Development of composition and evaluation of equivalence of diacerein hard gelatin capsules

Abstract

Diacerein is a new generation of symptomatic slow-acting agent for the treatment of osteoarthritis, when taken orally, it exhibits moderate anti-inflammatory and analgesic activity, slows down the decay of cartilage tissue and relieves pain and swelling, but its physicochemical properties it is practically insoluble in water, due to which only 35‒56% the drug reaches systemic circulation. Therefore, the search for approaches to increase the dissolution rate of a practically insoluble API using the formulation, type of excipients, degree of solubility and kinetics of the substance release from hard gelatin capsules should provide guaranteed drug efficacy. The aim of the work is to develop the composition of the drug in the form of hard gelatin capsules based on diacerein, to experimentally study the solubility of diacerein, and to evaluate the composition by studying the kinetics of dissolution of the drug. Determination of the pH-dependent solubility of diacerein was carried out in the conditions: the volume of the dissolution medium is 250 ml; dissolution temperature 37.0 ± 0.5 ºС. The highest recommended single dose of 50 mg was investigated. The development of the composition of the drug Diacerein, capsules, 50 mg was carried out with the use of various types of excipients and their modifications to achieve the proper technological properties in terms of fluidity (flowability) and a short disintegration time of the capsules for the release of the active substance. Comparative studies of the kinetics of dissolution were carried out by the in vitro method, the test «Dissolution» was studied a «Paddle apparatus» with a rotation speed of 75 rpm, a dissolution medium with a pH value of 1.2, 4.5 and 6.8, in a volume of 900 ml at a temperature of 37 ± 0.5 ºС. The reference drug was used «Artrodarin®», capsules of 50 mg, manufactured by TRB PHARMA S. A.,vArgentina. It was found that diacerein is practically insoluble in a buffer solution with a pH of 1.2, has a relatively low solubility in a buffer solution with a pH of 4.5, while the solubility of diacerein increases with an increase in the pH of the medium to 6.8. The optimal composition of capsules with diacerein using the wet granulation technology has been developed. The obtained data for bulk density and Carr's index indicate satisfactory flowability of the encapsulating mass. Comparative studies of the dissolution kinetics of the investigational medicinal product and the original drug «Artrodarin®», capsules of 50 mg were carried out. According to the calculations, all the obtained values of the similarity factor are in the range from 50 to 100 and indicate the similarity in buffer media with pH 1.2, 4.5 and 6.8. The developed composition of the preparation is equivalent in dissolution kinetics to the original medicine.