Nanodosing: A path to higher sensitivity and lower toxicity pharmaceuticals

描述（由申请人提供）：目前可获得的iobenguane i123仅限于在区域放射性药厂标记的单剂量，具有可变配方和特定活性。该快速通道1/2期SBIR的目标是生产一种新的诊断药物制剂iobenguane i123并在人体中进行安全性测试。请求快速通道考虑的理由是利用利用为开发治疗性I-131制剂而建立的起始材料和设施开发高比活度iobenguane i123的诊断版本的协同作用。本提案的目标是在正常人体志愿者中生产和测试高比活性的超痕量碘苯123。低比活性iobenguane i123已被证明对成人和儿童神经内分泌肿瘤的检测和分期以及心脏神经元活动成像有用。该提案的创新之处在于，通过使用专利的固相技术来生产一种经过验证的具有极高比活性的诊断试剂，以增加敏感性和特异性，并降低正常器官的辐射暴露，而不需要药效学上活性的冷载体化合物。FDA认为用两种不同的碘同位素[i131和i123]标记的iobenguane是两种不同的药物，需要不同的监管应用。为了满足新药申请的化学、制造和控制组件的质量标准要求，GMP质量聚合物药物前体将用于生产Ultratrace诊断碘- 123剂。分析方法必须与建议的最终药物配方一起验证，以证明最终药物不会干扰用于确定制剂的特性、纯度和强度的测试。在开始人体试验之前，还必须验证药品溶液的无致孕性和无菌性。最终药品的配方将在表达去甲肾上腺素转运体的细胞和动物中进行稳定性和生物等效性测试。所需的IND申请将被书面提交给FDA和杜克医学中心IRB。MIP将生产临床试验材料，并在正常健康志愿者中进行放射性药物物质的安全性和与传统苯二胍i123相比的优越性的人体试验。

DESCRIPTION (provided by applicant): Current availability of iobenguane I 123 is limited to single doses labeled at regional radiopharmacies with variable formulations and specific activities. The objective of this Fast track phase 1/2 SBIR is to produce and perform safety testing in humans of a new diagnostic drug product formulation of iobenguane I 123. The justification for requesting Fast Track consideration is to take advantage of the synergy of developing a diagnostic version of the high specific activity iobenguane I 123 using starting materials and facilities established for the development of the therapeutic I-131 agent. The goal of this proposal is to produce and test high specific activity Ultratrace iobenguane I 123 in normal human volunteers. The low specific activity iobenguane I 123 has been shown to be useful for the detection and staging of neuroendocrine tumors in adults and children and imaging neuronal activity in the heart. The innovation in this proposal is through the use of patented solid phase technology to produce a proven diagnostic agent at extremely high specific activity to increase sensitivity and specificity and lower radiation exposure to normal organs without the pharmacologically active cold carrier compound. The FDA considers iobenguane labeled with two different isotopes of iodine [I 131 and I 123] as two distinct drugs requiring distinct regulatory applications. To meet the required quality standards for the chemistry, manufacturing and controls component of an IND application, GMP quality polymer drug precursor will be used to generate the Ultratrace diagnostic iodine- 123 agent. Analytical methods must be validated with the proposed final drug formulation to demonstrate the final drug does not interfere with tests used to define the identity, purity, and strength of the agent. The drug product solution must also be verified to be apyrogenicity and sterility before human testing can be initiated. The formulation of the final drug product will be tested for stability and bioequivalence in norepinephrine-transporter expressing cells and in animals. The required IND application will be written and submitted to the FDA and the Duke Medical Center IRB. MIP will produce clinical trial material and conduct human testing of the radioactive drug substance for safety and superiority compared to conventional iobenguane I 123 in normal healthy volunteers.