Gallstone dissolving agent and Pharmaceutical composition for treating gallbladder disease comprising the same

Abstract

The present invention relates to a pharmaceutical composition for treating gallbladder disease comprising a gallstone dissolving agent, and more specifically, to a pharmaceutical composition for treating gallbladder disease comprising a gallstone dissolving agent that has an excellent effect in dissolving gallstones, which are the cause of gallbladder disease, and alleviating or treating one or more symptoms selected from the group consisting of asymptomatic chloelithiasis, billary colic, cholecystitis, cholelithiasis, and billary pancreatitis.

Description

Technology Field

[0001] The present invention relates to a gallstone dissolving agent and a pharmaceutical composition for treating gallbladder disease containing the same, and more specifically, to a gallstone dissolving agent having the effect of dissolving gallstones that are the cause of gallbladder disease and a pharmaceutical composition for treating gallbladder disease containing the same. Background Technology

[0003] The gallbladder is located beneath the liver and to the right of the stomach, connecting the liver to the duodenum. The gallbladder serves as a storage pouch for bile secreted by the liver. Once food is primarily mixed in the stomach, it descends into the small intestine, which is the region it passes through before the small intestine. In the duodenum, fat-digesting enzymes from the gallbladder and digestive enzymes from the pancreas meet and travel together with the food through the duct connected to the duodenum into the small intestine. There, absorption begins in earnest, aided by the activity of these digestive enzymes.

[0004] Meanwhile, cholelithiasis, the most representative gallbladder disease, occurs when the fluid stored in the gallbladder hardens into stone-like substances. Cholelithiasis is a disease in which stones form in the gallbladder or bile ducts, occurring in 10% of the total population in Western countries and about 4% of the population in Korea.

[0005] Here, gallstones are classified according to the proportion of cholesterol, and are divided into cholesterol gallstones with a cholesterol proportion of 70% or more, pigment gallstones with a cholesterol proportion of 40% or less, and mixed gallstones with a cholesterol proportion of 40% to 70%.

[0006] Cholesterol stones are typically yellowish-green and are formed primarily from solidified cholesterol; they account for 80% of all gallstones. Another type, pigmented stones, are small, black stones formed from bilirubin (a type of waste product generated when hemoglobin contained in red blood cells breaks down). Gallstones can be as small as a grain of sand or as large as a golf ball. In the gallbladder, a single large stone may develop, there may be hundreds of tiny stones, or a combination of both types may occur.

[0007] If a gallstone detaches from the gallbladder and gets stuck in any part of the duct that carries bile from the liver to the small intestine, it can block the normal flow of bile.

[0008] To treat such gallstones, surgical or non-surgical treatment methods are available; in particular, non-surgical methods include oral gallstone dissolving agents or direct gallstone dissolution therapy.

[0009] Here, oral gallstone dissolving agents are used to dissolve gallstones using drugs derived from bile acids. These include ursodiol (brand name: Ursa) and kenodiol, which are particularly effective against small cholesterol gallstones. With the use of these drugs, it may take several months to several years for all gallstones to be dissolved. Both drugs have minor side effects, including mild diarrhea, abdominal pain, and abdominal discomfort. Additionally, kenodiol has the problem of temporarily increasing blood cholesterol levels and liver enzyme levels.

[0010] Meanwhile, gallstone dissolution therapy involves injecting medication directly into the gallbladder to dissolve cholesterol gallstones. While this method can dissolve several gallstones within a few days, it has been reported to cause irritation and complications.

[0011] Accordingly, prior art regarding gallstone dissolving agents includes Japanese Registered Patent Publication No. 4593918, which describes a type of drug composition having bile secretion-promoting and stone-dissolving effects and a method for manufacturing the same, and a drug composition that loosens smooth muscle spasms by mainly containing peppermint oil and geranium oil in a volume ratio of 2 to 6:1 to 2, and Japanese Published Patent Publication No. 1997-059162, which describes a pharmaceutical composition for treating calcium gallstones having ursodeoxycholic acid aminocitric acid and its sodium salt as active ingredients, and provides a pharmaceutical composition for dissolving calcium gallstones that has resistance to human pancreatic enzymes or coryglycine hydrase and excellent oral absorption. The problem to be solved

[0013] One objective of the present invention is to provide a gallstone dissolving agent with excellent gallstone dissolving properties and a pharmaceutical composition for the prevention or treatment of gallbladder disease containing the same. means of solving the problem

[0015] Various embodiments described herein are described with reference to the drawings. In the following description, various specific details, such as specific forms, compositions, and processes, are described for a complete understanding of the invention. However, specific embodiments may be practiced without one or more of these specific details, or in combination with other known methods and forms. In other examples, known processes and manufacturing techniques are not described as specific details so as not to unnecessarily obscure the invention. Reference throughout this specification to "one embodiment" or "an embodiment" means that the particular features, forms, compositions, or characteristics described in association with the embodiment are included in one or more embodiments of the invention. Accordingly, the context of "in one embodiment" or "an embodiment" expressed at various places throughout this specification does not necessarily represent the same embodiment of the invention. Additionally, particular features, forms, compositions, or characteristics may be combined in any suitable way in one or more embodiments.

[0016] Unless otherwise specifically defined in the specification, all scientific and technical terms used herein have the same meaning as commonly understood by a person skilled in the art to which the present invention pertains.

[0017] According to one embodiment of the present invention, a gallstone dissolving agent comprising a compound represented by the following chemical formula 1 and a pharmaceutical composition for the prevention or treatment of gallbladder disease comprising the same as an active ingredient are provided:

[0018] [Chemical Formula 1]

[0019]

[0020] In the above chemical formula 1,

[0021] One of R1 to R3 is a C1 to C6 alkyl group, and the rest is hydrogen.

[0022] The above alkyl group may be an ethyl group.

[0023] In the present invention, the compound represented by the above chemical formula 1 may be 4-ethylpyridine (4-ethylpyridine; hereinafter, '4E'), 3-ethylpyridine (3-ethylpyridine; hereinafter, '3E'), or 2-ethylpyridine (2-ethylpyridine; hereinafter, '2E').

[0024] In the present invention, the gallstone may include a cholesterol stone or a pigmented stone.

[0025] In the present invention, gallbladder disease may include, but is not limited to, one or more diseases selected from the group consisting of asymptomatic chloelithiasis, billary colic, cholecystitis, cholelithiasis, and billary pancreatitis.

[0026] According to another embodiment of the present invention, a food composition for improving gallbladder disease is provided, comprising a compound represented by the chemical formula 1. Effects of the invention

[0028] The compound represented by Chemical Formula 1 provided in the present invention has excellent solubility against gallstones, which are the cause of gallbladder disease, and is not toxic to gallbladder epithelial cells, so it can be usefully used as a preventive or therapeutic agent for various diseases related to gallbladder disease. Brief explanation of the drawing

[0030] Figure 1 is a photograph showing the degree of dissolution over time of cholesterol-based gallstones with a cholesterol content of 70% or more using the gallstone dissolving agents of Examples 1 to 3. Figure 2 is a graph showing the degree of gallstone dissolution ability over time of cholesterol-based gallstones with a cholesterol content of 70% or more using the gallstone dissolving agents of Examples 1 to 3. Figure 3 is a photograph showing the degree of dissolution over time of mixed gallstones with a cholesterol content of 40-70% using the gallstone dissolving agents of Examples 1 to 3. Figure 4 is a graph showing the degree of gallstone dissolution ability over time of mixed gallstones with a cholesterol content of 40-70% using the gallstone dissolving agents of Examples 1 to 3. Figure 5 is a photograph showing the degree of dissolution over time of pigment gallstones with a cholesterol content of 40% or less using the gallstone dissolving agents of Examples 1 to 3. Figure 6 is a graph showing the degree of gallstone dissolution ability over time of pigment gallstones with a cholesterol content of 40% or less using the gallstone dissolving agents of Examples 1 to 3 and Comparative Example 1. Specific details for implementing the invention

[0031] Preferred embodiments of the present invention are described below. However, embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. Furthermore, embodiments of the present invention are provided to more fully explain the present invention to those skilled in the art.

[0032] According to one embodiment of the present invention, a gallstone dissolving agent comprising a compound represented by the following chemical formula 1 is provided.

[0033] [Chemical Formula 1]

[0034]

[0035] In the above chemical formula 1,

[0036] One of R1 to R3 is a C1 to C6 alkyl group, and the rest is hydrogen.

[0037] The above alkyl group may be an ethyl group.

[0038] In the present invention, the compound represented by the above chemical formula 1 may be 4-ethylpyridine (4-ethylpyridine; hereinafter, '4E'), 3-ethylpyridine (3-ethylpyridine; hereinafter, '3E'), or 2-ethylpyridine (2-ethylpyridine; hereinafter, '2E').

[0039] In the present invention, the compound represented by the chemical formula 1 can effectively dissolve cholesterol-based gallstones and pigment gallstones, and in particular, the 2-ethylpyridine (2E) compound has excellent gallstone dissolving ability.

[0040] In the present invention, the gallstone may include a cholesterol stone or a pigmented stone.

[0041] In the present invention, gallbladder disease may include, but is not limited to, one or more diseases selected from the group consisting of asymptomatic chloelithiasis, billary colic, cholecystitis, cholelithiasis, and billary pancreatitis.

[0042] According to one embodiment of the present invention, a pharmaceutical composition for the prevention or treatment of gallbladder disease is provided, comprising a compound represented by the chemical formula 1 as an active ingredient.

[0043] In the present invention, the compound can prevent or treat various gallbladder diseases that may be caused by gallstones by dissolving gallstones.

[0044] Here, the gallstone may include a cholesterol stone or a pigmented stone.

[0045] In the present invention, the gallbladder disease to be prevented or treated by the compound represented by Chemical Formula 1 may include, but is not limited to, one or more diseases selected from the group consisting of asymptomatic chloelithiasis, billary colic, cholecystitis, cholecholithiasis, and billary pancreatitis.

[0046] As used in this specification, the term "asymptomatic cholelithiasis" refers to a condition in which a patient is unaware of the presence of gallstones due to a lack of symptoms.

[0047] As used in this specification, the term 'abdominal pain' refers to severe abdominal pain that starts below the right rib cage and spreads to the abdomen and lower back, accompanied by nausea and vomiting, and is felt for 30 minutes to several hours. It often occurs after eating fatty foods and is accompanied by chronic nausea.

[0048] As used in this specification, the term 'cholecystitis' refers to a serious disease caused by infection or inflammation of the gallbladder, resulting from a blockage of the bile duct. The symptoms are similar to abdominal pain but last longer, and include fever, sensitivity to cold, and an increase in white blood cell count upon examination.

[0049] As used in this specification, the term 'cholelithiasis' refers to a condition in which gallstones from the gallbladder pass through the bile duct without causing any problems, but become blocked in the bile duct, causing problems, severe abdominal pain and jaundice, and sometimes life-threatening infections.

[0050] As used in this specification, the term 'gallstone pancreatitis' refers to symptoms that occur when gallstones pass through the bile duct and pancreatic duct, causing inflammation, accompanied by nausea and vomiting, and resulting in sporadic abdominal pain.

[0051] As used herein, the term "prevention" refers to any act of suppressing gallbladder disease or delaying its onset by administering the pharmaceutical composition of the present invention.

[0052] As used herein, the term "treatment" refers to any act of improving or beneficially altering symptoms caused by gallbladder disease through the administration of the pharmaceutical composition of the present invention.

[0053] In the present invention, the pharmaceutical composition may be characterized in that it is in the form of a capsule, tablet, granule, injection, ointment, powder, or beverage, and the pharmaceutical composition may be characterized in that it is intended for humans.

[0054] The pharmaceutical composition of the present invention is not limited to these, but may be formulated and used in the form of oral formulations such as powders, granules, capsules, tablets, and aqueous suspensions, as well as topical preparations, suppositories, and sterile injectable solutions, according to conventional methods. The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. For oral administration, the pharmaceutically acceptable carrier may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, colorants, flavorings, etc. For injectable preparations, it may include buffers, preservatives, analgesics, solubilizers, isotonic agents, stabilizers, etc., in combination; and for topical administration, it may include bases, excipients, lubricants, preservatives, etc. The formulations of the pharmaceutical composition of the present invention may be prepared in various ways by mixing with the pharmaceutically acceptable carriers described above. For example, for oral administration, it can be manufactured in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and for injectables, it can be manufactured in the form of unit dosing ampoules or multiple dosing ampoules. In addition, it can be formulated as a solution, suspension, tablet, capsule, sustained-release formulation, etc.

[0055] Meanwhile, examples of carriers, excipients, and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil. Additionally, fillers, anticoagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, etc. may be additionally included.

[0056] The routes of administration of the pharmaceutical composition according to the present invention are not limited to but include oral, intravenous, intramuscular, intra-arterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual, or rectal. Oral or parenteral administration is preferred.

[0057] In the present invention, 'parenteral' includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intradural, intralesional, and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.

[0058] The pharmaceutical composition of the present invention may vary depending on various factors including the activity of the specific compound used, age, body weight, general health, gender, diet, time of administration, route of administration, release rate, drug combination, and the severity of the specific disease to be prevented or treated, and the dosage of the pharmaceutical composition may be appropriately selected by a person skilled in the art, depending on the patient's condition, body weight, degree of disease, drug form, route of administration, and duration, and may be administered at a dose of 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg per day. Administration may be administered once a day or divided into several doses. The dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as a pill, coated tablet, capsule, liquid, gel, syrup, slurry, or suspension.

[0059] According to another embodiment of the present invention, a food composition for improving gallbladder disease is provided, comprising a compound represented by Chemical Formula 1 as an active ingredient.

[0060] The food composition of the present invention can be manufactured in the form of various food products, such as beverages, chewing gum, tea, vitamin complexes, powders, granules, tablets, capsules, confectionery, rice cakes, bread, etc. Since the food composition of the present invention is composed of plant extracts with almost no toxicity or side effects, it can be used safely even when taken for a long period for preventive purposes.

[0061] In the present invention, when the compound represented by Chemical Formula 1 is included in a food composition, the amount thereof may be added in a ratio of 0.1 to 50% of the total weight.

[0062] Here, when the above food composition is prepared in the form of a beverage, there are no special limitations other than containing the above food composition in the indicated proportions, and it may contain various flavoring agents or natural carbohydrates as additional ingredients, as in ordinary beverages. That is, as natural carbohydrates, it may include monosaccharides such as glucose, disaccharides such as fructose, polysaccharides such as sucrose, conventional sugars such as dextrin, cyclodextrin, etc., and sugar alcohols such as xylitol, sorbitol, erythritol, etc. Examples of the above flavoring agents include natural flavoring agents (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.).

[0063] In addition, the food composition of the present invention may contain various nutritional agents, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.

[0064] These components may be used independently or in combination. The proportion of these additives is not particularly important, but is generally selected in the range of 0.1 to about 50 parts by weight per 100 parts by weight of the composition of the present invention.

[0066] The present invention will be described in detail below through examples. However, the following examples are merely illustrative of the present invention, and the present invention is not limited by the following examples.

[0068] Examples

[0069] Experiment 1. Dissolution of cholesterol-based gallstones with a cholesterol content of 70% or more

[0070] In order to evaluate the solubility of each cholesterol-based gallstone and pigment gallstone of Examples 1 to 3 and Comparative Example 1 according to Table 1 below, a cholesterol-based pigment gallstone was provided in which the cholesterol content removed during surgery of a patient with gallstones was 70% by weight or more, and the gallstone was prepared.

[0071] division Example 1 Example 2 Example 3 Comparative Example 1 ingredient 4-ethylpyridine(4E) 3-ethylpyridine(3E) 2-ethylpyridine(2E) 2-methoxy-6-methylpyridine (MMP)

[0072] After placing 0.5g of each prepared gallstone into a glass vial, 0.5ml of the gallstone dissolving agents of Examples 1 to 3 and Comparative Example 1 were added to the glass vial containing the gallstone. The mixture was left at 37°C, and the mass was measured at a set time to evaluate the dissolving ability of the gallstone before and after treatment with each compound. The results of the dissolving ability of Examples 1 to 3 for cholesterol-based gallstones with a cholesterol content of 70% or more are shown in Figures 1 and 2, respectively.

[0073] For reference, in the above experiment, the gallstone dissolving ability was calculated using the following formula.

[0074] Gallstone dissolution capacity (%) = (Weight of gallstone after dissolution) / (Weight of gallstone before dissolution) X 100

[0076] As a result, it was confirmed that the compounds of Examples 1 to 3 have excellent dissolving ability against cholesterol-based gallstones, and in particular, it was confirmed that the compound of Example 3 (2E) has relatively superior dissolving ability against cholesterol-based gallstones compared to the other examples.

[0078] Experiment 2. Dissolution of mixed gallstones with a cholesterol content of 40–70%

[0079] The experiment was conducted under the same conditions as Experiment 1, except that mixed gallstones with a cholesterol content of 40 to 70 weight%, i.e., gallstones composed of a mixture of cholesterol, bile pigment, and calcium salts, were used, and the results of the dissolution ability of Examples 1 to 3 and Comparative Example 1 for the said mixed gallstones are shown in Figures 3 and 4, respectively.

[0080] As a result, it was confirmed that the compounds of Examples 1 to 3 had excellent dissolving ability against mixed gallstones compared to the conventional Comparative Example 1 (MMP) compound.

[0082] Experiment 3. Dissolution of pigment gallstones with a cholesterol content of 40% or less

[0083] The experiment was conducted under the same conditions as Experiment 1, except that pigment gallstones with a cholesterol content of 40% by weight or less were used, and the results of Examples 1 to 3 for pigment gallstones with a cholesterol content of 40% or less are shown in Figures 5 and 6, respectively.

[0085] As a result, it was confirmed that the compounds of Examples 1 to 3 have excellent dissolving ability against pigment gallstones, and in particular, the compound of Example 3 (2E) was confirmed to have relatively superior dissolving ability against pigment gallstones compared to the other examples.

[0087] Although embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and it will be obvious to those skilled in the art that various modifications and variations are possible within the scope of the technical concept of the present invention as described in the claims.

Claims

Claim 1 Gallstone dissolving agent comprising a compound represented by the following chemical formula 1: [Chemical Formula 1] In the above chemical formula 1, any one of R1 to R3 is an ethyl group, and the rest are hydrogen. Claim 2 delete Claim 3 A gallstone dissolving agent according to claim 1, wherein the compound represented by the above chemical formula 1 is 4-ethylpyridine, 3-ethylpyridine, or 2-ethylpyridine. Claim 4 In claim 1, the gallstone dissolving agent comprises cholesterol-based gallstones or pigment gallstones. Claim 5 A pharmaceutical composition for the treatment or prevention of gallbladder disease, comprising a gallstone dissolving agent according to claim 1 as an active ingredient. Claim 6 A pharmaceutical composition according to claim 5, wherein the gallbladder disease comprises one or more diseases selected from the group consisting of asymptomatic chloelithiasis, billary colic, cholecystitis, cholelithiasis, and billary pancreatitis. Claim 7 A food composition for improving gallbladder disease comprising a gallstone dissolving agent according to claim 1 as an active ingredient.

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