Injectable depot compositions and uses thereof

• US 20040024069A1
• Filed: 11/14/2002
• Published: 02/05/2004
• Est. Priority Date: 07/31/2002
• Status: Active Grant

• Current Assignee: DURECT Corporation
• Original Assignee: DURECT Corporation
• Inventors: Chen, Guohua, Houston, Paul R., Spaltro, John J., Kleiner, Lothar Walter
• Granted Patent: US 8,252,303 B2
• Time in Patent Office: Days
• US Class Current: 514/772.3
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 38/1858 Platelet-derived growth factor [PDGF]
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 9/0002 Galenical forms characterised by the drug release technique; Application systems commanded by energy
• 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: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Injectable depot compositions are provided that include a bioerodible, biocompatible polymer, a solvent having a miscibility in water of less than or equal to 7 wt. % at 25° C., in an amount effective to plasticize the polymer and form a gel therewith, a thixotropic agent, and a beneficial agent. The solvent comprises an aromatic alcohol, an ester of an aromatic acid, an aromatic ketone, or mixtures thereof. The compositions have substantially improved the shear thinning behavior and reduced injection force, rendering the compositions readily implanted beneath a patient'"'"'s body surface by injection.

Claims

1. An injectable depot composition comprising:

(a) a bioerodible, biocompatible polymer;

(b) a solvent having a miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the polymer and form a gel therewith, wherein said solvent is an aromatic alcohol;

(c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and

(d) a beneficial agent.

3. The injectable depot composition of claim 1 or claim 2, wherein the aromatic alcohol has the structural formula (I)

Ar-(L)_n-OH

wherein Ar is aryl or heteroaryl, n is zero or 1, and L is a linking moiety.

4. The injectable depot composition of claim 3, wherein Ar is monocyclic aryl or heteroaryl, n is 1, and L is lower alkylene optionally containing at least one heteroatom.

5. The injectable depot composition of claim 4, wherein Ar is monocyclic aryl and L is lower alkylene.

6. The injectable depot composition of claim 5, wherein Ar is phenyl and L is methylene.

10. The injectable depot composition of claim 1 or claim 2 wherein the thixotropic agent is ethanol.

11. The injectable depot composition of claim 10 wherein the amount of ethanol is greater than or equal to 0.01 weight percent and less than or equal to 15 weight percent of the combined weight of the solvent and the thixotropic agent.

12. The injectable depot composition of claim 10 wherein the amount of ethanol is greater than or equal to 0.1 weight percent and less than or equal to 5 weight percent of the combined weight of the solvent and the thixotropic agent.

13. The injectable depot composition of claim 10 wherein the amount of ethanol is greater than or equal to 0.5 weight percent and less than or equal to 5 weight percent of the combined weight of the solvent and the thixotropic agent.

14. The injectable depot composition of claim 1 or claim 2, wherein the polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, hyaluronic acid, and copolymers, terpolymers and mixtures thereof.

15. The injectable depot composition of claim 1 or claim 2, wherein the polymer is a lactic acid-based polymer.

16. The injectable depot composition of claim 15, wherein the polymer is a copolymer of at least two of the following monomers:

lactic acid, glycolic acid and caprolactone.

17. The injectable depot composition of claim 1 or claim 2, further including at least one of the following:

a pore former;

a solubility modulator for the beneficial agent; and

an osmotic agent.

18. The injectable depot of claim 1 or claim 2 wherein the beneficial agent is selected from a drug, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, chemotherapeutic agents, immunosuppressive agents, anti-inflammatory agents, antiproliferative agents, antimitotic agents, angiogenic agents, anticoagulants, fibrinolytic agents, growth factors, antibodies, ocular drugs, and metabolites, analogs, derivatives, and fragments thereof.

19. The injectable depot of claim 18 wherein the beneficial agent is a growth hormone.

20. The injectable depot of claim 18 wherein the beneficial agent is a growth factor.

21. The injectable depot of claim 18 wherein the beneficial agent is present in an amount of from 0.1 to 50% by weight of the combined amounts of the polymer, the solvent and the beneficial agent.

22. The injectable depot of claim 18 wherein the beneficial agent is in the form of particles dispersed or dissolved in the viscous gel.

23. The injectable depot of claim 22 wherein the beneficial agent is in the form of particles having an average particle size of from 0.1 to 250 microns.

115. The injectable depot of claim 22 wherein the beneficial agent is in the form of particles wherein the particle further comprises a component selected from the group consisting of a stabilizing agent, bulking agent, chelating agent and a buffering agent.

2. An injectable depot composition comprising:

(a) a bioerodible, biocompatible polymer;

(b) a solvent selected from the group consisting of aromatic alcohols, esters of aromatic acids, aromatic ketones, and mixtures thereof, said solvent having a miscibility in water of less than or equal to 7% at 25°

C., and present in an amount effective to plasticize the polymer and form a gel therewith;

(c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and

(d) a beneficial agent.

7. The injectable depot composition of claim 2, wherein the solvent is mixture of an aromatic alcohol and an ester of an aromatic acid.

8. The injectable depot composition of claim 7, wherein the aromatic alcohol is benzyl alcohol and the ester of an aromatic acid is a lower alkyl ester or an aralkyl ester of benzoic acid.

9. The injectable depot composition of claim 8, wherein the ester of an aromatic acid is benzyl benzoate and the lower alkyl ester of an aromatic acid is ethyl benzoate.

24. An injectable depot composition comprising:

(a) approximately 5 wt. % to approximately 90 wt. % of a bioerodible, biocompatible polymer;

(b) an aromatic alcohol having a miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the polymer and form a gel therewith, wherein the aromatic alcohol has the structural formula (I)

Ar-(L)_n-OH 

 

(I)

in which Ar is a substituted or unsubstituted aryl or heteroaryl group, n is zero or 1, and L is a linking moiety;

(c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and

(d) a beneficial agent.

27. The injectable depot composition of any one of claims 24, 25 or 26, wherein the polymer represents approximately 10 wt. % to approximately 85 wt. % of the composition.

28. The injectable depot composition of claim 27, wherein the polymer represents approximately 20 wt. % to approximately 75 wt. % of the composition.

29. The injectable depot composition of claim 24, wherein the polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, hyaluronic acid, and copolymers, terpolymers and mixtures thereof.

30. The injectable depot composition of any one of claims 24, 25 or 26, wherein the polymer is a copolymer of lactic acid and glycolic acid.

31. The injectable depot composition of claim 30, wherein the polymer is a copolymer of at least two of the following monomers:

lactic acid, glycolic acid and caprolactone.

32. The injectable depot composition of any one of claims 24, 25 or 26, wherein Ar is monocyclic aryl or heteroaryl, n is 1, and L is lower alkylene optionally containing at least one heteroatom.

33. The injectable depot composition of claim 32, wherein Ar is monocyclic aryl and L is lower alkylene.

34. The injectable depot composition of claim 33, wherein Ar is phenyl and L is methylene.

35. The injectable depot composition of any one of claims 24, 25 or 26, wherein the aromatic alcohol is benzyl alcohol.

41. The injectable depot composition of any one of claims 24, 25 or 26, wherein the thixotropic agent is ethanol.

42. The injectable depot composition of claim 41 wherein the amount of ethanol is greater than or equal to 0.01 weight percent and less than or equal to 15 weight percent of the combined weight of the solvent and the thixotropic agent.

43. The injectable depot composition of claim 42 wherein the amount of ethanol is greater than or equal to 0.1 weight percent and less than or equal to 5 weight percent of the combined weight of the solvent and the thixotropic agent.

44. The injectable depot composition of claim 43 wherein the amount of ethanol is greater than or equal to 0.5 weight percent and less than or equal to 5 weight percent of the combined weight of the solvent and the thixotropic agent.

45. The injectable depot composition of claim 35 wherein the thixotropic agent is ethanol.

47. The injectable depot composition of any one of claims 24, 25 or 26, further including at least one of the following:

a pore former;

a solubility modulator for the beneficial agent; and

an osmotic agent.

48. The injectable depot of any one of claim 24, 25 or 26, wherein the beneficial agent is selected from a drug, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, chemotherapeutic agents, immunosuppressive agents, anti-inflammatory agents, antiproliferative agents, antimitotic agents, angiogenic agents, anticoagulants, fibrinolytic agents, growth factors, antibodies, ocular drugs, and metabolites, analogs, derivatives, and fragments thereof.

49. The injectable depot of claim 48 wherein the beneficial agent is a growth hormone.

50. The injectable depot of claim 48 wherein the beneficial agent is a growth factor.

51. The injectable depot of claim 48 wherein the beneficial agent is present in an amount of from 0.1 to 50% by weight of the combined amounts of the polymer, the solvent and the beneficial agent.

52. The injectable depot of claim 48 wherein the beneficial agent is in the form of particles dispersed or dissolved in the viscous gel.

53. The injectable depot of claim 52 wherein the beneficial agent is in the form of particles having an average particle size of from 0.1 to 250 microns.

116. The injectable depot of claim 52 wherein the beneficial agent is in the form of particles wherein the particle further comprises a component selected from the group consisting of a stabilizing agent, bulking agent, chelating agent and a buffering agent.

25. An injectable depot composition comprising:

(a) approximately 5 wt. % to approximately 90 wt. % of a biodegradable, biocompatible lactic acid-based polymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000;

(b) an aromatic alcohol having a miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the polymer and form a gel therewith, wherein the aromatic alcohol has the structural formula (I)

Ar-(L)_n-OH 

 

(I)

in which Ar is a substituted or unsubstituted aryl or heteroaryl group, n is zero or 1, and L is a linking moiety;

(c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and

(d) a beneficial agent.

26. An injectable depot composition comprising:

(a) approximately 5 wt. % to approximately 90 wt. % of a biodegradable, biocompatible lactic acid-based polymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000;

(b) a solvent selected from the group consisting of an aromatic alcohol, an ester of an aromatic acid, and mixtures thereof, said solvent having a miscibility in water of less than or equal to 7% at 25°

C., and present in an amount effective to plasticize the polymer and form a gel therewith, wherein the aromatic alcohol has the structural formula (I)

Ar-(L)_n-OH 

 

(I)

in which Ar is a substituted or unsubstituted aryl or heteroaryl group, n is zero or 1, and L is a linking moiety;

(c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and

(d) a beneficial agent.

36. The injectable depot composition of claim 26, wherein the solvent is mixture of an aromatic alcohol and an ester of an aromatic acid.

37. The injectable depot composition of claim 36, wherein the aromatic alcohol is benzyl alcohol and the ester of an aromatic acid is a lower alkyl ester or an aralkyl ester of benzoic acid.

38. The injectable depot composition of claim 37, wherein the ester of an aromatic acid is benzyl benzoate and the lower alkyl ester of an aromatic acid is ethyl benzoate.

39. The injectable depot composition of claim 36, wherein the ratio of the aromatic alcohol to the ester of an aromatic acid is in the range of about 1% to about 99% by weight.

40. The injectable depot composition of claim 39, wherein the ratio of the aromatic alcohol to the ester of an aromatic acid is in the range of about 20% to about 80% by weight.

46. The injectable depot composition of claim 38 wherein the thixotropic agent is ethanol.

54. An injectable depot composition comprising:

(a) approximately 5 wt. % to approximately 90 wt. % a poly(lactide-co-glycolide) (PLGA) copolymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000;

(b) approximately 5 wt. % to approximately 90 wt. % an aromatic alcohol solvent having a miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the polymer and form a gel therewith;

(c) a thixotropic amount of thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, wherein the thixotropic agent is ethanol and the amount of ethanol is greater than or equal to 0.01 weight percent and less than or equal to 15 weight percent of the combined weight of the solvent and the thixotropic agent; and

(d) a beneficial agent.

55. The injectable depot composition of claim 54, wherein the aromatic alcohol is benzyl alcohol.

56. An injectable depot composition comprising:

(a) approximately 5 wt. % to approximately 90 wt. % of a poly(lactide-co-glycolide) (PLGA) copolymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000;

(b) approximately 5 wt. % to approximately 90 wt. % of a solvent selected from the group consisting of an aromatic alcohol, an ester of an aromatic acid, and mixtures thereof, said solvent having a miscibility in water of less than or equal to 7% at 25°

C., and present in an amount effective to plasticize the polymer and form a gel therewith,

(c) a thixotropic amount of thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, wherein the thixotropic agent is ethanol and the amount of ethanol is greater than or equal to 0.01 weight percent and less than or equal to 15 weight percent of the combined weight of the solvent and the thixotropic agent; and

(d) a beneficial agent.

57. The injectable depot composition of claim 56, wherein the aromatic alcohol is benzyl alcohol and the ester of an aromatic acid is benzyl benzoate.

58. A method of administering a beneficial agent to a subject comprising the steps of:

(1) administering an injectable depot composition to the subject at a site within the subject, the composition comprising;

(a) a bioerodible, biocompatible polymer;

(b) a solvent having a miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the polymer and form a gel therewith, wherein said solvent is an aromatic alcohol;

(c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and

(d) a beneficial agent; and

(2) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.

60. The method of claim 58 or claim 59, wherein the aromatic alcohol has the structural formula (I)

Ar-(L)_n-OH

wherein Ar is aryl or heteroaryl, n is zero or 1, and L is a linking moiety.

61. The method of claim 60, wherein Ar is monocyclic aryl or heteroaryl, n is 1, and L is lower alkylene optionally containing at least one heteroatom.

62. The method of claim 61, wherein Ar is monocyclic aryl and L is lower alkylene.

63. The method of claim 62, wherein Ar is phenyl and L is methylene.

67. The method of claim 58 or claim 59 wherein the thixotropic agent is ethanol.

68. The method of claim 67 wherein the amount of ethanol is greater than or equal to 0.01 weight percent and less than or equal to 15 weight percent of the combined weight of the solvent and the thixotropic agent.

69. The method of claim 67 wherein the amount of ethanol is greater than or equal to 0.1 weight percent and less than or equal to 5 weight percent of the combined weight of the solvent and the thixotropic agent.

70. The method of claim 67 wherein the amount of ethanol is greater than or equal to 0.5 weight percent and less than or equal to 5 weight percent of the combined weight of the solvent and the thixotropic agent.

71. The method of claim 58 or claim 59, wherein the polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, hyaluronic acid, and copolymers, terpolymers and mixtures thereof.

72. The method of claim 58 or claim 59, wherein the polymer is a lactic acid-based polymer.

73. The method of claim 72, wherein the polymer is a copolymer of at least two of the following monomers:

lactic acid, glycolic acid and caprolactone.

74. The method of claim 58 or claim 59, further including at least one of the following:

a pore former;

a solubility modulator for the beneficial agent; and

an osmotic agent.

75. The method of claim 58 or claim 59 wherein the beneficial agent is selected from a drug, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, chemotherapeutic agents, immunosuppressive agents, anti-inflammatory agents, antiproliferative agents, antimitotic agents, angiogenic agents, anticoagulants, fibrinolytic agents, growth factors, antibodies, ocular drugs, and metabolites, analogs, derivatives, and fragments thereof.

76. The method of claim 75 wherein the beneficial agent is a growth hormone.

77. The method of claim 75 wherein the beneficial agent is a growth factor.

78. The method of claim 75 wherein the beneficial agent is present in an amount of from 0.1 to 50% by weight of the combined amounts of the polymer, the solvent and the beneficial agent.

79. The method of claim 75 wherein the beneficial agent is in the form of particles dispersed or dissolved in the viscous gel.

80. The method of claim 79 wherein the beneficial agent is in the form of particles having an average particle size of from 0.1 to 250 microns.

117. The method of claim 79 wherein the beneficial agent is in the form of particles wherein the particle further comprises a component selected from the group consisting of a stabilizing agent, bulking agent, chelating agent and a buffering agent.

59. A method of administering a beneficial agent to a subject comprising the steps of:

(1) administering an injectable depot composition to the subject at a site within the subject, the composition comprising;

(a) a bioerodible, biocompatible polymer;

(b) a solvent selected from the group consisting of aromatic alcohols, esters of aromatic acids, aromatic ketones, and mixtures thereof, said solvent having a miscibility in water of less than or equal to 7% at 25°

C., and present in an amount effective to plasticize the polymer and form a gel therewith;

(c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and

(d) a beneficial agent; and

(2) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.

64. The method of claim 59, wherein the solvent is mixture of an aromatic alcohol and an ester of an aromatic acid.

65. The method of claim 64, wherein the aromatic alcohol is benzyl alcohol and the ester of an aromatic acid is a lower alkyl ester or an aralkyl ester of benzoic acid.

66. The method of claim 65, wherein the ester of an aromatic acid is benzyl benzoate and the lower alkyl ester of an aromatic acid is ethyl benzoate.

81. A method of administering a beneficial agent to a subject comprising the steps of:

(1) administering an injectable depot composition to the subject at a site within the subject, the composition comprising;

(a) approximately 5 wt. % to approximately 90 wt. % of a bioerodible, biocompatible polymer;

(b) an aromatic alcohol having a miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the polymer and form a gel therewith, wherein the aromatic alcohol has the structural formula (I)

Ar-(L)_n-OH 

 

(I)

in which Ar is a substituted or unsubstituted aryl or heteroaryl group, n is zero or 1, and L is a linking moiety;

(c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and

(d) a beneficial agent; and

(2) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.

84. The method of any one of claims 81, 82 or 83, wherein the polymer represents approximately 10 wt. % to approximately 85 wt. % of the composition.

85. The method of claim 84, wherein the polymer represents approximately 20 wt. % to approximately 75 wt. % of the composition.

86. The method of claim 81, wherein the polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, hyaluronic acid, and copolymers, terpolymers and mixtures thereof.

87. The method of any one of claims 81, 82 or 83, wherein the polymer is a copolymer of lactic acid and glycolic acid.

88. The method of claim 87, wherein the polymer is a copolymer of at least two of the following monomers:

lactic acid, glycolic acid and caprolactone.

89. The method of any one of claims 81, 82 or 83, wherein Ar is monocyclic aryl or heteroaryl, n is 1, and L is lower alkylene optionally containing at least one heteroatom.

90. The method of claim 89, wherein Ar is monocyclic aryl and L is lower alkylene.

91. The method of claim 90, wherein Ar is phenyl and L is methylene.

92. The method of any one of claims 81, 82 or 83, wherein the aromatic alcohol is benzyl alcohol.

98. The method of any one of claims 81, 82 or 83, wherein the thixotropic agent is ethanol.

99. The method of claim 98 wherein the amount of ethanol is greater than or equal to 0.01 weight percent and less than or equal to 15 weight percent of the combined weight of the solvent and the thixotropic agent.

100. The method of claim 99 wherein the amount of ethanol is greater than or equal to 0.1 weight percent and less than or equal to 5 weight percent of the combined weight of the solvent and the thixotropic agent.

101. The method of claim 100 wherein the amount of ethanol is greater than or equal to 0.5 weight percent and less than or equal to 5 weight percent of the combined weight of the solvent and the thixotropic agent.

102. The method of claim 92 wherein the thixotropic agent is ethanol.

104. The method of any one of claims 81, 82 or 83, further including at least one of the following:

a pore former;

a solubility modulator for the beneficial agent; and

an osmotic agent.

105. The method of any one of claim 81, 82 or 83, wherein the beneficial agent is selected from a drug, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, chemotherapeutic agents, immunosuppressive agents, anti-inflammatory agents, antiproliferative agents, antimitotic agents, angiogenic agents, anticoagulants, fibrinolytic agents, growth factors, antibodies, ocular drugs, and metabolites, analogs, derivatives, and fragments thereof.

106. The method of claim 105 wherein the beneficial agent is a growth hormone.

107. The method of claim 105 wherein the beneficial agent is a growth factor.

108. The method of claim 105 wherein the beneficial agent is present in an amount of from 0.1 to 50% by weight of the combined amounts of the polymer, the solvent and the beneficial agent.

109. The method of claim 105 wherein the beneficial agent is in the form of particles dispersed or dissolved in the viscous gel.

110. The method of claim 105 wherein the beneficial agent is in the form of particles having an average particle size of from 0.1 to 250 microns.

118. The method of claim 109 wherein the beneficial agent is in the form of particles wherein the particle further comprises a component selected from the group consisting of a stabilizing agent, bulking agent, chelating agent and a buffering agent.

82. A method of administering a beneficial agent to a subject comprising the steps of:

(1) administering an injectable depot composition to the subject at a site within the subject, the composition comprising;

(a) approximately 5 wt. % to approximately 90 wt. % of a biodegradable, biocompatible lactic acid-based polymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000;

(b) an aromatic alcohol having a miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the polymer and form a gel therewith, wherein the aromatic alcohol has the structural formula (I)

Ar-(L)_n-OH 

 

(I)

in which Ar is a substituted or unsubstituted aryl or heteroaryl group, n is zero or 1, and L is a linking moiety;

(c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and

(d) a beneficial agent; and

(2) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.

83. A method of administering a beneficial agent to a subject comprising the steps of:

(1) administering an injectable depot composition to the subject at a site within the subject, the composition comprising;

(a) approximately 5 wt. % to approximately 90 wt. % of a biodegradable, biocompatible lactic acid-based polymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000;

(b) a solvent selected from the group consisting of an aromatic alcohol, an ester of an aromatic acid, and mixtures thereof, said solvent having a miscibility in water of less than or equal to 7% at 25°

C., and present in an amount effective to plasticize the polymer and form a gel therewith, wherein the aromatic alcohol has the structural formula (I)

Ar-(L)_n-OH 

 

(I)

in which Ar is a substituted or unsubstituted aryl or heteroaryl group, n is zero or 1, and L is a linking moiety;

(c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and

(d) a beneficial agent; and

(2) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.

93. The method of claim 83, wherein the solvent is mixture of an aromatic alcohol and an ester of an aromatic acid.

94. The method of claim 93, wherein the aromatic alcohol is benzyl alcohol and the ester of an aromatic acid is a lower alkyl ester or an aralkyl ester of benzoic acid.

95. The method of claim 94, wherein the ester of an aromatic acid is benzyl benzoate and the lower alkyl ester of an aromatic acid is ethyl benzoate.

96. The method of claim 95, wherein the ratio of the aromatic alcohol to the ester of an aromatic acid is in the range of about 1% to about 99% by weight.

97. The method of claim 96, wherein the ratio of the aromatic alcohol to the ester of an aromatic acid is in the range of about 20% to about 80% by weight.

103. The method of claim 94 wherein the thixotropic agent is ethanol.

111. A method of administering a beneficial agent to a subject comprising the steps of:

(1) administering an injectable depot composition to the subject at a site within the subject, the composition comprising;

(a) approximately 5 wt. % to approximately 90 wt. % a poly(lactide-co-glycolide) (PLGA) copolymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000;

(b) approximately 5 wt. % to approximately 90 wt. % an aromatic alcohol solvent having a miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the polymer and form a gel therewith;

(c) a thixotropic amount of thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, wherein the thixotropic agent is ethanol and the amount of ethanol is greater than or equal to 0.01 weight percent and less than or equal to 15 weight percent of the combined weight of the solvent and the thixotropic agent; and

(d) a beneficial agent; and

(2) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.

112. The method of claim 111, wherein the aromatic alcohol is benzyl alcohol.

113. A method of administering a beneficial agent to a subject comprising the steps of:

(1) administering an injectable depot composition to the subject at a site within the subject, the composition comprising;

(a) approximately 5 wt. % to approximately 90 wt. % of a poly(lactide-co-glycolide) (PLGA) copolymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000;

(b) approximately 5 wt. % to approximately 90 wt. % of a solvent selected from the group consisting of an aromatic alcohol, an ester of an aromatic acid, and mixtures thereof, said solvent having a miscibility in water of less than or equal to 7% at 25°

C., and present in an amount effective to plasticize the polymer and form a gel therewith,

(c) a thixotropic amount of thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, wherein the thixotropic agent is ethanol and the amount of ethanol is greater than or equal to 0.01 weight percent and less than or equal to 15 weight percent of the combined weight of the solvent and the thixotropic agent; and

(d) a beneficial agent; and

(2) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.

114. The method of claim 113, wherein the aromatic alcohol is benzyl alcohol and the ester of an aromatic acid is benzyl benzoate.