GI-Safer Formulation of Indomethacin for use in Preterm Neonates

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DESCRIPTION (provided by applicant): This application is a Phase I SBIR grant application. One of the major causes of morbidity and mortality of low birth weight neonates relates to injury, inflammation, perforation and obstruction of the lower GI tract, which can be manifest in the related diseases Necrotizing Enterocolitis (NEC) and Spontaneous Intestinal Perforation (SIP). These digestive diseases, which affect 2-5% of preterm babies, frequently require major surgery and are associated with a mortality rate of 20-50%, and have replaced respiratory distress syndrome as the major complication that afflicts these high-risk neonatal patients. The etiology of both NEC and SIP have yet to be elucidated, and risk factors that have been identified, in addition to a weight of < 1.5 kg, include formula feeding and the use of indomethacin, the standard of care to treat and/or prevent the development of Patent Ductus Arteriosus (PDA). PDA is a condition which results in the circulation short circuiting the pulmonary vasculature, leading to inadequate oxygenation, increasing the risk of intraventricular hemorrhage, bronchopulmonary dysplasia, and death. In this Phase I application we will further develop and evaluate a novel indomethacin parenteral, in which the NSAID is associated with phosphatidylcholine (PC), utilizing the proprietary formulation method developed by PLx Pharma Inc; this composition non-covalently associates indomethacin with PC, which appears to reduce the GI injury caused by indomethacin alone. In the initial experiments we will validate our preliminary observations that indicate that intravenously (i.v.) administered Indomethacin-PC has a greatly reduced GI toxicity than indomethacin alone utilizing adult rodent models of NSAID-induced GI bleeding. These studies will then be followed by a series of pilot studies performed on neonatal rat pups using established rodent models of NEC and PDA closure to evaluate the GI safety and efficacy of our drug formulation. Also in Phase I, we propose to optimize the laboratory formulation of Indomethacin-PC so that it can be sterile filtered and packaged to assure a sufficiently long shelf-life for it to be used parenterally as a "hospital care" product. These studies will be continued and expanded, during Phase II in a more involved, piglet model of NEC which may more closely simulate the clinical condition, and carry out further formulation development in partnership with a commercial manufacturer. The results of these experiments will allow selection of a single, validated lead Indomethacin-PC formulation. The activities encompassed in this grant proposal will significantly advance the Indomethacin-PC development toward commercialization and are explicitly designed to serve as the basis for a Phase II SBIR grant proposal. If the Indomethacin-PC formulation is shown in subsequent development efforts to possess an improved GI safety profile, together with equivalent efficacy compared with indomethacin, it will represent an important improvement in the standard of care for the treatment of low birth weight neonates with potential or confirmed PDA, with reduced risk of developing NEC and SIP, devastating diseases of the GI tract. PUBLIC HEALTH RELEVANCE: Nearly all currently available non-steroidal anti-inflammatory drugs (NSAIDs), including indomethacin, naproxen, ibuprofen, and aspirin, cause significant GI damage. Intravenously administered indomethacin is the standard of care for the treatment of a serious cardiac defect that is common in low- and very-low birth weight infants, called patent ductus arteriosus. However, IV indomethacin frequently causes or contributes to serious GI damage that can be lethal to these infants. This grant proposal will partially fund the development of a new molecular complex of indomethacin and phosphatidylcholine, a new formulation of indomethacin that significantly reduces GI injury.