A device containing an immobilized chelator to remove aluminum from total parente

描述（由申请人提供）：在美国每年约50万早产儿中，有很大一部分在出生后需要静脉喂养，因为他们不能耐受口服喂养。这是通过总肠外营养（TPN）溶液完成的，该溶液由成分溶液制备：小体积和大体积肠外营养（svp和LVPs）。铝（Al）是一些svp中常见的污染物，特别是葡萄糖酸钙溶液。过量的铝会对骨骼系统和大脑产生毒性，可能还会对肝脏产生毒性。人类，如肾功能下降的早产儿，铝中毒的可能性要大得多；照顾新生儿的医务人员几十年来一直建议，这些溶液中的铝需要大大降低，以避免铝引起的毒性。FDA对这些成分溶液实施了标签要求，设定了LVPs中的最大Al浓度，并要求在到期时声明SVPs中的最大Al浓度。这仅仅记录了估计的最大铝浓度。它不是实际的Al浓度，也不会减少svp中的Al。基于先前开发结合Al（螯合剂）的新化学物质的工作，长期目标是开发一种包含螯合剂的流动过滤装置，该装置固定在小聚合物珠上以去除溶液中的Al。基于计算化学预测新型固定化螯合剂与Al结合强度的结果，以及我们所合成的新型螯合剂在I期获奖前和获奖期间的结果，提出了推进铅树脂（固定化在树脂珠上的螯合剂），开发含铅树脂的原型装置，并测试这些装置对葡萄糖酸钙溶液中Al的去除效果和安全性。然后，我们将在接受TPN的新生儿仔猪模型的临床前原理验证中评估所得到的优化装置的安全性和有效性。该结果将使该项目进入第三阶段，其中树脂和设备将在cGMP条件下生产，该设备将在新生儿重症监护病房接受TPN的新生儿中进行临床原理验证研究。

DESCRIPTION (provided by applicant): A high percentage of the ~ 500,000 children born prematurely each year in the US require intravenous feeding after birth because they do not tolerate oral feeding. This is accomplished with a total parenteral nutrition (TPN) solution, which is prepared from component solutions: small and large volume parenterals (SVPs and LVPs). Aluminum (Al) is a common contaminant in some SVPs, particularly calcium gluconate solution. Excessive Al can produce toxicity to the skeletal system and brain, and perhaps the liver. The potential for Al toxicity is significantly greater in humans, such as premature infants, who have reduced renal function; because the kidneys excrete Al. Medical personnel who care for neonates have suggested for decades that the Al in these solutions needs to be greatly decreased to avoid Al-induced toxicity. The FDA implemented a labeling requirement for these component solutions that sets a maximum Al concentration in LVPs and requires a statement of the maximum Al concentration in SVPs at expiry. This merely documents estimated maximum Al concentration. It is not the actual Al concentration nor does this reduce the Al in SVPs. Based on prior work to develop new chemicals that bind Al (chelators), the long- term objective is to develop a flow-through filter device containing a chelator that is immobilized on small polymer beads to remove Al from solutions. Based on results obtained using computational chemistry, which predicted the strength of binding of novel immobilized chelators with Al, and results obtained before and during the Phase I award from novel chelators we have synthesized, it is proposed to advance the lead resin (a chelator immobilized on a resin bead), and develop prototype devices containing the lead resin, and test these devices for their efficacy to remove Al from calcium gluconate solution and their safety. We will then assess the safety and efficacy of the resultant optimized device in a pre-clinical proof- of-principle piglet model of the neonate, receiving TPN. The results will position this project to advance to Phase III, in which the resin and device will be manufactured under cGMP conditions and the device tested in a clinical proof-of-principle study in neonates receiving TPN in a neonatal intensive care unit. PUBLIC HEALTH RELEVANCE: The proposed work will advance the lead resin (immobilized chelator) and develop and test prototype devices to contain the resin, to create a medical device to remove a toxic contaminant, aluminum (Al), from intravenous solutions. This device will be tested in a pre- clinical proof-of-principle study in an animal model of the neonate receiving intravenous feeding. This will remove the potential for Al to produce toxicity to premature infants and other patients who are exposed to Al through intravenous fluids, solving a decades-old problem that has escaped resolution to date.