Power law IVIVC: an application of fractional kinetics for drug release and absorption.

Most correlations between in vitro and in vivo data (IVIVC) rely on linear relationships. However, non-linear IVIVC can be also observed, justified and validated. The purpose of the present work was the development of a methodology for power law IVIVC, which mirror power law kinetics under in vitro and in vivo conditions. Fractional calculus was used to justify power law kinetics for zero-order processes in disordered media. Power law kinetics was observed in a large number of in vitro data sets. When "zero-order" release and absorption is considered in terms of fractional calculus the following power law IVIVC between the fraction released F(r) and the fraction absorbed F(a), is obtained: F(a)=microF(r)(lambda)-beta, where mu is a constant related to the rate constants and the orders of the release/absorption kinetics, lambda is the ratio of the orders of the kinetics under in vitro and in vivo conditions and beta accounts for a time shift between the in vitro and in vivo processes; We used literature data to develop power law IVIVC and derive estimates for mu, lambda and beta; the simulated pharmacokinetic profiles using the in vitro release data and the IVIVC developed compared well with the actual in vivo data.

Novel milk-based oral formulations: proof of concept.

The aim of this study is to develop milk-based formulations for ionized and unionized lipophilic drugs. Solubility studies of the following non-steroidal anti-inflammatory drugs (NSAIDs): mefenamic acid, tolfenamic acid, ketoprofen, meloxicam, tenoxicam and nimesulide in phosphate- and glycine-NaOH buffers at nominal pH 8-12, were performed. The solubilities of cyclosporine and danazol in water-ethanol solutions were studied. NSAIDs-, cyclosporine-, danazol-, aspirin-milk oral liquid formulations were prepared by adding the appropriate volume of (i) NSAIDs-alkaline buffer solutions, (ii) water-ethanol solutions of cyclosporine and danazol and (iii) aspirin aqueous solution to 150-200ml of milk. All the non-steroidal anti-inflammatory drugs exhibited increased solubility in the alkaline buffers. The actual pH values (range 6.7-7.7) of the final NSAIDs-milk formulations were very close to milk pH. The higher ethanol content in ethanol-water mixtures increased the solubility of danazol and cyclosporine. A 15mg meloxicam-, a 100mg cyclosporine- and a 500mg aspirin-milk formulation was administered orally to healthy volunteers. All these formulations showed a satisfactory in vivo performance. The strong buffering capacity of milk that was observed and the high solubility of unionized drugs in ethanol allow the preparation of drug-milk formulations with enhanced pharmacokinetic properties.

Novel scaled bioequivalence limits with leveling-off properties.

PURPOSE: (1) To develop novel scaled bioequivalence (BE) limits with levelling-off properties based solely on variability considerations and (2) to evaluate their performance in comparison to the classic unscaled BE limits 0.80-1.25, the expanded BE limits 0.75-1.33 and the recently proposed Geometric Mean Ratio (GMR)-dependent scaled BE limits BELscW (Karalis et al., Eur. J. Pharm. Sci., 26:54-61, 2005). MATERIALS AND METHODS: Two model functions were used to ensure the gradual change of the BE limits from a starting value towards a predefined plateau value. Plots of the new BE limits and extreme GMR values ensuring BE as a function of the coefficient of variation (CV) were constructed. Two-period crossover BE studies with 12, 24, or 36 subjects were simulated assuming CV values from 10 to 60%. Power curves were constructed by recording the percentage of accepted BE studies as the true GMR was raised from 1.00 to 1.50. The percentage of the true GMR within the simulated BE limits vs. true GMR was used to evaluate the estimation accuracy of the scaled methods. RESULTS: Depending on the parameters' values of the model functions, the scaled BE limits exhibit different performance. Four new scaled BE limits, showing favourable performance for the evaluation of average BE are presented. At low variability levels two of the novel BE limits show similar performance to the 0.80-1.25 criterion, while the other two (as expected from their design) appear to be less permissive. At high CV values (30, 40%) all new BE limits exhibit much higher statistical power than the 0.80-1.25 criterion. They show almost identical behavior with the expanded 0.75-1.33 limits and appear to be less permissive than BELscW. Finally, the percentage of the true GMR within the simulated BE limits vs. true GMR shows a sharp decline. Due to the absence of the GMR factor in the model functions a more accurate estimation of the new scaled BE limits, compared to BELscW, is observed. CONCLUSIONS: The new scaled BE limits appear to be highly effective at all levels of variation investigated and present satisfactory estimation accuracy.