Preparation method for biodegradable micro-particles containing drugs

• US 8,034,382 B2
• Filed: 07/31/2008
• Issued: 10/11/2011
• Est. Priority Date: 07/31/2008
• Status: Active Grant

• Current Assignee: The Board of Trustees of the University of Arkansas (University of Arkansas System)
• Original Assignee: The Board of Trustees of the University of Arkansas (University of Arkansas System)
• Inventors: Kim, Cherng-Ju
• Primary Examiner(s): Haghighatian; Mina
• Application Number:
  US12/221,096
• Publication Number:
  US 20100028454A1
• Time in Patent Office: 1,167 Days
• Field of Search: 424/451, 424/452, 424/460, 424/489, 424/491
• US Class Current: 424/489
• 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: A61P 13/08 of the prostate
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The disclosure provides a method to form sustained release drug-containing microparticles with a biodegradable polymer. The method involves forming a polymer-drug-organic solvent phase, and dispersing the polymer-drug-organic solvent phase in an aqueous suspension of an inorganic gel, which may be hydroxyapatite. The hydroxyapatite appears to coat the polymer-drug-solvent droplets to prevent them coalescing. The solvent then evaporates with stirring of the dispersion, at which time the droplets solidify to drug-containing microparticles. The inorganic gel allows suitably small microparticles to form without use of an organic emulsifier.

Claims

1. A method of preparing drug-containing microparticles comprising:

dissolving a biodegradable polymer in organic solvent to form a polymer solution;

dissolving or dispersing a drug in the polymer solution to form a polymer-drug-solvent phase;

mixing the polymer-drug-solvent phase with an aqueous suspension comprising an inorganic gel to form a dispersion comprising polymer-drug droplets dispersed in the aqueous suspension, wherein the inorganic gel can be dissolved by acid, and the dispersion is essentially free of organic surfactants and organic emulsifiers;

evaporating the organic solvent from the dispersion to convert the polymer-drug droplets to drug-containing microparticles; and

recovering the drug-containing microparticles from the dispersion, wherein the step of recovering the drug-containing microparticles from the dispersion comprises adding acid to the dispersion to dissolve the inorganic gel.

2. The method of claim 1 wherein the organic solvent is a mixture of organic solvents.

3. The method of claim 2 wherein the organic solvent comprises methanol and dichloromethane.

4. The method of claim 1 wherein the drug is hydrophobic.

5. The method of claim 1 wherein the drug is hydrophilic.

6. The method of claim 1 wherein the drug is a peptide or polypeptide.

7. The method of claim 6 wherein the drug is leuprolide.

8. The method of claim 5 wherein the drug is dissolved in an aqueous solution to form a drug-containing aqueous solution, and the drug-containing aqueous solution is dispersed in the polymer solution to form the polymer-drug-solvent phase.

9. The method of claim 1 wherein the inorganic gel is an apatite.

10. The method of claim 9 wherein the apatite is hydroxyapatite.

11. The method of claim 9 wherein the apatite is carbapatite, fluorapatite, or chlorapatite.

12. The method of claim 1 wherein the inorganic gel is dihyroxyaluminum aminoacetate, Al(OH)₃, AIPO₄, or Mg(OH)₃.

13. The method of claim 1 wherein the dispersion does not comprise poly(vinyl alcohol).

14. The method of claim 1 wherein the dispersion comprises an organic antistatic agent, and said organic antistatic agent is present in no more than 0.05% (w/w) of the dispersion.

15. The method of claim 1 wherein the biodegradable polymer is polylactic acid or polyglycolic acid or polylactic acid-co-glycolic acid).

16. The method of claim 1, wherein said drug is an amine-containing drug, and said method further comprises adjusting the pH value of said aqueous suspension comprising an inorganic gel to about 9.0 to 10.0.

17. The method of claim 1, wherein said drug is an acidic carboxyl-containing drug or an anionic drug, and said method further comprises adjusting the pH value of said aqueous suspension comprising an inorganic gel to about 5.0.

18. A method of preparing microparticles containing a hydrophilic drug, said method comprising:

dissolving a biodegradable polymer in organic solvent to form a polymer solution;

dispersing said drug as a solid powder into the polymer solution to form a polymer-drug-solvent phase;

mixing the polymer-drug-solvent phase with an aqueous suspension comprising an inorganic gel to form a dispersion comprising polymer-drug droplets dispersed in the aqueous suspension, wherein the inorganic gel can be dissolved by acid, and the dispersion is essentially free of organic surfactants and organic emulsifiers;

evaporating the organic solvent from the dispersion to convert the polymer-drug droplets to drug-containing microparticles; and

recovering the drug-containing microparticles from the dispersion, wherein the step of recovering the drug-containing microparticles from the dispersion comprises adding acid to the dispersion to dissolve the inorganic gel.