Dehydrated hydrogel precursor-based, tissue adherent compositions and methods of use

• US 6,703,047 B2
• Filed: 02/02/2001
• Issued: 03/09/2004
• Est. Priority Date: 02/02/2001
• Status: Expired due to Term

• Current Assignee: Incept LLC
• Original Assignee: Incept LLC
• Inventors: Edelman, Peter G., Sawhney, Amarpreet S.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): DI NOLA BARON, LILIANA
• Application Number:
  US09/776,120
• Publication Number:
  US 20020106409A1
• Time in Patent Office: 1,131 Days
• Field of Search: 424/422, 424/423, 424/426, 424/484, 424/486, 424/487, 424/488, 424/489, 424/490, 424/491, 424/493, 424/497, 424/499, 424/501, 424/400
• US Class Current: 424/489
• 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 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/7023 Transdermal patches and similar drug-containing composite devices, e.g. cataplasms galenical aspects of iontophoretic devices A61K9/0009; microneedle arrays A61K9/0021; buccal patches A61K9/006

Abstract

Compositions and methods are provided for forming tissue-adherent hydrogels using substantially dry precursors. The dehydrated precursors are premixed prior to in situ therapy and utilize naturally-occurring body fluids as an aqueous environment that initiates transformation, which causes dissolution and nearly simultaneous crosslinking of the precursors, thus forming an insoluble hydrogel implant. The dehydrated precursor-based hydrogels may be used as sealants for fluid leaks from tissue, as adherent drug delivery depots, as means for augmenting and/or supporting tissue, and as means for serving a variety of other useful medical and surgical purposes.

Claims

1. A hydrogel system for in situ therapy comprising an applicator associated with at least two substantially dry hydrogel precursors for delivery to a common location, the dry hydrogel precursors being water soluble and having functional groups for forming chemical crosslinks with each other at physiological pH to form a hydrogel in situ upon exposure to an aqueous fluid from a physiological environment.

2. The hydrogel system of claim 1, wherein the dry hydrogel precursors upon exposure to an aqueous physiological environment further form crosslinks that are physical in nature, the physical crosslinks being formed by a mechanism selected from the group consisting of ionic interactions, hydrophobic interactions, hydrogen bonding, Van der Waals forces and desolvation.

3. The hydrogel system of claim 1, wherein the functional groups form chemical crosslinks by a mechanism selected from the group consisting of free radical polymerization, condensation polymerization, anionic or cationic polymerization and step growth polymerization.

4. The hydrogel system of claim 1, wherein the chemical crosslinks are both chemical and physical in nature.

5. The hydrogel system of claim 1, wherein the substantially dry hydrogel precursors comprise a form chosen from the group consisting of lyophilized, spray dried, or in a solvent that is inert to interaction between the dry precursors.

6. The hydrogel system of claim 1, wherein the substantially dry hydrogel precursors are compounded together prior to exposure to the fluid from the physiological environment.

7. The hydrogel system of claim 5, wherein the substantially dry hydrogel precursors in lyophilized form comprise a corrugated structure.

8. The hydrogel system of claim 5, wherein the substantially dry hydrogel precursors in spray dried form comprise granules of controlled size.

9. The hydrogel system of claim 8, wherein the granules comprise a coating of a binding agent that helps create a shaped article configuration.

10. The hydrogel system of claim 9, wherein the hydrogel comprises a configuration chosen from the group consisting of a sheet, a cone, and a composite granule.

11. The hydrogel system of claim 1, wherein the hydrogel precursors are adapted to form a hydrogel that is biodegradable.

12. The hydrogel system of claim 1 wherein the applicator is chosen from the group consisting of a non-adhesive backing material, an absorbable backing material, a syringe applicator, a powder atomization system, and a needle-less injector.

13. The hydrogel system of claim 12, wherein the non-adhesive backing material is non-absorbable.

14. The hydrogel system of claim 13, wherein the non-adhesive backing material is fabricated from a material chosen from the group consisting of polytetrafluoroethylene, polyethylene, polyurethane, and silastic.

15. The hydrogel system of claim 12, wherein the non-adhesive backing material further comprises a coating, the coating configured to facilitate release of the hydrogel from the non-adhesive backing material.

16. The hydrogel system of claim 15, wherein the coating is fabricated from a material chosen from the group consisting of poly(ethylene glycol) with a molecular weight less than 2000 Da, glycerol, fatty acid, and sugar.

17. The hydrogel system of claim 1 further comprising therapeutic agents in communication with the hydrogel precursors.

18. The hydrogel system of claim 17, wherein the therapeutic agents are chosen from the group consisting of thrombin, anti-infective agents, bone growth factors, angiogenic factors, anti-angiogenic factors, growth factors, proteins, peptides, oligonucleotides, genes, polysaccharides, proteoglycans, microparticles, glycosaminoglycans, and drugs.

19. The hydrogel system of claim 1 wherein the hydrogel system is provided in a form chosen from the group consisting of a kit and a patch.

32. The hydrogel system of claim 1, wherein the functional groups include an electrophile and a nucleophile.

33. The hydrogel system of claim 32 wherein at least one of the hydrogel precursors comprises poly(ethylene) glycol and the electrophile or the nucleophile.

34. The hydrogel system of claim 1, wherein the dry precursors are powders.

20. A method of forming a dehydrated precursor-based water-insoluble hydrogel medical implant in situ comprising:

providing at least two substantially dry hydrogel precursors that are water soluble and include functional groups that make chemical crosslinks to each other to form the water-insoluble hydrogel medical implant when mixed together in an aqueous environment at physiological PH;

delivering the hydrogel precursors to an implantation site in situ in a patient; and

exposing the precursors to aqueous physiological fluids at physiological pH at the implantation site.

21. The method of claim 20, wherein providing a hydrogel precursor comprises providing a hydrogel precursor associated with a bioactive species.

22. The method of claim 20 further comprising using the hydrogel medical implant for delivering drugs.

23. The method of claim 20, wherein forming the medical implant seals fluid leaks from the implantation site.

24. The method of claim 20, wherein forming the medical implant supports or augments the implantation site.

25. The method of claim 20, wherein delivering the hydrogel precursors to the implantation site comprises inhaling the hydrogel precursors.

26. A method of forming hydrogel particulates comprising:

providing a hydrogel;

removing water from the hydrogel;

pulverizing the hydrogel to particulates of controlled size; and

treating the particulates to provide synthetic organic functional groups on a surface of the particulates, the functional groups configured to form chemical crosslinks with tissue and/or blood components.

27. The method of claim 26 further comprising lyophilizing the particulates.

28. The method of claim 26, wherein providing synthetic organic functional groups comprises providing electrophilic groups on at least a portion of the particulates.

29. The method of claim 28 wherein providing the electrophilic groups comprises a step of providing N-hydroxysuccinimide groups.

30. The method of claim 26 further comprising applying the particulates into a body space, thereby forming a bioreactive, degradable hydrogel in situ.

31. The method of claim 30, wherein forming a bioreactive, degradable hydrogel in situ comprises:

hydrating the particulates, thereby causing the particulates to swell and partially or completely fill the body space; and

reacting the particulates with tissue and/or blood components to form the biocompatible, degradable hydrogel.