Pharmaceutical compositions

Abstract

When a pharmaceutical composition containing a glycyrrhizic acid and an antacid such as synthetic hydrotalcite is taken, the glycyrrhizic acid is released into gastric juice, but the glycyrrhizic acid is trapped by the antacid, resulting in a decrease in bioavailability. This decrease in bioavailability is suppressed.SOLUTION: The pharmaceutical composition comprises (A) at least one selected from glycyrrhizic acid and pharmaceutically acceptable salts thereof, (B) antacids, (C) Sucralfate Hydrate, and (D) Corydalis Tuber.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition containing one or more members selected from glycyrrhizinic acid and pharmaceutically acceptable salts thereof. [Background technology]

[0002] Glycyrrhizic acid and its pharmaceutically acceptable salts (hereinafter sometimes referred to as glycyrrhizic acids) are compounds obtained from licorice and have anti-inflammatory and tissue repair effects, and are widely used in cosmetics, pharmaceuticals (combined cold remedies, gastrointestinal medicines, eye drops, dermatological medications, etc.) and quasi-drugs. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Japanese Patent Publication No. 2023-10636 Summary of the Invention [Problem to be solved by the invention]

[0004] The present inventors have found that when a pharmaceutical composition containing glycyrrhizic acids and an antacid such as synthetic hydrotalcite is ingested, the glycyrrhizic acids are released into gastric juice and become glycyrrhizic acid, but the glycyrrhizic acid is trapped in the antacid, resulting in a decrease in bioavailability (an index showing how much of an administered drug circulates throughout the body).The present invention aims to suppress this decrease in bioavailability. [Means for solving the problem]

[0005] As a result of extensive research into achieving the above-mentioned object, the present inventors have found that the above-mentioned problems can be solved by adding sucralfate hydrate and Corydalis rotundifolia to a pharmaceutical composition containing glycyrrhizinic acids and an antacid such as synthetic hydrotalcite, and have thus completed the present invention.

[0006] Accordingly, the present invention provides the following pharmaceutical compositions. 1. (A) one or more selected from glycyrrhizinic acid and pharmaceutically acceptable salts thereof; (B) antacids, (C) sucralfate hydrate, and (D) Corydalis A pharmaceutical composition comprising: 2. The pharmaceutical composition according to 1, wherein (B) the antacid is one or more selected from magnesium hydroxide, magnesium aluminosilicate, magnesium aluminometasilicate, synthetic hydrotalcite, and precipitated calcium carbonate. 3. A pharmaceutical composition according to 1 or 2, wherein component (A) is derived from licorice. 4. The pharmaceutical composition according to 3, wherein component (A) is derived from licorice powder or licorice extract. 5. A pharmaceutical composition according to any one of 1 to 4, wherein component (D) is Corydalis rotundifolia powder or Corydalis rotundifolia extract. 6. A pharmaceutical composition according to any one of 1 to 5, wherein the mass ratio of the components contained represented by ((C)+(D))×(A) / (B) is 0.3 or more. 7. The pharmaceutical composition according to any one of 1 to 6, which is in a dosage form selected from tablets, granules, fine granules, capsules, powders, powders, lozenges and pills. [Effects of the Invention]

[0007] According to the present invention, it is possible to provide a pharmaceutical composition in which the decrease in the bioavailability of glycyrrhizinic acids is suppressed. DETAILED DESCRIPTION OF THE INVENTION

[0008] The present invention will be described in detail below. [Component (A)] Component (A) of the present invention is one or more selected from glycyrrhizinic acid and its pharmaceutically acceptable salts, and can be used alone or in combination of two or more. As described above, component (A) has anti-inflammatory, antiallergic, analgesic, sedative, etc. Examples of component (A) include glycyrrhizinic acid, trisodium glycyrrhizinate, disodium glycyrrhizinate, monoammonium glycyrrhizinate, monopotassium glycyrrhizinate, dipotassium glycyrrhizinate, etc., with glycyrrhizinic acid, trisodium glycyrrhizinate, monoammonium glycyrrhizinate, and dipotassium glycyrrhizinate being preferred, and glycyrrhizinic acid and dipotassium glycyrrhizinate being more preferred.

[0009] Glycyrrhizic acids are preferably derived from licorice, and more preferably from licorice powder or licorice extract, as this enhances the effects of the present invention. Licorice (Glycyrrhiza glabra) is one of the herbal medicines widely used in traditional Chinese medicine and folk medicine. Licorice powder and licorice extract are made from the roots and stems of licorice and have various effects, such as relieving coughs and gastrointestinal discomfort. The main active ingredient in licorice is glycyrrhizic acid.

[0010] Component (A) has anti-inflammatory, anti-allergic, analgesic, and sedative effects. This is achieved by glycyrrhizic acids inhibiting the release and activation of substances that cause inflammation. Licorice also has the effect of suppressing allergy-related symptoms such as hay fever, allergic rhinitis, and atopic dermatitis. Glycyrrhizic acids inhibit the production of substances that cause allergic reactions, thereby alleviating allergic symptoms. Licorice also has analgesic and sedative effects. This is achieved by glycyrrhizic acid's ability to promote the release of analgesic substances and its effect on the central nervous system, resulting in a relaxing effect.

[0011] The form of licorice in the present invention can be adjusted as needed. Whole herbs may be cut or crushed into small pieces or chunks, or ground into powder (licorice powder). Alternatively, licorice may be cut to an appropriate size, and then an appropriate extraction solvent is added to the resulting infusion, which is then concentrated and dried (dried extract, etc.). The method for producing the herbal extract is not particularly limited, and it can be produced by referring to known methods for producing plant extracts, such as those described in the "Extracts" section of the General Provisions for Preparations of the Japanese Pharmacopoeia, 18th Edition. Specifically, licorice can be produced by cutting, heating, crushing, etc., as needed, and then extracting with an appropriate extraction solvent. The resulting extract may be further concentrated, dried, etc., as needed. The dried licorice extract used in the present invention can be, for example, extracted from "licorice" with water, followed by concentration and drying. Licorice powder contains 1 to 5% by mass of glycyrrhizinic acid, and commercially available products include "Licorice Powder" (manufactured by Nippon Powder Pharmaceuticals Co., Ltd.) and "Licorice Powder (Sterilized)" (manufactured by Nippon Powder Pharmaceuticals Co., Ltd.). Licorice dry extract contains 7 to 15% by mass of glycyrrhizinic acid, and commercially available products include "Licorice Extract Powder-A" (manufactured by Nippon Powder Pharmaceuticals Co., Ltd.) and "Licorice Dry Extract" (manufactured by Alps Pharmaceutical Co., Ltd.).

[0012] The amount of component (A) in the pharmaceutical composition is preferably 0.02 to 1.4% by mass, more preferably 0.08 to 1.3% by mass. The amount of licorice powder in the pharmaceutical composition corresponding to this amount of component (A) is preferably 1 to 60% by mass, more preferably 2 to 55% by mass, in terms of the amount of licorice powder, in the pharmaceutical composition. The amount of licorice powder in a daily dose of the pharmaceutical composition is selected to be preferably 50 to 1500 mg, more preferably 300 to 500 mg. The amount of licorice dry extract in the pharmaceutical composition corresponding to the amount of component (A) is preferably 0.8 to 20% by mass, more preferably 1.0 to 10% by mass, in terms of the amount of licorice dry extract, in the pharmaceutical composition. The amount of licorice dry extract in a daily dose of the pharmaceutical composition is selected to be preferably 22 to 214 mg, more preferably 42 to 120 mg. By setting the content at or above the lower limit, the (A) component, licorice powder, and licorice dry extract exhibit good efficacy, and the effect of improving the bioavailability of glycyrrhizic acids is more easily achieved. By setting the content at or below the upper limit, the size and dosage of the pharmaceutical composition (preparation, for example, tablet) can be further reduced, resulting in a pharmaceutical composition with excellent administrability.

[0013] [(B) Component] Component (B) of the present invention is an antacid agent, and refers to an antacid agent having an antacid power of 120 mL or more, preferably 200 mL or more, as determined by the antacid power test method of the Japanese Pharmacopoeia (18th Pharmacopoeia). The antacid power determined by the antacid power test method of the Japanese Pharmacopoeia (18th Pharmacopoeia) is expressed as the consumption (mL) of 0.1 mol / L hydrochloric acid per 1 g. Specific examples include magnesium hydroxide (340 mL), magnesium aluminosilicate (250 mL), magnesium aluminometasilicate (230 mL), synthetic hydrotalcite (270 mL), precipitated calcium carbonate (200 mL), sodium bicarbonate (121 mL), magnesium oxide (480 mL), magnesium alumina hydroxide (300 mL), magnesium carbonate (210 mL), calcium carbonate (200 mL), and calcium hydroxide (260 mL). These can be used alone or in combination.

[0014] The amount of component (B) in the pharmaceutical composition is appropriately selected within the range typically used in treatment as an antacid. For example, the amount determined by the antacid power test method specified in the Japanese Pharmacopoeia (18th Edition) is preferably approximately 50 to 1000 mL per day, more preferably 160 to 800 mL. As long as the antacid power derived from the component (B) falls within the above range, one or more components (B) can be used in combination, making it easier to achieve the gastric acid neutralizing power required for the gastrointestinal drug's efficacy. An example of a preferred range for the amount of component (B) in the pharmaceutical composition is as follows: The amount of component (B) in the pharmaceutical composition is preferably 4 to 70% by mass, more preferably 5 to 40% by mass. Furthermore, the amount of component (B) in the daily dose of the pharmaceutical composition is appropriately selected to be 100 to 3000 mg, preferably 250 to 2000 mg. By setting the amount of component (B) at or above the lower limit, the pharmacological effect as an antacid is more effectively achieved. By setting the amount of component (B) to the upper limit or less, the dosage can be further reduced, resulting in a pharmaceutical composition with better ingestibility. In addition, the combination of components (C) and (D) makes it easier to achieve the effect of improving the bioavailability of glycyrrhizinic acids.

[0015] [(C) component] The component (C) of the present invention is sucralfate hydrate (also known as sucrose octasulfate aluminum salt, hereinafter sometimes abbreviated as sucralfate). Sucralfate binds to proteins in inflamed mucosal areas, covering and protecting the inflamed areas while repairing them, and is therefore sometimes referred to as a "gastric bandage." In the present invention, in addition to its effect on inflamed stomach areas, its mucosal protective effect in the stomach and duodenum inhibits the permeation of gastric acid, exhibiting excellent effects in suppressing the continued inflammation and improving the bioavailability of glycyrrhizic acids. Sucralfate can be formulated as is, or granulated particles can be used. Granulation can be performed by any known granulation method, such as fluidized bed granulation, tumbling granulation, or kneading granulation. For example, slurries made with a binder such as polyethylene glycol and spray-dried can be used. Examples of such commercially available products include Stomaccin (manufactured by Fuji Chemical Industry Co., Ltd.).

[0016] The amount of component (C) in the pharmaceutical composition is preferably 5 to 80% by mass, more preferably 16 to 75% by mass. The amount of component (C) in the daily dose of the pharmaceutical composition is appropriately selected to be preferably 100 to 3,000 mg, more preferably 250 to 2,000 mg, and even more preferably 1,000 to 1,500 mg. By setting the amount at or above the lower limit, the efficacy of component (C) is demonstrated and the effect of improving the bioavailability of the glycyrrhizic acids of the present invention is more easily achieved. By setting the amount at or below the upper limit, the dose can be further reduced, resulting in a pharmaceutical composition with better administrability. Component (C) is usually present in the form of a hydrate, and the water content of the drug substance powder is approximately 12% by mass. In the present invention, the amount and content of component (C) are determined by the quantitative determination method for sucralfate hydrate in the Japanese Pharmacopoeia (18th Bureau).

[0017] [(D) component] Corydalis rotundifolia (Corydalis rotundifolia) is a herbal medicine used in traditional Chinese medicine in Japan and China, primarily known for its analgesic and antispasmodic properties. Corydalis rotundifolia is made from the roots of a plant in the Scleractinian family. This plant grows wild in China and Japan, and its roots are dried and used. Corydalis rotundifolia contains active ingredients such as tetrahydropalmatine and protopine, which are thought to cause its analgesic and antispasmodic effects. It exerts its analgesic effects by inhibiting the production and release of pain-causing inflammatory substances and balancing neurotransmitters, with an analgesic effect approximately 1 / 100th that of opium. It also relieves muscle tension and spasms. This is achieved by Corydalis rotundifolia's suppression of muscle-controlling nerve excitation and adjustment of neurotransmitter balance. Additionally, the present invention improves the bioavailability of glycyrrhizic acids.

[0018] The form of Corydalis rotundifolia in the present invention can be adjusted as needed. The whole herb may be cut or crushed into small pieces or chunks, or pulverized into powder (Corydalis rotundifolia powder). Alternatively, Corydalis rotundifolia may be cut to an appropriate size, added with an appropriate extraction solvent, and the resulting infusion solution may be concentrated and dried (dried extract, etc.). The method for producing the herbal extract is not particularly limited, and it can be produced by referring to known methods for producing plant extracts, such as those described in the "Extracts" section of the General Provisions for Preparations of the Japanese Pharmacopoeia, 18th Edition. Specifically, Corydalis rotundifolia is cut, heated, crushed, etc., as needed, and then extracted with an appropriate extraction solvent. Examples of the extraction solvent include 30-60% v / v ethanol (aqueous solution). The resulting extract may be further concentrated, dried, etc., as needed. Among these, Corydalis rotundifolia powder is preferred because it provides a more effective improvement in the bioavailability of glycyrrhizic acids. Commercially available Corydalis powder includes "Japanese Pharmacopoeia Corydalis Powder" (manufactured by Nippon Powder Pharmaceuticals Co., Ltd.) and "Corydalis Powder (sterilized)" (manufactured by Nippon Powder Pharmaceuticals Co., Ltd.).

[0019] When Corydalis rotundifolia powder is used as component (D), the amount thereof is preferably 1 to 60% by mass, more preferably 2 to 55% by mass, of the pharmaceutical composition as Corydalis rotundifolia powder. The amount of Corydalis rotundifolia powder in the daily dose of the pharmaceutical composition is preferably 50 to 1500 mg, more preferably 300 to 700 mg. By adjusting the amount to above the lower limit, the efficacy of component (D) is exhibited and the bioavailability of the glycyrrhizic acids of the present invention is further improved. By adjusting the amount to below the upper limit, the bitterness characteristic of Corydalis rotundifolia can be reduced, tablet size can be reduced, and tablets with excellent swallowability can be obtained.

[0020] When Corydalis rotundifolia dried extract is used as component (D), the amount thereof is preferably 0.5 to 40% by mass, more preferably 3 to 15% by mass, of the pharmaceutical composition as Corydalis rotundifolia dried extract. The amount of Corydalis rotundifolia dried extract in a daily dose of the pharmaceutical composition is preferably 16 to 166 mg, more preferably 33 to 78 mg. By adjusting the amount to above the lower limit, the efficacy of component (D) is demonstrated and the bioavailability of the glycyrrhizic acids of the present invention is further improved. By adjusting the amount to below the upper limit, the bitterness characteristic of Corydalis rotundifolia can be reduced, and the tablet size can be reduced, resulting in a tablet with excellent swallowability.

[0021] The mass ratio of the contents represented by ((C) + (D)) × (A) / (B) is preferably 0.3 or more, more preferably 1 to 33, even more preferably 1.5 to 24, and even more preferably 3 to 20. This is due to the discovery that the effect of improving the bioavailability of component (A) is correlated with the value obtained by multiplying the sum of the amounts of components (C) and (D) by the ratio of the amount of component (A) to the amount of component (B). By setting the content at or above the lower limit, the bioavailability of glycyrrhizinic acids is further improved. By setting the content at or below the upper limit, both the effect of improving the bioavailability of glycyrrhizinic acids and the antacid power required for the manifestation of the effects of a gastrointestinal drug can be achieved. Furthermore, the bitterness specific to component (D) is further reduced and the dosage can be further reduced, resulting in a pharmaceutical composition with excellent administrability in any dosage form, such as tablets, granules, or powder. In the above formula, Corydalis powder refers to the amount of Corydalis powder, and Corydalis dry extract refers to the amount of Corydalis dry extract.

[0022] [Other ingredients] The composition of the present invention can contain optional ingredients as appropriate, provided that the effects of the present invention are not impaired. Optional ingredients include other active ingredients (other than the ingredients (A) to (D)), organic acids, excipients, binders, disintegrants, sweeteners, lubricants, fluidizing agents, preservatives, flavorings, flavoring agents, and colorings. These can be used singly or in combination of two or more, and can be contained in appropriate amounts.

[0023] Other active ingredients include, for example, mucosal repair ingredients such as aldioxa, copper chlorophyllin sodium, methylmethionine sulfonium chloride, teprenone, sulpiride, plaunotol, gefarnate, cetraxate hydrochloride, and L-glutamine; gastric acid secretion inhibitors such as ranitidine or ranitidine hydrochloride, famotidine, cimetidine, roxatidine acetate hydrochloride, nizatidine, lafutidine, lansoprazole, rabeprazole, omeprazole, and vonoprazan; digestive agents such as ursodeoxycholic acid; and rotoex. In addition to muscarinic receptor antagonists such as sucralose, atropine, and scopolamine, stomachic herbal ingredients such as magnolia bark fluid extract, atractylodes rhizome fluid extract, turmeric fluid extract, ginseng fluid extract, coptis tincture, clove tincture, gentian tincture, cinnamon tincture, dried atractylodes rhizome extract, dried magnolia bark extract, dried tangerine peel extract, fennel powder, turmeric powder, pheasant's eye powder, cinnamon powder, ginger powder, atractylodes rhizome powder, tangerine peel powder, Atractylodes rhizome powder, and rhubarb powder, as well as digestive enzymes such as lipase, biodiastase, and diasmen may be included. Among these other active ingredients, it is preferable to include a mucosal repair component, as it can directly address the repair of mucosal damage, which causes various unpleasant symptoms such as pain, heaviness, and burning sensation. The amount of these other active ingredients in the pharmaceutical composition can be selected to ensure the effective amount of each active ingredient. Components (A) to (D) and other active ingredients can also be used in combination with an organic acid. In particular, the combined use of component (C) and an organic acid can enhance the adhesion of component (C) to ulcerated mucosal areas even in non-acidic environments (e.g., esophageal mucosa, oral mucosa, duodenal, small intestinal, and large intestinal mucosa). The organic acid is not particularly limited, and one type may be used alone, or two or more types may be used in appropriate combination. Among these, from the standpoints of flavor and dispersion stability, one or more types selected from alginic acid, citric acid, malic acid, ascorbic acid, glucuronic acid, aspartic acid, glutamic acid, adipic acid, gluconic acid, tartaric acid, succinic acid, lactic acid, acetic acid, butyric acid, maleic acid, and fumaric acid are preferred, with citric acid, malic acid, and lactic acid being particularly preferred.

[0024] Examples of the excipient include sugar alcohols such as mannitol, erythritol, xylitol, sorbitol, palatinit, lactitol, etc., saccharides such as monosaccharides, oligosaccharides such as lactose, polysaccharides, corn starch, crystalline cellulose, potato starch, sodium bicarbonate, calcium carbonate, sucrose, carboxymethyl cellulose, etc. The amount of an excipient, when included, can be determined appropriately taking into consideration the dosage form of the pharmaceutical preparation, but is preferably 2 to 20% by mass, more preferably 5 to 10% by mass, of the pharmaceutical composition, for example.

[0025] Examples of binders include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, hydroxyethylcellulose, gum arabic, pregelatinized starch, carboxyvinyl polymer, agar, honey, etc. When a binder is contained, the amount thereof is preferably 0.01 to 30% by mass, more preferably 0.1 to 10% by mass, of the pharmaceutical composition.

[0026] Examples of disintegrants include crospovidone, croscarmellose sodium, carmellose, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, etc. When a disintegrant is contained, the amount thereof is preferably 0.1 to 30% by mass, more preferably 0.2 to 20% by mass, of the pharmaceutical composition.

[0027] Examples of sweeteners include sucrose, fructose, aspartame, sucralose, thaumatin, acesulfame potassium, sorbitol, stevia, refined white sugar, saccharin, and glycyrrhizin.

[0028] Examples of lubricants include magnesium stearate, calcium stearate, sodium stearyl fumarate, sucrose fatty acid esters, light anhydrous silicic acid, hydrous silicon dioxide, talc, hydrogenated oil, etc. When a lubricant is contained, the amount thereof is preferably 0.01 to 5% by mass, more preferably 0.05 to 2% by mass, of the pharmaceutical composition.

[0029] The fluidizing agent may include hydrous silicon dioxide. Examples of preservatives include parabens such as alkylparabens, benzoic acid, and sodium benzoate. Examples of the flavoring agent include known essential oils, such as limonene, orange flavor, lychee flavor, lemon flavor, lime flavor, strawberry flavor, pineapple flavor, mint flavor, and grapefruit flavor. Flavoring agents include menthol and the like. Examples of pigments include caramel, carmine, carotene liquid, β-carotene, copper chlorophyll, and copper chlorophyllin sodium.

[0030] <Moisture content> The water content of the pharmaceutical composition is preferably 15% by mass or less, more preferably 13% by mass or less, based on the total mass of the pharmaceutical composition. A water content below the upper limit mentioned above can maintain the stability of other co-administered ingredients and, when the pharmaceutical composition is in tablet form, reduce tableting problems. While a lower water content of the pharmaceutical composition is preferable, taking into account the water carried over from each ingredient, the water content of the pharmaceutical composition is, for example, 0.1% by mass or more, preferably 0.5% by mass or more, based on the total mass of the pharmaceutical composition. The water content of the pharmaceutical composition can be calculated from the loss on drying when the pharmaceutical composition is heated at 120°C for 10 minutes using an electronic moisture meter (e.g., Shimadzu MOISTURE BALANCE MOC-120H). When the pharmaceutical composition is in the form of a tablet, the tablet is crushed and the water content is measured.

[0031] The pharmaceutical composition of the present invention can be used in the form of tablets (including orally disintegrating tablets, chewable tablets, and effervescent tablets), granules, fine granules, capsules, powders, powders, lozenges, pills, liquids, emulsions, suspensions, jellies, and the like. Among these, tablets (including orally disintegrating tablets, chewable tablets, and effervescent tablets), granules, fine granules, capsules, powders, powders, lozenges, and pills are preferred. Formulation into these dosage forms can be carried out by adding suitable pharmaceutically acceptable liquid or solid carriers, excipients, dispersants, fillers, extenders, solvents, emulsifiers, additives, lubricants, flow agents, preservatives, flavorings, humectants, flavor correctors, dyes, buffer substances, and other auxiliary agents.

[0032] Solid dosage forms such as tablets, granules, fine granules, capsules, powders, powders, and lozenges can be prepared by conventional methods using excipients such as sodium bicarbonate, calcium carbonate, starch, sucrose, mannitol, and carboxymethylcellulose, binders such as hydroxypropyl methylcellulose and polyvinylpyrrolidone, disintegrants such as croscarmellose sodium, carmellose calcium, and low-substituted hydroxypropylcellulose, and lubricants such as calcium stearate and magnesium stearate. These formulations are suitable for oral administration and can effectively reach the stomach and duodenum. They can also be formulated as enteric-coated preparations that disintegrate and dissolve in the small intestine by applying an enteric coating such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol phthalate, styrene-maleic anhydride copolymer, or methacrylic acid-methyl methacrylate copolymer. The organic acids, excipients, binders, disintegrants, sweeteners, lubricants, preservatives, flavors, flavoring agents, and coloring agents may be the same as those listed as optional ingredients.

[0033] The pharmaceutical composition of the present invention may consist solely of the pharmaceutical composition of the present invention, or may be a combination of the pharmaceutical composition of the present invention with other components (carriers, coatings, etc.). Examples of carriers include containers (capsules, etc.) that contain the pharmaceutical composition, and substrates (adhesive substrates, etc.) that support a layer of the pharmaceutical composition on their surface.

[0034] The pharmaceutical composition of the present invention can be administered orally, and the dosage can be appropriately selected depending on the dosage form, the sex, body type, constitution, age, etc. of the patient. Generally, the dosage is 1 to 4 times a day, preferably 0.1 to 200 mg / kg, more preferably 0.5 to 100 mg / kg per dose.

[0035] [Manufacturing method] The pharmaceutical composition of the present invention can be obtained by mixing component (A), component (B), component (C), and component (D), and, if necessary, optional components. Each component may be used as is or after granulation. Granulation may be performed individually, or two or more components may be granulated together. For example, one or more of component (A), component (B), component (C), and optional components may be used alone or mixed together, and then processed, for example, by adding appropriate excipients, binders, etc., and granulating. The resulting mixture may then be mixed in powder form and formed into a formulation, either as powder or into capsules, tablets, etc.

[0036] The granulation method is not particularly limited as long as it is a known granulation method such as fluidized bed granulation, tumbling granulation, or kneading granulation. For example, a spray-dried slurry of the components to be granulated and a binder such as polyethylene glycol can be used. Commercially available granules of component (C) can be used, such as "Stomaccin," a product name manufactured by Fuji Chemical Industry Co., Ltd.

[0037] The pharmaceutical composition thus obtained is housed in a package. Examples of the package include bottles (plastic bottles, glass bottles, etc.), stick packaging, SP packaging, three-sided seal packaging, aluminum pouches, and zipper bags. When the pharmaceutical composition is, for example, a tablet, capsule, lozenge, pill, or chewable tablet, a PTP (press-through pack) may be used as the package. The pharmaceutical composition housed in the PTP may further be housed in an aluminum gusset bag.

[0038] The material forming the container is not particularly limited, and examples thereof include paper, glass, resin or resin film, metal or metal film, etc., and may also be a composite structure or multi-layer structure in which these materials are appropriately combined. Furthermore, it is preferable that moisture-permeable materials such as paper are subjected to moisture-proofing treatment.

[0039] The pharmaceutical composition of the present invention, which is a combination of components (A) and (B), further includes components (C) and (D), thereby preventing component (A) from being trapped by component (B), thereby effectively preventing a decrease in the bioavailability of glycyrrhizic acids in the pharmaceutical composition. This effect is suppressed even when component (A) is derived from a herbal medicine, and is particularly effective when licorice powder is used. Furthermore, the composition contains component (A), which has anti-inflammatory activity; component (B), which has antacid activity; component (C), which protects the gastric mucosa and suppresses inflammation; and component (D), which has an analgesic activity, resulting in a gastrointestinal drug that is effective against stomach pain and various gastric discomforts. The effects and efficacy of the pharmaceutical composition of the present invention include stomach pain, fullness (heavy stomach feeling), heaviness in the stomach, feeling of fullness in the stomach, stomach discomfort, indigestion, feeling of fullness in the stomach and abdomen due to indigestion, digestion promotion, loss of appetite (loss of appetite), overeating (overeating), overdrinking (overdrinking), nausea (queasiness, hangover / over-intoxication queasiness, stomach queasiness, retching, nausea), chest tightness, vomiting, heartburn, excessive stomach acid, and belching.

[0040] [Method for improving the bioavailability of glycyrrhizic acids] The method for improving the bioavailability of glycyrrhizinic acids of the present invention comprises: (A) one or more selected from glycyrrhizinic acid and pharmaceutically acceptable salts thereof, and (B) antacids, A pharmaceutical composition comprising (C) sucralfate hydrate, and (D) Corydalis This is a method for improving the bioavailability of the above-mentioned component (A), which comprises incorporating: In this improvement method, the types and amounts of component (A), component (B), component (C), and component (D) contained in the pharmaceutical composition, the types and amounts of components (optional components) that can be blended in addition to component (A), component (B), component (C), and component (D), and the dosage form of the pharmaceutical composition are the same as those in the pharmaceutical composition of the present invention described above. [Example]

[0041] The present invention will be described in detail below with reference to examples and comparative examples, but the present invention is not limited to the following examples. In the following examples, unless otherwise specified, "%" in the composition indicates % by mass, and the ratio indicates the mass ratio.

[0042] [Examples and Comparative Examples] According to the formulation shown in the table below, components (A), (B), (C), (D), and optional components were mixed to prepare pharmaceutical compositions (powder compositions). The dissolution of glycyrrhizinic acid in the resulting pharmaceutical compositions was evaluated as follows, and the bioavailability improvement rate was determined. The results are also shown in the table.

[0043] [Improvement rate of glycyrrhizinic acid bioavailability] The test was conducted in a manner that simulated the actual administration. Specifically, each ingredient was weighed out in the proportions shown in the table below, mixed by hand, and then the entire amount was weighed out and suspended in a mixture of 50 mL of 0.1 mol / hydrochloric acid and 150 mL of purified water. After stirring at 300 rpm for 30 minutes, the pharmaceutical composition was neutralized with 0.1 mol / L sodium hydroxide solution and analyzed using high-performance liquid chromatography under the following measurement conditions. <Measurement conditions> Measurement equipment: Shimadzu Corporation, product name "Integrated HPLC Prominence-i" Separation column: Shimadzu GLC, product name "InertSustain C18 (5.0 μm, 250 mm x 4.6 mm)" Mobile phase: Dissolve 3.85 g of ammonium acetate in 720 mL of water, add 5 mL of acetic acid (100) and 280 mL of acetonitrile. Mobile phase flow rate: 1.0 mL / min Sample injection volume: 10 μL ·Measurement temperature: 40℃ <evaluation> The amount of glycyrrhizinic acid in licorice powder (dried extract) alone was defined as the "index content," and the amount of glycyrrhizinic acid dissolved and quantified under the above conditions was defined as the "amount of glycyrrhizinic acid dissolved from the pharmaceutical composition," and the "content relative to the index" was calculated using the following formula (1). A higher content relative to the index indicates better bioavailability of glycyrrhizinic acid. Index content (%) = (amount of glycyrrhizinic acid dissolved from the pharmaceutical composition / index content) × 100 (1) (Calculation of bioavailability improvement rate) The bioavailability improvement rate was calculated using the following formula (2). Bioavailability improvement rate (%) = ((index content of example - index content of corresponding comparative example) / index content of corresponding comparative example) × 100 (2) [Comparative Example 1 corresponds to Examples 1 and 2] [Comparative Example 5 corresponds to Examples 3 and 4] [Comparative Example 6 corresponds to Examples 5 and 6] [Comparative Example 7 corresponds to Example 7] [Comparative Example 8 corresponds to Example 8] [Comparative Example 11 corresponds to Example 9] [Comparative Example 14 corresponds to Examples 10, 11, 15, and 16] [Comparative Example 18 corresponds to Example 12] [Comparative Example 19 corresponds to Example 13] [Comparative Example 20 corresponds to Example 14]

[0044] [Table 1]

[0045] As is clear from the above results obtained by a method simulating the time of ingestion, when a pharmaceutical composition containing glycyrrhizinic acids and an antacid such as synthetic hydrotalcite is ingested, the glycyrrhizinic acids are released into gastric juice, but the glycyrrhizinic acid is trapped in the antacid, reducing its bioavailability; however, this reduction was suppressed in the present invention.

[0046] [Table 2]

[0047] [Table 3]

[0048] [Table 4]

[0049] [Table 5]

[0050] [Table 6]

[0051] [Table 7]

[0052] [Table 8]

[0053] [Table 9]

[0054] [Table 10]

[0055] [Prescription example] Pharmaceutical compositions (gastrointestinal drugs, amounts per dose [mg]) shown in the table below were obtained.

[0056] [Table 11]

[0057] [Table 12]

[0058] [Table 13]

[0059] [Table 14]

[0060] [Table 15]

[0061] [Table 16]

[0062] [Table 17]

[0063] The raw materials used in the above example are listed below. Unless otherwise specified, the amount of each ingredient in the table is the pure equivalent. The terms "JP," "Extra-Pharmacopoeia Standards," and "Pharmaceutical Additive Standards" below refer to raw materials that comply with the 18th Revised Japanese Pharmacopoeia Standards, the Japanese Pharmacopoeia Standards for Pharmaceuticals and Medical Supplies, and the Pharmaceutical Additive Standards (2018), respectively. "Raw materials used" Licorice powder: Manufactured by Nippon Funa Yakuhin Co., Ltd., trade name "Licorice Powder" (Licorice powder is powdered licorice). 1g of "Japanese Pharmacopoeia" licorice powder contains 24mg of glycyrrhizinic acid. Licorice Dried Extract: Manufactured by Nippon Funa Yakuhin Co., Ltd., product name "Licorice Extract Powder-A" (Licorice dried extract is made by extracting liquorice with water, then concentrating and drying it. The amount equivalent to the crude drug is 1 / 7 of the amount of "Japanese Pharmacopoeia Licorice") "Attached Specifications" 1g of licorice dried extract contains 105mg of glycyrrhizinic acid. Magnesium hydroxide: Kyowa Chemical Industry Co., Ltd., product name "Kyowa Sui Mag", antacid capacity: 340 mL. Magnesium aluminosilicate: Fuji Chemical Industry Co., Ltd., product name "Neusilin A AS", antacid capacity: 250 mL. "Japanese Pharmacopoeia" Magnesium aluminometasilicate: Fuji Chemical Industry Co., Ltd., product name "Neusilin", antacid capacity: 230 mL. "Japanese Pharmacopoeia" Synthetic hydrotalcite: Kyowa Chemical Industry Co., Ltd., product name "Alkamac SN", antacid capacity: 270 mL. Precipitated calcium carbonate: Bihoku Funka Kogyo Co., Ltd., product name "Precipitated calcium carbonate", antacid capacity: 200 mL. "Japanese Pharmacopoeia" Sodium bicarbonate: AGC Corporation, trade name "Sodium Bicarbonate KP", antacid capacity: 121 mL. "JP" Sucralfate hydrate: Manufactured by Fuji Chemical Industry Co., Ltd., trade name "Sucralfate hydrate." "Japanese Pharmacopoeia" Corydalis root powder: Manufactured by Nippon Powder Pharmaceutical Co., Ltd., product name: "Japanese Pharmacopoeia Corydalis root powder" (Corydalis root powder is powdered "Corydalis root"). "JP" Corydalis rotundifolia dried extract: Manufactured by Nippon Funa Pharmaceutical Co., Ltd., product name "Corydalis rotundifolia dried extract" (Corydalis rotundifolia dried extract is extracted from Corydalis rotundifolia with 30% v / v ethanol solution, then concentrated and dried. The amount of crude drug equivalent is 1 / 9 of the amount of Corydalis rotundifolia in the Japanese Pharmacopoeia). "Appendix Specifications" Fennel powder: Manufactured by Nippon Powder Pharmaceuticals Co., Ltd., product name "Japanese Pharmacopoeia Fennel Powder" (Fennel powder is powdered fennel.) "JP" Cinnamon bark powder: Manufactured by Nippon Powder Pharmaceuticals Co., Ltd., product name "Japanese Pharmacopoeia Cinnamon Bark Powder" (Cinnamon bark powder is powdered cinnamon bark). Soujutsu powder: Manufactured by Nippon Powder Pharmaceutical Co., Ltd., product name "Japanese Pharmacopoeia Soujutsu Powder" (Soujutsu powder is powdered "Soujutsu") "Japanese Pharmacopoeia" Soujutsu dried extract: Manufactured by Nippon Funa Pharmaceutical Co., Ltd., product name "Soujutsu dried extract-S" (Soujutsu dried extract is extracted with water, then concentrated and dried. The amount of raw herbal medicine equivalent is 1 / 10 of the amount of "Soujutsu" as prescribed by the Japanese Pharmacopoeia). "Appendix Specifications" Chinpi Powder: Manufactured by Nippon Powder Pharmaceutical Co., Ltd., product name "Japanese Pharmacopoeia Chinpi Powder" (Chinpi powder is powdered "Chinpi") "Japan Pharmacopoeia" Dried tangerine extract: Manufactured by Alps Pharmaceuticals Co., Ltd., product name "Dried tangerine extract" (Dried tangerine extract is extracted with water, then concentrated and dried. The amount of raw herbal medicine equivalent is 1 / 5 of the amount of "tangerine") "Attached specifications" Ryokyo Powder: Manufactured by Nippon Powder Pharmaceuticals Co., Ltd., product name "Japanese Pharmacopoeia Ryokyo Powder" (Ryokyo powder is powdered "Ryokyo") "Attached Specifications" Magnolia bark powder: Manufactured by Nippon Powder Pharmaceuticals Co., Ltd., product name "Japanese Pharmacopoeia Magnolia Bark Powder" (Magnolia bark powder is powdered Magnolia bark.) "JP" Magnolia bark dried extract: Manufactured by Nippon Funa Pharmaceutical Co., Ltd., product name "Magnolia bark dried extract" (Magnolia bark dried extract is extracted with water, then concentrated and dried. The amount of raw herbal medicine equivalent is 1 / 12 of the amount of "Magnolia bark" as prescribed by the Japanese Pharmacopoeia). "Appendix Specifications" Ginger powder: Manufactured by Nippon Powder Pharmaceuticals Co., Ltd., product name "Japanese Pharmacopoeia Ginger Powder" (Ginger powder is powdered ginger root). Turmeric powder: Manufactured by Nippon Powder Pharmaceuticals Co., Ltd., product name "Japanese Pharmacopoeia Turmeric Powder" (Turmeric powder is powdered turmeric.) "JP" Turmeric dry extract: Matsuura Pharmaceutical Co., Ltd., product name "Turmeric dry extract" (Turmeric dry extract is extracted with water, then concentrated and dried. The amount of raw herbal medicine equivalent is 1 / 10 of the amount of "Japanese Pharmacopoeia Turmeric") "Attached Specifications" Byakushu Root Powder: Manufactured by Nippon Powder Pharmaceuticals Co., Ltd., product name "Japanese Pharmacopoeia Byakushu Root Powder" (Byakushu Root powder is powdered "Byakushu Root") "Japanese Pharmacopoeia" Byaku Atractylodes Rhizome Dried Extract: Manufactured by Alps Pharmaceutical Co., Ltd., product name "Byaku Atractylodes Rhizome Dried Extract" (Byaku Atractylodes Rhizome Dried Extract is extracted with water, then concentrated and dried. The amount of raw herbal medicine equivalent is 1 / 5 of the amount of "Japanese Pharmacopoeia Byaku Atractylodes Rhizome") "Attached Specifications" Pheasant's Root Powder: Manufactured by Nippon Powder Pharmaceuticals Co., Ltd., product name "Japanese Pharmacopoeia Pheasant's Root Powder" (Peasant's Root Powder is powdered 'Peasant'). Clove powder: Manufactured by Nippon Powder Pharmaceuticals Co., Ltd., product name "Japanese Pharmacopoeia Clove Powder" (Clove powder is powdered clove). Gentian powder: Manufactured by Nippon Powder Pharmaceutical Co., Ltd., product name "Japanese Pharmacopoeia Gentian Powder" (Gentian powder is powdered gentian). Shukusha Powder: Manufactured by Nippon Powder Pharmaceuticals Co., Ltd., product name "Japanese Pharmacopoeia Shukusha Powder" (Shukusha Powder is powdered "Shukusha") "JP" Perilla Root Powder: Manufactured by Nippon Powder Pharmaceuticals Co., Ltd., product name "Japanese Pharmacopoeia Perilla Root Powder" (Perilla Root Powder is powdered "Perilla Root") "Attached Specifications" Borax powder: Manufactured by Nippon Funa Yakuhin Co., Ltd., product name "Japanese Pharmacopoeia Borax Powder" (borax powder is powdered borax). "JP" Peppermint oil: Manufactured by Takasago International Corporation, trade name "Peppermint Oil." "Japanese Pharmacopoeia" Ursodeoxycholic acid: Zhongshan Belling Biotechnology Co., trade name "ursodeoxycholic acid". "Japanese Pharmacopoeia" Lipase AP12: Manufactured by Amano Enzyme Co., Ltd., product name "Lipase AP12". "Appendix Specifications" Lipase AP6: Manufactured by Amano Enzyme Co., Ltd., product name "Lipase AP6". "Appendix Specifications" Biodiastase 2000: Manufactured by Amano Enzyme Co., Ltd., trade name "Lipase AP6." "Appendix Specifications" Diasmen SS: Manufactured by Amano Enzyme Co., Ltd., product name "Diasmen SS". "Attached specifications" Crystalline cellulose: manufactured by Asahi Kasei Corporation, product name "Ceolas" TM PH-101”. "Japanese station" Carmellose: Manufactured by Nichirin Chemical Industry Co., Ltd., trade name "Carmellose NS-300". "Japanese Pharmacopoeia" Sodium carboxymethyl starch: Manufactured by DMV Fondela Exipients, trade name "PRIMOJEL". "Japanese Pharmacopoeia" Hardened oil: Freund Corporation, trade name "Lubriwax-101". "Japanese Pharmacopoeia" Calcium stearate: Taihei Chemical Industry Co., Ltd., product name "Calcium stearate (vegetable-based)." "Japanese Pharmacopoeia" Hydroxypropyl cellulose: Manufactured by Nippon Soda Co., Ltd., trade name "Nisso HPC Brand L". "Japanese Pharmacopoeia" D-mannitol: Mitsubishi Corporation Life Sciences Co., Ltd., trade name "Mannit P." "JP" Aspartame: Ajinomoto Co., Inc., product name "Aspartame." "Pharmaceutical Additives Regulations" Hydrous silicon dioxide: DSL Japan Co., Ltd., product name "Carplex #80". l-Menthol: Manufactured by Takasago International Corporation, trade name "Menthol JP". "Japanese Pharmacopoeia"

Claims

1. (A) one or more selected from glycyrrhizinic acid and pharmaceutically acceptable salts thereof; (B) antacids, (C) sucralfate hydrate, and (D) Corydalis A pharmaceutical composition comprising:

2. 2. The pharmaceutical composition according to claim 1, wherein the antacid (B) is at least one selected from the group consisting of magnesium hydroxide, magnesium aluminosilicate, magnesium aluminometasilicate, synthetic hydrotalcite, and precipitated calcium carbonate.

3. 2. The pharmaceutical composition according to claim 1, wherein the component (A) is derived from licorice.

4. 4. The pharmaceutical composition according to claim 3, wherein the component (A) is derived from licorice powder or licorice extract.

5. 2. The pharmaceutical composition according to claim 1, wherein component (D) is Corydalis rotundifolia powder or Corydalis rotundifolia extract.

6. 2. The pharmaceutical composition according to claim 1, wherein the mass ratio of the components contained represented by ((C) + (D)) × (A) / (B) is 0.3 or more.

7. 7. The pharmaceutical composition according to any one of claims 1 to 6, which is in a dosage form selected from tablets, granules, fine granules, capsules, powders, powders, lozenges and pills.

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