Water insoluble derivatives of polyanionic polysaccharides

• US 5,760,200 A
• Filed: 01/25/1995
• Issued: 06/02/1998
• Est. Priority Date: 09/18/1987
• Status: Expired due to Term

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Miller, Robert J., Xu, Xuejian
• Primary Examiner(s): Kight, John
• Assistant Examiner(s): White, Everett
• Application Number:
  US08/377,949
• Time in Patent Office: 1,224 Days
• Field of Search: 536/21, 536/56, 536/98, 536/119, 536/120, 536/123.1, 536/124, 514/54, 514/56
• US Class Current: 536/21
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61L 2300/00 Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
• CPC Class Codes: A61L 2300/424 Anti-adhesion agents
• CPC Class Codes: A61L 24/08 Polysaccharides A61L24/043 takes precedence
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/041 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 31/042 Polysaccharides
• CPC Class Codes: A61L 31/14 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: C08B 11/20 Post-etherification treatments of chemical or physical type, e.g. mixed etherification in two steps, including purification
• CPC Class Codes: C08B 33/00 Preparation of derivatives of amylose
• CPC Class Codes: C08B 33/04 Ethers
• CPC Class Codes: C08B 37/00 Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof cellulose D21; microbiological processes C12P
• CPC Class Codes: C08B 37/0063 Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
• 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: C08B 37/0075 : Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
• CPC Class Codes: C08L 1/28 : Alkyl ethers
• CPC Class Codes: C08L 2666/02 : Organic macromolecular compounds, natural resins, waxes or and bituminous materials
• CPC Class Codes: C08L 3/18 : Ethers
• CPC Class Codes: C08L 5/08 : Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

A water insoluble, biocompatible composition that is formed by a method which combines, in an aqueous mixture, a polyanionic polysaccharide, a nucleophile, and an activating agent, under conditions sufficient to form the composition. Also, a water insoluble, biocompatible composition that is formed by a method which combines, in an aqueous mixture, a polyanionic polysaccharide, a modifying compound, a nucleophile and an activating agent under conditions sufficient to form the composition.

Claims

1. A method of making a water insoluble biocompatible composition, said method comprising combining, in an aqueous mixture,

(a) a polyanionic polysaccharide at a concentration range between 0.005 to 0.1M, wherein said polyanionic polysaccharide has a molecular weight in the range of 9.0×

10⁴ to 3.0×

10⁶ daltons,

(b) at least 1 molar equivalent of a nucleophile per molar equivalent of said polyanionic polysaccharide, and

(c) at least 0.1 molar equivalent of an activating agent per molar equivalent of said polyanionic polysaccharide,

wherein the reaction is carried out at a pH of 3.5 to 8.0 under conditions sufficient to form said water insoluble biocompatible composition.

2. The method of claim 1 wherein two or more polyanionic polysaccharides are employed.

3. The method of claim 1 or 2 wherein said polyanionic polysaccharides are chosen from the group consisting of carboxymethyl cellulose, carboxymethyl amylose, hyaluronic acid, chondroitin-6-sulfate, and dermatin sulfate.

4. The method of claim 2 wherein two of said polyanionic polysaccharides are hyaluronic acid and carboxymethyl cellulose.

5. A water insoluble composition prepared according to the method of claim 1 or 2.

6. The composition of claim 5 wherein said composition is in the form of a gel.

7. The composition of claim 5 wherein said composition is in the form of fibers.

8. The composition of claim 5 wherein said composition is in the form of a membrane.

9. The composition of claim 5 wherein said composition is in the form of a foam.

10. The composition of claim 5, further comprising a drug dispersed within said composition.

11. The composition of claim 10 wherein said drug is selected from the group consisting of proteins, growth factors, enzymes, biopolymers, and biologically compatible synthetic polymers.

12. The composition of claim 5 wherein said polyanionic polysaccharides are chosen from the group consisting of carboxymethyl cellulose, carboxymethyl amylose, hyaluronic acid, chondroitin-6-sulfate, and dermatin sulfate.

13. The composition of claim 5 wherein said polyanionic polysaccharide is hyaluronic acid.

14. The composition of claim 5 wherein said polyanionic polysaccharide is carboxymethyl cellulose.

15. The composition of claim 5 wherein said polyanionic polysaccharide is carboxymethyl amylose.

16. The composition of claim 5 wherein two of said polyanionic polysaccharides are hyaluronic acid and carboxy methyl cellulose.

17. The composition of claim 5 wherein said nucleophile is chosen from the group consisting of an amino acid amide, a monofunctional amine, an amino acid ester, an amino alcohol, an amino thiol, an amino phenol, an amino catechol, an amino acid, a salt of an amino acid, a peptide, and a protein.

18. The method of claim 1 wherein said polyanionic polysaccharide is hyaluronic acid.

19. The method of claim 1 wherein said polyanionic polysaccharide is carboxymethyl cellulose.

20. The method of claim 1 wherein said polyanionic polysaccharide is carboxymethyl amylose.

21. The method of claim 1 wherein said nucleophile is selected from the group consisting of an amino acid amide, a monofunctional amine, an amino acid ester, an amino alcohol, an amino thiol, an amino phenol, an amino catechol, an amino acid, a salt of an amino acid, a peptide, and a protein.