Diacerein mutual prodrug for osteoarthritis: synthesis, in vitro kinetic studies and preliminary pharmacological screening

A gastro-sparing diacerein mutual prodrug was designed and synthesized by linking it to D-glucosamine as a promoiety with an objective of increasing the potential of its anti-inflammatory activity and improving its hydrophilic characteristics so as to make its parenteral administration feasible. Diacerein was linked with D-glucosamine through amide linkage and was subjected to in vitro release studies in aqueous buffers of varied pH range. 97% release of diacerein was achieved in phosphate buffer (pH 7.4) with a half-life of 48 min, following first order kinetics. Preliminary screening was carried in a one-month study in experimental osteoarthritis in rats induced by mono-iodoacetate and therapeutic efficacy of the conjugate was evaluated for changes in knee-diameter, spontaneous locomotor activity, alkaline phosphatase and glucosaminoglycan levels. The prodrug was also tested for anti-inflammatory activity in Freund’s adjuvant arthritis and local irritant effect on rat stomach by Rainsford’s cold stress method. The prodrug exhibited quicker onset of action than diacerein with respect to reduction in knee diameter, improved locomotor activity, better anti-inflammatory and gastro-sparing activity. The preliminary results are promising. In vivo kinetic studies and evaluation in mono-iodoacetate induced osteoarthritis over a period of three months is in progress to establish its effectiveness in the management of osteoarthritis.