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

• 批准号: 7910222
• 负责人: Upendra Marathi
• 金额: $ 15.79万
• 依托单位: PLX OPCO, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-05 至 2011-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7910222
• 关键词: Accounting; Acetone; Adult; Advanced Development; Affect; Animal Model; Animal Testing; Anti Inflammatory Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Aspirin; Attenuated; Bile fluid; Biological Models; Biology; Blood Circulation; Bronchopulmonary Dysplasia; Caliber; Caring; Cattle; Cells; Cessation of life; Childhood; Chronic; Clinical; Clinical Trials; Complex; Complication; Computer Systems Development; Congenital Heart Defects; Consumption; Data; Development; Digestive System Disorders; Dinoprostone; Disease; Dose; Drug Formulations; Emergency Situation; Ensure; Epithelium; Etiology; Evaluation; Family; Frequencies; Funding; Gastrointestinal Diseases; Gastrointestinal Injury; Gastrointestinal tract structure; Glucocorticoids; Goals; Grant; Health Sciences; Hemorrhage; Hospitals; Ibuprofen; Incidence; Indomethacin; Infant; Inflammation; Injury; Intestinal Perforation; Intestines; Intravenous; Investigational New Drug Application; Laboratories; Lead; Lecithin; Legal patent; Life; Low Birth Weight Infant; Lower Gastrointestinal Tract; Lung; Manufacturer Name; Methods; Modeling; Modification; Molecular; Morbidity - disease rate; Mucous Membrane; Mucous body substance; Naproxen; Necrotizing Enterocolitis; Neonatal; Neonatal Intensive Care Units; Non-Rodent Model; Non-Steroidal Anti-Inflammatory Agents; Obstruction; Operative Surgical Procedures; Particle Size; Patent Ductus Arteriosus; Pathway interactions; Patients; Perforation; Pharmaceutical Preparations; Pharmacology; Phase; Phospholipids; Pilot Projects; Play; Pre-Clinical Model; Pregnancy; Premature Infant; Preparation; Property; Rattus; Regimen; Replacement Therapy; Reporting; Research Personnel; Residual state; Risk; Risk Factors; Rodent; Rodent Model; Role; Safety; Series; Severities; Simulate; Small Business Innovation Research Grant; Solvents; Source; Sterility; Surface; Technology; Testing; Texas; Tissues; Toxic effect; Toxicology; Toxin; Treatment Efficacy; United States Food and Drug Administration; Universities; Very Low Birth Weight Infant; Weight; Work; base; commensal microbes; commercialization; comparative; comparative efficacy; design; effective therapy; feeding; gastrointestinal; high risk; human disease; improved; intravenous administration; intraventricular hemorrhage; medical schools; mortality; neonate; non-drug; novel; pre-clinical; premature; prevent; programs; prototype; public health relevance; pup; research and development; research study; respiratory distress syndrome; scale up; soy; stability testing; standard of care; success; surfactant; trend

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.

描述（由申请人提供）：本申请是第一阶段SBIR赠款申请。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%，并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，除了体重< 1.5 kg外，已确定的风险因素还包括配方奶粉喂养和使用吲哚美辛，这是治疗和/或预防动脉未闭（PDA）发展的护理标准。PDA是一种导致肺血管循环短路的疾病，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I期申请中，我们将进一步开发和评价一种新型吲哚美辛胃肠外制剂，其中NSAID与磷脂酰胆碱（PC）结合，采用PLx Pharma Inc开发的专有制剂方法;该组合物将吲哚美辛与PC非共价结合，似乎可减少单独使用吲哚美辛引起的GI损伤。在最初的实验中，我们将验证我们的初步观察，表明静脉内（i. v.）使用NSAID诱导的GI出血的成年啮齿动物模型，施用的吲哚美辛-PC具有比单独的吲哚美辛大大降低的GI毒性。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仔进行一系列初步研究，以评价我们的药物制剂的GI安全性和有效性。同样在第一阶段，我们建议优化吲哚美辛-PC的实验室配方，使其可以无菌过滤和包装，以确保其作为“医院护理”产品胃肠外使用的足够长的保质期。这些研究将在II期期间在参与程度更高的NEC仔猪模型中继续和扩展，该模型可能更接近模拟临床状况，并与商业生产商合作进行进一步的制剂开发。这些实验的结果将允许选择单一的、经验证的先导吲哚美辛-PC制剂。本赠款提案中包含的活动将显著推进吲哚美辛-PC的商业化开发，并明确设计为II期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显示具有改善的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进，并降低发生NEC和SIP（破坏性胃肠道疾病）的风险。 公共卫生关系：几乎所有目前可用的非甾体抗炎药（NSAID），包括吲哚美辛、萘普生、布洛芬和阿司匹林，都会引起严重的胃肠道损伤。静脉注射吲哚美辛是治疗严重心脏缺陷（称为动脉导管未闭）的标准治疗方法，这种心脏缺陷在低出生体重和极低出生体重婴儿中很常见。然而，静脉注射吲哚美辛经常引起或导致严重的胃肠道损伤，这可能是致命的。这项拨款提案将部分资助开发一种新的吲哚美辛和磷脂酰胆碱分子复合物，一种新的吲哚美辛制剂，可显著减少胃肠道损伤。