Water insoluble derivatives of polyanionic polysaccharides

• US 6,943,154 B2
• Filed: 01/09/2001
• Issued: 09/13/2005
• Est. Priority Date: 09/18/1987
• Status: Expired due to Fees

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Miller, Robert J., Xu, Xuejian
• Primary Examiner(s): White, Everett
• Application Number:
  US09/757,202
• Publication Number:
  US 20010039336A1
• Time in Patent Office: 1,708 Days
• Field of Search: 514/53, 514/54, 514/56, 514/57, 514/60, 514/62, 536/21, 536/56, 536/102, 536/124
• US Class Current: 514/53
• 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 for making a water insoluble biocompatible composition, said method comprising combining, in an aqueous mixture, one or more polyanionic polysaccharides, a modifying compound, a nucleophile, and an activating agent under conditions sufficient to form said composition wherein said one or more polyanionic polysaccharides and said activating agents react to form a first activated species of said one or more polyanionic polysaccharides and wherein said modifying compound causes the formation of a second activated species from said first activated species.

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, dermatin sulfate, heparin, and heparin sulfate.

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

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

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

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

8. The method of claim 1 wherein said modifying compound is chosen from the group consisting of 1-hydroxybenzotriazole hydrate, 1-hydroxybenzotriazole monohydrate, N-hydroxysulfosuccinimide, N-hydroxymiccinimide, 4-nitrophenol, 2-nitrophenol, 4-nitrothiophenol, 2-nitrothiophenol, pentachlorophenol, pentafluorophenol, imidazole, tetrazole, and 4-dimethylaminopyridine.

9. The method of claim 1 wherein said activating agent comprises a caxbodiimide.

10. The method of claim 9 wherein said carbodiimide comprises 1-ethyl-3-(3-dimiethylaminopropyl) carbodiimide, or 1-ethyl-3-(3-duimethylaminopropyl) carbodiimide methiodide.

11. The method of claim 1 wherein said polyanionic polysaccharide is present in a concentration of 0.0002-0.1 M.

12. The method of claim 11 wherein said polyanionic polysaccharide is present in a concentration of 0.0005 to 0.02M.

13. The method of claim 1 wherein said method is carried out at a pH 3.5-8.0.

14. The method of claim 1 wherein the stoichiometry of said polyanionic polysaccharide to said activating agent is at least 0.1 molar equivalent of said activating agent per molar equivalent of said polyanionic polysaccharide.

15. The method of claim 1 wherein the stoichiometry of said modifying agent to said activating agent is at least 1 molar equivalent of said modifying compound per molar equivalent of said activating agent.

16. The method of claim 1 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.