RESEARCH ARTICLE: Pharmaceutics, Drug Delivery and Pharmaceutical TechnologySolubility Profiling of HIV Protease Inhibitors in Human Intestinal Fluids
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INTRODUCTION
Treatment of HIV infection involves the use of first- and second-generation protease inhibitors (PIs). Despite their tremendous success worldwide, their low oral bioavailability remains a major drawback.1 The low bioavailability of the PIs led to the high intersubject variability, increasing the likelihood of subtherapeutic concentrations and thus affecting the in vivo performance of the PIs. The low and variable drug exposure could have serious clinical implications, given the dependence of
Chemicals
The HIV protease inhibitors APV, AZV, DRV ethanolate, and RTV were provided by the National Institutes of Health AIDS Research and Reference Reagent Program (Germantown, Maryland). SQV, IDV, NFV, and LPV were donated by Hetero Drugs Ltd. (Hyderabad, India). TPV was provided by Boehringer Ingelheim (Rheinland Pfalz, Germany). Water was purified with a Maxima system (Elga Ltd., High Wycombe, Buckinghamshire, UK). Dimethyl sulfoxide and sodium dihydrogen phosphate were obtained from Acros Organics
Characterization of Solubility Media
The initial pH, osmolality, and buffer capacity of the different solubility media are listed inTable 3. The pH of aspirated FaHIF from four volunteers (V1–V4) was clearly higher than FaSSIF (6.5), ranging between 6.6 and 7.4. Variety in pH appeared to be higher in FeHIF compared with FaHIF, ranging from 4.8 to 6.3. The pH of three of four FeHIF aspirates was higher than the pH of FeSSIF (5.0). The osmolality is also depicted inTable 3showing values around 200 mOsm/kg for FaHIF and around
CONCLUSIONS
This study generated an overview of the solubility of HIV PIs in fasted- and fed-state HIF aspirates. The results indicate a poor intestinal solubility for all PIs, stressing the importance of absorption-enabling formulation strategies. The determination of the HIF solubility of PIs allowed evaluating the predictive capacity of aqueous buffers and SIF. Although the use of blank FaSSIF failed to reliably estimate the intraluminal solubility, inclusion of mixed bile acid/phospholipid micelles
ACKNOWLEDGMENTS
We wish to thank the National Institutes of Health AIDS Research and Reference Reagent Program for providing us with the different HIV PIs. Financial support for this research was provided by the Institute for the promotion of Innovation by Science and Technology in Flanders (IWT) under grant SBO-IWT.
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