JPP 2006, 58: 1319–1326 © 2006 The Authors Received March 30, 2006 Accepted June 19, 2006 DOI 10.1211/jpp.58.10.0004 ISSN 0022-3573 1319 Fast-dissolving microparticles fail to show improved oral bioavailability S. M. Wong, I. W. Kellaway and S. Murdan 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 permeabil- ity. 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 parti- cles with hydrophilic surfactants (Brij 76/Tween 80 surfactant blend) and in-vivo studies were con- ducted in rats. The griseofulvin particles produced were bipyramidal in habit with a particle size of 2.18 ± 0.12 mm; 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 ~70% of drug compared with ~10% from the starting material (particle size 12.61 ± 1.11 mm). 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. Therapeutic agents can be administered by a variety of routes, such as the oral, transdermal and intravenous route. However, to achieve systemic effects, the oral route remains the most desirable as it allows easy and convenient self-medication, which encourages patient compliance. In addition, oral dosage forms are more cost-effective to manufacture as they do not require the sterile conditions needed by intravenous and ocular formulations. As a result, oral medication is generally the first avenue investigated by the pharmaceutical industry when discovering and developing new drug entities and/or new pharmaceutical formulations (Kim & Singh 2002). Developing oral dosage forms, however, becomes chal- lenging when the therapeutic agent is poorly absorbed from the gastrointestinal tract. Although a variety of reasons can cause poor absorption and subsequent therapeutic failure, the two main parameters that determine gastrointestinal drug absorption are considered to be the drug’s aqueous solubility and its gastrointestinal permeability. For absorption to occur following oral administration, the drug must dissolve in the aqueous gastrointestinal fluids and then permeate across the gastrointestinal membrane into the blood. These parameters were recognized when the Biopharmaceutics Classification System (BCS) was set up (Amidon et al 1995). Under this system, drugs are divided into four classes (Class I to Class IV) based on their solubility and permeability. Class I drugs have both good solubility and permeability; Class II drugs have good permeability but poor aqueous solubility; Class III drugs have good aqueous solubility but poor permeability; while Class IV drugs have both poor solubility and permeability. Thus, aqueous solubility and permeability are the rate-limiting factors in the absorption of Class II and III drugs, respectively. Poor permeability (of Class III drugs) is considered to be more of a problem than poor solubility (of Class II drugs) as, unlike poor permeability, insolubility can be addressed Introduction Department of Pharmaceutics, School of Pharmacy, London WC1N 1AX, UK S. M. Wong, I. W. Kellaway, S. Murdan Correspondence: S. Murdan, Department of Pharmaceutics, School of Pharmacy, London WC1N 1AX, UK. E-mail: sudax.murdan@pharmacy.ac.uk Acknowledgements: The authors thank Professor Graham Buckton for helpful discussions on particle characterizsation. David McCarthy and Steve Coppard are thanked for performing the scanning electron microscopy and for help with the animal work, respectively.