Gel delivery vehicles for anticellular proliferative agents

Abstract

Methods and compositions are provided for the treatment of a host suffering from a cellular proliferative disease. In the subject methods, antiproliferative agents are administered in a substantially non-aqueous gel delivery vehicle comprising at least one polar organic solvent in combination with one or more thickening agents. The subject methods and compositions provide for the enhanced efficacy of regionally or locally administered antiproliferative proliferative agents.

What is claimed is:  
     
         1 . A method for treating a host suffering from a cellular proliferative disease, said method comprising: 
 administering to said host at a target site at least proximal to a lesion associated with said cellular proliferative disease a composition comprising at least one antiproliferative agent in a pharmaceutically acceptable substantially non-aqueous delivery vehicle capable of acting as a depot for said agent, said vehicle comprising at least one polar, water soluble organic solvent in combination with at least one thickening agent, wherein said thickening agent is from about 0.5 to 20% (v/v) of said vehicle.    
     
     
         2 . The method according to  claim 1 , wherein said composition is regionally administered.  
     
     
         3 . The method according to  claim 1 , wherein said composition is intralesionally administered.  
     
     
         4 . The method according to  claim 1 , wherein said cellular proliferative disease is a neoplastic disease.  
     
     
         5 . A method for treating a host suffering from a neoplastic disease, said method comprising: 
 intralesionally administering a composition comprising at least one antiproliferative agent in a pharmaceutically acceptable substantially non-aqueous delivery vehicle capable of acting as a depot for said agent, said vehicle comprising: at least one polar, water soluble organic solvent having a dipole moment of at least about 1.5 D, wherein said solvent comprises at least one oxygen containing substituent selected from the group consisting of oxy and oxo substituents and is from about 75 to 99.5% (v/v) of said vehicle; and    at least one thickening agent, wherein said thickening agent is from about 0.5 to 20% (v/v) of said vehicle.    
     
     
         6 . The method according to  claim 5 , wherein said polar organic solvent is a lower alkanol of from 1 to 4 carbon atoms.  
     
     
         7 . The method according to  claim 5 , wherein said oxo substituent is selected from the group consisting of amides, carbonates, esters, ethers, acetals, and sulfoxides.  
     
     
         8 . The method according to  claim 5 , wherein said thickening agent is selected from the group consisting of fatty acids, fatty acid esters, aluminum or magnesium salts of fatty acids and crosslinked or noncrosslinked biocompatible polymers.  
     
     
         9 . A method for treating a host suffering from a neoplastic disease, said method comprising: 
 intralesionally administering a composition comprising an antiproliferative agent selected from the group consisting of cisplatin, camptothecin, vinblastine, paclitaxel, fluorouracil, doxorubicin, mechlorethamine, etoposide, mitomycin and bleomycin, in a pharmaceutically acceptable substantially non-aqueous delivery vehicle capable of acting as a depot for said agent, said vehicle comprising:    at least one polar, water soluble organic solvent selected from the group consisting of ethanol, dimethylacetamide and propylene carbonate, wherein said solvent is from about 80 to 99.5% (v/v) of said vehicle; and    at least one thickening agent selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxypolymethylene, and polyvinylpyrrolidone, wherein said thickening agent is from about 0.5 to 20% (v/v) of said vehicle.    
     
     
         10 . A method for treating a host suffering from a neoplastic disease, said method comprising: 
 intralesionally administering to said host a composition comprising an antiproliferative agent in a pharmaceutically acceptable substantially non-aqueous delivery vehicle capable of acting as a depot for said agent, said vehicle comprising ethanol in combination with hydroxypropyl cellulose and oleic acid.    
     
     
         11 . A method for treating a host suffering from a neoplastic disease, said method comprising: 
 intralesionally administering to said host a composition comprising an antiproliferative agent in a pharmaceutically acceptable substantially non-aqueous delivery vehicle capable of acting as a depot for said agent, said vehicle comprising dimethylacetamide in combination with methyl cellulose, hydroxypropyl methylcellulose, or carboxypolymethylene.    
     
     
         12 . A method for treating a host suffering from a neoplastic disease, said method comprising: 
 intralesionally administering to said host a composition comprising an antiproliferative agent in a pharmaceutically acceptable substantially non-aqueous delivery vehicle capable of acting as a depot for said agent, said vehicle comprising propylene carbonate in combination with polyvinylpyrrolidone.    
     
     
         13 . A substantially non-aqueous composition for use in the treatment of a host suffering from a cellular proliferative disease, said composition comprising: 
 at least one antiproliferative agent in a pharmaceutically acceptable substantially non-aqueous delivery vehicle capable of acting as a depot for said agent, said vehicle comprising:    at least one polar, water soluble organic solvent; and at least one thickening agent, wherein said thickening agent is from about 0.5 to 20% (v/v) of said vehicle formulation.    
     
     
         14 . The composition according to  claim 13 , wherein said vehicle has a viscosity ranging from about 500 to 50,000 mPa·sec.  
     
     
         15 . The composition according to  claim 13 , wherein said polar organic solvent is from about 80 to 99.5% (v/v) of said vehicle.  
     
     
         16 . The composition according to  claim 13 , wherein said polar organic solvent has a Hildebrand solubility parameter of at least about 8.0 and a dipole moment of at least 1.5D.  
     
     
         17 . The composition according to  claim 11 , wherein said composition further comprises a vasoconstrictive agent.  
     
     
         18 . A substantially non-aqueous composition for use in the treatment of a host suffering from a cellular proliferative disease, said composition comprising: 
 at least one antiproliferative agent in an a pharmaceutically acceptable substantially non-aqueous delivery vehicle capable of acting as a depot for said agent, said vehicle comprising:    at least one polar, water soluble organic solvent having a dipole moment of at least about 1.5 D, wherein said solvent comprises at least one oxygen containing substituent selected from the group consisting of oxy and oxo substituents and is from about 80 to 99.5% (v/v) of said vehicle; and    at least one thickening agent, wherein said thickening agent is from about 0.5 to 20% (v/v) of said vehicle.    
     
     
         19 . The composition according to  claim 18 , wherein said polar organic solvent is a lower alkanol of from 1 to 4 carbon atoms.  
     
     
         20 . The composition according to  claim 18 , wherein said oxo substituent is selected from the group consisting of amides, esters, carbonates, ethers, acetals, and sulfoxides.  
     
     
         21 . The composition according to  claim 18 , wherein said thickening agent is selected from the group consisting of fatty acids, fatty acid esters, aluminum or magnesium salts of fatty acids and crosslinked or noncrosslinked biocompatible polymers.  
     
     
         22 . A substantially non-aqueous composition for use in the treatment of a host suffering from a cellular proliferative disease, said composition comprising: 
 at least one antiproliferative agent in a pharmaceutically acceptable substantially non-aqueous delivery vehicle capable of acting as a depot for said agent, said vehicle comprising:    at least one polar, water soluble organic solvent selected from the group consisting of ethanol, dimethylacetamide and propylene carbonate in an amount ranging from about 80 to 99.5% (v/v) of said vehicle; and    at least one thickening agent selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxypropylmethylene and polyvinylpyrrolidone in an amount from about 0.5 to 20% (v/v) of said vehicle.    
     
     
         23 . A composition according to  claim 22 , wherein said antiproliferative agent is selected from the group consisting of cisplatin, camptothecin, vinblastine, paclitaxel, fluorouracil, doxorubicin, mechlorethamine, etoposide, mitomycin and bleomycin.  
     
     
         24 . A substantially non-aqueous composition for use in the treatment of a host suffering from a cellular proliferative disease, said composition comprising: 
 at least one antiproliferative agent in a pharmaceutically acceptable substantially non-aqueous delivery vehicle capable of acting as a depot for said agent, said vehicle comprising ethanol in combination with hydroxypropylcellulose and oleic acid.    
     
     
         25 . A substantially non-aqueous composition for use in the treatment of a host suffering from a cellular proliferative disease, said composition comprising: 
 at least one antiproliferative agent in a pharmaceutically acceptable substantially non-aqueous delivery vehicle capable of acting as a depot for said agent, said vehicle comprising dimethyl acetamide in combination with methylcellulose, hydroxypropyl methylcellulose, or carboxypropylmethylene.    
     
     
         26 . A substantially non-aqueous composition for use in the treatment of a host suffering from a cellular proliferative disease, said composition comprising: 
 at least one antiproliferative agent in a pharmaceutically acceptable substantially non-aqueous delivery vehicle capable of acting as a depot for said agent, said vehicle comprising propylene carbonate in combination with polyvinylpyrrolidone.    
     
     
         27 . A substantially non-aqueous delivery vehicle capable of acting as a depot for use in the regional or local delivery of an antiproliferative agent to a host suffering from a cellular proliferative disease, said vehicle consisting of: 
 at least one polar, water soluble organic solvent in combination with at least one thickening agent, wherein said thickening agent is from about 0.5 to 20% (v/v) of said vehicle and is selected from the group consisting of fatty acids, aluminum or magnesium salts of fatty acids and crosslinked or noncrosslinked biocompatible polymers.    
     
     
         28 . The vehicle according to  claim 27 , wherein said solvent is from about 80 to 99.5% (v/v) of said vehicle.  
     
     
         29 . The vehicle formulation according to  claim 27 , wherein said solvent comprises at least one oxygen containing substituent selected from the group consisting of oxy and oxo substituents.  
     
     
         30 . The vehicle according to  claim 29 , wherein said solvent is a lower alkanol of from 1 to 4 carbon atoms.  
     
     
         31 . The vehicle according to  claim 29 , wherein said oxo substituent is selected from the group consisting of amides, esters, carbonates, ethers, acetals, and sulfoxides.  
     
     
         32 . A pharmaceutically acceptable, substantially non-aqueous delivery vehicle for use in the regional or local delivery of an antiproliferative agent to a host suffering from a cellular proliferative disease, said vehicle consisting of: 
 at least one polar, water soluble organic solvent selected from the group consisting of ethanol, dimethylacetamide and propylene carbonate in an amount ranging from about 80 to 99.5% (v/v) of said vehicle; and    at least one thickening agent selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxypropylmethylene and polyvinylpyrrolidone in an amount ranging from about 0.5 to 20% (v/v) of said vehicle.    
     
     
         33 . A kit for use in the treatment of a host suffering from a cellular proliferative disease, said kit comprising: 
 at least one antiproliferative agent; and    a pharmaceutically acceptable substantially non-aqueous delivery vehicle comprising at least one polar organic solvent in combination with at least one thickening agent, wherein said thickening agent is from about 0.5 to 20% (v/v) of said vehicle.    
     
     
         34 . The kit according to  claim 33 , wherein said kit further comprises a means for combining said antiproliferative agent with said substantially non-aqueous delivery vehicle to produce a composition according to  claim 13.