguishing cancerous cells bound with the labeled PACAP or labeled VIP from epithelial cells or white blood cells that are not bound with the labeled PACAP or labeled VIP. 18. The method of claim 5, comprising diagnosing the subject as having or being susceptible to prostate cancer, bladder cancer, or renal cancer when the biological sample is a urine sample. 19. The method of claim 5, comprising diagnosing the subject as having or being susceptible to breast cancer, lung cancer, or ovarian cancer when the biological sample is a blood sample. | 1,600 |
418 | 14,996,093 | 1,663 | The invention relates to the novel cotton variety designated 14R913B2XF. Provided by the invention are the seeds, plants, plant parts and derivatives of the cotton variety 14R913B2XF. Also provided by the invention are methods of using cotton variety 14R913B2XF and products derived therefrom. Still further provided by the invention are methods for producing cotton plants by crossing the cotton variety 14R913B2XF with itself or another cotton variety and plants and seeds produced by such methods. | 1. A plant of cotton variety 14R913B2XF, wherein a sample of seed of said variety has been deposited under ATCC Accession No. ______. 2. A plant part of the plant of claim 1, wherein the plant part comprises at least one cell of said plant. 3. The plant part of claim 2, further defined as pollen, a meristem, a cell, or an ovule. 4. A seed of cotton variety 14R913B2XF, wherein a sample of seed of said variety has been deposited under ATCC Accession No. ______. 5. A cotton plant that expresses all of the physiological and morphological characteristics of cotton variety 14R913B2XF, wherein a sample of seed of said variety has been deposited under ATCC Accession No. ______. 6. A method of producing cotton seed, wherein the method comprises crossing the plant of claim 1 with itself or a second cotton plant. 7. The method of claim 6, wherein the method comprises crossing the plant of cotton variety 14R913B2XF with a second, distinct cotton plant to produce an F1 hybrid cotton seed. 8. An F1 hybrid cotton seed produced by the method of claim 7. 9. An F1 hybrid cotton plant produced by growing the seed of claim 8. 10. A composition comprising a seed of cotton variety 14R913B2XF comprised in plant seed growth media, wherein a sample of seed of said variety has been deposited under ATCC Accession No. ______. 11. The composition of claim 10, wherein the growth media is soil or a synthetic cultivation medium. 12. A plant of cotton variety 14R913B2XF further comprising a single locus conversion, wherein a sample of seed of cotton variety 14R913B2XF has been deposited under ATCC Accession No. ______. 13. The plant of claim 12, wherein the single locus conversion comprises a transgene. 14. A seed that produces the plant of claim 12. 15. The seed of claim 14, wherein the single locus confers a trait selected from the group consisting of male sterility, herbicide tolerance, insect or pest resistance, disease resistance, modified fatty acid metabolism, abiotic stress resistance, site-specific genetic recombination, modified carbohydrate metabolism and modified cotton fiber characteristics. 16. The seed of claim 15, wherein the single locus confers tolerance to an herbicide selected from the group consisting of glyphosate, sulfonylurea, imidazolinone, dicamba, glufosinate, phenoxy propionic acid, cyclohexanedione, triazine, benzonitrile, and bromoxynil. 17. The seed of claim 15, wherein the trait is insect resistance and said single locus comprises a transgene encoding a Bacillus thuringiensis (Bt) endotoxin. 18. The seed of claim 15, wherein the single locus comprises a transgene. 19. The method of claim 7, wherein the method further comprises:
(a) crossing a plant grown from said F1 hybrid cotton seed with itself or a different cotton plant to produce a seed of a progeny plant of a subsequent generation; (b) growing a progeny plant of a subsequent generation from said seed of a progeny plant of a subsequent generation and crossing the progeny plant of a subsequent generation with itself or a second plant to produce a progeny plant of a further subsequent generation; and (c) repeating steps (a) and (b) using said progeny plant of a further subsequent generation from step (b) in place of the plant grown from said F1 hybrid cotton seed in step (a), wherein steps (a) and (b) are repeated with sufficient inbreeding to produce an inbred cotton plant derived from the cotton variety 14R913B2XF. 20. The method of claim 19, comprising crossing said inbred cotton plant derived from the cotton variety 14R913B2XF with a plant of a different genotype to produce a seed of a hybrid cotton plant derived from the cotton variety 14R913B2XF. 21. A method of producing a commodity plant product comprising collecting the commodity plant product from a plant of cotton variety 14R913B2XF, wherein a sample of seed of said variety has been deposited under ATCC Accession No. ______. 22. The method of claim 21, wherein the commodity plant product is lint, seed oil, or seed. | The invention relates to the novel cotton variety designated 14R913B2XF. Provided by the invention are the seeds, plants, plant parts and derivatives of the cotton variety 14R913B2XF. Also provided by the invention are methods of using cotton variety 14R913B2XF and products derived therefrom. Still further provided by the invention are methods for producing cotton plants by crossing the cotton variety 14R913B2XF with itself or another cotton variety and plants and seeds produced by such methods.1. A plant of cotton variety 14R913B2XF, wherein a sample of seed of said variety has been deposited under ATCC Accession No. ______. 2. A plant part of the plant of claim 1, wherein the plant part comprises at least one cell of said plant. 3. The plant part of claim 2, further defined as pollen, a meristem, a cell, or an ovule. 4. A seed of cotton variety 14R913B2XF, wherein a sample of seed of said variety has been deposited under ATCC Accession No. ______. 5. A cotton plant that expresses all of the physiological and morphological characteristics of cotton variety 14R913B2XF, wherein a sample of seed of said variety has been deposited under ATCC Accession No. ______. 6. A method of producing cotton seed, wherein the method comprises crossing the plant of claim 1 with itself or a second cotton plant. 7. The method of claim 6, wherein the method comprises crossing the plant of cotton variety 14R913B2XF with a second, distinct cotton plant to produce an F1 hybrid cotton seed. 8. An F1 hybrid cotton seed produced by the method of claim 7. 9. An F1 hybrid cotton plant produced by growing the seed of claim 8. 10. A composition comprising a seed of cotton variety 14R913B2XF comprised in plant seed growth media, wherein a sample of seed of said variety has been deposited under ATCC Accession No. ______. 11. The composition of claim 10, wherein the growth media is soil or a synthetic cultivation medium. 12. A plant of cotton variety 14R913B2XF further comprising a single locus conversion, wherein a sample of seed of cotton variety 14R913B2XF has been deposited under ATCC Accession No. ______. 13. The plant of claim 12, wherein the single locus conversion comprises a transgene. 14. A seed that produces the plant of claim 12. 15. The seed of claim 14, wherein the single locus confers a trait selected from the group consisting of male sterility, herbicide tolerance, insect or pest resistance, disease resistance, modified fatty acid metabolism, abiotic stress resistance, site-specific genetic recombination, modified carbohydrate metabolism and modified cotton fiber characteristics. 16. The seed of claim 15, wherein the single locus confers tolerance to an herbicide selected from the group consisting of glyphosate, sulfonylurea, imidazolinone, dicamba, glufosinate, phenoxy propionic acid, cyclohexanedione, triazine, benzonitrile, and bromoxynil. 17. The seed of claim 15, wherein the trait is insect resistance and said single locus comprises a transgene encoding a Bacillus thuringiensis (Bt) endotoxin. 18. The seed of claim 15, wherein the single locus comprises a transgene. 19. The method of claim 7, wherein the method further comprises:
(a) crossing a plant grown from said F1 hybrid cotton seed with itself or a different cotton plant to produce a seed of a progeny plant of a subsequent generation; (b) growing a progeny plant of a subsequent generation from said seed of a progeny plant of a subsequent generation and crossing the progeny plant of a subsequent generation with itself or a second plant to produce a progeny plant of a further subsequent generation; and (c) repeating steps (a) and (b) using said progeny plant of a further subsequent generation from step (b) in place of the plant grown from said F1 hybrid cotton seed in step (a), wherein steps (a) and (b) are repeated with sufficient inbreeding to produce an inbred cotton plant derived from the cotton variety 14R913B2XF. 20. The method of claim 19, comprising crossing said inbred cotton plant derived from the cotton variety 14R913B2XF with a plant of a different genotype to produce a seed of a hybrid cotton plant derived from the cotton variety 14R913B2XF. 21. A method of producing a commodity plant product comprising collecting the commodity plant product from a plant of cotton variety 14R913B2XF, wherein a sample of seed of said variety has been deposited under ATCC Accession No. ______. 22. The method of claim 21, wherein the commodity plant product is lint, seed oil, or seed. | 1,600 |
419 | 15,655,075 | 1,618 | Disclosed are hair care compositions, such as conditioners, containing a metathesized unsaturated polyol ester; and a gel matrix phase comprising one or more high melting point fatty compounds, a cationic surfactant system an aqueous carrier. The oligomers provide beneficial hair benefits. Also disclosed are methods of using the hair care compositions. | 1. A hair care composition comprising: (a) from about 0.05% to about 15%, by weight of said hair care composition, of one or more metathesized unsaturated polyol esters, said metathesized unsaturated polyol ester having one or more of the following properties: (i) a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%; (ii) a weight average molecular weight of from about 5,000 Daltons to about 50,000 Daltons; (iii) an iodine value of from about 30 to about 200; and (b) a gel matrix phase 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% of a cationic surfactant system, 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 the metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%. 3. The hair care composition of claim 2 wherein the metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0.1% to about 4%. 4. The hair care composition of claim 3 wherein the metathesized unsaturated polyol ester has a weight average molecular weight of from about 5,000 Daltons to about 50,000 Daltons. 5. The hair care composition of claim 4 wherein the metathesized unsaturated polyol ester has a weight average molecular weight of from about 6,000 Daltons to about 30,000 Daltons. 6. The hair care composition of claim 1 wherein the metathesized unsaturated polyol ester has a weight average molecular weight of from about 5,000 Daltons to about 50,000 Daltons. 7. The hair care composition of claim 6 wherein the metathesized unsaturated polyol ester has an iodine value of from about 30 to about 200. 8. The hair care composition of claim 7 wherein the metathesized unsaturated polyol ester has an iodine value of from about 30 to about 120. 9. The hair care composition of claim 1 wherein the metathesized unsaturated polyol ester has an iodine value of from about 30 to about 200. 10. The hair care composition of claim 9 wherein the metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%. 11. The hair care composition according to claim 1 wherein said metathesized unsaturated polyol ester is selected from the group consisting of metathesized abyssinian oil, metathesized almond oil, metathesized apricot oil, metathesized apricot kernel oil, metathesized argan oil, metathesized avocado oil, metathesized babassu oil, metathesized baobab oil, metathesized black cumin oil, metathesized black currant oil, metathesized borage oil, metathesized camelina oil, metathesized carinata oil, metathesized canola oil, metathesized castor oil, metathesized cherry kernel oil, metathesized coconut oil, metathesized corn oil, metathesized cottonseed oil, metathesized echium oil, metathesized evening primrose oil, metathesized flax seed oil, metathesized grape seed oil, metathesized grapefruit seed oil, metathesized hazelnut oil, metathesized hemp seed oil, metathesized jatropha oil, metathesized jojoba oil, metathesized kukui nut oil, metathesized linseed oil, metathesized macadamia nut oil, metathesized meadowfoam seed oil, metathesized moringa oil, metathesized neem oil, metathesized olive oil, metathesized palm oil, metathesized palm kernel oil, metathesized peach kernel oil, metathesized peanut oil, metathesized pecan oil, metathesized pennycress oil, metathesized perilla seed oil, metathesized pistachio oil, metathesized pomegranate seed oil, metathesized pongamia oil, metathesized pumpkin seed oil, metathesized raspberry oil, metathesized red palm olein, metathesized rice bran oil, metathesized rosehip oil, metathesized safflower oil, metathesized seabuckthorn fruit oil, metathesized sesame seed oil, metathesized shea glein, metathesized sunflower oil, metathesized soybean oil, metathesized tonka bean oil, metathesized tung oil, metathesized walnut oil, metathesized wheat germ oil, metathesized high oleoyl soybean oil, metathesized high oleoyl sunflower oil, metathesized high oleoyl safflower oil, metathesized high erucic acid rapeseed oil, metathesized lard, metathesized tallow, metathesized poultry fat, metathesized yellow grease, metathesized fish oil, and mixtures thereof. 12. A hair care composition comprising: a) a metathesized unsaturated polyol ester, said metathesized unsaturated polyol ester having a weight average molecular weight of from about 2,000 Daltons to about 50,000 Daltons; and one or more of the following properties: (i) a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%; or (ii) an iodine value of from about 8 to about 200; and (b) a gel matrix phase 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% of a cationic surfactant system, by weight of said hair care composition; and (iii) at least about 20% of an aqueous carrier, by weight of said hair care composition. 13. The hair care composition according to claim 12 wherein said metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%. 14. The hair care composition according to claim 13 wherein said metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0.1% to about 4%. 15. The hair care composition according to claim 12 wherein said metathesized unsaturated polyol ester has an iodine value of from about 8 to about 200. 16. The hair care composition according to claim 15 wherein said metathesized unsaturated polyol ester has an iodine value of from about 30 to about 120. 17. The hair care composition according to claim 12 wherein said metathesized unsaturated polyol ester has a weight average molecular weight of from about 4,000 Daltons to about 30,000 Daltons. 18. The hair care composition according to claim 12 comprising a metathesized unsaturated polyol ester, said metathesized unsaturated polyol ester having i) a weight average molecular weight of from about 2,000 Daltons to about 30,000 Daltons; ii) a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0.1 to about 3%; and (iii) an iodine value of from about 30 to about 120. 19. The hair care composition according to claim 12 wherein said metathesized unsaturated polyol ester is selected from the group consisting of metathesized abyssinian oil, metathesized almond oil, metathesized apricot oil, metathesized apricot kernel oil, metathesized argan oil, metathesized avocado oil, metathesized babassu oil, metathesized baobab oil, metathesized black cumin oil, metathesized black currant oil, metathesized borage oil, metathesized camelina oil, metathesized carinata oil, metathesized canola oil, metathesized castor oil, metathesized cherry kernel oil, metathesized coconut oil, metathesized corn oil, metathesized cottonseed oil, metathesized echium oil, metathesized evening primrose oil, metathesized flax seed oil, metathesized grape seed oil, metathesized grapefruit seed oil, metathesized hazelnut oil, metathesized hemp seed oil, metathesized jatropha oil, metathesized jojoba oil, metathesized kukui nut oil, metathesized linseed oil, metathesized macadamia nut oil, metathesized meadowfoam seed oil, metathesized moringa oil, metathesized neem oil, metathesized olive oil, metathesized palm oil, metathesized palm kernel oil, metathesized peach kernel oil, metathesized peanut oil, metathesized pecan oil, metathesized pennycress oil, metathesized perilla seed oil, metathesized pistachio oil, metathesized pomegranate seed oil, metathesized pongamia oil, metathesized pumpkin seed oil, metathesized raspberry oil, metathesized red palm olein, metathesized rice bran oil, metathesized rosehip oil, metathesized safflower oil, metathesized seabuckthorn fruit oil, metathesized sesame seed oil, metathesized shea glein, metathesized sunflower oil, metathesized soybean oil, metathesized tonka bean oil, metathesized tung oil, metathesized walnut oil, metathesized wheat germ oil, metathesized high oleoyl soybean oil, metathesized high oleoyl sunflower oil, metathesized high oleoyl safflower oil, metathesized high erucic acid rapeseed oil, metathesized lard, metathesized tallow, metathesized poultry fat, metathesized yellow grease, metathesized fish oil, and mixtures thereof. 20. The hair care composition according to claim 12 wherein said hair care composition further 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 %. | Disclosed are hair care compositions, such as conditioners, containing a metathesized unsaturated polyol ester; and a gel matrix phase comprising one or more high melting point fatty compounds, a cationic surfactant system an aqueous carrier. The oligomers provide beneficial hair benefits. Also disclosed are methods of using the hair care compositions.1. A hair care composition comprising: (a) from about 0.05% to about 15%, by weight of said hair care composition, of one or more metathesized unsaturated polyol esters, said metathesized unsaturated polyol ester having one or more of the following properties: (i) a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%; (ii) a weight average molecular weight of from about 5,000 Daltons to about 50,000 Daltons; (iii) an iodine value of from about 30 to about 200; and (b) a gel matrix phase 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% of a cationic surfactant system, 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 the metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%. 3. The hair care composition of claim 2 wherein the metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0.1% to about 4%. 4. The hair care composition of claim 3 wherein the metathesized unsaturated polyol ester has a weight average molecular weight of from about 5,000 Daltons to about 50,000 Daltons. 5. The hair care composition of claim 4 wherein the metathesized unsaturated polyol ester has a weight average molecular weight of from about 6,000 Daltons to about 30,000 Daltons. 6. The hair care composition of claim 1 wherein the metathesized unsaturated polyol ester has a weight average molecular weight of from about 5,000 Daltons to about 50,000 Daltons. 7. The hair care composition of claim 6 wherein the metathesized unsaturated polyol ester has an iodine value of from about 30 to about 200. 8. The hair care composition of claim 7 wherein the metathesized unsaturated polyol ester has an iodine value of from about 30 to about 120. 9. The hair care composition of claim 1 wherein the metathesized unsaturated polyol ester has an iodine value of from about 30 to about 200. 10. The hair care composition of claim 9 wherein the metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%. 11. The hair care composition according to claim 1 wherein said metathesized unsaturated polyol ester is selected from the group consisting of metathesized abyssinian oil, metathesized almond oil, metathesized apricot oil, metathesized apricot kernel oil, metathesized argan oil, metathesized avocado oil, metathesized babassu oil, metathesized baobab oil, metathesized black cumin oil, metathesized black currant oil, metathesized borage oil, metathesized camelina oil, metathesized carinata oil, metathesized canola oil, metathesized castor oil, metathesized cherry kernel oil, metathesized coconut oil, metathesized corn oil, metathesized cottonseed oil, metathesized echium oil, metathesized evening primrose oil, metathesized flax seed oil, metathesized grape seed oil, metathesized grapefruit seed oil, metathesized hazelnut oil, metathesized hemp seed oil, metathesized jatropha oil, metathesized jojoba oil, metathesized kukui nut oil, metathesized linseed oil, metathesized macadamia nut oil, metathesized meadowfoam seed oil, metathesized moringa oil, metathesized neem oil, metathesized olive oil, metathesized palm oil, metathesized palm kernel oil, metathesized peach kernel oil, metathesized peanut oil, metathesized pecan oil, metathesized pennycress oil, metathesized perilla seed oil, metathesized pistachio oil, metathesized pomegranate seed oil, metathesized pongamia oil, metathesized pumpkin seed oil, metathesized raspberry oil, metathesized red palm olein, metathesized rice bran oil, metathesized rosehip oil, metathesized safflower oil, metathesized seabuckthorn fruit oil, metathesized sesame seed oil, metathesized shea glein, metathesized sunflower oil, metathesized soybean oil, metathesized tonka bean oil, metathesized tung oil, metathesized walnut oil, metathesized wheat germ oil, metathesized high oleoyl soybean oil, metathesized high oleoyl sunflower oil, metathesized high oleoyl safflower oil, metathesized high erucic acid rapeseed oil, metathesized lard, metathesized tallow, metathesized poultry fat, metathesized yellow grease, metathesized fish oil, and mixtures thereof. 12. A hair care composition comprising: a) a metathesized unsaturated polyol ester, said metathesized unsaturated polyol ester having a weight average molecular weight of from about 2,000 Daltons to about 50,000 Daltons; and one or more of the following properties: (i) a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%; or (ii) an iodine value of from about 8 to about 200; and (b) a gel matrix phase 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% of a cationic surfactant system, by weight of said hair care composition; and (iii) at least about 20% of an aqueous carrier, by weight of said hair care composition. 13. The hair care composition according to claim 12 wherein said metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%. 14. The hair care composition according to claim 13 wherein said metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0.1% to about 4%. 15. The hair care composition according to claim 12 wherein said metathesized unsaturated polyol ester has an iodine value of from about 8 to about 200. 16. The hair care composition according to claim 15 wherein said metathesized unsaturated polyol ester has an iodine value of from about 30 to about 120. 17. The hair care composition according to claim 12 wherein said metathesized unsaturated polyol ester has a weight average molecular weight of from about 4,000 Daltons to about 30,000 Daltons. 18. The hair care composition according to claim 12 comprising a metathesized unsaturated polyol ester, said metathesized unsaturated polyol ester having i) a weight average molecular weight of from about 2,000 Daltons to about 30,000 Daltons; ii) a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0.1 to about 3%; and (iii) an iodine value of from about 30 to about 120. 19. The hair care composition according to claim 12 wherein said metathesized unsaturated polyol ester is selected from the group consisting of metathesized abyssinian oil, metathesized almond oil, metathesized apricot oil, metathesized apricot kernel oil, metathesized argan oil, metathesized avocado oil, metathesized babassu oil, metathesized baobab oil, metathesized black cumin oil, metathesized black currant oil, metathesized borage oil, metathesized camelina oil, metathesized carinata oil, metathesized canola oil, metathesized castor oil, metathesized cherry kernel oil, metathesized coconut oil, metathesized corn oil, metathesized cottonseed oil, metathesized echium oil, metathesized evening primrose oil, metathesized flax seed oil, metathesized grape seed oil, metathesized grapefruit seed oil, metathesized hazelnut oil, metathesized hemp seed oil, metathesized jatropha oil, metathesized jojoba oil, metathesized kukui nut oil, metathesized linseed oil, metathesized macadamia nut oil, metathesized meadowfoam seed oil, metathesized moringa oil, metathesized neem oil, metathesized olive oil, metathesized palm oil, metathesized palm kernel oil, metathesized peach kernel oil, metathesized peanut oil, metathesized pecan oil, metathesized pennycress oil, metathesized perilla seed oil, metathesized pistachio oil, metathesized pomegranate seed oil, metathesized pongamia oil, metathesized pumpkin seed oil, metathesized raspberry oil, metathesized red palm olein, metathesized rice bran oil, metathesized rosehip oil, metathesized safflower oil, metathesized seabuckthorn fruit oil, metathesized sesame seed oil, metathesized shea glein, metathesized sunflower oil, metathesized soybean oil, metathesized tonka bean oil, metathesized tung oil, metathesized walnut oil, metathesized wheat germ oil, metathesized high oleoyl soybean oil, metathesized high oleoyl sunflower oil, metathesized high oleoyl safflower oil, metathesized high erucic acid rapeseed oil, metathesized lard, metathesized tallow, metathesized poultry fat, metathesized yellow grease, metathesized fish oil, and mixtures thereof. 20. The hair care composition according to claim 12 wherein said hair care composition further 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 %. | 1,600 |
420 | 15,655,038 | 1,618 | Disclosed are hair care compositions, such as shampoos, containing an anionic surfactant, an aqueous carrier, and one or more oligomers derived from metathesis of unsaturated polyol esters. The oligomers provide beneficial hair conditioning benefits. Also disclosed are methods of using the hair care compositions. | 1. A hair care composition comprising: a) a metathesized unsaturated polyol ester, said metathesized unsaturated polyol ester having one or more of the following properties: (i) a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%; (ii) a weight average molecular weight of from about 5,000 Daltons to about 50,000 Daltons; (iii) an iodine value of from about 30 to about 200; b) from about 5% to about 50% of one or more anionic surfactants, by weight of said hair care composition; and c) at least about 20% of an aqueous carrier, by weight of said hair care composition. 2. The hair care composition of claim 1 wherein the metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%. 3. The hair care composition of claim 2 wherein the metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0.1% to about 4%. 4. The hair care composition of claim 3 wherein the metathesized unsaturated polyol ester has a weight average molecular weight of from about 5,000 Daltons to about 50,000 Daltons. 5. The hair care composition of claim 4 wherein the metathesized unsaturated polyol ester has a weight average molecular weight of from about 6,000 Daltons to about 30,000 Daltons. 6. The hair care composition of claim 1 wherein the metathesized unsaturated polyol ester has a weight average molecular weight of from about 5,000 Daltons to about 50,000 Daltons. 7. The hair care composition of claim 6 wherein the metathesized unsaturated polyol ester has an iodine value of from about 30 to about 200. 8. The hair care composition of claim 7 wherein the metathesized unsaturated polyol ester has an iodine value of from about 30 to about 120. 9. The hair care composition of claim 1 wherein the metathesized unsaturated polyol ester has an iodine value of from about 30 to about 200. 10. The hair care composition of claim 9 wherein the metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%. 11. The hair care composition according to claim 1 wherein said metathesized unsaturated polyol ester is selected from the group consisting of metathesized abyssinian oil, metathesized almond oil, metathesized apricot oil, metathesized apricot kernel oil, metathesized argan oil, metathesized avocado oil, metathesized babassu oil, metathesized baobab oil, metathesized black cumin oil, metathesized black currant oil, metathesized borage oil, metathesized camelina oil, metathesized carinata oil, metathesized canola oil, metathesized castor oil, metathesized cherry kernel oil, metathesized coconut oil, metathesized corn oil, metathesized cottonseed oil, metathesized echium oil, metathesized evening primrose oil, metathesized flax seed oil, metathesized grape seed oil, metathesized grapefruit seed oil, metathesized hazelnut oil, metathesized hemp seed oil, metathesized j atropha oil, metathesized jojoba oil, metathesized kukui nut oil, metathesized linseed oil, metathesized macadamia nut oil, metathesized meadowfoam seed oil, metathesized moringa oil, metathesized neem oil, metathesized olive oil, metathesized palm oil, metathesized palm kernel oil, metathesized peach kernel oil, metathesized peanut oil, metathesized pecan oil, metathesized pennycress oil, metathesized perilla seed oil, metathesized pistachio oil, metathesized pomegranate seed oil, metathesized pongamia oil, metathesized pumpkin seed oil, metathesized raspberry oil, metathesized red palm olein, metathesized rice bran oil, metathesized rosehip oil, metathesized safflower oil, metathesized seabuckthorn fruit oil, metathesized sesame seed oil, metathesized shea glein, metathesized sunflower oil, metathesized soybean oil, metathesized tonka bean oil, metathesized tung oil, metathesized walnut oil, metathesized wheat germ oil, metathesized high oleoyl soybean oil, metathesized high oleoyl sunflower oil, metathesized high oleoyl safflower oil, metathesized high erucic acid rapeseed oil, metathesized lard, metathesized tallow, metathesized poultry fat, metathesized yellow grease, metathesized fish oil, and mixtures thereof. 12. A hair care composition comprising: a) a metathesized unsaturated polyol ester, said metathesized unsaturated polyol ester having a weight average molecular weight of from about 2,000 Daltons to about 50,000 Daltons; and one or more of the following properties: (i) a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%; or (ii) an iodine value of from about 8 to about 200; b) from about 5% to about 50% of one or more anionic surfactants, by weight of said hair care composition; and c) at least about 20% of an aqueous carrier, by weight of said hair care composition. 13. The hair care composition according to claim 12 wherein said metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%. 14. The hair care composition according to claim 13 wherein said metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0.1% to about 4%. 15. The hair care composition according to claim 12 wherein said metathesized unsaturated polyol ester has an iodine value of from about 8 to about 200. 16. The hair care composition according to claim 15 wherein said metathesized unsaturated polyol ester has an iodine value of from about 30 to about 120. 17. The hair care composition according to claim 12 wherein said metathesized unsaturated polyol ester has a weight average molecular weight of from about 4,000 Daltons to about 30,000 Daltons. 18. The hair care composition according to claim 12 comprising a metathesized unsaturated polyol ester, said metathesized unsaturated polyol ester having i) a weight average molecular weight of from about 2,000 Daltons to about 30,000 Daltons; ii) a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0.1 to about 3%; and (iii) an iodine value of from about 30 to about 120. 19. The hair care composition according to claim 12 wherein said metathesized unsaturated polyol ester is selected from the group consisting of metathesized abyssinian oil, metathesized almond oil, metathesized apricot oil, metathesized apricot kernel oil, metathesized argan oil, metathesized avocado oil, metathesized babassu oil, metathesized baobab oil, metathesized black cumin oil, metathesized black currant oil, metathesized borage oil, metathesized camelina oil, metathesized carinata oil, metathesized canola oil, metathesized castor oil, metathesized cherry kernel oil, metathesized coconut oil, metathesized corn oil, metathesized cottonseed oil, metathesized echium oil, metathesized evening primrose oil, metathesized flax seed oil, metathesized grape seed oil, metathesized grapefruit seed oil, metathesized hazelnut oil, metathesized hemp seed oil, metathesized j atropha oil, metathesized jojoba oil, metathesized kukui nut oil, metathesized linseed oil, metathesized macadamia nut oil, metathesized meadowfoam seed oil, metathesized moringa oil, metathesized neem oil, metathesized olive oil, metathesized palm oil, metathesized palm kernel oil, metathesized peach kernel oil, metathesized peanut oil, metathesized pecan oil, metathesized pennycress oil, metathesized perilla seed oil, metathesized pistachio oil, metathesized pomegranate seed oil, metathesized pongamia oil, metathesized pumpkin seed oil, metathesized raspberry oil, metathesized red palm olein, metathesized rice bran oil, metathesized rosehip oil, metathesized safflower oil, metathesized seabuckthorn fruit oil, metathesized sesame seed oil, metathesized shea glein, metathesized sunflower oil, metathesized soybean oil, metathesized tonka bean oil, metathesized tung oil, metathesized walnut oil, metathesized wheat germ oil, metathesized high oleoyl soybean oil, metathesized high oleoyl sunflower oil, metathesized high oleoyl safflower oil, metathesized high erucic acid rapeseed oil, metathesized lard, metathesized tallow, metathesized poultry fat, metathesized yellow grease, metathesized fish oil, and mixtures thereof. 20. The hair care composition according to claim 19 wherein said metathesized unsaturated polyol ester is selected from the group consisting of metathesized canola oil, metathesized palm oil, metathesized soybean oil, and mixtures thereof. | Disclosed are hair care compositions, such as shampoos, containing an anionic surfactant, an aqueous carrier, and one or more oligomers derived from metathesis of unsaturated polyol esters. The oligomers provide beneficial hair conditioning benefits. Also disclosed are methods of using the hair care compositions.1. A hair care composition comprising: a) a metathesized unsaturated polyol ester, said metathesized unsaturated polyol ester having one or more of the following properties: (i) a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%; (ii) a weight average molecular weight of from about 5,000 Daltons to about 50,000 Daltons; (iii) an iodine value of from about 30 to about 200; b) from about 5% to about 50% of one or more anionic surfactants, by weight of said hair care composition; and c) at least about 20% of an aqueous carrier, by weight of said hair care composition. 2. The hair care composition of claim 1 wherein the metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%. 3. The hair care composition of claim 2 wherein the metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0.1% to about 4%. 4. The hair care composition of claim 3 wherein the metathesized unsaturated polyol ester has a weight average molecular weight of from about 5,000 Daltons to about 50,000 Daltons. 5. The hair care composition of claim 4 wherein the metathesized unsaturated polyol ester has a weight average molecular weight of from about 6,000 Daltons to about 30,000 Daltons. 6. The hair care composition of claim 1 wherein the metathesized unsaturated polyol ester has a weight average molecular weight of from about 5,000 Daltons to about 50,000 Daltons. 7. The hair care composition of claim 6 wherein the metathesized unsaturated polyol ester has an iodine value of from about 30 to about 200. 8. The hair care composition of claim 7 wherein the metathesized unsaturated polyol ester has an iodine value of from about 30 to about 120. 9. The hair care composition of claim 1 wherein the metathesized unsaturated polyol ester has an iodine value of from about 30 to about 200. 10. The hair care composition of claim 9 wherein the metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%. 11. The hair care composition according to claim 1 wherein said metathesized unsaturated polyol ester is selected from the group consisting of metathesized abyssinian oil, metathesized almond oil, metathesized apricot oil, metathesized apricot kernel oil, metathesized argan oil, metathesized avocado oil, metathesized babassu oil, metathesized baobab oil, metathesized black cumin oil, metathesized black currant oil, metathesized borage oil, metathesized camelina oil, metathesized carinata oil, metathesized canola oil, metathesized castor oil, metathesized cherry kernel oil, metathesized coconut oil, metathesized corn oil, metathesized cottonseed oil, metathesized echium oil, metathesized evening primrose oil, metathesized flax seed oil, metathesized grape seed oil, metathesized grapefruit seed oil, metathesized hazelnut oil, metathesized hemp seed oil, metathesized j atropha oil, metathesized jojoba oil, metathesized kukui nut oil, metathesized linseed oil, metathesized macadamia nut oil, metathesized meadowfoam seed oil, metathesized moringa oil, metathesized neem oil, metathesized olive oil, metathesized palm oil, metathesized palm kernel oil, metathesized peach kernel oil, metathesized peanut oil, metathesized pecan oil, metathesized pennycress oil, metathesized perilla seed oil, metathesized pistachio oil, metathesized pomegranate seed oil, metathesized pongamia oil, metathesized pumpkin seed oil, metathesized raspberry oil, metathesized red palm olein, metathesized rice bran oil, metathesized rosehip oil, metathesized safflower oil, metathesized seabuckthorn fruit oil, metathesized sesame seed oil, metathesized shea glein, metathesized sunflower oil, metathesized soybean oil, metathesized tonka bean oil, metathesized tung oil, metathesized walnut oil, metathesized wheat germ oil, metathesized high oleoyl soybean oil, metathesized high oleoyl sunflower oil, metathesized high oleoyl safflower oil, metathesized high erucic acid rapeseed oil, metathesized lard, metathesized tallow, metathesized poultry fat, metathesized yellow grease, metathesized fish oil, and mixtures thereof. 12. A hair care composition comprising: a) a metathesized unsaturated polyol ester, said metathesized unsaturated polyol ester having a weight average molecular weight of from about 2,000 Daltons to about 50,000 Daltons; and one or more of the following properties: (i) a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%; or (ii) an iodine value of from about 8 to about 200; b) from about 5% to about 50% of one or more anionic surfactants, by weight of said hair care composition; and c) at least about 20% of an aqueous carrier, by weight of said hair care composition. 13. The hair care composition according to claim 12 wherein said metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0% to about 5%. 14. The hair care composition according to claim 13 wherein said metathesized unsaturated polyol ester has a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0.1% to about 4%. 15. The hair care composition according to claim 12 wherein said metathesized unsaturated polyol ester has an iodine value of from about 8 to about 200. 16. The hair care composition according to claim 15 wherein said metathesized unsaturated polyol ester has an iodine value of from about 30 to about 120. 17. The hair care composition according to claim 12 wherein said metathesized unsaturated polyol ester has a weight average molecular weight of from about 4,000 Daltons to about 30,000 Daltons. 18. The hair care composition according to claim 12 comprising a metathesized unsaturated polyol ester, said metathesized unsaturated polyol ester having i) a weight average molecular weight of from about 2,000 Daltons to about 30,000 Daltons; ii) a free hydrocarbon content, based on total weight of metathesized unsaturated polyol ester, of from about 0.1 to about 3%; and (iii) an iodine value of from about 30 to about 120. 19. The hair care composition according to claim 12 wherein said metathesized unsaturated polyol ester is selected from the group consisting of metathesized abyssinian oil, metathesized almond oil, metathesized apricot oil, metathesized apricot kernel oil, metathesized argan oil, metathesized avocado oil, metathesized babassu oil, metathesized baobab oil, metathesized black cumin oil, metathesized black currant oil, metathesized borage oil, metathesized camelina oil, metathesized carinata oil, metathesized canola oil, metathesized castor oil, metathesized cherry kernel oil, metathesized coconut oil, metathesized corn oil, metathesized cottonseed oil, metathesized echium oil, metathesized evening primrose oil, metathesized flax seed oil, metathesized grape seed oil, metathesized grapefruit seed oil, metathesized hazelnut oil, metathesized hemp seed oil, metathesized j atropha oil, metathesized jojoba oil, metathesized kukui nut oil, metathesized linseed oil, metathesized macadamia nut oil, metathesized meadowfoam seed oil, metathesized moringa oil, metathesized neem oil, metathesized olive oil, metathesized palm oil, metathesized palm kernel oil, metathesized peach kernel oil, metathesized peanut oil, metathesized pecan oil, metathesized pennycress oil, metathesized perilla seed oil, metathesized pistachio oil, metathesized pomegranate seed oil, metathesized pongamia oil, metathesized pumpkin seed oil, metathesized raspberry oil, metathesized red palm olein, metathesized rice bran oil, metathesized rosehip oil, metathesized safflower oil, metathesized seabuckthorn fruit oil, metathesized sesame seed oil, metathesized shea glein, metathesized sunflower oil, metathesized soybean oil, metathesized tonka bean oil, metathesized tung oil, metathesized walnut oil, metathesized wheat germ oil, metathesized high oleoyl soybean oil, metathesized high oleoyl sunflower oil, metathesized high oleoyl safflower oil, metathesized high erucic acid rapeseed oil, metathesized lard, metathesized tallow, metathesized poultry fat, metathesized yellow grease, metathesized fish oil, and mixtures thereof. 20. The hair care composition according to claim 19 wherein said metathesized unsaturated polyol ester is selected from the group consisting of metathesized canola oil, metathesized palm oil, metathesized soybean oil, and mixtures thereof. | 1,600 |
421 | 14,784,418 | 1,618 | Suggested is a composition comprising (a) sclareolide and (b1) at least one tyrosinase inhibitor; and/or (b2) at least one sun protection factor; and/or (b3) at least one anti-oxidants; and/or (b4) at least one anti-inflammatory agent; and/or (b5) at least one desquamating agent, on condition that compound a is present in an amount of from 0.00001 to 0.001% b.w.—calculated on the total composition. | 1. A composition comprising
(a) sclareolide; and (b1) at least one skin lightening agent; and/or (b2) at least one sun protection factor; and/or (b3) at least one antioxidant; and/or (b4) at least one anti-inflammatory agent; and/or (b5) at least one desquamating agent, on condition the sclareolide is present in an amount of from 0.00001 to 0.001% b.w.—calculated on the total composition. 2. The composition of claim 1, wherein the skin lightening agent (component b1) is selected from the group consisting of kojic acid and phenylethyl resorcinol, beta- and alpha-arbutin, hydroquinone, nicotinamide, dioic acid, Mg ascorbyl phosphate and vitamin C and its derivatives, mulberry extract, Bengkoang extract, papaya extract, turmeric extract, nutgrass extract, licorice extract (containing glycyrrhizin), alpha-hydroxy-acids, 4-alkylresorcinols, 4-hydroxyanisole and mixtures thereof. 3. The composition of claim 1, wherein the primary sun protection factor (component b2) is selected from the group consisting of 4-aminobenzoic acid and derivatives, salicylic acid derivatives, benzophenone derivatives, dibenzoylmethane derivatives, diphenyl acrylates, 3-imidazol-4-yl acrylic acid and esters thereof, benzofuran derivatives, benzylidene malonate derivatives, polymeric UV absorbers containing one or more organosilicon radicals, cinnamic acid derivatives, camphor derivatives, trianilino-s-triazine derivatives, 2-hydroxyphenylbenzotriazole derivatives, phenylbenzimidazole sulfonic acid derivatives and salts thereof, anthranilic acid menthyl esters, benzotriazole derivatives and indole derivatives, and mixtures thereof. 4. The composition of claim 1, wherein the secondary sun protection factor (component b2) is selected from the group consisting of amino acids and derivatives thereof, imidazoles and derivatives thereof, D,L-carnosine, D-carnosine, L-carnosine and derivatives thereof, carotinoids, carotenes and derivatives thereof, chlorogenic acid and derivatives thereof, liponic acid and derivatives thereof, aurothioglucose, propylthiouracil and other thiols, dilaurylthiodipropionate, distearylthiodipropionate, thiodipropionic acid and derivatives thereof, sulfoximine compounds, humic acid, bile acid, bile extracts, bilirubin, biliverdin, EDTA, EGTA and derivatives thereof, unsaturated fatty acids and derivatives thereof, folic acid and derivatives thereof, ubiquinone and ubiquinol and derivatives thereof, vitamin C and derivatives thereo, tocopherols and derivatives, coniferyl benzoate of benzoin resin, rutinic acid and derivatives thereof, glycosyl rutin, ferulic acid, furfurylidene glucitol, carnosine, butyl hydroxytoluene, butyl hydroxyanisole, nordihydroguaiac resin acid, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and derivatives thereof, mannose and derivatives thereof, superoxide dismutase, titanium dioxide, zinc and derivatives thereof, selenium and derivatives thereof, stilbenes and derivatives thereof and mixtures thereof. 5. The composition of claim 1, wherein the antioxidant (component b3) is selected from the group consisting of vitamin A and derivatives, vitamin C and derivatives, tocopherol and derivatives and mixtures thereof. 6. The composition of claim 1, wherein the anti-inflammatory agent (component b4) is selected from the group consisting of corticosteroids, salicylates acetic acid derivatives fenamates propionic acid derivatives pyrazoles, anthranilic acid derivatives, alpha-bisabolol, apigenin, apigenin-7-glucoside, gingerols, shogaols, gingerdiols, dehydrogingerdiones, paradols, tranilast, avenanthramide A, avenanthramide B, avenanthramide C, boswellic acid, phytosterols, glycyrrhizin, and licochalcone A, allantoin, panthenol, lanolin, (pseudo-)ceramides, glycosphingolipids, phytosterols, chitosan, mannose, lactose, β-glucans, and extracts or fractions from camomile, aloe vera, oats, calendula, arnica, honeysuckle, rosemary, witch hazel, ginger or echinacea, and mixtures thereof. 7. The composition of claim 1, wherein the desquamating agent (component 5) is selected from the group consisting of sulphonic acids, calcium chelators, ascorbic acid and its derivatives, nicotinamide, urea, (N-2-hydroxyethylpiperazine-N-2-ethane)sulphonic acid (HEPES), β-hydroxy acids, retinoids and mixtures thereof. 8. The composition of claim 1, wherein the skin lightening agent is a tyrosinase inhibitor (component b1) present in an amount of about 0.00001 to about 30% b.w.—calculated on the final composition. 9. The composition of claim 1, wherein the sun protection factor, antioxidant and anti-inflammatory agent (components b2 to b4), independently from each other, are present in an amount of about 0.00001 to about 30% b.w.—calculated on the final composition. 10. The composition of claim 1, which is a cosmetic composition, a pharmaceutical composition or a dietary supplement composition. 11. A medicament comprising the composition of claim 1 including an effective amount of sclareolide for fighting diseases requiring an inhibition of melanin formation in melanocytes. 12. A medicament comprising the composition of claim 1 including an effective amount of sclareolide for fighting diseases requiring an inhibition of interleukin-(IL-) 1α biosynthesis. 13. A non-therapeutical method for lightening skin and hair comprising the step of applying the composition of claim 1 including a working amount of sclareolide to a human. 14. The composition of claim 1, comprising an effective amount of sclareolide for lightening skin and hair. 15. A composition comprising the combination of
(a) sclareolide, and (b) at least one skin lightening agent. | Suggested is a composition comprising (a) sclareolide and (b1) at least one tyrosinase inhibitor; and/or (b2) at least one sun protection factor; and/or (b3) at least one anti-oxidants; and/or (b4) at least one anti-inflammatory agent; and/or (b5) at least one desquamating agent, on condition that compound a is present in an amount of from 0.00001 to 0.001% b.w.—calculated on the total composition.1. A composition comprising
(a) sclareolide; and (b1) at least one skin lightening agent; and/or (b2) at least one sun protection factor; and/or (b3) at least one antioxidant; and/or (b4) at least one anti-inflammatory agent; and/or (b5) at least one desquamating agent, on condition the sclareolide is present in an amount of from 0.00001 to 0.001% b.w.—calculated on the total composition. 2. The composition of claim 1, wherein the skin lightening agent (component b1) is selected from the group consisting of kojic acid and phenylethyl resorcinol, beta- and alpha-arbutin, hydroquinone, nicotinamide, dioic acid, Mg ascorbyl phosphate and vitamin C and its derivatives, mulberry extract, Bengkoang extract, papaya extract, turmeric extract, nutgrass extract, licorice extract (containing glycyrrhizin), alpha-hydroxy-acids, 4-alkylresorcinols, 4-hydroxyanisole and mixtures thereof. 3. The composition of claim 1, wherein the primary sun protection factor (component b2) is selected from the group consisting of 4-aminobenzoic acid and derivatives, salicylic acid derivatives, benzophenone derivatives, dibenzoylmethane derivatives, diphenyl acrylates, 3-imidazol-4-yl acrylic acid and esters thereof, benzofuran derivatives, benzylidene malonate derivatives, polymeric UV absorbers containing one or more organosilicon radicals, cinnamic acid derivatives, camphor derivatives, trianilino-s-triazine derivatives, 2-hydroxyphenylbenzotriazole derivatives, phenylbenzimidazole sulfonic acid derivatives and salts thereof, anthranilic acid menthyl esters, benzotriazole derivatives and indole derivatives, and mixtures thereof. 4. The composition of claim 1, wherein the secondary sun protection factor (component b2) is selected from the group consisting of amino acids and derivatives thereof, imidazoles and derivatives thereof, D,L-carnosine, D-carnosine, L-carnosine and derivatives thereof, carotinoids, carotenes and derivatives thereof, chlorogenic acid and derivatives thereof, liponic acid and derivatives thereof, aurothioglucose, propylthiouracil and other thiols, dilaurylthiodipropionate, distearylthiodipropionate, thiodipropionic acid and derivatives thereof, sulfoximine compounds, humic acid, bile acid, bile extracts, bilirubin, biliverdin, EDTA, EGTA and derivatives thereof, unsaturated fatty acids and derivatives thereof, folic acid and derivatives thereof, ubiquinone and ubiquinol and derivatives thereof, vitamin C and derivatives thereo, tocopherols and derivatives, coniferyl benzoate of benzoin resin, rutinic acid and derivatives thereof, glycosyl rutin, ferulic acid, furfurylidene glucitol, carnosine, butyl hydroxytoluene, butyl hydroxyanisole, nordihydroguaiac resin acid, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and derivatives thereof, mannose and derivatives thereof, superoxide dismutase, titanium dioxide, zinc and derivatives thereof, selenium and derivatives thereof, stilbenes and derivatives thereof and mixtures thereof. 5. The composition of claim 1, wherein the antioxidant (component b3) is selected from the group consisting of vitamin A and derivatives, vitamin C and derivatives, tocopherol and derivatives and mixtures thereof. 6. The composition of claim 1, wherein the anti-inflammatory agent (component b4) is selected from the group consisting of corticosteroids, salicylates acetic acid derivatives fenamates propionic acid derivatives pyrazoles, anthranilic acid derivatives, alpha-bisabolol, apigenin, apigenin-7-glucoside, gingerols, shogaols, gingerdiols, dehydrogingerdiones, paradols, tranilast, avenanthramide A, avenanthramide B, avenanthramide C, boswellic acid, phytosterols, glycyrrhizin, and licochalcone A, allantoin, panthenol, lanolin, (pseudo-)ceramides, glycosphingolipids, phytosterols, chitosan, mannose, lactose, β-glucans, and extracts or fractions from camomile, aloe vera, oats, calendula, arnica, honeysuckle, rosemary, witch hazel, ginger or echinacea, and mixtures thereof. 7. The composition of claim 1, wherein the desquamating agent (component 5) is selected from the group consisting of sulphonic acids, calcium chelators, ascorbic acid and its derivatives, nicotinamide, urea, (N-2-hydroxyethylpiperazine-N-2-ethane)sulphonic acid (HEPES), β-hydroxy acids, retinoids and mixtures thereof. 8. The composition of claim 1, wherein the skin lightening agent is a tyrosinase inhibitor (component b1) present in an amount of about 0.00001 to about 30% b.w.—calculated on the final composition. 9. The composition of claim 1, wherein the sun protection factor, antioxidant and anti-inflammatory agent (components b2 to b4), independently from each other, are present in an amount of about 0.00001 to about 30% b.w.—calculated on the final composition. 10. The composition of claim 1, which is a cosmetic composition, a pharmaceutical composition or a dietary supplement composition. 11. A medicament comprising the composition of claim 1 including an effective amount of sclareolide for fighting diseases requiring an inhibition of melanin formation in melanocytes. 12. A medicament comprising the composition of claim 1 including an effective amount of sclareolide for fighting diseases requiring an inhibition of interleukin-(IL-) 1α biosynthesis. 13. A non-therapeutical method for lightening skin and hair comprising the step of applying the composition of claim 1 including a working amount of sclareolide to a human. 14. The composition of claim 1, comprising an effective amount of sclareolide for lightening skin and hair. 15. A composition comprising the combination of
(a) sclareolide, and (b) at least one skin lightening agent. | 1,600 |
422 | 15,730,565 | 1,627 | Pharmaceutically acceptable single parasiticidal agent compositions of imidacloprid for oral delivery to mammals to systemically control targeted blood-sucking or blood-consuming parasites, such as fleas, ticks and certain species of helminthes and scabies. | 1. A pharmaceutically acceptable composition of a parasiticidally effective, subtoxic amount of imidacloprid for oral delivery to mammals to control blood-sucking or consuming parasites thereon, wherein imidacloprid is the only parasiticidal agent present in the pharmaceutical composition. 2. The composition according to claim 1, wherein the composition provides imidacloprid in a single dose level of 0.01 mg/kg to 10 mg/kg. 3. The composition according to claim 1, wherein the imidacloprid is provided at a single dose level of 0.25 mg/kg. 4. The composition according to claim 1, wherein the composition is formulated as a chewable soft treat. 5. The composition according to claim 2, further comprising packaging and a label therefor, wherein the label directs use of the composition as a treatment for fleas. 6. The composition according to claim 1, wherein the parasiticidally effective amount is sufficient to kill adult fleas. 7. The composition according to claim 1, wherein the composition provides imidacloprid in a single dose level of 0.01 mg/kg to 30 mg/kg. 8. The composition according to claim 1, wherein the imidacloprid is provided at a single dose level of 3 mg/kg. 9. The composition according to claim 7, further comprising packaging and a label therefor, wherein the label directs use of the composition as a treatment for ticks. 10. The composition according to claim 1, wherein the parasiticidally effective amount is sufficient to kill adult ticks or tick nymphs. 11. The composition according to claim 1, wherein the parasiticidally effective amount is sufficient to kill blood-sucking or consuming helminthes. 12. The composition according to claim 1, wherein the parasiticidally effective amount is sufficient to kill blood-sucking or consuming scabies. 13. The composition according to claim 1, wherein the parasiticidally effective amount is sufficient to kill flea larvae or flea eggs. 14. The composition according to claim 1, wherein the parasiticidally effective amount is sufficient to kill tick larvae or tick eggs. 15. The composition according to claim 1, further comprising a flavoring. 16. The composition according to claim 1, wherein the composition is formulated as a pill, tablet or capsule. 17. The composition according to claim 1, wherein the mammal is a cat or dog. 18. The composition according to claim 1, wherein the composition provides imidacloprid in a single dose level of 0.25 mg/kg to 10 mg/kg. 19. The composition according to claim 1, wherein the composition provides imidacloprid in a single dose level of 0.5 mg/kg to 6 mg/kg and the parasite is a flea, flea larvae, or flea eggs. 20. The composition according to claim 1, wherein the composition provides imidacloprid in a single dose level of 15 mg/kg to 30 mg/kg and the parasite is a tick, tick larvae, or tick eggs. | Pharmaceutically acceptable single parasiticidal agent compositions of imidacloprid for oral delivery to mammals to systemically control targeted blood-sucking or blood-consuming parasites, such as fleas, ticks and certain species of helminthes and scabies.1. A pharmaceutically acceptable composition of a parasiticidally effective, subtoxic amount of imidacloprid for oral delivery to mammals to control blood-sucking or consuming parasites thereon, wherein imidacloprid is the only parasiticidal agent present in the pharmaceutical composition. 2. The composition according to claim 1, wherein the composition provides imidacloprid in a single dose level of 0.01 mg/kg to 10 mg/kg. 3. The composition according to claim 1, wherein the imidacloprid is provided at a single dose level of 0.25 mg/kg. 4. The composition according to claim 1, wherein the composition is formulated as a chewable soft treat. 5. The composition according to claim 2, further comprising packaging and a label therefor, wherein the label directs use of the composition as a treatment for fleas. 6. The composition according to claim 1, wherein the parasiticidally effective amount is sufficient to kill adult fleas. 7. The composition according to claim 1, wherein the composition provides imidacloprid in a single dose level of 0.01 mg/kg to 30 mg/kg. 8. The composition according to claim 1, wherein the imidacloprid is provided at a single dose level of 3 mg/kg. 9. The composition according to claim 7, further comprising packaging and a label therefor, wherein the label directs use of the composition as a treatment for ticks. 10. The composition according to claim 1, wherein the parasiticidally effective amount is sufficient to kill adult ticks or tick nymphs. 11. The composition according to claim 1, wherein the parasiticidally effective amount is sufficient to kill blood-sucking or consuming helminthes. 12. The composition according to claim 1, wherein the parasiticidally effective amount is sufficient to kill blood-sucking or consuming scabies. 13. The composition according to claim 1, wherein the parasiticidally effective amount is sufficient to kill flea larvae or flea eggs. 14. The composition according to claim 1, wherein the parasiticidally effective amount is sufficient to kill tick larvae or tick eggs. 15. The composition according to claim 1, further comprising a flavoring. 16. The composition according to claim 1, wherein the composition is formulated as a pill, tablet or capsule. 17. The composition according to claim 1, wherein the mammal is a cat or dog. 18. The composition according to claim 1, wherein the composition provides imidacloprid in a single dose level of 0.25 mg/kg to 10 mg/kg. 19. The composition according to claim 1, wherein the composition provides imidacloprid in a single dose level of 0.5 mg/kg to 6 mg/kg and the parasite is a flea, flea larvae, or flea eggs. 20. The composition according to claim 1, wherein the composition provides imidacloprid in a single dose level of 15 mg/kg to 30 mg/kg and the parasite is a tick, tick larvae, or tick eggs. | 1,600 |
423 | 14,233,602 | 1,657 | Method of detecting the presence of thermoduric microorganisms in a product that includes the steps of (i) placing an aliquot A of a product into a vessel 10 equipped with a probe 30 sensitive to a thermoduric microorganism metabolite, (ii) pasteurizing the aliquot A within the vessel 10, (iii) incubating the pasteurized aliquot A within the vessel 10 for an incubation period, and (iv) periodically interrogating the probe 30 during the incubation period. | 1. A method of detecting the presence of thermoduric microorganisms in a product, comprising the steps of:
(a) placing an aliquot of the product into a vessel equipped with an optical probe sensitive to a thermoduric microorganism metabolite, (b) pasteurizing the aliquot within the vessel, (c) incubating the pasteurized aliquot within the vessel for an incubation period, and (d) periodically interrogating the probe during the incubation period, wherein the interrogations measure changes in the probe reflective of changes in concentration of a thermoduric microorganism metabolite within the aliquot, with such changes in concentration indicative of the presence of viable thermoduric microorganisms in the aliquot. 2. The method of claim 1 wherein the thermoduric microorganism metabolite is oxygen. 3. The method of claim 1 further comprising the steps of (i) converting measured changes in the probe to a concentration of thermoduric microorganisms in the pasteurized aliquot prior to incubation based upon a known conversion algorithm, and (ii) reporting the ascertained concentration of thermoduric microorganisms. 4. The method of claim 1 further comprising the step of hermetically sealing the aliquot within the retention chamber of the vessel prior to pasteurization. 5. The method of claim 1 wherein the product is a food product intended for animal or human consumption. 6. The method of claim 5 wherein the product is milk. 7. The method of claim 1 wherein the vessel is a vial, cuvette or multi-well plate. 8. The method of claim 1 wherein the vessel defines a retention chamber having an elevated surface-to-volume ratio. 9. The method of claim 1 wherein pasteurization is effected at a defined temperature for a defined time period and thermal equilibration of the aliquot in the vessel is achieved within ½ of the pasteurization time period. 10. The method of claim 1 wherein pasteurization is effected at a defined temperature for a defined time period and thermal equilibration of the aliquot in the vessel is achieved within ¼th of the pasteurization time period. 11. The method of claim 7 wherein the vessel is a multi-well plate having more than 40 wells. 12. The method of claim 1 wherein (i) the vessel defines a retention chamber having an open top end and a closed bottom end, and (ii) the probe is positioned within the retention chamber proximate the bottom end. 13. The method of claim 2 wherein the probe is an oxygen sensitive photoluminescent dye. 14. The method of claim 13 wherein the oxygen sensitive photoluminescent dye is an oxygen sensitive transition metal complex. 15. The method of claim 14 wherein the oxygen sensitive transition metal complex is selected from the group consisting of a ruthenium bipyridyl, a ruthenium diphenylphenanotroline, a platinum porphyrin, a palladium porphyrin, a phosphorescent complex of a tetrabenzoporphyrin, a chlorin, a porphyrin-ketone, an aza-porphyrin and a long-decay luminescent complex of iridium(III) or osmium(II). 16. The method of claim 13 wherein interrogations measure photoluminescence lifetime. 17. The method of claim 1 wherein the aliquot within the vessel is pasteurized at 72° C. for 20 seconds and incubated at 30° to 50° C. for up to 24 hours. 18. The method of claim 1 wherein the aliquot within the vessel is pasteurized at 63° C. for 30 minutes and incubated at 30° to 55° C. for up to 24 hours. 19. The method of claim 17 or 18 wherein the aliquot within the vessel is incubated at 30° C. 20. The method of claim 1 wherein pasteurization temperatures are achieved with a dry block heater. 21. The method of claim 1 further comprising the step of adding nutrients effective for promoting growth of at least one thermoduric microorganism to the aliquot prior to pasteurization. 22. A method for comparatively detecting the presence of thermoduric microorganisms and total microorganisms in a product, comprising the steps of:
(a) obtaining a sample of the product, (b) placing a first aliquot of the sample into a first retention chamber equipped with a first probe sensitive to a thermoduric microorganism metabolite, (c) placing a second aliquot of the sample into a second retention chamber equipped with a second probe sensitive to a target-analyte, (d) pasteurizing the first aliquot within the first retention chamber but not the second aliquot, (e) incubating the pasteurized first aliquot within the first retention chamber and the second aliquot within the second retention chamber for an incubation period, and (f) periodically interrogating both probes during the incubation period, wherein the interrogations measure changes in the probe reflective of changes in concentration of a thermoduric microorganism metabolite within the first aliquot and changes in concentration of a target-analyte within the second aliquot, with such changes in concentration indicative of the presence of viable thermoduric microorganisms in the first aliquot and the presence of total viable microorganisms in the second aliquot. 23. The method of claim 22 wherein the thermoduric microorganism metabolite and the target-analyte are both oxygen. 24. The method of claim 22 further comprising the steps of (i) converting measured changes in the first probe to a concentration of thermoduric microorganisms in the pasteurized first aliquot prior to incubation based upon a known conversion algorithm, (ii) converting measured changes in the second probe to a concentration of total microorganisms in the second aliquot prior to incubation based upon a known conversion algorithm, and (ii) reporting the ascertained concentration of thermoduric microorganisms and total microorganisms. 25. The method of claim 22 further comprising the step of hermetically sealing the first and second aliquots within their respective retention chambers prior to pasteurization and incubation. 26. The method of claim 22 wherein the product is a food product intended for human consumption. 27. The method of claim 26 wherein the product is milk. 28. The method of claim 22 wherein the first and second retention chambers are defined by separate and independent vials or cuvettes. 29. The method of claim 22 wherein the first and second retention chambers are different wells in a multi-well plate. 30. The method of claim 22 wherein the first and second retention chambers have an elevated surface-to-volume ratio. 31. The method of claim 22 wherein pasteurization is effected at a defined temperature for a defined time period and thermal equilibration of the aliquot in the vessel is achieved within ½ of the pasteurization time period. 32. The method of claim 22 wherein pasteurization is effected at a defined temperature for a defined time period and thermal equilibration of the aliquot in the vessel is achieved within ¼th of the pasteurization time period. 33. The method of claim 29 wherein the multi-well plate has more than 40 wells. 34. The method of claim 22 wherein (i) the first and second retention chambers have open top ends and closed bottom ends, and (ii) each probe is positioned within the respective retention chamber proximate the bottom end. 35. The method of claim 22 wherein the first and second probes are the same type of probe. 36. The method of claim 35 wherein the first and second probes are oxygen sensitive photoluminescent dye. 37. The method of claim 36 wherein the oxygen sensitive photoluminescent dye is an oxygen sensitive transition metal complex. 38. The method of claim 37 wherein the oxygen sensitive transition metal complex is selected from the group consisting of a ruthenium bipyridyl, a ruthenium diphenylphenanotroline, a platinum porphyrin, a palladium porphyrin, a phosphorescent complex of a tetrabenzoporphyrin, a chlorin, a porphyrin-ketone, an aza-porphyrin and a long-decay luminescent complex of iridium(III) or osmium(II). 39. The method of claim 36 wherein interrogations measure photoluminescence lifetime. 40. The method of claim 22 wherein the first aliquot is pasteurized at 72° C. for 20 seconds and both the first and second aliquots are incubated at 30° to 50° C. for up to 24 hours. 41. The method of claim 22 wherein the first aliquot is pasteurized at 63° C. for 30 minutes and both the first and second aliquots are incubated at 30° to 55° C. for up to 24 hours. 42. The method of claim 40 or 41 wherein the first aliquot is incubated at 30° C. 43. The method of claim 22 wherein pasteurization temperatures are achieved with a dry block heater. 44. The method of claim 22 further comprising the step of adding nutrients effective for promoting growth of microorganisms to the first and second aliquots prior to pasteurization and incubation. | Method of detecting the presence of thermoduric microorganisms in a product that includes the steps of (i) placing an aliquot A of a product into a vessel 10 equipped with a probe 30 sensitive to a thermoduric microorganism metabolite, (ii) pasteurizing the aliquot A within the vessel 10, (iii) incubating the pasteurized aliquot A within the vessel 10 for an incubation period, and (iv) periodically interrogating the probe 30 during the incubation period.1. A method of detecting the presence of thermoduric microorganisms in a product, comprising the steps of:
(a) placing an aliquot of the product into a vessel equipped with an optical probe sensitive to a thermoduric microorganism metabolite, (b) pasteurizing the aliquot within the vessel, (c) incubating the pasteurized aliquot within the vessel for an incubation period, and (d) periodically interrogating the probe during the incubation period, wherein the interrogations measure changes in the probe reflective of changes in concentration of a thermoduric microorganism metabolite within the aliquot, with such changes in concentration indicative of the presence of viable thermoduric microorganisms in the aliquot. 2. The method of claim 1 wherein the thermoduric microorganism metabolite is oxygen. 3. The method of claim 1 further comprising the steps of (i) converting measured changes in the probe to a concentration of thermoduric microorganisms in the pasteurized aliquot prior to incubation based upon a known conversion algorithm, and (ii) reporting the ascertained concentration of thermoduric microorganisms. 4. The method of claim 1 further comprising the step of hermetically sealing the aliquot within the retention chamber of the vessel prior to pasteurization. 5. The method of claim 1 wherein the product is a food product intended for animal or human consumption. 6. The method of claim 5 wherein the product is milk. 7. The method of claim 1 wherein the vessel is a vial, cuvette or multi-well plate. 8. The method of claim 1 wherein the vessel defines a retention chamber having an elevated surface-to-volume ratio. 9. The method of claim 1 wherein pasteurization is effected at a defined temperature for a defined time period and thermal equilibration of the aliquot in the vessel is achieved within ½ of the pasteurization time period. 10. The method of claim 1 wherein pasteurization is effected at a defined temperature for a defined time period and thermal equilibration of the aliquot in the vessel is achieved within ¼th of the pasteurization time period. 11. The method of claim 7 wherein the vessel is a multi-well plate having more than 40 wells. 12. The method of claim 1 wherein (i) the vessel defines a retention chamber having an open top end and a closed bottom end, and (ii) the probe is positioned within the retention chamber proximate the bottom end. 13. The method of claim 2 wherein the probe is an oxygen sensitive photoluminescent dye. 14. The method of claim 13 wherein the oxygen sensitive photoluminescent dye is an oxygen sensitive transition metal complex. 15. The method of claim 14 wherein the oxygen sensitive transition metal complex is selected from the group consisting of a ruthenium bipyridyl, a ruthenium diphenylphenanotroline, a platinum porphyrin, a palladium porphyrin, a phosphorescent complex of a tetrabenzoporphyrin, a chlorin, a porphyrin-ketone, an aza-porphyrin and a long-decay luminescent complex of iridium(III) or osmium(II). 16. The method of claim 13 wherein interrogations measure photoluminescence lifetime. 17. The method of claim 1 wherein the aliquot within the vessel is pasteurized at 72° C. for 20 seconds and incubated at 30° to 50° C. for up to 24 hours. 18. The method of claim 1 wherein the aliquot within the vessel is pasteurized at 63° C. for 30 minutes and incubated at 30° to 55° C. for up to 24 hours. 19. The method of claim 17 or 18 wherein the aliquot within the vessel is incubated at 30° C. 20. The method of claim 1 wherein pasteurization temperatures are achieved with a dry block heater. 21. The method of claim 1 further comprising the step of adding nutrients effective for promoting growth of at least one thermoduric microorganism to the aliquot prior to pasteurization. 22. A method for comparatively detecting the presence of thermoduric microorganisms and total microorganisms in a product, comprising the steps of:
(a) obtaining a sample of the product, (b) placing a first aliquot of the sample into a first retention chamber equipped with a first probe sensitive to a thermoduric microorganism metabolite, (c) placing a second aliquot of the sample into a second retention chamber equipped with a second probe sensitive to a target-analyte, (d) pasteurizing the first aliquot within the first retention chamber but not the second aliquot, (e) incubating the pasteurized first aliquot within the first retention chamber and the second aliquot within the second retention chamber for an incubation period, and (f) periodically interrogating both probes during the incubation period, wherein the interrogations measure changes in the probe reflective of changes in concentration of a thermoduric microorganism metabolite within the first aliquot and changes in concentration of a target-analyte within the second aliquot, with such changes in concentration indicative of the presence of viable thermoduric microorganisms in the first aliquot and the presence of total viable microorganisms in the second aliquot. 23. The method of claim 22 wherein the thermoduric microorganism metabolite and the target-analyte are both oxygen. 24. The method of claim 22 further comprising the steps of (i) converting measured changes in the first probe to a concentration of thermoduric microorganisms in the pasteurized first aliquot prior to incubation based upon a known conversion algorithm, (ii) converting measured changes in the second probe to a concentration of total microorganisms in the second aliquot prior to incubation based upon a known conversion algorithm, and (ii) reporting the ascertained concentration of thermoduric microorganisms and total microorganisms. 25. The method of claim 22 further comprising the step of hermetically sealing the first and second aliquots within their respective retention chambers prior to pasteurization and incubation. 26. The method of claim 22 wherein the product is a food product intended for human consumption. 27. The method of claim 26 wherein the product is milk. 28. The method of claim 22 wherein the first and second retention chambers are defined by separate and independent vials or cuvettes. 29. The method of claim 22 wherein the first and second retention chambers are different wells in a multi-well plate. 30. The method of claim 22 wherein the first and second retention chambers have an elevated surface-to-volume ratio. 31. The method of claim 22 wherein pasteurization is effected at a defined temperature for a defined time period and thermal equilibration of the aliquot in the vessel is achieved within ½ of the pasteurization time period. 32. The method of claim 22 wherein pasteurization is effected at a defined temperature for a defined time period and thermal equilibration of the aliquot in the vessel is achieved within ¼th of the pasteurization time period. 33. The method of claim 29 wherein the multi-well plate has more than 40 wells. 34. The method of claim 22 wherein (i) the first and second retention chambers have open top ends and closed bottom ends, and (ii) each probe is positioned within the respective retention chamber proximate the bottom end. 35. The method of claim 22 wherein the first and second probes are the same type of probe. 36. The method of claim 35 wherein the first and second probes are oxygen sensitive photoluminescent dye. 37. The method of claim 36 wherein the oxygen sensitive photoluminescent dye is an oxygen sensitive transition metal complex. 38. The method of claim 37 wherein the oxygen sensitive transition metal complex is selected from the group consisting of a ruthenium bipyridyl, a ruthenium diphenylphenanotroline, a platinum porphyrin, a palladium porphyrin, a phosphorescent complex of a tetrabenzoporphyrin, a chlorin, a porphyrin-ketone, an aza-porphyrin and a long-decay luminescent complex of iridium(III) or osmium(II). 39. The method of claim 36 wherein interrogations measure photoluminescence lifetime. 40. The method of claim 22 wherein the first aliquot is pasteurized at 72° C. for 20 seconds and both the first and second aliquots are incubated at 30° to 50° C. for up to 24 hours. 41. The method of claim 22 wherein the first aliquot is pasteurized at 63° C. for 30 minutes and both the first and second aliquots are incubated at 30° to 55° C. for up to 24 hours. 42. The method of claim 40 or 41 wherein the first aliquot is incubated at 30° C. 43. The method of claim 22 wherein pasteurization temperatures are achieved with a dry block heater. 44. The method of claim 22 further comprising the step of adding nutrients effective for promoting growth of microorganisms to the first and second aliquots prior to pasteurization and incubation. | 1,600 |
424 | 14,913,614 | 1,662 | Compositions and methods are provided for genome modification of a target sequence in the genome of a plant or plant cell. The methods and compositions employ a guide RNA/Cas endonuclease system to provide an effective system for modifying or altering target sites within the genome of a plant, plant cell or seed. Also provided are compositions and methods employing a guide polynucleotide/Cas endonuclease system for genome modification of a nucleotide sequence in the genome of a cell or organism, for gene editing, and/or for inserting or deleting a polynucleotide of interest into or from the genome of a cell or organism. Once a genomic target site is identified, a variety of methods can be employed to further modify the target sites such that they contain a variety of polynucleotides of interest. Breeding methods and methods for selecting plants utilizing a two component RNA guide and Cas endonuclease system are also disclosed. Compositions and methods are also provided for editing a nucleotide sequence in the genome of a cell. | 1. A method for obtaining a progeny plant comprising an altered target site in its plant genome, the method comprising:
a) crossing a first plant comprising at least one Cas endonuclease capable of introducing a double strand break at a target site in the plant genome with a second plant comprising a guide RNA capable of forming a complex with the Cas endonuclease of, to obtain progeny plants; b) evaluating progeny plants of (a) for an alteration in the target site; and, c) obtaining a progeny plant that possesses the desired alteration of said target site. 2. (canceled) 3. A method for obtaining a progeny plant comprising an altered target site in its plant genome, the method comprising:
a) crossing a first plant comprising at least one Cas endonuclease capable of introducing a double strand break at a target site in the plant genome with a second plant comprising a guide RNA and a donor DNA to obtain progeny plants, wherein said guide RNA is capable of forming a complex with the Cas endonuclease, wherein said donor DNA comprises a polynucleotide of interest; b) evaluating progeny plants of (a) for an alteration in the target site; and, c) obtaining a progeny plant that comprises the polynucleotide of interest inserted at said target site. 4. (canceled) 5. A method for modifying a target site in the genome of a plant cell, the method comprising providing a guide RNA to a plant cell having a Cas endonuclease, wherein said guide RNA and Cas endonuclease are capable of forming a complex that enables the Cas endonuclease to introduce a double strand break at said target site. 6. (canceled) 7. The method of claim 5, further comprising providing a donor DNA to said plant cell, wherein said donor DNA comprises a polynucleotide of interest. 8-10. (canceled) 11. The method of claim 5, wherein the guide RNA is introduced directly by particle bombardment. 12. The method of claim 5, wherein the guide RNA is introduced via particle bombardment or Agrobacterium transformation of a recombinant DNA construct comprising the corresponding guide DNA operably linked to a plant U6 polymerase III promoter. 13. The method of claim 5, wherein the Cas endonuclease gene is a plant optimized Cas9 endonuclease. 14. The method of claim 5, wherein the Cas endonuclease gene is operably linked to a SV40 nuclear targeting signal upstream of the Cas codon region and a VirD2 nuclear localization signal downstream of the Cas codon region. 15. The method of claim 5, wherein the plant is a monocot or a dicot. 16. The method of claim 15, wherein the monocot is selected from the group consisting of maize, rice, sorghum, rye, barley, wheat, millet, oats, sugarcane, turfgrass, or switchgrass. 17. The method of claim 15, wherein the dicot is selected from the group consisting of soybean, canola, alfalfa, sunflower, cotton, tobacco, tomato peanut, potato, tobacco, Arabidopsis, or safflower. 18. (canceled) 19. A plant or seed produced by the method of claim 5. 20. A plant comprising a recombinant DNA construct, said recombinant DNA construct comprising a promoter operably linked to a nucleotide sequence encoding a plant optimized Cas9 endonuclease, wherein said plant optimized Cas9 endonuclease is capable of binding to and creating a double strand break in a genomic target sequence of said plant genome. 21-28. (canceled) 29. A method for editing a nucleotide sequence in the genome of a cell, the method comprising introducing at least one guide RNA and at least one polynucleotide modification template into a cell comprising at least one Cas endonuclease, wherein the Cas endonuclease introduces a double-strand break at a target site in the genome of said cell, wherein said polynucleotide modification template comprises at least one nucleotide modification of said nucleotide sequence. 30. The method of claim 29, wherein the cell is a plant cell. 31. The method of claim 29, wherein the nucleotide sequence in the genome of said cell is selected from the group consisting of a promoter sequence, a terminator sequence, a regulatory sequence, a splice site, a coding sequence, a polyubiquitination site, an intron site, an intron enhancing motif and a gene of interest. 32. The method of claim 31 wherein the gene of interest is an enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene or an acetolactate synthase (ALS) gene. 33. The method of claim 30 wherein the plant cell is a monocot or dicot plant cell. 34-36. (canceled) 37. A plant or seed produced from the plant cell of claim 30. 38. The method of claim 29, wherein the Cas endonuclease is a Cas9 endonuclease. 39-42. (canceled) 43. The method of claim 29, wherein the at least one nucleotide modification is not a modification at said target site. 44-66. (canceled) | Compositions and methods are provided for genome modification of a target sequence in the genome of a plant or plant cell. The methods and compositions employ a guide RNA/Cas endonuclease system to provide an effective system for modifying or altering target sites within the genome of a plant, plant cell or seed. Also provided are compositions and methods employing a guide polynucleotide/Cas endonuclease system for genome modification of a nucleotide sequence in the genome of a cell or organism, for gene editing, and/or for inserting or deleting a polynucleotide of interest into or from the genome of a cell or organism. Once a genomic target site is identified, a variety of methods can be employed to further modify the target sites such that they contain a variety of polynucleotides of interest. Breeding methods and methods for selecting plants utilizing a two component RNA guide and Cas endonuclease system are also disclosed. Compositions and methods are also provided for editing a nucleotide sequence in the genome of a cell.1. A method for obtaining a progeny plant comprising an altered target site in its plant genome, the method comprising:
a) crossing a first plant comprising at least one Cas endonuclease capable of introducing a double strand break at a target site in the plant genome with a second plant comprising a guide RNA capable of forming a complex with the Cas endonuclease of, to obtain progeny plants; b) evaluating progeny plants of (a) for an alteration in the target site; and, c) obtaining a progeny plant that possesses the desired alteration of said target site. 2. (canceled) 3. A method for obtaining a progeny plant comprising an altered target site in its plant genome, the method comprising:
a) crossing a first plant comprising at least one Cas endonuclease capable of introducing a double strand break at a target site in the plant genome with a second plant comprising a guide RNA and a donor DNA to obtain progeny plants, wherein said guide RNA is capable of forming a complex with the Cas endonuclease, wherein said donor DNA comprises a polynucleotide of interest; b) evaluating progeny plants of (a) for an alteration in the target site; and, c) obtaining a progeny plant that comprises the polynucleotide of interest inserted at said target site. 4. (canceled) 5. A method for modifying a target site in the genome of a plant cell, the method comprising providing a guide RNA to a plant cell having a Cas endonuclease, wherein said guide RNA and Cas endonuclease are capable of forming a complex that enables the Cas endonuclease to introduce a double strand break at said target site. 6. (canceled) 7. The method of claim 5, further comprising providing a donor DNA to said plant cell, wherein said donor DNA comprises a polynucleotide of interest. 8-10. (canceled) 11. The method of claim 5, wherein the guide RNA is introduced directly by particle bombardment. 12. The method of claim 5, wherein the guide RNA is introduced via particle bombardment or Agrobacterium transformation of a recombinant DNA construct comprising the corresponding guide DNA operably linked to a plant U6 polymerase III promoter. 13. The method of claim 5, wherein the Cas endonuclease gene is a plant optimized Cas9 endonuclease. 14. The method of claim 5, wherein the Cas endonuclease gene is operably linked to a SV40 nuclear targeting signal upstream of the Cas codon region and a VirD2 nuclear localization signal downstream of the Cas codon region. 15. The method of claim 5, wherein the plant is a monocot or a dicot. 16. The method of claim 15, wherein the monocot is selected from the group consisting of maize, rice, sorghum, rye, barley, wheat, millet, oats, sugarcane, turfgrass, or switchgrass. 17. The method of claim 15, wherein the dicot is selected from the group consisting of soybean, canola, alfalfa, sunflower, cotton, tobacco, tomato peanut, potato, tobacco, Arabidopsis, or safflower. 18. (canceled) 19. A plant or seed produced by the method of claim 5. 20. A plant comprising a recombinant DNA construct, said recombinant DNA construct comprising a promoter operably linked to a nucleotide sequence encoding a plant optimized Cas9 endonuclease, wherein said plant optimized Cas9 endonuclease is capable of binding to and creating a double strand break in a genomic target sequence of said plant genome. 21-28. (canceled) 29. A method for editing a nucleotide sequence in the genome of a cell, the method comprising introducing at least one guide RNA and at least one polynucleotide modification template into a cell comprising at least one Cas endonuclease, wherein the Cas endonuclease introduces a double-strand break at a target site in the genome of said cell, wherein said polynucleotide modification template comprises at least one nucleotide modification of said nucleotide sequence. 30. The method of claim 29, wherein the cell is a plant cell. 31. The method of claim 29, wherein the nucleotide sequence in the genome of said cell is selected from the group consisting of a promoter sequence, a terminator sequence, a regulatory sequence, a splice site, a coding sequence, a polyubiquitination site, an intron site, an intron enhancing motif and a gene of interest. 32. The method of claim 31 wherein the gene of interest is an enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene or an acetolactate synthase (ALS) gene. 33. The method of claim 30 wherein the plant cell is a monocot or dicot plant cell. 34-36. (canceled) 37. A plant or seed produced from the plant cell of claim 30. 38. The method of claim 29, wherein the Cas endonuclease is a Cas9 endonuclease. 39-42. (canceled) 43. The method of claim 29, wherein the at least one nucleotide modification is not a modification at said target site. 44-66. (canceled) | 1,600 |
425 | 14,552,566 | 1,619 | The present invention relates to a method of shaping a fibrous material and treatment compositions therefor. The method comprises providing a treatment composition comprising an active agent and a photocatalyst, applying the treatment composition to the fibrous material to form a treated fibrous material, mechanically shaping the treated fibrous material, and exposing the treated fibrous material to electromagnetic radiation. The treatment composition comprises an active agent, wherein the active agent comprises a monoamine, diamine, or polyamine; and a photocatalyst. | 1. A method for shaping fibrous material comprising:
(a) providing a treatment composition, wherein the treatment composition comprises:
(i) an active agent comprising a monoamine, diamine, or polyamine; and
(ii) a photocatalyst;
(b) applying the treatment composition to a fibrous material to form a treated fibrous material; (c) mechanically shaping the treated fibrous material; and (d) exposing the treated fibrous material to electromagnetic radiation. 2. The method of claim 1, wherein said active agent has a molecular weight below about 1000 g/mol. 3. The method of claim 1, wherein the electromagnetic radiation has a wavelength of from about 300 nm to about 750 nm. 4. The method of claim 1, wherein the photocatalyst is a photoacid. 5. The method of claim 4, wherein the photoacid is a hydroxyl-substituted aromatic compound. 6. The method of claim 1, wherein the step of mechanically shaping the fibrous material comprises using an implement. 7. The method of claim 6, wherein the implement comprises a light source. 8. The method of claim 7, wherein the light source is selected from the group consisting of incandescent light, fluorescent light, LED light, laser light, solar light, and combinations thereof. 9. The method of claim 1, wherein the treatment composition has not been exposed to electromagnetic radiation having a wavelength of less than 750 nm for a period of at least 1 second before the step of applying the treatment composition to the fibrous material. 10. The method of claim 1, wherein the photocatalyst is selected from the group consisting of: 8-hydroxyquinoline, 8-hydroxyquinoline sulfate, 8-quinolinol-1-oxide, 5-hydroxyquinoline, 6-hydroxyquinoline, 7-hydroxyquinoline, 5-iodo-7-sulfo-8-hydroxyquinoline, 5-fluoro-8-hydroxyquinoline, 5-fluoro-7-chloro-8-hydroxyquinoline, 5-fluoro-7-bromo-8-hydroxyquinoline, 5-fluoro-7-iodo-8-hydroxyquinoline, 7-fluoro-8-hydroxyquinoline, 5-chloro-8-hydroxyquinoline, 5,7-dichloro-8-hydroxyquinoline, 5-chloro-7-brono-8-hydroxyquinoline, 5-chloro-7-iodo-8-hydroxyquinoline, 7-chloro-8-hydroxyquinoline, 5-bromo-8-hydroxyquinoline, 5-bromo-7-chloro-8-hydroxyquinoline, 5,7-dibromo-8-hydroxyquinoline, 5-bromo-7-iodo-8-hydroxyquinoline, 7-bromo-8-hydroxyquinoline, 5-iodo-8-hydroxyquinoline, 5-iodo-7-chloro-8-hydroxyquinoline, 5,7-diiodo-8-hydroxyquinoline, 7-iodo-8-hydroxyquinoline, 5-sulfonic acid-8-hydroxyquinoline, 7-sulfonic acid-8-hydroxyquinoline, 5-sulfonic acid-7-iodo-8-hydroxyquinoline, 5-thiocyano-8-hydroxyquinoline, 5-chloro-8-hydroxyquinoline, 5-bromo-8-hydroxyquinoline, 5,7-dibromo-8-hydroxyquinoline, 5-iodo-8-hydroxyquinoline, 5,7-diiodo-8-hydroxyquinoline, 7-azaindole, 7-cyano-2-naphthol, 8-cyano-2-naphthol, 5-cyano-2-naphthol, 1-hydroxy-3,6,8-pyrenetrisulfonic acid, trans-3-hydroxystilbene, 2-hydroxymethylphenol, Pelargonidin, and mixtures thereof. 11. The method of claim 1, wherein the fibrous material is selected from the group consisting of keratin fibers, cellulosic fibers, synthetic fibers, and combinations thereof. 12. The method of claim 1, wherein the fibrous material is keratin fibers. 13. The method of claim 1, wherein the fibrous material is a woven or nonwoven fabric. 14. The method of claim 1, wherein the method further comprises elevating the temperature of the treated fibrous material to a temperature of from about 40° C. to about 150° C. 15. The method of claim 6, wherein the implement further comprises a heat source. 16. The method of claim 1, wherein the treatment composition is substantially free of formaldehyde, derivatives of formaldehyde, formalin, and any compound that produces formaldehyde upon heating. 17. The method of claim 1, wherein the treatment composition comprises from about 0.1% to about 99.99%, by weight of the treatment composition, of the active agent. 18. The method of claim 1, wherein the treatment composition further comprises a carrier. 19. The method of claim 18, wherein the carrier is water. 20. The method of claim 1, wherein the treatment composition is a solid, and wherein the method further comprises the step of dissolving the treatment composition in a carrier. 21. The method of claim 1, wherein the active agent is a diamine or polyamine. 22. The method of claim 1, wherein the active agent is a primary amine, a secondary amine, or mixtures thereof. 23. The method of claim 1, wherein said active agent is a tertiary amine having a molecular weight below about 300 g/mol. 24. The method of claim 1, wherein the active agent is a diamine selected from the group consisting of 1,7-diaminoheptane, 1,4-diaminobutane, and mixtures thereof. 25. The method of claim 1, wherein the treatment composition is packaged in an opaque package. 26. A treatment composition for shaping fibrous material comprising:
(a) an active agent, wherein the active agent comprises a primary or secondary monoamine, diamine, or polyamine; and (b) a photocatalyst. 27. A kit comprising:
(a) a treatment composition comprising:
(i) an active agent comprising a monoamine, diamine, or polyamine; and
(ii) a photocatalyst; and
(b) an appliance for mechanically shaping fibrous material, for providing electromagnetic radiation, and/or for providing heat. | The present invention relates to a method of shaping a fibrous material and treatment compositions therefor. The method comprises providing a treatment composition comprising an active agent and a photocatalyst, applying the treatment composition to the fibrous material to form a treated fibrous material, mechanically shaping the treated fibrous material, and exposing the treated fibrous material to electromagnetic radiation. The treatment composition comprises an active agent, wherein the active agent comprises a monoamine, diamine, or polyamine; and a photocatalyst.1. A method for shaping fibrous material comprising:
(a) providing a treatment composition, wherein the treatment composition comprises:
(i) an active agent comprising a monoamine, diamine, or polyamine; and
(ii) a photocatalyst;
(b) applying the treatment composition to a fibrous material to form a treated fibrous material; (c) mechanically shaping the treated fibrous material; and (d) exposing the treated fibrous material to electromagnetic radiation. 2. The method of claim 1, wherein said active agent has a molecular weight below about 1000 g/mol. 3. The method of claim 1, wherein the electromagnetic radiation has a wavelength of from about 300 nm to about 750 nm. 4. The method of claim 1, wherein the photocatalyst is a photoacid. 5. The method of claim 4, wherein the photoacid is a hydroxyl-substituted aromatic compound. 6. The method of claim 1, wherein the step of mechanically shaping the fibrous material comprises using an implement. 7. The method of claim 6, wherein the implement comprises a light source. 8. The method of claim 7, wherein the light source is selected from the group consisting of incandescent light, fluorescent light, LED light, laser light, solar light, and combinations thereof. 9. The method of claim 1, wherein the treatment composition has not been exposed to electromagnetic radiation having a wavelength of less than 750 nm for a period of at least 1 second before the step of applying the treatment composition to the fibrous material. 10. The method of claim 1, wherein the photocatalyst is selected from the group consisting of: 8-hydroxyquinoline, 8-hydroxyquinoline sulfate, 8-quinolinol-1-oxide, 5-hydroxyquinoline, 6-hydroxyquinoline, 7-hydroxyquinoline, 5-iodo-7-sulfo-8-hydroxyquinoline, 5-fluoro-8-hydroxyquinoline, 5-fluoro-7-chloro-8-hydroxyquinoline, 5-fluoro-7-bromo-8-hydroxyquinoline, 5-fluoro-7-iodo-8-hydroxyquinoline, 7-fluoro-8-hydroxyquinoline, 5-chloro-8-hydroxyquinoline, 5,7-dichloro-8-hydroxyquinoline, 5-chloro-7-brono-8-hydroxyquinoline, 5-chloro-7-iodo-8-hydroxyquinoline, 7-chloro-8-hydroxyquinoline, 5-bromo-8-hydroxyquinoline, 5-bromo-7-chloro-8-hydroxyquinoline, 5,7-dibromo-8-hydroxyquinoline, 5-bromo-7-iodo-8-hydroxyquinoline, 7-bromo-8-hydroxyquinoline, 5-iodo-8-hydroxyquinoline, 5-iodo-7-chloro-8-hydroxyquinoline, 5,7-diiodo-8-hydroxyquinoline, 7-iodo-8-hydroxyquinoline, 5-sulfonic acid-8-hydroxyquinoline, 7-sulfonic acid-8-hydroxyquinoline, 5-sulfonic acid-7-iodo-8-hydroxyquinoline, 5-thiocyano-8-hydroxyquinoline, 5-chloro-8-hydroxyquinoline, 5-bromo-8-hydroxyquinoline, 5,7-dibromo-8-hydroxyquinoline, 5-iodo-8-hydroxyquinoline, 5,7-diiodo-8-hydroxyquinoline, 7-azaindole, 7-cyano-2-naphthol, 8-cyano-2-naphthol, 5-cyano-2-naphthol, 1-hydroxy-3,6,8-pyrenetrisulfonic acid, trans-3-hydroxystilbene, 2-hydroxymethylphenol, Pelargonidin, and mixtures thereof. 11. The method of claim 1, wherein the fibrous material is selected from the group consisting of keratin fibers, cellulosic fibers, synthetic fibers, and combinations thereof. 12. The method of claim 1, wherein the fibrous material is keratin fibers. 13. The method of claim 1, wherein the fibrous material is a woven or nonwoven fabric. 14. The method of claim 1, wherein the method further comprises elevating the temperature of the treated fibrous material to a temperature of from about 40° C. to about 150° C. 15. The method of claim 6, wherein the implement further comprises a heat source. 16. The method of claim 1, wherein the treatment composition is substantially free of formaldehyde, derivatives of formaldehyde, formalin, and any compound that produces formaldehyde upon heating. 17. The method of claim 1, wherein the treatment composition comprises from about 0.1% to about 99.99%, by weight of the treatment composition, of the active agent. 18. The method of claim 1, wherein the treatment composition further comprises a carrier. 19. The method of claim 18, wherein the carrier is water. 20. The method of claim 1, wherein the treatment composition is a solid, and wherein the method further comprises the step of dissolving the treatment composition in a carrier. 21. The method of claim 1, wherein the active agent is a diamine or polyamine. 22. The method of claim 1, wherein the active agent is a primary amine, a secondary amine, or mixtures thereof. 23. The method of claim 1, wherein said active agent is a tertiary amine having a molecular weight below about 300 g/mol. 24. The method of claim 1, wherein the active agent is a diamine selected from the group consisting of 1,7-diaminoheptane, 1,4-diaminobutane, and mixtures thereof. 25. The method of claim 1, wherein the treatment composition is packaged in an opaque package. 26. A treatment composition for shaping fibrous material comprising:
(a) an active agent, wherein the active agent comprises a primary or secondary monoamine, diamine, or polyamine; and (b) a photocatalyst. 27. A kit comprising:
(a) a treatment composition comprising:
(i) an active agent comprising a monoamine, diamine, or polyamine; and
(ii) a photocatalyst; and
(b) an appliance for mechanically shaping fibrous material, for providing electromagnetic radiation, and/or for providing heat. | 1,600 |
426 | 15,422,314 | 1,655 | Low water tooth pastes contain a variety of plant extracts. The oral or dentifrice compositions containing humectants, abrasive compounds, and a variety of plant extracts, such as rosemary and green tea extracts, along with an additional antioxidant component. Examples of antioxidants include stannous compounds, sodium meta-bisulfite, BHT, ammonium sulfate, and potassium stannate. The compositions are resistant to browning. The invention also provides methods for promoting oral health of a subject animal comprising applying a composition as discussed above to the oral surfaces of the animal. | 1. An oral composition comprising
at least one humectant; at least one abrasive compound; at least one plant-derivable compound selected from the group consisting of flavonoids, catechins, polyphenols, and tannins; and less than 10% by weight water. 2. A composition according to claim 1, comprising 0.001% to 5% by weight of a plant extract, wherein the plant is selected from the group consisting of rosemary, oregano, green tea, baikal skullcap, S. lateriflora, S. orthocalyx, grape seed, and grape skin. 3. A composition according to claim 2, comprising rosemary extract or green tea extract. 4. A composition according to claim 1, comprising a free B-ring flavonoid. 5. A composition according to claim 1, comprising an extract of a Scutellaria species. 6. A composition according to claim 2, comprising less than 6% by weight water. 7. A composition according to claim 2, further comprising an antioxidant generally recognized as safe. 8. A composition according to claim 2, further comprising an antioxidant selected from the group consisting of stannous compounds, stannate compounds, ammonium sulfates, BHT, and sodium metabisulfite. 9. A method for promoting oral health of a subject animal, comprising applying a composition according to claim 1 to the oral surfaces of the animal. 10. An oral composition comprising
1-70% by weight of a humectant; 1-70% by weight of at least one abrasive compound; less than 10% by weight water; and 0.001-5% by weight of a plant extract comprising one or more flavonoid components. 11. A composition according to claim 10, comprising 0.05% to 1% of a plant extract, wherein the plant is selected from the group consisting of rosemary, oregano, green tea, baikal skullcap, S. lateriflora, S. orthocalyx, grape seed, and grape skin. 12. A composition according to claim 11, comprising rosemary extract or green tea extract. 13. A composition according to claim 11, comprising an extract of a Scutellaria species. 14. A composition according to claim 10, comprising less than 6% by weight water. 15. A composition according to claim 10, further comprising an antioxidant generally recognized as safe. 16. A composition according to claim 10, further comprising an antioxidant selected from the group consisting of stannous compounds, stannate compounds, ammonium sulfates, BHT, and sodium metabisulfite. 17. A composition according to claim 10, further comprising an anticalculus system comprising at least one phosphate compound and a anionic carboxylate component. 18. A composition according to claim 10, further comprising an antibacterial component comprising a halogenated diphenylether compound. 19. A composition according to claim 18, wherein the halogenated diphenylether compound comprises triclosan. 20. A method for promoting oral health of a subject animal, comprising applying a composition according to claim 10 to the oral surfaces of the animal. 21. A method for promoting oral health of a subject animal, comprising applying a composition according to claim 14 to the oral surfaces of the animal. 22. A method for reducing the extent of discoloration in a toothpaste, the toothpaste being formulated to contain at least one of rosemary extract, green tea extract, oregano extract, baikal skullcap extract, S. lateriflora extract, S. orthocalyx extract, grape seed extract, and grape skin extract, the extracts containing flavonoid, catechin, polyphenol, or tannin compounds that tend to oxidize and discolor the toothpaste composition over time, the method comprising at least one of
a) formulating the toothpaste to contain less than 10% by weight water; and b) adding to the toothpaste an amount effective to reduce discoloration of an antioxidant selected form the group consisting of stannous compounds, stannate compounds, ammonium sulfate, phenolic antioxidants, hydroquinone antioxidants, and sodium meta-bisulfite. 23. A method according to claim 22, comprising formulating the toothpaste to contain less than 6% by weight water. 24. A method according to claim 23, comprising adding 0.01-1% by weight of the antioxidant. 25. A method according to claim 22, wherein the toothpaste comprises rosemary extract or green tea extract. 26. A method according to claim 22, wherein the toothpaste formulation comprises an extract of a Scutellaria species. 27. A method according to claim 22, wherein the toothpaste composition comprises an antibacterial component comprising a halogenated diphenylether compound. 28. A composition according to claim 27, wherein the halogenated diphenylether compound comprises triclosan. | Low water tooth pastes contain a variety of plant extracts. The oral or dentifrice compositions containing humectants, abrasive compounds, and a variety of plant extracts, such as rosemary and green tea extracts, along with an additional antioxidant component. Examples of antioxidants include stannous compounds, sodium meta-bisulfite, BHT, ammonium sulfate, and potassium stannate. The compositions are resistant to browning. The invention also provides methods for promoting oral health of a subject animal comprising applying a composition as discussed above to the oral surfaces of the animal.1. An oral composition comprising
at least one humectant; at least one abrasive compound; at least one plant-derivable compound selected from the group consisting of flavonoids, catechins, polyphenols, and tannins; and less than 10% by weight water. 2. A composition according to claim 1, comprising 0.001% to 5% by weight of a plant extract, wherein the plant is selected from the group consisting of rosemary, oregano, green tea, baikal skullcap, S. lateriflora, S. orthocalyx, grape seed, and grape skin. 3. A composition according to claim 2, comprising rosemary extract or green tea extract. 4. A composition according to claim 1, comprising a free B-ring flavonoid. 5. A composition according to claim 1, comprising an extract of a Scutellaria species. 6. A composition according to claim 2, comprising less than 6% by weight water. 7. A composition according to claim 2, further comprising an antioxidant generally recognized as safe. 8. A composition according to claim 2, further comprising an antioxidant selected from the group consisting of stannous compounds, stannate compounds, ammonium sulfates, BHT, and sodium metabisulfite. 9. A method for promoting oral health of a subject animal, comprising applying a composition according to claim 1 to the oral surfaces of the animal. 10. An oral composition comprising
1-70% by weight of a humectant; 1-70% by weight of at least one abrasive compound; less than 10% by weight water; and 0.001-5% by weight of a plant extract comprising one or more flavonoid components. 11. A composition according to claim 10, comprising 0.05% to 1% of a plant extract, wherein the plant is selected from the group consisting of rosemary, oregano, green tea, baikal skullcap, S. lateriflora, S. orthocalyx, grape seed, and grape skin. 12. A composition according to claim 11, comprising rosemary extract or green tea extract. 13. A composition according to claim 11, comprising an extract of a Scutellaria species. 14. A composition according to claim 10, comprising less than 6% by weight water. 15. A composition according to claim 10, further comprising an antioxidant generally recognized as safe. 16. A composition according to claim 10, further comprising an antioxidant selected from the group consisting of stannous compounds, stannate compounds, ammonium sulfates, BHT, and sodium metabisulfite. 17. A composition according to claim 10, further comprising an anticalculus system comprising at least one phosphate compound and a anionic carboxylate component. 18. A composition according to claim 10, further comprising an antibacterial component comprising a halogenated diphenylether compound. 19. A composition according to claim 18, wherein the halogenated diphenylether compound comprises triclosan. 20. A method for promoting oral health of a subject animal, comprising applying a composition according to claim 10 to the oral surfaces of the animal. 21. A method for promoting oral health of a subject animal, comprising applying a composition according to claim 14 to the oral surfaces of the animal. 22. A method for reducing the extent of discoloration in a toothpaste, the toothpaste being formulated to contain at least one of rosemary extract, green tea extract, oregano extract, baikal skullcap extract, S. lateriflora extract, S. orthocalyx extract, grape seed extract, and grape skin extract, the extracts containing flavonoid, catechin, polyphenol, or tannin compounds that tend to oxidize and discolor the toothpaste composition over time, the method comprising at least one of
a) formulating the toothpaste to contain less than 10% by weight water; and b) adding to the toothpaste an amount effective to reduce discoloration of an antioxidant selected form the group consisting of stannous compounds, stannate compounds, ammonium sulfate, phenolic antioxidants, hydroquinone antioxidants, and sodium meta-bisulfite. 23. A method according to claim 22, comprising formulating the toothpaste to contain less than 6% by weight water. 24. A method according to claim 23, comprising adding 0.01-1% by weight of the antioxidant. 25. A method according to claim 22, wherein the toothpaste comprises rosemary extract or green tea extract. 26. A method according to claim 22, wherein the toothpaste formulation comprises an extract of a Scutellaria species. 27. A method according to claim 22, wherein the toothpaste composition comprises an antibacterial component comprising a halogenated diphenylether compound. 28. A composition according to claim 27, wherein the halogenated diphenylether compound comprises triclosan. | 1,600 |
427 | 14,426,014 | 1,627 | The present invention relates to compositions and methods for the treatment of epilepsy and related disorders. More specifically, the present invention relates to novel combinatorial therapies of epilepsy and related disorders. | 1.-10. (canceled) 11. A composition comprising at least acamprosate, or a salt, prodrug, derivative of any chemical purity, or sustained release formulation thereof, for use in the treatment of epilepsy, benign Rolandic epilepsy, frontal lobe epilepsy, infantile spasms, myoclonic epilepsy, absence epilepsy, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, Dravet syndrome, progressive myoclonus epilepsies, reflex epilepsy, Rasmussen's syndrome, temporal lobe epilepsy, limbic epilepsy, status epilepticus, abdominal epilepsy, massive bilateral myoclonus, catamenial epilepsy, Jacksonian seizure disorder, Lafora disease or photosensitive epilepsy in a subject in need thereof 12. The composition of claim 11, further comprising at least one compound selected from baclofen, cinacalcet, mexiletine, sulfisoxazole or torasemide, or a salt, prodrug, derivative of any chemical purity, or sustained release formulation thereof. 13. The composition of claim 12, wherein said composition comprises acamprosate and baclofen, or salt(s), prodrug(s), derivative(s) of any chemical purity, or sustained release formulation thereof. 14. The composition of claim 11, further comprising at least one compound selected from ezogabine, pregabalin, levetiracetam, lamotrigine, topiramate, valproate, rufinamide, gabapentin, carbamazepine, clonazepam, oxcarbazepine, phenobarbital and phenytoin, or salt(s) or prodrug(s) or derivative(s) of any purity or sustained release formulation(s) thereof. 15. The composition of claim 11, which further comprises a pharmaceutically acceptable carrier or excipient. 16. The composition of claim 12, wherein the compounds in said composition are formulated or administered together, separately or sequentially. 17. The composition of claim 11, wherein said composition is administered repeatedly to the subject. 18. The composition of claim 11, for use in inhibiting epileptogenesis and epileptic seizure. 19. A method of treating epilepsy, benign Rolandic epilepsy, frontal lobe epilepsy, infantile spasms, myoclonic epilepsy, absence epilepsy, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, Dravet syndrome, progressive myoclonus epilepsies, reflex epilepsy, Rasmussen's syndrome, temporal lobe epilepsy, limbic epilepsy, status epilepticus, abdominal epilepsy, massive bilateral myoclonus, catamenial epilepsy, Jacksonian seizure disorder, Lafora disease or photosensitive epilepsy, in a mammalian subject in need thereof, the method comprising administering to said subject an effective amount of acamprosate, or a salt, prodrug, derivative of any chemical purity, or sustained release formulation thereof. 20. The method of claim 19, comprising administering at least one further compound selected from baclofen, cinacalcet, mexiletine, sulfisoxazole or torasemide, or a salt, prodrug, derivative of any chemical purity, or sustained release formulation thereof. 21. The method of claim 19, further comprising administering at least one compound selected from ezogabine, pregabalin, levetiracetam, lamotrigine, topiramate, valproate, rufinamide, gabapentin, carbamazepine, clonazepam, oxcarbazepine, phenobarbital and phenytoin, or salt(s) or prodrug(s) or derivative(s) of any purity or sustained release formulation(s) thereof. 22. The method of claim 20, wherein acamprosate, or the salt, prodrug, derivative of any chemical purity, or sustained release formulation thereof, and said at least one further compound, are administered simultaneously, separately or sequentially to said subject. 23. The method of claim 19, for treating epilepsy in a subject in need thereof. 24. The method of claim 23, for inhibiting epileptogenesis and epileptic seizure in said subject. 25. The method of claim 23, comprising the simultaneous, separate or sequential administration to said subject of acamprosate or a salt, prodrug, derivative of any chemical purity, or sustained release formulation thereof, and at least one further compound selected from baclofen, cinacalcet, mexiletine, sulfisoxazole or torasemide, or a salt, prodrug, derivative of any chemical purity, or sustained release formulation thereof. 26. The method of claim 25, comprising the simultaneous, separate or sequential administration to said subject of acamprosate and baclofen, or salt(s), prodrug(s), derivative(s) of any chemical purity, or sustained release formulation(s) thereof. 27. The method of claim 23, wherein said subject is at risk of developing epilepsy. 28. The method of claim 23, wherein said subject in need thereof has undergone or will undergo surgical therapy for epilepsy. 29. The method of claim 23, wherein treating epilepsy comprises treating epilepsy comorbidities selected from memory impairment, cognitive decline, or anxiety, suicidal thoughts and/or depression. 30. The method of claim 19, wherein the derivative has a Tanimoto similarity index greater than 0.5. | The present invention relates to compositions and methods for the treatment of epilepsy and related disorders. More specifically, the present invention relates to novel combinatorial therapies of epilepsy and related disorders.1.-10. (canceled) 11. A composition comprising at least acamprosate, or a salt, prodrug, derivative of any chemical purity, or sustained release formulation thereof, for use in the treatment of epilepsy, benign Rolandic epilepsy, frontal lobe epilepsy, infantile spasms, myoclonic epilepsy, absence epilepsy, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, Dravet syndrome, progressive myoclonus epilepsies, reflex epilepsy, Rasmussen's syndrome, temporal lobe epilepsy, limbic epilepsy, status epilepticus, abdominal epilepsy, massive bilateral myoclonus, catamenial epilepsy, Jacksonian seizure disorder, Lafora disease or photosensitive epilepsy in a subject in need thereof 12. The composition of claim 11, further comprising at least one compound selected from baclofen, cinacalcet, mexiletine, sulfisoxazole or torasemide, or a salt, prodrug, derivative of any chemical purity, or sustained release formulation thereof. 13. The composition of claim 12, wherein said composition comprises acamprosate and baclofen, or salt(s), prodrug(s), derivative(s) of any chemical purity, or sustained release formulation thereof. 14. The composition of claim 11, further comprising at least one compound selected from ezogabine, pregabalin, levetiracetam, lamotrigine, topiramate, valproate, rufinamide, gabapentin, carbamazepine, clonazepam, oxcarbazepine, phenobarbital and phenytoin, or salt(s) or prodrug(s) or derivative(s) of any purity or sustained release formulation(s) thereof. 15. The composition of claim 11, which further comprises a pharmaceutically acceptable carrier or excipient. 16. The composition of claim 12, wherein the compounds in said composition are formulated or administered together, separately or sequentially. 17. The composition of claim 11, wherein said composition is administered repeatedly to the subject. 18. The composition of claim 11, for use in inhibiting epileptogenesis and epileptic seizure. 19. A method of treating epilepsy, benign Rolandic epilepsy, frontal lobe epilepsy, infantile spasms, myoclonic epilepsy, absence epilepsy, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, Dravet syndrome, progressive myoclonus epilepsies, reflex epilepsy, Rasmussen's syndrome, temporal lobe epilepsy, limbic epilepsy, status epilepticus, abdominal epilepsy, massive bilateral myoclonus, catamenial epilepsy, Jacksonian seizure disorder, Lafora disease or photosensitive epilepsy, in a mammalian subject in need thereof, the method comprising administering to said subject an effective amount of acamprosate, or a salt, prodrug, derivative of any chemical purity, or sustained release formulation thereof. 20. The method of claim 19, comprising administering at least one further compound selected from baclofen, cinacalcet, mexiletine, sulfisoxazole or torasemide, or a salt, prodrug, derivative of any chemical purity, or sustained release formulation thereof. 21. The method of claim 19, further comprising administering at least one compound selected from ezogabine, pregabalin, levetiracetam, lamotrigine, topiramate, valproate, rufinamide, gabapentin, carbamazepine, clonazepam, oxcarbazepine, phenobarbital and phenytoin, or salt(s) or prodrug(s) or derivative(s) of any purity or sustained release formulation(s) thereof. 22. The method of claim 20, wherein acamprosate, or the salt, prodrug, derivative of any chemical purity, or sustained release formulation thereof, and said at least one further compound, are administered simultaneously, separately or sequentially to said subject. 23. The method of claim 19, for treating epilepsy in a subject in need thereof. 24. The method of claim 23, for inhibiting epileptogenesis and epileptic seizure in said subject. 25. The method of claim 23, comprising the simultaneous, separate or sequential administration to said subject of acamprosate or a salt, prodrug, derivative of any chemical purity, or sustained release formulation thereof, and at least one further compound selected from baclofen, cinacalcet, mexiletine, sulfisoxazole or torasemide, or a salt, prodrug, derivative of any chemical purity, or sustained release formulation thereof. 26. The method of claim 25, comprising the simultaneous, separate or sequential administration to said subject of acamprosate and baclofen, or salt(s), prodrug(s), derivative(s) of any chemical purity, or sustained release formulation(s) thereof. 27. The method of claim 23, wherein said subject is at risk of developing epilepsy. 28. The method of claim 23, wherein said subject in need thereof has undergone or will undergo surgical therapy for epilepsy. 29. The method of claim 23, wherein treating epilepsy comprises treating epilepsy comorbidities selected from memory impairment, cognitive decline, or anxiety, suicidal thoughts and/or depression. 30. The method of claim 19, wherein the derivative has a Tanimoto similarity index greater than 0.5. | 1,600 |
428 | 14,128,232 | 1,649 | The present invention relates to compositions and methods for treatment of neurological disorders. In particular, the present invention relates to EGFR as a clinical target for treatment of neurological disorders. | 1. A method of treating a subject with a neurological disorder comprising administering to said subject an agent that inhibits at least one biological function of an EGFR polypeptide. 2. The method of claim 1, wherein said subject exhibits symptoms of a neurological disorder and said administering said agent reduces or modulates symptoms of said neurological disorder. 3. The method of claim 1, wherein said reagent is an antigen binding protein that binds to said EGFR polypeptide. 4. The method of claim 3, wherein said antigen binding protein is selected from the group consisting of cetuximab, matuzumab, necitumumab, nimotuzumab, panitumumab, and zalutumumab. 5. The method of claim 3, wherein said antigen binding protein is selected from the group consisting of Cetuximab or Panitumumab. 6. The method of claim 1, wherein said agent is a small molecule drug. 7. The method of claim 6, wherein said small molecule drug is selected from the group consisting of afatinib, erlotinib, gefitinib, lapatinib, and neratinib. 8. The method of claim 6, wherein said small molecule drug is selected from the group consisting of Gefitinib and Erlotinib. 9. The method of claim 1, wherein said subject is in an animal. 10. The method of claim 1, wherein said animal is a human. 11. The method of claim 1, wherein said neurological disorder is neuropathic pain. 12. The method of claim 1, wherein said neurological disorder is selected from the group consisting of pain, sciatica, multiple sclerosis, depression, dementia, Parkinson's disease, stroke, axotomia, and ischemia or reperfusion injury, Downs syndrome and autism. 13. The method of claim 1, wherein said agent that inhibits at least one biological function of an EGFR polypeptide is co-administered with at least additional therapeutic agent. 14. The method of claim 13, wherein said at least additional therapeutic agent is selected from the group consisting of non-steroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, opioid-based drugs, antidepressants, anticonvulsants, antiepileptics, anti-anxiety drugs, and cannibinoids and combinations thereof. 15. A method of treating a neurological disorder, comprising administering an agent that inhibits at least one biological function of an EGFR polypeptide to a subject exhibiting symptoms of a neurological disorder, wherein said administering reduces, modulates or eliminates said symptoms. 16. The method of claim 15, wherein said agent that inhibits at least one biological function of an EGFR polypeptide is co-administered with at least additional therapeutic agent. 17. The method of claim 16, wherein said at least additional therapeutic agent is selected from the group consisting of non-steroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, opioid-based drugs, antidepressants, anticonvulsants, antiepileptics, anti-anxiety drugs, and cannibinoids and combinations thereof. 18-28. (canceled) 29. A method of treating a subject suffering from neuropathic pain comprising administering to said subject an agent that inhibits at least one biological function of an EGFR polypeptide under conditions such that said neuropathic pain is relieved, wherein said agent is selected from the group consisting of cetuximab, matuzumab, necitumumab, nimotuzumab, panitumumab, and zalutumumab. 30. A method of treating a subject suffering from neuropathic pain comprising administering to said subject an agent that inhibits at least one biological function of an EGFR polypeptide under conditions such that said neuropathic pain is relieved, wherein said agent is selected from the group consisting of afatinib, erlotinib, gefitinib, lapatinib, and neratinib. | The present invention relates to compositions and methods for treatment of neurological disorders. In particular, the present invention relates to EGFR as a clinical target for treatment of neurological disorders.1. A method of treating a subject with a neurological disorder comprising administering to said subject an agent that inhibits at least one biological function of an EGFR polypeptide. 2. The method of claim 1, wherein said subject exhibits symptoms of a neurological disorder and said administering said agent reduces or modulates symptoms of said neurological disorder. 3. The method of claim 1, wherein said reagent is an antigen binding protein that binds to said EGFR polypeptide. 4. The method of claim 3, wherein said antigen binding protein is selected from the group consisting of cetuximab, matuzumab, necitumumab, nimotuzumab, panitumumab, and zalutumumab. 5. The method of claim 3, wherein said antigen binding protein is selected from the group consisting of Cetuximab or Panitumumab. 6. The method of claim 1, wherein said agent is a small molecule drug. 7. The method of claim 6, wherein said small molecule drug is selected from the group consisting of afatinib, erlotinib, gefitinib, lapatinib, and neratinib. 8. The method of claim 6, wherein said small molecule drug is selected from the group consisting of Gefitinib and Erlotinib. 9. The method of claim 1, wherein said subject is in an animal. 10. The method of claim 1, wherein said animal is a human. 11. The method of claim 1, wherein said neurological disorder is neuropathic pain. 12. The method of claim 1, wherein said neurological disorder is selected from the group consisting of pain, sciatica, multiple sclerosis, depression, dementia, Parkinson's disease, stroke, axotomia, and ischemia or reperfusion injury, Downs syndrome and autism. 13. The method of claim 1, wherein said agent that inhibits at least one biological function of an EGFR polypeptide is co-administered with at least additional therapeutic agent. 14. The method of claim 13, wherein said at least additional therapeutic agent is selected from the group consisting of non-steroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, opioid-based drugs, antidepressants, anticonvulsants, antiepileptics, anti-anxiety drugs, and cannibinoids and combinations thereof. 15. A method of treating a neurological disorder, comprising administering an agent that inhibits at least one biological function of an EGFR polypeptide to a subject exhibiting symptoms of a neurological disorder, wherein said administering reduces, modulates or eliminates said symptoms. 16. The method of claim 15, wherein said agent that inhibits at least one biological function of an EGFR polypeptide is co-administered with at least additional therapeutic agent. 17. The method of claim 16, wherein said at least additional therapeutic agent is selected from the group consisting of non-steroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, opioid-based drugs, antidepressants, anticonvulsants, antiepileptics, anti-anxiety drugs, and cannibinoids and combinations thereof. 18-28. (canceled) 29. A method of treating a subject suffering from neuropathic pain comprising administering to said subject an agent that inhibits at least one biological function of an EGFR polypeptide under conditions such that said neuropathic pain is relieved, wherein said agent is selected from the group consisting of cetuximab, matuzumab, necitumumab, nimotuzumab, panitumumab, and zalutumumab. 30. A method of treating a subject suffering from neuropathic pain comprising administering to said subject an agent that inhibits at least one biological function of an EGFR polypeptide under conditions such that said neuropathic pain is relieved, wherein said agent is selected from the group consisting of afatinib, erlotinib, gefitinib, lapatinib, and neratinib. | 1,600 |
429 | 14,828,365 | 1,618 | The present invention relates to an eye-drop composition comprising 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-Purin-6-one, and the use thereof for the diagnosis and treatment of herpetic eye infections in companion animals. | 1. A composition comprising:
at least 0.1% w/v 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-Purin-6-one; and at least 10% w/v of a cyclodextrin. 2. The composition according to claim 1, which is an aqueous solution. 3. The composition according to claim 1 or 2, wherein said composition is an ophthalmic solution. 4. The composition according to any one of claims 1 to 3, wherein said cyclodextrin is hydroxypropyl beta-cyclodextrin. 5. The composition according to any one of claims 1 to 4, further comprising at least 0.008% w/v thiomersal. 6. A composition according to any one of claims 1 to 5, for use as a diagnostic or a therapeutic composition. 7. The composition according to claim 6, for use in a method for the treatment of an ocular herpetic infection. 8. The composition according to claim 7, wherein said ocular infection is an ocular infection of a companion animal. 9. The composition according to claim 8, wherein said companion animal is a feline. 10. The composition according to any one of claims 7 to 9, wherein said method comprises applying said composition onto the eye two or three times per day for at least seven days. 11. The composition according to claim 6, for use in a method of diagnosis of an ocular herpetic infection. 12. The composition according to claim 10 or 11, wherein said ocular infection is an ocular infection in a companion animal. 13. The composition according to claim 12, wherein said companion animal is a feline. 14. A method for preparing an ophthalmic solution, comprising the steps of:
a) providing a solution comprising at least 10% w/v of a cyclodextrin; b) adding 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-Purin-6-one to said solution; c) solubilizing the 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-Purin-6-one added in step b); d) repeating steps b) and c) until a concentration of 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-Purin-6-one in said solution of at least 1 mg/mL is obtained; e) optionally, adding at least 0.008 mg/mL thiomersal. 15. The method according to claim 14, wherein said cyclodextrin is hydroxypropyl beta-cyclodextrin. | The present invention relates to an eye-drop composition comprising 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-Purin-6-one, and the use thereof for the diagnosis and treatment of herpetic eye infections in companion animals.1. A composition comprising:
at least 0.1% w/v 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-Purin-6-one; and at least 10% w/v of a cyclodextrin. 2. The composition according to claim 1, which is an aqueous solution. 3. The composition according to claim 1 or 2, wherein said composition is an ophthalmic solution. 4. The composition according to any one of claims 1 to 3, wherein said cyclodextrin is hydroxypropyl beta-cyclodextrin. 5. The composition according to any one of claims 1 to 4, further comprising at least 0.008% w/v thiomersal. 6. A composition according to any one of claims 1 to 5, for use as a diagnostic or a therapeutic composition. 7. The composition according to claim 6, for use in a method for the treatment of an ocular herpetic infection. 8. The composition according to claim 7, wherein said ocular infection is an ocular infection of a companion animal. 9. The composition according to claim 8, wherein said companion animal is a feline. 10. The composition according to any one of claims 7 to 9, wherein said method comprises applying said composition onto the eye two or three times per day for at least seven days. 11. The composition according to claim 6, for use in a method of diagnosis of an ocular herpetic infection. 12. The composition according to claim 10 or 11, wherein said ocular infection is an ocular infection in a companion animal. 13. The composition according to claim 12, wherein said companion animal is a feline. 14. A method for preparing an ophthalmic solution, comprising the steps of:
a) providing a solution comprising at least 10% w/v of a cyclodextrin; b) adding 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-Purin-6-one to said solution; c) solubilizing the 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-Purin-6-one added in step b); d) repeating steps b) and c) until a concentration of 2-amino-9-[[(1S,2R)-1,2-bis(hydroxymethyl)cyclopropyl]methyl]-1,9-dihydro-6H-Purin-6-one in said solution of at least 1 mg/mL is obtained; e) optionally, adding at least 0.008 mg/mL thiomersal. 15. The method according to claim 14, wherein said cyclodextrin is hydroxypropyl beta-cyclodextrin. | 1,600 |
430 | 15,421,621 | 1,639 | Laundry care compositions comprising thiophene azo carboxylate fabric shading dyes and methods of treating a textile comprising such laundry care compositions. | 1. A composition comprising a thiophene azo carboxylate dye having the structure of Formula I:
wherein R1 is selected from the group consisting of H and electron-withdrawing groups; wherein R2 is (CH2CH2O)yQ and R3 is (CH2CH2O)y′Q′;
wherein y and y′ are integers independently selected from 1 to 39,
wherein 8≦(y+y′)≦40;
wherein Q and Q′ are independently selected from the group consisting of H and Y wherein Y is as defined below; with the proviso that the dye comprises at least one Q or Q′ group that is Y; and
wherein Y is an organic radical represented by Formula II
wherein independently for each Y group,
M is H or a charge balancing cation; m is 0 to 5; n is 0 to 5; the sum of m+n is 1 to 10; each R4 is independently selected from the group consisting of H, C3-18 or C4-C18 linear or branched alkyl, and C3-18 or C4-C18 linear or branched alkenyl, and wherein at least one R4 group is not H. 2. A composition according to claim 1 wherein in the dye structure of Formula I, R1 comprises an electron-withdrawing group. 3. A composition according to claim 1 wherein in the dye structure of Formula I, R1 comprises an electron-withdrawing group selected from the group consisting of F, Cl and Br. 4. A composition according to claim 3 wherein in the dye structure of Formula I, R1 comprises Cl. 5. A composition according to claim 1 wherein in the dye structure of Formula I, R1 is H. 6. A composition according to claim 1 wherein in the dye structure of Formula I, (y+y′)≦35. 7. A composition according to claim 1 wherein in the dye structure of Formula I, (y+y′)≦30. 8. A composition according to claim 1 wherein in the dye structure of Formula I, Q and Q′ are each an independently selected Y. 9. A composition according to claim 1 wherein in the dye structure of Formula II, m is 0, 1, 2, or 3. 10. A composition according to claim 1 wherein in the dye structure of Formula II, m is 0 or 1. 11. A composition according to claim 1 wherein in the dye structure of Formula II, n is 0, 1, 2 or 3. 12. A composition according to claim 1 wherein in the dye structure of Formula II, n is 0 or 1. 13. A composition according to claim 1 wherein in the dye structure of Formula II, the sum of m+n is 1, 2 or 3. 14. A composition according to claim 1 wherein in the dye structure of Formula II, the sum of m+n is 1 or 2. 15. A composition according to claim 1 wherein in the dye structure of Formula II, 0.4(y+y′)≦ the sum of the number of carbon atoms in all the R4 groups ≦2.0(y+y′). 16. A composition according to claim 1 wherein the thiophene azo dye has a molecular weight from greater than about 760 Daltons to about 5000 Daltons. 17. A composition comprising a thiophene azo carboxylate dye having the structure of Formula I:
wherein R1 is selected from the group consisting of H and electron-withdrawing groups; wherein R2 is ((CH2CR′HO)x(CH2CR″HO)z)yQ and R3 is ((CH2CR′HO)x(CH2CR″HO)z)y′Q′;
wherein y and y′ are integers independently selected from 1 to 39, wherein 8≦(y+y′)≦40;
wherein x≧0 and z>1;
wherein R′ is selected from the group consisting of H, C1-4 alkyl, CH2O(CH2CH2O)zQ, phenyl and CH2OR5;
wherein R″ is selected from the group consisting of H, C1-4 alkyl, CH2O(CH2CH2O)zQ, phenyl and CH2OR5;
each R5 is selected from the group consisting of C1-C16 linear or branched alkyl, C6-C14 aryl and C7-C16 arylalkyl; preferably R5 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, t-butyl, hexyl, 2-ethylhexyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, phenyl, benzyl, 2-phenylethyl, and naphthyl;
and wherein Y is an organic radical represented by Formula II
wherein independently for each Y group,
M is H or a charge balancing cation; m is 0 to 5, preferably 0, 1, 2 or 3; n is 0 to 5, preferably 0, 1, 2 or 3; the sum of m+n is 1 to 10, preferably 1, 2 or 3; each R8 is independently selected from the group consisting of H and C3-18 or C4-C18 alkenyl, and wherein at least one R8 group is not H;
wherein Q and Q′ are independently selected from the group consisting of H and Y wherein Y is as defined below; with the proviso that the dye comprises at least one Q or Q′ group that is Y; and
wherein Y is an organic radical represented by Formula II
wherein independently for each Y group,
M is H or a charge balancing cation; m is 0 to 5; n is 0 to 5; the sum of m+n is 1 to 10; each R4 is independently selected from the group consisting of H, C3-18 or C4-C18 linear or branched alkyl, and C3-18 or C4-C18 linear or branched alkenyl, and wherein at least one R4 group is not H. | Laundry care compositions comprising thiophene azo carboxylate fabric shading dyes and methods of treating a textile comprising such laundry care compositions.1. A composition comprising a thiophene azo carboxylate dye having the structure of Formula I:
wherein R1 is selected from the group consisting of H and electron-withdrawing groups; wherein R2 is (CH2CH2O)yQ and R3 is (CH2CH2O)y′Q′;
wherein y and y′ are integers independently selected from 1 to 39,
wherein 8≦(y+y′)≦40;
wherein Q and Q′ are independently selected from the group consisting of H and Y wherein Y is as defined below; with the proviso that the dye comprises at least one Q or Q′ group that is Y; and
wherein Y is an organic radical represented by Formula II
wherein independently for each Y group,
M is H or a charge balancing cation; m is 0 to 5; n is 0 to 5; the sum of m+n is 1 to 10; each R4 is independently selected from the group consisting of H, C3-18 or C4-C18 linear or branched alkyl, and C3-18 or C4-C18 linear or branched alkenyl, and wherein at least one R4 group is not H. 2. A composition according to claim 1 wherein in the dye structure of Formula I, R1 comprises an electron-withdrawing group. 3. A composition according to claim 1 wherein in the dye structure of Formula I, R1 comprises an electron-withdrawing group selected from the group consisting of F, Cl and Br. 4. A composition according to claim 3 wherein in the dye structure of Formula I, R1 comprises Cl. 5. A composition according to claim 1 wherein in the dye structure of Formula I, R1 is H. 6. A composition according to claim 1 wherein in the dye structure of Formula I, (y+y′)≦35. 7. A composition according to claim 1 wherein in the dye structure of Formula I, (y+y′)≦30. 8. A composition according to claim 1 wherein in the dye structure of Formula I, Q and Q′ are each an independently selected Y. 9. A composition according to claim 1 wherein in the dye structure of Formula II, m is 0, 1, 2, or 3. 10. A composition according to claim 1 wherein in the dye structure of Formula II, m is 0 or 1. 11. A composition according to claim 1 wherein in the dye structure of Formula II, n is 0, 1, 2 or 3. 12. A composition according to claim 1 wherein in the dye structure of Formula II, n is 0 or 1. 13. A composition according to claim 1 wherein in the dye structure of Formula II, the sum of m+n is 1, 2 or 3. 14. A composition according to claim 1 wherein in the dye structure of Formula II, the sum of m+n is 1 or 2. 15. A composition according to claim 1 wherein in the dye structure of Formula II, 0.4(y+y′)≦ the sum of the number of carbon atoms in all the R4 groups ≦2.0(y+y′). 16. A composition according to claim 1 wherein the thiophene azo dye has a molecular weight from greater than about 760 Daltons to about 5000 Daltons. 17. A composition comprising a thiophene azo carboxylate dye having the structure of Formula I:
wherein R1 is selected from the group consisting of H and electron-withdrawing groups; wherein R2 is ((CH2CR′HO)x(CH2CR″HO)z)yQ and R3 is ((CH2CR′HO)x(CH2CR″HO)z)y′Q′;
wherein y and y′ are integers independently selected from 1 to 39, wherein 8≦(y+y′)≦40;
wherein x≧0 and z>1;
wherein R′ is selected from the group consisting of H, C1-4 alkyl, CH2O(CH2CH2O)zQ, phenyl and CH2OR5;
wherein R″ is selected from the group consisting of H, C1-4 alkyl, CH2O(CH2CH2O)zQ, phenyl and CH2OR5;
each R5 is selected from the group consisting of C1-C16 linear or branched alkyl, C6-C14 aryl and C7-C16 arylalkyl; preferably R5 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, t-butyl, hexyl, 2-ethylhexyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, phenyl, benzyl, 2-phenylethyl, and naphthyl;
and wherein Y is an organic radical represented by Formula II
wherein independently for each Y group,
M is H or a charge balancing cation; m is 0 to 5, preferably 0, 1, 2 or 3; n is 0 to 5, preferably 0, 1, 2 or 3; the sum of m+n is 1 to 10, preferably 1, 2 or 3; each R8 is independently selected from the group consisting of H and C3-18 or C4-C18 alkenyl, and wherein at least one R8 group is not H;
wherein Q and Q′ are independently selected from the group consisting of H and Y wherein Y is as defined below; with the proviso that the dye comprises at least one Q or Q′ group that is Y; and
wherein Y is an organic radical represented by Formula II
wherein independently for each Y group,
M is H or a charge balancing cation; m is 0 to 5; n is 0 to 5; the sum of m+n is 1 to 10; each R4 is independently selected from the group consisting of H, C3-18 or C4-C18 linear or branched alkyl, and C3-18 or C4-C18 linear or branched alkenyl, and wherein at least one R4 group is not H. | 1,600 |
431 | 14,531,472 | 1,649 | The present invention relates to peptides, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated cytotoxic T cell (CTL) peptide epitopes, alone or in combination with other tumor-associated peptides that serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses. The present invention relates to peptide sequences and their variants derived from HLA class I and class II molecules of human tumor cells that can be used in vaccine compositions for eliciting anti-tumor immune responses. | 1. A peptide or a variant peptide comprising an amino acid sequence selected from the group consisting of SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129, and variant sequences thereof which are at least 90% homologous to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129, and wherein a variant induces T cells cross-reacting with said variant peptide; and/or a pharmaceutical acceptable salt thereof, wherein said peptide is not a full-length polypeptide. 2. The peptide or variant peptide according to claim 1, wherein said peptide or variant peptide maintains an ability to bind to a molecule of the human major histocompatibility complex (MHC) class-I or -II, and wherein said peptide or variant peptide is capable of stimulating CD4 and/or CD8 T cells. 3. The peptide or variant peptide according to claim 1, wherein the amino acid sequence thereof comprises a continuous stretch of amino acids according the group of SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129. 4. The peptide or variant peptide according to claim 1, wherein said peptide or variant thereof has an overall length of from 8 to 100, optionally from 8 to 30, and/or optionally from 8 to 16 amino acids, and/or optionally wherein the peptide consists or consists essentially of an amino acid sequence according to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129. 5. The peptide or variant peptide according to claim 1, wherein said peptide or variant peptide is modified and/or includes non-peptide bonds. 6. The peptide or variant peptide according to claim 1, wherein said peptide or variant peptide is part of a fusion protein, optionally comprising N-terminal amino acids of the HLA-DR antigen-associated invariant chain (Ii). 7. A nucleic acid, encoding a peptide or variant peptide according to claim 1, optionally linked to a heterologous promoter sequence. 8. An expression vector capable of expressing the nucleic acid according to claim 7. 9. The peptide or variant peptide according to claim 1, capable of being used in medicine. 10. A host cell comprising the nucleic acid according to claim 7, wherein said host cell optionally is an antigen presenting cell or a dendritic cell. 11. A method for producing the peptide or variant peptide according to claim 1, the method comprising culturing a host cell that expresses a nucleic acid or an expression vector, and isolating the peptide or variant peptide from the host cell or a culture medium. 12. An in vitro method for producing activated cytotoxic T lymphocytes (CTL), the method comprising contacting in vitro CTL with antigen loaded human class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell or an artificial construct mimicking an antigen-presenting cell for a period of time sufficient to activate said CTL in an antigen specific manner, wherein said antigen is a peptide or variant according to claim 1. 13. An activated cytotoxic T lymphocyte (CTL), produced by an in vitro method for producing activated cytotoxic T lymphocytes (CTL), the method comprising contacting in vitro CTL with antigen loaded human class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell or an artificial construct mimicking an antigen-presenting cell for a period of time sufficient to activate said CTL in an antigen specific manner that selectively recognises a cell which aberrantly expresses a polypeptide comprising an amino acid sequence of a peptide or variant peptide of claim 1. 14. A method for killing target cells in a patient which target cells aberrantly express a polypeptide comprising an amino acid sequence of a peptide or variant peptide of claim 1, the method comprising administering to the patient an effective number of cytotoxic T lymphocytes (CTL). 15. An antibody that specifically recognizes the peptide or variant peptide according to claim 1 optionally wherein the peptide or variant peptide is bound to an MHC molecule. 16. A peptide or variant peptide according to claim 1, capable of being used for treatment of cancer or in the manufacture of a medicament against cancer, wherein said medicament optionally is a vaccine. 17. The peptide or variant peptide according to claim 16, wherein said cancer is selected from astrocytoma, pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor, oligodendrogliomas, ependymoma, glioblastoma multiforme, mixed gliomas, oligoastrocytomas, medulloblastoma, retinoblastoma, neuroblastoma, germinoma, teratoma, gangliogliomas, gangliocytoma, central gangliocytoma, primitive neuroectodermal tumors (PNET, e.g. medulloblastoma, medulloepithelioma, neuroblastoma, retinoblastoma, ependymoblastoma), tumors of the pineal parenchyma (e.g. pineocytoma, pineoblastoma), ependymal cell tumors, choroid plexus tumors, neuroepithelial tumors of uncertain origin (e.g. gliomatosis cerebri, astroblastoma), glioblastoma prostate tumor, breast cancer, esophageal cancer, colorectal cancer, clear cell renal cell carcinoma, lung cancer, CNS, ovarian, melanoma pancreatic cancer, squamous cell carcinoma, leukemia medulloblastoma, colon, rectum, stomach, kidney, lung, pancreas, prostate, skin and other tumors which show an overexpression of PTPRZ1, BCAN, and/or FABP7 and/or another protein from which a peptide of SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129 is derived from. 18. A kit comprising:
(a) a container comprising a pharmaceutical composition containing the peptide or variant peptide according to claim 1 in solution or in lyophilized form; (b) optionally, a second container containing a diluent or reconstituting solution for the lyophilized formulation; (c) optionally, at least one more peptide selected from the group consisting of SEQ ID No. 1 to SEQ ID No. 131, and (d) optionally, instructions for (i) use of the solution or (ii) reconstitution and/or use of the lyophilized formulation. 19. The kit according to claim 18, further comprising one or more of (iii) a buffer, (iv) a diluent, (v) a filter, (vi) a needle, or (v) a syringe. 20. The kit according to claim 18, wherein said peptide or variant peptide is selected from the group consisting of SEQ ID No. 1 to SEQ ID No. 19, SEQ ID No. 42 to 44, SEQ ID 50 to SEQ ID 65 and SEQ IDs No. 71 to SEQ ID 88. 21. A method for producing a personalized anti-cancer vaccine for an individual patient, said method comprising:
a) identifying tumor-associated peptides (TUMAPs) presented by a tumor sample from the individual patient; b) comparing the peptides as identified in a) with a warehouse of peptides that have been prescreened for immunogenicity and overpresentation in tumors as compared to corresponding normal tissue; c) selecting at least one peptide from the warehouse that correlates with a tumor-associated peptide identified in the patient; and d) manufacturing the personalized vaccine based on step c). 22. The method according to claim 21, wherein said TUMAPs are identified by:
a1) comparing expression data from the tumor sample to expression data from a sample of normal tissue corresponding to the tissue type of the tumor sample to identify proteins that are over-expressed or aberrantly expressed in the tumor sample; and a2) correlating the expression data with sequences of MHC ligands bound to MHC class I and/or class II molecules in the tumor sample to identify MHC ligands derived from proteins over-expressed or aberrantly expressed by the tumor. 23. The method according to claim 21, wherein the sequences of MHC ligands is identified by eluting bound peptides from MHC molecules isolated from the tumor sample, and sequencing the eluted ligands. 24. The method according to claim 21, wherein the normal tissue corresponding to the tissue type of the tumor sample is obtained from the patient. 25. The method according to claim 21, wherein the peptide or variant peptide included in the warehouse is identified according to:
a. HLA ligands from the malignant material are identified by mass spectrometry; b. Genome-wide messenger ribonucleic acid (mRNA) expression analysis by microarrays is used to identify genes over-expressed in the malignant tissue (GBM) compared with a range of normal organs and tissues; c. The identified HLA ligands are compared to gene expression data; d. Peptides encoded by selectively expressed or over-expressed genes as detected in step b are selected; e. the relevance of over-expression at the mRNA level is confirmed by redetection of selected TUMAPs from step c on tumor tissue and lack of or infrequent detection on healthy tissues; and f. To assess whether an induction of in vivo T-cell responses by the selected peptides is feasible, in vitro immunogenicity assays will performed using human T cells from healthy donors or the patient. 26. The method according to claim 21, wherein the immunogenicity of the peptide or variant peptide included in the warehouse is determined by a method comprising in vitro immunogenicity assays, patient immunomonitoring for individual HLA binding, MHC multimer staining, ELISPOT assays and/or intracellular cytokine staining. 27. The method according to claim 21, wherein said warehouse comprises a plurality of peptides or variant peptides selected from the group consisting of SEQ ID No 1 to SEQ ID No 131. 28. The method according to claim 21, further comprising d) identifying at least one mutation that is unique to the tumor sample relative to normal corresponding tissue from the individual patient, and selecting a peptide for inclusion in the vaccine that correlates with the mutation. 29. The method of claim 28, wherein said at least one mutation is identified by whole genome sequencing. 30. A T-cell receptor that is reactive with an HLA ligand having at least 80% identity to an amino acid sequence selected from the group consisting SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129. 31. The T-cell receptor according to claim 30, wherein said amino acid sequence is to least 90%, or to at least 95% identical to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129. 32. The T-cell receptor according to claim 30, wherein said amino acid sequence comprises any SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129. 33. The T-cell receptor according to claim 30, wherein said amino acid sequence consists of any of SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129. 34. A fusion protein, comprising
(a) an amino acid sequence that is to at least 80% identical to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129; and (b) N-terminal amino acids 1-80 of HLA-DR antigen-associated invariant chain (Ii). 35. The fusion protein according to claim 34, wherein said amino acid sequence of (a) is at least 90%, optionally at least 95% identical to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129. 36. The fusion protein according to claim 35, wherein said amino acid sequence of (a) comprises SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129. 37. A nucleic acid, encoding for:
(a) the peptide or variant peptide according to claim 1; (b) a T cell receptor that is reactive with an HLA ligand having at least 80% identity to an amino acid sequence selected from the group consisting SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129; or (c) a fusion protein comprising (a) an amino acid sequence that is to at least 80% identical to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129; and (b) N-terminal amino acids 1-80 of HLA-DR antigen-associated invariant chain (Ii). 38. The nucleic acid according to claim 37, which is DNA, cDNA, PNA, RNA, or combinations thereof. 39. An expression vector comprising a nucleic acid according to claim 37. 40. A host cell comprising the nucleic acid according to claim 37, or an expression vector thereof. 41. The host cell according to claim 40 that is an antigen presenting cell, optionally a dendritic cell. 42. A method for producing (a) the peptide or variant peptide according to claim 1; or
(b) the T cell receptor that is reactive with an HLA ligand having at least 80% identity to an amino acid sequence selected from the group consisting SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129 or (c) a fusion protein comprising: an amino acid sequence that is to at least 80% identical to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129; and N-terminal amino acids 1-80 of HLA-DR antigen-associated invariant chain (Ii), said method comprising culturing a host cell, and isolating said peptide or variant peptide, said T cell receptor, or said fusion protein from said host cell and/or culture medium. 43. An in vitro method for producing activated cytotoxic T lymphocytes (CTL), the method comprising contacting in vitro a CTL with antigen loaded human class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell for a period of time sufficient to activate said CTL in an antigen specific manner, wherein said antigen is said peptide or variant peptide according to claim 1. 44. The method according to claim 43, wherein said antigen is loaded onto class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell by contacting a sufficient amount of the antigen with an antigen-presenting cell. 45. The method according to claim 44, wherein said antigen-presenting cell comprises an expression vector capable of expressing said peptide or variant peptide according to claim 1. 46. An activated cytotoxic T lymphocyte (CTL), produced by the method according to claim 44. 47. A method of killing target cancer cells in a patient, the method comprising administering to said patient an effective number of cytotoxic T lymphocytes (CTL) according to claim 46. 48. A peptide or variant peptide according to claim 1, a T cell receptor that is reactive with an HLA ligand having at least 80% identity to an amino acid sequence selected from the group consisting SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129, a fusion protein comprising: an amino acid sequence that is to at least 80% identical to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129; and
N-terminal amino acids 1-80 of HLA-DR antigen-associated invariant chain (Ii), a nucleic acid, an expression vector a host cell, or an activated cytotoxic T lymphocyte capable of being used as a medicament, and/or in the manufacture of a medicament. | The present invention relates to peptides, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated cytotoxic T cell (CTL) peptide epitopes, alone or in combination with other tumor-associated peptides that serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses. The present invention relates to peptide sequences and their variants derived from HLA class I and class II molecules of human tumor cells that can be used in vaccine compositions for eliciting anti-tumor immune responses.1. A peptide or a variant peptide comprising an amino acid sequence selected from the group consisting of SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129, and variant sequences thereof which are at least 90% homologous to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129, and wherein a variant induces T cells cross-reacting with said variant peptide; and/or a pharmaceutical acceptable salt thereof, wherein said peptide is not a full-length polypeptide. 2. The peptide or variant peptide according to claim 1, wherein said peptide or variant peptide maintains an ability to bind to a molecule of the human major histocompatibility complex (MHC) class-I or -II, and wherein said peptide or variant peptide is capable of stimulating CD4 and/or CD8 T cells. 3. The peptide or variant peptide according to claim 1, wherein the amino acid sequence thereof comprises a continuous stretch of amino acids according the group of SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129. 4. The peptide or variant peptide according to claim 1, wherein said peptide or variant thereof has an overall length of from 8 to 100, optionally from 8 to 30, and/or optionally from 8 to 16 amino acids, and/or optionally wherein the peptide consists or consists essentially of an amino acid sequence according to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129. 5. The peptide or variant peptide according to claim 1, wherein said peptide or variant peptide is modified and/or includes non-peptide bonds. 6. The peptide or variant peptide according to claim 1, wherein said peptide or variant peptide is part of a fusion protein, optionally comprising N-terminal amino acids of the HLA-DR antigen-associated invariant chain (Ii). 7. A nucleic acid, encoding a peptide or variant peptide according to claim 1, optionally linked to a heterologous promoter sequence. 8. An expression vector capable of expressing the nucleic acid according to claim 7. 9. The peptide or variant peptide according to claim 1, capable of being used in medicine. 10. A host cell comprising the nucleic acid according to claim 7, wherein said host cell optionally is an antigen presenting cell or a dendritic cell. 11. A method for producing the peptide or variant peptide according to claim 1, the method comprising culturing a host cell that expresses a nucleic acid or an expression vector, and isolating the peptide or variant peptide from the host cell or a culture medium. 12. An in vitro method for producing activated cytotoxic T lymphocytes (CTL), the method comprising contacting in vitro CTL with antigen loaded human class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell or an artificial construct mimicking an antigen-presenting cell for a period of time sufficient to activate said CTL in an antigen specific manner, wherein said antigen is a peptide or variant according to claim 1. 13. An activated cytotoxic T lymphocyte (CTL), produced by an in vitro method for producing activated cytotoxic T lymphocytes (CTL), the method comprising contacting in vitro CTL with antigen loaded human class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell or an artificial construct mimicking an antigen-presenting cell for a period of time sufficient to activate said CTL in an antigen specific manner that selectively recognises a cell which aberrantly expresses a polypeptide comprising an amino acid sequence of a peptide or variant peptide of claim 1. 14. A method for killing target cells in a patient which target cells aberrantly express a polypeptide comprising an amino acid sequence of a peptide or variant peptide of claim 1, the method comprising administering to the patient an effective number of cytotoxic T lymphocytes (CTL). 15. An antibody that specifically recognizes the peptide or variant peptide according to claim 1 optionally wherein the peptide or variant peptide is bound to an MHC molecule. 16. A peptide or variant peptide according to claim 1, capable of being used for treatment of cancer or in the manufacture of a medicament against cancer, wherein said medicament optionally is a vaccine. 17. The peptide or variant peptide according to claim 16, wherein said cancer is selected from astrocytoma, pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor, oligodendrogliomas, ependymoma, glioblastoma multiforme, mixed gliomas, oligoastrocytomas, medulloblastoma, retinoblastoma, neuroblastoma, germinoma, teratoma, gangliogliomas, gangliocytoma, central gangliocytoma, primitive neuroectodermal tumors (PNET, e.g. medulloblastoma, medulloepithelioma, neuroblastoma, retinoblastoma, ependymoblastoma), tumors of the pineal parenchyma (e.g. pineocytoma, pineoblastoma), ependymal cell tumors, choroid plexus tumors, neuroepithelial tumors of uncertain origin (e.g. gliomatosis cerebri, astroblastoma), glioblastoma prostate tumor, breast cancer, esophageal cancer, colorectal cancer, clear cell renal cell carcinoma, lung cancer, CNS, ovarian, melanoma pancreatic cancer, squamous cell carcinoma, leukemia medulloblastoma, colon, rectum, stomach, kidney, lung, pancreas, prostate, skin and other tumors which show an overexpression of PTPRZ1, BCAN, and/or FABP7 and/or another protein from which a peptide of SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129 is derived from. 18. A kit comprising:
(a) a container comprising a pharmaceutical composition containing the peptide or variant peptide according to claim 1 in solution or in lyophilized form; (b) optionally, a second container containing a diluent or reconstituting solution for the lyophilized formulation; (c) optionally, at least one more peptide selected from the group consisting of SEQ ID No. 1 to SEQ ID No. 131, and (d) optionally, instructions for (i) use of the solution or (ii) reconstitution and/or use of the lyophilized formulation. 19. The kit according to claim 18, further comprising one or more of (iii) a buffer, (iv) a diluent, (v) a filter, (vi) a needle, or (v) a syringe. 20. The kit according to claim 18, wherein said peptide or variant peptide is selected from the group consisting of SEQ ID No. 1 to SEQ ID No. 19, SEQ ID No. 42 to 44, SEQ ID 50 to SEQ ID 65 and SEQ IDs No. 71 to SEQ ID 88. 21. A method for producing a personalized anti-cancer vaccine for an individual patient, said method comprising:
a) identifying tumor-associated peptides (TUMAPs) presented by a tumor sample from the individual patient; b) comparing the peptides as identified in a) with a warehouse of peptides that have been prescreened for immunogenicity and overpresentation in tumors as compared to corresponding normal tissue; c) selecting at least one peptide from the warehouse that correlates with a tumor-associated peptide identified in the patient; and d) manufacturing the personalized vaccine based on step c). 22. The method according to claim 21, wherein said TUMAPs are identified by:
a1) comparing expression data from the tumor sample to expression data from a sample of normal tissue corresponding to the tissue type of the tumor sample to identify proteins that are over-expressed or aberrantly expressed in the tumor sample; and a2) correlating the expression data with sequences of MHC ligands bound to MHC class I and/or class II molecules in the tumor sample to identify MHC ligands derived from proteins over-expressed or aberrantly expressed by the tumor. 23. The method according to claim 21, wherein the sequences of MHC ligands is identified by eluting bound peptides from MHC molecules isolated from the tumor sample, and sequencing the eluted ligands. 24. The method according to claim 21, wherein the normal tissue corresponding to the tissue type of the tumor sample is obtained from the patient. 25. The method according to claim 21, wherein the peptide or variant peptide included in the warehouse is identified according to:
a. HLA ligands from the malignant material are identified by mass spectrometry; b. Genome-wide messenger ribonucleic acid (mRNA) expression analysis by microarrays is used to identify genes over-expressed in the malignant tissue (GBM) compared with a range of normal organs and tissues; c. The identified HLA ligands are compared to gene expression data; d. Peptides encoded by selectively expressed or over-expressed genes as detected in step b are selected; e. the relevance of over-expression at the mRNA level is confirmed by redetection of selected TUMAPs from step c on tumor tissue and lack of or infrequent detection on healthy tissues; and f. To assess whether an induction of in vivo T-cell responses by the selected peptides is feasible, in vitro immunogenicity assays will performed using human T cells from healthy donors or the patient. 26. The method according to claim 21, wherein the immunogenicity of the peptide or variant peptide included in the warehouse is determined by a method comprising in vitro immunogenicity assays, patient immunomonitoring for individual HLA binding, MHC multimer staining, ELISPOT assays and/or intracellular cytokine staining. 27. The method according to claim 21, wherein said warehouse comprises a plurality of peptides or variant peptides selected from the group consisting of SEQ ID No 1 to SEQ ID No 131. 28. The method according to claim 21, further comprising d) identifying at least one mutation that is unique to the tumor sample relative to normal corresponding tissue from the individual patient, and selecting a peptide for inclusion in the vaccine that correlates with the mutation. 29. The method of claim 28, wherein said at least one mutation is identified by whole genome sequencing. 30. A T-cell receptor that is reactive with an HLA ligand having at least 80% identity to an amino acid sequence selected from the group consisting SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129. 31. The T-cell receptor according to claim 30, wherein said amino acid sequence is to least 90%, or to at least 95% identical to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129. 32. The T-cell receptor according to claim 30, wherein said amino acid sequence comprises any SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129. 33. The T-cell receptor according to claim 30, wherein said amino acid sequence consists of any of SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129. 34. A fusion protein, comprising
(a) an amino acid sequence that is to at least 80% identical to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129; and (b) N-terminal amino acids 1-80 of HLA-DR antigen-associated invariant chain (Ii). 35. The fusion protein according to claim 34, wherein said amino acid sequence of (a) is at least 90%, optionally at least 95% identical to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129. 36. The fusion protein according to claim 35, wherein said amino acid sequence of (a) comprises SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129. 37. A nucleic acid, encoding for:
(a) the peptide or variant peptide according to claim 1; (b) a T cell receptor that is reactive with an HLA ligand having at least 80% identity to an amino acid sequence selected from the group consisting SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129; or (c) a fusion protein comprising (a) an amino acid sequence that is to at least 80% identical to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129; and (b) N-terminal amino acids 1-80 of HLA-DR antigen-associated invariant chain (Ii). 38. The nucleic acid according to claim 37, which is DNA, cDNA, PNA, RNA, or combinations thereof. 39. An expression vector comprising a nucleic acid according to claim 37. 40. A host cell comprising the nucleic acid according to claim 37, or an expression vector thereof. 41. The host cell according to claim 40 that is an antigen presenting cell, optionally a dendritic cell. 42. A method for producing (a) the peptide or variant peptide according to claim 1; or
(b) the T cell receptor that is reactive with an HLA ligand having at least 80% identity to an amino acid sequence selected from the group consisting SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129 or (c) a fusion protein comprising: an amino acid sequence that is to at least 80% identical to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129; and N-terminal amino acids 1-80 of HLA-DR antigen-associated invariant chain (Ii), said method comprising culturing a host cell, and isolating said peptide or variant peptide, said T cell receptor, or said fusion protein from said host cell and/or culture medium. 43. An in vitro method for producing activated cytotoxic T lymphocytes (CTL), the method comprising contacting in vitro a CTL with antigen loaded human class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell for a period of time sufficient to activate said CTL in an antigen specific manner, wherein said antigen is said peptide or variant peptide according to claim 1. 44. The method according to claim 43, wherein said antigen is loaded onto class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell by contacting a sufficient amount of the antigen with an antigen-presenting cell. 45. The method according to claim 44, wherein said antigen-presenting cell comprises an expression vector capable of expressing said peptide or variant peptide according to claim 1. 46. An activated cytotoxic T lymphocyte (CTL), produced by the method according to claim 44. 47. A method of killing target cancer cells in a patient, the method comprising administering to said patient an effective number of cytotoxic T lymphocytes (CTL) according to claim 46. 48. A peptide or variant peptide according to claim 1, a T cell receptor that is reactive with an HLA ligand having at least 80% identity to an amino acid sequence selected from the group consisting SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129, a fusion protein comprising: an amino acid sequence that is to at least 80% identical to SEQ ID No. 1 to SEQ ID No. 49, SEQ ID No. 71, and SEQ ID No. 74 to 129; and
N-terminal amino acids 1-80 of HLA-DR antigen-associated invariant chain (Ii), a nucleic acid, an expression vector a host cell, or an activated cytotoxic T lymphocyte capable of being used as a medicament, and/or in the manufacture of a medicament. | 1,600 |
432 | 14,401,668 | 1,613 | An emulsion contains 50 to 90% by weight of an aqueous phase and 10 to 50% by weight of an oil phase containing 30 to 90% by weight of a diluent oil, and at least 10% by weight of at least one polyunsaturated fatty acid and/or derivative thereof. The emulsion has improved stability and/or organoleptic properties and can be used as a dietary supplement, particularly when packaged in a sachet or ‘stick shot’. | 1. An emulsion comprising;
(i) 50 to 90% by weight of an aqueous phase, and (ii) 10 to 50% by weight of an oil phase comprising (a) 30 to 90% by weight of a diluent oil, and (b) at least 10% by weight of at least one polyunsaturated fatty acid and/or derivative thereof. 2. The emulsion according to claim 1 wherein the oil phase comprises 10 to 70% by weight of a polyunsaturated fatty acid (PUFA) oil. 3. The emulsion according to claim 2 wherein the PUFA oil comprises greater than 35% by weight of omeqa-3 fatty acids and/or derivatives thereof. 4. The emulsion according to claim 2 wherein the PUFA oil comprises greater than 30% by weight of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). 5. The emulsion according to claim 1 wherein the oil phase comprises 12 to 25% by weight of eicosapentaenoic acid (EPA) EPA and docosahexaenoic acid (DHA). 6. The emulsion according to claim 2 wherein the PUFA oil comprises less than 20% by weight of saturated fatty acids and/or derivatives thereof having 10 to 24 carbon atoms. 7. The emulsion according to claim 1 wherein the diluent oil comprises substantially no hydrocarbyl groups comprising more than 16 carbon atoms. 8. The emulsion according to claim 1 additionally comprising less than 4% by weight of at least one emulsifier. 9. The emulsion according to claim 8 wherein the emulsifier is an alkoxylated sorbitan ester. 10. The emulsion according to claim 1 additionally comprising less than 7% by weight of at least one stabiliser. 11. The emulsion according to claim 10 wherein the stabiliser is guar gum and/or xanthan gum. 12. The emulsion according to claim 1 comprising capric/caprylic triglyceride, concentrated fish oil, alkoxylated sorbitan ester, guar gum and xanthan gum, and optionally xylitol and/or lemon oil. 13. The emulsion according to claim 8 wherein the emulsifier is acacia gum. 14. A dietary supplement comprising the emulsion defined in claim 1 packaged in a container. 15. A dietary supplement comprising an emulsion, wherein the emulsion comprises (i) 50 to 90% by weight of an aqueous phase, and (ii) 10 to 50% by weight of an oil phase comprising (a) 30 to 90% by weight of a diluent oil, and (b) at least 10% by weight of at least one polyunsaturated fatty acid and/or derivative thereof. 16. The dietary supplement according to claim 14 wherein the emulsion is packaged in a sachet or ‘stick shot’. | An emulsion contains 50 to 90% by weight of an aqueous phase and 10 to 50% by weight of an oil phase containing 30 to 90% by weight of a diluent oil, and at least 10% by weight of at least one polyunsaturated fatty acid and/or derivative thereof. The emulsion has improved stability and/or organoleptic properties and can be used as a dietary supplement, particularly when packaged in a sachet or ‘stick shot’.1. An emulsion comprising;
(i) 50 to 90% by weight of an aqueous phase, and (ii) 10 to 50% by weight of an oil phase comprising (a) 30 to 90% by weight of a diluent oil, and (b) at least 10% by weight of at least one polyunsaturated fatty acid and/or derivative thereof. 2. The emulsion according to claim 1 wherein the oil phase comprises 10 to 70% by weight of a polyunsaturated fatty acid (PUFA) oil. 3. The emulsion according to claim 2 wherein the PUFA oil comprises greater than 35% by weight of omeqa-3 fatty acids and/or derivatives thereof. 4. The emulsion according to claim 2 wherein the PUFA oil comprises greater than 30% by weight of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). 5. The emulsion according to claim 1 wherein the oil phase comprises 12 to 25% by weight of eicosapentaenoic acid (EPA) EPA and docosahexaenoic acid (DHA). 6. The emulsion according to claim 2 wherein the PUFA oil comprises less than 20% by weight of saturated fatty acids and/or derivatives thereof having 10 to 24 carbon atoms. 7. The emulsion according to claim 1 wherein the diluent oil comprises substantially no hydrocarbyl groups comprising more than 16 carbon atoms. 8. The emulsion according to claim 1 additionally comprising less than 4% by weight of at least one emulsifier. 9. The emulsion according to claim 8 wherein the emulsifier is an alkoxylated sorbitan ester. 10. The emulsion according to claim 1 additionally comprising less than 7% by weight of at least one stabiliser. 11. The emulsion according to claim 10 wherein the stabiliser is guar gum and/or xanthan gum. 12. The emulsion according to claim 1 comprising capric/caprylic triglyceride, concentrated fish oil, alkoxylated sorbitan ester, guar gum and xanthan gum, and optionally xylitol and/or lemon oil. 13. The emulsion according to claim 8 wherein the emulsifier is acacia gum. 14. A dietary supplement comprising the emulsion defined in claim 1 packaged in a container. 15. A dietary supplement comprising an emulsion, wherein the emulsion comprises (i) 50 to 90% by weight of an aqueous phase, and (ii) 10 to 50% by weight of an oil phase comprising (a) 30 to 90% by weight of a diluent oil, and (b) at least 10% by weight of at least one polyunsaturated fatty acid and/or derivative thereof. 16. The dietary supplement according to claim 14 wherein the emulsion is packaged in a sachet or ‘stick shot’. | 1,600 |
433 | 15,008,865 | 1,629 | Agents containing (A) cystine or a derivative thereof and (B) theanine, in combination, are useful for reducing side effects of cancer chemotherapy, can reduce various side effects of cancer chemotherapy, and can improve the treatment completion rate of cancer chemotherapy. | 1. An agent for reducing side effects of cancer chemotherapy, comprising:
(A) cystine or a derivative thereof; and (B) theanine,
in combination. 2. The agent according to claim 1, which is a composition comprising (A) cystine or a derivative thereof and (B) theanine. 3. The agent according to claim 1, wherein the weight ratio of (A) said cystine or a derivative thereof and (B) said theanine is A:B=100:1 to 1:100. 4. The agent according to claim 1, which is an agent for improving the treatment completion rate of cancer chemotherapy. 5. A prophylactic and/or therapeutic drug for cancer, comprising an agent according to claim 1 and at least one anticancer agent in combination. 6. A method of reducing side effects of cancer chemotherapy, comprising administering an effective amount of an agent according to claim 1 to a subject in need thereof. 7. A method of improving the treatment completion rate of cancer chemotherapy, comprising administering an effective amount of an agent according to claim 4 to a subject in need thereof. 8. A method of preventing and/or treating cancer, comprising administering an effective amount of a prophylactic and/or therapeutic drug according to claim 5 to a subject in need thereof. 9. A combination of (A) cystine or a derivative thereof and (B) theanine for use in reducing side effects of cancer chemotherapy. 10. The combination according to claim 9 for use in improving the treatment completion rate of cancer chemotherapy. 11. A combination of the combination according to claim 9 and at least one anticancer agent for use in preventing and/or treating cancer. | Agents containing (A) cystine or a derivative thereof and (B) theanine, in combination, are useful for reducing side effects of cancer chemotherapy, can reduce various side effects of cancer chemotherapy, and can improve the treatment completion rate of cancer chemotherapy.1. An agent for reducing side effects of cancer chemotherapy, comprising:
(A) cystine or a derivative thereof; and (B) theanine,
in combination. 2. The agent according to claim 1, which is a composition comprising (A) cystine or a derivative thereof and (B) theanine. 3. The agent according to claim 1, wherein the weight ratio of (A) said cystine or a derivative thereof and (B) said theanine is A:B=100:1 to 1:100. 4. The agent according to claim 1, which is an agent for improving the treatment completion rate of cancer chemotherapy. 5. A prophylactic and/or therapeutic drug for cancer, comprising an agent according to claim 1 and at least one anticancer agent in combination. 6. A method of reducing side effects of cancer chemotherapy, comprising administering an effective amount of an agent according to claim 1 to a subject in need thereof. 7. A method of improving the treatment completion rate of cancer chemotherapy, comprising administering an effective amount of an agent according to claim 4 to a subject in need thereof. 8. A method of preventing and/or treating cancer, comprising administering an effective amount of a prophylactic and/or therapeutic drug according to claim 5 to a subject in need thereof. 9. A combination of (A) cystine or a derivative thereof and (B) theanine for use in reducing side effects of cancer chemotherapy. 10. The combination according to claim 9 for use in improving the treatment completion rate of cancer chemotherapy. 11. A combination of the combination according to claim 9 and at least one anticancer agent for use in preventing and/or treating cancer. | 1,600 |
434 | 10,830,001 | 1,616 | A cosmetic or dermatological cleansing emulsion having a viscosity of from about 500 to about 3,500 mPas and comprising sodium laureth sulfate and/or sodium myreth sulfate, a polyacrylate, a paraffin oil, and an oil having a polarity of about 5 to about 50 mN/m. This abstract is neither intended to define the invention disclosed in this specification nor intended to limit the scope of the invention in any way. | 1. A cosmetic or dermatological cleansing emulsion comprising:
(a) from about 2% to about 17% by weight of at least one of sodium laureth sulfate and sodium myreth sulfate; (b) from about 0.20% to about 0.74% by weight of one or more polyacrylates selected from anionic homopolymers and anionic copolymers of at least one of acrylic acid, an alkylated acrylic acid and esters thereof; (c) from about 42% to about 51% by weight an oil phase comprising
(i) from about 25% to about 50% by weight of a paraffin oil,
(ii) from about 0.5% to about 25% by weight one or more oils having a polarity of from about 5 to about 50 mN/m;
the emulsion having a viscosity of from about 500 to about 3,500 mPa s at 100 s−1. 2. The emulsion of claim 1, wherein the emulsion comprises from about 4% to about 15% by weight of (a). 3. The emulsion of claim 2, wherein the emulsion comprises at least about 5% by weight of (a). 4. The emulsion of claim 2, wherein the emulsion comprises not more than about 10% by weight of (a). 5. The emulsion of claim 2, wherein the emulsion comprises sodium laureth sulfate. 6. The emulsion of claim 1, wherein the emulsion comprises sodium myreth sulfate. 7. The emulsion of claim 1, wherein the emulsion comprises from about 0.30% to about 0.70% by weight of (b). 8. The emulsion of claim 1, wherein the emulsion comprises at least about 0.35% by weight of (b). 9. The emulsion of claim 1, wherein the emulsion comprises from about 43% to about 46% by weight of (c). 10. The emulsion of claim 1, wherein the emulsion comprises at least about 43% by weight of (c). 11. The emulsion of claim 10, wherein the emulsion comprises not more than about 45.5% by weight of (c). 12. The emulsion of claim 9, wherein the emulsion comprises from about 30% to about 45% by weight of (c)(i). 13. The emulsion of claim 9, wherein the emulsion comprises from about 5% to about 20% by weight of (c)(ii). 14. The emulsion of claim 1, wherein the emulsion comprises at least about 1% by weight of (c)(ii). 15. The emulsion of claim 13, wherein (c)(ii) has a polarity of from about 10 to about 45 mN/m. 16. The emulsion of claim 1, wherein (c)(ii) comprises at least one fatty acid triglyceride. 17. The emulsion of claim 16, wherein the fatty acid triglyceride comprises at least one of soybean oil and almond oil. 18. The emulsion of claim 12, wherein (c)(ii) comprises at least one of a hydrocarbon, a fatty acid triglyceride, a silicone oil and a carboxylic acid ester. 19. The emulsion of claim 1, wherein the weight ratio (b): (c)(i) is from about 1:125 to about 1:68. 20. The emulsion of claim 12, wherein the weight ratio (b): (c)(i) is from about 1:100 to about 1:57. 21. The emulsion of claim 1, wherein the emulsion has a viscosity of from about 700 to about 3,000 mPa s at 100 s−1. 22. The emulsion of claim 1, wherein the emulsion further comprises at least one surfactant. 23. The emulsion of claim 22, wherein the at least one surfactant comprises a surfactant having an HLB value of higher than about 25. 24. The emulsion of claim 22, wherein the at least one surfactant comprises a surfactant having an HLB value of higher than about 35. 25. The emulsion of claim 22, wherein the emulsion comprises from about 1% to about 30% by weight of the at least one surfactant. 26. The emulsion of claim 1, wherein the emulsion further comprises at least one active ingredient. 27. The emulsion of claim 26, wherein the at least one active ingredient is present in a concentration of from about 0.001% to about 10% by weight. 28. A cosmetic or dermatological cleansing emulsion comprising:
(a) from about 5% to about 10% by weight of at least one of sodium laureth sulfate and sodium myreth sulfate; (b) from about 0.30% to about 0.70% by weight of one or more polyacrylates selected from anionic homopolymers and anionic copolymers of at least one of acrylic acid, an alkylated acrylic acid and esters thereof; (c) from about 43% to about 46% by weight an oil phase comprising
(i) from about 30% to about 45% by weight of a paraffin oil,
(ii) from about 5% to about 20% by weight of one or more oils having a polarity of from about 10 to about 45 mN/m;
the emulsion having a viscosity of from about 700 to about 3,000 mPa s at 100 s−1. 29. The emulsion of claim 28, wherein the emulsion comprises sodium laureth sulfate. 30. The emulsion of claim 28, wherein the emulsion comprises sodium myreth sulfate. 31. The emulsion of claim 28, wherein the emulsion comprises at least about 0.35% by weight of (b). 32. The emulsion of claim 31, wherein the emulsion comprises not more than about 45.5% by weight of (c). 33. The emulsion of claim 31, wherein (c)(ii) comprises at least one of soybean oil and almond oil. 34. The emulsion of claim 32, wherein the weight ratio (b): (c)(i) is from about 1:100 to about 1:57. 35. The emulsion of claim 28, wherein the emulsion further comprises from about 10% to about 20% by weight of at least one surfactant having an HLB value of higher than about 25. 36. The emulsion of claim 35, wherein the emulsion further comprises from about 0.05% to about 10% by weight of at least one active ingredient. 37. A foamed mousse which comprises the emulsion of claim 1. 38. A compressed gas bottle which comprises the emulsion of claim 1. 39. An aerosol container which comprises the emulsion of claim 1. 40. A foam bath which comprises the emulsion of claim 1. 41. A shower bath which comprises the emulsion of claim 1. 42. A tub bath which comprises the emulsion of claim 1. 43. A face cleanser which comprises the emulsion of claim 1. 44. A hair shampoo which comprises the emulsion of claim 1. 45. A method of cleansing the skin and its appendages, wherein the method comprises the application of a product which comprises the emulsion of claim 1 onto at least parts of the skin. 46. A process for making a cosmetic or dermatological cleansing emulsion, which process comprises combining
(a) from about 2% to about 17% by weight of at least one of sodium laureth sulfate and sodium myreth sulfate; (b) from about 0.20% to about 0.74% by weight of one or more polyacrylates selected from anionic homopolymers and anionic copolymers of at least one of acrylic acid, an alkylated acrylic acid and esters thereof; (c) from about 42% to about 51% by weight an oil phase comprising
(i) from about 25% to about 50% by weight of a paraffin oil,
(ii) from about 0.5% to about 25% by weight one or more oils having a polarity of from about 5 to about 50 mN/m;
to form an emulsion having a viscosity of from about 500 to about 3,500 mPa s at 100 s−1. | A cosmetic or dermatological cleansing emulsion having a viscosity of from about 500 to about 3,500 mPas and comprising sodium laureth sulfate and/or sodium myreth sulfate, a polyacrylate, a paraffin oil, and an oil having a polarity of about 5 to about 50 mN/m. This abstract is neither intended to define the invention disclosed in this specification nor intended to limit the scope of the invention in any way.1. A cosmetic or dermatological cleansing emulsion comprising:
(a) from about 2% to about 17% by weight of at least one of sodium laureth sulfate and sodium myreth sulfate; (b) from about 0.20% to about 0.74% by weight of one or more polyacrylates selected from anionic homopolymers and anionic copolymers of at least one of acrylic acid, an alkylated acrylic acid and esters thereof; (c) from about 42% to about 51% by weight an oil phase comprising
(i) from about 25% to about 50% by weight of a paraffin oil,
(ii) from about 0.5% to about 25% by weight one or more oils having a polarity of from about 5 to about 50 mN/m;
the emulsion having a viscosity of from about 500 to about 3,500 mPa s at 100 s−1. 2. The emulsion of claim 1, wherein the emulsion comprises from about 4% to about 15% by weight of (a). 3. The emulsion of claim 2, wherein the emulsion comprises at least about 5% by weight of (a). 4. The emulsion of claim 2, wherein the emulsion comprises not more than about 10% by weight of (a). 5. The emulsion of claim 2, wherein the emulsion comprises sodium laureth sulfate. 6. The emulsion of claim 1, wherein the emulsion comprises sodium myreth sulfate. 7. The emulsion of claim 1, wherein the emulsion comprises from about 0.30% to about 0.70% by weight of (b). 8. The emulsion of claim 1, wherein the emulsion comprises at least about 0.35% by weight of (b). 9. The emulsion of claim 1, wherein the emulsion comprises from about 43% to about 46% by weight of (c). 10. The emulsion of claim 1, wherein the emulsion comprises at least about 43% by weight of (c). 11. The emulsion of claim 10, wherein the emulsion comprises not more than about 45.5% by weight of (c). 12. The emulsion of claim 9, wherein the emulsion comprises from about 30% to about 45% by weight of (c)(i). 13. The emulsion of claim 9, wherein the emulsion comprises from about 5% to about 20% by weight of (c)(ii). 14. The emulsion of claim 1, wherein the emulsion comprises at least about 1% by weight of (c)(ii). 15. The emulsion of claim 13, wherein (c)(ii) has a polarity of from about 10 to about 45 mN/m. 16. The emulsion of claim 1, wherein (c)(ii) comprises at least one fatty acid triglyceride. 17. The emulsion of claim 16, wherein the fatty acid triglyceride comprises at least one of soybean oil and almond oil. 18. The emulsion of claim 12, wherein (c)(ii) comprises at least one of a hydrocarbon, a fatty acid triglyceride, a silicone oil and a carboxylic acid ester. 19. The emulsion of claim 1, wherein the weight ratio (b): (c)(i) is from about 1:125 to about 1:68. 20. The emulsion of claim 12, wherein the weight ratio (b): (c)(i) is from about 1:100 to about 1:57. 21. The emulsion of claim 1, wherein the emulsion has a viscosity of from about 700 to about 3,000 mPa s at 100 s−1. 22. The emulsion of claim 1, wherein the emulsion further comprises at least one surfactant. 23. The emulsion of claim 22, wherein the at least one surfactant comprises a surfactant having an HLB value of higher than about 25. 24. The emulsion of claim 22, wherein the at least one surfactant comprises a surfactant having an HLB value of higher than about 35. 25. The emulsion of claim 22, wherein the emulsion comprises from about 1% to about 30% by weight of the at least one surfactant. 26. The emulsion of claim 1, wherein the emulsion further comprises at least one active ingredient. 27. The emulsion of claim 26, wherein the at least one active ingredient is present in a concentration of from about 0.001% to about 10% by weight. 28. A cosmetic or dermatological cleansing emulsion comprising:
(a) from about 5% to about 10% by weight of at least one of sodium laureth sulfate and sodium myreth sulfate; (b) from about 0.30% to about 0.70% by weight of one or more polyacrylates selected from anionic homopolymers and anionic copolymers of at least one of acrylic acid, an alkylated acrylic acid and esters thereof; (c) from about 43% to about 46% by weight an oil phase comprising
(i) from about 30% to about 45% by weight of a paraffin oil,
(ii) from about 5% to about 20% by weight of one or more oils having a polarity of from about 10 to about 45 mN/m;
the emulsion having a viscosity of from about 700 to about 3,000 mPa s at 100 s−1. 29. The emulsion of claim 28, wherein the emulsion comprises sodium laureth sulfate. 30. The emulsion of claim 28, wherein the emulsion comprises sodium myreth sulfate. 31. The emulsion of claim 28, wherein the emulsion comprises at least about 0.35% by weight of (b). 32. The emulsion of claim 31, wherein the emulsion comprises not more than about 45.5% by weight of (c). 33. The emulsion of claim 31, wherein (c)(ii) comprises at least one of soybean oil and almond oil. 34. The emulsion of claim 32, wherein the weight ratio (b): (c)(i) is from about 1:100 to about 1:57. 35. The emulsion of claim 28, wherein the emulsion further comprises from about 10% to about 20% by weight of at least one surfactant having an HLB value of higher than about 25. 36. The emulsion of claim 35, wherein the emulsion further comprises from about 0.05% to about 10% by weight of at least one active ingredient. 37. A foamed mousse which comprises the emulsion of claim 1. 38. A compressed gas bottle which comprises the emulsion of claim 1. 39. An aerosol container which comprises the emulsion of claim 1. 40. A foam bath which comprises the emulsion of claim 1. 41. A shower bath which comprises the emulsion of claim 1. 42. A tub bath which comprises the emulsion of claim 1. 43. A face cleanser which comprises the emulsion of claim 1. 44. A hair shampoo which comprises the emulsion of claim 1. 45. A method of cleansing the skin and its appendages, wherein the method comprises the application of a product which comprises the emulsion of claim 1 onto at least parts of the skin. 46. A process for making a cosmetic or dermatological cleansing emulsion, which process comprises combining
(a) from about 2% to about 17% by weight of at least one of sodium laureth sulfate and sodium myreth sulfate; (b) from about 0.20% to about 0.74% by weight of one or more polyacrylates selected from anionic homopolymers and anionic copolymers of at least one of acrylic acid, an alkylated acrylic acid and esters thereof; (c) from about 42% to about 51% by weight an oil phase comprising
(i) from about 25% to about 50% by weight of a paraffin oil,
(ii) from about 0.5% to about 25% by weight one or more oils having a polarity of from about 5 to about 50 mN/m;
to form an emulsion having a viscosity of from about 500 to about 3,500 mPa s at 100 s−1. | 1,600 |
435 | 15,294,225 | 1,616 | Insecticidal compositions suitable for use in preparation of insecticidal liquid fertilizers are disclosed. The compositions include bifenthrin, a polymeric dispersant, a suspension agent, a freeze-thaw stabilizer, and optionally a preservative. | 1. An insecticidal composition comprising:
a) bifenthrin; b) a polymeric dispersant selected from the group consisting of polyacrylic acids, polymethacrylic acids, copolymers thereof, salts thereof, and combinations thereof; c) a suspension agent selected from the group consisting of attapulgite clay, fumed silica, and combinations thereof, d) a freeze-thaw stabilizer, and e) optionally, a preservative. 2. The composition of claim 1, wherein said polymeric dispersant is selected from the group consisting of polyacrylic acids, salts thereof, and combinations thereof. 3. The composition of claim 2, wherein said salt comprises a sodium salt. 4. The composition of claim 1, wherein said suspension agent is fumed silica. 5. A composition comprising:
a) from about 15% to about 30% of bifenthrin; b) from about 0.2% to about 20% of a polymeric dispersant selected from the group consisting of polyacrylic acids, polymethacrylic acids, copolymers thereof, salts thereof, and combinations thereof; c) from 0% to about 20% of a suspension agent selected from the group consisting of attapulgite clay, fumed silica, and combinations thereof; d) from about 1% to about 10% of a freeze-thaw stabilizer, and e) from 0% to about 1% of a preservative, wherein all % are % by weight based on the total weight of all components in the composition. 6. The composition of claim 5, wherein said polymeric dispersant is selected from the group consisting of polyacrylic acids, salts thereof, and combinations thereof. 7. The composition of claim 6, wherein said salt comprises a sodium salt. 8. The composition of claim 5, wherein said suspension agent is fumed silica. 9. The composition of claim 1 further comprising a liquid fertilizer. 10. The composition of claim 9, wherein said liquid fertilizer is aqueous-based. 11. The composition of claim 10, wherein said liquid fertilizer is present in a concentration of about 95.0% by weight to about 99.99% by weight based on the total weight of all components in the composition. 12. The composition of claim 11, wherein bifenthrin is present in about 0.75% to about 1.25%, the polymeric dispersant is present in about 0.1% to about 0.75%, and the suspension agent is present in about 0.05% to about 1.0% by weight based on the total weight of all components in the composition. 13. The composition of claim 1, further comprising at least one additive selected from the group consisting of surfactants, wetting agents, anti-foam agents, preservatives and biocides. 14. The composition of claim 5, further comprising at least one additive selected from the group consisting of surfactants, wetting agents, anti-foam agents, preservatives and biocides. 15. The composition of claim 12, further comprising at least one additive selected from the group consisting of freeze-thaw stabilizers, surfactants, wetting agents, anti-foam agents, preservatives and biocides. 16. The composition of claim 1, wherein said freeze-thaw stabilizer comprises ammonium sulfate. 17. The composition of claim 5, wherein said freeze-thaw stabilizer comprises ammonium sulfate. 18. The composition of claim 12, wherein said freeze-thaw stabilizer comprises ammonium sulfate. 19. The composition of claim 1, wherein said polymeric dispersant comprises a salt of polyacrylic acid, having an average molecular weight between about 1000 and about 100,000 Daltons. 20. The composition of claim 5, wherein said polymeric dispersant comprises a salt of polyacrylic acid, having an average molecular weight between about 1000 and about 100,000 Daltons. 21. The composition of claim 12, wherein said polymeric dispersant comprises a salt of polyacrylic acid, having an average molecular weight between about 1000 and about 100,000 Daltons. | Insecticidal compositions suitable for use in preparation of insecticidal liquid fertilizers are disclosed. The compositions include bifenthrin, a polymeric dispersant, a suspension agent, a freeze-thaw stabilizer, and optionally a preservative.1. An insecticidal composition comprising:
a) bifenthrin; b) a polymeric dispersant selected from the group consisting of polyacrylic acids, polymethacrylic acids, copolymers thereof, salts thereof, and combinations thereof; c) a suspension agent selected from the group consisting of attapulgite clay, fumed silica, and combinations thereof, d) a freeze-thaw stabilizer, and e) optionally, a preservative. 2. The composition of claim 1, wherein said polymeric dispersant is selected from the group consisting of polyacrylic acids, salts thereof, and combinations thereof. 3. The composition of claim 2, wherein said salt comprises a sodium salt. 4. The composition of claim 1, wherein said suspension agent is fumed silica. 5. A composition comprising:
a) from about 15% to about 30% of bifenthrin; b) from about 0.2% to about 20% of a polymeric dispersant selected from the group consisting of polyacrylic acids, polymethacrylic acids, copolymers thereof, salts thereof, and combinations thereof; c) from 0% to about 20% of a suspension agent selected from the group consisting of attapulgite clay, fumed silica, and combinations thereof; d) from about 1% to about 10% of a freeze-thaw stabilizer, and e) from 0% to about 1% of a preservative, wherein all % are % by weight based on the total weight of all components in the composition. 6. The composition of claim 5, wherein said polymeric dispersant is selected from the group consisting of polyacrylic acids, salts thereof, and combinations thereof. 7. The composition of claim 6, wherein said salt comprises a sodium salt. 8. The composition of claim 5, wherein said suspension agent is fumed silica. 9. The composition of claim 1 further comprising a liquid fertilizer. 10. The composition of claim 9, wherein said liquid fertilizer is aqueous-based. 11. The composition of claim 10, wherein said liquid fertilizer is present in a concentration of about 95.0% by weight to about 99.99% by weight based on the total weight of all components in the composition. 12. The composition of claim 11, wherein bifenthrin is present in about 0.75% to about 1.25%, the polymeric dispersant is present in about 0.1% to about 0.75%, and the suspension agent is present in about 0.05% to about 1.0% by weight based on the total weight of all components in the composition. 13. The composition of claim 1, further comprising at least one additive selected from the group consisting of surfactants, wetting agents, anti-foam agents, preservatives and biocides. 14. The composition of claim 5, further comprising at least one additive selected from the group consisting of surfactants, wetting agents, anti-foam agents, preservatives and biocides. 15. The composition of claim 12, further comprising at least one additive selected from the group consisting of freeze-thaw stabilizers, surfactants, wetting agents, anti-foam agents, preservatives and biocides. 16. The composition of claim 1, wherein said freeze-thaw stabilizer comprises ammonium sulfate. 17. The composition of claim 5, wherein said freeze-thaw stabilizer comprises ammonium sulfate. 18. The composition of claim 12, wherein said freeze-thaw stabilizer comprises ammonium sulfate. 19. The composition of claim 1, wherein said polymeric dispersant comprises a salt of polyacrylic acid, having an average molecular weight between about 1000 and about 100,000 Daltons. 20. The composition of claim 5, wherein said polymeric dispersant comprises a salt of polyacrylic acid, having an average molecular weight between about 1000 and about 100,000 Daltons. 21. The composition of claim 12, wherein said polymeric dispersant comprises a salt of polyacrylic acid, having an average molecular weight between about 1000 and about 100,000 Daltons. | 1,600 |
436 | 14,784,798 | 1,612 | A pharmaceutical composition is described that is suitable for delivery from a pressurised container. The composition is preferably free of polar excipients and comprises: (a) a propellant component that consists essentially of 1,1-difluoroethane (R-152a); (b) a surfactant component that comprises at least one surfactant compound other than oleic acid; and (c) a drug component that consists of salbutamol sulphate. The pharmaceutical composition can be delivered using a metered dose inhaler (MDI). | 1. A pharmaceutical composition that is free of polar excipients, said composition comprising:
(a) a propellant component consisting essentially of 1,1-difluoroethane (R-152a), (b) a surfactant component consisting entirely of at least one surfactant compound selected from the group consisting of polyvinylpyrrolidone and sorbitan monooleate; and (c) a drug component consisting of salbutamol sulphate. 2. The pharmaceutical composition of claim 1 which consists essentially of components (a), (b) and (c). 3. A pharmaceutical composition for delivery from a pressurised container, said composition consisting essentially of:
(a) a propellant component consisting essentially of 1,1-difluoroethane (R-152a), (b) a surfactant component consisting entirely of at least one surfactant compound selected from the group consisting of polyvinylpyrrolidone and sorbitan monooleate; and (c) a drug component consisting of salbutamol sulphate. 4. The pharmaceutical composition of claim 1 which consists entirely of components (a), (b) and (c). 5. The pharmaceutical composition of claim 1, wherein the propellant component consists entirely of 1,1-difluoroethane (R-152a). 6. A sealed container that contains a pharmaceutical composition as claimed in claim 1. 7. The sealed container of claim 6 which is a pressurized container for use with a metered dose inhaler (MDI). 8. A metered dose inhaler (MDI) fitted with a pressurized container as claimed in claim 7. 9. A method for treating a patient suffering or likely to suffer from a respiratory disorder which comprises administering to the patient a therapeutically or prophylactically effective amount of a pharmaceutical composition as claimed in claim 1. 10. The method of claim 9, wherein the respiratory disorder is asthma. 11. The method of claim 9, wherein the pharmaceutical composition is delivered to the patient using a metered dose inhaler (MDI). 12. A method for manufacturing a pharmaceutical composition as claimed in said method comprising the steps of:
introducing a weighed amount of the drug component into an open container from which the drug component will ultimately be released as an aerosol spray using a medication delivery device; fitting a valve device onto the container; introducing the propellant component, in liquid form, through the valve into the container under pressure; and introducing the surfactant component through the valve into the container under pressure. 13. The method of claim 12, wherein the liquid propellant is mixed together with the surfactant component and the resulting liquid mixture introduced into the container under pressure via the valve. 14. The pharmaceutical composition of claim 3 which consists entirely of components (a), (b) and (c). 15. The pharmaceutical composition of claim 14, wherein the propellant component consists entirely of 1,1-difluoroethane (R-152a). 16. The pharmaceutical composition of claim 2, wherein the propellant component consists entirely of 1,1-difluoroethane (R-152a). 17. The pharmaceutical composition of claim 3, wherein the propellant component consists entirely of 1,1-difluoroethane (R-152a). 18. The pharmaceutical composition of claim 4, wherein the propellant component consists entirely of 1,1-difluoroethane (R-152a). | A pharmaceutical composition is described that is suitable for delivery from a pressurised container. The composition is preferably free of polar excipients and comprises: (a) a propellant component that consists essentially of 1,1-difluoroethane (R-152a); (b) a surfactant component that comprises at least one surfactant compound other than oleic acid; and (c) a drug component that consists of salbutamol sulphate. The pharmaceutical composition can be delivered using a metered dose inhaler (MDI).1. A pharmaceutical composition that is free of polar excipients, said composition comprising:
(a) a propellant component consisting essentially of 1,1-difluoroethane (R-152a), (b) a surfactant component consisting entirely of at least one surfactant compound selected from the group consisting of polyvinylpyrrolidone and sorbitan monooleate; and (c) a drug component consisting of salbutamol sulphate. 2. The pharmaceutical composition of claim 1 which consists essentially of components (a), (b) and (c). 3. A pharmaceutical composition for delivery from a pressurised container, said composition consisting essentially of:
(a) a propellant component consisting essentially of 1,1-difluoroethane (R-152a), (b) a surfactant component consisting entirely of at least one surfactant compound selected from the group consisting of polyvinylpyrrolidone and sorbitan monooleate; and (c) a drug component consisting of salbutamol sulphate. 4. The pharmaceutical composition of claim 1 which consists entirely of components (a), (b) and (c). 5. The pharmaceutical composition of claim 1, wherein the propellant component consists entirely of 1,1-difluoroethane (R-152a). 6. A sealed container that contains a pharmaceutical composition as claimed in claim 1. 7. The sealed container of claim 6 which is a pressurized container for use with a metered dose inhaler (MDI). 8. A metered dose inhaler (MDI) fitted with a pressurized container as claimed in claim 7. 9. A method for treating a patient suffering or likely to suffer from a respiratory disorder which comprises administering to the patient a therapeutically or prophylactically effective amount of a pharmaceutical composition as claimed in claim 1. 10. The method of claim 9, wherein the respiratory disorder is asthma. 11. The method of claim 9, wherein the pharmaceutical composition is delivered to the patient using a metered dose inhaler (MDI). 12. A method for manufacturing a pharmaceutical composition as claimed in said method comprising the steps of:
introducing a weighed amount of the drug component into an open container from which the drug component will ultimately be released as an aerosol spray using a medication delivery device; fitting a valve device onto the container; introducing the propellant component, in liquid form, through the valve into the container under pressure; and introducing the surfactant component through the valve into the container under pressure. 13. The method of claim 12, wherein the liquid propellant is mixed together with the surfactant component and the resulting liquid mixture introduced into the container under pressure via the valve. 14. The pharmaceutical composition of claim 3 which consists entirely of components (a), (b) and (c). 15. The pharmaceutical composition of claim 14, wherein the propellant component consists entirely of 1,1-difluoroethane (R-152a). 16. The pharmaceutical composition of claim 2, wherein the propellant component consists entirely of 1,1-difluoroethane (R-152a). 17. The pharmaceutical composition of claim 3, wherein the propellant component consists entirely of 1,1-difluoroethane (R-152a). 18. The pharmaceutical composition of claim 4, wherein the propellant component consists entirely of 1,1-difluoroethane (R-152a). | 1,600 |
437 | 14,913,177 | 1,662 | Compositions and methods are provided for genome modification of a target sequence in the genome of a cell. The methods and compositions employ a guide polynucleotide/Cas endonuclease system to provide an effective system for modifying or altering target sites within the genome of a cell or organism. Once a genomic target site is identified, a variety of methods can be employed to further modify the target sites such that they contain a variety of polynucleotides of interest. Compositions and methods are also provided for editing a nucleotide sequence in the genome of a cell. Breeding methods and methods for selecting plants utilizing a two component RNA polynucleotide and Cas endonuclease system are also disclosed. | 1. A guide polynucleotide comprising:
(i) a first nucleotide sequence domain that is complementary to a nucleotide sequence in a target DNA; and, (ii) a second nucleotide sequence domain that interacts with a Cas endonuclease, wherein the first nucleotide sequence domain and the second nucleotide sequence domain are composed of deoxyribonucleic acids (DNA), ribonucleic acids (RNA), or a combination thereof, wherein the guide polynucleotide does not solely comprise ribonucleic acids. 2. The guide polynucleotide of claim 1, wherein the first nucleotide sequence domain and the second nucleotide sequence domain are located on a single molecule. 3. The guide polynucleotide of claim 1, wherein the second nucleotide sequence domain comprises two separate molecules that are capable of hybridizing along a region of complementarity. 4. The guide polynucleotide of claim 1, wherein the first nucleotide sequence domain is a DNA sequence and the second nucleotide sequence domain is selected from the group consisting of a DNA sequence, a RNA sequence, and a combination thereof. 5. The guide polynucleotide of claim 1, wherein the first nucleotide sequence domain and the second nucleotide sequence domain are DNA sequences. 6. The guide polynucleotide of claim 1, wherein the first nucleotide sequence domain and/or the second nucleotide sequence domain comprises at least one modification, wherein said at least one modification is selected from the group consisting of a 5′ cap, a 3′ polyadenylated tail, a riboswitch sequence, a stability control sequence, a sequence that forms a dsRNA duplex, a modification or sequence that targets the guide poly nucleotide to a subcellular location, a modification or sequence that provides for tracking, a modification or sequence that provides a binding site for proteins, a Locked Nucleic Acid (LNA), a 5-methyl dC nucleotide, a 2,6-Diaminopurine nucleotide, a 2′-Fluoro A nucleotide, a 2′-Fluoro U nucleotide; a 2′-O-Methyl RNA nucleotide, a phosphorothioate bond, linkage to a cholesterol molecule, linkage to a polyethylene glycol molecule, linkage to a spacer 18 molecule, a 5′ to 3′ covalent linkage, and any combination thereof. 7-8. (canceled) 9. A plant or seed comprising the guide polynucleotide of claim 1. 10. A guide polynucleotide/Cas endonuclease complex wherein the guide polynucleotide comprises:
(i) a first nucleotide sequence domain that is complementary to a nucleotide sequence in a target DNA; and, (ii) a second nucleotide sequence domain that interacts with a Cas endonuclease, wherein said guide polynucleotide does not solely comprise ribonucleic acids, wherein said guide polynucleotide and Cas endonuclease are capable of forming a complex that enables the Cas endonuclease to introduce a double strand break at said target site. 11. The guide polynucleotide/Cas endonuclease complex of claim 10, wherein the first nucleotide sequence domain and the second nucleotide sequence domain of the guide polynucleotide are composed of deoxyribonucleic acids (DNA), ribonucleic acids (RNA), or a combination thereof, wherein the guide polynucleotide does not solely comprise ribonucleic acids. 12. The guide polynucleotide/Cas endonuclease complex of claim 10, wherein the first nucleotide sequence domain and/or the second nucleotide sequence domain of said guide polynucleotide comprises at least one modification that provides for an additional beneficial feature, wherein said at least one modification is selected from the group consisting of a 5′ cap, a 3′ polyadenylated tail, a riboswitch sequence, a stability control sequence; a sequence that forms a dsRNA duplex, a modification or sequence that targets the guide poly nucleotide to a subcellular location, a modification or sequence that provides for tracking, a modification or sequence that provides a binding site for proteins, a Locked Nucleic Acid (LNA), a 5-methyl dC nucleotide, a 2,6-Diaminopurine nucleotide, a 2′-Fluoro A nucleotide, a 2′-Fluoro U nucleotide; a 2′-O-Methyl RNA nucleotide, a phosphorothioate bond, linkage to a cholesterol molecule, linkage to a polyethylene glycol molecule, linkage to a spacer 18 molecule, a 5′ to 3′ covalent linkage, and any combination thereof. 13. The guide polynucleotide/Cas endonuclease complex of claim 10, wherein the Cas endonuclease is a Cas9 endonuclease. 14. A plant or seed comprising the guide polynucleotide/Cas endonuclease complex of claim 10. 15. (canceled) 16. A method for modifying a target site in the genome of a cell, the method comprising providing a guide polynucleotide and a Cas endonuclease to a cell, wherein said guide polynucleotide does not solely comprise ribonucleic acids, wherein said guide polynucleotide and Cas endonuclease are capable of forming a complex that enables the Cas endonuclease to introduce a double strand break at said target site. 17. The method of claim 16, further comprising providing a donor DNA to said cell, wherein said donor DNA comprises a polynucleotide of interest. 18. The method of any one of claim 16, further comprising identifying at least one cell that has a modification at said target, wherein the modification at said target site is selected from the group consisting of (i) a replacement of at least one nucleotide, (ii) a deletion of at least one nucleotide, (iii) an insertion of at least one nucleotide, and (iv) any combination of (i)-(iii). 19-24. (canceled) 25. A method for modifying a target site in the genome of a cell, the method comprising:
a) providing to a cell a crNucleotide, a first recombinant DNA construct capable of expressing a tracrRNA, and a second recombinant DNA capable of expressing a Cas endonuclease, wherein said crNucleotide is a deoxyribonucleotide sequence or a combination of a deoxyribonucleotide and ribonucleotide sequence, wherein said crNucleotide, said tracrRNA and said Cas endonuclease are capable of forming a complex that enables the Cas endonuclease to introduce a double strand break at said target site; and, b) identifying at least one cell that has a modification at said target site, wherein the modification is selected from the group consisting of (i) a replacement of at least one nucleotide, (ii) a deletion of at least one nucleotide, (iii) an insertion of at least one nucleotide, and (iv) any combination of (i)-(iii). 26. A method for modifying a target site in the genome of a cell, the method comprising:
a) providing to a cell a tracrNucleotide, a first recombinant DNA construct capable of expressing a crRNA and a second recombinant DNA capable of expressing a Cas endonuclease, wherein said tracrNucleotide is selected a deoxyribonucleotide sequence or a combination of a deoxyribonucleotide and ribonucleotide sequence, wherein said tracrNucleotide, said crRNA and said Cas endonuclease are capable of forming a complex that enables the Cas endonuclease to introduce a double strand break at said target site; and, b) identifying at least one cell that has a modification at said target site, wherein the modification is selected from the group consisting of (i) a replacement of at least one nucleotide, (ii) a deletion of at least one nucleotide, (iii) an insertion of at least one nucleotide, and (iv) any combination of (i)-(iii). 27. (canceled) 28. A method for editing a nucleotide sequence in the genome of a cell, the method comprising introducing a guide polynucleotide, a polynucleotide modification template and at least one Cas endonuclease into a cell, wherein said guide polynucleotide does not solely comprise ribonucleic acids, wherein the Cas endonuclease introduces a double-strand break at a target site in the genome of said cell, wherein said polynucleotide modification template comprises at least one nucleotide modification of said nucleotide sequence. 29-31. (canceled) 32. A plant or seed comprising a guide polynucleotide and a Cas9 endonuclease, wherein said guide polynucleotide does not solely comprise ribonucleic acids, wherein said Cas9 endonuclease and guide polynucleotide are capable of forming a complex and creating a double strand break in a genomic target site of said plant. 33-43. (canceled) | Compositions and methods are provided for genome modification of a target sequence in the genome of a cell. The methods and compositions employ a guide polynucleotide/Cas endonuclease system to provide an effective system for modifying or altering target sites within the genome of a cell or organism. Once a genomic target site is identified, a variety of methods can be employed to further modify the target sites such that they contain a variety of polynucleotides of interest. Compositions and methods are also provided for editing a nucleotide sequence in the genome of a cell. Breeding methods and methods for selecting plants utilizing a two component RNA polynucleotide and Cas endonuclease system are also disclosed.1. A guide polynucleotide comprising:
(i) a first nucleotide sequence domain that is complementary to a nucleotide sequence in a target DNA; and, (ii) a second nucleotide sequence domain that interacts with a Cas endonuclease, wherein the first nucleotide sequence domain and the second nucleotide sequence domain are composed of deoxyribonucleic acids (DNA), ribonucleic acids (RNA), or a combination thereof, wherein the guide polynucleotide does not solely comprise ribonucleic acids. 2. The guide polynucleotide of claim 1, wherein the first nucleotide sequence domain and the second nucleotide sequence domain are located on a single molecule. 3. The guide polynucleotide of claim 1, wherein the second nucleotide sequence domain comprises two separate molecules that are capable of hybridizing along a region of complementarity. 4. The guide polynucleotide of claim 1, wherein the first nucleotide sequence domain is a DNA sequence and the second nucleotide sequence domain is selected from the group consisting of a DNA sequence, a RNA sequence, and a combination thereof. 5. The guide polynucleotide of claim 1, wherein the first nucleotide sequence domain and the second nucleotide sequence domain are DNA sequences. 6. The guide polynucleotide of claim 1, wherein the first nucleotide sequence domain and/or the second nucleotide sequence domain comprises at least one modification, wherein said at least one modification is selected from the group consisting of a 5′ cap, a 3′ polyadenylated tail, a riboswitch sequence, a stability control sequence, a sequence that forms a dsRNA duplex, a modification or sequence that targets the guide poly nucleotide to a subcellular location, a modification or sequence that provides for tracking, a modification or sequence that provides a binding site for proteins, a Locked Nucleic Acid (LNA), a 5-methyl dC nucleotide, a 2,6-Diaminopurine nucleotide, a 2′-Fluoro A nucleotide, a 2′-Fluoro U nucleotide; a 2′-O-Methyl RNA nucleotide, a phosphorothioate bond, linkage to a cholesterol molecule, linkage to a polyethylene glycol molecule, linkage to a spacer 18 molecule, a 5′ to 3′ covalent linkage, and any combination thereof. 7-8. (canceled) 9. A plant or seed comprising the guide polynucleotide of claim 1. 10. A guide polynucleotide/Cas endonuclease complex wherein the guide polynucleotide comprises:
(i) a first nucleotide sequence domain that is complementary to a nucleotide sequence in a target DNA; and, (ii) a second nucleotide sequence domain that interacts with a Cas endonuclease, wherein said guide polynucleotide does not solely comprise ribonucleic acids, wherein said guide polynucleotide and Cas endonuclease are capable of forming a complex that enables the Cas endonuclease to introduce a double strand break at said target site. 11. The guide polynucleotide/Cas endonuclease complex of claim 10, wherein the first nucleotide sequence domain and the second nucleotide sequence domain of the guide polynucleotide are composed of deoxyribonucleic acids (DNA), ribonucleic acids (RNA), or a combination thereof, wherein the guide polynucleotide does not solely comprise ribonucleic acids. 12. The guide polynucleotide/Cas endonuclease complex of claim 10, wherein the first nucleotide sequence domain and/or the second nucleotide sequence domain of said guide polynucleotide comprises at least one modification that provides for an additional beneficial feature, wherein said at least one modification is selected from the group consisting of a 5′ cap, a 3′ polyadenylated tail, a riboswitch sequence, a stability control sequence; a sequence that forms a dsRNA duplex, a modification or sequence that targets the guide poly nucleotide to a subcellular location, a modification or sequence that provides for tracking, a modification or sequence that provides a binding site for proteins, a Locked Nucleic Acid (LNA), a 5-methyl dC nucleotide, a 2,6-Diaminopurine nucleotide, a 2′-Fluoro A nucleotide, a 2′-Fluoro U nucleotide; a 2′-O-Methyl RNA nucleotide, a phosphorothioate bond, linkage to a cholesterol molecule, linkage to a polyethylene glycol molecule, linkage to a spacer 18 molecule, a 5′ to 3′ covalent linkage, and any combination thereof. 13. The guide polynucleotide/Cas endonuclease complex of claim 10, wherein the Cas endonuclease is a Cas9 endonuclease. 14. A plant or seed comprising the guide polynucleotide/Cas endonuclease complex of claim 10. 15. (canceled) 16. A method for modifying a target site in the genome of a cell, the method comprising providing a guide polynucleotide and a Cas endonuclease to a cell, wherein said guide polynucleotide does not solely comprise ribonucleic acids, wherein said guide polynucleotide and Cas endonuclease are capable of forming a complex that enables the Cas endonuclease to introduce a double strand break at said target site. 17. The method of claim 16, further comprising providing a donor DNA to said cell, wherein said donor DNA comprises a polynucleotide of interest. 18. The method of any one of claim 16, further comprising identifying at least one cell that has a modification at said target, wherein the modification at said target site is selected from the group consisting of (i) a replacement of at least one nucleotide, (ii) a deletion of at least one nucleotide, (iii) an insertion of at least one nucleotide, and (iv) any combination of (i)-(iii). 19-24. (canceled) 25. A method for modifying a target site in the genome of a cell, the method comprising:
a) providing to a cell a crNucleotide, a first recombinant DNA construct capable of expressing a tracrRNA, and a second recombinant DNA capable of expressing a Cas endonuclease, wherein said crNucleotide is a deoxyribonucleotide sequence or a combination of a deoxyribonucleotide and ribonucleotide sequence, wherein said crNucleotide, said tracrRNA and said Cas endonuclease are capable of forming a complex that enables the Cas endonuclease to introduce a double strand break at said target site; and, b) identifying at least one cell that has a modification at said target site, wherein the modification is selected from the group consisting of (i) a replacement of at least one nucleotide, (ii) a deletion of at least one nucleotide, (iii) an insertion of at least one nucleotide, and (iv) any combination of (i)-(iii). 26. A method for modifying a target site in the genome of a cell, the method comprising:
a) providing to a cell a tracrNucleotide, a first recombinant DNA construct capable of expressing a crRNA and a second recombinant DNA capable of expressing a Cas endonuclease, wherein said tracrNucleotide is selected a deoxyribonucleotide sequence or a combination of a deoxyribonucleotide and ribonucleotide sequence, wherein said tracrNucleotide, said crRNA and said Cas endonuclease are capable of forming a complex that enables the Cas endonuclease to introduce a double strand break at said target site; and, b) identifying at least one cell that has a modification at said target site, wherein the modification is selected from the group consisting of (i) a replacement of at least one nucleotide, (ii) a deletion of at least one nucleotide, (iii) an insertion of at least one nucleotide, and (iv) any combination of (i)-(iii). 27. (canceled) 28. A method for editing a nucleotide sequence in the genome of a cell, the method comprising introducing a guide polynucleotide, a polynucleotide modification template and at least one Cas endonuclease into a cell, wherein said guide polynucleotide does not solely comprise ribonucleic acids, wherein the Cas endonuclease introduces a double-strand break at a target site in the genome of said cell, wherein said polynucleotide modification template comprises at least one nucleotide modification of said nucleotide sequence. 29-31. (canceled) 32. A plant or seed comprising a guide polynucleotide and a Cas9 endonuclease, wherein said guide polynucleotide does not solely comprise ribonucleic acids, wherein said Cas9 endonuclease and guide polynucleotide are capable of forming a complex and creating a double strand break in a genomic target site of said plant. 33-43. (canceled) | 1,600 |
438 | 13,979,908 | 1,631 | The present invention relates to a method for processing a subject's genomic data comprising (a) obtaining a subject's genomic sequence; (b) reducing the complexity and/or amount of the genomic sequence information; and (c) storing the genomic sequence information of step (b) in a rapidly retrievable form. The present invention further relates to a method wherein the step of reducing the complexity and/or amount of the genomic sequence information is carried out by cropping said genomic sequence information except for signature data pertaining to a disease or disorder, or by aligning a subject's genomic sequence with a reference sequence comprising signature data pertaining to a disease or disorder. Furthermore, the invention relates to a method wherein the use of a subject's functional genetic information, in particular gene expression data is included, as well as to a method, wherein the information is encoded in matrices and decoded and represented based on Markov chain processes. The obtained information can also be used for diagnosing, detecting, monitoring or prognosticating a disease and/or for the preparation of a subject's molecular history. In addition, a corresponding clinical decision support and storage system, preferably in the form of an electronic picture/data archiving and communication system, is provided. | 1. A method for processing a subject's genomic data comprising
(a) obtaining a subject's genomic sequence information; (b) reducing the complexity and amount of said genomic sequence information comprising cropping said genomic sequence information except for the signature data pertaining to a disease or disorder; and (c) storing said genomic sequence information of step (b) in a rapidly retrievable form. 2. The method of claim 1, wherein said genomic sequence is obtained from a subject's sample, preferably from a mixture of tissues, organs, cells and/or fragments thereof, or from a tissue or organ specific sample, such as a tissue biopsy from vaginal tissue, tongue, pancreas, liver, spleen, ovary, muscle, joint tissue, neural tissue, gastrointestinal tissue, tumor tissue, body fluids, blood, serum, saliva, or urine. 3. The method of claim 1, wherein step (a) comprises a repeated acquisition of a subject's genomic sequence and wherein a comparison between the genomic sequence information obtained in the initial acquisition and the genomic sequence information obtained in a second or further acquisition is performed. 4. The method of claim 3, wherein in an additional step the incremental data comprising information which differs between the initially obtained genomic sequence information and the genomic sequence information obtained in a second or further acquisition is stored in a rapidly retrievable form. 5. (canceled) 6. The method of claim 1, wherein step (b) is carried out by aligning a subject's genomic sequence with a reference sequence comprising signature data pertaining to a disease or disorder and wherein said alignment is carried out by using reversed complementary sequences. 7. The method of claim 1, wherein said signature data is at least one variation specific to a disease or disorder selected from the group comprising missense mutation, nonsense mutation, single nucleotide polymorphism (SNP), copy number variation (CNV), splicing variation, variation of a regulatory sequence, small deletion, small insertion, small indel, gross deletion, gross insertion, complex genetic rearrangement, inter chromosomal rearrangement, intra chromosomal rearrangement, loss of heterozygosity, insertion of repeats and deletion of repeats. 8. The method of claim 1, wherein said method additionally comprises the steps of (d) obtaining the subject's functional genetic information, (e) reducing the complexity and/or amount of this information, and (f) storing the functional genetic information in a rapidly retrievable form, wherein the step of reducing the complexity and/or amount of said functional genetic information is carried out by cropping said functional genetic information except for signature data pertaining to a disease or disorder. 9. The method of claim 8, wherein said functional genetic information comprises (i) information on gene expression, preferably information on the presence of one or more RNA species, of one or more protein species, of the subject's transcriptome or a portion thereof, of the subject's proteome or a portion thereof, or a mixture thereof; and/or (ii) methylation sequencing information, preferably methylation sequencing information for each individual nucleotide (C or A); and/or (iii) information on histone marks which are indicative of active genes and/or silenced genes, preferably of H3K4 methylation and/or H3K27 methylation. 10. (canceled) 11. The method of claim 1, wherein changes in genomic and/or functional genetic information are encoded in matrices, and wherein information pertaining to the status of a gene, genomic region, regulatory region, promoter, exon or pathway, preferably in the context of a disease or disorder, is decoded and represented based on Markov chain processes. 12. Use of genomic sequence information, optionally in combination with gene expression information, as obtained and/or stored according to claim 1, for (i) the preparation of a subject's molecular history, in the form of various molecular profiling modalities by capturing information on the complete genome, the regulome, or the regulatory state of the genome, genomic regions, genes, promoters, introns, exons, pathways, pathway members or methylation states over a defined period of time; and/or for (ii) diagnosing, detecting, monitoring or prognosticating a disease. 13. The method of claim 1, wherein said disease is a cancerous disease, preferably breast cancer, ovarian cancer or prostate cancer. 14. A clinical decision support and storage system comprising:
an input for providing a subject's genomic sequence information, optionally in combination with a subject's s functional genetic information; a computer program product for enabling a processor to carry out step (b) and optionally step (e) of the method of claim 1, an output for outputting a subject's genomic variation, incremental genomic change or gene expression variation pattern, over a defined period of time, and a medium for storing the outputted information. 15. The system of claim 14, wherein said system is an electronic picture/data archiving and communication system. | The present invention relates to a method for processing a subject's genomic data comprising (a) obtaining a subject's genomic sequence; (b) reducing the complexity and/or amount of the genomic sequence information; and (c) storing the genomic sequence information of step (b) in a rapidly retrievable form. The present invention further relates to a method wherein the step of reducing the complexity and/or amount of the genomic sequence information is carried out by cropping said genomic sequence information except for signature data pertaining to a disease or disorder, or by aligning a subject's genomic sequence with a reference sequence comprising signature data pertaining to a disease or disorder. Furthermore, the invention relates to a method wherein the use of a subject's functional genetic information, in particular gene expression data is included, as well as to a method, wherein the information is encoded in matrices and decoded and represented based on Markov chain processes. The obtained information can also be used for diagnosing, detecting, monitoring or prognosticating a disease and/or for the preparation of a subject's molecular history. In addition, a corresponding clinical decision support and storage system, preferably in the form of an electronic picture/data archiving and communication system, is provided.1. A method for processing a subject's genomic data comprising
(a) obtaining a subject's genomic sequence information; (b) reducing the complexity and amount of said genomic sequence information comprising cropping said genomic sequence information except for the signature data pertaining to a disease or disorder; and (c) storing said genomic sequence information of step (b) in a rapidly retrievable form. 2. The method of claim 1, wherein said genomic sequence is obtained from a subject's sample, preferably from a mixture of tissues, organs, cells and/or fragments thereof, or from a tissue or organ specific sample, such as a tissue biopsy from vaginal tissue, tongue, pancreas, liver, spleen, ovary, muscle, joint tissue, neural tissue, gastrointestinal tissue, tumor tissue, body fluids, blood, serum, saliva, or urine. 3. The method of claim 1, wherein step (a) comprises a repeated acquisition of a subject's genomic sequence and wherein a comparison between the genomic sequence information obtained in the initial acquisition and the genomic sequence information obtained in a second or further acquisition is performed. 4. The method of claim 3, wherein in an additional step the incremental data comprising information which differs between the initially obtained genomic sequence information and the genomic sequence information obtained in a second or further acquisition is stored in a rapidly retrievable form. 5. (canceled) 6. The method of claim 1, wherein step (b) is carried out by aligning a subject's genomic sequence with a reference sequence comprising signature data pertaining to a disease or disorder and wherein said alignment is carried out by using reversed complementary sequences. 7. The method of claim 1, wherein said signature data is at least one variation specific to a disease or disorder selected from the group comprising missense mutation, nonsense mutation, single nucleotide polymorphism (SNP), copy number variation (CNV), splicing variation, variation of a regulatory sequence, small deletion, small insertion, small indel, gross deletion, gross insertion, complex genetic rearrangement, inter chromosomal rearrangement, intra chromosomal rearrangement, loss of heterozygosity, insertion of repeats and deletion of repeats. 8. The method of claim 1, wherein said method additionally comprises the steps of (d) obtaining the subject's functional genetic information, (e) reducing the complexity and/or amount of this information, and (f) storing the functional genetic information in a rapidly retrievable form, wherein the step of reducing the complexity and/or amount of said functional genetic information is carried out by cropping said functional genetic information except for signature data pertaining to a disease or disorder. 9. The method of claim 8, wherein said functional genetic information comprises (i) information on gene expression, preferably information on the presence of one or more RNA species, of one or more protein species, of the subject's transcriptome or a portion thereof, of the subject's proteome or a portion thereof, or a mixture thereof; and/or (ii) methylation sequencing information, preferably methylation sequencing information for each individual nucleotide (C or A); and/or (iii) information on histone marks which are indicative of active genes and/or silenced genes, preferably of H3K4 methylation and/or H3K27 methylation. 10. (canceled) 11. The method of claim 1, wherein changes in genomic and/or functional genetic information are encoded in matrices, and wherein information pertaining to the status of a gene, genomic region, regulatory region, promoter, exon or pathway, preferably in the context of a disease or disorder, is decoded and represented based on Markov chain processes. 12. Use of genomic sequence information, optionally in combination with gene expression information, as obtained and/or stored according to claim 1, for (i) the preparation of a subject's molecular history, in the form of various molecular profiling modalities by capturing information on the complete genome, the regulome, or the regulatory state of the genome, genomic regions, genes, promoters, introns, exons, pathways, pathway members or methylation states over a defined period of time; and/or for (ii) diagnosing, detecting, monitoring or prognosticating a disease. 13. The method of claim 1, wherein said disease is a cancerous disease, preferably breast cancer, ovarian cancer or prostate cancer. 14. A clinical decision support and storage system comprising:
an input for providing a subject's genomic sequence information, optionally in combination with a subject's s functional genetic information; a computer program product for enabling a processor to carry out step (b) and optionally step (e) of the method of claim 1, an output for outputting a subject's genomic variation, incremental genomic change or gene expression variation pattern, over a defined period of time, and a medium for storing the outputted information. 15. The system of claim 14, wherein said system is an electronic picture/data archiving and communication system. | 1,600 |
439 | 16,149,483 | 1,617 | A hygiene product, a hygiene product pod, and a method of using the hygiene product pod, the hygiene product pod including a water soluble envelope and the hygiene product sealed in the envelope. The hygiene product includes a carrier comprising butylene glycol in an amount ranging from about 40 wt % to about 70 wt %, based on the total weigh of hygiene product, and an active agent including at least one surfactant. | 1. A hygiene product comprising:
a carrier comprising butylene glycol in an amount ranging from about 40 wt % to about 70 wt %, based on the total weight of the hygiene product; and an active agent comprising at least one surfactant. 2. The hygiene product of claim 1, wherein the butylene glycol comprises 1,3-butanediol. 3. The hygiene product of claim 2, wherein the hygiene product comprises from about 50 wt % to about 65 wt % 1,3-butanediol, based on the total weight of the hygiene product. 4. The hygiene product of claim 1, wherein the hygiene product comprises the active agent in an amount ranging from about 45 wt % to about 70 wt %, based on the total weight of the hygiene product. 5. The hygiene product of claim 4, wherein the active agent comprises at least two compounds selected from:
sodium cocoyl isethionate; cocamidopropyl betaine; capryloyl/caproyl methyl glucamide and lauroyl/myristoyl methyl glucamide; or cocamidopropyl PG-dimonium chloride phosphate. 6. The hygiene product of claim 4, wherein the active agent comprises at least two compounds selected from:
sodium cocoyl isethionate; cocamidopropyl betaine; capryloyl/caproyl methyl glucamide and lauroyl/myristoyl methyl glucamide; cocamidopropyl PG-dimonium chloride phosphate; linoleamidopropyl PG-dimonium chloride phosphate; or lauramine oxide. 7. The hygiene product of claim 1, further comprising a lamellar gel network comprising a nonionic surfactant in an amount ranging from about 12 wt % to about 18 wt %, based on the total weight of the hygiene product. 8. The hygiene product of claim 1, further comprising a thickener comprising carboxymethyl cellulose in an amount ranging from about 0.15 wt % to about 0.25 wt %, based on the total weight of the hygiene product. 9. The hygiene product of claim 1, wherein the hygiene product comprises:
a shampoo, a conditioner, a bodywash, or any combination thereof; or a shaving product. 10. A single-use hygiene product pod comprising:
a water-soluble envelope; and the hygiene product of claim 1 sealed in the envelope. 11. A single-use hygiene product pod comprising:
a hygiene product comprising:
a carrier comprising butylene glycol in an amount ranging from about 25 wt % to about 70 wt %, based on the total weight of the hygiene product; and
an active agent comprising at least one surfactant; and
a water-soluble envelope encapsulating the hygiene product. | A hygiene product, a hygiene product pod, and a method of using the hygiene product pod, the hygiene product pod including a water soluble envelope and the hygiene product sealed in the envelope. The hygiene product includes a carrier comprising butylene glycol in an amount ranging from about 40 wt % to about 70 wt %, based on the total weigh of hygiene product, and an active agent including at least one surfactant.1. A hygiene product comprising:
a carrier comprising butylene glycol in an amount ranging from about 40 wt % to about 70 wt %, based on the total weight of the hygiene product; and an active agent comprising at least one surfactant. 2. The hygiene product of claim 1, wherein the butylene glycol comprises 1,3-butanediol. 3. The hygiene product of claim 2, wherein the hygiene product comprises from about 50 wt % to about 65 wt % 1,3-butanediol, based on the total weight of the hygiene product. 4. The hygiene product of claim 1, wherein the hygiene product comprises the active agent in an amount ranging from about 45 wt % to about 70 wt %, based on the total weight of the hygiene product. 5. The hygiene product of claim 4, wherein the active agent comprises at least two compounds selected from:
sodium cocoyl isethionate; cocamidopropyl betaine; capryloyl/caproyl methyl glucamide and lauroyl/myristoyl methyl glucamide; or cocamidopropyl PG-dimonium chloride phosphate. 6. The hygiene product of claim 4, wherein the active agent comprises at least two compounds selected from:
sodium cocoyl isethionate; cocamidopropyl betaine; capryloyl/caproyl methyl glucamide and lauroyl/myristoyl methyl glucamide; cocamidopropyl PG-dimonium chloride phosphate; linoleamidopropyl PG-dimonium chloride phosphate; or lauramine oxide. 7. The hygiene product of claim 1, further comprising a lamellar gel network comprising a nonionic surfactant in an amount ranging from about 12 wt % to about 18 wt %, based on the total weight of the hygiene product. 8. The hygiene product of claim 1, further comprising a thickener comprising carboxymethyl cellulose in an amount ranging from about 0.15 wt % to about 0.25 wt %, based on the total weight of the hygiene product. 9. The hygiene product of claim 1, wherein the hygiene product comprises:
a shampoo, a conditioner, a bodywash, or any combination thereof; or a shaving product. 10. A single-use hygiene product pod comprising:
a water-soluble envelope; and the hygiene product of claim 1 sealed in the envelope. 11. A single-use hygiene product pod comprising:
a hygiene product comprising:
a carrier comprising butylene glycol in an amount ranging from about 25 wt % to about 70 wt %, based on the total weight of the hygiene product; and
an active agent comprising at least one surfactant; and
a water-soluble envelope encapsulating the hygiene product. | 1,600 |
440 | 15,036,980 | 1,632 | The purpose of the present invention is to provide a novel urethane decomposing method by which urethane in the environment is treated efficiently and at a low cost, and a urethane decomposing agent. The above purpose is attained by employing a urethane decomposing method including: a step of treating a urethane-containing material to be treated using an unsaturated fatty acid; and a step of making a microorganism belonging to a Streptomyces genus and exhibiting urethane decomposing function, to act on the material treated using the unsaturated fatty acid. | 1. A urethane decomposing method including: a step of treating a urethane-containing material to be treated using an unsaturated fatty acid; and a step of making a microorganism belonging to a Streptomyces genus and exhibiting urethane decomposing function, to act on the material treated using the unsaturated fatty acid. 2. The urethane decomposing method according to claim 1, wherein in the step of treating the material to be treated using the unsaturated fatty acid, the unsaturated fatty acid and alcohol are mixed for use. 3. The urethane decomposing method according to claim 1, including the step of treating the material to be treated using alcohol before the step of treating the material to be treated using the unsaturated fatty acid. 4. The urethane decomposing method according to claim 1, wherein the microorganism belonging to a Streptomyces genus is a microorganism specified by Accession No. FERM P-21770. 5. The urethane decomposing method according to claim 1, wherein the unsaturated fatty acid is a mixture of one or more kinds selected from the group consisting of oleic acid, linoleic acid, and erucic acid. 6. The urethane decomposing method according to claim 1, wherein the alcohol is a mixture of one or more kinds selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-butanol, and 2-methyl-2-butanol. 7. The urethane decomposing method according to claim 1, wherein the microorganism is made to act on the material to be treated while treating the material to be treated using the unsaturated fatty acid. 8. A urethane decomposing agent containing the microorganism and the unsaturated fatty acid, according to claim 1. 9. The urethane decomposing agent according to claim 8, further containing alcohol. | The purpose of the present invention is to provide a novel urethane decomposing method by which urethane in the environment is treated efficiently and at a low cost, and a urethane decomposing agent. The above purpose is attained by employing a urethane decomposing method including: a step of treating a urethane-containing material to be treated using an unsaturated fatty acid; and a step of making a microorganism belonging to a Streptomyces genus and exhibiting urethane decomposing function, to act on the material treated using the unsaturated fatty acid.1. A urethane decomposing method including: a step of treating a urethane-containing material to be treated using an unsaturated fatty acid; and a step of making a microorganism belonging to a Streptomyces genus and exhibiting urethane decomposing function, to act on the material treated using the unsaturated fatty acid. 2. The urethane decomposing method according to claim 1, wherein in the step of treating the material to be treated using the unsaturated fatty acid, the unsaturated fatty acid and alcohol are mixed for use. 3. The urethane decomposing method according to claim 1, including the step of treating the material to be treated using alcohol before the step of treating the material to be treated using the unsaturated fatty acid. 4. The urethane decomposing method according to claim 1, wherein the microorganism belonging to a Streptomyces genus is a microorganism specified by Accession No. FERM P-21770. 5. The urethane decomposing method according to claim 1, wherein the unsaturated fatty acid is a mixture of one or more kinds selected from the group consisting of oleic acid, linoleic acid, and erucic acid. 6. The urethane decomposing method according to claim 1, wherein the alcohol is a mixture of one or more kinds selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-butanol, and 2-methyl-2-butanol. 7. The urethane decomposing method according to claim 1, wherein the microorganism is made to act on the material to be treated while treating the material to be treated using the unsaturated fatty acid. 8. A urethane decomposing agent containing the microorganism and the unsaturated fatty acid, according to claim 1. 9. The urethane decomposing agent according to claim 8, further containing alcohol. | 1,600 |
441 | 16,149,543 | 1,617 | A hygiene product, a hygiene product pod, and a method of using the hygiene product pod, the hygiene product pod including a water soluble envelope and the hygiene product sealed in the envelope. The hygiene product includes a carrier comprising butylene glycol in an amount ranging from about 40 wt % to about 70 wt %, based on the total weigh of hygiene product, and an active agent including at least one surfactant. | 1. A method of using a hygiene product pod comprising a water-soluble envelope and a hygiene product sealed in the envelope and comprising an active agent and a carrier comprising butylene glycol in an amount ranging from about 40 wt % to about 70 wt %, based on the total weight of the hygiene product, the method comprising:
applying water to the pod to dissolve the envelope and release the hygiene product; applying the hygiene product to at least one body part of a user; and rinsing the hygiene product from the body part. 2. The method of claim 1, wherein applying water comprises applying the water for a time period ranging from about 20 seconds to about 40 seconds to dissolve the envelope. 3. The method of claim 1, wherein applying the hygiene product comprises applying the hygiene product to hair and scalp of the user. 4. The method of claim 1, wherein applying the hygiene product comprises applying the hygiene product to the hair, scalp, and body of the user. 5. The method of claim 1, wherein the applying water comprises applying water to the pod while the user is holding the pod. 6. The method of claim 1, wherein the carrier comprises butylene glycol in an amount ranging from about 45 wt % to about 70 wt %, based on the total weight of the hygiene product. 7. A method of using a hygiene product pod comprising a water-soluble envelope and a hygiene product sealed in the envelope and comprising an active agent and a carrier comprising butylene glycol in an amount ranging from about 25 wt % to about 70 wt %, based on the total weight of the hygiene product, the method comprising:
applying water to the pod to dissolve the envelope and release the hygiene product; applying the hygiene product to at least one body part of a user; and rinsing the hygiene product from the body part. | A hygiene product, a hygiene product pod, and a method of using the hygiene product pod, the hygiene product pod including a water soluble envelope and the hygiene product sealed in the envelope. The hygiene product includes a carrier comprising butylene glycol in an amount ranging from about 40 wt % to about 70 wt %, based on the total weigh of hygiene product, and an active agent including at least one surfactant.1. A method of using a hygiene product pod comprising a water-soluble envelope and a hygiene product sealed in the envelope and comprising an active agent and a carrier comprising butylene glycol in an amount ranging from about 40 wt % to about 70 wt %, based on the total weight of the hygiene product, the method comprising:
applying water to the pod to dissolve the envelope and release the hygiene product; applying the hygiene product to at least one body part of a user; and rinsing the hygiene product from the body part. 2. The method of claim 1, wherein applying water comprises applying the water for a time period ranging from about 20 seconds to about 40 seconds to dissolve the envelope. 3. The method of claim 1, wherein applying the hygiene product comprises applying the hygiene product to hair and scalp of the user. 4. The method of claim 1, wherein applying the hygiene product comprises applying the hygiene product to the hair, scalp, and body of the user. 5. The method of claim 1, wherein the applying water comprises applying water to the pod while the user is holding the pod. 6. The method of claim 1, wherein the carrier comprises butylene glycol in an amount ranging from about 45 wt % to about 70 wt %, based on the total weight of the hygiene product. 7. A method of using a hygiene product pod comprising a water-soluble envelope and a hygiene product sealed in the envelope and comprising an active agent and a carrier comprising butylene glycol in an amount ranging from about 25 wt % to about 70 wt %, based on the total weight of the hygiene product, the method comprising:
applying water to the pod to dissolve the envelope and release the hygiene product; applying the hygiene product to at least one body part of a user; and rinsing the hygiene product from the body part. | 1,600 |
442 | 14,124,826 | 1,631 | Systems and methods are directed to computerized methods and one or more computer processors for quantifying the perturbation of a biological system in response to an agent. A set of treatment data corresponding to a response of a biological system to an agent and a set of control data are received. A computational causal network model represents the biological system and includes nodes representing biological entities, edges representing relationships between the biological entities, and direction values representing the expected direction of change between the control data and the treatment data. Activity measures are calculated and represent a difference between the treatment data and the control data, and weight values are calculated for the nodes. A score for the computational model is generated representative of the perturbation of the biological system to the agent and is based on the direction values, the weight values and the activity measures. | 1. A computerized method for quantifying the perturbation of a biological system in response to an agent, comprising
receiving, at a first processor, a set of treatment data corresponding to a response of a biological system to an agent, wherein the biological system includes or comprises a plurality of biological entities, each biological entity interacting with at least one other of the biological entities; receiving, at a second processor, a set of control data corresponding to the biological system not exposed to the agent; providing, at a third processor, a computational causal network model that represents the biological system and includes or comprises:
nodes representing the biological entities,
edges representing relationships between the biological entities, and
direction values, for the nodes, representing the expected direction of change between the control data and the treatment data;
calculating, with a fourth processor, activity measures, for the nodes, representing a difference between the treatment data and the control data;
calculating, with a fifth processor, weight values for the nodes, wherein at least one weight value is different from at least one other weight value; and
generating, with a sixth processor, a score for the computational model representative of the perturbation of the biological system to the agent, wherein the score is based on the direction values, the weight values and the activity measures. 2. The computerized method of claim 1, wherein the biological system is represented by at least one mechanism hypothesis. 3. The computerized method of claim 1, wherein the biological system is represented by a plurality of computational causal network models or at least one computational causal network model comprising a plurality of mechanism hypotheses. 4. The computerized method of claim 1, further comprising normalizing the score based on the number of measurable nodes in the respective computational model. 5. The computerized method of claim 1, wherein the weight values represent a confidence in at least one of the set of treatment data and control data. 6. The computerized method of claim 1, wherein the weight values include or comprise local false non-discovery rates. 7. The computerized method of claim 1, further comprising calculating, with a seventh processor, an approximate distribution of the activity measures of nodes over a model or a mechanism hypotheses in a model; calculating, with an eighth processor, an expected value of activity measures with respect to the approximate distribution; and generating, with a ninth processor, a score for each computational model representative of the perturbation of the subset of the biological system to the agent, wherein the score is based on expected value. 8. The computerized method of claim 7, wherein the approximate distribution is based on the activity measures. 9. The computerized method of claim 7, wherein calculating an expected value comprises performing a rectangular approximation. 10. The computerized method of claim 1, further comprising calculating, with a tenth processor, a positive activation metric and a negative activation metric based on the activity measures, the positive and negative activation metrics representative of consistency and inconsistency, respectively, between the activity measures and the direction values with respect to the model; and generating, with an eleventh processor, a score for each computational model representative of the perturbation of the subset of the biological system to the agent, wherein the score is based on the positive and negative activation scores. 11. The computerized method of claim 1, wherein the positive activation metric, negative activation metric or both are based on local false non-discovery rates. 12. The computerized method of claim 1, wherein the activity measure is a fold-change value, and the fold-change value for each node includes or comprises a logarithm of the difference between the treatment data and the control data for the biological entity represented by the respective node. 13. The computerized method of claim 1, wherein the subset of the biological system includes or comprises at least one of cell proliferation mechanism, cellular stress mechanism, cell inflammation mechanism, and DNA repair mechanism. 14. The computerized method of claim 1, wherein the agent includes or comprises at least one of aerosol generated by heating tobacco, aerosol generated by combusting tobacco, tobacco smoke or cigarette smoke. 15. The computerized method of claim 1, wherein the agent includes or comprises a heterogeneous substance, including a molecule or an entity that is not present in or derived from the biological system. 16. The computerized method of claim 1, wherein the agent includes or comprises toxins, therapeutic compounds, stimulants, relaxants, natural products, manufactured products, and food substances. 17. The computerized method of claim 1, wherein the set of treatment data includes or comprises a plurality of sets of treatment data such that each measurable node includes or comprises a plurality of fold-change values defined by a first probability distribution and a plurality of weight values defined by a second probability distribution. 18. The computerized method of claim 1, wherein the set of treatment data includes or comprises a plurality of sets of treatment data such that each measurable node includes or comprises a plurality of fold-change values and the corresponding weight values. 19. The computerized method of claim 1, wherein the step of generating the score comprises a linear or a non-linear combination of the activity measures, the weight values, and the direction values; and a normalization of the combination by a scale factor. 20. The computerized method of claim 19, wherein the combination is an arithmetic combination, and the scale factor is the square root of the number of biological entities for which measured data are received. 21. The computerized method of claim 1, wherein the score is generated by a geometric perturbation index scoring technique, a probabilistic perturbation index scoring technique, or an expected perturbation index scoring technique. 22. The computerized method of claim 1, further comprising determining a confidence interval for the score based on a parametric or non-parametric computational bootstrapping technique. 23. A computer system for quantifying the perturbation of a biological system in response to an agent, the system comprising at least one processor configured or adapted to:
receive a set of treatment data corresponding to a response of a biological system to an agent, wherein the biological system includes or comprises a plurality of biological entities, each biological entity interacting with at least one other of the biological entities; receive a set of control data corresponding to the biological system not exposed to the agent; provide a computational causal network model that represents the biological system and includes or comprises:
nodes representing the biological entities,
edges representing relationships between the biological entities, and
direction values, for the nodes, representing the expected direction of change between the control data and the treatment data;
calculate activity measures, for the nodes, representing a difference between the treatment data and the control data; calculate weight values for the nodes, wherein at least one weight value is different from at least one other weight value; and generate a score for the computational model representative of the perturbation of the biological system to the agent, wherein the score is based on the direction values, the weight values and the activity measures. 24. (canceled) 25. (canceled) | Systems and methods are directed to computerized methods and one or more computer processors for quantifying the perturbation of a biological system in response to an agent. A set of treatment data corresponding to a response of a biological system to an agent and a set of control data are received. A computational causal network model represents the biological system and includes nodes representing biological entities, edges representing relationships between the biological entities, and direction values representing the expected direction of change between the control data and the treatment data. Activity measures are calculated and represent a difference between the treatment data and the control data, and weight values are calculated for the nodes. A score for the computational model is generated representative of the perturbation of the biological system to the agent and is based on the direction values, the weight values and the activity measures.1. A computerized method for quantifying the perturbation of a biological system in response to an agent, comprising
receiving, at a first processor, a set of treatment data corresponding to a response of a biological system to an agent, wherein the biological system includes or comprises a plurality of biological entities, each biological entity interacting with at least one other of the biological entities; receiving, at a second processor, a set of control data corresponding to the biological system not exposed to the agent; providing, at a third processor, a computational causal network model that represents the biological system and includes or comprises:
nodes representing the biological entities,
edges representing relationships between the biological entities, and
direction values, for the nodes, representing the expected direction of change between the control data and the treatment data;
calculating, with a fourth processor, activity measures, for the nodes, representing a difference between the treatment data and the control data;
calculating, with a fifth processor, weight values for the nodes, wherein at least one weight value is different from at least one other weight value; and
generating, with a sixth processor, a score for the computational model representative of the perturbation of the biological system to the agent, wherein the score is based on the direction values, the weight values and the activity measures. 2. The computerized method of claim 1, wherein the biological system is represented by at least one mechanism hypothesis. 3. The computerized method of claim 1, wherein the biological system is represented by a plurality of computational causal network models or at least one computational causal network model comprising a plurality of mechanism hypotheses. 4. The computerized method of claim 1, further comprising normalizing the score based on the number of measurable nodes in the respective computational model. 5. The computerized method of claim 1, wherein the weight values represent a confidence in at least one of the set of treatment data and control data. 6. The computerized method of claim 1, wherein the weight values include or comprise local false non-discovery rates. 7. The computerized method of claim 1, further comprising calculating, with a seventh processor, an approximate distribution of the activity measures of nodes over a model or a mechanism hypotheses in a model; calculating, with an eighth processor, an expected value of activity measures with respect to the approximate distribution; and generating, with a ninth processor, a score for each computational model representative of the perturbation of the subset of the biological system to the agent, wherein the score is based on expected value. 8. The computerized method of claim 7, wherein the approximate distribution is based on the activity measures. 9. The computerized method of claim 7, wherein calculating an expected value comprises performing a rectangular approximation. 10. The computerized method of claim 1, further comprising calculating, with a tenth processor, a positive activation metric and a negative activation metric based on the activity measures, the positive and negative activation metrics representative of consistency and inconsistency, respectively, between the activity measures and the direction values with respect to the model; and generating, with an eleventh processor, a score for each computational model representative of the perturbation of the subset of the biological system to the agent, wherein the score is based on the positive and negative activation scores. 11. The computerized method of claim 1, wherein the positive activation metric, negative activation metric or both are based on local false non-discovery rates. 12. The computerized method of claim 1, wherein the activity measure is a fold-change value, and the fold-change value for each node includes or comprises a logarithm of the difference between the treatment data and the control data for the biological entity represented by the respective node. 13. The computerized method of claim 1, wherein the subset of the biological system includes or comprises at least one of cell proliferation mechanism, cellular stress mechanism, cell inflammation mechanism, and DNA repair mechanism. 14. The computerized method of claim 1, wherein the agent includes or comprises at least one of aerosol generated by heating tobacco, aerosol generated by combusting tobacco, tobacco smoke or cigarette smoke. 15. The computerized method of claim 1, wherein the agent includes or comprises a heterogeneous substance, including a molecule or an entity that is not present in or derived from the biological system. 16. The computerized method of claim 1, wherein the agent includes or comprises toxins, therapeutic compounds, stimulants, relaxants, natural products, manufactured products, and food substances. 17. The computerized method of claim 1, wherein the set of treatment data includes or comprises a plurality of sets of treatment data such that each measurable node includes or comprises a plurality of fold-change values defined by a first probability distribution and a plurality of weight values defined by a second probability distribution. 18. The computerized method of claim 1, wherein the set of treatment data includes or comprises a plurality of sets of treatment data such that each measurable node includes or comprises a plurality of fold-change values and the corresponding weight values. 19. The computerized method of claim 1, wherein the step of generating the score comprises a linear or a non-linear combination of the activity measures, the weight values, and the direction values; and a normalization of the combination by a scale factor. 20. The computerized method of claim 19, wherein the combination is an arithmetic combination, and the scale factor is the square root of the number of biological entities for which measured data are received. 21. The computerized method of claim 1, wherein the score is generated by a geometric perturbation index scoring technique, a probabilistic perturbation index scoring technique, or an expected perturbation index scoring technique. 22. The computerized method of claim 1, further comprising determining a confidence interval for the score based on a parametric or non-parametric computational bootstrapping technique. 23. A computer system for quantifying the perturbation of a biological system in response to an agent, the system comprising at least one processor configured or adapted to:
receive a set of treatment data corresponding to a response of a biological system to an agent, wherein the biological system includes or comprises a plurality of biological entities, each biological entity interacting with at least one other of the biological entities; receive a set of control data corresponding to the biological system not exposed to the agent; provide a computational causal network model that represents the biological system and includes or comprises:
nodes representing the biological entities,
edges representing relationships between the biological entities, and
direction values, for the nodes, representing the expected direction of change between the control data and the treatment data;
calculate activity measures, for the nodes, representing a difference between the treatment data and the control data; calculate weight values for the nodes, wherein at least one weight value is different from at least one other weight value; and generate a score for the computational model representative of the perturbation of the biological system to the agent, wherein the score is based on the direction values, the weight values and the activity measures. 24. (canceled) 25. (canceled) | 1,600 |
443 | 13,812,073 | 1,627 | The invention provides new therapeutic uses of 1-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]-piperazine and pharmaceutically acceptable salts thereof. | 1-8. (canceled) 9. A method for the long-term treatment of a CNS disease comprising the long term administration of a therapeutically effective amount of 1-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine and pharmaceutically acceptable salts thereof to a patient in need thereof wherein said administration is not associated with weight gain. 10. A method for the treatment of a CNS disease in a patient in need thereof who has previously received medication (or is still receiving it) for the treatment of said disease which medication was ceased (or has to be ceased) due to weight related adverse events, the method comprising the administration of a therapeutically effective amount of 1-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine and pharmaceutically acceptable salts thereof to said patient. 11. A method for the treatment of a CNS disease in a patient in need thereof who is overweight, the method comprising the administration of a therapeutically effective amount of 1-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine and pharmaceutically acceptable salts thereof to said patient. 12. The method according to claim 11 wherein said patient is characterised by a BMI above 25. 13. A method for treatment of a CNS disease in a patient in a need thereof, the method comprising the steps of a) determining the BMI of said patient; and b) administering a therapeutically effective amount of 1-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine and pharmaceutically acceptable salts thereof to said patient if the BMI is determined to be above 25. 14. A method of treating a CNS disease in a patient in need thereof, wherein said patient is suffering from a further disease wherein weight increase should be avoided, the method comprising the administration of a therapeutically effective amount of 1-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine and pharmaceutically acceptable salts thereof to said patient. 15. The method according to claim 14 wherein said further disease said patient is selected from type II diabetes, hypertension or coronary heart diseases, or said patient is abstaining from nicotine. 16. A method for the treatment of a CNS disease in a patient in need thereof, the method comprising the steps of a) diagnosing whether said patient is suffering from a disease wherein weight gain should be avoided; and b) administering a therapeutically effective amount of 1-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine and pharmaceutically acceptable salts thereof to said patient if said diagnosis shows that said patient is suffering from a disease wherein weight gain should be avoided. 17. The method according to claim 16, wherein the disease being diagnosed for in step a) is selected from type II diabetes, hypertension and coronary heart diseases, or whether said patient is abstaining from nicotine. 18. The method according to claim 9, wherein said CNS disease is selected from depression, anxiety, chronic pain and abuse. 19-28. (canceled) 29. The method according to claim 10, wherein said CNS disease is selected from depression, anxiety, chronic pain and abuse. 30. The method according to claim 11, wherein said CNS disease is selected from depression, anxiety, chronic pain and abuse. 31. The method according to claim 13, wherein said CNS disease is selected from depression, anxiety, chronic pain and abuse. 32. The method according to claim 14, wherein said CNS disease is selected from depression, anxiety, chronic pain and abuse. 33. The method according to claim 16, wherein said CNS disease is selected from depression, anxiety, chronic pain and abuse. | The invention provides new therapeutic uses of 1-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]-piperazine and pharmaceutically acceptable salts thereof.1-8. (canceled) 9. A method for the long-term treatment of a CNS disease comprising the long term administration of a therapeutically effective amount of 1-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine and pharmaceutically acceptable salts thereof to a patient in need thereof wherein said administration is not associated with weight gain. 10. A method for the treatment of a CNS disease in a patient in need thereof who has previously received medication (or is still receiving it) for the treatment of said disease which medication was ceased (or has to be ceased) due to weight related adverse events, the method comprising the administration of a therapeutically effective amount of 1-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine and pharmaceutically acceptable salts thereof to said patient. 11. A method for the treatment of a CNS disease in a patient in need thereof who is overweight, the method comprising the administration of a therapeutically effective amount of 1-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine and pharmaceutically acceptable salts thereof to said patient. 12. The method according to claim 11 wherein said patient is characterised by a BMI above 25. 13. A method for treatment of a CNS disease in a patient in a need thereof, the method comprising the steps of a) determining the BMI of said patient; and b) administering a therapeutically effective amount of 1-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine and pharmaceutically acceptable salts thereof to said patient if the BMI is determined to be above 25. 14. A method of treating a CNS disease in a patient in need thereof, wherein said patient is suffering from a further disease wherein weight increase should be avoided, the method comprising the administration of a therapeutically effective amount of 1-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine and pharmaceutically acceptable salts thereof to said patient. 15. The method according to claim 14 wherein said further disease said patient is selected from type II diabetes, hypertension or coronary heart diseases, or said patient is abstaining from nicotine. 16. A method for the treatment of a CNS disease in a patient in need thereof, the method comprising the steps of a) diagnosing whether said patient is suffering from a disease wherein weight gain should be avoided; and b) administering a therapeutically effective amount of 1-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine and pharmaceutically acceptable salts thereof to said patient if said diagnosis shows that said patient is suffering from a disease wherein weight gain should be avoided. 17. The method according to claim 16, wherein the disease being diagnosed for in step a) is selected from type II diabetes, hypertension and coronary heart diseases, or whether said patient is abstaining from nicotine. 18. The method according to claim 9, wherein said CNS disease is selected from depression, anxiety, chronic pain and abuse. 19-28. (canceled) 29. The method according to claim 10, wherein said CNS disease is selected from depression, anxiety, chronic pain and abuse. 30. The method according to claim 11, wherein said CNS disease is selected from depression, anxiety, chronic pain and abuse. 31. The method according to claim 13, wherein said CNS disease is selected from depression, anxiety, chronic pain and abuse. 32. The method according to claim 14, wherein said CNS disease is selected from depression, anxiety, chronic pain and abuse. 33. The method according to claim 16, wherein said CNS disease is selected from depression, anxiety, chronic pain and abuse. | 1,600 |
444 | 13,494,398 | 1,644 | Provided herein, in one aspect, are antibodies that immunospecifically bind to PSGL-1, polynucleotides comprising nucleotide sequences encoding such antibodies, and expression vectors and host cells for producing such antibodies. Also provided herein are kits and pharmaceutical compositions comprising antibodies that specifically bind to PSGL-1, as well as methods of treating a disorder or disease caused by or associated with increased proliferation and/or numbers of activated T cells using the antibodies described herein. | 1. A monoclonal antibody which immunospecifically binds to human PSGL-1 comprising:
(i) a variable light (“VL”) chain region comprising the amino acid sequence of SEQ ID NO: 3; (ii) a heavy chain comprising variable heavy (“VH”) chain region comprising the amino acid sequence of SEQ ID NO: 4; and (iii) a human IgG4 constant region which contains a Serine to Proline substitution at amino acid 228 of the heavy chain numbered according to the EU index. 2. A monoclonal antibody which immunospecifically binds to human PSGL-1 comprising:
(i) a light chain comprising the amino acid sequence of SEQ ID NO: 1; and (ii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 2. 3. A monoclonal antibody which immunospecifically binds to human PSGL-1, comprising:
(i) a heavy chain consisting of SEQ ID NO: 2; and (ii) a light chain consisting of SEQ ID NO: 1. 4. A monoclonal antibody which immunospecifically binds to human PSGL-1 and comprises a heavy chain comprising:
(i) a VH chain region comprising SEQ ID NOs: 8, 9, and 10; and (ii) a human IgG4 heavy chain constant region containing a Serine to Proline amino acid substitution at amino acid 228 of the heavy chain numbered according to the EU index. 5. The monoclonal antibody of claim 4, wherein the monoclonal antibody further comprises a light chain comprising a VL chain region comprising SEQ ID NOs: 5, 6, and 7. 6. The monoclonal antibody of claim 1, wherein the antibody is purified. 7. A pharmaceutical composition comprising the monoclonal antibody of claim 1 and a pharmaceutically acceptable carrier. 8. The pharmaceutical composition of claim 7, wherein the monoclonal antibody is purified. 9. An antibody heavy chain comprising SEQ ID NO: 2. 10. A kit comprising a first container containing the monoclonal antibody of claim 1. 11. An injection device containing the monoclonal antibody of claim 1. 12. The injection device of claim 11, wherein the injection device is a syringe. 13. A method for treating an inflammatory disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of the monoclonal antibody of claim 1. 14. A method for treating an inflammatory disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 7. 15. The method of claim 13, wherein the inflammatory disorder is an autoimmune disease. 16. The method of claim 13, wherein the inflammatory disorder is: psoriasis, plaque psoriasis, chronic plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, or diabetes. 17. The monoclonal antibody of claim 2, wherein the antibody is purified. 18. A pharmaceutical composition comprising the monoclonal antibody of claim and a pharmaceutically acceptable carrier. 19. The monoclonal antibody of claim 4, wherein the antibody is purified. 20. A pharmaceutical composition comprising the monoclonal antibody of claim 4 and a pharmaceutically acceptable carrier. | Provided herein, in one aspect, are antibodies that immunospecifically bind to PSGL-1, polynucleotides comprising nucleotide sequences encoding such antibodies, and expression vectors and host cells for producing such antibodies. Also provided herein are kits and pharmaceutical compositions comprising antibodies that specifically bind to PSGL-1, as well as methods of treating a disorder or disease caused by or associated with increased proliferation and/or numbers of activated T cells using the antibodies described herein.1. A monoclonal antibody which immunospecifically binds to human PSGL-1 comprising:
(i) a variable light (“VL”) chain region comprising the amino acid sequence of SEQ ID NO: 3; (ii) a heavy chain comprising variable heavy (“VH”) chain region comprising the amino acid sequence of SEQ ID NO: 4; and (iii) a human IgG4 constant region which contains a Serine to Proline substitution at amino acid 228 of the heavy chain numbered according to the EU index. 2. A monoclonal antibody which immunospecifically binds to human PSGL-1 comprising:
(i) a light chain comprising the amino acid sequence of SEQ ID NO: 1; and (ii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 2. 3. A monoclonal antibody which immunospecifically binds to human PSGL-1, comprising:
(i) a heavy chain consisting of SEQ ID NO: 2; and (ii) a light chain consisting of SEQ ID NO: 1. 4. A monoclonal antibody which immunospecifically binds to human PSGL-1 and comprises a heavy chain comprising:
(i) a VH chain region comprising SEQ ID NOs: 8, 9, and 10; and (ii) a human IgG4 heavy chain constant region containing a Serine to Proline amino acid substitution at amino acid 228 of the heavy chain numbered according to the EU index. 5. The monoclonal antibody of claim 4, wherein the monoclonal antibody further comprises a light chain comprising a VL chain region comprising SEQ ID NOs: 5, 6, and 7. 6. The monoclonal antibody of claim 1, wherein the antibody is purified. 7. A pharmaceutical composition comprising the monoclonal antibody of claim 1 and a pharmaceutically acceptable carrier. 8. The pharmaceutical composition of claim 7, wherein the monoclonal antibody is purified. 9. An antibody heavy chain comprising SEQ ID NO: 2. 10. A kit comprising a first container containing the monoclonal antibody of claim 1. 11. An injection device containing the monoclonal antibody of claim 1. 12. The injection device of claim 11, wherein the injection device is a syringe. 13. A method for treating an inflammatory disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of the monoclonal antibody of claim 1. 14. A method for treating an inflammatory disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 7. 15. The method of claim 13, wherein the inflammatory disorder is an autoimmune disease. 16. The method of claim 13, wherein the inflammatory disorder is: psoriasis, plaque psoriasis, chronic plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, or diabetes. 17. The monoclonal antibody of claim 2, wherein the antibody is purified. 18. A pharmaceutical composition comprising the monoclonal antibody of claim and a pharmaceutically acceptable carrier. 19. The monoclonal antibody of claim 4, wherein the antibody is purified. 20. A pharmaceutical composition comprising the monoclonal antibody of claim 4 and a pharmaceutically acceptable carrier. | 1,600 |
445 | 14,208,348 | 1,613 | Described are transdermal drug delivery systems for the transdermal administration of tertiary amine drugs, such as rivastigmine, fentanyl or rotigotine, comprising a polymer matrix comprising a free base form of the drug and at least one carboxyl group-containing compound. In some embodiments, the systems include a rate-controlling membrane and a skin-contacting face adhesive apart from the polymer matrix. | 1. A transdermal drug delivery system comprising a polymer matrix comprising the free base form of a tertiary amine drug and at least one carboxyl group-containing compound, wherein the relative amounts of free base and carboxyl group-containing compound is such that greater than 50% of the free base is associated with a carboxylic acid group to form a salt. 2. The transdermal drug delivery system according to claim 1, wherein the relative amounts of free base and carboxyl group-containing compound is such that at least 60% of the free base is associated with a carboxylic acid group to form a salt. 3. The transdermal drug delivery system according to claim 1, wherein the relative amounts of free base and carboxyl group-containing compound is such that at least 70% of the free base is associated with a carboxylic acid group to form a salt. 4. The transdermal drug delivery system according to claim 1, wherein the relative amounts of free base and carboxyl group-containing compound is such that at least 80% of the free base is associated with a carboxylic acid group to form a salt. 5. The transdermal drug delivery system according to claim 1, wherein the relative amounts of free base and carboxyl group-containing compound is such that at least 90% of the free base is associated with a carboxylic acid group to form a salt. 6. The transdermal drug delivery system according to claim 1, wherein the relative amounts of free base and carboxyl group-containing compound is such that about 100% of the free base is associated with a carboxylic acid group to form a salt. 7. The transdermal drug delivery system according to claim 1, wherein at least one carboxyl group-containing compound is a carrier polymer comprising carboxy-functional groups. 8. The transdermal drug delivery system according to claim 1, wherein at least one carboxyl group-containing compound is an acrylic pressure-sensitive adhesive polymer comprising carboxy-functional groups. 9. The transdermal drug delivery system according to claim 1, wherein at least one carboxyl group-containing compound is a polymeric carboxylic acid. 10. The transdermal drug delivery system according to claim 9, wherein the polymeric carboxylic acid is selected from the group consisting of anionic copolymers based on methacrylic acid and methyl methacrylate, carbomer polymers, carbopol polymers, vinyl polymers containing carboxylic acid groups, carboxyl group-containing cellulose polymers and carboxyl group-containing starches. 11. The transdermal drug delivery system according to claim 1, wherein the tertiary amine drug is selected from the group consisting of amiodarone, amitriptyline, atropine, benztropine, biperiden, bornaprine, bupivacaine, chlorpheniramine, cinnarizine, clomipramine, cyclopentolate, darifenacin, dexetimide, dicyclomine, diltiazem, diphenhydramine, doxepin, ethopropazine, fentanyl, flavoxate, homatropine, imipramine, loxapine, mazaticol, metixene, oxybutin, oxyphencyclimine, phenglutarimide, physostigmine, piperidolate, pirenzepine, procyclidine, profenamine, propiverine, rivastigmine, rotogotine, scopolamine, telenzepine, theophylline, tolterodine, trimipramine, trihexyphenidyl, tropatepine, and tropicamide.rivastigmine. 12. The transdermal drug delivery system according to claim 1, wherein the composition does not include a penetration enhancer comprising a carboxylic acid group. 13. The transdermal drug delivery system according to claim 1, wherein the composition does not include a monocarboxylic fatty acid. 14. The transdermal drug delivery system according to claim 1, wherein the polymer matrix further comprises an antioxidant. 15. The transdermal drug delivery system according to claim 1, wherein the polymer matrix further comprises a plasticizer. 16. The transdermal drug delivery system according to claim 1, wherein the polymer matrix comprises:
about 10% to about 40% by weight of a free base form of the tertiary amine drug; about 0% to about 90% by weight of a carrier polymer, optionally containing carboxyl-group containing carboxy-functional groups; about 0% to about 90% by weight of a carboxyl group-containing compound; optionally, about 0% to about 1% of an antioxidant; and optionally, about 0% to about 20% of a pharmaceutically acceptable excipient, wherein the relative amounts of free base and carboxyl groups is such that greater than 50% of the free base is associated with a carboxylic acid group to form a salt. 17. The transdermal drug delivery system according to claim 1, wherein the polymer matrix comprises an amount of tertiary amine drug effective to deliver a therapeutically effective amount of tertiary amine drug over a period of time selected from the group consisting of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days. 18. The transdermal drug delivery system according to claim 1, wherein the tertiary amine drug is rivastigmine and the polymer matrix comprises an amount of rivastigmine selected from the group consisting of (i) an amount effective to deliver at least about 4.6 mg/day over a period of time selected from the group consisting of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days; (ii) an amount effective to deliver at least about 9.5 mg/day over a period of time selected from the group consisting of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days; (iii) about 32-65 mg rivastigmine; and (iv) about 67-126 mg rivastigmine. 19. The transdermal drug delivery system according to claim 1, wherein the polymer matrix has a coat weight of about 10-15 mg/cm2. 20. A method for administering a tertiary amine drug, comprising applying to the skin or mucosa of a subject in need thereof a transdermal drug delivery system according to claim 1. 21. A method of making a transdermal drug delivery system for a tertiary amine drug, comprising forming a polymer matrix comprising a free base form of the tertiary amine drug and at least one carboxyl group-containing compound, wherein the relative amounts of free base and carboxyl group-containing compound is such that greater than 50% of the free base is associated with a carboxylic acid group to form a salt. 22. A transdermal drug delivery system comprising a polymer matrix comprising the free base form of a tertiary amine drug, a rate-controlling membrane, and a face adhesive comprising a carboxyl group-containing compound. 23. The transdermal drug delivery system according to claim 22, wherein the rate-controlling membrane comprises a polymer selected from the group consisting of polyethylene, polyolefin, and/or ethylene vinyl acetate polymers. 24. The transdermal drug delivery system according to claim 22, wherein the polymer matrix comprises a polymer selected from the group consisting of acrylic polymers, silicon polymers, polyisobutylene polymers, styrene-isoprene styrene block copolymers, and mixtures of two or more thereof. 25. The transdermal drug delivery system according to claim 22, wherein the face adhesive comprises a polymer selected from the group consisting of acrylic polymers, silicon polymers, and mixtures of two or more thereof. 26. The transdermal drug delivery system according to claim 22, wherein the system is effective to deliver a therapeutically effective amount of tertiary amine drug over a period of time selected from the group consisting of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days. 27. The transdermal drug delivery system according to claim 22, wherein the tertiary amine drug is rivastigmine and the polymer matrix comprises an amount of rivastigmine selected from the group consisting of (i) an amount effective to deliver at least about 4.6 mg/day over a period of time selected from the group consisting of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days; (ii) an amount effective to deliver at least about 9.5 mg/day over a period of time selected from the group consisting of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days; (iii) about 32-65 mg rivastigmine; and (iv) about 67-126 mg rivastigmine. 28. The transdermal drug delivery system according to claim 22, wherein the polymer matrix has a coat weight of about 10-15 mg/cm2. 29. A method for administering a tertiary amine drug, comprising applying to the skin or mucosa of a subject in need thereof a transdermal drug delivery system according to claim 22. 30. A method of making a transdermal drug delivery system for a tertiary amine drug, comprising combining
a polymer matrix comprising a free base form of the tertiary amine drug; a rate-controlling membrane; and a face adhesive comprising a carboxyl group-containing compound. | Described are transdermal drug delivery systems for the transdermal administration of tertiary amine drugs, such as rivastigmine, fentanyl or rotigotine, comprising a polymer matrix comprising a free base form of the drug and at least one carboxyl group-containing compound. In some embodiments, the systems include a rate-controlling membrane and a skin-contacting face adhesive apart from the polymer matrix.1. A transdermal drug delivery system comprising a polymer matrix comprising the free base form of a tertiary amine drug and at least one carboxyl group-containing compound, wherein the relative amounts of free base and carboxyl group-containing compound is such that greater than 50% of the free base is associated with a carboxylic acid group to form a salt. 2. The transdermal drug delivery system according to claim 1, wherein the relative amounts of free base and carboxyl group-containing compound is such that at least 60% of the free base is associated with a carboxylic acid group to form a salt. 3. The transdermal drug delivery system according to claim 1, wherein the relative amounts of free base and carboxyl group-containing compound is such that at least 70% of the free base is associated with a carboxylic acid group to form a salt. 4. The transdermal drug delivery system according to claim 1, wherein the relative amounts of free base and carboxyl group-containing compound is such that at least 80% of the free base is associated with a carboxylic acid group to form a salt. 5. The transdermal drug delivery system according to claim 1, wherein the relative amounts of free base and carboxyl group-containing compound is such that at least 90% of the free base is associated with a carboxylic acid group to form a salt. 6. The transdermal drug delivery system according to claim 1, wherein the relative amounts of free base and carboxyl group-containing compound is such that about 100% of the free base is associated with a carboxylic acid group to form a salt. 7. The transdermal drug delivery system according to claim 1, wherein at least one carboxyl group-containing compound is a carrier polymer comprising carboxy-functional groups. 8. The transdermal drug delivery system according to claim 1, wherein at least one carboxyl group-containing compound is an acrylic pressure-sensitive adhesive polymer comprising carboxy-functional groups. 9. The transdermal drug delivery system according to claim 1, wherein at least one carboxyl group-containing compound is a polymeric carboxylic acid. 10. The transdermal drug delivery system according to claim 9, wherein the polymeric carboxylic acid is selected from the group consisting of anionic copolymers based on methacrylic acid and methyl methacrylate, carbomer polymers, carbopol polymers, vinyl polymers containing carboxylic acid groups, carboxyl group-containing cellulose polymers and carboxyl group-containing starches. 11. The transdermal drug delivery system according to claim 1, wherein the tertiary amine drug is selected from the group consisting of amiodarone, amitriptyline, atropine, benztropine, biperiden, bornaprine, bupivacaine, chlorpheniramine, cinnarizine, clomipramine, cyclopentolate, darifenacin, dexetimide, dicyclomine, diltiazem, diphenhydramine, doxepin, ethopropazine, fentanyl, flavoxate, homatropine, imipramine, loxapine, mazaticol, metixene, oxybutin, oxyphencyclimine, phenglutarimide, physostigmine, piperidolate, pirenzepine, procyclidine, profenamine, propiverine, rivastigmine, rotogotine, scopolamine, telenzepine, theophylline, tolterodine, trimipramine, trihexyphenidyl, tropatepine, and tropicamide.rivastigmine. 12. The transdermal drug delivery system according to claim 1, wherein the composition does not include a penetration enhancer comprising a carboxylic acid group. 13. The transdermal drug delivery system according to claim 1, wherein the composition does not include a monocarboxylic fatty acid. 14. The transdermal drug delivery system according to claim 1, wherein the polymer matrix further comprises an antioxidant. 15. The transdermal drug delivery system according to claim 1, wherein the polymer matrix further comprises a plasticizer. 16. The transdermal drug delivery system according to claim 1, wherein the polymer matrix comprises:
about 10% to about 40% by weight of a free base form of the tertiary amine drug; about 0% to about 90% by weight of a carrier polymer, optionally containing carboxyl-group containing carboxy-functional groups; about 0% to about 90% by weight of a carboxyl group-containing compound; optionally, about 0% to about 1% of an antioxidant; and optionally, about 0% to about 20% of a pharmaceutically acceptable excipient, wherein the relative amounts of free base and carboxyl groups is such that greater than 50% of the free base is associated with a carboxylic acid group to form a salt. 17. The transdermal drug delivery system according to claim 1, wherein the polymer matrix comprises an amount of tertiary amine drug effective to deliver a therapeutically effective amount of tertiary amine drug over a period of time selected from the group consisting of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days. 18. The transdermal drug delivery system according to claim 1, wherein the tertiary amine drug is rivastigmine and the polymer matrix comprises an amount of rivastigmine selected from the group consisting of (i) an amount effective to deliver at least about 4.6 mg/day over a period of time selected from the group consisting of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days; (ii) an amount effective to deliver at least about 9.5 mg/day over a period of time selected from the group consisting of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days; (iii) about 32-65 mg rivastigmine; and (iv) about 67-126 mg rivastigmine. 19. The transdermal drug delivery system according to claim 1, wherein the polymer matrix has a coat weight of about 10-15 mg/cm2. 20. A method for administering a tertiary amine drug, comprising applying to the skin or mucosa of a subject in need thereof a transdermal drug delivery system according to claim 1. 21. A method of making a transdermal drug delivery system for a tertiary amine drug, comprising forming a polymer matrix comprising a free base form of the tertiary amine drug and at least one carboxyl group-containing compound, wherein the relative amounts of free base and carboxyl group-containing compound is such that greater than 50% of the free base is associated with a carboxylic acid group to form a salt. 22. A transdermal drug delivery system comprising a polymer matrix comprising the free base form of a tertiary amine drug, a rate-controlling membrane, and a face adhesive comprising a carboxyl group-containing compound. 23. The transdermal drug delivery system according to claim 22, wherein the rate-controlling membrane comprises a polymer selected from the group consisting of polyethylene, polyolefin, and/or ethylene vinyl acetate polymers. 24. The transdermal drug delivery system according to claim 22, wherein the polymer matrix comprises a polymer selected from the group consisting of acrylic polymers, silicon polymers, polyisobutylene polymers, styrene-isoprene styrene block copolymers, and mixtures of two or more thereof. 25. The transdermal drug delivery system according to claim 22, wherein the face adhesive comprises a polymer selected from the group consisting of acrylic polymers, silicon polymers, and mixtures of two or more thereof. 26. The transdermal drug delivery system according to claim 22, wherein the system is effective to deliver a therapeutically effective amount of tertiary amine drug over a period of time selected from the group consisting of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days. 27. The transdermal drug delivery system according to claim 22, wherein the tertiary amine drug is rivastigmine and the polymer matrix comprises an amount of rivastigmine selected from the group consisting of (i) an amount effective to deliver at least about 4.6 mg/day over a period of time selected from the group consisting of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days; (ii) an amount effective to deliver at least about 9.5 mg/day over a period of time selected from the group consisting of at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days and at least 7 days; (iii) about 32-65 mg rivastigmine; and (iv) about 67-126 mg rivastigmine. 28. The transdermal drug delivery system according to claim 22, wherein the polymer matrix has a coat weight of about 10-15 mg/cm2. 29. A method for administering a tertiary amine drug, comprising applying to the skin or mucosa of a subject in need thereof a transdermal drug delivery system according to claim 22. 30. A method of making a transdermal drug delivery system for a tertiary amine drug, comprising combining
a polymer matrix comprising a free base form of the tertiary amine drug; a rate-controlling membrane; and a face adhesive comprising a carboxyl group-containing compound. | 1,600 |
446 | 14,762,064 | 1,618 | An oil-in-water nanoemulsion composition for MRI, comprising an aqueous phase, a lipid phase as nanodroplets comprising an oil and magnetic particles based on an iron compound and covered with one or several C8-C22 fatty acids, and a mixture of surfactants at the interface between the aqueous and lipid phases, the mixture of surfactants comprising at least one amphiphilic lipid and at least one amphiphilic targeting ligand. | 1. An oil-in-water nanoemulsion composition, comprising:
50 to 90% by weight of aqueous phase; 9.5 to 49.5% by weight of lipid phase nanodroplets, wherein the lipid phase nanodroplets comprise an oil and magnetic particles, wherein the oil comprises at least 70% by weight of C6-C18 saturated fatty acid glycerides, and wherein the magnetic particles comprise an iron compound and are covered with one or more C8-C22 fatty acids; and 0.38 to 4.95% by weight of a mixture of surfactants at the interface between the aqueous and lipid phases, wherein the mixture of surfactants comprises at least one amphiphilic lipid and at least one amphiphilic targeting ligand, and wherein the mixture of surfactants is 4 to 10% by weight of the oil;
wherein the composition comprises more than 100 mmol of iron per liter of composition. 2. The composition according to claim 1, wherein the amphiphilic targeting ligand is 0.01 to 10% mole/mole of the total amount of surfactants. 3. The composition according to claim 1, wherein the saturated fatty acid glycerides are saturated fatty acid triglycerides. 4. The composition according to claim 1, wherein the at least 70% by weight of C6-C18 saturated fatty acid glycerides is at least 70% by weight of C6-C14 fatty acid glycerides or at least 70% by weight of C8+C10 fatty acid glycerides. 5. The composition according to claim 1, characterized in that the oil comprises a mixture of diglycerides and/or triglycerides of one or several fatty acids selected from caprylic acid, capric acid, linoleic acid, succinic acid, and a methyl, hydroperoxyl, hydroxyl, oxoyl, epoxyl, methoxyl, halogenated, amine, cyanyl, nitrosyl or thiol derivative of the foregoing. 6. The composition according to claim 1, wherein the iron compound is maghemite, magnetite or a mixture thereof. 7. The composition according to claim 1, wherein the magnetic particles are superparamagnetic. 8. The composition according to claim 1, wherein the mixture of surfactants comprises 80 to 96.95% mole/mole of amphiphilic lipid, 3 to 15% mole/mole of pegylated lipid, and 0.05 to 5% mole/mole of amphiphilic targeting ligand. 9. The composition according to claim 1, wherein the amphiphilic lipid is a phospholipid. 10. The composition according to claim 1, wherein the amphiphilic targeting ligand has the formula Bio-L-Lipo, wherein Bio is the targeting ligand localized at the external surface of the nanodroplets, Lipo is a lipophilic group extending within the mixture of surfactants, and L is a binding group connecting Bio and Lipo wherein L is selected from the group consisting of:
a simple bond; squarate; C1-C6 alkylene; polyethylene glycol; and P1-I-P2, wherein P1 and P2 are independently selected from the group consisting of 0, S, NH, a simple bond, CO2, NHCO, CONH, NHCONH, NHCSNH, SO2NH—, NHSO2—, and squarate; and wherein I is selected from the group consisting of: alkylene; alkoxyalkylene; polyalkoxyalkylene; alkylene interrupted with one or several squarates; alkylene interrupted with one or several aryls; alkylene interrupted with one or several groups selected from —NH—, —O—, —CO—, —NH(CO)—, —(CO)NH—, —O—(CO)—, and —(OC)O—; alkenylene; alkynylene; alkenylene interrupted with one or several groups selected from —NH—, —O—, —CO—, —NH(CO)—, —(CO)NH—, —O(CO)—, and —(OC)O—; and alkynylene interrupted with one or several groups selected from —NH—, —O—, —CO—, —NH(CO)—, —(CO)NH—, and —O(CO)—. 11. The composition according to claim 1, wherein the targeting ligand of the amphiphilic targeting ligand is selected from the group consisting of peptides, pseudopeptides, peptidomimetics, amino acids, agents for targeting integrins, glycoproteins, lectins, pteroic or aminopteroic derivatives, derivatives of folic and antifolic acid, antibodies or antibody fragments, steroids, oligonucleotides, sequences of ribonucleic acid, sequences of deoxyribonucleic acid, hormones, proteins, mono- or poly-saccharides, and compounds with a benzothiazole, benzofurane, styrylbenzoxazole/thiazole/imidazole/quinoline, or styrylpiridine backbone. 12. The composition according to claim 1, wherein the targeting ligand of the amphiphilic targeting ligand is a ligand of a target associated with angiogenesis. 13. The composition according to claim 1, wherein the amphiphilic targeting ligand has the formula:
or one of its salts. 14. A method for preparing the oil-in-water nanoemulsion composition of claim 1, the method comprising the steps of:
a) solubilizing the magnetic particles in the oil to form the lipid phase; and b) mixing the lipid phase and the aqueous phase, into which the mixture of surfactants is diffused, to form the lipid phase nanodroplets and thereby the oil-in-water nanoemulsion composition. 15. A contrast product comprising an oil-in-water nanoemulsion composition that comprises:
50 to 90% by weight of aqueous phase; 9.5 to 49.5% by weight of lipid phase nanodroplets, wherein the lipid phase nanodroplets comprise an oil and magnetic particles, wherein the oil comprises at least 70% by weight of C6-C18 saturated fatty acid glycerides, and wherein the magnetic particles comprise an iron compound and are covered with one or more C8-C22 fatty acids; and 0.38 to 4.95% by weight of a mixture of surfactants at the interface between the aqueous and lipid phases, wherein the mixture of surfactants comprises at least one amphiphilic lipid and at least one amphiphilic targeting ligand, and wherein the mixture of surfactants is 4 to 10% by weight of the oil;
wherein the composition comprises more than 100 mmol of iron per liter of composition. 16. The contrast product according to claim 15, wherein the targeting ligand of the amphiphilic targeting ligand is a ligand of a target associated with angiogenesis. 17. A method for obtaining one or several images of an entire body of an individual or a portion of the body of the individual, the method comprising performing a medical imaging technique on the entire body or the portion of the body of the individual, wherein said entire body or said portion of the body of the individual comprises the oil-in-water nanoemulsion composition according to claim 1 to obtain the one or several images thereof, wherein said image(s) is(are) associated with the magnetic particles of the oil-in-water nanoemulsion composition. 18. A method for evaluating angiogenesis in an individual comprising the steps of:
a) performing a medical imaging technique on the individual's entire body or of a portion of the individual's body, wherein said entire body or said portion of the body of the individual comprises the oil-in-water nanoemulsion composition according to claim 12, to obtain the one or several images thereof, wherein said image(s) is(are) associated with the magnetic particles of the oil-in-water nanoemulsion composition; and b) viewing said images to evaluate angiogenesis in the entire body or the portion of the body of the individual. 19. A method for evaluating the efficiency of an anti-angiogenic treatment administered to an individual, the method comprising the steps of:
a) evaluating angiogenesis in the individual having received the anti-angiogenic treatment by conducting the method of claim 18; and b) comparing the angiogenesis evaluated according to step a) with an angiogenesis reference from the individual from before the anti-angiogenic treatment was administered to the individual to evaluate the efficiency of the anti-angiogenic treatment. 20. (canceled) | An oil-in-water nanoemulsion composition for MRI, comprising an aqueous phase, a lipid phase as nanodroplets comprising an oil and magnetic particles based on an iron compound and covered with one or several C8-C22 fatty acids, and a mixture of surfactants at the interface between the aqueous and lipid phases, the mixture of surfactants comprising at least one amphiphilic lipid and at least one amphiphilic targeting ligand.1. An oil-in-water nanoemulsion composition, comprising:
50 to 90% by weight of aqueous phase; 9.5 to 49.5% by weight of lipid phase nanodroplets, wherein the lipid phase nanodroplets comprise an oil and magnetic particles, wherein the oil comprises at least 70% by weight of C6-C18 saturated fatty acid glycerides, and wherein the magnetic particles comprise an iron compound and are covered with one or more C8-C22 fatty acids; and 0.38 to 4.95% by weight of a mixture of surfactants at the interface between the aqueous and lipid phases, wherein the mixture of surfactants comprises at least one amphiphilic lipid and at least one amphiphilic targeting ligand, and wherein the mixture of surfactants is 4 to 10% by weight of the oil;
wherein the composition comprises more than 100 mmol of iron per liter of composition. 2. The composition according to claim 1, wherein the amphiphilic targeting ligand is 0.01 to 10% mole/mole of the total amount of surfactants. 3. The composition according to claim 1, wherein the saturated fatty acid glycerides are saturated fatty acid triglycerides. 4. The composition according to claim 1, wherein the at least 70% by weight of C6-C18 saturated fatty acid glycerides is at least 70% by weight of C6-C14 fatty acid glycerides or at least 70% by weight of C8+C10 fatty acid glycerides. 5. The composition according to claim 1, characterized in that the oil comprises a mixture of diglycerides and/or triglycerides of one or several fatty acids selected from caprylic acid, capric acid, linoleic acid, succinic acid, and a methyl, hydroperoxyl, hydroxyl, oxoyl, epoxyl, methoxyl, halogenated, amine, cyanyl, nitrosyl or thiol derivative of the foregoing. 6. The composition according to claim 1, wherein the iron compound is maghemite, magnetite or a mixture thereof. 7. The composition according to claim 1, wherein the magnetic particles are superparamagnetic. 8. The composition according to claim 1, wherein the mixture of surfactants comprises 80 to 96.95% mole/mole of amphiphilic lipid, 3 to 15% mole/mole of pegylated lipid, and 0.05 to 5% mole/mole of amphiphilic targeting ligand. 9. The composition according to claim 1, wherein the amphiphilic lipid is a phospholipid. 10. The composition according to claim 1, wherein the amphiphilic targeting ligand has the formula Bio-L-Lipo, wherein Bio is the targeting ligand localized at the external surface of the nanodroplets, Lipo is a lipophilic group extending within the mixture of surfactants, and L is a binding group connecting Bio and Lipo wherein L is selected from the group consisting of:
a simple bond; squarate; C1-C6 alkylene; polyethylene glycol; and P1-I-P2, wherein P1 and P2 are independently selected from the group consisting of 0, S, NH, a simple bond, CO2, NHCO, CONH, NHCONH, NHCSNH, SO2NH—, NHSO2—, and squarate; and wherein I is selected from the group consisting of: alkylene; alkoxyalkylene; polyalkoxyalkylene; alkylene interrupted with one or several squarates; alkylene interrupted with one or several aryls; alkylene interrupted with one or several groups selected from —NH—, —O—, —CO—, —NH(CO)—, —(CO)NH—, —O—(CO)—, and —(OC)O—; alkenylene; alkynylene; alkenylene interrupted with one or several groups selected from —NH—, —O—, —CO—, —NH(CO)—, —(CO)NH—, —O(CO)—, and —(OC)O—; and alkynylene interrupted with one or several groups selected from —NH—, —O—, —CO—, —NH(CO)—, —(CO)NH—, and —O(CO)—. 11. The composition according to claim 1, wherein the targeting ligand of the amphiphilic targeting ligand is selected from the group consisting of peptides, pseudopeptides, peptidomimetics, amino acids, agents for targeting integrins, glycoproteins, lectins, pteroic or aminopteroic derivatives, derivatives of folic and antifolic acid, antibodies or antibody fragments, steroids, oligonucleotides, sequences of ribonucleic acid, sequences of deoxyribonucleic acid, hormones, proteins, mono- or poly-saccharides, and compounds with a benzothiazole, benzofurane, styrylbenzoxazole/thiazole/imidazole/quinoline, or styrylpiridine backbone. 12. The composition according to claim 1, wherein the targeting ligand of the amphiphilic targeting ligand is a ligand of a target associated with angiogenesis. 13. The composition according to claim 1, wherein the amphiphilic targeting ligand has the formula:
or one of its salts. 14. A method for preparing the oil-in-water nanoemulsion composition of claim 1, the method comprising the steps of:
a) solubilizing the magnetic particles in the oil to form the lipid phase; and b) mixing the lipid phase and the aqueous phase, into which the mixture of surfactants is diffused, to form the lipid phase nanodroplets and thereby the oil-in-water nanoemulsion composition. 15. A contrast product comprising an oil-in-water nanoemulsion composition that comprises:
50 to 90% by weight of aqueous phase; 9.5 to 49.5% by weight of lipid phase nanodroplets, wherein the lipid phase nanodroplets comprise an oil and magnetic particles, wherein the oil comprises at least 70% by weight of C6-C18 saturated fatty acid glycerides, and wherein the magnetic particles comprise an iron compound and are covered with one or more C8-C22 fatty acids; and 0.38 to 4.95% by weight of a mixture of surfactants at the interface between the aqueous and lipid phases, wherein the mixture of surfactants comprises at least one amphiphilic lipid and at least one amphiphilic targeting ligand, and wherein the mixture of surfactants is 4 to 10% by weight of the oil;
wherein the composition comprises more than 100 mmol of iron per liter of composition. 16. The contrast product according to claim 15, wherein the targeting ligand of the amphiphilic targeting ligand is a ligand of a target associated with angiogenesis. 17. A method for obtaining one or several images of an entire body of an individual or a portion of the body of the individual, the method comprising performing a medical imaging technique on the entire body or the portion of the body of the individual, wherein said entire body or said portion of the body of the individual comprises the oil-in-water nanoemulsion composition according to claim 1 to obtain the one or several images thereof, wherein said image(s) is(are) associated with the magnetic particles of the oil-in-water nanoemulsion composition. 18. A method for evaluating angiogenesis in an individual comprising the steps of:
a) performing a medical imaging technique on the individual's entire body or of a portion of the individual's body, wherein said entire body or said portion of the body of the individual comprises the oil-in-water nanoemulsion composition according to claim 12, to obtain the one or several images thereof, wherein said image(s) is(are) associated with the magnetic particles of the oil-in-water nanoemulsion composition; and b) viewing said images to evaluate angiogenesis in the entire body or the portion of the body of the individual. 19. A method for evaluating the efficiency of an anti-angiogenic treatment administered to an individual, the method comprising the steps of:
a) evaluating angiogenesis in the individual having received the anti-angiogenic treatment by conducting the method of claim 18; and b) comparing the angiogenesis evaluated according to step a) with an angiogenesis reference from the individual from before the anti-angiogenic treatment was administered to the individual to evaluate the efficiency of the anti-angiogenic treatment. 20. (canceled) | 1,600 |
447 | 15,010,973 | 1,639 | Provided herein, among other things, is method comprising: a) placing a planar absorbent support comprising an in vitro transcription and translation (IVTT) mix impregnated therein in contact with an array of in situ-assembled expression cassettes; and b) incubating the planar absorbent support and array under conditions by which the expressed cassettes are transcribed and translated by the impregnated IVTT components, thereby producing an array of proteins. Screening methods that employ the array of proteins are also provided. | 1. A method comprising:
a) placing a planar absorbent support comprising an in vitro transcription and translation (IVTT) mix impregnated therein in contact with an array of in situ-assembled expression cassettes; and b) incubating the planar absorbent support and array under conditions by which the expressed cassettes are transcribed and translated by the impregnated IVTT components, thereby producing an array of proteins. 2. The method of claim 1, wherein the expression cassettes encode variants of an enzyme. 3. The method of claim 2, wherein the planar absorbent support further comprises a substrate for the enzyme. 4. The method of claim 3, wherein the enzyme converts the substrate into an optically detectable product. 5. The method of claim 3, wherein the planar absorbent support further comprises a reporter system for detecting a reaction product. 6. The method of claim 5, wherein the reporter system comprises a product-activated riboswitch reporter. 7. The method of claim 1, wherein the expression cassettes are tethered to the array. 8. The method of claim 1, wherein the expression cassettes are not tethered to the array. 9. The method of claim 1, wherein the features on the array that comprise the expression cassettes are 10 μm to 1 mm in size. 10. The method of claim 1, wherein the planar absorbent support has a width in the range of 1 mm to 10 cm and, independently, a length in the range of 1 mm to 10 cm. 11. The method of claim 1, wherein, wherein the array of in situ-assembled expression cassettes comprises at least 1,000 features. 12. The method of claim 1, wherein the method comprises moistening a planar absorbent support that comprises a freeze dried IVTT mix impregnated therein, and placing the planar absorbent support on the array. 13. The method of claim 1, wherein the array of in situ-assembled expression cassettes are made using the following method:
(i) obtaining a mixture of multiple sets of oligonucleotides, wherein the oligonucleotides within each set each comprise a terminal indexer sequence and can be assembled to produce an expression cassette; and (ii) hybridizing the oligonucleotide mixture to an array, thereby spatially-separating the different sets of oligonucleotides from one another; (iii) contacting the array with a solution, thereby producing, for each feature bound by the oligonucleotides, a discrete droplet comprising one or more features; (iv) placing an immiscible liquid over the droplets, thereby producing, for each feature bound by the oligonucleotides, a discrete reaction chamber defined by a droplet; and (v) incubating the array under conditions by which an expression cassette is assembled in each of the reaction chambers. 14. The method of claim 13, wherein the synthon is assembled in (v) via polymerase chain assembly or ordered ligation. 15. The method of claim 13, wherein the droplets comprise double-stranded oligonucleotides or double-stranded extension products, and the solution comprises a Type IIs restriction endonuclease, a DNA ligase and ATP, wherein the products of digestion of the double-stranded oligonucleotides or double-stranded extension products by the Type IIs restriction endonuclease are ligated to one another in a defined order by the DNA ligase in the discrete reaction chambers, thereby producing the expression cassettes. 16. The method of claim 13, wherein the oligonucleotides are single-stranded oligonucleotides and the method comprises:
cleaving the terminal indexer sequence from the oligonucleotides to release assembly sequences from at least some of the oligonucleotides; and assembling the expression cassettes from the assembly sequences by polymerase chain assembly or by ligation. 17. The method of claim 13, wherein the cleaving the terminal indexer sequence from the oligonucleotide comprises cleaving a photocleavable linkage. 18. A screening method comprising:
a) placing a planar absorbent support comprising an in vitro transcription and translation (IVTT) mix impregnated therein in contact with an array of in situ-assembled expression cassettes, wherein the expression cassettes encode variants of an enzyme and the planar absorbent support further comprises a substrate for the enzyme; b) incubating the filter planar absorbent support and array under conditions by which the expressed cassettes are transcribed and translated by the impregnated IVTT components, thereby producing an array of enzyme variants that are in the presence of the substrate; and c) detecting the production of a reaction product in the planar absorbent support. 19. The screening method of claim 18, further comprising:
d) identifying a site in the planar absorbent support that contains more or less reaction product relative to a control site; and e) mapping the site identified in (d) to a feature in the array of expression cassettes, thereby identifying an enzyme variant that has altered activity. 20. The screening method of claim 18, wherein the enzyme converts the substrate into an optically detectable product. | Provided herein, among other things, is method comprising: a) placing a planar absorbent support comprising an in vitro transcription and translation (IVTT) mix impregnated therein in contact with an array of in situ-assembled expression cassettes; and b) incubating the planar absorbent support and array under conditions by which the expressed cassettes are transcribed and translated by the impregnated IVTT components, thereby producing an array of proteins. Screening methods that employ the array of proteins are also provided.1. A method comprising:
a) placing a planar absorbent support comprising an in vitro transcription and translation (IVTT) mix impregnated therein in contact with an array of in situ-assembled expression cassettes; and b) incubating the planar absorbent support and array under conditions by which the expressed cassettes are transcribed and translated by the impregnated IVTT components, thereby producing an array of proteins. 2. The method of claim 1, wherein the expression cassettes encode variants of an enzyme. 3. The method of claim 2, wherein the planar absorbent support further comprises a substrate for the enzyme. 4. The method of claim 3, wherein the enzyme converts the substrate into an optically detectable product. 5. The method of claim 3, wherein the planar absorbent support further comprises a reporter system for detecting a reaction product. 6. The method of claim 5, wherein the reporter system comprises a product-activated riboswitch reporter. 7. The method of claim 1, wherein the expression cassettes are tethered to the array. 8. The method of claim 1, wherein the expression cassettes are not tethered to the array. 9. The method of claim 1, wherein the features on the array that comprise the expression cassettes are 10 μm to 1 mm in size. 10. The method of claim 1, wherein the planar absorbent support has a width in the range of 1 mm to 10 cm and, independently, a length in the range of 1 mm to 10 cm. 11. The method of claim 1, wherein, wherein the array of in situ-assembled expression cassettes comprises at least 1,000 features. 12. The method of claim 1, wherein the method comprises moistening a planar absorbent support that comprises a freeze dried IVTT mix impregnated therein, and placing the planar absorbent support on the array. 13. The method of claim 1, wherein the array of in situ-assembled expression cassettes are made using the following method:
(i) obtaining a mixture of multiple sets of oligonucleotides, wherein the oligonucleotides within each set each comprise a terminal indexer sequence and can be assembled to produce an expression cassette; and (ii) hybridizing the oligonucleotide mixture to an array, thereby spatially-separating the different sets of oligonucleotides from one another; (iii) contacting the array with a solution, thereby producing, for each feature bound by the oligonucleotides, a discrete droplet comprising one or more features; (iv) placing an immiscible liquid over the droplets, thereby producing, for each feature bound by the oligonucleotides, a discrete reaction chamber defined by a droplet; and (v) incubating the array under conditions by which an expression cassette is assembled in each of the reaction chambers. 14. The method of claim 13, wherein the synthon is assembled in (v) via polymerase chain assembly or ordered ligation. 15. The method of claim 13, wherein the droplets comprise double-stranded oligonucleotides or double-stranded extension products, and the solution comprises a Type IIs restriction endonuclease, a DNA ligase and ATP, wherein the products of digestion of the double-stranded oligonucleotides or double-stranded extension products by the Type IIs restriction endonuclease are ligated to one another in a defined order by the DNA ligase in the discrete reaction chambers, thereby producing the expression cassettes. 16. The method of claim 13, wherein the oligonucleotides are single-stranded oligonucleotides and the method comprises:
cleaving the terminal indexer sequence from the oligonucleotides to release assembly sequences from at least some of the oligonucleotides; and assembling the expression cassettes from the assembly sequences by polymerase chain assembly or by ligation. 17. The method of claim 13, wherein the cleaving the terminal indexer sequence from the oligonucleotide comprises cleaving a photocleavable linkage. 18. A screening method comprising:
a) placing a planar absorbent support comprising an in vitro transcription and translation (IVTT) mix impregnated therein in contact with an array of in situ-assembled expression cassettes, wherein the expression cassettes encode variants of an enzyme and the planar absorbent support further comprises a substrate for the enzyme; b) incubating the filter planar absorbent support and array under conditions by which the expressed cassettes are transcribed and translated by the impregnated IVTT components, thereby producing an array of enzyme variants that are in the presence of the substrate; and c) detecting the production of a reaction product in the planar absorbent support. 19. The screening method of claim 18, further comprising:
d) identifying a site in the planar absorbent support that contains more or less reaction product relative to a control site; and e) mapping the site identified in (d) to a feature in the array of expression cassettes, thereby identifying an enzyme variant that has altered activity. 20. The screening method of claim 18, wherein the enzyme converts the substrate into an optically detectable product. | 1,600 |
448 | 14,860,781 | 1,615 | The invention disclosed herein is directed to a porous wound healing foam composition that is made from an extracellular matrix of a mammal, method of making, and method of using. | 1. A method for making a medical foam device, comprising:
(a) solubilizing dehydrated extracellular matrix material obtained from a mammalian tissue in a solution comprising a pH less than 4.0 or a pH greater than 9.0 (b) blending said acidified (pH<4) or basic (pH>9) solubilized extracellular matrix material to form a foamy extracellular matrix material slurry; (c) neutralizing said blended foamy extracellular matrix material slurry in a solution to about pH 7; (d) mixing said extracellular matrix material in the solution in step (c) to aid in neutralization of said foamy extracellular matrix material slurry; and, (e) dehydrating said foamy extracellular matrix material slurry in step (d). 2. The method of claim 1 further comprising,
introducing said foamy extracellular matrix material slurry from step (d) into a mold before step (e). 3. The method of claim 1 wherein step (b) comprises blending said extracellular matrix material in an industrial blender at speeds of about 500 RPM to 2500 RPM. 4. The method of claim 1 wherein said extracellular matrix material is selected from the group consisting of submucosa, epithelial basement membrane, epithelial basement membrane and tunica propria, dermis, and liver basement membrane. 5. The method of claim 1 further comprising particularizing said foamy porous extracellular matrix material after step (e). 6. The method of claim 1 wherein said acid is selected from the group consisting of HCl, phosphoric acid, acetic acid or said base is selected from the group consisting of sodium hydroxide and ammonium hydroxide. 7. The method of claim 1 wherein said neutralizing solution of step (c) comprises a base selected from the group consisting of NaOH, NaHCO3 and KCl or if a base is used to blend, an acid selected from the group consisting of acetic acid and hydrochloric acid. 8. The method of claim 2 wherein said mold comprises a sheet-like shape. 9. The method of claim 1 further comprising, before step (e).
(g) introducing said extracellular matrix material slurry in step (d) into a three-dimensional (3D) printer; and
(h) printing said medical foam device by said 3-D printer. 10. A method for making a medical gel comprising,
providing the molded dehydrated porous extracellular matrix material of step of claim 2; milling said molded porous extracellular matrix material to form a powder; and mixing said powder with an aqueous solution to form said medical gel. 11. The method of claim 1 wherein said porous extracellular matrix material comprises a pore size in the range of about 1 micron to about 500 microns. 12. A medical device, comprising:
a devitalized, solidified, porous extracellular matrix foam material derived from a mammal comprising a plurality of pores having a diameter in the range of about 1 micron to 500 microns. 13. The medical device of claim 12 wherein said device further comprises a mineral selected from the group consisting of calcium, phosphate, calcium and phosphate salts, calcium nitrate, calcium hydroxide, calcium carbonate, calcium oxide, sodium phosphate, sodium dehydrogen phosphate, phosphoric acid, demineralized or decellularized bone matrix, powdered allogenic bone, hydroxyapatite and tricalcium phosphates. 14. The medical device of claim 12 wherein said device comprises a shape configured for implanting at a sight of tissue injury in a patient. 15. The medical device of claim 12 wherein said device is manufactured by three-dimensional (3-D) printing. | The invention disclosed herein is directed to a porous wound healing foam composition that is made from an extracellular matrix of a mammal, method of making, and method of using.1. A method for making a medical foam device, comprising:
(a) solubilizing dehydrated extracellular matrix material obtained from a mammalian tissue in a solution comprising a pH less than 4.0 or a pH greater than 9.0 (b) blending said acidified (pH<4) or basic (pH>9) solubilized extracellular matrix material to form a foamy extracellular matrix material slurry; (c) neutralizing said blended foamy extracellular matrix material slurry in a solution to about pH 7; (d) mixing said extracellular matrix material in the solution in step (c) to aid in neutralization of said foamy extracellular matrix material slurry; and, (e) dehydrating said foamy extracellular matrix material slurry in step (d). 2. The method of claim 1 further comprising,
introducing said foamy extracellular matrix material slurry from step (d) into a mold before step (e). 3. The method of claim 1 wherein step (b) comprises blending said extracellular matrix material in an industrial blender at speeds of about 500 RPM to 2500 RPM. 4. The method of claim 1 wherein said extracellular matrix material is selected from the group consisting of submucosa, epithelial basement membrane, epithelial basement membrane and tunica propria, dermis, and liver basement membrane. 5. The method of claim 1 further comprising particularizing said foamy porous extracellular matrix material after step (e). 6. The method of claim 1 wherein said acid is selected from the group consisting of HCl, phosphoric acid, acetic acid or said base is selected from the group consisting of sodium hydroxide and ammonium hydroxide. 7. The method of claim 1 wherein said neutralizing solution of step (c) comprises a base selected from the group consisting of NaOH, NaHCO3 and KCl or if a base is used to blend, an acid selected from the group consisting of acetic acid and hydrochloric acid. 8. The method of claim 2 wherein said mold comprises a sheet-like shape. 9. The method of claim 1 further comprising, before step (e).
(g) introducing said extracellular matrix material slurry in step (d) into a three-dimensional (3D) printer; and
(h) printing said medical foam device by said 3-D printer. 10. A method for making a medical gel comprising,
providing the molded dehydrated porous extracellular matrix material of step of claim 2; milling said molded porous extracellular matrix material to form a powder; and mixing said powder with an aqueous solution to form said medical gel. 11. The method of claim 1 wherein said porous extracellular matrix material comprises a pore size in the range of about 1 micron to about 500 microns. 12. A medical device, comprising:
a devitalized, solidified, porous extracellular matrix foam material derived from a mammal comprising a plurality of pores having a diameter in the range of about 1 micron to 500 microns. 13. The medical device of claim 12 wherein said device further comprises a mineral selected from the group consisting of calcium, phosphate, calcium and phosphate salts, calcium nitrate, calcium hydroxide, calcium carbonate, calcium oxide, sodium phosphate, sodium dehydrogen phosphate, phosphoric acid, demineralized or decellularized bone matrix, powdered allogenic bone, hydroxyapatite and tricalcium phosphates. 14. The medical device of claim 12 wherein said device comprises a shape configured for implanting at a sight of tissue injury in a patient. 15. The medical device of claim 12 wherein said device is manufactured by three-dimensional (3-D) printing. | 1,600 |
449 | 12,063,614 | 1,618 | The present invention is directed to an implantable device comprising a biocompatible and biodegradable matrix impregnated with a bioactive complex suitable for selectively targeting the lymphatic system, wherein the bioactive complex comprises one or more particle forming materials and one or more bioactive agents. The invention is further directed to methods of using and the process of preparing, the implantable device. | 1. An implantable device comprising
a biocompatible and biodegradable matrix impregnated with a bioactive complex suitable for selectively targeting the lymphatic system, wherein the bioactive complex comprises one or more particle forming materials and one or more bioactive agents. 2. The implantable device according to claim 1, wherein the particle forming material and the bioactive agent form particles suitable for selectively targeting the lymphatic system. 3. The implantable device according to claim 1, wherein the particles are of a sufficient size to selectively target the lymphatic system. 4. The implantable device according to claim 1, wherein the particles are microparticles or nanoparticles or a combination of microparticles and nanoparticles. 5. The implantable device according to claim 1, wherein the particle size is from about 0.3 μm to about 11.2 μm. 6. The implantable device according to claim 1, wherein the particles size is from about 0.7 μm to about 2 μm. 7. The implantable device according to claim 1, wherein the one or more bioactive agents is a therapeutic agent. 8. The implantable device according to claim 1, wherein the one or more bioactive agents is selected from the group consisting of radioisotopes, photosensitizers, radiosensitizers, radioprotectors, photodynamic agents, neutron capturing agents, antigens, vaccines, DNA RNA, peptides, biological response modifiers, antimicrobial agents and anti-proliferative agents. 9. The implantable device according to claim 1, wherein the one or more bioactive agents selected from the group consisting of anti-proliferative agents and anti-metastatic agents. 10. The implantable device according to claim 9, wherein the anti-proliferative agents and anti-metastatic agents are selected from the group consisting of microtubule-stabilizing agents, alkylating agents, anti-metabolites, epidophyllotoxin, antineoplastic enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum coordination complexes, biological response modifiers and growth inhibitors and haematopoietic growth factors. 11. The implantable device according to claim 10, wherein the antineoplastic agent is selected from an anthracycline drug, vinca drug, mitomycin drug, bleomycin drug, cytotoxic nucleoside, taxanes, epothilones, discodermolide, pteridine drugs, diynenes and podophyllotoxins. 12. The implantable device according to claim 10, wherein the bioactive agent is selected from doxorubicin, caminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, trastuzumab (Herceptin™), 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin, etoposide, etoposide phosphate, teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel, estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, pyridobenzoindole derivatives, interferons and interleukins. 13. The implantable device according claim 12, wherein the bioactive agent is selected from paclitaxel and doxorubicin. 14. The implantable device according to claim 1, wherein the bioactive agent is selected from nitrogen mustards, alkyl sulfonates, nitrosoureas, triazenes, antimetabolites, pyrimidine analogues, purine analogues, natural products, epipodophyllotoxins, antibiotics, enzymes, substituted ureas, methylhydrazine derivatives, adrenocorticoid suppressants, hormones and antagonists, adrenocorticosteroids, progestins, oestrogens, antioestrogens and androgens. 15. The implantable device according to claim 14, wherein the bioactive agent is selected from mechlorethamine, cyclophosphamide, melphatan, chlorambucil, busulphan, carmustine, lomusine, semustine, streptozocin, dacarbazine, folic acid analogues, methotrexate, fluorouracil cytarabine, mercaptopurine, thioguanine, vinca alkaloids, vinblastine, vincristine, vendesine, etoposide, teniposide, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin, L-asparaginase, hydroxyurea, procarbazine, mitotane, aminoglutethimide, adrenocorticosteroids, prednisone, hydroxyprogesterone caproate, methoxyprogesterone acetate, megestrol acetate, diethylstilboestrol, ethinyloestradiol, tamoxifen, testosterone propionate and fluoxymesterone. 16. The implantable device according to claim 1, wherein the bioactive agent is selected from a lymphagiogenesis suppressor, an angiogenesis suppressor, a cytostatic agent, macromolecules, antioxidants, cytokines, chemokines, antisense oligonucleotides, LyP-1 peptide-coated qdots to home to lympatics, hormones and hormone antagonists. 17. The implantable device according to claim 16, wherein the bioactive agent is selected from vascular endothelial growth factor C, D (VEGF-C,D) antibody, the antibody to VEGF-C,D receptor (VEGFR-3), and epidermal growth factor receptor (EGFR) antibody. 18. The implantable device according to claim 1, wherein the particle forming material is selected from the group consisting of biocompatible polymers, lipids, liposomes, metallic particles, magnetic particles, biotin, avidin and polysaccharides. 19. The implantable device according to claim 18, wherein the particle forming material is selected from the group consisting of polylactic acid, polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), poly-lactic acid (PLA), polyvinyl pyrrolidones (PVP), polylactic acid-co-caprolactone, polyethylene glycol (PEG), polyethylene oxide (PEO), polystyrene, poly lactic acid-block-poly ethylene glycol, poly glycolic acid-block-poly ethylene glycol, poly lactide-co-glycolide-block-poly ethylene glycol, poly ethylene glycol-block-lipid, poly vinyl alcohol (PVA), polyester, poly(orthoester), poly(phosphazine), poly(phosphate ester), polycaprolactaones, gelatin, collagen, a glycosaminoglycan, polyorthoesters, polysaccharides, polysaccharide derivatives, polyhyaluronic acid, polyalginic acid, chitin, chitosan, chitosan derivatives, cellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polypeptides, polylysine, polyglutamic acid, albumin, polyanhydrides, polyhydroxy alkonoates, polyhydroxy valerate, polyhydroxy butyrate, proteins, polyphosphate esters, polyacrylamide (PAA), and derivatives and mixtures thereof. 20. The implantable device according to claim 19, wherein the particle forming material is PLGA. 21. The implantable device according to claim 1, wherein the bioactive complex includes additives. 22. The implantable device according to claim 21, wherein additives are selected from adjuvants, coatings, colourants, binders, buffers, lubricants, dissintegrants, plasticizers and stabilizers. 23. The implantable device according to claim 1, wherein the bioactive agent comprises microparticles of PLGA and paclitaxel or lipid and doxorubicin. 24. The implantable device according to claim 1, wherein the biocompatible matrix degrades over a period of time to release the bioactive complex over a period of time. 25. The implantable device according to claim 24, wherein the period of time is about several hours to about 1 year. 26. The implantable device according to claim 25, wherein the period of time is from about several days to about several weeks. 27. The implantable device according to claim 1 wherein the biocompatible matrix is shapeable. 28. The implantable device according to claim 1, wherein the biocompatible matrix is in a form selected from the group consisting of a sponge, sheet, film, mesh, pledget, tampon and pad. 29. The implantable device according to claim 1, wherein the biocompatible matrix is a hydrogel film. 30. The implantable device according to claim 1, wherein the biocompatible matrix is selected from the group consisting of gelatin, collagen, gelatin-alginate. 31. The implantable device according to claim 1, wherein the bioactive matrix contains additives. 32. The implantable device according to claim 31, wherein the additive is radio opaque material detectable by x-ray. 33. The implantable device according to claim 1, wherein one or more free bioactive agents are incorporated into the biocompatible and bioactive agent matrix. 34. The implantable device according to claim 1, wherein the matrix is cross-linked. 35. The implantable device according to claim 1 wherein the concentration of bioactive agent delivered systemically is less that the concentration of bioactive agent delivered to the lymphatic system. 36. A method of treating a disease or condition comprising administering an implantable device according to claim 1 to a subject in need thereof, said implantable device comprising an effective amount of a bioactive agent to treat said disease. 37. The method according to claim 36, wherein the implantable device is administered by implantation into the subject. 38. The method according to claim 37, wherein the implantable device is implanted using laparoscopy or mediastinoscopy. 39. The method according to claim 37, wherein the implantable device is implanted during a diagnostic procedure. 40. The method according to claim 39, wherein the diagnostic procedure a biopsy. 41. The method according to claim 40, wherein the biopsy is a lymph node biopsy. 42. The method according to claim 37, wherein the implantable device is implanted during a surgical biopsy or surgical tumor excision. 43. The method according to claim 37, wherein the implantable device is implanted in the pleural cavity, the peritoneal cavity, a subcutaneous compartment, vaginally or rectally. 44. The method according to claim 36, wherein the disease or condition is selected from neoplasia, bacterial infection, microbial infection and viral infection. 45. The method according to claim 44, wherein the disease or condition is neoplasia. 46. The method according to claim 44, wherein the disease or condition is selected from lung cancer, ovarian cancer, esophageal cancer, breast cancer, colorectal cancer, gastrointestinal cancer, hepatic cancer, pancreatic cancer, head and neck cancer, skin cancer, lymphoma, sarcoma, thymoma, mesothelioma, lymphatic metastases, prostate cancer, filariasis, brucellosis, tuberculosis and HIV infection. 47. The method according to claim 46, wherein the disease or conditions is selected from lung cancer and lymphatic metastases of lung cancer. 48. A method of administering a bioactive agent to the lymphatic system of a subject comprising implanting in said subject an implantable device according to claim 1 wherein the implantable device comprises an effective amount of the bioactive agent. 49. The method according to claim 48, wherein the implantable device is implanted in the pleural cavity, the peritoneal cavity, a subcutaneous compartment, vaginally or rectally. 50. The method according to claim 48, wherein the implantable device is implanted surgically. 51. The method according to claim 50, wherein surgically includes laparoscopy, mediastinoscopy, biopsy and tumor excision. 52. The method according to claim 48, wherein the bioactive agent is for the treatment or prevention of neoplasia. 53. The method according to claim 52, wherein the neoplasia is cancer. 54. The method according to claim 53, wherein the cancer is selected from lung cancer, ovarian cancer, esophageal cancer, breast cancer, colorectal cancer, gastrointestinal cancer, hepatic cancer, pancreatic cancer, head and neck cancer, skin cancer, lymphoma, sarcoma, thymoma, mesothelioma and prostate cancer. 55. The method according to claim 48, wherein the bioactive agent is for treatment or prevention of metastasis to the lymphatic system. 56. The method according to claim 48, wherein the concentration of bioactive agent delivered to the lymphatic system is higher than the concentration of bioactive agent delivered systemically. 57-65. (canceled) 66. A method of imaging or visualizing the lymphatic system using gamma scintigraphy, Positron Emission Tomography (PET), Single Photon Emission Computer Tomography (SPECT), Magnetic Resonance Imaging (MRI), X-ray, Computer Assisted X-ray Tomography (CT), near infrared spectroscopy or ultrasound, comprising administering an implantable device according to claim 1 to a subject and performing gamma scintigraphy, Positron Emission Tomography (PET), Single Photon Emission Computer Tomography (SPECT), Magnetic Resonance Imaging (MRI), X-ray, Computer Assisted X-ray Tomography (CT), near infrared spectroscopy, or ultrasound to image or visualize the lymphatic system, wherein the implantable device comprises bioactive agents that are suitable contrast or imaging agents. 67. The method according to claim 66, wherein the contrast or imaging agent is selected from ferromagnetic materials, perfluorochemicals, dyes, gamma emitting radiolabels and positron emitting radiolabels. 68. The method according to claim 67 wherein the sentinel lymph node is visualized or imaged. 69-71. (canceled) 72. A process of preparing an implantable device according to claim 1 comprising
a) combining a bioactive active agent and a particle forming material in a suitable solvent to from a solution or suspension; b) spray drying the solution or suspension to form particles of the bioactive complex; c) combining the particles formed in b) with a biocompatible polymer suitable for forming a biocompatible matrix in a suitable solvents; d) removing the solvent of c) to form the implantable device. | The present invention is directed to an implantable device comprising a biocompatible and biodegradable matrix impregnated with a bioactive complex suitable for selectively targeting the lymphatic system, wherein the bioactive complex comprises one or more particle forming materials and one or more bioactive agents. The invention is further directed to methods of using and the process of preparing, the implantable device.1. An implantable device comprising
a biocompatible and biodegradable matrix impregnated with a bioactive complex suitable for selectively targeting the lymphatic system, wherein the bioactive complex comprises one or more particle forming materials and one or more bioactive agents. 2. The implantable device according to claim 1, wherein the particle forming material and the bioactive agent form particles suitable for selectively targeting the lymphatic system. 3. The implantable device according to claim 1, wherein the particles are of a sufficient size to selectively target the lymphatic system. 4. The implantable device according to claim 1, wherein the particles are microparticles or nanoparticles or a combination of microparticles and nanoparticles. 5. The implantable device according to claim 1, wherein the particle size is from about 0.3 μm to about 11.2 μm. 6. The implantable device according to claim 1, wherein the particles size is from about 0.7 μm to about 2 μm. 7. The implantable device according to claim 1, wherein the one or more bioactive agents is a therapeutic agent. 8. The implantable device according to claim 1, wherein the one or more bioactive agents is selected from the group consisting of radioisotopes, photosensitizers, radiosensitizers, radioprotectors, photodynamic agents, neutron capturing agents, antigens, vaccines, DNA RNA, peptides, biological response modifiers, antimicrobial agents and anti-proliferative agents. 9. The implantable device according to claim 1, wherein the one or more bioactive agents selected from the group consisting of anti-proliferative agents and anti-metastatic agents. 10. The implantable device according to claim 9, wherein the anti-proliferative agents and anti-metastatic agents are selected from the group consisting of microtubule-stabilizing agents, alkylating agents, anti-metabolites, epidophyllotoxin, antineoplastic enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum coordination complexes, biological response modifiers and growth inhibitors and haematopoietic growth factors. 11. The implantable device according to claim 10, wherein the antineoplastic agent is selected from an anthracycline drug, vinca drug, mitomycin drug, bleomycin drug, cytotoxic nucleoside, taxanes, epothilones, discodermolide, pteridine drugs, diynenes and podophyllotoxins. 12. The implantable device according to claim 10, wherein the bioactive agent is selected from doxorubicin, caminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, trastuzumab (Herceptin™), 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin, etoposide, etoposide phosphate, teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel, estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, pyridobenzoindole derivatives, interferons and interleukins. 13. The implantable device according claim 12, wherein the bioactive agent is selected from paclitaxel and doxorubicin. 14. The implantable device according to claim 1, wherein the bioactive agent is selected from nitrogen mustards, alkyl sulfonates, nitrosoureas, triazenes, antimetabolites, pyrimidine analogues, purine analogues, natural products, epipodophyllotoxins, antibiotics, enzymes, substituted ureas, methylhydrazine derivatives, adrenocorticoid suppressants, hormones and antagonists, adrenocorticosteroids, progestins, oestrogens, antioestrogens and androgens. 15. The implantable device according to claim 14, wherein the bioactive agent is selected from mechlorethamine, cyclophosphamide, melphatan, chlorambucil, busulphan, carmustine, lomusine, semustine, streptozocin, dacarbazine, folic acid analogues, methotrexate, fluorouracil cytarabine, mercaptopurine, thioguanine, vinca alkaloids, vinblastine, vincristine, vendesine, etoposide, teniposide, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin, L-asparaginase, hydroxyurea, procarbazine, mitotane, aminoglutethimide, adrenocorticosteroids, prednisone, hydroxyprogesterone caproate, methoxyprogesterone acetate, megestrol acetate, diethylstilboestrol, ethinyloestradiol, tamoxifen, testosterone propionate and fluoxymesterone. 16. The implantable device according to claim 1, wherein the bioactive agent is selected from a lymphagiogenesis suppressor, an angiogenesis suppressor, a cytostatic agent, macromolecules, antioxidants, cytokines, chemokines, antisense oligonucleotides, LyP-1 peptide-coated qdots to home to lympatics, hormones and hormone antagonists. 17. The implantable device according to claim 16, wherein the bioactive agent is selected from vascular endothelial growth factor C, D (VEGF-C,D) antibody, the antibody to VEGF-C,D receptor (VEGFR-3), and epidermal growth factor receptor (EGFR) antibody. 18. The implantable device according to claim 1, wherein the particle forming material is selected from the group consisting of biocompatible polymers, lipids, liposomes, metallic particles, magnetic particles, biotin, avidin and polysaccharides. 19. The implantable device according to claim 18, wherein the particle forming material is selected from the group consisting of polylactic acid, polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), poly-lactic acid (PLA), polyvinyl pyrrolidones (PVP), polylactic acid-co-caprolactone, polyethylene glycol (PEG), polyethylene oxide (PEO), polystyrene, poly lactic acid-block-poly ethylene glycol, poly glycolic acid-block-poly ethylene glycol, poly lactide-co-glycolide-block-poly ethylene glycol, poly ethylene glycol-block-lipid, poly vinyl alcohol (PVA), polyester, poly(orthoester), poly(phosphazine), poly(phosphate ester), polycaprolactaones, gelatin, collagen, a glycosaminoglycan, polyorthoesters, polysaccharides, polysaccharide derivatives, polyhyaluronic acid, polyalginic acid, chitin, chitosan, chitosan derivatives, cellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polypeptides, polylysine, polyglutamic acid, albumin, polyanhydrides, polyhydroxy alkonoates, polyhydroxy valerate, polyhydroxy butyrate, proteins, polyphosphate esters, polyacrylamide (PAA), and derivatives and mixtures thereof. 20. The implantable device according to claim 19, wherein the particle forming material is PLGA. 21. The implantable device according to claim 1, wherein the bioactive complex includes additives. 22. The implantable device according to claim 21, wherein additives are selected from adjuvants, coatings, colourants, binders, buffers, lubricants, dissintegrants, plasticizers and stabilizers. 23. The implantable device according to claim 1, wherein the bioactive agent comprises microparticles of PLGA and paclitaxel or lipid and doxorubicin. 24. The implantable device according to claim 1, wherein the biocompatible matrix degrades over a period of time to release the bioactive complex over a period of time. 25. The implantable device according to claim 24, wherein the period of time is about several hours to about 1 year. 26. The implantable device according to claim 25, wherein the period of time is from about several days to about several weeks. 27. The implantable device according to claim 1 wherein the biocompatible matrix is shapeable. 28. The implantable device according to claim 1, wherein the biocompatible matrix is in a form selected from the group consisting of a sponge, sheet, film, mesh, pledget, tampon and pad. 29. The implantable device according to claim 1, wherein the biocompatible matrix is a hydrogel film. 30. The implantable device according to claim 1, wherein the biocompatible matrix is selected from the group consisting of gelatin, collagen, gelatin-alginate. 31. The implantable device according to claim 1, wherein the bioactive matrix contains additives. 32. The implantable device according to claim 31, wherein the additive is radio opaque material detectable by x-ray. 33. The implantable device according to claim 1, wherein one or more free bioactive agents are incorporated into the biocompatible and bioactive agent matrix. 34. The implantable device according to claim 1, wherein the matrix is cross-linked. 35. The implantable device according to claim 1 wherein the concentration of bioactive agent delivered systemically is less that the concentration of bioactive agent delivered to the lymphatic system. 36. A method of treating a disease or condition comprising administering an implantable device according to claim 1 to a subject in need thereof, said implantable device comprising an effective amount of a bioactive agent to treat said disease. 37. The method according to claim 36, wherein the implantable device is administered by implantation into the subject. 38. The method according to claim 37, wherein the implantable device is implanted using laparoscopy or mediastinoscopy. 39. The method according to claim 37, wherein the implantable device is implanted during a diagnostic procedure. 40. The method according to claim 39, wherein the diagnostic procedure a biopsy. 41. The method according to claim 40, wherein the biopsy is a lymph node biopsy. 42. The method according to claim 37, wherein the implantable device is implanted during a surgical biopsy or surgical tumor excision. 43. The method according to claim 37, wherein the implantable device is implanted in the pleural cavity, the peritoneal cavity, a subcutaneous compartment, vaginally or rectally. 44. The method according to claim 36, wherein the disease or condition is selected from neoplasia, bacterial infection, microbial infection and viral infection. 45. The method according to claim 44, wherein the disease or condition is neoplasia. 46. The method according to claim 44, wherein the disease or condition is selected from lung cancer, ovarian cancer, esophageal cancer, breast cancer, colorectal cancer, gastrointestinal cancer, hepatic cancer, pancreatic cancer, head and neck cancer, skin cancer, lymphoma, sarcoma, thymoma, mesothelioma, lymphatic metastases, prostate cancer, filariasis, brucellosis, tuberculosis and HIV infection. 47. The method according to claim 46, wherein the disease or conditions is selected from lung cancer and lymphatic metastases of lung cancer. 48. A method of administering a bioactive agent to the lymphatic system of a subject comprising implanting in said subject an implantable device according to claim 1 wherein the implantable device comprises an effective amount of the bioactive agent. 49. The method according to claim 48, wherein the implantable device is implanted in the pleural cavity, the peritoneal cavity, a subcutaneous compartment, vaginally or rectally. 50. The method according to claim 48, wherein the implantable device is implanted surgically. 51. The method according to claim 50, wherein surgically includes laparoscopy, mediastinoscopy, biopsy and tumor excision. 52. The method according to claim 48, wherein the bioactive agent is for the treatment or prevention of neoplasia. 53. The method according to claim 52, wherein the neoplasia is cancer. 54. The method according to claim 53, wherein the cancer is selected from lung cancer, ovarian cancer, esophageal cancer, breast cancer, colorectal cancer, gastrointestinal cancer, hepatic cancer, pancreatic cancer, head and neck cancer, skin cancer, lymphoma, sarcoma, thymoma, mesothelioma and prostate cancer. 55. The method according to claim 48, wherein the bioactive agent is for treatment or prevention of metastasis to the lymphatic system. 56. The method according to claim 48, wherein the concentration of bioactive agent delivered to the lymphatic system is higher than the concentration of bioactive agent delivered systemically. 57-65. (canceled) 66. A method of imaging or visualizing the lymphatic system using gamma scintigraphy, Positron Emission Tomography (PET), Single Photon Emission Computer Tomography (SPECT), Magnetic Resonance Imaging (MRI), X-ray, Computer Assisted X-ray Tomography (CT), near infrared spectroscopy or ultrasound, comprising administering an implantable device according to claim 1 to a subject and performing gamma scintigraphy, Positron Emission Tomography (PET), Single Photon Emission Computer Tomography (SPECT), Magnetic Resonance Imaging (MRI), X-ray, Computer Assisted X-ray Tomography (CT), near infrared spectroscopy, or ultrasound to image or visualize the lymphatic system, wherein the implantable device comprises bioactive agents that are suitable contrast or imaging agents. 67. The method according to claim 66, wherein the contrast or imaging agent is selected from ferromagnetic materials, perfluorochemicals, dyes, gamma emitting radiolabels and positron emitting radiolabels. 68. The method according to claim 67 wherein the sentinel lymph node is visualized or imaged. 69-71. (canceled) 72. A process of preparing an implantable device according to claim 1 comprising
a) combining a bioactive active agent and a particle forming material in a suitable solvent to from a solution or suspension; b) spray drying the solution or suspension to form particles of the bioactive complex; c) combining the particles formed in b) with a biocompatible polymer suitable for forming a biocompatible matrix in a suitable solvents; d) removing the solvent of c) to form the implantable device. | 1,600 |
450 | 15,478,437 | 1,643 | Activation of 5-HT 2A receptors using agonists at surprisingly low concentrations was shown to potently inhibit TNF-α-induced inflammation in multiple cell types. Significantly, proinflammatory markers were also inhibited by the agonist, (R)-DOI, even many hours after treatment with TNF-α. With the exception of a few natural toxins, no current drugs or small molecule therapeutics demonstrate a comparable potency for any physiological effect. TNF-α and TNF-α receptor mediated inflammatory pathways have been strongly implicated in a number of diseases, including atherosclerosis, asthma, rheumatoid arthritis, psoriasis, type II diabetes, depression, schizophrenia, and Alzheimer's disease. Importantly, because (R)-DOI can significantly inhibit the effects of TNF-α many hours after the administration of TNF-α, potential therapies could be aimed not only at preventing inflammation, but also treating inflammatory injury that has already occurred or is ongoing. | 1. A method for the treatment of an inflammatory disorder in a mammal, said method comprising administering to a mammal in need of such treatment an therapeutically effective amount of a 5-HT2A receptor agonist in an amount no greater than that required to result in a body fluid concentration no greater than 5 nM in a pharmaceutically acceptable carrier. 2. The method of claim 1, wherein the 5-HT2A receptor agonist is selected from the group consisting of DOI, (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((R)-DOI), (4-Bromo-3,6 dimethoxybenzocyclobuten-1-yl) methylamine (2C-BCB), and (2′S,4′S)-(+)-9,10-Didehydro-6-methylergoline-8β-(trans-2,4-dimethylazetidide)(LA-SS-Az) 3. The method of claim 1, wherein the 5-HT2A receptor agonist is (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((R)-DOI). 4. The method of claim 3, wherein the ((R)-DOI) is administered in an amount in an amount no greater than that required to result in a body fluid concentration no greater than 1 nM. 5. The method of claim 3, wherein the ((R)-DOI) is administered in an amount in an amount no greater than that required to result in a body fluid concentration no greater than 50 pM. 6. The method of claim 3, wherein the (((R)-DOI) is administered in an amount in an amount no greater than that required to result in a body fluid concentration no greater than 20 pM. 7. The method of claim 1, wherein the inflammatory disorder is associated with a disease selected from the group consisting of atherosclerosis, asthma, rheumatoid arthritis, psoriasis, type II diabetes, irritable bowel syndrome, Crohn's disease, septicemia, depression, schizophrenia, and Alzheimer's disease. 8. The method of claim 1, additionally comprising administering one or more compounds selected from the group consisting of DOI, (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((R)-DOI), (4-Bromo-3,6 dimethoxybenzocyclobuten-1-yl) methylamine (2C-BCB), (2′S,4′S)-(+)-9,10-Didehydro-6-methylergoline-8β-(trans-2,4-dimethylazetidide)(LA-SS-Az), lysergic acid diethylamide (LSD), and known anti-inflammatory drugs. 9. A method to reduce the expression of the intracellular adhesion molecule 1 (ICAM-1) gene associated with stimulation of the tumor necrosis factor-alpha receptor in a mammal, said method comprising administering to a mammal in need of such reduction an therapeutically effective amount of a 5-HT2A receptor agonist in an amount no greater than that required to result in a body fluid concentration no greater than 5 nM in a pharmaceutically acceptable carrier. 10. A pharmaceutical composition which comprises a dose of a 5-HT2A receptor agonist in an amount no greater than that required to result in a body fluid concentration no greater than 5 nM in a pharmaceutically acceptable carrier. 11. The composition of claim 10, wherein the 5-HT2A receptor agonist is selected from the group consisting of DOI, (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((R)-DOI), (4-Bromo-3,6 dimethoxybenzocyclobuten-1-yl) methylamine (2C-BCB), and (2′S,4′S)-(+)-9,10-Didehydro-6-methylergoline-8β-(trans-2,4-dimethylazetidide)(LA-SS-Az) 12. The composition of claim 10, wherein the 5-HT2A receptor agonist is (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((R)-DOI). 13. The composition of claim 12, wherein the ((R)-DOI) is in an amount no greater than that required to result in a body fluid concentration no greater than 1 nM. 14. The composition of claim 12, wherein the ((R)-DOI) is in an amount no greater than that required to result in a body fluid concentration no greater than 50 pM. 15. The composition of claim 12, wherein the ((R)-DOI) is in an amount no greater than that required to result in a body fluid concentration no greater than 20 pM. 16. The composition of claim 9, additionally comprising administering one or more compounds selected from the group consisting of DOI, (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((R)-DOI), (4-Bromo-3,6 dimethoxybenzocyclobuten-1-yl) methylamine (2C-BCB), (2′S,4′S)-(+)-9,10-Didehydro-6-methylergoline-8β-(trans-2,4-dimethylazetidide)(LA-SS-Az), lysergic acid diethylamide (LSD), and known anti-inflammatory drugs. | Activation of 5-HT 2A receptors using agonists at surprisingly low concentrations was shown to potently inhibit TNF-α-induced inflammation in multiple cell types. Significantly, proinflammatory markers were also inhibited by the agonist, (R)-DOI, even many hours after treatment with TNF-α. With the exception of a few natural toxins, no current drugs or small molecule therapeutics demonstrate a comparable potency for any physiological effect. TNF-α and TNF-α receptor mediated inflammatory pathways have been strongly implicated in a number of diseases, including atherosclerosis, asthma, rheumatoid arthritis, psoriasis, type II diabetes, depression, schizophrenia, and Alzheimer's disease. Importantly, because (R)-DOI can significantly inhibit the effects of TNF-α many hours after the administration of TNF-α, potential therapies could be aimed not only at preventing inflammation, but also treating inflammatory injury that has already occurred or is ongoing.1. A method for the treatment of an inflammatory disorder in a mammal, said method comprising administering to a mammal in need of such treatment an therapeutically effective amount of a 5-HT2A receptor agonist in an amount no greater than that required to result in a body fluid concentration no greater than 5 nM in a pharmaceutically acceptable carrier. 2. The method of claim 1, wherein the 5-HT2A receptor agonist is selected from the group consisting of DOI, (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((R)-DOI), (4-Bromo-3,6 dimethoxybenzocyclobuten-1-yl) methylamine (2C-BCB), and (2′S,4′S)-(+)-9,10-Didehydro-6-methylergoline-8β-(trans-2,4-dimethylazetidide)(LA-SS-Az) 3. The method of claim 1, wherein the 5-HT2A receptor agonist is (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((R)-DOI). 4. The method of claim 3, wherein the ((R)-DOI) is administered in an amount in an amount no greater than that required to result in a body fluid concentration no greater than 1 nM. 5. The method of claim 3, wherein the ((R)-DOI) is administered in an amount in an amount no greater than that required to result in a body fluid concentration no greater than 50 pM. 6. The method of claim 3, wherein the (((R)-DOI) is administered in an amount in an amount no greater than that required to result in a body fluid concentration no greater than 20 pM. 7. The method of claim 1, wherein the inflammatory disorder is associated with a disease selected from the group consisting of atherosclerosis, asthma, rheumatoid arthritis, psoriasis, type II diabetes, irritable bowel syndrome, Crohn's disease, septicemia, depression, schizophrenia, and Alzheimer's disease. 8. The method of claim 1, additionally comprising administering one or more compounds selected from the group consisting of DOI, (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((R)-DOI), (4-Bromo-3,6 dimethoxybenzocyclobuten-1-yl) methylamine (2C-BCB), (2′S,4′S)-(+)-9,10-Didehydro-6-methylergoline-8β-(trans-2,4-dimethylazetidide)(LA-SS-Az), lysergic acid diethylamide (LSD), and known anti-inflammatory drugs. 9. A method to reduce the expression of the intracellular adhesion molecule 1 (ICAM-1) gene associated with stimulation of the tumor necrosis factor-alpha receptor in a mammal, said method comprising administering to a mammal in need of such reduction an therapeutically effective amount of a 5-HT2A receptor agonist in an amount no greater than that required to result in a body fluid concentration no greater than 5 nM in a pharmaceutically acceptable carrier. 10. A pharmaceutical composition which comprises a dose of a 5-HT2A receptor agonist in an amount no greater than that required to result in a body fluid concentration no greater than 5 nM in a pharmaceutically acceptable carrier. 11. The composition of claim 10, wherein the 5-HT2A receptor agonist is selected from the group consisting of DOI, (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((R)-DOI), (4-Bromo-3,6 dimethoxybenzocyclobuten-1-yl) methylamine (2C-BCB), and (2′S,4′S)-(+)-9,10-Didehydro-6-methylergoline-8β-(trans-2,4-dimethylazetidide)(LA-SS-Az) 12. The composition of claim 10, wherein the 5-HT2A receptor agonist is (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((R)-DOI). 13. The composition of claim 12, wherein the ((R)-DOI) is in an amount no greater than that required to result in a body fluid concentration no greater than 1 nM. 14. The composition of claim 12, wherein the ((R)-DOI) is in an amount no greater than that required to result in a body fluid concentration no greater than 50 pM. 15. The composition of claim 12, wherein the ((R)-DOI) is in an amount no greater than that required to result in a body fluid concentration no greater than 20 pM. 16. The composition of claim 9, additionally comprising administering one or more compounds selected from the group consisting of DOI, (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((R)-DOI), (4-Bromo-3,6 dimethoxybenzocyclobuten-1-yl) methylamine (2C-BCB), (2′S,4′S)-(+)-9,10-Didehydro-6-methylergoline-8β-(trans-2,4-dimethylazetidide)(LA-SS-Az), lysergic acid diethylamide (LSD), and known anti-inflammatory drugs. | 1,600 |
451 | 14,442,340 | 1,613 | Curable antifouling compositions include fluorinated polymers that contain a perfluoropolyether group, a poly(alkyleneoxide) group, a hydrolyzable silane group and a cationic curative. The curable antifouling compositions can be applied on a surface of a substrate, and at least partially cured to provide an article with antifouling properties. | 1-18. (canceled) 19. A curable antifouling composition comprising components:
a) at least one fluorinated polymer, wherein each said at least one fluorinated polymer independently comprises:
at least one divalent group A represented by the formula
wherein R1 independently represents H or methyl, X independently represents a covalent bond or a divalent organic linking group, L1 independently represents a covalent bond or a divalent organic linking group, and Rfl independently represents a monovalent perfluorinated organic group;
at least one divalent group B represented by the formula
wherein L2 independently represents a covalent bond or divalent organic linking group, k represents an integer in the range of from 1 to 4, R2 independently represents H or an alkyl group having from 1 to 18 carbon atoms, and f independently represents an integer in the range of from 3 to 200, inclusive;
at least one divalent group C represented by the formula
wherein L3 independently represents a covalent bond or a divalent organic linking group, and each Y1, Y2, and Y3 independently represents a hydrolyzable group or a hydrocarbyl group having from 1 to 10 carbon atoms, with the proviso that at least one of Y1, Y2, and Y3 is a hydrolyzable group; and
b) cationic curative. 20. A curable antifouling composition according to claim 19, wherein said cationic curative comprises a photoacid generator. 21. A curable antifouling composition according to claim 19, wherein the curable antifouling composition further comprises:
c) an epoxysilane compound. 22. A curable antifouling composition according to claim 19, wherein the fluorinated polymer has an average molecular weight in a range of from 2000 grams/mole to 30,000 grams/mole. 23. A curable antifouling composition according to claim 19, wherein f is in a range of from 5 to 100. 24. A curable antifouling composition according to claim 19, wherein components a) and b) are present in a weight ratio of from 95:5 to 99.5:0.5. 25. A curable antifouling composition according to claim 19, wherein the weight ratio of said at least one group A to the sum of said at least one group B and said at least one C is in a range of from 60:40 to 5:95. 26. A curable antifouling composition according to claim 19, wherein the weight ratio of said at least one group B to said at least one group C is in a range of from 1:99 to 90:10. 27. A method of using a curable antifouling composition, the method comprising:
applying a curable antifouling composition to at least a portion of a surface of a substrate, wherein the substrate is selected from the group consisting of marine vessel hulls, anchors, piers, docks, caissons, invasive medical devices, non-invasive medical devices, handrails, door knobs, countertops, membrane support frames, heat exchangers, microelectrochemical drug delivery devices, papermaking machines, tanks for holding liquid, water pipes, plumbing fixtures, and mariculture apparatuses; and at least partially curing the curable antifouling composition, wherein the curable antifouling composition comprises components: a) at least one fluorinated polymer, wherein each said at least one fluorinated polymer independently comprises:
at least one divalent group A represented by the formula
wherein R1 independently represents H or methyl, X independently represents a covalent bond or a divalent organic linking group, L1 independently represents a covalent bond or a divalent organic linking group, and Rfl independently represents a monovalent perfluorinated organic group;
at least one divalent group B represented by the formula
wherein L2 independently represents a covalent bond or divalent organic linking group, k represents an integer in the range of from 1 to 4, R2 independently represents H of an alkyl group having from 1 to 18 carbon atoms, and f independently represents an integer in the range of from 3 to 200, inclusive;
at least one divalent group C represented by the formula
wherein L3 independently represents a covalent bond or a divalent organic linking group, and wherein each Y1, Y2, and Y3 independently represents a hydrolyzable group or an alkyl group having from 1 to 7 carbon atoms, with the proviso that at least one of Y1, Y2, and Y3 is a hydrolyzable group; and
b) cationic curative. 28. A method according to claim 27, wherein said cationic curative comprises a photoacid generator. 29. A method according to claim 27, wherein f is in a range of from 5 to 100. 30. A method according to claim 27, wherein the curable antifouling composition further comprises:
c) an epoxysilane compound. 31. An article comprising a substrate having a surface, wherein at least a portion of the surface has an antifouling coating thereon, wherein the substrate is selected from the group consisting of marine vessel hulls, anchors, piers, docks, caissons, invasive medical devices, non-invasive medical devices, handrails, door knobs, countertops, membrane support frames, heat exchangers, microelectrochemical drug delivery devices, papermaking machines, tanks for holding liquid, water pipes, plumbing fixtures, and mariculture apparatuses, wherein the antifouling coating comprises an at least partially cured curable antifouling composition, and wherein the curable antifouling composition comprises components:
a) at least one fluorinated polymer, wherein each said at least one fluorinated polymer independently comprises:
at least one divalent group A represented by the formula
wherein R1 independently represents H or methyl, X independently represents a covalent bond or a divalent organic linking group, L1 independently represents a covalent bond or a divalent organic linking group, and Rfl independently represents a monovalent perfluorinated organic group;
at least one divalent group B represented by the formula
wherein L2 independently represents a covalent bond or divalent organic linking group, k represents an integer in the range of from 1 to 4, R2 independently represents H of an alkyl group having from 1 to 18 carbon atoms, and f independently represents an integer in the range of from 3 to 200, inclusive;
at least one divalent group C represented by the formula
wherein L3 independently represents a covalent bond or a divalent organic linking group, and wherein each Y1, Y2, and Y3 independently represents a hydrolyzable group or an alkyl group having from 1 to 7 carbon atoms, with the proviso that at least one of Y1, Y2, and Y3 is a hydrolyzable group; and
b) cationic curative. 32. An article according to claim 31, wherein said cationic curative comprises a photoacid generator. 33. An article according to claim 31, wherein f is in a range of from 5 to 68. 34. An article according to claim 31, wherein the curable antifouling composition further comprises:
c) an epoxysilane compound. 35. An article according to claim 31, wherein the weight ratio of said at least one group A to the sum of said at least one group B and said at least one C is in a range of from 60:40 to 5:95. 36. An article according to claim 31, wherein the weight ratio of said at least one group B to said at least one group C is in a range of from 1:99 to 90:10. | Curable antifouling compositions include fluorinated polymers that contain a perfluoropolyether group, a poly(alkyleneoxide) group, a hydrolyzable silane group and a cationic curative. The curable antifouling compositions can be applied on a surface of a substrate, and at least partially cured to provide an article with antifouling properties.1-18. (canceled) 19. A curable antifouling composition comprising components:
a) at least one fluorinated polymer, wherein each said at least one fluorinated polymer independently comprises:
at least one divalent group A represented by the formula
wherein R1 independently represents H or methyl, X independently represents a covalent bond or a divalent organic linking group, L1 independently represents a covalent bond or a divalent organic linking group, and Rfl independently represents a monovalent perfluorinated organic group;
at least one divalent group B represented by the formula
wherein L2 independently represents a covalent bond or divalent organic linking group, k represents an integer in the range of from 1 to 4, R2 independently represents H or an alkyl group having from 1 to 18 carbon atoms, and f independently represents an integer in the range of from 3 to 200, inclusive;
at least one divalent group C represented by the formula
wherein L3 independently represents a covalent bond or a divalent organic linking group, and each Y1, Y2, and Y3 independently represents a hydrolyzable group or a hydrocarbyl group having from 1 to 10 carbon atoms, with the proviso that at least one of Y1, Y2, and Y3 is a hydrolyzable group; and
b) cationic curative. 20. A curable antifouling composition according to claim 19, wherein said cationic curative comprises a photoacid generator. 21. A curable antifouling composition according to claim 19, wherein the curable antifouling composition further comprises:
c) an epoxysilane compound. 22. A curable antifouling composition according to claim 19, wherein the fluorinated polymer has an average molecular weight in a range of from 2000 grams/mole to 30,000 grams/mole. 23. A curable antifouling composition according to claim 19, wherein f is in a range of from 5 to 100. 24. A curable antifouling composition according to claim 19, wherein components a) and b) are present in a weight ratio of from 95:5 to 99.5:0.5. 25. A curable antifouling composition according to claim 19, wherein the weight ratio of said at least one group A to the sum of said at least one group B and said at least one C is in a range of from 60:40 to 5:95. 26. A curable antifouling composition according to claim 19, wherein the weight ratio of said at least one group B to said at least one group C is in a range of from 1:99 to 90:10. 27. A method of using a curable antifouling composition, the method comprising:
applying a curable antifouling composition to at least a portion of a surface of a substrate, wherein the substrate is selected from the group consisting of marine vessel hulls, anchors, piers, docks, caissons, invasive medical devices, non-invasive medical devices, handrails, door knobs, countertops, membrane support frames, heat exchangers, microelectrochemical drug delivery devices, papermaking machines, tanks for holding liquid, water pipes, plumbing fixtures, and mariculture apparatuses; and at least partially curing the curable antifouling composition, wherein the curable antifouling composition comprises components: a) at least one fluorinated polymer, wherein each said at least one fluorinated polymer independently comprises:
at least one divalent group A represented by the formula
wherein R1 independently represents H or methyl, X independently represents a covalent bond or a divalent organic linking group, L1 independently represents a covalent bond or a divalent organic linking group, and Rfl independently represents a monovalent perfluorinated organic group;
at least one divalent group B represented by the formula
wherein L2 independently represents a covalent bond or divalent organic linking group, k represents an integer in the range of from 1 to 4, R2 independently represents H of an alkyl group having from 1 to 18 carbon atoms, and f independently represents an integer in the range of from 3 to 200, inclusive;
at least one divalent group C represented by the formula
wherein L3 independently represents a covalent bond or a divalent organic linking group, and wherein each Y1, Y2, and Y3 independently represents a hydrolyzable group or an alkyl group having from 1 to 7 carbon atoms, with the proviso that at least one of Y1, Y2, and Y3 is a hydrolyzable group; and
b) cationic curative. 28. A method according to claim 27, wherein said cationic curative comprises a photoacid generator. 29. A method according to claim 27, wherein f is in a range of from 5 to 100. 30. A method according to claim 27, wherein the curable antifouling composition further comprises:
c) an epoxysilane compound. 31. An article comprising a substrate having a surface, wherein at least a portion of the surface has an antifouling coating thereon, wherein the substrate is selected from the group consisting of marine vessel hulls, anchors, piers, docks, caissons, invasive medical devices, non-invasive medical devices, handrails, door knobs, countertops, membrane support frames, heat exchangers, microelectrochemical drug delivery devices, papermaking machines, tanks for holding liquid, water pipes, plumbing fixtures, and mariculture apparatuses, wherein the antifouling coating comprises an at least partially cured curable antifouling composition, and wherein the curable antifouling composition comprises components:
a) at least one fluorinated polymer, wherein each said at least one fluorinated polymer independently comprises:
at least one divalent group A represented by the formula
wherein R1 independently represents H or methyl, X independently represents a covalent bond or a divalent organic linking group, L1 independently represents a covalent bond or a divalent organic linking group, and Rfl independently represents a monovalent perfluorinated organic group;
at least one divalent group B represented by the formula
wherein L2 independently represents a covalent bond or divalent organic linking group, k represents an integer in the range of from 1 to 4, R2 independently represents H of an alkyl group having from 1 to 18 carbon atoms, and f independently represents an integer in the range of from 3 to 200, inclusive;
at least one divalent group C represented by the formula
wherein L3 independently represents a covalent bond or a divalent organic linking group, and wherein each Y1, Y2, and Y3 independently represents a hydrolyzable group or an alkyl group having from 1 to 7 carbon atoms, with the proviso that at least one of Y1, Y2, and Y3 is a hydrolyzable group; and
b) cationic curative. 32. An article according to claim 31, wherein said cationic curative comprises a photoacid generator. 33. An article according to claim 31, wherein f is in a range of from 5 to 68. 34. An article according to claim 31, wherein the curable antifouling composition further comprises:
c) an epoxysilane compound. 35. An article according to claim 31, wherein the weight ratio of said at least one group A to the sum of said at least one group B and said at least one C is in a range of from 60:40 to 5:95. 36. An article according to claim 31, wherein the weight ratio of said at least one group B to said at least one group C is in a range of from 1:99 to 90:10. | 1,600 |
452 | 13,603,335 | 1,627 | The present invention relates to a thermodynamically stable, biocompatible, environment friendly, and temperature-insensitive microemulsion containing various botanical essential oils, sugar based surfactants, polyhydric alcohols, and an aqueous phase. | 1. A microemulsion for a topical cosmetic or a pharmaceutical application, said microemulsion comprising:
(a) 1% to 20% w/w of a sugar-based surfactant selected from the group consisting of a sucrose ester, an alkyl polyglucoside and a combination thereof; (b) 1% to 10% w/w of a polyhydric alcohol; (c) 0.5% to 10% w/w of an oil selected from the group consisting of an essential oil, a pharmaceutically acceptable oil, and combinations thereof; and (d) water, wherein the microemulsion is substantially free of an alkanol. 2. The microemulsion of claim 1, wherein said sugar-based surfactant is a sucrose ester having a HLB of 5 to 16. 3. The microemulsion of claim 1, wherein said sucrose ester is a member selected from the group consisting of sucrose myristate, sucrose laurate, sucrose oleate, sucrose palmitate, sucrose stearate and a combination thereof. 4. The microemulsion of claim 3, wherein said sucrose ester is sucrose laurate. 5. The microemulsion of claim 1, wherein said alkyl polyglucoside is a member selected from the group consisting of a C8-16 decyl glucoside, a C8-16 coco glucoside, a C12-16 lauryl glucoside and a combination thereof. 6. The microemulsion of claim 1, wherein said alkyl polyglucoside is present from about 1% w/w to about 5% w/w. 7. The microemulsion of claim 1, wherein said polyhydric alcohol is a member selected from the group consisting of a dihydric alcohol, a trihydric alcohol, a sugar alcohol and a combination thereof. 8. The microemulsion of claim 7, wherein said dihydric alcohol is a glycol. 9. The microemulsion of claim 8, wherein said glycol is a member selected from the group consisting of ethylene glycol, propylene glycol and a combination thereof. 10. The microemulsion of claim 7, wherein said trihydric alcohol is glycerol. 11. The microemulsion of claim 7, wherein said sugar alcohol is a member selected from the group consisting of sorbitol, manitol, xylitol and a combination thereof. 12. The microemulsion of claim 1, wherein said essential oil is derived from a plant extract. 13. The microemulsion of claim 12, wherein said essential oil is a member selected from the group consisting of eucalyptus oil, lavender oil, tea tree oil, green tea oil, rosemary oil, patchouli oil, cedar wood atlas oil, clove leaf oil, palmarosa oil, grapefruit oil, bergamot calabrian oil, pine oil, cardamom oil, peppermint oil, cinnamon leaf oil, ylang ylang oil and a combination thereof. 14. The microemulsion of claim 1, wherein said microemulsion further comprises a vitamin. 15. The microemulsion of claim 14, wherein said vitamin is present in an amount of 0.01% w/w to about 5% w/w. 16. The microemulsion of claim 14, wherein said vitamin is a member selected from the group consisting of vitamin A, vitamin E, vitamin K, a derivative thereof and a combination thereof. 17. The microemulsion of claim 1, wherein said microemulsion further comprises a thickening agent. 18. The microemulsion of claim 17, wherein said thickener is present in an amount of 0.01% w/w to about 5% w/w. 19. The microemulsion of claim 17, wherein said thickener is a member selected from the group consisting of xanthan gum, hydroxyethylcellulose, carrageenan and a combination thereof. 20. The microemulsion of claim 1, wherein said microemulsion further comprises an active agent. | The present invention relates to a thermodynamically stable, biocompatible, environment friendly, and temperature-insensitive microemulsion containing various botanical essential oils, sugar based surfactants, polyhydric alcohols, and an aqueous phase.1. A microemulsion for a topical cosmetic or a pharmaceutical application, said microemulsion comprising:
(a) 1% to 20% w/w of a sugar-based surfactant selected from the group consisting of a sucrose ester, an alkyl polyglucoside and a combination thereof; (b) 1% to 10% w/w of a polyhydric alcohol; (c) 0.5% to 10% w/w of an oil selected from the group consisting of an essential oil, a pharmaceutically acceptable oil, and combinations thereof; and (d) water, wherein the microemulsion is substantially free of an alkanol. 2. The microemulsion of claim 1, wherein said sugar-based surfactant is a sucrose ester having a HLB of 5 to 16. 3. The microemulsion of claim 1, wherein said sucrose ester is a member selected from the group consisting of sucrose myristate, sucrose laurate, sucrose oleate, sucrose palmitate, sucrose stearate and a combination thereof. 4. The microemulsion of claim 3, wherein said sucrose ester is sucrose laurate. 5. The microemulsion of claim 1, wherein said alkyl polyglucoside is a member selected from the group consisting of a C8-16 decyl glucoside, a C8-16 coco glucoside, a C12-16 lauryl glucoside and a combination thereof. 6. The microemulsion of claim 1, wherein said alkyl polyglucoside is present from about 1% w/w to about 5% w/w. 7. The microemulsion of claim 1, wherein said polyhydric alcohol is a member selected from the group consisting of a dihydric alcohol, a trihydric alcohol, a sugar alcohol and a combination thereof. 8. The microemulsion of claim 7, wherein said dihydric alcohol is a glycol. 9. The microemulsion of claim 8, wherein said glycol is a member selected from the group consisting of ethylene glycol, propylene glycol and a combination thereof. 10. The microemulsion of claim 7, wherein said trihydric alcohol is glycerol. 11. The microemulsion of claim 7, wherein said sugar alcohol is a member selected from the group consisting of sorbitol, manitol, xylitol and a combination thereof. 12. The microemulsion of claim 1, wherein said essential oil is derived from a plant extract. 13. The microemulsion of claim 12, wherein said essential oil is a member selected from the group consisting of eucalyptus oil, lavender oil, tea tree oil, green tea oil, rosemary oil, patchouli oil, cedar wood atlas oil, clove leaf oil, palmarosa oil, grapefruit oil, bergamot calabrian oil, pine oil, cardamom oil, peppermint oil, cinnamon leaf oil, ylang ylang oil and a combination thereof. 14. The microemulsion of claim 1, wherein said microemulsion further comprises a vitamin. 15. The microemulsion of claim 14, wherein said vitamin is present in an amount of 0.01% w/w to about 5% w/w. 16. The microemulsion of claim 14, wherein said vitamin is a member selected from the group consisting of vitamin A, vitamin E, vitamin K, a derivative thereof and a combination thereof. 17. The microemulsion of claim 1, wherein said microemulsion further comprises a thickening agent. 18. The microemulsion of claim 17, wherein said thickener is present in an amount of 0.01% w/w to about 5% w/w. 19. The microemulsion of claim 17, wherein said thickener is a member selected from the group consisting of xanthan gum, hydroxyethylcellulose, carrageenan and a combination thereof. 20. The microemulsion of claim 1, wherein said microemulsion further comprises an active agent. | 1,600 |
453 | 15,146,020 | 1,628 | The synthesis, growth inhibition and radioprotective activity of the PrC-210 aminothiol, 3-(methyl-amino)-2-((methylamino)methyl)propane-l-thiol, and its polyamine and thiolated polyamine progenitors are reported. All of the molecules significantly inhibited growth of cultured normal human fibroblasts. The combination of an ROS-scavenging thiol group and a positively charged alkyl-amine backbone provided the most radioprotective aminothiol molecule. | 1. A method for protecting a subject from ionizing radiation, the method comprising:
administering systemically to the subject a radioprotector compound comprising a free thiol and a positively-charged backbone, wherein the radioprotector compound comprises a structure according to:
wherein R and R′ are independently selected from H and CH3,
wherein systemic administration of the radioprotector compound to the subject protects the subject from ionizing radiation. 2-3. (canceled) 4. The method of claim 1 wherein administering systemically to the subject the radioprotector compound does not cause a side effect of nausea, vomiting, hypotension, or fainting in the subject. 5. The method of claim 1 further comprising blocking cell cycle progression at the G1/S cell cycle border. 6. The method of claim 1 wherein the radioprotector compound is sulfurous odor-free. 7. The method of claim 1 further comprising inhibiting the growth of a cell. 8. The method of claim 1 further comprising restoring cell cycle progression. 9. The method of claim 1 further comprising binding the positively-charged backbone to a DNA and displaying the free thiol away from the DNA. 10. The method of claim 1 further comprising scavenging reactive oxygen species. 11. The method of claim 1 wherein the subject is a mammal. 12. The method of claim 1 wherein the subject is a human. 13. The method of claim 1 wherein the subject is a human comprising a cell exposed to radiation for medical purposes. 14. The method of claim 1 wherein a cell or a tissue is protected from ionizing radiation. 15. A method of providing protection to a subject's DNA against a reactive oxygen species, the method comprising:
a) administering systemically to the subject a radioprotector compound comprising a free thiol and a positively-charged backbone, wherein the radioprotector compound comprises a structure according to:
wherein R and R′ are independently selected from H and CH3;
b) binding the positively-charged backbone of the radioprotector compound to a DNA of the subject; and
c) scavenging a reactive oxygen species with the free thiol, wherein the radioprotector compound provides protection to the subject's DNA against the reactive oxygen species. 16. (canceled) 17. The method of claim 15 further comprising inhibiting the growth of a cell. 18. A method of providing radioprotection to a subject, the method comprising:
a) providing a radioprotector compound that lacks the side effects of nausea/vomiting and hypotension/fainting, wherein the radioprotector compound comprises a structure according to:
wherein R and R′ are independently selected from H and CH3;
b) administering systemically the radioprotector compound to the subject, wherein the systemically administered radioprotector provides systemic radioprotection to the subject. 19. (canceled) 20. The method of claim 18 further comprising inhibiting the growth of a cell. 21. The method of claim 1, wherein the radioprotector compound is in a form of an acid-addition salt. 22. The method of claim 15, wherein the radioprotector compound is in a form of an acid-addition salt. 23. The method of claim 18, wherein the radioprotector compound is in a form of an acid-addition salt. | The synthesis, growth inhibition and radioprotective activity of the PrC-210 aminothiol, 3-(methyl-amino)-2-((methylamino)methyl)propane-l-thiol, and its polyamine and thiolated polyamine progenitors are reported. All of the molecules significantly inhibited growth of cultured normal human fibroblasts. The combination of an ROS-scavenging thiol group and a positively charged alkyl-amine backbone provided the most radioprotective aminothiol molecule.1. A method for protecting a subject from ionizing radiation, the method comprising:
administering systemically to the subject a radioprotector compound comprising a free thiol and a positively-charged backbone, wherein the radioprotector compound comprises a structure according to:
wherein R and R′ are independently selected from H and CH3,
wherein systemic administration of the radioprotector compound to the subject protects the subject from ionizing radiation. 2-3. (canceled) 4. The method of claim 1 wherein administering systemically to the subject the radioprotector compound does not cause a side effect of nausea, vomiting, hypotension, or fainting in the subject. 5. The method of claim 1 further comprising blocking cell cycle progression at the G1/S cell cycle border. 6. The method of claim 1 wherein the radioprotector compound is sulfurous odor-free. 7. The method of claim 1 further comprising inhibiting the growth of a cell. 8. The method of claim 1 further comprising restoring cell cycle progression. 9. The method of claim 1 further comprising binding the positively-charged backbone to a DNA and displaying the free thiol away from the DNA. 10. The method of claim 1 further comprising scavenging reactive oxygen species. 11. The method of claim 1 wherein the subject is a mammal. 12. The method of claim 1 wherein the subject is a human. 13. The method of claim 1 wherein the subject is a human comprising a cell exposed to radiation for medical purposes. 14. The method of claim 1 wherein a cell or a tissue is protected from ionizing radiation. 15. A method of providing protection to a subject's DNA against a reactive oxygen species, the method comprising:
a) administering systemically to the subject a radioprotector compound comprising a free thiol and a positively-charged backbone, wherein the radioprotector compound comprises a structure according to:
wherein R and R′ are independently selected from H and CH3;
b) binding the positively-charged backbone of the radioprotector compound to a DNA of the subject; and
c) scavenging a reactive oxygen species with the free thiol, wherein the radioprotector compound provides protection to the subject's DNA against the reactive oxygen species. 16. (canceled) 17. The method of claim 15 further comprising inhibiting the growth of a cell. 18. A method of providing radioprotection to a subject, the method comprising:
a) providing a radioprotector compound that lacks the side effects of nausea/vomiting and hypotension/fainting, wherein the radioprotector compound comprises a structure according to:
wherein R and R′ are independently selected from H and CH3;
b) administering systemically the radioprotector compound to the subject, wherein the systemically administered radioprotector provides systemic radioprotection to the subject. 19. (canceled) 20. The method of claim 18 further comprising inhibiting the growth of a cell. 21. The method of claim 1, wherein the radioprotector compound is in a form of an acid-addition salt. 22. The method of claim 15, wherein the radioprotector compound is in a form of an acid-addition salt. 23. The method of claim 18, wherein the radioprotector compound is in a form of an acid-addition salt. | 1,600 |
454 | 15,586,578 | 1,618 | A composition includes a therapeutically effective oral pharmaceutical dosage form that becomes buoyant upon contact with gastric fluid. The dosage form includes an active ingredient combination including an amino acid source and a zinc source, an anionic polymer, an effervescent agent, and a pH buffer. The dosage form is effective for releasing the active ingredient combination while buoyant on gastric fluid. | 1. A composition comprising:
a therapeutically effective oral pharmaceutical dosage form that becomes buoyant upon contact with gastric fluid, the dosage form having therein: an active ingredient combination including an amino acid source and a zinc source; an anionic polymer; an effervescent agent; and a pH buffer; wherein the dosage form is effective for releasing the active ingredient combination while buoyant on gastric fluid. 2. The composition of claim 1, wherein the zinc source is a water soluble zinc salt. 3. The composition of claim 1, wherein the anionic polymer has terminal carboxylate functional groups. 4. The composition of claim 1, wherein the pH buffer is in an amount capable of maintaining a substantially neutral pH within the dosage form while the dosage form is in contact with stomach acid. 5. The composition of claim 1, wherein the dosage form is therapeutically effective for treating a gastroesophageal condition. 6. The composition of claim 1, wherein the dosage form is a tablet. 7. The composition of claim 1, wherein the anionic polymer will swell upon contact with gastric fluid and a ratio of the anionic polymer to the zinc source is from 1:2 to 2:1. 8. The composition of claim 1, wherein the anionic polymer will swell upon contact with gastric fluid and the dosage form includes 100 to 500 mg zinc source and 100 to 500 mg of the anionic polymer. 9. The composition of claim 1, wherein the anionic polymer will swell upon contact with gastric fluid and the dosage form includes 200 to 300 mg zinc source and 200 to 300 mg of the anionic polymer. 10. The composition of claim 1, wherein the zinc source is 5% to 50% w/w of the dosage form. 11. The composition of claim 1, wherein the zinc source is 20% to 25% w/w of the dosage form. 12. The composition of claim 1, wherein the anionic polymer will swell upon contact with gastric fluid;
the anionic polymer is 20% to 25% w/w of the dosage form; and the zinc source is 20% to 25% w/w of the dosage form. 13. The composition of claim 1, wherein the amino acid source is 2% to 10% w/w of the dosage form. 14. A composition comprising:
a therapeutically effective oral pharmaceutical dosage form that becomes buoyant upon contact with gastric fluid, the dosage form having therein: 2% w/w to 10% w/w of an amino acid source; 9% w/w to 45% w/w of a zinc source; 10% w/w to 55% w/w of an anionic polymer; 1% w/w to 15% w/w of a bicarbonate; and wherein the dosage form is effective for releasing the amino acid source and zinc from the zinc source while buoyant on gastric fluid. 15. The composition of claim 14, wherein the zinc source is a water soluble zinc salt. 16. The composition of claim 14, wherein the anionic polymer has terminal carboxylate functional groups. 17. The composition of claim 14, wherein an amount of the bicarbonate is capable of maintaining a substantially neutral pH within the dosage form while the dosage form is in contact with stomach acid. 18. The composition of claim 14, wherein the dosage form is therapeutically effective for treating a gastroesophageal condition. 19. The composition of claim 14, wherein the dosage form is a tablet. 20. The composition of claim 14, wherein the anionic polymer will swell upon contact with gastric fluid and a ratio of the anionic polymer to the zinc source is from 1:2 to 2:1. 21. The composition of claim 14, wherein:
the anionic polymer will swell upon contact with gastric fluid; the anionic polymer is 20% to 25% w/w of the dosage form; and the zinc source is 20% to 25% w/w of the dosage form. 22. The composition of claim 14, wherein the anionic polymer will swell upon contact with gastric fluid and the dosage form includes 200 to 300 mg zinc source and 200 to 300 mg of the anionic polymer. 23. The composition of claim 14, wherein the amino acid source includes glutamine. 24. A method of treating a gastroesophageal condition associated with stomach acid, the method comprising locally delivering zinc and an amino acid to a distal esophagus of a patient by administering to a patient in need thereof:
a therapeutically effective oral pharmaceutical dosage form that becomes buoyant upon contact with the patient's gastric fluid, the dosage form having therein: an active ingredient combination including an amino acid source and a zinc source; an anionic polymer; an effervescent agent; and a pH buffer; wherein the dosage form releases the active ingredient combination while buoyant on gastric fluid and neutralizes stomach acid while promoting healing of epithelial cells in the distal esophagus. 25. The method of claim 24, wherein the zinc source is a water soluble zinc salt. 26. The method of claim 24, wherein the anionic polymer has terminal carboxylate functional groups. 27. The method of claim 24, wherein the pH buffer is capable of maintaining a substantially neutral pH within the dosage form while the dosage form is in contact with stomach acid. 28. The method of claim 24, wherein the dosage form is therapeutically effective for treating a gastroesophageal condition. 29. The method of claim 24, wherein the dosage form is a tablet. 30. The method of claim 24, wherein the anionic polymer will swell upon contact with gastric fluid and a ratio of the anionic polymer to the zinc source is from 1:2 to 2:1. 31. The method of claim 24, wherein the anionic polymer will swell upon contact with gastric fluid and the dosage form includes 100 to 500 mg zinc source and 100 to 500 mg of the anionic polymer. 32. The method of claim 24, wherein the anionic polymer will swell upon contact with gastric fluid and the dosage form includes 200 to 300 mg zinc source and 200 to 300 mg of the anionic polymer. 33. The method of claim 24, wherein the zinc source is 5% to 50% w/w of the dosage form. 34. The method of claim 24, wherein the zinc source is 20% to 25% w/w of the dosage form. 35. The method of claim 24, wherein the anionic polymer will swell upon contact with gastric fluid;
the anionic polymer is 20% to 25% w/w of the dosage form; and the zinc source is 20% to 25% w/w of the dosage form. 36. The method of claim 24, further comprising 2% to 10% w/w of an amino acid source. | A composition includes a therapeutically effective oral pharmaceutical dosage form that becomes buoyant upon contact with gastric fluid. The dosage form includes an active ingredient combination including an amino acid source and a zinc source, an anionic polymer, an effervescent agent, and a pH buffer. The dosage form is effective for releasing the active ingredient combination while buoyant on gastric fluid.1. A composition comprising:
a therapeutically effective oral pharmaceutical dosage form that becomes buoyant upon contact with gastric fluid, the dosage form having therein: an active ingredient combination including an amino acid source and a zinc source; an anionic polymer; an effervescent agent; and a pH buffer; wherein the dosage form is effective for releasing the active ingredient combination while buoyant on gastric fluid. 2. The composition of claim 1, wherein the zinc source is a water soluble zinc salt. 3. The composition of claim 1, wherein the anionic polymer has terminal carboxylate functional groups. 4. The composition of claim 1, wherein the pH buffer is in an amount capable of maintaining a substantially neutral pH within the dosage form while the dosage form is in contact with stomach acid. 5. The composition of claim 1, wherein the dosage form is therapeutically effective for treating a gastroesophageal condition. 6. The composition of claim 1, wherein the dosage form is a tablet. 7. The composition of claim 1, wherein the anionic polymer will swell upon contact with gastric fluid and a ratio of the anionic polymer to the zinc source is from 1:2 to 2:1. 8. The composition of claim 1, wherein the anionic polymer will swell upon contact with gastric fluid and the dosage form includes 100 to 500 mg zinc source and 100 to 500 mg of the anionic polymer. 9. The composition of claim 1, wherein the anionic polymer will swell upon contact with gastric fluid and the dosage form includes 200 to 300 mg zinc source and 200 to 300 mg of the anionic polymer. 10. The composition of claim 1, wherein the zinc source is 5% to 50% w/w of the dosage form. 11. The composition of claim 1, wherein the zinc source is 20% to 25% w/w of the dosage form. 12. The composition of claim 1, wherein the anionic polymer will swell upon contact with gastric fluid;
the anionic polymer is 20% to 25% w/w of the dosage form; and the zinc source is 20% to 25% w/w of the dosage form. 13. The composition of claim 1, wherein the amino acid source is 2% to 10% w/w of the dosage form. 14. A composition comprising:
a therapeutically effective oral pharmaceutical dosage form that becomes buoyant upon contact with gastric fluid, the dosage form having therein: 2% w/w to 10% w/w of an amino acid source; 9% w/w to 45% w/w of a zinc source; 10% w/w to 55% w/w of an anionic polymer; 1% w/w to 15% w/w of a bicarbonate; and wherein the dosage form is effective for releasing the amino acid source and zinc from the zinc source while buoyant on gastric fluid. 15. The composition of claim 14, wherein the zinc source is a water soluble zinc salt. 16. The composition of claim 14, wherein the anionic polymer has terminal carboxylate functional groups. 17. The composition of claim 14, wherein an amount of the bicarbonate is capable of maintaining a substantially neutral pH within the dosage form while the dosage form is in contact with stomach acid. 18. The composition of claim 14, wherein the dosage form is therapeutically effective for treating a gastroesophageal condition. 19. The composition of claim 14, wherein the dosage form is a tablet. 20. The composition of claim 14, wherein the anionic polymer will swell upon contact with gastric fluid and a ratio of the anionic polymer to the zinc source is from 1:2 to 2:1. 21. The composition of claim 14, wherein:
the anionic polymer will swell upon contact with gastric fluid; the anionic polymer is 20% to 25% w/w of the dosage form; and the zinc source is 20% to 25% w/w of the dosage form. 22. The composition of claim 14, wherein the anionic polymer will swell upon contact with gastric fluid and the dosage form includes 200 to 300 mg zinc source and 200 to 300 mg of the anionic polymer. 23. The composition of claim 14, wherein the amino acid source includes glutamine. 24. A method of treating a gastroesophageal condition associated with stomach acid, the method comprising locally delivering zinc and an amino acid to a distal esophagus of a patient by administering to a patient in need thereof:
a therapeutically effective oral pharmaceutical dosage form that becomes buoyant upon contact with the patient's gastric fluid, the dosage form having therein: an active ingredient combination including an amino acid source and a zinc source; an anionic polymer; an effervescent agent; and a pH buffer; wherein the dosage form releases the active ingredient combination while buoyant on gastric fluid and neutralizes stomach acid while promoting healing of epithelial cells in the distal esophagus. 25. The method of claim 24, wherein the zinc source is a water soluble zinc salt. 26. The method of claim 24, wherein the anionic polymer has terminal carboxylate functional groups. 27. The method of claim 24, wherein the pH buffer is capable of maintaining a substantially neutral pH within the dosage form while the dosage form is in contact with stomach acid. 28. The method of claim 24, wherein the dosage form is therapeutically effective for treating a gastroesophageal condition. 29. The method of claim 24, wherein the dosage form is a tablet. 30. The method of claim 24, wherein the anionic polymer will swell upon contact with gastric fluid and a ratio of the anionic polymer to the zinc source is from 1:2 to 2:1. 31. The method of claim 24, wherein the anionic polymer will swell upon contact with gastric fluid and the dosage form includes 100 to 500 mg zinc source and 100 to 500 mg of the anionic polymer. 32. The method of claim 24, wherein the anionic polymer will swell upon contact with gastric fluid and the dosage form includes 200 to 300 mg zinc source and 200 to 300 mg of the anionic polymer. 33. The method of claim 24, wherein the zinc source is 5% to 50% w/w of the dosage form. 34. The method of claim 24, wherein the zinc source is 20% to 25% w/w of the dosage form. 35. The method of claim 24, wherein the anionic polymer will swell upon contact with gastric fluid;
the anionic polymer is 20% to 25% w/w of the dosage form; and the zinc source is 20% to 25% w/w of the dosage form. 36. The method of claim 24, further comprising 2% to 10% w/w of an amino acid source. | 1,600 |
455 | 13,310,632 | 1,612 | This invention relates to rapidly dispersing microgranules comprising at least one sugar alcohol or saccharide, at least one super disintegrant, and a pharmaceutically acceptable additive with multi-functionality (e.g., starch acting as a binder, disintegrant, diluent/filler, glidant, etc) at a low level, which can be formed by not only eliminating a wet milling step but also avoiding an extensive dry milling step. Furthermore, such rapidly dispersing microgranules could also comprise a pharmaceutically active agent thereby providing for a pharmaceutical composition, or the rapidly dispersing microgranules thus produced are suitable for blending with a pharmaceutically active agent that is optionally taste-masked and/or controlled release coated microparticles to also provide for a pharmaceutical composition and the invention is also directed to a method for manufacturing such rapidly dispersing microgranules in a high useable yield, as well as orally disintegrating tablets comprising such rapidly dispersing microgranules. The rapidly dispersing microgranules are also free flowing. | 1. Rapidly dispersing microgranules with a median particle size in the range of about 100 μm to about 300 μm, comprising at least one sugar alcohol, saccharide, or a mixture thereof, at least one super disintegrant, and at least one multifunctional additive. 2. The microgranules of claim 1 wherein the at least one sugar alcohol, saccharide, or a mixture thereof, at least one super disintegrant, and at least one multifunctional additive are present at a ratio of about 88-98 (sugar alcohol):1-10 (disintegrant):1-3 (multi-functional additive). 3. The microgranules of claim 1 wherein the sugar alcohol that is selected from the group consisting of mannitol, xyletol, and mixture thereof, the saccharide that is selected from the group consisting of lactose, sucrose, fructose, and mixture thereof. 4. The microgranules of claim 1 wherein the super disintegrant that is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low substituted hydroxypropylcellulose, and mixture thereof. 5. The microgranules of claim 1 wherein the multi-functional additive is selected from the group consisting of starch, hydroxypropylcellulose, maltodextrin, and mixture thereof. 6. The microgranules of claim 1 wherein the sugar alcohol is mannitol having a median particle size of about 60 μm, said disintegrant is low substituted hydroxypropylcellulose, and said multi-functional additive is starch. 7. The microgranules of claim 1 wherein the sugar alcohol is mannitol having a median particle size of about 35 μm, said disintegrant is low substituted hydroxypropylcellulose, and said multi-functional additive is low viscosity hydroxypropylcellulose. 8. The microgranules of claim 1 wherein the sugar alcohol is mannitol having a median particle size of about 15 to about 30 μm, said disintegrant is low substituted hydroxypropylcellulose, and said multi-functional additive is starch. 9. A pharmaceutical dosage form, which is an orally disintegrating tablet, comprising the microgranules of claim 1 and a therapeutically effective amount of at least one active pharmaceutical ingredient. 10. The pharmaceutical dosage form of claim 9 which is an orally disintegrating tablet dosage form, further comprises at least one pharmaceutically acceptable excipient selected from a flavorant, sweetener, colorant, compression aid, and additional disintegrant. 11. The pharmaceutical dosage form of claim 9 wherein the active pharmaceutical ingredient further comprises one or more coatings of one or more functional polymers to impart taste-masking, controlled release characteristics, or a combination thereof, and optionally a pharmaceutically acceptable excipient. 12. (canceled) 13. The pharmaceutical dosage form of claim 11 wherein the taste-masked microparticles of the active pharmaceutical ingredient have a median particle size in the range of about 100-400 μm, and the orally disintegrating tablet dosage form rapidly disintegrates on contact with saliva in the buccal cavity of a mammal creating a smooth, non-gritty, and easy-to-swallow suspension containing the taste-masked drug microparticles, which provide a dissolution profiles similar to that of the reference listed drug in order to be bioequivalent. 14. The pharmaceutical dosage form of claim 11 wherein the microparticles of the active pharmaceutical ingredient which are imparted with taste-masking, controlled release, or a combination thereof characteristics, have a median particle size in the range of about 100-400 μm, and the orally disintegrating tablet dosage form rapidly disintegrates on contact with saliva in the buccal cavity of a mammal creating a smooth, non-gritty, and easy-to-swallow suspension of the drug microparticles with taste-masking, controlled release characteristics, or a combination thereof, which provide a plasma concentration-time profile that is suitable for a once-a-day or twice-a-day dosing regimen. 15. The pharmaceutical dosage form of claim 9 which is formed by compressing the ingredients of the orally disintegrating tablet composition on a rotary tablet press to achieve sufficiently high tablet hardness and low friability to withstand attrition during packaging in blisters or bottles, storage, transportation for commercial distribution and end use. 16. The pharmaceutical dosage form of claim 9 which disintegrates within 30 seconds when tested for disintegration time by the United States Pharmacopeia method <701>. 17. The pharmaceutical dosage form of claim 15 wherein the orally disintegrating tablet dosage form is compressed on a rotary tablet press equipped with an external lubrication device to lubricate material contacting punch surfaces and die wall prior to each compression using a lubricant selected from the group consisting of magnesium stearate, stearic acid, calcium stearate, zinc stearate, sodium stearyl fumarate, and glyceryl behenate. 18. The pharmaceutical dosage form of claim 15 wherein the ingredients of the orally disintegrating tablet dosage form are compressed after internally lubricating the ingredients with a lubricant selected from the group consisting of magnesium stearate, stearic acid, calcium stearate, zinc stearate, sodium stearyl fumarate, glyceryl behenate, and the like. 19. The pharmaceutical dosage form of claim 9 wherein the active pharmaceutical ingredient is selected from the group consisting of drugs for central nervous system, antidepressants, antiemetics, cardiovascular agents, antihypnotics/antianxiolytics sedatives, antiepileptics, analgesics/antipyretic agents, rheumatoid arthritis, antimigraine drugs, opioids, drugs for Parkinson's disease, antipsychotic agents, antiplatelet drugs, skeletal muscle relaxants, anti-Alzheimer drugs, antispasmodic agents, proton pump inhibitors, histamine H2 antagonists, gastrointestinal disorders aminosalicylates, metronidazole, corticosteroids, antidiabetics, antiallergics, and antibiotic agents. 20. The pharmaceutical dosage form of claim 9 wherein the active pharmaceutical ingredient is selected from the group approved or approvable for oral administration consisting of amphetamine, methylphenidate, citalpram, sertraline, ondansetron, pindolol, nicardipine, guanfacine, lisinalapril, valsartan, carvedilol, amlodipine, nifedipine, furosemide, nitrazepam, phenytoin; sedatives, clonazepa, temazepam, zolpidem, diphenhydramine, lamotrigine, ibuprofen, diclofenac sodium, sumatriptan, fentanyl, oxycodone, amantadine, selegeline, paliperidone, prasugrel, ticlopidine, dipyridamole, cilostazol, cyclobenzaprine, baclofen, tiznidine, galanthamine, dicyclomine, pantoprazole, famotidine, metoclopramide, cisapride, aminosalicylate, tegaserod, metronidazole, metformin, paramomycin, and cefalexin. 21. The microganules of claim 1, further comprising a therapeutically effective amount of at least one active pharmaceutical ingredient not requiring taste-masking coating with one or more functional polymers. 22. The microganules of claim 21, wherein the active pharmaceutical ingredient is selected from the group approved or approvable for oral administration consisting of amphetamine, methylphenidate, citalpram, sertraline, ondansetron, pindolol, nicardipine, guanfacine, lisinalapril, valsartan, carvedilol, amlodipine, nifedipine, furosemide, nitrazepam, phenytoin; sedatives, clonazepa, temazepam, zolpidem, diphenhydramine, lamotrigine, ibuprofen, diclofenac sodium, sumatriptan, fentanyl, oxycodone, amantadine, selegeline, paliperidone, prasugrel, ticlopidine, dipyridamole, cilostazol, cyclobenzaprine, baclofen, tiznidine, galanthamine, dicyclomine, pantoprazole, famotidine, metoclopramide, cisapride, aminosalicylate, tegaserod, metronidazole, metformin, paramomycin, and cefalexin. 23. The pharmaceutical dosage form of claim 19 further comprising at least one pharmaceutically acceptable excipient selected from a flavorant, sweetener, colorant, compression aid, or additional disintegrant and wherein the composition is compressed into an orally disintegrating tablet using a rotary tablet press with internal or external lubrication, and the tablet disintegrates within 30 seconds when tested for disintegration time by the United States Pharmacopeia method <701>. 24. The microgranules of claim 2 prepared by granulation
in a fluid bed granulator without the need for milling moist granulations and/or extensive milling of the dry granulation. 25. The microgranules of claim 1, further comprising a therapeutically effective amount active pharmaceutical ingredient not requiring a taste-masking coating to mask the drug taste prepared by granulating a powder mixture comprising a sugar alcohol, a saccharide, or a mixture thereof, each primary particle with a median particle size of about 60 μm or less, a super disintegrant, a pharmaceutically acceptable, multi-functional additive, and a therapeutic agent not requiring a taste-masking coating to mask the drug taste at a ratio of about 60-95(sugar alcohol):1-10 (disintegrant):1-3 (multi-functional additive):0.1-30 (therapeutic agent) in a fluid bed granulator without the need for milling of the moist granulation and/or extensive milling of the dry granulation. 26. (canceled) 27. A method of manufacturing an orally disintegrating tablet comprises the following steps:
a. preparing active pharmaceutical ingredient microparticles b. optionally coating drug microparticles with one or more functional polymers to impart taste-masking or controlled release characteristics, c. preparing a powder mixture comprising polymer coated drug microparticles having a median particle size in the range of about 100-400 μm from step (b), the microgranules of claim 1, and other optional pharmaceutically acceptable excipients selected from a flavorant, sweetener, colorant, compression aid, and additional disintegrant; and d. compressing the powder mixture on a rotary tablet press using internal or external lubrication, wherein the orally disintegrating tablet rapidly disintegrates on contact with saliva in the buccal cavity into a smooth, non-gritty, easy-to-swallow suspension containing polymer coated drug microparticles or drug microparticles taste-masked by granulating with a sugar alcohol, superdisintegrant and optionally a flavorant or sweetener. 28. A method of manufacturing an orally disintegrating tablets comprises:
a. preparing a powder mixture comprising the microganules of claim 25, and optional pharmaceutically acceptable excipients comprising a flavorant, sweetener, colorant, compression aid, additional disintegrant; b. compressing the powder mixture on a rotary tablet press using internal or external lubrication, wherein the orally disintegrating tablet rapidly disintegrates on contact with saliva in the buccal cavity into a smooth, non-gritty, easy-to-swallow suspension containing drug microparticles. 29. The tablet of claim 27 wherein the tablet is prepared by a method in which the powder mixture is compressed on a rotary tablet press without the addition of a lubricant to the blend, and the method includes a lubricating device to lubricate material contacting punch surfaces and die wall of the tablet press. 30. The tablet of claim 27 wherein the tablet is prepared by a method in which the powder mixture is compressed on a rotary tablet press after mixing with a lubricant selected from the group consisting of magnesium stearate, stearic acid, calcium stearate, zinc stearate, sodium stearyl fumarate, glyceryl behenate, and the like. 31. The tablet of claim 28 wherein the tablet is prepared by a method in which the powder mixture is compressed on a rotary tablet press without the addition of a lubricant to the blend, and the method includes a lubricating device to lubricate material contacting punch surfaces and die wall of the tablet press. 32. The tablet of claim 28 wherein the tablet is prepared by a method in which the powder mixture is compressed on a rotary tablet press after mixing with a lubricant selected from the group consisting of magnesium stearate, stearic acid, calcium stearate, zinc stearate, sodium stearyl fumarate, glyceryl behenate, and the like. | This invention relates to rapidly dispersing microgranules comprising at least one sugar alcohol or saccharide, at least one super disintegrant, and a pharmaceutically acceptable additive with multi-functionality (e.g., starch acting as a binder, disintegrant, diluent/filler, glidant, etc) at a low level, which can be formed by not only eliminating a wet milling step but also avoiding an extensive dry milling step. Furthermore, such rapidly dispersing microgranules could also comprise a pharmaceutically active agent thereby providing for a pharmaceutical composition, or the rapidly dispersing microgranules thus produced are suitable for blending with a pharmaceutically active agent that is optionally taste-masked and/or controlled release coated microparticles to also provide for a pharmaceutical composition and the invention is also directed to a method for manufacturing such rapidly dispersing microgranules in a high useable yield, as well as orally disintegrating tablets comprising such rapidly dispersing microgranules. The rapidly dispersing microgranules are also free flowing.1. Rapidly dispersing microgranules with a median particle size in the range of about 100 μm to about 300 μm, comprising at least one sugar alcohol, saccharide, or a mixture thereof, at least one super disintegrant, and at least one multifunctional additive. 2. The microgranules of claim 1 wherein the at least one sugar alcohol, saccharide, or a mixture thereof, at least one super disintegrant, and at least one multifunctional additive are present at a ratio of about 88-98 (sugar alcohol):1-10 (disintegrant):1-3 (multi-functional additive). 3. The microgranules of claim 1 wherein the sugar alcohol that is selected from the group consisting of mannitol, xyletol, and mixture thereof, the saccharide that is selected from the group consisting of lactose, sucrose, fructose, and mixture thereof. 4. The microgranules of claim 1 wherein the super disintegrant that is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, low substituted hydroxypropylcellulose, and mixture thereof. 5. The microgranules of claim 1 wherein the multi-functional additive is selected from the group consisting of starch, hydroxypropylcellulose, maltodextrin, and mixture thereof. 6. The microgranules of claim 1 wherein the sugar alcohol is mannitol having a median particle size of about 60 μm, said disintegrant is low substituted hydroxypropylcellulose, and said multi-functional additive is starch. 7. The microgranules of claim 1 wherein the sugar alcohol is mannitol having a median particle size of about 35 μm, said disintegrant is low substituted hydroxypropylcellulose, and said multi-functional additive is low viscosity hydroxypropylcellulose. 8. The microgranules of claim 1 wherein the sugar alcohol is mannitol having a median particle size of about 15 to about 30 μm, said disintegrant is low substituted hydroxypropylcellulose, and said multi-functional additive is starch. 9. A pharmaceutical dosage form, which is an orally disintegrating tablet, comprising the microgranules of claim 1 and a therapeutically effective amount of at least one active pharmaceutical ingredient. 10. The pharmaceutical dosage form of claim 9 which is an orally disintegrating tablet dosage form, further comprises at least one pharmaceutically acceptable excipient selected from a flavorant, sweetener, colorant, compression aid, and additional disintegrant. 11. The pharmaceutical dosage form of claim 9 wherein the active pharmaceutical ingredient further comprises one or more coatings of one or more functional polymers to impart taste-masking, controlled release characteristics, or a combination thereof, and optionally a pharmaceutically acceptable excipient. 12. (canceled) 13. The pharmaceutical dosage form of claim 11 wherein the taste-masked microparticles of the active pharmaceutical ingredient have a median particle size in the range of about 100-400 μm, and the orally disintegrating tablet dosage form rapidly disintegrates on contact with saliva in the buccal cavity of a mammal creating a smooth, non-gritty, and easy-to-swallow suspension containing the taste-masked drug microparticles, which provide a dissolution profiles similar to that of the reference listed drug in order to be bioequivalent. 14. The pharmaceutical dosage form of claim 11 wherein the microparticles of the active pharmaceutical ingredient which are imparted with taste-masking, controlled release, or a combination thereof characteristics, have a median particle size in the range of about 100-400 μm, and the orally disintegrating tablet dosage form rapidly disintegrates on contact with saliva in the buccal cavity of a mammal creating a smooth, non-gritty, and easy-to-swallow suspension of the drug microparticles with taste-masking, controlled release characteristics, or a combination thereof, which provide a plasma concentration-time profile that is suitable for a once-a-day or twice-a-day dosing regimen. 15. The pharmaceutical dosage form of claim 9 which is formed by compressing the ingredients of the orally disintegrating tablet composition on a rotary tablet press to achieve sufficiently high tablet hardness and low friability to withstand attrition during packaging in blisters or bottles, storage, transportation for commercial distribution and end use. 16. The pharmaceutical dosage form of claim 9 which disintegrates within 30 seconds when tested for disintegration time by the United States Pharmacopeia method <701>. 17. The pharmaceutical dosage form of claim 15 wherein the orally disintegrating tablet dosage form is compressed on a rotary tablet press equipped with an external lubrication device to lubricate material contacting punch surfaces and die wall prior to each compression using a lubricant selected from the group consisting of magnesium stearate, stearic acid, calcium stearate, zinc stearate, sodium stearyl fumarate, and glyceryl behenate. 18. The pharmaceutical dosage form of claim 15 wherein the ingredients of the orally disintegrating tablet dosage form are compressed after internally lubricating the ingredients with a lubricant selected from the group consisting of magnesium stearate, stearic acid, calcium stearate, zinc stearate, sodium stearyl fumarate, glyceryl behenate, and the like. 19. The pharmaceutical dosage form of claim 9 wherein the active pharmaceutical ingredient is selected from the group consisting of drugs for central nervous system, antidepressants, antiemetics, cardiovascular agents, antihypnotics/antianxiolytics sedatives, antiepileptics, analgesics/antipyretic agents, rheumatoid arthritis, antimigraine drugs, opioids, drugs for Parkinson's disease, antipsychotic agents, antiplatelet drugs, skeletal muscle relaxants, anti-Alzheimer drugs, antispasmodic agents, proton pump inhibitors, histamine H2 antagonists, gastrointestinal disorders aminosalicylates, metronidazole, corticosteroids, antidiabetics, antiallergics, and antibiotic agents. 20. The pharmaceutical dosage form of claim 9 wherein the active pharmaceutical ingredient is selected from the group approved or approvable for oral administration consisting of amphetamine, methylphenidate, citalpram, sertraline, ondansetron, pindolol, nicardipine, guanfacine, lisinalapril, valsartan, carvedilol, amlodipine, nifedipine, furosemide, nitrazepam, phenytoin; sedatives, clonazepa, temazepam, zolpidem, diphenhydramine, lamotrigine, ibuprofen, diclofenac sodium, sumatriptan, fentanyl, oxycodone, amantadine, selegeline, paliperidone, prasugrel, ticlopidine, dipyridamole, cilostazol, cyclobenzaprine, baclofen, tiznidine, galanthamine, dicyclomine, pantoprazole, famotidine, metoclopramide, cisapride, aminosalicylate, tegaserod, metronidazole, metformin, paramomycin, and cefalexin. 21. The microganules of claim 1, further comprising a therapeutically effective amount of at least one active pharmaceutical ingredient not requiring taste-masking coating with one or more functional polymers. 22. The microganules of claim 21, wherein the active pharmaceutical ingredient is selected from the group approved or approvable for oral administration consisting of amphetamine, methylphenidate, citalpram, sertraline, ondansetron, pindolol, nicardipine, guanfacine, lisinalapril, valsartan, carvedilol, amlodipine, nifedipine, furosemide, nitrazepam, phenytoin; sedatives, clonazepa, temazepam, zolpidem, diphenhydramine, lamotrigine, ibuprofen, diclofenac sodium, sumatriptan, fentanyl, oxycodone, amantadine, selegeline, paliperidone, prasugrel, ticlopidine, dipyridamole, cilostazol, cyclobenzaprine, baclofen, tiznidine, galanthamine, dicyclomine, pantoprazole, famotidine, metoclopramide, cisapride, aminosalicylate, tegaserod, metronidazole, metformin, paramomycin, and cefalexin. 23. The pharmaceutical dosage form of claim 19 further comprising at least one pharmaceutically acceptable excipient selected from a flavorant, sweetener, colorant, compression aid, or additional disintegrant and wherein the composition is compressed into an orally disintegrating tablet using a rotary tablet press with internal or external lubrication, and the tablet disintegrates within 30 seconds when tested for disintegration time by the United States Pharmacopeia method <701>. 24. The microgranules of claim 2 prepared by granulation
in a fluid bed granulator without the need for milling moist granulations and/or extensive milling of the dry granulation. 25. The microgranules of claim 1, further comprising a therapeutically effective amount active pharmaceutical ingredient not requiring a taste-masking coating to mask the drug taste prepared by granulating a powder mixture comprising a sugar alcohol, a saccharide, or a mixture thereof, each primary particle with a median particle size of about 60 μm or less, a super disintegrant, a pharmaceutically acceptable, multi-functional additive, and a therapeutic agent not requiring a taste-masking coating to mask the drug taste at a ratio of about 60-95(sugar alcohol):1-10 (disintegrant):1-3 (multi-functional additive):0.1-30 (therapeutic agent) in a fluid bed granulator without the need for milling of the moist granulation and/or extensive milling of the dry granulation. 26. (canceled) 27. A method of manufacturing an orally disintegrating tablet comprises the following steps:
a. preparing active pharmaceutical ingredient microparticles b. optionally coating drug microparticles with one or more functional polymers to impart taste-masking or controlled release characteristics, c. preparing a powder mixture comprising polymer coated drug microparticles having a median particle size in the range of about 100-400 μm from step (b), the microgranules of claim 1, and other optional pharmaceutically acceptable excipients selected from a flavorant, sweetener, colorant, compression aid, and additional disintegrant; and d. compressing the powder mixture on a rotary tablet press using internal or external lubrication, wherein the orally disintegrating tablet rapidly disintegrates on contact with saliva in the buccal cavity into a smooth, non-gritty, easy-to-swallow suspension containing polymer coated drug microparticles or drug microparticles taste-masked by granulating with a sugar alcohol, superdisintegrant and optionally a flavorant or sweetener. 28. A method of manufacturing an orally disintegrating tablets comprises:
a. preparing a powder mixture comprising the microganules of claim 25, and optional pharmaceutically acceptable excipients comprising a flavorant, sweetener, colorant, compression aid, additional disintegrant; b. compressing the powder mixture on a rotary tablet press using internal or external lubrication, wherein the orally disintegrating tablet rapidly disintegrates on contact with saliva in the buccal cavity into a smooth, non-gritty, easy-to-swallow suspension containing drug microparticles. 29. The tablet of claim 27 wherein the tablet is prepared by a method in which the powder mixture is compressed on a rotary tablet press without the addition of a lubricant to the blend, and the method includes a lubricating device to lubricate material contacting punch surfaces and die wall of the tablet press. 30. The tablet of claim 27 wherein the tablet is prepared by a method in which the powder mixture is compressed on a rotary tablet press after mixing with a lubricant selected from the group consisting of magnesium stearate, stearic acid, calcium stearate, zinc stearate, sodium stearyl fumarate, glyceryl behenate, and the like. 31. The tablet of claim 28 wherein the tablet is prepared by a method in which the powder mixture is compressed on a rotary tablet press without the addition of a lubricant to the blend, and the method includes a lubricating device to lubricate material contacting punch surfaces and die wall of the tablet press. 32. The tablet of claim 28 wherein the tablet is prepared by a method in which the powder mixture is compressed on a rotary tablet press after mixing with a lubricant selected from the group consisting of magnesium stearate, stearic acid, calcium stearate, zinc stearate, sodium stearyl fumarate, glyceryl behenate, and the like. | 1,600 |
456 | 15,347,996 | 1,636 | Disclosed are delivery platforms for use in gene editing that include a relatively short, highly efficient promoter that drives transcription of a nucleic acid sequence that encodes a gene-editing molecule, e.g., either a gRNA or a nuclease. In conjunction with this promoter, the vector includes one or more transcription factor binding elements (an Sp1 binding element and/or an NF-κB binding element) cloned into the vector upstream of a promoter that drives transcription of a gene-editing molecule. The vector can be a all-in-one CRISPR/Cas9 delivery platform and can incorporate one or more of the transcription factor binding elements upstream of a promoter for the gRNA component and/or of a promoter for the nuclease component. | 1. A viral vector comprising:
one or more structural components derived from a virus; a nucleic acid sequence encoding a gene-editing molecule; a promoter configured to initiate transcription of the nucleic acid sequence encoding the gene-editing molecule, wherein the promoter is free of introns; an Sp1 transcription factor binding element and/or a NF-κB transcription factor binding element upstream of the promoter. 2. The viral vector of claim 1, wherein the vector is a retroviral vector. 3. The viral vector of claim 2, wherein the vector is a lentiviral vector. 4. The viral vector of claim 3, wherein the vector is an HIV-1 vector. 5. The viral vector of claim 1, wherein the gene-editing molecule comprises a gRNA. 6. The viral vector of claim 1, wherein the gene-editing molecule comprises a Cas9. 7. The viral vector of claim 1, wherein the viral vector is a CRISPR/Cas9 all-in-one plasmid viral vector. 8. The viral vector of claim 7, wherein the vector further comprises a second promoter, the second promoter being free of introns, the promoter of claim 1 being configured to initiate transcription of either the gRNA element or the Cas9 element of the binary plasmid viral vector, and the second promoter being configured to initiate transcription of the other of the gRNA element or the Cas9 element of the viral vector. 9. The viral vector of claim 8, wherein the viral vector further comprises a second Sp1 transcription factor binding element and/or a NF-κB transcription factor binding element upstream of the second promoter. 10. The viral vector of claim 1, the viral vector comprising multiple Sp1 transcription factor binding elements and/or multiple NF-κB transcription factor binding elements upstream of the promoter. 11. The viral vector of claim 1, wherein the Sp1 transcription factor binding element and/or the NF-κB transcription factor binding element is immediately upstream of the promoter. 12. The viral vector of claim 1, wherein the promoter comprises about 300 or fewer base pairs. 13. The viral vector of claim 1, wherein the promoter is a polymerase III promoter. 14. The viral vector of claim 1, wherein the promoter is a polymerase II promoter that has been modified to remove internal elements. 15. The viral vector of claim 1, wherein the viral vector in an integrating viral vector. 16. The viral vector of claim 1, wherein the viral vector is a non-integrating viral vector. 17. A delivery platform for a gene-editing transgene, the delivery platform comprising a vector plasmid in conjunction with one or more additional plasmids, the vector plasmid comprising the viral vector of claim 1. 18. A vector particle comprising the viral vector of claim 1. | Disclosed are delivery platforms for use in gene editing that include a relatively short, highly efficient promoter that drives transcription of a nucleic acid sequence that encodes a gene-editing molecule, e.g., either a gRNA or a nuclease. In conjunction with this promoter, the vector includes one or more transcription factor binding elements (an Sp1 binding element and/or an NF-κB binding element) cloned into the vector upstream of a promoter that drives transcription of a gene-editing molecule. The vector can be a all-in-one CRISPR/Cas9 delivery platform and can incorporate one or more of the transcription factor binding elements upstream of a promoter for the gRNA component and/or of a promoter for the nuclease component.1. A viral vector comprising:
one or more structural components derived from a virus; a nucleic acid sequence encoding a gene-editing molecule; a promoter configured to initiate transcription of the nucleic acid sequence encoding the gene-editing molecule, wherein the promoter is free of introns; an Sp1 transcription factor binding element and/or a NF-κB transcription factor binding element upstream of the promoter. 2. The viral vector of claim 1, wherein the vector is a retroviral vector. 3. The viral vector of claim 2, wherein the vector is a lentiviral vector. 4. The viral vector of claim 3, wherein the vector is an HIV-1 vector. 5. The viral vector of claim 1, wherein the gene-editing molecule comprises a gRNA. 6. The viral vector of claim 1, wherein the gene-editing molecule comprises a Cas9. 7. The viral vector of claim 1, wherein the viral vector is a CRISPR/Cas9 all-in-one plasmid viral vector. 8. The viral vector of claim 7, wherein the vector further comprises a second promoter, the second promoter being free of introns, the promoter of claim 1 being configured to initiate transcription of either the gRNA element or the Cas9 element of the binary plasmid viral vector, and the second promoter being configured to initiate transcription of the other of the gRNA element or the Cas9 element of the viral vector. 9. The viral vector of claim 8, wherein the viral vector further comprises a second Sp1 transcription factor binding element and/or a NF-κB transcription factor binding element upstream of the second promoter. 10. The viral vector of claim 1, the viral vector comprising multiple Sp1 transcription factor binding elements and/or multiple NF-κB transcription factor binding elements upstream of the promoter. 11. The viral vector of claim 1, wherein the Sp1 transcription factor binding element and/or the NF-κB transcription factor binding element is immediately upstream of the promoter. 12. The viral vector of claim 1, wherein the promoter comprises about 300 or fewer base pairs. 13. The viral vector of claim 1, wherein the promoter is a polymerase III promoter. 14. The viral vector of claim 1, wherein the promoter is a polymerase II promoter that has been modified to remove internal elements. 15. The viral vector of claim 1, wherein the viral vector in an integrating viral vector. 16. The viral vector of claim 1, wherein the viral vector is a non-integrating viral vector. 17. A delivery platform for a gene-editing transgene, the delivery platform comprising a vector plasmid in conjunction with one or more additional plasmids, the vector plasmid comprising the viral vector of claim 1. 18. A vector particle comprising the viral vector of claim 1. | 1,600 |
457 | 14,540,754 | 1,615 | A composition intended to be employed for therapeutic purposes incorporates a nicotinic compound, a sugar substitute, and a sugar alcohol syrup. Representative forms of nicotine include free base (e.g., as a mixture of nicotine and microcrystalline cellulose), a nicotine salt (e.g., as nicotine bitartrate) or nicotine polacrilex. The composition is useful for treatment of central nervous system conditions, diseases, and disorders, and as a nicotine replacement therapy. | 1-27. (canceled) 28. A method of preparing a nicotine-containing pharmaceutical composition, comprising:
(i) mixing a non-hygroscopic sugar substitute capable of forming a glassy matrix in an amount of at least about 80% by weight and a sugar alcohol syrup in a melted state to form a mixture; (ii) cooling the mixture and incorporating a nicotinic compound into the cooled mixture; and (iii) further cooling the mixture to room temperature to form a solid nicotine-containing pharmaceutical composition. 29. The method of claim 28, wherein at least a portion of the nicotinic compound is in the form of a free base, a salt, a complex, or a solvate. 30. The method of claim 28, wherein the nicotinic compound is nicotine polacrilex. 31. The method of claim 28, wherein the nicotinic compound is sorbed onto a porous particulate carrier. 32. The method of claim 31, wherein the porous particulate carrier comprises microcrystalline cellulose. 33. The method of claim 28, wherein the sugar substitute is isomalt. 34. The method of claim 28, wherein the sugar alcohol syrup is in an amount sufficient to slow recrystallization of the sugar substitute in melted form. 35. The method of claim 28, wherein the sugar alcohol syrup is maltitol syrup or xylitol syrup. 36. The method of claim 28, wherein the pharmaceutical composition comprises at least about 85% by weight of the sugar substitute. 37. The method of claim 28, wherein the pharmaceutical composition comprises at least about 4.0% by weight of sugar alcohol syrup. 38. The method of claim 28, wherein the pharmaceutical composition comprises at least about 4.5% by weight of sugar alcohol syrup. 39. The method of claim 28, wherein the composition is in the form of a lozenge or tablet. 40. The method of claim 28, wherein the composition is translucent. 41. The method of claim 28, further comprising adding one or more components selected from the group consisting of flavorants, sweeteners, and NaCl. 42. The method of claim 41, wherein the amount of flavorant is from about 0.1 to about 0.5 percent by weight of the pharmaceutical composition. 43. The method of claim 41, wherein the flavorant is vanillin or mint flavor. 44. The method of claim 41, wherein the sweetener comprises sucralose. 45. The method of claim 41, wherein the amount of NaCl is from about 0.5 to about 1 percent by weight of the pharmaceutical composition. 46. The method of claim 28, wherein the mixing step comprises heating the sugar substitute and the sugar alcohol syrup to a temperature above the hard crack stage of the sugar substitute and wherein the incorporating step comprises adding a nicotinic compound to the mixture at a temperature below the hard crack stage of the sugar substitute. 47. The method of claim 46, wherein the hard crack stage is about 145° C. to about 155° C. and the sugar substitute and the sugar alcohol syrup are heated at a temperature between the hard crack stage and about 171° C. 48. A method of preparing a nicotine-containing pharmaceutical composition, comprising:
(i) mixing a first non-hygroscopic sugar alcohol capable of forming a glassy matrix in an amount of at least about 80% by weight and a second sugar alcohol in an amount of at least about 4.5% by weight and up to about 20% by weight in a melted state to form a mixture; (ii) cooling the mixture and incorporating a nicotinic compound into the cooled mixture; and (iii) further cooling the mixture to room temperature to form a solid nicotine-containing pharmaceutical composition. 49. The method of claim 48, wherein both the non-hygroscopic sugar alcohol and the second sugar alcohol are selected from the group consisting of erythritol, threitol, arabitol, xylitol, ribotol, mannitol, sorbitol, dulcitol, iditol, isomalt, maltitol, lactitol, polglycitol, and mixtures thereof. 50. The method of claim 48, wherein the first non-hygroscopic sugar alcohol is isomalt and the second sugar alcohol is maltitol. 51. The method of claim 48, wherein at least a portion of the nicotinic compound is in the form of a nicotine salt of tartrate. 52. The method of claim 48, wherein the composition is in the form of a lozenge or tablet. | A composition intended to be employed for therapeutic purposes incorporates a nicotinic compound, a sugar substitute, and a sugar alcohol syrup. Representative forms of nicotine include free base (e.g., as a mixture of nicotine and microcrystalline cellulose), a nicotine salt (e.g., as nicotine bitartrate) or nicotine polacrilex. The composition is useful for treatment of central nervous system conditions, diseases, and disorders, and as a nicotine replacement therapy.1-27. (canceled) 28. A method of preparing a nicotine-containing pharmaceutical composition, comprising:
(i) mixing a non-hygroscopic sugar substitute capable of forming a glassy matrix in an amount of at least about 80% by weight and a sugar alcohol syrup in a melted state to form a mixture; (ii) cooling the mixture and incorporating a nicotinic compound into the cooled mixture; and (iii) further cooling the mixture to room temperature to form a solid nicotine-containing pharmaceutical composition. 29. The method of claim 28, wherein at least a portion of the nicotinic compound is in the form of a free base, a salt, a complex, or a solvate. 30. The method of claim 28, wherein the nicotinic compound is nicotine polacrilex. 31. The method of claim 28, wherein the nicotinic compound is sorbed onto a porous particulate carrier. 32. The method of claim 31, wherein the porous particulate carrier comprises microcrystalline cellulose. 33. The method of claim 28, wherein the sugar substitute is isomalt. 34. The method of claim 28, wherein the sugar alcohol syrup is in an amount sufficient to slow recrystallization of the sugar substitute in melted form. 35. The method of claim 28, wherein the sugar alcohol syrup is maltitol syrup or xylitol syrup. 36. The method of claim 28, wherein the pharmaceutical composition comprises at least about 85% by weight of the sugar substitute. 37. The method of claim 28, wherein the pharmaceutical composition comprises at least about 4.0% by weight of sugar alcohol syrup. 38. The method of claim 28, wherein the pharmaceutical composition comprises at least about 4.5% by weight of sugar alcohol syrup. 39. The method of claim 28, wherein the composition is in the form of a lozenge or tablet. 40. The method of claim 28, wherein the composition is translucent. 41. The method of claim 28, further comprising adding one or more components selected from the group consisting of flavorants, sweeteners, and NaCl. 42. The method of claim 41, wherein the amount of flavorant is from about 0.1 to about 0.5 percent by weight of the pharmaceutical composition. 43. The method of claim 41, wherein the flavorant is vanillin or mint flavor. 44. The method of claim 41, wherein the sweetener comprises sucralose. 45. The method of claim 41, wherein the amount of NaCl is from about 0.5 to about 1 percent by weight of the pharmaceutical composition. 46. The method of claim 28, wherein the mixing step comprises heating the sugar substitute and the sugar alcohol syrup to a temperature above the hard crack stage of the sugar substitute and wherein the incorporating step comprises adding a nicotinic compound to the mixture at a temperature below the hard crack stage of the sugar substitute. 47. The method of claim 46, wherein the hard crack stage is about 145° C. to about 155° C. and the sugar substitute and the sugar alcohol syrup are heated at a temperature between the hard crack stage and about 171° C. 48. A method of preparing a nicotine-containing pharmaceutical composition, comprising:
(i) mixing a first non-hygroscopic sugar alcohol capable of forming a glassy matrix in an amount of at least about 80% by weight and a second sugar alcohol in an amount of at least about 4.5% by weight and up to about 20% by weight in a melted state to form a mixture; (ii) cooling the mixture and incorporating a nicotinic compound into the cooled mixture; and (iii) further cooling the mixture to room temperature to form a solid nicotine-containing pharmaceutical composition. 49. The method of claim 48, wherein both the non-hygroscopic sugar alcohol and the second sugar alcohol are selected from the group consisting of erythritol, threitol, arabitol, xylitol, ribotol, mannitol, sorbitol, dulcitol, iditol, isomalt, maltitol, lactitol, polglycitol, and mixtures thereof. 50. The method of claim 48, wherein the first non-hygroscopic sugar alcohol is isomalt and the second sugar alcohol is maltitol. 51. The method of claim 48, wherein at least a portion of the nicotinic compound is in the form of a nicotine salt of tartrate. 52. The method of claim 48, wherein the composition is in the form of a lozenge or tablet. | 1,600 |
458 | 15,198,248 | 1,612 | A method of making a consumer product providing multiple blooms of fragrance, the multiple blooms being provided for by different populations of microcapsules. | 1. A method of making a consumer product that provides multiple blooms of fragrance, the method comprising:
combining a first adjunct material, a first population of microcapsules, and a second population of microcapsules to form the consumer product; wherein the first population has a first median volume weighted particle size and comprises microcapsules comprising a partitioning modifier and a first perfume oil at a first weight ratio; and wherein the second population of microcapsules has a second median volume weighted particle size and comprises microcapsules comprising the partitioning modifier and a second perfume oil at a second weight ratio; wherein the first weight ratio and the second weight ratio are different, and/or the first median volume weighted particle size and the second median volume weighted particle size are different. 2. The method of claim 1, wherein at least one of the first population of microcapsules and the second population of microcapsules is contained in a slurry prior to combining with the adjunct material. 3. The method of claim 2, wherein the slurry includes one or more processing aids selected from the group consisting of a carrier, an aggregate inhibiting material, a deposition aid, a particle suspending polymer, and mixtures thereof. 4. The method of claim 1, wherein at least one of the first population of microcapsules and the second population of microcapsules is spray dried prior to combining with the adjunct material. 5. The method of claim 1, wherein the first weight ratio is a weight ratio of from 2:3 to 3:2 of the partitioning modifier to the first perfume oil; and wherein the second weight ratio is a weight ratio of greater than 0 to less than 2:3 of the partitioning modifier to the second perfume oil. 6. The method of claim 1, wherein a weight ratio of the first population of microcapsules to the second population of microcapsules is greater than 0 to less than 1:1. 7. The method of claim 1, wherein a weight ratio of the first population of microcapsules to the second population of microcapsules exceeds 1:1. 8. The method of claim 1, wherein the first and second median volume-weighted particle size is from 2 microns to 80 microns. 9. The method of claim 8, wherein the first and second median volume-weighted particle size is from 9 microns to 15 microns. 10. The method of claim 1, wherein the first population of microcapsules and the second population of microcapsules have a wall thickness of from 10 nm to 200 nm. 11. The method of claim 1, wherein the adjunct material comprises a non-encapsulated perfume oil. 12. The method of claim 11, wherein the non-encapsulated perfume oil is different from the first and second perfume oil. 13. The method of claim 1, wherein the partitioning modifier is selected from the group consisting of isopropyl myristate, mono-, di-, and tri-esters of C4-C24 fatty acids, castor oil, mineral oil, soybean oil, hexadecanoic acid, methyl ester isododecane, isoparaffin oil, polydimethylsiloxane, brominated vegetable oil, and mixtures thereof. 14. The method of claim 1, wherein the microcapsule further comprises a shell material selected from the group consisting of polyacrylates, polyethylenes, polyamides, polystyrenes, polyisoprenes, polycarbonates, polyesters, polyureas, polyurethanes, polyolefins, polysaccharides, epoxy resins, vinyl polymers, urea cross-linked with formaldehyde or gluteraldehyde, melamine cross-linked with formaldehyde; gelatin-polyphosphate coacervates optionally cross-linked with gluteraldehyde; gelatin-gum Arabic coacervates; cross-linked silicone fluids; polyamine reacted with polyisocyanates; acrylate monomers polymerized via free radical polymerization, silk, wool, gelatine, cellulose, proteins, and mixtures thereof. 15. The method of claim 1, wherein the microcapsule further comprises a shell material comprising a reaction product of a first substance in the presence of a second substance comprising an emulsifier, the first substance comprising a reaction product of i) an oil soluble or dispersible amine with ii) a multifunctional acrylate or methacrylate monomer or oligomer, an oil soluble acid and an initiator, the emulsifier comprising a water soluble or water dispersible acrylic acid alkyl acid copolymer, an alkali or alkali salt, and optionally a water phase initiator. 16. The method of claim 1, wherein the consumer product is a fabric and home care composition. 17. The method of claim 1, wherein the consumer product is a personal care composition. 18. The method of claim 1, wherein the consumer product further comprises a malodor reducing agent selected from the group consisting of pantothenic acid, petrolatum, menthyl acetate, uncomplexed cyclodextrin, talc, silica, and mixtures thereof. 19. The method of claim 1, wherein the first population of microcapsules and the second population of microcapsules have different partitioning modifiers. 20. The method of claim 1, wherein the adjunct material comprises a surfactant. 21. The method of claim 1, wherein the first perfume oil and the second perfume oil comprise at least one different material. 22. The method of claim 1, wherein the first population and second population comprise different shell materials. 23. The method of claim 1, wherein the first perfume oil and the second perfume oil are the same. 24. The method of claim 1, wherein at least one of the first population of microcapsules and the second population of microcapsules is contained in an agglomerate prior to combining with the adjunct material. | A method of making a consumer product providing multiple blooms of fragrance, the multiple blooms being provided for by different populations of microcapsules.1. A method of making a consumer product that provides multiple blooms of fragrance, the method comprising:
combining a first adjunct material, a first population of microcapsules, and a second population of microcapsules to form the consumer product; wherein the first population has a first median volume weighted particle size and comprises microcapsules comprising a partitioning modifier and a first perfume oil at a first weight ratio; and wherein the second population of microcapsules has a second median volume weighted particle size and comprises microcapsules comprising the partitioning modifier and a second perfume oil at a second weight ratio; wherein the first weight ratio and the second weight ratio are different, and/or the first median volume weighted particle size and the second median volume weighted particle size are different. 2. The method of claim 1, wherein at least one of the first population of microcapsules and the second population of microcapsules is contained in a slurry prior to combining with the adjunct material. 3. The method of claim 2, wherein the slurry includes one or more processing aids selected from the group consisting of a carrier, an aggregate inhibiting material, a deposition aid, a particle suspending polymer, and mixtures thereof. 4. The method of claim 1, wherein at least one of the first population of microcapsules and the second population of microcapsules is spray dried prior to combining with the adjunct material. 5. The method of claim 1, wherein the first weight ratio is a weight ratio of from 2:3 to 3:2 of the partitioning modifier to the first perfume oil; and wherein the second weight ratio is a weight ratio of greater than 0 to less than 2:3 of the partitioning modifier to the second perfume oil. 6. The method of claim 1, wherein a weight ratio of the first population of microcapsules to the second population of microcapsules is greater than 0 to less than 1:1. 7. The method of claim 1, wherein a weight ratio of the first population of microcapsules to the second population of microcapsules exceeds 1:1. 8. The method of claim 1, wherein the first and second median volume-weighted particle size is from 2 microns to 80 microns. 9. The method of claim 8, wherein the first and second median volume-weighted particle size is from 9 microns to 15 microns. 10. The method of claim 1, wherein the first population of microcapsules and the second population of microcapsules have a wall thickness of from 10 nm to 200 nm. 11. The method of claim 1, wherein the adjunct material comprises a non-encapsulated perfume oil. 12. The method of claim 11, wherein the non-encapsulated perfume oil is different from the first and second perfume oil. 13. The method of claim 1, wherein the partitioning modifier is selected from the group consisting of isopropyl myristate, mono-, di-, and tri-esters of C4-C24 fatty acids, castor oil, mineral oil, soybean oil, hexadecanoic acid, methyl ester isododecane, isoparaffin oil, polydimethylsiloxane, brominated vegetable oil, and mixtures thereof. 14. The method of claim 1, wherein the microcapsule further comprises a shell material selected from the group consisting of polyacrylates, polyethylenes, polyamides, polystyrenes, polyisoprenes, polycarbonates, polyesters, polyureas, polyurethanes, polyolefins, polysaccharides, epoxy resins, vinyl polymers, urea cross-linked with formaldehyde or gluteraldehyde, melamine cross-linked with formaldehyde; gelatin-polyphosphate coacervates optionally cross-linked with gluteraldehyde; gelatin-gum Arabic coacervates; cross-linked silicone fluids; polyamine reacted with polyisocyanates; acrylate monomers polymerized via free radical polymerization, silk, wool, gelatine, cellulose, proteins, and mixtures thereof. 15. The method of claim 1, wherein the microcapsule further comprises a shell material comprising a reaction product of a first substance in the presence of a second substance comprising an emulsifier, the first substance comprising a reaction product of i) an oil soluble or dispersible amine with ii) a multifunctional acrylate or methacrylate monomer or oligomer, an oil soluble acid and an initiator, the emulsifier comprising a water soluble or water dispersible acrylic acid alkyl acid copolymer, an alkali or alkali salt, and optionally a water phase initiator. 16. The method of claim 1, wherein the consumer product is a fabric and home care composition. 17. The method of claim 1, wherein the consumer product is a personal care composition. 18. The method of claim 1, wherein the consumer product further comprises a malodor reducing agent selected from the group consisting of pantothenic acid, petrolatum, menthyl acetate, uncomplexed cyclodextrin, talc, silica, and mixtures thereof. 19. The method of claim 1, wherein the first population of microcapsules and the second population of microcapsules have different partitioning modifiers. 20. The method of claim 1, wherein the adjunct material comprises a surfactant. 21. The method of claim 1, wherein the first perfume oil and the second perfume oil comprise at least one different material. 22. The method of claim 1, wherein the first population and second population comprise different shell materials. 23. The method of claim 1, wherein the first perfume oil and the second perfume oil are the same. 24. The method of claim 1, wherein at least one of the first population of microcapsules and the second population of microcapsules is contained in an agglomerate prior to combining with the adjunct material. | 1,600 |
459 | 15,152,835 | 1,615 | Crystalline microparticles consisting of a phenylalkylamino beta 2 -adrenergic agonist coated with a C12-C20 fatty acid are useful for the preparation of pharmaceutical aerosol formulations in form of suspension in a liquefied propellant gas or powder formulations. | 1-11. (canceled) 12. A process for preparing chemically stable crystalline microparticles, comprising a beta2-adrenergic agonist selected from the group consisting of formoterol, a pharmaceutically acceptable salt of formoterol, indacaterol, and a pharmaceutically acceptable salt of indacaterol, coated with at least one C12-C20 fatty acid in an amount of 0.5 to 2.0% by weight based on a total weight of the crystalline microparticles, the process comprising:
(a) preparing a solution of the C12-C20 fatty acid in a fluorinated model propellant in which the beta2-agonist is substantially insoluble, selected from the group consisting of perfluoropentane, 2H,3H-perfluoropentane (HPFP), perfluorohexane, and 1H-perfluorohexane; (b) adding the beta2-agonist as a micronized powder to said solution of the fatty acid, to obtain a mixture; (c) mixing the mixture to obtain a homogeneous suspension; and (d) subjecting the suspension to spray-drying, to obtain the coated microparticles; wherein the fatty acid forms a continuous film on a surface of the microparticles. 13. The process according to claim 12, wherein the fluorinated model propellant is 2H,3H-perfluoropentane (HPFP). 14-16. (canceled) 17. The process according to claim 12, wherein the beta2-adrenergic agonist is formoterol. 18. The process according to claim 17, wherein the fluorinated model propellant is 2H,3H-perfluoropentane (HPFP). 19. The process according to claim 17, wherein:
the C14-C20 saturated fatty acid is myristic acid; and the myristic acid is present in an amount of 1.0 to 2.0% by weight based on the total weight of the crystalline microparticles. 20. The process according to claim 17, further comprising:
preparing a pharmaceutical aerosol formulation comprising the coated microparticles in suspension in a liquefied propellant gas; and filling the pharmaceutical aerosol formulation into a pressurized metered dose inhaler. 21. The process according to claim 20, wherein the liquefied propellant gas is 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) or 1,1,1,2-tetrafluoroethane (HFA 134a), or a mixture thereof. 22. The process according to claim 20, wherein the formulation, upon storage, meets the requirements of EMEA Guideline CPMP/QWP/122/02. 23. The process according to claim 17, further comprising preparing a dry powder pharmaceutical formulation comprising the coated microparticles. 24. The process according to claim 12, wherein the beta2-adrenergic agonist is a fumarate dihydrate salt of formoterol. 25. The process according to claim 24, wherein the fluorinated model propellant is 2H,3H-perfluoropentane (HPFP). 26. The process according to claim 24, wherein:
the C14-C20 saturated fatty acid is myristic acid; and the myristic acid is present in an amount of 1.0 to 2.0% by weight based on the total weight of the crystalline microparticles. 27. The process according to claim 24, further comprising:
preparing a pharmaceutical aerosol formulation comprising the coated microparticles in suspension in a liquefied propellant gas; and filling the pharmaceutical aerosol formulation into a pressurized metered dose inhaler. 28. The process according to claim 27, wherein the liquefied propellant gas is 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) or 1,1,1,2-tetrafluoroethane (HFA 134a), or a mixture thereof. 29. The process according to claim 27, wherein the formulation, upon storage, meets the requirements of EMEA Guideline CPMP/QWP/122/02. 30. The process according to claim 24, further comprising preparing a dry powder pharmaceutical formulation comprising the coated microparticles. 31. The process according to claim 12, wherein the beta2-adrenergic agonist is indacaterol. 32. The process according to claim 31, wherein the fluorinated model propellant is 2H,3H-perfluoropentane (HPFP). 33. The process according to claim 31, wherein:
the C14-C20 saturated fatty acid is myristic acid; and the myristic acid is present in an amount of 1.0 to 2.0% by weight based on the total weight of the crystalline microparticles. 34. The process according to claim 31, further comprising:
preparing a pharmaceutical aerosol formulation comprising the coated microparticles in suspension in a liquefied propellant gas; and filling the pharmaceutical aerosol formulation into a pressurized metered dose inhaler. 35. The process according to claim 34, wherein the liquefied propellant gas is 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) or 1,1,1,2-tetrafluoroethane (HFA 134a), or a mixture thereof. 36. The process according to claim 34, wherein the formulation, upon storage, meets the requirements of EMEA Guideline CPMP/QWP/122/02. 37. The process according to claim 31, further comprising preparing a dry powder pharmaceutical formulation comprising the coated microparticles. 38. The process according to claim 12, wherein the beta2-adrenergic agonist is a maleate salt of indacaterol. 39. The process according to claim 38, wherein the fluorinated model propellant is 2H,3H-perfluoropentane (HPFP). 40. The process according to claim 38, wherein:
the C14-C20 saturated fatty acid is myristic acid; and the myristic acid is present in an amount of 1.0 to 2.0% by weight based on the total weight of the crystalline microparticles. 41. The process according to claim 38, further comprising:
preparing a pharmaceutical aerosol formulation comprising the coated microparticles in suspension in a liquefied propellant gas; and filling the pharmaceutical aerosol formulation into a pressurized metered dose inhaler. 42. The process according to claim 41, wherein the liquefied propellant gas is 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) or 1,1,1,2-tetrafluoroethane (HFA 134a), or a mixture thereof. 43. The process according to claim 41, wherein the formulation, upon storage, meets the requirements of EMEA Guideline CPMP/QWP/122/02. 44. The process according to claim 38, further comprising preparing a dry powder pharmaceutical formulation comprising the coated microparticles. | Crystalline microparticles consisting of a phenylalkylamino beta 2 -adrenergic agonist coated with a C12-C20 fatty acid are useful for the preparation of pharmaceutical aerosol formulations in form of suspension in a liquefied propellant gas or powder formulations.1-11. (canceled) 12. A process for preparing chemically stable crystalline microparticles, comprising a beta2-adrenergic agonist selected from the group consisting of formoterol, a pharmaceutically acceptable salt of formoterol, indacaterol, and a pharmaceutically acceptable salt of indacaterol, coated with at least one C12-C20 fatty acid in an amount of 0.5 to 2.0% by weight based on a total weight of the crystalline microparticles, the process comprising:
(a) preparing a solution of the C12-C20 fatty acid in a fluorinated model propellant in which the beta2-agonist is substantially insoluble, selected from the group consisting of perfluoropentane, 2H,3H-perfluoropentane (HPFP), perfluorohexane, and 1H-perfluorohexane; (b) adding the beta2-agonist as a micronized powder to said solution of the fatty acid, to obtain a mixture; (c) mixing the mixture to obtain a homogeneous suspension; and (d) subjecting the suspension to spray-drying, to obtain the coated microparticles; wherein the fatty acid forms a continuous film on a surface of the microparticles. 13. The process according to claim 12, wherein the fluorinated model propellant is 2H,3H-perfluoropentane (HPFP). 14-16. (canceled) 17. The process according to claim 12, wherein the beta2-adrenergic agonist is formoterol. 18. The process according to claim 17, wherein the fluorinated model propellant is 2H,3H-perfluoropentane (HPFP). 19. The process according to claim 17, wherein:
the C14-C20 saturated fatty acid is myristic acid; and the myristic acid is present in an amount of 1.0 to 2.0% by weight based on the total weight of the crystalline microparticles. 20. The process according to claim 17, further comprising:
preparing a pharmaceutical aerosol formulation comprising the coated microparticles in suspension in a liquefied propellant gas; and filling the pharmaceutical aerosol formulation into a pressurized metered dose inhaler. 21. The process according to claim 20, wherein the liquefied propellant gas is 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) or 1,1,1,2-tetrafluoroethane (HFA 134a), or a mixture thereof. 22. The process according to claim 20, wherein the formulation, upon storage, meets the requirements of EMEA Guideline CPMP/QWP/122/02. 23. The process according to claim 17, further comprising preparing a dry powder pharmaceutical formulation comprising the coated microparticles. 24. The process according to claim 12, wherein the beta2-adrenergic agonist is a fumarate dihydrate salt of formoterol. 25. The process according to claim 24, wherein the fluorinated model propellant is 2H,3H-perfluoropentane (HPFP). 26. The process according to claim 24, wherein:
the C14-C20 saturated fatty acid is myristic acid; and the myristic acid is present in an amount of 1.0 to 2.0% by weight based on the total weight of the crystalline microparticles. 27. The process according to claim 24, further comprising:
preparing a pharmaceutical aerosol formulation comprising the coated microparticles in suspension in a liquefied propellant gas; and filling the pharmaceutical aerosol formulation into a pressurized metered dose inhaler. 28. The process according to claim 27, wherein the liquefied propellant gas is 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) or 1,1,1,2-tetrafluoroethane (HFA 134a), or a mixture thereof. 29. The process according to claim 27, wherein the formulation, upon storage, meets the requirements of EMEA Guideline CPMP/QWP/122/02. 30. The process according to claim 24, further comprising preparing a dry powder pharmaceutical formulation comprising the coated microparticles. 31. The process according to claim 12, wherein the beta2-adrenergic agonist is indacaterol. 32. The process according to claim 31, wherein the fluorinated model propellant is 2H,3H-perfluoropentane (HPFP). 33. The process according to claim 31, wherein:
the C14-C20 saturated fatty acid is myristic acid; and the myristic acid is present in an amount of 1.0 to 2.0% by weight based on the total weight of the crystalline microparticles. 34. The process according to claim 31, further comprising:
preparing a pharmaceutical aerosol formulation comprising the coated microparticles in suspension in a liquefied propellant gas; and filling the pharmaceutical aerosol formulation into a pressurized metered dose inhaler. 35. The process according to claim 34, wherein the liquefied propellant gas is 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) or 1,1,1,2-tetrafluoroethane (HFA 134a), or a mixture thereof. 36. The process according to claim 34, wherein the formulation, upon storage, meets the requirements of EMEA Guideline CPMP/QWP/122/02. 37. The process according to claim 31, further comprising preparing a dry powder pharmaceutical formulation comprising the coated microparticles. 38. The process according to claim 12, wherein the beta2-adrenergic agonist is a maleate salt of indacaterol. 39. The process according to claim 38, wherein the fluorinated model propellant is 2H,3H-perfluoropentane (HPFP). 40. The process according to claim 38, wherein:
the C14-C20 saturated fatty acid is myristic acid; and the myristic acid is present in an amount of 1.0 to 2.0% by weight based on the total weight of the crystalline microparticles. 41. The process according to claim 38, further comprising:
preparing a pharmaceutical aerosol formulation comprising the coated microparticles in suspension in a liquefied propellant gas; and filling the pharmaceutical aerosol formulation into a pressurized metered dose inhaler. 42. The process according to claim 41, wherein the liquefied propellant gas is 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) or 1,1,1,2-tetrafluoroethane (HFA 134a), or a mixture thereof. 43. The process according to claim 41, wherein the formulation, upon storage, meets the requirements of EMEA Guideline CPMP/QWP/122/02. 44. The process according to claim 38, further comprising preparing a dry powder pharmaceutical formulation comprising the coated microparticles. | 1,600 |
460 | 12,456,567 | 1,617 | This invention relates to a storage stable, aqueous, herbicidal formulation containing an ultra-high concentration of glyphosate in the isopropylamine, potassium or mixed salt form in combination with a surfactant system, to a method of making the formulation, and to a method of treating unwanted vegetation employing the formulation. The surfactant system employed in the concentrate comprises dialkoxylated alkylamine, water miscible solubilizer and amine oxide. The surfactant system unexpectedly permits the formulation of storage stable, ultra-high loaded aqueous glyphosate salt concentrates possessing high or no cloud points. | 1. An ultra-high load, aqueous glyphosate salt-containing concentrate comprising:
a. water; b. glyphosate salt in solution in the water in an amount greater than about 39 weight percent of acid equivalent, based on the weight of the concentrate, said glyphosate salt being selected from the group consisting of the isopropylamine salt of glyphosate, the potassium salt of glyphosate, mixtures of the isopropylamine salt and the potassium salt of glyphosate and mixtures of the potassium salt and the ammonium salt of glyphosate; c. a surfactant system in an amount ranging from about 1 to about 20 weight percent, based on the weight of the concentrate, comprising:
i. from about 10 to about 60 weight percent, based on the weight of the surfactant system, of one or more dialkoxylated alkylamines;
ii. from about 5 to about 30 weight percent, based on the weight of the surfactant system, of one or more water miscible solubilizers; and
iii. from about 30 to about 75 weight percent, based on the weight of the surfactant system, of one or more amine oxides;
said concentrate having a cloud point above at least 70° C. or no cloud point when the concentrate is heated to its boiling point. 2. The concentrate of claim 1 wherein the glyphosate salt is the isopropylamine salt of glyphosate. 3. The concentrate of claim 1 wherein the glyphosate salt is the potassium salt of glyphosate. 4. The concentrate of claim 1 wherein the glyphosate salt is a mixture of the isopropylamine salt and the potassium salt of glyphosate. 5. The concentrate of claim 1 wherein the glyphosate salt is a mixture of the potassium salt and the ammonium salt of glyphosate. 6. The concentrate of claim 1 wherein the glyphosate salt is in solution in the water in an amount greater than about 43 weight percent of acid equivalent. 7. The concentrate of claim 1 wherein the glyphosate salt is in solution in the water in an amount greater than about 47 weight percent of acid equivalent. 8. The concentrate of claim 1 wherein the surfactant system comprises from about 2 to about 10 weight percent of the concentrate. 9. The concentrate of claim 1 wherein the surfactant system comprises from about 3 to about 8 weight percent of the concentrate. 10. The concentrate of claim 1 wherein the dialkoxylated alkylamine comprises from about 25 to about 45 weight percent of the surfactant system. 11. The concentrate of claim 1 wherein the water miscible solvent comprises from about 10 to about 20 weight percent of the surfactant system. 12. The concentrate of claim 1 wherein the amine oxide comprises from about 40 to about 50 weight percent of the surfactant system. 13. The concentrate of claim 1 having no cloud point. 14. The concentrate of claim 1 having a cloud point above 100° C. 15. The concentrate of claim 1 having a cloud point above 90° C. 16. The concentrate of claim 1 having a cloud point above 80° C. 17. The concentrate of claim 1 wherein the dialkoxylated alkylamine corresponds to the formula:
R1—N(R2)(R3) wherein R1 is a C8-C24 straight or branched chain, saturated or unsaturated hydrocarbyl group, R2 is an (AO)nH group and R3 is an (AO)n′H group wherein A represents an alkylene group and n and n′ are integers such that n+n′ has an average value of from 2 to 20. 18. The concentrate of claim 17 wherein n+n′ has an average value of from 2 to 15. 19. The concentrate of claim 17 wherein n+n′ has an average value of from 5 to 15. 20. The concentrate of claim 1 wherein the dialkoxylated alkylamine is a diethoxylated derivative of cocoamine, tallowamine or oleylamine. 21. The concentrate of claim 1 wherein the dialkoxylated alkylamine is diethoxylated tallow amine. 22. The concentrate of claim 21 wherein the diethoxylated tallow amine possesses an average of from 2 to 20 moles of ethoxy groups. 23. The concentrate of claim 21 wherein the diethoxylated tallow amine possesses an average of from 2 to 15 moles of ethoxy groups. 24. The concentrate of claim 21 wherein the diethoxylated tallow amine possesses an average of from 5 to 15 moles of ethoxy groups. 25. The concentrate of claim 1 wherein the water miscible solvent is selected from the group consisting of monohydric alcohol, dihydric alcohol, polyhydric alcohol, alkylene glycol and polyalkylene glycol. 26. The concentrate of claim 25 wherein the water miscible solvent comprises polyalkylene glycol possessing a molecular weight of from about 200 to about 1000. 27. The concentrate of claim 26 wherein the polyalkylene glycol is polyethylene glycol. 28. The concentrate of claim 1 wherein the amine oxide corresponds to the formula R4R5R6N→O wherein R4 is a C8-C24 straight or branched chain, saturated or unsaturated hydrocarbyl group or R7CONH(CH2)n, wherein R7 is a C8-C24 straight or branched chain, saturated or unsaturated hydrocarbyl group and n is from 1 to 3; R5 and R6 are independently C1-C3 hydrocarbyl groups or substituted C1-C3 hydrocarbyl groups. 29. The concentrate of claim 28 wherein the amine oxide is selected from the group consisting of coconut dimethyl amine oxide, capric/capryllic dimethyl amine oxide, capric dimethyl amine oxide, lauryl dimethyl amine oxide, lauryl/myristyl dimethyl amido propyl amine oxide, and coco dimethyl amido propyl amine oxide. 30. The concentrate of claim 1 wherein the dialkoxylated alkylamine corresponds to the formula R1—N(R2)(R3) wherein R1 is a C8-C24 straight or branched chain, saturated or unsaturated hydrocarbyl group, R2 is an (AO)nH group and R3is an (AO)n′H group wherein A represents an alkylene group and n and n′ are integers such that n+n′ has an average value of from 2 to 20, the water miscible solubilizer is selected from the group consisting of monohydric alcohol, dihydric alcohol, polyhydric alcohol, alkylene glycol and polyalkylene glycol and the amine oxide corresponds to the formula R4 R5R6N→O wherein R4is a C8-C24 straight or branched chain, saturated or unsaturated hydrocarbyl group or R7CONH(CH2)n, wherein R7 is a C8-C24 straight or branched chain, saturated or unsaturated hydrocarbyl group and n is from 1 to 3; R5 and R6 are independently C1-C3 hydrocarbyl groups or substituted C1-C3 hydrocarbyl groups. 31. The concentrate of claim 1 further comprising a co-herbicide. 32. A method of controlling unwanted vegetation which comprises applying to the vegetation a water-diluted composition of claim 1. 33. A method of controlling unwanted vegetation which comprises applying to the vegetation a water-diluted composition of claim 30. 34. A method of making a glyphosate salt-containing composition which comprises:
(a) providing a glyphosate salt-containing reaction product wherein said glyphosate salt is selected from the group consisting of the isopropylamine salt of glyphosate, the potassium salt of glyphosate, mixtures of the isopropylamine salt and the potassium salt of glyphosate and mixtures of the potassium salt and the ammonium salt of glyphosate; and (b) contacting the reaction product with a surfactant system while the temperature of said reaction product is at least 70° C. to provide a glyphosate salt-containing composition which possesses a cloud point above at least 70° C. or no cloud point when the composition is heated to its boiling point, said surfactant system comprising:
i. from about 10 to about 60 weight percent, based on the weight of the surfactant system, of one or more dialkoxylated alkylamines;
ii. from about 5 to about 30 weight percent, based on the weight of the surfactant system, of one or more water miscible solubilizers; and
iii. from about 30 to about 75 weight percent, based on the weight of the surfactant system, of one or more amine oxides. 35. The method of claim 34 wherein the reaction product and surfactant system are contacted when the reaction product possesses a temperature of at least about 75° C. 36. The method of claim 34 wherein the reaction product and surfactant system are contacted when the reaction product possesses a temperature of at least about 80° C. 37. The method of claim 34 wherein the glyphosate salt-containing composition is a concentrate comprising glyphosate salt in an amount greater than about 39 weight percent of acid equivalent, based on the weight of the concentrate. 38. The method of claim 34 wherein the glyphosate salt-containing composition is optically transparent at 70° C. 39. The method of claim 34 wherein the glyphosate salt is the isopropylamine salt of glyphosate. 40. The method of claim 34 wherein the glyphosate salt is the potassium salt of glyphosate. 41. The method of claim 34 wherein the glyphosate salt is a mixture of the isopropylamine salt and the potassium salt of glyphosate. 42. The method of claim 34 wherein the glyphosate salt is a mixture of the potassium salt and the ammonium salt of glyphosate. 43. The method of claim 34 wherein the dialkoxylated amine corresponds to the formula
R1—N(R2)(R3) wherein R1 is a C8-C24 straight or branched chain, saturated or unsaturated hydrocarbyl group, R2 is an (AO)nH group and R3 is an (AO)n′H group wherein A represents an alkylene group and n and n′ are integers such that n+n′ has an average value of from 2 to 20. 44. The method of claim 43 wherein n+n′ has an average value of from 2 to 15. 45. The method of claim 43 wherein n+n′ has an average value of from 5 to 15. 46. The method of claim 34 wherein the dialkoxylated amine is a diethoxylated derivative of cocoamine, tallowamine or oleylamine. 47. The method of claim 46 wherein the dialkoxylated amine is diethoxylated tallow amine. 48. The method of claim 47 wherein the diethoxylated tallow amine possesses an average of from 2 to 15 moles of ethoxy groups. 49. The method of claim 47 wherein the diethoxylated tallow amine possesses an average of from 2 to 15 moles of ethoxy groups. 50. The method of claim 47 wherein the diethoxylated tallow amine possesses an average of from 5 to 10 moles of ethoxy groups. 51. The method of claim 34 wherein the water miscible solvent is selected from the group consisting of monohydric alcohol, dihydric alcohol, polyhydric alcohol, alkylene glycol and polyalkylene glycol. 52. The method of claim 51 wherein the water miscible solvent comprises polyalkylene glycol possessing a molecular weight of from about 200 to about 1000. 53. The method of claim 52 wherein the polyalkylene glycol is polyethylene glycol. 54. The method of claim 34 wherein the amine oxide corresponds to the formula R4R5R6N→O wherein R4 is a C8-C24 straight or branched chain, saturated or unsaturated hydrocarbyl group, or R7CONH(CH2)n, wherein R7 is a C8-C24 straight or branched chain, saturated or unsaturated hydrocarbyl group and n is from 1 to 3; R5 and R6 are independently C1-C3 hydrocarbyl groups or substituted C1-C3 hydrocarbyl groups. 55. The method of claim 54 wherein the amine oxide is selected from the group consisting of coconut dimethyl amine oxide, capric/capryllic dimethyl amine oxide, capric dimethyl amine oxide, lauryl dimethyl amine oxide, lauryl/myristyl dimethyl amido propyl amine oxide, and coco dimethyl amido propyl amine oxide. | This invention relates to a storage stable, aqueous, herbicidal formulation containing an ultra-high concentration of glyphosate in the isopropylamine, potassium or mixed salt form in combination with a surfactant system, to a method of making the formulation, and to a method of treating unwanted vegetation employing the formulation. The surfactant system employed in the concentrate comprises dialkoxylated alkylamine, water miscible solubilizer and amine oxide. The surfactant system unexpectedly permits the formulation of storage stable, ultra-high loaded aqueous glyphosate salt concentrates possessing high or no cloud points.1. An ultra-high load, aqueous glyphosate salt-containing concentrate comprising:
a. water; b. glyphosate salt in solution in the water in an amount greater than about 39 weight percent of acid equivalent, based on the weight of the concentrate, said glyphosate salt being selected from the group consisting of the isopropylamine salt of glyphosate, the potassium salt of glyphosate, mixtures of the isopropylamine salt and the potassium salt of glyphosate and mixtures of the potassium salt and the ammonium salt of glyphosate; c. a surfactant system in an amount ranging from about 1 to about 20 weight percent, based on the weight of the concentrate, comprising:
i. from about 10 to about 60 weight percent, based on the weight of the surfactant system, of one or more dialkoxylated alkylamines;
ii. from about 5 to about 30 weight percent, based on the weight of the surfactant system, of one or more water miscible solubilizers; and
iii. from about 30 to about 75 weight percent, based on the weight of the surfactant system, of one or more amine oxides;
said concentrate having a cloud point above at least 70° C. or no cloud point when the concentrate is heated to its boiling point. 2. The concentrate of claim 1 wherein the glyphosate salt is the isopropylamine salt of glyphosate. 3. The concentrate of claim 1 wherein the glyphosate salt is the potassium salt of glyphosate. 4. The concentrate of claim 1 wherein the glyphosate salt is a mixture of the isopropylamine salt and the potassium salt of glyphosate. 5. The concentrate of claim 1 wherein the glyphosate salt is a mixture of the potassium salt and the ammonium salt of glyphosate. 6. The concentrate of claim 1 wherein the glyphosate salt is in solution in the water in an amount greater than about 43 weight percent of acid equivalent. 7. The concentrate of claim 1 wherein the glyphosate salt is in solution in the water in an amount greater than about 47 weight percent of acid equivalent. 8. The concentrate of claim 1 wherein the surfactant system comprises from about 2 to about 10 weight percent of the concentrate. 9. The concentrate of claim 1 wherein the surfactant system comprises from about 3 to about 8 weight percent of the concentrate. 10. The concentrate of claim 1 wherein the dialkoxylated alkylamine comprises from about 25 to about 45 weight percent of the surfactant system. 11. The concentrate of claim 1 wherein the water miscible solvent comprises from about 10 to about 20 weight percent of the surfactant system. 12. The concentrate of claim 1 wherein the amine oxide comprises from about 40 to about 50 weight percent of the surfactant system. 13. The concentrate of claim 1 having no cloud point. 14. The concentrate of claim 1 having a cloud point above 100° C. 15. The concentrate of claim 1 having a cloud point above 90° C. 16. The concentrate of claim 1 having a cloud point above 80° C. 17. The concentrate of claim 1 wherein the dialkoxylated alkylamine corresponds to the formula:
R1—N(R2)(R3) wherein R1 is a C8-C24 straight or branched chain, saturated or unsaturated hydrocarbyl group, R2 is an (AO)nH group and R3 is an (AO)n′H group wherein A represents an alkylene group and n and n′ are integers such that n+n′ has an average value of from 2 to 20. 18. The concentrate of claim 17 wherein n+n′ has an average value of from 2 to 15. 19. The concentrate of claim 17 wherein n+n′ has an average value of from 5 to 15. 20. The concentrate of claim 1 wherein the dialkoxylated alkylamine is a diethoxylated derivative of cocoamine, tallowamine or oleylamine. 21. The concentrate of claim 1 wherein the dialkoxylated alkylamine is diethoxylated tallow amine. 22. The concentrate of claim 21 wherein the diethoxylated tallow amine possesses an average of from 2 to 20 moles of ethoxy groups. 23. The concentrate of claim 21 wherein the diethoxylated tallow amine possesses an average of from 2 to 15 moles of ethoxy groups. 24. The concentrate of claim 21 wherein the diethoxylated tallow amine possesses an average of from 5 to 15 moles of ethoxy groups. 25. The concentrate of claim 1 wherein the water miscible solvent is selected from the group consisting of monohydric alcohol, dihydric alcohol, polyhydric alcohol, alkylene glycol and polyalkylene glycol. 26. The concentrate of claim 25 wherein the water miscible solvent comprises polyalkylene glycol possessing a molecular weight of from about 200 to about 1000. 27. The concentrate of claim 26 wherein the polyalkylene glycol is polyethylene glycol. 28. The concentrate of claim 1 wherein the amine oxide corresponds to the formula R4R5R6N→O wherein R4 is a C8-C24 straight or branched chain, saturated or unsaturated hydrocarbyl group or R7CONH(CH2)n, wherein R7 is a C8-C24 straight or branched chain, saturated or unsaturated hydrocarbyl group and n is from 1 to 3; R5 and R6 are independently C1-C3 hydrocarbyl groups or substituted C1-C3 hydrocarbyl groups. 29. The concentrate of claim 28 wherein the amine oxide is selected from the group consisting of coconut dimethyl amine oxide, capric/capryllic dimethyl amine oxide, capric dimethyl amine oxide, lauryl dimethyl amine oxide, lauryl/myristyl dimethyl amido propyl amine oxide, and coco dimethyl amido propyl amine oxide. 30. The concentrate of claim 1 wherein the dialkoxylated alkylamine corresponds to the formula R1—N(R2)(R3) wherein R1 is a C8-C24 straight or branched chain, saturated or unsaturated hydrocarbyl group, R2 is an (AO)nH group and R3is an (AO)n′H group wherein A represents an alkylene group and n and n′ are integers such that n+n′ has an average value of from 2 to 20, the water miscible solubilizer is selected from the group consisting of monohydric alcohol, dihydric alcohol, polyhydric alcohol, alkylene glycol and polyalkylene glycol and the amine oxide corresponds to the formula R4 R5R6N→O wherein R4is a C8-C24 straight or branched chain, saturated or unsaturated hydrocarbyl group or R7CONH(CH2)n, wherein R7 is a C8-C24 straight or branched chain, saturated or unsaturated hydrocarbyl group and n is from 1 to 3; R5 and R6 are independently C1-C3 hydrocarbyl groups or substituted C1-C3 hydrocarbyl groups. 31. The concentrate of claim 1 further comprising a co-herbicide. 32. A method of controlling unwanted vegetation which comprises applying to the vegetation a water-diluted composition of claim 1. 33. A method of controlling unwanted vegetation which comprises applying to the vegetation a water-diluted composition of claim 30. 34. A method of making a glyphosate salt-containing composition which comprises:
(a) providing a glyphosate salt-containing reaction product wherein said glyphosate salt is selected from the group consisting of the isopropylamine salt of glyphosate, the potassium salt of glyphosate, mixtures of the isopropylamine salt and the potassium salt of glyphosate and mixtures of the potassium salt and the ammonium salt of glyphosate; and (b) contacting the reaction product with a surfactant system while the temperature of said reaction product is at least 70° C. to provide a glyphosate salt-containing composition which possesses a cloud point above at least 70° C. or no cloud point when the composition is heated to its boiling point, said surfactant system comprising:
i. from about 10 to about 60 weight percent, based on the weight of the surfactant system, of one or more dialkoxylated alkylamines;
ii. from about 5 to about 30 weight percent, based on the weight of the surfactant system, of one or more water miscible solubilizers; and
iii. from about 30 to about 75 weight percent, based on the weight of the surfactant system, of one or more amine oxides. 35. The method of claim 34 wherein the reaction product and surfactant system are contacted when the reaction product possesses a temperature of at least about 75° C. 36. The method of claim 34 wherein the reaction product and surfactant system are contacted when the reaction product possesses a temperature of at least about 80° C. 37. The method of claim 34 wherein the glyphosate salt-containing composition is a concentrate comprising glyphosate salt in an amount greater than about 39 weight percent of acid equivalent, based on the weight of the concentrate. 38. The method of claim 34 wherein the glyphosate salt-containing composition is optically transparent at 70° C. 39. The method of claim 34 wherein the glyphosate salt is the isopropylamine salt of glyphosate. 40. The method of claim 34 wherein the glyphosate salt is the potassium salt of glyphosate. 41. The method of claim 34 wherein the glyphosate salt is a mixture of the isopropylamine salt and the potassium salt of glyphosate. 42. The method of claim 34 wherein the glyphosate salt is a mixture of the potassium salt and the ammonium salt of glyphosate. 43. The method of claim 34 wherein the dialkoxylated amine corresponds to the formula
R1—N(R2)(R3) wherein R1 is a C8-C24 straight or branched chain, saturated or unsaturated hydrocarbyl group, R2 is an (AO)nH group and R3 is an (AO)n′H group wherein A represents an alkylene group and n and n′ are integers such that n+n′ has an average value of from 2 to 20. 44. The method of claim 43 wherein n+n′ has an average value of from 2 to 15. 45. The method of claim 43 wherein n+n′ has an average value of from 5 to 15. 46. The method of claim 34 wherein the dialkoxylated amine is a diethoxylated derivative of cocoamine, tallowamine or oleylamine. 47. The method of claim 46 wherein the dialkoxylated amine is diethoxylated tallow amine. 48. The method of claim 47 wherein the diethoxylated tallow amine possesses an average of from 2 to 15 moles of ethoxy groups. 49. The method of claim 47 wherein the diethoxylated tallow amine possesses an average of from 2 to 15 moles of ethoxy groups. 50. The method of claim 47 wherein the diethoxylated tallow amine possesses an average of from 5 to 10 moles of ethoxy groups. 51. The method of claim 34 wherein the water miscible solvent is selected from the group consisting of monohydric alcohol, dihydric alcohol, polyhydric alcohol, alkylene glycol and polyalkylene glycol. 52. The method of claim 51 wherein the water miscible solvent comprises polyalkylene glycol possessing a molecular weight of from about 200 to about 1000. 53. The method of claim 52 wherein the polyalkylene glycol is polyethylene glycol. 54. The method of claim 34 wherein the amine oxide corresponds to the formula R4R5R6N→O wherein R4 is a C8-C24 straight or branched chain, saturated or unsaturated hydrocarbyl group, or R7CONH(CH2)n, wherein R7 is a C8-C24 straight or branched chain, saturated or unsaturated hydrocarbyl group and n is from 1 to 3; R5 and R6 are independently C1-C3 hydrocarbyl groups or substituted C1-C3 hydrocarbyl groups. 55. The method of claim 54 wherein the amine oxide is selected from the group consisting of coconut dimethyl amine oxide, capric/capryllic dimethyl amine oxide, capric dimethyl amine oxide, lauryl dimethyl amine oxide, lauryl/myristyl dimethyl amido propyl amine oxide, and coco dimethyl amido propyl amine oxide. | 1,600 |
461 | 14,020,205 | 1,627 | The invention generally pertains to the discovery that agents capable of inhibiting the binding of cortisol to its receptor can be used in methods for treating patients diagnosed with Amyotrophic Lateral Sclerosis (ALS). | 1. A method for ameliorating the symptoms and/or slowing the rate of disease progression in a patient diagnosed with amyotrophic lateral sclerosis (ALS), the method comprising administering a therapeutically effective amount of a glucocorticoid receptor specific antagonist (GRA) to a subject in need thereof, with the proviso that the subject not be otherwise in need of treatment with a glucocorticoid receptor antagonist. 2. The method of claim 1, wherein the glucocorticoid receptor antagonist comprises a steroid compound. 3. The method of claim 2, wherein the glucocorticoid receptor antagonist comprises a steroidal skeleton with at least one phenyl-containing moiety in the 11-β position of the steroidal skeleton. 4. The method of claim 3, wherein the phenyl-containing moiety in the 11-β position of the steroidal skeleton is a dimethylaminophenyl moiety. 5. The method of claim 4, wherein the glucocorticoid receptor antagonist is mifepristone. 6. The method of claim 4, wherein the glucocorticoid receptor antagonist is selected from the group consisting of 11β-(4-dimethylaminoethoxyphenyl)-17α-propynyl-17β-hydroxy-4,9-estradien-3-one and 17β-hydroxy-17α-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one. 7. The method of claim 1, wherein the glucocorticoid receptor antagonist is (11β,17β)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one. 8. The method of claim 1, wherein the glucocorticoid receptor antagonist is a non-steroidal compound. 9. The method of claim 8, wherein the glucocorticoid receptor antagonist is selected from the group consisting of 1-(o-chloro-α,α-diphenylbenzyl)imidazole; N(triphenylmethyl)imidazole; N-([2-fluoro-9-phenyl]fluorenyl)imidazole; N-([2-pyridyl]diphenylmethyl)imidazole; N-([4,4′,41]-trichlorotrityl)imidazole; and N((2,6 dichloro-3-methylphenyl)diphenyl)methylimidazole. 10. The method of claim 8, wherein the glucocorticoid receptor antagonist is selected from the group consisting of 6-substituted-1,2-dihydro-N protected-quinoline; octahydrophenanthrenyl carbamate; oxadiazolylalkoxyoctahydrophenanthrene; and octahydrophenanthrene hydrazine. 11. The method of claim 8, wherein the glucocorticoid receptor antagonist is selected from the group consisting of octahydro-2-H-naphthol[1,2,-f]indole-4 carboxamide; cyclopent[f]indazole; and benz[f]indazole. 12. The method of claim 8, wherein the glucocorticoid receptor antagonist is selected from the group consisting of a 6H-dibenzo[b,d]pyran derivative; a substituted aminobenzene derivative; a triphenylmethane derivative; a diphenyl ether derivative; and a modified pyrimidine compound. 13. The method of claim 8, wherein the glucocorticoid receptor antagonist is selected from the group consisting of 1-(2-chlorotrityl)-2-methylimidazole; N-(2-chlorotrityl)-L-prolinol acetate; 1 -(2-chlorotrityl)-1,2,4-triazole; and 1-(2-chlorotrityl)-3,5-dimethylpyrazole. 14. The method of claim 8, wherein the glucocortiocoid receptor antagonist is selected from the group consisting of 4α(S)-Benzyl-2(R)-prop-1-ynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-diol and 4α(S)-Benzyl-2(R)-chloroethynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-diol. 15. The method of claim 1, wherein the glucocorticoid receptor antagonist is an azadecalin or a fused ring azadecalin compound 16. The method of claim 1, wherein the glucocorticoid receptor antagonist is administered in a daily amount of between about 0.5 mg and about 40 mg per kg of body weight per day. 17. The method of claim 1, wherein the glucocorticoid receptor antagonist is administered in a daily amount of between about 5 mg and about 20 mg per kg of body weight per day. 18. The method of claim 1 wherein the administration of the glucocorticoid receptor antagonist is once per day. 19. The method of claim 1 wherein the mode of administration of the glucocorticoid receptor antagonist is selected from the group consisting of: a transdermal application, a nebulized suspension, an aerosol spray, intravenously, intraarterially, intrathecally, intramuscularly and intraperitoneally. 20. The method of claim 1, wherein the mode of administration of the glucocorticoid receptor antagonist is oral. | The invention generally pertains to the discovery that agents capable of inhibiting the binding of cortisol to its receptor can be used in methods for treating patients diagnosed with Amyotrophic Lateral Sclerosis (ALS).1. A method for ameliorating the symptoms and/or slowing the rate of disease progression in a patient diagnosed with amyotrophic lateral sclerosis (ALS), the method comprising administering a therapeutically effective amount of a glucocorticoid receptor specific antagonist (GRA) to a subject in need thereof, with the proviso that the subject not be otherwise in need of treatment with a glucocorticoid receptor antagonist. 2. The method of claim 1, wherein the glucocorticoid receptor antagonist comprises a steroid compound. 3. The method of claim 2, wherein the glucocorticoid receptor antagonist comprises a steroidal skeleton with at least one phenyl-containing moiety in the 11-β position of the steroidal skeleton. 4. The method of claim 3, wherein the phenyl-containing moiety in the 11-β position of the steroidal skeleton is a dimethylaminophenyl moiety. 5. The method of claim 4, wherein the glucocorticoid receptor antagonist is mifepristone. 6. The method of claim 4, wherein the glucocorticoid receptor antagonist is selected from the group consisting of 11β-(4-dimethylaminoethoxyphenyl)-17α-propynyl-17β-hydroxy-4,9-estradien-3-one and 17β-hydroxy-17α-19-(4-methylphenyl)androsta-4,9(11)-dien-3-one. 7. The method of claim 1, wherein the glucocorticoid receptor antagonist is (11β,17β)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one. 8. The method of claim 1, wherein the glucocorticoid receptor antagonist is a non-steroidal compound. 9. The method of claim 8, wherein the glucocorticoid receptor antagonist is selected from the group consisting of 1-(o-chloro-α,α-diphenylbenzyl)imidazole; N(triphenylmethyl)imidazole; N-([2-fluoro-9-phenyl]fluorenyl)imidazole; N-([2-pyridyl]diphenylmethyl)imidazole; N-([4,4′,41]-trichlorotrityl)imidazole; and N((2,6 dichloro-3-methylphenyl)diphenyl)methylimidazole. 10. The method of claim 8, wherein the glucocorticoid receptor antagonist is selected from the group consisting of 6-substituted-1,2-dihydro-N protected-quinoline; octahydrophenanthrenyl carbamate; oxadiazolylalkoxyoctahydrophenanthrene; and octahydrophenanthrene hydrazine. 11. The method of claim 8, wherein the glucocorticoid receptor antagonist is selected from the group consisting of octahydro-2-H-naphthol[1,2,-f]indole-4 carboxamide; cyclopent[f]indazole; and benz[f]indazole. 12. The method of claim 8, wherein the glucocorticoid receptor antagonist is selected from the group consisting of a 6H-dibenzo[b,d]pyran derivative; a substituted aminobenzene derivative; a triphenylmethane derivative; a diphenyl ether derivative; and a modified pyrimidine compound. 13. The method of claim 8, wherein the glucocorticoid receptor antagonist is selected from the group consisting of 1-(2-chlorotrityl)-2-methylimidazole; N-(2-chlorotrityl)-L-prolinol acetate; 1 -(2-chlorotrityl)-1,2,4-triazole; and 1-(2-chlorotrityl)-3,5-dimethylpyrazole. 14. The method of claim 8, wherein the glucocortiocoid receptor antagonist is selected from the group consisting of 4α(S)-Benzyl-2(R)-prop-1-ynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-diol and 4α(S)-Benzyl-2(R)-chloroethynyl-1,2,3,4,4α,9,10,10α(R)-octahydro-phenanthrene-2,7-diol. 15. The method of claim 1, wherein the glucocorticoid receptor antagonist is an azadecalin or a fused ring azadecalin compound 16. The method of claim 1, wherein the glucocorticoid receptor antagonist is administered in a daily amount of between about 0.5 mg and about 40 mg per kg of body weight per day. 17. The method of claim 1, wherein the glucocorticoid receptor antagonist is administered in a daily amount of between about 5 mg and about 20 mg per kg of body weight per day. 18. The method of claim 1 wherein the administration of the glucocorticoid receptor antagonist is once per day. 19. The method of claim 1 wherein the mode of administration of the glucocorticoid receptor antagonist is selected from the group consisting of: a transdermal application, a nebulized suspension, an aerosol spray, intravenously, intraarterially, intrathecally, intramuscularly and intraperitoneally. 20. The method of claim 1, wherein the mode of administration of the glucocorticoid receptor antagonist is oral. | 1,600 |
462 | 14,388,115 | 1,615 | Provided is a pharmaceutical composition having a single dosage form including a compartment including olmesartan medoxomil; and a compartment including rosuvastatin or its salt, wherein said compartments are formulated in a separate form. In the pharmaceutical composition of the present invention, olmesartan medoxomil and rosuvastatin or its salt are formulated into a combination dosage form having separate compartments, thereby being able to solve the absorption-inhibition problem originated from drug interaction. In addition, the use of a certain disintegrant(s) makes it possible to obtain a combination formulation bioequivalent to the single formulation of each of drugs. | 1. A pharmaceutical composition having a single dosage form comprising a compartment comprising olmesartan medoxomil; and a compartment comprising rosuvastatin or its salt, wherein said compartments are formulated in a separate form. 2. The pharmaceutical composition according to claim 1, having a double-layered tablet form, a tablet form consisting essentially of an inner core and an outer layer, or a pellet-containing capsule form. 3. The pharmaceutical composition according to claim 1, having a double-layered tablet form consisting essentially of a layer comprising rosuvastatin or its salt and a layer comprising olmesartan medoxomil. 4. The pharmaceutical composition according to claim 1, having a tablet form consisting essentially of an inner core comprising rosuvastatin or its salt and an outer layer comprising olmesartan medoxomil. 5. The pharmaceutical composition according to claim 1, having a capsule form filled with pellets comprising rosuvastatin or its salt and pellets comprising olmesartan medoxomil. 6. The pharmaceutical composition according to claim 1, wherein the compartment comprising rosuvastatin or its salt comprises one or more disintegrant selected from the group consisting of povidone, crospovidone, low substituted hydroxypropyl cellulose, croscarmellose sodium, and carboxymethylcellulose calcium. 7. The pharmaceutical composition according to claim 6, wherein the disintegrant is present in an amount ranging from 2 to 20% by weight, based on the total weight of the compartment comprising rosuvastatin or its salt. 8. The pharmaceutical composition according to claim 1, wherein the compartment comprising olmesartan medoxomil comprises one or more disintegrant selected from the group consisting of low substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, sodium starch glycolate, and pregelatinized starch. 9. The pharmaceutical composition according to claim 8, wherein the compartment comprising olmesartan medoxomil comprises 7.5 or more % by weight of low substituted hydroxypropyl cellulose, 5 or more % by weight of carboxymethylcellulose calcium, 15 or more % by weight of croscarmellose sodium, 10 or more % by weight of crospovidone, 5 or more % by weight of sodium starch glycolate, or 5 or more % by weight of pregelatinized starch, based on the total weight of the compartment comprising olmesartan medoxomil. 10. The pharmaceutical composition according to claim 8, wherein the compartment comprising olmesartan medoxomil comprises 7.5 to 65% by weight of low substituted hydroxypropyl cellulose, 5 to 60% by weight of carboxymethylcellulose calcium, 15 to 30% by weight of croscarmellose sodium, 10 to 40% by weight of crospovidone, 5 to 40% by weight of sodium starch glycolate, or 5 to 60% by weight of pregelatinized starch, based on the total weight of the compartment comprising olmesartan medoxomil. 11. The pharmaceutical composition according to claim 8, wherein the compartment comprising olmesartan medoxomil comprises 7.5 to 65% by weight of low substituted hydroxypropyl cellulose, based on the total weight of the compartment comprising olmesartan medoxomil. 12. The pharmaceutical composition according to claim 8, wherein the compartment comprising olmesartan medoxomil comprises 10 to 60% by weight of low substituted hydroxypropyl cellulose, based on the total weight of the compartment comprising olmesartan medoxomil. | Provided is a pharmaceutical composition having a single dosage form including a compartment including olmesartan medoxomil; and a compartment including rosuvastatin or its salt, wherein said compartments are formulated in a separate form. In the pharmaceutical composition of the present invention, olmesartan medoxomil and rosuvastatin or its salt are formulated into a combination dosage form having separate compartments, thereby being able to solve the absorption-inhibition problem originated from drug interaction. In addition, the use of a certain disintegrant(s) makes it possible to obtain a combination formulation bioequivalent to the single formulation of each of drugs.1. A pharmaceutical composition having a single dosage form comprising a compartment comprising olmesartan medoxomil; and a compartment comprising rosuvastatin or its salt, wherein said compartments are formulated in a separate form. 2. The pharmaceutical composition according to claim 1, having a double-layered tablet form, a tablet form consisting essentially of an inner core and an outer layer, or a pellet-containing capsule form. 3. The pharmaceutical composition according to claim 1, having a double-layered tablet form consisting essentially of a layer comprising rosuvastatin or its salt and a layer comprising olmesartan medoxomil. 4. The pharmaceutical composition according to claim 1, having a tablet form consisting essentially of an inner core comprising rosuvastatin or its salt and an outer layer comprising olmesartan medoxomil. 5. The pharmaceutical composition according to claim 1, having a capsule form filled with pellets comprising rosuvastatin or its salt and pellets comprising olmesartan medoxomil. 6. The pharmaceutical composition according to claim 1, wherein the compartment comprising rosuvastatin or its salt comprises one or more disintegrant selected from the group consisting of povidone, crospovidone, low substituted hydroxypropyl cellulose, croscarmellose sodium, and carboxymethylcellulose calcium. 7. The pharmaceutical composition according to claim 6, wherein the disintegrant is present in an amount ranging from 2 to 20% by weight, based on the total weight of the compartment comprising rosuvastatin or its salt. 8. The pharmaceutical composition according to claim 1, wherein the compartment comprising olmesartan medoxomil comprises one or more disintegrant selected from the group consisting of low substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, sodium starch glycolate, and pregelatinized starch. 9. The pharmaceutical composition according to claim 8, wherein the compartment comprising olmesartan medoxomil comprises 7.5 or more % by weight of low substituted hydroxypropyl cellulose, 5 or more % by weight of carboxymethylcellulose calcium, 15 or more % by weight of croscarmellose sodium, 10 or more % by weight of crospovidone, 5 or more % by weight of sodium starch glycolate, or 5 or more % by weight of pregelatinized starch, based on the total weight of the compartment comprising olmesartan medoxomil. 10. The pharmaceutical composition according to claim 8, wherein the compartment comprising olmesartan medoxomil comprises 7.5 to 65% by weight of low substituted hydroxypropyl cellulose, 5 to 60% by weight of carboxymethylcellulose calcium, 15 to 30% by weight of croscarmellose sodium, 10 to 40% by weight of crospovidone, 5 to 40% by weight of sodium starch glycolate, or 5 to 60% by weight of pregelatinized starch, based on the total weight of the compartment comprising olmesartan medoxomil. 11. The pharmaceutical composition according to claim 8, wherein the compartment comprising olmesartan medoxomil comprises 7.5 to 65% by weight of low substituted hydroxypropyl cellulose, based on the total weight of the compartment comprising olmesartan medoxomil. 12. The pharmaceutical composition according to claim 8, wherein the compartment comprising olmesartan medoxomil comprises 10 to 60% by weight of low substituted hydroxypropyl cellulose, based on the total weight of the compartment comprising olmesartan medoxomil. | 1,600 |
463 | 15,366,278 | 1,619 | Hair treatment agents including: at least one anionic surfactant from the group of alkyl sulfates and/or alkyl ether sulfates; at least one amphoteric and/or nonionic surfactant; at least one divalent or trivalent metal salt; at least one cationic polymer; and ethyl lauroyl arginate. | 1. A hair treatment agent, comprising:
at least one anionic surfactant from the group of alkyl sulfates and/or alkyl ether sulfates, at least one amphoteric and/or nonionic surfactant, at least one divalent or trivalent metal salt, at least one cationic polymer, and ethyl lauroyl arginate. 2. The agent of claim 1, wherein the at least one anionic surfactant from the group of alkyl sulfates and/or alkyl ether sulfates comprises 0.5% to 20% by weight of the agent. 3. The agent of claim 1, wherein the at least one anionic surfactant from the group of alkyl sulfates and/or alkyl ether sulfates comprises 5% to 10% by weight of the agent. 4. The agent of claim 1, wherein the at least one anionic surfactant from the group of alkyl sulfates and/or alkyl ether sulfates comprises alkyl(ether) sulfates of the general formula R—(OCH2—CH2)n—OSO3X, in which R signifies a straight-chain or branched saturated or unsaturated alkyl group having 8 to 24 carbon atoms, n signifies the numbers 0 or 1 to 12, and X signifies an alkali, alkaline earth, ammonium, or alkanolamine ion. 5. The agent of claim 1, wherein the at least one amphoteric and/or nonionic surfactant comprises 0.3% to 10% by weight of the agent. 6. The agent of claim 1, wherein the at least one amphoteric and/or nonionic surfactant comprises 1% to 5% by weight of the agent. 7. The agent of claim 1, wherein the at least one amphoteric and/or nonionic surfactant comprises an amphoteric surfactant. 8. The agent of claim 1, wherein the at least one amphoteric and/or nonionic surfactant comprises 1% to 5% by weight of the agent of a nonionic surfactant. 9. The agent of claim 1, wherein the at least one divalent or trivalent metal salt comprises 0.01% to 10% by weight of the agent. 10. The agent of claim 1, wherein the at least one divalent or trivalent metal salt comprises 0.3% to 3% by weight of the agent. 11. The agent of claim 1, wherein the at least one divalent or trivalent metal salt comprises a copper, zinc, iron(II), calcium, magnesium, iron(III), and/or aluminum salt and/or mixtures thereof. 12. The agent of claim 1, wherein the at least one cationic polymer comprises 0.01% to 3% by weight of the agent. 13. The agent of claim 12, wherein the at least one cationic polymer comprises at least one polymer selected from the group consisting of: cationic cellulose polymers, cationic guar derivatives, and mixtures thereof. 13. The agent of claim 1, wherein the at least one cationic polymer comprises 0.15% to 0.8% by weight of the agent. 14. The agent of claim 1, wherein the agent comprises 0.001% to 2% by weight of ethyl lauroyl arginate HCl. 15. The agent of claim 1, wherein the agent comprises 0.05% to 0.4% by weight of ethyl lauroyl arginate HCl. 16. The agent of claim 1, wherein the agent further comprise two mutually different oligopeptides A and B, which both include the amino acid sequence Glu-Glu-Glu and oligopeptides A and B each comprise 0.00005% to 0.1% by weight of the agent. 17. A hair treatment agent, comprising:
5% to 10% by weight of the agent of at least one anionic surfactant from the group of alkyl sulfates and/or alkyl ether sulfates, 1% to 5% by weight of the agent of at least one amphoteric and/or nonionic surfactant, 0.3% to 3% by weight of the agent of at least one divalent or trivalent metal salt, 0.15% to 0.8% by weight of the agent of at least one cationic polymer, and 0.05% to 0.4% by weight of the agent of ethyl lauroyl arginate. 18. The agent of claim 17, further comprising 0.001% to 10% by weight of the agent glycerol. 19. A method of hair treatment, comprising:
applying a hair treatment agent to hair, the hair treatment agent comprising:
at least one anionic surfactant from the group of alkyl sulfates and/or alkyl ether sulfates,
at least one amphoteric and/or nonionic surfactant,
at least one divalent or trivalent metal salt,
at least one cationic polymer, and
ethyl lauroyl arginate; and
rinsing the hair treatment agent out after 30 sec to 300 sec of contact with the hair. 20. The method of claim 19, wherein the hair treatment agent structurally strengthens both inner and outer hair structures of the contacted hair. | Hair treatment agents including: at least one anionic surfactant from the group of alkyl sulfates and/or alkyl ether sulfates; at least one amphoteric and/or nonionic surfactant; at least one divalent or trivalent metal salt; at least one cationic polymer; and ethyl lauroyl arginate.1. A hair treatment agent, comprising:
at least one anionic surfactant from the group of alkyl sulfates and/or alkyl ether sulfates, at least one amphoteric and/or nonionic surfactant, at least one divalent or trivalent metal salt, at least one cationic polymer, and ethyl lauroyl arginate. 2. The agent of claim 1, wherein the at least one anionic surfactant from the group of alkyl sulfates and/or alkyl ether sulfates comprises 0.5% to 20% by weight of the agent. 3. The agent of claim 1, wherein the at least one anionic surfactant from the group of alkyl sulfates and/or alkyl ether sulfates comprises 5% to 10% by weight of the agent. 4. The agent of claim 1, wherein the at least one anionic surfactant from the group of alkyl sulfates and/or alkyl ether sulfates comprises alkyl(ether) sulfates of the general formula R—(OCH2—CH2)n—OSO3X, in which R signifies a straight-chain or branched saturated or unsaturated alkyl group having 8 to 24 carbon atoms, n signifies the numbers 0 or 1 to 12, and X signifies an alkali, alkaline earth, ammonium, or alkanolamine ion. 5. The agent of claim 1, wherein the at least one amphoteric and/or nonionic surfactant comprises 0.3% to 10% by weight of the agent. 6. The agent of claim 1, wherein the at least one amphoteric and/or nonionic surfactant comprises 1% to 5% by weight of the agent. 7. The agent of claim 1, wherein the at least one amphoteric and/or nonionic surfactant comprises an amphoteric surfactant. 8. The agent of claim 1, wherein the at least one amphoteric and/or nonionic surfactant comprises 1% to 5% by weight of the agent of a nonionic surfactant. 9. The agent of claim 1, wherein the at least one divalent or trivalent metal salt comprises 0.01% to 10% by weight of the agent. 10. The agent of claim 1, wherein the at least one divalent or trivalent metal salt comprises 0.3% to 3% by weight of the agent. 11. The agent of claim 1, wherein the at least one divalent or trivalent metal salt comprises a copper, zinc, iron(II), calcium, magnesium, iron(III), and/or aluminum salt and/or mixtures thereof. 12. The agent of claim 1, wherein the at least one cationic polymer comprises 0.01% to 3% by weight of the agent. 13. The agent of claim 12, wherein the at least one cationic polymer comprises at least one polymer selected from the group consisting of: cationic cellulose polymers, cationic guar derivatives, and mixtures thereof. 13. The agent of claim 1, wherein the at least one cationic polymer comprises 0.15% to 0.8% by weight of the agent. 14. The agent of claim 1, wherein the agent comprises 0.001% to 2% by weight of ethyl lauroyl arginate HCl. 15. The agent of claim 1, wherein the agent comprises 0.05% to 0.4% by weight of ethyl lauroyl arginate HCl. 16. The agent of claim 1, wherein the agent further comprise two mutually different oligopeptides A and B, which both include the amino acid sequence Glu-Glu-Glu and oligopeptides A and B each comprise 0.00005% to 0.1% by weight of the agent. 17. A hair treatment agent, comprising:
5% to 10% by weight of the agent of at least one anionic surfactant from the group of alkyl sulfates and/or alkyl ether sulfates, 1% to 5% by weight of the agent of at least one amphoteric and/or nonionic surfactant, 0.3% to 3% by weight of the agent of at least one divalent or trivalent metal salt, 0.15% to 0.8% by weight of the agent of at least one cationic polymer, and 0.05% to 0.4% by weight of the agent of ethyl lauroyl arginate. 18. The agent of claim 17, further comprising 0.001% to 10% by weight of the agent glycerol. 19. A method of hair treatment, comprising:
applying a hair treatment agent to hair, the hair treatment agent comprising:
at least one anionic surfactant from the group of alkyl sulfates and/or alkyl ether sulfates,
at least one amphoteric and/or nonionic surfactant,
at least one divalent or trivalent metal salt,
at least one cationic polymer, and
ethyl lauroyl arginate; and
rinsing the hair treatment agent out after 30 sec to 300 sec of contact with the hair. 20. The method of claim 19, wherein the hair treatment agent structurally strengthens both inner and outer hair structures of the contacted hair. | 1,600 |
464 | 14,383,010 | 1,611 | The present invention provides a sunscreen composition comprising two or more oil-soluble ultraviolet absorbers and composite silicone particles having an average particle diameter of 10 μm or less. | 1. A sunscreen composition comprising two or more oil-soluble ultraviolet absorbers and composite silicone particles having an average particle diameter of 10 μm or less. 2. The sunscreen composition according to claim 1, wherein the oil-soluble ultraviolet absorbers are at least two members selected from the group consisting of ethylhexyl methoxycinnamate, octocrylene, diethylamino hydroxybenzoyl hexyl benzoate, polysilicone-based ultraviolet absorbers, homosalate, t-butyl methoxybenzoyl methane, ethylhexyl salicylate, ethylhexyl triazone, bis-ethylhexyloxyphenol methoxyphenyl triazine, methylene-bis-benzotriazolyl tetramethylbutylphenol, oxybenzone-3, and drometrizole trisiloxane. 3. The sunscreen composition according to claim 1, wherein the oil-soluble ultraviolet absorbers are at least two members selected from the group consisting of ethylhexyl methoxycinnamate, octocrylene, diethylamino hydroxybenzoyl hexyl benzoate, and polysilicone-15. 4. The sunscreen composition according to claim 1, wherein the composite silicone particles are composite silicone particles in which silicone rubber is coated with a silicone resin. 5. The sunscreen composition according to claim 4, wherein the composite silicone particles are composite silicone particles in which spherical silicone rubber is coated with a silicone resin. 6. The sunscreen composition according to claim 1, wherein the oil-soluble ultraviolet absorbers are contained in a total amount of 10 wt. % or more. 7. The sunscreen composition according to claim 1, which is in the form of a water-in-oil type (W/O) emulsion. 8. The sunscreen composition according to claim 1, further comprising at least one electrolyte selected from the group consisting of inorganic salts, purine-based compounds, and water-soluble vitamins, water-soluble vitamin derivatives, and salts thereof. 9. The sunscreen composition according to claim 8, wherein the electrolyte is contained in an amount of 0.5 wt. % or more. 10. The sunscreen composition according to claim 1, wherein 10 to 40 wt. % of water is contained in the sunscreen composition. | The present invention provides a sunscreen composition comprising two or more oil-soluble ultraviolet absorbers and composite silicone particles having an average particle diameter of 10 μm or less.1. A sunscreen composition comprising two or more oil-soluble ultraviolet absorbers and composite silicone particles having an average particle diameter of 10 μm or less. 2. The sunscreen composition according to claim 1, wherein the oil-soluble ultraviolet absorbers are at least two members selected from the group consisting of ethylhexyl methoxycinnamate, octocrylene, diethylamino hydroxybenzoyl hexyl benzoate, polysilicone-based ultraviolet absorbers, homosalate, t-butyl methoxybenzoyl methane, ethylhexyl salicylate, ethylhexyl triazone, bis-ethylhexyloxyphenol methoxyphenyl triazine, methylene-bis-benzotriazolyl tetramethylbutylphenol, oxybenzone-3, and drometrizole trisiloxane. 3. The sunscreen composition according to claim 1, wherein the oil-soluble ultraviolet absorbers are at least two members selected from the group consisting of ethylhexyl methoxycinnamate, octocrylene, diethylamino hydroxybenzoyl hexyl benzoate, and polysilicone-15. 4. The sunscreen composition according to claim 1, wherein the composite silicone particles are composite silicone particles in which silicone rubber is coated with a silicone resin. 5. The sunscreen composition according to claim 4, wherein the composite silicone particles are composite silicone particles in which spherical silicone rubber is coated with a silicone resin. 6. The sunscreen composition according to claim 1, wherein the oil-soluble ultraviolet absorbers are contained in a total amount of 10 wt. % or more. 7. The sunscreen composition according to claim 1, which is in the form of a water-in-oil type (W/O) emulsion. 8. The sunscreen composition according to claim 1, further comprising at least one electrolyte selected from the group consisting of inorganic salts, purine-based compounds, and water-soluble vitamins, water-soluble vitamin derivatives, and salts thereof. 9. The sunscreen composition according to claim 8, wherein the electrolyte is contained in an amount of 0.5 wt. % or more. 10. The sunscreen composition according to claim 1, wherein 10 to 40 wt. % of water is contained in the sunscreen composition. | 1,600 |
465 | 15,800,719 | 1,617 | The present invention concerns a dialysis acid precursor composition for use during preparation of a dialysis acid concentrate solution and for mixing with water, a sodium containing concentrate, and a bicarbonate containing concentrate into a ready-for-use dialysis solution. The dialysis acid precursor composition consists of powder components comprising glucose, at least one dry acid and at least one magnesium salt, and optionally potassium salt, and calcium salt. According to the invention the glucose and the at least one magnesium salt, are present as anhydrous components in the dialysis acid precursor composition. | 1. A dialysis acid precursor composition product comprising:
an anhydrous powdered composition including a sodium containing concentrate, a bicarbonate containing concentrate, a dry acid and a magnesium salt, and a sealed moisture-resistant container housing the anhydrous powdered composition, wherein the container has a water vapor transmission rate less than 0.3 g/m2/d at 38° C./90% RH. 2. The dialysis precursor composition product of claim 1, wherein the dry acid includes at least one of lactic acid, citric acid, gluconic acid, glucono-δ-lactone, N-acetyl cysteine and α-lipoic acid. 3. The dialysis precursor composition product of claim 1, wherein the magnesium salt includes at least one of anhydrous magnesium chloride, magnesium gluconate, magnesium citrate, magnesium lactate, and magnesium α-ketoglutarate. 4. The dialysis precursor composition product of claim 1, wherein the anhydrous powdered composition includes at least one of calcium chloride dihydrate, calcium chloride monohydrate, anhydrous calcium chloride, calcium gluconate, calcium citrate, calcium lactate, and calcium α-ketoglutarate. 5. The dialysis precursor composition product of claim 1, wherein the water vapor transmission rate is less than 0.2 g/m2/d at 38° C./90% RH. 6. The dialysis precursor composition product of claim 1, wherein the water vapor transmission rate is greater than 0.1 g/m2/d at 38° C./90% RH. 7. The dialysis precursor composition product of claim 1, wherein the container is configured to receive water which mixes with the anhydrous powdered composition in the container to provide a dialysis acid concentrate solution. 8. The dialysis precursor composition product of claim 7, wherein the magnesium salt is in a quantity such that a concentration of 7.5-50 mM magnesium ions is provided in the dialysis acid concentrate solution. 9. The dialysis acid precursor composition of claim 7, wherein the anhydrous powdered composition includes a calcium salt in a quantity such that a concentration of 300-500 mM calcium ions is provided in the dialysis acid concentrate solution. 10. The dialysis acid precursor composition of claim 7, wherein the one dry acid is in a quantity such that a concentration of 60-800 mEq/L H+(acid) is provided in the dialysis acid concentrate solution. 11. The dialysis acid precursor composition of claim 7, wherein the anhydrous powdered composition includes glucose in a quantity such that a concentration of 30-400 g/L is provided in the dialysis acid concentrate solution. | The present invention concerns a dialysis acid precursor composition for use during preparation of a dialysis acid concentrate solution and for mixing with water, a sodium containing concentrate, and a bicarbonate containing concentrate into a ready-for-use dialysis solution. The dialysis acid precursor composition consists of powder components comprising glucose, at least one dry acid and at least one magnesium salt, and optionally potassium salt, and calcium salt. According to the invention the glucose and the at least one magnesium salt, are present as anhydrous components in the dialysis acid precursor composition.1. A dialysis acid precursor composition product comprising:
an anhydrous powdered composition including a sodium containing concentrate, a bicarbonate containing concentrate, a dry acid and a magnesium salt, and a sealed moisture-resistant container housing the anhydrous powdered composition, wherein the container has a water vapor transmission rate less than 0.3 g/m2/d at 38° C./90% RH. 2. The dialysis precursor composition product of claim 1, wherein the dry acid includes at least one of lactic acid, citric acid, gluconic acid, glucono-δ-lactone, N-acetyl cysteine and α-lipoic acid. 3. The dialysis precursor composition product of claim 1, wherein the magnesium salt includes at least one of anhydrous magnesium chloride, magnesium gluconate, magnesium citrate, magnesium lactate, and magnesium α-ketoglutarate. 4. The dialysis precursor composition product of claim 1, wherein the anhydrous powdered composition includes at least one of calcium chloride dihydrate, calcium chloride monohydrate, anhydrous calcium chloride, calcium gluconate, calcium citrate, calcium lactate, and calcium α-ketoglutarate. 5. The dialysis precursor composition product of claim 1, wherein the water vapor transmission rate is less than 0.2 g/m2/d at 38° C./90% RH. 6. The dialysis precursor composition product of claim 1, wherein the water vapor transmission rate is greater than 0.1 g/m2/d at 38° C./90% RH. 7. The dialysis precursor composition product of claim 1, wherein the container is configured to receive water which mixes with the anhydrous powdered composition in the container to provide a dialysis acid concentrate solution. 8. The dialysis precursor composition product of claim 7, wherein the magnesium salt is in a quantity such that a concentration of 7.5-50 mM magnesium ions is provided in the dialysis acid concentrate solution. 9. The dialysis acid precursor composition of claim 7, wherein the anhydrous powdered composition includes a calcium salt in a quantity such that a concentration of 300-500 mM calcium ions is provided in the dialysis acid concentrate solution. 10. The dialysis acid precursor composition of claim 7, wherein the one dry acid is in a quantity such that a concentration of 60-800 mEq/L H+(acid) is provided in the dialysis acid concentrate solution. 11. The dialysis acid precursor composition of claim 7, wherein the anhydrous powdered composition includes glucose in a quantity such that a concentration of 30-400 g/L is provided in the dialysis acid concentrate solution. | 1,600 |
466 | 14,510,912 | 1,633 | The method of making a compressed biocomposite body includes compressing a mass of biocomposite material comprised of discrete particles and a network of interconnected glucan-containing mycelia cells in the presence of heat and moisture into a compressed body having a density in excess of 18 pcf. Compression may take place batch wise in a press or continuously in a path of narrowing cross-section defined by a series of heated rollers. | 1. A method of making a composite body comprising the steps of
obtaining a mass of biocomposite material comprised of discrete particles, a network of interconnected glucan-containing mycelia cells extending around the discrete particles and a moisture content of from 45% to 70%; placing the biocomposite material in a compression fixture; heating the biocomposite material in the compression fixture while compressing the biocomposite material into a compressed body of a desired density and shape within said compression fixture; maintaining the compressed body under heat and compression for a time sufficient to allow cross-linking between the glucans in said mycelia cells to bind the discrete particles together in the compressed body; removing the compressed body from the compression fixture; and heating the removed compressed body to dehydrate the compressed body to reduce said moisture content to less than 30% and to deactivate the mycelia cells. 2. A method as set forth in claim 1 wherein said step of heating reduces said moisture content to a range of from 6% to 30% to impart electrical conductivity to the removed compressed body. 3. A method as set forth in claim 1 wherein said step of heating reduces said moisture content of less than 10%. 4. A method as set forth in claim 1 wherein said step of heating includes heating the biocomposite material to a temperature of from 250° F. to and 650° F. while compressing the biocomposite material at a pressure of from 10 to 1500 psi. 5. A method as set forth in claim 4 wherein said step of heating includes heating the biocomposite material to 300° F. 6. A method as set forth in claim 4 wherein the biocomposite material is compressed for a time of between 4 minutes and 15 minutes. 7. A method as set forth in claim 1 further comprising the step of placing a lamination on a surface of the biocomposite material in the compression fixture prior to said step of heating the biocomposite material whereby the lamination is integrated into the compressed body. 8. A method as set forth in claim 1 wherein said compression fixture includes at least one insert for pressing into the biocomposite material during said step of heating the biocomposite material. 9. A method as set forth in claim 1 wherein said compression fixture is a pinch press for compressing the biocomposite material into a compressed body in a batch-like manner. 10. A method as set forth in claim 1 wherein said compression fixture includes a series of heated rollers defining a path of narrowing cross-section for compressing the biocomposite material into a compressed body in a continuous manner. 11. A method of making a composite body comprising the steps of
obtaining a mass of biocomposite material comprised of discrete particles, a network of interconnected glucan-containing mycelia cells extending around the discrete particles and a moisture content of greater than 10% by weight; molding said mass into a plurality of tiles of rectangular shape; stacking said tiles in alternating manner with a plurality of wooden veneers and with a plate of porous plastic on an underside thereof to from a stack; compressing said stack to compress said tiles to approximately three times density while drying the compressed tiles to obtain a pre-compressed biocomposite body; thereafter compressing said pre-compressed biocomposite body at a force of 20 tons and at a temperature of 600° F. for a time of two minutes while reducing the moisture content to less than 10% to obtain a compressed composite body. 12. A method as set forth in claim 11 wherein said compressed composite body has a density of 20 lbs/ft3, a modulus of elasticity around 80 ksi, a modulus of rupture around 800 psi, and a screw hold strength around 100 lbf. 13. A method of making a composite body comprising the steps of
obtaining a mass of biocomposite material comprised of discrete particles, a network of interconnected glucan-containing mycelia cells extending around the discrete particles and a moisture content of greater than 10% by weight; and thereafter compressing said mass at a pressure between 25 psi and 5000 psi and at a temperature of 600° F. for a time of four minutes while reducing the moisture content to less than 10% to obtain a compressed composite body. 14. A method as set forth in claim 13 wherein said compressed composite body has a density of 34 lbs/ft3, a modulus of elasticity around 132 ksi, a modulus of rupture around 1698 psi, and a screw hold strength around 24 lbf at half an inch thickness. 15. A method as set forth in claim 13 wherein said compressed composite body has a density of 29 lbs/ft3, a modulus of elasticity around 120 ksi, a modulus of rupture around 819 psi, and a screw hold strength around 132 lbf at an inch thickness. 16. A method of making a composite body comprising the steps of
obtaining a mass of biocomposite material comprised of discrete particles, a network of interconnected glucan-containing mycelia cells extending around the discrete particles and a moisture content of greater than 10% by weight; and thereafter compressing said mass at a pressure between 25 psi and 5000 psi and at a temperature of 300° F. for a time of one minute while reducing the moisture content to less than 10% to obtain a compressed composite body. 17. A method as set forth in claim 16 wherein said mass is molded into a sheet prior to said step of compressing and pressed into a deformed geometric shape. 18. A method as set forth in claim 17 wherein said sheet has dimensions of 18 inches by 18 inches by 1 inch and said deformed geometric shape is a semi-cylindrical shape. 19. A method of making a composite body comprising the steps of
obtaining a mass of biocomposite material comprised of discrete particles, a network of interconnected glucan-containing mycelia cells extending around the discrete particles and a moisture content of greater than 10% by weight; forming said mass of biocomposite material into a flat blank board of 1.25″ thickness with a 0.25″ hemp nonwoven matt grown into at least one face of said flat blank board; thereafter compressing said flat blank board into the predetermined curved shape under a compressive force of 3000 psi and at a temperature of 340° F. for a time of 10 minutes while reducing the moisture content to less than 10% to obtain a compressed composite body of curved shape. 20. A method as set forth in claim 19 wherein said step of forming said mass of biocomposite material into a flat blank board includes embossing said at least one face with a predetermined sculptured feature. 21. A method of making a composite body comprising the steps of
cultivating mycelium into a sheet; freeze drying said sheet; thereafter milling said dried sheet to form a first mass of particles; milling Kenaf pith to form a second mass of particles; blending said first mass of particles and said second mass of particles into a mixture; thereafter heating and compressing said mixture in a mold cavity for a time sufficient to form a cohesive product; and removing said product from the mold as a self-supporting composite body. 22. A method as set forth in claim 21 wherein said step of cultivating mycelium into a sheet includes cultivating the mycelium on malt extract at a rate of 32 g per liter for 7 days at ambient conditions of 75° F., 20% relative humidity and 2000 ppm C02 until said sheet of mycelium is formed. 23. A method as set forth in claim 21 wherein said step of milling said dried sheet includes hammer milling through a 0.0625″ screen. 24. A method as set forth in claim 21 wherein said step of milling Kenaf pith includes hammer milling through a 22 mesh and over a 38 mesh screen. 25. A method as set forth in claim 21 wherein said step of blending blends said kenaf pith and said mycelium together at a 9:1 ratio. 26. A method as set forth in claim 21 wherein said step of heating and compressing said mixture includes heating the mold cavity to 380° F. and compressing said mixture under 30 tons of force for four minutes to form the cohesive product. 27. A self-supporting composite body comprising a substrate of discrete particles and a network of interconnected mycelia cells extending through and around the discrete particles and bonding the discrete particles together, said composite body being characterized in being stiff and in having a density between 18 and 60 pounds per cubic foot (pcf), a modulus of elasticity of up to 250 ksi and a modulus of rupture of up to 2500 psi. 28. A self-supporting composite body comprising a substrate of discrete fibers and a network of interconnected mycelia cells extending through and around the discrete fibers and bonding the discrete fibers together, said composite body being characterized in being stiff and in having a density between 18 and 60 pounds per cubic foot (pcf), a modulus of elasticity greater than 250 ksi and a modulus of rupture of up to 2500 psi. | The method of making a compressed biocomposite body includes compressing a mass of biocomposite material comprised of discrete particles and a network of interconnected glucan-containing mycelia cells in the presence of heat and moisture into a compressed body having a density in excess of 18 pcf. Compression may take place batch wise in a press or continuously in a path of narrowing cross-section defined by a series of heated rollers.1. A method of making a composite body comprising the steps of
obtaining a mass of biocomposite material comprised of discrete particles, a network of interconnected glucan-containing mycelia cells extending around the discrete particles and a moisture content of from 45% to 70%; placing the biocomposite material in a compression fixture; heating the biocomposite material in the compression fixture while compressing the biocomposite material into a compressed body of a desired density and shape within said compression fixture; maintaining the compressed body under heat and compression for a time sufficient to allow cross-linking between the glucans in said mycelia cells to bind the discrete particles together in the compressed body; removing the compressed body from the compression fixture; and heating the removed compressed body to dehydrate the compressed body to reduce said moisture content to less than 30% and to deactivate the mycelia cells. 2. A method as set forth in claim 1 wherein said step of heating reduces said moisture content to a range of from 6% to 30% to impart electrical conductivity to the removed compressed body. 3. A method as set forth in claim 1 wherein said step of heating reduces said moisture content of less than 10%. 4. A method as set forth in claim 1 wherein said step of heating includes heating the biocomposite material to a temperature of from 250° F. to and 650° F. while compressing the biocomposite material at a pressure of from 10 to 1500 psi. 5. A method as set forth in claim 4 wherein said step of heating includes heating the biocomposite material to 300° F. 6. A method as set forth in claim 4 wherein the biocomposite material is compressed for a time of between 4 minutes and 15 minutes. 7. A method as set forth in claim 1 further comprising the step of placing a lamination on a surface of the biocomposite material in the compression fixture prior to said step of heating the biocomposite material whereby the lamination is integrated into the compressed body. 8. A method as set forth in claim 1 wherein said compression fixture includes at least one insert for pressing into the biocomposite material during said step of heating the biocomposite material. 9. A method as set forth in claim 1 wherein said compression fixture is a pinch press for compressing the biocomposite material into a compressed body in a batch-like manner. 10. A method as set forth in claim 1 wherein said compression fixture includes a series of heated rollers defining a path of narrowing cross-section for compressing the biocomposite material into a compressed body in a continuous manner. 11. A method of making a composite body comprising the steps of
obtaining a mass of biocomposite material comprised of discrete particles, a network of interconnected glucan-containing mycelia cells extending around the discrete particles and a moisture content of greater than 10% by weight; molding said mass into a plurality of tiles of rectangular shape; stacking said tiles in alternating manner with a plurality of wooden veneers and with a plate of porous plastic on an underside thereof to from a stack; compressing said stack to compress said tiles to approximately three times density while drying the compressed tiles to obtain a pre-compressed biocomposite body; thereafter compressing said pre-compressed biocomposite body at a force of 20 tons and at a temperature of 600° F. for a time of two minutes while reducing the moisture content to less than 10% to obtain a compressed composite body. 12. A method as set forth in claim 11 wherein said compressed composite body has a density of 20 lbs/ft3, a modulus of elasticity around 80 ksi, a modulus of rupture around 800 psi, and a screw hold strength around 100 lbf. 13. A method of making a composite body comprising the steps of
obtaining a mass of biocomposite material comprised of discrete particles, a network of interconnected glucan-containing mycelia cells extending around the discrete particles and a moisture content of greater than 10% by weight; and thereafter compressing said mass at a pressure between 25 psi and 5000 psi and at a temperature of 600° F. for a time of four minutes while reducing the moisture content to less than 10% to obtain a compressed composite body. 14. A method as set forth in claim 13 wherein said compressed composite body has a density of 34 lbs/ft3, a modulus of elasticity around 132 ksi, a modulus of rupture around 1698 psi, and a screw hold strength around 24 lbf at half an inch thickness. 15. A method as set forth in claim 13 wherein said compressed composite body has a density of 29 lbs/ft3, a modulus of elasticity around 120 ksi, a modulus of rupture around 819 psi, and a screw hold strength around 132 lbf at an inch thickness. 16. A method of making a composite body comprising the steps of
obtaining a mass of biocomposite material comprised of discrete particles, a network of interconnected glucan-containing mycelia cells extending around the discrete particles and a moisture content of greater than 10% by weight; and thereafter compressing said mass at a pressure between 25 psi and 5000 psi and at a temperature of 300° F. for a time of one minute while reducing the moisture content to less than 10% to obtain a compressed composite body. 17. A method as set forth in claim 16 wherein said mass is molded into a sheet prior to said step of compressing and pressed into a deformed geometric shape. 18. A method as set forth in claim 17 wherein said sheet has dimensions of 18 inches by 18 inches by 1 inch and said deformed geometric shape is a semi-cylindrical shape. 19. A method of making a composite body comprising the steps of
obtaining a mass of biocomposite material comprised of discrete particles, a network of interconnected glucan-containing mycelia cells extending around the discrete particles and a moisture content of greater than 10% by weight; forming said mass of biocomposite material into a flat blank board of 1.25″ thickness with a 0.25″ hemp nonwoven matt grown into at least one face of said flat blank board; thereafter compressing said flat blank board into the predetermined curved shape under a compressive force of 3000 psi and at a temperature of 340° F. for a time of 10 minutes while reducing the moisture content to less than 10% to obtain a compressed composite body of curved shape. 20. A method as set forth in claim 19 wherein said step of forming said mass of biocomposite material into a flat blank board includes embossing said at least one face with a predetermined sculptured feature. 21. A method of making a composite body comprising the steps of
cultivating mycelium into a sheet; freeze drying said sheet; thereafter milling said dried sheet to form a first mass of particles; milling Kenaf pith to form a second mass of particles; blending said first mass of particles and said second mass of particles into a mixture; thereafter heating and compressing said mixture in a mold cavity for a time sufficient to form a cohesive product; and removing said product from the mold as a self-supporting composite body. 22. A method as set forth in claim 21 wherein said step of cultivating mycelium into a sheet includes cultivating the mycelium on malt extract at a rate of 32 g per liter for 7 days at ambient conditions of 75° F., 20% relative humidity and 2000 ppm C02 until said sheet of mycelium is formed. 23. A method as set forth in claim 21 wherein said step of milling said dried sheet includes hammer milling through a 0.0625″ screen. 24. A method as set forth in claim 21 wherein said step of milling Kenaf pith includes hammer milling through a 22 mesh and over a 38 mesh screen. 25. A method as set forth in claim 21 wherein said step of blending blends said kenaf pith and said mycelium together at a 9:1 ratio. 26. A method as set forth in claim 21 wherein said step of heating and compressing said mixture includes heating the mold cavity to 380° F. and compressing said mixture under 30 tons of force for four minutes to form the cohesive product. 27. A self-supporting composite body comprising a substrate of discrete particles and a network of interconnected mycelia cells extending through and around the discrete particles and bonding the discrete particles together, said composite body being characterized in being stiff and in having a density between 18 and 60 pounds per cubic foot (pcf), a modulus of elasticity of up to 250 ksi and a modulus of rupture of up to 2500 psi. 28. A self-supporting composite body comprising a substrate of discrete fibers and a network of interconnected mycelia cells extending through and around the discrete fibers and bonding the discrete fibers together, said composite body being characterized in being stiff and in having a density between 18 and 60 pounds per cubic foot (pcf), a modulus of elasticity greater than 250 ksi and a modulus of rupture of up to 2500 psi. | 1,600 |
467 | 15,273,098 | 1,617 | A hydrogel delivery composition, including degradable microcapsules suspended in a degradable thermo-responsive hydrogel. The hydrogel is thermo-responsive at a physiological temperature and changes after application to a more solid state due to body temperatures. The composition includes one or more treatment agents to be released over time as the composition degrades. The composition can be varied to modify the structure and/or release of the treatment agent. | 1. A delivery composition, comprising degradable microcapsules suspended in a degradable thermo-responsive hydrogel, wherein the hydrogel is thermo-responsive at a physiological temperature of about 32° C. to about 37° C. 2. The composition of claim 1, wherein the microcapsules encapsulate and release a treatment agent. 3. The composition of claim 2, further comprising a non-encapsulated treatment agent dispersed within the hydrogel. 4. The composition of claim 2, further comprising microcapsules having at least two release rates. 5. The composition of claim 2, wherein the treatment agent is selected from one an anti-VEGF agent, an anti-PDGF agent, cells, delivery cells, an antibiotic, a corticosteroid, enzymes, peptides, nucleic acids, or combinations thereof. 6. The composition of claim 1, wherein the microcapsules comprise poly(lactic-co-glycolic acid), poly(latic acid), polysaccharide chitin, alginate, or combinations or block copolymers thereof. 7. The composition of claim 1, wherein the hydrogel comprises poly(N-isopropylacrylamide), poly(latic acid), polysaccharide chitin, alginate, diacrylate, or combinations or block copolymers thereof. 8. The composition of claim 7, wherein the microcapsules comprise poly(lactic-co-glycolic acid), poly(latic acid), polysaccharide chitin, alginate, or combinations or block copolymers thereof. 9. The composition of claim 1, wherein the thermo-responsive hydrogels are in a liquid-like state at room temperature and more solid state at body temperature. 10. A method of delivering a compound to an eye, the method comprising:
applying to or into an eye of a mammal a composition in a first physicochemical state, wherein the composition comprises a microencapsulated treatment agent suspended in a thermo-responsive hydrogel; and the composition changing to a second physicochemical state upon administration, wherein the second physicochemical state is more solid than the first physicochemical state and degradable to release the microencapsulated treatment agent. 11. The method of claim 10, wherein microcapsules release the bioactive treatment agent over time after injecting. 12. The method of claim 10, further comprising a non-encapsulated treatment agent dispersed within the hydrogel. 13. The method of claim 10, wherein the microencapsulated treatment agent comprises an anti-VEGF agent, an anti-PDGF agent, cells, delivery cells, antibiotic, a corticosteroid, enzymes, peptides, nucleic acids, or combinations thereof. 14. The method of claim 13, wherein the microencapsulated treatment agent comprises poly(lactic-co-glycolic acid), poly(latic acid), polysaccharide chitin, alginate, or combinations or block copolymers thereof. 15. The method of claim 10, wherein the hydrogel comprises poly(N-isopropylacrylamide), poly(latic acid), polysaccharide chitin, alginate, diacrylate, or combinations or block copolymers thereof. 16. The method of claim 10, further comprising controlling the degradation by type and/or amount of crosslinking to control the release the microencapsulated treatment agent. 17. The method of claim 10, wherein the composition comprises a second microencapsulated treatment agent suspended in the thermo-responsive hydrogel, the second microencapsulated treatment agent having a different rate of release than the microencapsulated treatment agent. 18. The method of claim 10, further comprising applying the composition in a first physicochemical state by intravitreal injection, by periocular or transcleral injection, by topical application, by intracameral application, by suprachoroidal application, within ocular implants, or combinations thereof. 19. The method of claim 10, further comprising applying the composition in a first physicochemical state by small gauge needle or microcatheter. 20. The method of claim 10, further comprising applying the composition in a first physicochemical state as a scleral structure during retinal detachment treatment. | A hydrogel delivery composition, including degradable microcapsules suspended in a degradable thermo-responsive hydrogel. The hydrogel is thermo-responsive at a physiological temperature and changes after application to a more solid state due to body temperatures. The composition includes one or more treatment agents to be released over time as the composition degrades. The composition can be varied to modify the structure and/or release of the treatment agent.1. A delivery composition, comprising degradable microcapsules suspended in a degradable thermo-responsive hydrogel, wherein the hydrogel is thermo-responsive at a physiological temperature of about 32° C. to about 37° C. 2. The composition of claim 1, wherein the microcapsules encapsulate and release a treatment agent. 3. The composition of claim 2, further comprising a non-encapsulated treatment agent dispersed within the hydrogel. 4. The composition of claim 2, further comprising microcapsules having at least two release rates. 5. The composition of claim 2, wherein the treatment agent is selected from one an anti-VEGF agent, an anti-PDGF agent, cells, delivery cells, an antibiotic, a corticosteroid, enzymes, peptides, nucleic acids, or combinations thereof. 6. The composition of claim 1, wherein the microcapsules comprise poly(lactic-co-glycolic acid), poly(latic acid), polysaccharide chitin, alginate, or combinations or block copolymers thereof. 7. The composition of claim 1, wherein the hydrogel comprises poly(N-isopropylacrylamide), poly(latic acid), polysaccharide chitin, alginate, diacrylate, or combinations or block copolymers thereof. 8. The composition of claim 7, wherein the microcapsules comprise poly(lactic-co-glycolic acid), poly(latic acid), polysaccharide chitin, alginate, or combinations or block copolymers thereof. 9. The composition of claim 1, wherein the thermo-responsive hydrogels are in a liquid-like state at room temperature and more solid state at body temperature. 10. A method of delivering a compound to an eye, the method comprising:
applying to or into an eye of a mammal a composition in a first physicochemical state, wherein the composition comprises a microencapsulated treatment agent suspended in a thermo-responsive hydrogel; and the composition changing to a second physicochemical state upon administration, wherein the second physicochemical state is more solid than the first physicochemical state and degradable to release the microencapsulated treatment agent. 11. The method of claim 10, wherein microcapsules release the bioactive treatment agent over time after injecting. 12. The method of claim 10, further comprising a non-encapsulated treatment agent dispersed within the hydrogel. 13. The method of claim 10, wherein the microencapsulated treatment agent comprises an anti-VEGF agent, an anti-PDGF agent, cells, delivery cells, antibiotic, a corticosteroid, enzymes, peptides, nucleic acids, or combinations thereof. 14. The method of claim 13, wherein the microencapsulated treatment agent comprises poly(lactic-co-glycolic acid), poly(latic acid), polysaccharide chitin, alginate, or combinations or block copolymers thereof. 15. The method of claim 10, wherein the hydrogel comprises poly(N-isopropylacrylamide), poly(latic acid), polysaccharide chitin, alginate, diacrylate, or combinations or block copolymers thereof. 16. The method of claim 10, further comprising controlling the degradation by type and/or amount of crosslinking to control the release the microencapsulated treatment agent. 17. The method of claim 10, wherein the composition comprises a second microencapsulated treatment agent suspended in the thermo-responsive hydrogel, the second microencapsulated treatment agent having a different rate of release than the microencapsulated treatment agent. 18. The method of claim 10, further comprising applying the composition in a first physicochemical state by intravitreal injection, by periocular or transcleral injection, by topical application, by intracameral application, by suprachoroidal application, within ocular implants, or combinations thereof. 19. The method of claim 10, further comprising applying the composition in a first physicochemical state by small gauge needle or microcatheter. 20. The method of claim 10, further comprising applying the composition in a first physicochemical state as a scleral structure during retinal detachment treatment. | 1,600 |
468 | 15,202,378 | 1,631 | The invention provides an unbiased method to assess the binding of a test compound to a multiplicity of proteins in the same sample, including samples from living cells by applying the unbiased determination technique of SWATH-MS or the biased technique of SRM-MS to a thermal shift assay to evaluate drug target interactions. In addition, the results created by SWATH-MS can be analyzed by SRM-MS in a biased manner to assess the binding of a test compound to a multiplicity of proteins in the same sample, including samples from living cells. | 1. A multiplexed method to identify proteins to which a test compound binds in a sample containing numerous proteins or for identifying a compound capable of binding to a target protein contained in a sample comprising numerous proteins, including said target protein, which method comprises:
(a) subjecting a first portion of the sample that contains test compound and a second portion of the sample that does not contain test compound to at least one temperature at which at least some of the proteins in said sample are more soluble when bound to the test compound and less soluble when not bound to said test compound; (b) separating each of said first and second portions to obtain a soluble fraction and an insoluble fraction of each; (c) determining the concentration of a multiplicity of proteins in either the soluble fraction or the insoluble fraction of each portion or both; wherein said determining is performed in an unbiased manner by Sequential Windowed data independent Acquisition of the Total High resolution Mass Spectroscopy (SWATH-MS); or wherein said determining is performed in a biased manner by Selected Reaction Monitoring (SRM-MS); wherein a protein whose concentration in the soluble fraction of the first portion is increased at said temperature as compared to the soluble fraction of the second portion and/or whose concentration in the insoluble fraction of the first portion is decreased at said temperature as compared to the insoluble fraction of the second portion is identified as a protein that binds said test compound, or wherein a higher concentration of said target protein in the soluble fraction of the first portion at said temperature as compared to the soluble fraction of the second portion and/or a lower concentration of target protein in the insoluble fraction in the first portion at said temperature as compared to the insoluble fraction of the second portion identifies said test compound as binding the target protein. 2. The method of claim 1 wherein the sample is a cell lysate. 3. The method of claim 2 wherein the lysate is of cells from human, mouse, rat, bovine, rabbit, E. coli or M. tuberculosis. 4. The method of claim 1 wherein said sample comprises living cells and said cells are lysed prior to step (a). 5. A multiplexed method to identify proteins to which a test compound binds in a sample containing numerous proteins or for identifying a compound capable of binding to a target protein contained in a sample comprising numerous proteins, including said target protein which method comprises:
(a) subjecting a first portion of the sample that contains test compound and a second portion of the sample that does not contain test compound or aliquots thereof to a series of different temperatures, including a temperature which is equal to or greater than the initial melting temperature of at least some of the proteins in said sample; (b) separating each of said first and second portions or each aliquot thereof to obtain a soluble and insoluble fraction; (c) determining the concentration of a multiplicity of proteins in either the soluble fraction or the insoluble fraction of each portion or both; wherein said determining is performed in an unbiased manner by SWATH-MS; or wherein said determining is performed in a biased manner by SRM-MS; wherein a protein whose concentration is maintained in the soluble fraction of said first portion or aliquots thereof at a higher temperature as compared to the soluble fraction of the second portion or aliquots thereof and/or whose concentration in the insoluble fraction of said first portion or aliquots thereof is decreased at a higher temperature as compared to the insoluble portion of the second portion or aliquots thereof is identified as a protein that binds said test compound, or wherein when the concentration of said target protein is maintained in the soluble fraction of the first portion or aliquots thereof at a higher temperature as compared to the soluble fraction of the second portion or aliquots thereof and/or when the concentration of target protein in the insoluble fraction of said first portion or aliquots thereof is decreased at a higher temperature than in the insoluble fraction of the second portion or aliquots thereof the test compound is identified as binding said target protein. 6. The method of claim 5 wherein the sample is a cell lysate. 7. The method of claim 6 wherein the lysate is of cells from speciaes such as human, mouse, rat, bovine, rabbit, E. coli or M. tuberculosis. 8. The method of claim 5 wherein said sample comprises living cells and said cells are lysed prior to step (a). 9. A multiplexed method to identify proteins to which a test compound binds in a sample containing numerous proteins or for identifying a compound capable of binding to a target protein contained in a sample comprising numerous proteins, including said target protein which method comprises:
(a) determining the inflection melting temperatures (Tm's) of a multiplicity of proteins in a first portion of the sample that contains test compound; and (b) determining the Tm's of said multiplicity of proteins in a second portion of the sample that does not contain test compound and/or ascertaining Tm values of said multiplicity of proteins in unbound form from stored or literature values; wherein said determining is performed in an unbiased manner by SWATH-MS; or wherein said determining is performed in a biased manner by SRM-MS; wherein a protein that exhibits a higher Tm in the first portion as compared to the second portion or as compared to the stored or literature value is identified as a protein that binds to said test compound, or wherein when said target protein exhibits a higher Tm in the first potion as compared to the second portion or as compared to the stored or literature value of said protein, the test compound is identified as binding the target protein. 10. The method of claim 9 wherein the sample is a cell lysate. 11. The method of claim 10 wherein the lysate is of cells from species such as human, mouse, rat, bovine, rabbit, E. coli or M. tuberculosis. 12. The method of claim 9 wherein said sample comprises living cells and said cells are lysed prior to step (a). 13. An improved method of determining whether a sample containing a multiplicity of proteins contains a target protein bound to a ligand of interest comprising the steps of:
(a) exposing the sample to a temperature which is capable of causing or enhancing precipitation of unbound protein to a greater extent than it is capable of causing or enhancing precipitation of protein bound to the ligand; (b) separating soluble from insoluble protein in the product of step a); and (c) analyzing either or both the soluble and insoluble protein fractions of step b) for the amount of said protein, wherein a protein whose concentration in the soluble fraction at said temperature is increased in the presence as opposed to the absence of the test compound, or whose concentration in the insoluble fraction is decreased in the presence as opposed to the absence of the test compound, is identified as a protein that binds said test compound, wherein the improvement comprises analyzing said fraction(s) in an unbiased manner by SWATH-MS, or wherein the improvement comprises analyzing said fraction(s) in a biased manner by SRM-MS. 14. The method of claim 13 wherein said sample contains numerous proteins and the presence of more than one of said proteins is determined. 15. The method of claim 13 wherein the sample is a cell lysate. 16. The method of claim 15 wherein the lysate is of cells from species such as human, mouse, rat, bovine, rabbit, E. coli or M. tuberculosis. 17. The method of claim 13 wherein said sample comprises living cells and said cells are lysed prior to step (a). 18. A method for identifying proteins of living cells to which a test compound binds, comprising the steps of:
(a) contacting a portion of said living cells with the test compound; (b) subjecting the living cells to lysis conditions to generate a first sample and subjecting said living cells that have not been contacted with said compound to lysis conditions to generate a second sample; (c) subjecting said first sample and said second sample to at least one temperature at which at least some of the proteins in said sample are more soluble when bound to the test compound and less soluble when not bound to said test compound; (d) separating each of said first and second samples to obtain a soluble fraction and an insoluble fraction of each; (e) determining the concentration of a multiplicity of proteins in either the soluble fraction or the insoluble fraction of each sample or both; wherein said determining is performed in an unbiased manner by SWATH-MS; or wherein said determining is performed in a biased manner by SRM-MS; wherein any protein whose concentration in the soluble fraction of the first sample is increased at said temperature as compared to soluble fraction of the second sample and/or whose concentration in the insoluble fraction of the first sample is decreased at said temperature as compared to the insoluble portion of the second sample is identified as a protein that binds said test compound. 19. A method for identifying proteins of living cells to which a test compound binds, comprising the steps of:
(a) contacting a portion of said living cells with the test compound; (b) subjecting the living cells to lysis conditions to generate a first sample and subjecting said living cells that have not been contacted with said compound to lysis conditions to generate a second sample; (c) subjecting said first and second samples or aliquots thereof to a series of different temperatures, including a temperature which is equal to or greater than the initial melting temperature of at least some of the proteins in said sample; (d) separating each of said first and second samples or each aliquot to obtain a soluble and insoluble fraction; (e) determining the concentrations of a multiplicity of proteins in either the soluble fraction or the insoluble fraction of each sample or both; wherein said determining is performed in an unbiased manner by SWATH-MS; or wherein said determining is performed in a biased manner by SRM-MS; wherein a protein whose concentration is maintained in the soluble fraction of the first sample or aliquots thereof at a higher temperature as compared to the soluble fraction of the second sample or aliquots thereof and/or whose concentration in the insoluble fraction of the first sample or aliquots thereof is decreased at a higher temperature as compared to the insoluble portion of the second sample or aliquots thereof is identified as a protein that binds said test compound. 20. A method for identifying proteins of living cells to which a test compound binds, comprising the steps of:
(a) contacting a portion of said living cells with the test compound; (b) subjecting the living cells in (a) to lysis conditions to generate a first sample and subjecting said living cells that have not been contacted with said compound to lysis conditions to generate a second sample; (c) determining the inflection melting temperature (Tm) of a multiplicity of proteins in said first sample and in said second sample and/or ascertaining Tm values of at least some of said multiplicity of proteins in unbound form from stored or literature values; wherein said determining is performed in an unbiased manner by SWATH-MS; or wherein said determining is performed in a biased manner by SRM MS; wherein a protein that exhibits a higher Tm in the first sample as compared to the second sample or as compared to said stored or literature values is identified as a protein that binds to said test compound. | The invention provides an unbiased method to assess the binding of a test compound to a multiplicity of proteins in the same sample, including samples from living cells by applying the unbiased determination technique of SWATH-MS or the biased technique of SRM-MS to a thermal shift assay to evaluate drug target interactions. In addition, the results created by SWATH-MS can be analyzed by SRM-MS in a biased manner to assess the binding of a test compound to a multiplicity of proteins in the same sample, including samples from living cells.1. A multiplexed method to identify proteins to which a test compound binds in a sample containing numerous proteins or for identifying a compound capable of binding to a target protein contained in a sample comprising numerous proteins, including said target protein, which method comprises:
(a) subjecting a first portion of the sample that contains test compound and a second portion of the sample that does not contain test compound to at least one temperature at which at least some of the proteins in said sample are more soluble when bound to the test compound and less soluble when not bound to said test compound; (b) separating each of said first and second portions to obtain a soluble fraction and an insoluble fraction of each; (c) determining the concentration of a multiplicity of proteins in either the soluble fraction or the insoluble fraction of each portion or both; wherein said determining is performed in an unbiased manner by Sequential Windowed data independent Acquisition of the Total High resolution Mass Spectroscopy (SWATH-MS); or wherein said determining is performed in a biased manner by Selected Reaction Monitoring (SRM-MS); wherein a protein whose concentration in the soluble fraction of the first portion is increased at said temperature as compared to the soluble fraction of the second portion and/or whose concentration in the insoluble fraction of the first portion is decreased at said temperature as compared to the insoluble fraction of the second portion is identified as a protein that binds said test compound, or wherein a higher concentration of said target protein in the soluble fraction of the first portion at said temperature as compared to the soluble fraction of the second portion and/or a lower concentration of target protein in the insoluble fraction in the first portion at said temperature as compared to the insoluble fraction of the second portion identifies said test compound as binding the target protein. 2. The method of claim 1 wherein the sample is a cell lysate. 3. The method of claim 2 wherein the lysate is of cells from human, mouse, rat, bovine, rabbit, E. coli or M. tuberculosis. 4. The method of claim 1 wherein said sample comprises living cells and said cells are lysed prior to step (a). 5. A multiplexed method to identify proteins to which a test compound binds in a sample containing numerous proteins or for identifying a compound capable of binding to a target protein contained in a sample comprising numerous proteins, including said target protein which method comprises:
(a) subjecting a first portion of the sample that contains test compound and a second portion of the sample that does not contain test compound or aliquots thereof to a series of different temperatures, including a temperature which is equal to or greater than the initial melting temperature of at least some of the proteins in said sample; (b) separating each of said first and second portions or each aliquot thereof to obtain a soluble and insoluble fraction; (c) determining the concentration of a multiplicity of proteins in either the soluble fraction or the insoluble fraction of each portion or both; wherein said determining is performed in an unbiased manner by SWATH-MS; or wherein said determining is performed in a biased manner by SRM-MS; wherein a protein whose concentration is maintained in the soluble fraction of said first portion or aliquots thereof at a higher temperature as compared to the soluble fraction of the second portion or aliquots thereof and/or whose concentration in the insoluble fraction of said first portion or aliquots thereof is decreased at a higher temperature as compared to the insoluble portion of the second portion or aliquots thereof is identified as a protein that binds said test compound, or wherein when the concentration of said target protein is maintained in the soluble fraction of the first portion or aliquots thereof at a higher temperature as compared to the soluble fraction of the second portion or aliquots thereof and/or when the concentration of target protein in the insoluble fraction of said first portion or aliquots thereof is decreased at a higher temperature than in the insoluble fraction of the second portion or aliquots thereof the test compound is identified as binding said target protein. 6. The method of claim 5 wherein the sample is a cell lysate. 7. The method of claim 6 wherein the lysate is of cells from speciaes such as human, mouse, rat, bovine, rabbit, E. coli or M. tuberculosis. 8. The method of claim 5 wherein said sample comprises living cells and said cells are lysed prior to step (a). 9. A multiplexed method to identify proteins to which a test compound binds in a sample containing numerous proteins or for identifying a compound capable of binding to a target protein contained in a sample comprising numerous proteins, including said target protein which method comprises:
(a) determining the inflection melting temperatures (Tm's) of a multiplicity of proteins in a first portion of the sample that contains test compound; and (b) determining the Tm's of said multiplicity of proteins in a second portion of the sample that does not contain test compound and/or ascertaining Tm values of said multiplicity of proteins in unbound form from stored or literature values; wherein said determining is performed in an unbiased manner by SWATH-MS; or wherein said determining is performed in a biased manner by SRM-MS; wherein a protein that exhibits a higher Tm in the first portion as compared to the second portion or as compared to the stored or literature value is identified as a protein that binds to said test compound, or wherein when said target protein exhibits a higher Tm in the first potion as compared to the second portion or as compared to the stored or literature value of said protein, the test compound is identified as binding the target protein. 10. The method of claim 9 wherein the sample is a cell lysate. 11. The method of claim 10 wherein the lysate is of cells from species such as human, mouse, rat, bovine, rabbit, E. coli or M. tuberculosis. 12. The method of claim 9 wherein said sample comprises living cells and said cells are lysed prior to step (a). 13. An improved method of determining whether a sample containing a multiplicity of proteins contains a target protein bound to a ligand of interest comprising the steps of:
(a) exposing the sample to a temperature which is capable of causing or enhancing precipitation of unbound protein to a greater extent than it is capable of causing or enhancing precipitation of protein bound to the ligand; (b) separating soluble from insoluble protein in the product of step a); and (c) analyzing either or both the soluble and insoluble protein fractions of step b) for the amount of said protein, wherein a protein whose concentration in the soluble fraction at said temperature is increased in the presence as opposed to the absence of the test compound, or whose concentration in the insoluble fraction is decreased in the presence as opposed to the absence of the test compound, is identified as a protein that binds said test compound, wherein the improvement comprises analyzing said fraction(s) in an unbiased manner by SWATH-MS, or wherein the improvement comprises analyzing said fraction(s) in a biased manner by SRM-MS. 14. The method of claim 13 wherein said sample contains numerous proteins and the presence of more than one of said proteins is determined. 15. The method of claim 13 wherein the sample is a cell lysate. 16. The method of claim 15 wherein the lysate is of cells from species such as human, mouse, rat, bovine, rabbit, E. coli or M. tuberculosis. 17. The method of claim 13 wherein said sample comprises living cells and said cells are lysed prior to step (a). 18. A method for identifying proteins of living cells to which a test compound binds, comprising the steps of:
(a) contacting a portion of said living cells with the test compound; (b) subjecting the living cells to lysis conditions to generate a first sample and subjecting said living cells that have not been contacted with said compound to lysis conditions to generate a second sample; (c) subjecting said first sample and said second sample to at least one temperature at which at least some of the proteins in said sample are more soluble when bound to the test compound and less soluble when not bound to said test compound; (d) separating each of said first and second samples to obtain a soluble fraction and an insoluble fraction of each; (e) determining the concentration of a multiplicity of proteins in either the soluble fraction or the insoluble fraction of each sample or both; wherein said determining is performed in an unbiased manner by SWATH-MS; or wherein said determining is performed in a biased manner by SRM-MS; wherein any protein whose concentration in the soluble fraction of the first sample is increased at said temperature as compared to soluble fraction of the second sample and/or whose concentration in the insoluble fraction of the first sample is decreased at said temperature as compared to the insoluble portion of the second sample is identified as a protein that binds said test compound. 19. A method for identifying proteins of living cells to which a test compound binds, comprising the steps of:
(a) contacting a portion of said living cells with the test compound; (b) subjecting the living cells to lysis conditions to generate a first sample and subjecting said living cells that have not been contacted with said compound to lysis conditions to generate a second sample; (c) subjecting said first and second samples or aliquots thereof to a series of different temperatures, including a temperature which is equal to or greater than the initial melting temperature of at least some of the proteins in said sample; (d) separating each of said first and second samples or each aliquot to obtain a soluble and insoluble fraction; (e) determining the concentrations of a multiplicity of proteins in either the soluble fraction or the insoluble fraction of each sample or both; wherein said determining is performed in an unbiased manner by SWATH-MS; or wherein said determining is performed in a biased manner by SRM-MS; wherein a protein whose concentration is maintained in the soluble fraction of the first sample or aliquots thereof at a higher temperature as compared to the soluble fraction of the second sample or aliquots thereof and/or whose concentration in the insoluble fraction of the first sample or aliquots thereof is decreased at a higher temperature as compared to the insoluble portion of the second sample or aliquots thereof is identified as a protein that binds said test compound. 20. A method for identifying proteins of living cells to which a test compound binds, comprising the steps of:
(a) contacting a portion of said living cells with the test compound; (b) subjecting the living cells in (a) to lysis conditions to generate a first sample and subjecting said living cells that have not been contacted with said compound to lysis conditions to generate a second sample; (c) determining the inflection melting temperature (Tm) of a multiplicity of proteins in said first sample and in said second sample and/or ascertaining Tm values of at least some of said multiplicity of proteins in unbound form from stored or literature values; wherein said determining is performed in an unbiased manner by SWATH-MS; or wherein said determining is performed in a biased manner by SRM MS; wherein a protein that exhibits a higher Tm in the first sample as compared to the second sample or as compared to said stored or literature values is identified as a protein that binds to said test compound. | 1,600 |
469 | 15,106,064 | 1,631 | The invention relates to a computer implemented method of analysing data comprising measured values of characteristics of objects in samples, the data comprising —a first set of data (X ireference ) with measured values of characteristics of objects in reference samples; —a test set of data (X itest ) with measured values of the characteristics of objects in a test sample; characterised by the method comprising; —fitting a control model to the first set of data to determine control loadings (P control ) each representing an independent correlation between characteristics; —projecting the first set of data (X ireference ) onto the control loadings (P control ) for determining a first set control scores (T control,ireference ) and determining one or more confidence intervals for the first set of control scores (T control,ireference ); —projecting the test data onto the control loadings (P control ) for determining test control scores; —determining if the test control scores are within one or more the confidence intervals. | 1.-17. (canceled) 18. Computer implemented method of analysing data comprising measured values of characteristics of objects in samples, the data stored on a computer readable medium comprising
a first set of data (Xi reference ) with measured values of characteristics of objects in reference samples; a test set of data (Xi test ) with measured values of the characteristics of objects in a test sample;
the method comprising using a computer for;
reading the first set of data from the computer readable medium and fitting a control model to the first set of data to determine control loadings (Pcontrol) each representing an independent correlation between characteristics;
projecting the first set of data (Xi reference ) onto the control loadings (Pcontrol) for determining a first set control scores (Tcontrol,i reference ) and determining one or more confidence intervals for the first set of control scores (Tcontrol,i reference );
projecting the test data onto the control loadings (Pcontrol) for determining test control scores;
using a comparator to determine if the test control scores are within one or more the confidence intervals
characterized in that
a first set of control residuals (Yi reference ) is determined by using computation means for projecting the first set of data (Xi reference ) onto the control loadings (Pcontrol), and
wherein a test set of control residuals is determined by using computation means for projecting the test set of data onto the control loadings (Pcontrol),
comprising
using computation means projecting a second set of data (Xi perturbed ) with measured values of the characteristics of objects in perturbed samples onto the control loadings (Pcontrol) for determining a second set of control residuals (Yi perturbed )
using computation means for fitting a perturbation model to the second set of control residuals (Yi perturbed ) to determine perturbation loadings (Pperturbation each representing an independent correlation between characteristics;
using computation means for projecting the first set of control residuals (Yi reference ) onto the perturbation loadings (Pperturbation and determining a first set of perturbation scores (TCT,i reference );
determining one or more further confidence intervals for the first set of perturbation scores (TCT,i reference );
projecting the test data onto the control loadings (Pcontrol) to determine test control residuals;
projecting the test control residuals onto the perturbation loadings (Presponse and determining test perturbation scores;
comparing the test perturbation scores with the one or more further confidence intervals with a comparator. 19. Computer implemented method according to claim 18, wherein the step of fitting a control model comprises using the computer to conduct a principal component analysis to determine the control loadings (Pcontrol). 20. Computer implemented method according to claim 18, wherein the first set of data (Xi reference ) is centered per sample by using a computer for determining per reference sample (ireference) the mean value (mi reference ) of each characteristic and subtracting for each reference sample (ireference) the corresponding mean value (mi reference ) of the characteristic from the measured value in the first set of data (Xi reference ) of the corresponding characteristic before fitting the control model. 21. Computer implemented method according to claim 18, wherein the test set of data (Xi test ) is centered per sample by using a computer for determining per test sample (itest) the mean value of each characteristic and subtracting for each test sample (itest) the corresponding mean value of the characteristic from the measured value in the test set of data of the corresponding characteristic before projecting the test data onto the control loadings (Pcontrol). 22. Computer implemented method according to claim 18, comprising
using the principal component analysis to determine at least two principal control loadings (Pcontrol) using output means of the computer for producing a biplot of the test control scores, the biplot comprising a vector corresponding to a characteristic of the objects of the data projected onto two principal control loadings (Pcontrol) of the at least two principal control loadings; determining if the test control scores along the vector are within the one or more confidence intervals. 23. Computer implemented method according to claim 18, wherein the step of fitting a perturbation model comprises using a principal component analysis to determine the perturbation loadings. 24. Computer implemented method according to claim 18, wherein the test set of data is the second set of data. 25. Computer implemented method according to claim 24, comprising removing data corresponding to test scores falling within the one or more confidence intervals from the second set of data before fitting the perturbation model. 26. Computer implemented method according to claim 24 comprising
projecting the second set of control residuals (Yi perturbed ) onto the perturbation loadings to determine a second set of perturbation scores;
determining an additional confidence interval for the second set of perturbation scores. 27. Computer implemented method according to claim 23, comprising
using the further principal component analysis to determine at least two principal perturbation loadings (Pperturbation ; producing a biplot of the test perturbation scores, the biplot comprising a vector corresponding to a characteristic of the objects of the data projected onto two principal perturbation loadings (Pperturbation of the at least two principal perturbation loadings; determining if the test perturbation scores along the vector are within the one or more further confidence intervals. 28. Method for analysing data comprising the steps of the computer implemented method according to claim 18; and
using a cytometer to measure the values of characteristics of the objects in the test sample. 29. Computer program comprising program code for performing the steps of claim 18 when said computer program is executed on a computer. 30. Computer readable medium comprising the computer program according to claim 29. 31. Data analysis system for analysing data comprising measured values of characteristics of objects in samples, comprising computation means arranged to carry out the steps of claim 18. 32. Cytometer for measuring values of characteristics of objects in test samples comprising analysing means for analysing data, the data stored on a computer readable medium and comprising:
a first set of data (Xi reference ) with measured values of characteristics of objects in reference samples; a test set of data (Xi test ) with the measured values of the characteristics of objects in a test sample;
characterised by the cytometer comprising a computer arranged to carry out the steps of claim 18. 33. Cytometer according to claim 32, comprising a gating device for selecting objects, the gating device separating the objects of the test sample based on corresponding test control scores and checking if the corresponding test control scores are inside the one or more confidence intervals. | The invention relates to a computer implemented method of analysing data comprising measured values of characteristics of objects in samples, the data comprising —a first set of data (X ireference ) with measured values of characteristics of objects in reference samples; —a test set of data (X itest ) with measured values of the characteristics of objects in a test sample; characterised by the method comprising; —fitting a control model to the first set of data to determine control loadings (P control ) each representing an independent correlation between characteristics; —projecting the first set of data (X ireference ) onto the control loadings (P control ) for determining a first set control scores (T control,ireference ) and determining one or more confidence intervals for the first set of control scores (T control,ireference ); —projecting the test data onto the control loadings (P control ) for determining test control scores; —determining if the test control scores are within one or more the confidence intervals.1.-17. (canceled) 18. Computer implemented method of analysing data comprising measured values of characteristics of objects in samples, the data stored on a computer readable medium comprising
a first set of data (Xi reference ) with measured values of characteristics of objects in reference samples; a test set of data (Xi test ) with measured values of the characteristics of objects in a test sample;
the method comprising using a computer for;
reading the first set of data from the computer readable medium and fitting a control model to the first set of data to determine control loadings (Pcontrol) each representing an independent correlation between characteristics;
projecting the first set of data (Xi reference ) onto the control loadings (Pcontrol) for determining a first set control scores (Tcontrol,i reference ) and determining one or more confidence intervals for the first set of control scores (Tcontrol,i reference );
projecting the test data onto the control loadings (Pcontrol) for determining test control scores;
using a comparator to determine if the test control scores are within one or more the confidence intervals
characterized in that
a first set of control residuals (Yi reference ) is determined by using computation means for projecting the first set of data (Xi reference ) onto the control loadings (Pcontrol), and
wherein a test set of control residuals is determined by using computation means for projecting the test set of data onto the control loadings (Pcontrol),
comprising
using computation means projecting a second set of data (Xi perturbed ) with measured values of the characteristics of objects in perturbed samples onto the control loadings (Pcontrol) for determining a second set of control residuals (Yi perturbed )
using computation means for fitting a perturbation model to the second set of control residuals (Yi perturbed ) to determine perturbation loadings (Pperturbation each representing an independent correlation between characteristics;
using computation means for projecting the first set of control residuals (Yi reference ) onto the perturbation loadings (Pperturbation and determining a first set of perturbation scores (TCT,i reference );
determining one or more further confidence intervals for the first set of perturbation scores (TCT,i reference );
projecting the test data onto the control loadings (Pcontrol) to determine test control residuals;
projecting the test control residuals onto the perturbation loadings (Presponse and determining test perturbation scores;
comparing the test perturbation scores with the one or more further confidence intervals with a comparator. 19. Computer implemented method according to claim 18, wherein the step of fitting a control model comprises using the computer to conduct a principal component analysis to determine the control loadings (Pcontrol). 20. Computer implemented method according to claim 18, wherein the first set of data (Xi reference ) is centered per sample by using a computer for determining per reference sample (ireference) the mean value (mi reference ) of each characteristic and subtracting for each reference sample (ireference) the corresponding mean value (mi reference ) of the characteristic from the measured value in the first set of data (Xi reference ) of the corresponding characteristic before fitting the control model. 21. Computer implemented method according to claim 18, wherein the test set of data (Xi test ) is centered per sample by using a computer for determining per test sample (itest) the mean value of each characteristic and subtracting for each test sample (itest) the corresponding mean value of the characteristic from the measured value in the test set of data of the corresponding characteristic before projecting the test data onto the control loadings (Pcontrol). 22. Computer implemented method according to claim 18, comprising
using the principal component analysis to determine at least two principal control loadings (Pcontrol) using output means of the computer for producing a biplot of the test control scores, the biplot comprising a vector corresponding to a characteristic of the objects of the data projected onto two principal control loadings (Pcontrol) of the at least two principal control loadings; determining if the test control scores along the vector are within the one or more confidence intervals. 23. Computer implemented method according to claim 18, wherein the step of fitting a perturbation model comprises using a principal component analysis to determine the perturbation loadings. 24. Computer implemented method according to claim 18, wherein the test set of data is the second set of data. 25. Computer implemented method according to claim 24, comprising removing data corresponding to test scores falling within the one or more confidence intervals from the second set of data before fitting the perturbation model. 26. Computer implemented method according to claim 24 comprising
projecting the second set of control residuals (Yi perturbed ) onto the perturbation loadings to determine a second set of perturbation scores;
determining an additional confidence interval for the second set of perturbation scores. 27. Computer implemented method according to claim 23, comprising
using the further principal component analysis to determine at least two principal perturbation loadings (Pperturbation ; producing a biplot of the test perturbation scores, the biplot comprising a vector corresponding to a characteristic of the objects of the data projected onto two principal perturbation loadings (Pperturbation of the at least two principal perturbation loadings; determining if the test perturbation scores along the vector are within the one or more further confidence intervals. 28. Method for analysing data comprising the steps of the computer implemented method according to claim 18; and
using a cytometer to measure the values of characteristics of the objects in the test sample. 29. Computer program comprising program code for performing the steps of claim 18 when said computer program is executed on a computer. 30. Computer readable medium comprising the computer program according to claim 29. 31. Data analysis system for analysing data comprising measured values of characteristics of objects in samples, comprising computation means arranged to carry out the steps of claim 18. 32. Cytometer for measuring values of characteristics of objects in test samples comprising analysing means for analysing data, the data stored on a computer readable medium and comprising:
a first set of data (Xi reference ) with measured values of characteristics of objects in reference samples; a test set of data (Xi test ) with the measured values of the characteristics of objects in a test sample;
characterised by the cytometer comprising a computer arranged to carry out the steps of claim 18. 33. Cytometer according to claim 32, comprising a gating device for selecting objects, the gating device separating the objects of the test sample based on corresponding test control scores and checking if the corresponding test control scores are inside the one or more confidence intervals. | 1,600 |
470 | 14,894,083 | 1,612 | The present invention relates to a drawn antimicrobial, such as an antibacterial, antiparasitic and antiviral polymeric fiber and materials containing same, wherein the fiber is a polymeric fiber containing cuprous iodide particles dispersed therein of about 0.50 to about 2.0 micron in size. The invention also provides processes for preparing such fibers and fiber-based materials. | 1. An antimicrobial fiber comprising a polymer and cuprous iodide particles dispersed therein, wherein said particle size of the cuprous iodide particles ranges from about 0.50 to about 2.0 micron. 2. The antimicrobial fiber of claim 1, wherein at least 80% of cuprous iodide particles within said antimicrobial fiber have a size ranging from about 0.50 to about 2.0 micron. 3.-4. (canceled) 5. The antimicrobial fiber, comprising a polymer and crystalline cuprous iodide particles dispersed therein, wherein said particle size of the crystalline iodide particles ranges from about 0.50 to about 2.0 microns and at least 80% of crystalline cuprous iodide particles within said antimicrobial fiber have a size ranging from about 0.50 to about 2.0 micron. 6. The antimicrobial fiber of claim 1, wherein said antimicrobial fiber contains a blend of at least one synthetic polymer and a natural fiber. 7. The antimicrobial fiber of claim 1, wherein said antimicrobial fiber possesses at least one of fungicidal, fungistatic, bactericidal, sporicidal, and bacteriostatic activity. 8. (canceled) 9. The antimicrobial fiber of claim 1, wherein said polymer comprises cellulose, cellulose derivatives, acrylic, polyolefin, polyurethane, vinyl, polyamide, polyester, polypropylene or blends thereof. 10. A product comprising the antimicrobial fiber of claim 1. 11. The product of claim 10, wherein said antimicrobial fiber exhibits an antimicrobial kill rate of at least 90% within a 15-minute exposure time. 12. The product of claim 11, wherein said antimicrobial fiber exhibits an antimicrobial kill rate of at least 99% within a 15-minute exposure time. 13. The product of claim 10, wherein said product comprises antimicrobial fibers of uniform polymer composition. 14. The product of claim 10, wherein said product comprises antimicrobial fibers of nonuniform composition. 15. The antimicrobial fiber of claim 1, wherein said product comprises 1%-15% crystaline cuprous iodide w/w per fiber. 16. The product of claim 10, wherein said product comprises from 10%-100% of the antimicrobial fibers comprising cuprous iodide. 17. The product of claim 10, wherein said product is one of a yarn, a textile, a product used in a medical setting, and a textile product used in a health care facility. 18.-20. (canceled) 21. A method for imparting at least one of antimicrobial activity and anti-odor activity to a fiber-containing material, said method comprising preparing a antimicrobial fiber comprising a polymer and crystalline cuprous iodide particles dispersed therein, wherein said particle size ranges from about 0.50 to about 2.0 micron. 22. The method of claim 21, wherein said antimicrobial activity is evidenced within minutes of exposure to said fiber-containing material 23. The method of claim 21, comprising providing said fiber-containing material to a subject as an article of clothing or bedding. 24.-25. (canceled) | The present invention relates to a drawn antimicrobial, such as an antibacterial, antiparasitic and antiviral polymeric fiber and materials containing same, wherein the fiber is a polymeric fiber containing cuprous iodide particles dispersed therein of about 0.50 to about 2.0 micron in size. The invention also provides processes for preparing such fibers and fiber-based materials.1. An antimicrobial fiber comprising a polymer and cuprous iodide particles dispersed therein, wherein said particle size of the cuprous iodide particles ranges from about 0.50 to about 2.0 micron. 2. The antimicrobial fiber of claim 1, wherein at least 80% of cuprous iodide particles within said antimicrobial fiber have a size ranging from about 0.50 to about 2.0 micron. 3.-4. (canceled) 5. The antimicrobial fiber, comprising a polymer and crystalline cuprous iodide particles dispersed therein, wherein said particle size of the crystalline iodide particles ranges from about 0.50 to about 2.0 microns and at least 80% of crystalline cuprous iodide particles within said antimicrobial fiber have a size ranging from about 0.50 to about 2.0 micron. 6. The antimicrobial fiber of claim 1, wherein said antimicrobial fiber contains a blend of at least one synthetic polymer and a natural fiber. 7. The antimicrobial fiber of claim 1, wherein said antimicrobial fiber possesses at least one of fungicidal, fungistatic, bactericidal, sporicidal, and bacteriostatic activity. 8. (canceled) 9. The antimicrobial fiber of claim 1, wherein said polymer comprises cellulose, cellulose derivatives, acrylic, polyolefin, polyurethane, vinyl, polyamide, polyester, polypropylene or blends thereof. 10. A product comprising the antimicrobial fiber of claim 1. 11. The product of claim 10, wherein said antimicrobial fiber exhibits an antimicrobial kill rate of at least 90% within a 15-minute exposure time. 12. The product of claim 11, wherein said antimicrobial fiber exhibits an antimicrobial kill rate of at least 99% within a 15-minute exposure time. 13. The product of claim 10, wherein said product comprises antimicrobial fibers of uniform polymer composition. 14. The product of claim 10, wherein said product comprises antimicrobial fibers of nonuniform composition. 15. The antimicrobial fiber of claim 1, wherein said product comprises 1%-15% crystaline cuprous iodide w/w per fiber. 16. The product of claim 10, wherein said product comprises from 10%-100% of the antimicrobial fibers comprising cuprous iodide. 17. The product of claim 10, wherein said product is one of a yarn, a textile, a product used in a medical setting, and a textile product used in a health care facility. 18.-20. (canceled) 21. A method for imparting at least one of antimicrobial activity and anti-odor activity to a fiber-containing material, said method comprising preparing a antimicrobial fiber comprising a polymer and crystalline cuprous iodide particles dispersed therein, wherein said particle size ranges from about 0.50 to about 2.0 micron. 22. The method of claim 21, wherein said antimicrobial activity is evidenced within minutes of exposure to said fiber-containing material 23. The method of claim 21, comprising providing said fiber-containing material to a subject as an article of clothing or bedding. 24.-25. (canceled) | 1,600 |
471 | 16,166,893 | 1,624 | This invention provides efficient and scalable enantioselective methods that yield 2-alkyl-2-allylcycloalkyanone compounds with quaternary stereogenic centers. Methods include the method for the preparation of a compound of formula (I):
comprising treating a compound of formula (II) or (III):
with a palladium (II) catalyst under alkylation conditions. | 1-40. (canceled) 41. A method for the preparation of a compound of formula (I):
the preparing comprising treating, with a Pd(II) catalyst in an organic solvent,
(i) a compound of formula (II) or (III) or a salt thereof:
or
(ii) a compound of formula (IV) or (V) or a salt thereof:
and a compound of formula (X):
wherein the Pd(II) catalyst is used in an amount from about 0.01 mol % to about 3 mol % relative to the compound of formula (II), (III), (IV), or (V),
wherein, as valence and stability permit,
R1 represents hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (3- to 10-membered heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkoxy, amino, or halo;
R2, R3, R4, R5, R12, R13, R14, and R15 are independently selected for each occurrence from hydrogen, hydroxyl, halo, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate group, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, ether group, thioether group, ester group, amide, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, acylamino, aryl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl, 3- to 10-membered heterocyclyl, aralkyl, arylalkoxy, (5- to 10-membered heteroaryl)alkyl, (cycloalkyl)alkyl, and (3- to 10-membered heterocyclyl)alkyl;
W represents, as valence permits, —O—, —S—, —NR6—, —CR7R8—, —C(O)—, —CR7═, or —N═;
R6 represents hydrogen or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O) (5- to 10-membered heteroaryl), —C(O)-(5- to 10-membered heteroaryl)alkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(5- to 10-membered heteroaryl), —C(O)O-(5- to 10-membered heteroaryl)alkyl, —S(O)2(aryl), —S(O)2(alkyl), —S(O)2(haloalkyl), —OR10, —SR10, or —NR10R11;
R7 and R8 each independently represent hydrogen, hydroxyl, halo, nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, haloalkyl, ether group, thioether group, ester group, amido, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, or acylamino;
or R6, R7, and R8 taken together with a substituent on ring A and the intervening atoms, form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-membered heterocyclyl)alkenyl;
R10 and R11 are independently selected for each occurrence from hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, and alkynyl; and
ring A represents an optionally substituted cycloalkyl, 5- to 10-membered heterocyclyl, cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl,
wherein each heteroaryl or heterocyclyl comprises 1 to 4 heteroatoms selected from N, O, and S; and
wherein substituents on the alkyl, haloalkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkoxy, or amino are selected from halo, hydroxyl, carboxyl, alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group, thioformate group, alkoxy, phosphate group, phosphonate group, phosphinate, amino, amido, amidine group, imine group, cyano, nitro, azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate group, sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered heterocyclyl, aralkyl, aromatic group, and 5- to 10-membered heteroaromatic group. 42. A method of preparing a pharmaceutical agent, comprising preparing a compound of formula (I):
the preparing comprising treating, with a Pd(II) catalyst in an organic solvent,
(i) a compound of formula (II) or (III) or a salt thereof:
or
(ii) a compound of formula (IV) or (V) or a salt thereof:
and a compound of formula (X):
wherein the Pd(II) catalyst is used in an amount from about 0.01 mol % to about 3 mol % relative to the compound of formula (II), (III), (IV), or (V),
wherein, as valence and stability permit,
R1 represents hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (3- to 10-membered heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkoxy, amino, or halo;
R2, R3, R4, R5, R12, R13, R14, and R15 are independently selected for each occurrence from hydrogen, hydroxyl, halo, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate group, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, ether group, thioether group, ester group, amide, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, acylamino, aryl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl, 3- to 10-membered heterocyclyl, aralkyl, arylalkoxy, (5- to 10-membered heteroaryl)alkyl, (cycloalkyl)alkyl, and (3- to 10-membered heterocyclyl)alkyl;
W represents, as valence permits, —O—, —S—, —NR6—, —CR7R8—, —C(O)—, —CR7═, or —N═;
R6 represents hydrogen or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O) (5- to 10-membered heteroaryl), —C(O)-(5- to 10-membered heteroaryl)alkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(5- to 10-membered heteroaryl), —C(O)O-(5- to 10-membered heteroaryl)alkyl, —S(O)2(aryl), —S(O)2(alkyl), —S(O)2(haloalkyl), —OR10, —SR10, or —NR10R11;
R7 and R8 each independently represent hydrogen, hydroxyl, halo, nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, haloalkyl, ether group, thioether group, ester group, amido, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, or acylamino;
or R6, R7, and R8 taken together with a substituent on ring A and the intervening atoms, form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-membered heterocyclyl)alkenyl;
R10 and R11 are independently selected for each occurrence from hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, and alkynyl; and
ring A represents an optionally substituted cycloalkyl, 5- to 10-membered heterocyclyl, cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl,
wherein each heteroaryl or heterocyclyl comprises 1 to 4 heteroatoms selected from N, O, and S; and
wherein substituents on the alkyl, haloalkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkoxy, or amino are selected from halo, hydroxyl, carboxyl, alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group, thioformate group, alkoxy, phosphate group, phosphonate group, phosphinate, amino, amido, amidine group, imine group, cyano, nitro, azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate group, sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered heterocyclyl, aralkyl, aromatic group, and 5- to 10-membered heteroaromatic group. 43. A method comprising
(a) preparing a compound of formula (I):
the preparing comprising treating with a Pd(II) catalyst in an organic solvent,
(i) a compound of formula (II) or (III) or a salt thereof:
or
(ii) a compound of formula (IV) or (V) or a salt thereof:
and a compound of formula (X):
wherein the Pd(II) catalyst is used in an amount from about 0.01 mol % to about 3 mol % relative to the compound of formula (II), (III), (IV), or (V); and
(b) synthesizing a pharmaceutical agent from the compound of formula (I),
wherein, as valence and stability permit,
R1 represents hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (3- to 10-membered heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkoxy, amino, or halo;
R2, R3, R4, R5, R12, R13, R14, and R15 are independently selected for each occurrence from hydrogen, hydroxyl, halo, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate group, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, ether group, thioether group, ester group, amide, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, acylamino, aryl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl, 3- to 10-membered heterocyclyl, aralkyl, arylalkoxy, (5- to 10-membered heteroaryl)alkyl, (cycloalkyl)alkyl, and (3- to 10-membered heterocyclyl)alkyl;
W represents, as valence permits, —O—, —S—, —NR6—, —CR7R8—, —C(O)—, —CR7═, or —N═;
R6 represents hydrogen or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O) (5- to 10-membered heteroaryl), —C(O)-(5- to 10-membered heteroaryl)alkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(5- to 10-membered heteroaryl), —C(O)O-(5- to 10-membered heteroaryl)alkyl, —S(O)2(aryl), —S(O)2(alkyl), —S(O)2(haloalkyl), —OR10, —SR10, or —NR10R11;
R7 and R8 each independently represent hydrogen, hydroxyl, halo, nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, haloalkyl, ether group, thioether group, ester group, amido, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, or acylamino;
or R6, R7, and R8 taken together with a substituent on ring A and the intervening atoms, form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-membered heterocyclyl)alkenyl;
R10 and R11 are independently selected for each occurrence from hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, and alkynyl; and
ring A represents an optionally substituted cycloalkyl, 5- to 10-membered heterocyclyl, cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl,
wherein each heteroaryl or heterocyclyl comprises 1 to 4 heteroatoms selected from N, O, and S; and
wherein substituents on the alkyl, haloalkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkoxy, or amino are selected from halo, hydroxyl, carboxyl, alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group, thioformate group, alkoxy, phosphate group, phosphonate group, phosphinate, amino, amido, amidine group, imine group, cyano, nitro, azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate group, sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered heterocyclyl, aralkyl, aromatic group, and 5- to 10-membered heteroaromatic group. 44. The method of claim 43, wherein the compound of formula (I) is represented by formula (Ia):
and
the compound of formula (II) is represented by formula (IIa):
and
the compound of formula (III) is represented by formula (IIIa):
wherein:
B, D, and E independently for each occurrence represent, as valence permits, O, S, NR6, CR7R8, C(O), CR7, or N; provided that no two adjacent occurrences of W, B, D, and E are NR6, O, S, or N;
or any two occurrences of R6, R7, and R8 on adjacent W, B, D, or E groups, taken together with the intervening atoms, form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-membered heterocyclyl)alkenyl;
each occurrence of independently represents a double bond or a single bond as permitted by valence; and
m and n are integers each independently selected from 0, 1, and 2. 45. The method of claim 44, wherein the sum of m and n is 0, 1, 2, or 3. 46. The method of claim 44, wherein each occurrence of W, B, D, and E is each independently —CR7R8—, or —CR7—, or —C(O)—. 47. The method of claim 46, wherein one occurrence of W, B, D, and E is —CR7R8— or —C(O)—, and the remaining three are —CR7R8—;
optionally wherein R7 and R8, independently for each occurrence, are selected from hydrogen, hydroxyl, halo, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, and amido. 48. The method of claim 44, wherein at least two adjacent occurrences of W, B, D, and E are —CR7—. 49. The method of claim 48, wherein W and B are each —CR7— and m is 1;
optionally wherein R7 is independently selected for each occurrence from hydrogen, hydroxyl, halo, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl heteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl, amino, alkoxy, aryloxy, alkylamino, amido, and acylamino; or
the occurrence of R7 on W and the occurrence of R7 on B are taken together to form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl. 50. The method of claim 44, wherein at least one occurrence of W, B, D, and E is —NR6—. 51. The method of claim 50, wherein W is —NR6—; optionally wherein at least one occurrence of the remaining B, D, and E is —NR6— or O. 52. The method of claim 50, wherein R6 represents, independently for each occurrence, hydrogen or optionally substituted alkyl, aralkyl, (5- to 10-membered heteroaryl)alkyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), or —S(O)2(aryl). 53. The method of claim 44, wherein at least one occurrence of W, B, D, and E is —O—. 54. The method of claim 43, wherein W represents —O—, —S—, —NR6—, —CR7R8—, or —CR7═. 55. The method of claim 43, wherein R2, R3, R4, R5, R12, R13, R14, and R15 are each hydrogen. 56. The method of claim 43, wherein R1 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, or halo. 57. The method of claim 43, wherein the Pd(II) catalyst is selected from Pd(OC(O)R)2, Pd(OAc)2, PdCl2, Pd(PhCN)2Cl2, Pd(CH3CN)2Cl2, PdBr2, Pd(acac)2, [Pd(allyl)Cl]2, Pd(TFA)2, and pre-formed Pd(II)-ligand complex;
wherein Rc is optionally substituted alkyl, alkenyl, alkynyl, aryl, 5- to 10-membered heteroaryl, aralkyl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl, 5- to 10-membered heterocyclyl, (cycloalkyl)alkyl, or (5- to 10-membered heterocyclyl)alkyl. 58. The method of claim 43, wherein the Pd(II) catalyst is Pd(OAc)2. 59. The method of claim 43, wherein the Pd(II) catalyst is used in an amount from about 0.02 mol % to about 2.5 mol % relative to the compound of formula (II), (III), (IV), or (V). 60. The method of claim 43, wherein the Pd(II) catalyst further comprises a chiral ligand. 61. The method of claim 60, wherein the chiral ligand is used in an amount from about 0.1 mol % to about 100 mol % relative to the compound of formula (II), (III), (IV), or (V). 62. The method of claim 43, wherein the organic solvent is selected from methyl tert-butyl ether, toluene, and 2-methyltetrahydrofuran. 63. The method of claim 43, whereby the compound of formula (I) is enantioenriched. | This invention provides efficient and scalable enantioselective methods that yield 2-alkyl-2-allylcycloalkyanone compounds with quaternary stereogenic centers. Methods include the method for the preparation of a compound of formula (I):
comprising treating a compound of formula (II) or (III):
with a palladium (II) catalyst under alkylation conditions.1-40. (canceled) 41. A method for the preparation of a compound of formula (I):
the preparing comprising treating, with a Pd(II) catalyst in an organic solvent,
(i) a compound of formula (II) or (III) or a salt thereof:
or
(ii) a compound of formula (IV) or (V) or a salt thereof:
and a compound of formula (X):
wherein the Pd(II) catalyst is used in an amount from about 0.01 mol % to about 3 mol % relative to the compound of formula (II), (III), (IV), or (V),
wherein, as valence and stability permit,
R1 represents hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (3- to 10-membered heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkoxy, amino, or halo;
R2, R3, R4, R5, R12, R13, R14, and R15 are independently selected for each occurrence from hydrogen, hydroxyl, halo, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate group, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, ether group, thioether group, ester group, amide, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, acylamino, aryl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl, 3- to 10-membered heterocyclyl, aralkyl, arylalkoxy, (5- to 10-membered heteroaryl)alkyl, (cycloalkyl)alkyl, and (3- to 10-membered heterocyclyl)alkyl;
W represents, as valence permits, —O—, —S—, —NR6—, —CR7R8—, —C(O)—, —CR7═, or —N═;
R6 represents hydrogen or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O) (5- to 10-membered heteroaryl), —C(O)-(5- to 10-membered heteroaryl)alkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(5- to 10-membered heteroaryl), —C(O)O-(5- to 10-membered heteroaryl)alkyl, —S(O)2(aryl), —S(O)2(alkyl), —S(O)2(haloalkyl), —OR10, —SR10, or —NR10R11;
R7 and R8 each independently represent hydrogen, hydroxyl, halo, nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, haloalkyl, ether group, thioether group, ester group, amido, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, or acylamino;
or R6, R7, and R8 taken together with a substituent on ring A and the intervening atoms, form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-membered heterocyclyl)alkenyl;
R10 and R11 are independently selected for each occurrence from hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, and alkynyl; and
ring A represents an optionally substituted cycloalkyl, 5- to 10-membered heterocyclyl, cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl,
wherein each heteroaryl or heterocyclyl comprises 1 to 4 heteroatoms selected from N, O, and S; and
wherein substituents on the alkyl, haloalkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkoxy, or amino are selected from halo, hydroxyl, carboxyl, alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group, thioformate group, alkoxy, phosphate group, phosphonate group, phosphinate, amino, amido, amidine group, imine group, cyano, nitro, azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate group, sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered heterocyclyl, aralkyl, aromatic group, and 5- to 10-membered heteroaromatic group. 42. A method of preparing a pharmaceutical agent, comprising preparing a compound of formula (I):
the preparing comprising treating, with a Pd(II) catalyst in an organic solvent,
(i) a compound of formula (II) or (III) or a salt thereof:
or
(ii) a compound of formula (IV) or (V) or a salt thereof:
and a compound of formula (X):
wherein the Pd(II) catalyst is used in an amount from about 0.01 mol % to about 3 mol % relative to the compound of formula (II), (III), (IV), or (V),
wherein, as valence and stability permit,
R1 represents hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (3- to 10-membered heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkoxy, amino, or halo;
R2, R3, R4, R5, R12, R13, R14, and R15 are independently selected for each occurrence from hydrogen, hydroxyl, halo, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate group, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, ether group, thioether group, ester group, amide, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, acylamino, aryl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl, 3- to 10-membered heterocyclyl, aralkyl, arylalkoxy, (5- to 10-membered heteroaryl)alkyl, (cycloalkyl)alkyl, and (3- to 10-membered heterocyclyl)alkyl;
W represents, as valence permits, —O—, —S—, —NR6—, —CR7R8—, —C(O)—, —CR7═, or —N═;
R6 represents hydrogen or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O) (5- to 10-membered heteroaryl), —C(O)-(5- to 10-membered heteroaryl)alkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(5- to 10-membered heteroaryl), —C(O)O-(5- to 10-membered heteroaryl)alkyl, —S(O)2(aryl), —S(O)2(alkyl), —S(O)2(haloalkyl), —OR10, —SR10, or —NR10R11;
R7 and R8 each independently represent hydrogen, hydroxyl, halo, nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, haloalkyl, ether group, thioether group, ester group, amido, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, or acylamino;
or R6, R7, and R8 taken together with a substituent on ring A and the intervening atoms, form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-membered heterocyclyl)alkenyl;
R10 and R11 are independently selected for each occurrence from hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, and alkynyl; and
ring A represents an optionally substituted cycloalkyl, 5- to 10-membered heterocyclyl, cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl,
wherein each heteroaryl or heterocyclyl comprises 1 to 4 heteroatoms selected from N, O, and S; and
wherein substituents on the alkyl, haloalkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkoxy, or amino are selected from halo, hydroxyl, carboxyl, alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group, thioformate group, alkoxy, phosphate group, phosphonate group, phosphinate, amino, amido, amidine group, imine group, cyano, nitro, azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate group, sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered heterocyclyl, aralkyl, aromatic group, and 5- to 10-membered heteroaromatic group. 43. A method comprising
(a) preparing a compound of formula (I):
the preparing comprising treating with a Pd(II) catalyst in an organic solvent,
(i) a compound of formula (II) or (III) or a salt thereof:
or
(ii) a compound of formula (IV) or (V) or a salt thereof:
and a compound of formula (X):
wherein the Pd(II) catalyst is used in an amount from about 0.01 mol % to about 3 mol % relative to the compound of formula (II), (III), (IV), or (V); and
(b) synthesizing a pharmaceutical agent from the compound of formula (I),
wherein, as valence and stability permit,
R1 represents hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (3- to 10-membered heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkoxy, amino, or halo;
R2, R3, R4, R5, R12, R13, R14, and R15 are independently selected for each occurrence from hydrogen, hydroxyl, halo, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate group, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, ether group, thioether group, ester group, amide, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, acylamino, aryl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl, 3- to 10-membered heterocyclyl, aralkyl, arylalkoxy, (5- to 10-membered heteroaryl)alkyl, (cycloalkyl)alkyl, and (3- to 10-membered heterocyclyl)alkyl;
W represents, as valence permits, —O—, —S—, —NR6—, —CR7R8—, —C(O)—, —CR7═, or —N═;
R6 represents hydrogen or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O) (5- to 10-membered heteroaryl), —C(O)-(5- to 10-membered heteroaryl)alkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(5- to 10-membered heteroaryl), —C(O)O-(5- to 10-membered heteroaryl)alkyl, —S(O)2(aryl), —S(O)2(alkyl), —S(O)2(haloalkyl), —OR10, —SR10, or —NR10R11;
R7 and R8 each independently represent hydrogen, hydroxyl, halo, nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, haloalkyl, ether group, thioether group, ester group, amido, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, or acylamino;
or R6, R7, and R8 taken together with a substituent on ring A and the intervening atoms, form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-membered heterocyclyl)alkenyl;
R10 and R11 are independently selected for each occurrence from hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, and alkynyl; and
ring A represents an optionally substituted cycloalkyl, 5- to 10-membered heterocyclyl, cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl,
wherein each heteroaryl or heterocyclyl comprises 1 to 4 heteroatoms selected from N, O, and S; and
wherein substituents on the alkyl, haloalkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkoxy, or amino are selected from halo, hydroxyl, carboxyl, alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group, thioformate group, alkoxy, phosphate group, phosphonate group, phosphinate, amino, amido, amidine group, imine group, cyano, nitro, azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate group, sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered heterocyclyl, aralkyl, aromatic group, and 5- to 10-membered heteroaromatic group. 44. The method of claim 43, wherein the compound of formula (I) is represented by formula (Ia):
and
the compound of formula (II) is represented by formula (IIa):
and
the compound of formula (III) is represented by formula (IIIa):
wherein:
B, D, and E independently for each occurrence represent, as valence permits, O, S, NR6, CR7R8, C(O), CR7, or N; provided that no two adjacent occurrences of W, B, D, and E are NR6, O, S, or N;
or any two occurrences of R6, R7, and R8 on adjacent W, B, D, or E groups, taken together with the intervening atoms, form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-membered heterocyclyl)alkenyl;
each occurrence of independently represents a double bond or a single bond as permitted by valence; and
m and n are integers each independently selected from 0, 1, and 2. 45. The method of claim 44, wherein the sum of m and n is 0, 1, 2, or 3. 46. The method of claim 44, wherein each occurrence of W, B, D, and E is each independently —CR7R8—, or —CR7—, or —C(O)—. 47. The method of claim 46, wherein one occurrence of W, B, D, and E is —CR7R8— or —C(O)—, and the remaining three are —CR7R8—;
optionally wherein R7 and R8, independently for each occurrence, are selected from hydrogen, hydroxyl, halo, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, and amido. 48. The method of claim 44, wherein at least two adjacent occurrences of W, B, D, and E are —CR7—. 49. The method of claim 48, wherein W and B are each —CR7— and m is 1;
optionally wherein R7 is independently selected for each occurrence from hydrogen, hydroxyl, halo, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl heteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl, amino, alkoxy, aryloxy, alkylamino, amido, and acylamino; or
the occurrence of R7 on W and the occurrence of R7 on B are taken together to form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl. 50. The method of claim 44, wherein at least one occurrence of W, B, D, and E is —NR6—. 51. The method of claim 50, wherein W is —NR6—; optionally wherein at least one occurrence of the remaining B, D, and E is —NR6— or O. 52. The method of claim 50, wherein R6 represents, independently for each occurrence, hydrogen or optionally substituted alkyl, aralkyl, (5- to 10-membered heteroaryl)alkyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), or —S(O)2(aryl). 53. The method of claim 44, wherein at least one occurrence of W, B, D, and E is —O—. 54. The method of claim 43, wherein W represents —O—, —S—, —NR6—, —CR7R8—, or —CR7═. 55. The method of claim 43, wherein R2, R3, R4, R5, R12, R13, R14, and R15 are each hydrogen. 56. The method of claim 43, wherein R1 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, or halo. 57. The method of claim 43, wherein the Pd(II) catalyst is selected from Pd(OC(O)R)2, Pd(OAc)2, PdCl2, Pd(PhCN)2Cl2, Pd(CH3CN)2Cl2, PdBr2, Pd(acac)2, [Pd(allyl)Cl]2, Pd(TFA)2, and pre-formed Pd(II)-ligand complex;
wherein Rc is optionally substituted alkyl, alkenyl, alkynyl, aryl, 5- to 10-membered heteroaryl, aralkyl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl, 5- to 10-membered heterocyclyl, (cycloalkyl)alkyl, or (5- to 10-membered heterocyclyl)alkyl. 58. The method of claim 43, wherein the Pd(II) catalyst is Pd(OAc)2. 59. The method of claim 43, wherein the Pd(II) catalyst is used in an amount from about 0.02 mol % to about 2.5 mol % relative to the compound of formula (II), (III), (IV), or (V). 60. The method of claim 43, wherein the Pd(II) catalyst further comprises a chiral ligand. 61. The method of claim 60, wherein the chiral ligand is used in an amount from about 0.1 mol % to about 100 mol % relative to the compound of formula (II), (III), (IV), or (V). 62. The method of claim 43, wherein the organic solvent is selected from methyl tert-butyl ether, toluene, and 2-methyltetrahydrofuran. 63. The method of claim 43, whereby the compound of formula (I) is enantioenriched. | 1,600 |
472 | 14,563,866 | 1,633 | Methods are provided herein for modifying antigenic carbohydrate epitopes within a xenographic bioprosthetic tissue by oxidation of vicinal diols to form aldehydes or acids and subsequence reductive amination of aldehydes to form stable secondary amines, or amidation or esterification of acids to form stable amides or esters. Advantageously, methods provided herein mitigate the antigenicity of the bioprosthetic tissue while leaving the overall tissue structure substantially undisturbed, and thereby enhance the durability, safety and performance of the bioprosthetic implant. | 1. A method for improving the performance of a bioprosthetic implant, the method comprising:
treating a bioprosthetic tissue with an oxidizing agent that selectively oxidizes antigenic carbohydrates having vicinal diols to produce free aldehyde or acid moieties on the antigenic carbohydrate. 2. The method of claim 1, further comprising fixing the bioprosthetic tissue with a fixation agent before treating the bioprosthetic tissue with the oxidizing agent. 3. The method of claim 2, wherein the fixation agent is selected from the group consisting of: an aldehyde, a formaldehyde, a dialdehyde, a glutaraldehyde, a polyaldehyde, a diisocyanate, a hexamethylene diisocyanate, a diacid, a diamine with a carbodiimide, a 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC), a dipeoxy, and combinations thereof. 4. The method of claim 1, further comprising treating the bioprosthetic tissue with a bioburden reduction solution before treating the bioprosthetic tissue with the oxidizing agent. 5. The method of claim 4, wherein the bioburden reduction solution comprises formaldehyde. 6. The method of claim 1, further comprising treating the bioprosthetic tissue with a capping agent after treating the bioprosthetic tissue with the oxidizing agent. 7. The method of claim 6, wherein the capping agent blocks, removes or alters a functional group that would have an adverse effect on the bioprosthesis properties. 8. The method of claim 7, wherein the capping agent is a primary amine or an alcohol which combines with the aldehyde or acid to form an imine, amide or ester. 9. The method of claim 7, wherein the capping agent is selected from the group consisting of: an ethanolamine, a taurine, an amino sulfate, a dextran sulfate, a chrondroitin sulfate, a polyvinyl alcohol, a polyethyleneimine, an alpha-dicarbonyl, an amino acid, a glycine, a lysine, an alkoxy alkyl amine, a 2-methoxyethylamine, an alkyl amine, a hydroxylamine, an aminoether, an amino sulfonate, an ethylamine, a propylamine, a N-hydroxysuccinamide (NHS), a N-hydroxysulfosuccinamide (NHSS), a hydrazide, an oxirane, and combinations thereof. 10. The method of claim 1, further comprising treating the bioprosthetic tissue with a stabilizing agent. 11. The method of claim 10, wherein the stabilizing agent reacts with the free aldehyde or acids or is a reducing agent. 12. The method of claim 10, wherein the stabilizing agent is one or more selected from the group consisting of: a sodium borohydride, a sodium cyanoborohydride, a lithium aluminum hydride, a carbodiimide, a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), a pyridine, a 2-chloro 1-methylpyridinium iodide (CMPI), and a Mukaiyama condensation reagent. 13. The method of claim 1, wherein the oxidizing agent is a periodate or acetate. 14. The method of claim 13, wherein the periodate is a sodium periodate. 15. The method of claim 1, further comprising treating the tissue with a secondary oxidizing agent to convert the aldehydes to acids. 16. The method of claim 15, wherein the secondary oxidizing agent is a sodium chlorite or hydrogen peroxide. 17. The method of claim 16, further comprising capping the acids with a capping agent to form an ester, the capping agent being selected from the group consisting of N-hydroxysuccinamide and N-hydroxysulfosuccinamide. 18. The method of claim 17, further comprising treating the tissue with a carbodiimide stabilizing agent to convert the ester to an amide. 19. The method of claim 18, wherein the carbodiimide stabilizing agent is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). 20. The method of claim 1, further comprising decellularizing the bioprosthetic tissue before treating the bioprosthetic tissue with the oxidizing agent. | Methods are provided herein for modifying antigenic carbohydrate epitopes within a xenographic bioprosthetic tissue by oxidation of vicinal diols to form aldehydes or acids and subsequence reductive amination of aldehydes to form stable secondary amines, or amidation or esterification of acids to form stable amides or esters. Advantageously, methods provided herein mitigate the antigenicity of the bioprosthetic tissue while leaving the overall tissue structure substantially undisturbed, and thereby enhance the durability, safety and performance of the bioprosthetic implant.1. A method for improving the performance of a bioprosthetic implant, the method comprising:
treating a bioprosthetic tissue with an oxidizing agent that selectively oxidizes antigenic carbohydrates having vicinal diols to produce free aldehyde or acid moieties on the antigenic carbohydrate. 2. The method of claim 1, further comprising fixing the bioprosthetic tissue with a fixation agent before treating the bioprosthetic tissue with the oxidizing agent. 3. The method of claim 2, wherein the fixation agent is selected from the group consisting of: an aldehyde, a formaldehyde, a dialdehyde, a glutaraldehyde, a polyaldehyde, a diisocyanate, a hexamethylene diisocyanate, a diacid, a diamine with a carbodiimide, a 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC), a dipeoxy, and combinations thereof. 4. The method of claim 1, further comprising treating the bioprosthetic tissue with a bioburden reduction solution before treating the bioprosthetic tissue with the oxidizing agent. 5. The method of claim 4, wherein the bioburden reduction solution comprises formaldehyde. 6. The method of claim 1, further comprising treating the bioprosthetic tissue with a capping agent after treating the bioprosthetic tissue with the oxidizing agent. 7. The method of claim 6, wherein the capping agent blocks, removes or alters a functional group that would have an adverse effect on the bioprosthesis properties. 8. The method of claim 7, wherein the capping agent is a primary amine or an alcohol which combines with the aldehyde or acid to form an imine, amide or ester. 9. The method of claim 7, wherein the capping agent is selected from the group consisting of: an ethanolamine, a taurine, an amino sulfate, a dextran sulfate, a chrondroitin sulfate, a polyvinyl alcohol, a polyethyleneimine, an alpha-dicarbonyl, an amino acid, a glycine, a lysine, an alkoxy alkyl amine, a 2-methoxyethylamine, an alkyl amine, a hydroxylamine, an aminoether, an amino sulfonate, an ethylamine, a propylamine, a N-hydroxysuccinamide (NHS), a N-hydroxysulfosuccinamide (NHSS), a hydrazide, an oxirane, and combinations thereof. 10. The method of claim 1, further comprising treating the bioprosthetic tissue with a stabilizing agent. 11. The method of claim 10, wherein the stabilizing agent reacts with the free aldehyde or acids or is a reducing agent. 12. The method of claim 10, wherein the stabilizing agent is one or more selected from the group consisting of: a sodium borohydride, a sodium cyanoborohydride, a lithium aluminum hydride, a carbodiimide, a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), a pyridine, a 2-chloro 1-methylpyridinium iodide (CMPI), and a Mukaiyama condensation reagent. 13. The method of claim 1, wherein the oxidizing agent is a periodate or acetate. 14. The method of claim 13, wherein the periodate is a sodium periodate. 15. The method of claim 1, further comprising treating the tissue with a secondary oxidizing agent to convert the aldehydes to acids. 16. The method of claim 15, wherein the secondary oxidizing agent is a sodium chlorite or hydrogen peroxide. 17. The method of claim 16, further comprising capping the acids with a capping agent to form an ester, the capping agent being selected from the group consisting of N-hydroxysuccinamide and N-hydroxysulfosuccinamide. 18. The method of claim 17, further comprising treating the tissue with a carbodiimide stabilizing agent to convert the ester to an amide. 19. The method of claim 18, wherein the carbodiimide stabilizing agent is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). 20. The method of claim 1, further comprising decellularizing the bioprosthetic tissue before treating the bioprosthetic tissue with the oxidizing agent. | 1,600 |
473 | 13,645,595 | 1,612 | A pharmaceutical dosage form for oral administration having a breaking strength of at least 300 N and comprising an opioid agonist, an opioid antagonist, and a polyalkylene oxide having an average molecular weight of at least 200,000 g/mol, wherein in accordance with Ph. Eur. the in vitro release profile of the opioid agonist essentially corresponds to the in vitro release profile of the opioid antagonist, and wherein the opioid agonist and the opioid antagonist are intimately mixed with one another and homogeneously dispersed in the polyalkylene oxide. The pharmaceutical dosage form is useful, for example, to treat pain in a patient in need of such treatment. | 1. A pharmaceutical dosage form for oral administration having a breaking strength of at least 300 N and comprising an opioid agonist, an opioid antagonist, and a polyalkylene oxide having an average molecular weight of at least 200,000 g/mol, wherein in accordance with Ph. Eur. the in vitro release profile of the opioid agonist essentially corresponds to the in vitro release profile of the opioid antagonist, and wherein the opioid agonist and the opioid antagonist are intimately mixed with one another and homogeneously dispersed in the polyalkylene oxide 2. The pharmaceutical dosage form according to claim 1, wherein at every point in time the in vitro release profile of the opioid agonist does not deviate by more than 10% from the in vitro release profile of the opioid antagonist. 3. The pharmaceutical dosage form according to claim 1, wherein the opioid agonist and the opioid antagonist are homogeneously distributed over the pharmaceutical dosage form or, when the pharmaceutical dosage form comprises a film coating, over the coated core of the pharmaceutical dosage form. 4. The pharmaceutical dosage form according to claim 1, wherein the opioid agonist and the opioid antagonist are embedded in a prolonged release matrix comprising the polyalkylene oxide. 5. The pharmaceutical dosage form according to claim 4, wherein the prolonged release matrix comprises an additional matrix polymer. 6. The pharmaceutical dosage form according to claim 1, which is configured for administration once daily or twice daily. 7. The pharmaceutical dosage form according to claim 1, which is monolithic. 8. The pharmaceutical dosage form according to claim 1, wherein the content of the polyalkylene oxide is at least 30 wt.-%, based on the total weight of the pharmaceutical dosage form. 9. The pharmaceutical dosage form according to claim 1, which is thermoformed. 10. The pharmaceutical dosage form according to claim 9, which is hot-melt extruded. 11. The pharmaceutical dosage form according to claim 1, which is tamper-resistant. 12. The pharmaceutical dosage form according to claim 1, wherein the opioid agonist is oxycodone or a physiologically acceptable salt thereof. 13. The pharmaceutical dosage form according to claim 1, wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, cyclazacine, levallorphan, pharmaceutically acceptable salts thereof and mixtures thereof. 14. The pharmaceutical dosage form according to claim 1, which contains a plasticizer. 15. The pharmaceutical dosage form according to claim 1, which contains an antioxidant. 16. A method of treating pain in a patient in need thereof, said method comprising administering to said patient a pharmaceutical dosage form according to claim 1. | A pharmaceutical dosage form for oral administration having a breaking strength of at least 300 N and comprising an opioid agonist, an opioid antagonist, and a polyalkylene oxide having an average molecular weight of at least 200,000 g/mol, wherein in accordance with Ph. Eur. the in vitro release profile of the opioid agonist essentially corresponds to the in vitro release profile of the opioid antagonist, and wherein the opioid agonist and the opioid antagonist are intimately mixed with one another and homogeneously dispersed in the polyalkylene oxide. The pharmaceutical dosage form is useful, for example, to treat pain in a patient in need of such treatment.1. A pharmaceutical dosage form for oral administration having a breaking strength of at least 300 N and comprising an opioid agonist, an opioid antagonist, and a polyalkylene oxide having an average molecular weight of at least 200,000 g/mol, wherein in accordance with Ph. Eur. the in vitro release profile of the opioid agonist essentially corresponds to the in vitro release profile of the opioid antagonist, and wherein the opioid agonist and the opioid antagonist are intimately mixed with one another and homogeneously dispersed in the polyalkylene oxide 2. The pharmaceutical dosage form according to claim 1, wherein at every point in time the in vitro release profile of the opioid agonist does not deviate by more than 10% from the in vitro release profile of the opioid antagonist. 3. The pharmaceutical dosage form according to claim 1, wherein the opioid agonist and the opioid antagonist are homogeneously distributed over the pharmaceutical dosage form or, when the pharmaceutical dosage form comprises a film coating, over the coated core of the pharmaceutical dosage form. 4. The pharmaceutical dosage form according to claim 1, wherein the opioid agonist and the opioid antagonist are embedded in a prolonged release matrix comprising the polyalkylene oxide. 5. The pharmaceutical dosage form according to claim 4, wherein the prolonged release matrix comprises an additional matrix polymer. 6. The pharmaceutical dosage form according to claim 1, which is configured for administration once daily or twice daily. 7. The pharmaceutical dosage form according to claim 1, which is monolithic. 8. The pharmaceutical dosage form according to claim 1, wherein the content of the polyalkylene oxide is at least 30 wt.-%, based on the total weight of the pharmaceutical dosage form. 9. The pharmaceutical dosage form according to claim 1, which is thermoformed. 10. The pharmaceutical dosage form according to claim 9, which is hot-melt extruded. 11. The pharmaceutical dosage form according to claim 1, which is tamper-resistant. 12. The pharmaceutical dosage form according to claim 1, wherein the opioid agonist is oxycodone or a physiologically acceptable salt thereof. 13. The pharmaceutical dosage form according to claim 1, wherein the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, cyclazacine, levallorphan, pharmaceutically acceptable salts thereof and mixtures thereof. 14. The pharmaceutical dosage form according to claim 1, which contains a plasticizer. 15. The pharmaceutical dosage form according to claim 1, which contains an antioxidant. 16. A method of treating pain in a patient in need thereof, said method comprising administering to said patient a pharmaceutical dosage form according to claim 1. | 1,600 |
474 | 13,982,470 | 1,631 | The present invention relates to a method of discovering pharmacogenomic biomarkers that are correlated with varied individual responses (efficacy, adverse effect, and other end points) to therapeutic agents. The present invention provides a mean to utilize archived clinical samples to perform genome-wide association study in order to identify novel pharmacogenomic biomarkers. The newly discovered biomarkers can then be developed into companion diagnostic tests which can help to predict drug responses and apply drugs only to those who will be benefited, or exclude those who might have adverse effects, by the treatment. | 1. A method to identify one or more pharmacogenomic biomarkers, which method comprises:
a) isolating DNA from archived clinical samples of at least two patients exhibiting different values in a relevant phenotype; b) amplifying said isolated DNA; c) obtaining high-density genotyping data of said amplified DNA; and d) performing association analysis based on said genotyping data and said different values in said relevant phenotype, wherein said pharmacogenomic biomarker(s) are identified. 2. The method of claim 1, wherein the archived clinical samples are selected from the group consisting of plasma samples, serum samples, dried blood spots, urine samples, tissue samples, tumor cells and buccal swabs. 3. The method of claim 2, wherein the archived clinical samples are plasma samples. 4. The method of claim 1, wherein the isolated DNA is suboptimal genomic DNA. 5. The method of claim 1, wherein the amplification is whole-genome amplification (WGA), and the resulting DNA is whole-genome amplified DNA (wgaDNA). 6. The method of claim 1, wherein the high-density genotyping is whole-genome genotyping. 7. The method of claim 1, wherein the high-density genotyping is by using single nucleotide polymorphisms (SNPs). 8-9. (canceled) 10. The method of claim 1, wherein the high-density genotyping is array based, bead based, or high-throughput sequencing based. 11. (canceled) 12. The method of claim 1, wherein the genotyping data is obtained by using a genome-wide genotype calling algorithm, further comprising:
e) adjusting the call rate cut-off value of the genome-wide genotype calling algorithm. 13-14. (canceled) 15. The method of claim 12, wherein the genotype calls are made by using a call rate cut-off that is lower than a typical call rate cut-off used for whole-genome genotyping of high quality genomic DNA. 16. The method of claim 12, wherein the call rate cut-off used is about 50-95%. 17-29. (canceled) 30. The method of claim 1, further comprising performing association analysis based on additional genotyping data using the identified pharmacogenomic biomarkers, wherein some or all of the archived clinical samples from step a) and/or additional clinical samples are used for the additional genotyping. 31-34. (canceled) 35. The method of claim 30, further comprising comparing the additional genotyping data obtained by using the verification genotype calling algorithm to the genotyping data obtained by using the genome-wide genotype calling algorithm. 36. The method of claim 30, wherein a subset of the pharmacogenomic biomarkers from step d) is identified, wherein the method is used for retrospective study of archived clinical samples from a previously conducted clinical trial. 37-42. (canceled) 43. A pharmacogenomic biomarker identified by the method of claim 36, for use to develop a companion diagnostic test. 44. A companion diagnostic test using a pharmacogenomic biomarker identified by the method of claim 36. 45-49. (canceled) 50. A genotyping method using suboptimal genomic DNA samples, which method comprises:
a) receiving sequence information of said suboptimal genomic DNA samples; b) optimizing an inclusion criterion based on said sequence information; and c) calculating genotypes based on said sequence information and said optimized inclusion criterion. 51. The method of claim 50, wherein the optimization is repeated multiple times to include and/or exclude samples. 52-62. (canceled) 63. A computer readable medium comprising a plurality of instructions for a genotyping method using suboptimal genomic DNA samples, which comprises the steps of:
a) receiving sequence information of said suboptimal genomic DNA samples; b) optimizing an inclusion criterion based on said sequence information using the method of claim 50; and c) calculating genotypes based on said sequence information and said optimized inclusion criterion. 64. A method to conduct GWAS using suboptimal genomic DNA. 65-72. (canceled) | The present invention relates to a method of discovering pharmacogenomic biomarkers that are correlated with varied individual responses (efficacy, adverse effect, and other end points) to therapeutic agents. The present invention provides a mean to utilize archived clinical samples to perform genome-wide association study in order to identify novel pharmacogenomic biomarkers. The newly discovered biomarkers can then be developed into companion diagnostic tests which can help to predict drug responses and apply drugs only to those who will be benefited, or exclude those who might have adverse effects, by the treatment.1. A method to identify one or more pharmacogenomic biomarkers, which method comprises:
a) isolating DNA from archived clinical samples of at least two patients exhibiting different values in a relevant phenotype; b) amplifying said isolated DNA; c) obtaining high-density genotyping data of said amplified DNA; and d) performing association analysis based on said genotyping data and said different values in said relevant phenotype, wherein said pharmacogenomic biomarker(s) are identified. 2. The method of claim 1, wherein the archived clinical samples are selected from the group consisting of plasma samples, serum samples, dried blood spots, urine samples, tissue samples, tumor cells and buccal swabs. 3. The method of claim 2, wherein the archived clinical samples are plasma samples. 4. The method of claim 1, wherein the isolated DNA is suboptimal genomic DNA. 5. The method of claim 1, wherein the amplification is whole-genome amplification (WGA), and the resulting DNA is whole-genome amplified DNA (wgaDNA). 6. The method of claim 1, wherein the high-density genotyping is whole-genome genotyping. 7. The method of claim 1, wherein the high-density genotyping is by using single nucleotide polymorphisms (SNPs). 8-9. (canceled) 10. The method of claim 1, wherein the high-density genotyping is array based, bead based, or high-throughput sequencing based. 11. (canceled) 12. The method of claim 1, wherein the genotyping data is obtained by using a genome-wide genotype calling algorithm, further comprising:
e) adjusting the call rate cut-off value of the genome-wide genotype calling algorithm. 13-14. (canceled) 15. The method of claim 12, wherein the genotype calls are made by using a call rate cut-off that is lower than a typical call rate cut-off used for whole-genome genotyping of high quality genomic DNA. 16. The method of claim 12, wherein the call rate cut-off used is about 50-95%. 17-29. (canceled) 30. The method of claim 1, further comprising performing association analysis based on additional genotyping data using the identified pharmacogenomic biomarkers, wherein some or all of the archived clinical samples from step a) and/or additional clinical samples are used for the additional genotyping. 31-34. (canceled) 35. The method of claim 30, further comprising comparing the additional genotyping data obtained by using the verification genotype calling algorithm to the genotyping data obtained by using the genome-wide genotype calling algorithm. 36. The method of claim 30, wherein a subset of the pharmacogenomic biomarkers from step d) is identified, wherein the method is used for retrospective study of archived clinical samples from a previously conducted clinical trial. 37-42. (canceled) 43. A pharmacogenomic biomarker identified by the method of claim 36, for use to develop a companion diagnostic test. 44. A companion diagnostic test using a pharmacogenomic biomarker identified by the method of claim 36. 45-49. (canceled) 50. A genotyping method using suboptimal genomic DNA samples, which method comprises:
a) receiving sequence information of said suboptimal genomic DNA samples; b) optimizing an inclusion criterion based on said sequence information; and c) calculating genotypes based on said sequence information and said optimized inclusion criterion. 51. The method of claim 50, wherein the optimization is repeated multiple times to include and/or exclude samples. 52-62. (canceled) 63. A computer readable medium comprising a plurality of instructions for a genotyping method using suboptimal genomic DNA samples, which comprises the steps of:
a) receiving sequence information of said suboptimal genomic DNA samples; b) optimizing an inclusion criterion based on said sequence information using the method of claim 50; and c) calculating genotypes based on said sequence information and said optimized inclusion criterion. 64. A method to conduct GWAS using suboptimal genomic DNA. 65-72. (canceled) | 1,600 |
475 | 14,938,663 | 1,616 | This invention relates to a “high lower alcohol content”(>40% v/v of a C 1-4 alcohol) liquid composition able to be dispensed as a stable foam with the use of non-propellant foam dispensing devices from non-pressurized containers. The liquid compositions comprise an alcohol, C 1-4 (>40% v/v), a silicone-based surfactant of at least 0.001% by weight to prepare a foamable composition, 0-10% w/w of additional minor components added to obtain the desired performance (a foamable composition), and the balance being purified water. The compositions may include emulsifier-emollients and mosturizers, secondary surfactants, foam stabilizers, fragrances, antimicrobial agents, other type of medicinal ingredients, and the like ingredients or additives or combinations thereof commonly added to alcohol gels or foams, aerosol compositions or to toiletries, cosmetics, pharmaceuticals and the like. | 1. A foamable alcohol composition, comprising;
a) at least one C1-4 alcohol, or mixtures thereof, present in an amount greater than about 40% v/v of the total composition; b) at least one effective physiologically acceptable silicone-based surface active agent, which includes a lipophilic chain containing a silicone backbone, for foaming present in an amount of at least 0.01% by weight of the total composition; and c) water present in an amount to balance the total composition to 100% by weight. 2. The composition according to claim 1 wherein the composition is foamable when mixed with air at low pressure, wherein when the composition is mixed with air, the mixture of the composition and air forms a foam. 3. The composition according to claim 1 wherein the effective silicone-based surface active agent for foaming is physiologically compatible, and wherein the silicone-based surfactant is selected from the group consisting of silicone ethoxylates, silicone glycerol esters, silicone amine oxides, silicone acetylenic alcohol derivatives, silicone carboxylates, silicone sulphates, silicone phosphates, silicone imidazole quats, silicone amino quats, silicone phosphate esters, silicone carbohydrate derivatives, silicone isethionates, silicone sulfonates, silicone betaines, silicone alkyl quats, silicone amino propionates, silicone esters, silicone polyamides, and silicone hydrocarbon surfactants. 4. The composition according to claim 1, wherein the effective silicone-based surface active agent is a physiologically acceptable silicone-based surface active agent selected from the group consisting of Bis-PEG-[10-20]dimethicones, 3-(3-Hydroxypropyl)-heptamethyltrisiloxane, ethoxylated, acetate, polyether-modified polysiloxanes, polysiloxane betaine and mixtures thereof from about 0.01% to about 10.0% by weight percept of the total composition. 5. (canceled) 6. The composition according to claim 1, wherein the silicone-based surface active agent is selected from the group consisting of PEG-8 dimethicone PEG-17 dimethicone, Bis-PEG-12 dimethicone, Bis-PEG-17 dimethicone, Bis-PEG/PPG 18/6 dimethicone Bis-PEG/PPG 15/15 dimethicom, Bis-PEG-20 dimethicone and combinations thereof. 7. (canceled) 8. The composition according to claim 1, wherein the silicone-based surfactant is a polyether-modified polysiloxane. 9-16. (canceled) 17. The composition according to claim 1, further including at least one additional surfactant for adjusting properties of the foam produced from the composition. 18. The composition according to claim 17 wherein the additional surfactant is selected from the group consisting of alkylglucosides, a poly(ethoxylated and/or propoxylated)alcohol, a poly(ethoxylated and/or propoxylated)ester, an alkyl alcohol, an alkenyl alcohol, an ester of a polyhydric alcohol, an ether of a polyhydric alcohol, an ester of a polyalkoxylated polyhydric alcohol, an ether of a polyalkoxylated polyhydric alcohol, a sorbitan fatty acid ester, a polyalkoxylated sorbitan fatty acid ester, a betaine, a sulfobetaine, an imidazoline, an amino acid, a lecithin, a phosphatide, an amine oxide, a sulfoxide and mixtures thereof. 19. The composition according to claim 18 wherein the additional surfactant is a betaine. 20. The composition according to claim 19 wherein the additional surfactant is an alkylglucoside. 21-26. (canceled) 27. The composition according to claim 1 further including a foam stabilizing agent present in an amount up to about 10% by weight of the total composition. 28. The composition according to claim 27 wherein the foam stabilizing agent is selected from the group consisting of
lactic acid esters of monoglycerides,
cationic emulsifiers,
quaternary ammonium compounds,
triquatemized stearic phospholipid complex,
hydroxystearamide propyltriamine salts,
lactic acid monoglycerides,
food emulsifiers selected from the group consisting of glyceryl monostearate, propylene glycol monostearate, and sodium stearoyl lactylate, cetyl betaine,
glycolether,
n-propanol,
butyleneglycol,
silicone wax,
an encapsulated oil,
Microcapsule Mineral Oil,
and combinations thereof. 29. The composition according to claim 27 wherein the foam stabilizing agent is selected from the group consisting of glycolether, glycerine, butyleneglycol, behentrimonium chloride, or cetrimonium chloride and combinations thereof. 30. The composition according to claim 1 further including one or more moisturizers, emollients, lipid layer enhancers or combinations thereof selected from the group consisting of
lanolin,
vinyl alcohol,
polyvinyl pyrrolidone, and
polyols selected from the group consisting of glycerol, propylene glycol, butyleneglycol, glyceryl oleate and sorbitol,
cocoglucoside,
a fatty alcohol selected from the group consisting of cetyl alcohol, stearyl alcohol, lauryl alcohol, myristyl alcohol and palmityl alcohol,
ceteareth 20,
an alkylgiucoside,
mixtures of alkylglucoside and glyceryl oleate,
PEG-200 Hydrogentated Glyceryl palmate,
dihydroxypropyl PEG-5 linoleammonium chloride,
PEG-7 glyceryl cocoate,
and combinations thereof, present in an amount up to about 5% by weight of the total composition. 31. The composition according to claim 1 further comprising an acid or a base to adjust a pH of the composition to a preselected pH present in an amount from about 0.05 to about 0.5 by weight of the total composition. 32. (canceled) 33. The composition according to claim 1 further including a preservative in an amount from about 0.01 to about 5% weight percent of the total composition. 34. The composition according to claim 1 including an antimicrobial agent. 35. The composition according to claim 34 wherein the antimicrobial agent is selected from the group of chlorhexidine salts, iodine, complexed forms of iodine, parachlorometaxylenol, triclosan, hexachlorophene, a phenol, a surfactant having a long chain hydrophobic group and a quaternary group, hydrogen peroxide, silver, a silver salt, silver oxide, behenyl alcohol, and mixtures thereof. 36-39. (canceled) 40. The composition claim 1 further comprising constituents selected from the group consisting of organic gums and colloids, lower alkanolamides of higher fatty acids, short chain dials and/or triols, fragrance, coloring matter, ultraviolet absorbers, solvents, suspending agents, buffers, conditioning agents, antioxidants, bactericides and medicinally active ingredients, and combinations thereof. 41. The composition according to claim 1 stored in an unpressurized dispenser having a dispenser pump for mixing the composition with air and dispensing foam therefrom. 42-87. (canceled) | This invention relates to a “high lower alcohol content”(>40% v/v of a C 1-4 alcohol) liquid composition able to be dispensed as a stable foam with the use of non-propellant foam dispensing devices from non-pressurized containers. The liquid compositions comprise an alcohol, C 1-4 (>40% v/v), a silicone-based surfactant of at least 0.001% by weight to prepare a foamable composition, 0-10% w/w of additional minor components added to obtain the desired performance (a foamable composition), and the balance being purified water. The compositions may include emulsifier-emollients and mosturizers, secondary surfactants, foam stabilizers, fragrances, antimicrobial agents, other type of medicinal ingredients, and the like ingredients or additives or combinations thereof commonly added to alcohol gels or foams, aerosol compositions or to toiletries, cosmetics, pharmaceuticals and the like.1. A foamable alcohol composition, comprising;
a) at least one C1-4 alcohol, or mixtures thereof, present in an amount greater than about 40% v/v of the total composition; b) at least one effective physiologically acceptable silicone-based surface active agent, which includes a lipophilic chain containing a silicone backbone, for foaming present in an amount of at least 0.01% by weight of the total composition; and c) water present in an amount to balance the total composition to 100% by weight. 2. The composition according to claim 1 wherein the composition is foamable when mixed with air at low pressure, wherein when the composition is mixed with air, the mixture of the composition and air forms a foam. 3. The composition according to claim 1 wherein the effective silicone-based surface active agent for foaming is physiologically compatible, and wherein the silicone-based surfactant is selected from the group consisting of silicone ethoxylates, silicone glycerol esters, silicone amine oxides, silicone acetylenic alcohol derivatives, silicone carboxylates, silicone sulphates, silicone phosphates, silicone imidazole quats, silicone amino quats, silicone phosphate esters, silicone carbohydrate derivatives, silicone isethionates, silicone sulfonates, silicone betaines, silicone alkyl quats, silicone amino propionates, silicone esters, silicone polyamides, and silicone hydrocarbon surfactants. 4. The composition according to claim 1, wherein the effective silicone-based surface active agent is a physiologically acceptable silicone-based surface active agent selected from the group consisting of Bis-PEG-[10-20]dimethicones, 3-(3-Hydroxypropyl)-heptamethyltrisiloxane, ethoxylated, acetate, polyether-modified polysiloxanes, polysiloxane betaine and mixtures thereof from about 0.01% to about 10.0% by weight percept of the total composition. 5. (canceled) 6. The composition according to claim 1, wherein the silicone-based surface active agent is selected from the group consisting of PEG-8 dimethicone PEG-17 dimethicone, Bis-PEG-12 dimethicone, Bis-PEG-17 dimethicone, Bis-PEG/PPG 18/6 dimethicone Bis-PEG/PPG 15/15 dimethicom, Bis-PEG-20 dimethicone and combinations thereof. 7. (canceled) 8. The composition according to claim 1, wherein the silicone-based surfactant is a polyether-modified polysiloxane. 9-16. (canceled) 17. The composition according to claim 1, further including at least one additional surfactant for adjusting properties of the foam produced from the composition. 18. The composition according to claim 17 wherein the additional surfactant is selected from the group consisting of alkylglucosides, a poly(ethoxylated and/or propoxylated)alcohol, a poly(ethoxylated and/or propoxylated)ester, an alkyl alcohol, an alkenyl alcohol, an ester of a polyhydric alcohol, an ether of a polyhydric alcohol, an ester of a polyalkoxylated polyhydric alcohol, an ether of a polyalkoxylated polyhydric alcohol, a sorbitan fatty acid ester, a polyalkoxylated sorbitan fatty acid ester, a betaine, a sulfobetaine, an imidazoline, an amino acid, a lecithin, a phosphatide, an amine oxide, a sulfoxide and mixtures thereof. 19. The composition according to claim 18 wherein the additional surfactant is a betaine. 20. The composition according to claim 19 wherein the additional surfactant is an alkylglucoside. 21-26. (canceled) 27. The composition according to claim 1 further including a foam stabilizing agent present in an amount up to about 10% by weight of the total composition. 28. The composition according to claim 27 wherein the foam stabilizing agent is selected from the group consisting of
lactic acid esters of monoglycerides,
cationic emulsifiers,
quaternary ammonium compounds,
triquatemized stearic phospholipid complex,
hydroxystearamide propyltriamine salts,
lactic acid monoglycerides,
food emulsifiers selected from the group consisting of glyceryl monostearate, propylene glycol monostearate, and sodium stearoyl lactylate, cetyl betaine,
glycolether,
n-propanol,
butyleneglycol,
silicone wax,
an encapsulated oil,
Microcapsule Mineral Oil,
and combinations thereof. 29. The composition according to claim 27 wherein the foam stabilizing agent is selected from the group consisting of glycolether, glycerine, butyleneglycol, behentrimonium chloride, or cetrimonium chloride and combinations thereof. 30. The composition according to claim 1 further including one or more moisturizers, emollients, lipid layer enhancers or combinations thereof selected from the group consisting of
lanolin,
vinyl alcohol,
polyvinyl pyrrolidone, and
polyols selected from the group consisting of glycerol, propylene glycol, butyleneglycol, glyceryl oleate and sorbitol,
cocoglucoside,
a fatty alcohol selected from the group consisting of cetyl alcohol, stearyl alcohol, lauryl alcohol, myristyl alcohol and palmityl alcohol,
ceteareth 20,
an alkylgiucoside,
mixtures of alkylglucoside and glyceryl oleate,
PEG-200 Hydrogentated Glyceryl palmate,
dihydroxypropyl PEG-5 linoleammonium chloride,
PEG-7 glyceryl cocoate,
and combinations thereof, present in an amount up to about 5% by weight of the total composition. 31. The composition according to claim 1 further comprising an acid or a base to adjust a pH of the composition to a preselected pH present in an amount from about 0.05 to about 0.5 by weight of the total composition. 32. (canceled) 33. The composition according to claim 1 further including a preservative in an amount from about 0.01 to about 5% weight percent of the total composition. 34. The composition according to claim 1 including an antimicrobial agent. 35. The composition according to claim 34 wherein the antimicrobial agent is selected from the group of chlorhexidine salts, iodine, complexed forms of iodine, parachlorometaxylenol, triclosan, hexachlorophene, a phenol, a surfactant having a long chain hydrophobic group and a quaternary group, hydrogen peroxide, silver, a silver salt, silver oxide, behenyl alcohol, and mixtures thereof. 36-39. (canceled) 40. The composition claim 1 further comprising constituents selected from the group consisting of organic gums and colloids, lower alkanolamides of higher fatty acids, short chain dials and/or triols, fragrance, coloring matter, ultraviolet absorbers, solvents, suspending agents, buffers, conditioning agents, antioxidants, bactericides and medicinally active ingredients, and combinations thereof. 41. The composition according to claim 1 stored in an unpressurized dispenser having a dispenser pump for mixing the composition with air and dispensing foam therefrom. 42-87. (canceled) | 1,600 |
476 | 13,892,805 | 1,633 | Methods for developing engineered T-cells for immunotherapy that are both non-alloreactive and resistant to immunosuppressive drugs. The present invention relates to methods for modifying T-cells by inactivating both genes encoding target for an immunosuppressive agent and T-cell receptor, in particular genes encoding CD52 and TCR. This method involves the use of specific rare cutting endonucleases, in particular TALE-nucleases (TAL effector endonuclease) and polynucleotides encoding such polypeptides, to precisely target a selection of key genes in T-cells, which are available from donors or from culture of primary cells. The invention opens the way to standard and affordable adoptive immunotherapy strategies for treating cancer and viral infections. | 1) A method of preparing T-cells for immunotherapy comprising
(a) modifying T-cells by inactivating at least:
a first gene expressing a target for an immunosuppressive agent, and
a second gene encoding a component of a T-cell receptor (TCR); and
(b) expanding said cells, optionally in presence of said immunosuppressive agent. 2) The method according to claim 1 comprising:
(a) providing a T-cell;
(b) selecting a gene in said T-cell expressing a target for an immunosuppressive agent;
(c) introducing into said T-cell a rare-cutting endonuclease(s) able to selectively inactivate a gene by DNA cleavage respectively:
said gene encoding a target for said immunosuppressive agent, and
at least one gene encoding one component of the T-cell receptor (TCR); and
(d) expanding said cells, optionally in presence of said immunosuppressive agent. 3) The method according to claim 1, wherein said target for an immunosuppressive agent is a receptor for an immunosuppressive agent. 4) The method according to claim 1, wherein said modified T-cells are expanded in a patient's blood. 5) The method according to claim 1, wherein said transformed T-cells are expanded in-vivo. 6) The method according to claim 1, wherein said transformed T-cells are expanded in presence of said immunosuppressive agent. 7) The method according to claim 1, wherein said gene expresses a target for an immunosuppressive agent which is CD52, and said immunosuppressive agent is an antibody targeting CD52 antigen. 8) The method according to claim 1, wherein said gene expresses a glucocorticoid receptor (GR) and said immunosuppressive agent specific is dexamthasone or another corticosteroid. 9) The method according to claim 1, wherein the at least two inactivated genes are selected from the group consisting of CD52 and TCR alpha, CD52 and TCR beta, GR and TCR alpha, and GR and TCR beta. 10) The method according to claim 2, wherein said rare-cutting endonucleases are co-transfected in step c). 11) The method according to claim 2, wherein said rare-cutting endonucleases are encoded by mRNA. 12) The method according to claim 2 that comprises introducing one or more rare-cutting endonucleases into said cell in step (c) by way of RNA electroporation. 13) The method according to claim 2, wherein said rare-cutting endonucleases are TALE-nucleases. 14) The method according to claim 13, wherein at least one of these TALE-nuclease is directed against one of the gene target sequences of TCRalpha selected from SEQ ID NO: 37, SEQ ID NO: 57 to SEQ ID NO: 60. 15) The method according to claim 13, wherein at least one of these TALE-nuclease is directed against one of the gene target sequences of TCRbeta selected from SEQ ID NO: 38 and SEQ ID NO: 39. 16) The method according to claim 13, wherein at least one of these TALE-nucleases is directed against one of the gene target sequences of GR selected from SEQ ID NO:1 to SEQ ID NO: 6. 17) The method according to claim 13, wherein at least one of these TALE-nucleases is directed against one of the gene target sequences of CD52 selected from SEQ ID NO: 40, SEQ ID NO: 61 to SEQ ID NO: 65. 18) The method according to claim 1, further comprising introducing into said T-cells a chimeric antigen receptor (CAR). 19) The method according to claim 1 comprising introducing into said T-cell a pTalpha polypeptide or a functional variant thereof. 20) The method according to claim 1, wherein said T-cells in step a) are derived from inflammatory T-lymphocytes, cytotoxic T-lymphocytes, regulatory T-lymphocytes or helper T-lymphocytes. 21) The method according to claim 1, wherein said T-cells in step a) are derived from CD4+T-lymphocytes and/or CD8+T-lymphocytes. 22) An isolated T-cell or cell line obtainable by the method of claim 1. 23) A method for treating a patient comprising:
(a) preparing a population of modified T-cells according to the method of claim 1; and (b) administering said transformed T-cells to a patient in need thereof. 24) The method according to claim 23, wherein said patient is being treated with an immunosuppressive agent for the target expressed by said first gene. 25) The method according to claim 23, wherein said patient is diagnosed with cancer, a viral infection, an autoimmune disorder or Graft versus Host Disease (GvHD). | Methods for developing engineered T-cells for immunotherapy that are both non-alloreactive and resistant to immunosuppressive drugs. The present invention relates to methods for modifying T-cells by inactivating both genes encoding target for an immunosuppressive agent and T-cell receptor, in particular genes encoding CD52 and TCR. This method involves the use of specific rare cutting endonucleases, in particular TALE-nucleases (TAL effector endonuclease) and polynucleotides encoding such polypeptides, to precisely target a selection of key genes in T-cells, which are available from donors or from culture of primary cells. The invention opens the way to standard and affordable adoptive immunotherapy strategies for treating cancer and viral infections.1) A method of preparing T-cells for immunotherapy comprising
(a) modifying T-cells by inactivating at least:
a first gene expressing a target for an immunosuppressive agent, and
a second gene encoding a component of a T-cell receptor (TCR); and
(b) expanding said cells, optionally in presence of said immunosuppressive agent. 2) The method according to claim 1 comprising:
(a) providing a T-cell;
(b) selecting a gene in said T-cell expressing a target for an immunosuppressive agent;
(c) introducing into said T-cell a rare-cutting endonuclease(s) able to selectively inactivate a gene by DNA cleavage respectively:
said gene encoding a target for said immunosuppressive agent, and
at least one gene encoding one component of the T-cell receptor (TCR); and
(d) expanding said cells, optionally in presence of said immunosuppressive agent. 3) The method according to claim 1, wherein said target for an immunosuppressive agent is a receptor for an immunosuppressive agent. 4) The method according to claim 1, wherein said modified T-cells are expanded in a patient's blood. 5) The method according to claim 1, wherein said transformed T-cells are expanded in-vivo. 6) The method according to claim 1, wherein said transformed T-cells are expanded in presence of said immunosuppressive agent. 7) The method according to claim 1, wherein said gene expresses a target for an immunosuppressive agent which is CD52, and said immunosuppressive agent is an antibody targeting CD52 antigen. 8) The method according to claim 1, wherein said gene expresses a glucocorticoid receptor (GR) and said immunosuppressive agent specific is dexamthasone or another corticosteroid. 9) The method according to claim 1, wherein the at least two inactivated genes are selected from the group consisting of CD52 and TCR alpha, CD52 and TCR beta, GR and TCR alpha, and GR and TCR beta. 10) The method according to claim 2, wherein said rare-cutting endonucleases are co-transfected in step c). 11) The method according to claim 2, wherein said rare-cutting endonucleases are encoded by mRNA. 12) The method according to claim 2 that comprises introducing one or more rare-cutting endonucleases into said cell in step (c) by way of RNA electroporation. 13) The method according to claim 2, wherein said rare-cutting endonucleases are TALE-nucleases. 14) The method according to claim 13, wherein at least one of these TALE-nuclease is directed against one of the gene target sequences of TCRalpha selected from SEQ ID NO: 37, SEQ ID NO: 57 to SEQ ID NO: 60. 15) The method according to claim 13, wherein at least one of these TALE-nuclease is directed against one of the gene target sequences of TCRbeta selected from SEQ ID NO: 38 and SEQ ID NO: 39. 16) The method according to claim 13, wherein at least one of these TALE-nucleases is directed against one of the gene target sequences of GR selected from SEQ ID NO:1 to SEQ ID NO: 6. 17) The method according to claim 13, wherein at least one of these TALE-nucleases is directed against one of the gene target sequences of CD52 selected from SEQ ID NO: 40, SEQ ID NO: 61 to SEQ ID NO: 65. 18) The method according to claim 1, further comprising introducing into said T-cells a chimeric antigen receptor (CAR). 19) The method according to claim 1 comprising introducing into said T-cell a pTalpha polypeptide or a functional variant thereof. 20) The method according to claim 1, wherein said T-cells in step a) are derived from inflammatory T-lymphocytes, cytotoxic T-lymphocytes, regulatory T-lymphocytes or helper T-lymphocytes. 21) The method according to claim 1, wherein said T-cells in step a) are derived from CD4+T-lymphocytes and/or CD8+T-lymphocytes. 22) An isolated T-cell or cell line obtainable by the method of claim 1. 23) A method for treating a patient comprising:
(a) preparing a population of modified T-cells according to the method of claim 1; and (b) administering said transformed T-cells to a patient in need thereof. 24) The method according to claim 23, wherein said patient is being treated with an immunosuppressive agent for the target expressed by said first gene. 25) The method according to claim 23, wherein said patient is diagnosed with cancer, a viral infection, an autoimmune disorder or Graft versus Host Disease (GvHD). | 1,600 |
477 | 14,684,242 | 1,631 | Provided herein are methods for simultaneously identifying genomic copy number variations (CNVs) and sequence variations in an enriched genomic sample and compositions, systems, and kits for performing such methods. In some aspects, the methods include: (a) obtaining a plurality of sequence reads from an enriched genomic sample that includes a plurality of genomic backbone regions and a plurality of genomic mutation regions of interest in a genomic locus of a subject; (b) obtaining a plurality of sequence reads from corresponding genomic backbone regions and genomic mutation regions of at least one reference genomic sample; (c) assembling the plurality sequence reads from the enriched genomic sample and the at least one reference genomic sample; and (d) determining, based on computational analysis of the assembly, whether the genomic locus has a copy number variation (CNV) and/or a sequence variation. The present disclosure further includes aspects in which the methods are performed by a computer and provide an output to a user identifying a genomic CNV and/or sequence variation. | 1. A method for detecting genomic alterations, comprising:
(a) obtaining a plurality of sequence reads from an enriched genomic sample that includes a plurality of genomic backbone regions and a plurality of genomic mutation regions of interest in a genomic locus of a subject; (b) obtaining a plurality of sequence reads from corresponding genomic backbone regions and genomic mutation regions of at least one reference genomic sample; (c) assembling the plurality of sequence reads from the enriched genomic sample and the at least one reference genomic sample; and (d) determining, based on computational analysis of the assembly, whether the genomic locus has a copy number variation (CNV) or a sequence variation, or a CNV and a sequence variation. 2. The method of claim 1, wherein determining whether the genomic locus has a sequence variation comprises:
(i) identifying genetic differences in the plurality of sequence reads of the enriched genomic sample as compared to the sequence reads from the enriched genomic sample; and (ii) determining which of the potential variants are true and which of the potential variants are artifacts by examining the sequence reads that make up each of the discrete sequence assemblies. 3. The method of claim 2, wherein determining whether the genomic locus has a sequence variation comprises using a SNPPET algorithm. 4. The method of claim 1, wherein determining whether the genomic locus comprises a sequence variation further comprises determining whether the genomic locus has a loss of heterozygosity (LOH), comprising:
(i) identifying genetic differences in the sequence reads of the enriched genomic sample as compared to the sequence reads from the at least one reference genomic sample; and (ii) comparing the identified genetic differences to known frequencies of genetic differences in a population to identify a genomic region in the first genomic locus that has an LOH. 5. The method of claim 1, wherein determining whether the genomic locus has a CNV comprises:
(i) comparing the log ratios of the number of sequence reads from the enriched genomic sample to the number of sequence reads of the at least one reference genomic sample across the first genomic locus; and (ii) determining a genomic location of one or more break points in the log ratios and selecting one or more of the break points that are statistically significant to detect regions in the first genomic locus that have a CNV. 6. The method of claim 1, wherein determining whether the genomic locus has a sequence variation comprises:
(i) processing sequence reads from two different regions of the enriched genome which differ in at least one statistical property or characteristic to make them amenable to analysis. 7. The method of claim 1, wherein the genomic mutation regions of interest comprise high minor allele frequency single polynucleotide polymorphic sites. 8. The method of claim 1, further comprising (e) outputting a report indicating whether the enriched genomic sample comprises a CNV or a sequence variation, or a CNV and a sequence variation. 9. The method of claim 8, wherein the report indicates whether the enriched genomic sample contains a mutation and provides publicly available information about the reference sequence. 10. The method of claim 1, wherein one or more of the genomic mutation regions are associated with cancer. 11. The method of claim 1, wherein the enriched genomic sample is from a human. 12. The method of claim 1, wherein the assembling uses graph theory. 13. The method of claim 11, wherein the assembling is done using a minimal de-Bruijn sequence. 14. The method of claim 11, wherein the assembling is done using a BEST theorem. 15. The method of claim 1, wherein the enriched genomic sample is obtained using baits designed to target locations in the genome based on known SNP allelic frequency and estimated properties of the genomic regions of interest in the reference genome. 16. A system for detecting genomic alterations comprising:
a database configured to store reference sequence reads for one or more reference genomes; and a computing device configured to:
(a) obtain a plurality of sequence reads from an enriched genomic sample that includes a plurality of genomic backbone regions and a plurality of genomic mutation regions of interest in a genomic locus of a subject;
(b) obtain from the database a plurality of reference sequence reads from corresponding genomic backbone regions and genomic mutation regions of at least one reference genome;
(c) assemble the plurality of sequence reads from the enriched genomic sample and the at least one reference genomic sample; and
(d) determine, based on computational analysis of the assembly, whether the genomic locus has a copy number variation (CNV) or a sequence variation, or a CNV and a sequence variation. 17. A computer readable medium comprising:
(a) a code sequence to obtain a plurality of sequence reads from an enriched genomic sample that includes a plurality of genomic backbone regions and a plurality of genomic mutation regions of interest in a genomic locus of a subject; (b) a code sequence to obtain a plurality of sequence reads from corresponding genomic backbone regions and genomic mutation regions of at least one reference genomic sample; (c) a code sequence to assemble the plurality of sequence reads from the enriched genomic sample and the at least one reference genomic sample; and (d) a code sequence to determine, based on computational analysis of the assembly, whether the genomic locus has a copy number variation (CNV) or a sequence variation, or a CNV and a sequence variation. | Provided herein are methods for simultaneously identifying genomic copy number variations (CNVs) and sequence variations in an enriched genomic sample and compositions, systems, and kits for performing such methods. In some aspects, the methods include: (a) obtaining a plurality of sequence reads from an enriched genomic sample that includes a plurality of genomic backbone regions and a plurality of genomic mutation regions of interest in a genomic locus of a subject; (b) obtaining a plurality of sequence reads from corresponding genomic backbone regions and genomic mutation regions of at least one reference genomic sample; (c) assembling the plurality sequence reads from the enriched genomic sample and the at least one reference genomic sample; and (d) determining, based on computational analysis of the assembly, whether the genomic locus has a copy number variation (CNV) and/or a sequence variation. The present disclosure further includes aspects in which the methods are performed by a computer and provide an output to a user identifying a genomic CNV and/or sequence variation.1. A method for detecting genomic alterations, comprising:
(a) obtaining a plurality of sequence reads from an enriched genomic sample that includes a plurality of genomic backbone regions and a plurality of genomic mutation regions of interest in a genomic locus of a subject; (b) obtaining a plurality of sequence reads from corresponding genomic backbone regions and genomic mutation regions of at least one reference genomic sample; (c) assembling the plurality of sequence reads from the enriched genomic sample and the at least one reference genomic sample; and (d) determining, based on computational analysis of the assembly, whether the genomic locus has a copy number variation (CNV) or a sequence variation, or a CNV and a sequence variation. 2. The method of claim 1, wherein determining whether the genomic locus has a sequence variation comprises:
(i) identifying genetic differences in the plurality of sequence reads of the enriched genomic sample as compared to the sequence reads from the enriched genomic sample; and (ii) determining which of the potential variants are true and which of the potential variants are artifacts by examining the sequence reads that make up each of the discrete sequence assemblies. 3. The method of claim 2, wherein determining whether the genomic locus has a sequence variation comprises using a SNPPET algorithm. 4. The method of claim 1, wherein determining whether the genomic locus comprises a sequence variation further comprises determining whether the genomic locus has a loss of heterozygosity (LOH), comprising:
(i) identifying genetic differences in the sequence reads of the enriched genomic sample as compared to the sequence reads from the at least one reference genomic sample; and (ii) comparing the identified genetic differences to known frequencies of genetic differences in a population to identify a genomic region in the first genomic locus that has an LOH. 5. The method of claim 1, wherein determining whether the genomic locus has a CNV comprises:
(i) comparing the log ratios of the number of sequence reads from the enriched genomic sample to the number of sequence reads of the at least one reference genomic sample across the first genomic locus; and (ii) determining a genomic location of one or more break points in the log ratios and selecting one or more of the break points that are statistically significant to detect regions in the first genomic locus that have a CNV. 6. The method of claim 1, wherein determining whether the genomic locus has a sequence variation comprises:
(i) processing sequence reads from two different regions of the enriched genome which differ in at least one statistical property or characteristic to make them amenable to analysis. 7. The method of claim 1, wherein the genomic mutation regions of interest comprise high minor allele frequency single polynucleotide polymorphic sites. 8. The method of claim 1, further comprising (e) outputting a report indicating whether the enriched genomic sample comprises a CNV or a sequence variation, or a CNV and a sequence variation. 9. The method of claim 8, wherein the report indicates whether the enriched genomic sample contains a mutation and provides publicly available information about the reference sequence. 10. The method of claim 1, wherein one or more of the genomic mutation regions are associated with cancer. 11. The method of claim 1, wherein the enriched genomic sample is from a human. 12. The method of claim 1, wherein the assembling uses graph theory. 13. The method of claim 11, wherein the assembling is done using a minimal de-Bruijn sequence. 14. The method of claim 11, wherein the assembling is done using a BEST theorem. 15. The method of claim 1, wherein the enriched genomic sample is obtained using baits designed to target locations in the genome based on known SNP allelic frequency and estimated properties of the genomic regions of interest in the reference genome. 16. A system for detecting genomic alterations comprising:
a database configured to store reference sequence reads for one or more reference genomes; and a computing device configured to:
(a) obtain a plurality of sequence reads from an enriched genomic sample that includes a plurality of genomic backbone regions and a plurality of genomic mutation regions of interest in a genomic locus of a subject;
(b) obtain from the database a plurality of reference sequence reads from corresponding genomic backbone regions and genomic mutation regions of at least one reference genome;
(c) assemble the plurality of sequence reads from the enriched genomic sample and the at least one reference genomic sample; and
(d) determine, based on computational analysis of the assembly, whether the genomic locus has a copy number variation (CNV) or a sequence variation, or a CNV and a sequence variation. 17. A computer readable medium comprising:
(a) a code sequence to obtain a plurality of sequence reads from an enriched genomic sample that includes a plurality of genomic backbone regions and a plurality of genomic mutation regions of interest in a genomic locus of a subject; (b) a code sequence to obtain a plurality of sequence reads from corresponding genomic backbone regions and genomic mutation regions of at least one reference genomic sample; (c) a code sequence to assemble the plurality of sequence reads from the enriched genomic sample and the at least one reference genomic sample; and (d) a code sequence to determine, based on computational analysis of the assembly, whether the genomic locus has a copy number variation (CNV) or a sequence variation, or a CNV and a sequence variation. | 1,600 |
478 | 15,408,924 | 1,611 | An avermectin-based topical formulation is disclosed which is useful for prevention and treatment of head lice ( Pediculus humanus capitis ). This topical formulation may be formulated as a shampoo-condition which comprises an effective amount of avermectin, solubilizers, suspending agents, preservatives, nonionic surfactants, humectants, a silicone compound, and water. Also disclosed are methods of using the topical formulations disclosed within this specification to treat either a susceptible or treatment-resistant strain of lice, as well as uses in the manufacture of a medicament for treating or preventing a lice infestation from a susceptible or treatment-resistant strain in a human patient. | 1.-20. (canceled) 21. A method for the treatment or prophylaxis of a lice infestation, the method comprising:
(a) applying to an area of a human a topical pediculicidal formulation comprising
about 0.1% to about 2.0% by weight ivermectin,
a solubilizer,
about 20% to 30% by weight olive oil,
a non-ionic surfactant, and
about 30% to 40% by weight water; and
(b) maintaining the topical pediculicidal formulation on the area. 22. The method of claim 21, wherein the topical pediculicidal formulation is maintained in (b) for from about 1 to about 60 minutes. 23. The method of claim 22, wherein the topical pediculicidal formulation is maintained in (b) for about 10 minutes. 24. The method of claim 21, further comprising rinsing the area with water. 25. The method of claim 21, wherein the lice are treatment-resistant lice. 26. The method of claim 21, wherein the lice are head lice and the area comprises hair. 27. The method of claim 26, wherein the topical pediculicidal formulation is rubbed into the hair until saturation occurs. 28. The method of claim 26, wherein the topical pediculicidal formulation is in the form of a shampoo-conditioner. 29. The method of claim 28, wherein the method is repeated at least once within seven days of the initial method. 30. The method of claim 1, wherein a dose of about 1 mL to about 100 mL of the topical pediculicidal formulation is applied in (a). 31. The method of claim 21, wherein the lice are pubic lice and the area is selected from the group consisting of the pubic area, facial hair, eyelashes, eyebrows, armpits, chest hair and the scalp. 32. The method of claim 21, wherein the topical pediculicidal formulation comprises about 0.5% by weight ivermectin. 33. The method of claim 21, wherein the topical pediculicidal formulation further comprises shea butter. 34. The method of claim 21, wherein the solubilizer comprises polysorbate 80, cetyl acetate, acetylated lanolin alcohol or a combination thereof. 35. The method of claim 21, wherein the topical pediculicidal formulation further comprising one or more paraben preservatives selected from the group consisting of methylparaben, propylparaben, ethylparaben, butylparaben, isobutylparaben, isopropylparaben, benzylparaben, sodium salts thereof, and any combination thereof. 36. The method of claim 21, wherein the nonionic surfactant comprises oleyl alcohol, lanolin alcohol, a sorbitan tristearate or a combination thereof. 37. The method of claim 21, wherein the topical pediculicidal formulation further comprising a conditioner selected from the group consisting of cyclomethicone, dimethicone, hexamethyldisiloxane, octamethyltrisiloxane, decamethyltetrasiloxane, dodecamethylpentasiloxane, polydimethylsiloxanes, and combinations thereof. 38. The method of claim 21, wherein the topical pediculicidal formulation is selected from the group consisting of a cream, a gel and a pomade. 39. The method of claim 21, wherein the topical pediculicidal formulation has a rate of killing permethrin resistant SF-HL head lice that is 3.2 to 3.8 times faster than ivermectin in solution at the same weight %. 40. The method of claim 21, wherein the topical pediculicidal formulation is indirectly ovicidal. | An avermectin-based topical formulation is disclosed which is useful for prevention and treatment of head lice ( Pediculus humanus capitis ). This topical formulation may be formulated as a shampoo-condition which comprises an effective amount of avermectin, solubilizers, suspending agents, preservatives, nonionic surfactants, humectants, a silicone compound, and water. Also disclosed are methods of using the topical formulations disclosed within this specification to treat either a susceptible or treatment-resistant strain of lice, as well as uses in the manufacture of a medicament for treating or preventing a lice infestation from a susceptible or treatment-resistant strain in a human patient.1.-20. (canceled) 21. A method for the treatment or prophylaxis of a lice infestation, the method comprising:
(a) applying to an area of a human a topical pediculicidal formulation comprising
about 0.1% to about 2.0% by weight ivermectin,
a solubilizer,
about 20% to 30% by weight olive oil,
a non-ionic surfactant, and
about 30% to 40% by weight water; and
(b) maintaining the topical pediculicidal formulation on the area. 22. The method of claim 21, wherein the topical pediculicidal formulation is maintained in (b) for from about 1 to about 60 minutes. 23. The method of claim 22, wherein the topical pediculicidal formulation is maintained in (b) for about 10 minutes. 24. The method of claim 21, further comprising rinsing the area with water. 25. The method of claim 21, wherein the lice are treatment-resistant lice. 26. The method of claim 21, wherein the lice are head lice and the area comprises hair. 27. The method of claim 26, wherein the topical pediculicidal formulation is rubbed into the hair until saturation occurs. 28. The method of claim 26, wherein the topical pediculicidal formulation is in the form of a shampoo-conditioner. 29. The method of claim 28, wherein the method is repeated at least once within seven days of the initial method. 30. The method of claim 1, wherein a dose of about 1 mL to about 100 mL of the topical pediculicidal formulation is applied in (a). 31. The method of claim 21, wherein the lice are pubic lice and the area is selected from the group consisting of the pubic area, facial hair, eyelashes, eyebrows, armpits, chest hair and the scalp. 32. The method of claim 21, wherein the topical pediculicidal formulation comprises about 0.5% by weight ivermectin. 33. The method of claim 21, wherein the topical pediculicidal formulation further comprises shea butter. 34. The method of claim 21, wherein the solubilizer comprises polysorbate 80, cetyl acetate, acetylated lanolin alcohol or a combination thereof. 35. The method of claim 21, wherein the topical pediculicidal formulation further comprising one or more paraben preservatives selected from the group consisting of methylparaben, propylparaben, ethylparaben, butylparaben, isobutylparaben, isopropylparaben, benzylparaben, sodium salts thereof, and any combination thereof. 36. The method of claim 21, wherein the nonionic surfactant comprises oleyl alcohol, lanolin alcohol, a sorbitan tristearate or a combination thereof. 37. The method of claim 21, wherein the topical pediculicidal formulation further comprising a conditioner selected from the group consisting of cyclomethicone, dimethicone, hexamethyldisiloxane, octamethyltrisiloxane, decamethyltetrasiloxane, dodecamethylpentasiloxane, polydimethylsiloxanes, and combinations thereof. 38. The method of claim 21, wherein the topical pediculicidal formulation is selected from the group consisting of a cream, a gel and a pomade. 39. The method of claim 21, wherein the topical pediculicidal formulation has a rate of killing permethrin resistant SF-HL head lice that is 3.2 to 3.8 times faster than ivermectin in solution at the same weight %. 40. The method of claim 21, wherein the topical pediculicidal formulation is indirectly ovicidal. | 1,600 |
479 | 13,386,111 | 1,653 | The present invention relates to a method of processing allograft skin for transplantation and a cryopreserved allograft skin produced thereby. More specifically, the present invention relates to a method in which a cryoprotectant is prepared by adding sucrose to basic constituents comprising dimethyl sulfoxide, an animal cell culture medium and fetal bovine serum, and then the resulting solution is used to subject skin tissue for transplantation to a freezing process. | 1. A method of processing allograft skin for transplantation comprising:
i) mixing dimethyl sulfoxide, an animal cell culture medium and fetal bovine serum; ii) dissolving sucrose in the solution to obtain a cryoprotectant; iii) penetrating the cryoprotectant into a separated skin; and iv) freezing the cryoprotectant-penetrated skin in a controlled rate freezer. 2. The method of processing allograft skin for transplantation according to claim 1, wherein sucrose is dissolved in the solution of step (i) as 25 to 40 wt % in the final concentration. 3. The method of processing allograft skin for transplantation according to claim 2, wherein the final concentration of sucrose is 30 wt %. 4. The method of processing allograft skin for transplantation according to claim 1, wherein the mixing ratio of dimethyl sulfoxide, the animal cell culture medium and fetal bovine serum is 1:3˜5:4˜6 based on weight. 5. The method of processing allograft skin for transplantation according to claim 1, wherein the animal cell culture medium is selected from the group consisting of MEM, DMEM, RPMI 1640 and IMDM. 6. The method of processing allograft skin for transplantation according to claim 1, wherein the cryoprotectant is penetrated into the separated skin in a 4° C. low temperature bath for 6-24 hours. 7. The method of processing allograft skin for transplantation according to claim 1, wherein the cryoprotectant-penetrated skin is frozen in a controlled rate freezer with a freezing rate of −1° C. per minute. 8. A cryopreserved allograft skin which is processed by the method according to any one of claims 1 to 7. | The present invention relates to a method of processing allograft skin for transplantation and a cryopreserved allograft skin produced thereby. More specifically, the present invention relates to a method in which a cryoprotectant is prepared by adding sucrose to basic constituents comprising dimethyl sulfoxide, an animal cell culture medium and fetal bovine serum, and then the resulting solution is used to subject skin tissue for transplantation to a freezing process.1. A method of processing allograft skin for transplantation comprising:
i) mixing dimethyl sulfoxide, an animal cell culture medium and fetal bovine serum; ii) dissolving sucrose in the solution to obtain a cryoprotectant; iii) penetrating the cryoprotectant into a separated skin; and iv) freezing the cryoprotectant-penetrated skin in a controlled rate freezer. 2. The method of processing allograft skin for transplantation according to claim 1, wherein sucrose is dissolved in the solution of step (i) as 25 to 40 wt % in the final concentration. 3. The method of processing allograft skin for transplantation according to claim 2, wherein the final concentration of sucrose is 30 wt %. 4. The method of processing allograft skin for transplantation according to claim 1, wherein the mixing ratio of dimethyl sulfoxide, the animal cell culture medium and fetal bovine serum is 1:3˜5:4˜6 based on weight. 5. The method of processing allograft skin for transplantation according to claim 1, wherein the animal cell culture medium is selected from the group consisting of MEM, DMEM, RPMI 1640 and IMDM. 6. The method of processing allograft skin for transplantation according to claim 1, wherein the cryoprotectant is penetrated into the separated skin in a 4° C. low temperature bath for 6-24 hours. 7. The method of processing allograft skin for transplantation according to claim 1, wherein the cryoprotectant-penetrated skin is frozen in a controlled rate freezer with a freezing rate of −1° C. per minute. 8. A cryopreserved allograft skin which is processed by the method according to any one of claims 1 to 7. | 1,600 |
480 | 12,129,935 | 1,627 | The present invention provides 4-anilino-3-quinolinecarbonitriles compounds useful for treating a subject having an BcrAbl positive leukemia that is resistant to imatinib. | 1. A method for treating a BcrAbl positive leukemia in a subject that is resistant to imatinib which comprises administering to the subject a therapeutically effective amount of a compound of the Formula:
wherein:
n is 1, 2 or 3;
X is N or CH, provided that when X is N, then n is 2 or 3;
R is alkyl of from 1 to 3 carbon atoms;
R1 is selected from the group consisting of 2,4-dichloro-5-methoxyphenyl; 2,4-dichlorophenyl; 3,4,5-trimethoxyphenyl; 2-chloro-5-methoxyphenyl; 2-methyl-5-methoxyphenyl; 2,4-dimethylphenyl; 2,4-dimethyl-5-methoxyphenyl; and 2,4-dichloro-5-ethoxyphenyl; and
R2 is alkyl of from 1 to 2 carbon atoms;
or a pharmaceutically acceptable salt thereof. 2. The method of claim 1 wherein the compound is of the formula:
wherein:
n is an integer from 2-3;
X is N or CH;
R is alkyl of 1 to 3 carbon atoms;
R1 is selected from the group consisting of 2,4-dichloro-5-methoxyphenyl; 2,4-dichlorophenyl; 3,4,5-trimethoxyphenyl; 2-chloro-5-methoxyphenyl; 2-methyl-5-methoxyphenyl; 2,4-dimethylphenyl; 2,4-dimethyl-5-methoxyphenyl; and 2,4-dichloro-5-ethoxyphenyl;
R2 is alkyl of 1 to 2 carbon atoms;
or a pharmaceutically acceptable salt thereof. 3. The method of claim 1 wherein the compound is of the formula:
wherein:
X is N or CH;
n is 3;
R2 and R are methyl;
or a pharmaceutically acceptable salt thereof. 4. The method of claim 1 wherein R2 is methyl. 5. The method of claim 1 wherein X is N. 6. The method of claim 1 wherein X is CH. 7. The method of claim 1 wherein the compound is: 4-[(2,4-Dichloro-5-methoxy-phenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile. 8. The method of claim 1 wherein the compound is: 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[3-(4-ethyl-1-piperazinyl)propoxy]-6-methoxy-3-quinolinecarbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[2-(4-methyl-1-piperazinyl)ethoxy]-3-quinolinecarbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[2-(4-ethyl-1-piperazinyl)ethoxy]-6-methoxy-3-quinolinecarbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-3-quinolinecarbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[2-(1-methylpiperidin-4-yl)ethoxy]-3-quinolinecarbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(1-methylpiperidin-4-yl)propoxy]quinoline-3-carbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[(1-ethylpiperidin-4-yl)methoxy]-6-methoxyquinoline-3-carbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)-amino]-6-ethoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[3-(4-ethylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[3-(1-methylpiperidin-4-yl)propoxy]quinoline-3-carbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[2-(4-methyl-1-piperazinyl)ethoxy]quinoline-3-carbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[2-(1-methylpiperidin-4-yl)ethoxy]quinoline-3-carbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-propyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile; or a pharmaceutically acceptable salt thereof. 9. The method of claim 1 wherein the compound is: 4-[(2,4-Dichlorophenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-3-quinolinecarbonitrile; 6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-4-[(3,4,5-trimethoxyphenyl)amino]quinoline-3-carbonitrile; 4-[(2-chloro-5-methoxyphenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile; 6-methoxy-4-[(5-methoxy-2-methylphenyl)amino]-7-[(1-methylpiperidin-4-yl)-methoxy]quinoline-3-carbonitrile; 4-[(2,4-dimethylphenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile; 6-methoxy-4-[(5-methoxy-2,4-dimethylphenyl)amino]-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile; 4-[(2,4-dichloro-5-ethoxyphenyl)-amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile; or a pharmaceutically acceptable salt thereof. 10. The method of claim 1 wherein the leukemia is Chronic Myelogenous Leukemia. 11. The method of claim 1 wherein the leukemia is Acute Lymphocytic Leukemia. 12. The method of claim 1 wherein the leukemia has a resistance-associated nucleic acid mutation in the brlabl gene selected from the group consisting of: 1052T>C; 1075T>G; 1187A>C; 1295T>C; 1457T>C; 730A>G; 742C>G; 749G>A; 757T>C; 758A>T; 763G>A; 787A>G; 817T>A; 944C>T; 949T>C; and 992A>G. 13. The method of claim 12 wherein the leukemia has a resistance-associated amino acid mutation in the bcrabl protein selected from the group consisting of: M351T; F359V; H396P; 1432T; F486S; M244V; L248V; G250E; Y253H; Y253F; E255K; K263E; L273M; T3151; F317L; and N331S. 14. The method of claim 1 wherein the compound administered to the subject is an Src inhibitor and an Abl Kinase inhibitor. 15. The method of claim 1 wherein the compounds are administered to a subject in combination with one or more other compounds used to treat a BcrAbl positive leukemia. 16. The method of claim 15 wherein the one or more other compounds includes GLEEVEC. 17. A method for treating a BcrAbl positive leukemia in a subject that is resistant to imatinib which comprises administering to the subject a therapeutically effective amount of 4-[(2,4-Dichloro-5-methoxy-phenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile, wherein the subject has at least one mutation in BcrAbl protein selected from M351T; F359V; H396P; 1432T; F486S; M244V; L248V; G250E; Y253H; Y253F; E255K; K263E; L273M; T3151; F317L; and N331S. | The present invention provides 4-anilino-3-quinolinecarbonitriles compounds useful for treating a subject having an BcrAbl positive leukemia that is resistant to imatinib.1. A method for treating a BcrAbl positive leukemia in a subject that is resistant to imatinib which comprises administering to the subject a therapeutically effective amount of a compound of the Formula:
wherein:
n is 1, 2 or 3;
X is N or CH, provided that when X is N, then n is 2 or 3;
R is alkyl of from 1 to 3 carbon atoms;
R1 is selected from the group consisting of 2,4-dichloro-5-methoxyphenyl; 2,4-dichlorophenyl; 3,4,5-trimethoxyphenyl; 2-chloro-5-methoxyphenyl; 2-methyl-5-methoxyphenyl; 2,4-dimethylphenyl; 2,4-dimethyl-5-methoxyphenyl; and 2,4-dichloro-5-ethoxyphenyl; and
R2 is alkyl of from 1 to 2 carbon atoms;
or a pharmaceutically acceptable salt thereof. 2. The method of claim 1 wherein the compound is of the formula:
wherein:
n is an integer from 2-3;
X is N or CH;
R is alkyl of 1 to 3 carbon atoms;
R1 is selected from the group consisting of 2,4-dichloro-5-methoxyphenyl; 2,4-dichlorophenyl; 3,4,5-trimethoxyphenyl; 2-chloro-5-methoxyphenyl; 2-methyl-5-methoxyphenyl; 2,4-dimethylphenyl; 2,4-dimethyl-5-methoxyphenyl; and 2,4-dichloro-5-ethoxyphenyl;
R2 is alkyl of 1 to 2 carbon atoms;
or a pharmaceutically acceptable salt thereof. 3. The method of claim 1 wherein the compound is of the formula:
wherein:
X is N or CH;
n is 3;
R2 and R are methyl;
or a pharmaceutically acceptable salt thereof. 4. The method of claim 1 wherein R2 is methyl. 5. The method of claim 1 wherein X is N. 6. The method of claim 1 wherein X is CH. 7. The method of claim 1 wherein the compound is: 4-[(2,4-Dichloro-5-methoxy-phenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile. 8. The method of claim 1 wherein the compound is: 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[3-(4-ethyl-1-piperazinyl)propoxy]-6-methoxy-3-quinolinecarbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[2-(4-methyl-1-piperazinyl)ethoxy]-3-quinolinecarbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[2-(4-ethyl-1-piperazinyl)ethoxy]-6-methoxy-3-quinolinecarbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-3-quinolinecarbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[2-(1-methylpiperidin-4-yl)ethoxy]-3-quinolinecarbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(1-methylpiperidin-4-yl)propoxy]quinoline-3-carbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-[(1-ethylpiperidin-4-yl)methoxy]-6-methoxyquinoline-3-carbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)-amino]-6-ethoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[3-(4-ethylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[3-(1-methylpiperidin-4-yl)propoxy]quinoline-3-carbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[2-(4-methyl-1-piperazinyl)ethoxy]quinoline-3-carbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[2-(1-methylpiperidin-4-yl)ethoxy]quinoline-3-carbonitrile; 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-propyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile; or a pharmaceutically acceptable salt thereof. 9. The method of claim 1 wherein the compound is: 4-[(2,4-Dichlorophenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-3-quinolinecarbonitrile; 6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-4-[(3,4,5-trimethoxyphenyl)amino]quinoline-3-carbonitrile; 4-[(2-chloro-5-methoxyphenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile; 6-methoxy-4-[(5-methoxy-2-methylphenyl)amino]-7-[(1-methylpiperidin-4-yl)-methoxy]quinoline-3-carbonitrile; 4-[(2,4-dimethylphenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile; 6-methoxy-4-[(5-methoxy-2,4-dimethylphenyl)amino]-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile; 4-[(2,4-dichloro-5-ethoxyphenyl)-amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile; or a pharmaceutically acceptable salt thereof. 10. The method of claim 1 wherein the leukemia is Chronic Myelogenous Leukemia. 11. The method of claim 1 wherein the leukemia is Acute Lymphocytic Leukemia. 12. The method of claim 1 wherein the leukemia has a resistance-associated nucleic acid mutation in the brlabl gene selected from the group consisting of: 1052T>C; 1075T>G; 1187A>C; 1295T>C; 1457T>C; 730A>G; 742C>G; 749G>A; 757T>C; 758A>T; 763G>A; 787A>G; 817T>A; 944C>T; 949T>C; and 992A>G. 13. The method of claim 12 wherein the leukemia has a resistance-associated amino acid mutation in the bcrabl protein selected from the group consisting of: M351T; F359V; H396P; 1432T; F486S; M244V; L248V; G250E; Y253H; Y253F; E255K; K263E; L273M; T3151; F317L; and N331S. 14. The method of claim 1 wherein the compound administered to the subject is an Src inhibitor and an Abl Kinase inhibitor. 15. The method of claim 1 wherein the compounds are administered to a subject in combination with one or more other compounds used to treat a BcrAbl positive leukemia. 16. The method of claim 15 wherein the one or more other compounds includes GLEEVEC. 17. A method for treating a BcrAbl positive leukemia in a subject that is resistant to imatinib which comprises administering to the subject a therapeutically effective amount of 4-[(2,4-Dichloro-5-methoxy-phenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile, wherein the subject has at least one mutation in BcrAbl protein selected from M351T; F359V; H396P; 1432T; F486S; M244V; L248V; G250E; Y253H; Y253F; E255K; K263E; L273M; T3151; F317L; and N331S. | 1,600 |
481 | 15,226,126 | 1,643 | The present invention relates to peptides, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated cytotoxic T cell (CTL) peptide epitopes, alone or in combination with other tumor-associated peptides that serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses. The present invention relates to 30 peptide sequences and their variants derived from HLA class I and class II molecules of human tumor cells that can be used in vaccine compositions for eliciting anti-tumor immune responses. | 1. A peptide consisting of the amino acid sequence of SEQ ID NO: 21, or a pharmaceutically acceptable salt thereof. 2. A fusion protein comprising the peptide of SEQ ID NO: 21 adjoined at the N-terminus and/or the C-terminus by one or more heterologous peptides, or a pharmaceutically acceptable salt thereof. 3. A kit comprising:
(a) a container that contains a composition containing, in solution and/or in lyophilized. form, a peptide or salt of claim 1; (b) optionally, a second container comprising a diluent and/or reconstituting solution; (c) optionally, at least one additional peptide consisting of an amino acid sequence selected from SEQ ID NOs 1-20 and 22-30, and (d) optionally, instructions for (i) use of the diluent and/or (ii) reconstitution and/or use of a lyophilized formulation. 4. The kit according to claim 3, further comprising one or more of (e) a buffer, (f) a diluent, (g) a filter, (h) a needle, and (i) a syringe. 5. The fusion protein of claim 2, wherein said one or more heterologous peptides is a carrier protein selected from keyhole limpet haemocyanin (KLH) and mannan. 6. The fusion protein of claim 2, wherein the fusion protein maintains an ability to bind to a molecule of the human major histocompatibility complex (MHC) class-1 or II, so as to be capable of stimulating CD4+ and/or CD8+ T cells specific. 7. The fusion protein of claim 2, wherein said fusion protein has an overall length of between 10 and 100 amino acids. 8. The fusion protein of claim 2, wherein the heterologous peptide comprises the 80 N-terminal amino acids of the HLA-DR antigen-associated invariant chain, li. 9. An acylated peptide consisting of SEQ ID NO: 21 or a pharmaceutically acceptable salt thereof. 10. A pegylated peptide consisting of SEQ ID NO: 21 or a pharmaceutically acceptable salt thereof. 11. A composition comprising a peptide of claim 1 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 12. A composition comprising a fusion protein of claim 2 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 13. A composition comprising an acylated peptide of claim 9 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 14. A composition comprising a pegylated peptide of claim 10 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 15. A method of inducing an immune response in a subject, the method comprising administering to the subject a peptide of claim 1 or a pharmaceutically acceptable salt thereof. 16. A method of inducing an immune response in a subject, the method comprising administering to the subject a fusion protein of claim 2 or a pharmaceutically acceptable salt thereof. 17. A method for producing activated cytotoxic T lymphocytes (CTL), the method comprising contacting in vitro CTL with antigen-loaded human class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell or an artificial construct mimicking an antigen-presenting cell for a period of time sufficient to activate said CTL in an antigen specific manner, wherein said antigen is a peptide comprising SEQ ID NO: 21 wherein said peptide is not an underlying full-length polypeptide 18. An activated cytotoxic T lymphocyte (CTL) produced according to claim 1. 19. A method of inducing an immune response in a subject, the method comprising administering to the subject an acylated peptide of claim 9 or a pharmaceutically acceptable salt thereof. 20. A method of inducing an immune response in a subject, the method comprising administering to the subject a pegylated peptide of claim 10 or a pharmaceutically acceptable salt thereof. | The present invention relates to peptides, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated cytotoxic T cell (CTL) peptide epitopes, alone or in combination with other tumor-associated peptides that serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses. The present invention relates to 30 peptide sequences and their variants derived from HLA class I and class II molecules of human tumor cells that can be used in vaccine compositions for eliciting anti-tumor immune responses.1. A peptide consisting of the amino acid sequence of SEQ ID NO: 21, or a pharmaceutically acceptable salt thereof. 2. A fusion protein comprising the peptide of SEQ ID NO: 21 adjoined at the N-terminus and/or the C-terminus by one or more heterologous peptides, or a pharmaceutically acceptable salt thereof. 3. A kit comprising:
(a) a container that contains a composition containing, in solution and/or in lyophilized. form, a peptide or salt of claim 1; (b) optionally, a second container comprising a diluent and/or reconstituting solution; (c) optionally, at least one additional peptide consisting of an amino acid sequence selected from SEQ ID NOs 1-20 and 22-30, and (d) optionally, instructions for (i) use of the diluent and/or (ii) reconstitution and/or use of a lyophilized formulation. 4. The kit according to claim 3, further comprising one or more of (e) a buffer, (f) a diluent, (g) a filter, (h) a needle, and (i) a syringe. 5. The fusion protein of claim 2, wherein said one or more heterologous peptides is a carrier protein selected from keyhole limpet haemocyanin (KLH) and mannan. 6. The fusion protein of claim 2, wherein the fusion protein maintains an ability to bind to a molecule of the human major histocompatibility complex (MHC) class-1 or II, so as to be capable of stimulating CD4+ and/or CD8+ T cells specific. 7. The fusion protein of claim 2, wherein said fusion protein has an overall length of between 10 and 100 amino acids. 8. The fusion protein of claim 2, wherein the heterologous peptide comprises the 80 N-terminal amino acids of the HLA-DR antigen-associated invariant chain, li. 9. An acylated peptide consisting of SEQ ID NO: 21 or a pharmaceutically acceptable salt thereof. 10. A pegylated peptide consisting of SEQ ID NO: 21 or a pharmaceutically acceptable salt thereof. 11. A composition comprising a peptide of claim 1 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 12. A composition comprising a fusion protein of claim 2 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 13. A composition comprising an acylated peptide of claim 9 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 14. A composition comprising a pegylated peptide of claim 10 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 15. A method of inducing an immune response in a subject, the method comprising administering to the subject a peptide of claim 1 or a pharmaceutically acceptable salt thereof. 16. A method of inducing an immune response in a subject, the method comprising administering to the subject a fusion protein of claim 2 or a pharmaceutically acceptable salt thereof. 17. A method for producing activated cytotoxic T lymphocytes (CTL), the method comprising contacting in vitro CTL with antigen-loaded human class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell or an artificial construct mimicking an antigen-presenting cell for a period of time sufficient to activate said CTL in an antigen specific manner, wherein said antigen is a peptide comprising SEQ ID NO: 21 wherein said peptide is not an underlying full-length polypeptide 18. An activated cytotoxic T lymphocyte (CTL) produced according to claim 1. 19. A method of inducing an immune response in a subject, the method comprising administering to the subject an acylated peptide of claim 9 or a pharmaceutically acceptable salt thereof. 20. A method of inducing an immune response in a subject, the method comprising administering to the subject a pegylated peptide of claim 10 or a pharmaceutically acceptable salt thereof. | 1,600 |
482 | 15,226,098 | 1,643 | The present invention relates to peptides, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated cytotoxic T cell (CTL) peptide epitopes, alone or in combination with other tumor-associated peptides that serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses. The present invention relates to 30 peptide sequences and their variants derived from HLA class I and class II molecules of human tumor cells that can be used in vaccine compositions for eliciting anti-tumor immune responses. | 1. A peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof. 2. A fusion protein comprising the peptide of SEQ ID NO: 1 adjoined at the N-terminus and/or the C-terminus by one or more heterologous peptides, or a pharmaceutically acceptable salt thereof. 3. A kit comprising:
(a) a container that contains a composition containing, in solution and/or in lyophilized form, a peptide or salt of claim 1; (b) optionally, a second container comprising a diluent and/or reconstituting solution; (c) optionally, at least one additional peptide consisting of an amino acid sequence selected from SEQ ID NOs 2-30, and (d) optionally, instructions for (i) use of the diluent and/or (ii) reconstitution and/or use of a lyophilized formulation. 4. The kit according to claim 3, further comprising one or more of (e) a buffer, (f) a diluent, (g) a filter, (h) a needle, and (i) a syringe. 5. The fusion protein of claim 2, wherein said one or more heterologous peptides is a carrier protein selected from keyhole limpet haemocyanin (KLH) and mannan. 6. The fusion protein of claim 2, wherein the fusion protein maintains an ability to bind to a molecule of the human major histocompatibility complex (MHC) class-1 or II, so as to be capable of stimulating CD4+ and/or CD8+ T cells specific. 7. The fusion protein of claim 2, wherein said fusion protein has an overall length of between 10 and 100 amino acids. 8. The fusion protein of claim 2, wherein the heterologous peptide comprises the 80 N-terminal amino acids of the HLA-DR antigen-associated invariant chain, li. 9. An acylated peptide consisting of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof. 10. A pegylated peptide consisting of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof. 11. A composition comprising a peptide of claim 1 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 12. A composition comprising a fusion protein of claim 2 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 13. A composition comprising an acylated peptide of claim 9 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 14. A composition comprising a pegylated peptide of claim 10 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 15. A method of inducing an immune response in a subject, the method comprising administering to the subject a peptide of claim 1 or a pharmaceutically acceptable salt thereof. 16. A method of inducing an immune response in a subject, the method comprising administering to the subject a fusion protein of claim 2 or a pharmaceutically acceptable salt thereof. 17. A method for producing activated cytotoxic T lymphocytes (CTL), the method comprising
contacting in vitro CTL with antigen-loaded human class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell or an artificial construct mimicking an antigen-presenting cell for a period of time sufficient to activate said CTL in an antigen specific manner, wherein said antigen is a peptide comprising SEQ ID NO: 1 wherein said peptide is not an underlying full-length polypeptide 18. An activated cytotoxic T lymphocyte (CTL) produced according to claim 1. 19. A method of inducing an immune response in a subject, the method comprising administering to the subject an acylated peptide of claim 9 or a pharmaceutically acceptable salt thereof. 20. A method of inducing an immune response in a subject, the method comprising administering to the subject a pegylated peptide of claim 10 or a pharmaceutically acceptable salt thereof. | The present invention relates to peptides, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated cytotoxic T cell (CTL) peptide epitopes, alone or in combination with other tumor-associated peptides that serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses. The present invention relates to 30 peptide sequences and their variants derived from HLA class I and class II molecules of human tumor cells that can be used in vaccine compositions for eliciting anti-tumor immune responses.1. A peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof. 2. A fusion protein comprising the peptide of SEQ ID NO: 1 adjoined at the N-terminus and/or the C-terminus by one or more heterologous peptides, or a pharmaceutically acceptable salt thereof. 3. A kit comprising:
(a) a container that contains a composition containing, in solution and/or in lyophilized form, a peptide or salt of claim 1; (b) optionally, a second container comprising a diluent and/or reconstituting solution; (c) optionally, at least one additional peptide consisting of an amino acid sequence selected from SEQ ID NOs 2-30, and (d) optionally, instructions for (i) use of the diluent and/or (ii) reconstitution and/or use of a lyophilized formulation. 4. The kit according to claim 3, further comprising one or more of (e) a buffer, (f) a diluent, (g) a filter, (h) a needle, and (i) a syringe. 5. The fusion protein of claim 2, wherein said one or more heterologous peptides is a carrier protein selected from keyhole limpet haemocyanin (KLH) and mannan. 6. The fusion protein of claim 2, wherein the fusion protein maintains an ability to bind to a molecule of the human major histocompatibility complex (MHC) class-1 or II, so as to be capable of stimulating CD4+ and/or CD8+ T cells specific. 7. The fusion protein of claim 2, wherein said fusion protein has an overall length of between 10 and 100 amino acids. 8. The fusion protein of claim 2, wherein the heterologous peptide comprises the 80 N-terminal amino acids of the HLA-DR antigen-associated invariant chain, li. 9. An acylated peptide consisting of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof. 10. A pegylated peptide consisting of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof. 11. A composition comprising a peptide of claim 1 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 12. A composition comprising a fusion protein of claim 2 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 13. A composition comprising an acylated peptide of claim 9 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 14. A composition comprising a pegylated peptide of claim 10 or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 15. A method of inducing an immune response in a subject, the method comprising administering to the subject a peptide of claim 1 or a pharmaceutically acceptable salt thereof. 16. A method of inducing an immune response in a subject, the method comprising administering to the subject a fusion protein of claim 2 or a pharmaceutically acceptable salt thereof. 17. A method for producing activated cytotoxic T lymphocytes (CTL), the method comprising
contacting in vitro CTL with antigen-loaded human class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell or an artificial construct mimicking an antigen-presenting cell for a period of time sufficient to activate said CTL in an antigen specific manner, wherein said antigen is a peptide comprising SEQ ID NO: 1 wherein said peptide is not an underlying full-length polypeptide 18. An activated cytotoxic T lymphocyte (CTL) produced according to claim 1. 19. A method of inducing an immune response in a subject, the method comprising administering to the subject an acylated peptide of claim 9 or a pharmaceutically acceptable salt thereof. 20. A method of inducing an immune response in a subject, the method comprising administering to the subject a pegylated peptide of claim 10 or a pharmaceutically acceptable salt thereof. | 1,600 |
483 | 15,887,164 | 1,634 | Disclosed are nucleic acid molecules from the genome of Dirofilaria spp. nematodes that contain single nucleotide polymorphisms related to reduced responsiveness of the nematodes to macrocyclic lactones. In one example, the species of Dirofilaria is Dirofilaria immitis (the agent of heartworm in animals). Also disclosed are methods for determining the responsiveness of Dirofilaria spp. nematodes to macrocyclic lactones, methods for selecting a treatment to treat an animal infected with a Dirofilaria spp. nematode, and kits for determining the responsiveness of Dirofilaria spp. nematodes to macrocyclic lactones. | 1.-12. (canceled) 13. An isolated nucleic acid molecule comprising 5-300 nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 1-113 and 115-127, or a reverse complement thereof,
wherein the oligonucleotide includes a disclosed polymorphic site that correlates with resistance to a macrocyclic lactone, and wherein the oligonucleotide further includes a label. 14.-16. (canceled) 17. The isolated nucleic acid molecule of claim 13, wherein the nucleic acid molecule includes a fragment having a length of at least 10 nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 1-113 and 115-127, or a reverse complement thereof,
wherein the oligonucleotide includes a disclosed polymorphic site that correlates with resistance to a macrocyclic lactone. 18. The isolated nucleic acid molecule of claim 13, wherein the nucleic acid molecule includes a fragment having a length of at least 50 nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 1-113 and 115-127, or a reverse complement thereof,
wherein the oligonucleotide includes a disclosed polymorphic site that correlates with resistance to a macrocyclic lactone. 19. The isolated nucleic acid molecule of claim 13, wherein the nucleic acid molecule includes a fragment having a length of at least 100 nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 1-113 and 115-127, or a reverse complement thereof
wherein the oligonucleotide includes a disclosed polymorphic site that correlates with resistance to a macrocyclic lactone. 20. A kit for determining the responsiveness of a Dirofilaria spp. nematode to a macrocyclic lactone, the kit comprising: an isolated nucleic acid molecule comprising 5-300 nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 1-113 and 115-127, or a reverse complement thereof,
wherein the oligonucleotide includes a disclosed polymorphic site that correlates with resistance to a macrocyclic lactone, and wherein the oligonucleotide further includes a label. 21. The kit of claim 20, wherein the oligonucleotide is a probe, a primer or an aptamer. 22. The kit of claim 20, wherein the genotype of the nematode is determined by DNA sequencing, hybridization-based methods including with allele specific oligonucleotides, microarray analysis, enzyme-based methods, single strand conformational polymorphism (SSCP), high resolution melt (HRM) or approaches based on PCR, RT-PCR, or qRT-PCR. 23. The kit of claim 20, wherein the Dirofilaria spp. nematode is Dirofilaria immitis. 24. The kit of claim 20, wherein the macrocyclic lactone includes ivermectin, selamectin, milbemycin oxime or moxidectin. 25.-36. (canceled) | Disclosed are nucleic acid molecules from the genome of Dirofilaria spp. nematodes that contain single nucleotide polymorphisms related to reduced responsiveness of the nematodes to macrocyclic lactones. In one example, the species of Dirofilaria is Dirofilaria immitis (the agent of heartworm in animals). Also disclosed are methods for determining the responsiveness of Dirofilaria spp. nematodes to macrocyclic lactones, methods for selecting a treatment to treat an animal infected with a Dirofilaria spp. nematode, and kits for determining the responsiveness of Dirofilaria spp. nematodes to macrocyclic lactones.1.-12. (canceled) 13. An isolated nucleic acid molecule comprising 5-300 nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 1-113 and 115-127, or a reverse complement thereof,
wherein the oligonucleotide includes a disclosed polymorphic site that correlates with resistance to a macrocyclic lactone, and wherein the oligonucleotide further includes a label. 14.-16. (canceled) 17. The isolated nucleic acid molecule of claim 13, wherein the nucleic acid molecule includes a fragment having a length of at least 10 nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 1-113 and 115-127, or a reverse complement thereof,
wherein the oligonucleotide includes a disclosed polymorphic site that correlates with resistance to a macrocyclic lactone. 18. The isolated nucleic acid molecule of claim 13, wherein the nucleic acid molecule includes a fragment having a length of at least 50 nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 1-113 and 115-127, or a reverse complement thereof,
wherein the oligonucleotide includes a disclosed polymorphic site that correlates with resistance to a macrocyclic lactone. 19. The isolated nucleic acid molecule of claim 13, wherein the nucleic acid molecule includes a fragment having a length of at least 100 nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 1-113 and 115-127, or a reverse complement thereof
wherein the oligonucleotide includes a disclosed polymorphic site that correlates with resistance to a macrocyclic lactone. 20. A kit for determining the responsiveness of a Dirofilaria spp. nematode to a macrocyclic lactone, the kit comprising: an isolated nucleic acid molecule comprising 5-300 nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 1-113 and 115-127, or a reverse complement thereof,
wherein the oligonucleotide includes a disclosed polymorphic site that correlates with resistance to a macrocyclic lactone, and wherein the oligonucleotide further includes a label. 21. The kit of claim 20, wherein the oligonucleotide is a probe, a primer or an aptamer. 22. The kit of claim 20, wherein the genotype of the nematode is determined by DNA sequencing, hybridization-based methods including with allele specific oligonucleotides, microarray analysis, enzyme-based methods, single strand conformational polymorphism (SSCP), high resolution melt (HRM) or approaches based on PCR, RT-PCR, or qRT-PCR. 23. The kit of claim 20, wherein the Dirofilaria spp. nematode is Dirofilaria immitis. 24. The kit of claim 20, wherein the macrocyclic lactone includes ivermectin, selamectin, milbemycin oxime or moxidectin. 25.-36. (canceled) | 1,600 |
484 | 14,438,718 | 1,612 | Encapsulated bitter peptides, methods of encapsulating bitter peptides, and nutritional compositions including encapsulated bitter peptides are provided. The bitter peptides can be encapsulated in a hydrophobic matrix, such as an organogel, a solid lipid nanoparticle, a liposome or combinations thereof. The encapsulated bitter peptides can be bioavailable, can be selectively encapsulated such that peptides needed for emulsion stabilization are not encapsulated and can maintain encapsulation during further processing such as heat treatment and homogenization. | 1. A nutritional composition comprising bitter peptides encapsulated in a structure selected from the group consisting of organogels, liposomes, solid lipid nanoparticles and combinations thereof. 2. The nutritional composition of claim 1, wherein the structure is an organogel comprising an oil or melted fat and a gelator selected from the group consisting of phospholipids, lecithin, monoglyceride, amphiphilic peptides, sorbitan monostearate, mono-, di- and/or triacyglycerols, fatty acids, fatty alcohol, wax, phytosterol, and/or combinations thereof. 3. The nutritional composition of claim 1, wherein the structure is a liposome comprising phospholipids extracted from at least one of egg, milk or soya. 4. The nutritional composition of claim 1, wherein the structure is a solid lipid nanoparticle. 5. A method of encapsulating bitter peptides comprising the steps of:
forming an emulsion comprising a water phase containing protein hydrolysate and an oil phase comprising at least one of an oil or a melted fat; and adding a gelator to the emulsion to form an organogel after the bitter peptides from the protein hydrolysate migrate into oil droplets in the oil phase, the addition of the gelator entrapping the bitter peptides in the organogel. 6. The method of claim 5 comprising hydrolysis of a protein to form a solution comprising the protein hydrolysate, the bitter peptides being entrapped in the organogel in line such that the emulsion is formed after the hydrolysis directly in the solution comprising the protein hydrolysate. 7. A method of encapsulating bitter peptides comprising the steps of:
forming an emulsion comprising a water phase containing protein hydrolysate and an oil phase containing melted fat at a temperature above the melting point of the melted fat; and cooling the emulsion to generate solid lipid nanoparticles in which bitter peptides from the protein hydrolysate are entrapped. 8. The method of claim 7 comprising hydrolysis of a protein to form a solution comprising the protein hydrolysate, the bitter peptides being entrapped in the solid lipid nanoparticles in line such that the emulsion is formed after the hydrolysis directly in the solution comprising the protein hydrolysate. 9. A method of encapsulating bitter peptides comprising the steps of:
adding phospholipids to protein hydrolysate; and homogenizing the protein hydrolysate and the phospholipids to form liposomes that entrap bitter peptides from the protein hydrolysate. 10. The method of claim 9 comprising hydrolysis of at least one protein to form a solution comprising the protein hydrolysate, the bitter peptides being entrapped in the liposomes in line such that the phospholipids are added after the hydrolysis directly in the solution comprising the protein hydrolysate. 11. The method of claim 5, wherein the protein hydrolysate is a dairy protein hydrolysate. 12. The method of claim 5, wherein the hydrolysis forms non-bitter peptides, and at least a portion of the non-bitter peptides are not entrapped in the oil phase. 13. Bitter peptides encapsulated in a structure selected from the group consisting of organogels, liposomes, solid lipid nanoparticles and combinations thereof. 14. A method of providing nutrition to a person, comprising administering to the person a nutritional composition comprising bitter peptides from protein hydrolysate, the bitter peptides encapsulated in a structure selected from the group consisting of organogels, liposomes, solid lipid nanoparticles and combinations thereof. 15. The method of claim 7, wherein the protein hydrolysate is a dairy protein hydrolysate. 16. The method of claim 7, wherein the hydrolysis forms non-bitter peptides, and at least a portion of the non-bitter peptides are not entrapped in the oil phase. 17. The method of claim 9, wherein the protein hydrolysate is a dairy protein hydrolysate. 18. The method of claim 9, wherein the hydrolysis forms non-bitter peptides, and at least a portion of the non-bitter peptides are not entrapped in the oil phase. | Encapsulated bitter peptides, methods of encapsulating bitter peptides, and nutritional compositions including encapsulated bitter peptides are provided. The bitter peptides can be encapsulated in a hydrophobic matrix, such as an organogel, a solid lipid nanoparticle, a liposome or combinations thereof. The encapsulated bitter peptides can be bioavailable, can be selectively encapsulated such that peptides needed for emulsion stabilization are not encapsulated and can maintain encapsulation during further processing such as heat treatment and homogenization.1. A nutritional composition comprising bitter peptides encapsulated in a structure selected from the group consisting of organogels, liposomes, solid lipid nanoparticles and combinations thereof. 2. The nutritional composition of claim 1, wherein the structure is an organogel comprising an oil or melted fat and a gelator selected from the group consisting of phospholipids, lecithin, monoglyceride, amphiphilic peptides, sorbitan monostearate, mono-, di- and/or triacyglycerols, fatty acids, fatty alcohol, wax, phytosterol, and/or combinations thereof. 3. The nutritional composition of claim 1, wherein the structure is a liposome comprising phospholipids extracted from at least one of egg, milk or soya. 4. The nutritional composition of claim 1, wherein the structure is a solid lipid nanoparticle. 5. A method of encapsulating bitter peptides comprising the steps of:
forming an emulsion comprising a water phase containing protein hydrolysate and an oil phase comprising at least one of an oil or a melted fat; and adding a gelator to the emulsion to form an organogel after the bitter peptides from the protein hydrolysate migrate into oil droplets in the oil phase, the addition of the gelator entrapping the bitter peptides in the organogel. 6. The method of claim 5 comprising hydrolysis of a protein to form a solution comprising the protein hydrolysate, the bitter peptides being entrapped in the organogel in line such that the emulsion is formed after the hydrolysis directly in the solution comprising the protein hydrolysate. 7. A method of encapsulating bitter peptides comprising the steps of:
forming an emulsion comprising a water phase containing protein hydrolysate and an oil phase containing melted fat at a temperature above the melting point of the melted fat; and cooling the emulsion to generate solid lipid nanoparticles in which bitter peptides from the protein hydrolysate are entrapped. 8. The method of claim 7 comprising hydrolysis of a protein to form a solution comprising the protein hydrolysate, the bitter peptides being entrapped in the solid lipid nanoparticles in line such that the emulsion is formed after the hydrolysis directly in the solution comprising the protein hydrolysate. 9. A method of encapsulating bitter peptides comprising the steps of:
adding phospholipids to protein hydrolysate; and homogenizing the protein hydrolysate and the phospholipids to form liposomes that entrap bitter peptides from the protein hydrolysate. 10. The method of claim 9 comprising hydrolysis of at least one protein to form a solution comprising the protein hydrolysate, the bitter peptides being entrapped in the liposomes in line such that the phospholipids are added after the hydrolysis directly in the solution comprising the protein hydrolysate. 11. The method of claim 5, wherein the protein hydrolysate is a dairy protein hydrolysate. 12. The method of claim 5, wherein the hydrolysis forms non-bitter peptides, and at least a portion of the non-bitter peptides are not entrapped in the oil phase. 13. Bitter peptides encapsulated in a structure selected from the group consisting of organogels, liposomes, solid lipid nanoparticles and combinations thereof. 14. A method of providing nutrition to a person, comprising administering to the person a nutritional composition comprising bitter peptides from protein hydrolysate, the bitter peptides encapsulated in a structure selected from the group consisting of organogels, liposomes, solid lipid nanoparticles and combinations thereof. 15. The method of claim 7, wherein the protein hydrolysate is a dairy protein hydrolysate. 16. The method of claim 7, wherein the hydrolysis forms non-bitter peptides, and at least a portion of the non-bitter peptides are not entrapped in the oil phase. 17. The method of claim 9, wherein the protein hydrolysate is a dairy protein hydrolysate. 18. The method of claim 9, wherein the hydrolysis forms non-bitter peptides, and at least a portion of the non-bitter peptides are not entrapped in the oil phase. | 1,600 |
485 | 15,010,549 | 1,653 | The claimed subject matter comprises a device to collect and preserve cells comprising of: (1) a collection container comprised of a tube having an open end and a closed end, a closure in the open end of the tube, a vacuum drawn to a predetermined level inside the container; and (2) compounds including an anticoagulant agent and a fixative agent, wherein the compounds are in a sufficient amount to preserve said cells” original morphology and antigenic sites without significant dilution of said cells, and thereby allowing said cells to be directly analyzed by a flow cytometer without further treatment. The claimed subject matter further comprises of a method of making a collection device for cells comprising of: (1) providing a tube having an open end and a closed end; (2) preloading compounds including: an anticoagulant agent, and a fixative agent into the tube, wherein the compounds are in a sufficient amount to preserve the cells” original morphology and antigenic sites without significant dilution of the cells, and thereby allowing the cells to be directly analyzed by a flow cytometer without further treatment; (3) inserting a closure into the open end of the tube; and (4) drawing a vacuum inside the tube to a predetermined level to form the collection device. | 1-27. (canceled) 28. A method of inhibiting cellular aggregation in a biologically active sample comprising mixing an effective amount of diazolidinyl urea with a sample of viable cells, wherein the effective amount of diazolidinyl urea is in a concentration that is less than about 2:100 upon mixing with the sample of viable cells. 29. The method of claim 28, further comprising mixing an effective amount of diazolidinyl urea in combination with a non-chelating agent based anti-coagulating agent selected from hirudin, heparin, citric acid, salts of citric acid, oxalic acid, salts of oxalic acid, acid citrate dextrose, or mixtures thereof may be used, with the sample. 30. The method of claim 28, further comprising mixing an effective amount of diazolidinyl urea in combination with acid citrate dextrose with the biological sample. 31. The method of claim 28, wherein the diazolidinyl urea is mixed with the sample before a biological sample processing or testing. 32. The method of claim 28, wherein the diazolidinyl urea is in a solid or liquid form in a container and wherein the biological sample is added to the container. 33. The method of claim 28, wherein the biological sample is selected from the group consisting of whole blood, blood and bone marrow. 34. The method of claim 28, wherein upon mixing with the effective amount of diazolidinyl urea the biological sample is suitable for use in a microchannel for cell capturing. 35. The method of claim 28, wherein the effective amount of diazolidinyl urea in the biological sample provides for improved cell capture in a microchannel as compared to that in the absence of diazolidinyl urea in the biological sample. 36. A method of inhibiting cellular aggregation in a biological sample comprising mixing an effective amount of diazolidinyl urea with the sample, wherein cellular aggregation is reduced in the presence of diazolidinyl urea compared to the absence of diazolidinyl urea in the sample, wherein the effective amount of diazolidinyl urea is in a concentration that is less than about 2:100 upon mixing with the biological sample, and wherein upon mixing with the effective amount of diazolidinyl urea the biological sample is suitable for use in a microchannel for cell capturing. | The claimed subject matter comprises a device to collect and preserve cells comprising of: (1) a collection container comprised of a tube having an open end and a closed end, a closure in the open end of the tube, a vacuum drawn to a predetermined level inside the container; and (2) compounds including an anticoagulant agent and a fixative agent, wherein the compounds are in a sufficient amount to preserve said cells” original morphology and antigenic sites without significant dilution of said cells, and thereby allowing said cells to be directly analyzed by a flow cytometer without further treatment. The claimed subject matter further comprises of a method of making a collection device for cells comprising of: (1) providing a tube having an open end and a closed end; (2) preloading compounds including: an anticoagulant agent, and a fixative agent into the tube, wherein the compounds are in a sufficient amount to preserve the cells” original morphology and antigenic sites without significant dilution of the cells, and thereby allowing the cells to be directly analyzed by a flow cytometer without further treatment; (3) inserting a closure into the open end of the tube; and (4) drawing a vacuum inside the tube to a predetermined level to form the collection device.1-27. (canceled) 28. A method of inhibiting cellular aggregation in a biologically active sample comprising mixing an effective amount of diazolidinyl urea with a sample of viable cells, wherein the effective amount of diazolidinyl urea is in a concentration that is less than about 2:100 upon mixing with the sample of viable cells. 29. The method of claim 28, further comprising mixing an effective amount of diazolidinyl urea in combination with a non-chelating agent based anti-coagulating agent selected from hirudin, heparin, citric acid, salts of citric acid, oxalic acid, salts of oxalic acid, acid citrate dextrose, or mixtures thereof may be used, with the sample. 30. The method of claim 28, further comprising mixing an effective amount of diazolidinyl urea in combination with acid citrate dextrose with the biological sample. 31. The method of claim 28, wherein the diazolidinyl urea is mixed with the sample before a biological sample processing or testing. 32. The method of claim 28, wherein the diazolidinyl urea is in a solid or liquid form in a container and wherein the biological sample is added to the container. 33. The method of claim 28, wherein the biological sample is selected from the group consisting of whole blood, blood and bone marrow. 34. The method of claim 28, wherein upon mixing with the effective amount of diazolidinyl urea the biological sample is suitable for use in a microchannel for cell capturing. 35. The method of claim 28, wherein the effective amount of diazolidinyl urea in the biological sample provides for improved cell capture in a microchannel as compared to that in the absence of diazolidinyl urea in the biological sample. 36. A method of inhibiting cellular aggregation in a biological sample comprising mixing an effective amount of diazolidinyl urea with the sample, wherein cellular aggregation is reduced in the presence of diazolidinyl urea compared to the absence of diazolidinyl urea in the sample, wherein the effective amount of diazolidinyl urea is in a concentration that is less than about 2:100 upon mixing with the biological sample, and wherein upon mixing with the effective amount of diazolidinyl urea the biological sample is suitable for use in a microchannel for cell capturing. | 1,600 |
486 | 13,891,562 | 1,632 | Described herein are compositions comprising decellularized cardiac extracellular matrix and therapeutic uses thereof. Methods for treating, repairing or regenerating defective, diseased, damaged or ischemic cells, tissues or organs in a subject, preferably a human, using a decellularized cardiac extracellular matrix of the invention are provided. Methods of preparing cardiomyocyte culture surfaces and culturing cells with absorbed decellularized cardiac extracellular matrix are provided. | 1. A composition comprising decellularized extracellular matrix derived from cardiac or skeletal muscle tissue, wherein said decellularized extracellular matrix retains native tissue specific proteins and glycosaminoglycans, and wherein said composition is in a solution form at a temperature between 20° C-25° C. and in a gel form at a temperature greater than 25° C. 2. The composition of claim 1, wherein said composition comprises naturally or non-naturally occurring factors that recruit cells into the composition. 3. The composition of claim 1, wherein said composition is injectable and is formulated to be delivered through a 27G or smaller needle for tissue repair or regeneration. 4. The composition of claim 1, wherein said composition further comprises cells selected from the group consisting of pluripotent stem cells, multipotent stem cells, cardiomyocytes, cardiac progenitor cells, skeletal myoblasts, or skeletal muscle progenitor cells. 5. The composition of claim 1, wherein said composition further comprises an exogenous therapeutic agent or a polymer in a therapeutically acceptable formulation. 6. The composition of claim 1, wherein said composition further comprises cells, drugs, proteins, or polysaccharides that can be delivered inside, attached to the composition before, during, or after gelation. 7. The composition of claim 1, wherein said composition comprising the decellularized extracellular matrix from cardiac tissue is formulated to coat tissue culture plates to culture cardiomyocytes or other cardiac cell progenitors. 8. The composition of claim 1, wherein the composition comprising the decellularized extracellular matrix from cardiac tissue is formulated to be injected or implanted into the infarct wall following a myocardial infarction for cardiac tissue repair or regeneration. 9. The composition of claim 1, wherein said composition comprising the decellularized extracellular matrix from skeletal muscle tissue is formulated to coat tissue culture plates to culture skeletal myoblasts or other skeletal muscle progenitor cells. 10. The composition of claim 1, wherein the composition comprising the decellularized extracellular matrix from skeletal muscle tissue is formulated to be injected or implanted in a body for skeletal muscle repair or regeneration. 11. A method of producing a composition comprising decellularized extracellular matrix from cardiac or skeletal muscle tissue, comprising:
(a) obtaining a cardiac or skeletal muscle tissue sample having an extracellular matrix component and a non-extracellular matrix component; (b) processing the cardiac or skeletal muscle tissue sample with a detergent to remove the non-extracellular matrix component to obtain decellularized cardiac extracellular matrix; and (c) sterilizing the decellularized cardiac or skeletal muscle extracellular matrix. 12. The method of claim 11, further comprising a step of lyophilizing and grinding up the decellularized cardiac or skeletal muscle extracellular matrix. 13. The method of claim 11, further comprising a step of enzymatically treating the decellularized cardiac or skeletal muscle extracellular matrix. 14. The method of claim 11, further comprising a step of suspending and neutralizing said decellularized cardiac or skeletal muscle extracellular matrix in a saline buffered solution. 15. The method of claim 14, wherein said resulting saline buffered solution comprising said decellularized cardiac or skeletal muscle extracellular matrix is injectable through a 27G or smaller needle at 20° C-25° C., and spontaneously forms in a gel form at a temperature greater than 25° C. 16. The method of claim 14, wherein said resulting saline buffered solution comprising said decellularized cardiac or skeletal muscle extracellular matrix further comprises cells, drugs, proteins, or polysaccharides that can be delivered inside, attached to the solution before, during, or after gelation. 17. The method of claim 14, further comprising placing said resulting saline buffered solution comprising said decellularized cardiac or skeletal muscle extracellular matrix into tissue culture plates or wells to form into an adsorbed matrix for culturing cells. 18. A method of culturing cells on an adsorbed matrix comprising the steps of:
(a) providing a solution comprising decellularized extracellular matrix derived from cardiac or skeletal muscle tissue into a tissue culture device; (b) incubating said tissue culture device to absorb at least some of the decellularized extracellular matrix onto the device; (c) removing said solution; and (d) culturing cells on the adsorbed matrix. 19. The method of claim 18, wherein said cells are cardiomyocytes, cardiac cell progenitors, or other cell types relevant to cardiac tissue repair. 20. The method of claim 18, wherein said cells are skeletal myoblasts, skeletal muscle progenitor cells, or other cell types relevant to skeletal muscle tissue repair. | Described herein are compositions comprising decellularized cardiac extracellular matrix and therapeutic uses thereof. Methods for treating, repairing or regenerating defective, diseased, damaged or ischemic cells, tissues or organs in a subject, preferably a human, using a decellularized cardiac extracellular matrix of the invention are provided. Methods of preparing cardiomyocyte culture surfaces and culturing cells with absorbed decellularized cardiac extracellular matrix are provided.1. A composition comprising decellularized extracellular matrix derived from cardiac or skeletal muscle tissue, wherein said decellularized extracellular matrix retains native tissue specific proteins and glycosaminoglycans, and wherein said composition is in a solution form at a temperature between 20° C-25° C. and in a gel form at a temperature greater than 25° C. 2. The composition of claim 1, wherein said composition comprises naturally or non-naturally occurring factors that recruit cells into the composition. 3. The composition of claim 1, wherein said composition is injectable and is formulated to be delivered through a 27G or smaller needle for tissue repair or regeneration. 4. The composition of claim 1, wherein said composition further comprises cells selected from the group consisting of pluripotent stem cells, multipotent stem cells, cardiomyocytes, cardiac progenitor cells, skeletal myoblasts, or skeletal muscle progenitor cells. 5. The composition of claim 1, wherein said composition further comprises an exogenous therapeutic agent or a polymer in a therapeutically acceptable formulation. 6. The composition of claim 1, wherein said composition further comprises cells, drugs, proteins, or polysaccharides that can be delivered inside, attached to the composition before, during, or after gelation. 7. The composition of claim 1, wherein said composition comprising the decellularized extracellular matrix from cardiac tissue is formulated to coat tissue culture plates to culture cardiomyocytes or other cardiac cell progenitors. 8. The composition of claim 1, wherein the composition comprising the decellularized extracellular matrix from cardiac tissue is formulated to be injected or implanted into the infarct wall following a myocardial infarction for cardiac tissue repair or regeneration. 9. The composition of claim 1, wherein said composition comprising the decellularized extracellular matrix from skeletal muscle tissue is formulated to coat tissue culture plates to culture skeletal myoblasts or other skeletal muscle progenitor cells. 10. The composition of claim 1, wherein the composition comprising the decellularized extracellular matrix from skeletal muscle tissue is formulated to be injected or implanted in a body for skeletal muscle repair or regeneration. 11. A method of producing a composition comprising decellularized extracellular matrix from cardiac or skeletal muscle tissue, comprising:
(a) obtaining a cardiac or skeletal muscle tissue sample having an extracellular matrix component and a non-extracellular matrix component; (b) processing the cardiac or skeletal muscle tissue sample with a detergent to remove the non-extracellular matrix component to obtain decellularized cardiac extracellular matrix; and (c) sterilizing the decellularized cardiac or skeletal muscle extracellular matrix. 12. The method of claim 11, further comprising a step of lyophilizing and grinding up the decellularized cardiac or skeletal muscle extracellular matrix. 13. The method of claim 11, further comprising a step of enzymatically treating the decellularized cardiac or skeletal muscle extracellular matrix. 14. The method of claim 11, further comprising a step of suspending and neutralizing said decellularized cardiac or skeletal muscle extracellular matrix in a saline buffered solution. 15. The method of claim 14, wherein said resulting saline buffered solution comprising said decellularized cardiac or skeletal muscle extracellular matrix is injectable through a 27G or smaller needle at 20° C-25° C., and spontaneously forms in a gel form at a temperature greater than 25° C. 16. The method of claim 14, wherein said resulting saline buffered solution comprising said decellularized cardiac or skeletal muscle extracellular matrix further comprises cells, drugs, proteins, or polysaccharides that can be delivered inside, attached to the solution before, during, or after gelation. 17. The method of claim 14, further comprising placing said resulting saline buffered solution comprising said decellularized cardiac or skeletal muscle extracellular matrix into tissue culture plates or wells to form into an adsorbed matrix for culturing cells. 18. A method of culturing cells on an adsorbed matrix comprising the steps of:
(a) providing a solution comprising decellularized extracellular matrix derived from cardiac or skeletal muscle tissue into a tissue culture device; (b) incubating said tissue culture device to absorb at least some of the decellularized extracellular matrix onto the device; (c) removing said solution; and (d) culturing cells on the adsorbed matrix. 19. The method of claim 18, wherein said cells are cardiomyocytes, cardiac cell progenitors, or other cell types relevant to cardiac tissue repair. 20. The method of claim 18, wherein said cells are skeletal myoblasts, skeletal muscle progenitor cells, or other cell types relevant to skeletal muscle tissue repair. | 1,600 |
487 | 13,996,097 | 1,642 | Disclosed are CD39 antagonists that can inhibit the immunosuppressive effect of a CD39-expressing cancerous cell, and methods of using the CD39 antagonists. | 1. A method for inhibiting the immunosuppressive effects of a CD39-expressing cancerous cell, comprising contacting said cancerous cell with a CD39 antagonist. 2. The method according to claim 1, wherein said cancerous cell is selected from haematological cancer cells, melanoma cells, ovarian cancer, thyroid cancer, lung cancer, kidney cancer. 3. The method according to claim 1, wherein said antagonist is selected from the group consisting of antibodies and chemical compounds, said antibodies and chemical compounds having activity that can down regulate the cell membrane expression of CD39, block or decrease CD39 ATPase/ADPase activity, block or decrease cancer cells-mediated inhibition or suppression of the immune antitumor response, or block or decrease cancer cells-mediated inhibition or suppression of the CD4 and/or CDS T cell response. 4. The method according to claim 3, wherein said antagonist is a CD39 monoclonal antibody. 5. The method according to claim 4, wherein said monoclonal antibody comprises:
a heavy chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO:2 for CDR-H1, SEQ ID NO:3 for CDR-H2 and SEQ ID NO:4 for CDR-H3; and/or a light chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO:6 for CDR-L1, SEQ ID NO:7 for CDR-L2 and SEQ ID NO:S for CDR-L3. 6. The method according to claim 4, wherein said monoclonal antibody comprises:
a heavy chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO: 12 for CDR-H1, SEQ ID NO: 13 for CDR-H2 and SEQ ID NO: 14 for CDR-H3; and/or a light chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO: 16 for CDR SEQ ID NO:17 for CDR-L2 and SEQ ID NO;18 for CDR-L3. 7. The method according to claim 4, wherein said monoclonal antibody is selected from the group consisting of BYI2, BY40 and BA54g. 8. The method according to claim 4, wherein said monoclonal antibody is selected from the group consisting of:
the monoclonal antibody produced by the hybridoma cell line deposited with the CNCM under the accession number I-3889; and the monoclonal antibody produced by the hybridoma cell line deposited with the CNCM under the accession number CNCM I-4171. 9. A method of treating cancer comprising administering to a subject in need of treatment an effective amount of a CD39 antagonist selected from the group consisting of antibodies and chemical compounds. 10. The method according to claim 9, wherein said cancer is selected from the group consisting of melanoma, haematological cancer, ovarian cancer, thyroid cancer, lung cancer, and kidney cancer. 11. The method according to claim 10 wherein said cancer is selected from the group consisting of haematological cancer and melanoma. 12. The method according to claim 11, wherein said CD39 antagonist comprises a monoclonal antibody is selected from the group consisting of BY12, BY4O and BA54g. 13. A method for identifying a subject suffering from a cancer comprising the step of determining the presence of CD39 expression on the cancerous cells of a sample from said subject, using the CD39 antibody according to claim 18. 14. The method according to claim 9, wherein said CD39 antagonist comprises a monoclonal antibody comprising:
a heavy chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO:2 for CDR-H1, SEQ ID NO:3 for CDR-H2 and SEQ ID NO:4 for CDR-H3; and/or a light chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO:6 for CDR-L1, SEQ ID NO:7 for CDR-L2 and SEQ IDNO:S for CDR-L3. 15. The method according to claim 9, wherein said CD39 antagonist comprises a monoclonal antibody comprising:
a heavy chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO: 12 for CDR-H1, SEQ ID NO: 13 for CDR-H2 and SEQ ID NO: 14 for CDR-H3: and/or a light chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO: 16 for CDR -L1, SEQ ID NO:17 for CDR-L2 and SEQ ID NO:18 for CDR-L3. 16. The method according to claim 9, wherein said CD39 antagonist comprises a monoclonal antibody selected from the group consisting of:
the antibody produced by the hybridoma cell line deposited with the CNCM under the accession number I-3889; and the antibody produced by the hybridoma cell line deposited with the CNCM under the accession number CNCM I-4171. 17. A hybridoma deposited with the CNCM having accession number I-3889 or I-4171. 18. An isolated CD39 monoclonal antibody produced by the hybridoma of claim 17. 19. The monoclonal antibody according to claim 18, or a CD39 binding fragment thereof, comprising:
a heavy chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO:2 for CDR-H1, SEQ ID NO:3 for CDR-H2 and SEQ ID NO:4 for CDR-H3; and/or a light chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO:6 for CDR-L1, SEQ ID NO:7 for CDR-L2 and SEQ IDNO:S for CDR-L3. 20. The monoclonal antibody according to claim 18, or a CD39 binding fragment thereof, comprising:
a heavy chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO: 12 for CDR-H1, SEQ ID NO: 13 for CDR-H2 and SEQ ID NO: 14 for CDR-H3; and/or a light chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO: 16 for CDR -L1 SEQ ID NO:17 for CDR-L2 and SEQ ID NO:18 for CDR-L3. | Disclosed are CD39 antagonists that can inhibit the immunosuppressive effect of a CD39-expressing cancerous cell, and methods of using the CD39 antagonists.1. A method for inhibiting the immunosuppressive effects of a CD39-expressing cancerous cell, comprising contacting said cancerous cell with a CD39 antagonist. 2. The method according to claim 1, wherein said cancerous cell is selected from haematological cancer cells, melanoma cells, ovarian cancer, thyroid cancer, lung cancer, kidney cancer. 3. The method according to claim 1, wherein said antagonist is selected from the group consisting of antibodies and chemical compounds, said antibodies and chemical compounds having activity that can down regulate the cell membrane expression of CD39, block or decrease CD39 ATPase/ADPase activity, block or decrease cancer cells-mediated inhibition or suppression of the immune antitumor response, or block or decrease cancer cells-mediated inhibition or suppression of the CD4 and/or CDS T cell response. 4. The method according to claim 3, wherein said antagonist is a CD39 monoclonal antibody. 5. The method according to claim 4, wherein said monoclonal antibody comprises:
a heavy chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO:2 for CDR-H1, SEQ ID NO:3 for CDR-H2 and SEQ ID NO:4 for CDR-H3; and/or a light chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO:6 for CDR-L1, SEQ ID NO:7 for CDR-L2 and SEQ ID NO:S for CDR-L3. 6. The method according to claim 4, wherein said monoclonal antibody comprises:
a heavy chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO: 12 for CDR-H1, SEQ ID NO: 13 for CDR-H2 and SEQ ID NO: 14 for CDR-H3; and/or a light chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO: 16 for CDR SEQ ID NO:17 for CDR-L2 and SEQ ID NO;18 for CDR-L3. 7. The method according to claim 4, wherein said monoclonal antibody is selected from the group consisting of BYI2, BY40 and BA54g. 8. The method according to claim 4, wherein said monoclonal antibody is selected from the group consisting of:
the monoclonal antibody produced by the hybridoma cell line deposited with the CNCM under the accession number I-3889; and the monoclonal antibody produced by the hybridoma cell line deposited with the CNCM under the accession number CNCM I-4171. 9. A method of treating cancer comprising administering to a subject in need of treatment an effective amount of a CD39 antagonist selected from the group consisting of antibodies and chemical compounds. 10. The method according to claim 9, wherein said cancer is selected from the group consisting of melanoma, haematological cancer, ovarian cancer, thyroid cancer, lung cancer, and kidney cancer. 11. The method according to claim 10 wherein said cancer is selected from the group consisting of haematological cancer and melanoma. 12. The method according to claim 11, wherein said CD39 antagonist comprises a monoclonal antibody is selected from the group consisting of BY12, BY4O and BA54g. 13. A method for identifying a subject suffering from a cancer comprising the step of determining the presence of CD39 expression on the cancerous cells of a sample from said subject, using the CD39 antibody according to claim 18. 14. The method according to claim 9, wherein said CD39 antagonist comprises a monoclonal antibody comprising:
a heavy chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO:2 for CDR-H1, SEQ ID NO:3 for CDR-H2 and SEQ ID NO:4 for CDR-H3; and/or a light chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO:6 for CDR-L1, SEQ ID NO:7 for CDR-L2 and SEQ IDNO:S for CDR-L3. 15. The method according to claim 9, wherein said CD39 antagonist comprises a monoclonal antibody comprising:
a heavy chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO: 12 for CDR-H1, SEQ ID NO: 13 for CDR-H2 and SEQ ID NO: 14 for CDR-H3: and/or a light chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO: 16 for CDR -L1, SEQ ID NO:17 for CDR-L2 and SEQ ID NO:18 for CDR-L3. 16. The method according to claim 9, wherein said CD39 antagonist comprises a monoclonal antibody selected from the group consisting of:
the antibody produced by the hybridoma cell line deposited with the CNCM under the accession number I-3889; and the antibody produced by the hybridoma cell line deposited with the CNCM under the accession number CNCM I-4171. 17. A hybridoma deposited with the CNCM having accession number I-3889 or I-4171. 18. An isolated CD39 monoclonal antibody produced by the hybridoma of claim 17. 19. The monoclonal antibody according to claim 18, or a CD39 binding fragment thereof, comprising:
a heavy chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO:2 for CDR-H1, SEQ ID NO:3 for CDR-H2 and SEQ ID NO:4 for CDR-H3; and/or a light chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO:6 for CDR-L1, SEQ ID NO:7 for CDR-L2 and SEQ IDNO:S for CDR-L3. 20. The monoclonal antibody according to claim 18, or a CD39 binding fragment thereof, comprising:
a heavy chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO: 12 for CDR-H1, SEQ ID NO: 13 for CDR-H2 and SEQ ID NO: 14 for CDR-H3; and/or a light chain wherein the variable domain comprises at least one CDR having a sequence selected from the group consisting of SEQ ID NO: 16 for CDR -L1 SEQ ID NO:17 for CDR-L2 and SEQ ID NO:18 for CDR-L3. | 1,600 |
488 | 12,640,913 | 1,653 | The present invention relates to apparatus, methods, and applications for treating wastewater, and more particularly to biological processes for removing pollutants from wastewater. This invention further relates to apparatus and methods for growing microbes on-site at a wastewater treatment facility, and for economically inoculating sufficient microbes to solve various treatment problems rapidly | 1-92. (canceled) 93. A method of reducing the amount of settling aid required by a wastewater treatment plant comprising:
providing an on-site system for growing of microbes at the wastewater treatment plant, the on-site system comprising: a main tank, an input for water, an output for a treatment batch, a mixing apparatus, and a temperature control apparatus; depositing nutrient, water and an inoculum comprising microbes into the on-site system; growing the inoculum in the on-site system to provide a treatment batch comprising an increased number of the microbes; and directly applying at least a portion of the treatment batch, said portion containing microbes, to the polluted wastewater, such that the microbes are not isolated, concentrated or freeze dried between the steps of growing and applying, and wherein the microbes reduce the pollutants in the wastewater as measured by at least one of biochemical oxygen demand, chemical oxygen demand, total organic carbon, or total carbon; wherein the amount of settling aid used in the wastewater treatment plant is reduced by at least about 50 percent. 94. The method of claim 93, wherein the amount of settling aid used in the wastewater treatment plant is reduced by at least about 25 percent. 95. The method of claim 93, wherein the amount of settling aid used in the wastewater treatment plant is reduced by 100 percent. 96. The method of claim 74, wherein growing the inoculum is for about 8 to 24 hours. 97. The method of claim 74, wherein the on-site system comprises at least one growth tank, aeration, and a controller. 98. The method of claim 97, wherein the on-site system comprises at least two growth tanks. 99. The method of claim 97, wherein the growth tank holds from about 250 gallons to about 1000 gallons. 100. The method of claim 97, wherein the growth tank holds from about 0.25 gallons to about 250 gallons. 101. The method of claim 97, wherein the growth tank holds about 1000 gallons. 102. The method of claim 74, wherein the step of applying comprises releasing the portion of the treatment batch from the on-site system directly onto the polluted wastewater. 103. The method of claim 74, wherein the step of growing further comprises aerating the inoculum. 104. The method of claim 74, comprising depositing a defoamer. | The present invention relates to apparatus, methods, and applications for treating wastewater, and more particularly to biological processes for removing pollutants from wastewater. This invention further relates to apparatus and methods for growing microbes on-site at a wastewater treatment facility, and for economically inoculating sufficient microbes to solve various treatment problems rapidly1-92. (canceled) 93. A method of reducing the amount of settling aid required by a wastewater treatment plant comprising:
providing an on-site system for growing of microbes at the wastewater treatment plant, the on-site system comprising: a main tank, an input for water, an output for a treatment batch, a mixing apparatus, and a temperature control apparatus; depositing nutrient, water and an inoculum comprising microbes into the on-site system; growing the inoculum in the on-site system to provide a treatment batch comprising an increased number of the microbes; and directly applying at least a portion of the treatment batch, said portion containing microbes, to the polluted wastewater, such that the microbes are not isolated, concentrated or freeze dried between the steps of growing and applying, and wherein the microbes reduce the pollutants in the wastewater as measured by at least one of biochemical oxygen demand, chemical oxygen demand, total organic carbon, or total carbon; wherein the amount of settling aid used in the wastewater treatment plant is reduced by at least about 50 percent. 94. The method of claim 93, wherein the amount of settling aid used in the wastewater treatment plant is reduced by at least about 25 percent. 95. The method of claim 93, wherein the amount of settling aid used in the wastewater treatment plant is reduced by 100 percent. 96. The method of claim 74, wherein growing the inoculum is for about 8 to 24 hours. 97. The method of claim 74, wherein the on-site system comprises at least one growth tank, aeration, and a controller. 98. The method of claim 97, wherein the on-site system comprises at least two growth tanks. 99. The method of claim 97, wherein the growth tank holds from about 250 gallons to about 1000 gallons. 100. The method of claim 97, wherein the growth tank holds from about 0.25 gallons to about 250 gallons. 101. The method of claim 97, wherein the growth tank holds about 1000 gallons. 102. The method of claim 74, wherein the step of applying comprises releasing the portion of the treatment batch from the on-site system directly onto the polluted wastewater. 103. The method of claim 74, wherein the step of growing further comprises aerating the inoculum. 104. The method of claim 74, comprising depositing a defoamer. | 1,600 |
489 | 13,676,806 | 1,699 | The invention herein comprises amyloid beta-derived diffusible ligands (ADDLs), compositions comprising ADDLs, ADDL-surrogates, ADDL-binding molecules, and methods of using any of the foregoing compounds and compositions. ADDLs comprise amyloid β protein assembled into soluble, globular, non-fibrillar, oligomeric structures capable of activating specific cellular processes. The invention also comprises methods of generating ADDL-specific antibodies and methods of using ADDL-specific antibodies for assaying the formation, presence, receptor protein binding and cellular activity of ADDLs, as well as using such antibodies to detect compounds that block the formation or activity of ADDLs, and methods of identifying such compounds. The invention further provides methods of using ADDL-specific antibodies in modulating ADDL formation and/or activity, inter alia in the treatment of learning and/or memory disorders. | 1. A method for producing an amyloid beta-derived diffusible ligand (ADDL) neutralizing antibody comprising
(a) injecting ADDLs into an animal to induce an immune response to the ADDLs; (b) isolating antibodies that bind to ADDLs; (c) identifying antibodies of (b) that neutralize ADDL neurotoxicity thereby producing an ADDL neutralizing antibody. 2. The method of claim 1, wherein the ADDLs of step (a) are obtained by
(i) dissolving monomeric amyloid beta peptide in a solvent to form a stock solution; (ii) diluting the stock solution; and (iii) incubating the diluted stock solution so that ADDLs are formed. 3. The method of claim 2, wherein the monomeric amyloid beta peptide of step (i) is prepared by
(A) dissolving amyloid beta peptide in hexafluoroisopropanol; and (B) removing the hexafluoroisopropanol to obtain monomeric amyloid beta peptide. 4. The method of claim 2, wherein the solvent of step (i) is dimethyl sulfoxide. 5. The method of claim 2, wherein step (ii) comprises diluting the stock solution in cell culture medium. 6. The method of claim 1, further comprising selecting antibodies that do not bind to monomeric amyloid beta peptide. 7. The method of claim 1, further comprising selecting antibodies that do not bind to amyloid fibrils. 8. The method of claim 1, further comprising selecting antibodies that do not bind to monomeric amyloid beta peptide or amyloid fibrils. 9. An amyloid beta-derived diffusible ligand (ADDL) neutralizing antibody produced by the method of claim 1. | The invention herein comprises amyloid beta-derived diffusible ligands (ADDLs), compositions comprising ADDLs, ADDL-surrogates, ADDL-binding molecules, and methods of using any of the foregoing compounds and compositions. ADDLs comprise amyloid β protein assembled into soluble, globular, non-fibrillar, oligomeric structures capable of activating specific cellular processes. The invention also comprises methods of generating ADDL-specific antibodies and methods of using ADDL-specific antibodies for assaying the formation, presence, receptor protein binding and cellular activity of ADDLs, as well as using such antibodies to detect compounds that block the formation or activity of ADDLs, and methods of identifying such compounds. The invention further provides methods of using ADDL-specific antibodies in modulating ADDL formation and/or activity, inter alia in the treatment of learning and/or memory disorders.1. A method for producing an amyloid beta-derived diffusible ligand (ADDL) neutralizing antibody comprising
(a) injecting ADDLs into an animal to induce an immune response to the ADDLs; (b) isolating antibodies that bind to ADDLs; (c) identifying antibodies of (b) that neutralize ADDL neurotoxicity thereby producing an ADDL neutralizing antibody. 2. The method of claim 1, wherein the ADDLs of step (a) are obtained by
(i) dissolving monomeric amyloid beta peptide in a solvent to form a stock solution; (ii) diluting the stock solution; and (iii) incubating the diluted stock solution so that ADDLs are formed. 3. The method of claim 2, wherein the monomeric amyloid beta peptide of step (i) is prepared by
(A) dissolving amyloid beta peptide in hexafluoroisopropanol; and (B) removing the hexafluoroisopropanol to obtain monomeric amyloid beta peptide. 4. The method of claim 2, wherein the solvent of step (i) is dimethyl sulfoxide. 5. The method of claim 2, wherein step (ii) comprises diluting the stock solution in cell culture medium. 6. The method of claim 1, further comprising selecting antibodies that do not bind to monomeric amyloid beta peptide. 7. The method of claim 1, further comprising selecting antibodies that do not bind to amyloid fibrils. 8. The method of claim 1, further comprising selecting antibodies that do not bind to monomeric amyloid beta peptide or amyloid fibrils. 9. An amyloid beta-derived diffusible ligand (ADDL) neutralizing antibody produced by the method of claim 1. | 1,600 |
490 | 15,547,067 | 1,617 | Agent for lightening keratin fibers and method for changing the color of keratinic fibers are provided herein. In an embodiment, an agent for lightening keratin fibers includes, relative to the weight thereof, a) from about 0.01 to about 5 wt % ethyl cellulose, b) from about 5 to about 70 wt % oil component(s), c) from about 1 to about 70 wt % peroxydisulphate(s) from the group of sodium peroxydisulphate and/or potassium peroxydisulphate and/or ammonium peroxydisulphate. | 1. An agent for lightening keratin fibers, comprising relative to the weight thereof
a) from about 0.01 to about 5 wt % ethyl cellulose, b) from about 5 to about 70 wt % oil component(s), c) from about 1 to about 70 wt % peroxydisulphate(s) from the group of sodium peroxydisulphate and/or potassium peroxydisulphate and/or ammonium peroxydisulphate. 2. The agent according to claim 1, comprising from about 0.05 to about 7.5 wt % ethyl cellulose having formula (I)
wherein n stands for integers from about 50 to about 500. 3. The agent according to either claim 1, comprising from about 0.05 to about 7.5 wt % ethyl cellulose(s) whose degree of ethoxylation is from about 45 to about 50%. 4. The agent according to claim 1, comprising from about 22.5 to about 70 wt % oil(s) chosen from the group of paraffin oil, polyisobutene, the alkyl benzoates, isopropyl palmitate, isohexadecane, isododecane, isononyl isononanoate, or combinations thereof. 5. The agent according to claim 1, comprising from about 1 to about 15 wt % cetearyl alcohol. 6. The agent according to claim 1, comprising from about 2.5 to about 65 wt % peroxydisulphate(s) from the group of sodium peroxydisulphate and/or potassium peroxydisulphate. 7. The agent according to claim 1, comprising from about 0 to about <0.1 wt % ammonia. 8. The agent according to claim 1, wherein after preparation, the agent has a viscosity (Brookfield RV-2, Helipath, Spindle TF, 4 rpm, 60 s) of from about 100 Pas to about 10,000 Pas (from about 105 mPas to about 107 mPas). 9. A method for changing the color of keratinic fibers, in which at least two separately packaged preparations (A) and (B), of which preparation (A) comprises at least one persulphate and preparation (B) comprises at least one oxidizing agent, wherein the preparations (A) and (B) are mixed to form an application mixture, wherein the application mixture is applied to the fibers and is rinsed off again after a contact time, and wherein preparation (A) comprises
a) from about 0.01 to about 5 wt % ethyl cellulose, b) from about 5 to about 70 wt % oil component(s), c) from about 1 to about 70 wt % peroxydisulphate(s) from the group of sodium peroxydisulphate and/or potassium peroxydisulphate and/or ammonium peroxydisulphate. 10. The method according to claim 9, wherein the application mixture has a viscosity (Brookfield RV-2, Helipath, spindle TF, 4 rpm, 60 s) of from about 1 Pas to about 100 Pas (from about 103 mPas to about 105 mPas). 11. The agent according to claim 1, comprising from about 0.3 to about 1.5 wt %, ethyl cellulose having formula (I)
wherein n stands for integers from about 50 to about 500. 12. The agent according to claim 1, comprising from about 0.05 to about 7.5 wt %, ethyl cellulose having formula (I)
wherein n stands for integers from about 200 to about 250. 13. The agent according to claim 1, comprising from about 0.3 to about 1.5 wt %, ethyl cellulose(s) whose degree of ethoxylation is from about 45 to about 50%. 14. The agent according to claim 1, comprising from about 0.05 to about 7.5 wt % ethyl cellulose(s) whose degree of ethoxylation is from about 48 to about 49.5%. 15. The agent according to claim 1, comprising from about 32.5 to about 50 wt % oil(s) chosen from the group of paraffin oil, polyisobutene, the alkyl benzoates, isopropyl palmitate, isohexadecane, isododecane, isononyl isononanoate, or combinations thereof. 16. The agent according to claim 1, comprising from about 5 to about 7.5 wt % cetearyl alcohol. 17. The agent according to claim 1, comprising from about 12.5 to about 45 wt % peroxydisulphate(s) chosen from the group of sodium peroxydisulphate and/or potassium peroxydisulphate. 18. The agent according to claim 1, comprising from 0 wt % ammonia. 19. The agent according to claim 1, wherein after preparation, the agent has a viscosity (Brookfield RV-2, Helipath, Spindle TF, 4 rpm, 60 s) of from about 250 Pas to about 2,000 Pas (from about 2.5×105 mPas to about 2×106 mPas) at 25° C. 20. An agent for lightening keratin fibers, comprising relative to the weight thereof
a) from about 0.3 to about 1.5 wt % ethyl cellulose having formula (I)
wherein n stands for integers from about 200 to about 250,
b) from about 5 to about 70 wt % oil component(s),
c) from about 12.5 to about 45 wt % peroxydisulphate(s) chosen from the group of sodium peroxydisulphate and/or potassium peroxydisulphate. | Agent for lightening keratin fibers and method for changing the color of keratinic fibers are provided herein. In an embodiment, an agent for lightening keratin fibers includes, relative to the weight thereof, a) from about 0.01 to about 5 wt % ethyl cellulose, b) from about 5 to about 70 wt % oil component(s), c) from about 1 to about 70 wt % peroxydisulphate(s) from the group of sodium peroxydisulphate and/or potassium peroxydisulphate and/or ammonium peroxydisulphate.1. An agent for lightening keratin fibers, comprising relative to the weight thereof
a) from about 0.01 to about 5 wt % ethyl cellulose, b) from about 5 to about 70 wt % oil component(s), c) from about 1 to about 70 wt % peroxydisulphate(s) from the group of sodium peroxydisulphate and/or potassium peroxydisulphate and/or ammonium peroxydisulphate. 2. The agent according to claim 1, comprising from about 0.05 to about 7.5 wt % ethyl cellulose having formula (I)
wherein n stands for integers from about 50 to about 500. 3. The agent according to either claim 1, comprising from about 0.05 to about 7.5 wt % ethyl cellulose(s) whose degree of ethoxylation is from about 45 to about 50%. 4. The agent according to claim 1, comprising from about 22.5 to about 70 wt % oil(s) chosen from the group of paraffin oil, polyisobutene, the alkyl benzoates, isopropyl palmitate, isohexadecane, isododecane, isononyl isononanoate, or combinations thereof. 5. The agent according to claim 1, comprising from about 1 to about 15 wt % cetearyl alcohol. 6. The agent according to claim 1, comprising from about 2.5 to about 65 wt % peroxydisulphate(s) from the group of sodium peroxydisulphate and/or potassium peroxydisulphate. 7. The agent according to claim 1, comprising from about 0 to about <0.1 wt % ammonia. 8. The agent according to claim 1, wherein after preparation, the agent has a viscosity (Brookfield RV-2, Helipath, Spindle TF, 4 rpm, 60 s) of from about 100 Pas to about 10,000 Pas (from about 105 mPas to about 107 mPas). 9. A method for changing the color of keratinic fibers, in which at least two separately packaged preparations (A) and (B), of which preparation (A) comprises at least one persulphate and preparation (B) comprises at least one oxidizing agent, wherein the preparations (A) and (B) are mixed to form an application mixture, wherein the application mixture is applied to the fibers and is rinsed off again after a contact time, and wherein preparation (A) comprises
a) from about 0.01 to about 5 wt % ethyl cellulose, b) from about 5 to about 70 wt % oil component(s), c) from about 1 to about 70 wt % peroxydisulphate(s) from the group of sodium peroxydisulphate and/or potassium peroxydisulphate and/or ammonium peroxydisulphate. 10. The method according to claim 9, wherein the application mixture has a viscosity (Brookfield RV-2, Helipath, spindle TF, 4 rpm, 60 s) of from about 1 Pas to about 100 Pas (from about 103 mPas to about 105 mPas). 11. The agent according to claim 1, comprising from about 0.3 to about 1.5 wt %, ethyl cellulose having formula (I)
wherein n stands for integers from about 50 to about 500. 12. The agent according to claim 1, comprising from about 0.05 to about 7.5 wt %, ethyl cellulose having formula (I)
wherein n stands for integers from about 200 to about 250. 13. The agent according to claim 1, comprising from about 0.3 to about 1.5 wt %, ethyl cellulose(s) whose degree of ethoxylation is from about 45 to about 50%. 14. The agent according to claim 1, comprising from about 0.05 to about 7.5 wt % ethyl cellulose(s) whose degree of ethoxylation is from about 48 to about 49.5%. 15. The agent according to claim 1, comprising from about 32.5 to about 50 wt % oil(s) chosen from the group of paraffin oil, polyisobutene, the alkyl benzoates, isopropyl palmitate, isohexadecane, isododecane, isononyl isononanoate, or combinations thereof. 16. The agent according to claim 1, comprising from about 5 to about 7.5 wt % cetearyl alcohol. 17. The agent according to claim 1, comprising from about 12.5 to about 45 wt % peroxydisulphate(s) chosen from the group of sodium peroxydisulphate and/or potassium peroxydisulphate. 18. The agent according to claim 1, comprising from 0 wt % ammonia. 19. The agent according to claim 1, wherein after preparation, the agent has a viscosity (Brookfield RV-2, Helipath, Spindle TF, 4 rpm, 60 s) of from about 250 Pas to about 2,000 Pas (from about 2.5×105 mPas to about 2×106 mPas) at 25° C. 20. An agent for lightening keratin fibers, comprising relative to the weight thereof
a) from about 0.3 to about 1.5 wt % ethyl cellulose having formula (I)
wherein n stands for integers from about 200 to about 250,
b) from about 5 to about 70 wt % oil component(s),
c) from about 12.5 to about 45 wt % peroxydisulphate(s) chosen from the group of sodium peroxydisulphate and/or potassium peroxydisulphate. | 1,600 |
491 | 15,123,272 | 1,653 | A thin film culture device for detecting aerobic bacteria in a sample is provided. The culture device comprises a self-supporting substrate sheet having a first major surface and a second major surface; a cover sheet attached to the substrate sheet, a sample-receiving zone disposed between the substrate sheet and the cover sheet, a first layer comprising a substantially dry, cold-water-soluble first hydrogel-forming composition adhered to a portion of the sample-receiving zone; and a plurality of indicator agents disposed in at least one layer adhered to the substrate sheet or the cover sheet. The plurality of indicator agents comprises three indicator agents for detecting distinct glycosidase enzyme activities, an indicator agent for detecting an alkyl esterase enzyme activity, an indicator agent for detecting a phosphatase enzyme activity, and a redox indicator. A method of using the culture device is also provided. | 1. A device for culturing and detecting microorganisms, the device comprising:
a self-supporting substrate sheet having a first major surface and a second major surface; a cover sheet attached to the substrate sheet; a sample-receiving zone disposed between the substrate sheet and the cover sheet; a first layer comprising a substantially dry, cold-water-soluble first hydrogel-forming composition adhered to the first major surface of the substrate sheet; and a plurality of indicator agents, the plurality of indicator agents comprising:
three enzyme activity indicator reagents for detecting distinct glycosidase enzyme activities;
an enzyme activity indicator reagent for detecting an alkyl esterase enzyme activity;
an enzyme activity indicator reagent for detecting a phosphatase enzyme activity;
a redox indicator comprising a tetrazolium dye;
wherein each of the plurality of enzyme activity indicator reagents comprises a detectable reporter group; wherein each of the plurality of indicator agents is disposed in at least one layer adhered to the substrate sheet or the cover sheet, wherein the at least one layer is in fluid communication with the sample-receiving zone when a predetermined volume of aqueous liquid is deposited in the sample-receiving zone. 2. The device of claim 1, further comprising a second layer comprising a first adhesive composition disposed between the substrate sheet and the first layer. 3. The device of claim 2, further comprising an air-permeable membrane adhered to the substrate sheet. 4. The device of claim 1, wherein the first hydrogel-forming composition further comprises a nutrient to facilitate growth of an aerobic bacterium, wherein the first hydrogel-forming composition is adhered to at least a portion of the substrate sheet or the cover sheet, wherein the portion is in fluid communication with the sample-receiving zone. 5. The device of claim 1, wherein the cover sheet comprises a first major surface, wherein the first major surface of the cover sheet faces the first major surface of the substrate sheet, wherein the culture device further comprises:
a third layer comprising a second adhesive composition, wherein the third layer is adhered to a portion of the cover sheet; and a fourth layer comprising a substantially dry, cold-water-soluble second hydrogel-forming composition, wherein the fourth layer is adhered to the third layer. 6. The device of claim 1, wherein at least one of the plurality of indicator agents is disposed in the first adhesive composition, the second adhesive composition, the first hydrogel-forming composition, and/or the second hydrogel-forming composition. 7. The device of claim 6, wherein at least three of the plurality of indicator agents are disposed in the first adhesive composition and/or the second adhesive composition. 8. The device of claim 1, wherein the first hydrogel-forming composition, and/or the second hydrogel-forming composition comprises a mixture of gelling agents. 9. The device of claim 1, wherein the at least three enzyme activity indicator reagents for detecting distinct glycosidase enzyme activities include a compound to detect alpha-glucosidase enzyme activity, a compound to detect beta-glucosidase enzyme activity, and a compound to detect beta-galactosidase enzyme activity. 10. The device of claim 9, wherein the at least three enzyme activity indicator reagents for detecting distinct glycosidase enzyme activities comprise 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside or a salt thereof, 5-bromo-4-chloro-3-indolyl-alpha-D-glucopyranoside or a salt thereof, and 5-bromo-4-chloro-3-indolyl-beta-D-glucopyranoside or a salt thereof. 11. The device of claim 1, wherein the enzyme activity indicator reagent for detecting an alkyl esterase enzyme activity comprises 3-indolyl-acetate or a salt thereof. 12. The device of claim 1, wherein the enzyme activity indicator reagent for detecting a phosphatase enzyme activity comprises 5-bromo-4-chloro-3-indolyl-phosphate or a salt thereof. 13. The device of claim 1, further comprising a predefined volume of aqueous liquid disposed between the substrate sheet and the cover sheet in the sample receiving zone. 14. The device of claim 1, wherein the first hydrogel-forming composition or second hydrogel-forming composition further comprises an effective amount of at least one nutrient for growing an aerobic bacterium. 15. The device of claim 1, further comprising a nutrient selected from the group consisting of L-arginine, skim milk, D-trehalose, and a combination of any two or more of the foregoing nutrients. 16. The device of claim 1, wherein the first hydrogel-forming composition or the second hydrogel-forming composition comprises substantially dry agglomerated powders. 17. A method of detecting an aerobic bacterium in a sample, the method comprising:
contacting a sample material and an aqueous liquid in the sample-receiving zone of the device of claim 1 to form an inoculated culture device; incubating the inoculated culture device for a period of time; and detecting a bacterial colony in the inoculated culture device. 18. The method of claim 17, wherein detecting a bacterial colony in the inoculated culture device comprises detecting in the inoculated culture device a presence of a formazan dye or the detectable reporter group of at least one of the indicator agents, wherein detecting the presence of the formazan dye or the detectable reporter group is indicative of a presence of a colony of bacteria. 19. The method of claim 17, wherein contacting a sample material with the first hydrogel-forming composition or second hydrogel-forming composition of the device comprises placing the sample in fluid communication with a nutrient to facilitate growth of an aerobic bacterium. 20. The method of claim 17, wherein incubating the inoculated culture device for a period of time comprises incubating the inoculated culture device for about 22 hours to about 26 hours, inclusive. | A thin film culture device for detecting aerobic bacteria in a sample is provided. The culture device comprises a self-supporting substrate sheet having a first major surface and a second major surface; a cover sheet attached to the substrate sheet, a sample-receiving zone disposed between the substrate sheet and the cover sheet, a first layer comprising a substantially dry, cold-water-soluble first hydrogel-forming composition adhered to a portion of the sample-receiving zone; and a plurality of indicator agents disposed in at least one layer adhered to the substrate sheet or the cover sheet. The plurality of indicator agents comprises three indicator agents for detecting distinct glycosidase enzyme activities, an indicator agent for detecting an alkyl esterase enzyme activity, an indicator agent for detecting a phosphatase enzyme activity, and a redox indicator. A method of using the culture device is also provided.1. A device for culturing and detecting microorganisms, the device comprising:
a self-supporting substrate sheet having a first major surface and a second major surface; a cover sheet attached to the substrate sheet; a sample-receiving zone disposed between the substrate sheet and the cover sheet; a first layer comprising a substantially dry, cold-water-soluble first hydrogel-forming composition adhered to the first major surface of the substrate sheet; and a plurality of indicator agents, the plurality of indicator agents comprising:
three enzyme activity indicator reagents for detecting distinct glycosidase enzyme activities;
an enzyme activity indicator reagent for detecting an alkyl esterase enzyme activity;
an enzyme activity indicator reagent for detecting a phosphatase enzyme activity;
a redox indicator comprising a tetrazolium dye;
wherein each of the plurality of enzyme activity indicator reagents comprises a detectable reporter group; wherein each of the plurality of indicator agents is disposed in at least one layer adhered to the substrate sheet or the cover sheet, wherein the at least one layer is in fluid communication with the sample-receiving zone when a predetermined volume of aqueous liquid is deposited in the sample-receiving zone. 2. The device of claim 1, further comprising a second layer comprising a first adhesive composition disposed between the substrate sheet and the first layer. 3. The device of claim 2, further comprising an air-permeable membrane adhered to the substrate sheet. 4. The device of claim 1, wherein the first hydrogel-forming composition further comprises a nutrient to facilitate growth of an aerobic bacterium, wherein the first hydrogel-forming composition is adhered to at least a portion of the substrate sheet or the cover sheet, wherein the portion is in fluid communication with the sample-receiving zone. 5. The device of claim 1, wherein the cover sheet comprises a first major surface, wherein the first major surface of the cover sheet faces the first major surface of the substrate sheet, wherein the culture device further comprises:
a third layer comprising a second adhesive composition, wherein the third layer is adhered to a portion of the cover sheet; and a fourth layer comprising a substantially dry, cold-water-soluble second hydrogel-forming composition, wherein the fourth layer is adhered to the third layer. 6. The device of claim 1, wherein at least one of the plurality of indicator agents is disposed in the first adhesive composition, the second adhesive composition, the first hydrogel-forming composition, and/or the second hydrogel-forming composition. 7. The device of claim 6, wherein at least three of the plurality of indicator agents are disposed in the first adhesive composition and/or the second adhesive composition. 8. The device of claim 1, wherein the first hydrogel-forming composition, and/or the second hydrogel-forming composition comprises a mixture of gelling agents. 9. The device of claim 1, wherein the at least three enzyme activity indicator reagents for detecting distinct glycosidase enzyme activities include a compound to detect alpha-glucosidase enzyme activity, a compound to detect beta-glucosidase enzyme activity, and a compound to detect beta-galactosidase enzyme activity. 10. The device of claim 9, wherein the at least three enzyme activity indicator reagents for detecting distinct glycosidase enzyme activities comprise 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside or a salt thereof, 5-bromo-4-chloro-3-indolyl-alpha-D-glucopyranoside or a salt thereof, and 5-bromo-4-chloro-3-indolyl-beta-D-glucopyranoside or a salt thereof. 11. The device of claim 1, wherein the enzyme activity indicator reagent for detecting an alkyl esterase enzyme activity comprises 3-indolyl-acetate or a salt thereof. 12. The device of claim 1, wherein the enzyme activity indicator reagent for detecting a phosphatase enzyme activity comprises 5-bromo-4-chloro-3-indolyl-phosphate or a salt thereof. 13. The device of claim 1, further comprising a predefined volume of aqueous liquid disposed between the substrate sheet and the cover sheet in the sample receiving zone. 14. The device of claim 1, wherein the first hydrogel-forming composition or second hydrogel-forming composition further comprises an effective amount of at least one nutrient for growing an aerobic bacterium. 15. The device of claim 1, further comprising a nutrient selected from the group consisting of L-arginine, skim milk, D-trehalose, and a combination of any two or more of the foregoing nutrients. 16. The device of claim 1, wherein the first hydrogel-forming composition or the second hydrogel-forming composition comprises substantially dry agglomerated powders. 17. A method of detecting an aerobic bacterium in a sample, the method comprising:
contacting a sample material and an aqueous liquid in the sample-receiving zone of the device of claim 1 to form an inoculated culture device; incubating the inoculated culture device for a period of time; and detecting a bacterial colony in the inoculated culture device. 18. The method of claim 17, wherein detecting a bacterial colony in the inoculated culture device comprises detecting in the inoculated culture device a presence of a formazan dye or the detectable reporter group of at least one of the indicator agents, wherein detecting the presence of the formazan dye or the detectable reporter group is indicative of a presence of a colony of bacteria. 19. The method of claim 17, wherein contacting a sample material with the first hydrogel-forming composition or second hydrogel-forming composition of the device comprises placing the sample in fluid communication with a nutrient to facilitate growth of an aerobic bacterium. 20. The method of claim 17, wherein incubating the inoculated culture device for a period of time comprises incubating the inoculated culture device for about 22 hours to about 26 hours, inclusive. | 1,600 |
492 | 15,051,463 | 1,633 | Compositions and methods are disclosed herein for cloning a synthetic or a semi-synthetic donor genome in a heterologous host cell. In one embodiment, the donor genome can be further modified within a host cell. Modified or unmodified genomes can be further isolated from the host cell and transferred to a recipient cell. Methods disclosed herein can be used to alter donor genomes from intractable donor cells in more tractable host cells. | 1. A method for seamlessly introducing a modification in a target nucleic acid molecule present in a host cell, comprising:
a. introducing a mutagenesis construct and a host vector into the host cell whereby the host vector recombines with the mutagenesis construct in the host cell, wherein the mutagenesis construct contains
a first portion of homology to a 5′ portion of the target nucleic acid molecule upstream of the modification;
an endonuclease recognition site;
a promoter;
a gene encoding the endonuclease; and
a selectable marker;
a second repeat portion of homology that is homologous to a sequence of the target nucleic acid molecule upstream of a target region on the target nucleic acid molecule;
a third portion of homology that is homologous to a 3′ portion of the target region on the target nucleic acid molecule downstream of the modification; and
b. incubating the cells under conditions
i. whereby recombination occurs between the first portion of homology and the upstream or downstream portion, thereby seamlessly removing a portion of the construct,
ii. that promote one or more double-strand break cleavages in the target nucleic acid molecule near the target region containing the construct,
whereby a modification is seamlessly introduced into the target nucleic acid molecule. 2. The method of claim 1 wherein the endonuclease recognition site is an I-SceI recognition site. 3. The method of claim 1 wherein the promoter is a GAL-1 promoter. 4. The method of claim 1 wherein the selectable marker is URA3. 5. The method of claim 1 wherein the endonuclease recognition site is an I-SceI recognition site, the promoter is a GAL-1 promoter, and the selectable marker is URA3. 6. The method of claim 1 wherein the portion of the construct that is removed is the selectable marker. 7. The method of claim 6 wherein the endonuclease is inducibly expressed. 8. The method of claim 7 wherein the double strand break cleavage is generated by the inducibly expressed endonuclease. 9. The method of claim 8 further comprising the introduction of a sequence generating tandem repeat regions that flank the target region or portion thereof on the target nucleic acid molecule. 10. The method of claim 9 wherein the tandem repeat regions that flank the target region or portion thereof flank the selectable marker. 11. The method of claim 1 wherein the host cell is a yeast cell. 12. The method of claim 11 wherein the yeast cell is Saccharomyces cerevisiae or Saccharomyces pombe. 13. The method of claim 11 wherein the target nucleic acid molecule is a bacterial, cyanobacterial, or microalgal donor genome. 14. The method of claim 13 wherein the target nucleic acid molecule is a bacterial genome. 15. The method of claim 14 wherein the target nucleic acid molecule is a Mycoplasma genome. 16. The method of claim 11 wherein the modification is a homologous recombination. 17. The method of claim 15 wherein the modification is a homologous recombination. 18. The method of claim 16 wherein the homologous recombination is selected from the group consisting of: a point mutation, a substitution, an insertion, and the modification of a nucleotide. 19. The method of claim 17 wherein the homologous recombination is selected from the group consisting of: a point mutation, a substitution, an insertion, and the modification of a nucleotide. 20. The method of claim 1 wherein:
a. the host cell is a yeast of the genus Saccharomyces;
b. the endonuclease recognition site is a I-SceI recognition site;
c. the promoter is a GAL-1 promoter;
d. the selectable marker is URA3; and
e. the endonuclease is inducibly expressed and the double strand break cleavage is generated by the inducibly expressed endonuclease. | Compositions and methods are disclosed herein for cloning a synthetic or a semi-synthetic donor genome in a heterologous host cell. In one embodiment, the donor genome can be further modified within a host cell. Modified or unmodified genomes can be further isolated from the host cell and transferred to a recipient cell. Methods disclosed herein can be used to alter donor genomes from intractable donor cells in more tractable host cells.1. A method for seamlessly introducing a modification in a target nucleic acid molecule present in a host cell, comprising:
a. introducing a mutagenesis construct and a host vector into the host cell whereby the host vector recombines with the mutagenesis construct in the host cell, wherein the mutagenesis construct contains
a first portion of homology to a 5′ portion of the target nucleic acid molecule upstream of the modification;
an endonuclease recognition site;
a promoter;
a gene encoding the endonuclease; and
a selectable marker;
a second repeat portion of homology that is homologous to a sequence of the target nucleic acid molecule upstream of a target region on the target nucleic acid molecule;
a third portion of homology that is homologous to a 3′ portion of the target region on the target nucleic acid molecule downstream of the modification; and
b. incubating the cells under conditions
i. whereby recombination occurs between the first portion of homology and the upstream or downstream portion, thereby seamlessly removing a portion of the construct,
ii. that promote one or more double-strand break cleavages in the target nucleic acid molecule near the target region containing the construct,
whereby a modification is seamlessly introduced into the target nucleic acid molecule. 2. The method of claim 1 wherein the endonuclease recognition site is an I-SceI recognition site. 3. The method of claim 1 wherein the promoter is a GAL-1 promoter. 4. The method of claim 1 wherein the selectable marker is URA3. 5. The method of claim 1 wherein the endonuclease recognition site is an I-SceI recognition site, the promoter is a GAL-1 promoter, and the selectable marker is URA3. 6. The method of claim 1 wherein the portion of the construct that is removed is the selectable marker. 7. The method of claim 6 wherein the endonuclease is inducibly expressed. 8. The method of claim 7 wherein the double strand break cleavage is generated by the inducibly expressed endonuclease. 9. The method of claim 8 further comprising the introduction of a sequence generating tandem repeat regions that flank the target region or portion thereof on the target nucleic acid molecule. 10. The method of claim 9 wherein the tandem repeat regions that flank the target region or portion thereof flank the selectable marker. 11. The method of claim 1 wherein the host cell is a yeast cell. 12. The method of claim 11 wherein the yeast cell is Saccharomyces cerevisiae or Saccharomyces pombe. 13. The method of claim 11 wherein the target nucleic acid molecule is a bacterial, cyanobacterial, or microalgal donor genome. 14. The method of claim 13 wherein the target nucleic acid molecule is a bacterial genome. 15. The method of claim 14 wherein the target nucleic acid molecule is a Mycoplasma genome. 16. The method of claim 11 wherein the modification is a homologous recombination. 17. The method of claim 15 wherein the modification is a homologous recombination. 18. The method of claim 16 wherein the homologous recombination is selected from the group consisting of: a point mutation, a substitution, an insertion, and the modification of a nucleotide. 19. The method of claim 17 wherein the homologous recombination is selected from the group consisting of: a point mutation, a substitution, an insertion, and the modification of a nucleotide. 20. The method of claim 1 wherein:
a. the host cell is a yeast of the genus Saccharomyces;
b. the endonuclease recognition site is a I-SceI recognition site;
c. the promoter is a GAL-1 promoter;
d. the selectable marker is URA3; and
e. the endonuclease is inducibly expressed and the double strand break cleavage is generated by the inducibly expressed endonuclease. | 1,600 |
493 | 13,470,250 | 1,699 | A guided mode resonance (GMR) sensor that can be used to simultaneously detect an array of analytes. It provides a diagnostic system that can rapidly detect an array of biomarker proteins in patient samples (such as blood, serum or plasma for example) which can be used as an accurate means to conduct a differential analysis of proteins that allows the discrimination of early and late stages of disease, such as metastatic versus primary ovarian serous carcinomas. The GMR sensor can be provided in a compact size such that it can be portable. | 1. A biomarker sensor, comprising
GMR sensor assembly comprising: a waveguide structure configured for operation at or near one or more leaky modes; means for receiving input light from a source of light that includes one or more line focusing elements to focus input light onto the waveguide structure to cause one or more leaky TE and TM resonant modes; means for the detecting presence of a biomarker indicative of a disease state that may be present in a media in contact with said waveguide structure, comprising means for detecting changes in one or more of the angle, phase, waveshape and/or magnitude of each of a TE resonance and/or a TM resonance to permit distinguishing between first and second physical states of said waveguide structure or its immediate environment, said immediate environment including said media. 2. The system of claim 1 where the source of light comprises multiple sources of light having distinct wavelengths. 3. A measurement system for detecting the presence of an array of ovarian cancer biomarker proteins in a sample, the array of biomarker proteins including at least three proteins taken from the group: Fibronectin, Apolipoprotein A-I, Calreticulin, Complement C7, Collagen Type I, MAP Kinase 13, TIMP 3, and Ryanodine receptor. 4. The array of biomarker proteins in claim 3, wherein the Ryanodine receptor is Ryanodine receptor 2 and/or Ryanodine receptor 3. 5. The array of biomarker proteins in claim 3, further comprising other biomarker proteins relevant in ovarian cancer. 6. The measurement system of claim 3, wherein the system is used to determine the stage of ovarian cancer 7. The measurement system of claim 3, wherein the system is used to monitor ovarian cancer treatment efficacy. 8. The measurement system of claim 3, wherein the system is used to determine appropriate ovarian cancer treatment modalities. 9. The measurement system of claim 3, wherein the system incorporates biologically selective agents which are selected from a group of antibodies, aptamers, peptides, DNA/RNA, or other agents designed to be selective for biomarker proteins. 10. The measurement system of claim 3, wherein the sample is selected from a group of: serum, blood, urine or other biological fluids. 11. The measurement system of claim 3, wherein the system utilizes a guided-mode resonance waveguide grating to detect the presence of the array of ovarian cancer biomarker proteins. 12. A GMR biosensor for detecting the presence of an array of ovarian cancer biomarker proteins in a sample, the array of biomarker proteins including at least three proteins taken from the group: Fibronectin, Apolipoprotein A-I, Calreticulin, Complement C7, Collagen Type I, MAP Kinase 13, TIMP 3, and Ryanodine receptor, said GMR biosensor comprising
a waveguide structure configured for operation at or near one or more leaky modes; means for receiving input light from a source of light that includes one or more line focusing elements to focus input light onto the waveguide structure to cause one or more leaky TE and TM resonant modes; means for the detecting presence of a biomarker indicative of a disease state that may be present in a media in contact with said waveguide structure, comprising means for detecting changes in one or more of the angle, phase, waveshape and/or magnitude of each of a TE resonance and/or a TM resonance to permit distinguishing between first and second physical states of said waveguide structure or its immediate environment, said immediate environment including said media. 13. The array of biomarker proteins in claim 12, wherein the Ryanodine receptor is Ryanodine receptor 2 and/or Ryanodine receptor 3. 14. The array of biomarker proteins in claim 12, further comprising other biomarker proteins relevant in ovarian cancer. 15. The measurement system of claim 12, wherein the system is used to determine the stage of ovarian cancer 16. The measurement system of claim 12, wherein the system is used to monitor ovarian cancer treatment efficacy. 17. The measurement system of claim 12, wherein the system is used to determine appropriate ovarian cancer treatment modalities. 18. The measurement system of claim 12, wherein the system incorporates biologically selective agents which are selected from a group of antibodies, aptamers, peptides, DNA/RNA, or other agents designed to be selective for biomarker proteins. 19. The measurement system of claim 12, wherein the sample is selected from a group of: serum, blood, urine or other biological fluids. 20. The measurement system of claim 12, wherein the system utilizes a guided-mode resonance waveguide grating to detect the presence of the array of ovarian cancer biomarker proteins. | A guided mode resonance (GMR) sensor that can be used to simultaneously detect an array of analytes. It provides a diagnostic system that can rapidly detect an array of biomarker proteins in patient samples (such as blood, serum or plasma for example) which can be used as an accurate means to conduct a differential analysis of proteins that allows the discrimination of early and late stages of disease, such as metastatic versus primary ovarian serous carcinomas. The GMR sensor can be provided in a compact size such that it can be portable.1. A biomarker sensor, comprising
GMR sensor assembly comprising: a waveguide structure configured for operation at or near one or more leaky modes; means for receiving input light from a source of light that includes one or more line focusing elements to focus input light onto the waveguide structure to cause one or more leaky TE and TM resonant modes; means for the detecting presence of a biomarker indicative of a disease state that may be present in a media in contact with said waveguide structure, comprising means for detecting changes in one or more of the angle, phase, waveshape and/or magnitude of each of a TE resonance and/or a TM resonance to permit distinguishing between first and second physical states of said waveguide structure or its immediate environment, said immediate environment including said media. 2. The system of claim 1 where the source of light comprises multiple sources of light having distinct wavelengths. 3. A measurement system for detecting the presence of an array of ovarian cancer biomarker proteins in a sample, the array of biomarker proteins including at least three proteins taken from the group: Fibronectin, Apolipoprotein A-I, Calreticulin, Complement C7, Collagen Type I, MAP Kinase 13, TIMP 3, and Ryanodine receptor. 4. The array of biomarker proteins in claim 3, wherein the Ryanodine receptor is Ryanodine receptor 2 and/or Ryanodine receptor 3. 5. The array of biomarker proteins in claim 3, further comprising other biomarker proteins relevant in ovarian cancer. 6. The measurement system of claim 3, wherein the system is used to determine the stage of ovarian cancer 7. The measurement system of claim 3, wherein the system is used to monitor ovarian cancer treatment efficacy. 8. The measurement system of claim 3, wherein the system is used to determine appropriate ovarian cancer treatment modalities. 9. The measurement system of claim 3, wherein the system incorporates biologically selective agents which are selected from a group of antibodies, aptamers, peptides, DNA/RNA, or other agents designed to be selective for biomarker proteins. 10. The measurement system of claim 3, wherein the sample is selected from a group of: serum, blood, urine or other biological fluids. 11. The measurement system of claim 3, wherein the system utilizes a guided-mode resonance waveguide grating to detect the presence of the array of ovarian cancer biomarker proteins. 12. A GMR biosensor for detecting the presence of an array of ovarian cancer biomarker proteins in a sample, the array of biomarker proteins including at least three proteins taken from the group: Fibronectin, Apolipoprotein A-I, Calreticulin, Complement C7, Collagen Type I, MAP Kinase 13, TIMP 3, and Ryanodine receptor, said GMR biosensor comprising
a waveguide structure configured for operation at or near one or more leaky modes; means for receiving input light from a source of light that includes one or more line focusing elements to focus input light onto the waveguide structure to cause one or more leaky TE and TM resonant modes; means for the detecting presence of a biomarker indicative of a disease state that may be present in a media in contact with said waveguide structure, comprising means for detecting changes in one or more of the angle, phase, waveshape and/or magnitude of each of a TE resonance and/or a TM resonance to permit distinguishing between first and second physical states of said waveguide structure or its immediate environment, said immediate environment including said media. 13. The array of biomarker proteins in claim 12, wherein the Ryanodine receptor is Ryanodine receptor 2 and/or Ryanodine receptor 3. 14. The array of biomarker proteins in claim 12, further comprising other biomarker proteins relevant in ovarian cancer. 15. The measurement system of claim 12, wherein the system is used to determine the stage of ovarian cancer 16. The measurement system of claim 12, wherein the system is used to monitor ovarian cancer treatment efficacy. 17. The measurement system of claim 12, wherein the system is used to determine appropriate ovarian cancer treatment modalities. 18. The measurement system of claim 12, wherein the system incorporates biologically selective agents which are selected from a group of antibodies, aptamers, peptides, DNA/RNA, or other agents designed to be selective for biomarker proteins. 19. The measurement system of claim 12, wherein the sample is selected from a group of: serum, blood, urine or other biological fluids. 20. The measurement system of claim 12, wherein the system utilizes a guided-mode resonance waveguide grating to detect the presence of the array of ovarian cancer biomarker proteins. | 1,600 |
494 | 14,904,199 | 1,619 | The present invention relates to a composition comprising, in a cosmetically acceptable medium, at least one water-insoluble solid organic UV-screening agent (A) at least one compound (B) that may be obtained by reaction between: an oil bearing at least one nucleophilic and/or electrophilic reactive function, and a junction group capable of establishing hydrogen bonds with one or more partner junction groups, each junction group pairing involving at least 3 hydrogen bonds, the said junction group bearing at least one reactive function capable of reacting with the reactive function borne by the oil, the said junction group also comprising at least one unit of formula (I) or (II): in which: R1 and R3, which may be identical or different, represent a divalent carbon-based radical; R2 represents a hydrogen atom or a linear, branched or cyclic, saturated or unsaturated, optionally aromatic, C1-C32 carbon-based and especially hydrocarbon-based radical, which may comprise one or more heteroatoms chosen from O, N, S, F, Si and P. | 1. Composition comprising, in a cosmetically acceptable medium,
a) at least one water-insoluble solid organic UV-screening agent (A) and b) at least one compound (B) that may be obtained by reaction between:
an oil bearing at least one nucleophilic and/or electrophilic reactive function, and
a junction group capable of establishing hydrogen bonds with one or more partner junction groups, each junction group pairing involving at least 3 hydrogen bonds, the said junction group bearing at least one reactive function capable of reacting with the reactive function borne by the oil, the said junction group also comprising at least one unit of formula (I) or (II):
in which:
R1 and R3, which may be identical or different, represent a divalent carbon-based radical chosen from (i) a linear or branched C1-C32 alkyl group, (ii) a C4-C16 cycloalkyl group and (iii) a C4-C16 aryl group; optionally comprising 1 to 8 heteroatoms chosen from O, N, S, F, Si and P; and/or optionally substituted with an ester or amide function or with a C1-C12 alkyl radical; or a mixture of these groups;
R2 represents a hydrogen atom or a linear, branched or cyclic, saturated or unsaturated, optionally aromatic, C1-C32 carbon-based and especially hydrocarbon-based radical, which may comprise one or more heteroatoms chosen from O, N, S, F, Si and P. 2. Composition according to claim 1, in which the oil bearing the reactive function is chosen, alone or as a mixture, from:
(i) saturated or unsaturated, linear, branched or cyclic fatty alcohols comprising 6 to 50 carbon atoms, comprising one or more OH; optionally comprising one or more NH2; (ii) esters and ethers bearing at least one free OH group, and especially partial polyol esters and ethers, and hydroxylated carboxylic acid esters; (iii) natural or modified natural or plant hydroxylated oils. 3. Composition according to claim 1, in which the oil is chosen from 2-octyldodecanol, diisostearyl malate, 2-butyloctanol, 2-hexyldecanol, 2-decyltetradecanol; hydrogenated or non-hydrogenated castor oil; hydroxylated modified soybean oil; and mixtures thereof. 4. Composition according to claim 1, in which, in the junction group, the radical R1 represents:
a linear or branched, divalent C2-C12 alkylene group, especially a 1,2-ethylene, 1,6-hexylene, 1,4-butylene, 1,6-(2,4,4-trimethylhexylene), 1,4-(4-methylpentylene), 1,5-(5-methylhexylene), 1,6-(6-methylheptylene), 1,5-(2,2,5-trimethylhexylene) or 1,7-(3,7-dimethyloctylene) group; a divalent C4-C16 cycloalkylene or arylene group. 5. Composition according to claim 1, in which, in the junction group, the radical R2 represents H, or alternatively:
a C1-C32; a C4-C12 cycloalkyl group; a C4-C12 aryl group; a (C4-C12)aryl(C1-C18)alkyl group; a C1-C4 alkoxy group; an arylalkoxy group; a C4-C12 heterocycle;
or a combination of these radicals, which may be optionally substituted with an amino, ester and/or hydroxyl function. 6. Composition according to claim 1, in which, in the junction group, the radical R3 represents a divalent radical —R′3-O—C(O)—NH—R′4- in which R′3 and R′4, which may be identical or different, represent a divalent carbon-based radical chosen from a linear or branched C1-C32 alkyl group, a C4-C16 cycloalkyl group and a C4-C16 aryl group; or a mixture thereof. 7. Composition according to claim 1, in which
a) the compounds of formula (I) are such that: R1 is Y and R2 denotes hydrogen, methyl, ethyl, n-propyl or isobutyl; b) the compounds of formula (II) are such that: R1 is Y and R2 denotes hydrogen, methyl or ethyl and R3 denotes —R3′—O—CO—NH—R4′ and R3′ denotes 1,2-ethylene and R4′ is Y. 8. Composition according to claim 1, in which the junction group is chosen from the following groups:
or has the formula: 9. Composition according to claim 1, in which the junction group is chosen from the following groups: 10. Composition according to claim 1, in which the compounds (B) are chosen from:
ureidopyrimidone-functionalized diisostearyl malate of structure:
or of structure:
ureidopyrimidone-functionalized 2-decyltetradecanol of structure:
or of structure: 11. Composition according to claim 1, in which the amount of compound (B) present in the compositions ranges between 1% and 80% by weight. 12. Composition according to claim 1, in which the water-insoluble solid organic UV-screening agent (A) is chosen from:
(i) water-insoluble solid UV-screening agents of the dibenzoylmethane type (ii) water-insoluble solid UV-screening agents of the triazine type (iii) water-insoluble solid UV-screening agents of the benzophenone type (iv) water-insoluble solid UV-screening agents of the merocyanine type (v) water-insoluble solid UV-screening agents of the benzylidenecamphor type (vi) water-insoluble solid UV-screening agents of the phenylbenzotriazole type (vii) water-insoluble solid UV-screening agents of the para-aminobenzoic type and (viii) mixtures thereof. 13. Composition according to claim 12, in which the water-insoluble solid UV-screening agent (A) of the dibenzoylmethane type is 4-(tert-butyl)-4′-methoxydibenzoylmethane or Butylmethoxydibenzoylmethane. 14. Composition according to claim 12, in which the water-insoluble solid UV-screening agent (A) of the triazine type is chosen from:
(i) the 1,3,5-triazine derivatives of formula (1) below
in which the radicals A1, A2 and A3, which may be identical or different, are chosen from the groups of formula (2):
in which:
Xa, which may be identical or different, represent oxygen or an —NH— radical;
Ra, which may be identical or different, are chosen from a linear or branched C1-C18 alkyl radical; a C5-C12 cycloalkyl radical optionally substituted with one or more C1-C4 alkyl radicals; a polyoxyethylene radical comprising from 1 to 6 ethylene oxide units and in which the end OH group is methylated; a radical of formula (3), (4) or (5) below:
in which:
R1 is hydrogen or a methyl radical;
R2 is a C1-C9 alkyl radical;
q is an integer ranging from 0 to 3;
r is an integer ranging from 1 to 10;
A′ is a C4-C8 alkyl radical or a C5-C8 cycloalkyl radical;
B′ is chosen from: a linear or branched C1-C8 alkyl radical; a C5-C8 cycloalkyl radical; an aryl radical optionally substituted with one or more C1-C4 alkyl radicals;
it being understood that when A1, A2 and A3 are identical and Xa denotes an oxygen atom, then Ra represents a branched C6-C18 alkyl radical;
(ii) the bis-resorcinyl-triazines of formula (6)
in which:
the radicals R3 and R4, which may be identical or different, denote a C3-C18 alkyl radical; a C2-C18 alkenyl radical or a residue of formula —CH2—CH(OH)—CH2-OT1 in which T1 is a hydrogen atom or a C1-C8 alkyl radical;
A4 denotes a residue corresponding to one of the following formulae:
in which:
R5 denotes a hydrogen atom, a C1-C10 alkyl radical, a radical of formula —(CH2CHR7—O)n1R6 in which n1 is a number from 1 to 16, or a residue of structure —CH2—CH—(OH)—CH2OT1 with T1 having the same meaning indicated above;
R6 denotes hydrogen, a metal cation M, a C1-C5 alkyl radical or a residue of formula —(CH2)m2-OT1 in which m2 is a number from 1 to 4 and T1 has the same meaning indicated above;
R7 is hydrogen or methyl,
Q1 is a C1-C18 alkyl radical;
(iii) the silicone triazines of formula (10) below or a tautomeric form thereof:
in which:
R, which may be identical or different, represent a linear or branched C1-C30 alkyl radical which is optionally halogenated or unsaturated, a C6-C12 aryl radical, a C1-C10 alkoxy radical, a hydroxyl radical or the trimethylsilyloxy group;
a=1 to 3; in addition to the units of formula -A-(Si)(R)a(O)(3-a)/2,
the group (D) denotes an s-triazine compound of formula (11) below:
where:
X represents —O— or —NR10—, with R10 representing hydrogen or a C1-C5 alkyl radical,
R8 represents a linear or branched C1-C30 alkyl radical which is optionally unsaturated and which may contain a silicon atom, a C5-C20 cycloalkyl group, optionally substituted with 1 to 3 linear or branched C1-C4 alkyl radicals, the group —(CH2CHR10-0)mR11 or the group —CH2—CH(OH)—CH2—O—R12,
R9, which may be identical or different, represent a hydroxyl radical, a linear or branched C1-C8 alkyl radical or a C1-C8 alkoxy radical, it being possible for two adjacent R2 groups on the same aromatic nucleus together to form an alkylidenedioxy group in which the alkylidene group contains 1 or 2 carbon atoms,
R10 represents hydrogen or methyl; it being possible for the group (C═O)XR8 to be in the ortho, meta or para position relative to the amino group,
R11 represents hydrogen or a C1-C8 alkyl group,
R12 represents hydrogen or a C4-C8 alkyl group,
m is an integer ranging from 2 to 20,
n=0 to 2,
A is a divalent radical chosen from methylene or a group corresponding to one of the formulae (12), (13), (14) or (15) below:
in which:
Z is a saturated or unsaturated, linear or branched C1-C10 alkylene diradical, optionally substituted with a hydroxyl radical or oxygen atoms and optionally containing an amino group,
W represents a hydrogen atom, a hydroxyl radical or a saturated or unsaturated, linear or branched C1-C8 alkyl radical; the compound of formula (9)
possibly comprising units of formula: (R)b—(Si)(O)(4-b)/2 in which R has the same meaning as in formula (10), b=1, 2 or 3. 15. Composition according to claim 14, in which the water-insoluble solid UV-screening agent (A) of the triazine type is chosen from the following compounds, or mixtures thereof:
Bis-Ethylhexyloxyphenol methoxyphenyl triazine, Ethylhexyl triazone, Diethylhexylbutamidotriazone, 2,4-Bis(n-butyl 4′-aminobenzoate)-6-[(3-{1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-disiloxanyl}propyl)amino]-s-triazine. 16. Composition according to claim 12, in which the water-insoluble UV-screening agent (A) of the benzophenone type is chosen from the following compounds, or mixtures thereof:
Benzophenone-1, Benzophenone-2, Benzophenone-3 or Oxybenzone, Benzophenone-5, Benzophenone-6, Benzophenone-8, Benzophenone-12, n-Hexyl 2-(4-diethylamino-2-hydroxybenzoyl)benzoate. 17. Composition according to claim 12, in which the water-insoluble UV-screening agent (A) of the merocyanine type is chosen from the following compounds, or mixtures thereof:
Octyl 5-N,N-diethylamino-2-phenylsulfonyl-2,4-pentadienoate; solid merocyanine dicyano or cyanoacetate derivatives chosen from the group consisting of:
(i) compounds thus corresponding to the general formula (16) below:
in which:
A is the —C≡N or —(C═O)OR3 group;
R1 and R2, which may be identical or different, denote a linear or branched C1-C3 alkyl radical, the hydroxyethyl group or a C5-C6 cycloalkyl;
R3 denotes a linear or branched C1-C8 alkyl radical;
n is 1 or 2;
with the proviso that, when n=2, R1, R2 or R3 is a C2-C16 alkyl diradical or else R1 and R2 form, with 2 nitrogen atoms, a cyclic divalent —(CH2)m— radical with m being an integer ranging from 3 to 7;
(ii) compound (a):
(iii) compound (b):
(iv) compound (c):
(v) compound (1):
(vi) compound (aa)
(vii) compound (bb) 18. Composition according to claim 12, in which the water-insoluble solid UV-screening agent (A) of the phenylbenzotriazole type is a silane or polyorganosiloxane compound comprising at least one unit of formula (17) below:
O(3-a′)/2Si(R4)a′-G′ (17)
in which:
R4 represents an optionally halogenated C1-C10 alkyl radical or a phenyl radical or a trimethylsilyloxy radical,
a′ is an integer chosen between 0 and 3 inclusive,
and the symbol G′ denotes a monovalent radical linked directly to a silicon atom, and which corresponds to formula (18) below:
in which:
Y′, which may be identical or different, are chosen from C1-C8 alkyl radicals, halogens and C1-C4 alkoxy radicals, it being understood that, in the latter case, two adjacent radicals Y′ on the same aromatic nucleus can together form an alkylidenedioxy group in which the alkylidene group contains from 1 to 2 carbon atoms,
X′ represents O or NH,
Z′ represents hydrogen or a C1-C4 alkyl radical,
n′ is an integer between 0 and 3 inclusive,
m′ is 0 or 1,
p′ represents an integer between 1 and 10 inclusive. 19. Composition according to claim 18, in which the water-insoluble solid UV-screening agent (A) of the phenylbenzotriazole type is Drometrizole trisiloxane of structure: 20. Cosmetic process for treating keratin materials, especially bodily or facial skin, the lips, the nails and/or the eyelashes or the hair, comprising the application to the said materials of a composition as defined according to claim 1. 21. Process for making up and/or caring for keratin materials, especially bodily or facial skin, the lips, the nails and/or the eyelashes or the hair, comprising the application to the said materials of a composition as defined according to claim 1. 22. Use of at least one compound (B) as defined in claim 1 as solvent for a water-insoluble solid organic UV-screening agent (A). | The present invention relates to a composition comprising, in a cosmetically acceptable medium, at least one water-insoluble solid organic UV-screening agent (A) at least one compound (B) that may be obtained by reaction between: an oil bearing at least one nucleophilic and/or electrophilic reactive function, and a junction group capable of establishing hydrogen bonds with one or more partner junction groups, each junction group pairing involving at least 3 hydrogen bonds, the said junction group bearing at least one reactive function capable of reacting with the reactive function borne by the oil, the said junction group also comprising at least one unit of formula (I) or (II): in which: R1 and R3, which may be identical or different, represent a divalent carbon-based radical; R2 represents a hydrogen atom or a linear, branched or cyclic, saturated or unsaturated, optionally aromatic, C1-C32 carbon-based and especially hydrocarbon-based radical, which may comprise one or more heteroatoms chosen from O, N, S, F, Si and P.1. Composition comprising, in a cosmetically acceptable medium,
a) at least one water-insoluble solid organic UV-screening agent (A) and b) at least one compound (B) that may be obtained by reaction between:
an oil bearing at least one nucleophilic and/or electrophilic reactive function, and
a junction group capable of establishing hydrogen bonds with one or more partner junction groups, each junction group pairing involving at least 3 hydrogen bonds, the said junction group bearing at least one reactive function capable of reacting with the reactive function borne by the oil, the said junction group also comprising at least one unit of formula (I) or (II):
in which:
R1 and R3, which may be identical or different, represent a divalent carbon-based radical chosen from (i) a linear or branched C1-C32 alkyl group, (ii) a C4-C16 cycloalkyl group and (iii) a C4-C16 aryl group; optionally comprising 1 to 8 heteroatoms chosen from O, N, S, F, Si and P; and/or optionally substituted with an ester or amide function or with a C1-C12 alkyl radical; or a mixture of these groups;
R2 represents a hydrogen atom or a linear, branched or cyclic, saturated or unsaturated, optionally aromatic, C1-C32 carbon-based and especially hydrocarbon-based radical, which may comprise one or more heteroatoms chosen from O, N, S, F, Si and P. 2. Composition according to claim 1, in which the oil bearing the reactive function is chosen, alone or as a mixture, from:
(i) saturated or unsaturated, linear, branched or cyclic fatty alcohols comprising 6 to 50 carbon atoms, comprising one or more OH; optionally comprising one or more NH2; (ii) esters and ethers bearing at least one free OH group, and especially partial polyol esters and ethers, and hydroxylated carboxylic acid esters; (iii) natural or modified natural or plant hydroxylated oils. 3. Composition according to claim 1, in which the oil is chosen from 2-octyldodecanol, diisostearyl malate, 2-butyloctanol, 2-hexyldecanol, 2-decyltetradecanol; hydrogenated or non-hydrogenated castor oil; hydroxylated modified soybean oil; and mixtures thereof. 4. Composition according to claim 1, in which, in the junction group, the radical R1 represents:
a linear or branched, divalent C2-C12 alkylene group, especially a 1,2-ethylene, 1,6-hexylene, 1,4-butylene, 1,6-(2,4,4-trimethylhexylene), 1,4-(4-methylpentylene), 1,5-(5-methylhexylene), 1,6-(6-methylheptylene), 1,5-(2,2,5-trimethylhexylene) or 1,7-(3,7-dimethyloctylene) group; a divalent C4-C16 cycloalkylene or arylene group. 5. Composition according to claim 1, in which, in the junction group, the radical R2 represents H, or alternatively:
a C1-C32; a C4-C12 cycloalkyl group; a C4-C12 aryl group; a (C4-C12)aryl(C1-C18)alkyl group; a C1-C4 alkoxy group; an arylalkoxy group; a C4-C12 heterocycle;
or a combination of these radicals, which may be optionally substituted with an amino, ester and/or hydroxyl function. 6. Composition according to claim 1, in which, in the junction group, the radical R3 represents a divalent radical —R′3-O—C(O)—NH—R′4- in which R′3 and R′4, which may be identical or different, represent a divalent carbon-based radical chosen from a linear or branched C1-C32 alkyl group, a C4-C16 cycloalkyl group and a C4-C16 aryl group; or a mixture thereof. 7. Composition according to claim 1, in which
a) the compounds of formula (I) are such that: R1 is Y and R2 denotes hydrogen, methyl, ethyl, n-propyl or isobutyl; b) the compounds of formula (II) are such that: R1 is Y and R2 denotes hydrogen, methyl or ethyl and R3 denotes —R3′—O—CO—NH—R4′ and R3′ denotes 1,2-ethylene and R4′ is Y. 8. Composition according to claim 1, in which the junction group is chosen from the following groups:
or has the formula: 9. Composition according to claim 1, in which the junction group is chosen from the following groups: 10. Composition according to claim 1, in which the compounds (B) are chosen from:
ureidopyrimidone-functionalized diisostearyl malate of structure:
or of structure:
ureidopyrimidone-functionalized 2-decyltetradecanol of structure:
or of structure: 11. Composition according to claim 1, in which the amount of compound (B) present in the compositions ranges between 1% and 80% by weight. 12. Composition according to claim 1, in which the water-insoluble solid organic UV-screening agent (A) is chosen from:
(i) water-insoluble solid UV-screening agents of the dibenzoylmethane type (ii) water-insoluble solid UV-screening agents of the triazine type (iii) water-insoluble solid UV-screening agents of the benzophenone type (iv) water-insoluble solid UV-screening agents of the merocyanine type (v) water-insoluble solid UV-screening agents of the benzylidenecamphor type (vi) water-insoluble solid UV-screening agents of the phenylbenzotriazole type (vii) water-insoluble solid UV-screening agents of the para-aminobenzoic type and (viii) mixtures thereof. 13. Composition according to claim 12, in which the water-insoluble solid UV-screening agent (A) of the dibenzoylmethane type is 4-(tert-butyl)-4′-methoxydibenzoylmethane or Butylmethoxydibenzoylmethane. 14. Composition according to claim 12, in which the water-insoluble solid UV-screening agent (A) of the triazine type is chosen from:
(i) the 1,3,5-triazine derivatives of formula (1) below
in which the radicals A1, A2 and A3, which may be identical or different, are chosen from the groups of formula (2):
in which:
Xa, which may be identical or different, represent oxygen or an —NH— radical;
Ra, which may be identical or different, are chosen from a linear or branched C1-C18 alkyl radical; a C5-C12 cycloalkyl radical optionally substituted with one or more C1-C4 alkyl radicals; a polyoxyethylene radical comprising from 1 to 6 ethylene oxide units and in which the end OH group is methylated; a radical of formula (3), (4) or (5) below:
in which:
R1 is hydrogen or a methyl radical;
R2 is a C1-C9 alkyl radical;
q is an integer ranging from 0 to 3;
r is an integer ranging from 1 to 10;
A′ is a C4-C8 alkyl radical or a C5-C8 cycloalkyl radical;
B′ is chosen from: a linear or branched C1-C8 alkyl radical; a C5-C8 cycloalkyl radical; an aryl radical optionally substituted with one or more C1-C4 alkyl radicals;
it being understood that when A1, A2 and A3 are identical and Xa denotes an oxygen atom, then Ra represents a branched C6-C18 alkyl radical;
(ii) the bis-resorcinyl-triazines of formula (6)
in which:
the radicals R3 and R4, which may be identical or different, denote a C3-C18 alkyl radical; a C2-C18 alkenyl radical or a residue of formula —CH2—CH(OH)—CH2-OT1 in which T1 is a hydrogen atom or a C1-C8 alkyl radical;
A4 denotes a residue corresponding to one of the following formulae:
in which:
R5 denotes a hydrogen atom, a C1-C10 alkyl radical, a radical of formula —(CH2CHR7—O)n1R6 in which n1 is a number from 1 to 16, or a residue of structure —CH2—CH—(OH)—CH2OT1 with T1 having the same meaning indicated above;
R6 denotes hydrogen, a metal cation M, a C1-C5 alkyl radical or a residue of formula —(CH2)m2-OT1 in which m2 is a number from 1 to 4 and T1 has the same meaning indicated above;
R7 is hydrogen or methyl,
Q1 is a C1-C18 alkyl radical;
(iii) the silicone triazines of formula (10) below or a tautomeric form thereof:
in which:
R, which may be identical or different, represent a linear or branched C1-C30 alkyl radical which is optionally halogenated or unsaturated, a C6-C12 aryl radical, a C1-C10 alkoxy radical, a hydroxyl radical or the trimethylsilyloxy group;
a=1 to 3; in addition to the units of formula -A-(Si)(R)a(O)(3-a)/2,
the group (D) denotes an s-triazine compound of formula (11) below:
where:
X represents —O— or —NR10—, with R10 representing hydrogen or a C1-C5 alkyl radical,
R8 represents a linear or branched C1-C30 alkyl radical which is optionally unsaturated and which may contain a silicon atom, a C5-C20 cycloalkyl group, optionally substituted with 1 to 3 linear or branched C1-C4 alkyl radicals, the group —(CH2CHR10-0)mR11 or the group —CH2—CH(OH)—CH2—O—R12,
R9, which may be identical or different, represent a hydroxyl radical, a linear or branched C1-C8 alkyl radical or a C1-C8 alkoxy radical, it being possible for two adjacent R2 groups on the same aromatic nucleus together to form an alkylidenedioxy group in which the alkylidene group contains 1 or 2 carbon atoms,
R10 represents hydrogen or methyl; it being possible for the group (C═O)XR8 to be in the ortho, meta or para position relative to the amino group,
R11 represents hydrogen or a C1-C8 alkyl group,
R12 represents hydrogen or a C4-C8 alkyl group,
m is an integer ranging from 2 to 20,
n=0 to 2,
A is a divalent radical chosen from methylene or a group corresponding to one of the formulae (12), (13), (14) or (15) below:
in which:
Z is a saturated or unsaturated, linear or branched C1-C10 alkylene diradical, optionally substituted with a hydroxyl radical or oxygen atoms and optionally containing an amino group,
W represents a hydrogen atom, a hydroxyl radical or a saturated or unsaturated, linear or branched C1-C8 alkyl radical; the compound of formula (9)
possibly comprising units of formula: (R)b—(Si)(O)(4-b)/2 in which R has the same meaning as in formula (10), b=1, 2 or 3. 15. Composition according to claim 14, in which the water-insoluble solid UV-screening agent (A) of the triazine type is chosen from the following compounds, or mixtures thereof:
Bis-Ethylhexyloxyphenol methoxyphenyl triazine, Ethylhexyl triazone, Diethylhexylbutamidotriazone, 2,4-Bis(n-butyl 4′-aminobenzoate)-6-[(3-{1,3,3,3-tetramethyl-1-[(trimethylsilyl)oxy]-disiloxanyl}propyl)amino]-s-triazine. 16. Composition according to claim 12, in which the water-insoluble UV-screening agent (A) of the benzophenone type is chosen from the following compounds, or mixtures thereof:
Benzophenone-1, Benzophenone-2, Benzophenone-3 or Oxybenzone, Benzophenone-5, Benzophenone-6, Benzophenone-8, Benzophenone-12, n-Hexyl 2-(4-diethylamino-2-hydroxybenzoyl)benzoate. 17. Composition according to claim 12, in which the water-insoluble UV-screening agent (A) of the merocyanine type is chosen from the following compounds, or mixtures thereof:
Octyl 5-N,N-diethylamino-2-phenylsulfonyl-2,4-pentadienoate; solid merocyanine dicyano or cyanoacetate derivatives chosen from the group consisting of:
(i) compounds thus corresponding to the general formula (16) below:
in which:
A is the —C≡N or —(C═O)OR3 group;
R1 and R2, which may be identical or different, denote a linear or branched C1-C3 alkyl radical, the hydroxyethyl group or a C5-C6 cycloalkyl;
R3 denotes a linear or branched C1-C8 alkyl radical;
n is 1 or 2;
with the proviso that, when n=2, R1, R2 or R3 is a C2-C16 alkyl diradical or else R1 and R2 form, with 2 nitrogen atoms, a cyclic divalent —(CH2)m— radical with m being an integer ranging from 3 to 7;
(ii) compound (a):
(iii) compound (b):
(iv) compound (c):
(v) compound (1):
(vi) compound (aa)
(vii) compound (bb) 18. Composition according to claim 12, in which the water-insoluble solid UV-screening agent (A) of the phenylbenzotriazole type is a silane or polyorganosiloxane compound comprising at least one unit of formula (17) below:
O(3-a′)/2Si(R4)a′-G′ (17)
in which:
R4 represents an optionally halogenated C1-C10 alkyl radical or a phenyl radical or a trimethylsilyloxy radical,
a′ is an integer chosen between 0 and 3 inclusive,
and the symbol G′ denotes a monovalent radical linked directly to a silicon atom, and which corresponds to formula (18) below:
in which:
Y′, which may be identical or different, are chosen from C1-C8 alkyl radicals, halogens and C1-C4 alkoxy radicals, it being understood that, in the latter case, two adjacent radicals Y′ on the same aromatic nucleus can together form an alkylidenedioxy group in which the alkylidene group contains from 1 to 2 carbon atoms,
X′ represents O or NH,
Z′ represents hydrogen or a C1-C4 alkyl radical,
n′ is an integer between 0 and 3 inclusive,
m′ is 0 or 1,
p′ represents an integer between 1 and 10 inclusive. 19. Composition according to claim 18, in which the water-insoluble solid UV-screening agent (A) of the phenylbenzotriazole type is Drometrizole trisiloxane of structure: 20. Cosmetic process for treating keratin materials, especially bodily or facial skin, the lips, the nails and/or the eyelashes or the hair, comprising the application to the said materials of a composition as defined according to claim 1. 21. Process for making up and/or caring for keratin materials, especially bodily or facial skin, the lips, the nails and/or the eyelashes or the hair, comprising the application to the said materials of a composition as defined according to claim 1. 22. Use of at least one compound (B) as defined in claim 1 as solvent for a water-insoluble solid organic UV-screening agent (A). | 1,600 |
495 | 15,270,876 | 1,615 | This disclosure relates to medical devices incorporating one or more cationic steroidal antimicrobials (CSAs). The CSAs are incorporated into the medical devices to provide effective antimicrobial, anti-inflammatory, and/or tissue-healing properties. A medical device includes a component formed from a polymeric material. One or more CSA compounds are mixed with the polymeric material so that the one or more CSA compounds are incorporated into the structure of the medical device as formed from the polymeric material. A medical device can additionally or alternatively include a lubricious coating containing one or more CSA compounds. | 1. An implantable medical device, the implantable medical device comprising:
a structural component formed at least in part from a polymeric material; and one or more CSA compounds, the one or more CSA compounds being incorporated into the polymeric material of the structural component so as to be distributed throughout the structural component. 2. The medical device of claim 1, wherein the medical device is a catheter, endotracheal tube, intravenous line, feeder tube, drain, prosthesis component, peristaltic pump component, tympsanostomy tube, or tracheostomy tube. 3. The medical device of claim 1, wherein the polymeric material is extrudable. 4. The medical device of claim 1, wherein the polymeric material is a thermoset polymer. 5. The medical device of claim 1, wherein the polymeric material comprises silicone. 6. The medical device of claim 1, further comprising a coating disposed on a surface of the structural component of the medical device, the coating including one or more CSA compounds incorporated therein. 7. The medical device of claim 6, wherein the coating comprises a hydrogel. 8. The medical device of claim 6, wherein the coating is configured as a lubricious coating reducing the coefficient of friction of the surface of the medical device upon which it is disposed by a factor of 5 to 30. 9. The medical device of claim 6, wherein the one or more CSA compounds in the structural component or the coating includes CSA-131 or a salt thereof. 10. The medical device of claim 9, wherein the one or more CSA compounds includes an NDSA salt of CSA-131. 11. The medical device of claim 6, wherein the medical device is an endotracheal tube, and wherein the coating is applied only to a distal tip of the endotracheal tube. 12. The medical device of claim 1, wherein the one or more CSA compounds includes one or more sulfonic acid addition salts. 13. The medical device of claim 12, wherein the one or more sulfonic acid addition salts includes a 1,5-naphthalenedisulfonic acid salt. 14. The medical device of claim 1, wherein the medical device provides protection against biofouling longer than a medical device not having one or more incorporated CSA compounds. 15. The medical device of claim 1, wherein the medical device provides enhanced anti-inflammatory activity as compared to a medical device not having one or more incorporated CSA compounds. 16. The medical device of claim 1, wherein the medical device is an endotracheal tube, and wherein the endotracheal tube better maintains the integrity of the tracheal mucosa when used in intubation as compared to an endotracheal tube not having one or more incorporated CSA compounds. 17. An endotracheal tube, comprising:
a catheter component; and a coating disposed on at least a portion of a surface of the catheter component, the coating including one or more CSA compounds so as to enable one or more of enhanced antimicrobial activity, enhanced anti-inflammatory activity, and enhanced tissue healing activity, as compared to an endotracheal tube not having a coating with one or more CSA compounds. 18. The endotracheal tube of claim 17, wherein the coating is formed as a hydrogel. 19. The endotracheal tube of claim 17, wherein the one or more CSA compounds includes CSA-131 or a salt thereof. 20. A method of manufacturing an implantable medical device having enhanced antimicrobial, anti-inflammatory, and/or tissue healing properties, the method comprising:
providing a biologically compatible polymeric material; mixing one or more CSA compounds with the moldable polymeric material; and forming the moldable polymeric material into an implantable medical device, the one or more CSA compounds thereby being incorporated into the medical device to provide the enhanced antimicrobial, anti-inflammatory, and/or tissue healing properties. 21. The method of claim 20, wherein the polymeric material is formed into the implantable medical device by extrusion. 22. The method of claim 20, wherein the polymeric material includes silicone, and wherein the one or more CSA compounds includes a naphthalenedisulfonic acid (NDSA) salt of a CSA compound. 23. The method of claim 22, wherein the naphthalenedisulfonic acid (NDSA) salt of a CSA compound is the NSDA salt of CSA-131. | This disclosure relates to medical devices incorporating one or more cationic steroidal antimicrobials (CSAs). The CSAs are incorporated into the medical devices to provide effective antimicrobial, anti-inflammatory, and/or tissue-healing properties. A medical device includes a component formed from a polymeric material. One or more CSA compounds are mixed with the polymeric material so that the one or more CSA compounds are incorporated into the structure of the medical device as formed from the polymeric material. A medical device can additionally or alternatively include a lubricious coating containing one or more CSA compounds.1. An implantable medical device, the implantable medical device comprising:
a structural component formed at least in part from a polymeric material; and one or more CSA compounds, the one or more CSA compounds being incorporated into the polymeric material of the structural component so as to be distributed throughout the structural component. 2. The medical device of claim 1, wherein the medical device is a catheter, endotracheal tube, intravenous line, feeder tube, drain, prosthesis component, peristaltic pump component, tympsanostomy tube, or tracheostomy tube. 3. The medical device of claim 1, wherein the polymeric material is extrudable. 4. The medical device of claim 1, wherein the polymeric material is a thermoset polymer. 5. The medical device of claim 1, wherein the polymeric material comprises silicone. 6. The medical device of claim 1, further comprising a coating disposed on a surface of the structural component of the medical device, the coating including one or more CSA compounds incorporated therein. 7. The medical device of claim 6, wherein the coating comprises a hydrogel. 8. The medical device of claim 6, wherein the coating is configured as a lubricious coating reducing the coefficient of friction of the surface of the medical device upon which it is disposed by a factor of 5 to 30. 9. The medical device of claim 6, wherein the one or more CSA compounds in the structural component or the coating includes CSA-131 or a salt thereof. 10. The medical device of claim 9, wherein the one or more CSA compounds includes an NDSA salt of CSA-131. 11. The medical device of claim 6, wherein the medical device is an endotracheal tube, and wherein the coating is applied only to a distal tip of the endotracheal tube. 12. The medical device of claim 1, wherein the one or more CSA compounds includes one or more sulfonic acid addition salts. 13. The medical device of claim 12, wherein the one or more sulfonic acid addition salts includes a 1,5-naphthalenedisulfonic acid salt. 14. The medical device of claim 1, wherein the medical device provides protection against biofouling longer than a medical device not having one or more incorporated CSA compounds. 15. The medical device of claim 1, wherein the medical device provides enhanced anti-inflammatory activity as compared to a medical device not having one or more incorporated CSA compounds. 16. The medical device of claim 1, wherein the medical device is an endotracheal tube, and wherein the endotracheal tube better maintains the integrity of the tracheal mucosa when used in intubation as compared to an endotracheal tube not having one or more incorporated CSA compounds. 17. An endotracheal tube, comprising:
a catheter component; and a coating disposed on at least a portion of a surface of the catheter component, the coating including one or more CSA compounds so as to enable one or more of enhanced antimicrobial activity, enhanced anti-inflammatory activity, and enhanced tissue healing activity, as compared to an endotracheal tube not having a coating with one or more CSA compounds. 18. The endotracheal tube of claim 17, wherein the coating is formed as a hydrogel. 19. The endotracheal tube of claim 17, wherein the one or more CSA compounds includes CSA-131 or a salt thereof. 20. A method of manufacturing an implantable medical device having enhanced antimicrobial, anti-inflammatory, and/or tissue healing properties, the method comprising:
providing a biologically compatible polymeric material; mixing one or more CSA compounds with the moldable polymeric material; and forming the moldable polymeric material into an implantable medical device, the one or more CSA compounds thereby being incorporated into the medical device to provide the enhanced antimicrobial, anti-inflammatory, and/or tissue healing properties. 21. The method of claim 20, wherein the polymeric material is formed into the implantable medical device by extrusion. 22. The method of claim 20, wherein the polymeric material includes silicone, and wherein the one or more CSA compounds includes a naphthalenedisulfonic acid (NDSA) salt of a CSA compound. 23. The method of claim 22, wherein the naphthalenedisulfonic acid (NDSA) salt of a CSA compound is the NSDA salt of CSA-131. | 1,600 |
496 | 15,407,037 | 1,635 | The present invention provides gapped oligomeric compounds. More particularly the gapped oligomeric compounds provided herein comprise at least one modified internucleoside linkage in the gap region. Such gapped oligomeric compounds have one or more improved properties such as selectivity, potency, improved toxicity profile and or improved proinflammatory profile. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell. | 1. A gapped oligomeric compound comprising a contiguous sequence of linked monomer subunits having a gap region located between a 5′-region and a 3′-region wherein the 5′ and 3′-regions each, independently, have from 2 to 8 contiguous RNA-like modified nucleosides, each independently selected from a bicyclic nucleoside comprising a bicyclic furanosyl sugar moiety and a modified nucleoside comprising a furanosyl sugar moiety having at least one substituent group that each adopt a 3′-endo conformational geometry when put into an oligomeric compound and wherein the gap region has from 8 to 10 contiguous β-D-2′-deoxyribonucleosides and wherein from one to three of the internucleoside linking groups located between β-D-2′-deoxyribonucleosides in the gap region have Formula I:
wherein:
each X is O or S;
each Q is, independently, selected from C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, C(═O)OH and CH2C(═O)OH; and
each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ1, SJ1 and OC(═O)J1;
each J1 is, independently, H or C1-C6 alkyl; and
wherein each internucleoside linking group other than internucleoside linking groups having Formula I is, independently, a phosphodiester or a phosphorothioate internucleoside linking group. 2. The gapped oligomeric compound of claim 1 having only one internucleoside linking group of Formula I. 3. The gapped oligomeric compound of claim 2 wherein the internucleoside linking group of Formula I is located between nucleosides 1 and 2, 2 and 3, or 3 and 4, counting from the 5′ gap junction. 4. The gapped oligomeric compound of claim 1 having only two internucleoside linking groups of Formula I. 5. The gapped oligomeric compound of claim 4 wherein the internucleoside linking groups of Formula I are located between nucleosides 1 and 3, or 2 and 4, counting from the 5′ gap junction. 6. The gapped oligomeric compound of claim 1 wherein each internucleoside linking group other than internucleoside linking groups having Formula I is a phosphorothioate internucleoside linking group. 7. The gapped oligomeric compound of claim 1 wherein each monomer subunit comprises a heterocyclic base independently selected from uracil, thymine, cytosine, 4-N-benzoylcytosine, 5-methylcytosine, 4-N-benzoyl-5-methylcytosine, adenine, 6-N-benzoyladenine, guanine and 2-N-isobutyrylguanine. 8. The gapped oligomeric compound of claim 1 wherein each Q is, independently, selected from CH3, C(═O)OH, CH2C(═O)OH, (CH2)2OCH3, CH═CH2, CH2CH═CH2 and C≡CH. 9. The gapped oligomeric compound of claim 1 wherein each Q is, independently, selected from C1-C6 alkyl and substituted C1-C6 alkyl. 10. The gapped oligomeric compound of claim 9 wherein each Q is, independently, substituted C1-C6 alkyl wherein the substituent group is OJ1 and J1 is C1-C6 alkyl. 11. The gapped oligomeric compound of claim 9 wherein each Q is CH3. 12. The gapped oligomeric compound of claim 1 wherein each X is S. 13. The gapped oligomeric compound of claim 1 wherein one or more of the RNA-like modified nucleosides each comprising a 2′-substituted furanosyl sugar moiety wherein each 2′-substituent group is, independently, selected from halogen, OCH3, OCH2F, OCHF2, OCF3, OCH2CH3, O(CH2)2F, OCH2CHF2, OCH2CF3, OCH2—CH═CH2, O(CH2)2—OCH3, O(CH2)2—SCH3, O(CH2)2—OCF3, O(CH2)3—N(R3)(R4), O(CH2)2—ON(R3)(R4), O(CH2)2—O(CH2)2—N(R3)(R4), OCH2C(═O)—N(R4)(R4), OCH2C(═O)—N(R5)—(CH2)2—N(R3)(R4) and O(CH2)2—N(R5)—C(═NR6)[N(R3)(R4)] wherein R3, R4, R5 and R6 are each, independently, H or C1-C6 alkyl. 14. The gapped oligomeric compound of claim 13 wherein each 2′-substituent group is independently selected from F, OCH3, O(CH2)2—OCH3 and OCH2C(═O)—N(H)CH3. 15. The gapped oligomeric compound of claim 14 wherein each 2′-substituent group is O(CH2)2—OCH3. 16. The gapped oligomeric compound of claim 1 wherein one or more of the RNA-like modified nucleosides comprises a bicyclic furanosyl sugar moiety each having a bridging group independently selected from 4′-(CH2)—O-2′, 4′-(CH2)—S-2′, 4′-(CH2)2—O-2′, 4′-CH(CH3)—O-2′, 4′-C—H(CH2OCH3)—O-2′, 4′-C(CH3)2—O-2′, 4′-CH2—N(OCH3)-2′, 4′-CH2—O—N(CH3)-2′, 4′-CH2—C(H)(CH3)-2′ and 4′-CH2—C(═CH2)-2′. 17. The gapped oligomeric compound of claim 18 wherein each bridging group is 4′-CH[(S)—(CH3)]—O-2′ or 4′-(CH2)—O-2′. 18. The gapped oligomeric compound of claim 1 wherein the sugar moiety of each RNA-like modified nucleoside is the same. 19. The gapped oligomeric compound of claim 1 comprising at least two different types of RNA-like modified nucleosides wherein the different types of modified nucleosides have at least different modified sugar moieties. 20. The gapped oligomeric compound of claim 19 wherein the different types of RNA-like modified nucleosides include 4′-CH[(S)—(CH3)]—O-2′ bicyclic nucleosides and 2′-O(CH2)2—OCH3 substituted nucleosides. 21. The gapped oligomeric compound of claim 1 wherein the 5′ and 3′-regions each, independently, have from 3 to 6 RNA-like modified nucleosides. 21. The gapped oligomeric compound of claim 1 further comprising at least one 5′ or 3′-conjugate group. 23. A method of inhibiting gene expression comprising contacting one or more cells, a tissue or an animal with an oligomeric compound of claim 1 wherein said oligomeric compound is complementary to a target RNA. | The present invention provides gapped oligomeric compounds. More particularly the gapped oligomeric compounds provided herein comprise at least one modified internucleoside linkage in the gap region. Such gapped oligomeric compounds have one or more improved properties such as selectivity, potency, improved toxicity profile and or improved proinflammatory profile. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell.1. A gapped oligomeric compound comprising a contiguous sequence of linked monomer subunits having a gap region located between a 5′-region and a 3′-region wherein the 5′ and 3′-regions each, independently, have from 2 to 8 contiguous RNA-like modified nucleosides, each independently selected from a bicyclic nucleoside comprising a bicyclic furanosyl sugar moiety and a modified nucleoside comprising a furanosyl sugar moiety having at least one substituent group that each adopt a 3′-endo conformational geometry when put into an oligomeric compound and wherein the gap region has from 8 to 10 contiguous β-D-2′-deoxyribonucleosides and wherein from one to three of the internucleoside linking groups located between β-D-2′-deoxyribonucleosides in the gap region have Formula I:
wherein:
each X is O or S;
each Q is, independently, selected from C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, C(═O)OH and CH2C(═O)OH; and
each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ1, SJ1 and OC(═O)J1;
each J1 is, independently, H or C1-C6 alkyl; and
wherein each internucleoside linking group other than internucleoside linking groups having Formula I is, independently, a phosphodiester or a phosphorothioate internucleoside linking group. 2. The gapped oligomeric compound of claim 1 having only one internucleoside linking group of Formula I. 3. The gapped oligomeric compound of claim 2 wherein the internucleoside linking group of Formula I is located between nucleosides 1 and 2, 2 and 3, or 3 and 4, counting from the 5′ gap junction. 4. The gapped oligomeric compound of claim 1 having only two internucleoside linking groups of Formula I. 5. The gapped oligomeric compound of claim 4 wherein the internucleoside linking groups of Formula I are located between nucleosides 1 and 3, or 2 and 4, counting from the 5′ gap junction. 6. The gapped oligomeric compound of claim 1 wherein each internucleoside linking group other than internucleoside linking groups having Formula I is a phosphorothioate internucleoside linking group. 7. The gapped oligomeric compound of claim 1 wherein each monomer subunit comprises a heterocyclic base independently selected from uracil, thymine, cytosine, 4-N-benzoylcytosine, 5-methylcytosine, 4-N-benzoyl-5-methylcytosine, adenine, 6-N-benzoyladenine, guanine and 2-N-isobutyrylguanine. 8. The gapped oligomeric compound of claim 1 wherein each Q is, independently, selected from CH3, C(═O)OH, CH2C(═O)OH, (CH2)2OCH3, CH═CH2, CH2CH═CH2 and C≡CH. 9. The gapped oligomeric compound of claim 1 wherein each Q is, independently, selected from C1-C6 alkyl and substituted C1-C6 alkyl. 10. The gapped oligomeric compound of claim 9 wherein each Q is, independently, substituted C1-C6 alkyl wherein the substituent group is OJ1 and J1 is C1-C6 alkyl. 11. The gapped oligomeric compound of claim 9 wherein each Q is CH3. 12. The gapped oligomeric compound of claim 1 wherein each X is S. 13. The gapped oligomeric compound of claim 1 wherein one or more of the RNA-like modified nucleosides each comprising a 2′-substituted furanosyl sugar moiety wherein each 2′-substituent group is, independently, selected from halogen, OCH3, OCH2F, OCHF2, OCF3, OCH2CH3, O(CH2)2F, OCH2CHF2, OCH2CF3, OCH2—CH═CH2, O(CH2)2—OCH3, O(CH2)2—SCH3, O(CH2)2—OCF3, O(CH2)3—N(R3)(R4), O(CH2)2—ON(R3)(R4), O(CH2)2—O(CH2)2—N(R3)(R4), OCH2C(═O)—N(R4)(R4), OCH2C(═O)—N(R5)—(CH2)2—N(R3)(R4) and O(CH2)2—N(R5)—C(═NR6)[N(R3)(R4)] wherein R3, R4, R5 and R6 are each, independently, H or C1-C6 alkyl. 14. The gapped oligomeric compound of claim 13 wherein each 2′-substituent group is independently selected from F, OCH3, O(CH2)2—OCH3 and OCH2C(═O)—N(H)CH3. 15. The gapped oligomeric compound of claim 14 wherein each 2′-substituent group is O(CH2)2—OCH3. 16. The gapped oligomeric compound of claim 1 wherein one or more of the RNA-like modified nucleosides comprises a bicyclic furanosyl sugar moiety each having a bridging group independently selected from 4′-(CH2)—O-2′, 4′-(CH2)—S-2′, 4′-(CH2)2—O-2′, 4′-CH(CH3)—O-2′, 4′-C—H(CH2OCH3)—O-2′, 4′-C(CH3)2—O-2′, 4′-CH2—N(OCH3)-2′, 4′-CH2—O—N(CH3)-2′, 4′-CH2—C(H)(CH3)-2′ and 4′-CH2—C(═CH2)-2′. 17. The gapped oligomeric compound of claim 18 wherein each bridging group is 4′-CH[(S)—(CH3)]—O-2′ or 4′-(CH2)—O-2′. 18. The gapped oligomeric compound of claim 1 wherein the sugar moiety of each RNA-like modified nucleoside is the same. 19. The gapped oligomeric compound of claim 1 comprising at least two different types of RNA-like modified nucleosides wherein the different types of modified nucleosides have at least different modified sugar moieties. 20. The gapped oligomeric compound of claim 19 wherein the different types of RNA-like modified nucleosides include 4′-CH[(S)—(CH3)]—O-2′ bicyclic nucleosides and 2′-O(CH2)2—OCH3 substituted nucleosides. 21. The gapped oligomeric compound of claim 1 wherein the 5′ and 3′-regions each, independently, have from 3 to 6 RNA-like modified nucleosides. 21. The gapped oligomeric compound of claim 1 further comprising at least one 5′ or 3′-conjugate group. 23. A method of inhibiting gene expression comprising contacting one or more cells, a tissue or an animal with an oligomeric compound of claim 1 wherein said oligomeric compound is complementary to a target RNA. | 1,600 |
497 | 14,763,973 | 1,613 | The present invention provides a freshness-retentive film having high antibacterial characteristics. In the freshness-retentive film according to the present invention, at least one compound selected from the group consisting of palmityldiethanolamine, stearyldiethanolamine, glycerol monolaurate, and diglycerol monolaurate is present on at least one surface of the film at 0.002 to 0.5 g/m 2 . | 1. A freshness-retentive film, comprising at least one compound selected from the group consisting of palmityldiethanolamine, stearyldiethanolamine, glycerol monolaurate, and diglycerol monolaurate, wherein the at least one compound is present on at least one surface at 0.002 to 0.5 g/m2. 2. The freshness-retentive film according to claim 1, wherein the freshness-retentive film comprises the compound in an amount of 0.001 to 3% by mass. 3. The freshness-retentive film according to claim 1, wherein the freshness-retentive film comprises at least one of a propylene-based polymer and an ethylene-based polymer. 4. The freshness-retentive film according to claim 1, wherein at least one surface has a wetting index of 35 dyn or more. 5. The freshness-retentive film according to claim 1, wherein the freshness-retentive film further comprises at least one of myristyldiethanolamine monostearate and stearyldiethanolamine monostearate. 6. The freshness-retentive film according to claim 1, wherein a region comprises the compound in a thickness-wise direction from a surface of the film to be in contact with a content, the region ranging from 50 to 90% of the overall thickness of the film. 7. The freshness-retentive film according to claim 1, wherein the freshness-retentive film comprises two or more layers, and wherein the freshness-retentive film comprises the compound only in a layer having a surface of the film to be in contact with a content. 8. The freshness-retentive film according to claim 1, wherein the freshness-retentive film comprises an ethylene-based polymer, and the density of the ethylene-based polymer increases in a thickness-wise direction from the surface of the film to be in contact with a content. 9. A freshness-retentive film, comprising:
0.01 to 1.0% by mass of alkyldiethanolamine, and 0.01 to 1.0% by mass of at least one of diglycerol monopalmitate and diglycerol monomyristate. 10. The freshness-retentive film according to claim 9, wherein the alkyldiethanolamine is present on at least one surface at 0.002 to 0.5 g/m2. 11. The freshness-retentive film according to claim 9, wherein the alkyldiethanolamine is at least one of palmityldiethanolamine and stearyldiethanolamine. 12. A freshness-retentive film, comprising:
50 to 95% by mass of a linear low density polyethylene (A) having a density of 0.85 to 0.95 g/cm3, and 5 to 50% by mass of a high pressure low density polyethylene (B) having a density of 0.91 to 0.93 g/cm3, where the total amount of the linear low density polyethylene (A) and the high pressure low density polyethylene (B) is 100% by mass, 0.5 to 10 parts by mass of an adhesive (C), 0.5 to 5 parts by mass of an antifog additive (D), and 0.001 to 3 parts by mass of at least one specific compound (E) selected from the group consisting of palmityldiethanolamine, stearyldiethanolamine, glycerol monolaurate, and glycerol monocaprate relative to 100 parts by mass of the total amount of the linear low density polyethylene (A) and the high pressure low density polyethylene (B), wherein the specific compound (E) is present on at least one surface at 0.002 to 0.5 g/m2. 13. A packaging material, comprising a freshness-retentive film according to claim 1. | The present invention provides a freshness-retentive film having high antibacterial characteristics. In the freshness-retentive film according to the present invention, at least one compound selected from the group consisting of palmityldiethanolamine, stearyldiethanolamine, glycerol monolaurate, and diglycerol monolaurate is present on at least one surface of the film at 0.002 to 0.5 g/m 2 .1. A freshness-retentive film, comprising at least one compound selected from the group consisting of palmityldiethanolamine, stearyldiethanolamine, glycerol monolaurate, and diglycerol monolaurate, wherein the at least one compound is present on at least one surface at 0.002 to 0.5 g/m2. 2. The freshness-retentive film according to claim 1, wherein the freshness-retentive film comprises the compound in an amount of 0.001 to 3% by mass. 3. The freshness-retentive film according to claim 1, wherein the freshness-retentive film comprises at least one of a propylene-based polymer and an ethylene-based polymer. 4. The freshness-retentive film according to claim 1, wherein at least one surface has a wetting index of 35 dyn or more. 5. The freshness-retentive film according to claim 1, wherein the freshness-retentive film further comprises at least one of myristyldiethanolamine monostearate and stearyldiethanolamine monostearate. 6. The freshness-retentive film according to claim 1, wherein a region comprises the compound in a thickness-wise direction from a surface of the film to be in contact with a content, the region ranging from 50 to 90% of the overall thickness of the film. 7. The freshness-retentive film according to claim 1, wherein the freshness-retentive film comprises two or more layers, and wherein the freshness-retentive film comprises the compound only in a layer having a surface of the film to be in contact with a content. 8. The freshness-retentive film according to claim 1, wherein the freshness-retentive film comprises an ethylene-based polymer, and the density of the ethylene-based polymer increases in a thickness-wise direction from the surface of the film to be in contact with a content. 9. A freshness-retentive film, comprising:
0.01 to 1.0% by mass of alkyldiethanolamine, and 0.01 to 1.0% by mass of at least one of diglycerol monopalmitate and diglycerol monomyristate. 10. The freshness-retentive film according to claim 9, wherein the alkyldiethanolamine is present on at least one surface at 0.002 to 0.5 g/m2. 11. The freshness-retentive film according to claim 9, wherein the alkyldiethanolamine is at least one of palmityldiethanolamine and stearyldiethanolamine. 12. A freshness-retentive film, comprising:
50 to 95% by mass of a linear low density polyethylene (A) having a density of 0.85 to 0.95 g/cm3, and 5 to 50% by mass of a high pressure low density polyethylene (B) having a density of 0.91 to 0.93 g/cm3, where the total amount of the linear low density polyethylene (A) and the high pressure low density polyethylene (B) is 100% by mass, 0.5 to 10 parts by mass of an adhesive (C), 0.5 to 5 parts by mass of an antifog additive (D), and 0.001 to 3 parts by mass of at least one specific compound (E) selected from the group consisting of palmityldiethanolamine, stearyldiethanolamine, glycerol monolaurate, and glycerol monocaprate relative to 100 parts by mass of the total amount of the linear low density polyethylene (A) and the high pressure low density polyethylene (B), wherein the specific compound (E) is present on at least one surface at 0.002 to 0.5 g/m2. 13. A packaging material, comprising a freshness-retentive film according to claim 1. | 1,600 |
498 | 13,729,631 | 1,615 | The invention relates to a composition, especially a cosmetic composition, comprising at least one silicon resin comprising at least one T unit and at least one acrylic film forming agent, as well as to methods of using such compositions. | 1. A composition comprising at least one film forming silicon resin comprising at least one T unit and at least one acrylic film forming agent. 2. The composition of claim 1, further comprising at least one wax. 3. The composition of claim 2, wherein the wax is a silicone wax. 4. The composition of claim 1, further comprising at least one coloring agent. 5. The composition of claim 1, further comprising at least one oil. 6. The composition of claim 5, wherein the oil is a volatile oil. 7. The composition of claim 1, in the form of a stick. 8. The composition of claim 1, wherein the composition is anhydrous. 9. The composition of claim 1, wherein the silicon resin comprising at least one T unit is a polypropylsilsesquioxane. 10. The composition of claim 1, wherein more silicon resin comprising at least one T unit is present in the composition than acrylic acid film forming agent. 11. The composition of claim 10, wherein the silicon resin comprising at least one T unit to acrylic acid film forming agent weight ratio is at least 7:1. 12. The composition of claim 10, wherein the silicon resin comprising at least one T unit to acrylic acid film forming agent weight ratio is at least 9:1. 13. The composition of claim 1, wherein the same weight amount of silicon resin comprising at least one T unit and acrylic film forming agent are present in the composition. 14. A method of making up lips comprising applying the composition of claim 1 to the lips. 15. A method of making up skin comprising applying the composition of claim 1 to the skin. | The invention relates to a composition, especially a cosmetic composition, comprising at least one silicon resin comprising at least one T unit and at least one acrylic film forming agent, as well as to methods of using such compositions.1. A composition comprising at least one film forming silicon resin comprising at least one T unit and at least one acrylic film forming agent. 2. The composition of claim 1, further comprising at least one wax. 3. The composition of claim 2, wherein the wax is a silicone wax. 4. The composition of claim 1, further comprising at least one coloring agent. 5. The composition of claim 1, further comprising at least one oil. 6. The composition of claim 5, wherein the oil is a volatile oil. 7. The composition of claim 1, in the form of a stick. 8. The composition of claim 1, wherein the composition is anhydrous. 9. The composition of claim 1, wherein the silicon resin comprising at least one T unit is a polypropylsilsesquioxane. 10. The composition of claim 1, wherein more silicon resin comprising at least one T unit is present in the composition than acrylic acid film forming agent. 11. The composition of claim 10, wherein the silicon resin comprising at least one T unit to acrylic acid film forming agent weight ratio is at least 7:1. 12. The composition of claim 10, wherein the silicon resin comprising at least one T unit to acrylic acid film forming agent weight ratio is at least 9:1. 13. The composition of claim 1, wherein the same weight amount of silicon resin comprising at least one T unit and acrylic film forming agent are present in the composition. 14. A method of making up lips comprising applying the composition of claim 1 to the lips. 15. A method of making up skin comprising applying the composition of claim 1 to the skin. | 1,600 |
499 | 14,419,149 | 1,632 | The invention relates to a method for culturing a subpopulation of circulating epithelial tumour cells from a body fluid of a human or animal suffering from an epithelial tumour, wherein cells contained in the body fluid each containing at least one cell nucleus are separated from the body fluid and cultured over at least 24 hours in suspension, with formation of spheroids. | 1. A method for culturing circulating epithelial tumor cells from a body fluid from a human or animal affected by an epithelial tumor, comprising:
separating cells present in the body fluid and containing at least one nucleus in each case are separated from the body fluid without selection of certain of these cells; transferring said separated cells to a cell culture medium; and culturing said transferred separated cells under cell culture conditions in said cell culture medium with addition of at least one growth factor, wherein the cells are cultured for at least 24 hours in suspension at least until a subpopulation of tumor cells which does not require adherence to a surface for proliferation has formed spheroids by proliferation. 2. The method as claimed in claim 1, wherein the body fluid is lymph or blood. 3. The method as claimed in claim 1, wherein the body fluid contains intact erythrocytes and the cells containing at least one nucleus in each case are separated from the intact erythrocytes. 4. (canceled) 5. The method as claimed in claim 1, wherein the cell culture conditions comprise a temperature within the range of 35.5° C. to 37.5° C., and an atmosphere containing 4.5% to 5.5% CO2. 6. The method as claimed in claim 1, wherein fresh cell culture medium is added to the cell culture medium repeatedly or regularly, or wherein the cells are transferred to fresh cell culture medium repeatedly or regularly. 7. The method as claimed in claim 1, wherein tumor cells which have formed the spheroids during culturing are separated from the cultured tumor cells, by separating the spheroids formed during culturing. 8. A method of testing sensitivity of tumor cells with respect to a medicament or a therapeutic measure for treating a tumor disease underlying the occurrence of circulating epithelial tumor cells in a human or animal, comprising,
providing the spheroids obtained by the method according to claim 7 and, testing of sensitivity of tumor cells in the spheroids with respect to the medicament or the therapeutic measure. 9. The method as claimed in claim 8, wherein the tumor cells present in the spheroids are fluorescently labeled using antibodies directed against the human epithelial antigen EpCAM (epithelial cell adhesion molecule) and then analyzed using an image analysis method. 10. The method as claimed in claim 9, wherein the tumor cells present in the spheroids are stained with a substance, which is detectable by fluorescence and stains dead cells. 11. The method as claimed in claim 9, wherein labeling, measuring and/or staining are carried out in the presence of a Ca2+ chelator. 12. The method as claimed in claim 8, wherein the therapeutic measure is a physical measure, or a pharmaceutical measure. 13. Spheroid-forming tumor cells which have been cultured according to a method as claimed in claim 7 for use in the immunological treatment of a tumor disease in a human or animal, wherein the tumor cells present in the spheroids are treated such that they can no longer proliferate and are subsequently administered, suspended in an adjuvant, to the human or animal. 14. The method as claimed in claim 2, wherein the body fluid is peripheral blood. 15. The method as claimed in claim 3, wherein the cells containing at least one nucleus in each case are separated from the intact erythrocytes by lysing the intact erythrocytes. 16. The method as claimed in claim 5, wherein the temperature is within the range of 36.8° C. to 37.1° C. 17. The method as claimed in claim 5, wherein the temperature is 37° C. and the atmosphere contains 5% CO2. 18. A method for examining a self-renewal capacity of tumor cells comprising,
providing the spheroids obtained by the method according to claim 7 and, examining the self-renewal capacity of tumor cells present in the spheroids and/or of progenitor cells generated in the spheroids. | The invention relates to a method for culturing a subpopulation of circulating epithelial tumour cells from a body fluid of a human or animal suffering from an epithelial tumour, wherein cells contained in the body fluid each containing at least one cell nucleus are separated from the body fluid and cultured over at least 24 hours in suspension, with formation of spheroids.1. A method for culturing circulating epithelial tumor cells from a body fluid from a human or animal affected by an epithelial tumor, comprising:
separating cells present in the body fluid and containing at least one nucleus in each case are separated from the body fluid without selection of certain of these cells; transferring said separated cells to a cell culture medium; and culturing said transferred separated cells under cell culture conditions in said cell culture medium with addition of at least one growth factor, wherein the cells are cultured for at least 24 hours in suspension at least until a subpopulation of tumor cells which does not require adherence to a surface for proliferation has formed spheroids by proliferation. 2. The method as claimed in claim 1, wherein the body fluid is lymph or blood. 3. The method as claimed in claim 1, wherein the body fluid contains intact erythrocytes and the cells containing at least one nucleus in each case are separated from the intact erythrocytes. 4. (canceled) 5. The method as claimed in claim 1, wherein the cell culture conditions comprise a temperature within the range of 35.5° C. to 37.5° C., and an atmosphere containing 4.5% to 5.5% CO2. 6. The method as claimed in claim 1, wherein fresh cell culture medium is added to the cell culture medium repeatedly or regularly, or wherein the cells are transferred to fresh cell culture medium repeatedly or regularly. 7. The method as claimed in claim 1, wherein tumor cells which have formed the spheroids during culturing are separated from the cultured tumor cells, by separating the spheroids formed during culturing. 8. A method of testing sensitivity of tumor cells with respect to a medicament or a therapeutic measure for treating a tumor disease underlying the occurrence of circulating epithelial tumor cells in a human or animal, comprising,
providing the spheroids obtained by the method according to claim 7 and, testing of sensitivity of tumor cells in the spheroids with respect to the medicament or the therapeutic measure. 9. The method as claimed in claim 8, wherein the tumor cells present in the spheroids are fluorescently labeled using antibodies directed against the human epithelial antigen EpCAM (epithelial cell adhesion molecule) and then analyzed using an image analysis method. 10. The method as claimed in claim 9, wherein the tumor cells present in the spheroids are stained with a substance, which is detectable by fluorescence and stains dead cells. 11. The method as claimed in claim 9, wherein labeling, measuring and/or staining are carried out in the presence of a Ca2+ chelator. 12. The method as claimed in claim 8, wherein the therapeutic measure is a physical measure, or a pharmaceutical measure. 13. Spheroid-forming tumor cells which have been cultured according to a method as claimed in claim 7 for use in the immunological treatment of a tumor disease in a human or animal, wherein the tumor cells present in the spheroids are treated such that they can no longer proliferate and are subsequently administered, suspended in an adjuvant, to the human or animal. 14. The method as claimed in claim 2, wherein the body fluid is peripheral blood. 15. The method as claimed in claim 3, wherein the cells containing at least one nucleus in each case are separated from the intact erythrocytes by lysing the intact erythrocytes. 16. The method as claimed in claim 5, wherein the temperature is within the range of 36.8° C. to 37.1° C. 17. The method as claimed in claim 5, wherein the temperature is 37° C. and the atmosphere contains 5% CO2. 18. A method for examining a self-renewal capacity of tumor cells comprising,
providing the spheroids obtained by the method according to claim 7 and, examining the self-renewal capacity of tumor cells present in the spheroids and/or of progenitor cells generated in the spheroids. | 1,600 |
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