Parenteral Formulations for Synthetic Retinoids

描述(申请人提供)：维甲酸是一类维生素A的结构类似物，可影响细胞的增殖和分化，并在致癌模型中显示出广泛的化学预防活性。一些具有化学预防活性的合成类似物也不通过经典的细胞内维甲酸受体诱导肿瘤细胞系的凋亡。除了可以静脉给药的维甲酸异构体和衍生物外，大多数合成维甲酸具有中性电荷，溶解性差，目前的口服剂型无法达到药理活性的血液水平。Fenretinide(4HPR)最近的一项I期临床试验发现，口服剂型可达到的血药浓度上限远低于在临床前模型中诱导肿瘤细胞凋亡所需的水平。维甲酸类药物的给药选择有限，是实现其治疗潜力的主要障碍。科学技术公司已经开展了一项研究计划，以开发用于静脉注射难溶合成维甲酸的制剂。该SBIR项目的长期目标是开发耐受性良好的制剂(例如，不含乳油、吐温和其他多氧表面活性剂)和药理活性，并具有实体肿瘤患者多天输液所需的良好药学特性。在SBIR第一阶段期间，评估了五种配方战略，并证明了其中三种战略达到稳定和较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，尽管体内呈现的药物的物理形式发生了实质性变化。这一SBIR第二阶段应用的目标是优化先导产品，开发可在第三阶段无菌产品设施中实施的文件化制造工艺，并了解支配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.