Fast-dissolving microparticles fail to show improved oral bioavailability

Abstract

Oral dosage forms are the preferred means of delivering drugs for systemic absorption. However, development problems occur for drugs with poor water solubility and/or gastrointestinal permeability. It is generally believed that the in-vivo bioavailability of poorly water-soluble drugs from Class II of the Biopharmaceutics Classification System can be improved by increasing the dissolution rate. We have attempted to increase the in-vivo oral bioavailability of a model Class II drug (griseofulvin) by preparing rapidly-dissolving particles. The solvent-diffusion method was used to prepare particles with hydrophilic surfactants (Brij 76/Tween 80 surfactant blend) and in-vivo studies were conducted in rats. The griseofulvin particles produced were bipyramidal in habit with a particle size of 2.18 +/- 0.12 microm; they contained crystalline drug and a relatively large proportion (12% w/w) of hydrophilic surfactant. The latter and the small particle size ensured rapid particle dispersion and dissolution in-vitro. Thus, within 30 min of the in-vitro dissolution test, the bipyramidal particles had released approximately 70% of drug compared with approximately 10% from the starting material (particle size 12.61 +/- 1.11 microm). However, the rapid and increased drug dissolution in-vitro was not translated to rapid and enhanced absorption in-vivo, and the oral bioavailability of the model drug was found to be the same from the control and from the bipyramidal particles. The poor in-vivo performance of the bipyramidal particles showed that although the dissolution rate of a Class II drug is thought to be a good indicator of its in-vivo bioavailability, this is not always the case.

The Evaluation of In Vitro Drug Dissolution of Commercially Available Oral Dosage Forms for Itraconazole in Gastrointestinal Simulator With Biorelevant Media

“…2 However, formulation development has often been misled when those formulations for low-soluble drugs are assessed in conventional in vitro dissolution tests using United States Pharmacopeia (USP) apparatus I and II. 3,4 It is because these dissolution tests use a constant fluid volume, pH, and buffer species, which are not physiologically relevant in human gastrointestinal (GI) tract. As a result, it is difficult to predict in vivo performance of oral drug products and to obtain good in vitroein vivo correlation.…”

Measurements of rat and mouse gastrointestinal pH, fluid and lymphoid tissue, and implications for in-vivo experiments

“…To our knowledge, there are no reports of mouse and rat stomach volume, although maximum volumes to be administered by the oral route have been suggested (Wolfensohn & Lloyd 1994). Gelatin capsule shells and mini-tablets have been administered to rats (Hu et al 1999;Wong et al 2006). Knowledge of the animal stomach volume would enable calculation of dosage form:stomach volume ratio, which would give an indication of the likely fate of the dosage forms, with respect to disintegration and drug dissolution and absorption.…”

Concept of fast dissolving formulations for use in acute treatment conditions - introspection, thoughts and perspectives

“…Recently a wellcharacterized griseofulvin fast dissolving tablet that showed superior in vitro dissolution profile as compared to the tablets that used regular griseofulvin particles failed to achieve enhanced and/or rapid absorption in vivo. [8] The in vivo bioavailability/bioequivalence carried out in human subjects suggested comparable bioavailability between the new/ improved formulation (i.e. fast dissolving) and the regular formulation of griseofulvin.…”

“…fast dissolving) and the regular formulation of griseofulvin. [8] In conclusion, in spite of establishing a well-designed fast dissolving tablet prototype with detailed in vitro characterization, the utility of such a formulation is dependent on its in vivo performance. It appears prudent to investigate at least in an indirect fashion the utility of the newly developed fast dissolving formulation by the various scenarios detailed in this communication, if an in vivo testing option is not possible.…”