Investigation of microemulsions and their microstructures for transdermal and dermal drug delivery
Creators: name: Zhang, Ji
Publisher: name: No Publisher Supplied
Year: 2017

description: Drug delivery through the skin, transdermally and topically, offers many advantages including reduced systemic toxicity and side-effects, avoidance of the hepatic first pass metabolism, improved patient compliance, enabling sustained or controlled drug release, and enhanced delivery to local target tissues. However, there are many challenges for this route of administration, the major one is the skin barrier function to drug permeation. Many different approaches have been studied and used for enhancing the drug skin permeation. Among them, chemical permeation enhancers and microemulsion formulations are some of widely studied approaches. The thesis work focused on microemulsion (ME) formulations for enhancing transdermal or dermal drug delivery. Specifically, the ME microstructures were investigated and correlated with enhancement effects of drug skin permeation or skin deposition. The results showed that a critical factor influencing ME formulation behavior was the water content that also correlated to the formulation microstructure, and the drug skin permeation increased significantly corresponding to the microstructure change from W/O, to Bi-continuous, and to O/W. This was the first time that this phenomenon had been systematically studied and reported, the microstructure of a microemulsion affected both hydrophobic and hydrophilic model drugs’ transdermal permeation. The extent of trandermal permeation enhancement effect was more significant for hydrophobic drugs than hydrophilic drugs as water content increased and the corresponding microstructure changed in the ME formulation. Furthermore, at fixed water content, increasing oil content would result in higher transdermal permeation enhancement. The model drugs used in the study were lidocaine, ketoprofen, and caffeine, which represented compounds of varied physical and chemical properties. The findings were of practical significance for microemulsion formulation design and development in transdermal drug delivery.   Secondly, in the present study, a combination of analytical methodologies was utilized to examine microemulsion microstructures. It was found that the cooling thermogram generated by Differential Scanning Calorimetry (DSC) provided a simple approach for microstructure determination, which to the author’s knowledge, had not been reported before. Extensive DSC cooling experiments had been conducted to analyze three ME systems that had their microstructure characterized and known in the literature. It was showed that DSC derived microstructure results were in complete concordance with literature reports, and thus demonstrated that the cooling DSC method was an effective analytical technique for ME microstructure assessment. The results also showed that the DSC method provided additional advantages over conventional methods for being sensitive, accurate, and versatile. The developed cooling DSC methodology for ME microstructure analysis would greatly facilitate ME formulation characterization and development in the future.   Finally, dermal delivery of hydrophobic drugs by microemulsion (ME) formulations and effect from ME microstructures were studied. The antifungal drug, clotrimazole (CLOT), was used as the model compound. ME formulations of different microstructures were prepared along water dilution line at fixed oil/(surfactant and co-surfactant) ratio of 1/9 (w/w) using isopropyl myristate as oil, Labrasol and Cremophor EL as surfactant and co-surfactant, and water. Permeation experiments on human cadaver skin were conducted for ME and the control formulations of different CLOT loads. Dermal delivery of CLOT assessed by the dermal drug concentrations was found to be significantly higher for MEs when compared with the control formulation, and the highest concentration was observed with O/W ME, suggesting ME microstructure was an important formulation variable for enhancing dermal delivery. ME gel formulations prepared by incorporating 1.0% (w/w) of Carbopol 980 showed comparable dermal CLOT concentration to MEs but up to 2.4 fold higher than the commercial CLOT cream product, Lotrimin®. Furthermore, FITC used as a model compound for highly hydrophobic drugs, was also studied for its dermal delivery by MEs in porcine skin penetration experiments. Results showed a consistent ME microstructure effect, suggested by significantly higher FITC concentrations in all skin layers, stratum corneum, viable epidermis, and dermis, from O/W ME over Bi-continuous and W/O MEs. Results from the present study highlighted ME microstructure effect on ME dermal delivery of hydrophobic drugs, and provided insight to drug dermal retention and transdermal permeation enhancements and their interplay.