Preformulation and formulation development of Fenrock, an Abuse-resistant Fentanyl Transdermal Patch

7.项目总结/摘要 根据这一快速通道的建议，我们将开发FenrockTM，一种滥用威慑透皮 芬太尼贴剂基于我们专有的纳洛酮（NTX）共晶体及其精心挑选的 构象异构体5-甲基糠醛（5-MFF）。这种NTX/5-MFF）共晶体（NTX-Co）具有所需的 当按预期施用于皮肤时， 当通过咀嚼、吞咽、溶剂提取、吸烟或其他方式滥用时， 加热和吸入。我们将首先开发测量三个贴片所需的分析方法 成分（芬太尼，NTX和5-MFF）。我们将进行处方前研究，以评估固体 说明NTX-Co与芬太尼和各种赋形剂相互作用以及与 各种压敏粘合剂。NTX-Co在芬太尼存在下的稳定性和 可接受的赋形剂和粘合剂列表将决定潜在的隔室设计。我们 然后将开始配方开发，测试几种潜在的芬太尼和NTX-Co贴剂 组分/隔室，并在体外单独表征它们的溶出度和通量 在使用和滥用模拟下穿过人造膜。这些结果和粘附性 测试将决定第一阶段的里程碑：选择多达三个补丁原型概念 有芬太尼和NTX-Co的隔离室本提案的第二阶段将开始， 这三种贴剂原型设计的生产及其在使用和滥用情况下的体外测试 范例这些包括经皮和口腔吸收的3D组织模型以及体外 模拟咀嚼、吞咽、溶剂提取和通过加热或吸烟挥发的试验。一 最后的离体试验将评估离体人皮肤中的透皮吸收。最多两个贴片 将选择原型用于大鼠的PK研究，以比较芬太尼吸收率与 芬太尼贴剂根据这些数据，将选择一个或两个原型进行 大鼠皮肤刺激性研究和小型猪PK研究，将指导IND使能研究， 迷你猪，透皮产品所需的物种。我们将使用老鼠空调的地方 偏好范式来确定NTX-Co和芬太尼的最佳相对剂量， 在滥用的情况下释放足够的NTX，以减少芬太尼的奖励作用， 提供一种安全措施。通过PK、皮肤刺激性和相对剂量测定 完成后，将选择一种制剂并生产GLP毒性批次。然后我们将进行 小型猪的剂量范围探索研究和关键28天GLP毒性。完成时 拟议的工作，芬洛克将准备GMP规模扩大和临床试验。

7. Project Summary/Abstract Under this Fast-Track proposal, we will develop FenrockTM, an abuse-deterrent transdermal fentanyl patch based on our proprietary co-crystal of naltrexone (NTX) and its carefully selected conformer 5-methyl furfural (5-MFF). This NTX/5-MFF) co-crystal (NTX-Co) has the desired properties to stay in a crystalline solid form in the patch when applied to skin as intended but to dissociate to deliver NTX when abused by chewing, swallowing, solvent extraction, smoking or heating and inhaling. We will first develop analytical methods needed to measure the three patch components (fentanyl, NTX and 5-MFF). We will perform preformulation studies to assess solid state interaction of NTX-Co with fentanyl and various excipients as well as compatibility with various pressure sensitive adhesives. The stability of NTX-Co in the presence of fentanyl and the list of acceptable excipients and adhesives will determine potential compartmental designs. We will then begin formulation development by testing several potential fentanyl and NTX-Co patch components/compartments and characterizing them individually in in vitro in dissolution and flux across an artificial membrane under use and abuse simulations. These results and adhesion testing will determine the Phase I milestone: selection of up to three patch prototype concepts with integrated fentanyl and NTX-Co compartments. Phase II of this proposal will begin with production of these three patch prototype designs and their in vitro testing under use and abuse paradigms. These include 3D tissue models of transdermal and buccal absorption and in vitro tests to mimic chewing, swallowing, solvent extraction and volatilization by heating or smoking. A final ex vitro test will assess transdermal absorption in excised human skin. Up to two patch prototypes will be selected for a PK study in rats to compare fentanyl absorption rate to that of the Duragesic® fentanyl patch. Based on these data, one or two prototypes will be selected for a dermal irritation study in rats and a PK study in minipig that will guide the IND-enabling studies in minipig, the required species for transdermal products. We will use the rat conditioned place preference paradigm to determine the optimal relative doses of NTX-Co and fentanyl such that enough NTX is released under scenarios of abuse to reduce the rewarding effects of fentanyl and provide a measure of safety. With the PK, dermal irritation and relative dose determination completed, one formulation will be selected and a GLP tox lot manufactured. We will then conduct a dose range finding study and the pivotal 28-day GLP tox in minipig. At the completion of the proposed work, Fenrock will be ready for GMP scale-up and clinical trials.