GI-Safer Formulation of Indomethacin for use in Preterm Neonates

描述(由申请人提供)：本申请为SBIR第二阶段拨款。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，死亡率为20%-50%。NEC和SIP的病因尚未完全阐明，已确定的危险因素，除了出生体重小于1.5公斤外，还包括配方奶喂养和吲哚美辛的使用，治疗和/或预防动脉导管未闭(PDA)的护理标准，这种情况会导致循环短路，导致肺血管系统短路，导致氧合不足，增加脑室出血、支气管肺发育不良和死亡的风险。在这一第二阶段的应用中，我们将进一步开发和评估一种新的专有的吲哚美辛肠外制剂，其中非甾体抗炎药与磷脂酰胆碱(PC)非共价结合，使其对胃肠道更安全。吲哚美辛-PC(PL4500)的这种组合物似乎可以减轻单独使用吲哚美辛对成年动物造成的胃肠道损伤。在之前的第一阶段实验中，我们发现，如果断奶的大鼠在断奶前对吲哚美辛的胃肠道毒性有明显的抵抗力，但如果他们是配方奶喂养的，则不是这样。此外，在断奶期间，肠道胆汁酸和回肠胆汁酸摄取转运体(顶端钠依赖胆汁酸转运体，ASBT)的水平都在发育中增加，这可能与吲哚美辛的胃肠道毒性有关。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，对于以后提交FDA的文件是重要的。因此，第一个目的是通过比较母乳喂养和配方奶喂养的小鼠在不同出生年龄的毒性；比较NEC模型的毒性；比较野生型和ASBT基因敲除小鼠以及诱导早期表达ASBT的小鼠的毒性，来评估吲哚美辛-PC对新生小鼠的胃肠道毒性。第二个目的是确定消炎痛-PC与消炎痛在PDA模型中的疗效。第三个目标是将技术转让给一家合同商业制造商，并开始扩大吲哚美辛-PC的生产规模，目标是生产一种适用于稳定性、分散性和随后的I期临床试验安全性评估的原型注射用制剂。这项赠款提案中包含的开发活动将极大地推动PL4500走向商业化。如果吲哚美辛-PC制剂继续具有改善的胃肠道安全性，以及与吲哚美辛同等的疗效，它将通过降低发生NEC和SIP的风险，在治疗潜在或确诊为PDA的低出生体重儿的护理标准方面取得重要进展。 公共卫生相关性：早产的低出生体重儿极易患上多种潜在威胁生命的疾病，包括动脉导管未闭(PDA)和坏死性小肠结肠炎(NEC)。PDA是一种先天性心脏疾病，常见于早产儿，可导致氧合不足和死亡。治疗PDA的标准疗法是静脉注射吲哚美辛(Indocin(R))，这种药物已知与胃肠道(GI)副作用有关，包括在成年动物和人类中的肠道出血、穿孔和败血症。NEC是新生儿重症监护病房中影响早产儿的最常见的外科急症，会导致穿孔、胃肠道出血过多以及病原菌和共生菌的入侵。我们的假设是，在低出生体重婴儿中使用吲哚(R)治疗PDA可能是NEC的一个重要病因。这项提案中正在开发的产品名为PL4500，是一种与磷脂酰胆碱相关的吲哚美辛配方，使其对胃肠道更安全，并有助于保护低出生体重婴儿免受NEC样疾病的影响。

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. PUBLIC HEALTH RELEVANCE: Low birth weight infants, that are born prematurely, are highly susceptible to a number of potentially life- threatening conditions including Patent Ductus Arteriosus (PDA) and Necrotizing Enterocolitis (NEC). PDA is a congenital disease of the heart commonly found in premature infants that can lead to inadequate oxygenation and death. The standard treatment for PDA is intravenous indomethacin (Indocin(R)) which is known to be associated with gastrointestinal (GI) tract side effects including: intestinal bleeding, perforatios and sepsis in mature animals and humans. NEC is the most common surgical emergency that affects premature infants in the neonatal intensive care unit causing perforations, excessive GI bleeding, and an invasion of pathogenic and commensal bacteria. It is our hypothesis that the use of Indocin(R) in low birth weight infants to treat PDA may be an important etiological factor in NEC. The product under development in this proposal, designated PL4500, is a formulation of indomethacin that is associated with phosphatidylcholine to make it safer for the GI tract, and help protect low birth weight babies from developing NEC-like disease.