Gel composition and methods

• US 6,673,767 B1
• Filed: 03/21/2000
• Issued: 01/06/2004
• Est. Priority Date: 12/20/1996
• Status: Expired due to Fees

• Current Assignee: DURECT Corporation
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Brodbeck, Kevin J., Shen, Theodore Tao-Ian, Gaynor-Duarte, Ann T.
• Primary Examiner(s): PRATS, FRANCISCO CHANDLER
• Application Number:
  US09/532,337
• Time in Patent Office: 1,386 Days
• Field of Search: 514/2, 514/772.3, 514/777, 424/422, 424/423, 424/426, 424/486, 424/487, 424/488, 604/51, 604/891.1, 604/48, 604/49, 530/399, 530/351
• US Class Current: 424/85.4
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system

Abstract

Methods and compositions for systemically or locally administering by implantation a beneficial agent to a subject are described, and include, for example, compositions having burst indices of 8 or less for systemic applications and systems releasing 10% or less of the total dose of beneficial agent in the first 24 hours after implantation for local applications. The compositions include a biocompatible polymer, a biocompatible solvent having low water miscibility that forms a viscous gel with the polymer and limits water uptake by the implant, and a beneficial agent.

Claims

1. A method of systemically administering a beneficial agent to a subject which comprises implanting a system comprising a polylactide polymer;

an effective plasticizing amount of a solvent comprising a lower alkyl or aralkyl ester of benzoic acid to form a gel with the polymer; and

a beneficial agent;

wherein said beneficial agent is dissolved or dispersed substantially throughout the gel.

2. The method of claim 1 in which the gel includes one or more of the following:

an emulsifying agent, a pore former, a solubility modulator for the beneficial agent and an osmotic agent.

3. The method of claim 1 wherein the solvent comprises a solvent having a miscibility in water of less than 7% by weight.

4. The method of claim 3 wherein the solvent is selected from the group consisting of benzyl benzoate and ethyl benzoate.

7. The method of claim 1 wherein the beneficial agent is present in an amount of from 1 to 50% by weight of the combined amounts of the polymer, the solvent and the beneficial agent.

8. The method of claim 1 wherein the beneficial agent is cDNA, DNA, a protein, a peptide, and derivatives or fragments thereof, or a chemotherapeutic agent.

9. The method of claim 8 wherein the beneficial agent is human growth hormone, methionine-human growth hormone, des-phenylalanine human growth hormone, interferon alpha-2a, interferon alpha-2b, or consensus interferon.

10. The method of claim 1 wherein the system is non-rigid after implantation.

11. The method of claim 10 wherein the system maintains a glass transition temperature below 37°

C. for at least 24 hours after implantation.

12. The method of claim 4 comprising a solubility modulator of the beneficial agent.

13. The method of claim 4 comprising a pore former.

14. The method of claim 4 comprising an emulsifying agent.

15. The method of claim 4 comprising an osmotic agent.

16. The method of claim 2 or claim 12 wherein the solubility modulator is selected from salts of divalent metals.

17. The method of claim 2 or claim 13 in which the pore former is water soluble.

18. The method of claim 17 wherein the pore former is selected from group consisting of water soluble sugars, salts, solvents and polymers.

19. The method of claim 2 or claim 14 in which the emulsifying agent is capable of forming a dispersed droplet phase in said gel.

20. The method of claim 19 in which the emulsifying agent is selected from the group consisting of alcohols, propylene glycol, ethylene glycol, glycerol, water and solutions and mixtures thereof.

21. The method of claim 20 wherein the emulsifying agent is selected from the group consisting of ethanol, isopropyl alcohol, water, solutions thereof, and mixtures thereof.

22. The method of claim 1 wherein the polylactide polymer is a copolymer of lactic acid and glycolic acid and the copolymer has a monomer ratio of lactic acid to glycolic acid in the range of about 100:

0 to about 15;

85.

23. The method of claim 22 wherein the copolymer has a number average molecular weight of from 1,000 to 120,000.

24. The method of claim 4 wherein the solvent comprises a component solvent miscible with the solvent.

25. The method of claim 24 wherein the component solvent is selected from the group consisting of triacetin, diacetin, tributyrin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethylglycerides, triethyl phosphate, diethyl phthalate, diethyl tartrate, mineral oil, polybutene, silicone fluid, glylcerin, ethylene glycol, polyethylene glycol, octanol, ethyl lactate, propylene glycol, propylene carbonate, ethylene carbonate, butyrolactone, ethylene oxide, propylene oxide, N-methyl-2-pyrrolidone, 2-pyrrolidone, glycerol formal, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid, and 1-dodecylazacyclo-heptan-2-one, and mixtures thereof.

26. The method of claim 24 wherein the component solvent is selected from the group consisting of triacetin and N-methyl-2-pyrrolidone, and mixtures thereof.

27. The method of claim 24 wherein the component solvent is triacetin.

28. The method of claim 4 wherein the beneficial agent is present in an amount of from 1 to 50% by weight of the combined amounts of the polymer, the solvent and the beneficial agent.

29. The method of claim 4 wherein the beneficial agent is cDNA, DNA, a protein, a peptide, and derivatives or fragments thereof, or a chemotherapeutic agent.

30. The method of claim 4 wherein the beneficial agent is a human growth hormone, methionine-human growth hormone, des-pheylalanine human growth hormone, interferon alpha-2a, or consessus interferon.

5. A method of administering a beneficial agent to a subject which comprises implanting a system comprising a beneficial agent dissolved or dispersed substantially throughout a gel formed of a polylactide polymer and a solvent having a solubility in water of 7% or less, wherein said solvent is a lower alkyl or aralkyl ester of benzoic acid, and a solubility modulator of the beneficial agent.

6. The method of claim 5 wherein the polymer is a lactic acid-based polymer.

31. A method of systemically administering a beneficial agent to a subject which comprises implanting a system comprising a poly(lactide-co-glycolide) copolymer;

an effective plasticizing amount of a solvent comprising a lower alkyl or aralkyl ester of benzoic acid to form a gel with the polymer; and

a beneficial agent;

said beneficial agent dissolved or dispersed substantially throughout the gel.

32. The method of claim 31 wherein the solvent has a miscibility in water by weight of less than 7%.

33. The method of claim 31 wherein the solvent is benzyl benzoate.

34. The method of claim 31 comprising a solubility modulator of the beneficial agent.

35. The method of claim 31 comprising a pore former.

36. The method of claim 31 comprising an emulsifying agent.

37. The method of claim 31 comprising an osmotic agent.

38. The method of claim 34 wherein the solubility modulator is selected from salts of divalent metals.

39. The method of claim 35 in which the pore former is water soluble.

40. The method of claim 35 wherein the pore former is selected from group consisting of water soluble sugars, salts, solvents and polymers.

41. The method of claim 36 in which the emulsifying agent is capable of forming a dispersed droplet phase in said gel.

42. The method of claim 36 in which the emulsifying agent is selected from the group consisting of alcohols, propylene glycol, ethylene glycol, glycerol, water and solutions and mixtures thereof.

43. The method of claim 36 wherein the emulsifying agent is selected from the group consisting of ethanol, isopropyl alcohol, water, solutions thereof, and mixtures thereof.

44. The method of claim 31 wherein the copolymer has a monomer ratio of lactic acid to glycolic acid in the range of 100:

0 to about 15;

85.

45. The method of claim 31 wherein the copolymer has a number average molecular weight of from 1,000 to 120,000.

46. The method of claim 31 wherein the solvent comprises a component solvent miscible with the solvent.

47. The method of claim 46 wherein the component solvent is selected from the group consisting of triacetin, diacetin, tributyrin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethylglycerides, triethyl phosphate, diethyl phthalate, diethyl tartrate, mineral oil, polybutene, silicone fluid, glylcerin, ethylene glycol, polyethylene glycol, octanol, ethyl lactate, propylene glycol, propylene carbonate, ethylene carbonate, butyrolactone, ethylene oxide, propylene oxide, N-methyl-2-pyrrolidone, 2-pyrrolidone, glycerol formal, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid, and 1-dodecylazacyclo-heptan-2-one, and mixtures thereof.

48. The method of claim 46 wherein the component solvent is selected from the group consisting of triacetin and N-methyl-2-pyrrolidone, and mixtures thereof.

49. The method of claim 46 wherein the component solvent is triacetin.

50. The method of claim 31 wherein the beneficial agent is present in an amount of from 1 to 50% by weight of the combined amounts of the polymer, the solvent, and the beneficial agent.

51. The method of claim 31 wherein the beneficial agent is cDNA, DNA, a protein, a peptide, and derivatives or fragments thereof, or a chemotherapeutic agent.

52. The method of claim 31 wherein the beneficial agent is human growth hormone, methionine-human growth hormone, des-phenylalanine human growth hormone, interferon alpha-2a, interferon alpha-2b, or consensus interferon.

53. The method of claim 31 wherein the solvent is ethyl benzoate.

54. The method of claim 31 wherein the system is non-rigid after implantation.

55. The method of claim 54 wherein the system maintains a glass transition temperature below 37°

C. for at least 24 hours after implantation.

56. A method of systemically administering a beneficial agent to a subject which comprises implanting a system comprising a beneficial agent dissolved or dispersed substantially throughout a gel formed of a polylactide polymer;

an amount of a solvent comprising a lower alkyl or aralkyl ester of benzoic acid effective to form a viscous gel, having a viscosity of from about 1,000 poise to about 200,000 poise, with the polymer; and

a beneficial agent.

58. The method of claim 56 or claim 57 wherein the solvent has a miscibility in water by weight of less than 7%.

59. The method of claim 56 or claim 57 wherein the solvent is benzyl benzoate.

60. The method of claim 56 or claim 57 comprising a solubility modulator of the beneficial agent.

61. The method of claim 56 or claim 57 comprising a pore former.

62. The method of claim 56 or claim 57 comprising an emulsifying agent.

63. The method of claim 56 or claim 57 comprising an osmotic agent.

64. The method of claim 60 wherein the solubility modulator is selected from salts of divalent metals.

65. The method of claim 61 in which the pore former is water soluble.

66. The method of claim 61 wherein the pore former is selected from group consisting of water soluble sugars, salts, solvents and polymers.

67. The method of claim 62 in which the emulsifying agent is capable of forming a dispersed droplet phase in said gel.

68. The method of claim 62 in which the emulsifying agent is selected from the group consisting of alcohols, propylene glycol, ethylene glycol, glycerol, water and solutions and mixtures thereof.

69. The method of claim 62 wherein the emulsifying agent is selected from the group consisting of ethanol, isopropyl alcohol, water, solutions thereof, and mixtures thereof.

70. The method of claim 56 or claim 57 wherein the copolymer has a monomer ratio of lactic acid to glycolic acid in the range of 100:

0 to about 15;

85.

71. The method of claim 56 or claim 57 wherein the copolymer has a number average molecular weight of from 1,000 to 120,000.

72. The method of claim 56 or claim 57 wherein the solvent comprises a component solvent miscible with the solvent.

73. The method of claim 72 wherein the component solvent is selected from the group consisting of triacetin, diacetin, tributyrin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethylglycerides, triethyl phosphate, diethyl phthalate, diethyl tartrate, mineral oil, polybutene, silicone fluid, glylcerin, ethylene glycol, polyethylene glycol, octanol, ethyl lactate, propylene glycol, propylene carbonate, ethylene carbonate, butyrolactone, ethylene oxide, propylene oxide, N-methyl-2-pyrrolidone, 2-pyrrolidone, glycerol formal, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid, and 1-dodecylazacyclo-heptan-2-one, and mixtures thereof.

74. The method of claim 72 wherein the component solvent is selected from the group consisting of triacetin and N-methyl-2-pyrrolidone, and mixtures thereof.

75. The method of claim 72 wherein the component solvent is triacetin.

76. The method of claim 56 or claim 57 wherein the beneficial agent is present in an amount of from 1 to 50% by weight of the combined amounts of the polymer, the solvent, and the beneficial agent.

77. The method of claim 56 or claim 57 wherein the beneficial agent is cDNA, DNA, a protein, a peptide, and derivatives or fragments thereof, or a chemotherapeutic agent.

78. The method of claim 56 or claim 57 wherein the beneficial agent is human growth hormone, methionine-human growth hormone, des-phenylalanine human growth hormone, interferon alpha-2a, interferon alpha-2b, or consensus interferon.

79. The method of claim 56 or claim 57 wherein the solvent is ethyl benzoate.

80. The method of claim 56 or claim 57 wherein the system is non-rigid after implantation.

81. The method of claim 80 wherein the system maintains a glass transition temperature below 37°

C. for at least 24 hours after implantation.

57. A method of systemically administering a beneficial agent to a subject which comprises implanting a system comprising a beneficial agent dissolved or dispersed substantially throughout a gel formed of a poly(lactide-co-glycolide) copolymer;

an amount of a solvent comprising a lower alkyl or aralkyl ester of benzoic acid effective to form a viscous gel, having a viscosity of from about 1,000 poise to about 200,000 poise, with the polymer; and

a beneficial agent.