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

一种含有固定螯合剂的装置，用于去除总母体中的铝

• 批准号: 8079641
• 负责人: Robert Allen Yokel
• 金额: $ 21.35万
• 依托单位: ALKYMOS, INC
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079641
• 关键词: Address; Adult; Advocacy; Aluminum; Alzheimer' s Disease; Animal Model; Award; Binding; Birth; Brain; Businesses; Calcium; Calcium Gluconate; Caliber; Caring; Chelating Agents; Child; Childhood; Cholestasis; Clinical; Cyclic GMP; Development; Devices; Encephalopathies; Endotoxins; European; Excision; Filtration; Goals; Guidelines; HDPE; Health Personnel; Hemodialysis; Housing; Human; IV Fluid; Infant; Infant formula; Injection of therapeutic agent; Intake; Intravenous; Intravenous Feeding; Kentucky; Kidney; Label; Lead; Ligand Binding; Liver; Marketing; Medical Device; Membrane; Metabolic Bone Diseases; Metals; Methods; Modeling; Neonatal; Neonatal Intensive Care Units; Oral; Particulate Matter; Patients; Pharmacopoeias; Pharmacy facility; Phase; Plant Resins; Plastics; Polymers; Positioning Attribute; Premature Infant; Preparation; Price; Process; Production; Property; Pyrogens; Recommendation; Renal function; Research; Research Institute; Residual state; Resolution; Respondent; Risk; Safety; Skeletal system; Small Business Technology Transfer Research; Sodium Chloride; Solutions; Solvents; Stage 5 renal failure; Staging; Sterility; Stress; Surveys; Testing; Total Parenteral Nutrition; Toxic effect; United States; Universities; Variant; Work; base; chemical binding; chemical release; computational chemistry; design; drinking water; feeding; fluid flow; gluconate; meetings; mental development; neonate; novel; phase 2 study; pre-clinical; pressure; prototype; public health relevance; safety study

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.

描述（由申请人提供）：美国每年约有 500,000 名早产儿，其中很大一部分在出生后需要静脉喂养，因为他们不耐受口服喂养。这是通过全肠外营养 (TPN) 溶液来实现的，该溶液由以下组分溶液制备：小容量和大容量肠外营养剂（SVP 和 LVP）。铝 (Al) 是一些 SVP 中的常见污染物，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，也许还会对肝脏产生毒性。对于肾功能下降的早产儿等人类来说，铝中毒的可能性要大得多；因为肾脏排泄铝。几十年来，护理新生儿的医务人员一直建议，需要大幅降低这些溶液中的铝含量，以避免铝引起的毒性。 FDA 对这些成分解决方案实施了标签要求，规定了 LVP 中的最大铝浓度，并要求在到期时声明 SVP 中的最大铝浓度。这仅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 中的铝含量。基于先前开发结合铝（螯合剂）的新化学品的工作，长期目标是开发一种包含固定在小聚合物珠上的螯合剂的流通过滤装置，以去除溶液中的铝。基于使用计算化学获得的结果（预测新型固定化螯合剂与 Al 的结合强度）以及我们合成的新型螯合剂在第一阶段授予之前和期间获得的结果，建议推进先导树脂（一种固定化螯合剂）在树脂珠上），并开发含有先导树脂的原型装置，并测试这些装置从葡萄糖酸钙溶液中去除铝的功效及其安全性。然后，我们将在接受 TPN 的新生儿的临床前原理验证仔猪模型中评估由此产生的优化装置的安全性和有效性。结果将使该项目进入第三阶段，其中树脂和设备将在 cGMP 条件下制造，并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中对设备进行测试。 公共健康相关性：拟议的工作将推进主导树脂（固定螯合剂）的发展，并开发和测试包含该树脂的原型装置，以创建一种医疗装置，以去除静脉溶液中的有毒污染物铝（Al）。该装置将在接受静脉喂养的新生儿动物模型的临床前原理验证研究中进行测试。这将消除铝对早产儿和其他通过静脉输液接触铝的患者产生毒性的可能性，解决了一个数十年来一直未能得到解决的问题。

项目成果

A Filtration System That Greatly Reduces Aluminum in Calcium Gluconate Injection, USP Used to Prepare Parenteral Nutrition Solutions.

一种可大大减少葡萄糖酸钙注射液中铝含量的过滤系统，USP 用于制备肠外营养溶液。

• DOI: 10.5863/1551-6776-19.3.189
• 发表时间: 2014
• 期刊: The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG
• 作者: Yokel,RobertA;Harris,WesleyR;Spilling,ChristopherD;Abramov,VasiliyP;Lone,JasonM;Kuhn,RobertJ
• 通讯作者: Kuhn,RobertJ