(T1030-12-72) Pharmaceutical Formulation and In Vitro Analyses of a Paediatric Fixed-Dose Combination Antimycobacterial Reconstitutable Oral Suspension

Purpose: Tuberculosis (TB) is a contagious disease caused by Mycobacterium tuberculosis (Mtb) and has always been a lasting challenge over the course of human history, because of its severe social implications. About one-quarter of the world’s population are known to be infected with Mtb worldwide. Globally, over 10 million people were reported to have been ill with TB in 2021, of which children aged 15 years and below accounted for 11% of this number. Treatment failure and death in this age group continue to be significantly attributed to the widespread shortages of effective pharmaceutical products that are suitable for use in paediatrics. Moreover, organoleptic properties such as bad taste that can potentially reduce paediatric patient compliance are drawbacks that are often neglected in the design of antitubercular medications.With the shortage of suitable child-friendly anti-TB pharmaceutical formulations, it is common global practice to make use of commercially available adult solid dosage forms (e.g., tablets), which may pose the risk of choking especially for infants and young children. Consequently, clinical practices globally usually administer these unsuitable preparations by dividing them into segments, crushing and mixing with food, milk, water, or other liquids or in some cases compounding them extemporaneously in pharmacies for easy use in pediatric patients. These behaviors may lead to dosage errors, active medication instability, decreased bioavailability, patient noncompliance, and drug resistance. As such, there still exist the need for emerging novel pharmaceutical technologies founded on the World Health Organization’s current body weight dosing guidelines that can tackle TB management in children, thus contributing towards the global goal of reaching “zero deaths” in pediatrics. This work therefore aims to design and evaluate a paediatric fixed-dose combination (FDC) reconstitutable oral suspension containing key antitubercular agents namely pyrazinamide (PZA) and rifampicin (RIF).

Methods: A 150 mg RIF/300 mg INH per 5 ml fixed-dose oral suspension formulation was prepared employing a combination of a solid-liquid direct dispersion, dehydration, and mechanical pulverization techniques. Formulation drug-loading capacity and release behavior were determined in pH 7.4 phosphate buffer utilizing UV/VIS spectrophotometric analyses at a λ_max of 274 nm and 334 nm for PZA and RIF respectively. The FDC formulation was characterized using scanning electron microscopy, thermogravimetry, porosimetery, differential scanning calorimetery, X-ray diffraction, Fourier transform infrared spectroscopy and rheology. The organoleptic quality of the FDC preparation was examined by a 5-member volunteer panel using a 4-point for general appearance and color, as well as a 5-point scale for taste and smell (flavour). Cytobiocompatibility was assessed in vitro by performing the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide (MTT) assay on CaCo2 cells and environmental stability investigated under robust storage conditions according to the International Conference on Harmonization (ICH) guidelines.

Results: The FDC formulation was a reddish free-flowing powder. A drug content of 97.23 ± 2.57%w/w and 97.61 ± 0.02%w/w were accomplished for PZA and RIF respectively indicating that uniform encapsulation and distribution occurred. It was semi-crystalline with an average BET total surface area of 0.43 ± 0.02 m²/g and average particle size distribution of 329.79 µm. Both PZ A and RIF release followed a zero-order kinetics with 99.00% ± 0.05 RIF and 102.00% ± 0.05 PZA released over 12 hours. The formulation was physicochemically stable with no evidence of any destructive drug-excipient interactions based on outcomes of the characterization experiments performed. Upon reconstitution, the FDC suspension demonstrated a non-Newtonian behaviour. Findings from organoleptic evaluations generated an overall rating of 4.00 ± 0.00 (out of 4) for its attractive appearance and colour and 5.00 ± 0.00 (out of 5) confirming its excellent taste and extremely pleasant smell. Preliminary inquiries revealed that the FDC formulation was cytobiocompatible and environmentally stable either as a dry powder or reconstituted suspension.

Conclusion: A tasty, attractive, biocompatible, and stable antimycobacterial fixed-dose combination reconstitutable oral suspension, for tuberculosis management in children of all age brackets, was successfully developed.

References: Acharya et al., 2020. Advances in diagnosis of Tuberculosis: an update into molecular diagnosis of Mycobacterium tuberculosis. Mol. Biol. Rep., 47(5), pp.4065-4075.
Tsiligiannis et al., 2019. Optimization of a paediatric fixed dose combination mini-tablet and dosing regimen for the first line treatment of tuberculosis. European Journal of Pharmaceutical Sciences. 138, p.105016.
World Health Organization, 2019. Report of the high-level consultation on accelerating the development of the M72/AS01E tuberculosis vaccine candidate. Geneva (Accessed: 13 July 2022).

Acknowledgments: This work was funded by the South African National Research Foundation (Grant Number: 113143) and Sefako Makgatho Health Sciences University-DHET Research Development Grant (Grant Number: D112-RDG).