Compositions for promoting healing of bone fracture

Abstract

A composition for accelerating fracture healing, which comprises a PDE4 inhibitor as an active ingredient, specifically a composition comprising a PDE4 inhibitor and a biocompatible and biodegradable polymer is provided, which composition, when formulated into a form suitable for local administration such as microsphere preparation, can provide a pharmaceutical composition showing an excellent effect in the early healing of bone fracture. The said composition is useful in the healing of refractory fracture of elderly people and diabetic or osteoporosis patients.

1 . A composition for accelerating fracture healing, which comprises a PDE4 inhibitor as an active ingredient.  
     
     
         2 . The composition according to  claim 1 , which is prepared so as to release the PDE4 inhibitor gradually at the fracture region.  
     
     
         3 . The composition according to  claim 2 , which comprises a biocompatible and biodegradable polymer.  
     
     
         4 . The composition according to  claim 3 , wherein the biocompatible and biodegradable polymer is water-insoluble.  
     
     
         5 . The composition according to  claim 4 , which is in the form of microsphere preparation.  
     
     
         6 . The composition according to  claim 5 , wherein the particle size of a microsphere is 0.1-150 μm.  
     
     
         7 . The composition according to  claim 5  or  6 , wherein the PDE4 inhibitor content is 0.0001-80% by weight.  
     
     
         8 . The composition according to any one of  claims 4  to  7 , wherein the water-insoluble biocompatible and biodegradable polymer is a hydroxy fatty acid polyester.  
     
     
         9 . The composition according to  claim 8 , wherein the water-insoluble biocompatible and biodegradable polymer is one or more polymers selected from the group consisting of poly lactic acid, lactic acid-glycolic acid copolymer and 2-hydroxybutyric acid-glycolic acid copolymer.  
     
     
         10 . The composition according to  claim 8  or  9 , wherein the water-insoluble biocompatible and biodegradable polymer has an average molecular weight of 2000-800000.  
     
     
         11 . The composition according to any one of claims  5  to 10, which is an injectable microsphere preparation prepared by dispersing at a concentration of 0.0001-1000 mg/ml microspheres in an aqueous solution containing a dispersant.  
     
     
         12 . The composition according to  claim 11 , which comprises a dispersant at a concentration of 0.01-2% by weight.  
     
     
         13 . The composition according to  claim 11  or  12 , wherein the dispersant is one or more selected from the group consisting of polyoxyethylene sorbitan fatty acid ester, polyethylene castor oil, carboxymethyl cellulose sodium, sodium alginate, dextran and sodium hyaluronate.  
     
     
         14 . The composition according to any one of  claims 1  to  13 , wherein the PDE4 inhibitor is a selective PDE4 inhibitor.  
     
     
         15 . The composition according to any one of  claims 1  to  14 , wherein IC 50  of the PDE4 inhibitor is less than 100 nM.  
     
     
         16 . The composition according to any one of  claims 1  to  15 , wherein the PDE4 inhibitor is a compound having a partial structure having PDE4 inhibitory activity as follows: 
 (A) naphthalene or an analogous chemical structure thereof; or  
 (B) 3-cyclopentyloxy-4-methoxyphenyl or an analogous chemical structure thereof.  
 
     
     
         17 . The composition according to any one of  claims 1  to  16 , wherein the PDE4 inhibitor is a compound having a partial structure of naphthalene or isoquinoline skeleton having PDE4 inhibitory activity or a pharmaceutically acceptable salt thereof.  
     
     
         18 . The composition according to claims  17 , wherein the PDE4 inhibitor is 2,3-bis(hydroxymethyl)-6,7-diethoxy-1-[1-(2-metoxyethyl)-2-oxo-4-pyridyl]naphthalene or 2,3-bis(hydroxymethyl)-6,7-diethoxy-1-[2-(4-(3-pyridyl)-1(2H)-phthaladinon-2-yl)-4-pyridyl]naphthalene or a pharmaceutically acceptable salt thereof.  
     
     
         19 . A composition for preparing an injectable preparation, which is obtainable by suspending microspheres set forth in any one of claims  5 - 10  into an aqueous solution containing an aggregation inhibitor, and lyophilizing the resultant suspension.