Polymer nanoparticle injection formulation composition containing rapamycin with improved water solubility, preparation method thereof, and anticancer composition for combined use with radiotherapy

Abstract

The present invention relates to a polymer nanoparticle injection formulation composition containing rapamycin with improved water solubility, and more specifically, to an injection formulation composition containing rapamycin wherein water solubility is improved by solubilizing rapamycin having low water solubility with polymer nanoparticles, a preparation method thereof, and an anticancer composition for a combined use with radiotherapy.

1 . An injectable composition comprising polymeric nanoparticles containing rapamycin, the composition comprising:
 (i) an A-B type diblock copolymer having a hydrophilic block (A) and a hydrophobic block (B),   (ii) an alkali metal salt of polylactic acid or its derivative having at least one carboxyl group on its end, and   (iii) rapamycin as an active ingredient,   wherein rapamycin is entrapped within the micelle formed from the A-B type diblock copolymer and the alkali metal salt of polylactic acid or its derivative.   
     
     
         2 . The injectable composition comprising polymeric nanoparticles containing rapamycin according to  claim 1 , wherein the number average molecular weight of the hydrophilic block (A) of the diblock copolymer is 500 to 20,000 daltons, the number average molecular weight of the hydrophobic block (B) of the diblock copolymer is 500 to 10,000 daltons, and the content of the hydrophilic block (A) in the diblock copolymer is 40 to 70 wt % on the basis of total 100 wt % of the diblock copolymer. 
     
     
         3 . The injectable composition comprising polymeric nanoparticles containing rapamycin according to  claim 1 , wherein the hydrophilic block (A) is polyethylene glycol or methoxy polyethylene glycol, and the hydrophobic block (B) is one or more selected from the group consisting of polylactic acid, polylactide, polyglycolide, polymandelic acid, polycaprolactone, polydioxan-2-one, polyamino acid, polyortho ester, polyanhydride and copolymers thereof. 
     
     
         4 . The injectable composition comprising polymeric nanoparticles containing rapamycin according to  claim 1 , wherein the polylactic acid or its derivative having at least one carboxyl group on its end is one or more selected from the group consisting of polylactic acid, polylactide, polyglycolide, polymandelic acid, polycaprolactone, polyanhydride and copolymers thereof, and its number average molecular weight is 500 to 2,500 daltons. 
     
     
         5 . The injectable composition comprising polymeric nanoparticles containing rapamycin according to  claim 1 , wherein the alkali metal is one or more monovalent metals selected from the group consisting of sodium, potassium and lithium. 
     
     
         6 . The injectable composition comprising polymeric nanoparticles containing rapamycin according to  claim 1 , further comprising divalent or trivalent metal ion. 
     
     
         7 . The injectable composition comprising polymeric nanoparticles containing rapamycin according to  claim 6 , wherein the divalent or trivalent metal ion is divalent or trivalent cation of the metal selected from the group consisting of calcium, magnesium, barium, chrome, iron, manganese, nickel, copper, zinc and aluminum. 
     
     
         8 . The injectable composition comprising polymeric nanoparticles containing rapamycin according to  claim 1 , wherein the weight ratio of the A-B type diblock copolymer and the alkali metal salt of polylactic acid or its derivative having at least one carboxyl group on its end is 9:1 to 3:7. 
     
     
         9 . The injectable composition comprising polymeric nanoparticles containing rapamycin according to  claim 1 , which is reconstituted to the rapamycin concentration of 0.1 to 25 mg/ml. 
     
     
         10 . A method for preparing an injectable composition comprising polymeric nanoparticles containing rapamycin, comprising the steps of:
 (a) solubilizing, in an organic solvent
 (i) an A-B type diblock copolymer having a hydrophilic block (A) and a hydrophobic block (B), 
 (ii) an alkali metal salt of polylactic acid or its derivative having at least one carboxyl group on its end, and 
 (iii) rapamycin as an active ingredient; 
   (b) removing the organic solvent from the product of step (a); and   (c) adding an aqueous medium to the product of step (b).   
     
     
         11 . The method for preparing an injectable composition comprising polymeric nanoparticles containing rapamycin according to  claim 10 , after step (c) further comprising the step of (c-1) adding divalent or trivalent metal ion to the product of step (c). 
     
     
         12 . An anticancer composition for a combination therapy with radiation, comprising
 (i) an A-B type diblock copolymer having a hydrophilic block (A) and a hydrophobic block (B),   (ii) an alkali metal salt of polylactic acid or its derivative having at least one carboxyl group on its end, and   (iii) rapamycin as an active ingredient,   wherein rapamycin is entrapped within the micelle formed from the A-B type diblock copolymer and the alkali metal salt of polylactic acid or its derivative.   
     
     
         13 . The anticancer composition for a combination therapy with radiation according to  claim 12 , further comprising divalent or trivalent metal ion. 
     
     
         14 . The anticancer composition for a combination therapy with radiation according to  claim 12 , which is administered at a timing of 1 minute to 7 days before irradiation. 
     
     
         15 . The anticancer composition for a combination therapy with radiation according to  claim 12 , which is used for the combination therapy wherein chemotherapy in combination with radiotherapy is practiced 1 to 5 times per week over a period of 4 to 12 weeks. 
     
     
         16 . A method for treating mammalian cancer cell with radiotherapy, wherein the injectable composition comprising polymeric nanoparticles containing rapamycin according to  claim 1  is administered at the time of, before or after irradiation to mammalian cancer cell to increase a sensitivity of mammalian cancer cell to radiotherapy.