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theses

Skin has significant barrier properties that inhibit the passive transport of many active molecules. Different strategies are developed to overcome this skin barrier such as, chemical enhancement techniques using penetration enhancers and targeted drug delivery using topical and/or transdermal formulations. Usually these approaches are tested using human or animal skin. Human skin is not easily accessible and animal skin has significant biological and barrier differences when compared with human skin. Due to these issues the possibility of having a synthetic skin membrane is an attractive option. In this thesis, firstly, we investigated different formulations containing various enhancers from the aspect of their ability to enhance or reduce the delivery of nicotine through human cadaver skin and correlated that to Strat-M® synthetic membrane to examine the usefulness of this membrane as a convenient screening tool to investigate topically applied formulations and TDDS (Transdermal Delivery System). Formulations containing nicotine and a chemical penetration enhancer (CPE) were used for evaluating drug penetration to understand how each enhancer impacts the permeability of nicotine as a model compound. The permeability measurements of human cadaver skin and Strat-M® membrane were performed with Franz diffusion cell methods accompanied by HPLC analysis. The study demonstrated the good correlation (R2=0.99) of the permeability data obtained through human cadaver skin and Strat-M® membrane. Our data suggests that although Strat-M® lacks the highly organized stratum corneum (SC) intercellular structure and provided higher nicotine flux compared to human cadaver skin where the highly structured SC significantly reduced nicotine permeability, both membranes still provided similar enhancement factors for a given enhancer. These studies suggest that the Strat-M® synthetic membrane lipid composition probably closely mimics that of human cadaver skin based on the data obtained. The time point correlation between Strat-M® and human cadaver skin were in the range 0.90-0.99. This work suggests that some of the main transport mechanisms for drug diffusion and permeation of Strat-M® membrane could be similar to an ex vivo human skin model.

Secondly, we report on that the overall mechanism of action of skin penetration enhancers is best explained by the Solubility-Physicochemical-Thermodynamic (SPT) theory. The SPT theory puts forward the concept that the mode of action of enhancers is related to solubility parameters, physicochemical interactions and thermodynamic activity. We have discussed these concepts by using experimentally derived permeation data, various physicochemical and solubility parameters (ingredient active gap (IAG), ingredient skin gap (ISG), solubility of active in the formulation (SolV) and the formulation solubility in the skin (SolS)) generated by using FFE (Formulating for EfficacyTM - ACT Solutions Corp) software. Our data suggests that there is an inverse relationship between measured flux and IAG values given that there is an optimum ingredient skin gap, SolV and SolS ratio. The study demonstrated that the flux is actually proportional to a gradient of thermodynamic activity rather than the concentration and maximum skin penetration and deposition can be achieved when the drug is at its highest thermodynamic activity. This work will connect the solubility and physicochemical properties of the active and enhancers/ingredients with the thermodynamic activity of the model drug used in order to explain the mode of action of enhancers in a given formulation with that specific drug.

Thirdly, we studied the effect of an ethanol and propylene glycol donor solvent system along with various compositions of receptor solvents to investigate the feasibility of transdermal delivery of thymoquinone (TQ). The effects of penetration enhancers on the in vitro skin permeation and TQ skin absorption were studied using human cadaver skin in Franz diffusion cells. The permeation of saturated solutions of TQ was investigated with 5% v/v of each of the following enhancers: Azone (laurocapram), Transcutol® P (Tc), oleic acid, ethanol, Polysorbate 80 (Tween 80), and N-methyl-pyrrolidone (NMP). Our data suggests that Azone, oleic Acid and Tc were able to provide adequate TQ flux and may be the agents of choice for use in a novel transdermal formulation of TQ. These penetration enhancers were also able to generate TQ reservoirs in the skin that may be useful to provide sustained release of TQ from the stratum corneum over longer periods of time. The study also demonstrated pull or drag effect of permeation enhancers and vehicle on TQ skin deposition. These studies suggest that ethanol was able to pull more drug into the skin and all the enhancers used in this study showed low “pulling” effect. Rather these enhancers (Azone, oleic acid and Tc) showed enhanced permeation as the enhancers has permeation enhancing effect. Finally, we synthesized and characterized a biocompatible novel topical polymeric film system that has the potential to deliver antibacterial/anti-inflammatory agent thymoquinone (TQ) directly to the skin target site and that may be useful for the treatment and management of wound infections. The polyvinyl pyrrolidone (PVP) matrix-type films containing TQ were prepared by the solvent casting method using dibutyl phthalate as a plasticizer and Azone (laurocapram) as a penetration enhancer. The developed films were evaluated for thickness, drug content uniformity, weight variation, flatness, folding endurance, percentage of moisture content and uptake which were found to 1.17 ± 0.04 mm, 100 ± 6.4 %, 82.04 ± 1.9 mg, 100%, 68 ± 2.38, 14.12 ± 0.42 %, and 2.26 ± 0.47 % respectively. FESEM photograph of the film showed polymer networks inside the film and a homogeneous dispersion of drug inside the polymer networks. In vitro skin permeation studies on human cadaver skin produced a mean flux of 2.3 µg/cm2/h. In vitro scratch assay results revealed that 100 ng of TQ had significant wound closure activity in human dermal fibroblast cells compared to both control (p = 0.0014) and positive control (p = 0.0004). Using human keratinocyte cell line, 100 ng TQ group showed 85% wound closure activity at day six which was significantly higher (p = 0.0001) than the control group. In a zone-of-inhibition (ZOI) assay, the presence of TQ-containing films completely wiped out Staphylococcus aureus in a 10 cm in diameter TSA (Tryptone soya agar) plates while 500 ug/mL gentamicin containing filters gave 10 mm of ZOI. In an ex vivo model, the presence of TQ-film eradicated the bacterial colonization on human cadaver skin. Furthermore, in the BALB/c mice wound model, TQ-films showed significant activity in controlling Staphylococcus aureus infection and promoting wound closure compared to control film. These results indicate, TQ/PVP films developed in this study have potential for the treatment and management of wound infection.

ETD_10682

Ph.D.

Includes bibliographical references

doi:10.7282/t3-hpmw-rc22

ETD doctoral

The author owns the copyright to this work.