GI safety and therapeutics of oil-based PC-NSAIDs

在这个II期申请中，我们建议继续和扩大在I期进行的非常有前途的实验线，以确认一个新的磷脂酰胆碱（PC）相关非甾体抗炎药（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 -NSAID的配方从水悬浮液修改为含有NSAID（阿司匹林或布洛芬）和等量的三倍强度卵磷脂的油基配方的可行性，这在药物稳定性、商品成本和减少生产步骤方面都有好处。I期最终报告中的数据显示，与未修饰的非甾体抗炎药相比，油基pc -布洛芬和pc -阿司匹林可减少急性和慢性胃肠道溃疡，促进溃疡愈合，并具有优越的镇痛活性。在概述的II期研究中，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，以比较pc -布洛芬和pc -阿司匹林，我们的两种主要化合物，分别与未改性的布洛芬和阿司匹林相比，对胃肠道溃疡/出血和溃疡愈合的影响。我们还计划进行一系列类似的实验来比较我们的测试PC-NSAID配方在急性和慢性后爪炎症模型中的镇痛/抗炎活性。此外，我们还提出了一些体外研究，使用红外、光散射光谱和选择性挤压过滤技术来证明PC与布洛芬或阿司匹林的分子关联，以及这种关联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 - nsaid治疗活性增加的分子，细胞和生理基础，重点是膜通透性，环氧化酶（COX）抑制活性和药物的生物利用度。在后面的研究中，我们将研究PC是否促进非甾体抗炎药在进入淋巴系统的乳糜微粒中的摄取和分布。最后，我们进行了一系列实验，以证实油基pc -布洛芬或pc -阿司匹林的配方中的任何修改都是必要的，以应对生产和稳定性问题，保持这种新型非甾体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.