Method of inhibiting restenosis using bisphosphonates

Abstract

A method of inhibiting the activity or production of cytokines or growth factors associated with vascular restenosis, by administering to an individual an effective amount of an active ingredient comprising a bisphosphonate particle or a bisphosphonate particulate. The bisphosphonate may be encapsulated, embedded or adsorbed within the particle, dispersed uniformly in the polymer matrix, adsorbed on the particle surface, or in combination of any of these forms. The particles include liposomes or inert polymeric particles, such as microcapsules, nanocapsules, nanoparticles, nanospheres, or microparticles. The particulates include any suspended or dispersed form of the bisphosphonate which is not encapsulated, entrapped, or adsorbed within a polymeric particle. The particulates include suspended or dispersed colloids, aggregates, flocculates, insoluble salts and insoluble complexes of the active ingredient. The cytokines and growth factors include, but are not limited to interleukin 1-β, matrix metalloproteinase-2, and platelet-derived growth factor β (PDGFβ).

1 . A pharmaceutical composition comprising bisphosphonate that has been formulated into an insoluble particulate having a size of 0.01-1.0 microns, together with a pharmaceutically acceptable carrier.  
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the bisphosphonate particulate is selected from the group consisting of aggregates, flocculates, colloids, polymer chains, insoluble salts and insoluble complexes.  
     
     
         3 . The pharmaceutical composition according to  claim 1 , further comprising a diluent.  
     
     
         4 . The pharmaceutical composition according to  claim 1  further comprising a stabilizer.  
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the bisphosphonate has the following formula (I):  
       
         
           
           
               
               
           
         
         wherein R 1  is H, OH or a halogen atom; and  
         R 2  is a halogen; linear or branched C 1 -C 10  alkyl or C 2 -C 10  alkenyl optionally substituted by heteroaryl or heterocyclyl C 1 -C 10  alkylamino or C 3 -C 8  cycloalkylamino where the amino may be a primary, secondary or tertiary; —NHY where Y is hydrogen, C 3 -C 8  cycloalkyl, aryl or heteroaryl; or R 2  is —SZ where Z is chlorosubstituted phenyl or pyridinyl.  
       
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein said bisphosphonate is clodronate, etidronate, tiludronate, pamidronate, alendronate, or ISA.  
     
     
         7 . The pharmaceutical composition according to  claim 1 , for intravenous (IV), intrarterial (IA), intramuscular (IM), subcutaneous (SC), parenteral, or intraperitoneal (IP) administration.  
     
     
         8 . A pharmaceutical composition comprising an active ingredient encapsulated in, embedded in, absorbed onto, or linked to an insoluble particle wherein the particle is non-liposomal and is selected from the group consisting of a bisphosphonate microparticle, a bisphosphonate nanoparticle, a bisphosphonate nanosphere, a bisphosphonate microcapsule, a bisphosphonate nanocapsule, and a bisphosphonate polymeric particle together with a pharmaceutically acceptable carrier, the particle having a size of 0.01-1.0 microns in diameter.  
     
     
         9 . The pharmaceutical composition according to  claim 8 , wherein the size of the particle is 100-300 nm in diameter.  
     
     
         10 . The pharmaceutical composition according to  claim 8 , further comprising a diluent.  
     
     
         11 . The pharmaceutical composition according to  claim 8  further comprising a stabilizer.  
     
     
         12 . The pharmaceutical composition according to  claim 8 , wherein the bisphosphonate has the following formula (I):  
       
         
           
           
               
               
           
         
         wherein R 1  is H, OH or a halogen atom; and  
         R 2  is a halogen; linear or branched C 1 -C 10  alkyl or C 2 -C 10  alkenyl optionally substituted by heteroaryl or heterocyclyl C 1 -C 10  alkylamino or C 3 -C 8  cycloalkylamino where the amino may be a primary, secondary or tertiary; —NHY where Y is hydrogen, C 3 -C 8  cycloalkyl, aryl or heteroaryl; or R 2  is —SZ where Z is chlorosubstituted phenyl or pyridinyl.  
       
     
     
         13 . The pharmaceutical composition according to  claim 8 , wherein said bisphosphonate is clodronate, etidronate, tiludronate, pamidronate, alendronate, or ISA.  
     
     
         14 . The pharmaceutical composition according to  claim 8 , for intravenous (IV), intrarterial (IA), intramuscular (IM), subcutaneous (SC), or intraperitoneal (IP) administration.  
     
     
         15 . A pharmaceutical composition comprising an active ingredient encapsulated in, embedded in, absorbed onto, or linked to an insoluble particle wherein the particle is a liposome having a size of 0.01-1.0 microns in diameter.  
     
     
         16 . The pharmaceutical composition according to  claim 15 , wherein the size of the liposome is 100-300 nm in diameter.  
     
     
         17 . The pharmaceutical composition according to  claim 15 , wherein the liposome comprisies distearoyl-phosphatidylcholine (DSPC) and cholesterol.  
     
     
         18 . The pharmaceutical composition according to  claim 17 , wherein the liposome comprisies DSPC and cholesterol in a weight ratio of 3:1.  
     
     
         19 . The pharmaceutical composition according to  claim 17 , wherein the liposome further comprisies distearoylphosphatidylglycerol (DSPG).  
     
     
         20 . The pharmaceutical composition according to  claim 19 , wherein the liposome comprises DSPG, DSPC, and cholesterol in a weight ratio of 1:3:1.  
     
     
         21 . The pharmaceutical composition according to  claim 15 , further comprising a diluent.  
     
     
         22 . The pharmaceutical composition according to  claim 15  further comprising a stabilizer.  
     
     
         23 . The pharmaceutical composition according to  claim 15 , wherein the bisphosphonate has the following formula (I):  
       
         
           
           
               
               
           
         
         wherein R 1  is H, OH or a halogen atom; and  
         R 2  is a halogen; linear or branched C 1 -C 10  alkyl or C 2 -C 10  alkenyl optionally substituted by heteroaryl or heterocyclyl C 1 -C 10  alkylamino or C 3 -C 8  cycloalkylamino where the amino may be a primary, secondary or tertiary; —NHY where Y is hydrogen, C 3 -C 8  cycloalkyl, aryl or heteroaryl; or R 2  is —SZ where Z is chlorosubstituted phenyl or pyridinyl.  
       
     
     
         24 . The pharmaceutical composition according to  claim 15 , wherein said bisphospho nate is clodronate, etidronate, tiludronate, pamidronate, alendronate, or ISA.  
     
     
         25 . The pharmaceutical composition according to  claim 15 , for intravenous (IV), intrarterial (IA), intramuscular (IM), subcutaneous (SC), or intraperitoneal (IP) administration.