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/总结 估计有170万0-14岁儿童感染艾滋病毒，至少有30万儿童新感染了艾滋病毒。 2020年感染艾滋病。在同一时期，另有120 000名儿童死于与艾滋病有关的原因。 抗逆转录病毒药物的联合治疗显著改善了艾滋病相关的发病率， mortality.在所有因素中，坚持艾滋病毒治疗是实现预期目标的主要挑战。 治疗效果坚持抗逆转录病毒治疗的一个主要障碍是缺乏剂量灵活的儿科友好的 制剂。替诺福韦酯是推荐用于2至12岁儿童的抗逆转录病毒药物组合之一 富马酸盐（TDF）和拉米夫定（3 TC）。TDF-3 TC复方制剂的剂量灵活性不可用。 因此，药剂师必须从成人药物产品中合成儿科制剂。然而，医生， FDA和NIH都对剂量准确性、稳定性、无菌性、生物利用度、有效性、安全性提出了担忧， 和一致性的即兴准备。剂量调整/灵活性很难在固体中实现- 剂型，因为每个剂量规格必须单独生产。然而，较新的制造业 例如3D打印的方法可以用于剂量定制或柔性固体剂型，其可以容易地被制造。 在临床医院环境中设置/准备，供儿科使用。基于上述考虑， 和支持部署在得克萨斯州南部的Drivel儿童医院，该提案的目的是 证明了打印两种药物的剂量灵活的儿科共同输送系统（printlets）的可行性，即 3 TC和TDF在一个单一的printlet系统。这一建议的前提得到了我们初步的支持。 关于TDF的数据，以及关于异烟肼、洛匹那韦、双氯芬酸和克林霉素的已发表工作。此外，需要 抗逆转录病毒药物的儿科给药系统在NICHD 2020-2021优先列表中报告。因此，在本发明中， 将TDF/3 TC作为适合年龄的灵活儿科联合给药系统给药将克服以下局限性： 成人剂量操作，用于在药房中进行复合，并解决以下方面的重大未满足的医疗需求： 孩子目的我涉及机械理解印刷儿科共同交付系统，和表征 质量、稳定性和适口性符合FDA和USP要求。目标II涉及适口性（人类）， 通过药代动力学评价柔性儿科联合给药系统（printlets）的安全性和有效性， 药效学方法该提案将推进剂量灵活的输送系统的科学知识 将3D打印用于儿科艾滋病毒治疗，可应用于其他类别的药物， 公式存在。该提案的成功完成将对 实现输送系统在临床使用和医院部署中的进一步发展， 向FDA提交监管备案以供更广泛使用。PI和他的团队在拟议的 问题研究PI领导FDA的科学家和评审员团队批准了第一个也是唯一一个3D打印的 药物产品（Spritam®）。