GI safety and therapeutics of oil-based PC-NSAIDs

描述（由申请人提供）：在本II期申请中，我们建议继续并扩展在I期期间进行的非常有前景的实验系列，以确认磷脂酰胆碱（PC）相关非甾体抗炎药（NSAID）新家族的GI安全性和治疗活性。在I期研究中，我们确定了将PC-NSAID的配方从水性混悬剂修改为含有NSAID（阿司匹林或布洛芬）和等量三倍强度卵磷脂的油基制剂的可行性，这在药物稳定性、商品成本和减少制造步骤方面具有益处。I期最终报告中提供的数据表明，与未改性NSAID相比，油基PC-布洛芬和PC-阿司匹林可减少急性和慢性GI溃疡，促进溃疡愈合，并具有上级镇痛活性。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，以比较我们的两种先导化合物PC-布洛芬和PC-阿司匹林分别与未修饰的布洛芬和阿司匹林对GI溃疡/出血和溃疡愈合的影响。还计划进行类似的一系列实验以比较我们的测试PC-NSAID制剂在后爪炎症的急性和慢性模型中的镇痛/抗炎活性。此外，我们还提出了一些体外研究，使用红外和光散射光谱，和选择性挤出过滤技术，以证明与布洛芬或阿司匹林的PC的分子缔合，以及这如何影响大分子结构的布洛芬颗粒。我们还描述了一些实验，以确定PC-NSAID的治疗活性增加的分子，细胞和生理基础，重点是膜渗透性，环氧合酶（考克斯）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NSAID吸收和分布到进入淋巴系统的乳糜微粒中。最后，我们包括一系列实验以证实油基PC-布洛芬或PC-阿司匹林的制剂中的任何改变（其是响应于制造和稳定性问题所必需的）保持了该新NSAID家族的上级GI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.