(M1030-01-06) Development of a Child-Friendly Antibiotic Packed Multiparticulate Oral Sprinkle Formulation for Tuberculosis Pharmacotherapy

Purpose: Tuberculosis (TB) is one of the key causes of morbidity and mortality in children worldwide, with over a million diagnosed with active disease and approximately two-hundred and thirty thousand avoidable deaths annually. Recently, the Global Alliance for TB Drug Development in conjunction with the World Health Organization and Macleods Pharmaceuticals established a child-friendly dispersible tablet to treat drug-susceptible TB in children. This is so far one of the most significant ground-breaking scientific developments made to attain appropriate therapeutic levels and improve the quality of lives of children living with active TB infection, as most research and development efforts are majorly focused on the management of adult patients. Despite these disturbing statistics and recent invention, there still exists a shortage of paediatric antitubercular dosage forms and the need for improved drug delivery technologies. Most employed universal treatment schemes still utilize adult fixed-dose combination preparations which are often split into halves, thirds or even administered as crushed tablets. Multiparticulate drug delivery systems are mainly preparations that are made up of an assortment of small discrete units with each exhibiting desired physicochemical characteristics. They have found good use in paediatric patients because of their flexibility. This study therefore seeks to develop a palatable multiparticulate formulation containing pyrazinamide, a first line antitubercular agent, as a model drug. This will be prepared in the form of a powder sprinkle dosage form, which can be administered with soft foods (e.g., yoghurt, porridge) in paediatric patients infected with TB.

Methods: An optimized 300 mg/5 g pyrazinamide-loaded sprinkle formulation was prepared using combined wet and dry milling techniques coupled with temperature-controlled drying employing various quantities of bulking agent, sweetener, flavor, stabilizer, and cellulose based matrix formers as excipients. A Taguchi experimental design was used to aid formulation development and optimization. The optimized formulation structural backbone, porosity, surface area and geometry, thermal behavior, crystallinity were evaluated with Fourier transformed infrared spectrometry (FTIR), Brunauer-Emmett-Teller (BET) analysis, scanning electron microscopy, thermogravimetry and differential scanning calorimetry respectively. Measurement of in vitro pyrazinamide content occurred in pH 7.4 buffer using ultraviolet spectrophotometry. The in vitro drug release behavior was evaluated under biorelevant conditions (pH 7.4) using a shaking water bath set at 37 ± 0.5°C and 100 rpm. Furthermore, in vitro cytotoxicity assays were performed to determine potential biocompatibility of the pyrazinamide-loaded sprinkles using hepatocyte cell line (HepG2) as a model. The cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) at different medium concentrations ranging from 0.0005 – 50 mg/ml over 24 hours. A panel of five volunteers carried out the organoleptic studies and rated the sprinkles’ appearance, taste, colour, consistency after mixing with a soft food (porridge) and acceptability. Short-term formulation stability was monitored under varying environmental conditions over three months.

Results: The optimized pyrazinamide packed multiparticulate sprinkle formulation was whitish in colour, with close to a 100% yield and drug content of 92.66 ± 12.60%. The in vitro release studies showed that drug liberation began at 5 minutes with 24.40 ± 6.59% released after formulation came into contact with the dissolution medium. Thereafter, the amount of drug released continued to increase and maintained a profile until 180 minutes when complete matrix dissolution occurred and maximum drug release 101.83 ± 2.02% was reached. The pyrazinamide containing sprinkles had cell viability values higher than 70% (77.00 ± 3.40%) for all concentrations except for the highest (50mg/ml) which proved that the formulation is safe to use and non-toxic. The panel of volunteers rated the sprinkles as satisfactory. Over the three-month period of environmental stability studies, the sprinkles’ retained their shape, colour, and showed minimal variation in stability indicators compared to values recorded at the starting point. All the physicochemical tests showed that the multiparticulate formulation was stable and drug-excipient interaction were non-existent, which was an indication of intrinsic compatibility.

Conclusion: It can be inferred that a physicochemically stable, edible, and taste-satisfactory TB antibiotic loaded multiparticulate oral sprinkle formulation potentially suitable for flexible paediatric dosing was successfully developed.

References: 1. Suárez-González, J. et al., Drug Dev Ind Pharm. 2020, 46(2):309-317.
2. Pérez R.P. et al., Anales de Pediatria (Barcelona, Spain:2003), 2016, 85(6):323.
3. Martinez, L. et al., The Lancet, 2020, 395(10228):973-984.
4. Reuter et al., Paediatr Respir Rev, 2020, March 5.
5. Martínez-Terán, et al., Pediatr Ther, 2017, 7(314):2161-0665.

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).