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

Abstract

The severity of tuberculosis (TB) in children is considered a global crisis compounded by the scarcity of pharmaceutical formulations suitable for pediatric use. The purpose of this study was to optimally develop and evaluate a pyrazinamide containing edible orodispersible film formulation potentially suitable for use in pediatrics actively infected with TB. The formulation was prepared employing aqueous-particulate blending and solvent casting methods facilitated by a high performance Box Behnken experimental design template. The optimized orodispersible formulation was mechanically robust, flexible, easy to handle, exhibited rapid disintegration with initial matrix collapse occurring under 60 s (0.58 ± 0.05 min ≡ 34.98 ± 3.00 s) and pyrazinamide release was controlled by anomalous diffusion coupled with matrix disintegration and erosion mechanisms. It was microporous in nature, light weight (57.5 ± 0.5 mg) with an average diameter of 10.5 mm and uniformly distributed pyrazinamide load of 101.13 ± 2.03 %w/w. The formulation was physicochemically stable with no evidence of destructive drug–excipient interactions founded on outcomes of characterization and environmental stability investigations. Preliminary inquiries revealed that the orodispersible formulation was cytobiocompatible, palatable and remained intact under specific storage conditions. Summarily, an edible pyrazinamide containing orodispersible film formulation was optimally designed to potentially improve TB pharmacotherapy in children, particularly the under 5 year olds.

Pediatric Tuberculosis Management: A Global Challenge or Breakthrough?

“…In some instances, physicians prescribe extemporaneously compounded antitubercular formulations for children, and the common challenge often associated with these kinds of orders is that their preparation and concentrations tend to vary from pharmacy to pharmacy and even one hospital to the other ([ 7 , 215 , 216 , 217 ]). These administration methods can potentially result in dosing inaccuracies, unwanted drug–food interactions, reduced drug potency, impaired formulation stability, disruption of formulation coating/external layering, compromised bioavailability, and inconvenience associated with caregiving, which ultimately leads to poor patient compliance, undesired pharmacotherapeutic outcomes and eventual onset of resistance [ 7 , 112 , 218 , 219 , 220 ].…”

“…Other dosage forms that have been explored include double-fixed dose combinations (FDCs) of isoniazid and rifampicin, triple FDCs of isoniazid, rifampicin, and pyrazinamide, as well as FDCs containing all four first-line drugs, i.e., isoniazid, pyrazinamide, rifampicin, and ethambutol. Other quality-assured pharmaceutical dosage forms for the treatment of TB have not yet been successfully explored up to the commercialization phase, particularly the second-line drugs, which are now required by the growing number of children infected with the drug-resistant TB strain worldwide [ 216 , 218 , 221 ]. Scientists are continuously working toward improving pediatric antitubercular formulations, particularly the fixed-dose combinations, by optimizing the dosing parameters in a way that makes the medications effective and suitable for use in children of all age groups [ 118 , 218 , 222 ].…”

“…Liquid antitubercular preparations, on the other hand, are more child friendly and easier to swallow, but are often limited by their poor palatability and lack of dose uniformity, often resulting in the need to use more excipients such as sweeteners, stabilizers, etc. These excipients can improve their chemical, physical, and microbiological stability, but may not be suitable for pediatric application [ 7 , 218 , 222 , 224 ]. To successfully treat TB in pediatric patients, it is important that specially designed, age-appropriate pharmaceutical formulations are available to ensure safe and efficient pharmacotherapy [ 233 , 234 , 235 ].…”

“…It has been reported that less than fifty percent of all the drugs that are currently being prescribed for children infected with TB are not commercially available in forms suitable for pediatric consumption [ 7 , 218 , 230 , 238 ]. This can be attributed to the fact that the market for pediatric dosage forms is relatively small, risky, and less profitable than that for adult pharmaceutical formulations [ 213 , 227 ].…”

“…Further, the development of age-appropriate, anti-TB pharmaceutical formulations for children is challenging because of the differences in their developmental stages and effective taste masking problems, which greatly impacts compliance as well as limitations surrounding safe excipient selection and large-scale manufacturing [ 223 , 226 , 229 ]. The most commonly available branded dosage forms for TB treatment in pediatrics include oral solutions, suspensions, and single and fixed-dose combination solid dosage forms [ 215 , 218 , 230 , 239 ]. In most cases, adequate drug management of TB infection in children can be cumbersome because the treatment is entirely comprised of antimicrobial agents with unpredictable permeability, solubility, absorption and stability, unpleasant taste, plus almost inevitable side effects, especially when developed into different pharmaceutical formulations for patient consumption.…”