Synthesis and properties of diprazin in a PVA-based prolonged-release medication form

Abstract

Diprazin (promethazine) is a drug used in medical practice as an antihistamine. However, this compound is rather rapidly eliminated from the organism. In this connection, it would be important to develop a prolonged-release form of diprazin. In practice, prolongation of drug release is achieved by a number of methods such as binding to magnetic carriers, liposome filling, creation ofmacromolecular therapeutic systems, and covalent or noncovalent binding to hydrophilic polymer carriers [1]. The last method is simpler from the technological standpoint, and a wide assortment of medical polymers is available that provides the means for directed modification of the biopharmaceutical properties of drugs.The products of interaction between drugs and polymers are most frequently obtained by the method of joint mechanical dispersion, also called mechanical activation [2].The joint dispersion procedure usually involves an initial stage of breaking weak intermolecular bonds and intramolecular contacts in polymer macromolecules, which increases their reactivity. This is followed by the stage of product formation leading to the appearance of inclusion complexes or grafted complexes, depending on the particular polymer structure employed.We have developed a prolonged-release medication form of diprazin on the basis of poly(vinyl alcohol) (PVA). This polymer contains a large number of hydroxy groups readily forming hydrogen bonds with substances of different natures. Moreover, PVA belongs to the class of high-molecularweight compounds with limited swelling-a factor that can be used to reduce the rate of dissociation of the products of PVA -diprazin interaction [3].I Pyatigorsk State Pharmaceutical Academy, Pyatigorsk, Russia. EXPERIMENTAL CHEMICAL PARTWe have used diprazin (Akrikhin Joint-Stock Company) meeting the State Pharmacopeia (Ch. X) requirements, and a commercial PVA with an average molecular weight of 30,000. The interaction products were obtained by triturating diprazin with PVA in a porcelain mortar. The components were taken in drug-to-PVA ratios 1:0.05, 1:0.1 and 1:0.2, and triturated for 20, 40, or 60 rain. The products were studied upon dialysis through a cellophane membrane. An amount of the reaction products corresponding to a total diprazin content of 10 mg was dialyzed against 20 ml of water at 37~ The reference sample was obtained by parallel dialysis of 10 mg of the intact drug ground in the mortar. The contents of diprazin in the dialysates were determined by spectrophotometry at ;L = 250 nrn (~ = 887.25) [4].The results were compared upon calculating [5] the drug diffusion coefficient D by the formula 2 where Ct, mg/ ml, is the concentration of diprazin in a sample dialyzed during a time period oft, rain, Co, mg/mg is the maximum possible drug concentration in the dialysate, and S, cm 2 is the area of diffusion.The D values corresponding to a diprazin diffusion time of t = 90 min are presented in Table 1. As is seen from these data, a maximum reduction in the rate of diprazin diffusion (from 1.71 x 10-3 ...