Enhanced Oral Bioavailability of Alitretinoin by Lipid Drug Delivery System

Abstract

Alitretinoin is an endogenous retinoid and acts as a pan-agonist at retinoid receptors, binding with high affinity to both retinoic acid receptors and retinoid X receptors. Oral alitretinoin once daily is approved for use in patients with severe chronic hand eczema unresponsive to treatment with potent topical corticosteroids. The bioavailability of alitretinoin after oral admin istration is low and subject to large inter-individual variation. The purpose of this study was to evaluate the relationship of solubility and dissolution profiles of alitretinoin in vitro and their impact on the oral bioavailability of alitretinoin in rats. The work plan involves using simple and widely used practices under small scale pharmaceutical industry setups in India. The solubility of alitretinoin in vehicles of varying Hydrophilic lipophilic balance (HLB) values was determined and selected components were used to formulate different compositions for in vitro drug release dissolutions studies. The prototypes composition of soybean oil and stearoyl macrogol-32 glycerides provided a stable and maximum drug releasing product. The pharmacokinetic study in rats for the optimized formulation was performed and compared against innovator composition. Lipid formulation system of alitretinoin had significantly increased the peak serum concentration (C max), area under the curve (AUC) and reduction was observed in time to reach peak serum concentration (T max) compared to marketed formulation. The data although reaffirms established correlations between dissolution and bioavailability, it interestingly points towards a complex relationship exist between HLB and thermodynamic activity profile of drug in vehicles in affecting alitretinoin's solubility, dissolution and bioavailability.