Gel composition and methods

• US 6,468,961 B1
• Filed: 07/13/2000
• Issued: 10/22/2002
• 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:
  US09/615,568
• Time in Patent Office: 831 Days
• Field of Search: 604/891.1, 604/51, 604/48, 604/49, 424/426, 424/486, 424/487, 424/488, 514/772.3, 514/777, 514/2, 530/399, 530/351
• US Class Current: 424/428
• 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. An implantable composition for the sustained delivery of a beneficial agent comprising 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.

2. The composition of claim 1 wherein the solvent has a miscibility in water by weight of less than 7%.

3. The composition of claim 1 wherein the solvent is benzyl benzoate.

4. The composition of claim 1 comprising a solubility modulator of the beneficial agent.

5. The composition of claim 1 comprising a pore former.

6. The composition of claim 1 comprising an emulsifying agent.

7. The composition of claim 1 comprising an osmotic agent.

8. The composition of claim 4 wherein the solubility modulator is selected from salts of divalent metals.

9. The composition of claim 5 in which the pore former is water soluble.

10. The composition of claim 5 wherein the pore former is selected from group consisting of water soluble sugars, salts, solvents and polymers.

11. The composition of claim 6 in which the emulsifying agent is capable of forming a dispersed droplet phase in said viscous gel.

12. The composition of claim 6 in which the emulsifying agent is selected from the group consisting of alcohols, propylene glycol, ethylene glycol, glycerol, water and solutions and mixtures thereof.

13. The composition of claim 6 wherein the emulsifying agent is selected from the group consisting of ethanol, isopropyl alcohol, water, solutions thereof, and mixtures thereof.

14. The composition 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.

15. The composition of claim 14 wherein the copolymer has a number average molecular weight of from 1,000 to 120,000.

16. The composition of claim 1 wherein the solvent comprises a component solvent miscible with the solvent.

17. The composition of claim 16 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.

18. The composition of claim 16 wherein the component solvent is selected from the group consisting of triacetin and N-methyl-2-pyrrolidone, and mixtures thereof.

19. The composition of claim 16 wherein the component solvent is triacetin.

20. The composition of claim 1 wherein the gel remains non-rigid after implantation.

21. The composition of claim 20 wherein the gel maintains a glass transition temperature below 37°

C. for at least 24 hours after implantation.

22. The composition 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.

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

24. The composition of claim 23 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.

25. The composition of claim 1 wherein the solvent is ethyl benzoate.