Scale-up and GMP Manufacturing of Polyurethane Vaginal Rings

HIV预防领域的最新临床进展，Lib替诺福韦(TFV)凝胶试验的成功，加上我们在本U19的项目2中成功开发了用于热塑性聚氨酯弹性体(TPU)的稳定的替诺福韦双丙醇富马酸酯(TDF)配方，支持了这一临床前和临床开发与监管评估核心下的工作的扩展，将30天的TDF阴道内环转移到第一阶段前试验，以评估TDF的药代动力学和安全性。支持将是 用于制定产品的GMP生产方法，生产临床用品并提交试探性文件。在TPU中形成和稳定TDF的能力是一项重大的科学突破，因为TDF前药的药代动力学和抗病毒活性比天然TFV有了很大改善；此外，TDF所需的剂量比TFV少两到三个数量级，使TDF的配方和多日持续给药比TFV更可行。我们还表明， 其他生物医用弹性体(EVA和Nusil硅胶)疏水性太强，无法有效释放1阳离子TDV。在扩大的核心中，我们将利用粒子科学丰富的药物制造和开发经验来(I)开发生产规模的原型；(Ii)验证支持临床供应制造的分析分析；以及(Iii)进行中试规模环的开发。这些研究将导致根据GMP指南全面生产TPU TDF IVR， 完成必要的药物产品生物相容性研究，并开发IND以支持该产品的临床评估。将同时进行cGMP环稳定性计划和辅助释放测试，以支持试验的成功完成。在补充资料的第一年初期，我们还将在亚特兰大疾病控制中心(CDC)对猪尾猕猴进行TDF和安慰剂静脉注射受体的研究，以确认我们在体内的结果以及我们在NHP模型中实现适当药物动力学的能力。

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.