Evaluation of polyethylene oxide compacts as gastroretentive delivery systems.

Compacts containing selected bioadhesive polymers, fillers, and binders were investigated for their potential as a bioadhesive gastroretentive delivery system to deliver water soluble and water insoluble compounds in the stomach. Compacts with 90:10, 75:25, and 60:40 of polyvinylpyrrolidone (PVP) and polyethylene oxide (PEO) were evaluated for swelling, dissolution, bioadhesion, and in vitro gastric retention. Compacts containing higher PEO showed higher swelling (111.13%) and bioadhesion (0.62 +/- 0.03 N/cm(2)), and retained their integrity and adherence onto gastric mucosa for about 9 h under in vitro conditions. In vivo gastroretentive property of compacts were evaluated in Yorkshire cross swine. Compacts containing 58% PVP, 40% PEO and 2% of water soluble or water insoluble marker compounds showed gastroadhesive and retentive properties in vivo. It is concluded that PEO in combination with PVP yields a non disintegrating type bioadhesive dosage form which is suitable for gastroretentive applications.

Screening of octanol-water partition coefficients for pharmaceuticals by pressure-assisted microemulsion electrokinetic chromatography.

A rapid screening assay for the determination of octanol-water partition coefficients (log P(OW)) of pharmaceuticals was developed by using pressure-assisted microemulsion electrokinetic chromatography (MEEKC). The microemulsion system contains 50 mM sodium dodecyl sulfate, 0.87 M l-butanol, 82 mM heptane, and 50 mM borate-phosphate (2:3) at pH 10. Ten standard compounds with known log P(OW) values from -0.26 to 4.88 were used for constructing the calibration curve of log P(OW) against the MEEKC retention factor, log k. The log P(OW) values of the compounds were calculated based on the log k values measured by MEEKC and the slope and intercept of the calibration curve. For 13 literature and 32 Roche compounds, about 90% of the log P(OW) values measured by MEEKC are within 0.5 log units of the values from the literature and potentiometric titration. The throughput is about 2 samples/h using +20 kV voltage plus 5 mbar air pressure for separation. This MEEKC method is applicable for log P(OW) screening of weakly basic, weakly acidic, and neutral pharmaceuticals with log P(OW) = 0-5 and pKa < or = 10.

Pre-clinical and clinical evaluation of solution and soft gelatin capsule formulations for a BCS class 3 compound with atypical physicochemical properties.

R1481 is a sub-type selective muscarinic receptor antagonist with the potential treatment of overactive bladder. R1481 presents two challenges for drug development. The first is the viscous semi-solid nature of the active pharmaceutical ingredient (API). The second challenge is the poor oral bioavailability of this water soluble, metabolically stable compound due to low intestinal permeability, and the P-glycoprotein (P-gp) efflux mechanism. Vitamin E TPGS is reported by others to enhance bioavailability by increasing the solubility of active compounds and by inhibiting P-gp in the intestine. In this report, compatibility of R1481 in Capmul MCM-based formulations with and without vitamin E TPGS is summarized. Review of accelerated stability studies of oral formulations led to the identification of a soft gelatin capsule formulation using neat Capmul MCM as an acceptable formulation for Phase 1 clinical studies. Soft gelatin capsules (5 mg strength) were manufactured with and without the addition of vitamin E TPGS. Clinical data show that vitamin E TPGS does not improve systemic exposure of R1481 in humans.