Injectable calcium-phosphate cement releasing a bone resorption inhibitor

Abstract

The present invention relates to a macroporous, resorbable and injectable apatitic calcium-phosphate cement with a high compressive strength useful as bone cement and releasing a bone resorption inhibitor, preparation method and uses thereof.

1 . A method for preparing an injectable calcium-phosphate bone cement releasing a gem-bisphosphonic compound, said method comprising the addition of a bisphosphonic acid or a salt thereof or a calcium solid precursor modified with a bisphosphonic acid or a salt thereof, in the cement solid phase or in the cement liquid phase, said calcium solid precursor being chosen from calcium orthophosphates, and non phosphate calcium salts, such as CaCO 3  or CaSO 4    
   
   
       2 . The method according to  claim 1 , wherein the amount of the bisphosphonic acid or salt thereof is up to 2.5% by weight in respect with the weight of solid phase. 
   
   
       3 . The method according to  claim 1 , wherein the bisphosphonic acid or salt thereof is dissolved in the cement liquid phase and the amount of the bisphosphonic acid or salt thereof is up to 0.3% by weight in respect with the weight of solid phase. 
   
   
       4 . The method according to  claim 1 , wherein the bisphosphonic acid or salt thereof is added in the cement solid phase and the amount of bisphosphonic acid or salt thereof is up to 3.5% by weight in respect with the weight of solid phase. 
   
   
       5 . The method according to  claim 1 , wherein a calcium solid precursor modified with a bisphosphonic acid or salt thereof is added in the cement solid phase and the amount of the bisphosphonic acid or a salt thereof is up to 0.15% by weight in respect with the weight of solid phase. 
   
   
       6 . The method according to  claim 1 , wherein the bisphosphonic acid or salt thereof is selected in the group consisting of etidronate, clodronate, pamidronate, alendronate, risedronate, tiludronate, ibandronate, zoledronate, incadronate, olpadronate, and neridronate. 
   
   
       7 . The method according to  claim 6 , wherein said bisphosphonic acid or salt thereof is alendronate. 
   
   
       8 . The method according to  claim 1 , wherein said calcium solid precursor is chosen from the group consisting of: calcium-deficient apatite (CDA), α-TCP, DCPD, and CaCO 3 . 
   
   
       9 . The method according to  claim 1 , wherein said solid phase comprises one or more calcium and/or phosphate compounds selected from the group consisting of HA, α-TCP, β-TCP, ACP, MCPH, DCPA, CDA, CaCO 3  and mixtures thereof. 
   
   
       10 . The method according to  claim 1 , wherein the solid phase also comprises at least one synthetic polymer or biopolymer. 
   
   
       11 . The method according to  claim 1 , wherein said liquid phase consists in a Na 2 HPO 4  aqueous solution, a NaH 2 PO 4  aqueous solution or a citric acid aqueous solution. 
   
   
       12 . The method according to  claim 1 , wherein said liquid phase consists in a NaH 2 PO 4  aqueous solution. 
   
   
       13 . The method according to  claim 1 , wherein the pH of the liquid phase is between 5 to 10, preferably between 5 and 9, most preferably between 5 and 7. 
   
   
       14 . The method according to  claim 1 , wherein the liquid phase/solid phase (L/S) ratio is between 0.20 to 0.9 ml/g, more preferably between 0.25 to 0.8 ml/g, still preferably between 0.25 to 0.45 ml/g, the most preferably 0.30 to 0.45 ml/g. 
   
   
       15 . An injectable apatitic calcium-phosphate cement obtainable according to the method of  claim 1 . 
   
   
       16 . An injectable apatitic calcium phosphate cement according to  claim 15 , with a compressive strength above 10 MPa. 
   
   
       17 . An injectable apatitic calcium phosphate cement according to  claim 15 , including further a contrasting agent, preferably barium sulphate. 
   
   
       18 . The use of an injectable apatitic CPC according to  claim 15 , for the manufacture of a medicament to fill a bony defect or fracture. 
   
   
       19 . The use according to  claim 18 , wherein said bony defect is associated with osteoporosis. 
   
   
       20 . The use of an injectable apatitic CPC according to  claim 15 , for the manufacture of a medicament to fill a tooth defect. 
   
   
       21 . A kit for preparing an injectable calcium-phosphate bone cement releasing a bisphosphonic acid or salt thereof according to  claim 15  comprising a bisphosphonic acid or salt thereof or a calcium solid precursor modified with a bisphosphonic acid or salt thereof, a solid phase and a liquid phase, said calcium solid precursor being chosen from calcium orthophosphates, and non phosphate calcium salts, such as CaCO 3  or CaSO 4 .