Pharmaceutical composition

Abstract

A pharmaceutical composition includes polymer units α and β, each having a hydrophilic polymer chain bound to a cationic polymer chain, and a drug. The polymer units α and β are radially arranged such that the cationic polymer chains are directed inward and the hydrophilic polymer chains are directed outward, thereby forming a micelle with the drug encapsulated in the micelle. The cationic polymer chain of the polymer unit α has a phenylboronic acid group in a side chain, and the cationic polymer chain of the polymer unit β has a phenylboronic acid binding site in a side chain. The phenylboronic acid group and the phenylboronic acid binding site form a cross-linked structure that can dissociate in an acidic environment and/or in the presence of a substance capable of competitive binding.

1 .- 5 . (canceled) 
     
     
         6 . A pharmaceutical composition, comprising:
 a polymer unit α having a hydrophilic polymer chain segment and a cationic polymer chain segment;   a polymer unit β having a hydrophilic polymer chain segment and a cationic polymer chain segment; and   a drug;   wherein:   (a) the polymer unit α and the polymer unit β are arranged such that the cationic polymer chain segments are directed radially inward and the hydrophilic polymer chain segments are directed radially outward, and form a micelle, and the drug is encapsulated in the micelle,   (b) the cationic polymer chain segment of the polymer unit α contains at least one cationic amino acid residue having an amino group in a side chain and at least one substituted phenylboronic acid (PBA) group-containing amino acid residue having a substituted PBA group represented by the following formula (I) in a side chain:   
       
         
           
           
               
               
           
         
       
       F('s) is (are) present independently; n is 1, 2, 3, or 4; and when n is 1, the attachment positions of F and B(OH) 2  may be at any one of ortho, meta, and para,
 (c) a ratio of the number of the substituted PBA group-containing amino acid residue with respect to the total number of the cationic amino acid residue in the polymer unit α is 10-80%, 
 (d) the cationic polymer chain segment of the polymer unit β contains a cationic amino acid residue having an amino group in a side chain and a PBA binding site-containing amino acid residue having a cis-diol structure in a side chain, and 
 (e) a ratio of the number of the PBA binding site-containing amino acid residue with respect to the total number of the cationic amino acid residue in the polymer unit is 5-80%. 
 
     
     
         7 . The pharmaceutical composition according to  claim 6 , wherein the drug is a nucleic acid selected from the group consisting of pDNA or mRNA. 
     
     
         8 . The pharmaceutical composition according to  claim 6 , wherein the substituted PBA group has a pKa of approximately physiological pH. 
     
     
         9 . The pharmaceutical composition according to  claim 6 , wherein the cis-diol structure of the PBA binding site-containing amino acid residue is derived from a gluconic acid derivative. 
     
     
         10 . The pharmaceutical composition according to  claim 6 , wherein:
 at least some of the substituted PBA groups of polymer unit α form ester bonds with at least some of the cis-diol structure of polymer unit β when the micelle is disposed in an environment of pH 7 or higher, and   the ester bonds are prone to dissociate when the micelle is disposed in an environment of pH 4-6.   
     
     
         11 . The pharmaceutical composition according to  claim 6 , wherein the hydrophilic polymer chain segment of both the polymer unit α and the polymer unit β comprises poly(ethylene glycol). 
     
     
         12 . The pharmaceutical composition according to  claim 6 , wherein the cationic amino acid residues in the cationic polymer chain segment of the polymer unit α are derived from an amino acid derivative obtained by substituting the —OH moiety of a carboxyl group (—C(═O)OH) of an acidic amino acid with a group selected from the following formulae (i) to (iv):
   —NH—(CH 2 ) p1 —[NH—(CH 2 ) q1 —] r1 NH 2   (i);
 
   —NH—(CH 2 ) p2 —N[—(CH 2 ) q2 —NH 2 ] 2   (ii);
 
   —NH—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NH 2 ][—(CH 2 ) q4 —NH—] r2 H}  (iii); and
 
   —NH—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NH 2 ] 2 } 2   (iv);
 
 in the formulae (i) to (iv): p1 to p4, q1 to q6, and r and r2 are each independently an integer of from 1 to 5. 
 
     
     
         13 . The pharmaceutical composition according to  claim 12 , wherein the cationic amino acid residues in the cationic polymer chain segment of the polymer unit α are derived from the amino acid derivative obtained by substituting the —OH moiety of a carboxyl group (—C(═O)OH) of an acidic amino acid with the group of formula (i). 
     
     
         14 . The pharmaceutical composition according to  claim 6 , wherein the cationic amino acid residues in the cationic polymer chain segment of the polymer unit β are derived from an amino acid derivative obtained by substituting the —OH moiety of a carboxyl group (—C(═O)OH) of an acidic amino acid with a group selected from the following formulae (i) to (iv):
   —NH—(CH 2 ) p1 —[NH—(CH 2 ) q1 —] r1 NH 2   (i);
 
   —NH—(CH 2 ) p2 —N[—(CH 2 ) q2 —NH 2 ] 2   (ii);
 
   —NH—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NH 2 ][—(CH 2 ) q4 —NH—] r2 H}  (iii); and
 
   —NH—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NH 2 ] 2 } 2   (iv);
 
 in the formulae (i) to (iv): p1 to p4, q1 to q6, and r and r2 are independently an integer of from 1 to 5. 
 
     
     
         15 . The pharmaceutical composition according to  claim 14 , wherein the cationic amino acid residues in the cationic polymer chain segment of the polymer unit β are derived from the amino acid derivative obtained by substituting the —OH moiety of a carboxyl group (—C(═O)OH) of an acidic amino acid with the group of formula (i). 
     
     
         16 . The pharmaceutical composition according to  claim 7 , wherein the cis-diol structure of the PBA binding site-containing amino acid residue is derived from a gluconic acid derivative. 
     
     
         17 . The pharmaceutical composition according to  claim 16 , wherein:
 at least some of the substituted PBA groups of polymer unit α form ester bonds with at least some of the cis-diol structure of polymer unit β when the micelle is disposed in an environment of pH 7 or higher, and   the ester bonds are prone to dissociate when the micelle is disposed in an environment of pH 4-6.   
     
     
         18 . The pharmaceutical composition according to  claim 17 , wherein the hydrophilic polymer chain segment of both the polymer unit α and the polymer unit β comprises poly(ethylene glycol). 
     
     
         19 . The pharmaceutical composition according to  claim 18 , wherein the substituted PBA group has a pKa of approximately physiological pH. 
     
     
         20 . The pharmaceutical composition according to  claim 19 , wherein the cationic amino acid residues in the cationic polymer chain segment of the polymer unit α are derived from an amino acid derivative obtained by substituting the —OH moiety of a carboxyl group (—C(═O)OH) of an acidic amino acid with a group selected from the following formulae (i) to (iv):
   —NH—(CH 2 ) p1 —[NH—(CH 2 ) q1 —] r1 NH 2   (i);
 
   —NH—(CH 2 ) p2 —N[—(CH 2 ) q2 —NH 2 ] 2   (ii);
 
   —NH—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NH 2 ][—(CH 2 ) q4 —NH—] r2 H}  (iii); and
 
   —NH—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NH 2 ] 2 } 2   (iv);
 
 in the formulae (i) to (iv): p1 to p4, q1 to q6, and r1 and r2 are each independently an integer of from 1 to 5. 
 
     
     
         21 . The pharmaceutical composition according to  claim 20 , wherein the cationic amino acid residues in the cationic polymer chain segment of the polymer unit α are derived from the amino acid derivative obtained by substituting the —OH moiety of a carboxyl group (—C(═O)OH) of an acidic amino acid with the group of formula (i). 
     
     
         22 . The pharmaceutical composition according to  claim 19 , wherein the cationic amino acid residues in the cationic polymer chain segment of the polymer unit β are derived from an amino acid derivative obtained by substituting the —OH moiety of a carboxyl group (—C(═O)OH) of an acidic amino acid with a group selected from the following formulae (i) to (iv):
   —NH—(CH 2 ) p1 —[NH—(CH 2 ) q1 —] r1 NH 2   (i);
 
   —NH—(CH 2 ) p2 —N[—(CH 2 ) q2 —NH 2 ] 2   (ii);
 
   —NH—(CH 2 ) p3 —N{[—(CH 2 ) q3 —NH 2 ][—(CH 2 ) q4 —NH—] r2 H}  (iii); and
 
   —NH—(CH 2 ) p4 —N{—(CH 2 ) q5 —N[—(CH 2 ) q6 —NH 2 ] 2 } 2   (iv);
 
 in the formulae (i) to (iv): p1 to p4, q1 to q6, and r1 and r2 are independently an integer of from 1 to 5. 
 
     
     
         23 . The pharmaceutical composition according to  claim 22 , wherein the cationic amino acid residues in the cationic polymer chain segment of the polymer unit β are derived from the amino acid derivative obtained by substituting the —OH moiety of a carboxyl group (—C(═O)OH) of an acidic amino acid with the group of formula (i).