Samaras, Eleftherios G. (2012) Effect of formulation factors on the skin penetration of drugs. MPhil thesis, Universities of Kent and Greenwich.

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Abstract

Permeation of chemicals through skin can lead to systemic effects of drugs or toxic exogenous chemicals. Skin permeation of compounds and the effect of mixture ingredients can be related to their chemical structures as expressed by molecular properties. This approach, known as Quantitative Structure-Activity Relationship (QSAR) analysis, is used to estimate the skin absorption of compounds from different mixtures and may aid the understanding of the mechanisms involved.

In this investigation, using datasets of skin absorption of a model penetrant formulated in different solvents and a model penetrant formulated in mixtures containing various penetration enhancers, models were developed that could unravel the connection between structural features of such mixture ingredients and the skin permeation of the permeants. This work was further developed by investigating the combined effect of solvents and the permeant molecules in complex mixtures in order to identify the (permeant-mixture ingredient) interaction parameters as well. In order to obtain more applicable models, compounds were suggested for experimental measurements of skin permeation from the solvent mixtures through the comparison of the applicability domain of the available dataset with a commonly used skin absorption dataset (in water). With the addition of new data, the resulting QSAR models were able to estimate skin absorption of permeants from a complex mixture of solvents with a satisfactory level of accuracy.

QSAR models are needed to predict the effect of the varying experimental conditions along with the effects of formulation components and the permeant molecular properties. For this purpose, the skin permeation database, EDETOX was updated with more recent data from 2001 to 2010 and a large dataset was constructed. This made it possible to investigate the effect of experimental conditions such as Occlusion, Hydration, Infinite/Finite dosing and Donor concentration at a large scale for the first time. In conclusion, the project resulted in well validated universal QSAR models for the prediction of skin absorption of compounds. The most notable predictor variables were donor concentration, wetting level of skin (affected by occlusion, donor volume and pre-hydration), the gap between melting and boiling points of the vehicle, molecular size and lipophilicity and electronic descriptors of the permeants.

Item Type:	Thesis (MPhil)
Uncontrolled Keywords:	quantitative structure-activity relationship, QSAR analysis, skin permeation, compounds
Subjects:	Q Science > QD Chemistry
Faculty / School / Research Centre / Research Group:	Faculty of Engineering & Science > Medway School of Pharmacy Faculty of Engineering & Science > School of Science (SCI)
Last Modified:	17 Oct 2016 09:12
URI:	http://gala.gre.ac.uk/id/eprint/11102

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