GI safety and therapeutics of oil-based PC-NSAIDs

描述（由申请人提供）：该I期STTR资助的主要目的是评价一类新型非甾体抗炎药（NSAID）的GI安全性、治疗活性和稳定性，该类药物采用富含磷脂酰胆碱（PC）的大豆油配制。这代表了PI及其同事开发的第二代PC-NSAID，在药物的成本和稳定性方面具有额外的益处。本申请的具体目的集中于确认初步数据，即油基PC-NSAID（特别是PC-阿司匹林和PC-布洛芬）具有低GI毒性和增强的治疗活性，采用急性和慢性NSAID诱导的溃疡疾病和关节炎症/疼痛的啮齿动物模型。我们还提出了一系列的体内和体外研究，以确定增强治疗的PC-NSAID的分子基础，评价药物的生物利用度，膜通透性和环氧合酶（考克斯）抑制活性。在最后一个具体目标中，我们将采用限制NSAID暴露于水的包封技术，在存在和不存在流化剂和抗氧化剂的情况下评价硬胶囊中PC-阿司匹林和PC-布洛芬的稳定性，这对阿司匹林特别重要。上述研究将为我们启动PC-NSAID的临床试验和商业化提供重要信息。

DESCRIPTION (provided by applicant): The major objective of this Phase I STTR grant is to evaluate the GI safety, therapeutic activity and stability of a new class of non-steroidal anti-inflammatory drugs (NSAIDs) that are formulated with a soy bean oil that is enriched in phosphatidylcholine (PC). This represents a second generation of PC-NSAIDs, developed by the PI and associates, that would have additional benefits with regards to cost and stability of the drug. The specific aims of this application are focused on confirming preliminary data that the oil-based PC-NSAIDs (and specifically PC-aspirin and PC-ibuprofen) possess low GI toxicity and enhanced therapeutic activity employing rodent models of acute and chronic NSAID-induced ulcer disease, and joint inflammation/pain. We also propose a series of in vivo and in vitro studies to define the molecular basis of the enhanced therapeutics of the PC-NSAIDs, evaluating the drugs' bioavailability, membrane permeability and cyclooxygenase (COX) inhibitory activity. In the last specific aim, we will evaluate the stability of PC-aspirin and PC-ibuprofen in the presence and absence of fluidizers and anti-oxidants in hard capsules employing an encapsulation technique that would limit the NSAIDs' exposure to water, which is particularly critical for aspirin. The above studies will provide us with important information required for the initiation of clinical trials and commercialization of PC-NSAIDs.