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The main objective of this work was to develop antifungal matrix tablet for vaginal applications using mucoadhesive thiolated polymer. Econazole nitrate (EN) and miconazole nitrate (MN) were used as antifungal drugs to prepare the vaginal tablet formulations. Thiolated poly(acrylic acid)-cysteine (PAA-Cys) conjugate was synthesized by the covalent attachment of L-cysteine to PAA with the formation of amide bonds between the primary amino group of L-cysteine and the carboxylic acid group of the polymer. Vaginal mucoadhesive matrix tablets were prepared by direct compression technique. The investigation focused on the influence of modified polymer on water uptake behavior, mucoadhesive property and release rate of drug. Thiolated polymer increased the water uptake ratio and mucoadhesive property of the formulations. A new simple dissolution technique was developed to simulate the vaginal environment for the evaluation of release behavior of vaginal tablets. In this technique, daily production amount and rate of the vaginal fluid was used without any rotational movement. The drug release was found to be slower from PAA-Cys compared to that from PAA formulations. The similarity study results confirmed that the difference in particle size of EN and MN did not affect their release profile. The release process was described by plotting the fraction released drug versus time and n fitting data to the simple exponential model: M(t)/M(∞)=kt(n). The release kinetics were determined as Super Case II for all the formulations prepared with PAA or PAA-Cys. According to these results the mucoadhesive vaginal tablet formulations prepared with PAA-Cys represent good example for delivery systems which prolong the residence time of drugs at the vaginal mucosal surface.

Model prodrugs of resveratrol carrying protecting substituents at the hydroxyls have been synthesised and tested. Resveratrol triacetate and resveratrol-tri-mPEG(1900) were formed by linking methyl groups or poly(ethylene glycol) chains, respectively, via carboxyester bonds. Resveratrol trimesylate, a molecule less susceptible to hydrolytic attack, was synthesised as well. This latter compound proved to be stable in vitro, while the carboxyester derivatives were slowly hydrolysed in solutions mimicking the gastric or intestinal environment, and rapidly converted to resveratrol in blood. In ex vivo permeation experiments with explanted intestinal segments, resveratrol and its triacetate derivative appeared in the basolateral compartment essentially as a mixture of Phase II metabolites. When the PEGylated derivative was provided on the apical side, unconjugated resveratrol accounted for about 50% of the compounds in the basolateral-side chamber. The same result was obtained by providing an equivalent physical mixture of resveratrol and PEG polymer, indicating that this behaviour is likely due to an adjuvating effect of PEG rather than to the covalent polymer conjugation. These observations suggest that the ester derivatives are rapidly hydrolysed at the intestinal surface or inside enterocytes, and are then processed as resveratrol. On the other hand, the mesylate was transported from the apical to the basolateral side without modification. It may thus be possible to enhance absorption and hinder metabolism of natural polyphenols by constructing pro-drugs incorporating bonds with appropriate resistance to enzymatic hydrolysis., (2009 S. Karger AG, Basel.)