Particle size reduction for improvement of oral absorption of the poorly soluble drug UG558 in rats during early development
- 20 November 2009
- journal article
- research article
- Published by Taylor & Francis Ltd in Drug Development and Industrial Pharmacy
- Vol. 35 (12), 1479-1486
- https://doi.org/10.3109/03639040903025855
Abstract
The exposure of UG558 was not good enough using traditional microsuspensions.The aim of this study was to find out whether nanosuspensions were a better choice compared with a microsuspension, for an acidic substance with a water solubility in the order of 2 microM (pH 6.8, small intestinal pH) and no permeability limitations.UG558 was ground by a planetary ball mill. The particle size was measured by laser diffraction and the stability of the particle sizes was followed. The pharmacokinetic parameters of UG558 administered as nanosuspension have been compared with those from microsuspension using rat as in vivo specie. Both formulations were administered orally. The nanosuspension was also administered intravenously.The particle size of the nanosuspensions was about 190 nm and about 12 microm for the microsuspensions. At the administered doses, solutions were no alternative (e.g. due to limited solubility). Already at the lowest dose, 5 micromol/kg (5 ml/kg), a significant difference was observed between the two suspensions. These results were further confirmed at a high dose (500 micromol/kg, 5 mL/kg). Thus, the study demonstrated a clear correlation between particle size and in vivo exposures, where the nanosuspensions provided the highest exposure. Furthermore, no adverse events were observed for the substance nor the nanosuspension formulations (i.e., the particles) in spite of the higher exposures obtained with the nanoparticles. To make it possible to calculate the bioavailability, 5 micromol/kg doses of the nanosuspensions (5 ml/kg) were also administered intravenously. No adverse events were observed.The nanoparticles have a larger surface, resulting in faster in vivo dissolution rate, faster absorption, and increased bioavailability, compared to microparticles. The lower overall bioavailability observed at the high dose, compared with the low dose, was due to a combination of low dissolution rate, low solubility, and a narrow intestinal absorption window for UG558.Keywords
This publication has 24 references indexed in Scilit:
- Excipient–Drug Interactions in Parenteral FormulationsJournal of Pharmaceutical Sciences, 2002
- Drug Safety EvaluationPublished by Wiley ,2002
- Places of emulsions in drug deliveryAdvanced Drug Delivery Reviews, 2000
- Microemulsion-based media as novel drug delivery systemsAdvanced Drug Delivery Reviews, 2000
- Top ten considerations in the development of parenteral emulsionsPharmaceutical Science & Technology Today, 1999
- Cyclodextrins: Their Future in Drug Formulation and DeliveryPharmaceutical Research, 1997
- Pharmaceutical Applications of Cyclodextrins. 1. Drug Solubilization and StabilizationJournal of Pharmaceutical Sciences, 1996
- Nonlinear assessment of nitrofurantoin bioavailability in rabbitsJournal of Pharmacokinetics and Biopharmaceutics, 1983
- Oral versus Vaginal Absorption in Oestradiol in Postmenopausal Women. Effects of Different Particles SizesUpsala Journal of Medical Sciences, 1981
- Dependence of area under the curve on proquazone particle size and in vitro dissolution rateJournal of Pharmaceutical Sciences, 1980