International journal of pharmaceutics
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Comparative Study
CDs as solubilizers: effects of excipients and competing drugs.
In recent years cyclodextrins (CDs) have been acknowledged by the pharmaceutical industry as very useful enabling excipients for solubilization and stabilization of drugs in aqueous formulations. Their effect is however strongly influenced by other commonly used excipients. The purpose of this investigation was to examine the effects of excipients and drug combinations on the effects of CD solubilization of drugs and drug availability. ⋯ Drugs that have little affinity for CDs (e.g. amphotericin B) did in some cases improve the CD solubilization of dexamethasone. Flux diagrams obtained through semi-permeable cellophane membrane indicated that drug/CD complexes self-assemble to form aggregates, especially at CD concentrations above 5% (w/v). This aggregate formation was affected by the excipients and did influence drug availability from the formulations.
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The use of solubilizing agents to improve the solubility of poorly water-soluble drugs often results in an alteration of intestinal membrane barrier function and intestinal membrane damage. In this study, 5(6)-carboxyfluorescein (CF) and fluorescein isothiocyanate-labeled dextran (MW 4400, FD4) were used as model compounds to examine the effects of twelve common solubilizing agents, sodium taurocholate (NaTC), Labrasol, polyethylene glycol 400 (PEG 400), Transcutol P, propylene glycol, Gelucire 44/14, HCO-60, ethanol, Cremophor EL, Tween 80, 2 hydroxypropyl-beta-cyclodextrin (2HP-beta-CyD) and dimethylsulfoxide (DMSO), on intestinal membrane barrier function and membrane toxicity in rats. Intestinal transport and absorption of CF were examined using an in vitro diffusion chamber and an in situ closed-loop technique. ⋯ The LDH level was also increased in the presence of 10% (v/v) of Cremophor EL. These findings suggest that the solubilizing agents at these concentrations except for NaTC, Gelucire 44/14 and Cremophor EL are considered safe and do not cause intestinal membrane damage. In conclusion, this study provides a basic approach in screening and predicting the effects of solubilizing agents for intestinal absorption studies using drugs poorly soluble in water.