Category: Formulation and Quality
Purpose: Inducing supersaturation is an attractive approach for increasing the bioavailability of poorly soluble drugs. Delayed precipitation of weakly basic drugs in supersaturated state following their transition from the acidic gastric environment to the near-neutral proximal small intestinal fluid is emerging as a promising tactic for achieving higher transitional solubility and improved bioavailability of such drugs. The purpose of this study was to assess the effect of pH-shift induced supersaturation on drug dissolution and permeation in vitro, and to evaluate the approach of extending supersaturation to enhance drug oral absorption in vivo.
Methods: Dissolution and permeation of testing drugs in tablet form were measured using the in vitro dissolution absorption system 2 (IDAS2). Supersaturation of weakly basic drugs was induced in vitro using a 2-stage procedure mimicking the shift from gastric pH 1.6 to intestinal pH 6.5; as controls drugs were also tested under non-inducing condition with 1-stage procedure at constant pH 6.5. Delaying precipitation of drug in supersaturated state was accomplished with a polymeric precipitation inhibitor, hydroxypropyl methycellulose acetate succinate (HPMC-AS). The weakly basic drug ketoconazole was selected for further in vivo evaluation. Excess amount of ketoconazole was formulated in acidic aqueous medium to produce a high concentration, which was administered orally, in the presence or absence of HPMC-AS, to rats. The plasma samples were collected up to 24 hrs and analyzed by LC-MS/MS.
Results: In vitro dissolution under 2-stage conditions, BCS 2 weakly basic drugs dipyridamole, ketoconazole and itraconazole exhibited supersaturation, accompanied with enhanced drug permeation. More specifically, compared to 1-stage conditions, dissolution of dipyridamole, ketoconazole and itraconazole increased by 393%, 161% and 71%, respectively; led to 543%, 264% and 46% increase in in vitro permeation. In contrast, the BCS2 acidic drug warfarin exhibited 9% decrease in dissolution and resulted in 21% decrease in permeation. BCS 1 drugs (minoxidil and metoprolol) exhibited no change in dissolution or permeation. In the rat study, HPMC-AS increased ketoconazole systemic exposure (plasma AUC0-24h increased by 54%), presumably by enhancing dissolution or prolonging supersaturation.
Conclusion: This study demonstrates an in vitro dissolution – absorption methodology to evaluate the potential utility of supersaturation as a means to improve the oral absorption of weak basic drugs with poor aqueous solubility.
Yuri Bukhtiyarov– Associate Director, In Vitro Pharmacology and Pharmacokinetics, Absorption Systems, Exton, Pennsylvania
Nicole Spivey– Exton, Pennsylvania
Svitlana Silchenko– Exton, Pennsylvania
Christopher Force– Exton, Pennsylvania
Carlos Hidalgo– Associate Scientist, Absorption Systems, Exton, Pennsylvania
Yuehua Huang– Senior Scientist, Absorption Systems, Exton, Pennsylvania
Albert Owen– Exton, Pennsylvania
Ismael Hidalgo– Chief Scientific Officer, Absorption Systems, Exton, Pennsylvania