Submucous lifting compositions and methods thereof

Abstract

Provided herein are submucosal lifting compositions and methods of use thereof. The submucosal lifting agents of the present disclosure include a polysaccharide, a polyol, and a colorant.

Description

Divisional application statement This application is a divisional application of Chinese invention patent application No. 202180006329.7, filed on June 1, 2021, entitled "Submucosal Lifting Composition and Method Thereof". Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 042,836, filed on June 23, 2020, the disclosure of which is incorporated herein by reference in its entirety. Background Technology

[0002] An endoscope is a medical device that allows visualization of the interior of body cavities or hollow organs without invasive surgical procedures. An endoscope comprises a flexible, elongated body (e.g., a tube) with suitable imaging devices at its distal end. Endoscopes can be inserted through naturally occurring openings such as the esophagus or rectum, or through small incisions created surgically in the body. Suitable surgical instruments can be passed through the endoscope to perform a variety of medical procedures, such as tissue sampling or removal of diseased tissue or polyps.

[0003] Endoscopic procedures are commonly used for the diagnosis and / or treatment of the gastrointestinal (GI) tract. For example, endoscopic procedures can be performed to obtain tissue samples from the GI tract for pathological evaluation and / or for therapeutic purposes. For instance, with advancements in imaging technology, endoscopic procedures can be used to accurately detect and remove precancerous mucosal tissue or tumors from various locations within the GI tract.

[0004] Interventional endoscopists perform a variety of tasks, including fluid-assisted polypectomy, endoscopic mucosal resection (EMR), and endoscopic submucosal dissection (ESD) procedures, to remove precancerous or cancerous mucosal tissue from the GI tract. Such fluid-assisted procedures may involve injecting fluid pads into the submucosal tissue (e.g., for cushioning) or injecting fluid between target tissue layers (e.g., for dissection) to elevate or separate the target tissue layers to safely perform the procedure (e.g., by preventing or reducing the risk of GI tract perforation).

[0005] However, injectable compositions dissipate and therefore may not elevate or separate the target tissue layer for the entire duration of the procedure. If the fluid dissipates, the endoscopist must re-inject the fluid to ensure the target tissue layer remains elevated or expanded. The more times the tissue is punctured with the needle to inject fluid, the more leaks and pores are created. Summary of the Invention

[0006] This document provides a submucosal lifting composition comprising: a polysaccharide present in an amount ranging from about 0.05% to 0.5% by weight, based on the total weight of the composition; a polyol present in an amount ranging from about 10% to 20% by weight, based on the total weight of the composition; and a colorant present in an amount ranging from about 0.0001% to 0.005% by weight, based on the total weight of the composition.

[0007] This disclosure further provides a sealed and sterile syringe comprising a composition according to this disclosure.

[0008] A method for lifting the submucosal layer is also provided, comprising injecting the composition of the present disclosure into the submucosal layer of an individual to provide an lifted submucosal layer having a first lifting height.

[0009] A method of gastrointestinal submucosal resection is further provided, comprising injecting the composition of the present disclosure into the gastrointestinal submucosal tissue of an individual to elevate the tissue to a first elevation height, thereby providing elevated gastrointestinal submucosal tissue, and surgically removing the elevated gastrointestinal submucosal tissue.

[0010] Other aspects and advantages will become clear to those skilled in the art from the following summary of specific embodiments. Although the compositions and methods are susceptible to various forms of embodiments, the following description includes specific embodiments in order to ensure that this disclosure is illustrative and not intended to limit this disclosure to the specific embodiments described herein. Attached Figure Description

[0011] Figure 1 This is a graph showing the change in the average elevation height of the submucosa of the compositions according to this disclosure and three comparative compositions over time. Detailed Implementation

[0012] This document provides submucosal lifting compositions and methods of using them. The compositions disclosed herein offer one or more advantages, including, but not limited to, requiring lower injection force than commercially available lifting agents, delayed dispersion in the submucosal layer relative to commercially available lifting agents, and / or substantially maintained lifting height over time (e.g., maintaining at least about 50% of the first lifting height about 30 minutes after injection). Submucosal lifting composition

[0013] In embodiments, this disclosure provides a submucosal lifting composition comprising a polysaccharide present in an amount ranging from about 0.05% (w / v) to about 0.5% (w / v); a polyol present in an amount ranging from about 10% (w / v) to about 20% (w / v); and a colorant present in an amount ranging from about 0.0001% (w / v) to about 0.005% (w / v). In embodiments, this disclosure provides a submucosal lifting composition comprising: a polysaccharide present in an amount ranging from about 0.05% by weight to about 0.5% by weight, based on the total weight of the composition; a polyol present in an amount ranging from about 10% by weight to about 20% by weight, based on the total weight of the composition; and a colorant present in an amount ranging from about 0.0001% by weight to about 0.005% by weight, based on the total weight of the composition.

[0014] The compositions disclosed herein include polysaccharides. Polysaccharides may include linear polysaccharides such as cellulose, amylose, pectin, alginate, and derivatives thereof, including alkyl cellulose polymers (such as methyl cellulose (MC)), hydroxyalkyl celluloses (such as hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose (HPMC)), and carboxyl cellulose and its salts, including carboxymethyl cellulose (CMC). Counterions for carboxyl cellulose include Group I cations such as sodium and potassium; Group II cations such as magnesium and calcium; and mixtures thereof.

[0015] The polysaccharides used in the compositions of this disclosure may further include glucosamine, preferably non-sulfated glucosamine, such as hyaluronic acid and its salts, desulfated heparin, desulfated chondroitin sulfate, and desulfated dermatan sulfate. Hyaluronic acid and its salts (also known as hyaluronic acid, hyaluronic acid salts, or HA) are anionic, non-sulfated glucosamine. HA is widely distributed in connective tissue, epithelial tissue, and nerve tissue. Counterions for hyaluronic acid salts include Group I cations, such as sodium and potassium; Group II cations, such as magnesium and calcium; and mixtures thereof.

[0016] The polysaccharides used in the compositions of this disclosure also include polysaccharides comprising a backbone and multiple monosaccharide side groups. Examples of such compounds include galactomannans, which are polysaccharides having a mannose backbone with galactose side groups, such as (1-4)-linked β-D-mannopyranoyl glycoside backbones (i.e., 1-6-linked α-D-galactopyranoyl glycosides) having a branch point from its 6-position linked to α-D-galactose, such as guar gum, fenugreek gum, tara gum, locust bean gum, and carob gum. Polysaccharides used in conjunction with this disclosure also include polysaccharides comprising a backbone and multiple oligosaccharide side groups (wherein “oligosaccharide” is defined herein as a polysaccharide chain having 2, 3, 4, 5, 6, 7, 8, 9, or 10 glycosides), including xanthan gum.

[0017] Polysaccharides can further include branched-branched polysaccharides, such as amylopectin, gum arabic, and arabinoxylan.

[0018] In embodiments, the polysaccharide is selected from the group consisting of: methylcellulose (MC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxycellulose, hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC), hyaluronic acid, desulfated heparin, desulfated chondroitin sulfate, desulfated dermatan sulfate, guar gum, fenugreek gum, tara gum, locust bean gum, carob gum, amylopectin, gum arabic, arabinoxylan, any salt thereof, and any combination thereof. In embodiments, the polysaccharide comprises hydroxyethylcellulose. In embodiments, the polysaccharide comprises methylcellulose (MC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxycellulose, hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC), or combinations thereof. In some embodiments, the polysaccharide comprises hydroxyethylcellulose, hydroxypropylcellulose, glucan, guar gum, or any combination thereof.

[0019] Polysaccharides can typically be present in any amount in a composition. Unbound by theory, it is believed that as the amount of polysaccharide decreases, the amount of time the composition maintains its initial elevation when delivered to tissue decreases, and the composition disperses more quickly within the submucosa of the individual. Furthermore, unbound by theory, it is believed that as the amount of polysaccharide increases, the viscosity of the composition generally increases, and therefore greater force will be required to pass the composition through a syringe needle or a smaller gauge needle (i.e., a needle with a larger diameter). In the embodiments, the polysaccharide may be present in the composition in amounts ranging from about 0.05% (w / v) to about 0.5% (w / v), about 0.1% (w / v) to about 0.5% (w / v), about 0.15% (w / v) to about 0.45% (w / v), or about 0.2% (w / v) to about 0.3% (w / v), for example, about 0.05% (w / v), 0.075% (w / v), 0.1% (w / v), 0.15% (w / v), 0.2% (w / v), 0.25% (w / v), 0.3% (w / v), 0.35% (w / v), 0.4% (w / v), 0.45% (w / v), or 0.5% (w / v). In the embodiments, the polysaccharide may be present in the composition in an amount ranging from about 0.05 wt% to about 0.5 wt%, about 0.1 wt% to about 0.5 wt%, about 0.15 wt% to about 0.45 wt%, or about 0.2 wt% to about 0.3 wt% based on the total weight of the composition, for example, about 0.05 wt%, 0.075 wt%, 0.1 wt%, 0.15 wt%, 0.2 wt%, 0.25 wt%, 0.3 wt%, 0.35 wt%, 0.4 wt%, 0.45 wt%, or 0.5 wt%. If the polysaccharide is provided at a concentration of 0.5% (w / v) or more than about 0.5 wt%, the advantageous enhancements and resistance to dispersion demonstrated by the compositions of this disclosure are not significantly increased. Rather, it should be understood that the maximum limit of the polysaccharide amount is a functional limit based on the limitations of the end-use (e.g., needle specifications, desired flow rate, etc.).

[0020] Polysaccharides can exist in any suitable form, such as powders, aqueous solutions, etc. Adding polysaccharides to water generally increases the viscosity of the water. In some cases, polysaccharides can be defined by their viscosity. The viscosity of a polysaccharide is usually defined by the viscosity of a 1% or 2% aqueous solution of the polysaccharide in water at 25°C. In the embodiments, the viscosity of the polysaccharide is in the range of about 500 cP to about 10,000 cP, about 1,000 cP to about 9,000 cP, about 2,500 cP to about 7,500 cP, and about 4,000 cP to about 6,000 cP, for example, about 500 cP, 750 cP, 1,000 cP, 1,250 cP, 1,500 cP, 1,750 cP, 2,000 cP, 2,250 cP, 2,500 cP, 2,750 cP, 3,000 cP, 3,250 cP, 3,500 cP, 3,750 cP, 4,000 cP, 4,250 cP, 4,500 cP, 4,750 cP, 5,000 cP, 5,250 cP, 5,500 cP, 5,750 cP, 6,000 cP, 6,250 cP, 6,500 cP. cP, 6750 cP, 7000 cP, 7250 cP, 7500 cP, 7750 cP, 8000 cP, 8250 cP, 8500 cP, 8750 cP, 9000 cP, 9250 cP, 9500 cP, 9750 cP or 10,000 cP.

[0021] The compositions disclosed herein include polyols. In the examples, polyols may be included to help reduce the surface tension of the composition. Advantageously, polyols may be included to help emulsify and disperse polysaccharides in the composition and to protect the polysaccharides during sterilization. Polyols may include, but are not limited to, glycerol, diglycerol, propylene glycol, dipropylene glycol, butanediol, pentanediol, butylene glycol, ethylene glycol, diethylene glycol, triethylene glycol, or any combination thereof. In the examples, the polyol includes glycerol or diglycerol. In some embodiments, the polyol includes glycerol.

[0022] Unbound by theory, polyols are believed to help emulsify and protect polysaccharides in compositions. Polyols may also help reduce the surface tension of compositions. Polyols may be included in compositions in amounts ranging from about 10% (w / v) to about 20% (w / v), about 12% (w / v) to about 18% (w / v), or about 15% (w / v) to about 17% (w / v), for example, about 10% (w / v), 11% (w / v), 12% (w / v), 13% (w / v), 14% (w / v), 15% (w / v), 16% (w / v), 17% (w / v), 18% (w / v), 19% (w / v), or 20% (w / v). Based on the total weight of the composition, the polyol may be included in the composition in an amount ranging from about 10% to about 20% by weight, about 12% to about 18% by weight, or about 15% to about 17% by weight, for example, about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by weight. When the polyol is present in an amount of about 10% (w / v) or less, the surface tension of the composition is high, requiring increased injection force and / or smaller needles (i.e., needles with larger diameters) to inject the composition into the submucosal layer. Not bound by theory, although it is believed that increasing the amount of polyol to 20% (w / v) or more can provide additional protection for the polysaccharides in the composition, the amount of additional protection expected to provide has little effect on the properties of the final composition, and further, it is believed that as the amount of polyol in the composition increases to 20% (w / v) or more, the likelihood of improved dispersion of the composition in the submucosal layer increases.

[0023] The compositions disclosed herein further include a colorant. The colorant may be included to visually mark the submucosa for surgical resection. The colorant may include, but is not limited to, methylene blue, isosulfan blue, indocyanin green, fluorescein, rose bengal, gentian violet, or any combination thereof.

[0024] The colorant may be included in the composition in amounts ranging from about 0.0001% (w / v) to about 0.005% (w / v), about 0.0005% (w / v) to about 0.004% (w / v), or about 0.001% (w / v) to about 0.003% (w / v), for example, about 0.0005% (w / v), 0.0006% (w / v), or 0.0007% (w / v). , 0.0008% (w / v), 0.0009% (w / v), 0.001% (w / v), 0.0015% (w / v), 0.002% (w / v), 0.002 5% (w / v), 0.003% (w / v), 0.0035% (w / v), 0.004% (w / v), 0.0045% (w / v) or 0.005% (w / v). The composition may include a colorant in amounts ranging from about 0.0001 wt% to about 0.005 wt%, about 0.0005 wt% to about 0.004 wt%, or about 0.001 wt% to about 0.003 wt%, for example, about 0.0005 wt%, 0.0006 wt%, 0.0007 wt%, 0.0008 wt%, 0.0009 wt%, 0.001 wt%, 0.0015 wt%, 0.002 wt%, 0.0025 wt%, 0.003 wt%, 0.0035 wt%, 0.004 wt%, 0.0045 wt%, or 0.005 wt%, based on the total weight of the composition. Typically, the amount of colorant included is sufficient to mark the target submucosal layer without obscuring the surgeon's view during resection. Advantageously, the compositions described herein can stain and / or mark the target submucosal layer at lower levels of colorant than currently commercially available products.

[0025] In the embodiments, the polysaccharide includes hydroxyethyl cellulose, the polyol includes glycerol, and the colorant includes methylene blue.

[0026] The composition may further include a variety of suitable excipients and / or carriers. Examples of suitable excipients and / or carriers include, but are not limited to, preservatives, buffers, and water.

[0027] Examples of suitable preservatives include, but are not limited to, benzyl alcohol, methylparaben, ethylparaben, benzalkonium chloride, or combinations thereof. The composition may include a preservative in an amount of up to about 4.0% (w / v) or about 4.0% by weight, based on the total weight of the composition. For example, in embodiments, the preservative may be included in amounts ranging from about 0% (w / v) to about 4.0% (w / v), about 0.01% (w / v) to about 4.0% (w / v), about 0.05% (w / v) to about 2.0% (w / v), about 0.075% (w / v) to about 1.5% (w / v), or about 0.5% (w / v) to about 1.0% (w / v). In embodiments, the preservative may be included in amounts ranging from about 0% to about 4.0% by weight, about 0.01% to about 4.0% by weight, about 0.05% to about 2.0% by weight, about 0.075% to about 1.5% by weight, or about 0.5% to about 1.0% by weight, based on the total weight of the composition. In embodiments, the preservative includes benzyl alcohol. In embodiments, the preservative includes about 1% by weight of benzyl alcohol based on the total weight of the composition.

[0028] In the embodiments, the composition comprises sterile water for injection (WFI). Water may be included in amounts ranging from about 50% to about 90% by weight, about 60% to about 85% by weight, about 70% to about 85% by weight, or about 75% to about 80% by weight, based on the total weight of the composition. For example, about 50% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight, or 90% by weight.

[0029] Suitable buffers may include, but are not limited to, phosphate-buffered saline (PBS), tris(hydroxymethyl)aminomethane (Tris), triple-buffered saline, 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES), HEPES-buffered saline, anhydrous disodium hydrogen phosphate, anhydrous dipotassium hydrogen phosphate, and any combination thereof. In examples, the buffer comprises anhydrous disodium hydrogen phosphate and anhydrous dipotassium hydrogen phosphate. The buffer may be included in any amount sufficient to achieve a suitable in vivo pH at the target site. In examples, the buffer is present in amounts ranging from about 0.01 wt% to about 0.25 wt%, about 0.05 wt% to about 0.2 wt%, about 0.1 wt% to about 0.2 wt%, or about 0.15 wt% to about 0.2 wt% by total weight of the composition, for example, about 0.01 wt%, 0.05 wt%, 0.1 wt%, 0.15 wt%, 0.2 wt%, or 0.25 wt%. In the examples, the buffer comprises, by total weight of the composition, about 0.16% by weight of anhydrous disodium hydrogen phosphate and anhydrous dipotassium hydrogen phosphate. In the examples, the pH of the composition is in the range of about 5.5 to about 8.0, about 6.0 to about 7.5, or about 6.5 to about 7.0, for example, about 5.5, 6.0, 6.5, 7.0, 7.5, or 8.0.

[0030] The compositions according to this disclosure can be sterile. The compositions can also be pyrogen-free. In some cases, each component of the composition is sterilized. That is, each component can be subjected to sterilization conditions (e.g., autoclaving, filtration, ionizing radiation) before being added to the composition. Alternatively, or additionally, the composition can be terminally sterilized. For example, the composition can be prepared by combining sterilized or unsterilized components, and once the final composition is prepared, it is subsequently sterilized (e.g., autoclaving, filtration, exposure to ionizing radiation). Additionally, the composition can be sterilized before and / or after packaging, for example, in a syringe. The sterilization method can generally depend on the components of the composition. For example, autoclaving is generally not suitable for compositions containing non-thermally stable components (e.g., HPMC, non-crosslinked hyaluronic acid, xanthan gum, pectin, etc.).

[0031] In the embodiments, the compositions of this disclosure are aqueous solutions. In the embodiments, the compositions are not emulsions.

[0032] The viscosities of the compositions disclosed herein can be in the range of about 5 cP to about 150 cP, about 25 cP to about 150 cP, about 50 cP to 150 cP, about 75 cP to about 150 cP, about 100 cP to about 150 cP, about 110 cP to about 140 cP, about 100 cP to about 120 cP, about 5.0 cP to about 15 cP, about 7.5 cP to about 12.5 cP, or about 8 cP to about 12 cP, for example, about 5 cP, 5.5 cP, 6 cP, 6.5 cP, 7 cP, 7.5 cP, 8 cP, 8.5 cP, 9 cP, 9.5 cP, 10 cP, 10.5 cP, 11 cP, 11.5 cP, 12 cP, 12.5 cP, 13 cP, 13.5 cP, 14 cP, 14.5 cP, 15 cP, etc. cP, 25 cP, 30 cP, 35 cP, 40 cP, 45 cP, 50 cP, 55 cP, 60 cP, 65 cP, 70 cP, 75 cP, 80 cP, 85 cP, 90 cP, 95 cP, 100 cP, 105 cP, 110 cP, 115 cP, 120 cP, 125 cP, 130 cP, 135 cP, 140 cP, 145 cP, or 150 cP. In embodiments, the viscosity of the composition is from about 100 cP to about 125 cP, such as about 110 cP or about 112 cP. When the viscosity of the composition is below about 5.0 cP, the composition can disperse more quickly within the submucosal layer, resulting in lower lift and shorter lift duration. When the viscosity of the composition is greater than about 150 cP, a greater injection force is required to inject the composition into the submucosal layer. Alternatively, or additionally, when the viscosity of the composition is greater than about 150 cP, a needle with a smaller specification (i.e., a needle with a larger diameter) may be required to properly inject the composition into the submucosa. As reported herein, viscosity measurements were obtained at 12 RPM (i.e., rotations per minute) using a Brookfield DV-E viscometer at ambient room temperature (i.e., about 20°C or about 25°C).

[0033] The compositions disclosed herein may have densities of about 1.0 g / mL to about 1.3 g / mL, for example, about 1.0 g / mL to about 1.2 g / mL, about 1.0 g / mL to about 1.1 g / mL to about 1.0 g / mL to about 1.05 g / mL, for example, about 1.0 g / mL, 1.01 g / mL, 1.02 g / mL, 1.03 g / mL, 1.04 g / mL, 1.05 g / mL, 1.06 g / mL, 1.07 g / mL, 1.08 g / mL, 1.09 g / mL, 1.1 g / mL, 1.2 g / mL, or 1.3 g / mL. In the examples, the composition density is about 1.02 g / mL. In the examples, the composition density is about 1.03 g / mL. Density can be determined by measuring the weight of a specific volume of the composition under ambient conditions (approximately 20°C to 25°C) and dividing that weight by the specific volume (e.g., the weight of a 2 mL sample in grams divided by 2 mL).

[0034] The compositions described herein can be packaged in any packaging suitable for storing and / or delivering the compositions to the submucosa. For example, in an embodiment, the compositions can be loaded into a syringe in which they can be terminally sterilized, sealed, and stored until use. Syringes typically include a syringe barrel having an opening at its proximal end to receive a plunger and a fitting at its distal end to directly or indirectly engage with an injection needle, thereby positioning the interior of the syringe barrel in fluid communication with the interior of the syringe needle.

[0035] There are no particular restrictions on the size and diameter of the syringe syringe, and the volume can generally range from about 5 cc to about 50 cc, about 10 cc to about 40 cc, or about 20 cc to about 30 cc, for example, about 5 cc, 7.5 cc, 10 cc, 12.5 cc, 15 cc, 20 cc, 25 cc, 30 cc, 40 cc, or 50 cc.

[0036] Similarly, the size or specification of the needle is not particularly limited and can be selected based on the specific submucosal enhancement composition's final properties and desired injection parameters (e.g., injection force, flow rate, etc.). For example, the viscosity of the composition and the size (or specification) of the syringe needle can be selected and adjusted to achieve acceptable injection force and / or flow rate. An example of a suitable needle is the Carr-Locke 25 ga injection needle, available from US Endoscopy, with a needle length of 5 mm and a working length of 230 cm. Another example of a suitable needle is the 23 ga interjection needle, available from Boston Scientific, with a needle length of 4 mm and a working length of 240 cm. Other suitable needle specifications can be from 20 ga to 27 ga, such as 20 ga, 21 ga, 22 ga, 23 ga, 24 ga, 25 ga, 26 ga, or 27 ga. In this embodiment, an injection force is continuously applied (during the injection), and the injection force can range from about 4.00 lbF (17.8 N) to about 7.00 lbF (31.1 N), for example, about 4.00 lbF, 4.50 lbF (20.0 N), 5.00 lbF (22.2 N), 5.25 lbF (23.4 N), 5.50 lbF (24.5 N), 5.75 lbF (25.6 N), 6.00 lbF (26.7 N), 6.50 lbF (28.9 N), or 7.00 lbF. In this embodiment, a 23 ga injection needle with a needle length of 4 mm and a working length of 240 cm is used, with a continuous injection force of about 5.25 lbF, providing a flow rate of at least about 0.100 mL / s. In the embodiments, the viscosity of the composition and the syringe are configured such that the injection flow rate is at least about 0.05 mL / s, as described in more detail below.

[0037] After sterilization and packaging, the compositions of this disclosure can be stored and maintain stability for at least about 1 year, at least about 2 years, or at least about 3 years, for example, about 1, 2, 3, 4, or 5 years after sterilization and packaging. The compositions are generally stable at room temperature, i.e., from about 20°C to about 25°C. How to use

[0038] This disclosure further provides methods for using the compositions described herein.

[0039] In an embodiment, this disclosure provides a method for lifting the submucosal layer, comprising injecting a composition of this disclosure into the submucosal layer of an individual to provide an lifted submucosal layer having a first lifting height.

[0040] This disclosure also provides a method of gastrointestinal submucosal resection, comprising injecting the composition of this disclosure into the submucosal tissue of an individual to elevate the tissue to a first elevation height, thereby providing the elevated submucosal tissue, and surgically removing (using, for example, a snare, a scalpel, biopsy forceps, scissors, etc.) the elevated submucosal tissue.

[0041] As used herein, the term "first lift height" refers to the change in submucosal height from before the injection of the composition to immediately after the injection. That is, the first lift height is measured relative to the height of the submucosal layer before the injection of the composition. In embodiments, the first lift height is at least about 2.0 mm. The first lift height can, for example, depend on the type of submucosal layer and the size of the area to be lifted. In embodiments, the first lift height can be in the range of about 2.0 mm to about 11.0 mm, about 4.0 mm to about 10.0 mm, or about 6.0 mm to about 8.0 mm, for example, about 2.0 mm, 2.5 mm, 3.0 mm, 3.5 mm, 4.0 mm, 4.5 mm, 5.0 mm, 5.5 mm, 6.0 mm, 6.5 mm, 7.0 mm, 7.5 mm, 8.0 mm, 8.5 mm, 9.0 mm, 9.5 mm, 10.0 mm, 10.5 mm, or 11.0 mm, measured relative to the height of the submucosal layer before injection.

[0042] In an embodiment, the method includes injecting a composition in an amount sufficient to elevate the tissue to a first elevation height of about 2.0 mm. For example, the method may include injecting a composition in an amount sufficient to elevate the tissue to a first elevation height in the range of about 2.0 mm to about 11.0 mm, about 4.0 mm to about 10.00 mm, or about 6.0 mm to about 8.0 mm. The amount of composition required to elevate the tissue to the first elevation height may depend in part on the type of submucosal tissue and / or the desired size of the elevated submucosal layer (e.g., elevation height and / or elevation diameter). An amount sufficient to elevate the tissue is within the capabilities of a person skilled in the art (e.g., a resection surgeon). In an embodiment, the method includes injecting a composition of about 5 mL to about 50 mL, about 5 mL to about 40 mL, about 10 mL to about 35 mL, about 15 mL to about 30 mL, or about 20 mL to about 25 mL into a patient, for example, about 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, 15 mL, 16 mL, 17 mL, 18 mL, 19 mL, 20 mL, 21 mL, 22 mL, 23 mL, 24 mL, 25 mL, 26 mL, 27 mL, 28 mL, 29 mL, 30 mL, 31 mL, 32 mL, 33 mL, 34 mL, 35 mL, 36 mL, 37 mL, 38 mL, 39 mL, 40 mL, 41 mL, 42 mL, 43 mL, 44 mL, 45 mL, 6 mL, 47 mL, 48 mL, 49 mL, or 50 mL.

[0043] In an embodiment, the method includes injecting the composition at a flow rate of at least 0.05 mL / s. As provided above, the flow rate can be varied depending on the final viscosity of the composition, the size or specification of the needle, and / or the injection force applied to the syringe. The flow rate can be in the range of about 0.05 mL / s to about 0.20 mL / s, about 0.05 mL / s to about 0.15 mL / s, for example, about 0.05 mL / s, 0.075 mL / s, 0.10 mL / s, 0.125 mL / s, 0.15 mL / s, 0.175 mL / s, or 0.20 mL / s. In an embodiment, the flow rate is at least about 0.10 mL / s.

[0044] Advantageously, the compositions and methods of this disclosure can provide a submucosal elevation that retains at least 50% of the first elevation height 30 minutes after injection, for example, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the first elevation height 30 minutes after injection. Unbound by theory, it is believed that due to the unexpected synergistic effect between the polyol and the polysaccharide, the compositions of this disclosure disperse more slowly from the injection site, thereby providing a localized and durable elevation to the submucosal layer.

[0045] In the embodiments, the composition is injected into the submucosa of an individual. In the embodiments, the individual is a mammal, such as a human. The composition can be injected into any submucosa of the individual, such as the submucosa of the gastrointestinal tract, respiratory tract, or genitourinary tract. The compositions disclosed herein are particularly suitable for elevating the submucosa of the gastrointestinal (GI) tract. In the embodiments, the submucosa includes lesions such as polyps, adenomas, early-stage cancers, and / or any combination thereof.

[0046] The foregoing description is provided for clarity only and should not be construed as limiting in any way, as modifications within the scope of this disclosure will be readily apparent to those skilled in the art.

[0047] The compositions and methods according to this disclosure can be better understood through the following examples, which are intended to illustrate the compositions and methods only and are not intended to limit their scope in any way. Example

[0048] This document describes specific embodiments of the present disclosure in the following numbered paragraphs. These embodiments are illustrative in nature and not restrictive.

[0049] A submucosal lifting composition comprising: The polysaccharide is present in an amount ranging from about 0.05% (w / v) to about 0.5% (w / v) or from about 0.05% by weight to about 0.5% by weight, based on the total weight of the composition; The polyol present, based on the total weight of the composition, in an amount ranging from about 10% (w / v) to about 20% (w / v) or from about 10% by weight to about 20% by weight; and The colorant is present in an amount ranging from about 0.0001% (w / v) to about 0.005% (w / v) or from about 0.0001% by weight to about 0.005% by weight, based on the total weight of the composition.

[0050] The composition of paragraph

[0049] , wherein the polysaccharide is selected from the group consisting of: methylcellulose (MC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxycellulose, hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC), hyaluronic acid, desulfated heparin, desulfated chondroitin sulfate, desulfated dermatan sulfate, guar gum, fenugreek gum, tara gum, locust bean gum, carob gum, amylopectin, gum arabic, arabinoxylan, any salt thereof, and any combination thereof.

[0051] As in paragraphs

[0049] or

[0050] , the composition wherein the polysaccharide comprises methylcellulose (MC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxycellulose, hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC), or a combination thereof.

[0052] Compositions as described in any of paragraphs

[0049] to

[0051] , wherein the polysaccharide comprises hydroxyethyl cellulose.

[0053] The composition of any one of paragraphs

[0049] to

[0052] , wherein the viscosity of the polysaccharide is in the range of about 500 cP to about 10,000 cP.

[0054] The composition of any one of paragraphs

[0049] to

[0053] , wherein the polyol is selected from the group consisting of glycerol, diglycerol, propylene glycol, dipropylene glycol, butanediol, pentanediol, butyleneglycol, ethylene glycol, diethylene glycol, triethylene glycol, and any combination thereof.

[0055] Compositions as described in any of paragraphs

[0049] to

[0054] , wherein the polyol comprises glycerol or diglycerol.

[0056] Compositions as described in any of paragraphs

[0049] to

[0055] , wherein the polyol comprises glycerol.

[0057] The composition of any one of paragraphs

[0049] to

[0056] , wherein the colorant is selected from the group consisting of methylene blue, isosulfan blue, indocyanin green, fluorescein, rosebengal, gentian violet and combinations thereof.

[0058] Compositions as described in any of paragraphs

[0049] to

[0057] , wherein the colorant comprises methylene blue.

[0059] The composition of any one of paragraphs

[0049] to

[0058] further comprises one or more of water, a preservative and a buffer.

[0060] The composition as described in paragraph

[0059] , wherein the composition comprises sterile water for injection (WFI).

[0061] The composition of any one of paragraphs

[0049] to

[0060] , wherein the composition is sterile.

[0062] The composition as described in paragraph

[0061] , wherein each component of the composition is sterilized.

[0063] The composition as described in paragraphs

[0061] or

[0062] , wherein the composition is terminally sterilized.

[0064] The composition of any one of paragraphs

[0049] to

[0063] , wherein the composition is an aqueous solution.

[0065] Compositions as described in any of paragraphs

[0049] to

[0064] , wherein the composition is not an emulsion.

[0066] The composition of any one of paragraphs

[0049] to

[0065] , wherein the viscosity of the composition is in the range of about 5.0 cP to about 150 cP.

[0067] The composition of any one of paragraphs

[0049] to

[0066] , wherein the pH of the composition is in the range of about 5.5 to about 8.0.

[0068] The composition of any one of paragraphs

[0049] to

[0067] , wherein the polysaccharide comprises hydroxyethyl cellulose, the polyol comprises glycerol, and the colorant comprises methylene blue.

[0069] A sealed and sterile syringe comprising a composition as described in any one of paragraphs

[0049] to

[0068] .

[0070] A method for enhancing the submucosa, comprising: The composition of any one of paragraphs

[0049] to

[0068] is injected into the submucosal layer of an individual to provide an elevated submucosal layer having a first elevation height.

[0071] The method as described in paragraph

[0070] , wherein the first lifting height is at least about 2.0 mm and is measured relative to the height of the submucosa before the injection of the composition.

[0072] The method as described in paragraphs

[0070] or

[0071] , wherein the first lifting height is in the range of about 2.0 mm to about 11.0 mm and is measured relative to the height of the submucosa before the composition is injected.

[0073] The method of any of paragraphs

[0070] to

[0072] , wherein the elevated submucosal layer retains at least 50% of the first elevation height after 30 minutes.

[0074] The method of any of paragraphs

[0070] to

[0073] , wherein the individual is a mammal, such as a human.

[0075] The method of any one of paragraphs

[0070] to

[0074] comprises injecting the composition at a flow rate of at least 0.05 mL / s.

[0076] The method of any one of paragraphs

[0070] to

[0075] , wherein the submucosa comprises the submucosa of the gastrointestinal tract.

[0077] The method described in paragraph

[0076] , wherein the submucosal tissue contains a lesion.

[0078] The method described in paragraph

[0077] , wherein the lesion is selected from the group consisting of: polyps, adenomas, early-stage cancers, and any combination thereof.

[0079] A method for submucosal resection of the gastrointestinal tract, the method comprising: Injecting the composition of any one of paragraphs

[0049] to

[0068] into the submucosal tissue of an individual to elevate the tissue to a first elevation height, thereby providing elevated submucosal tissue; and The elevated submucosal tissue of the gastrointestinal tract is surgically removed.

[0080] The method described in paragraph

[0079] involves injecting the composition in an amount sufficient to elevate the tissue to the first elevation height.

[0081] The method as described in paragraphs

[0079] or

[0080] , wherein the first lifting height is at least about 2.0 mm and is measured relative to the height of the submucosal tissue of the gastrointestinal tract before the injection of the composition.

[0082] The method of any of paragraphs

[0079] to

[0081] , wherein the elevated gastrointestinal submucosal tissue retains at least 50% of the first elevation height after 30 minutes.

[0083] The method of any of paragraphs

[0079] to

[0082] , wherein the individual is a mammal, such as a human. Example Example 1 - In Vitro Lifting and Retention

[0084] A composition according to the present disclosure (Composition 1) was prepared and compared with two commercially available submucosal lifting compositions (Compositions A and B) and a saline control (Composition C). Composition 1 is a composition according to the present disclosure comprising about 0.125% (w / v) (about 0.120% by weight) of hydroxyethyl cellulose, about 19% (w / v) (about 18.131% by weight) of glycerol, and about 0.001% (w / v) (about 0.001% by weight) of methylene blue. Composition 1 further comprises water for injection (WFI), preservatives, and buffers in amounts according to the present disclosure. A 1% solution of the hydroxyethyl cellulose in Composition 1 has a viscosity of about 5000 cP. The final viscosity of Composition 1, as measured according to the present disclosure, is about 100 cP to 120 cP.

[0085] Composition A is a commercial product supplied by Aries Pharmaceuticals, Inc. Eleview® is an emulsion consisting of water for injection, medium-chain triglycerides, Polasamer 188, polyoxy-15-hydroxystearate, sodium chloride, and methylene blue.

[0086] Composition B is a commercial ORISE™ gel supplied by Boston Scientific. ORISE™ gel is a viscous gel solution.

[0087] Composition C is a 0.9% saline solution.

[0088] Each composition was injected in a volume of 3.0 ± 0.2 mL. The width and height of the elevated submucosal layer were measured and recorded immediately after injection. It was observed that the width depended on the specific tissue, not the composition itself. The height of the elevated submucosal layer was then measured every 5 minutes relative to the pre-elevation height of the submucosal layer (e.g., pre-elevation height = 0 mm) for a total of 60 minutes. As described in this disclosure, the height of the submucosal layer immediately after injection (i.e., at time = 0) is the first elevation height. Each composition was tested a total of five times. The measured elevation heights over time can be found in Table 1 below. Figure 1 I saw it in the middle. Table 1. In vitro lifting height after injection (mm)

[0089] Table 2 below shows the average retention rate (%) of the lift height over time for each test composition. The lift height retention rate was measured according to the following equation (1): (1) Where h L h is the retention percentage of the first lift height (%), h0 is the average first lift height (at t=0) (mm), h xIt is the elevation height (mm) at each given time. Table 2 Average Lift Height Retention Rate (%)

[0090] As shown in Table 1, Table 2 and Figure 1 As shown, the compositions according to this disclosure not only have a high first lift height (9.40 mm) but also maintain the lift for a longer period of time. At 15 minutes post-injection, composition 1 was the only composition with a retention rate greater than 60% of the first lift height. At 30 minutes post-injection, composition 1 maintained an average of 51.1% of the first lift height, compared to compositions A, B, and C maintaining average first lift heights of 25.0%, 38.5%, and 22.0%, respectively. As shown in Table 1, although composition B maintained almost 85% of the first lift height after 5 minutes, composition B did not offer an advantage over composition 1 at that time point, as the lift height of each of these compositions was between approximately 6.5 mm and 7 mm.

[0091] Therefore, Example 1 demonstrates that, relative to commercially available products, the composition according to this disclosure can advantageously provide an equivalent, if not a better submucosal lifting, then a longer duration of lifting.

Claims

1. A submucosal lifting composition comprising: The polysaccharide is present in an amount ranging from about 0.05% by weight to about 0.5% by weight, based on the total weight of the composition. The polyol present in an amount ranging from about 10% to about 20% by weight, based on the total weight of the composition; and The colorant is present in an amount ranging from about 0.0001% by weight to about 0.005% by weight, based on the total weight of the composition.

2. The composition of claim 1, wherein the polysaccharide is selected from the group consisting of: methylcellulose (MC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxycellulose, hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC), hyaluronic acid, desulfated heparin, desulfated chondroitin sulfate, desulfated dermatan sulfate, guar gum, fenugreek gum, tara gum, locust bean gum, carob gum, amylopectin, gum arabic, arabinoxylan, any salt thereof, and any combination thereof.

3. The composition of claim 1 or 2, wherein the polysaccharide comprises methylcellulose (MC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxycellulose, hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC), or a combination thereof.

4. The composition of any one of claims 1 to 3, wherein the polysaccharide comprises hydroxyethyl cellulose.

5. The composition according to any one of claims 1 to 4, wherein the viscosity of the polysaccharide is in the range of about 500 cP to about 10,000 cP.

6. The composition according to any one of claims 1 to 5, wherein the polyol is selected from the group consisting of glycerol, diglycerol, propylene glycol, dipropylene glycol, butanediol, pentanediol, butanediol, ethylene glycol, diethylene glycol, triethylene glycol, and any combination thereof.

7. The composition of any one of claims 1 to 6, wherein the polyol comprises glycerol or diglycerol.

8. The composition of any one of claims 1 to 7, wherein the polyol comprises glycerol.

9. The composition of any one of claims 1 to 8, wherein the colorant is selected from the group consisting of methylene blue, isosulfur blue, indocyanine green, fluorescein, rose red, gentian violet, and any combination thereof.

10. The composition of any one of claims 1 to 9, wherein the colorant comprises methylene blue.

11. The composition according to any one of claims 1 to 10, further comprising one or more of water, preservatives, and buffers.

12. The composition of claim 11, wherein the composition comprises sterile water for injection (WFI).

13. The composition of any one of claims 1 to 12, wherein the composition is sterile.

14. The composition of claim 13, wherein each component of the composition is sterilized.

15. The composition of claim 13 or 14, wherein the composition is terminally sterilized.

16. The composition of any one of claims 1 to 15, wherein the composition is an aqueous solution.

17. The composition of any one of claims 1 to 16, wherein the composition is not an emulsion.

18. The composition of any one of claims 1 to 17, wherein the viscosity of the composition is in the range of about 5.0 cP to about 150 cP.

19. The composition of any one of claims 1 to 18, wherein the pH of the composition is in the range of about 5.5 to about 8.

0.

20. The composition of any one of claims 1 to 19, wherein the polysaccharide comprises hydroxyethyl cellulose, the polyol comprises glycerol, and the colorant comprises methylene blue.

21. A sealed and sterile syringe comprising the composition as described in any one of claims 1 to 20.

22. A method for enhancing the submucosa, comprising: Injecting the composition of any one of claims 1 to 20 into the submucosal layer of an individual thereby providing an elevated submucosal layer having a first elevation height.

23. The method of claim 22, wherein the first lifting height is at least about 2.0 mm and is measured relative to the height of the submucosal layer prior to injection of the composition.

24. The method of claim 22 or 23, wherein the first lifting height is in the range of about 2.0 mm to about 11.0 mm and is measured relative to the height of the submucosal layer before the injection of the composition.

25. The method of any one of claims 22 to 24, wherein the elevated submucosal layer retains at least 50% of the first elevation height after 30 minutes.

26. The method of any one of claims 22 to 25, wherein the individual is a mammal, such as a human.

27. The method of any one of claims 22 to 26, comprising injecting the composition at a flow rate of at least 0.05 mL / s.

28. The method of any one of claims 22 to 27, wherein the submucosal layer comprises the submucosal tissue of the gastrointestinal tract.

29. The method of claim 28, wherein the submucosal tissue comprises a lesion.

30. The method of claim 29, wherein the lesion is selected from the group consisting of: polyps, adenomas, early-stage cancers, and any combination thereof.

31. A method for submucosal resection of the gastrointestinal tract, the method comprising: Injecting the composition of any one of claims 1 to 20 into the gastrointestinal submucosal tissue of an individual to elevate the tissue to a first elevation height, thereby providing elevated gastrointestinal submucosal tissue; and The elevated submucosal tissue of the gastrointestinal tract was surgically removed.

32. The method of claim 31, wherein the composition is injected in an amount sufficient to elevate the tissue to the first elevation height.

33. The method of claim 31 or 32, wherein the first lifting height is at least about 2.0 mm and is measured relative to the height of the gastrointestinal submucosal tissue prior to injection of the composition.

34. The method of any one of claims 31 to 33, wherein the elevated gastrointestinal submucosal tissue retains at least 50% of the first elevation height after 30 minutes.

35. The method of any one of claims 31 to 34, wherein the individual is a mammal, such as a human.

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