Topical delivery of clofazimine from an avocado oil nano-emulsion

Abstract

The skin is the largest organ of the human body (Finch, 2003:29). The outermost layer of the skin, the stratum corneum, offers a protective barrier that prevents foreign substances from penetrating into the body through the skin (Madison, 2003:231). Although the skin acts as a penetration barrier towards substances, it also offers an attractive alternative for the topical administration of drugs and their transdermal delivery. The skin is considered as the preferred route for drug administration, since it avoids the first-pass liver metabolism of drugs and offers an alternative to systemic drug treatments (Gratieri et al., 2013:610; Ruby et al., 2014:1421; Zhang et al., 2015:2713). The skin barrier can be bridged if (1) the topical/transdermal preparation, (2) the active pharmaceutical ingredients (APIs) in the preparation and (3) the skin‟s physiochemical properties correlate. Factors, such as drug polarity and molecular weight have proven to affect the permeation of a drug through the skin (Lipinski et al., 2001:9; Yamashita & Hashida, 2003:1188). Cutaneous tuberculosis (CTB) is a form of extra-pulmonary tuberculosis, which is sometimes caused by resistant forms of bacteria, called the Mycobacterium tuberculosis complex, for which there are currently no topical treatments available (Barbagallo et al., 2002:319; Wirth et al., 2008:2). CTB often leads to unsightly skin lesions, especially on the face, hands and feet, which are often difficult to hide. Clofazimine is classified as a riminophenazine antibiotic and it is a last-line drug that is reserved for the treatment of drug-resistant tuberculosis (Chopra & Brennan, 1996:93; Xu et al., 2012:1104). CTB is currently only systemically treated with treatment regimens similar to those that are used for the treatment of pulmonary tuberculosis (Semaan et al., 2008:476-477). It may consequently be advantageous to develop a topical treatment for CTB, for using concurrently with systemic treatment, in order to try and improve CTB lesions faster. During this study, clofazimine was incorporated into dispersions, called nano-emulsions, aimed at enhancing the topical diffusion of the API. A nano-emulsion is a dispersion consisting of immiscible liquids, typically when one liquid is dispersed within the other in nano-scale droplets, by adding a surfactant or emulsifying agent to the dispersion. A nano-emulsion has droplet sizes ranging from 20 nm to 300 nm or even from 50 nm to 1000 nm (Anton & Vandamme, 2009:142; Sharma et al., 2010:2; Tyagi et al., 2011:1382). The nano-emulsion being prepared in this study was an oil-in-water nano-emulsion, in which natural avocado oil was used as the oil phase. Avocado oil contains linoleic acid that aids as a penetration enhancer, since it is also found naturally in the skin (Bouwstra et al., 2003:7; Hussain et al., 2014:22; Morena et al., 2003:2220). The lipophilic clofazimine was incorporated into the oil phase of the dispersion to aid with its possible topical delivery and skin permeation (Peters et al., 2000:82). The nano-emulsion was incorporated into an emulgel to improve the viscosity of the topical application. A conventional emulsion (emulgel) was prepared for comparison purposes to determine whether the emulgel, containing the nano-emulsion, would show any advantages over the emulgel containing the coarse emulsion, with regards to topical drug delivery and skin permeation. The aim of this study therefore was to determine whether it would be possible to deliver clofazimine topically through a natural oil (avocado oil) nano-emulsion. Three pharmaceutical preparations were formulated for the investigation of their abilities to aid in the topical delivery of the API, i.e. a nano-emulsion and two emulgel preparations (one containing a conventional (coarse) emulsion and the other containing a nano-emulsion). The targeted delivery areas of the API were the stratum corneum-epidermis and the epidermis-dermis, since CTB presents topically. Characterisation of the three pharmaceutical preparations was performed in order to assure that the preparations were optimised to ease the possible topical delivery of clofazimine. A suitable, accurate and reliable high performance liquid chromatography (HPLC) method was developed for evaluating and quantifying the presence and concentration of clofazimine after possible topical application and skin delivery. The membrane release studies confirmed drug release from all three preparations. The nano-emulsion yielded the best drug release, compared to the emulgel formulations, while the emulgel formulation, containing the coarse emulsion, yielded a slightly better API release than the emulgel containing the nano-emulsion. The nano-emulsion was the only pharmaceutical preparation that has yielded a limited degree of topical drug release at low values, as well as minimal, non-quantifiable traces of permeation during the diffusion studies. This could have been as a result of the low solubility of the clofazimine in avocado oil and due to the lipophilic characteristic of the API (Drugbank, 2015; O‟Driscoll & Griffin, 2008:618). Traces of the API were found in the stratum corneum-epidermis, the epidermis-dermis and the receptor phase in very small and non-quantifiable amounts. The topical delivery of clofazimine during this study therefore only occurred to a very small extent and only from the nano-emulsion