Pharmaceutical microparticles

• US 8,110,224 B2
• Filed: 07/17/2008
• Issued: 02/07/2012
• Est. Priority Date: 03/13/2002
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Ausborn, Michael, Lambert, Olivier, Nagele, Oskar
• Primary Examiner(s): BARHAM, BETHANY P
• Application Number:
  US12/218,639
• Publication Number:
  US 20080279955A1
• Time in Patent Office: 1,300 Days
• Field of Search: None
• US Class Current: 424/489
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Microparticles consisting of (a) a matrix with a mixture of (a1) at least one hydrophobic, biologically degradable polymer and (a2) optionally at least one water-soluble polymer, (b) a pharmaceutical active ingredient distributed in the matrix, and (c) in addition at least one water-insoluble, surface-active substance from the group of lecithins and phospholipids, distributed in the matrix, and a three-phase emulsion process for their preparation.

Claims

1. A process for producing microparticles comprising the steps of:

a) dissolving at least one polypeptide in an aqueous buffer to produce an active ingredient solution,

b) dissolving a biologically degradable polymer, a water-soluble polymer, and lecithin in an organic solvent to produce a polymer solution containing about 20% lecithin,

c) mixing a water-soluble polymer with an aqueous buffer to form an aqueous solution,

d) mixing the active ingredient solution of a) and the polymer solution of b) using a gear pump to form an emulsion,

e) pumping the emulsion of d) and the aqueous solution of c) with a gear pump to a static mixer and mixing the same in the static mixer to form a water in oil in water emulsion,

f) removing the solvent from the emulsion of e), and

g) separating the microparticles by filtering and freeze-drying,

wherein the microparticles do not exhibit an initial burst release of the therapeutic polypeptide contained therein.

2. The process according to claim 1 wherein the solvent is removed from the microparticles using cross-filtration technology by:

a) circulating emulsion e) tangentially to a membrane at a constant flow wherein methylenehloride, salts and excipients are removed through the membrane,

b) replacing the water removed through the membrane by fresh water, and

c) separating the microparticles by filtering and freeze-drying.

3. The process of claim 1 wherein the aqueous buffer is a phosphate buffer.

4. The process of claim 1 wherein the organic solvent is methylenechloride.

5. The process of claim 1 wherein the surfactant is polyvinyl alcohol.

6. The process of claim 1 wherein the removing of step t) is performed by evaporation.

7. The process of claim 1 wherein the amount of phospholipid or lecithin is from 0.01 to 90% w/w of the final microparticle weight.

8. The process of claim 1 wherein the biologically degradable polymer is selected from the group consisting of a polycarbonate;

a polyester of an aliphatic hydroxycarboxylic acid;

a polyester of an aminocarboxylic acid;

a polyamide of an aliphatic hydroxycarboxylic acid;

a polyamide of an aminocarboxylic acids;

a homo-condensate of α

-hydroxycarboxylic acid;

a copolycondensate of α

-hydroxycarboxylic acid;

glycolic acid;

lactic acid;

poly-L-lactic acid;

poly-D,L-lactic acid;

a copolycondensate of poly-D,L-lactide/glycolide with a monomer ratio selected from the group consisting of 10;

1 to 1;

10, 1;

4 to 4;

1, and 1;

1, and a molecular weight of 5000 to 100,000 daltons; and

mixtures thereof.

9. The process of claim 8 wherein the biologically degradable polymer is a copolycondensate of D,L-lactic acid and glycolic acid (1:

1).

10. The process of claim 2 wherein the membrane is selected from the group consisting of a polymer membrane, ceramic membrane, hollow fiber, and spiral wound system.

11. A microparticle prepared by the process of claim 1, the microparticle comprising

a) at least one biologically degradable polymer,

b) optionally at least one water soluble polymer,

c) at least one pharmacologically active ingredient distributed in the biologically degradable polymer, and

d) a phospholipid or lecithin.

12. A microparticle according to claim 11 wherein the amount of phospholipid or lecithin is from about 0.01 to about 90%, preferably from about 0.1 to about 70%, most preferably from about 0.1 to about 20% w/w of the final MP weight.

13. A microparticle according to claim 11, which have a diameter of 0.1 to 200 μ

m.

14. A microparticle according to claim 11, in which the biologically degradable polymer comprises homo- or copolyester of dicarboxylic acid, alkylene diol, polyalkylene glycol and/or aliphatic hydroxycarboxylic acid;

homo- or copolyamide of dicarboxylic acids, alkylene diamine and/or aliphatic aminocarboxylic acid;

corresponding polyester-polyamide copolymer;

polyanhydride;

polyorthoester;

polyphosphazene; and

polycarbonates.

15. A microparticle according to claim 14, in which the polymer is poly-L- or poly-D,L-lactic acid or poly-D,L-lactide/glycolide with a monomer ratio of ca. 1:

1 and a molecular weight of 5000 to 100,000 daltons.

16. A microparticle according to claim 15 comprising optionally at least one water-soluble polymer.

17. A microparticle according to claim 16, wherein the water-soluble polymer is polyvinyl pyrrolidone.

18. A microparticle according to claim 11, in which the amount of biologically degradable polymers is 99 to 1% by weight, and the amount of water-soluble polymers is 1 to 99% by weight, based on the composition of the polymers.

19. A microparticle according to claim 11, in which the phospholipid is phosphatidyl choline.

20. A microparticle according to claim 11, in which the active ingredients are peptides, polypeptides and proteins.

21. A microparticle according to claim 20, in which the active ingredients are antibodies, growth hormones, insulin, interferons, erythropoietin, calcitonin, heparin, somatostatins, cell-stimulating factors and parathyroid hormones.

22. A microparticle according to claim 21 wherein the interferon is interferon alpha 2b.

23. A microparticle according to claim 11, which contain 1 to 20% by weight active ingredient, based on the weight of the microparticles.