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

Fenrock（一种防滥用芬太尼透皮贴剂）的预配制和配方开发

• 批准号: 9408170
• 负责人: Shawn Kucera
• 金额: $ 34.99万
• 依托单位: CASSAVA SCIENCES, INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9408170
• 关键词: Adhesions; Adhesives; Artificial Membranes; Biological Assay; Breathing; Child; Clinical Trials; Crystallization; Dangerousness; Data; Deglutition; Dermal; Development; Dissociation; Dose; Drug Kinetics; Enhancers; Ensure; Evaluation; Excipients; Fentanyl; Film; Formulation; Genetic Polymorphism; Health; Heating; Heroin; Human; In Vitro; Individual; Liquid substance; Mastication; Measures; Methods; Miniature Swine; Modeling; Morphine; Naltrexone; Opiates; Oral cavity; Overdose; Pharmaceutical Preparations; Phase; Polymers; Preclinical Testing; Process; Production; Property; Rattus; Resistance; Rewards; Risk; Safety; Skin; Smoking; Solid; Solubility; System; Technology; Testing; Tissue Model; Toxic effect; Volatilization; Work; absorption; addiction; analytical method; base; clinical lot; conformer; crystallinity; design; experience; in vitro testing; in vivo; irritation; method development; preference; prescription opioid abuse; pressure; process optimization; prototype; scale up; simulation; solid state; solvent extraction; stability testing

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.

7.项目摘要/摘要 根据这项快速通道提案，我们将开发FenrockTM，一种防止滥用的透皮产品 基于我们的专利纳曲酮(NTX)共晶的芬太尼贴片及其精心挑选的 异构体5-甲基呋喃甲醛(5-MFF)。这种NTX/5-MFF)共晶(NTX-Co)具有所需的 按预期应用于皮肤时在贴片中保持晶体固体形式的属性，但 当被咀嚼、吞咽、溶剂提取、吸烟或 加热和吸气。我们将首先开发测量这三个补丁所需的分析方法 成分(芬太尼、甲氨蝶呤和5-甲氧基呋喃)。我们将进行配方前研究，以评估固体 NTX-Co与芬太尼和各种赋形剂的状态相互作用及其配伍 各种压敏胶。NTX-Co在芬太尼存在下的稳定性 可接受的辅料和粘合剂清单将决定潜在的隔室设计。我们 然后将通过测试几种潜在的芬太尼和NTX-Co贴片来开始配方开发 组分/隔室及其体外溶出度和助熔剂的单独表征 在人造薄膜上进行使用和滥用模拟。这些结果与粘附性 测试将确定第一阶段的里程碑：选择最多三个补丁原型概念 带有集成的芬太尼和NTX-Co隔间。该提案的第二阶段将从以下内容开始 这三种贴片原型设计的制作及其在使用和滥用情况下的体外测试 范例。其中包括经皮吸收、口腔吸收和体外吸收的3D组织模型 模拟咀嚼、吞咽、溶剂提取和通过加热或吸烟挥发的测试。一个 最终的体外试验将评估人体皮肤的透皮吸收。最多两个补丁 将选择原型进行大鼠的PK研究，以比较芬太尼的吸收速度和 Duragesic®芬太尼贴片。根据这些数据，将选择一到两个原型进行 大鼠的皮肤刺激性研究和小型猪的PK研究将指导在 小型猪，透皮产品所需的物种。我们将使用老鼠调节的地方 偏好范式以确定NTX-Co和芬太尼的最佳相对剂量 在滥用情况下释放足够的NTX以减少芬太尼和 提供一定的安全措施。用PK、皮肤刺激性和相对剂量测定 完成后，将选择一个配方并生产一批GLP毒素。然后我们将进行 小型猪的剂量范围发现研究和关键的28天GLP毒素。在完成 拟议的工作，FenRock将为GMP扩大和临床试验做好准备。