Local delivery of fibrinolysis enhancing agents

• US 5,468,505 A
• Filed: 12/10/1993
• Issued: 11/21/1995
• Est. Priority Date: 02/28/1992
• Status: Expired due to Term

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Hubbell, Jeffrey A., Hill-West, Jennifer L., Dunn, Randall C.
• Primary Examiner(s): Nutter, Nathan M.
• Application Number:
  US08/165,392
• Time in Patent Office: 711 Days
• Field of Search: 424/484, 424/485, 424/486, 424/487, 424/488, 514/2, 514/21
• US Class Current: 424/484
• CPC Class Codes: A61K 2035/128 capsules, e.g. microcapsules
• CPC Class Codes: A61K 38/482 Serine endopeptidases (3.4.21)
• CPC Class Codes: A61K 38/49 Urokinase; Tissue plasminogen activator
• CPC Class Codes: A61K 38/58 from leeches, e.g. hirudin, eglin
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• 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 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61L 2300/254 Enzymes, proenzymes
• CPC Class Codes: A61L 2300/424 Anti-adhesion agents
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/604 Biodegradation
• CPC Class Codes: A61L 24/0031 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 24/0042 Materials resorbable by the body
• CPC Class Codes: A61L 24/046 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043 takes precedence
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 29/085 Macromolecular materials
• 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: A61L 31/16 : Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: A61P 41/00 : Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C08F 290/00 : Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
• CPC Class Codes: C08F 290/06 : Polymers provided for in subclass C08G
• CPC Class Codes: C08F 291/00 : Macromolecular compounds obtained by polymerising monomers on to macromolecular compounds according to more than one of the groups C08F251/00 - C08F289/00
• CPC Class Codes: C09D 153/00 : Coating compositions based on block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Coating compositions based on derivatives of such polymers
• CPC Class Codes: C12N 11/04 : entrapped within the carrier, e.g. gel or hollow fibres
• CPC Class Codes: C12N 2533/30 : Synthetic polymers thermoreactive polymers, e.g. PNIPAm, C12N2539/10
• CPC Class Codes: C12N 2533/32 : Polylysine, polyornithine
• CPC Class Codes: C12N 2533/40 : Polyhydroxyacids, e.g. polymers of glycolic or lactic acid (PGA, PLA, PLGA); Bioresorbable polymers
• CPC Class Codes: C12N 2533/74 : Alginate
• CPC Class Codes: C12N 5/0012 : Cell encapsulation
• CPC Class Codes: C12N 5/0677 : Three-dimensional culture, tissue culture or organ culture; Encapsulated cells
• CPC Class Codes: C12Y 304/21 : Serine endopeptidases (3.4.21)
• CPC Class Codes: C12Y 304/21073 : u-Plasminogen activator (3.4.21.73), i.e. urokinase

Abstract

A method of preventing adhesions by topical administration of fibrinolysis enhancing agents is described. The method uses a topically applied polymeric matrix for delivery of a fibrinolyic agent, preferably urokinase, or tPA. In the most preferred embodiment, the matrix is extremely thin and is polymerized in situ to form a biodegradable polymeric matrix. The matrix provides controlled release of the agent over a period of time effective to prevent surgical adhesions and is biodegradable, usually within the same time frame. Examples demonstrate that the combination of the matrix and the urokinase or tPA is effective in preventing surgical adhesions.

Claims

1. A method for preventing tissue adhesions comprising administering to a site where adhesion is to be prevented an effective amount of a fibrinolytic enhancing agent selected from the group consisting of urokinase, thrombolytic agents, proteases specifically cleaving fibrin, anti-plasmin inhibitors, and fibrin deposition blockers in a topically applied biocompatible, biodegradable polymeric matrix which conforms in situ to the tissue and releases the agent in a controlled manner over a period of between one and thirty days.

2. The method of claim 1 wherein the fibrinolytic enhancing agent is urokinase.

3. The method of claim 1 wherein the polymeric matrix degrades over a period of between one and thirty days.

4. The method of claim 1 wherein the polymeric matrix is applied as a liquid or gel and further solidified in situ.

5. The method of claim 4 wherein the matrix is polymerized on the tissue and binds to the tissue.

6. The method of claim 4 wherein the matrix is crosslinked on the tissue and binds to the tissue.

7. The method of claim 4 wherein the matrix is polymerized by free radical initiation.

8. The method of claim 4 wherein the matrix is solidified by a change in temperature or ionic environment.

9. A composition for preventing tissue adhesions comprising an effective amount to prevent tissue adhesions of a fibrinolytic enhancing agent selected from the group consisting of urokinase, thrombolytic agents, proteases specifically cleaving fibrin, anti-plasmin inhibitors, and fibrin deposition blockers in a topically applied biocompatible, biodegradable polymeric matrix which is applicable as a liquid or gel and is further solidified in situ to conform to the tissue and releases the agent in a controlled manner over a period of between one and thirty days.

10. The composition of claim 9 wherein the fibrinolytic enhancing agent is urokinase.

11. The composition of claim 9 wherein the polymeric matrix degrades over a period of between one and thirty days.

12. A method for preventing tissue adhesions comprising administering to a patient at a site where adhesion is to be prevented an effective amount of urokinase in a biocompatible, biodegradable polymeric matrix which releases the urokinase in a controlled manner over a period of between one and thirty days to prevent adhesions.

13. The method of claim 12 wherein the matrix is topically applied to the site where adhesion is to be prevented.

14. A composition for preventing tissue adhesions comprising as the active agent in preventing adhesions the combination of an effective amount of urokinase and a biocompatible, biodegradable polymeric matrix releasing the urokinase in a controlled manner over a period of between one and thirty days.

15. The composition of claim 14 wherein the composition is a liquid which can be solidified when in contact with tissue.

16. The composition of claim 14 wherein the composition is a suspension of polymeric microparticles.

17. The composition of claim 14 wherein the matrix is a hydrogel.