Colloidal suspension of submicronic particles for carrying active principles and their mode of preparation

Abstract

The invention concerns a suspension of biocompatible particles for carrying active principles. Said carrier particles are based on a double-block hydrophilic neutral polyaminoacid/hydrophobic neutral polyaminoacid copolymer. Said hydrophilic neutral polyaminoacid/hydrophobic neutral polyaminoacid particles are capable of combining in colloidal suspension in non-dissolved state, at least an active principle and of releasing same, in particular in vivo, in prolonged and/or delayed delivery. The invention also concerns a powdery solid from which are derived the carrier particles and the preparation of said solid and of said suspension of active principle based on hydrophilic neutral polyaminoacids/hydrophobic neutral polyaminoacids. Said carrier particles form spontaneously and in the absence of surfactants or organic solvents, stable aqueous suspensions. The invention also concerns the carrier particles in dry form, the method for preparing them, and pharmaceutical compositions (in dry form or suspension) comprising said carrier particles associated with an active principle.

1 - 20 . (canceled)  
   
   
       21 . A method of preparing a copolymer that is a particle precursor, comprising: 
 a) copolymerizing monomers of amino acid N-carboxy anhydrides (NCA) of at least types (i) and (ii), wherein:    type (i) NCA monomers comprise NCA-Glu-OR CR (R=alkyl), NCA-Asp-OR (R=alkyl), NCA forms of hydrophilic neutral amino acids (NCA-AANI), or mixtures thereof, and    type (ii) NCA monomers comprise NCA forms of hydrophobic neutral amino acids (NCA-AANO), wherein the copolymerization is in the presence of at least one non-aromatic polar solvent selected from the group consist of N-methylpyrrolidone (NMP)), dimethylformamide (DFM), dimethyl sulfoxide (DMSO), dimethylacetamide (DMAc), pyrrolidone, and mixtures thereof; and    b) precipitating the copolymer to obtain a particle precursor.    
   
   
       22 . A copolymer that is a particle precursor produced by the method of  claim 21 .  
   
   
       23 . The method of  claim 21 , whereby step a) further comprises copolymerization in the presence of at least one cosolvent selected from the group consisting of aprotic solvents, protic solvents, water, alcohols, and mixtures thereof.  
   
   
       24 . The method of  claim 21 , whereby the copolymer formed is a random copolymer with a molecular weight that is ≧2,000 Da.  
   
   
       25 . The method of  claim 21 , whereby the degree of polymerization is 30-600%.  
   
   
       26 . The method of  claim 21 , whereby the particle size of the copolymer is 0.01 to 0.5 μM.  
   
   
       27 . The method of  claim 21 , whereby the type (i) NCA monomers are NCA-Glu-OR and/or NCA-Asp-OR, and whereby the method further comprises an acid hydrolysis step comprising: 
 c) contact the copolymer formed with an aqueous phase comprising at least one amine.    
   
   
       28 . The method of  claim 27 , whereby said step c) is carried out with water and at least one mineral acid and/or at least one organic acid.  
   
   
       29 . The method of  claim 28 , whereby the mineral acid is hydrochloric acid.  
   
   
       30 . The method of  claim 28 , whereby the organic acid is selected from the group consisting of: trifluoroacetic acid (TFA), acetic acid, dichloroacetic acid, organosulfonic acids, and mixtures thereof.  
   
   
       31 . The method of  claim 27 , whereby the proportions of water to acid, as expressed in parts by water, is 60/1 to 2/1.  
   
   
       32 . The method of  claim 27 , further comprising the step of: 
 d) dialyzing the reaction medium to obtain an aqueous suspension of submicron particles comprising the copolymer.    
   
   
       33 . The method of  claim 32 , further comprising the step of: 
 e) concentrating the aqueous suspension by converting the hydrophilic part of the glutamate monomers to acid, thereby resulting in acidic amphiphilic polyamino acids intermediates that are insoluble in water.    
   
   
       34 . The method of  claim 33 , further comprising the step of: 
 f) filtering, washing, and drying the acidic amphiphilic polyamino acids intermediates to thereby obtain a copolymer that is a particle precursor.    
   
   
       35 . A copolymer that is a particle precursor produced by the method of  claim 34 .  
   
   
       36 . The method of  claim 21 , whereby the NCA-pAAI is a NCA of O-alkylated gluatamic or aspartic acid.  
   
   
       37 . The method of  claim 26 , whereby the NCA-pAAI is selected from the group consisting of: NCA-Glu-O-Methyl, NCA-Glu-O-Ethyl, NCA-Glu-O-Benzyl, and mixtures thereof.  
   
   
       38 . The method of  claim 21 , whereby the copolymerization takes place between a temperature of 20 to 120° C., a atmospheric pressure and in the presence of an amine initiator.