Core--Drug Development

描述（由申请人提供）：针对紫外线信号转导途径的分子靶向药物可以加入局部配方中，以优化皮肤递送，并最大限度地提高临床前和临床评估成功的可能性。I-III项目的长期临床前致癌研究和IV项目的临床试验，如果没有制备和适当测试表征良好、稳定的外用制剂，就无法启动。药物开发核心为该计划项目提供这项至关重要的服务。药物开发核心的目标是有效地设计、制备、测试和提供新的皮肤癌化学预防药物的药学上合适的局部配方给项目研究人员，并为有希望的候选药物的临床开发提供监管支持。这一竞争性应用的一个创新补充是合成化学实体作为前药的能力和专业知识，以提高溶解度、吸收和向表皮的递送。这一目标将通过以下具体目标来实现：1)为有前景的新药制备稳定的制剂，使其在局部应用后能有效地传递到表皮；2)为长期体内致癌研究制备批量制剂，并进行必要的临床前毒理学、药代动力学和稳定性研究；3)协调和准备FDA批准的研究新药（IND）申请，并监督临床级药物的生产和销售

DESCRIPTION (provided by applicant): Molecularly targeted agents against UV signal transduction pathways can be incorporated into topical formulations engineered to optimize delivery to skin and maximize the probability of success in preclinical and clinical evaluation. Long-term preclinical carcinogenesis studies in Projects I-III and clinical trials in Project IV cannot be initiated without the preparation and proper testing of well-characterized, stable formulations of topical agents. The Drug Development Core provides this crucial service to the Program Project. The objective of the Drug Development Core is to efficiently design, prepare, test, and provide pharmaceutically suitable topical formulations of new skin cancer chemopreventive agents to Program Project investigators and to provide regulatory support for clinical development of candidates that show promise. An innovative addition to this competing application is the ability and expertise to synthesize chemical entities as prodrugs in order to enhance solubility, absorption, and delivery to the epidermis. This objective will be accomplished by the following Specific Aims: 1) To prepare stable formulations of promising new agents that can be effectively delivered to the epidermis following topical application, 2) To prepare batch formulations for long-term carcinogenesis studies in vivo and perform necessary preclinical toxicology, pharmacokinetic, and stability studies, and 3) To coordinate and prepare Investigational New Drug (IND) applications for FDA approval, and supervise production and distribution of clinicalgrade supply for human trials in Project IV. The Drug Development Core will oversee all aspects of topical agent preparation, formulation, and supply for each of the Projects. Quality control and assurance methods developed by the Drug Development Core in consultation with the Biometry Core will ensure regulatory compliance and enhance efficiency. The Drug Development Core will work closely with each Project to provide necessary and appropriate topical formulations for each stage of mechanistic and efficacy studies in vivo. This will allow us to circumvent problems with epidermal delivery that normally hinder development of otherwise promising topical agents, and optimize the crucial selection criteria for advancement of new agents to clinical testing. This will greatly enhance our ability to translate basic science discoveries into new skin cancer chemopreventive drugs.