Pharmaceutical preparations

Abstract

Even in formulations that exclude sodium-based antacids and belladonna extract, stability is improved. The objective is to provide improved pharmaceutical formulations. [Solution] (A) Select from the group consisting of calcium-based antacids and magnesium-based antacids (B) a digestive enzyme, comprising at least one selected antacid, and a sodium-based The present invention provides a pharmaceutical formulation that substantially does not contain an acid agent or belladonna extract.

Description

Technical Field

[0001] The present invention relates to pharmaceutical preparations. More specifically, it relates to pharmaceutical preparations in which the effects on blood pressure, the kidneys, and anticholinergic action are suppressed.

Background Art

[0002] Conventional gastrointestinal drugs often contain sodium-based antacids such as sodium bicarbonate (sodium hydrogen carbonate) with rapid efficacy for the purpose of treating gastrointestinal symptoms, and many contain Rauwolfia extracts that suppress spasms and gastric acid secretion. For example, Patent Document 1 discloses an antacid composition containing magnesium-based antacids, sodium-based antacids, and calcium-based antacids and not containing aluminum. ( However, there are also components that are not suitable for application to the elderly, those with reduced physical strength (physiological functions), and those with underlying diseases, and there are situations where the needs of the elderly and others cannot be met. For example, sodium-based antacids such as sodium bicarbonate (sodium hydrogen carbonate) raise blood pressure in the same way as when salt is ingested, so they must be used carefully in those with hypertension, heart disease, kidney disease, etc.

[0003] In addition, Rauwolfia extracts can suppress acetylcholine and weaken the stimulation of the parasympathetic nerve (anticholinergic action), thereby suppressing abdominal pain caused by spasms of the visceral smooth muscle. On the other hand, the action on this nerve also acts on organs other than the gastrointestinal tract, so it is known to affect those with heart diseases such as arrhythmia, and to promote urinary disorders in those with prostatic hypertrophy. Also, it is known that in lactating women, Rauwolfia extracts migrate into breast milk and affect the pulse of the infant.

[0004] ​​​​​​​​​​​​ [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 2004 / 082692 [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] The inventors of this application removed sodium-based antacids and belladonna extract from the prescription of a gastrointestinal medicine. When we attempted to formulate it using this prescription, we found that both of these components not only have a stomach-strengthening effect but also contribute to the formulation. It was found that these ingredients also contribute to stability, and formulations excluding both of these ingredients resulted in impaired formulation stability. A new finding was discovered.

[0007] Specifically, in gastrointestinal medicines excluding sodium-based antacids and belladonna extract, at least Furthermore, the stability of the formulation may be impaired in terms of adhesion, hygroscopicity, or turbidity in aqueous media. It was newly discovered.

[0008] To address these new challenges, the stability of gastrointestinal drugs is being improved by using other antacids or stomachic ingredients. Improvements are needed.

[0009] Therefore, the present invention also applies to formulations that exclude sodium-based antacids and belladonna extract. The objective is to provide pharmaceutical formulations with improved formulation stability. [Means for solving the problem]

[0010] In order to solve the above problems, the present inventors have diligently studied and found a sodium-based antacid, and Furthermore, even in formulations that exclude belladonna extract, (A) calcium-based antacids and magnesium At least one antacid selected from the group consisting of aluminum-based antacids, and (B) digestive enzymes By coexisting, it was found that the stability of gastrointestinal drugs can be improved, and the present invention has been completed and led to this.

[0011] That is, the present invention provides the pharmaceutical preparations listed below. [1] (A) At least one antacid selected from the group consisting of calcium-based antacids and magnesium-based antacids, and and (B) digestive enzymes, containing A pharmaceutical preparation substantially free of sodium-based antacids and licorice extract. [2] The pharmaceutical preparation according to [1], wherein the (A) antacid is 30% by mass or more based on the total amount of the preparation. Pharmaceutical preparation. [3] The calcium-based antacid is at least one selected from the group consisting of calcium carbonate, precipitated calcium carbonate, calcium hydroxide , anhydrous calcium hydrogen phosphate, and calcium hydrogen phosphate, and the pharmaceutical preparation according to [1] or [2]. [4] The magnesium-based antacid is at least one selected from the group consisting of magnesium oxide, magnesium hydroxide, magnesium carbonate um, and magnesium silicate, and the pharmaceutical preparation according to any one of [1 to [3]. [5] The (B) digestive enzyme is at least one selected from the group consisting of amylase, lipase, protease, galactosidase, and cellulase, and the pharmaceutical preparation according to any one of [1] to [4]. [6] Furthermore, the pharmaceutical preparation according to any one of [1] to [5], which contains a cooling agent. [7] ​​The cooling agent is selected from the group consisting of menthol, camphor, and borneol. A pharmaceutical preparation as described in [6], which is at least one of the following: [8] Furthermore, it is described in any of [1] to [7] as not substantially containing aluminum-based antacids. A pharmaceutical preparation. [9] A gastrointestinal medicine, a pharmaceutical preparation as described in any of [1] to [8].

[10] A pharmaceutical preparation intended for the elderly, as described in any of [1] to [9].

[11] A pharmaceutical preparation according to any one of [1] to

[0010] , for improving the absorption of the aforementioned (A) antacid and / or for suppressing the decrease in potency.

[12] [9] Or a pharmaceutical preparation as described in either

[10] . [Effects of the Invention]

[0012] According to the present invention, even in formulations that exclude sodium-based antacids and belladonna extract, This makes it possible to provide gastrointestinal medications with improved stability. [Modes for carrying out the invention]

[0013] [Pharmaceutical preparations] The pharmaceutical formulation of the present invention is formulated in a manner that excludes sodium-based antacids and belladonna extract. It has been modified. As mentioned above, sodium-based antacids have the same effect as when salt is ingested. It has the effect of raising blood pressure, and belladonna extract has an anticholinergic effect, which is beneficial for the elderly and the body Caution is required when applying this treatment to individuals with weakened physical function or underlying medical conditions.

[0014] By removing sodium-based antacids and belladonna extract, the above-mentioned application to the elderly, etc. Although this has become possible, at least in terms of adhesion, hygroscopicity, or turbidity in aqueous media It was found that the formulation stability was impaired. When the stability related to adhesion is impaired, the manufacturing During the formulation process, ingredients may adhere to equipment, leading to a decrease in the quality of the formulation. Furthermore, moisture absorption can also occur. If the stability of the formulation is compromised, the water content in the formulation will increase, affecting the active ingredients and other components. This can lead to deterioration of the material, etc. Also, if the stability of turbidity in an aqueous medium is impaired, the dispersibility This decline can lead to reduced absorption of the active ingredients, among other things.

[0015] The pharmaceutical formulation of the present invention comprises (A) a calcium-based antacid and a magnesium-based antacid. (B) a digestive enzyme is provided in the presence of at least one antacid selected from the group. This improves the stability of the formulation.

[0016] [(A) Antacids] (Calcium-based antacids) The calcium-based antacid is not limited as long as it achieves the effects of the present invention, for example, calcium It consists of oxides, hydroxides, carbonates, phosphates, silicates, and composites thereof. It can be at least one selected from the group. Also, calcium-based antacids are From the viewpoint of significantly demonstrating the effects of the invention, calcium carbonate, precipitated calcium carbonate, calcium hydroxide Selected from the group consisting of calcium, anhydrous calcium hydrogen phosphate, and calcium hydrogen phosphate. Preferably, it is at least one of the following: calcium carbonate and precipitated calcium carbonate. It is more preferable that it be at least one selected from the group consisting of the following:

[0017] As a calcium-based antacid, it is also possible to use herbal ingredients containing the above components. Such herbal ingredients include oyster shell powder containing precipitated calcium carbonate. Examples include derived components.

[0018] (Magnesium-based antacids) The magnesium-based antacid is not limited as long as it achieves the effects of the present invention; for example, magnesium From nesium oxides, hydroxides, carbonates, phosphates, silicates, and composites thereof It can be at least one selected from the group. Also, magnesium-based antacids From the viewpoint of significantly achieving the effects of the present invention, magnesium oxide, magnesium hydroxide, and carbon At least one selected from the group consisting of magnesium oxide and magnesium silicate. Preferably, it is selected from the group consisting of magnesium hydroxide and magnesium carbonate. It is more preferable that there be at least one such type.

[0019] (A) The amount of antacid is not limited as long as it achieves the effects of the present invention, but the total amount of the formulation In contrast, for example, it is preferable to have 10% by mass or more, 20% by mass or more, and 30% by mass or more. The above can be 40% by mass or more, or 45% by mass or more. (A) The amount of antacid is not limited as long as it achieves the effects of the present invention, but the total amount of the formulation In contrast, for example, it is preferable that it be 98% by mass or less, 95% by mass or less, and 93% by mass or less. Lower, 90% by mass or less, 85% by mass or less, 80% by mass or less, 75% by mass or less, 70% by mass or less It can be set below. (A) The amount of antacid is not limited as long as it achieves the effects of the present invention, but the total amount of the formulation In contrast, for example, it is preferable to have 10-95% by mass, 20-90% by mass, and 30-8% by mass. It can be 0 mass%, 40-80 mass%, or 40-70 mass%. Of these, magnesium The amount of sodium-based antacid is not limited as long as the effects of the present invention are achieved, but the total amount of the formulation should be In contrast, consider, for example, 10% to 80% by mass, 15% to 75% by mass, and 20% to 70% by mass. It is possible.

[0020] (A) The antacid is prepared by using a bromocresol green (BCG) solution. When subjected to the BCG test, preferably 5 minutes or less, more preferably 3 minutes or less, even more preferably Or less than 2 minutes, more preferably less than 1 minute, particularly preferably less than 45 seconds, most preferably Alternatively, it is preferable to include an amount that causes discoloration to be observed within 30 seconds or less.

[0021] [BCG test] Dilute approximately 30 mL of 1 M hydrochloric acid solution with purified water to make a total volume of 3000 mL. Add 5 mg of BCG (bromocresol green) per 500 mL of solution and visually check for BCG Stir until G is completely dissolved and the liquid color turns yellow to orange. Then, add a 500 mL volume of... Place 500 mL of the BCG solution into an Erlenmeyer flask and stir with a stirrer at a constant speed. Stirring, add 500 mg of the measurement sample, and observe from immediately after addition until the color change is complete. Measure the time.

[0022] (A) The daily dose of antacids is not particularly limited, but the total amount of antacids is (A) Preferably, 10 to 5000 mg, more preferably 100 to 4000 mg, and further Preferably, the amount can be 800 to 3000 mg.

[0023] The pharmaceutical formulation of the present invention substantially does not contain sodium-based antacids or belladonna extract. It is. Examples of sodium-based antacids include sodium bicarbonate, sodium citrate, and vinegar. Examples include sodium phosphate.

[0024] In this specification, belladonna extract refers to the rhizome of the Solanaceae family, *Scopolia japonica*. This refers to an extract obtained by conventional methods from (con) or its dried product, etc.

[0025] The pharmaceutical formulation of the present invention further substantially does not contain aluminum-based antacids. This can be done. Examples of aluminum-based antacids include synthetic aluminum silicate and hydroxide Examples include aluminum.

[0026] In this specification, "substantially free of" a certain component means "not containing," that is, In addition to 0% by mass, other cases include the presence of trace amounts of the component in the composition. This may vary depending on the component, but for example, it can be 0.15% by mass or less, and 0.1% by mass or less. Examples include 0.08% by mass or less, 0.06% by mass or less, etc. For example, sodium-based If the product does not substantially contain an acidifying agent, ingredients such as sodium bicarbonate may be used as antacids. In addition to cases where trace amounts are present, if additives or herbal ingredients contain sodium bicarbonate or other similar components, the amount may be higher. This may include trace amounts.

[0027] [(B) Digestive enzyme] The digestive enzyme is not limited as long as it achieves the effects of the present invention; for example, starch digestive enzymes. Examples include protein-digesting enzymes, fat-digesting enzymes, and fiber-digesting enzymes. Furthermore, digestive enzymes are... From the viewpoint of significantly achieving the effects of the present invention, amylase, lipase, protease, galactose It is preferable that it be at least one selected from the group consisting of sidase and cellulase. Furthermore, at least one selected from the group consisting of amylase, lipase, and protease. It is more preferable to have only one type.

[0028] The amylase is not limited as long as it achieves the effects of the present invention, and can be various types of amylase derived from animals and microorganisms. Examples of amylases include α-amylase and β-amylase. It can be used, and as α-amylase, it can be liquefied α-amylase and sugar Any form of α-amylase can be used. When using an enzyme, it is not limited to α-amylase, but is preferably a glycation type. It is more preferably α-amylase, and even more preferably biodiastase. Commercially available amylase products include Biodiastase, Biodiastase 500, and Biodia Stase 700, Biodiastase 1000, Biodiastase 2000 (all from Amano E.) Examples include products manufactured by Nzyme Inc.

[0029] Lipase is not limited as long as it achieves the effects of the present invention, and various lipases of animal and microbial origin are also available. Lipase is one example. Commercially available lipases include lipase AP4, lipase AP6, and Lipase AP12, Lipase M-AP5, Lipase M-AP10, Lipase M-AP20 ( Examples include those manufactured by Amano Enzyme Co., Ltd.

[0030] The protease is not limited as long as it achieves the effects of the present invention, and may be of animal or microbial origin. Examples include various lipases. A commercially available protease is Prozyme 6 (Amano Enzyme). Examples include products manufactured by Company M.

[0031] (B) The amount of digestive enzymes is not limited as long as the effects of the present invention are achieved, but the total amount of the formulation Preferably, 0.01 to 30% by mass, more preferably 0.05 to 25% by mass. More preferably 0.1 to 20% by mass, even more preferably 0.5 to 15% by mass, Preferably, it can be 1 to 10% by mass, and most preferably 2 to 8% by mass.

[0032] (B) The daily dose of digestive enzymes is not particularly limited, but (B) the total amount of digestive enzymes Preferably, 10 to 1000 mg, more preferably 20 to 800 mg, and further Preferably, the amount can be 30 to 500 mg.

[0033] The pharmaceutical formulation of the present invention, from the viewpoint of formulation stability, contains (A) 1 part by mass of antacid, and (B) antacid. The enzyme is preferably 0.0001 to 3 parts by mass, more preferably 0.001 to 1 part by mass. It contains parts, more preferably 0.01 to 0.3 parts by mass.

[0034] [Cooling agent] The pharmaceutical formulation of the present invention preferably further contains a cooling agent. The cooling agent may be: Insofar as the effects of the present invention are achieved, the present invention may be used with monoterpenes and / or monoterpenes, but is not limited to these. Examples include essential oils containing ions.

[0035] Specifically, as monoterpenes, geraniol, nerol, myrcenol, and linalool. Acyclic monoterpenes such as linalool acetate and lavandulol; menthol, limonol Monocyclic monoterpenes such as ne, anethole, eugenol, and hinokitiol; camphor Bicyclic monoterpenes such as oleu, borneol, isoborneol, cineole, and pinene. Examples include, but are not limited to, those listed above.

[0036] Essential oils containing monoterpenes include cool mint oil, peppermint oil, spearmint oil, and eucalyptus oil. Examples include potassium oil, bergamot oil, spearmint oil, rose oil, and camphor oil. Essential oils containing menthol and camphor include cool mint oil, peppermint oil, and spearmint oil. Examples include oils, camphor oil, fennel oil, cinnamon oil, and lemon oil. Oil can be extracted from plants by known methods. Such known methods for extracting essential oils and Then, using steam distillation, plant material is added to the deodorized animal fat to adsorb the essential oil, and then ethanol Oil adsorption method for extracting essential oils, plant material is subjected to organic solvents such as hexane or benzene or supercritical fluids. The material is extracted using a fluid, the extraction solvent is dissolved in ethanol, and then the ethanol is evaporated to collect the residue. Methods of extraction include solvent extraction and pressing. Monoterpenes are extracted from essential oils using various chromatography techniques. It can also be recovered using Graph.

[0037] Among these, cooling agents consist of menthol, camphor, and borneol. Preferably, at least one of the following is selected: menthol and / or camphor. It is more preferable that it be present, and even more preferable that it be menthol.

[0038] The amount of cooling agent is not limited as long as it achieves the effects of the present invention, but is relative to the total amount of the formulation. For example, it is preferable to have 0.0001% by mass or more, 0.0005% by mass or more, 0 .001 mass% or more, 0.005 mass% or more, 0.01 mass% or more, 0.05 mass% or more It can be 0.1% by mass or more, 0.5% by mass or more, or 1% by mass or more. The amount of cooling agent is not limited as long as it achieves the effects of the present invention, but is relative to the total amount of the formulation. For example, it is preferable that it be 20% by mass or less, 10% by mass or less, 5% by mass or less, and 2% by mass. The amount can be less than or equal to a percent. The amount of cooling agent is not limited as long as it achieves the effects of the present invention, but is relative to the total amount of the formulation. For example, it is preferably 0.01 to 10% by mass, and preferably 0.05 to 5% by mass. This is more preferable, and even more preferable is 0.1 to 2% by mass.

[0039] The daily dose of the cooling agent is not particularly limited, but the total amount of the cooling agent is preferably The amount is 0.1 to 30 mg, more preferably 0.5 to 25 mg, and even more preferably 1 to 20 mg. It can be expressed as mg.

[0040] The pharmaceutical formulation of the present invention, from the viewpoint of formulation stability and the like, contains (A) 1 part by mass of antacid and a cooling agent Preferably, 0.0001 to 1 part by mass, more preferably 0.0005 to 0.25 parts by mass. It contains parts by mass, more preferably 0.001 to 0.07 parts by mass.

[0041] The pharmaceutical formulation of the present invention, insofar as the effects of the present invention are fully achieved, does not require any other necessary actions. Depending on the circumstances, it may contain various additional components (pharmacologically active components or physiologically active components), or they It can be used in combination with other ingredients. The type of such ingredients is not particularly limited, for example, stomachic agents. Examples of the present invention include digestive agents, intestinal regulators, antidiarrheal agents, analgesic and antispasmodic agents, mucosal repair agents, and antifoaming agents. The following are some examples of components, but the list is not limited to these. The amounts of these ingredients are selected appropriately depending on the type of formulation, the type of active ingredient, etc.

[0042] Stomach tonic: Japanese red oak extract, anise fruit, aloe, fennel, turmeric, rhizome, life-prolonging agent Grass, golden scutellaria, golden oak, coptis, processed garlic, turmeric, cuckoo, kale root, dried ginger , bitter orange, pheasant, cinnamon, gentian, corn lily, amber tree, evodia, pepper, Colombo Conslango, Japanese pepper, mountain lily, shiso, scutellaria, ginger, citrus, Blue bark, sweet flag, Centaurum, Swertia japonica, hibiscus, star anise, rhubarb, bamboo shoots Ginger, clove, dried tangerine peel, chili pepper, spruce, bitter oak, nutmeg, carrot, mint ( (Contains peppermint), long pepper, Atractylodes lancea, hops, humicin extract, water lily Herbal medicines such as leaves (Suisaiyo), Mokkou, Yakuchi, Ryutan, Ryokyo, or Extracts, ginger oil, cardamom oil, clove oil, spruce oil, animal bile (including bear bile) (m), betaine hydrochloride, glutamate hydrochloride, carnitine chloride, betanethol chloride, dried yeast Mother etc.

[0043] Digestive agents: Ursodeoxycholic acid, oxycoranates, cholic acid, bile powder, bile Extract (powder), dehydrocholic acid, animal bile (including bear bile), etc.

[0044] Intestinal regulators: Herbal medicines such as red bud oak, catechu, bud oak, cassia seed, geranium or other Extracts of [unclear], intestinal regulating bacteria components (lactic acid bacteria, butyric acid bacteria, natto bacteria, etc.).

[0045] Antidiarrheal agents: Catechuan, Ubai, Oubaku, Ouren, Kujin, Geranium, Gallnut Crude drugs such as hawthorn, swertia japonica, and hibiscus, or their extracts, acrinol, bell chloride Berine, guaiacol, creosote, phenyl salicylate, guaiacol carbonate, tannin Berberine nitrate, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, subgallic acid Bismuth, tannic acid, tannic acid albumin, methylenethimole tannin, kaolin, Natural aluminum silicate, aluminum hydroxynaphthoate, pectin, medicinal charcoal, lactic acid Calcium, etc.

[0046] Analgesic and antispasmodic agents: Herbal medicines such as Corydalis, Licorice, Peony, Belladonna, or their extracts. Substances, oxyphencycline hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, hydrobromic acid Scopolamine, methylatropine bromide, methylanisotropine bromide, methylscopolamine Mine, methyl-l-hyoscyamine bromide, methylbenactidium bromide, isopropamine iodide D, diphenylpiperidinomethyldioxolane iodide, papaverine hydrochloride, aminobenzoic acid Ethyl, etc.

[0047] Mucosal repair agents: Herbal medicines such as red oak, Corydalis, and licorice, or their extracts, azulene Sodium phosphate, aldioxa, glycyrrhizic acid and its salts, L-glutamine, copper Potassium chlorophyllin, sodium copper chlorophyllin, histidine hydrochloride, porcine stomach wall tetrapeptide Syn hydrolysate, porcine gastric acid hydrolysate, methylmethionine sulfonium chloride, gefa Lunart, Cetraxate Hydrochloride, Sucralfate Hydrate (Aluminum Sucrose Sulfate) (Nium salt), solcon, etc.

[0048] Antifoaming agent: Dimethylpolysimethane, etc.

[0049] The pharmaceutical formulation of the present invention is preferably an orally administered formulation. The dosage form is a tablet (oral). (Including tablets that disintegrate rapidly in the mouth, chewable tablets, effervescent tablets, jelly-like drops, etc.), lozenges, granules Granules, pills, dry syrups, powders (including fine granules), capsules (hard capsules, soft capsules) In addition to solid dosage forms such as capsules, there are also liquids, suspensions, emulsions, syrups, and elixirs. Examples include stimulants, limonades, tinctures, extracts, jellies, gels, liposomes, etc. In particular, from the viewpoint of further demonstrating the effects of the present invention and versatility, solid-type A preparation is preferred, and in particular, a solid preparation prepared by granulation may be used. These include tablets, granules, lozenges, hard capsules, soft capsules, and dry syrups. It is included, and tablets and granules are particularly preferred.

[0050] Furthermore, the pharmaceutical formulation of the present invention may be used in accordance with its dosage form, to the extent that it does not impair the effects of the present invention. It may also contain appropriate additives. Such additives include solid dosage forms (for example, tablets). In the case of capsules, powders, etc., excipients (e.g., sucrose, lactose, crystalline cellulose, light (e.g., anhydrous silicic acid), lubricants (e.g., sucrose fatty acid ester, magnesium stearate) (e.g., talc), disintegrants (e.g., low-substituted hydroxypropylcellulose, cross-pollination) Vidone, croscarmellose sodium, etc.), foaming agents (e.g., sodium bicarbonate) (etc.), fluidizing agents (e.g., sodium aluminometasilicate, light anhydrous silicic acid, etc.), Examples include the above. The pharmaceutical uses of these additives may be other than those listed above.

[0051] Also, liquid formulations (e.g., syrups, liquids, suspensions, soft capsule contents, hard capsule contents) In the case of liquid containers, the additives include oily bases (for example, olive oil, Vegetable oils such as corn oil, soybean oil, sesame oil, and cottonseed oil; medium-chain triglycerides, etc. ), aqueous base (e.g., macrogol 400, water), gel base (e.g., carboxyvinyl (Polypolymers, gums, etc.), surfactants (e.g., polysorbate 80, hydrogenated castor oil, Glycerin fatty acid ester, sorbitan sesquioleate, etc.), suspending agent (e.g., saturates, sorbitan sesquioleate (Beeswax, various surfactants, soy lecithin, etc.), dispersants, emulsifiers, stabilizers, buffers These include solvents, solubilizers, pH adjusters, and preservatives. In any case, antioxidants, sweeteners, acidulants, colorants, flavorings, and taste enhancers may be used appropriately. It may be added as appropriate.

[0052] The pharmaceutical formulations of the present invention, depending on their dosage form, include (A) antacids, (B) digestive enzymes, and, if desired Other physiologically active ingredients and additives used in the process are formulated by conventional methods to obtain It is possible.

[0053] [Application] The pharmaceutical formulation of the present invention specifically provides benefits such as protection of the gastric mucosa, enhancement of gastric mucus, and enhancement of gastric mucosal blood flow. It has the effect of increasing resistance to stomach acid, and combined with its effect of regulating the amount of stomach acid, it is an excellent remedy for gastritis and other gastritis. It exhibits efficacy as a gastrointestinal medicine for stomach ulcers, stomach upset, etc. In particular, the pharmaceutical formulation of the present invention is effective for stomach Improvement of ulcers and gastric mucosal lesions (erosion, bleeding, redness, edema), acute gastritis, and acute exacerbation of chronic gastritis. It is used in the treatment of various conditions. It is also used for indigestion, overeating, and excessive drinking. Excessive drinking, heartburn, loss of appetite, bloating (including due to indigestion), abdominal Bloating (including those caused by indigestion), nausea (upset stomach, hangover, etc.) Nausea from drinking, vomiting, vomiting, feeling of fullness in the chest, excessive stomach acid, feeling of heaviness in the stomach, weak stomach, stomach pain, stomach discomfort Sensation, digestive aid, indigestion, abdominal pain, colic (colic, epilepsy), belching (Belting), vomiting and diarrhea, loose stools, diarrhea (including diarrhea due to indigestion and diarrhea accompanied by abdominal pain) It is suitable for use in treating food poisoning, waterborne illnesses, regulating bowel movements, loose stools, and constipation. This is possible. Among these, the pharmaceutical formulation of the present invention is a sodium-based antacid and belladonna extract. Even in formulations that exclude (A) antacids and (B) digestive enzymes, This ensures, at a minimum, the stability of the formulation in terms of adhesion, hygroscopicity, or turbidity in an aqueous medium. Because this is improved, it suppresses the decline or deterioration of the formulation quality, or the decline in the absorption of the active ingredient, and This makes it possible to stably exert the original effects of the active ingredients listed above.

[0054] Furthermore, the pharmaceutical formulation of the present invention has improved formulation stability, for example, (A) antacid absorption It is suitably used to improve yield and / or to suppress the decrease in potency of (A) antacids.

[0055] The pharmaceutical formulation of the present invention is a sodium-based antacid and anticholinergic agent, which are of concern due to their effects on blood pressure and kidneys. Because it is formulated without belladonna extract, which is of concern regarding its effects, it is suitable for the elderly and those with weak physical strength. It is suitable for use in individuals with reduced physiological function or those with underlying medical conditions. Elderly people, also known as older adults, generally experience age-related decline and stomach discomfort such as indigestion. This refers to people aged 55 and older who are prone to experiencing symptoms such as a decline in stomach function.

[0056] The pharmaceutical formulation of the present invention can usually be administered 1 to 3 times a day, preferably 3 times a day. Therefore, the pharmaceutical formulation of the present invention for a single dose is the above daily dose per day It is preferable to include an amount obtained by dividing by the number of times it is administered.

[0057] [Method of manufacturing solid dosage forms] The present invention also relates to (A) calcium-based antacids and magnesium-based antacids from the group consisting of these. At least one antacid selected, and (B) Contains digestive enzymes, Pharmaceutical preparations that substantially do not contain sodium-based antacids and belladonna extract. This relates to a method for manufacturing this product.

[0058] In this method as well, (A) the type and amount of the component, (B) the type and amount of the component, and their component ratios. Other ingredients, etc., are the same as those in the above-mentioned pharmaceutical preparations.

[0059] The pharmaceutical formulation of the present invention comprises, for example, component (A), component (B), and other components to be added as desired. The components, and any additives to be added as desired, are mixed in a manner conventional in the art. It is manufactured by stirring.

[0060] The apparatus for mixing and stirring is not particularly limited, and for example, a commercially available biomixer, etc. A high-speed agitator or high-speed grinder such as a motorizer can be used.

[0061] [Manufacturing method for compressed solid dosage forms] The pharmaceutical formulations of the present invention are, but are not limited to, compressed solid compositions molded to a size that is easy to swallow. It can be manufactured as a physical product. In this way, the ease of taking it is improved, and swallowing ability does not decline. It can be used effectively even by elderly people.

[0062] When the pharmaceutical formulation of the present invention is a compressed solid composition, from the viewpoint of facilitating swallowing, The size of the object is preferably in the range of 2.5 to 8.5 mm in maximum diameter, and more preferably 2.5 to 8.0 mm. A range of mm is preferred, particularly a range of 2.5 to 7.5 mm, and even more preferably 2.5 to A range of 7.0 mm is preferred, more preferably a range of 3.0 to 6.5 mm, and particularly preferably 3.5 to A range of 6.0 mm is preferred. The ease of swallowing within this range is such that humans can swallow the pharmaceutical formulation of the present invention. The throat muscle potential when taking the medication can be verified by measuring it using an electromyograph. Furthermore, using a compression molding machine equipped with a die and pestle of the desired diameter, a molding pressure of 3kN to 20kN is applied. By compression molding, the desired compressed solid can be obtained.

[0063] Furthermore, it is preferable to take more tablets at once to absorb the active ingredients. It is preferable that the number of tablets to be taken is individually packaged. Here, the number of tablets to be taken at one time is For example, 5 to 30 pieces, preferably 6 to 28 pieces, more preferably 8 to 26 pieces. The amount to be taken at one time is, for example, 1 to 3000 mg, preferably 10 to 2000 mg. More preferably, the amount is 100 to 1500 mg.

[0064] Furthermore, the compressed solid composition obtained in this manner can be applied in a single application, for example, if the container is 20m wide. By packaging in a stick-shaped aluminum laminate packaging material with a length of 70 mm, once This also makes it easier to apply dosage units.

[0065] [Methods for stabilizing solid dosage forms] In another embodiment, the present invention relates to (A) a calcium-based antacid and a magnesium-based At least one antacid selected from the group consisting of antacids, and (B) Contains digestive enzymes, Pharmaceutical preparations that substantially do not contain sodium-based antacids and belladonna extract. Regarding methods for stabilizing it.

[0066] The stabilization described above preferably involves improving adhesion, hygroscopicity, or turbidity in an aqueous medium. If the stability regarding hygroscopicity is compromised, the water content in the formulation will increase, affecting the active ingredients, etc. Since this can lead to deterioration of the pharmaceutical formulation, the present invention provides a method for suppressing the deterioration of the active ingredient in a pharmaceutical formulation. It is also possible to provide this.

[0067] Furthermore, if the stability of turbidity in aqueous media is impaired, the dispersibility decreases, leading to a decrease in effective production. This can lead to a decrease in absorption, etc., therefore, the present invention improves the dispersibility of the active ingredient in pharmaceutical formulations. It is also possible to provide a better method or a method for improving the absorption of the active ingredient. [Examples]

[0068] [Test Example 1-1. Turbidity Evaluation Test for Pharmaceutical Preparations 1] According to Table 1, each component was weighed, mixed and homogenized by conventional methods to obtain a powder. Regarding this, the time until the color change is completed by the BCG test is 3 minutes, preferably 2 minutes or less. I confirmed that it was there. I put 30 ml of water and each powder into a 100 ml beaker and stirred it with a stirrer. - Stirred for 7 minutes and transferred 8 ml to a turbidimeter tube. Stirred with a vortex mixer. Immediately after mixing, the turbidity was measured for 7 minutes using a turbidimeter (model number: 2100AN, manufactured by HACH). As shown in Table 1, pharmaceutical formulations containing sodium-based antacids and belladonna extract were compared. Furthermore, excluding these two components, a calcium-based antacid or a magnesium-based antacid is used, and digestive A pharmaceutical formulation containing an enzyme was used as the example. Correction value when the result of the above comparative example is set to "0". This is shown along with the results for each turbidity change rate (Table 1).

[0069] The turbidity change rate was calculated according to the following formula. Rate of change (%) = {(Turbidity at 7 minutes after stirring [NTU] - Turbidity at 0 minutes [NTU]) / Turbidity at 0 minutes [NTU] × 100

[0070] The improvement rate was calculated according to the following formula. Improvement rate (%) = {(Turbidity change rate of Comparative Example 1-1-2 - Turbidity change rate of each test formulation) / Comparative Example 1-1-2 (Turbidity change rate of -2) × 100

[0071] [Table 1]

[0072] Comparative Example 1-1-1, which contains a sodium-based antacid and belladonna extract, When the compound was omitted, the rate of change in turbidity worsened (Comparative Example 1-1-2). Specifically, Comparative Example 1 Compared to -1-1 as the baseline, the turbidity change rate decreased by -62.1% in comparative example 1-1-2. In other words, the dispersed state was maintained, suggesting a decrease in absorption and solubility in living organisms. Therefore, the combination of sodium-based antacids and belladonna extract is beneficial in terms of formulation stability from the standpoint of turbidity. It was confirmed that he had contributed to it.

[0073] In comparison with Comparative Example 1-1-2, the sodium-based antacid was omitted, and instead, a calcium-based antacid was added. When an antacid was added, the rate of change in turbidity improved, but it did not reach a sufficient level of improvement (comparative example). 1-1-3).

[0074] When digestive enzymes were further added to Comparative Example 1-1-3, the rate of change in turbidity was significantly improved. Example 1-1-1): It was confirmed that the improvement effect is further enhanced by adding menthol. (Example 1-1-2). Even if component (A) and component (B) are replaced with other components, Similar improvement trends were observed (Examples 1-1-3 to 1-1-6).

[0075] [Test Example 1-2. Turbidity Evaluation Test of Pharmaceutical Preparations 2] Except for measuring turbidity 3 minutes after stirring, the method was the same as in Test Example 1-1. A turbidity evaluation test was conducted. Specifically, according to Table 2, each component is weighed, mixed and homogenized by conventional methods, and the powder is prepared. Obtained. Add 30 ml of water and each powder to a 100 ml beaker and stir with a stirrer for 3 minutes. 8 ml was transferred to a turbidimeter tube. After stirring with a vortex mixer, the turbidity was immediately measured. Turbidity was measured for 7 minutes using a turbidity meter (model number: 2100AN, manufactured by HACH). As shown in Table 2, pharmaceutical formulations containing sodium-based antacids and belladonna extract were compared as comparative examples. Furthermore, excluding these two components, a calcium-based antacid or a magnesium-based antacid is used, and digestive A pharmaceutical formulation containing an enzyme was used as the example. Correction value when the result of the above comparative example is set to "0". This is shown along with the results for each turbidity change rate (Table 2).

[0076] The turbidity change rate was calculated according to the following formula. Rate of change (%) = {(Turbidity at 3 minutes after stirring [NTU] - Turbidity at 0 minutes [NTU]) / Turbidity at 0 minutes [NTU] × 100

[0077] The improvement rate was calculated according to the following formula. Improvement rate (%) = {(Turbidity change rate of Comparative Example 1-2-2 - Turbidity change rate of each test formulation) / Comparative Example 1-2 (Turbidity change rate of -2) × 100

[0078] [Table 2]

[0079] Comparative Example 1-2-1, which contains a sodium-based antacid and belladonna extract, When the compound was omitted, the rate of change in turbidity worsened (Comparative Example 1-2-2). Specifically, Comparative Example 1 Compared to -2-1 as the baseline, the turbidity change rate decreased by -63.2% in comparative example 1-2-2. In other words, the dispersed state was maintained, suggesting a decrease in absorption and solubility in living organisms. Therefore, the combination of sodium-based antacids and belladonna extract is beneficial in terms of formulation stability from the standpoint of turbidity. It was confirmed that he had contributed to it.

[0080] In comparison with Comparative Example 1-2-2, the sodium-based antacid was omitted, and instead, a calcium-based antacid was added. When antacids and digestive enzymes were added, the rate of change in turbidity improved significantly (Example 1-2-1). ). A similar improvement trend was observed even when component (A) and component (B) were replaced with other components. (Examples 1-2-2 to 1-2-4).

[0081] [Test Example 2. Adhesion Evaluation Test of Pharmaceutical Formulations] According to Table 3, each component was weighed, mixed and homogenized by conventional methods to obtain a powder. Regarding this, the time until the color change is completed by the BCG test is 3 minutes, preferably 2 minutes or less. I confirmed that... the weight of an empty glass bottle of size 10 and the metal cap (tinplate) After measuring the weight of each powder, each powder was added and the lid was closed. Mixing took place over approximately 20 seconds. The procedure was performed 20 times in total, and afterwards the weight of the metal cap was measured, and the amount of the preparation adhering to the metal cap was measured. The quantity was determined. The adhesion rate (%) is shown in Table 3.

[0082] The adhesion rate (%) was calculated according to the following formula. Adhesion rate (%)= (Weight of lid after 20 inversions [g] / Initial weight of lid [g]) / Initial weight of lid [g] ×100

[0083] The improvement rate was calculated according to the following formula. Improvement rate (%) = {(Adhesion rate of Comparative Example 2-2 - Adhesion rate of each test formulation) / Adhesion rate of Comparative Example 2-2} Arrival rate}×100

[0084] [Table 3]

[0085] From Comparative Example 2-1, which contained a sodium-based antacid and belladonna extract, belladonna extract was removed. When this formulation was used, the adhesion rate improved (deteriorated) (Comparative Example 2-2). Specifically, Comparative Example 2-1 Using this as a baseline, Comparative Example 2-2 showed an improvement in adhesion rate of -120.8%. The results showed that the combination of sodium-based antacids and belladonna extract was produced in terms of adhesion. It was confirmed that this contributed to the stability of the drug.

[0086] In comparison with Comparative Example 2-2, a sodium-based antacid was omitted, and instead, a calcium-based antacid was added. When the agent is added, and then digestive enzymes are added, the adhesion rate is significantly reduced (improved) (Example 2-1) Examples 2-3) show that the improvement effect is further enhanced by adding menthol. (Examples 2-4).

[0087] A similar improvement trend was observed when components (A) and (B) were replaced with other components. (Examples 2-3 to 2-6).

[0088] [Test Example 3. Hygroscopicity Evaluation Test of Pharmaceutical Formulations] According to Tables 4 and 5, each component was weighed, mixed and homogenized by conventional methods, and a powder was obtained. For each powder, the time until the color change is completed by the BCG test is preferably 3 minutes. It was confirmed that it was less than a minute. 2g of each powder was weighed and placed in a petri dish. Including the petri dish The weight was measured and taken as the weight at 0h. Each powder was desiccated in 33%RH and 93%RH environments. The weight was measured after 48 hours and 120 hours in a container. The results for hygroscopicity (%) are shown in Tables 4 and 5. Table 4 shows the test results at 93%RH after 48 hours, and Table 5 shows the results after 33 hours. The %RH test results after 120 hours are shown.

[0089] The hygroscopicity (%) was calculated according to the following formula. Hygroscopicity (%)= (Weight after 48 hours or 120 hours [g] - Weight after 0 hours [g]) / Weight after 0 hours [g] ]×100

[0090] The improvement rate was calculated according to the following formula. Improvement rate (%) at 93% RH (after 48 hours) = {(Hygroscopicity of Comparative Example 3-1 - Hygroscopicity of each test formulation) / Hygroscopicity of Comparative Example 3-1} × 100 Improvement rate (%) at 33%RH (after 120 hours) = {(Hygroscopicity of Comparative Example 3-3 - Hygroscopicity of each test formulation) / Hygroscopicity of Comparative Example 3-3} × 100

[0091] [Table 4]

[0092] [Table 5]

[0093] Compared to Comparative Example 3-1, which contains a sodium-based antacid, this product does not contain a sodium-based antacid. In addition, in the example in which a calcium-based antacid or a magnesium-based antacid was combined with a digestive enzyme... It was confirmed that the hygroscopic properties were significantly improved (Examples 3-1 to 3-7). Furthermore, It was found that the hygroscopic properties were further improved by incorporating ethanol (Examples 3-5). to 3-7).

[0094] [Test Example 4. Turbidity Evaluation Test for Pharmaceutical Preparations 2] According to Table 6, each component was weighed, mixed and homogenized by conventional methods to obtain a powder. Regarding this, the time until the color change is completed by the BCG test is 3 minutes, preferably 2 minutes or less. I confirmed that it was there. I put 30 ml of water and each powder into a 100 ml beaker and stirred it with a stirrer. - Stirred for 7 minutes and transferred 8 ml to a turbidimeter tube. Stirred with a vortex mixer. Immediately after mixing, the turbidity was measured for 7 minutes using a turbidimeter (model number: 2100AN, manufactured by HACH). As shown in Table 6, comparative example 4-1 is a pharmaceutical preparation that does not contain digestive enzymes, and calcium-based antacids are also included. Comparative Example 4-2 is a pharmaceutical preparation that does not contain the agent, magnesium-based antacid, or digestive enzyme. Comparative Example 4-3 was a pharmaceutical preparation containing digestive enzymes compared to Comparative Example 4-2. Example 4 describes a pharmaceutical formulation containing a magnesium-based antacid, a magnesium-based antacid, and a digestive enzyme. I set it to -1.

[0095] The turbidity change rate was calculated according to the following formula. Rate of change (%) = {(Turbidity at 7 minutes after stirring [NTU] - Turbidity at 0 minutes [NTU]) / Turbidity at 0 minutes [NTU] × 100

[0096] The improvement rate was calculated according to the following formula. Improvement rate (%) = {(Turbidity change rate of the reference comparative example - Turbidity change rate of each test formulation) / Reference} The turbidity change rate of the comparative example is { × 100

[0097] [Table 6]

[0098] Compared to Comparative Example 4-1, the rate of change in turbidity was significantly improved when digestive enzymes were added (Example). 4-2). However, when calcium-based antacids and magnesium-based antacids are combined... In pharmaceutical formulations that do not contain digestive enzymes, the rate of change in turbidity does not improve even if digestive enzymes are added. Rather, it was shown that the rate of change in turbidity worsened. The reason for this result is unknown. However, calcium-based or magnesium-based antacids can be used in combination with digestive enzymes. It is presumed that this contributes to a significant improvement in the rate of change in turbidity. Also, sodium In cases where a antacid containing a lium-based agent or an aluminum-based agent is substantially (in trace amounts) However, it was confirmed that the effects of the present invention are achieved.

[0099] [Examples of formulations] The pharmaceutical formulations of the present invention were prepared according to conventional methods based on the formulations shown in Tables 7-9 below.

[0100] [Table 7]

[0101] [Table 8]

[0102] [Table 9]

Claims

1. (A) At least one antacid selected from the group consisting of calcium-based antacids and magnesium-based antacids, (B) Contains digestive enzymes, A pharmaceutical preparation that substantially does not contain sodium-based antacids or belladonna extract.

2. The pharmaceutical preparation according to claim 1, wherein the antacid (A) is present in an amount of 30% by mass or more of the total amount of the preparation.

3. The pharmaceutical preparation according to claim 1 or 2, wherein the calcium-based antacid is at least one selected from the group consisting of calcium carbonate, precipitated calcium carbonate, calcium hydroxide, anhydrous calcium hydrogen phosphate, and calcium hydrogen phosphate.

4. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the magnesium-based antacid is at least one selected from the group consisting of magnesium oxide, magnesium hydroxide, magnesium carbonate, and magnesium silicate.

5. The pharmaceutical preparation according to any one of claims 1 to 4, wherein the digestive enzyme (B) is at least one selected from the group consisting of amylase, lipase, protease, galactosidase, and cellulase.

6. Furthermore, the pharmaceutical preparation according to any one of claims 1 to 5, further containing a cooling agent.

7. The pharmaceutical preparation according to claim 6, wherein the cooling agent is at least one selected from the group consisting of menthol, camphor, and borneol.

8. Furthermore, the pharmaceutical preparation according to any one of claims 1 to 7, which substantially does not contain an aluminum-based antacid.

9. A pharmaceutical preparation according to any one of claims 1 to 8, which is a gastrointestinal drug.

10. A pharmaceutical preparation according to any one of claims 1 to 9, which is intended for the elderly.

11. A pharmaceutical preparation according to any one of claims 1 to 10, for improving the absorption of the aforementioned (A) antacid and / or for suppressing the decrease in potency.

12. The pharmaceutical preparation according to claim 9 or 10, characterized in that it is a compressed solid composition having a maximum diameter of 2.5 to 8.5 mm.

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