Nanodosing: A path to higher sensitivity and lower toxicity pharmaceuticals

描述（由申请方提供）：目前碘苯胍I 123的可用性仅限于在区域放射性药物管理局标示的单剂量，具有不同的制剂和特定活性。本快速通道I/II期SBIR的目的是生产碘苯胍I 123的新诊断制剂并进行人体安全性试验。请求快速通道审议的理由是利用利用为开发治疗性I-131药剂而建立的起始材料和设施开发高比活度碘苯胍I 123的诊断版本的协同作用。本提案的目的是在正常人类志愿者中生产和测试高比活度的Ultratrace碘苯胍I 123。低比活度碘苯胍I 123已被证明可用于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的成像。该提案的创新之处在于，通过使用专利固相技术，生产出一种具有极高比活度的经验证的诊断剂，以提高灵敏度和特异性，并降低对正常器官的辐射暴露，而无需使用具有生物活性的冷载体化合物。FDA认为用两种不同的碘同位素[I 131和I 123]标记的碘苯胍是两种不同的药物，需要不同的监管申请。为了满足IND申请的化学、生产和控制组件的质量标准要求，将使用GMP质量聚合物药物前体生产Ultratrace诊断碘-123试剂。分析方法必须用拟定的最终药物处方进行验证，以证明最终药物不会干扰用于确定药物鉴别、纯度和规格的检测。在开始人体试验之前，还必须验证制剂溶液的无热原性和无菌性。将在去甲肾上腺素转运蛋白表达细胞和动物中检测最终制剂的稳定性和生物等效性。将编写所需的IND申请并提交给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原料药的人体试验，以确定与常规碘苯胍I 123相比的安全性和优效性。

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.