GI safety and therapeutics of oil-based PC-NSAIDs

描述(申请人提供)：在这项第二阶段的申请中，我们建议继续并扩大在第一阶段进行的非常有希望的实验系列，以证实一种新的磷脂酰胆碱(PC)相关非类固醇抗炎药物(NSAIDs)家族的胃肠道安全性和治疗活性。在第一阶段，我们确定了将PC-NSAIDs的配方从水悬浮液修改为含有NSAID(阿司匹林或布洛芬)和等量三倍强度卵磷脂的油基配方的可行性，这在药物稳定性、商品成本和减少制造步骤方面都有好处。第一阶段最终报告中提供的数据表明，与未经修改的非甾体抗炎药相比，油基PC-布洛芬和PC-阿司匹林减少了急性和慢性胃肠道溃疡，促进了溃疡愈合，并具有更好的止痛活性。在概述的第二阶段研究中，我们建议在更全面的慢性动物模型系统中继续进行这些研究，将我们的两种先导化合物PC-布洛芬和PC-阿司匹林分别与未经修饰的布洛芬和阿司匹林在胃肠道溃疡/出血和溃疡愈合方面进行比较。我们还计划进行一系列类似的实验，以比较我们测试的PC-NSAID制剂在急性和慢性后爪炎模型中的止痛/抗炎活性。此外，我们还提出了一些使用红外光谱和光散射光谱以及选择性挤出过滤技术的体外研究，以证明PC与布洛芬或阿司匹林的分子结合以及这如何影响脂质颗粒的大分子结构。我们还描述了一些实验，以确定PC-NSAIDs提高治疗活性的分子、细胞和生理基础，重点是膜通透性、环氧合酶(COX)抑制活性和药物的生物利用度。在后一项研究中，我们将研究PC是否促进NSAIDs在进入淋巴系统的乳糜粒中的摄取和分布。最后，我们包括了一系列实验，以证实对油基PC-布洛芬或PC-阿司匹林配方的任何修改都是必要的，以应对制造和稳定性问题，保持这一新的非类固醇抗炎药家族优越的胃肠道安全性和治疗活性。

DESCRIPTION (provided by applicant): In this Phase II application we propose to continue and expand the very promising line of experiments, performed during Phase I, to confirm the GI safety and therapeutic activity of a new family of phosphatidylcholine (PC) - associated nonsteroidal anti-inflammatory drugs (NSAIDs). In Phase I, we established the feasibility of modifying the formulae of PC-NSAIDs from an aqueous suspension to an oil-based formulation containing the NSAID (aspirin or ibuprofen) and equal parts of triple strength lecithin, which has benefits with regards to drug stability, cost of goods, and reduction in manufacturing steps. The data presented in the Phase I final report show that oil-based PC-ibuprofen and PC-aspirin reduced acute and chronic GI ulceration, promoted ulcer healing and had superior analgesic activity in comparison to the unmodified NSAID. In the outlined Phase II studies we propose to continue with these studies in more comprehensive chronic animal model systems, to compare PC-ibuprofen and PC-aspirin, our two lead compounds, on GI ulceration/bleeding and ulcer healing vs unmodified ibuprofen and aspirin, respectively. A similar series of experiments are also planned to compare the analgesic/anti-inflammatory activity of our test PC-NSAID formulations in acute and chronic models of hind paw inflammation. Further, we also propose a number of in vitro studies using Infrared and light scattering spectroscopy, and selective extrusion filtration techniques to demonstrate the molecular association of PC with either ibuprofen or aspirin and how this affects macromolecular structure of the lipidic particles. We also describe a number of experiments to define the molecular, cellular and physiological basis for the increased therapeutic activity of PC-NSAIDs, with a focus on membrane permeability, cyclooxygenase (COX)-inhibitory activity and bioavailability of the drugs. In the latter studies, we will investigate whether PC promotes the uptake and distribution of the NSAIDs into chylomicrons that enter the lymphatic system. Lastly, we include a series of experiments to confirm that any modification in the formulation of either oil-based PC-ibuprofen or PC-aspirin that are necessitated in response to manufacturing and stability issues, maintains the superior GI safety and therapeutic activity of this new family of NSAIDs.