Drug delivery via therapeutic hydrogels

Abstract

The present invention is directed to a vehicle for effecting drug delivery from a solid substrate. Hydrogels loaded with liposomal therapeutic agents such as antibiotics are covalently bonded to the surface of substrates such as in-dwelling medical devices, such as implants, catheters, and the like. The present invention is particularly useful in the treatment and prevention of biofilm mediated infection often associated with the use of in-dwelling medical devices.

What is claimed is:  
     
         1 . A medical device comprising: 
 a. a polymeric substrate;    b. a hydrogel matrix material covalently bound to said substrate; and    c. a liposomal therapeutic agent confined within said matrix material.    
     
     
         2 . The medical device of  claim 1 , wherein the hydrogel matrix material is a polyethylene glycol-protein matrix.  
     
     
         3 . The medical device of  claim 1 , wherein the polymeric substrate is silicone rubber.  
     
     
         4 . The medical device of  claim 3 , wherein the silicone rubber comprises polydimethylsiloxane.  
     
     
         5 . The medical device of  claim 3 , wherein the hydrogel matrix material is a polyethylene glycol-gelatin matrix.  
     
     
         6 . The medical device of  claim 5 , comprising a bifunctional linker molecule situated between said silicone rubber substrate and said polyethylene glycol-gelatin matrix material.  
     
     
         7 . The medical device of  claim 5 , wherein said linker molecule is a 4-amino-2,3,5,6-tetrafluorobenzoyl radical.  
     
     
         8 . The medical device of  claim 1 , wherein the liposomal therapeutic agent is selected from among the group consisting of: antibiotics, antihistamines, anti-inflammatories, hormones, steroids, growth factors, colony stimulating factors, interleukins, and combinations thereof.  
     
     
         9 . The medical device of  claim 1 , wherein the liposomal therapeutic agent is an antibiotic.  
     
     
         10 . The medical device of  claim 1 , wherein the liposomal therapeutic agent is a fluoroquinolone antibiotic.  
     
     
         11 . The medical device of  claim 10 , wherein the fluoroquinolone antibiotic is selected from the group consisting of: ciprofloxacin, norfloxacin, ofloxacin, pefloxacin, enoxacin, rosoxacin, amifioxacin, fleroxacin, temafloxacin, and lomefloxacin.  
     
     
         12 . The medical device of  claim 10 , wherein the fluoroquinolone is ciprofloxacin.  
     
     
         13 . The medical device of  claim 1 , wherein the liposomes are formed of a material selected from the group consisting of dipalmitoylphosphatidylcholine and polyethyleneglycol-distearoylphosphatidylethanolamine.  
     
     
         14 . A medical device comprising: 
 a. a silicone rubber substrate;    b. a fluorinated aroyl amine group covalently bound to said substrate;    c. a polyethylene glycol-gelatin matrix material covalently bound to said fluorinated aroyl amine; and    d. liposomal ciprofloxacin dispersed throughout said matrix material.    
     
     
         15 . A medical device comprising a silicone rubber substrate covalently binding a therapeutic hydrogel such that the surface of the device is loaded with about 10-1,000 μg active agent per cm 2  of substrate.  
     
     
         16 . The medical device of  claim 15 , wherein the active agent is ciprofloxacin.  
     
     
         17 . A medical device comprising a silicone rubber substrate covalently binding a therapeutic hydrogel such that the surface of the device is loaded with about 50-200 μg ciprofloxacin per cm 2  of substrate.  
     
     
         18 . A therapeutic hydrogel composition comprising a liposomal therapeutic agent dispersed throughout a hydrogel.  
     
     
         19 . The therapeutic hydrogel of  claim 17 , wherein the hydrogel contains about 100-10,000 μg of the liposomal therapeutic agent per cm 3  of hydrogel.  
     
     
         20 . The therapeutic hydrogel of  claim 19 , wherein the liposomal therapeutic agent is ciprofloxacin.  
     
     
         21 . The therapeutic hydrogel of  claim 17 , wherein the hydrogel is a polyethylene glycol-gelatin hydrogel.  
     
     
         22 . The therapeutic hydrogel of  claim 17 , wherein the liposomal therapeutic agent is a fluoroquinolone antibiotic.  
     
     
         23 . A therapeutic hydrogel composition comprising liposomal ciprofloxacin dispersed throughout a polyethylene glycol-gelatin hydrogel.  
     
     
         24 . The therapeutic hydrogel composition of  claim 23 , wherein said gelatin hydrogel is derivatized with 4-azido-2,3,5,6-tetrafluorobenzoic acid or a derivative thereof.  
     
     
         25 . A method for loading a liposomal therapeutic agent on a medical device by mixing said liposomal therapeutic agent with a hydrogel, and covalently binding said hydrogel to a pre-formed polymeric surface of a medical device.  
     
     
         26 . The method of  claim 25 , wherein the polymeric surface is a silicone rubber.  
     
     
         27 . The method of  claim 25 , wherein the liposomal therapeutic agent is an antibiotic.  
     
     
         28 . A method for covalently attaching a therapeutic hydrogel to a polymeric substrate comprising: 
 a. derivatizing the hydrogel by covalently binding a protein within the hydrogel to a functional group of a bifunctional linker molecule; and    b. covalently attaching the remaining functional group of the bifunctional linker molecule to the substrate.    
     
     
         29 . The method of  claim 28 , wherein the hydrogel comprises gelatin.  
     
     
         30 . The method of  claim 28 , wherein the bifunctional linker molecule is a fluorinated aroyl azide.  
     
     
         31 . The method of  claim 30 , wherein the bifunctional liner molecule further comprises a carbonyl moiety.  
     
     
         32 . The method of  claim 28 , wherein the bifunctional linker molecule is 4-azido-2,3,5,6-tetrafluoro benzoic acid or a derivative thereof.  
     
     
         33 . The method of  claim 31 , wherein said polymeric substrate is silicone rubber.  
     
     
         34 . A method for covalently attaching a therapeutic gelatin hydrogel to a silicone rubber substrate comprising: 
 a. derivatizing the gelatin of a therapeutic gelatin hydrogel by forming an amide linkage from free amino groups of the gelatin and a carbonyl carbon of a fluorinated aroyl azide; and    b. covalently binding an aryl nitrogen of the azide group of the fluorinated aroyl azide to the silicone rubber substrate.    
     
     
         35 . The method of  claim 34 , wherein the step of binding the azide moiety to the silicone rubber substrate is effected by exposure of the reactants to U.V. light.  
     
     
         36 . A method for the prophylaxis or treatment of patients at risk of or suffering from biofilm mediated infection associated with the use of a medical device comprising inserting or applying a medical device formed of a polymeric substrate covalently binding a therapeutic hydrogel matrix.  
     
     
         37 . The method of  claim 36 , wherein said therapeutic hydrogel matrix comprises a liposomal fluoroquinolone antibiotic dispersed throughout said matrix.  
     
     
         38 . The method of  claim 37 , wherein said fluoroquinolone antibiotic is ciprofloxacin.  
     
     
         39 . The method of  claim 36 , wherein said polymeric substrate is a silicone rubber.  
     
     
         40 . The method of  claim 36 , wherein said hydrogel is a polyethylene glycol-gelatin matrix.  
     
     
         41 . A method for the prophylaxis or treatment of patients at risk of or suffering from biofilm mediated infection associated with the use of an in-dwelling medical device comprising inserting a medical device formed of a silicone rubber substrate covalently binding a polyethylene glycol-gelatin matrix material, and wherein dispersed within said matrix material is a liposomal fluoroquinolone antibiotic.  
     
     
         42 . The method of claim  41 , wherein said fluoroquinolone is ciprofloxacin.