Scale-up and GMP Manufacturing of Polyurethane Vaginal Rings

最近在HIV预防领域的临床进展，成功的IIb期替诺福韦（TFV）凝胶试验，加上我们成功开发了热塑性聚氨酯弹性体（TPU）中稳定的替诺福韦二异丙酯富马酸酯（TDF）制剂，在本U19的项目2中，支持扩展本临床前和临床开发以及监管评价核心项下的工作，将30天TDF阴道环转移到评价TDF药代动力学和安全性的1期前试验。支持将是 用于开发产品的GMP生产方法，生产临床供应品并提交探索性IND。在TPU中配制和稳定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有很大改善;此外，TDF所需的剂量比TFV小两到三个数量级，使得TDF的制剂和多日持续递送比TFV更可行。我们还表明， 其它生物医学弹性体（伊娃和NuSil硅酮）太疏水而不能有效地释放+1阳离子TDV。在扩展的核心中，我们将利用Particle Sciences丰富的制药和开发经验，（i）开发生产规模原型;（ii）验证分析测定以支持临床供应制造;以及（iii）进行中试规模环开发。 这些研究将导致TPU TDF IVR的全面生产符合GMP指南， 完成制剂的必要生物相容性研究，并开发IND以支持本产品的临床评价。将同时进行cGMP环稳定性项目和支持性放行检测，以支持试验的成功完成。在补充剂第1年的早期，我们还将在亚特兰大疾病控制中心（CDC）的猪尾猕猴中进行TDF和安慰剂IVR研究，以确认我们的体内结果以及我们在NHP模型中实现适当药代动力学的能力。

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.