Proteins deposited onto sparingly soluble biocompatible particles for controlled protein release into a biological environment from a polymer matrix

• US 6,998,137 B2
• Filed: 04/05/2001
• Issued: 02/14/2006
• Est. Priority Date: 04/07/2000
• Status: Expired due to Term

• Current Assignee: BTG International Limited (Boston Scientific Corporation)
• Original Assignee: Macromedia Incorporated (Protherics Incorporated)
• Inventors: Shih, Chung, Zentner, Gaylen, Piao, Ai-Zhi
• Primary Examiner(s): Dodson, Shelley A.
• Application Number:
  US09/827,100
• Publication Number:
  US 20020015737A1
• Time in Patent Office: 1,776 Days
• Field of Search: 424/502, 424/484, 424/108, 424/426, 424/423, 424/78.08, 514/2
• US Class Current: 424/426
• CPC Class Codes: A61K 9/143 with inorganic compounds
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system

Abstract

The present invention relates to compositions and methods for the modulated release of one or more proteins or peptides. The composition is comprised of a biocompatible polymeric matrix, a protein and/or peptide, and a sparingly water-soluble or essentially insoluble particle. The protein is deposited by adsorption or some other mechanism onto the sparingly water-soluble biocompatible particle wherein the protein-particle combination is dispersed within the polymeric matrix. The deposition of the protein onto the particle acts to modulate the release of the protein or peptide from dosage forms including long-acting dosage systems.

Claims

1. A drug delivery system for controlled protein release into a biological environment comprising:

a) a sparingly soluble biocompatible particle;

b) an effective amount of a protein or peptide deposited onto the particle forming a substantially insoluble protein-particle combination; and

c) a biocompatible polymeric matrix having dispersed therein the protein-particle combination.

2. The drug delivery system of claim 1 wherein the protein-particle combination has a biocompatible particle to protein or peptide ratio from about 1:

10 to 100,000;

1 by weight.

3. The drug delivery system of claim 1 wherein the protein-particle combination has a biocompatible particle to protein or peptide ratio from about 1:

10 to 1000;

1 by weight.

4. The drug delivery system of claim 1 wherein the protein-particle combination is present in relation to polymeric matrix at from about 0.01 to 30% by weight.

5. The drug delivery system of claim 1 wherein said biocompatible particle is a sparingly soluble salt or oxide selected from the group consisting of zinc salts, zinc oxides, magnesium salts, magnesium oxides, calcium salts, and calcium oxides.

6. The drug delivery system of claim 1 wherein said biocompatible particle is selected from the group consisting of zinc carbonate, zinc oxide, zinc tartrate, zinc hydroxide, zinc phosphate, zinc citrate, magnesium oxide, magnesium hydroxide, magnesium carbonate, calcium oxide, calcium phosphate, calcium sulfate, calcium carbonate, and combinations thereof.

7. The drug delivery system of claim 1 wherein said protein or peptide is selected from the group consisting of oxytocin, vasopressin, adrenocorticotropic hormone, epidermal growth factor, platelet-derived growth factor (PDGF), prolactin, luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRH agonists, growth hormone, growth hormone releasing factor, insulin, erythropoietin, somatostatin, glucagon, interleukin (including IL-2, IL-11, IL-12, etc.), interferon-α

, interferon-β

, interferon-γ

, gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, angiotensins, thyrotropin releasing hormone (TRH), tumor necrosis factor (TNF), parathyroid hormone (PTH), nerve growth factor (NGF), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), heparinase, vascular endothelial growth factor (VEG-F), bone morphogenic protein (BMP), hANP, glucagon-like peptide (GLP-1), renin, bradykinin, bacitracins, polymyxins, colistins, tyrocidine, gramicidins, cyclosporins, enzymes, cytokines, antibodies, vaccines, antibiotics, antibodies, glycoproteins, and combinations thereof.

8. The drug delivery system of claim 1 wherein said protein is selected from the group consisting of human growth hormone and insulin.

9. The drug delivery system of claim 1 wherein said biocompatible polymeric matrix is selected from the group consisting of polymeric particles, implants, microcapsules, microspheres, nanospheres, polymeric gels, environment responsive polymers or gels, and combinations thereof.

10. The drug delivery system of claim 1 wherein said biocompatible polymeric matrix is comprised of a polymer or gel material selected from the group consisting of nondegradable polymers, biodegradable polymers, absorbable polymers, bioerodible polymers, block copolymers, and combinations thereof.

11. The drug delivery system of claim 10 wherein said biocompatible polymeric matrix is comprised of a biodegradable polymer selected from the group consisting of poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, polyanhydrides, poly(ortho ester)s, poly(ε

-caprolactone), poly(hydroxybutyric acid), polyaminoacids, and blends and copolymers thereof.

12. The drug delivery system of claim 10 wherein said biocompatible polymeric matrix is a block copolymer selected from the group consisting of A-B-A block copolymers, B-A-B block copolymers, A-B block copolymers, and combinations thereof, and wherein said A block is a biodegradable polymer selected from the group consisting of poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, polyanhydrides, poly(ε

-caprolactone)s, poly(hydroxybutyric acid)s, poly(aminoacids)s, poly(ortho ester)s, and blends and copolymers thereof, and said B block is polyethylene glycol.

13. The drug delivery system of claim 10 wherein said biocompatible polymeric matrix is comprised of a nondegradable polymer selected from the group consisting of polyacrylates, polyacrylate esters, silicone rubbers, poloxamers, tetronics, polyethylenes, poly(methyl methacrylate)s, polymethyl methacrylate esters, polystyrenes, ethylene-vinyl acetate copolymers, polyethylene-maleic anhydride copolymers, polyamides, polymers of ethylene-vinyl acetates, acyl substituted cellulose acetates, nondegradable polyurethanes, poly(vinyl chloride)s, poly(vinyl fluoride)s, poly(vinyl imidazole)s, chlorosulphonate polyolefins, poly(ethylene oxide)s, and blends and copolymers thereof.

14. The drug delivery system of claim 1 wherein the protein or peptide is deposited onto a surface of the particle.

15. A method of preparing a protein delivery system comprising:

a) depositing a protein or peptide onto a sparingly soluble biocompatible particle to form a protein-particle combination; and

b) loading the protein-particle combination in a biocompatible polymeric matrix.

16. The method of claim 15 wherein the protein-particle combination has a biocompatible particle to protein or peptide ratio from about 1:

10 to 100,000;

1 by weight.

17. The method of claim 15 wherein the protein-particle combination has a biocompatible particle to protein or peptide ratio from about 1:

10 to 1000;

1 by weight.

18. The method of claim 15 wherein the protein-particle combination is present in relation to polymeric matrix at from about 0.01 to 30% by weight.

19. The method of claim 15 wherein the protein or peptide is deposited onto the particle by a mechanism selected from the group consisting of adsorption, absorption, and coprecipitation.

20. The method of claim 15 wherein the protein or peptide is deposited onto a surface of the particle.

21. The method of claim 15 wherein said biocompatible particle is a sparingly soluble salt or oxide selected from the group consisting of zinc salts, zinc oxides, magnesium salts, magnesium oxides, calcium salts, and calcium oxides.

22. The method of claim 15 wherein said sparingly soluble particle is selected from the group consisting of zinc carbonate, zinc oxide, zinc tartrate, zinc hydroxide, zinc phosphate, zinc citrate, magnesium oxide, magnesium hydroxide, magnesium carbonate, calcium oxide, calcium phosphate, calcium sulfate, calcium carbonate, and combinations thereof.

23. The method of claim 15 wherein said protein or peptide is selected from the group consisting of oxytocin, vasopressin, adrenocorticotropic hormone, epidermal growth factor, platelet-derived growth factor (PDGF), prolactin, luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRH agonists, growth hormone, growth hormone releasing factor, insulin, erythropoietin, somatostatin, glucagon, interleukin (including IL-2, IL-11, IL-12, ect,), interferon-α

, interferon-β

, interferon-γ

, gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, angiotensins, thyrotropin releasing hormone (TRH), tumor necrosis factor (TNF), parathyroid hormone (PTH), nerve growth factor (NGF), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), heparinase, vascular endothelial growth factor (VEG-F), bone morphogenic protein (BMP), hANP, glucagon-like peptide (GLP-1), renin, bradykinin, bacitracins, polymyxins, colistins, tyrocidine, gramicidins, cyclosporins, enzymes, cytokines, antibodies, vaccines, antibiotics, antibodies, glycoproteins, and combinations thereof.

24. The method of claim 15 wherein said protein is selected from the group consisting of human growth hormone and insulin.

25. The method of claim 15 wherein said biocompatible polymeric matrix is selected from the group consisting of polymeric particles, implants, microcapsules, microspheres, nanospheres, polymeric gels, environment responsive polymers or gels, and combinations thereof.

26. The method of claim 15 wherein said biocompatible polymeric matrix is comprised of a polymer material selected from the group consisting of nondegradable polymers, biodegradable polymers, absorbable polymers, bioerodible polymers, block copolymers, and combinations thereof.

27. The method of claim 26 wherein said biocompatible polymeric matrix is comprised of a biodegradable polymer selected from the group consisting of poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, polyanhydrides, poly(ortho ester)s, poly(ε

-caprolactone), poly(hydroxybutyric acid), polyaminoacids, and blends and copolymers thereof.

28. The method of claim 26 wherein said biocompatible polymeric matrix is a block copolymer selected from the group consisting of A-B-A block copolymers, B-A-B block copolymers, A-B block copolymers, and combinations thereof, and wherein said A block is a biodegradable polymer selected from the group consisting of poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, polyanhydrides, poly(ε

-caprolactone)s, poly(hydroxybutyric acid)s, poly(aminoacids)s, poly(ortho ester)s, and blends and copolymers thereof, and said B block is polyethylene glycol.

29. The method of claim 26 wherein said biocompatible polymeric matrix is comprised of a nondegradable polymer selected from the group consisting of polyacrylates, polyacrylate esters, silicone rubbers, poloxamers, tetronics, polyethylenes, poly(methyl methacrylate)s, polymethyl methacrylate esters, polystyrenes, ethylene-vinyl acetate copolymers, polyethylene-maleic anhydride copolymers, polyamides, polymers of ethylene-vinyl acetates, acyl substituted cellulose acetates, nondegradable polyurethanes, poly(vinyl chloride)s, poly(vinyl fluoride)s, poly(vinyl imidazole)s, chlorosulphonate polyolefins, poly(ethylene oxide)s, and blends and copolymers thereof.

30. A drug delivery system for controlled protein release into a biological environment comprising:

a) a sparingly soluble biocompatible particle selected from the group consisting of zinc salts, zinc oxides, magnesium salts, magnesium oxides, calcium salts, calcium oxides, and combinations thereof;

b) an effective amount of a protein or peptide deposited onto the particle forming a substantially insoluble protein-particle combination, wherein the protein-particle combination has a biocompatible particle to protein or peptide ratio from about 1;

10 to 100,000;

1 by weight; and

c) a biocompatible polymeric matrix having dispersed therein the protein-particle combination, wherein the protein-particle combination is present in relation to polymeric matrix at from about 0.01 to 30% by weight.

31. A drug delivery system for controlled protein release into a biological environment comprising:

a) a sparingly soluble biocompatible particle;

b) an effective amount of a protein or peptide deposited onto the particle forming a substantially insoluble protein-particle combination; and

c) a biocompatible polymeric matrix said comprised of a polymer or gel material selected from the group consisting of nondegradable polymers, biodegradable polymers, absorbable polymers, bioerodible polymers, block copolymers, and combinations thereof, said polymeric matrix in a form selected from the group consisting of polymeric particles, implants, microcapsules, microspheres, nanospheres, polymeric gels, environment responsive polymers or gels, and combinations thereof, said polymeric matrix having dispersed therein the protein-particle combination.