Development of a topical self-emulsifying drug delivery system for optimised delivery

Abstract

In order to achieve successful receptor binding affinity at complex pharmacological targets the majority of drugs are of a lipophilic nature. However, optimisation of drug delivery systems for lipophilic drugs presents challenges. Self-emulsifying drug delivery systems (SEDDSs) can provide potential solutions to development problems of lipid-based drug delivery systems. Research reported successful development of SEDDSs designed for oral-, vaginal-, ocular-, rectal- and nasal administration. In contrast, SEDDSs intended for optimised for topical drug delivery has received limited attention. Clofazimine (log P of 7.66) has been incorporated into multidrug-resistant tuberculosis (MDR-TB) regimens in an attempt to decrease treatment times and enhance activity against resistant bacteria. However, clofazimine poses oral drug delivery challenges as well as adverse effects including gastric accumulation. SEDDSs indicated for topical application can bypass liver metabolism together with gastric accumulation. Nonetheless, the lipophilic outermost skin layer remains a formidable barrier, especially to a drug as lipophilic as clofazimine. Therefore, SEDDSs were chosen as a vehicle since skin penetration enhancers can be included in the form of natural oils, utilised to solubilise clofazimine while establishing stratum corneum (SC) lipid disruption to enhance topical delivery. Furthermore, development of a topical SEDDS can provide alternative treatment in terms of extra-pulmonary tuberculosis (EPTB) infections, specifically cutaneous tuberculosis (CTB). This incidence of this otherwise rare EPTB manifestation has increased in recent time due to MDR-TB strains coupled with enhanced tuberculosis (TB) incidence in immunocompromised patients. Currently similar oral anti-tubercular regimens are employed to treat both pulmonary TB and CTB. However, topical SEDDS may have a beneficial outcome in terms of localised effect which will thereby minimise drug interactions if patients are also receiving pulmonary TB treatment. An approach of quality-by-design and characterisation was followed during development of SEDDS formulations intended for optimised topical delivery of clofazimine. Solubility of clofazimine was determined in water, argan-, avocado-, coconut-, macadamia- and olive oil. Next, water titration experiments were conducted for the purpose of identifying the spontaneous emulsification capacity of different excipients. After establishing self-emulsification regions, check-point formulations were selected within the self-emulsification area itself where favourable drug delivery system properties, in terms of topical application, could be predicted. Hereafter, check-point formulations, that did not depict phase separation at an ambient temperature after a period of 24 h, were submitted to characterisation experiments. Subsequently, characterisation profiles identified SEDDSs with favourable topical drug delivery properties. Dermal diffusion studies involving in vitro topical delivery of clofazimine were successful. Remarkably, olive oil SEDDS achieved the highest topical clofazimine delivery. This may have been facilitated by increased oleic acid content of olive oil, as oleic acid is known to enhance SC lipid disruption and thereby enhance dermal delivery of drugs. Isothermal microcalometric experiments were conducted in order to confirm compatibility of the SEDDS excipients. Potential interactions were observed between argan oil and clofazimine in addition to the combinations of Span®60 and argan-, macadamia- and olive oil, respectively. Nonetheless, the aim of this study was successfully met through the development of selected topical SEDDS that achieved optimised topical clofazimine delivery.