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This paper describes the denaturation of protein drugs by dichloromethane (DCM) during the primary emulsification step of the microencapsulation process using biodegradable polymer matrix for controlled-release application. It was found that interaction of proteins such as tetanus toxoid (TT), diphtheria toxoid (DT), ovine growth hormone (oGH), and human chorionic gonadotropin-based antifertility vaccine (beta-hCG-TT) with DCM during primary emulsification stages of particle formulation led to the precipitation of the proteins at the aqueous organic interface with concomitant reduction in their immunoreactivity. On the other hand, the B subunit of E. coli enterotoxin (LTB) was found to be comparatively stable toward the denaturing action of DCM. Attempts were made to overcome the DCM-induced denaturation by incorporation of stabilizers during the primary emulsification step of the particle formulation. Of the many additives tested to overcome the DCM-induced denaturation of proteins, serum albumins and polyvinyl alcohol (PVA) showed promising results in terms of retention of the immunoreactivity of the protein. TT stabilized by the incorporation of serum albumin during the primary emulsification step not only showed immunoreactivity in vitro, but also invoked antibody titers in rats comparable to those obtained for the native protein molecules. Incorporation of 2.5% of serum albumins in the internal aqueous phase not only protected the protein from the degradative action of DCM but also led to stabilized primary emulsion, which is necessary for uniform entrapment of protein drugs in the polymer matrix.

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The present research investigates development and in vivo evaluation of oral diacerein formulations with quicker and complete absorption. In vivo, diacerein gets completely metabolized to its active metabolite rhein in gut and liver, which is the only analyte detected in plasma. Incomplete absorption of diacerein from the formulation leads to colonic availability of rhein, which is associated with increased laxative effect as one of the side effects of diacerein therapy. Thus solubility improved immediate release formulation (IR) and a gastroretentive formulation (GR) was designed to achieve rapid absorption preferentially through upper part of gastro-intestinal tract; thus controlling the amount of rhein reaching to colon and minimizing the associated increased laxative effect. In vitro drug release studies of the developed formulations revealed faster and complete release of diacerein from IR and GR formulations compared to commercially available diacerein capsule Art50. Comparative bioavailability studies conducted in healthy human volunteers revealed 1.7 fold and 1.2 fold rise in AUC(0-6h) for IR and GR formulations respectively, compared to Art50 capsules. A Levy plot analysis comparing association between the time of in vitro dissolution (Tvitro) of diacerein and time of in vivo absorption (Tvivo) of rhein confirmed faster release and absorption from upper part of gastrointestinal region for both the optimized formulations.

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