Dose Flexible Combination 3D-Printed Delivery Systems for Antiviral Therapy in Children

用于儿童抗病毒治疗的剂量灵活组合 3D 打印输送系统

• 批准号: 10682185
• 负责人: MANSOOR A KHAN
• 金额: $ 54.37万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682185
• 关键词: 3D Print; Acquired Immunodeficiency Syndrome; Address; Adherence; Adult; Adverse event; Age; Animal Model; Animals; Anti-Retroviral Agents; Antiretroviral drug resistance; Antiviral Therapy; Biological Availability; Child; Childhood; Clindamycin; Clinical; Color; Combined Modality Therapy; Computer software; Data; Deglutition; Development; Diamond; Diclofenac; Dosage Forms; Dose; Drug Combinations; Drug Kinetics; Drug Modelings; Drug usage; Environment; Failure; Formulation; Friends; Fumarates; Funding Mechanisms; HIV; HIV therapy; Hospitals; Hour; Human; Incidence; Knowledge; Lamivudine; Lasers; Liquid substance; Lopinavir; Medical; Methods; Morbidity - disease rate; National Institute of Child Health and Human Development; Overdose; Overdose reduction; Patients; Pediatric Hospitals; Persons; Pharmaceutical Preparations; Pharmacists; Pharmacodynamics; Pharmacy facility; Physicians; Population; Porosity; Preparation; Printing; Probability; Publishing; Recommendation; Reporting; Resources; Safety; Scientific Advances and Accomplishments; Scientist; Shapes; Solid; South Texas; Sterility; System; Tablets; Taste preferences; Tenofovir; Therapeutic; Titrations; Tongue; Toxic effect; Treatment Efficacy; Treatment Failure; United States Food and Drug Administration; United States National Institutes of Health; Viral Load result; Work; age group; aged; antiretroviral therapy; appropriate dose; compliance behavior; dosage; efficacy evaluation; epivir; experience; flexibility; improved; innovation; isoniazid; liquid formulation; manufacture; melting; microbial; mortality; novel; pediatric human immunodeficiency virus; pediatric patients; pharmacokinetics and pharmacodynamics; point of care; reduce symptoms; safety assessment; tablet formulation; therapy outcome; treatment adherence; viral resistance; virtual

ABSTRACT/SUMMARY An estimated 1.7 million children aged 0-14 were living with HIV, and at least 300,000 children were newly infected with HIV in 2020. Another 120,000 children died from AIDS-related causes during the same period. Combination therapy with antiretroviral (ARV) drugs has significantly improved AIDS-related morbidity and mortality. Among all the factors, adherence to HIV treatment pose major challenges in achieving desired therapeutic outcome. A major barrier to ARV treatment adherence is the lack of dose-flexible pediatric-friendly formulations. One of the combination ARV drugs recommended for children ≥2 to 12 years is tenofovir disoproxil fumarate (TDF) and lamivudine (3TC). Dose flexible formulation of TDF-3TC combination is not available. Pharmacists, thus, have to compound pediatric formulations from adult drug products. However, physicians, FDA, and NIH alike have raised concerns on dose accuracy, stability, sterility, bioavailability, efficacy, safety, and consistency of extemporaneous preparations. The dose adjustment/flexibility is difficult to achieve in solid- dosage forms, as each dose strength must be manufactured separately. However, newer manufacturing methods such as 3D printing can be used for dose-tailored or flexible solid-dosage forms, which can easily be set-up/prepared in a clinical hospital environment for pediatric use. Based on the aforementioned considerations, and support for deployment at Driscoll Children’s Hospital in South Texas, the objective of the proposal is to demonstrate the feasibility of printing dose-flexible pediatric co-delivery system (printlets) of two drugs, namely 3TC and TDF in a single printlet system. The premise of this proposal is further supported by our preliminary data on TDF, and published work on isoniazid, lopinavir, diclofenac, and clindamycin. Furthermore, the need for a pediatric delivery system of antiretroviral drugs is reported in the NICHD 2020-2021 priority list. Thus, administering TDF/3TC as age-appropriate flexible pediatric co-delivery systems will overcome the limitations of adult dose manipulations for compounding in pharmacies and address a significant unmet medical need in children. Aim I involves mechanistic understanding printing pediatric co-delivery systems, and characterization for quality, stability, and palatability as per FDA and USP requirements. Aim II involves palatability (human), safety and efficacy evaluation of flexible pediatric co-delivery systems (printlets) by pharmacokinetics and pharmacodynamics methods. The proposal will advance scientific knowledge of a dose-flexible delivery system using 3D printing for pediatric HIV treatment that can be applied to other classes of drugs where no pediatric formulation exists. The successful completion of the proposal will have a significant positive impact on the realization of the delivery system in clinical use and deployment in hospitals with further development and regulatory filing to the FDA for broader use. The PI and his team have ample experience with the proposed studies. The PI led the FDA team of scientists and reviewers through the approval of the first and only 3D printed drug product (Spritam®).

摘要/摘要 估计有170万名0-14岁的儿童患有艾滋病毒，至少有30万儿童是新的 2020年感染了艾滋病毒。在同一时期，另外12万名儿童死于与艾滋病相关的原因。 与抗逆转录病毒（ARV）药物的联合疗法可显着改善与艾滋病相关的发病率和 死亡。在所有因素中，遵守艾滋病毒治疗在实现所需的方面构成了重大挑战 治疗结果。 ARV治疗依从性的主要障碍是缺乏可剂量的儿科友好 公式。建议儿童≥2至12岁的ARV药物之一是Tenofovir disoproxil 富马酸盐（TDF）和拉米夫丁（3TC）。 TDF-3TC组合的剂量柔性公式不可用。 因此，药剂师必须从成人药品中复合小儿配方。但是，医生， FDA和NIH都引起了人们对剂量准确性，稳定性，不育，生物利用度，效率，安全性， 和延长的精美制剂的一致性。在固体中很难实现剂量调整/灵活性 剂型形式，因为每个剂量强度都必须单独制造。但是，较新的制造业 诸如3D打印之类的方法可用于剂量量表或灵活的固体剂量形式，很容易成为 在临床医院环境中设置/准备小儿使用。根据Priore的重要事项 并支持在德克萨斯州南部的Driscoll儿童医院部署，该提案的目的是 证明了两种药物的印刷剂量芬兰儿科共递送系统（Printlets）的可行性，即 单个打印机系统中的3TC和TDF。该提案的前提得到了我们的初步支持 有关TDF的数据，并发表了有关异尼氏菌，洛皮那韦，双氯芬酸和克林霉素的研究。此外，需要 NICHD 2020-2021优先级报告了抗逆转录病毒药物的小儿递送系统。那， 将TDF/3TC作为适合年龄的柔性小儿共同交付系统来克服的局限性 成人剂量操纵以在药房中复合并满足医疗需求 孩子们。目的我涉及理解印刷小儿共同交付系统和表征的机理 AIM II涉及可口（人）， 由药代动力学和 药效学方法。该提案将进一步了解剂量芬兰交付系统的科学知识 使用3D打印进行小儿艾滋病毒治疗，可以应用于其他无儿科的药物 形成存在。该提案的成功完成将对 在进一步发展和 向FDA提交的监管申请，以供更广泛使用。 PI和他的团队在拟议中有丰富的经验 研究。 PI通过第一个和仅3D印刷的批准，带领FDA科学家和审阅者团队 药品（Spritam®）。