Disposition of Lipid-Based Formulation in the Intestinal Tract Affects the Absorption of Poorly Water-Soluble Drugs

Abstract

Recently, drug discovery strategies, based on the technology of combinatorial chemistry and high throughput screening, have often produced compounds with poor water-solubility.1,2) Most of those compounds will drop out as candidates at the pre-formulation or formulation study stage because of their low intestinal absorption despite their high pharmacological activity in vitro. Therefore, the investigation of new dosage formulations for poorly water-soluble compounds will contribute to drug development.Since a new oral dosage formulation for an immunosuppressant drug (cyclosporine A), named "Neoral R ", was developed and used clinically, 3) lipid-based formulations 4,5) to improve the oral absorption of poorly water-soluble drugs have received considerable attention in the pharmaceutical industry. Neoral R contains various ingredients to form an emulsion in the intestinal tract and works as a Self-microemulsifying drug delivery system (SMEDDS).6) This system is regarded as an advanced system of lipid-based formulations. As SMEDDS generally consists of lipid(s) and surfactant(s), these components may affect the absorption mechanism of poorly water-soluble drugs. However, the disposition of lipidbased formulation components in the intestinal tract has not yet been clarified.In this study, we investigated the role of lipid-based formulation components for the intestinal absorption of poorly water-soluble drug by focusing on the disposition of the formulation after oral administration. , the mixture of saturated polyglycolized glyceride and mono-or di-fatty acid esters of polyethylene glycol (Lauroyl macrogol-32 glycerides), was a kind gift from Gattefosse (Gennevilliers Cedex, France). All other chemicals used were of analytical grade. MATERIALS AND METHODS MaterialsPreparation of Lipid-Based Formulations SG (M.W. 418.5), an anthraquinone derivative, was used as a poorly water-soluble model compound. This compound is a poorly water-soluble dye, and its logP value was 7.40. Soybean oil emulsion was prepared by the conventional method. 7) Briefly, 3 mg of SG was added to 0.5 ml of soybean oil preheated at 60°C in a hot water bath and dissolved completely. 0.25 ml of Tween 80 and 4.25 ml of distilled water were added to the oil and sonicated at 20 W for 5 min using an Ultrasonic Disrupter UD-201, Tomy Co. (Tokyo, Japan). For SMEDDS, 3 mg of SG was dissolved in 5 ml of Gelucire 44/14 R preheated at 60°C in a hot water bath. It was then cooled down immediately before use because Gelucire 44/14 R becomes semi-solid at room temperature.In Vivo Oral Administration to Rats All animal experiments were approved by the Animal Experimentation Committee of Osaka University of Pharmaceutical Sciences. Male Wistar rats weighing 300-350 g were obtained from Japan SLC, Inc. (Shizuoka, Japan). The day before the experiment, the rats were lightly anesthetized with ether, and were implanted surgically with a combination of Phicon (Fuji Systems Ltd., Tokyo, Japan) and PE50 (Clay Adams, Parsippany, NJ, U.S.A.) in a catheter, which was ins...

Characterization and evaluation of an oral microemulsion containing the antitumor diterpenoid compound ent-11alpha-hydroxy-15-oxo-kaur-16-en-19-oic-acid

“…Droplet size has been thought to have an effect on drug absorption, ie, the smaller the droplet size, the larger the interfacial surface area. 21 The effect of the medium on droplet size was also investigated in our study. When the microemulsion was respectively diluted 100-fold in distilled water, 0.9% NaCl, 0.1 mol/L HCl, or pH 6.8 phosphate buffer, there was no significant difference in the resulting droplet size or spherical shape among the four different types of medium, indicating that the microemulsion would not be affected by pH in the gastrointestinal tract.…”

Relation between Macroscopic Binding Constant and the Anticancer Efficacy of the Bovine Serum Albumin-Quercetin Complex against Drug-Sensitive and Drug-Resistant Cells

“…These studies have also provided evidence that such binding can increase the solubility of ligands and thus increase its cytotoxicity. Contrary the binding of bilirubin to albumin caused a decreased its cytotoxicity (Jones et al, 2008;Watanabe et al, 2008;Iwanaga et al, 2006;Lupidi et al, 2010;Yue et al, 2009).…”

“…It was known that lipids and proteins can considerable increase in the solubility of various drugs (Jones et al, 2008;Watanabe et al, 2008;Iwanaga et al, 2006). Many research groups have studied the in vivo consequences of binding of drugs and their metabolites to serum albumins (Lupidi et al, 2010;Yue et al, 2009).…”

The direct comparison of health and ulcerated stomach tissue: A multiple probe microdialysis sampling approach

“…Traditional methods of studying absorption across the stomach include blood sampling, in situ closed loop methods and excised tissue studies [5][6][7][8]. Blood sampling, although sufficient for measuring overall bioavailability, does not give an assessment of local absorption.…”