Radiation cross-linked hydrogels

• US 6,537,569 B2
• Filed: 02/14/2001
• Issued: 03/25/2003
• Est. Priority Date: 02/14/2001
• Status: Active Grant

• Current Assignee: Microvention Incorporated (Terumo Corporation)
• Original Assignee: Microvention Incorporated (Terumo Corporation)
• Inventors: Cruise, Gregory M.
• Primary Examiner(s): AZPURU, CARLOS A
• Application Number:
  US09/783,762
• Publication Number:
  US 20020111392A1
• Time in Patent Office: 769 Days
• Field of Search: 424/423, 424/426, 514/772.3
• US Class Current: 424/426
• CPC Class Codes: A61K 31/765 Polymers containing oxygen
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61L 24/0031 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 26/008 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids

Abstract

Radiation-crosslinked, biodrgradable, synthetic hydrogels and their use in various applications, including certain medical applications wherein the hydrogel(s) are implanted on or in the body of a human or animal patient. Radiation-crosslinked, biodrgradable, synthetic hydrogels of this invention may be prepared by irradiating monomers (e.g., ethylenically unsaturated hydrocarbons such as acrylic monomers and methacrylic monomers) or polymers, some or which are biodegradable or which contain biodegradable units or subunits. Specific medical applications of these radiation-crosslinked, biodrgradable, synthetic hydrogels include applicatins wherein the hydrogel is used for hemostasis, tissue augmentation, tissue engineering, embolization, closure of vascular punctures or wounds and other medical applications.

Claims

1. A method for treating a disease, deformation or disorder of a human or veterinary patient, said method comprising the steps of:

(A) providing a quantity of a biocompatible, hydrophilic polymer which biodegrades to form polymer fragments that are of sufficiently low molecular weight to undergo renal clearance without causing substantial irreversible damage to the patient'"'"'s kidneys;

(B) irradiating the polymer so as to cause crosslinking of the polymer; and

,

(C) introducing the crosslinked polymer into or onto the patient'"'"'s body.

2. A method according to claim 1 wherein Step A comprises providing a synthetic hydrophilic polymer.

3. A method according to claim 1 wherein the crosslinked polymer is biodegradable.

4. A method according to claim 3 wherein the crosslinked polymer biodegrades to form polymer fragments that are of sufficiently low molecular weight to undergo renal clearance without causing substantial irreversible damage to the patient'"'"'s kidneys.

5. A method according to claim 3 wherein the polymer provided in Step A is dimerized prior to performance of Step B to form a dimer that has biodegradable dimer bonds and wherein Step B comprises irradiating the dimer with radiation effective to cause crosslinking of the dimer molecules.

6. A method according to claim 1 wherein the polymer provided in Step A is a polymerized polyhydric alcohol.

7. A method according to claim 6 wherein the polymer provided in Step A is poly(ethylene glycol).

8. A method according to claim 6 wherein the polymer provided in Step A comprises poly(propylene glycol).

9. A method according to claim 7 further comprising the step of dimerizing the poly(ethylene glycol) provided in Step A to form poly(ethylene glycol) dimer having biodegradable dimer bonds and wherein Step B comprises irradiating the poly(ethylene glycol) dimer.

10. A method according to claim 9 wherein the poly(ethylene glycol) provided in Step A comprises monomethoxy-poly(ethylene glycol) and wherein the monomethoxy-poly(ethylene glycol) is dimerized prior to Step B by:

i. reacting the monomethoxy-poly(ethylene glycol) with a diacid chloride to form monomethoxy-poly(ethylene glycol) dimer;

ii preparing an aqueous solution containing the monomethoxy-poly(ethylene glycol) dimer and having a pH of about 5;

iii. removing any dissolved oxygen from the monomethoxy-poly(ethylene glycol) dimer aqueous solution; and

,

iv. irradiating the monomethoxy poly(ethylene glycol) dimer solution with radiation to crosslink the monomethoxy-poly(ethylene glycol) dimer molecules.

11. A method according to claim 10 wherein Step i is performed by:

(a) dissolving the monomethoxy-poly(ethylene glycol) in a solvent;

(b) adding the diacid chloride and a chloride scavenger;

allowing the dimerization reaction to proceed; and

,

(c) percipitating out the monomethoxy-poly(ethylene glycol) dimer.

12. A method according to claim 11 wherein the solvent in which the monomethoxty poly(ethylene glycol) is dissolved is toluene.

13. A method according to claim 12 further comprising:

distilling off a portion of the toluene prior to addition of the diacid chloride and chloride scavenger.

14. A method according to claim 11 wherein the diacid chloride is succinic chloride.

15. A method according to claim 11 wherein the diacid chloride is glutaric chloride.

16. A method according to claim 13 wherein the chloride scavenger is triethylamine.

17. A method according to claim 8 wherein Step ii is performed by dissolving the monomethoxy-poly(ethylene glycol) in phosphate buffer having a pH of approximately 5.

18. A method according to claim 17 wherein each 17.5 g of monomethoxy-poly(ethylene glycol) is dissolved in approximately 82.5 g of 50 mM phosphate buffer having a pH of approximately 5.

19. A method according to claim 8 wherein Step iii is performed by bubbling argon through the solution for a sufficient time to remove substantially all dissolved oxygen from the solution.

20. A method according to claim 8 wherein Step iv comprises placing the solution in a closed radiation-permiable container and subsequently passing radiation through the container to irradiate the solution.

21. A method according to claim 20 wherein the container is a glass syringe.

22. A method according to claim 8 wherein Step iv comprises irradiating the solution with electron beam radiation.

23. A method according to claim 8 wherein Step iv comprises irradiating the solution with 30 kGy electron beam radiation.

24. A method according to claim 1 wherein the method is carried out for the purpose of wound closure and Step C comprises placing a quantity of the radiation crosslinked hydrogel in a wound.

25. A method according to claim 1 wherein the method is carried out for the purpose of embolizing a blood vessel or other anatomical conduit having a lumen and wherein Step C comprises placing a quantity of the radiation crosslinked hydrogel in the lumen of the blood vessel or anatomical conduit to block flow therethrough.

26. A method according to claim 1 wherein the method is carried out for the purpose of absorbing body fluid and Step C comprises placing a quantity of the radiation crosslinked hydrogel in or on an area of the patient'"'"'s body from which it is desired to absorb fluid.

27. A method according to claim 1 wherein the method is carried out for the purpose of sealing and Step C comprises placing a quantity of the radiation crosslinked hydrogel in or on the area of the patient'"'"'s body desired to be sealed.

28. A method according to claim 1 wherein the method is carried out for the purpose of hemostasis and Step C comprises placing a quantity of the radiation crosslinked hydrogel in or on the site of bleeding so as to effect hemostasis at the site of bleeding.

29. A method according to claim 1 wherein the method is carried out for the purpose of tissue augmentation and wherein Step C comprises placing the radiation crosslinked hydrogel in or on the portion of the patient'"'"'s body where tissue augmentation is desired.