Multifunctional injectable agent for endoscopic mucosal resection

项目摘要 根据发病率，全球粘膜下注射溶液市场估计约为30亿美元 以及已知与内窥镜黏膜相关的医学诊断的患病率 切除/内窥镜黏膜下剥离(EMR/ESD)，市场是由改进的需求推动的 可注射性和粘膜下抬高时间延长。到目前为止，只有三种粘膜下提升液，EleviewTM(Aries PharmPharmticals，Inc.)、OriseTM Gel(波士顿科学公司)和EverliftTM(GI Supply)在 美国。这些产品受到临床前和临床上不一致的粘膜下提升持续时间的限制 临床环境或其注射效果不令人满意。此外，没有一种产品能够解决出血问题 问题，这是EMR/ESD最常见的并发症之一。第一阶段提案的主要目标是 开发Aleo BME的专利多功能粘膜下注射剂(Aleo BMESolution)，可以促进 通过EMR/ESD安全手术切除胃肠道肿瘤，并使术后出血成为可能 管理层。Aleo BMESolution是一种混合流体凝胶组合物，主要由海藻酸钠(SA)作为 凝胶组分，钙结合低聚物为关键改性剂，钙离子为交联剂。这个 新奇之处在于它的设计策略，其中借鉴了食物中的液体凝胶概念的独特组合 行业和通过引入钙结合修饰剂的竞争结合机制 同时实现了相对高粘度溶液的低注射压力，并有很大改进 止血性能。该提案的前期研究的严谨性得到了我们的初步支持 资料包括：1)Aleo BMESolution是一种剪切稀释型海藻酸盐凝胶，它是钙的悬浮液- 凝胶颗粒通过颗粒间相互作用弱结合在一起；2)低聚物的策略性加成 在藻酸盐流体凝胶中加入改性剂，即使在升高的情况下也能显著降低系统的注入压力 钙浓度；3)注射到狭窄的粘膜下间隙后，增厚的水凝胶垫 形成；4)切除后，增稠的液体凝胶残留物在皮肤上形成稳定的保护密封剂(敷料)。 伤口。5)钙结合低聚体修饰剂的加入使剪切变稀成为可能。 含有高浓度海藻酸盐和钙的粘附性/粘附性保护液凝胶 协同作用有助于Aleo BMESolution急需的止血性能。预期中的 这项建议的结果是，我们将开发一种多功能多功能黏膜下注射剂， 性能优于现有产品，如理想的注射压力、延长的粘膜下时间 使用寿命、优先的流变性和保质期、出色的生物兼容性和无与伦比的止血效果 功能，以满足服务不足的EMR/ESD注入解决方案市场不断增长的需求。

Project Summary The global submucosal injection solution market is estimated to be around $3 billion according to the incidence and prevalence rates of medical diagnoses known to be associated with endoscopic mucosal resection/endoscopic submucosal dissection (EMR/ESD), and the market is driven by the need to improve injectability and prolonged submucosal elevation. To date, only three submucosal lift solutions, EleviewTM (Aries Pharmaceuticals, Inc), OriseTM Gel (Boston Scientific), and EverliftTM (GI supply) are approved by FDA in the United States. These products are limited either by the inconsistent submucosal lift duration in preclinical and clinical settings or by their unsatisfactory injectability. Also, none of the products are able to address the bleeding problem, one of the most common complications for EMR/ESD. The primary goal of the Phase I proposal is to develop Aleo BME’s proprietary multifunctional submucosal injection agent (Aleo BMESolution) that can facilitate the safe surgical removal of gastrointestinal neoplasms via EMR/ESD, and enable post-surgical bleeding management. Aleo BMESolution is a mixed fluid gel composition mainly composed of sodium alginate (SA) as the gelling component, calcium-binding oligomer as the key modifier, and calcium ions as the crosslinker. The novelty lies in its design strategy in which a unique combination of a fluid gel concept borrowed from the food industry and a competitive binding mechanism via the introduction of a calcium-binding modifier was adopted to simultaneously achieve low injection pressure for relatively high viscosity solutions and much-improved hemostatic property. The Rigor of The Prior Research of the proposal is strongly supported by our preliminary data, including: 1) Aleo BMESolution is a shear-thinning alginate fluid gel that is a suspension of calcium- crosslinked gelled particles weakly held together via inter-particle interactions; 2) The tactic addition of oligomeric modifiers into alginate fluid gels significantly reduces the injection pressure of the system even at elevated calcium concentrations; 3) After injection into the confined submucosal space, a thickened hydrogel cushion is formed; 4) After resection, the residual of thickened fluid gels form a stable protective sealant (dressing) on the wound. 5) The addition of calcium-binding oligomeric modifiers makes it possible to make the shear-thinning mucoadhesive/mucoprotective fluid gels with elevated concentrations of alginate and calcium which synergistically contribute to the much-needed hemostaic properties of Aleo BMESolution. The expected outcome of this proposal is that we will develop an all-in-one multifunctional submucosal injection agent with superior performance over the existing products, such as desirable injection pressure, prolonged submucosal life, preferred rheological properties and shelf life, excellent biocompatibility, and unparalleled hemostatic function, to address ever-increasing needs in the underserved EMR/ESD injection solution market.