Attenuated total reflectance Fourier transform (ATR-FTIR) spectroscopy and ATR-FTIR spectroscopic imaging was used for the in vitro monitoring of the mechanisms of drug permeation and the effects of penetration enhancers on silicone membrane and human stratum corneum (SC). Simulated spectroscopic imaging data sets were used to validate the scope and application of quantitative iterative target transformation factor analysis (QITTFA) which is a variant of target factor analysis (TFA) in the presence of instrumental noise and collinearity. The results show that QITTFA is robust in the presence of noise levels up to 35 %. The flexibility in the implementation and execution of the QITTFA approaches enabled the analysis of spectroscopic data even with a high degree of collinearity. It was deduced that the use of percentage % negativity values of calculated permeation profiles and R-values between target and predicted spectrum provided a good indication of the quality of target testing. These parameters can be used to estimate the accuracy of the extracted distribution and evolution profiles. Permeation experiments were conducted to monitor the effects of ethanol, octanol, polyethylene glycol 400 (PEG 400) and isopropyl myristate (IPM) on a model compound, 4-cyanophenol (CNP) across silicone membrane and human SC. The application of the developed multivariate analytical strategy to analyse ATR-FTIR spectroscopic data of the SC experiments allowed a semi-quantitative determination of permeation profiles of CNP administered from ethanol, octanol, PEG 400 and IPM across SC as well as solvent membrane interactions. The ability of QITTFA to simultaneously investigate major SC and formulation components was demonstrated. This opens up the possibility to study the effects of solvents on SC lipids and proteins on molecular level in situ. ATR-FTIR spectroscopic imaging experiments of two model formulations; (I) CNP in PEG 600+water and (II) benzyl nicotinate (BN) in a PEG 400+ethanol+water across SC were conducted to acquire further understanding of the heterogeneity of skin and the mechanism of drug permeation. The image analysis demonstrated the ability to simultaneously map distributions of major SC and formulation components. As such these distributions maps can be used to investigate affinities of drug solvent to the lipid rich and lipid poor skin domains during permeation. The results show that ATIR-FTIR spectroscopic imaging permeation experiments together with QITTFA allows the simultaneous in situ monitoring of both spatial and time domain profiles of several components of a highly complex sample in a dynamic and flexible manner. The obtained information will help to probe mechanisms of drug permeation and the influence of penetration enhancers on these mechanisms at a molecular level.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:515138 |
| Date | January 2009 |
| Creators | Mader, Kerstin T. |
| Publisher | University of Greenwich |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://gala.gre.ac.uk/8102/ |
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