Collagen-synthetic polymer matrices prepared using a multiple step reaction

• US 5,475,052 A
• Filed: 05/02/1994
• Issued: 12/12/1995
• Est. Priority Date: 11/21/1988
• Status: Expired due to Term

• Current Assignee: Angiotech Pharmaceuticals Incorporated
• Original Assignee: Collagen Corp. (Abbvie Incorporated)
• Inventors: Rhee, Woonza M., Berg, Richard A.
• Primary Examiner(s): Nutter, Nathan M.
• Application Number:
  US08/236,769
• Time in Patent Office: 589 Days
• Field of Search: 525/54.1, 525/54.2, 525/54.21, 525/54.22, 525/54.23, 525/54.24, 523/113, 530/356, 530/840
• US Class Current: 525/54.1
• CPC Class Codes: A61F 2/06 Blood vessels
• CPC Class Codes: A61F 2/07 Stent-grafts
• CPC Class Codes: A61F 2002/072 Encapsulated stents, e.g. wire or whole stent embedded in lining
• CPC Class Codes: A61F 2310/00365 Proteins; Polypeptides; Degradation products thereof
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61L 15/225 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 15/44 Medicaments
• CPC Class Codes: A61L 2300/236 Glycosaminoglycans, e.g. heparin, hyaluronic acid, chondroitin
• CPC Class Codes: A61L 2300/25 Peptides having up to 20 amino acids in a defined sequence
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/406 Antibiotics
• CPC Class Codes: A61L 2300/41 Anti-inflammatory agents, e.g. NSAIDs
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/42 Anti-thrombotic agents, anticoagulants, anti-platelet agents
• CPC Class Codes: A61L 2300/426 Immunomodulating agents, i.e. cytokines, interleukins, interferons
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/62 Encapsulated active agents, e.g. emulsified droplets
• CPC Class Codes: A61L 24/102 Collagen
• CPC Class Codes: A61L 2430/16 : for reconstruction of eye parts, e.g. intraocular lens, cornea
• CPC Class Codes: A61L 26/0033 : Collagen
• CPC Class Codes: A61L 27/18 : obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/20 : Polysaccharides
• CPC Class Codes: A61L 27/24 : Collagen
• CPC Class Codes: A61L 27/26 : Mixtures of macromolecular compounds
• CPC Class Codes: A61L 27/34 : Macromolecular materials
• CPC Class Codes: A61L 27/44 : having a macromolecular matrix
• CPC Class Codes: A61L 27/54 : Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 29/043 : Polysaccharides
• CPC Class Codes: A61L 29/045 : Collagen
• CPC Class Codes: A61L 29/06 : obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 29/16 : Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence
• CPC Class Codes: A61L 31/041 : Mixtures of macromolecular compounds
• CPC Class Codes: A61L 31/044 : Collagen
• CPC Class Codes: A61L 31/10 : Macromolecular materials
• CPC Class Codes: A61L 31/125 : having a macromolecular matrix
• CPC Class Codes: A61L 31/16 : Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: C07K 14/495 : Transforming growth factor [TGF]
• CPC Class Codes: C07K 14/78 : Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
• CPC Class Codes: C08B 37/0069 : Chondroitin-4-sulfate, i.e. chondroitin sulfate A; Dermatan sulfate, i.e. chondroitin sulfate B or beta-heparin; Chondroitin-6-sulfate, i.e. chondroitin sulfate C; Derivatives thereof
• CPC Class Codes: C08B 37/0072 : Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
• CPC Class Codes: C08H 1/06 : derived from horn, hoofs, hair, skin or leather
• CPC Class Codes: C08L 2666/02 : Organic macromolecular compounds, natural resins, waxes or and bituminous materials
• CPC Class Codes: C08L 71/02 : Polyalkylene oxides
• CPC Class Codes: C08L 89/00 : Compositions of proteins; Compositions of derivatives thereof foodstuff preparations A23J3/00
• CPC Class Codes: C08L 89/06 : derived from leather or skin , e.g. gelatin
• CPC Class Codes: C09J 189/06 : derived from leather or skin
• CPC Class Codes: G02B 1/043 : Contact lenses

Abstract

The present invention discloses collagen-synthetic polymer matrices which are prepared using a multiple step reaction. The first step of the reaction generally involves reacting collagen with a functionally activated synthetic hydrophilic polymer to form a collagen-synthetic polymer matrix. The synthetic hydrophilic polymer may be mono- or multifunctionally activated, but is preferably difunctionally activated, resulting in the formation of a crosslinked collagen matrix. The second step comprises modifying the collagen-synthetic polymer matrix according to one or more of the following methods: further crosslinking the matrix using a multifunctionally activated synthetic polymer, conjugating the matrix using a monofunctionally activated synthetic polymer, coupling biologically active molecules or glycosaminoglycans to the matrix, crosslinking the matrix using conventional chemical crosslinking agents, or modifying the collagen in the matrix by means of various chemical reactions. An optional third step may include further modification of the collagen-synthetic polymer matrix by covalently binding, for example, biologically active molecules or glycosaminoglycans to the matrix by means of available active groups on the synthetic hydrophilic polymers. Collagen-synthetic polymer matrices prepared according to the methods of the present invention have very low immunogenicity and can therefore be used to prepare biocompatible implants for use in a variety of medical applications.

Claims

1. A collagen-polyethylene glycol matrix prepared by the process of:

reacting collagen with a first functionally activated polyethylene glycol to form a collagen-polyethylene glycol matrix; and

further reacting the collagen-polyethylene glycol matrix with a chemical substance selected from the group consisting of;

a second functionally activated polyethylene glycol, a biologically active agent, a glycosaminoglycan and its derivatives, a chemical crosslinking agent, an esterifying agent, an amidating agent, an acylating agent, an amino acid, a peptide, and combinations thereof.

2. The matrix of claim 1, wherein the collagen is atelopeptide fibrillar collagen.

3. The matrix of claim 1, wherein the first functionally activated polyethylene glycol is a difunctionally activated polyethylene glycol.

4. The matrix of claim 1, wherein the collagen and the first functionally activated polyethylene glycol are covalently bound by means of a linkage selected from the group consisting of an ether linkage, an ester linkage, and a urethane linkage.

5. The matrix of claim 1, wherein the chemical substance is a second functionally activated polyethylene glycol.

6. The matrix of claim 5, wherein the second functionally activated polyethylene glycol is selected from the group consisting of a difunctionally activated polyethylene glycol and a monofunctionally activated polyethylene glycol.

7. The matrix of claim 6, wherein the collagen and the second functionally activated polyethylene glycol are covalently bound by means of a linkage selected from the group consisting of an ether linkage, an ester linkage, and a urethane linkage.

11. The matrix of claim 4, wherein the collagen and the first functionally activated polyethylene glycol are covalently bound by means of a linkage selected from the group consisting of an ether linkage, an ester linkage, and a urethane linkage.

12. The matrix of claim 11, wherein the second functionally activated polyethylene glycol is selected from the group consisting of a difunctionally activated polyethylene glycol and a monofunctionally activated polyethylene glycol.

8. A collagen-polyethylene glycol matrix prepared by the process of:

reacting collagen with a first functionally activated polyethylene glycol to form a collagen-polyethylene glycol matrix; and

further reacting the collagen-polyethylene glycol matrix with a second functionally activated polyethylene glycol.

9. The matrix of claim 8, wherein the collagen is atelopeptide fibrillar collagen.

10. The matrix of claim 8, wherein the first functionally activated polyethylene glycol is a difunctionally activated polyethylene glycol.

13. The matrix of claim 8, wherein the collagen and the second functionally activated polyethylene glycol are covalently bound by means of a linkage selected from the group consisting of an ether linkage, an ester linkage, and a urethane linkage.

14. A process for preparing a collagen-polyethylene glycol matrix comprising:

reacting collagen with a first functionally activated polyethylene glycol to form a collagen-polyethylene glycol matrix; and

further reacting the collagen-polyethylene glycol matrix with a chemical substance selected from the group consisting of;

a second functionally activated polyethylene glycol, a biologically active agent, a glycosaminoglycan and its derivatives, a chemical crosslinking agent, an esterifying agent, an amidating agent, an acylating agent, an amino acid, a peptide, and combinations thereof.

15. The process of claim 14, wherein the collagen is atelopeptide fibrillar collagen.

16. The process of claim 14, wherein the first functionally activated polyethylene glycol is a difunctionally activated polyethylene glycol.

17. The process of claim 14, wherein the collagen and the first functionally activated polyethylene glycol are covalently bound by means of a linkage selected from the group consisting of an ether linkage, an ester linkage, and a urethane linkage.

18. The process of claim 14, wherein the chemical substance is a second functionally activated polyethylene glycol.

19. The process of claim 18, wherein the second functionally activated polyethylene glycol is selected from the group consisting of a difunctionally activated polyethylene glycol and a monofunctionally activated polyethylene glycol.

20. The process of claim 18, wherein the collagen and the second functionally activated polyethylene glycol are covalently bound by means of a linkage selected from the group consisting of an ether linkage, an ester linkage, and a urethane linkage.

21. A process for preparing a collagen-polyethylene glycol matrix comprising:

reacting collagen with a first functionally activated polyethylene glycol to form a collagen-polyethylene glycol matrix; and

further reacting the collagen-polyethylene glycol matrix with a second functionally activated polyethylene glycol.

22. The process of claim 21, wherein the collagen is atelopeptide fibrillar collagen.

23. The process of claim 21, wherein the first functionally activated polyethylene glycol is a difunctionally activated polyethylene glycol.

24. The process of claim 21, wherein the collagen and the first functionally activated polyethylene glycol are covalently bound by means of a linkage selected from the group consisting of an ether linkage, an ester linkage, and a urethane linkage.

25. The process of claim 21, wherein the second functionally activated polyethylene glycol is selected from the group consisting of a difunctionally activated polyethylene glycol and a monofunctionally activated polyethylene glycol.

26. The process of claim 21, wherein the collagen and the second functionally activated polyethylene glycol are covalently bound by means of a linkage selected from the group consisting of an ether linkage, an ester linkage, and a urethane linkage.