Modified release dosage from design for pediatric age group using pharmacokinetic models

Abstract

The shift towards personalized medicine in the pharmaceutical industry highlights a significant unmet need for age-appropriate dosage forms for children. Pediatric drug development faces challenges due to limited clinical data, ethical restrictions, and fewer commercial incentives. Traditional methods of scaling adult doses for children can lead to overdoses, necessitating a more mechanistic approach like the Physiology Based Pharmacokinetic (PBPK) model. newlineAim and Objective: The research aimed to develop an extended-release (Modified Release) powder for oral suspension of Paracetamol using a Quality by Design (QbD) approach suitable for pediatric use. Objectives included developing a dosage form, validating analytical methods to characterize the formulation, conducting bioavailability studies in healthy adult volunteers, and developing a PBPK model for the pediatric population. newlineDosage Form development: Pharmaceutical dosage forms are essential for delivering drugs effectively and safely. Extended-release powders for oral suspension are particularly beneficial for pediatric patients due to ease of administration, improved compliance, consistent therapeutic levels, and customizable dosages. These formulations can be mixed with water, making them easier for children to ingest, and allow for less frequent dosing. newlineThe development of an extended-release powder for oral suspension of Acetaminophen 500 mg aimed to create a pediatric formulation using a Quality by Design (QbD) approach. The Target Product Profile (TPP) was defined based on the release profile of TYLENOL® extended-release tablets. The formulation process involved selecting suitable excipients and using the Wurster coater to create free-flowing pellets that provide extended-release. Critical Quality Attributes (CQAs) were identified to ensure safety and efficacy. The analytical methods for assay, dissolution, and related substances were adapted from the USP monograph and validated. newlineProduct was packed using triple laminated bags and low-density polyethylene (LDPE) to ensure product stability. Stability studies were conducted under accelerated and room temperature conditions, analysing for key attributes like description, assay, newlinex newlinedissolution, and water content. The stable product, meeting the defined TPP was established and subjected to bioavailability studies in healthy adult volunteers to predict the in vivo profile. newlineBioavailability Studies: An open-label, randomized, two-way crossover bioavailability study compared the test product (Paracetamol extended-release suspension 500 mg/10 ml) with the reference product (Calpol® suspension 250 mg/5 ml) in healthy adult male subjects under fed conditions. The test product, dosed once every eight hours, showed comparable bioavailability to the reference product dosed twice at four-hour intervals. Safety assessments confirmed that both products were well-tolerated with no significant adverse events. newlinePBPK Modelling: The validated PBPK model used bioavailability data to predict appropriate pediatric dosages. Simulations indicated that a dose of 20 mg/kg is optimal for achieving therapeutic efficacy, with a minimal effective concentration of 10 and#956;g. This approach aims to create a safe, effective, and ethically acceptable modified release dosage form for pediatric use, reducing the need for pediatric clinical trials. newlineConclusions: newline1. Development of a stable, modified-release dosage form for pediatric use, meeting the defined TPP. newline2. Characterization of the dosage form using validated analytical methods, ensuring specificity, precision, accuracy, and robustness. newline3. Bioavailability studies demonstrated that the test product is safe, well-tolerated, and potentially bioequivalent to the reference product. newline4. The validated PBPK model predicted suitable pediatric dosages, confirming that the Extended-Release suspension formulation effectively reduces dosing frequency while maintaining therapeutic efficacy. newline