Formulation, in vitro release and transdermal diffusion of isoniazide and rifampicin for dermal tuberculosis / Reinette Benade
Extra pulmonary tuberculosis makes up 10% of all tuberculosis cases and cutaneous tuberculosis (CTB) only a fraction of this 10%. CTB is caused by mainly Mycobacterium tuberculosis and can lead to scarring and deformities. The disease presents in different forms, from superficial granulomas to deeper ulceration and necrosis. Tissue cultures, polymerase chain reactions or purified protein derivative staining is used for the diagnosis of CTB (Barbagallo etal., 2002:320). Since the current treatment for CTB is oral anti-tubercular regimens and no topical treatment is available yet (Barbagallo et a!., 2002:320), this study aims to provide a topical preparation of isoniazide and rifampicin which will prevent the deformities and scarring caused by CTB and deliver quicker healing. This topical preparation is to be used in addition to oral treatment. Isoniazide and rifampicin are powerful first-line anti-tubercular drugs, active against both intra- and extracellular bacteria (SAMF, 2005:293). Human skin is a resistant and protective barrier against the external environment and the stratum corneum is the main barrier against diffusion of compounds through the skin (Williams, 2003:9). The physicochemical characteristics (lipophilicity and molecular size) of neither isoniazide nor rifampicin are optimal for penetration of the stratum corneum and the skin-friendly Pheroid™ delivery system was incorporated in two of the formulations to investigate the possibility of improving drug delivery. In this study the transdermal delivery of isoniazide and rifampicin was studied after formulation into four different topical preparations. The stability of these formulations were determined over a six month period under three different conditions of temperature and humidity (25°C/60% RH (relative humidity), 30°C/60% RH and 40°C/75% RH). Isoniazide and rifampicin were formulated into two Pheroid™ and two non-Pheroid™ spray formulations: lotion, Pheroid™ lotion, emulgel and Pheroid™ emulgel. Micrographs were taken with a confocal laser scanning microscope and it was seen that the formulations were homogenous and oil droplets were smaller than 10 urn, allowing permeation through skin. Vertical Franz diffusion cells were used for in vitro permeation studies, with cellulose acetate membranes, for 12 h periods at pH 7.4, to determine drug release. The donor phase was the formulation, with 5 mg/ml of isoniazide and 10 mg/ml of rifampicin. The actives were released from the formulations and small concentrations penetrated the membranes. Release for isoniazide was best from the Pheroid™ emulgel and for rifampicin from the Pheroid™ lotion. Thus it can be concluded that the Pheroid™ improved drug release. The diffusion study was repeated, substituting the membranes with female abdominal skin in order to investigate transdermal delivery. Isoniazide and rifampicin failed to permeate the skin from any of the formulations and no isoniazide or rifampicin could be found in the skin by means of tape stripping after 12 h. Stability tests performed at 4, 8, 12 and 24 weeks was the determination of drug concentrations, pH, weight loss, viscosity, particle size, physical appearance and colour change tests. In these emulsion-type formulations, rifampicin proved to be more stable than isoniazide and after 24 weeks minimal concentrations of isoniazide (20.2 ug/ml) was left. The Pheroid™ formulations were proven to be more stable than the non-Pheroid™ formulations.
- ETD@PUK