Age-appropriate flexible pediatric drug delivery systems

摘要/总结 儿科药物需要剂量灵活性以获得所需的治疗浓度。大多数药物都是生产的 用于成人的胶囊和片剂，通常不适合儿童。药物缺乏或供应有限 对于儿科人群来说，这主要是由于儿童生理学的不断发展，固定剂型不起作用。 临时配方是儿科患者调整药物剂量的常用方法。然而，担忧 已提出此类制剂缺乏剂量准确性、稳定性、生物利用度和一致性 医疗保健专业人员和 FDA。可以解决临时制剂的质量、安全性和有效性问题 通过初步数据支持的选择性激光烧结 (SLS) 3D 打印方法打印药物。 SLS 该方法非常适合在临床医院环境中打印精确的剂型，并且具有剂量灵活性、多种 药物掺入能力、打印时间短、材料需求最少、功耗低、占地面积小 设备。由于打印是通过分层机制进行的，因此可以通过打印层数轻松调整剂量。 该提案的目的是证明打印剂量灵活的儿科给药系统（printlet）的可行性 使用选择性激光烧结（SLS）。富马酸替诺福韦二吡呋酯和拉米夫定将用作模型药物，因为两者 药物通常单独或联合用于儿科患者。然而，只有单一强度的组合产品 （两种药物）均可市售。将这些药物作为适合年龄的灵活儿科给药系统 将减少过量和剂量不足的情况，这是针对儿科人群的临时准备的情况。 这将转化为较低的不良事件发生率并降低产生艾滋病毒耐药性的可能性 药物剂量不足时。此外，剂量灵活的儿科给药系统应符合 FDA 的质量标准， 除有效外，在保质期和使用期内应稳定。交付系统将按照 FDA 和 USP 推荐进行测试以确保质量。儿科分娩系统将接受长期、加速和 使用中的稳定性条件。安全性和有效性将通过比较药代动力学和 剂量灵活的儿科给药系统和商业片剂配方之间的药效学研究。的PI 该提案促使 FDA 的科学家和评审团队批准了第一个也是唯一一个 3D 打印药品 （斯普利坦®）。该提案的具体目标如下： 目标 I：证明打印联合药物（替诺福韦）儿科给药系统（printlet）的可行性 通过短时间（<2 小时）选择性激光烧结（富马酸二吡呋酯和拉米夫定），表征质量 并评估稳定性以满足美国药典 (USP) 和食品药品监督管理局 (FDA) 的要求 身份、品质、纯度和强度的要求。 目标 II：通过药代动力学和方法证明灵活的儿科给药系统（printlet）的安全性和有效性 药效学研究。

ABSTRACT/SUMMARY Pediatric medications require dose flexibility to obtain desired therapeutic concentration. Most medications are produced for adults as capsules and tablets, which are often not suitable for children. The lack of or limited availability of medications for the pediatrics population is primarily due to the evolving physiology of children where fixed dosage forms do not work. Extemporaneous formulations are a common way to adjust the dose of the drug for pediatrics patient. However, concerns have been raised regarding lack of dose accuracy, stability, bioavailability and consistency for such formulations by healthcare professionals and FDA. Quality, safety and efficacy concerns of extemporaneous preparations can be addressed by printing medications by selective laser sintering (SLS) 3D printing method as supported by preliminary data. The SLS method is ideally suited to print precision dosage forms in a clinical hospital environment, and has dose-flexibility, multiple drug incorporation capability, short-time to print, minimal material requirement, low-power needs, and small footprint of the equipment. Doses can easily be adjusted by number of printed layer since printing is performed by layering mechnaism. The objective of the proposal is to demonstrate the feasibility of printing dose-flexible pediatric delivery system (printlets) using selective laser sintering (SLS). Tenofovir disoproxil fumarate and lamivudine will be used as model drugs, as both drugs are commonly used alone or in combination in pediatric patients. However, only a single strength combination product (of both drugs) is commercially available. Administering these drugs as age appropriate flexible pediatric delivery systems will reduce overdose and underdose, which is the case with extemporaneous preparation intended for pediatric population. This would be translated into lower incidence of adverse events and reduce probability of development of HIV resistance to medications when underdose. Furthermore, dose-flexible pediatric delivery systems should meet quality criteria of FDA, and should be stable during shelf-life and usage periods besides being effective. The delivery systems will be tested as per FDA and USP recommended tests to ensure quality. Pediatric delivery systems will be tested for long-term, accelerated and in-use stability conditions. Safety and efficacy will be demonstrated by comparative pharmacokinetics and pharmacodynamics studies between dose flexible pediatric delivery system and commercial tablets formulation. The PI of the proposal led the FDA team of scientists and reviewers to the approval of the first and only 3D printed drug product (Spritam®). Following are the specific aims of the proposal: Aim I: To demonstrate the feasibility of printing pediatric delivery systems (printlets) of combination drugs (tenofovir disoproxil fumarate and lamivudine) by selective laser sintering in short timeframes (<2 hours), characterize the quality and assess stability that will meet United States Pharmacopeia (USP) and Food and Drug Administration (FDA) requirements of identity, quality, purity, and strength. Aim II: To demonstrate the safety and efficacy of flexible pediatric delivery systems (printlets) by pharmacokinetics and pharmacodynamics studies.