Keating, Alison; (2017) Formulation and Assessment of Taste Masked Combination Therapies for the Treatment of Paediatric Tuberculosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Tuberculosis is a major global health problem, which ranks alongside HIV as a leading cause of death worldwide. Adherence to tuberculosis treatment regimens is quite low, particularly in paediatric patients, and the aversive taste of these medicines is often cited as a major reason for this. In the first part of this thesis, the taste of these four drugs was assessed using both a human taste panel and the rodent Brief Access Taste Aversion (BATA) model. Human EC50 (i.e. the concentration of drug which elicits 50% of the maximum taste response) values were determined for each drug and the BATA model was identified as being useful for the assessment of formulations containing isoniazid, rifampicin and ethambutol. The ability of an in vitro technique, the Insent TS-5000Z electronic tongue, to detect and assess the taste of isoniazid, rifampicin, pyrazinamide and ethambutol dihydrochloride was investigated. The best correlation between human responses and electronic tongue responses was observed for ethambutol dihydrochloride. The latter half of this thesis focused on the use of hot melt extrusion (HME) as a processing technique to develop taste masked polymeric formulations of isoniazid and rifampicin and a fixed dose combination containing both isoniazid and rifampicin. A fixed dose combination (FDC) formulation containing 20% w/w isoniazid and 30% w/w rifampicin was produced using Eudragit E-PO as a carrier. The extrudate was milled and incorporated into a dispersible tablet. The weight uniformity, thickness, hardness, disintigration time and content uniformity of the tablets were investigated and found to conform to the specifications for solid dosage forms. The dispersible tablet was found to effectively mask the taste of the drugs when dispersed in water with the drug release remaining below the human EC50 value for each drug.

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