Method of producing submicron particles of a labile agent and use thereof

• US 6,713,087 B2
• Filed: 07/18/2002
• Issued: 03/30/2004
• Est. Priority Date: 05/28/1999
• 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., Ward, Kevin L., Tracy, Mark A.
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US10/200,057
• Publication Number:
  US 20030096011A1
• Time in Patent Office: 621 Days
• Field of Search: 424/486-87, 424/497, 424/489, 264/140, 514/951-52, 451/28, 451/36
• US Class Current: 424/486
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• 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: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5192 Processes
• CPC Class Codes: A61P 5/02 of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin

Abstract

The present invention relates to a sustained release composition comprising micron particles of labile agent and a method of preparing and using the sustained release composition. The invention further relates to micron particles of a labile agent and a method of preparing the micron particles.

The method of the invention for preparing a composition for the sustained release of a labile agent, comprises forming a suspension comprising the labile agent dispersed in a polymer solution comprising at least one biocompatible polymer and at least one polymer solvent. The suspension is then wet milled to achieve micron particles of the labile agent. The polymer solvent is then removed resulting in a solid polymer/labile agent matrix. The composition for sustained release of a labile agent is likewise prepared according to the method of the invention.

The sustained release composition of the present invention can be used in a method for providing a therapeutically effective blood level of a labile agent, in a subject in need of treatment with said agent, for a sustained period comprising administering to the subject the sustained release composition described herein.

The method for preparing micron particles of a labile agent comprises forming a suspension comprising the labile agent, dispersed in a polymer solution comprising at least one biocompatible polymer and at least one polymer solvent, and wet milling of the suspension. The submicron particles of labile agent, as described herein, are prepared according to this method.

Claims

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

a) forming a suspension comprising the labile agent dispersed in a polymer solution comprising at least one biocompatible polymer and at least one polymer solvent;

b) wet milling the suspension to achieve submicron particles of the labile agent; and

c) removing the polymer solvent thereby forming a solid polymer matrix having the labile agent dispersed therein.

2. The method of claim 1 wherein the submicron particles have a volume median particle size of less than 1 micron, measured by laser diffraction.

3. The method of claim 1 wherein step (b) is conducted at a temperature of less than about 30°

C.

4. The method of claim 3 wherein the temperature is less than about 10°

C.

5. The method of claim 3 wherein the temperature is less than about 4°

C.

6. The method of claim 1 wherein the labile agent is present in the suspension at a concentration of from about 0.01 to about 50% w/w of the combined weight of polymer and labile agent.

7. The method of claim 6 wherein the labile agent is present at a concentration of about 0.01 to 30% w/w of the combined weight of the polymer and labile agent.

8. The method of claim 1 wherein the labile agent is a protein.

9. The method of claim 1 wherein the labile agent is complexed to a stabilizing metal cation.

10. The method of claim 9 wherein said stabilizing metal cation is selected from the group consisting of Zn⁺², Ca⁺², Cu⁺², Mg⁺², K⁺ and any combination thereof.

11. The method of claim 10 wherein said stabilizing metal cation is Zn⁺².

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 12 wherein the biocompatible polymer is non-biodegradable.

15. The method of claim 1 wherein the polymer solvent is methylene chloride.

16. The method of claim 1, wherein wet milling comprises the steps of:

a) adding a grinding media to the suspension; and

b) applying a mechanical means thereto.

17. The method of claim 16, wherein the mechanical means is a dispersion mill or rotary blender.

18. The method of claim 17, wherein the dispersion mill is selected from the group consisting of:

a rotary mill, a ball mill, an attrition mill, a vibratory mill, a planetary mill, a media mill or a bead mill.