CN110691615A - Bimodal treatment method and composition for gastrointestinal lesions with active bleeding - Google Patents

Abstract

The present invention relates to a long-acting medical product for the protection or treatment of lesions in the gastrointestinal tract. The medical product includes a protective covering, wherein the medical product, when applied at and near the site of the lesion, adheres to gastrointestinal tract tissue and is capable of remaining at and near the site of the lesion for a time sufficient to allow the lesion to heal or be treated.

Description

Bimodal treatment method and composition for gastrointestinal lesions with active bleeding

RELATED APPLICATIONS

This patent document claims priority to U.S. patent application serial No. 15/581,876 filed on day 28, 4, 2017, U.S. patent application serial No. 15/581,876 is a continuation-in-part application of U.S. patent application serial No. 14/209,718 filed on day 13, 3, 2014, U.S. patent application serial No. 14/209,718 claims the benefit of U.S. provisional patent application serial No. 61/793,586 filed on day 15, 3, 2013 at 35u.s.c. § 119 (e); U.S. patent application serial No. 15/581,876 filed on 28.4.2017, which is also a continuation-in-part application of U.S. patent application serial No. 14/044,040 filed on 2.10.2015, is hereby incorporated by reference.

Background

Technical Field

Medical products and methods are described for delivering therapeutic agents and treating lesions in the gastrointestinal tract, such as lesions resulting from gastrointestinal disorders and or medical procedures requiring removal of the mucosal or submucosal layer of the gastrointestinal tract wall.

Background

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 bioactive materials can be introduced to achieve a biological effect. The biological effect may include a range of targeted outcomes, such as inducing hemostasis, sealing perforations, reducing the likelihood of restenosis, or treating cancerous tumors or other diseases.

There are several gastrointestinal disorders that can cause gastrointestinal lesions, such as gastrointestinal inflammation, gastrointestinal cancer, gastrointestinal infection, gastrointestinal motor dysfunction, or lesions, wounds, or contusions in a portion of the gastrointestinal tissue. In addition, there are numerous medical procedures that require removal of the mucosal or submucosal layer of the gastrointestinal tract wall that can also cause injury or damage in the gastrointestinal tract. These procedures include Endoscopic Mucosal Resection (EMR), endoscopic submucosal dissection, polypectomy, oral endoscopic myotomy, biopsy, and ablation (thermal, chemical, radiofrequency, and cryogenic). As with these gastrointestinal disorders, similar adverse events can occur following removal of the mucosal or submucosal layer, including bleeding and structuring.

Many therapeutic agents are injected using Intravenous (IV) techniques, as well as via oral medication. While such techniques allow for the general introduction of drugs, in many instances it may be desirable to provide local or targeted delivery of therapeutic agents, which may enable the directed and accurate delivery of the agent to a selected target site. For example, local delivery of a therapeutic agent to a tumor can reduce exposure of the therapeutic agent to normal, healthy tissue, which can reduce potentially harmful side effects.

Local delivery of therapeutic agents has been performed using catheters and similar introducer devices. For example, a catheter may be advanced toward a target site within a patient's body, and then a therapeutic agent may be injected through a lumen of the catheter to the target site. Typically, a syringe (with or without a needle) or similar device may 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 the injected therapeutic agent.

Furthermore, it may be difficult or impossible to deliver a therapeutic agent in some form, such as a powder form, to a desired site in a targeted manner. For example, if the therapeutic powder is held within a syringe or other container, it may not be easy to deliver it to the target site through a catheter in a localized manner that may also reduce potentially harmful side effects.

The use of chitosan, Carbopol is known^TMMucoadhesives and bioadhesives, including various chemical derivatives of polycarbophil (polycarbophil), can open epithelial tight junctions, prevent intestinal ulceration, maintain drugs in open wounds, prolong ocular surface residence, and have vaccine-assisted activity, however, the use of mucoadhesives to treat gastrointestinal lesions has not been previously suggested or documented.

Currently, the standard method of treating a gastrointestinal lesion is to fold the tissue over itself using a clip, thereby separating the lesion from the gastrointestinal environment. However, this method has a low success rate (failure rate 10% -20%), is expensive, and is technically difficult.

Therefore, there is a great need in the art for new or improved devices and methods for long-term topical treatment to address problems caused by gastrointestinal disorders and or medical procedures requiring removal of the mucosal or submucosal layer of the gastrointestinal tract wall.

Disclosure of Invention

One embodiment is directed to a multilayer coating for achieving and maintaining hemostasis of an active bleeding lesion, the multilayer coating comprising: (i) a haemostatic layer comprising a haemostatic agent in liquid, gel or powder form in direct contact with the active bleeding lesion; (ii) a protective covering comprising an adhesive in liquid, gel or powder form in direct contact with both the haemostatic layer and surrounding tissue, wherein the protective covering is capable of remaining at and near the site of the lesion for a minimum of 30 minutes. The hemostatic layer and the protective covering are delivered at and near the site of the lesion 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 materials, sodium alginate, cellulose derivatives, ethers, lectins, thiamine, pathogens, thiols, amino acid sequences, ion exchange resins, any biomolecule comprising an amino acid sequence, mucin, guar gum, karaya gum, xanthan gum, locust bean gum, acacia gum, gellan gum, tragacanth gum, soluble starch, gelatin, pectin, and any biomolecule having an affinity for mucosal 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, sclerosant, and absorbent clays (e.g., laponite, montmorillonite, zeolite, kaolin). The hemostatic agent may be a hemostatic clay. The protective covering may further comprise a pH adjuster. The protective covering may be capable of remaining at and near the site of the lesion 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, wherein the powder consists of particles of binder particles and barrier-forming particles bonded together.

Another embodiment relates to a method for protecting and treating a lesion with active bleeding in the gastrointestinal tract, the method comprising: (i) directly applying a hemostatic composition comprising a hemostatic agent at and near the site of the lesion in the gastrointestinal tract in an amount and for a time sufficient to stop the active bleeding; and (ii) once the active bleeding has stopped or slowed, applying a protective covering comprising an adhesive directly on top of and adjacent to at least a portion of a previously applied hemostatic composition, wherein the protective covering, when applied on top of and adjacent to at least a portion of the hemostatic composition, is in direct contact with both the hemostatic composition and the tissue surrounding the lesion, provides a continuous protective barrier, and is capable of remaining at and adjacent to the site of the lesion for a minimum of 30 minutes. The applying step (i) may comprise spraying, jetting or spreading the haemostatic agent at and near the site of the lesion with 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 a previously applied hemostatic composition at and adjacent to the site of the lesion in the gastrointestinal tract. The binder may 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 materials, sodium alginate, cellulose derivatives, ethers, lectins, thiamine, pathogens, thiols, amino acid sequences, ion exchange resins, any biomolecule comprising an amino acid sequence, mucin, guar gum, karaya gum, xanthan gum, locust bean gum, acacia gum, gellan gum, tragacanth gum, soluble starch, gelatin, pectin, and any biomolecule having an affinity for mucosal 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 site of the lesion. The method may further comprise applying a crosslinking initiator selected from the group consisting of: chemical, thermal, light, curing agents, and catalysts. The method may further comprise: instructing the physician to first apply the hemostatic agent to and near the site of the lesion having the active bleeding in the gastrointestinal tract; instructing the physician to determine whether the active bleeding has ceased; and instructing the practitioner to apply the protective covering on top of and adjacent to at least a portion of the hemostatic composition at and adjacent to the site of the lesion in the gastrointestinal tract.

Drawings

This patent or application document 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.

Fig. 1 is a photograph showing an example of the mucoadhesive covering of the present invention.

Fig. 2 is a photograph showing an example of bonded particles in which fine mucoadhesive particles are bonded to larger barrier-forming particles.

FIG. 3 shows the use of Hemospray^TMPhotographs of active gastrointestinal bleeding in pigs treated with powder and mucoadhesive powder sprayed on top as a protective covering.

Figure 4 shows a photograph of an endoscopic submucosal resection at 72 hours. In forming the lesion, the lesion has active bleeding and Hemospray is administered by bimodal^TMAnd protective mucoadhesives. At 72 hours, a protective mucoadhesive covering was present and relatively little severe inflammation was seen compared to lesions not receiving bimodal treatment (fig. 5).

Figure 5 shows a photograph of an endoscopic submucosal resection at 72 hours. When a lesion is formed, the lesion has active bleeding, and Hemospray is used^TMAnd (6) treating. No protective mucoadhesive is applied. At 72 hours, no protective covering was present and increased severe inflammation (redness) was observed compared to lesions receiving bimodal treatment (fig. 4).

Detailed Description

Described herein are long acting adhesive medical products and methods for protecting or treating lesions in the gastrointestinal tract caused by: gastrointestinal disorders and/or medical procedures requiring removal of a mucosal or submucosal layer of the gastrointestinal tract, for example, Endoscopic Submucosal Dissection (ESD), endoscopic mucosal resection, polypectomy, ulceration, cancer, varicose veins, barrett's esophageal ablation, or a combination thereof.

In addition, described herein are long-acting medical products and methods for protecting or treating lesions with active bleeding in the gastrointestinal tract, which lesions are caused by: gastrointestinal disorders and/or medical procedures requiring removal of a mucosal or submucosal layer of the gastrointestinal tract, e.g., ESD, endoscopic mucosectomy, polypectomy, ulcers, cancer, varicose veins, barrett's esophageal ablation, or a combination thereof.

The long-acting adhesive medical products described herein (i.e., the multilayer coatings used to achieve hemostasis of actively bleeding lesions and maintain hemostasis of lesions) 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 a binder (referred to throughout this application as a "protective covering"). The two components may be, for example, in the form of a powder, gel or liquid, or may be a solid material, such as a bandage, dressing, patch, or the like. For example, the hemostatic layer includes a hemostatic agent in liquid, gel, or powder form in direct contact with the active bleeding lesion. For example, the protective covering includes an adhesive in liquid, gel, or powder form that is in direct contact with both the hemostatic layer and the surrounding tissue. The thickness of the multilayer coating is at least 0.1 mm.

The hemostatic composition and the protective coating are delivered to and near, respectively, a lesion with active bleeding in the gastrointestinal tract. First delivering and applying a hemostatic composition to a lesion having active bleeding to slow or stop bleeding, and/or prevent delayed bleeding; the protective covering is delivered after delivery of the hemostatic composition and once active bleeding has stopped or slowed, and is applied on top of, over, and/or around (i.e., such that the protective covering is in direct contact with both the hemostatic layer and surrounding tissue) the hemostatic composition to protect or treat the lesion from further injury or infection, prevent delayed perforation, prevent re-bleeding, seal anastomotic fistulas or fistulas, and/or promote healing of the exposed site.

The hemostatic composition functions to reduce or stop active bleeding from the lesion by forming a mechanical barrier at the site of bleeding; protective coverings containing adhesives help protect these lesions from complications such as re-bleeding, ulcer formation, scar formation, and stenosis. Described herein are methods of using these two treatments in combination as a "bimodal therapy" for gastrointestinal lesions with active bleeding.

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 can be any anti-bleeding agent that promotes hemostasis (i.e., stops, slows, or reduces bleeding). Topically acting hemostatic agents act 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, e.g., modified and unmodified starches (e.g., potato starch); inorganic agents, such as absorbent clays (e.g., hectorite, montmorillonite, zeolite, kaolin); a hemostatic drug; amylopectin, including modified (cross-linked) pregelatinized amylopectin. Other hemostatic agents that may be used may include epinephrine, sclerosant, sefadex and dextrans. Natural plant based polysaccharides tend to be biocompatible, absorbable and free of animal components. While vegetable-based polysaccharides are preferred as hemostatic agents, gelatin and other polysaccharides of animal origin may also be used.

The terms "protective coating" or "protective covering" or "covering" encompass powder and/or liquid coatings (e.g., solids, powders, liquids, or gels suitable for application at and near the site of the lesion by, for example, spraying or coating or other known methods, wherein the liquid or gel coating cures at the site) as well as solid materials such as bandages, dressings, patches and the like. In particular, these terms encompass powder, liquid and gel coatings as well as solid materials (e.g., bandages, dressings, patches) for treating or protecting lesions in the gastrointestinal tract. The protective covering includes an adhesive, such as a mucoadhesive. Exemplary mucoadhesives include carbomers, polycyclic aromatic hydrocarbons, carboxylic acids, polyvinyl pyrrolidone, polyvinyl alcohol, polycarbophil, chitosan materials, sodium alginate, cellulose derivatives, ethers, lectins, thiamine, pathogenic bacteria, thiols, amino acid sequences, ion exchange resins, any biomolecule comprising an amino acid sequence, mucin, guar gum, karaya gum, xanthan gum, locust bean gum, acacia gum, gellan gum, tragacanth gum, soluble starch, gelatin, pectin, and any biomolecule having an affinity for mucosal membranes.

The term "lesion" refers to any tissue defect or bodily injury that is accompanied by a disruption of the normal integrity of the tissue structure and/or a pathological change in a bodily organ or tissue (and specifically, any bodily organ or tissue in the gastrointestinal tract). The term is also intended to encompass the terms "wound", "injury", "sore", "necrosis" and "ulcer", particularly wounds, injuries, sores, necrosis and ulcers having active bleeding. The term "sore" generally refers to any lesion of the mucosa. The term "ulcer" refers to a local defect or excavation of an organ or tissue surface in the gastrointestinal tract, which results from the shedding of necrotic tissue. The term "necrosis" refers to dead tissue resulting from infection, injury, inflammation, or infarction. The lesion may be any lesion resulting from a gastrointestinal disorder and or a medical procedure requiring removal of the mucosal or submucosal layer of the gastrointestinal wall. For example, lesions may result from endoscopic submucosal dissection, endoscopic mucosal resection, polypectomy, ulceration, cancer, varicose veins, barrett's esophageal ablation, or a combination thereof, which leads to active bleeding.

The term "active bleeding" refers to all forms of bleeding in the gastrointestinal tract. It is also known as gastrointestinal bleeding. Bleeding in the gastrointestinal tract may occur anywhere in the gastrointestinal tract, from the mouth to the rectum. If a large amount of blood loss occurs within a short period of time, symptoms may include vomiting of red blood, vomiting of black blood, bloody stool, or black stool.

The phrase "to and in the vicinity of" or "at and in the vicinity of" in connection with the delivery of a hemostatic composition and a protective covering means that the hemostatic composition and/or the protective covering is placed on the lesion itself, including within the lesion, as well as in close proximity to the lesion to ensure the most complete coverage of the lesion as possible.

The phrase "on top of and near" or "above and near" in conjunction with the delivery of a protective covering means that the protective covering is placed on top of and immediately around the hemostatic composition previously applied at the lesion to ensure the most complete coverage of the lesion as possible.

Specifically, in the method for protecting or treating a lesion having active bleeding in the gastrointestinal tract, a hemostatic composition is first delivered and applied locally/directly at and near the site of the lesion in the gastrointestinal tract to stop active bleeding at the lesion; and applying a protective covering comprising an adhesive locally and directly on top of, over, and near at least a portion of the hemostatic composition at and near the site of the lesion in the gastrointestinal tract once active bleeding has stopped or slowed. When applied over and about at least a portion of the hemostatic composition at and about the site of the lesion, the protective covering adheres to the gastrointestinal tract tissue, provides a durable protective barrier, and is capable of remaining at and about the site of the lesion for a minimum of 30 minutes.

Specifically, when the long-acting protective covering described herein is delivered directly and locally over and adjacent to a hemostatic composition at and adjacent to a site of a lesion having active bleeding, it will form a protective covering at and adjacent to the site of the lesion by at least partially or completely covering the hemostatic composition and the lesion. The protective covering is retained at and adjacent the site of the lesion for a time sufficient to allow the site to be treated or healed (a minimum of 30 minutes; preferably 24 hours; more preferably at least 48 or 72 hours; most preferably the protective covering is retained at and adjacent the site of the lesion for 24-72 hours or more; thus the term "long-lasting" refers to the length of time the protective covering of the invention is retained at and adjacent the site of the lesion and means any time from 30 minutes to 72 hours or more). The term "protect" refers to protecting the site of the lesion from further damage or infection. The term "treating" refers to slowing or stopping bleeding at the site of the lesion, preventing delayed bleeding, preventing delayed perforation of the lesion, and/or promoting healing at the exposed site of the lesion, and/or promoting new tissue formation. The term "healing" when referring to a lesion refers to a process of repairing gastrointestinal tissue by natural processes, such as by scarring for example, such that after "healing" the lesion is reduced in size or absent, at least as compared to the initial size of the lesion.

One embodiment is directed to a multilayer coating for achieving and maintaining hemostasis of an active bleeding lesion, the multilayer coating comprising: (i) a haemostatic layer comprising a haemostatic agent in liquid, gel or powder form in direct contact with the active bleeding lesion; (ii) a protective covering comprising an adhesive in liquid, gel or powder form in direct contact with both the haemostatic layer and surrounding tissue, wherein the protective covering is capable of remaining at and near the site of the lesion for a minimum of 30 minutes. The hemostatic layer and the protective covering are delivered at and near the site of the lesion by flow through a catheter. The lesion may be a mucosal lesion. The thickness of the cover is at least 0.1 mm. The protective covering may further comprise a pH adjuster. The protective covering may be capable of remaining at and near the site of the lesion 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, wherein the powder consists of particles of binder particles and barrier-forming particles bonded together.

The hemostatic layer includes a hemostatic agent, which can be any anti-bleeding agent that promotes hemostasis (i.e., 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, e.g., modified and unmodified starches (e.g., potato starch); inorganic agents, such as absorbent clays (e.g., hectorite, montmorillonite, zeolite, kaolin); a hemostatic drug; amylopectin, including modified (cross-linked) pregelatinized amylopectin. Other hemostatic agents that may be used may include epinephrine, sclerosant, sefadex and dextrans. Natural plant based polysaccharides tend to be biocompatible, absorbable and free of animal components. While vegetable-based polysaccharides are preferred as hemostatic agents, gelatin and other polysaccharides of animal origin may also be used. In certain embodiments, the hemostatic agent is a hemostatic clay.

In certain embodiments, the protective covering includes an adhesive.

The adhesive may comprise any tissue adhesive currently known or hereafter developed. The adhesive may 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 mucosa, which may line the body vessel wall or body cavity wall, such as the surface of the gastrointestinal tract (e.g., one or both of the gastrointestinal epithelium or mucosa (including submucosa) and, in particular, at and near the site of a lesion. The adhesive film may include a moist mucus layer to which the mucoadhesive may adhere. In general, mucoadhesives are hydrophilic polymers containing a plurality of functional groups capable of forming hydrogen bonds.

One example of a mucoadhesive suitable for use herein includes macromolecules (e.g., polymers) that contain repeating monomeric units. Other examples of mucoadhesives useful in the long acting adhesive medical products of the present invention include, for example, hydrophilic polymers, hydrogels, copolymers or thiolated polymers. These hydrogen bond-forming functional groups may include carboxyl, hydroxyl, carbonyl, sulfate, amide groups, or any other functional group capable of forming a hydrogen bond. Examples of mucoadhesives or components thereof can include, for example, carbomers (e.g., polyacrylic acid), polycyclic aromatic hydrocarbons (e.g., limonene), carboxylic acids, polyvinylpyrrolidone, polyvinyl alcohol, polycarbophil, chitosan materials (i.e., chitosan, or poly (D) glucosamine), sodium alginate, cellulose derivatives (e.g., methylcellulose, methylethylcellulose, carboxymethylcellulose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, or hydroxyethylcellulose), ethers (e.g., polyethylene glycol), lectins (e.g., cockscomb agglutinin, concanavalin a lectin, vitex agglutinin, and type C agglutinin), thiamine (e.g., thiamine capped polymer chains); pathogenic bacteria (e.g., bacterial tow proteins), thiols (e.g., chitosan-cysteine, chitosan-thiol butylamidine, chitosan-thioglycolic acid, polyacrylic acid-cysteine, polyacrylic acid-cysteamine, carboxymethyl cellulose-cysteine, or alginate-cysteine), amino acid sequences, ion exchange resins (e.g., cholestyramine), or any biomolecule (e.g., peptide) that includes an amino acid sequence. Other examples of mucoadhesives or components thereof may include mucin, guar gum, karaya gum, xanthan gum, locust bean gum, acacia gum, gellan gum, tragacanth gum, soluble starch, gelatin, or pectin. In some examples, the mucosal adhesive can include any biomolecule having an affinity for mucosal tissue, such as a protein (e.g., a pilin or affinity ligand).

The mucoadhesive adheres to the hemostatic composition and/or the mucosa by physical and/or chemical forces, including, for example, ionic bonding, covalent bonding, hydrogen bonding, Van der Waals (Van-der-Waals) bonding, or hydrophobic bonding (i.e., hydrophobic interactions).

Other types of tissue adhesives include cyanoacrylate glue and sealants, glutaraldehyde, DOPA or any other known polymeric or biological adhesive.

In certain embodiments, the protective covering may comprise a mucoadhesive, which may be in the form of a powder, a solid solution, an emulsion, a liquid or semi-liquid solution, a liquid suspension, a gel, a foam, or a combination 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 may also be converted between the various forms or phases previously described.

The amount of hemostatic composition and protective covering to be applied to and about a lesion with active bleeding will depend on the type and size of the lesion, the form of the hemostatic agent and mucoadhesive used, and the delivery system used to deliver the hemostatic agent and mucoadhesive. 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 several grams (e.g., any amount from about 0.01 grams to about 60 grams) of each component can be delivered and placed on and near the site of the lesion to provide adequate coverage at and near the site of the lesion with active bleeding, e.g., 10 microns to 2mm thick. When delivering the hemostatic composition, any amount from a few tenths of a gram to several grams (e.g., any amount from about 0.01 grams to about 25 grams) can be delivered and placed on and near the site of the lesion to provide adequate coverage and stop bleeding at and near the site of the lesion with active bleeding. More typically, about 2 grams of the hemostatic composition and/or protective covering will be sufficient to stop bleeding and cover the lesion site (to any thickness from 10 microns to 2mm thick), respectively. If the hemostatic composition and/or protective covering is in the form of a gel or liquid, sufficient two components are provided at and near the site of the lesion to stop active bleeding and allow adequate coverage of the lesion to be achieved, e.g., at least 10 microns to 2mm thick, respectively.

The amount of haemostat and/or mucoadhesive in liquid or gel form may vary from 0.1% to 99.5%.

In certain embodiments, any of the hemostatic compositions described herein comprise 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, 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, 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, the hemostatic agent can stop active bleeding from lesions in the gastrointestinal tract (e.g., the surface of the stomach).

In certain embodiments, any of the protective coverings described herein comprise 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, 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, 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, the mucoadhesive may prolong the time that the covering is in contact with the surface of the gastrointestinal tract (e.g., the surface of the stomach), and protect or treat the lesion from further injury or infection, prevent delayed perforation, prevent delayed or recurrent bleeding, seal anastomotic fistulas or fistulas, and/or promote healing of the exposed site.

As provided herein, the hemostatic composition and/or protective covering in powder form may include a fine or finely divided formulation, a coarsely pulverized product, or an intermediate particle size product. The component in powder form may comprise very coarse particles having a size of about 10,000 microns or 10mm, or very fine particles having a size approaching about 1 micron or less, or particles having any size between coarse and fine. The size of the particles will depend on the type of haemostat and mucoadhesive used in the composition and protective cover, respectively, and may be highly variable, especially for particulate mucoadhesives.

Alternatively, the powder may contain a proportion of liquid that is substantially uniformly dispersed in the solid components of the mixture, or may consist entirely of solid material.

In certain embodiments, the hemostatic composition may comprise one or more hemostatic agents. For example, the hemostatic composition in powder form may be a physical mixture of two or more pure hemostatic agents in powder form present in a defined or different ratio. For example, the hemostatic composition in liquid form may be a physical mixture of two or more powdered pure hemostatic agents present in a defined or different ratio mixed with a solvent.

In certain embodiments, the protective covering may include one or more mucoadhesives. For example, the protective covering in powder form may be a physical mixture of two or more pure mucoadhesives in powder form present in defined or different proportions. For example, the protective covering in liquid form may be a physical mixture of two or more pure mucoadhesives in powder form, present in a defined or different ratio, mixed with a solvent.

In some embodiments, the therapeutic agent and or excipient may be mixed with the hemostatic agent and/or mucoadhesive powder into a formulation suitable for use in accordance with the methods of the present invention, or with the hemostatic agent and/or mucoadhesive liquid into a liquid formulation.

In alternative embodiments, the hemostatic composition and/or protective covering in powder or particulate form may be reconstituted with a solvent or water or other liquid prior to use. Upon reconstitution, these formulations in powder or particle form may be mixed with dyes, colorants, flavors and/or other desired medicinal ingredients, so that the reconstitution solution may have the medicinal characteristics of a liquid medicine.

In alternative embodiments, the 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 may be mixed with dyes, colorants, flavors and/or other desired medicinal ingredients, so that the reconstitution solution may have the medicinal characteristics of a liquid medicine.

Powders for the purposes of the formulations provided herein include formulations wherein the physician can use the formulation as is (i.e., in powder form), or mix the instructional amount of powder with an instructional amount of solvent or water or other liquid, prior to topical application at and near the site of the lesion with active bleeding and can stop the bleeding.

In certain embodiments, the protective covering may comprise a plurality of materials.

In one embodiment, the protective covering may include, for example, adhesive materials (to adhere to tissue) and superabsorbent materials (to act as barriers to prevent liquid from contacting the lesion or blood exiting the lesion site). Additionally or alternatively, the protective covering may include a hemostatic material (to clot blood in the event of bleeding from the lesion) as one of its components. Additionally or alternatively, the protective covering may also include a pH adjusting material, such as a base or acid, or a buffer to remain adherent in extreme pH or salinity environments.

For protective coverings comprising acidic polymers (e.g., carbomers), ingredients that neutralize the polymer (to a pH range of 5-9) and thereby increase viscosity include bases such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, arginine, aminomethyl propanol, tetrahydroxypropyl ethylenediamine, 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 before delivery. Also, the protective covering, which is basic, may contain an acidic component to achieve a more neutral pH and thus increase adhesion. For protective coverings applied in powder form, the mentioned pH regulators can also be used in powder form and dissolve upon hydration in vivo. To help make a protective covering containing a pH adjusting powder, it may be advantageous to avoid using hygroscopic powders and use less absorptive powders such as calcium carbonate.

For multi-component protective coverings that are delivered in powder form, the components may be bonded together or composed of separate particles. The components combined together produce a single particle comprising multiple ingredients. An exemplary embodiment of the bound particles may be fine mucoadhesive particles bound to larger barrier-forming particles (fig. 2).

In another embodiment, one or more healing promoting additives may be included in the protective covering.

Some examples of superabsorbent materials include absorbent clays (e.g., hectorite, montmorillonite, zeolite), diatomaceous earth, and superabsorbent polymers (e.g., sodium polyacrylate, polyacrylamide copolymers, ethylene maleic anhydride copolymers, cross-linked carboxymethylcellulose, polyvinyl alcohol copolymers, cross-linked polyethylene oxide, and starch-acrylonitrile copolymers).

In some embodiments, the protective covering may also include a hemostatic agent. The hemostatic agent can be the same or different hemostatic agent as 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 clay, and zeolites.

Some examples of additives used to promote healing include Aloe vera (Aloe vera) and derivatives, honey and derivatives (i.e., rubus championii (r)) honey, and growth factors.

In certain embodiments, the protective covering may also include mechanical braces to form bandages, patches, dressings, and the like. The term "scaffold" refers to any natural (e.g., extracellular matrix material or "ECM"), synthetic (e.g., woven or non-woven) material (e.g., woven or non-woven) that can provide mechanical and structural support and strength to a protective covering，Dacron^TMElectrospun materials, and expanded PTFE).

The protective covering may take the form of a scaffold that may be applied in a variety of forms, including single or multi-layered sheet or mesh constructs, fluidized formulations, and/or combinations thereof.

Examples of synthetic scaffolds include biocompatible materials, such as polyesters, e.g., polyethylene; poly (ethylene terephthalate); fluorinated polymers such as Polytetrafluoroethylene (PTFE) and expanded PTFE fibers; a polyurethane; silicone, and the like. An example of a biocompatible polyester includes Dacron^TM(DuPont, Wilmington, Del.) of Wilmington, Del.).

Examples of natural scaffold materials include bioremodelable ECM-based materials, such as naturally occurring collagenous ECM materials isolated from a suitable animal or human tissue source. As used herein, cleaning, delaminating and/or comminuting 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. The bioremodelable ECM material has a biotropic property capable of inducing tissue remodeling. Suitable ECM materials that can be processed to provide a scaffold material include, for example, submucosa (including, for example, Small Intestine Submucosa (SIS), stomach submucosa, bladder submucosa, or uterine submucosa, each of which is isolated from a juvenile or adult animal), kidney capsule, dermal collagen, amniotic membrane, dura mater, pericardium, serous membrane, peritoneum, or a basal membrane layer or material, including liver basement membrane or epithelial basement membrane material, and other materials.

An exemplary ECM sheet material is a sheet of submucosa tissue graft material (OASIS)^TMWound matrix, Cook Biotech Incorporated, West lafaye, USA, West lava, indiana.

A protective covering comprising a stent and a mucoadhesive may be used to treat a lesion in the gastrointestinal tract. For these purposes, the stent material may be processed into a sheet, bandage or other form to at least partially occlude or cover the lesion in the gastrointestinal tract.

In certain embodiments of the invention, one or more binders (e.g., mucoadhesives) may be mixed with the fluidized ECM material to form a substantially homogeneous binder solution. The fluidized ECM material can be dried or formed into a gel for immediate use.

In certain embodiments, the comminuted submucosa or other ECM material can be dried by freeze-drying to form a powder that can be hydrated, i.e., combined with water or buffered saline and optionally other pharmaceutically acceptable excipients, to form a fluid ECM binder medical product. The viscosity of the fluidized ECM composition can be manipulated by controlling the concentration of submucosa or other ECM components, the degree of hydration, and adjusting the pH of the submucosa or other ECM digest. The viscosity can be adjusted to a range of about 2cps to about 300,000cps at 25 ℃. The higher viscosity gel formulation may have a gel or paste consistency and may be prepared by adjusting the pH of the digest solution to about 6.0 to about 7.0.

Alternatively, the fluidized ECM material can be dried and adhered to or coated with a mucoadhesive.

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 may be homogeneous.

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 covering may be a top sheet or impermeable layer to restrict the passage of fluid, such as gastric acid, back toward the lesion. Alternatively or additionally, the cover may include other backing layers that provide further barrier or structural support.

In certain embodiments, the adhesive may be incorporated into the stent by mixing, coating, spraying, impregnating the stent with the adhesive, or the adhesive may be provided as a separate adhesive layer, forming an adhesive coated edge. Certain preparative techniques, such as lyophilization, critical point drying, or the use of low surface tension solvents (e.g., ethyl acetate, alcohols, benzene), can be used to maintain adhesive properties during incorporation.

In certain embodiments, the protective covering may include a mucoadhesive covering on the interface that is placed over the gastrointestinal tissue and other materials (e.g., woven mesh stents) on the luminal interface to provide improved mechanical strength to the covering.

In certain embodiments, the hemostatic compositions and/or protective coverings disclosed herein and used herein may comprise one or more excipients. In particular, other excipients useful herein include, but are not limited to, solvents, binders, fillers, lubricants, suspending agents, flavoring agents, color indicators (e.g., dyes), sweeteners, preservatives, antioxidants, buffering agents, wetting agents, chelating agents, surfactants, disintegrating agents, crosslinking agents, and the like. These excipients may prolong the time that the hemostatic composition and/or protective covering is in contact with the site of the lesion in the gastrointestinal tract, and/or may increase the interaction of the hemostatic composition and/or protective covering with the surface of the gastrointestinal tract, for example, viscosity or absorption enhancers may be used.

In certain embodiments, the hemostatic composition and/or protective covering includes a solvent. Exemplary solvents include ethyl acetate, ethanol, water, DMSO, saline, acetone, isopropanol, or combinations thereof. If a solvent is used, the resulting components are in the form of a liquid or gel and can be delivered as is to the site of the lesion with active bleeding.

Optionally, the hemostatic composition and/or protective covering may comprise one or more binders, optionally one or more fillers, optionally one or more lubricants, optionally one or more suspending agents, optionally one or more flavoring agents, optionally one or more coloring agents, optionally one or more sweeteners, optionally one or more 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.

In addition, 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 site of the lesion. Water soluble dyes are preferred. Exemplary dyes include indigo carmine, methylene blue, fluorescent proteins, rose bengal, indian ink (indian ink) and other dyes.

Preservatives include, for example, benzalkonium chloride (benzalkonium chloride), cetrimide (cetrimide) (cetyltrimethylammonium bromide), benzoic acid, benzyl alcohol, methyl, ethyl, propyl and butyl parabens, chlorhexidine (chlorohexidine), chlorobutanol, phenylmercuric acetate, borates and nitrates, potassium sorbate, sodium benzoate, sorbic acid, thimerosal (mercuril thiosalicylic acid), combinations thereof, and the like.

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) (e.g., disodium ethylenediaminetetraacetate), diethylenetriaminepentaacetic acid (DTPA), Nitrilotriacetate (NT), combinations thereof, and the like.

Additionally, in certain embodiments, a buffering agent, wetting agent, or chelating agent can also be incorporated into the hemostatic composition and/or protective covering.

Exemplary buffers include citrate buffers (i.e., citric acid and citrate), phosphate buffers, acetate buffers, carbonate buffers (e.g., calcium carbonate, sodium bicarbonate, and the like), hydroxides (e.g., magnesium hydroxide, sodium hydroxide, and the like), combinations thereof, and the like.

Humectants include, for example, glycerol, propylene glycol, ethylene glycol, glyceryl triacetate, polyols (e.g., sorbitol, xylitol, maltitol, polydextrose), and the like.

Chelating agents include, for example, Ethylenediaminetetraacetate (EDTA) (e.g., sodium ethylenediaminetetraacetate), diethylenetriaminepentaacetic acid (DTPA), Nitrilotriacetate (NT), and the like.

In some embodiments, the hemostatic composition and/or protective covering may further comprise at least one therapeutic agent. Exemplary therapeutic agents that may be incorporated into the hemostatic composition and/or protective covering include antibiotics, antiseptics, proton pump inhibitors, matrix metalloproteinases, or tissue growth promoting compounds.

Other therapeutic agents may also be included and may be known to those skilled in the art.

The contrast agent may be used in conjunction with the injection of the hemostatic composition and the protective covering. The contrast agent may be injected prior to the injection of both materials. Alternatively, the contrast agent is included in a hemostatic component or protective cover component that is injected at and near the site of a lesion with active bleeding in the gastrointestinal tract. Contrast agents and their use are well known to those skilled in the art.

In certain embodiments, a composition comprising a hemostatic agent may be delivered to and near a lesion with active bleeding for the purpose of hemostasis and prior to delivery of a protective covering comprising a binder.

For example, if used for hemostatic purposes, thrombin, epinephrine, hemostatic powder, or a sclerosant may be provided to reduce local bleeding at the site of the lesion. 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 may itself act as a mechanical packing by providing a compressive force, thereby reducing the time required to achieve hemostasis.

As noted above, the hemostatic composition may be delivered in any suitable form. For example, the hemostatic composition may comprise a powder, liquid, gel, aerosol, or other substance.

In certain embodiments, the protective covering is prepared for local and direct delivery at and near the site of the lesion, wherein the protective covering forms a coating or patch or the like at and near the site of the lesion upon delivery or application to the lesion and is capable of remaining at and near the site of the lesion for a sufficient time to allow the site to be treated or healed. Preferably, at least partial coverage of the lesion site is achieved; most preferably, complete coverage of the lesion site is achieved. The time sufficient to allow the site to be treated or healed may vary depending on the location, type and size of the lesion, and may be any time from 30 minutes (sufficient to stop bleeding) to 72 hours or more (sufficient to allow the tissue to heal almost completely). 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 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 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 48-72 hours.

Methods and delivery

Certain embodiments relate to methods for protecting or treating lesions with active bleeding in the gastrointestinal tract. The method comprises applying a composition comprising a hemostatic agent directly at and near the site of the lesion in the gastrointestinal tract to stop active bleeding; and applying a protective covering comprising an adhesive directly over and adjacent to at least a portion of the previously applied composition comprising a hemostatic agent at and adjacent to the site of the lesion in the gastrointestinal tract once active bleeding has ceased. When applied over and about at least a portion of the hemostatic composition at and about the site of the lesion, the protective covering adheres to and is in direct contact with both the hemostatic composition/layer and the surrounding gastrointestinal tissue, provides a durable protective barrier, and is capable of remaining at and about the site of the lesion for a minimum of 30 minutes.

In certain embodiments, the hemostatic composition and protective covering may be applied or delivered to the site of the lesion and its vicinity by endoscopic techniques, laparoscopic techniques, or by direct access (i.e., surgically) using, for example, any suitable catheter delivery system.

In certain embodiments, the hemostatic composition and protective covering may be delivered via an intraluminal delivery system. The hemostatic composition and protective covering may be applied via spraying, jetting, injecting, or spreading.

An advantage of this bimodal treatment is that the delivery of the hemostatic composition and the protective covering occur in the same process, which can minimize and/or eliminate repetitive processes.

In certain embodiments, the hemostatic composition and protective covering may be passed through a multi-lumen catheter.

In particular, the delivery system may include a delivery device sized and configured to deliver and apply the hemostatic composition and protective covering directly to a target tissue region (i.e., e.g., a lesion site, such as a lesion with active bleeding in the gastrointestinal tract) within a body cavity or hollow body organ.

In addition, the delivery device may be sized and configured to accommodate passage over a guidewire. In this way, the device can be introduced via the guide wire under direct visualization of the endoscope. In particular, the guidewire may be advanced against the endoscope and thus not occupy the working channel of the endoscope. In alternative embodiments, the delivery device may be sized and configured to be piggybacked over a working channel of the endoscope. The working channel of the endoscope is thus used to guide the delivery device while providing direct visualization.

Various delivery systems for the local delivery of therapeutic agents are known and may be used to deliver the two components described herein.

In certain embodiments, delivery of the hemostatic composition and protective covering may be by, for example, a system suitable for delivering the therapeutic agent to the target site. An exemplary system was previously described in U.S. patent publication No. 2015/0094649, which is incorporated herein in its entirety.

In certain embodiments, delivery of the hemostatic composition and protective covering may be by, for example, a "twin-tub" device. An exemplary twin-tub device was previously described in U.S. patent publication No. 2008/0060970, which is incorporated herein in its entirety.

Briefly, an exemplary dual barrel device may include a cartridge having at least two cylindrical bores for delivering a hemostatic agent and a protective covering, wherein each cylinder includes an outlet for the hemostatic agent and the protective 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 comprises an adapter to receive and lock a manifold operatively connected to an outlet of the cartridge; at least two toothed pistons, wherein each toothed piston is at least partially located within a cylindrical bore; a trigger coupled to the housing, wherein the trigger includes a toothed drive rack; a gear assembly cooperating with the toothed drive rack and with the toothed piston.

An alternative delivery system may be the system described in U.S. patent publication No. 2002/0170926, which is incorporated herein in its entirety.

In certain embodiments, the step of applying the hemostatic composition may include inserting a first hemostatic device, such as a syringe containing the hemostatic composition, at and near the site of the lesion having active bleeding, and applying the hemostatic composition at and over the site of the lesion having active bleeding to stop the active bleeding. Application may be by spraying, jetting, or spreading the hemostatic composition at and near the site of the lesion with active bleeding.

In certain embodiments, the step of applying the protective covering may include inserting a second delivery device, such as a syringe containing the protective covering, at and near the site of the lesion having active bleeding, and applying the protective covering on top of and near at least a portion of the hemostatic composition. Application may be by spraying, jetting, or spreading a protective covering on top of and near at least a portion of a previously applied hemostatic composition at and near the site of the lesion in the gastrointestinal tract.

Certain other embodiments relate to a method for protecting or treating a lesion in the gastrointestinal tract having active bleeding caused by a gastrointestinal disorder and or a medical procedure requiring removal of a mucosal or submucosal layer of a gastrointestinal tract wall. The lesion may be a post-mucotomy lesion.

The method includes topically applying a hemostatic composition and an adhesive protective covering to and about the lesion in the gastrointestinal tract. After application of the two components, the product forms a protective coating or covering at the site of the lesion, wherein the coating is capable of remaining at and near the site of the lesion for at least 30 minutes, more preferably 24-72 hours or more.

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 cover products and formulations suitable for use in the methods of the present invention have been described above in detail.

In certain embodiments, the step of applying the adhesive medical product comprises inserting a syringe containing the protective covering in the vicinity of the lesion and applying the covering at and in the vicinity of the lesion by spraying, injecting, jetting or spreading the composition directly at and in the vicinity of the lesion to provide at least partial, but more preferably complete, coverage of the lesion. As previously discussed in connection with the delivery method, the application may be performed endoscopically, laparoscopically, or directly (i.e., surgically) using a catheter-based delivery system (single or multi-lumen catheter system).

In certain embodiments, a crosslinking initiator, such as a chemical, thermal, light, curing agent, or catalyst, may be used to aid in the curing process of the coating at and near the site of the lesion. The crosslinking initiator may interact with the coating uniformly or non-uniformly and may be applied to the coating before, after, or during delivery of the coating.

Without being bound by theory, bleeding will stop when the hemostatic composition is applied to a lesion with active bleeding. After applying the protective covering on top of and near the hemostatic composition and the lesion, the covering will remain at and near the lesion for a time sufficient to allow the lesion to heal (anywhere from 30 minutes to 72 hours or more). Once the lesion heals, the covering will be washed away or eroded over time; the cover will then be removed from the body by the digestive system. Alternatively, the covering will remain at the lesion until the outermost mucosal layer falls off or sloughs off over 2-3 weeks during normal biological processes and the coating or covering comes off with the mucosal layer.

Use of

The medical products described herein may be used in a wide variety of medical fields, and in this regard may be adapted to provide a wide variety of devices and objects suitable for application to and/or implantation within a patient, particularly in the gastrointestinal tract. The invention also provides, in certain aspects, various methods of using these materials, e.g., for replacing, augmenting, repairing, and/or otherwise suitably treating diseased or otherwise damaged or defective gastrointestinal tissue in a patient.

Illustratively, the medical products of the present invention may be configured as medical products (e.g., bandages, dressings, patches, etc.) adapted to heal tissue, provide hemostasis, and/or provide occlusion in a patient.

In some embodiments, the adhesive medical products of the present invention are configured as single or multi-layer patches or other sheet or sheet-like devices for providing support to or otherwise treating the gastrointestinal tract tissue of a patient.

In particular, the long acting adhesive medical products of the present invention may be used to protect, treat or heal the site of a lesion in the gastrointestinal tract. In particular, the adhesive medical products of the present invention may be used to treat lesions resulting from gastrointestinal disorders and or medical procedures requiring removal of the mucosal or submucosal layer of the gastrointestinal tract wall (e.g., endoscopic submucosal dissection, endoscopic mucosal resection, polypectomy, ulcerations, cancer, varicose veins, barrett's esophageal ablation, combinations thereof, or others).

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.

In other embodiments, the medical products of the present invention may be used to seal a perforation, anastomosis or fistula in the gastrointestinal tract. The medical product comprises a protective covering as discussed above, wherein the protective covering forms a seal over the perforation, anastomosis or fistula after application of the medical product. The medical product may be used in combination with other medical products, such as clips or sutures.

The following examples are included to illustrate certain embodiments of the invention. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. The following examples are, therefore, to be construed in an illustrative and not a restrictive sense.

Examples of the invention

Example 1: liquid mucoadhesive bench test

Carbopol was tested^TMThe various solutions of (a): (1) carbopol^TMDissolved in ethyl acetate, (2) Carbopol^TMDissolved in ethanol, and (3) Carbopol^TMDissolved in water. These carbopols are prepared by reacting^TMThe solution is applied to the resected stomach and intestinal tissue.

Specifically, Carbopol is added^TMAll three solutions were loaded into a syringe and injected directly through the catheter at the site of the lesion. It was found that ethyl acetate (as shown in FIG. 1) was the highest concentration of Carbopol that could be achieved^TMMost suitable solvent of (4). The less optimal solvent is ethanol, again water, which is necessary for high dilution.

Thereafter, the dye indigo carmine is mixed with the ethanol solvent. This solution remained white with some small blue dye particles suspended. However, after application to the tissue, the suspension turns blue as water from the tissue is absorbed into the adhesive. This indicates that the use of dyes may be suitable for visualization of the lesion site being treated.

Example 2: bimodal animal survival test

To determine the sustainability and protective effect of the coating on top of the haemostatic treatment, Hemospray was used^TMThe powder treats active gastrointestinal bleeding in pigs and a mucoadhesive powder (consisting of Carbopol mucoadhesive, montmorillonite clay as a barrier and calcium carbonate as a pH regulator) is sprayed on top as a protective covering. FIG. 3 shows a sample taken with Hemospray^TMPowder acute treatment followed by gastrointestinal hemostasis before and after application of the mucoadhesive powder (figure 4 shows the 72 hour time point). Control sites with Hemospray alone^TMPowder treatment (72 hour time point is shown in figure 5).

To increase the likelihood of recurrent bleeding, anti-platelet drugs (rivaroxaban) were administered to pigs post-operatively. Hemoglobin values were measured at 0, 12, 24, 36, 48, 60 and 72 hours to quantify blood loss.

The average net hemoglobin reduction (indicator of total blood loss) was 6.6g/dL for animals treated with Hemospray alone over a 72 hour period, while animals with protective coverings on top of Hemospray were 3.35 d/gL. Referring to fig. 4, adhered material was still visible on the site containing the protective covering, but not on the site treated with Hemospray alone (fig. 5).

Claims (20)

1. A multilayer coating for achieving hemostasis of an active bleeding lesion and maintaining hemostasis of the lesion, the multilayer coating comprising:

(i) a haemostatic layer comprising a haemostatic agent in liquid, gel or powder form in direct contact with the active bleeding lesion;

(ii) a protective covering comprising an adhesive in liquid, gel or powder form in direct contact with both the haemostatic layer and the surrounding tissue;

wherein the protective covering is capable of remaining at and near the site of the lesion for a minimum of 30 minutes.

2. The coating of claim 1, wherein the hemostatic layer and the protective covering are delivered at and near the site of the lesion by flow through a catheter.

3. The coating of claim 1, wherein the lesion is a mucosal lesion.

4. The coating of claim 1, wherein the binder is a mucoadhesive.

5. The coating of claim 1, wherein the multi-layer coating has a thickness of at least 0.1 mm.

6. The coating of claim 1, wherein the hemostatic agent is a hemostatic clay.

7. The coating of claim 1, wherein the protective covering further comprises a pH adjuster.

8. The coating of claim 1, wherein the protective covering is capable of remaining at and near the site of the lesion for a minimum of 24 hours.

9. The coating of claim 1, wherein the protective covering is capable of remaining at and near the site of the lesion for a minimum of 48 hours.

10. The coating of claim 1, wherein the protective covering is capable of remaining at and near the site of the lesion for a minimum of 72 hours.

11. The coating of claim 1, wherein the protective covering is in the form of a powder, wherein the powder consists of particles of binder particles and barrier-forming particles bonded together.

12. A method for protecting and treating a lesion with active bleeding in the gastrointestinal tract, the method comprising:

(i) directly applying a hemostatic composition comprising a hemostatic agent at and near the site of the lesion in the gastrointestinal tract in an amount and for a time sufficient to stop the active bleeding; and

(ii) once the active bleeding has stopped or slowed, a protective covering comprising an adhesive is applied directly on top of and adjacent to at least a portion of the previously applied hemostatic composition, wherein the protective covering, when applied on top of and adjacent to at least a portion of the hemostatic composition, is in direct contact with both the hemostatic composition and the tissue surrounding the lesion, provides a continuous protective barrier, and is capable of remaining at and adjacent to the site of the lesion for a minimum of 30 minutes.

13. The method of claim 12, wherein the applying step (i) comprises spraying, jetting, or spreading the hemostatic agent at and near the site of the lesion with the active bleeding.

14. The method of claim 12, wherein the applying step (ii) comprises spraying, jetting, or spreading the protective covering on top of and near at least a portion of a previously applied hemostatic composition at and near the site of the lesion in the gastrointestinal tract.

15. The method of claim 12, wherein the binder is in the form of a powder, liquid, or gel.

16. The method of claim 12, wherein the adhesive is a mucoadhesive.

17. The method of claim 12, wherein the protective covering comprises a solid material in the form of a bandage, patch, or dressing.

18. The method of claim 12, wherein the protective covering is 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 site of the lesion.

19. The method of claim 12, further comprising applying a crosslinking initiator selected from the group consisting of chemical, thermal, light, curing agent, or catalyst.

20. The method of claim 12, further comprising:

(i) instructing the physician to first apply the hemostatic agent to and near the site of the lesion having the active bleeding in the gastrointestinal tract;

(ii) instructing the physician to determine whether the active bleeding has ceased; and

(iii) the physician is instructed to apply the protective covering on top of and adjacent to at least a portion of the hemostatic composition at and adjacent to the site of the lesion in the gastrointestinal tract.

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