Design and optimization of a child-friendly dispersible tablet containing Isoniazid, Pyrazinamide and Rifampicin for treating Tuberculosis in pediatrics.

Abstract

Objective: Develop a child-friendly Fixed Dose Combination (FDC) water-dispersible tablet for Tuberculosis (TB) treatment, with 50, 150 and 75 mg of isoniazid (INH), pyrazinamide (PZA) and rifampicin (RFP) respectively. This new formulation must contain the lowest possible number of excipients, all accepted for pediatrics, and fulfill all the pharmacopoeia requirements for this type of tablet (friability, disintegration time, fineness of dispersion and content uniformity). Significance: TB is an infectious disease which caused the death of 233,000 children in 2017. At present there is no adequate market dosage form available for children. There is, however, one in a prequalification phase by the World Health Organization but its composition contains some excipients which may not be suitable for pediatrics. Therefore, this new formulation would cover this therapeutic gap. Methods: A factorial design, based on 3 quantitative factors (compression force and concentration of AcDiSol® and Explosol®) at three levels each, was performed to elucidate their influence over disintegration time and friability. In addition, the influence of the press speed on disintegration time, friability, tensile strength, fineness of dispersion and content uniformity over the target tablet was tested. A stability test was done following ICH guideline for accelerated conditions. Results: A water-dispersible tablet was developed according to international recommendations in terms of excipients for pediatrics and meeting Ph. Eur. requirements. In addition, its production has been optimized to be elaborated at maximum eccentric press speed but maintaining quality requirements. Conclusion: A high-quality child-friendly FDC water-dispersible tablet was developed improving the treatment of TB in pediatric.