KR101297363B1 - Composition comprising local injection preparation for endoscopic mucosal resection - Google Patents

Abstract

The present invention relates to an injectable composition used for endoscopic mucosal resection (EMR), and more particularly, to a hydrogel injectable composition for endoscopic mucosal resection comprising alginate and a cation.

Description

Composition comprising local injection preparation for endoscopic mucosal resection}

The present invention relates to an injectable composition used for endoscopic mucosal resection (EMR), and more particularly, to a hydrogel injectable composition for endoscopic mucosal resection comprising alginate and a cation.

Endoscopic mucosal resection (EMR) is a non-invasive procedure that involves endoscopic resection of small lesions, such as polyps and cancers, formed on the gastrointestinal mucosa, such as the stomach and intestines, without open surgery. Endoscopic mucosal resection may develop into cancer and treatment of early esophageal cancer, gastric cancer, papillary cancer, colon cancer, etc. Applied to resection of probable precancerous lesions. In early cancer, endoscopic mucosal resection is important in terms of cost and effectiveness compared to surgical procedures and improves the quality of life of patients.

In general, endoscopic mucosal resection is performed by local injection of physiological saline into the submucosa of the site to be resected to improve resection efficiency, operability, and safety, and the lesions are raised and protruded to cover the normal mucosa around the lesion. Use moderation Recently, a method using a variety of assistive devices, such as a transparent cap, a specially shaped noose, and a needle-shaped incision, has been developed to increase the success rate of the procedure.

During endoscopic mucosal resection, topical injection of physiological saline is injected into the submucosa to raise the lesion. Submucosal injection is used to prevent the instrument from directly damaging the myocardium. Used for the purpose of minimizing perforation. Topical infusions should be selected based on factors such as ridge duration, tissue injury, and price. In addition, the topical injection solution should be selected to be harmless to the human body because it should be injected in a sufficient amount to reduce the risk of perforation and to obtain the vascular compression effect and contraction effect.

Physiological saline, which is generally used as an injection for topical injection, is an isotonic solution, which is inexpensive and has no tissue injury.However, when excision is applied, the ridge is easily deformed, the ridge is low, and spreads over time As the ridges are easily lost, it is difficult to reliably ablate the targeted area.

It is also possible to use hypertonic saline, 50% glucose solution, or glycerol solution (consisting of 10% glycerin, 5% fructose and physiological saline) in order to increase the duration of the elevation, but the sustained effect of these hypertonic solutions is not so great. There is a tissue injury, and the thin wall of the large intestine, such as perforation risks, there is a problem in stability.

In addition, a method of using dextrose water has been developed, but when used at a high concentration of 20% or more, tissue damage occurs.

In the case of using a fibrinogen melt, the viscosity is high, so it is difficult to inject and there is a problem of the risk of virus transmission.

In addition, in recent years there has been an attempt to use hyaluronic acid (hyaluronic acid) having high viscoelasticity and excellent sustainability, but has a disadvantage in that a high viscosity and high injection cost are high.

In addition, a method of inflating a site to be resected using carbon dioxide gas and performing a resection and a method of performing a resection after injecting the patient's own blood have been tried, but there are still limitations in that the sustaining effect of the elevation is not large. .

Accordingly, the present inventors have tried to develop a new injection material that can replace the existing topical injection used in endoscopic mucosal resection, and as a result, when the hydrogel is formed by using alginate and various cations, the elevation time is long, and the tissue The present invention was completed by confirming that there is no damage, no toxicity, and that various applications are easy. This is the first attempt to use hydrogel as a submucosal topical injection for endoscopic mucosal resection. According to the present invention, it is possible to control the viscosity of hydrogel by adjusting the concentration of alginate and the concentration of cation. It is distinguished from the existing technology in that it can maintain a long time, have a low cost and excellent bio stability.

It is an object of the present invention to provide a hydrogel injectable composition for endoscopic mucosal resection comprising alginate and a cation.

In one embodiment, the present invention relates to a hydrogel injectable composition for endoscopic mucosal resection comprising alginate and a cation.

For the purposes of the present invention, the term “alginate” refers to β-D-mannuronic acid and α-L-guluronic acid monomers, or salts or derivatives thereof, or polysaccharides comprising them. In one example, the alginate may be a copolymer in which a mannuronic acid (or salt thereof) monomer and a gluuronic acid (or salt thereof) monomer are crosslinked. Alternatively, it may be a copolymer in which a comonomer of mannuronic acid (or a salt thereof) and a monomer of gluuronic acid (or a salt thereof) are crosslinked. Alternatively, the copolymer may be a crosslinked monomer of a comonomer of gluuronic acid (or a salt thereof) and a monomer of mannuronic acid (or a salt thereof). Alternatively, the copolymer may be a crosslinked comonomer of mannuronic acid (or a salt thereof) and a comonomer of gluuronic acid (or a salt thereof). It also includes alkali metal salts of alginates such as sodium alginate or potassium alginate.

The alginates of the present invention can be obtained through conventional access channels well known in the art or obtained naturally or synthetically. Naturally, it can be extracted from the brown algae Laminaria, Ecklonia, Macrocystis, Pelvetia, Lessonia or Alaria. In addition, algin, which is a constituent of the cell wall of seaweed, may be obtained by extracting an aqueous solution using an aqueous sodium carbonate solution and then extracting it with an inorganic acid such as hydrochloric acid, but is not limited thereto.

In the present invention, the term "cationic" is a concept including monovalent, divalent or polyvalent cations, or salts thereof, and promotes ionic bonds between alginate chains to form a hydrogel through crosslinking.

The cations are calcium, potassium, sodium, barium, magnesium, gadolinium, lithium, copper, iron, aluminum, strontium, tin, zinc, chromium, or di-, tri- and tetra-functional organic cations, poly (amino acids), But not limited to those selected from the group consisting of poly (ethyleneimine), poly (vinylamine), poly (allylamine), and polysaccharides. Preferably barium or calcium ions.

The cation can be used in the form of a salt compound. Salts usable in the present invention include pharmaceutically acceptable inorganic and organic acid salts. Specifically, hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, gluconic acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid , Formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid and the like.

For example, calcium-gluconate, calcium chloride (CaCl ₂ ) or calcium acetate (Ca (CH ₃ COO) ₂ ) for calcium ions, barium chloride (BaCl ₂ ) for barium ions, magnesium chloride for magnesium It may be used in the form of salt compounds such as (MgCl ₂ ).

As used herein, the term "hydrogel" refers to a state in which a large amount of water is filled in a lattice of a high molecular material to swell to maintain a three-dimensional structure, and a hydrogel may absorb at least 20% or more of the total weight of water. Among them, absorbing more than 95% of water is called a super absorbent hydrogel. After the hydrogel is swollen in solution, it is thermodynamically stable and has mechanical and physicochemical properties that correspond to the intermediate form of liquid and solid.

In the hydrogel composition of the present invention, the concentration of alginate is preferably contained in the range of 0.1 to 10 wt%, preferably 0.2 to 3 wt%, and the concentration of the cation is included in the range of 0.1 to 150 mmol, preferably 5 to 50 mmol. It is desirable to be.

As used herein, the term "endoscopic mucosal resection (EMR)" refers to a non-invasive procedure for endoscopically resecting small lesions such as polyps and cancers formed in the gastrointestinal mucosa, such as the stomach or intestine, without open surgery. .

The hydrogel composition of the present invention can be applied to any type of cancer or lesion in which endoscopic mucosal resection can be performed. For example, it can be used as a submucosal topical injection for the treatment of esophageal cancer, gastric cancer, papillary cancer, colon cancer, and endoscopic resection of precancerous lesions that are likely to develop into cancer. In a specific embodiment, the end portion of the lesion to be excised, such as a polyp or cancer, is injected through an endoscope needle to raise the site to be excised, and the raised portion can be excised with a snare, a needle knife, or the like.

The hydrogel composition of the present invention may further comprise functional nanoparticles.

Functional nanoparticles may impart additional functions, such as therapeutic or preventive measures, in addition to the role of simple injectors in endoscopic mucosal resection. Functional nanoparticles exhibit a diagnostic effect using a magnetic field and a therapeutic effect using heat, or additionally exhibit a biological therapeutic effect by a tissue-specific binding component, thereby diagnosing and / or treating a cancer targeted for endoscopic mucosal resection. This can have additional effects.

The functional nanoparticles are gadolinium nanoparticles, iron oxide nanoparticles, barium nanoparticles, gold or silver nanoparticles, gadolinium oxide (gadolinium oxide), barium sulfate, functional silica nanoparticles (functional silica nanoparticles) or iodine nanoparticles Particles (Iodine nanoparticles) can be illustrated, but is not limited thereto.

When the nanoparticles are further included, the nanoparticles in the hydrogel composition may be included in a content range that does not significantly affect the viscosity of the hydrogel. For example, it may be included in an amount of 0.01wt% to 10wt%, preferably 0.1wt% to 1wt%, but is not limited thereto, and may exhibit nanoparticle functionality without significantly affecting the viscosity of the hydrogel. The concentration can be determined. For example, gadolinium nanoparticles, iron oxide nanoparticles, etc. should be set to a concentration that can have a diagnostic effect using a magnetic field. In addition, barium nanoparticles, iodine nanoparticles, etc. should be determined at a concentration that can have a diagnostic effect on CT diagnostics (X-ray). For the therapeutic effect of heat, the coreshell gold or silver nanoparticles must be adjusted to the appropriate concentration to respond to the external frequency.

In addition to the hydrophilic polymers set forth above, the present invention may further include other hydrophilic polymers or additives having biocompatibility within the scope not departing from the object of the present invention and having the physical properties and effects required by the present invention.

In addition to the above components, as a component constituting the hydrogel composition of the present invention, an additive which does not inhibit the achievement of the desired effect of the present invention, such as a solvent or a gelling agent commonly used in the art may be further included.

For example, as the solvent, any one that can increase the gelation or sustainability of the hydrogel of the present invention can be used, and as the solvent, one having hydrophilic property can be used. For example, propylene glycol, polyethylene glycol 400, polyethylene glycol 1000, polyethylene glycol 2000, polyethylene glycol 5000, glycerin, or mixtures thereof can be used. As a hydrophilic gelling agent, an additive capable of forming a gel in contact with water may be used. Specifically, a carboxyvinyl polymer, xanthan gum, poloxamer, or a mixture thereof may be used.

In addition, the hydrogel composition of the present invention may further comprise water of pharmaceutically acceptable grade as purified water.

In the present invention, it is preferable to use the injection agent adjusted appropriately so that the injection pressure when injected using the endoscope needle is 0.5 to 4 atm, preferably 2 to 3 atm. Moreover, in this invention, when the injection | pouring agent inject | pours into a mucosal tissue at the pressure of 2-3 atmosphere using the said endoscope needle, it is suitable so that it may become 0.05-0.1 ml / sec, Preferably it is 0.07-0.09 ml / sec. It is preferable to operate it so that it may be adjusted. At this time, the injection can be adjusted by appropriately selecting the concentration of alginate or cation, salt concentration, pH (adjusted appropriately in the range of pH 4.5 to 8.0) and the like.

In a specific embodiment of the present invention, when the alginate and various kinds of cations were mixed, the hydrogel composition of alginate and calcium gloconate was treated as compared with the alginate alone. The viscosity increased by about 1.5 times, and when the hydrogel composition of alginate and barium chloride was treated, it was confirmed that the viscosity increased by 4 to 5 times (Tables 1 to 4).

In addition, as a result of measuring the sustaining effect in the submucosal layer of the extracted pig gut, the portion of the saline-injected portion was reduced in volume with time, but the hydrogel composition composed of alginate and calcium-gluconate, and In the case of the hydrogel composition composed of alginate and barium chloride, the volume was almost maintained intact (FIG. 2).

Therefore, the hydrogel composition according to the present invention can be usefully used for endoscopic resection procedures.

Since the hydrogel composition according to the present invention has a prolonged elevation of the mucosal lesions by injection and excellent operability at the time of injection, it is a precancerous lesion highly likely to develop into cancer and treatment of esophageal cancer, gastric cancer, papillary cancer, and colon cancer. It can be useful as a submucosal topical injector for endoscopic resection.

Figure 1 (A) is a diagram showing a representative example of the components of the hydrogel composition of the present invention, (B) is a diagram showing the process of forming a hydrogel.
Figure 2 is a volume according to the change of time for 10 minutes after injecting saline, alginate and calcium solution (Ca-Gluconate), alginate and barium solution (BaCl ₂ ) into the lower mucosa of the internal organs of the extracted pig The photo shows the change.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

Example  1. According to the invention Hydrogel  Viscosity measurement

When the alginate and various kinds of cations were mixed, the viscosity of each hydrogel was measured at room temperature (Tables 1 to 4). Hydrogel was prepared by the following method.

Distilled water was prepared in a 300 ml bottle, the magnetic stirrer was cleaned and then placed in the bottle, and the alginate to be adjusted to 0.3% (w / v) was quantified. Alginate was added to the distilled water little by little by turning the stirrer because alginate could be solidified due to hygroscopicity and rapid gelation of alginate. When water is added to the quantified alginate, it is difficult to dissolve it, and therefore, alginate was added to the distilled water in the present invention. After all the alginate was added, the alginate solution was sufficiently stirred at room temperature for 4-6 hours. The agitated alginate solution was packaged in aluminum foil and stored in a refrigerator to prevent light from passing through. After preparing 0.3% (w / v) alginate solution in this way, hydrogel was prepared by mixing calcium gluconate, barium chloride, or calcium chloride, respectively.

As a result, in the case of the hydrogel solution in which the alginate and calcium gluconate 10 mmol solution were mixed, the viscosity did not change when 200 microliters of calcium gluconate solution was mixed, but when mixed with 400 microliters, the viscosity was 1.5 times higher than that of the basic alginate. It could be confirmed that the increase. That is, it was found that gelation occurred well.

In the case of the hydrogel solution mixed with alginate and barium chloride 10mmol solution, it was confirmed that the viscosity increased 1.5 times even when using 200 microliters of barium chloride solution, and the average viscosity increased by 4 to 5 times when using 400 microliters. I could confirm it.

In the case of the hydrogel solution mixed with alginate and calcium chloride 10mmol solution, it was confirmed that the viscosity increased about 2 times when using 200 microliters of calcium chloride solution, and the viscosity increased about 60 times when using 400 microliters.

As a result, it was found that the viscosity was maintained even when using 400 microliters when using a 10 mmol solution of barium chloride. When using a calcium chloride solution, a high viscosity hydrogel was used by using 300 to 400 microliters of solution. It could be confirmed that it could be formed.

Tables 1 to 4 show the results of measuring the viscosity of the hydrogel at room temperature, respectively, when the alginate and various kinds of cations were mixed, and all of the viscosity units used cP.

Alginate (rpm) 1 time Episode 2 10.00 6.00 6.00 20.00 9.00 8.00 30.00 12.00 11.00 50.00 14.40 12.50 60.00 15.00 13.07 100.00 16.80 15.60

Alginate
Calcium Gluconate (rpm) 200ul 400ul 10.00 no data no data 20.00 no data 6.00 30.00 3.00 20.00 50.00 10.80 22.80 60.00 12.50 31.50 100.00 16.20 36.00

Alginate-BaCl ₂ (rpm) 200ul 400ul 10.00 24.00 132.00 20.00 30.00 99.75 30.00 28.00 93.50 50.00 28.00 57.40 60.00 31.00 64.20 100.00 30.00 75.47

Alginate-CaCl ₂ (rpm) 200ul 400ul 10.00 12.60 2754.00 20.00 21.00 1675.00 30.00 26.00 1500.00 50.00 35.60 921.50 60.00 31.33 500.00 100.00 40.33 994.00

Example  2. In pig's intestines Hydrogel  Elevation persistence measurement

The internal organs were removed from the carcasses and divided into half, and saline, alginate and calcium-gluconate solution (Ca-Gluconate, 10 mmol, 400 ul), alginate and barium chloride solution (BaCl) were found in the mucosa of various parts. ₂ , 10 mmol, 400 ul), after 1 minute, 2 minutes, 5 minutes, 10 minutes after the change of volume was observed.

As a result, as shown in FIG. 2, the portion of the physiological saline injected portion decreased in volume with time, and the hydrogel composition composed of alginate and calcium-gluconate, and the hydrogel composition composed of alginate and barium chloride When the volume was confirmed to remain almost intact.

Claims (6)

Hydrogel injection composition for endoscopic mucosal resection comprising alginate and cation.
The method according to claim 1, wherein the cation is calcium, potassium, sodium, barium, magnesium, gadolinium, lithium, copper, iron, aluminum, strontium, tin, zinc, chromium or organic cations, calcium glutamate, poly (amino acid), A hydrogel composition which is at least one cation or salt thereof selected from the group consisting of poly (ethyleneimine), poly (vinylamine), poly (allylamine) and polysaccharides.
The hydrogel composition of claim 1, wherein the cation is included in the form of calcium-gluconate, calcium chloride (CaCl ₂ ), barium chloride (BaCl ₂ ), or magnesium chloride (MgCl ₂ ).
The hydrogel composition of claim 1, further comprising nanoparticles. The hydrogel composition of claim 4, wherein the nanoparticles are gadolinium nanoparticles, iron oxide nanoparticles, barium nanoparticles, gold or silver nanoparticles, gadolinium oxide, barium sulfate, silica nanoparticles, or iodine nanoparticles.
The composition of claim 1, wherein the endoscopic mucosal resection is performed for esophageal cancer, gastric cancer, papillary cancer, or colorectal cancer.

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