Unnamed: 0
int64 0
350k
| ApplicationNumber
int64 9.75M
96.1M
| ArtUnit
int64 1.6k
3.99k
| Abstract
stringlengths 7
8.37k
| Claims
stringlengths 3
292k
| abstract-claims
stringlengths 68
293k
| TechCenter
int64 1.6k
3.9k
|
|---|---|---|---|---|---|---|
1,400 | 16,370,679 | 1,623 | Methods of treating chin retrusion in a subject by increasing a glabella-subnasale-pogonion (G-Sn-Pog) facial angle of the subject are provided, which may include injecting a first volume of a dermal filler into a pogonion, injecting a second volume of a dermal filler into a mentum, and/or injecting a third volume of the dermal filler into a left pre-j owl sulcus and/or a right pre-jowl sulcus, wherein the G-Sn-Pog facial angle of the subject is increased by at least about 1 or more. Methods of treating chin retrusion are provided that may include injecting a first volume of a dermal filler into a pogonion, injecting a second volume of a dermal filler into a mentum, and/or injecting a third volume of the dermal filler into a left pre-j owl sulcus and/or a right pre-jowl sulcus, wherein the chin retrusion of the subject is decreased by at least about 2 mm. | 1. A method of treating chin retrusion in a subject by increasing a glabella-subnasale-pogonion (G-Sn-Pog) facial angle of the subject, the method comprising:
injecting a first volume of a composition comprising a dermal filler into a pogonion; injecting a second volume of the dermal filler into a mentum; and injecting a third volume of the dermal filler into a left pre-j owl sulcus and a right pre-jowl sulcus, wherein the G-Sn-Pog facial angle of the subject is increased after injection of the dermal filler into the pogonion, mentum, left pre-jowl sulcus, and right pre-jowl sulcus by at least about 1°. 2. The method of claim 1, wherein the increase in the G-Sn-Pog facial angle of the subject is maintained for at least about 3 months. 3. The method of claim 1, wherein the increase in the G-Sn-Pog facial angle of the subject is maintained for at least about 12 months. 4. The method of claim 1, wherein the increase in the G-Sn-Pog facial angle of the subject is maintained for at least about 18 months. 5. The method of claim 1, wherein the G-Sn-Pog facial angle of the subject is increased by at least about 2°. 6. The method of claim 5, wherein an increase in the G-Sn-Pog facial angle of the subject of at least about 1° is maintained for at least about 18 months. 7. The method of claim 1, wherein the injection of the dermal filler into the pogonion, mentum, left pre-jowl sulcus, right pre-j owl sulcus, and sublabial crease occurs at a first treatment session. 8. The method of claim 7 further comprising a second treatment session about 18 months to about 24 months after the first treatment session. 9. The method of claim 8, wherein the second treatment session further increases the G-Sn-Pog facial angle of the subject by at least about 1°. 10. The method of claim 1, wherein the injections into the pogonion, mentum, left pre-jowl sulcus, and right pre-j owl sulcus comprise a serial puncture technique. 11. The method of claim 1, wherein the injections into the pogonion, mentum, left pre-jowl sulcus, and right pre-jowl sulcus comprise a supraperiosteal injection. 12. The method of claim 1 further comprising injecting a fourth volume of the dermal filler into a sublabial crease. 13. The method of claim 12, wherein the injection into the sublabial crease comprises a subcutaneous injection. 14. The method of claim 12, wherein a total volume of the dermal filler injected into the pogonion, mentum, left pre-jowl sulcus, right pre-jowl sulcus, and sublabial crease is no greater than about 4.0 mL. 15. The method of claim 1, wherein each injection volume is no greater than about 2.0 mL. 16. The method of claim 1, wherein the subject has an initial G-Sn-Pog facial angle of about 145° to about 165°. 17. The method of claim 1, wherein the dermal filler comprises a hyaluronic acid. 18. The method of claim 1, wherein the dermal filler comprises a crosslinked hyaluronic acid. 19. The method of claim 1, wherein the dermal filler comprises a hyaluronic acid crosslinked with 1,4-butanedioldiglycidyl ether (BDDE). 20. A method of treating chin retrusion in a subject in need thereof, the method comprising:
injecting a first volume of a composition comprising a dermal filler into a pogonion; injecting a second volume of the dermal filler into a mentum; and injecting a third volume of the dermal filler into a left pre-j owl sulcus and a right pre-jowl sulcus, wherein the chin retrusion of the subject is decreased after injection of the dermal filler into the pogonion, mentum, left pre-jowl sulcus, and right pre-jowl sulcus by at least about 2 mm. 21. The method of claim 20, wherein the decrease in chin retrusion of the subject is maintained for at least about 3 months. 22. The method of claim 20, wherein the decrease in chin retrusion of the subject is maintained for at least about 12 months. 23. The method of claim 20, wherein the decrease in chin retrusion of the subject is maintained for at least about 18 months. 24. The method of claim 20, wherein the dermal filler comprises a hyaluronic acid. 25. The method of claim 20, wherein the dermal filler comprises a crosslinked hyaluronic acid. 26. The method of claim 20, wherein the dermal filler comprises a hyaluronic acid crosslinked with 1,4-butanedioldiglycidyl ether (BDDE). 27. A method of increasing a glabella-subnasale-pogonion (G-Sn-Pog) facial angle in a subject in need thereof, the method comprising:
injecting a first volume of a dermal filler into a pogonion; injecting a second volume of the dermal filler into a mentum; and injecting a third volume of the dermal filler into a left pre-j owl sulcus and a right pre-jowl sulcus, wherein the G-Sn-Pog facial angle of the subject is increased after injection of the dermal filler into the pogonion, mentum, left pre-jowl sulcus, and right pre-jowl sulcus by at least about 1°, wherein the increase in the G-Sn-Pog facial angle of the subject is maintained for at least about 18 months. | Methods of treating chin retrusion in a subject by increasing a glabella-subnasale-pogonion (G-Sn-Pog) facial angle of the subject are provided, which may include injecting a first volume of a dermal filler into a pogonion, injecting a second volume of a dermal filler into a mentum, and/or injecting a third volume of the dermal filler into a left pre-j owl sulcus and/or a right pre-jowl sulcus, wherein the G-Sn-Pog facial angle of the subject is increased by at least about 1 or more. Methods of treating chin retrusion are provided that may include injecting a first volume of a dermal filler into a pogonion, injecting a second volume of a dermal filler into a mentum, and/or injecting a third volume of the dermal filler into a left pre-j owl sulcus and/or a right pre-jowl sulcus, wherein the chin retrusion of the subject is decreased by at least about 2 mm.1. A method of treating chin retrusion in a subject by increasing a glabella-subnasale-pogonion (G-Sn-Pog) facial angle of the subject, the method comprising:
injecting a first volume of a composition comprising a dermal filler into a pogonion; injecting a second volume of the dermal filler into a mentum; and injecting a third volume of the dermal filler into a left pre-j owl sulcus and a right pre-jowl sulcus, wherein the G-Sn-Pog facial angle of the subject is increased after injection of the dermal filler into the pogonion, mentum, left pre-jowl sulcus, and right pre-jowl sulcus by at least about 1°. 2. The method of claim 1, wherein the increase in the G-Sn-Pog facial angle of the subject is maintained for at least about 3 months. 3. The method of claim 1, wherein the increase in the G-Sn-Pog facial angle of the subject is maintained for at least about 12 months. 4. The method of claim 1, wherein the increase in the G-Sn-Pog facial angle of the subject is maintained for at least about 18 months. 5. The method of claim 1, wherein the G-Sn-Pog facial angle of the subject is increased by at least about 2°. 6. The method of claim 5, wherein an increase in the G-Sn-Pog facial angle of the subject of at least about 1° is maintained for at least about 18 months. 7. The method of claim 1, wherein the injection of the dermal filler into the pogonion, mentum, left pre-jowl sulcus, right pre-j owl sulcus, and sublabial crease occurs at a first treatment session. 8. The method of claim 7 further comprising a second treatment session about 18 months to about 24 months after the first treatment session. 9. The method of claim 8, wherein the second treatment session further increases the G-Sn-Pog facial angle of the subject by at least about 1°. 10. The method of claim 1, wherein the injections into the pogonion, mentum, left pre-jowl sulcus, and right pre-j owl sulcus comprise a serial puncture technique. 11. The method of claim 1, wherein the injections into the pogonion, mentum, left pre-jowl sulcus, and right pre-jowl sulcus comprise a supraperiosteal injection. 12. The method of claim 1 further comprising injecting a fourth volume of the dermal filler into a sublabial crease. 13. The method of claim 12, wherein the injection into the sublabial crease comprises a subcutaneous injection. 14. The method of claim 12, wherein a total volume of the dermal filler injected into the pogonion, mentum, left pre-jowl sulcus, right pre-jowl sulcus, and sublabial crease is no greater than about 4.0 mL. 15. The method of claim 1, wherein each injection volume is no greater than about 2.0 mL. 16. The method of claim 1, wherein the subject has an initial G-Sn-Pog facial angle of about 145° to about 165°. 17. The method of claim 1, wherein the dermal filler comprises a hyaluronic acid. 18. The method of claim 1, wherein the dermal filler comprises a crosslinked hyaluronic acid. 19. The method of claim 1, wherein the dermal filler comprises a hyaluronic acid crosslinked with 1,4-butanedioldiglycidyl ether (BDDE). 20. A method of treating chin retrusion in a subject in need thereof, the method comprising:
injecting a first volume of a composition comprising a dermal filler into a pogonion; injecting a second volume of the dermal filler into a mentum; and injecting a third volume of the dermal filler into a left pre-j owl sulcus and a right pre-jowl sulcus, wherein the chin retrusion of the subject is decreased after injection of the dermal filler into the pogonion, mentum, left pre-jowl sulcus, and right pre-jowl sulcus by at least about 2 mm. 21. The method of claim 20, wherein the decrease in chin retrusion of the subject is maintained for at least about 3 months. 22. The method of claim 20, wherein the decrease in chin retrusion of the subject is maintained for at least about 12 months. 23. The method of claim 20, wherein the decrease in chin retrusion of the subject is maintained for at least about 18 months. 24. The method of claim 20, wherein the dermal filler comprises a hyaluronic acid. 25. The method of claim 20, wherein the dermal filler comprises a crosslinked hyaluronic acid. 26. The method of claim 20, wherein the dermal filler comprises a hyaluronic acid crosslinked with 1,4-butanedioldiglycidyl ether (BDDE). 27. A method of increasing a glabella-subnasale-pogonion (G-Sn-Pog) facial angle in a subject in need thereof, the method comprising:
injecting a first volume of a dermal filler into a pogonion; injecting a second volume of the dermal filler into a mentum; and injecting a third volume of the dermal filler into a left pre-j owl sulcus and a right pre-jowl sulcus, wherein the G-Sn-Pog facial angle of the subject is increased after injection of the dermal filler into the pogonion, mentum, left pre-jowl sulcus, and right pre-jowl sulcus by at least about 1°, wherein the increase in the G-Sn-Pog facial angle of the subject is maintained for at least about 18 months. | 1,600 |
1,401 | 16,059,522 | 1,613 | A medical device, comprising: an array of microneedles, and a coating disposed on the microneedles, wherein the coating comprises: a local anesthetic selected from the group consisting of lidocaine, prilocaine, and a combination thereof; and a local anesthetic dose-extending component selected from the group consisting of tetracaine, ropivacaine, bupivacaine, procaine and a combination thereof; wherein the local anesthetic is present in an amount of at least 1 wt-% based upon total weight of solids in the coating, and wherein the local anesthetic and dose-extending component are in a non-eutectic weight ratio; a medical device, comprising an array of dissolvable microneedles, the microneedles comprising: a dissolvable matrix material; at least 1 wt-% of a local anesthetic selected from the group consisting of lidocaine, prilocaine, and a combination thereof; and a local anesthetic dose-extending component selected from the group consisting of tetracaine, ropivacaine, bupivacaine, procaine and a combination thereof; wherein the local anesthetic and dose-extending component are in a non-eutectic weight ratio, and wherein wt-% is based upon total weight of solids in all portions of the dissolvable microneedles which contain the local anesthetic; a method of extending a topically delivered local anesthetic dose in mammalian tissue using the devices; and methods of making the devices are provided. | 1-15. (canceled) 16. A medical device, comprising:
an array of microneedles, and a coating disposed on the microneedles, wherein the coating comprises:
a local anesthetic selected from the group consisting of lidocaine, prilocaine, and a combination thereof, and
a local anesthetic dose-extending component selected from the group consisting of tetracaine, ropivacaine, bupivacaine, procaine and a combination thereof,
wherein the local anesthetic and the local anesthetic dose-extending component are in a non-eutectic weight ratio; and
wherein the dose-extending component/local anesthetic weight ratio is 0.1 to 0.9; wherein the coating further comprising at least one excipient; and
wherein upon topically delivering the local anesthetic and the local anesthetic dose-extending component to mammalian tissue, a concentration of the local anesthetic in the mammalian tissue 30 minutes after delivery is about 31% to about 54% than a concentration of 17. The device of claim 16, wherein the coating comprises 10 to 75 wt-% of the at least one excipient, based upon total weight of solids in the coating. 18. The device of claim 16, wherein the excipient is selected from the group consisting of sucrose, dextrins, dextrans, hyroxyethyl cellulose (HEC), polyvinyl pyrrolidone (PVP), polyethylene glycols, amino acids, peptides, polysorbate, human serum albumin, saccharin sodium dehydrate, and a combination thereof. 19. The device of claim 16, wherein the at least one excipient is a saccharide. 20. The device of claim 18, wherein the saccharide is selected from the group consisting of dextran, sucrose, trehalose, and a combination thereof. 21. The device of claim 16, wherein the local anesthetic is present in an amount of 20 to 90 wt %, based upon total weight of solids in the coating. 22. The device of claim 16, wherein the dose-extending component is present in an amount of 2 to 48 wt %, based upon total weight of solids in the coating. 23. The device of claim 16, wherein the coating is present on the microneedles in an average amount of 0.01 to 2 micrograms per microneedle. 24. The device of claim 16, wherein the microneedles have a height of 200 to 1000 micrometers. 25. The device of claim 23, wherein at least 50% of the microneedles have the coating present on the microneedles near the tip and extending not more than 50 percent of the distance toward the base. 26. A medical device, comprising an array of dissolvable microneedles, the microneedles comprising:
a dissolvable matrix material; a local anesthetic selected from the group consisting of lidocaine, prilocaine, and a combination thereof, and a local anesthetic dose-extending component selected from the group consisting of tetracaine, ropivacaine, bupivacaine, procaine and a combination thereof, wherein the local anesthetic and the local anesthetic dose-extending component are in a non-eutectic weight ratio, and wherein the dose-extending component/local anesthetic weight ratio is 0.1 to 0.9; and wherein upon topically delivering the local anesthetic and the local anesthetic dose-extending component to mammalian tissue, a concentration of the local anesthetic in the mammalian tissue 30 minutes after delivery is about 31% to about 54% than a concentration of the local anesthetic in the mammalian tissue immediately after delivery. | A medical device, comprising: an array of microneedles, and a coating disposed on the microneedles, wherein the coating comprises: a local anesthetic selected from the group consisting of lidocaine, prilocaine, and a combination thereof; and a local anesthetic dose-extending component selected from the group consisting of tetracaine, ropivacaine, bupivacaine, procaine and a combination thereof; wherein the local anesthetic is present in an amount of at least 1 wt-% based upon total weight of solids in the coating, and wherein the local anesthetic and dose-extending component are in a non-eutectic weight ratio; a medical device, comprising an array of dissolvable microneedles, the microneedles comprising: a dissolvable matrix material; at least 1 wt-% of a local anesthetic selected from the group consisting of lidocaine, prilocaine, and a combination thereof; and a local anesthetic dose-extending component selected from the group consisting of tetracaine, ropivacaine, bupivacaine, procaine and a combination thereof; wherein the local anesthetic and dose-extending component are in a non-eutectic weight ratio, and wherein wt-% is based upon total weight of solids in all portions of the dissolvable microneedles which contain the local anesthetic; a method of extending a topically delivered local anesthetic dose in mammalian tissue using the devices; and methods of making the devices are provided.1-15. (canceled) 16. A medical device, comprising:
an array of microneedles, and a coating disposed on the microneedles, wherein the coating comprises:
a local anesthetic selected from the group consisting of lidocaine, prilocaine, and a combination thereof, and
a local anesthetic dose-extending component selected from the group consisting of tetracaine, ropivacaine, bupivacaine, procaine and a combination thereof,
wherein the local anesthetic and the local anesthetic dose-extending component are in a non-eutectic weight ratio; and
wherein the dose-extending component/local anesthetic weight ratio is 0.1 to 0.9; wherein the coating further comprising at least one excipient; and
wherein upon topically delivering the local anesthetic and the local anesthetic dose-extending component to mammalian tissue, a concentration of the local anesthetic in the mammalian tissue 30 minutes after delivery is about 31% to about 54% than a concentration of 17. The device of claim 16, wherein the coating comprises 10 to 75 wt-% of the at least one excipient, based upon total weight of solids in the coating. 18. The device of claim 16, wherein the excipient is selected from the group consisting of sucrose, dextrins, dextrans, hyroxyethyl cellulose (HEC), polyvinyl pyrrolidone (PVP), polyethylene glycols, amino acids, peptides, polysorbate, human serum albumin, saccharin sodium dehydrate, and a combination thereof. 19. The device of claim 16, wherein the at least one excipient is a saccharide. 20. The device of claim 18, wherein the saccharide is selected from the group consisting of dextran, sucrose, trehalose, and a combination thereof. 21. The device of claim 16, wherein the local anesthetic is present in an amount of 20 to 90 wt %, based upon total weight of solids in the coating. 22. The device of claim 16, wherein the dose-extending component is present in an amount of 2 to 48 wt %, based upon total weight of solids in the coating. 23. The device of claim 16, wherein the coating is present on the microneedles in an average amount of 0.01 to 2 micrograms per microneedle. 24. The device of claim 16, wherein the microneedles have a height of 200 to 1000 micrometers. 25. The device of claim 23, wherein at least 50% of the microneedles have the coating present on the microneedles near the tip and extending not more than 50 percent of the distance toward the base. 26. A medical device, comprising an array of dissolvable microneedles, the microneedles comprising:
a dissolvable matrix material; a local anesthetic selected from the group consisting of lidocaine, prilocaine, and a combination thereof, and a local anesthetic dose-extending component selected from the group consisting of tetracaine, ropivacaine, bupivacaine, procaine and a combination thereof, wherein the local anesthetic and the local anesthetic dose-extending component are in a non-eutectic weight ratio, and wherein the dose-extending component/local anesthetic weight ratio is 0.1 to 0.9; and wherein upon topically delivering the local anesthetic and the local anesthetic dose-extending component to mammalian tissue, a concentration of the local anesthetic in the mammalian tissue 30 minutes after delivery is about 31% to about 54% than a concentration of the local anesthetic in the mammalian tissue immediately after delivery. | 1,600 |
1,402 | 14,513,735 | 1,615 | The present invention relates to water treatment, In one example, there is provided a method of treating an aqueous system comprising dissolved solids to inhibit growth of one or more micro-organisms therein and/or to reduce the number of live micro-organisms therein. The method includes adding treatment agents to said aqueous system wherein said treatment agents include:
(a) a phosphonium compound; and (b) a stabilised halogen containing composition. | 1. A method of treating an aqueous system comprising dissolved solids to inhibit growth of one or more micro-organisms therein and/or to reduce the number of live micro-organisms therein, wherein the method comprises adding treatment agents to said aqueous system and wherein said treatment agents comprise:
(a) a phosphonium compound; and (b) a stabilised halogen containing composition. 2. A method according to claim 1, wherein the stabilised halogen containing composition (b) comprises a chlorine containing composition. 3. A method according to claim 1, wherein the stabilised halogen containing composition (b) comprises chlorosulfamate. 4. A method according to claim 1, wherein the phosphonium compound (a) comprises tri n-butyl n-tetradecyl phosphonium chloride (TTPC). 5. A method according to claim 1, wherein the stabilised halogen containing composition (b) comprises a stabiliser (c) and a halogen containing compound (d) and/or wherein the stabilised halogen containing composition (b) comprises a stabilised halogen containing compound (e). 6. A method according to claim 5, wherein the halogen containing compound (d) comprises sodium hypochlorite and wherein the stabiliser comprises sulfamic acid and wherein the halogen containing compound (e) comprises chlorosulfamate. 7. A method according to claim 1, wherein the method comprises treating said aqueous system to inhibit growth of facultative anaerobic bacteria and/or to reduce the number of live facultative anaerobic bacteria therein. 8. A method according to claim 1, wherein the method comprises treating an aqueous system having a total dissolved solids (TDS) of 30,000 mg l−1 or greater. 9. A method according to claim 1, wherein the method comprises adding a phosphonium compound to said aqueous system in an amount of at least 0.1 ppm. 10. A method according to claim 1, wherein the method comprises adding the composition (b) to provide a treated aqueous system comprising halogen containing compound (d) and/or stabilised halogen containing compound (e) in an amount of at least 0.1 ppm. 11. A method according to claim 1, wherein the method comprises adding stabilised halogen containing composition (b) to said aqueous system in an amount of at least 10 ppm. 12. A method according to claim 1, wherein the method comprises adding a phosphonium compound (a) and a stabilised halogen containing composition (b) to an aqueous system in a weight ratio, expressed as active compound and composition, respectively, of phosphonium compound:stabilised halogen containing composition of from 1.0:0.5 to 1.0:100.0 13. A method of treating an aqueous system comprising dissolved solids to inhibit growth of one or more micro-organisms therein and/or to reduce the number of live micro-organisms therein, wherein the method comprises adding treatment agents to said aqueous system and wherein said treatment agents comprise:
(i) tri n-butyl n-tetradecyl phosphonium chloride (TTPC); and (ii) chlorosulfamate. 14. A method of treating an aqueous system comprising dissolved solids to inhibit growth of one or more micro-organisms therein and/or to reduce the number of live micro-organisms therein, wherein the method comprises adding treatment agents to said aqueous system and wherein said treatment agents comprise:
(i) tri n-butyl n-tetradecyl phosphonium chloride (TTPC); and (ii) stabilised sodium hypochlorite 15. A method according to claim 14, wherein the method comprises treating an aqueous system having a total dissolved solids (TDS) of 1000 mg l−1 or greater and wherein the method comprises adding TTPC to said aqueous system in an amount of at least 0.1 ppm and adding chlorosulfamate to said aqueous system in an amount of at least 0.1 ppm and wherein the method comprises treating an aqueous system to inhibit growth of facultative anaerobic bacteria and/or to reduce the number of live facultative anaerobic bacteria therein. 16. An aqueous system comprising dissolved solids and incorporating a combination of:
(a) a phosphonium compound; and (b) a stabilised halogen containing composition. 17. A method of inhibiting or preventing the growth of one or more micro-organisms in an aqueous media, wherein the method comprises adding treatment agents to an aqueous media comprising dissolved solids and wherein said treatment agents comprise:
(a) a phosphonium compound; and (b) a stabilised halogen containing composition. 18. An aqueous media comprising dissolved solids and incorporating a combination of:
(a) a phosphonium compound; and (b) a stabilised halogen containing composition. 19. A biocidal composition comprising a combination of:
(a) a phosphonium compound; and (b) a stabilised halogen containing composition. 20. A method of treating an aqueous system to inhibit growth of one or more micro-organisms therein and/or to reduce the number of live micro-organisms therein, wherein the method comprises adding treatment agents to said aqueous system and wherein said treatment agents comprise:
(a) a phosphonium compound; and (b) a stabilised halogen containing composition. | The present invention relates to water treatment, In one example, there is provided a method of treating an aqueous system comprising dissolved solids to inhibit growth of one or more micro-organisms therein and/or to reduce the number of live micro-organisms therein. The method includes adding treatment agents to said aqueous system wherein said treatment agents include:
(a) a phosphonium compound; and (b) a stabilised halogen containing composition.1. A method of treating an aqueous system comprising dissolved solids to inhibit growth of one or more micro-organisms therein and/or to reduce the number of live micro-organisms therein, wherein the method comprises adding treatment agents to said aqueous system and wherein said treatment agents comprise:
(a) a phosphonium compound; and (b) a stabilised halogen containing composition. 2. A method according to claim 1, wherein the stabilised halogen containing composition (b) comprises a chlorine containing composition. 3. A method according to claim 1, wherein the stabilised halogen containing composition (b) comprises chlorosulfamate. 4. A method according to claim 1, wherein the phosphonium compound (a) comprises tri n-butyl n-tetradecyl phosphonium chloride (TTPC). 5. A method according to claim 1, wherein the stabilised halogen containing composition (b) comprises a stabiliser (c) and a halogen containing compound (d) and/or wherein the stabilised halogen containing composition (b) comprises a stabilised halogen containing compound (e). 6. A method according to claim 5, wherein the halogen containing compound (d) comprises sodium hypochlorite and wherein the stabiliser comprises sulfamic acid and wherein the halogen containing compound (e) comprises chlorosulfamate. 7. A method according to claim 1, wherein the method comprises treating said aqueous system to inhibit growth of facultative anaerobic bacteria and/or to reduce the number of live facultative anaerobic bacteria therein. 8. A method according to claim 1, wherein the method comprises treating an aqueous system having a total dissolved solids (TDS) of 30,000 mg l−1 or greater. 9. A method according to claim 1, wherein the method comprises adding a phosphonium compound to said aqueous system in an amount of at least 0.1 ppm. 10. A method according to claim 1, wherein the method comprises adding the composition (b) to provide a treated aqueous system comprising halogen containing compound (d) and/or stabilised halogen containing compound (e) in an amount of at least 0.1 ppm. 11. A method according to claim 1, wherein the method comprises adding stabilised halogen containing composition (b) to said aqueous system in an amount of at least 10 ppm. 12. A method according to claim 1, wherein the method comprises adding a phosphonium compound (a) and a stabilised halogen containing composition (b) to an aqueous system in a weight ratio, expressed as active compound and composition, respectively, of phosphonium compound:stabilised halogen containing composition of from 1.0:0.5 to 1.0:100.0 13. A method of treating an aqueous system comprising dissolved solids to inhibit growth of one or more micro-organisms therein and/or to reduce the number of live micro-organisms therein, wherein the method comprises adding treatment agents to said aqueous system and wherein said treatment agents comprise:
(i) tri n-butyl n-tetradecyl phosphonium chloride (TTPC); and (ii) chlorosulfamate. 14. A method of treating an aqueous system comprising dissolved solids to inhibit growth of one or more micro-organisms therein and/or to reduce the number of live micro-organisms therein, wherein the method comprises adding treatment agents to said aqueous system and wherein said treatment agents comprise:
(i) tri n-butyl n-tetradecyl phosphonium chloride (TTPC); and (ii) stabilised sodium hypochlorite 15. A method according to claim 14, wherein the method comprises treating an aqueous system having a total dissolved solids (TDS) of 1000 mg l−1 or greater and wherein the method comprises adding TTPC to said aqueous system in an amount of at least 0.1 ppm and adding chlorosulfamate to said aqueous system in an amount of at least 0.1 ppm and wherein the method comprises treating an aqueous system to inhibit growth of facultative anaerobic bacteria and/or to reduce the number of live facultative anaerobic bacteria therein. 16. An aqueous system comprising dissolved solids and incorporating a combination of:
(a) a phosphonium compound; and (b) a stabilised halogen containing composition. 17. A method of inhibiting or preventing the growth of one or more micro-organisms in an aqueous media, wherein the method comprises adding treatment agents to an aqueous media comprising dissolved solids and wherein said treatment agents comprise:
(a) a phosphonium compound; and (b) a stabilised halogen containing composition. 18. An aqueous media comprising dissolved solids and incorporating a combination of:
(a) a phosphonium compound; and (b) a stabilised halogen containing composition. 19. A biocidal composition comprising a combination of:
(a) a phosphonium compound; and (b) a stabilised halogen containing composition. 20. A method of treating an aqueous system to inhibit growth of one or more micro-organisms therein and/or to reduce the number of live micro-organisms therein, wherein the method comprises adding treatment agents to said aqueous system and wherein said treatment agents comprise:
(a) a phosphonium compound; and (b) a stabilised halogen containing composition. | 1,600 |
1,403 | 14,625,086 | 1,646 | The invention provides compositions and methods for detecting thyroid hormone blocking immunoglobulin (TBI). The invention's methods are sensitive and specific for TBI, and may be used for the dual detection of both TBI and TSI. The invention's compositions and methods are useful for the diagnosis of diseases that are associated with the presence of TBI and/or TSI, for monitoring the progress of disease and/or treatment regimens, therapeutics, vaccines, etc., and for assisting clinicians in making treatment decisions. | 1-20. (canceled) 21. A method for detecting thyroid hormone blocking immunoglobulin (TBI) in a biologic sample, comprising
i) combining:
a) transgenic cells stably transfected with
a first nucleic acid sequence which encodes a reporter wherein the first nucleic acid is operably linked to a cAMP-inducible promoter, and a second nucleic acid sequence which encodes a chimeric thyroid stimulating hormone receptor (TSHR), wherein the second nucleic acid sequence is operably linked to a constitutive promoter; and
b) a thyroid stimulating polypeptide that stimulates the chimeric TSHR upon binding to the chimeric TSHR, to generate a reagent mix;
ii) combining the reagent mix with
a) a control sample to generate a first sample; or
b) a test sample comprising the biological sample to generate a second sample; and
iii) measuring the level of expression of said reporter in said first sample and in said second sample, wherein a reduced level of expression of said reporter in said second sample compared to said first sample indicates the presence of TBI in said biologic sample. 22. The method of claim 21, further comprising determining the level of TBI in the biologic sample comprising measuring the level of expression of said reporter in one or more standard samples which each contain a known concentration of thyroid stimulating hormone (TSH) and comparing the level of expression of said reporter in said second sample with the level of expression of said reporter in said one or more standard samples. 23. The method of claim 21, wherein said first nucleic acid sequence encodes a protein which can generate a fluorescent or a bioluminescent signal. 24. The method of claim 21, wherein the first nucleic acid sequence encodes the amino acid sequence of SEQ ID NO:3. 25. The method of claim 21, wherein the transgenic cells are Chinese hamster ovary (CHO) cells or human Rhabdomyosarcoma (RD) cells. 26. The method of claim 21, wherein the thyroid stimulating polypeptide is selected from the group consisting of TSH, a thyroid stimulating monoclonal antibody, an a thyroid stimulating polyclonal antibody. 27. The method of claim 21, wherein the constitutive promoter is an SV40 promoter sequence. 28. The method of claim 21, wherein the second nucleic acid comprises SEQ ID NO:2. 29. The method of claim 21, wherein the thyroid stimulating polypeptide is TSH and wherein said TSH is present in at least one of said first sample at a concentration of about 0.2 mIU/ml to 100 mIU/ml. 30. The method of claim 22, wherein the IC50 for TBI is about 5-fold to 15-fold smaller than the IC50 for TBI when the method is performed with said transgenic cells stably transfected with wild type TSHR. 31. The method of claim 22, wherein the IC50 for TBI is about 10-fold to 30-fold smaller when the thyroid stimulating polypeptide is TSH than when the thyroid stimulating polypeptide is an anti-TBI monoclonal antibody. 32. A kit comprising
a) transgenic cells stably transfected with a first nucleic acid sequence which encodes a reporter wherein the first nucleic acid is operably linked to a cAMP-inducible promoter, and a second nucleic acid sequence which encodes a chimeric thyroid stimulating hormone receptor (TSHR), wherein the second nucleic acid sequence is operably linked to a constitutive promoter, wherein said cells express a chimeric TSHR on the cell membrane; b) a thyroid stimulating polypeptide that stimulates the chimeric TSHR upon binding to the chimeric TSHR on the cell membrane; c) instructions for use. 33. The kit of claim 32, wherein said kit further comprises a positive control sample that contains thyroid hormone blocking immunoglobulin (TBI). 34. The kit of claim 32, wherein said thyroid stimulating polypeptide is thyroid stimulating hormone (TSH). 35. The kit of claim 32, wherein said instructions are for detecting thyroid hormone stimulating immunoglobulin (TSI) in a biologic sample. 36. The kit of claim 32, wherein said kit further comprises a thyroid hormone stimulating immunoglobulin (TSI). | The invention provides compositions and methods for detecting thyroid hormone blocking immunoglobulin (TBI). The invention's methods are sensitive and specific for TBI, and may be used for the dual detection of both TBI and TSI. The invention's compositions and methods are useful for the diagnosis of diseases that are associated with the presence of TBI and/or TSI, for monitoring the progress of disease and/or treatment regimens, therapeutics, vaccines, etc., and for assisting clinicians in making treatment decisions.1-20. (canceled) 21. A method for detecting thyroid hormone blocking immunoglobulin (TBI) in a biologic sample, comprising
i) combining:
a) transgenic cells stably transfected with
a first nucleic acid sequence which encodes a reporter wherein the first nucleic acid is operably linked to a cAMP-inducible promoter, and a second nucleic acid sequence which encodes a chimeric thyroid stimulating hormone receptor (TSHR), wherein the second nucleic acid sequence is operably linked to a constitutive promoter; and
b) a thyroid stimulating polypeptide that stimulates the chimeric TSHR upon binding to the chimeric TSHR, to generate a reagent mix;
ii) combining the reagent mix with
a) a control sample to generate a first sample; or
b) a test sample comprising the biological sample to generate a second sample; and
iii) measuring the level of expression of said reporter in said first sample and in said second sample, wherein a reduced level of expression of said reporter in said second sample compared to said first sample indicates the presence of TBI in said biologic sample. 22. The method of claim 21, further comprising determining the level of TBI in the biologic sample comprising measuring the level of expression of said reporter in one or more standard samples which each contain a known concentration of thyroid stimulating hormone (TSH) and comparing the level of expression of said reporter in said second sample with the level of expression of said reporter in said one or more standard samples. 23. The method of claim 21, wherein said first nucleic acid sequence encodes a protein which can generate a fluorescent or a bioluminescent signal. 24. The method of claim 21, wherein the first nucleic acid sequence encodes the amino acid sequence of SEQ ID NO:3. 25. The method of claim 21, wherein the transgenic cells are Chinese hamster ovary (CHO) cells or human Rhabdomyosarcoma (RD) cells. 26. The method of claim 21, wherein the thyroid stimulating polypeptide is selected from the group consisting of TSH, a thyroid stimulating monoclonal antibody, an a thyroid stimulating polyclonal antibody. 27. The method of claim 21, wherein the constitutive promoter is an SV40 promoter sequence. 28. The method of claim 21, wherein the second nucleic acid comprises SEQ ID NO:2. 29. The method of claim 21, wherein the thyroid stimulating polypeptide is TSH and wherein said TSH is present in at least one of said first sample at a concentration of about 0.2 mIU/ml to 100 mIU/ml. 30. The method of claim 22, wherein the IC50 for TBI is about 5-fold to 15-fold smaller than the IC50 for TBI when the method is performed with said transgenic cells stably transfected with wild type TSHR. 31. The method of claim 22, wherein the IC50 for TBI is about 10-fold to 30-fold smaller when the thyroid stimulating polypeptide is TSH than when the thyroid stimulating polypeptide is an anti-TBI monoclonal antibody. 32. A kit comprising
a) transgenic cells stably transfected with a first nucleic acid sequence which encodes a reporter wherein the first nucleic acid is operably linked to a cAMP-inducible promoter, and a second nucleic acid sequence which encodes a chimeric thyroid stimulating hormone receptor (TSHR), wherein the second nucleic acid sequence is operably linked to a constitutive promoter, wherein said cells express a chimeric TSHR on the cell membrane; b) a thyroid stimulating polypeptide that stimulates the chimeric TSHR upon binding to the chimeric TSHR on the cell membrane; c) instructions for use. 33. The kit of claim 32, wherein said kit further comprises a positive control sample that contains thyroid hormone blocking immunoglobulin (TBI). 34. The kit of claim 32, wherein said thyroid stimulating polypeptide is thyroid stimulating hormone (TSH). 35. The kit of claim 32, wherein said instructions are for detecting thyroid hormone stimulating immunoglobulin (TSI) in a biologic sample. 36. The kit of claim 32, wherein said kit further comprises a thyroid hormone stimulating immunoglobulin (TSI). | 1,600 |
1,404 | 14,914,792 | 1,654 | Methods of treating bacterial infections in a subject using oritavancin, including bacteremia, osteomyelitis and endocarditis, are disclosed. | 1. A method of treating bacteremia in a subject, comprising administering a therapeutically-effective amount of oritavancin or a salt thereof to a subject having bacteremia, thereby treating bacteremia in a subject. 2. The method of claim 1, wherein (i) the bacteremia was resistant to previous antibiotic treatment, (ii) the subject was intolerant to other antibiotics, and/or (iii) the subject also has osteomyelitis or endocarditis, or both. 3. The method of claim 1, wherein the bacteremia is caused by a Gram-positive organism. 4. The method of claim 3, wherein the Gram-positive organism is a multi-drug resistant (MDR) strain of methicillin-resistant Staphylococcus aureus (MRSA). 5. The method of claim 1, wherein the therapeutically-effective amount of oritavancin or a salt thereof is at least about 1200 mg. 6. The method of claim 1, wherein treatment is achieved by administering a single, 1200 mg dose of oritavancin or a salt thereof to the subject. 7. A method of treating bacteremia and osteomyelitis in a subject, comprising administering a therapeutically-effective amount of oritavancin or a salt thereof to a subject having bacteremia and osteomyelitis, thereby treating bacteremia and osteomyelitis in a subject. 8. The method of claim 7, wherein (i) the bacteremia was resistant to previous antibiotic treatment, (ii) the subject was intolerant to other antibiotics, and/or (iii) the subject also has endocarditis, or both. 9. The method of claim 7, wherein the bacteremia is caused by a Gram-positive organism. 10. The method of claim 9, wherein the Gram-positive organism is a multi-drug resistant (MDR) strain of methicillin-resistant Staphylococcus aureus (MRSA). 11. The method of claim 7, wherein the therapeutically-effective amount of oritavancin or a salt thereof is at least about 1200 mg. 12. The method of claim 7, wherein treatment is achieved by administering a single, 1200 mg dose of oritavancin or a salt thereof to the subject. 13. A method of treating bacteremia and endocarditis in a subject, comprising administering a therapeutically-effective amount of oritavancin or a salt thereof to a subject having bacteremia and endocarditis, thereby treating bacteremia and endocarditis in a subject. 14. The method of claim 13, wherein (i) the bacteremia was resistant to previous antibiotic treatment, (ii) the subject was intolerant to other antibiotics, and/or (iii) the subject also has osteomyelitis. 15. The method of claim 13, wherein the bacteremia is caused by a Gram-positive organism. 16. The method of claim 15, wherein the Gram-positive organism is a multi-drug resistant (MDR) strain of methicillin-resistant Staphylococcus aureus (MRSA). 17. The method of claim 13, wherein the therapeutically-effective amount of oritavancin or a salt thereof is at least about 1200 mg. 18. The method of claim 13, wherein treatment is achieved by administering a single, 1200 mg dose of oritavancin or a salt thereof to the subject. | Methods of treating bacterial infections in a subject using oritavancin, including bacteremia, osteomyelitis and endocarditis, are disclosed.1. A method of treating bacteremia in a subject, comprising administering a therapeutically-effective amount of oritavancin or a salt thereof to a subject having bacteremia, thereby treating bacteremia in a subject. 2. The method of claim 1, wherein (i) the bacteremia was resistant to previous antibiotic treatment, (ii) the subject was intolerant to other antibiotics, and/or (iii) the subject also has osteomyelitis or endocarditis, or both. 3. The method of claim 1, wherein the bacteremia is caused by a Gram-positive organism. 4. The method of claim 3, wherein the Gram-positive organism is a multi-drug resistant (MDR) strain of methicillin-resistant Staphylococcus aureus (MRSA). 5. The method of claim 1, wherein the therapeutically-effective amount of oritavancin or a salt thereof is at least about 1200 mg. 6. The method of claim 1, wherein treatment is achieved by administering a single, 1200 mg dose of oritavancin or a salt thereof to the subject. 7. A method of treating bacteremia and osteomyelitis in a subject, comprising administering a therapeutically-effective amount of oritavancin or a salt thereof to a subject having bacteremia and osteomyelitis, thereby treating bacteremia and osteomyelitis in a subject. 8. The method of claim 7, wherein (i) the bacteremia was resistant to previous antibiotic treatment, (ii) the subject was intolerant to other antibiotics, and/or (iii) the subject also has endocarditis, or both. 9. The method of claim 7, wherein the bacteremia is caused by a Gram-positive organism. 10. The method of claim 9, wherein the Gram-positive organism is a multi-drug resistant (MDR) strain of methicillin-resistant Staphylococcus aureus (MRSA). 11. The method of claim 7, wherein the therapeutically-effective amount of oritavancin or a salt thereof is at least about 1200 mg. 12. The method of claim 7, wherein treatment is achieved by administering a single, 1200 mg dose of oritavancin or a salt thereof to the subject. 13. A method of treating bacteremia and endocarditis in a subject, comprising administering a therapeutically-effective amount of oritavancin or a salt thereof to a subject having bacteremia and endocarditis, thereby treating bacteremia and endocarditis in a subject. 14. The method of claim 13, wherein (i) the bacteremia was resistant to previous antibiotic treatment, (ii) the subject was intolerant to other antibiotics, and/or (iii) the subject also has osteomyelitis. 15. The method of claim 13, wherein the bacteremia is caused by a Gram-positive organism. 16. The method of claim 15, wherein the Gram-positive organism is a multi-drug resistant (MDR) strain of methicillin-resistant Staphylococcus aureus (MRSA). 17. The method of claim 13, wherein the therapeutically-effective amount of oritavancin or a salt thereof is at least about 1200 mg. 18. The method of claim 13, wherein treatment is achieved by administering a single, 1200 mg dose of oritavancin or a salt thereof to the subject. | 1,600 |
1,405 | 16,780,365 | 1,612 | Provided are methods for labeling a pharmaceutical product to indicate the origin, and/or intended recipient, and/or a predetermined characteristic (e.g. geographic location) of an intended recipient of the pharmaceutical product. The methods include incorporating certain pharmaceutically inactive marker substances into the pharmaceutical product at manufacture. | 1. A method of labeling a pharmaceutical product, the method comprising incorporating into the pharmaceutical product during manufacture a unique marker profile comprising one or more pharmaceutically inactive marker substances, wherein the one or more marker substances comprise one or more polyethylene glycols. 2. The method of claim 1, wherein the one or more marker substances comprise two or more polyethylene glycols having different molecular weights. 3. The method of claim 1, further comprising identifying an origin of the pharmaceutical product; and encoding the origin of the pharmaceutical product by the unique marker profile comprising the one or more marker substances, wherein the one or more marker substances each have an identity, and the identities of the one or more marker substances indicate the origin of the pharmaceutical product. 4. The method of claim 3, wherein the origin of the pharmaceutical product is a location and/or a facility where the pharmaceutical product is manufactured. 5. The method of claim 3, further comprising authenticating the origin of the pharmaceutical product, wherein the authenticating comprises testing the pharmaceutical product and identifying existence of the one or more marker substances in the tested pharmaceutical product to confirm the origin of the pharmaceutical product. 6. The method of claim 1, further comprising identifying an origin of the pharmaceutical product; and encoding the origin of the pharmaceutical product by the unique marker profile comprising two or more marker substances, wherein the two or more marker substances each have an identity and an absolute amount, and the identities and the absolute or relative amounts of the two or more marker substances indicate the origin of the pharmaceutical product. 7. The method of claim 6, further comprising authenticating the origin of the pharmaceutical product, wherein the authenticating comprises testing the pharmaceutical product and identifying existence and the absolute or relative amounts of the two or more marker substances in the tested pharmaceutical product to confirm the origin of the pharmaceutical product. 8. The method of claim 1, further comprising identifying a source of the pharmaceutical product; and encoding the source of the pharmaceutical product by the unique marker profile comprising the one or more marker substances, wherein the one or more marker substances each have an identity, and the identities of the one or more marker substances indicate the source of the pharmaceutical product. 9. The method of claim 8, wherein the source of the pharmaceutical product is a supplier, a manufacturer or a batch of the pharmaceutical product, a third party who is distributing the pharmaceutical product, or combinations thereof. 10. The method of claim 1, further comprising identifying a source of the pharmaceutical product; and encoding the source of the pharmaceutical product by the unique marker profile comprising two or more marker substances, wherein the two or more marker substances each have an identity and an absolute amount, and the identities and the absolute or relative amounts of the two or more marker substances indicate the source of the pharmaceutical product. 11. The method of claim 10, further comprising authenticating the source of the pharmaceutical product, wherein the authenticating comprises testing the pharmaceutical product and identifying existence and the absolute or relative amounts of the two or more marker substances in the tested pharmaceutical product to confirm the source of the pharmaceutical product. 12. The method of claim 1, further comprising identifying a geographic region of an intended recipient of the pharmaceutical product; and encoding the geographic region of the intended recipient by the unique marker profile comprising the one or more marker substances, wherein the one or more marker substances each have an identity, and the identities of the one or more marker substances indicate the geographic region of the intended recipient, and the geographic region of the intended recipient is where the intended recipient is located. 13. The method of claim 1, further comprising identifying a geographic region of an intended recipient of the pharmaceutical product; and encoding the geographic region of the intended recipient by the unique marker profile comprising two or more marker substances, wherein the two or more marker substances each have an identity and an absolute amount, and the identities and the absolute or relative amounts of the two or more marker substances indicate the geographic region of the intended recipient, and the geographic region of the intended recipient is where the intended recipient is located. 14. The method of claim 13, further comprising authenticating the geographic region of the intended recipient of the pharmaceutical product, wherein the authenticating comprises testing the pharmaceutical product and identifying existence and the absolute or relative amounts of the two or more marker substances in the tested pharmaceutical product to confirm the geographic region of the intended recipient of the pharmaceutical product. 15. The method of claim 1, further comprising identifying a batch of the pharmaceutical product that is manufactured for an intended recipient; and encoding the batch of the pharmaceutical product by the unique marker profile comprising the one or more marker substances, wherein the one or more marker substances each have an identity, and the identities of the one or more marker substances indicate the batch of the pharmaceutical product. 16. The method of claim 1, further comprising identifying a batch of the pharmaceutical product that is manufactured for an intended recipient; and encoding the batch of the pharmaceutical product by the unique marker profile comprising two or more marker substances, wherein the two or more marker substances each have an identity and an absolute amount, and the identities and the absolute or relative amounts of the two or more marker substances indicate the batch of the pharmaceutical product. 17. The method of claim 16, further comprising authenticating the batch of the pharmaceutical product, wherein the authenticating comprises testing the pharmaceutical product and identifying existence and the absolute or relative amounts of the two or more marker substances in the tested pharmaceutical product to confirm the batch of the pharmaceutical product. 18. The method of claim 1, wherein the unique marker profile comprises at least one monodisperse polyethylene glycol. 19. The method of claim 1, wherein the unique marker profile comprises two or more monodisperse polyethylene glycols each having a different molecular weight. 20. The method of claim 1, wherein the pharmaceutical product further comprises at least one pharmaceutically active ingredient. | Provided are methods for labeling a pharmaceutical product to indicate the origin, and/or intended recipient, and/or a predetermined characteristic (e.g. geographic location) of an intended recipient of the pharmaceutical product. The methods include incorporating certain pharmaceutically inactive marker substances into the pharmaceutical product at manufacture.1. A method of labeling a pharmaceutical product, the method comprising incorporating into the pharmaceutical product during manufacture a unique marker profile comprising one or more pharmaceutically inactive marker substances, wherein the one or more marker substances comprise one or more polyethylene glycols. 2. The method of claim 1, wherein the one or more marker substances comprise two or more polyethylene glycols having different molecular weights. 3. The method of claim 1, further comprising identifying an origin of the pharmaceutical product; and encoding the origin of the pharmaceutical product by the unique marker profile comprising the one or more marker substances, wherein the one or more marker substances each have an identity, and the identities of the one or more marker substances indicate the origin of the pharmaceutical product. 4. The method of claim 3, wherein the origin of the pharmaceutical product is a location and/or a facility where the pharmaceutical product is manufactured. 5. The method of claim 3, further comprising authenticating the origin of the pharmaceutical product, wherein the authenticating comprises testing the pharmaceutical product and identifying existence of the one or more marker substances in the tested pharmaceutical product to confirm the origin of the pharmaceutical product. 6. The method of claim 1, further comprising identifying an origin of the pharmaceutical product; and encoding the origin of the pharmaceutical product by the unique marker profile comprising two or more marker substances, wherein the two or more marker substances each have an identity and an absolute amount, and the identities and the absolute or relative amounts of the two or more marker substances indicate the origin of the pharmaceutical product. 7. The method of claim 6, further comprising authenticating the origin of the pharmaceutical product, wherein the authenticating comprises testing the pharmaceutical product and identifying existence and the absolute or relative amounts of the two or more marker substances in the tested pharmaceutical product to confirm the origin of the pharmaceutical product. 8. The method of claim 1, further comprising identifying a source of the pharmaceutical product; and encoding the source of the pharmaceutical product by the unique marker profile comprising the one or more marker substances, wherein the one or more marker substances each have an identity, and the identities of the one or more marker substances indicate the source of the pharmaceutical product. 9. The method of claim 8, wherein the source of the pharmaceutical product is a supplier, a manufacturer or a batch of the pharmaceutical product, a third party who is distributing the pharmaceutical product, or combinations thereof. 10. The method of claim 1, further comprising identifying a source of the pharmaceutical product; and encoding the source of the pharmaceutical product by the unique marker profile comprising two or more marker substances, wherein the two or more marker substances each have an identity and an absolute amount, and the identities and the absolute or relative amounts of the two or more marker substances indicate the source of the pharmaceutical product. 11. The method of claim 10, further comprising authenticating the source of the pharmaceutical product, wherein the authenticating comprises testing the pharmaceutical product and identifying existence and the absolute or relative amounts of the two or more marker substances in the tested pharmaceutical product to confirm the source of the pharmaceutical product. 12. The method of claim 1, further comprising identifying a geographic region of an intended recipient of the pharmaceutical product; and encoding the geographic region of the intended recipient by the unique marker profile comprising the one or more marker substances, wherein the one or more marker substances each have an identity, and the identities of the one or more marker substances indicate the geographic region of the intended recipient, and the geographic region of the intended recipient is where the intended recipient is located. 13. The method of claim 1, further comprising identifying a geographic region of an intended recipient of the pharmaceutical product; and encoding the geographic region of the intended recipient by the unique marker profile comprising two or more marker substances, wherein the two or more marker substances each have an identity and an absolute amount, and the identities and the absolute or relative amounts of the two or more marker substances indicate the geographic region of the intended recipient, and the geographic region of the intended recipient is where the intended recipient is located. 14. The method of claim 13, further comprising authenticating the geographic region of the intended recipient of the pharmaceutical product, wherein the authenticating comprises testing the pharmaceutical product and identifying existence and the absolute or relative amounts of the two or more marker substances in the tested pharmaceutical product to confirm the geographic region of the intended recipient of the pharmaceutical product. 15. The method of claim 1, further comprising identifying a batch of the pharmaceutical product that is manufactured for an intended recipient; and encoding the batch of the pharmaceutical product by the unique marker profile comprising the one or more marker substances, wherein the one or more marker substances each have an identity, and the identities of the one or more marker substances indicate the batch of the pharmaceutical product. 16. The method of claim 1, further comprising identifying a batch of the pharmaceutical product that is manufactured for an intended recipient; and encoding the batch of the pharmaceutical product by the unique marker profile comprising two or more marker substances, wherein the two or more marker substances each have an identity and an absolute amount, and the identities and the absolute or relative amounts of the two or more marker substances indicate the batch of the pharmaceutical product. 17. The method of claim 16, further comprising authenticating the batch of the pharmaceutical product, wherein the authenticating comprises testing the pharmaceutical product and identifying existence and the absolute or relative amounts of the two or more marker substances in the tested pharmaceutical product to confirm the batch of the pharmaceutical product. 18. The method of claim 1, wherein the unique marker profile comprises at least one monodisperse polyethylene glycol. 19. The method of claim 1, wherein the unique marker profile comprises two or more monodisperse polyethylene glycols each having a different molecular weight. 20. The method of claim 1, wherein the pharmaceutical product further comprises at least one pharmaceutically active ingredient. | 1,600 |
1,406 | 14,130,995 | 1,627 | The method of the present application is directed towards a method for suppressing an allergic response in response to an allergic trigger. This method comprises the following steps; applying, topically, to an affected area an effective amount of a minocycline composition so that the minocycline composition contacts the affected area for an effective amount of time and removing the minocycline composition from the affected area. | 1. A method for suppressing an allergic response in response to an allergic trigger in an affected area, the method comprising:
applying, topically, to the affected area an effective amount of a minocycline composition so that the minocycline composition contacts the affected area for an effective amount of time, and removing the minocycline composition from the affected area. 2. The method of claim 1, wherein minocycline is present in the minocycline composition at a concentration from about 0.1% to about 10%. 3. The method of claim 1, wherein the effective amount of time is from about 1 minute to about 48 hours. 4. The method of claim 1, wherein the composition is selected from the group consisting of liquids, gels, creams, lotions, pastes, ointments, foams, sprays, mists, aerosols and combinations thereof. 5. The method of claim 1, wherein the composition is applied as one of the group selected from a coating on a dressing, a filler in a dressing, a coating on a substrate, a filler in a substrate, a coating in a patch and a filler in a patch. 6. The method of claim 1, wherein the affected area is selected from the group consisting of skin, eyes, exposed mucosa and combinations thereof. 7. The method of claim 6, wherein the mucosa is selected from the group consisting of oral, nasal, ano-genital, tympanic and combinations thereof. 8. The method of claim 1, wherein the subject is a human. 9. The method of claim 1, wherein the applying and removing steps are repeated. 10. The method of claim 1, wherein the allergic response of the affected area is selected from the group consisting of dermatitis, atopic dermatitis, urticaria, contact dermatitis, eczema, conjunctivitis, rhinoconjunctivitis and combinations thereof. 11. The method of claim 1, wherein the allergic trigger is selected from the group consisting of an environmental trigger, a dietary trigger, a pharmaceutical trigger, a contact trigger. 12. The method of claim 11, wherein the environmental trigger is selected from the group consisting of pollen, pet dander and mold. 13. The method of claim 11, wherein the dietary trigger is selected from the group consisting of shellfish, nuts and gluten containing products 14. The method of claim 11, wherein the pharmaceutical trigger is selected from the group consisting of penicillin and pharmaceuticals comprising sulfur. 15. The method of claim 11, wherein the contact trigger is selected from the group consisting of latex, poison ivy, poison oak, poison sumac, metal jewelry and combinations thereof. | The method of the present application is directed towards a method for suppressing an allergic response in response to an allergic trigger. This method comprises the following steps; applying, topically, to an affected area an effective amount of a minocycline composition so that the minocycline composition contacts the affected area for an effective amount of time and removing the minocycline composition from the affected area.1. A method for suppressing an allergic response in response to an allergic trigger in an affected area, the method comprising:
applying, topically, to the affected area an effective amount of a minocycline composition so that the minocycline composition contacts the affected area for an effective amount of time, and removing the minocycline composition from the affected area. 2. The method of claim 1, wherein minocycline is present in the minocycline composition at a concentration from about 0.1% to about 10%. 3. The method of claim 1, wherein the effective amount of time is from about 1 minute to about 48 hours. 4. The method of claim 1, wherein the composition is selected from the group consisting of liquids, gels, creams, lotions, pastes, ointments, foams, sprays, mists, aerosols and combinations thereof. 5. The method of claim 1, wherein the composition is applied as one of the group selected from a coating on a dressing, a filler in a dressing, a coating on a substrate, a filler in a substrate, a coating in a patch and a filler in a patch. 6. The method of claim 1, wherein the affected area is selected from the group consisting of skin, eyes, exposed mucosa and combinations thereof. 7. The method of claim 6, wherein the mucosa is selected from the group consisting of oral, nasal, ano-genital, tympanic and combinations thereof. 8. The method of claim 1, wherein the subject is a human. 9. The method of claim 1, wherein the applying and removing steps are repeated. 10. The method of claim 1, wherein the allergic response of the affected area is selected from the group consisting of dermatitis, atopic dermatitis, urticaria, contact dermatitis, eczema, conjunctivitis, rhinoconjunctivitis and combinations thereof. 11. The method of claim 1, wherein the allergic trigger is selected from the group consisting of an environmental trigger, a dietary trigger, a pharmaceutical trigger, a contact trigger. 12. The method of claim 11, wherein the environmental trigger is selected from the group consisting of pollen, pet dander and mold. 13. The method of claim 11, wherein the dietary trigger is selected from the group consisting of shellfish, nuts and gluten containing products 14. The method of claim 11, wherein the pharmaceutical trigger is selected from the group consisting of penicillin and pharmaceuticals comprising sulfur. 15. The method of claim 11, wherein the contact trigger is selected from the group consisting of latex, poison ivy, poison oak, poison sumac, metal jewelry and combinations thereof. | 1,600 |
1,407 | 14,649,796 | 1,635 | In accordance with an embodiment of the invention, a system and method is provided for determining a probability of a progeny having one or more phenotypes Ph j each associated with a single gene Q j . A score sip may be assigned to each allele hip at a plurality of genetic loci (i) in a haploid genome profile H p of a parent (p). A plurality (Nj) of the alleles hkp (k=1, . . . , Nj) associated with the gene Q j may be identified. The scores sip may be mapped or indexed to gene-specific scores ŝj,kp associated with gene Q j for the plurality of (Nj) alleles hkp. A probability may be computed for altering the gene product from gene Q j in a progeny of the parent (p) to be a function of the gene-specific scores ŝj,kp. | 1. A method of determining a probability of a progeny having one or more phenotypes Phj each associated with a single gene Qj, the method implemented by a computer processor executing program instructions, the method comprising the steps of:
a. assigning a score si p to each allele hi p at a plurality of genetic loci (i) in a haploid virtual gamete profile Hp of a parent (p); b. identifying a plurality (Nj) of the alleles hk p (k=1, . . . , Nj) associated with the gene Qj; c. mapping the scores si p to gene-specific scores ŝj,k p associated with gene Qj for the plurality of (Nj) alleles hk p; and d. computing a probability of altering gene product from gene Qj in a progeny of the parent (p) to be a function of the gene-specific scores ŝj,k p. 2. A method of determining a probability of a virtual progeny having one or more phenotypes Phj each associated with a single gene Qj, the method implemented by a computer processor executing program instructions, the method comprising the steps of:
a. generating a haplopath Hp={h1 p, h2 p, . . . , hN p} including a single allele hi pε(1,2) at each of a plurality of loci (i=1, . . . , N) from a genome profile of a potential parent (p); b. assigning a variance score si p to each of a plurality of the alleles hi p in the haplopath, each of the variance scores si p indicating a probability that the allele hi p results in altering gene product from gene Qj in the progeny; c. associating each variant allele hi p1, which has a variance score si p indicating a non-zero probability, with a corresponding one of a plurality of (k=1, . . . , Nj) variant alleles hk p known to alter the gene product from gene Qj; d. for each gene Qj, assigning a gene-specific penetrance score ŝj,k p to each of the (Nj) variant alleles hk p associated with the gene Qj; e. for each gene Qj, determining a probability of altering the gene product from gene Qj in the virtual progeny of the parent (p) based on the gene-specific penetrance scores ŝj,k p of the plurality of (Nj) variant alleles hk p; and f. for each gene Qj, outputting the probability of altering the gene product or a derivation of the probability of altering the gene product. 3. The method of claim 1 or 2, wherein the probability of having the phenotype Phj in the progeny of the parent (p) is Pj p=1−Πk=1 Nj[1−ŝj,k p], or a derivation thereof. 4. The method of claim 1 comprising:
repeating steps (a)-(d) for each of two parents p=(p1, p2) using two respective genome profiles thereof; and
combining the probabilities for each parent to determine the probability of having the phenotype Phj associated with each gene Qj in a progeny of the two parents (p1) and (p2). 5. The method of claim 4, wherein the probability of having a recessive phenotype (Phj) in the progeny of the two parents (p1) and (p2) is Pj p1,p2=(1−Πk=1 Nj[1−ŝj,k p1])(1−Πk=1 Nj[1−ŝj,k p2]), or a derivation thereof. 6. The method of claim 4, wherein the probability of having a dominant phenotype Phj in the progeny of the two parents (p1) and (p2) is Pj p1,p2=(1−Πk=1 Nj[1−ŝj,k p1])+(1−Πk=1 Nj[1−ŝj,k p2]), or a derivation thereof. 7. The method of claim 1 comprising:
e. repeating steps (a)-(d) for a plurality of different haploid genome profiles or Haplopaths Hp of the genome profile of the parent (p), each pair of progeny genome samplings differing from each other by at least one allele hi p; and
f. determining a probability or probability distribution of having the phenotype Phj by combining the probabilities of expression determined for each of the plurality of progeny genome samplings. 8. The method of any of the preceding claims, wherein each of the scores si p defines a likelihood that the variant allele hi p is an amino acid substitution at the locus (i) that will damage protein function. 9. The method of any of claims 1-7, wherein each of the scores si p defines the probability that for a change in one or more amino acids that the change will occur randomly based on natural selection. 10. The method of any of the preceding claims, wherein the progeny is a virtual progeny including virtual alleles hi p analyzed to predict phenotypes Phj in a potential progeny. 11. The method of any of claims 1-9, wherein the progeny is a living organism including real alleles hi p analyzed to predict a future emergence of phenotypes Phj in the living progeny. 12. The method of any of the preceding claims, wherein when the probability indicates a likelihood of having the phenotype Phj in the virtual progeny, further comprising generating a random number to determine if the progeny will have the phenotype Phi. 13. The method of any of claims 1-11, wherein the probability indicates a degree of expressivity of the phenotype Phj in the progeny. 14. The method of any of the preceding claims comprising comparing the probability to one or more thresholds to determine a category of expressivity of the phenotype Phj. 15. The method of any of the preceding claims, wherein the genotype of the gene Qj alters an amino acid sequence known to damage a protein product of the gene causing a disease phenotype. 16. The method of any of the preceding claims, wherein the probability of a progeny having one or more phenotypes Phj is a probability of protein damage in one or more gene products, each associated with a single gene Qj. 17. A method of determining a probability of having a phenotype in a virtual progeny, the method implemented by a computer processor executing program instructions, the method comprising the steps of:
a. generating a virtual progeny genome sampling G, wherein at each of a plurality of genetic loci i=1, . . . , N the sampling comprises one allele hi p1 from a first genome profile of a first potential parent (p1) and one allele hi p2 from a second genome profile of a second potential parent (p2); b. using the processor, comparing genotypes of said virtual progeny genome sampling G to one or more databases of genotype-phenotype associations to determine a phenotype associated with database genotypes matching genotypes of said virtual progeny genome sampling G, wherein the phenotype is associated with a penetrance value; c. using the processor, generating a random number to determine if the virtual progeny is predicted to have the phenotype; d. wherein if the virtual progeny is predicted to have the phenotype, using the processor, associating the penetrance value with a degree of expressivity of the phenotype in the virtual progeny. 18. The method of claim 17 comprising:
e. repeating steps (a)-(c) for a plurality of different virtual progeny genome samplings GVP={G1, G2, . . . , Gm} each sampling differing from each other sampling by at least one allele; and
f. outputting the predicted expression of the phenotype in the virtual progeny if said determination of step (c) converges to the same result in multiple iterations. 19. The method of claim 17 or 18 comprising repeating steps (b)-(d) for each of a plurality of genotype-phenotype associations. 20. The method of any of claims 17-19, wherein the set of alleles i=1, . . . , N) for each potential parent p=(p1, p2) is a haplopath Hp generated by selecting one of the two alleles hi pε(1,2) at each genetic locus along a path of the genome profile of the potential parent. 21. A system comprising a processor configured to implement the steps of the method of any preceding claim. 22. A system comprising a processor configured to implement the steps of the method of any of claims 15-18, wherein the processor is operatively connected to one or more databases of genotype-phenotype with which to comparing database genotypes with genotypes of said virtual progeny genome sampling G. | In accordance with an embodiment of the invention, a system and method is provided for determining a probability of a progeny having one or more phenotypes Ph j each associated with a single gene Q j . A score sip may be assigned to each allele hip at a plurality of genetic loci (i) in a haploid genome profile H p of a parent (p). A plurality (Nj) of the alleles hkp (k=1, . . . , Nj) associated with the gene Q j may be identified. The scores sip may be mapped or indexed to gene-specific scores ŝj,kp associated with gene Q j for the plurality of (Nj) alleles hkp. A probability may be computed for altering the gene product from gene Q j in a progeny of the parent (p) to be a function of the gene-specific scores ŝj,kp.1. A method of determining a probability of a progeny having one or more phenotypes Phj each associated with a single gene Qj, the method implemented by a computer processor executing program instructions, the method comprising the steps of:
a. assigning a score si p to each allele hi p at a plurality of genetic loci (i) in a haploid virtual gamete profile Hp of a parent (p); b. identifying a plurality (Nj) of the alleles hk p (k=1, . . . , Nj) associated with the gene Qj; c. mapping the scores si p to gene-specific scores ŝj,k p associated with gene Qj for the plurality of (Nj) alleles hk p; and d. computing a probability of altering gene product from gene Qj in a progeny of the parent (p) to be a function of the gene-specific scores ŝj,k p. 2. A method of determining a probability of a virtual progeny having one or more phenotypes Phj each associated with a single gene Qj, the method implemented by a computer processor executing program instructions, the method comprising the steps of:
a. generating a haplopath Hp={h1 p, h2 p, . . . , hN p} including a single allele hi pε(1,2) at each of a plurality of loci (i=1, . . . , N) from a genome profile of a potential parent (p); b. assigning a variance score si p to each of a plurality of the alleles hi p in the haplopath, each of the variance scores si p indicating a probability that the allele hi p results in altering gene product from gene Qj in the progeny; c. associating each variant allele hi p1, which has a variance score si p indicating a non-zero probability, with a corresponding one of a plurality of (k=1, . . . , Nj) variant alleles hk p known to alter the gene product from gene Qj; d. for each gene Qj, assigning a gene-specific penetrance score ŝj,k p to each of the (Nj) variant alleles hk p associated with the gene Qj; e. for each gene Qj, determining a probability of altering the gene product from gene Qj in the virtual progeny of the parent (p) based on the gene-specific penetrance scores ŝj,k p of the plurality of (Nj) variant alleles hk p; and f. for each gene Qj, outputting the probability of altering the gene product or a derivation of the probability of altering the gene product. 3. The method of claim 1 or 2, wherein the probability of having the phenotype Phj in the progeny of the parent (p) is Pj p=1−Πk=1 Nj[1−ŝj,k p], or a derivation thereof. 4. The method of claim 1 comprising:
repeating steps (a)-(d) for each of two parents p=(p1, p2) using two respective genome profiles thereof; and
combining the probabilities for each parent to determine the probability of having the phenotype Phj associated with each gene Qj in a progeny of the two parents (p1) and (p2). 5. The method of claim 4, wherein the probability of having a recessive phenotype (Phj) in the progeny of the two parents (p1) and (p2) is Pj p1,p2=(1−Πk=1 Nj[1−ŝj,k p1])(1−Πk=1 Nj[1−ŝj,k p2]), or a derivation thereof. 6. The method of claim 4, wherein the probability of having a dominant phenotype Phj in the progeny of the two parents (p1) and (p2) is Pj p1,p2=(1−Πk=1 Nj[1−ŝj,k p1])+(1−Πk=1 Nj[1−ŝj,k p2]), or a derivation thereof. 7. The method of claim 1 comprising:
e. repeating steps (a)-(d) for a plurality of different haploid genome profiles or Haplopaths Hp of the genome profile of the parent (p), each pair of progeny genome samplings differing from each other by at least one allele hi p; and
f. determining a probability or probability distribution of having the phenotype Phj by combining the probabilities of expression determined for each of the plurality of progeny genome samplings. 8. The method of any of the preceding claims, wherein each of the scores si p defines a likelihood that the variant allele hi p is an amino acid substitution at the locus (i) that will damage protein function. 9. The method of any of claims 1-7, wherein each of the scores si p defines the probability that for a change in one or more amino acids that the change will occur randomly based on natural selection. 10. The method of any of the preceding claims, wherein the progeny is a virtual progeny including virtual alleles hi p analyzed to predict phenotypes Phj in a potential progeny. 11. The method of any of claims 1-9, wherein the progeny is a living organism including real alleles hi p analyzed to predict a future emergence of phenotypes Phj in the living progeny. 12. The method of any of the preceding claims, wherein when the probability indicates a likelihood of having the phenotype Phj in the virtual progeny, further comprising generating a random number to determine if the progeny will have the phenotype Phi. 13. The method of any of claims 1-11, wherein the probability indicates a degree of expressivity of the phenotype Phj in the progeny. 14. The method of any of the preceding claims comprising comparing the probability to one or more thresholds to determine a category of expressivity of the phenotype Phj. 15. The method of any of the preceding claims, wherein the genotype of the gene Qj alters an amino acid sequence known to damage a protein product of the gene causing a disease phenotype. 16. The method of any of the preceding claims, wherein the probability of a progeny having one or more phenotypes Phj is a probability of protein damage in one or more gene products, each associated with a single gene Qj. 17. A method of determining a probability of having a phenotype in a virtual progeny, the method implemented by a computer processor executing program instructions, the method comprising the steps of:
a. generating a virtual progeny genome sampling G, wherein at each of a plurality of genetic loci i=1, . . . , N the sampling comprises one allele hi p1 from a first genome profile of a first potential parent (p1) and one allele hi p2 from a second genome profile of a second potential parent (p2); b. using the processor, comparing genotypes of said virtual progeny genome sampling G to one or more databases of genotype-phenotype associations to determine a phenotype associated with database genotypes matching genotypes of said virtual progeny genome sampling G, wherein the phenotype is associated with a penetrance value; c. using the processor, generating a random number to determine if the virtual progeny is predicted to have the phenotype; d. wherein if the virtual progeny is predicted to have the phenotype, using the processor, associating the penetrance value with a degree of expressivity of the phenotype in the virtual progeny. 18. The method of claim 17 comprising:
e. repeating steps (a)-(c) for a plurality of different virtual progeny genome samplings GVP={G1, G2, . . . , Gm} each sampling differing from each other sampling by at least one allele; and
f. outputting the predicted expression of the phenotype in the virtual progeny if said determination of step (c) converges to the same result in multiple iterations. 19. The method of claim 17 or 18 comprising repeating steps (b)-(d) for each of a plurality of genotype-phenotype associations. 20. The method of any of claims 17-19, wherein the set of alleles i=1, . . . , N) for each potential parent p=(p1, p2) is a haplopath Hp generated by selecting one of the two alleles hi pε(1,2) at each genetic locus along a path of the genome profile of the potential parent. 21. A system comprising a processor configured to implement the steps of the method of any preceding claim. 22. A system comprising a processor configured to implement the steps of the method of any of claims 15-18, wherein the processor is operatively connected to one or more databases of genotype-phenotype with which to comparing database genotypes with genotypes of said virtual progeny genome sampling G. | 1,600 |
1,408 | 16,109,127 | 1,654 | The invention provides pharmaceutical compositions comprising about 0.05 to 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane for use in the topical treatment of dry eye disease and provides for dosing and treatment methods thereof. The invention further provides kits comprising such compositions. | 1-15. (canceled) 16. A method of treating dry eye disease, the method comprising topically administering twice daily to an eye of a human with dry eye disease a composition comprising about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane, wherein said composition is substantially free of water and is substantially free of a preservative, wherein the amount of cyclosporine administered in a single dose per eye is about 10 μg cyclosporine. 17. The method according to claim 16, wherein the composition comprises up to about 1% (w/w) ethanol. 18. The method according to claim 16, wherein the composition comprises about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol. 19. The method according to claim 18, wherein the composition consists of about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol. 20. The method according to claim 18, wherein
i. a reduction in corneal staining, ii. an early onset of action, iii. a reduction of visual impairment associated with dry eye disease, or iv. a reduction of ocular surface damage associated with dry eye disease is achieved. 21. The method according to claim 16, wherein the dry eye disease is moderate to severe dry eye disease, and optionally wherein the subject is not responsive to treatment with artificial tears. 22. The method according to claim 16, wherein the subject suffering from dry eye disease experiences symptoms such as blurring, pain, irritation or corneal surface damage. 23. The method according to claim 16, wherein the composition further comprises up to about 2% (w/w) 2-perfluorobutyl-pentane. 24. A method of reducing reading impairment associated with dry eye disease, the method comprising topically administering twice daily to an eye of a human with dry eye disease a composition comprising about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane, wherein said composition is substantially free of water and is substantially free of a preservative, wherein the amount of cyclosporine administered in a single dose per eye is about 10 μg cyclosporine. 25. The method according to any of the claim 24, wherein the composition further comprises up to about 1% (w/w) ethanol. 26. The method according to claim 24, wherein the composition comprises about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol. 27. The method according to claim 26 wherein the composition consists about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol. 28. The method according to claim 26, wherein
i. a reduction in corneal staining, ii. an early onset of action, or iii. a reduction of ocular surface damage associated with dry eye disease is achieved. 29. The method according to claim 24, wherein the composition further comprises up to about 2% (w/w) 2-perfluorobutyl-pentane. 30. A method of reducing ocular surface damage associated with dry eye disease, the method comprising topically administering twice daily to an eye of a human with dry eye disease a composition comprising about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane, wherein said composition is substantially free of water and is substantially free of a preservative, wherein the amount of cyclosporine administered in a single dose per eye is about 10 μg cyclosporine. 31. The method according to any of the claim 30, wherein the composition comprises up to about 1% (w/w) ethanol. 32. The method according to claim 30, wherein the composition comprises about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol. 33. The method according to claim 32, wherein the composition consists of about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol. 34. The method according to claim 32, wherein
i. a reduction in corneal staining, ii. an early onset of action, or iii. a reduction of visual impairment associated with dry eye disease is achieved. 35. The method according to claim 30, wherein the composition further comprises up to about 2% (w/w) 2-perfluorobutyl-pentane. 36. A pharmaceutical composition for (a) treating dry eye disease or (b) reducing ocular surface damage associated with dry eye disease, the composition comprising about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane, wherein said composition is substantially free of water and is substantially free of a preservative, and wherein said composition is topically administered twice daily in a single dose per eye of about 10 μg cyclosporine. 37. The composition according to claim 36, wherein the composition comprises up to about 1% (w/w) ethanol. 38. The composition according to claim 36, wherein the composition comprises about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol. 39. The composition according to claim 38, wherein the composition consists about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol. 40. The composition according to claim 36, wherein said composition is safe, well tolerated and comfortable to the eye of the human. 41. The composition according to claim 36, wherein the composition further comprises up to about 2% (w/w) 2-perfluorobutyl-pentane. 42. The composition according to claim 36, wherein the composition is essentially free of ethanol. 43. A kit comprising the pharmaceutical composition according to claim 36, wherein the kit comprises a container for holding the composition and a drop dispenser adapted for administering about 10 μL volume of the composition per drop. 44. The kit according to claim 43, wherein the ratio of the volume of the pharmaceutical composition in the container to the total volume of the container is between 0.4 to 0.7, or wherein the ratio of the volume of the head space of the container to the volume of the pharmaceutical composition is between 0.5 to 1.5. 45. The kit according to claim 43, wherein the container and/or drop dispenser is manufactured from a thermoplastic material, optionally selected from polyethylene or polypropylene. | The invention provides pharmaceutical compositions comprising about 0.05 to 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane for use in the topical treatment of dry eye disease and provides for dosing and treatment methods thereof. The invention further provides kits comprising such compositions.1-15. (canceled) 16. A method of treating dry eye disease, the method comprising topically administering twice daily to an eye of a human with dry eye disease a composition comprising about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane, wherein said composition is substantially free of water and is substantially free of a preservative, wherein the amount of cyclosporine administered in a single dose per eye is about 10 μg cyclosporine. 17. The method according to claim 16, wherein the composition comprises up to about 1% (w/w) ethanol. 18. The method according to claim 16, wherein the composition comprises about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol. 19. The method according to claim 18, wherein the composition consists of about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol. 20. The method according to claim 18, wherein
i. a reduction in corneal staining, ii. an early onset of action, iii. a reduction of visual impairment associated with dry eye disease, or iv. a reduction of ocular surface damage associated with dry eye disease is achieved. 21. The method according to claim 16, wherein the dry eye disease is moderate to severe dry eye disease, and optionally wherein the subject is not responsive to treatment with artificial tears. 22. The method according to claim 16, wherein the subject suffering from dry eye disease experiences symptoms such as blurring, pain, irritation or corneal surface damage. 23. The method according to claim 16, wherein the composition further comprises up to about 2% (w/w) 2-perfluorobutyl-pentane. 24. A method of reducing reading impairment associated with dry eye disease, the method comprising topically administering twice daily to an eye of a human with dry eye disease a composition comprising about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane, wherein said composition is substantially free of water and is substantially free of a preservative, wherein the amount of cyclosporine administered in a single dose per eye is about 10 μg cyclosporine. 25. The method according to any of the claim 24, wherein the composition further comprises up to about 1% (w/w) ethanol. 26. The method according to claim 24, wherein the composition comprises about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol. 27. The method according to claim 26 wherein the composition consists about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol. 28. The method according to claim 26, wherein
i. a reduction in corneal staining, ii. an early onset of action, or iii. a reduction of ocular surface damage associated with dry eye disease is achieved. 29. The method according to claim 24, wherein the composition further comprises up to about 2% (w/w) 2-perfluorobutyl-pentane. 30. A method of reducing ocular surface damage associated with dry eye disease, the method comprising topically administering twice daily to an eye of a human with dry eye disease a composition comprising about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane, wherein said composition is substantially free of water and is substantially free of a preservative, wherein the amount of cyclosporine administered in a single dose per eye is about 10 μg cyclosporine. 31. The method according to any of the claim 30, wherein the composition comprises up to about 1% (w/w) ethanol. 32. The method according to claim 30, wherein the composition comprises about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol. 33. The method according to claim 32, wherein the composition consists of about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol. 34. The method according to claim 32, wherein
i. a reduction in corneal staining, ii. an early onset of action, or iii. a reduction of visual impairment associated with dry eye disease is achieved. 35. The method according to claim 30, wherein the composition further comprises up to about 2% (w/w) 2-perfluorobutyl-pentane. 36. A pharmaceutical composition for (a) treating dry eye disease or (b) reducing ocular surface damage associated with dry eye disease, the composition comprising about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane, wherein said composition is substantially free of water and is substantially free of a preservative, and wherein said composition is topically administered twice daily in a single dose per eye of about 10 μg cyclosporine. 37. The composition according to claim 36, wherein the composition comprises up to about 1% (w/w) ethanol. 38. The composition according to claim 36, wherein the composition comprises about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol. 39. The composition according to claim 38, wherein the composition consists about 0.1% (w/v) cyclosporine dissolved in 1-perfluorobutyl-pentane and about 1.0% (w/w) of ethanol. 40. The composition according to claim 36, wherein said composition is safe, well tolerated and comfortable to the eye of the human. 41. The composition according to claim 36, wherein the composition further comprises up to about 2% (w/w) 2-perfluorobutyl-pentane. 42. The composition according to claim 36, wherein the composition is essentially free of ethanol. 43. A kit comprising the pharmaceutical composition according to claim 36, wherein the kit comprises a container for holding the composition and a drop dispenser adapted for administering about 10 μL volume of the composition per drop. 44. The kit according to claim 43, wherein the ratio of the volume of the pharmaceutical composition in the container to the total volume of the container is between 0.4 to 0.7, or wherein the ratio of the volume of the head space of the container to the volume of the pharmaceutical composition is between 0.5 to 1.5. 45. The kit according to claim 43, wherein the container and/or drop dispenser is manufactured from a thermoplastic material, optionally selected from polyethylene or polypropylene. | 1,600 |
1,409 | 14,115,362 | 1,616 | An agricultural oil-based suspension formulation comprising an active ingredient suspended in finely divided form in an oil; and at least one surfactant selected from a polyalkylene glycol-fatty acid condensate or a polyalkylene glycolether fatty acid condensate formed from a reaction between a compound having Structure (1) and a compound having Structure (2):
wherein
R 1 =H or a C 1 -C 30 alkyl radical; A and B are ethylene or propylene groups in succession or random; n=0 or >1; and m=0 or >1,
and wherein
n+m>34; R 2 =C 8 -C 30 alkyl or alkylene radical (branched or linear); and x=>1. | 1. An agricultural oil-based suspension formulation comprising an active ingredient suspended in finely divided form in an oil; and at least one surfactant selected from a polyalkylene glycol-fatty acid condensate or a polyalkylene glycolether fatty acid condensate formed from a reaction between a compound having Structure (1) and a compound having Structure (2):
wherein
R1=H or a C1-C30 alkyl radical;
A and B are ethylene or propylene groups in succession or random;
n=0 or >1; and
m=0 or >1,
and wherein
n+m>34;
R2=C8-C30 alkyl or alkylene radical (branched or linear); and
x=>1. 2. An agricultural oil-based suspension formulation according to claim 1, wherein the surfactant comprises a diblock condensate of polyethylene glycol having a molecular weight greater than 1500 amu and a polyhydroxystearic acid copolymer of condensation range greater than 2 units. 3. An agricultural oil-based suspension formulation according to claim 1, wherein the surfactant comprises at least one monoblock condensate of a polyalkylene glycol ether-fatty acid condensate, wherein the polyalkylene glycol ether is an ethylene oxide-propylene oxide copolymer butyl ether having a molecular weight of greater than 1800 amu and the fatty acid condensate is a polyhydroxystearic acid copolymer of condensation range greater than 2 units. 4. An agricultural oil-based suspension formulation according to claim 1, wherein the formulation is selected from an Oil Dispersion (“OD”) or an Oil-miscible Flowable (“OF”) formulation. 5. An agricultural oil-based suspension formulation according to claim 4, wherein the OD formulation further comprises an emulsifying agent and/or a rubber-type copolymer as an additional anti-settling agent. 6. An agricultural oil-based suspension formulation according to claim 1, wherein the active ingredient is selected from Mancozeb, Diuron, Atrazine and Captan, or mixtures thereof. 7. An agricultural oil-based suspension formulation according to claim 6, wherein the active ingredient is Mancozeb. 8. An agricultural oil-based suspension according to claim 7, wherein the Mancozeb is present in a concentration greater than 400 g/L. 9. An agricultural oil-based suspension formulation according to claim 8, wherein the Mancozeb is present in a concentration greater than 580 g/L. 10. A method of application of the agricultural oil-based suspension formulation according to claim 1, having a rate of use of polyalkylene glycol-fatty acid condensate or polyalkylene glycolether fatty acid condensate in a range of from 2-10% w/v in the formulation. 11. A method of application according to claim 10, wherein the rate of use is in the range of 3-8% w/v in the formulation. 12. The method according to claim 10, wherein the active ingredient is selected from Mancozeb, Diuron, Atrazine and Captan, or mixtures thereof. 13. The method according to claim 12, wherein the active ingredient is Mancozeb. 14. The method according to claim 13, wherein the Mancozeb is present in a concentration greater than 400 g/L. 15. The method according to claim 14, wherein Mancozeb is present in a concentration greater than 580 g/L. 16. A method of preparing an OD formulation comprising an active ingredient comprising the steps of:
a) preparing a surfactant solution premix by combining at least one surfactant selected from a polyalkylene glycol-fatty acid condensate or a polyalkylene glycolether fatty acid condensate of the present invention with a surfactant and an oil to give a liquid; b) dispersing the active ingredient in the surfactant solution by either stirring or high shear mixing; c) milling the active ingredient dispersion to achieve a particle size average in the range 1-12 microns; d) adding surfactant emulsifying agents; and e) optionally adjusting the final concentration of active ingredient content by adding additional oil and other required ingredients, wherein steps a) to d) are carried out in any order. 17. The method according to claim 16, wherein step (e) includes adding a rubber-type copolymer as an additional anti-settling agent. 18. The method according to claim 17, wherein the active ingredient is selected from Mancozeb, Diuron, Atrazine or Captan, or mixtures thereof. 19. The method according to claim 18, wherein the active ingredient is Mancozeb. 20. The method according to claim 19, wherein the Mancozeb is present in a concentration greater than 400 g/L. | An agricultural oil-based suspension formulation comprising an active ingredient suspended in finely divided form in an oil; and at least one surfactant selected from a polyalkylene glycol-fatty acid condensate or a polyalkylene glycolether fatty acid condensate formed from a reaction between a compound having Structure (1) and a compound having Structure (2):
wherein
R 1 =H or a C 1 -C 30 alkyl radical; A and B are ethylene or propylene groups in succession or random; n=0 or >1; and m=0 or >1,
and wherein
n+m>34; R 2 =C 8 -C 30 alkyl or alkylene radical (branched or linear); and x=>1.1. An agricultural oil-based suspension formulation comprising an active ingredient suspended in finely divided form in an oil; and at least one surfactant selected from a polyalkylene glycol-fatty acid condensate or a polyalkylene glycolether fatty acid condensate formed from a reaction between a compound having Structure (1) and a compound having Structure (2):
wherein
R1=H or a C1-C30 alkyl radical;
A and B are ethylene or propylene groups in succession or random;
n=0 or >1; and
m=0 or >1,
and wherein
n+m>34;
R2=C8-C30 alkyl or alkylene radical (branched or linear); and
x=>1. 2. An agricultural oil-based suspension formulation according to claim 1, wherein the surfactant comprises a diblock condensate of polyethylene glycol having a molecular weight greater than 1500 amu and a polyhydroxystearic acid copolymer of condensation range greater than 2 units. 3. An agricultural oil-based suspension formulation according to claim 1, wherein the surfactant comprises at least one monoblock condensate of a polyalkylene glycol ether-fatty acid condensate, wherein the polyalkylene glycol ether is an ethylene oxide-propylene oxide copolymer butyl ether having a molecular weight of greater than 1800 amu and the fatty acid condensate is a polyhydroxystearic acid copolymer of condensation range greater than 2 units. 4. An agricultural oil-based suspension formulation according to claim 1, wherein the formulation is selected from an Oil Dispersion (“OD”) or an Oil-miscible Flowable (“OF”) formulation. 5. An agricultural oil-based suspension formulation according to claim 4, wherein the OD formulation further comprises an emulsifying agent and/or a rubber-type copolymer as an additional anti-settling agent. 6. An agricultural oil-based suspension formulation according to claim 1, wherein the active ingredient is selected from Mancozeb, Diuron, Atrazine and Captan, or mixtures thereof. 7. An agricultural oil-based suspension formulation according to claim 6, wherein the active ingredient is Mancozeb. 8. An agricultural oil-based suspension according to claim 7, wherein the Mancozeb is present in a concentration greater than 400 g/L. 9. An agricultural oil-based suspension formulation according to claim 8, wherein the Mancozeb is present in a concentration greater than 580 g/L. 10. A method of application of the agricultural oil-based suspension formulation according to claim 1, having a rate of use of polyalkylene glycol-fatty acid condensate or polyalkylene glycolether fatty acid condensate in a range of from 2-10% w/v in the formulation. 11. A method of application according to claim 10, wherein the rate of use is in the range of 3-8% w/v in the formulation. 12. The method according to claim 10, wherein the active ingredient is selected from Mancozeb, Diuron, Atrazine and Captan, or mixtures thereof. 13. The method according to claim 12, wherein the active ingredient is Mancozeb. 14. The method according to claim 13, wherein the Mancozeb is present in a concentration greater than 400 g/L. 15. The method according to claim 14, wherein Mancozeb is present in a concentration greater than 580 g/L. 16. A method of preparing an OD formulation comprising an active ingredient comprising the steps of:
a) preparing a surfactant solution premix by combining at least one surfactant selected from a polyalkylene glycol-fatty acid condensate or a polyalkylene glycolether fatty acid condensate of the present invention with a surfactant and an oil to give a liquid; b) dispersing the active ingredient in the surfactant solution by either stirring or high shear mixing; c) milling the active ingredient dispersion to achieve a particle size average in the range 1-12 microns; d) adding surfactant emulsifying agents; and e) optionally adjusting the final concentration of active ingredient content by adding additional oil and other required ingredients, wherein steps a) to d) are carried out in any order. 17. The method according to claim 16, wherein step (e) includes adding a rubber-type copolymer as an additional anti-settling agent. 18. The method according to claim 17, wherein the active ingredient is selected from Mancozeb, Diuron, Atrazine or Captan, or mixtures thereof. 19. The method according to claim 18, wherein the active ingredient is Mancozeb. 20. The method according to claim 19, wherein the Mancozeb is present in a concentration greater than 400 g/L. | 1,600 |
1,410 | 15,870,344 | 1,658 | Conjugates of a cholinesterase moiety and one or more nonpeptidic, water-soluble polymers are provided. Typically, the nonpeptidic, water-soluble polymer is poly(ethylene glycol) or a derivative thereof. Also provided, among other things, are compositions comprising conjugates, methods of making conjugates, and methods of administering compositions to a patient. | 1. A conjugate comprising a residue of a cholinesterase moiety covalently attached to a water-soluble polymer, wherein the residue of the cholinesterase moiety is covalently attached to the water-soluble polymer through a cysteine residue within the residue of the cholinesterase moiety. 2. A conjugate comprising a residue of a cholinesterase moiety covalently attached to a water-soluble polymer, wherein the water-soluble polymer, prior to being covalently attached, is a polymeric reagent bearing a maleimide group. 3. The conjugate of claim 1, wherein the water-soluble polymer is a branched water-soluble polymer. 4. The conjugate of claim 1, wherein the cholinesterase moiety is acetylcholinesterase. 5. The conjugate of claim 1, wherein the cholinesterase moiety is butyrylcholinesterase. 6. The conjugate of claim 1, wherein the cholinesterase moiety is recombinantly prepared. 7. The conjugate of claim 1, wherein the water-soluble polymer is a polymer selected from the group consisting of poly(alkylene oxide), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, and poly(acryloylmorpholine). 8. The conjugate of claim 7, wherein the water-soluble polymer is a poly(alkylene oxide). 9. The conjugate of claim 8, wherein the poly(alkylene oxide) is a poly(ethylene glycol). 10. The conjugate of claim 9, wherein the poly(ethylene glycol) is terminally capped with an end-capping moiety selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, alkynoxy, substituted alkynoxy, aryloxy and substituted aryloxy. 11. The conjugate of claim 1, wherein the water-soluble polymer has a weight-average molecular weight in a range of from about 500 Daltons to about 100,000 Daltons. 12. The conjugate of claim 1, wherein the cysteine residue within the residue of the cholinesterase moiety corresponds to Cys66 of butyrylcholinesterase. 13. The conjugate of claim 2, wherein the polymeric reagent bearing a maleimide group has the following structure:
wherein:
X is a spacer moiety comprised of one or more atoms; and
each (n) is independently an integer having a value of from about 2 to about 4000. 14. The conjugate of claim 13, wherein the polymeric reagent bearing a maleimide group has the following structure:
wherein each (n) is independently an integer having a value of from about 225 to about 1930. 15. The conjugate of claim 14, wherein each (n) is defined so as to provide —(OCH2CH2)— as having a molecular weight of about 20 kDa. 16. The conjugate of claim 3, wherein the branched water-soluble polymer includes the following structure:
wherein each (n) is independently an integer having a value of from 2 to 4000. 17. The conjugate of claim 1, having the following structure:
wherein:
each (n) is independently an integer having a value of from 2 to 4000;
X is a spacer moiety comprised of one or more atoms; and
ChE is a residue of a cholinesterase moiety. 18. The conjugate of claim 17, having the following structure:
wherein each (n) is independently an integer having a value of from 2 to 4000. 19. The conjugate of claim 1, wherein the conjugate has from one to two water-soluble polymers attached to the residue of the cholinesterase moiety. 20. The conjugate of claim 19, wherein the conjugate has two water-soluble polymers attached to the residue of the cholinesterase moiety. 21. The conjugate of claim 1, wherein the residue of the cholinesterase moiety is in the form of a dimer derived from two separate cholinesterase moieties. 22. The conjugate of claim 21, wherein the conjugate has two water-soluble polymers attached to the residue of the cholinesterase moiety, one water-soluble polymer attached to each of the cholinesterase moieties forming the dimer. 23. The conjugate of claim 2, wherein the polymeric reagent bearing a maleimide group has a single maleimide group. 24. The conjugate of claim 1, wherein the cholinesterase moiety is glycosylated. 25. The conjugate of claim 1, wherein the conjugate is in an isolated and monoPEGylated form. 26. (canceled) 27. The conjugate of claim 1, wherein the cholinesterase moiety is a precursor cholinesterase moiety. 28. A pharmaceutical composition comprising a conjugate of claim 1 and a pharmaceutically acceptable excipient. 29. A method for making a conjugate comprising contacting, under conjugation conditions, a cholinesterase moiety with a polymeric reagent bearing a thiol-reactive functional group. 30. The method of claim 29, wherein the contact step is carried out at a pH of greater than 8.0. 31. A method for making a conjugate comprising:
(a) combining, under conjugation conditions, a reagent composition comprising a plurality of thiol-selective polymeric reagent molecules with a cholinesterase moiety composition comprising a plurality of cholinesterase moiety molecules, each molecule in the form of a dimer to form a conjugate mixture comprising monoconjugated dimers and diconjugated dimers; (b) subjecting the conjugate mixture to reducing conditions to form a reduced mixture comprising reduced unconjugated monomers and reduced monoconjugated monomers; (c) separating the reduced monoconjugated monomers from the reduced mixture to form a composition comprising reduced monoconjugated monomers; and (d) removing the reducing conditions from the composition comprising reduced monoconjugated monomers to thereby form a composition of diconjugated dimers. 32. The method of claim 31, wherein the composition comprising reduced monoconjugated monomers is substantially free of reduced unconjugated monomers. | Conjugates of a cholinesterase moiety and one or more nonpeptidic, water-soluble polymers are provided. Typically, the nonpeptidic, water-soluble polymer is poly(ethylene glycol) or a derivative thereof. Also provided, among other things, are compositions comprising conjugates, methods of making conjugates, and methods of administering compositions to a patient.1. A conjugate comprising a residue of a cholinesterase moiety covalently attached to a water-soluble polymer, wherein the residue of the cholinesterase moiety is covalently attached to the water-soluble polymer through a cysteine residue within the residue of the cholinesterase moiety. 2. A conjugate comprising a residue of a cholinesterase moiety covalently attached to a water-soluble polymer, wherein the water-soluble polymer, prior to being covalently attached, is a polymeric reagent bearing a maleimide group. 3. The conjugate of claim 1, wherein the water-soluble polymer is a branched water-soluble polymer. 4. The conjugate of claim 1, wherein the cholinesterase moiety is acetylcholinesterase. 5. The conjugate of claim 1, wherein the cholinesterase moiety is butyrylcholinesterase. 6. The conjugate of claim 1, wherein the cholinesterase moiety is recombinantly prepared. 7. The conjugate of claim 1, wherein the water-soluble polymer is a polymer selected from the group consisting of poly(alkylene oxide), poly(vinyl pyrrolidone), poly(vinyl alcohol), polyoxazoline, and poly(acryloylmorpholine). 8. The conjugate of claim 7, wherein the water-soluble polymer is a poly(alkylene oxide). 9. The conjugate of claim 8, wherein the poly(alkylene oxide) is a poly(ethylene glycol). 10. The conjugate of claim 9, wherein the poly(ethylene glycol) is terminally capped with an end-capping moiety selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, alkynoxy, substituted alkynoxy, aryloxy and substituted aryloxy. 11. The conjugate of claim 1, wherein the water-soluble polymer has a weight-average molecular weight in a range of from about 500 Daltons to about 100,000 Daltons. 12. The conjugate of claim 1, wherein the cysteine residue within the residue of the cholinesterase moiety corresponds to Cys66 of butyrylcholinesterase. 13. The conjugate of claim 2, wherein the polymeric reagent bearing a maleimide group has the following structure:
wherein:
X is a spacer moiety comprised of one or more atoms; and
each (n) is independently an integer having a value of from about 2 to about 4000. 14. The conjugate of claim 13, wherein the polymeric reagent bearing a maleimide group has the following structure:
wherein each (n) is independently an integer having a value of from about 225 to about 1930. 15. The conjugate of claim 14, wherein each (n) is defined so as to provide —(OCH2CH2)— as having a molecular weight of about 20 kDa. 16. The conjugate of claim 3, wherein the branched water-soluble polymer includes the following structure:
wherein each (n) is independently an integer having a value of from 2 to 4000. 17. The conjugate of claim 1, having the following structure:
wherein:
each (n) is independently an integer having a value of from 2 to 4000;
X is a spacer moiety comprised of one or more atoms; and
ChE is a residue of a cholinesterase moiety. 18. The conjugate of claim 17, having the following structure:
wherein each (n) is independently an integer having a value of from 2 to 4000. 19. The conjugate of claim 1, wherein the conjugate has from one to two water-soluble polymers attached to the residue of the cholinesterase moiety. 20. The conjugate of claim 19, wherein the conjugate has two water-soluble polymers attached to the residue of the cholinesterase moiety. 21. The conjugate of claim 1, wherein the residue of the cholinesterase moiety is in the form of a dimer derived from two separate cholinesterase moieties. 22. The conjugate of claim 21, wherein the conjugate has two water-soluble polymers attached to the residue of the cholinesterase moiety, one water-soluble polymer attached to each of the cholinesterase moieties forming the dimer. 23. The conjugate of claim 2, wherein the polymeric reagent bearing a maleimide group has a single maleimide group. 24. The conjugate of claim 1, wherein the cholinesterase moiety is glycosylated. 25. The conjugate of claim 1, wherein the conjugate is in an isolated and monoPEGylated form. 26. (canceled) 27. The conjugate of claim 1, wherein the cholinesterase moiety is a precursor cholinesterase moiety. 28. A pharmaceutical composition comprising a conjugate of claim 1 and a pharmaceutically acceptable excipient. 29. A method for making a conjugate comprising contacting, under conjugation conditions, a cholinesterase moiety with a polymeric reagent bearing a thiol-reactive functional group. 30. The method of claim 29, wherein the contact step is carried out at a pH of greater than 8.0. 31. A method for making a conjugate comprising:
(a) combining, under conjugation conditions, a reagent composition comprising a plurality of thiol-selective polymeric reagent molecules with a cholinesterase moiety composition comprising a plurality of cholinesterase moiety molecules, each molecule in the form of a dimer to form a conjugate mixture comprising monoconjugated dimers and diconjugated dimers; (b) subjecting the conjugate mixture to reducing conditions to form a reduced mixture comprising reduced unconjugated monomers and reduced monoconjugated monomers; (c) separating the reduced monoconjugated monomers from the reduced mixture to form a composition comprising reduced monoconjugated monomers; and (d) removing the reducing conditions from the composition comprising reduced monoconjugated monomers to thereby form a composition of diconjugated dimers. 32. The method of claim 31, wherein the composition comprising reduced monoconjugated monomers is substantially free of reduced unconjugated monomers. | 1,600 |
1,411 | 15,371,977 | 1,617 | The invention relates to a bracelet or strap, in particular a watch band, comprising at least one organic material based portion intended to be placed in contact with the user's skin, said organic material containing at least one functional agent, such as an antibacterial agent. According to the invention, said organic material also contains a cosmetic agent for the skin, arranged to be able to be in contact with the user's skin when the bracelet is worn.
The invention also concerns methods for manufacturing such a bracelet or strap. | 1. A bracelet or strap, comprising at least one organic material, said organic material containing at least one functional agent, wherein said organic material also contains at least one cosmetic agent for skin arranged to be able to be in contact with the user's skin when the bracelet or strap is worn. 2. The bracelet or strap according to claim 1, wherein the organic material is chosen from the group consisting of leather, elastomers, and thermoplastic elastomers. 3. The bracelet or strap according to claim 1, wherein the functional agent is chosen from the group consisting of antibacterial agents, perfumes, cooling agents and mixtures thereof. 4. The bracelet or strap according to claim 3, wherein the antibacterial agent is chosen from the group consisting of zinc pyrithione, silver phosphate and aluminium salts. 5. The bracelet or strap according to claim 1, wherein the cosmetic agent for skin is chosen from the group consisting of a repair agent, an anti-irritant agent and mixtures thereof. 6. The bracelet or strap according to claim 5, wherein the repair agent is chosen from the group consisting of ceramides and hyaluronic acid. 7. The bracelet or strap according to claim 5, wherein the anti-irritant agent is chosen from the group consisting of acetyl tetrapeptide-15 and oat extract. 8. The bracelet or strap according to claim 1, wherein the cosmetic agent for skin is in encapsulated form arranged to release said cosmetic agent through friction on the skin. 9. A method for manufacture of a bracelet or strap, comprising at least one organic material, said organic material containing at least one functional agent and at least one cosmetic agent for the skin arranged to be able to be in contact with the user's skin when the bracelet or strap is worn, the method comprising:
a) preparing at least one cosmetic agent for skin in encapsulated form arranged to release said cosmetic agent through friction on the skin; b) producing a formulation using said organic material; c) adding to the formulation obtained in b) at least one cosmetic agent for skin in the encapsulated form obtained in a) and at least one functional agent; and d) making the bracelet or strap from the formulation obtained in c). 10. The method according to claim 9, wherein the organic material is chosen from the group consisting of leather, elastomers, and thermoplastic elastomers. 11. The method for manufacture of a bracelet or strap, comprising at least one organic material, said organic material containing at least one functional agent and at least one cosmetic agent for the skin arranged to be able to be in contact with the user's skin when the bracelet or strap is worn, method comprising:
a′) taking an element intended to form the organic material based portion of the bracelet or strap, said organic material having no cosmetic agent for skin, and optionally no functional agent. b′) incorporating at least one cosmetic agent for skin, and optionally at least one functional agent if the latter is not already present, in the organic material based portion of the bracelet or strap in a′) by a method of impregnation; and c′) making the bracelet or strap, said making c′) being performed between a′) and b′) or after b′). 12. The method according to claim 11, wherein the impregnation method is a supercritical fluid impregnation method. 13. The method according to claim 12, wherein the supercritical fluid impregnation b′) is performed after c′). 14. The method according to claim 12, wherein the element intended to form the organic material based portion of the bracelet or strap is chosen from the group consisting of leather, elastomers and thermoplastic elastomers. 15. The method according to claim 12, wherein the element intended to form the organic material based portion is leather, and wherein a′) is a leather cutting step, and supercritical fluid impregnation b′) is performed close to a′) and before c′). 16. The method according to claim 11, wherein the element intended to form the organic material based portion is leather, wherein a′) is a dyeing step or a leather nourishing step, and wherein the impregnation b′) is performed jointly with a′), the cosmetic agent for skin having been pre-prepared in an encapsulated form. 17. The method according to claim 9, wherein the functional agent is chosen from the group consisting of antibacterial agents, perfumes, cooling agents and mixtures thereof. 18. The method according to claim 17, wherein the antibacterial agent is chosen from the group consisting of zinc pyrithione, silver phosphate and aluminium salts. 19. The method according to claim 9, wherein the cosmetic agent for skin is chosen from the group consisting of a repair agent, an anti-irritant agent and mixtures thereof. 20. The method according to claim 19, wherein the repair agent is chosen from the group consisting of ceramides and hyaluronic acid. 21. The method according to claim 19, wherein the anti-irritant agent is chosen from the group consisting of acetyl tetrapeptide-15 and oat extract. 22. The method according to claim 11, wherein the functional agent is chosen from the group consisting of antibacterial agents, perfumes, cooling agents and mixtures thereof. 23. The method according to claim 22, wherein the antibacterial agent is chosen from the group consisting of zinc pyrithione, silver phosphate and aluminium salts. 24. The method according to claim 11, wherein the cosmetic agent for skin is chosen from the group consisting of a repair agent, an anti-irritant agent and mixtures thereof. 25. The method according to claim 24, wherein the repair agent is chosen from the group consisting of ceramides and hyaluronic acid. 26. The method according to claim 24, wherein the anti-irritant agent is chosen from the group consisting of acetyl tetrapeptide-15 and oat extract. | The invention relates to a bracelet or strap, in particular a watch band, comprising at least one organic material based portion intended to be placed in contact with the user's skin, said organic material containing at least one functional agent, such as an antibacterial agent. According to the invention, said organic material also contains a cosmetic agent for the skin, arranged to be able to be in contact with the user's skin when the bracelet is worn.
The invention also concerns methods for manufacturing such a bracelet or strap.1. A bracelet or strap, comprising at least one organic material, said organic material containing at least one functional agent, wherein said organic material also contains at least one cosmetic agent for skin arranged to be able to be in contact with the user's skin when the bracelet or strap is worn. 2. The bracelet or strap according to claim 1, wherein the organic material is chosen from the group consisting of leather, elastomers, and thermoplastic elastomers. 3. The bracelet or strap according to claim 1, wherein the functional agent is chosen from the group consisting of antibacterial agents, perfumes, cooling agents and mixtures thereof. 4. The bracelet or strap according to claim 3, wherein the antibacterial agent is chosen from the group consisting of zinc pyrithione, silver phosphate and aluminium salts. 5. The bracelet or strap according to claim 1, wherein the cosmetic agent for skin is chosen from the group consisting of a repair agent, an anti-irritant agent and mixtures thereof. 6. The bracelet or strap according to claim 5, wherein the repair agent is chosen from the group consisting of ceramides and hyaluronic acid. 7. The bracelet or strap according to claim 5, wherein the anti-irritant agent is chosen from the group consisting of acetyl tetrapeptide-15 and oat extract. 8. The bracelet or strap according to claim 1, wherein the cosmetic agent for skin is in encapsulated form arranged to release said cosmetic agent through friction on the skin. 9. A method for manufacture of a bracelet or strap, comprising at least one organic material, said organic material containing at least one functional agent and at least one cosmetic agent for the skin arranged to be able to be in contact with the user's skin when the bracelet or strap is worn, the method comprising:
a) preparing at least one cosmetic agent for skin in encapsulated form arranged to release said cosmetic agent through friction on the skin; b) producing a formulation using said organic material; c) adding to the formulation obtained in b) at least one cosmetic agent for skin in the encapsulated form obtained in a) and at least one functional agent; and d) making the bracelet or strap from the formulation obtained in c). 10. The method according to claim 9, wherein the organic material is chosen from the group consisting of leather, elastomers, and thermoplastic elastomers. 11. The method for manufacture of a bracelet or strap, comprising at least one organic material, said organic material containing at least one functional agent and at least one cosmetic agent for the skin arranged to be able to be in contact with the user's skin when the bracelet or strap is worn, method comprising:
a′) taking an element intended to form the organic material based portion of the bracelet or strap, said organic material having no cosmetic agent for skin, and optionally no functional agent. b′) incorporating at least one cosmetic agent for skin, and optionally at least one functional agent if the latter is not already present, in the organic material based portion of the bracelet or strap in a′) by a method of impregnation; and c′) making the bracelet or strap, said making c′) being performed between a′) and b′) or after b′). 12. The method according to claim 11, wherein the impregnation method is a supercritical fluid impregnation method. 13. The method according to claim 12, wherein the supercritical fluid impregnation b′) is performed after c′). 14. The method according to claim 12, wherein the element intended to form the organic material based portion of the bracelet or strap is chosen from the group consisting of leather, elastomers and thermoplastic elastomers. 15. The method according to claim 12, wherein the element intended to form the organic material based portion is leather, and wherein a′) is a leather cutting step, and supercritical fluid impregnation b′) is performed close to a′) and before c′). 16. The method according to claim 11, wherein the element intended to form the organic material based portion is leather, wherein a′) is a dyeing step or a leather nourishing step, and wherein the impregnation b′) is performed jointly with a′), the cosmetic agent for skin having been pre-prepared in an encapsulated form. 17. The method according to claim 9, wherein the functional agent is chosen from the group consisting of antibacterial agents, perfumes, cooling agents and mixtures thereof. 18. The method according to claim 17, wherein the antibacterial agent is chosen from the group consisting of zinc pyrithione, silver phosphate and aluminium salts. 19. The method according to claim 9, wherein the cosmetic agent for skin is chosen from the group consisting of a repair agent, an anti-irritant agent and mixtures thereof. 20. The method according to claim 19, wherein the repair agent is chosen from the group consisting of ceramides and hyaluronic acid. 21. The method according to claim 19, wherein the anti-irritant agent is chosen from the group consisting of acetyl tetrapeptide-15 and oat extract. 22. The method according to claim 11, wherein the functional agent is chosen from the group consisting of antibacterial agents, perfumes, cooling agents and mixtures thereof. 23. The method according to claim 22, wherein the antibacterial agent is chosen from the group consisting of zinc pyrithione, silver phosphate and aluminium salts. 24. The method according to claim 11, wherein the cosmetic agent for skin is chosen from the group consisting of a repair agent, an anti-irritant agent and mixtures thereof. 25. The method according to claim 24, wherein the repair agent is chosen from the group consisting of ceramides and hyaluronic acid. 26. The method according to claim 24, wherein the anti-irritant agent is chosen from the group consisting of acetyl tetrapeptide-15 and oat extract. | 1,600 |
1,412 | 15,857,145 | 1,618 | Drift reduction adjuvant composition and agricultural sprays containing such agricultural compositions contain water, a Newtonian responding polymer such as guar gum, an emulsifier such as a polyoxyethylene sorbitan emulsifier, and an oil. When the agricultural spray containing the drift reduction adjuvant composition and a pesticide is delivered from an agricultural nozzle, it produces fewer droplets less than 150 μm in diameter and either reduces, maintains or increases (e.g., by up to 30 percentage points) the number of ultra-coarse droplets above 622 μm in diameter compared to an agricultural spray of the pesticide without the drift reduction adjuvant composition sprayed under the same conditions. | 1. A drift reduction adjuvant composition, comprising:
water; guar gum; a polyoxyethylene sorbitan emulsifier; and a seed oil. 2. The drift reduction adjuvant composition of claim 1, wherein the polyoxyethylene sorbitan emulsifier comprises one or more of: polyoxyethylene sorbitan fatty acid ester, polyoxyethylene 20 sorbital trioleate, polyoxyethylene sorbitan mixed fatty acid ester, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monotallate, polyoxyethylene sorbitol hexaoleate, polyoxyethylene sorbitol oleate-laurate, polyoxyethylene sorbitol penta tall oil ester (40 moles), polyoxyethylene sorbitol tetraoleate, or polyoxyethylene sorbitol, mixed ethyl ester. 3. The drift reduction adjuvant composition of claim 1, wherein the seed oil comprises modified seed oil. 4. The drift reduction adjuvant composition of claim 3, wherein the modified seed oil comprises one or more of methylated soybean oil, methylated palm oil or methylated rapeseed oil. 5. The drift reduction adjuvant composition of claim 1, wherein the guar gum forms about 0.01 to about 0.08 g/ml of the drift reduction adjuvant composition. 6. The drift reduction adjuvant composition of claim 1, wherein the seed oil forms about 20 to about 40% (v/v) of the drift reduction adjuvant composition. 7. The drift reduction adjuvant composition of claim 1, wherein the polyoxyethylene sorbitan emulsifier forms up to about 3.2% (v/v) of the drift reduction adjuvant composition. 8. An agricultural spray, comprising:
an drift reduction adjuvant composition, the drift reduction adjuvant composition comprising:
water;
guar gum;
an emulsifier comprising a polyoxyethylene sorbitan fatty acid ester; and
one or more of a seed oil or a vegetable oil; and
a pesticide, wherein the agricultural spray is delivered from an agricultural nozzle and produces fewer droplets less than 150 μm in diameter and either reduces, maintains or increases by up to 30 percentage points the number of ultra-coarse droplets above 622 μm in diameter compared to an agricultural spray of the pesticide without the drift reduction adjuvant composition sprayed under the same conditions. 9. The agricultural spray of claim 8, wherein the agricultural nozzle is configured to produce a flat fan spray. 10. The agricultural spray of claim 8, wherein the one or more of a seed oil or a vegetable oil comprises modified seed oil or modified vegetable oil. 11. The agricultural spray of claim 8, wherein a pH of the spray is about 5 to about 7. 12. The agricultural spray of claim 8, wherein the guar gum forms about 0.7×10−4 g/mo to about 5×10−4 g/ml of the spray. 13. The agricultural spray of claim 8, wherein the one or more of a seed oil or a vegetable oil forms about 0.04% (v/v) to 0.8% (v/v) of the spray. 14. The agricultural spray of claim 8, wherein the emulsifier forms up to about 0.04% (v/v) of the spray. 15. The agricultural spray of claim 8, wherein the pesticide comprises a herbicide. 16. The agricultural spray of claim 8, wherein the agricultural spray delivered from the agricultural nozzle either reduces, maintains or increases by up to 15 percentage points the number of ultra-coarse droplets above 622 μm in diameter compared to an agricultural spray of the pesticide without the drift reduction adjuvant composition sprayed under the same conditions. | Drift reduction adjuvant composition and agricultural sprays containing such agricultural compositions contain water, a Newtonian responding polymer such as guar gum, an emulsifier such as a polyoxyethylene sorbitan emulsifier, and an oil. When the agricultural spray containing the drift reduction adjuvant composition and a pesticide is delivered from an agricultural nozzle, it produces fewer droplets less than 150 μm in diameter and either reduces, maintains or increases (e.g., by up to 30 percentage points) the number of ultra-coarse droplets above 622 μm in diameter compared to an agricultural spray of the pesticide without the drift reduction adjuvant composition sprayed under the same conditions.1. A drift reduction adjuvant composition, comprising:
water; guar gum; a polyoxyethylene sorbitan emulsifier; and a seed oil. 2. The drift reduction adjuvant composition of claim 1, wherein the polyoxyethylene sorbitan emulsifier comprises one or more of: polyoxyethylene sorbitan fatty acid ester, polyoxyethylene 20 sorbital trioleate, polyoxyethylene sorbitan mixed fatty acid ester, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monotallate, polyoxyethylene sorbitol hexaoleate, polyoxyethylene sorbitol oleate-laurate, polyoxyethylene sorbitol penta tall oil ester (40 moles), polyoxyethylene sorbitol tetraoleate, or polyoxyethylene sorbitol, mixed ethyl ester. 3. The drift reduction adjuvant composition of claim 1, wherein the seed oil comprises modified seed oil. 4. The drift reduction adjuvant composition of claim 3, wherein the modified seed oil comprises one or more of methylated soybean oil, methylated palm oil or methylated rapeseed oil. 5. The drift reduction adjuvant composition of claim 1, wherein the guar gum forms about 0.01 to about 0.08 g/ml of the drift reduction adjuvant composition. 6. The drift reduction adjuvant composition of claim 1, wherein the seed oil forms about 20 to about 40% (v/v) of the drift reduction adjuvant composition. 7. The drift reduction adjuvant composition of claim 1, wherein the polyoxyethylene sorbitan emulsifier forms up to about 3.2% (v/v) of the drift reduction adjuvant composition. 8. An agricultural spray, comprising:
an drift reduction adjuvant composition, the drift reduction adjuvant composition comprising:
water;
guar gum;
an emulsifier comprising a polyoxyethylene sorbitan fatty acid ester; and
one or more of a seed oil or a vegetable oil; and
a pesticide, wherein the agricultural spray is delivered from an agricultural nozzle and produces fewer droplets less than 150 μm in diameter and either reduces, maintains or increases by up to 30 percentage points the number of ultra-coarse droplets above 622 μm in diameter compared to an agricultural spray of the pesticide without the drift reduction adjuvant composition sprayed under the same conditions. 9. The agricultural spray of claim 8, wherein the agricultural nozzle is configured to produce a flat fan spray. 10. The agricultural spray of claim 8, wherein the one or more of a seed oil or a vegetable oil comprises modified seed oil or modified vegetable oil. 11. The agricultural spray of claim 8, wherein a pH of the spray is about 5 to about 7. 12. The agricultural spray of claim 8, wherein the guar gum forms about 0.7×10−4 g/mo to about 5×10−4 g/ml of the spray. 13. The agricultural spray of claim 8, wherein the one or more of a seed oil or a vegetable oil forms about 0.04% (v/v) to 0.8% (v/v) of the spray. 14. The agricultural spray of claim 8, wherein the emulsifier forms up to about 0.04% (v/v) of the spray. 15. The agricultural spray of claim 8, wherein the pesticide comprises a herbicide. 16. The agricultural spray of claim 8, wherein the agricultural spray delivered from the agricultural nozzle either reduces, maintains or increases by up to 15 percentage points the number of ultra-coarse droplets above 622 μm in diameter compared to an agricultural spray of the pesticide without the drift reduction adjuvant composition sprayed under the same conditions. | 1,600 |
1,413 | 15,318,518 | 1,628 | The present invention is directed to a composition comprising a buspirone metabolite, alone or in combination with a second active ingredient, for use in the treatment of movement disorders. | 1-30. (canceled) 31. A method for treating dyskinesia or reducing abnormal involuntary movements in movement disorders, comprising:
administering to a subject in need thereof a pharmaceutical composition comprising 6-hydroxybuspirone (6-OH-Busp) or a pharmaceutically acceptable derivative thereof. 32. The method of claim 31, wherein said 6-OH-Busp is selected from the group consisting of the racemate of 6-OH-Busp, the S-form of 6-OH-Busp and the R-form of 6-OH-Busp. 33. The method of claim 31, wherein said 6-OH-Busp is the racemate of 6-OH-Busp. 34. The method of claim 31, wherein said movement disorder is dyskinesia. 35. The method of claim 31, wherein said dyskinesia is tardive dyskinesia. 36. The method of claim 31, wherein said dyskinesia is L-DOPA induced dyskinesia (LID). 37. The method of claim 31, wherein the movement disorder is selected from the group of consisting of: Parkinson's disease; bradykinesia, akinesia and dyskinesia; L-DOPA induced dyskinesia (LID); tardive dyskinesia and akathisia. 38. The method of claim 31, wherein the movement disorder is selected from the group of consisting of:
a. a movement disorder is selected from the group of consisting of: ataxia, dystonia, essential tremor, Huntington's disease, myoclonus, Rett syndrome, Tourette syndrome, Wilson's disease, chorea, Machado-Joseph disease, restless leg syndrome, spasmodic torticollis, and geniospasm or movement disorders associated therewith; b. a movement disorder caused by or associated with drug therapy including neuroleptic drugs, antipsychotics, antidepressants and antiemetic drugs; c. a movement disorder caused by or associated with withdrawal of drugs including opioids, barbiturates, cocaine, benzodiazepines, 5 alcohol and amphetamine; or d. a movement disorder caused by idiopathic disease, genetic dysfunctions, or infection or other conditions which lead to dysfunction of the basal ganglia and/or lead to altered synaptic dopamine levels. 39. The method of claim 31, wherein said composition is to be administered to a subject suffering from a movement disorder or an individual being in risk of suffering from a movement disorder. 40. The method of claim 31, wherein said composition is to be administered to a subject suffering from dyskinesia or an individual being in risk of suffering from dyskinesia. 41. The method of claim 31, wherein said subject is, or is to be, treated with a dopamine prodrug such as L-DOPA. 42. The method of claim 31, wherein said composition is a pharmaceutically acceptable composition. 43. The method of claim 31, wherein said composition further comprises a second active pharmaceutical ingredient. 44. The method of claim 35, wherein said second active pharmaceutical ingredient is to be administered separately, sequentially or simultaneously from said pharmaceutical composition. 45. The method of claim 35, wherein the second active pharmaceutical ingredient is an agonist of two or more of the 5-HT1B, 5-HT1D and 5-HT1F receptors. 46. The method of claim 37, wherein the agonist of two or more of the 5-HT1B, 5-HT1D and 5-HT1F receptors is a triptan. 47. The method of claim 37, wherein the agonist of two or more of the 5-HT1B, 5-HT1D and 5-HT1F receptors is selected from the group consisting of zolmitriptan, rizatriptan, sumatriptan, naratriptan, almotriptan, frovatriptan, avitriptan, alniditan and eletriptan, or pharmaceutically acceptable derivatives thereof. 48. The method of claim 35, wherein the second active pharmaceutical ingredient is selected from the group consisting of a selective 5-HT1B receptor agonist, a selective 5-HT1D receptor agonist, a selective 5-HT1E receptor agonist and a selective 5-HT1F receptor agonist. 49. The method of claim 35, wherein the second active pharmaceutical ingredient is a modulator of glutamate neurotransmission. 50. The method of claim 35, wherein the second active pharmaceutical ingredient is a glutamate receptor antagonist. 51. The method of claim 35, wherein the second active pharmaceutical ingredient is selected from the group consisting of an NMDA receptor antagonist, an AMPA receptor antagonist, a kainite receptor antagonist, a AMPAR/kainite receptor antagonist, a mGluR Group 1 antagonist, a mGluR Group 2 agonist and a mGluR Group 3 agonist. 52. The method of claim 35, wherein the second active pharmaceutical ingredient is an inhibitor of glutamate release. 53. The method of claim 35, wherein the second active pharmaceutical ingredient is an ion-channel antagonist. 54. The method of claim 35, wherein the second active pharmaceutical ingredient is selected from the group consisting of a calcium channel antagonist, a T-Type calcium channel antagonist, an L-Type calcium channels antagonist, a K+ channel antagonist and/or a Na+ channel antagonist. 55. The method of claim 35, wherein the second active pharmaceutical ingredient is a KCNQ channel modulator. 56. The method of claim 35, wherein said composition further comprises one or more further active pharmaceutical ingredients. 57. The method of claim 56, wherein said one or more further active pharmaceutical ingredients are to be administered separately, sequentially or simultaneously from said pharmaceutical composition. 58. The method of claim 56, wherein said further active pharmaceutical ingredient is selected form the group consisting of: agents increasing the dopamine concentration in the synaptic cleft; agents which are used for treatment of Parkinson's disease; dopamine; dopamine prodrugs such as L-DOPA or levodopa; dopamine receptor agonists such as bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride; decarboxylase inhibitors such as carbidopa or benserazide; COMT inhibitors such as tolcapone, entacapone and nitecapone; MAO-B inhibitors such as selegiline and rasagiline; serotonin receptor modulators; kappa opioid receptors agonists such as TRK-820; GABA modulators; and modulators of neuronal potassium channels such as flupirtine and retigabine; or pharmaceutically acceptable derivatives thereof. 59. The method of claim 56, wherein said composition comprises the 6-hydroxybuspirone (6-OH-Busp) and optionally a second active pharmaceutical ingredient and further comprises a dopamine prodrug such as L-DOPA or levodopa. | The present invention is directed to a composition comprising a buspirone metabolite, alone or in combination with a second active ingredient, for use in the treatment of movement disorders.1-30. (canceled) 31. A method for treating dyskinesia or reducing abnormal involuntary movements in movement disorders, comprising:
administering to a subject in need thereof a pharmaceutical composition comprising 6-hydroxybuspirone (6-OH-Busp) or a pharmaceutically acceptable derivative thereof. 32. The method of claim 31, wherein said 6-OH-Busp is selected from the group consisting of the racemate of 6-OH-Busp, the S-form of 6-OH-Busp and the R-form of 6-OH-Busp. 33. The method of claim 31, wherein said 6-OH-Busp is the racemate of 6-OH-Busp. 34. The method of claim 31, wherein said movement disorder is dyskinesia. 35. The method of claim 31, wherein said dyskinesia is tardive dyskinesia. 36. The method of claim 31, wherein said dyskinesia is L-DOPA induced dyskinesia (LID). 37. The method of claim 31, wherein the movement disorder is selected from the group of consisting of: Parkinson's disease; bradykinesia, akinesia and dyskinesia; L-DOPA induced dyskinesia (LID); tardive dyskinesia and akathisia. 38. The method of claim 31, wherein the movement disorder is selected from the group of consisting of:
a. a movement disorder is selected from the group of consisting of: ataxia, dystonia, essential tremor, Huntington's disease, myoclonus, Rett syndrome, Tourette syndrome, Wilson's disease, chorea, Machado-Joseph disease, restless leg syndrome, spasmodic torticollis, and geniospasm or movement disorders associated therewith; b. a movement disorder caused by or associated with drug therapy including neuroleptic drugs, antipsychotics, antidepressants and antiemetic drugs; c. a movement disorder caused by or associated with withdrawal of drugs including opioids, barbiturates, cocaine, benzodiazepines, 5 alcohol and amphetamine; or d. a movement disorder caused by idiopathic disease, genetic dysfunctions, or infection or other conditions which lead to dysfunction of the basal ganglia and/or lead to altered synaptic dopamine levels. 39. The method of claim 31, wherein said composition is to be administered to a subject suffering from a movement disorder or an individual being in risk of suffering from a movement disorder. 40. The method of claim 31, wherein said composition is to be administered to a subject suffering from dyskinesia or an individual being in risk of suffering from dyskinesia. 41. The method of claim 31, wherein said subject is, or is to be, treated with a dopamine prodrug such as L-DOPA. 42. The method of claim 31, wherein said composition is a pharmaceutically acceptable composition. 43. The method of claim 31, wherein said composition further comprises a second active pharmaceutical ingredient. 44. The method of claim 35, wherein said second active pharmaceutical ingredient is to be administered separately, sequentially or simultaneously from said pharmaceutical composition. 45. The method of claim 35, wherein the second active pharmaceutical ingredient is an agonist of two or more of the 5-HT1B, 5-HT1D and 5-HT1F receptors. 46. The method of claim 37, wherein the agonist of two or more of the 5-HT1B, 5-HT1D and 5-HT1F receptors is a triptan. 47. The method of claim 37, wherein the agonist of two or more of the 5-HT1B, 5-HT1D and 5-HT1F receptors is selected from the group consisting of zolmitriptan, rizatriptan, sumatriptan, naratriptan, almotriptan, frovatriptan, avitriptan, alniditan and eletriptan, or pharmaceutically acceptable derivatives thereof. 48. The method of claim 35, wherein the second active pharmaceutical ingredient is selected from the group consisting of a selective 5-HT1B receptor agonist, a selective 5-HT1D receptor agonist, a selective 5-HT1E receptor agonist and a selective 5-HT1F receptor agonist. 49. The method of claim 35, wherein the second active pharmaceutical ingredient is a modulator of glutamate neurotransmission. 50. The method of claim 35, wherein the second active pharmaceutical ingredient is a glutamate receptor antagonist. 51. The method of claim 35, wherein the second active pharmaceutical ingredient is selected from the group consisting of an NMDA receptor antagonist, an AMPA receptor antagonist, a kainite receptor antagonist, a AMPAR/kainite receptor antagonist, a mGluR Group 1 antagonist, a mGluR Group 2 agonist and a mGluR Group 3 agonist. 52. The method of claim 35, wherein the second active pharmaceutical ingredient is an inhibitor of glutamate release. 53. The method of claim 35, wherein the second active pharmaceutical ingredient is an ion-channel antagonist. 54. The method of claim 35, wherein the second active pharmaceutical ingredient is selected from the group consisting of a calcium channel antagonist, a T-Type calcium channel antagonist, an L-Type calcium channels antagonist, a K+ channel antagonist and/or a Na+ channel antagonist. 55. The method of claim 35, wherein the second active pharmaceutical ingredient is a KCNQ channel modulator. 56. The method of claim 35, wherein said composition further comprises one or more further active pharmaceutical ingredients. 57. The method of claim 56, wherein said one or more further active pharmaceutical ingredients are to be administered separately, sequentially or simultaneously from said pharmaceutical composition. 58. The method of claim 56, wherein said further active pharmaceutical ingredient is selected form the group consisting of: agents increasing the dopamine concentration in the synaptic cleft; agents which are used for treatment of Parkinson's disease; dopamine; dopamine prodrugs such as L-DOPA or levodopa; dopamine receptor agonists such as bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride; decarboxylase inhibitors such as carbidopa or benserazide; COMT inhibitors such as tolcapone, entacapone and nitecapone; MAO-B inhibitors such as selegiline and rasagiline; serotonin receptor modulators; kappa opioid receptors agonists such as TRK-820; GABA modulators; and modulators of neuronal potassium channels such as flupirtine and retigabine; or pharmaceutically acceptable derivatives thereof. 59. The method of claim 56, wherein said composition comprises the 6-hydroxybuspirone (6-OH-Busp) and optionally a second active pharmaceutical ingredient and further comprises a dopamine prodrug such as L-DOPA or levodopa. | 1,600 |
1,414 | 15,094,542 | 1,619 | Pressurized compositions propelled by a pressurizing component (preferably a propellant such as compressed gas) and further including at least one active ingredient, at least one high molecular weight nonionic surfactant, and water which is a major component of the composition and is at least substantially ion-free and/or salt-free (preferably ion-free and salt-free), wherein the composition is stored in and dispensed from a plastic pressurized container. The plastic is preferably PET or PEN. The composition has a pH of about 4 to about 8.5. The composition can include as active ingredient(s), one or more of a fragrance component, an odor eliminating compound, an insecticide, an antimicrobial, and a disinfectant. | 1. A pressurized article comprising
(a) a pressurized container for storing and dispensing a composition, wherein said container includes a spray nozzle and a plastic body for containing said composition; and (b) said composition for storing in and dispensing from said container comprising
(i) at least one pressurizing component;
(ii) at least one active ingredient;
(iii) at least one high molecular weight nonionic surfactant having greater than 8 carbon atoms;
(iv) water as a solvent carrier in an amount to serve as a major component of said composition,
wherein said water is at least substantially ion-free and at least substantially salt-free; wherein said composition has a pH of about 4 to about 8.5, and is present in said container under an initial pressure of about 80 to about 150 psig at 50° C. (122° F.). 2. The pressurized article of claim 1, wherein said plastic of said body of said container is selected from polyethylene terephthalate (PET), polyethylene naphthalate (PEN), polyethylene furanoate (PEF), polycarbonate (PC), polyolefins, or a blend thereof, and said plastic is structured to withhold pressure of the composition. 3. The pressurized article of claim 1, wherein said at least one high molecular weight nonionic surfactant has from 30-220 carbon atoms. 4. The pressurized article of claim 1, wherein said at least one pressurizing component is a non-flammable propellant, or a non-compressed pressurizing element. 5. The pressurized article of claim 1, wherein said at least one pressurizing component is a compressed gas propellant. 6. The pressurized article of claim 5, wherein said compressed gas propellant is one or more of nitrogen, air, carbon dioxide, nitrous oxide, argon, neon, xenon, an inert gas, and blends thereof. 7. The pressurized article of claim 1, wherein said at least one active ingredient is one or more of a fragrance component, an odor eliminating compound, an insecticide, an antimicrobial, and a disinfectant. 8. The pressurized article of claim 1, wherein said spray nozzle is configured to dispense said composition at an initial spray rate in a range of from greater than about 1.5 grams/second (g/s) to about 3.0 g/s, and has an initial average particle size in a range of up to about 100 microns. 9. The pressurized article of claim 8, wherein said initial spray rate is in a range of from about 1.6 to about 2.5 g/s, and said initial average particle size is in a range of about 60 to about 90 microns. 10. The pressurized article of claim 1, wherein said at least one pressurizing component is present in an amount of about 0.25 to about 2 wt. %; said at least one active ingredient is present in an amount of about 0.1 to about 2.5 wt. %; said at least one high molecular weight nonionic surfactant is present in an amount of about 0.1 to about 2 wt. %; and said water is present in an amount of about 80 to about 99 wt. %; wherein the total composition is based on 100 wt. %. 11. A pressurized article for fragrance dispensing and/or odor treating comprising
(1) a composition comprising
(a) at least one compressed gas propellant;
(b) at least one active ingredient including at least one fragrance component and, optionally, at least one additional active ingredient;
(c) at least one high molecular weight nonionic surfactant having about 30 to about 220 carbon atoms; and
(d) water as a solvent carrier and in an amount to serve as a major component of said composition wherein said water is at least substantially ion-free and at least substantially salt-free;
wherein said composition has a pH of about 4 to about 8.5, and has a VOC content of zero to 4%; (2) a pressurized dispensing container adapted to contain and dispense said composition wherein said composition has
(i) an initial pressure in said container of about 80 to about 150 psig at a temperature of 50° C. (122° F.); and
(ii) said aerosol dispensing container includes a body for holding said composition and said body is made of plastic. 12. The article of claim 11, wherein said plastic is PET, PEN, PEF, PC, polyolefins, or a blend thereof, and said plastic is structured to withhold pressure of the composition. 13. The article of claim 11, wherein said at least one compressed gas propellant is one or more of air, nitrogen, carbon dioxide, nitrous oxide, argon, neon, xenon, an inert gas, and blends thereof, and said plastic is structure to withhold pressure of the composition. 14. The article of claim 11, wherein said at least one active ingredient is one or more of an odor eliminating compound, an insecticide, an antimicrobial, and a disinfectant. 15. The article of claim 11, further comprising a spray nozzle which dispenses said composition at an initial spray rate of greater than about 1.5 g/s to about 3.0 g/s and in an initial average particle size of up to about 100 microns. 16. The article of claim 15, wherein said initial spray rate is from about 1.6 g/s to about 2.5 g/s. 17. The article of claim 15, wherein said initial average particle size is from about 60 to less than 90 microns. 18. The article of claim 11, wherein said at least one compressed gas propellant is present in an amount of about 0.25 to about 2 wt. %; said at least one active ingredient is present in an amount of about 0.1 to about 2.5 wt. %; said at least one high molecular weight nonionic surfactant is present in an amount of about 0.1 to about 2 wt. %; and said water is present in an amount of about 80 to about 99 wt. %; wherein the total composition is based on 100 wt. %. 19. A pressurized plastic article comprising
(a) a pressurized container for storing and dispensing a composition, wherein said container includes a spray nozzle and a body composed of polymer resin for containing said composition, said polymer resin being structured to withhold working pressure of the composition; and (b) said composition for storing in and dispensing from said container comprising
(i) at least one compressed gas propellant;
(ii) at least one active ingredient;
(iii) at least one high molecular weight nonionic surfactant having greater than 8 carbon atoms;
(iv) water as a solvent carrier in an amount to serve as a major component of said composition, wherein said water is at least substantially ion-free and at least substantially salt-free;
wherein said composition has a pH of about 4 to about 8.5, is present in said container under an initial pressure of about 80 to about 150 psig at 50° C. (122° F.), and wherein said polymer resin and said water has a Hansen Solubility Parameters with a distance value (Ra) of about 10 to about 35. 20. The pressurized plastic article of claim 19, wherein said at least one high molecular weight nonionic surfactant has from 30-220 carbon atoms. 21. The pressurized plastic article of claim 19, wherein said at least one compressed gas propellant is one or more of air, nitrogen, carbon dioxide, nitrous oxide, argon, neon, xenon, an inert gas and blends thereof. 22. The pressurized plastic article of claim 19, wherein said at least one active ingredient is one or more of a fragrance component, an odor eliminating compound, an insecticide, an antimicrobial, and a disinfectant. 23. The pressurized plastic article of claim 19, wherein said composition is dispensed from said plastic body by said spray nozzle at an initial spray rate upon dispensing of greater than about 1.5 to about 3.0 grams/second (g/s), and with an initial average particle size in a range of up to about 100 microns. 24. The pressurized plastic article of claim 23, wherein the initial spray rate is about 1.6 g/s to about 2.5 g/s and wherein the initial average particle size is about 60 to about 90 microns. 25. The pressurized plastic article of claim 19, wherein the plastic of the container is selected from PET, PEN, PEF, PC, polyolefins, and blends thereof. 26. A method of dispensing a fragranced composition comprising dispensing said fragranced composition from a pressurized dispensing container including a spray nozzle and a body made of plastic; wherein said composition is dispensed under an initial pressure in said container of about 80 to about 150 psig at 50° C. (122° F.); wherein said composition comprises (a) at least one compressed gas propellant, (b) at least one active ingredient, (c) at least one high molecular weight nonionic surfactant having from about 30 to about 220 carbon atoms; and (d) water as a solvent carrier and in an amount to serve as a major component of said composition, wherein said water is at least substantially ion-free and at least substantially salt-free; and wherein said composition has a pH of about 4 to about 8.5. 27. The method of claim 26, wherein said plastic is PET, PEN, PEF, PC, polyolefins, or a blend thereof, and said plastic is structured to withhold working pressure of the composition. 28. The method of claim 26, wherein said at least one active ingredient is one or more of a fragrance component, an odor reducing compound, an insecticide, an antimicrobial, and a disinfectant. 29. The method of claim 26, wherein said composition is dispensed from said container through said spray nozzle at an initial spray rate upon dispensing of greater than about 1.5 grams/second (g/s) to about 3.0 g/s, and with an initial average particle size in a range of up to about 100 microns. 30. The method of claim 26, wherein said at least one compressed gas propellant is present in an amount of about 0.25 to about 2 wt. %; said at least one active ingredient is present in an amount of about 0.1 to about 2.5 wt. %;
said at least one high molecular weight nonionic surfactant is present in an amount of about 0.1 to about 2 wt. %; and said water is present in an amount of about 80 to about 99 wt. %; wherein the total composition is based on 100 wt. %. | Pressurized compositions propelled by a pressurizing component (preferably a propellant such as compressed gas) and further including at least one active ingredient, at least one high molecular weight nonionic surfactant, and water which is a major component of the composition and is at least substantially ion-free and/or salt-free (preferably ion-free and salt-free), wherein the composition is stored in and dispensed from a plastic pressurized container. The plastic is preferably PET or PEN. The composition has a pH of about 4 to about 8.5. The composition can include as active ingredient(s), one or more of a fragrance component, an odor eliminating compound, an insecticide, an antimicrobial, and a disinfectant.1. A pressurized article comprising
(a) a pressurized container for storing and dispensing a composition, wherein said container includes a spray nozzle and a plastic body for containing said composition; and (b) said composition for storing in and dispensing from said container comprising
(i) at least one pressurizing component;
(ii) at least one active ingredient;
(iii) at least one high molecular weight nonionic surfactant having greater than 8 carbon atoms;
(iv) water as a solvent carrier in an amount to serve as a major component of said composition,
wherein said water is at least substantially ion-free and at least substantially salt-free; wherein said composition has a pH of about 4 to about 8.5, and is present in said container under an initial pressure of about 80 to about 150 psig at 50° C. (122° F.). 2. The pressurized article of claim 1, wherein said plastic of said body of said container is selected from polyethylene terephthalate (PET), polyethylene naphthalate (PEN), polyethylene furanoate (PEF), polycarbonate (PC), polyolefins, or a blend thereof, and said plastic is structured to withhold pressure of the composition. 3. The pressurized article of claim 1, wherein said at least one high molecular weight nonionic surfactant has from 30-220 carbon atoms. 4. The pressurized article of claim 1, wherein said at least one pressurizing component is a non-flammable propellant, or a non-compressed pressurizing element. 5. The pressurized article of claim 1, wherein said at least one pressurizing component is a compressed gas propellant. 6. The pressurized article of claim 5, wherein said compressed gas propellant is one or more of nitrogen, air, carbon dioxide, nitrous oxide, argon, neon, xenon, an inert gas, and blends thereof. 7. The pressurized article of claim 1, wherein said at least one active ingredient is one or more of a fragrance component, an odor eliminating compound, an insecticide, an antimicrobial, and a disinfectant. 8. The pressurized article of claim 1, wherein said spray nozzle is configured to dispense said composition at an initial spray rate in a range of from greater than about 1.5 grams/second (g/s) to about 3.0 g/s, and has an initial average particle size in a range of up to about 100 microns. 9. The pressurized article of claim 8, wherein said initial spray rate is in a range of from about 1.6 to about 2.5 g/s, and said initial average particle size is in a range of about 60 to about 90 microns. 10. The pressurized article of claim 1, wherein said at least one pressurizing component is present in an amount of about 0.25 to about 2 wt. %; said at least one active ingredient is present in an amount of about 0.1 to about 2.5 wt. %; said at least one high molecular weight nonionic surfactant is present in an amount of about 0.1 to about 2 wt. %; and said water is present in an amount of about 80 to about 99 wt. %; wherein the total composition is based on 100 wt. %. 11. A pressurized article for fragrance dispensing and/or odor treating comprising
(1) a composition comprising
(a) at least one compressed gas propellant;
(b) at least one active ingredient including at least one fragrance component and, optionally, at least one additional active ingredient;
(c) at least one high molecular weight nonionic surfactant having about 30 to about 220 carbon atoms; and
(d) water as a solvent carrier and in an amount to serve as a major component of said composition wherein said water is at least substantially ion-free and at least substantially salt-free;
wherein said composition has a pH of about 4 to about 8.5, and has a VOC content of zero to 4%; (2) a pressurized dispensing container adapted to contain and dispense said composition wherein said composition has
(i) an initial pressure in said container of about 80 to about 150 psig at a temperature of 50° C. (122° F.); and
(ii) said aerosol dispensing container includes a body for holding said composition and said body is made of plastic. 12. The article of claim 11, wherein said plastic is PET, PEN, PEF, PC, polyolefins, or a blend thereof, and said plastic is structured to withhold pressure of the composition. 13. The article of claim 11, wherein said at least one compressed gas propellant is one or more of air, nitrogen, carbon dioxide, nitrous oxide, argon, neon, xenon, an inert gas, and blends thereof, and said plastic is structure to withhold pressure of the composition. 14. The article of claim 11, wherein said at least one active ingredient is one or more of an odor eliminating compound, an insecticide, an antimicrobial, and a disinfectant. 15. The article of claim 11, further comprising a spray nozzle which dispenses said composition at an initial spray rate of greater than about 1.5 g/s to about 3.0 g/s and in an initial average particle size of up to about 100 microns. 16. The article of claim 15, wherein said initial spray rate is from about 1.6 g/s to about 2.5 g/s. 17. The article of claim 15, wherein said initial average particle size is from about 60 to less than 90 microns. 18. The article of claim 11, wherein said at least one compressed gas propellant is present in an amount of about 0.25 to about 2 wt. %; said at least one active ingredient is present in an amount of about 0.1 to about 2.5 wt. %; said at least one high molecular weight nonionic surfactant is present in an amount of about 0.1 to about 2 wt. %; and said water is present in an amount of about 80 to about 99 wt. %; wherein the total composition is based on 100 wt. %. 19. A pressurized plastic article comprising
(a) a pressurized container for storing and dispensing a composition, wherein said container includes a spray nozzle and a body composed of polymer resin for containing said composition, said polymer resin being structured to withhold working pressure of the composition; and (b) said composition for storing in and dispensing from said container comprising
(i) at least one compressed gas propellant;
(ii) at least one active ingredient;
(iii) at least one high molecular weight nonionic surfactant having greater than 8 carbon atoms;
(iv) water as a solvent carrier in an amount to serve as a major component of said composition, wherein said water is at least substantially ion-free and at least substantially salt-free;
wherein said composition has a pH of about 4 to about 8.5, is present in said container under an initial pressure of about 80 to about 150 psig at 50° C. (122° F.), and wherein said polymer resin and said water has a Hansen Solubility Parameters with a distance value (Ra) of about 10 to about 35. 20. The pressurized plastic article of claim 19, wherein said at least one high molecular weight nonionic surfactant has from 30-220 carbon atoms. 21. The pressurized plastic article of claim 19, wherein said at least one compressed gas propellant is one or more of air, nitrogen, carbon dioxide, nitrous oxide, argon, neon, xenon, an inert gas and blends thereof. 22. The pressurized plastic article of claim 19, wherein said at least one active ingredient is one or more of a fragrance component, an odor eliminating compound, an insecticide, an antimicrobial, and a disinfectant. 23. The pressurized plastic article of claim 19, wherein said composition is dispensed from said plastic body by said spray nozzle at an initial spray rate upon dispensing of greater than about 1.5 to about 3.0 grams/second (g/s), and with an initial average particle size in a range of up to about 100 microns. 24. The pressurized plastic article of claim 23, wherein the initial spray rate is about 1.6 g/s to about 2.5 g/s and wherein the initial average particle size is about 60 to about 90 microns. 25. The pressurized plastic article of claim 19, wherein the plastic of the container is selected from PET, PEN, PEF, PC, polyolefins, and blends thereof. 26. A method of dispensing a fragranced composition comprising dispensing said fragranced composition from a pressurized dispensing container including a spray nozzle and a body made of plastic; wherein said composition is dispensed under an initial pressure in said container of about 80 to about 150 psig at 50° C. (122° F.); wherein said composition comprises (a) at least one compressed gas propellant, (b) at least one active ingredient, (c) at least one high molecular weight nonionic surfactant having from about 30 to about 220 carbon atoms; and (d) water as a solvent carrier and in an amount to serve as a major component of said composition, wherein said water is at least substantially ion-free and at least substantially salt-free; and wherein said composition has a pH of about 4 to about 8.5. 27. The method of claim 26, wherein said plastic is PET, PEN, PEF, PC, polyolefins, or a blend thereof, and said plastic is structured to withhold working pressure of the composition. 28. The method of claim 26, wherein said at least one active ingredient is one or more of a fragrance component, an odor reducing compound, an insecticide, an antimicrobial, and a disinfectant. 29. The method of claim 26, wherein said composition is dispensed from said container through said spray nozzle at an initial spray rate upon dispensing of greater than about 1.5 grams/second (g/s) to about 3.0 g/s, and with an initial average particle size in a range of up to about 100 microns. 30. The method of claim 26, wherein said at least one compressed gas propellant is present in an amount of about 0.25 to about 2 wt. %; said at least one active ingredient is present in an amount of about 0.1 to about 2.5 wt. %;
said at least one high molecular weight nonionic surfactant is present in an amount of about 0.1 to about 2 wt. %; and said water is present in an amount of about 80 to about 99 wt. %; wherein the total composition is based on 100 wt. %. | 1,600 |
1,415 | 14,761,824 | 1,655 | We found that Andrographolide binds to GSK-3β:
In so doing, andrographolide prevents changes in neuropathology in an Alzheimer's model, reducing Amyloid-β peptide levels, changing the ontogeny of hippocampus and cortex amyloid plaques, and reducing tau phosphorylation around Amyloid-β. Andrographolide recovers spatial memory functions in an Alzheimer's model. Andrographolide and its derivatives may be used to treat Alzheimer's disease. | 1. Administering to human diagnosed with dementia, a therapeutically effective amount of a compound of Formula (I):
wherein
R1 is selected from the group consisting of hydrogen, alkyl or hydroxyl,
R2 is selected from the group consisting of hydroxyalkyl or alkyl-O-L1, wherein L1 is a carbohydrate moiety,
R3 is selected from the group consisting of hydrogen or hydroxyl,
X is selected from the group consisting of C(═CH2), CH(OH), or a spirooxirane-2 moiety,
Z is selected from the group consisting of CH2, CH(OH) or C(═O), and
R4 is selected from the group consisting of an optionally substituted L2-alkyl or L2-alkenyl, wherein L2 is an optionally substituted 3-furanyl or 3-fur-3-enyl moiety,
or a pharmaceutically acceptable salt, ester, ether or prodrug thereof, 2. A method comprising: administering to a human diagnosed with dementia a therapeutically effective amount of a compound of the formula:
wherein X1-X3 and X5-X7 are each individually selected from the group consisting of: H, OH, CH and COHn where n=0-3, and where X4 is selected from the group consisting of: H, OH, and optionally-substituted hydrocarbon. 3. The method of claim 2, where said compound comprises a therapeutically effective amount of a compound selected from the group consisting of: andrographolide, 14-deoxyandrographolide, neoandrographolide and a combination thereof. 4. The method of claim 3, where said compound comprises a therapeutically effective amount of andrographolide. 5. The method of claim 2, where said dementia is selected from the group consisting of: non-progressive dementia, slowly progressive dementia and rapidly progressive dementia. 6. The method of claim 5, wherein said dementia is slowly progressive dementia. 7. The method of claim 6, wherein said slowly progressive dementia is suspected of being caused by a condition selected from the group consisting of: Alzheimers-type dementia, senile dementia of Lewy type and vascular dementia. 8. The method of claim 2, where said dementia is associated with a chronic inflammatory condition of the brain. 9. The method of claim 8, wherein said chronic inflammatory condition of the brain is selected from the group consisting of: Behçet's Disease, multiple sclerosis, sarcoidosis, Sjögren's syndrome and systemic lupus erythematosus. 10. The method of claim 2, wherein said therapeutically effective amount comprises a daily oral dosage of from about 1 to about 4 milligrams of said compound per kilogram of body weight for said human. 11. The method of claim 6, wherein said therapeutically effective amount comprises a daily oral dosage of from about 1 to about 4 milligrams of said compound per kilogram of body weight for said human. 12. A method comprising:
a) Administering to a human a test selected from the group consisting of: the Mini Mental Status Exam (MMSE), the Alzheimer Disease Assessment Scale (ADAS), the Boston Naming Test (BNT) and the Token Test (TT); and then b) Administering to said human, for at least about 30 days, a daily dosage effective to preserve or improve cognitive function, of a compound of claim 1. 13. The method of claim 12, where said compound comprises a therapeutically effective amount of a compound selected from the group consisting of: andrographolide, 14-deoxyandrographolide, neoandrographolide and a combination thereof. 14. The method of claim 13, where said compound comprises a therapeutically effective amount of andrographolide. 15. The method of claim 12, wherein said daily dosage comprises a daily dosage of from about 1 to about 4 milligrams of said compound per kilogram of body weight for said human. 16. The method of claim 3, wherein said compound(s) is provided as an extract of Andrographis paniculata, standardized to contain not less than about 50% (w/w) of said compound(s). 17. The method of claim 13, wherein said compound(s) is provided as an extract of Andrographis paniculata, standardized to contain not less than about 50% (w/w) of said compound(s). | We found that Andrographolide binds to GSK-3β:
In so doing, andrographolide prevents changes in neuropathology in an Alzheimer's model, reducing Amyloid-β peptide levels, changing the ontogeny of hippocampus and cortex amyloid plaques, and reducing tau phosphorylation around Amyloid-β. Andrographolide recovers spatial memory functions in an Alzheimer's model. Andrographolide and its derivatives may be used to treat Alzheimer's disease.1. Administering to human diagnosed with dementia, a therapeutically effective amount of a compound of Formula (I):
wherein
R1 is selected from the group consisting of hydrogen, alkyl or hydroxyl,
R2 is selected from the group consisting of hydroxyalkyl or alkyl-O-L1, wherein L1 is a carbohydrate moiety,
R3 is selected from the group consisting of hydrogen or hydroxyl,
X is selected from the group consisting of C(═CH2), CH(OH), or a spirooxirane-2 moiety,
Z is selected from the group consisting of CH2, CH(OH) or C(═O), and
R4 is selected from the group consisting of an optionally substituted L2-alkyl or L2-alkenyl, wherein L2 is an optionally substituted 3-furanyl or 3-fur-3-enyl moiety,
or a pharmaceutically acceptable salt, ester, ether or prodrug thereof, 2. A method comprising: administering to a human diagnosed with dementia a therapeutically effective amount of a compound of the formula:
wherein X1-X3 and X5-X7 are each individually selected from the group consisting of: H, OH, CH and COHn where n=0-3, and where X4 is selected from the group consisting of: H, OH, and optionally-substituted hydrocarbon. 3. The method of claim 2, where said compound comprises a therapeutically effective amount of a compound selected from the group consisting of: andrographolide, 14-deoxyandrographolide, neoandrographolide and a combination thereof. 4. The method of claim 3, where said compound comprises a therapeutically effective amount of andrographolide. 5. The method of claim 2, where said dementia is selected from the group consisting of: non-progressive dementia, slowly progressive dementia and rapidly progressive dementia. 6. The method of claim 5, wherein said dementia is slowly progressive dementia. 7. The method of claim 6, wherein said slowly progressive dementia is suspected of being caused by a condition selected from the group consisting of: Alzheimers-type dementia, senile dementia of Lewy type and vascular dementia. 8. The method of claim 2, where said dementia is associated with a chronic inflammatory condition of the brain. 9. The method of claim 8, wherein said chronic inflammatory condition of the brain is selected from the group consisting of: Behçet's Disease, multiple sclerosis, sarcoidosis, Sjögren's syndrome and systemic lupus erythematosus. 10. The method of claim 2, wherein said therapeutically effective amount comprises a daily oral dosage of from about 1 to about 4 milligrams of said compound per kilogram of body weight for said human. 11. The method of claim 6, wherein said therapeutically effective amount comprises a daily oral dosage of from about 1 to about 4 milligrams of said compound per kilogram of body weight for said human. 12. A method comprising:
a) Administering to a human a test selected from the group consisting of: the Mini Mental Status Exam (MMSE), the Alzheimer Disease Assessment Scale (ADAS), the Boston Naming Test (BNT) and the Token Test (TT); and then b) Administering to said human, for at least about 30 days, a daily dosage effective to preserve or improve cognitive function, of a compound of claim 1. 13. The method of claim 12, where said compound comprises a therapeutically effective amount of a compound selected from the group consisting of: andrographolide, 14-deoxyandrographolide, neoandrographolide and a combination thereof. 14. The method of claim 13, where said compound comprises a therapeutically effective amount of andrographolide. 15. The method of claim 12, wherein said daily dosage comprises a daily dosage of from about 1 to about 4 milligrams of said compound per kilogram of body weight for said human. 16. The method of claim 3, wherein said compound(s) is provided as an extract of Andrographis paniculata, standardized to contain not less than about 50% (w/w) of said compound(s). 17. The method of claim 13, wherein said compound(s) is provided as an extract of Andrographis paniculata, standardized to contain not less than about 50% (w/w) of said compound(s). | 1,600 |
1,416 | 13,072,084 | 1,632 | The invention provides methods for treating pathological conditions associated with an undesirable inflammatory component. The invention is generally directed to reducing inflammation by administering cells that modulate microglia activation. The invention is also directed to drug discovery methods to screen for agents that modulate the ability of the cells to modulate microglia activation. The invention is also directed to cell banks that can be used to provide cells for administration to a subject, the banks comprising cells having desired levels of potency to modulate microglia activation. | 1. A method for treating inflammation in a subject having a condition, the method comprising selecting cells that have a desired potency for modulating microglia activation, assaying the selected cells for the desired potency, and administering the cells having the desired potency to the subject, in a therapeutically effective amount and for a time sufficient to achieve a therapeutic result, the cells being non-embryonic stem, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1 and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers. 2. A method for treating inflammation in a subject having a condition, the method comprising administering cells having a desired potency for modulating microglia activation to the subject, in a therapeutically effective amount and for a time sufficient to achieve a therapeutic result, the cells being non-embryonic stem, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1 and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers, wherein, prior to administration, the cells were validated as having the desired potency. 3. A method for modulating microglia activation in a subject having a condition, the method comprising selecting cells that have a desired potency for modulating microglia activation, assaying the cells for the desired potency, and administering the cells having the desired potency to the subject, in a therapeutically effective amount and for a time sufficient to achieve a therapeutic result, the cells being non-embryonic stem, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1 and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers. 4. A method for modulating microglia activation in a subject having a condition, the method comprising administering cells having a desired potency for modulating microglia activation to the subject, in a therapeutically effective amount and for a time sufficient to achieve a therapeutic result, the cells being non-embryonic stem, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1 and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers, wherein, prior to administration, the cells were validated as having the desired potency. 5. The method of any of claims 1-4, wherein the administered cells are allogeneic. 6. The method of any of claims 1-5, wherein the administered cells increase neuroprotective and/or decrease neurotoxic activation. 7. The method of any of claims 1-6 wherein potency is assessed by an assay selected from the group consisting of (1) assay for microglial activation factor expressed in or secreted by the cells, (2) assay for microglial activation, (3) assay for antigen presentation of microglia, and (4) assay for morphological changes of microglia during activation. 8. A method for determining a therapeutically effective amount of cells administered to a subject having a condition, the cells being non-embryonic stem, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1, and/or can differentiate into cell types of at least two of endodermal, ectodermal, or mesodermal germ layers, the method comprising assessing, following administration of the cells to the subject, an in vivo biomarker of activated microglia in a subject in vivo, wherein the cells express and secrete one or more factors that modulate microglia activation. 9. The method of any of claims 1-8, wherein the condition is selected from the group consisting of acute and chronic conditions in central nervous system injury, e.g., stroke; ischemic stroke, multiple sclerosis, Alzheimer's Disease, ALS, Parkinson's Disease, hypoxic-ischemia, neonatal hypoxic ischemia, and traumatic brain or spinal cord injury. 10. The method of any of claims 1-9, wherein the subject is human. 11. A method for constructing a cell bank, the method comprising selecting cells that have a desired potency for modulating microglia activation and expanding and storing said cells for future administration to a subject, the cells being non-embryonic stem, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1 and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers. 12. A method for constructing a cell bank, the method comprising expanding and storing cells for future administration to a subject, the cells being non-embryonic stem, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1 and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers, the cells having been validated for having a desired potency for modulating microglia activation. 13. A method for drug discovery, the method comprising selecting cells that have a desired potency for modulating microglia activation and exposing said cells to an agent to assess the effect of the agent on the ability of the cells to modulate microglia activation, the cells being non-embryonic stem, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1 and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers. | The invention provides methods for treating pathological conditions associated with an undesirable inflammatory component. The invention is generally directed to reducing inflammation by administering cells that modulate microglia activation. The invention is also directed to drug discovery methods to screen for agents that modulate the ability of the cells to modulate microglia activation. The invention is also directed to cell banks that can be used to provide cells for administration to a subject, the banks comprising cells having desired levels of potency to modulate microglia activation.1. A method for treating inflammation in a subject having a condition, the method comprising selecting cells that have a desired potency for modulating microglia activation, assaying the selected cells for the desired potency, and administering the cells having the desired potency to the subject, in a therapeutically effective amount and for a time sufficient to achieve a therapeutic result, the cells being non-embryonic stem, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1 and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers. 2. A method for treating inflammation in a subject having a condition, the method comprising administering cells having a desired potency for modulating microglia activation to the subject, in a therapeutically effective amount and for a time sufficient to achieve a therapeutic result, the cells being non-embryonic stem, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1 and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers, wherein, prior to administration, the cells were validated as having the desired potency. 3. A method for modulating microglia activation in a subject having a condition, the method comprising selecting cells that have a desired potency for modulating microglia activation, assaying the cells for the desired potency, and administering the cells having the desired potency to the subject, in a therapeutically effective amount and for a time sufficient to achieve a therapeutic result, the cells being non-embryonic stem, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1 and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers. 4. A method for modulating microglia activation in a subject having a condition, the method comprising administering cells having a desired potency for modulating microglia activation to the subject, in a therapeutically effective amount and for a time sufficient to achieve a therapeutic result, the cells being non-embryonic stem, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1 and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers, wherein, prior to administration, the cells were validated as having the desired potency. 5. The method of any of claims 1-4, wherein the administered cells are allogeneic. 6. The method of any of claims 1-5, wherein the administered cells increase neuroprotective and/or decrease neurotoxic activation. 7. The method of any of claims 1-6 wherein potency is assessed by an assay selected from the group consisting of (1) assay for microglial activation factor expressed in or secreted by the cells, (2) assay for microglial activation, (3) assay for antigen presentation of microglia, and (4) assay for morphological changes of microglia during activation. 8. A method for determining a therapeutically effective amount of cells administered to a subject having a condition, the cells being non-embryonic stem, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1, and/or can differentiate into cell types of at least two of endodermal, ectodermal, or mesodermal germ layers, the method comprising assessing, following administration of the cells to the subject, an in vivo biomarker of activated microglia in a subject in vivo, wherein the cells express and secrete one or more factors that modulate microglia activation. 9. The method of any of claims 1-8, wherein the condition is selected from the group consisting of acute and chronic conditions in central nervous system injury, e.g., stroke; ischemic stroke, multiple sclerosis, Alzheimer's Disease, ALS, Parkinson's Disease, hypoxic-ischemia, neonatal hypoxic ischemia, and traumatic brain or spinal cord injury. 10. The method of any of claims 1-9, wherein the subject is human. 11. A method for constructing a cell bank, the method comprising selecting cells that have a desired potency for modulating microglia activation and expanding and storing said cells for future administration to a subject, the cells being non-embryonic stem, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1 and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers. 12. A method for constructing a cell bank, the method comprising expanding and storing cells for future administration to a subject, the cells being non-embryonic stem, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1 and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers, the cells having been validated for having a desired potency for modulating microglia activation. 13. A method for drug discovery, the method comprising selecting cells that have a desired potency for modulating microglia activation and exposing said cells to an agent to assess the effect of the agent on the ability of the cells to modulate microglia activation, the cells being non-embryonic stem, non-germ cells that express one or more of oct4, telomerase, rex-1, or rox-1 and/or can differentiate into cell types of at least two of endodermal, ectodermal, and mesodermal germ layers. | 1,600 |
1,417 | 14,752,511 | 1,634 | Provided herein are methods for determining if a urine sample comprises synthetic urine, methods for matching a urine sample to a subject, and methods for amplifying DNA. Also provided are kits that include a set of at least 3 pairs of a pre-amplification forward and reverse primer, where each pair of pre-amplification forward and reverse primers is designed to amplify 250 to 300 nucleotides of genomic DNA that contains one of at least 3 SNPs, where the pre-amplification forward and reverse primers in each of the three or more pairs of pre-amplification primers contains (i) a sequence of about 17 to about 25 contiguous nucleotides that is complementary to a sequence in the genomic DNA and (i) a tag sequence of about 17 to about 25 contiguous nucleotides that is not complementary to a sequence in the genomic DNA. | 1. A method of determining if a urine sample comprises synthetic urine comprising:
(a) providing a urine sample from a subject; (b) enriching the urine sample for mammalian cells, if present; (c) isolating any genomic DNA from the enriched sample of step (b) to form an isolated genomic DNA test sample; (d) adding to the isolated genomic DNA test sample of step (c) a control DNA to form a control sample or adding the control DNA to the enriched sample of step (b) and then isolating DNA to form a control sample; (e) performing an assay to determine the presence of genomic DNA in the isolated genomic DNA sample of step (c) or the control sample of step (d); (f) performing an assay to determine the presence of the control DNA in the control sample of step (d); and (g) identifying a urine sample having no detectable level of genomic DNA and having detectable control DNA as containing synthetic urine, or identifying a urine sample having a detectable level of genomic DNA and having detectable control DNA as not comprising a synthetic urine. 2. The method of claim 1, wherein:
the determination of the presence of genomic DNA comprises performing an assay to determine the presence of at least three single nucleotide polymorphisms in the isolated genomic DNA sample of step (c) or the control sample of step (d), and a urine sample having no detectable level of the at least three SNPs and having detectable control DNA is identified in step (g) as containing synthetic urine, or a urine sample having a detectable level of the at least three SNPs and having detectable control DNA is identified in step (g) as not comprising synthetic urine. 3. The method of claim 2, wherein the urine sample is identified in step (g) as not comprising synthetic urine. 4. (canceled) 5. The method of claim 3, further comprising:
(h) performing an assay to determine the genotype of at least 6 single nucleotide polymorphisms (SNPs) in the isolated genomic DNA test sample of step (c) or the control sample of step (d); (i) comparing the genotype of the at least 6 SNPs in the isolated genomic DNA test sample of step (c) or the control sample of step (d) with the genotype of the at least 6 SNPs in a control cell sample from the subject; and (j) identifying a urine sample having a detectable level of the control DNA and having the same genotype of the at least 6 SNPs in the isolated genomic DNA test sample of step (c) or the control sample of step (d) as the genotype of the at least 6 SNPs in the control cell sample as originating from the subject; or identifying a urine sample having a detectable level of the control DNA and not having the same genotype of the at least 6 SNPs in the isolated genomic DNA test sample of (c) or the control sample of step (d) as the genotype of the at least 6 SNPs in the control cell sample as not originating from the subject. 6.-17. (canceled) 18. The method of claim 2, wherein the assay in step (e) comprises a pre-amplification step. 19. The method of claim 18, wherein the pre-amplification step includes: hybridization of three or more pairs of a pre-amplification forward and reverse primer, wherein each pair of pre-amplification forward and reverse primers is designed to amplify 250 to 300 nucleotides of genomic DNA that contains one of the at least 3 SNPs, wherein the pre-amplification forward and reverse primers in each of the three or more pairs of pre-amplification primers contain (i) a sequence of about 17 to about 25 contiguous nucleotides that is complementary to a sequence in the genomic DNA and (ii) a tag sequence of about 17 to about 25 contiguous nucleotides that is not complementary to a sequence in the genomic DNA; and amplification of the genomic DNA using the three or more pairs of pre-amplification forward and reverse primers to generate 250 to 300 nucleotide amplification product(s). 20. The method of claim 19, wherein the pre-amplification step further comprises amplification of the 250 to 300 nucleotide amplification product(s) using a primer that comprises a sequence of about 17 to about 25 contiguous nucleotides of the tag sequence. 21.-28. (canceled) 29. The method of claim 1, further comprising:
(h) performing an assay to identify the presence of one or more of statherin, alpha-amylase, and lysozyme in the urine sample; and (i) identifying a urine sample having a detectable level of genomic DNA, a detectable control DNA, and a detectable level of one or more of statherin, alpha-amylase, and lysozyme as being adulterated. 30.-35. (canceled) 36. The method of claim 1, further comprising:
(h) selecting a subject having a urine sample identified in step (g) as containing synthetic urine; and (i) obtaining an additional urine sample from the selected subject. 37. (canceled) 38. The method of claim 36, further comprising:
(j) performing an assay to determine the level of one or more drugs and/or the level of one or more drug metabolites in the additional urine sample. 39. The method of claim 38, further comprising:
(k) identifying a subject having an elevated level of one or more drugs and/or an elevated level of one or more drug metabolites in the additional urine sample as compared to a reference level of the one or more drugs and/or a reference level of the one or more drug metabolites, wherein the drugs are an illegal or controlled substance and/or the drug metabolites are metabolites of an illegal or controlled substance; and (l) admitting the subject into a drug dependency program, ceasing administration of the controlled substance to the subject, or reducing the dose and/or frequency of administration of the controlled substance to the subject. 40. (canceled) 41. The method of claim 1, further comprising:
(h) selecting a subject having a urine sample identified in step (g) as containing synthetic urine; (i) obtaining a sample comprising blood, serum, hair, or plasma from the subject; and (j) performing an assay to determine the level of one or more drugs and/or one or more drug metabolites in the sample from step (i). 42. The method of claim 41, further comprising:
(k) identifying a subject having an elevated level of one or more drugs and/or an elevated level of one or more drug metabolites in the sample from step (i) as compared to a reference level of the one or more drugs and/or a reference level of the one or more drug metabolites, wherein the drugs are an illegal or controlled substance and/or the drug metabolites are metabolites of an illegal or controlled substance; and (l) admitting the subject into a drug dependency program, ceasing administration of the controlled substance to the subject, or reducing the dose or frequency of administration of the controlled substance to the subject. 43.-46. (canceled) 47. A method of determining if a urine sample comprises synthetic urine and/or is diluted comprising:
(a) providing a urine sample from a subject; (b) detecting the absorbance at 280 nm of the urine sample; and (c) identifying a urine sample having an absorbance at 280 nm that is less than a reference 280 nm absorbance value as comprising synthetic urine and/or being diluted, or identifying a urine sample having an absorbance at 280 nm that is equal to or greater than the reference 280 nm absorbance value as not comprising synthetic urine and not being diluted. 48. (canceled) 49. The method of claim 47, further comprising:
(d) determining the absorbance at 240 nm of the urine sample; and (e) further identifying a urine sample having an absorbance at 280 nm that is less than a reference 280 nm absorbance value and an absorbance at 240 nm that is less than a reference 240 nm absorbance value as being diluted. 50.-104. (canceled) 105. The method of claim 47, further comprising:
(d) selecting a subject having a urine sample identified in step (c) as comprising synthetic urine and/or being diluted; (e) obtaining an additional sample comprising blood, serum, hair, or plasma from the subject; and (f) performing an assay to determine the level of one or more drugs and/or the level of one or more drug metabolites in the additional sample from step (e). 106.-112. (canceled) 113. A method of matching a urine sample to a subject comprising:
(a) providing a urine sample from a subject; (b) enriching the urine sample for mammalian cells, if present; (c) isolating any genomic DNA from the enriched sample of step (b) to form an isolated genomic DNA test sample; (d) adding to the isolated genomic DNA test sample of step (c) a control DNA to form a control sample or adding the control DNA to the enriched sample of step (b) and then isolating the DNA to form a control sample; (e) performing an assay to determine the genotype of at least 6 single nucleotide polymorphisms (SNPs) in the isolated genomic DNA test sample of step (c) or the control sample of step (d); (f) comparing the genotype of the at least 6 SNPs in the isolated genomic DNA test sample of step (c) or the control sample of step (d) with the genotype of the at least 6 SNPs in a control cell sample from the subject; (g) performing an assay to determine the presence of the control DNA in the control sample of step (d); and (h) identifying a urine sample having a detectable level of the control DNA and having the same genotype of the at least 6 SNPs in the isolated genomic DNA test sample of step (c) or the control sample of step (d) as the genotype of the at least 6 SNPs in the control cell sample as originating from the subject; or identifying a urine sample having a detectable level of the control DNA and not having the same genotype of the at least 6 SNPs in the isolated genomic DNA test sample of step (c) or the control sample of step (d) as the genotype of the at least 6 SNPs in the control cell sample as not originating from the subject. 114.-147. (canceled) 148. The method of claim 113, further comprising:
(i) performing an assay to identify the presence of one or more of statherin, alpha-amylase, and lysozyme in the urine sample; and (j) identifying a urine sample having a genotype of the at least 6 SNPs in the isolated genomic DNA test sample of step (c) or the control sample of step (d) that is the same as the genotype of the 6 SNPs in the control cell sample, a detectable level of control DNA, and a detectable level of one or more of statherin, alpha-amylase, and lysozyme as being adulterated. 149.-165. (canceled) 166. A kit consisting essentially of:
(i) a set of at least 3 pairs of a pre-amplification forward and reverse primer, wherein each pair of pre-amplification forward and reverse primers is designed to amplify 250 to 300 nucleotides of genomic DNA that contains one of at least 3 SNPs, wherein the pre-amplification forward and reverse primers in each of the three or more pairs of pre-amplification primers contains (i) a sequence of about 17 to about 25 contiguous nucleotides that is complementary to a sequence in the genomic DNA and (i) a tag sequence of about 17 to about 25 contiguous nucleotides that is not complementary to a sequence in the genomic DNA; and (ii) a primer that comprises a sequence of about 17 to about 25 contiguous nucleotides of the tag sequence. 167.-192. (canceled) 193. A method for amplifying DNA comprising: hybridizing six or more pairs of a pre-amplification forward and reverse primer, wherein each pair of pre-amplification forward and reverse primers is designed to amplify 250 to 300 nucleotides of genomic DNA that contains one of the at least 6 SNPs, wherein the pre-amplification forward and reverse primers in each of the six or more pairs of pre-amplification primers contains (i) a sequence of about 17 to about 25 contiguous nucleotides that is complementary to a sequence in the genomic DNA and (i) a tag sequence of about 17 to about 25 contiguous nucleotides that is not complementary to a sequence in the genomic DNA; amplifying the genomic DNA using the six or more pairs of pre-amplification forward and reverse primers to generate 250 to 300 nucleotide amplification product(s); and
amplifying the 250 to 300 nucleotide amplification product(s) using a single generic primer that comprises a sequence of about 17 to about 25 contiguous nucleotides of the tag sequence. | Provided herein are methods for determining if a urine sample comprises synthetic urine, methods for matching a urine sample to a subject, and methods for amplifying DNA. Also provided are kits that include a set of at least 3 pairs of a pre-amplification forward and reverse primer, where each pair of pre-amplification forward and reverse primers is designed to amplify 250 to 300 nucleotides of genomic DNA that contains one of at least 3 SNPs, where the pre-amplification forward and reverse primers in each of the three or more pairs of pre-amplification primers contains (i) a sequence of about 17 to about 25 contiguous nucleotides that is complementary to a sequence in the genomic DNA and (i) a tag sequence of about 17 to about 25 contiguous nucleotides that is not complementary to a sequence in the genomic DNA.1. A method of determining if a urine sample comprises synthetic urine comprising:
(a) providing a urine sample from a subject; (b) enriching the urine sample for mammalian cells, if present; (c) isolating any genomic DNA from the enriched sample of step (b) to form an isolated genomic DNA test sample; (d) adding to the isolated genomic DNA test sample of step (c) a control DNA to form a control sample or adding the control DNA to the enriched sample of step (b) and then isolating DNA to form a control sample; (e) performing an assay to determine the presence of genomic DNA in the isolated genomic DNA sample of step (c) or the control sample of step (d); (f) performing an assay to determine the presence of the control DNA in the control sample of step (d); and (g) identifying a urine sample having no detectable level of genomic DNA and having detectable control DNA as containing synthetic urine, or identifying a urine sample having a detectable level of genomic DNA and having detectable control DNA as not comprising a synthetic urine. 2. The method of claim 1, wherein:
the determination of the presence of genomic DNA comprises performing an assay to determine the presence of at least three single nucleotide polymorphisms in the isolated genomic DNA sample of step (c) or the control sample of step (d), and a urine sample having no detectable level of the at least three SNPs and having detectable control DNA is identified in step (g) as containing synthetic urine, or a urine sample having a detectable level of the at least three SNPs and having detectable control DNA is identified in step (g) as not comprising synthetic urine. 3. The method of claim 2, wherein the urine sample is identified in step (g) as not comprising synthetic urine. 4. (canceled) 5. The method of claim 3, further comprising:
(h) performing an assay to determine the genotype of at least 6 single nucleotide polymorphisms (SNPs) in the isolated genomic DNA test sample of step (c) or the control sample of step (d); (i) comparing the genotype of the at least 6 SNPs in the isolated genomic DNA test sample of step (c) or the control sample of step (d) with the genotype of the at least 6 SNPs in a control cell sample from the subject; and (j) identifying a urine sample having a detectable level of the control DNA and having the same genotype of the at least 6 SNPs in the isolated genomic DNA test sample of step (c) or the control sample of step (d) as the genotype of the at least 6 SNPs in the control cell sample as originating from the subject; or identifying a urine sample having a detectable level of the control DNA and not having the same genotype of the at least 6 SNPs in the isolated genomic DNA test sample of (c) or the control sample of step (d) as the genotype of the at least 6 SNPs in the control cell sample as not originating from the subject. 6.-17. (canceled) 18. The method of claim 2, wherein the assay in step (e) comprises a pre-amplification step. 19. The method of claim 18, wherein the pre-amplification step includes: hybridization of three or more pairs of a pre-amplification forward and reverse primer, wherein each pair of pre-amplification forward and reverse primers is designed to amplify 250 to 300 nucleotides of genomic DNA that contains one of the at least 3 SNPs, wherein the pre-amplification forward and reverse primers in each of the three or more pairs of pre-amplification primers contain (i) a sequence of about 17 to about 25 contiguous nucleotides that is complementary to a sequence in the genomic DNA and (ii) a tag sequence of about 17 to about 25 contiguous nucleotides that is not complementary to a sequence in the genomic DNA; and amplification of the genomic DNA using the three or more pairs of pre-amplification forward and reverse primers to generate 250 to 300 nucleotide amplification product(s). 20. The method of claim 19, wherein the pre-amplification step further comprises amplification of the 250 to 300 nucleotide amplification product(s) using a primer that comprises a sequence of about 17 to about 25 contiguous nucleotides of the tag sequence. 21.-28. (canceled) 29. The method of claim 1, further comprising:
(h) performing an assay to identify the presence of one or more of statherin, alpha-amylase, and lysozyme in the urine sample; and (i) identifying a urine sample having a detectable level of genomic DNA, a detectable control DNA, and a detectable level of one or more of statherin, alpha-amylase, and lysozyme as being adulterated. 30.-35. (canceled) 36. The method of claim 1, further comprising:
(h) selecting a subject having a urine sample identified in step (g) as containing synthetic urine; and (i) obtaining an additional urine sample from the selected subject. 37. (canceled) 38. The method of claim 36, further comprising:
(j) performing an assay to determine the level of one or more drugs and/or the level of one or more drug metabolites in the additional urine sample. 39. The method of claim 38, further comprising:
(k) identifying a subject having an elevated level of one or more drugs and/or an elevated level of one or more drug metabolites in the additional urine sample as compared to a reference level of the one or more drugs and/or a reference level of the one or more drug metabolites, wherein the drugs are an illegal or controlled substance and/or the drug metabolites are metabolites of an illegal or controlled substance; and (l) admitting the subject into a drug dependency program, ceasing administration of the controlled substance to the subject, or reducing the dose and/or frequency of administration of the controlled substance to the subject. 40. (canceled) 41. The method of claim 1, further comprising:
(h) selecting a subject having a urine sample identified in step (g) as containing synthetic urine; (i) obtaining a sample comprising blood, serum, hair, or plasma from the subject; and (j) performing an assay to determine the level of one or more drugs and/or one or more drug metabolites in the sample from step (i). 42. The method of claim 41, further comprising:
(k) identifying a subject having an elevated level of one or more drugs and/or an elevated level of one or more drug metabolites in the sample from step (i) as compared to a reference level of the one or more drugs and/or a reference level of the one or more drug metabolites, wherein the drugs are an illegal or controlled substance and/or the drug metabolites are metabolites of an illegal or controlled substance; and (l) admitting the subject into a drug dependency program, ceasing administration of the controlled substance to the subject, or reducing the dose or frequency of administration of the controlled substance to the subject. 43.-46. (canceled) 47. A method of determining if a urine sample comprises synthetic urine and/or is diluted comprising:
(a) providing a urine sample from a subject; (b) detecting the absorbance at 280 nm of the urine sample; and (c) identifying a urine sample having an absorbance at 280 nm that is less than a reference 280 nm absorbance value as comprising synthetic urine and/or being diluted, or identifying a urine sample having an absorbance at 280 nm that is equal to or greater than the reference 280 nm absorbance value as not comprising synthetic urine and not being diluted. 48. (canceled) 49. The method of claim 47, further comprising:
(d) determining the absorbance at 240 nm of the urine sample; and (e) further identifying a urine sample having an absorbance at 280 nm that is less than a reference 280 nm absorbance value and an absorbance at 240 nm that is less than a reference 240 nm absorbance value as being diluted. 50.-104. (canceled) 105. The method of claim 47, further comprising:
(d) selecting a subject having a urine sample identified in step (c) as comprising synthetic urine and/or being diluted; (e) obtaining an additional sample comprising blood, serum, hair, or plasma from the subject; and (f) performing an assay to determine the level of one or more drugs and/or the level of one or more drug metabolites in the additional sample from step (e). 106.-112. (canceled) 113. A method of matching a urine sample to a subject comprising:
(a) providing a urine sample from a subject; (b) enriching the urine sample for mammalian cells, if present; (c) isolating any genomic DNA from the enriched sample of step (b) to form an isolated genomic DNA test sample; (d) adding to the isolated genomic DNA test sample of step (c) a control DNA to form a control sample or adding the control DNA to the enriched sample of step (b) and then isolating the DNA to form a control sample; (e) performing an assay to determine the genotype of at least 6 single nucleotide polymorphisms (SNPs) in the isolated genomic DNA test sample of step (c) or the control sample of step (d); (f) comparing the genotype of the at least 6 SNPs in the isolated genomic DNA test sample of step (c) or the control sample of step (d) with the genotype of the at least 6 SNPs in a control cell sample from the subject; (g) performing an assay to determine the presence of the control DNA in the control sample of step (d); and (h) identifying a urine sample having a detectable level of the control DNA and having the same genotype of the at least 6 SNPs in the isolated genomic DNA test sample of step (c) or the control sample of step (d) as the genotype of the at least 6 SNPs in the control cell sample as originating from the subject; or identifying a urine sample having a detectable level of the control DNA and not having the same genotype of the at least 6 SNPs in the isolated genomic DNA test sample of step (c) or the control sample of step (d) as the genotype of the at least 6 SNPs in the control cell sample as not originating from the subject. 114.-147. (canceled) 148. The method of claim 113, further comprising:
(i) performing an assay to identify the presence of one or more of statherin, alpha-amylase, and lysozyme in the urine sample; and (j) identifying a urine sample having a genotype of the at least 6 SNPs in the isolated genomic DNA test sample of step (c) or the control sample of step (d) that is the same as the genotype of the 6 SNPs in the control cell sample, a detectable level of control DNA, and a detectable level of one or more of statherin, alpha-amylase, and lysozyme as being adulterated. 149.-165. (canceled) 166. A kit consisting essentially of:
(i) a set of at least 3 pairs of a pre-amplification forward and reverse primer, wherein each pair of pre-amplification forward and reverse primers is designed to amplify 250 to 300 nucleotides of genomic DNA that contains one of at least 3 SNPs, wherein the pre-amplification forward and reverse primers in each of the three or more pairs of pre-amplification primers contains (i) a sequence of about 17 to about 25 contiguous nucleotides that is complementary to a sequence in the genomic DNA and (i) a tag sequence of about 17 to about 25 contiguous nucleotides that is not complementary to a sequence in the genomic DNA; and (ii) a primer that comprises a sequence of about 17 to about 25 contiguous nucleotides of the tag sequence. 167.-192. (canceled) 193. A method for amplifying DNA comprising: hybridizing six or more pairs of a pre-amplification forward and reverse primer, wherein each pair of pre-amplification forward and reverse primers is designed to amplify 250 to 300 nucleotides of genomic DNA that contains one of the at least 6 SNPs, wherein the pre-amplification forward and reverse primers in each of the six or more pairs of pre-amplification primers contains (i) a sequence of about 17 to about 25 contiguous nucleotides that is complementary to a sequence in the genomic DNA and (i) a tag sequence of about 17 to about 25 contiguous nucleotides that is not complementary to a sequence in the genomic DNA; amplifying the genomic DNA using the six or more pairs of pre-amplification forward and reverse primers to generate 250 to 300 nucleotide amplification product(s); and
amplifying the 250 to 300 nucleotide amplification product(s) using a single generic primer that comprises a sequence of about 17 to about 25 contiguous nucleotides of the tag sequence. | 1,600 |
1,418 | 15,167,866 | 1,653 | Mass spectrometric methods are described for determining the amount of analyte in a sample collected by a microsampling device. Provided herein are methods directed to quantitating the amount of an analyte in a sample by extracting an analyte from a sample collected by a microsampling device, purifying the sample by liquid chromatography, ionizing the analyte to generate one or more ions detectable by mass spectrometry; and determining the amount of the one or more ions by mass spectrometry. The amount of analyte in the sample is related to the amount of analyte in the patient. | 1. A method for determining the amount of an analyte in a sample by mass spectrometry, the method comprising:
(a) extracting an analyte from a sample collected by a microsampling device; (b) ionizing the analyte to generate one or more ions detectable by mass spectrometry; and (c) determining the amount of the one or more ions by mass spectrometry; wherein the amount of the one or more ions determined is used to determine the amount of analyte in the sample. 2. The method of claim 1, wherein the amount of analyte in the sample is related to the amount of analyte in the patient. 3. The method of claim 1, wherein said sample comprises a whole blood, urine, saliva, plasma or serum sample. 4. The method of claim 1, wherein the extracting step comprises adding an extraction buffer to the sample collected by a microsampling device. 5. The method of claim 4, wherein the extracting step comprises drying down under nitrogen gas. 6. The method of claim 1, wherein the extracting step comprises reconstituting the sample into solution. 7. The method of claim 1, wherein the microsampling device comprises an apparatus that enables automation of extraction and mass spectrometric analysis of multiple samples at the same time. 8. The method of claim 1, wherein the extraction and mass spectrometry steps are performed in an on-line fashion to allow for automated sample analysis. 9. The method of claim 1, the sample collected by the microsampling device has a volume of less than or equal to 100 pt. 10. The method of claim 1, wherein the sample collected by the microsampling device has a volume of less than or equal to 50 pt. 11. The method of claim 1, wherein the sample collected by the microsampling device has a volume of about 10 μL, about 15 μL, or about 20 pt. 12. The method of claim 1, wherein the sample is hydrolyzed prior to quantitation by mass spectrometry. 13. The method of claim 1, further comprising purifying the sample prior to mass spectrometry. 14. The method of claim 1, wherein said purifying comprises subjecting the sample to liquid chromatography. 15. The method of claim 14, wherein liquid chromatography comprises high performance liquid chromatography (HPLC) or high turbulence liquid chromatograph (HTLC). 16. The method of claim 1, wherein the sample is capillary blood. 17. The method of claim 1, wherein the mass spectrometry is tandem mass spectrometry. 18. The method of claim 1, wherein ionization is atmospheric pressure chemical ionization (APCI). 19. The method of claim 1, wherein ionization is in positive ion mode. 20. The method of claim 1, wherein an internal standard for said analyte is added to the sample. 21. The method of claim 20, wherein the internal standard is deuterated or isotopically labeled. 22. The method of claim 1, wherein the microsampling device is encased in a cartridge designed for automation of extraction and mass spectrometric analysis. 23. The method of claim 1, wherein the microsampling device is a MITRA® tip. 24. The method of claim 1, wherein the analyte is a steroid. 25. The method of claim 24, wherein the steroid is cortisol, cortisone, progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, dehydroepiandrosterone, corticosterone, deoxycorticosterone, 11-deoxycortisol, pregnenolone, 17-hydroxypregnenolone, 18-hydroxycorticosterone, 21-deoxycortisol, 25-hydroxyvitamin D2 or 25-hydroxyvitamin D3. 26. The method of claim 1, wherein the analyte is an opiate. 27. The method of claim 26, wherein the opiate is cis-tramadol, O-desmethyl tramadol, tapentadol, N-desmethyltapentadol, codeine, morphine, oxymorphone, norhydrocodone, oxycodone, noroxycodone, hydromorphone, hydrocodone, buprenorphine, norbuprenorphine, fentanyl, norfentanyl, 6-monoacetylmorphine (6-MAM), methadone, dihydrocodeine, naloxone, naltrexone, 6β-naltrexol, nalorphine, nalbuphine, or 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). 28. The method of claim 1, wherein the analyte is a benzodiazepine. 29. The method of claim 28, wherein the benzodiazepine is oxazepam, temazepam, lorazepam, nordiazepam, diazepam, chlordiazepoxide, triazolam, midazolam, alprazolam, clonazepam, bromazepam, clobazam, nitrazepam, phenazepam, prazepam, medazepam, flunitrazepam, or flurazepam. 30. The method of claim 1, wherein the analyte is an anti-epileptic drug. 31. The method of claim 30, wherein the anti-epileptic drug is valproic acid, tiagabine, topiramate, levitiracetum, lamotrigine, lacosamide, ethosuximide, carbamazepine, eslicarbamazepine, 10,11-carbamazepine, phenobarbital, rufinamide, primidone, phenytoin, zonisamide, felbamate, gabapentin, or pregablin. 32. The method of claim 1, wherein the analyte is an immunosuppressant. 33. The method of claim 32, wherein the immunosuppressant is cyclosporine A, sirolimus, tacrolimus, or everolimus. 34. The method of claim 1, wherein the analyte is a barbiturate. 35. The method of claim 35, wherein the barbiturate is phenobarbitol, amobarbitol, butalbital, pentobarbitol, secobarbitol, or thiopental. 36. The method of claim 1, wherein the analyte is tamoxifen or a metabolite thereof. 37. The method of claim 36, wherein the metabolite is norendoxifen, N-Desmethyl-4-Hydroxy Tamoxifen, 4′-Hydroxy Tamoxifen, 4-Hydroxy Tamoxifen, N-Desmethyl-4′-Hydroxy Tamoxifen, N-Desmethyl Tamoxifen. 38. The method of claim 1, wherein the analyte is an oncology drug. 39. The method of claim 38, wherein the analyte is anastrozole, letrozole, or exemestane. 40. The method of claim 1, wherein the analyte is tetrahydrocannabinol (THC) or a metabolite thereof. 41. A method for determining the amount of an analyte in a sample by mass spectrometry, the method comprising:
(a) extracting an analyte from a sample collected by a microsampling device; (b) purifying the sample by liquid chromatography; (c) ionizing the analyte to generate one or more ions detectable by mass spectrometry; and (d) determining the amount of the one or more ions by mass spectrometry; wherein the amount of the one or more ions determined is used to determine the amount of analyte in the sample. 42. A method for determining the amount of an analyte in a sample by mass spectrometry, the method comprising:
(a) extracting an analyte from a sample of less than or equal to 100 μL; (b) purifying the sample by liquid chromatography; (c) ionizing the analyte to generate one or more ions detectable by mass spectrometry; and (d) determining the amount of the one or more ions by mass spectrometry; wherein the amount of the one or more ions determined is used to determine the amount of analyte in the sample. 43. The method of claim 42, wherein the method comprises extracting an analyte from a sample of less than or equal to 50 μL or less than or equal to 30 μL. | Mass spectrometric methods are described for determining the amount of analyte in a sample collected by a microsampling device. Provided herein are methods directed to quantitating the amount of an analyte in a sample by extracting an analyte from a sample collected by a microsampling device, purifying the sample by liquid chromatography, ionizing the analyte to generate one or more ions detectable by mass spectrometry; and determining the amount of the one or more ions by mass spectrometry. The amount of analyte in the sample is related to the amount of analyte in the patient.1. A method for determining the amount of an analyte in a sample by mass spectrometry, the method comprising:
(a) extracting an analyte from a sample collected by a microsampling device; (b) ionizing the analyte to generate one or more ions detectable by mass spectrometry; and (c) determining the amount of the one or more ions by mass spectrometry; wherein the amount of the one or more ions determined is used to determine the amount of analyte in the sample. 2. The method of claim 1, wherein the amount of analyte in the sample is related to the amount of analyte in the patient. 3. The method of claim 1, wherein said sample comprises a whole blood, urine, saliva, plasma or serum sample. 4. The method of claim 1, wherein the extracting step comprises adding an extraction buffer to the sample collected by a microsampling device. 5. The method of claim 4, wherein the extracting step comprises drying down under nitrogen gas. 6. The method of claim 1, wherein the extracting step comprises reconstituting the sample into solution. 7. The method of claim 1, wherein the microsampling device comprises an apparatus that enables automation of extraction and mass spectrometric analysis of multiple samples at the same time. 8. The method of claim 1, wherein the extraction and mass spectrometry steps are performed in an on-line fashion to allow for automated sample analysis. 9. The method of claim 1, the sample collected by the microsampling device has a volume of less than or equal to 100 pt. 10. The method of claim 1, wherein the sample collected by the microsampling device has a volume of less than or equal to 50 pt. 11. The method of claim 1, wherein the sample collected by the microsampling device has a volume of about 10 μL, about 15 μL, or about 20 pt. 12. The method of claim 1, wherein the sample is hydrolyzed prior to quantitation by mass spectrometry. 13. The method of claim 1, further comprising purifying the sample prior to mass spectrometry. 14. The method of claim 1, wherein said purifying comprises subjecting the sample to liquid chromatography. 15. The method of claim 14, wherein liquid chromatography comprises high performance liquid chromatography (HPLC) or high turbulence liquid chromatograph (HTLC). 16. The method of claim 1, wherein the sample is capillary blood. 17. The method of claim 1, wherein the mass spectrometry is tandem mass spectrometry. 18. The method of claim 1, wherein ionization is atmospheric pressure chemical ionization (APCI). 19. The method of claim 1, wherein ionization is in positive ion mode. 20. The method of claim 1, wherein an internal standard for said analyte is added to the sample. 21. The method of claim 20, wherein the internal standard is deuterated or isotopically labeled. 22. The method of claim 1, wherein the microsampling device is encased in a cartridge designed for automation of extraction and mass spectrometric analysis. 23. The method of claim 1, wherein the microsampling device is a MITRA® tip. 24. The method of claim 1, wherein the analyte is a steroid. 25. The method of claim 24, wherein the steroid is cortisol, cortisone, progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, dehydroepiandrosterone, corticosterone, deoxycorticosterone, 11-deoxycortisol, pregnenolone, 17-hydroxypregnenolone, 18-hydroxycorticosterone, 21-deoxycortisol, 25-hydroxyvitamin D2 or 25-hydroxyvitamin D3. 26. The method of claim 1, wherein the analyte is an opiate. 27. The method of claim 26, wherein the opiate is cis-tramadol, O-desmethyl tramadol, tapentadol, N-desmethyltapentadol, codeine, morphine, oxymorphone, norhydrocodone, oxycodone, noroxycodone, hydromorphone, hydrocodone, buprenorphine, norbuprenorphine, fentanyl, norfentanyl, 6-monoacetylmorphine (6-MAM), methadone, dihydrocodeine, naloxone, naltrexone, 6β-naltrexol, nalorphine, nalbuphine, or 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). 28. The method of claim 1, wherein the analyte is a benzodiazepine. 29. The method of claim 28, wherein the benzodiazepine is oxazepam, temazepam, lorazepam, nordiazepam, diazepam, chlordiazepoxide, triazolam, midazolam, alprazolam, clonazepam, bromazepam, clobazam, nitrazepam, phenazepam, prazepam, medazepam, flunitrazepam, or flurazepam. 30. The method of claim 1, wherein the analyte is an anti-epileptic drug. 31. The method of claim 30, wherein the anti-epileptic drug is valproic acid, tiagabine, topiramate, levitiracetum, lamotrigine, lacosamide, ethosuximide, carbamazepine, eslicarbamazepine, 10,11-carbamazepine, phenobarbital, rufinamide, primidone, phenytoin, zonisamide, felbamate, gabapentin, or pregablin. 32. The method of claim 1, wherein the analyte is an immunosuppressant. 33. The method of claim 32, wherein the immunosuppressant is cyclosporine A, sirolimus, tacrolimus, or everolimus. 34. The method of claim 1, wherein the analyte is a barbiturate. 35. The method of claim 35, wherein the barbiturate is phenobarbitol, amobarbitol, butalbital, pentobarbitol, secobarbitol, or thiopental. 36. The method of claim 1, wherein the analyte is tamoxifen or a metabolite thereof. 37. The method of claim 36, wherein the metabolite is norendoxifen, N-Desmethyl-4-Hydroxy Tamoxifen, 4′-Hydroxy Tamoxifen, 4-Hydroxy Tamoxifen, N-Desmethyl-4′-Hydroxy Tamoxifen, N-Desmethyl Tamoxifen. 38. The method of claim 1, wherein the analyte is an oncology drug. 39. The method of claim 38, wherein the analyte is anastrozole, letrozole, or exemestane. 40. The method of claim 1, wherein the analyte is tetrahydrocannabinol (THC) or a metabolite thereof. 41. A method for determining the amount of an analyte in a sample by mass spectrometry, the method comprising:
(a) extracting an analyte from a sample collected by a microsampling device; (b) purifying the sample by liquid chromatography; (c) ionizing the analyte to generate one or more ions detectable by mass spectrometry; and (d) determining the amount of the one or more ions by mass spectrometry; wherein the amount of the one or more ions determined is used to determine the amount of analyte in the sample. 42. A method for determining the amount of an analyte in a sample by mass spectrometry, the method comprising:
(a) extracting an analyte from a sample of less than or equal to 100 μL; (b) purifying the sample by liquid chromatography; (c) ionizing the analyte to generate one or more ions detectable by mass spectrometry; and (d) determining the amount of the one or more ions by mass spectrometry; wherein the amount of the one or more ions determined is used to determine the amount of analyte in the sample. 43. The method of claim 42, wherein the method comprises extracting an analyte from a sample of less than or equal to 50 μL or less than or equal to 30 μL. | 1,600 |
1,419 | 16,073,778 | 1,633 | The invention pertains to therapies that require gene editing, and more specifically to non-viral methods for in vivo delivery of endonuclease reagents to specific tissues or cells. According to the invention, the endonuclease reagents are encapsulated into micelle structures of 50 to 150 nm diameter for intravenous injection. The invention thus provides therapeutic composition including such micelles structures, by which endonuclease reagents can be released into cell under RNA form for their use in the treatment of gene related diseases. | 1) A method for encapsulating an endonuclease reagent, comprising the steps of:
a) Engineering a endonuclease reagent under RNA form; b) Complexing said endonuclease reagent with at least one biodegradable matrix comprising at least a core hydrophobic domain and a proximal polar domain to favor interactions with water molecules; c) Forming particles encapsulating said endonuclease reagent of 50 to 100 nm diameter range. 2) A method according to claim 1, wherein said endonuclease reagent is a sequence-specific endonuclease reagent. 3) A method according to claim 1, wherein said endonuclease reagent is a rare-cutting endonuclease, such as a homing endonuclease, a zing finger nuclease, a TALE-Nuclease or a MegaTAL-endonuclease. 4) A method according to claim 3, wherein said rare-cutting endonuclease is a TALE-nuclease. 5) A method according to claim 1, wherein said RNA encodes an endonuclease reagent, which is a RNA-guided endonuclease. 6) A method according to claim 5, wherein said RNA-guided endonuclease is cas9 or Cpf1. 7) A method according to claim 1, wherein said RNA is a RNA-guide. 8) A method according to claim 7, wherein said RNA guide is complexed with a RNA-guided endonuclease protein. 9) A method according to any one of claims 1 to 8, wherein at least two different endonuclease reagents are encapsulated under RNA form into the particles. 10) A method according to claim 9, wherein said different endonuclease reagents are at least a RNA encoding a RNA-guided endonuclease and a guide RNA. 11) A method according to claim 1, wherein said core hydrophobic domain is a biodegradable conjugate of hydrophobic monomers. 12) A method according to claim 1, wherein said core hydrophobic and proximal polar domains are covalently linked. 13) A method according to claim 1, wherein said core hydrophobic and proximal polar domains are linked by peptide linkers. 14) A method according to claim 11, wherein said hydrophobic monomers conjugate are of aminolipids, such as ionized cationic lipid 1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA). 15) A method according to claim 14, wherein said aminolipids are mixed with PEG-lipids to form said polar domain. 16) A method according to any one of claims 14 and 15, wherein said aminolipids allows binding of ApoE in-vivo, said ApoE facilitating Apo E mediated endocytosis. 17) A method according to any one of claims 1 to 16, wherein said endonuclease reagent endocytosis is mediated via a receptor of the LDL or VLDL receptor family. 18) A method according to any one of claims 1 to 17, wherein said at least one polar domain is poly-N,N-di(C1-C6)alkyl-amino(C1-C6)alkyl-ethacrylate, poly-N,N-di(C1-C6)alkyl-amino(C1-C6)alkyl-methacrylate, or poly-N,N-di(C1-C6)alkyl-amino(C1-C6)alkyl-acrylate, or a combination thereof. 19) A method according to claim 18, wherein said hydrophobic monomers include at least (C2-C8)alkyl-ethacrylate, a (C2-C8)alkyl-methacrylate, or a (C2-C8)alkyl-acrylate. 20) A method according to any one of claims 1 to 19, wherein said hydrophobic monomers conjugate are mixed with carboxylic acid monomers and tertiary amino monomers. 21) A method according to any one of claims 1 to 20, wherein said at least one polar domain is linked to a targeting domain. 22) A method according to claim 21, wherein said targeting domain comprises ScFv of an antibody targeting a cell surface antigen. 23) A method according to claim 22, wherein said cell surface antigen is a protein is selected from a LDL, VLDL receptors or cell surface heparin sulfate proteoglycans. 24) A method according to any one of claims 1 to 23, wherein said at least one polar domain is linked to a N-acetylgalactosamine ligand. 25) A method according to any one of claims 21, 22 and 24, wherein said targeting domain is a ligand of asiaglycoprotein. 26) A method according to claim 1, wherein said particles encapsulating said endonuclease reagent are of 50 to 90 nm diameter range. 27) A biodegradable delivery capsule obtainable by the method according to any one of claims 1 to 26. 28) A biodegradable delivery capsule for gene targeting of a cell in-vivo, characterized in that a RNA endonuclease reagent is complexed with at least one polar domain, which is linked to biodegradable conjugate(s) of hydrophobic monomers to form spherical particles of 50 to 100 nm diameter range. 29) A biodegradable delivery capsule according to claim 27 or 28, wherein at least two RNA endonuclease reagents are included into said spherical particles. 30) A biodegradable delivery capsule according to any one of claims 27 to 29, wherein said biodegradable matrix comprises at least two polar domains, such that the inner core particle is hydrophilic. 31) A biodegradable delivery capsule according to claim 30, wherein said hydrophilic inner core particle encapsulates a further endonuclease reagent. 32) A biodegradable delivery capsule according to claim 31, wherein said further endonuclease reagent comprises a polypeptide. 33) A biodegradable delivery capsule according to claim 32, wherein said polypeptide encodes a RNA or DNA guided endonuclease. 34) A pharmaceutical composition comprising a biodegradable delivery system according to any one of claims 27 to 33 with a pharmaceutically injectable medium. 35) A pharmaceutical composition according to 34, for use in the treatment of a liver disease. 36) A pharmaceutical composition according to claim 34 or 35, for use in the treatment of an infectious disease. 37) A pharmaceutical composition according to any one of claims 34 to 36, wherein said disease is a viral disease such as hepatitis. 38) A pharmaceutical composition according to claim 36 or 37, wherein said infectious disease is due to an infectious agent that presents a DNA intermediate into the liver. 39) A pharmaceutical composition according to claim 38, wherein said infectious agent is a Hepadnavirus, such as HBV. 40) A pharmaceutical composition according to 34, for use in the treatment of malignant cells. 41) A method for delivering an endonuclease reagent to a cell in vivo, comprising the step of:
Producing a biodegradable delivery capsule by a method according to any one of claims 1 to 26 ; Injecting intravenously said capsule into the blood circulation of a patient; 42) A method for gene editing a target gene into a cell in-vivo, comprising the steps of introducing a biodegradable delivery capsule according to any one of claims 27 to 33 into the blood stream of an animal. 43) A method for gene editing according to claim 42, wherein the target gene is one from the cccDNA of HBV. 44) A TALE-nuclease monomer engineered to target the cccDNA of HBV in-vivo which binds one target sequence selected from SEQ ID NO: 1 to 20. 45) A TALE-nuclease monomer engineered to target the cccDNA of HBV in-vivo according to claim 44, which polypeptide sequence has at least 80% identity with SEQ ID NO.1 to 20. | The invention pertains to therapies that require gene editing, and more specifically to non-viral methods for in vivo delivery of endonuclease reagents to specific tissues or cells. According to the invention, the endonuclease reagents are encapsulated into micelle structures of 50 to 150 nm diameter for intravenous injection. The invention thus provides therapeutic composition including such micelles structures, by which endonuclease reagents can be released into cell under RNA form for their use in the treatment of gene related diseases.1) A method for encapsulating an endonuclease reagent, comprising the steps of:
a) Engineering a endonuclease reagent under RNA form; b) Complexing said endonuclease reagent with at least one biodegradable matrix comprising at least a core hydrophobic domain and a proximal polar domain to favor interactions with water molecules; c) Forming particles encapsulating said endonuclease reagent of 50 to 100 nm diameter range. 2) A method according to claim 1, wherein said endonuclease reagent is a sequence-specific endonuclease reagent. 3) A method according to claim 1, wherein said endonuclease reagent is a rare-cutting endonuclease, such as a homing endonuclease, a zing finger nuclease, a TALE-Nuclease or a MegaTAL-endonuclease. 4) A method according to claim 3, wherein said rare-cutting endonuclease is a TALE-nuclease. 5) A method according to claim 1, wherein said RNA encodes an endonuclease reagent, which is a RNA-guided endonuclease. 6) A method according to claim 5, wherein said RNA-guided endonuclease is cas9 or Cpf1. 7) A method according to claim 1, wherein said RNA is a RNA-guide. 8) A method according to claim 7, wherein said RNA guide is complexed with a RNA-guided endonuclease protein. 9) A method according to any one of claims 1 to 8, wherein at least two different endonuclease reagents are encapsulated under RNA form into the particles. 10) A method according to claim 9, wherein said different endonuclease reagents are at least a RNA encoding a RNA-guided endonuclease and a guide RNA. 11) A method according to claim 1, wherein said core hydrophobic domain is a biodegradable conjugate of hydrophobic monomers. 12) A method according to claim 1, wherein said core hydrophobic and proximal polar domains are covalently linked. 13) A method according to claim 1, wherein said core hydrophobic and proximal polar domains are linked by peptide linkers. 14) A method according to claim 11, wherein said hydrophobic monomers conjugate are of aminolipids, such as ionized cationic lipid 1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA). 15) A method according to claim 14, wherein said aminolipids are mixed with PEG-lipids to form said polar domain. 16) A method according to any one of claims 14 and 15, wherein said aminolipids allows binding of ApoE in-vivo, said ApoE facilitating Apo E mediated endocytosis. 17) A method according to any one of claims 1 to 16, wherein said endonuclease reagent endocytosis is mediated via a receptor of the LDL or VLDL receptor family. 18) A method according to any one of claims 1 to 17, wherein said at least one polar domain is poly-N,N-di(C1-C6)alkyl-amino(C1-C6)alkyl-ethacrylate, poly-N,N-di(C1-C6)alkyl-amino(C1-C6)alkyl-methacrylate, or poly-N,N-di(C1-C6)alkyl-amino(C1-C6)alkyl-acrylate, or a combination thereof. 19) A method according to claim 18, wherein said hydrophobic monomers include at least (C2-C8)alkyl-ethacrylate, a (C2-C8)alkyl-methacrylate, or a (C2-C8)alkyl-acrylate. 20) A method according to any one of claims 1 to 19, wherein said hydrophobic monomers conjugate are mixed with carboxylic acid monomers and tertiary amino monomers. 21) A method according to any one of claims 1 to 20, wherein said at least one polar domain is linked to a targeting domain. 22) A method according to claim 21, wherein said targeting domain comprises ScFv of an antibody targeting a cell surface antigen. 23) A method according to claim 22, wherein said cell surface antigen is a protein is selected from a LDL, VLDL receptors or cell surface heparin sulfate proteoglycans. 24) A method according to any one of claims 1 to 23, wherein said at least one polar domain is linked to a N-acetylgalactosamine ligand. 25) A method according to any one of claims 21, 22 and 24, wherein said targeting domain is a ligand of asiaglycoprotein. 26) A method according to claim 1, wherein said particles encapsulating said endonuclease reagent are of 50 to 90 nm diameter range. 27) A biodegradable delivery capsule obtainable by the method according to any one of claims 1 to 26. 28) A biodegradable delivery capsule for gene targeting of a cell in-vivo, characterized in that a RNA endonuclease reagent is complexed with at least one polar domain, which is linked to biodegradable conjugate(s) of hydrophobic monomers to form spherical particles of 50 to 100 nm diameter range. 29) A biodegradable delivery capsule according to claim 27 or 28, wherein at least two RNA endonuclease reagents are included into said spherical particles. 30) A biodegradable delivery capsule according to any one of claims 27 to 29, wherein said biodegradable matrix comprises at least two polar domains, such that the inner core particle is hydrophilic. 31) A biodegradable delivery capsule according to claim 30, wherein said hydrophilic inner core particle encapsulates a further endonuclease reagent. 32) A biodegradable delivery capsule according to claim 31, wherein said further endonuclease reagent comprises a polypeptide. 33) A biodegradable delivery capsule according to claim 32, wherein said polypeptide encodes a RNA or DNA guided endonuclease. 34) A pharmaceutical composition comprising a biodegradable delivery system according to any one of claims 27 to 33 with a pharmaceutically injectable medium. 35) A pharmaceutical composition according to 34, for use in the treatment of a liver disease. 36) A pharmaceutical composition according to claim 34 or 35, for use in the treatment of an infectious disease. 37) A pharmaceutical composition according to any one of claims 34 to 36, wherein said disease is a viral disease such as hepatitis. 38) A pharmaceutical composition according to claim 36 or 37, wherein said infectious disease is due to an infectious agent that presents a DNA intermediate into the liver. 39) A pharmaceutical composition according to claim 38, wherein said infectious agent is a Hepadnavirus, such as HBV. 40) A pharmaceutical composition according to 34, for use in the treatment of malignant cells. 41) A method for delivering an endonuclease reagent to a cell in vivo, comprising the step of:
Producing a biodegradable delivery capsule by a method according to any one of claims 1 to 26 ; Injecting intravenously said capsule into the blood circulation of a patient; 42) A method for gene editing a target gene into a cell in-vivo, comprising the steps of introducing a biodegradable delivery capsule according to any one of claims 27 to 33 into the blood stream of an animal. 43) A method for gene editing according to claim 42, wherein the target gene is one from the cccDNA of HBV. 44) A TALE-nuclease monomer engineered to target the cccDNA of HBV in-vivo which binds one target sequence selected from SEQ ID NO: 1 to 20. 45) A TALE-nuclease monomer engineered to target the cccDNA of HBV in-vivo according to claim 44, which polypeptide sequence has at least 80% identity with SEQ ID NO.1 to 20. | 1,600 |
1,420 | 15,840,283 | 1,656 | A nanoparticle (for example, quantum dot) serves as a substrate for immobilizing enzymes involved in consecutive reactions as a cascade. This results in a significant increase in the rate of catalysis as well as final product yield compared to non-immobilized enzymes. | 1. An enzymatic cascade cluster comprising:
a plurality of nanoparticles associated together as a cluster, wherein each nanoparticle is bound to a plurality of enzymes configured as an enzymatic cascade wherein the product of a first enzyme is the substrate of a second enzyme and so forth; wherein the enzymatic cascade comprises at least two different enzymes; and wherein the nanoparticles in the cluster are closely associated with one another such that, on average, each nanoparticle is separated from the nearest neighboring nanoparticle by a distance of no more than about one nanoparticle diameter. 2. The cluster of claim 1, wherein the nanoparticle is a quantum dot and the enzymes are bound to the quantum dot via polyhistidine sequences in the enzymes. 3. The cluster of claim 1, wherein said plurality of enzymes comprises pyruvate kinase (PykA) and lactate dehydrogenase (LDH). 4. The cluster of claim 1, wherein said plurality of enzymes comprises glucokinase, phosphoglucose isomerase, phosphofructokinase, fructose-bisphosphate aldolase, triose phosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, and phosphoglycerate mutase. 5. An enzymatic cascade comprising:
a nanoparticle bound to a plurality of enzymes configured as an enzymatic cascade wherein the product of a first enzyme is the substrate of a second enzyme and so forth; wherein the enzymatic cascade comprises at least two different enzymes. 6. The cascade of claim 5, wherein the nanoparticle is a quantum dot and the enzymes are bound to the quantum dot via polyhistidine sequences in the enzymes. 7. The cascade of claim 5, wherein said plurality of enzymes comprises pyruvate kinase (PykA) and lactate dehydrogenase (LDH). 8. The cascade of claim 5, wherein said plurality of enzymes comprises glucokinase, phosphoglucose isomerase, phosphofructokinase, fructose-bisphosphate aldolase, triose phosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, and phosphoglycerate mutase. 9. An enzymatic cascade cluster comprising:
a plurality of quantum dots (QDs) associated together as a cluster, wherein each nanoparticle is bound to a plurality of enzymes configured as an enzymatic cascade wherein the product of a first enzyme is the substrate of a second enzyme and so forth; wherein the enzymatic cascade consists of the enzymes glucokinase, phosphoglucose isomerase, phosphofructokinase, fructose-bisphosphate aldolase, triose phosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, and phosphoglycerate mutase, each enzyme incorporating a polyhistidine sequence associating the enzyme to the QD; and wherein the QDs in the cluster are closely associated with one another such that, on average, each QD is separated from the nearest neighboring QD by a distance of no more than about one QD diameter. 10. A method of conducting a cascade reaction, comprising:
providing a cascade cluster comprising a plurality of nanoparticles associated together as a cluster, wherein each nanoparticle is bound to a plurality of enzymes configured as an enzymatic cascade wherein the product of a first enzyme is the substrate of a second enzyme and so forth, wherein the enzymatic cascade comprises at least two different enzymes, and wherein the nanoparticles in the cluster are closely associated with one another such that, on average, each nanoparticle is separated from the nearest neighboring nanoparticle by a distance of no more than about one nanoparticle diameter; contacting the cascade cluster with a substrate of the first enzyme; and allowing a reaction to proceed so that each of the plurality of enzymes acts in succession to produce an end product, wherein the reaction is performed while minimizing stirring or mixing. 11. The method of claim 10, wherein the nanoparticle is a quantum dot and the enzymes are bound to the quantum dot via polyhistidine sequences in the enzymes. 12. The method of claim 10, wherein said plurality of enzymes comprises pyruvate kinase (PykA) and lactate dehydrogenase (LDH). 13. The method of claim 10, wherein said plurality of enzymes comprises glucokinase, phosphoglucose isomerase, phosphofructokinase, fructose-bisphosphate aldolase, triose phosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, and phosphoglycerate mutase. | A nanoparticle (for example, quantum dot) serves as a substrate for immobilizing enzymes involved in consecutive reactions as a cascade. This results in a significant increase in the rate of catalysis as well as final product yield compared to non-immobilized enzymes.1. An enzymatic cascade cluster comprising:
a plurality of nanoparticles associated together as a cluster, wherein each nanoparticle is bound to a plurality of enzymes configured as an enzymatic cascade wherein the product of a first enzyme is the substrate of a second enzyme and so forth; wherein the enzymatic cascade comprises at least two different enzymes; and wherein the nanoparticles in the cluster are closely associated with one another such that, on average, each nanoparticle is separated from the nearest neighboring nanoparticle by a distance of no more than about one nanoparticle diameter. 2. The cluster of claim 1, wherein the nanoparticle is a quantum dot and the enzymes are bound to the quantum dot via polyhistidine sequences in the enzymes. 3. The cluster of claim 1, wherein said plurality of enzymes comprises pyruvate kinase (PykA) and lactate dehydrogenase (LDH). 4. The cluster of claim 1, wherein said plurality of enzymes comprises glucokinase, phosphoglucose isomerase, phosphofructokinase, fructose-bisphosphate aldolase, triose phosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, and phosphoglycerate mutase. 5. An enzymatic cascade comprising:
a nanoparticle bound to a plurality of enzymes configured as an enzymatic cascade wherein the product of a first enzyme is the substrate of a second enzyme and so forth; wherein the enzymatic cascade comprises at least two different enzymes. 6. The cascade of claim 5, wherein the nanoparticle is a quantum dot and the enzymes are bound to the quantum dot via polyhistidine sequences in the enzymes. 7. The cascade of claim 5, wherein said plurality of enzymes comprises pyruvate kinase (PykA) and lactate dehydrogenase (LDH). 8. The cascade of claim 5, wherein said plurality of enzymes comprises glucokinase, phosphoglucose isomerase, phosphofructokinase, fructose-bisphosphate aldolase, triose phosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, and phosphoglycerate mutase. 9. An enzymatic cascade cluster comprising:
a plurality of quantum dots (QDs) associated together as a cluster, wherein each nanoparticle is bound to a plurality of enzymes configured as an enzymatic cascade wherein the product of a first enzyme is the substrate of a second enzyme and so forth; wherein the enzymatic cascade consists of the enzymes glucokinase, phosphoglucose isomerase, phosphofructokinase, fructose-bisphosphate aldolase, triose phosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, and phosphoglycerate mutase, each enzyme incorporating a polyhistidine sequence associating the enzyme to the QD; and wherein the QDs in the cluster are closely associated with one another such that, on average, each QD is separated from the nearest neighboring QD by a distance of no more than about one QD diameter. 10. A method of conducting a cascade reaction, comprising:
providing a cascade cluster comprising a plurality of nanoparticles associated together as a cluster, wherein each nanoparticle is bound to a plurality of enzymes configured as an enzymatic cascade wherein the product of a first enzyme is the substrate of a second enzyme and so forth, wherein the enzymatic cascade comprises at least two different enzymes, and wherein the nanoparticles in the cluster are closely associated with one another such that, on average, each nanoparticle is separated from the nearest neighboring nanoparticle by a distance of no more than about one nanoparticle diameter; contacting the cascade cluster with a substrate of the first enzyme; and allowing a reaction to proceed so that each of the plurality of enzymes acts in succession to produce an end product, wherein the reaction is performed while minimizing stirring or mixing. 11. The method of claim 10, wherein the nanoparticle is a quantum dot and the enzymes are bound to the quantum dot via polyhistidine sequences in the enzymes. 12. The method of claim 10, wherein said plurality of enzymes comprises pyruvate kinase (PykA) and lactate dehydrogenase (LDH). 13. The method of claim 10, wherein said plurality of enzymes comprises glucokinase, phosphoglucose isomerase, phosphofructokinase, fructose-bisphosphate aldolase, triose phosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, and phosphoglycerate mutase. | 1,600 |
1,421 | 16,306,113 | 1,613 | The present invention belongs to the fields of pharmaceuticals and cosmetics, and concerns on the one hand a medicament for the inhibition of and refers also on the cosmetic, non-therapeutic use for the treatment of hyperpigmentation, particularly induced by sun light radiation, preferably induced by visible light radiation. | 1. A medicament containing sclareolide for use in the treatment, prevention and/or amelioration of hyperpigmentation. 2. The medicament of claim 1, wherein the hyperpigmentation is induced by the radiation of sunlight. 3. The medicament of claim 2, wherein the hyperpigmentation is induced by the radiation of visible light and/or UVB, preferably with a wavelength in the range from 100 nm to 1500 nm. 4. The medicament of claim 1, wherein the medicament further comprises at least one UV filter selected from the group consisting of UV-A filters, UV-B filters, light protection pigments and mixtures thereof. 5. The medicament of claim 1, wherein the medicament further comprises at least one skin lightening agent. 6. The medicament of claim 1, wherein sclareolide is present in an active amount to reduce, retard, suppress and/or protect against sunlight, preferably visible light induced and/or UVB hyperpigmentation. 7. The medicament of claim 1, comprising
(a) from 0.01 wt. % to 10 wt. %, preferably from 0.02 wt. % to 2 wt. %, particularly preferably from 0.05 wt. % to 0.2 wt % sclareolide or a pharmaceutically acceptable salt of sclareolide, (b) at least one compound selected from (b1), (b2) and (b3):
(b1) from 0.05 wt. % to 60 wt. %, preferably 0.1 to 50 wt. %, particularly preferably 0.5 wt. % to 40 wt % of UV filters,
(b2) from 0.005 wt. % to 20 wt. %, preferably 0.01 wt. % to 10 wt. % of skin lightening agents,
(b3) from 0.0001 wt. % to 30 wt. %, preferably 0.5 wt. % to 20 wt. % of antioxidants,
and optionally (c) from 0.2 wt. % to 99 wt. %, preferably from 0.5 wt. % to 20 wt. %, particularly preferably from 1 wt. % to 10 wt. % of carriers, and/or (d) 0.1 wt. % to 90 wt. % further additives, wherein the weight percents of the compounds a) to d) are based on the total amount of the preparation and the sum of all compounds adds to 100 wt. %. 8. A cosmetic composition comprising
(a) sclareolide or a pharmaceutically acceptable salt thereof, at least one compound selected from (b1), (b2) and (b3):
(b1) at least one UV filter,
(b2) at least one skin lightening agent,
(b3) at least an antioxidant,
and at least one compound selected from (c1), (c2) and (c3): (c1) carriers, (c2) oil components (c3) emulsifiers. 9. The composition of claim 7, wherein the composition is a cream, lotion, gel, paste or capsule. 10. A non-therapeutical method for treating hyperpigmentation, comprising the following steps:
(i) providing a cosmetic composition according to claim 8, and (ii) applying said composition of step (i) to human skin. 11. The method claim 10, wherein said cosmetic composition comprises sclareolide in an amount from 0.01 wt. % to 10 wt. %, based on the total amount of the cosmetic composition. 12. The method of claim 11, wherein the cosmetic composition comprises at least one UV filter selected from the group consisting of UV-A filters, UV-B filters, light protection pigments and mixtures thereof. 13. The method of claim 11, wherein the cosmetic composition comprises at least one skin lightening agent. 14. The Method of claim 10, comprising treatment, prevention and/or amelioration of hyperpigmentation. 15. The method of claim 14, wherein the hyperpigmentation is induced by the radiation of sunlight, preferably induced by the radiation of visible light and/or UVB within a wavelength from 280 nm to 750 nm. | The present invention belongs to the fields of pharmaceuticals and cosmetics, and concerns on the one hand a medicament for the inhibition of and refers also on the cosmetic, non-therapeutic use for the treatment of hyperpigmentation, particularly induced by sun light radiation, preferably induced by visible light radiation.1. A medicament containing sclareolide for use in the treatment, prevention and/or amelioration of hyperpigmentation. 2. The medicament of claim 1, wherein the hyperpigmentation is induced by the radiation of sunlight. 3. The medicament of claim 2, wherein the hyperpigmentation is induced by the radiation of visible light and/or UVB, preferably with a wavelength in the range from 100 nm to 1500 nm. 4. The medicament of claim 1, wherein the medicament further comprises at least one UV filter selected from the group consisting of UV-A filters, UV-B filters, light protection pigments and mixtures thereof. 5. The medicament of claim 1, wherein the medicament further comprises at least one skin lightening agent. 6. The medicament of claim 1, wherein sclareolide is present in an active amount to reduce, retard, suppress and/or protect against sunlight, preferably visible light induced and/or UVB hyperpigmentation. 7. The medicament of claim 1, comprising
(a) from 0.01 wt. % to 10 wt. %, preferably from 0.02 wt. % to 2 wt. %, particularly preferably from 0.05 wt. % to 0.2 wt % sclareolide or a pharmaceutically acceptable salt of sclareolide, (b) at least one compound selected from (b1), (b2) and (b3):
(b1) from 0.05 wt. % to 60 wt. %, preferably 0.1 to 50 wt. %, particularly preferably 0.5 wt. % to 40 wt % of UV filters,
(b2) from 0.005 wt. % to 20 wt. %, preferably 0.01 wt. % to 10 wt. % of skin lightening agents,
(b3) from 0.0001 wt. % to 30 wt. %, preferably 0.5 wt. % to 20 wt. % of antioxidants,
and optionally (c) from 0.2 wt. % to 99 wt. %, preferably from 0.5 wt. % to 20 wt. %, particularly preferably from 1 wt. % to 10 wt. % of carriers, and/or (d) 0.1 wt. % to 90 wt. % further additives, wherein the weight percents of the compounds a) to d) are based on the total amount of the preparation and the sum of all compounds adds to 100 wt. %. 8. A cosmetic composition comprising
(a) sclareolide or a pharmaceutically acceptable salt thereof, at least one compound selected from (b1), (b2) and (b3):
(b1) at least one UV filter,
(b2) at least one skin lightening agent,
(b3) at least an antioxidant,
and at least one compound selected from (c1), (c2) and (c3): (c1) carriers, (c2) oil components (c3) emulsifiers. 9. The composition of claim 7, wherein the composition is a cream, lotion, gel, paste or capsule. 10. A non-therapeutical method for treating hyperpigmentation, comprising the following steps:
(i) providing a cosmetic composition according to claim 8, and (ii) applying said composition of step (i) to human skin. 11. The method claim 10, wherein said cosmetic composition comprises sclareolide in an amount from 0.01 wt. % to 10 wt. %, based on the total amount of the cosmetic composition. 12. The method of claim 11, wherein the cosmetic composition comprises at least one UV filter selected from the group consisting of UV-A filters, UV-B filters, light protection pigments and mixtures thereof. 13. The method of claim 11, wherein the cosmetic composition comprises at least one skin lightening agent. 14. The Method of claim 10, comprising treatment, prevention and/or amelioration of hyperpigmentation. 15. The method of claim 14, wherein the hyperpigmentation is induced by the radiation of sunlight, preferably induced by the radiation of visible light and/or UVB within a wavelength from 280 nm to 750 nm. | 1,600 |
1,422 | 15,610,267 | 1,646 | The present invention provides methods for treating atopic dermatitis (AD). Also provided are methods for improving one or more AD-associated parameter(s), and methods for decreasing the level of at least one AD-associated biomarker in a subject in need thereof. The methods of the present invention comprise administering to a subject in need thereof a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist such as an anti-IL-4R antibody. | 1. A method for reducing pruritus associated with atopic dermatitis (AD) in a patient, the method comprising:
(a) selecting a patient with moderate-to-severe atopic dermatitis, wherein the patient exhibits a Pruritus Numeric Rating Scale (NRS) score ≧5 and/or a 5-D Pruritus score ≧18; and (b) administering to the patient one or more doses of a pharmaceutical composition comprising a therapeutically effective amount of an anti-interleukin-4-receptor (IL-4R) antibody or antigen-binding fragment thereof;
wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain complementarity determining regions (CDRs) in a heavy chain variable region/light chain variable region (HCVR/LCVR) amino acid sequence pair comprising SEQ ID NOs: 162/164. 2. The method of claim 1, wherein the patient is resistant, inadequately responsive or intolerant to topical corticosteroids or topical calcineurin inhibitors. 3. The method of claim 1, wherein the patient has a history of side effects or safety risks associated with topical corticosteroids or topical calcineurin inhibitors. 4. The method of claim 1, wherein the patient, following administration of the pharmaceutical composition, exhibits reduced pruritus as measured by a decrease from baseline in NRS score of at least 30%; and/or a decrease from baseline in 5-D Pruritus score of at least 30%. 5. The method of claim 4, wherein the patient, following administration of the pharmaceutical composition exhibits an improvement in at least one AD-associated parameter selected from the group consisting of:
(i) a decrease from baseline in Investigator's Global Assessment (IGA) score of at least 25%; (ii) a decrease from baseline in Eczema Area and Severity Index (EASI) score of at least 50%; (iii) a decrease from baseline in SCORing Atopic Dermatitis (SCORAD) score of at least 30%; and (iv) a decrease from baseline in Body Surface Area Involvement of Atopic Dermatitis (BSA) score of at least 25%. 6. The method of claim 5, wherein the improvement comprises a decrease from baseline in IGA score to achieve an IGA score of 0 or 1 by week 16 after administration of the first dose of the pharmaceutical composition. 7. The method of claim 5, wherein the improvement comprises an IGA score reduction of ≧2 by week 16 after administration of the first dose of the pharmaceutical composition. 8. The method of claim 5, wherein the improvement comprises a decrease from baseline in IGA of at least 30% on day 29 after administration of the first dose of the pharmaceutical composition. 9. The method of claim 5 wherein the improvement comprises a decrease from baseline in NRS of at least 40% on day 29 after administration of the first dose of the pharmaceutical composition. 10. The method of claim 5, wherein the improvement comprises a decrease from baseline in EASI of at least 60% on day 29 after administration of the first dose of the pharmaceutical composition. 11. The method of claim 5, wherein the improvement comprises a decrease from baseline in SCORAD of at least 40% on day 29 after administration of the first dose of the pharmaceutical composition. 12. The method of claim 5, wherein the improvement comprises a decrease from baseline in 5-D Pruritus score of at least 35% on day 29 after administration of the first dose of the pharmaceutical composition. 13. The method of claim 5, wherein the improvement comprises a decrease from baseline in BSA score of at least 35% on day 29 after administration of the first dose of the pharmaceutical composition. 14. The method of claim 5, wherein the improvement comprises a decrease from baseline in EASI score of 75% by week 16 after administration of the first dose of the pharmaceutical composition. 15. The method of claim 1, wherein each dose of the pharmaceutical composition comprises about 50 to about 600 mg of the anti-IL-4R antibody or antigen-binding fragment thereof. 16. The method of claim 1, wherein each dose of the pharmaceutical composition comprises about 300 mg of the anti-IL-4R antibody or antigen-binding fragment thereof. 17. The method of claim 1, wherein step (b) comprises: administering an initial dose of the pharmaceutical composition to the patient; followed by administering one or more subsequent doses of the pharmaceutical composition to the patient. 18. The method of claim 17, wherein the initial dose comprises about 600 mg of the anti-IL-4R antibody or antigen-binding fragment thereof; and wherein each subsequent dose comprises about 300 mg of the anti-IL-4R antibody or antigen-binding fragment thereof. 19. The method of claim 18, wherein each subsequent dose is administered to the patient one week after the immediately preceding dose. 20. The method of claim 18, wherein each subsequent dose is administered to the patient two weeks after the immediately preceding dose. 21. The method of claim 1, wherein step (b) further comprises concomitantly administering topical corticosteroids daily for up to 28 days. 22. The method of claim 21, wherein the daily amount of topical corticosteroids used by the patient is gradually reduced following administration of the first dose of the pharmaceutical composition. 23. The method of claim 22, wherein the daily amount of topical corticosteroids used by the patient is reduced by about 20% to about 50% over 4 weeks following administration of the first dose of the pharmaceutical composition. 24. The method of claim 1, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDRs (HCDRs) comprising SEQ ID NOs: 148, 150 and 152, respectively, and three light chain CDRs (LCDRs) comprising SEQ ID NOs: 156, 158 and 160, respectively. | The present invention provides methods for treating atopic dermatitis (AD). Also provided are methods for improving one or more AD-associated parameter(s), and methods for decreasing the level of at least one AD-associated biomarker in a subject in need thereof. The methods of the present invention comprise administering to a subject in need thereof a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist such as an anti-IL-4R antibody.1. A method for reducing pruritus associated with atopic dermatitis (AD) in a patient, the method comprising:
(a) selecting a patient with moderate-to-severe atopic dermatitis, wherein the patient exhibits a Pruritus Numeric Rating Scale (NRS) score ≧5 and/or a 5-D Pruritus score ≧18; and (b) administering to the patient one or more doses of a pharmaceutical composition comprising a therapeutically effective amount of an anti-interleukin-4-receptor (IL-4R) antibody or antigen-binding fragment thereof;
wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain complementarity determining regions (CDRs) in a heavy chain variable region/light chain variable region (HCVR/LCVR) amino acid sequence pair comprising SEQ ID NOs: 162/164. 2. The method of claim 1, wherein the patient is resistant, inadequately responsive or intolerant to topical corticosteroids or topical calcineurin inhibitors. 3. The method of claim 1, wherein the patient has a history of side effects or safety risks associated with topical corticosteroids or topical calcineurin inhibitors. 4. The method of claim 1, wherein the patient, following administration of the pharmaceutical composition, exhibits reduced pruritus as measured by a decrease from baseline in NRS score of at least 30%; and/or a decrease from baseline in 5-D Pruritus score of at least 30%. 5. The method of claim 4, wherein the patient, following administration of the pharmaceutical composition exhibits an improvement in at least one AD-associated parameter selected from the group consisting of:
(i) a decrease from baseline in Investigator's Global Assessment (IGA) score of at least 25%; (ii) a decrease from baseline in Eczema Area and Severity Index (EASI) score of at least 50%; (iii) a decrease from baseline in SCORing Atopic Dermatitis (SCORAD) score of at least 30%; and (iv) a decrease from baseline in Body Surface Area Involvement of Atopic Dermatitis (BSA) score of at least 25%. 6. The method of claim 5, wherein the improvement comprises a decrease from baseline in IGA score to achieve an IGA score of 0 or 1 by week 16 after administration of the first dose of the pharmaceutical composition. 7. The method of claim 5, wherein the improvement comprises an IGA score reduction of ≧2 by week 16 after administration of the first dose of the pharmaceutical composition. 8. The method of claim 5, wherein the improvement comprises a decrease from baseline in IGA of at least 30% on day 29 after administration of the first dose of the pharmaceutical composition. 9. The method of claim 5 wherein the improvement comprises a decrease from baseline in NRS of at least 40% on day 29 after administration of the first dose of the pharmaceutical composition. 10. The method of claim 5, wherein the improvement comprises a decrease from baseline in EASI of at least 60% on day 29 after administration of the first dose of the pharmaceutical composition. 11. The method of claim 5, wherein the improvement comprises a decrease from baseline in SCORAD of at least 40% on day 29 after administration of the first dose of the pharmaceutical composition. 12. The method of claim 5, wherein the improvement comprises a decrease from baseline in 5-D Pruritus score of at least 35% on day 29 after administration of the first dose of the pharmaceutical composition. 13. The method of claim 5, wherein the improvement comprises a decrease from baseline in BSA score of at least 35% on day 29 after administration of the first dose of the pharmaceutical composition. 14. The method of claim 5, wherein the improvement comprises a decrease from baseline in EASI score of 75% by week 16 after administration of the first dose of the pharmaceutical composition. 15. The method of claim 1, wherein each dose of the pharmaceutical composition comprises about 50 to about 600 mg of the anti-IL-4R antibody or antigen-binding fragment thereof. 16. The method of claim 1, wherein each dose of the pharmaceutical composition comprises about 300 mg of the anti-IL-4R antibody or antigen-binding fragment thereof. 17. The method of claim 1, wherein step (b) comprises: administering an initial dose of the pharmaceutical composition to the patient; followed by administering one or more subsequent doses of the pharmaceutical composition to the patient. 18. The method of claim 17, wherein the initial dose comprises about 600 mg of the anti-IL-4R antibody or antigen-binding fragment thereof; and wherein each subsequent dose comprises about 300 mg of the anti-IL-4R antibody or antigen-binding fragment thereof. 19. The method of claim 18, wherein each subsequent dose is administered to the patient one week after the immediately preceding dose. 20. The method of claim 18, wherein each subsequent dose is administered to the patient two weeks after the immediately preceding dose. 21. The method of claim 1, wherein step (b) further comprises concomitantly administering topical corticosteroids daily for up to 28 days. 22. The method of claim 21, wherein the daily amount of topical corticosteroids used by the patient is gradually reduced following administration of the first dose of the pharmaceutical composition. 23. The method of claim 22, wherein the daily amount of topical corticosteroids used by the patient is reduced by about 20% to about 50% over 4 weeks following administration of the first dose of the pharmaceutical composition. 24. The method of claim 1, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDRs (HCDRs) comprising SEQ ID NOs: 148, 150 and 152, respectively, and three light chain CDRs (LCDRs) comprising SEQ ID NOs: 156, 158 and 160, respectively. | 1,600 |
1,423 | 15,603,279 | 1,654 | Methods for treating subjects suffering from chronic kidney disease-mineral and bone disorder or other disorders resulting in primary or secondary hyperparathyroidism are described. The methods are effective in reducing serum parathyroid hormone (PTH) levels and calcium levels in patients who undergo hemodialysis. The methods described herein are also effective in slowing the progression of kidney disease and preserving kidney function. Compositions used in the described methods are also provided and comprise calcimimetics which function as agonists of the calcium sensing receptor (CaSR). | 1. A method for treating chronic kidney disease-mineral bone disorder (CKD-MBD) characterized by soft tissue calcification in a subject, comprising:
administering to the subject a composition comprising a therapeutically effective amount of a calcimimetic having a sequence Ac-c(C)arrrar-NH2 (SEQ ID NO:3) or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of the calcimimetic reduces the amount of soft tissue calcification in the subject. 2. The method of claim 1, wherein the subject has been diagnosed with Stage 3 or Stage 4 chronic kidney disease. 3. The method of claim 1, wherein the disorder is characterized by uremia. 4. The method of claim 1, wherein the disorder is characterized by parathyroid gland hyperplasia. 5. The method of claim 1, wherein the disorder is characterized by renal insufficiency. 6. The method of claim 1, wherein the soft tissue calcification is vascular calcification. 7. The method of claim 1, wherein the composition is administered to CKD-MBD patients in end stage renal disease receiving hemodialysis, and wherein the composition is administered intravenously three times per week. | Methods for treating subjects suffering from chronic kidney disease-mineral and bone disorder or other disorders resulting in primary or secondary hyperparathyroidism are described. The methods are effective in reducing serum parathyroid hormone (PTH) levels and calcium levels in patients who undergo hemodialysis. The methods described herein are also effective in slowing the progression of kidney disease and preserving kidney function. Compositions used in the described methods are also provided and comprise calcimimetics which function as agonists of the calcium sensing receptor (CaSR).1. A method for treating chronic kidney disease-mineral bone disorder (CKD-MBD) characterized by soft tissue calcification in a subject, comprising:
administering to the subject a composition comprising a therapeutically effective amount of a calcimimetic having a sequence Ac-c(C)arrrar-NH2 (SEQ ID NO:3) or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount of the calcimimetic reduces the amount of soft tissue calcification in the subject. 2. The method of claim 1, wherein the subject has been diagnosed with Stage 3 or Stage 4 chronic kidney disease. 3. The method of claim 1, wherein the disorder is characterized by uremia. 4. The method of claim 1, wherein the disorder is characterized by parathyroid gland hyperplasia. 5. The method of claim 1, wherein the disorder is characterized by renal insufficiency. 6. The method of claim 1, wherein the soft tissue calcification is vascular calcification. 7. The method of claim 1, wherein the composition is administered to CKD-MBD patients in end stage renal disease receiving hemodialysis, and wherein the composition is administered intravenously three times per week. | 1,600 |
1,424 | 14,942,592 | 1,631 | The disclosed computerized system and method facilitates predicting the onset of diabetes or symptom progression in those patients already suffering from the disease. The computerized system and method applies steps to segment the population by predefined member characteristics. Once segmented, the computerized system and method applies a plurality of prediction models to the segmented population data to provide a ranking of members of the population that indicates the likelihood of onset or progression of diabetes for each member. | 1. A method for predicting the onset of diabetes in a population without diabetes comprising:
receiving health related patient data from a plurality of sources; performing an extraction process upon the received data to extract features that describe at least one patient; processing the extracted data using a summarization process, a standardization process, and a filtration process; segmenting the processed data according to data characteristics; and applying a plurality of models to the segmented data that identify the relationships between characteristics of the data and onset of diabetes for at least one patient. 2. The method of claim 1, wherein the plurality of models applied comprise at least one of a neural network, logistic regression, or a decision tree. 3. The method of claim 1, wherein the model applied is selected by verifying each of the plurality of models using holdout data to determine the accuracy of each model and the model with the greatest accuracy is selected. 4. The method of claim 1, wherein the received data comprises at least one of: health surveys received from a group of individuals, data representing demographics of the group of individuals, data comprising summarized medical lab test results for the group of individuals, insurance claims by members of the group of individuals for medical care, insurance claims by members of the group for pharmacy services, and consumer data regarding the members. 5. The method of claim 1, wherein the extracted features comprise at least one of: a patient's demographic profile, a patient's clinical profile, a patient's behavior profile, a patient's medication profile, and disease progression profiles. 6. The method of claim 1, wherein the plurality of models are applied in response to a user input selection. 7. A method for predicting the progression of diabetes in patients with diabetes comprising:
receiving health related data from a plurality of sources; performing an extraction process upon the received data to extract features that describe at least one patient; processing the extracted data using a summarization process, a standardization process, and a filtration process; segmenting the processed data according to data characteristics; and applying a plurality of models to the segmented data which identify the relationships between characteristics of the data and progression of diabetes in patients with diabetes. 8. The method of claim 7, wherein the progression is represented by an index comprising a plurality of complications associated with diabetes. 9. The method of claim 7, wherein application of the model produces a list of patients arranged progressively from a low severity range to a medium to a high severity range on a scale of progression of diabetes. 10. The method of claim 7, wherein application of the model identifies patients at risk of progressing from lower severity level to a high severity level. 11. The method of claim 7, wherein the plurality of models applied comprise at least one of a neural network, logistic regression, or a decision tree. 12. The method of claim 7, wherein the model applied is selected by verifying each of the plurality of models using holdout data to determine the accuracy of each model and the model with the greatest accuracy is selected. 13. The method of claim 7, wherein the received data comprises at least one of:
health surveys received from a group of individuals, data representing demographics of the group of individuals, data comprising summarized medical lab test results for the group of individuals, insurance claims by members of the group of individuals for medical care, insurance claims by members of the group for pharmacy services, and consumer data regarding the members. 14. The method of claim 7, wherein the extracted features comprise at least one of: a patient's demographic profile, a patient's clinical profile, a patient's behavior profile, a patient's medication profile, and disease progression profiles. 15. The method of claim 7, wherein the plurality of models are applied in response to a user input selection. | The disclosed computerized system and method facilitates predicting the onset of diabetes or symptom progression in those patients already suffering from the disease. The computerized system and method applies steps to segment the population by predefined member characteristics. Once segmented, the computerized system and method applies a plurality of prediction models to the segmented population data to provide a ranking of members of the population that indicates the likelihood of onset or progression of diabetes for each member.1. A method for predicting the onset of diabetes in a population without diabetes comprising:
receiving health related patient data from a plurality of sources; performing an extraction process upon the received data to extract features that describe at least one patient; processing the extracted data using a summarization process, a standardization process, and a filtration process; segmenting the processed data according to data characteristics; and applying a plurality of models to the segmented data that identify the relationships between characteristics of the data and onset of diabetes for at least one patient. 2. The method of claim 1, wherein the plurality of models applied comprise at least one of a neural network, logistic regression, or a decision tree. 3. The method of claim 1, wherein the model applied is selected by verifying each of the plurality of models using holdout data to determine the accuracy of each model and the model with the greatest accuracy is selected. 4. The method of claim 1, wherein the received data comprises at least one of: health surveys received from a group of individuals, data representing demographics of the group of individuals, data comprising summarized medical lab test results for the group of individuals, insurance claims by members of the group of individuals for medical care, insurance claims by members of the group for pharmacy services, and consumer data regarding the members. 5. The method of claim 1, wherein the extracted features comprise at least one of: a patient's demographic profile, a patient's clinical profile, a patient's behavior profile, a patient's medication profile, and disease progression profiles. 6. The method of claim 1, wherein the plurality of models are applied in response to a user input selection. 7. A method for predicting the progression of diabetes in patients with diabetes comprising:
receiving health related data from a plurality of sources; performing an extraction process upon the received data to extract features that describe at least one patient; processing the extracted data using a summarization process, a standardization process, and a filtration process; segmenting the processed data according to data characteristics; and applying a plurality of models to the segmented data which identify the relationships between characteristics of the data and progression of diabetes in patients with diabetes. 8. The method of claim 7, wherein the progression is represented by an index comprising a plurality of complications associated with diabetes. 9. The method of claim 7, wherein application of the model produces a list of patients arranged progressively from a low severity range to a medium to a high severity range on a scale of progression of diabetes. 10. The method of claim 7, wherein application of the model identifies patients at risk of progressing from lower severity level to a high severity level. 11. The method of claim 7, wherein the plurality of models applied comprise at least one of a neural network, logistic regression, or a decision tree. 12. The method of claim 7, wherein the model applied is selected by verifying each of the plurality of models using holdout data to determine the accuracy of each model and the model with the greatest accuracy is selected. 13. The method of claim 7, wherein the received data comprises at least one of:
health surveys received from a group of individuals, data representing demographics of the group of individuals, data comprising summarized medical lab test results for the group of individuals, insurance claims by members of the group of individuals for medical care, insurance claims by members of the group for pharmacy services, and consumer data regarding the members. 14. The method of claim 7, wherein the extracted features comprise at least one of: a patient's demographic profile, a patient's clinical profile, a patient's behavior profile, a patient's medication profile, and disease progression profiles. 15. The method of claim 7, wherein the plurality of models are applied in response to a user input selection. | 1,600 |
1,425 | 14,240,273 | 1,644 | The present invention is concerned with a protein oligomer comprising at least two NC-1 monomers of human collagen 18 or fragments of an NC-1 monomer of human collagen 18 for use in the treatment or prevention of an angiogenesis-related disease. The invention further pertains to a fusion protein comprising a NC-1 monomer of human collagen 18 and a Fc domain of an immunoglobulin. The invention also relates to a fusion protein comprising: a) an endostatin peptide or endostatin-derived peptide and b) the RGD motif and/or PHSRN motif of Fibronectin. The invention further relates to a kit comprising the protein oligomer or fusion proteins of the invention. | 1-19. (canceled) 20. A method for treating or preventing an angiogenesis-related disease in a patient in the need thereof, comprising administering to the patient a therapeutically effective dose of a protein oligomer comprising at least two NC-1 monomers of human collagen 18 or fragments of an NC-1 monomer of human collagen 18, thereby treating or preventing the angiogenesis-related disease in the patient. 21. The method of claim 20, wherein the NC-1 monomer of human collagen 18 comprises an oligomerization domain, a hinge region, and/or an endostatin domain or fragments of the endostatin domain and, optionally a recombinant protease cleavage site within the hinge region. 22. The method of claim 21, wherein the oligomerization domain comprises a non-triple helical trimerization domain of human collagen 18, an Fc domain and/or an artificial oligomerization domain. 23. The method of claim 22, wherein the Fc domain is from IgG. 24. The method of claim 22, wherein the artificial oligomerization domain comprises a single mutation at position 7 of the endostatin domain in which glutamine is replaced by cysteine. 25. The method of claim 21, wherein the recombinant protease cleavage site within the hinge region is an enterokinase or thrombin cleavage site. 26. The method of claim 20, wherein the domain arrangement within the NC-1 monomer of human collagen 18 is oligomerization domain—hinge region—endostatin domain or endostatin domain—hinge region—oligomerization domain. 27. The method of claim 20, wherein the angiogenesis-related disease is selected from the group consisting of angiogenesis-dependent cancer, solid tumors, melanomas, tumor metastases, blood born tumors, leukemias, benign tumors, hemangiomas, acoustic neuromas, neurofibromas, trachomas, pyogenic granulomas, rheumatoid arthritis, psoriasis, ocular angiogenic diseases, diabetic retinopathy, retinopathy of prematurity, macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasias, rubeosis, Osler-Webber syndrome, myocardial angiogenesis, plaque neovascularization, telangiectasia, hemophiliac joints, angiofibroma, wound granulation, diseases of excessive or abnormal stimulation of endothelial cells, intestinal adhesions, atherosclerosis, scleroderma, hypertrophic scars (keloids), diseases that have angiogenesis as a pathologic consequence, cat scratch disease (Rochele minalia quintosa), and ulcers (Helobacter pylori). 28. A fusion protein comprising an NC-1 monomer of human collagen 18 and an Fc domain of an immunoglobulin. 29. The fusion protein of claim 28, wherein the NC-1 monomer of human collagen 18 comprises an oligomerization domain, a hinge region and/or an endostatin domain and, optionally a recombinant protease cleavage site within the hinge region. 30. The fusion protein of claim 29, wherein the oligomerization domain comprises a non-triple helical trimerization domain of human collagen 18 and/or an artificial oligomerization domain. 31. The fusion protein of claim 29, wherein the Fc domain is from IgG. 32. The fusion protein of claim 30, wherein the artificial oligomerization domain comprises a single mutation at position 7 of the endostatin domain in which glutamine is replaced by cysteine. 33. The fusion protein of claim 29, wherein the recombinant protease cleavage site within the hinge region is an enterokinase or thrombin cleavage site. 34. The fusion protein of claim 28, wherein the domain arrangement of the fusion protein is (a) Fc domain—oligomerization domain—hinge region—endostatin domain or (b) oligomerization domain—hinge region—endostatin domain—Fc domain or (c) Fc domain—endostatin domain—hinge region—oligomerization domain or (d) endostatin domain—hinge region—oligomerization domain—Fc domain. 35. A fusion protein comprising:
(a) an endostatin peptide or endostatin-derived peptide; and (b) the ROD motif and/or PHSRN motif of fibronectin. 36. A medicament or diagnostic composition comprising the fusion protein of claim 28. 37. A medicament or diagnostic composition comprising the fusion protein of claim 35. 38. A kit comprising the fusion protein of claim 28. 39. A kit comprising the fusion protein of claim 35. 40. A method for predicting the response of a cancer patient to an applied cancer therapy, comprising the steps of:
(a) measuring the level of fibronectin, in a sample of the patient by using the NC-1 oligomer referred to in claim 20, and (b) predicting the response of the patient to the cancer therapy, wherein low levels of fibronectin as compared to a reference level of a healthy subject is indicative for a non-response of the patient to the applied cancer therapy. 41. A method for predicting the response of a cancer patient to an applied cancer therapy, comprising the steps of:
(a) measuring the level of fibronectin in a sample of the patient by using the fusion protein of claim 28, and (b) predicting the response of the patient to the cancer therapy, wherein low levels of fibronectin as compared to a reference level of a healthy subject is indicative for a non-response of the patient to the applied cancer therapy. 42. A method for treating or preventing an angiogenesis-related disease in a patient in need thereof, comprising administering to the patient a therapeutically effective dose of the fusion protein of claim 28, thereby treating or preventing the angiogenesis-related disease in the patient. 43. A method for treating or preventing an angiogenesis-related disease in a patient in need thereof, comprising administering to the patient a therapeutically effective dose of the fusion protein of claim 35, thereby treating or preventing the angiogenesis-related disease in the patient. | The present invention is concerned with a protein oligomer comprising at least two NC-1 monomers of human collagen 18 or fragments of an NC-1 monomer of human collagen 18 for use in the treatment or prevention of an angiogenesis-related disease. The invention further pertains to a fusion protein comprising a NC-1 monomer of human collagen 18 and a Fc domain of an immunoglobulin. The invention also relates to a fusion protein comprising: a) an endostatin peptide or endostatin-derived peptide and b) the RGD motif and/or PHSRN motif of Fibronectin. The invention further relates to a kit comprising the protein oligomer or fusion proteins of the invention.1-19. (canceled) 20. A method for treating or preventing an angiogenesis-related disease in a patient in the need thereof, comprising administering to the patient a therapeutically effective dose of a protein oligomer comprising at least two NC-1 monomers of human collagen 18 or fragments of an NC-1 monomer of human collagen 18, thereby treating or preventing the angiogenesis-related disease in the patient. 21. The method of claim 20, wherein the NC-1 monomer of human collagen 18 comprises an oligomerization domain, a hinge region, and/or an endostatin domain or fragments of the endostatin domain and, optionally a recombinant protease cleavage site within the hinge region. 22. The method of claim 21, wherein the oligomerization domain comprises a non-triple helical trimerization domain of human collagen 18, an Fc domain and/or an artificial oligomerization domain. 23. The method of claim 22, wherein the Fc domain is from IgG. 24. The method of claim 22, wherein the artificial oligomerization domain comprises a single mutation at position 7 of the endostatin domain in which glutamine is replaced by cysteine. 25. The method of claim 21, wherein the recombinant protease cleavage site within the hinge region is an enterokinase or thrombin cleavage site. 26. The method of claim 20, wherein the domain arrangement within the NC-1 monomer of human collagen 18 is oligomerization domain—hinge region—endostatin domain or endostatin domain—hinge region—oligomerization domain. 27. The method of claim 20, wherein the angiogenesis-related disease is selected from the group consisting of angiogenesis-dependent cancer, solid tumors, melanomas, tumor metastases, blood born tumors, leukemias, benign tumors, hemangiomas, acoustic neuromas, neurofibromas, trachomas, pyogenic granulomas, rheumatoid arthritis, psoriasis, ocular angiogenic diseases, diabetic retinopathy, retinopathy of prematurity, macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasias, rubeosis, Osler-Webber syndrome, myocardial angiogenesis, plaque neovascularization, telangiectasia, hemophiliac joints, angiofibroma, wound granulation, diseases of excessive or abnormal stimulation of endothelial cells, intestinal adhesions, atherosclerosis, scleroderma, hypertrophic scars (keloids), diseases that have angiogenesis as a pathologic consequence, cat scratch disease (Rochele minalia quintosa), and ulcers (Helobacter pylori). 28. A fusion protein comprising an NC-1 monomer of human collagen 18 and an Fc domain of an immunoglobulin. 29. The fusion protein of claim 28, wherein the NC-1 monomer of human collagen 18 comprises an oligomerization domain, a hinge region and/or an endostatin domain and, optionally a recombinant protease cleavage site within the hinge region. 30. The fusion protein of claim 29, wherein the oligomerization domain comprises a non-triple helical trimerization domain of human collagen 18 and/or an artificial oligomerization domain. 31. The fusion protein of claim 29, wherein the Fc domain is from IgG. 32. The fusion protein of claim 30, wherein the artificial oligomerization domain comprises a single mutation at position 7 of the endostatin domain in which glutamine is replaced by cysteine. 33. The fusion protein of claim 29, wherein the recombinant protease cleavage site within the hinge region is an enterokinase or thrombin cleavage site. 34. The fusion protein of claim 28, wherein the domain arrangement of the fusion protein is (a) Fc domain—oligomerization domain—hinge region—endostatin domain or (b) oligomerization domain—hinge region—endostatin domain—Fc domain or (c) Fc domain—endostatin domain—hinge region—oligomerization domain or (d) endostatin domain—hinge region—oligomerization domain—Fc domain. 35. A fusion protein comprising:
(a) an endostatin peptide or endostatin-derived peptide; and (b) the ROD motif and/or PHSRN motif of fibronectin. 36. A medicament or diagnostic composition comprising the fusion protein of claim 28. 37. A medicament or diagnostic composition comprising the fusion protein of claim 35. 38. A kit comprising the fusion protein of claim 28. 39. A kit comprising the fusion protein of claim 35. 40. A method for predicting the response of a cancer patient to an applied cancer therapy, comprising the steps of:
(a) measuring the level of fibronectin, in a sample of the patient by using the NC-1 oligomer referred to in claim 20, and (b) predicting the response of the patient to the cancer therapy, wherein low levels of fibronectin as compared to a reference level of a healthy subject is indicative for a non-response of the patient to the applied cancer therapy. 41. A method for predicting the response of a cancer patient to an applied cancer therapy, comprising the steps of:
(a) measuring the level of fibronectin in a sample of the patient by using the fusion protein of claim 28, and (b) predicting the response of the patient to the cancer therapy, wherein low levels of fibronectin as compared to a reference level of a healthy subject is indicative for a non-response of the patient to the applied cancer therapy. 42. A method for treating or preventing an angiogenesis-related disease in a patient in need thereof, comprising administering to the patient a therapeutically effective dose of the fusion protein of claim 28, thereby treating or preventing the angiogenesis-related disease in the patient. 43. A method for treating or preventing an angiogenesis-related disease in a patient in need thereof, comprising administering to the patient a therapeutically effective dose of the fusion protein of claim 35, thereby treating or preventing the angiogenesis-related disease in the patient. | 1,600 |
1,426 | 16,062,151 | 1,612 | Disclosed herein are oral care compositions comprising at least one phosphate/acrylate copolymer, at least one cationic antibacterial agent, at least one synthetic anionic linear polycarboxylate polymer, at least one surfactant, and zinc lactate. Also disclosed herein are methods for the treatment and/or inhibition of gum disease or halitosis comprising contacting the oral cavity with the oral care compositions disclosed herein, as well as methods of making the oral care compositions disclose herein. | 1. An oral care composition comprising:
at least one phosphate/acrylate copolymer; at least one cationic antibacterial agent; at least one synthetic anionic linear polycarboxylate polymer; at least one surfactant; and zinc lactate. 2. The oral care composition according to claim 1, wherein the at least one cationic antibacterial agent is cetylpyridinium chloride. 3. The oral care composition according to claim 1, wherein the oral care composition has a turbidity of less than or equal to 20 Nephelometric Turbidity Units at 25° C. 4. The oral care composition according to claim 1, wherein the oral care composition has a turbidity of less than or equal to 15 Nephelometric Turbidity Units at 25° C. 5. The oral care composition according to claim 1, wherein the at least one surfactant is a nonionic poly(oxyethylene)-poly(oxypropylene) block copolymer. 6. The oral care composition according to claim 1, wherein the at least one phosphate/acrylate copolymer is present in an amount of at least about 2.5% by weight. 7. The oral care composition according to claim 1, wherein the at least one synthetic anionic linear polycarboxylate polymer is present in an amount of about 1% by weight. 8. The oral care composition according to claim 1, wherein the at least one cationic antibacterial agent is present in an amount ranging from about 0.03% to about 1.2% by weight. 9. The oral care composition according to claim 1, wherein the at least one surfactant is present in an amount of about 1% by weight. 10. The oral care composition according to claim 1, wherein the zinc lactate is present in an amount ranging from about 0.1% to about 0.5%. 11. An oral care composition comprising:
at least one phosphate/acrylate copolymer present in an amount of about 2.5% by weight; cetylpyridinium chloride present in an amount of about 0.07% by weight; at least one synthetic anionic linear polycarboxylate polymer present in an amount of about 1% by weight; at least one surfactant; and zinc lactate. 12. The oral care composition according to claim 11, wherein the at least one surfactant is a nonionic poly(oxyethylene)-poly(oxypropylene) block copolymer. 13. The oral care composition according to claim 11, wherein the at least one surfactant is present in an amount ranging from about 0.1% to about 1% by weight. 14. A method for the treatment and/or inhibition of gum disease or halitosis comprising contacting the oral cavity with an oral care composition according to any of the preceding claims. 15. A method of making the oral care composition of claim 1, comprising:
(i) mixing water, the at least one surfactant, the at least one cationic antibacterial agent, the zinc lactate, the synthetic anionic linear polycarboxylate polymer, and the phosphate/acrylate copolymer to form a main mix; and (ii) optionally mixing flavorants and/or cooling agents with a glycol to form a premix and adding the premix to the main mix after the main mix has been formulated. | Disclosed herein are oral care compositions comprising at least one phosphate/acrylate copolymer, at least one cationic antibacterial agent, at least one synthetic anionic linear polycarboxylate polymer, at least one surfactant, and zinc lactate. Also disclosed herein are methods for the treatment and/or inhibition of gum disease or halitosis comprising contacting the oral cavity with the oral care compositions disclosed herein, as well as methods of making the oral care compositions disclose herein.1. An oral care composition comprising:
at least one phosphate/acrylate copolymer; at least one cationic antibacterial agent; at least one synthetic anionic linear polycarboxylate polymer; at least one surfactant; and zinc lactate. 2. The oral care composition according to claim 1, wherein the at least one cationic antibacterial agent is cetylpyridinium chloride. 3. The oral care composition according to claim 1, wherein the oral care composition has a turbidity of less than or equal to 20 Nephelometric Turbidity Units at 25° C. 4. The oral care composition according to claim 1, wherein the oral care composition has a turbidity of less than or equal to 15 Nephelometric Turbidity Units at 25° C. 5. The oral care composition according to claim 1, wherein the at least one surfactant is a nonionic poly(oxyethylene)-poly(oxypropylene) block copolymer. 6. The oral care composition according to claim 1, wherein the at least one phosphate/acrylate copolymer is present in an amount of at least about 2.5% by weight. 7. The oral care composition according to claim 1, wherein the at least one synthetic anionic linear polycarboxylate polymer is present in an amount of about 1% by weight. 8. The oral care composition according to claim 1, wherein the at least one cationic antibacterial agent is present in an amount ranging from about 0.03% to about 1.2% by weight. 9. The oral care composition according to claim 1, wherein the at least one surfactant is present in an amount of about 1% by weight. 10. The oral care composition according to claim 1, wherein the zinc lactate is present in an amount ranging from about 0.1% to about 0.5%. 11. An oral care composition comprising:
at least one phosphate/acrylate copolymer present in an amount of about 2.5% by weight; cetylpyridinium chloride present in an amount of about 0.07% by weight; at least one synthetic anionic linear polycarboxylate polymer present in an amount of about 1% by weight; at least one surfactant; and zinc lactate. 12. The oral care composition according to claim 11, wherein the at least one surfactant is a nonionic poly(oxyethylene)-poly(oxypropylene) block copolymer. 13. The oral care composition according to claim 11, wherein the at least one surfactant is present in an amount ranging from about 0.1% to about 1% by weight. 14. A method for the treatment and/or inhibition of gum disease or halitosis comprising contacting the oral cavity with an oral care composition according to any of the preceding claims. 15. A method of making the oral care composition of claim 1, comprising:
(i) mixing water, the at least one surfactant, the at least one cationic antibacterial agent, the zinc lactate, the synthetic anionic linear polycarboxylate polymer, and the phosphate/acrylate copolymer to form a main mix; and (ii) optionally mixing flavorants and/or cooling agents with a glycol to form a premix and adding the premix to the main mix after the main mix has been formulated. | 1,600 |
1,427 | 15,766,517 | 1,612 | An oral care composition comprising at least one metal phosphate chosen from stannous phosphate, magnesium phosphate or aluminum phosphate; and at least one fluoride ion source. The at least one phosphate is added to the oral care composition as a preformed salt. Methods of administering the oral care composition to a subject are also disclosed. | 1. An oral care composition, comprising:
at least one metal phosphate chosen from stannous phosphate, magnesium phosphate or aluminum phosphate, wherein the at least one phosphate is added to the oral care composition as a preformed salt; and at least one fluoride ion source. 2. The oral care composition of claim 1, wherein the at least one metal phosphate is stannous phosphate. 3. The oral care composition of claim 1, wherein the amount of the at least one phosphate is from 0.1 to 10% by weight, relative to the weight of the oral care composition. 4. The oral care composition of claim 1, wherein the at least one fluoride ion source is chosen from stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride, ammonium fluoride, or combinations thereof. 5. The oral care composition of claim 1, wherein the amount of the at least one fluoride salt is from 0.01 to 10% by weight, relative to the weight of the oral care composition. 6. The oral care composition of claim 1, wherein the dentifrice composition further comprises an abrasive. 7. The oral care composition of claim 1, further comprising one or more humectants and one or more surfactants. 8. The oral care composition of claim 1, further comprising an effective amount of one or more alkali phosphate salts that is different from the at least one metal phosphate. 9. The oral care composition of claim 1, further comprising a whitening agent. 10. The oral care composition of claim 1, with the proviso that the oral care composition is essentially free of acyl sarcosinate or salts thereof, an antioxidant, a phytic acid compound, a copper containing compound, ethylenediaminetetracetates and polyorganosilsesquioxane. 11. The oral care composition of claim 1, wherein the oral care composition is a dentifrice. 12. The oral care composition of claim 1, wherein the oral care composition comprises:
from 0.1 to 10% by weight stannous phosphate; from 1 to 8% by weight alkali phosphate salts selected from sodium phosphate dibasic, potassium phosphate dibasic, dicalcium phosphate dihydrate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, calcium pyrophosphate, sodium tripolyphosphate, and mixtures of any two or more of these; from 0.05 to 0.5% by weight fluoride; and a silica abrasive dentifrice base. 13. The oral care composition of claim 1, wherein the oral care composition is a gel. 14. The oral care composition of claim 1, wherein the oral care composition is in the form of a lozenge or mint. 15. The oral care composition of claim 1, wherein the oral care composition is a chewing gum. 16. The oral care composition of claim 1, further comprising an effective amount of one or more anti-microbial agents. 17. The oral care composition of claim 1, wherein the pH of the composition is acidic. 18. The oral care composition of claim 1, wherein the pH of the composition is basic. 19. A method of treating or reducing dental enamel erosion comprising administering a composition according to claim 1 to the oral cavity of a subject in need thereof. | An oral care composition comprising at least one metal phosphate chosen from stannous phosphate, magnesium phosphate or aluminum phosphate; and at least one fluoride ion source. The at least one phosphate is added to the oral care composition as a preformed salt. Methods of administering the oral care composition to a subject are also disclosed.1. An oral care composition, comprising:
at least one metal phosphate chosen from stannous phosphate, magnesium phosphate or aluminum phosphate, wherein the at least one phosphate is added to the oral care composition as a preformed salt; and at least one fluoride ion source. 2. The oral care composition of claim 1, wherein the at least one metal phosphate is stannous phosphate. 3. The oral care composition of claim 1, wherein the amount of the at least one phosphate is from 0.1 to 10% by weight, relative to the weight of the oral care composition. 4. The oral care composition of claim 1, wherein the at least one fluoride ion source is chosen from stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride, ammonium fluoride, or combinations thereof. 5. The oral care composition of claim 1, wherein the amount of the at least one fluoride salt is from 0.01 to 10% by weight, relative to the weight of the oral care composition. 6. The oral care composition of claim 1, wherein the dentifrice composition further comprises an abrasive. 7. The oral care composition of claim 1, further comprising one or more humectants and one or more surfactants. 8. The oral care composition of claim 1, further comprising an effective amount of one or more alkali phosphate salts that is different from the at least one metal phosphate. 9. The oral care composition of claim 1, further comprising a whitening agent. 10. The oral care composition of claim 1, with the proviso that the oral care composition is essentially free of acyl sarcosinate or salts thereof, an antioxidant, a phytic acid compound, a copper containing compound, ethylenediaminetetracetates and polyorganosilsesquioxane. 11. The oral care composition of claim 1, wherein the oral care composition is a dentifrice. 12. The oral care composition of claim 1, wherein the oral care composition comprises:
from 0.1 to 10% by weight stannous phosphate; from 1 to 8% by weight alkali phosphate salts selected from sodium phosphate dibasic, potassium phosphate dibasic, dicalcium phosphate dihydrate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, calcium pyrophosphate, sodium tripolyphosphate, and mixtures of any two or more of these; from 0.05 to 0.5% by weight fluoride; and a silica abrasive dentifrice base. 13. The oral care composition of claim 1, wherein the oral care composition is a gel. 14. The oral care composition of claim 1, wherein the oral care composition is in the form of a lozenge or mint. 15. The oral care composition of claim 1, wherein the oral care composition is a chewing gum. 16. The oral care composition of claim 1, further comprising an effective amount of one or more anti-microbial agents. 17. The oral care composition of claim 1, wherein the pH of the composition is acidic. 18. The oral care composition of claim 1, wherein the pH of the composition is basic. 19. A method of treating or reducing dental enamel erosion comprising administering a composition according to claim 1 to the oral cavity of a subject in need thereof. | 1,600 |
1,428 | 15,839,491 | 1,623 | The invention provides methods of reducing inflammation and improving the catabolic/anabolic state to promote healing of the cartilage in a joint by providing an oral dosage of either an anthocyanin or an anthocyanidin or their metabolites or a combination thereof. The treatment can occur before surgery, injury or inflammation occurs as a prophylactic treatment and/or can continue during or after the surgery, injury or inflammation has begun. | 1. A method of treating osteoarthritis in a patient having an osteoarthritic joint, comprising orally administering a therapeutically effective amount of PCA to the patient;
wherein the therapeutically effective amount elicits an osteoarthritis disease modifying response comprising:
decreased inflammation and an altered catabolic to anabolic state of the osteoarthritic joint and
improved chondronutrition and chondro-protection of articular cartilage of the osteoarthritic joint. 2. The method of claim 1, wherein the osteoarthritis disease modifying response further comprises:
increased IGF-1 expression and IGF-1 levels in a synovium and synovial fluid of the osteoarthritic joint, a reduction of MMP3 expression and MMP3 levels in a synovium and cartilage of the osteoarthritic joint, and increased expression levels of lubricin, aggrecan and type II collagen in a cartilage of the osteoarthritic joint. 3. The method of claim 1, wherein the osteoarthritis disease modifying response further comprises decreased levels of at least one of MMP1 and MMP13 in a synovial fluid of the osteoarthritic joint. 4. The method of claim 1, wherein the osteoarthritis disease modifying response further comprises increased levels of at least one of TIMP-1, VEGF, IL-10, and IL-4 in a synovial fluid of the osteoarthritic joint. 5. The method of claim 1, wherein the altered catabolic to anabolic state of the osteoarthritic joint comprises one or more of:
a reduction in levels of at least one of MMP3, MMP-1, MMP13, IL-1B, TNF-alpha, and ADAMTS-5 in a synovial fluid or synovium of the osteoarthritic joint; an increase in levels of at least one of IGF-1, TIMP-1, VEGF, IL-10, and IL-4, in a synovial fluid or synovium of the osteoarthritic joint; an increase in levels of lubricin in a synovium of the osteoarthritic join or an articular cartilage of the osteoarthritic joint; an increase in aggrecan and collagen II in an articular cartilage matrix of the osteoarthritic joint. 6. The method of claim 1, wherein the therapeutically effective amount comprises administering an oral daily dose of 0.100 to 0.200 mmoles of PCA per kg of body weight of the patient. 7. The method of claim 1 wherein the therapeutically effective amount comprises administering a daily dose of the PCA for at least 6 weeks of a dose of 0.100 to 0.200 millimoles per kg body weight of the patient. 8. The method of claim 1, wherein the therapeutically effective amount comprises administering a daily dose of the PCA for at least 10 weeks of a dose of 0.100 to 0.200 millimoles per kg body weight of the patient. 9. The method of claim 1, wherein the therapeutically effective amount comprises administering a daily dose of the PCA for at least 4 weeks of a dose of 0.100 to 0.200 millimoles per kg body weight of the patient, starting at day 42 after an injury of a joint or surgery of a joint. 10. The method of claim 5, wherein increasing expression levels of a lubricin, aggrecan and type II collagen in the cartilage of an osteoarthritic joint, results in a chondro-protective and/or chondro-nutritive effect on the synovial joint. 11. The method of claim 1, wherein the PCA is provided as a prophylactic treatment to the patient in advance of a surgery to the osteoarthritic joint. 12. The method of claim 1, further comprising providing PCA to the patient after a surgery. 13. A dosing regimen for modifying an osteoarthritic disease process in a patient having an osteoarthritic joint, wherein the dosing regimen comprises an oral administration of 0.100 to 0.200 mmoles of PCA per kg of body weight of PCA to the patient, thereby modifying the osteoarthritic disease process. 14. The dosing regimen of claim 13, wherein modifying the osteoarthritic disease process comprises one or more of:
decreased inflammation and an altered catabolic to anabolicstate of the osteoarthritic joint, thereby restoring a synovial cytokine homeostasis; improved chondronutrition and chondro-protection of articular cartilage of the osteoarthritic joint; decreased levels of MMP1 and MMP13 in a synovial fluid of the osteoarthritic joint; increased IGF-1 expression and IGF-1 levels in a synovium and synovial fluid of the osteoarthritic joint; a reduction of MMP3 expression and MMP3 levels in a synovium and cartilage of the osteoarthritic joint; increased expression levels of lubricin, aggrecan and type II collagen in a cartilage of the osteoarthritic joint; increased levels of TIMP-1, VEGF, IL-10, and IL-4 in the synovial fluid of the osteoarthritic joint; a reduction in the levels of MMP3, MMP-1, MMP13, IL-1B, TNF-alpha, ADAMTS-5 in a synovial fluid or synovium of the osteoarthritic joint; an increase in levels of IGF-1, TIMP-1, VEGF, IL-10, and IL-4 in the synovial fluid or synovium of the osteoarthritic joint; an increase in levels of lubricin in a synovium of the osteoarthritic join or an articular cartilage of the osteoarthritic joint; an increase in aggrecan and collagen II in an articular cartilage matrix of the osteoarthritic joint. 15. The dosing regimen of claim 13, wherein 0.100 to 0.200 millimoles per kg body weight of PCA is administered as a daily dose for at least 6 weeks. 16. The dosing regimen of claim 13, wherein 0.100 to 0.200 millimoles per kg body weight of PCA is administered as a daily dose for at least 10 weeks. 17. The dosing regimen of claim 13, wherein 0.100 to 0.200 millimoles per kg body weight of PCA is administered as a daily dose for at least 4 weeks starting at day 42 after an injury of a joint or surgery of an osteoarthritic joint. 18. A disease modifying osteoarthritic composition comprising PCA and one or more pharmaceutically acceptable carriers; wherein the PCA is at least 97% pure; and wherein the composition contains no additional therapeutic active ingredients. 19. The composition of claim 18, wherein the composition is formulated for an administration of an oral daily dose of 0.100 to 0.200 mmoles of PCA per kg of body weight of a patient. 20. The composition of claim 18, wherein the composition elicits an osteoarthritis disease modifying response comprising one or more of:
decreased inflammation and an altered catabolic to anabolic state of the osteoarthritic joint; improved chondronutrition and chondro-protection of articular cartilage of an osteoarthritic joint; decreased levels of MMP1 and MMP13 in a synovial fluid of an osteoarthritic joint; increased IGF-1 expression and IGF-1 levels in a synovium and synovial fluid of the osteoarthritic joint; a reduction of MMP3 expression and MMP3 levels in a synovium and cartilage of the osteoarthritic joint; increased expression levels of lubricin, aggrecan and type II collagen in a cartilage of an osteoarthritic joint; increased levels of TIMP-1, VEGF, IL-10, and IL-4 in the synovial fluid of an osteoarthritic joint; a reduction in the levels of MMP3, MMP-1, MMP13, IL-1B, TNF-alpha, ADAMTS-5 in a synovial fluid or synovium of the osteoarthritic joint; an increase in levels of IGF-1, TIMP-1, VEGF, IL-10, and IL-4 in the synovial fluid or synovium of an osteoarthritic joint; an increase in levels of lubricin in a synovium of the osteoarthritic join or an articular cartilage of the osteoarthritic joint; and an increase in aggrecan and collagen II in an articular cartilage matrix of the osteoarthritic joint. | The invention provides methods of reducing inflammation and improving the catabolic/anabolic state to promote healing of the cartilage in a joint by providing an oral dosage of either an anthocyanin or an anthocyanidin or their metabolites or a combination thereof. The treatment can occur before surgery, injury or inflammation occurs as a prophylactic treatment and/or can continue during or after the surgery, injury or inflammation has begun.1. A method of treating osteoarthritis in a patient having an osteoarthritic joint, comprising orally administering a therapeutically effective amount of PCA to the patient;
wherein the therapeutically effective amount elicits an osteoarthritis disease modifying response comprising:
decreased inflammation and an altered catabolic to anabolic state of the osteoarthritic joint and
improved chondronutrition and chondro-protection of articular cartilage of the osteoarthritic joint. 2. The method of claim 1, wherein the osteoarthritis disease modifying response further comprises:
increased IGF-1 expression and IGF-1 levels in a synovium and synovial fluid of the osteoarthritic joint, a reduction of MMP3 expression and MMP3 levels in a synovium and cartilage of the osteoarthritic joint, and increased expression levels of lubricin, aggrecan and type II collagen in a cartilage of the osteoarthritic joint. 3. The method of claim 1, wherein the osteoarthritis disease modifying response further comprises decreased levels of at least one of MMP1 and MMP13 in a synovial fluid of the osteoarthritic joint. 4. The method of claim 1, wherein the osteoarthritis disease modifying response further comprises increased levels of at least one of TIMP-1, VEGF, IL-10, and IL-4 in a synovial fluid of the osteoarthritic joint. 5. The method of claim 1, wherein the altered catabolic to anabolic state of the osteoarthritic joint comprises one or more of:
a reduction in levels of at least one of MMP3, MMP-1, MMP13, IL-1B, TNF-alpha, and ADAMTS-5 in a synovial fluid or synovium of the osteoarthritic joint; an increase in levels of at least one of IGF-1, TIMP-1, VEGF, IL-10, and IL-4, in a synovial fluid or synovium of the osteoarthritic joint; an increase in levels of lubricin in a synovium of the osteoarthritic join or an articular cartilage of the osteoarthritic joint; an increase in aggrecan and collagen II in an articular cartilage matrix of the osteoarthritic joint. 6. The method of claim 1, wherein the therapeutically effective amount comprises administering an oral daily dose of 0.100 to 0.200 mmoles of PCA per kg of body weight of the patient. 7. The method of claim 1 wherein the therapeutically effective amount comprises administering a daily dose of the PCA for at least 6 weeks of a dose of 0.100 to 0.200 millimoles per kg body weight of the patient. 8. The method of claim 1, wherein the therapeutically effective amount comprises administering a daily dose of the PCA for at least 10 weeks of a dose of 0.100 to 0.200 millimoles per kg body weight of the patient. 9. The method of claim 1, wherein the therapeutically effective amount comprises administering a daily dose of the PCA for at least 4 weeks of a dose of 0.100 to 0.200 millimoles per kg body weight of the patient, starting at day 42 after an injury of a joint or surgery of a joint. 10. The method of claim 5, wherein increasing expression levels of a lubricin, aggrecan and type II collagen in the cartilage of an osteoarthritic joint, results in a chondro-protective and/or chondro-nutritive effect on the synovial joint. 11. The method of claim 1, wherein the PCA is provided as a prophylactic treatment to the patient in advance of a surgery to the osteoarthritic joint. 12. The method of claim 1, further comprising providing PCA to the patient after a surgery. 13. A dosing regimen for modifying an osteoarthritic disease process in a patient having an osteoarthritic joint, wherein the dosing regimen comprises an oral administration of 0.100 to 0.200 mmoles of PCA per kg of body weight of PCA to the patient, thereby modifying the osteoarthritic disease process. 14. The dosing regimen of claim 13, wherein modifying the osteoarthritic disease process comprises one or more of:
decreased inflammation and an altered catabolic to anabolicstate of the osteoarthritic joint, thereby restoring a synovial cytokine homeostasis; improved chondronutrition and chondro-protection of articular cartilage of the osteoarthritic joint; decreased levels of MMP1 and MMP13 in a synovial fluid of the osteoarthritic joint; increased IGF-1 expression and IGF-1 levels in a synovium and synovial fluid of the osteoarthritic joint; a reduction of MMP3 expression and MMP3 levels in a synovium and cartilage of the osteoarthritic joint; increased expression levels of lubricin, aggrecan and type II collagen in a cartilage of the osteoarthritic joint; increased levels of TIMP-1, VEGF, IL-10, and IL-4 in the synovial fluid of the osteoarthritic joint; a reduction in the levels of MMP3, MMP-1, MMP13, IL-1B, TNF-alpha, ADAMTS-5 in a synovial fluid or synovium of the osteoarthritic joint; an increase in levels of IGF-1, TIMP-1, VEGF, IL-10, and IL-4 in the synovial fluid or synovium of the osteoarthritic joint; an increase in levels of lubricin in a synovium of the osteoarthritic join or an articular cartilage of the osteoarthritic joint; an increase in aggrecan and collagen II in an articular cartilage matrix of the osteoarthritic joint. 15. The dosing regimen of claim 13, wherein 0.100 to 0.200 millimoles per kg body weight of PCA is administered as a daily dose for at least 6 weeks. 16. The dosing regimen of claim 13, wherein 0.100 to 0.200 millimoles per kg body weight of PCA is administered as a daily dose for at least 10 weeks. 17. The dosing regimen of claim 13, wherein 0.100 to 0.200 millimoles per kg body weight of PCA is administered as a daily dose for at least 4 weeks starting at day 42 after an injury of a joint or surgery of an osteoarthritic joint. 18. A disease modifying osteoarthritic composition comprising PCA and one or more pharmaceutically acceptable carriers; wherein the PCA is at least 97% pure; and wherein the composition contains no additional therapeutic active ingredients. 19. The composition of claim 18, wherein the composition is formulated for an administration of an oral daily dose of 0.100 to 0.200 mmoles of PCA per kg of body weight of a patient. 20. The composition of claim 18, wherein the composition elicits an osteoarthritis disease modifying response comprising one or more of:
decreased inflammation and an altered catabolic to anabolic state of the osteoarthritic joint; improved chondronutrition and chondro-protection of articular cartilage of an osteoarthritic joint; decreased levels of MMP1 and MMP13 in a synovial fluid of an osteoarthritic joint; increased IGF-1 expression and IGF-1 levels in a synovium and synovial fluid of the osteoarthritic joint; a reduction of MMP3 expression and MMP3 levels in a synovium and cartilage of the osteoarthritic joint; increased expression levels of lubricin, aggrecan and type II collagen in a cartilage of an osteoarthritic joint; increased levels of TIMP-1, VEGF, IL-10, and IL-4 in the synovial fluid of an osteoarthritic joint; a reduction in the levels of MMP3, MMP-1, MMP13, IL-1B, TNF-alpha, ADAMTS-5 in a synovial fluid or synovium of the osteoarthritic joint; an increase in levels of IGF-1, TIMP-1, VEGF, IL-10, and IL-4 in the synovial fluid or synovium of an osteoarthritic joint; an increase in levels of lubricin in a synovium of the osteoarthritic join or an articular cartilage of the osteoarthritic joint; and an increase in aggrecan and collagen II in an articular cartilage matrix of the osteoarthritic joint. | 1,600 |
1,429 | 16,288,571 | 1,654 | Provided herein are water soluble salts of Formula I, wherein R 1 , A, and M are defined herein. Also provided herein are methods of preparing the salts of Formula I and methods of using the same. | 1. A compound having Formula I,
wherein
M is Li, Na, or K,
or M is SrX, MgX, CaX or ZnX, wherein X is a monovalent anion of Formula I-Acid;
A is a bond, or
A represents a monopeptide or dipeptide linker, wherein the monopeptide or dipeptide is comprised of one or two amino acid units, each independently selected from the group consisting of alanine, (Ala, A), arginine (Arg, R), asparagine (Asn, N), aspartic acid (Asp, D), cysteine (Cys, C), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), leucine (Leu, L), lysine (Lys, K), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), and valine (Val, V), wherein the N and C terminals of the monopeptide or dipeptide is linked to R1C(═O) and the pyrrolidine nitrogen atom through amide bonds, respectively; and
R1 is a straight chain or branched chain C1-36 alkyl, a straight chain or branched chain C2-36 alkenyl, or a straight chain or branched chain C2-36 alkynyl. 2. The compound of claim 1, wherein M is Na. 3. The compound of claim 1, wherein A is an L-proline linker. 4. The compound of claim 1, having a formula selected from compounds I-1 to I-10: 5. The compound of claim 4, wherein the compound is amorphous, Form A, Form B, Form C, Form D, Form E or Form F of compound I-1. 6. The compound of claim 5, wherein the compound is amorphous of compound I-1. 7. The compound of claim 6, wherein the amorphous of compound I-1 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 3. 8. A pharmaceutical composition comprising the compound I-1 in an amorphous form,
wherein upon storage at 40° C. at a relative humidity of 75% or at 25° C. at a relative humidity of 60% for 6 month, the pharmaceutical composition is substantially free of the compound I-1 in a crystalline form. 9. The pharmaceutical composition of claim 8, wherein upon storage at 40° C. at a relative humidity of 75% for 6 month, the pharmaceutical composition is characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 12, at the respective time point. 10. A method of preparing a compound having Formula I-C,
comprising the steps of
(a) providing a mixture comprising the compound I-C-Acid in water;
(b) adding M2CO3, MHCO3 or MOH to the mixture of step (a);
(c) heating and stirring the mixture of step (b);
(d) cooling the mixture of step (c); and
(e) filtering the mixture of step (d),
wherein M is Li, Na, or K; and
R1 is a straight chain or branched chain C1-36 alkyl, a straight chain or branched chain C2-36 alkenyl, or a straight chain or branched chain C2-36 alkynyl. 11. The method of claim 10, wherein M is Na. 12. A method of preparing a compound having Formula I-C,
comprising the steps of
(a) providing a mixture comprising the compound I-C-Acid in protic organic solvents with or without water;
(b) adding M2CO3, MHCO3 or MOH to the mixture of step (a);
(c) stirring the mixture of step (b);
(d) removing solvents from the mixture of step (c) under reduced pressure; and
(e) removing water from the mixture of step (d) by lyophilization,
wherein M is Li, Na, or K; and
R1 is a straight chain or branched chain C1-36 alkyl, a straight chain or branched chain C2-36 alkenyl, or a straight chain or branched chain C2-36 alkynyl. 13. The method of claim 12, wherein M is Na. 14. A method of preparing amorphous form of a compound having Formula I-C
comprising the steps of
(a) providing a crystalline form of the Formula I-C in organic solvents;
(b) heating and stirring the mixture of step (a); and
(c) removing organic solvents from the mixture of step (b)
wherein M is Li, Na, or K; and
R1 is a straight chain or branched chain C1-36 alkyl, a straight chain or branched chain C2-36 alkenyl, or a straight chain or branched chain C2-36 alkynyl. 15. The method of claim 14, wherein M is Na. | Provided herein are water soluble salts of Formula I, wherein R 1 , A, and M are defined herein. Also provided herein are methods of preparing the salts of Formula I and methods of using the same.1. A compound having Formula I,
wherein
M is Li, Na, or K,
or M is SrX, MgX, CaX or ZnX, wherein X is a monovalent anion of Formula I-Acid;
A is a bond, or
A represents a monopeptide or dipeptide linker, wherein the monopeptide or dipeptide is comprised of one or two amino acid units, each independently selected from the group consisting of alanine, (Ala, A), arginine (Arg, R), asparagine (Asn, N), aspartic acid (Asp, D), cysteine (Cys, C), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), leucine (Leu, L), lysine (Lys, K), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), and valine (Val, V), wherein the N and C terminals of the monopeptide or dipeptide is linked to R1C(═O) and the pyrrolidine nitrogen atom through amide bonds, respectively; and
R1 is a straight chain or branched chain C1-36 alkyl, a straight chain or branched chain C2-36 alkenyl, or a straight chain or branched chain C2-36 alkynyl. 2. The compound of claim 1, wherein M is Na. 3. The compound of claim 1, wherein A is an L-proline linker. 4. The compound of claim 1, having a formula selected from compounds I-1 to I-10: 5. The compound of claim 4, wherein the compound is amorphous, Form A, Form B, Form C, Form D, Form E or Form F of compound I-1. 6. The compound of claim 5, wherein the compound is amorphous of compound I-1. 7. The compound of claim 6, wherein the amorphous of compound I-1 has an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 3. 8. A pharmaceutical composition comprising the compound I-1 in an amorphous form,
wherein upon storage at 40° C. at a relative humidity of 75% or at 25° C. at a relative humidity of 60% for 6 month, the pharmaceutical composition is substantially free of the compound I-1 in a crystalline form. 9. The pharmaceutical composition of claim 8, wherein upon storage at 40° C. at a relative humidity of 75% for 6 month, the pharmaceutical composition is characterized by an X-ray powder diffraction (XRPD) pattern substantially the same as shown in FIG. 12, at the respective time point. 10. A method of preparing a compound having Formula I-C,
comprising the steps of
(a) providing a mixture comprising the compound I-C-Acid in water;
(b) adding M2CO3, MHCO3 or MOH to the mixture of step (a);
(c) heating and stirring the mixture of step (b);
(d) cooling the mixture of step (c); and
(e) filtering the mixture of step (d),
wherein M is Li, Na, or K; and
R1 is a straight chain or branched chain C1-36 alkyl, a straight chain or branched chain C2-36 alkenyl, or a straight chain or branched chain C2-36 alkynyl. 11. The method of claim 10, wherein M is Na. 12. A method of preparing a compound having Formula I-C,
comprising the steps of
(a) providing a mixture comprising the compound I-C-Acid in protic organic solvents with or without water;
(b) adding M2CO3, MHCO3 or MOH to the mixture of step (a);
(c) stirring the mixture of step (b);
(d) removing solvents from the mixture of step (c) under reduced pressure; and
(e) removing water from the mixture of step (d) by lyophilization,
wherein M is Li, Na, or K; and
R1 is a straight chain or branched chain C1-36 alkyl, a straight chain or branched chain C2-36 alkenyl, or a straight chain or branched chain C2-36 alkynyl. 13. The method of claim 12, wherein M is Na. 14. A method of preparing amorphous form of a compound having Formula I-C
comprising the steps of
(a) providing a crystalline form of the Formula I-C in organic solvents;
(b) heating and stirring the mixture of step (a); and
(c) removing organic solvents from the mixture of step (b)
wherein M is Li, Na, or K; and
R1 is a straight chain or branched chain C1-36 alkyl, a straight chain or branched chain C2-36 alkenyl, or a straight chain or branched chain C2-36 alkynyl. 15. The method of claim 14, wherein M is Na. | 1,600 |
1,430 | 15,858,237 | 1,611 | The present disclosure relates to stable cosmetic compositions that include high levels of free glycolic acid. The cosmetic compositions typically include: glycolic acid and/or a salt thereof; at least one non-silicone fatty compound; at least one emulsifier; at least one water-soluble solvent; at least one silicone; and water. The cosmetic compositions are in the form of an emulsion, in particular, a water-in-oil emulsion, and typically have a low pH of below 7. Also, the cosmetic compositions have high amount of free glycolic acid, for example, at least 6 wt. % of free glycolic acid, based on the total weight of the cosmetic composition. The cosmetic compositions are particularly useful for improving the appearance of skin. Accordingly, the instant disclosure relates to methods of treating skin, for example, improving the appearance of skin using the cosmetic compositions. | 1. A cosmetic composition comprising:
at least 6 to about 25 wt. % of free glycolic acid and/or a salt thereof, provided that the cosmetic composition comprises at least 6 wt. % of free glycolic acid; about 5 to about 40 wt. % of at least one non-silicone fatty compound; about 0.1 to about 20 wt. % of at least one emulsifier; about 1 to about 40 wt. % of at least one water-soluble solvent; about 0.1 to about 40 wt. % of at least one silicone; and about 15 to about 80 wt. % of water;
wherein the cosmetic composition is a water-in-oil emulsion having a pH of about 3 to about 6 and all wt. % values are based on the total weight of the cosmetic composition. 2. The cosmetic composition of claim 1, wherein the at least one non-silicone fatty compound is selected from the group consisting of oils, waxes, mineral oil, fatty alcohols, fatty acids, fatty alcohol derivatives, fatty acid derivatives, esters of fatty alcohols, hydroxy-substituted fatty acids, linear or branched hydrocarbons of mineral or synthetic origin, triglyceride compounds, lanolin, and a mixture thereof. 3. The cosmetic composition of claim 1, wherein the at least one emulsifier comprises at least one silicone-based emulsifier. 4. The cosmetic composition of claim 3, wherein the at least one silicone-based emulsifier is a polyalkylene glycol-modified silicone emulsifier. 5. The cosmetic composition of claim 4, wherein the polyalkylene glycol-modified silicone emulsifier is selected from the group consisting of cetyl PEG/PPG-10/1 dimethicone, cetyl PEG/PPG-7/3 dimethicone, PEG/PPG-10/3 oleyl ether dimethicone, lauryl Dimethicone PEG-15 crosspolymer, cetyl PEG/PPG-15/15 butyl ether dimethicone, alkyl methicone copolyols, and alkyl dimethicone ethoxy glucoside, and a mixture thereof. 6. The cosmetic composition of claim 3, further comprising at least one non-silicone based nonionic emulsifier. 7. The cosmetic composition of claim 6, wherein the at least one non-silicone based nonionic emulsifier is selected from the group consisting of polyol esters, glycerol ethers, oxyethylenated and/or oxypropylenated ethers, ethylene glycol polymers, and mixtures thereof. 8. The cosmetic composition of claim 6, wherein the at least one non-silicone based nonionic emulsifier is selected from the group consisting of glyceryl lanolate, glyceryl monostearate, glyceryl distearate, glyceryl monoisostearate, glyceryl monomyristate, glyceryl monooleate, diglyceryl monostearate, glyceryl monolaurate, glyceryl monocaprinate, glyceryl monocaprylate, diglyceryl monoisostearate, diglyceryl diisostearate, propylene glycol monostearate, propylene glycol monolaurate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monocaprylate, sorbitan sesquistearate, sorbitan monoisooleate, sucrose distearate, cetyl alcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol, isobehenyl alcohol, 2-ethylhexylglycerol ether, selachyl alcohol, chimyl alcohol, polyethylene glycol(2)stearyl ether(Steareth-2), glyceryl sorbitan stearate, polyglyceryl-4 isostearate, polyglyceryl-2 sesquiisostearate, PEG-7 hydrogenated castor oil, isostearyldiglyceryl succinate, PEG-5 cholesteryl ether, PEG-30 dipolyhydroxystearate, decaglyceryl heptaoleate, polyglyceryl-3 diisostearate, PEG-8 distearate, diglycerol dipolyhydroxystearate, glycerol isostearate, sorbitan isostearate, polyglyceryl-3 methyl glucose distearate, PEG-2 stearate, PEG-45/dodecyl glycol copolymer, PEG-22/dodecyl glycol copolymer, methoxy PEG-22/dodecyl glycol copolymer, and a mixture thereof. 9. The cosmetic composition of claim 1 comprising at least one silicone-based emulsifier and at least one non-silicone based nonionic emulsifier. 10. The cosmetic composition of claim 1, wherein the at least one water-soluble solvent is selected from the group consisting of glycerin, alcohols, organic solvents, polyols, glycols, and a mixture thereof. 11. The cosmetic composition of claim 1, wherein the at least one silicone is selected from the group consisting of polyorganosiloxanes, polyalkylsiloxanes, polyarylsiloxanes, polyalkarylsiloxanes, polyestersiloxanes, and a mixture thereof. 12. The cosmetic composition of claim 11, wherein the at least one silicone is selected from the group consisting of dimethicone, cyclomethicone (cyclopentasiloxane), amodimethicone, trimethyl silyl amodimethicone, phenyl trimethicone, trimethyl siloxy silicate, and a mixture thereof. 13. The cosmetic composition of claim 1, further comprising at least one mattifying agent. 14. The cosmetic composition of claim 13, wherein the at least one mattifying agent is selected from the group consisting of methyl methacrylate/glycol dimethacrylate crosspolymer, vinyl dimethicone/methicone silsesquioxane crosspolymer, methyl methacrylate crosspolymer, nylon-12, polyamides, polyethylene, talc, titanium dioxide, silica, aluminum starch octenylsuccinate, or a mixture thereof. 15. The cosmetic composition of claim 13, wherein the total amount of mattifying agent(s) is about 0.1 to about 10 wt. %, based on the total weight of the cosmetic composition. 16. (canceled) 17. A cosmetic composition comprising:
about 10 to about 25 wt. % of free glycolic acid and/or a salt thereof, provided that the cosmetic composition comprises at least 8 wt. % of free glycolic acid; optionally, about 1 to about 20 wt. % of phytic acid and/or a salt thereof; about 5 to about 40 wt. % of at least one non-silicone fatty compound selected from the group consisting of oils, waxes, mineral oil, fatty alcohols, fatty acids, fatty alcohol derivatives, fatty acid derivatives, esters of fatty alcohols, hydroxy-substituted fatty acids, triglyceride compounds, lanolin, linear or branched hydrocarbons of mineral or synthetic origin, and a mixture thereof; about 0.1 to about 10 wt. % of at least one silicone-based emulsifier; about 0.01 to about 10 wt. % of at least one non-silicone based nonionic emulsifier; about 5 to about 30 wt. % of at least one water-soluble solvent selected from the group consisting of glycerin, alcohols, organic solvents, polyols, glycols, and a mixture thereof; about 0.1 to about 40 wt. % of at least one silicone selected from the group consisting of polyorganosiloxanes, polyalkylsiloxanes, polyarylsiloxanes, polyalkarylsiloxanes, polyestersiloxanes, and a mixture thereof; and about 15 to about 80 wt. % of water; wherein the cosmetic composition is a water-in-oil emulsion having a pH of about 3 to about 5, and all wt. % values are based on the total weight of the cosmetic composition. 18. The cosmetic composition of claim 17 comprising:
about 10 to about 20 wt. % of free glycolic acid and/or a salt thereof;
about 1 to about 10 wt. % of phytic acid and/or a salt thereof;
about 10 to about 30 wt. % of at least one non-silicone fatty compound selected from the group consisting of oils, waxes, mineral oil, lanolin, linear or branched hydrocarbons of mineral or synthetic origin, and a mixture thereof;
about 0.1 to about 10 wt. % of at least one polyalkylene glycol-modified silicone emulsifier;
about 0.01 to about 10 wt. % of at least one non-silicone based nonionic emulsifier
about 1 to about 40 wt. % of at least one water-soluble solvent selected from the group consisting of glycerin, alcohols, organic solvents, polyols, glycols, and a mixture thereof;
about 1 to about 25 wt. % of at least one silicone selected from the group consisting of dimethicone, cyclomethicone (cyclopentasiloxane),
amodimethicone, trimethyl silyl amodimethicone, phenyl trimethicone, trimethyl siloxy silicate, and a mixture thereof; and
about 20 to about 60 wt. % of water. 19. A method for improving the appearance of skin comprising applying a cosmetic composition of claim 1 to the skin. 20. The method of claim 19, wherein the method comprises:
reducing the appearance of fine lines of the skin; reducing the appearance of wrinkles of the skin; improving the tone of skin and/or improving the evenness of skin tone; improving skin softness and/or smoothness; and/or increasing the radiance, luminosity, and/or glow of the skin. 21. The cosmetic composition of claim 1 having a pH of about 3 to about 5. 22. A cosmetic composition comprising:
at least 6 to about 25 wt. % of free glycolic acid and/or a salt thereof, provided that the cosmetic composition comprises at least 6 wt. % of free glycolic acid; about 5 to about 40 wt. % of at least one non-silicone fatty compound; about 0.1 to about 20 wt. % of at least one emulsifier; about 1 to about 40 wt. % of at least one water-soluble solvent; about 0.1 to about 40 wt. % of dimethicone; and about 15 to about 80 wt. % of water;
wherein the cosmetic composition is a water-in-oil emulsion having a pH of about 3 to about 6 and all wt. % values are based on the total weight of the cosmetic composition. | The present disclosure relates to stable cosmetic compositions that include high levels of free glycolic acid. The cosmetic compositions typically include: glycolic acid and/or a salt thereof; at least one non-silicone fatty compound; at least one emulsifier; at least one water-soluble solvent; at least one silicone; and water. The cosmetic compositions are in the form of an emulsion, in particular, a water-in-oil emulsion, and typically have a low pH of below 7. Also, the cosmetic compositions have high amount of free glycolic acid, for example, at least 6 wt. % of free glycolic acid, based on the total weight of the cosmetic composition. The cosmetic compositions are particularly useful for improving the appearance of skin. Accordingly, the instant disclosure relates to methods of treating skin, for example, improving the appearance of skin using the cosmetic compositions.1. A cosmetic composition comprising:
at least 6 to about 25 wt. % of free glycolic acid and/or a salt thereof, provided that the cosmetic composition comprises at least 6 wt. % of free glycolic acid; about 5 to about 40 wt. % of at least one non-silicone fatty compound; about 0.1 to about 20 wt. % of at least one emulsifier; about 1 to about 40 wt. % of at least one water-soluble solvent; about 0.1 to about 40 wt. % of at least one silicone; and about 15 to about 80 wt. % of water;
wherein the cosmetic composition is a water-in-oil emulsion having a pH of about 3 to about 6 and all wt. % values are based on the total weight of the cosmetic composition. 2. The cosmetic composition of claim 1, wherein the at least one non-silicone fatty compound is selected from the group consisting of oils, waxes, mineral oil, fatty alcohols, fatty acids, fatty alcohol derivatives, fatty acid derivatives, esters of fatty alcohols, hydroxy-substituted fatty acids, linear or branched hydrocarbons of mineral or synthetic origin, triglyceride compounds, lanolin, and a mixture thereof. 3. The cosmetic composition of claim 1, wherein the at least one emulsifier comprises at least one silicone-based emulsifier. 4. The cosmetic composition of claim 3, wherein the at least one silicone-based emulsifier is a polyalkylene glycol-modified silicone emulsifier. 5. The cosmetic composition of claim 4, wherein the polyalkylene glycol-modified silicone emulsifier is selected from the group consisting of cetyl PEG/PPG-10/1 dimethicone, cetyl PEG/PPG-7/3 dimethicone, PEG/PPG-10/3 oleyl ether dimethicone, lauryl Dimethicone PEG-15 crosspolymer, cetyl PEG/PPG-15/15 butyl ether dimethicone, alkyl methicone copolyols, and alkyl dimethicone ethoxy glucoside, and a mixture thereof. 6. The cosmetic composition of claim 3, further comprising at least one non-silicone based nonionic emulsifier. 7. The cosmetic composition of claim 6, wherein the at least one non-silicone based nonionic emulsifier is selected from the group consisting of polyol esters, glycerol ethers, oxyethylenated and/or oxypropylenated ethers, ethylene glycol polymers, and mixtures thereof. 8. The cosmetic composition of claim 6, wherein the at least one non-silicone based nonionic emulsifier is selected from the group consisting of glyceryl lanolate, glyceryl monostearate, glyceryl distearate, glyceryl monoisostearate, glyceryl monomyristate, glyceryl monooleate, diglyceryl monostearate, glyceryl monolaurate, glyceryl monocaprinate, glyceryl monocaprylate, diglyceryl monoisostearate, diglyceryl diisostearate, propylene glycol monostearate, propylene glycol monolaurate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monocaprylate, sorbitan sesquistearate, sorbitan monoisooleate, sucrose distearate, cetyl alcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol, isobehenyl alcohol, 2-ethylhexylglycerol ether, selachyl alcohol, chimyl alcohol, polyethylene glycol(2)stearyl ether(Steareth-2), glyceryl sorbitan stearate, polyglyceryl-4 isostearate, polyglyceryl-2 sesquiisostearate, PEG-7 hydrogenated castor oil, isostearyldiglyceryl succinate, PEG-5 cholesteryl ether, PEG-30 dipolyhydroxystearate, decaglyceryl heptaoleate, polyglyceryl-3 diisostearate, PEG-8 distearate, diglycerol dipolyhydroxystearate, glycerol isostearate, sorbitan isostearate, polyglyceryl-3 methyl glucose distearate, PEG-2 stearate, PEG-45/dodecyl glycol copolymer, PEG-22/dodecyl glycol copolymer, methoxy PEG-22/dodecyl glycol copolymer, and a mixture thereof. 9. The cosmetic composition of claim 1 comprising at least one silicone-based emulsifier and at least one non-silicone based nonionic emulsifier. 10. The cosmetic composition of claim 1, wherein the at least one water-soluble solvent is selected from the group consisting of glycerin, alcohols, organic solvents, polyols, glycols, and a mixture thereof. 11. The cosmetic composition of claim 1, wherein the at least one silicone is selected from the group consisting of polyorganosiloxanes, polyalkylsiloxanes, polyarylsiloxanes, polyalkarylsiloxanes, polyestersiloxanes, and a mixture thereof. 12. The cosmetic composition of claim 11, wherein the at least one silicone is selected from the group consisting of dimethicone, cyclomethicone (cyclopentasiloxane), amodimethicone, trimethyl silyl amodimethicone, phenyl trimethicone, trimethyl siloxy silicate, and a mixture thereof. 13. The cosmetic composition of claim 1, further comprising at least one mattifying agent. 14. The cosmetic composition of claim 13, wherein the at least one mattifying agent is selected from the group consisting of methyl methacrylate/glycol dimethacrylate crosspolymer, vinyl dimethicone/methicone silsesquioxane crosspolymer, methyl methacrylate crosspolymer, nylon-12, polyamides, polyethylene, talc, titanium dioxide, silica, aluminum starch octenylsuccinate, or a mixture thereof. 15. The cosmetic composition of claim 13, wherein the total amount of mattifying agent(s) is about 0.1 to about 10 wt. %, based on the total weight of the cosmetic composition. 16. (canceled) 17. A cosmetic composition comprising:
about 10 to about 25 wt. % of free glycolic acid and/or a salt thereof, provided that the cosmetic composition comprises at least 8 wt. % of free glycolic acid; optionally, about 1 to about 20 wt. % of phytic acid and/or a salt thereof; about 5 to about 40 wt. % of at least one non-silicone fatty compound selected from the group consisting of oils, waxes, mineral oil, fatty alcohols, fatty acids, fatty alcohol derivatives, fatty acid derivatives, esters of fatty alcohols, hydroxy-substituted fatty acids, triglyceride compounds, lanolin, linear or branched hydrocarbons of mineral or synthetic origin, and a mixture thereof; about 0.1 to about 10 wt. % of at least one silicone-based emulsifier; about 0.01 to about 10 wt. % of at least one non-silicone based nonionic emulsifier; about 5 to about 30 wt. % of at least one water-soluble solvent selected from the group consisting of glycerin, alcohols, organic solvents, polyols, glycols, and a mixture thereof; about 0.1 to about 40 wt. % of at least one silicone selected from the group consisting of polyorganosiloxanes, polyalkylsiloxanes, polyarylsiloxanes, polyalkarylsiloxanes, polyestersiloxanes, and a mixture thereof; and about 15 to about 80 wt. % of water; wherein the cosmetic composition is a water-in-oil emulsion having a pH of about 3 to about 5, and all wt. % values are based on the total weight of the cosmetic composition. 18. The cosmetic composition of claim 17 comprising:
about 10 to about 20 wt. % of free glycolic acid and/or a salt thereof;
about 1 to about 10 wt. % of phytic acid and/or a salt thereof;
about 10 to about 30 wt. % of at least one non-silicone fatty compound selected from the group consisting of oils, waxes, mineral oil, lanolin, linear or branched hydrocarbons of mineral or synthetic origin, and a mixture thereof;
about 0.1 to about 10 wt. % of at least one polyalkylene glycol-modified silicone emulsifier;
about 0.01 to about 10 wt. % of at least one non-silicone based nonionic emulsifier
about 1 to about 40 wt. % of at least one water-soluble solvent selected from the group consisting of glycerin, alcohols, organic solvents, polyols, glycols, and a mixture thereof;
about 1 to about 25 wt. % of at least one silicone selected from the group consisting of dimethicone, cyclomethicone (cyclopentasiloxane),
amodimethicone, trimethyl silyl amodimethicone, phenyl trimethicone, trimethyl siloxy silicate, and a mixture thereof; and
about 20 to about 60 wt. % of water. 19. A method for improving the appearance of skin comprising applying a cosmetic composition of claim 1 to the skin. 20. The method of claim 19, wherein the method comprises:
reducing the appearance of fine lines of the skin; reducing the appearance of wrinkles of the skin; improving the tone of skin and/or improving the evenness of skin tone; improving skin softness and/or smoothness; and/or increasing the radiance, luminosity, and/or glow of the skin. 21. The cosmetic composition of claim 1 having a pH of about 3 to about 5. 22. A cosmetic composition comprising:
at least 6 to about 25 wt. % of free glycolic acid and/or a salt thereof, provided that the cosmetic composition comprises at least 6 wt. % of free glycolic acid; about 5 to about 40 wt. % of at least one non-silicone fatty compound; about 0.1 to about 20 wt. % of at least one emulsifier; about 1 to about 40 wt. % of at least one water-soluble solvent; about 0.1 to about 40 wt. % of dimethicone; and about 15 to about 80 wt. % of water;
wherein the cosmetic composition is a water-in-oil emulsion having a pH of about 3 to about 6 and all wt. % values are based on the total weight of the cosmetic composition. | 1,600 |
1,431 | 15,497,640 | 1,611 | Provided herein are materials and methods of reducing contamination in a biological substance or treating contamination in a subject by one or more toxins comprising contacting the biological substance with an effective amount of a sorbent capable of sorbing the toxin, wherein the sorbent comprises a plurality of pores ranging from 50 Å to 40,000 Å with a pore volume of 0.5 cc/g to 5.0 cc/g and a size of 0.05 mm to 2 cm and sorbing the toxin. Also provided are kits to reduce contamination by one or more toxins in a biological substance comprising a sorbent capable of sorbing a toxin, wherein the sorbent comprises a plurality of pores ranging from 50 Å to 40,000 Å with a pore volume of 0.5 cc/g to 5.0 cc/g and a size of 0.05 mm to 2 cm and a vessel to store said sorbent when not in use together with packaging for same. | 1. A method of reducing contamination by one or more toxins in a biological substance, said method comprising:
a. contacting the biological substance with an effective amount of a sorbent capable of sorbing the toxin, wherein the sorbent comprises a plurality of pores ranging from 50 Å to 40,000 Å with a pore volume of 0.5 cc/g to 5.0 cc/g and a size of 0.05 mm to 2 cm, wherein the sorbent comprises a coated polymer comprising at least one crosslinking agent and wherein said toxins comprise endogenous toxins having a molecular weight of greater than 50,000 Daltons; and b. sorbing the toxin. 2. (canceled) 3. The method of claim 1, wherein the sorbent is biocompatible. 4-5. (canceled) 6. The method of claim 5, wherein the polymer is a macroporous polymeric sorbent. cm 7. The method of claim 1, wherein the sorbing occurs in vivo. 8. The method of claim 1, wherein the sorbing occurs ex vivo. 9-36. (canceled) 37. The method of claim 1, wherein the biological substance comprises cells or physiologic fluids such as saliva, nasopharyngeal fluid, blood, plasma, serum, saliva, gastrointestinal fluid, bile, cerebrospinal fluid, pericardial, vaginal fluid, seminal fluid, prostatic fluid, peritoneal fluid, pleural fluid, urine, synovial fluid, interstitial fluid, intracellular fluid, extracellular fluid, lymph, mucus, or vitreous humor. 38-39. (canceled) 40. The method of claim 1, wherein the method further comprises the steps of producing or purifying a blood product or biologic. 41. The method of claim 40, wherein the blood product comprises whole blood, packed red blood cells, platelets, plasma, cryoprecipitate, white blood cells, pleuripotent stem cells, T-cells, B-cells, or other cells of myloid or lymphoid origin and their progenitors. 42-44. (canceled) 45. The method of claim 1, wherein contamination by the toxin is systemic or localized. 46. The method of claim 1, wherein the sorbent is introduced through a body cavity. 47. The method of claim 46, wherein the sorbent is introduced orally, vaginally, rectally or nasally, through a feeding tube or topically. 48-51. (canceled) 52. The method of claim 1, wherein the sorbent is introduced by hemoperfusion. 53. The method of claim 1 wherein the sorbent is used for extracorporeal treatment of a biological substance comprising saliva, blood, plasma, serum, gastrointestinal fluid, cerebrospinal fluid, vaginal fluid, peritoneal fluid, pleural fluid, urine, synovial fluid, lymph, alveolar mucus or vitreous humor. 54. The method of claim 1, wherein the sorbent has a pore structure such that the total pore volume of pore size in the range of 50 Å to 40,000 Å is greater than 0.5 cc/g to 5.0 cc/g dry sorbent; wherein the ratio of pore volume between 50 Å to 40,000 Å (pore diameter) to pore volume between 100 Å to 1,000 Å (pore diameter) of the sorbent is smaller than 3:1. 55. (canceled) 56. The method of claim 1, wherein the sorbent has a pore structure such that the total pore volume of pore size in the range of 50 Å to 40,000 Å is greater than 0.5 cc/g to 5.0 cc/g dry sorbent; wherein the ratio of pore volume between 50 Å to 40,000 Å (pore diameter) to pore volume between 1,000 Å to 10,000 Å (pore diameter) of the sorbent is smaller than 2:1. 57. The method of claim 56, wherein the toxin has a molecular weight in the range of from about 50,000 Daltons to about 450,000 Daltons. 58. The method of claim 1 wherein the sorbent has a pore structure such that the total pore volume of pore size in the range of 50 Å to 40,000 Å is greater than 0.5 cc/g to 5.0 cc/g dry sorbent; wherein the ratio of pore volume between 50 Å to 40,000 Å (pore diameter) to pore volume between 10,000 Å to 40,000 Å (pore diameter) of the sorbent is smaller than 3:1. 59. (canceled) 60. The method of claim 1, wherein the sorbent comprises a plurality of pores comprising at least one crosslinking agent, at least one monomer, at least one dispersing agent and at least one porogen. 61. The method of claim 60, wherein the dispersing agent is one or more of hydroxyethyl cellulose, hydroxypropyl cellulose, poly (hydroxyethyl methacrylate), poly (hydroxyethyl acrylate), poly (hydroxypropyl methacrylate), poly (hydroxypropyl acrylate), poly (dimethylaminoethyl methacrylate), poly (dimethylaminoethyl acrylate), poly (diethylamimoethyl methacrylate), poly (diethylaminoethyl acrylate), poly(vinyl alcohol), poly (N-vinylpyrrolidinone), salts of poly (methacrylic acid), or salts of poly(acrylic acid). 62. The method of claim 60, wherein the crosslinking agent is one or more of divinylbenzene, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane diacrylate, pentaerythrital dimethacrylates, pentaerythrital trimethacrylates, pentaerythrital, tetramethacrylates, pentaerythritol diacrylates, pentaerythritol triiacrylates, pentaerythritol tetraacrylates, dipentaerythritol dimethacrylates, dipentaerythritol trimethacrylates, dipentaerythritol tetramethacrylates, dipentaerythritol diacrylates, dipentaerythritol triacrylates, dipentaerythritol tetraacrylates, or divinylformamide. 63. (canceled) 64. The method of claim 60, wherein monomer is one or more of divinylbenzene and ethylvinylbezene, styrene, ethylstyrene, acrylonitrile, butyl methacrylate, octyl methacrylate, butyl acrylate, octyl acrylate, cetyl methacrylate, cetyl acrylate, ethyl methacrylate, ethyl acrylate, vinyltoluene, vinylnaphthalene, vinylbenzyl alcohol, vinylformamide, methyl methacrylate, methyl acrylate, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane diacrylate, pentaerythritol dimethacrylate, pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate, pentaerythritol diacrylate, pentaerythritol triiacrylate, pentaerythritol tetraacrylate, dipentaerythritol dimethacrylate, dipentaerythritol trimethacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol diacrylate, dipentaerythritol triacrylate, dipentaerythritol tetraacrylate, divinylformamide and mixtures thereof. 65. The method of claim 60, wherein the porogen is one or more of benzyl alcohol, cyclohexane, cyclohexanol, cyclohexanol/toluene mixtures, cyclohexanone, decane, decane/toluene mixtures, di-2-ethylhexylphosphoric acid, di-2-ethylhexyl phthalate, 2-ethyl-1-hexanoic acid, 2-ethyl-1-hexanol, 2-ethyl-1-hexanol/n-heptane mixtures, 2-ethyl-1-hexanol/toluene mixtures, isoamyl alcohol, n-heptane, n-heptane/ethylacetate, n-heptane/isoamyl acetate, n-heptane/tetraline mixtures, n-heptane/toluene mixtures, n-hexane/toluene mixtures, pentanol, poly(styrene-co-methyl methacrylate)/dibutyl phthalate, poly styrene/2-ethyl-1-hexanol mixtures, polystyrene/dibutyl phthalate, polystyrene/n-hexane mixtures, polystyrene/toluene mixtures, toluene, tri-n-butylphosphate, 1,2,3-trichloropropane/2-ethyl-1-hexanol mixtures, 2,2,4-trimethyl pentane (isooctane), trimethyl pentane/toluene mixtures, poly(propylene glycol)/toluene mixtures poly(propylene glycol)/cyclohexanol mixtures, and poly(propylene glycol)/2-ethyl-1-hexanol mixtures. 66. (canceled) 67. The method of claim 1, wherein the sorbent is a mixture of sorb ents with two or more different pore sizes. 68. The method of claim 1, wherein the sorbent is formulated as a powder, tablet, capsule, solution, gel tab, dispersion, slurry, suppository, or suspension. 69. The method of claim 1, wherein the sorbent is admixed with food, fluid, or any combination thereof. 70. A kit to reduce contamination by one or more toxins in a biological substance comprising:
a. a sorbent capable of sorbing a toxin, wherein the sorbent comprises a plurality of pores ranging from 50 Å to 40,000 Å with a pore volume of 0.5 cc/g to 5.0 cc/g and a size of 0.05 mm to 2 cm; and b. a vessel to store said sorbent when not in use together with packaging for same. 71-93. (canceled) | Provided herein are materials and methods of reducing contamination in a biological substance or treating contamination in a subject by one or more toxins comprising contacting the biological substance with an effective amount of a sorbent capable of sorbing the toxin, wherein the sorbent comprises a plurality of pores ranging from 50 Å to 40,000 Å with a pore volume of 0.5 cc/g to 5.0 cc/g and a size of 0.05 mm to 2 cm and sorbing the toxin. Also provided are kits to reduce contamination by one or more toxins in a biological substance comprising a sorbent capable of sorbing a toxin, wherein the sorbent comprises a plurality of pores ranging from 50 Å to 40,000 Å with a pore volume of 0.5 cc/g to 5.0 cc/g and a size of 0.05 mm to 2 cm and a vessel to store said sorbent when not in use together with packaging for same.1. A method of reducing contamination by one or more toxins in a biological substance, said method comprising:
a. contacting the biological substance with an effective amount of a sorbent capable of sorbing the toxin, wherein the sorbent comprises a plurality of pores ranging from 50 Å to 40,000 Å with a pore volume of 0.5 cc/g to 5.0 cc/g and a size of 0.05 mm to 2 cm, wherein the sorbent comprises a coated polymer comprising at least one crosslinking agent and wherein said toxins comprise endogenous toxins having a molecular weight of greater than 50,000 Daltons; and b. sorbing the toxin. 2. (canceled) 3. The method of claim 1, wherein the sorbent is biocompatible. 4-5. (canceled) 6. The method of claim 5, wherein the polymer is a macroporous polymeric sorbent. cm 7. The method of claim 1, wherein the sorbing occurs in vivo. 8. The method of claim 1, wherein the sorbing occurs ex vivo. 9-36. (canceled) 37. The method of claim 1, wherein the biological substance comprises cells or physiologic fluids such as saliva, nasopharyngeal fluid, blood, plasma, serum, saliva, gastrointestinal fluid, bile, cerebrospinal fluid, pericardial, vaginal fluid, seminal fluid, prostatic fluid, peritoneal fluid, pleural fluid, urine, synovial fluid, interstitial fluid, intracellular fluid, extracellular fluid, lymph, mucus, or vitreous humor. 38-39. (canceled) 40. The method of claim 1, wherein the method further comprises the steps of producing or purifying a blood product or biologic. 41. The method of claim 40, wherein the blood product comprises whole blood, packed red blood cells, platelets, plasma, cryoprecipitate, white blood cells, pleuripotent stem cells, T-cells, B-cells, or other cells of myloid or lymphoid origin and their progenitors. 42-44. (canceled) 45. The method of claim 1, wherein contamination by the toxin is systemic or localized. 46. The method of claim 1, wherein the sorbent is introduced through a body cavity. 47. The method of claim 46, wherein the sorbent is introduced orally, vaginally, rectally or nasally, through a feeding tube or topically. 48-51. (canceled) 52. The method of claim 1, wherein the sorbent is introduced by hemoperfusion. 53. The method of claim 1 wherein the sorbent is used for extracorporeal treatment of a biological substance comprising saliva, blood, plasma, serum, gastrointestinal fluid, cerebrospinal fluid, vaginal fluid, peritoneal fluid, pleural fluid, urine, synovial fluid, lymph, alveolar mucus or vitreous humor. 54. The method of claim 1, wherein the sorbent has a pore structure such that the total pore volume of pore size in the range of 50 Å to 40,000 Å is greater than 0.5 cc/g to 5.0 cc/g dry sorbent; wherein the ratio of pore volume between 50 Å to 40,000 Å (pore diameter) to pore volume between 100 Å to 1,000 Å (pore diameter) of the sorbent is smaller than 3:1. 55. (canceled) 56. The method of claim 1, wherein the sorbent has a pore structure such that the total pore volume of pore size in the range of 50 Å to 40,000 Å is greater than 0.5 cc/g to 5.0 cc/g dry sorbent; wherein the ratio of pore volume between 50 Å to 40,000 Å (pore diameter) to pore volume between 1,000 Å to 10,000 Å (pore diameter) of the sorbent is smaller than 2:1. 57. The method of claim 56, wherein the toxin has a molecular weight in the range of from about 50,000 Daltons to about 450,000 Daltons. 58. The method of claim 1 wherein the sorbent has a pore structure such that the total pore volume of pore size in the range of 50 Å to 40,000 Å is greater than 0.5 cc/g to 5.0 cc/g dry sorbent; wherein the ratio of pore volume between 50 Å to 40,000 Å (pore diameter) to pore volume between 10,000 Å to 40,000 Å (pore diameter) of the sorbent is smaller than 3:1. 59. (canceled) 60. The method of claim 1, wherein the sorbent comprises a plurality of pores comprising at least one crosslinking agent, at least one monomer, at least one dispersing agent and at least one porogen. 61. The method of claim 60, wherein the dispersing agent is one or more of hydroxyethyl cellulose, hydroxypropyl cellulose, poly (hydroxyethyl methacrylate), poly (hydroxyethyl acrylate), poly (hydroxypropyl methacrylate), poly (hydroxypropyl acrylate), poly (dimethylaminoethyl methacrylate), poly (dimethylaminoethyl acrylate), poly (diethylamimoethyl methacrylate), poly (diethylaminoethyl acrylate), poly(vinyl alcohol), poly (N-vinylpyrrolidinone), salts of poly (methacrylic acid), or salts of poly(acrylic acid). 62. The method of claim 60, wherein the crosslinking agent is one or more of divinylbenzene, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane diacrylate, pentaerythrital dimethacrylates, pentaerythrital trimethacrylates, pentaerythrital, tetramethacrylates, pentaerythritol diacrylates, pentaerythritol triiacrylates, pentaerythritol tetraacrylates, dipentaerythritol dimethacrylates, dipentaerythritol trimethacrylates, dipentaerythritol tetramethacrylates, dipentaerythritol diacrylates, dipentaerythritol triacrylates, dipentaerythritol tetraacrylates, or divinylformamide. 63. (canceled) 64. The method of claim 60, wherein monomer is one or more of divinylbenzene and ethylvinylbezene, styrene, ethylstyrene, acrylonitrile, butyl methacrylate, octyl methacrylate, butyl acrylate, octyl acrylate, cetyl methacrylate, cetyl acrylate, ethyl methacrylate, ethyl acrylate, vinyltoluene, vinylnaphthalene, vinylbenzyl alcohol, vinylformamide, methyl methacrylate, methyl acrylate, trivinylbenzene, divinylnaphthalene, trivinylcyclohexane, divinylsulfone, trimethylolpropane trimethacrylate, trimethylolpropane dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane diacrylate, pentaerythritol dimethacrylate, pentaerythritol trimethacrylate, pentaerythritol tetramethacrylate, pentaerythritol diacrylate, pentaerythritol triiacrylate, pentaerythritol tetraacrylate, dipentaerythritol dimethacrylate, dipentaerythritol trimethacrylate, dipentaerythritol tetramethacrylate, dipentaerythritol diacrylate, dipentaerythritol triacrylate, dipentaerythritol tetraacrylate, divinylformamide and mixtures thereof. 65. The method of claim 60, wherein the porogen is one or more of benzyl alcohol, cyclohexane, cyclohexanol, cyclohexanol/toluene mixtures, cyclohexanone, decane, decane/toluene mixtures, di-2-ethylhexylphosphoric acid, di-2-ethylhexyl phthalate, 2-ethyl-1-hexanoic acid, 2-ethyl-1-hexanol, 2-ethyl-1-hexanol/n-heptane mixtures, 2-ethyl-1-hexanol/toluene mixtures, isoamyl alcohol, n-heptane, n-heptane/ethylacetate, n-heptane/isoamyl acetate, n-heptane/tetraline mixtures, n-heptane/toluene mixtures, n-hexane/toluene mixtures, pentanol, poly(styrene-co-methyl methacrylate)/dibutyl phthalate, poly styrene/2-ethyl-1-hexanol mixtures, polystyrene/dibutyl phthalate, polystyrene/n-hexane mixtures, polystyrene/toluene mixtures, toluene, tri-n-butylphosphate, 1,2,3-trichloropropane/2-ethyl-1-hexanol mixtures, 2,2,4-trimethyl pentane (isooctane), trimethyl pentane/toluene mixtures, poly(propylene glycol)/toluene mixtures poly(propylene glycol)/cyclohexanol mixtures, and poly(propylene glycol)/2-ethyl-1-hexanol mixtures. 66. (canceled) 67. The method of claim 1, wherein the sorbent is a mixture of sorb ents with two or more different pore sizes. 68. The method of claim 1, wherein the sorbent is formulated as a powder, tablet, capsule, solution, gel tab, dispersion, slurry, suppository, or suspension. 69. The method of claim 1, wherein the sorbent is admixed with food, fluid, or any combination thereof. 70. A kit to reduce contamination by one or more toxins in a biological substance comprising:
a. a sorbent capable of sorbing a toxin, wherein the sorbent comprises a plurality of pores ranging from 50 Å to 40,000 Å with a pore volume of 0.5 cc/g to 5.0 cc/g and a size of 0.05 mm to 2 cm; and b. a vessel to store said sorbent when not in use together with packaging for same. 71-93. (canceled) | 1,600 |
1,432 | 15,166,339 | 1,619 | Provided, among other things, is a packaged condom comprising: a sealed package; within the package, an polyisoprene condom; and within the package and substantially coating the condom, a lubricant comprising solvent and one or more sensation-providing agents comprising one or more of vanillyl butyl ether, menthyl lactate, and menthol, wherein the solvent comprises non-water soluble silicone oil and 99% or more of the lubricant by weight is the non-water soluble silicone oil. | 1. A packaged condom comprising:
a sealed package; within the package, a synthetic polyisoprene condom; and within the package and substantially coating the condom, a lubricant comprising solvent and one or more sensation-providing agents comprising one or more of vanillyl butyl ether, menthyl lactate, and menthol, wherein the solvent comprises non-water soluble silicone oil and 99% or more of the lubricant by weight is the non-water soluble silicone oil. 2. The packaged condom of claim 1, wherein if the lubricant comprises vanillyl butyl ether but neither menthyl lactate nor menthol in effective amounts, then (a) the solvent consists essentially of non-water soluble silicone oil, and (b) the lubricant is essentially free of compounds that enhance the solubility of vanillyl butyl ether in the non-water soluble silicone oil. 3. The packaged condom claim 1, wherein sensation-providing agents comprise menthyl lactate or menthol. 4. The packaged condom of claim 1, wherein sensation-providing agents comprise menthyl lactate and menthol, wherein the menthol can comprises about 30% to about 45% (wt.) of the total of menthol and menthyl lactate. 5. The packaged condom of claim 1, wherein sensation-providing agents comprise vanillyl butyl ether. 6. The packaged condom of claim 1, wherein the sensation-providing agents comprise vanillyl butyl ether, menthyl lactate and menthol. 7. The packaged condom of claim 6, wherein the menthol can comprises about 10% to about 30% (wt.) of the total of menthol and menthyl lactate. 8. The packaged condom of claim 1, wherein the solvent consists essentially of non-water soluble silicone oil. 9. The packaged condom of claim 8, wherein the solvent consists essentially of non-water soluble silicone oil, and that silicone oil consists essentially of silicone compounds with LogP greater than 6. 10. The packaged condom of claim 1, wherein the package comprises a layer of aluminum between condom and an external environment. 11. A method of packaging condom comprising:
providing an agitated lubricant composition comprising solvent and one or more sensation-providing agents comprising one or more of vanillyl butyl ether, menthyl lactate, and menthol, wherein the solvent comprises non-water soluble silicone oil and 99% or more of the lubricant by weight is the non-water soluble silicone oil; applying to a synthetic polyisoprene condom a dose of agitated lubricant composition; and placing the condom within a package and sealing it therein. 12. The method of claim 11, wherein if the lubricant composition comprises vanillyl butyl ether but neither menthyl lactate nor menthol in effective amounts, then (a) the solvent consists essentially of non-water soluble silicone oil, and (b) the lubricant is essentially free of compounds that enhance the solubility of vanillyl butyl ether in the non-water soluble silicone oil. 13. The method of claim 11, wherein sensation-providing agents comprise menthyl lactate or menthol. 14. The method of claim 11, wherein sensation-providing agents comprise menthyl lactate and menthol, wherein the menthol can comprises about 30% to about 45% (wt.) of the total of menthol and menthyl lactate. 15. The method of claim 11, wherein sensation-providing agents comprise vanillyl butyl ether. 16. The method of claim 11, wherein the sensation-providing agents comprise vanillyl butyl ether, menthyl lactate and menthol. 17. The method of claim 16, wherein the menthol can comprises about 10% to about 30% (wt.) of the total of menthol and menthyl lactate. 18. The method of claim 11, wherein the solvent consists essentially of non-water soluble silicone oil. 19. The method of claim 11, wherein the solvent consists essentially of non-water soluble silicone oil, and that silicone oil consists essentially of silicone compounds with LogP greater than 6. 20. The method of claim 11, wherein the package comprises a layer of aluminum between the condom and an external environment. | Provided, among other things, is a packaged condom comprising: a sealed package; within the package, an polyisoprene condom; and within the package and substantially coating the condom, a lubricant comprising solvent and one or more sensation-providing agents comprising one or more of vanillyl butyl ether, menthyl lactate, and menthol, wherein the solvent comprises non-water soluble silicone oil and 99% or more of the lubricant by weight is the non-water soluble silicone oil.1. A packaged condom comprising:
a sealed package; within the package, a synthetic polyisoprene condom; and within the package and substantially coating the condom, a lubricant comprising solvent and one or more sensation-providing agents comprising one or more of vanillyl butyl ether, menthyl lactate, and menthol, wherein the solvent comprises non-water soluble silicone oil and 99% or more of the lubricant by weight is the non-water soluble silicone oil. 2. The packaged condom of claim 1, wherein if the lubricant comprises vanillyl butyl ether but neither menthyl lactate nor menthol in effective amounts, then (a) the solvent consists essentially of non-water soluble silicone oil, and (b) the lubricant is essentially free of compounds that enhance the solubility of vanillyl butyl ether in the non-water soluble silicone oil. 3. The packaged condom claim 1, wherein sensation-providing agents comprise menthyl lactate or menthol. 4. The packaged condom of claim 1, wherein sensation-providing agents comprise menthyl lactate and menthol, wherein the menthol can comprises about 30% to about 45% (wt.) of the total of menthol and menthyl lactate. 5. The packaged condom of claim 1, wherein sensation-providing agents comprise vanillyl butyl ether. 6. The packaged condom of claim 1, wherein the sensation-providing agents comprise vanillyl butyl ether, menthyl lactate and menthol. 7. The packaged condom of claim 6, wherein the menthol can comprises about 10% to about 30% (wt.) of the total of menthol and menthyl lactate. 8. The packaged condom of claim 1, wherein the solvent consists essentially of non-water soluble silicone oil. 9. The packaged condom of claim 8, wherein the solvent consists essentially of non-water soluble silicone oil, and that silicone oil consists essentially of silicone compounds with LogP greater than 6. 10. The packaged condom of claim 1, wherein the package comprises a layer of aluminum between condom and an external environment. 11. A method of packaging condom comprising:
providing an agitated lubricant composition comprising solvent and one or more sensation-providing agents comprising one or more of vanillyl butyl ether, menthyl lactate, and menthol, wherein the solvent comprises non-water soluble silicone oil and 99% or more of the lubricant by weight is the non-water soluble silicone oil; applying to a synthetic polyisoprene condom a dose of agitated lubricant composition; and placing the condom within a package and sealing it therein. 12. The method of claim 11, wherein if the lubricant composition comprises vanillyl butyl ether but neither menthyl lactate nor menthol in effective amounts, then (a) the solvent consists essentially of non-water soluble silicone oil, and (b) the lubricant is essentially free of compounds that enhance the solubility of vanillyl butyl ether in the non-water soluble silicone oil. 13. The method of claim 11, wherein sensation-providing agents comprise menthyl lactate or menthol. 14. The method of claim 11, wherein sensation-providing agents comprise menthyl lactate and menthol, wherein the menthol can comprises about 30% to about 45% (wt.) of the total of menthol and menthyl lactate. 15. The method of claim 11, wherein sensation-providing agents comprise vanillyl butyl ether. 16. The method of claim 11, wherein the sensation-providing agents comprise vanillyl butyl ether, menthyl lactate and menthol. 17. The method of claim 16, wherein the menthol can comprises about 10% to about 30% (wt.) of the total of menthol and menthyl lactate. 18. The method of claim 11, wherein the solvent consists essentially of non-water soluble silicone oil. 19. The method of claim 11, wherein the solvent consists essentially of non-water soluble silicone oil, and that silicone oil consists essentially of silicone compounds with LogP greater than 6. 20. The method of claim 11, wherein the package comprises a layer of aluminum between the condom and an external environment. | 1,600 |
1,433 | 15,238,408 | 1,617 | Liquid formulations containing picosulfate and magnesium citrate are provided. The formulations are useful to treat constipation or for the clearance of the bowel prior to X-ray examination, endoscopy or surgery. | 1. A liquid formulation comprising:
sodium picosulfate; magnesium citrate; and at least one precipitation inhibitor, wherein the precipitation inhibitor is a carboxylic acid, an ammonium salt or a soluble anionic polymer; wherein the precipitation inhibitor is malonic acid or tartaric acid if the formulation does not comprise an ammonium salt or a soluble anionic polymer; wherein the formulation is in the form of an aqueous solution having a pH in the range from about 4.0 to about 6.5. 2. The liquid formulation of claim 1, wherein the sodium picosulfate is present at a concentration in the range from about 0.10 mM to about 0.15 mM, the magnesium citrate comprises magnesium and citrate in a molar ratio in the range from about 1:1 to about 1.5:1, and wherein the magnesium citrate is present at a concentration of magnesium in the range from about 0.2 to about 0.8 M. 3. The liquid formulation of claim 2, wherein the sodium picosulfate is present at a concentration in the range from about 0.12 mM to about 0.14 mM, the magnesium citrate comprises magnesium and citrate in a molar ratio of about 1.4:1, and wherein the magnesium citrate is present at a concentration of magnesium in the range from about 0.5 to about 0.6 M. 4-7. (canceled) 8. The liquid formulation of claim 1, wherein the magnesium citrate is formed from magnesium oxide and citric acid. 9. The liquid formulation of claim 1, comprising a carboxylic acid. 10. The liquid formulation of claim 9, wherein the carboxylic acid is selected from the group consisting of malonic acid, tartaric acid, acetic acid, arginine, ascorbic acid, asparagine, aspartic acid, citric acid, cysteine, fumaric acid, formic acid, gluconic acid, glucuronic acid, glutamic acid, glutamine, glutaric acid, glycolic acid, histidine, lactic acid, lysine, maleic acid, malic acid, methionine, oxalic acid, propionic acid, serine, succinic acid, threonine, tryptophan, and tyrosine. 11. (canceled) 12. The liquid formulation of claim 9, wherein the carboxylic acid is selected from the group consisting of gluconic acid, malic acid, malonic acid, and tartaric acid. 13. The liquid formulation of claim 10, wherein the carboxylic acid is malonic acid. 14. The liquid formulation of claim 13, wherein the formulation does not comprise an ammonium salt or a soluble anionic polymer. 15. The liquid formulation of claim 10, wherein the carboxylic acid is tartaric acid. 16. (canceled) 17. The liquid formulation of claim 1, wherein the carboxylic acid is present at a concentration in the range from about 0.1 M to about 1 M. 18. The liquid formulation of claim 1, comprising a soluble anionic polymer. 19-20. (canceled) 21. The liquid formulation of claim 18, wherein the soluble anionic polymer is selected from the group consisting of alginic acid, carboxymethylcellulose, carrageenans, polyacrylic acid and copolymers thereof, and xanthan gum. 22. The liquid formulation of claim 21, wherein the soluble anionic polymer is alginic acid. 23. The liquid formulation of claim 21, wherein the soluble anionic polymer is carboxymethylcellulose. 24. The liquid formulation of claim 21, wherein the soluble anionic polymer is a carrageenan. 25. The liquid formulation of claim 21, wherein the soluble anionic polymer is xanthan gum. 26-27. (canceled) 28. The liquid formulation of claim 21, wherein the soluble anionic polymer is present at a concentration in the range from about 1 g/L to about 20 g/L. 29. (canceled) 30. The liquid formulation of claim 1, comprising a carboxylic acid and a soluble anionic polymer. 31. The liquid formulation of any claim 30, comprising a carboxylic acid selected from the group consisting of gluconic acid, malic acid, malonic acid, succinic acid and tartaric acid, and a soluble anionic polymer selected from the group consisting of alginic acid, carboxymethylcellulose, carrageenans, and xanthan gum. 32. (canceled) 33. The liquid formulation of claim 30, wherein the carboxylic acid is present at a concentration in the range from about 0.1 M to about 1 M and the soluble anionic polymer is present at a concentration in the range from about 1 g/L to about 20 g/L. 34-37. (canceled) 38. The liquid formulation of claim 1, comprising an ammonium salt. 39. The liquid formulation of claim 38, wherein the ammonium salt is selected from the group consisting of ammonium acetate, ammonium chloride, and ammonium sulfate. 40. The liquid formulation of claim 38, comprising an ammonium salt at a concentration in the range from about 1 g/L to about 40 g/L. 41-42. (canceled) 43. The liquid formulation of claim 1, wherein the formulation has a pH in the range from about 4.5 to about 5.2. 44-46. (canceled) 47. The liquid formulation of claim 1, wherein the solution is stable for at least 1 year when stored at a temperature of about 25° C. 48. (canceled) 49. A pharmaceutical composition comprising:
sodium picosulfate; magnesium oxide; citric acid; and at least one precipitation inhibitor, wherein the precipitation inhibitor is a carboxylic acid, an ammonium salt or a soluble anionic polymer; wherein the precipitation inhibitor is malonic acid or tartaric acid if the composition does not comprise an ammonium salt or a soluble anionic polymer. 50. A method of preparing a liquid formulation comprising dissolving ingredients comprising sodium picosulfate, magnesium oxide, citric acid and at least one precipitation inhibitor selected from a carboxylic acid, an ammonium salt and a soluble anionic polymer to form an aqueous liquid formulation, wherein the precipitation inhibitor is malonic acid or tartaric acid if the liquid formulation does not comprise an ammonium salt or a soluble anionic polymer. 51-55. (canceled) 56. A liquid formulation prepared by the method of claim 50. 57. A method of clearing the bowel of a subject in need thereof, comprising administering to the subject an effective amount of a liquid formulation according to claim 1. 58. (canceled) 59. A method for determining the stability of a liquid formulation comprising sodium picosulfate and magnesium citrate comprising:
(a) freezing the liquid formulation to provide a frozen formulation; (b) thawing the frozen liquid to provide a thawed formulation; (c) observing the thawed formulation to determine the absence or presence of a precipitate in the thawed formulation; and (d) determining, based on the absence of a precipitate in the thawed formulation, that the liquid formulation is stable, or determining, based on the presence of a precipitate in the thawed formulation, that the liquid formulation is unstable. 60-61. (canceled) | Liquid formulations containing picosulfate and magnesium citrate are provided. The formulations are useful to treat constipation or for the clearance of the bowel prior to X-ray examination, endoscopy or surgery.1. A liquid formulation comprising:
sodium picosulfate; magnesium citrate; and at least one precipitation inhibitor, wherein the precipitation inhibitor is a carboxylic acid, an ammonium salt or a soluble anionic polymer; wherein the precipitation inhibitor is malonic acid or tartaric acid if the formulation does not comprise an ammonium salt or a soluble anionic polymer; wherein the formulation is in the form of an aqueous solution having a pH in the range from about 4.0 to about 6.5. 2. The liquid formulation of claim 1, wherein the sodium picosulfate is present at a concentration in the range from about 0.10 mM to about 0.15 mM, the magnesium citrate comprises magnesium and citrate in a molar ratio in the range from about 1:1 to about 1.5:1, and wherein the magnesium citrate is present at a concentration of magnesium in the range from about 0.2 to about 0.8 M. 3. The liquid formulation of claim 2, wherein the sodium picosulfate is present at a concentration in the range from about 0.12 mM to about 0.14 mM, the magnesium citrate comprises magnesium and citrate in a molar ratio of about 1.4:1, and wherein the magnesium citrate is present at a concentration of magnesium in the range from about 0.5 to about 0.6 M. 4-7. (canceled) 8. The liquid formulation of claim 1, wherein the magnesium citrate is formed from magnesium oxide and citric acid. 9. The liquid formulation of claim 1, comprising a carboxylic acid. 10. The liquid formulation of claim 9, wherein the carboxylic acid is selected from the group consisting of malonic acid, tartaric acid, acetic acid, arginine, ascorbic acid, asparagine, aspartic acid, citric acid, cysteine, fumaric acid, formic acid, gluconic acid, glucuronic acid, glutamic acid, glutamine, glutaric acid, glycolic acid, histidine, lactic acid, lysine, maleic acid, malic acid, methionine, oxalic acid, propionic acid, serine, succinic acid, threonine, tryptophan, and tyrosine. 11. (canceled) 12. The liquid formulation of claim 9, wherein the carboxylic acid is selected from the group consisting of gluconic acid, malic acid, malonic acid, and tartaric acid. 13. The liquid formulation of claim 10, wherein the carboxylic acid is malonic acid. 14. The liquid formulation of claim 13, wherein the formulation does not comprise an ammonium salt or a soluble anionic polymer. 15. The liquid formulation of claim 10, wherein the carboxylic acid is tartaric acid. 16. (canceled) 17. The liquid formulation of claim 1, wherein the carboxylic acid is present at a concentration in the range from about 0.1 M to about 1 M. 18. The liquid formulation of claim 1, comprising a soluble anionic polymer. 19-20. (canceled) 21. The liquid formulation of claim 18, wherein the soluble anionic polymer is selected from the group consisting of alginic acid, carboxymethylcellulose, carrageenans, polyacrylic acid and copolymers thereof, and xanthan gum. 22. The liquid formulation of claim 21, wherein the soluble anionic polymer is alginic acid. 23. The liquid formulation of claim 21, wherein the soluble anionic polymer is carboxymethylcellulose. 24. The liquid formulation of claim 21, wherein the soluble anionic polymer is a carrageenan. 25. The liquid formulation of claim 21, wherein the soluble anionic polymer is xanthan gum. 26-27. (canceled) 28. The liquid formulation of claim 21, wherein the soluble anionic polymer is present at a concentration in the range from about 1 g/L to about 20 g/L. 29. (canceled) 30. The liquid formulation of claim 1, comprising a carboxylic acid and a soluble anionic polymer. 31. The liquid formulation of any claim 30, comprising a carboxylic acid selected from the group consisting of gluconic acid, malic acid, malonic acid, succinic acid and tartaric acid, and a soluble anionic polymer selected from the group consisting of alginic acid, carboxymethylcellulose, carrageenans, and xanthan gum. 32. (canceled) 33. The liquid formulation of claim 30, wherein the carboxylic acid is present at a concentration in the range from about 0.1 M to about 1 M and the soluble anionic polymer is present at a concentration in the range from about 1 g/L to about 20 g/L. 34-37. (canceled) 38. The liquid formulation of claim 1, comprising an ammonium salt. 39. The liquid formulation of claim 38, wherein the ammonium salt is selected from the group consisting of ammonium acetate, ammonium chloride, and ammonium sulfate. 40. The liquid formulation of claim 38, comprising an ammonium salt at a concentration in the range from about 1 g/L to about 40 g/L. 41-42. (canceled) 43. The liquid formulation of claim 1, wherein the formulation has a pH in the range from about 4.5 to about 5.2. 44-46. (canceled) 47. The liquid formulation of claim 1, wherein the solution is stable for at least 1 year when stored at a temperature of about 25° C. 48. (canceled) 49. A pharmaceutical composition comprising:
sodium picosulfate; magnesium oxide; citric acid; and at least one precipitation inhibitor, wherein the precipitation inhibitor is a carboxylic acid, an ammonium salt or a soluble anionic polymer; wherein the precipitation inhibitor is malonic acid or tartaric acid if the composition does not comprise an ammonium salt or a soluble anionic polymer. 50. A method of preparing a liquid formulation comprising dissolving ingredients comprising sodium picosulfate, magnesium oxide, citric acid and at least one precipitation inhibitor selected from a carboxylic acid, an ammonium salt and a soluble anionic polymer to form an aqueous liquid formulation, wherein the precipitation inhibitor is malonic acid or tartaric acid if the liquid formulation does not comprise an ammonium salt or a soluble anionic polymer. 51-55. (canceled) 56. A liquid formulation prepared by the method of claim 50. 57. A method of clearing the bowel of a subject in need thereof, comprising administering to the subject an effective amount of a liquid formulation according to claim 1. 58. (canceled) 59. A method for determining the stability of a liquid formulation comprising sodium picosulfate and magnesium citrate comprising:
(a) freezing the liquid formulation to provide a frozen formulation; (b) thawing the frozen liquid to provide a thawed formulation; (c) observing the thawed formulation to determine the absence or presence of a precipitate in the thawed formulation; and (d) determining, based on the absence of a precipitate in the thawed formulation, that the liquid formulation is stable, or determining, based on the presence of a precipitate in the thawed formulation, that the liquid formulation is unstable. 60-61. (canceled) | 1,600 |
1,434 | 14,442,662 | 1,617 | The present invention relates to shaped articles which are suitable for controlling Varroa mites in bees. | 1. A solid shaped article5 of a polyvinyl chloride matrix comprising
0.1 to 30% by weight of an acaricidal active substance,.
1 to 30% by weight of a glycerol ester or propylene glycol ester with C8-C12-fatty acids, and
optionally an adjuvant or additive,
wherein the shaped article has a thickness from 0.5 to 20 mm and includes one or more openings passing therethrough having a width of 6-9 mm. 2. A solid shaped article according to claim 1, wherein the acaricidal active substance is cymiazole, etoxazole, fluvalinate, flumethrin, coumaphos or amitraz. 3. A solid shaped article according to claim 1, wherein
as the acaricidal active substance is flumethrin, coumaphos or amitraz, and the glycerol ester or propylene glycol ester with C8-C12-fatty acids is caprylic/capric acid triglyceride or propylene glycol dicaprylate/dicaprate. 4. A solid shaped article according to claim 1, wherein the acaricidal active substance is flumethrin. 5. A solid shaped article according to claim 4, containing 0.1 to 5% by weight of flumethrin. 6. A solid shaped article according to claim 1, wherein the acaricidal active substance is coumaphos. 7. A solid shaped article according to claim 6, containing 6 to 12% by weight of coumaphos. 8. A solid shaped article according to claim 1, wherein the acaricidal active substance is amitraz. 9. A solid shaped article according to claim 8, containing 1 to 10% by weight of amitraz. 10. A solid shaped article of a polyvinyl chloride matrix comprising
1 to 30% by weight of a glycerol ester or propylene glycol ester with C8-C12-fatty acids, and optionally an adjuvant additive, wherein the shaped article has a thickness from 0.5 to 20 mm and includes one or more openings passing therethrough having a width of 6-9 mm. 11. A solid shaped article according to claim 10, wherein the glycerol ester or propylene glycol ester with C8-C12-fatty acids is caprylic/capric acid triglyceride or propylene glycol dicaprylate/dicaprate. 12. A solid shaped article according to claim 1, comprising propylene glycol dicaprylate/dicaprate. 13. A solid shaped article according to claim 1, including 10 to 100 openings. 14. A beehive comprising a solid shaped article according to claim 1. | The present invention relates to shaped articles which are suitable for controlling Varroa mites in bees.1. A solid shaped article5 of a polyvinyl chloride matrix comprising
0.1 to 30% by weight of an acaricidal active substance,.
1 to 30% by weight of a glycerol ester or propylene glycol ester with C8-C12-fatty acids, and
optionally an adjuvant or additive,
wherein the shaped article has a thickness from 0.5 to 20 mm and includes one or more openings passing therethrough having a width of 6-9 mm. 2. A solid shaped article according to claim 1, wherein the acaricidal active substance is cymiazole, etoxazole, fluvalinate, flumethrin, coumaphos or amitraz. 3. A solid shaped article according to claim 1, wherein
as the acaricidal active substance is flumethrin, coumaphos or amitraz, and the glycerol ester or propylene glycol ester with C8-C12-fatty acids is caprylic/capric acid triglyceride or propylene glycol dicaprylate/dicaprate. 4. A solid shaped article according to claim 1, wherein the acaricidal active substance is flumethrin. 5. A solid shaped article according to claim 4, containing 0.1 to 5% by weight of flumethrin. 6. A solid shaped article according to claim 1, wherein the acaricidal active substance is coumaphos. 7. A solid shaped article according to claim 6, containing 6 to 12% by weight of coumaphos. 8. A solid shaped article according to claim 1, wherein the acaricidal active substance is amitraz. 9. A solid shaped article according to claim 8, containing 1 to 10% by weight of amitraz. 10. A solid shaped article of a polyvinyl chloride matrix comprising
1 to 30% by weight of a glycerol ester or propylene glycol ester with C8-C12-fatty acids, and optionally an adjuvant additive, wherein the shaped article has a thickness from 0.5 to 20 mm and includes one or more openings passing therethrough having a width of 6-9 mm. 11. A solid shaped article according to claim 10, wherein the glycerol ester or propylene glycol ester with C8-C12-fatty acids is caprylic/capric acid triglyceride or propylene glycol dicaprylate/dicaprate. 12. A solid shaped article according to claim 1, comprising propylene glycol dicaprylate/dicaprate. 13. A solid shaped article according to claim 1, including 10 to 100 openings. 14. A beehive comprising a solid shaped article according to claim 1. | 1,600 |
1,435 | 15,579,030 | 1,613 | The present inventions concerns use of a certain methoxyacrylate compound to control mosquitoes, and vector control solutions comprising a defined methoxyacrylate compound, in particular the invention relates to a substrate, to a composition, for controlling mosquitoes comprising a defined methoxyacrylate compound, and to certain methoxyacrylate compounds. | 1. A method of controlling mosquitos, the method comprising: applying to a mosquito or to a locus of interaction of a mosquito, one or more methoxyacrylate compounds selected from Table 1 below:
TABLE 1
Compound
no.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23 2. The method according to claim 1 wherein the development of vector-borne diseases are reduced by the mosquito control defined in claim 1. 3. An integrated mosquito vector control solution comprising one or more methoxyacrylate compounds defined in claim 1. 4. The vector control solution according to claim 3 wherein the solution is a net incorporated with one or more methoxyacrylate compounds defined in claim 1. 5. The vector control solution according to claim 3, wherein the solution is a composition for coating a net, which composition comprises one or more methoxyacrylate compounds defined in claim 1. 6. The vector control solution according to claim 3, wherein the solution is a composition for spraying surfaces of a dwelling, which composition comprises one or more methoxyacrylate compounds as defined in claim 1. 7. The vector control solution according to claim 3, wherein a further insecticide and/or synergist is present. 8. A polymeric material incorporated with a compound defined in claim 1, which material is useful for making substrate or non-living material, such as threads, fibres, yarns, pellets, nets and weaves. 9. A method of controlling mosquitoes, preferably mosquito vectors of pathogenic disease, with one or more compounds defined in claim 1. 10. A kit for treating a fibre, yarn, net and weave by coating wash resistant insecticidal properties thereto comprising: a first sachet comprising a pre-measured amount of at least one compound defined in claim 1, and a second sachet comprising a pre-measured amount of at least one polymeric binder. 11. A method for treating a fibre, yarn, net and weave by coating wash resistant insecticidal properties thereto comprising (i) preparing a treatment composition, which comprises at least one compound defined in claim 1, (ii) treating said fibre, yarn, net or weave and (iii) drying the resulting treated fibre, yarn, net or weave. 12. A method of preparing a polymeric material impregnated with a compound defined in claim 1, which material is useful for making substrate or non-living material, such as threads, fibres, yarns, pellets, nets and weaves, which method comprises mixing a polymer with a compound defined in claim 1 at a temperature between 120 to 250° C. 13. A method for mosquito vector-control, the method comprising (a) applying an effective amount of a liquid composition comprising a compound defined in claim 1, and a polymeric binder, and optionally, one or more other insecticides, or synergists, to a surface of a dwelling; or (b) placing a substrate or non-living material incorporated with a compound defined in claim 1, and optionally an additive, one or more other insecticides, or synergists, within a dwelling. 14. A net incorporated with a compound defined in claim 1 having a biological activity in accordance with the WHOPES guidelines of a knockdown after 60 minutes of between 95 percent and 100 percent and/or a mortality after 24 hours of between 80 percent and 100 percent after 20 washes. 15. A methoxyacrylate compound listed as compound 3, 5, 9, 11, 13, 14, 16, 17, 19, 20, 21 and 23 in Table 1 as defined in claim 1. | The present inventions concerns use of a certain methoxyacrylate compound to control mosquitoes, and vector control solutions comprising a defined methoxyacrylate compound, in particular the invention relates to a substrate, to a composition, for controlling mosquitoes comprising a defined methoxyacrylate compound, and to certain methoxyacrylate compounds.1. A method of controlling mosquitos, the method comprising: applying to a mosquito or to a locus of interaction of a mosquito, one or more methoxyacrylate compounds selected from Table 1 below:
TABLE 1
Compound
no.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23 2. The method according to claim 1 wherein the development of vector-borne diseases are reduced by the mosquito control defined in claim 1. 3. An integrated mosquito vector control solution comprising one or more methoxyacrylate compounds defined in claim 1. 4. The vector control solution according to claim 3 wherein the solution is a net incorporated with one or more methoxyacrylate compounds defined in claim 1. 5. The vector control solution according to claim 3, wherein the solution is a composition for coating a net, which composition comprises one or more methoxyacrylate compounds defined in claim 1. 6. The vector control solution according to claim 3, wherein the solution is a composition for spraying surfaces of a dwelling, which composition comprises one or more methoxyacrylate compounds as defined in claim 1. 7. The vector control solution according to claim 3, wherein a further insecticide and/or synergist is present. 8. A polymeric material incorporated with a compound defined in claim 1, which material is useful for making substrate or non-living material, such as threads, fibres, yarns, pellets, nets and weaves. 9. A method of controlling mosquitoes, preferably mosquito vectors of pathogenic disease, with one or more compounds defined in claim 1. 10. A kit for treating a fibre, yarn, net and weave by coating wash resistant insecticidal properties thereto comprising: a first sachet comprising a pre-measured amount of at least one compound defined in claim 1, and a second sachet comprising a pre-measured amount of at least one polymeric binder. 11. A method for treating a fibre, yarn, net and weave by coating wash resistant insecticidal properties thereto comprising (i) preparing a treatment composition, which comprises at least one compound defined in claim 1, (ii) treating said fibre, yarn, net or weave and (iii) drying the resulting treated fibre, yarn, net or weave. 12. A method of preparing a polymeric material impregnated with a compound defined in claim 1, which material is useful for making substrate or non-living material, such as threads, fibres, yarns, pellets, nets and weaves, which method comprises mixing a polymer with a compound defined in claim 1 at a temperature between 120 to 250° C. 13. A method for mosquito vector-control, the method comprising (a) applying an effective amount of a liquid composition comprising a compound defined in claim 1, and a polymeric binder, and optionally, one or more other insecticides, or synergists, to a surface of a dwelling; or (b) placing a substrate or non-living material incorporated with a compound defined in claim 1, and optionally an additive, one or more other insecticides, or synergists, within a dwelling. 14. A net incorporated with a compound defined in claim 1 having a biological activity in accordance with the WHOPES guidelines of a knockdown after 60 minutes of between 95 percent and 100 percent and/or a mortality after 24 hours of between 80 percent and 100 percent after 20 washes. 15. A methoxyacrylate compound listed as compound 3, 5, 9, 11, 13, 14, 16, 17, 19, 20, 21 and 23 in Table 1 as defined in claim 1. | 1,600 |
1,436 | 16,377,465 | 1,641 | The present invention relates to an in vitro method for the prognosis of an adverse event in asymptomatic subjects comprising the determination of the level of Procalcitonin (PCT) or a fragment thereof or a precursor or fragment thereof having at least 12 amino acid residues in a sample of a bodily fluid from said subject and the correlation of the determined level to a potential risk of sustaining an adverse event. | 1-17. (canceled) 18. A method for determining an increased risk of an apparently healthy subject, preferably a human, for suffering from an adverse event, comprising:
providing a sample from said subject; determining the level of procalcitonin (PCT) or of a fragment thereof in said sample; and determining whether said subject has an increased risk for suffering from an adverse event based on said PCT level,
wherein said adverse event is not an event caused by an acute exogene induced adverse event and/or exogene induced trauma and wherein the following subjects are excluded from the group of apparently healthy subjects:
neonates between 1 day to 3 days and
patients after surgery wherein the surgery has been conducted within the last 7 days and
post-trauma patients and persons which experienced said trauma within the last 7 days. 19. The method of claim 18, wherein PCT has the amino acid sequence shown as SEQ ID NO. 1. 20. The method of claim 18, wherein said PCT fragment comprises (contains)
at least 12 amino acids, preferably more than 50 amino acids, most preferably more than 100 amino acids, or the amino acids 2 to 116 or 3 to 116 of the amino acid sequence shown as SEQ ID NO. 1. 21. The method of claim 18, wherein said level determination is performed using a diagnostic assay, preferably an immunoassay. 22. The method of claim 18, wherein the adverse event is chosen from the group consisting of cardiac events, cardiovascular events, cerebrovascular events, cardiovascular mortality, diabetes, cancer mortality, and death. 23. The method of claim 18, wherein the risk determination is performed by
comparing the determined PCT or PCT fragment level with the median of the level of PCT or fragments thereof in an ensemble of predetermined samples from a population of apparently healthy subjects, or comparing the determined PCT or PCT fragment level with a quantile of the level of PCT or fragments thereof in an ensemble of predetermined samples from a population of apparently healthy subjects, or performing calculations based on Cox Proportional Hazards analysis or on risk index calculations such as the Net Reclassification Index (NRI) or the Integrated Discrimination Index (IDI). 24. The method of claim 18, wherein the subject is free of symptomatic infections. (PCT level not increased above normal range) 25. The method of claim 18, wherein the sample is a bodily fluid, in particular blood, serum, plasma, cerebrospinal fluid, urine, saliva, sputum, or a pleural effusion. 26. The method of claim 18, wherein said subject is determined of being at risk for suffering from an adverse event when said PCT level in a serum or plasma sample is at least 0.015 ng/ml, preferably at least 0.02 ng/ml. 27. The method of claim 18, wherein said subject is determined of being at an increased risk for suffering from a cardiac event or a cardiovascular event when said PCT level in a serum sample is at least 0.0155 ng/ml. 28. The method of claim 18, wherein said subject is determined of being at an increased risk for suffering from a cerebrovascular event or from dying due to a cardiovascular cause when said PCT level in a serum sample is at least 0.0215 ng/ml. 29. The method of claim 18, wherein said subject is determined of being at an increased risk for dying from cancer when said PCT level in a serum sample is at least 0.0155 ng/ml. 30. The method of claim 18, wherein said subject is determined of being at an increased risk for dying when said PCT level in a serum sample is at least 0.0205 ng/ml. 31. The method of claim 18, wherein said subject is determined of being at an increased risk for suffering from diabetes when said PCT level in a serum sample is at least 0.0185 ng/ml. 32. The method of claim 18, further comprising determining
a clinical parameter that is selected from the group consisting of gender, age, systolic blood pressure, systolic blood pressure, diastolic blood pressure, body mass index, waist circumference, waist-hip ratio, and smoking habit; or a laboratory parameter that is selected from the group consisting of fasting blood or plasma glucose concentration, triglycerides, cholesterol concentration, and HDL cholesterol concentration and subfractions thereof, LDL cholesterol concentration and subfractions thereof, cystatin C, insulin, CRP, natriuretic peptides of the A- and B-type as well as their precursors and fragments thereof including ANP, proANP, NT-proANP, MR-proANP, BNP, proBNP, NT-proBNP, GDF15, ST2, procalcitonin and fragments thereof, pro-adrenomedullin and fragments thereof including ADM, PAMP, MR-proADM, CT-proADM, pro-Endothelin-1 and fragments thereof including CT-proET-1, NT-proET-1, big-Endothelin-1, and Endothelin-1; or a genetic parameter that is selected from the group consisting of single nucleotide polymorphisms (SNP), and mutations, in particular related to diabetes heredity. 33. The method of claim 18, further comprising taking at least one preventive measure for avoiding said adverse event from occurring in said subject. 34. Use of a method of claim 18 for determining an increased risk of an apparently healthy subject for suffering from an adverse event. | The present invention relates to an in vitro method for the prognosis of an adverse event in asymptomatic subjects comprising the determination of the level of Procalcitonin (PCT) or a fragment thereof or a precursor or fragment thereof having at least 12 amino acid residues in a sample of a bodily fluid from said subject and the correlation of the determined level to a potential risk of sustaining an adverse event.1-17. (canceled) 18. A method for determining an increased risk of an apparently healthy subject, preferably a human, for suffering from an adverse event, comprising:
providing a sample from said subject; determining the level of procalcitonin (PCT) or of a fragment thereof in said sample; and determining whether said subject has an increased risk for suffering from an adverse event based on said PCT level,
wherein said adverse event is not an event caused by an acute exogene induced adverse event and/or exogene induced trauma and wherein the following subjects are excluded from the group of apparently healthy subjects:
neonates between 1 day to 3 days and
patients after surgery wherein the surgery has been conducted within the last 7 days and
post-trauma patients and persons which experienced said trauma within the last 7 days. 19. The method of claim 18, wherein PCT has the amino acid sequence shown as SEQ ID NO. 1. 20. The method of claim 18, wherein said PCT fragment comprises (contains)
at least 12 amino acids, preferably more than 50 amino acids, most preferably more than 100 amino acids, or the amino acids 2 to 116 or 3 to 116 of the amino acid sequence shown as SEQ ID NO. 1. 21. The method of claim 18, wherein said level determination is performed using a diagnostic assay, preferably an immunoassay. 22. The method of claim 18, wherein the adverse event is chosen from the group consisting of cardiac events, cardiovascular events, cerebrovascular events, cardiovascular mortality, diabetes, cancer mortality, and death. 23. The method of claim 18, wherein the risk determination is performed by
comparing the determined PCT or PCT fragment level with the median of the level of PCT or fragments thereof in an ensemble of predetermined samples from a population of apparently healthy subjects, or comparing the determined PCT or PCT fragment level with a quantile of the level of PCT or fragments thereof in an ensemble of predetermined samples from a population of apparently healthy subjects, or performing calculations based on Cox Proportional Hazards analysis or on risk index calculations such as the Net Reclassification Index (NRI) or the Integrated Discrimination Index (IDI). 24. The method of claim 18, wherein the subject is free of symptomatic infections. (PCT level not increased above normal range) 25. The method of claim 18, wherein the sample is a bodily fluid, in particular blood, serum, plasma, cerebrospinal fluid, urine, saliva, sputum, or a pleural effusion. 26. The method of claim 18, wherein said subject is determined of being at risk for suffering from an adverse event when said PCT level in a serum or plasma sample is at least 0.015 ng/ml, preferably at least 0.02 ng/ml. 27. The method of claim 18, wherein said subject is determined of being at an increased risk for suffering from a cardiac event or a cardiovascular event when said PCT level in a serum sample is at least 0.0155 ng/ml. 28. The method of claim 18, wherein said subject is determined of being at an increased risk for suffering from a cerebrovascular event or from dying due to a cardiovascular cause when said PCT level in a serum sample is at least 0.0215 ng/ml. 29. The method of claim 18, wherein said subject is determined of being at an increased risk for dying from cancer when said PCT level in a serum sample is at least 0.0155 ng/ml. 30. The method of claim 18, wherein said subject is determined of being at an increased risk for dying when said PCT level in a serum sample is at least 0.0205 ng/ml. 31. The method of claim 18, wherein said subject is determined of being at an increased risk for suffering from diabetes when said PCT level in a serum sample is at least 0.0185 ng/ml. 32. The method of claim 18, further comprising determining
a clinical parameter that is selected from the group consisting of gender, age, systolic blood pressure, systolic blood pressure, diastolic blood pressure, body mass index, waist circumference, waist-hip ratio, and smoking habit; or a laboratory parameter that is selected from the group consisting of fasting blood or plasma glucose concentration, triglycerides, cholesterol concentration, and HDL cholesterol concentration and subfractions thereof, LDL cholesterol concentration and subfractions thereof, cystatin C, insulin, CRP, natriuretic peptides of the A- and B-type as well as their precursors and fragments thereof including ANP, proANP, NT-proANP, MR-proANP, BNP, proBNP, NT-proBNP, GDF15, ST2, procalcitonin and fragments thereof, pro-adrenomedullin and fragments thereof including ADM, PAMP, MR-proADM, CT-proADM, pro-Endothelin-1 and fragments thereof including CT-proET-1, NT-proET-1, big-Endothelin-1, and Endothelin-1; or a genetic parameter that is selected from the group consisting of single nucleotide polymorphisms (SNP), and mutations, in particular related to diabetes heredity. 33. The method of claim 18, further comprising taking at least one preventive measure for avoiding said adverse event from occurring in said subject. 34. Use of a method of claim 18 for determining an increased risk of an apparently healthy subject for suffering from an adverse event. | 1,600 |
1,437 | 14,571,781 | 1,611 | Described herein are an aspirin or active aspirin derivative and a COX-2 inhibitor, at least one of which has an enteric or partial enteric coating, administered in combination yet delivered sequentially, for the treatment and prophylactic treatment of diseases, symptoms and conditions. In some embodiments, the COX-2 inhibitor has the enteric coating; however, the aspirin or active aspirin derivative may additionally or alternately have the enteric coating. In all embodiments, the drug having the enteric coating or enteric formulation is targeted for absorption in the small intestine or colon, or both the small intestine and the colon. | 1. A method of sequentially administering an aspirin or active aspirin derivative and a COX-2 inhibitor for partitioned absorption, at least one of which has an enteric or partial enteric coating for bioabsorption in a patient's small intestine or colon. 2. The method of claim 1, wherein the COX-2 inhibitor has the enteric or partial enteric coating. 3. The method of claim 1, wherein the aspirin or active aspirin derivative has the enteric or partial enteric coating. 4. The method of claim 1, for treatment of diseases and conditions where bioabsorption in the small intestine is desired. 5. The method of claim 1, for prophylactic treatment of diseases and conditions where bioabsorption in the colon is desired. 6. The method of claim 4, where the administering of the aspirin or active aspirin derivative and the COX-2 inhibitor is short-term. 7. The method of claim 5, wherein the administering of the aspirin or active aspirin derivative and the COX-2 inhibitor is short-term. 8. The method of claim 1, wherein the diseases and conditions include acute pain, fever, dysmenorrhea, acute migraine, prevention of migraine in a time window, and prevention of intra-abdominal adhesions. 9. The method of claim 4, where the administering of the aspirin or active aspirin derivative and the COX-2 inhibitor is long-term. 10. The method of claim 5, where the administering of the aspirin or active aspirin derivative and the COX-2 inhibitor is long-term. 11. The method of claim 1, wherein the diseases and conditions include osteoarthritis, other arthritides, subacute and chronic pain, prophylaxis of subacute or chronic migraine, cancer prevention, cancer treatment, and prevention or treatment of pre-cancerous intestinal (colon or rectal) polyps, and familial adenomatous polyposis (FAP). 12. The method of claim 4, where the administering of the aspirin or active derivative of aspirin and the COX-2 inhibitor is periodic. 13. The method of claim 5, where the administering of the aspirin or active derivative of aspirin and the COX-2 inhibitor is periodic. 14. The method of claim 1, wherein the diseases and conditions include dysmenorrhea, prevention of dysmenorrhea, menstrual or pen-menstrual migraine, prevention of menstrual or peri-menstrual migraine, prevention or treatment of dysmenorrhea and menstrual or pen-menstrual migraine in patients with both conditions, and prevention or treatment of migraine in a patient with recurring time windows where there is a need to be free of migraine symptoms during the time windows. 15. The method of claim 1, wherein the aspirin or active derivative of aspirin comprises at least one of ASA, PC-ASA, PL2200, PA8140, and PA32540. 16. The method of claim 1, wherein the COX-2 inhibitor comprises celecoxib, celecoxib analogue, PC-celecoxib, or PC-celecoxib analogue. 17. The method of claim 1, wherein the coating is pH-sensitive, time-sensitive, and/or microflora-activated. 18. A kit comprising an aspirin or active aspirin derivative and a COX-2 inhibitor for partitioned absorption, at least one of which has an enteric or partial enteric coating. 19. The kit of claim 18, wherein the COX-2 inhibitor has the enteric or partial enteric coating. 20. The kit of claim 18, wherein the aspirin or active aspirin derivative has the enteric or partial enteric coating. | Described herein are an aspirin or active aspirin derivative and a COX-2 inhibitor, at least one of which has an enteric or partial enteric coating, administered in combination yet delivered sequentially, for the treatment and prophylactic treatment of diseases, symptoms and conditions. In some embodiments, the COX-2 inhibitor has the enteric coating; however, the aspirin or active aspirin derivative may additionally or alternately have the enteric coating. In all embodiments, the drug having the enteric coating or enteric formulation is targeted for absorption in the small intestine or colon, or both the small intestine and the colon.1. A method of sequentially administering an aspirin or active aspirin derivative and a COX-2 inhibitor for partitioned absorption, at least one of which has an enteric or partial enteric coating for bioabsorption in a patient's small intestine or colon. 2. The method of claim 1, wherein the COX-2 inhibitor has the enteric or partial enteric coating. 3. The method of claim 1, wherein the aspirin or active aspirin derivative has the enteric or partial enteric coating. 4. The method of claim 1, for treatment of diseases and conditions where bioabsorption in the small intestine is desired. 5. The method of claim 1, for prophylactic treatment of diseases and conditions where bioabsorption in the colon is desired. 6. The method of claim 4, where the administering of the aspirin or active aspirin derivative and the COX-2 inhibitor is short-term. 7. The method of claim 5, wherein the administering of the aspirin or active aspirin derivative and the COX-2 inhibitor is short-term. 8. The method of claim 1, wherein the diseases and conditions include acute pain, fever, dysmenorrhea, acute migraine, prevention of migraine in a time window, and prevention of intra-abdominal adhesions. 9. The method of claim 4, where the administering of the aspirin or active aspirin derivative and the COX-2 inhibitor is long-term. 10. The method of claim 5, where the administering of the aspirin or active aspirin derivative and the COX-2 inhibitor is long-term. 11. The method of claim 1, wherein the diseases and conditions include osteoarthritis, other arthritides, subacute and chronic pain, prophylaxis of subacute or chronic migraine, cancer prevention, cancer treatment, and prevention or treatment of pre-cancerous intestinal (colon or rectal) polyps, and familial adenomatous polyposis (FAP). 12. The method of claim 4, where the administering of the aspirin or active derivative of aspirin and the COX-2 inhibitor is periodic. 13. The method of claim 5, where the administering of the aspirin or active derivative of aspirin and the COX-2 inhibitor is periodic. 14. The method of claim 1, wherein the diseases and conditions include dysmenorrhea, prevention of dysmenorrhea, menstrual or pen-menstrual migraine, prevention of menstrual or peri-menstrual migraine, prevention or treatment of dysmenorrhea and menstrual or pen-menstrual migraine in patients with both conditions, and prevention or treatment of migraine in a patient with recurring time windows where there is a need to be free of migraine symptoms during the time windows. 15. The method of claim 1, wherein the aspirin or active derivative of aspirin comprises at least one of ASA, PC-ASA, PL2200, PA8140, and PA32540. 16. The method of claim 1, wherein the COX-2 inhibitor comprises celecoxib, celecoxib analogue, PC-celecoxib, or PC-celecoxib analogue. 17. The method of claim 1, wherein the coating is pH-sensitive, time-sensitive, and/or microflora-activated. 18. A kit comprising an aspirin or active aspirin derivative and a COX-2 inhibitor for partitioned absorption, at least one of which has an enteric or partial enteric coating. 19. The kit of claim 18, wherein the COX-2 inhibitor has the enteric or partial enteric coating. 20. The kit of claim 18, wherein the aspirin or active aspirin derivative has the enteric or partial enteric coating. | 1,600 |
1,438 | 14,147,143 | 1,617 | A composition and method useful in promoting healing of a bleeding wound site. The composition preferably includes a substantially anhydrous acid form of a cation exchange resin, which when applied over blood, provides an antimicrobial against planktonic microorganisms and biofilms in the wound. The resin is also capable, when applied in sufficient quantities, of providing a continuing and persistent antimicrobial against planktonic microorganisms and biofilms through dehydration and ion exchange with cations present in the blood and other body fluids. When the resin has a concentration of at least 26 mg/ml, it provides a >3 log reduction in biological activity of MRSA, MRSE and Pseudomonas aeruginosa. | 1-9. (canceled) 10. A method for providing a continuing and persistent antimicrobial against planktonic microorganisms and biofilms in the area of an open wound, said method comprising applying a substantially anhydrous hydrogen form of a cation exchange resin to said wound. 11. The method of claim 10, wherein said resin is a hydrogen form of a sulfonated 2% crosslinked polystyrene resin. 12. The method of claim 11, wherein said resin has a concentration of at least 26 mg/ml when diluted in fluid at said wound to provide a greater than 3 log reduction in biological activity of Methicillin-resistant Staphylococcus aureus (MRSA), Methicillin-resistant Staphylococcus epidermidis (MRSE) and Pseudomonas aeruginosa. 13. The method of claim 10, further comprising applying one or more of a silver cation exchange resin, an alkali metal cation exchange resin, or a quaternary ammonium cation exchange resin. 14. The method of claim 10, wherein said resin is applied in a containment device on said wound, wherein said containment device builds the height of said resin and contains said resin within the device. 15. The method of claim 10, wherein a secondary dressing is applied over said resin. 16. The method of claim 10, wherein said wound results from a vascular access procedure or a percutaneous catheter or tube. 17. The method of claim 10, wherein said wound is a surgical wound. 18. A method for stopping bleeding at a wound site, said method comprising applying a substantially anhydrous hydrogen form of a cation exchange resin to said wound. 19. The method of claim 18, wherein said resin is a hydrogen form of a sulfonated 2% crosslinked polystyrene resin. 20. The method of claim 18, further comprising applying one or more of a silver cation exchange resin, an alkali metal cation exchange resin, or a quaternary ammonium cation exchange resin. 21. The method of claim 18, wherein said resin is applied in a containment device on said wound, wherein said containment device builds the height of said resin and contains said resin within the device. 22. The method of claim 18, wherein a secondary dressing is applied over said resin. 23. The method of claim 18, wherein said wound is a surgical wound. 24. A method for treating an exuding wound, said method comprising applying a substantially anhydrous hydrogen form of a cation exchange resin to said wound. 25. The method of claim 24, wherein said exuding wound is a pressure ulcer, a venous ulcer, a diabetic ulcer, or an arterial ulcer. 26. The method of claim 24, wherein said resin is a hydrogen form of a sulfonated 2% crosslinked polystyrene resin. 27. The method of claim 24, further comprising applying one or more of a silver cation exchange resin, an alkali metal cation exchange resin, or a quaternary ammonium cation exchange resin. 28. The method of claim 24, wherein said resin is applied in a containment device on said wound, wherein said containment device builds the height of said resin and contains said resin within the device. 29. The method of claim 24, wherein a secondary dressing is applied over said resin. | A composition and method useful in promoting healing of a bleeding wound site. The composition preferably includes a substantially anhydrous acid form of a cation exchange resin, which when applied over blood, provides an antimicrobial against planktonic microorganisms and biofilms in the wound. The resin is also capable, when applied in sufficient quantities, of providing a continuing and persistent antimicrobial against planktonic microorganisms and biofilms through dehydration and ion exchange with cations present in the blood and other body fluids. When the resin has a concentration of at least 26 mg/ml, it provides a >3 log reduction in biological activity of MRSA, MRSE and Pseudomonas aeruginosa.1-9. (canceled) 10. A method for providing a continuing and persistent antimicrobial against planktonic microorganisms and biofilms in the area of an open wound, said method comprising applying a substantially anhydrous hydrogen form of a cation exchange resin to said wound. 11. The method of claim 10, wherein said resin is a hydrogen form of a sulfonated 2% crosslinked polystyrene resin. 12. The method of claim 11, wherein said resin has a concentration of at least 26 mg/ml when diluted in fluid at said wound to provide a greater than 3 log reduction in biological activity of Methicillin-resistant Staphylococcus aureus (MRSA), Methicillin-resistant Staphylococcus epidermidis (MRSE) and Pseudomonas aeruginosa. 13. The method of claim 10, further comprising applying one or more of a silver cation exchange resin, an alkali metal cation exchange resin, or a quaternary ammonium cation exchange resin. 14. The method of claim 10, wherein said resin is applied in a containment device on said wound, wherein said containment device builds the height of said resin and contains said resin within the device. 15. The method of claim 10, wherein a secondary dressing is applied over said resin. 16. The method of claim 10, wherein said wound results from a vascular access procedure or a percutaneous catheter or tube. 17. The method of claim 10, wherein said wound is a surgical wound. 18. A method for stopping bleeding at a wound site, said method comprising applying a substantially anhydrous hydrogen form of a cation exchange resin to said wound. 19. The method of claim 18, wherein said resin is a hydrogen form of a sulfonated 2% crosslinked polystyrene resin. 20. The method of claim 18, further comprising applying one or more of a silver cation exchange resin, an alkali metal cation exchange resin, or a quaternary ammonium cation exchange resin. 21. The method of claim 18, wherein said resin is applied in a containment device on said wound, wherein said containment device builds the height of said resin and contains said resin within the device. 22. The method of claim 18, wherein a secondary dressing is applied over said resin. 23. The method of claim 18, wherein said wound is a surgical wound. 24. A method for treating an exuding wound, said method comprising applying a substantially anhydrous hydrogen form of a cation exchange resin to said wound. 25. The method of claim 24, wherein said exuding wound is a pressure ulcer, a venous ulcer, a diabetic ulcer, or an arterial ulcer. 26. The method of claim 24, wherein said resin is a hydrogen form of a sulfonated 2% crosslinked polystyrene resin. 27. The method of claim 24, further comprising applying one or more of a silver cation exchange resin, an alkali metal cation exchange resin, or a quaternary ammonium cation exchange resin. 28. The method of claim 24, wherein said resin is applied in a containment device on said wound, wherein said containment device builds the height of said resin and contains said resin within the device. 29. The method of claim 24, wherein a secondary dressing is applied over said resin. | 1,600 |
1,439 | 15,450,233 | 1,658 | The present invention relates to nanoparticles comprising nucleic acids coated with a (biodegradable) polymer for reversible immobilization and/or controlled release of the nucleic acid comprising nanoparticles. Furthermore, the present invention is directed to medical or diagnostic devices, particularly stents and implants coated by a (biodegradable) polymer with the nucleic acid comprising nanoparticles for reversible immobilization and/or controlled release. Furthermore, the present invention is directed to the use of these nanoparticles coated with a (biodegradable) polymer and to the use of medical devices and implants coated by the (biodegradable) polymer with these nucleic acid comprising nanoparticles in the prophylactic or therapeutic treatment of diseases, particularly in the prevention or treatment of restenosis, calicification, foreign body reaction, or inflammation. Additionally, the present invention is directed to a method of preparing these nucleic acid comprising nanoparticles coated with a (biodegradable) polymer and to a method for coating nucleic acid comprising nanoparticles by a (biodegradable) polymer on medical or diagnostic devices. | 1.-35. (canceled) 36. A method for preparing a coated nanoparticle, the method comprising the following steps:
a) providing a nanoparticle comprising a complex of a nucleic acid and a polymeric carrier molecule according to generic formula (I):
L-P1—S—[S—P2—S]n—S—P3-L
wherein, P1 and P3 are different or identical to each other and represent a linear or branched hydrophilic polymer chain, the linear or branched hydrophilic polymer chain selected independent from each other from polyethylene glycol (PEG), poly-N-(2-hydroxypropyl)methacrylamide, poly-2-(methacryloyloxy)ethyl phosphorylcholines, poly(hydroxyalkyl L-asparagine), poly(2-(methacryloyloxy)ethyl phosphorylcholine), hydroxyethylstarch or poly(hydroxyalkyl L-glutamine), wherein the hydrophilic polymer chain exhibits a molecular weight of 1 kDa to 100 kDa, P2 is a cationic or polycationic polypeptide, having a length of about 3 to about 100 amino acids, and comprising at least 2 cysteine residues; —S—S— is a (reversible) disulfide bond, wherein one of the sulfur positions of each of the disulfide bonds is provided by the at least 2 cysteine residues of the polypeptide P2; L is an optional ligand, which may be present or not, and may be selected independent from the other from RGD, Transferrin, Folate, a signal peptide or signal sequence, a localization signal or sequence, a nuclear localization signal or sequence (NLS), an antibody, a cell penetrating peptide, TAT, a ligand of a receptor, cytokines, hormones, growth factors, small molecules, carbohydrates, mannose, galactose, synthetic ligands, small molecule agonists, inhibitors or antagonists of receptors, or RGD peptidomimetic analogues; and n is an integer, selected from a range of 1 to 50; and b) contacting the nanoparticle of a) with a biodegradable polymer in an organic solvent containing solution. 37. The method of claim 36, wherein contacting is further defined as mixing. 38. The method of claim 36, further comprising removing the organic solvent and/or any other solvent in the organic solvent containing solution. 39. The method of claim 37, wherein removing comprises drying. 40. The method of claim 36, wherein the biodegradable polymer is a PLGA polymer. 41. The method of claim 40, wherein the PLGA polymer is defined by an average molecular weight in the range of 4 kDa to 210 kDa. 42. The method of claim 40, wherein the PLGA polymer is defined by an average molecular weight in the range of 10 kDa to 110 kDa. 43. The method of claim 40, wherein the proportion of lactic acid in the PLGA polymer is greater than 50%. 44. The method of claim 36, wherein the linear or branched hydrophilic polymer chain is PEG. 45. The method of claim 36, wherein preparing the polymeric carrier of step (a) comprising the following steps:
a) providing at least one cationic or polycationic polypeptide comprising at least two cysteine residues as component P2, and optionally at least one further component (AA)x, wherein x is an integer selected from a range of 1 to 100, and wherein (AA)x comprises at least two cysteine residues, mixing these components to mild oxidation conditions, and thereby condensing and thus polymerizing these components with each other via disulfide bonds in a polymerization condensation or polycondensation to obtain a repetitive component H—[S—P2—S]n—H or H{[S—P2—S]a[S-(AA)x-S]b}H; H{[S—P2—S]a[S-(AA)x-S]b}H; b) providing a hydrophilic polymer P1 and/or P3 optionally modified with a ligand L and/or an amino acid component (AA)x as defined according to claim 1; and c) mixing the hydrophilic polymer P1 and/or P3 according to step b) with the repetitive component H—[S—P2—S]n—H or H{[S—P2—S]a[S-(AA)x-S]b}H obtained according to step a) in a ratio of about 2:1, and thereby typically terminating the polymerization condensation or polycondensation reaction and obtaining the polymeric carrier molecule of claim 1. 46. The method of claim 44, further comprising purifying the polymeric carrier molecule obtained according to step c). 47. The method of claim 44, further comprising complexing the nucleic acid to the polymeric carrier of step c) to obtain the nanoparticle. 48. The method of claim 47, wherein the nucleic acid is a DNA, a coding mRNA, a siRNA or an immunostimulatory RNA (isRNA). 49. The method of claim 47, wherein the nucleic acid encodes a therapeutically active polypeptide, tumor antigen, pathogenic antigen, animal antigen, viral antigen, protozoal antigen, bacterial antigen, allergic antigen, autoimmune antigen, allergen, antibody, immunostimulatory protein or an antigen-specific T-cell receptor. 50. The method of claim 47, further comprising lyophilizing the nanoparticle and reconstituting the nanoparticle in an organic solvent containing solution prior to contacting the nanoparticle with the biodegradable polymer. 51. The method of claim 36, wherein the organic solvent containing solution comprises acetone, ethanol and/or THF. 52. The method of claim 36, wherein the organic solvent containing solution comprises 80% to 95% organic solvent. 53. The method of claim 36, wherein the polymeric carrier molecule additionally comprises an amino acid component (AA)x, wherein x is an integer selected from a range of about 1 to 100. 54. The method of claim 36, wherein component P2 of the polymeric carrier is selected from a polypeptide comprising the formula (IIb):
Cys{(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x}Cys, (formula IIb)
wherein
l+m+n+o+x=8-16, and l, m, n or o are independently any number selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, provided that the overall content of Arg, Lys, His and Orn represents at least 10% of all amino acids of the polypeptide; and Xaa may be any amino acid selected from native or non-native amino acids except of Arg, Lys, His or Orn; and x may be any number selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, provided, that the overall content of Xaa does not exceed 90% of all amino acids of the polypeptide. 55. The method of claim 36, wherein component P2 of the polymeric carrier comprises at least 3 Arg amino acids. | The present invention relates to nanoparticles comprising nucleic acids coated with a (biodegradable) polymer for reversible immobilization and/or controlled release of the nucleic acid comprising nanoparticles. Furthermore, the present invention is directed to medical or diagnostic devices, particularly stents and implants coated by a (biodegradable) polymer with the nucleic acid comprising nanoparticles for reversible immobilization and/or controlled release. Furthermore, the present invention is directed to the use of these nanoparticles coated with a (biodegradable) polymer and to the use of medical devices and implants coated by the (biodegradable) polymer with these nucleic acid comprising nanoparticles in the prophylactic or therapeutic treatment of diseases, particularly in the prevention or treatment of restenosis, calicification, foreign body reaction, or inflammation. Additionally, the present invention is directed to a method of preparing these nucleic acid comprising nanoparticles coated with a (biodegradable) polymer and to a method for coating nucleic acid comprising nanoparticles by a (biodegradable) polymer on medical or diagnostic devices.1.-35. (canceled) 36. A method for preparing a coated nanoparticle, the method comprising the following steps:
a) providing a nanoparticle comprising a complex of a nucleic acid and a polymeric carrier molecule according to generic formula (I):
L-P1—S—[S—P2—S]n—S—P3-L
wherein, P1 and P3 are different or identical to each other and represent a linear or branched hydrophilic polymer chain, the linear or branched hydrophilic polymer chain selected independent from each other from polyethylene glycol (PEG), poly-N-(2-hydroxypropyl)methacrylamide, poly-2-(methacryloyloxy)ethyl phosphorylcholines, poly(hydroxyalkyl L-asparagine), poly(2-(methacryloyloxy)ethyl phosphorylcholine), hydroxyethylstarch or poly(hydroxyalkyl L-glutamine), wherein the hydrophilic polymer chain exhibits a molecular weight of 1 kDa to 100 kDa, P2 is a cationic or polycationic polypeptide, having a length of about 3 to about 100 amino acids, and comprising at least 2 cysteine residues; —S—S— is a (reversible) disulfide bond, wherein one of the sulfur positions of each of the disulfide bonds is provided by the at least 2 cysteine residues of the polypeptide P2; L is an optional ligand, which may be present or not, and may be selected independent from the other from RGD, Transferrin, Folate, a signal peptide or signal sequence, a localization signal or sequence, a nuclear localization signal or sequence (NLS), an antibody, a cell penetrating peptide, TAT, a ligand of a receptor, cytokines, hormones, growth factors, small molecules, carbohydrates, mannose, galactose, synthetic ligands, small molecule agonists, inhibitors or antagonists of receptors, or RGD peptidomimetic analogues; and n is an integer, selected from a range of 1 to 50; and b) contacting the nanoparticle of a) with a biodegradable polymer in an organic solvent containing solution. 37. The method of claim 36, wherein contacting is further defined as mixing. 38. The method of claim 36, further comprising removing the organic solvent and/or any other solvent in the organic solvent containing solution. 39. The method of claim 37, wherein removing comprises drying. 40. The method of claim 36, wherein the biodegradable polymer is a PLGA polymer. 41. The method of claim 40, wherein the PLGA polymer is defined by an average molecular weight in the range of 4 kDa to 210 kDa. 42. The method of claim 40, wherein the PLGA polymer is defined by an average molecular weight in the range of 10 kDa to 110 kDa. 43. The method of claim 40, wherein the proportion of lactic acid in the PLGA polymer is greater than 50%. 44. The method of claim 36, wherein the linear or branched hydrophilic polymer chain is PEG. 45. The method of claim 36, wherein preparing the polymeric carrier of step (a) comprising the following steps:
a) providing at least one cationic or polycationic polypeptide comprising at least two cysteine residues as component P2, and optionally at least one further component (AA)x, wherein x is an integer selected from a range of 1 to 100, and wherein (AA)x comprises at least two cysteine residues, mixing these components to mild oxidation conditions, and thereby condensing and thus polymerizing these components with each other via disulfide bonds in a polymerization condensation or polycondensation to obtain a repetitive component H—[S—P2—S]n—H or H{[S—P2—S]a[S-(AA)x-S]b}H; H{[S—P2—S]a[S-(AA)x-S]b}H; b) providing a hydrophilic polymer P1 and/or P3 optionally modified with a ligand L and/or an amino acid component (AA)x as defined according to claim 1; and c) mixing the hydrophilic polymer P1 and/or P3 according to step b) with the repetitive component H—[S—P2—S]n—H or H{[S—P2—S]a[S-(AA)x-S]b}H obtained according to step a) in a ratio of about 2:1, and thereby typically terminating the polymerization condensation or polycondensation reaction and obtaining the polymeric carrier molecule of claim 1. 46. The method of claim 44, further comprising purifying the polymeric carrier molecule obtained according to step c). 47. The method of claim 44, further comprising complexing the nucleic acid to the polymeric carrier of step c) to obtain the nanoparticle. 48. The method of claim 47, wherein the nucleic acid is a DNA, a coding mRNA, a siRNA or an immunostimulatory RNA (isRNA). 49. The method of claim 47, wherein the nucleic acid encodes a therapeutically active polypeptide, tumor antigen, pathogenic antigen, animal antigen, viral antigen, protozoal antigen, bacterial antigen, allergic antigen, autoimmune antigen, allergen, antibody, immunostimulatory protein or an antigen-specific T-cell receptor. 50. The method of claim 47, further comprising lyophilizing the nanoparticle and reconstituting the nanoparticle in an organic solvent containing solution prior to contacting the nanoparticle with the biodegradable polymer. 51. The method of claim 36, wherein the organic solvent containing solution comprises acetone, ethanol and/or THF. 52. The method of claim 36, wherein the organic solvent containing solution comprises 80% to 95% organic solvent. 53. The method of claim 36, wherein the polymeric carrier molecule additionally comprises an amino acid component (AA)x, wherein x is an integer selected from a range of about 1 to 100. 54. The method of claim 36, wherein component P2 of the polymeric carrier is selected from a polypeptide comprising the formula (IIb):
Cys{(Arg)l;(Lys)m;(His)n;(Orn)o;(Xaa)x}Cys, (formula IIb)
wherein
l+m+n+o+x=8-16, and l, m, n or o are independently any number selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, provided that the overall content of Arg, Lys, His and Orn represents at least 10% of all amino acids of the polypeptide; and Xaa may be any amino acid selected from native or non-native amino acids except of Arg, Lys, His or Orn; and x may be any number selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14, provided, that the overall content of Xaa does not exceed 90% of all amino acids of the polypeptide. 55. The method of claim 36, wherein component P2 of the polymeric carrier comprises at least 3 Arg amino acids. | 1,600 |
1,440 | 15,378,447 | 1,658 | Methods for shaping tissue matrices are provided. The methods can be used to produce shaped tissue products that retain desired biologic properties without using chemical crosslinking agents. | 1. A method for shaping a tissue matrix to support a breast implant, comprising:
selecting a collagen-containing tissue matrix; partially dehydrating the tissue matrix; applying mechanical forces to the tissue matrix to form a cup shape; and exposing the tissue matrix while partially dehydrated to ionizing radiation to stabilize at least a portion of the tissue matrix. 2. The method of claim 1, wherein the tissue matrix is an acellular tissue matrix. 3. The method of claim 1, wherein the tissue matrix comprises a dermal tissue matrix. 4. The method of claim 1, wherein the tissue matrix is produced from a tissue selected from fascia, pericardial tissue, dura, umbilical cord tissue, placental tissue, cardiac valve tissue, ligament tissue, tendon tissue, arterial tissue, venous tissue, neural connective tissue, urinary bladder tissue, ureter tissue, or intestinal tissue. 5. The method of claim 1, wherein partially dehydrating the tissue matrix includes removing water to produce a tissue matrix containing between 95% (w/w) and 50% (w/w) water content. 6. The method of claim 5, wherein the water content is between 80% (w/w) and 65% (w/w). 7. The method of claim 5, wherein the water content is between 85% (w/w) and 50% (w/w). 8. The method of claim 5, wherein the water content is between 80% (w/w) and 50% (w/w). 9. The method of claim 5, wherein the water content is between 90% (w/w) and 50% (w/w). 10. The method of claim 5, wherein the water content is between 90% (w/w) and 60% (w/w). 11. The method of claim 5, wherein the water content is between 90% (w/w) and 65% (w/w). 12. The method of claim 1, further comprising rehydrating the tissue matrix. 13. The method of claim 1, wherein the radiation is applied at a dose between 5 Gy and 50 kGy. 14. The method of claim 1, wherein the radiation is applied at a dose between 5 Gy and 20 kGy. 15. The method of claim 1, wherein the radiation is applied at a dose of less than 10 kGy. 16. The method of claim 1, wherein the radiation is applied at a dose of less than 5 kGy. 17. The method of claim 1, wherein the radiation is applied at a dose of less than 1 kGy. 18. The method of claim 1, wherein the radiation is selected from gamma radiation, e-beam radiation, and X-ray radiation. 19. The method of claim 1, the radiation causes cross-linking sufficient to stabilize the tissue matrix to form a stable three-dimensional structure. 20. The method of claim 1, wherein selecting a tissue matrix includes selecting a tissue matrix in the form of a flexible sheet. 21. The method of claim 20, wherein applying mechanical forces to the tissue matrix to form a cup shape includes:
placing the tissue matrix in a cup shaped mold; and applying mechanical forces to change the orientation of collagen fibers within the tissue matrix to produce a tissue matrix having a shape corresponding to the mold. 22. The method of claim 2, wherein selecting a tissue matrix includes selecting a tissue matrix in the form of a flexible sheet. 23. The method of claim 22, wherein applying mechanical forces to the tissue matrix to form a cup shape includes:
placing the tissue matrix in a cup shaped mold; and applying mechanical forces to change the orientation of collagen fibers within the tissue matrix to produce a tissue matrix having a shape corresponding to the mold. 24. The method of claim 1, further comprising:
placing an inner surface of the tissue matrix around a breast implant. 25. The method of claim 24, further comprising:
attaching the tissue matrix to surrounding fascia, muscle, or other tissue. 26. The method of claim 1, further comprising:
applying mechanical forces to the tissue matrix to change the orientation of collagen fibers within the tissue matrix. 27. A tissue product for supporting a breast implant, comprising:
a collagen-containing tissue matrix, wherein the collagen-containing tissue matrix has a cup shape formed by a process comprising:
partially dehydrating the collagen-containing tissue matrix;
applying mechanical forces to the collagen-containing tissue matrix to form a cup shape; and
exposing the collagen-containing tissue matrix to radiation to stabilize at least a portion of the matrix. 28. A tissue product for supporting a breast implant, comprising:
a collagen-containing tissue matrix, wherein the collagen-containing tissue matrix has a mechanically formed cup shape, the cup shape stabilized by radiation without chemical cross-linking agents. | Methods for shaping tissue matrices are provided. The methods can be used to produce shaped tissue products that retain desired biologic properties without using chemical crosslinking agents.1. A method for shaping a tissue matrix to support a breast implant, comprising:
selecting a collagen-containing tissue matrix; partially dehydrating the tissue matrix; applying mechanical forces to the tissue matrix to form a cup shape; and exposing the tissue matrix while partially dehydrated to ionizing radiation to stabilize at least a portion of the tissue matrix. 2. The method of claim 1, wherein the tissue matrix is an acellular tissue matrix. 3. The method of claim 1, wherein the tissue matrix comprises a dermal tissue matrix. 4. The method of claim 1, wherein the tissue matrix is produced from a tissue selected from fascia, pericardial tissue, dura, umbilical cord tissue, placental tissue, cardiac valve tissue, ligament tissue, tendon tissue, arterial tissue, venous tissue, neural connective tissue, urinary bladder tissue, ureter tissue, or intestinal tissue. 5. The method of claim 1, wherein partially dehydrating the tissue matrix includes removing water to produce a tissue matrix containing between 95% (w/w) and 50% (w/w) water content. 6. The method of claim 5, wherein the water content is between 80% (w/w) and 65% (w/w). 7. The method of claim 5, wherein the water content is between 85% (w/w) and 50% (w/w). 8. The method of claim 5, wherein the water content is between 80% (w/w) and 50% (w/w). 9. The method of claim 5, wherein the water content is between 90% (w/w) and 50% (w/w). 10. The method of claim 5, wherein the water content is between 90% (w/w) and 60% (w/w). 11. The method of claim 5, wherein the water content is between 90% (w/w) and 65% (w/w). 12. The method of claim 1, further comprising rehydrating the tissue matrix. 13. The method of claim 1, wherein the radiation is applied at a dose between 5 Gy and 50 kGy. 14. The method of claim 1, wherein the radiation is applied at a dose between 5 Gy and 20 kGy. 15. The method of claim 1, wherein the radiation is applied at a dose of less than 10 kGy. 16. The method of claim 1, wherein the radiation is applied at a dose of less than 5 kGy. 17. The method of claim 1, wherein the radiation is applied at a dose of less than 1 kGy. 18. The method of claim 1, wherein the radiation is selected from gamma radiation, e-beam radiation, and X-ray radiation. 19. The method of claim 1, the radiation causes cross-linking sufficient to stabilize the tissue matrix to form a stable three-dimensional structure. 20. The method of claim 1, wherein selecting a tissue matrix includes selecting a tissue matrix in the form of a flexible sheet. 21. The method of claim 20, wherein applying mechanical forces to the tissue matrix to form a cup shape includes:
placing the tissue matrix in a cup shaped mold; and applying mechanical forces to change the orientation of collagen fibers within the tissue matrix to produce a tissue matrix having a shape corresponding to the mold. 22. The method of claim 2, wherein selecting a tissue matrix includes selecting a tissue matrix in the form of a flexible sheet. 23. The method of claim 22, wherein applying mechanical forces to the tissue matrix to form a cup shape includes:
placing the tissue matrix in a cup shaped mold; and applying mechanical forces to change the orientation of collagen fibers within the tissue matrix to produce a tissue matrix having a shape corresponding to the mold. 24. The method of claim 1, further comprising:
placing an inner surface of the tissue matrix around a breast implant. 25. The method of claim 24, further comprising:
attaching the tissue matrix to surrounding fascia, muscle, or other tissue. 26. The method of claim 1, further comprising:
applying mechanical forces to the tissue matrix to change the orientation of collagen fibers within the tissue matrix. 27. A tissue product for supporting a breast implant, comprising:
a collagen-containing tissue matrix, wherein the collagen-containing tissue matrix has a cup shape formed by a process comprising:
partially dehydrating the collagen-containing tissue matrix;
applying mechanical forces to the collagen-containing tissue matrix to form a cup shape; and
exposing the collagen-containing tissue matrix to radiation to stabilize at least a portion of the matrix. 28. A tissue product for supporting a breast implant, comprising:
a collagen-containing tissue matrix, wherein the collagen-containing tissue matrix has a mechanically formed cup shape, the cup shape stabilized by radiation without chemical cross-linking agents. | 1,600 |
1,441 | 15,763,920 | 1,612 | A personal wash composition which provides an effective antimicrobial benefit against fungi, gram positive and gram negative bacteria, which composition comprises: a) from 0.1% to 10 wt % betaine surfactant, b) from 0.1% to 5.0 wt % lactic acid, c) from 0.1% to 20 wt % polyhydric C 2 -C 6 alcohol, d) from 0% to 10 wt % alkyl polyethoxy carboxylate of the formula RO(CH 2 CH 2 O) k CH 2 COO − M + wherein R is a C 8 -C 22 alkyl, k is an integer from 0 to 20, and M is a soluble salt-forming cation, e) from 0% to 10 wt % alkyl polyethoxy amides of the formula RO(CH 2 CH 2 O) k CH 2 CONH 2 wherein R is a C 8 -C 22 alkyl, k is an integer from 0 to 20, f) >8 wt % alkyl ether sulphate, g) water, h) a pH of 3.8-4.5, i) 10-20 wt % total surfactant, j) from 0.1 to 10 wt % metal salt. | 1. A personal wash composition comprising:
from 0.1% to 10 wt % betaine surfactant; from 0.1% to 5.0 wt % lactic acid; from 0.1% to 20 wt % polyhydric C2-C6 alcohol; from 0% to 10 wt % alkyl polyethoxy carboxylate; from 0% to 10 wt % alkyl polyethoxy amides; greater than 8 wt % alkyl ether sulphate; water; a pH of 3.8-4.5; from 10-20 wt % total surfactant; and from 0.1 to 10 wt % metal salt. 2. The composition according to claim 1, wherein the alkyl polyethoxy carboxylate has the formula RO(CH2CH2O)kCH2COO−M+;
wherein R is a C8-C22 alkyl; wherein k is an integer from 0 to 20; wherein M is a soluble salt-forming cation; and wherein the alkyl polyethoxy carboxylate is present in an amount of from 2-7 wt %. 3. The composition according to claim 2, wherein in the alkyl polyethoxy carboxylate, R is a C12 alkyl, K is 11, and M is Na. 4. The composition according to claim 1, wherein the betaine surfactant is present in an amount of from 1-3 wt %. 5. The composition according to claim 1, wherein the betaine comprises cocoamidopropyl betaine. 6. The composition according to claim 1, wherein the lactic acid is present in an amount of from 0.2-8 wt %. 7. The composition according to claim 1, wherein the polyhydric C2-C6 alcohol is present in an amount of from 2-18 wt %. 8. The composition according to claim 1, wherein the polyhydric C2-C6 alcohol comprises glycerol. 9. The composition according to claim 1, wherein the alkyl polyethoxy amide comprises PEG 4 rapeseed amide. 10. The composition according to claim 1, wherein the metal salt is present in an amount of from 0.1-5 wt %. 11. The composition according to claim 1, wherein the metal salt comprises one or both of an alkali and an alkaline metal halide. 12. The composition according to claim 1, wherein the alkyl ether sulphate comprises sodium laureth sulphate. 13. A personal wash composition in the form of a foam comprising:
from 0.1 wt % to 5 wt % betaine surfactant; from 0.1 wt % to 5 wt % lactic acid; from 0.1 wt % to 20 wt % polyhydric C2-C6 alcohol; water; a pH of 3.8-4.5; and from 0.1-5 wt % total surfactant. 14. The composition according to claim 13, wherein the foam has a density of less than 500 g/liter. 15. The composition according to claim 13, wherein the betaine surfactant is present in an amount of from 0.1-2 wt %. 16. The composition according to claim 13, wherein the betaine comprises cocoamidopropyl betaine. 17. The composition according to claim 13, wherein the lactic acid is present in an amount of from 0.2-5 wt %. 18. The composition according to claim 13, wherein the polyhydric C2-C6 alcohol is present in an amount of from 2-18 wt %. 19. The composition according to claim 13, wherein the polyhydric C2-C6 alcohol comprises glycerol. 20. A method for providing a germicidal benefit to a topical surface comprising:
contacting a topical surface with the composition according to claim 13; and providing an effective germicidal benefit against fungi, gram-positive and gram-negative bacteria if the topical surface, prior to contact with the composition, had the presence of one or more of fungi, gram-positive and gram-negative bacteria. 21. A method for providing a germicidal benefit to a dermal surface comprising:
contacting a dermal surface with the composition according to claim 13; and providing an effective germicidal benefit against undesired pathogens if the dermal surface, prior to contact with the composition, had the presence of one or more undesired pathogens, while not upsetting or disrupting the natural balance of microflora or microbiome on the dermal surface. 22. A method for stabilizing the pH of a surface comprising contacting a surface upon which the presence of one or more undesired pathogens are known or suspected, with the composition according to claim 13. 23. A method for stabilizing microbiome or microflora of a surface comprising contacting a surface upon which the presence of one or more undesired pathogens are known or suspected, with the composition according to claim 13. 24. A method of moisturizing a surface comprising contacting a surface upon which the presence of one or more undesired pathogens are known or suspected, with the composition according to claim 13. 25. The composition according to claim 1, wherein the alkyl polyethoxy amides has the formula RO(CH2CH2O)kCH2CONH2, wherein R is a C8-C22 alkyl, and k is an integer from 0 to 20;
wherein the alkyl polyethoxy carboxylate has the formula RO(CH2CH2O)kCH2COO−M+, wherein R is a C8-C22 alkyl, wherein k is an integer from 0 to 20, wherein M is a soluble salt-forming cation, and wherein the alkyl polyethoxy carboxylate is present in an amount of about 4.8 wt %; wherein the betaine surfactant is present in an amount of about 1.3 wt %; wherein the lactic acid is present in an amount of about 2.25 wt %; wherein the polyhydric C2-C6 alcohol is present in an amount of from 10-15 wt %; and wherein the metal salt is present in an amount of about 2 wt %. 26. The composition according to claim 13, wherein the foam has a density of less than 200 g/liter;
wherein the betaine surfactant is present in an amount of about 0.6 wt %; wherein the lactic acid is present in an amount of about 2.75 wt %; and wherein the polyhydric C2-C6 alcohol is present in an amount of from 10-15 wt %. | A personal wash composition which provides an effective antimicrobial benefit against fungi, gram positive and gram negative bacteria, which composition comprises: a) from 0.1% to 10 wt % betaine surfactant, b) from 0.1% to 5.0 wt % lactic acid, c) from 0.1% to 20 wt % polyhydric C 2 -C 6 alcohol, d) from 0% to 10 wt % alkyl polyethoxy carboxylate of the formula RO(CH 2 CH 2 O) k CH 2 COO − M + wherein R is a C 8 -C 22 alkyl, k is an integer from 0 to 20, and M is a soluble salt-forming cation, e) from 0% to 10 wt % alkyl polyethoxy amides of the formula RO(CH 2 CH 2 O) k CH 2 CONH 2 wherein R is a C 8 -C 22 alkyl, k is an integer from 0 to 20, f) >8 wt % alkyl ether sulphate, g) water, h) a pH of 3.8-4.5, i) 10-20 wt % total surfactant, j) from 0.1 to 10 wt % metal salt.1. A personal wash composition comprising:
from 0.1% to 10 wt % betaine surfactant; from 0.1% to 5.0 wt % lactic acid; from 0.1% to 20 wt % polyhydric C2-C6 alcohol; from 0% to 10 wt % alkyl polyethoxy carboxylate; from 0% to 10 wt % alkyl polyethoxy amides; greater than 8 wt % alkyl ether sulphate; water; a pH of 3.8-4.5; from 10-20 wt % total surfactant; and from 0.1 to 10 wt % metal salt. 2. The composition according to claim 1, wherein the alkyl polyethoxy carboxylate has the formula RO(CH2CH2O)kCH2COO−M+;
wherein R is a C8-C22 alkyl; wherein k is an integer from 0 to 20; wherein M is a soluble salt-forming cation; and wherein the alkyl polyethoxy carboxylate is present in an amount of from 2-7 wt %. 3. The composition according to claim 2, wherein in the alkyl polyethoxy carboxylate, R is a C12 alkyl, K is 11, and M is Na. 4. The composition according to claim 1, wherein the betaine surfactant is present in an amount of from 1-3 wt %. 5. The composition according to claim 1, wherein the betaine comprises cocoamidopropyl betaine. 6. The composition according to claim 1, wherein the lactic acid is present in an amount of from 0.2-8 wt %. 7. The composition according to claim 1, wherein the polyhydric C2-C6 alcohol is present in an amount of from 2-18 wt %. 8. The composition according to claim 1, wherein the polyhydric C2-C6 alcohol comprises glycerol. 9. The composition according to claim 1, wherein the alkyl polyethoxy amide comprises PEG 4 rapeseed amide. 10. The composition according to claim 1, wherein the metal salt is present in an amount of from 0.1-5 wt %. 11. The composition according to claim 1, wherein the metal salt comprises one or both of an alkali and an alkaline metal halide. 12. The composition according to claim 1, wherein the alkyl ether sulphate comprises sodium laureth sulphate. 13. A personal wash composition in the form of a foam comprising:
from 0.1 wt % to 5 wt % betaine surfactant; from 0.1 wt % to 5 wt % lactic acid; from 0.1 wt % to 20 wt % polyhydric C2-C6 alcohol; water; a pH of 3.8-4.5; and from 0.1-5 wt % total surfactant. 14. The composition according to claim 13, wherein the foam has a density of less than 500 g/liter. 15. The composition according to claim 13, wherein the betaine surfactant is present in an amount of from 0.1-2 wt %. 16. The composition according to claim 13, wherein the betaine comprises cocoamidopropyl betaine. 17. The composition according to claim 13, wherein the lactic acid is present in an amount of from 0.2-5 wt %. 18. The composition according to claim 13, wherein the polyhydric C2-C6 alcohol is present in an amount of from 2-18 wt %. 19. The composition according to claim 13, wherein the polyhydric C2-C6 alcohol comprises glycerol. 20. A method for providing a germicidal benefit to a topical surface comprising:
contacting a topical surface with the composition according to claim 13; and providing an effective germicidal benefit against fungi, gram-positive and gram-negative bacteria if the topical surface, prior to contact with the composition, had the presence of one or more of fungi, gram-positive and gram-negative bacteria. 21. A method for providing a germicidal benefit to a dermal surface comprising:
contacting a dermal surface with the composition according to claim 13; and providing an effective germicidal benefit against undesired pathogens if the dermal surface, prior to contact with the composition, had the presence of one or more undesired pathogens, while not upsetting or disrupting the natural balance of microflora or microbiome on the dermal surface. 22. A method for stabilizing the pH of a surface comprising contacting a surface upon which the presence of one or more undesired pathogens are known or suspected, with the composition according to claim 13. 23. A method for stabilizing microbiome or microflora of a surface comprising contacting a surface upon which the presence of one or more undesired pathogens are known or suspected, with the composition according to claim 13. 24. A method of moisturizing a surface comprising contacting a surface upon which the presence of one or more undesired pathogens are known or suspected, with the composition according to claim 13. 25. The composition according to claim 1, wherein the alkyl polyethoxy amides has the formula RO(CH2CH2O)kCH2CONH2, wherein R is a C8-C22 alkyl, and k is an integer from 0 to 20;
wherein the alkyl polyethoxy carboxylate has the formula RO(CH2CH2O)kCH2COO−M+, wherein R is a C8-C22 alkyl, wherein k is an integer from 0 to 20, wherein M is a soluble salt-forming cation, and wherein the alkyl polyethoxy carboxylate is present in an amount of about 4.8 wt %; wherein the betaine surfactant is present in an amount of about 1.3 wt %; wherein the lactic acid is present in an amount of about 2.25 wt %; wherein the polyhydric C2-C6 alcohol is present in an amount of from 10-15 wt %; and wherein the metal salt is present in an amount of about 2 wt %. 26. The composition according to claim 13, wherein the foam has a density of less than 200 g/liter;
wherein the betaine surfactant is present in an amount of about 0.6 wt %; wherein the lactic acid is present in an amount of about 2.75 wt %; and wherein the polyhydric C2-C6 alcohol is present in an amount of from 10-15 wt %. | 1,600 |
1,442 | 12,898,307 | 1,641 | Microfluidic devices may be fabricated from thermoplastics using, for example, hot embossing techniques. In some embodiments, the devices feature non-uniform surface modifications. | 1. A microfluidic device, comprising:
a thermoplastic polymer structure defining therein (i) first and second microchannels, and (ii) a chamber laterally separating and fluidically coupling the first and second microchannels; and a three-dimensional scaffold contained in the chamber. 2. The device of claim 1, wherein portions of the first and second microchannels on opposite sides of the chamber are substantially parallel. 3. The device of claim 1, wherein the first and second microchannels have respective first and second inlets. 4. The device of claim 1, wherein the first and second microchannels have respective first and second outlets. 5. The device of claim 1, wherein the first and second microchannels merge into a common channel portion having an outlet. 6. The device of claim 1, wherein the three-dimensional scaffold comprises a gel matrix. 7. The device of claim 6, wherein the gel matrix comprises at least one of collagen, fibronectin, hyaluronan, a hydrogel, a peptide gel, or gel-like proteins secreted by animal cells. 8. The device of claim 1, wherein the thermoplastic polymer comprises at least one of polystyrene, polydimethylsiloxane, polycarbonate, poly(methyl methacrylate), cyclic olefin copolymer, polyethylene, polyethylene terephthalate, polyurethane, polycaproleacton, polylactic acid, polyglycolic acid, or poly(lactic-co-glycolic acid). 9. The device of claim 1, wherein the chamber features a surface modification to at least one of an upper and a lower surface thereof for holding the scaffold in place. 10. The device of claim 9, wherein the surface modification comprises microposts disposed on the at least one surface of the chamber. 11. The device of claim 1, wherein at least a portion of a surface of at least one of the first and second microchannels is patterned. 12. The device of claim 11, wherein the surface patterning is non-uniform. 13. The device of claim 11, wherein the surface patterning comprises at least one of chemical or topographical patterning. 14. The device of claim 1, wherein the polymer structure is substantially optically transparent. 15. A microfluidic device, comprising:
a polymer structure defining first and second microchannel portions therein, the first and second microchannel portions having respective first and second inlets at first ends thereof, and merging into a third microchannel portion at second ends thereof, the third microchannel portion having an outlet; and a three-dimensional scaffold laterally separating and fluidically coupling the first and second microchannel portions. 16. The device of claim 15, wherein subportions of the first and second microchannel portions on opposite sides of the chamber are substantially parallel. 17. The device of claim 15, wherein the three-dimensional scaffold comprises a gel matrix. 18. The device of claim 15, wherein the polymer structure is substantially optically transparent. 19. A method of manufacturing a microfluidic device, comprising:
hot-embossing a master mold into a polymer substrate on a first side thereof so as to define two microchannels separated and fluidically coupled by a chamber in the polymer substrate; and bonding a polymer sheet to the first side of the polymer substrate using lamination. 20. The method of claim 19, further comprising plasma-treating at least a portion of at least one of the first side of the polymer substrate and the polymer sheet. 21. The method of claim 19, wherein the lamination comprises roller lamination. 22. The method of claim 19, wherein the lamination comprises thermal lamination. 23. The method of claim 19, wherein the master mold comprises a material selected from the group consisting of epoxy, silicon, and metal. 24. A microfluidic device, comprising:
a polymer scaffold defining at least one microchannel therein, an interior surface of the microchannel featuring inhomogeneous chemical modifications along a direction substantially perpendicular to a longitudinal axis of the channel. 25. The device of claim 24, wherein the modifications comprise chemically treated islands. 26. The device of claim 24, wherein the modifications comprise chemically treated regions defining untreated islands. 27. The device of claim 24, wherein the chemical modifications comprise chemically treated strips oriented along the longitudinal axis of the channel. 28. The device of claim 24, further comprising topographical modifications. 29. A microfluidic device, comprising:
a polymer scaffold defining at least one microchannel therein, an interior surface of the microchannel featuring a plurality of microposts disposed on the surface at an oblique angle thereto. 30. The device of claim 29, wherein a density of the microposts varies along a longitudinal axis of the channel. 31. The device of claim 29, wherein a size of the microposts varies along a longitudinal axis of the channel. 32. The device of claim 29, wherein the angle is in the range from about 10° to about 80°. 33. A microfluidic device, comprising:
a polymer scaffold defining at least one microchannel therein, an interior surface of the microchannel featuring chemical modifications patterned along at least one of a direction substantially perpendicular to a longitudinal axis of the channel or a direction substantially parallel to the longitudinal axis of the channel. | Microfluidic devices may be fabricated from thermoplastics using, for example, hot embossing techniques. In some embodiments, the devices feature non-uniform surface modifications.1. A microfluidic device, comprising:
a thermoplastic polymer structure defining therein (i) first and second microchannels, and (ii) a chamber laterally separating and fluidically coupling the first and second microchannels; and a three-dimensional scaffold contained in the chamber. 2. The device of claim 1, wherein portions of the first and second microchannels on opposite sides of the chamber are substantially parallel. 3. The device of claim 1, wherein the first and second microchannels have respective first and second inlets. 4. The device of claim 1, wherein the first and second microchannels have respective first and second outlets. 5. The device of claim 1, wherein the first and second microchannels merge into a common channel portion having an outlet. 6. The device of claim 1, wherein the three-dimensional scaffold comprises a gel matrix. 7. The device of claim 6, wherein the gel matrix comprises at least one of collagen, fibronectin, hyaluronan, a hydrogel, a peptide gel, or gel-like proteins secreted by animal cells. 8. The device of claim 1, wherein the thermoplastic polymer comprises at least one of polystyrene, polydimethylsiloxane, polycarbonate, poly(methyl methacrylate), cyclic olefin copolymer, polyethylene, polyethylene terephthalate, polyurethane, polycaproleacton, polylactic acid, polyglycolic acid, or poly(lactic-co-glycolic acid). 9. The device of claim 1, wherein the chamber features a surface modification to at least one of an upper and a lower surface thereof for holding the scaffold in place. 10. The device of claim 9, wherein the surface modification comprises microposts disposed on the at least one surface of the chamber. 11. The device of claim 1, wherein at least a portion of a surface of at least one of the first and second microchannels is patterned. 12. The device of claim 11, wherein the surface patterning is non-uniform. 13. The device of claim 11, wherein the surface patterning comprises at least one of chemical or topographical patterning. 14. The device of claim 1, wherein the polymer structure is substantially optically transparent. 15. A microfluidic device, comprising:
a polymer structure defining first and second microchannel portions therein, the first and second microchannel portions having respective first and second inlets at first ends thereof, and merging into a third microchannel portion at second ends thereof, the third microchannel portion having an outlet; and a three-dimensional scaffold laterally separating and fluidically coupling the first and second microchannel portions. 16. The device of claim 15, wherein subportions of the first and second microchannel portions on opposite sides of the chamber are substantially parallel. 17. The device of claim 15, wherein the three-dimensional scaffold comprises a gel matrix. 18. The device of claim 15, wherein the polymer structure is substantially optically transparent. 19. A method of manufacturing a microfluidic device, comprising:
hot-embossing a master mold into a polymer substrate on a first side thereof so as to define two microchannels separated and fluidically coupled by a chamber in the polymer substrate; and bonding a polymer sheet to the first side of the polymer substrate using lamination. 20. The method of claim 19, further comprising plasma-treating at least a portion of at least one of the first side of the polymer substrate and the polymer sheet. 21. The method of claim 19, wherein the lamination comprises roller lamination. 22. The method of claim 19, wherein the lamination comprises thermal lamination. 23. The method of claim 19, wherein the master mold comprises a material selected from the group consisting of epoxy, silicon, and metal. 24. A microfluidic device, comprising:
a polymer scaffold defining at least one microchannel therein, an interior surface of the microchannel featuring inhomogeneous chemical modifications along a direction substantially perpendicular to a longitudinal axis of the channel. 25. The device of claim 24, wherein the modifications comprise chemically treated islands. 26. The device of claim 24, wherein the modifications comprise chemically treated regions defining untreated islands. 27. The device of claim 24, wherein the chemical modifications comprise chemically treated strips oriented along the longitudinal axis of the channel. 28. The device of claim 24, further comprising topographical modifications. 29. A microfluidic device, comprising:
a polymer scaffold defining at least one microchannel therein, an interior surface of the microchannel featuring a plurality of microposts disposed on the surface at an oblique angle thereto. 30. The device of claim 29, wherein a density of the microposts varies along a longitudinal axis of the channel. 31. The device of claim 29, wherein a size of the microposts varies along a longitudinal axis of the channel. 32. The device of claim 29, wherein the angle is in the range from about 10° to about 80°. 33. A microfluidic device, comprising:
a polymer scaffold defining at least one microchannel therein, an interior surface of the microchannel featuring chemical modifications patterned along at least one of a direction substantially perpendicular to a longitudinal axis of the channel or a direction substantially parallel to the longitudinal axis of the channel. | 1,600 |
1,443 | 13,205,899 | 1,632 | Methods, mixtures, and kits related to treating tissue are provided. The methods, mixtures, and kits can include an acellular tissue matrix, a polymer, and a solvent and may be capable of producing tissue scaffolds. The tissue scaffolds may be able to form a stable, three-dimensional shape in situ and elicit a limited immunologic or inflammatory response. | 1. A method comprising:
providing a particulate acellular tissue matrix (ATM) and a solution comprising a polymer dissolved in a solvent; mixing the solution with the particulate ATM to create a mixture; and placing the mixture in contact with an aqueous media to allow the solvent to diffuse from the mixture to form a tissue scaffold from the polymer and ATM. 2. The method of claim 1, wherein placing the mixture in contact with an aqueous media comprises placing the mixture in, on, or proximate to a tissue site. 3. The method of claim 1, wherein the tissue scaffold has a stable three-dimensional shape. 4. The method of claim 1, wherein the tissue scaffold has a reduced immunological or inflammatory response when implanted in an animal than the polymer alone. 5. The method of claim 4, wherein the immunological or inflammatory response is measured by the number of inflammatory cells present. 6. The method of claim 1, wherein the solvent is biocompatible and water miscible. 7. The method of claim 2, further comprising injecting the mixture into the tissue site. 8. The method of claim 2, further comprising injecting the mixture onto the tissue site. 9. The method of claim 1, wherein the polymer comprises polycaprolactone. 10. The method of claim 9, wherein the solvent comprises at least one of dioxane and N-methyl-2-pyrrolidone. 11. The method of claim 9, wherein the polycaprolactone in solvent is present in an amount ranging from about 5-30% (w/v). 12. The method of claim 9, wherein the polycaprolactone in solvent is present in an amount ranging from about 10-20% (w/v). 13. The method of claim 1, wherein the polymer comprises a poly-4-hydroxybutyrate. 14. The method of claim 13, wherein the solvent comprises at least one of dioxane and N-methyl-2-pyrrolidone. 15. The method of claim 13, wherein the poly-4-hydroxybutyrate in solvent is present in an amount ranging from about 5-40% (w/v). 16. The method of claim 13, wherein the poly-4-hydroxybutyrate in solvent is present in an amount ranging from about 10-30% (w/v). 17. The method of claim 1, wherein the polymer comprises a benzyl ester derivative of hyaluronic acid. 18. The method of claim 17, wherein the solvent comprises at least one of dimethyl sulfoxide and N-methyl-2-pyrrolidone. 19. The method of claim 17, wherein the benzyl ester derivative of hyaluronic acid in solvent is present in an amount ranging from about 5-50% (w/v). 20. The method of claim 17, wherein the benzyl ester derivative of hyaluronic acid in solvent is present in an amount ranging from about 5-40% (w/v). 21. The method of claim 1, wherein the particulate ATM comprises uniform size particles. 22. The method of claim 1, wherein the particulate ATM comprises a dermal ATM. 23. The method of claim 22, wherein the dermal ATM is a human tissue matrix or a porcine tissue matrix. 24. The method of claim 1, wherein the particulate ATM is a cartilage tissue matrix. 25. The method of claim 24, wherein the cartilage tissue matrix comprises a human cartilage matrix or a porcine cartilage matrix. 26. The method of claim 1, wherein the particulate ATM comprises a bone tissue matrix. 27. The method of claim 26, wherein the bone tissue matrix comprises a human bone or a porcine bone. 28. The method of claim 1, wherein the particulate ATM comprises ATM from two or more different types of tissues. 29. The method of claim 28, wherein the two or more different types of tissues comprise dermis and cartilage, cartilage and bone, human tissue matrices, porcine tissue matrices, or human tissue matrices and porcine tissue matrices. 30. The method of claim 2, wherein the tissue site comprises bone, cartilaginous tissue, or breast tissue. 31. The method of claim 1, wherein placing the mixture in contact with an aqueous media comprises placing the mixture in a mold. 32. The method of claim 31, wherein the mold is in the form of a tissue or organ defect. 33. The method of claim 31, wherein the mold is an eppendorf tube, a metal tube, or an injection tube. 34. The method of claim 1, wherein placing the mixture in contact with an aqueous media comprises at least one of rinsing, washing, or soaking the mixture in an aqueous media. 35. A tissue scaffold mixture comprising:
a particulate acellular tissue matrix (ATM); a polymer; and a water miscible solvent, wherein when the mixture is implanted in an animal, the water miscible solvent is capable of diffusing from the mixture to form a tissue scaffold from the polymer and ATM. 36. The tissue scaffold mixture of claim 35, wherein the tissue scaffold has a fixed three dimensional shape. 37. The tissue scaffold mixture of claim 35, wherein the tissue scaffold has a reduced immunological or inflammatory response when implanted than the polymer alone. 38. The tissue scaffold mixture of claim 37, wherein the immunological or inflammatory response is measured by the number of inflammatory cells present. 39. The tissue scaffold mixture of claim 35, wherein the solvent is biocompatible. 40. The tissue scaffold mixture of claim 35, wherein the polymer comprises a polycaprolactone. 41. The tissue scaffold mixture of claim 40, wherein the solvent comprises at least one of dioxane and N-methyl-2-pyrrolidone. 42. The tissue scaffold mixture of claim 40, wherein the polycaprolactone in solvent is present in an amount ranging from about 5-30% (w/v). 43. The tissue scaffold mixture of claim 40, wherein the polycaprolactone in solvent is present in an amount ranging from about 10-30% (w/v). 44. The tissue scaffold mixture of claim 35, wherein the polymer comprises a poly-4-hydroxybutyrate. 45. The tissue scaffold mixture of claim 44, wherein the solvent comprises at least one of dioxane and N-methyl-2-pyrrolidone. 46. The tissue scaffold mixture of claim 44, wherein the poly-4-hydroxybutyrate in solvent is present in an amount ranging from about 5-40% (w/v). 47. The tissue scaffold mixture of claim 44, wherein the poly-4-hydroxybutyrate in solvent is present in an amount ranging from about 10-30% (w/v). 48. The tissue scaffold mixture of claim 35, wherein the polymer comprises a benzyl ester derivative of hyaluronic acid. 49. The tissue scaffold mixture of claim 48, wherein the solvent comprises at least one of dimethyl sulfoxide and N-methyl-2-pyrrolidone. 50. The tissue scaffold mixture of claim 48, wherein the benzyl ester derivative of hyaluronic acid in solvent is present in an amount ranging from about 5-50% (w/v). 51. The tissue scaffold mixture of claim 48, wherein the benzyl ester derivative of hyaluronic acid in solvent is present in an amount ranging from about 5-40% (w/v). 52. The tissue scaffold mixture of claim 35, wherein the particulate ATM comprises uniform size particles. 53. The tissue scaffold mixture of claim 35, wherein the particulate ATM comprises a dermal ATM. 54. The tissue scaffold mixture of claim 53, wherein the dermal ATM is a human tissue matrix or a porcine tissue matrix. 55. The tissue scaffold mixture of claim 35, wherein the particulate ATM is a cartilage tissue matrix. 56. The tissue scaffold mixture of claim 55, wherein the cartilage tissue matrix comprises a human cartilage matrix or a porcine cartilage matrix. 57. The tissue scaffold mixture of claim 35, wherein the particulate ATM comprises a bone tissue matrix. 58. The tissue scaffold mixture of claim 57, wherein the bone tissue matrix comprises a human bone or a porcine bone. 59. The tissue scaffold mixture of claim 35, wherein the particulate ATM comprises ATM from two or more different types of tissues. 60. The tissue scaffold mixture of claim 59, wherein the two or more different types of tissues comprise dermis and cartilage, cartilage and bone, human tissue matrices, porcine tissue matrices, or human tissue matrix and porcine tissue matrix. 61. A kit comprising:
a particulate acellular tissue matrix (ATM); a polymer; and a solvent. | Methods, mixtures, and kits related to treating tissue are provided. The methods, mixtures, and kits can include an acellular tissue matrix, a polymer, and a solvent and may be capable of producing tissue scaffolds. The tissue scaffolds may be able to form a stable, three-dimensional shape in situ and elicit a limited immunologic or inflammatory response.1. A method comprising:
providing a particulate acellular tissue matrix (ATM) and a solution comprising a polymer dissolved in a solvent; mixing the solution with the particulate ATM to create a mixture; and placing the mixture in contact with an aqueous media to allow the solvent to diffuse from the mixture to form a tissue scaffold from the polymer and ATM. 2. The method of claim 1, wherein placing the mixture in contact with an aqueous media comprises placing the mixture in, on, or proximate to a tissue site. 3. The method of claim 1, wherein the tissue scaffold has a stable three-dimensional shape. 4. The method of claim 1, wherein the tissue scaffold has a reduced immunological or inflammatory response when implanted in an animal than the polymer alone. 5. The method of claim 4, wherein the immunological or inflammatory response is measured by the number of inflammatory cells present. 6. The method of claim 1, wherein the solvent is biocompatible and water miscible. 7. The method of claim 2, further comprising injecting the mixture into the tissue site. 8. The method of claim 2, further comprising injecting the mixture onto the tissue site. 9. The method of claim 1, wherein the polymer comprises polycaprolactone. 10. The method of claim 9, wherein the solvent comprises at least one of dioxane and N-methyl-2-pyrrolidone. 11. The method of claim 9, wherein the polycaprolactone in solvent is present in an amount ranging from about 5-30% (w/v). 12. The method of claim 9, wherein the polycaprolactone in solvent is present in an amount ranging from about 10-20% (w/v). 13. The method of claim 1, wherein the polymer comprises a poly-4-hydroxybutyrate. 14. The method of claim 13, wherein the solvent comprises at least one of dioxane and N-methyl-2-pyrrolidone. 15. The method of claim 13, wherein the poly-4-hydroxybutyrate in solvent is present in an amount ranging from about 5-40% (w/v). 16. The method of claim 13, wherein the poly-4-hydroxybutyrate in solvent is present in an amount ranging from about 10-30% (w/v). 17. The method of claim 1, wherein the polymer comprises a benzyl ester derivative of hyaluronic acid. 18. The method of claim 17, wherein the solvent comprises at least one of dimethyl sulfoxide and N-methyl-2-pyrrolidone. 19. The method of claim 17, wherein the benzyl ester derivative of hyaluronic acid in solvent is present in an amount ranging from about 5-50% (w/v). 20. The method of claim 17, wherein the benzyl ester derivative of hyaluronic acid in solvent is present in an amount ranging from about 5-40% (w/v). 21. The method of claim 1, wherein the particulate ATM comprises uniform size particles. 22. The method of claim 1, wherein the particulate ATM comprises a dermal ATM. 23. The method of claim 22, wherein the dermal ATM is a human tissue matrix or a porcine tissue matrix. 24. The method of claim 1, wherein the particulate ATM is a cartilage tissue matrix. 25. The method of claim 24, wherein the cartilage tissue matrix comprises a human cartilage matrix or a porcine cartilage matrix. 26. The method of claim 1, wherein the particulate ATM comprises a bone tissue matrix. 27. The method of claim 26, wherein the bone tissue matrix comprises a human bone or a porcine bone. 28. The method of claim 1, wherein the particulate ATM comprises ATM from two or more different types of tissues. 29. The method of claim 28, wherein the two or more different types of tissues comprise dermis and cartilage, cartilage and bone, human tissue matrices, porcine tissue matrices, or human tissue matrices and porcine tissue matrices. 30. The method of claim 2, wherein the tissue site comprises bone, cartilaginous tissue, or breast tissue. 31. The method of claim 1, wherein placing the mixture in contact with an aqueous media comprises placing the mixture in a mold. 32. The method of claim 31, wherein the mold is in the form of a tissue or organ defect. 33. The method of claim 31, wherein the mold is an eppendorf tube, a metal tube, or an injection tube. 34. The method of claim 1, wherein placing the mixture in contact with an aqueous media comprises at least one of rinsing, washing, or soaking the mixture in an aqueous media. 35. A tissue scaffold mixture comprising:
a particulate acellular tissue matrix (ATM); a polymer; and a water miscible solvent, wherein when the mixture is implanted in an animal, the water miscible solvent is capable of diffusing from the mixture to form a tissue scaffold from the polymer and ATM. 36. The tissue scaffold mixture of claim 35, wherein the tissue scaffold has a fixed three dimensional shape. 37. The tissue scaffold mixture of claim 35, wherein the tissue scaffold has a reduced immunological or inflammatory response when implanted than the polymer alone. 38. The tissue scaffold mixture of claim 37, wherein the immunological or inflammatory response is measured by the number of inflammatory cells present. 39. The tissue scaffold mixture of claim 35, wherein the solvent is biocompatible. 40. The tissue scaffold mixture of claim 35, wherein the polymer comprises a polycaprolactone. 41. The tissue scaffold mixture of claim 40, wherein the solvent comprises at least one of dioxane and N-methyl-2-pyrrolidone. 42. The tissue scaffold mixture of claim 40, wherein the polycaprolactone in solvent is present in an amount ranging from about 5-30% (w/v). 43. The tissue scaffold mixture of claim 40, wherein the polycaprolactone in solvent is present in an amount ranging from about 10-30% (w/v). 44. The tissue scaffold mixture of claim 35, wherein the polymer comprises a poly-4-hydroxybutyrate. 45. The tissue scaffold mixture of claim 44, wherein the solvent comprises at least one of dioxane and N-methyl-2-pyrrolidone. 46. The tissue scaffold mixture of claim 44, wherein the poly-4-hydroxybutyrate in solvent is present in an amount ranging from about 5-40% (w/v). 47. The tissue scaffold mixture of claim 44, wherein the poly-4-hydroxybutyrate in solvent is present in an amount ranging from about 10-30% (w/v). 48. The tissue scaffold mixture of claim 35, wherein the polymer comprises a benzyl ester derivative of hyaluronic acid. 49. The tissue scaffold mixture of claim 48, wherein the solvent comprises at least one of dimethyl sulfoxide and N-methyl-2-pyrrolidone. 50. The tissue scaffold mixture of claim 48, wherein the benzyl ester derivative of hyaluronic acid in solvent is present in an amount ranging from about 5-50% (w/v). 51. The tissue scaffold mixture of claim 48, wherein the benzyl ester derivative of hyaluronic acid in solvent is present in an amount ranging from about 5-40% (w/v). 52. The tissue scaffold mixture of claim 35, wherein the particulate ATM comprises uniform size particles. 53. The tissue scaffold mixture of claim 35, wherein the particulate ATM comprises a dermal ATM. 54. The tissue scaffold mixture of claim 53, wherein the dermal ATM is a human tissue matrix or a porcine tissue matrix. 55. The tissue scaffold mixture of claim 35, wherein the particulate ATM is a cartilage tissue matrix. 56. The tissue scaffold mixture of claim 55, wherein the cartilage tissue matrix comprises a human cartilage matrix or a porcine cartilage matrix. 57. The tissue scaffold mixture of claim 35, wherein the particulate ATM comprises a bone tissue matrix. 58. The tissue scaffold mixture of claim 57, wherein the bone tissue matrix comprises a human bone or a porcine bone. 59. The tissue scaffold mixture of claim 35, wherein the particulate ATM comprises ATM from two or more different types of tissues. 60. The tissue scaffold mixture of claim 59, wherein the two or more different types of tissues comprise dermis and cartilage, cartilage and bone, human tissue matrices, porcine tissue matrices, or human tissue matrix and porcine tissue matrix. 61. A kit comprising:
a particulate acellular tissue matrix (ATM); a polymer; and a solvent. | 1,600 |
1,444 | 12,234,589 | 1,652 | Provided herein are methods for a robust production of isoprenoids via one or more biosynthetic pathways. Also provided herein are nucleic acids, enzymes, expression vectors, and genetically modified host cells for carrying out the subject methods. Also provided herein are fermentation methods for high productivity of isoprenoids from genetically modified host cells. | 1. A method for producing an isoprenoid compound comprising:
(a) obtaining a plurality of host cells that are capable of making the isoprenoid compound comprising a chromosomally integrated heterologous nucleic acid sequence encoding an enzyme of the MEV or DXP pathway; (b) culturing the host cells in a medium under conditions wherein the host cells use ethanol as a carbon source and make the isoprenoid compound; and (c) recovering the isoprenoid compound from the medium. 2. The method of claim 1, wherein the ethanol that is consumed by the host cells as the carbon source was made by the host cell. 3. The method of claim 1, wherein the ethanol that is consumed by the host cell as the carbon source is exogenously supplied to the medium. 4. The method of claim 1 wherein the medium comprises ethanol at a concentration equal to or greater than about 1 gram of ethanol per liter for at least four hours. 5. The method of claim 1 wherein the host cells have an ethanol consumption rate equal to or greater than of between about 0.2 gram and about 5 grams of ethanol per gram of dry cell weight per day. 6. The method of claim 1, wherein the host cells are not oxygen limited while making the isoprenoid compound. 7. The method of claim 1, wherein the culturing conditions includes a period of time where the specific oxygen uptake rate of less than 10 mmoles of oxygen per gram of dry cell weight per hour. 8. The method of claim 1, wherein the culturing conditions includes a period of time where the host cells are phosphate limited. 9. The method of claim 1 wherein the host cells are prokaryotes. 10. The method of claim 9 wherein the host cells are E. coli. 11. The method of claim 1 wherein the host cells are eukaryotes. 12. The method of claim 1 wherein the host cells are fungi. 13. The method of claim 11 wherein the host cells are S. cerevisiae. 14. The method of claim 1 wherein the isoprenoid compound is produced in an amount greater than about 10 grams per liter of medium. 15. The method of claim 1 wherein the isoprenoid compound is produced in an amount greater than about 50 mg per gram of dry cell weight. 16. The method of claim 1, where the amount of isoprenoid compound is produced in less than about 72 hours. 17. The method of claim 1, where the amount of isoprenoid compound is produced in less than about 48 hours. 18. The method of claim 1, where the amount of isoprenoid compound is produced in less than about 24 hours. 19. The method of claim 1 wherein the isoprenoid is selected from the group consisting of a hemiterpene, monoterpene, diterpene, triterpene, tetraterpene, and polyterpene. 20. The method of claim 1, wherein the isoprenoid is a C5-C20 isoprenoid. 21. The method of claim 1 wherein the isoprenoid is selected from the group consisting of abietadiene, amorphadiene, carene, α-farnesene, β-farnesene, farnesol, geraniol, geranylgeraniol, isoprene, linalool, limonene, myrcene, nerolidol, ocimene, patchoulol, β-pinene, sabinene, γ-terpinene, terpinolene and valencene. 22. A method for making a C5-C20 isoprenoid compound comprising:
(a) obtaining a plurality of host cells that are capable of making the isoprenoid compound; (b) culturing the host cells in a medium comprising ethanol in an amount equal to or greater than about 1 gram per liter of medium for at least four hours; and (c) recovering at least 5 grams per liter of medium of the isoprenoid compound. 23. The method of claim 20 wherein the medium comprises between about 1 and about 5 grams of ethanol per liter of medium. 24. The method of claim 20 wherein the medium comprises between about 1 and about 20 grams of ethanol per liter of medium. 25. The method of claim 20 wherein the medium comprises ethanol in an amount greater than about 20 grams of ethanol per liter of medium. 26. The method of claim 22 wherein the host cells are yeast cells. 27. The method of claim 22 wherein at least some portion of the ethanol in the medium was made by the host cells. 28. A method for making a C5-C20 isoprenoid compound comprising:
(a) obtaining a plurality of host cells that are capable of making the isoprenoid compound; (b) culturing the yeast cells to build biomass by providing a bolus of a carbon source to the medium; (c) maintaining the cells under conditions whereby the yeast cells have an ethanol consumption rate equal to or greater than about 0.01 gram of ethanol per gram of dry cell weight per hour; and (d) recovering at least 5 grams per liter of medium of the isoprenoid compound. 29. The method of claim 28 wherein at least some portion of the ethanol being consumed was made by the host cells. 30. The method of claim 28 wherein the ethanol consumption rate is between about 0.01 and about 0.20 grams of ethanol per gram of dry cell weight per hour. 31. The method of claim 28 wherein the ethanol consumption rate is greater than about 0.1 grams of ethanol per gram of dry cell weight per hour. 32. The method of claim 28 wherein the carbon source is a carbohydrate. 33. The method of claim 28 wherein the carbon source is a mixture of a carbohydrate and ethanol. 34. The method of claim 28 wherein the carbon source is ethanol. 35. The method of claim 28 wherein the conditions that the cells are maintained include oxygen limitation for at least four hours. 36. The method of claim 28 wherein the conditions that the cells are maintained include phosphate limitation for at least four hours. 37. The method of claim 28 wherein the host cells are yeast cells. 38. The method of claim 28 wherein the host cells are S. cerevisiae. | Provided herein are methods for a robust production of isoprenoids via one or more biosynthetic pathways. Also provided herein are nucleic acids, enzymes, expression vectors, and genetically modified host cells for carrying out the subject methods. Also provided herein are fermentation methods for high productivity of isoprenoids from genetically modified host cells.1. A method for producing an isoprenoid compound comprising:
(a) obtaining a plurality of host cells that are capable of making the isoprenoid compound comprising a chromosomally integrated heterologous nucleic acid sequence encoding an enzyme of the MEV or DXP pathway; (b) culturing the host cells in a medium under conditions wherein the host cells use ethanol as a carbon source and make the isoprenoid compound; and (c) recovering the isoprenoid compound from the medium. 2. The method of claim 1, wherein the ethanol that is consumed by the host cells as the carbon source was made by the host cell. 3. The method of claim 1, wherein the ethanol that is consumed by the host cell as the carbon source is exogenously supplied to the medium. 4. The method of claim 1 wherein the medium comprises ethanol at a concentration equal to or greater than about 1 gram of ethanol per liter for at least four hours. 5. The method of claim 1 wherein the host cells have an ethanol consumption rate equal to or greater than of between about 0.2 gram and about 5 grams of ethanol per gram of dry cell weight per day. 6. The method of claim 1, wherein the host cells are not oxygen limited while making the isoprenoid compound. 7. The method of claim 1, wherein the culturing conditions includes a period of time where the specific oxygen uptake rate of less than 10 mmoles of oxygen per gram of dry cell weight per hour. 8. The method of claim 1, wherein the culturing conditions includes a period of time where the host cells are phosphate limited. 9. The method of claim 1 wherein the host cells are prokaryotes. 10. The method of claim 9 wherein the host cells are E. coli. 11. The method of claim 1 wherein the host cells are eukaryotes. 12. The method of claim 1 wherein the host cells are fungi. 13. The method of claim 11 wherein the host cells are S. cerevisiae. 14. The method of claim 1 wherein the isoprenoid compound is produced in an amount greater than about 10 grams per liter of medium. 15. The method of claim 1 wherein the isoprenoid compound is produced in an amount greater than about 50 mg per gram of dry cell weight. 16. The method of claim 1, where the amount of isoprenoid compound is produced in less than about 72 hours. 17. The method of claim 1, where the amount of isoprenoid compound is produced in less than about 48 hours. 18. The method of claim 1, where the amount of isoprenoid compound is produced in less than about 24 hours. 19. The method of claim 1 wherein the isoprenoid is selected from the group consisting of a hemiterpene, monoterpene, diterpene, triterpene, tetraterpene, and polyterpene. 20. The method of claim 1, wherein the isoprenoid is a C5-C20 isoprenoid. 21. The method of claim 1 wherein the isoprenoid is selected from the group consisting of abietadiene, amorphadiene, carene, α-farnesene, β-farnesene, farnesol, geraniol, geranylgeraniol, isoprene, linalool, limonene, myrcene, nerolidol, ocimene, patchoulol, β-pinene, sabinene, γ-terpinene, terpinolene and valencene. 22. A method for making a C5-C20 isoprenoid compound comprising:
(a) obtaining a plurality of host cells that are capable of making the isoprenoid compound; (b) culturing the host cells in a medium comprising ethanol in an amount equal to or greater than about 1 gram per liter of medium for at least four hours; and (c) recovering at least 5 grams per liter of medium of the isoprenoid compound. 23. The method of claim 20 wherein the medium comprises between about 1 and about 5 grams of ethanol per liter of medium. 24. The method of claim 20 wherein the medium comprises between about 1 and about 20 grams of ethanol per liter of medium. 25. The method of claim 20 wherein the medium comprises ethanol in an amount greater than about 20 grams of ethanol per liter of medium. 26. The method of claim 22 wherein the host cells are yeast cells. 27. The method of claim 22 wherein at least some portion of the ethanol in the medium was made by the host cells. 28. A method for making a C5-C20 isoprenoid compound comprising:
(a) obtaining a plurality of host cells that are capable of making the isoprenoid compound; (b) culturing the yeast cells to build biomass by providing a bolus of a carbon source to the medium; (c) maintaining the cells under conditions whereby the yeast cells have an ethanol consumption rate equal to or greater than about 0.01 gram of ethanol per gram of dry cell weight per hour; and (d) recovering at least 5 grams per liter of medium of the isoprenoid compound. 29. The method of claim 28 wherein at least some portion of the ethanol being consumed was made by the host cells. 30. The method of claim 28 wherein the ethanol consumption rate is between about 0.01 and about 0.20 grams of ethanol per gram of dry cell weight per hour. 31. The method of claim 28 wherein the ethanol consumption rate is greater than about 0.1 grams of ethanol per gram of dry cell weight per hour. 32. The method of claim 28 wherein the carbon source is a carbohydrate. 33. The method of claim 28 wherein the carbon source is a mixture of a carbohydrate and ethanol. 34. The method of claim 28 wherein the carbon source is ethanol. 35. The method of claim 28 wherein the conditions that the cells are maintained include oxygen limitation for at least four hours. 36. The method of claim 28 wherein the conditions that the cells are maintained include phosphate limitation for at least four hours. 37. The method of claim 28 wherein the host cells are yeast cells. 38. The method of claim 28 wherein the host cells are S. cerevisiae. | 1,600 |
1,445 | 15,133,206 | 1,618 | There is provided a method of producing a mixed metal compound that includes at least Mg 2+ and at least Fe 3+ having an aluminum content of less than 10000 ppm, having an average crystal size of less than 20 nm (200 Å) comprising the steps of: (a) combining a Mg 2+ salt and a Fe 3+ salt with Na 2 CO 3 and NaOH to produce a slurry, wherein the pH of the slurry is maintained at from 9.5 to 11, and wherein the Na2CO3 is provided at an excess of 0 to 4.0 moles than is required to complete the reaction (b) subjecting the slurry to mixing under conditions providing a power per unit volume of 0.03 to 1.6 kW/m 3 (c) separating the mixed metal compound from the slurry, to obtain a crude product having a dry solid content of at least 10 wt % (d) drying the crude product. | 1. A method of producing a mixed metal compound comprising
at least Mg2+ and at least Fe3+ having an aluminium content of less than 10000 ppm, having an average crystal size of less than 20 nm (200 Å) comprising the steps of:
(a) combining a Mg2+ salt and a Fe3+ salt with Na2CO3 and NaOH to produce a slurry, wherein the pH of the slurry is maintained at from 9.5 to 11, and wherein the Na2CO3 is provided at an excess of 0 to 4.0 moles than is required to complete the reaction
(b) subjecting the slurry to mixing under conditions providing a power per unit volume of 0.03 to 1.6 kW/m3
(c) separating the mixed metal compound from the slurry, to obtain a crude product having a dry solid content of at least 10 wt %
(d) drying the crude product either by
(i) heating the crude product to a temperature of no greater than 150° C. and sufficient to provide a water evaporation rate of 0.05 to 1.5 kg water per hour per kg of dry product, or
(ii) exposing the crude product to rapid drying at a water evaporation rate of 500 to 50000 kg water per hour per kg of dry product. 2. A method according to claim 1 wherein the compound is of the formula
MII 1-xMIII x(OH)2An− y .mH2O (II)
wherein MII is one or more bivalent metals and is at least Mg2+;
MIII is one or more trivalent metals and is at least Fe3+;
An− is one or more n-valent anions and is at least CO3 2−;
x/Σyn is from 1 to 1.2
0<x≦0.4,
0<y≦1 and
0<m≦10. 3. (canceled) 4. (canceled) 5. A method according to claim 1 wherein the molar ratio of Mg2+ to Fe3+ is 2.5:1 to 1.5:1. 6. A method according to claim 1 wherein the compound has an average crystal size of from 10 to 20 nm (100 to 200 Å). 7. (canceled) 8. (canceled) 9. A method according to claim 1 wherein the total sulphate content of the compound is from 1.8 to 4.2 wt %. 10. A method according to claim 1 wherein the interlayer sulphate content of the compound is from 2.1 to 5 wt %. 11.-20. (canceled) 21. A method according to claim 1 wherein in step (b) the slurry conditions are controlled such that a d50 particle size distribution of at least 40 μm is provided. 22. A method according to claim 1 wherein in step (c) the mixed metal compound is separated from the slurry, to obtain a crude product having a dry solid content of at least 15 wt %. 23.-26. (canceled) 27. A method according to claim 1 wherein in step (d) the crude product is dried to a moisture content less than 15 wt %. 28.-31. (canceled) 32. A method according to claim 1 wherein the dried crude product is milled to a d50 average particle size of less than 200 μm. 33.-39. (canceled) 40. A method according to claim 1 for the production of a mixed metal compound having a sodium content expressed as Na2O of less than 0.5 wt %. 41. (canceled) 42. A method according to claim 1 for the production of a mixed metal compound having a phosphate binding capacity of more than 0.6 mmol phosphate/g mixed metal compound. 43.-47. (canceled) 48. A mixed metal compound comprising at least Mg2+ and at least Fe3+, wherein
the molar ratio of Mg2+ to Fe3+ is 2.5:1 to 1.5:1,
the mixed metal compound has an aluminium content of less than 10000 ppm,
the average crystal size of the mixed metal compound is from 10 to 20 nm (100 to 200 Å),
and the d50 average particle size of the mixed metal compound is less than 300 μm. 49. A mixed metal compound according to claim 48 wherein the d50 average particle size of the mixed metal compound is less than 200 μm. 50.-52. (canceled) 53. A mixed metal compound comprising at least Mg2+ and at least Fe3+, wherein
the molar ratio of Mg2+ to Fe3+ is 2.5:1 to 1.5:1,
the mixed metal compound has an aluminium content of less than 10000 ppm, the average crystal size of the mixed metal compound is from 10 to 20 nm (100 to 200 Å),
and the interlayer sulphate content of the compound is from 2 to 5 wt % 54.-63. (canceled) 64. A compound according to claim 48 wherein the compound is of the formula
MII 1-xMIII x(OH)2An− y .mH2O
wherein MII is one or more bivalent metals and is at least Mg2+;
MIII is one or more trivalent metals and is at least Fe3+;
An− is one or more n-valent anions and is at least CO3 2−;
x/Σyn is from 1 to 1.2
0<x≦0.4,
0<y≦1 and
0<m≦10. 65.-76. (canceled) 77. A mixed metal compound according to claim 48 for use in the treatment of hyperphosphataemia. 78. A pharmaceutical composition comprising a mixed metal compound as defined in claim 48 and optionally one or more pharmaceutically acceptable adjuvants, excipients, diluents or carriers. 79.-82. (canceled) | There is provided a method of producing a mixed metal compound that includes at least Mg 2+ and at least Fe 3+ having an aluminum content of less than 10000 ppm, having an average crystal size of less than 20 nm (200 Å) comprising the steps of: (a) combining a Mg 2+ salt and a Fe 3+ salt with Na 2 CO 3 and NaOH to produce a slurry, wherein the pH of the slurry is maintained at from 9.5 to 11, and wherein the Na2CO3 is provided at an excess of 0 to 4.0 moles than is required to complete the reaction (b) subjecting the slurry to mixing under conditions providing a power per unit volume of 0.03 to 1.6 kW/m 3 (c) separating the mixed metal compound from the slurry, to obtain a crude product having a dry solid content of at least 10 wt % (d) drying the crude product.1. A method of producing a mixed metal compound comprising
at least Mg2+ and at least Fe3+ having an aluminium content of less than 10000 ppm, having an average crystal size of less than 20 nm (200 Å) comprising the steps of:
(a) combining a Mg2+ salt and a Fe3+ salt with Na2CO3 and NaOH to produce a slurry, wherein the pH of the slurry is maintained at from 9.5 to 11, and wherein the Na2CO3 is provided at an excess of 0 to 4.0 moles than is required to complete the reaction
(b) subjecting the slurry to mixing under conditions providing a power per unit volume of 0.03 to 1.6 kW/m3
(c) separating the mixed metal compound from the slurry, to obtain a crude product having a dry solid content of at least 10 wt %
(d) drying the crude product either by
(i) heating the crude product to a temperature of no greater than 150° C. and sufficient to provide a water evaporation rate of 0.05 to 1.5 kg water per hour per kg of dry product, or
(ii) exposing the crude product to rapid drying at a water evaporation rate of 500 to 50000 kg water per hour per kg of dry product. 2. A method according to claim 1 wherein the compound is of the formula
MII 1-xMIII x(OH)2An− y .mH2O (II)
wherein MII is one or more bivalent metals and is at least Mg2+;
MIII is one or more trivalent metals and is at least Fe3+;
An− is one or more n-valent anions and is at least CO3 2−;
x/Σyn is from 1 to 1.2
0<x≦0.4,
0<y≦1 and
0<m≦10. 3. (canceled) 4. (canceled) 5. A method according to claim 1 wherein the molar ratio of Mg2+ to Fe3+ is 2.5:1 to 1.5:1. 6. A method according to claim 1 wherein the compound has an average crystal size of from 10 to 20 nm (100 to 200 Å). 7. (canceled) 8. (canceled) 9. A method according to claim 1 wherein the total sulphate content of the compound is from 1.8 to 4.2 wt %. 10. A method according to claim 1 wherein the interlayer sulphate content of the compound is from 2.1 to 5 wt %. 11.-20. (canceled) 21. A method according to claim 1 wherein in step (b) the slurry conditions are controlled such that a d50 particle size distribution of at least 40 μm is provided. 22. A method according to claim 1 wherein in step (c) the mixed metal compound is separated from the slurry, to obtain a crude product having a dry solid content of at least 15 wt %. 23.-26. (canceled) 27. A method according to claim 1 wherein in step (d) the crude product is dried to a moisture content less than 15 wt %. 28.-31. (canceled) 32. A method according to claim 1 wherein the dried crude product is milled to a d50 average particle size of less than 200 μm. 33.-39. (canceled) 40. A method according to claim 1 for the production of a mixed metal compound having a sodium content expressed as Na2O of less than 0.5 wt %. 41. (canceled) 42. A method according to claim 1 for the production of a mixed metal compound having a phosphate binding capacity of more than 0.6 mmol phosphate/g mixed metal compound. 43.-47. (canceled) 48. A mixed metal compound comprising at least Mg2+ and at least Fe3+, wherein
the molar ratio of Mg2+ to Fe3+ is 2.5:1 to 1.5:1,
the mixed metal compound has an aluminium content of less than 10000 ppm,
the average crystal size of the mixed metal compound is from 10 to 20 nm (100 to 200 Å),
and the d50 average particle size of the mixed metal compound is less than 300 μm. 49. A mixed metal compound according to claim 48 wherein the d50 average particle size of the mixed metal compound is less than 200 μm. 50.-52. (canceled) 53. A mixed metal compound comprising at least Mg2+ and at least Fe3+, wherein
the molar ratio of Mg2+ to Fe3+ is 2.5:1 to 1.5:1,
the mixed metal compound has an aluminium content of less than 10000 ppm, the average crystal size of the mixed metal compound is from 10 to 20 nm (100 to 200 Å),
and the interlayer sulphate content of the compound is from 2 to 5 wt % 54.-63. (canceled) 64. A compound according to claim 48 wherein the compound is of the formula
MII 1-xMIII x(OH)2An− y .mH2O
wherein MII is one or more bivalent metals and is at least Mg2+;
MIII is one or more trivalent metals and is at least Fe3+;
An− is one or more n-valent anions and is at least CO3 2−;
x/Σyn is from 1 to 1.2
0<x≦0.4,
0<y≦1 and
0<m≦10. 65.-76. (canceled) 77. A mixed metal compound according to claim 48 for use in the treatment of hyperphosphataemia. 78. A pharmaceutical composition comprising a mixed metal compound as defined in claim 48 and optionally one or more pharmaceutically acceptable adjuvants, excipients, diluents or carriers. 79.-82. (canceled) | 1,600 |
1,446 | 12,344,361 | 1,615 | The present invention relates to biocompatible protein-based particles and their methods of preparation and use. More specifically the present invention relates protein-based particles including protein matrix, spread matrix and/or biocoacervate materials derived from one or more biocompatible purified proteins combined with one or more biocompatible solvents that are used to replace or repair tissue and/or bone in treatments for spinal disc(s), joint(s) (e.g. knee, hip, finger, ankle, elbow, shoulder . . . ) and organ(s) (e.g. bladder, lips, vagina, penis, urethra . . . ). In various embodiments of the present invention the protein-based particles may also include one or more pharmacologically active agents and/or one or more additives. | 1. A method of treating or enhancing the function of a spinal disc comprising:
administering a plurality of particles to the spinal disc or the surrounding fluid, space, tissue or bone of the spinal disc, said particles comprising one or more protein-based biomaterials at least partially produced from one or more biocoacervate material(s), the biocoacervate material(s) precipitated from a solution including one or more biocompatible protein(s), one or more glycosaminioglycans and one or more biocompatible solvents. 2. The method of claim 1 wherein the particles have a size of approximately 500 nm to 1000 μm. 3. The method of claim 1 wherein the one or more biocompatible protein(s) that are selected from the group consisting of elastin, collagen, albumin, keratin, laminin, fibronectin, silk, silk fibroin, actin, myosin, fibrinogen, thrombin, aprotinin, antithrombin III, elastinlike blocks, silklike blocks, collagenlike blocks, lamininlike blocks, fibronectinlike blocks and silklike, elastinlike blocks, collagen-heparin, collagen-elastin-heparin and collagen-chondroiten. 4. The method of claim 1 wherein the one or more biocompatible solvent(s) is selected from the group consisting of water, dimethyl sulfoxide (DMSO), biocompatible alcohols, biocompatible acids, oils and biocompatible glycols. 5. The method of claim 1 wherein the particles further includes one or more pharmacologically active agents selected from the group consisting of analgesics, anesthetics, antipsychotic agents, angiogenic growth factors, bone mending biochemicals, steroids, antisteroids, corticosteroids, antiglacoma agents, antialcohol agents, anti-coagulants agents, genetic material, antithrombolytic agents, anticancer agents, anti-Parkinson agents, antiepileptic agents, permeation enhancers, anti-inflammatory agents, anticonception agents, enzymes agents, cells, growth factors, antiviral agents, antibacterial agents, antifungal agents, hypoglycemic agents, antihistamine agents, chemoattractants, neutraceuticals, antiobesity, smoking cessation agents, obstetric agents and antiasmatic agents. 6. The method of claim 5 wherein the pharmacologically active agent is selected from anesthetics, analgesics, anti-coagulant agents or neurotoxins. 7. The method of claim 1 wherein the particles further include one or more biocompatible additives. 8. The method of claim 7 wherein the one or more biocompatible additives are selected from the group consisting of epoxies, polyesters, acrylics, nylons, silicones, polyanhydride, polyurethane, polycarbonate, poly(tetrafluoroethylene), polycaprolactone, polyethylene oxide, polyethylene glycol, poly(vinyl chloride), polylactic acid, polyglycolic acid, polypropylene oxide, poly(akylene)glycol, polyoxyethylene, sebacic acid, polyvinyl alcohol, 2-hydroxyethyl methacrylate, polymethyl methacrylate, 1,3-bis(carboxyphenoxy)propane, lipids, phosphatidylcholine, triglycerides, humectants, polyhydroxybutyrate, polyhydroxyvalerate, poly(ethylene oxide), poly ortho esters, poly(amino acids), polycyanoacrylates, polyphophazenes, polysulfone, polyamine, poly(amido amines), fibrin, graphite, flexible fluoropolymer, isobutyl-based, isopropyl styrene, vinyl pyrrolidone, cellulose acetate dibutyrate, silicone rubber, and copolymers or combinations of these. 9. The method of claim 1 wherein all or a portion of the particles are crosslinked with one or more crosslinking agents. 10. The method of claim 9 wherein the one or more crosslinking agents are selected from the group consisting of glutaraldehyde, formaldehyde, p-Azidobenzolyl Hydazide, N-5-Azido 2-nitrobenzoyloxysuccinimide, 1,4-butandiol diglycidylether, N-Succinimidyl 6-[4′azido-2′nitro-phenylamino]hexanoate, tannic acid and 4-[p-Azidosalicylamido]butylamine. 11. A method of treating or enhancing the function of a joint comprising:
administering a plurality of particles to the joint or the surrounding fluid, space, tissue or bone of the joint, said particles comprising one or more protein-based biomaterials at least partially produced from one or more biocoacervate material(s), the biocoacervate material(s) precipitated from a solution including one or more biocompatible protein(s), one or more glycosaminioglycans and one or more biocompatible solvents. 12. The method of claim 11 wherein the particles have a size of approximately 500 nm to 1000 μm. 13. The method of claim 11 wherein the one or more biocompatible protein(s) that are selected from the group consisting of elastin, collagen, albumin, keratin, laminin, fibronectin, silk, silk fibroin, actin, myosin, fibrinogen, thrombin, aprotinin, antithrombin III, elastinlike blocks, silklike blocks, collagenlike blocks, lamininlike blocks, fibronectinlike blocks and silklike, elastinlike blocks, collagen-heparin, collagen-elastin-heparin and collagen-chondroiten. 14. The method of claim 11 wherein the one or more biocompatible solvent(s) is selected from the group consisting of water, dimethyl sulfoxide (DMSO), biocompatible alcohols, biocompatible acids, oils and biocompatible glycols. 15. The method of claim 11 wherein the particles further includes one or more pharmacologically active agents selected from the group consisting of analgesics, anesthetics, antipsychotic agents, angiogenic growth factors, bone mending biochemicals, steroids, antisteroids, corticosteroids, antiglacoma agents, antialcohol agents, anti-coagulants agents, genetic material, antithrombolytic agents, anticancer agents, anti-Parkinson agents, antiepileptic agents, permeation enhancers, anti-inflammatory agents, anticonception agents, enzymes agents, cells, growth factors, antiviral agents, antibacterial agents, antifungal agents, hypoglycemic agents, antihistamine agents, chemoattractants, neutraceuticals, antiobesity, smoking cessation agents, obstetric agents and antiasmatic agents. 16. The method of claim 15 wherein the pharmacologically active agent is selected from anesthetics, analgesics, anti-coagulant agents or neurotoxins. 17. The method of claim 11 wherein the particles further include one or more biocompatible additives. 18. The method of claim 17 wherein the one or more biocompatible additives are selected from the group consisting of epoxies, polyesters, acrylics, nylons, silicones, polyanhydride, polyurethane, polycarbonate, poly(tetrafluoroethylene), polycaprolactone, polyethylene oxide, polyethylene glycol, poly(vinyl chloride), polylactic acid, polyglycolic acid, polypropylene oxide, poly(akylene)glycol, polyoxyethylene, sebacic acid, polyvinyl alcohol, 2-hydroxyethyl methacrylate, polymethyl methacrylate, 1,3-bis(carboxyphenoxy)propane, lipids, phosphatidylcholine, triglycerides, humectants, polyhydroxybutyrate, polyhydroxyvalerate, poly(ethylene oxide), poly ortho esters, poly(amino acids), polycyanoacrylates, polyphophazenes, polysulfone, polyamine, poly(amido amines), fibrin, graphite, flexible fluoropolymer, isobutyl-based, isopropyl styrene, vinyl pyrrolidone, cellulose acetate dibutyrate, silicone rubber, and copolymers or combinations of these. 19. The method of claim 11 wherein all or a portion of the particles are crosslinked with one or more crosslinking agents. 20. The method of claim 19 wherein the one or more crosslinking agents are selected from the group consisting of glutaraldehyde, formaldehyde, p-Azidobenzolyl Hydazide, N-5-Azido 2-nitrobenzoyloxysuccinimide, 1,4-butandiol diglycidylether, N-Succinimidyl 6-[4′azido-2′nitro-phenylamino]hexanoate, tannic acid and 4-[p-Azidosalicylamido]butylamine. 21. A method of treating or enhancing the function of an organ comprising:
administering a plurality of particles to the organ or the surrounding fluid, space, tissue or bone of the organ, said particles comprising one or more protein-based biomaterials at least partially produced from one or more biocoacervate material(s), the biocoacervate material(s) precipitated from a solution including one or more biocompatible protein(s), one or more glycosaminioglycans and one or more biocompatible solvents. 22. The method of claim 21 wherein the particles have a size of approximately 500 nm to 1000 μm. 23. The method of claim 21 wherein the one or more biocompatible protein(s) that are selected from the group consisting of elastin, collagen, albumin, keratin, laminin, fibronectin, silk, silk fibroin, actin, myosin, fibrinogen, thrombin, aprotinin, antithrombin III, elastinlike blocks, silklike blocks, collagenlike blocks, lamininlike blocks, fibronectinlike blocks and silklike, elastinlike blocks, collagen-heparin, collagen-elastin-heparin and collagen-chondroiten. 24. The method of claim 21 wherein the one or more biocompatible solvent(s) is selected from the group consisting of water, dimethyl sulfoxide (DMSO), biocompatible alcohols, biocompatible acids, oils and biocompatible glycols. 25. The method of claim 21 wherein the particles further includes one or more pharmacologically active agents selected from the group consisting of analgesics, anesthetics, antipsychotic agents, angiogenic growth factors, bone mending biochemicals, steroids, antisteroids, corticosteroids, antiglacoma agents, antialcohol agents, anti-coagulants agents, genetic material, antithrombolytic agents, anticancer agents, anti-Parkinson agents, antiepileptic agents, permeation enhancers, anti-inflammatory agents, anticonception agents, enzymes agents, cells, growth factors, antiviral agents, antibacterial agents, antifungal agents, hypoglycemic agents, antihistamine agents, chemoattractants, neutraceuticals, antiobesity, smoking cessation agents, obstetric agents and antiasmatic agents. 26. The method of claim 25 wherein the pharmacologically active agent is selected from anesthetics, analgesics, anti-coagulant agents or neurotoxins. 27. The method of claim 21 wherein the particles further include one or more biocompatible additives. 28. The method of claim 27 wherein the one or more biocompatible additives are selected from the group consisting of epoxies, polyesters, acrylics, nylons, silicones, polyanhydride, polyurethane, polycarbonate, poly(tetrafluoroethylene), polycaprolactone, polyethylene oxide, polyethylene glycol, poly(vinyl chloride), polylactic acid, polyglycolic acid, polypropylene oxide, poly(akylene)glycol, polyoxyethylene, sebacic acid, polyvinyl alcohol, 2-hydroxyethyl methacrylate, polymethyl methacrylate, 1,3-bis(carboxyphenoxy)propane, lipids, phosphatidylcholine, triglycerides, humectants, polyhydroxybutyrate, polyhydroxyvalerate, poly(ethylene oxide), poly ortho esters, poly(amino acids), polycyanoacrylates, polyphophazenes, polysulfone, polyamine, poly(amido amines), fibrin, graphite, flexible fluoropolymer, isobutyl-based, isopropyl styrene, vinyl pyrrolidone, cellulose acetate dibutyrate, silicone rubber, and copolymers or combinations of these. 29. The method of claim 21 wherein all or a portion of the particles are crosslinked with one or more crosslinking agents. 30. The method of claim 29 wherein the one or more crosslinking agents are selected from the group consisting of glutaraldehyde, formaldehyde, p-Azidobenzolyl Hydazide, N-5-Azido 2-nitrobenzoyloxysuccinimide, 1,4-butandiol diglycidylether, N-Succinimidyl 6-[4′azido-2′nitro-phenylamino]hexanoate, tannic acid and 4-[p-Azidosalicylamido]butylamine. | The present invention relates to biocompatible protein-based particles and their methods of preparation and use. More specifically the present invention relates protein-based particles including protein matrix, spread matrix and/or biocoacervate materials derived from one or more biocompatible purified proteins combined with one or more biocompatible solvents that are used to replace or repair tissue and/or bone in treatments for spinal disc(s), joint(s) (e.g. knee, hip, finger, ankle, elbow, shoulder . . . ) and organ(s) (e.g. bladder, lips, vagina, penis, urethra . . . ). In various embodiments of the present invention the protein-based particles may also include one or more pharmacologically active agents and/or one or more additives.1. A method of treating or enhancing the function of a spinal disc comprising:
administering a plurality of particles to the spinal disc or the surrounding fluid, space, tissue or bone of the spinal disc, said particles comprising one or more protein-based biomaterials at least partially produced from one or more biocoacervate material(s), the biocoacervate material(s) precipitated from a solution including one or more biocompatible protein(s), one or more glycosaminioglycans and one or more biocompatible solvents. 2. The method of claim 1 wherein the particles have a size of approximately 500 nm to 1000 μm. 3. The method of claim 1 wherein the one or more biocompatible protein(s) that are selected from the group consisting of elastin, collagen, albumin, keratin, laminin, fibronectin, silk, silk fibroin, actin, myosin, fibrinogen, thrombin, aprotinin, antithrombin III, elastinlike blocks, silklike blocks, collagenlike blocks, lamininlike blocks, fibronectinlike blocks and silklike, elastinlike blocks, collagen-heparin, collagen-elastin-heparin and collagen-chondroiten. 4. The method of claim 1 wherein the one or more biocompatible solvent(s) is selected from the group consisting of water, dimethyl sulfoxide (DMSO), biocompatible alcohols, biocompatible acids, oils and biocompatible glycols. 5. The method of claim 1 wherein the particles further includes one or more pharmacologically active agents selected from the group consisting of analgesics, anesthetics, antipsychotic agents, angiogenic growth factors, bone mending biochemicals, steroids, antisteroids, corticosteroids, antiglacoma agents, antialcohol agents, anti-coagulants agents, genetic material, antithrombolytic agents, anticancer agents, anti-Parkinson agents, antiepileptic agents, permeation enhancers, anti-inflammatory agents, anticonception agents, enzymes agents, cells, growth factors, antiviral agents, antibacterial agents, antifungal agents, hypoglycemic agents, antihistamine agents, chemoattractants, neutraceuticals, antiobesity, smoking cessation agents, obstetric agents and antiasmatic agents. 6. The method of claim 5 wherein the pharmacologically active agent is selected from anesthetics, analgesics, anti-coagulant agents or neurotoxins. 7. The method of claim 1 wherein the particles further include one or more biocompatible additives. 8. The method of claim 7 wherein the one or more biocompatible additives are selected from the group consisting of epoxies, polyesters, acrylics, nylons, silicones, polyanhydride, polyurethane, polycarbonate, poly(tetrafluoroethylene), polycaprolactone, polyethylene oxide, polyethylene glycol, poly(vinyl chloride), polylactic acid, polyglycolic acid, polypropylene oxide, poly(akylene)glycol, polyoxyethylene, sebacic acid, polyvinyl alcohol, 2-hydroxyethyl methacrylate, polymethyl methacrylate, 1,3-bis(carboxyphenoxy)propane, lipids, phosphatidylcholine, triglycerides, humectants, polyhydroxybutyrate, polyhydroxyvalerate, poly(ethylene oxide), poly ortho esters, poly(amino acids), polycyanoacrylates, polyphophazenes, polysulfone, polyamine, poly(amido amines), fibrin, graphite, flexible fluoropolymer, isobutyl-based, isopropyl styrene, vinyl pyrrolidone, cellulose acetate dibutyrate, silicone rubber, and copolymers or combinations of these. 9. The method of claim 1 wherein all or a portion of the particles are crosslinked with one or more crosslinking agents. 10. The method of claim 9 wherein the one or more crosslinking agents are selected from the group consisting of glutaraldehyde, formaldehyde, p-Azidobenzolyl Hydazide, N-5-Azido 2-nitrobenzoyloxysuccinimide, 1,4-butandiol diglycidylether, N-Succinimidyl 6-[4′azido-2′nitro-phenylamino]hexanoate, tannic acid and 4-[p-Azidosalicylamido]butylamine. 11. A method of treating or enhancing the function of a joint comprising:
administering a plurality of particles to the joint or the surrounding fluid, space, tissue or bone of the joint, said particles comprising one or more protein-based biomaterials at least partially produced from one or more biocoacervate material(s), the biocoacervate material(s) precipitated from a solution including one or more biocompatible protein(s), one or more glycosaminioglycans and one or more biocompatible solvents. 12. The method of claim 11 wherein the particles have a size of approximately 500 nm to 1000 μm. 13. The method of claim 11 wherein the one or more biocompatible protein(s) that are selected from the group consisting of elastin, collagen, albumin, keratin, laminin, fibronectin, silk, silk fibroin, actin, myosin, fibrinogen, thrombin, aprotinin, antithrombin III, elastinlike blocks, silklike blocks, collagenlike blocks, lamininlike blocks, fibronectinlike blocks and silklike, elastinlike blocks, collagen-heparin, collagen-elastin-heparin and collagen-chondroiten. 14. The method of claim 11 wherein the one or more biocompatible solvent(s) is selected from the group consisting of water, dimethyl sulfoxide (DMSO), biocompatible alcohols, biocompatible acids, oils and biocompatible glycols. 15. The method of claim 11 wherein the particles further includes one or more pharmacologically active agents selected from the group consisting of analgesics, anesthetics, antipsychotic agents, angiogenic growth factors, bone mending biochemicals, steroids, antisteroids, corticosteroids, antiglacoma agents, antialcohol agents, anti-coagulants agents, genetic material, antithrombolytic agents, anticancer agents, anti-Parkinson agents, antiepileptic agents, permeation enhancers, anti-inflammatory agents, anticonception agents, enzymes agents, cells, growth factors, antiviral agents, antibacterial agents, antifungal agents, hypoglycemic agents, antihistamine agents, chemoattractants, neutraceuticals, antiobesity, smoking cessation agents, obstetric agents and antiasmatic agents. 16. The method of claim 15 wherein the pharmacologically active agent is selected from anesthetics, analgesics, anti-coagulant agents or neurotoxins. 17. The method of claim 11 wherein the particles further include one or more biocompatible additives. 18. The method of claim 17 wherein the one or more biocompatible additives are selected from the group consisting of epoxies, polyesters, acrylics, nylons, silicones, polyanhydride, polyurethane, polycarbonate, poly(tetrafluoroethylene), polycaprolactone, polyethylene oxide, polyethylene glycol, poly(vinyl chloride), polylactic acid, polyglycolic acid, polypropylene oxide, poly(akylene)glycol, polyoxyethylene, sebacic acid, polyvinyl alcohol, 2-hydroxyethyl methacrylate, polymethyl methacrylate, 1,3-bis(carboxyphenoxy)propane, lipids, phosphatidylcholine, triglycerides, humectants, polyhydroxybutyrate, polyhydroxyvalerate, poly(ethylene oxide), poly ortho esters, poly(amino acids), polycyanoacrylates, polyphophazenes, polysulfone, polyamine, poly(amido amines), fibrin, graphite, flexible fluoropolymer, isobutyl-based, isopropyl styrene, vinyl pyrrolidone, cellulose acetate dibutyrate, silicone rubber, and copolymers or combinations of these. 19. The method of claim 11 wherein all or a portion of the particles are crosslinked with one or more crosslinking agents. 20. The method of claim 19 wherein the one or more crosslinking agents are selected from the group consisting of glutaraldehyde, formaldehyde, p-Azidobenzolyl Hydazide, N-5-Azido 2-nitrobenzoyloxysuccinimide, 1,4-butandiol diglycidylether, N-Succinimidyl 6-[4′azido-2′nitro-phenylamino]hexanoate, tannic acid and 4-[p-Azidosalicylamido]butylamine. 21. A method of treating or enhancing the function of an organ comprising:
administering a plurality of particles to the organ or the surrounding fluid, space, tissue or bone of the organ, said particles comprising one or more protein-based biomaterials at least partially produced from one or more biocoacervate material(s), the biocoacervate material(s) precipitated from a solution including one or more biocompatible protein(s), one or more glycosaminioglycans and one or more biocompatible solvents. 22. The method of claim 21 wherein the particles have a size of approximately 500 nm to 1000 μm. 23. The method of claim 21 wherein the one or more biocompatible protein(s) that are selected from the group consisting of elastin, collagen, albumin, keratin, laminin, fibronectin, silk, silk fibroin, actin, myosin, fibrinogen, thrombin, aprotinin, antithrombin III, elastinlike blocks, silklike blocks, collagenlike blocks, lamininlike blocks, fibronectinlike blocks and silklike, elastinlike blocks, collagen-heparin, collagen-elastin-heparin and collagen-chondroiten. 24. The method of claim 21 wherein the one or more biocompatible solvent(s) is selected from the group consisting of water, dimethyl sulfoxide (DMSO), biocompatible alcohols, biocompatible acids, oils and biocompatible glycols. 25. The method of claim 21 wherein the particles further includes one or more pharmacologically active agents selected from the group consisting of analgesics, anesthetics, antipsychotic agents, angiogenic growth factors, bone mending biochemicals, steroids, antisteroids, corticosteroids, antiglacoma agents, antialcohol agents, anti-coagulants agents, genetic material, antithrombolytic agents, anticancer agents, anti-Parkinson agents, antiepileptic agents, permeation enhancers, anti-inflammatory agents, anticonception agents, enzymes agents, cells, growth factors, antiviral agents, antibacterial agents, antifungal agents, hypoglycemic agents, antihistamine agents, chemoattractants, neutraceuticals, antiobesity, smoking cessation agents, obstetric agents and antiasmatic agents. 26. The method of claim 25 wherein the pharmacologically active agent is selected from anesthetics, analgesics, anti-coagulant agents or neurotoxins. 27. The method of claim 21 wherein the particles further include one or more biocompatible additives. 28. The method of claim 27 wherein the one or more biocompatible additives are selected from the group consisting of epoxies, polyesters, acrylics, nylons, silicones, polyanhydride, polyurethane, polycarbonate, poly(tetrafluoroethylene), polycaprolactone, polyethylene oxide, polyethylene glycol, poly(vinyl chloride), polylactic acid, polyglycolic acid, polypropylene oxide, poly(akylene)glycol, polyoxyethylene, sebacic acid, polyvinyl alcohol, 2-hydroxyethyl methacrylate, polymethyl methacrylate, 1,3-bis(carboxyphenoxy)propane, lipids, phosphatidylcholine, triglycerides, humectants, polyhydroxybutyrate, polyhydroxyvalerate, poly(ethylene oxide), poly ortho esters, poly(amino acids), polycyanoacrylates, polyphophazenes, polysulfone, polyamine, poly(amido amines), fibrin, graphite, flexible fluoropolymer, isobutyl-based, isopropyl styrene, vinyl pyrrolidone, cellulose acetate dibutyrate, silicone rubber, and copolymers or combinations of these. 29. The method of claim 21 wherein all or a portion of the particles are crosslinked with one or more crosslinking agents. 30. The method of claim 29 wherein the one or more crosslinking agents are selected from the group consisting of glutaraldehyde, formaldehyde, p-Azidobenzolyl Hydazide, N-5-Azido 2-nitrobenzoyloxysuccinimide, 1,4-butandiol diglycidylether, N-Succinimidyl 6-[4′azido-2′nitro-phenylamino]hexanoate, tannic acid and 4-[p-Azidosalicylamido]butylamine. | 1,600 |
1,447 | 16,494,902 | 1,639 | Systems, methods and compositions provided herein relate to the preparation of nucleic acid libraries. Some embodiments include the preparation of nucleic acid libraries by ligation of single-stranded nucleic acids. | 1. A method of preparing a nucleic acid library, comprising:
(a) obtaining a plurality of nucleic acids, wherein the plurality of nucleic acids is single-stranded nucleic acids; (b) dephosphorylating the 5′ ends of the single-stranded nucleic acids; (c) ligating a first adaptor to the 3′ ends of the single-stranded nucleic acids in the presence of a ligase, wherein the 3′ end of the first adaptor comprises a blocking group; (d) phosphorylating the 5′ ends of the ligated single-stranded nucleic acids; and (e) ligating a second adaptor to the 5′ ends of the phosphorylated ligated single-stranded nucleic acids in the presence of the ligase, thereby obtaining a library of nucleic acids. 2. The method of claim 1, wherein the 5′ end of the second adaptor is non-phosphorylated. 3. The method of claim 1, wherein the second adaptor is attached to a substrate. 4. The method of claim 3, wherein the substrate comprises a bead or a flow cell. 5. The method of claim 1, comprising prior to step (e) removing non-ligated single-stranded first adaptors. 6. The method of claim 5, comprising hybridizing the non-ligated single-stranded first adaptors with a capture probe. 7. The method of claim 6, wherein the capture probe comprises a sequence complementary to at least a portion of the first adaptor. 8. The method of claim 6 or 7, wherein the 3′ end of the capture probe comprises a blocking group. 9. The method of claim 6, wherein the 5′ end of the capture probe comprises a blocking group. 10. The method of claim 5, comprising digesting the non-ligated single-stranded first adaptors. 11. The method of claim 10, wherein digesting the non-ligated single-stranded first adaptors comprises contacting the non-ligated single-stranded first adaptors with a 5′-phophate-dependent exonuclease. 12. The method of claim 10, wherein digesting the non-ligated single-stranded first adaptors comprises contacting the non-ligated single-stranded first adaptors with a 5′ phosphate-dependent exonuclease and a 5′-deadenylase. 13. The method of claim 1, wherein phosphorylating the 5′ end of the ligated single-stranded nucleic acids comprises contacting the ligated single-stranded nucleic acids with a kinase. 14. A method of preparing a nucleic acid library, comprising:
(a) obtaining a plurality of nucleic acids, wherein the plurality of nucleic acids is double-stranded nucleic acids; (b) contacting the double-stranded nucleic acids with a 5′ exonuclease to obtain a plurality of modified double-stranded nucleic acids with single-stranded 3′ overhangs; (c) ligating a first adaptor to the 3′ ends of the modified double-stranded nucleic acids in the presence of a ligase, wherein the 3′ end of the first adaptor comprises a blocking group; (d) dehybridizing the modified double-stranded nucleic acids ligated to the first adaptors to obtain a plurality of single-stranded nucleic acids; and (e) ligating a second adaptor to the 5′ ends of the single-stranded nucleic acids in the presence of the ligase, thereby obtaining a library of nucleic acids. 15. The method of claim 14, wherein the 5′ end of the second adaptor is non-phosphorylated. 16. A method of preparing a nucleic acid library, comprising:
(a) obtaining a plurality of nucleic acids, wherein the plurality of nucleic acids is single-stranded nucleic acids; (b) dephosphorylating the 5′ ends of the single-stranded nucleic acids; (c) ligating a first adaptor to the 3′ ends of the single-stranded nucleic acids in the presence of a ligase, wherein the 3′ end of the first adaptor comprises a blocking group; (d) hybridizing the ligated first adaptor with a capture probe; (e) extending the capture probe, and ligating a second adaptor to the 3′ end of the extended capture probe in the presence of the ligase, wherein the 3′ end of the second adaptor comprises a blocking group, thereby obtaining a library of nucleic acids. 17. The method of claim 16, comprising removing the hybridized ligated first adaptor from the extended capture probe. 18. The method of claim 16, wherein the capture probe is attached to a substrate. 19. The method of claim 18, wherein the substrate comprises a bead or a flow cell. 20. The method of claim 16, wherein the capture probe comprises a capture probe index. 21.-84. (canceled) | Systems, methods and compositions provided herein relate to the preparation of nucleic acid libraries. Some embodiments include the preparation of nucleic acid libraries by ligation of single-stranded nucleic acids.1. A method of preparing a nucleic acid library, comprising:
(a) obtaining a plurality of nucleic acids, wherein the plurality of nucleic acids is single-stranded nucleic acids; (b) dephosphorylating the 5′ ends of the single-stranded nucleic acids; (c) ligating a first adaptor to the 3′ ends of the single-stranded nucleic acids in the presence of a ligase, wherein the 3′ end of the first adaptor comprises a blocking group; (d) phosphorylating the 5′ ends of the ligated single-stranded nucleic acids; and (e) ligating a second adaptor to the 5′ ends of the phosphorylated ligated single-stranded nucleic acids in the presence of the ligase, thereby obtaining a library of nucleic acids. 2. The method of claim 1, wherein the 5′ end of the second adaptor is non-phosphorylated. 3. The method of claim 1, wherein the second adaptor is attached to a substrate. 4. The method of claim 3, wherein the substrate comprises a bead or a flow cell. 5. The method of claim 1, comprising prior to step (e) removing non-ligated single-stranded first adaptors. 6. The method of claim 5, comprising hybridizing the non-ligated single-stranded first adaptors with a capture probe. 7. The method of claim 6, wherein the capture probe comprises a sequence complementary to at least a portion of the first adaptor. 8. The method of claim 6 or 7, wherein the 3′ end of the capture probe comprises a blocking group. 9. The method of claim 6, wherein the 5′ end of the capture probe comprises a blocking group. 10. The method of claim 5, comprising digesting the non-ligated single-stranded first adaptors. 11. The method of claim 10, wherein digesting the non-ligated single-stranded first adaptors comprises contacting the non-ligated single-stranded first adaptors with a 5′-phophate-dependent exonuclease. 12. The method of claim 10, wherein digesting the non-ligated single-stranded first adaptors comprises contacting the non-ligated single-stranded first adaptors with a 5′ phosphate-dependent exonuclease and a 5′-deadenylase. 13. The method of claim 1, wherein phosphorylating the 5′ end of the ligated single-stranded nucleic acids comprises contacting the ligated single-stranded nucleic acids with a kinase. 14. A method of preparing a nucleic acid library, comprising:
(a) obtaining a plurality of nucleic acids, wherein the plurality of nucleic acids is double-stranded nucleic acids; (b) contacting the double-stranded nucleic acids with a 5′ exonuclease to obtain a plurality of modified double-stranded nucleic acids with single-stranded 3′ overhangs; (c) ligating a first adaptor to the 3′ ends of the modified double-stranded nucleic acids in the presence of a ligase, wherein the 3′ end of the first adaptor comprises a blocking group; (d) dehybridizing the modified double-stranded nucleic acids ligated to the first adaptors to obtain a plurality of single-stranded nucleic acids; and (e) ligating a second adaptor to the 5′ ends of the single-stranded nucleic acids in the presence of the ligase, thereby obtaining a library of nucleic acids. 15. The method of claim 14, wherein the 5′ end of the second adaptor is non-phosphorylated. 16. A method of preparing a nucleic acid library, comprising:
(a) obtaining a plurality of nucleic acids, wherein the plurality of nucleic acids is single-stranded nucleic acids; (b) dephosphorylating the 5′ ends of the single-stranded nucleic acids; (c) ligating a first adaptor to the 3′ ends of the single-stranded nucleic acids in the presence of a ligase, wherein the 3′ end of the first adaptor comprises a blocking group; (d) hybridizing the ligated first adaptor with a capture probe; (e) extending the capture probe, and ligating a second adaptor to the 3′ end of the extended capture probe in the presence of the ligase, wherein the 3′ end of the second adaptor comprises a blocking group, thereby obtaining a library of nucleic acids. 17. The method of claim 16, comprising removing the hybridized ligated first adaptor from the extended capture probe. 18. The method of claim 16, wherein the capture probe is attached to a substrate. 19. The method of claim 18, wherein the substrate comprises a bead or a flow cell. 20. The method of claim 16, wherein the capture probe comprises a capture probe index. 21.-84. (canceled) | 1,600 |
1,448 | 13,764,548 | 1,651 | A flow cytometry system ( 1 ) for sorting haploid cells, specifically irradiatable sperm cells, with an intermittingly punctuated radiation emitter ( 56 ). Embodiments include a beam manipulator ( 21 ) and even split radiation beams directed to multiple nozzles ( 5 ). Differentiation of sperm characteristics with increased resolution may efficiently allow differentiated sperm cells to be separated higher speeds and even into subpopulations having higher purity. | 1-231. (canceled) 232. A flow cytometry system for sorting sperm comprising:
a) a nozzle for producing a stream comprising stained sperm cells in a sample and sheath fluid; b) a pulsed laser for exciting stained sperm cells in the stream; c) a detection system for detecting the emitted fluorescence of stained sperm cells; d) a processing unit for differentiating X chromosome sperm from Y chromosome sperm; e) an oscillator to which the stream is responsive for forming droplets; f) a drop charge circuit to apply a charge to the droplets, wherein the charge applied to each droplet is based on the presence of an X-chromosome and/or Y-chromosome as determined by the processing unit; g) a first and second deflection plate each disposed adjacent to a free fall area in which a droplet forms; and h) at least one collector to collect sorted sperm. 233. The flow cytometry system for sorting sperm as claimed in claim 232, further comprising a radiation beam manipulator selected from a group consisting mirrors, deflectors, beam splitters, prisms, refractive objects, lenses and filters. 234. The flow cytometry system for sorting sperm as claimed in claim 233, wherein the detection system comprises a photomultiplier tube. 235. The flow cytometry system for sorting sperm as claimed in claim 232, wherein the stained sperm cells are stained with a fluorescent dye. 236. The flow cytometry system for sorting sperm as claimed in claim 232, wherein the fluorescent dye comprises Hoechst 33342. 237. The flow cytometry system for sorting sperm as claimed in claim 232, wherein the pulsed laser comprises an average power less than about 300 mW. 238. The flow cytometry system for sorting sperm as claimed in claim 232, further comprising a beam splitter. 239. The flow cytometry system for sorting sperm as claimed in claim 232, further comprising a high purity sorted population of said X chromosome bearing sperm and said Y chromosome bearing sperm. 240. The flow cytometry system for sorting sperm as claimed in claim 232, wherein said high purity is selected from a group consisting of:
greater than 85% purity; greater than 90% purity; greater than 95% purity; greater than 96% purity; and greater than 98% purity. 241. The flow cytometry system for sorting sperm as claimed in claim 232, wherein the pulsed laser comprises a pulse duration between about 5 to about 20 picoseconds. 242. The flow cytometry system for sorting sperm as claimed in claim 232, wherein the pulsed laser comprises a pulse resting period between about 0.5 to about 20 nanoseconds. 243. The flow cytometry system for sorting sperm as claimed in claim 232, the pulsed laser has a repetition rate comprises between about 50 to about 200 MHz. 244. The flow cytometry system for sorting sperm as claimed in claim 243, wherein the repetition rate comprises up to about 80 MHz. 245. The flow cytometry system for sorting sperm as claimed in claim 232, wherein the sperm cells are stained with a reduced amount of stain. 246. The flow cytometry system for sorting sperm as claimed in claim 245, wherein the reduced amount of stain comprises a percentage of stain selected from a group consisting of about 90%, about 80%, about 70% and about 60% of a maximum stain. 247. The flow cytometry system for sorting sperm as claimed in claim 232, further comprising at least one shared resource, wherein said shared resource comprises a pulsed laser and a beam splitter. | A flow cytometry system ( 1 ) for sorting haploid cells, specifically irradiatable sperm cells, with an intermittingly punctuated radiation emitter ( 56 ). Embodiments include a beam manipulator ( 21 ) and even split radiation beams directed to multiple nozzles ( 5 ). Differentiation of sperm characteristics with increased resolution may efficiently allow differentiated sperm cells to be separated higher speeds and even into subpopulations having higher purity.1-231. (canceled) 232. A flow cytometry system for sorting sperm comprising:
a) a nozzle for producing a stream comprising stained sperm cells in a sample and sheath fluid; b) a pulsed laser for exciting stained sperm cells in the stream; c) a detection system for detecting the emitted fluorescence of stained sperm cells; d) a processing unit for differentiating X chromosome sperm from Y chromosome sperm; e) an oscillator to which the stream is responsive for forming droplets; f) a drop charge circuit to apply a charge to the droplets, wherein the charge applied to each droplet is based on the presence of an X-chromosome and/or Y-chromosome as determined by the processing unit; g) a first and second deflection plate each disposed adjacent to a free fall area in which a droplet forms; and h) at least one collector to collect sorted sperm. 233. The flow cytometry system for sorting sperm as claimed in claim 232, further comprising a radiation beam manipulator selected from a group consisting mirrors, deflectors, beam splitters, prisms, refractive objects, lenses and filters. 234. The flow cytometry system for sorting sperm as claimed in claim 233, wherein the detection system comprises a photomultiplier tube. 235. The flow cytometry system for sorting sperm as claimed in claim 232, wherein the stained sperm cells are stained with a fluorescent dye. 236. The flow cytometry system for sorting sperm as claimed in claim 232, wherein the fluorescent dye comprises Hoechst 33342. 237. The flow cytometry system for sorting sperm as claimed in claim 232, wherein the pulsed laser comprises an average power less than about 300 mW. 238. The flow cytometry system for sorting sperm as claimed in claim 232, further comprising a beam splitter. 239. The flow cytometry system for sorting sperm as claimed in claim 232, further comprising a high purity sorted population of said X chromosome bearing sperm and said Y chromosome bearing sperm. 240. The flow cytometry system for sorting sperm as claimed in claim 232, wherein said high purity is selected from a group consisting of:
greater than 85% purity; greater than 90% purity; greater than 95% purity; greater than 96% purity; and greater than 98% purity. 241. The flow cytometry system for sorting sperm as claimed in claim 232, wherein the pulsed laser comprises a pulse duration between about 5 to about 20 picoseconds. 242. The flow cytometry system for sorting sperm as claimed in claim 232, wherein the pulsed laser comprises a pulse resting period between about 0.5 to about 20 nanoseconds. 243. The flow cytometry system for sorting sperm as claimed in claim 232, the pulsed laser has a repetition rate comprises between about 50 to about 200 MHz. 244. The flow cytometry system for sorting sperm as claimed in claim 243, wherein the repetition rate comprises up to about 80 MHz. 245. The flow cytometry system for sorting sperm as claimed in claim 232, wherein the sperm cells are stained with a reduced amount of stain. 246. The flow cytometry system for sorting sperm as claimed in claim 245, wherein the reduced amount of stain comprises a percentage of stain selected from a group consisting of about 90%, about 80%, about 70% and about 60% of a maximum stain. 247. The flow cytometry system for sorting sperm as claimed in claim 232, further comprising at least one shared resource, wherein said shared resource comprises a pulsed laser and a beam splitter. | 1,600 |
1,449 | 15,173,753 | 1,658 | Provided are processes of functionalizing a microparticle that include reacting a microparticle expressing a carboxylic acid with a functionalization linker including the structure N-L 1 -A where N is a free amine, L 1 is a linker, and A is an azide and an alkyne terminated group, to form a functional group terminated microparticle, and forming a functionalized microparticle by reacting the functional group terminated microparticle with a peptide including a terminal functional group comprising an alkyne or azide, where the peptide includes the structure F-L 2 -Peptide, where F is a functional group and L 2 is a linker. Also provided are compositions suitable for effectively coupling a peptide to a microsphere and functionalized microspheres suitable for reacting with a detection agent. | 1. A process of functionalizing a microparticle comprising:
reacting a microparticle expressing a carboxylic acid with a functionalization linker comprising N-L1-A where N is a free amine, L1 is a linker, and A is an azide or an alkyne terminated group, to form a functional group terminated microparticle; forming a functionalized microparticle by reacting said functional group terminated microparticle with a peptide comprising an N- or C-terminal functional group comprising an alkyne or azide, said peptide comprising the structure F-L2-Peptide, where F is a functional group and L2 is a linker; and further wherein said microparticle is a dye. 2. The process of claim 1 wherein L1, L2, or both comprise oxyethylene. 3. The process of claim 1 wherein L1 comprises an oxyethylene with greater than ten (10) oxyethylene moieties. 4. The process of claim 1 wherein said step of reacting said azide terminated microparticle proceeds for a reaction time of 2 hours or less. 5. The process of claim 4 wherein said reaction time is 1 hour or less. 6. The process of claim 1 wherein said step of forming comprises reacting said azide terminated microparticle with said peptide in an organic solvent comprising dimethyl sulfoxide. 7. The process of claim 6 wherein said dimethyl sulfoxide is at a concentration between 5 percent and 50 percent by volume. 8. The process of claim 1 wherein said L1 comprises a polyoxyethylene with 6 to 200 oxyethylene moieties. 9. The process of claim 1 wherein said functionalization linker consists of 10. The process of claim 1 wherein said peptide comprises 11. (canceled) 12. The process of claim 1 wherein said peptide comprises 2 to 100 amino acids. 13. A composition for analysis of a biomolecule comprising:
where P represents a microparticle and n is from 1 to 200. 14. The composition of claim 13 further comprising a peptide comprising 2 to 100 amino acids. 15. The composition of claim 14 wherein said peptide is covalently linked to said composition by an azide-alkyne cycloaddition. 16. The composition of claim 13 wherein P comprises a dye. 17. The composition of claim 16 wherein said dye is a fluorescent dye. | Provided are processes of functionalizing a microparticle that include reacting a microparticle expressing a carboxylic acid with a functionalization linker including the structure N-L 1 -A where N is a free amine, L 1 is a linker, and A is an azide and an alkyne terminated group, to form a functional group terminated microparticle, and forming a functionalized microparticle by reacting the functional group terminated microparticle with a peptide including a terminal functional group comprising an alkyne or azide, where the peptide includes the structure F-L 2 -Peptide, where F is a functional group and L 2 is a linker. Also provided are compositions suitable for effectively coupling a peptide to a microsphere and functionalized microspheres suitable for reacting with a detection agent.1. A process of functionalizing a microparticle comprising:
reacting a microparticle expressing a carboxylic acid with a functionalization linker comprising N-L1-A where N is a free amine, L1 is a linker, and A is an azide or an alkyne terminated group, to form a functional group terminated microparticle; forming a functionalized microparticle by reacting said functional group terminated microparticle with a peptide comprising an N- or C-terminal functional group comprising an alkyne or azide, said peptide comprising the structure F-L2-Peptide, where F is a functional group and L2 is a linker; and further wherein said microparticle is a dye. 2. The process of claim 1 wherein L1, L2, or both comprise oxyethylene. 3. The process of claim 1 wherein L1 comprises an oxyethylene with greater than ten (10) oxyethylene moieties. 4. The process of claim 1 wherein said step of reacting said azide terminated microparticle proceeds for a reaction time of 2 hours or less. 5. The process of claim 4 wherein said reaction time is 1 hour or less. 6. The process of claim 1 wherein said step of forming comprises reacting said azide terminated microparticle with said peptide in an organic solvent comprising dimethyl sulfoxide. 7. The process of claim 6 wherein said dimethyl sulfoxide is at a concentration between 5 percent and 50 percent by volume. 8. The process of claim 1 wherein said L1 comprises a polyoxyethylene with 6 to 200 oxyethylene moieties. 9. The process of claim 1 wherein said functionalization linker consists of 10. The process of claim 1 wherein said peptide comprises 11. (canceled) 12. The process of claim 1 wherein said peptide comprises 2 to 100 amino acids. 13. A composition for analysis of a biomolecule comprising:
where P represents a microparticle and n is from 1 to 200. 14. The composition of claim 13 further comprising a peptide comprising 2 to 100 amino acids. 15. The composition of claim 14 wherein said peptide is covalently linked to said composition by an azide-alkyne cycloaddition. 16. The composition of claim 13 wherein P comprises a dye. 17. The composition of claim 16 wherein said dye is a fluorescent dye. | 1,600 |
1,450 | 14,414,936 | 1,635 | Disclosed herein are methods of discovering and validating select endophenotypes encompassing tumorigenic cancer stem cells. | 1. A method of assessing the tumorigenic potential of individual tumor populations in a population of cancer cells comprising:
a) isolating a sample from the subject comprising the population of cancer cells; b) separating individual tumor populations in the population of cancer cells from each other based on differential RNA or protein expression; and c) assessing the tumorigenic potential of the separated individual tumor populations. 2. The method of claim 1, wherein the separation is performed using fluorescence activated cell sorting (FACS). 3. The method of claim 1, wherein the assessment of tumorigenic potential is performed in vitro. 4. The method of claim 3, wherein the in vitro assessment of tumorigenic potential is performed using a soft agar test. 5. The method of claim 2, wherein the assessment of tumorigenic potential is performed in vivo. 6. The method of claim 5, wherein the in vivo assessment of tumorigenic potential is performed using immunocompromised mice. 7. The method of claim 1, further comprising obtaining a single cell suspension of the population of cancer cells after step a) and prior to step b). 8. The method of claim 1, wherein the population of cancer cells is isolated from a single tumor in the subject. 9. The method of claim 1, wherein the tumor population comprises cells that are CD24+, CD44hi, Nkx2.1 (TTF-1)+, SOX-2+, Kras+, p53+, Sca1+, miR34alo or CD133+. 10. The method of claim 9, wherein the cancer is lung cancer. 11. The method of claim 10, wherein the sample is a malignant pleural effusion (MPE). 12. A method of screening for an effective therapeutic for treatment of a cancer comprising:
a) separating individual tumor populations in a population of cancer cells from the cancer to be treated from each other based on differential RNA or protein expression; and b) assessing the tumorigenic potential of the separated individual tumor populations; c) screening the individual tumor populations with tumorigenic potential for susceptibility to various cancer therapeutics; wherein, if the screened cancer therapeutic reduces the proliferative capacity of the individual tumor populations with tumorigenic potential then the screened cancer therapeutic is an effective therapeutic for treatment of the cancer in the subject. 13. The method of claim 12, wherein the separation is performed using fluorescence activated cell sorting (FACS). 14. The method of claim 12, wherein the assessment of tumorigenic potential is performed in vitro. 15. The method of claim 14, wherein the in vitro assessment of tumorigenic potential is performed using a soft agar test. 16. The method of claim 12, wherein the assessment of tumorigenic potential is performed in vivo. 17. The method of claim 16, wherein the in vivo assessment of tumorigenic potential is performed using immunocompromised mice. 18. The method of claim 12, further comprising obtaining a single cell suspension of the population of cancer cells after step a) and prior to step b). 19. The method of claim 12, wherein the population of cancer cells is isolated from a single tumor in the subject. 20. The method of claim 12, wherein the tumor population comprises cells that are CD24+, CD166+; CD44hi, Nkx2.1 (TTF-1)+, SOX-2+, mutated Kras+, mutated or lost p53+, miR34alo or CD133+. 21. The method of claim 20, wherein the cancer is lung cancer. 22. The method of claim 21, wherein the sample is a malignant pleural effusion (MPE). 23. A method of treating cancer in a subject in need thereof comprising:
a) isolating a sample from the subject comprising cancer cells; b) separating individual tumor populations from each other; c) assessing the tumorigenic potential of the individual tumor populations; d) screening the individual tumor populations with high tumorigenic potential for susceptibility to various cancer treatments; and e) administering to the subject a cancer treatment that one or more of the individual tumor populations with high tumorigenic potential is susceptible to, thereby treating cancer in the subject in need thereof. 24. The method of claim 23, wherein the separation is performed using fluorescence activated cell sorting (FACS). 25. The method of claim 23, wherein the assessment of tumorigenic potential is performed in vitro. 26. The method of claim 25, wherein the in vitro assessment of tumorigenic potential is performed using a soft agar test. 27. The method of claim 23, wherein the assessment of tumorigenic potential is performed in vivo. 28. The method of claim 27, wherein the in vivo assessment of tumorigenic potential is performed using immunocompromised mice. 29. The method of claim 23, further comprising obtaining a single cell suspension of the population of cancer cells after step a) and prior to step b). 30. The method of claim 23, wherein the population of cancer cells is isolated from a single tumor in the subject. 31. The method of claim 23, wherein the tumor population comprises cells that are CD24+, CD44hi, Nkx2.1 (TTF-1)+, SOX-2+, Kras+, p53+, Sca1+, miR34alo or CD133+. 32. The method of claim 31, wherein the cancer is lung cancer. 33. The method of claim 32, wherein the sample is a malignant pleural effusion (MPE). 34. A method of screening for a biomarker of an individual tumor population with tumorigenic potential comprising:
a) separating individual tumor populations in a population of cancer cells from the cancer to be treated from each other based on differential RNA or protein expression; and b) assessing the tumorigenic potential of the separated individual tumor populations; and wherein, if the individual tumor population has tumorigenic potential then the RNA or protein that was used to separate the individual tumor population based on differential expression is a biomarker of an individual tumor population with tumorigenic potential. 35. The method of claim 34, wherein the separation is performed using fluorescence activated cell sorting (FACS). 36. The method of claim 34, wherein the assessment of tumorigenic potential is performed in vitro. 37. The method of claim 36, wherein the in vitro assessment of tumorigenic potential is performed using a soft agar test. 38. The method of claim 34, wherein the assessment of tumorigenic potential is performed in vivo. 39. The method of claim 38, wherein the in vivo assessment of tumorigenic potential is performed using immunocompromised mice. 40. The method of claim 34, further comprising obtaining a single cell suspension of the population of cancer cells after step a) and prior to step b). 41. The method of claim 34, wherein the population of cancer cells is isolated from a single tumor in the subject. 42. The method of claim 34, wherein the tumor population comprises cells that CD24+, CD44hi, Nkx2.1 (TTF-1)+, SOX-2+, Kras+, p53+, Sca1+, miR34alo or CD133+. 43. The method of claim 42, wherein the cancer is lung cancer. 44. The method of claim 43, wherein the sample is a malignant pleural effusion (MPE). 45. A cell line wherein the cell line is derived from lung cancer cells and wherein the cell line over expresses a protein selected from the group consisting of CD24, CD44, Nkx2.1 (TTF-1), SOX-2, Kras, p53, Sca1 and CD133. 46. The cell line of claim 45, wherein the cell line derived from lung cells is selected from the group consisting of NCI-H1373, NCI-H1395, SK-LU-1, HCC2935, HCC4006, HCC827, NCI-H1581, NCI-H23, Human, NCI-H522, NCI-H1435, NCI-H1563, NCI-H1651, NCI-H1734, NCI-H1793, NCI-H1838, NCI-H1975, NCI-H2073, NCI-H2085, NCI-H2228 and NCI-H2342. 47. The cell line of claim 45, wherein the cell line comprises an expression vector wherein the expression vector expresses a protein selected from the group consisting of CD24, CD44, Nkx2.1 (TTF-1), SOX-2, Kras, p53, Sca1 and CD133 in the cell line. 48. A cell line wherein the cell line is derived from lung cancer cells and wherein the cell line under expresses miR34a. 49. The cell line of claim 48, wherein the cell line derived from lung cells is selected from the group consisting of NCI-H1373, NCI-H1395, SK-LU-1, HCC2935, HCC4006, HCC827, NCI-H1581, NCI-H23, Human, NCI-H522, NCI-H1435, NCI-H1563, NCI-H1651, NCI-H1734, NCI-H1793, NCI-H1838, NCI-H1975, NCI-H2073, NCI-H2085, NCI-H2228 and NCI-H2342. 50. The cell line of claim 48, wherein the cell line comprises a vector wherein the vector knocks down the expression of miR34a in the cell line. | Disclosed herein are methods of discovering and validating select endophenotypes encompassing tumorigenic cancer stem cells.1. A method of assessing the tumorigenic potential of individual tumor populations in a population of cancer cells comprising:
a) isolating a sample from the subject comprising the population of cancer cells; b) separating individual tumor populations in the population of cancer cells from each other based on differential RNA or protein expression; and c) assessing the tumorigenic potential of the separated individual tumor populations. 2. The method of claim 1, wherein the separation is performed using fluorescence activated cell sorting (FACS). 3. The method of claim 1, wherein the assessment of tumorigenic potential is performed in vitro. 4. The method of claim 3, wherein the in vitro assessment of tumorigenic potential is performed using a soft agar test. 5. The method of claim 2, wherein the assessment of tumorigenic potential is performed in vivo. 6. The method of claim 5, wherein the in vivo assessment of tumorigenic potential is performed using immunocompromised mice. 7. The method of claim 1, further comprising obtaining a single cell suspension of the population of cancer cells after step a) and prior to step b). 8. The method of claim 1, wherein the population of cancer cells is isolated from a single tumor in the subject. 9. The method of claim 1, wherein the tumor population comprises cells that are CD24+, CD44hi, Nkx2.1 (TTF-1)+, SOX-2+, Kras+, p53+, Sca1+, miR34alo or CD133+. 10. The method of claim 9, wherein the cancer is lung cancer. 11. The method of claim 10, wherein the sample is a malignant pleural effusion (MPE). 12. A method of screening for an effective therapeutic for treatment of a cancer comprising:
a) separating individual tumor populations in a population of cancer cells from the cancer to be treated from each other based on differential RNA or protein expression; and b) assessing the tumorigenic potential of the separated individual tumor populations; c) screening the individual tumor populations with tumorigenic potential for susceptibility to various cancer therapeutics; wherein, if the screened cancer therapeutic reduces the proliferative capacity of the individual tumor populations with tumorigenic potential then the screened cancer therapeutic is an effective therapeutic for treatment of the cancer in the subject. 13. The method of claim 12, wherein the separation is performed using fluorescence activated cell sorting (FACS). 14. The method of claim 12, wherein the assessment of tumorigenic potential is performed in vitro. 15. The method of claim 14, wherein the in vitro assessment of tumorigenic potential is performed using a soft agar test. 16. The method of claim 12, wherein the assessment of tumorigenic potential is performed in vivo. 17. The method of claim 16, wherein the in vivo assessment of tumorigenic potential is performed using immunocompromised mice. 18. The method of claim 12, further comprising obtaining a single cell suspension of the population of cancer cells after step a) and prior to step b). 19. The method of claim 12, wherein the population of cancer cells is isolated from a single tumor in the subject. 20. The method of claim 12, wherein the tumor population comprises cells that are CD24+, CD166+; CD44hi, Nkx2.1 (TTF-1)+, SOX-2+, mutated Kras+, mutated or lost p53+, miR34alo or CD133+. 21. The method of claim 20, wherein the cancer is lung cancer. 22. The method of claim 21, wherein the sample is a malignant pleural effusion (MPE). 23. A method of treating cancer in a subject in need thereof comprising:
a) isolating a sample from the subject comprising cancer cells; b) separating individual tumor populations from each other; c) assessing the tumorigenic potential of the individual tumor populations; d) screening the individual tumor populations with high tumorigenic potential for susceptibility to various cancer treatments; and e) administering to the subject a cancer treatment that one or more of the individual tumor populations with high tumorigenic potential is susceptible to, thereby treating cancer in the subject in need thereof. 24. The method of claim 23, wherein the separation is performed using fluorescence activated cell sorting (FACS). 25. The method of claim 23, wherein the assessment of tumorigenic potential is performed in vitro. 26. The method of claim 25, wherein the in vitro assessment of tumorigenic potential is performed using a soft agar test. 27. The method of claim 23, wherein the assessment of tumorigenic potential is performed in vivo. 28. The method of claim 27, wherein the in vivo assessment of tumorigenic potential is performed using immunocompromised mice. 29. The method of claim 23, further comprising obtaining a single cell suspension of the population of cancer cells after step a) and prior to step b). 30. The method of claim 23, wherein the population of cancer cells is isolated from a single tumor in the subject. 31. The method of claim 23, wherein the tumor population comprises cells that are CD24+, CD44hi, Nkx2.1 (TTF-1)+, SOX-2+, Kras+, p53+, Sca1+, miR34alo or CD133+. 32. The method of claim 31, wherein the cancer is lung cancer. 33. The method of claim 32, wherein the sample is a malignant pleural effusion (MPE). 34. A method of screening for a biomarker of an individual tumor population with tumorigenic potential comprising:
a) separating individual tumor populations in a population of cancer cells from the cancer to be treated from each other based on differential RNA or protein expression; and b) assessing the tumorigenic potential of the separated individual tumor populations; and wherein, if the individual tumor population has tumorigenic potential then the RNA or protein that was used to separate the individual tumor population based on differential expression is a biomarker of an individual tumor population with tumorigenic potential. 35. The method of claim 34, wherein the separation is performed using fluorescence activated cell sorting (FACS). 36. The method of claim 34, wherein the assessment of tumorigenic potential is performed in vitro. 37. The method of claim 36, wherein the in vitro assessment of tumorigenic potential is performed using a soft agar test. 38. The method of claim 34, wherein the assessment of tumorigenic potential is performed in vivo. 39. The method of claim 38, wherein the in vivo assessment of tumorigenic potential is performed using immunocompromised mice. 40. The method of claim 34, further comprising obtaining a single cell suspension of the population of cancer cells after step a) and prior to step b). 41. The method of claim 34, wherein the population of cancer cells is isolated from a single tumor in the subject. 42. The method of claim 34, wherein the tumor population comprises cells that CD24+, CD44hi, Nkx2.1 (TTF-1)+, SOX-2+, Kras+, p53+, Sca1+, miR34alo or CD133+. 43. The method of claim 42, wherein the cancer is lung cancer. 44. The method of claim 43, wherein the sample is a malignant pleural effusion (MPE). 45. A cell line wherein the cell line is derived from lung cancer cells and wherein the cell line over expresses a protein selected from the group consisting of CD24, CD44, Nkx2.1 (TTF-1), SOX-2, Kras, p53, Sca1 and CD133. 46. The cell line of claim 45, wherein the cell line derived from lung cells is selected from the group consisting of NCI-H1373, NCI-H1395, SK-LU-1, HCC2935, HCC4006, HCC827, NCI-H1581, NCI-H23, Human, NCI-H522, NCI-H1435, NCI-H1563, NCI-H1651, NCI-H1734, NCI-H1793, NCI-H1838, NCI-H1975, NCI-H2073, NCI-H2085, NCI-H2228 and NCI-H2342. 47. The cell line of claim 45, wherein the cell line comprises an expression vector wherein the expression vector expresses a protein selected from the group consisting of CD24, CD44, Nkx2.1 (TTF-1), SOX-2, Kras, p53, Sca1 and CD133 in the cell line. 48. A cell line wherein the cell line is derived from lung cancer cells and wherein the cell line under expresses miR34a. 49. The cell line of claim 48, wherein the cell line derived from lung cells is selected from the group consisting of NCI-H1373, NCI-H1395, SK-LU-1, HCC2935, HCC4006, HCC827, NCI-H1581, NCI-H23, Human, NCI-H522, NCI-H1435, NCI-H1563, NCI-H1651, NCI-H1734, NCI-H1793, NCI-H1838, NCI-H1975, NCI-H2073, NCI-H2085, NCI-H2228 and NCI-H2342. 50. The cell line of claim 48, wherein the cell line comprises a vector wherein the vector knocks down the expression of miR34a in the cell line. | 1,600 |
1,451 | 16,644,279 | 1,611 | The present invention relates to a formulation in the form of an aqueous suspension comprising calcium citrate. Said formulation exhibits excellent stability and compliance and finds use in calcium supplementation in subjects in need of such supplementation. | 1. A formulation in the form of an aqueous suspension comprising calcium citrate and isomalt. 2. The formulation in the form of an aqueous suspension according to claim 1, wherein calcium citrate is calcium citrate tetrahydrate. 3. The formulation in the form of an aqueous suspension according to claim 1, further comprising sorbitol. 4. The formulation in the form of an aqueous suspension according to claim 1, wherein calcium citrate is in a concentration, expressed with reference to calcium, in the range from 20 to 100 mg per 1 ml of suspension, preferably in the range from 40 to 70 per 1 ml of suspension, more preferably of about 50 mg per 1 ml of suspension. 5. The formulation in the form of an aqueous suspension according to claim 1, wherein isomalt is in a percentage concentration (w/w) in the range from 0.5 to 10% (w/w), preferably from 2 to 6% (w/w) with respect to the weight of the final formulation. 6. The formulation in the form of an aqueous suspension according to claim 1, wherein sorbitol is in a percentage concentration (w/w) in the range from 10 to 30% (w/w), preferably from 17 to 28% (w/w) with respect to the weight of the final formulation. 7. The formulation in the form of an aqueous suspension according to claim 1, wherein the aqueous suspension is in the form of a unitary dose. 8. The formulation in the form of an aqueous suspension according to claim 7, wherein the aqueous suspension in the form of a unitary dose comprises calcium citrate in an amount corresponding to a unitary dose of calcium in the range from 200 to 1500 mg, preferably from 400 to 1200 mg, still more preferably of about 500 mg or about 1000 mg. 9. The formulation in the form of an aqueous suspension according to claim 7, wherein isomalt is in an amount from 0.1 to 1 g, preferably from 0.4 to 1 g. 10. The formulation in the form of an aqueous suspension according to claim 7, wherein sorbitol is in an amount in the range from 1 to 5 g, preferably from 2.5 to 5 g. 11. The formulation in the form of an aqueous suspension according to claim 7, wherein the total volume of said aqueous suspension is in the range from 5 to 30 ml, preferably from 8 to 25 ml, more preferably from 9 to 15 ml, still more preferably is of about 10 ml. 12. The formulation in the form of an aqueous suspension according to claim 7 comprising calcium citrate in an amount corresponding to a unitary dose of calcium of 1000 mg in a total volume of about 10 ml. 13. The formulation in the form of an aqueous suspension according to claim 11 wherein the total weight of said aqueous suspension is in the range from 5 to 20 g, preferably comprised in the range from 6 to 10-g for the unitary dose delivering an equivalent amount of calcium of about 500 mg, and in the range from 16 a 20 g for the unitary dose delivering an equivalent amount of calcium of about 1000 mg. 14. The formulation in the form of an aqueous suspension according to claim 1, further comprising citric acid and sodium citrate. 15. A single-dose flexible container containing a unitary dose of a pharmaceutical preparation or nutritional supplement comprising a formulation according to claim 1. 16. The container according to claim 15, wherein the flexible container is a cheer pack or a stick pack, preferably a stick pack. 17. A method for treating a subject in need of calcium supplementation comprising the step of administering to said subject a supplementation comprising the step of administering to said subject a formulation in the form of an aqueous suspension according to claim 1. 18. The method according to claim 17, wherein said subject in need of calcium supplementation is an elderly patient or a pediatric patient. 19. The method according to claim 17, wherein said subject in need of calcium supplementation is a patient affected by a disease related to bone mass loss, said disease_being selected from the group consisting of osteoporosis, fractures, chronic diarrhea syndromes, hypertension and colon cancer. | The present invention relates to a formulation in the form of an aqueous suspension comprising calcium citrate. Said formulation exhibits excellent stability and compliance and finds use in calcium supplementation in subjects in need of such supplementation.1. A formulation in the form of an aqueous suspension comprising calcium citrate and isomalt. 2. The formulation in the form of an aqueous suspension according to claim 1, wherein calcium citrate is calcium citrate tetrahydrate. 3. The formulation in the form of an aqueous suspension according to claim 1, further comprising sorbitol. 4. The formulation in the form of an aqueous suspension according to claim 1, wherein calcium citrate is in a concentration, expressed with reference to calcium, in the range from 20 to 100 mg per 1 ml of suspension, preferably in the range from 40 to 70 per 1 ml of suspension, more preferably of about 50 mg per 1 ml of suspension. 5. The formulation in the form of an aqueous suspension according to claim 1, wherein isomalt is in a percentage concentration (w/w) in the range from 0.5 to 10% (w/w), preferably from 2 to 6% (w/w) with respect to the weight of the final formulation. 6. The formulation in the form of an aqueous suspension according to claim 1, wherein sorbitol is in a percentage concentration (w/w) in the range from 10 to 30% (w/w), preferably from 17 to 28% (w/w) with respect to the weight of the final formulation. 7. The formulation in the form of an aqueous suspension according to claim 1, wherein the aqueous suspension is in the form of a unitary dose. 8. The formulation in the form of an aqueous suspension according to claim 7, wherein the aqueous suspension in the form of a unitary dose comprises calcium citrate in an amount corresponding to a unitary dose of calcium in the range from 200 to 1500 mg, preferably from 400 to 1200 mg, still more preferably of about 500 mg or about 1000 mg. 9. The formulation in the form of an aqueous suspension according to claim 7, wherein isomalt is in an amount from 0.1 to 1 g, preferably from 0.4 to 1 g. 10. The formulation in the form of an aqueous suspension according to claim 7, wherein sorbitol is in an amount in the range from 1 to 5 g, preferably from 2.5 to 5 g. 11. The formulation in the form of an aqueous suspension according to claim 7, wherein the total volume of said aqueous suspension is in the range from 5 to 30 ml, preferably from 8 to 25 ml, more preferably from 9 to 15 ml, still more preferably is of about 10 ml. 12. The formulation in the form of an aqueous suspension according to claim 7 comprising calcium citrate in an amount corresponding to a unitary dose of calcium of 1000 mg in a total volume of about 10 ml. 13. The formulation in the form of an aqueous suspension according to claim 11 wherein the total weight of said aqueous suspension is in the range from 5 to 20 g, preferably comprised in the range from 6 to 10-g for the unitary dose delivering an equivalent amount of calcium of about 500 mg, and in the range from 16 a 20 g for the unitary dose delivering an equivalent amount of calcium of about 1000 mg. 14. The formulation in the form of an aqueous suspension according to claim 1, further comprising citric acid and sodium citrate. 15. A single-dose flexible container containing a unitary dose of a pharmaceutical preparation or nutritional supplement comprising a formulation according to claim 1. 16. The container according to claim 15, wherein the flexible container is a cheer pack or a stick pack, preferably a stick pack. 17. A method for treating a subject in need of calcium supplementation comprising the step of administering to said subject a supplementation comprising the step of administering to said subject a formulation in the form of an aqueous suspension according to claim 1. 18. The method according to claim 17, wherein said subject in need of calcium supplementation is an elderly patient or a pediatric patient. 19. The method according to claim 17, wherein said subject in need of calcium supplementation is a patient affected by a disease related to bone mass loss, said disease_being selected from the group consisting of osteoporosis, fractures, chronic diarrhea syndromes, hypertension and colon cancer. | 1,600 |
1,452 | 16,100,369 | 1,644 | Biopharmaceutical compositions and drug products disclosed herein exhibit reduced amounts of subvisible particle formation. Compositions and drug products disclosed herein comprise a protein and a surfactant or stabilizer including high percentage amounts (e.g., at least 97%) of a long-chain fatty acid ester. Also disclosed herein are methods of preparing and storing such compositions and drug products. | 1. A method of reducing subvisible and visible particle formation in a drug product, the method comprising:
including at least 100 mg/mL of an IgG antibody in the drug product; and including a mixture of fatty acid esters of polyoxyethylene sorbitan in the drug product, wherein a content of oleic acid esters in the mixture is greater than 98% of all fatty acid esters in the mixture. 2. The method of claim 1, further comprising storing the drug product at a temperature of between 30° C. and 50° C. for between 1 and 5 months, after which fewer than 3000 particles having a diameter of 10 microns or greater are detectable in the drug product as detected by one of flow imaging microscopy or membrane microscopy. 3. The method of claim 1, further comprising storing the drug product at a temperature of between 2° C. and 8° C. for between 18 and 36 months, after which fewer than 3000 particles having a diameter of 10 microns or greater are detectable in the drug product as detected by one of flow imaging microscopy or membrane microscopy. 4. The method of claim 1, further comprising adding an agent to reduce viscosity to the drug product. 5. The method of claim 1, wherein the IgG antibody is an IgG4 antibody. 6. The method of claim 1, wherein the IgG antibody is capable of being co-purified with a lipase, and the drug product includes the lipase. 7. The method of claim 1, wherein the IgG antibody has been purified using an affinity purification step prior to inclusion in the drug product. 8. The method of claim 1, wherein the step of including at least 100 mg/mL of the IgG antibody in the drug product comprises including at least 150 mg/mL of the IgG antibody in the drug product. 9. The method of claim 1, wherein the IgG antibody has not been purified using hydrophobic interaction chromatography (HIC) prior to inclusion in the drug product. 10. The method of claim 1, wherein the IgG antibody is an IgG4 antibody, and the drug product includes phospholipase B-like 2 protein. 11. The method of claim 1, further comprising purifying the IgG antibody using a Protein A purification step before including the IgG antibody in the drug product. 12. The method of claim 1, wherein the content of oleic acid esters in the mixture is at least 99% of all fatty acid esters in the mixture. 13. The method of claim 1, wherein the drug product further includes an esterase. 14. A drug product prepared according to the method of claim 1. 15. The method of claim 1, wherein the content of oleic acid esters in the mixture is determined by one of gas-liquid chromatography, liquid chromatography, a colorimetric assay, or a fluorometric assay. 16. The method of claim 1, wherein the drug product is configured for parenteral administration. 17. A method of reducing particulate formation in a drug product including an IgG antibody and an esterase, the method comprising:
including in the drug product a mixture of polyoxyethylene sorbitan fatty acid esters, wherein a content of oleic acid esters in the mixture is greater than 98% of all fatty acid esters in the mixture, wherein the method does not include purifying the IgG antibody using hydrophobic interaction chromatography. 18. The method of claim 17, wherein the IgG antibody is an IgG4 antibody and the esterase is a phospholipase B-like 2 protein. 19. A formulation, comprising:
at least 100 mg/mL of an IgG antibody; and a mixture of fatty acid esters, wherein a content of oleic acid esters in the mixture is greater than 98% of all fatty acid esters in the mixture. 20. The formulation of claim 19, comprising at least 150 mg/mL of the IgG antibody. 21. The formulation of claim 19, wherein the mixture of fatty acid esters is polysorbate 80. 22. The formulation of claim 19, wherein the IgG antibody is an IgG4 antibody, and the formulation includes phospholipase B-like 2 protein. 23. A drug product including the formulation of claim 19. 24. The drug product of claim 23, wherein fewer than 3000 particles having a diameter of 10 microns or greater are detectable in the drug product by one of flow imaging microscopy or membrane microscopy, after the drug product has been stored at a temperature of between 30° C. and 50° C. for between 1 and 5 months. 25. The drug product of claim 23, wherein fewer than 3000 particles having a diameter of 10 microns or greater are detectable in the drug product by one of flow imaging microscopy or membrane microscopy, after the drug product has been stored at a temperature of between 2° C. and 8° C. for between 18 and 36 months. | Biopharmaceutical compositions and drug products disclosed herein exhibit reduced amounts of subvisible particle formation. Compositions and drug products disclosed herein comprise a protein and a surfactant or stabilizer including high percentage amounts (e.g., at least 97%) of a long-chain fatty acid ester. Also disclosed herein are methods of preparing and storing such compositions and drug products.1. A method of reducing subvisible and visible particle formation in a drug product, the method comprising:
including at least 100 mg/mL of an IgG antibody in the drug product; and including a mixture of fatty acid esters of polyoxyethylene sorbitan in the drug product, wherein a content of oleic acid esters in the mixture is greater than 98% of all fatty acid esters in the mixture. 2. The method of claim 1, further comprising storing the drug product at a temperature of between 30° C. and 50° C. for between 1 and 5 months, after which fewer than 3000 particles having a diameter of 10 microns or greater are detectable in the drug product as detected by one of flow imaging microscopy or membrane microscopy. 3. The method of claim 1, further comprising storing the drug product at a temperature of between 2° C. and 8° C. for between 18 and 36 months, after which fewer than 3000 particles having a diameter of 10 microns or greater are detectable in the drug product as detected by one of flow imaging microscopy or membrane microscopy. 4. The method of claim 1, further comprising adding an agent to reduce viscosity to the drug product. 5. The method of claim 1, wherein the IgG antibody is an IgG4 antibody. 6. The method of claim 1, wherein the IgG antibody is capable of being co-purified with a lipase, and the drug product includes the lipase. 7. The method of claim 1, wherein the IgG antibody has been purified using an affinity purification step prior to inclusion in the drug product. 8. The method of claim 1, wherein the step of including at least 100 mg/mL of the IgG antibody in the drug product comprises including at least 150 mg/mL of the IgG antibody in the drug product. 9. The method of claim 1, wherein the IgG antibody has not been purified using hydrophobic interaction chromatography (HIC) prior to inclusion in the drug product. 10. The method of claim 1, wherein the IgG antibody is an IgG4 antibody, and the drug product includes phospholipase B-like 2 protein. 11. The method of claim 1, further comprising purifying the IgG antibody using a Protein A purification step before including the IgG antibody in the drug product. 12. The method of claim 1, wherein the content of oleic acid esters in the mixture is at least 99% of all fatty acid esters in the mixture. 13. The method of claim 1, wherein the drug product further includes an esterase. 14. A drug product prepared according to the method of claim 1. 15. The method of claim 1, wherein the content of oleic acid esters in the mixture is determined by one of gas-liquid chromatography, liquid chromatography, a colorimetric assay, or a fluorometric assay. 16. The method of claim 1, wherein the drug product is configured for parenteral administration. 17. A method of reducing particulate formation in a drug product including an IgG antibody and an esterase, the method comprising:
including in the drug product a mixture of polyoxyethylene sorbitan fatty acid esters, wherein a content of oleic acid esters in the mixture is greater than 98% of all fatty acid esters in the mixture, wherein the method does not include purifying the IgG antibody using hydrophobic interaction chromatography. 18. The method of claim 17, wherein the IgG antibody is an IgG4 antibody and the esterase is a phospholipase B-like 2 protein. 19. A formulation, comprising:
at least 100 mg/mL of an IgG antibody; and a mixture of fatty acid esters, wherein a content of oleic acid esters in the mixture is greater than 98% of all fatty acid esters in the mixture. 20. The formulation of claim 19, comprising at least 150 mg/mL of the IgG antibody. 21. The formulation of claim 19, wherein the mixture of fatty acid esters is polysorbate 80. 22. The formulation of claim 19, wherein the IgG antibody is an IgG4 antibody, and the formulation includes phospholipase B-like 2 protein. 23. A drug product including the formulation of claim 19. 24. The drug product of claim 23, wherein fewer than 3000 particles having a diameter of 10 microns or greater are detectable in the drug product by one of flow imaging microscopy or membrane microscopy, after the drug product has been stored at a temperature of between 30° C. and 50° C. for between 1 and 5 months. 25. The drug product of claim 23, wherein fewer than 3000 particles having a diameter of 10 microns or greater are detectable in the drug product by one of flow imaging microscopy or membrane microscopy, after the drug product has been stored at a temperature of between 2° C. and 8° C. for between 18 and 36 months. | 1,600 |
1,453 | 15,292,021 | 1,631 | Systems and methods are presented that allow for predicting treatment response of a tumor to a checkpoint inhibitor. In one exemplary aspect, the treatment response is directly associated with a relatively high number of patient- and tumor-specific immunologically visible neoepitopes. Specific mutational patterns in the nucleic acid encoding the neoepitope may be further indicative of treatment response. | 1. A method of improving treatment of a cancer using immunotherapy, comprising:
obtaining from a patient omics data from a tumor tissue and a matched normal tissue, and using the omics data to determine a plurality of missense based patient- and tumor-specific neoepitopes; filtering the neoepitopes to obtain HLA-matched neoepitopes, and quantifying the HLA-matched neoepitopes; and administering a checkpoint inhibitor to the patient upon determination that the quantity of HLA-matched neoepitopes has exceeded a predetermined threshold quantity. 2. The method of claim 1 wherein the step of filtering the neoepitopes is performed for each of the neoepitopes using a plurality of distinct individual neoepitope sequences in which a changed amino acid has a distinct position within the neoepitope sequence. 3. The method of claim 2 wherein the individual neoepitope sequences have a length of between 7 and 20 amino acids. 4. The method of claim 1 wherein the step of filtering further comprises a step of filtering by at least one of an a priori known molecular variation selected from the group consisting of a single nucleotide polymorphism, a short deletion and insertion polymorphism, a microsatellite marker, a short tandem repeat, a heterozygous sequence, a multinucleotide polymorphism, and a named variant. 5. The method of claim 1 wherein the step of filtering comprises determination of affinity of the neoepitopes to at least one MHC Class I sub-type and to at least one MHC Class II sub-type of the patient. 6. The method of claim 1 wherein the step of filtering further comprises a determination of expression level of the neoepitope. 7. The method of claim 1 wherein the HLA-matched neoepitopes have an affinity to at least one MHC Class I sub-type or to at least one MHC Class II sub-type of the patient of equal or less than 150 nM. 8. The method of claim 1 wherein the step of quantifying the HLA-matched neoepitopes comprises quantification of affinity of the neoepitopes to at least one MHC Class I sub-type or to at least one MHC Class II sub-type of the patient, and determination of a total number of HLA-matched neoepitopes. 9. The method claim 1 further comprising a step of filtering the HLA-matched neoepitopes by a mutation signature. 10. The method of claim 9 wherein the mutation signature is a signature characteristic for UV-induced DNA damage or smoking-induced DNA damage. 11. The method of claim 1 wherein the predetermined threshold quantity of HLA-matched neoepitopes is at least 100 HLA-matched neoepitopes. 12. The method of claim 11 wherein the at least 100 HLA-matched neoepitopes have an affinity to at least one MHC Class I sub-type or to at least one MHC Class II sub-type of the patient of equal or less than 150 nM. 13. The method of claim 1 further comprising a step of using the omics data to detect microsatellite instability (MSI) in the diseased tissue. 14. The method of claim 1 further comprising a step of using the omics data to detect defective mismatch repair (MMR) in the diseased tissue. 15. The method of claim 1 wherein the checkpoint inhibitor is a CTLA-4 inhibitor or a PD-1 inhibitor. 16. A method of predicting positive treatment response of a tumor to a checkpoint inhibitor, comprising:
obtaining from a patient omics data from a tumor tissue and a matched normal tissue, and using the omics data to determine a plurality of missense based patient- and tumor-specific neoepitopes; filtering the neoepitopes to obtain HLA-matched neoepitopes, and quantifying the HLA-matched neoepitopes; and determining, upon ascertaining that the quantity of HLA-matched neoepitopes has exceeded a predetermined threshold quantity, that the tumor is responsive to treatment with the checkpoint inhibitor. 17. The method of claim 16 further comprising a step of filtering the HLA-matched neoepitopes by a mutation signature. 18. The method of claim 16 further comprising a step of using the omics data to detect at least one of microsatellite instability (MSI) and defective mismatch repair (MMR) in the diseased tissue. 19. A method of predicting positive treatment response of a tumor to a checkpoint inhibitor, comprising
obtaining from a patient omics data from a tumor tissue and a matched normal tissue, and using the omics data to determine a plurality of missense based patient- and tumor-specific neoepitopes; filtering the neoepitopes to obtain HLA-matched neoepitopes, and quantifying the HLA-matched neoepitopes; identifying a mutation signature for the quantified HLA-matched neoepitopes; and using the quantity of neoepitopes and the mutation signature as determinants for positive treatment response of the tumor to the checkpoint inhibitor. 20. The method of claim 19 wherein the mutation signature is characteristic for UV-induced DNA damage or smoking-induced DNA damage. | Systems and methods are presented that allow for predicting treatment response of a tumor to a checkpoint inhibitor. In one exemplary aspect, the treatment response is directly associated with a relatively high number of patient- and tumor-specific immunologically visible neoepitopes. Specific mutational patterns in the nucleic acid encoding the neoepitope may be further indicative of treatment response.1. A method of improving treatment of a cancer using immunotherapy, comprising:
obtaining from a patient omics data from a tumor tissue and a matched normal tissue, and using the omics data to determine a plurality of missense based patient- and tumor-specific neoepitopes; filtering the neoepitopes to obtain HLA-matched neoepitopes, and quantifying the HLA-matched neoepitopes; and administering a checkpoint inhibitor to the patient upon determination that the quantity of HLA-matched neoepitopes has exceeded a predetermined threshold quantity. 2. The method of claim 1 wherein the step of filtering the neoepitopes is performed for each of the neoepitopes using a plurality of distinct individual neoepitope sequences in which a changed amino acid has a distinct position within the neoepitope sequence. 3. The method of claim 2 wherein the individual neoepitope sequences have a length of between 7 and 20 amino acids. 4. The method of claim 1 wherein the step of filtering further comprises a step of filtering by at least one of an a priori known molecular variation selected from the group consisting of a single nucleotide polymorphism, a short deletion and insertion polymorphism, a microsatellite marker, a short tandem repeat, a heterozygous sequence, a multinucleotide polymorphism, and a named variant. 5. The method of claim 1 wherein the step of filtering comprises determination of affinity of the neoepitopes to at least one MHC Class I sub-type and to at least one MHC Class II sub-type of the patient. 6. The method of claim 1 wherein the step of filtering further comprises a determination of expression level of the neoepitope. 7. The method of claim 1 wherein the HLA-matched neoepitopes have an affinity to at least one MHC Class I sub-type or to at least one MHC Class II sub-type of the patient of equal or less than 150 nM. 8. The method of claim 1 wherein the step of quantifying the HLA-matched neoepitopes comprises quantification of affinity of the neoepitopes to at least one MHC Class I sub-type or to at least one MHC Class II sub-type of the patient, and determination of a total number of HLA-matched neoepitopes. 9. The method claim 1 further comprising a step of filtering the HLA-matched neoepitopes by a mutation signature. 10. The method of claim 9 wherein the mutation signature is a signature characteristic for UV-induced DNA damage or smoking-induced DNA damage. 11. The method of claim 1 wherein the predetermined threshold quantity of HLA-matched neoepitopes is at least 100 HLA-matched neoepitopes. 12. The method of claim 11 wherein the at least 100 HLA-matched neoepitopes have an affinity to at least one MHC Class I sub-type or to at least one MHC Class II sub-type of the patient of equal or less than 150 nM. 13. The method of claim 1 further comprising a step of using the omics data to detect microsatellite instability (MSI) in the diseased tissue. 14. The method of claim 1 further comprising a step of using the omics data to detect defective mismatch repair (MMR) in the diseased tissue. 15. The method of claim 1 wherein the checkpoint inhibitor is a CTLA-4 inhibitor or a PD-1 inhibitor. 16. A method of predicting positive treatment response of a tumor to a checkpoint inhibitor, comprising:
obtaining from a patient omics data from a tumor tissue and a matched normal tissue, and using the omics data to determine a plurality of missense based patient- and tumor-specific neoepitopes; filtering the neoepitopes to obtain HLA-matched neoepitopes, and quantifying the HLA-matched neoepitopes; and determining, upon ascertaining that the quantity of HLA-matched neoepitopes has exceeded a predetermined threshold quantity, that the tumor is responsive to treatment with the checkpoint inhibitor. 17. The method of claim 16 further comprising a step of filtering the HLA-matched neoepitopes by a mutation signature. 18. The method of claim 16 further comprising a step of using the omics data to detect at least one of microsatellite instability (MSI) and defective mismatch repair (MMR) in the diseased tissue. 19. A method of predicting positive treatment response of a tumor to a checkpoint inhibitor, comprising
obtaining from a patient omics data from a tumor tissue and a matched normal tissue, and using the omics data to determine a plurality of missense based patient- and tumor-specific neoepitopes; filtering the neoepitopes to obtain HLA-matched neoepitopes, and quantifying the HLA-matched neoepitopes; identifying a mutation signature for the quantified HLA-matched neoepitopes; and using the quantity of neoepitopes and the mutation signature as determinants for positive treatment response of the tumor to the checkpoint inhibitor. 20. The method of claim 19 wherein the mutation signature is characteristic for UV-induced DNA damage or smoking-induced DNA damage. | 1,600 |
1,454 | 14,788,908 | 1,617 | The present disclosure provides pharmaceutical compositions that provide immediate release of active ingredients and have abuse deterrent properties. In particular, the pharmaceutical compositions comprise at least one pharmaceutically active ingredient, at least one non-cellulose polysaccharide, at least one hydrophilic gelling polymer, and an effervescent system. | 1. A pharmaceutical composition comprising at least one active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt thereof, at least one non-cellulose polysaccharide, at least one hydrophilic gelling polymer, and an effervescent system. 2. The pharmaceutical composition of claim 1, wherein at least about 70% of the API is released within about 45 minutes when dissolution is measured using an USP-approved in vitro release procedure. 3. The pharmaceutical composition of claim 1, wherein a plurality of particles having an average diameter greater than about 250 microns is formed when the composition is crushed, ground, or pulverized. 4. The pharmaceutical composition of claim 1, wherein the non-cellulose polysaccharide is a natural gum, hemicellulose, pectin, chitin, starch, or a combination thereof; and the non-cellulose polysaccharide is present in an amount from about 2% to about 60% by weight of the pharmaceutical composition. 5. The pharmaceutical composition of claim 1, wherein the hydrophilic gelling polymer is a cellulose ether, a polyalkylene oxide, a polyacrylic acid, or a combination thereof; and the hydrophilic gelling polymer is present in an amount from about 5% to about 80% by weight of the pharmaceutical composition. 6. The pharmaceutical composition of claim 1, wherein the effervescent system comprises a) an acid component chosen from an organic acid, an inorganic acid, or a combination thereof, and b) a base component chosen from an alkali metal bicarbonate, an alkaline earth metal bicarbonate, an alkali metal carbonate, an organic carbonate, or a combination thereof; and the effervescent system is present in an amount from about 20% to about 90% by weight of the pharmaceutical composition. 7. The pharmaceutical composition of claim 1, wherein the API is an opioid or a combination of an opioid and a non-opioid analgesic, and the opioid is oxycodone, oxymorphone, hydrocodone, hydromorphone, codeine, or morphine. 8. The pharmaceutical composition of claim 1, wherein the non-cellulose polysaccharide is glucomannan, xanthan gum, or a combination thereof; the hydrophilic gelling polymer is polyethylene oxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, or a combination thereof; and the effervescent system comprises a) an acid component comprising an organic acid and b) a base component comprising an alkali metal bicarbonate. 9. The pharmaceutical composition of claim 8, wherein the non-cellulose polysaccharide is present in an amount from about 5% to about 40% by weight of the pharmaceutical composition; the hydrophilic gelling polymer is present in an amount from about 10% to about 50% by weight of the pharmaceutical composition; and the effervescent system is present in an amount from about 30% to about 60% by weight of the pharmaceutical composition. 10. The pharmaceutical composition of claim 9, wherein the API is oxycodone, oxymorphone, hydrocodone, hydromorphone, codeine, or morphine. 11. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a solid dosage form. 12. The pharmaceutical composition of claim 11, wherein the solid dosage form is prepared by a process comprising:
a) forming a mixture comprising the API or pharmaceutically acceptable salt thereof, the non-cellulose polysaccharide, the hydrophilic gelling polymer, and the effervescent system; b) forming the mixture into a solid dosage unit; and c) heating the solid dosage unit to yield the solid dosage form. 13. An abuse deterrent solid dosage form comprising at least one active pharmaceutical ingredient (API) susceptible to abuse or a pharmaceutically acceptable salt thereof, at least one natural gum, at least one hydrophilic gelling polymer, and an effervescent system. 14. The abuse deterrent solid dosage form of claim 13, wherein the solid dosage from is resistant to crushing, grinding, cutting, or pulverizing to form a fine powder and is resistant to extraction with an aqueous solvent. 15. The abuse deterrent solid dosage form of claim 13, wherein at least about 70% of the API is released within about 45 minutes when dissolution is measured using an USP-approved in vitro release procedure. 16. The abuse deterrent solid dosage form of claim 13, wherein the gum is glucomannan, xanthan gum, or a combination thereof; the hydrophilic gelling polymer is polyethylene oxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, or a combination thereof; and the effervescent system comprises an organic acid and an alkali metal bicarbonate. 17. The abuse deterrent solid dosage form of claim 16, wherein the natural gum is present in an amount from about 5% to about 40% by weight of the solid dosage form; the hydrophilic gelling polymer is present in an amount from about 10% to about 50% by weight of the solid dosage form; and the effervescent system is present in an amount from about 30% to about 60% by weight of the solid dosage form. 18. The abuse deterrent solid dosage form of claim 17, wherein the API is an opioid or a combination of an opioid and a non-opioid analgesic, and the opioid is oxycodone, oxymorphone, hydrocodone, hydromorphone, codeine, or morphine. 19. The abuse deterrent solid dosage of claim 18, wherein the API is oxycodone. 20. The abuse deterrent solid dosage form of claim 13, wherein the solid dosage form is cured by heating at a temperature of less than about 90° C. | The present disclosure provides pharmaceutical compositions that provide immediate release of active ingredients and have abuse deterrent properties. In particular, the pharmaceutical compositions comprise at least one pharmaceutically active ingredient, at least one non-cellulose polysaccharide, at least one hydrophilic gelling polymer, and an effervescent system.1. A pharmaceutical composition comprising at least one active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt thereof, at least one non-cellulose polysaccharide, at least one hydrophilic gelling polymer, and an effervescent system. 2. The pharmaceutical composition of claim 1, wherein at least about 70% of the API is released within about 45 minutes when dissolution is measured using an USP-approved in vitro release procedure. 3. The pharmaceutical composition of claim 1, wherein a plurality of particles having an average diameter greater than about 250 microns is formed when the composition is crushed, ground, or pulverized. 4. The pharmaceutical composition of claim 1, wherein the non-cellulose polysaccharide is a natural gum, hemicellulose, pectin, chitin, starch, or a combination thereof; and the non-cellulose polysaccharide is present in an amount from about 2% to about 60% by weight of the pharmaceutical composition. 5. The pharmaceutical composition of claim 1, wherein the hydrophilic gelling polymer is a cellulose ether, a polyalkylene oxide, a polyacrylic acid, or a combination thereof; and the hydrophilic gelling polymer is present in an amount from about 5% to about 80% by weight of the pharmaceutical composition. 6. The pharmaceutical composition of claim 1, wherein the effervescent system comprises a) an acid component chosen from an organic acid, an inorganic acid, or a combination thereof, and b) a base component chosen from an alkali metal bicarbonate, an alkaline earth metal bicarbonate, an alkali metal carbonate, an organic carbonate, or a combination thereof; and the effervescent system is present in an amount from about 20% to about 90% by weight of the pharmaceutical composition. 7. The pharmaceutical composition of claim 1, wherein the API is an opioid or a combination of an opioid and a non-opioid analgesic, and the opioid is oxycodone, oxymorphone, hydrocodone, hydromorphone, codeine, or morphine. 8. The pharmaceutical composition of claim 1, wherein the non-cellulose polysaccharide is glucomannan, xanthan gum, or a combination thereof; the hydrophilic gelling polymer is polyethylene oxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, or a combination thereof; and the effervescent system comprises a) an acid component comprising an organic acid and b) a base component comprising an alkali metal bicarbonate. 9. The pharmaceutical composition of claim 8, wherein the non-cellulose polysaccharide is present in an amount from about 5% to about 40% by weight of the pharmaceutical composition; the hydrophilic gelling polymer is present in an amount from about 10% to about 50% by weight of the pharmaceutical composition; and the effervescent system is present in an amount from about 30% to about 60% by weight of the pharmaceutical composition. 10. The pharmaceutical composition of claim 9, wherein the API is oxycodone, oxymorphone, hydrocodone, hydromorphone, codeine, or morphine. 11. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a solid dosage form. 12. The pharmaceutical composition of claim 11, wherein the solid dosage form is prepared by a process comprising:
a) forming a mixture comprising the API or pharmaceutically acceptable salt thereof, the non-cellulose polysaccharide, the hydrophilic gelling polymer, and the effervescent system; b) forming the mixture into a solid dosage unit; and c) heating the solid dosage unit to yield the solid dosage form. 13. An abuse deterrent solid dosage form comprising at least one active pharmaceutical ingredient (API) susceptible to abuse or a pharmaceutically acceptable salt thereof, at least one natural gum, at least one hydrophilic gelling polymer, and an effervescent system. 14. The abuse deterrent solid dosage form of claim 13, wherein the solid dosage from is resistant to crushing, grinding, cutting, or pulverizing to form a fine powder and is resistant to extraction with an aqueous solvent. 15. The abuse deterrent solid dosage form of claim 13, wherein at least about 70% of the API is released within about 45 minutes when dissolution is measured using an USP-approved in vitro release procedure. 16. The abuse deterrent solid dosage form of claim 13, wherein the gum is glucomannan, xanthan gum, or a combination thereof; the hydrophilic gelling polymer is polyethylene oxide, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, or a combination thereof; and the effervescent system comprises an organic acid and an alkali metal bicarbonate. 17. The abuse deterrent solid dosage form of claim 16, wherein the natural gum is present in an amount from about 5% to about 40% by weight of the solid dosage form; the hydrophilic gelling polymer is present in an amount from about 10% to about 50% by weight of the solid dosage form; and the effervescent system is present in an amount from about 30% to about 60% by weight of the solid dosage form. 18. The abuse deterrent solid dosage form of claim 17, wherein the API is an opioid or a combination of an opioid and a non-opioid analgesic, and the opioid is oxycodone, oxymorphone, hydrocodone, hydromorphone, codeine, or morphine. 19. The abuse deterrent solid dosage of claim 18, wherein the API is oxycodone. 20. The abuse deterrent solid dosage form of claim 13, wherein the solid dosage form is cured by heating at a temperature of less than about 90° C. | 1,600 |
1,455 | 16,011,118 | 1,658 | compositions and kits comprising this compound and their use for preventing or treating pain, or inducing hypothermia or hypotension. | 1. A compound of formula (I)
wherein:
(i) X is —CH and R1=H; or
X is N and R1 is H, (C1-12)alkyl, (C4-C14)aralkyl, SO2(C3-C7) aryl, —SO2(C1-12)alkyl, —SO2aralkyl, —CO(C1-12)alkyl, CO(C4-C14)aralkyl, or —C(═NH)NH2;
(ii) R2 is H or —CH3; and R3 is H, —NH2, —NHalkyl, NHaralkyl, —NHCOalkyl, —NHSO2aryl, or —NH(C═NH)NH2; or
R2 is H, —NH2, —NHalkyl, NHaralkyl, —NHCOalkyl, —NHSO2aryl, or —NH(C═NH)NH2; and R3 is H or —CH3;
(iii) R4, R7, R8 and R9 are each independently H, (C1-12)alkyl, or (C4-C14)aralkyl;
(iv) R5 is H or —CH3; and R6 is —(CH2)pNHR20 or the side chin of histidine; or
R6 is H or —CH3; and R5 is —(CH2)pNHR20 or the side chain of histidine,
wherein p is 1-5; and R20 is H, —C(═NH)—NH2, (C1-12)alkyl, or (C4-C12)aralkyl;
(v) R10 is H, benzyl, (C4-C14)aralkyl, or (C1-12)alkyl;
(vi) R11 is H or —CH3; and R12 is —CH2Si(CH3)3, or the side chain of a valine, alanine, glycine, leucine, isoleucine, allo-isoleucine, tert-butyl glycine, tert-butyl alanine, cyclohexylglycine, cyclopentylglycine, cyclobutylglycine, cyclopropylglycine, norvaline or norleucine; or
R12 is H or —CH3; and R11 is —CH2Si(CH3)3, or the side chain of a valine, alanine, glycine, leucine, isoleucine, allo-isoleucine, tert-butyl glycine, tert-butyl alanine, cyclohexylglycine, cyclopentylglycine, cyclobutylglycine, cyclopropylglycine, norvaline or norleucine;
(vii) R13 is H or —CH3; and R14 is the side chain of a valine, alanine, glycine, leucine, isoleucine, allo-isoleucine, tert-butyl glycine, tert-butyl alanine, cyclohexylalanine, cyclopentylalanine, cyclobutylalanine, cyclopropylalanine, norvaline or norleucine; or
R14 is H or —CH3; and R13 is the side chain of a valine, alanine, glycine, leucine, isoleucine, allo-isoleucine, tert-butyl glycine, tert-butyl alanine, cyclohexylalanine, cyclopentylalanine, cyclobutylalanine, cyclopropylalanine, norvaline or norleucine;
(viii) R15 is H or —CH3;
(ix) R16 is H, (C1-C12)alkyl, (C4-C14)aralkyl, or C(═O)R21, wherein R21 is (C1-C12)alkyl or (C4-C14)aralkyl;
(x) R17 is H or —CH3;
(xi) R18 is H or —CH3; and R19 is H, —OH, (C1-C10)alkyl, —(C1-C10)Oalkyl or —(C1-C10)NHalkyl; or
R19 is H or —CH3; and R18 is H, —OH, (C1-C10)alkyl, —(C1-C10)Oalkyl or —(C1-C10)NHalkyl;
(xii) m is 1-4;
(xiii) n is 0-4;
(xiv) q is 0-3;
(xv) r is 0-3;
(xvi) s is 0-3;
(xvii) Y is —CH═CH— (E or Z), —CH2—CH2—, or —C≡C—;
(xviii) W is O, —NH or S; and
(xix) Z1, Z2 and Z3 are each independently ═O or absent,
or an ester, solvate, hydrate or pharmaceutical salt thereof. 2. The compound of claim 1, wherein:
(iv) R5 is H or —CH3; and R6 is —(CH2)pNHR20, wherein p and R20 are as defined in claim 1 or is the side chain of histidine; (vi) R11 is H or —CH3; and R12 is —CH2Si(CH3)3, or the side chain of a valine, alanine, glycine, leucine, isoleucine, allo-isoleucine, tert-butyl glycine, tert-butyl alanine, cyclohexylglycine, cyclopentylglycine, cyclobutylglycine, cyclopropylglycine, norvaline or norleucine; (vii) R13 is H or —CH3; and R14 is the side chain of a valine, alanine, glycine, leucine, isoleucine, allo-isoleucine, tert-butyl glycine, tert-butyl alanine, cyclohexylalanine, cyclopentylalanine, cyclobutylalanine, cyclopropylalanine, norvaline or norleucine; (viii) R15 is (S)—H (S) or (S)—CH3; and (x) R17 is (S)—H (S) or (S)—CH3. 3. The compound of claim 1, wherein R12 is the side chain of a leucine, isoleucine, allo-isoleucine, tert-butyl glycine, tert-butyl alanine, cyclohexylglycine, cyclopentylglycine, cyclobutylglycine, cyclopropylglycine, norvaline or norleucine. 4. The compound of claim 1, wherein R13 is the side chain of a leucine, isoleucine, allo-isoleucine, tert-butyl glycine, tert-butyl alanine, cyclohexylalanine, cyclopentylalanine, cyclobutylalanine, cyclopropylalanine, norvaline or norleucine. 5. The compound of claim 1, wherein:
(iii) R4, R7, R8 and R9 are each H; (iv) R5 is H; and R6 is —(CH2)pNHR20;
wherein p is 3 or 4; and R20 is H or —C(═NH)—NH2 or R6 is the side chain of histidine;
(vi) R11 is H; and R12 is the side chain of an isoleucine; (vii) R13 is H; and R14 is the side chain of a leucine; (viii) R15 is H; (x) R17 is H; (xi) R18 and R19 are each H; (xiv) q is 1; (xv) r is 1; (xvi) s is 1; (xvii) Y is —CH═CH—; (xviii) W is O; and/or (xix) Z1, Z2 and Z3 are each ═O, or an ester, solvate, hydrate or pharmaceutical salt thereof. 6. The compound of claim 1, wherein:
(iv) R5 is H; and R6 is —(CH2)pNHR20; wherein p is 4; and R20 is H or R6 is the side chain of a histidine. 7. The compound of claim 1, wherein:
(iv) R5 is H; and R6 is —(CH2)pNHR20; wherein p is 3; and R20 is —C(═NH)—NH2. 8. The compound of claim 1, wherein:
(iv) R5 is H; and R6 is is the side chain of a histidine 9. The composition of claim 1, wherein the compound is of formula (Ia)
wherein X, R1, R2, R3, n and m are as defined in claim 1,
or an ester, solvate, hydrate or pharmaceutical salt thereof. 10. The compound of claim 1, wherein X is N and R1 is H, (C1-12)alkyl, (C4-C14)aralkyl, —SO2(C3-C7)aryl, —SO2(C1-12)alkyl, —SO2aralkyl, —CO(C1-12)alkyl, CO(C4-C14)aralkyl, or —C(═NH)NH2. 11. The compound of claim 1, wherein R1 is H. 12. The compound of claim 1, wherein R1 is S(═O)2(o-nitrophenyl). 13. The compound of claim 1, wherein X is CH and R1 is H. 14. The compound of claim 13, wherein n+m=3 15. The compound of claim 1, wherein n is 1-3. 16. The compound of claim 1, wherein n is 0. 17. The compound of claim 1, wherein n is 1. 18. The compound of claim 1, wherein n is 2. 19. The compound of claim 1, wherein n is 3. 20. The compound of claim 1, wherein m is 1-3. 21. The compound of claim 1, wherein m is 1. 22. The compound of claim 1, wherein m is 2. 23. The compound of claim 1, wherein m is 3. 24. The compound of claim 1, wherein
R2 is H; and/or R3 is H or CH3. 25. The compound of claim 1, wherein
R2 is —NH2; and/or R3 is H or CH3. 26. The compound of claim 1, wherein R2 is —NH2 and R3 is H. 27. The compound of claim 1, wherein R2 and R3 are H. 28. The compound of claim 1, wherein the compound is:
or an ester, solvate, hydrate or pharmaceutical salt thereof. 29. A composition comprising (a) the compound defined claim 1 and (b) (i) at least another compound defined in claim 1; (ii) another antalgic agent; (iii) an anxiolytic agent; (iv) an antidepressant agent; (v) a pharmaceutically acceptable carrier; or (vi) a combination of at least two of (i) and (v). 30. A method of (a) preventing or treating pain; (b) reducing body temperature; and/or (c) inducing hypotension, in a subject in need thereof, comprising administering to the subject an effective amount of the compound defined in claim 1, or a composition comprising the compound and a pharmaceutically acceptable carrier. | compositions and kits comprising this compound and their use for preventing or treating pain, or inducing hypothermia or hypotension.1. A compound of formula (I)
wherein:
(i) X is —CH and R1=H; or
X is N and R1 is H, (C1-12)alkyl, (C4-C14)aralkyl, SO2(C3-C7) aryl, —SO2(C1-12)alkyl, —SO2aralkyl, —CO(C1-12)alkyl, CO(C4-C14)aralkyl, or —C(═NH)NH2;
(ii) R2 is H or —CH3; and R3 is H, —NH2, —NHalkyl, NHaralkyl, —NHCOalkyl, —NHSO2aryl, or —NH(C═NH)NH2; or
R2 is H, —NH2, —NHalkyl, NHaralkyl, —NHCOalkyl, —NHSO2aryl, or —NH(C═NH)NH2; and R3 is H or —CH3;
(iii) R4, R7, R8 and R9 are each independently H, (C1-12)alkyl, or (C4-C14)aralkyl;
(iv) R5 is H or —CH3; and R6 is —(CH2)pNHR20 or the side chin of histidine; or
R6 is H or —CH3; and R5 is —(CH2)pNHR20 or the side chain of histidine,
wherein p is 1-5; and R20 is H, —C(═NH)—NH2, (C1-12)alkyl, or (C4-C12)aralkyl;
(v) R10 is H, benzyl, (C4-C14)aralkyl, or (C1-12)alkyl;
(vi) R11 is H or —CH3; and R12 is —CH2Si(CH3)3, or the side chain of a valine, alanine, glycine, leucine, isoleucine, allo-isoleucine, tert-butyl glycine, tert-butyl alanine, cyclohexylglycine, cyclopentylglycine, cyclobutylglycine, cyclopropylglycine, norvaline or norleucine; or
R12 is H or —CH3; and R11 is —CH2Si(CH3)3, or the side chain of a valine, alanine, glycine, leucine, isoleucine, allo-isoleucine, tert-butyl glycine, tert-butyl alanine, cyclohexylglycine, cyclopentylglycine, cyclobutylglycine, cyclopropylglycine, norvaline or norleucine;
(vii) R13 is H or —CH3; and R14 is the side chain of a valine, alanine, glycine, leucine, isoleucine, allo-isoleucine, tert-butyl glycine, tert-butyl alanine, cyclohexylalanine, cyclopentylalanine, cyclobutylalanine, cyclopropylalanine, norvaline or norleucine; or
R14 is H or —CH3; and R13 is the side chain of a valine, alanine, glycine, leucine, isoleucine, allo-isoleucine, tert-butyl glycine, tert-butyl alanine, cyclohexylalanine, cyclopentylalanine, cyclobutylalanine, cyclopropylalanine, norvaline or norleucine;
(viii) R15 is H or —CH3;
(ix) R16 is H, (C1-C12)alkyl, (C4-C14)aralkyl, or C(═O)R21, wherein R21 is (C1-C12)alkyl or (C4-C14)aralkyl;
(x) R17 is H or —CH3;
(xi) R18 is H or —CH3; and R19 is H, —OH, (C1-C10)alkyl, —(C1-C10)Oalkyl or —(C1-C10)NHalkyl; or
R19 is H or —CH3; and R18 is H, —OH, (C1-C10)alkyl, —(C1-C10)Oalkyl or —(C1-C10)NHalkyl;
(xii) m is 1-4;
(xiii) n is 0-4;
(xiv) q is 0-3;
(xv) r is 0-3;
(xvi) s is 0-3;
(xvii) Y is —CH═CH— (E or Z), —CH2—CH2—, or —C≡C—;
(xviii) W is O, —NH or S; and
(xix) Z1, Z2 and Z3 are each independently ═O or absent,
or an ester, solvate, hydrate or pharmaceutical salt thereof. 2. The compound of claim 1, wherein:
(iv) R5 is H or —CH3; and R6 is —(CH2)pNHR20, wherein p and R20 are as defined in claim 1 or is the side chain of histidine; (vi) R11 is H or —CH3; and R12 is —CH2Si(CH3)3, or the side chain of a valine, alanine, glycine, leucine, isoleucine, allo-isoleucine, tert-butyl glycine, tert-butyl alanine, cyclohexylglycine, cyclopentylglycine, cyclobutylglycine, cyclopropylglycine, norvaline or norleucine; (vii) R13 is H or —CH3; and R14 is the side chain of a valine, alanine, glycine, leucine, isoleucine, allo-isoleucine, tert-butyl glycine, tert-butyl alanine, cyclohexylalanine, cyclopentylalanine, cyclobutylalanine, cyclopropylalanine, norvaline or norleucine; (viii) R15 is (S)—H (S) or (S)—CH3; and (x) R17 is (S)—H (S) or (S)—CH3. 3. The compound of claim 1, wherein R12 is the side chain of a leucine, isoleucine, allo-isoleucine, tert-butyl glycine, tert-butyl alanine, cyclohexylglycine, cyclopentylglycine, cyclobutylglycine, cyclopropylglycine, norvaline or norleucine. 4. The compound of claim 1, wherein R13 is the side chain of a leucine, isoleucine, allo-isoleucine, tert-butyl glycine, tert-butyl alanine, cyclohexylalanine, cyclopentylalanine, cyclobutylalanine, cyclopropylalanine, norvaline or norleucine. 5. The compound of claim 1, wherein:
(iii) R4, R7, R8 and R9 are each H; (iv) R5 is H; and R6 is —(CH2)pNHR20;
wherein p is 3 or 4; and R20 is H or —C(═NH)—NH2 or R6 is the side chain of histidine;
(vi) R11 is H; and R12 is the side chain of an isoleucine; (vii) R13 is H; and R14 is the side chain of a leucine; (viii) R15 is H; (x) R17 is H; (xi) R18 and R19 are each H; (xiv) q is 1; (xv) r is 1; (xvi) s is 1; (xvii) Y is —CH═CH—; (xviii) W is O; and/or (xix) Z1, Z2 and Z3 are each ═O, or an ester, solvate, hydrate or pharmaceutical salt thereof. 6. The compound of claim 1, wherein:
(iv) R5 is H; and R6 is —(CH2)pNHR20; wherein p is 4; and R20 is H or R6 is the side chain of a histidine. 7. The compound of claim 1, wherein:
(iv) R5 is H; and R6 is —(CH2)pNHR20; wherein p is 3; and R20 is —C(═NH)—NH2. 8. The compound of claim 1, wherein:
(iv) R5 is H; and R6 is is the side chain of a histidine 9. The composition of claim 1, wherein the compound is of formula (Ia)
wherein X, R1, R2, R3, n and m are as defined in claim 1,
or an ester, solvate, hydrate or pharmaceutical salt thereof. 10. The compound of claim 1, wherein X is N and R1 is H, (C1-12)alkyl, (C4-C14)aralkyl, —SO2(C3-C7)aryl, —SO2(C1-12)alkyl, —SO2aralkyl, —CO(C1-12)alkyl, CO(C4-C14)aralkyl, or —C(═NH)NH2. 11. The compound of claim 1, wherein R1 is H. 12. The compound of claim 1, wherein R1 is S(═O)2(o-nitrophenyl). 13. The compound of claim 1, wherein X is CH and R1 is H. 14. The compound of claim 13, wherein n+m=3 15. The compound of claim 1, wherein n is 1-3. 16. The compound of claim 1, wherein n is 0. 17. The compound of claim 1, wherein n is 1. 18. The compound of claim 1, wherein n is 2. 19. The compound of claim 1, wherein n is 3. 20. The compound of claim 1, wherein m is 1-3. 21. The compound of claim 1, wherein m is 1. 22. The compound of claim 1, wherein m is 2. 23. The compound of claim 1, wherein m is 3. 24. The compound of claim 1, wherein
R2 is H; and/or R3 is H or CH3. 25. The compound of claim 1, wherein
R2 is —NH2; and/or R3 is H or CH3. 26. The compound of claim 1, wherein R2 is —NH2 and R3 is H. 27. The compound of claim 1, wherein R2 and R3 are H. 28. The compound of claim 1, wherein the compound is:
or an ester, solvate, hydrate or pharmaceutical salt thereof. 29. A composition comprising (a) the compound defined claim 1 and (b) (i) at least another compound defined in claim 1; (ii) another antalgic agent; (iii) an anxiolytic agent; (iv) an antidepressant agent; (v) a pharmaceutically acceptable carrier; or (vi) a combination of at least two of (i) and (v). 30. A method of (a) preventing or treating pain; (b) reducing body temperature; and/or (c) inducing hypotension, in a subject in need thereof, comprising administering to the subject an effective amount of the compound defined in claim 1, or a composition comprising the compound and a pharmaceutically acceptable carrier. | 1,600 |
1,456 | 16,176,458 | 1,618 | The present invention relates to customized implants for bone replacement that are prepared from poly(ether ketone ketone) or PEKK, and to a computer-based imaging and rapid prototyping (RP)-based manufacturing method for the design and manufacture of these customized implants. The PEKK customized implants made using rapid prototyping demonstrate biomechanical properties similar (if not identical) to that of natural bone even when prepared without the use of processing aids such as carbon black and aluminum powder. | 1. A method of forming an implant for use in a mammal, the method comprising the steps of:
providing a model of an implant; providing a powder comprising polyetherketoneketone (PEKK) and excluding calcium phosphate; forming the implant by selective laser sintering the powder in accordance with the model of the implant. 2. The method of claim 1, wherein the step of forming the implant by selective laser sintering comprises the steps of:
applying a layer of the powder on a bed of a laser sintering machine; solidifying selected points of the applied layer of powder by irradiation in accordance with a corresponding layer of the model; successively repeating the step of applying the powder and the step of solidifying the applied layer of powder until a plurality of cross sections of the implant are solidified. 3. The method of claim 2, wherein the selective laser sintering further comprises the step of:
maintaining a bed temperature between 280 degrees Celsius and 350 degrees Celsius during the successive steps of powder application and solidification. 4. The method of claim 2, wherein the powder comprises a semi-crystalline PEKK powder having a crystallinity between 15% and 90% as determined by DSC and an average particle size between 10 to 150 microns. 5. The method of claim 4, wherein the powder has a crystallinity between 15% and 35% as determined by DSC and an average particle size between 50 to 70 microns. 6. The method of claim of claim 2, wherein the powder comprises a quasi-amorphous PEKK powder having a crystallinity of 2% or less as determined by DSC, and wherein the powder has an average particle size between 50 to 70 microns. 7. The method of claim 6, wherein the selective laser sintering further comprises the step of maintaining a bed temperature between 280 degrees Celsius and 350 degrees Celsius during the successive steps of powder application and solidification. 8. The method of claim 2 wherein the step of selectively laser sintering forms a mechanical fastener interface in a surface of the implant. 9. The method of claim 2 wherein the powder consists essentially of PEKK. 10. The implant of claim 2, wherein the implant replaces a load-bearing bone. 11. The implant 2, wherein the implant replaces a portion of a spine, a long bone of an arm or a leg, a hip bone, or a cranial bone. 12. The method of claim 2, wherein the step of providing the model comprises the steps of:
(a) scanning a patient to obtain tomographic information; (b) designing a bone implant model using from the tomographic information obtained from the patient. 13. A method of forming an implant for use in a mammal, the method comprising the steps of:
providing a model of an implant; providing a powder for manufacturing the implant, the powder comprising a a semi-crystalline polyetherketoneketone PEKK powder having a crystallinity between 15% and 90% and excluding calcium phosphate, the powder having an average particle size of between 50 to 70 microns; forming the implant by selective laser sintering the powder in accordance with the implant model, the step of forming the implant by selective laser sintering comprises the following steps:
applying a layer of the powder on a bed of a laser sintering machine;
solidifying selected points of the applied layer of powder by irradiation in accordance with a corresponding layer of the model;
successively repeating the step of applying the powder and the step of solidifying the applied layer of powder until a plurality of cross sections of the implant are solidified;
maintaining a bed temperature between 280 degrees Celsius and 295 degrees Celsius during the successive steps of powder application and solidification. 14. The method of claim 13 wherein the step of selectively laser sintering forms a mechanical fastener interface in a surface of the implant. 15. The method of claim 13 wherein the powder consists essentially of PEKK. 16. The method of claim 13, wherein the implant replaces a spine bone or a cranial bone. 17. An implant for use in a mammal, the implant comprising laser sintered polyetherketoneketone (PEKK) and excluding calcium phosphate. 18. The implant of claim 17, wherein the laser sintered PEKK is prepared by applying a layer of the powder on a bed of a laser sintering machine, solidifying selected points of the applied layer of powder by irradiation in accordance with a corresponding layer of a model, successively repeating the step of applying the powder and the step of solidifying the applied layer of powder until a plurality of cross sections of the implant are solidified. 19. The implant of claim 18, wherein a bed temperature between 280 degrees Celsius and 295 degrees Celsius is maintained during the successive steps of powder application and solidification. 20. The implant of claim 19 wherein the implant comprises a mechanical fastener interface in a surface of the implant. | The present invention relates to customized implants for bone replacement that are prepared from poly(ether ketone ketone) or PEKK, and to a computer-based imaging and rapid prototyping (RP)-based manufacturing method for the design and manufacture of these customized implants. The PEKK customized implants made using rapid prototyping demonstrate biomechanical properties similar (if not identical) to that of natural bone even when prepared without the use of processing aids such as carbon black and aluminum powder.1. A method of forming an implant for use in a mammal, the method comprising the steps of:
providing a model of an implant; providing a powder comprising polyetherketoneketone (PEKK) and excluding calcium phosphate; forming the implant by selective laser sintering the powder in accordance with the model of the implant. 2. The method of claim 1, wherein the step of forming the implant by selective laser sintering comprises the steps of:
applying a layer of the powder on a bed of a laser sintering machine; solidifying selected points of the applied layer of powder by irradiation in accordance with a corresponding layer of the model; successively repeating the step of applying the powder and the step of solidifying the applied layer of powder until a plurality of cross sections of the implant are solidified. 3. The method of claim 2, wherein the selective laser sintering further comprises the step of:
maintaining a bed temperature between 280 degrees Celsius and 350 degrees Celsius during the successive steps of powder application and solidification. 4. The method of claim 2, wherein the powder comprises a semi-crystalline PEKK powder having a crystallinity between 15% and 90% as determined by DSC and an average particle size between 10 to 150 microns. 5. The method of claim 4, wherein the powder has a crystallinity between 15% and 35% as determined by DSC and an average particle size between 50 to 70 microns. 6. The method of claim of claim 2, wherein the powder comprises a quasi-amorphous PEKK powder having a crystallinity of 2% or less as determined by DSC, and wherein the powder has an average particle size between 50 to 70 microns. 7. The method of claim 6, wherein the selective laser sintering further comprises the step of maintaining a bed temperature between 280 degrees Celsius and 350 degrees Celsius during the successive steps of powder application and solidification. 8. The method of claim 2 wherein the step of selectively laser sintering forms a mechanical fastener interface in a surface of the implant. 9. The method of claim 2 wherein the powder consists essentially of PEKK. 10. The implant of claim 2, wherein the implant replaces a load-bearing bone. 11. The implant 2, wherein the implant replaces a portion of a spine, a long bone of an arm or a leg, a hip bone, or a cranial bone. 12. The method of claim 2, wherein the step of providing the model comprises the steps of:
(a) scanning a patient to obtain tomographic information; (b) designing a bone implant model using from the tomographic information obtained from the patient. 13. A method of forming an implant for use in a mammal, the method comprising the steps of:
providing a model of an implant; providing a powder for manufacturing the implant, the powder comprising a a semi-crystalline polyetherketoneketone PEKK powder having a crystallinity between 15% and 90% and excluding calcium phosphate, the powder having an average particle size of between 50 to 70 microns; forming the implant by selective laser sintering the powder in accordance with the implant model, the step of forming the implant by selective laser sintering comprises the following steps:
applying a layer of the powder on a bed of a laser sintering machine;
solidifying selected points of the applied layer of powder by irradiation in accordance with a corresponding layer of the model;
successively repeating the step of applying the powder and the step of solidifying the applied layer of powder until a plurality of cross sections of the implant are solidified;
maintaining a bed temperature between 280 degrees Celsius and 295 degrees Celsius during the successive steps of powder application and solidification. 14. The method of claim 13 wherein the step of selectively laser sintering forms a mechanical fastener interface in a surface of the implant. 15. The method of claim 13 wherein the powder consists essentially of PEKK. 16. The method of claim 13, wherein the implant replaces a spine bone or a cranial bone. 17. An implant for use in a mammal, the implant comprising laser sintered polyetherketoneketone (PEKK) and excluding calcium phosphate. 18. The implant of claim 17, wherein the laser sintered PEKK is prepared by applying a layer of the powder on a bed of a laser sintering machine, solidifying selected points of the applied layer of powder by irradiation in accordance with a corresponding layer of a model, successively repeating the step of applying the powder and the step of solidifying the applied layer of powder until a plurality of cross sections of the implant are solidified. 19. The implant of claim 18, wherein a bed temperature between 280 degrees Celsius and 295 degrees Celsius is maintained during the successive steps of powder application and solidification. 20. The implant of claim 19 wherein the implant comprises a mechanical fastener interface in a surface of the implant. | 1,600 |
1,457 | 15,849,129 | 1,617 | Disclosed are oral care compositions, for example dentifrice compositions, comprising an oral care composition comprising an orally acceptable vehicle, metal oxide particles having an average particle size of no greater than a dentin tubule and at least one amino acid capable of chelating the metal oxide. The composition may comprise a polymeric adherent material for adhering the metal oxide particles in the dentin tubule. The metal oxide particles have a median particle size of 5 microns or less, and may comprise zinc oxide. | 1. An oral care composition comprising:
an orally acceptable vehicle; a source of metal oxide particles, wherein said metal oxide particles have a median particle size of from 1 to 7 microns;
one or more amino acids capable of chelating said metal oxide particles, wherein the metal oxide comprises at least one metal oxide selected from zinc oxide, stannous oxide, titanium oxide, calcium oxide, copper oxide and iron oxide or a mixture thereof; and
further comprising a polymeric adherent material. 2. The oral care composition according to claim 1 wherein the metal oxide particles have a median particle size of 5 microns or less. 3. The oral care composition according to claim 1 wherein the metal oxide comprises zinc oxide. 4. The oral care composition according to claim 1 wherein the metal oxide particles have a particle size distribution of 3 to 4 microns, a particle size distribution of 5 to 7 microns, a particle size distribution of 3 to 5 microns, a particle size distribution of 2 to 5 microns, or a particle size distribution of 2 to 4 microns. 5. The oral care composition according to claim 1 wherein the metal oxide particles are present in an amount of up to 5% by weight, based on the total weight of the oral care composition. 6. The oral care composition according to claim 4 wherein the metal oxide particles are present in an amount of from 0.5 to 2% by weight, based on the total weight of the oral care composition. 7. The oral care composition according to claim 1 wherein the source of metal oxide particles is selected from a powder, a nanoparticle solution; a nanoparticle suspension; a capsule; and a bead. 8. The oral care composition according to claim 1 wherein at least one of said one or more amino acids is selected from arginine, L-arginine, cysteine, leucine, isoleucine, lysine, L-lysine, alanine, asparagine, aspartate, phenylalanine, glutamate, glutamic acid, threonine, glutamine, tryptophan, glycine, valine, praline, serine, tyrosine, and histidine, and a combination of two or more thereof. 9. The oral care composition according to claim 7 wherein at least one of said one or more amino acids is selected from L-arginine, cysteine, isoleucine, L-lysine, glutamic acid, serine, and a combination of two or more thereof. 10. The oral care composition according to claim 8 wherein at least one of said one or more amino acids is L-arginine. 11. The oral care composition according to claim 1 wherein at least one of said one or more amino acids is present in an amount of up to 5% by weight, based on the total weight of the oral care composition. 12. The oral care composition according to claim 10 wherein at least one of said one or more amino acids is present in an amount of from 0.5 to 5% by weight, based on the total weight of the oral care composition. 13. The oral care composition according to claim 11 wherein at least one of said one or more amino acids is present in an amount of from 2.5 to 4.5% by weight, based on the total weight of the oral care composition. 14. The oral care composition according to claim 1 wherein the metal oxide is encapsulated in the polymeric adherent material. 15. The oral care composition according to claim 14 wherein the polymeric adherent material comprises one or more cellulose polymers. 16. The oral care composition according to claim 15 wherein at least one of said one or more cellulose polymers is a hydroxyalkyl cellulose polymer selected from hydroxypropylmethyl cellulose (HPMC), hydroxyethylpropyl cellulose (HEPC), hydroxybutylmethyl cellulose (HBMC), and carboxymethyl cellulose (CMC). 17. The oral care composition according to claim 16 wherein the polymeric adherent material comprises a mixture of two hydroxyalkyl cellulose polymers having different molecular weights and the metal oxide comprises zinc oxide which is encapsulated in the mixture of two hydroxyalkyl cellulose polymers. 18. The oral care composition according to claim 14 wherein the polymeric adherent material comprises one or more polymers selected from a poly (ethylene oxide) polymer, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG)/polypropylene glycol (PPG) copolymer, ethylene oxide (EO)-propylene oxide (PO) block copolymers, ester gum, shellac, pressure sensitive silicone adhesives, methacrylates, or mixtures thereof. 19. The oral care composition according to claim 1 which is a dentifrice composition. 20. The oral care composition according to claim 19, which is a toothpaste or a gel. 21. The oral care composition according to claim 1, wherein the composition is formulated into a form selected from a mouth rinse, a gum, a dissolvable lozenge, and a dissolvable film. 22. A method of reducing dental sensitivity comprising applying to the surface of a mammalian tooth an oral care composition of claim 1. 23. A method of protecting dental surfaces from acid-mediated degradation, comprising applying to the surface of a mammalian tooth an oral care composition of claim 1. 24. A method of maintaining or increasing the systemic health of a mammal comprising applying a composition to an oral surface of a mammal at least once a day for a duration of time, wherein the composition comprises:
a. an oral care composition of claim 1, and b. an agent selected from triclosan; triclosan monophosphate; chlorhexidine; alexidine; hexetidine; sanguinarine; benzalkonium chloride; salicylanilide; domiphen bromide; cetylpyridinium chloride (CPC); tetradecylpyridinium chloride (TPC); N-tetradecyl-4ethylpyridinium chloride (TDEPC); octenidine; delmopinol; octapinol; nisin; zinc ion agent; copper ion agent; essential oils; furanones; bacteriocins, ethyllauroyl arginate, extracts of magnolia, a metal ion source, fluoride, stannous ions, arginine bicarbonate, honokiol, magonol, ursolic acid, ursic acid, morin, extract of sea buckthorn, a peroxide, an enzyme, a Camellia extract, a flavonoid, a flavan, halogenated diphenyl ether, creative, and propolis. 25. A method of occluding a dentin tubule within the surface of a mammalian tooth comprising applying to the tooth surface a composition according to claim 1. 26. An oral care composition according to claim 1 and further comprising an agent selected from triclosan; triclosan monophosphate; chlorhexidine; alexidine; hexetidine; sanguinarine; benzalkonium chloride; salicylanilide; domiphen bromide; cetylpyridinium chloride (CPC); tetradecylpyridinium chloride (TPC); N-tetradecyl-4ethylpyridinium chloride (TDEPC); octenidine; delmopinol; octapinol; nisin; zinc ion agent; copper ion agent; essential oils; furanones; bacteriocins, ethyllauroyl arginate, extracts of magnolia, a metal ion source, fluoride, stannous ions, arginine bicarbonate, honokiol, magonol, ursolic acid, ursic acid, morin, extract of sea buckthorn, a peroxide, an enzyme, a Camellia extract, a flavonoid, a flavan, halogenated diphenyl ether, creative, and propolis, for use in a method of maintaining or increasing the systemic health of a mammal. 27. The oral care composition according to claim 17 wherein the metal oxide particles are present in an amount of from 0.5 to 2% by weight, based on the total weight of the oral care composition. 28. The oral care composition according to claim 27 wherein at least one of said one or more amino acids is present in an amount of from 0.5 to 5% by weight, based on the total weight of the oral care composition. 29. The oral care composition according to claim 28 wherein the metal oxide comprises zinc oxide. 30. The oral care composition according to claim 29 wherein at least one of said one or more amino acids is selected from L-arginine, cysteine, isoleucine, L-lysine, glutamic acid, serine, and a combination of two or more thereof. 31. The oral care composition according to claim 30 wherein at least one of said one or more amino acids is L-arginine. 32. An oral care composition of claim 1 comprising:
an orally acceptable vehicle;
a source of metal oxide particles, wherein said metal oxide particles have a median particle size of from 1 to 7 microns;
one or more amino acids capable of chelating said metal oxide particles, wherein the metal oxide comprises at least one metal oxide selected from zinc oxide, stannous oxide, calcium oxide, and copper oxide or a mixture thereof; wherein at least one of said one or more amino acids is selected from arginine, L-arginine, cysteine, leucine, isoleucine, lysine, L-lysine, alanine, asparagine, aspartate, phenylalanine, glutamate, threonine, glutamine, tryptophan, valine, praline, serine, tyrosine, and histidine, and a combination of two or more thereof; and further comprising a polymeric adherent material. | Disclosed are oral care compositions, for example dentifrice compositions, comprising an oral care composition comprising an orally acceptable vehicle, metal oxide particles having an average particle size of no greater than a dentin tubule and at least one amino acid capable of chelating the metal oxide. The composition may comprise a polymeric adherent material for adhering the metal oxide particles in the dentin tubule. The metal oxide particles have a median particle size of 5 microns or less, and may comprise zinc oxide.1. An oral care composition comprising:
an orally acceptable vehicle; a source of metal oxide particles, wherein said metal oxide particles have a median particle size of from 1 to 7 microns;
one or more amino acids capable of chelating said metal oxide particles, wherein the metal oxide comprises at least one metal oxide selected from zinc oxide, stannous oxide, titanium oxide, calcium oxide, copper oxide and iron oxide or a mixture thereof; and
further comprising a polymeric adherent material. 2. The oral care composition according to claim 1 wherein the metal oxide particles have a median particle size of 5 microns or less. 3. The oral care composition according to claim 1 wherein the metal oxide comprises zinc oxide. 4. The oral care composition according to claim 1 wherein the metal oxide particles have a particle size distribution of 3 to 4 microns, a particle size distribution of 5 to 7 microns, a particle size distribution of 3 to 5 microns, a particle size distribution of 2 to 5 microns, or a particle size distribution of 2 to 4 microns. 5. The oral care composition according to claim 1 wherein the metal oxide particles are present in an amount of up to 5% by weight, based on the total weight of the oral care composition. 6. The oral care composition according to claim 4 wherein the metal oxide particles are present in an amount of from 0.5 to 2% by weight, based on the total weight of the oral care composition. 7. The oral care composition according to claim 1 wherein the source of metal oxide particles is selected from a powder, a nanoparticle solution; a nanoparticle suspension; a capsule; and a bead. 8. The oral care composition according to claim 1 wherein at least one of said one or more amino acids is selected from arginine, L-arginine, cysteine, leucine, isoleucine, lysine, L-lysine, alanine, asparagine, aspartate, phenylalanine, glutamate, glutamic acid, threonine, glutamine, tryptophan, glycine, valine, praline, serine, tyrosine, and histidine, and a combination of two or more thereof. 9. The oral care composition according to claim 7 wherein at least one of said one or more amino acids is selected from L-arginine, cysteine, isoleucine, L-lysine, glutamic acid, serine, and a combination of two or more thereof. 10. The oral care composition according to claim 8 wherein at least one of said one or more amino acids is L-arginine. 11. The oral care composition according to claim 1 wherein at least one of said one or more amino acids is present in an amount of up to 5% by weight, based on the total weight of the oral care composition. 12. The oral care composition according to claim 10 wherein at least one of said one or more amino acids is present in an amount of from 0.5 to 5% by weight, based on the total weight of the oral care composition. 13. The oral care composition according to claim 11 wherein at least one of said one or more amino acids is present in an amount of from 2.5 to 4.5% by weight, based on the total weight of the oral care composition. 14. The oral care composition according to claim 1 wherein the metal oxide is encapsulated in the polymeric adherent material. 15. The oral care composition according to claim 14 wherein the polymeric adherent material comprises one or more cellulose polymers. 16. The oral care composition according to claim 15 wherein at least one of said one or more cellulose polymers is a hydroxyalkyl cellulose polymer selected from hydroxypropylmethyl cellulose (HPMC), hydroxyethylpropyl cellulose (HEPC), hydroxybutylmethyl cellulose (HBMC), and carboxymethyl cellulose (CMC). 17. The oral care composition according to claim 16 wherein the polymeric adherent material comprises a mixture of two hydroxyalkyl cellulose polymers having different molecular weights and the metal oxide comprises zinc oxide which is encapsulated in the mixture of two hydroxyalkyl cellulose polymers. 18. The oral care composition according to claim 14 wherein the polymeric adherent material comprises one or more polymers selected from a poly (ethylene oxide) polymer, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG)/polypropylene glycol (PPG) copolymer, ethylene oxide (EO)-propylene oxide (PO) block copolymers, ester gum, shellac, pressure sensitive silicone adhesives, methacrylates, or mixtures thereof. 19. The oral care composition according to claim 1 which is a dentifrice composition. 20. The oral care composition according to claim 19, which is a toothpaste or a gel. 21. The oral care composition according to claim 1, wherein the composition is formulated into a form selected from a mouth rinse, a gum, a dissolvable lozenge, and a dissolvable film. 22. A method of reducing dental sensitivity comprising applying to the surface of a mammalian tooth an oral care composition of claim 1. 23. A method of protecting dental surfaces from acid-mediated degradation, comprising applying to the surface of a mammalian tooth an oral care composition of claim 1. 24. A method of maintaining or increasing the systemic health of a mammal comprising applying a composition to an oral surface of a mammal at least once a day for a duration of time, wherein the composition comprises:
a. an oral care composition of claim 1, and b. an agent selected from triclosan; triclosan monophosphate; chlorhexidine; alexidine; hexetidine; sanguinarine; benzalkonium chloride; salicylanilide; domiphen bromide; cetylpyridinium chloride (CPC); tetradecylpyridinium chloride (TPC); N-tetradecyl-4ethylpyridinium chloride (TDEPC); octenidine; delmopinol; octapinol; nisin; zinc ion agent; copper ion agent; essential oils; furanones; bacteriocins, ethyllauroyl arginate, extracts of magnolia, a metal ion source, fluoride, stannous ions, arginine bicarbonate, honokiol, magonol, ursolic acid, ursic acid, morin, extract of sea buckthorn, a peroxide, an enzyme, a Camellia extract, a flavonoid, a flavan, halogenated diphenyl ether, creative, and propolis. 25. A method of occluding a dentin tubule within the surface of a mammalian tooth comprising applying to the tooth surface a composition according to claim 1. 26. An oral care composition according to claim 1 and further comprising an agent selected from triclosan; triclosan monophosphate; chlorhexidine; alexidine; hexetidine; sanguinarine; benzalkonium chloride; salicylanilide; domiphen bromide; cetylpyridinium chloride (CPC); tetradecylpyridinium chloride (TPC); N-tetradecyl-4ethylpyridinium chloride (TDEPC); octenidine; delmopinol; octapinol; nisin; zinc ion agent; copper ion agent; essential oils; furanones; bacteriocins, ethyllauroyl arginate, extracts of magnolia, a metal ion source, fluoride, stannous ions, arginine bicarbonate, honokiol, magonol, ursolic acid, ursic acid, morin, extract of sea buckthorn, a peroxide, an enzyme, a Camellia extract, a flavonoid, a flavan, halogenated diphenyl ether, creative, and propolis, for use in a method of maintaining or increasing the systemic health of a mammal. 27. The oral care composition according to claim 17 wherein the metal oxide particles are present in an amount of from 0.5 to 2% by weight, based on the total weight of the oral care composition. 28. The oral care composition according to claim 27 wherein at least one of said one or more amino acids is present in an amount of from 0.5 to 5% by weight, based on the total weight of the oral care composition. 29. The oral care composition according to claim 28 wherein the metal oxide comprises zinc oxide. 30. The oral care composition according to claim 29 wherein at least one of said one or more amino acids is selected from L-arginine, cysteine, isoleucine, L-lysine, glutamic acid, serine, and a combination of two or more thereof. 31. The oral care composition according to claim 30 wherein at least one of said one or more amino acids is L-arginine. 32. An oral care composition of claim 1 comprising:
an orally acceptable vehicle;
a source of metal oxide particles, wherein said metal oxide particles have a median particle size of from 1 to 7 microns;
one or more amino acids capable of chelating said metal oxide particles, wherein the metal oxide comprises at least one metal oxide selected from zinc oxide, stannous oxide, calcium oxide, and copper oxide or a mixture thereof; wherein at least one of said one or more amino acids is selected from arginine, L-arginine, cysteine, leucine, isoleucine, lysine, L-lysine, alanine, asparagine, aspartate, phenylalanine, glutamate, threonine, glutamine, tryptophan, valine, praline, serine, tyrosine, and histidine, and a combination of two or more thereof; and further comprising a polymeric adherent material. | 1,600 |
1,458 | 15,749,541 | 1,612 | Described herein are oral care compositions comprising a basic amino acid; a combination of zinc ion sources; and a thickening system comprising a nonionic cellulose ether having a viscosity, measured at 2% in water at 25° C., of 4500 to 7500 cps; and a polysaccharide gum; along with methods of making and using same. | 1. An oral care composition comprising:
a. a basic amino acid in free or salt form wherein the basic amino acid is selected from arginine, lysine, and a combination thereof, b. a combination of zinc ion sources: and c. a thickening system comprising:
i. from about 0.1 wt. % to about 1 wt. % of a nonionic cellulose ether: and
ii. from about 0.25 wt. % to about 1 wt. % of a polysaccharide gum. 2. The oral care composition according to claim 1, wherein the nonionic cellulose ether has a viscosity, measured at 2% in water at 25° C., of from about 4500 to about 7500 cps. 3. The oral care composition according to claim 1, wherein the nonionic cellulose ether has a viscosity, measured at 2% in water at 25° C., of from about 4500 to about 6500 cps. 4. The oral care composition according to claim 1, wherein the nonionic cellulose ether has a viscosity, measured at 2% in water at 25° C., of from about 6000 to about 7500 cps. 5. The oral care composition according to claim 1, comprising from about 0.1 wt. % to about 0.8 wt. % of a nonionic cellulose ether. 6. The oral care composition according to claim 1, comprising from about 0.1 wt. % to about 0.5 wt. % of a nonionic cellulose ether. 7. The oral care composition according to claim 1, comprising from about 0.1 wt. % to about 0.3 wt. % of a nonionic cellulose ether. 8. The oral care composition according to claim 1, comprising 0.1 wt. %, 0.15 wt. %, 0.2 wt. %, 0.25 wt. % or 0.3 wt. % of a nonionic cellulose ether. 9. The oral care composition according to claim 1, wherein the nonionic cellulose ether comprises hydroxyethylcellulose. 10. The oral care composition according to claim 1, comprising from about 0.3 wt. % to about 1 wt. % of a polysaccharide gum. 11. The oral care composition according to claim 1, comprising from about 0.4 wt. % to about 1 wt. % of a polysaccharide gum. 12. The oral care composition according to claim 1, comprising from about 0.5 wt. % to about 1 wt. % of a polysaccharide gum. 13. The oral care composition according to claim 1, comprising from about 0.6 wt. % to about 0.9 wt. % of a polysaccharide gum. 14. The oral care composition according to claim 1, comprising about 0.3 wt. %, 0.4 wt. %, 0.5 wt. %, 0.6 wt. %, 0.7 wt. %, 0.8 wt. %, 0.9 wt. % or 1 wt. % of a polysaccharide gum. 15. The oral care composition according to claim 1, wherein the polysaccharide gum is xanthan gum. 16. The oral care composition according to claim 1, wherein the thickening system further comprises from about 5 wt. % to to about 10 wt. % 17. The oral care composition according to claim 1, wherein the thickening system comprises from about 0.5 wt. % to about 15 wt. % of the oral care composition. 18. The oral care composition according to claim 1, wherein the nonionic cellulose ether and the polysaccharide gum are present in a weight ratio of from about 1:1 to about 1:10. 19. The oral care composition according to claim 1, wherein the nonionic cellulose ether and the polysaccharide gum are present in a weight ratio of from about 1:2 to about 1:10. 20. The oral care composition according to claim 1, wherein the nonionic cellulose ether and the polysaccharide gum are present in a weight ratio of from about 1:3 to about 1:10. 21. The oral care composition according to claim 1, wherein the nonionic cellulose ether and the polysaccharide gum are present in a weight ratio of 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9. 22. The oral care composition according to claim 1, wherein the combination of zinc ion sources comprises zinc oxide and zinc citrate. 23. The oral care composition according to claim 1, wherein the amino acid is arginine, and is present at about 1.5 wt. %, 5 wt. %, or about 8 wt. %, of the oral care composition. 24. The oral care composition according to claim 22, wherein the weight ratio of zinc oxide to zinc citrate is about 2:1. 25. The oral care composition according to claim 22, wherein the zinc citrate is in an amount of about 0.5 wt. % and zinc oxide is present in an amount of about 1.0 wt. % based on the total weight of the oral care composition. 26. The oral care composition according to claim 1, further comprising a fluoride ion source selected from sodium fluoride, sodium monofluorophosphate, and stannous fluoride. 27. The oral care composition according to claim 26, wherein the fluoride ion source provides soluble fluoride in an amount of about 1450 ppm. 28. The oral care composition according to claim 26, wherein the fluoride ion source comprises stannous fluoride. 29. The oral care composition according to claim 1, comprising:
a. about 1.0 wt. % zinc oxide b. about 0.5 wt. % zinc citrate c. about 1.5 wt. % L-arginine d. from about 0.3 wt. % to about 0.9 wt. % of xanthan gum; and e. from about 0.1 wt. % to about 0.5 wt. % of hydroxyethylcellulose. 30. The oral care composition according to claim 29, comprising from about 0.6 wt. % to about 0.8 wt. % of xanthan gum. 31. The oral care composition according to claim 29, comprising from about 0.1 wt. % to about 0.3 wt. % of hydroxyethylcellulose. 32. The oral care composition according to claim 1, wherein the oral care composition is in a form selected from: a toothpaste, a mouthwash, and a gel. 33. The oral care composition according to claim 1, having a static yield stress greater than about 20 Pa, 25 Pa, 30 Pa, 35 Pa, or 40 Pa. 34. The oral care composition according to claim 1, having a drainage time of less than about 10 minutes, about 9 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, about 4 minutes, about 3 minutes or about 2 minutes. 35. The oral care composition according to claim 1, demonstrating less than about 225 grams of left-overs. 36. The oral care composition according to claim 1, wherein the oral care composition loses no more than about 25% of its initial viscosity after one year. 37. A method to improve oral health comprising applying an effective amount of the oral care composition according to claim 1 to the oral cavity of a subject in need thereof, wherein the method is effective to:
i. reduce or inhibit formation of dental caries,
ii. reduce, repair or inhibit early enamel lesions, e.g., as detected by quantitative light-induced fluorescence (QLF) or electrical caries measurement (ECM),
iii. reduce or inhibit demineralization and promote remineralization of the teeth,
iv. reduce hypersensitivity of the teeth,
v. reduce or inhibit gingivitis,
vi. promote healing of sores or cuts in the mouth,
vii. reduce levels of acid producing bacteria,
viii. to increase relative levels of arginolytic bacteria,
ix. inhibit microbial bio film formation in the oral cavity,
x. raise and/or maintain plaque pH at levels of at least 5.5 following sugar challenge,
xi. reduce plaque accumulation,
xii. treat dry mouth,
xiii. enhance systemic health, including cardiovascular health,
xiv. whiten teeth,
xv. reduce erosion of the teeth,
xvi. immunize (or protect) the teeth against cariogenic bacteria and their effects, and/or
xvii. clean the teeth and oral cavity. | Described herein are oral care compositions comprising a basic amino acid; a combination of zinc ion sources; and a thickening system comprising a nonionic cellulose ether having a viscosity, measured at 2% in water at 25° C., of 4500 to 7500 cps; and a polysaccharide gum; along with methods of making and using same.1. An oral care composition comprising:
a. a basic amino acid in free or salt form wherein the basic amino acid is selected from arginine, lysine, and a combination thereof, b. a combination of zinc ion sources: and c. a thickening system comprising:
i. from about 0.1 wt. % to about 1 wt. % of a nonionic cellulose ether: and
ii. from about 0.25 wt. % to about 1 wt. % of a polysaccharide gum. 2. The oral care composition according to claim 1, wherein the nonionic cellulose ether has a viscosity, measured at 2% in water at 25° C., of from about 4500 to about 7500 cps. 3. The oral care composition according to claim 1, wherein the nonionic cellulose ether has a viscosity, measured at 2% in water at 25° C., of from about 4500 to about 6500 cps. 4. The oral care composition according to claim 1, wherein the nonionic cellulose ether has a viscosity, measured at 2% in water at 25° C., of from about 6000 to about 7500 cps. 5. The oral care composition according to claim 1, comprising from about 0.1 wt. % to about 0.8 wt. % of a nonionic cellulose ether. 6. The oral care composition according to claim 1, comprising from about 0.1 wt. % to about 0.5 wt. % of a nonionic cellulose ether. 7. The oral care composition according to claim 1, comprising from about 0.1 wt. % to about 0.3 wt. % of a nonionic cellulose ether. 8. The oral care composition according to claim 1, comprising 0.1 wt. %, 0.15 wt. %, 0.2 wt. %, 0.25 wt. % or 0.3 wt. % of a nonionic cellulose ether. 9. The oral care composition according to claim 1, wherein the nonionic cellulose ether comprises hydroxyethylcellulose. 10. The oral care composition according to claim 1, comprising from about 0.3 wt. % to about 1 wt. % of a polysaccharide gum. 11. The oral care composition according to claim 1, comprising from about 0.4 wt. % to about 1 wt. % of a polysaccharide gum. 12. The oral care composition according to claim 1, comprising from about 0.5 wt. % to about 1 wt. % of a polysaccharide gum. 13. The oral care composition according to claim 1, comprising from about 0.6 wt. % to about 0.9 wt. % of a polysaccharide gum. 14. The oral care composition according to claim 1, comprising about 0.3 wt. %, 0.4 wt. %, 0.5 wt. %, 0.6 wt. %, 0.7 wt. %, 0.8 wt. %, 0.9 wt. % or 1 wt. % of a polysaccharide gum. 15. The oral care composition according to claim 1, wherein the polysaccharide gum is xanthan gum. 16. The oral care composition according to claim 1, wherein the thickening system further comprises from about 5 wt. % to to about 10 wt. % 17. The oral care composition according to claim 1, wherein the thickening system comprises from about 0.5 wt. % to about 15 wt. % of the oral care composition. 18. The oral care composition according to claim 1, wherein the nonionic cellulose ether and the polysaccharide gum are present in a weight ratio of from about 1:1 to about 1:10. 19. The oral care composition according to claim 1, wherein the nonionic cellulose ether and the polysaccharide gum are present in a weight ratio of from about 1:2 to about 1:10. 20. The oral care composition according to claim 1, wherein the nonionic cellulose ether and the polysaccharide gum are present in a weight ratio of from about 1:3 to about 1:10. 21. The oral care composition according to claim 1, wherein the nonionic cellulose ether and the polysaccharide gum are present in a weight ratio of 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, or 1:9. 22. The oral care composition according to claim 1, wherein the combination of zinc ion sources comprises zinc oxide and zinc citrate. 23. The oral care composition according to claim 1, wherein the amino acid is arginine, and is present at about 1.5 wt. %, 5 wt. %, or about 8 wt. %, of the oral care composition. 24. The oral care composition according to claim 22, wherein the weight ratio of zinc oxide to zinc citrate is about 2:1. 25. The oral care composition according to claim 22, wherein the zinc citrate is in an amount of about 0.5 wt. % and zinc oxide is present in an amount of about 1.0 wt. % based on the total weight of the oral care composition. 26. The oral care composition according to claim 1, further comprising a fluoride ion source selected from sodium fluoride, sodium monofluorophosphate, and stannous fluoride. 27. The oral care composition according to claim 26, wherein the fluoride ion source provides soluble fluoride in an amount of about 1450 ppm. 28. The oral care composition according to claim 26, wherein the fluoride ion source comprises stannous fluoride. 29. The oral care composition according to claim 1, comprising:
a. about 1.0 wt. % zinc oxide b. about 0.5 wt. % zinc citrate c. about 1.5 wt. % L-arginine d. from about 0.3 wt. % to about 0.9 wt. % of xanthan gum; and e. from about 0.1 wt. % to about 0.5 wt. % of hydroxyethylcellulose. 30. The oral care composition according to claim 29, comprising from about 0.6 wt. % to about 0.8 wt. % of xanthan gum. 31. The oral care composition according to claim 29, comprising from about 0.1 wt. % to about 0.3 wt. % of hydroxyethylcellulose. 32. The oral care composition according to claim 1, wherein the oral care composition is in a form selected from: a toothpaste, a mouthwash, and a gel. 33. The oral care composition according to claim 1, having a static yield stress greater than about 20 Pa, 25 Pa, 30 Pa, 35 Pa, or 40 Pa. 34. The oral care composition according to claim 1, having a drainage time of less than about 10 minutes, about 9 minutes, about 8 minutes, about 7 minutes, about 6 minutes, about 5 minutes, about 4 minutes, about 3 minutes or about 2 minutes. 35. The oral care composition according to claim 1, demonstrating less than about 225 grams of left-overs. 36. The oral care composition according to claim 1, wherein the oral care composition loses no more than about 25% of its initial viscosity after one year. 37. A method to improve oral health comprising applying an effective amount of the oral care composition according to claim 1 to the oral cavity of a subject in need thereof, wherein the method is effective to:
i. reduce or inhibit formation of dental caries,
ii. reduce, repair or inhibit early enamel lesions, e.g., as detected by quantitative light-induced fluorescence (QLF) or electrical caries measurement (ECM),
iii. reduce or inhibit demineralization and promote remineralization of the teeth,
iv. reduce hypersensitivity of the teeth,
v. reduce or inhibit gingivitis,
vi. promote healing of sores or cuts in the mouth,
vii. reduce levels of acid producing bacteria,
viii. to increase relative levels of arginolytic bacteria,
ix. inhibit microbial bio film formation in the oral cavity,
x. raise and/or maintain plaque pH at levels of at least 5.5 following sugar challenge,
xi. reduce plaque accumulation,
xii. treat dry mouth,
xiii. enhance systemic health, including cardiovascular health,
xiv. whiten teeth,
xv. reduce erosion of the teeth,
xvi. immunize (or protect) the teeth against cariogenic bacteria and their effects, and/or
xvii. clean the teeth and oral cavity. | 1,600 |
1,459 | 15,125,932 | 1,617 | The present invention relates to an implantable paste comprising bioactive glass powder having a size distribution of 0.5-45 μm, bioactive glass granules having a size distribution between 100 and 4000 μm, low molecular weight polyethylene glycol having a molecular weight range of 200-700 g/mol, medium molecular weight polyethylene glycol having a molecular weight range of 700-2500 g/mol, high molecular weight polyethylene glycol having a molecular weight range of 2500-8000 g/mol and glycerol. The composition of the bioactive glass is 45-55 weight-% of SiO 2 , 20-25 weight-% of Na 2 O, 18-25 weight-% of CaO and 3-6 weight-% of P 2 O 5 , and the molecular weight of the low molecular weight polyethylene glycol and of the medium molecular weight polyethylene glycol differ from each other by at least 80 g/mol and that the molecular weight of the medium molecular weight polyethylene glycol and of the high molecular weight polyethylene glycol differ from each other by at least 300 g/mol. | 1. An implantable paste comprising
(a) bioactive glass powder having a size distribution of 0.5-45 μm in an amount of 10-30 wt-% of the total weight of the bioactive glass, (b) bioactive glass granules having a size distribution between 100 and 4000 μm in an amount of 90-70 wt-% of the total weight of the bioactive glass, (c) low molecular weight polyethylene glycol having a molecular weight range of 200-700 g/mol, (d) medium molecular weight polyethylene glycol having a molecular weight range of 700-2500 g/mol, (e) high molecular weight polyethylene glycol having a molecular weight range of 2500-8000 g/mol and (f) glycerol, wherein the composition of the bioactive glass is 45-55 weight-% of SiO2, 20-25 weight-% of Na2O, 18-25 weight-% of CaO and 3-6 weight-% of P2O5, with the proviso that the molecular weight of the low molecular weight polyethylene glycol and of the medium molecular weight polyethylene glycol differ from each other by at least 80 g/mol and that the molecular weight of the medium molecular weight polyethylene glycol and of the high molecular weight polyethylene glycol differ from each other by at least 300 g/mol. 2. The paste according to claim 1, characterised in that it further comprises
(g) therapeutically active agent. 3. The paste according to claim 1, characterised in that it comprises bioactive glass granules (b) having a size distribution of 125-315 μm. 4. The paste according to claim 1, characterised in that it comprises bioactive glass granules (b) having a size distribution of 315-500 μm. 5. The paste according to claim 1, characterised in that it comprises bioactive glass granules (b) having a size distribution of 500-800 μm. 6. The paste according to claim 1, characterised in that it comprises bioactive glass granules (b) having a size distribution of 1000-2000 μm. 7. (canceled) 8. The paste according to claim 1, characterised in that the total amount of bioactive glass is 50-80 wt-% of the total weight of the paste. 9. The paste according to claim 1, characterised in that the amount of low molecular weight polyethylene glycol having a molecular weight range of 200-700 g/mol (c) is 2-15 wt-%, amount of medium molecular weight polyethylene glycol having a molecular weight range of 700-2500 g/mol (d) is 8-48 wt-% of the total weight of the paste and that the amount of high molecular weight polyethylene glycol (e) is 1-10 wt-% of the total weight of the paste. 10. The paste according to claim 1, characterised in that the total amount of polyethylene glycols is 20-50 wt-% of the total weight of the paste and that the amount of glycerol (f) is up to 10 wt-% of the total weight of the paste. 11. The paste according to claim 2, characterised in that the amount of therapeutically active agent (g) is up to 30 wt-% of the total weight of the paste. 12. The paste according to claim 1, characterised in that the composition of the bioactive glass is 45-54 weight-% of SiO2, 22-25 weight-% of Na2O, 19-25 weight-% of CaO and 3.5-6 weight-% of P2O5. 13. The paste according to claim 12, characterised in that the composition of the bioactive glass is 53 weight-% of SiO2, 23 weight-% of Na2O, 20 weight-% of CaO and 4 weight-% of P2O5 or 45 weight-% of SiO2, 24.5 weight-% of Na2O, 24.5 weight-% of CaO and 6 weight-% of P2O5. 14. Use of a paste according to claim 1 in manufacturing an implant for use in bone formation or for coating an implant. 15. An implant coated with a paste according to claim 1. | The present invention relates to an implantable paste comprising bioactive glass powder having a size distribution of 0.5-45 μm, bioactive glass granules having a size distribution between 100 and 4000 μm, low molecular weight polyethylene glycol having a molecular weight range of 200-700 g/mol, medium molecular weight polyethylene glycol having a molecular weight range of 700-2500 g/mol, high molecular weight polyethylene glycol having a molecular weight range of 2500-8000 g/mol and glycerol. The composition of the bioactive glass is 45-55 weight-% of SiO 2 , 20-25 weight-% of Na 2 O, 18-25 weight-% of CaO and 3-6 weight-% of P 2 O 5 , and the molecular weight of the low molecular weight polyethylene glycol and of the medium molecular weight polyethylene glycol differ from each other by at least 80 g/mol and that the molecular weight of the medium molecular weight polyethylene glycol and of the high molecular weight polyethylene glycol differ from each other by at least 300 g/mol.1. An implantable paste comprising
(a) bioactive glass powder having a size distribution of 0.5-45 μm in an amount of 10-30 wt-% of the total weight of the bioactive glass, (b) bioactive glass granules having a size distribution between 100 and 4000 μm in an amount of 90-70 wt-% of the total weight of the bioactive glass, (c) low molecular weight polyethylene glycol having a molecular weight range of 200-700 g/mol, (d) medium molecular weight polyethylene glycol having a molecular weight range of 700-2500 g/mol, (e) high molecular weight polyethylene glycol having a molecular weight range of 2500-8000 g/mol and (f) glycerol, wherein the composition of the bioactive glass is 45-55 weight-% of SiO2, 20-25 weight-% of Na2O, 18-25 weight-% of CaO and 3-6 weight-% of P2O5, with the proviso that the molecular weight of the low molecular weight polyethylene glycol and of the medium molecular weight polyethylene glycol differ from each other by at least 80 g/mol and that the molecular weight of the medium molecular weight polyethylene glycol and of the high molecular weight polyethylene glycol differ from each other by at least 300 g/mol. 2. The paste according to claim 1, characterised in that it further comprises
(g) therapeutically active agent. 3. The paste according to claim 1, characterised in that it comprises bioactive glass granules (b) having a size distribution of 125-315 μm. 4. The paste according to claim 1, characterised in that it comprises bioactive glass granules (b) having a size distribution of 315-500 μm. 5. The paste according to claim 1, characterised in that it comprises bioactive glass granules (b) having a size distribution of 500-800 μm. 6. The paste according to claim 1, characterised in that it comprises bioactive glass granules (b) having a size distribution of 1000-2000 μm. 7. (canceled) 8. The paste according to claim 1, characterised in that the total amount of bioactive glass is 50-80 wt-% of the total weight of the paste. 9. The paste according to claim 1, characterised in that the amount of low molecular weight polyethylene glycol having a molecular weight range of 200-700 g/mol (c) is 2-15 wt-%, amount of medium molecular weight polyethylene glycol having a molecular weight range of 700-2500 g/mol (d) is 8-48 wt-% of the total weight of the paste and that the amount of high molecular weight polyethylene glycol (e) is 1-10 wt-% of the total weight of the paste. 10. The paste according to claim 1, characterised in that the total amount of polyethylene glycols is 20-50 wt-% of the total weight of the paste and that the amount of glycerol (f) is up to 10 wt-% of the total weight of the paste. 11. The paste according to claim 2, characterised in that the amount of therapeutically active agent (g) is up to 30 wt-% of the total weight of the paste. 12. The paste according to claim 1, characterised in that the composition of the bioactive glass is 45-54 weight-% of SiO2, 22-25 weight-% of Na2O, 19-25 weight-% of CaO and 3.5-6 weight-% of P2O5. 13. The paste according to claim 12, characterised in that the composition of the bioactive glass is 53 weight-% of SiO2, 23 weight-% of Na2O, 20 weight-% of CaO and 4 weight-% of P2O5 or 45 weight-% of SiO2, 24.5 weight-% of Na2O, 24.5 weight-% of CaO and 6 weight-% of P2O5. 14. Use of a paste according to claim 1 in manufacturing an implant for use in bone formation or for coating an implant. 15. An implant coated with a paste according to claim 1. | 1,600 |
1,460 | 15,318,310 | 1,611 | The present invention relates to a biphasic composition or consisting of alcohol, a polar compound, a fragrance and a branched hydrocarbon. | 1. Biphasic composition comprising or consisting of alcohol, a polar compound, a fragrance and a branched hydrocarbon. 2. Biphasic composition according to claim 1, wherein the biphasic composition comprises or consists of:
20 to 75 wt % alcohol; 0.5 to 30 wt % polar compound; 1 to 50 wt % fragrance and 5 to 60 wt % branched hydrocarbon, based on the total weight of the composition. 3. The biphasic composition according to claim 1, wherein the alcohol is contained in the composition in an amount of 20 to 75 wt %, preferably in an amount of 30 to 70 wt % and more preferred in an amount of 40 to 85 wt % based on the total weight of the composition. 4. The biphasic composition according to claim 1, wherein the alcohol is ethanol. 5. The biphasic composition according to claim 1, wherein the polar compound is contained in the composition in an amount of 0.5 to 30 wt %, preferably in an amount of 0.75 to 15 wt %, more preferred in an amount of 1 to 10 wt % and even more preferred in an amount of 2 to 9 wt % based on the total weight of the composition. 6. The biphasic composition according to claim 1, wherein the polar compound is water. 7. The biphasic composition according to claim 1, wherein the fragrance is contained in the composition in an amount of 1 to 50 wt %, preferably in an amount of 2 to 30 wt % and more preferred in an amount of 5 to 20 wt % based on the total weight of the composition. 8. The biphasic composition according to claim 1, wherein the branched hydrocarbon is contained in the composition in an amount of 5 to 80 wt %, preferably in an amount of 10 to 40 wt % and more preferred in an amount of 15 to 35 wt % based on the total weight of the composition. 9. The biphasic composition according to claim 1, wherein the branched hydrocarbon(s) comprises 5 to 20 carbon atoms, preferably 8 to 19 and snore preferred 9 to 18 carbon atoms. 10. The biphasic composition according to claim 1, wherein the branched hydrocarbon is an alkane. 11. The biphasic composition according to claim 10, wherein the alkane is isododecane 12. The biphasic composition according to claim 1, wherein the fragrance comprises at least a first fragrance and a second fragrance. 13. The biphasic composition according to claim 12, wherein the first fragrance and the second fragrance are predominantly in different phases of the composition. 14. The biphasic composition according to claim 1, wherein the composition comprises a colorant. 15. The biphasic composition according to claim 14, wherein the colorant comprises at least a first colorant and a second colorant. 16. The biphasic composition according to claim 15, wherein the first colorant and the second colorant are predominantly in different phases of the composition. | The present invention relates to a biphasic composition or consisting of alcohol, a polar compound, a fragrance and a branched hydrocarbon.1. Biphasic composition comprising or consisting of alcohol, a polar compound, a fragrance and a branched hydrocarbon. 2. Biphasic composition according to claim 1, wherein the biphasic composition comprises or consists of:
20 to 75 wt % alcohol; 0.5 to 30 wt % polar compound; 1 to 50 wt % fragrance and 5 to 60 wt % branched hydrocarbon, based on the total weight of the composition. 3. The biphasic composition according to claim 1, wherein the alcohol is contained in the composition in an amount of 20 to 75 wt %, preferably in an amount of 30 to 70 wt % and more preferred in an amount of 40 to 85 wt % based on the total weight of the composition. 4. The biphasic composition according to claim 1, wherein the alcohol is ethanol. 5. The biphasic composition according to claim 1, wherein the polar compound is contained in the composition in an amount of 0.5 to 30 wt %, preferably in an amount of 0.75 to 15 wt %, more preferred in an amount of 1 to 10 wt % and even more preferred in an amount of 2 to 9 wt % based on the total weight of the composition. 6. The biphasic composition according to claim 1, wherein the polar compound is water. 7. The biphasic composition according to claim 1, wherein the fragrance is contained in the composition in an amount of 1 to 50 wt %, preferably in an amount of 2 to 30 wt % and more preferred in an amount of 5 to 20 wt % based on the total weight of the composition. 8. The biphasic composition according to claim 1, wherein the branched hydrocarbon is contained in the composition in an amount of 5 to 80 wt %, preferably in an amount of 10 to 40 wt % and more preferred in an amount of 15 to 35 wt % based on the total weight of the composition. 9. The biphasic composition according to claim 1, wherein the branched hydrocarbon(s) comprises 5 to 20 carbon atoms, preferably 8 to 19 and snore preferred 9 to 18 carbon atoms. 10. The biphasic composition according to claim 1, wherein the branched hydrocarbon is an alkane. 11. The biphasic composition according to claim 10, wherein the alkane is isododecane 12. The biphasic composition according to claim 1, wherein the fragrance comprises at least a first fragrance and a second fragrance. 13. The biphasic composition according to claim 12, wherein the first fragrance and the second fragrance are predominantly in different phases of the composition. 14. The biphasic composition according to claim 1, wherein the composition comprises a colorant. 15. The biphasic composition according to claim 14, wherein the colorant comprises at least a first colorant and a second colorant. 16. The biphasic composition according to claim 15, wherein the first colorant and the second colorant are predominantly in different phases of the composition. | 1,600 |
1,461 | 15,104,149 | 1,649 | Alzheimer's disease, the most common cause of dementia in older individuals, is a debilitating neurodegenerative disease for which there is currently no cure. In the past, AD could only be definitively diagnosed by brain biopsy or upon autopsy after a patient died. These methods, which demonstrate the presence of the characteristic plaque and tangle lesions in the brain, are still considered the gold standard for the pathological diagnoses of AD. However, in the clinical setting brain biopsy is rarely performed and diagnosis depends on a battery of neurological, psychometric and biochemical tests, including the measurement of biochemical markers such as the ApoE and tau proteins or the beta-amyloid peptide in cerebrospinal fluid and blood. The present invention discloses and describes panels of makers that are differentially expressed in the disease state relative to their expression in the normal state and, in particular, identifies and describes panels of makers associated with neurocognitive disorders. Such biomarker panel might have considerable value in triaging patients with early memory disorders to yet more specific but more invasive and costly approaches such as molecular markers in CSF and on PET imaging in clinical trials and possibly in clinical practice. | 1-45. (canceled) 46. A method for determining the progression and/or the prognosis of a neurocognitive disorder in a subject, said method comprises the steps of:
a) providing a sample comprising a tissue sample or a body fluid obtained from the subject having a neurocognitive disorder or symptoms thereof at a test time point; b) determining an amount or concentration of one or more biomarkers selected from a biomarker panel in the sample; c) comparing the amount or concentration of the selected biomarkers in the sample at the test time point with reference values for each of the selected biomarkers; wherein the test time point corresponds to a time when the method for determining the progression and/or the prognosis of a neurocognitive disorder is carried out; and wherein the amount or concentration of the selected biomarkers in the sample is indicative of the progression and/or the prognosis of the neurocognitive disorder in said subject, and wherein said biomarker panel comprises: transthyretin (TTR), Clusterin, Cystatin C (CST3), Alpha-1-Acid glycoprotein (A1AcidG). Intercellular adhesion molecule 1 (ICAM1), Complement C4 (CC4), pigment epithelium derived factor (PEDF) and Alpha1 antitrypsin (A1AT). 47. The method according to claim 46, wherein the amount or concentration of said selected markers in said sample is indicative of the progression and/or the prognosis of the neurocognitive disease. 48. The method according to claim 46, wherein the nature or degree of the neurocognitive disorder is determined. 49. The method according to claim 46, wherein the neurocognitive disorder is selected from the group consisting of: mild cognitive impairment (MCI), Alzheimer's disease (AD), vascular dementia, dementia with leery bodies, fronto-temporal dementia and combinations thereof. 50. The method according to claim 49, wherein the neurocognitive disorder is mild cognitive impairment (MCI) or Alzheimer's disease (AD). 51. The method according to claim 49, wherein the progression of the neurocognitive disorder is the conversion of mild cognitive impairment (MCI) to Alzheimer's disease (AD). 52. The method according to claim 51, wherein the conversion is determined over 12 months or less. 53. A method of diagnosing or assessing a neurocognitive disorder in a subject, said method comprises the steps of:
a) providing a sample comprising a tissue sample or a body fluid sample obtained from said subject having a neurocognitive disorder or symptoms thereof at a test time point; b) determining an amount or concentration of one or more biornarkers selected from a biomarker panel in the provided sample; c) comparing the amount or concentration of said one or more biomarkers in the provided sample with reference values for each of the selected biomarkers; wherein the test time point corresponds to a time when the method of diagnosing or assessing a neurocognitive disorder in the subject is carried out; and wherein the amount or concentration of the selected biomarkers in the sample is indicative of a presence absence or degree of progression of the neurocognitive disorder in said subject. 54. The method according to claim 46, wherein the amount or concentration of the selected biomarkers in the provided sample is used to predict the most appropriate and effective therapy to alleviate the neurocognitive disorder and to monitor the success of the therapy. 55. The method according to claim 46, wherein the amount or concentration of the selected biomarkers in the provided sample is detected by:
a) using one or more binding agents that specifically bind to the selected biomarkers, b) detecting autoantibodies in the sample specific to each of the selected biomarkers, c) mass spectrometry, or any combination of a), b) and c). 56. A kit comprising reagents for the detection of one or more biomarkers selected from a biomarker panel in a tissue sample or body fluid sample, wherein said biomarker panel comprises at least one of the following biomarkers: transthyretin (TTR), Clusterin, Cystatin C (CST3), Alpha-1-Acid glycoprotein (A1AcidG), Intercellular adhesion molecule 1 (ICAM1), Complement C4 (CC4), pigment epithelium derived factor (PELF) and Alpha1 antitrypsin (A1AT). 57. The kit according to claim 56, wherein the kit further comprises one or more binding agents which specifically bind to the one or more selected biomarkers. 58. The kit according to claim 57, wherein the one or more binding agents comprise a plurality of primary antibodies, wherein each primary antibody specifically binds to a different selected biomarker. 59. The kit according to claim 58, wherein the kit further comprises one or more secondary antibodies which specifically bind to one or more of the primary antibodies. 60. The kit according to claim 59, wherein the secondary antibodies are labeled. 61. The kit according to claim 56, wherein the kit further comprises a control sample for one or more of the selected biomarkers. 62. The kit according to claim 56, wherein the biomarker panel further comprises one or more of the following biomarkers: biomarkers that are regulated on activation, normal T cell expressed and secreted (RANTES), and Apolipoprotein C-III (ApoC3). 63. The kit according to claim 62, wherein the biomarker panel further comprises one or more of the following biomarkers: plasminogen activator inhibitor type 1 (PAI-1), C-reactive protein (CRP), Cathepsin D (CTSD) and apolipoprotein E (ApoE). 64. The kit according to claim 63, wherein the biomarker panel farther comprises one or more biomarkers selected from the group consisting of: alpha-2-macroglobulin (A2M), serum amyloid P component (SAP), advanced glycosylation end product-specific receptor (sRAGE), Neuron specific enolase (NSE), complement factor H (CFH), amyloid beta (A4) precursor protein (AB40 or Aβ40), Ceruloplasmin, neural cell adhesion molecule (NCAM), ApoA1, Abeta 42, BDNF, Beta-2-microglobulin (B2M), and VCAM-1. 65. The kit according to claim 56, wherein the biomarker panel further comprises ApoE ε4 allele presence (ApoE genotype). | Alzheimer's disease, the most common cause of dementia in older individuals, is a debilitating neurodegenerative disease for which there is currently no cure. In the past, AD could only be definitively diagnosed by brain biopsy or upon autopsy after a patient died. These methods, which demonstrate the presence of the characteristic plaque and tangle lesions in the brain, are still considered the gold standard for the pathological diagnoses of AD. However, in the clinical setting brain biopsy is rarely performed and diagnosis depends on a battery of neurological, psychometric and biochemical tests, including the measurement of biochemical markers such as the ApoE and tau proteins or the beta-amyloid peptide in cerebrospinal fluid and blood. The present invention discloses and describes panels of makers that are differentially expressed in the disease state relative to their expression in the normal state and, in particular, identifies and describes panels of makers associated with neurocognitive disorders. Such biomarker panel might have considerable value in triaging patients with early memory disorders to yet more specific but more invasive and costly approaches such as molecular markers in CSF and on PET imaging in clinical trials and possibly in clinical practice.1-45. (canceled) 46. A method for determining the progression and/or the prognosis of a neurocognitive disorder in a subject, said method comprises the steps of:
a) providing a sample comprising a tissue sample or a body fluid obtained from the subject having a neurocognitive disorder or symptoms thereof at a test time point; b) determining an amount or concentration of one or more biomarkers selected from a biomarker panel in the sample; c) comparing the amount or concentration of the selected biomarkers in the sample at the test time point with reference values for each of the selected biomarkers; wherein the test time point corresponds to a time when the method for determining the progression and/or the prognosis of a neurocognitive disorder is carried out; and wherein the amount or concentration of the selected biomarkers in the sample is indicative of the progression and/or the prognosis of the neurocognitive disorder in said subject, and wherein said biomarker panel comprises: transthyretin (TTR), Clusterin, Cystatin C (CST3), Alpha-1-Acid glycoprotein (A1AcidG). Intercellular adhesion molecule 1 (ICAM1), Complement C4 (CC4), pigment epithelium derived factor (PEDF) and Alpha1 antitrypsin (A1AT). 47. The method according to claim 46, wherein the amount or concentration of said selected markers in said sample is indicative of the progression and/or the prognosis of the neurocognitive disease. 48. The method according to claim 46, wherein the nature or degree of the neurocognitive disorder is determined. 49. The method according to claim 46, wherein the neurocognitive disorder is selected from the group consisting of: mild cognitive impairment (MCI), Alzheimer's disease (AD), vascular dementia, dementia with leery bodies, fronto-temporal dementia and combinations thereof. 50. The method according to claim 49, wherein the neurocognitive disorder is mild cognitive impairment (MCI) or Alzheimer's disease (AD). 51. The method according to claim 49, wherein the progression of the neurocognitive disorder is the conversion of mild cognitive impairment (MCI) to Alzheimer's disease (AD). 52. The method according to claim 51, wherein the conversion is determined over 12 months or less. 53. A method of diagnosing or assessing a neurocognitive disorder in a subject, said method comprises the steps of:
a) providing a sample comprising a tissue sample or a body fluid sample obtained from said subject having a neurocognitive disorder or symptoms thereof at a test time point; b) determining an amount or concentration of one or more biornarkers selected from a biomarker panel in the provided sample; c) comparing the amount or concentration of said one or more biomarkers in the provided sample with reference values for each of the selected biomarkers; wherein the test time point corresponds to a time when the method of diagnosing or assessing a neurocognitive disorder in the subject is carried out; and wherein the amount or concentration of the selected biomarkers in the sample is indicative of a presence absence or degree of progression of the neurocognitive disorder in said subject. 54. The method according to claim 46, wherein the amount or concentration of the selected biomarkers in the provided sample is used to predict the most appropriate and effective therapy to alleviate the neurocognitive disorder and to monitor the success of the therapy. 55. The method according to claim 46, wherein the amount or concentration of the selected biomarkers in the provided sample is detected by:
a) using one or more binding agents that specifically bind to the selected biomarkers, b) detecting autoantibodies in the sample specific to each of the selected biomarkers, c) mass spectrometry, or any combination of a), b) and c). 56. A kit comprising reagents for the detection of one or more biomarkers selected from a biomarker panel in a tissue sample or body fluid sample, wherein said biomarker panel comprises at least one of the following biomarkers: transthyretin (TTR), Clusterin, Cystatin C (CST3), Alpha-1-Acid glycoprotein (A1AcidG), Intercellular adhesion molecule 1 (ICAM1), Complement C4 (CC4), pigment epithelium derived factor (PELF) and Alpha1 antitrypsin (A1AT). 57. The kit according to claim 56, wherein the kit further comprises one or more binding agents which specifically bind to the one or more selected biomarkers. 58. The kit according to claim 57, wherein the one or more binding agents comprise a plurality of primary antibodies, wherein each primary antibody specifically binds to a different selected biomarker. 59. The kit according to claim 58, wherein the kit further comprises one or more secondary antibodies which specifically bind to one or more of the primary antibodies. 60. The kit according to claim 59, wherein the secondary antibodies are labeled. 61. The kit according to claim 56, wherein the kit further comprises a control sample for one or more of the selected biomarkers. 62. The kit according to claim 56, wherein the biomarker panel further comprises one or more of the following biomarkers: biomarkers that are regulated on activation, normal T cell expressed and secreted (RANTES), and Apolipoprotein C-III (ApoC3). 63. The kit according to claim 62, wherein the biomarker panel further comprises one or more of the following biomarkers: plasminogen activator inhibitor type 1 (PAI-1), C-reactive protein (CRP), Cathepsin D (CTSD) and apolipoprotein E (ApoE). 64. The kit according to claim 63, wherein the biomarker panel farther comprises one or more biomarkers selected from the group consisting of: alpha-2-macroglobulin (A2M), serum amyloid P component (SAP), advanced glycosylation end product-specific receptor (sRAGE), Neuron specific enolase (NSE), complement factor H (CFH), amyloid beta (A4) precursor protein (AB40 or Aβ40), Ceruloplasmin, neural cell adhesion molecule (NCAM), ApoA1, Abeta 42, BDNF, Beta-2-microglobulin (B2M), and VCAM-1. 65. The kit according to claim 56, wherein the biomarker panel further comprises ApoE ε4 allele presence (ApoE genotype). | 1,600 |
1,462 | 15,855,162 | 1,658 | The present invention relates to a method for purification of viral vectors, more closely it relates to purification of viral vectors from producer cells by using a single automated process. The method comprises the following steps: a) adding producer cells and cell lysis buffer to a processing container; b) mixing said producer cells and cell lysis buffer in said processing container to obtain a mixture; c) flowing said mixture through a chromatography column for purification of viral vectors, wherein the viral vectors are adsorbed on said chromatography column; and d) eluting viral vectors from the chromatography column into a product container. | 1. A method for isolation of viral vectors comprising a gene of interest following production by cultivation of said viral vectors in producer cells, comprising the following steps in a continuous workflow: a) adding producer cells and cell lysis buffer to a processing container; b) mixing said producer cells and cell lysis buffer in said processing container to form a mixture; c) flowing said mixture from the processing container through a chromatography column comprising affinity resin for purification of viral vectors, wherein the viral vectors are adsorbed on said resin in said chromatography column; and d) eluting viral vectors from the resin in the chromatography column into a product container. 2. Method according to claim 1, further comprising following step d) transfecting fresh producer cells with the eluted viral vectors; cultivating the transfected cells; and repeating steps a)-d) with the cultivated and transfected cells at least once. 3. Method according to claim 1, wherein the viral vectors eluted from the method is directed by the volume and saturation point of the resin in the chromatography column. 4. Method according to claim 1, comprising the following step after step c) or d): releasing wash buffer into the processing container to flush out cells/debris and eject it into a waste container. 5. Method according to claim 4, wherein the processing container, product container and column are mounted in a cassette, and wherein the cell lysis buffer, the wash buffer, an elution buffer and optionally a waste container are located outside the cassette. 6. Method according to claim 1, wherein the chromatography column is interchangeable with another chromatography column in the cassette and comprises affinity resin specific for a chosen viral vector. 7. Method according to claim 1, wherein the processing container is provided with an exit port completed with a filter to retain any intact cells/cellular debris within the processing container. 8. Method according to claim 1, wherein the viral vectors are lentivirus or gamma retrovirus. 9. Method according to claim 1, wherein the gene of interest comprises a disease-regulating gene, such as a gene encoding a chimeric antigen (CAR). 10. Method according to claim 2, further comprising the intermediate step of testing the purity of the eluted viral vectors in the product container in a quality assay involving SPR (surface plasmon resonance) detection before transfecting the fresh producer cells and repeating steps a)-d). 11. A method of cell therapy treatment in a patient in need thereof, comprising administering to the patient a treatment effective amount of viral vectors isolated according to claim 1. 12. The method according to claim 11, wherein the viral vectors are used for transformation of T cells into CAR T cells. 13. A kit comprising a processing container, a product container and an affinity column each mounted to a single cassette, and further comprising a source container for producer cells, a cell lysis buffer, a wash buffer, an elution buffer and optionally a waste container located outside the cassette. | The present invention relates to a method for purification of viral vectors, more closely it relates to purification of viral vectors from producer cells by using a single automated process. The method comprises the following steps: a) adding producer cells and cell lysis buffer to a processing container; b) mixing said producer cells and cell lysis buffer in said processing container to obtain a mixture; c) flowing said mixture through a chromatography column for purification of viral vectors, wherein the viral vectors are adsorbed on said chromatography column; and d) eluting viral vectors from the chromatography column into a product container.1. A method for isolation of viral vectors comprising a gene of interest following production by cultivation of said viral vectors in producer cells, comprising the following steps in a continuous workflow: a) adding producer cells and cell lysis buffer to a processing container; b) mixing said producer cells and cell lysis buffer in said processing container to form a mixture; c) flowing said mixture from the processing container through a chromatography column comprising affinity resin for purification of viral vectors, wherein the viral vectors are adsorbed on said resin in said chromatography column; and d) eluting viral vectors from the resin in the chromatography column into a product container. 2. Method according to claim 1, further comprising following step d) transfecting fresh producer cells with the eluted viral vectors; cultivating the transfected cells; and repeating steps a)-d) with the cultivated and transfected cells at least once. 3. Method according to claim 1, wherein the viral vectors eluted from the method is directed by the volume and saturation point of the resin in the chromatography column. 4. Method according to claim 1, comprising the following step after step c) or d): releasing wash buffer into the processing container to flush out cells/debris and eject it into a waste container. 5. Method according to claim 4, wherein the processing container, product container and column are mounted in a cassette, and wherein the cell lysis buffer, the wash buffer, an elution buffer and optionally a waste container are located outside the cassette. 6. Method according to claim 1, wherein the chromatography column is interchangeable with another chromatography column in the cassette and comprises affinity resin specific for a chosen viral vector. 7. Method according to claim 1, wherein the processing container is provided with an exit port completed with a filter to retain any intact cells/cellular debris within the processing container. 8. Method according to claim 1, wherein the viral vectors are lentivirus or gamma retrovirus. 9. Method according to claim 1, wherein the gene of interest comprises a disease-regulating gene, such as a gene encoding a chimeric antigen (CAR). 10. Method according to claim 2, further comprising the intermediate step of testing the purity of the eluted viral vectors in the product container in a quality assay involving SPR (surface plasmon resonance) detection before transfecting the fresh producer cells and repeating steps a)-d). 11. A method of cell therapy treatment in a patient in need thereof, comprising administering to the patient a treatment effective amount of viral vectors isolated according to claim 1. 12. The method according to claim 11, wherein the viral vectors are used for transformation of T cells into CAR T cells. 13. A kit comprising a processing container, a product container and an affinity column each mounted to a single cassette, and further comprising a source container for producer cells, a cell lysis buffer, a wash buffer, an elution buffer and optionally a waste container located outside the cassette. | 1,600 |
1,463 | 15,420,888 | 1,611 | The present invention relates to a topcoat composition for long-wear lip compositions comprising at least one silicone film-forming agent, as well as to systems, kits and methods of treating, making-up and enhancing the appearance of lips, including a long-wear lip composition comprising at least one silicone film-forming agent and a topcoat composition for application to the long-wear lip composition. | 1. (canceled) 2. (canceled) 3. A kit comprising (1) a long-wear lip composition comprising at least one silicone film-forming agent, and (2) a topcoat composition consisting essentially of at least one phenylated silicone oil and at least one wax. 4. A kit comprising (1) a long-wear lip composition comprising at least one silicone film-forming agent, and (2) a topcoat composition comprising at least one phenylated silicone oil and at least one wax, wherein the topcoat composition does not comprise diglyceryl polyacyladipate in an amount which inhibits the transfer-resistance of the long-wear lip composition after application. 5. A method for making-up lips with the kit of claim 4, comprising applying the long-wear lip composition (1) comprising at least one silicone film-forming agent to the lips, and applying the topcoat composition (2) comprising at least one phenylated silicone oil and at least one wax to the long-wear lip composition. 6. A method for making-up lips with the kit of claim 3, comprising applying the long-wear lip composition (1) comprising at least one silicone film-forming agent to the lips, and applying the topcoat composition (2) consisting essentially of at least one phenylated silicone oil and at least one wax to the long-wear lip composition. 7. (canceled) 8. (canceled) 9. (canceled) 10. (canceled) 11. The kit of claim 4, wherein the long-wear lip composition comprises:
from about 1% to about 30% by weight of at least one silicone elastomer; from about 2% to about 30% by weight of at least one non-volatile oil; from about 2% to about 35% by weight of at least one polyorganosiloxane copolymer; from about 5% to about 30% by weight of at least one silicone resin; from about 5% to about 50% of at least one volatile solvent; optionally at least one wax; optionally at least one colorant; and optionally at least one filler; wherein a ratio of the silicone elastomer to the at least one non-volatile oil is from about 1:0.02 to about 1:10; the weights being relative to the total weight of the long-wear lip composition, and wherein the topcoat composition comprises trimethyl pentaphenyl trisiloxane and at least one wax selected from the group consisting of beeswax, paraffin wax, microcrystalline wax, synthetic wax, and mixtures thereof. 12. The kit of claim 4, wherein the long-wear lip composition comprises:
from about 1% to about 30% by weight of at least one dimethicone crosspolymer; from about 2% to about 30% by weight of at least one non-volatile silicone oil having viscosity greater than or equal to 350 cSt; from about 2% to about 35% by weight of Nylon-611/Dimethicone copolymer; from about 5% to about 30% by weight of at least one siloxysilicate resin; from about 5% to about 50% of at least one volatile hydrocarbon solvent; optionally at least one wax; optionally at least one colorant; and optionally at least one filler; wherein a ratio of the silicone elastomer (a) to the at least one non-volatile oil (b) is from about 1:0.02 to about 1:10; the weights being relative to the total weight of the long-wear lip composition, and the topcoat composition comprises trimethyl pentaphenyl trisiloxane and at least one wax selected from the group consisting of beeswax, paraffin wax, microcrystalline wax, synthetic wax, and mixtures thereof. 13. (canceled) 14. The kit of claim 4, wherein the topcoat composition does not comprise: (1) synthetic esters of formula R1COOR2 in which R1 represents the residue of a linear or branched higher fatty acid containing from 7 to 40 carbon atoms and R2 represents a branched hydrocarbon-based chain containing from 3 to 40 carbon atoms (2) C8-C26 higher fatty acids; or (3) C8-C26 higher fatty alcohols in an amount which inhibits the transfer-resistance of the long-wear lip composition after application. 15. The kit of claim 11, wherein the topcoat composition does not comprise: (1) synthetic esters of formula R1COOR7 in which R1 represents the residue of a linear or branched higher fatty acid containing from 7 to 40 carbon atoms and R2 represents a branched hydrocarbon-based chain containing from 3 to 40 carbon atoms (2) C8-C26 higher fatty acids; or (3) C8-C26 higher fatty alcohols in an amount which inhibits the transfer-resistance of the long-wear lip composition after application. 16. The kit of claim 12, wherein the topcoat composition does not comprise: (1) synthetic esters of formula R1COOR7 in which R1 represents the residue of a linear or branched higher fatty acid containing from 7 to 40 carbon atoms and R2 represents a branched hydrocarbon-based chain containing from 3 to 40 carbon atoms (2) C8-C26 higher fatty acids; or (3) C8-C26 higher fatty alcohols in an amount which inhibits the transfer-resistance of the long-wear lip composition after application. 17. The kit of claim 4, wherein the topcoat composition consists of:
(a) about 75% to about 95% trimethyl pentaphenyl trisiloxane; (b) about 1% to about 5% beeswax; (c) about 5% to about 10% wax selected from the group consisting of ozokerite, paraffin wax, microcrystalline wax, synthetic wax, and mixtures thereof; (d) 0% to about 5% silicone film forming agent; (e) 0% to about 1% tocopheryl acetate; (f) 0% to 10% sucrose acetate isobutyrate; and (g) 0% to 0.25% fragrance. 18. The kit of claim 4, wherein the phenylated silicone oil is a linear or branched non-volatile polydimethylsiloxanes (PDMS) comprising phenyl groups which are pendent or at the end of the silicone chain. 19. The kit of claim 4, wherein the phenylated silicone oil is selected from the group consisting of a phenyl trimethylsiloxy trisiloxane, a phenyl trimethylsiloxy diphenylsiloxane, a diphenyl dimethicone, a diphenyl methyldiphenyl trisiloxane, a 2-phenylethyl trimethylsiloxysilicate, a trimethyl pentaphenyl trisiloxane and a trimethyl siloxyphenyl dimethicone. 20. The kit of claim 4, wherein a content of the phenylated silicone oil in the topcoat composition is an amount ranging from about 50% to about 96% by weight of the topcoat composition. 21. The kit of claim 4, wherein the wax is a lipophilic fatty compound that has a melting point greater than 45° C., and has anisotropic crystal organization in the solid state. 22. The kit of claim 3, wherein the wax is selected from the group consisting of beeswax, carnauba wax, candelilla wax, ouricoury wax, Japan wax, cork fiber wax, sugar cane wax, paraffin wax, lignite wax, microcrystalline waxes, lanolin wax, montan wax, ozokerites, hydrogenated oils, polyethylene waxes and esters of fatty acids and of glycerides that are solid at 40° C. 23. The kit of claim 3, wherein the phenylated silicone oil is a linear or branched non-volatile polydimethylsiloxanes (PDMS) comprising phenyl groups Which are pendent or at the end of the silicone chain. 24. The kit of claim 3, wherein the phenylated silicone oil is selected from the group consisting of a phenyl trimethylsiloxy trisiloxane, a phenyl trimethylsiloxy diphenylsiloxane, a diphenyl dimethicone, a diphenyl methyldiphenyl trisiloxane, a 2-phenylethyl trimethylsiloxysilicate, a trimethyl pentaphenyl trisiloxane and a trimethyl siloxyphenyl dimethicone. 25. The kit of claim 3, wherein a content of the phenylated silicone oil in the topcoat composition is an amount ranging from about 50% to about 96% by weight of the topcoat composition. 26. The kit of claim 3, wherein the wax is a lipophilic fatty compound that has a melting point greater than 45° C., and has anisotropic crystal organization in the solid state. 27. The kit of claim 3, wherein the wax is selected from the group consisting of beeswax, carnauba wax, candelilla wax, ouricoury wax, Japan wax, cork fiber wax, sugar cane wax, paraffin wax, lignite wax, mkrocrystalline waxes, lanolin wax, montan wax, ozokerites, hydrogenated oils, polyethylene waxes and esters of fatty acids and of glycerides that are solid at 40° C. | The present invention relates to a topcoat composition for long-wear lip compositions comprising at least one silicone film-forming agent, as well as to systems, kits and methods of treating, making-up and enhancing the appearance of lips, including a long-wear lip composition comprising at least one silicone film-forming agent and a topcoat composition for application to the long-wear lip composition.1. (canceled) 2. (canceled) 3. A kit comprising (1) a long-wear lip composition comprising at least one silicone film-forming agent, and (2) a topcoat composition consisting essentially of at least one phenylated silicone oil and at least one wax. 4. A kit comprising (1) a long-wear lip composition comprising at least one silicone film-forming agent, and (2) a topcoat composition comprising at least one phenylated silicone oil and at least one wax, wherein the topcoat composition does not comprise diglyceryl polyacyladipate in an amount which inhibits the transfer-resistance of the long-wear lip composition after application. 5. A method for making-up lips with the kit of claim 4, comprising applying the long-wear lip composition (1) comprising at least one silicone film-forming agent to the lips, and applying the topcoat composition (2) comprising at least one phenylated silicone oil and at least one wax to the long-wear lip composition. 6. A method for making-up lips with the kit of claim 3, comprising applying the long-wear lip composition (1) comprising at least one silicone film-forming agent to the lips, and applying the topcoat composition (2) consisting essentially of at least one phenylated silicone oil and at least one wax to the long-wear lip composition. 7. (canceled) 8. (canceled) 9. (canceled) 10. (canceled) 11. The kit of claim 4, wherein the long-wear lip composition comprises:
from about 1% to about 30% by weight of at least one silicone elastomer; from about 2% to about 30% by weight of at least one non-volatile oil; from about 2% to about 35% by weight of at least one polyorganosiloxane copolymer; from about 5% to about 30% by weight of at least one silicone resin; from about 5% to about 50% of at least one volatile solvent; optionally at least one wax; optionally at least one colorant; and optionally at least one filler; wherein a ratio of the silicone elastomer to the at least one non-volatile oil is from about 1:0.02 to about 1:10; the weights being relative to the total weight of the long-wear lip composition, and wherein the topcoat composition comprises trimethyl pentaphenyl trisiloxane and at least one wax selected from the group consisting of beeswax, paraffin wax, microcrystalline wax, synthetic wax, and mixtures thereof. 12. The kit of claim 4, wherein the long-wear lip composition comprises:
from about 1% to about 30% by weight of at least one dimethicone crosspolymer; from about 2% to about 30% by weight of at least one non-volatile silicone oil having viscosity greater than or equal to 350 cSt; from about 2% to about 35% by weight of Nylon-611/Dimethicone copolymer; from about 5% to about 30% by weight of at least one siloxysilicate resin; from about 5% to about 50% of at least one volatile hydrocarbon solvent; optionally at least one wax; optionally at least one colorant; and optionally at least one filler; wherein a ratio of the silicone elastomer (a) to the at least one non-volatile oil (b) is from about 1:0.02 to about 1:10; the weights being relative to the total weight of the long-wear lip composition, and the topcoat composition comprises trimethyl pentaphenyl trisiloxane and at least one wax selected from the group consisting of beeswax, paraffin wax, microcrystalline wax, synthetic wax, and mixtures thereof. 13. (canceled) 14. The kit of claim 4, wherein the topcoat composition does not comprise: (1) synthetic esters of formula R1COOR2 in which R1 represents the residue of a linear or branched higher fatty acid containing from 7 to 40 carbon atoms and R2 represents a branched hydrocarbon-based chain containing from 3 to 40 carbon atoms (2) C8-C26 higher fatty acids; or (3) C8-C26 higher fatty alcohols in an amount which inhibits the transfer-resistance of the long-wear lip composition after application. 15. The kit of claim 11, wherein the topcoat composition does not comprise: (1) synthetic esters of formula R1COOR7 in which R1 represents the residue of a linear or branched higher fatty acid containing from 7 to 40 carbon atoms and R2 represents a branched hydrocarbon-based chain containing from 3 to 40 carbon atoms (2) C8-C26 higher fatty acids; or (3) C8-C26 higher fatty alcohols in an amount which inhibits the transfer-resistance of the long-wear lip composition after application. 16. The kit of claim 12, wherein the topcoat composition does not comprise: (1) synthetic esters of formula R1COOR7 in which R1 represents the residue of a linear or branched higher fatty acid containing from 7 to 40 carbon atoms and R2 represents a branched hydrocarbon-based chain containing from 3 to 40 carbon atoms (2) C8-C26 higher fatty acids; or (3) C8-C26 higher fatty alcohols in an amount which inhibits the transfer-resistance of the long-wear lip composition after application. 17. The kit of claim 4, wherein the topcoat composition consists of:
(a) about 75% to about 95% trimethyl pentaphenyl trisiloxane; (b) about 1% to about 5% beeswax; (c) about 5% to about 10% wax selected from the group consisting of ozokerite, paraffin wax, microcrystalline wax, synthetic wax, and mixtures thereof; (d) 0% to about 5% silicone film forming agent; (e) 0% to about 1% tocopheryl acetate; (f) 0% to 10% sucrose acetate isobutyrate; and (g) 0% to 0.25% fragrance. 18. The kit of claim 4, wherein the phenylated silicone oil is a linear or branched non-volatile polydimethylsiloxanes (PDMS) comprising phenyl groups which are pendent or at the end of the silicone chain. 19. The kit of claim 4, wherein the phenylated silicone oil is selected from the group consisting of a phenyl trimethylsiloxy trisiloxane, a phenyl trimethylsiloxy diphenylsiloxane, a diphenyl dimethicone, a diphenyl methyldiphenyl trisiloxane, a 2-phenylethyl trimethylsiloxysilicate, a trimethyl pentaphenyl trisiloxane and a trimethyl siloxyphenyl dimethicone. 20. The kit of claim 4, wherein a content of the phenylated silicone oil in the topcoat composition is an amount ranging from about 50% to about 96% by weight of the topcoat composition. 21. The kit of claim 4, wherein the wax is a lipophilic fatty compound that has a melting point greater than 45° C., and has anisotropic crystal organization in the solid state. 22. The kit of claim 3, wherein the wax is selected from the group consisting of beeswax, carnauba wax, candelilla wax, ouricoury wax, Japan wax, cork fiber wax, sugar cane wax, paraffin wax, lignite wax, microcrystalline waxes, lanolin wax, montan wax, ozokerites, hydrogenated oils, polyethylene waxes and esters of fatty acids and of glycerides that are solid at 40° C. 23. The kit of claim 3, wherein the phenylated silicone oil is a linear or branched non-volatile polydimethylsiloxanes (PDMS) comprising phenyl groups Which are pendent or at the end of the silicone chain. 24. The kit of claim 3, wherein the phenylated silicone oil is selected from the group consisting of a phenyl trimethylsiloxy trisiloxane, a phenyl trimethylsiloxy diphenylsiloxane, a diphenyl dimethicone, a diphenyl methyldiphenyl trisiloxane, a 2-phenylethyl trimethylsiloxysilicate, a trimethyl pentaphenyl trisiloxane and a trimethyl siloxyphenyl dimethicone. 25. The kit of claim 3, wherein a content of the phenylated silicone oil in the topcoat composition is an amount ranging from about 50% to about 96% by weight of the topcoat composition. 26. The kit of claim 3, wherein the wax is a lipophilic fatty compound that has a melting point greater than 45° C., and has anisotropic crystal organization in the solid state. 27. The kit of claim 3, wherein the wax is selected from the group consisting of beeswax, carnauba wax, candelilla wax, ouricoury wax, Japan wax, cork fiber wax, sugar cane wax, paraffin wax, lignite wax, mkrocrystalline waxes, lanolin wax, montan wax, ozokerites, hydrogenated oils, polyethylene waxes and esters of fatty acids and of glycerides that are solid at 40° C. | 1,600 |
1,464 | 15,565,226 | 1,658 | The present invention relates to the cosmetic use of a composition including, as the active agent, 0.1 to 1 μM of a synthetic peptide of sequence His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 or one of the salts thereof in a physiologically suitable medium, in order to reduce or delay the appearance of cell senescence and signs of skin aging. The present invention also relates to a method for cosmetic treatment which relates to these novel uses, including comprising the steps of applying the composition, topically, at least once per day, for a period of at least two days. | 1. A method for reducing or delaying the appearance of cellular senescence and signs of skin aging selected from thinning of the skin, sagging, loss of moisture, skin atony, deep wrinkles and fine lines, loss of firmness and tone, dermal atrophy with the exception of pigmentary anomalies of the skin, the method comprising topically applying a composition comprising, as the active agent, between 0.1 and 1 μM of a synthetic peptide with sequence His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (SEQ ID NO: 1) or one of its salts in a physiologically acceptable medium, wherein the composition is applied topically, at least once per day, for a period of at least 2 days. 2. The method of claim 1, wherein the composition comprises between 0.5 and 1 μM of said synthetic peptide. 3. The method of claim 1, wherein the composition comprises less than 1 μM of said synthetic peptide. 4. The method of claim 1, wherein the composition is applied 2 times per day. 5. The method of claim 1, wherein the composition is applied over a period of at least 6 weeks. 6. The method of claim 1, wherein the composition is applied over a period of at least 3 months. 7. The method of claim 1, wherein said synthetic peptide increases the activity of prolidase and the synthesis of collagen. 8. The method of claim 1, wherein the signs of skin aging are wrinkles. 9. The method of claim 1, wherein the composition further comprises at least one other active agent for reinforcing the action of the active agent, selected from peptides, vitamin C and its derivatives, vitamins from group B, DHEA, phytosterols, salicylic acid and its derivatives, retinoids, flavonoids, amino sugars, azoles, metallic salts, peptide extracts of plant origin or polymers. 10. A cosmetic treatment method for reducing or delaying the appearance of cellular senescence and the signs of skin aging, the method comprising the topical application, at least once per day over a period of at least 2 days, of a composition comprising, as the active agent, between 0.1 and 1 μM of a synthetic peptide with the sequence His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (SEQ ID NO: 1) in a physiologically acceptable medium. | The present invention relates to the cosmetic use of a composition including, as the active agent, 0.1 to 1 μM of a synthetic peptide of sequence His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 or one of the salts thereof in a physiologically suitable medium, in order to reduce or delay the appearance of cell senescence and signs of skin aging. The present invention also relates to a method for cosmetic treatment which relates to these novel uses, including comprising the steps of applying the composition, topically, at least once per day, for a period of at least two days.1. A method for reducing or delaying the appearance of cellular senescence and signs of skin aging selected from thinning of the skin, sagging, loss of moisture, skin atony, deep wrinkles and fine lines, loss of firmness and tone, dermal atrophy with the exception of pigmentary anomalies of the skin, the method comprising topically applying a composition comprising, as the active agent, between 0.1 and 1 μM of a synthetic peptide with sequence His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (SEQ ID NO: 1) or one of its salts in a physiologically acceptable medium, wherein the composition is applied topically, at least once per day, for a period of at least 2 days. 2. The method of claim 1, wherein the composition comprises between 0.5 and 1 μM of said synthetic peptide. 3. The method of claim 1, wherein the composition comprises less than 1 μM of said synthetic peptide. 4. The method of claim 1, wherein the composition is applied 2 times per day. 5. The method of claim 1, wherein the composition is applied over a period of at least 6 weeks. 6. The method of claim 1, wherein the composition is applied over a period of at least 3 months. 7. The method of claim 1, wherein said synthetic peptide increases the activity of prolidase and the synthesis of collagen. 8. The method of claim 1, wherein the signs of skin aging are wrinkles. 9. The method of claim 1, wherein the composition further comprises at least one other active agent for reinforcing the action of the active agent, selected from peptides, vitamin C and its derivatives, vitamins from group B, DHEA, phytosterols, salicylic acid and its derivatives, retinoids, flavonoids, amino sugars, azoles, metallic salts, peptide extracts of plant origin or polymers. 10. A cosmetic treatment method for reducing or delaying the appearance of cellular senescence and the signs of skin aging, the method comprising the topical application, at least once per day over a period of at least 2 days, of a composition comprising, as the active agent, between 0.1 and 1 μM of a synthetic peptide with the sequence His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (SEQ ID NO: 1) in a physiologically acceptable medium. | 1,600 |
1,465 | 16,225,823 | 1,612 | The present invention relates to an oral care composition with a high water content which has improved robustness towards microbial challenge. The oral care composition includes compositions comprising from 0.125 wt % to 0.75 wt % of a water soluble source of stannous ions, wherein the composition comprises at least 50 wt % water and wherein the source of stannous ions is selected from the group consisting of stannous chloride, stannous pyrophosphate, stannous formate, stannous acetate, stannous gluconate, stannous lactate, stannous tartrate, stannous oxalate, stannous malonate, stannous citrate, stannous ethylene glyoxide, and mixtures thereof. | 1. An aqueous oral care composition comprising from 0.125 wt % to 0.75 wt % of a water soluble source of stannous ions, wherein the composition comprises at least 50 wt % water and wherein the source of stannous ions is selected from the group consisting of stannous chloride, stannous pyrophosphate, stannous formate, stannous acetate, stannous gluconate, stannous lactate, stannous tartrate, stannous oxalate, stannous malonate, stannous citrate, stannous ethylene glyoxide, and mixtures thereof. 2. The oral care composition of claim 1, wherein the composition comprises from 0.125 wt % to 0.5 wt % of the source of stannous ions. 3. The oral care composition of claim 2, wherein the composition comprises from 0.125 wt % to 0.3 wt % of the source of stannous ions. 4. The oral care composition of claim 2, wherein the composition comprises from 0.15 wt % to 0.3 wt % of the source of stannous ions. 5. The oral care composition of claim 1, wherein the source of stannous ions is stannous chloride. 6. The oral care composition of claim 1, wherein the composition comprises from 50 wt % to 65 wt % water. 7. The oral care composition of claim 6, wherein the composition comprises from 52 wt % to 60 wt % water. 8. The oral care composition of claim 6, wherein the composition comprises from 54 wt % to 55 wt % water. 9. The oral care composition of claim 1, further comprising a fluoride ion source selected from the group consisting of sodium fluoride, potassium fluoride, potassium monofluorophosphate, sodium monofluorophosphate, ammonium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, an amine fluoride, ammonium fluoride, and combinations thereof. 10. The oral care composition of claim 1, further comprising a source of zinc ions. 11. The oral care composition of claim 10, wherein the source of zinc ions comprises zinc oxide, zinc citrate, or mixtures thereof. 12. The oral care composition of claim 11, wherein the composition comprises zinc citrate in an amount of from 1.5 wt % to 2.5 wt %. 13. The oral care composition of claim 11, wherein the composition comprises zinc oxide in an amount of from 0.5 wt % to 1.5 wt %. 14. The oral care composition of claim 1, wherein the composition is a toothpaste, a tooth gel, a mouthrinse, a cream or an ointment. 15. The oral care composition of claim 1, wherein the composition is free of additional antibacterial or preservative agents. 16. The oral care composition of claim 1, wherein the composition has improved robustness towards microbial challenge. 17. A method of improving the robustness of an oral care composition containing at least 50 wt % water towards microbial challenge comprising adding to the oral care composition a water soluble source of stannous ions, wherein the source of stannous ions is present in the oral care composition at a concentration of from 0.1 wt % to 0.75 wt %, and wherein the source of stannous ions is selected from the group consisting of stannous chloride, stannous pyrophosphate, stannous formate, stannous acetate, stannous gluconate, stannous lactate, stannous tartrate, stannous oxalate, stannous malonate, stannous citrate, stannous ethylene glyoxide, and mixtures thereof. 18. The method of claim 17, wherein the composition comprises from 0.15 wt % to 0.3 wt % of the source of stannous ions. 19. The method of claim 17, wherein the source of stannous ions is stannous chloride. 20. The method of claim 17, wherein the composition comprises from 50 wt % to 60 wt % water. | The present invention relates to an oral care composition with a high water content which has improved robustness towards microbial challenge. The oral care composition includes compositions comprising from 0.125 wt % to 0.75 wt % of a water soluble source of stannous ions, wherein the composition comprises at least 50 wt % water and wherein the source of stannous ions is selected from the group consisting of stannous chloride, stannous pyrophosphate, stannous formate, stannous acetate, stannous gluconate, stannous lactate, stannous tartrate, stannous oxalate, stannous malonate, stannous citrate, stannous ethylene glyoxide, and mixtures thereof.1. An aqueous oral care composition comprising from 0.125 wt % to 0.75 wt % of a water soluble source of stannous ions, wherein the composition comprises at least 50 wt % water and wherein the source of stannous ions is selected from the group consisting of stannous chloride, stannous pyrophosphate, stannous formate, stannous acetate, stannous gluconate, stannous lactate, stannous tartrate, stannous oxalate, stannous malonate, stannous citrate, stannous ethylene glyoxide, and mixtures thereof. 2. The oral care composition of claim 1, wherein the composition comprises from 0.125 wt % to 0.5 wt % of the source of stannous ions. 3. The oral care composition of claim 2, wherein the composition comprises from 0.125 wt % to 0.3 wt % of the source of stannous ions. 4. The oral care composition of claim 2, wherein the composition comprises from 0.15 wt % to 0.3 wt % of the source of stannous ions. 5. The oral care composition of claim 1, wherein the source of stannous ions is stannous chloride. 6. The oral care composition of claim 1, wherein the composition comprises from 50 wt % to 65 wt % water. 7. The oral care composition of claim 6, wherein the composition comprises from 52 wt % to 60 wt % water. 8. The oral care composition of claim 6, wherein the composition comprises from 54 wt % to 55 wt % water. 9. The oral care composition of claim 1, further comprising a fluoride ion source selected from the group consisting of sodium fluoride, potassium fluoride, potassium monofluorophosphate, sodium monofluorophosphate, ammonium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, an amine fluoride, ammonium fluoride, and combinations thereof. 10. The oral care composition of claim 1, further comprising a source of zinc ions. 11. The oral care composition of claim 10, wherein the source of zinc ions comprises zinc oxide, zinc citrate, or mixtures thereof. 12. The oral care composition of claim 11, wherein the composition comprises zinc citrate in an amount of from 1.5 wt % to 2.5 wt %. 13. The oral care composition of claim 11, wherein the composition comprises zinc oxide in an amount of from 0.5 wt % to 1.5 wt %. 14. The oral care composition of claim 1, wherein the composition is a toothpaste, a tooth gel, a mouthrinse, a cream or an ointment. 15. The oral care composition of claim 1, wherein the composition is free of additional antibacterial or preservative agents. 16. The oral care composition of claim 1, wherein the composition has improved robustness towards microbial challenge. 17. A method of improving the robustness of an oral care composition containing at least 50 wt % water towards microbial challenge comprising adding to the oral care composition a water soluble source of stannous ions, wherein the source of stannous ions is present in the oral care composition at a concentration of from 0.1 wt % to 0.75 wt %, and wherein the source of stannous ions is selected from the group consisting of stannous chloride, stannous pyrophosphate, stannous formate, stannous acetate, stannous gluconate, stannous lactate, stannous tartrate, stannous oxalate, stannous malonate, stannous citrate, stannous ethylene glyoxide, and mixtures thereof. 18. The method of claim 17, wherein the composition comprises from 0.15 wt % to 0.3 wt % of the source of stannous ions. 19. The method of claim 17, wherein the source of stannous ions is stannous chloride. 20. The method of claim 17, wherein the composition comprises from 50 wt % to 60 wt % water. | 1,600 |
1,466 | 14,524,115 | 1,699 | A method for obtaining MNCs is set forth. The method includes: separating mononuclear cells from a biological fluid that includes red blood cells, plasma and platelets and collecting a targeted number of mononuclear cells in a suspension including plasma and residual red blood cells and platelets; concentrating the separated mononuclear cells; removing plasma from the concentrated mononuclear cells until the amount of residual plasma remaining with the concentrated mononuclear cells reaches a pre-determined volume; and adding a crystalloid solution to the concentrated mononuclear cells. Related apparatus and resultant MNC products are also disclosed. | 1. A method for obtaining mononuclear cells and preparing the mononuclear cells for photopheresis with a separation device comprising:
a) separating mononuclear cells from a biological fluid that includes red blood cells, plasma and platelets; b) collecting a targeted number of mononuclear cells in a suspension including plasma and residual red blood cells and platelets; c) concentrating said separated mononuclear cells; d) removing plasma from the concentrated mononuclear cells until the amount of residual plasma remaining with the concentrated mononuclear cells reaches a pre-determined volume; and e) adding a crystalloid solution to the concentrated mononuclear cells. 2. The method of claim 1 wherein said volume of residual plasma remaining with said concentrated mononuclear cells is less than or equal to (≦) 50 ml. 3. The method of claim 1 wherein the concentrated mononuclear cells after adding the crystalloid solution has a hematocrit of less than or equal to (≦) 2%. 4. The method of claim 1 wherein crystalloid solution is added to the concentrated mononuclear cells so that the volume % of plasma is less than or equal to (≦) 25%. 5. The method of claim 1 in which from 150 mL to 200 mL of crystalloid solution is added to the suspension. 6. The method of claim 1 further comprising collecting said mononuclear cells in a collection container suitable for irradiation of the mononuclear cells. 7. The method of claim 1 comprising separating and concentrating said mononuclear cells in one or more chambers of a processing apparatus. 8. The method of claim 7 comprising subjecting said processing apparatus to a centrifugal field sufficient to separate and concentrate said mononuclear cells. 9. The method of claim 1 wherein said biological fluid comprises whole blood. 10. The method of claim 1 wherein the suspension comprises a quantity of mononuclear cells recovered from separation device by flushing the separation device. 11. The method of claim 10 wherein the separation device is flushed with a crystalloid solution. 12. The method of claim 10 wherein the separation device is flushed with plasma. 13. The method of claim 11 wherein the separation device is flushed with 10 mL of crystalloid solution. 14. The method of claim 12 wherein the separation device is flushed with 10 mL of plasma. 15. A system for the collection of mononuclear cells comprising:
a) a reusable hardware apparatus, said apparatus including a separation device and a programmable microprocessor driven controller including instructions for processing a biological fluid; b) a disposable processing circuit associated with said apparatus, said circuit including a processing chamber for receiving a biological fluid and one or more containers for collecting mononuclear cells; c) wherein said controller is programmed to:
i. separate mononuclear cells from a biological fluid that includes red blood cells, plasma and platelets;
ii. concentrate said obtained mononuclear cells and remove plasma from the concentrated mononuclear cells until the amount of residual plasma remaining with the concentrated mononuclear cells reaches a pre-determined volume; and
iii. combine said obtained platelets with a crystalloid solution. 16. The system of claim 15 wherein said separation device comprises a rotatable element. 17. The system of claim 15 wherein said rotatable element generates a centrifugal field sufficient to separate mononuclear cells from other components of a biological fluid. 18. The system of claim 15 further comprising a source of a crystalloid solution. 19. The system of claim 15 wherein said controller is programmed to deliver a selected volume of said crystalloid solution to concentrated mononuclear cells in said residual amount of plasma. 20. A mononuclear cell product comprising mononuclear cells, plasma, crystalloid solution and residual red blood cells and platelets having a total volume of less than or equal to (≦) 200 mL and a hematocrit of less than or equal to (≦) 2%, wherein the volume % of plasma is less than or equal to (≦) 25% and the volume of residual plasma remaining with said concentrated mononuclear cells is less than or equal to (≦) 50 ml. 21. (canceled) 22. (canceled) | A method for obtaining MNCs is set forth. The method includes: separating mononuclear cells from a biological fluid that includes red blood cells, plasma and platelets and collecting a targeted number of mononuclear cells in a suspension including plasma and residual red blood cells and platelets; concentrating the separated mononuclear cells; removing plasma from the concentrated mononuclear cells until the amount of residual plasma remaining with the concentrated mononuclear cells reaches a pre-determined volume; and adding a crystalloid solution to the concentrated mononuclear cells. Related apparatus and resultant MNC products are also disclosed.1. A method for obtaining mononuclear cells and preparing the mononuclear cells for photopheresis with a separation device comprising:
a) separating mononuclear cells from a biological fluid that includes red blood cells, plasma and platelets; b) collecting a targeted number of mononuclear cells in a suspension including plasma and residual red blood cells and platelets; c) concentrating said separated mononuclear cells; d) removing plasma from the concentrated mononuclear cells until the amount of residual plasma remaining with the concentrated mononuclear cells reaches a pre-determined volume; and e) adding a crystalloid solution to the concentrated mononuclear cells. 2. The method of claim 1 wherein said volume of residual plasma remaining with said concentrated mononuclear cells is less than or equal to (≦) 50 ml. 3. The method of claim 1 wherein the concentrated mononuclear cells after adding the crystalloid solution has a hematocrit of less than or equal to (≦) 2%. 4. The method of claim 1 wherein crystalloid solution is added to the concentrated mononuclear cells so that the volume % of plasma is less than or equal to (≦) 25%. 5. The method of claim 1 in which from 150 mL to 200 mL of crystalloid solution is added to the suspension. 6. The method of claim 1 further comprising collecting said mononuclear cells in a collection container suitable for irradiation of the mononuclear cells. 7. The method of claim 1 comprising separating and concentrating said mononuclear cells in one or more chambers of a processing apparatus. 8. The method of claim 7 comprising subjecting said processing apparatus to a centrifugal field sufficient to separate and concentrate said mononuclear cells. 9. The method of claim 1 wherein said biological fluid comprises whole blood. 10. The method of claim 1 wherein the suspension comprises a quantity of mononuclear cells recovered from separation device by flushing the separation device. 11. The method of claim 10 wherein the separation device is flushed with a crystalloid solution. 12. The method of claim 10 wherein the separation device is flushed with plasma. 13. The method of claim 11 wherein the separation device is flushed with 10 mL of crystalloid solution. 14. The method of claim 12 wherein the separation device is flushed with 10 mL of plasma. 15. A system for the collection of mononuclear cells comprising:
a) a reusable hardware apparatus, said apparatus including a separation device and a programmable microprocessor driven controller including instructions for processing a biological fluid; b) a disposable processing circuit associated with said apparatus, said circuit including a processing chamber for receiving a biological fluid and one or more containers for collecting mononuclear cells; c) wherein said controller is programmed to:
i. separate mononuclear cells from a biological fluid that includes red blood cells, plasma and platelets;
ii. concentrate said obtained mononuclear cells and remove plasma from the concentrated mononuclear cells until the amount of residual plasma remaining with the concentrated mononuclear cells reaches a pre-determined volume; and
iii. combine said obtained platelets with a crystalloid solution. 16. The system of claim 15 wherein said separation device comprises a rotatable element. 17. The system of claim 15 wherein said rotatable element generates a centrifugal field sufficient to separate mononuclear cells from other components of a biological fluid. 18. The system of claim 15 further comprising a source of a crystalloid solution. 19. The system of claim 15 wherein said controller is programmed to deliver a selected volume of said crystalloid solution to concentrated mononuclear cells in said residual amount of plasma. 20. A mononuclear cell product comprising mononuclear cells, plasma, crystalloid solution and residual red blood cells and platelets having a total volume of less than or equal to (≦) 200 mL and a hematocrit of less than or equal to (≦) 2%, wherein the volume % of plasma is less than or equal to (≦) 25% and the volume of residual plasma remaining with said concentrated mononuclear cells is less than or equal to (≦) 50 ml. 21. (canceled) 22. (canceled) | 1,600 |
1,467 | 11,545,986 | 1,634 | Described herein are novel SCCmec right extremity junction (MREJ) sequences for the detection and/or identification of methicillin-resistant Staphylococcus aureus (MRSA). Disclosed are methods and compositions based on DNA sequences for the specific detection of MREJ sequences designated types xi, xii, xiii, xiv, xv, xvi, xvii, xviii, xix, and xx for diagnostic purposes and/or epidemiological typing. | 1. A method of detecting the presence of a methicillin-resistant Staphylococcus aureus (MRSA) strain in a sample comprising nucleic acids, wherein the MRSA strain comprises an SCCmec insert comprising a mecA gene inserted in bacterial nucleic acids, and wherein the insertion of said SSCmec insert in the bacterial nucleic acids generates a polymorphic right extremity junction (MREJ), said method comprising:
providing at least one primer and/or probe that is specific for MRSA strains, wherein the primer and/or probe anneals to at least one polymorphic MREJ nucleic acid of types xi to xx; annealing the nucleic acids of the sample with the primer(s) and/or probe(s), wherein annealed primer(s) and/or probe(s) indicate the presence of an MRSA strain in the sample; and detecting the presence and/or amount of annealed probe(s), or detecting the amount of an amplification product produced through annealing of the primers to the nucleic acids, as an indication of the presence and/or amount of MRSA. 2. The method of claim 1, wherein the providing step further comprises providing a plurality of primers and/or probes that can anneal with at least one MREJ type selected from MREJ type xi, xii, xiii, xiv, xv, xvi, xvii, xviii, xix, and xx. 3. The method of claim 2, further comprising a DNA amplification step, wherein the DNA amplification is PCR, LCR, NABSA, 3SR, SDA, bDNA, TMA, CPT, SPA, NDSA, rolling circle amplification, anchored strand displacement amplification, solid phase (immobilized) rolling circle amplification, or Q beta replicase amplification. 4. The method of claim 2, wherein the plurality of primers and/or probes can anneal with at least four MREJ types selected from MREJ type xi, xii, xiii, xiv, xv, xvi, xvii, xviii, xix, and xx. 5. The method of claim 2, wherein the primers and/or probes anneal under common annealing conditions. 6. The method of claim 5, wherein the primer and/or probes are provided in the same physical enclosure. 7. The method of claim 1, wherein the primers and/or probes are at least 10, 12, 14, 16, 18, 20, 25, or 30 nucleotides in length. 8. The method of claim 1, wherein the primers and/or probes are capable of annealing to at least one of SEQ ID NOs: 15, 16, 17, 18, 19, 20, 21, 25, 26, 39, 40, 41, 42, 55, and 56. 9. The method of claim 2, wherein at least one primer and/or probe of the plurality of primers and/or probes is capable of annealing to each of SEQ ID NOs: 15, 16, 17, 18, 19, 20, 21, 25, 26, 39, 40, 41, 42, 55, and 56. 10. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 51, 30, 31, 32, and 33 for the detection of MREJ type xi. 11. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 52, 30, 31, 32, and 33, for the detection of MREJ type xii. 12. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 29, 30, 31, 32, and 33 for the detection of MREJ type xiii. 13. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 29, 30, 31, 32, and 33 for the detection of MREJ type xiv. 14. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 24, 30, 31, 32, and 33 for the detection of MREJ type xv. 15. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 36 and 44 for the detection of MREJ type xvi. 16. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 4, 30, 31, 32, and 33 for the detection of MREJ type xvii. 17. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 7, 30, 31, 32, and 33 for the detection of MREJ type xviii. 18. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 9, 30, 31, 32, and 33 for the detection of MREJ type xix. 19. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 8, 30, 31, 32, and 33 for the detection of MREJ type xx. 20. The method of claim 2, wherein the plurality of primers and/or probes comprises
SEQ ID NOs: 51, 30, 31, 32, and 33 for the detection of MREJ type xi, SEQ ID NOs: 52, 30, 31, 32, and 33 for the detection of MREJ type xii, SEQ ID NOs: 29, 30, 31, 32, and 33 for the detection of MREJ type xiii SEQ ID NOs: 29, 30, 31, 32, and 33 for the detection of MREJ type xiv, SEQ ID NOs: 24, 30, 31, 32, and 33 for the detection of MREJ type xv SEQ ID NOs: 36 and 44 for the detection of MREJ type xvi, SEQ ID NOs: 4, 30, 31, 32, and 33 for the detection of MREJ type xvii, SEQ ID NOs: 7, 30, 31, 32, and 33 for the detection of MREJ type xviii, SEQ ID NOs: 9, 30, 31, 32, and 33 for the detection of MREJ type xix, and SEQ ID NOs: 8, 30, 31, 32, and 33 for the detection of MREJ type xx. 21. The method of claim 10, wherein the plurality of primers and/or probes further comprises the primers and/or probes of SEQ ID NOs: 34, 44, 45, and 76 for the detection of MREJ type xi. 22. The method of claim 11, wherein the plurality of primers and/or probes further comprises the primers and/or probes of SEQ ID NOs: 34, 44, 45, 52, and 62 for the detection of MREJ type xii. 23. The method of claim 12, wherein the plurality of primers and/or probes further comprises the primers and/or probes of SEQ ID NOs: 33, 44, 45, and 76, for the detection of MREJ type xiii. 24. The method of claim 13, wherein the plurality of primers and/or probes further comprises the primers and/or probes of SEQ ID NOs: 44, 45, and 59 for the detection of MREJ type xiv. 25. The method of claim 14, wherein the plurality of primers and/or probes further comprises the primers and/or probes of SEQ ID NOs: 4, 45, and 62 for the detection of MREJ type xv. 26. The method of claim 16, wherein the plurality of primers and/or probes further comprises the primers and/or probes of SEQ ID NOs: 44, 45, and 62 for the detection of MREJ type xvii. 27. The method of claim 17, wherein the plurality of primers and/or probes further comprises the primers and/or probes of SEQ ID NOs: 44, 45, and 59 for the detection of MREJ type xviii. 28. The method of claim 18, wherein the plurality of primers and/or probes further comprises the primers and/or probes of SEQ ID NOs: 44, 45, and 59 for the detection of MREJ type xix. 29. The method of claim 19, wherein the plurality of primers and/or probes further comprises the primers and/or probes of SEQ ID NOs: 44, 45, and 59 for the detection of MREJ type xx. 30. The method of claim 20, further comprising the primers and/or probes of SEQ ID NOs: 34, 35, 44, 45, 52, 59, 62, 76. 31. The method of claim 21, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 34/45, 34/30, 34/76, and 34/44, for the detection of MREJ type xi. 32. The method of claim 22, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 35/45, 35/30, 35/62, and 35/44, for the detection of MREJ type xii. 33. The method of claim 23, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 29/45, 29/30, 29/76, and 29/44, for the detection of MREJ type xiii. 34. The method of claim 24, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 29/45, 29/30, 29/59, and 29/44, for the detection of MREJ type xiv. 35. The method of claim 25, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 24/45, 24/30, 24/62, and 24/44, for the detection of MREJ type xv. 36. The method of claim 26, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 4/45, 4/30, 4/62, and 4/44 for the detection of MREJ type xvii. 37. The method of claim 27, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 7/45, 7/30, 7/59, and 7/44 for the detection of MREJ type xviii. 38. The method of claim 28, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 9/45, 9/30, 9/59, and 9/44 for the detection of MREJ type xix. 39. The method of claim 29, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 8/45, 8/30, 8/59, and 8/44 for the detection of MREJ type xx. 40. The method of claim 30, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 34/45, 34/30, 34/76, and 34/44 for the detection of MREJ type xi; SEQ ID NOs: 35/45, 35/30, 35/62, and 35/44 for the detection of MREJ type xii; SEQ ID NOs: 29/45, 29/30, 29/76, and 29/44 for the detection of MREJ type xiii; SEQ ID NOs: 29/45, 29/30, 29/59, and 29/44 for the detection of MREJ type xiv; SEQ ID NOs: 24/45, 24/30, 24/62, and 24/44 for the detection of MREJ type xv′ SEQ ID NOs: 36/44 for the detection of MREJ type xvi; SEQ ID NOs: 4/45, 4/30, 4/62, and 4/44 for the detection of MREJ type xvii; SEQ ID NOs: 7/45, 7/30, 7/59, and 7/44 for the detection of MREJ type xviii; SEQ ID NOs: 9/45, 9/30, 9/59, and 9/44 for the detection of MREJ type xix; and SEQ ID NOs: 8/45, 8/30, 8/59, and 8/44 for the detection of MREJ type xx. 41. The method of claim 40, further comprising probes having the following sequences:
SEQ ID NOs: 30, 31, and 32 for the detection of MREJ types to xi to xx. 42. The method of claim 40, wherein said probes and primers are used together. 43. The method of claim 42, wherein said probes and/or primers are used together in the same physical enclosure. 44. The method of claim 1, further comprising detecting an annealed probe and/or primer as an indication of the presence of a determined MREJ type from type xi to xx. 45. The method of claim 44, wherein the method of detection is selected from the group comprising: agarose gel electrophoresis, fluorescence resonance energy transfer, TaqMan probe, molecular beacon probe, Scorpion probe, nanoparticle probe, Ampliflour probe, chemiluminescence, potentiometry, mass spectrometry, plasmon resonance, polarimetry, colorimetry, flow cytometry, scanometry, and DNA sequencing. 46. A nucleic acid selected from the group consisting of:
SEQ ID NOs: 17, 18, 19 (MREJ type xi); SEQ ID NO: 20 (MREJ type xii); SEQ ID NOs: 15, 25, 26 (MREJ type xiii); SEQ ID NO: 16 (MREJ type xiv); SEQ ID NO: 56 (MREJ type xv); SEQ ID NO: 21 (MREJ type xvi); SEQ ID NO: 55 (MREJ type xvii); SEQ ID NOs: 39, 40 (MREJ type xviii); SEQ ID NO: 41 (MREJ type xix); and SEQ ID NO: 42 (MREJ type xx), or the complement thereof. 47. An oligonucleotide of at least 10 nucleotides in length which hybridizes under stringent conditions with a nucleic acid of claim 46. 48. An oligonucleotide pair selected from the group consisting of:
oligonucleotides comprising the sequences of SEQ ID NOs: 34/45, 34/30, 34/76, and 34/44, for the detection of MREJ type xi, oligonucleotides comprising the sequences of SEQ ID NOs: 35/45, 35/30, 35/62, and 35/44 for the detection of MREJ type xii, oligonucleotides comprising the sequences of SEQ ID NOs: 29/45, 29/30, 29/76, and 29/44 for the detection of MREJ type xiii, oligonucleotides comprising the sequences of SEQ ID NOs: 29/45, 29/30, 29/59, and 29/44 for the detection of MREJ type xiv, oligonucleotides comprising the sequences of SEQ ID NOs: 24/45, 24/30, 24/62, and 24/44 for the detection of MREJ type xv, oligonucleotides comprising the sequences of SEQ ID NOs: 36/44 for the detection of MREJ type xvi, oligonucleotides comprising the sequences of SEQ ID NOs: 4/45, 4/30, 4/62, and 4/44 for the detection of MREJ type xvii, oligonucleotides comprising the sequences of SEQ ID NOs: 7/45, 7/30, 7/59, and 7/44 for the detection of MREJ type xviii, oligonucleotides comprising the sequences of SEQ ID NOs: 9/45, 9/30, 9/59, and 9/44 for the detection of MREJ type xix, and oligonucleotides comprising the sequences of SEQ ID NOs: 8/45, 8/30, 8/59, and 8/44 for the detection of MREJ type xx. 49. An oligonucleotide comprising the sequence of SEQ ID NO: 31, 32, or 33. 50. A kit comprising a plurality of primers and/or probes, wherein the primers and/or probes are at least 10, 12, 14, 16, 18, 20, 25, or 30 nucleotides in length, and wherein the primers and/or probes hybridize under stringent conditions to at least one of the nucleic acids of claim 46, and wherein the plurality of primers and/or probes hybridizes with at least one MREJ of types selected from xi to xx. 51. The kit of claim 50, further comprising primers and/or probes, which hybridize with one or more MREJ of types selected from i to x. 52. The kit of claim 51, further comprising primer pairs, wherein the primer pairs comprise the nucleotide sequences of SEQ ID NOs:
30/36 for the detection of MREJ type i; 30/36 for the detection of MREJ type ii; 30/70 for the detection of MREJ type iii; 30/71 for the detection of MREJ type iv; 30/72 for the detection of MREJ type v; 30/65 for the detection of MREJ type vi; 30/74 for the detection of MREJ type vii; 30/75 for the detection of MREJ type viii; 30/29 for the detection of MREJ type ix; 73/77 for the detection of MREJ type x; 34/45, 34/30, 34/76, 34/44 for the detection of MREJ type xi; 35/45, 35/30, 35/62, 35/44 for the detection of MREJ type xii; 29/45, 29/30, 29/76, 29/44 for the detection of MREJ type xiii; 29/45, 29/30, 29/59, 29/44 for the detection of MREJ type xiv; 24/45, 24/30, 24/62, 24/44 for the detection of MREJ type xv; 36/44 for the detection of MREJ type xvi; 4/45, 4/30, 4/62, 4/44 for the detection of MREJ type xvii; 7/45, 7/30, 7/59, 7/44 for the detection of MREJ type xviii; 9/45, 9/30, 9/59, 9/44 for the detection of MREJ type xix; and 8/45, 8/30, 8/59, 8/44 for the detection of MREJ type xx. 53. The kit of claim 51, further comprising probes, wherein the probes comprise the nucleic acid sequence of SEQ ID NOs: 31, 32, 33. | Described herein are novel SCCmec right extremity junction (MREJ) sequences for the detection and/or identification of methicillin-resistant Staphylococcus aureus (MRSA). Disclosed are methods and compositions based on DNA sequences for the specific detection of MREJ sequences designated types xi, xii, xiii, xiv, xv, xvi, xvii, xviii, xix, and xx for diagnostic purposes and/or epidemiological typing.1. A method of detecting the presence of a methicillin-resistant Staphylococcus aureus (MRSA) strain in a sample comprising nucleic acids, wherein the MRSA strain comprises an SCCmec insert comprising a mecA gene inserted in bacterial nucleic acids, and wherein the insertion of said SSCmec insert in the bacterial nucleic acids generates a polymorphic right extremity junction (MREJ), said method comprising:
providing at least one primer and/or probe that is specific for MRSA strains, wherein the primer and/or probe anneals to at least one polymorphic MREJ nucleic acid of types xi to xx; annealing the nucleic acids of the sample with the primer(s) and/or probe(s), wherein annealed primer(s) and/or probe(s) indicate the presence of an MRSA strain in the sample; and detecting the presence and/or amount of annealed probe(s), or detecting the amount of an amplification product produced through annealing of the primers to the nucleic acids, as an indication of the presence and/or amount of MRSA. 2. The method of claim 1, wherein the providing step further comprises providing a plurality of primers and/or probes that can anneal with at least one MREJ type selected from MREJ type xi, xii, xiii, xiv, xv, xvi, xvii, xviii, xix, and xx. 3. The method of claim 2, further comprising a DNA amplification step, wherein the DNA amplification is PCR, LCR, NABSA, 3SR, SDA, bDNA, TMA, CPT, SPA, NDSA, rolling circle amplification, anchored strand displacement amplification, solid phase (immobilized) rolling circle amplification, or Q beta replicase amplification. 4. The method of claim 2, wherein the plurality of primers and/or probes can anneal with at least four MREJ types selected from MREJ type xi, xii, xiii, xiv, xv, xvi, xvii, xviii, xix, and xx. 5. The method of claim 2, wherein the primers and/or probes anneal under common annealing conditions. 6. The method of claim 5, wherein the primer and/or probes are provided in the same physical enclosure. 7. The method of claim 1, wherein the primers and/or probes are at least 10, 12, 14, 16, 18, 20, 25, or 30 nucleotides in length. 8. The method of claim 1, wherein the primers and/or probes are capable of annealing to at least one of SEQ ID NOs: 15, 16, 17, 18, 19, 20, 21, 25, 26, 39, 40, 41, 42, 55, and 56. 9. The method of claim 2, wherein at least one primer and/or probe of the plurality of primers and/or probes is capable of annealing to each of SEQ ID NOs: 15, 16, 17, 18, 19, 20, 21, 25, 26, 39, 40, 41, 42, 55, and 56. 10. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 51, 30, 31, 32, and 33 for the detection of MREJ type xi. 11. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 52, 30, 31, 32, and 33, for the detection of MREJ type xii. 12. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 29, 30, 31, 32, and 33 for the detection of MREJ type xiii. 13. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 29, 30, 31, 32, and 33 for the detection of MREJ type xiv. 14. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 24, 30, 31, 32, and 33 for the detection of MREJ type xv. 15. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 36 and 44 for the detection of MREJ type xvi. 16. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 4, 30, 31, 32, and 33 for the detection of MREJ type xvii. 17. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 7, 30, 31, 32, and 33 for the detection of MREJ type xviii. 18. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 9, 30, 31, 32, and 33 for the detection of MREJ type xix. 19. The method of claim 2, wherein the plurality of primers and/or probes comprises SEQ ID NOs: 8, 30, 31, 32, and 33 for the detection of MREJ type xx. 20. The method of claim 2, wherein the plurality of primers and/or probes comprises
SEQ ID NOs: 51, 30, 31, 32, and 33 for the detection of MREJ type xi, SEQ ID NOs: 52, 30, 31, 32, and 33 for the detection of MREJ type xii, SEQ ID NOs: 29, 30, 31, 32, and 33 for the detection of MREJ type xiii SEQ ID NOs: 29, 30, 31, 32, and 33 for the detection of MREJ type xiv, SEQ ID NOs: 24, 30, 31, 32, and 33 for the detection of MREJ type xv SEQ ID NOs: 36 and 44 for the detection of MREJ type xvi, SEQ ID NOs: 4, 30, 31, 32, and 33 for the detection of MREJ type xvii, SEQ ID NOs: 7, 30, 31, 32, and 33 for the detection of MREJ type xviii, SEQ ID NOs: 9, 30, 31, 32, and 33 for the detection of MREJ type xix, and SEQ ID NOs: 8, 30, 31, 32, and 33 for the detection of MREJ type xx. 21. The method of claim 10, wherein the plurality of primers and/or probes further comprises the primers and/or probes of SEQ ID NOs: 34, 44, 45, and 76 for the detection of MREJ type xi. 22. The method of claim 11, wherein the plurality of primers and/or probes further comprises the primers and/or probes of SEQ ID NOs: 34, 44, 45, 52, and 62 for the detection of MREJ type xii. 23. The method of claim 12, wherein the plurality of primers and/or probes further comprises the primers and/or probes of SEQ ID NOs: 33, 44, 45, and 76, for the detection of MREJ type xiii. 24. The method of claim 13, wherein the plurality of primers and/or probes further comprises the primers and/or probes of SEQ ID NOs: 44, 45, and 59 for the detection of MREJ type xiv. 25. The method of claim 14, wherein the plurality of primers and/or probes further comprises the primers and/or probes of SEQ ID NOs: 4, 45, and 62 for the detection of MREJ type xv. 26. The method of claim 16, wherein the plurality of primers and/or probes further comprises the primers and/or probes of SEQ ID NOs: 44, 45, and 62 for the detection of MREJ type xvii. 27. The method of claim 17, wherein the plurality of primers and/or probes further comprises the primers and/or probes of SEQ ID NOs: 44, 45, and 59 for the detection of MREJ type xviii. 28. The method of claim 18, wherein the plurality of primers and/or probes further comprises the primers and/or probes of SEQ ID NOs: 44, 45, and 59 for the detection of MREJ type xix. 29. The method of claim 19, wherein the plurality of primers and/or probes further comprises the primers and/or probes of SEQ ID NOs: 44, 45, and 59 for the detection of MREJ type xx. 30. The method of claim 20, further comprising the primers and/or probes of SEQ ID NOs: 34, 35, 44, 45, 52, 59, 62, 76. 31. The method of claim 21, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 34/45, 34/30, 34/76, and 34/44, for the detection of MREJ type xi. 32. The method of claim 22, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 35/45, 35/30, 35/62, and 35/44, for the detection of MREJ type xii. 33. The method of claim 23, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 29/45, 29/30, 29/76, and 29/44, for the detection of MREJ type xiii. 34. The method of claim 24, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 29/45, 29/30, 29/59, and 29/44, for the detection of MREJ type xiv. 35. The method of claim 25, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 24/45, 24/30, 24/62, and 24/44, for the detection of MREJ type xv. 36. The method of claim 26, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 4/45, 4/30, 4/62, and 4/44 for the detection of MREJ type xvii. 37. The method of claim 27, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 7/45, 7/30, 7/59, and 7/44 for the detection of MREJ type xviii. 38. The method of claim 28, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 9/45, 9/30, 9/59, and 9/44 for the detection of MREJ type xix. 39. The method of claim 29, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 8/45, 8/30, 8/59, and 8/44 for the detection of MREJ type xx. 40. The method of claim 30, wherein the primers are provided in pairs, wherein the primer pair is selected from the group consisting of:
SEQ ID NOs: 34/45, 34/30, 34/76, and 34/44 for the detection of MREJ type xi; SEQ ID NOs: 35/45, 35/30, 35/62, and 35/44 for the detection of MREJ type xii; SEQ ID NOs: 29/45, 29/30, 29/76, and 29/44 for the detection of MREJ type xiii; SEQ ID NOs: 29/45, 29/30, 29/59, and 29/44 for the detection of MREJ type xiv; SEQ ID NOs: 24/45, 24/30, 24/62, and 24/44 for the detection of MREJ type xv′ SEQ ID NOs: 36/44 for the detection of MREJ type xvi; SEQ ID NOs: 4/45, 4/30, 4/62, and 4/44 for the detection of MREJ type xvii; SEQ ID NOs: 7/45, 7/30, 7/59, and 7/44 for the detection of MREJ type xviii; SEQ ID NOs: 9/45, 9/30, 9/59, and 9/44 for the detection of MREJ type xix; and SEQ ID NOs: 8/45, 8/30, 8/59, and 8/44 for the detection of MREJ type xx. 41. The method of claim 40, further comprising probes having the following sequences:
SEQ ID NOs: 30, 31, and 32 for the detection of MREJ types to xi to xx. 42. The method of claim 40, wherein said probes and primers are used together. 43. The method of claim 42, wherein said probes and/or primers are used together in the same physical enclosure. 44. The method of claim 1, further comprising detecting an annealed probe and/or primer as an indication of the presence of a determined MREJ type from type xi to xx. 45. The method of claim 44, wherein the method of detection is selected from the group comprising: agarose gel electrophoresis, fluorescence resonance energy transfer, TaqMan probe, molecular beacon probe, Scorpion probe, nanoparticle probe, Ampliflour probe, chemiluminescence, potentiometry, mass spectrometry, plasmon resonance, polarimetry, colorimetry, flow cytometry, scanometry, and DNA sequencing. 46. A nucleic acid selected from the group consisting of:
SEQ ID NOs: 17, 18, 19 (MREJ type xi); SEQ ID NO: 20 (MREJ type xii); SEQ ID NOs: 15, 25, 26 (MREJ type xiii); SEQ ID NO: 16 (MREJ type xiv); SEQ ID NO: 56 (MREJ type xv); SEQ ID NO: 21 (MREJ type xvi); SEQ ID NO: 55 (MREJ type xvii); SEQ ID NOs: 39, 40 (MREJ type xviii); SEQ ID NO: 41 (MREJ type xix); and SEQ ID NO: 42 (MREJ type xx), or the complement thereof. 47. An oligonucleotide of at least 10 nucleotides in length which hybridizes under stringent conditions with a nucleic acid of claim 46. 48. An oligonucleotide pair selected from the group consisting of:
oligonucleotides comprising the sequences of SEQ ID NOs: 34/45, 34/30, 34/76, and 34/44, for the detection of MREJ type xi, oligonucleotides comprising the sequences of SEQ ID NOs: 35/45, 35/30, 35/62, and 35/44 for the detection of MREJ type xii, oligonucleotides comprising the sequences of SEQ ID NOs: 29/45, 29/30, 29/76, and 29/44 for the detection of MREJ type xiii, oligonucleotides comprising the sequences of SEQ ID NOs: 29/45, 29/30, 29/59, and 29/44 for the detection of MREJ type xiv, oligonucleotides comprising the sequences of SEQ ID NOs: 24/45, 24/30, 24/62, and 24/44 for the detection of MREJ type xv, oligonucleotides comprising the sequences of SEQ ID NOs: 36/44 for the detection of MREJ type xvi, oligonucleotides comprising the sequences of SEQ ID NOs: 4/45, 4/30, 4/62, and 4/44 for the detection of MREJ type xvii, oligonucleotides comprising the sequences of SEQ ID NOs: 7/45, 7/30, 7/59, and 7/44 for the detection of MREJ type xviii, oligonucleotides comprising the sequences of SEQ ID NOs: 9/45, 9/30, 9/59, and 9/44 for the detection of MREJ type xix, and oligonucleotides comprising the sequences of SEQ ID NOs: 8/45, 8/30, 8/59, and 8/44 for the detection of MREJ type xx. 49. An oligonucleotide comprising the sequence of SEQ ID NO: 31, 32, or 33. 50. A kit comprising a plurality of primers and/or probes, wherein the primers and/or probes are at least 10, 12, 14, 16, 18, 20, 25, or 30 nucleotides in length, and wherein the primers and/or probes hybridize under stringent conditions to at least one of the nucleic acids of claim 46, and wherein the plurality of primers and/or probes hybridizes with at least one MREJ of types selected from xi to xx. 51. The kit of claim 50, further comprising primers and/or probes, which hybridize with one or more MREJ of types selected from i to x. 52. The kit of claim 51, further comprising primer pairs, wherein the primer pairs comprise the nucleotide sequences of SEQ ID NOs:
30/36 for the detection of MREJ type i; 30/36 for the detection of MREJ type ii; 30/70 for the detection of MREJ type iii; 30/71 for the detection of MREJ type iv; 30/72 for the detection of MREJ type v; 30/65 for the detection of MREJ type vi; 30/74 for the detection of MREJ type vii; 30/75 for the detection of MREJ type viii; 30/29 for the detection of MREJ type ix; 73/77 for the detection of MREJ type x; 34/45, 34/30, 34/76, 34/44 for the detection of MREJ type xi; 35/45, 35/30, 35/62, 35/44 for the detection of MREJ type xii; 29/45, 29/30, 29/76, 29/44 for the detection of MREJ type xiii; 29/45, 29/30, 29/59, 29/44 for the detection of MREJ type xiv; 24/45, 24/30, 24/62, 24/44 for the detection of MREJ type xv; 36/44 for the detection of MREJ type xvi; 4/45, 4/30, 4/62, 4/44 for the detection of MREJ type xvii; 7/45, 7/30, 7/59, 7/44 for the detection of MREJ type xviii; 9/45, 9/30, 9/59, 9/44 for the detection of MREJ type xix; and 8/45, 8/30, 8/59, 8/44 for the detection of MREJ type xx. 53. The kit of claim 51, further comprising probes, wherein the probes comprise the nucleic acid sequence of SEQ ID NOs: 31, 32, 33. | 1,600 |
1,468 | 16,520,936 | 1,631 | A method of administering insulin includes receiving subcutaneous information for a patient at a computing device and executing a subcutaneous outpatient program for determining recommended insulin dosages. The subcutaneous outpatient program includes obtaining blood glucose data of the patient from a glucometer in communication with the computing device, aggregating blood glucose measurements to determine a representative aggregate blood glucose measurement associated with at least one scheduled blood glucose time interval, and determining a next recommended insulin dosage for the patient based on the representative aggregate blood glucose measurement and the subcutaneous information. The method also includes transmitting the next recommended insulin dosage to a portable device associated with the patient. The portable device displays the next recommended insulin dosage. | 1. A method comprising:
receiving, at data processing hardware of a patient device, glucose data of a patient associated with the patient device, the glucose data including glucose measurements of the patient and glucose times associated with the glucose measurements; transmitting, by the data processing hardware, the glucose data to a remote server, the remote server executing a subcutaneous outpatient process configured to:
receive sequential scheduled glucose time intervals throughout a day, each scheduled glucose time interval associated with a corresponding adjustable time boundary that does not overlap with other time boundaries associated with the other scheduled glucose time intervals;
for each scheduled glucose time interval, aggregate the glucose measurements of the glucose data received from the patient device that are associated with the corresponding scheduled glucose time interval based on the glucose times to determine a corresponding representative aggregate glucose measurement associated with the corresponding scheduled glucose time interval; and
determine a next recommended carbohydrate-to-insulin ratio for the patient during a selected time interval based on the representative aggregate glucose measurement associated with the scheduled glucose time interval that occurs immediately after the selected time interval;
receiving, at the data processing hardware, the next recommended carbohydrate-to-insulin ratio for the patient during the selected time interval from the remote server; receiving, at the data processing hardware, a number of carbohydrates consumed by the patient during the selected time interval; determining, by the data processing hardware, a recommended meal bolus for the patient based on the number of carbohydrates consumed by the patient and the next recommended carbohydrate-to-insulin ratio for the patient during the selected time; and displaying, by the data processing hardware, the recommended meal bolus on a display of the patient device. 2. The method of claim 1, wherein the subcutaneous outpatient process is configured to receive the sequential scheduled glucose time intervals throughout the day from a healthcare provider computing device in communication with the remote server. 3. The method of claim 1, further comprising displaying, by the data processing hardware, the number of carbohydrates consumed by the patient during the selected time interval on the display of the patient device. 4. The method of claim 1, wherein receiving the glucose data comprises receiving the glucose data from a remote computing device in communication with the data processing hardware during a batch download process, the remote computing device executing a download program for downloading the glucose data from a glucometer or a continuous glucose monitoring system associated with the patient. 5. The method of claim 1, wherein receiving the glucose data comprises receiving the glucose data from a glucometer associated with the patient and in communication with the patient device. 6. The method of claim 1, wherein receiving the glucose data comprises receiving the glucose data from a continuous glucose monitoring system associated with the patient and in communication with the patient device. 7. The method of claim 1, further comprising transmitting the recommended meal bolus from the data processing hardware to an administration device in communication with the data processing hardware, the administration device configured to automatically dial in a number of units of insulin for the recommended meal bolus and administer the number of units of insulin for the recommended meal bolus. 8. The method of claim 7, wherein the administration device comprises a smart insulin pen. 9. The method of claim 7, wherein the administration device comprises an insulin pump. 10. The method of claim 1, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a breakfast glucose time interval to determine a representative aggregate breakfast glucose measurement; aggregate one or more of the glucose measurements associated with a midsleep glucose time interval to determine a representative aggregate midsleep glucose measurement; select a governing glucose as a lesser one of the representative aggregate midsleep glucose measurement or the representative aggregate breakfast glucose measurement; determine an adjustment factor for adjusting a next recommended basal dosage based on the selected governing glucose measurement; obtain a previous day recommended basal dosage; and determine the next recommended basal dosage by multiplying the adjustment factor times the previous day recommended basal dosage. 11. The method of claim 1, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a lunch glucose time interval to determine a representative aggregate lunch glucose measurement; select a governing glucose as the representative aggregate lunch glucose measurement; determine an adjustment factor for adjusting a next recommended breakfast carbohydrate-to-insulin ratio based on the selected governing glucose measurement; obtain a previous day recommended breakfast carbohydrate-to-insulin ratio; and determine the next recommended breakfast carbohydrate-to-insulin ratio by dividing the previous day recommended breakfast carbohydrate-to-insulin ratio by the adjustment factor. 12. The method of claim 1, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a dinner glucose time interval to determine a representative aggregate dinner glucose measurement; select a governing glucose as the representative aggregate dinner glucose measurement; determine an adjustment factor for adjusting a next recommended lunch carbohydrate-to-insulin ratio based on the selected governing glucose measurement; obtain a previous day recommended lunch carbohydrate-to-insulin ratio; and determine the next recommended lunch carbohydrate-to-insulin ratio by dividing the previous day recommended lunch carbohydrate-to-insulin ratio by the adjustment factor. 13. The method of claim 1, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a bedtime glucose time interval to determine a representative aggregate bedtime glucose measurement; select a governing glucose as the representative aggregate bedtime glucose measurement; determine an adjustment factor for adjusting a next recommended dinner carbohydrate-to-insulin ratio based on the selected governing glucose measurement; obtain a previous day recommended dinner carbohydrate-to-insulin ratio; and determine the next recommended dinner carbohydrate-to-insulin ratio by dividing the previous day recommended dinner carbohydrate-to-insulin ratio by the adjustment factor. 14. The method of claim 1, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a selected one of the scheduled glucose time intervals to determine a representative aggregate glucose measurement associated with the selected scheduled glucose time interval; select a governing glucose as the representative aggregate glucose measurement associated with the selected scheduled glucose time interval; determine an adjustment factor for adjusting a next recommended meal bolus governed by the selected scheduled glucose time interval based on the selected governing glucose measurement; obtain a previous day recommended meal bolus governed by the selected scheduled glucose time interval; and determine the next recommended meal bolus by multiplying the adjustment factor times the previous day recommended meal bolus. 15. The method of claim 1, wherein the representative aggregate glucose measurement includes one of:
a mean glucose value for the associated scheduled glucose time interval; or a median glucose value for the associated scheduled glucose time interval. 16. A patient device comprising:
data processing hardware; and memory hardware in communication with the data processing hardware, the memory hardware storing instructions that when executed on the data processing hardware cause the data processing hardware to perform operations comprising:
receiving glucose data of a patient associated with the patient device, the glucose data including glucose measurements of the patient and glucose times associated with the glucose measurements;
transmitting the glucose data to a remote server, the remote server executing a subcutaneous outpatient process configured to:
receive sequential scheduled glucose time intervals throughout a day, each scheduled glucose time interval associated with a corresponding adjustable time boundary that does not overlap with other time boundaries associated with the other scheduled glucose time intervals;
for each scheduled glucose time interval, aggregate the glucose measurements of the glucose data received from the patient device that are associated with the corresponding scheduled glucose time interval based on the glucose times to determine a corresponding representative aggregate glucose measurement associated with the corresponding scheduled glucose time interval; and
determine a next recommended carbohydrate-to-insulin ratio for the patient during a selected time interval based on the representative aggregate glucose measurement associated with the scheduled glucose time interval that occurs immediately after the selected time interval;
receiving the next recommended carbohydrate-to-insulin ratio for the patient during the selected time interval from the remote server;
receiving a number of carbohydrates consumed by the patient during the selected time interval;
determining a recommended meal bolus for the patient based on the number of carbohydrates consumed by the patient and the next recommended carbohydrate-to-insulin ratio for the patient during the selected time; and
displaying the recommended meal bolus on a display of the patient device. 17. The patient device of claim 16, wherein the subcutaneous outpatient process is configured to receive the sequential scheduled glucose time intervals throughout the day from a healthcare provider computing device in communication with the remote server. 18. The patient device of claim 16, wherein the operations further comprise displaying the number of carbohydrates consumed by the patient during the selected time interval on the display of the patient device. 19. The patient device of claim 16, wherein receiving the glucose data comprises receiving the glucose data from a remote computing device in communication with the data processing hardware during a batch download process, the remote computing device executing a download program for downloading the glucose data from a glucometer or a continuous glucose monitoring system associated with the patient. 20. The patient device of claim 16, wherein receiving the glucose data comprises receiving the glucose data from a glucometer associated with the patient and in communication with the patient device. 21. The patient device of claim 16, wherein receiving the glucose data comprises receiving the glucose data from a continuous glucose monitoring system associated with the patient and in communication with the patient device. 22. The patient device of claim 16, wherein the operations further comprise transmitting the recommended meal bolus from the data processing hardware to an administration device in communication with the data processing hardware, the administration device configured to automatically dial in a number of units of insulin for the recommended meal bolus and administer the number of units of insulin for the recommended meal bolus. 23. The patient device of claim 22, wherein the administration device comprises a smart insulin pen. 24. The patient device of claim 22, wherein the administration device comprises an insulin pump. 25. The patient device of claim 16, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a breakfast glucose time interval to determine a representative aggregate breakfast glucose measurement; aggregate one or more of the glucose measurements associated with a midsleep glucose time interval to determine a representative aggregate midsleep glucose measurement; select a governing glucose as a lesser one of the representative aggregate midsleep glucose measurement or the representative aggregate breakfast glucose measurement; determine an adjustment factor for adjusting a next recommended basal dosage based on the selected governing glucose measurement; obtain a previous day recommended basal dosage; and determine the next recommended basal dosage by multiplying the adjustment factor times the previous day recommended basal dosage. 26. The patient device of claim 16, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a lunch glucose time interval to determine a representative aggregate lunch glucose measurement; select a governing glucose as the representative aggregate lunch glucose measurement; determine an adjustment factor for adjusting a next recommended breakfast carbohydrate-to-insulin ratio based on the selected governing glucose measurement; obtain a previous day recommended breakfast carbohydrate-to-insulin ratio; and determine the next recommended breakfast carbohydrate-to-insulin ratio by dividing the previous day recommended breakfast carbohydrate-to-insulin ratio by the adjustment factor. 27. The patient device of claim 16, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a dinner glucose time interval to determine a representative aggregate dinner glucose measurement; select a governing glucose as the representative aggregate dinner glucose measurement; determine an adjustment factor for adjusting a next recommended lunch carbohydrate-to-insulin ratio based on the selected governing glucose measurement; obtain a previous day recommended lunch carbohydrate-to-insulin ratio; and determine the next recommended lunch carbohydrate-to-insulin ratio by dividing the previous day recommended lunch carbohydrate-to-insulin ratio by the adjustment factor. 28. The patient device of claim 16, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a bedtime glucose time interval to determine a representative aggregate bedtime glucose measurement; select a governing glucose as the representative aggregate bedtime glucose measurement; determine an adjustment factor for adjusting a next recommended dinner carbohydrate-to-insulin ratio based on the selected governing glucose measurement; obtain a previous day recommended dinner carbohydrate-to-insulin ratio; and determine the next recommended dinner carbohydrate-to-insulin ratio by dividing the previous day recommended dinner carbohydrate-to-insulin ratio by the adjustment factor. 29. The patient device of claim 16, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a selected one of the scheduled glucose time intervals to determine a representative aggregate glucose measurement associated with the selected scheduled glucose time interval; select a governing glucose as the representative aggregate glucose measurement associated with the selected scheduled glucose time interval; determine an adjustment factor for adjusting a next recommended meal bolus governed by the selected scheduled glucose time interval based on the selected governing glucose measurement; obtain a previous day recommended meal bolus governed by the selected scheduled glucose time interval; and determine the next recommended meal bolus by multiplying the adjustment factor times the previous day recommended meal bolus. 30. The patient device of claim 16, wherein the representative aggregate glucose measurement includes one of:
a mean glucose value for the associated scheduled glucose time interval; or a median glucose value for the associated scheduled glucose time interval. | A method of administering insulin includes receiving subcutaneous information for a patient at a computing device and executing a subcutaneous outpatient program for determining recommended insulin dosages. The subcutaneous outpatient program includes obtaining blood glucose data of the patient from a glucometer in communication with the computing device, aggregating blood glucose measurements to determine a representative aggregate blood glucose measurement associated with at least one scheduled blood glucose time interval, and determining a next recommended insulin dosage for the patient based on the representative aggregate blood glucose measurement and the subcutaneous information. The method also includes transmitting the next recommended insulin dosage to a portable device associated with the patient. The portable device displays the next recommended insulin dosage.1. A method comprising:
receiving, at data processing hardware of a patient device, glucose data of a patient associated with the patient device, the glucose data including glucose measurements of the patient and glucose times associated with the glucose measurements; transmitting, by the data processing hardware, the glucose data to a remote server, the remote server executing a subcutaneous outpatient process configured to:
receive sequential scheduled glucose time intervals throughout a day, each scheduled glucose time interval associated with a corresponding adjustable time boundary that does not overlap with other time boundaries associated with the other scheduled glucose time intervals;
for each scheduled glucose time interval, aggregate the glucose measurements of the glucose data received from the patient device that are associated with the corresponding scheduled glucose time interval based on the glucose times to determine a corresponding representative aggregate glucose measurement associated with the corresponding scheduled glucose time interval; and
determine a next recommended carbohydrate-to-insulin ratio for the patient during a selected time interval based on the representative aggregate glucose measurement associated with the scheduled glucose time interval that occurs immediately after the selected time interval;
receiving, at the data processing hardware, the next recommended carbohydrate-to-insulin ratio for the patient during the selected time interval from the remote server; receiving, at the data processing hardware, a number of carbohydrates consumed by the patient during the selected time interval; determining, by the data processing hardware, a recommended meal bolus for the patient based on the number of carbohydrates consumed by the patient and the next recommended carbohydrate-to-insulin ratio for the patient during the selected time; and displaying, by the data processing hardware, the recommended meal bolus on a display of the patient device. 2. The method of claim 1, wherein the subcutaneous outpatient process is configured to receive the sequential scheduled glucose time intervals throughout the day from a healthcare provider computing device in communication with the remote server. 3. The method of claim 1, further comprising displaying, by the data processing hardware, the number of carbohydrates consumed by the patient during the selected time interval on the display of the patient device. 4. The method of claim 1, wherein receiving the glucose data comprises receiving the glucose data from a remote computing device in communication with the data processing hardware during a batch download process, the remote computing device executing a download program for downloading the glucose data from a glucometer or a continuous glucose monitoring system associated with the patient. 5. The method of claim 1, wherein receiving the glucose data comprises receiving the glucose data from a glucometer associated with the patient and in communication with the patient device. 6. The method of claim 1, wherein receiving the glucose data comprises receiving the glucose data from a continuous glucose monitoring system associated with the patient and in communication with the patient device. 7. The method of claim 1, further comprising transmitting the recommended meal bolus from the data processing hardware to an administration device in communication with the data processing hardware, the administration device configured to automatically dial in a number of units of insulin for the recommended meal bolus and administer the number of units of insulin for the recommended meal bolus. 8. The method of claim 7, wherein the administration device comprises a smart insulin pen. 9. The method of claim 7, wherein the administration device comprises an insulin pump. 10. The method of claim 1, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a breakfast glucose time interval to determine a representative aggregate breakfast glucose measurement; aggregate one or more of the glucose measurements associated with a midsleep glucose time interval to determine a representative aggregate midsleep glucose measurement; select a governing glucose as a lesser one of the representative aggregate midsleep glucose measurement or the representative aggregate breakfast glucose measurement; determine an adjustment factor for adjusting a next recommended basal dosage based on the selected governing glucose measurement; obtain a previous day recommended basal dosage; and determine the next recommended basal dosage by multiplying the adjustment factor times the previous day recommended basal dosage. 11. The method of claim 1, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a lunch glucose time interval to determine a representative aggregate lunch glucose measurement; select a governing glucose as the representative aggregate lunch glucose measurement; determine an adjustment factor for adjusting a next recommended breakfast carbohydrate-to-insulin ratio based on the selected governing glucose measurement; obtain a previous day recommended breakfast carbohydrate-to-insulin ratio; and determine the next recommended breakfast carbohydrate-to-insulin ratio by dividing the previous day recommended breakfast carbohydrate-to-insulin ratio by the adjustment factor. 12. The method of claim 1, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a dinner glucose time interval to determine a representative aggregate dinner glucose measurement; select a governing glucose as the representative aggregate dinner glucose measurement; determine an adjustment factor for adjusting a next recommended lunch carbohydrate-to-insulin ratio based on the selected governing glucose measurement; obtain a previous day recommended lunch carbohydrate-to-insulin ratio; and determine the next recommended lunch carbohydrate-to-insulin ratio by dividing the previous day recommended lunch carbohydrate-to-insulin ratio by the adjustment factor. 13. The method of claim 1, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a bedtime glucose time interval to determine a representative aggregate bedtime glucose measurement; select a governing glucose as the representative aggregate bedtime glucose measurement; determine an adjustment factor for adjusting a next recommended dinner carbohydrate-to-insulin ratio based on the selected governing glucose measurement; obtain a previous day recommended dinner carbohydrate-to-insulin ratio; and determine the next recommended dinner carbohydrate-to-insulin ratio by dividing the previous day recommended dinner carbohydrate-to-insulin ratio by the adjustment factor. 14. The method of claim 1, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a selected one of the scheduled glucose time intervals to determine a representative aggregate glucose measurement associated with the selected scheduled glucose time interval; select a governing glucose as the representative aggregate glucose measurement associated with the selected scheduled glucose time interval; determine an adjustment factor for adjusting a next recommended meal bolus governed by the selected scheduled glucose time interval based on the selected governing glucose measurement; obtain a previous day recommended meal bolus governed by the selected scheduled glucose time interval; and determine the next recommended meal bolus by multiplying the adjustment factor times the previous day recommended meal bolus. 15. The method of claim 1, wherein the representative aggregate glucose measurement includes one of:
a mean glucose value for the associated scheduled glucose time interval; or a median glucose value for the associated scheduled glucose time interval. 16. A patient device comprising:
data processing hardware; and memory hardware in communication with the data processing hardware, the memory hardware storing instructions that when executed on the data processing hardware cause the data processing hardware to perform operations comprising:
receiving glucose data of a patient associated with the patient device, the glucose data including glucose measurements of the patient and glucose times associated with the glucose measurements;
transmitting the glucose data to a remote server, the remote server executing a subcutaneous outpatient process configured to:
receive sequential scheduled glucose time intervals throughout a day, each scheduled glucose time interval associated with a corresponding adjustable time boundary that does not overlap with other time boundaries associated with the other scheduled glucose time intervals;
for each scheduled glucose time interval, aggregate the glucose measurements of the glucose data received from the patient device that are associated with the corresponding scheduled glucose time interval based on the glucose times to determine a corresponding representative aggregate glucose measurement associated with the corresponding scheduled glucose time interval; and
determine a next recommended carbohydrate-to-insulin ratio for the patient during a selected time interval based on the representative aggregate glucose measurement associated with the scheduled glucose time interval that occurs immediately after the selected time interval;
receiving the next recommended carbohydrate-to-insulin ratio for the patient during the selected time interval from the remote server;
receiving a number of carbohydrates consumed by the patient during the selected time interval;
determining a recommended meal bolus for the patient based on the number of carbohydrates consumed by the patient and the next recommended carbohydrate-to-insulin ratio for the patient during the selected time; and
displaying the recommended meal bolus on a display of the patient device. 17. The patient device of claim 16, wherein the subcutaneous outpatient process is configured to receive the sequential scheduled glucose time intervals throughout the day from a healthcare provider computing device in communication with the remote server. 18. The patient device of claim 16, wherein the operations further comprise displaying the number of carbohydrates consumed by the patient during the selected time interval on the display of the patient device. 19. The patient device of claim 16, wherein receiving the glucose data comprises receiving the glucose data from a remote computing device in communication with the data processing hardware during a batch download process, the remote computing device executing a download program for downloading the glucose data from a glucometer or a continuous glucose monitoring system associated with the patient. 20. The patient device of claim 16, wherein receiving the glucose data comprises receiving the glucose data from a glucometer associated with the patient and in communication with the patient device. 21. The patient device of claim 16, wherein receiving the glucose data comprises receiving the glucose data from a continuous glucose monitoring system associated with the patient and in communication with the patient device. 22. The patient device of claim 16, wherein the operations further comprise transmitting the recommended meal bolus from the data processing hardware to an administration device in communication with the data processing hardware, the administration device configured to automatically dial in a number of units of insulin for the recommended meal bolus and administer the number of units of insulin for the recommended meal bolus. 23. The patient device of claim 22, wherein the administration device comprises a smart insulin pen. 24. The patient device of claim 22, wherein the administration device comprises an insulin pump. 25. The patient device of claim 16, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a breakfast glucose time interval to determine a representative aggregate breakfast glucose measurement; aggregate one or more of the glucose measurements associated with a midsleep glucose time interval to determine a representative aggregate midsleep glucose measurement; select a governing glucose as a lesser one of the representative aggregate midsleep glucose measurement or the representative aggregate breakfast glucose measurement; determine an adjustment factor for adjusting a next recommended basal dosage based on the selected governing glucose measurement; obtain a previous day recommended basal dosage; and determine the next recommended basal dosage by multiplying the adjustment factor times the previous day recommended basal dosage. 26. The patient device of claim 16, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a lunch glucose time interval to determine a representative aggregate lunch glucose measurement; select a governing glucose as the representative aggregate lunch glucose measurement; determine an adjustment factor for adjusting a next recommended breakfast carbohydrate-to-insulin ratio based on the selected governing glucose measurement; obtain a previous day recommended breakfast carbohydrate-to-insulin ratio; and determine the next recommended breakfast carbohydrate-to-insulin ratio by dividing the previous day recommended breakfast carbohydrate-to-insulin ratio by the adjustment factor. 27. The patient device of claim 16, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a dinner glucose time interval to determine a representative aggregate dinner glucose measurement; select a governing glucose as the representative aggregate dinner glucose measurement; determine an adjustment factor for adjusting a next recommended lunch carbohydrate-to-insulin ratio based on the selected governing glucose measurement; obtain a previous day recommended lunch carbohydrate-to-insulin ratio; and determine the next recommended lunch carbohydrate-to-insulin ratio by dividing the previous day recommended lunch carbohydrate-to-insulin ratio by the adjustment factor. 28. The patient device of claim 16, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a bedtime glucose time interval to determine a representative aggregate bedtime glucose measurement; select a governing glucose as the representative aggregate bedtime glucose measurement; determine an adjustment factor for adjusting a next recommended dinner carbohydrate-to-insulin ratio based on the selected governing glucose measurement; obtain a previous day recommended dinner carbohydrate-to-insulin ratio; and determine the next recommended dinner carbohydrate-to-insulin ratio by dividing the previous day recommended dinner carbohydrate-to-insulin ratio by the adjustment factor. 29. The patient device of claim 16, wherein the subcutaneous outpatient process is further configured to:
aggregate one or more of the glucose measurements associated with a selected one of the scheduled glucose time intervals to determine a representative aggregate glucose measurement associated with the selected scheduled glucose time interval; select a governing glucose as the representative aggregate glucose measurement associated with the selected scheduled glucose time interval; determine an adjustment factor for adjusting a next recommended meal bolus governed by the selected scheduled glucose time interval based on the selected governing glucose measurement; obtain a previous day recommended meal bolus governed by the selected scheduled glucose time interval; and determine the next recommended meal bolus by multiplying the adjustment factor times the previous day recommended meal bolus. 30. The patient device of claim 16, wherein the representative aggregate glucose measurement includes one of:
a mean glucose value for the associated scheduled glucose time interval; or a median glucose value for the associated scheduled glucose time interval. | 1,600 |
1,469 | 15,919,273 | 1,613 | A consumer product composition comprises a consumer product adjunct ingredient, a microcapsule, and chitosan disposed on an outer surface of the microcapsule. The chitosan has a weight average molecular weight of at least about 100 kDa and/or a degree of deacetylation of at least about 60%. The microcapsule comprises a shell material encapsulating a core material, wherein the shell material comprises a polyacrylate and the core material comprises a benefit agent. | 1. A consumer product composition comprising
a consumer product adjunct ingredient; microcapsules comprising a shell material encapsulating a core material, said core material being disposed within said shell material, wherein said shell material comprises a polyacrylate polymer and said core material comprises a benefit agent; and chitosan disposed on an outer surface of said microcapsule, and wherein said chitosan has a weight average molecular weight of at least about 100 kDa and/or a degree of deacetylation of at least about 60%. 2. The consumer product composition of claim 1, wherein said chitosan has a degree of deacetylation of at least about 60%. 3. The consumer product composition of claim 2, wherein said chitosan has a degree of deacetylation of at least about 70%. 4. The consumer product composition of claim 1, wherein said chitosan has a weight average molecular weight of at least about 100 kDa. 5. The consumer product composition of claim 4, wherein said chitosan has a weight average molecular weight of at least about 200 kDa. 6. The consumer product composition of claim 1, wherein said chitosan has a degree of de-acetylation of at least about 60% and a weight average molecular weight of at least about 10 kDa. 7. The consumer product composition of claim 1, wherein said chitosan has a weight average molecular weight of at least about 100 kDa and a degree of de-acetylation of at least about 50%. 8. The consumer product composition of claim 1, wherein said chitosan has either:
said weight average molecular weight of at least about 500 kDa and said degree of de-acetylation of at least about 50%, or said weight average molecular weight of at least about 10 kDa and said degree of de-acetylation of at least about 70%. 9. The consumer product composition of claim 1, wherein said chitosan has a Water Uptake Value of at least about 2 g/g. 10. The consumer product composition of claim 1, wherein said chitosan has a viscosity of at least about 0.01 poise. 11. The consumer product composition of claim 1, wherein said chitosan is present in an amount of from about 0.01% to about 8%, by weight of the microcapsules. 12. The consumer product composition of claim 1, wherein said benefit agent is a perfume. 13. The consumer product composition of claim 1, wherein said core material further comprises a partitioning modifier selected from the group consisting of vegetable oil, modified vegetable oil, isopropyl myristate, propan-2-yl tetradecanoate, and mixtures thereof. 14. The consumer product composition of claim 1, wherein said polyacrylate polymer comprises a cross-linked polyacrylate polymer. 15. The consumer product composition of claim 1, wherein said polyacrylate polymer comprises a polymer derived from a material comprising a multifunctional acrylate moiety selected from the group consisting of tri-functional acrylate, tetra-functional acrylate, penta-functional acrylate, hexa-functional acrylate, hepta-functional acrylate, and mixtures thereof. 16. The consumer product composition of claim 1, wherein said polyacrylate polymer comprises a moiety selected from the group consisting of amine acrylate moiety, methacrylate moiety, a carboxylic acid acrylate moiety, carboxylic acid methacrylate moiety, and combinations thereof. 17. The consumer product composition of claim 1, wherein said polyacrylate polymer comprises a polymer derived from a first material comprising a multifunctional acrylate moiety. 18. The consumer product composition of claim 1, wherein said shell material further comprises from about 0.5% to about 40%, by weight of said shell material, of polyvinyl alcohol. 19. The consumer product composition of claim 1, wherein said microcapsules have a volume weighted median particle size of from about 3 to about 60 microns. 20. The consumer product composition of claim 1, wherein said chitosan is combined with said microcapsules before said microcapsules are combined with said consumer product adjunct ingredient. 21. The consumer product composition of claim 1, wherein said consumer product composition comprises from about 0.001% to about 25%, by weight of the consumer product composition, of said microcapsules. 22. The consumer product composition of claim 1, wherein said consumer product adjunct ingredient is selected from the group consisting of surfactant, conditioning agent, and mixtures thereof. 23. The consumer product composition of claim 22, wherein said surfactant is selected from the group consisting of anionic surfactant, nonionic surfactant, and mixtures thereof. 24. The consumer product composition of claim 22, wherein said conditioning agent is selected from the group consisting of cationic surfactant, a silicone material, and mixtures thereof. 25. The consumer product composition of claim 1, wherein said consumer product composition is encased in a film to form an encased consumer product composition. 26. A method of depositing a microcapsule on a surface, said method comprising the step of contacting said surface with a consumer product composition of claim 1. 27. The method of claim 26, wherein said surface is a fabric. 28. The method of claim 26, wherein said surface is hair. | A consumer product composition comprises a consumer product adjunct ingredient, a microcapsule, and chitosan disposed on an outer surface of the microcapsule. The chitosan has a weight average molecular weight of at least about 100 kDa and/or a degree of deacetylation of at least about 60%. The microcapsule comprises a shell material encapsulating a core material, wherein the shell material comprises a polyacrylate and the core material comprises a benefit agent.1. A consumer product composition comprising
a consumer product adjunct ingredient; microcapsules comprising a shell material encapsulating a core material, said core material being disposed within said shell material, wherein said shell material comprises a polyacrylate polymer and said core material comprises a benefit agent; and chitosan disposed on an outer surface of said microcapsule, and wherein said chitosan has a weight average molecular weight of at least about 100 kDa and/or a degree of deacetylation of at least about 60%. 2. The consumer product composition of claim 1, wherein said chitosan has a degree of deacetylation of at least about 60%. 3. The consumer product composition of claim 2, wherein said chitosan has a degree of deacetylation of at least about 70%. 4. The consumer product composition of claim 1, wherein said chitosan has a weight average molecular weight of at least about 100 kDa. 5. The consumer product composition of claim 4, wherein said chitosan has a weight average molecular weight of at least about 200 kDa. 6. The consumer product composition of claim 1, wherein said chitosan has a degree of de-acetylation of at least about 60% and a weight average molecular weight of at least about 10 kDa. 7. The consumer product composition of claim 1, wherein said chitosan has a weight average molecular weight of at least about 100 kDa and a degree of de-acetylation of at least about 50%. 8. The consumer product composition of claim 1, wherein said chitosan has either:
said weight average molecular weight of at least about 500 kDa and said degree of de-acetylation of at least about 50%, or said weight average molecular weight of at least about 10 kDa and said degree of de-acetylation of at least about 70%. 9. The consumer product composition of claim 1, wherein said chitosan has a Water Uptake Value of at least about 2 g/g. 10. The consumer product composition of claim 1, wherein said chitosan has a viscosity of at least about 0.01 poise. 11. The consumer product composition of claim 1, wherein said chitosan is present in an amount of from about 0.01% to about 8%, by weight of the microcapsules. 12. The consumer product composition of claim 1, wherein said benefit agent is a perfume. 13. The consumer product composition of claim 1, wherein said core material further comprises a partitioning modifier selected from the group consisting of vegetable oil, modified vegetable oil, isopropyl myristate, propan-2-yl tetradecanoate, and mixtures thereof. 14. The consumer product composition of claim 1, wherein said polyacrylate polymer comprises a cross-linked polyacrylate polymer. 15. The consumer product composition of claim 1, wherein said polyacrylate polymer comprises a polymer derived from a material comprising a multifunctional acrylate moiety selected from the group consisting of tri-functional acrylate, tetra-functional acrylate, penta-functional acrylate, hexa-functional acrylate, hepta-functional acrylate, and mixtures thereof. 16. The consumer product composition of claim 1, wherein said polyacrylate polymer comprises a moiety selected from the group consisting of amine acrylate moiety, methacrylate moiety, a carboxylic acid acrylate moiety, carboxylic acid methacrylate moiety, and combinations thereof. 17. The consumer product composition of claim 1, wherein said polyacrylate polymer comprises a polymer derived from a first material comprising a multifunctional acrylate moiety. 18. The consumer product composition of claim 1, wherein said shell material further comprises from about 0.5% to about 40%, by weight of said shell material, of polyvinyl alcohol. 19. The consumer product composition of claim 1, wherein said microcapsules have a volume weighted median particle size of from about 3 to about 60 microns. 20. The consumer product composition of claim 1, wherein said chitosan is combined with said microcapsules before said microcapsules are combined with said consumer product adjunct ingredient. 21. The consumer product composition of claim 1, wherein said consumer product composition comprises from about 0.001% to about 25%, by weight of the consumer product composition, of said microcapsules. 22. The consumer product composition of claim 1, wherein said consumer product adjunct ingredient is selected from the group consisting of surfactant, conditioning agent, and mixtures thereof. 23. The consumer product composition of claim 22, wherein said surfactant is selected from the group consisting of anionic surfactant, nonionic surfactant, and mixtures thereof. 24. The consumer product composition of claim 22, wherein said conditioning agent is selected from the group consisting of cationic surfactant, a silicone material, and mixtures thereof. 25. The consumer product composition of claim 1, wherein said consumer product composition is encased in a film to form an encased consumer product composition. 26. A method of depositing a microcapsule on a surface, said method comprising the step of contacting said surface with a consumer product composition of claim 1. 27. The method of claim 26, wherein said surface is a fabric. 28. The method of claim 26, wherein said surface is hair. | 1,600 |
1,470 | 14,738,551 | 1,643 | The embodiments include methods of treating conditions requiring removal or destruction of cellular elements, such as benign or malignant tumors using compounds based on small peptides in combination with additional active agent(s). The method includes, but is not limited to, administering the compounds intramuscularly, orally, intravenously, intrathecally, intraprostatically, intratumorally, intranasally, topically, transdermally, etc., either alone or conjugated to a carrier to a mammal in need thereof. | 1. A method of treating a mammal for removal or destruction of unwanted cellular proliferations comprising administering to the mammal a therapeutically effective amount of an isolated peptide comprising the amino acid sequence in SEQ ID NO. 66 (Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu-Ile-Lys-Arg-Cys-Leu), in combination with at least one active agent capable of treating symptoms of, reducing, blocking, inhibiting treating and/or killing unwanted cellular proliferations in mammals, wherein the method removes or destroys unwanted cellular proliferations. 2. The method of claim 1, wherein the method comprises administration of a therapeutically effective amount of at least one of the peptides as claimed in claim 1 and a carrier. 3. The method of claim 1, wherein the at least one active agent capable of treating symptoms of, reducing, blocking, inhibiting treating and/or killing unwanted cellular proliferations in mammals, is one or more agents selected from the group consisting of of tamsulosin, finasteride, terazosin, doxazosin, prazosin, tadalafil, alfuzosin, silodosin, dutasteride, combinations of dutasteride and tamsulosin, and mixtures and combinations thereof. 4. The method of claim 3, wherein the at least one active agent capable of treating symptoms of, reducing, blocking, inhibiting treating and/or killing unwanted cellular proliferations in mammals is one or more agents selected from the group consisting of tamsulosin, finasteride, terazosin, doxazosin, tadalafil, dutasteride, combinations of dutasteride and tamsulosin, and mixtures and combinations thereof. 5. The method of claim 1, wherein the method comprises administration of a therapeutically effective amount of at least one of the peptides as claimed in claim 1 and at least one and up to 25 additional amino acids flanking either the N-terminus or C-terminus of the isolated peptide of claim 1. 6. The method of claim 1, wherein the peptide is administered by a method selected from the group consisting of orally, subcutaneously, intradermally, intranasally, intravenously, intramuscularly, intrathecally, intranasally, intratumorally, topically, and transdermally. 7. The method of claim 1, wherein the method is carried out on the mammal before, during, or after treatment of the mammal with a treatment selected from the group consisting of surgical excision, transplantation, grafting, chemotherapy, immunotherapy, vaccination, thermal or electrical ablation, cryotherapy, laser therapy, phototherapy, gene therapy, and radiation. 8. The method of claim 1, wherein the condition is a benign or malignant tumor of a tissue selected from the group consisting of lung, breast, stomach, pancreas, prostate, bladder, bone, ovary, skin, kidney, sinus, colon, intestine, stomach, rectum, esophagus, heart, spleen, salivary gland, blood, brain and its coverings, spinal cord and its coverings, muscle, connective tissue, adrenal, parathyroid, thyroid, uterus, testis, pituitary, reproductive organs, liver, gall bladder, eye, ear, nose, throat, tonsils, mouth, and lymph nodes and lymphoid system. 9. The method of claim 1, wherein the condition is a hyperplasia, hypertrophy, or overgrowth of a tissue selected from the group consisting of lung, breast, stomach, pancreas, prostate, bladder, bone, ovary, skin, kidney, sinus, colon, intestine, stomach, rectum, esophagus, heart, spleen, salivary gland, blood, brain and its coverings, spinal cord and its coverings, muscle, connective tissue, adrenal, parathyroid, thyroid, uterus, testis, pituitary, reproductive organs, liver, gall bladder, eye, ear, nose, throat, tonsils, mouth, and lymph nodes and lymphoid system. 10. The method of claim 1, wherein the condition is a virally, bacterially, or parasitically altered tissue selected from the group consisting of lung, breast, stomach, pancreas, prostate, bladder, bone, ovary, skin, kidney, sinus, colon, intestine, stomach, rectum, esophagus, heart, spleen, salivary gland, blood, brain and its coverings, spinal cord and its coverings, muscle, connective tissue, adrenal, parathyroid, thyroid, uterus, testis, pituitary, reproductive organs, liver, gall bladder, eye, ear, nose, throat, tonsils, mouth, and lymph nodes and lymphoid system. 11. The method of claim 1, wherein the condition is a malformation of a tissue selected from the group consisting of lung, breast, stomach, pancreas, prostate, bladder, bone, ovary, skin, kidney, sinus, colon, intestine, stomach, rectum, esophagus, heart, spleen, salivary gland, blood, brain and its coverings, spinal cord and its coverings, muscle, connective tissue, adrenal, parathyroid, thyroid, uterus, testis, pituitary, reproductive organs, liver, gall bladder, eye, ear, nose, throat, tonsils, mouth, and lymph nodes and lymphoid system. 12. The method of claim 1, wherein the condition is benign prostatic hyperplasia (BPH). 13. The method of claim 1, wherein the method provides a Mean IPSS (International Prostate Symptom Score) improvement, when compared to the improvement found by treating a mammal with a placebo in combination with an additional active agent capable of treating symptoms of, reducing, blocking, inhibiting treating and/or killing unwanted cellular proliferations in mammals, of from about 15% to about 150%. 14. The method of claim 13, wherein the improvement is about 40%. 15. The method of claim 1, wherein the at least one active agent is administered separately or at different times from the at least one isolated peptide. 16. The method of claim 15 wherein the at least one isolated peptide is administered by a method selected from the group consisting of intravenously, intramuscularly, intrathecally, intranasally, intratumorally, topically, and transdermally, and the at least one active agent is administered orally. 17. A method of treating mammal for removal or destruction of unwanted cellular proliferations comprising administering to the mammal a therapeutically effective amount of an isolated peptide comprising the amino acid sequence in SEQ ID NO. 66 (Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu-Ile-Lys-Arg-Cys-Leu), followed by surgical treatment of the unwanted cellular proliferations. 18. The method of claim 17, wherein the method provides a Mean IPSS (International Prostate Symptom Score) improvement, when compared to the improvement found by treating a mammal with a placebo in combination with surgical treatment of from about 15% to about 150%. | The embodiments include methods of treating conditions requiring removal or destruction of cellular elements, such as benign or malignant tumors using compounds based on small peptides in combination with additional active agent(s). The method includes, but is not limited to, administering the compounds intramuscularly, orally, intravenously, intrathecally, intraprostatically, intratumorally, intranasally, topically, transdermally, etc., either alone or conjugated to a carrier to a mammal in need thereof.1. A method of treating a mammal for removal or destruction of unwanted cellular proliferations comprising administering to the mammal a therapeutically effective amount of an isolated peptide comprising the amino acid sequence in SEQ ID NO. 66 (Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu-Ile-Lys-Arg-Cys-Leu), in combination with at least one active agent capable of treating symptoms of, reducing, blocking, inhibiting treating and/or killing unwanted cellular proliferations in mammals, wherein the method removes or destroys unwanted cellular proliferations. 2. The method of claim 1, wherein the method comprises administration of a therapeutically effective amount of at least one of the peptides as claimed in claim 1 and a carrier. 3. The method of claim 1, wherein the at least one active agent capable of treating symptoms of, reducing, blocking, inhibiting treating and/or killing unwanted cellular proliferations in mammals, is one or more agents selected from the group consisting of of tamsulosin, finasteride, terazosin, doxazosin, prazosin, tadalafil, alfuzosin, silodosin, dutasteride, combinations of dutasteride and tamsulosin, and mixtures and combinations thereof. 4. The method of claim 3, wherein the at least one active agent capable of treating symptoms of, reducing, blocking, inhibiting treating and/or killing unwanted cellular proliferations in mammals is one or more agents selected from the group consisting of tamsulosin, finasteride, terazosin, doxazosin, tadalafil, dutasteride, combinations of dutasteride and tamsulosin, and mixtures and combinations thereof. 5. The method of claim 1, wherein the method comprises administration of a therapeutically effective amount of at least one of the peptides as claimed in claim 1 and at least one and up to 25 additional amino acids flanking either the N-terminus or C-terminus of the isolated peptide of claim 1. 6. The method of claim 1, wherein the peptide is administered by a method selected from the group consisting of orally, subcutaneously, intradermally, intranasally, intravenously, intramuscularly, intrathecally, intranasally, intratumorally, topically, and transdermally. 7. The method of claim 1, wherein the method is carried out on the mammal before, during, or after treatment of the mammal with a treatment selected from the group consisting of surgical excision, transplantation, grafting, chemotherapy, immunotherapy, vaccination, thermal or electrical ablation, cryotherapy, laser therapy, phototherapy, gene therapy, and radiation. 8. The method of claim 1, wherein the condition is a benign or malignant tumor of a tissue selected from the group consisting of lung, breast, stomach, pancreas, prostate, bladder, bone, ovary, skin, kidney, sinus, colon, intestine, stomach, rectum, esophagus, heart, spleen, salivary gland, blood, brain and its coverings, spinal cord and its coverings, muscle, connective tissue, adrenal, parathyroid, thyroid, uterus, testis, pituitary, reproductive organs, liver, gall bladder, eye, ear, nose, throat, tonsils, mouth, and lymph nodes and lymphoid system. 9. The method of claim 1, wherein the condition is a hyperplasia, hypertrophy, or overgrowth of a tissue selected from the group consisting of lung, breast, stomach, pancreas, prostate, bladder, bone, ovary, skin, kidney, sinus, colon, intestine, stomach, rectum, esophagus, heart, spleen, salivary gland, blood, brain and its coverings, spinal cord and its coverings, muscle, connective tissue, adrenal, parathyroid, thyroid, uterus, testis, pituitary, reproductive organs, liver, gall bladder, eye, ear, nose, throat, tonsils, mouth, and lymph nodes and lymphoid system. 10. The method of claim 1, wherein the condition is a virally, bacterially, or parasitically altered tissue selected from the group consisting of lung, breast, stomach, pancreas, prostate, bladder, bone, ovary, skin, kidney, sinus, colon, intestine, stomach, rectum, esophagus, heart, spleen, salivary gland, blood, brain and its coverings, spinal cord and its coverings, muscle, connective tissue, adrenal, parathyroid, thyroid, uterus, testis, pituitary, reproductive organs, liver, gall bladder, eye, ear, nose, throat, tonsils, mouth, and lymph nodes and lymphoid system. 11. The method of claim 1, wherein the condition is a malformation of a tissue selected from the group consisting of lung, breast, stomach, pancreas, prostate, bladder, bone, ovary, skin, kidney, sinus, colon, intestine, stomach, rectum, esophagus, heart, spleen, salivary gland, blood, brain and its coverings, spinal cord and its coverings, muscle, connective tissue, adrenal, parathyroid, thyroid, uterus, testis, pituitary, reproductive organs, liver, gall bladder, eye, ear, nose, throat, tonsils, mouth, and lymph nodes and lymphoid system. 12. The method of claim 1, wherein the condition is benign prostatic hyperplasia (BPH). 13. The method of claim 1, wherein the method provides a Mean IPSS (International Prostate Symptom Score) improvement, when compared to the improvement found by treating a mammal with a placebo in combination with an additional active agent capable of treating symptoms of, reducing, blocking, inhibiting treating and/or killing unwanted cellular proliferations in mammals, of from about 15% to about 150%. 14. The method of claim 13, wherein the improvement is about 40%. 15. The method of claim 1, wherein the at least one active agent is administered separately or at different times from the at least one isolated peptide. 16. The method of claim 15 wherein the at least one isolated peptide is administered by a method selected from the group consisting of intravenously, intramuscularly, intrathecally, intranasally, intratumorally, topically, and transdermally, and the at least one active agent is administered orally. 17. A method of treating mammal for removal or destruction of unwanted cellular proliferations comprising administering to the mammal a therapeutically effective amount of an isolated peptide comprising the amino acid sequence in SEQ ID NO. 66 (Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu-Ile-Lys-Arg-Cys-Leu), followed by surgical treatment of the unwanted cellular proliferations. 18. The method of claim 17, wherein the method provides a Mean IPSS (International Prostate Symptom Score) improvement, when compared to the improvement found by treating a mammal with a placebo in combination with surgical treatment of from about 15% to about 150%. | 1,600 |
1,471 | 15,845,608 | 1,615 | Disclosed is a stable anhydrous dispersion comprising a dispersed sugar phase comprising granulated sugar and powdered sugar, wherein the dispersion comprises 55% to 75% by weight, based on the total weight of the composition, of a combination of granulated sugar and powdered sugar, and a continuous oil phase, wherein the dispersion comprises at least 20% by weight, based on the total weight of the composition, of an oil. | 1.-28. (canceled) 29. A method of treating skin, the method comprising topically applying to skin in need thereof a stable anhydrous dispersion, wherein topical application of the anhydrous dispersion treats the skin, and wherein the anhydrous dispersion consists essentially of:
(a) a dispersed sugar phase comprising granulated sugar having a mean aperture (MA) size between 200 μm to 1000 μm and powdered sugar having an average particle size between 30 μm to 150 μm, wherein the anhydrous dispersion comprises 55% to 75% by weight, based on the total weight of the anhydrous dispersion, of a combination of granulated sugar and powdered sugar; and (b) a continuous oil phase, wherein the anhydrous dispersion comprises at least 20% by weight, based on the total weight of the anhydrous dispersion, of an oil or a mixture of oils, wherein the weight ratio of granulated sugar to powdered sugar within the anhydrous dispersion is 1:1 to 2:1, and wherein the anhydrous dispersion does not include a surfactant, an emulsifier, and a thickening agent. 30. The method of claim 29, wherein the anhydrous dispersion comprises:
60% to 70% by weight, based on the total weight of the anhydrous dispersion, of a combination of the granulated sugar and the powdered sugar; and 20% to 35% by weight, based on the total weight of the anhydrous dispersion, of the oil or the mixture of oils. 31. The method of claim 30, wherein the weight ratio of the granulated sugar to the powdered sugar is 1.3:1 to 2:1. 32. The method of claim 29, wherein the oil is mineral oil, a plant derived oil, or a triglyceride or a combination thereof. 33. The method of claim 32, wherein the oil is a plant derived oil selected from the group consisting of safflower oil, sweet almond oil, sunflower oil, jojoba oil, or olive or, or a combination thereof. 34. The method of claim 32, wherein the oil is mineral oil. 35. The method of claim 29, wherein the anhydrous dispersion does not include a triglyceride and a silicone-containing compound. 36. The method of 29, wherein the anhydrous dispersion moisturizes skin. 37. The method of claim 36, wherein the anhydrous dispersion is applied to dry, flaky, or cracked skin. 38. The method of claim 29, wherein the anhydrous dispersion remains stable when stored at 20° C. to 25° C. 39. The method of claim 29, wherein the anhydrous dispersion consists of the granulated sugar, the powdered sugar, and the oil or mixture of oils. 40. The method of claim 29, wherein the anhydrous dispersion further includes at least one plant extract. 41. The method of claim 29, wherein the anhydrous dispersion consists of the granulated sugar, the powdered sugar, the oil or mixture of oils, and the at least one plant extract. | Disclosed is a stable anhydrous dispersion comprising a dispersed sugar phase comprising granulated sugar and powdered sugar, wherein the dispersion comprises 55% to 75% by weight, based on the total weight of the composition, of a combination of granulated sugar and powdered sugar, and a continuous oil phase, wherein the dispersion comprises at least 20% by weight, based on the total weight of the composition, of an oil.1.-28. (canceled) 29. A method of treating skin, the method comprising topically applying to skin in need thereof a stable anhydrous dispersion, wherein topical application of the anhydrous dispersion treats the skin, and wherein the anhydrous dispersion consists essentially of:
(a) a dispersed sugar phase comprising granulated sugar having a mean aperture (MA) size between 200 μm to 1000 μm and powdered sugar having an average particle size between 30 μm to 150 μm, wherein the anhydrous dispersion comprises 55% to 75% by weight, based on the total weight of the anhydrous dispersion, of a combination of granulated sugar and powdered sugar; and (b) a continuous oil phase, wherein the anhydrous dispersion comprises at least 20% by weight, based on the total weight of the anhydrous dispersion, of an oil or a mixture of oils, wherein the weight ratio of granulated sugar to powdered sugar within the anhydrous dispersion is 1:1 to 2:1, and wherein the anhydrous dispersion does not include a surfactant, an emulsifier, and a thickening agent. 30. The method of claim 29, wherein the anhydrous dispersion comprises:
60% to 70% by weight, based on the total weight of the anhydrous dispersion, of a combination of the granulated sugar and the powdered sugar; and 20% to 35% by weight, based on the total weight of the anhydrous dispersion, of the oil or the mixture of oils. 31. The method of claim 30, wherein the weight ratio of the granulated sugar to the powdered sugar is 1.3:1 to 2:1. 32. The method of claim 29, wherein the oil is mineral oil, a plant derived oil, or a triglyceride or a combination thereof. 33. The method of claim 32, wherein the oil is a plant derived oil selected from the group consisting of safflower oil, sweet almond oil, sunflower oil, jojoba oil, or olive or, or a combination thereof. 34. The method of claim 32, wherein the oil is mineral oil. 35. The method of claim 29, wherein the anhydrous dispersion does not include a triglyceride and a silicone-containing compound. 36. The method of 29, wherein the anhydrous dispersion moisturizes skin. 37. The method of claim 36, wherein the anhydrous dispersion is applied to dry, flaky, or cracked skin. 38. The method of claim 29, wherein the anhydrous dispersion remains stable when stored at 20° C. to 25° C. 39. The method of claim 29, wherein the anhydrous dispersion consists of the granulated sugar, the powdered sugar, and the oil or mixture of oils. 40. The method of claim 29, wherein the anhydrous dispersion further includes at least one plant extract. 41. The method of claim 29, wherein the anhydrous dispersion consists of the granulated sugar, the powdered sugar, the oil or mixture of oils, and the at least one plant extract. | 1,600 |
1,472 | 14,905,539 | 1,629 | A pharmaceutical composition for inducing reactivation of latent provirus in an HIV infected cell includes an ESR-1 antagonist or an ESR-1 coactivator antagonist and a pharmaceutically acceptable carrier. | 1-15. (canceled) 16. A method for inducing activation of latent provirus expression in an HIV infected cell, the method comprising:
contacting the cell with an effective amount of a pharmaceutical composition, the pharmaceutical composition comprising an ESR-1 antagonist or an ESR-1 coactivator antagonist, an activator of latent HIV expression and a pharmaceutically acceptable carrier. 17. The method of claim 16, wherein the ESR-1 antagonist or the ESR-1 coactivator antagonist and the activator of latent HIV expression synergize to generate greater reactivation of latent HIV expression compared to either agent alone when contacted with the cell. 18. The method of claim 16, the HIV infected cell comprising a human CD4+ T cell. 19. The method of claim 16, the ESR-1 antagonist comprising a selective estrogen receptor down-regulator of ESR-1. 20. The method of claim 19, the selective estrogen receptor down-regulator of ESR-1 comprising Fulvestrant. 21. The method of claim 16, the ESR-1 antagonist comprising an ESR-1 shRNA. 22. The method of claim 16, the activator of latent HIV expression selected from an HDAC inhibitor and a protein kinase C agonist. 23. The method of claim 16, the HDAC inhibitor comprising a compound selected from the group consisting of a hydroxamic acid derivative, a short-chain fatty acid, a benzamide derivative, and a cyclic peptide. 24. The method of claim 23, the HDAC inhibitor comprising a hydroxamic acid derivative, wherein the hydroxamic acid derivative is suberoylanilide hydroxamic acid (SAHA). 25. The method of claim 22, the protein kinase C agonist comprising a compound selected from the group consisting of prostratin, 12-deoxyphorbol 13-phenylacetate (DPP), Ingenol mebutate, and a bryostatin. 26. The method of claim 16, wherein ESR-1 antagonist is Fulvestrant and the activator of latent HIV expression is suberoylanilide hydroxamic acid (SAHA). 27. The method of claim 16, the ESR-1 coactivator antagonist comprising Gossypol. 28. The method of claim 16, the pharmaceutical composition additionally comprising one or more antiviral agents. 29. The method of claim 28, the one or more antiviral agents comprising a component of HAART, the component of HAART selected from a nucleoside reverse transcriptase inhibitor, a non-nucleoside HIV reverse transcriptase inhibitor, and a protease inhibitor. 30. The method of claim 16, wherein the pharmaceutical composition fails to significantly activate the NF-kB signaling cascade in the HIV infected cell. 31. A method of treating HIV infection in a subject comprising:
administering to the subject a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising an ESR-1 antagonist or an ESR-1 coactivator antagonist, an activator of latent HIV expression, and a pharmaceutically acceptable carrier. 32. The method of claim 31, wherein the ESR-1 antagonist or the ESR-1 coactivator antagonist and the activator of latent HIV expression administered to the subject synergize to generate greater reactivation of latent HIV expression in an HIV infected cell of the subject compared to administration of either agent alone. 33. The method of claim 32, the HIV infected cell comprising a human CD4+ T cell. 34. The method of claim 31, the ESR-1 antagonist comprising a selective estrogen receptor down-regulator of ESR-1. 35. The method of claim 34, the selective estrogen receptor down-regulator of ESR-1 comprising Fulvestrant. 36. The method of claim 31, the ESR-1 antagonist comprising an ESR-1 shRNA. 37. The method of claim 31, the activator of latent HIV expression selected from an HDAC inhibitor and a protein kinase C agonist. 38. The method of claim 31, the HDAC inhibitor comprising a compound selected from the group consisting of a hydroxamic acid derivative, a short-chain fatty acid, a benzamide derivative, and a cyclic peptide. 39. The method of claim 38, the HDAC inhibitor comprising a hydroxamic acid derivative, wherein the hydroxamic acid derivative is suberoylanilide hydroxamic acid (SAHA). 40. The method of claim 37, the protein kinase C agonist comprising a compound selected from the group consisting of prostratin, 12-deoxyphorbol 13-phenylacetate (DPP), Ingenol mebutate, and a bryostatin. 41. The method of claim 31, wherein ESR-1 antagonist is Fulvestrant and the activator of latent HIV expression is suberoylanilide hydroxamic acid (SAHA). 42. The method of claim 31, the ESR-1 coactivator antagonist comprising Gossypol. 43. The method of claim 31, further comprising the step of administering to the subject a therapeutically effective amount of or more antiviral agents. 44. The method of claim 43, the one or more antiviral agents comprising a component of HAART, the component of HAART selected from a nucleoside reverse transcriptase inhibitor, a non-nucleoside HIV reverse transcriptase inhibitor, and a protease inhibitor. 45. The method of claim 31, the pharmaceutical composition additionally comprising one or more antiviral agents. 46. The method of claim 45, the one or more antiviral agents comprising a component of HAART, the component of HAART selected from a nucleoside reverse transcriptase inhibitor, a non-nucleoside HIV reverse transcriptase inhibitor, and a protease inhibitor. 47. The method of claim 31, wherein the pharmaceutical composition fails to significantly activate the NF-kB signaling cascade in the HIV infected cell. 48. A method of treating HIV infection in a subject comprising:
administering to the subject a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising an ESR-1 agonist or an ESR-1 coactivator agonist and a pharmaceutically acceptable carrier, wherein the therapeutically effective amount is the amount required to inhibit HIV transcription in a latent HIV infected CD4+ T cell of the subject. 49. The method of claim 48, the ESR-1 agonist comprising propylpyrazole triol (PPT). 50. The method of claim 48, further comprising the step of administering to the subject a therapeutically effective HAART regimen. | A pharmaceutical composition for inducing reactivation of latent provirus in an HIV infected cell includes an ESR-1 antagonist or an ESR-1 coactivator antagonist and a pharmaceutically acceptable carrier.1-15. (canceled) 16. A method for inducing activation of latent provirus expression in an HIV infected cell, the method comprising:
contacting the cell with an effective amount of a pharmaceutical composition, the pharmaceutical composition comprising an ESR-1 antagonist or an ESR-1 coactivator antagonist, an activator of latent HIV expression and a pharmaceutically acceptable carrier. 17. The method of claim 16, wherein the ESR-1 antagonist or the ESR-1 coactivator antagonist and the activator of latent HIV expression synergize to generate greater reactivation of latent HIV expression compared to either agent alone when contacted with the cell. 18. The method of claim 16, the HIV infected cell comprising a human CD4+ T cell. 19. The method of claim 16, the ESR-1 antagonist comprising a selective estrogen receptor down-regulator of ESR-1. 20. The method of claim 19, the selective estrogen receptor down-regulator of ESR-1 comprising Fulvestrant. 21. The method of claim 16, the ESR-1 antagonist comprising an ESR-1 shRNA. 22. The method of claim 16, the activator of latent HIV expression selected from an HDAC inhibitor and a protein kinase C agonist. 23. The method of claim 16, the HDAC inhibitor comprising a compound selected from the group consisting of a hydroxamic acid derivative, a short-chain fatty acid, a benzamide derivative, and a cyclic peptide. 24. The method of claim 23, the HDAC inhibitor comprising a hydroxamic acid derivative, wherein the hydroxamic acid derivative is suberoylanilide hydroxamic acid (SAHA). 25. The method of claim 22, the protein kinase C agonist comprising a compound selected from the group consisting of prostratin, 12-deoxyphorbol 13-phenylacetate (DPP), Ingenol mebutate, and a bryostatin. 26. The method of claim 16, wherein ESR-1 antagonist is Fulvestrant and the activator of latent HIV expression is suberoylanilide hydroxamic acid (SAHA). 27. The method of claim 16, the ESR-1 coactivator antagonist comprising Gossypol. 28. The method of claim 16, the pharmaceutical composition additionally comprising one or more antiviral agents. 29. The method of claim 28, the one or more antiviral agents comprising a component of HAART, the component of HAART selected from a nucleoside reverse transcriptase inhibitor, a non-nucleoside HIV reverse transcriptase inhibitor, and a protease inhibitor. 30. The method of claim 16, wherein the pharmaceutical composition fails to significantly activate the NF-kB signaling cascade in the HIV infected cell. 31. A method of treating HIV infection in a subject comprising:
administering to the subject a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising an ESR-1 antagonist or an ESR-1 coactivator antagonist, an activator of latent HIV expression, and a pharmaceutically acceptable carrier. 32. The method of claim 31, wherein the ESR-1 antagonist or the ESR-1 coactivator antagonist and the activator of latent HIV expression administered to the subject synergize to generate greater reactivation of latent HIV expression in an HIV infected cell of the subject compared to administration of either agent alone. 33. The method of claim 32, the HIV infected cell comprising a human CD4+ T cell. 34. The method of claim 31, the ESR-1 antagonist comprising a selective estrogen receptor down-regulator of ESR-1. 35. The method of claim 34, the selective estrogen receptor down-regulator of ESR-1 comprising Fulvestrant. 36. The method of claim 31, the ESR-1 antagonist comprising an ESR-1 shRNA. 37. The method of claim 31, the activator of latent HIV expression selected from an HDAC inhibitor and a protein kinase C agonist. 38. The method of claim 31, the HDAC inhibitor comprising a compound selected from the group consisting of a hydroxamic acid derivative, a short-chain fatty acid, a benzamide derivative, and a cyclic peptide. 39. The method of claim 38, the HDAC inhibitor comprising a hydroxamic acid derivative, wherein the hydroxamic acid derivative is suberoylanilide hydroxamic acid (SAHA). 40. The method of claim 37, the protein kinase C agonist comprising a compound selected from the group consisting of prostratin, 12-deoxyphorbol 13-phenylacetate (DPP), Ingenol mebutate, and a bryostatin. 41. The method of claim 31, wherein ESR-1 antagonist is Fulvestrant and the activator of latent HIV expression is suberoylanilide hydroxamic acid (SAHA). 42. The method of claim 31, the ESR-1 coactivator antagonist comprising Gossypol. 43. The method of claim 31, further comprising the step of administering to the subject a therapeutically effective amount of or more antiviral agents. 44. The method of claim 43, the one or more antiviral agents comprising a component of HAART, the component of HAART selected from a nucleoside reverse transcriptase inhibitor, a non-nucleoside HIV reverse transcriptase inhibitor, and a protease inhibitor. 45. The method of claim 31, the pharmaceutical composition additionally comprising one or more antiviral agents. 46. The method of claim 45, the one or more antiviral agents comprising a component of HAART, the component of HAART selected from a nucleoside reverse transcriptase inhibitor, a non-nucleoside HIV reverse transcriptase inhibitor, and a protease inhibitor. 47. The method of claim 31, wherein the pharmaceutical composition fails to significantly activate the NF-kB signaling cascade in the HIV infected cell. 48. A method of treating HIV infection in a subject comprising:
administering to the subject a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition comprising an ESR-1 agonist or an ESR-1 coactivator agonist and a pharmaceutically acceptable carrier, wherein the therapeutically effective amount is the amount required to inhibit HIV transcription in a latent HIV infected CD4+ T cell of the subject. 49. The method of claim 48, the ESR-1 agonist comprising propylpyrazole triol (PPT). 50. The method of claim 48, further comprising the step of administering to the subject a therapeutically effective HAART regimen. | 1,600 |
1,473 | 15,660,928 | 1,619 | A method for delivering a therapeutic agent to a subject from a transdermal delivery system is described, where the therapeutic agent (i) has a half-life in the blood when delivered orally of greater than about 48 hours and (ii) is for the treatment of a chronic condition. The transdermal delivery system achieves transdermal delivery of the therapeutic agent at steady state that is bioequivalent to administration of the therapeutic agent orally, wherein bioequivalency is established by (a) a 90% confidence interval of the relative mean Cmax and AUC of the therapeutic agent administered from the transdermal delivery system and via oral delivery between 0.70 and 1.43 or between 0.80 and 1.25, or (b) a 90% confidence interval of the ratios for AUC and Cmax of the therapeutic agent administered from the transdermal delivery system and via oral delivery between 0.70 and 1.43 or between 0.80 and 1.25. | 1. A method for delivering a therapeutic agent to a subject, comprising:
providing a transdermal delivery system comprised of a therapeutic agent and a reservoir comprising the therapeutic agent, wherein the therapeutic agent (i) has a half-life in the blood when delivered orally of greater than about 48 hours and (ii) is for the treatment of a chronic condition, and administering or instructing to administer the transdermal delivery system to the skin of a subject, whereby said administering achieves transdermal delivery of the therapeutic agent at steady state that is bioequivalent to administration of the therapeutic agent orally, wherein bioequivalency is established by (a) a 90% confidence interval of the relative mean Cmax and AUC of the therapeutic agent administered from the transdermal delivery system and via oral delivery are between 0.70 and 1.43, or (b) a 90% confidence interval of the geometric mean ratios for AUC and Cmax of the therapeutic agent administered from the transdermal delivery system and via oral delivery are between 0.70 and 1.43. 2. The method of claim 1, wherein the therapeutic agent is a poorly water soluble agent. 3. The method of claim 1, wherein bioequivalency is established in healthy subjects. 4. The method of claim 1, wherein bioequivalency is established in a fasting condition. 5. The method of claim 1, wherein bioequivalency is established by (a) a 90% confidence interval of the relative mean Cmax and AUC of the therapeutic agent administered from the transdermal delivery system and via oral delivery are between 0.80 and 1.25, or (b) a 90% confidence interval of the ratios for AUC and Cmax of the therapeutic agent administered from the transdermal delivery system and via oral delivery are between 0.80 and 1.25. 6. The method of claim 1, wherein the therapeutic agent is selected from the group consisting of donepezil base, a donepezil salt, memantine base, a memantine salt, fingolimod base and a fingolimod salt. 7. The method claim 1, wherein the chronic condition is Alzheimer's disease or wherein the chronic condition is multiple sclerosis. 8. The method of claim 1, wherein the administering or instructing to administer comprises administering or instructing to administer once weekly. 9. The method of claim 1, wherein the therapeutic agent is donepezil base or a donepezil salt, and wherein the transdermal delivery system comprises a dose of donepezil base or a donepezil salt to provide between 1-25 mg/24 hours. 10. The method of claim 9, wherein the transdermal delivery system comprises a drug reservoir and a contact adhesive, wherein the drug reservoir and/or the contact adhesive comprises one of (i) lauryl lactate, (ii) triethyl citrate, (iii) a polyvinylpyrrolidone. 11. The method of claim 9, wherein the transdermal delivery system comprises a drug reservoir and a contact adhesive, wherein the drug reservoir and/or the contact adhesive comprises one of (i) lauryl lactate, (ii) triethyl citrate, and (iii) glycerol. 12. The method claim 9, wherein the transdermal delivery system comprises a drug reservoir comprises two of (i) lauryl lactate, (ii) triethyl citrate, and (iii) glycerol. 13. The method of claim 11, wherein the drug reservoir comprises donepezil hydrochloride and sodium bicarbonate. 14. The method of claim 13, wherein the drug reservoir additionally comprises one or both of sorbitan monolaurate and lauryl lactate. 15. The method of claim 1, wherein the therapeutic agent is memantine base or a memantine salt, and wherein the transdermal delivery system comprises a dose of memantine base or memantine salt to provide between 7-28 mg/24 hours. 16. The method of claim 15, wherein the transdermal delivery system comprises a drug reservoir and a contact adhesive, and wherein the drug reservoir is manufactured from a formulation comprising a memantine salt and an alkaline salt. 17. The method of claim 16, wherein the memantine salt is memantine hydrochloride and the alkaline salt is sodium bicarbonate or potassium bicarbonate. 18. The method of claim 16, wherein the contact adhesive comprises a higher alcohol and a biocompatible polymer. 19. The method of claim 18, wherein the higher alcohol is selected from the group consisting of lauryl alcohol, isostearyl alcohol, octyldodecanol, and oleyl alcohol. 20. The method of claim 16, wherein the drug reservoir consists essentially of: (a) memantine base generated in situ by reaction of between about 10-30 wt % memantine HCl and between about 5-15 wt % sodium bicarbonate; (b) about 5-15 wt % octyldodecanol; (c) about 5-15 wt % glycerol; (d) about 10-30 wt % crosslinked polyvinylpyrrolidone; and (e) about 20-50 wt % acrylate polymer. 21. The method of claim 1, wherein the therapeutic agent is fingolimod base or a fingolimod salt, and wherein the transdermal delivery system comprises a dose of fingolimod base or fingolimod salt to provide between 0.05-2 mg/24 hours. 22. A method for evaluating a transdermal system, comprising:
administering or instructing to administer a transdermal delivery system to a subject, the transdermal delivery system comprised of a therapeutic agent and a reservoir comprising the therapeutic agent, wherein the therapeutic agent (i) has a half-life in the blood when delivered orally of greater than about 48 hours and (ii) is for the treatment of a chronic condition, and administering or instructing to administer to a subject via oral administration the therapeutic agent, whereby said administering achieves transdermal delivery of the therapeutic agent that is bioequivalent to administration of the therapeutic agent orally, wherein bioequivalency is established by (a) a 90% confidence interval of the relative mean Cmax and AUC of the therapeutic agent administered from the transdermal delivery system and via oral delivery are between 0.70 and 1.43, or (b) a 90% confidence interval of the geometric mean ratios for AUC and Cmax of the therapeutic agent administered from the transdermal delivery system and via oral delivery are between 0.70 and 1.43. 23. The method of claim 22, wherein the transdermal delivery system administers a dose of x mg/day to the subject, and wherein the subject administered via oral administration the therapeutic agent receives a dose within 20% of the x mg/day, wherein x is between 0.05-25. 24. The method of claim 22, wherein the transdermal delivery system administers a dose of x mg/day to the subject, and wherein the subject administered the therapeutic agent via oral administration receives x mg/day, wherein x is between 0.05-25. 25. The method of claim 22, wherein the subject administered the transdermal delivery system and the subject administered the therapeutic agent via oral administration are the same subject. 26. The method of claim 22, wherein the subject administered the transdermal delivery system and the subject administered the therapeutic agent via oral administration are different subjects. | A method for delivering a therapeutic agent to a subject from a transdermal delivery system is described, where the therapeutic agent (i) has a half-life in the blood when delivered orally of greater than about 48 hours and (ii) is for the treatment of a chronic condition. The transdermal delivery system achieves transdermal delivery of the therapeutic agent at steady state that is bioequivalent to administration of the therapeutic agent orally, wherein bioequivalency is established by (a) a 90% confidence interval of the relative mean Cmax and AUC of the therapeutic agent administered from the transdermal delivery system and via oral delivery between 0.70 and 1.43 or between 0.80 and 1.25, or (b) a 90% confidence interval of the ratios for AUC and Cmax of the therapeutic agent administered from the transdermal delivery system and via oral delivery between 0.70 and 1.43 or between 0.80 and 1.25.1. A method for delivering a therapeutic agent to a subject, comprising:
providing a transdermal delivery system comprised of a therapeutic agent and a reservoir comprising the therapeutic agent, wherein the therapeutic agent (i) has a half-life in the blood when delivered orally of greater than about 48 hours and (ii) is for the treatment of a chronic condition, and administering or instructing to administer the transdermal delivery system to the skin of a subject, whereby said administering achieves transdermal delivery of the therapeutic agent at steady state that is bioequivalent to administration of the therapeutic agent orally, wherein bioequivalency is established by (a) a 90% confidence interval of the relative mean Cmax and AUC of the therapeutic agent administered from the transdermal delivery system and via oral delivery are between 0.70 and 1.43, or (b) a 90% confidence interval of the geometric mean ratios for AUC and Cmax of the therapeutic agent administered from the transdermal delivery system and via oral delivery are between 0.70 and 1.43. 2. The method of claim 1, wherein the therapeutic agent is a poorly water soluble agent. 3. The method of claim 1, wherein bioequivalency is established in healthy subjects. 4. The method of claim 1, wherein bioequivalency is established in a fasting condition. 5. The method of claim 1, wherein bioequivalency is established by (a) a 90% confidence interval of the relative mean Cmax and AUC of the therapeutic agent administered from the transdermal delivery system and via oral delivery are between 0.80 and 1.25, or (b) a 90% confidence interval of the ratios for AUC and Cmax of the therapeutic agent administered from the transdermal delivery system and via oral delivery are between 0.80 and 1.25. 6. The method of claim 1, wherein the therapeutic agent is selected from the group consisting of donepezil base, a donepezil salt, memantine base, a memantine salt, fingolimod base and a fingolimod salt. 7. The method claim 1, wherein the chronic condition is Alzheimer's disease or wherein the chronic condition is multiple sclerosis. 8. The method of claim 1, wherein the administering or instructing to administer comprises administering or instructing to administer once weekly. 9. The method of claim 1, wherein the therapeutic agent is donepezil base or a donepezil salt, and wherein the transdermal delivery system comprises a dose of donepezil base or a donepezil salt to provide between 1-25 mg/24 hours. 10. The method of claim 9, wherein the transdermal delivery system comprises a drug reservoir and a contact adhesive, wherein the drug reservoir and/or the contact adhesive comprises one of (i) lauryl lactate, (ii) triethyl citrate, (iii) a polyvinylpyrrolidone. 11. The method of claim 9, wherein the transdermal delivery system comprises a drug reservoir and a contact adhesive, wherein the drug reservoir and/or the contact adhesive comprises one of (i) lauryl lactate, (ii) triethyl citrate, and (iii) glycerol. 12. The method claim 9, wherein the transdermal delivery system comprises a drug reservoir comprises two of (i) lauryl lactate, (ii) triethyl citrate, and (iii) glycerol. 13. The method of claim 11, wherein the drug reservoir comprises donepezil hydrochloride and sodium bicarbonate. 14. The method of claim 13, wherein the drug reservoir additionally comprises one or both of sorbitan monolaurate and lauryl lactate. 15. The method of claim 1, wherein the therapeutic agent is memantine base or a memantine salt, and wherein the transdermal delivery system comprises a dose of memantine base or memantine salt to provide between 7-28 mg/24 hours. 16. The method of claim 15, wherein the transdermal delivery system comprises a drug reservoir and a contact adhesive, and wherein the drug reservoir is manufactured from a formulation comprising a memantine salt and an alkaline salt. 17. The method of claim 16, wherein the memantine salt is memantine hydrochloride and the alkaline salt is sodium bicarbonate or potassium bicarbonate. 18. The method of claim 16, wherein the contact adhesive comprises a higher alcohol and a biocompatible polymer. 19. The method of claim 18, wherein the higher alcohol is selected from the group consisting of lauryl alcohol, isostearyl alcohol, octyldodecanol, and oleyl alcohol. 20. The method of claim 16, wherein the drug reservoir consists essentially of: (a) memantine base generated in situ by reaction of between about 10-30 wt % memantine HCl and between about 5-15 wt % sodium bicarbonate; (b) about 5-15 wt % octyldodecanol; (c) about 5-15 wt % glycerol; (d) about 10-30 wt % crosslinked polyvinylpyrrolidone; and (e) about 20-50 wt % acrylate polymer. 21. The method of claim 1, wherein the therapeutic agent is fingolimod base or a fingolimod salt, and wherein the transdermal delivery system comprises a dose of fingolimod base or fingolimod salt to provide between 0.05-2 mg/24 hours. 22. A method for evaluating a transdermal system, comprising:
administering or instructing to administer a transdermal delivery system to a subject, the transdermal delivery system comprised of a therapeutic agent and a reservoir comprising the therapeutic agent, wherein the therapeutic agent (i) has a half-life in the blood when delivered orally of greater than about 48 hours and (ii) is for the treatment of a chronic condition, and administering or instructing to administer to a subject via oral administration the therapeutic agent, whereby said administering achieves transdermal delivery of the therapeutic agent that is bioequivalent to administration of the therapeutic agent orally, wherein bioequivalency is established by (a) a 90% confidence interval of the relative mean Cmax and AUC of the therapeutic agent administered from the transdermal delivery system and via oral delivery are between 0.70 and 1.43, or (b) a 90% confidence interval of the geometric mean ratios for AUC and Cmax of the therapeutic agent administered from the transdermal delivery system and via oral delivery are between 0.70 and 1.43. 23. The method of claim 22, wherein the transdermal delivery system administers a dose of x mg/day to the subject, and wherein the subject administered via oral administration the therapeutic agent receives a dose within 20% of the x mg/day, wherein x is between 0.05-25. 24. The method of claim 22, wherein the transdermal delivery system administers a dose of x mg/day to the subject, and wherein the subject administered the therapeutic agent via oral administration receives x mg/day, wherein x is between 0.05-25. 25. The method of claim 22, wherein the subject administered the transdermal delivery system and the subject administered the therapeutic agent via oral administration are the same subject. 26. The method of claim 22, wherein the subject administered the transdermal delivery system and the subject administered the therapeutic agent via oral administration are different subjects. | 1,600 |
1,474 | 14,525,951 | 1,646 | The present invention provides a method for treating or delaying the onset of an autoimmune condition in a human subject. An effective oral dose of ustekinumab is administered to the subject. Oral administration of ustekinumab also is useful in a method of decreasing innate inflammatory cytokines, such as IL-1β and TNF-α, Th1-like cytokines IL-2 and IFN-γ, IL-17 (T eff ), IL-12p70, and increasing Th2-like counter-regulatory cytokine IL-13 in a subject. | 1. A method for treating or delaying the onset of an autoimmune condition in a human subject comprising orally administering to the subject an effective dose of an anti-interleukin 12/23 antibody. 2. The method of claim 1, wherein the anti-interleukin 12/23 antibody is administered in a fully humanized antibody. 3. The method of claim 1, wherein said fully humanized antibody is ustekinumab. 4. The method of claim 1, wherein the condition is rheumatoid arthritis, psoriasis, type 1 diabetes, systemic lupus erythematosus, transplant rejection, autoimmune thyroid disease (Hashimoto's disease), sarcoidosis, scleroderma, granulomatous vasculitis, Crohn's disease, ulcerative colitis, Sjogren's disease, ankylosing spondylitis, polymyositis dermatomyositis, polyarteritis nodosa, immunologically mediated blistering skin diseases, Behcet's syndrome, multiple sclerosis, systemic sclerosis, Goodpasture's disease or immune mediated glomerulonephritis. 5. The method of claim 3, wherein ustekinumab is administered in a dose from about 0.001 mg to about 50 mg. 6. The method of claim 5, wherein ustekinumab is administered in a solid or liquid form. 7. The method of claim 1, wherein said ustekinumab administration decreases levels of IL-6, Th1-like cytokines IL-2, IL-12, TNF-α and IFN-g. 8. The method of claim 1, wherein said ustekinumab administration increases levels of IL-4, IL-10 and IL-13. 9. (canceled) 10. A method of decreasing innate inflammatory cytokines IL-1b and TNF-α, Th1-like cytokines IL-2 and IFN-g, IL-17 (Teff), IL-12p70 and increasing the Th2-like counter-regulatory cytokine IL-13 in a human subject comprising orally administering to the subject an effective dose of ustekinumab. 11. The method of claim 10, wherein the anti-interleukin 12/23 antibody is administered in a fully humanized antibody. 12. The method of claim 11, wherein said fully humanized antibody is ustekinumab. 13. The method of claim 10, wherein the condition is rheumatoid arthritis, psoriasis, type 1 diabetes, systemic lupus erythematosus, transplant rejection, autoimmune thyroid disease (Hashimoto's disease), sarcoidosis, scleroderma, granulomatous vasculitis, Crohn's disease, ulcerative colitis, Sjogren's disease, ankylosing spondylitis, polymyositis dermatomyositis, polyarteritis nodosa, immunologically mediated blistering skin diseases, Behcet's syndrome, multiple sclerosis, systemic sclerosis, Goodpasture's disease or immune mediated glomerulonephritis. 14. The method of claim 12, wherein ustekinumab is administered in a dose from about 0.001 mg to about 50 mg. 15. The method of claim 12, wherein ustekinumab is administered in a solid or liquid form. 16. The method of claim 12, wherein said ustekinumab administration decreases levels of IL-6, Th1-like cytokines IL-2, IL-12, TNF-α and IFN-g. 17. The method of claim 12, wherein said ustekinumab administration increases levels of IL-4, IL-10 and IL-13. 18. (canceled) | The present invention provides a method for treating or delaying the onset of an autoimmune condition in a human subject. An effective oral dose of ustekinumab is administered to the subject. Oral administration of ustekinumab also is useful in a method of decreasing innate inflammatory cytokines, such as IL-1β and TNF-α, Th1-like cytokines IL-2 and IFN-γ, IL-17 (T eff ), IL-12p70, and increasing Th2-like counter-regulatory cytokine IL-13 in a subject.1. A method for treating or delaying the onset of an autoimmune condition in a human subject comprising orally administering to the subject an effective dose of an anti-interleukin 12/23 antibody. 2. The method of claim 1, wherein the anti-interleukin 12/23 antibody is administered in a fully humanized antibody. 3. The method of claim 1, wherein said fully humanized antibody is ustekinumab. 4. The method of claim 1, wherein the condition is rheumatoid arthritis, psoriasis, type 1 diabetes, systemic lupus erythematosus, transplant rejection, autoimmune thyroid disease (Hashimoto's disease), sarcoidosis, scleroderma, granulomatous vasculitis, Crohn's disease, ulcerative colitis, Sjogren's disease, ankylosing spondylitis, polymyositis dermatomyositis, polyarteritis nodosa, immunologically mediated blistering skin diseases, Behcet's syndrome, multiple sclerosis, systemic sclerosis, Goodpasture's disease or immune mediated glomerulonephritis. 5. The method of claim 3, wherein ustekinumab is administered in a dose from about 0.001 mg to about 50 mg. 6. The method of claim 5, wherein ustekinumab is administered in a solid or liquid form. 7. The method of claim 1, wherein said ustekinumab administration decreases levels of IL-6, Th1-like cytokines IL-2, IL-12, TNF-α and IFN-g. 8. The method of claim 1, wherein said ustekinumab administration increases levels of IL-4, IL-10 and IL-13. 9. (canceled) 10. A method of decreasing innate inflammatory cytokines IL-1b and TNF-α, Th1-like cytokines IL-2 and IFN-g, IL-17 (Teff), IL-12p70 and increasing the Th2-like counter-regulatory cytokine IL-13 in a human subject comprising orally administering to the subject an effective dose of ustekinumab. 11. The method of claim 10, wherein the anti-interleukin 12/23 antibody is administered in a fully humanized antibody. 12. The method of claim 11, wherein said fully humanized antibody is ustekinumab. 13. The method of claim 10, wherein the condition is rheumatoid arthritis, psoriasis, type 1 diabetes, systemic lupus erythematosus, transplant rejection, autoimmune thyroid disease (Hashimoto's disease), sarcoidosis, scleroderma, granulomatous vasculitis, Crohn's disease, ulcerative colitis, Sjogren's disease, ankylosing spondylitis, polymyositis dermatomyositis, polyarteritis nodosa, immunologically mediated blistering skin diseases, Behcet's syndrome, multiple sclerosis, systemic sclerosis, Goodpasture's disease or immune mediated glomerulonephritis. 14. The method of claim 12, wherein ustekinumab is administered in a dose from about 0.001 mg to about 50 mg. 15. The method of claim 12, wherein ustekinumab is administered in a solid or liquid form. 16. The method of claim 12, wherein said ustekinumab administration decreases levels of IL-6, Th1-like cytokines IL-2, IL-12, TNF-α and IFN-g. 17. The method of claim 12, wherein said ustekinumab administration increases levels of IL-4, IL-10 and IL-13. 18. (canceled) | 1,600 |
1,475 | 16,851,999 | 1,628 | Disclosed herein are methods of for treating hyperammonemia in a patient having renal impairment, comprising administering carglumic acid to said patient at a reduced daily dosage. | 1. A method for treating hyperammonemia in a patient in need thereof, comprising:
identifying the patient as having moderate renal impairment; and administering carglumic acid to the patient at a daily dosage of 5 mg/kg/day to 125 mg/kg/day divided into two to four doses. 2. The method of claim 1, wherein the patient has a glomerular filtration rate (GFR) of 30-59 mL/min/1.73 m2. 3. The method of claim 1, wherein the hyperammonemia is acute hyperammonemia, and the patient is administered a daily dosage of 50 mg/kg/day to 125 mg/kg/day. 4. The method of claim 3, wherein the hyperammonemia is acute hyperammonemia, and the patient is administered a daily dosage of 50 mg/kg/day to 95 mg/kg/day. 5. The method of claim 3, wherein the hyperammonemia is acute hyperammonemia, and the patient is administered a daily dosage of 50 mg/kg/day to 90 mg/kg/day. 6. The method of claim 1, wherein the hyperammonemia is chronic hyperammonemia, and the patient is administered a daily dosage of 5 mg/kg/day to 50 mg/kg/day. The method of claim 1, wherein the hyperammonemia is due to hepatic enzyme N-acetylglutamate synthase (NAGS) deficiency, propionic acidemia (PA), methylmalonic acidemia (MMA) or isovaleric acidemia (IVA). 8. A method for treating hyperammonemia in a patient in need thereof, comprising:
identifying the patient as having severe renal impairment; and administering carglumic acid to the patient at a daily dosage of 2 mg/kg/day to 60 mg/kg/day divided into two to four doses. 9. The method of claim 8, wherein the patient has a glomerular filtration rate (GFR) of 15 to 29 mL/min/1.73 m2. 10. The method of claim 8, wherein the hyperammonemia is acute hyperammonemia, and the patient is administered a daily dosage of 15 mg/kg/day to 60 mg/kg/day. 11. The method of claim 8 wherein the hyperammonemia is chronic hyperammonemia, and the patient is administered a daily dosage of 2 mg/kg/day to 25 mg/kg/day. 12. The method of claim 8, wherein the hyperammonemia is due to hepatic enzyme N-acetylglutamate synthase (NAGS) deficiency, propionic acidemia (PA), methylmalonic acidemia (MMA) or isovaleric acidemia (IVA). 13. A method for treating hyperammonemia in a patient in need thereof, comprising:
identifying the patient as having end-stage renal impairment; and administering carglumic acid to the patient at a daily dosage of 2 mg/kg/day to 60 mg/kg/day divided into two to four doses. 14. The method of claim 13, wherein the patient has a glomerular filtration rate (GFR) of less than 15 mL/min/1.73 m2. 15. The method of claim 13, wherein the hyperammonemia is acute hyperammonemia, and the patient is administered a daily dosage of 15 mg/kg/day to 60 mg/kg/day. 16. The method of claim 13, wherein the hyperammonemia is chronic hyperammonemia, and the patient is administered a daily dosage of 2 mg/kg/day to 25 mg/kg/day. 17. The method of claim 13 wherein the hyperammonemia is due to hepatic enzyme N-acetylglutamate synthase (NAGS) deficiency, propionic acidemia (PA), methylmalonic acidemia (MMA) or isovaleric acidemia (IVA). | Disclosed herein are methods of for treating hyperammonemia in a patient having renal impairment, comprising administering carglumic acid to said patient at a reduced daily dosage.1. A method for treating hyperammonemia in a patient in need thereof, comprising:
identifying the patient as having moderate renal impairment; and administering carglumic acid to the patient at a daily dosage of 5 mg/kg/day to 125 mg/kg/day divided into two to four doses. 2. The method of claim 1, wherein the patient has a glomerular filtration rate (GFR) of 30-59 mL/min/1.73 m2. 3. The method of claim 1, wherein the hyperammonemia is acute hyperammonemia, and the patient is administered a daily dosage of 50 mg/kg/day to 125 mg/kg/day. 4. The method of claim 3, wherein the hyperammonemia is acute hyperammonemia, and the patient is administered a daily dosage of 50 mg/kg/day to 95 mg/kg/day. 5. The method of claim 3, wherein the hyperammonemia is acute hyperammonemia, and the patient is administered a daily dosage of 50 mg/kg/day to 90 mg/kg/day. 6. The method of claim 1, wherein the hyperammonemia is chronic hyperammonemia, and the patient is administered a daily dosage of 5 mg/kg/day to 50 mg/kg/day. The method of claim 1, wherein the hyperammonemia is due to hepatic enzyme N-acetylglutamate synthase (NAGS) deficiency, propionic acidemia (PA), methylmalonic acidemia (MMA) or isovaleric acidemia (IVA). 8. A method for treating hyperammonemia in a patient in need thereof, comprising:
identifying the patient as having severe renal impairment; and administering carglumic acid to the patient at a daily dosage of 2 mg/kg/day to 60 mg/kg/day divided into two to four doses. 9. The method of claim 8, wherein the patient has a glomerular filtration rate (GFR) of 15 to 29 mL/min/1.73 m2. 10. The method of claim 8, wherein the hyperammonemia is acute hyperammonemia, and the patient is administered a daily dosage of 15 mg/kg/day to 60 mg/kg/day. 11. The method of claim 8 wherein the hyperammonemia is chronic hyperammonemia, and the patient is administered a daily dosage of 2 mg/kg/day to 25 mg/kg/day. 12. The method of claim 8, wherein the hyperammonemia is due to hepatic enzyme N-acetylglutamate synthase (NAGS) deficiency, propionic acidemia (PA), methylmalonic acidemia (MMA) or isovaleric acidemia (IVA). 13. A method for treating hyperammonemia in a patient in need thereof, comprising:
identifying the patient as having end-stage renal impairment; and administering carglumic acid to the patient at a daily dosage of 2 mg/kg/day to 60 mg/kg/day divided into two to four doses. 14. The method of claim 13, wherein the patient has a glomerular filtration rate (GFR) of less than 15 mL/min/1.73 m2. 15. The method of claim 13, wherein the hyperammonemia is acute hyperammonemia, and the patient is administered a daily dosage of 15 mg/kg/day to 60 mg/kg/day. 16. The method of claim 13, wherein the hyperammonemia is chronic hyperammonemia, and the patient is administered a daily dosage of 2 mg/kg/day to 25 mg/kg/day. 17. The method of claim 13 wherein the hyperammonemia is due to hepatic enzyme N-acetylglutamate synthase (NAGS) deficiency, propionic acidemia (PA), methylmalonic acidemia (MMA) or isovaleric acidemia (IVA). | 1,600 |
1,476 | 14,807,989 | 1,619 | The present invention provides methods for preparing an absorbent antimicrobial wound dressing which comprise steps of (a) preparing an antimicrobial coating composition by mixing an antimicrobial agent and one or more polymers in a solvent system that comprises a non-aqueous solvent, (b) contacting the antimicrobial coating composition of step (a) with a wound dressing substrate which comprises absorbent fibers or absorbent particles, and (c) drying the product of step (b). The present invention also provides absorbent antimicrobial wound dressings including those prepared by these methods as well as antimicrobial coating compositions and methods of producing antimicrobial coating compositions. | 1. A method of preparing an absorbent antimicrobial wound dressing comprising:
(a) preparing an antimicrobial coating composition by mixing an antimicrobial agent and one or more polymers in a solvent system that comprises a non-aqueous solvent; (b) contacting the antimicrobial coating composition of step (a) with a wound dressing substrate which comprises absorbent fibers or absorbent particles; and (c) drying the product of step (b). 2. The method of claim 1 wherein the one or more polymers are selected from the group consisting of cellulosic polymers, neutral poly(meth)acrylate esters, polyvinylpyrrolidone, polyvinylpolypyrrolidone, and combinations thereof. 3. The method of claim 1, wherein the absorbent fibers comprise polyvinyl alcohol. 4. The method of claim 3, wherein the polyvinyl alcohol is cross-linked. 5. The method of claim 1, wherein the absorbent fibers comprise a cellulosic polymer. 6. The method of claim 5, wherein the absorbent fibers comprise carboxymethyl cellulose. 7. The method of claim 1, wherein the one or more polymers in the antimicrobial coating composition have an average molecular weight between 50-1500 kDa. 8. The method of claim 1, wherein the one or more polymers in the antimicrobial coating composition are cellulosic polymers. 9. The method of claim 8, wherein the one or more polymers in the antimicrobial coating composition are cellulosic polymers selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose (MC), and ethylcellulose (EC). 10. The method of claim 9, wherein the one or more polymers in the antimicrobial coating composition comprise hydroxypropylcellulose (HPC). 11. The method of claim 1, wherein the antimicrobial agent comprises silver. 12. The method of claim 11, wherein the antimicrobial agent is silver oxide or a silver salt. 13. The method of claim 12, wherein the silver salt is selected from the group consisting of silver sulfate, silver chloride, silver nitrate, silver sulfadiazine, silver carbonate, silver phosphate, silver lactate, silver bromide, silver acetate, and silver citrate. 14. The method of claim 1, wherein the non-aqueous solvent comprises a polar protic solvent. 15. The method of claim 14, wherein the polar protic solvent comprises an alcohol. 16. The method of claim 15, wherein the alcohol comprises a C1-4 alkyl alcohol. 17. The method of claim 16, wherein the C1-4 alkyl alcohol is methanol, ethanol, n-propanol, isopropanol, n-butanol, or s-butanol. 18. The method of claim 17, wherein the C1-4 alkyl alcohol is ethanol. 19. The method of claim 1, wherein step (a) comprises the substeps of:
(1) adding the one or more polymers to a solvent system that comprises a non-aqueous solvent; and (2) adding the antimicrobial agent to the mixture resulting from substep (1). 20. The method of claim 1, wherein step (b) is performed using slot die, foulard, or kiss-coating. 21. An absorbent antimicrobial wound dressing prepared according to the method of claim 1. 22. An absorbent antimicrobial wound dressing that includes a substrate comprising an absorbent fiber or absorbent particle coated with an antimicrobial coating that comprises an antimicrobial agent and one or more polymers, wherein the one or more polymers are selected from the group consisting of cellulosic polymers, neutral poly(meth)acrylate esters, polyvinylpyrrolidone, polyvinylpolypyrrolidone, and combinations thereof. 23. The wound dressing of claim 22, wherein the absorbent fiber comprises polyvinyl alcohol. 24. The wound dressing of claim 23, wherein the polyvinyl alcohol is cross-linked. 25. The wound dressing of claim 22, wherein the absorbent particle comprises polyacrylic acid. 26. The wound dressing of claim 22, wherein the absorbent fiber comprise a cellulosic polymer. 27. The wound dressing of claim 26, wherein the absorbent fiber comprise carboxymethyl cellulose. 28. The wound dressing of claim 22, wherein the one or more polymers in the antimicrobial coating have an average molecular weight between 50-1500 kDa. 29. The wound dressing of claim 22, wherein the one or more polymers in the antimicrobial coating are cellulosic polymers. 30. The wound dressing of claim 29, wherein the one or more polymers in the antimicrobial coating are cellulosic polymers selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose (MC), and ethylcellulose (EC). 31. The wound dressing of claim 29, wherein the one or more polymers in the antimicrobial coating comprise hydroxypropylcellulose (HPC). 32. The wound dressing of claim 22, wherein the antimicrobial agent comprises silver. 33. The wound dressing of claim 32, wherein the antimicrobial agent is silver oxide or a silver salt. 34. The wound dressing of claim 33, wherein the silver salt is selected from the group consisting of silver sulfate, silver chloride, silver nitrate, silver sulfadiazine, silver carbonate, silver phosphate, silver lactate, silver bromide, silver acetate, and silver citrate. 35. A process for preparing an antibacterial coating composition comprising the step(s) of mixing an antimicrobial agent and one or more polymers in a solvent system that comprises a non-aqueous solvent. 36. The process of claim 35, wherein the step(s) of mixing comprising:
(1) adding one or more polymers to a solvent system that comprises a non-aqueous solvent; and (2) adding an antimicrobial agent to the mixture resulting from step (1). 37. The process of claim 36, wherein the antibacterial agent comprises silver. 38. The process of claim 37, wherein the silver is silver oxide or a silver salt. 39. The process of claim 38, wherein the silver salt is selected from the group consisting of silver sulfate, silver chloride, silver nitrate, silver sulfadiazine, silver carbonate, silver phosphate, silver lactate, silver bromide, silver acetate, and silver citrate. 40. The process of claim 35, wherein one or more polymers are selected from the group consisting of cellulosic polymers, neutral poly(meth)acrylate esters, polyvinylpyrrolidone, polyvinylpolypyrrolidone, and combinations thereof. 41. The process of claim 40, wherein the cellulosic polymer is hydroxypropylcellulose. 42. The process of claim 36, wherein the non-aqueous solvent in steps (1) and (2) comprises an alcohol. 43. The process of claim 42, wherein the non-aqueous solvent in steps (1) and (2) comprises ethanol. 44. The process of claim 36 further comprising:
(3) treating the mixture resulting from step (2) to increase its viscosity. 45. The process of claim 44, wherein step (3) comprises mixing the mixture resulting from step (2) for at least 60 minutes. 46. The process of claim 35, wherein the amount of hydroxypropylcellulose in the antibacterial coating composition is between 1.0 and 1.5% w/w. 47. The process of claim 35, wherein the amount of water in the antibacterial coating composition is between 1% and 20% w/w. 48. The process of claim 35, wherein the amount of water in the antibacterial coating composition is less than 15% w/w. 49. The process of claim 35, wherein the amount of antimicrobial agent in the antibacterial coating composition is at least 0.1% w/w. 50. The process of claim 35, wherein the amount of antimicrobial agent in the antibacterial coating composition is between 0.1% and 40% w/w. 51. An antibacterial coating composition produced by the method of claim 35. | The present invention provides methods for preparing an absorbent antimicrobial wound dressing which comprise steps of (a) preparing an antimicrobial coating composition by mixing an antimicrobial agent and one or more polymers in a solvent system that comprises a non-aqueous solvent, (b) contacting the antimicrobial coating composition of step (a) with a wound dressing substrate which comprises absorbent fibers or absorbent particles, and (c) drying the product of step (b). The present invention also provides absorbent antimicrobial wound dressings including those prepared by these methods as well as antimicrobial coating compositions and methods of producing antimicrobial coating compositions.1. A method of preparing an absorbent antimicrobial wound dressing comprising:
(a) preparing an antimicrobial coating composition by mixing an antimicrobial agent and one or more polymers in a solvent system that comprises a non-aqueous solvent; (b) contacting the antimicrobial coating composition of step (a) with a wound dressing substrate which comprises absorbent fibers or absorbent particles; and (c) drying the product of step (b). 2. The method of claim 1 wherein the one or more polymers are selected from the group consisting of cellulosic polymers, neutral poly(meth)acrylate esters, polyvinylpyrrolidone, polyvinylpolypyrrolidone, and combinations thereof. 3. The method of claim 1, wherein the absorbent fibers comprise polyvinyl alcohol. 4. The method of claim 3, wherein the polyvinyl alcohol is cross-linked. 5. The method of claim 1, wherein the absorbent fibers comprise a cellulosic polymer. 6. The method of claim 5, wherein the absorbent fibers comprise carboxymethyl cellulose. 7. The method of claim 1, wherein the one or more polymers in the antimicrobial coating composition have an average molecular weight between 50-1500 kDa. 8. The method of claim 1, wherein the one or more polymers in the antimicrobial coating composition are cellulosic polymers. 9. The method of claim 8, wherein the one or more polymers in the antimicrobial coating composition are cellulosic polymers selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose (MC), and ethylcellulose (EC). 10. The method of claim 9, wherein the one or more polymers in the antimicrobial coating composition comprise hydroxypropylcellulose (HPC). 11. The method of claim 1, wherein the antimicrobial agent comprises silver. 12. The method of claim 11, wherein the antimicrobial agent is silver oxide or a silver salt. 13. The method of claim 12, wherein the silver salt is selected from the group consisting of silver sulfate, silver chloride, silver nitrate, silver sulfadiazine, silver carbonate, silver phosphate, silver lactate, silver bromide, silver acetate, and silver citrate. 14. The method of claim 1, wherein the non-aqueous solvent comprises a polar protic solvent. 15. The method of claim 14, wherein the polar protic solvent comprises an alcohol. 16. The method of claim 15, wherein the alcohol comprises a C1-4 alkyl alcohol. 17. The method of claim 16, wherein the C1-4 alkyl alcohol is methanol, ethanol, n-propanol, isopropanol, n-butanol, or s-butanol. 18. The method of claim 17, wherein the C1-4 alkyl alcohol is ethanol. 19. The method of claim 1, wherein step (a) comprises the substeps of:
(1) adding the one or more polymers to a solvent system that comprises a non-aqueous solvent; and (2) adding the antimicrobial agent to the mixture resulting from substep (1). 20. The method of claim 1, wherein step (b) is performed using slot die, foulard, or kiss-coating. 21. An absorbent antimicrobial wound dressing prepared according to the method of claim 1. 22. An absorbent antimicrobial wound dressing that includes a substrate comprising an absorbent fiber or absorbent particle coated with an antimicrobial coating that comprises an antimicrobial agent and one or more polymers, wherein the one or more polymers are selected from the group consisting of cellulosic polymers, neutral poly(meth)acrylate esters, polyvinylpyrrolidone, polyvinylpolypyrrolidone, and combinations thereof. 23. The wound dressing of claim 22, wherein the absorbent fiber comprises polyvinyl alcohol. 24. The wound dressing of claim 23, wherein the polyvinyl alcohol is cross-linked. 25. The wound dressing of claim 22, wherein the absorbent particle comprises polyacrylic acid. 26. The wound dressing of claim 22, wherein the absorbent fiber comprise a cellulosic polymer. 27. The wound dressing of claim 26, wherein the absorbent fiber comprise carboxymethyl cellulose. 28. The wound dressing of claim 22, wherein the one or more polymers in the antimicrobial coating have an average molecular weight between 50-1500 kDa. 29. The wound dressing of claim 22, wherein the one or more polymers in the antimicrobial coating are cellulosic polymers. 30. The wound dressing of claim 29, wherein the one or more polymers in the antimicrobial coating are cellulosic polymers selected from the group consisting of hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose (MC), and ethylcellulose (EC). 31. The wound dressing of claim 29, wherein the one or more polymers in the antimicrobial coating comprise hydroxypropylcellulose (HPC). 32. The wound dressing of claim 22, wherein the antimicrobial agent comprises silver. 33. The wound dressing of claim 32, wherein the antimicrobial agent is silver oxide or a silver salt. 34. The wound dressing of claim 33, wherein the silver salt is selected from the group consisting of silver sulfate, silver chloride, silver nitrate, silver sulfadiazine, silver carbonate, silver phosphate, silver lactate, silver bromide, silver acetate, and silver citrate. 35. A process for preparing an antibacterial coating composition comprising the step(s) of mixing an antimicrobial agent and one or more polymers in a solvent system that comprises a non-aqueous solvent. 36. The process of claim 35, wherein the step(s) of mixing comprising:
(1) adding one or more polymers to a solvent system that comprises a non-aqueous solvent; and (2) adding an antimicrobial agent to the mixture resulting from step (1). 37. The process of claim 36, wherein the antibacterial agent comprises silver. 38. The process of claim 37, wherein the silver is silver oxide or a silver salt. 39. The process of claim 38, wherein the silver salt is selected from the group consisting of silver sulfate, silver chloride, silver nitrate, silver sulfadiazine, silver carbonate, silver phosphate, silver lactate, silver bromide, silver acetate, and silver citrate. 40. The process of claim 35, wherein one or more polymers are selected from the group consisting of cellulosic polymers, neutral poly(meth)acrylate esters, polyvinylpyrrolidone, polyvinylpolypyrrolidone, and combinations thereof. 41. The process of claim 40, wherein the cellulosic polymer is hydroxypropylcellulose. 42. The process of claim 36, wherein the non-aqueous solvent in steps (1) and (2) comprises an alcohol. 43. The process of claim 42, wherein the non-aqueous solvent in steps (1) and (2) comprises ethanol. 44. The process of claim 36 further comprising:
(3) treating the mixture resulting from step (2) to increase its viscosity. 45. The process of claim 44, wherein step (3) comprises mixing the mixture resulting from step (2) for at least 60 minutes. 46. The process of claim 35, wherein the amount of hydroxypropylcellulose in the antibacterial coating composition is between 1.0 and 1.5% w/w. 47. The process of claim 35, wherein the amount of water in the antibacterial coating composition is between 1% and 20% w/w. 48. The process of claim 35, wherein the amount of water in the antibacterial coating composition is less than 15% w/w. 49. The process of claim 35, wherein the amount of antimicrobial agent in the antibacterial coating composition is at least 0.1% w/w. 50. The process of claim 35, wherein the amount of antimicrobial agent in the antibacterial coating composition is between 0.1% and 40% w/w. 51. An antibacterial coating composition produced by the method of claim 35. | 1,600 |
1,477 | 15,769,192 | 1,645 | The present invention pertains to a vaccine comprising inactivated Lawsonia intracellularis antigen for intradermal administration to an animal that has maternally derived antibodies directed against Lawsonia intracellularis , for use in a method to protect the animal against a disorder arising from an infection with Lawsonia intracellularis. | 1. (canceled) 2. (canceled) 3. (canceled) 4. (canceled) 5. (canceled) 6. A method for protecting an animal that has maternally derived antibodies against Lawsonia intracellularis, against a disorder arising from an infection with Lawsonia intracellularis, by intradermally administering a vaccine comprising inactivated Lawsonia intracellularis antigens to the animal. 7. The method of claim 1, wherein said method consists of administering a single vaccination after which protection is induced. 8. The method of claim 1, wherein said antigens comprise killed Lawsonia intracellularis bacteria. | The present invention pertains to a vaccine comprising inactivated Lawsonia intracellularis antigen for intradermal administration to an animal that has maternally derived antibodies directed against Lawsonia intracellularis , for use in a method to protect the animal against a disorder arising from an infection with Lawsonia intracellularis.1. (canceled) 2. (canceled) 3. (canceled) 4. (canceled) 5. (canceled) 6. A method for protecting an animal that has maternally derived antibodies against Lawsonia intracellularis, against a disorder arising from an infection with Lawsonia intracellularis, by intradermally administering a vaccine comprising inactivated Lawsonia intracellularis antigens to the animal. 7. The method of claim 1, wherein said method consists of administering a single vaccination after which protection is induced. 8. The method of claim 1, wherein said antigens comprise killed Lawsonia intracellularis bacteria. | 1,600 |
1,478 | 15,738,954 | 1,615 | The disclosure provides, among other things, compositions that bind to and inhibit the biological activity of soluble biomolecules, as well as pharmaceutical compositions thereof. The compositions may comprise a plurality of particles that specifically bind a target, such as a soluble biomolecule or a biomolecule on the surface of a pathogen, to inhibit the target (or pathogen) from interacting with other molecules or cells. Also provided herein are a number of applications (e.g., therapeutic applications) in which the compositions are useful. | 1. A particle having at least one surface and an agent immobilized on the surface, wherein:
the agent selectively binds to a target that is a first member of a specific binding pair; and binding of the target to the particle inhibits the interaction of the target with a second member of the specific binding pair. 2. A particle, comprising a surface and an agent immobilized on the surface, wherein:
the agent can selectively bind to a target; and binding of an agent to the target inhibits interactions between the target and a cell. 3. The particle of claim 1 or 2, wherein the particle is shaped and sized to circulate in the vasculature of a subject. 4. The particle of any one of the preceding claims, wherein the particle is larger than 1 μm. 5. The particle of any one of the preceding claims, wherein the longest dimension of the particle is no greater than about 5 μm. 6. The particle of any one of the preceding claims, wherein the smallest dimension of the particle is at least about 300 nm. 7. The particle of any one of the preceding claims, further comprising a plurality of coating molecules. 8. The particle of claim 7, wherein:
the particle comprises an interior surface and an exterior surface; the agent is immobilized on the interior surface and the exterior surface; the plurality of coating molecules are bound to the exterior surface; and the coating molecules inhibit interactions between the agent and molecules on a cell surface. 9. The particle of claim 7 or 8, wherein the plurality of coating molecules increases the clearance of the particle in vivo. 10. The particle of claim 9, wherein the plurality of coating molecules increase the clearance of the particle by phagocytosis, renal clearance, or hepatobiliary clearance. 11. The particle of claim 7 or 8, wherein the plurality of coating molecules decreases the clearance of the particle in vivo. 12. The particle of claim 7 or 8, wherein the plurality of coating molecules inhibits interactions between the agent and either cells or extracellular proteins. 13. The particle of any one of claims 7 to 12, wherein the plurality of coating molecules comprises a polymer. 14. The particle of any one of claims 7 to 13, wherein the plurality of coating molecules is biodegradable. 15. The particle of any one of the preceding claims, wherein the particle is dendritic. 16. The particle of any one of the preceding claims, wherein:
the particle is porous; the surface comprises outer surfaces and inner surfaces; and the inner surfaces consist of the inner walls of the pores of the particle. 17. The particle of claim 16, wherein the agent is immobilized on the inner surfaces. 18. The particle of claim 16 or 17, wherein a plurality of pores have a cross-sectional dimension of at least 50 nm. 19. The particle of any one of claims 16 to 18, wherein the particle has a porosity of about 40% to about 95%. 20. The particle of any one of claims 16 to 19, wherein the particle comprises metal, gold, alumina, glass, silica, silicon, starch, agarose, latex, plastic, polyacrylamide, methacrylate, a polymer, or a nucleic acid. 21. The particle of claim 20, wherein the particle comprises porous silicon. 22. The particle of any one of the preceding claims, wherein the particle is substantially cubic, pyramidal, conic, spherical, tetrahedral, hexahedral, octahedral, dodecahedral, or icosahedral. 23. The particle of any one of the preceding claims, wherein the particle comprises one or more outward-facing protrusions. 24. The particle of claim 23, wherein the particle comprises more than one outward-facing protrusion. 25. The particle of any one of the preceding claims, wherein the particle comprises:
one or more vertices; and one or more outward-facing protrusions pointing outward from at least one of its vertices. 26. The particle of any one of claims 23 to 25, wherein one or more protrusions are sized and oriented to inhibit: (i) the agent immobilized on the surface of the particle from binding or activating a cell surface receptor protein and/or (ii) when the target is bound to the agent, the interaction of the target and a second member of a specific binding pair of which the target is the first member. 27. The particle of any one of the preceding claims, wherein the particle comprises two intersecting ridges extending from the surface of the particle, and the ridges are sized and oriented to inhibit: (i) the agent immobilized on the surface of the particle from binding or activating a cell surface receptor protein and/or (ii) when the target is bound to the agent, the interaction of the target and a second member of a specific binding pair of which the target is the first member. 28. The particle of any one of the preceding claims, wherein the particle comprise a tube. 29. The particle of claim 28, wherein the agent is immobilized on the inner surface of the tube. 30. The particle of claim 28 or 29, wherein the tube comprises at least one open end. 31. The particle of any one of claims 28 to 30, wherein the tube is a cylindrical tube, triangular tube, square tube, pentagonal tube, hexagonal tube, heptagonal tube, octahedral tube, or an irregularly-shaped tube. 32. The particle of any one of claims 28 to 31, wherein the particle comprises more than one tube. 33. The particle of claim 32, wherein the particle comprises a lattice defined by a plurality of tubes. 34. The particle of any one of claims 28 to 33, wherein the tube comprises a protein, nucleic acid, or polymer. 35. The particle of any one of claims 1 to 22, wherein:
the particle comprises a core subparticle and a plurality of protecting subparticles; and
the agent is immobilized on the core subparticle. 36. The particle of claim 35, wherein the core subparticle is about 100 nm to about 2 μm in size. 37. The particle of claim 35 or claim 36, wherein the protecting subparticles are about 10 nm to about 1 μm in size. 38. The particle of any one of claims 35 to 37, wherein the particle comprises 4 to 106 protecting subparticles. 39. The particle of any one of claims 35 to 38, wherein the particle comprises more than one core subparticle. 40. The particle of any one of claims 1 to 14, wherein the particle is a 2-dimensional shape. 41. The particle of claim 40, wherein the shape is a circle, ring, cross, fishbone, ellipse, triangle, square, pentagon, hexagon, heptagon, octagon, or star. 42. The particle of any one of the preceding claims, wherein the agent is oriented on the particle such that it has a reduced ability to bind to a molecule on the surface of a cell. 43. The particle of claim 42, wherein the agent is oriented on the particle such that it has a reduced ability to bind to a target on the surface of a cell. 44. The particle of any one of the preceding claims, wherein the agent is oriented on the particle such that it is sterically inhibited from binding to a molecule on the surface of a cell. 45. The particle of claim 44, wherein the agent is oriented on the particle such that it is sterically inhibited from binding to a target on the surface of a cell. 46. The particle of any one of the preceding claims, wherein the surface is oriented such that the agent has a reduced ability to bind to a molecule on the surface of a cell. 47. The particle of any one of the preceding claims, wherein the agent has a reduced ability to activate a cell surface receptor protein, relative to the ability of a natural ligand of the cell surface receptor protein. 48. The particle of claim 47, wherein the agent does not activate the cell surface receptor protein. 49. The particle of any one of claims 1 to 48, wherein the particle comprises void space. 50. The particle of any one of claims 1 to 49, wherein the isoelectric point of the particle is about 5 to about 9. 51. The particle of any one of claims 1 to 50, wherein the target is a viral protein. 52. The particle of claim 51, wherein the viral protein is from arbovirus, adenovirus, alphavirus, arenaviruses, astrovirus, BK virus, bunyaviruses, calicivirus, cercopithecine herpes virus 1, Colorado tick fever virus, coronavirus, Coxsackie virus, Crimean-Congo hemorrhagic fever virus, cytomegalovirus, Dengue virus, ebola virus, echinovirus, echovirus, enterovirus, Epstein-Barr virus, flavivirus, foot-and-mouth disease virus, hantavirus, hepatitis A, hepatitis B, hepatitis C, herpes simplex virus I, herpes simplex virus II, human herpes virus, human immunodeficiency virus type I (HIV-I), human immunodeficiency virus type II (HIV-II),human papillomavirus, human T-cell leukemia virus type I, human T-cell leukemia virus type II, influenza, Japanese encephalitis, JC virus, Junin virus, lentivirus, Machupo virus, Marburg virus, measles virus, mumps virus, naples virus, norovirus, Norwalk virus, orbiviruses, orthomyxovirus, papillomavirus, papovavirus, parainfluenza virus, paramyxovirus, parvovirus, picornaviridae, poliovirus, polyomavirus, poxvirus, rabies virus, reovirus, respiratory syncytial virus, rhinovirus, rotavirus, rubella virus, sapovirus, smallpox, togaviruses, Toscana virus, varicella zoster virus, West Nile virus, or Yellow Fever virus. 53. The particle of claim 51 or 52, wherein the viral protein is a viral capsid protein or a viral envelope protein. 54. The particle of any one or claims 1 to 50, wherein the target is a bacterial protein or a component of a bacterial cell wall. 55. The particle of claim 54, wherein the bacterial protein or cell wall component is from Actinomyces israelii, Bacillus anthracis, Bacillus cereus, Bacteroides fragilis, Bartonella henselae, Bartonella Quintana, Bordetella pertussis, Borrelia burgdorferi, Borrelia garinii, Borrelia afzelii, Borrelia recurrentis, Brucella abortus, Brucella canis, Brucella melitensis, Brucella suis, Campylobacter jejuni, Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydophila psittaci, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, Corynebacterium diptheriae, Ehrlichia canis, Ehrlichia chaffeensis, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Francisella tularensis, Haemophilus influenzae, Haemophilus vaginalis, Helicobacter pylori, Klebsiella pneumoniae, Legionella pneumophila, Leptospira interrogans, Leptospira santarosai, Leptospira weilii, Leptospira noguchii, Listeria monocytogenes, Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium ulcerans, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pseudomonas aeruginosa, Nocardia asteroides, Rickettsia rickettsii, Salmonella typhi, Salmonella typhimurium, Shigella sonnei, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, Treponema pallidum, Ureaplasma urealyticum, Vibrio cholerae, Yersinia pestis, Yersinia enterocolitica, or Yersinia pseudotuberculosis. 56. The particle of any one of claims 1 to 50, wherein the target is a yeast or fungal protein or a component of a yeast or fungal cell wall. 57. The particle of claim 56, wherein the yeast or fungal protein or cell wall component is from Apophysomyces variabilis, Aspergillus clavatus, Aspergillus flavus, Aspergillus fumigatus, Basidiobolus ranarum, Candida albicans, Candida glabrata, Candida guilliermondii, Candida krusei, Candida lusitaniae, Candida parapsilosis, Candida tropicalis, Candida stellatoidea, Candida viswanathii, Conidiobolus coronatus, Conidiobolus incongruous, Cryptococcus albidus, Cryptococcus gattii, Cryptococcus laurentii, Cryptococcus neoformans, Encephalitozoon intestinalis, Enterocytozoon bieneusi, Exophiala jeanselmei, Fonsecaea compacta, Fonsecaea pedrosoi, Geotrichum candidum, Histoplasma capsulatum, Lichtheimia corymbifera, Mucor indicus, Paracoccidioides brasiliensis, Phialophora verrucosa, Pneumocystis carinii, Pneumocystis jirovecii, Pseudallescheria boydii, Rhinosporidium seeberi, Rhodotorula mucilaginosa, Stachybotrys chartarum, Syncephalastrum racemosum, or Rhizopus oryzae. 58. The particle of any one of claims 1 to 50, wherein the target is a protozoan protein. 59. The particle of claim 58, wherein the protozoan protein is from Cryptosporidium, Giardia intestinalis, Giardia lamblia, Leishmania aethiopica, Leishmania braziliensis, Leishmania donovani, Leishmania infantum, Leishmania major, Leishmania mexicana, Leishmania tropica, Plasmodium coatneyi, Plasmodium falciparum, Plasmodium garnhami, Plasmodium inui, Plasmodium odocoilei, Trichomonas gallinae, Trichomonas vaginalis, Tritrichomonas foetus, Trypanosoma brucei, Trypanosoma cruzi, Trypanosoma equiperdum, Trypanosoma evansi, Trypanosoma lewisi, Trypanosoma pestanai, Trypanosoma suis, or Trypanosoma vivax, 60. The particle of any one of claims 1 to 50, wherein the target is a toxin. 61. The particle of claim 60, wherein the toxin is a bacterial toxin, a plant toxin, or a zootoxin. 62. The particle of claim 60 or 61, wherein the toxin is melittin, brevetoxin, tetrodotoxin, chlorotoxin, tetanus toxin, bungarotoxin, Clostridium botulinum toxin, ricin, epsilon toxin of Clostridium perfringens, Staphylococcus enterotoxin B, or endotoxin. 63. The particle of any one of claims 1 to 50, wherein the target is a poison, venom, allergen, carcinogen, psychoactive drug, or an agent of a chemical weapon. 64. The particle of any one of claims 1 to 50, wherein the target is selected from TNFα, TNFβ, a soluble TNF receptor, soluble TNFR-1, soluble TNFR-2, lymphotoxin, lymphotoxin alpha, lymphotoxin beta, 4-1BB Ligand, CD30 Ligand, EDA-A1, LIGHT, TL1A, TWEAK, TRAIL, soluble TRAIL receptor, IL-1, soluble IL-1 receptor, IL-1A, soluble IL-1A receptor, IL-1B, soluble IL-1B receptor, IL-2, soluble IL-2 receptor, IL-5, soluble IL-5 receptor, IL-6, soluble IL-6 receptor, IL-8, IL-10, soluble IL-10 receptor, CXCL1, CXCL8, CXCL9, CXCL10, CX3CL1, FAS ligand, soluble death receptor-3, soluble death receptor-4, soluble death receptor-5, TNF-related weak inducer of apoptosis, MMP1, MMP2, MMP3, MMP9, MMP10, MMP12, CD28, a soluble member of the B7 family, soluble CD80/B7-1, soluble CD86/B7-2, soluble CTLA4, soluble PD-L1, soluble PD-1, soluble Tim3, Tim3L, galectin 3, galectin 9, soluble CEACAM1, soluble LAG3, TGF-β, TGF-β1, TGF-β2, TGF-β3, anti-mullerian hormone, artemin, glial cell-derived neurotrophic factor, a bone morphogenic protein (e.g., BMP2, BMP3, BMP3B, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BMP10, BMP 11, BMP 12, BMP13, BMP15), a growth differentiation factor (e.g., GDF1, GDF2, GDF3, GDF3A, GDF5, GDF6, GDF7, GDF8, GDF9, GDF10, GDF11, GDF15), inhibin alpha, inhibin beta (e.g., inhibin beta A, B, C, E), lefty, nodal, neurturin, persephin, myostatin, ghrelin, sLR11, CCL2, CCL5, CCL11, CCL12, CCL19, interferon alpha, interferon beta, interferon gamma, clusterin, VEGF-A, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), prostaglandin E2, hepatocyte growth factor, nerve growth factor, sclerostin, complement C5, angiopoietin 2, angiopoietin 3, PCSK9, amyloid beta, activin, activin A, activin B, β2 microglobulin, soluble NOTCH1, soluble NOTCH2, soluble NOTCH3, soluble NOTCH4, haptoglobin, fibrinogen alpha chain, corticotropin releasing factor, corticotropin releasing factor type 1, corticotropin releasing factor type 2, urocortin 1, urocortin 2, urocortin 3, CD47, an anti-interferon γ autoantibody, an anti-interleukin 6 autoantibody, an anti-interleukin 17 autoantibody, an anti-ghrelin autoantibody, wnt, indoleamine 2,3-dioxygenase, C-reactive protein, and HIV-1 gp120. 65. The particle of any one of claims 1 to 50 and 64, wherein the agent comprises an antibody, or an antigen-binding portion thereof, which specifically binds to TNFα, TNFβ, a soluble TNF receptor, soluble TNFR-1, soluble TNFR-2, lymphotoxin, lymphotoxin alpha, lymphotoxin beta, 4-1BB Ligand, CD30 Ligand, EDA-A1, LIGHT, TL1A, TWEAK, TRAIL, soluble TRAIL receptor, IL-1, soluble IL-1 receptor, IL-1A, soluble IL-1A receptor, IL-1B, soluble IL-1B receptor, IL-2, soluble IL-2 receptor, IL-5, soluble IL-5 receptor, IL-6, soluble IL-6 receptor, IL-8, IL-10, soluble IL-10 receptor, CXCL1, CXCL8, CXCL9, CXCL10, CX3CL1, FAS ligand, soluble death receptor-3, soluble death receptor-4, soluble death receptor-5, TNF-related weak inducer of apoptosis, MMP1, MMP2, MMP3, MMP9, MMP10, MMP12, CD28, a soluble member of the B7 family, soluble CD80/B7-1, soluble CD86/B7-2, soluble CTLA4, soluble PD-L1, soluble PD-1, soluble Tim3, Tim3L, galectin 3, galectin 9, soluble CEACAM1, soluble LAG3, TGF-β, TGF-β1, TGF-β2, TGF-β3, anti-mullerian hormone, artemin, glial cell-derived neurotrophic factor, a bone morphogenic protein (e.g., BMP2, BMP3, BMP3B, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BMP10, BMP 11, BMP 12, BMP13, BMP15), a growth differentiation factor (e.g., GDF1, GDF2, GDF3, GDF3A, GDF5, GDF6, GDF7, GDF8, GDF9, GDF10, GDF11, GDF15), inhibin alpha, inhibin beta (e.g., inhibin beta A, B, C, E), lefty, nodal, neurturin, persephin, myostatin, ghrelin, sLR11, CCL2, CCL5, CCL11, CCL12, CCL19, interferon alpha, interferon beta, interferon gamma, clusterin, VEGF-A, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), prostaglandin E2, hepatocyte growth factor, nerve growth factor, sclerostin, complement C5, angiopoietin 2, angiopoietin 3, PCSK9, amyloid beta, activin, activin A, activin B, β2 microglobulin, soluble NOTCH1, soluble NOTCH2, soluble NOTCH3, soluble NOTCH4, haptoglobin, fibrinogen alpha chain, corticotropin releasing factor, corticotropin releasing factor type 1, corticotropin releasing factor type 2, urocortin 1, urocortin 2, urocortin 3, CD47, an anti-interferon γ autoantibody, an anti-interleukin 6 autoantibody, an anti-interleukin 17 autoantibody, an anti-ghrelin autoantibody, wnt, indoleamine 2,3-dioxygenase, C-reactive protein, or HIV-1 gp120. 66. The particle of any one of claims 1 to 50 and 64, wherein the agent comprises TNFα, TNFβ, a soluble TNF receptor, soluble TNFR-1, soluble TNFR-2, vTNF, lymphotoxin, lymphotoxin alpha, lymphotoxin beta, 4-1BB Ligand, CD30 Ligand, EDA-A1, LIGHT, TL1A, TWEAK, TRAIL, soluble TRAIL receptor, IL-1, soluble IL-1 receptor, IL-1A, soluble IL-1A receptor, IL-1B, soluble IL-1B receptor, IL-2, soluble IL-2 receptor, IL-5, soluble IL-5 receptor, IL-6, soluble IL-6 receptor, IL-8, IL-10, soluble IL-10 receptor, CXCL1, CXCL8, CXCL9, CXCL10, CX3CL1, FAS ligand, soluble death receptor-3, soluble death receptor-4, soluble death receptor-5, TNF-related weak inducer of apoptosis, MMP1, MMP2, MMP3, MMP9, MMP10, MMP12, CD28, a soluble member of the B7 family, soluble CD80/B7-1, soluble CD86/B7-2, soluble CTLA4, soluble PD-L1, soluble PD-1, soluble Tim3, Tim3L, galectin 3, galectin 9, soluble CEACAM1, soluble LAG3, TGF-β, TGF-β1, TGF-β2, TGF-β3, sLR11, CCL2, CCL5, CCL11, CCL12, CCL19, activin, activin A, activin B, soluble NOTCH1, soluble NOTCH2, soluble NOTCH3, soluble NOTCH4, soluble Jagged1, soluble Jagged2, soluble DLL1, soluble DLL3, soluble DLL4, or haptoglobin. 67. The particle of any one of claims 1 to 50, 64, and 65, wherein the agent comprises ipilimumab, pembrolizumab, nivolumab, infliximab, adalimumab, certolizumab, golimumab, etanercept, stamulumab, fresolimumab, metelimumab, demcizumab, tarextumab, brontictuzumab, mepolizumab, urelumab, canakinumab, daclizumab, belimumab, denosumab, eculizumab, tocilizumab, atlizumab, ustekinumab, palivizumab, bevacizumab, brolucizumab, ranibizumab, aflibercept, actoxumab, elsilimomab, siltuximab, afelimomab, nerelimomab, ozoralizumab, pateclizumab, sirukumab, omalizumab, aducanumab, bapineuzumab, crenezumab, gantenerumab, ponezumab, solanezumab, dapirolizumab, ruplizumab, toralizumab, enoticumab, alacizumab, cetuximab, futuximab, icrucumab, imgatuzumab, matuzumab, necitumumab, nimotuzumab, panitumumab, ramucirumab, zalutumumab, duligotumab, patritumab, ertumaxomab, pertuzumab, trastuzumab, alirocumab, anrukinzumab, diridavumab, drozitumab, dupilumab, dusigitumab, eculizumab, edobacomab, efungumab, eldelumab, enoblituzumab, enokizumab, evinacumab, evolocumab, exbivirumab, exbivirumab, fasinumab, felvizumab, fezakinumab, ficlatuzumab, firivumab, fletikumab, foralumab, foravirumab, fulranumab, faliximab, ganitumab, gevokizumab, fuselkumab, idarucizumab, imalumab, inolimomab, iratumumab, ixekizumab, lampalizumab, lebrikizumab, lenzilumab, lerdelimumab, lexatumumab, libivirumab, ligelizumab, lodelcizumab, lulizumab, mapatumumab, motavizumab, namilumab, nebacumab, nesvacumab, obiltoxaximab, olokizumab, orticumab, pagibaximab, palivizumab, panobacumab, pascolizumab, perakizumab, pidilizumab, pexelizumab, pritoxaximab, quilizumab, radretumab, rafivirumab, ralpancizumab, raxibacumab, regavirumab, reslizumab, rilotumumab, romosozumab, rontalizumab, sarilumab, secukinumab, setoxaximab, sevirumab, sifalimumab, siltuximab, suvizumab, tabalumab, tacatuzumab, talizumab, tanezumab, tefibazumab, TGN1412, tildrakizumab, tigatuzumab, TNX-650, tosatoxumab, tralokinumab, tremelimumab, trevogrumab, tuvirumab, urtoxazumab, vantictumab, vanucizumab, or an antigen-binding portion of any one of the foregoing. 68. The particle of any one of the preceding claims, wherein the target is a soluble biomolecule. 69. The particle of any one of the preceding claims, wherein the target is:
a target as described anywhere herein, supra; a biomolecule as described anywhere herein, supra; a soluble biomolecule as described anywhere herein, supra; or an antigen of an antibody as described anywhere herein, supra. 70. The particle of any one of the preceding claims, wherein:
the agent is an agent as described anywhere herein, supra; the agent comprises an antibody, wherein the antibody is described anywhere herein, supra; the agent comprises an antigen-binding portion of an antibody, wherein the antibody is described anywhere herein, supra; or the agent comprises an antibody, or an antigen-binding portion thereof, that specifically binds to a target, biomolecule, or soluble biomolecule, wherein the target, biomolecule, or soluble biomolecule is described anywhere herein, supra. 71. The particle of any one of the preceding claims, wherein the longest dimension of the particle is no greater than about 1 μm. 72. The particle of any one of the preceding claims, wherein:
the target is a soluble biomolecule; the soluble biomolecule is a form of a cell surface receptor protein; and the agent is oriented on the particle such that it is sterically inhibited from binding or activating the cell surface receptor protein on the surface of a cell. 73. A particle having at least one surface and an agent immobilized on the surface, wherein:
the agent selectively binds to a soluble biomolecule; the soluble biomolecule is a form of a cell surface receptor protein; and the agent is oriented on the particle such that the agent is sterically inhibited from binding or activating the cell surface receptor protein on the surface of a cell. 74. The particle of any one of the preceding claims, wherein the agent is a ligand of a cell surface receptor protein. 75. The particle of claim 74, wherein the agent is a natural ligand of the cell surface receptor protein. 76. The particle of any one of claims 72 to 75, wherein the cell surface receptor protein is expressed by a cancer cell. 77. The particle of any one of claims 72 to 76, wherein the cell surface receptor protein is a protein shed by a cancer cell as a soluble form of the cell surface receptor protein. 78. The particle of any one of claims 72 to 77, wherein the cell surface receptor protein, when activated on a cell surface, induces apoptosis. 79. The particle of any one of claims 72 to 78, wherein the cell surface receptor protein is a tumor necrosis factor receptor (TNFR) protein. 80. The particle of any one of claims 72 to 78, wherein the cell surface receptor protein is a Fas receptor protein. 81. The particle of any one of claims 72 to 78, wherein the cell surface receptor protein is a TNF-related apoptosis-inducing ligand receptor (TRAILR) protein, 4-1BB receptor protein, CD30 protein, EDA receptor protein, HVEM protein, lymphotoxin beta receptor protein, DR3 protein, or TWEAK receptor protein. 82. The particle of any one of claims 72 to 81, wherein the agent comprises a tumor necrosis factor (TNF) family ligand or a variant thereof. 83. The particle of claim 82, wherein the TNF family ligand is TNFα. 84. The particle of claim 82, wherein the TNF family ligand is selected from Fas ligand, lymphotoxin, lymphotoxin alpha, lymphotoxin beta, 4-1BB Ligand, CD30 Ligand, EDA-A1, LIGHT, TL1A, TWEAK, TNFβ, and TRAIL. 85. The particle of any one of claims 72 to 78, wherein the cell surface receptor protein is an interleukin receptor protein. 86. The particle of claim 85, wherein the interleukin receptor protein is an IL-2 receptor protein. 87. The particle of claim 85 or 86, wherein the agent is an interleukin protein or variant thereof. 88. The particle of claim 87, wherein the interleukin protein is an IL-2 protein. 89. A plurality of particles according to any one of the preceding claims. 90. The plurality of particles of claim 89, wherein the mean particle size is greater than 1 μm. 91. The plurality of particles of claim 89, wherein the mean particle size is 1 μm to 5 μm. 92. A method for treating a subject afflicted with a cancer, comprising administering to the subject the plurality of particles of any one of claims 89 to 91, wherein:
the cancer comprises cells that shed a soluble form of at least one cell surface receptor protein; and
the plurality of particles inhibits the biological activity of the shed soluble form of the at least one cell surface receptor protein, thereby treating the cancer. 93. The method of claim 92, wherein the cancer cells shed a soluble form of TNF receptor. 94. The method of claim 93, wherein each particle of the plurality comprises an agent comprising a TNFα polypeptide or a variant thereof. 95. The method of claim 92, wherein the cancer cells shed a soluble form of IL-2 receptor. 96. The method of claim 95, wherein each particle of the plurality comprises an agent comprising a IL-2 polypeptide or a variant thereof. 97. The method of any one of claims 92 to 96, wherein the subject has received adoptive cell transfer therapy (ACT). 98. The method of any one of claims 92 to 97, further comprising administering adoptive cell transfer therapy to the subject. 99. The method of claim 97 or 98, wherein the adoptive cell transfer therapy is the administration of a composition comprising lymphocytes to the subject. 100. The method of claim 99, wherein the lymphocytes are tumor-infiltrating lymphocytes (TILs). 101. The method of claim 99 or 100, wherein the lymphocytes comprise a chimeric antigen receptor (CAR). 102. A method for treating a subject afflicted with an autoimmune disease, comprising administering to the subject a plurality of particles of any one of claims 89 to 91. 103. The method of claim 102, wherein the target is interleukin 1A, interleukin 1B, interleukin 2, interleukin 5, interleukin 6, interleukin 8, tumor necrosis factor alpha, fas ligand, TNF-related apoptosis inducing ligand, CXCL8, CXCL1, CD80/B7-1, CD86/B7-2, or PD-L1. 104. A method for treating a subject afflicted with a neurodegenerative disease, comprising administering to the subject a plurality of particles of any one of claims 89 to 91. 105. The method of claim 104, wherein the target is amyloid (3. 106. A method of promoting healthy aging in a subject, comprising administering to the subject a plurality of particles of any one of claims 89 to 91. 107. The method of claim 106, wherein the target is TGF-β1, CCL11, MCP-1/CCL2, beta-2 microglobulin, GDF-8/myostatin, or haptoglobin. 108. A method for treating a metabolic disorder in a subject, comprising administering to the subject a plurality of particles of any one of claims 89 to 91. 109. The method of claim 108, wherein the target is ghrelin, an anti-ghrelin autoantibody, or cortisol. 110. A method for increasing muscle mass in a subject, comprising administering to the subject a plurality of particles of any one of claims 89 to 91. 111. The method of claim 110, wherein the target is myostatin or TGF-β1. 112. The method of any one of claims 92 to 111, wherein the subject is a mammal. 113. The method of claim 112, wherein the subject is a human. | The disclosure provides, among other things, compositions that bind to and inhibit the biological activity of soluble biomolecules, as well as pharmaceutical compositions thereof. The compositions may comprise a plurality of particles that specifically bind a target, such as a soluble biomolecule or a biomolecule on the surface of a pathogen, to inhibit the target (or pathogen) from interacting with other molecules or cells. Also provided herein are a number of applications (e.g., therapeutic applications) in which the compositions are useful.1. A particle having at least one surface and an agent immobilized on the surface, wherein:
the agent selectively binds to a target that is a first member of a specific binding pair; and binding of the target to the particle inhibits the interaction of the target with a second member of the specific binding pair. 2. A particle, comprising a surface and an agent immobilized on the surface, wherein:
the agent can selectively bind to a target; and binding of an agent to the target inhibits interactions between the target and a cell. 3. The particle of claim 1 or 2, wherein the particle is shaped and sized to circulate in the vasculature of a subject. 4. The particle of any one of the preceding claims, wherein the particle is larger than 1 μm. 5. The particle of any one of the preceding claims, wherein the longest dimension of the particle is no greater than about 5 μm. 6. The particle of any one of the preceding claims, wherein the smallest dimension of the particle is at least about 300 nm. 7. The particle of any one of the preceding claims, further comprising a plurality of coating molecules. 8. The particle of claim 7, wherein:
the particle comprises an interior surface and an exterior surface; the agent is immobilized on the interior surface and the exterior surface; the plurality of coating molecules are bound to the exterior surface; and the coating molecules inhibit interactions between the agent and molecules on a cell surface. 9. The particle of claim 7 or 8, wherein the plurality of coating molecules increases the clearance of the particle in vivo. 10. The particle of claim 9, wherein the plurality of coating molecules increase the clearance of the particle by phagocytosis, renal clearance, or hepatobiliary clearance. 11. The particle of claim 7 or 8, wherein the plurality of coating molecules decreases the clearance of the particle in vivo. 12. The particle of claim 7 or 8, wherein the plurality of coating molecules inhibits interactions between the agent and either cells or extracellular proteins. 13. The particle of any one of claims 7 to 12, wherein the plurality of coating molecules comprises a polymer. 14. The particle of any one of claims 7 to 13, wherein the plurality of coating molecules is biodegradable. 15. The particle of any one of the preceding claims, wherein the particle is dendritic. 16. The particle of any one of the preceding claims, wherein:
the particle is porous; the surface comprises outer surfaces and inner surfaces; and the inner surfaces consist of the inner walls of the pores of the particle. 17. The particle of claim 16, wherein the agent is immobilized on the inner surfaces. 18. The particle of claim 16 or 17, wherein a plurality of pores have a cross-sectional dimension of at least 50 nm. 19. The particle of any one of claims 16 to 18, wherein the particle has a porosity of about 40% to about 95%. 20. The particle of any one of claims 16 to 19, wherein the particle comprises metal, gold, alumina, glass, silica, silicon, starch, agarose, latex, plastic, polyacrylamide, methacrylate, a polymer, or a nucleic acid. 21. The particle of claim 20, wherein the particle comprises porous silicon. 22. The particle of any one of the preceding claims, wherein the particle is substantially cubic, pyramidal, conic, spherical, tetrahedral, hexahedral, octahedral, dodecahedral, or icosahedral. 23. The particle of any one of the preceding claims, wherein the particle comprises one or more outward-facing protrusions. 24. The particle of claim 23, wherein the particle comprises more than one outward-facing protrusion. 25. The particle of any one of the preceding claims, wherein the particle comprises:
one or more vertices; and one or more outward-facing protrusions pointing outward from at least one of its vertices. 26. The particle of any one of claims 23 to 25, wherein one or more protrusions are sized and oriented to inhibit: (i) the agent immobilized on the surface of the particle from binding or activating a cell surface receptor protein and/or (ii) when the target is bound to the agent, the interaction of the target and a second member of a specific binding pair of which the target is the first member. 27. The particle of any one of the preceding claims, wherein the particle comprises two intersecting ridges extending from the surface of the particle, and the ridges are sized and oriented to inhibit: (i) the agent immobilized on the surface of the particle from binding or activating a cell surface receptor protein and/or (ii) when the target is bound to the agent, the interaction of the target and a second member of a specific binding pair of which the target is the first member. 28. The particle of any one of the preceding claims, wherein the particle comprise a tube. 29. The particle of claim 28, wherein the agent is immobilized on the inner surface of the tube. 30. The particle of claim 28 or 29, wherein the tube comprises at least one open end. 31. The particle of any one of claims 28 to 30, wherein the tube is a cylindrical tube, triangular tube, square tube, pentagonal tube, hexagonal tube, heptagonal tube, octahedral tube, or an irregularly-shaped tube. 32. The particle of any one of claims 28 to 31, wherein the particle comprises more than one tube. 33. The particle of claim 32, wherein the particle comprises a lattice defined by a plurality of tubes. 34. The particle of any one of claims 28 to 33, wherein the tube comprises a protein, nucleic acid, or polymer. 35. The particle of any one of claims 1 to 22, wherein:
the particle comprises a core subparticle and a plurality of protecting subparticles; and
the agent is immobilized on the core subparticle. 36. The particle of claim 35, wherein the core subparticle is about 100 nm to about 2 μm in size. 37. The particle of claim 35 or claim 36, wherein the protecting subparticles are about 10 nm to about 1 μm in size. 38. The particle of any one of claims 35 to 37, wherein the particle comprises 4 to 106 protecting subparticles. 39. The particle of any one of claims 35 to 38, wherein the particle comprises more than one core subparticle. 40. The particle of any one of claims 1 to 14, wherein the particle is a 2-dimensional shape. 41. The particle of claim 40, wherein the shape is a circle, ring, cross, fishbone, ellipse, triangle, square, pentagon, hexagon, heptagon, octagon, or star. 42. The particle of any one of the preceding claims, wherein the agent is oriented on the particle such that it has a reduced ability to bind to a molecule on the surface of a cell. 43. The particle of claim 42, wherein the agent is oriented on the particle such that it has a reduced ability to bind to a target on the surface of a cell. 44. The particle of any one of the preceding claims, wherein the agent is oriented on the particle such that it is sterically inhibited from binding to a molecule on the surface of a cell. 45. The particle of claim 44, wherein the agent is oriented on the particle such that it is sterically inhibited from binding to a target on the surface of a cell. 46. The particle of any one of the preceding claims, wherein the surface is oriented such that the agent has a reduced ability to bind to a molecule on the surface of a cell. 47. The particle of any one of the preceding claims, wherein the agent has a reduced ability to activate a cell surface receptor protein, relative to the ability of a natural ligand of the cell surface receptor protein. 48. The particle of claim 47, wherein the agent does not activate the cell surface receptor protein. 49. The particle of any one of claims 1 to 48, wherein the particle comprises void space. 50. The particle of any one of claims 1 to 49, wherein the isoelectric point of the particle is about 5 to about 9. 51. The particle of any one of claims 1 to 50, wherein the target is a viral protein. 52. The particle of claim 51, wherein the viral protein is from arbovirus, adenovirus, alphavirus, arenaviruses, astrovirus, BK virus, bunyaviruses, calicivirus, cercopithecine herpes virus 1, Colorado tick fever virus, coronavirus, Coxsackie virus, Crimean-Congo hemorrhagic fever virus, cytomegalovirus, Dengue virus, ebola virus, echinovirus, echovirus, enterovirus, Epstein-Barr virus, flavivirus, foot-and-mouth disease virus, hantavirus, hepatitis A, hepatitis B, hepatitis C, herpes simplex virus I, herpes simplex virus II, human herpes virus, human immunodeficiency virus type I (HIV-I), human immunodeficiency virus type II (HIV-II),human papillomavirus, human T-cell leukemia virus type I, human T-cell leukemia virus type II, influenza, Japanese encephalitis, JC virus, Junin virus, lentivirus, Machupo virus, Marburg virus, measles virus, mumps virus, naples virus, norovirus, Norwalk virus, orbiviruses, orthomyxovirus, papillomavirus, papovavirus, parainfluenza virus, paramyxovirus, parvovirus, picornaviridae, poliovirus, polyomavirus, poxvirus, rabies virus, reovirus, respiratory syncytial virus, rhinovirus, rotavirus, rubella virus, sapovirus, smallpox, togaviruses, Toscana virus, varicella zoster virus, West Nile virus, or Yellow Fever virus. 53. The particle of claim 51 or 52, wherein the viral protein is a viral capsid protein or a viral envelope protein. 54. The particle of any one or claims 1 to 50, wherein the target is a bacterial protein or a component of a bacterial cell wall. 55. The particle of claim 54, wherein the bacterial protein or cell wall component is from Actinomyces israelii, Bacillus anthracis, Bacillus cereus, Bacteroides fragilis, Bartonella henselae, Bartonella Quintana, Bordetella pertussis, Borrelia burgdorferi, Borrelia garinii, Borrelia afzelii, Borrelia recurrentis, Brucella abortus, Brucella canis, Brucella melitensis, Brucella suis, Campylobacter jejuni, Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydophila psittaci, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, Corynebacterium diptheriae, Ehrlichia canis, Ehrlichia chaffeensis, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Francisella tularensis, Haemophilus influenzae, Haemophilus vaginalis, Helicobacter pylori, Klebsiella pneumoniae, Legionella pneumophila, Leptospira interrogans, Leptospira santarosai, Leptospira weilii, Leptospira noguchii, Listeria monocytogenes, Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium ulcerans, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pseudomonas aeruginosa, Nocardia asteroides, Rickettsia rickettsii, Salmonella typhi, Salmonella typhimurium, Shigella sonnei, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, Treponema pallidum, Ureaplasma urealyticum, Vibrio cholerae, Yersinia pestis, Yersinia enterocolitica, or Yersinia pseudotuberculosis. 56. The particle of any one of claims 1 to 50, wherein the target is a yeast or fungal protein or a component of a yeast or fungal cell wall. 57. The particle of claim 56, wherein the yeast or fungal protein or cell wall component is from Apophysomyces variabilis, Aspergillus clavatus, Aspergillus flavus, Aspergillus fumigatus, Basidiobolus ranarum, Candida albicans, Candida glabrata, Candida guilliermondii, Candida krusei, Candida lusitaniae, Candida parapsilosis, Candida tropicalis, Candida stellatoidea, Candida viswanathii, Conidiobolus coronatus, Conidiobolus incongruous, Cryptococcus albidus, Cryptococcus gattii, Cryptococcus laurentii, Cryptococcus neoformans, Encephalitozoon intestinalis, Enterocytozoon bieneusi, Exophiala jeanselmei, Fonsecaea compacta, Fonsecaea pedrosoi, Geotrichum candidum, Histoplasma capsulatum, Lichtheimia corymbifera, Mucor indicus, Paracoccidioides brasiliensis, Phialophora verrucosa, Pneumocystis carinii, Pneumocystis jirovecii, Pseudallescheria boydii, Rhinosporidium seeberi, Rhodotorula mucilaginosa, Stachybotrys chartarum, Syncephalastrum racemosum, or Rhizopus oryzae. 58. The particle of any one of claims 1 to 50, wherein the target is a protozoan protein. 59. The particle of claim 58, wherein the protozoan protein is from Cryptosporidium, Giardia intestinalis, Giardia lamblia, Leishmania aethiopica, Leishmania braziliensis, Leishmania donovani, Leishmania infantum, Leishmania major, Leishmania mexicana, Leishmania tropica, Plasmodium coatneyi, Plasmodium falciparum, Plasmodium garnhami, Plasmodium inui, Plasmodium odocoilei, Trichomonas gallinae, Trichomonas vaginalis, Tritrichomonas foetus, Trypanosoma brucei, Trypanosoma cruzi, Trypanosoma equiperdum, Trypanosoma evansi, Trypanosoma lewisi, Trypanosoma pestanai, Trypanosoma suis, or Trypanosoma vivax, 60. The particle of any one of claims 1 to 50, wherein the target is a toxin. 61. The particle of claim 60, wherein the toxin is a bacterial toxin, a plant toxin, or a zootoxin. 62. The particle of claim 60 or 61, wherein the toxin is melittin, brevetoxin, tetrodotoxin, chlorotoxin, tetanus toxin, bungarotoxin, Clostridium botulinum toxin, ricin, epsilon toxin of Clostridium perfringens, Staphylococcus enterotoxin B, or endotoxin. 63. The particle of any one of claims 1 to 50, wherein the target is a poison, venom, allergen, carcinogen, psychoactive drug, or an agent of a chemical weapon. 64. The particle of any one of claims 1 to 50, wherein the target is selected from TNFα, TNFβ, a soluble TNF receptor, soluble TNFR-1, soluble TNFR-2, lymphotoxin, lymphotoxin alpha, lymphotoxin beta, 4-1BB Ligand, CD30 Ligand, EDA-A1, LIGHT, TL1A, TWEAK, TRAIL, soluble TRAIL receptor, IL-1, soluble IL-1 receptor, IL-1A, soluble IL-1A receptor, IL-1B, soluble IL-1B receptor, IL-2, soluble IL-2 receptor, IL-5, soluble IL-5 receptor, IL-6, soluble IL-6 receptor, IL-8, IL-10, soluble IL-10 receptor, CXCL1, CXCL8, CXCL9, CXCL10, CX3CL1, FAS ligand, soluble death receptor-3, soluble death receptor-4, soluble death receptor-5, TNF-related weak inducer of apoptosis, MMP1, MMP2, MMP3, MMP9, MMP10, MMP12, CD28, a soluble member of the B7 family, soluble CD80/B7-1, soluble CD86/B7-2, soluble CTLA4, soluble PD-L1, soluble PD-1, soluble Tim3, Tim3L, galectin 3, galectin 9, soluble CEACAM1, soluble LAG3, TGF-β, TGF-β1, TGF-β2, TGF-β3, anti-mullerian hormone, artemin, glial cell-derived neurotrophic factor, a bone morphogenic protein (e.g., BMP2, BMP3, BMP3B, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BMP10, BMP 11, BMP 12, BMP13, BMP15), a growth differentiation factor (e.g., GDF1, GDF2, GDF3, GDF3A, GDF5, GDF6, GDF7, GDF8, GDF9, GDF10, GDF11, GDF15), inhibin alpha, inhibin beta (e.g., inhibin beta A, B, C, E), lefty, nodal, neurturin, persephin, myostatin, ghrelin, sLR11, CCL2, CCL5, CCL11, CCL12, CCL19, interferon alpha, interferon beta, interferon gamma, clusterin, VEGF-A, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), prostaglandin E2, hepatocyte growth factor, nerve growth factor, sclerostin, complement C5, angiopoietin 2, angiopoietin 3, PCSK9, amyloid beta, activin, activin A, activin B, β2 microglobulin, soluble NOTCH1, soluble NOTCH2, soluble NOTCH3, soluble NOTCH4, haptoglobin, fibrinogen alpha chain, corticotropin releasing factor, corticotropin releasing factor type 1, corticotropin releasing factor type 2, urocortin 1, urocortin 2, urocortin 3, CD47, an anti-interferon γ autoantibody, an anti-interleukin 6 autoantibody, an anti-interleukin 17 autoantibody, an anti-ghrelin autoantibody, wnt, indoleamine 2,3-dioxygenase, C-reactive protein, and HIV-1 gp120. 65. The particle of any one of claims 1 to 50 and 64, wherein the agent comprises an antibody, or an antigen-binding portion thereof, which specifically binds to TNFα, TNFβ, a soluble TNF receptor, soluble TNFR-1, soluble TNFR-2, lymphotoxin, lymphotoxin alpha, lymphotoxin beta, 4-1BB Ligand, CD30 Ligand, EDA-A1, LIGHT, TL1A, TWEAK, TRAIL, soluble TRAIL receptor, IL-1, soluble IL-1 receptor, IL-1A, soluble IL-1A receptor, IL-1B, soluble IL-1B receptor, IL-2, soluble IL-2 receptor, IL-5, soluble IL-5 receptor, IL-6, soluble IL-6 receptor, IL-8, IL-10, soluble IL-10 receptor, CXCL1, CXCL8, CXCL9, CXCL10, CX3CL1, FAS ligand, soluble death receptor-3, soluble death receptor-4, soluble death receptor-5, TNF-related weak inducer of apoptosis, MMP1, MMP2, MMP3, MMP9, MMP10, MMP12, CD28, a soluble member of the B7 family, soluble CD80/B7-1, soluble CD86/B7-2, soluble CTLA4, soluble PD-L1, soluble PD-1, soluble Tim3, Tim3L, galectin 3, galectin 9, soluble CEACAM1, soluble LAG3, TGF-β, TGF-β1, TGF-β2, TGF-β3, anti-mullerian hormone, artemin, glial cell-derived neurotrophic factor, a bone morphogenic protein (e.g., BMP2, BMP3, BMP3B, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BMP10, BMP 11, BMP 12, BMP13, BMP15), a growth differentiation factor (e.g., GDF1, GDF2, GDF3, GDF3A, GDF5, GDF6, GDF7, GDF8, GDF9, GDF10, GDF11, GDF15), inhibin alpha, inhibin beta (e.g., inhibin beta A, B, C, E), lefty, nodal, neurturin, persephin, myostatin, ghrelin, sLR11, CCL2, CCL5, CCL11, CCL12, CCL19, interferon alpha, interferon beta, interferon gamma, clusterin, VEGF-A, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), prostaglandin E2, hepatocyte growth factor, nerve growth factor, sclerostin, complement C5, angiopoietin 2, angiopoietin 3, PCSK9, amyloid beta, activin, activin A, activin B, β2 microglobulin, soluble NOTCH1, soluble NOTCH2, soluble NOTCH3, soluble NOTCH4, haptoglobin, fibrinogen alpha chain, corticotropin releasing factor, corticotropin releasing factor type 1, corticotropin releasing factor type 2, urocortin 1, urocortin 2, urocortin 3, CD47, an anti-interferon γ autoantibody, an anti-interleukin 6 autoantibody, an anti-interleukin 17 autoantibody, an anti-ghrelin autoantibody, wnt, indoleamine 2,3-dioxygenase, C-reactive protein, or HIV-1 gp120. 66. The particle of any one of claims 1 to 50 and 64, wherein the agent comprises TNFα, TNFβ, a soluble TNF receptor, soluble TNFR-1, soluble TNFR-2, vTNF, lymphotoxin, lymphotoxin alpha, lymphotoxin beta, 4-1BB Ligand, CD30 Ligand, EDA-A1, LIGHT, TL1A, TWEAK, TRAIL, soluble TRAIL receptor, IL-1, soluble IL-1 receptor, IL-1A, soluble IL-1A receptor, IL-1B, soluble IL-1B receptor, IL-2, soluble IL-2 receptor, IL-5, soluble IL-5 receptor, IL-6, soluble IL-6 receptor, IL-8, IL-10, soluble IL-10 receptor, CXCL1, CXCL8, CXCL9, CXCL10, CX3CL1, FAS ligand, soluble death receptor-3, soluble death receptor-4, soluble death receptor-5, TNF-related weak inducer of apoptosis, MMP1, MMP2, MMP3, MMP9, MMP10, MMP12, CD28, a soluble member of the B7 family, soluble CD80/B7-1, soluble CD86/B7-2, soluble CTLA4, soluble PD-L1, soluble PD-1, soluble Tim3, Tim3L, galectin 3, galectin 9, soluble CEACAM1, soluble LAG3, TGF-β, TGF-β1, TGF-β2, TGF-β3, sLR11, CCL2, CCL5, CCL11, CCL12, CCL19, activin, activin A, activin B, soluble NOTCH1, soluble NOTCH2, soluble NOTCH3, soluble NOTCH4, soluble Jagged1, soluble Jagged2, soluble DLL1, soluble DLL3, soluble DLL4, or haptoglobin. 67. The particle of any one of claims 1 to 50, 64, and 65, wherein the agent comprises ipilimumab, pembrolizumab, nivolumab, infliximab, adalimumab, certolizumab, golimumab, etanercept, stamulumab, fresolimumab, metelimumab, demcizumab, tarextumab, brontictuzumab, mepolizumab, urelumab, canakinumab, daclizumab, belimumab, denosumab, eculizumab, tocilizumab, atlizumab, ustekinumab, palivizumab, bevacizumab, brolucizumab, ranibizumab, aflibercept, actoxumab, elsilimomab, siltuximab, afelimomab, nerelimomab, ozoralizumab, pateclizumab, sirukumab, omalizumab, aducanumab, bapineuzumab, crenezumab, gantenerumab, ponezumab, solanezumab, dapirolizumab, ruplizumab, toralizumab, enoticumab, alacizumab, cetuximab, futuximab, icrucumab, imgatuzumab, matuzumab, necitumumab, nimotuzumab, panitumumab, ramucirumab, zalutumumab, duligotumab, patritumab, ertumaxomab, pertuzumab, trastuzumab, alirocumab, anrukinzumab, diridavumab, drozitumab, dupilumab, dusigitumab, eculizumab, edobacomab, efungumab, eldelumab, enoblituzumab, enokizumab, evinacumab, evolocumab, exbivirumab, exbivirumab, fasinumab, felvizumab, fezakinumab, ficlatuzumab, firivumab, fletikumab, foralumab, foravirumab, fulranumab, faliximab, ganitumab, gevokizumab, fuselkumab, idarucizumab, imalumab, inolimomab, iratumumab, ixekizumab, lampalizumab, lebrikizumab, lenzilumab, lerdelimumab, lexatumumab, libivirumab, ligelizumab, lodelcizumab, lulizumab, mapatumumab, motavizumab, namilumab, nebacumab, nesvacumab, obiltoxaximab, olokizumab, orticumab, pagibaximab, palivizumab, panobacumab, pascolizumab, perakizumab, pidilizumab, pexelizumab, pritoxaximab, quilizumab, radretumab, rafivirumab, ralpancizumab, raxibacumab, regavirumab, reslizumab, rilotumumab, romosozumab, rontalizumab, sarilumab, secukinumab, setoxaximab, sevirumab, sifalimumab, siltuximab, suvizumab, tabalumab, tacatuzumab, talizumab, tanezumab, tefibazumab, TGN1412, tildrakizumab, tigatuzumab, TNX-650, tosatoxumab, tralokinumab, tremelimumab, trevogrumab, tuvirumab, urtoxazumab, vantictumab, vanucizumab, or an antigen-binding portion of any one of the foregoing. 68. The particle of any one of the preceding claims, wherein the target is a soluble biomolecule. 69. The particle of any one of the preceding claims, wherein the target is:
a target as described anywhere herein, supra; a biomolecule as described anywhere herein, supra; a soluble biomolecule as described anywhere herein, supra; or an antigen of an antibody as described anywhere herein, supra. 70. The particle of any one of the preceding claims, wherein:
the agent is an agent as described anywhere herein, supra; the agent comprises an antibody, wherein the antibody is described anywhere herein, supra; the agent comprises an antigen-binding portion of an antibody, wherein the antibody is described anywhere herein, supra; or the agent comprises an antibody, or an antigen-binding portion thereof, that specifically binds to a target, biomolecule, or soluble biomolecule, wherein the target, biomolecule, or soluble biomolecule is described anywhere herein, supra. 71. The particle of any one of the preceding claims, wherein the longest dimension of the particle is no greater than about 1 μm. 72. The particle of any one of the preceding claims, wherein:
the target is a soluble biomolecule; the soluble biomolecule is a form of a cell surface receptor protein; and the agent is oriented on the particle such that it is sterically inhibited from binding or activating the cell surface receptor protein on the surface of a cell. 73. A particle having at least one surface and an agent immobilized on the surface, wherein:
the agent selectively binds to a soluble biomolecule; the soluble biomolecule is a form of a cell surface receptor protein; and the agent is oriented on the particle such that the agent is sterically inhibited from binding or activating the cell surface receptor protein on the surface of a cell. 74. The particle of any one of the preceding claims, wherein the agent is a ligand of a cell surface receptor protein. 75. The particle of claim 74, wherein the agent is a natural ligand of the cell surface receptor protein. 76. The particle of any one of claims 72 to 75, wherein the cell surface receptor protein is expressed by a cancer cell. 77. The particle of any one of claims 72 to 76, wherein the cell surface receptor protein is a protein shed by a cancer cell as a soluble form of the cell surface receptor protein. 78. The particle of any one of claims 72 to 77, wherein the cell surface receptor protein, when activated on a cell surface, induces apoptosis. 79. The particle of any one of claims 72 to 78, wherein the cell surface receptor protein is a tumor necrosis factor receptor (TNFR) protein. 80. The particle of any one of claims 72 to 78, wherein the cell surface receptor protein is a Fas receptor protein. 81. The particle of any one of claims 72 to 78, wherein the cell surface receptor protein is a TNF-related apoptosis-inducing ligand receptor (TRAILR) protein, 4-1BB receptor protein, CD30 protein, EDA receptor protein, HVEM protein, lymphotoxin beta receptor protein, DR3 protein, or TWEAK receptor protein. 82. The particle of any one of claims 72 to 81, wherein the agent comprises a tumor necrosis factor (TNF) family ligand or a variant thereof. 83. The particle of claim 82, wherein the TNF family ligand is TNFα. 84. The particle of claim 82, wherein the TNF family ligand is selected from Fas ligand, lymphotoxin, lymphotoxin alpha, lymphotoxin beta, 4-1BB Ligand, CD30 Ligand, EDA-A1, LIGHT, TL1A, TWEAK, TNFβ, and TRAIL. 85. The particle of any one of claims 72 to 78, wherein the cell surface receptor protein is an interleukin receptor protein. 86. The particle of claim 85, wherein the interleukin receptor protein is an IL-2 receptor protein. 87. The particle of claim 85 or 86, wherein the agent is an interleukin protein or variant thereof. 88. The particle of claim 87, wherein the interleukin protein is an IL-2 protein. 89. A plurality of particles according to any one of the preceding claims. 90. The plurality of particles of claim 89, wherein the mean particle size is greater than 1 μm. 91. The plurality of particles of claim 89, wherein the mean particle size is 1 μm to 5 μm. 92. A method for treating a subject afflicted with a cancer, comprising administering to the subject the plurality of particles of any one of claims 89 to 91, wherein:
the cancer comprises cells that shed a soluble form of at least one cell surface receptor protein; and
the plurality of particles inhibits the biological activity of the shed soluble form of the at least one cell surface receptor protein, thereby treating the cancer. 93. The method of claim 92, wherein the cancer cells shed a soluble form of TNF receptor. 94. The method of claim 93, wherein each particle of the plurality comprises an agent comprising a TNFα polypeptide or a variant thereof. 95. The method of claim 92, wherein the cancer cells shed a soluble form of IL-2 receptor. 96. The method of claim 95, wherein each particle of the plurality comprises an agent comprising a IL-2 polypeptide or a variant thereof. 97. The method of any one of claims 92 to 96, wherein the subject has received adoptive cell transfer therapy (ACT). 98. The method of any one of claims 92 to 97, further comprising administering adoptive cell transfer therapy to the subject. 99. The method of claim 97 or 98, wherein the adoptive cell transfer therapy is the administration of a composition comprising lymphocytes to the subject. 100. The method of claim 99, wherein the lymphocytes are tumor-infiltrating lymphocytes (TILs). 101. The method of claim 99 or 100, wherein the lymphocytes comprise a chimeric antigen receptor (CAR). 102. A method for treating a subject afflicted with an autoimmune disease, comprising administering to the subject a plurality of particles of any one of claims 89 to 91. 103. The method of claim 102, wherein the target is interleukin 1A, interleukin 1B, interleukin 2, interleukin 5, interleukin 6, interleukin 8, tumor necrosis factor alpha, fas ligand, TNF-related apoptosis inducing ligand, CXCL8, CXCL1, CD80/B7-1, CD86/B7-2, or PD-L1. 104. A method for treating a subject afflicted with a neurodegenerative disease, comprising administering to the subject a plurality of particles of any one of claims 89 to 91. 105. The method of claim 104, wherein the target is amyloid (3. 106. A method of promoting healthy aging in a subject, comprising administering to the subject a plurality of particles of any one of claims 89 to 91. 107. The method of claim 106, wherein the target is TGF-β1, CCL11, MCP-1/CCL2, beta-2 microglobulin, GDF-8/myostatin, or haptoglobin. 108. A method for treating a metabolic disorder in a subject, comprising administering to the subject a plurality of particles of any one of claims 89 to 91. 109. The method of claim 108, wherein the target is ghrelin, an anti-ghrelin autoantibody, or cortisol. 110. A method for increasing muscle mass in a subject, comprising administering to the subject a plurality of particles of any one of claims 89 to 91. 111. The method of claim 110, wherein the target is myostatin or TGF-β1. 112. The method of any one of claims 92 to 111, wherein the subject is a mammal. 113. The method of claim 112, wherein the subject is a human. | 1,600 |
1,479 | 13,981,229 | 1,619 | The present invention provides a medical device containing a cake composition comprising aripiprazole as an active ingredient and capable of suppressing agglomeration of aripiprazole in a suspension obtained by resuspending a freeze-dried substance; and a cake composition comprising aripiprazole as an active ingredient. The present invention relates to a medical device containing, in a storage container whose inner wall is treated with silicone, a freeze-dried cake composition comprising separately prepared aripiprazole as an active ingredient, wherein there is a space between the inner wall and the cake composition; and a cake composition comprising aripiprazole as an active ingredient and having a strength of 5 to 100 N. | 1. A medical device containing a separately prepared freeze-dried cake composition comprising aripiprazole as an active ingredient in a storage container whose inner wall is treated with silicone, wherein there is a space between the inner wall of the storage container and the cake composition. 2. The medical device containing the cake composition according to claim 1, wherein the cake composition is a cake composition that was freeze-dried in a container separate from the storage container. 3. The medical device containing the cake composition according to claim 1 or 2, wherein the apparent volume of the cake composition accounts for 30 to 99% of the volume of the storage container. 4. The medical device containing the cake composition according to any one of claims 1 to 3, wherein the cake composition has a cylindrical shape. 5. The medical device containing the cake composition according to claim 4, wherein a top surface of the cylindrical cake composition is raised. 6. The medical device containing the cake composition according to claim 4 or 5, wherein a side surface of the cylindrical cake composition is sloped. 7. The medical device containing the cake composition according to any one of claims 1 to 6, wherein the storage container treated with silicone is a vial or syringe. 8. The medical device containing the cake composition according to claim 7, wherein the syringe has multiple chambers and the cake composition is contained in at least one chamber. 9. The medical device containing the cake composition according to claim 7, wherein the syringe has a chamber (A) for containing the cake composition, and a chamber (B) for containing an injection liquid;
the chamber (A) is arranged on the side where a needle is placed, and the chamber (B) is arranged on the side where a plunger is placed; and the cake composition is contained in the chamber (A) and the injection liquid is contained in the chamber (B). 10. The medical device containing the cake composition according to any one of claims 1 to 9, wherein the cake composition has a strength of 5 to 100 N. 11. A cake composition comprising aripiprazole as an active ingredient and having a strength of 5 to 100 N. 12. The cake composition according to claim 11, wherein the percentage of aripiprazole in the cake composition is 60 to 95% by mass. 13. The cake composition according to claim 11 or 12, wherein the amount of aripiprazole in the cake composition is 0.1 to 0.6 g. 14. The cake composition according to any one of claims 11 to 13, obtained by freeze-drying 0.25 to 12 g of a suspension having an aripiprazole solids content of 5 to 45% by mass. 15. The cake composition according to any one of claims 11 to 14, wherein the cake composition has a cylindrical shape. 16. The cake composition according to claim 15, wherein a top surface of the cylindrical cake composition is raised. 17. The cake composition according to claim 15 or 16, wherein a side surface of the cylindrical cake composition is sloped. 18. The cake composition according to any one of claims 11 to 17, wherein the cake composition is used for being placed in a medical device. 19. The cake composition according to claim 18, wherein the cake composition is a mass that was freeze-dried in a container separate from a storage container in the medical device. 20. A method for producing a medical device containing a cake composition comprising aripiprazole as an active ingredient, the method comprising
a step of enclosing a separately prepared freeze-dried cake composition comprising aripiprazole as an active ingredient in a storage container whose inner wall is treated with silicone. 21. The method for producing the medical device according to claim 20, wherein the storage container treated with silicone is a vial or syringe. 22. The method for producing the medical device according to claim 21, wherein the syringe has multiple chambers and the cake composition is contained in at least one chamber. 23. The method for producing the medical device according to claim 22, wherein the syringe has a chamber (A) for containing the cake composition, and a chamber (B) for containing an injection liquid;
the chamber (A) is arranged on the side where a needle is placed, and the chamber (B) is arranged on the side where a plunger is placed; and the cake composition is contained in the chamber (A) and the injection liquid is contained in the chamber (B). 24. A method for producing a cake composition comprising aripiprazole as an active ingredient and having a strength of 5 to 100 N, the method comprising
a step of freeze-drying a suspension comprising aripiprazole as an active ingredient. | The present invention provides a medical device containing a cake composition comprising aripiprazole as an active ingredient and capable of suppressing agglomeration of aripiprazole in a suspension obtained by resuspending a freeze-dried substance; and a cake composition comprising aripiprazole as an active ingredient. The present invention relates to a medical device containing, in a storage container whose inner wall is treated with silicone, a freeze-dried cake composition comprising separately prepared aripiprazole as an active ingredient, wherein there is a space between the inner wall and the cake composition; and a cake composition comprising aripiprazole as an active ingredient and having a strength of 5 to 100 N.1. A medical device containing a separately prepared freeze-dried cake composition comprising aripiprazole as an active ingredient in a storage container whose inner wall is treated with silicone, wherein there is a space between the inner wall of the storage container and the cake composition. 2. The medical device containing the cake composition according to claim 1, wherein the cake composition is a cake composition that was freeze-dried in a container separate from the storage container. 3. The medical device containing the cake composition according to claim 1 or 2, wherein the apparent volume of the cake composition accounts for 30 to 99% of the volume of the storage container. 4. The medical device containing the cake composition according to any one of claims 1 to 3, wherein the cake composition has a cylindrical shape. 5. The medical device containing the cake composition according to claim 4, wherein a top surface of the cylindrical cake composition is raised. 6. The medical device containing the cake composition according to claim 4 or 5, wherein a side surface of the cylindrical cake composition is sloped. 7. The medical device containing the cake composition according to any one of claims 1 to 6, wherein the storage container treated with silicone is a vial or syringe. 8. The medical device containing the cake composition according to claim 7, wherein the syringe has multiple chambers and the cake composition is contained in at least one chamber. 9. The medical device containing the cake composition according to claim 7, wherein the syringe has a chamber (A) for containing the cake composition, and a chamber (B) for containing an injection liquid;
the chamber (A) is arranged on the side where a needle is placed, and the chamber (B) is arranged on the side where a plunger is placed; and the cake composition is contained in the chamber (A) and the injection liquid is contained in the chamber (B). 10. The medical device containing the cake composition according to any one of claims 1 to 9, wherein the cake composition has a strength of 5 to 100 N. 11. A cake composition comprising aripiprazole as an active ingredient and having a strength of 5 to 100 N. 12. The cake composition according to claim 11, wherein the percentage of aripiprazole in the cake composition is 60 to 95% by mass. 13. The cake composition according to claim 11 or 12, wherein the amount of aripiprazole in the cake composition is 0.1 to 0.6 g. 14. The cake composition according to any one of claims 11 to 13, obtained by freeze-drying 0.25 to 12 g of a suspension having an aripiprazole solids content of 5 to 45% by mass. 15. The cake composition according to any one of claims 11 to 14, wherein the cake composition has a cylindrical shape. 16. The cake composition according to claim 15, wherein a top surface of the cylindrical cake composition is raised. 17. The cake composition according to claim 15 or 16, wherein a side surface of the cylindrical cake composition is sloped. 18. The cake composition according to any one of claims 11 to 17, wherein the cake composition is used for being placed in a medical device. 19. The cake composition according to claim 18, wherein the cake composition is a mass that was freeze-dried in a container separate from a storage container in the medical device. 20. A method for producing a medical device containing a cake composition comprising aripiprazole as an active ingredient, the method comprising
a step of enclosing a separately prepared freeze-dried cake composition comprising aripiprazole as an active ingredient in a storage container whose inner wall is treated with silicone. 21. The method for producing the medical device according to claim 20, wherein the storage container treated with silicone is a vial or syringe. 22. The method for producing the medical device according to claim 21, wherein the syringe has multiple chambers and the cake composition is contained in at least one chamber. 23. The method for producing the medical device according to claim 22, wherein the syringe has a chamber (A) for containing the cake composition, and a chamber (B) for containing an injection liquid;
the chamber (A) is arranged on the side where a needle is placed, and the chamber (B) is arranged on the side where a plunger is placed; and the cake composition is contained in the chamber (A) and the injection liquid is contained in the chamber (B). 24. A method for producing a cake composition comprising aripiprazole as an active ingredient and having a strength of 5 to 100 N, the method comprising
a step of freeze-drying a suspension comprising aripiprazole as an active ingredient. | 1,600 |
1,480 | 16,289,775 | 1,612 | The present invention relates to a liposomal formulation containing a therapeutic agent and a process for producing the formulation. The liposomal formulation comprises particular characteristics that enhance uniformity and stability of the formulation. The manufacturing process is a novel process that produces a liposomal formulation of a uniform size with many desirable properties that may be independently controlled. Further, the invention relates to a liposome formulation made in accordance with the manufacturing process. | 1. A liposome having a lipid ingredient and encapsulating a therapeutic agent, wherein a mass ratio of said therapeutic agent to lipid ingredient is about 1:5 to 1:8, and wherein the liposome has osmolality internal to the liposome in a range of 340-440 mO/kg. 2. A formulation comprising a liposome, said liposome having a lipid ingredient and a therapeutic agent, a mass ratio of the therapeutic agent to lipid ingredient being about 1:5 to 1:8, and wherein the liposome has osmolality internal to the liposome in a range of 340-440 mO/kg. 3. The liposome of claim 1 or 2, wherein the lipid ingredient comprises DSPC, DSPG and cholesterol in a molar ratio of about 3:1:2. 4. The liposome of claim 1 or 2, wherein the therapeutic agent comprises one of a cytotoxic and cytostatic agent, the therapeutic agent selected from the group consisting essentially of: gallium, gold, silica, 5-fluorouracil, cisplatin, alkylating agents, mithramycin and paclitaxel. 5. The liposome of claim 1 or 2, wherein the therapeutic agent at least one of decreases activity and amount of phagocytic cells. 6. The liposome of claim 1 or 2, wherein said liposome has compressibility less than 0.70 ml/g. 7. The liposome of claim 1 or 2, wherein the liposome has osmolality external to the liposome in a range of 270-340 mO/kg, and wherein the liposome has conductivity internal to the liposome in a range of 13.5-17.5 ms/cm. 8. The liposome of claim 1 or 2, wherein the therapeutic agent is a bisphosphonate. 9. The liposome of claim 8, wherein the bisphosphonate has a bisphosphonate concentration range of 0.1 to 5 mg/ml within the liposome. 10. The liposome of claim 8, wherein the bisphosphonate comprises a compound having formula (I):
wherein R1 is H, OH or halogen group; and
R2 is halogen; linear or branched C1-C10 alkyl or C2-C10 alkenyl, optionally substituted by heteroaryl or heterocyclyl C1-C10 alkylamino or C3-C8 cycloalkylamino; —NHY where Y is hydrogen, C3-C8 cycloalkyl, aryl or heteroaryl; or —SZ, where Z is chlorosubstituted phenyl or pyridinyl. 11. The liposome of claim 8, wherein the bisphosphonate is selected from the group consisting of: clodronate, etidronate, tiludronate, alendronate and risendronate. 12. The liposome of claim 1 or 2, wherein the liposome has an internal liposomal pH in a range of 6.8-7.0. 13. The liposome of claim 1 or 2, wherein the liposome has an average size of about 80±5 nm. 14. The liposome of claim 1 or 2, wherein the liposome is stable when stored at one of: 25° C. for at least 7 months, and stable when stored at 2-8° C. for at least 36 months. 15. The liposome of claim 1 or 2, wherein the liposome has a dynamic viscosity of about 1.0 mPas at 20° C. 16. The formulation of claim 2, wherein the formulation comprises less than 4% unencapsulated therapeutic agent. 17. The formulation of claim 2, wherein the formulation has a Poly Dispersity Index less than 0.075. 18. The formulation of claim 17, wherein the Poly Dispersity Index is between 0.02 and 0.05. | The present invention relates to a liposomal formulation containing a therapeutic agent and a process for producing the formulation. The liposomal formulation comprises particular characteristics that enhance uniformity and stability of the formulation. The manufacturing process is a novel process that produces a liposomal formulation of a uniform size with many desirable properties that may be independently controlled. Further, the invention relates to a liposome formulation made in accordance with the manufacturing process.1. A liposome having a lipid ingredient and encapsulating a therapeutic agent, wherein a mass ratio of said therapeutic agent to lipid ingredient is about 1:5 to 1:8, and wherein the liposome has osmolality internal to the liposome in a range of 340-440 mO/kg. 2. A formulation comprising a liposome, said liposome having a lipid ingredient and a therapeutic agent, a mass ratio of the therapeutic agent to lipid ingredient being about 1:5 to 1:8, and wherein the liposome has osmolality internal to the liposome in a range of 340-440 mO/kg. 3. The liposome of claim 1 or 2, wherein the lipid ingredient comprises DSPC, DSPG and cholesterol in a molar ratio of about 3:1:2. 4. The liposome of claim 1 or 2, wherein the therapeutic agent comprises one of a cytotoxic and cytostatic agent, the therapeutic agent selected from the group consisting essentially of: gallium, gold, silica, 5-fluorouracil, cisplatin, alkylating agents, mithramycin and paclitaxel. 5. The liposome of claim 1 or 2, wherein the therapeutic agent at least one of decreases activity and amount of phagocytic cells. 6. The liposome of claim 1 or 2, wherein said liposome has compressibility less than 0.70 ml/g. 7. The liposome of claim 1 or 2, wherein the liposome has osmolality external to the liposome in a range of 270-340 mO/kg, and wherein the liposome has conductivity internal to the liposome in a range of 13.5-17.5 ms/cm. 8. The liposome of claim 1 or 2, wherein the therapeutic agent is a bisphosphonate. 9. The liposome of claim 8, wherein the bisphosphonate has a bisphosphonate concentration range of 0.1 to 5 mg/ml within the liposome. 10. The liposome of claim 8, wherein the bisphosphonate comprises a compound having formula (I):
wherein R1 is H, OH or halogen group; and
R2 is halogen; linear or branched C1-C10 alkyl or C2-C10 alkenyl, optionally substituted by heteroaryl or heterocyclyl C1-C10 alkylamino or C3-C8 cycloalkylamino; —NHY where Y is hydrogen, C3-C8 cycloalkyl, aryl or heteroaryl; or —SZ, where Z is chlorosubstituted phenyl or pyridinyl. 11. The liposome of claim 8, wherein the bisphosphonate is selected from the group consisting of: clodronate, etidronate, tiludronate, alendronate and risendronate. 12. The liposome of claim 1 or 2, wherein the liposome has an internal liposomal pH in a range of 6.8-7.0. 13. The liposome of claim 1 or 2, wherein the liposome has an average size of about 80±5 nm. 14. The liposome of claim 1 or 2, wherein the liposome is stable when stored at one of: 25° C. for at least 7 months, and stable when stored at 2-8° C. for at least 36 months. 15. The liposome of claim 1 or 2, wherein the liposome has a dynamic viscosity of about 1.0 mPas at 20° C. 16. The formulation of claim 2, wherein the formulation comprises less than 4% unencapsulated therapeutic agent. 17. The formulation of claim 2, wherein the formulation has a Poly Dispersity Index less than 0.075. 18. The formulation of claim 17, wherein the Poly Dispersity Index is between 0.02 and 0.05. | 1,600 |
1,481 | 15,646,601 | 1,619 | Provided herein relates to methods and compositions for preparing a silk microsphere and the resulting silk microsphere. In some embodiments, the methods and compositions described herein are all aqueous, which can be used for encapsulating an active agent in a silk microsphere, while maintaining activity of the active agent during processing. In some embodiments, the resulting silk microsphere can be used for sustained delivery of an active agent encapsulated therein. | 1.-75. (canceled) 76. A method of preparing a silk microsphere, the method comprising:
atomizing a silk solution to form silk microspheres with a diameter of at least 50 μm; freezing the silk microspheres, and lyophilizing the silk microspheres to form porous silk microspheres, wherein the porous silk microspheres have a porosity of at least 30%. 77. The method of claim 76, wherein atomizing comprises spraying, exposure to coaxial air flow, exposure to mechanical disturbance, and/or exposure to electrostatic force. 78. The method of claim 76, wherein freezing is selected from the group consisting of exposure to sub-zero temperatures and contacting with a cooling agent. 79. The method of claim 76, wherein the silk microsphere is exposed to the sub-zero temperature by collecting the silk microsphere in a container cooled by a cooling agent. 80. The method of claim 76, wherein the silk microsphere is not subject to any post treatment step. 81. The method of claim 80, wherein the silk microsphere has a water solubility of less than 30%. 82. The method of claim 81, wherein the silk microsphere is substantially insoluble. 83. The method of claim 76, wherein the silk microsphere has a beta sheet crystalline content of at least 20%. 84. The method of claim 76, wherein the silk microsphere is not exposed to any non-aqueous solutions. 85. The method of claim 76, further comprising subjecting the porous silk microspheres to a post-treatment. 86. The method of claim 85, wherein the post-treatment is selected from the group consisting of water annealing, water vapor annealing, solvent immersion, heat annealing, and any combination thereof. 87. The method of claim 76, wherein the porous silk microspheres have a porosity of at least 50%. 88. The method of claim 76, wherein the porous silk microspheres have a porosity of at least 80%. | Provided herein relates to methods and compositions for preparing a silk microsphere and the resulting silk microsphere. In some embodiments, the methods and compositions described herein are all aqueous, which can be used for encapsulating an active agent in a silk microsphere, while maintaining activity of the active agent during processing. In some embodiments, the resulting silk microsphere can be used for sustained delivery of an active agent encapsulated therein.1.-75. (canceled) 76. A method of preparing a silk microsphere, the method comprising:
atomizing a silk solution to form silk microspheres with a diameter of at least 50 μm; freezing the silk microspheres, and lyophilizing the silk microspheres to form porous silk microspheres, wherein the porous silk microspheres have a porosity of at least 30%. 77. The method of claim 76, wherein atomizing comprises spraying, exposure to coaxial air flow, exposure to mechanical disturbance, and/or exposure to electrostatic force. 78. The method of claim 76, wherein freezing is selected from the group consisting of exposure to sub-zero temperatures and contacting with a cooling agent. 79. The method of claim 76, wherein the silk microsphere is exposed to the sub-zero temperature by collecting the silk microsphere in a container cooled by a cooling agent. 80. The method of claim 76, wherein the silk microsphere is not subject to any post treatment step. 81. The method of claim 80, wherein the silk microsphere has a water solubility of less than 30%. 82. The method of claim 81, wherein the silk microsphere is substantially insoluble. 83. The method of claim 76, wherein the silk microsphere has a beta sheet crystalline content of at least 20%. 84. The method of claim 76, wherein the silk microsphere is not exposed to any non-aqueous solutions. 85. The method of claim 76, further comprising subjecting the porous silk microspheres to a post-treatment. 86. The method of claim 85, wherein the post-treatment is selected from the group consisting of water annealing, water vapor annealing, solvent immersion, heat annealing, and any combination thereof. 87. The method of claim 76, wherein the porous silk microspheres have a porosity of at least 50%. 88. The method of claim 76, wherein the porous silk microspheres have a porosity of at least 80%. | 1,600 |
1,482 | 15,832,190 | 1,619 | The present disclosure provides dry shampoo compositions effective for cleaning hair and also moisturizing hair. The dry shampoo compositions can comprise a starch component, a conditioning agent, and optional further ingredients, such as propellants and fragrances. | 1. A dry shampoo composition, comprising:
a starch material; a hydrophobic emollient; and optionally a propellant. 2. The dry shampoo composition of claim 1, wherein the dry shampoo is substantially free of silicones. 3. The dry shampoo composition of claim 1, wherein the dry shampoo is substantially free of petroleum based cationic surfactants. 4. The dry shampoo composition of claim 1, wherein the dry shampoo is substantially free of distearyldimonium chloride. 5. The dry shampoo composition of claim 1, wherein the hydrophobic emollient comprises a long chain alkane. 6. The dry shampoo composition of claim 1, wherein the hydrophobic emollient comprises a C13-C15 alkane. 7. The dry shampoo composition of claim 1, wherein the hydrophobic emollient comprises hemisqualane. 8. The dry shampoo composition of claim 1, wherein the starch material comprises a rice starch. 9. The dry shampoo composition of claim 1, comprising:
at least 0.1 weight percent of the starch material, based on the total weight of the dry shampoo composition; at least 0.1 weight percent of the hydrophobic emollient, based on the total weight of the dry shampoo composition; and at least 50 weight percent of the propellant, based on the total weight of the dry shampoo composition. 10. The dry shampoo composition of claim 1, comprising:
about 1 to about 12 weight percent of the starch material, based on the total weight of the dry shampoo composition; about 1 to about 12 weight percent of the hydrophobic emollient, based on the total weight of the dry shampoo composition; and about 40 to about 95 weight percent of the propellant, based on the total weight of the dry shampoo composition. 11. The dry shampoo composition of claim 1, further comprising a fragrance. 12. A method of cleansing and conditioning hair, the method comprising applying a dry shampoo composition according to claim 1 to the hair. 13. The method of claim 12, comprising spraying the dry shampoo composition on the hair and combing the dry shampoo composition through the hair. 14. The method of claim 12, wherein conditioning of the hair is improved such that the mean force required to comb through a tress of the hair after application of the dry shampoo composition is reduced by at least 20% relative to the mean force required to comb through the tress of the hair immediately prior to application of the dry shampoo composition. | The present disclosure provides dry shampoo compositions effective for cleaning hair and also moisturizing hair. The dry shampoo compositions can comprise a starch component, a conditioning agent, and optional further ingredients, such as propellants and fragrances.1. A dry shampoo composition, comprising:
a starch material; a hydrophobic emollient; and optionally a propellant. 2. The dry shampoo composition of claim 1, wherein the dry shampoo is substantially free of silicones. 3. The dry shampoo composition of claim 1, wherein the dry shampoo is substantially free of petroleum based cationic surfactants. 4. The dry shampoo composition of claim 1, wherein the dry shampoo is substantially free of distearyldimonium chloride. 5. The dry shampoo composition of claim 1, wherein the hydrophobic emollient comprises a long chain alkane. 6. The dry shampoo composition of claim 1, wherein the hydrophobic emollient comprises a C13-C15 alkane. 7. The dry shampoo composition of claim 1, wherein the hydrophobic emollient comprises hemisqualane. 8. The dry shampoo composition of claim 1, wherein the starch material comprises a rice starch. 9. The dry shampoo composition of claim 1, comprising:
at least 0.1 weight percent of the starch material, based on the total weight of the dry shampoo composition; at least 0.1 weight percent of the hydrophobic emollient, based on the total weight of the dry shampoo composition; and at least 50 weight percent of the propellant, based on the total weight of the dry shampoo composition. 10. The dry shampoo composition of claim 1, comprising:
about 1 to about 12 weight percent of the starch material, based on the total weight of the dry shampoo composition; about 1 to about 12 weight percent of the hydrophobic emollient, based on the total weight of the dry shampoo composition; and about 40 to about 95 weight percent of the propellant, based on the total weight of the dry shampoo composition. 11. The dry shampoo composition of claim 1, further comprising a fragrance. 12. A method of cleansing and conditioning hair, the method comprising applying a dry shampoo composition according to claim 1 to the hair. 13. The method of claim 12, comprising spraying the dry shampoo composition on the hair and combing the dry shampoo composition through the hair. 14. The method of claim 12, wherein conditioning of the hair is improved such that the mean force required to comb through a tress of the hair after application of the dry shampoo composition is reduced by at least 20% relative to the mean force required to comb through the tress of the hair immediately prior to application of the dry shampoo composition. | 1,600 |
1,483 | 15,773,044 | 1,635 | Mycotoxin-deactivating aptamers, especially DNA aptamers, bind to mycotoxins in feed and feed ingredients resulting in the reduction or elimination of toxic and carcinogenic effects of mycotoxins. The invention also discloses a composition comprising a mycotoxin-deactivating aptamer, a binding agent, a biotransforming agent and an antioxidant for detoxifying mycotoxins in feeds. In addition, the invention teaches the methods of preparing said mycotoxin-deactivating aptamer-based composition and also the methods of using it as a feed additive. Furthermore, the invention relates to the use of said mycotoxin-deactivator/s alone, or in a composition comprising said aptamers and other mycotoxin-detoxifying agents, in feeds and feed ingredients for detoxifying the major mycotoxins such as aflatoxins, deoxynivalenol, zearalenone, fumonisins and ochratoxin A. | 1. A use of a composition comprising a mycotoxin-deactivating aptamer for inhibiting the toxicity of mycotoxin and preventing absorption of active mycotoxin in a gastrointestinal tract. 2. The use as claimed in claim 1, said composition further comprising one or more of: a mycotoxin-specific antibody, a mycotoxin-adsorbing agent, a mycotoxin-biotransforming agent, a mycotoxin-degrading enzyme and a mycotoxin toxicity-reducing antioxidant. 3. The use as claimed in claim 1, said composition further comprising animal feed. 4. The use according to claim 1, wherein the aptamers are either individual mycotoxin-specific single stranded DNA (ssDNA) or single stranded RNA (ssRNA) molecules. 5. The use according to claim 1, wherein the composition is capable of detoxifying a wide spectrum of mycotoxins, including those selected from the group consisting of aflatoxins (AFB1, AFB2, AFG1, AFG2), deoxynivalenol, nivalenol, T-2 toxin, zearalenone, fumonisins (FB1, FB2, FB3), ochratoxin A, citrinin and ergotamine. 6. The use according to claim 1, wherein the mycotoxin-deactivating aptamer is AFB1-specific aptamer. 7. The use according to claim 3, wherein the mycotoxin-deactivating aptamer is at a concentration ranging from about 0.01% to about 2% by weight of the animal's daily feed ration. 8. (canceled) 9. The use according to claim 3, wherein the aptamer is at a concentration ranging from about 0.1% to about 0.3% by weight of the animal's daily feed ration. 10. The use according to claim 3, wherein the ingredients of feed are selected from the group consisting of corn (maize), wheat, barley, rye, rice, sorghum, soybean, peanut, millet, brewers spent grain, distiller's spent grain, distiller's wet grain, and distiller's dried grain, forage and silage. 11. The use of claim 2, wherein the mycotoxin-adsorbing agents is selected from the group consisting of sodium bentonite, calcium bentonite, sodium-calcium montmorillonite, clinoptilolite, calcium/potassium/sodium hydrated aluminosilicate, hydrated sodium calcium aluminosilicate (HSCAS), activated carbon, dry yeast (Saccharomyces cerevisiae) cells, polymeric glucomannan, esterified glucomannan and beta-glucan fractions of dry yeast cell wall, cholestyramine, polyvinylpolypyrrolidone, activated diatomaceous earth, plant fibres, kaolinite, and hydrated sodium-potassium-calcium aluminosilicate. 12. The use of claim 2, wherein the biotransforming agent is selected from the group consisting of Eubacterium sp. BBSH 797, Nocardia asteroids, Mycobacterium fluoranthenivorans sp., Rhodococcus erythropolis, Alcaligenes species., Bacillus species., Achromobacter species., Flavobacterium species, Pseudomonas species, Lactobacillus rhamnosus strain GG, Lactobacillus helveticus 46 & 72, Lactobacillus casei, Lactobacillus lactis, Streptococcus thermophilus C5 and NG40Z, Lactobacillus paraplantarum, Stenotrophomonas maltophila, Saccharomyces cerevisiae, Cupriavidus basilensis OR16 Aspergillus niger, Eurotium herbariorum, Rhizopus species., Trichosporon mycotoxinivorans, Phaffia rhodozyma, and Xanthophyllomyces dendrorhous. 13. The use of claim 2, wherein the mycotoxin-degrading enzyme is selected from the group consisting of protease A, pancreatin, carboxypeptidase, epoxidase from Eubacterium, lactonohydrolase, catalase, laccase, xylanase, esterase, lipase, oxidase, amino acid oxidase, peroxidase, lactanase, lactoperoxidase, lactonase, manganese peroxidase, polysaccharase and dehydrogenase. 14. The use of claim 2, wherein the mycotoxin toxicity-reducing antioxidant is selected from the group consisting of rutin, quercetin, lutein, lecithin, melatonin, curcumin, curcuminoids, allyl sulfides, chlorophyll and derivatives, sodium thiosulfate, glutathione, methionine, aspartame, selenium, zinc, catechin, vitamin E, vitamin C, vitamin A, vitamin B, coenzyme Q10, carotene and carotenoids. 15. The use of claims 1-14, wherein the composition comprises aptamers, egg-yolk antibodies and hydrated sodium calcium aluminosilicate (HSCAS). 16. The use of claim 1, wherein the composition comprises aptamers, hydrated sodium calcium aluminosilicate (HSCAS), activated carbon, cholestyramine, Saccharomyces cerevisiae, Lactobacillus species, Eubacterium sp. BBSH 797, epoxidase and rutin. 17. The use of claim 1, wherein the aptamer is specific to each mycotoxin selected from the group consisting of aflatoxin B1, deoxynivalenol, zearalenone, fumonisin B1 and ochratoxin A. 18. The use of claim 1, wherein each mycotoxin-specific aptamer is produced using SELEX technology. 19. The use of claim 1, wherein mycotoxin-deactivating aptamers are protected from nuclease degradation by aptamer modifications including changes on the 2′-position of the deoxy-ribose sugar unit (in nucleoside triphosphate backbone and nucleobases located at the C5-position of the pyrimidines and the N7 of 7-deaza-purines. 20. (canceled) 21. (canceled) 22. The use according to claim 1, wherein the composition is aqueous. 23. The use according to claim 1, wherein the composition is a powder. | Mycotoxin-deactivating aptamers, especially DNA aptamers, bind to mycotoxins in feed and feed ingredients resulting in the reduction or elimination of toxic and carcinogenic effects of mycotoxins. The invention also discloses a composition comprising a mycotoxin-deactivating aptamer, a binding agent, a biotransforming agent and an antioxidant for detoxifying mycotoxins in feeds. In addition, the invention teaches the methods of preparing said mycotoxin-deactivating aptamer-based composition and also the methods of using it as a feed additive. Furthermore, the invention relates to the use of said mycotoxin-deactivator/s alone, or in a composition comprising said aptamers and other mycotoxin-detoxifying agents, in feeds and feed ingredients for detoxifying the major mycotoxins such as aflatoxins, deoxynivalenol, zearalenone, fumonisins and ochratoxin A.1. A use of a composition comprising a mycotoxin-deactivating aptamer for inhibiting the toxicity of mycotoxin and preventing absorption of active mycotoxin in a gastrointestinal tract. 2. The use as claimed in claim 1, said composition further comprising one or more of: a mycotoxin-specific antibody, a mycotoxin-adsorbing agent, a mycotoxin-biotransforming agent, a mycotoxin-degrading enzyme and a mycotoxin toxicity-reducing antioxidant. 3. The use as claimed in claim 1, said composition further comprising animal feed. 4. The use according to claim 1, wherein the aptamers are either individual mycotoxin-specific single stranded DNA (ssDNA) or single stranded RNA (ssRNA) molecules. 5. The use according to claim 1, wherein the composition is capable of detoxifying a wide spectrum of mycotoxins, including those selected from the group consisting of aflatoxins (AFB1, AFB2, AFG1, AFG2), deoxynivalenol, nivalenol, T-2 toxin, zearalenone, fumonisins (FB1, FB2, FB3), ochratoxin A, citrinin and ergotamine. 6. The use according to claim 1, wherein the mycotoxin-deactivating aptamer is AFB1-specific aptamer. 7. The use according to claim 3, wherein the mycotoxin-deactivating aptamer is at a concentration ranging from about 0.01% to about 2% by weight of the animal's daily feed ration. 8. (canceled) 9. The use according to claim 3, wherein the aptamer is at a concentration ranging from about 0.1% to about 0.3% by weight of the animal's daily feed ration. 10. The use according to claim 3, wherein the ingredients of feed are selected from the group consisting of corn (maize), wheat, barley, rye, rice, sorghum, soybean, peanut, millet, brewers spent grain, distiller's spent grain, distiller's wet grain, and distiller's dried grain, forage and silage. 11. The use of claim 2, wherein the mycotoxin-adsorbing agents is selected from the group consisting of sodium bentonite, calcium bentonite, sodium-calcium montmorillonite, clinoptilolite, calcium/potassium/sodium hydrated aluminosilicate, hydrated sodium calcium aluminosilicate (HSCAS), activated carbon, dry yeast (Saccharomyces cerevisiae) cells, polymeric glucomannan, esterified glucomannan and beta-glucan fractions of dry yeast cell wall, cholestyramine, polyvinylpolypyrrolidone, activated diatomaceous earth, plant fibres, kaolinite, and hydrated sodium-potassium-calcium aluminosilicate. 12. The use of claim 2, wherein the biotransforming agent is selected from the group consisting of Eubacterium sp. BBSH 797, Nocardia asteroids, Mycobacterium fluoranthenivorans sp., Rhodococcus erythropolis, Alcaligenes species., Bacillus species., Achromobacter species., Flavobacterium species, Pseudomonas species, Lactobacillus rhamnosus strain GG, Lactobacillus helveticus 46 & 72, Lactobacillus casei, Lactobacillus lactis, Streptococcus thermophilus C5 and NG40Z, Lactobacillus paraplantarum, Stenotrophomonas maltophila, Saccharomyces cerevisiae, Cupriavidus basilensis OR16 Aspergillus niger, Eurotium herbariorum, Rhizopus species., Trichosporon mycotoxinivorans, Phaffia rhodozyma, and Xanthophyllomyces dendrorhous. 13. The use of claim 2, wherein the mycotoxin-degrading enzyme is selected from the group consisting of protease A, pancreatin, carboxypeptidase, epoxidase from Eubacterium, lactonohydrolase, catalase, laccase, xylanase, esterase, lipase, oxidase, amino acid oxidase, peroxidase, lactanase, lactoperoxidase, lactonase, manganese peroxidase, polysaccharase and dehydrogenase. 14. The use of claim 2, wherein the mycotoxin toxicity-reducing antioxidant is selected from the group consisting of rutin, quercetin, lutein, lecithin, melatonin, curcumin, curcuminoids, allyl sulfides, chlorophyll and derivatives, sodium thiosulfate, glutathione, methionine, aspartame, selenium, zinc, catechin, vitamin E, vitamin C, vitamin A, vitamin B, coenzyme Q10, carotene and carotenoids. 15. The use of claims 1-14, wherein the composition comprises aptamers, egg-yolk antibodies and hydrated sodium calcium aluminosilicate (HSCAS). 16. The use of claim 1, wherein the composition comprises aptamers, hydrated sodium calcium aluminosilicate (HSCAS), activated carbon, cholestyramine, Saccharomyces cerevisiae, Lactobacillus species, Eubacterium sp. BBSH 797, epoxidase and rutin. 17. The use of claim 1, wherein the aptamer is specific to each mycotoxin selected from the group consisting of aflatoxin B1, deoxynivalenol, zearalenone, fumonisin B1 and ochratoxin A. 18. The use of claim 1, wherein each mycotoxin-specific aptamer is produced using SELEX technology. 19. The use of claim 1, wherein mycotoxin-deactivating aptamers are protected from nuclease degradation by aptamer modifications including changes on the 2′-position of the deoxy-ribose sugar unit (in nucleoside triphosphate backbone and nucleobases located at the C5-position of the pyrimidines and the N7 of 7-deaza-purines. 20. (canceled) 21. (canceled) 22. The use according to claim 1, wherein the composition is aqueous. 23. The use according to claim 1, wherein the composition is a powder. | 1,600 |
1,484 | 16,387,185 | 1,653 | The present disclosure relates to testing, analysis and treatment of an environment, wherein one or more baseline(s) is established for the environment. Systems and methods for detecting, treating, comparing and testing for mold, mold spores and mold fragments physically present or in the air of an environment are disclosed herein, as well as methods for remediating the effects of mold in the environment. | 1. A method for remediating the effect of mold in an indoor environment, comprising:
detecting the physical presence of mold, mold spores and mold fragments; sampling in real time for both physical and airborne mold, mold spores and mold fragments by using adhesive tape for physical surfaces located in the environment, and air sampling cassettes, impact samplers, and Wideband Integrated Bioaerosol Sensors for airborne molds; categorizing each mold detected based on its type and location in the indoor environment by photographing and labeling each mold, mold spore or mold fragment detected; establishing a first baseline relating to an outdoor environment, the first baseline comprising a physical mold baseline and an airborne mold baseline; establishing a second baseline relating to the indoor environment, the second baseline comprising a physical mold baseline and an airborne mold baseline; applying a first solution to address the physical presence of mold detected in the indoor environment, wherein the first solution comprises at least sodium hypochlorite 12.5% and a surfactant selected from the group consisting of alcohol ethoxylates; applying a second solution to the air in the indoor environment, wherein the second solution comprises a fog-based, electrolyzed salt water solution having particle size less than 1 micron; ventilating the indoor environment, for a predetermined length of time determined from the first baseline and the second baseline, wherein the step of ventilating occurs at a rate of about 1 to 3 exchanges per hour; disinfecting the indoor environment by use of a micro aerosol generator to distribute one or more disinfectants throughout the indoor environment; testing for molds remaining in the indoor environment to determine an updated second baseline; and comparing the test results and the updated second baseline to the first baseline. 2. The method of claim 1, further comprising the step of interpreting the comparison of the test results to at least one of the first baseline and the second baseline. 3. The method of claim 1, wherein the steps of detecting, sampling, categorizing, applying a first solution, applying a second solution, ventilating the indoor environment, and testing for molds are repeated until the updated second baseline is substantially the same as the first baseline. 4. A method for remediating the effect of mold in an indoor environment, comprising:
establishing a first baseline relating to an indoor environment, the first baseline comprising a physical mold baseline and an airborne mold baseline; establishing a second baseline relating to an outdoor environment, the second baseline comprising a physical mold baseline and an airborne mold baseline; sampling in real time the indoor environment for the presence of one or more physical and airborne molds; applying a first solution to physical molds detected in the indoor environment; applying a second solution to the airborne molds in the indoor environment; ventilating the indoor environment for a predetermined length of time; comparing the test results to the first baseline and the second baseline; establishing an updated first baseline; and repeating the sampling, applying a first solution, applying a second solution, and ventilating steps until the test results are improved, by comparing the updated first baseline to the second baseline, until the updated first baseline is in proximity to the second baseline by a predetermined value. 5. The method of claim 4, wherein the first solution comprises sodium hypochlorite 12.5% in combination with at least one surfactant. 6. The method of claim 4, wherein the second solution comprises electrolyzed salt water having particle size less than 1 micron. 7. The method of claim 4, further comprising the use of a micro aerosol generator to distribute one or more disinfectants throughout the environment. 8. A method for remediating the effect of mold in an indoor environment, comprising:
detecting the physical presence of mold, mold spores and mold fragments; sampling in real time for both physical and airborne mold, mold spores and mold fragments using adhesive tape for physical surfaces located in the environment, and air sampling cassettes, impact samplers, and Wideband Integrated Bioaerosol Sensors that quantify airborne mold spores and mold fragments; categorizing each physical and airborne mold detected based on its type and location in the indoor environment; establishing an airborne mold baseline associated with the indoor environment; establishing a physical mold baseline associated with the indoor environment; establishing an airborne mold baseline associated with an outdoor environment; establishing a physical mold baseline associated with an outdoor environment; applying a first solution to address the physical presence of mold detected in the indoor environment; applying a second solution to the air in the indoor environment; ventilating the environment, for a predetermined length of time; disinfecting the indoor environment by use of a micro aerosol generator to distribute one or more disinfectants throughout the indoor environment; testing for molds remaining in the indoor environment; and comparing the test results to the baselines associated with the indoor environment and the outdoor environment. 9. The method of claim 8, wherein the first solution comprises at least sodium hypochlorite 12.5% and a surfactant. 10. The method of claim 9, wherein the surfactant is selected from the group consisting of alcohol ethoxylates. 11. The method of claim 8, wherein the second solution comprises a fog-based, electrolyzed salt water solution having particle size less than 1 micron. 12. The method of claim 8, wherein the categorizing comprises photographing and labeling each mold, mold spore or mold fragment detected. 13. The method of claim 8, wherein the step of ventilating occurs at a rate of about 1 to 3 exchanges per hour. | The present disclosure relates to testing, analysis and treatment of an environment, wherein one or more baseline(s) is established for the environment. Systems and methods for detecting, treating, comparing and testing for mold, mold spores and mold fragments physically present or in the air of an environment are disclosed herein, as well as methods for remediating the effects of mold in the environment.1. A method for remediating the effect of mold in an indoor environment, comprising:
detecting the physical presence of mold, mold spores and mold fragments; sampling in real time for both physical and airborne mold, mold spores and mold fragments by using adhesive tape for physical surfaces located in the environment, and air sampling cassettes, impact samplers, and Wideband Integrated Bioaerosol Sensors for airborne molds; categorizing each mold detected based on its type and location in the indoor environment by photographing and labeling each mold, mold spore or mold fragment detected; establishing a first baseline relating to an outdoor environment, the first baseline comprising a physical mold baseline and an airborne mold baseline; establishing a second baseline relating to the indoor environment, the second baseline comprising a physical mold baseline and an airborne mold baseline; applying a first solution to address the physical presence of mold detected in the indoor environment, wherein the first solution comprises at least sodium hypochlorite 12.5% and a surfactant selected from the group consisting of alcohol ethoxylates; applying a second solution to the air in the indoor environment, wherein the second solution comprises a fog-based, electrolyzed salt water solution having particle size less than 1 micron; ventilating the indoor environment, for a predetermined length of time determined from the first baseline and the second baseline, wherein the step of ventilating occurs at a rate of about 1 to 3 exchanges per hour; disinfecting the indoor environment by use of a micro aerosol generator to distribute one or more disinfectants throughout the indoor environment; testing for molds remaining in the indoor environment to determine an updated second baseline; and comparing the test results and the updated second baseline to the first baseline. 2. The method of claim 1, further comprising the step of interpreting the comparison of the test results to at least one of the first baseline and the second baseline. 3. The method of claim 1, wherein the steps of detecting, sampling, categorizing, applying a first solution, applying a second solution, ventilating the indoor environment, and testing for molds are repeated until the updated second baseline is substantially the same as the first baseline. 4. A method for remediating the effect of mold in an indoor environment, comprising:
establishing a first baseline relating to an indoor environment, the first baseline comprising a physical mold baseline and an airborne mold baseline; establishing a second baseline relating to an outdoor environment, the second baseline comprising a physical mold baseline and an airborne mold baseline; sampling in real time the indoor environment for the presence of one or more physical and airborne molds; applying a first solution to physical molds detected in the indoor environment; applying a second solution to the airborne molds in the indoor environment; ventilating the indoor environment for a predetermined length of time; comparing the test results to the first baseline and the second baseline; establishing an updated first baseline; and repeating the sampling, applying a first solution, applying a second solution, and ventilating steps until the test results are improved, by comparing the updated first baseline to the second baseline, until the updated first baseline is in proximity to the second baseline by a predetermined value. 5. The method of claim 4, wherein the first solution comprises sodium hypochlorite 12.5% in combination with at least one surfactant. 6. The method of claim 4, wherein the second solution comprises electrolyzed salt water having particle size less than 1 micron. 7. The method of claim 4, further comprising the use of a micro aerosol generator to distribute one or more disinfectants throughout the environment. 8. A method for remediating the effect of mold in an indoor environment, comprising:
detecting the physical presence of mold, mold spores and mold fragments; sampling in real time for both physical and airborne mold, mold spores and mold fragments using adhesive tape for physical surfaces located in the environment, and air sampling cassettes, impact samplers, and Wideband Integrated Bioaerosol Sensors that quantify airborne mold spores and mold fragments; categorizing each physical and airborne mold detected based on its type and location in the indoor environment; establishing an airborne mold baseline associated with the indoor environment; establishing a physical mold baseline associated with the indoor environment; establishing an airborne mold baseline associated with an outdoor environment; establishing a physical mold baseline associated with an outdoor environment; applying a first solution to address the physical presence of mold detected in the indoor environment; applying a second solution to the air in the indoor environment; ventilating the environment, for a predetermined length of time; disinfecting the indoor environment by use of a micro aerosol generator to distribute one or more disinfectants throughout the indoor environment; testing for molds remaining in the indoor environment; and comparing the test results to the baselines associated with the indoor environment and the outdoor environment. 9. The method of claim 8, wherein the first solution comprises at least sodium hypochlorite 12.5% and a surfactant. 10. The method of claim 9, wherein the surfactant is selected from the group consisting of alcohol ethoxylates. 11. The method of claim 8, wherein the second solution comprises a fog-based, electrolyzed salt water solution having particle size less than 1 micron. 12. The method of claim 8, wherein the categorizing comprises photographing and labeling each mold, mold spore or mold fragment detected. 13. The method of claim 8, wherein the step of ventilating occurs at a rate of about 1 to 3 exchanges per hour. | 1,600 |
1,485 | 16,696,095 | 1,617 | Provided herein are methods of treating a peripheral nerve injury in a subject. The methods include administering to the subject at or near the site of the peripheral nerve injury an effective amount of a composition comprising an agent that promotes remyelination of the peripheral nerve. Also provided are methods of determining whether a peripheral nerve injury has a capacity for recovery. The methods include selecting a subject with a peripheral nerve injury, administering to the subject a first dose of a composition comprising and agent that promote remyelination and detecting after the first dose one or more characteristics of peripheral nerve recovery, the presence of one or more characteristics of peripheral nerve recovery indicating a peripheral nerve injury has a capacity for recovery and the absence of characteristics of peripheral nerve recovery indicating a peripheral nerve injury without a capacity for recovery. | 1.-12. (canceled) 13. A method of treating a peripheral nerve injury in a subject comprising administering to the subject an effective amount of a composition comprising 4-aminopyridine (4-AP) and a pharmaceutically acceptable carrier, wherein administration promotes remyelination of the peripheral nerve in the subject, thereby treating the peripheral nerve injury. 14. The method of claim 13, wherein the nerve injury is selected from the group consisting of a stretched nerve, a pinched nerve, a compressed nerve, a traumatized nerve and a crushed nerve. 15. The method of claim 13, wherein the peripheral nerve injury is not a transected nerve. 16. The method of claim 13, wherein the peripheral nerve injury is an acute peripheral nerve injury. 17. The method of claim 16, wherein the 4-AP or derivative thereof is provided in an amount of at least one ng/kg/day microgram for at least one day. 18. The method of claim 13, wherein the composition comprises a polymer or hydrogel. 19. The method of claim 0, wherein the polymer comprises poly(lactic-co-glycolic acid) (PLGA). 20. The method of claim 13, wherein the composition comprises a fibrin glue. 21. The method of claim 13, wherein the composition is administered by insertion, implantation or injection into the subject at or near the site of the peripheral nerve injury. 22. The method of claim 13, wherein the composition is administered by a sustained delivery device. 23. The method of claim 22, wherein the sustained delivery device is an implant or osmotic pump. 24. The method of claim 23, wherein the implant is a nerve cuff. 25. The method of claim 23, wherein the implant is a bioerodible or reservoir-based implant. 26. The method of claim 13, further comprising administering an additional therapeutic agent to the subject. 27. The method of claim 26, wherein the additional therapeutic agent is a steroid. 28. The method of claim 13, wherein the peripheral nerve injury is caused by surgery. 29. The method of claim 3, wherein the peripheral nerve injury is associated with traumatic injury, carpel tunnel syndrome or sciatica. 30. The method of claim 13, wherein the composition is administered at least once daily. 31. The method of claim 13, wherein the composition is administered at least twice daily. 32. The method of claim 13, wherein the 4-AP is in the form of a pharmaceutically acceptable salt. | Provided herein are methods of treating a peripheral nerve injury in a subject. The methods include administering to the subject at or near the site of the peripheral nerve injury an effective amount of a composition comprising an agent that promotes remyelination of the peripheral nerve. Also provided are methods of determining whether a peripheral nerve injury has a capacity for recovery. The methods include selecting a subject with a peripheral nerve injury, administering to the subject a first dose of a composition comprising and agent that promote remyelination and detecting after the first dose one or more characteristics of peripheral nerve recovery, the presence of one or more characteristics of peripheral nerve recovery indicating a peripheral nerve injury has a capacity for recovery and the absence of characteristics of peripheral nerve recovery indicating a peripheral nerve injury without a capacity for recovery.1.-12. (canceled) 13. A method of treating a peripheral nerve injury in a subject comprising administering to the subject an effective amount of a composition comprising 4-aminopyridine (4-AP) and a pharmaceutically acceptable carrier, wherein administration promotes remyelination of the peripheral nerve in the subject, thereby treating the peripheral nerve injury. 14. The method of claim 13, wherein the nerve injury is selected from the group consisting of a stretched nerve, a pinched nerve, a compressed nerve, a traumatized nerve and a crushed nerve. 15. The method of claim 13, wherein the peripheral nerve injury is not a transected nerve. 16. The method of claim 13, wherein the peripheral nerve injury is an acute peripheral nerve injury. 17. The method of claim 16, wherein the 4-AP or derivative thereof is provided in an amount of at least one ng/kg/day microgram for at least one day. 18. The method of claim 13, wherein the composition comprises a polymer or hydrogel. 19. The method of claim 0, wherein the polymer comprises poly(lactic-co-glycolic acid) (PLGA). 20. The method of claim 13, wherein the composition comprises a fibrin glue. 21. The method of claim 13, wherein the composition is administered by insertion, implantation or injection into the subject at or near the site of the peripheral nerve injury. 22. The method of claim 13, wherein the composition is administered by a sustained delivery device. 23. The method of claim 22, wherein the sustained delivery device is an implant or osmotic pump. 24. The method of claim 23, wherein the implant is a nerve cuff. 25. The method of claim 23, wherein the implant is a bioerodible or reservoir-based implant. 26. The method of claim 13, further comprising administering an additional therapeutic agent to the subject. 27. The method of claim 26, wherein the additional therapeutic agent is a steroid. 28. The method of claim 13, wherein the peripheral nerve injury is caused by surgery. 29. The method of claim 3, wherein the peripheral nerve injury is associated with traumatic injury, carpel tunnel syndrome or sciatica. 30. The method of claim 13, wherein the composition is administered at least once daily. 31. The method of claim 13, wherein the composition is administered at least twice daily. 32. The method of claim 13, wherein the 4-AP is in the form of a pharmaceutically acceptable salt. | 1,600 |
1,486 | 14,803,677 | 1,656 | This invention relates to Factor VIII muteins that are covalently bound, at a predefined site that is not an N-terminal amine, to one or more biocompatible polymers such as polyethylene glycol. The mutein conjugates retain FVIII procoagulant activity and have improved pharmacokinetic properties. | 1.-35. (canceled) 36. A method for the treatment of hemophilia in a patient who has already developed factor VIII inhibitory antibodies comprising administering a therapeutically effective amount of a pharmaceutical composition of a conjugate having factor VIII procoagulant activity comprising a functional factor VIII polypeptide covalently attached to one or more biocompatible polymers. 37. The method of claim 36, wherein the biocompatible polymer comprises polyalkylene oxide. 38. The method of claim 36, wherein the biocompatible polymer comprises polyethylene glycol. 39. The method of claim 38, wherein the polyethylene glycol comprises methoxypolyethylene glycol. 40. The method of claim 39, wherein the methoxypolyethylene glycol has a size range of from 3 kD to 100 kD. 41. The method of claim 40, wherein the methoxypolyethylene glycol has a size range of from 5 kD to 64 kD. 42. The method of claim 41, wherein the methoxypolyethylene glycol has a size range of from 5 kD to 43 kD. 43. The method of claim 36, wherein the biocompatible polymer is covalently attached to the functional factor VIII polypeptide at a site that is or is within 20 angstrom of a binding site for factor VIII inhibitory antibodies. 44. The method of claim 36, wherein the binding of factor VIII inhibitory antibodies to the conjugate is less than binding of the antibodies to the polypeptide when it is not conjugated. 45. The method of claim 36, wherein the conjugate comprises a functional factor VIII polypeptide comprising the amino acid sequence of SEQ ID NO: 3 or 4. 46. The method of claim 38, wherein the conjugate is monopegylated or dipegylated. 47. The method of claim 38, wherein the conjugate comprises a functional factor VIII polypeptide comprising the amino acid sequence of SEQ ID NO: 4 or an allelic variant thereof. | This invention relates to Factor VIII muteins that are covalently bound, at a predefined site that is not an N-terminal amine, to one or more biocompatible polymers such as polyethylene glycol. The mutein conjugates retain FVIII procoagulant activity and have improved pharmacokinetic properties.1.-35. (canceled) 36. A method for the treatment of hemophilia in a patient who has already developed factor VIII inhibitory antibodies comprising administering a therapeutically effective amount of a pharmaceutical composition of a conjugate having factor VIII procoagulant activity comprising a functional factor VIII polypeptide covalently attached to one or more biocompatible polymers. 37. The method of claim 36, wherein the biocompatible polymer comprises polyalkylene oxide. 38. The method of claim 36, wherein the biocompatible polymer comprises polyethylene glycol. 39. The method of claim 38, wherein the polyethylene glycol comprises methoxypolyethylene glycol. 40. The method of claim 39, wherein the methoxypolyethylene glycol has a size range of from 3 kD to 100 kD. 41. The method of claim 40, wherein the methoxypolyethylene glycol has a size range of from 5 kD to 64 kD. 42. The method of claim 41, wherein the methoxypolyethylene glycol has a size range of from 5 kD to 43 kD. 43. The method of claim 36, wherein the biocompatible polymer is covalently attached to the functional factor VIII polypeptide at a site that is or is within 20 angstrom of a binding site for factor VIII inhibitory antibodies. 44. The method of claim 36, wherein the binding of factor VIII inhibitory antibodies to the conjugate is less than binding of the antibodies to the polypeptide when it is not conjugated. 45. The method of claim 36, wherein the conjugate comprises a functional factor VIII polypeptide comprising the amino acid sequence of SEQ ID NO: 3 or 4. 46. The method of claim 38, wherein the conjugate is monopegylated or dipegylated. 47. The method of claim 38, wherein the conjugate comprises a functional factor VIII polypeptide comprising the amino acid sequence of SEQ ID NO: 4 or an allelic variant thereof. | 1,600 |
1,487 | 15,376,298 | 1,651 | Provided are nutritional compositions containing dietary butyrate. Further disclosed are methods for promoting and/or accelerating myelination in a target subject via administering the nutritional composition containing dietary butyrate to the target subject. | 1. A nutritional composition comprising:
a carbohydrate source; a protein equivalent source; a fat or lipid source; and dietary butyrate. 2. The nutritional composition of claim 1, wherein the nutritional composition further comprise a probiotic. 3. The nutritional composition of claim 1, wherein 1% to 99% of the protein equivalent source includes a peptide component comprising SEQ ID NO 4, SEQ ID NO 13, SEQ ID NO 17, SEQ ID NO 21, SEQ ID NO 24, SEQ ID NO 30, SEQ ID NO 31, SEQ ID NO 32, SEQ ID NO 51, SEQ ID NO 57, SEQ ID NO 60, and SEQ ID NO 63; and 1% to 99% of the protein equivalent source comprises a partially hydrolyzed protein, an extensively hydrolyzed protein, or combinations thereof. 3. The nutritional composition of claim 1, wherein the nutritional composition further comprises inositol. 4. The nutritional composition of claim 1, wherein the nutritional composition comprises a prebiotic. 5. The nutritional composition of claim 1, wherein the nutritional composition comprises dietary butyrate, and further wherein the dietary butyrate is present in an amount of from about 0.1 mg/100 Kcal to about 300 mg/100 Kcal. 6. The nutritional composition of claim 1, wherein the dietary butyrate comprises sodium butyrate. 7. The nutritional composition of claim 1, wherein the nutritional composition comprises dietary butyrate that is provided by an enriched lipid fraction derived from bovine milk. 8. The nutritional composition of claim 7, wherein the enriched lipid fraction derived from milk further comprises milk fat globule membrane. 9. The nutritional composition of claim 1, further comprising one or more long chain polyunsaturated fatty acids. 10. The nutritional composition of claim 9, wherein the one or more long chain polyunsaturated fatty acids comprises docosahexaenoic acid, arachidonic acid, and combinations thereof. 11. The nutritional composition of claim 1, further comprising β-glucan. 12. The nutritional composition of claim 1, further comprising a culture supernatant from a late-exponential growth phase of a probiotic batch-cultivation process. 13. The nutritional composition of claim 1, wherein the nutritional composition is an infant formula. 14. A nutritional composition, comprising per 100 Kcal:
(i) between about 6 g and about 22 g of a carbohydrate source; (ii) between about 1 g and about 7 g of a protein source; (iii) between about 1 g and about 10.3 g of a fat source; and (v) between about 0.1 mg and 300 mg of dietary butyrate. 15. The nutritional composition of claim 14, wherein 1% to 99% of the protein equivalent source includes a peptide component comprising SEQ ID NO 4, SEQ ID NO 13, SEQ ID NO 17, SEQ ID NO 21, SEQ ID NO 24, SEQ ID NO 30, SEQ ID NO 31, SEQ ID NO 32, SEQ ID NO 51, SEQ ID NO 57, SEQ ID NO 60, and SEQ ID NO 63; and 1% to 99% of the protein equivalent source comprises a partially hydrolyzed protein, and extensively hydrolyzed protein, or combinations thereof. 16. The nutritional composition of claim 14, further comprising one or more long chain polyunsaturated fatty acids. 17. The nutritional composition of claim 14, further comprising one or more prebiotics. 18. A method of accelerating myelination in a formula-fed infant, the method comprising the step of administering to the formula fed infant a nutritional composition comprising a carbohydrate source; a protein equivalent source; a fat or lipid source; and dietary butyrate. 19. The method of claim 18, wherein the nutritional composition comprises Lactobacillus rhamnosus GG. 20. The method of claim 18, wherein the nutritional composition is an infant formula. 21. A staged feeding regimen for an infant or child, comprising the steps of:
A) administering a first nutritional composition comprising from about 4 μg/mL to about 36 μg/mL of dietary butyrate to the infant from birth to about 3 months of age; B) administering a second nutritional composition comprising from about 6 μg/mL to about 33 μg/mL of butyrate to the infant from 3 months of age to about 6 months of age; and C) administering a third nutritional composition comprising from about 8 μg/mL to about 40 μg/mL of butyrate to the infant from 6 months of age to about 12 months of age,
wherein each of the first nutritional composition, the second nutritional composition and the third nutritional composition are different from each other. 22. The staged feeding regimen of claim 21, wherein the first nutritional composition comprises from about 7 μg/mL to about 22 μg/mL of dietary butyrate; the second nutritional composition comprises from about 17 μg/mL to about 24 μg/mL of butyrate; and the third nutritional composition comprises from about 17 μg/mL to about 22 μg/mL of butyrate. 23. The staged feeding regimen of claim 21, wherein the first nutritional composition further comprises at least one of the following selected from the group consisting of: i) up to about 0.2 mg/100 kcal of iron; ii) up to about 0.7 mg/100 kcal of zinc; iii) up to about 2 g/100 kcal of protein; iv) a protein source comprising a whey:casein ratio of at least about 72:28; v) up to 35 mg/100 kcal of inositol; and vii) from about 1.8 μg/100 kcal to about 2.0 μg/100 kcal of vitamin D. 24. The staged feeding regimen of claim 21, wherein the second nutritional composition further comprises at least one of the following selected from the group consisting of: i) from about 0.3 mg/100 kcal to about 0.6 mg/100 kcal of iron; ii) up to about 0.9 mg/100 kcal of zinc; iii) up to about 1.9 g/100 kcal of protein; iv) a protein source comprising a whey:casein ratio of about 56:44 to about 68:32; v) up to 25 mg/100 kcal of inositol; vi) up to 9.0 mg/100 kcal of butyrate; and vii) from about 1.8 μg/100 kcal to about 2.0 μg/100 kcal of vitamin D. 25. The staged feeding regimen of claim 21, wherein the third nutritional composition further comprises at least one of the following selected from the group consisting of: i) from about 0.3 mg/100 kcal to about 1.2 mg/100 kcal of iron; ii) up to about 1 mg/100 kcal of zinc; iii) up to about 1.5 g/100 kcal of protein; iv) a protein source comprising a whey:casein ratio of about 45:55 to about 56:44; v) up to 20 mg/100 kcal of inositol; vi) up to 9.0 mg/100 kcal of butyrate; and vii) from about 1.8 μg/100 kcal to about 2.0 μg/100 kcal of vitamin D. 26. The staged feeding regimen of claim 21, wherein the first nutritional composition, second nutritional composition, and third nutritional composition each further comprise docosahexaenoic acid. 27. The staged feeding regimen of claim 21, wherein the first nutritional composition, second nutritional composition, and third nutritional composition each further comprise a carbohydrate source, a fat source, and a protein source. 28. The staged feeding regimen of claim 21, wherein the first nutritional composition, second nutritional composition, and third nutritional composition each further comprise prebiotics. 29. The staged feeding regimen of claim 21, wherein the first nutritional composition, second nutritional composition, and third nutritional composition each further comprise Lactobacillus rhamnosus GG. 30. The staged feeding regimen of claim 21, wherein the first nutritional composition, second nutritional composition, and third nutritional composition each further comprise β-glucan. | Provided are nutritional compositions containing dietary butyrate. Further disclosed are methods for promoting and/or accelerating myelination in a target subject via administering the nutritional composition containing dietary butyrate to the target subject.1. A nutritional composition comprising:
a carbohydrate source; a protein equivalent source; a fat or lipid source; and dietary butyrate. 2. The nutritional composition of claim 1, wherein the nutritional composition further comprise a probiotic. 3. The nutritional composition of claim 1, wherein 1% to 99% of the protein equivalent source includes a peptide component comprising SEQ ID NO 4, SEQ ID NO 13, SEQ ID NO 17, SEQ ID NO 21, SEQ ID NO 24, SEQ ID NO 30, SEQ ID NO 31, SEQ ID NO 32, SEQ ID NO 51, SEQ ID NO 57, SEQ ID NO 60, and SEQ ID NO 63; and 1% to 99% of the protein equivalent source comprises a partially hydrolyzed protein, an extensively hydrolyzed protein, or combinations thereof. 3. The nutritional composition of claim 1, wherein the nutritional composition further comprises inositol. 4. The nutritional composition of claim 1, wherein the nutritional composition comprises a prebiotic. 5. The nutritional composition of claim 1, wherein the nutritional composition comprises dietary butyrate, and further wherein the dietary butyrate is present in an amount of from about 0.1 mg/100 Kcal to about 300 mg/100 Kcal. 6. The nutritional composition of claim 1, wherein the dietary butyrate comprises sodium butyrate. 7. The nutritional composition of claim 1, wherein the nutritional composition comprises dietary butyrate that is provided by an enriched lipid fraction derived from bovine milk. 8. The nutritional composition of claim 7, wherein the enriched lipid fraction derived from milk further comprises milk fat globule membrane. 9. The nutritional composition of claim 1, further comprising one or more long chain polyunsaturated fatty acids. 10. The nutritional composition of claim 9, wherein the one or more long chain polyunsaturated fatty acids comprises docosahexaenoic acid, arachidonic acid, and combinations thereof. 11. The nutritional composition of claim 1, further comprising β-glucan. 12. The nutritional composition of claim 1, further comprising a culture supernatant from a late-exponential growth phase of a probiotic batch-cultivation process. 13. The nutritional composition of claim 1, wherein the nutritional composition is an infant formula. 14. A nutritional composition, comprising per 100 Kcal:
(i) between about 6 g and about 22 g of a carbohydrate source; (ii) between about 1 g and about 7 g of a protein source; (iii) between about 1 g and about 10.3 g of a fat source; and (v) between about 0.1 mg and 300 mg of dietary butyrate. 15. The nutritional composition of claim 14, wherein 1% to 99% of the protein equivalent source includes a peptide component comprising SEQ ID NO 4, SEQ ID NO 13, SEQ ID NO 17, SEQ ID NO 21, SEQ ID NO 24, SEQ ID NO 30, SEQ ID NO 31, SEQ ID NO 32, SEQ ID NO 51, SEQ ID NO 57, SEQ ID NO 60, and SEQ ID NO 63; and 1% to 99% of the protein equivalent source comprises a partially hydrolyzed protein, and extensively hydrolyzed protein, or combinations thereof. 16. The nutritional composition of claim 14, further comprising one or more long chain polyunsaturated fatty acids. 17. The nutritional composition of claim 14, further comprising one or more prebiotics. 18. A method of accelerating myelination in a formula-fed infant, the method comprising the step of administering to the formula fed infant a nutritional composition comprising a carbohydrate source; a protein equivalent source; a fat or lipid source; and dietary butyrate. 19. The method of claim 18, wherein the nutritional composition comprises Lactobacillus rhamnosus GG. 20. The method of claim 18, wherein the nutritional composition is an infant formula. 21. A staged feeding regimen for an infant or child, comprising the steps of:
A) administering a first nutritional composition comprising from about 4 μg/mL to about 36 μg/mL of dietary butyrate to the infant from birth to about 3 months of age; B) administering a second nutritional composition comprising from about 6 μg/mL to about 33 μg/mL of butyrate to the infant from 3 months of age to about 6 months of age; and C) administering a third nutritional composition comprising from about 8 μg/mL to about 40 μg/mL of butyrate to the infant from 6 months of age to about 12 months of age,
wherein each of the first nutritional composition, the second nutritional composition and the third nutritional composition are different from each other. 22. The staged feeding regimen of claim 21, wherein the first nutritional composition comprises from about 7 μg/mL to about 22 μg/mL of dietary butyrate; the second nutritional composition comprises from about 17 μg/mL to about 24 μg/mL of butyrate; and the third nutritional composition comprises from about 17 μg/mL to about 22 μg/mL of butyrate. 23. The staged feeding regimen of claim 21, wherein the first nutritional composition further comprises at least one of the following selected from the group consisting of: i) up to about 0.2 mg/100 kcal of iron; ii) up to about 0.7 mg/100 kcal of zinc; iii) up to about 2 g/100 kcal of protein; iv) a protein source comprising a whey:casein ratio of at least about 72:28; v) up to 35 mg/100 kcal of inositol; and vii) from about 1.8 μg/100 kcal to about 2.0 μg/100 kcal of vitamin D. 24. The staged feeding regimen of claim 21, wherein the second nutritional composition further comprises at least one of the following selected from the group consisting of: i) from about 0.3 mg/100 kcal to about 0.6 mg/100 kcal of iron; ii) up to about 0.9 mg/100 kcal of zinc; iii) up to about 1.9 g/100 kcal of protein; iv) a protein source comprising a whey:casein ratio of about 56:44 to about 68:32; v) up to 25 mg/100 kcal of inositol; vi) up to 9.0 mg/100 kcal of butyrate; and vii) from about 1.8 μg/100 kcal to about 2.0 μg/100 kcal of vitamin D. 25. The staged feeding regimen of claim 21, wherein the third nutritional composition further comprises at least one of the following selected from the group consisting of: i) from about 0.3 mg/100 kcal to about 1.2 mg/100 kcal of iron; ii) up to about 1 mg/100 kcal of zinc; iii) up to about 1.5 g/100 kcal of protein; iv) a protein source comprising a whey:casein ratio of about 45:55 to about 56:44; v) up to 20 mg/100 kcal of inositol; vi) up to 9.0 mg/100 kcal of butyrate; and vii) from about 1.8 μg/100 kcal to about 2.0 μg/100 kcal of vitamin D. 26. The staged feeding regimen of claim 21, wherein the first nutritional composition, second nutritional composition, and third nutritional composition each further comprise docosahexaenoic acid. 27. The staged feeding regimen of claim 21, wherein the first nutritional composition, second nutritional composition, and third nutritional composition each further comprise a carbohydrate source, a fat source, and a protein source. 28. The staged feeding regimen of claim 21, wherein the first nutritional composition, second nutritional composition, and third nutritional composition each further comprise prebiotics. 29. The staged feeding regimen of claim 21, wherein the first nutritional composition, second nutritional composition, and third nutritional composition each further comprise Lactobacillus rhamnosus GG. 30. The staged feeding regimen of claim 21, wherein the first nutritional composition, second nutritional composition, and third nutritional composition each further comprise β-glucan. | 1,600 |
1,488 | 13,336,477 | 1,662 | The invention relates to a celery plant ( Apium graveolens L. dulce) carrying a genetic determinant that leads to short leaf blades and/or a more uniform distribution of stem lengths as compared to celery plants not carrying the genetic determinant, wherein said determinant is obtainable by introgression from a plant grown from seed of which a representative sample was deposited with the NCIMB under accession number NCIMB 41513. The invention also relates to seeds and other propagation material of the plant and to its progeny as well as to food products that comprise the consumable parts of the plant. | 1. Celery plant (Apium graveolens L. dulce) carrying a genetic determinant that lead to short leaf blades and/or a more uniform distribution of stem lengths as compared to celery plants not carrying the genetic determinant, wherein said determinant is obtainable by introgression from a plant grown from seed of which a representative sample was deposited with the NCIMB under accession number NCIMB 41513. 2. A celery plant as claimed in claim 1, wherein the determinant is introgressed from a plant grown from seed of which a representative sample was deposited with the NCIMB under accession number NCIMB 41513. 3. A celery plant as claimed in claim 1, obtainable by:
a) growing plants from seed that was deposited with the NCIMB under accession number NCIMB 41513; b) crossing the said plant with a plant not showing the trait to obtain an F1 population; c) selfing plants from the F1 to obtain an F2 population; d) selecting plants that have short leaf blades and/or a more uniform distribution of stem lengths; and e) optionally performing one or more additional rounds of selfing or crossing, and subsequently selecting, for the trait. 4. A celery plant as claimed in claim 1, wherein the short leaf blades are at least 20% shorter, preferably at least 30% shorter, more preferably at least 40% shorter, even more preferably at least 45% shorter, most preferably at least 50% shorter than the leaf blades of a celery plant not carrying the genetic determinant. 5. A celery plant as claimed in claim 1, wherein the short leaf blades are shorter than 30 cm, preferably shorter than 27 cm, more preferably shorter than 24 cm, even more preferably shorter than 21 cm, most preferably shorter than 18 cm. 6. A celery plant as claimed in claim 5, wherein the short leaf blades are due to short internodes. 7. A celery plant as claimed in claim 6, wherein at least the first internode is at least 30% shorter, preferably at least 40% shorter, more preferably at least 50% shorter, even more preferably at least 60% shorter, most preferably at least 70% shorter than the first internode of a celery plant not carrying the genetic determinant. 8. A celery plant as claimed in claim 1, wherein the stem length is the length of the petiole, more in particular the distance between the leaf base and the first joint of the petiole. 9. A celery plant as claimed in claim 1, wherein the standard deviation of stick lengths in cm within a celery plant is not more than 2.4, preferably not more than 2.2, more preferably not more than 1.8, even more preferably not more than 1.5, most preferably not more than 1.3. 10. A celery plant as claimed in claim 1, wherein the plant shows a shorter total plant length than a celery plant with comparable stem length not carrying the said genetic determinant. 11. A celery plant as claimed in claim 1, wherein the celery plant is a hybrid, doubled haploid, or inbred. 12. Seed of a celery plant as claimed in claim 1. 13. Propagation material suitable for producing a plant as claimed in claim 1, wherein the propagation material is suitable for sexual reproduction, and is in particular selected from microspores, pollen, ovaries, ovules, embryo sacs and egg cells, or is suitable for vegetative reproduction, and is in particular selected from cuttings, roots, stems, cells, protoplasts, or is suitable for tissue cultures of regenerable cells, and is in particular selected from leaves, pollen, embryos, cotyledon, hypocotyls, meristematic cells, roots, root tips, anthers, flowers, seeds and stems, wherein a plant produced from the propagation material has one or more of the following features:
short leaf blades, in particular due to short internodes; a more uniform distribution of stem lengths within a plant as compared to the lengths of the stems of a celery plant not carrying the said genetic determinant; a total plant length significantly shorter than a celery plant with comparable stem lengths not carrying said genetic determinant. 14. A celery plant produced from the propagation material as claimed in claim 13, which plant has one or more of the following features:
short leaf blades, in particular due to short internodes; a more uniform distribution of stem lengths within a plant as compared to the lengths of the stems of a celery plant not carrying the said genetic determinant; a total plant length significantly shorter than a celery plant with comparable stem lengths not carrying said genetic determinant. 15. Progeny of a plant as claimed in claim 1, and wherein the progeny plant has one or more of the following features:
short leaf blades, in particular due to short internodes; a more uniform distribution of stem lengths within a plant as compared to the lengths of the stems of a celery plant not carrying the said genetic determinant; a total plant length significantly shorter than a celery plant with comparable stem lengths not carrying said genetic determinant. 16. Food product, comprising the stalks of a celery plant as claimed in claim 7, or parts thereof. | The invention relates to a celery plant ( Apium graveolens L. dulce) carrying a genetic determinant that leads to short leaf blades and/or a more uniform distribution of stem lengths as compared to celery plants not carrying the genetic determinant, wherein said determinant is obtainable by introgression from a plant grown from seed of which a representative sample was deposited with the NCIMB under accession number NCIMB 41513. The invention also relates to seeds and other propagation material of the plant and to its progeny as well as to food products that comprise the consumable parts of the plant.1. Celery plant (Apium graveolens L. dulce) carrying a genetic determinant that lead to short leaf blades and/or a more uniform distribution of stem lengths as compared to celery plants not carrying the genetic determinant, wherein said determinant is obtainable by introgression from a plant grown from seed of which a representative sample was deposited with the NCIMB under accession number NCIMB 41513. 2. A celery plant as claimed in claim 1, wherein the determinant is introgressed from a plant grown from seed of which a representative sample was deposited with the NCIMB under accession number NCIMB 41513. 3. A celery plant as claimed in claim 1, obtainable by:
a) growing plants from seed that was deposited with the NCIMB under accession number NCIMB 41513; b) crossing the said plant with a plant not showing the trait to obtain an F1 population; c) selfing plants from the F1 to obtain an F2 population; d) selecting plants that have short leaf blades and/or a more uniform distribution of stem lengths; and e) optionally performing one or more additional rounds of selfing or crossing, and subsequently selecting, for the trait. 4. A celery plant as claimed in claim 1, wherein the short leaf blades are at least 20% shorter, preferably at least 30% shorter, more preferably at least 40% shorter, even more preferably at least 45% shorter, most preferably at least 50% shorter than the leaf blades of a celery plant not carrying the genetic determinant. 5. A celery plant as claimed in claim 1, wherein the short leaf blades are shorter than 30 cm, preferably shorter than 27 cm, more preferably shorter than 24 cm, even more preferably shorter than 21 cm, most preferably shorter than 18 cm. 6. A celery plant as claimed in claim 5, wherein the short leaf blades are due to short internodes. 7. A celery plant as claimed in claim 6, wherein at least the first internode is at least 30% shorter, preferably at least 40% shorter, more preferably at least 50% shorter, even more preferably at least 60% shorter, most preferably at least 70% shorter than the first internode of a celery plant not carrying the genetic determinant. 8. A celery plant as claimed in claim 1, wherein the stem length is the length of the petiole, more in particular the distance between the leaf base and the first joint of the petiole. 9. A celery plant as claimed in claim 1, wherein the standard deviation of stick lengths in cm within a celery plant is not more than 2.4, preferably not more than 2.2, more preferably not more than 1.8, even more preferably not more than 1.5, most preferably not more than 1.3. 10. A celery plant as claimed in claim 1, wherein the plant shows a shorter total plant length than a celery plant with comparable stem length not carrying the said genetic determinant. 11. A celery plant as claimed in claim 1, wherein the celery plant is a hybrid, doubled haploid, or inbred. 12. Seed of a celery plant as claimed in claim 1. 13. Propagation material suitable for producing a plant as claimed in claim 1, wherein the propagation material is suitable for sexual reproduction, and is in particular selected from microspores, pollen, ovaries, ovules, embryo sacs and egg cells, or is suitable for vegetative reproduction, and is in particular selected from cuttings, roots, stems, cells, protoplasts, or is suitable for tissue cultures of regenerable cells, and is in particular selected from leaves, pollen, embryos, cotyledon, hypocotyls, meristematic cells, roots, root tips, anthers, flowers, seeds and stems, wherein a plant produced from the propagation material has one or more of the following features:
short leaf blades, in particular due to short internodes; a more uniform distribution of stem lengths within a plant as compared to the lengths of the stems of a celery plant not carrying the said genetic determinant; a total plant length significantly shorter than a celery plant with comparable stem lengths not carrying said genetic determinant. 14. A celery plant produced from the propagation material as claimed in claim 13, which plant has one or more of the following features:
short leaf blades, in particular due to short internodes; a more uniform distribution of stem lengths within a plant as compared to the lengths of the stems of a celery plant not carrying the said genetic determinant; a total plant length significantly shorter than a celery plant with comparable stem lengths not carrying said genetic determinant. 15. Progeny of a plant as claimed in claim 1, and wherein the progeny plant has one or more of the following features:
short leaf blades, in particular due to short internodes; a more uniform distribution of stem lengths within a plant as compared to the lengths of the stems of a celery plant not carrying the said genetic determinant; a total plant length significantly shorter than a celery plant with comparable stem lengths not carrying said genetic determinant. 16. Food product, comprising the stalks of a celery plant as claimed in claim 7, or parts thereof. | 1,600 |
1,489 | 15,600,299 | 1,658 | An intrauterine device having at least one first pharmaceutically active ingredient and at least one first layer made of at least a first polymeric material, wherein between about 10 and about 60 v/v % of at least one particulate material is dispersed and/or incorporated in the first polymeric material. The presence of the particulate material will reduce the porosity of the polymer or otherwise obstruct the diffusion of the pharmaceutically active ingredient being released, thereby slowing its rate of release. In this way, it is possible to regulate the release rate and/or initial burst of the device, simply by adjusting the amount of particles/particulate material in the first layer, instead of having to adapt the size of the device to the desired release pattern, which requires expensive changes in production equipment and manufacturing processes. | 1. An intrauterine device comprising at least one first pharmaceutically active ingredient and at least one first layer made of at least a first polymeric material having dispersed therein between 10 and 60 v/v % of at least one particulate material that obstructs the diffusion of the pharmaceutically active ingredient being released, wherein the particulate material is inert, has a mean particle diameter of between 3.6 μm and 100 μm as measured by laser scattering using volumetric measurements based on an approximately spherical particle shape, and has forms a geometric structure wherein molecules of the at least one active ingredient are contained within spaces of the geometric structure between the particulate material. 2. An intrauterine device according to claim 1, wherein the at least one particulate material is an inert inorganic or organic material. 3. An intrauterine device according to claim 1, wherein the at least one particulate material has a mean particle size of no greater than 50 μm; no greater than 30 μm, no greater than 20 μm, or 10 μm. 4. An intrauterine device according to claim 1, wherein the at least one particulate material is selected from the group comprising magnesium stearate, bentonite, talc, clay, calcium stearate, stearic acid, sodium steatyl fumarate and calcium sulphate. 5. An intrauterine device according to claim 1, wherein the at least one particulate Material is talc. 6. An intrauterine device according to claim 1, where the at least one particulate material is surface-treated and/or modified to alter the three-dimensional shape or the hydrophilic/hydrophobic properties of the material. 7. An intrauterine device according to claim 1, wherein the thickness of the at least one first layer is between 0.05 mm and 3 mm, between 0.05 mm and 2 mm, between 0.1 mm and 2 mm or between 0.2 mm and 1 mm. 8. An intrauterine device according to claim 1, wherein an outer layer of the intrauterine device is the at least one first layer. 9. An intrauterine device according to claim 1, wherein the at least one pharmaceutically active ingredient is incorporated/dissolved in at least one second layer which may be made of at least one second polymeric material, and wherein said at least one first layer at least partly encapsulates said second layer. 10. An intrauterine device according to claim 9, wherein said at least one second layer is divided into sections, each of which comprises an individual active ingredient. 11. An intrauterine device according to claim 9, wherein said at least one first layer does not contain any pharmaceutically active ingredient(s). 12. An intrauterine device according to claim 9, which further comprises a central inert core that does not contain any active ingredient, and wherein said at least one second layer at least partly encapsulates the core, and said at least one first layer at least partly encapsulates said second layer. 13. An intrauterine device according to claim 12, wherein the core is made of a thermoplastic polymer, and the first and second polymeric material of the first and second layers respectively, are a thermoset elastomer or silicone. 14. An intrauterine device according to claim 9, wherein the at least first polymeric material of the first and/or second layer, and optionally the core, is at least one inert thermoset or thermoplastic elastomer. 15. An intrauterine device according to claim 14, wherein the thermoset elastomer is a pharmaceutically acceptable silicone or polydimethylsiloxane. 16. An intrauterine device according to claim 1, wherein the at least one active ingredient is at least one contraceptive agent, an estrogenic steroid, or a progestational steroid. 17. An intrauterine device according to claim 1, wherein the at least one active ingredient is at least one spermicide, an antimicrobial agent or an anti-viral agent. 18. An intrauterine device according to claim 1, which is a vaginal ring. 19. A method for reducing the rate of diffusion of an active ingredient though a polymeric material in an intrauterine device, wherein said method comprises incorporating the at least one particulate material into said polymeric material, thus forming the intrauterine device of claim 1. 20. A method of manufacturing an intravaginal ring according to claim 19, wherein the at least one first layer is prepared by injection moulding or by extrusion. | An intrauterine device having at least one first pharmaceutically active ingredient and at least one first layer made of at least a first polymeric material, wherein between about 10 and about 60 v/v % of at least one particulate material is dispersed and/or incorporated in the first polymeric material. The presence of the particulate material will reduce the porosity of the polymer or otherwise obstruct the diffusion of the pharmaceutically active ingredient being released, thereby slowing its rate of release. In this way, it is possible to regulate the release rate and/or initial burst of the device, simply by adjusting the amount of particles/particulate material in the first layer, instead of having to adapt the size of the device to the desired release pattern, which requires expensive changes in production equipment and manufacturing processes.1. An intrauterine device comprising at least one first pharmaceutically active ingredient and at least one first layer made of at least a first polymeric material having dispersed therein between 10 and 60 v/v % of at least one particulate material that obstructs the diffusion of the pharmaceutically active ingredient being released, wherein the particulate material is inert, has a mean particle diameter of between 3.6 μm and 100 μm as measured by laser scattering using volumetric measurements based on an approximately spherical particle shape, and has forms a geometric structure wherein molecules of the at least one active ingredient are contained within spaces of the geometric structure between the particulate material. 2. An intrauterine device according to claim 1, wherein the at least one particulate material is an inert inorganic or organic material. 3. An intrauterine device according to claim 1, wherein the at least one particulate material has a mean particle size of no greater than 50 μm; no greater than 30 μm, no greater than 20 μm, or 10 μm. 4. An intrauterine device according to claim 1, wherein the at least one particulate material is selected from the group comprising magnesium stearate, bentonite, talc, clay, calcium stearate, stearic acid, sodium steatyl fumarate and calcium sulphate. 5. An intrauterine device according to claim 1, wherein the at least one particulate Material is talc. 6. An intrauterine device according to claim 1, where the at least one particulate material is surface-treated and/or modified to alter the three-dimensional shape or the hydrophilic/hydrophobic properties of the material. 7. An intrauterine device according to claim 1, wherein the thickness of the at least one first layer is between 0.05 mm and 3 mm, between 0.05 mm and 2 mm, between 0.1 mm and 2 mm or between 0.2 mm and 1 mm. 8. An intrauterine device according to claim 1, wherein an outer layer of the intrauterine device is the at least one first layer. 9. An intrauterine device according to claim 1, wherein the at least one pharmaceutically active ingredient is incorporated/dissolved in at least one second layer which may be made of at least one second polymeric material, and wherein said at least one first layer at least partly encapsulates said second layer. 10. An intrauterine device according to claim 9, wherein said at least one second layer is divided into sections, each of which comprises an individual active ingredient. 11. An intrauterine device according to claim 9, wherein said at least one first layer does not contain any pharmaceutically active ingredient(s). 12. An intrauterine device according to claim 9, which further comprises a central inert core that does not contain any active ingredient, and wherein said at least one second layer at least partly encapsulates the core, and said at least one first layer at least partly encapsulates said second layer. 13. An intrauterine device according to claim 12, wherein the core is made of a thermoplastic polymer, and the first and second polymeric material of the first and second layers respectively, are a thermoset elastomer or silicone. 14. An intrauterine device according to claim 9, wherein the at least first polymeric material of the first and/or second layer, and optionally the core, is at least one inert thermoset or thermoplastic elastomer. 15. An intrauterine device according to claim 14, wherein the thermoset elastomer is a pharmaceutically acceptable silicone or polydimethylsiloxane. 16. An intrauterine device according to claim 1, wherein the at least one active ingredient is at least one contraceptive agent, an estrogenic steroid, or a progestational steroid. 17. An intrauterine device according to claim 1, wherein the at least one active ingredient is at least one spermicide, an antimicrobial agent or an anti-viral agent. 18. An intrauterine device according to claim 1, which is a vaginal ring. 19. A method for reducing the rate of diffusion of an active ingredient though a polymeric material in an intrauterine device, wherein said method comprises incorporating the at least one particulate material into said polymeric material, thus forming the intrauterine device of claim 1. 20. A method of manufacturing an intravaginal ring according to claim 19, wherein the at least one first layer is prepared by injection moulding or by extrusion. | 1,600 |
1,490 | 15,478,352 | 1,619 | A shampoo composition having from about 0.025% to about 0.25% histidine, by weight of the shampoo composition; from about 2% to about 50% of one or more detersive surfactants, by weight of the shampoo composition; and a gel matrix having from about 0.1% to about 20% of one or more fatty alcohols, by weight of the gel matrix; from about 0.1% to about 10% of one or more gel matrix surfactants, by weight of the gel matrix; and from about 20% to about 95% of an aqueous carrier, by weight of the gel matrix. | 1) A shampoo composition comprising:
a. from about 0.025% to about 0.25% histidine, by weight of the shampoo composition; b. from about 2% to about 50% of one or more detersive surfactants, by weight of the shampoo composition; and c. a gel matrix comprising:
i. from about 0.1% to about 20% of one or more fatty alcohols, by weight of the gel matrix;
ii. from about 0.1% to about 10% of one or more gel matrix surfactants, by weight of the gel matrix; and
iii. from about 20% to about 95% of an aqueous carrier, by weight of the gel matrix;
wherein the shampoo composition inhibits copper deposition on hair and facilitates the removal of copper deposited on hair. 2) The shampoo composition of claim 1, wherein the shampoo composition comprises from about 0.05% to about 0.2% histidine, by weight of the shampoo composition. 3) The shampoo composition of claim 1, wherein the shampoo composition comprises from about 0.1% to about 0.15% histidine, by weight of the shampoo composition. 4) The shampoo composition of claim 1, wherein the aqueous carrier is water. 5) The shampoo composition of claim 1, wherein the shampoo composition further comprises one or more additional benefit agents. 6) The shampoo composition of claim 5, wherein the one or more additional benefit agents is selected from the group consisting of anti-dandruff agents, vitamins, chelants, perfumes, brighteners, enzymes, sensates, attractants, anti-bacterial agents, dyes, pigments, bleaches, and mixtures thereof. 7) The shampoo composition of claim 5, wherein the one or more additional benefit agents is an anti-dandruff agent. 8) The shampoo composition of claim 1, wherein the shampoo composition further comprises citric acid. 9) The shampoo composition of claim 1, wherein the shampoo composition has a pH of from about 5.25 to about 7. 10) A method of inhibiting copper deposition on hair and facilitating the removal of copper deposited on hair comprising:
a. applying to the hair the shampoo composition of claim 1; and b. rinsing the shampoo composition from the hair. | A shampoo composition having from about 0.025% to about 0.25% histidine, by weight of the shampoo composition; from about 2% to about 50% of one or more detersive surfactants, by weight of the shampoo composition; and a gel matrix having from about 0.1% to about 20% of one or more fatty alcohols, by weight of the gel matrix; from about 0.1% to about 10% of one or more gel matrix surfactants, by weight of the gel matrix; and from about 20% to about 95% of an aqueous carrier, by weight of the gel matrix.1) A shampoo composition comprising:
a. from about 0.025% to about 0.25% histidine, by weight of the shampoo composition; b. from about 2% to about 50% of one or more detersive surfactants, by weight of the shampoo composition; and c. a gel matrix comprising:
i. from about 0.1% to about 20% of one or more fatty alcohols, by weight of the gel matrix;
ii. from about 0.1% to about 10% of one or more gel matrix surfactants, by weight of the gel matrix; and
iii. from about 20% to about 95% of an aqueous carrier, by weight of the gel matrix;
wherein the shampoo composition inhibits copper deposition on hair and facilitates the removal of copper deposited on hair. 2) The shampoo composition of claim 1, wherein the shampoo composition comprises from about 0.05% to about 0.2% histidine, by weight of the shampoo composition. 3) The shampoo composition of claim 1, wherein the shampoo composition comprises from about 0.1% to about 0.15% histidine, by weight of the shampoo composition. 4) The shampoo composition of claim 1, wherein the aqueous carrier is water. 5) The shampoo composition of claim 1, wherein the shampoo composition further comprises one or more additional benefit agents. 6) The shampoo composition of claim 5, wherein the one or more additional benefit agents is selected from the group consisting of anti-dandruff agents, vitamins, chelants, perfumes, brighteners, enzymes, sensates, attractants, anti-bacterial agents, dyes, pigments, bleaches, and mixtures thereof. 7) The shampoo composition of claim 5, wherein the one or more additional benefit agents is an anti-dandruff agent. 8) The shampoo composition of claim 1, wherein the shampoo composition further comprises citric acid. 9) The shampoo composition of claim 1, wherein the shampoo composition has a pH of from about 5.25 to about 7. 10) A method of inhibiting copper deposition on hair and facilitating the removal of copper deposited on hair comprising:
a. applying to the hair the shampoo composition of claim 1; and b. rinsing the shampoo composition from the hair. | 1,600 |
1,491 | 13,792,361 | 1,627 | The described invention provides a method for treating a behavioral deficit, such as irritability and stereotypic/repetitive behaviors, in a subject with autism spectrum disorder by administering a composition comprising a therapeutic amount of N-acetylcysteine, a derivative of N-acetylcysteine, or a pharmaceutically acceptable salt of N-acetylcysteine. | 1. A method for treating a behavioral deficit in a subject with autism spectrum disorder characterized by glutamatergic dysfunction and redox imbalance, the method comprising:
(a) administering to the subject a pharmaceutical composition comprising a therapeutic amount of N-acetylcysteine, a derivative of N-acetylcysteine, or a pharmaceutically acceptable salt of N-acetylcysteine, wherein the therapeutic amount is from about 900 mg per day to about 2,700 mg per day, and wherein the therapeutic amount is effective to treat the behavioral deficit in the subject. 2. The method according to claim 1, wherein the behavioral deficit is irritability and stereotypic or repetitive behavior. 3. The method according to claim 1, wherein the autism spectrum disorder comprises autism, Asperger syndrome, or a pervasive developmental disorder. 4. The method according to claim 1, wherein the N-acetylcysteine derivative comprises at least one functional group selected from the group consisting of aliphatic, aromatic, heterocyclic radical, epoxide, and arene oxide. 5. The method according to claim 1, wherein the pharmaceutical composition further comprises a carrier. 6. The method according to claim 1, wherein the pharmaceutical composition is a tablet. 7. The method according to claim 6, wherein the pharmaceutical composition is an effervescent tablet. 8. The method according to claim 6, wherein each dose of the pharmaceutical composition is individually wrapped to avoid oxidation. 9. The method according to claim 1, wherein the composition is administered orally. 10. The method according to claim 1, wherein administering comprises parental, intravenous, intratracheal, intramuscular, or intraperitoneal administration. 11. The method according to claim 1, wherein the patient is administered orally about 900 mg of N-acetylcysteine, the derivative of N-acetylcysteine, or the pharmaceutically acceptable salt of N-acetylcysteine each time, three times a day. 12. The method according to claim 9, wherein the composition is administered 900 mg per day for four weeks. 13. The method according to claim 9, wherein the composition is administered 900 mg twice daily for four weeks. 14. The method according to claim 9, wherein the composition is administered 900 mg three times daily for four weeks. 15. The method according to claim 1, wherein the method further comprises monitoring a behavioral measure of the subject at a plurality of time points during treatment, relative to the measure of the behavior of the subject prior to treatment, wherein the behavioral measure comprises a primary behavioral outcome measure and a secondary behavioral outcome measure. 16. The method according to claim 15, wherein the primary behavioral outcome measure comprises an Aberrant Behavior Checklist (ABC) irritability subscale, a Dosage Record and Treatment Emergent Symptom Scale (DOTES), or a combination thereof. 17. The method according to claim 15, wherein the secondary behavioral outcome measure comprises Clinical Global Impression (CGI), ABC-Stereotypy subscale, Repetitive Behavior Scale (RBS), Social responsiveness scale (SRS), or a combination thereof. 18. The method according to claim 15, wherein the behavioral measure is assessed before treatment, at 4 weeks, at 8 weeks, or at 12 weeks. 19. The method according to claim 1, wherein the pharmaceutical composition comprises at least one additional therapeutic agent. 20. The method according to claim 19, wherein the at least one additional therapeutic agent is selected from the group consisting of an antipsychotic agent, an antibiotic agent, an antiviral agent, an anti-inflammatory agent, an antipyretic agent, an analgesic agent, and an anti-proliferative agent. 21. The method according to claim 19, wherein the at least one additional therapeutic agent is capable of depleting glutathione (GSH) levels in the subject. 22. The method according to claim 1, wherein at least one additional therapeutic agent is administered before the administration of the pharmaceutical composition. 23. The method according to claim 22, wherein the at least one additional therapeutic agent is selected from the group consisting of an antipsychotic agent, an antibiotic agent, an antiviral agent, an anti-inflammatory agent, an antipyretic agent, an analgesic agent, and an anti-proliferative agent. 24. The method according to claim 22, wherein the at least one additional therapeutic agent is capable of depleting glutathione (GSH) levels in the subject. 25. The method according to claim 1, wherein at least one additional therapeutic agent is administered after the administration of the pharmaceutical composition. 26. The method according to claim 25, wherein the at least one additional therapeutic agent is selected from the group consisting of an antipsychotic agent, an antibiotic agent, an antiviral agent, an anti-inflammatory agent, an antipyretic agent, an analgesic agent, and an anti-proliferative agent. 27. The method according to claim 25, wherein the at least one additional therapeutic agent is capable of depleting glutathione (GSH) levels in the subject. | The described invention provides a method for treating a behavioral deficit, such as irritability and stereotypic/repetitive behaviors, in a subject with autism spectrum disorder by administering a composition comprising a therapeutic amount of N-acetylcysteine, a derivative of N-acetylcysteine, or a pharmaceutically acceptable salt of N-acetylcysteine.1. A method for treating a behavioral deficit in a subject with autism spectrum disorder characterized by glutamatergic dysfunction and redox imbalance, the method comprising:
(a) administering to the subject a pharmaceutical composition comprising a therapeutic amount of N-acetylcysteine, a derivative of N-acetylcysteine, or a pharmaceutically acceptable salt of N-acetylcysteine, wherein the therapeutic amount is from about 900 mg per day to about 2,700 mg per day, and wherein the therapeutic amount is effective to treat the behavioral deficit in the subject. 2. The method according to claim 1, wherein the behavioral deficit is irritability and stereotypic or repetitive behavior. 3. The method according to claim 1, wherein the autism spectrum disorder comprises autism, Asperger syndrome, or a pervasive developmental disorder. 4. The method according to claim 1, wherein the N-acetylcysteine derivative comprises at least one functional group selected from the group consisting of aliphatic, aromatic, heterocyclic radical, epoxide, and arene oxide. 5. The method according to claim 1, wherein the pharmaceutical composition further comprises a carrier. 6. The method according to claim 1, wherein the pharmaceutical composition is a tablet. 7. The method according to claim 6, wherein the pharmaceutical composition is an effervescent tablet. 8. The method according to claim 6, wherein each dose of the pharmaceutical composition is individually wrapped to avoid oxidation. 9. The method according to claim 1, wherein the composition is administered orally. 10. The method according to claim 1, wherein administering comprises parental, intravenous, intratracheal, intramuscular, or intraperitoneal administration. 11. The method according to claim 1, wherein the patient is administered orally about 900 mg of N-acetylcysteine, the derivative of N-acetylcysteine, or the pharmaceutically acceptable salt of N-acetylcysteine each time, three times a day. 12. The method according to claim 9, wherein the composition is administered 900 mg per day for four weeks. 13. The method according to claim 9, wherein the composition is administered 900 mg twice daily for four weeks. 14. The method according to claim 9, wherein the composition is administered 900 mg three times daily for four weeks. 15. The method according to claim 1, wherein the method further comprises monitoring a behavioral measure of the subject at a plurality of time points during treatment, relative to the measure of the behavior of the subject prior to treatment, wherein the behavioral measure comprises a primary behavioral outcome measure and a secondary behavioral outcome measure. 16. The method according to claim 15, wherein the primary behavioral outcome measure comprises an Aberrant Behavior Checklist (ABC) irritability subscale, a Dosage Record and Treatment Emergent Symptom Scale (DOTES), or a combination thereof. 17. The method according to claim 15, wherein the secondary behavioral outcome measure comprises Clinical Global Impression (CGI), ABC-Stereotypy subscale, Repetitive Behavior Scale (RBS), Social responsiveness scale (SRS), or a combination thereof. 18. The method according to claim 15, wherein the behavioral measure is assessed before treatment, at 4 weeks, at 8 weeks, or at 12 weeks. 19. The method according to claim 1, wherein the pharmaceutical composition comprises at least one additional therapeutic agent. 20. The method according to claim 19, wherein the at least one additional therapeutic agent is selected from the group consisting of an antipsychotic agent, an antibiotic agent, an antiviral agent, an anti-inflammatory agent, an antipyretic agent, an analgesic agent, and an anti-proliferative agent. 21. The method according to claim 19, wherein the at least one additional therapeutic agent is capable of depleting glutathione (GSH) levels in the subject. 22. The method according to claim 1, wherein at least one additional therapeutic agent is administered before the administration of the pharmaceutical composition. 23. The method according to claim 22, wherein the at least one additional therapeutic agent is selected from the group consisting of an antipsychotic agent, an antibiotic agent, an antiviral agent, an anti-inflammatory agent, an antipyretic agent, an analgesic agent, and an anti-proliferative agent. 24. The method according to claim 22, wherein the at least one additional therapeutic agent is capable of depleting glutathione (GSH) levels in the subject. 25. The method according to claim 1, wherein at least one additional therapeutic agent is administered after the administration of the pharmaceutical composition. 26. The method according to claim 25, wherein the at least one additional therapeutic agent is selected from the group consisting of an antipsychotic agent, an antibiotic agent, an antiviral agent, an anti-inflammatory agent, an antipyretic agent, an analgesic agent, and an anti-proliferative agent. 27. The method according to claim 25, wherein the at least one additional therapeutic agent is capable of depleting glutathione (GSH) levels in the subject. | 1,600 |
1,492 | 16,368,907 | 1,627 | Methods of treating eye disorders with (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid are provided. Methods of treating eye disorders with (1S,3S)-3-amino-4-(difluoromethylidene) cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof are provided. Also provided are therapeutic compositions that may be used to improve one or more symptoms of eye disorders. | 1. A method of treating an eye disorder comprising administering to a patient in need thereof (1 S,3 S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof in an amount of from 0.01 mg to 500 mg, wherein the method provides improvement in one or more symptoms of eye disorder in the patient. 2. The method of claim 1, wherein the improvement is provided for more than 6 hours after administration. 3. The method of claim 1, wherein the patient is administered a composition comprising about 1 mg to 100 mg of (1S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof. 4. The method of claim 1, wherein the total amount of (1S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject in a twenty-four hour period is between 1 mg and 500 mg. 5. The method of claim 1, wherein (1S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered from one to four times a day. 6. The method of claim 1, wherein administering is accomplished via a route selected from the group consisting of oral, buccal, sublingual, rectal, topical, intranasal, ophthalmic, vaginal and parenteral. 7. The method of claim 1, wherein the eye disorder is Stargardt disease, age-related macular degeneration, juvenile macular degeneration, retinal degeneration, glaucoma, retinal dystrophy, Doyne honeycomb retinal dystrophy, light induced retinal damage, uveitis, scleritis, ocular sarcoidosis, optic neuritis, cone-rod dystrophy, macular edema, diabetic retinopathy, diabetic macular edema, corneal ulcer, an autoimmune disorder, ophthalmic manifestations of AIDS, optic nerve degeneration, geographic atrophy, choroidal dystrophy, retinitis, CMV retinitis, reticular pseudodrusen, eye floaters, eye flashes, keratoconus, ocular hypertension, presbyopia, dry eyes, Bietti's Crystalline Dystrophy, retinoblastoma, Usher syndrome, Behçet's disease, Achromatopsia 2, acute posterior multifocal placoid pigment epitheliopathy, acute zonal occult outer retinopathy, adult-onset vitelliform macular dystrophy, ocular albinism with late-onset sensorineural deafness, Alström syndrome, anterior ischemic optic neuropathy, corneal amyloidosis, gelatinous drop-like corneal dystrophy, Axenfeld-Rieger syndrome, Bardet-Biedl syndrome, Behr syndrome, Best disease aka vitelliform macular dystrophy, Bietti crystalline corneoretinal dystrophy, birdshot chorioretinopathy, blue cone monochromatism, central areolar choroidal dystrophy, choroideremia, Coats disease, iridocorneal endothelial syndrome, Avellino type corneal dystrophy, Schnyder corneal dystrophy, Thiel-Behnke corneal dystrophy, Eales disease, epithelial basement membrane corneal dystrophy, Fish-eye disease, Fuchs endothelial corneal dystrophy, Goldmann-Favre syndrome, juvenile retinoschisis, late-onset retinal degeneration, Leber congenital amaurosis, retinitis pigmentosa, Peters anomaly, punctate inner choroidopathy, Senior Loken syndrome, snowflake vitreoretinal degeneration, Usher syndrome, visual snow syndrome, or Wagner syndrome. 8. The method of claim 1, wherein the method provides improvement in at least one symptom selected from the group consisting vision loss, drusen amount, pigment changes in the retina, abnormal blood vessel growth, leaky blood vessels, macular swelling, corneal swelling, corneal thinning, accumulation of lipofuscin, night blindness, distorted vision, blurry vision, rod damage, cone damage, uvea inflammation, eye redness, pain, sensitivity to light (photophobia), floaters, eye flashes, nodules, orbital inflammation, lacrimal gland enlargement, decreased visual acuity, decrease in contrast sensitivity, blind spots, loss of color perception, loss of peripheral vision, fluid build-up in the macula, retinal scarring, double vision, pigment clumps, tunnel vision, thin cornea, spotting, leukocoria, lesions, crystals, and nystagmus. 9. A method of treating an eye disorder comprising administering to a subject with an eye disorder (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof in an amount of from 0.01 mg to 75 mg. 10. The method of claim 9, wherein the subject is administered from 0.1 mg to 50 mg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. 11. The method of claim 9, wherein the total amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject in a twenty-four hour period is between 1 mg and 10 mg. 12. The method of claim 9, wherein (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered from one to four times a day. 13. The method of claim 9, wherein administering is accomplished via a route selected from the group consisting of oral, buccal, sublingual, rectal, topical, intranasal, ophthalmic, vaginal and parenteral. 14. The method of claim 9 wherein the eye disorder is Stargardt disease, age-related macular degeneration, juvenile macular degeneration, retinal degeneration, glaucoma, retinal dystrophy, Doyne honeycomb retinal dystrophy, light induced retinal damage, uveitis, scleritis, ocular sarcoidosis, optic neuritis, cone-rod dystrophy, macular edema, diabetic retinopathy, diabetic macular edema, corneal ulcer, an autoimmune disorder, ophthalmic manifestations of AIDS, optic nerve degeneration, geographic atrophy, choroidal dystrophy, retinitis, CMV retinitis, reticular pseudodrusen, eye floaters, eye flashes, keratoconus, ocular hypertension, presbyopia, dry eyes, Bietti's Crystalline Dystrophy, retinoblastoma, Usher syndrome, Behçet's disease, Achromatopsia 2, acute posterior multifocal placoid pigment epitheliopathy, acute zonal occult outer retinopathy, adult-onset vitelliform macular dystrophy, ocular albinism with late-onset sensorineural deafness, Alström syndrome, anterior ischemic optic neuropathy, corneal amyloidosis, gelatinous drop-like corneal dystrophy, Axenfeld-Rieger syndrome, Bardet-Biedl syndrome, Behr syndrome, Best disease aka vitelliform macular dystrophy, Bietti crystalline corneoretinal dystrophy, birdshot chorioretinopathy, blue cone monochromatism, central areolar choroidal dystrophy, iridocorneal endothelial syndrome, Avellino type corneal dystrophy, Schnyder corneal dystrophy, Thiel-Behnke corneal dystrophy, Eales disease, epithelial basement membrane corneal dystrophy, Fish-eye disease, Fuchs endothelial corneal dystrophy, Goldmann-Favre syndrome, juvenile retinoschisis, late-onset retinal degeneration, Leber congenital amaurosis, retinitis pigmentosa, Peters anomaly, punctate inner choroidopathy, Senior Loken syndrome, snowflake vitreoretinal degeneration, Usher syndrome, visual snow syndrome, or Wagner syndrome. 15. The method of claim 9, wherein the method provides improvement in at least one symptom selected from the group consisting of vision loss, drusen amount, pigment changes in the retina, abnormal blood vessel growth, leaky blood vessels, macular swelling, corneal swelling, corneal thinning, accumulation of lipofuscin, night blindness, distorted vision, blurry vision, rod damage, cone damage, uvea inflammation, eye redness, pain, sensitivity to light (photophobia), floaters, eye flashes, nodules, orbital inflammation, lacrimal gland enlargement, decreased visual acuity, decrease in contrast sensitivity, blind spots, loss of color perception, loss of peripheral vision, fluid build-up in the macula, retinal scarring, double vision, pigment clumps, tunnel vision, thin cornea, spotting, leukocoria, lesions, crystals, and nystagmus. 16. A method of treating Stargardt disease comprising administering to a patient in need thereof (1 S,3 S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof in an amount of from 0.01 mg to 500 mg, wherein the method provides improvement in one or more symptoms of Stargardt disease in the patient. 17. The method of claim 16, wherein the improvement is provided for more than 6 hours after administration. 18. The method of claim 16, wherein the patient is administered a composition comprising about 1 mg to 100 mg of (1S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof. 19. The method of claim 16, wherein the total amount of (1S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject in a twenty-four hour period is between 1 mg and 500 mg. 20. The method of claim 16, wherein (1S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered from one to four times a day. 21. The method of claim 16, wherein administering is accomplished via a route selected from the group consisting of oral, buccal, sublingual, rectal, topical, intranasal, ophthalmic, vaginal and parenteral. 22. The method of claim 16, wherein the method provides improvement in at least one symptom selected from the group consisting of macular degeneration, vision loss, accumulation of lipofuscin in the macula, night blindness, and loss of color vision. 23. A method of treating Stargardt disease comprising administering to a patient in need thereof (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof in an amount of from 0.01 mg to 500 mg, wherein the method provides improvement in one or more symptoms of Stargardt disease in the patient. 24. The method of claim 23, wherein the improvement is provided for more than 6 hours after administration. 25. The method of claim 23, wherein the patient is administered a composition comprising about 0.01 mg to 50 mg of (1 S,3 S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof. 26. The method of claim 23, wherein the total amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject in a twenty-four hour period is between 1 mg and 500 mg. 27. The method of claim 23, wherein (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered from one to four times a day. 28. The method of claim 23, wherein administering is accomplished via a route selected from the group consisting of oral, buccal, sublingual, rectal, topical, intranasal, ophthalmic, vaginal and parenteral. 29. The method of claim 23, wherein the method provides improvement in at least one symptom selected from the group consisting of macular degeneration, vision loss, accumulation of lipofuscin in the macula, night blindness, and loss of color vision. | Methods of treating eye disorders with (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid are provided. Methods of treating eye disorders with (1S,3S)-3-amino-4-(difluoromethylidene) cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof are provided. Also provided are therapeutic compositions that may be used to improve one or more symptoms of eye disorders.1. A method of treating an eye disorder comprising administering to a patient in need thereof (1 S,3 S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof in an amount of from 0.01 mg to 500 mg, wherein the method provides improvement in one or more symptoms of eye disorder in the patient. 2. The method of claim 1, wherein the improvement is provided for more than 6 hours after administration. 3. The method of claim 1, wherein the patient is administered a composition comprising about 1 mg to 100 mg of (1S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof. 4. The method of claim 1, wherein the total amount of (1S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject in a twenty-four hour period is between 1 mg and 500 mg. 5. The method of claim 1, wherein (1S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered from one to four times a day. 6. The method of claim 1, wherein administering is accomplished via a route selected from the group consisting of oral, buccal, sublingual, rectal, topical, intranasal, ophthalmic, vaginal and parenteral. 7. The method of claim 1, wherein the eye disorder is Stargardt disease, age-related macular degeneration, juvenile macular degeneration, retinal degeneration, glaucoma, retinal dystrophy, Doyne honeycomb retinal dystrophy, light induced retinal damage, uveitis, scleritis, ocular sarcoidosis, optic neuritis, cone-rod dystrophy, macular edema, diabetic retinopathy, diabetic macular edema, corneal ulcer, an autoimmune disorder, ophthalmic manifestations of AIDS, optic nerve degeneration, geographic atrophy, choroidal dystrophy, retinitis, CMV retinitis, reticular pseudodrusen, eye floaters, eye flashes, keratoconus, ocular hypertension, presbyopia, dry eyes, Bietti's Crystalline Dystrophy, retinoblastoma, Usher syndrome, Behçet's disease, Achromatopsia 2, acute posterior multifocal placoid pigment epitheliopathy, acute zonal occult outer retinopathy, adult-onset vitelliform macular dystrophy, ocular albinism with late-onset sensorineural deafness, Alström syndrome, anterior ischemic optic neuropathy, corneal amyloidosis, gelatinous drop-like corneal dystrophy, Axenfeld-Rieger syndrome, Bardet-Biedl syndrome, Behr syndrome, Best disease aka vitelliform macular dystrophy, Bietti crystalline corneoretinal dystrophy, birdshot chorioretinopathy, blue cone monochromatism, central areolar choroidal dystrophy, choroideremia, Coats disease, iridocorneal endothelial syndrome, Avellino type corneal dystrophy, Schnyder corneal dystrophy, Thiel-Behnke corneal dystrophy, Eales disease, epithelial basement membrane corneal dystrophy, Fish-eye disease, Fuchs endothelial corneal dystrophy, Goldmann-Favre syndrome, juvenile retinoschisis, late-onset retinal degeneration, Leber congenital amaurosis, retinitis pigmentosa, Peters anomaly, punctate inner choroidopathy, Senior Loken syndrome, snowflake vitreoretinal degeneration, Usher syndrome, visual snow syndrome, or Wagner syndrome. 8. The method of claim 1, wherein the method provides improvement in at least one symptom selected from the group consisting vision loss, drusen amount, pigment changes in the retina, abnormal blood vessel growth, leaky blood vessels, macular swelling, corneal swelling, corneal thinning, accumulation of lipofuscin, night blindness, distorted vision, blurry vision, rod damage, cone damage, uvea inflammation, eye redness, pain, sensitivity to light (photophobia), floaters, eye flashes, nodules, orbital inflammation, lacrimal gland enlargement, decreased visual acuity, decrease in contrast sensitivity, blind spots, loss of color perception, loss of peripheral vision, fluid build-up in the macula, retinal scarring, double vision, pigment clumps, tunnel vision, thin cornea, spotting, leukocoria, lesions, crystals, and nystagmus. 9. A method of treating an eye disorder comprising administering to a subject with an eye disorder (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof in an amount of from 0.01 mg to 75 mg. 10. The method of claim 9, wherein the subject is administered from 0.1 mg to 50 mg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. 11. The method of claim 9, wherein the total amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject in a twenty-four hour period is between 1 mg and 10 mg. 12. The method of claim 9, wherein (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered from one to four times a day. 13. The method of claim 9, wherein administering is accomplished via a route selected from the group consisting of oral, buccal, sublingual, rectal, topical, intranasal, ophthalmic, vaginal and parenteral. 14. The method of claim 9 wherein the eye disorder is Stargardt disease, age-related macular degeneration, juvenile macular degeneration, retinal degeneration, glaucoma, retinal dystrophy, Doyne honeycomb retinal dystrophy, light induced retinal damage, uveitis, scleritis, ocular sarcoidosis, optic neuritis, cone-rod dystrophy, macular edema, diabetic retinopathy, diabetic macular edema, corneal ulcer, an autoimmune disorder, ophthalmic manifestations of AIDS, optic nerve degeneration, geographic atrophy, choroidal dystrophy, retinitis, CMV retinitis, reticular pseudodrusen, eye floaters, eye flashes, keratoconus, ocular hypertension, presbyopia, dry eyes, Bietti's Crystalline Dystrophy, retinoblastoma, Usher syndrome, Behçet's disease, Achromatopsia 2, acute posterior multifocal placoid pigment epitheliopathy, acute zonal occult outer retinopathy, adult-onset vitelliform macular dystrophy, ocular albinism with late-onset sensorineural deafness, Alström syndrome, anterior ischemic optic neuropathy, corneal amyloidosis, gelatinous drop-like corneal dystrophy, Axenfeld-Rieger syndrome, Bardet-Biedl syndrome, Behr syndrome, Best disease aka vitelliform macular dystrophy, Bietti crystalline corneoretinal dystrophy, birdshot chorioretinopathy, blue cone monochromatism, central areolar choroidal dystrophy, iridocorneal endothelial syndrome, Avellino type corneal dystrophy, Schnyder corneal dystrophy, Thiel-Behnke corneal dystrophy, Eales disease, epithelial basement membrane corneal dystrophy, Fish-eye disease, Fuchs endothelial corneal dystrophy, Goldmann-Favre syndrome, juvenile retinoschisis, late-onset retinal degeneration, Leber congenital amaurosis, retinitis pigmentosa, Peters anomaly, punctate inner choroidopathy, Senior Loken syndrome, snowflake vitreoretinal degeneration, Usher syndrome, visual snow syndrome, or Wagner syndrome. 15. The method of claim 9, wherein the method provides improvement in at least one symptom selected from the group consisting of vision loss, drusen amount, pigment changes in the retina, abnormal blood vessel growth, leaky blood vessels, macular swelling, corneal swelling, corneal thinning, accumulation of lipofuscin, night blindness, distorted vision, blurry vision, rod damage, cone damage, uvea inflammation, eye redness, pain, sensitivity to light (photophobia), floaters, eye flashes, nodules, orbital inflammation, lacrimal gland enlargement, decreased visual acuity, decrease in contrast sensitivity, blind spots, loss of color perception, loss of peripheral vision, fluid build-up in the macula, retinal scarring, double vision, pigment clumps, tunnel vision, thin cornea, spotting, leukocoria, lesions, crystals, and nystagmus. 16. A method of treating Stargardt disease comprising administering to a patient in need thereof (1 S,3 S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof in an amount of from 0.01 mg to 500 mg, wherein the method provides improvement in one or more symptoms of Stargardt disease in the patient. 17. The method of claim 16, wherein the improvement is provided for more than 6 hours after administration. 18. The method of claim 16, wherein the patient is administered a composition comprising about 1 mg to 100 mg of (1S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof. 19. The method of claim 16, wherein the total amount of (1S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject in a twenty-four hour period is between 1 mg and 500 mg. 20. The method of claim 16, wherein (1S,3S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered from one to four times a day. 21. The method of claim 16, wherein administering is accomplished via a route selected from the group consisting of oral, buccal, sublingual, rectal, topical, intranasal, ophthalmic, vaginal and parenteral. 22. The method of claim 16, wherein the method provides improvement in at least one symptom selected from the group consisting of macular degeneration, vision loss, accumulation of lipofuscin in the macula, night blindness, and loss of color vision. 23. A method of treating Stargardt disease comprising administering to a patient in need thereof (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof in an amount of from 0.01 mg to 500 mg, wherein the method provides improvement in one or more symptoms of Stargardt disease in the patient. 24. The method of claim 23, wherein the improvement is provided for more than 6 hours after administration. 25. The method of claim 23, wherein the patient is administered a composition comprising about 0.01 mg to 50 mg of (1 S,3 S)-3-amino-4-(difluoromethylidene)cyclopentane-1-carboxylic acid or a pharmaceutically acceptable salt thereof. 26. The method of claim 23, wherein the total amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject in a twenty-four hour period is between 1 mg and 500 mg. 27. The method of claim 23, wherein (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered from one to four times a day. 28. The method of claim 23, wherein administering is accomplished via a route selected from the group consisting of oral, buccal, sublingual, rectal, topical, intranasal, ophthalmic, vaginal and parenteral. 29. The method of claim 23, wherein the method provides improvement in at least one symptom selected from the group consisting of macular degeneration, vision loss, accumulation of lipofuscin in the macula, night blindness, and loss of color vision. | 1,600 |
1,493 | 14,483,483 | 1,743 | A non-pneumatic tire includes a plurality of springs. Each spring comprises a first end portion, a second end portion, and an arching middle portion. Each spring is interwoven with at least one other spring thereby forming a toroidal structure extending about an entire circumference of the non-pneumatic tire. The toroidal structure is at least partially coated with an elastomer. | 1. A method for constructing a non-pneumatic tire comprises the steps of:
sliding a carcass ply structure into engagement with a bladder; seating a first circular bead of the carcass ply structure onto a mold; partially inflating the bladder to form a bulged carcass ply structure; pouring an elastomer into the mold; seating a second circular bead of the carcass ply structure onto a mold cap; closing the mold with the mold cap for enclosing the elastomer; fully inflating the bladder for facilitating engagement of the elastomer with the carcass ply structure; curing the elastomer; and removing the combined carcass ply structure/elastomer which now defines the non-pneumatic tire. 2. The method as set forth in claim 1 wherein the carcass ply structure comprises a plurality of springs, each spring extending from the first circular bead to the second circular bead. 3. The method as set forth in claim 2 wherein each spring comprises a first end portion, a second end portion, and an arching middle portion interconnecting the first end portion and the second end portion. 4. The method as set forth in claim 2 wherein each spring is interwoven with an adjacent spring on a first side of the spring and further is interwoven with an adjacent spring on a second opposite side of the spring thereby forming a toroidal carcass ply structure extending about an entire circumference of the non-pneumatic tire. 5. The method as set forth in claim 1 wherein the elastomer is urethane. 6. The method as set forth in claim 1 further including the step of relocating the self-contained mold/mold cap subsequent to said closing step. 7-20. (canceled) | A non-pneumatic tire includes a plurality of springs. Each spring comprises a first end portion, a second end portion, and an arching middle portion. Each spring is interwoven with at least one other spring thereby forming a toroidal structure extending about an entire circumference of the non-pneumatic tire. The toroidal structure is at least partially coated with an elastomer.1. A method for constructing a non-pneumatic tire comprises the steps of:
sliding a carcass ply structure into engagement with a bladder; seating a first circular bead of the carcass ply structure onto a mold; partially inflating the bladder to form a bulged carcass ply structure; pouring an elastomer into the mold; seating a second circular bead of the carcass ply structure onto a mold cap; closing the mold with the mold cap for enclosing the elastomer; fully inflating the bladder for facilitating engagement of the elastomer with the carcass ply structure; curing the elastomer; and removing the combined carcass ply structure/elastomer which now defines the non-pneumatic tire. 2. The method as set forth in claim 1 wherein the carcass ply structure comprises a plurality of springs, each spring extending from the first circular bead to the second circular bead. 3. The method as set forth in claim 2 wherein each spring comprises a first end portion, a second end portion, and an arching middle portion interconnecting the first end portion and the second end portion. 4. The method as set forth in claim 2 wherein each spring is interwoven with an adjacent spring on a first side of the spring and further is interwoven with an adjacent spring on a second opposite side of the spring thereby forming a toroidal carcass ply structure extending about an entire circumference of the non-pneumatic tire. 5. The method as set forth in claim 1 wherein the elastomer is urethane. 6. The method as set forth in claim 1 further including the step of relocating the self-contained mold/mold cap subsequent to said closing step. 7-20. (canceled) | 1,700 |
1,494 | 14,665,835 | 1,799 | The invention relates mainly to an apparatus comprising a chamber for physically and/or chemically treating one or more samples or products, said apparatus comprising a door for introducing samples inside the apparatus chamber or bringing samples outside the apparatus, said apparatus comprising a membrane or film defining a chamber wall inside said apparatus when the door is closed. | 1.-15. (canceled) 16. An apparatus comprising:
a disinfector including a chamber for receiving one or more samples or products and a door adapted for moving between a closed position and an open position for introducing the one or more samples or products inside the chamber or bringing the one or more samples or products outside the chamber; a membrane or film for isolating the chamber from the outside atmosphere, said membrane or film defining a chamber wall inside said apparatus when the door is in the closed position, said membrane or film including a sealable passage for passing the one or more samples or products through the membrane or film into the chamber. 17. The apparatus of claim 16, wherein said membrane or film comprises a joint or seal for sealing the membrane or film along a periphery of the chamber. 18. The apparatus of claim 17, further comprising a channel along the periphery for receiving the joint or seal. 19. The apparatus of claim 17, wherein said joint or seal is inserted within a fold of the membrane or film. 20. The apparatus of claim 16, wherein said membrane or film is made of a material selected from the group consisting of a polymer selected from the group of a thermoplastic, a polyethylene (PE), a polypropylene (PP), a polyaryletherketone, a PEEK (Poly(ether ether ketone), in particular poly(oxy-1,4-phenylene- oxy-1,4-phenylene-carbonyl-1,4-phenylene); a polytetrafluoroethylene (PTFE); a perfluoroalkoxy (PFA) polymer; a poly(tetrafluoroethylene-co-perfluoromethyl vinyl ether) (MFA); a polyperfluoro(ethylene-co-propylene) (FEP); a poly(ethylene-alt-chlorotrifluoroethylene) (ECTFE); a poly(ethylene-co-tetrafluoroethylene) (ETFE); a poly(vinylidene fluoride) (PDVF); a tetrafluoroethylene-co-hexafluoropropylene-co-vinylidene fluoride terpolymer (THV); a poly(bisphenol A-co-4-nitrophthalic anhydride-co-1,3-phenylenediamine) (PEI); a poly(4-methyl-1-pentene) (PMP); and suitable mixtures thereof. 21. The apparatus of claim 16, wherein said membrane or film comprises a proximal end and a distal end, said proximal end comprising an to the passage and_said distal end defining a section essentially complementary to a periphery of said chamber, said distal end of said membrane or film comprising a fold in which an inflatable seal is inserted, said fold being inserted in a channel extending along the periphery of the chamber to isolate a chamber inner part from a chamber outer part. 22. The apparatus of claim 16, wherein a closure is provided for closing the passage through the membrane or film into the chamber, and wherein said closure in an open position allows the passage of the one or more samples or products. 23. The apparatus of claim 16, wherein said film or membrane comprises one or more gloves for manipulating the one or more samples or products inside said chamber. 24. The apparatus of claim 16, wherein the disinfector is selected from the group consisting of comprises an oven, a drying equipment, a dryer, a freeze-dryer, an autoclave, a sterilizer, a gas chamber, and a depyrogenation apparatus. 25. The apparatus of claim 16, wherein the disinfector comprises an oven. 26. An apparatus comprising:
a housing including a chamber for receiving one or more samples or products, said chamber surrounded by a periphery; and a membrane or film forming a chamber wall inside said housing for isolating the chamber from the outside atmosphere, said membrane or film further comprising a joint or seal for sealing the membrane or film about the periphery of the chamber and a sealable passage for passing the one or more samples or products though the membrane or film into the chamber. 27. The apparatus of claim 26, wherein the housing forms part of a device selected from the group consisting of an oven, a drying equipment, a dryer, a freeze-dryer, an autoclave, a sterilizer, a gas chamber, and a depyrogenation apparatus. 28. The apparatus of claim 26, wherein the passage comprises a tubular structure extending in a direction opposite the chamber for passing the one or more samples of products to or from the chamber, and further including a closure for closing the passage. 29. The apparatus of claim 26, wherein the housing includes a door adapted for being opened and closed, and wherein at least part of the membrane or film is sandwiched between the door and the periphery of the chamber when the door is closed. 30. An apparatus comprising:
an oven including a chamber for receiving one or more samples or products, said chamber surrounded by a periphery; and a membrane or film forming a chamber wall inside said housing for isolating the chamber from the outside atmosphere, said membrane or film further comprising a joint or seal for sealing the membrane or film about the periphery of the chamber and a sealable passage for passing the one or more samples or products though the membrane or film into the chamber. | The invention relates mainly to an apparatus comprising a chamber for physically and/or chemically treating one or more samples or products, said apparatus comprising a door for introducing samples inside the apparatus chamber or bringing samples outside the apparatus, said apparatus comprising a membrane or film defining a chamber wall inside said apparatus when the door is closed.1.-15. (canceled) 16. An apparatus comprising:
a disinfector including a chamber for receiving one or more samples or products and a door adapted for moving between a closed position and an open position for introducing the one or more samples or products inside the chamber or bringing the one or more samples or products outside the chamber; a membrane or film for isolating the chamber from the outside atmosphere, said membrane or film defining a chamber wall inside said apparatus when the door is in the closed position, said membrane or film including a sealable passage for passing the one or more samples or products through the membrane or film into the chamber. 17. The apparatus of claim 16, wherein said membrane or film comprises a joint or seal for sealing the membrane or film along a periphery of the chamber. 18. The apparatus of claim 17, further comprising a channel along the periphery for receiving the joint or seal. 19. The apparatus of claim 17, wherein said joint or seal is inserted within a fold of the membrane or film. 20. The apparatus of claim 16, wherein said membrane or film is made of a material selected from the group consisting of a polymer selected from the group of a thermoplastic, a polyethylene (PE), a polypropylene (PP), a polyaryletherketone, a PEEK (Poly(ether ether ketone), in particular poly(oxy-1,4-phenylene- oxy-1,4-phenylene-carbonyl-1,4-phenylene); a polytetrafluoroethylene (PTFE); a perfluoroalkoxy (PFA) polymer; a poly(tetrafluoroethylene-co-perfluoromethyl vinyl ether) (MFA); a polyperfluoro(ethylene-co-propylene) (FEP); a poly(ethylene-alt-chlorotrifluoroethylene) (ECTFE); a poly(ethylene-co-tetrafluoroethylene) (ETFE); a poly(vinylidene fluoride) (PDVF); a tetrafluoroethylene-co-hexafluoropropylene-co-vinylidene fluoride terpolymer (THV); a poly(bisphenol A-co-4-nitrophthalic anhydride-co-1,3-phenylenediamine) (PEI); a poly(4-methyl-1-pentene) (PMP); and suitable mixtures thereof. 21. The apparatus of claim 16, wherein said membrane or film comprises a proximal end and a distal end, said proximal end comprising an to the passage and_said distal end defining a section essentially complementary to a periphery of said chamber, said distal end of said membrane or film comprising a fold in which an inflatable seal is inserted, said fold being inserted in a channel extending along the periphery of the chamber to isolate a chamber inner part from a chamber outer part. 22. The apparatus of claim 16, wherein a closure is provided for closing the passage through the membrane or film into the chamber, and wherein said closure in an open position allows the passage of the one or more samples or products. 23. The apparatus of claim 16, wherein said film or membrane comprises one or more gloves for manipulating the one or more samples or products inside said chamber. 24. The apparatus of claim 16, wherein the disinfector is selected from the group consisting of comprises an oven, a drying equipment, a dryer, a freeze-dryer, an autoclave, a sterilizer, a gas chamber, and a depyrogenation apparatus. 25. The apparatus of claim 16, wherein the disinfector comprises an oven. 26. An apparatus comprising:
a housing including a chamber for receiving one or more samples or products, said chamber surrounded by a periphery; and a membrane or film forming a chamber wall inside said housing for isolating the chamber from the outside atmosphere, said membrane or film further comprising a joint or seal for sealing the membrane or film about the periphery of the chamber and a sealable passage for passing the one or more samples or products though the membrane or film into the chamber. 27. The apparatus of claim 26, wherein the housing forms part of a device selected from the group consisting of an oven, a drying equipment, a dryer, a freeze-dryer, an autoclave, a sterilizer, a gas chamber, and a depyrogenation apparatus. 28. The apparatus of claim 26, wherein the passage comprises a tubular structure extending in a direction opposite the chamber for passing the one or more samples of products to or from the chamber, and further including a closure for closing the passage. 29. The apparatus of claim 26, wherein the housing includes a door adapted for being opened and closed, and wherein at least part of the membrane or film is sandwiched between the door and the periphery of the chamber when the door is closed. 30. An apparatus comprising:
an oven including a chamber for receiving one or more samples or products, said chamber surrounded by a periphery; and a membrane or film forming a chamber wall inside said housing for isolating the chamber from the outside atmosphere, said membrane or film further comprising a joint or seal for sealing the membrane or film about the periphery of the chamber and a sealable passage for passing the one or more samples or products though the membrane or film into the chamber. | 1,700 |
1,495 | 14,075,555 | 1,735 | A blade for a gas turbine has a leading edge and a trailing edge, and an interior cavity, which is delimited by internal surfaces, for guiding cooling air therethrough. A multiplicity of turbulators or pins, which are formed on the wall, are arranged in a distributed manner in the region of the trailing edge and project from the internal surfaces into the cavity, to improve the transfer of heat between the wall of the blade and the cooling air. An improvement of the internal cooling is achieved by the turbulators or pins extending into the cavity in a direction which can be freely selected within an angular range. | 1. A method for producing a blade for a gas turbine by a casting technique, the blade having a leading edge and a trailing edge, and an interior cavity, which is delimited by internal surfaces, for guiding cooling air therethrough, wherein for improving the transfer of heat between the wall of the blade and the cooling air, a multiplicity of members, which are formed on the wall to improve cooling, are arranged in a distributed manner in the region of the trailing edge and project from the internal surfaces into the cavity, the members extending into the cavity in a direction which can be freely selected within an angular range, the method comprising:
providing a core mold for forming a casting core which keeps the cavity of the blade free; producing the casting core by means of the core mold; removing the casting core from the core mold; and casting the blade by the casting core, wherein: the provided core mold comprises two mold halves, which during demolding are drawn apart in a first direction; at least one mold insert, which is provided for forming the members, is arranged in the mold halves in the trailing edge region, and in the removing of the casting core from the core mold, after the parting of the mold halves in the first direction, the at least one mold insert is withdrawn from the formed casting core in a second direction which differs from the first direction. 2. The method as claimed in claim 1, wherein the second direction is perpendicular to the internal surface which is associated with the members. 3. The method as claimed in claim 2, wherein a plurality of mold inserts are arranged in the mold halves and during demolding are withdrawn from the formed casting core in different directions which differ from the first direction. | A blade for a gas turbine has a leading edge and a trailing edge, and an interior cavity, which is delimited by internal surfaces, for guiding cooling air therethrough. A multiplicity of turbulators or pins, which are formed on the wall, are arranged in a distributed manner in the region of the trailing edge and project from the internal surfaces into the cavity, to improve the transfer of heat between the wall of the blade and the cooling air. An improvement of the internal cooling is achieved by the turbulators or pins extending into the cavity in a direction which can be freely selected within an angular range.1. A method for producing a blade for a gas turbine by a casting technique, the blade having a leading edge and a trailing edge, and an interior cavity, which is delimited by internal surfaces, for guiding cooling air therethrough, wherein for improving the transfer of heat between the wall of the blade and the cooling air, a multiplicity of members, which are formed on the wall to improve cooling, are arranged in a distributed manner in the region of the trailing edge and project from the internal surfaces into the cavity, the members extending into the cavity in a direction which can be freely selected within an angular range, the method comprising:
providing a core mold for forming a casting core which keeps the cavity of the blade free; producing the casting core by means of the core mold; removing the casting core from the core mold; and casting the blade by the casting core, wherein: the provided core mold comprises two mold halves, which during demolding are drawn apart in a first direction; at least one mold insert, which is provided for forming the members, is arranged in the mold halves in the trailing edge region, and in the removing of the casting core from the core mold, after the parting of the mold halves in the first direction, the at least one mold insert is withdrawn from the formed casting core in a second direction which differs from the first direction. 2. The method as claimed in claim 1, wherein the second direction is perpendicular to the internal surface which is associated with the members. 3. The method as claimed in claim 2, wherein a plurality of mold inserts are arranged in the mold halves and during demolding are withdrawn from the formed casting core in different directions which differ from the first direction. | 1,700 |
1,496 | 13,242,014 | 1,797 | The invention is directed towards methods, compositions, and apparatus for accurately detecting the presence and amounts of contaminants in wastewater. The method comprises the steps of adding to a volume of wastewater at least one tracer molecule, observing the tracer for indications of particular contaminants, conducting at least one second form of contamination detection, and interrelating the two measured properties to identify the specific composition of the contamination. Using a tracer molecule allows for the detection of otherwise hard to detect oils and grease. Use of the second method however compensates for tracer interfering contaminants and allows for more accurate readings. The invention includes feeding of functional chemicals in response to the detections and conducting the detections online and continuously. | 1. A method of accurately detecting the presence and amounts of specific contaminants in at least one liquid comprising the steps of:
providing a volume of liquid, conducting a method of contamination detection capable of measuring the amount of turbidity in the volume of liquid and inferring from that the amount of turbidity causing contaminants within the liquid, selecting a correcting factor by identifying which of a series of pre-determined correction factors corresponds with the degree to which the measured amount of turbidity scatters light coming from a specific tracer and thereby alters the amount of a change in fluorescence that occurs within the specific liquid when the tracer is in the presence of an oil, introducing the specific tracer into the liquid, measuring the change in fluorescence emitted by introducing the specific tracer into the liquid, correcting the measured change in fluorescence by adjusting the measured change according to the selected correction factor, calculating the amount of oil within the liquid from the corrected measured change in fluorescence, and calculating the amount of non-oil contaminant within the liquid by subtracting the calculated amount of oil from the calculated amount of turbidity causing contaminants. 2. The method of claim 1 wherein, the tracer is polarity-sensitive and displays detectable properties when in water in the presence of oil but not when in water absent the oil. 3. The method of claim 1 wherein the tracer's fluorescence is quenched when in the presence of oil. 4. The method of claim 1 wherein the tracer's fluorescence is enhanced when in the presence of oil. 5. The method of claim 1 further comprising the step of measuring the tracer both before and after adding the adding the non-polar-contaminant removing chemical and using the difference in measurements to determine the amount of non-polar-contaminant in the liquid. 6. The method of claim 1 in which the liquid is wastewater clarifier effluent or influent. 7. The method of claim 1 further comprising using an optical emission source, which emits light into the liquid thereby facilitating the detection of the tracer's properties. 8. The method of claim 1 in which the detectable properties are detected by an apparatus to constructed and arranged to detect at a particular setting selected from the list consisting of:
wavelength, emission intensity, absorbance of emitted light or energy, and any combination thereof. 9. The method of claim 1 in which the liquid is selected from the list consisting of water, alcohol, and any combination thereof. 10. The method of claim 1 in which the non-oil turbidity is identified as solid particulates. 11. The method of claim 1 further comprising the step of adding a functional chemical to the liquid in response to the detected contaminant, the functional chemical being one that which is particularly suited to remediate the presence of the particular contaminant detected. 12. The method of claim 11 wherein the functional chemical is selected from the list consisting of: biocides, dispersants, flocculant, surfactants, emulsifiers, demulsifiers, inorganics, acid, base, corrosion inhibitors, water, and solvent, 12. The method of claim 1 wherein the liquid is a sample diverted from a process stream and the detection is performed on the sample. 13. The method of claim 1 wherein the detection is performed on a continuous basis and the tracer detection is optimized for a specific flow of liquid past a sensor. 14. The method of claim 11 further comprising control equipment in informational connection with the detections wherein the control equipment receives data from the detection and appropriately releases at least one functional chemical into the liquid. 15. The method of claim 1 in which the material causing the turbidity emits its own fluorescence and the correction factor takes the turbidity emitted fluorescence into account. | The invention is directed towards methods, compositions, and apparatus for accurately detecting the presence and amounts of contaminants in wastewater. The method comprises the steps of adding to a volume of wastewater at least one tracer molecule, observing the tracer for indications of particular contaminants, conducting at least one second form of contamination detection, and interrelating the two measured properties to identify the specific composition of the contamination. Using a tracer molecule allows for the detection of otherwise hard to detect oils and grease. Use of the second method however compensates for tracer interfering contaminants and allows for more accurate readings. The invention includes feeding of functional chemicals in response to the detections and conducting the detections online and continuously.1. A method of accurately detecting the presence and amounts of specific contaminants in at least one liquid comprising the steps of:
providing a volume of liquid, conducting a method of contamination detection capable of measuring the amount of turbidity in the volume of liquid and inferring from that the amount of turbidity causing contaminants within the liquid, selecting a correcting factor by identifying which of a series of pre-determined correction factors corresponds with the degree to which the measured amount of turbidity scatters light coming from a specific tracer and thereby alters the amount of a change in fluorescence that occurs within the specific liquid when the tracer is in the presence of an oil, introducing the specific tracer into the liquid, measuring the change in fluorescence emitted by introducing the specific tracer into the liquid, correcting the measured change in fluorescence by adjusting the measured change according to the selected correction factor, calculating the amount of oil within the liquid from the corrected measured change in fluorescence, and calculating the amount of non-oil contaminant within the liquid by subtracting the calculated amount of oil from the calculated amount of turbidity causing contaminants. 2. The method of claim 1 wherein, the tracer is polarity-sensitive and displays detectable properties when in water in the presence of oil but not when in water absent the oil. 3. The method of claim 1 wherein the tracer's fluorescence is quenched when in the presence of oil. 4. The method of claim 1 wherein the tracer's fluorescence is enhanced when in the presence of oil. 5. The method of claim 1 further comprising the step of measuring the tracer both before and after adding the adding the non-polar-contaminant removing chemical and using the difference in measurements to determine the amount of non-polar-contaminant in the liquid. 6. The method of claim 1 in which the liquid is wastewater clarifier effluent or influent. 7. The method of claim 1 further comprising using an optical emission source, which emits light into the liquid thereby facilitating the detection of the tracer's properties. 8. The method of claim 1 in which the detectable properties are detected by an apparatus to constructed and arranged to detect at a particular setting selected from the list consisting of:
wavelength, emission intensity, absorbance of emitted light or energy, and any combination thereof. 9. The method of claim 1 in which the liquid is selected from the list consisting of water, alcohol, and any combination thereof. 10. The method of claim 1 in which the non-oil turbidity is identified as solid particulates. 11. The method of claim 1 further comprising the step of adding a functional chemical to the liquid in response to the detected contaminant, the functional chemical being one that which is particularly suited to remediate the presence of the particular contaminant detected. 12. The method of claim 11 wherein the functional chemical is selected from the list consisting of: biocides, dispersants, flocculant, surfactants, emulsifiers, demulsifiers, inorganics, acid, base, corrosion inhibitors, water, and solvent, 12. The method of claim 1 wherein the liquid is a sample diverted from a process stream and the detection is performed on the sample. 13. The method of claim 1 wherein the detection is performed on a continuous basis and the tracer detection is optimized for a specific flow of liquid past a sensor. 14. The method of claim 11 further comprising control equipment in informational connection with the detections wherein the control equipment receives data from the detection and appropriately releases at least one functional chemical into the liquid. 15. The method of claim 1 in which the material causing the turbidity emits its own fluorescence and the correction factor takes the turbidity emitted fluorescence into account. | 1,700 |
1,497 | 14,116,991 | 1,734 | The present invention provides a method for the fabrication of a steel sheet with a completely martensitic structure which has an average lath size of less than 1 micrometer and an average elongation factor of the laths is between 2 and 5. The elongation factor of a lath is defined as a maximum dimension divided by and a minimum dimension 1 max . The steel sheet has a yield stress greater than 1300 MPa and a mechanical strength greater than (3220(C)+958) megapascals. A composition of a semi-finished steel product includes, expressed in percent by weight, is, 0.15%≦C≦0.40%, 1.5%≦Mn≦3%, 0.005%≦Si≦2%, 0.005%≦Al≦0.1%, 1.8%≦Cr≦4%, 0%≦Mo≦2%, whereby: 2.7%≦0.5 (Mn)+(Cr)+3(Mo)≦5.7%, S≦0.05%, P≦0.1%, optionally: 0%≦Nb≦0.050%, 0.01%≦Ti≦0.1%, 0.0005%≦B≦0.005%, 0.0005%≦Ca≦0.005%. The semi-finished product is reheated to a temperature T 1 in the range between 1050° C. and 1250° C., then subjected to a roughing rolling at a temperature T 2 in the range between 1000 and 880° C., with a cumulative rate of reduction ε a greater than 30%, to obtain a sheet with a completely recrystallized austenitic structure with an average grain size less than 40 micrometers and preferably less than 5 micrometers. The sheet is then partially cooled to prevent a transformation of the austenite at a rate V R1 greater than 2° C./s to a temperature T 3 between 600° C. and 400° C. in the metastable austenitic range, and subjected to a finishing hot rolling at the temperature T 3 of the partially cooled sheet, with a cumulative rate of reduction ε b greater than 30% to obtain a sheet that is then cooled at a rate V R2 which is greater than the critical martensitic quenching rate. | 1-9. (canceled) 10. A method for the fabrication of steel sheet with a completely martensitic structure with an average lath size of less than 1 micrometer, an average elongation factor of the laths being between 2 and 5, an elongation factor of a lath having a maximum dimension 1max and a minimum dimension 1min being defined by
l
max
l
min
,
the steel sheeting having a yield stress greater than 1300 MPa, a mechanical strength greater than (3220)(C)+958 megapascals, (C) designating a carbon content of the steel in percent by weight, the method comprising the steps of:
providing a semi-finished steel product, a composition of the semi-finished steel product including, whereby the contents are expressed by weight,
0.15%≦C≦0.40%,
1.5%≦Mn≦3%,
0.005%≦Si≦2%,
0.005%≦Al≦0.1%,
1.8%≦Cr≦4%,
0%≦Mo≦2%
whereby
2.7%≦0.5(Mn)+(Cr)+3(Mo)≦5.7%,
the remainder of the composition consisting of iron and the inevitable impurities resulting from processing,
heating the semi-finished product to a temperature T1 between 1050° C. and 1250° C.;
subjecting the heated semi-finished product to a roughing rolling at a temperature T2 between 1000 and 880° C., with a cumulative rate of reduction Ca greater than 30% to obtain a sheet with a completely recrystallized austenitic grain structure with an average grain size less than 40 micrometers, the cumulative rate of reduction εa being defined by:
Ln
e
ia
e
f
a
,
.
where eia designates a thickness of the semi-finished product before hot roughing rolling and efa designates a thickness of the sheet after the roughing rolling;
partially cooling the sheet to a temperature T3 between 600° C. and 400° C. in the metastable austenitic range at a rate VR1 which is greater than 2° C./s;
subjecting the partially cooled sheet to a hot finish rolling at the temperature T3, with a cumulative rate of reduction Eb greater than 30% to obtain a sheet, whereby the cumulative rate of reduction εb is defined by:
Ln
e
ib
e
f
b
,
.
where εib designates a thickness of the semi-finished product before hot finish rolling and efa a thickness of the sheet after the hot finish rolling; and
cooling the sheet at a rate VR2 which is greater than the critical martensitic quenching rate. 11. A method for the fabrication of a steel part with a completely martensitic structure having an average lath size of less than 1 micrometer, an average elongation factor of the laths being between 2 and 5, the elongation factor of a lath with a maximum dimension 1max and minimum dimension 1min being defined by
l
max
l
min
,
the method comprising the following:
obtaining a steel blank, a composition of the steel blank including, whereby the contents are expressed by weight,
0.15%≦C≦0.40%,
1.5%≦Mn≦3%,
0.005%≦Si≦2%,
0.005%≦Al≦0.1%,
1.8% 4%,
0%≦Mo≦2%
whereby
2.7%≦0.5(Mn)+(Cr)+3(Mo)≦5.7%,
S≦0.05%,
P≦0.1%,
the remainder of the composition consisting of iron and the inevitable impurities resulting from processing,
heating the blank to a temperature T1 in a range between AC3 and AC3+250° C. so that the average austenitic grain size is less than 40 micrometers;
transferring the heated blank to a hot stamping press or a hot forming device;
cooling the blank to a temperature T3 in a range between 600° C. and 400° C. at a rate VR1 which is greater than 2° C./s to prevent a transformation of the austenite;
hot stamping or hot forming the cooled blank at the temperature T3 by a quantity ε c greater than 30% in at least one zone, to obtain a part, ε c being defined by
ɛ
c
_
=
2
3
(
ɛ
1
2
+
ɛ
1
ɛ
2
+
ɛ
2
2
)
,
where ε1 and ε2 are principal deformations accumulated over all of the deformation steps at the temperature T3; and
cooling the part at a rate VR2 which is greater than a critical martensitic quenching rate. 12. The method for the fabrication of a part as recited in claim 11, wherein the blank is hot-stamped to obtain a part, the part is held in a stamping tool to cool the part at a rate VR2 which is greater than a critical martensitic quenching rate. 13. The method for the fabrication of a steel part as recited in claim 11, wherein the blank is pre-coated with aluminum or an aluminum-based alloy. 14. The method for the fabrication of a steel part as recited in claim 11, wherein the blank is pre-coated with zinc or a zinc-based alloy. 15. The method for the fabrication of steel sheet as recited in claim 10, further comprising the step of subjecting the sheet to a tempering heat treatment at a temperature T4 which is between 150 and 600° C. for a period of time between 5 and 30 minutes. 16. A steel sheet with a yield stress greater than 1300 MPa, a mechanical strength greater than (3220)(C)+958) megapascals, whereby (C) designates the carbon content of the steel in percent by weight, comprising:
a sheet fabricated by the method recited in claim 10; a completely martensitic structure, with an average lath size being less than 1 micrometer; and an average elongation factor of the laths being between 2 and 5. 17. A steel part comprising:
a steel part fabricated by the method recited in claim 11; at least one zone with a completely martensitic structure with an average lath size of less than 1 micrometer; an average elongation factor of the laths being between 2 and 5; a yield stress in the at least one zone being greater than 1300 MPa; and a mechanical strength being greater than (3220)(C)+958 megapascals, whereby (C) designates the carbon content of the steel in percent by weight. 18. A steel sheet comprising:
a sheet fabricated by the method recited in claim 15; a completely martensitic structure, with an average lath grain size in at least one zone being less than 1.2 micrometers; and an average elongation factor of the laths being between 2 and 5. 19. The method for the fabrication of a steel sheet as recited in claim 10, wherein the average grain size less is less than 5 micrometers. 20. The method for the fabrication of a steel sheet as recited in claim 10, wherein the composition of the semi-finished steel product includes 0%≦Nb≦0.050%. 21. The method for the fabrication of a steel sheet as recited in claim 10, wherein the composition of the semi-finished steel product includes 0.01%. 22. The method for the fabrication of a steel sheet as recited in claim 10, wherein the composition of the semi-finished steel product includes 0.0005%≦B≦0.005%. 23. The method for the fabrication of a steel sheet as recited in claim 10, wherein the composition of the semi-finished steel product includes 0.0005%≦Ca≦0.005%. 24. The method for the fabrication of steel part as recited in claim 11, further comprising the step of subjecting the part to a tempering heat treatment at a temperature T4 which is between 150 and 600° C. for a period of time between 5 and 30 minutes. 25. The method for the fabrication of a steel part as recited in claim 11, wherein the average grain size less is less than 5 micrometers. 26. The method for the fabrication of a steel part as recited in claim 11, wherein the transferring step may occur before or after the step of cooling the blank to a temperature T3. 27. The method for the fabrication of a steel part as recited in claim 11, wherein the composition of the steel blank includes 0%≦Nb≦0.050%. 28. The method for the fabrication of a steel part as recited in claim 11, wherein the composition of the steel blank includes 0.01%. 29. The method for the fabrication of a steel part as recited in claim 11, wherein the composition of the steel blank includes 0.0005%≦B≦0.005%. 30. The method for the fabrication of a steel part as recited in claim 11, wherein the composition of the steel blank includes 0.0005%≦Ca≦0.005%. | The present invention provides a method for the fabrication of a steel sheet with a completely martensitic structure which has an average lath size of less than 1 micrometer and an average elongation factor of the laths is between 2 and 5. The elongation factor of a lath is defined as a maximum dimension divided by and a minimum dimension 1 max . The steel sheet has a yield stress greater than 1300 MPa and a mechanical strength greater than (3220(C)+958) megapascals. A composition of a semi-finished steel product includes, expressed in percent by weight, is, 0.15%≦C≦0.40%, 1.5%≦Mn≦3%, 0.005%≦Si≦2%, 0.005%≦Al≦0.1%, 1.8%≦Cr≦4%, 0%≦Mo≦2%, whereby: 2.7%≦0.5 (Mn)+(Cr)+3(Mo)≦5.7%, S≦0.05%, P≦0.1%, optionally: 0%≦Nb≦0.050%, 0.01%≦Ti≦0.1%, 0.0005%≦B≦0.005%, 0.0005%≦Ca≦0.005%. The semi-finished product is reheated to a temperature T 1 in the range between 1050° C. and 1250° C., then subjected to a roughing rolling at a temperature T 2 in the range between 1000 and 880° C., with a cumulative rate of reduction ε a greater than 30%, to obtain a sheet with a completely recrystallized austenitic structure with an average grain size less than 40 micrometers and preferably less than 5 micrometers. The sheet is then partially cooled to prevent a transformation of the austenite at a rate V R1 greater than 2° C./s to a temperature T 3 between 600° C. and 400° C. in the metastable austenitic range, and subjected to a finishing hot rolling at the temperature T 3 of the partially cooled sheet, with a cumulative rate of reduction ε b greater than 30% to obtain a sheet that is then cooled at a rate V R2 which is greater than the critical martensitic quenching rate.1-9. (canceled) 10. A method for the fabrication of steel sheet with a completely martensitic structure with an average lath size of less than 1 micrometer, an average elongation factor of the laths being between 2 and 5, an elongation factor of a lath having a maximum dimension 1max and a minimum dimension 1min being defined by
l
max
l
min
,
the steel sheeting having a yield stress greater than 1300 MPa, a mechanical strength greater than (3220)(C)+958 megapascals, (C) designating a carbon content of the steel in percent by weight, the method comprising the steps of:
providing a semi-finished steel product, a composition of the semi-finished steel product including, whereby the contents are expressed by weight,
0.15%≦C≦0.40%,
1.5%≦Mn≦3%,
0.005%≦Si≦2%,
0.005%≦Al≦0.1%,
1.8%≦Cr≦4%,
0%≦Mo≦2%
whereby
2.7%≦0.5(Mn)+(Cr)+3(Mo)≦5.7%,
the remainder of the composition consisting of iron and the inevitable impurities resulting from processing,
heating the semi-finished product to a temperature T1 between 1050° C. and 1250° C.;
subjecting the heated semi-finished product to a roughing rolling at a temperature T2 between 1000 and 880° C., with a cumulative rate of reduction Ca greater than 30% to obtain a sheet with a completely recrystallized austenitic grain structure with an average grain size less than 40 micrometers, the cumulative rate of reduction εa being defined by:
Ln
e
ia
e
f
a
,
.
where eia designates a thickness of the semi-finished product before hot roughing rolling and efa designates a thickness of the sheet after the roughing rolling;
partially cooling the sheet to a temperature T3 between 600° C. and 400° C. in the metastable austenitic range at a rate VR1 which is greater than 2° C./s;
subjecting the partially cooled sheet to a hot finish rolling at the temperature T3, with a cumulative rate of reduction Eb greater than 30% to obtain a sheet, whereby the cumulative rate of reduction εb is defined by:
Ln
e
ib
e
f
b
,
.
where εib designates a thickness of the semi-finished product before hot finish rolling and efa a thickness of the sheet after the hot finish rolling; and
cooling the sheet at a rate VR2 which is greater than the critical martensitic quenching rate. 11. A method for the fabrication of a steel part with a completely martensitic structure having an average lath size of less than 1 micrometer, an average elongation factor of the laths being between 2 and 5, the elongation factor of a lath with a maximum dimension 1max and minimum dimension 1min being defined by
l
max
l
min
,
the method comprising the following:
obtaining a steel blank, a composition of the steel blank including, whereby the contents are expressed by weight,
0.15%≦C≦0.40%,
1.5%≦Mn≦3%,
0.005%≦Si≦2%,
0.005%≦Al≦0.1%,
1.8% 4%,
0%≦Mo≦2%
whereby
2.7%≦0.5(Mn)+(Cr)+3(Mo)≦5.7%,
S≦0.05%,
P≦0.1%,
the remainder of the composition consisting of iron and the inevitable impurities resulting from processing,
heating the blank to a temperature T1 in a range between AC3 and AC3+250° C. so that the average austenitic grain size is less than 40 micrometers;
transferring the heated blank to a hot stamping press or a hot forming device;
cooling the blank to a temperature T3 in a range between 600° C. and 400° C. at a rate VR1 which is greater than 2° C./s to prevent a transformation of the austenite;
hot stamping or hot forming the cooled blank at the temperature T3 by a quantity ε c greater than 30% in at least one zone, to obtain a part, ε c being defined by
ɛ
c
_
=
2
3
(
ɛ
1
2
+
ɛ
1
ɛ
2
+
ɛ
2
2
)
,
where ε1 and ε2 are principal deformations accumulated over all of the deformation steps at the temperature T3; and
cooling the part at a rate VR2 which is greater than a critical martensitic quenching rate. 12. The method for the fabrication of a part as recited in claim 11, wherein the blank is hot-stamped to obtain a part, the part is held in a stamping tool to cool the part at a rate VR2 which is greater than a critical martensitic quenching rate. 13. The method for the fabrication of a steel part as recited in claim 11, wherein the blank is pre-coated with aluminum or an aluminum-based alloy. 14. The method for the fabrication of a steel part as recited in claim 11, wherein the blank is pre-coated with zinc or a zinc-based alloy. 15. The method for the fabrication of steel sheet as recited in claim 10, further comprising the step of subjecting the sheet to a tempering heat treatment at a temperature T4 which is between 150 and 600° C. for a period of time between 5 and 30 minutes. 16. A steel sheet with a yield stress greater than 1300 MPa, a mechanical strength greater than (3220)(C)+958) megapascals, whereby (C) designates the carbon content of the steel in percent by weight, comprising:
a sheet fabricated by the method recited in claim 10; a completely martensitic structure, with an average lath size being less than 1 micrometer; and an average elongation factor of the laths being between 2 and 5. 17. A steel part comprising:
a steel part fabricated by the method recited in claim 11; at least one zone with a completely martensitic structure with an average lath size of less than 1 micrometer; an average elongation factor of the laths being between 2 and 5; a yield stress in the at least one zone being greater than 1300 MPa; and a mechanical strength being greater than (3220)(C)+958 megapascals, whereby (C) designates the carbon content of the steel in percent by weight. 18. A steel sheet comprising:
a sheet fabricated by the method recited in claim 15; a completely martensitic structure, with an average lath grain size in at least one zone being less than 1.2 micrometers; and an average elongation factor of the laths being between 2 and 5. 19. The method for the fabrication of a steel sheet as recited in claim 10, wherein the average grain size less is less than 5 micrometers. 20. The method for the fabrication of a steel sheet as recited in claim 10, wherein the composition of the semi-finished steel product includes 0%≦Nb≦0.050%. 21. The method for the fabrication of a steel sheet as recited in claim 10, wherein the composition of the semi-finished steel product includes 0.01%. 22. The method for the fabrication of a steel sheet as recited in claim 10, wherein the composition of the semi-finished steel product includes 0.0005%≦B≦0.005%. 23. The method for the fabrication of a steel sheet as recited in claim 10, wherein the composition of the semi-finished steel product includes 0.0005%≦Ca≦0.005%. 24. The method for the fabrication of steel part as recited in claim 11, further comprising the step of subjecting the part to a tempering heat treatment at a temperature T4 which is between 150 and 600° C. for a period of time between 5 and 30 minutes. 25. The method for the fabrication of a steel part as recited in claim 11, wherein the average grain size less is less than 5 micrometers. 26. The method for the fabrication of a steel part as recited in claim 11, wherein the transferring step may occur before or after the step of cooling the blank to a temperature T3. 27. The method for the fabrication of a steel part as recited in claim 11, wherein the composition of the steel blank includes 0%≦Nb≦0.050%. 28. The method for the fabrication of a steel part as recited in claim 11, wherein the composition of the steel blank includes 0.01%. 29. The method for the fabrication of a steel part as recited in claim 11, wherein the composition of the steel blank includes 0.0005%≦B≦0.005%. 30. The method for the fabrication of a steel part as recited in claim 11, wherein the composition of the steel blank includes 0.0005%≦Ca≦0.005%. | 1,700 |
1,498 | 11,418,457 | 1,791 | A retorted liquid soup concentrate package (of about 70 to 100 g contents) expressible from the package when opened and dilutable with boiling or near boiling water (at a dilution ratio water/concentrate of from 1.9:1 to 2.5:1) to a lump free ready to eat soup form at at least 55° C. (preferably 60 to 65° C.) and a target volume less than 400 mls (preferably 250-300 mls). | 1. A soup concentrate product comprising or including
a sealed container, a liquid including soup concentrate adapted to be diluted by boiling or near boiling water to a ready to serve soup form, the concentrate being within the container, wherein said concentrate is capable of being expressed, poured or otherwise removed from the container once opened, and wherein the concentrate without heating and at an ambient temperature within the range 10 to 30° C. can, if desired, be diluted with boiling water in a volume in excess to that of the liquid including concentrate thereby to achieve a soup, to a target volume less than 400 mls at a temperature of at least 55° C. 2. The product of claim 1 wherein the concentrate is or includes a puree and/or broth. 3. The product of claim 1 wherein the concentrate has been cold or cool (e.g. at ambient temperature(s)) filled into the container prior to sealing. 4. The product of claim 1 that has been retorted after sealing of the container. 5. The product of claim 1 wherein the container bears instructions to dilute the content of the container with boiling (or near boiling water) to provide such a soup. 6. The product of any claim 1 the concentrate has a texturiser and/or thickener at least one of (i) a suitable starch and/or starch derivative and (ii) a suitable fruit and/or vegetable fibre. 7. The product of claim 1 wherein the concentrate includes water. 8. The product of claim 1 wherein the concentrate without heating and at an ambient temperature within the range 10 to 30° C. can, if desired, be diluted with boiling water or near boiling water to achieve a target soup volume substantially lump free within the range of from 200 to 350 mls at a temperature of at least 55° C. 9. The product of claim 1 wherein the concentrate has a starch and/or starch derivative inclusion and the concentrate without heating and at an ambient temperature within the range 10 to 30° C. can, if desired, be diluted with boiling water in a volume in excess to that of the liquid including concentrate thereby to achieve a substantially lump free soup to a target volume less than 400 mls at a temperature of at least 55° C. 10. The product of claim 1 wherein the concentrate is of a weight of from 70 g to 100 g. 11. The product of claim 10 wherein that weight is from 80 g to 90 g. 12. The product of claim 11 wherein that weight is about 85 g. 13. The product of claim 1 wherein the dilution ratio of water to concentrate is in a range of 1.5:1 and above. 14. The product of claim 13 wherein the dilution ratio of water to concentrate range is not above 5:1. 15. The product of claim 14 wherein the dilution ratio of water to concentrate is at least 1.9:1. 16. The product of claim 1 wherein the dilution ratio of water to concentrate is in the range of 1.9:1 to 2.5:1. 17. The product or concentrate of claim 1 wherein at the target volume with the use of boiling water the temperature will be at least 60° C. 18. The product or concentrate of claim 31 wherein the temperature will be from 60 to 65° C. 19. A retorted soup product comprising or including
a sealed container, a water and pomace, pomace fibre or pomace fibre derivative including concentrate adapted to be diluted by boiling or near boiling water, the concentrate being within the container, wherein said concentrate is capable of being expressed, poured or otherwise removed from the container once opened, and wherein the concentrate without heating and at an ambient temperature within the range 10 to 30° C. can, if desired, be diluted with boiling water in a volume in excess to that of the liquid including concentrate thereby to achieve a substantially lump free soup to a target volume less than 400 mls at a temperature of at least 55° C. 20. A retorted soup product comprising or including
a sealed container, a water and citrus fibre including soup concentrate adapted to be diluted by boiling or near boiling water, the concentrate being within the container, wherein said concentrate is capable of being expressed, poured or otherwise removed from the container once opened, and wherein the concentrate without heating and at an ambient temperature within the range 10 to 30° C. can, if desired, be diluted with boiling water in a volume in excess to that of the liquid including concentrate thereby to achieve a soup to a target volume less than 400 mls at a temperature of at least 55° C., and wherein the container bears instructions to dilute the content of the container with boiling (or near boiling water) to provide such a soup. 21. A packaged wet form food and retorted concentrate where the concentrate itself is capable of dilution with boiling water, or near boiling water, to the form of a ready to serve soup, said concentrate comprising or including
a food stuff and/or food stuff flavouring derived from one or more of the group consisting of vegetables, fruits, fungi, mammalian and poultry meats fish and shellfish, water (whether added and/or inherently in any ingredient), a viscosity and/or perceived viscosity increasing ingredient or ingredients, optionally a bulking and/or texturising ingredient or ingredients, optionally a flavouring agent or flavouring agents, optionally an emulsifier or emulsifiers, optionally a preservative or preservatives, optionally a colouring agent or agents, optionally a stabiliser or stabilisers, and optionally a pH adjustment agent or agents. 22. A packaged and retorted wet form food concentrate where the concentrate itself is capable of dilution with boiling water, or near boiling water to the form of a ready to serve soup, said concentrate comprising or including
a food stuff and/or food stuff flavouring in line derived from one or more of the group consisting of vegetables, fruits, fungi, mammalian and poultry meats, fish and shellfish, water (whether added and/or inherently in any ingredient), a viscosity and/or perceived viscosity increasing ingredient or ingredients, optionally a bulking and/or texturising ingredient or ingredients, optionally a flavouring agent or flavouring agents, optionally an emulsifier or emulsifiers, optionally a preservative or preservatives, optionally a colouring agent or agents, optionally a stabiliser or stabilisers, and optionally a pH adjustment agent or agents. 23. The product or concentrate of claim 1 wherein the dilution ratio of water to concentrate on a weight basis is to be at least 1.5:1. 24. The product or concentrate of claim 23 wherein said ratio is at least 1.9:1. 25. The product or concentrate of claim 23 wherein said dilution ratio is below 5:1. 26. The product or concentrate of claim 25 wherein the dilution ratio is from 1.5:1 to 2.5:1. 27. The product or concentrate of claim 1 wherein target diluted volume is from 200 to 350 mls. 28. The product or concentrate of claim 23 wherein said target volume is from 250-300 mls. 29. The product or concentrate of claim 1 wherein the concentrate is of a weight from 70 g to 100 g. 30. The product or concentrate of claim 29 wherein the concentrate is of a weight from 80 g to 90 g. 31. The product or concentrate of claim 30 wherein said weight is about 85 g. 32. The product or concentrate of claim 1 wherein the concentrate has been cool or cold filled into the container prior to the sealing thereof. 33. The product of claim 1 wherein the sealed container has been retorted. 34. The product or concentrate claim 1 wherein a suitable starch or starch derivative is present. 35. The product of claim 1 wherein a suitable fruit and/or vegetable fibre is present. 36. The product or concentrate of claim 35 wherein the fibre present is at least one of (a) a dry citrus fibre (b) that of the tomato and/or (c) vegetable fibre. 37. The product of claim 1 wherein viscosity and/or perceived viscosity increasing agent(s) selected from one or more the following are present:
Native starch or starches, Physically modified starch or starches, Chemically modified starch or starches, Starch or starches originating from Wheat, Potato, Corn, Waxy Maize and/or Tapioca, Locust Bean Gum, Pectins (inc. different types), MCC, CMC, Guar Gum, Citrus Fibre, Pea Flour, Pumpkin Powder, Dried fibres (cereal, vegetable and/or fruit), Fat mimetic, Apple pomace, and Wet vegetable purees. 38. A process for in line producing a concentrate in a container capable of dilution with boiling or near boiling water to a hot ready to serve soup form, said process comprising or including the steps of
preparing a dilutable wet concentrate puree and/or broth of an ingredient or ingredients selected at least from
(i) the group consisting of vegetables, fruits, fungi, mammalian and poultry meats, fish and shellfish, and optionally also (ii) one or more viscosity and/or perceived viscosity increasing agent, and
filling and sealing a quantity of the dilutable wet concentrate into a suitable container, (and optionally retorting the container sealed concentrate), the process being further characterised by any one or more of:
(ii) the mass of the concentrate in the container is from 70 to 100 gms (preferably about 85 gms),
(iii) the concentrate is cold or cool filled into the container prior to its sealing,
(iv) the concentrate without the heating and at an ambient temperature within the range 10 to 30° C. can, if desired, be diluted with boiling water in a volume in excess to that of the liquid including concentrate thereby to achieve a soup to a target volume less than 400 mls at a temperature of at least 55° C.,
(v) the dilution instructed on the pack provides at least a ready to serve soup of a temperature and viscosity appropriate for such a soup, and/or
(vi) the sealed concentrate has been retorted. 39. The product made by a process of claim 38. 40. The product of claim 39 wherein the dilution instructed is not outside the range of from 1.5:1 to 5:1. 41. The product of claim 39 wherein the dilution instructed corresponds to within the range from about 1.9:1 to about 2.5:1. 42. The use of a product of claim 1, such use involving dilution with boiling or near boiling water. | A retorted liquid soup concentrate package (of about 70 to 100 g contents) expressible from the package when opened and dilutable with boiling or near boiling water (at a dilution ratio water/concentrate of from 1.9:1 to 2.5:1) to a lump free ready to eat soup form at at least 55° C. (preferably 60 to 65° C.) and a target volume less than 400 mls (preferably 250-300 mls).1. A soup concentrate product comprising or including
a sealed container, a liquid including soup concentrate adapted to be diluted by boiling or near boiling water to a ready to serve soup form, the concentrate being within the container, wherein said concentrate is capable of being expressed, poured or otherwise removed from the container once opened, and wherein the concentrate without heating and at an ambient temperature within the range 10 to 30° C. can, if desired, be diluted with boiling water in a volume in excess to that of the liquid including concentrate thereby to achieve a soup, to a target volume less than 400 mls at a temperature of at least 55° C. 2. The product of claim 1 wherein the concentrate is or includes a puree and/or broth. 3. The product of claim 1 wherein the concentrate has been cold or cool (e.g. at ambient temperature(s)) filled into the container prior to sealing. 4. The product of claim 1 that has been retorted after sealing of the container. 5. The product of claim 1 wherein the container bears instructions to dilute the content of the container with boiling (or near boiling water) to provide such a soup. 6. The product of any claim 1 the concentrate has a texturiser and/or thickener at least one of (i) a suitable starch and/or starch derivative and (ii) a suitable fruit and/or vegetable fibre. 7. The product of claim 1 wherein the concentrate includes water. 8. The product of claim 1 wherein the concentrate without heating and at an ambient temperature within the range 10 to 30° C. can, if desired, be diluted with boiling water or near boiling water to achieve a target soup volume substantially lump free within the range of from 200 to 350 mls at a temperature of at least 55° C. 9. The product of claim 1 wherein the concentrate has a starch and/or starch derivative inclusion and the concentrate without heating and at an ambient temperature within the range 10 to 30° C. can, if desired, be diluted with boiling water in a volume in excess to that of the liquid including concentrate thereby to achieve a substantially lump free soup to a target volume less than 400 mls at a temperature of at least 55° C. 10. The product of claim 1 wherein the concentrate is of a weight of from 70 g to 100 g. 11. The product of claim 10 wherein that weight is from 80 g to 90 g. 12. The product of claim 11 wherein that weight is about 85 g. 13. The product of claim 1 wherein the dilution ratio of water to concentrate is in a range of 1.5:1 and above. 14. The product of claim 13 wherein the dilution ratio of water to concentrate range is not above 5:1. 15. The product of claim 14 wherein the dilution ratio of water to concentrate is at least 1.9:1. 16. The product of claim 1 wherein the dilution ratio of water to concentrate is in the range of 1.9:1 to 2.5:1. 17. The product or concentrate of claim 1 wherein at the target volume with the use of boiling water the temperature will be at least 60° C. 18. The product or concentrate of claim 31 wherein the temperature will be from 60 to 65° C. 19. A retorted soup product comprising or including
a sealed container, a water and pomace, pomace fibre or pomace fibre derivative including concentrate adapted to be diluted by boiling or near boiling water, the concentrate being within the container, wherein said concentrate is capable of being expressed, poured or otherwise removed from the container once opened, and wherein the concentrate without heating and at an ambient temperature within the range 10 to 30° C. can, if desired, be diluted with boiling water in a volume in excess to that of the liquid including concentrate thereby to achieve a substantially lump free soup to a target volume less than 400 mls at a temperature of at least 55° C. 20. A retorted soup product comprising or including
a sealed container, a water and citrus fibre including soup concentrate adapted to be diluted by boiling or near boiling water, the concentrate being within the container, wherein said concentrate is capable of being expressed, poured or otherwise removed from the container once opened, and wherein the concentrate without heating and at an ambient temperature within the range 10 to 30° C. can, if desired, be diluted with boiling water in a volume in excess to that of the liquid including concentrate thereby to achieve a soup to a target volume less than 400 mls at a temperature of at least 55° C., and wherein the container bears instructions to dilute the content of the container with boiling (or near boiling water) to provide such a soup. 21. A packaged wet form food and retorted concentrate where the concentrate itself is capable of dilution with boiling water, or near boiling water, to the form of a ready to serve soup, said concentrate comprising or including
a food stuff and/or food stuff flavouring derived from one or more of the group consisting of vegetables, fruits, fungi, mammalian and poultry meats fish and shellfish, water (whether added and/or inherently in any ingredient), a viscosity and/or perceived viscosity increasing ingredient or ingredients, optionally a bulking and/or texturising ingredient or ingredients, optionally a flavouring agent or flavouring agents, optionally an emulsifier or emulsifiers, optionally a preservative or preservatives, optionally a colouring agent or agents, optionally a stabiliser or stabilisers, and optionally a pH adjustment agent or agents. 22. A packaged and retorted wet form food concentrate where the concentrate itself is capable of dilution with boiling water, or near boiling water to the form of a ready to serve soup, said concentrate comprising or including
a food stuff and/or food stuff flavouring in line derived from one or more of the group consisting of vegetables, fruits, fungi, mammalian and poultry meats, fish and shellfish, water (whether added and/or inherently in any ingredient), a viscosity and/or perceived viscosity increasing ingredient or ingredients, optionally a bulking and/or texturising ingredient or ingredients, optionally a flavouring agent or flavouring agents, optionally an emulsifier or emulsifiers, optionally a preservative or preservatives, optionally a colouring agent or agents, optionally a stabiliser or stabilisers, and optionally a pH adjustment agent or agents. 23. The product or concentrate of claim 1 wherein the dilution ratio of water to concentrate on a weight basis is to be at least 1.5:1. 24. The product or concentrate of claim 23 wherein said ratio is at least 1.9:1. 25. The product or concentrate of claim 23 wherein said dilution ratio is below 5:1. 26. The product or concentrate of claim 25 wherein the dilution ratio is from 1.5:1 to 2.5:1. 27. The product or concentrate of claim 1 wherein target diluted volume is from 200 to 350 mls. 28. The product or concentrate of claim 23 wherein said target volume is from 250-300 mls. 29. The product or concentrate of claim 1 wherein the concentrate is of a weight from 70 g to 100 g. 30. The product or concentrate of claim 29 wherein the concentrate is of a weight from 80 g to 90 g. 31. The product or concentrate of claim 30 wherein said weight is about 85 g. 32. The product or concentrate of claim 1 wherein the concentrate has been cool or cold filled into the container prior to the sealing thereof. 33. The product of claim 1 wherein the sealed container has been retorted. 34. The product or concentrate claim 1 wherein a suitable starch or starch derivative is present. 35. The product of claim 1 wherein a suitable fruit and/or vegetable fibre is present. 36. The product or concentrate of claim 35 wherein the fibre present is at least one of (a) a dry citrus fibre (b) that of the tomato and/or (c) vegetable fibre. 37. The product of claim 1 wherein viscosity and/or perceived viscosity increasing agent(s) selected from one or more the following are present:
Native starch or starches, Physically modified starch or starches, Chemically modified starch or starches, Starch or starches originating from Wheat, Potato, Corn, Waxy Maize and/or Tapioca, Locust Bean Gum, Pectins (inc. different types), MCC, CMC, Guar Gum, Citrus Fibre, Pea Flour, Pumpkin Powder, Dried fibres (cereal, vegetable and/or fruit), Fat mimetic, Apple pomace, and Wet vegetable purees. 38. A process for in line producing a concentrate in a container capable of dilution with boiling or near boiling water to a hot ready to serve soup form, said process comprising or including the steps of
preparing a dilutable wet concentrate puree and/or broth of an ingredient or ingredients selected at least from
(i) the group consisting of vegetables, fruits, fungi, mammalian and poultry meats, fish and shellfish, and optionally also (ii) one or more viscosity and/or perceived viscosity increasing agent, and
filling and sealing a quantity of the dilutable wet concentrate into a suitable container, (and optionally retorting the container sealed concentrate), the process being further characterised by any one or more of:
(ii) the mass of the concentrate in the container is from 70 to 100 gms (preferably about 85 gms),
(iii) the concentrate is cold or cool filled into the container prior to its sealing,
(iv) the concentrate without the heating and at an ambient temperature within the range 10 to 30° C. can, if desired, be diluted with boiling water in a volume in excess to that of the liquid including concentrate thereby to achieve a soup to a target volume less than 400 mls at a temperature of at least 55° C.,
(v) the dilution instructed on the pack provides at least a ready to serve soup of a temperature and viscosity appropriate for such a soup, and/or
(vi) the sealed concentrate has been retorted. 39. The product made by a process of claim 38. 40. The product of claim 39 wherein the dilution instructed is not outside the range of from 1.5:1 to 5:1. 41. The product of claim 39 wherein the dilution instructed corresponds to within the range from about 1.9:1 to about 2.5:1. 42. The use of a product of claim 1, such use involving dilution with boiling or near boiling water. | 1,700 |
1,499 | 12,875,521 | 1,791 | A method for producing a processed meat product begins at the supplier, where whole muscle meat is reduced into whole muscle meat pieces and the pieces may be macerated to increase their surface area. Prior to shipment of the whole muscle meat from the supplier to the meat processing plant, the whole muscle meat pieces are mixed with an initial ingredient mixture to create a raw base mixture and then packed into a container. The containers are shipped to a meat processing plant, whereby upon receipt of the raw base mixture at the processing plant, the raw base mixture is mixed with a customized ingredient mix to create a processed whole muscle mixture. The processed whole muscle mixture may then be stuffed and thermally processed. | 1. A method for preparing a raw base material for use in a processed meat product, the method comprising:
at a meat packing plant, deboning whole muscle meat to thereby create boneless whole muscle meat having a surface area; increasing the surface area of the whole muscle meat at said meat packing plant; mixing an initial mixture with the whole muscle meat at said meat packing plant; packing the whole muscle meat and the initial mixture into a container at said meat packing plant; and shipping the container with the whole muscle meat and the initial mixture to a meat processing plant such that the initial mixture is in contact with said whole muscle meat over a time period of at least 2 hours such that the initial mixture has the effect of at least partially processing the whole muscle meat during shipping. 2. The method of claim 1, wherein increasing the surface area of the whole muscle meat comprises reducing the whole muscle meat into whole muscle meat pieces. 3. The method of claim 2, wherein increasing a surface area of the whole muscle meat further comprises macerating the whole muscle meat pieces to further increase the surface area of the whole muscle pieces. 4. The method of claim 2 wherein reducing the whole muscle meat to whole muscle meat pieces utilizes at least one of:
a macerator;
a slicer;
a kidney plate;
a dicer;
a double macerator;
a manual knife size reduction;
a water jet;
a harping unit;
a slasher;
a chopper;
a grinder; and
a laser cutter. 5. The method of claim 4 wherein the macerator includes first and second arbors configured to counter-rotate during operation wherein at least one of the first and second arbors has protrusions that extend into channels of the other of the first and second arbors. 6. The method of claim 6 wherein the first and second arbors have an integral assembly of alternating radially projecting and axially extending protrusions and channels. 7. The method of claim 2 wherein the initial mixture comprises at least one of:
a salt concentration;
a nitrite;
a cure accelerator; and
an alternative preservation ingredient. 8. The method of claim 7 wherein the cure accelerator includes at least one of:
erythorbate;
ascorbate;
ascorbic acid;
glucono-delta-lactone; and
acid pyrophosphate. 9. The method of claim 7 wherein the mixing of the initial mixture with the whole muscle meat occurs in steps such that the salt concentration and the nitrite area mixed with the whole muscle meat prior to the mixing of the cure accelerator. 10. The method of claim 7 wherein the mixing of the initial mixture with the whole muscle meat occurs such that all ingredients of the initial mixture are mixed simultaneously. 11. The method of claim 2 wherein the initial mixture comprises a salt concentration of about 0.5% to 6% of the weight of the whole muscle meat pieces and further comprises 70 ppm to 160 ppm of nitrite and less than about 500 ppm of sodium ascorbate. 12. The method of claim 2 wherein the initial mixture comprises a salt concentration and nitrite and at least one of:
flavorings;
water; and
additional cure components. 13. The method of claim 2, wherein the whole muscle pieces have an average thickness of approximately ¼ in. to 3 in. 14. The method of claim 2 further comprising adding ground meat trimmings and other meat ingredients to the whole muscle pieces along with the initial mixture. 15. The method of claim 2, wherein mixing the initial mixture with the whole muscle meat pieces further comprises mixing the initial mixture and the whole muscle meat pieces in a mixing apparatus for less than about fifteen minutes. 16. The method of claim 2 further comprising cooling the combined whole muscle meat and the initial mixture. 17. A method for customizing a raw base material into a whole muscle meat product at a meat processing plant, the method comprising:
receiving a raw base material of whole muscle meat pieces and initial mixture that have been shipped from a packing plant and arrives at the meat processing plant having undergone at least some protein extraction and color development; mixing the raw base material with a customized ingredient mix thereby creating a processed whole muscle mixture; thermally processing the processed whole muscle mixture to produce a cooked processed whole muscle meat product. 18. The method of claim 17, wherein the customized ingredient mix includes at least one of:
salt; sugar; phosphates; ascorbate; sodium erythorbate; brown sugar; honey; flavorings; mesquite seasonings; sea salt; vinegar; sodium lactate; sodium diacetate; and liquid smoke flavoring. 19. The method of claim 17 wherein the raw base material is mixed with the customized ingredient mix in at least one of:
a mixer;
a continuous mixer;
a massager; and
a tumbler. 20. A method of processing whole muscle meat, the method comprising:
deboning whole muscle meat to thereby create boneless whole muscle meat; reducing the whole muscle meat into whole muscle meat pieces and macerating the whole muscle meat pieces to increase surface area and rupture at least some individual muscle cell walls of the whole muscle meat pieces; mixing a first mixture with the whole muscle meat pieces; packing the whole muscle meat pieces and the first mixture into a container; transporting the container with the whole muscle meat pieces and the first mixture to a meat processing plant thereby delivering a base meat mixture to the meat processing plant for further processing; and mixing the base meat mixture with a second mixture. 21. The method of claim 20 wherein the second mixture comprises at least one of:
salt;
sugar;
phosphates;
ascorbate;
sodium erythorbate;
brown sugar;
honey;
flavorings;
mesquite seasonings
sea salt;
vinegar;
sodium lactate;
sodium diacetate; and
liquid smoke flavoring. 22. The method of claim 20 wherein mixing the base meat material comprising a second mixing step comprising a continuous mixing processes wherein the base meat mixture is input at the same time that a whole muscle meat product is output. 23. The method of claim 20 wherein mixing the base meat material comprising a second mixing step comprising a continuous massaging processes wherein the base meat mixture is input at the same time that a whole muscle meat product is output such that during the continuous massaging process a plurality of rotating massaging elements. 24. The method of claim 20 further comprises thermally processing the whole muscle meat product. 25. The method of claim 20 wherein macerating the whole muscle meat pieces to increase the surface area includes passing the whole muscle meat pieces through a gap between a first and a second arbors configured to counter-rotate wherein at least the first arbor has protrusions that extend into channels on the second arbor 26. A method of processing a whole muscle meat product:
providing boneless whole muscle meat; combining an initial cure mixture with the whole muscle meat and mixing the initial cure mixture and the whole muscle meat to create a raw base mix including the whole muscle meat and the initial cure mixture; after mixing the initial cure mixture with the whole muscle meat, filling a container with the raw base mix; transporting the container with the raw base mix to a meat processing plant; and upon receipt of the raw base mix at the meat processing plant, combining and mixing the raw base mix with a customized ingredient mix and water to produce a processed whole muscle mixture. | A method for producing a processed meat product begins at the supplier, where whole muscle meat is reduced into whole muscle meat pieces and the pieces may be macerated to increase their surface area. Prior to shipment of the whole muscle meat from the supplier to the meat processing plant, the whole muscle meat pieces are mixed with an initial ingredient mixture to create a raw base mixture and then packed into a container. The containers are shipped to a meat processing plant, whereby upon receipt of the raw base mixture at the processing plant, the raw base mixture is mixed with a customized ingredient mix to create a processed whole muscle mixture. The processed whole muscle mixture may then be stuffed and thermally processed.1. A method for preparing a raw base material for use in a processed meat product, the method comprising:
at a meat packing plant, deboning whole muscle meat to thereby create boneless whole muscle meat having a surface area; increasing the surface area of the whole muscle meat at said meat packing plant; mixing an initial mixture with the whole muscle meat at said meat packing plant; packing the whole muscle meat and the initial mixture into a container at said meat packing plant; and shipping the container with the whole muscle meat and the initial mixture to a meat processing plant such that the initial mixture is in contact with said whole muscle meat over a time period of at least 2 hours such that the initial mixture has the effect of at least partially processing the whole muscle meat during shipping. 2. The method of claim 1, wherein increasing the surface area of the whole muscle meat comprises reducing the whole muscle meat into whole muscle meat pieces. 3. The method of claim 2, wherein increasing a surface area of the whole muscle meat further comprises macerating the whole muscle meat pieces to further increase the surface area of the whole muscle pieces. 4. The method of claim 2 wherein reducing the whole muscle meat to whole muscle meat pieces utilizes at least one of:
a macerator;
a slicer;
a kidney plate;
a dicer;
a double macerator;
a manual knife size reduction;
a water jet;
a harping unit;
a slasher;
a chopper;
a grinder; and
a laser cutter. 5. The method of claim 4 wherein the macerator includes first and second arbors configured to counter-rotate during operation wherein at least one of the first and second arbors has protrusions that extend into channels of the other of the first and second arbors. 6. The method of claim 6 wherein the first and second arbors have an integral assembly of alternating radially projecting and axially extending protrusions and channels. 7. The method of claim 2 wherein the initial mixture comprises at least one of:
a salt concentration;
a nitrite;
a cure accelerator; and
an alternative preservation ingredient. 8. The method of claim 7 wherein the cure accelerator includes at least one of:
erythorbate;
ascorbate;
ascorbic acid;
glucono-delta-lactone; and
acid pyrophosphate. 9. The method of claim 7 wherein the mixing of the initial mixture with the whole muscle meat occurs in steps such that the salt concentration and the nitrite area mixed with the whole muscle meat prior to the mixing of the cure accelerator. 10. The method of claim 7 wherein the mixing of the initial mixture with the whole muscle meat occurs such that all ingredients of the initial mixture are mixed simultaneously. 11. The method of claim 2 wherein the initial mixture comprises a salt concentration of about 0.5% to 6% of the weight of the whole muscle meat pieces and further comprises 70 ppm to 160 ppm of nitrite and less than about 500 ppm of sodium ascorbate. 12. The method of claim 2 wherein the initial mixture comprises a salt concentration and nitrite and at least one of:
flavorings;
water; and
additional cure components. 13. The method of claim 2, wherein the whole muscle pieces have an average thickness of approximately ¼ in. to 3 in. 14. The method of claim 2 further comprising adding ground meat trimmings and other meat ingredients to the whole muscle pieces along with the initial mixture. 15. The method of claim 2, wherein mixing the initial mixture with the whole muscle meat pieces further comprises mixing the initial mixture and the whole muscle meat pieces in a mixing apparatus for less than about fifteen minutes. 16. The method of claim 2 further comprising cooling the combined whole muscle meat and the initial mixture. 17. A method for customizing a raw base material into a whole muscle meat product at a meat processing plant, the method comprising:
receiving a raw base material of whole muscle meat pieces and initial mixture that have been shipped from a packing plant and arrives at the meat processing plant having undergone at least some protein extraction and color development; mixing the raw base material with a customized ingredient mix thereby creating a processed whole muscle mixture; thermally processing the processed whole muscle mixture to produce a cooked processed whole muscle meat product. 18. The method of claim 17, wherein the customized ingredient mix includes at least one of:
salt; sugar; phosphates; ascorbate; sodium erythorbate; brown sugar; honey; flavorings; mesquite seasonings; sea salt; vinegar; sodium lactate; sodium diacetate; and liquid smoke flavoring. 19. The method of claim 17 wherein the raw base material is mixed with the customized ingredient mix in at least one of:
a mixer;
a continuous mixer;
a massager; and
a tumbler. 20. A method of processing whole muscle meat, the method comprising:
deboning whole muscle meat to thereby create boneless whole muscle meat; reducing the whole muscle meat into whole muscle meat pieces and macerating the whole muscle meat pieces to increase surface area and rupture at least some individual muscle cell walls of the whole muscle meat pieces; mixing a first mixture with the whole muscle meat pieces; packing the whole muscle meat pieces and the first mixture into a container; transporting the container with the whole muscle meat pieces and the first mixture to a meat processing plant thereby delivering a base meat mixture to the meat processing plant for further processing; and mixing the base meat mixture with a second mixture. 21. The method of claim 20 wherein the second mixture comprises at least one of:
salt;
sugar;
phosphates;
ascorbate;
sodium erythorbate;
brown sugar;
honey;
flavorings;
mesquite seasonings
sea salt;
vinegar;
sodium lactate;
sodium diacetate; and
liquid smoke flavoring. 22. The method of claim 20 wherein mixing the base meat material comprising a second mixing step comprising a continuous mixing processes wherein the base meat mixture is input at the same time that a whole muscle meat product is output. 23. The method of claim 20 wherein mixing the base meat material comprising a second mixing step comprising a continuous massaging processes wherein the base meat mixture is input at the same time that a whole muscle meat product is output such that during the continuous massaging process a plurality of rotating massaging elements. 24. The method of claim 20 further comprises thermally processing the whole muscle meat product. 25. The method of claim 20 wherein macerating the whole muscle meat pieces to increase the surface area includes passing the whole muscle meat pieces through a gap between a first and a second arbors configured to counter-rotate wherein at least the first arbor has protrusions that extend into channels on the second arbor 26. A method of processing a whole muscle meat product:
providing boneless whole muscle meat; combining an initial cure mixture with the whole muscle meat and mixing the initial cure mixture and the whole muscle meat to create a raw base mix including the whole muscle meat and the initial cure mixture; after mixing the initial cure mixture with the whole muscle meat, filling a container with the raw base mix; transporting the container with the raw base mix to a meat processing plant; and upon receipt of the raw base mix at the meat processing plant, combining and mixing the raw base mix with a customized ingredient mix and water to produce a processed whole muscle mixture. | 1,700 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.