Methods for forming regional tissue adherent barriers and drug delivery systems

• US 6,514,534 B1
• Filed: 08/14/1998
• Issued: 02/04/2003
• Est. Priority Date: 08/14/1998
• Status: Expired due to Term

• Current Assignee: Incept LLC
• Original Assignee: Incept LLC
• Inventors: Sawhney, Amarpreet S.
• Primary Examiner(s): Padmanabhan, Sreeni
• Application Number:
  US09/134,748
• Time in Patent Office: 1,635 Days
• Field of Search: 424/484, 424/486-488, 424/78.17, 514/944
• US Class Current: 424/486
• 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: A61L 31/145 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/148 Materials at least partially resorbable by the body
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution

Abstract

Methods are provided for forming hydrogel barriers in situ that adhere to tissue and prevent the formation of post-surgical adhesions or deliver drugs or other therapeutic agents to a body cavity. The hydrogels are crosslinked, resorb or degrade over a period of time, and may be formed by free radical polymerization initiated by a redox system or thermal initiation, or electrophilic-nucleophilic mechanism, wherein two components of an initiating system are simultaneously or sequentially poured into a body cavity to obtain widespread dispersal and coating of all or most visceral organs within that cavity prior to gelation and polymerization of the regional barrier. The hydrogel materials are selected to have a low stress at break in tension or torsion, and so as to have a close to equilibrium hydration level when formed.

Claims

1. A method of forming a regional barrier to reduce adhesion of tissue to internal structures in a body cavity following surgery comprising:

providing a pharmaceutically acceptable synthetic hydrogel system, comprising first and second components, each of the first and second components comprising macromers, having at least one water soluble and degradable region, and statistically more than one polymerizable region on average per macromer;

instilling the first component within the body cavity to coat the internal structures;

instilling the second component within the body cavity to coat the internal structures; and

polymerizing, without application energy from an external source, the first and second components in situ to form a tissue inherent hydrogel that coats the internal structures to reduce adhesion of tissue to the internal structures.

2. The method of claim 1 wherein polymerizing the first and second components comprises mixing the first and second components.

3. The method of claim 1 wherein instilling the first and second components comprises instilling the first and second components simultaneously.

4. The method of claim 1 wherein instilling the first and second components comprises instilling the first and second components sequentially.

5. The method of claim 4 wherein instilling the first component protects the internal structures during surgery and instilling the second component is performed upon completion of surgery.

6. The method of claim 1 wherein providing a pharmaceutically acceptable synthetic hydrogel system, having at least one water soluble and degradable region, and statistically more than one polymerizable region on average per macromer, comprises providing a first component having at least one water soluble region, at least one degradable region, and at least one polymerizable region.

7. The method of claim 2 wherein each of the first and second components includes a polymerizable region, being composed of monomeric, oligomeric or polymeric units and crosslinking the first and second components comprises polymerizing the first and second components so that polymerizable regions of the first and second components react.

8. The method of claim 2 wherein polymerizing the first and second components comprises polymerizing the first and second components by a mechanism selected from a group consisting of a free radical mechanism, and an electrophilic-nucleophilic mechanism.

9. The method of claim 1 wherein polymerizing the first and second components comprises polymerizing the first and second components to form a tissue adherent hydrogel at a substantially equilibrium hydration level.

10. The method of claim 1 wherein polymerizing the first and second components comprises polymerizing the first and second components to form a tissue adherent hydrogel that is substantially isotonic.

11. The method of claim 1 wherein polymerizing the first and second components comprises polymerizing the first and second components to form a tissue adherent hydrogel having a tensile strength less than 1 MPa.

12. The method of claim 1 further comprising biodegrading the tissue adherent hydrogel within a pretermined period of time, wherein biodegrading means hydrolytic, enzymatic, or thermal decomposition by bond scission of linkages to produce ultimately soluble and physiologically cleared molecules.

13. The method of claim 12 wherein biodegrading the tissue adherent hydrogel within a predetermined period of time comprises biodegrading the tissue adherent hydrogel within one month, wherein biodegrading means hydrolytic, enzymatic, or thermal decomposition by bond scission of linkages to produce ultimately soluble and physiologically cleared molecules.

14. The method of claim 1 wherein providing a pharmaceutically acceptable hydrogel system comprises providing a pharmaceutically acceptable hydrogel system wherein at least one of the first and second components contains a bioactive molecule that provides a therapeutic benefit.

15. The method of claim 14 wherein providing a pharmaceutically acceptable hydrogel system wherein at least one of the first and second components contains a bioactive molecule comprises providing a pharmaceutically acceptable hydrogel system wherein at least one of the first and second components contains a drug selected from the group consisting of small molecules, macromolecules, proteins, peptides, oligonucleotides, carbohydrates and proteoglycans.

16. The method of claim 14 wherein providing a pharmaceutically acceptable hydrogel system wherein at least one of the first and second components contains a bioactive molecule comprises providing a pharmaceutically acceptable hydrogel system wherein at least one of the first and second components contains a drug selected from the group consisting of drugs that interfere with the process of adhesion formation and drugs that are used to treat inflammation, cancer and endometriosis.

17. The method of claim 1 wherein the first component contains a color indicator, the method further comprising changing the color of the indicator responsive to a degree of mixing of the first and second components.

18. A method of delivering bioactive molecules to internal structures in a body cavity following surgery comprising:

providing a pharmaceutically acceptable synthetic hydrogel system, comprising first and second components, at least one of the first and second components containing a bioactive molecule that provides a therapeutic benefit, each of the first and second components comprising macromers having at least one water soluble and degradable region, and statistically more than one polymerizable region on average per macromer;

instilling the first component within the body cavity to coat the internal structures;

instilling the second component within the body cavity to coat the internal structures; and

polymerizing, without application of energy from an external source, the first and second components in situ to form a tissue adherent hydrogel that coats the internal structures.

19. The method of claim 18 wherein polymerizing the first and second components comprises mixing the first and second components.

20. The method of claim 18 wherein instilling the first and second components comprises instilling the first and second components simultaneously.

21. The method of claim 18 wherein instilling the first and second components comprises instilling the first and second components sequentially.

22. The method of claim 21 wherein instilling the first component protects the internal structures during surgery and instilling the second component is performed upon completion of surgery.

23. The method of claim 18 wherein providing a pharmaceutically acceptable hydrogel system comprises providing a first component including at least one water soluble region, at least one degradable region, and at least one polymerizable region.

24. The method of claim 23 wherein each of the first and second components includes a polymerizable region, being composed of monomeric, oligomeric or polymeric units, and polymerizing the first and second components comprises polymerizing the first and second components so that polymerizable regions of the first and second components interact.

25. The method of claim 18 wherein polymerizing at least the first component comprises polymerizing the first component by a mechanism selected from the group consisting of:

a free radical mechanism, and an electrophilic-nucleophilic mechanism.

26. The method of claim 18 wherein polymerizing the first and second components comprises polymerizing the first and second components to form a tissue adherent hydrogel at a substantially equilibrium hydration level.

27. The method of claim 18 wherein polymerizing the first and second components comprises polymerizing the first and second components to form a tissue adherent hydrogel that is substantially isotonic.

28. The method of claim 18 wherein polymerizing the first and second components comprises polymerizing the first and second components to form a tissue adherent hydrogel having a tensile strength less than 1 MPa.

29. The method of claim 18 further comprising biodegrading the tissue adherent hydrogel within a predetermined period of time, wherein biodegrading means hydrolytic, enzymatic, or thermal decomposition by bond scission of linkages to produce ultimately soluble and physiologically cleared molecules.

30. The method of claim 18 wherein the first component contains a color indicator, the method further comprising changing the color of the indicator responsive to a degree of mixing of the first and second components.