Injectable depot gel composition and method of preparing the composition

• US 6,331,311 B1
• Filed: 12/18/1997
• Issued: 12/18/2001
• Est. Priority Date: 12/20/1996
• Status: Expired due to Term

• Current Assignee: DURECT Corporation
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Shen, Theodore T., Brodbeck, Kevin J.
• Primary Examiner(s): Criares, Theodore J.
• Application Number:
  US08/993,031
• Time in Patent Office: 1,461 Days
• Field of Search: 424/423, 424/425, 424/426, 424/486, 424/501, 424/871.1
• US Class Current: 424/425
• 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

An injectable depot gel composition containing a polymer, a solvent that can dissolve the polymer and thereby form a viscous gel, a beneficial agent; and an emulsifying agent in the form of a dispersed droplet phase in the viscous gel. The injectable depot gel composition can be prepared by mixing the polymer and the solvent so that the solvent dissolves the polymer and forms a viscous gel. The beneficial agent is dissolved or dispersed in the viscous gel and the emulsifying agent is mixed with the beneficial agent containing viscous gel. The emulsifying agent forms a dispersed droplet phase in the viscous gel to provide the injectable depot gel composition. The injectable depot gel composition can deliver a beneficial agent to a human or animal with a desired release profile.

Claims

1. An injectable depot gel composition comprising:

a continuous, viscous gel phase comprising

a biocompatible polymer and

an organic solvent that dissolves the biocompatible polymer and forms a viscous gel;

a beneficial agent; and

a separate, droplet phase dispersed in the viscous gel phase comprising

an emulsifying agent, whereby the depot gel composition is thixotropic.

2. The injectable gel depot composition of claim 1 wherein the biocompatible 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.

3. The injectable depot gel composition of claim 1 wherein the biocompatible polymer is a lactic acid-based polymer.

4. The injectable depot gel composition of claim 3 wherein the lactic acid-based polymer has a monomer ratio of lactic acid to glycolic acid in the range of 100:

0 to about 15;

85.

5. The injectable depot gel composition of claim 3 wherein the lactic acid-based polymer has a number average molecular weight of from 1,000 to 120,000.

6. The injectable depot gel composition of claim 1 wherein the solvent that can dissolve the biocompatible polymer to form a viscous gel is selected from the group consisting of triacetin, 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.

7. The injectable depot gel composition of claim 1 wherein the solvent is selected from the group consisting of triacetin and N-methyl-2-pyrrolidone, and mixtures thereof.

8. The injectable depot gel composition of claim 1 wherein the solvent is triacetin.

9. The injectable depot gel composition of claim 1 wherein the polymer is present in an amount of from 5 to 80% by weight of the combined amounts of the polymer and the solvent.

10. The injectable depot gel composition of claim 1 wherein the solvent is present in an amount of from 95 to 20% by weight of the combined amounts of the polymer and the solvent.

11. The injectable depot gel composition of claim 1 wherein the viscous gel formed by the polymer and the solvent has a viscosity of from 1,000 to 200,000 poise.

12. The injectable depot gel composition of claim 1 wherein the beneficial agent is a drug.

13. The injectable depot gel composition of claim 1 wherein the beneficial agent is a peptide.

14. The injectable depot gel composition of claim 1 wherein the beneficial agent is a protein.

15. The injectable depot gel composition of claim 1 wherein the beneficial agent is growth hormone.

16. The injectable depot gel 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.

17. The injectable depot gel composition of claim 1 wherein the beneficial agent is in the form of particles dispersed or dissolved in the viscous gel.

18. The injectable depot gel composition of claim 17 wherein the beneficial agent is in the form of particles having an average particle size of from 0.1 to 100 microns.

19. The injectable depot gel composition of claim 1 wherein the emulsifying agent is selected from the group consisting of water, alcohols, polyols, esters, carboxylic acids, ketones, aldehydes and mixtures thereof.

20. The injectable depot gel composition of claim 1 wherein the emulsifying agent is selected from the group consisting of alcohols, propylene glycol, ethylene glycol, glycerol, water and solutions and mixtures thereof.

21. The injectable depot gel composition of claim 1 wherein the emulsifying agent is selected from the group consisting of ethanol, isopropyl alcohol, water, solutions thereof, and mixtures thereof.

22. The injectable depot gel composition of claim 1 wherein the emulsifying agent is water.

23. The injectable depot gel composition of claim 1 wherein the emulsifying agent is present in an amount of from 5 to 80% by weight of the injectable depot gel composition.

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

A) mixing a biocompatible polymer and an organic solvent whereby the solvent dissolves the polymer and forms a viscous gel as a continuous phase;

B) dispersing or dissolving a beneficial agent in the viscous gel to form a beneficial agent containing viscous gel; and

C) mixing an emulsifying agent with the beneficial agent containing viscous gel, thereby forming a separate, dispersed droplet phase of the emulsifying agent in the beneficial agent containing viscous gel to provide a thixotropic injectable depot gel composition.

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

A) mixing a biocompatible polymer and an organic solvent whereby the solvent dissolves the polymer to form a viscous gel as a continuous phase;

B) dispersing or dissolving a beneficial agent 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 to form a separate, dispersed droplet phase of the beneficial agent containing emulsifying agent in the viscous gel and provide a thixotropic injectable depot gel composition.

26. An injectable depot gel composition comprising:

a continuous, viscous, gel phase comprising

a biocompatible polymer and

an organic solvent that dissolves the polymer and forms a viscous gel; and

a separate, droplet phase dispersed in the viscous gel phase comprising

an emulsifying agent, whereby the depot gel composition is thixotropic.

27. A kit adapted to provide a thixotropic injectable depot composition having a continuous phase formed as a viscous polymer-solvent gel in which an emulsifying agent is present in the form of a dispersed droplet phase, comprising as kit components:

(a) a biocompatible polymer and an organic solvent that dissolves the polymer and forms a viscous gel;

(b) emulsifying agent; and

(c) beneficial agent dispersible or dissolvable in the emulsifying agent.