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Claims for Patent: 5,023,082

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Claims for Patent: 5,023,082

Title: Sustained-release pharmaceutical compositions
Abstract:The present invention pertains to biodegradable sustained-release composins capable of achieving the sustained release of a pharmaceutical or other agent. The compositions can be formed into implant devices which may be used to treat a wide variety of diseases and conditions. The implants are especially useful in treating diseases such as periodontal disease which require prolonged drug release.
Inventor(s): Friedman; Michael (Jerusalem, IL), Steinberg; Doron (Jerusalem, IL), Soskolne; Aubrey (Jerusalem, IL)
Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem (Jerusalem, IL)
Application Number:07/175,623
Patent Claims: 1. A liquid precursor composition for the preparation of a biodegradable sustained-release composition for the administration of an active agent, wherein said sustained-release composition is formed by solidification of said liquid precursor composition, said liquid precursor composition comprising:

(1) a plasticizing agent, wherein said plasticizing agent is selected from the group consisting of a phthalate ester, a phosphate ester, a glycol derivative, a hydrocarbon, an oil, and a fatty acid;

(2) said active agent, wherein said active agent is present in an amount sufficient to impart a desired therapeutic, agricultural, or catalytic property to said sustained-release composition;

(3) a cross-linking agent, wherein said cross-linking agent is selected from the group consisting of aldehydes, alcohols, aluminum, chromium, titanium, zirconium, an acyl chloride, bis-diazobenzidine, phenol-2,4-disulfonyl chloride, 1,5-difluoro-2,4-dinitrobenzene, urea, 3,6-bis(mercurimethyl)-dioxane urea, dimethyl adipimidate and N,N'-ethylene-bis-iodacetamide; and

(4) a water-soluble protein which is capable of being cross-linked into a water-insoluble, biodegradable polymeric matrix, wherein said water-soluble protein is present at a concentration sufficient to provide said sustained-release composition with structural stability after being cross-linked, but not at so great a concentration as to render said sustained-release composition (i) incapable of biodegradation or (ii) incapable of permitting the release of said active agent.

2. A biodegradable sustained-release composition for the administration of an active agent, wherein said sustained-release composition comprises:

(1) a plasticizing agent, wherein said plasticizing agent is selected from the group consisting of a phthalate ester, a phosphate ester, a glycol derivative, a hydrocarbon, an oil, and a fatty acid;

(2) said active agent, wherein said active agent is present in an amount sufficient to impart a desired therapeutic, agricultural, or catalytic property to said sustained-release composition;

(3) a cross-linking agent, wherein said cross-linking agent is selected from the group consisting of aldehydes, alcohols, aluminum, chromium, titanium, zirconium, an acyl chloride, bis-diazobenzidine, phenol-2,4-disulfonyl chloride, 1,5-difluoro-2,4-dinitrobenzene, urea, 3,6-bis(mercurimethyl)-dioxane urea, dimethyl adipimidate and N,N'-ethylene-bis-iodacetamide; and

(4) a biodegradable polymeric matrix comprising a cross-linked, water-insoluble protein, wherein said matrix formed upon the cross-linking of a water-soluble protein, and wherein said cross-linked, water-insoluble, protein is present at a concentration sufficient to provide said sustained-release composition with structural stability after being cross-linked, but not at so great a concentration as to render said sustained-release composition (i) incapable of biodegradation or (ii) incapable of permitting the release of said active agent.

3. A method for the administration of an active agent, wherein said method comprises the administration of a liquid precursor composition, wherein said liquid precursor composition solidifies to form a biodegradable sustained-release composition after said administration, said liquid precursor composition comprising:

(1) a plasticizing agent, wherein said plasticizing agent is selected from the group consisting of a phthalate ester, a phosphate ester, a glycol derivative, a hydrocarbon, an oil, and a fatty acid;

(2) said active agent, wherein said active agent is present in an amount sufficient to impart a desired therapeutic, agricultural, or catalytic property to said sustained-release composition;

(3) a cross-linking agent, wherein said cross-linking agent is selected from the group consisting of aldehydes, alcohols, aluminum, chromium, titanium, zirconium, an acyl chloride, bis-diazobenzidine, phenol-2,4-disulfonyl chloride, 1,5-difluoro-2,4-dinitrobenzene, urea, 3,6-bis(mercurimethyl)-dioxane urea, dimethyl adipimidate and N,N'-ethylene-bis-iodacetamide; and

(4) a water-soluble protein which is capable of being cross-linked into a water-insoluble, biodegradable polymeric matrix, wherein said water-soluble protein is present at a concentration sufficient to provide said sustained-release composition with structural stability after being cross-linked, but not at so great a concentration as to render said sustained-release composition (i) incapable of biodegradation or (ii) incapable of permitting the release of said active agent.

4. The composition of claim 2, wherein said cross-linking agent is present in said sustained-release composition in an amount sufficient to render said water soluble protein insoluble but not in an amount which prevents the release of said active agent from said sustained-release composition.

5. The composition of claim 1 or 2 wherein said cross-linking agent is present in said sustained-release composition in an amount of from about 0.01% to about 26%.

6. The composition of claim 1 or 2 wherein said cross-linking agent is an aldehyde selected from the group consisting of formaldehyde and glutaraldehyde.

7. The composition of claim 6 wherein said cross-linking agent is glutaraldehyde.

8. The composition of claim 1 or 2 wherein said cross-linked protein is cross-linked by incubation in the presence of cross-linking means, said means being selected from the group consisting of: heat, pressure, radiation, and the vapors of a cross-linking agent.

9. The composition of claim 8 wherein said cross-linked protein is cross-linked to an extent sufficient to render said water soluble protein insoluble but not to an extent which prevents the release of the active agent from said sustained-release composition.

10. A method for the administration of an active agent, wherein said method comprises the administration of a biodegradable sustained-release composition, said sustained-release composition comprising:

(1) a plasticizing agent, wherein said plasticizing agent is selected from the group consisting of a phthalate ester, a phosphate ester, a glycol derivative, a hydrocarbon, an oil, and a fatty acid;

(2) said active agent, wherein said active agent is present in an amount sufficient to impart a desired therapeutic, agricultural or catalytic property to said sustained-release composition;

(3) a cross-linking agent, wherein said cross-linking agent is selected from the group consisting of aldehydes, alcohols, aluminum, chromium, titanium, zirconium, an acyl chloride, bis-diazobenzidine, phenol-2,4-disulfonyl chloride, 1,5-difluoro-2,4-dinitrobenzene, urea, 3,6-bis(mercurimethyl)-dioxane urea, dimethyl adipimidate and N,N'-ethylene-bis-iodacetamide; and

(4) a biodegradable polymeric matrix comprising a cross-linked, water-insoluble protein, wherein said matrix formed upon the cross-linking of a water-soluble protein, and wherein said cross-linked, water-insoluble protein is present at a concentration sufficient to provide said sustained-release composition with structural stability after being cross-linked, but not at so great a concentration as to render said sustained-release composition (i) incapable of biodegradation or (ii) incapable of permitting the release of said active agent.

11. The composition of any one of claims 1 or 2 wherein said protein is selected from the group consisting of: gelatin, collagen, albumin, an enzyme, and fibrinogen.

12. The composition of claim 11 wherein said protein is gelatin.

13. The composition of claim 12 wherein said gelatin is hydrolyzed gelatin.

14. The composition of any one of claims 1 or 2 wherein said protein is present in said sustained release composition at a concentration of from about 14% to about 93%.

15. The composition of any one of claims 1 or 2 wherein said plasticizing agent is present in an amount sufficient to effect brittleness but not at so great a concentration as to prevent the release of the active agent.

16. The composition of claim 1 or 2 wherein said plasticizing agent is a glycol derivative.

17. The composition of claim 16 wherein said glycol derivative is selected from the group consisting of: glycerin and sorbitol.

18. The composition of claim 17 wherein said glycol derivative is glycerin.

19. The composition of any one of claims 1 or 2 wherein said plasticizing agent is in said sustained-release composition present at a concentration of from about 0.01% to about 52%.

20. The composition of any one of claims 1 or 2 wherein said active agent is a pharmacological agent.

21. The composition of claim 20 wherein said pharmacological .agent is selected from the group consisting of: an analgesic, an anti-arrthymic drug, an anti-bacterial agent, an antibiotic, an antiviral agent, an anti-convulsant agent, an anti-fungal agent, an anti-pyretic agent, an anti-inflammatory agent, an anti-tumor agent, an anti-ulcer drug, a cardiovascular drug, a diuretic, a hormone, a hypoglycemic drug, a hypotensive drug, an ophthalmocological agent, a sedative, a hypnotic, and a tranquilizer.

22. The composition of claim 21 wherein said pharmacological agent is an antibacterial agent.

23. The composition of claim 22 wherein said antibacterial agent is selected from the group consisting of penicillin, cephalosporin, tetracycline, oxytetracycline, chlortetracycline, metronidazole, chloramphenicol, streptomycin, neomycin, a sulfonamide, a phenolic compound, a mercurial, a quarternary ammonium compound, and chlorhexidine.

24. The composition of claim 23 wherein said antibacterial agent is chlorhexidine.

25. The composition of claim 20 wherein said composition contains more than one pharmacological agent, said agent being selected from the group consisting of: an analgesic, an anti-arrthymic drug, an anti-bacterial agent, an antibiotic, an antiviral agent, an anti-convulsant agent, an anti-fungal agent, an anti-pyretic agent, an anti-inflammatory agent, an anti-tumor agent, an anti-ulcer drug, a cardiovascular drug, a diuretic, a hormone, a hypoglycemic drug, a hypotensive drug, an ophthalmocological agent, a sedative, a hypnotic, and a tranquilizer.

26. The composition of claim 25 wherein all of said pharmacological agents are selected from the same group of therapeutic agents, and wherein said group of therapeutic agents is selected from the group consisting of: an analgesic, an anti-arrthymic drug, an anti-bacterial agent, an antibiotic, an antiviral agent, an anti-convulsant agent, an anti-fungal agent, an anti-pyretic agent, an anti-inflammatory agent, an anti-tumor agent, an anti-ulcer drug, a cardiovascular drug, a diuretic, a hormone, a hypoglycemic drug, a hypotensive drug, an ophthalmocological agent, a sedative, a hypnotic, and a tranquilizer.

27. The composition of claim 20 wherein said sustained-release composition is substantially a two-dimensional film.

28. The composition of claim 27 wherein said film is from about 3 to about 10 mm in length, and from about 1 to about 5 mm in width, and from about 0.01 to 0.5 mm in depth.

29. A composition of claim 20 wherein said pharmacological agent and said protein are present in said sustained-release composition at a relative weight ratio which ranges from about 0.01:7 to about 3:1.

30. The composition of claim 20 wherein said plasticizing agent and said protein are present in said sustained-release composition at a relative weight ratio which ranges from about 0.01:7 to about 4:7.

31. The composition of claim 20 wherein said sustained-release composition has a flexibility which ranges from about 0.1 kg/mm.sup.2 to about 50 kg/mm.sup.2.

32. The method of any one of claims 3 or 10 wherein said composition is administered to said patient by means selected from the group consisting of: intra-nasal means, intra-ocular means, intra-aural means, subcutaneous means, transdermal means, topical application, and parenteral means.

33. The method of any one of claim 3 or 10 wherein said composition is administered as an implant selected from the group consisting of: a gingival crevice implant; a vaginal implant; and a testicular implant.

34. The method of claim 33 wherein said composition is administered as a gingival crevice implant.

35. A method for the treatment of a condition wherein said method comprises providing to a patient in need of such treatment the composition of any one of claims 1 or 2, wherein said composition contains a pharmacological agent capable of providing said treatment and wherein said pharmacological agent is present in an amount sufficient to impart therapeutic effect to said sustained-release composition.

36. The method of claim 35 wherein said composition is provided to said patient as an implant into a periodontal pocket of said patient.

37. The method of claim 36 wherein said pharmacological agent of said pharmaceutical composition is an antibacterial agent.

38. The method of claim 37 wherein said condition is periodontal disease, and wherein said antibacterial agent is effective in the treatment of said periodontal disease.

39. The method of claim 35 wherein said condition is pericoronitis.

40. The method of claim 35 wherein said treatment is an adjunct to endodontic treatment.

41. The method of claim 35 wherein said treatment is an adjunct to a tooth implantation procedure.

42. The method of claim 35 wherein said treatment is an adjunct to an epiectomy.
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