Acid end group poly(D,L-lactide-co-glycolide) copolymers with high glycolide content

• US 7,074,883 B2
• Filed: 12/01/2003
• Issued: 07/11/2006
• Est. Priority Date: 08/10/2000
• Status: Expired due to Fees

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Inventors: Pham, Chiem V.
• Primary Examiner(s): HAMPTON HIGHTOWER, PATRICIA
• Application Number:
  US10/724,107
• Publication Number:
  US 20040108609A1
• Time in Patent Office: 953 Days
• Field of Search: 528354-355, 528357-359, 525/411, 525/413, 428/402, 428/402.2, 428/402.21, 424/426, 424/457, 424/455, 264/4.33, 264/4.6, 264/4.1, 264/4.3, 427/212
• US Class Current: 528/354
• CPC Class Codes: A61K 38/09 Luteinising hormone-releasing hormone [LHRH] , i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: C08G 63/08 Lactones or lactides
• CPC Class Codes: C08G 63/823 for the preparation of polylactones or polylactides
• CPC Class Codes: Y10T 428/2982 Particulate matter [e.g., sphere, flake, etc.]
• CPC Class Codes: Y10T 428/2985 Solid-walled microcapsule from synthetic polymer

Abstract

Copolymers of lactide and glycolide with high glycolide content. The average glycolate block length is less then about 3, which allows the copolymer to be soluble in slightly polar solvents such as methylene chloride.

Claims

1. A method for making microparticles, comprising:

preparing a solution of a solvent and a copolymer of D,L-lactide and glycolide comprising greater than 40 and less than 50 mole percent lactide and greater than 50 and less than 60 mole percent glycolide, wherein the average glycolate monomer block length is less than about 3;

dissolving or dispersing an active agent in the solution; and

removing the solvent under vacuum to form microparticles.

2. The method of claim 1, wherein the solvent is selected from the group consisting of methylene chloride, chloroform, ethyl acetate, methyl acetate, N-methyl 2-pyrrolidone, 2-pyrrolidone, propylene glycol, tetrahydrofuran (THF), acetone, dimethylformamide (DMF), dimethylsulfoxide (DMSO), benzene, toluene, oleic acid, methyl ethyl ketone, and mixtures thereof.

3. The method of claim 1, wherein the active agent is selected from the group consisting of human growth hormone (hGH), luteinizing hormone releasing hormone (LHRH), an analog of LHRH, insulin, an anti-inflammatory compound, and an anesthetic compound.

4. Microparticles prepared by the method of claim 1.

5. The microparticles of claim 4, wherein the active agent is selected from the group consisting of human growth hormone (hGH), luteinizing hormone releasing hormone (LHRH), an analog of LHRH, insulin, an anti-inflammatory compound, or an anesthetic compound.

6. A method for making microparticles, comprising:

passing an aqueous solution and an organic solution through a static mixer to form an emulsion, wherein the organic solution comprises an active agent dissolved or dispersed therein, a solvent, and a copolymer of D,L-lactide and glycolide comprising greater than 40 and less than 50 mole percent lactide and greater than 50 and less than 60 mole percent glycolide, wherein the average glycolate monomer block length is less than about 3;

quenching the emulsion in a quench liquid comprising water; and

separating microparticles from the quench liquid.

7. The method of claim 6, wherein the solvent is selected from the group consisting of methylene chloride, chloroform, ethyl acetate, methyl acetate, N-methyl 2-pyrrolidone, 2-pyrrolidone, propylene glycol, tetrahydrofuran (THF), acetone, dimethylformamide (DMF), dimethylsulfoxide (DMSO), benzene, toluene, oleic acid, methyl ethyl ketone, and mixtures thereof.

8. The method of claim 6, wherein the active agent is selected from the group consisting of human growth hormone (hGH), luteinizing hormone releasing hormone (LHRH), an analog of LHRH, insulin, an anti-inflammatory compound, and an anesthetic compound.

9. Microparticles prepared by the method of claim 6.

10. The microparticles of claim 9, wherein the active agent is selected from the group consisting of human growth hormone (hGH), luteinizing hormone releasing hormone (LHRH), an analog of LHRH, insulin, an anti-inflammatory compound, or an anesthetic compound.

11. A method for making microparticles, comprising:

preparing a mixture comprising an active agent dissolved or dispersed therein, a solvent, and a copolymer of D,L-lactide and glycolide comprising greater than 40 and less than 50 mole percent lactide and greater than 50 and less than 60 mole percent glycolide, wherein the average glycolate monomer block length is less than about 3;

adding a non-solvent to the mixture to form a coacervate, wherein the non-solvent is not a solvent for either the copolymer or for the active agent;

removing the solvent; and

recovering microparticles.

12. The method of claim 11, wherein the solvent is selected from the group consisting of methylene chloride, chloroform, ethyl acetate, methyl acetate, N-methyl 2-pyrrolidone, 2-pyrrolidone, propylene glycol, tetrahydrofuran (THF), acetone, dimethylformamide (DMF), dimethylsulfoxide (DMSO), benzene, toluene, oleic acid, methyl ethyl ketone, and mixtures thereof.

13. The method of claim 11, wherein the active agent is selected from the group consisting of human growth hormone (hGH), luteinizing hormone releasing hormone (LHRH), an analog of LHRH, insulin, an anti-inflammatory compound, and an anesthetic compound.

14. Microparticles prepared by the method of claim 11.

15. The microparticles of claim 14, wherein the active agent is selected from the group consisting of human growth hormone (hGH), luteinizing hormone releasing hormone (LHRH), an analog of LHRH, insulin, an anti-inflammatory compound, or an anesthetic compound.

16. The method of claim 11, wherein the non-solvent is silicone oil.

17. The microparticles of claim 14, wherein the non-solvent is silicone oil.