Biocompatible crosslinked polymers

• US 6,566,406 B1
• Filed: 12/03/1999
• Issued: 05/20/2003
• Est. Priority Date: 12/04/1998
• Status: Expired due to Term

• Current Assignee: Incept LLC
• Original Assignee: Incept LLC
• Inventors: Pathak, Chandrashekhar P., Sawhney, Amarpreet S., Edelman, Peter G.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): DI NOLA BARON, LILIANA
• Application Number:
  US09/454,900
• Time in Patent Office: 1,264 Days
• Field of Search: 424/422, 424/423, 424/424, 424/426, 424/484, 424/486, 424/78.08, 424/78.16, 424/78.17, 424/78.24, 424/78.26, 424/78.28, 424/78.35, 514/772.1
• US Class Current: 514/772.1
• CPC Class Codes: A61K 31/74 Synthetic polymeric materials
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 47/46 Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/06 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L31/041 takes precedence
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/148 Materials at least partially resorbable by the body
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C08G 63/08 Lactones or lactides
• CPC Class Codes: C08G 63/912 derived from hydroxycarboxylic acids

Abstract

Biocompatible crosslinked polymers, and methods for their preparation and use, are disclosed in which the biocompatible crosslinked polymers are formed from water soluble precursors having electrophilic and nucleophilic groups capable of reacting and crosslinking in situ. Methods for making the resulting biocompatible crosslinked polymers biodegradable or not are provided, as are methods for controlling the rate of degradation. The crosslinking reactions may be carried out in situ on organs or tissues or outside the body. Applications for such biocompatible crosslinked polymers and their precursors include controlled delivery of drugs, prevention of post-operative adhesions, coating of medical devices such as vascular grafts, wound dressings and surgical sealants.

Claims

1. A method for preparing a biocompatible crosslinked polymer hydrogel, comprising:

providing a biocompatible small molecule crosslinker with a molecular weight of 2000 or less, the crosslinker having n crosslinker functional groups, wherein n is two or more, and wherein the crosslinker functional groups are either electrophilic or nucleophilic;

providing a synthetic biocompatible functional polymer with a molecular weight of at least about 7 times more than the crosslinker, the functional polymer having m functional polymer functional groups, wherein m is two or more and the sum of n and m functional polymer functional groups, wherein m is two or more and the sum of n and m is five or more, and wherein the functional polymer functional groups are nucleophilic if the crosslinker functional groups are electrophilic, and the functional polymer functional groups are electrophilic if the crosslinker functional groups are nucleophilic; and

combining the crosslinker and functional polymer to react the crosslinker functional groups with the functional polymer functional groups to form a hydrogel for which the crosslinked polymer gel time is less than 60 seconds as measured by a gel time measurement.

2. The method of claim 1, wherein providing a biocompatible small molecule crosslinker further comprises providing a biocompatible small molecule crosslinker having a solubility of at least 1 g/100 ml in an aqueous solution.

3. The method of claim 1, wherein providing a biocompatible small molecule crosslinker further comprises providing a biocompatible small molecule crosslinker having crosslinker functional groups that are electrophilic.

4. The method of claim 3, wherein providing a biocompatible small molecule crosslinker having crosslinker functional groups that are electrophilic further comprises providing a biocompatible small molecule crosslinker wherein the electrophilic crosslinker functional groups are N-hydroxysuccinimide-based crosslinker groups.

5. The method of claim 4, wherein providing a synthetic biocompatible functional polymer further comprises providing a synthetic biocompatible functional polymer wherein the functional polymer functional groups are amines.

6. The method of claim 1, wherein providing a biocompatible small molecule crosslinker further comprises providing a biocompatible small molecule crosslinker having crosslinker functional groups that are nucleophilic.

7. The method of claim 6, wherein providing a biocompatible small molecule crosslinker having crosslinker functional groups that are nucleophilic further comprises providing a biocompatible small molecule crosslinker wherein the crosslinker functional groups are amines.

8. The method of claim 7, wherein providing a synthetic biocompatible functional polymer further comprises providing a synthetic biocompatible functional polymer wherein the functional polymer functional groups are N-hydroxysuccinimide groups.

9. The method of claim 1, wherein providing a biocompatible small molecule crosslinker further comprises providing a biocompatible small molecule crosslinker having a biodegradable link.

10. The method of claim 1, wherein providing a synthetic biocompatible functional polymer further comprises providing a synthetic biocompatible functional polymer having a biodegradable link.

11. The method of claim 1, wherein combining the crosslinker and functional polymer further comprises reacting the crosslinker functional groups and the functional polymer functional groups to produce a biodegradable link.

12. A method for preparing a biocompatible crosslinked polymer hydrogel, comprising:

combining a biocompatible small molecule crosslinker having at least two first functional groups and a molecular weight of 2000 or less with a synthetic biocompatible functional polymer having at least two second functional groups and having a molecular weight at least about 7 times more than the small molecule crosslinker wherein each of the first functional groups are different than each of the second functional groups and the first and the second functional groups are chosen from the group consisting of electrophiles and nucleophiles, such that the combination of the first and second functional groups results in the formation of the biocompatible crosslinked polymer hydrogel.

13. The method of claim 12 wherein the small molecule crosslinker is chosen from the group consisting of dilysine, trilysine, and tetralysine.

14. The method of claim 12 wherein the formation of the biocompatible crosslinked polymer requires less than about 45 seconds as measured by a gel time measurement.

15. The method of claim 12 wherein the formation of the biocompatible crosslinked polymer requires less than about 4 seconds as measured by a gel time measurement.

16. The method of claim 12 wherein the small molecule crosslinker has at least 3 functional groups.

17. The method of claim 16 wherein the concentration of solids in the hydrogel is about 8-20 percent.

18. The method of claim 17 wherein the first functional groups are the nucleophiles and are amines and the second functional groups are the electrophiles and are succinimides.

19. A biocompatible crosslinked polymer hydrogel, comprising:

at least one biocompatible crosslinker region consisting essentially of a crosslinked synthetic crosslinker molecule with a pre-crosslinked molecular weight of less than 2000;

at least one biocompatible functional polymer region consisting essentially of a crosslinked synthetic polymer molecule with a pre-crosslinked molecular weight of more than about 7 times the molecular weight of the pre-crosslinked crosslinker molecule,

wherein the biocompatible crosslinked polymer comprises at least three links between the crosslinker region and the functional polymer region, and the links are a reaction product of at least one electrophilic functional group with of at least one nucleophilic functional group that react to form the hydrogel.

20. The biocompatible crosslinked polymer of claim 19, wherein the biocompatible crosslinker region has a solubility of at least 1 g/100 ml in an aqueous solution.

21. The biocompatible crosslinked polymer of claim 19, wherein the biocompatible crosslinked polymer further comprises at least one biodegradable link.

22. The biocompatible crosslinked polymer of claim 19, wherein at least one of the links between the crosslinker and functional polymer region is biodegradable.

23. A crosslinked biocompatible material comprising a crosslinker and a synthetic polymer joined to the crosslinker by covalent bonds to form a hydrogel;

with the crosslinker having a water solubility of at least 1 gram per 100 milliliters and being of a molecular weight of 100 to 2000 when not bonded to the polymer; and

the synthetic polymer being water soluble and being of a molecular weight of at least about 7 times the molecular weight of the crosslinker when not bonded with the crosslinker;

with the covalent bonds being a reaction product of at least one electrophile and at least one nucleophile.

24. The crosslinked biocompatible material of claim 23 wherein the electrophiles and nucleophiles cause the biocompatible material to have a gel time of less than 120 seconds as measured by a gel time measurement.

25. The crosslinked biocompatible material of claim 24 having a gel time of less than 4 seconds.

26. The crosslinked biocompatible material of claim 23 wherein the synthetic polymer molecular weight is at least about 20 times the molecular weight of the crosslinker.

27. The crosslinked biocompatible material of claim 23 comprising at least one crosslinker that is a member of the group consisting of dilysine, trilysine, and tetralysine.