GI-Safer Formulation of Indomethacin for use in Preterm Neonates

描述（由申请人提供）：本申请是SBIR第二阶段赠款。低出生体重新生儿发病率和死亡率的主要原因之一与下胃肠道的损伤、炎症、穿孔和梗阻有关，其可表现为相关疾病坏死性小肠结肠炎（NEC）和自发性肠穿孔（SIP）。这些消化系统疾病影响2 - 5%的早产儿，经常需要大手术，死亡率为20 - 50%。NEC和SIP的病因尚未完全阐明，并且除了出生体重<1.5 kg之外，已经确定的风险因素包括配方奶粉喂养和吲哚美辛的使用，吲哚美辛是治疗和/或预防动脉未闭（PDA）发展的护理标准，PDA是导致肺血管循环短路的病症，导致氧合不足，增加脑室内出血、支气管肺发育不良和死亡的风险。在该II期申请中，我们将进一步开发和评估吲哚美辛的新型专有胃肠外制剂，其中NSAID与磷脂酰胆碱（PC）非共价结合，使其对胃肠道更安全。吲哚美辛-PC（PL 4500）的这种组合物似乎减少了成年动物中单独由吲哚美辛引起的GI损伤。在之前的I期实验中，我们发现，如果动物是母乳喂养的，则断奶前新生大鼠对吲哚美辛的GI毒性具有明显的抗性，但如果它们是配方奶喂养的，则没有。此外，在断奶期间，肠胆汁酸和回肠胆汁酸摄取转运蛋白（顶端钠依赖性胆汁酸转运蛋白，ASBT）的水平发育性增加，这可能与吲哚美辛GI毒性相关。对于以后的FDA文件来说，了解吲哚美辛对胃肠道损伤的可能机制以及吲哚美辛-PC如何提供保护是很重要的。因此，第一个目的是通过比较不同出生后年龄的母乳喂养和配方奶粉喂养的小鼠中的毒性;比较NEC模型中的毒性;以及比较野生型和ASBT敲除小鼠以及诱导早期表达ASBT的小鼠中的毒性，来评价吲哚美辛-PC与未修饰吲哚美辛在新生小鼠中的GI毒性。第二个目的是确定吲哚美辛-PC与吲哚美辛在PDA模型中的疗效。第三个目标是向合同商业制造商进行技术转让，并开始扩大吲哚美辛-PC的生产规模，目的是生产一种原型胃肠外制剂，适用于I期临床试验的稳定性、可重复性和随后的安全性评价。本资助提案中包含的开发活动将显著推进PL 4500的商业化。如果吲哚美辛-PC制剂继续具有改善的GI安全性特征，以及与吲哚美辛相当的疗效，则其将通过降低发生NEC和SIP（破坏性胃肠道疾病）的风险，代表治疗潜在或确诊PDA的低出生体重新生儿的护理标准的重要改善。

DESCRIPTION (provided by applicant): This application is for a SBIR Phase II grant. 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%. The etiology of both NEC and SIP have yet to be fully elucidated, and risk factors that have been identified, in addition to a birth weight o <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), 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 II application we will further develop and evaluate a novel proprietary parenteral formulation of indomethacin, in which the NSAID is non-covalently associated with phosphatidylcholine (PC) to make it safer for the GI tract. This composition of Indomethacin-PC (PL4500) appears to reduce the GI injury caused by indomethacin alone in adult animals. In the prior Phase I experiments, we found that there was an apparent resistance to GI toxicity of indomethacin in rat neonates before weaning if the animals were breast- fed, but not if they were formula-fed. Also, during weaning there were developmentally increasing levels of both intestinal bile acid and ileal bile acid uptake transporter (apical sodium-dependent bile acid transporter, ASBT) which may be associated with indomethacin GI toxicity. It is important for later FDA filings to understand the possible mechanism of GI injury by indomethacin and how indomethacin-PC may offer protection. Thus, the first aim is to evaluate the GI toxicity of indomethacin-PC versus unmodified indomethacin in neonatal mice by comparing toxicity in breast-fed and formula-fed mice at different postnatal ages; comparing toxicity in a model of NEC; and comparing toxicity in wildtype and ASBT knockout mice and in mice induced to express ASBT early. The second aim is to determine the efficacy of indomethacin-PC versus indomethacin in a model of PDA. The third aim is to carry out technology transfer to a contract commercial manufacturer and initiate scale- up of Indomethacin-PC production, with the goal of yielding a prototype parenteral formulation that is suitable for stability, dispersibility, and subsequent safety evaluation in Phase I clinical trials. The development activities encompassed in this grant proposal will significantly advance PL4500 toward commercialization. If the Indomethacin-PC formulation continues 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, by reducing risk of developing NEC and SIP, devastating diseases of the GI tract.