Patent ID: 6458347
Filing Date: 2002-10-01
Classification: A61K,A61P

Abstract:
A drug complex of a drug having a hydroxyl group, which is capable of controlling the rate of the release of the drug therefrom in blood,said drug complex comprising: (A) at least one carrier selected from the group consisting of saccharides each having at least one carboxyl group, polyethylene glycols each having at least one carboxyl group, straight or branched C2-C8 aliphatic carboxylic acids each having at least one carboxyl group, and derivatives thereof each having at least one carboxyl group; (B) at least one spacer comprised of a compound having at least one amino group and at least one carboxyl group, which is selected from the group consisting of amino acids and peptides, said at least one spacer (B) having a substituent X at the &agr;-position relative to said carboxyl group of said at least one spacer (B); and (C) at least one drug having a hydroxyl group, wherein said at least one drug (C) is bonded to said at least one spacer (B) through an ester bond formed between the hydroxyl group of said drug (C) and the carboxyl group of said spacer (B) to form at least one drug-spacer block, and wherein said at least one drug-spacer block is bonded to said at least one carrier (A) through an amide bond formed between the amino group of said spacer (B) of said at least one drug-spacer block and the carboxyl group of said at least one carrier (A), and wherein, when the hydroxyl group of said at least one drug (C), which is bonded to the carboxyl group of said at least one spacer (B) to form the ester bond, is a primary hydroxyl group, said substituent X has a steric hindrance parameter (Es) value of from âˆ’1.0 to âˆ’2.5, and when the hydroxyl group of said at least one drug (C), which is bonded to the carboxyl group of said at least one spacer (B) to form the ester bond, is a secondary hydroxyl group, said substituent X has a steric hindrance parameter (Es) value of from âˆ’0.0 to âˆ’2.5, said Es value being defined by the following formula (1): Es=log(kX/kH)â€ƒâ€ƒ(1) wherein kX is the reaction rate constant for the acid hydrolysis reaction of an &agr;-monosubstituted acetic acid ester, wherein the acid hydrolysis reaction is represented by the following formula: Xâ€”CH2COORx+H2Oâ†’Xâ€”CH2COOH+RxOH wherein X is as defined above and Rxis a group selected from the group consisting of C1-C8 alkyl groups and C6-C18 aryl groups; and kH is the reaction rate constant for the acid hydrolysis reaction of an unsubstituted acetic acid ester corresponding to said &agr;-monosubstituted acetic acid ester, wherein the acid hydrolysis reaction is represented by the following formula: CH3COORy+H2Oâ†’CH3COOH+RyOH wherein Ry has the same meaning as defined for Rx; and wherein said X substituent is selected in relation to said drug to provide an Es value causing dissociation of said ester bond in vivo to occur at a selected and controlled rate.