GI-Safer Formulation of Indomethacin for use in Preterm Neonates

用于早产新生儿的胃肠道安全吲哚美辛制剂

基本信息

批准号：
8313502
负责人：
Upendra Marathi
金额：
$ 56.54万
依托单位：
PLX OPCO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-05 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8313502
关键词：
ASBT protein Accounting Adverse effects Affect Age Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Applications Grants Attenuated Bile Acids Bile fluid Birth Weight Blood Circulation Breast Feeding Bronchopulmonary Dysplasia Cardiovascular system Cessation of life Chronic Consultations Consumption Contracts Development Diet Digestive System Disorders Disease Drug Formulations Drug toxicity Emergency Situation Etiology Evaluation Gastrointestinal Diseases Gastrointestinal Injury Gastrointestinal tract structure Glucocorticoids Goals Grant Health Sciences Hemorrhage Hospitals Human Indomethacin Inflammation Injury Institution Intestinal Perforation Intestines Intravenous Knockout Mice Lead Lecithin Legal patent Life Low Birth Weight Infant Lower Gastrointestinal Tract Lung Manufacturer Name Medicine Modeling Morbidity - disease rate Mucous Membrane Mus Necrotizing Enterocolitis Neonatal Neonatal Intensive Care Units Obstruction Operative Surgical Procedures Patent Ductus Arteriosus Pathogenesis Pathway interactions Perforation Pharmaceutical Preparations Phase Phase I Clinical Trials Play Pregnancy Premature Infant Production Property Rattus Research Personnel Resistance Risk Risk Factors Rodent Role Safety Sepsis Small Business Innovation Research Grant Surface Technology Transfer Testing Texas Tissues Toxic effect Universities Very Low Birth Weight Infant Weaning bile acid transporter college commensal microbes commercialization comparative efficacy congenital heart disorder feeding forest gastrointestinal high risk improved intraventricular hemorrhage lung development mature animal medical schools mortality neonate novel pathogenic bacteria postnatal premature prevent prototype research study scale up standard care standard of care surfactant therapy development uptake

项目摘要

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.

描述（申请人提供）：此申请适用于SBIR II期赠款。低出生体重新生儿的发病率和死亡率的主要原因之一与胃胃肠道的损伤，炎症，穿孔和阻塞有关，这可能在相关疾病中表现出坏死性小肠结肠炎（NEC）和自发性肠道灌注（SIP）。这些消化系统疾病影响了2-5％的早产儿，经常需要进行大型手术，并且死亡率为20-50％。 NEC和SIP的病因尚未得到充分阐明，除了出生体重O <1.5 kg外，还鉴定出已鉴定出的危险因素包括配方奶粉喂养和使用放病蛋白的使用，是治疗和/或预防专利性导管（PDA）的护理标准（PDA），这是在循环中导致circulature the Pulmary cillmon-cirdone cillony cillmon-cirton cirton cirton cirton cirton cirton cirton cirton cirton cirton cirton cirton cirton cirton cirton cirton cirtone cirton cirton cirtone cirtone cirt的良好状态。氧合，增加脑室内出血，支气管肺发育不良和死亡的风险。在此II期应用中，我们将进一步开发和评估一种新型的吲哚美辛的专有肠胃菜制剂，其中NSAID与磷脂酰胆碱（PC）无共价相关，以使其更安全。这种吲哚美辛-PC（PL4500）的组成似乎减少了成年动物中单独氨基霉素引起的胃肠道损伤。在上一阶段的实验中，我们发现在断奶之前，如果动物是乳房喂养的，则对大鼠新生儿的胃肠菌毒性具有明显的抗药性，但如果它们是配方奶粉的，则不会。同样，在断奶期间，肠道胆汁酸和回肠胆酸摄取转运蛋白（顶钠依赖性胆汁酸转运蛋白，ASBT）的发展水平也可能与吲哚美辛GI毒性有关。以后的FDA申请了解吲哚美辛可能的胃肠道损伤机制以及吲哚美辛 - PC如何提供保护很重要。因此，第一个目的是通过比较不同年龄在不同年龄的母乳喂养和配方奶粉小鼠中的毒性来评估新生儿小鼠中炎辛-PC与未修饰的吲哚美辛的GI毒性；比较NEC模型中的毒性；并比较野生型和ASBT敲除小鼠的毒性以及诱发的小鼠早期表达ASBT的毒性。第二个目的是确定PDA模型中吲哚美辛PC与吲哚美辛的功效。第三个目的是将技术转移到合同商业制造商中，并启动吲哚美辛PC生产的规模，目的是产生适合于稳定性，分散性和随后在I期临床试验中的安全性评估的原型肠胃外配方。该赠款提案中包含的开发活动将大大推动PL4500朝着商业化发展。如果与吲哚美辛相比，吲哚美辛PC的配方继续具有改善的GI安全性，以及同等的疗效，这将代表着护理标准的重要改善，用于治疗潜在的或确认的PDA，通过降低NEC和SIP的风险，患有NEC和SIP的风险，破坏GI Tract的疾病。公共卫生相关性：过早出生的低出生体重婴儿非常容易受到许多潜在威胁生命的疾病，包括专利性导管（PDA）（PDA）和坏死性小肠结肠炎（NEC）。 PDA是早产婴儿通常发现的心脏的先天性疾病，可能导致氧合和死亡不足。 PDA的标准处理是静脉注射吲哚美辛（吲哚美蛋白（R）），已知与胃肠道（GI）副作用有关，包括：成熟动物和人类中的肠道出血，性格性和败血症。 NEC是影响新生儿重症监护病房过早婴儿的最常见手术紧急事件，导致穿孔，胃肠道出血过多以及病原和共生细菌的入侵。我们的假设是，在低出生体重婴儿治疗PDA中，使用吲哚美素（R）可能是NEC中重要的病因因素。该提案中正在开发的产品（指定的PL4500）是一种与磷脂酰胆碱相关的吲哚美辛的制定，使其对GI区域更安全，并有助于保护低出生体重婴儿免受NEC样疾病的发展。