Self-Double-emulsifying drug delivery Systems: A novel approach to topical fixed-dose anti-tubercular drug delivery

Abstract

Mycobacteria cause numerous skin infections that are difficult to treat due to intrinsic difficulties of drug permeation into mycobacteria, and their ability to develop resistance to antibiotics. Therefore, the incidence of nontuberculosis mycobacteria (NTM) related dermal infections and cutaneous tuberculosis (CTB) are increasing drastically as a consequence of antimicrobial resistance. This can also be attributed to the inability to carry out vaccinations, proper diagnosis, and treatment of TB during the Corona Virus Disease of 2019 (COVID-19) pandemic. Furthermore, currently no topical dosage form is marketed to locally treat mycobacterial skin infections. Therefore, this work introduces the possibility of exploring self-double emulsifying drug delivery systems (SDEDDSs) as dermal drug delivery vehicles through incorporation of four antitubercular agents, namely clofazimine, isoniazid, pyrazinamide, and rifampicin. Clofazimine is a highly lipophilic drug (log P of 7.66), followed by rifampicin with a log P value of 3.80. Isoniazid and pyrazinamide, on the other hand, are polar compounds with log P values of −0.64 and −1.88, respectively. The differences in lipophilicity of the four drugs present a unique challenge to choose excipients capable of solubilising all of the selected drugs while also exhibiting excipient-excipient compatibility, drug-excipient compatibility, and dermal drug delivery properties such as skin penetration enhancement characteristics and skin tolerability of excipients. Hence, during this study, a ‘Formulation Recommendation System’ (FRS) was developed to enable the optimal selection of excipients during the development of dermal SDEDDSs and self-emulsifying drug delivery systems (SEDDSs) based on the biopharmaceutical classification of drugs intended for incorporation into SEDDSs or SDEDDSs. This represents a novel contribution to the development of dermal spontaneous emulsions. The usefulness of considering auxiliary excipients such as emollients, humectants, preservatives, antioxidants, and cosolvents is discussed. A highperformance liquid chromatographic (HPLC) method was developed to enable the reliable, repeatable, and accurate simultaneous quantification of the selected anti-tubercular drugs. As the highlight of this study, intensive preformulation studies enabled the development of a dermal SDEDDS with the smallest droplet size yet reported in the literature. The droplet size was an average of 92.46 ± 5.52 nm, and the polydispersity index (PDI) value was 0.391 ± 0.05. Furthermore, the transmission electron microscopy (TEM) images revealed that the small droplets contained within the larger droplets of the SDEDDS were smaller than 92.46 nm since droplet size measurement only allowed detection of the larger droplets. Last, the mechanism of selfemulsification was captured at a nanoscale via TEM observation, which confirmed the generation of the first dermal nano-SDEDDS described in the literature. Therefore, use of SDEDDSs represents a novel approach for topical delivery of fixed-dose anti-tubercular drugs.