HYDROGEL IMPLANTS WITH VARYING DEGREES OF CROSSLINKING

• US 20110293699A1
• Filed: 05/24/2011
• Published: 12/01/2011
• Est. Priority Date: 05/27/2010
• Status: Active Grant

• Current Assignee: Covidien LP (Medtronic Plc)
• Original Assignee: Covidien LP (Medtronic Plc)
• Inventors: Sargeant, Timothy, Stopek, Joshua, Lavigne, Kevin, Bennett, Steven, Mast, Nathaniel, Skalla, Walter
• Granted Patent: US 8,591,950 B2
• Time in Patent Office: Days
• US Class Current: 424/450
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• 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 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: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C08J 2371/02 Polyalkylene oxides
• CPC Class Codes: C08J 3/075 Macromolecular gels
• CPC Class Codes: C08J 3/246 Intercrosslinking of at least two polymers

Abstract

The present disclosure relates to a hydrogel composition and methods of using the same. The hydrogel composition may include precursors that react with each other upon contact as well as precursors that react upon contact with an initiator. In embodiments, the resulting hydrogels may have varying levels of crosslinking with both denser and less dense regions.

Claims

1. A composite hydrogel composition comprising:

a first hydrogel comprising a reactive precursor comprising a multi-arm polyether possessing electrophilic groups in combination with a second reactive precursor comprising nucleophilic groups; and

a second hydrogel comprising at least one initiated precursor comprising at least one vinyl group,

wherein the second hydrogel forms a disperse region within the first hydrogel.

2. The composite hydrogel composition of claim 1, wherein the first reactive precursor, comprises a core selected from the group consisting of polyethylene glycol, polyethylene oxide, polyethylene oxide-co-polypropylene oxide, co-polyethylene oxide block copolymers, co-polyethylene oxide random copolymers, and combinations thereof, and wherein the second reactive precursor comprises a core comprising a component selected from the group consisting of polyethylene glycol, polyethylene oxide, polyethylene oxide-co-polypropylene oxide, co-polyethylene oxide block copolymers, co-polyethylene oxide random copolymers, polyvinyl alcohol, poly(vinyl pyrrolidinone), poly(amino acids), dextran, chitosan, alginates, carboxymethylcellulose, oxidized cellulose, hydroxyethylcellulose, hydroxymethylcellulose, hyaluronic acid, albumin, collagen, casein, gelatin, and combinations thereof.

3. The composite hydrogel composition of claim 1, wherein the first reactive precursor possesses N-hydroxysuccinimide groups and the second reactive precursor possesses amine groups.

4. The composite hydrogel composition of claim 1, wherein the initiated precursor is selected from the group consisting of acrylic acid, methacrylic acid, phosphorylcholine containing monomers, furanone functional vinyl monomers, potassium sulfopropyl acrylate, potassium sulfopropyl methacrylate, n-vinyl pyrrolidone, hydroxyethyl methacrylate, vinyl monomers having a high refractive index, siloxane functional vinyl compounds, polyethylene glycol-silicone co-monomers having vinyl groups, tris acrylate, pyrrole, liquid crystalline vinyl monomers, liquid crystalline vinyl polymers, and combinations thereof.

5. The composite hydrogel composition of claim 1, further comprising an initiator selected from the group consisting of redox initiators, free radical initiators, radiation, and combinations thereof.

6. The composite hydrogel composition of claim 5, wherein the radiation is selected from the group consisting of heat, visible light, ultraviolet light, gamma ray, and electron beam.

7. The composite hydrogel composition of claim 1, further comprising a bioactive agent.

8. The composite hydrogel composition of claim 7, wherein the bioactive agent is in both the first hydrogel and the second hydrogel.

9. The composite hydrogel composition of claim 8, wherein the bioactive agent in the first hydrogel is the same as the bioactive agent in the second hydrogel.

10. The composite hydrogel composition of claim 8, wherein the bioactive agent in the first hydrogel is different than the bioactive agent in the second hydrogel.

11. The composite hydrogel composition of claim 8, wherein the bioactive agent is released from the first hydrogel over a period of time from about 1 day to about 6 weeks, and the bioactive agent is released from the second hydrogel over a period of time from about 5 days to about 12 weeks.

12. The composite hydrogel composition of claim 1, wherein the second hydrogel comprises from about 5% to about 30% by weight of the composite hydrogel composition.

13. The composite hydrogel composition of claim 1, wherein the first hydrogel has a modulus of from about 5 kPa to about 50 kPa, and the second hydrogel has a modulus of from about 10 kPa to about 100 kPa.

14. The composite hydrogel composition of claim 1, wherein the first hydrogel degrades over a period of from about 1 week to about 4 weeks, and the second hydrogel degrades over a period of from about 2 weeks to about 8 weeks.

15. The composite hydrogel composition of claim 1, further comprising a barrier layer comprising a third hydrogel comprising at least one initiated precursor over at least a portion of the surface of the first hydrogel.

16. The composite hydrogel composition of claim 15, wherein the second hydrogel and the third hydrogel comprise the same initiated precursor.

17. The composite hydrogel composition of claim 15, wherein the third hydrogel layer directs delivery of a bioactive agent from the first hydrogel, the second hydrogel, or both, in a direction opposite the barrier layer.

18. A drug delivery device comprising the composite hydrogel composition of claim 1.

19. The drug delivery device of claim 18, wherein a bioactive agent is present in the drug delivery device in a form selected from the group consisting of liposomes, microspheres, microbubbles, and combinations thereof.

20. The drug delivery device of claim 19, wherein a first bioactive agent is released from the first hydrogel over a period of from about 1 day to about 6 weeks, and a second bioactive agent is released from the second hydrogel over a period of from about 5 days to about 12 weeks.

21. A method comprising:

applying a first composition comprising a first reactive precursor comprising electrophilic groups, a second reactive precursor comprising nucleophilic groups, and an initiated precursor comprising at least one vinyl group to a template to form a first hydrogel layer;

exposing the first hydrogel layer to an initiator to form a first crosslinked layer;

applying a second composition comprising the first reactive precursor and the second reactive precursor to the first crosslinked layer to form a second hydrogel layer;

applying a third composition comprising the first reactive precursor, the second reactive precursor, and an initiated precursor comprising at least one vinyl group to the second hydrogel layer to form a third hydrogel layer; and

exposing said third hydrogel layer to the initiator to form a second crosslinked layer.

22. The method of claim 21, wherein the first reactive precursor, the second reactive precursor, or both, comprise a core comprising a component selected from the group consisting of polyethylene glycol, polyethylene oxide, polyethylene oxide-co-polypropylene oxide, co-polyethylene oxide block copolymers, co-polyethylene oxide random copolymers, polyvinyl alcohol, poly(vinyl pyrrolidinone), poly(amino acids), dextran, chitosan, alginates, carboxymethylcellulose, oxidized cellulose, hydroxyethylcellulose, hydroxymethylcellulose, hyaluronic acid, albumin, collagen, casein, gelatin, and combinations thereof.

23. The method of claim 21, wherein the first reactive precursor possesses N-hydroxysuccinimide groups and the second reactive precursor possesses amine groups.

24. The method of claim 21, wherein the initiated precursor is selected from the group consisting of acrylic acid, methacrylic acid, phosphorylcholine containing monomers, furanone functional vinyl monomers, potassium sulfopropyl acrylate, potassium sulfopropyl methacrylate, n-vinyl pyrrolidone, hydroxyethyl methacrylate, vinyl monomers having a high refractive index, siloxane functional vinyl compounds, polyethylene glycol-silicone co-monomers having vinyl groups, tris acrylate, pyrrole, liquid crystalline vinyl monomers, liquid crystalline vinyl polymers, and combinations thereof.

25. The method of claim 21, wherein the initiator is selected from the group consisting of redox initiators, free radical initiators, radiation, and combinations thereof.

26. The method of claim 25, wherein the radiation is selected from the group consisting of heat, visible light, ultraviolet light, gamma ray, and electron beam.

27. The method of claim 21, wherein the second hydrogel layer further comprises a bioactive agent.

28. The method of claim 21, further comprising:

including an initiated precursor in the second hydrogel; and

covering the second hydrogel with a screen and exposing the second hydrogel to an initiator to form a third crosslinked layer prior to applying the third hydrogel,

wherein the screen blocks exposure of at least a portion of the initiated precursor in the second hydrogel to the initiator applied to the second hydrogel, thereby preventing crosslinking of at least a portion of the initiated precursor in the second hydrogel.