Formulation toolbox for topically applied drugs to account for physical parameters, dynamic metamorphosis and influence of excipients

局部应用药物的配方工具箱，可考虑物理参数、动态变形和赋形剂的影响

• 批准号: 10812717
• 负责人: James Clarke
• 金额: $ 25万
• 依托单位: CERTARA UK LIMITED
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10812717
• 关键词: Formulation; toolbox; topically; applied; drugs

Project Summary/ Abstract Physiologically-based pharmacokinetic (PBPK) modelling has emerged as a valuable tool in the drug development process for both novel and generic drug products. In particular, simulation tools can be utilised for generic drug products to assess virtual bioequivalence between the reference and test products. Dermal PBPK modelling has been applied to the development of topical formulations by predicting drug absorption into skin in virtual populations that are constructed using realistic physiology data. It is important to recognise that topical products undergo changes immediately upon application due to formulation metamorphosis, which may alter the critical characteristics of the formulations. To accurately simulate drug permeation through the skin, precise parameterisation of the dynamic changes that occur during formulation metamorphosis is crucial. A primary objective of this grant proposal is to improve the formulation parameterisation integrated in the MPML MechDermA model by integrating dynamic formulation compositions and feedback to critical quality attributes using advanced prediction methods. The other primary objective is to systematically verify the model’s predictive capability by assessing its ability to account for variations in drug product attributes and to predict the influence of these variations on the local bioavailability. Specifically, Aim 1 will focus on the enhancement of the formulation toolbox by enabling the input of complete formulation composition data (Q2) and implementing predictive methods to estimate formulation Q3 properties based on known Q2 characterisation. The proposed framework will be used in pursuit of Aim 2, wherein individual volatile constituents will be allowed to evaporate and dynamic re-calculation of formulation Q2 and Q3 metrics implemented. In addition to evaporation, the depletion of excipient through skin absorption will be investigated under Aim 3. Commercial and custom desoximetasone drug products featuring modified formulation attributes will be designed and characterised under Aim 4. These formulations will serve as challenges for the PBPK models, which will be used to verify the models’ ability to differentiate between formulation variations and assess bio(in)equivalence. Aim 5 will focus on the evaluation of skin hydration following formulation application involving the development and validation of a PBPK model of skin hydration and absorption of water from topical drug products. Aim 6 will develop a model for simulating microdialysis and open-flow microperfusion data; this model will be leveraged to simulate available data on local concentrations in vivo and further verify local concentration predictions.

项目总结/摘要 基于生理学的药代动力学（PBPK）建模已成为一种有价值的工具， 新药和仿制药的药物开发过程。特别是，委员会认为， 模拟工具可用于仿制药产品，以评估虚拟生物等效性 参比品和供试品之间的差异。皮肤PBPK建模已应用于 通过预测虚拟皮肤中药物吸收来开发局部制剂 使用真实的生理学数据构建的群体。重要的是要认识到 局部产品在应用后立即发生变化， 变态，这可能会改变制剂的关键特性。准确 模拟药物通过皮肤的渗透，动态变化的精确参数化 是至关重要的。这笔赠款的主要目的是 建议是改进MPML MechDermA中集成的配方参数化 通过整合动态配方成分和关键质量反馈的模型 属性使用先进的预测方法。另一个主要目标是系统地 通过评估模型解释药物变化的能力来验证模型的预测能力 产品属性，并预测这些变化对局部生物利用度的影响。 具体而言，目标1将侧重于通过启用 输入完整的配方组成数据（Q2），并实施预测方法， 基于已知的Q2表征估计制剂Q3性质。拟议 框架将用于追求目标2，其中将单独的挥发性成分 允许蒸发并动态重新计算配方Q2和Q3指标 切实贯彻除蒸发外，赋形剂通过皮肤吸收的消耗将 根据目标3进行调查。商业和定制的去羟米松药物产品 将根据目标4设计和表征具有改良配方属性的产品。 这些制剂将作为PBPK模型的挑战，该模型将用于验证 模型区分配方变化和评估 生物等效性。目标5将侧重于评价配方后的皮肤水合作用 涉及皮肤水合作用的PBPK模型的开发和验证的应用， 从局部药物产品中吸收水分。Aim 6将开发一个模型， 微透析和开放流微灌注数据;该模型将用于模拟 关于体内局部浓度的现有数据，并进一步验证局部浓度预测。