Polyaminoacids functionalized wtih alpha-tocopherol, and uses thereof, especially therapeutic uses

Abstract

The invention concerns novel biodegradable polyaminoacid materials, useful in particular for vectoring active principles(s). The invention also concerns novel pharmaceutical, cosmetic dietetic or phytosanitary compositions based on said polyaminoacids. The invention aims at providing a novel polymer raw material, capable of being used for vectoring active principles and enabling optimal fulfillment of all specified requirements: biocompatibility, biodegradability, easy and inexpensive transformation into particles vectoring active principles, said particles being themselves capable of forming colloidal suspensions, of being easily associated with numerous active principles, and of releasing said active principles in vivo. Therefor, the present invention concerns first of all amphiphilic polyaminoacids comprising aspartic acid units and/or glutamic acid units, characterized in that at least part of said units carry grafts, including at least one alphα-tocopherol motif, for example (polyglutamate or polyaspartate grafted with alphα-tocopherol of synthetic or natural origin).

1 . Method of making a polyamino acid where at least some polyamino acid units bear side chains comprising at least one α-tocopherol unit, said method comprising:
 i) manufacturing polyamino acid polymer comprising at least one aspartic unit and/or glutamic unit;   ii) dissolving the polyamino acid polymer in a first solvent to form a mixture;   iii) adding α-tocopherol, at least one nucleophilic catalyst and at least one carbodiimide to said mixture to form a reaction mixture;   iv) forming a precipitated polymer by reacting the reaction mixture with a precipitating agent, where at least some of the polyamino acid units have side chains comprising at least one α-tocopherol unit.   
   
   
       2 . The method of  claim 1 , wherein said method further comprises:
 v) purifying the precipitated polymer by dissolving the precipitated polymer in a second solvent, and precipitating the polymer out of solution to form a precipitated polymer.   
   
   
       3 . The method of  claim 2 , wherein said first solvent and second solvent are the same. 
   
   
       4 . The method of  claim 1 , wherein said first solvent is dimethylformamide. 
   
   
       5 . The method of  claim 1 , wherein said at least one nucleophilic catalyst is dimethylaminopyridine. 
   
   
       6 . The method of  claim 1 , wherein said at least one carbodiimide is diisopropylcarbodiimide. 
   
   
       7 . The method of  claim 1 , wherein said precipitating agent comprises sodium chloride and hydrochloric acid. 
   
   
       8 . The method of  claim 1 , wherein said manufacturing of α-L-polyamino acid polymer comprises polymerization of NCAGLuOMe followed by hydrolysis. 
   
   
       9 . The method of  claim 1 , wherein said precipitated polymer has the general formula (I) below: 
     
       
         
         
             
             
         
       
     
     in which:
 R 1  represents H, a linear C2 to C10 or branched C3 to C10 acyl group, or a pyroglutamate; 
 R represents H, a C2 to C10 linear or C3 to C10 branched alkyl, benzyl or a terminal amino acid unit; 
 R 3  is H or a cationic species; 
 R 4  represents a direct bond or a “spacer” based on 1 to 4 amino acid units; 
 A independently represents a —CH 2 — (aspartic unit) or —CH 2 —H 2 — (glutamic unit) radical; and 
 T represents an α-tocopherol unit. 
 
   
   
       10 . The method of  claim 1 , wherein the polyamino acid has a α-L-configuration. 
   
   
       11 . The method of  claim 10 , wherein the polamino acids are α-L-glutamate or α-L-glutamic homopolymers. 
   
   
       12 . The method of  claim 10 , wherein the polamino acids are α-L-aspartate or α-L-aspartic homopolymers. 
   
   
       13 . The method of  claim 10 , wherein the polamino acids are α-L-aspartate α-L-glutamate or α-L-aspartic α-L-glutamic copolymers. 
   
   
       14 . The method of  claim 1 , wherein the molar grafting with α-tocopherol is between 3% and 70%. 
   
   
       15 . The method of  claim 1 , wherein the molar grafting with α-tocopherol is between 5% and 50%. 
   
   
       16 . Method of making a polyamino acid where at least some units of the polyamino acids bear side chains comprising at least one α-tocopherol unit, said method comprising:
 i) manufacturing polyamino acid polymer comprising at least one aspartic unit and/or glutamic unit;   ii) forming a first mixture by adding the polyamino acid polymer to a first solvent at a temperature of ≧40° C.;   iii) reducing the temperature of the first mixture when the polyamino acid polymer dissolves;   iv) dissolving α-tocopherol, at least one nucleophilic catalyst and at least one carbodiimide in a second solvent;   v) adding ii), iv), at least one nucleophilic catalyst and at least one carbodiimide, to form a reaction mixture;   vi) reacting the precipitating agent after a pre-determined amount of time to form precipitated polymer, where at least some units of the polyamino acids bear side chains comprising at least one α-tocopherol unit.   
   
   
       17 . The method of  claim 16 , wherein said first solvent and/or second solvent is dimethylformamide. 
   
   
       18 . The method of  claim 16 , wherein said at least one nucleophilic catalyst is dimethylaminopyridine. 
   
   
       19 . The method of  claim 16 , wherein said at least one carbodiimide is diisopropylcarbodiimide. 
   
   
       20 . The method of  claim 16 , wherein said precipitating agent comprises sodium chloride and hydrochloric acid. 
   
   
       21 . The method of  claim 16 , wherein said precipitating agent has the general formula (I) of: 
     
       
         
         
             
             
         
       
     
     in which:
 R 1  represents H, a linear C2 to C10 or branched C3 to C10 acyl group, or a pyroglutamate; 
 R 2  represents H, a C2 to C10 linear or C3 to C10 branched alkyl, benzyl or a terminal amino acid unit; 
 R 3  is H or a cationic species selected from the group consisting of: sodium metallic cations, potassium metallic cations, calcium metallic cations, magnesium metallic cations, amine-based cations, oligoamine-based cations, cations based on polyamine, cations based on lysine, cations based on arginine, polylysine and oligolysine; 
 R 4  represents a direct bond or a “spacer” based on 1 to 4 amino acid units; 
 A independently represents a —CH 2 — (aspartic unit) or —CH 2 —H 2 — (glutamic unit) radical; 
 n/(n+m) ranges from 0.5 to 100 mol %; 
 n+m ranges from 3 to 1000; and 
 T represents an α-tocopherol unit. 
 
   
   
       22 . Method of preparing a pharmaceutical composition comprising a polyamino acid where at least some units of the polyamino acid bear side chains comprising at least one α-tocopherol unit, said method comprising:
 i) manufacturing polyamino acid polymer comprising at least one aspartic unit and/or glutamic unit;   ii) forming a first mixture by dissolving the polyamino acid polymer in a first solvent;   iii) forming a second mixture by dissolving α-tocopherol, at least one nucleophilic catalyst and at least one carbodiimide in a second solvent;   iv) combining ii) with iii) to form a reaction mixture;   v) reacting iv) with a precipitating agent to form precipitated polymer;   vi) incubating the precipitated polymer and at least one active principle together in solution under conditions such that a fraction of the at least one active principle associates with the precipitated polymer;   vii) separating the at least one active principle that is associated with the precipitated polymer from the unassociated active principle and precipitated polymer, whereby the pharmaceutical composition comprises the at least one active principle that is associated with the precipitated polymer, and where at least some units of the polyamino acid bear side chains comprising at least one α-tocopherol unit.   
   
   
       23 . The method of  claim 22 , wherein the polamino acids are α-L-glutamate or α-L-glutamic homopolymers. 
   
   
       24 . The method of  claim 22 , wherein the polamino acids are α-L-aspartate or α-L-aspartic homopolymers. 
   
   
       25 . The method of  claim 22 , wherein the polamino acids are α-L-aspartate α-L-glutamate or α-L-aspartic α-L-glutamic copolymers.