Comparison of artificial sebum with human and hamster sebum samples

https://doi.org/10.1016/j.ijpharm.2008.09.025Get rights and content

Abstract

To understand drug delivery to the sebum filled hair and sebaceous follicles, it is essential to use an artificial sebum as a surrogate of the human sebum for the investigation of drug transport properties. Artificial sebum L was developed in-house based on the chemical similarity to human sebum. The partition and diffusion of model compounds (ethyl 4-hydroxybenzoate, butyl 4-hydroxybenzoate, and hexyl 4-hydroxybenzoate) were measured in human sebum, hamster ear and body sebum (a commonly used animal model), and four representative artificial sebum samples (N, S, F, and L) in which artificial sebums, N, S and F were selected based on the available literature. DSC and NMR studies were also conducted on all sebums to compare their melting properties and chemical compositions. In vitro studies show that the partition coefficients of the three model compounds in artificial sebum L were similar to that of human sebum, whereas the hamster ear and body sebum, and other three artificial sebum samples were different from that of human sebum. Additionally, the in vitro sebum flux (μg/(cm2 min) of three model compounds through artificial sebum L was closer to that of human sebum when compared with the other three artificial sebum (N, S and F), hamster body and hamster ear sebum. The results of this study indicate that the artificial sebum L could be used as an alternative to human sebum, as the physicochemical properties of this artificial sebum is relatively similar to human sebum.

Introduction

Traditionally, the transepidermal route has been recognized as the primary pathway for topically applied therapeutic agents, despite the fact that the stratum corneum functions more as a rate-limiting barrier and less as a pathway for the absorption of topically applied compounds (Lauer et al., 1995, Williams and Elias, 1987, Scheuplein, 1967). However, transfollicular delivery of topically applied agents has been increasingly recognized as an efficient approach to enhance regional efficacy and reduce systemic exposure (Bertolino et al., 1993, Grams et al., 2004, Lademann et al., 2001). While it is estimated that hair and sebaceous follicles cover only about 0.1% of the total skin area of the body, this fraction rises to as much as 10% in the scalp and facial regions, making transfollicular delivery into and/or through these regions very significant (Schaefer and Redelmeier, 1996). Further, the barrier function through the follicular surface is substantially lower due to the lack of multiple-layer, tightly integrated corneocytes (as found in the stratum corneum). Transfollicular delivery of topical agents is possible as long as the drug permeation into follicles is faster than the outflow of sebum from sebaceous glands to the skin surface (Agarwal et al., 2000).

Since the upper sections of hair and sebaceous follicles are filled with sebum, the efficiency of follicular drug delivery substantially depends on the partition/diffusion of the drug molecules in the sebum. Partition/diffusion properties of drug molecules in human sebum have not been investigated due to limitations in collecting sebum samples from human subjects. Hence, it is desirable to develop an appropriate artificial sebum as an alternative to human sebum for the investigation of follicular drug delivery. There are about 18 artificial sebum recipes reported in the literature (Stefaniak and Harvey, 2006) and the composition of the reported artificial sebum samples varied significantly. The partition and diffusion properties of topical molecules in these artificial sebum and human sebum samples have not been investigated. Having compared the chemical compositions of these artificial sebum samples with human sebum, we formulated an artificial sebum (L) which has closer chemical composition and so physicochemical properties to human sebum, and determined the melting points, NMR profiles and the partition/diffusion properties of several model compounds to ensure the usefulness of the newly developed artificial sebum. Artificial sebum L has been used as a tool for screening potential sebum-targeted drug molecules (Valiveti et al., 2008, Valiveti and Lu, 2007). Since hamster ear models have been commonly accepted as an animal model for follicular drug delivery (Meidan et al., 2005), we also compared hamster sebum samples with human sebum and the artificial sebums to bridge various models.

Section snippets

Materials

Ethyl 4-hydroxy benzoate and butyl 4-hydroxybenzoate from Lancaster synthesis, Inc. (Pelham, NH). Hexyl 4-hydroxybenzoate was obtained from TCI America (Portland, OR). Paraffin wax (melting point, 58–62 °C), and oleic acid were obtained from Aldrich Chemical Company, Inc. (Milwaukee, WI). Cottonseed oil, palmitoleic acid, squalene, palmitic acid myristyl ester, palmitic acid palmitic ester, oleic acid palmitic ester, stearic acid, oleic acid, and myristic acid were obtained from M.P. Biomedical,

Results and discussion

Human sebum constantly secretes from sebaceous glands onto the skin surface, especially on the facial and scalp skin areas. Therefore, sebum acts as the first layer of transport medium to a topically applied cosmetic or pharmaceutical compound. Due to its high lipophilicity, sebum functions as a permeation barrier to hydrophilic compounds while serving as a good solvent for lipophilic compounds. The interaction of sebum with topical formulation significantly affects both the barrier function of

Conclusions

An artificial sebum (L) was designed based on the chemical compositions and thermal property of human sebum as well as the commercially availability of excipients. Artificial sebum L has similar DSC and NMR profiles to human sebum and provides an excellent alternative artificial sebum for drug partition and diffusion studies. Hamster sebum, either from the ear or the body, appears to be different from human sebum. The hamster body sebum is not recommended as a model for drug transport study

Acknowledgment

The authors would like to acknowledge James Wesley, Susan Ciotti, Howard Ando, Robert Conradi, and Tycho Heimbach.

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