SBIR-STTR Award

A high percentage of the ~ 470,000 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. 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 years 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. 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, it is proposed to synthesize 3 new chelators which are predicted to be effective in this application, and to synthesize 1 of these new chelators with 3 different tethers, that link it to a resin bead (creating immobilized chelators). These novel chelators will then be characterized to determine their stability constants with Al and their rate and efficiency to complex Al when introduced in Ca gluconate solution. It is proposed to load this immobilized chelator into a filter cartridge that can be used to remove Al from the SVP solutions as they are dispensed through the cartridge from the SVP storage bottles into the final TPN solution.

Project narrative:
The proposed work will develop new chemicals (chelators) that can be put into a medical device to remove a toxic contaminant, aluminum (Al), from intravenous solutions. 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.

Thesaurus Terms:
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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.

Thesaurus Terms:
0-11 Years Old; 21+ Years Old; Abbott Brand Of Calcium Gluconate; Abscission; Address; Adult; Advocacy; Al Element; Aluminum; Alzheimer; Alzheimer Disease; Alzheimer Sclerosis; Alzheimer Syndrome; Alzheimer's; Alzheimer's Disease; Alzheimers Dementia; Alzheimers Disease; American Pharmaceutical Partners Brand Of Calcium Gluconate; American Regent Brand Of Calcium Gluconate; Animal Model; Animal Models And Related Studies; Award; Baby Formula; Bile Duct Obstruction; Biliary Stasis; Binding; Binding (Molecular Function); Birth; Blood Coagulation Factor Iv; Bone Diseases, Metabolic; Brain; Businesses; Ca++ Element; Calcium; Calcium Gluconate; Caliber; Caring; Chelating Agents; Chelators; Child; Child Youth; Childhood; Children (0-21); Cholestasis; Clinical; Coagulation Factor Iv; Complexons; Cyclic Gmp; D-Gluconic Acid, Calcium Salt (2[{..}]1); D-Gluconate; D-Gluconic Acid; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Development; Devices; Diameter; Encephalon; Encephalons; Encephalopathies; Endotoxins; European; Excision; Extirpation; Factor Iv; Filtration; Fractionation, Filtration; Goals; Guanosine Cyclic 3',5'-Monophosphate; Guanosine Cyclic Monophosphate; Guanosine, Cyclic 3',5'-(Hydrogen Phosphate); Guidelines; Hdpe; Health Care Providers; Health Personnel; Healthcare Providers; Healthcare Worker; Hemodialyses; Hemodialysis; Housing; Human; Human, Adult; Human, Child; Human, General; Iv Fluid; Infant; Infant Formula; Infant, Premature; Injection Of Therapeutic Agent; Injections; Intake; Intensive Care Units, Neonatal; Intravenous; Intravenous Feeding; Intravenous Fluid; Kentucky; Kidney; Label; Lead; Ligand Binding; Liver; Man (Taxonomy); Man, Modern; Marketing; Medical Device; Membrane; Metabolic Bone Diseases; Metabolic Disorder Of Bone; Metals; Methods; Modeling; Molecular Interaction; Neonatal; Neonatal Intensive Care Units; Nervous System, Brain; Newborn Intensive Care Units; Oral; Parenteral Hyperalimentation; Parenteral Nutrition, Total; Particulate Matter; Parturition; Patients; Pb Element; Pharmacies; Pharmacopoeias; Pharmacy Facility; Phase; Plant Resins; Plastics; Polyethylene, High-Density; Polymers; Position; Positioning Attribute; Premature Infant; Preparation; Pressure; Pressure- Physical Agent; Price; Primary Senile Degenerative Dementia; Process; Production; Property; Property, Loinc Axis 2; Pyrogens; Recommendation; Removal; Renal Function; Research; Research Institute; Residual; Residual State; Resins, Plant; Resolution; Respondent; Risk; Sttr; Safety; Skeletal System; Small Business Technology Transfer Research; Sodium Chloride; Sodium Chloride (Nacl); Solutions; Solvents; Stage 5 Kidney Failure; Stage 5 Renal Failure; Staging; Sterility; Stress; Surgical Removal; Survey Instrument; Surveys; Testing; Total Parenteral Nutrition; Toxic Effect; Toxicities; United States; Universities; Urinary System, Kidney; Variant; Variation; Work; Adult Human (21+); Base; Bile Obstruction; Bile Occlusion; Body System, Hepatic; Bone Metabolism Disorder; Cgmp; Chemical Binding; Chemical Release; Children; Computational Chemistry; Dementia Of The Alzheimer Type; Design; Designing; Drinking Water; Feeding; Fluid Flow; Gluconate; Gluconic Acid; Guanosine 3'5' Monophosphate; Health Care Personnel; Health Care Worker; Health Provider; Healthcare Personnel; Heavy Metal Pb; Heavy Metal Lead; Kidney Function; Medical Personnel; Meetings; Membrane Structure; Mental Development; Metabolic Bone Disease; Model Organism; Neonate; Novel; Organ System, Hepatic; Pediatric; Phase 2 Study; Pre-Clinical; Preclinical; Premature Baby; Premature Infant Human; Pressure; Preterm Baby; Preterm Infant; Preterm Infant Human; Preterm Neonate; Pricing; Primary Degenerative Dementia; Prototype; Public Health Relevance; Renal; Resection; Resin; Safety Study; Salt; Senile Dementia Of The Alzheimer Type; Skeletal; Sterile; Treatment Provider; Youngster