Investigation of drug partition property in artificial sebum.
ABSTRACT Targeted delivery of a therapeutic agent into the hair and sebaceous follicles greatly depends on the extent of drug partitioning/diffusion in the sebum. The objective of the present research was to develop a method to determine the sebum partition coefficient in order to facilitate the selection of sebum-targeted drug candidates. Partition coefficients of model drugs with different chemical structures and 4-hydroxybenzoate series compounds were measured in artificial sebum/water (K(sebum)) and human stratum corneum/water (K(sc)) at 37 degrees C. The relationship was evaluated between logK(sebum), logK(sc) and clogP. The results of the partition coefficient studies indicate that the K(sebum) of some drugs was significantly higher than the K(sc), whereas some drugs showed lower or similar K(sebum) when compared with K(sc). Overall, a relatively poor correlation was observed between logK(sebum), logK(sc) and clog P. However, a linear relationship exists between logK(sebum) and clog P in the 4-hydroxybenzoate series compounds, indicating that K(sebum) depends on the lipophilicity and chemical structure of the compounds. The results of the present study demonstrate that K(sebum) is different from K(sc) and calculated P and is likely to be a critical parameter reflecting drug delivery into hair and sebaceous follicles.
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ABSTRACT: NB-003 and NB-003 gel formulations are oil-in-water nanoemulsions designed for use in bacterial infections. In vitro susceptibility of Propionibacterium acnes to NB-003 formulations and comparator drugs was evaluated. Both NB-003 formulations were bactericidal against all P. acnes isolates, including those that were erythromycin, clindamycin, and/or tetracycline resistant. In the absence of sebum, the MIC(90)s/minimum bactericidal concentrations (MBC(90)s) for NB-003, NB-003 gel, salicylic acid (SA), and benzoyl peroxide (BPO) were 0.5/2.0, 1.0/2.0, 1,000/2,000, and 50/200 μg/ml, respectively. In the presence of 50% sebum, the MIC(90)s/MBC(90)s of NB003 and BPOs increased to 128/1,024 and 400/1,600 μg/ml, respectively. The MIC(90)s/MBC(90)s of SA were not significantly impacted by the presence of sebum. A reduction in the MBC(90)s for NB-003 and BPO was observed when 2% SA or 0.5% BPO was integrated into the formulation, resulting in MIC(90)s/MBC(90)s of 128/256 μg/ml for NB003 and 214/428 μg/ml for BPO. The addition of EDTA enhanced the in vitro efficacy of 0.5% NB-003 in the presence or absence of 25% sebum. The addition of 5 mM EDTA to each well of the microtiter plate resulted in a >16- and >256-fold decrease in MIC(90) and MBC(90), yielding a more potent MIC(90)/MBC(90) of ≤1/<1 μg/ml. The kinetics of bactericidal activity of NB-003 against P. acnes were compared to those of a commercially available product of BPO. Electron micrographs of P. acnes treated with NB-003 showed complete disruption of bacteria. Assessment of spontaneous resistance of P. acnes revealed no stably resistant mutant strains.Antimicrobial Agents and Chemotherapy 09/2011; 55(9):4211-7. · 4.57 Impact Factor
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ABSTRACT: Synopsis Materials in contact with liquids on the human skin surface may dissolve and permeate into skin. Release and permeation of chemicals in contact with skin is often estimated in vitro using artificial skin liquids, although sebum lipids are generally not included in these models. The purposes of this research were to develop a representative artificial sebum that contains the appropriate types of lipids at levels that match human values and quantitatively characterize the model to understand its utility for in vitro testing. Artificial sebum that consisted of 10 lipids at proportions that closely resembled human sebum was characterized using thin layer chromatography under a variety of storage and use conditions (dry and liquid, 4 degrees C and 32 degrees C, with and without vitamin E) for 28 days. Levels of sebum constituents maintained in solution and dry at 4 degrees C were stable through the duration of the test period. Levels of all sebum lipids maintained dry at 32 degrees C were stable in the presence of vitamin E; however, squalene oxidized rapidly in the absence of vitamin E. Liquids on the human skin surface consist of sebum and sweat with minor amounts of cellular debris and intercellular lipid from the stratum corneum. The relative importance of each component for release of chemicals from materials in contact with skin will depend upon the type of material (metal, organic, etc.). A model artificial sebum was formulated and characterized to aid researchers in understanding potential release of chemicals from materials in contact with skin and subsequent partitioning and absorption.International journal of cosmetic science 05/2010;
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ABSTRACT: Many drugs are presently delivered through the skin from products developed for topical and transdermal applications. Underpinning these technologies are the interactions between the drug, product and skin that define drug penetration, distribution, and elimination in and through the skin. Most work has been focused on modeling transport of drugs through the stratum corneum, the outermost skin layer widely recognized as presenting the rate-determining step for the penetration of most compounds. However, a growing body of literature is dedicated to considering the influence of the rest of the skin on drug penetration and distribution. In this article we review how our understanding of skin physiology and the experimentally observed mechanisms of transdermal drug transport inform the current models of drug penetration and distribution in the skin. Our focus is on models that have been developed to describe particular phenomena observed at particular sites of the skin, reflecting the most recent directions of investigation.Advanced drug delivery reviews 04/2012; · 11.96 Impact Factor