Gel composition and methods

• US 20030211974A1
• Filed: 06/04/2003
• Published: 11/13/2003
• Est. Priority Date: 03/21/2000
• Status: Abandoned Application

• Current Assignee: DURECT Corporation
• Original Assignee: DURECT Corporation
• Inventors: Brodbeck, Kevin J., Shen, Theodore Tao-Ian, Gaynor-Duarte, Ann T.
• Application Number:
  US10/454,415
• Publication Number:
  US 20030211974A1
• Time in Patent Office: Days
• US Class Current: 514/2
• 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

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 beneficial agent dissolved or dispersed substantially throughout a viscous gel, the system having a burst index of 8 or less.

2. The method of claim 1 wherein the viscous gel comprises a biocompatible polymer and a solvent.

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

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

4. The method of claim 2 wherein the solvent comprises a solvent having a miscibility in water of less than 7% by weight.

5. The method of claim 4 wherein the solvent is selected from lower alkyl and aralkyl esters of aryl acids;

aryl, aralkyl and lower alkyl ketones; and

lower alkyl esters of citric acid.

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

7. The method of claim 5 wherein the polymer is a lactic acid-based polymer and the solvent is selected from lower alkyl and aralkyl esters of benzoic acid.

49. The method of claim 2 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.

50. 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.

51. The method of claim 50 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 1 wherein the beneficial agent is released from the system over a prolonged period.

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

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

C. for at least 24 hours after implantation.

8. A method of locally administering a beneficial agent to a subject which comprises implanting a system comprising a beneficial agent dissolved or dispersed substantially throughout a viscous gel, the system releasing within 24 hours after implantation not greater than 20% by weight of the amount of beneficial agent to be delivered over the duration of the delivery period.

9. The method of claim 8 wherein the viscous gel comprises a biocompatible polymer and a solvent.

10. The method of claim 9 in which the viscous gel optionally includes one or more of the following:

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

11. The method of claim 10 wherein the solvent comprises a solvent having a miscibility in water of less than 7% by weight.

12. The method of claim 11 wherein the solvent is selected from lower alkyl and aralkyl esters of aryl acids;

aryl, aralkyl and lower alkyl ketones; and

lower alkyl esters of citric acid.

13. The method of claim 9 wherein the polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, and copolymers, terpolymers and mixtures thereof.

14. The method of claim 12 wherein the polymer is a lactic acid-based polymer and the solvent is selected from lower alkyl and aralkyl esters of benzoic acid.

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

54. The method of claim 8 wherein the beneficial agent is released from the system over a prolonged period.

57. The method of claim 9 wherein the system is non-rigid after implantation.

58. The method of claim 57 wherein the system maintains a glass transition temperature below 37°

C. for at least 24 hours after implantation.

15. A method of administering a beneficial agent to a subject in a controlled manner approximating zero order release by implanting a gel composition comprising a biocompatible polymer, a biocompatible solvent having a solubility in water of less than 7%, and a beneficial agent, wherein the loading of the beneficial agent in the interior of the polymer is above that required to saturate the beneficial agent in water.

16. 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 viscous gel formed of a biocompatible polymer and a solvent having a solubility in water of 7% or less, and a solubility modulator of the beneficial agent, the system having a burst index of 8 or less.

17. The method of claim 16 wherein the polymer is a lactic acid-based polymer.

18. An implantable composition for the systemic delivery of a beneficial agent to a subject wherein the composition comprises a polymer;

an amount of a solvent to form a viscous gel with the polymer, and a beneficial agent dissolved or dispersed in the gel, wherein the solvent comprises a single solvent or a mixture of solvents with at least one solvent having a miscibility in water of less than 7% by weight and the total amount of solvent constituting 40% or more by weight of the gel vehicle, said composition having a burst index of 8 or less.

59. The composition of claim 18 wherein the gel remains non-rigid after implantation.

60. The composition of claim 59 wherein the gel maintains a glass transition temperature below 37°

C. for at least 24 hours after implantation.

19. An implantable, biodegradable composition for the sustained delivery of a beneficial agent to a subject wherein the composition comprises a polymer;

an effective plasticizing amount of a solvent to form a viscous gel with the polymer; and

a beneficial agent dissolved or dispersed in the gel, wherein the solvent comprises a mixture of solvents with at least one solvent in the mixture having a miscibility in water of less than 7% by weight.

20. The composition of claim 19 wherein the miscibility in water of the solvent mixture is 10% or less by weight.

21. An implantable, biodegradable composition for delivery of a beneficial agent to a subject wherein the composition comprises a polymer;

an effective plasticizing amount of a solvent to form a viscous gel with the polymer; and

a beneficial agent dissolved or dispersed in the gel, wherein the solvent comprises a single solvent or a mixture of solvents with at least one solvent having a miscibility in water of less than 7% by weight selected from lower alkyl and aralkyl esters of benzoic acid.

22. An implantable gel composition for delivery of a beneficial agent to a subject comprising:

A) a biocompatible polymer;

B) a biocompatible solvent, having miscibility in water of less than 7% by weight and capable of dissolving the polymer and forming a viscous gel;

said solvent being selected from the group comprising compounds having the following structural formula;

 

wherein R₁ is lower alkyl, aryl or aralkyl and R₂ is aralkyl or lower alkyl; and

R₁ and R₂ may be the same or different;

with the proviso that when R₁ and R₂ are each lower alkyl, the number of total carbon atoms represented by R₁ and R₂ combined is 4 or more;

C) a beneficial agent; and

, optionally, one or more of the following;

D) an emulsifying agent;

E) a pore former; and

F) a solubility modulator for the beneficial agent; and

G) an osmotic agent.

23. An implantable gel composition for delivery of a beneficial agent to a subject comprising:

A) a biocompatible lactic acid-based polymer;

B) a biocompatible solvent, having miscibility in water of less than 7% by weight and capable of dissolving the polymer and forming a viscous gel;

said solvent being selected from the group comprising compounds having the following structural formula;

 

wherein R₁ is lower alkyl, aryl or aralkyl and R₂ is aralkyl or lower alkyl; and

R₁ and R₂ may be the same or different;

with the proviso that when R₁ and R₂ are each lower alkyl, the number of total carbon atoms represented by R₁ and R₂ combined is 4 or more;

C) a beneficial agent; and

, optionally, one or more of the following;

D) an emulsifying agent;

E) a pore former;

F) a solubility modulator for the beneficial agent; and

G) an osmotic agent.

24. The composition of claim 23 wherein R₁ is phenyl.

25. The composition of claim 24 wherein R₂ is benzyl.

26. A method of preparing an injectable depot gel composition comprising:

A) mixing a biocompatible polymer and a solvent having a miscibility in water of 7% or less selected from lower alkyl and aralkyl esters of benzoic acid to form a viscous gel;

B) dispersing or dissolving a beneficial agent, optionally associated with a solubility modulator, in an emulsifying agent to form a beneficial agent containing emulsifying agent; and

C) mixing the beneficial agent containing emulsifying agent with the viscous gel, said beneficial agent containing emulsifying agent forming a dispersed droplet phase in the viscous gel, and optionally,

D) mixing one or more of a pore former and an osmotic agent with said viscous gel, to provide an injectable gel composition.

27. A gel composition for systemic administration comprising:

A) a biocompatible polymer;

B) a biocompatible solvent having a miscibility in water of less than 7%;

C) a beneficial agent selected from the group consisting of cDNA, DNA, peptides, proteins and fragments and derivatives thereof, and optionally, one or more of the following;

D) an emulsifying agent;

E) a pore former;

F) a solubility modulator for the beneficial agent; and

G) an osmotic agent.

wherein the composition has a burst index of less than 8.

28. A kit for administration of a beneficial agent to a subject comprising:

A) a biocompatible polymer;

B) a solvent having a miscibility in water of 7% or less by weight that is suitable for dissolving the polymer and forming a viscous gel;

C) a beneficial agent; and

optionally, one or more of the following;

D) an emulsifying agent;

E) a pore former;

F) a solubility modulator for the beneficial agent, optionally associated with the beneficial agent; and

G) an osmotic agent;

wherein at least the beneficial agent, optionally associated with the solubility modulator, is maintained separated from the solvent until the time of administration of the beneficial agent to a subject.

29. An implantable composition for the systemic delivery of a beneficial agent comprising a poly(lactide-co-glycolide) copolymer;

an effective plasticizing amount of a solvent to form a viscous gel with the polymer; and

a beneficial agent selected from the group consisting of cDNA, DNA, peptides, proteins and fragments and derivatives thereof, said composition having a burst index of equal to or less than 8.

30. An implantable composition for the sustained delivery of a beneficial agent 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 viscous gel with the polymer; and

a beneficial agent.

31. The composition of claim 30 wherein the solvent has a miscibility in water by weight of less than 7%.

32. The composition of claim 30 wherein the solvent is benzyl benzoate.

33. The composition of claim 30 comprising a solubility modulator of the beneficial agent.

34. The composition of claim 30 comprising a pore former.

35. The composition of claim 30 comprising an emulsifying agent.

36. The composition of claim 30 comprising an osmotic agent.

37. The composition of claim 33 wherein the solubility modulator is selected from salts of divalent metals.

38. The composition of claim 34 in which the pore former is water soluble.

39. The composition of claim 34 wherein the pore former is selected from group consisting of water soluble sugars, salts, solvents and polymers.

40. The composition of claim 35 in which the emulsifying agent is capable of forming a dispersed droplet phase in said viscous gel.

41. The composition of claim 35 in which the emulsifying agent is selected from the group consisting of alcohols, propylene glycol, ethylene glycol, glycerol, water and solutions and mixtures thereof.

42. The composition of claim 35 wherein the emulsifying agent is selected from the group consisting of ethanol, isopropyl alcohol, water, solutions thereof, and mixtures thereof.

43. The composition of claim 30 wherein the copolymer has a monomer ratio of lactic acid to glycolic acid in the range of 100:

0 to about 15;

85.

44. The composition of claim 30 wherein the copolymer has a number average molecular weight of from 1,000 to 120,000.

45. The composition of claim 30 wherein the solvent comprises a component solvent miscible with the solvent.

46. The composition of claim 45 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.

47. The composition of claim 45 wherein the component solvent is selected from the group consisting of triacetin and N-methyl-2-pyrrolidone, and mixtures thereof.

48. The composition of claim 45 wherein the component solvent is triacetin.

61. An implantable gel composition comprising a biocompatible polymer, a biocompatible solvent forming a viscous gel with the polymer, and a beneficial agent, the composition imbibing 40% or less of its bulk weight in water within the first 21 days after implantation.

62. The composition of claim 61 wherein the composition imbibes less than 30% of its bulk weight in water within the first 14 days after implantation.

63. The composition of claim 62 wherein the composition imbibes less than 25% of its bulk weight in water within the first 7 days after implantation.