Enhanced oral absorption of saquinavir with Methyl-Beta-Cyclodextrin—Preparation and in vitro and in vivo evaluation

Pathak, Shriram M and Musmade, Prashant B and Dengle, Swapnil and Karthik, Arumugam and Bhat, Krishnamurthy and Udupa, Nayanabhirama (2010) Enhanced oral absorption of saquinavir with Methyl-Beta-Cyclodextrin—Preparation and in vitro and in vivo evaluation. European Journal of Pharmaceutical Sciences, 41. pp. 440-451.

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Saquinavir (SQV) is a weak base compound, whose solubility is strongly influenced by pH variations. Thus, in the present work, we thought it worthy of interest to investigate in-depth the combined effect of pH control and cyclodextrin (CyD) complexation on SQV solubilization. Phase-solubility studies were performed by adding excess drug to buffered (pH from 1.1 to 7.4) aqueous solutions containing increasing concentrations of Methyl-Beta-CyD (M-�-CyD) in order to evaluate the role of the unionized species of SQV in improving solubility by CyD complexation and to be able to select the most suitable conditions for optimizing drug solubilization. Our study reveals that the integrated approach of pH adjustment and CyD complexation can be successfully used for improving the CyD solubilizing power towards an ionizable drug such as SQV, thus allowing a smaller quantity of CyD to solubilize a given amount of drug, offering clear economic and technologic advantages as well. When biopharmaceutics of the optimized cyclodextrin-based formulation of SQV was studied in Wistar rats after intravenous and oral administrations, we found that inclusion of SQV into M-�-CyD could dramatically improve its oral bioavailability and decrease the variation of its oral pharmacokinetics. Compared to the control, the presence of M-�-CyD significantly increased the area under the plasma concentration–time curve (439.7±161.35 to 2312.03±159.53, p < 0.01) and the peak plasma concentration (117.24±35.77 to 1347.88±276.76, p < 0.01) of orally administered SQV. The modulating effect of M-�-CyD on the bidirectional transport of SQV was also investigated using a modified Ussing chamber system. The results demonstrated that the enhancing effect of M-�-CyD on the oral bioavailability of SQV is due not only to its solubilizing effect on SQV but also, at least in part, to the inhibitory effect of M-�-CyD on the P-glycoprotein (P-gp) mediated efflux of SQV in the gastrointestinal tract. The present results suggest that M-�-CyD is particularly useful in designing oral preparations of SQV with an enhanced bioavailability and a reduced variability in absorption.

Item Type: Article
Uncontrolled Keywords: Saquinavir Methyl-�-Cyclodextrin Solubility P-glycoprotein In-vitro Pharmacokinetics
Subjects: Pharmacy > MCOPS Manipal > Pharmaceutical Quality Assurance
Depositing User: KMC Manipal
Date Deposited: 21 Apr 2012 06:38
Last Modified: 05 Nov 2016 09:53
URI: http://eprints.manipal.edu/id/eprint/76275

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