Compound and device for treating bone and/or cartilage defects

• US 20100028404A1
• Filed: 09/07/2009
• Published: 02/04/2010
• Est. Priority Date: 03/08/2007
• Status: Active Grant

• Current Assignee: Arne Briest
• Original Assignee: Arne Briest
• Inventors: Briest, Arne
• Granted Patent: US 8,114,428 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• 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 composition for treating bone and/or cartilage defects, comprising at least one recombinant collagen

wherein the recombinant collagen is characterized in that it is at least of animal origin, such as mammalian, preferably human, bovine, porcine, or equine;

and 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, wherein the differentiation or growth factor is characterized in that it is at least one of;

a protein or peptide;

a glycoprotein or glycopeptides;

a cytokine;

a human differentiation or growth factor;

is recombinantly produced; and

is at least one selected from the group of a of Transforming Growth Factor (TGF) family including TGF P and a Vascular Endothelial Growth Factor (VEGF); and

a Bone Morphogenetic Protein (BMP) including BMP-2 and/or BMP-7;

and at least one filling material, wherein the composition is in the form of a lyophil and has a sponge-like consistency, is at least partially bioresorbable, and comprises a substantially form-stable body.

2. The composition according to claim 1, wherein the differentiation or growth factor in relation to the amount of collagen, osteo-inductive or chondro-inductive activity, comprises a percent share by weight in a range selected from:

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 from about 0.5 to about 3 percent by weight.

3. The composition according to claim 1 further comprising at least one scaffold material further characterized in that the scaffold material comprises at least one of:

a material having osteo-conductive properties, a collagen;

a type I collagen;

a recombinant collagen;

at least one of a ceramic, a biologically compatible metal and a biologically compatible polymer;

a plurality of pores; and

ores having a diameter of about 100 μ

m to about 300 μ

m.

4. The composition according to claim 1, wherein the composition further comprises at least one additional active substance selected from the group of, a cytostatic;

an antibiotic;

a recruiting factor;

an adhesion factor;

a growth factor; and

a maturation factor for osteogenesis or chondrogenesis.

9. A method for aseptically manufacturing the composition according to claim 1, the method comprising:

contacting the collagen with a peptidase or protease, preferably trypsin, wherein the collagen is of nonhuman origin and has at least one osteo-inductive or chondro-inductive activity,

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, preferably DBM, and mixing, preferably coating, with collagen,

mixing components comprising the collagen, wherein the collagen is of animal origin and has at least one osteo-inductive or chondro-inductive activity, with the 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.

5. A composition for treating bone and/or cartilage defects comprising at least one recombinant collagen of human origin, and at least one recombinant bone morphogenesis protein (BMP) having an osteo-inductive or chondro-inductive activity, wherein the BMP, in relation to the amount of collagen comprises a proportion in a range selected from the group of about 0.005 to about 5 weight percent, about 0.01 to about 4 weight percent, about 0.05 to about 2 weight percent, from about 0.1 to about 5 weight percent, and from about 0.5 to about 3 weight percent wherein the recombinant BMP is of mammalian origin, preferably of human, equine, porcine or bovine origin.

6. The composition according to claim 5, further additionally comprising at least one scaffold material having osteo-conductive properties wherein the scaffold material comprises at least one selected from the group of:

recombinant collagen, type I collagen, human type I collagen, tricalcium phosphate, a biphasic material comprising tricalcium phosphate, a ceramic material, a biologically compatible metal, and a biologically compatible polymer, wherein the composition comprises a porous form with pores, preferably interconnecting pores, having diameters in the range of about 100 μ

m to about 300 μ

m wherein the composition has a spongy consistency.

7. The composition according to claim 5, further comprising at least one additional active substance selected from a cytostatic and an antibiotic, a recruiting factor, an adhesion factor, a growth factor and a maturation factor for osteogenesis or chondrogenesis.

8. A composition for treating bone and/or cartilage defects comprising an aseptically prepared admixture of a recombinant human collagen and a recombinant human bone morphogenesis protein (BMP) wherein the collagen and the BMP are sterile and are aseptically mixed and co-lyophilized or co-granulated, wherein the BMP has an amino acid sequence that is at least about 70%, about 80%, about 85%, about 90%, or at least about 95% identical to an amino acid sequence of a BMP of human origin, wherein the BMP is produced in a bacterium and is non-glycosylated or in a cell selected from the group of mammalian, bird, yeast and insect and is glycosylated;

wherein BMP in relation to collagen comprises a proportion of weight percent 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 weight percent

10. A use of at least one differentiation and/or growth factor with osteo-stimulative and/or chondro-stimulative effect the use comprising mixing aseptically a sterile solution of the growth factor with a sterile solution of at least one collagen, preferably of animal origin and preferably having at least one osteo-inductive or chondro-inductive, active substance;

and, co-lyophilizing aseptically the resulting mixture in a container for single use as an implant in surgery.

11. A use of at least one human bone morphogenesis protein (BMP) for treating a bone and/or cartilage defect during a surgical procedure, the use comprising adding the BMP to at least one human collagen and at least one scaffold material to obtain an admixture, wherein the admixture is a lyophil, a gel or a paste, and providing the admixture as an aseptic device for treating a bone and/or cartilage defect during a surgical procedure, wherein the device is provided as a surgery-ready unit dose.

12. 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 or is filter sterilized;

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

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

13. The method according to claim 12, 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, preferably DBM;

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

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

14. A kit for treating a bone and/or cartilage defect during a surgical procedure comprising an aseptically prepared admixture in the form of a lyophil, a gel or a paste, the admixture comprising a recombinant human bone morphogenesis protein (BMP) and a recombinant human collagen, in a containers wherein the admixture is present in a surgery-ready unit dose, and further comprising instructions for direct use of the aseptic admixture as an implant without additional manipulation.

15. An aseptic device for surgical implantation for treating bone and/or cartilage defects comprising an admixture of a recombinantly produced human differentiation and/or growth factor having osteo-stimulative and/or chondro-stimulative effect and at least one scaffold material, wherein the factor 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 Bone Morphogenetic Proteins (BMP) comprising BMP-2, BMP-7, BMP-9, BMP-16;

Vascular Endothelial Growth Factor (VEGF);

Transforming Growth Factor β

(TGFβ

), Platelet Derived Growth Factor (PDGF), Insulin-like Growth Factor (IGF) and p15, wherein the admixture is aspetically prepared from aseptic or sterile components, wherein the device is provided as a single component for surgical implantation, wherein the device further comprises a closed container and the admixture is lyophilized in the container.

16. The device according to claim 15, further comprising at least one scaffold material, wherein the material has an osteo-conductive activity wherein the scaffold is selected from the group consisting of:

a collagen having an amino acid sequence substantially identical to a human collagen and is recombinantly produced, a ceramic, a biologically compatible metal and a biologically compatible polymer.

17. The device according to claim 15, further comprising at least one additional active substance selected from the group of at least one cytostatic agent, an antibiotic, a recruiting factor, an adhesion factor, a growth factor, and a maturation factor for osteogenesis or chondrogenesis.

18. The device according to claim 15, wherein the admixture is at least partially bio-resorbable, preferably completely bio-resorbable.

19. The device according to claim 15, wherein the container is aseptically covered with a material capable of unidirectional passage of solvent molecules during lyophilization.

20. The device according to claim 15 comprising materials that are aseptic, wherein the device has a reduced microbial content.

21. The device according to claim 15, further comprising at least one additional component capable of retarding release of the growth factor from the scaffold, wherein the component is preferably a plasma protein such as fibrin.

22. The device according to claim 16, wherein the scaffold is collagen, and the collagen is cross-linked.

23. The device according to claim 22, wherein the collagen is covalently linked to the growth factor aseptically with a reagent commonly known to be used to cross-link proteins selected from the group consisting of:

bidentate low molecular cross-linking reagent selected from the group of commonly used in protein and peptide chemistry reagents;

1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC), succinic anhydride, a di-isocyanates, an activated and properly protected amino acids, a double activated polyethylene-glycol, and an activated carbon hydrate.

24. The device according to claim 23, wherein following implanting into a subject, the device is subsequently metabolized releasing the covalently bound growth factor slowly, compared to release in a burst at an early time point following implant into the subject of an otherwise identically constituted and non-covalently bound growth factor.

25. The device according to claim 23, wherein following quantitative binding of the reagent to collagen, the device is further prepared by the steps of:

removing excess reagent by dialyzing to obtain a modified collagen that retains protein features having a biological activity selected from the group of osteo-inductive, chondro-inductive, osteo-conductive and chrondo-conductive;

mixing the modified collagen with the growth factor/s for a time appropriate for cross-linking; and

lyophilyzing, wherein the steps are performed aseptically.