CN110691615A - Bimodal treatment method and composition for gastrointestinal lesions with active bleeding - Google Patents
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Abstract
Translated fromChinese
Description
Translated fromChinese相关申请Related applications
本专利文件要求2017年4月28日提交的美国专利申请序列号15/581,876的优先权，美国专利申请序列号15/581,876是2014年3月13日提交的美国专利申请序列号14/209,718的部分继续申请，美国专利申请序列号14/209,718在35U.S.C.§119(e)下要求2013年3月15日提交的美国临时专利申请序列号61/793,586的权益；2017年4月28日提交的美国专利申请序列号15/581,876也是2015年10月2日提交的美国专利申请序列号14/044,040的部分继续申请，这些申请特此通过援引并入。This patent document claims priority to US Patent Application Serial No. 15/581,876, filed on April 28, 2017, which is a benefit of US Patent Application Serial No. 14/209,718, filed March 13, 2014 Continuation-in-Part, US Patent Application Serial No. 14/209,718 claims the benefit of US Provisional Patent Application Serial No. 61/793,586, filed March 15, 2013, under 35 U.S.C. §119(e); filed April 28, 2017 US Patent Application Serial No. 15/581,876 is also a continuation-in-part of US Patent Application Serial No. 14/044,040, filed October 2, 2015, which is hereby incorporated by reference.
发明背景Background of the Invention
技术领域technical field
描述了用于递送治疗剂和治疗胃肠道中的病损的医学产品和方法，这些病损是例如因胃肠道障碍和或需要去除胃肠道壁的粘膜层或粘膜下层的医学程序引起的病损。Described are medical products and methods for delivering therapeutic agents and treating lesions in the gastrointestinal tract, resulting, for example, from disorders of the gastrointestinal tract and or medical procedures requiring removal of the mucosal or submucosa of the gastrointestinal wall lesions.
背景技术Background technique
存在可能希望将治疗剂引入人体或动物体内的若干例子。例如，可以引入治疗药物或生物活性材料，以实现生物效应。该生物效应可以包括一系列目标结果，例如诱导止血、密封穿孔、降低再狭窄可能性、或治疗癌性肿瘤或其他疾病。There are several examples where it may be desirable to introduce a therapeutic agent into a human or animal body. For example, therapeutic drugs or biologically active materials can be introduced to achieve biological effects. This biological effect can include a range of targeted outcomes, such as inducing hemostasis, sealing a perforation, reducing the likelihood of restenosis, or treating a cancerous tumor or other disease.
有若干种胃肠道障碍可引起胃肠道病损，例如胃肠道炎症、胃肠道癌、胃肠道感染、胃肠道运动功能失调，或一部分胃肠道组织中的病损、伤口或挫伤。另外，有众多种需要去除胃肠道壁的粘膜层或粘膜下层的医学程序也可引起胃肠道中的损伤或病损。这些程序包括内镜粘膜切除术(EMR)、内镜粘膜下解剖、息肉切除术、经口内镜肌切开术、活组织检查和消融(热、化学、射频和低温)。与这些胃肠道障碍一样，类似的不良事件可在去除粘膜层或粘膜下层后发生，包括出血和结构化。There are several gastrointestinal disorders that can cause gastrointestinal lesions, such as gastrointestinal inflammation, gastrointestinal cancer, gastrointestinal infection, gastrointestinal motility disorders, or lesions in a portion of the gastrointestinal tissue, wounds or contusion. In addition, a variety of medical procedures requiring removal of the mucosal or submucosa of the gastrointestinal tract wall can also cause injury or lesions in the gastrointestinal tract. These procedures include endoscopic mucosal resection (EMR), endoscopic submucosal dissection, polypectomy, peroral endoscopic myotomy, biopsy, and ablation (thermal, chemical, radiofrequency, and hypothermia). As with these gastrointestinal disorders, similar adverse events can occur following removal of the mucosal or submucosa, including bleeding and structuring.
许多治疗剂使用静脉内(IV)技术来注射，以及经由口服药物。尽管此类技术允许药物的一般引入，但是在许多情况下，可能希望提供治疗剂的局部或靶向递送，这可实现药剂向所选目标部位的有引导且准确的递送。例如，治疗剂向肿瘤的局部递送可以减少治疗剂暴露于正常、健康的组织，这可以降低潜在有害的副作用。Many therapeutic agents are injected using intravenous (IV) techniques, as well as via oral medications. While such techniques allow for general introduction of drugs, in many cases it may be desirable to provide local or targeted delivery of therapeutic agents, which enables guided and accurate delivery of agents to selected target sites. For example, local delivery of a therapeutic agent to a tumor can reduce the exposure of the therapeutic agent to normal, healthy tissue, which can reduce potentially harmful side effects.
已经使用导管和类似导入器装置，进行了治疗剂的局部递送。举例来说，可以朝向患者体内的目标部位推进导管，然后可以通过导管的内腔将治疗剂注射至目标部位。典型地，可以使用注射器(具有或不具有针头)或类似装置将治疗剂注入导管的内腔。然而，这种递送技术可能导致注射的治疗剂的相对弱的流。Local delivery of therapeutic agents has been performed using catheters and similar introducer devices. For example, a catheter can be advanced toward a target site in a patient, and a therapeutic agent can then be injected through the lumen of the catheter to the target site. Typically, a syringe (with or without a needle) or similar device can be used to inject the therapeutic agent into the lumen of the catheter. However, this delivery technique may result in a relatively weak flow of injected therapeutic agent.
此外，可能难以或不可能以靶向方式将呈某些形式例如粉末形式的治疗剂递送至希望的部位。例如，如果治疗粉末保持在注射器或其他容器内，则可能不易按照也可以降低潜在有害的副作用的局部方式通过导管将它递送至目标部位。Furthermore, it may be difficult or impossible to deliver therapeutic agents in certain forms, such as powder forms, to the desired site in a targeted manner. For example, if the therapeutic powder is held in a syringe or other container, it may not be easily delivered to the target site through a catheter in a topical manner that also reduces potentially harmful side effects.
已知使用包括壳聚糖、CarbopolTM和聚卡波非(polycarbophil)的各种化学衍生物在内的粘膜粘合剂和生物粘合剂可以打开上皮紧密连接，防止肠溃疡，将药物保持在开放性伤口，延长眼表面停留，并且具有疫苗辅助活性，然而，先前并未提出或记载过使用粘膜粘合剂来治疗胃肠道病损。The use of mucoadhesives and bioadhesives, including chitosan, Carbopol™ and various chemical derivatives of polycarbophil, is known to open epithelial tight junctions, prevent intestinal ulcers, and keep drugs at Open wounds, prolonged ocular surface retention, and vaccine adjunctive activity, however, the use of mucoadhesives for the treatment of gastrointestinal lesions has not been previously proposed or documented.
目前，治疗胃肠道病损的标准方法是使用夹子将该组织自身折叠，由此将该病损与胃肠道环境分离。然而，这种方法的成功率较低(失败率10％-20％)，价格昂贵，并且技术上困难。Currently, the standard approach to treating gastrointestinal lesions is to use clips to fold the tissue upon itself, thereby separating the lesion from the gastrointestinal environment. However, this approach has a low success rate (10%-20% failure rate), is expensive, and is technically difficult.
因此，业内非常需要用于长期局部性治疗的新颖的或改良的装置和方法，以解决因胃肠道障碍和或需要去除胃肠道壁的粘膜层或粘膜下层的医学程序引起的问题。Accordingly, there is a strong need in the industry for novel or improved devices and methods for long-term topical therapy to address problems arising from gastrointestinal disorders and or medical procedures requiring removal of the mucosal or submucosa of the gastrointestinal wall.
发明内容SUMMARY OF THE INVENTION
一个实施例涉及一种用于实现活动性出血病损的止血并维持所述病损的止血的多层涂层，该多层涂层包括：(i)止血层，该止血层包括与该活动性出血病损直接接触的呈液体、凝胶或粉末形式的止血剂；(ii)保护性覆盖物，该保护性覆盖物包括与该止血层和周围组织均直接接触的呈液体、凝胶或粉末形式的粘合剂，其中该保护性覆盖物能够在该病损部位处及其附近保留最少30分钟。该止血层和该保护性覆盖物通过流过导管而递送在该病损部位处及其附近。该病损可以是粘膜病损。该粘合剂可以是选自下组的粘膜粘合剂，该组由以下各项组成：卡波姆、多环芳烃、羧酸、聚乙烯吡咯烷酮、聚乙烯醇、聚卡波非、壳聚糖材料、海藻酸钠、纤维素衍生物、醚、凝集素、硫胺素、病原菌、硫醇、氨基酸序列、离子交换树脂、包含氨基酸序列的任何生物分子、粘蛋白、瓜尔胶、刺梧桐胶、黄原胶、刺槐豆胶、阿拉伯胶、结冷胶、黄蓍胶、可溶性淀粉、明胶、果胶，以及具有对粘膜的亲和力的任何生物分子。该多层涂层的厚度最少为0.1mm。该止血剂可以选自下组，该组由以下各项组成：凝血酶、肾上腺素、组织硬化剂和吸收性粘土(例如锂皂石、蒙脱石、沸石、高岭土)。该止血剂可以是止血粘土。该保护性覆盖物可以进一步包含pH调节剂。该保护性覆盖物可以能够在该病损部位处及其附近保留最少24小时；最少48小时；或最少72小时。该保护性覆盖物可以呈粉末的形式，其中该粉末由结合在一起的粘合剂颗粒和屏障形成颗粒构成的颗粒组成。One embodiment relates to a multi-layer coating for achieving and maintaining hemostasis of an active bleeding lesion, the multi-layer coating comprising: (i) a hemostatic layer comprising a hemostatic layer associated with the active bleeding lesion. Hemostatic agents in liquid, gel or powder form in direct contact with bleeding lesions; (ii) protective coverings including liquids, gels or in direct contact with both the hemostatic layer and surrounding tissue Adhesive in powder form, wherein the protective covering is able to remain at and near the lesion site for a minimum of 30 minutes. The haemostatic layer and the protective covering are delivered at and near the lesion site by flow through a catheter. The lesion may be a mucosal lesion. The adhesive may be a mucoadhesive selected from the group consisting of carbomers, polycyclic aromatic hydrocarbons, carboxylic acids, polyvinylpyrrolidone, polyvinyl alcohol, polycarbophil, chitosan Sugar materials, sodium alginate, cellulose derivatives, ethers, lectins, thiamines, pathogenic bacteria, thiols, amino acid sequences, ion exchange resins, any biomolecule containing amino acid sequences, mucins, guar gum, sycamore Gum, xanthan gum, locust bean gum, acacia, gellan gum, tragacanth, soluble starch, gelatin, pectin, and any biomolecule that has an affinity for mucous membranes. The thickness of the multilayer coating is at least 0.1 mm. The hemostatic agent may be selected from the group consisting of thrombin, epinephrine, tissue sclerosing agents, and absorbing clays (eg, hectorite, montmorillonite, zeolite, kaolin). The hemostatic agent may be hemostatic clay. The protective covering may further comprise a pH adjusting agent. The protective covering may be able to remain at and near the lesion site for a minimum of 24 hours; a minimum of 48 hours; or a minimum of 72 hours. The protective covering may be in the form of a powder consisting of particles of binder particles and barrier-forming particles bound together.
另一个实施例涉及一种用于保护和治疗胃肠道中的具有活动性出血的病损的方法，该方法包括：(i)在该胃肠道中的该病损部位处及其附近以足以停止该活动性出血的量和时间直接施加包含止血剂的止血组合物；以及(ii)一旦该活动性出血停止或减慢，便在先前施加的止血组合物的至少一部分的顶部及其附近直接施加包含粘合剂的保护性覆盖物，其中该保护性覆盖物在施加到该止血组合物的至少一部分的顶部及其附近时与该止血组合物和该病损周围的组织均直接接触、提供持续的保护性屏障并且能够在该病损部位处及其附近保留最少30分钟。该施加步骤(i)可以包括在具有该活动性出血的该病损部位处及其附近喷洒、喷射或铺展该止血剂。该施加步骤(ii)可以包括在该胃肠道中的该病损部位处及其附近的先前施加的止血组合物的至少一部分的顶部及其附近喷洒、喷射或铺展该保护性覆盖物。该粘合剂可呈粉末、液体或凝胶形式。该粘合剂可以是粘膜粘合剂。该粘合剂可以是选自下组的粘膜粘合剂，该组由以下各项组成：卡波姆、多环芳烃、羧酸、聚乙烯吡咯烷酮、聚乙烯醇、聚卡波非、壳聚糖材料、海藻酸钠、纤维素衍生物、醚、凝集素、硫胺素、病原菌、硫醇、氨基酸序列、离子交换树脂、包含氨基酸序列的任何生物分子、粘蛋白、瓜尔胶、刺梧桐胶、黄原胶、刺槐豆胶、阿拉伯胶、结冷胶、黄蓍胶、可溶性淀粉、明胶、果胶，以及具有对粘膜的亲和力的任何生物分子。该保护性覆盖物可以包括呈绷带、贴片或敷料形式的固体材料。该保护性覆盖物可以适于以液体形式递送，该液体形式在递送到该病损部位处及其附近的该止血组合物的至少一部分的顶部及其附近时固化。该方法可以进一步包括施加选自下组的交联引发剂，该组选自由以下各项组成：化学、热、光、固化剂和催化剂。该方法可以进一步包括：指导医生首先向该胃肠道中的具有该活动性出血的该病损部位及其附近施加该止血剂；指导该医生确定该活动性出血是否已经停止；以及指导该医生在该胃肠道中的该病损部位处及其附近的该止血组合物的至少一部分的顶部及其附近施加该保护性覆盖物。Another embodiment relates to a method for protecting and treating a lesion with active bleeding in the gastrointestinal tract, the method comprising: (i) at and near the lesion in the gastrointestinal tract sufficient to stop The amount and timing of the active bleeding directly applies a hemostatic composition comprising a hemostatic agent; and (ii) once the active bleeding stops or slows, directly on top of and adjacent to at least a portion of the previously applied hemostatic composition A protective covering comprising an adhesive, wherein the protective covering, when applied to the top of and near at least a portion of the hemostatic composition, is in direct contact with both the hemostatic composition and the tissue surrounding the lesion, providing continuous protective barrier and can remain at and near the lesion site for a minimum of 30 minutes. The applying step (i) may comprise spraying, jetting or spreading the hemostatic agent at and near the lesion with the active bleeding. The applying step (ii) may comprise spraying, jetting or spreading the protective covering on top of and adjacent to at least a portion of the previously applied hemostatic composition at and near the lesion in the gastrointestinal tract. The binder can be in powder, liquid or gel form. The adhesive may be a mucoadhesive. The adhesive may be a mucoadhesive selected from the group consisting of carbomers, polycyclic aromatic hydrocarbons, carboxylic acids, polyvinylpyrrolidone, polyvinyl alcohol, polycarbophil, chitosan Sugar materials, sodium alginate, cellulose derivatives, ethers, lectins, thiamines, pathogenic bacteria, thiols, amino acid sequences, ion exchange resins, any biomolecule containing amino acid sequences, mucins, guar gum, sycamore Gum, xanthan gum, locust bean gum, acacia, gellan gum, tragacanth, soluble starch, gelatin, pectin, and any biomolecule that has an affinity for mucous membranes. The protective covering may comprise a solid material in the form of a bandage, patch or dressing. The protective covering may be adapted to be delivered in a liquid form that solidifies upon delivery to and near the top of at least a portion of the hemostatic composition at and near the lesion. The method may further include applying a crosslinking initiator selected from the group consisting of chemical, thermal, light, curing agents, and catalysts. The method may further include: instructing a physician to first apply the hemostatic agent to and near the lesion in the gastrointestinal tract with the active bleeding; instructing the physician to determine whether the active bleeding has ceased; and instructing the physician in The protective covering is applied on top of and adjacent to at least a portion of the hemostatic composition at and near the lesion in the gastrointestinal tract.
附图说明Description of drawings
本专利或申请文件包含至少一张彩色附图。应请求并且支付必要的费用后，具有彩色附图的本专利或专利申请公开的副本将由专利局提供。The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
图1是显示本发明的粘膜粘合剂覆盖物的实例的照片。Figure 1 is a photograph showing an example of the mucoadhesive covering of the present invention.
图2是显示结合的颗粒的实例的照片，其中细的粘膜粘合剂颗粒结合到较大的屏障形成颗粒。Figure 2 is a photograph showing an example of bonded particles, wherein fine mucoadhesive particles are bonded to larger barrier forming particles.
图3显示用HemosprayTM粉末和喷洒在顶部的粘膜粘合剂粉末作为保护性覆盖物而治疗的猪中活动性胃肠道出血的照片。Figure 3 shows photographs of active gastrointestinal bleeding in pigs treated with Hemospray™ powder and mucoadhesive powder sprayed on top as a protective covering.
图4显示72小时处内镜下粘膜下切除术的照片。在形成病损时，病损具有活动性出血，并通过双峰施加HemosprayTM和保护性粘膜粘合剂来治疗。在72小时处，与未接受双峰治疗的病损相比，存在保护性粘膜粘合剂覆盖物并且可以看到相对少的严重炎症(图5)。Figure 4 shows photographs of endoscopic submucosal resection at 72 hours. As the lesions formed, the lesions had active bleeding and were treated by bimodal application of Hemospray™ and protective mucoadhesive. At 72 hours, a protective mucoadhesive covering was present and relatively less severe inflammation was seen compared to lesions that did not receive bimodal treatment (Figure 5).
图5显示72小处时内镜下粘膜下切除术的照片。在形成病损时，病损具有活动性出血，并用HemosprayTM治疗。没有施加保护性粘膜粘合剂。在72小时处，与接受双峰治疗的病损相比，不存在保护性覆盖物，并且可以观察到增加的严重炎症(发红)(图4)。Figure 5 shows a photograph of endoscopic submucosal resection at 72 hours. At the time the lesions were formed, the lesions had active bleeding and were treated with Hemospray™ . No protective mucoadhesive was applied. At 72 hours, no protective covering was present and increased severe inflammation (redness) was observed compared to lesions receiving bimodal treatment (Figure 4).
具体实施方式Detailed ways
本文描述了用于保护或治疗胃肠道中的病损的长效粘合剂医学产品和方法，这些病损是因以下引起的：胃肠道障碍和/或需要去除胃肠道的粘膜层或粘膜下层的医学程序，例如，内镜粘膜下解剖(ESD)、内镜粘膜切除术、息肉切除术、溃疡、癌症、静脉曲张、巴雷特氏食管消融或其组合。Described herein are long-acting adhesive medical products and methods for protecting or treating lesions in the gastrointestinal tract resulting from gastrointestinal disorders and/or the need to remove the mucosal layer of the gastrointestinal tract or Submucosa medical procedures, eg, endoscopic submucosal dissection (ESD), endoscopic mucosal resection, polypectomy, ulcers, cancer, varicose veins, Barrett's esophagus ablation, or a combination thereof.
另外，本文描述了用于保护或治疗胃肠道中的具有活动性出血的病损的长效医学产品和方法，这些病损是因以下引起的：胃肠道障碍和/或需要去除胃肠道的粘膜层或粘膜下层的医学程序，例如，ESD、内镜粘膜切除术、息肉切除术、溃疡、癌症、静脉曲张、巴雷特氏食管消融或其组合。In addition, described herein are long-acting medical products and methods for protecting or treating active bleeding lesions in the gastrointestinal tract resulting from gastrointestinal disorders and/or the need to remove the gastrointestinal tract Medical procedures of the mucosal or submucosa, eg, ESD, endoscopic mucosal resection, polypectomy, ulcers, cancer, varicose veins, Barrett's esophagus ablation, or a combination thereof.
本文所述的长效粘合剂医学产品(即，用于实现活动性出血病损的止血并维持病损止血的多层涂层)包括两种组分：(i)包含止血剂的组合物(在整个本申请中也称为“止血组合物”或“止血层”)，以及(ii)包含粘合剂的保护性覆盖物(在整个本申请中称为“保护性覆盖物”)。这两种组分可以例如呈粉末、凝胶或液体的形式，或者可以是固体材料，例如绷带、敷料、贴片等。例如，止血层包括与活动性出血病损直接接触的呈液体、凝胶或粉末形式的止血剂。例如，保护性覆盖物包括与止血层和周围组织均直接接触的呈液体、凝胶或粉末形式的粘合剂。该多层涂层的厚度最少为0.1mm。The long-lasting adhesive medical products described herein (ie, multi-layer coatings for achieving hemostasis in active bleeding lesions and maintaining lesion hemostasis) include two components: (i) a composition comprising a hemostatic agent (also referred to throughout this application as a "hemostatic composition" or "hemostatic layer"), and (ii) a protective covering comprising an adhesive (referred to throughout this application as a "protective covering"). The two components may be in the form of, for example, powders, gels or liquids, or may be solid materials such as bandages, dressings, patches, and the like. For example, a hemostatic layer includes a hemostatic agent in the form of a liquid, gel, or powder in direct contact with an active bleeding lesion. For example, protective coverings include adhesives in liquid, gel, or powder form in direct contact with both the hemostatic layer and surrounding tissue. The thickness of the multilayer coating is at least 0.1 mm.
止血组合物和保护性涂层分别递送至胃肠道中的具有活动性出血的病损部位及其附近。首先将止血组合物递送并施加到具有活动性出血的病损，以减慢或停止出血，和/或防止延迟性出血；保护性覆盖物在止血组合物递送之后并且一旦活动性出血停止或减慢时递送，并施加在止血组合物的顶部、上方和/或周围(即，使得保护性覆盖物与止血层和周围组织均直接接触)以保护或治疗病损以免受进一步的损伤或感染、防止延迟性穿孔、防止再出血、密封吻合口瘘或瘘管和/或促进暴露部位的愈合。The hemostatic composition and protective coating are delivered to and adjacent to lesions with active bleeding in the gastrointestinal tract, respectively. The hemostatic composition is first delivered and applied to a lesion with active bleeding to slow or stop bleeding, and/or prevent delayed bleeding; a protective covering follows the delivery of the hemostatic composition and once the active bleeding stops or reduces delivered slowly and applied on top of, over and/or around the hemostatic composition (ie, such that the protective covering is in direct contact with both the hemostatic layer and surrounding tissue) to protect or treat the lesion from further damage or infection, Prevent delayed perforation, prevent rebleeding, seal anastomotic leaks or fistulas and/or promote healing of exposed sites.
止血组合物的功能是通过在出血部位形成机械屏障来减少或停止病损的活动性出血；包含粘合剂的保护性覆盖物有助于保护这些病损免受并发症的影响，例如再出血、溃疡形成、疤痕形成和狭窄。本文描述了将这两种治疗联合用作具有活动性出血的胃肠道病损的“双峰疗法”的方法。The function of the hemostatic composition is to reduce or stop active bleeding of lesions by forming a mechanical barrier at the site of bleeding; a protective covering containing adhesive helps protect these lesions from complications such as rebleeding , ulceration, scarring and strictures. Described herein are methods of combining these two treatments as "bimodal therapy" for gastrointestinal lesions with active bleeding.
因此，某些实施例涉及用于保护或治疗胃肠道中的具有活动性出血的病损的长效粘合剂医学产品和方法。术语“止血组合物”是指包含止血剂的组合物，该止血剂可以是促进止血(即，停止、减慢或减少出血)的任何抗出血剂。局部作用的止血剂通过引起血管收缩或促进血小板聚集而起作用。示例性止血剂包括有机试剂，例如微原纤维胶原蛋白、凝血酶和壳聚糖；以及天然的基于植物的多糖，例如各种淀粉，例如改性和未改性淀粉(例如马铃薯淀粉)；无机试剂，例如吸收性粘土(例如锂皂石、蒙脱石、沸石、高岭土)；止血药；支链淀粉，包括改性的(交联的)预胶化支链淀粉。可以使用的其他止血剂可以包括肾上腺素、组织硬化剂、塞法戴克斯(sephadex)和聚糖酐(debrisan)。天然植物基多糖往往具有生物相容性、可吸收性并且不含动物组分。尽管优选基于植物的多糖作为止血剂，但也可以使用明胶和其他动物来源的多糖。Accordingly, certain embodiments relate to long-acting adhesive medical products and methods for protecting or treating lesions with active bleeding in the gastrointestinal tract. The term "hemostatic composition" refers to a composition comprising a hemostatic agent, which may be any anti-hemorrhagic agent that promotes hemostasis (ie, stops, slows, or reduces bleeding). Topically acting hemostatic agents work by causing vasoconstriction or promoting platelet aggregation. Exemplary hemostatic agents include organic agents, such as microfibrillar collagen, thrombin, and chitosan; and natural plant-based polysaccharides, such as various starches, such as modified and unmodified starches (eg, potato starch); inorganic Agents, eg, absorbing clays (eg, laponite, montmorillonite, zeolite, kaolin); hemostatic agents; pullulan, including modified (cross-linked) pregelatinized pullulan. Other hemostatic agents that can be used can include epinephrine, tissue sclerosing agents, sephadex, and debrisan. Natural plant-based polysaccharides tend to be biocompatible, absorbable and free of animal components. Although plant-based polysaccharides are preferred as hemostatic agents, gelatin and other polysaccharides of animal origin can also be used.
术语“保护性涂层”或“涂层”或“保护性覆盖物”或“覆盖物”涵盖粉末和/或液体涂层(例如，适于通过例如喷洒或涂布或其他已知方法在该病损部位处及其附近施加的固体、粉末、液体或凝胶，其中这些液体或凝胶涂层在该部位固化)以及固体材料，例如绷带、敷料、贴片等等。具体地，这些术语涵盖用于治疗或保护胃肠道中的病损的粉末、液体和凝胶涂层以及固体材料(例如，绷带、敷料、贴片)。保护性覆盖物包括粘合剂，例如粘膜粘合剂。示例性粘膜粘合剂包括卡波姆、多环芳烃、羧酸、聚乙烯吡咯烷酮、聚乙烯醇、聚卡波非、壳聚糖材料、海藻酸钠、纤维素衍生物、醚、凝集素、硫胺素、病原菌、硫醇、氨基酸序列、离子交换树脂、包含氨基酸序列的任何生物分子、粘蛋白、瓜尔胶、刺梧桐胶、黄原胶、刺槐豆胶、阿拉伯胶、结冷胶、黄蓍胶、可溶性淀粉、明胶、果胶，以及具有对粘膜的亲和力的任何生物分子。The term "protective coating" or "coating" or "protective covering" or "covering" encompasses powder and/or liquid coatings (e.g., suitable for Solids, powders, liquids, or gels applied at and near the lesion where the coating of these liquids or gels cures) and solid materials such as bandages, dressings, patches, and the like. Specifically, these terms encompass powder, liquid and gel coatings as well as solid materials (eg, bandages, dressings, patches) for treating or protecting lesions in the gastrointestinal tract. Protective coverings include adhesives, such as mucoadhesives. Exemplary mucoadhesives include carbomers, polycyclic aromatic hydrocarbons, carboxylic acids, polyvinylpyrrolidone, polyvinyl alcohol, polycarbophil, chitosan materials, sodium alginate, cellulose derivatives, ethers, lectins, Thiamine, Pathogens, Thiols, Amino Acid Sequences, Ion Exchange Resins, Any Biomolecule Containing Amino Acid Sequences, Mucins, Guar Gum, Karaya Gum, Xanthan Gum, Locust Bean Gum, Acacia Gum, Gellan Gum, Gum tragacanth, soluble starch, gelatin, pectin, and any biomolecule that has an affinity for mucous membranes.
术语“病损”是指任何组织缺损或身体损伤，其伴随组织结构的正常完整性破坏和/或身体器官或组织(并且具体地，胃肠道中的任何身体器官或组织)的病理性变化。该术语还意在涵盖术语“伤口”、“损伤”、“疮”、“坏死”和“溃疡”，尤其是具有活动性出血的伤口、损伤、疮、坏死和溃疡。术语“疮”通常是指粘膜的任何病损。术语“溃疡”是指胃肠道中器官或组织表面的局部缺损或挖除，其是因坏死组织的脱落而产生的。术语“坏死”是指因感染、损伤、炎症或梗塞产生的死组织。该病损可为由于胃肠道障碍和或需要去除胃肠道壁的粘膜层或粘膜下层的医学程序所致的任何病损。例如，病损可因内镜粘膜下解剖、内镜粘膜切除术、息肉切除术、溃疡、癌症、静脉曲张、巴雷特氏食管消融或其组合所致，这导致了活动性出血。The term "lesion" refers to any tissue defect or bodily injury that is accompanied by disruption of the normal integrity of tissue structure and/or pathological changes in a bodily organ or tissue (and in particular, any bodily organ or tissue in the gastrointestinal tract). The term is also intended to cover the terms "wound", "injury", "sore", "necrosis" and "ulcer", especially wounds, lesions, sores, necrosis and ulcers with active bleeding. The term "sore" generally refers to any lesion of the mucosa. The term "ulcer" refers to a local defect or excavation of the surface of an organ or tissue in the gastrointestinal tract that results from the sloughing of necrotic tissue. The term "necrosis" refers to dead tissue resulting from infection, injury, inflammation or infarction. The lesion can be any lesion due to a disorder of the gastrointestinal tract and or a medical procedure that requires removal of the mucosal or submucosa of the gastrointestinal wall. For example, lesions can result from endoscopic submucosal dissection, endoscopic mucosal resection, polypectomy, ulcers, cancer, varicose veins, ablation of Barrett's esophagus, or a combination thereof, which results in active bleeding.
术语“活动性出血”是指胃肠道中所有形式的出血。它也被称为胃肠道出血。胃肠道中的出血可能在该胃肠道中的任何地方，从口腔到直肠。如果在短时间内出现大量失血，则症状可能包括呕吐红血、呕吐黑血、血便或黑便。The term "active bleeding" refers to all forms of bleeding in the gastrointestinal tract. It is also called gastrointestinal bleeding. Bleeding in the gastrointestinal tract can be anywhere in this gastrointestinal tract, from the mouth to the rectum. If a large amount of blood loss occurs in a short period of time, symptoms may include vomiting red blood, vomiting black blood, bloody stools, or black stools.
结合止血组合物和保护性覆盖物的递送的词组“到...及其附近”或“...处及其附近”意指将止血组合物和/或保护性覆盖物放置在病损本身上，包括病损内，以及紧邻病损周围以确保尽可能最完全覆盖病损。The phrase "to and near" or "at and near" in conjunction with the delivery of the hemostatic composition and protective covering means placing the hemostatic composition and/or protective covering on the lesion itself above, including within the lesion, and immediately surrounding the lesion to ensure the most complete coverage of the lesion possible.
结合保护性覆盖物的递送的词组“在...的顶部及其附近”或“在...的上方及其附近”是指将保护性覆盖物放置在病损处的先前施加的止血组合物的顶部以及紧邻止血组合物和病损周围，以确保尽可能最完全覆盖病损。The phrases "on and near the top of" or "over and near" in connection with the delivery of a protective covering refer to a previously applied hemostatic combination that places the protective covering at the lesion on top of the material and immediately around the hemostatic composition and the lesion to ensure the most complete coverage of the lesion possible.
具体地，在用于保护或治疗胃肠道中的具有活动性出血的病损的所述方法中，首先递送止血组合物并局部/直接施加在胃肠道中的病损部位处及其附近以停止该病损处的活动性出血；以及一旦活动性出血停止或减慢，便将包含粘合剂的保护性覆盖物局部且直接施加在胃肠道中的病损部位处及其附近的止血组合物的至少一部分的顶部、上方及其附近。当在病损部位处及其附近的止血组合物的至少一部分上方及其附近施加时，保护性覆盖物粘附到胃肠道组织、提供持久的保护屏障并且能够在病损部位处及其附近保留最少30分钟。Specifically, in the method for protecting or treating a lesion with active bleeding in the gastrointestinal tract, a hemostatic composition is first delivered and applied topically/directly at and near the lesion in the gastrointestinal tract to stop Active bleeding at the lesion; and a hemostatic composition for topical and direct application of a protective covering comprising an adhesive to and near the lesion in the gastrointestinal tract once the active bleeding has ceased or slowed down at least part of the top, above and adjacent to it. When applied over and near at least a portion of the hemostatic composition at and near the lesion, the protective covering adheres to the tissue of the gastrointestinal tract, provides a durable protective barrier and is capable of being at and near the lesion Leave for a minimum of 30 minutes.
具体地，在将本文所述的长效保护性覆盖物直接和局部递送到具有活动性出血的病损部位处及其附近的止血组合物的上方及其附近时，它将通过至少部分地或完全覆盖止血组合物和病损而在病损部位处及其附近形成保护性覆盖物。保护性覆盖物在病损部位处及其附近保留足以容许该部位被治疗或愈合的时间(最少30分钟；优选地24小时；更优选地至少48或72小时；最优选地该保护性覆盖物能在该病损部位处及其附近保留24-72小时或更久；因此术语“长效的”是指本发明的保护性覆盖物在该病损处及其附近保留的时间长度并且意指从30分钟到72小时或更久中的任何时间)。术语“保护”是指保护该病损部位以免其受到进一步损伤或感染。术语“治疗”是指在该病损部位减慢或停止出血，防止延迟性出血，防止该病损的延迟性穿孔，和/或促进该病损的暴露部位的愈合，和/或促进新组织形成。术语“愈合”在提到病损时是指通过自然过程、如通过例如瘢痕形成修复胃肠道组织的过程，使得在“愈合”后，该病损至少与该病损的初始大小相比大小减小或不存在。Specifically, when the long-lasting protective covering described herein is delivered directly and locally over and adjacent to the hemostatic composition at and near a lesion with active bleeding, it will pass at least partially or Complete coverage of the hemostatic composition and lesion to form a protective covering at and near the lesion site. The protective covering remains at and near the lesion site for a time sufficient to allow the site to be treated or healed (minimum 30 minutes; preferably 24 hours; more preferably at least 48 or 72 hours; most preferably the protective covering Can remain at and near the lesion for 24-72 hours or more; thus the term "long-lasting" refers to the length of time the protective covering of the present invention remains at and near the lesion and means anywhere from 30 minutes to 72 hours or more). The term "protect" refers to protecting the lesion from further damage or infection. The term "treating" refers to slowing or stopping bleeding at the lesion site, preventing delayed bleeding, preventing delayed perforation of the lesion, and/or promoting healing of the exposed site of the lesion, and/or promoting new tissue form. The term "healing" when referring to a lesion refers to the process of repairing the tissue of the gastrointestinal tract by natural processes, such as by, for example, scarring, such that after "healing" the lesion is at least in size compared to the original size of the lesion reduced or absent.
一个实施例涉及一种用于实现活动性出血病损的止血并维持所述病损的止血的多层涂层，该多层涂层包括：(i)止血层，该止血层包括与该活动性出血病损直接接触的呈液体、凝胶或粉末形式的止血剂；(ii)保护性覆盖物，该保护性覆盖物包括与该止血层和周围组织均直接接触的呈液体、凝胶或粉末形式的粘合剂，其中该保护性覆盖物能够在该病损部位处及其附近保留最少30分钟。该止血层和该保护性覆盖物通过流过导管而递送在该病损部位处及其附近。该病损可以是粘膜病损。覆盖物的厚度最少为0.1mm。该保护性覆盖物可以进一步包含pH调节剂。该保护性覆盖物可以能够在该病损部位处及其附近保留最少24小时；最少48小时；或最少72小时。该保护性覆盖物可以呈粉末的形式，其中该粉末由结合在一起的粘合剂颗粒和屏障形成颗粒构成的颗粒组成。One embodiment relates to a multi-layer coating for achieving and maintaining hemostasis of an active bleeding lesion, the multi-layer coating comprising: (i) a hemostatic layer comprising a hemostatic layer associated with the active bleeding lesion. Hemostatic agents in liquid, gel or powder form in direct contact with bleeding lesions; (ii) protective coverings including liquids, gels or in direct contact with both the hemostatic layer and surrounding tissue Adhesive in powder form, wherein the protective covering is able to remain at and near the lesion site for a minimum of 30 minutes. The haemostatic layer and the protective covering are delivered at and near the lesion site by flow through a catheter. The lesion may be a mucosal lesion. The thickness of the covering is at least 0.1mm. The protective covering may further comprise a pH adjusting agent. The protective covering may be able to remain at and near the lesion site for a minimum of 24 hours; a minimum of 48 hours; or a minimum of 72 hours. The protective covering may be in the form of a powder consisting of particles of binder particles and barrier-forming particles bound together.
止血层包括止血剂，该止血剂可以是促进止血(即，停止、减慢或减少出血)的任何抗出血剂。示例性止血剂包括有机试剂，例如微原纤维胶原蛋白、凝血酶和壳聚糖；以及天然的基于植物的多糖，例如各种淀粉，例如改性和未改性淀粉(例如马铃薯淀粉)；无机试剂，例如吸收性粘土(例如锂皂石、蒙脱石、沸石、高岭土)；止血药；支链淀粉，包括改性的(交联的)预胶化支链淀粉。可以使用的其他止血剂可以包括肾上腺素、组织硬化剂、塞法戴克斯(sephadex)和聚糖酐(debrisan)。天然植物基多糖往往具有生物相容性、可吸收性并且不含动物组分。尽管优选基于植物的多糖作为止血剂，但也可以使用明胶和其他动物来源的多糖。在某些实施例中，止血剂是止血粘土。The hemostatic layer includes a hemostatic agent, which can be any anti-bleeding agent that promotes hemostasis (ie, stops, slows, or reduces bleeding). Exemplary hemostatic agents include organic agents, such as microfibrillar collagen, thrombin, and chitosan; and natural plant-based polysaccharides, such as various starches, such as modified and unmodified starches (eg, potato starch); inorganic Agents, eg, absorbing clays (eg, laponite, montmorillonite, zeolite, kaolin); hemostatic agents; pullulan, including modified (cross-linked) pregelatinized pullulan. Other hemostatic agents that can be used can include epinephrine, tissue sclerosing agents, sephadex, and debrisan. Natural plant-based polysaccharides tend to be biocompatible, absorbable and free of animal components. Although plant-based polysaccharides are preferred as hemostatic agents, gelatin and other polysaccharides of animal origin can also be used. In certain embodiments, the hemostatic agent is hemostatic clay.
在某些实施例中，保护性覆盖物包括粘合剂。In certain embodiments, the protective covering includes an adhesive.
粘合剂可包括当前已知的或今后研发的任何组织粘合剂。该粘合剂可以是粘膜粘合剂或任何其他类型的组织粘合剂。粘膜粘合剂是优选的。如本文所用，术语“粘膜粘合剂”是指粘附到粘膜的试剂，其可内衬身体脉管壁或体腔壁，例如胃肠道表面(例如，胃肠道上皮或粘膜(包括粘膜下层)中的一者或二者)，并且具体地，在病损部位处及其附近。该粘膜可包括潮湿粘液层，该粘膜粘合剂可粘附到该粘液层上。一般来说，粘膜粘合剂是亲水高分子，含有多个能形成氢键的官能团。The adhesive may include any tissue adhesive currently known or later developed. The adhesive can be a mucoadhesive or any other type of tissue adhesive. Mucoadhesives are preferred. As used herein, the term "mucoadhesive" refers to an agent that adheres to the mucosa, which can line the walls of body vessels or body cavities, such as the surfaces of the gastrointestinal tract (eg, the epithelium or mucosa of the gastrointestinal tract (including the submucosa). ), and in particular, at and near the lesion site. The mucosa can include a moist mucus layer to which the mucoadhesive can adhere. In general, mucoadhesives are hydrophilic polymers containing multiple functional groups capable of forming hydrogen bonds.
适用于本文中的粘膜粘合剂的一个实例包括含有重复单体单元的高分子(例如，聚合物)。用于本发明的长效粘合剂医学产品中的粘膜粘合剂的其他实例包括例如亲水聚合物、水凝胶、共聚物或巯基化聚合物。这些形成氢键的官能团可包括羧基、羟基、羰基、硫酸根基、酰胺基团或任何其他能形成氢键的官能团。粘膜粘合剂或其组分的实例可包括例如卡波姆(例如，聚丙烯酸)、多环芳烃(例如，惹烯)、羧酸、聚乙烯吡咯烷酮、聚乙烯醇、聚卡波非、壳聚糖材料(即，聚氨葡糖、脱乙酰几丁质或聚(D)葡萄糖胺)、海藻酸钠、纤维素衍生物(例如，甲基纤维素、甲基乙基纤维素、羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素或羟乙基纤维素)、醚(例如，聚乙二醇)、凝集素(例如，鸡冠刺桐凝集素、伴刀豆蛋白a凝集素、荆豆凝集素和C型凝集素)、硫胺素(例如硫胺素封端聚合物链)；病原性细菌(例如，细菌丝束蛋白)、硫醇(例如壳聚糖-半胱氨酸、壳聚糖-硫醇丁基脒、壳聚糖-巯基乙酸、聚丙烯酸-半胱氨酸、聚丙烯酸-半胱胺、羧甲基纤维素-半胱氨酸，或海藻酸盐-半胱氨酸)、氨基酸序列、离子交换树脂(例如，消胆胺)，或包括氨基酸序列的任何生物分子(例如肽)。粘膜粘合剂或其组分的其他实例可包括粘蛋白、瓜尔胶、刺梧桐胶、黄原胶、刺槐豆胶、阿拉伯胶、结冷胶、黄蓍胶、可溶性淀粉、明胶或果胶。在一些实例中，粘膜粘合剂可包括任何对粘膜组织具有亲和性的生物分子，例如蛋白质(例如，菌毛蛋白或亲和性配体)。One example of a mucoadhesive suitable for use herein includes macromolecules (eg, polymers) containing repeating monomeric units. Other examples of mucoadhesives for use in the depot adhesive medical products of the present invention include, for example, hydrophilic polymers, hydrogels, copolymers, or thiolated polymers. These hydrogen bonding functional groups may include carboxyl, hydroxyl, carbonyl, sulfate, amide, or any other functional groups capable of hydrogen bonding. Examples of mucoadhesives or components thereof may include, for example, carbomers (eg, polyacrylic acid), polycyclic aromatic hydrocarbons (eg, pyrenoid), carboxylic acids, polyvinylpyrrolidone, polyvinyl alcohol, polycarbophil, shell Glycan materials (ie, polyglucosamine, chitosan, or poly(D)glucosamine), sodium alginate, cellulose derivatives (eg, methyl cellulose, methyl ethyl cellulose, carboxymethyl cellulose) sodium cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, or hydroxyethyl cellulose), ethers (eg, polyethylene glycol), lectins (eg, Erythrina japonica lectin, concanavali Protein a lectins, Ulex lectins, and C-type lectins), thiamines (eg, thiamine-terminated polymer chains); pathogenic bacteria (eg, bacterial plastins), thiols (eg, chitosan) - cysteine, chitosan-thiolbutylamidine, chitosan-thioglycolic acid, polyacrylic acid-cysteine, polyacrylic acid-cysteine, carboxymethylcellulose-cysteine, or alginate-cysteine), amino acid sequence, ion exchange resin (eg, cholestyramine), or any biomolecule (eg, peptide) that includes an amino acid sequence. Other examples of mucoadhesives or components thereof may include mucin, guar, karaya, xanthan, locust bean, acacia, gellan, tragacanth, soluble starch, gelatin, or pectin . In some examples, the mucoadhesive can include any biomolecule that has an affinity for mucosal tissue, such as a protein (eg, pilin or affinity ligand).
粘膜粘合剂通过物理和/或化学力粘附到止血组合物和/或粘膜，这些力包括例如离子键结、共价键结、氢键结、范德瓦尔斯(Van-der-Waals)键结或疏水键结(即，疏水相互作用)。Mucoadhesives adhere to the hemostatic composition and/or mucosa by physical and/or chemical forces including, for example, ionic bonding, covalent bonding, hydrogen bonding, Van-der-Waals Bonding or hydrophobic bonding (ie, hydrophobic interactions).
其他类型的组织粘合剂包括氰基丙烯酸盐胶水和密封剂、戊二醛、DOPA或任何其他已知的聚合物或生物粘合剂。Other types of tissue adhesives include cyanoacrylate glues and sealants, glutaraldehyde, DOPA, or any other known polymeric or biological adhesive.
在某些实施例中，保护性覆盖物可以包含粘膜粘合剂，该粘膜粘合剂可以呈粉末、固溶体、乳液、液体或半液体溶液、液体悬浮液、凝胶、泡沫或其组合的形式。其他已知类型的配制品也可适于使用且将为所属领域技术人员所知。保护性覆盖物也可以在先前描述的多种形式或相之间转变。In certain embodiments, the protective covering may comprise a mucoadhesive, which may be in the form of a powder, solid solution, emulsion, liquid or semi-liquid solution, liquid suspension, gel, foam, or combinations thereof . Other known types of formulations may also be suitable for use and will be known to those skilled in the art. The protective covering can also transition between the various forms or phases previously described.
待施用到具有活动性出血的病损及其附近的止血组合物和保护性覆盖物的量将取决于病损的类型和大小、所用止血剂和粘膜粘合剂的形式以及用于递送止血剂和粘膜粘合剂的递送系统。例如，如果止血组合物和/或保护性覆盖物呈粉末的形式，则可以在病损部位上及其附近递送并置放从十分之几克到数克中的任意量(例如，从约0.01克到约60克中的任意量)的每种组分，以在具有活动性出血的病损部位处及其附近提供足够的覆盖，例如10微米到2mm厚。当递送止血组合物时，可以在病损部位上及其附近递送并置放从十分之几克到数克中的任意量(例如，从约0.01克到约25克中的任意量)，以在具有活动性出血的病损部位处及其附近提供足够的覆盖并停止出血。更典型地，约2克的止血组合物和/或保护性覆盖物将足以分别停止出血并包覆病损部位(以达到从10微米至2mm厚中的任意厚度)。如果止血组合物和/或保护性覆盖物呈凝胶或液体的形式，则在病损处及其附近提供足够的两种组分以分别停止活动性出血并允许实现对病损的充分覆盖，例如至少10微米至2mm厚。The amount of hemostatic composition and protective covering to be applied to and near a lesion with active bleeding will depend on the type and size of the lesion, the form of hemostatic agent and mucoadhesive used, and the type of hemostatic agent used to deliver the hemostatic agent and mucoadhesive delivery systems. For example, if the hemostatic composition and/or protective covering is in the form of a powder, any amount from a few tenths of a gram to a few grams (eg, from about 0.01 gram) can be delivered and placed on and near the lesion. gram to about 60 grams) of each component to provide adequate coverage at and near a lesion with active bleeding, eg, 10 microns to 2 mm thick. When delivering a hemostatic composition, any amount from a few tenths of a gram to a few grams (eg, any amount from about 0.01 gram to about 25 grams) can be delivered and placed on and near the lesion to provide Provide adequate coverage and stop bleeding at and near lesions with active bleeding. More typically, about 2 grams of the hemostatic composition and/or protective covering will be sufficient to stop bleeding and coat the lesion, respectively (to any thickness from 10 microns to 2 mm thick). If the hemostatic composition and/or protective covering is in the form of a gel or liquid, sufficient of both components are provided at and near the lesion to stop active bleeding and allow adequate coverage of the lesion, respectively, For example at least 10 microns to 2 mm thick.
呈液体或凝胶形式的止血剂和/或粘膜粘合剂的量可以在从0.1％至99.5％之间变化。The amount of hemostatic agent and/or mucoadhesive in liquid or gel form can vary from 0.1% to 99.5%.
在某些实施例中，本文所述的任何止血组合物包含大于约0.1％w/w、大于约0.2％w/w、大于约0.5％w/w、大于约1％w/w、大于约2％w/w、大于约3％w/w、大于约4％w/w、大于约5％w/w、大于约6％w/w、大于约7％w/w、大于约8％w/w、大于约9％w/w、大于约10％w/w、大于约11％w/w、大于约12％w/w、大于约13％w/w、大于约14％w/w、大于约15％w/w、大于约16％w/w、大于约17％w/w、大于约18％w/w、大于约19％w/w、大于约20％w/w、大于约21％w/w、大于约22％w/w、大于约23％w/w、大于约24％w/w、大于约25％w/w、大于约26％w/w、大于约27％w/w、大于约28％w/w、大于约29％w/w、大于约30％w/w、大于约35％w/w、大于约40％w/w、大于约45％w/w、大于约50％w/w、大于约55％w/w、大于约60％w/w、大于约65％w/w、大于约70％w/w、大于约80％w/w、大于约85％w/w、大于约90％w/w、大于约95％w/w或大于约99.5％w/w的止血剂，该止血剂可以停止胃肠道中的病损处(例如胃表面)的活动性出血。In certain embodiments, any hemostatic composition described herein comprises greater than about 0.1% w/w, greater than about 0.2% w/w, greater than about 0.5% w/w, greater than about 1% w/w, greater than about 2% w/w, greater than about 3% w/w, greater than about 4% w/w, greater than about 5% w/w, greater than about 6% w/w, greater than about 7% w/w, greater than about 8% w/w, greater than about 9% w/w, greater than about 10% w/w, greater than about 11% w/w, greater than about 12% w/w, greater than about 13% w/w, greater than about 14% w/w w, greater than about 15% w/w, greater than about 16% w/w, greater than about 17% w/w, greater than about 18% w/w, greater than about 19% w/w, greater than about 20% w/w, greater than about 21% w/w, greater than about 22% w/w, greater than about 23% w/w, greater than about 24% w/w, greater than about 25% w/w, greater than about 26% w/w, greater than about 27% w/w, greater than about 28% w/w, greater than about 29% w/w, greater than about 30% w/w, greater than about 35% w/w, greater than about 40% w/w, greater than about 45% w/w, greater than about 50% w/w, greater than about 55% w/w, greater than about 60% w/w, greater than about 65% w/w, greater than about 70% w/w, greater than about 80% w/w w, greater than about 85% w/w, greater than about 90% w/w, greater than about 95% w/w, or greater than about 99.5% w/w a hemostatic agent that can stop lesions in the gastrointestinal tract ( such as active bleeding on the stomach surface).
在某些实施例中，本文描述的任何保护性覆盖物包括大于约0.1％w/w、大于约0.2％w/w、大于约0.5％w/w、大于约1％w/w、大于约2％w/w、大于约3％w/w、大于约4％w/w、大于约5％w/w、大于约6％w/w、大于约7％w/w、大于约8％w/w、大于约9％w/w、大于约10％w/w、大于约11％w/w、大于约12％w/w、大于约13％w/w、大于约14％w/w、大于约15％w/w、大于约16％w/w、大于约17％w/w、大于约18％w/w、大于约19％w/w、大于约20％w/w、大于约21％w/w、大于约22％w/w、大于约23％w/w、大于约24％w/w、大于约25％w/w、大于约26％w/w、大于约27％w/w、大于约28％w/w、大于约29％w/w、大于约30％w/w、大于约35％w/w、大于约40％w/w、大于约45％w/w、大于约50％w/w、大于约55％w/w、大于约60％w/w、大于约65％w/w、大于约70％w/w、大于约80％w/w、大于约85％w/w、大于约90％w/w、大于约95％w/w或大于约99.5％w/w的粘膜粘合剂，该粘膜粘合剂可以延长覆盖物与胃肠道表面(例如胃表面)接触的时间，并保护或治疗病损以免进一步的损伤或感染、防止延迟性穿孔、防止延迟性或复发性出血、密封吻合口瘘或瘘管和/或促进暴露部位的愈合。In certain embodiments, any protective covering described herein comprises greater than about 0.1% w/w, greater than about 0.2% w/w, greater than about 0.5% w/w, greater than about 1% w/w, greater than about 2% w/w, greater than about 3% w/w, greater than about 4% w/w, greater than about 5% w/w, greater than about 6% w/w, greater than about 7% w/w, greater than about 8% w/w, greater than about 9% w/w, greater than about 10% w/w, greater than about 11% w/w, greater than about 12% w/w, greater than about 13% w/w, greater than about 14% w/w w, greater than about 15% w/w, greater than about 16% w/w, greater than about 17% w/w, greater than about 18% w/w, greater than about 19% w/w, greater than about 20% w/w, greater than about 21% w/w, greater than about 22% w/w, greater than about 23% w/w, greater than about 24% w/w, greater than about 25% w/w, greater than about 26% w/w, greater than about 27% w/w, greater than about 28% w/w, greater than about 29% w/w, greater than about 30% w/w, greater than about 35% w/w, greater than about 40% w/w, greater than about 45% w/w, greater than about 50% w/w, greater than about 55% w/w, greater than about 60% w/w, greater than about 65% w/w, greater than about 70% w/w, greater than about 80% w/w w, greater than about 85% w/w, greater than about 90% w/w, greater than about 95% w/w, or greater than about 99.5% w/w mucoadhesive that can extend the covering and the stomach The duration of exposure to intestinal surfaces (eg, stomach surfaces) and to protect or treat lesions from further injury or infection, prevent delayed perforation, prevent delayed or recurrent bleeding, seal anastomotic or fistulae, and/or facilitate exposed sites of healing.
如本文所提供的，呈粉末形式的止血组合物和/或保护性覆盖物可以包括精细或细分制剂、粗粉碎产品或中间粒径产品。呈粉末形式的组分可包含尺寸为约10,000微米或10mm的极粗颗粒，或尺寸接近约1微米或更小的极细颗粒，或具有介于粗粒与细粒之间的任一大小的颗粒。颗粒的大小将分别取决于组合物和保护性覆盖物中使用的止血剂和粘膜粘合剂的类型，并且可以是高度可变的，尤其是对于粒状粘膜粘合剂来说。As provided herein, hemostatic compositions and/or protective coverings in powder form may include fine or finely divided formulations, coarsely pulverized products, or intermediate particle size products. The components in powder form may contain very coarse particles having a size of about 10,000 microns or 10 mm, or very fine particles approaching about 1 micron or less in size, or having any size between coarse and fine particles. particles. The size of the particles will depend on the type of hemostatic agent and mucoadhesive used in the composition and protective covering, respectively, and can be highly variable, especially for granular mucoadhesives.
另外，粉末可含有一定比例的在混合物的固体组分中充分均匀分散的液体，或可完全由固体材料组成。Additionally, the powder may contain a proportion of liquid that is sufficiently uniformly dispersed among the solid components of the mixture, or may consist entirely of solid material.
在某些实施例中，止血组合物可以包含一种或多种止血剂。例如，呈粉末形式的止血组合物可以是两种或更多种以确定或不同比例存在的粉末状纯止血剂的物理混合剂。例如，呈液体形式的止血组合物可以是与溶剂混合的两种或更多种以确定或不同比例存在的粉末状纯止血剂的物理混合剂。In certain embodiments, the hemostatic composition can include one or more hemostatic agents. For example, a hemostatic composition in powder form can be a physical admixture of two or more pure hemostatic agents in powder form present in defined or varying proportions. For example, a hemostatic composition in liquid form may be a physical admixture of two or more pure hemostatic agents in powder form mixed with a solvent in defined or varying proportions.
在某些实施例中，保护性覆盖物可以包括一种或多种粘膜粘合剂。例如，呈粉末形式的保护性覆盖物可以是两种或更多种以确定或不同比例存在的粉末状纯粘膜粘合剂的物理混合剂。例如，呈液体形式的保护性覆盖物可以是与溶剂混合的两种或更多种以确定或不同比例存在的粉末状纯粘膜粘合剂的物理混合剂。In certain embodiments, the protective covering may include one or more mucoadhesives. For example, the protective covering in powder form may be a physical admixture of two or more powdered pure mucoadhesives present in defined or varying proportions. For example, the protective covering in liquid form may be a physical admixture of two or more powdered pure mucoadhesives present in determined or varying proportions mixed with a solvent.
在一些实施例中，可以将治疗剂和或赋形剂与止血剂和/或粘膜粘合剂粉末混合成适合根据本发明的方法使用的配制品，或与止血剂和/或粘膜粘合剂液体混合成液体配制品。In some embodiments, therapeutic agents and/or excipients may be mixed with hemostatic agents and/or mucoadhesive powders into formulations suitable for use in accordance with the methods of the present invention, or with hemostatic agents and/or mucoadhesives Liquids are mixed into liquid formulations.
在替代性实施例中，呈粉末或粒子形式的止血组合物和/或保护性覆盖物可在使用前用溶剂或水或其他液体重构。在重构时，可以将这些呈粉末或粒子形式的配制品与染料、着色剂、调味剂和/或其他所需医药成分混合，因此重构溶液可以具有液体医药的医药特征。In alternative embodiments, the hemostatic composition and/or protective covering in powder or particle form may be reconstituted with a solvent or water or other liquid prior to use. Upon reconstitution, these formulations in powder or particle form can be mixed with dyes, colorants, flavors, and/or other desired pharmaceutical ingredients so that the reconstituted solution can have the medicinal properties of a liquid medicine.
在替代性实施例中，呈粉末或粒子形式的保护性覆盖物可在使用前用溶剂或水或其他液体重构。在重构时，可以将这些呈粉末或粒子形式的配制品与染料、着色剂、调味剂和/或其他所需医药成分混合，因此重构溶液可以具有液体医药的医药特征。In alternative embodiments, the protective covering in powder or particle form can be reconstituted with a solvent or water or other liquid prior to use. Upon reconstitution, these formulations in powder or particle form can be mixed with dyes, colorants, flavors, and/or other desired pharmaceutical ingredients so that the reconstituted solution can have the medicinal properties of a liquid medicine.
用于本文中所提供的配制品目的的粉末包括以下配制品，其中医师可按原样使用该配制品(即，以粉末形式)，或将指导量的粉末与指导量的溶剂或水或其他液体混合，之后在具有活动性出血的病损部位处及其附近局部施用并且能够停止出血。Powders for the purposes of the formulations provided herein include those formulations that a physician can use as is (ie, in powder form), or by combining an indicated amount of powder with an indicated amount of solvent or water or other liquid Mixed, then topically applied at and near the lesion site with active bleeding and able to stop bleeding.
在某些实施例中，该保护性覆盖物可包括多种材料。In certain embodiments, the protective covering may comprise a variety of materials.
在一个实施例中，该保护性覆盖物可包括例如粘合材料(以粘附到组织)和超强吸收性材料(以用作屏障来防止液体与该病损或离开该病损部位的血液接触)。附加地或替代性地，该保护性覆盖物可包括止血材料(以在该病损出血的事件中使血液凝结)作为其组分之一。附加地或替代性地，保护性覆盖物还可以包括pH调节材料，例如碱或酸，或缓冲剂，以在极端pH或盐度环境中保持粘附。In one embodiment, the protective covering may include, for example, an adhesive material (to adhere to tissue) and a superabsorbent material (to act as a barrier to prevent fluids from interacting with the lesion or blood leaving the lesion). touch). Additionally or alternatively, the protective covering may include as one of its components a hemostatic material (to coagulate blood in the event of bleeding from the lesion). Additionally or alternatively, the protective covering may also include pH adjusting materials, such as bases or acids, or buffers, to maintain adhesion in extreme pH or salinity environments.
对于包含酸性聚合物(例如卡波姆)的保护性覆盖物，中和聚合物(达到5-9的pH范围)并因此增加粘度的成分包括碱，例如氢氧化钠、氢氧化铵、氢氧化钾、精氨酸、氨基甲基丙醇、四羟丙基乙二胺、三乙醇胺、三甲胺、PEG-15椰油胺、二异丙醇胺、三异丙醇胺和碳酸钙。对于以凝胶或液体形式施加的保护性覆盖物，在递送之前，将所提及的碱与保护性覆盖物一起溶解。同样，呈碱性的保护性覆盖物可以包含酸性成分，以实现更中性的pH值并因而增加粘附力。对于以粉末形式施加的保护性覆盖物，所提及的pH调节剂也可以按粉末形式使用，并在体内水合作用下溶解。为了帮助制造包含pH调节粉末的保护性覆盖物，避免使用吸湿性粉末而使用吸收性较小的粉末例如碳酸钙可能是有利的。For protective coverings containing acidic polymers such as carbomers, ingredients that neutralize the polymer (to a pH range of 5-9) and thus increase viscosity include bases such as sodium hydroxide, ammonium hydroxide, hydroxide Potassium, arginine, aminomethylpropanol, tetrahydroxypropylethylenediamine, triethanolamine, trimethylamine, PEG-15 cocoamine, diisopropanolamine, triisopropanolamine, and calcium carbonate. For protective coverings applied in gel or liquid form, the bases mentioned are dissolved together with the protective covering prior to delivery. Likewise, protective coverings that are alkaline may contain acidic components to achieve a more neutral pH and thus increase adhesion. For protective coverings applied in powder form, the pH adjusting agents mentioned can also be used in powder form and dissolve under body hydration. To aid in the manufacture of protective coverings comprising pH adjusting powders, it may be advantageous to avoid the use of hygroscopic powders in favor of less absorbent powders such as calcium carbonate.
对于以粉末形式递送的多组分保护性覆盖物，组分可以结合在一起或由独立的颗粒组成。结合在一起的组分产生包含多种成分的单个颗粒。结合的颗粒的示例实施例可以是与较大的屏障形成颗粒结合的细粘膜粘附剂颗粒(图2)。For multi-component protective coverings delivered in powder form, the components may be combined together or composed of separate particles. The components combined together produce a single particle containing multiple components. An exemplary embodiment of a bound particle may be a fine mucoadhesive particle bound to a larger barrier-forming particle (FIG. 2).
在另一个实施例中，在该保护性覆盖物中可包括一种或多种促进愈合的添加剂。In another embodiment, one or more healing-promoting additives may be included in the protective covering.
超强吸收性材料的一些实例包括吸收性粘土(例如，锂皂石、蒙脱石、沸石)、硅藻土和超强吸收性聚合物(例如，聚丙烯酸钠、聚丙烯酰胺共聚物、乙烯顺丁烯二酸酐共聚物、交联羧甲基纤维素、聚乙烯醇共聚物、交联聚环氧乙烷和淀粉-丙烯腈共聚物)。Some examples of superabsorbent materials include absorbent clays (eg, laponite, montmorillonite, zeolites), diatomaceous earth, and superabsorbent polymers (eg, sodium polyacrylate, polyacrylamide copolymers, ethylene maleic anhydride copolymer, cross-linked carboxymethyl cellulose, polyvinyl alcohol copolymer, cross-linked polyethylene oxide and starch-acrylonitrile copolymer).
在一些实施例中，保护性覆盖物还可以包括止血剂。止血剂可以是与止血组合物中提供的止血剂相同或不同的止血剂。保护性覆盖物还可以包括两种或更多种止血剂的组合。止血剂的一些实例包括海藻酸盐、几丁质、壳聚糖、胶原蛋白、纤维蛋白、高岭土粘土、氧化纤维素、植物基多糖、血小板、蒙脱石粘土和沸石。In some embodiments, the protective covering may also include a hemostatic agent. The hemostatic agent may be the same or a different hemostatic agent than that provided in the hemostatic composition. The protective covering may also include a combination of two or more hemostatic agents. Some examples of hemostatic agents include alginates, chitin, chitosan, collagen, fibrin, kaolin clay, oxidized cellulose, plant-based polysaccharides, platelets, montmorillonite clays, and zeolites.
用于促进愈合的添加剂的一些实例包括芦荟(Aloe vera)和衍生物、蜂蜜和衍生物(即松红梅(Leptospermum scoparium)蜂蜜)和生长因子。Some examples of additives for promoting healing include Aloe vera and derivatives, honey and derivatives (ie Leptospermum scoparium honey) and growth factors.
在某些实施例中，保护性覆盖物还可以包括机械支架以形成绷带、贴片、敷料等。该术语“支架”是指能向保护性覆盖物提供机械和结构支撑和强度的任何天然(例如，细胞外基质材料或“ECM”)、合成(例如，织造或非织造)材料(例如，DacronTM、静电纺丝材料和膨胀PTFE)。In certain embodiments, the protective covering may also include mechanical supports to form bandages, patches, dressings, and the like. The term "scaffold" refers to any natural (eg, extracellular matrix material or "ECM"), synthetic (eg, woven or nonwoven) material (eg, Dacron) that provides mechanical and structural support and strength to a protective coveringTM , electrospun materials and expanded PTFE).
保护性覆盖物可以采用支架，这些支架可以按多种形式施加，包括单层或多层薄片或网状物构建体、流动化配制品和/或其组合。Protective coverings can take the form of stents, which can be applied in a variety of forms, including single- or multi-layer sheet or mesh constructs, fluidized formulations, and/or combinations thereof.
合成支架的实例包括生物相容性材料，例如聚酯，例如聚乙烯；聚(对苯二甲酸乙二酯)；氟化聚合物，例如聚四氟乙烯(PTFE)和膨胀PTFE纤维；聚氨酯；硅酮等。生物相容性聚酯的一个实例包括DacronTM(特拉华州威明顿的杜邦公司(DuPONT,Wilmington,Del.))。Examples of synthetic stents include biocompatible materials such as polyesters such as polyethylene; poly(ethylene terephthalate); fluorinated polymers such as polytetrafluoroethylene (PTFE) and expanded PTFE fibers; polyurethanes; Silicone etc. An example of a biocompatible polyester includes Dacron™ (DuPONT, Wilmington, Del.).
天然支架材料的实例包括生物可重塑性基于ECM的材料，例如从合适的动物或人类组织来源分离的天然产生的胶原性ECM材料。如本文所用，清洁、脱层和/或粉碎ECM或使胶原蛋白或其他组分在ECM内交联在“天然衍生的ECM”的定义内。完全或部分去除天然基质的一种或多种组分或子组分也在天然ECM的定义内。生物可重塑性ECM材料具有能诱导组织重塑的向生体性质。可经加工以提供支架材料的合适ECM材料包括例如粘膜下层(包括例如小肠粘膜下层(SIS)、胃粘膜下层、膀胱粘膜下层或子宫粘膜下层，这些粘膜下层各自是从幼年或成年动物分离)、肾被膜、真皮胶原蛋白、羊膜、硬脑膜、心包膜、浆膜、腹膜或基底膜层或材料，包括肝基底膜或上皮基底膜材料和其他材料。Examples of natural scaffold materials include bioremodelable ECM-based materials, such as naturally occurring collagenous ECM materials isolated from suitable animal or human tissue sources. As used herein, cleaning, delaminating and/or pulverizing the ECM or cross-linking collagen or other components within the ECM is within the definition of "naturally derived ECM." Complete or partial removal of one or more components or subcomponents of the native matrix is also within the definition of native ECM. Bioremodelable ECM materials have biotropic properties that induce tissue remodeling. Suitable ECM materials that can be processed to provide scaffold materials include, for example, submucosa (including, for example, small intestinal submucosa (SIS), gastric submucosa, bladder submucosa, or uterine submucosa, each of which is isolated from juvenile or adult animals), Renal capsule, dermal collagen, amniotic membrane, dura mater, pericardium, serosa, peritoneum or basement membrane layers or materials, including liver basement membrane or epithelial basement membrane materials and other materials.
示例性ECM薄片材料是粘膜下层组织移植材料的薄片(OASISTM伤口基质，美国印第安纳州西拉法叶城的库克生物技术公司(Cook Biotech Incorporated,West Lafayette,Ind.,USA))。An exemplary ECM sheet material is a sheet of submucosa tissue graft material (OASIS™ wound matrix, Cook Biotech Incorporated, West Lafayette, Ind., USA).
包含支架和粘膜粘合剂的保护性覆盖物可以用于治疗胃肠道病损中的病损。出于这些目的，可将该支架材料加工为薄片、绷带或其他形状的形式，以至少部分封闭或覆盖胃肠道中的该病损部位。Protective coverings comprising stents and mucoadhesives can be used to treat lesions in the gastrointestinal tract. For these purposes, the scaffold material can be processed into the form of a sheet, bandage, or other shape to at least partially seal or cover the lesion in the gastrointestinal tract.
在本发明的某些实施例中，一种或多种粘合剂(例如，粘膜粘合剂)可与流动化ECM材料混合，以形成实质上均匀的粘合剂溶液。该流动化ECM材料可经干燥或形成凝胶以供直接使用。In certain embodiments of the invention, one or more adhesives (eg, mucoadhesives) can be mixed with the fluidized ECM material to form a substantially homogeneous adhesive solution. The fluidized ECM material can be dried or gelled for immediate use.
在某些实施例中，粉碎的粘膜下层或其他ECM材料可通过冷冻干燥来干燥以形成粉末，其可水合，也就是与水或缓冲盐水和任选地其他医药上可接受的赋形剂组合，以形成流体ECM粘合剂医学产品。流动化ECM组合物的粘度可通过控制粘膜下层或其他ECM组分的浓度、水合程度以及调节该粘膜下层或其他ECM消化物的pH来操纵。可将该粘度在25℃下调节到约2cps到约300,000cps的范围。较高粘度凝胶配制品可具有凝胶或糊剂稠度并且可通过将消化物溶液的pH调节到约6.0到约7.0来制备。In certain embodiments, the pulverized submucosa or other ECM material can be dried by freeze-drying to form a powder, which can be hydrated, that is, combined with water or buffered saline and optionally other pharmaceutically acceptable excipients , to form fluid ECM adhesive medical products. The viscosity of the fluidized ECM composition can be manipulated by controlling the concentration of the submucosa or other ECM components, the degree of hydration, and adjusting the pH of the submucosa or other ECM digests. The viscosity can be adjusted to range from about 2 cps to about 300,000 cps at 25°C. Higher viscosity gel formulations can have a gel or paste consistency and can be prepared by adjusting the pH of the digestate solution to about 6.0 to about 7.0.
替代性地，该流动化ECM材料可经干燥并粘附到粘膜粘合剂或经粘膜粘合剂涂布。Alternatively, the fluidized ECM material may be dried and adhered to a mucoadhesive or transmucoadhesive coated.
在某些实施例中，止血组合物是均质的。术语“均质的”是指该层的各个组分充分分布以表现为单一组分。同样，在某些实施例中，保护性覆盖物可以是均质的。In certain embodiments, the hemostatic composition is homogeneous. The term "homogeneous" means that the individual components of the layer are sufficiently distributed to appear as a single component. Also, in certain embodiments, the protective covering can be homogeneous.
在某些实施例中，保护性覆盖物可以是包括其他层例如生物相容性基底膜或层的复合覆盖物。例如，覆盖物可以顶部薄片或不可渗透层，以限制液体的通过，例如胃酸朝向病损返回。替代性地或另外，覆盖物可以包括提供进一步的屏障或结构支撑的其他背衬层。In certain embodiments, the protective covering may be a composite covering that includes other layers such as a biocompatible base film or layer. For example, the cover may be a top sheet or impermeable layer to limit the passage of fluids, such as gastric acid back towards the lesion. Alternatively or additionally, the cover may include other backing layers that provide further barrier or structural support.
在某些实施例中，可通过用粘合剂混合、涂布、喷洒、浸渍支架将该粘合剂纳入该支架中，或该粘合剂可以作为单独粘合剂层来提供，形成经粘合剂涂布的边缘。某些制备技术，例如冻干、临界点干燥或使用低表面张力溶剂(例如乙酸乙酯、醇、苯)，可用于在纳入过程中保持粘合性能。In certain embodiments, the adhesive can be incorporated into the stent by mixing, coating, spraying, dipping the stent with the adhesive, or the adhesive can be provided as a separate adhesive layer, forming a bonded Mixture-coated edges. Certain preparation techniques, such as lyophilization, critical point drying, or the use of low surface tension solvents (eg, ethyl acetate, alcohol, benzene), can be used to maintain adhesive properties during incorporation.
在某些实施例中，保护性覆盖物可以包括置于胃肠道组织上的在界面上的粘膜粘合剂覆盖物以及在腔界面上的其他材料(例如织造网状物支架)以向覆盖物提供改善的机械强度。In certain embodiments, the protective covering may include a mucoadhesive covering at the interface placed over the gastrointestinal tissue and other materials (eg, woven mesh stents) at the lumen interface to provide protection to the covering material provides improved mechanical strength.
在某些实施例中，本文披露和本文使用的止血组合物和/或保护性覆盖物可以包含一种或多种赋形剂。具体地，本文可用的其他赋形剂包括但不限于溶剂、粘结剂、填充剂、润滑剂、悬浮剂、调味剂、颜色指示剂(例如，染料)、甜味剂、防腐剂、抗氧化剂、缓冲剂、湿润剂、螯合剂、表面活性剂、崩解剂、交联剂等等。这些赋形剂可以延长止血组合物和/或保护性覆盖物与胃肠道中的病损部位接触的时间，和/或可以增加止血组合物和/或保护性覆盖物与胃肠道表面的相互作用，例如可以使用粘度增强剂或吸收增强剂。In certain embodiments, the hemostatic compositions and/or protective coverings disclosed and used herein may include one or more excipients. Specifically, other excipients useful herein include, but are not limited to, solvents, binders, fillers, lubricants, suspending agents, flavoring agents, color indicators (eg, dyes), sweeteners, preservatives, antioxidants , buffers, wetting agents, chelating agents, surfactants, disintegrating agents, cross-linking agents, and the like. These excipients can prolong the time that the hemostatic composition and/or protective covering is in contact with the lesion in the gastrointestinal tract, and/or can increase the interaction of the hemostatic composition and/or protective covering with the surfaces of the gastrointestinal tract For example, viscosity enhancers or absorption enhancers can be used.
在某些实施例中，止血组合物和/或保护性覆盖物包括溶剂。示例性溶剂包括乙酸乙酯、乙醇、水、DMSO、盐水、丙酮、异丙醇或其组合。如果使用溶剂，则所得的组分呈液体或凝胶的形式，并且可以原样递送至具有活动性出血的病损部位。In certain embodiments, the hemostatic composition and/or protective covering includes a solvent. Exemplary solvents include ethyl acetate, ethanol, water, DMSO, brine, acetone, isopropanol, or combinations thereof. If a solvent is used, the resulting component is in the form of a liquid or gel and can be delivered as is to a lesion with active bleeding.
任选地，该止血组合物和/或保护性覆盖物可包括一种或多种粘结剂、任选地一种或多种填充剂、任选地一种或多种润滑剂、任选地一种或多种悬浮剂、任选地一种或多种调味剂、任选地一种或多种着色剂、任选地一种或多种甜味剂、任选地一种或多种防腐剂、任选地一种或多种抗氧化剂、任选地一种或多种缓冲剂、任选地一种或多种湿润剂、任选地一种或多种螯合剂、任选地一种或多种崩解剂和任选地一种或多种表面活性剂。Optionally, the hemostatic composition and/or protective covering may include one or more binders, optionally one or more fillers, optionally one or more lubricants, optionally optionally one or more suspending agents, optionally one or more flavoring agents, optionally one or more coloring agents, optionally one or more sweetening agents, optionally one or more flavoring agents preservatives, optionally one or more antioxidants, optionally one or more buffering agents, optionally one or more wetting agents, optionally one or more chelating agents, optionally one or more disintegrants and optionally one or more surfactants.
另外，该止血组合物和/或保护性覆盖物可包括例如颜色指示剂，例如在施加到病损部位及其附近后变色的染料。水溶性染料是优选的。示例性染料包括靛胭脂、亚甲蓝、荧光蛋白质、玫瑰红、印度墨水(India ink)和其他染料。Additionally, the hemostatic composition and/or protective covering may include, for example, a color indicator, such as a dye that changes color upon application to and near the lesion. Water-soluble dyes are preferred. Exemplary dyes include indigo carmine, methylene blue, fluorescent proteins, rose bengal, India ink, and others.
防腐剂包括例如苯扎氯铵(benzalkonium chloride)、西曲溴铵(cetrimide)(溴化十六烷基三甲铵)、苯甲酸、苯甲醇、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯和对羟基苯甲酸丁酯、氯己定(chlorhexidine)、氯丁醇、乙酸苯汞、硼酸盐和硝酸盐、山梨酸钾、苯甲酸钠、山梨酸、硫柳汞(汞基硫代水杨酸)、其组合等等。Preservatives include, for example, benzalkonium chloride, cetrimide (cetyltrimethylammonium bromide), benzoic acid, benzyl alcohol, methylparaben, ethylparaben , propyl and butylparaben, chlorhexidine, chlorobutanol, phenylmercuric acetate, borates and nitrates, potassium sorbate, sodium benzoate, sorbic acid, thimerosal (mercury thiosalicylic acid), combinations thereof, and the like.
抗氧化剂包括例如抗坏血酸棕榈酸酯、丁羟茴香醚、丁羟甲苯、硫代甘油、抗坏血酸钠、甲醛次硫酸氢钠、焦亚硫酸钠、BHT、BHA、亚硫酸氢钠、维生素E或其衍生物、没食子酸丙酯、乙二胺四乙酸盐(EDTA)(例如，乙二胺四乙酸二钠)、二乙烯三胺五乙酸(DTPA)、氨三乙酸盐(Triglycollamate)(NT)、其组合等等。Antioxidants include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, thioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, BHT, BHA, sodium bisulfite, vitamin E or derivatives thereof, Propyl gallate, ethylenediaminetetraacetate (EDTA) (eg, disodium EDTA), diethylenetriaminepentaacetic acid (DTPA), triglycollamate (NT), its combination and so on.
另外，在某些实施例中，缓冲剂、湿润剂或螯合剂也可纳入该止血组合物和/或保护性覆盖物中。Additionally, in certain embodiments, buffers, wetting agents, or chelating agents may also be incorporated into the hemostatic composition and/or protective covering.
示例性缓冲剂包括柠檬酸盐缓冲剂(即，柠檬酸和柠檬酸盐)、磷酸盐缓冲剂、乙酸盐缓冲剂、碳酸盐缓冲剂(例如，碳酸钙、碳酸氢钠等等)、氢氧化物(例如，氢氧化镁、氢氧化钠等等)、其组合等等。Exemplary buffers include citrate buffers (ie, citric acid and citrate), phosphate buffers, acetate buffers, carbonate buffers (eg, calcium carbonate, sodium bicarbonate, etc.), Hydroxides (eg, magnesium hydroxide, sodium hydroxide, etc.), combinations thereof, and the like.
湿润剂包括例如甘油、丙二醇、乙二醇、三乙酸甘油酯、多元醇(例如，山梨醇、木糖醇、麦芽糖醇、聚右旋糖)等等。Humectants include, for example, glycerol, propylene glycol, ethylene glycol, triacetin, polyols (eg, sorbitol, xylitol, maltitol, polydextrose), and the like.
螯合剂包括例如乙二胺四乙酸盐(EDTA)(例如，乙二胺四乙酸钠)、二乙烯三胺五乙酸(DTPA)、氨三乙酸盐(NT)等等。Chelating agents include, for example, ethylenediaminetetraacetate (EDTA) (eg, sodium ethylenediaminetetraacetate), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetate (NT), and the like.
在一些实施例中，该止血组合物和/或保护性覆盖物可以进一步包括至少一种治疗剂。可纳入止血组合物和/或保护性覆盖物中的示例性治疗剂包括抗生素、防腐剂、质子泵抑制剂、基质金属蛋白酶或组织生长促进化合物。In some embodiments, the hemostatic composition and/or protective covering may further comprise at least one therapeutic agent. Exemplary therapeutic agents that can be incorporated into the hemostatic composition and/or protective covering include antibiotics, antiseptics, proton pump inhibitors, matrix metalloproteinases, or tissue growth promoting compounds.
还可包括其他治疗剂并且可为所属领域技术人员已知。Other therapeutic agents may also be included and may be known to those skilled in the art.
造影剂可以与止血组合物和保护性覆盖物的注射结合使用。可以在注射这两种材料之前注射造影剂。替代性地，将造影剂包括在止血组分或保护性覆盖物组分中，该止血组分或保护性覆盖物组分在胃肠道中的具有活动性出血的病损部位处及其附近注射。造影剂及其使用是本领域技术人员所熟知的。Contrast agents can be used in conjunction with injections of hemostatic compositions and protective coverings. The contrast agent can be injected prior to the injection of the two materials. Alternatively, the contrast agent is included in a hemostatic component or protective covering component that is injected at and near a lesion in the gastrointestinal tract with active bleeding . Contrast agents and their use are well known to those skilled in the art.
在某些实施例中，为了止血的目的并且在递送包括粘合剂的保护性覆盖物之前，可以将包含止血剂的组合物递送到具有活动性出血的病损部位及其附近。In certain embodiments, a composition comprising a haemostatic agent can be delivered to and near a lesion with active bleeding for the purpose of haemostasis and prior to delivery of a protective covering comprising an adhesive.
例如，如果用于止血目的，则可以提供凝血酶、肾上腺素、止血粉或组织硬化剂来减少病损部位处的局部出血。除了止血剂的止血特性外，还应注意的是，流体和治疗剂的相对高的压力本身可以通过提供压缩力而充当机械填塞，从而减少实现止血所需的时间。For example, if used for hemostatic purposes, thrombin, epinephrine, hemostatic powder, or tissue sclerosing agents may be provided to reduce local bleeding at the lesion site. In addition to the hemostatic properties of the hemostatic agent, it should also be noted that the relatively high pressure of the fluid and therapeutic agent can itself act as a mechanical packing by providing a compressive force, thereby reducing the time required to achieve hemostasis.
如上所述，止血组合物可以按任何合适的形式递送。例如，止血组合物可以包含粉末、液体、凝胶、气溶胶或其他物质。As mentioned above, the hemostatic composition can be delivered in any suitable form. For example, the hemostatic composition may comprise powder, liquid, gel, aerosol or other substances.
在某些实施例中，保护性覆盖物经制备用于在病损部位处及其附近局部和直接递送，其中该保护性覆盖物在递送或施加到该病损时在该病损部位处及其附近形成涂层或贴片等，并且能在该病损部位处及其附近保留足够的时间以允许该部位被治疗或愈合。优选地，实现该病损部位的至少部分覆盖；最优选地，实现该病损部位的完全覆盖。足以容许该部位被治疗或愈合的时间可根据该病损的位置、类型和大小而变化，并且可为从30分钟(足以停止出血)到72小时或更久(足以容许组织几乎完全愈合)中的任一时间。优选地，足以容许该部位被治疗或愈合的时间为至少1小时；更优选地，足以容许该部位被治疗或愈合的时间为至少3小时；更优选地，足以容许该部位被治疗或愈合的时间为至少6小时；更优选地，足以容许该部位被治疗或愈合的时间为至少10小时；更优选地，足以容许该部位被治疗或愈合的时间为至少12小时；更优选地，足以容许该部位被治疗或愈合的时间为至少18小时；更优选地，足以容许该部位被治疗或愈合的时间为至少24小时；更优选地，足以容许该部位被治疗或愈合的时间为至少36小时；更优选地，足以容许该部位被治疗或愈合的时间为至少48小时；更优选地，足以容许该部位被治疗或愈合的时间为至少72小时；最优选地，足以容许该部位被治疗或愈合的时间为48-72小时。In certain embodiments, a protective covering is prepared for topical and direct delivery at and near a lesion, wherein the protective covering is delivered or applied to the lesion at the lesion and A coating or patch or the like is formed near it and can remain at and near the lesion site for sufficient time to allow the site to be treated or healed. Preferably, at least partial coverage of the lesion is achieved; most preferably, complete coverage of the lesion is achieved. The time sufficient to allow the site to be treated or healed can vary depending on the location, type and size of the lesion, and can range from 30 minutes (enough to stop bleeding) to 72 hours or more (enough to allow nearly complete healing of the tissue) any time. Preferably, the time sufficient to allow the site to be treated or healed is at least 1 hour; more preferably, the time sufficient to allow the site to be treated or healed is at least 3 hours; more preferably, the time sufficient to allow the site to be treated or healed is at least 3 hours The time is at least 6 hours; more preferably, the time sufficient to allow the site to be treated or healed is at least 10 hours; more preferably, the time sufficient to allow the site to be treated or healed is at least 12 hours; more preferably, the time sufficient to allow the site to be treated or healed is at least 12 hours The time for the site to be treated or healed is at least 18 hours; more preferably, the time sufficient to allow the site to be treated or healed is at least 24 hours; more preferably, the time sufficient to allow the site to be treated or healed is at least 36 hours more preferably, the time sufficient to allow the site to be treated or healed is at least 48 hours; more preferably, the time sufficient to allow the site to be treated or healed is at least 72 hours; most preferably, the time sufficient to allow the site to be treated or healed is at least 72 hours; The healing time is 48-72 hours.
方法和递送method and delivery
某些实施例涉及用于保护或治疗胃肠道中的具有活动性出血的病损的方法。该方法包括在胃肠道中的病损部位处及其附近直接施加包含止血剂的组合物以停止活动性出血；以及一旦活动性出血停止，便在胃肠道中的病损部位处及其附近的先前施加的包含止血剂的组合物的至少一部分上方及其附近直接施加包含粘合剂的保护性覆盖物。当在病损部位处及其附近的止血组合物的至少一部分上方及其附近施加时，保护性覆盖物粘附到止血组合物/层和周围的胃肠道组织两者并与它们直接接触、提供持久的保护屏障并且能够在病损部位处及周围保留最少30分钟。Certain embodiments relate to methods for protecting or treating a lesion with active bleeding in the gastrointestinal tract. The method includes directly applying a composition comprising a hemostatic agent at and near the lesion in the gastrointestinal tract to stop active bleeding; and once the active bleeding has ceased, applying a composition comprising a hemostatic agent at and near the lesion in the gastrointestinal tract A protective covering comprising an adhesive is applied directly over and adjacent to at least a portion of the previously applied hemostatic agent-containing composition. When applied over and near at least a portion of the hemostatic composition at and near the lesion, the protective covering adheres to and is in direct contact with both the hemostatic composition/layer and surrounding gastrointestinal tissue, Provides a long-lasting protective barrier and is able to remain at and around the lesion for a minimum of 30 minutes.
在某些实施例中，止血组合物和保护性覆盖物可以通过内镜技术、腹腔镜技术或通过直接进入(即，以手术方式)使用例如任何合适的导管递送系统将止血组合物和保护性覆盖物施加或递送到病损部位及其附近。In certain embodiments, the hemostatic composition and protective covering can be delivered to the hemostatic composition and protective covering by endoscopic techniques, laparoscopic techniques, or by direct access (ie, surgically) using, for example, any suitable catheter delivery system. A covering is applied or delivered to and near the lesion.
在某些实施例中，止血组合物和保护性覆盖物可以经由管腔内递送系统递送。止血组合物和保护性覆盖物可以经由喷洒、喷射、注射或铺展来施加。In certain embodiments, the hemostatic composition and protective covering can be delivered via an intraluminal delivery system. The hemostatic composition and protective covering can be applied via spraying, jetting, injection or spreading.
此双峰治疗的优点是止血组合物和保护性覆盖物的递送在同一过程中进行，这可以最大程度减少和/或消除重复过程。The advantage of this bimodal treatment is that the delivery of the hemostatic composition and protective covering takes place in the same process, which can minimize and/or eliminate duplication of processes.
在某些实施例中，止血组合物和保护性覆盖物可以穿过多腔导管。In certain embodiments, the hemostatic composition and protective covering can be passed through a multi-lumen catheter.
具体地，递送系统可以包括递送装置，该递送装置的大小和构造被设定成在体腔或中空身体器官内的目标组织区域(即，例如病损部位，例如胃肠道中的具有活动性出血的病损)直接递送并施加止血组合物和保护性覆盖物。In particular, a delivery system may include a delivery device sized and configured to target a tissue region within a body cavity or hollow body organ (ie, eg, a lesion site, eg, a gastrointestinal tract with active bleeding lesions) direct delivery and application of the hemostatic composition and protective covering.
另外，该递送装置可经定大小和配置以适应经由导丝通过。按这种方式，可经由该导丝在内镜的直接可视化下引入该装置。具体地，该导丝可紧靠该内镜前行并且因此不占用该内镜的工作通道。在替代性实施例中，该递送装置可经定大小和配置以通过该内镜的工作通道背载。该内镜的工作通道由此用于在提供直接可视化的同时引导该递送装置。Additionally, the delivery device can be sized and configured to accommodate passage through a guide wire. In this way, the device can be introduced under direct visualization of the endoscope via the guide wire. In particular, the guide wire can be advanced against the endoscope and thus does not occupy the working channel of the endoscope. In alternative embodiments, the delivery device may be sized and configured to be carried through the working channel of the endoscope. The working channel of the endoscope is thus used to guide the delivery device while providing direct visualization.
用于局部递送治疗剂的各种递送系统是已知的，并且可以用于递送本文所述的两种组分。Various delivery systems for topical delivery of therapeutic agents are known and can be used to deliver the two components described herein.
在某些实施例中，止血组合物和保护性覆盖物的递送可以通过例如适合于将治疗剂递送至目标部位的系统进行。示例性系统先前在美国专利公开号2015/0094649中进行了描述，该美国专利公开全文并入本文。In certain embodiments, delivery of the hemostatic composition and protective covering can be by, for example, a system suitable for delivering therapeutic agents to a target site. Exemplary systems were previously described in US Patent Publication No. 2015/0094649, which is incorporated herein in its entirety.
在某些实施例中，止血组合物和保护性覆盖物的递送可以通过例如“双桶”装置进行。示例性双桶装置先前在美国专利公开号2008/0060970中进行了描述，该美国专利公开全文并入本文。In certain embodiments, the delivery of the hemostatic composition and protective covering can be by, for example, a "dual barrel" device. An exemplary dual barrel device was previously described in US Patent Publication No. 2008/0060970, which is incorporated herein in its entirety.
简而言之，示例性双桶装置可以包括药筒，该药筒具有用于递送止血剂和保护性覆盖物的至少两个圆柱体钻孔，其中每个圆柱体包括用于止血剂和保护性覆盖物的出口；每个圆柱体内的用于将材料推出圆柱体的柱塞；适于接纳药筒的壳体，其中壳体或药筒包括接纳和锁定可操作地连接到药筒的出口的歧管的适配器；至少两个带齿的活塞，其中每个带齿的活塞至少部分地位于圆柱体钻孔内；连接到壳体的触发器，其中触发器包括带齿的驱动齿条；与带齿的驱动齿条并与带齿的活塞配合的齿轮组件。Briefly, an exemplary dual-barrel device can include a cartridge having at least two cylindrical bores for delivering a hemostatic agent and a protective covering, wherein each cylinder includes a hemostatic agent and a protective covering. an outlet for a sexual covering; a plunger within each cylinder for pushing material out of the cylinder; a housing adapted to receive a cartridge, wherein the housing or cartridge includes an outlet to receive and lock operably connected to the cartridge an adapter for the manifold; at least two toothed pistons, wherein each toothed piston is located at least partially within the cylindrical bore; a trigger connected to the housing, wherein the trigger includes a toothed drive rack; A gear assembly that mates with a toothed drive rack and with a toothed piston.
一种替代性递送系统可以是美国专利公开号2002/0170926中所述的系统，该美国专利公开全文并入本文。An alternative delivery system may be the system described in US Patent Publication No. 2002/0170926, which is incorporated herein in its entirety.
在某些实施例中，施加止血组合物的步骤可以包括在具有活动性出血的病损部位处及其附近插入第一止血装置，例如装有止血组合物的注射器，并在该具有活动性出血的病损处及上方施加止血组合物以停止活动性出血。施加可以通过在具有活动性出血的病损部位处及其附近喷洒、喷射或铺展止血组合物而进行。In certain embodiments, the step of applying the hemostatic composition can include inserting a first hemostatic device, such as a syringe containing the hemostatic composition, at or near the site of the active bleeding lesion, and inserting a hemostatic composition at the site of the active bleeding A hemostatic composition is applied to and above the lesion to stop active bleeding. Application may be by spraying, jetting or spreading the hemostatic composition at and near the site of the lesion with active bleeding.
在某些实施例中，施加保护性覆盖物的步骤可以包括在具有活动性出血的病损部位处及其附近插入第二递送装置，例如装有保护性覆盖物的注射器，并在止血组合物的至少一部分顶部及其附近施加保护性覆盖物。施加可以通过在胃肠道中的病损部位处及其附近的先前施加的止血组合物的至少一部分的顶部及其附近喷洒、喷射或铺展保护性覆盖物而进行。In certain embodiments, the step of applying the protective covering can include inserting a second delivery device, such as a protective covering-filled syringe, at and near the site of the lesion with active bleeding, and inserting the hemostatic composition A protective covering is applied to at least a portion of the top and its vicinity. Application may be by spraying, jetting, or spreading a protective covering on top of and adjacent to at least a portion of the previously applied hemostatic composition at and near the lesion in the gastrointestinal tract.
某些其他实施例涉及一种用于保护或治疗因胃肠道障碍和或需要去除胃肠道壁的粘膜层或粘膜下层的医学程序引起的胃肠道中的病损的方法，该病损具有活动性出血。该病损可以是粘膜切除术后病损。Certain other embodiments relate to a method for protecting or treating a lesion in the gastrointestinal tract resulting from a disorder of the gastrointestinal tract and or a medical procedure requiring removal of the mucosal or submucosa of the gastrointestinal tract, the lesion having Active bleeding. The lesion may be a postmucosal resection lesion.
该方法包括将止血组合物和粘合剂保护性覆盖物局部施加到胃肠道中的病损处及其附近。在施加两种组分后，产品在病损部位处形成保护性涂层或覆盖物，其中该涂层能够在病损部位处及其附近保留至少30分钟，更优选地24-72小时或更长。The method includes topically applying a hemostatic composition and an adhesive protective covering to and near a lesion in the gastrointestinal tract. After application of the two components, the product forms a protective coating or covering at the lesion, wherein the coating is able to remain at and near the lesion for at least 30 minutes, more preferably 24-72 hours or more long.
在某些实施例中，两种组分都可以按粉末形式施加。替代性地，这些组分可以按液体或凝胶形式施加。上文已详细描述了适用于本发明的方法的止血组合物和保护性覆盖物产品及配制品的类型。In certain embodiments, both components may be applied in powder form. Alternatively, the components may be applied in liquid or gel form. The types of hemostatic compositions and protective covering products and formulations suitable for use in the methods of the present invention have been described in detail above.
在某些实施例中，施加该粘合剂医学产品的步骤包含将装有该保护性覆盖物的注射器插入病损部位附近和通过直接在该病损部位处及其附近喷洒、注射、喷射或铺展该组合物在该病损部位处及其附近施加该覆盖物，以提供该病损的至少部分、但更优选完全的覆盖。如先前结合递送方法所讨论，该施加可通过内镜、腹腔镜技术或直接进入(即，手术方式)使用基于导管的递送系统(单腔或多腔导管系统)来进行。In certain embodiments, the step of applying the adhesive medical product comprises inserting a syringe containing the protective covering near the lesion and by spraying, injecting, jetting or spraying directly at and near the lesion Spreading the composition applies the covering at and near the lesion site to provide at least partial, but more preferably complete coverage of the lesion. As previously discussed in connection with delivery methods, this application can be performed by endoscopic, laparoscopic techniques, or direct access (ie, surgically) using a catheter-based delivery system (single-lumen or multi-lumen catheter system).
在某些实施例中，可以使用交联引发剂，例如化学、热、光、固化剂或催化剂，以帮助在病损部位处及其附近的涂层的固化过程。交联引发剂可以与涂层均匀或不均匀地相互作用，并且可以在涂层递送之前、之后或期间施加到涂层上。In certain embodiments, a crosslinking initiator, such as chemical, thermal, light, curing agents, or catalysts, may be used to assist the curing process of the coating at and near the lesion site. The crosslinking initiator can interact with the coating uniformly or nonuniformly, and can be applied to the coating before, after, or during delivery of the coating.
不受理论的束缚，在将止血组合物施加到具有活动性出血的病损时，出血将停止。在止血组合物和病损部位的顶部及其附近施加保护性覆盖物后，覆盖物将留在病损部位及其附近足以使病损愈合的时间(从30分钟到72小时或更久中的任意时间)。一旦该病损愈合，该覆盖物将被洗掉或随时间而侵蚀；然后该覆盖物将通过消化系统从体内去除。替代性地，该覆盖物将保留在该病损部位，直到最外侧粘膜层在正常生物过程期间经2-3周脱落或脱去并且该涂层或覆盖物与该粘膜层一起脱离。Without being bound by theory, when the hemostatic composition is applied to a lesion with active bleeding, the bleeding will cease. After the hemostatic composition and protective covering is applied on top of and near the lesion, the covering will remain in and near the lesion for a time sufficient to allow the lesion to heal (from 30 minutes to 72 hours or more in anytime). Once the lesion has healed, the covering will wash off or erode over time; the covering will then be removed from the body by the digestive system. Alternatively, the covering will remain at the lesion site until the outermost mucosal layer is shed or shed during normal biological processes over 2-3 weeks and the coating or covering is detached with the mucosal layer.
用途use
本文所述的医学产品可广泛用于医药领域，并且就此而言可适于提供众多种适于施加到和/或植入患者体内、尤其胃肠道中的装置和物体。本发明在某些方面中还提供各种使用这些材料的方法，例如，其用于置换、增加、修复和/或以其他适当方式治疗患者的患病的或以其他方式受损或缺损的胃肠道组织。The medical products described herein can be widely used in the field of medicine, and in this regard can be adapted to provide a wide variety of devices and objects suitable for application to and/or implantation in a patient, particularly in the gastrointestinal tract. The invention also provides, in certain aspects, various methods of using these materials, eg, for replacing, augmenting, repairing, and/or otherwise appropriately treating a diseased or otherwise damaged or defective stomach of a patient Intestinal tissue.
说明性地，本发明的医学产品可作为适于在患者体内使组织愈合、提供止血和/或提供封闭的医学产品来配置(例如，绷带、敷料、贴片等)。Illustratively, the medical products of the present invention may be formulated as medical products (eg, bandages, dressings, patches, etc.) suitable for healing tissue, providing hemostasis, and/or providing occlusion in a patient.
在一些实施例中，本发明的粘合剂医学产品是作为用于为患者组织提供支撑或以其他方式治疗患者的胃肠道组织的单层或多层贴片或其他薄片或薄片状装置来配置。In some embodiments, the adhesive medical products of the present invention are provided as monolayer or multilayer patches or other sheet or sheet-like devices for providing support to or otherwise treating tissue of a patient's gastrointestinal tract. configuration.
具体地，本发明的长效粘合剂医学产品可用于保护、治疗或愈合胃肠道中的病损部位。具体地，本发明的粘合剂医学产品可用于治疗因胃肠道障碍和或需要去除胃肠道壁的粘膜层或粘膜下层的医学程序(例如内镜粘膜下解剖、内镜粘膜切除术、息肉切除术、溃疡、癌症、静脉曲张、巴雷特氏食管消融、其组合或其他)引起的病损。In particular, the long-acting adhesive medical products of the present invention can be used to protect, treat or heal lesions in the gastrointestinal tract. In particular, the adhesive medical products of the present invention may be used in the treatment of medical procedures due to disorders of the gastrointestinal tract and or requiring removal of the mucosal or submucosa of the gastrointestinal wall (eg, endoscopic submucosal dissection, endoscopic mucosal resection, Lesions from polypectomy, ulcers, cancer, varicose veins, Barrett's esophagus ablation, combinations thereof, or others).
说明性地，可将本发明的医学产品加工为各种形状和配置，例如薄片形式，其可用作绷带、贴片、涂层等。Illustratively, the medical products of the present invention can be processed into various shapes and configurations, such as in sheet form, which can be used as bandages, patches, coatings, and the like.
在其他实施例中，本发明的医学产品可用于封闭胃肠道的穿孔、吻合或瘘管。该医学产品包含如上文所讨论的保护性覆盖物，其中在施加该医学产品后，该保护性覆盖物在该穿孔、吻合或瘘管上方形成密封。该医学产品可与其他医学产品(例如夹子或缝线)组合使用。In other embodiments, the medical products of the present invention can be used to close perforations, anastomosis or fistulas of the gastrointestinal tract. The medical product comprises a protective covering as discussed above, wherein upon application of the medical product, the protective covering forms a seal over the perforation, anastomosis or fistula. The medical product can be used in combination with other medical products such as clips or sutures.
包括以下实例来说明本发明的某些实施例。然而，所属领域技术人员根据本发明的披露内容应了解，在不背离本发明的精神和范围的情况下，可在所披露的具体实施例中作出修改并仍然获得相同或相似的结果。因此，应将以下实例理解为说明性而非限制性含义。The following examples are included to illustrate certain embodiments of the invention. However, those of ordinary skill in the art should, in light of the present disclosure, appreciate that changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. Accordingly, the following examples should be understood in an illustrative rather than a restrictive sense.
实例Example
实例1：液体粘膜粘合剂工作台测试Example 1: Liquid Mucoadhesive Bench Test
测试了CarbopolTM的多种溶液：(1)CarbopolTM溶于乙酸乙酯，(2)CarbopolTM溶于乙醇，以及(3)CarbopolTM溶于水。将这些CarbopolTM溶液施加到切除的胃和肠组织。Various solutions of Carbopol™ were tested: (1) Carbopol™ in ethyl acetate, (2) Carbopol™ in ethanol, and (3) Carbopol™ in water. These Carbopol™ solutions were applied to resected gastric and intestinal tissue.
具体地，将CarbopolTM的所有三种溶液装到注射器中并在病损部位通过导管直接注射。据发现，乙酸乙酯(如图1中所示)是可实现最高浓度的CarbopolTM的最合适溶剂。次最佳溶剂是乙醇，再次是水，其为高稀释度所必需。Specifically, all three solutions of Carbopol™ were loaded into syringes and injected directly through the catheter at the lesion site. Ethyl acetate (as shown in Figure 1) was found to be the most suitable solvent to achieve the highest concentrations of Carbopol™ . The next best solvent is ethanol, again water, which is necessary for high dilutions.
之后，将染料靛胭脂与该乙醇溶剂混合。这种溶液保持为白色，其中悬浮着一些小的蓝色染料颗粒。然而，在施加到该组织后，该悬浮液随着来自该组织的水被吸收到该粘合剂而变蓝。这表明，使用染料可适于所治疗病损部位的可视化。After that, the dye indigo carmine was mixed with the ethanol solvent. This solution remains white with some small blue dye particles suspended in it. However, upon application to the tissue, the suspension turned blue as water from the tissue was absorbed into the adhesive. This suggests that the use of dyes can be adapted for visualization of the treated lesions.
实例2：双峰动物生存测试Example 2: Bimodal Animal Survival Test
为了确定在止血剂治疗顶部上的涂层的可持续性和保护性效果，用HemosprayTM粉末治疗猪中的活动性胃肠道出血，并将粘膜粘合剂粉末(由Carbopol粘膜粘合剂、作为屏障的蒙脱石粘土和作为pH调节剂的碳酸钙组成)喷洒在顶部作为保护性覆盖物。图3示出了用HemosprayTM粉末急性治疗然后施加粘膜粘合剂粉末前后的胃肠道止血(图4显示了72小时的时间点)。对照部位仅用HemosprayTM粉末治疗(图5显示了72小时的时间点)。To determine the sustainability and protective effect of the coating on top of the hemostatic treatment, active gastrointestinal bleeding in pigs was treated with Hemospray™ powder and a mucoadhesive powder (made by Carbopol Mucoadhesive, Composed of smectite clay as a barrier and calcium carbonate as a pH adjuster) sprayed on top as a protective covering. Figure 3 shows gastrointestinal hemostasis before and after acute treatment with Hemospray™ powder followed by application of the mucoadhesive powder (Figure 4 shows the 72 hour time point). Control sites were treated with Hemospray™ powder alone (Figure 5 shows the 72 hour time point).
为了增加发生复发性出血的可能性，在术后向猪给予抗血小板药物(利伐沙班)。在0、12、24、36、48、60和72小时测量血红蛋白值以量化失血量。To increase the likelihood of recurrent bleeding, pigs were given an antiplatelet drug (rivaroxaban) postoperatively. Hemoglobin values were measured at 0, 12, 24, 36, 48, 60 and 72 hours to quantify blood loss.
在72小时的时间段内，单独用Hemospray治疗的动物的平均血红蛋白净下降量(总失血量的指标)为6.6g/dL，而在Hemospray的顶部具有保护性覆盖物的动物为3.35d/gL。参考图4，在包含保护性覆盖物的部位上仍可以看到粘附的材料，而在单独用Hemospray治疗的部位上则看不到(图5)。Over the 72-hour period, the mean net decrease in hemoglobin (an indicator of total blood loss) was 6.6 g/dL in animals treated with Hemospray alone, compared to 3.35 d/gL in animals with a protective covering on top of Hemospray . Referring to Figure 4, the adhered material was still visible on the site containing the protective covering, but not on the site treated with Hemospray alone (Figure 5).
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