Scale-up and GMP Manufacturing of Polyurethane Vaginal Rings

聚氨酯阴道环的放大和 GMP 制造

• 批准号: 8380246
• 负责人: Mark Mitchnick
• 金额: $ 33.65万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8380246
• 关键词: AIDS prevention; Antiviral Agents; Biological; Biological Assay; Cations; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Trials; Coupled; Cyclic GMP; Data; Detection; Development; Dose; Drug Formulations; Drug Kinetics; Elastomers; Epithelial; Equipment; Evaluation; Family suidae; Funding; Gel; Guidelines; HIV; Human; Inflammatory Response; Lead; Macaca; Manufactured Supplies; Methods; Modeling; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase I Clinical Trials; Placebos; Polyurethanes; Preparation; Process; Prodrugs; Production; Qualifying; Safety; Science; Silicones; Simplexvirus; Solutions; Tail; Technology; Tenofovir; Tenofovir disoproxil fumarate; Testing; Utah; Vaginal Ring; Work; absorption; analytical method; biomaterial compatibility; experience; improved; in vivo; irritation; microbicide; nonhuman primate; particle; phase 1 study; pre-clinical; prevent; product development; programs; prototype; research clinical testing; safety study; safety testing; scale up

The recent clinical advance in the HIV prevention field with a successful Phase lib tenofovir (TFV) gel trial coupled to our successful development of a stable tenofovir disoproxil fumarate (TDF) formulation in thermoplastic polyurethane elastomers (TPU) in Project 2 of this U19 supports the expansion of work under this Preclinical and Clinical Development and Regulatory Evaluations Core to move a 30 day TDF intravaginal ring into a pre-Phase 1 trial to evaluate TDF pharmacokinetics and safety. The support will be used to develop GMP manufacturing methods for the product, to produce the clinical supplies and file an exploratory IND. The ability to formulate and stabilize TDF in TPUs is a significant scientific breakthrough as the pharmacokinetics and antiviral activity of the TDF prodrug is much improved over the native TFV; furthermore, the dose required for TDF is two to three orders of magnitude less than TFV, making the formulation and multiday duration delivery of TDF much more feasible than TFV. We have also shown that the other biomedical elastomers (EVA and NuSil Silicone) are too hydrophobic to effectively release the +1 cation TDV. In the expanded core we will use the extensive pharmaceutical manufacturing and development experience at Particle Sciences to (i) develop production scale prototypes; (ii) validate analytical assays to support the clinical supply manufacturing; and (iii) perform pilot scale ring development. These studies will lead to full-scale production of TPU TDF IVRs in accordance with GMP guidelines, completion of the necessary biocompatibility studies on the drug product and the development of an IND to support the clinical evaluation of this product. A cGMP ring stability program with supporting release testing will be conducted in parallel to support the successful completion of the trial. In the early part of year 1 of the supplement, we will also conduct studies in pig-tail macaques at the Center for Disease Control (CDC) in Atlanta with TDF and placebo IVRs to confirm our results in vivo and our ability to achieve appropriate pharmacokinetics in the NHP model.

最近在HIV预防领域的临床进展，包括成功的lib期替诺福韦（TFV）凝胶试验，以及我们在U19项目2中成功开发稳定的富马酸替诺福韦二氧丙酯（TDF）配方热塑性聚氨酯弹性体（TPU），支持了临床前和临床开发和监管评估核心下的工作扩展，将30天的TDF阴道内环转移到1期前试验，以评估TDF的药代动力学和安全性。支持将是