GI-Safer Formulation of Indomethacin for use in Preterm Neonates

描述(申请人提供)：本申请是第一阶段的SBIR资助申请。低出生体重儿的发病率和死亡率的主要原因之一与下消化道损伤、炎症、穿孔和梗阻有关，可在相关疾病坏死性小肠结肠炎(NEC)和自发性肠穿孔(SIP)中表现出来。这些消化系统疾病影响2%-5%的早产儿，经常需要进行大手术，死亡率高达20%-50%，已取代呼吸窘迫综合征成为困扰这些高危新生儿患者的主要并发症。NEC和SIP的病因尚未阐明，已确定的风险因素除了体重1.5公斤外，还包括配方奶喂养和吲哚美辛的使用，这是治疗和/或防止动脉导管未闭(PDA)发展的护理标准。动脉导管未闭是一种导致循环短路的肺血管系统，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。在这一第一阶段的应用中，我们将利用PLx制药公司开发的专利配方方法，进一步开发和评估一种新型的吲哚美辛肠外制剂，其中非甾体抗炎药与磷脂酰胆碱(PC)有关；这种组合物将吲哚美辛与PC非共价结合，似乎可以减少单独由吲哚美辛引起的胃肠道损伤。在最初的实验中，我们将验证我们的初步观察，表明静脉(静脉)。在非甾体类抗炎药诱导的胃肠道出血的成年啮齿动物模型上，使用吲哚美辛-PC比单独使用吲哚美辛的胃肠道毒性要低得多。在这些研究之后，将使用已建立的NEC和PDA闭合啮齿动物模型对新生大鼠幼鼠进行一系列先导性研究，以评估我们药物配方的GI安全性和有效性。此外，在第一阶段，我们建议优化吲哚美辛-PC的实验室配方，以便它可以经过无菌过滤和包装，以确保足够长的保质期，使其能够作为非肠道治疗产品使用。这些研究将在第二阶段继续并扩大，在更复杂的NEC仔猪模型中进行，该模型可能更接近临床情况，并与商业制造商合作进行进一步的配方开发。这些实验的结果将允许选择单一的、有效的吲哚美辛-PC铅配方。这项赠款提案中包含的活动将极大地推动吲哚美辛-PC的开发走向商业化，并明确地设计作为第二阶段SBIR赠款提案的基础。如果吲哚美辛-PC制剂在随后的开发工作中被证明具有更好的胃肠道安全性，以及与吲哚美辛同等的疗效，它将代表着治疗潜在或确诊PDA的低出生体重儿护理标准的重要改进，降低了发生NEC和SIP的风险，这是胃肠道的毁灭性疾病。 公共卫生相关性：目前几乎所有可用的非类固醇抗炎药(NSAID)，包括消炎痛、萘普生、布洛芬和阿司匹林，都会对胃肠道造成重大损害。静脉注射吲哚美辛是治疗一种严重心脏缺陷的标准护理方法，这种缺陷在低出生体重和极低出生体重的婴儿中很常见，称为动脉导管未闭。然而，静脉注射吲哚美辛经常会导致或促成严重的胃肠道损害，可能会对这些婴儿造成致命的损害。这项赠款提案将部分资助开发一种新的吲哚美辛和磷脂酰胆碱的分子复合体，这是一种显著减少胃肠道损伤的吲哚美辛新配方。

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.