Enhancement of Bioavailability of Cinnarizine from Its β-Cyclodextrin Complex on Oral Administration with dl-Phenylalanine as a Competing Agent

Abstract

The present investigation is concerned with an improvement of the bioavailability of cinnarizine by administering its beta-cyclodextrin complex together with another compound which competes with the beta-cyclodextrin molecule in complex formation in aqueous solution (competing agent). The bioavailability of cinnarizine on oral administration of the cinnarizine-beta-cyclodextrin inclusion complex was enhanced by the simultaneous administration of DL-phenylalanine as a competing agent, e.g., the AUC was 1.9 and 2.7 times as large as those of the cinnarizine-beta-cyclodextrin complex alone and cinnarizine alone, respectively. The enhancement of AUC and Cmax completely depended on the dose of DL-phenylalanine. It was found from these results that DL-phenylalanine acted as a competing agent in the GI tract and the minimum effective dose required of DL-phenylalanine might be 1 g for 50 mg of cinnarizine in the cinnarizine-beta-cyclodextrin complex. Evaluating the competing effect of DL-phenylalanine in vitro using an absorption simulator, it was found that the decreased penetration rate of cinnarizine through the artificial lipid barrier with addition of beta-cyclodextrin was restored with the addition of DL-phenylalanine.

Drug/Cyclodextrin/Hydroxy Acid Multicomponent Systems. Properties and Pharmaceutical Applications

“…Blood samples were drawn for approximately 24 h postdosing, and TNF carboxylate metabolite levels were determined by HPLC 35. The multicomponent complex gave a better absorption profile in terms of C max and T max , but the bioavailability of TFN was not significantly affected, probably due to the large stability constant of the complex 36, 37…”

Cyclodextrins in drug delivery: An updated review

“…20,32,[47][48][49][50][51] Certain additives may compete with drug molecules for CD cavities and thus decrease the apparent complex stability constant, eg, additives with positive and negative hydrotropic effect. 54,55 Though water structure forming agents added to CD solutions generally increase the total drug solubility, they showed opposite effects with clotrimazole. 52 Simultaneous complexation and salt formation with hydroxy carboxylic acid (HA) significantly increased the CD solubilizing power for a sparingly water-soluble amine type drug by forming drug/ CD/HA multicomponent systems.…”

Utility of nuclear magnetic resonance spectroscopy to characterize the structure of dexamethasone sodium phosphate inclusion complexes with cyclodextrins in solution and to analyze potential competitive effects

“…The displacement of a drug from the CyD cavity usually modifies the effect of complexation 13–15. Therefore, it is important to investigate the interaction of the molecules present in the formulation with the CyD to avoid undesirable outcomes.…”

“…In CyD complexation technology, it is very important to analyze the interaction of the drug molecules present with the elected CyD derivatives because if there is competition for the cavity, the more stable inclusion complex will form, and this complex may not be desirable 13–15. To prevent such undesirable competitions, knowledge of the stability constants of the complex in the formulation conditions is very useful.…”