Pharmaceutical microparticles

• US 8,460,709 B2
• Filed: 01/11/2012
• Issued: 06/11/2013
• 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:
  US13/348,114
• Publication Number:
  US 20120107408A1
• Time in Patent Office: 517 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 microparticle comprising:

a) at least one biologically degradable polymer,

b) optionally at least one water soluble polymer,

c) at least one pharmacologically active ingredient selected from the group consisting of a peptide, polypeptide, and protein distributed in the biologically degradable polymer, and

d) lecithin,

wherein the microparticle;

is produced using a polymer solution containing about 20% lecithin; and

,

does not exhibit an initial burst release of the peptide, polypeptide or protein contained therein.

2. The microparticle according to claim 1 wherein the amount of lecithin is from about 0.01 to about 90% w/w of the final microparticle weight.

3. The microparticle according to claim 1 having a diameter of 0.1 to 200 μ

m.

4. A microparticle according to claim 1, in which the biologically degradable polymer is selected from the group consisting of a homo- or copolyester of dicarboxylic acid, alkylene diol, polyalkylene glycol and/or aliphatic hydroxycarboxylic acid;

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

a polyester-polyamide copolymer;

polyanhydride;

polyorthoester;

polyphosphazene;

polycarbonates;

a polyester or polyamide of an aliphatic hydroxycarboxylic acid;

a polyester or polyamide of an aminocarboxylic acid;

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;

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.

5. A microparticle according to claim 4, in which the biologically degradable 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.

6. A microparticle according to claim 5 optionally comprising at least one water-soluble polymer.

7. A microparticle according to claim 6, wherein the water-soluble polymer is selected from the group consisting of a homo-alkylene oxide of ethylene, a copolyoxa-alkylene oxide of ethylene, a homo-alkylene oxide of polypropylene glycol, a copolyoxa-alkylene oxide of polypropylene glycol, polyacrylamide, hydroxylated polyacrylamide, polymaleic acid, partial ester of polymaleic acid, partial ether of polymaleic acid, polyacrylic acid, partial ester of polyacrylic acid, partial ether of polyacrylic acid, polyvinyl alcohol, partial ester of polyvinyl alcohol, partial ether of polyvinyl alcohol, polyvinyl imidazole, polyvinyl pyrrolidone, starch, chitosan, and mixtures thereof.

8. A microparticle according to claim 1, 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.

9. A microparticle according to claim 1, in which the at least one pharmaceutically active ingredient is selected from the group consisting of an antibody, growth hormones, insulin, interferons, erythropoietin, calcitonin, heparin, somatostatins, cell-stimulating factor, and parathyroid hormones.

10. A microparticle according to claim 9 wherein the interferon is interferon alpha 2a or 2b.

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

12. The microparticle of claim 1 further comprising at least one phospholipid selected from the group consisting of phosphatidyl choline, phosphatidyl ethanolamine, lysophosphatidyl choline, phosphatidyl glycerine, phosphatidic acid, phosphatidyl serine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, 1,2-dimyristol-sn-glycero-3-phospho-rac-glycerine, 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-glycerine, and 1,2-distearoyl-sn-glycero-3-phospho-rac-glycerine.

13. The microparticle of claim 12 wherein the phospholipid is phosphatidyl choline.

14. The microparticle of claim 1 wherein the lecithin is selected from the group consisting of a natural lecithin, a partly hydrogenated lecithin, and sphingolipid.

15. The microparticle of claim 2 wherein the amount of lecithin is from about about 0.1 to about 70% w/w of the final microparticle weight.

16. The microparticle of claim 2 wherein the amount of lecithin is from about about 0.1 to about 20% w/w of the final microparticle weight.

17. A microparticle according to claim 8, in which the amount of biologically degradable polymers is 99 to 50% by weight.

18. A microparticle according to claim 8, in which the amount of biologically degradable polymers is 10 to 50% by weight.

19. A microparticle according to claim 10 wherein the interferon is interferon alpha 2b.

20. A lyophilized microparticle of claim 1.

21. A powder comprising microparticles of claim 1.

22. A microparticle of claim 1 in an aqueous solution.

23. A microparticle of claim 22 wherein the aqueous solution is a buffer.

24. A microparticle of claim 22 wherein the aqueous solution optionally comprises at least one bulking agent.

25. A microparticle of claim 24 wherein the bulking agent is mannitol or sucrose.

26. A formulation comprising microparticles of claim 1 for oral application, parenteral application, as a suppository, an aerosol, a powder, a cream, a gel, a nasal drop, an ophthalmic drop, or as part of a transdermal system.