Methods for manufacturing a composition for treating bone and/or cartilage defects

• US 8,114,428 B2
• Filed: 09/07/2009
• Issued: 02/14/2012
• Est. Priority Date: 03/08/2007
• Status: Expired due to Fees

• Current Assignee: SBF Synthetic BONE Factory GmbH
• Original Assignee: SBF Synthetic BONE Factory GmbH
• Inventors: Briest, Arne
• Primary Examiner(s): KEMMERER, ELIZABETH
• Application Number:
  US12/554,940
• Publication Number:
  US 20100028404A1
• Time in Patent Office: 890 Days
• Field of Search: None
• US Class Current: 424/422
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/1866 Vascular endothelial growth factor [VEGF]
• CPC Class Codes: A61K 38/1875 Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: A61K 38/39 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
• CPC Class Codes: A61L 27/227 Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
• CPC Class Codes: A61L 27/24 Collagen
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders

Abstract

The present invention relates to compositions devices and methods for treating bone and/or cartilage defects, and a method for manufacturing such a composition or device. In a certain embodiment, the invention provides a device and/or composition for treating bone and/or cartilage defects, having at least one collagen, for example of animal origin, and further containing at least one substance having an osteo-inductive or chondro-inductive activity, at least one differentiation and/or growth factor having osteo-stimulative and/or chondro-stimulative effect, and at least one filling material, in which the composition is in the form of a lyophil.

Claims

1. A method for aseptically manufacturing a mammalian recombinant collagen composition, the method comprising:

contacting the collagen with a peptidase or protease, wherein the mammalian collagen is of non-human origin and has at least one of an osteo-inductive activity or a chondro-inductive activity, and is filter sterilized;

adding at least one scaffold material, wherein the scaffold material has osteo-conductive properties and is selected from the group of ceramic materials, biologically compatible metals, biologically compatible polymers and extracts of native bone, and mixing with the collagen;

adding at least one differentiation or growth factor having osteo-stimulative and/or chondro-stimulative activity and the scaffold; and

, co-lyophilizing the components to obtain an at least partly form-stable, spongy body, wherein the method is performed under aseptic conditions, thereby aseptically manufacturing the composition.

4. The method according to claim 1, wherein the differentiation or growth factor having osteo-stimulative and/or chondro-stimulative activity is at least about 70% identical in amino acid sequence to a human growth factor, wherein the growth factor is at least one selected from the group of a Bone Morphogenesis Protein (BMP);

a Vascular Endothelial Growth Factor (VEGF);

a Transforming Growth Factor β

(TGFβ

);

a Platelet Derived Growth Factor (PDGF); and

Insulin-like Growth Factor (IGF); and

a p15.

5. The method according to claim 1, further comprising after contacting the collagen with peptidase or protease, aseptically filtering the collagen.

16. The method according to claim 1, wherein the native bone comprises demineralized bone matrix (DBM).

17. The method according to claim 1, wherein mixing the scaffold with the collagen further comprises coating the scaffold with collagen.

2. A method for formulating a composition for treating bone and cartilage defects, the method comprising:

concentrating a solution of recombinant human collagen, wherein the collagen is treated with acid, and is filter sterilized;

mixing aseptically the recombinant human collagen with a solution of a recombinant human bone morphogenesis protein (BMP), wherein the collagen and bone morphogenesis protein are sterile or have a reduced microbial content; and

granulating or co-lyophilizing aseptically the admixture to a gel, paste or a lyophil having an at least partly form-stable shape and a spongy consistency.

3. The method according to claim 2, further comprising prior to mixing, providing at least one scaffold material selected from the group of ceramic materials, biologically compatible metals, biologically compatible polymers and extracts of native bone;

mixing the scaffold material with the collagen, wherein the scaffold material is irradiated prior to mixing with the collagen; and

co-lyophilizing or co-granulating the admixture to obtain an at least partly form-stable, spongy body.

6. The method according to claim 2, wherein the recombinant human bone morphogenesis protein (BMP) in relation to the amount of collagen comprises a proportion in weight percent in a range selected from the group of:

about 0.005 to about 5, about 0.01 to about 4, about 0.05 to about 2, about 0.1 to about 5, and about 0.5 to about 3.

7. The method according to claim 2, further comprising after mixing covalently linking the collagen to the bone morphogenesis protein aseptically with a protein cross-linking the reagent selected from the group consisting of:

1-ethyl-3-(3-dimethlyaminopropyl)-carbodiimide (EDC), succinic anhydride, di-isocyanates, activated and protected amino acid, double activated polyethylene-glycol, and activated carbon hydrate.

8. The method according to claim 7, further comprising after cross-linking:

removing the excess cross-linking reagent by dialyzing to obtain a modified collagen that retains a biological activity selected from the group of osteo-inductive, chondro-inductive, osteo-conductive and chondro-conductive.

9. The method according to claim 2, further comprising prior to co-lyophilizing, adding at least one agent selected from the group of:

an anti-microbial agent, a cytostatic agent, an anti-inflammatory agent, and a vitamin.

10. The method according to claim 2, further comprising prior to co-lyophilizing, adding at least one additional active substance selected from the group of:

a cytokine, a recruiting factor, an adhesion factor, a growth factor, and a maturation factor for osteogenesis or chondrogenesis.

11. The method according to claim 2 further comprising prior to co-lyophilizing, adding at least one agent for retarding release of the growth factor from the scaffold.

12. The method according to claim 11, wherein the agent for retarding release is a plasma protein.

13. The method according to claim 2, further comprising after concentrating the recombinant human collagen, mixing the collagen with the BMP and at least one additional differentiation and/or growth factor having osteo-stimulative and/or chondro-stimulative effect, wherein the additional differentiation or the growth factor having osteo-stimulative and/or chondro-stimulative activity is at least about 70% identical in amino acid sequence to a human growth factor, wherein the growth factor is at least one selected from the group of Vascular Endothelial Growth Factor (VEGF), Transforming Growth Factor β

(TGFβ

), Platelet Derived Growth Factor (PDGF), Insulin-like Growth Factor (IGF) and p15.

14. The method according to claim 13, wherein the additional differentiation or growth factor in relation to the amount of collagen comprises a percent share by weight percent in a range selected from:

about 0.005 to about 5;

about 0.01 to about 4;

about 0.05 to about 2;

about 0.1 to about 5; and

about 0.5 to about 3.

15. The method according to claim 13, further comprising covalently linking the collagen to the BMP and the additional growth factor aseptically.

18. The method according to claim 3, wherein the native bone comprises demineralized bone matrix (DBM).

19. The method according to claim 3, wherein mixing the scaffold with the collagen further comprises coating the scaffold with collagen.

20. The method according to claim 12, wherein the plasma protein comprises fibrin.