DEPOT COMPOSITIONS WITH MULTIPLE DRUG RELEASE RATE CONTROLS AND USES THEREOF

• US 20070196415A1
• Filed: 10/27/2006
• Published: 08/23/2007
• Est. Priority Date: 11/14/2002
• Status: Abandoned Application

• Current Assignee: DURECT Corporation
• Original Assignee: DURECT Corporation
• Inventors: Chen, Guohua, Kleiner, Lothar, Houston, Paul, Wright, Jeremy
• Application Number:
  US11/553,925
• Publication Number:
  US 20070196415A1
• Time in Patent Office: Days
• US Class Current: 424/422
• 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 9/0024 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 9/143 with inorganic compounds
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00

Abstract

Injectable depot compositions with dual mechanisms of release rate control are provided for sustained beneficial agent delivery in a patient. The composition includes bioerodible particles and an injectable depot vehicle containing a bioerodible polymer in an organic solvent, for forming a bioerodible depot implant after administration to the patient. The bioerodible particles are dispersed in the depot vehicle and contain a beneficial agent and a release rate controlling agent retarding the release of the beneficial agent from the bioerodible particles and from the depot implant.

Claims

1. A composition for sustained beneficial agent delivery in a patient, comprising;

a. an injectable depot vehicle containing a bioerodible polymer in an organic solvent, for forming a bioerodible depot implant after administration to a patient;

b. bioerodible particles comprising a beneficial agent and a non-complex release rate controlling agent retarding the release of the beneficial agent from the bioerodible particles;

the bioerodible particles being dispersed in the injectable depot vehicle.

2. The composition of claim 1 wherein the non-complex release rate controlling agent hinders movement of the beneficial agent in the bioerodible particles.

3. The composition of claim 2 wherein the non-complex release rate controlling agent functions as at least one of hindering water access by hydrophobicity, being polymeric to form a gel in physiological condition, thermally reversing between ambient condition and physiological condition, having ionic crosslink network which breaks down by ion exchange.

4. The composition of claim 2 wherein the non-complex release rate controlling agent is selected from the group consisting of fatty acid, esters of fatty acid, thermally reversible polymer, and ionic polymer network forming agent.

5. The composition of claim 2 wherein the non-complex release rate controlling agent is selected from the group consisting of fatty acid, esters of fatty acid and thermally reversible gel forming polymer.

6. The composition of claim 2 wherein non-complex release rate controlling agent comprises a fatty acid.

7. The composition of claim 2 wherein non-complex release rate controlling agent comprises an ester of fatty acid.

8. The composition of claim 2 wherein non-complex release rate controlling agent comprises a thermally reversible polymer.

9. The composition of claim 2 wherein non-complex release rate controlling agent is one of two or more release rate controlling agents, a second release rate controlling agent of the two or more release rate controlling agents being selected from the group consisting of fatty acid, ester of fatty acid, thermally reversible polymer, ionic polymer with a network forming agent, and a complex forming agent.

10. The composition of claim 2 wherein there are at least two release rate controlling agents and the bioerodible particles comprising fatty acid and complex forming agent.

11. The composition of claim 1 wherein the non-complex release rate controlling agent is solid in body temperature entrapping the beneficial agent in the bioerodible particles and erodes in vivo.

12. The composition of claim 1 comprising bioerodible subparticles enclosed within the bioerodible particles, the bioerodible subparticles comprising the beneficial agent and a release rate controlling agent.

13. The composition of claim 12 wherein the non-complex release rate controlling agent is one of at least two release rate controlling agents in the bioerodible particle, one of the release rate controlling agents being outside the bioerodible subparticles, another of the release rate controlling agents being inside the bioerodible subparticles and being different from the one outside the bioerodible subparticles.

14. The composition of claim 13 wherein the release rate controlling agent in the subparticles functions in at least one of hindering water access by hydrophobicity, being polymeric to form a gel in physiological condition, complexing with the beneficial agent, thermally reversing between ambient condition and physiological condition, and having ionic crosslink network that breaks down by ion exchange.

15. The composition of claim 13 wherein the release rate controlling agent in the subparticles is selected from the group consisting of fatty acid, thermally reversible polymer, ionic polymer network forming agent, and complex forming agent.

16. The composition of claim 2 wherein the organic solvent is selected from the group consisting of:

an aromatic alcohol, lower alkyl esters of aryl acids, lower aralkyl esters of aryl acids;

aryl ketones, aralkyl ketones, lower alkyl ketones, lower alkyl esters of citric acid, and combinations thereof.

17. The composition of claim 2 wherein the organic solvent comprises at least one of benzyl alcohol, benzyl benzoate, ethyl benzoate and triacetin.

18. The composition of claim 2 wherein the organic solvent comprises benzyl alcohol and wherein the composition is free of monohydric lower alkanols and free of solvents having miscibility in water that is greater than 7 wt % at 25°

C.

19. The composition of claim 2 wherein the bioerodible polymer comprises a lactic acid-based polymer.

20. A method of forming a composition for sustained beneficial agent delivery in a patient, comprising;

a. preparing an injectable depot vehicle containing a bioerodible polymer in an organic solvent, for forming a bioerodible depot implant after administration to the patient;

b. preparing bioerodible particles comprising a beneficial agent and a non-complex release rate controlling agent retarding the release of the beneficial agent from the bioerodible particles; and

c. dispersing the bioerodible beneficial agent particles in the injectable depot vehicle.

21. The method of claim 20 wherein the release rate controlling agent hinders movement of the beneficial agent in the bioerodible particles.

22. The method of claim 21 wherein the non-complex release rate controlling agent functions as at least one of hindering water access by hydrophobicity, being polymeric to form a gel in physiological condition, thermally reversing between ambient condition and physiological condition, having ionic crosslink network which breaks down by ion exchange.

23. The method of claim 21 wherein the non-complex release rate controlling agent is selected from the group consisting of fatty acid, thermally reversible polymer, and gel forming polymer.

24. The method of claim 21 wherein the non-complex release rate controlling agent is selected from the group consisting of fatty acid and thermally reversible gel forming polymer.

25. The method of claim 20 comprising forming the bioerodible particles via a step of forming and compacting particles into larger particles.

26. The method of claim 20 comprising forming the bioerodible particles via a step of forming and compacting particles into larger particles and then reducing the size of the larger particles.

27. The method of claim 20 comprising forming the bioerodible particles via a step of forming pre-compacting particles by spray-drying or lyophilization, compacting the pre-compacting particles into larger particles and then reducing the size of the larger particles by grinding and sieving.

28. The method of claim 20 comprising forming the bioerodible particles via a step of forming pre-compacting particles by spray-drying or lyophilization, compacting the pre-compacting particles into larger particles and then reducing the size of the larger particles by grinding and sieving to achieve particle size of 30 microns to 250 microns.

29. The method of claim 20 comprising forming the bioerodible particles by including subparticles in the bioerodible particles, the bioerodible subparticles comprising the beneficial agent and a release rate controlling agent.

30. The method of claim 20 wherein the non-complex release rate controlling agent is one of at least two release rate controlling agents in the bioerodible particle, one of the release rate controlling agents being outside the bioerodible subparticles, another of the release rate controlling agents being inside the bioerodible subparticles and being different from the one outside the bioerodible subparticles.

31. The method of claim 30 wherein the release rate controlling agent in the subparticles functions in at least one of hindering water access by hydrophobicity, being polymeric to form a gel in physiological condition, complexing with the beneficial agent, thermally reversing between ambient condition and physiological condition, and having ionic crosslink network which breaks down by ion exchange.

32. The method of claim 31 wherein the organic solvent comprises benzyl alcohol and wherein the composition is free of monohydric lower alkanols and free of solvents having miscibility in water that is greater than 7 wt. % at 25°

C.

33. A method of administering a beneficial agent to an individual in need thereof, comprising,

a. providing a composition that includes an injectable depot vehicle containing a bioerodible polymer in an organic solvent, for forming a bioerodible depot implant after administration to the individual;

and bioerodible particles comprising a beneficial agent and a non-complex release rate controlling agent retarding the release of the beneficial agent from the bioerodible particles;

the bioerodible particles being dispersed in the injectable depot vehicle; and

b. administering into the patient the composition.

34. The method of claim 33 wherein the release rate controlling hinders movement of the beneficial agent in the bioerodible particles.

35. The method of claim 34 wherein the non-complex release rate controlling agent functions in at least one of hindering water access by hydrophobicity, being polymeric to form a gel in physiological condition, thermally reversing between ambient condition and physiological condition, having ionic crosslink network which breaks down by ion exchange.

36. The method of claim 33 wherein the organic solvent comprises benzyl alcohol and wherein the composition is free of monohydric lower alkanols and free of solvents having miscibility in water that is greater than 7 wt % at 25°

C.

37. The method of claim 33 wherein the bioerodible particles include subparticles in the bioerodible particles, the bioerodible subparticles comprising the beneficial agent and a release rate controlling agent.

38. The method of claim 33 wherein the non-complex release rate controlling agent is one of at least two release rate controlling agents in the bioerodible particle, the bioerodible particle having bioerodible subparticles, one of the release rate controlling agents being outside the bioerodible subparticles, another of the release rate controlling agents being inside the bioerodible subparticles and being different from the one outside the bioerodible subparticles.

39. The method of claim 33 wherein the bioerodible particle having bioerodible subparticles having release rate controlling agent, the release rate controlling agent in the subparticles functions in at least one of hindering water access by hydrophobicity, being polymeric to form a gel in physiological condition, complexing with the beneficial agent, thermally reversing between ambient condition and physiological condition, and having ionic crosslink network which breaks down by ion exchange.

40. A composition for sustained beneficial agent delivery in a patient, comprising;

a. an injectable depot vehicle containing a bioerodible polymer in an organic solvent comprising benzyl alcohol, for forming a bioerodible depot implant after administration to a patient;

b. bioerodible particles comprising a beneficial agent and a non-complex release rate controlling agent retarding the release of the beneficial agent from the bioerodible particles;

the bioerodible particles being dispersed in the injectable depot vehicle.

41. A composition for sustained beneficial agent delivery in a patient, comprising;

a. an injectable depot vehicle containing a bioerodible polymer in an organic solvent, for forming a bioerodible depot implant after administration to the patient;

b. bioerodible particles comprising subparticles and a first release rate controlling agent retarding the release of beneficial agent from the bioerodible particles;

the bioerodible particles being dispersed in the injectable depot vehicle, the subparticles comprising the beneficial agent and a second release rate controlling agent different from the first release rate controlling agent.