An analytical investigation of the physiochemical properties of crushed rifapentine administered to paediatricsby
Date
2024-12
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Stellenbosch : Stellenbosch University
Abstract
Introduction: Tuberculosis (TB) remains a leading cause of mortality, particularly in paediatric populations where it accounts for a significant proportion of global TB burden. Rifapentine (RPT), a key antibiotic in TB treatment, poses challenges in paediatric care due to the lack of child-friendly formulations. Children under five years are often unable to swallow whole tablets, leading caregivers to resort to off-label practices like crushing tablets, which can significantly reduce the drug's bioavailability and therapeutic efficacy. This study aimed to investigate the physiochemical properties of crushed and dispersible RPT formulations and to explore potential interventions that could improve drug delivery and bioavailability in paediatric patients.
Methods: A high-performance liquid chromatography (HPLC) method was developed and validated for the quantification of RPT. Three RPT formulations (Rifapentine 150 mg, Rifapentine 150 mg/Isoniazid 150 mg and Rifapentine 300 mg/Isoniazid 300 mg) were crushed and used to determine the aqueous solubility and stability in simulated gastric and intestinal fluid, with and without mechanical and chemical interventions. An extraction method was developed for RPT and used to evaluate its recovery in food and beverage products. The adsorption of crushed drug to a glass beaker and syringe walls was also analysed. The concentration and stability of a partial dose of a dispersible RPT tablet was assessed.
Results and Discussion: The HPLC method developed for RPT quantification demonstrated robustness and accuracy across a calibration range of 0.156–10.0 μg/mL, with inter- and intra-day validations confirming precision within acceptable limits. Mechanical interventions and additives (cyclodextrin, NADES, ascorbic acid) improved RPT solubility, with effectiveness varying among formulations. Recovery of crushed RPT tablets from food and beverages was lower than the reference standard, with yogurt yielding the best results. Adsorption studies revealed that glass beakers minimized drug loss compared to syringes, and double rinsing further reduced drug lost due to adsorption. Stability in simulated gastrointestinal fluids varied among formulations, with ascorbic acid showing formulation-specific benefits. The new dispersible tablet formulation demonstrated challenges in achieving consistent dosing, with preparation method significantly influencing final concentrations.
Conclusion: This study underscores the critical need for paediatric-specific RPT formulations that ensure adequate drug stability, solubility, and bioavailability. Crushing adult RPT tablets for paediatric use compromises drug efficacy, potentially leading to treatment failure and drug resistance. When crushing RPT tablets is necessary, using a glass beaker rather than a syringe for preparation and administration in liquid vehicles minimizes drug loss. Clinicians should advise caregivers to co-administer the crushed drug with high-fat foods to enhance absorption. Evaluation of the new investigational RPT dispersible tablet revealed challenges in achieving consistent and accurate dosing. The preparation method significantly influenced the final concentration, with dissolution in a glass beaker followed by a 5-minute equilibration period providing the most reliable results in the presence of INH. Future studies should evaluate syrups containing cyclodextrin, NADES, or similar carrier liquids which improve the solubility of the crushed RPT. This also provides an opportunity for flavour masking to make the formulation more tolerable to children.
Description
Thesis (MA)--Stellenbosch University, 2024.