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，影响细胞增殖和分化，并在癌变模型中表现出广泛的化学预防活性。一些具有化学预防作用的合成类似物也可以诱导恶性细胞系的细胞凋亡，而不通过经典的细胞内类视黄醇受体起作用。除了维甲酸异构体和衍生物可以静脉给药外，大多数合成类维甲酸具有中性电荷且难溶性，目前的口服剂型无法达到药理学活性血液水平。最近的一项I期临床试验发现，在临床前模型中，口服剂量形式的芬瑞啶（4HPR）可达到的血浆水平上限远低于诱导肿瘤细胞凋亡所需的水平。类维生素a管理的有限选择是实现其治疗潜力的主要障碍。sciitech已经开展了一项研究计划，开发用于静脉注射难溶性合成类维生素a的配方。该SBIR项目的长期目标是开发耐受性良好（例如，不含cremophor、tween和其他多氧表面活性剂）、具有药理活性的制剂，并具有实体瘤患者多日输注所需的良好药物特性。在SBIR一期研究期间，对5种剂型策略进行了评估，并证明了其中3种剂型策略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活性，尽管药物在体内的物理形态发生了实质性变化。SBIR二期申请的目标是优化先导产品，开发可在三期无菌生产设施中实施的有文件记录的生产工艺，并了解控制HPR组织分布的生理和药理学原理。

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.