Angiogenesis inhibition

Abstract

Angiogenesis is inhibited by the local administration of a pharmaceutical preparation formed from the reaction of hyaluronic acid, carboxymethylcellulose and a carbodiimide. The preparation, which can be in the form of a film or a gel, is advantageously applied directly to the site of a tumor, such as a cancerous tumor, used in conjunction with other chemotherapeutic techniques, or used to treat a chronic inflammatory condition, such as rheumatoid arthritis, endometriosis, arteriosclerosis, intimal hyperplasia, proliferative retinopathy, and the like.

What is claimed is:  
     
         1 . A method for inhibiting angiogenesis in a mammal comprising locally administering to the site of tumor formation or inflammation in said mammal an effective angiogenesis inhibiting amount of a pharmaceutical preparation comprising the reaction product of a polyanionic polysaccharide and an activating agent or crosslinking agent.  
     
     
         2 . The method of  claim 1  wherein the mammal is a human.  
     
     
         3 . The method of  claim 2  wherein the pharmaceutical preparation is administered to a solid tumor and surrounding tissue in said human.  
     
     
         4 . The method of  claim 3  wherein the tumor is a cancerous tumor.  
     
     
         5 . The method of  claim 2  wherein the pharmaceutical preparation is administered to the site of inflammation in said human.  
     
     
         6 . The method of  claim 5  wherein the inflammatory condition is selected from the group consisting of rheumatoid arthritis, psoriasis, purogenic granuloma, scleroderma, trachoma, endometriosis, arteriosclerosis, intimal hyperplasia, proliferative retinopathy, and the like.  
     
     
         7 . The method of  claim 1  wherein the pharmaceutical preparation also reduces the formation of surgical adhesions.  
     
     
         8 . The method of  claim 1  wherein the polyanionic polysaccharide is selected from the group consisting of hyaluronic acid, carboxymethylcellulose, carboxymethylamylose, chondroitin sulfate, dermatin sulfate, heparin, and heparin sulfate.  
     
     
         9 . The method of  claim 8  wherein the polyanionic polysaccharide is hyaluronic acid.  
     
     
         10 . The method of  claim 8  wherein said polyanionic polysaccharide is carboxymethylcellulose.  
     
     
         11 . The method of  claim 1  wherein the polyanionic polysaccharide comprises, in combination, two or more different polyanionic polysaccharides.  
     
     
         12 . The method of  claim 1  wherein one of the polyanionic polysaccharides hyaluronic acid, and the other polyanionic polysaccharide is carboxymethylcellulose.  
     
     
         13 . The method of  claim 1 ,  9  or  12  wherein the activating agent is a carbodiimide.  
     
     
         14 . The method of  claim 13  wherein said carbodiimide comprises 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide methiodide.  
     
     
         15 . The method of  claim 13  wherein the reaction is carried out in an aqueous medium at a pH of from about 3.5 -8.0.  
     
     
         16 . The method of  claim 13  wherein the polyanionic polysaccharide is present in a 10 concentration of 0.005-0.1 M.  
     
     
         17 . The method of  claim 16  wherein the polyanionic polysaccharide is present in a concentration of 0.01-0.02 M.  
     
     
         18 . The method of  claim 13  wherein the molar ratio of the polyanionic polysaccharide to the activating agent is at least 1:1.  
     
     
         19 . The method of  claim 18  wherein the molar ratio of the polyanionic polysaccharide to the activating agent is about 1:4.  
     
     
         20 . The method of  claim 1  wherein the crosslinking agent is divinyl sulfone.  
     
     
         21 . The method of  claim 1  wherein the pharmaceutical preparation is administered to the patient using a minimally invasive or open surgical procedure.  
     
     
         22 . The method of  claim 1  wherein the pharmaceutical preparation is in the form of a film.  
     
     
         23 . The method of  claim 1  or  21  wherein the pharmaceutical preparation is in the form of a gel.  
     
     
         24 . The method of  claim 1  wherein the pharmaceutical preparation is water insoluble.  
     
     
         25 . The method of  claim 1  wherein the pharmaceutical preparation includes a pharmaceutically active substance dispersed within the preparation.  
     
     
         26 . The composition of  claim 25  wherein said pharmaceutically active substance is a chosen from the group consisting of proteins, growth factors, soluble receptors, antibodies, enzymes, drugs, biopolymers, and biologically compatible synthetic polymers.  
     
     
         27 . The pharmaceutical preparation of  claim 26  wherein the pharmaceutically active substance is a steroid.  
     
     
         28 . The method of  claim 1  wherein the local administration of the pharmaceutical preparation is performed in conjunction with chemotherapy to treat a cancer patient.  
     
     
         29 . A method for inhibiting angiogenesis in a mammal comprising locally administering to the site of tumor formation in said mammal an angiogenesis inhibiting amount of a pharmaceutical preparation comprising the reaction product of hyaluronic acid, carboxymethylcellulose, and a carbodiimide.  
     
     
         30 . The method of  claim 29  wherein the pharmaceutical preparation is in the form of a film.  
     
     
         31 . The method of  claim 29  wherein the pharmaceutical preparation is in the form of a gel.