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Abstract. The objective of the present study was to formulate and evaluate microemulsion systems for topical delivery of clotrimazole (CTM). The solubility of CTM in various oils was determined to select the oil phase of the microemulsion systems. Pseudoternary phase diagrams were constructed to identify the area of microemulsion existence. Five CTM microemulsion formulations (M1-M5) were prepared and evaluated for their thermodynamic stability, pH, refractive index, droplet size, viscosity, and in vitro release across cellulose membrane. Among the prepared microemulsion formulations, M3 (lemon oil/ Tween 80/n-butanol/water) and M4 (isopropyl myristate/Tween 80/n-butanol/water) microemulsion systems were found to be promising according to their physical properties and CTM cumulative percentage release. Gel form of M3 and M4 were prepared using 1% Carbopol 940 as the hydrogel matrix. Both formulations were evaluated in the liquid and gel forms for drug retention in the skin in comparison to the marketed CTM topical cream and their stability examined after storage at 40°C for 6 months. Microemulsion formulations achieved significantly higher skin retention for CTM over the CTM cream. Stability studies showed that M4 preparations were more stable than M3. The in vitro antifungal activity of M4 against Candida albicans was higher than that of the conventional cream. Moreover, clinical evaluation proved the efficacy and tolerability of this preparation in the treatment of various topical fungal infections.

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Objectives: Clotrimazole is a broad-spectrum antimycotic that widely used to treat fungal infections topically. However, poor water solubility of clotrimazole and low skin retention of its topical products present a hindrance for local availability and effectiveness of this drug. This study aimed to formulate and evaluate cubosomes as skin retentive system for topical delivery of clotrimazole. Methods: Six clotrimazole cubosomal dispersions (F1-F6) were prepared by emulsification of glyceryl monoloeate (GMO) and poloxamer 407 at different compositions in water with and without polyvinyl alcohol (PVA).The dispersions were examined under polarizing microscope and transmission electron microscope (TEM) for confirming cubosomes formation. The four cubosomal dispersions (F3-F6) that found to be successfully developed were evaluated in terms of pH, particle size, zeta potential, rheological behavior, entrapment efficiency and in vitro drug release. The formulae F3 (without PVA) and F6 (with PVA) comprising the highest concentration of poloxamer in the disperse phase (15%w/w) provided the highest clotrimazole cumulative percentage release and subjected to comparative ex vivo skin retention and permeation studies with marketed clotrimazole cream. Results: Both F3and F6 showed significantly lower clotrimazole permeation compared to the cream. Moreover, F6achieved the highest skin retention for clotrimazole. The F6 was compared with the cream for its irritation potential in rats and also for antifungal activity in rats inducted with candida albicans. The investigations showed that F6 was well tolerated as the cream. Also,F6 showed superior antifungal activity compared to the available marketed cream. Conclusions: The developed F6 cubosomes is a promising dosage form for safe and effective topical delivery of clotrimazole.

Abstract. The objective of this study was to prepare and evaluate terbutaline sulphate (TBS) bi-layer tablets for once-daily administration. The bi-layer tablets consisted of an immediate-release layer and a sustained-release layer containing 5 and 10 mg TBS, respectively. The sustained-release layer was developed by using Compritol®888 ATO, Precirol® ATO 5, stearic acid, and tristearin, separately, as slowly eroding lipid matrices. A full 4×2 2 factorial design was employed for optimization of the sustainedrelease layer and to explore the effect of lipid type (X 1 ), drug-lipid ratio (X 2 ), and filler type (X 3 ) on the percentage drug released at 8, 12, and 24 h (Y 1 , Y 2 , and Y 3 ) as dependent variables. Sixteen TBS sustained-release matrices (F1-F16) were prepared by melt solid dispersion method. None of the prepared matrices achieved the targeted release profile. However, F2 that showed a relatively promising drug release was subjected to trial and error optimization for the filler composition to develop two optimized matrices (F17 and F18). F18 which consisted of drug-Compritol®888 ATO at ratio (1:6 w/w) and Avicel PH 101/dibasic calcium phosphate mixture of 2:1 (w/w) was selected as sustained-release layer. TBS bilayer tablets were evaluated for their physical properties, in vitro drug release, effect of storage on drug content, and in vivo performance in rabbits. The bi-layer tablets showed acceptable physical properties and release characteristics. In vivo absorption in rabbits revealed initial high TBS plasma levels followed by sustained levels over 24 h compared to immediate-release tablets.