Parenteral Formulations for Synthetic Retinoids

描述（由申请人提供）：类维生素A是一类维生素A的结构类似物，其影响细胞增殖和分化，并在致癌模型中表现出广泛的化学预防活性。一些合成的类似物，作为化学预防剂的活性也诱导恶性细胞系的细胞凋亡，而不通过经典的细胞内类维生素A受体。除了可以静脉内给药的视黄酸异构体和衍生物之外，大多数合成的类视黄酸具有中性电荷并且溶解性差，并且目前的口服剂型不能达到抗肿瘤的血液水平。芬维A胺（4HPR）最近的一项I期临床试验发现，口服剂型可达到的药物血浆水平的上限远低于临床前模型中诱导肿瘤细胞凋亡所需的水平。类维生素A给药的有限选择是实现其治疗潜力的主要障碍。SciTech已经开展了一项研究计划，以开发用于静脉注射难溶性合成类维生素A的制剂。该SBIR项目的长期目标是开发耐受性良好的制剂（例如，不含Cremophor、Tween和其它聚氧表面活性剂）和抗肿瘤活性剂，并且具有实体瘤患者多日输注所需的有利的药物特性。在SBIR第1阶段期间，评估了5种制剂策略，并证明了其中3种达到稳定和高药物浓度的可行性。其中一种被选为先导产品，并在动物模型中被证明具有药理学活性，尽管药物在体内的物理形式发生了实质性变化。本SBIR第2阶段应用的目标是优化主导产品，开发可在第3阶段无菌产品设施中实施的书面制造过程，并了解控制HPR组织分布的生理学和药理学原理。

DESCRIPTION (provided by applicant): Retinoids are a class of structural analogs of Vitamin A which influence cellular proliferation and differentiation, and exhibit broad chemopreventive activity in carcinogenesis models. Some synthetic analogs that are active as chemopreventive agents also induce apoptosis in malignant cell lines without acting through classical intracellular retinoid receptors. With the exception of retinoic acid isomers and derivatives that can be administered intravenously, most synthetic retinoids have neutral charge and are poorly soluble, and current oral dosage forms are unable to achieve pharmacologically active blood levels. A recent Phase I clinical trial of fenretinide (4HPR) found a ceiling on achievable plasma levels of drug with an oral dosage form that were well below levels required to induce tumor cell apoptosis in preclinical models. The limited options for administration of retinoids are a major impediment to realizing their therapeutic potential. SciTech has undertaken a research program to develop formulations for the intravenous administration of poorly soluble synthetic retinoids. The long-term goals of this SBIR project are to develop formulations that are well tolerated (e.g., without cremophor, tween, and other polyoxy surfactants) and pharmacologically active, and possess favorable pharmaceutical characteristics required for multi-day infusion in patients with solid tumors. During the SBIR Phase 1 period, five formulation strategies were evaluated and the feasibility of reaching stable and high drug concentrations was proven for three of them. One was selected as the lead product and was proven to possess pharmacological activity in animal models despite substantial changes in the physical form of drug presented in vivo. The goals of this SBIR Phase 2 application are to optimize the lead product, develop a documented manufacturing process that could be implemented in a sterile product facility in Phase 3, and understand the physiological and pharmacological principles that govern tissue distribution of HPR.