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.

Stability Study of Isoniazid and Rifampicin Oral Solutions Using Hydroxypropyl-Β-Cyclodextrin to Treat Tuberculosis in Paediatrics

“…All samples and solvents were filtered with 0.2 µm pore-size filters (Millipore, Billerica, MA, USA) and degassed. The method has been validated in a previous work [19] and is a simple stability-indicating method, which allowed us to detect and quantify the first-line drugs used in TB treatment as pure patterns and after its extraction from formulations, accurately and precisely. Figure 1 shows the control charts for the methods where the areas of the peaks stay between the established limits every time.…”

Development and Evaluation of a Reconstitutable Dry Suspension Containing Isoniazid for Flexible Pediatric Dosing

“…Tuberculosis (TB) remains a major global health problem present in every country in the world, regardless of the availability of standard treatment guidelines [1,2]. It is the leading cause of death from a single infectious agent, ranking above the Human Immunodeficiency Virus (HIV) with about 10 million new active infections and 1.5-2 million fatalities annually [1,[3][4][5]. TB is an airborne, highly contagious disease often spread by coughing and sneezing.…”

“…Pharmaceutics 2020, 12, 286 2 of 15 childhood deaths each year [1,3,6]. The TB mortality rate is 70% higher in children under the age of five than it is in adults in high burden areas [1,8].…”

Optimal Design, Characterization and Preliminary Safety Evaluation of an Edible Orodispersible Formulation for Pediatric Tuberculosis Pharmacotherapy

“…To date, commonly used pharmaceutical formulations are either liquid dosage forms (e.g., solutions, suspensions), fixed dose dispersible tablets and in most instances, adult tablets are often broken, crushed or mixed with food or water (co-administration) to make pediatric management possible [12][13][14][15]. Despite the availability of a few commercialized pediatric preparations, considerable global scarcity still exists, meaning that many children are unable to access these medicines [15][16][17][18][19]. Moreover, studies have shown that co-administration (with food, water etc.)…”

“…Dispersible tablets on the other end are deemed more child-friendly but still limited in that they are difficult to administer while in transit or when there is reduced/no access to potable water-like in most underdeveloped and developing countries where TB is endemic. They usually contain additives that are either not safe for use in children or hygroscopic in nature, making them prone to atmospheric moisture/water absorption that can lead to active drug instability, eventual inactivity and possible pharmacotherapeutic inefficacy [17,19,23]. Other potentially applicable delivery systems for children include chewable tablets, which are often more suitable for older children (>3 years) with teeth, and sprinkles, though they are more acceptable for older children that can eat solid food [23,24].…”