Reducing the maximum plasma concentration whilst maintaining the exposure was shown to ameliorate adverse events following the oral administration of 6-hydroxybuspirone. This observation, along with a desire to provide for once daily dosing of this compound, provided the basis for the development of an extended release formulation. Hydrophilic matrix tablets based on hydroxypropyl methylcellulose and containing citric acid to provide for an acid microenvironment were prepared and evaluated by in vitro drug release studies and in vivo pharmacokinetic and scintigraphic studies using samarium oxide (¹⁵³Sm) labelled dosage forms. The dosage forms were found to release the contained drug by a predominantly diffusion mechanism and the release rate was relatively independent of environmental pH. Following administration of the extended release formulations to volunteers, comparative pharmacokinetic data indicated that the extended release formulations provided for a reduction in the maximum plasma concentration of 64-70% relative to that provided by the same dose given as an oral solution, whilst maintaining exposure relative to the oral solution. By examination of absorption curves derived by Wagner-Nelson analysis of pharmacokinetic data it was noted that drug release in vivo correlated well with drug release observed in vitro and no marked change in rate of absorption was noted when dosage forms were located in and releasing drug in the colon. The robust control of drug release seen in vitro translated to a good in vivo performance.
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