Solid preparations and pharmaceutical products

Abstract

The solid preparation of the present application contains: (A) at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof, (B) at least one selected from the group consisting of tranexamic acid and salts thereof, and (C) at least one selected from the group consisting of magnesium oxide, glycine, erythritol, and caffeine; in the form of a tablet or a pill, which satisfies the dissolution test in which the dissolution rate of the component (A) is 60% or more at the time point of 15 minutes, and the hardness is 50 N or more.

Description

Technical Field

[0001] This invention relates to solid dosage forms and pharmaceuticals. Background Technology

[0002] Currently, compound cold medicines and antipyretic analgesics widely use formulations that combine multiple active ingredients. For example, compound cold medicines are known to contain multiple ingredients such as antipyretics, analgesics, antitussives, expectorants, and rhinitis medications. These medications are widely sold as over-the-counter drugs, and from the perspective of efficacy and safety, they need to have excellent stability as formulations.

[0003] Loxoprofen sodium or its hydrate is widely used clinically as a nonsteroidal antipyretic analgesic. In addition, tranexamic acid, as an anti-inflammatory agent, is often used as an active ingredient in compound cold medicines.

[0004] There are reports on pharmaceutical compositions involving the combined use of loxoprofen sodium or its hydrate with tranexamic acid, and combinations thereof (see Patent Document 1). This document describes how, by further containing magnesium oxide, a solid formulation possessing the contradictory properties of high hardness and good disintegration can be obtained.

[0005] Existing technical documents

[0006] Patent documents

[0007] Patent Document 1: Japanese Patent Application Publication No. 2014-162743 Summary of the Invention

[0008] However, the inventors' research found that there is still room for improvement in the dissolution of loxoprofen in tablets containing magnesium oxide, as described in Patent Document 1 above.

[0009] Further research by the inventors revealed that magnesium oxide delays the dissolution of loxoprofen, while component (C) selected from at least one of glycine, erythritol, and caffeine can promote the dissolution of loxoprofen.

[0010] However, when some or all of the magnesium oxide was changed to component (C), the hardness of the solid dosage form was found to decrease.

[0011] Based on the above understanding, in-depth research has revealed that in solid dosage forms containing at least one of loxoprofen, its salts and their hydrates, at least one of tranexamic acid and its salts, and at least one of component (C), by appropriately controlling the particle size in the formulation process, the decrease in hardness of the solid dosage form can be suppressed and the shape retention improved, thereby completing the present invention.

[0012] According to one aspect of the present invention, the following solid dosage forms and pharmaceutical products are provided.

[0013] 1. A solid dosage form comprising the following components (A), (B) and (C):

[0014] (A) Selected from at least one of loxoprofen, its salts and their hydrates.

[0015] (B) Selected from at least one of tranexamic acid and its salts.

[0016] (C) Selected from at least one of glycine, erythritol, and caffeine.

[0017] This solid dosage form is in tablet or pill form.

[0018] At the 15-minute time point in the dissolution test, the dissolution rate of component (A) above is 60% or more, and the hardness is 50N or more.

[0019] 2. The solid dosage form according to claim 1, wherein,

[0020] The above solid dosage form does not contain magnesium oxide, or the content of magnesium oxide is less than 30% by mass relative to the total content of the above components (A), (B) and (C) of 100% by mass.

[0021] 3. The solid dosage form according to 1 or 2, wherein,

[0022] The above solid dosage form does not contain crystalline cellulose, or the content of the above crystalline cellulose is less than 30% by mass relative to the total content of the above components (A), (B) and (C) of 100% by mass.

[0023] 4. The solid dosage form according to any one of 1 to 3, wherein,

[0024] The above solid dosage form meets the following requirement: at the 30-minute time point in the dissolution test, the dissolution rate of component (A) is above 90%.

[0025] 5. The solid dosage form according to any one of 1 to 4, wherein,

[0026] Let C be the content (by mass%) of the above-mentioned component (A) contained in 100% by mass of this tablet. A The content (mass%) of the above component (B) is set as C. B The content (mass%) of the above component (C) is set as C. C hour,

[0027] C C / (C A +C B +C C The value ranges from 0.02 to 0.95.

[0028] 6. A pharmaceutical product comprising any one of the solid dosage forms described in 1 to 5.

[0029] According to the present invention, a solid dosage form of loxoprofen with excellent dissolution and shape retention, and a pharmaceutical product using the solid dosage form are provided. Detailed Implementation

[0030] The following describes the solid dosage form of this embodiment.

[0031] (Solid dosage form)

[0032] The solid dosage form of this embodiment contains the following components (A), (B) and (C):

[0033] (A) Selected from at least one of loxoprofen, its salts and their hydrates.

[0034] (B) Selected from at least one of tranexamic acid and its salts.

[0035] (C) Selected from at least one of glycine, erythritol, and caffeine.

[0036] The above-mentioned solid dosage forms are in tablet or pill form.

[0037] The above solid dosage form meets the following requirements: the dissolution rate of component (A) at time point 15 minutes in the dissolution test is 60% or more, and the hardness is 50N or more.

[0038] According to the inventors' understanding, the solubility of loxoprofen in solid dosage forms can be improved by replacing part or all of magnesium oxide with component (C), but conversely, shape retention may not be adequately achieved due to the reduction in hardness.

[0039] Based on the above understanding, further research has shown that by appropriately increasing the particle size during granulation in the formulation process, the decrease in hardness of solid dosage forms can be suppressed and the shape retention can be improved.

[0040] Based on the above understanding, the inventors' in-depth research revealed that using the initial dissolution rate of component (A), i.e., the dissolution rate of component (A) at the 15-minute time point in the dissolution test, as an indicator can stably evaluate the extent to which part or all of magnesium oxide can be replaced by component (C). In addition, by using hardness as an indicator, the appropriate particle size during granulation in the formulation process can be evaluated, thus improving the dissolution of loxoprofen and improving shape retention.

[0041] In this embodiment, for example, by appropriately selecting the types and amounts of each component contained in the solid dosage form, and the preparation method of the solid dosage form, the dissolution rate and hardness of component (A) at the 15-minute time point in the above-mentioned dissolution test can be controlled. Among them, factors for setting the dissolution rate and hardness of component (A) at the 15-minute time point in the above-mentioned dissolution test to a desired range can be listed as, for example, replacing part or all of magnesium oxide with component (C), and appropriately increasing the particle size (average particle size) of the solid dosage form during granulation in the formulation process.

[0042] Here, the dissolution rate of component (A) at time points of 15 minutes and 30 minutes in the dissolution test is referred to as the dissolution rate at 15 minutes and the dissolution rate at 30 minutes, respectively.

[0043] The lower limit of the dissolution rate at 15 minutes is 50% or more, preferably 55% or more, and more preferably 60% or more.

[0044] On the other hand, there is no specific limit to the upper limit of the dissolution rate at 15 minutes, which can be below 95%.

[0045] The lower limit of the hardness of solid dosage forms is, for example, 50 N or more, preferably 52 N or more, and more preferably 55 N or more. This helps to prevent cracks and defects from forming during manufacturing and transportation, thus minimizing damage to the appearance of the dosage form.

[0046] On the other hand, there is no specific upper limit to the hardness of solid dosage forms, which can be below 200N.

[0047] The lower limit of the dissolution rate at 30 minutes is 90% or more, preferably 95% or more, and more preferably 98% or more. This can further improve the dissolution properties of loxoprofen.

[0048] On the other hand, there is no specific upper limit to the dissolution rate at 30 minutes; it can be below 100%.

[0049] As a solid dosage form, specific examples include tablets or pills as described in the 18th revised edition of the Japanese Pharmacopoeia. In this invention, "solid dosage form" is preferably a tablet, and more preferably a tablet.

[0050] The tablets mentioned above are preferably coated with water-soluble polymers or sugars. Specifically, preferred forms of granules and tablets include film-coated tablets and sugar-coated tablets.

[0051] In addition, among the tablets mentioned above, multi-layer tablets are also preferred, which are formed by stacking and compressing powders or granules of different compositions in two or three or more layers.

[0052] Furthermore, the solid dosage form of this embodiment has excellent antipyretic effects, making it suitable for use as a cold medicine, such as a compound cold medicine, or as an antipyretic analgesic. For example, by adding various ingredients, it can be administered to patients with various cold symptoms, especially fever, chills, headache, sore throat, runny nose, nasal congestion, cough, phlegm, joint pain, muscle pain, sneezing, etc., to relieve these symptoms.

[0053] Solid dosage forms are considered from the point of view of easy intake, for example, they can be used as oral solid dosage forms.

[0054] (Manufacturing method of solid dosage form)

[0055] An example of the solid dosage form manufacturing method of this embodiment includes: a wet granulation step in which water is added to and mixed with a raw material containing component (A), component (B) and component (C) for granulation, and a drying step in which the granules after the wet granulation step are dried.

[0056] For example, particle size can be controlled by adjusting the amount of purified water added during granulation. A higher amount tends to increase particle size. Other methods to adjust particle size include changing granulation conditions (gas supply temperature, liquid addition rate, etc.) during pulverization or fluidized bed granulation, and using raw materials with different particle sizes.

[0057] In the wet granulation process, it is preferred to implement a granulation treatment selected from fluidized bed granulation, extrusion granulation, and stirred granulation. However, it is not limited to these granulation treatments, and known methods may also be used.

[0058] The drying process is not particularly limited; for example, the heating temperature can be 30–100°C, preferably 60–90°C. Furthermore, the heating time can be, for example, 0.01–24 h, preferably 0.1–6 h.

[0059] In addition, the environmental conditions in the drying process can be, for example, at atmospheric pressure.

[0060] Furthermore, without affecting the scope of the present invention, other pharmaceutically active ingredients may be added to the raw material components in the wet granulation process according to conventional methods, and additives may also be added as needed.

[0061] For example, when the solid dosage form is a tablet, the mixture of component (A), component (B), component (C) and appropriate other components is wet-granulated, the granules are dried, and a post-component is added to the resulting granules in a manner that forms the exterior of the granules. The tablets are then compressed to manufacture tablets.

[0062] That is, tablets can be manufactured, for example, by the following steps: manufacturing granulated particles (at least one type of granulated particle) containing ingredient (A), ingredient (B), ingredient (C) and suitable other ingredients; and mixing the granulated particles with desired additives (post-added ingredients) and manufacturing tablets by compression. In addition, ingredients disposed on the outside of the particles may also optionally be made into granules.

[0063] The average particle size of the granulated particles is preferably 100 μm or larger, but can also be, for example, 850 μm or smaller. Specifically, the average particle size refers to the arithmetic mean of the mass-based particle size distribution obtained by sieving, i.e., the mass-average diameter. For example, a Robot Shifter RPS-105M (manufactured by SEISHIN Corporation) can be used for evaluation.

[0064] The added component (exterior of the granulated particles) is the portion that forms the exterior of the granulated particles in the tablet. For example, it can be a portion formed to cover one granulated particle in the tablet, or it can be a portion formed to cover multiple granulated particles. Alternatively, it can be a portion that covers at least one granulated particle in the tablet and forms the outer surface of the tablet.

[0065] In another embodiment of the present invention, the solid dosage form may be used as a material (intermediate material) composed of component (A), component (B) and component (C), or it may be manufactured as a solid dosage form (material / intermediate material) composed of component (A), component (B) and component (C), thereby including components other than component (A), component (B) and component (C).

[0066] That is, the solid dosage form in this invention may contain a solid dosage form consisting of component (A), component (B) and component (C) as an intermediate material, and may be used in the form of pills or tablets.

[0067] In other words, the pharmaceutical product in one embodiment of the present invention comprises the solid dosage form of the present invention, and may be in the form of pills or tablets.

[0068] The preferred method for preserving solid dosage forms is to seal them in glass bottles, PTP containers, or other suitable containers. For stringent preservation conditions, an external ambient temperature of 30°C or higher and / or an external ambient humidity of 60%RH or higher may be used.

[0069] The following details the components contained in solid dosage forms.

[0070] <Ingredients (A)>

[0071] Component (A) contains at least one selected from loxoprofen, its salts and their hydrates.

[0072] At least one of loxoprofen, its salts and their hydrates, including one or more of loxoprofen, loxoprofen sodium, loxoprofen sodium monohydrate and loxoprofen sodium dihydrate.

[0073] Loxoprofen sodium dihydrate is listed as loxoprofen sodium hydrate in the 18th revised edition of the Japanese Pharmacopoeia.

[0074] The amount of component (A) contained in the solid dosage form is not particularly limited, but is 1 to 80 parts by weight per 100 parts by weight of the solid dosage form, preferably 2 to 50 parts by weight, more preferably 5 to 30 parts by weight, and may also be 7 to 20 parts by weight.

[0075] <Ingredient (B)>

[0076] Component (B) contains at least one selected from tranexamic acid and its salts.

[0077] Ingredient (B) is a known compound that can be manufactured by known methods or is available commercially available. Tranexamic acid is described in the 18th revised edition of the Japanese Pharmacopoeia.

[0078] Furthermore, the content of component (B) is not particularly limited, but from the viewpoint of improving the antipyretic effect, it is preferably 10% or more by mass in 100% by mass of the solid dosage form, and more preferably 12.5% ​​or more by mass.

[0079] Furthermore, without particular limitation, from the viewpoint of making the formulation more favorable, the content of component (B) in 100% by mass of solid dosage form is preferably 50% by mass or less, more preferably 40% by mass or less.

[0080] The drying loss (mass%) of the solid dosage form measured at 80°C at a time point where the mass loss is less than 1 mg per 50 seconds is taken as the moisture content.

[0081] The moisture content of the solid dosage form is, for example, 2.5% by mass or less, preferably 1.5% by mass or less, and more preferably 1.0% by mass or less. Therefore, even after storage under stringent conditions, the decrease in the proportion of component (A) in the solid dosage form can be suppressed.

[0082] <Ingredient (C)>

[0083] Ingredient (C) contains at least one selected from glycine, erythritol and caffeine.

[0084] Let the content of component (A) in the solid dosage form be C. A The content of component (B) is set as C. B The content of component (C) is set as C. C .

[0085] At this time, CC / (C A +C B +C C For example, the value can be 0.02–0.95, 0.1–0.9, or 0.15–0.8, preferably 0.2–0.7, and more preferably 0.21–0.65. Setting it to a value above the lower limit improves leaching properties. Setting it to a value below the upper limit improves moldability.

[0086] Glycine is listed in the 18th revised edition of the Japanese Pharmacopoeia and is readily available commercially. Commercially available glycine can be used by appropriate pulverization. Examples include glycine (Organic Synthetic Pharmaceuticals Co., Ltd.), glycine "Manufacturing Specific" (Fujifilm and Wako Pure Chemical Industries Co., Ltd.), glycine (Ajinomoto Health Supply Co., Ltd.), glycine (crystals) (Merck Corporation), and glycine (granules) (Merck Corporation). The amount of glycine contained in solid dosage forms is not particularly limited, but can be 0.01 to 90 parts by weight per 100 parts by weight of the solid dosage form, preferably 0.05 to 80 parts by weight, and more preferably 0.1 to 70 parts by weight.

[0087] Erythritol is readily available from the market. Examples of erythritol include erythritol (Busan Food Science Co., Ltd.). There are no particular limitations on the amount of erythritol contained in solid dosage forms; the amount may be 0.1 to 95 parts by weight, 0.5 to 90 parts by weight, or 1 to 80 parts by weight per 100 parts by weight of the solid dosage form, more preferably 10 to 75 parts by weight, and even more preferably 20 to 70 parts by weight.

[0088] Caffeine derivatives are selected from one or more of anhydrous caffeine, caffeine hydrate, and sodium caffeine benzoate. These are included in the 18th revised edition of the Japanese Pharmacopoeia.

[0089] There is no particular limitation on the amount of caffeine contained in the solid dosage form, but it is 1 to 80 parts by weight per 100 parts by weight, preferably 2 to 50 parts by weight, and more preferably 5 to 30 parts by weight.

[0090] In this embodiment, the solid dosage form may further include components other than (A), (B) and (C).

[0091] Furthermore, the solid dosage form of the present invention can be used as a material (intermediate material) composed of components (A), (B) and (C), and can also be in the form of containing components other than components (A), (B) and (C).

[0092] Examples of these ingredients are listed below.

[0093] The solid dosage form does not contain magnesium oxide, or, relative to the total content of component (A), component (B) and the aforementioned component (C) of 100% by mass, the content of magnesium oxide is, for example, 30% by mass or less, preferably 28% by mass or less, and more preferably 25% by mass or less.

[0094] The solid dosage form does not contain crystalline cellulose, or, relative to the total content of component (A), component (B) and the aforementioned component (C) of 100% by mass, the content of crystalline cellulose is, for example, 30% by mass or less, preferably 28% by mass or less, and more preferably 25% by mass or less.

[0095] <Acid neutralizer>

[0096] In this embodiment, from the viewpoint of inhibiting gastric mucosal damage, the solid dosage form is preferably also to include an antacid.

[0097] As an antacid, for example, as an alkaline earth metal and / or alkaline earth metal-based basic inorganic compound, examples include magnesium silicate, magnesium aluminosilicate, magnesium aluminum silicate, magnesium hydroxide, magnesium hydroxide-potassium aluminum sulfate coprecipitate, magnesium carbonate, synthetic hydrotalcite, magnesium aluminum metasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium aluminum hydroxide, aluminum hydroxide gel, aluminum hydroxide-sodium bicarbonate coprecipitate, aluminum hydroxide-magnesium carbonate mixed dried gel, aluminum hydroxide-magnesium carbonate-calcium carbonate coprecipitate, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, dicalcium phosphate, anhydrous dicalcium phosphate, and other metal inorganic salts selected from magnesium, aluminum, and calcium; in addition, as an alkali metal-based basic inorganic compound, examples include dried sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous sodium monohydrogen phosphate, potassium hydroxide, potassium bicarbonate, potassium carbonate, and other metal inorganic salts selected from sodium and potassium, and others include oyster shells, etc., which can be combined with one or more components selected from these compositions. Preferably, it is selected from one or more of magnesium aluminum metasilicate, synthetic aluminum silicate, and precipitated calcium carbonate.

[0098] When using magnesium aluminum silicate, the magnesium aluminum silicate listed in the 18th revised edition of the Japanese Pharmacopoeia can also be used, as it is readily available.

[0099] There are no particular limitations on commercially available aluminum magnesium metasilicate; for example, there is Neusilin manufactured by Fuji Chemical Industry Co., Ltd.

[0100] The proportion of magnesium aluminum metasilicate in solid dosage forms can be appropriately selected considering the disintegration properties of the solid dosage form, drug solubility, and its function as an antacid. There are no particular limitations. Based on the total mass of the solid dosage form, it can be 0-80% by mass or more than 0-80% by mass, or 0.1-70% by mass, preferably 1-50% by mass.

[0101] <Crude Drugs (Crude Drug Components)>

[0102] The solid dosage forms of this invention may also include medicinal herbs.

[0103] The types of raw medicinal materials used in this invention are not particularly limited. For example, they can be selected from ephedra, nandina, cherry bark, polygala, licorice, platycodon, plantain seed, plantain herb, lycoris, polygala tenuifolia, fritillaria, fennel, phellodendron bark, coptis, turmeric, chamomile, cinnamon, gentian, bezoar, animal bile (including bear bile), glehnia, ginger, atractylodes, clove, tangerine peel, atractylodes macrocephala, earthworm, bamboo rhizome, ginseng, wild parasol tree, asarum, epimedium, corydalis, scutellaria, polygonatum, etc. Valerian, Trichosanthes fruit, apricot kernel, wolfberry, wolfberry leaf, schizonepeta, cassia seed, geranium, cyperus rhizome, schisandra fruit, asarum, Sichuan pepper, aster root, lycium bark, peony root, musk, magnolia flower, chuanxiong rhizome, angelica root, mulberry bark, perilla, garlic, angelica root, ipecac root, ophiopogon root, pinellia tuber, saffron, rhinoceros horn, angelica dahurica, poria cocos, peony bark, oyster shell, deer antler, fangji, and other crude medicinal herbs and their extracts (extracts, tinctures, dried extracts, etc.).

[0104] The solid preparation of the present invention preferably contains at least one of licorice extract, peony extract, and valerian extract.

[0105] The proportion of crude drugs in the solid dosage form of the present invention is not particularly limited. For example, when each crude drug is an extract, the proportion is 1 to 80% by mass based on the total mass of the solid dosage form, or it can be 1 to 50% by mass, or it can be 1 to 40% by mass, or it can be 1 to 30% by mass.

[0106] The raw medicinal herbs used in this invention, such as licorice, peony, and valerian, have been used medicinally since ancient times as single-ingredient formulas or in traditional Chinese medicine prescriptions. The raw herb powder or extracts obtained according to their respective conventional methods can be used directly. The form of the raw herb powder or extracts can also be commercially available products or their processed forms. For example, the raw herb powder can be used as a powder (micro-powder) obtained by further micronizing dried and finely chopped products. Furthermore, there are no particular limitations on the form of the extracts from the raw herbs; for example, they can be used in any form, such as dried extracts, extract powders, soft extracts, fluid extracts, tinctures containing ethanol or ethanol and water. Preferably, the raw herbs contain extracts with high formulation flexibility, such as soft extracts or dried extract powders.

[0107] The extracted components are obtained from the aforementioned crude drugs using conventional methods, such as extraction with an extraction solvent, to extract the active ingredients with antibacterial effects. As extraction solvents, water, hydrophilic solvents, or mixtures thereof are commonly used. Examples of such hydrophilic solvents include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, and tert-butanol; cellolytic agents such as methyl cellolytic agents and ethyl cellolytic agents; ketones such as acetone; and diethyl cellolytic agents. Ethers such as alkanes and tetrahydrofurans; nitrogen-containing solvents such as pyridine, morpholine, acetonitrile, N,N-dimethylformamide, dimethylacetamide, and N-methylpyrrolidone. These hydrophilic solvents can be used alone or as a mixture of two or more solvents.

[0108] As always, licorice can be used as an anti-inflammatory agent, cold medicine, antipyretic analgesic, antitussive and expectorant, gastrointestinal medicine, anthelmintic, oral medicine for rhinitis, throat cooler, stomachic cooler, vitamin supplement, sweetener, flavoring agent, coloring agent, flavoring agent, spice or excipient.

[0109] When using "licorice" in this invention, it is preferable to use the licorice described in the 18th revised edition of the Japanese Pharmacopoeia.

[0110] Other types of licorice besides those mentioned above are also commercially available and readily accessible.

[0111] Commercially available licorice products include extracts that use water or 30% ethanol aqueous solutions as extraction solvents. These products are sold with different conversion ratios of the raw herb depending on the type of extract, such as licorice extract, dried licorice extract, soft licorice extract, or fluid licorice extract. In addition to these licorice extracts, licorice extracts and licorice extract solutions may also be used appropriately, without particular limitations.

[0112] When commercially available licorice is used in oral pharmaceutical compositions, licorice can be used in a manner appropriate to the amount of licorice in a tablet, for example, taking into account the conversion ratio of raw drug.

[0113] There is no particular limitation on the content of licorice (licorice or licorice extract) in the solid dosage form of the present invention. The amount of the ingredient contained in the tablets as a daily dosage is preferably 10 mg to 10 g, more preferably 150 mg to 5 g, and even more preferably 500 mg to 3000 mg, or 500 mg to 1500 mg, and is administered 1 to 3 times a day.

[0114] In the solid dosage form of the present invention, for example, when using dried licorice extract, the content of dried licorice extract is not particularly limited, and can be 0.1 to 80% by mass or 1 to 50% by mass based on the total mass of the tablet, preferably 5 to 40% by mass, and more preferably 10 to 30% by mass.

[0115] When using "valerian" in this invention, the valerian described in the 18th revised edition of the Japanese Pharmacopoeia is preferred.

[0116] Valerian other than those mentioned above is also commercially available and readily accessible.

[0117] As commercially available valerian, valerian powder, valerian extract (such as soft extract, dry extract, etc.) can be used, without particular limitation.

[0118] When using commercially available valerian in oral pharmaceutical compositions, the conversion ratio of the raw drug should be taken into account, and valerian should be used in a manner that is appropriate for the content of valerian in the tablet.

[0119] When using "valerian (valerian or valerian extract)" in this invention, there is no particular limitation on the content. For example, the amount of the ingredient contained in a tablet for a daily dosage is 1 to 6000 mg, preferably 10 to 2000 mg, more preferably 20 to 1440 mg, and even more preferably 60 mg to 1000 mg, or 60 to 450 mg, and the dosage is 1 to 3 times a day.

[0120] In the solid dosage form of the present invention, for example when valerian extract is used, the content of valerian extract is not particularly limited, but is 1 to 50% by mass based on the total mass of the tablet, preferably 2 to 40% by mass, and more preferably 3 to 20% by mass.

[0121] When using "peony" in this invention, the peony described in the 18th revised edition of the Japanese Pharmacopoeia is preferred.

[0122] Peonies other than those mentioned above are also commercially available and readily accessible.

[0123] As commercially available peony, peony powder or peony extract (such as dried extract or soft extract) can be used, without any particular limitation.

[0124] When using commercially available peony in oral drug compositions, the conversion ratio of raw peony should be considered, and peony should be used in a manner that is appropriate for the content of peony in tablets.

[0125] When using "peony (peony or its extract)" in this invention, there is no particular limitation on the content. The preferred dosage, converted from raw peony, is 100-5000 mg per day, more preferably 150-2000 mg, and particularly preferably 200-900 mg, and the dosage is 1-3 times per day.

[0126] In the solid dosage form of the present invention, for example, when using dried peony extract, the content of dried peony extract is not particularly limited, but is 1 to 50% by mass based on the total mass of the tablet, preferably 2 to 40% by mass, and more preferably 3 to 20% by mass.

[0127] During formulation, known methods and additives may be used appropriately. Additives may be added appropriately without impairing the effects of the present invention.

[0128] As additives, pharmaceutically permissible carriers, such as excipients, binders, disintegrants, disintegrant aids, lubricants, flow aids, gloss agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, emulsifiers, antioxidants, fillers, preservatives, preservatives, sweeteners, flavoring agents, cooling agents, fragrances, aromas, colorants, bases, coating agents, sugar coatings, plasticizers, dispersants, and defoamers, can be used for the purposes described above. These can be used alone or in combination of two or more.

[0129] Examples of excipients include powdered sugar, gum arabic, gum arabic powder, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silica, anhydrous amorphous silica, xylitol, magnesium aluminum silicate, calcium silicate, magnesium silicate, anhydrous dicalcium phosphate, anhydrous dicalcium phosphate granules, monodicalcium phosphate, dicalcium phosphate hydrate, dicalcium phosphate granules, dicalcium phosphate hydrate, didicalcium phosphate hydrate, powdered cellulose, synthetic aluminum silicate, wheat starch, rice flour, rice starch, heavy silicic anhydride, refined white sugar, and refined... This product is used to produce spherical sugar granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low-substituted hydroxypropyl cellulose, dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, lactose hydrate, lactose granules, white sugar, potato starch, hydroxypropyl starch, powdered sugar, powdered maltose, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene-cured castor oil, polyoxyethylene-cured castor oil 60, maltitol, D-mannitol, magnesium aluminum metasilicate, calcium sulfate, glucose, fructose, etc. These can be used alone or in combination of two or more.

[0130] As an adhesive, it can be combined with one or more components selected from gum arabic, gum arabic powder, plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pullulan, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate-methyl methacrylate copolymer, methylcellulose, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0131] Examples of disintegrants include carboxymethyl ethyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, and hydroxypropyl starch. These can be used alone or in combination of two or more.

[0132] Examples of disintegrating agents include sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, polyethylene glycol (macrogol) 1500, and polyethylene glycol 4000.

[0133] Examples of lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, glycerol fatty acid esters, polyethylene glycol, hardened oil, and sodium fumarate stearate.

[0134] As a flow aid, it can be combined with one or more components selected from synthetic aluminum silicate, heavy anhydrous silicate, magnesium aluminum hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, and dicalcium phosphate granules.

[0135] As a glossing agent, it can be combined with one or more ingredients selected from carnauba wax, white beeswax, refined shellac, polyethylene glycol 400, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, beeswax, etc.

[0136] As a foaming agent, it can be combined with one or more components selected from dried sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium bicarbonate, anhydrous citric acid, etc.

[0137] As a desiccant, it can be combined with one or more of the following components: ethyl cellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, hardened oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, refined shellac, refined white sugar, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, and polyvinyl acetal diethylaminoacetate.

[0138] As a surfactant, it may be combined with one or more components selected from sucrose fatty acid esters, polyoxyethylene hardened castor oil 20, polyoxyethylene hardened castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) diol, polyoxyethylene (105) polyoxypropylene (5) diol, polyoxyethylene (120) polyoxypropylene (40) diol, polyoxyethylene (160) polyoxypropylene (30) diol, polyoxyethylene (10) polyoxypropylene (4) cetyl ether, polysorbate 20, polysorbate 60, polysorbate 80, polyethylene glycol 400, monooleic sorbitan, glyceryl monostearate, monostearate sorbitan, monolaurate sorbitan, sodium lauryl sulfate, etc.

[0139] As a stabilizer, it can be combined with, for example, diacid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate, benzoic acid, sodium benzoate, ethylenediamine, calcium disodium ethylenediaminetetraacetate, sodium ethylenediaminetetraacetate, tetrasodium ethylenediaminetetraacetate, tetrasodium ethylenediaminetetraacetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, cetylpyridine chloride, ferric chloride, sodium chloride, magnesium chloride, cysteine ​​hydrochloride, histidine L-hydrochloride, cocoa butter, and carboxyvinyl polymers. Carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, hydrated silica, dried sodium carbonate, glycerol, glycerol fatty acid esters, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, monosodium L-glutamate, L-glutamic acid, L-lysine, crystalline sodium dihydrogen phosphate, sodium chondroitin sulfate, zinc oxide, L-cysteine, L-cysteine, tartaric acid, sucrose fatty acid esters, stearic acid, refined gelatin, refined soybean lecithin, gelatin, gelatin hydrolysate, sorbitan fatty acid esters, taurine, talc, calcium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate Hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopheryl acetate, lactose, concentrated glycerol, povidone, polyoxyethylene hardened castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene hardened castor oil, polyoxyethylene (42)polyoxypropylene (67) glycol, polyoxyethylene (54)polyoxypropylene (39) glycol, polyoxyethylene (160)polyoxypropylene (30) glycol, polyoxyethylene (196)polyoxypropylene (67) glycol, polyoxyethylene coconut oil fatty acid glyceride (7E.O.), The following are one or more of the following components: polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methylcellulose, L-menthol, glyceryl monostearate, pharmaceutical charcoal, magnesium sulfate hydrate, DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0140] Examples of emulsifiers include glycerol fatty acid esters, propylene glycol fatty acid esters, polyoxyethylene glycerol fatty acid esters, polyglycerol fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty acid esters, and hydrogenated soybean lecithin.

[0141] Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soybean lecithin, natural vitamin E, tocopherol, tocopheryl acetate, palmitic acid ascorbate, and sodium metabisulfite.

[0142] Examples of fillers include RSS No.1 raw rubber, acrylic starch 1000, hydrated silica, titanium dioxide, silica, and dicalcium phosphate.

[0143] Examples of preservatives include benzoic acid, sodium benzoate, ethylparaben, propylparaben, methylparaben, dehydroacetic acid, sodium dehydroacetate, sorbic acid, and phenoxyethanol.

[0144] As a sweetener, it can be combined with one or more ingredients selected from aspartame, acesulfame potassium, sweet tea, sweet tea powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizate, disodium glycyrrhizate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, refined stevia extract, refined white sugar, fructose, white sugar, maltitol, D-mannitol, etc.

[0145] As a flavoring agent, it can be combined with one or more ingredients selected from sodium chloride, orange, orange oil, cocoa powder, fructose, caramel, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, monosodium glutamate, grapefruit extract, brown sugar, saccharin, sodium saccharin hydrate, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, sodium DL-tartrate, sucralose, stevia extract, stevia extract, saccharin, D-sorbitol, tannic acid, trehalose hydrate, fructooligosaccharides, powdered sugar, peppermint powder, D-mannitol, dl-menthol, l-menthol, menthol powder, green tea powder, DL-malic acid, sodium DL-malate, lemon oil, rose oil, etc.

[0146] Examples of cooling agents include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0147] As a flavoring, it can be combined with one or more ingredients selected from orange flavoring, guarana extract, sweet orange, strawberry, brown sugar flavoring, strawberry flavoring, cherry flavoring, banana powder flavoring, peach extract, fruit extract, peppermint, melon powder flavoring, L-menthol, peppermint oil, etc.

[0148] Examples of aromatic agents include fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, spearmint oil, turpentine oil, pineapple powder flavoring 51357, pineapple powder flavoring 59492, peppermint water, peppermint oil, vanilla powder flavoring 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, rose oil, etc.

[0149] As a coloring agent, it can be combined with one or more of the following ingredients: yellow ferric oxide, yellow ferric oxide, orange flavoring, brown ferric oxide, carbon black, caramel, β-carotene, gold leaf, black ferric oxide, titanium dioxide, ferric oxide, diazo yellow, edible blue No. 1, edible yellow No. 4, edible yellow No. 5, edible blue No. 2 aluminum lake, edible yellow No. 4 aluminum lake, edible red No. 2, edible red No. 3, edible red No. 102, ferric oxide-glycerol suspension, sodium copper chlorophyllin, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, sodium riboflavin phosphate, green tea powder, rose oil, etc.

[0150] As a base agent, it can be formulated with, for example, gum arabic powder, α-starch, partially α-starch, ethyl cellulose, cocoa butter, carnauba wax, carboxyvinyl polymer, carboxymethyl cellulose, sodium carboxymethyl cellulose, reduced maltose syrup, hydrated silica, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycine, glycerol, glycerol fatty acid esters, light anhydrous silicate, crystalline cellulose, hardened oil, synthetic aluminum silicate, synthetic magnesium silicate sodium, titanium dioxide, tartaric acid, sucrose fatty acid esters, silicone oil, stearic acid, magnesium stearate, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid-glycolic acid copolymer, concentrated glycerol, potato starch, hydroxypropyl The product contains one or more of the following components: cellulose, hydroxypropyl methylcellulose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, polyethylene glycol 20000, D-mannitol, glyceryl monostearate, sorbitan monostearate, shark liver oil monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

[0151] Examples of coating agents include: ethyl acrylate-methyl methacrylate copolymer dispersions, aminoalkyl methacrylate copolymers E and RS, gum arabic, gum arabic powder, ethyl cellulose, ethyl cellulose aqueous dispersions, carnauba wax, carboxyvinyl polymers, gold foil, silver foil, triethyl citrate, glycerol, glycerol fatty acid esters, cured oil, titanium dioxide, sucrose fatty acid esters, stearyl alcohol, stearic acid, magnesium stearate, refined gelatin, refined shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold foil, precipitated calcium carbonate, concentrated glycerol, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose 2910-titanium dioxide-polyethylene glycol 400 mixture, hydroxypropyl methylcellulose, fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methylcellulose 2 Mixture 910, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, polyethylene glycol 20000, polyethylene glycol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminum metasilicate, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, methyl cellulose, 2-methyl-5-vinylpyridine methacrylate-methacrylic acid copolymer, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0152] As a sugar coating agent, it can be combined with one or more components selected from gum arabic, gum arabic powder, ethyl cellulose, carnauba wax, sodium carboxymethyl cellulose, titanium dioxide, stearic acid, polyoxyethylene stearate 40, refined gelatin, refined shellac, refined white sugar, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, white sugar, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pullulan, povidone, polyvinyl alcohol (partially saponified), polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0153] As a plasticizer, it can be combined with one or more components selected from triethyl citrate, glycerol, glyceryl fatty acid esters, D-sorbitol, medium-chain fatty acid triglycerides, triacetic acid glycerides, concentrated glycerol, castor oil, polyoxyethylene hardened castor oil 60, propylene glycol, polyoxyethylene (105)polyoxypropylene (5) glycol, polysorbate 80, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, glyceryl monostearate, isopropyl linoleate, liquid paraffin, etc.

[0154] As a dispersant, it can be formulated with, for example, aminoalkyl methacrylate polymers RS, gum arabic, gum arabic powder, carboxyvinyl polymers, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerol, glycerol fatty acid esters, magnesium silicate, light alumina, crystalline cellulose, titanium dioxide, sucrose fatty acid esters, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, low-substituted hydroxypropyl cellulose, dextrin, corn starch, lactose hydrate, concentrated glycerol, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, and polymethyl methacrylate. The following are one or more of the following components: ethylene oxide-cured castor oil, polyoxyethylene-cured castor oil 40, polyoxyethylene-cured castor oil 50, polyoxyethylene-cured castor oil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, polyethylene glycol 300, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, anhydrous sodium citrate, magnesium aluminum metasilicate, methylcellulose, glyceryl monooleate, sorbitan monooleate, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, etc.

[0155] As an antifoaming agent, it can be combined with one or more ingredients selected from ethanol, glycerol fatty acid esters, dimethyl polysiloxane (for internal use), a mixture of dimethyl polysiloxane and silica, sucrose fatty acid esters, silicone defoamers, silicone oil, sorbitan fatty acid esters, polysorbate 80, etc.

[0156] These additives are not limited to those listed above; in addition, one of them may be used, or two or more may be used in combination.

[0157] Furthermore, in solid dosage forms, as needed, pharmacologically active ingredients other than components (A), (B), and (C) may be appropriately added within the scope that does not impair the effects of the present invention, such as antipyretics, analgesics, antitussives and expectorants, antihistamines, anti-inflammatory agents, anticholinergic agents, other vitamins, xanthine derivatives, and sedatives; if there are contraindications to these, appropriate formulations such as particle separation can be carried out.

[0158] As an antipyretic and analgesic, it can be combined with one or more of the following ingredients: aspirin, aluminum aspirin, acetaminophen, ethylsalicylate, salicylates, salicylamide, lactylfenatidine, ibuprofen, isopropyl antipyrine, pranoprofen, diclofenac sodium, mefenamic acid, indomethacin, farnesyl ester, acemetacin, etodoxacin, naproxen, meloxicam, celecoxib, sodium salicylate, and thiamide hydrochloride.

[0159] Examples of antitussive and expectorant agents include codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, sodium bis(2-naphthyl)sulfonate, dimethionine phosphate, tepperidine citrate, tepperidine hypothalamic acid salt, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthalein, alopramide hydrochloride, clopidogrel hydrochloride, clopidogrel fendizole salt, pentoxyverine citrate, noscapine, noscapine hydrochloride, tratoquinol hydrochloride, norephedrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, L-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, guaiacol glyceryl ether, guaiacol potassium sulfonate, cresol potassium sulfonate, L-carboxycysteine, ambroxol hydrochloride, bromhexine hydrochloride, and L-ethylcysteine ​​hydrochloride.

[0160] Examples of antihistamines include azelastine hydrochloride, alimazine tartrate, ebastine, epinastine hydrochloride, emesamtine fumarate, oxamide, olopatadine hydrochloride, carbixamine, chlormastine fumarate, diphenyl disulfonate, carbixamine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, diphenylpiraline hydrochloride, and diphenylpiraline tea. Chloride, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannic acid, triprolidine hydrochloride, tripenamin hydrochloride, sinepromine hydrochloride, fexofenadine, fenethazine hydrochloride, promethazine hydrochloride, methaqualone hydrochloride, methaqualone hydrochloride, loratadine, isoamyl ester hydrochloride, dibenzyl terbutaline hydrochloride, methaqualone hydrochloride, methaqualone disulfonic acid, promethazine methylene disalicylic acid, dibenzyl terbutaline phosphate, etc.

[0161] Examples of anti-inflammatory agents include glycyrrhizic acid and its derivatives, as well as their salts (e.g., dipotassium glycyrrhizate, monoammonium glycyrrhizate, etc.).

[0162] Examples of anticholinergic agents include scopolamine hydrobromide, datura extract, methyl scopolamine bromide, methyl-l-scopolamine bromide, pirenzepine hydrochloride, butyl scopolamine bromide, belladonna alkaloids, belladonna extract, total belladonna alkaloids, isopropylamide iodide, diphenylpiperidinylmethyldioxane iodide, scopolamine extract, scopolamine root, and total scopolamine root alkaloids citrate.

[0163] Examples of vitamins include vitamin A, vitamin C, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin P, vitamin E, hesperidin, niacin, nicotinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, potassium magnesium aspartate mixture, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine ​​hydrochloride, orotic acid, γ-oryzanol, calcium glycerophosphate, calcium gluconate, glucuronide lactone, glucuronide, sodium chondroitin sulfate, ginseng, coix seed, and iodic acid.

[0164] Examples of sedatives include allyl isopropyl acetylurea and brominal.

[0165] These additives are not limited to those listed above; in addition, one of them may be used, or two or more may be used in combination.

[0166] Solid dosage forms are preferably intended for the purpose of suppressing fever, pain, and inflammation. Since the active ingredient is selected from at least one of loxoprofen, its salts, and their hydrates, which has antipyretic, analgesic, and anti-inflammatory effects, it is suitable for use as an antipyretic analgesic. Specifically, it is suitable for analgesia of headache, dysmenorrhea, toothache, post-extraction pain, sore throat, back pain, joint pain, muscle pain, stiff neck and shoulder, earache, sprains, fracture pain, strain pain, and traumatic pain, as well as for reducing fever and chills. Furthermore, it is suitable for use as a cold treatment to relieve various cold symptoms (runny nose, nasal congestion, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, muscle pain).

[0167] (Dosage form)

[0168] Solid dosage forms may include, for example, oral administration preparations (including tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.) and intraoral preparations (including oral tablets, lozenges, sublingual tablets, buccal tablets, attached tablets, gels, etc.) as specified in the 18th revised Japanese Pharmacopoeia General Rules for Preparations.

[0169] Furthermore, examples of solid dosage forms include pills or tablets. These solid dosage forms may also be coated with sugar coating, film coating, etc., by known methods as needed. Solid dosage forms are preferably uncoated tablets, film-coated tablets, or sugar-coated tablets, and more preferably uncoated tablets, film-coated tablets, or sugar-coated tablets.

[0170] (Packaging)

[0171] The packaging refers to the container in which the solid dosage form described in this embodiment is housed. By creating a packaging, for example, the convenience of using the solid dosage form can be improved.

[0172] (Packaging format)

[0173] Regarding the packaging form of solid dosage forms, they can be preserved airtightly through single-use packaging such as strip packages, press-through packages, strip packages, bottle packages, and bag packages. That is, solid dosage forms can also be stored in airtight packaging. Furthermore, they can also be packaged in pillow-type containers and stored in boxes, etc.

[0174] In other words, a pharmaceutical product according to one embodiment of the present invention may also include the solid dosage form and packaging material for packaging the solid dosage form as described above.

[0175] There are no limitations on the materials used for SP packaging, PTP packaging, strip packaging, and pillow packaging. For example, single-layer resin films such as polyvinyl chloride film, polyvinylidene chloride film, polypropylene film, polyethylene terephthalate film, and polyethylene film, as well as multilayer films composed of these resin films, and materials on which aluminum foil is attached.

[0176] The packaging material for solid dosage forms is preferably a material that is not easily affected by moisture (a package formed from at least one of moisture-proof material and gas barrier material).

[0177] For example, packaging made of materials with low moisture impact (moisture-proof materials) can also be designed as PTP (polypropylene) + polyethylene aluminum pillow packaging (a combination of PTP and polyethylene aluminum pillow packaging). Furthermore, considering factors such as inhibition of moisture level rise in tablets, tablet storage stability, and tablet stability after opening, packaging made of materials less susceptible to moisture impact (moisture-proof materials) can use PTP packaging with aluminum on both sides (Al-Al packaging).

[0178] In addition, if hygroscopicity is a concern, desiccants can be stored in bottle packaging, pillow packaging, or other similar containers.

[0179] As a gas barrier material, any known gas barrier material can be used without particular limitation. For example, it can be a laminate with a functional barrier layer, which can have the functions of the aforementioned moisture-proof materials or be used in combination with the aforementioned moisture-proof materials.

[0180] In addition, packaging containers can be designed with environmental considerations in mind. For example, some or all of the packaging materials can be made from environmentally friendly materials such as recycled plastics, biomass plastics, and biodegradable plastics.

[0181] The embodiments of the present invention have been described above, but these are merely examples, and various configurations other than those described can be employed. Furthermore, the present invention is not limited to the above embodiments, and modifications and alterations that can be made without departing from the spirit and scope of the present invention are also included in the present invention.

[0182] Example

[0183] The present invention will be described in detail below with reference to the embodiments, but the present invention is not limited in any way by these embodiments.

[0184] <Manufacturing of Solid Dosage Forms>

[0185] (Examples 2, 3, and Comparative Example 2)

[0186] Loxoprofen sodium hydrate (manufactured by KOLON Corporation), tranexamic acid (manufactured by Kyowa Pharmaceutical Chemical Co., Ltd.), erythritol (manufactured by Buchan Food Science Co., Ltd.), hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.), and calcium carboxymethyl cellulose (manufactured by Gotoku Pharmaceutical Co., Ltd.) were weighed, kneaded in a mortar, and dried at 80°C for 1 hour to obtain granules. During kneading in the mortar, the particle size was adjusted by changing the amount of purified water added to achieve the average particle size shown in Table 1. The average particle size in Table 1 is the arithmetic mean of the mass-based particle size distribution obtained by sieving, i.e., the mass-average diameter.

[0187] After sieving the obtained granules through an 18-mesh sieve, weigh them and add magnesium stearate (manufactured by Taiping Chemical Company) as an additive. Mix the mixture 100 times in a 10K bottle to obtain a mixture of granules and additive.

[0188] The resulting mixture was compressed using a hydraulic pump tableting machine (manufactured by Riken Seiki Co., Ltd.) with a die ring of 9.0 mm in diameter and a punch with an R-surface of 10.8 mm in curvature at a tableting pressure of 10 kN, thereby obtaining tablets (solid dosage forms) with a weight of 341.9 mg per tablet.

[0189] The components and content (mg) of each tablet in the resulting compressed tablets are shown in Table 1.

[0190] (Examples 1 and 4)

[0191] Except for using glycine (manufactured by Fujifilm and Hikari Pure Chemical Industries Co., Ltd.) or replacing erythritol (manufactured by Busan Food Science Co., Ltd.) with crystalline cellulose (manufactured by Asahi Kasei Corporation) and anhydrous caffeine (manufactured by Shizuoka Caffeine Industrial Co., Ltd.), and adjusting the amount of purified water added, the same procedure as in Example 2 was followed to obtain tablets.

[0192] (Comparative Example 1)

[0193] Weigh loxoprofen sodium hydrate (KOLON Corporation), tranexamic acid (Kyowa Pharmaceutical Chemical Co., Ltd.), magnesium oxide (Kyowa Chemical Industry Co., Ltd.), hydroxypropyl cellulose (Nippon Soda Co., Ltd.), and calcium carboxymethyl cellulose (Wutoku Pharmaceutical Co., Ltd.), add an appropriate amount of purified water, mix in a mortar and pestle, and dry at 80°C for 1 hour to obtain granules.

[0194] After sieving the obtained granules through an 18-mesh sieve, weigh them and add magnesium stearate (manufactured by Taiping Chemical Company) as an additive. Mix the mixture 100 times in a 10K bottle to obtain a mixture of granules and additive.

[0195] The resulting mixture was compressed using a hydraulic pump tableting machine (manufactured by Riken Seiki Co., Ltd.) with a die ring of 9.0 mm in diameter and a punch with an R-surface of 10.8 mm in curvature at a tableting pressure of 10 kN, thereby obtaining tablets (solid dosage forms) with a weight of 341.9 mg per tablet.

[0196]

[0197] The following evaluations were performed on the resulting tablets.

[0198] <Hardness>

[0199] The tablet hardness (N) was determined using a tablet tester (Tablet Tester 8M, manufactured by Dr. Schleuniger Pharmatron). The hardness was the average of two samples (n=2). The results are shown in Table 1.

[0200] In addition, the hardness of Comparative Example 1 was higher than that of Comparative Example 2.

[0201] <Disintegration Time>

[0202] The disintegration time (min) of the tablets in Comparative Example 1 was determined using a disintegration tester (NT-2HSF, manufactured by Toyama Sangyo Co., Ltd.) according to the 18th revised edition of the Japanese Pharmacopoeia's "Disintegration Test Method". The disintegration time is the average of the two sample sizes. The results are shown in Table 1.

[0203] Dissolution Test

[0204] The dissolution rate of loxoprofen sodium hydrate in the tablets was determined according to the 18th revised edition of the Japanese Pharmacopoeia's Dissolution Test Method, specifically Method 2 (paddle method). 900 mL of purified water was used as the test solution, and the dissolution test was conducted at 50 rpm. The dissolution rate (%) was measured at 15 minutes and 30 minutes. The average dissolution rate was calculated using the measured values ​​from three samples. The results are shown in Table 1. Furthermore, a dissolution rate (%) of 90% or higher at 30 minutes was considered good, while a rate lower than 90% was considered poor.

[0205] Compared with Comparative Example 1, the solid dosage forms of Examples 1-4 showed excellent dissolution of loxoprofen (component (A)) and excellent shape retention in practical applications compared with Comparative Example 2.

[0206] The preferred embodiments and examples of the present invention have been described above, but the present invention is not limited thereto. Additions, omissions, substitutions, and other changes to the configuration may be made without departing from the spirit of the present invention.

[0207] Industrial availability

[0208] In this invention, solid dosage forms are extremely useful in terms of quality due to their excellent storage stability.

[0209] Solid dosage forms are suitable for use as antipyretic analgesics. Specifically, they are suitable for relieving pain in headaches, dysmenorrhea (menstrual pain), toothaches, post-extraction pain, sore throats, back pain, joint pain, muscle pain, stiff neck and shoulder pain, earaches, sprains, fractures, strains, and traumatic pain, as well as for reducing fever in cases of chills and fever. In addition, they are suitable for use as cold medicines to relieve various cold symptoms (runny nose, nasal congestion, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

[0210] This application claims priority based on Japanese Patent Application No. 2024-045285, filed on March 21, 2024, the entire disclosure of which is incorporated herein by reference.

Claims

1. A solid dosage form comprising the following components (A), (B) and (C): (A) Selected from at least one of loxoprofen, its salts and their hydrates. (B) Selected from at least one of tranexamic acid and its salts. (C) Selected from at least one of glycine, erythritol, and caffeine; The solid dosage form is in the form of tablets or pills. At the 15-minute time point in the dissolution test, the dissolution rate of component (A) was above 60%, and the hardness was above 50N.

2. The solid dosage form according to claim 1, wherein, The solid dosage form does not contain magnesium oxide, or the content of magnesium oxide is less than 30% by mass relative to the total content of the components (A), (B) and (C) of 100% by mass.

3. The solid dosage form according to claim 1 or 2, wherein, The solid dosage form does not contain crystalline cellulose, or the content of crystalline cellulose is less than 30% by mass relative to the total content of the components (A), (B) and (C) of 100% by mass.

4. The solid dosage form according to any one of claims 1 to 3, wherein, The solid dosage form satisfies the following condition: at the 30-minute time point in the dissolution test, the dissolution rate of component (A) is above 90%.

5. The solid dosage form according to any one of claims 1 to 4, wherein, Let C be the content (by mass%) of component (A) contained in 100% by mass of the tablet. A The content (mass%) of the aforementioned component (B) is set as C. B The content (mass%) of the aforementioned component (C) is set as C. C hour, C C / (C A +C B +C C The value ranges from 0.02 to 0.

95.

6. A pharmaceutical product comprising the solid dosage form according to any one of claims 1 to 5.

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