High Throughput Approaches to Assess Formulation Effects on Topical Drug Delivery / Karadzovska, Daniela
- Bib ID:
- 7124149
- Format:
- Book and Microform
- Author:
- Karadzovska, Daniela, author
- Description:
-
- Ann Arbor : ProQuest Dissertations & Theses, 2013
- 182 p.
- ISBN:
- 9781303547423
- Summary:
-
Conventional in vitro and in vivo techniques used in the assessment of the rate and extent of topical drug absorption are neither high throughput nor economical. Further complications arise due to the ethical concerns associated with the use of experimental animals or human volunteers. Coupling all this with the vast variation in drug-vehicle combinations possible and available for testing, the task of evaluating all combinations is virtually impossible. Therefore, three specific approaches were evaluated as high throughput solutions; an in silico approach (quantitative structure-permeability relationship (QSPeR) model) and two novel in vitro techniques (membrane coated fiber (MCF) array and skin-parallel artificial membrane permeability assay (PAMPA)). The performance of each method was compared to a comprehensive data set generated as part of this project using the traditional in vitro testing technique of diffusion cells.
Here, issues inherent to the fiber membrane for studying non-volatile compounds were observed, resulting in poor linearity and reproducibility of the extracted compounds. Furthermore, incompatibility between the MCF and vehicle was observed, disputing its potential use as a formulation screening technique. In the skin-PAMPA experiment, three artificial membranes (isopropyl myristate/silicone oil, certramides and Strat-M(TM)) were evaluated for their ability to predict skin permeability. Correlations between membrane and diffusion cell absorption data were observed. A correlation between membrane retention and the amount remaining in skin was also noted. For each membrane, QSPeR models identified different physicochemical factors influencing the absorption process. Whilst issues inherent to the fiber eliminated it as a potential high throughput solution, the QSPeR models and skin-PAMPA showed more promise for use in drug delivery and toxicology research.
The generation of a data set was deemed necessary following a literature review which identified numerous diffusion cell protocols employed. Such variation complicates the direct comparison and interpretation of data. Therefore a full factorial study was conducted to evaluate the effect of several commonly used experimental variables including dose volume (finite and infinite), saturation level (saturated and unsaturated), the presence or absence of albumin in the receptor fluid, and diffusion cell type (flow-through and static); on the absorption of six model compounds across porcine skin. The six compounds were selected for their differing physicochemical properties, and were applied in one of three vehicles.
The QSPeR models demonstrated the importance of including experimental variables when assessing percutaneous absorption hence making it possible to predict absorption from data collected under different experimental conditions. The skin-PAMPA showed potential use as an initial screen of formulations, assisting in narrowing the selection for evaluation by a more biologically intact model, and thereby assisting in the development of new topical formulations.
Using this data set, QSPeR models that incorporated the effects of the compound, vehicle and experimental conditions were developed and statistically validated. A composite parameter termed a mixture factor was also included to account for the physicochemical properties of the compound-vehicle mixture components. The resultant models effectively described skin flux and absorption. The MCF array technique employed three commercially available fiber coatings (polydimethylsiloxane, polyacrylate and carbowax) representative of molecular interactions relevant to the skin absorption of volatile compounds, with the addition of a re-extraction step to obtain analytes appropriate for liquid chromatography.
- Notes:
-
- Advisors: Jim Riviere.
- Source: Dissertation Abstracts International, Volume: 75-03(E), Section: B.
- English
- Subject:
- Pharmacology
- Other authors/contributors:
- North Carolina State University, degree granting institution
- Copyright:
-
In Copyright
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Copyright status was determined using the following information:
- Material type:
- Literary Dramatic Musical
- Published status:
- Published
- Publication date:
- 2013
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