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

描述(申请人提供)：在美国每年约500,000名早产儿中，有很高比例的人在出生后需要静脉喂养，因为他们不能容忍口服喂养。这是通过完全肠外营养(TPN)解决方案实现的，该解决方案由成分溶液：小容量和大容量肠外营养(SVP和LVP)配制而成。铝是一些SVP中的常见污染物，尤其是葡萄糖酸钙溶液。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。铝中毒的可能性在人类中明显更大，例如早产儿，他们的肾功能下降；因为肾脏排泄铝。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幅减少，以避免铝中毒。FDA对这些成分溶液实施了标签要求，设定了LVP中的最大铝浓度，并要求在到期时说明SVP中的最大Al浓度。这只是记录了估计的最大铝浓度。它不是实际的铝浓度，也不会减少SVP中的铝。基于之前开发结合铝(螯合剂)的新化学品的工作，长期目标是开发一种包含螯合剂的流过过滤装置，该装置固定在小的聚合物珠子上，以从溶液中去除铝。基于计算化学的结果，预测了新型固定化螯合剂与铝的结合强度，以及我们合成的新型螯合剂在第一阶段奖之前和期间获得的结果，建议改进铅树脂(固定在树脂珠上的螯合剂)，开发含有铅树脂的原型装置，并测试这些装置从葡萄糖酸钙溶液中去除铝的有效性和安全性。然后，我们将在接受TPN的新生儿临床前原则验证模型中评估所产生的优化装置的安全性和有效性。这一结果将使该项目进入第三阶段，在该阶段，树脂和设备将在cGMP条件下制造，并在新生儿重症监护病房接受TPN的新生儿的临床原则验证研究中进行测试。 与公众健康相关：拟议的工作将推动铅树脂(固定化螯合剂)的发展，并开发和测试包含该树脂的原型设备，创造一种从静脉溶液中去除有毒污染物铝(Al)的医疗设备。该装置将在接受静脉喂养的新生儿的动物模型上进行临床前原理验证研究。这将消除铝对早产儿和通过静脉输液暴露于铝的其他患者产生毒性的可能性，解决了一个数十年来一直未能解决的问题。

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.