Development of antibiotic microneedle delivery systems for tuberculosis treatment

Abstract

Current therapy of tuberculosis (TB) has several limitations, such as risk of liver injury and intestinal dysbiosis due to frequent oral administration of antibiotics. Transdermal administration could be used to improve antibiotic delivery for treatment of Mycobacterium tuberculosis infection. Therefore, this thesis described a novel approach, using hydrogel-forming microneedle (MN) arrays to transdermally deliver TB drugs, namely rifampicin, isoniazid, pyrazinamide and ethambutol, which have different physicochemical properties. These drugs were individually prepared into three types of drug reservoirs, including lyophilised tablets, directly compressed tablets and poly(ethylene glycol) tablets. In the specific case of RIF, as the most hydrophobic drug compared to the other three, the inclusion complex between RIF and cyclodextrin was developed. Moreover, formulations of each drug reservoir type were optimised to achieve a rapidly dissolving tablet, and further integrated with hydrogel-forming MN arrays for in vitro permeation studies. Three types of hydrogel formulation were manufactured using different type of polymers and crosslinking processes. These MN arrays were then evaluated in terms of swelling ability, morphology and physical properties. Results of solute diffusion studies showed that drug permeation across the swollen hydrogel membrane was affected mostly by physiochemical properties and functional groups of each drug. In the in vitro studies, the amount of permeated drug through the hydrogel-forming MN arrays across the dermatomed neonatal porcine skin was affected by the drug solubility and reservoir design. The development of this transdermal TB drug regimen is still in the early stage, thus a further investigation to evaluate the effectivity, stability, safety, and efficacy prior to the clinical application will be required. For instance, in vivo pharmacokinetic studies must be done to determine the plasma concentration of the drug in the animal model. Besides, to ensure the efficacy of this system, pharmacodynamic studies must be also performed. On this basis, to reach clinical practice and ensure the benefit for TB treatment application, this novel approach should be tested in terms of the usability and acceptability to achieve the maximum impact of this work. Thesis is embargoed until 31 December 2030.