Hydrogels that undergo volumetric expansion in response to changes in their environment and their methods of manufacture and use

• US 20050196426A1
• Filed: 03/24/2005
• Published: 09/08/2005
• Est. Priority Date: 03/13/2001
• Status: Active Grant

• Current Assignee: Microvention Incorporated (Terumo Corporation)
• Original Assignee: Microvention Incorporated (Terumo Corporation)
• Inventors: Cruise, Gregory M., Constant, Michael J.
• Granted Patent: US 8,231,890 B2
• Time in Patent Office: Days
• US Class Current: 424/426
• CPC Class Codes: A61K 49/0457 Semi-solid forms, ointments, gels, hydrogels
• 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 31/145 Hydrogels or hydrocolloids
• CPC Class Codes: C08F 22/385 Monomers containing two or more (meth)acrylamide groups, e.g. N,N'-methylenebisacrylamide

Abstract

Hydrogels that expand volumetrically in response to a change in their environment (e.g., a change in pH or temperature) and their methods of manufacture and use. Generally, the hydrogels are prepared by forming a liquid reaction mixture that contains a) monomer(s) and/or polymer(s) at least portion(s) of which are sensitive to environmental changes (e.g., changes in pH or temperature), b) a crosslinker and c) a polymerization initiator. If desired, a porosigen may be incorporated into the liquid reaction mixture to create pores. After the hydrogel is formed, the porosigen is removed to create pores in the hydrogel. The hydrogel may also be treated to cause it to assume a non-expanded volume in which it remains until a change in its environment causes it to expand. These hydrogels may be prepared in many forms including pellets, filaments, and particles. Biomedical uses of these hydrogels include applications wherein the hydrogel is implanted in the body of a patient and an environmental condition at the implantation site causes the hydrogel to expand in situ.

Claims

1. A method for treating a disease, deformation or disorder of a human or veterinary patient by implantation of a hydrogel polymer at an implantation site within the patient'"'"'s body, said method comprising the steps of:

(A) providing a quantity of an environmentally-sensitive porous hydrogel polymer that i) occupies a first volume prior to implantation at the implantation site and ii) expands to a second volume, larger than said first volume, in response to an environmental condition that is present at the implantation site; and

,

(B) introducing the environmentally-sensitive porous hydrogel polymer into the implantation site such that it becomes exposed to the environmental condition present at the implantation site and, in response to said environmental condition, expands to the second volume.

2. A method according to claim 1 wherein the environmental condition to which the porous hydrogel polymer is sensitive is pH.

3. A method according to claim 1 wherein the hydrogel is non-porous.

4. A method according to claim 1 wherein the hydrogel is rendered radiopaque by the incorporation of radiopaque particles.

5. A method according to claim 1 wherein the hydrogel is rendered radiopaque by the incorporation of radiopaque monomers.

6. A method according to claim 2 wherein the hydrogel expands to its second volume when the pH of its environment is a physiological pH of about 7.4.

7. A method according to claim 1 wherein the hydrogel is in the form of pellets when delivered to the implantation site.

8. A method according to claim 1 wherein the hydrogel is in the form of an elongate filament or tube when delivered to the implantation site.

9. A method according to claim 1 wherein the hydrogel is in the form of particles when delivered to the implantation site.

10. A method according to claim 1 wherein the hydrogel is delivered to the implantation site through a catheter.

11. A method according to claim 10 wherein the catheter is a microcatheter.

12. A method according to claim 11 wherein the microcatheter has a lumen of 0.005-0.050 inch diameter, through which the hydrogel is delivered.

13. A method according to claim 10 wherein the hydrogel is mixed with a liquid carrier and the liquid carrier/hydrogel mixture is then injected through a lumen of the catheter.

14. A method according to claim 10 wherein the hydrogel is initially attached to a detachable delivery member, the delivery member with the attached hydrogel is advanced transluminally to the implantation site and, thereafter, the hydrogel is detached from the delivery member such that the hydrogel remains implanted in the implantation site after the delivery member has been withdrawn and removed.

15. A method according to claim 2 wherein the hydrogel expands more rapidly as the pH of its environment increases.

16. A method for preparing an environmentally-sensitive hydrogel polymer, said method comprising the steps of:

(A) forming a reaction mixture that contains at least i) an environmentally sensitive monomer and/or prepolymer, ii) a crosslinker, and iii) an initiator;

(B) allowing the monomer and/or prepolymer to become crosslinked by the crosslinker to form a hydrogel that will expand when immersed in an aqueous liquid; and

,

(C) treating the hydrogel to render it environmentally sensitive such that the environment in which the hydrogel resides affects the rate at which the the hydrogel expands.

17. A method according to claim 16 wherein the materials combined to form the hydrogel includes an ethylenically unsaturated monomer that has an ionizable functional group.

18. A method according to claim 17 wherein the ionizable functional group is an amine group.

19. A method according to claim 17 wherein the ionizable functional group is a carboxylic acid group.

20. A method according to claim 19 wherein the monomer is selected from the group consisting of;

acrylc acid, derivatives of acrylic acid, methacrylic acid, derivatives of methacrylic acid and possible combinations thereof.

21. A method according to claim 16 wherein the crosslinker comprises an ethylenically unsaturated crosslinker.

22. A method according to claim 21 wherein the crosslinker comprises N,N′

-methylenebisacrylamide.

23. A method according to claim 16 wherein the crosslinker is biodegradable thereby causing the resultant hydrogel to be biodegradable.

24. A method according to claim 16 wherein the reaction mixture prepared in Step A further comprises a porosigen such that the hydrogel formed in Step B has porosigen particles dispersed therein and wherein the method further comprises the step of:

removing to porosigen from the hydrogel to create pores in the hydrogel.

25. A method according to claim 24 wherein the reaction mixture is prepared in a solvent and wherein the porosigen is not soluble in the solvent but is soluble in a washing solution, said washing solution being used to remove the porosigen from the hydrogel.

26. A method according to claim 24 wherein the porosigen is selected from the group consisting of:

sodium chloride, potassium chloride, ice, sucrose, sodium bicarbonate and possible combinations thereof.

27. A method according to claim 16 wherein the initiator is a reduction/oxidation initiator.

28. A method according to claim 26 wherein the reduction/oxidation initiator comprises N,N, N′

,N′

-tetramethylethylenediamine.

29. A method according to claim 16 wherein Step A comprises:

combining acrylamide, sodium acrylate, N,N′

-methylenebisacrylamide, sodium chloride and at least one initiator selected from the group of;

N,N, N′

,N′

-tetramethylethylenediamine;

amonium persulfate; and

,

combinations thereof.

30. A method according to claim 29 wherein the hydrogel is pH sensitive such that it expands from its first volume to its second volume as the pH of its environment increases, wherein Step C comprises treating the hydrogel with a solution that has a pH lower that of an environment into which the hydrogel is to be implanted.

31. A method according to claim 16 wherein Step C comprises protonating chemical groups present on the hydrogel and wherein subsequent deprotonation of those chemical groups will cause the hydrogel to expand volumetrically.

32. A method according to claim 16 wherein Step C comprises contacting the hydrogel with and acidic solution that causes protonation of the chemical groups.

33. A method according to claim 16 wherein the monomer and/or prepolymer used in Step A is radiopaque, thereby resulting in the preparation of a radiopaque hydrogel.

34. A method According to claim 16 wherein the reaction mixture prepared in Step A further comprises a radiopaque material, thereby resulting in the preparation of a radiopaque hydrogel.

35. A method according to claim 34 wherein the radiopaque material is selected from the group consisting of:

tantalum,

gold,

platinum, and,

the possible combinations thereof.

37. A hydrogel prepared by the method of claims 16 or any claim dependent directly or indirectly therefrom.