Process for the preparation of polymer-based sustained release compositions

• US 6,296,842 B1
• Filed: 08/10/2000
• Issued: 10/02/2001
• Est. Priority Date: 08/10/2000
• Status: Expired due to Fees

• Current Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Original Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Inventors: Jaworowicz, Warren E., Wright, James I.
• Primary Examiner(s): Foelak, Morton
• Application Number:
  US09/638,165
• Time in Patent Office: 418 Days
• Field of Search: 424/78.02, 424/78.17, 424/78.29, 424/78.31, 424/78.35, 424/78.37, 424/468, 424/469, 521/64, 521/182, 521/918
• US Class Current: 424/78.02
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: Y10S 521/918 Physical aftertreatment of a cellular product

Abstract

The invention relates to a sustained release composition and methods of forming and using said composition for the sustained release of biologically active agent. The sustained release compositions of the invention comprise a biocompatible polymer and a biologically active agent characterized by a porous center and a less porous outer layer wherein the center and outer layer consist of essentially the same materials. The sustained release compositions can be prepared by annealing at least a substantial portion of the exterior surface of a polymer/active agent matrix. The compositions which have been annealed exhibit a decrease in the release of agent over the first 24 hours following administration (i.e., reduced burst) and as a result can show an increase in the duration of sustained release thereby providing increased therapeutic benefits.

Claims

1. A method for preparing a composition for the sustained release of a biologically active agent, comprising the steps of:

a) forming a mixture comprising a biologically active agent, a biocompatible polymer, and a polymer solvent;

b) removing the polymer solvent thereby forming a solid polymer/active agent matrix; and

c) annealing at least a substantial portion of the exterior surface of the polymer/active agent matrix by the application of an annealing solvent.

2. The method of claim 1 wherein annealing is accomplished by the application of an annealing solvent to the polymer/active agent matrix in a fluidized bed system.

3. The method of claim 2 wherein the fluidized bed system is a bottom spray system.

4. The method of claim 1 wherein the annealing solvent is selected from the group consisting of:

methylene chloride, chloroform, acetone, ethyl acetate, anisole, methyl acetate, hexafluoroisopropanol, tetrahydrofuran, dimethylsulfoxide and any combination thereof.

5. The method of claim 1 wherein the temperature of the fluidized bed is below the flashpoint and above the freezing point of the annealing solvent.

6. The method of claim 1 wherein the polymer/active agent matrix is in the form of microparticles.

7. The method of claim 1 wherein about 25% or more of the exterior surface is annealed.

8. The method of claim 1 wherein about 40% or more of the exterior surface is annealed.

9. The method of claim 1 wherein between about 50% and about 100% of the exterior surface is annealed.

10. The method of claim 1 further comprising the steps of:

forming droplets of the polymer/active agent mixture and freezing the droplets of the polymer/active agent mixture, wherein said forming and freezing steps are performed prior to removing the polymer solvent.

11. The method of claim 10 wherein the droplets are microdroplets.

12. The method of claim 1 wherein the biocompatible polymer is biodegradable.

13. The method of claim 12 wherein the biodegradable polymer is selected from the group consisting of poly(lactide)s, poly(glycolide)s, poly(lactide-coglycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, poly(caprolactone), polycarbonates, polyesteramides, polyanhydrides, poly(amino acid)s, poly(ortho ester)s, polycyanoacrylates, polyamides, polyacetals, poly(ether ester)s, copolymers of poly(ethylene glycol) and poly(ortho ester)s, poly(dioxanone)s, poly(alkylene alkylate)s, biodegradable polyurethanes, blends and copolymers thereof.

14. The method of claim 13 wherein said polymer is poly(lactide-co-glycolide).

15. The method of claim 1 wherein the biocompatible polymer is non-biodegradable.

16. The method of claim 1 wherein the polymer solvent is methylene chloride, chloroform, acetone, ethyl acetate, anisole, methyl acetate, dimethylsulfoxide, hexafluoroisopropanol or any combinations thereof.

17. The method of claim 1 wherein the biologically active agent is a protein, peptide or nucleic acid.