DEGRADABLE CROSSLINKED AMINATED DEXTRAN MICROSPHERES AND METHODS OF USE

• US 20110033548A1
• Filed: 08/03/2010
• Published: 02/10/2011
• Est. Priority Date: 08/05/2009
• Status: Abandoned Application

• Current Assignee: E. I. du Pont de Nemours and Company (Corteva, Inc.)
• Original Assignee: E. I. du Pont de Nemours and Company (Corteva, Inc.)
• Inventors: LAI, Cheng-Yu, Radu, Daniela Rodica
• Application Number:
  US12/849,035
• Publication Number:
  US 20110033548A1
• Time in Patent Office: Days
• US Class Current: 424/499
• CPC Class Codes: A61K 31/721 Dextrans
• 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 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 49/00 Preparations for testing in vivo
• CPC Class Codes: A61L 24/0042 Materials resorbable by the body
• CPC Class Codes: A61L 24/043 Mixtures of macromolecular materials
• CPC Class Codes: A61L 24/06 obtained by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043, A61L24/046 take precedence
• CPC Class Codes: A61L 24/08 Polysaccharides A61L24/043 takes precedence
• CPC Class Codes: A61L 2430/36 for embolization or occlusion, e.g. vaso-occlusive compositions or devices artificial blood vessels A61L27/507
• CPC Class Codes: A61L 31/00 Materials for other surgical articles , e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices shape or structure of stent-grafts A61F2/07, of stents A61F2/82, of surgical gloves A61B42/00, of surgical drapes A61B46/00, of occluding devices A61B17/12022
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C08B 37/0021 Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
• CPC Class Codes: C08J 2305/02 Dextran; Derivatives thereof
• CPC Class Codes: C08J 2389/00 Characterised by the use of proteins; Derivatives thereof
• CPC Class Codes: C08J 3/12 Powdering or granulating
• CPC Class Codes: C08J 3/24 Crosslinking, e.g. vulcanising, of macromolecules mechanical aspects B29C35/00; crosslinking agents C08K
• CPC Class Codes: C08J 3/246 Intercrosslinking of at least two polymers
• CPC Class Codes: C08L 2201/06 Biodegradable
• CPC Class Codes: C08L 5/02 Dextran; Derivatives thereof
• CPC Class Codes: C08L 89/06 derived from leather or skin , e.g. gelatin
• CPC Class Codes: G01N 1/00 : Sampling; Preparing specimens for investigation
• CPC Class Codes: Y10T 428/2982 : Particulate matter [e.g., sphere, flake, etc.]

Abstract

Degradable, crosslinked aminated dextran microspheres are described. The microspheres contain aminated dextran crosslinked with a crosslinking agent having two or more functional groups that are capable of reacting with the primary amine groups of the aminated dextran to form covalent bonds. The degradable, crosslinked aminated dextran microspheres may be useful for temporary therapeutic embolization and drug delivery.

Claims

1. A composition comprising the reaction products obtained by the reaction of:

a) at least one aminated dextran containing primary amine groups, said at least one aminated dextran having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons and an amine substitution level of about 1% to about 65%; and

b) at least one crosslinking agent containing at least two functional groups capable of reacting with the primary amine groups of the aminated dextran;

wherein;

(i) said at least one aminated dextran and said at least one crosslinking agent are crosslinked through covalent bonds formed between the primary amine groups of the aminated dextran and the functional groups of the crosslinking agent; and

(ii) the composition is degradable and in the form of microspheres having a size of about 10 microns to about 750 microns in diameter.

2. The composition according to claim 1 wherein the functional groups contained on the crosslinking agent are selected from the group consisting of aldehyde, ketone, glyoxal, acetoacetate, activated ester, imidoester, maleimide, p-nitrophenyl ester, activated halide, anhydride, carbonyl imidazole, epoxide, alkylhalide, and isocyanate.

3. The composition according to claim 1 wherein the crosslinking agent is selected from the group consisting of glutaraldehyde, genipin, and dimethy 3,3-dithiopropionimidate.

4. The composition according to claim 3 wherein the crosslinking agent is genipin.

5. The composition according to claim 1 wherein the microspheres have a size of about 10 microns to about 125 microns in diameter.

6. The composition according to claim 1 wherein said composition further comprises an additional crosslinkable component that contains at least two primary amine groups.

7. The composition according to claim 6 wherein said additional crosslinkable component is gelatin.

8. The composition according to claim 1 wherein the composition comprises the crosslinking agent at less than 10 weight percent relative to the weight of the aminated dextran.

9. The composition according to claim 8 wherein the composition comprises the crosslinking agent at about 1 weight percent to about 5 weight percent relative to the weight of the aminated dextran.

10. A method for embolization in a mammal comprising administering into the vasculature of said mammal a composition comprising:

a) at least one aminated dextran containing primary amine groups, said at least one aminated dextran having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons and an amine substitution level of about 1% to about 65%; and

b) at least one crosslinking agent containing at least two functional groups capable of reacting with the primary amine groups of the aminated dextran;

wherein;

(i) said at least one aminated dextran and said at least one crosslinking agent are crosslinked through covalent bonds formed between the primary amine groups of the aminated dextran and the functional groups of the crosslinking agent; and

(ii) the composition is in the form of degradable, microspheres having a size of about 10 microns to about 750 microns in diameter.

11. The method according to claim 10 wherein the functional groups contained on the crosslinking agent are selected from the group consisting of aldehyde, ketone, glyoxal, acetoacetate, activated ester, imidoester, maleimide, p-nitrophenyl ester, activated halide, anhydride, carbonyl imidazole, epoxide, alkylhalide, and isocyanate.

12. The method according to claim 10 wherein the crosslinking agent is selected from the group consisting of glutaraldehyde, genipin, and dimethy 3,3-dithiopropionimidate.

13. The method according to claim 12 wherein the crosslinking agent is genipin.

14. The method according to claim 10 wherein the microspheres have a size of about 10 microns to about 125 microns in diameter.

15. The method according to claim 10 wherein said composition further comprises an additional crosslinkable component that contains at least two primary amine groups.

16. The method according to claim 15 wherein said additional crosslinkable component is gelatin.

17. The method according to claim 10 wherein the composition comprises the crosslinking agent at less than 10 weight percent relative to the weight of the aminated dextran.

18. The method according to claim 17 wherein the composition comprises the crosslinking agent at about 1 weight percent to about 5 weight percent relative to the weight of the aminated dextran.