Process for the manufacture of solid formulations and tablets

Abstract

Provided is a method for producing a solid preparation containing (A) at least one selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof and (B) at least one selected from the group consisting of tranexamic acid and salts thereof, the method comprising: a wet granulation step in which a granulation is obtained by supplying water to a raw material powder containing components (A) and (B), wherein, when the addition rate of the water supplied in the wet granulation step is set to X, the plastic limit water addition rate of the raw material powder is set to PL, and the granulation index represented by X / PL is set to Ig, X is adjusted so as to satisfy 0.20 ≤ Ig ≤ 0.99.

Description

Technical Field

[0001] This invention relates to a method for manufacturing solid dosage forms and tablets. Background Technology

[0002] Currently, many cold and flu medications, as well as antipyretics and analgesics, widely use formulations containing multiple active ingredients. For example, cold and flu medications are known to contain a large number of ingredients, including antipyretics, analgesics, antitussives, expectorants, and rhinitis medications. These medications are widely sold as general medicines, and from the perspective of efficacy and safety, it is necessary for them to have excellent formulation stability.

[0003] Loxoprofen sodium or its hydrate is widely used clinically as a nonsteroidal antipyretic analgesic. Additionally, tranexamic acid, as an anti-inflammatory agent, is often incorporated as an active ingredient in cold and flu medications.

[0004] There have been reports on solid dosage forms containing loxoprofen or its salts, tranexamic acid or its salts, and magnesium oxide (see Patent Document 1). This document describes a solid dosage form with so-called contradictory properties of high hardness and good disintegration achieved by containing magnesium oxide.

[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 has shown that, in the manufacturing method of the formulation described in Patent Document 1, there is room for improvement in terms of the shape retention and dissolution unevenness of the resulting formulation.

[0009] In further research, the inventors discovered that by appropriately controlling the amount of water added to the raw material powder according to a specified granulation index during the wet granulation process of the raw material powder containing (A) loxoprofen or its salt and (B) tranexamic acid or its salt, a solid formulation with excellent shape retention and stable dissolution can be obtained due to its higher hardness and reduced dissolution unevenness, thus completing the present invention.

[0010] According to one embodiment of the present invention, a method for manufacturing a solid dosage form and a tablet are provided.

[0011] 1. A method for manufacturing a solid dosage form, comprising the following components (A) and (B),

[0012] (A) at least one selected from loxoprofen, its salts and their hydrates

[0013] (B) Selected from at least one of tranexamic acid and its salts.

[0014] The process includes a wet granulation step of obtaining granules by supplying water to a raw material powder containing the above-mentioned components (A) and (B).

[0015] Let X be the addition rate of the water supplied in the above wet granulation process, let PL be the plastic limit water addition rate of the raw material powder determined according to the following steps, and let the granulation index represented by X / PL be Ig, then adjust X to satisfy 0.20≤Ig≤0.99.

[0016] (Procedure for determining the plastic limit water addition ratio PL)

[0017] Using a mixer torque rheometer equipped with a main blade with four blades rotating in opposite directions within the mixing container and an auxiliary blade with two blades, 25g of the above-mentioned raw material powder was placed in the mixing container, water was added dropwise at the specified addition rate, and the main blade was stirred at 50 rpm for 45 seconds.

[0018] After stirring for 20 seconds, the torque of the stirring blades during this period was measured using a strain gauge.

[0019] By changing the addition rate, the water addition and torque measurement were repeated. The relationship between the water addition rate for the above raw material powder and the average torque value (N·m) of the stirring blade for 20 seconds was plotted and determined. The water addition rate when the torque value is the maximum was set as the plastic limit water addition rate (PL).

[0020] The water addition rate is defined as "the mass of water (g) / the mass of the raw material powder (g)".

[0021] 2. The method for manufacturing solid dosage forms according to 1.

[0022] In the above raw material powder, the mass ratio of the above component (A) to the mass of the above component (B), calculated using acid anhydride, is 0.01 to 4.0.

[0023] 3. The method for manufacturing solid dosage forms according to 1. or 2.

[0024] In the volume-based cumulative distribution determined by laser diffraction scattering, when the particle size of the point where the cumulative volume from the small particle side becomes 50% is set as D50, the D50 of at least one of the above-mentioned components (A) and (B) contained in the above-mentioned raw material powder is 10 μm to 200 μm.

[0025] 4. The method for manufacturing solid dosage forms according to any one of 1. to 3,

[0026] In the above-mentioned wet granulation process, a granulation treatment selected from fluidized bed granulation, extrusion granulation and stirring granulation is carried out.

[0027] 5. The method for manufacturing solid dosage forms according to any one of 1. to 4,

[0028] The process includes a drying step that dries the resulting granules.

[0029] 6. The method for manufacturing solid dosage forms according to any one of 1. to 5,

[0030] The process includes performing one or more steps selected from crushing, screening and grading on the resulting granules.

[0031] 7. A method for manufacturing a solid dosage form, comprising the method for manufacturing a solid dosage form as described in any one of 1. to 6.

[0032] The process includes shaping the obtained granules into granules, powders, capsules, pills or tablets.

[0033] 8. A tablet comprising the following ingredients (A) and (B),

[0034] (A) at least one selected from loxoprofen, its salts and their hydrates

[0035] (B) Selected from at least one of tranexamic acid and its salts.

[0036] The above tablets meet the following requirements:

[0037] (1) Hardness is above 30N

[0038] (2) The dissolution rate at the 15-minute time point in the dissolution test is above 50%, and the standard deviation of the dissolution rate is below 3.0.

[0039] According to the present invention, a method for manufacturing solid dosage forms and tablets with excellent shape retention and stable dissolution can be provided. Detailed Implementation

[0040] The method for manufacturing the solid dosage form according to this embodiment will be described.

[0041] (Manufacturing method of solid dosage forms)

[0042] The method for manufacturing solid dosage forms in this embodiment is a method for manufacturing solid dosage forms containing the following components (A) and (B).

[0043] (A) at least one selected from loxoprofen, its salts and their hydrates

[0044] (B) at least one of tranexamic acid and its salts

[0045] The method for manufacturing this solid dosage form includes a wet granulation step of obtaining granules by supplying water to a raw material powder containing components (A) and (B), wherein the water addition rate supplied in the wet granulation step is set as X, the plastic limit water addition rate of the raw material powder determined according to the following steps is set as PL, and the granulation index represented by X / PL is set as Ig, and X is adjusted to satisfy 0.20≤Ig≤0.99.

[0046] The procedure for determining the plastic limit water addition rate (PL) of the raw material powder is as follows.

[0047] Using a mixer torque rheometer equipped with a main blade with 4 blades rotating in opposite directions within a mixing container and an auxiliary blade with 2 blades, 25g of the above-mentioned raw material powder was placed in the mixing container, water was added dropwise at a specified addition rate, and the main blade was stirred at 50 rpm for 45 seconds.

[0048] After stirring for 20 seconds, the torque of the stirring blades during this period was measured using a strain gauge.

[0049] By varying the addition rate, the water addition and torque measurement were repeated. A plot was created showing the relationship between the water addition rate for the aforementioned raw material powder and the average torque value (N·m) of the stirring blade over 20 seconds. The water addition rate at which this torque value is maximized was defined as the plastic limit water addition rate (PL).

[0050] The water addition rate is defined as "the mass of water (g) / the mass of the raw material powder (g)".

[0051] According to the inventors' findings, it is determined that by appropriately controlling the amount of water added in the wet granulation process of raw material powder containing ingredients (A) and (B) according to a specified granulation index, the shape retention of solid dosage forms can be improved and stable dissolution can be ensured.

[0052] The lower limit of the granulation index Ig in the wet granulation process is 0.20 or higher, preferably 0.30 or higher, more preferably 0.40 or higher, and even more preferably 0.55 or higher. This improves the shape retention properties of the solid dosage form, such as hardness. It also helps to suppress damage to the appearance of the dosage form caused by breakage or chipping during manufacturing or transportation. Furthermore, the disintegration time can be adjusted if necessary.

[0053] On the other hand, the upper limit of the granulation index Ig in the wet granulation process is 0.99 or less, preferably 0.90 or less, more preferably 0.80 or less, and even more preferably 0.75 or less. This reduces the uneven dissolution of solid dosage forms.

[0054] In the wet granulation process, the ratio of the mass of component (A) to the mass of component (B) in the raw material powder, calculated using acid anhydride, is, for example, 0.01 to 4.0, preferably 0.05 to 3.0, and more preferably 0.1 to 2.0. By setting this numerical range, the plastic limit water addition rate (PL) of the raw material powder can be stably controlled.

[0055] In the volume-based cumulative distribution of raw material powder determined by laser diffraction scattering, the particle size of the point where the cumulative volume from the small particle side is 50% is set as D50.

[0056] In the wet granulation process, the D50 of at least one of components (A) and (B) contained in the raw material powder is, for example, 10 μm to 200 μm, preferably 15 μm to 180 μm, and more preferably 20 μm to 150 μm. Preferably, the D50 of both components (A) and (B) is within the range of the aforementioned upper and lower limits. By setting such a numerical range, the plastic limit water addition (PL) of the raw material powder can be stably controlled.

[0057] In the wet granulation process, it is preferable to perform a granulation treatment selected from fluidized bed granulation, extrusion granulation, and stirred granulation. However, it is not limited to this granulation treatment, and known methods may be used.

[0058] In other embodiments, the method for manufacturing the solid dosage form may include a drying step of the granules obtained from the drying process. Therefore, even after storage, the decrease in the content ratio of component (A) in the solid dosage form can be suppressed. Furthermore, since the decrease in the content ratio of component (A) during storage of the solid dosage form can be suppressed, storage stability is improved.

[0059] While the drying process is not particularly limited, the heating temperature can be, for example, 30–100°C, preferably 60–90°C. Additionally, the heating time can be, for example, 0.01–24 h, preferably 0.1–6 h.

[0060] In addition, the environmental conditions in the drying process can be set to atmospheric pressure, for example.

[0061] In this specification, unless otherwise stated, “~” indicates that both the upper and lower limits are included.

[0062] In other embodiments, the method for manufacturing solid dosage forms may, if necessary, include performing one or more particle size adjustment steps selected from crushing, sieving, and grading on the resulting granules. This allows for more stable control over the quality of the final product.

[0063] In other embodiments, the method for manufacturing solid dosage forms may include a molding step of shaping the resulting granules into granules, powders, capsules, pills, or tablets.

[0064] Specifically, as a form of solid dosage form, examples include granules, powders, capsules, tablets, or pills as described in the 18th revised Japanese Pharmacopoeia. The "solid dosage form" of the present invention is preferably granules, powders, capsules, or tablets, and more preferably tablets.

[0065] One embodiment of the tablet of this embodiment contains the above-described components (A) and (B).

[0066] Satisfies: (1) Hardness is above 30N,

[0067] (2) The dissolution rate at the 15-minute time point in the dissolution test is above 50%, and the standard deviation of the dissolution rate is below 3.0.

[0068] (1) The lower limit of the hardness is 30 N or more, preferably 40 N or more, and more preferably 50 N or more. This can suppress damage to the appearance of the formulation caused by cracks or gaps during manufacturing or transportation.

[0069] On the other hand, (1) although there is no specific limit to the upper limit of hardness, it can be below 200N.

[0070] (2) The lower limit of the dissolution rate at the 15-minute time point is 50% or more, preferably 55% or more, more preferably 60% or more, and even more preferably 75% or more. At this time, the upper limit of the standard deviation of the dissolution rate at the 15-minute time point is, for example, 3.0 or less, preferably 2.5 or less, and more preferably 2.0 or less. As a result, the active ingredient in the tablet can be stabilized and the drug efficacy can be exerted.

[0071] On the other hand, (2) although there is no specific limit to the upper limit of the dissolution rate at the 15-minute time point, it can be below 95%. (2) although there is no specific limit to the lower limit of the standard deviation of the dissolution rate at the 15-minute time point, it can be above 0.

[0072] It should be noted that in the determination of the standard deviation of dissolution rate described above, any number of tablets contained in the same package can be used as samples. While there is no particular limitation on the number of samples measured, for example, three or more can be used.

[0073] Of the aforementioned granules or tablets, it is preferable to coat the formulation with a water-soluble polymer or to coat the tablets with sugar. That is, film-coated granules, film-coated tablets, sugar-coated tablets, etc., are preferred forms of granules and tablets.

[0074] In addition, among the tablets mentioned above, multi-layer tablets made by overlapping powders or granules of different compositions into two or three or more layers and then compressing them are also preferred.

[0075] Solid dosage forms are preferably a mixed phase in which components (A) and (B) are in contact with each other. While the dispersion state of components (A) and (B) in the mixed phase is not particularly limited, they can be uniformly dispersed separately. It should be noted that while a solid dosage form may have a portion of a separate phase in which components (A) and (B) are not substantially in contact with each other, it may also lack such a separate phase.

[0076] <Ingredients (A)>

[0077] Ingredient (A) contains at least one selected from loxoprofen, its salts and their hydrates.

[0078] Ingredient (A) is a known compound, which can be manufactured by known methods or is available commercially available. Loxoprofen salts are listed as loxoprofen sodium hydrate in the 18th revised edition of the Japanese Pharmacopoeia.

[0079] Examples of loxoprofen, its salts, and their hydrates include, for instance, loxoprofen, loxoprofen sodium, loxoprofen sodium dihydrate, and loxoprofen sodium dihydrate. These can be used individually or in combination of two or more.

[0080] Component (A) preferably contains loxoprofen sodium, and more preferably contains hydrated salts such as loxoprofen sodium dihydrate.

[0081] Although there is no limitation on the amount of component (A) contained in the solid dosage form, it is 1 to 80 parts by weight relative to 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.

[0082] <Ingredient (B)>

[0083] Component (B) contains at least one selected from tranexamic acid and its salts.

[0084] Component (B) is a known compound, which can be manufactured using known methods or commercially available products. Tranexamic acid is listed in the 18th revised edition of the Japanese Pharmacopoeia.

[0085] Specific examples of salts of tranexamic acid in component (B) include hydrohalides such as hydrofluoric acid salts, hydrochloride salts, hydrobromide salts, and hydroiodide salts; inorganic acid salts such as nitrates, perchlorates, sulfates, and phosphates; alkyl sulfonates with 1 to 4 carbon atoms such as methanesulfonates, trifluoromethanesulfonates, and ethanesulfonates; aryl sulfonates such as benzenesulfonates and p-toluenesulfonates; and acetates, malates, fumarates, succinates, citrates, and ascorbic acid. Organic acid salts such as salts, tartrates, oxalates, and maleates; alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; organic amine salts such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolylpyridine, and methylpyridine; and salts of amino acids such as glycine, lysine, arginine, ornithine, glutamate, and aspartate. These can be used individually or in combination of two or more.

[0086] Furthermore, although the content of component (B) is not limited, from the viewpoint of making the formulation more favorable, it is preferably 10% by mass or more in 100% by mass of solid dosage form, and more preferably 12.5% ​​by mass or more.

[0087] In addition, although there is no limitation, from the viewpoint of improving the antipyretic effect, the content of component (B) in 100% by mass of the solid dosage form is preferably 40% by mass or less, and more preferably 36% by mass or less.

[0088] The determination will be carried out at 80°C, and the mass loss per 50 seconds is defined as the drying loss (mass %) in the solid dosage form at time points where the mass loss is less than 1 mg, which is set as the moisture content.

[0089] 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 harsh conditions, the decrease in the content ratio of component (A) in the solid dosage form can be suppressed.

[0090] <Acid neutralizer>

[0091] In this embodiment, from the viewpoint of inhibiting gastric mucosal diseases, the solid dosage form is preferably further containing an antacid.

[0092] Examples of antacids, such as alkaline earth metals and / or earth metal-based basic inorganic compounds, include magnesium oxide, magnesium silicate, magnesium aluminosilicate, magnesium aluminum silicate, magnesium hydroxide, coprecipitates of magnesium hydroxide and potassium aluminum sulfate, magnesium carbonate, synthetic hydrotalcite, magnesium metasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium aluminate hydroxide, aluminum hydroxide gel, coprecipitates of aluminum hydroxide and sodium bicarbonate, mixed dried gels of aluminum hydroxide and magnesium carbonate, and aluminum hydroxide, magnesium carbonate, and carbon dioxide. Inorganic salts of magnesium, aluminum, and calcium, including calcium coprecipitates, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate, are permitted. Additionally, alkali metal-based basic inorganic compounds may include, for example, inorganic salts of sodium and potassium, selected from dry sodium carbonate, sodium hydroxide, sodium bicarbonate, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous sodium monohydrogen phosphate, potassium hydroxide, potassium bicarbonate, and potassium carbonate. Other examples include boric acid and glycine. One or more of these components may be incorporated. Preferably, one or more of magnesium oxide, magnesium aluminosilicate, synthetic aluminum silicate, precipitated calcium carbonate, and glycine are preferred.

[0093] When using magnesium oxide as an antacid, the magnesium oxide listed in the 18th revised Japanese Pharmacopoeia can be used, and it is readily available.

[0094] While there are no restrictions on the commercially available magnesium oxide, for example, magnesium oxide (light grade) manufactured by Tomita Pharmaceutical Co., Ltd., or magnesium oxide (heavy grade) manufactured by Kyowa Chemical Co., Ltd., can be used.

[0095] The content of magnesium oxide in solid dosage forms can be selected by taking into account the disintegration of the solid dosage form, the solubility of the drug, and its function as an antacid. Although there is no limitation, the total mass of the solid dosage form can be used as a benchmark. It can be 0 to 80% by mass or greater than 0 to 80% by mass, or 0.1 to 70% by mass, preferably 1 to 25% by mass.

[0096] When using magnesium aluminosilicate, the magnesium aluminosilicate listed in the 18th revised Japanese Pharmacopoeia can be used and is readily available.

[0097] While there are no restrictions on the commercially available magnesium aluminate metasilicate, one example is Neusilin manufactured by Fuji Chemical Industry Co., Ltd.

[0098] The content of magnesium aluminate metasilicate in solid dosage forms can be selected by considering the disintegration of the solid dosage form, the solubility of the drug, and its function as an antacid. Although there is no limitation, the total mass of the solid dosage form can be used as a benchmark. It can be 0 to 80% by mass or greater than 0 to 80% by mass, or 0.1 to 70% by mass, preferably 1 to 50% by mass.

[0099] <Crude Drugs (Crude Drug Components)>

[0100] The solid dosage form of the present invention may include medicinal herbs.

[0101] While the types of medicinal herbs used in this invention are not particularly limited, they may be selected from, for example, ephedra, nandina, cherry bark, polygala, licorice, platycodon, plantain seed, plantain herb, lycoris radiata, polygala tenuifolia, fritillaria, fennel, phellodendron bark, coptis chinensis, turmeric, chamomile, cinnamon, gentian, bezoar, animal bile (including bear bile), glehnia, ginger, atractylodes lancea, clove, tangerine peel, atractylodes macrocephala, earthworm, bamboo ginseng, carrot, wild parasol tree, uncaria, epimedium, corydalis, scutellaria baicalensis, polygonatum, valerian. The crude drugs and extracts (extracts, tinctures, dried extracts, etc.) of herbs such as Trichosanthes kirilowii, apricot kernel, wolfberry, wolfberry leaf, schizonepeta, cassia seed, Chinese and Japanese geranium, cyperus rotundus, schisandra, asarum, Sichuan pepper, aster, lycium bark, peony root, musk, magnolia flower, chuanxiong, angelica dahurica, Japanese angelica, mulberry bark, perilla, garlic, angelica sinensis, ipecac tincture, ophiopogon japonicus, pinellia ternata, saffron, roe, angelica dahurica, poria cocos, peony bark, oyster shell, deer antler, and fangji, as well as one or more of these components.

[0102] In the solid dosage form of the present invention, it is preferred to include at least one of licorice extract, peony extract, and valerian extract.

[0103] Although the proportion of medicinal materials in the solid dosage form of the present invention is not particularly limited, for example, when each medicinal material is an extract, the total mass of the solid dosage form is used as a benchmark, and it can be 1 to 80% by mass, or 1 to 50% by mass, or 1 to 40% by mass, or 1 to 30% by mass.

[0104] The medicinal herbs used in this invention, such as licorice, peony, and valerian, have been used medicinally since ancient times as single-ingredient remedies or in traditional Chinese medicine formulas. The raw herb powder or extract obtained according to their respective conventional methods can be used directly. The form of the raw herb powder or extract can also be a commonly available commercial product or its processed form. For example, the raw herb powder can be used as a dried powder (micro-powder) obtained by further finely pulverizing a dried and finely processed product. Furthermore, the form of the extract from the raw herb is not particularly limited; for example, it can be used in any form, such as a dried extract, extract powder, soft extract, fluid extract, ethanol, or a tincture containing ethanol and water. Preferred raw herbs include extracts with high formulation flexibility, such as soft extracts or dried extract powders.

[0105] The extracted components can be obtained by conventional methods, such as extracting the antibacterial active ingredients from the aforementioned medicinal materials using an extraction solvent. Commonly used extraction solvents include, for example, water, hydrophilic solvents, or mixtures thereof. Examples of such hydrophilic solvents include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, S-butanol, and T-butanol; cellulose solvents such as methylcellulose and ethylcellulose; ketone solvents such as acetone; and diethylcellulose. Hydrophilic solvents include 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.

[0106] Licorice, as in the existing technology, can be used as an anti-inflammatory agent, cold medicine, antipyretic analgesic, antitussive and expectorant, gastrointestinal medicine, anthelmintic, oral medicine for rhinitis, throat freshener, stomachic and cooling agent, health supplement containing vitamins, sweetener, flavoring agent, coloring agent, flavoring agent, spice or excipient.

[0107] When using "licorice" in this invention, it is preferable to use the licorice listed in the 18th revised Japanese Pharmacopoeia.

[0108] The licorice mentioned above is also commercially available and therefore readily available.

[0109] Commercially available licorice extracts include those using water or a 30% ethanol aqueous solution as extraction solvents. For example, there are extracts available with varying conversion ratios depending on the type of licorice extract, such as licorice root extract, dried licorice root extract, soft licorice root extract, or liquid licorice root extract. In addition to these licorice root extracts, licorice root extract solution, etc., can also be used appropriately, without particular limitation.

[0110] When commercially available licorice is used in oral pharmaceutical compositions, for example, licorice can be used in a manner that is appropriate for the licorice content in tablets, taking into account the conversion ratio of the original drug.

[0111] While 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 a tablet for daily administration is preferably 10 mg to 10 g, more preferably 150 mg to 5 g, even more preferably 500 mg to 3000 mg, or 500 mg to 1500 mg, and is administered 1 to 3 times daily.

[0112] 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, but based on the total mass of the tablet, it can be 0.1 to 80% by mass, or 1 to 50% by mass, preferably 5 to 40% by mass, and more preferably 10 to 30% by mass.

[0113] When the present invention uses "valerian", the valerian listed in the 18th revised Japanese Pharmacopoeia is preferred.

[0114] Valerian other than those mentioned above is readily available as it is also a commercially available product.

[0115] As commercially available valerian, valerian powder or valerian extract (such as soft extract or dried extract) can be used, without particular limitation.

[0116] When commercially available valerian is used in oral pharmaceutical compositions, valerian can be used in a manner that is appropriate for the valerian content in the tablet, taking into account the conversion ratio of the raw drug.

[0117] When the present invention uses "valerian (valerian or valerian extract)", the content is not particularly limited, but for example, the amount of the ingredient contained in a tablet for daily administration, converted from the amount of raw drug, can be 1 to 6000 mg, preferably 10 to 2000 mg, more preferably 20 to 1440 mg, even more preferably 60 mg to 1000 mg, or 60 to 450 mg, and the administration frequency is 1 to 3 times a day.

[0118] In the solid dosage form of the present invention, for example when valerian extract is used, although the content of valerian extract is not particularly limited, it can be 1 to 50% by mass, preferably 2 to 40% by mass, and more preferably 3 to 20% by mass, based on the total mass of the tablet.

[0119] When the term "peony" is used in this invention, the peony listed in the 18th revised Japanese Pharmacopoeia is preferably used as "peony".

[0120] Peonies other than those mentioned above are readily available as they are also commercially available products.

[0121] As for commercially available peony, for example, peony powder or peony extract (such as containing dried extract or soft extract) can be used, without particular limitation.

[0122] When commercially available peony is used in oral pharmaceutical compositions, peony can be used in a manner that is appropriate for the peony content in tablets, as long as the conversion ratio of the raw drug is taken into account.

[0123] When “peony (peony or its extract)” is used in this invention, although there is no particular limitation on the content, it is preferred to administer 100 to 5000 mg per day, more preferably 150 to 2000 mg, and particularly preferably 200 to 900 mg per day, based on the original peony drug. The number of times the drug is administered is 1 to 3 times per day.

[0124] 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 based on the total mass of the tablet, it can be 1 to 50% by mass, preferably 2 to 40% by mass, and more preferably 3 to 20% by mass.

[0125] Furthermore, without affecting the scope of this invention, other pharmaceutical ingredients may be added to the raw material components in the wet granulation process if necessary, and additives may be added if necessary, in accordance with conventional methods.

[0126] For example, when the solid dosage form is a tablet, it can be manufactured by mixing component (A) and component (B) and appropriate other components, performing wet granulation, drying the granules, adding the final component to the resulting granulated particles in a manner that forms the exterior of the granulated particles, and then tableting.

[0127] That is, tablets can be manufactured, for example, by a process of producing granulated particles (at least one granulated particle) containing ingredient (A) and ingredient (B) and suitable other ingredients; and a process of mixing the granulated particles with a desired additive (final ingredient) and then beating them to produce tablets. In addition, ingredients disposed on the outside of the particles can be arbitrarily made into granules.

[0128] The final component (exterior of the granulated particles) is the portion in the tablet that forms the exterior of the granulated particles. For example, it can be a portion in the tablet that is coated with one granulated particle, or a portion that is coated with multiple granulated particles. Alternatively, it can be a portion in the tablet that is coated with at least one granulated particle and forms the exterior of the tablet.

[0129] As a method for storing solid dosage forms, it is preferable to store the prepared solid dosage forms in sealed containers such as glass bottles or PTP bottles. As harsh storage conditions, an external ambient temperature of 30°C or higher and / or an external ambient humidity of 60%RH or higher may be used.

[0130] During formulation, additives may be appropriately used in conjunction with known methods. Additives should be added appropriately without impairing the effectiveness of the invention.

[0131] As additives, pharmaceutically permissible carriers can be cited as examples, such as excipients, binders, disintegrants, disintegration aids, lubricants, flow agents, gloss enhancers, 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. Pharmaceutical additives that are conventionally known for solid dosage forms can be used for the aforementioned purposes. These can be used alone or in combination of two or more.

[0132] Examples of excipients include powdered sugar, gum arabic, gum arabic powder, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silica, anhydrous amorphous silica, xylitol, magnesium aluminosilicate, calcium silicate, magnesium silicate, anhydrous dicalcium phosphate, anhydrous dicalcium phosphate granules, monodicalcium phosphate, dicalcium phosphate hydrate, dicalcium phosphate granules, sodium hydrogen phosphate hydrate, didicalcium phosphate hydrate, crystalline cellulose, crystalline cellulose·sodium carboxymethyl cellulose, crystalline cellulose (microparticles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate·hydroxypropyl starch·crystalline cellulose Vitamins, wheat starch, rice flour, rice starch, heavy silicic anhydride, purified white sugar, purified white 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 syrup, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene cured castor oil, polyoxyethylene cured castor oil 60, maltitol, D-mannitol, magnesium aluminate metasilicate, calcium sulfate, erythritol, glucose, fructose, etc. These can be used individually or in combination of two or more.

[0133] As a binder, 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 gum, povidone, polyvinyl alcohol (fully saponified), polyvinyl alcohol (partially saponified), methacrylic acid oligomer L, methacrylic acid oligomer LD, methacrylic acid oligomer S, butyl methacrylate-methyl methacrylate oligomer, methylcellulose, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0134] 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 individually or in combination of two or more.

[0135] Examples of disintegration aids include sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, polyethylene glycol 1500, and polyethylene glycol 4000.

[0136] Examples of lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, glycerol fatty acid esters, polyethylene glycol, hardened oil, and sodium stearate fumarate.

[0137] As a flow agent, it can be combined with one or more components selected from synthetic aluminum silicate, heavy silica anhydride, magnesium aluminum oxide hydroxide, stearic acid, calcium stearate, magnesium stearate, tertiary calcium phosphate, talc, and dicalcium phosphate granules.

[0138] As a gloss enhancer, it can be combined with one or more components selected from carnauba wax, white beeswax, purified shellac, polyethylene glycol 400, polyethylene glycol 1500, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 6000NF, beeswax, etc.

[0139] 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.

[0140] As a desiccant, it can be combined with one or more components selected from ethyl cellulose, olive oil, dried aluminum hydroxide gel, glycerin, magnesium silicate, hardened oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, purified shellac, purified white sugar, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, fumaric acid-stearic acid-polyvinyl acetal diethylamino acetate-hydroxypropyl methylcellulose 2910 mixture, polyvinyl acetal diethylamino acetate, etc.

[0141] 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 sorbitol beeswax, polyoxyethylene nonylphenyl ether, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, 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.

[0142] As a stabilizer, it can be added to, for example, bisaccharide, 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, disodium calcium ethoxide, sodium ethoxide, tetrasodium ethoxide, tetrasodium ethoxide tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, cetylpyridinium chloride, ferric chloride, sodium chloride, magnesium chloride, cysteine ​​hydrochloride, histidine hydrochloride, cocoa butter, carboxyvinyl polymers, carboxymethyl cellulose (Carbamide). Calcium, sodium carboxymethyl cellulose, hydrated silica, dried sodium carbonate, glycine, glycerol, glycerol fatty acid esters, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, sodium L-glutamate, L-glutamate, L-lysine, crystalline sodium dihydrogen phosphate, sodium chondroitin sulfate, zinc oxide, L-cysteine, L-cysteine, tartaric acid, sucrose fatty acid esters, stearic acid, purified gelatin, purified soybean lecithin, gelatin, gelatin hydrolysate, sorbitan fatty acid esters, taurine, talc, calcium carbonate, potassium bicarbonate, bicarbonate Sodium, sodium carbonate hydrate, magnesium carbonate, natural vitamin E, tocopherol, tocopheryl acetate, lactose, concentrated glycerin, 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 glycerol base (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, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0143] 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.

[0144] Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soybean lecithin, natural vitamin E, tocopherol, tocopheryl acetate, ascorbic acid palmitate, and sodium metabisulfite.

[0145] Examples of fillers include RSS No.1 raw gum, acrylic starch 1000, hydrated silica, titanium dioxide, silica, and dicalcium phosphate.

[0146] Examples of preservatives include benzoic acid, sodium benzoate, ethylparaben, propylparaben, methylparaben, dehydroacetic acid, sodium dehydroacetate, sorbic acid, and phenoxyethanol.

[0147] As a sweetener, it can be combined with one or more ingredients selected from aspartame, potassium acetamide sulfonate, gancha, gancha powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizate, disodium glycyrrhizate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, purified stevia extract, purified white sugar, fructose, white sugar, maltitol, D-mannitol, erythritol, etc.

[0148] 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, citrate hydrate, sodium citrate hydrate, L-glutamic acid, sodium L-glutamic acid, grapefruit extract, black sugar, saccharin, sodium saccharin hydrate, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, sodium DL-tartrate, sucralose, stevia extract, purified stevia extract, Japanese herbal medicine, 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.

[0149] Examples of cooling agents include fennel oil, d-camphor, dl-camphor, cinnamon oil, peppermint water, peppermint oil, and l-menthol.

[0150] As a flavoring agent, it can be combined with one or more ingredients selected from orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder flavor, peach extract, fruit flavor, mint, cantaloupe powder flavor, L-menthol, peppermint oil, etc.

[0151] Examples of aromatic agents include anise powder, anise oil, ethyl vanillin, d-camphor, dl-camphor, spearmint oil, turpentine oil, pineapple powder fragrance 51357, pineapple powder fragrance 59492, peppermint water, peppermint oil, vanilla powder fragrance 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, rose oil, etc.

[0152] As a coloring agent, it can be combined with one or more of the following ingredients: yellow iron oxide, yellow ferric oxide, orange flavoring, brown iron oxide, carbon black, caramel, β-carotene, gold leaf, black iron 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, copper chlorophyllin sodium, chlorophyll copper, phenol red, malachite green, methane blue, medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin phosphate sodium, green tea powder, rose oil, etc.

[0153] As a base agent, it can be formulated with, for example, gum arabic powder, pregelatinized starch, partially pregelatinized starch, ethyl cellulose, cocoa butter, carbamate wax, carboxyvinyl polymer, carboxymethyl cellulose, sodium carboxymethyl cellulose, reduced maltose syrup, hydrated silica, dried aluminum hydroxide gel, agar, agar powder, xanthan gum, glycine, glycerol, glyceryl fatty acid esters, light silicic anhydride, crystalline cellulose, hardened oil, synthetic aluminum silicate, synthetic sodium magnesium silicate, 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 cellulose, hydroxypropyl methylcellulose, pullulan gum, 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, butyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc., one or more of the following components.

[0154] Examples of coating agents include, for instance, ethyl acrylate-methyl methacrylate oligomer dispersions, aminoalkyl methacrylate oligomer E, aminoalkyl methacrylate oligomer 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, purified gelatin, purified shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold foil, precipitated calcium carbonate, concentrated glycerol, white shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose 2910-titanium dioxide-polyethylene glycol 400 mixture, hydroxypropyl methyl cellulose, fumaric acid-stearic acid-polyethylene acetal diethylamino acetate-hydroxypropyl methyl cellulose Mixtures of 2910, pullulan gum, polysorbate 80, diethylamino acetate of polyethylene acetal, 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 oligomer L, methacrylic acid oligomer LD, methacrylic acid oligomer S, magnesium aluminate metasilicate, methacrylate-methacrylic acid-methyl methacrylate oligomer, methylcellulose, 2-methyl-5-vinylpyridine methacrylate-methacrylic acid oligomer, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

[0155] 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, polyethylene glycol stearate 40, purified gelatin, purified shellac, purified white sugar, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, white sugar, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pullulan gum, 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.

[0156] 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 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, and flowing paraffin.

[0157] 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 methylcellulose, and povidone. The following are one or more of the following components: polyoxyethylene hardened castor oil, polyoxyethylene hardened castor oil 40, polyoxyethylene hardened castor oil 50, polyoxyethylene hardened 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 aluminate metasilicate, methylcellulose, glyceryl monooleate, sorbitan monooleate, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, etc.

[0158] 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.

[0159] These additives are not limited to those listed above. In addition, one of these additives may be used, or two or more may be used in combination.

[0160] Furthermore, in solid dosage forms, pharmacologically active ingredients other than components (A) and (B), such as antipyretics, analgesics, antitussives and expectorants, antihistamines, anti-inflammatory agents, anticholinergic agents, other vitamins, xanthine derivatives, and sedatives, can be appropriately combined within the scope that does not impair the effects of the present invention. If there are contraindications to these combinations, they can be formulated by appropriately separating the particles.

[0161] As an antipyretic and analgesic, it may be combined with one or more ingredients selected from aspirin, aluminum aspirin, acetaminophen, ethylsalicylic acid, sapiridylene, salicylamide, phenacetin lactate, ibuprofen, isopropyl antipyrine, pranoprofen, diclofenac sodium, mefenamic acid, farnesin, acemetacin, etodoxacin, naproxen, meloxicam, celecoxib, sodium salicylate, and thiamethoxazole hydrochloride.

[0162] Examples of antitussive and expectorant agents include codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, sodium naphthalene sulfonate dibutyrate, dimethionine phosphate, tepidine citrate, tepidine dihydroxynaphthalene, dextromethorphan, dextromethorphan hydrobromide hydrate, phenolphthalein dextromethorphan, alloramicin hydrochloride, clopidogrel hydrochloride, clopidogrel fendezol, pentoxyverine citrate, noscapine, noscapine hydrochloride, trimequinol hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, levo-methylephedrine hydrochloride, racemic methylephedrine hydrochloride, saccharin salt racemic methylephedrine, guaiacol, potassium guaiacol sulfonate, potassium cresol sulfonate, L-carboxymethylcysteine, ambroxol hydrochloride, bromhexine hydrochloride, and L-ethylcysteine ​​hydrochloride.

[0163] Examples of antihistamines include azelastine hydrochloride, alimazine tartrate, ebastine, epinastine hydrochloride, emesamtine fumarate, oxamide, olopatadine hydrochloride, carbinoxamine, chlormastine fumarate, diphenyl disulfonate, carbinoxamine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, diphenylpiraline hydrochloride, and diphenylpiraline chlorpheniramine maleate. Larin, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannic acid, triprolidine hydrochloride, tripiramine hydrochloride, toprolamine hydrochloride, fexofenadine, fenazine hydrochloride, promethazine hydrochloride, promethazine, mesotrazine hydrochloride, loratadine, isoamylamine hydrochloride, diphenoxylate hydrochloride, medeprozin hydrochloride, mebendazim hydrochloride, naphthalene disulfonic acid mebuprofen, methylene disalicylic acid promethazine, diphenoxylate phosphate, etc.

[0164] Examples of anti-inflammatory agents include glycyrrhizic acid and its derivatives, as well as their salts (e.g., dipotassium glycyrrhizate, monoammonium glycyrrhizate, etc.).

[0165] Examples of anticholinergic agents include scopolamine hydrobromide, belladonna extract, methyl scopolamine bromide, methyl-l-scopolamine bromide, pirenzepine hydrochloride, butyl scopolamine bromide, belladonna alkaloids, belladonna extract, total belladonna alkaloids, iodopropamide, diphenylpiperidinylmethyldioxolane iodide, hyoscyamine extract, hyoscyamine root, and total hyoscyamine root alkaloids citrate.

[0166] 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, a mixture of potassium magnesium aspartate, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine ​​hydrochloride, orotic acid, γ-oryzanol, calcium glycerophosphate, calcium gluconate, glucuronolactone, glucuronide, sodium chondroitin sulfate, ginseng, coix seed, and iodic acid.

[0167] Examples of xanthine derivatives include caffeine hydrate, anhydrous caffeine, sodium caffeine benzoate, and caffeine citrate.

[0168] Examples of sedatives include allyl isopropyl acetylurea and bromovalerate.

[0169] These additives are not limited to those listed above. In addition, one of these additives may be used, or two or more may be used in combination.

[0170] Solid dosage forms are preferably used for the purpose of suppressing fever, pain, and inflammation. At least one of the active ingredients, namely loxoprofen, its salts, and their hydrates, has antipyretic, analgesic, and anti-inflammatory effects. Therefore, as an antipyretic and analgesic, it is particularly preferred for relieving headaches, menstrual pain (menstrual cramps), toothaches, post-extraction pain, sore throats, back pain, joint pain, muscle pain, stiff shoulders, earaches, bruises, fractures, sprains, and traumatic pain, as well as for reducing fever and chills. Furthermore, as a cold treatment, it is preferably used to alleviate various symptoms of the cold (runny nose, nasal congestion, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, muscle pain).

[0171] (Dosage Form)

[0172] Solid dosage forms, such as those described in the General Principles of Pharmaceutical Preparations of the Japanese Pharmacopoeia (18th Amendment), include those that can be administered orally (including tablets, intraorally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.) and those intended for use in the oral cavity (including oral tablets, lozenges, sublingual tablets, buccal lozenges, adhesive tablets, chewing gum, etc.).

[0173] In addition, examples of solid dosage forms include capsules, pills, granules, fine granules, powders, and tablets. These solid dosage forms can be coated with sugar or film using known methods, if necessary. The preferred dosage forms for solid dosage forms are uncoated tablets, film-coated tablets, sugar-coated tablets, granules, fine granules, or capsules, more preferably granules, uncoated tablets, film-coated tablets, or sugar-coated tablets.

[0174] (Packaging)

[0175] The packaging body houses the solid dosage form of this embodiment within a packaging container. By becoming a packaging body, the convenience of using, for example, the solid dosage form can be improved.

[0176] (Packaging format)

[0177] Regarding the packaging form of solid dosage forms, they can be preserved airtightly using temporary packaging such as strip packages, press-through packages, pouches, bottles, and sticks. In other words, solid dosage forms can be contained in airtight packaging. Furthermore, they can be packaged in pillow-shaped containers or stored in boxes or similar containers.

[0178] In other words, a pharmaceutical product according to one embodiment of the present invention may include the solid dosage form of the above embodiment and packaging materials for packaging the solid dosage form.

[0179] The materials used for SP packaging, PTP packaging, bag packaging, and pillow packaging are not limited. For example, single-layer resin films such as polyvinyl chloride film, polyvinylidene chloride film, polypropylene film, polyethylene terephthalate film, and polyethylene film, or multilayer films obtained by combining these resin films, and materials with aluminum foil attached to these resin films can be used.

[0180] Packaging materials for solid dosage forms are preferably those made of materials that are resistant to moisture (packages formed by at least one of moisture-proof materials and gas-barrier materials).

[0181] For example, packaging made of materials with low moisture content (moisture-proof materials) can be designed as PTP (polypropylene) + polyethylene aluminum pillow packaging (a combination of PTP and polyethylene aluminum pillow packaging). Furthermore, considering factors such as inhibiting the rise in tablet moisture content, tablet storage stability, and tablet stability after opening, packaging made of materials less susceptible to moisture effects (moisture-proof materials) can use PTP packaging with aluminum on both sides (Al-Al packaging).

[0182] It should be noted that, in view of hygroscopicity, desiccants can also be stored in bottle packaging or pillow packaging or other packaging containers.

[0183] The known materials that can be used as gas barrier materials are not limited, but for example, they can be laminated films with functional barrier layers, or they can also function as the aforementioned moisture-proof materials or be used together with the aforementioned moisture-proof materials.

[0184] In addition, packaging containers can be designed to be environmentally friendly. For example, recycled plastics, bio-based plastics, and biodegradable plastics can be used in part or all of the packaging materials.

[0185] The embodiments of the present invention have been described above, but these are merely examples, and various configurations other than those described above may be employed. Furthermore, the present invention is not limited to the embodiments described above; modifications and improvements made within the scope of achieving the objectives of the present invention are also included in the present invention.

[0186] Example

[0187] The present invention will now be described in detail with reference to embodiments, but the present invention is not limited to these embodiments in any way.

[0188] <Determination of the plastic limit water addition ratio (PL) of raw material powder containing components (A) and (B)>

[0189] Using a mixer torque rheometer (manufactured by Higuchi Shokai Co., Ltd., MTR-3) equipped with a main blade with 4 blades rotating in opposite directions within the mixing container and an auxiliary blade with 2 blades, 25g of raw material powder (component (A): loxoprofen sodium hydrate (manufactured by KOLON Co., Ltd., D50=64μm) 6.25g and component (B): tranexamic acid (manufactured by AMI Co., Ltd., D50=34μm) 18.75g) was placed in the mixing container, and water (purified water) at the specified addition rate was added dropwise. The main blade was stirred and mixed at 50 rpm for 45 seconds.

[0190] After stirring for 20 seconds, the torque of the stirring blades during this period was measured using a strain gauge.

[0191] By varying the water addition rate (0.02% each time, between 0.00 and 0.16%), the water addition and torque measurements were repeatedly performed. The relationship between the water addition rate for the raw material powder and the average torque value (N·m) of the stirring blade over 20 seconds was plotted and determined. The water addition rate at which this torque value is maximized was defined as the plastic limit water addition rate (PL). However, the water addition rate (g / g) was defined as "mass of water (g) / mass of raw material powder (g)". It should be noted that the specific gravity of purified water is 1.0.

[0192] The PL (plastic limit water addition ratio) of the above-mentioned raw material powder is 0.08 (g / g).

[0193] It should be noted that the above-mentioned D50 is the cumulative distribution of the particle size of the powder measured by laser diffraction scattering method based on volume, and is set as the particle size (median diameter) at the point where the cumulative volume from the small particle side is 50%.

[0194] <Manufacturing of Solid Dosage Forms>

[0195] (Examples 1-5)

[0196] According to the conditions of adding water with 10.0 g of mixed loxoprofen sodium hydrate (manufactured by KOLON) and 30.0 g of tranexamic acid (manufactured by AMI) to make 1 g of water 0.20, 0.63, 0.85, 0.95 or 0.99, 0.6 g, 2.0 g, 2.72 g, 3.04 g and 3.17 g of purified water were added respectively, kneaded in a mortar, and dried at 80 °C for 1 h to obtain the granules of Examples 1 to 5.

[0197] (Comparative Example 1)

[0198] Under the condition of adding 10.0 g of mixed loxoprofen sodium hydrate (manufactured by KOLON) and 30.0 g of tranexamic acid (manufactured by AMI) to make 1 g of water 0.09, 0.3 g of purified water was added, kneaded in a mortar, and dried at 80°C for 1 h to obtain the granules of Comparative Example 1.

[0199] (Comparative Example 2)

[0200] According to the conditions of adding water with 10.0 g of mixed loxoprofen sodium hydrate (manufactured by KOLON) and 30.0 g of tranexamic acid (manufactured by AMI) to make 1 g of water 1.00, 3.2 g of purified water was added, kneaded in a mortar, and dried at 80°C for 1 h to obtain the particles of Comparative Example 2.

[0201]

[0202] The following evaluation was performed on the obtained particulate samples (solid dosage forms).

[0203] (Preparation of tablet samples)

[0204] Regarding Examples 2-5 and Comparative Example 2, for the 9.0g of particles obtained above, as the final component, 0.8g of crystalline cellulose (manufactured by Asahi Kasei Corporation), 0.1g of low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Industry Co., Ltd.), and 0.1g of magnesium stearate (manufactured by Taihei Chemical Co., Ltd.) were added and mixed 100 times in a 10K specification bottle to obtain a mixture of particles and final component of 10.0g.

[0205] The resulting mixture was tableted in a hydraulic pump tableting machine (manufactured by Riken Seiki Co., Ltd.) using a mortar with a diameter of 9.5 mm and a punch with an R-surface having a radius of curvature of 11.4 mm, under a tableting pressure of 10 kN, to obtain tablet samples.

[0206] In addition, regarding Example 1 and Comparative Example 1, for the 9.0g of particles obtained above, as the final component, 0.6g of crystalline cellulose (manufactured by Asahi Kasei Corporation), 0.3g of croscarmellose sodium (manufactured by DuPont Corporation) and 0.1g of magnesium stearate (manufactured by Taihei Chemical Co., Ltd.) were added and mixed 100 times in a 10K specification bottle to obtain 10.0g of a mixture of particles and final component.

[0207] The resulting mixture was tableted in a hydraulic pump tableting machine (manufactured by Riken Seiki Co., Ltd.) using a mortar with a diameter of 9.5 mm and a punch with an R-surface having a radius of curvature of 11.4 mm, under a tableting pressure of 10 kN, to obtain tablet samples.

[0208] <Hardness>

[0209] The hardness (N) of the tablet samples was measured using a hardness tester (Tablet Tester 8M, manufactured by Dr. Schleuniger Pharmatron). The hardness was set as the average of two samples. The results are shown in Table 1.

[0210] <Disintegration Time>

[0211] The disintegration time (in minutes) of the tablet samples was determined using a disintegration tester (NT-2HSF, manufactured by Toyama Sangyo Co., Ltd.) according to the 18th revised version of the "Disintegration Test Method" of the Japanese Pharmacopoeia. Hardness was set as the average of two samples. The results are shown in Table 1.

[0212] Dissolution Test

[0213] The dissolution rate of the tablet samples was determined according to the 18th revised Japanese Pharmacopoeia's "Dissolution Test Method," using the Japanese Pharmacopoeia's Dissolution Test No. 2 (Paddle Method). 900 mL of purified water was used to perform the dissolution test on the test solution at 50 rpm. The dissolution rate (%) was measured at 15 minutes and 30 minutes. Using the measured values ​​of 3 samples, the standard deviation of each dissolution rate was calculated. The results are shown in Table 1.

[0214] It should be noted that the average dissolution rates of Examples 1-5 were all above 69% at the 15-minute time point and above 97% at the 30-minute time point.

[0215] Compared with Comparative Example 1, the solid dosage forms of Examples 1-5 showed higher hardness when made into tablets, and compared with Comparative Example 2, they showed improved results in suppressing uneven dissolution of tablets. It is understood that the solid dosage forms of these examples yield tablets with excellent shape retention and stable dissolution properties.

[0216] While the preferred embodiments and examples of the present invention have been described above, the present invention is not limited thereto. Additions, omissions, substitutions, and other modifications to the configuration may be made without departing from the spirit of the present invention.

[0217] Industrial availability

[0218] In this invention, solid dosage forms are extremely useful in terms of quality due to their excellent storage stability.

[0219] Solid dosage forms, as antipyretic analgesics, are specifically preferred for relieving pain in headaches, menstrual pain (menstrual cramps), toothaches, post-extraction pain, sore throats, back pain, joint pain, muscle pain, stiff and painful shoulders, earaches, bruises, fractures, sprains, and traumatic pain, as well as for reducing fever and chills. In addition, as a cold treatment, they are preferred for relieving various symptoms of the cold (runny nose, nasal congestion, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

[0220] This application claims priority based on Japanese Patent Application No. 2023-192199, filed on November 10, 2023, and incorporates all of its disclosures into this application.

Claims

1. A method for manufacturing a solid dosage form, comprising component A and component B. Ingredient A: Selected from at least one of loxoprofen, its salts, and their hydrates. Component B: Selected from at least one of tranexamic acid and its salts. The manufacturing method includes a wet granulation step of supplying water to a raw material powder containing components A and B to obtain granules. Let X be the addition rate of the water supplied in the wet granulation process, let PL be the plastic limit water addition rate of the raw material powder determined according to the following steps, and let X / PL represent the granulation index as Ig, then adjust X to satisfy 0.20≤Ig≤0.

99. The procedure for determining the plastic limit water addition ratio (PL) is as follows: Using a mixer torque rheometer equipped with a main blade with four blades and an auxiliary blade with two blades rotating in opposite directions within the mixing container, 25g of the raw material powder was placed in the mixing container, water was added dropwise at a specified addition rate, and the main blade was stirred at 50 rpm for 45 seconds. After stirring for 20 seconds, the torque of the stirring blades during this period was measured using a strain gauge. By changing the addition rate, the water addition and torque measurement were repeated. A plot was drawn showing the water addition rate for the raw material powder and the average torque value of the stirring blade over 20 seconds. The relationship was determined, and the water addition rate at which this torque value was maximized was set as the plastic limit water addition rate, PL. The unit of the average torque value is N·m. in, The water addition rate is defined as "the mass of water / the mass of the raw material powder", where the unit of mass is g.

2. The method for manufacturing solid dosage forms according to claim 1, wherein, In the raw material powder, the ratio of the mass of component A (converted to anhydride) to the mass of component B is 0.01 to 4.

0.

3. The method for manufacturing solid dosage forms according to claim 1 or 2, wherein, In the volume-based cumulative distribution determined by laser diffraction scattering, when the particle size of the point where the cumulative volume from the small particle side becomes 50% is set as D50, the D50 of at least one of the components A and B contained in the raw material powder is 10 μm to 200 μm.

4. The method for manufacturing a solid dosage form according to any one of claims 1 to 3, wherein, In the wet granulation process, a granulation treatment selected from fluidized bed granulation, extrusion granulation and stirred granulation is performed.

5. The method for manufacturing a solid dosage form according to any one of claims 1 to 4, wherein, The process includes a drying step that dries the resulting granules.

6. A method for manufacturing a solid dosage form according to any one of claims 1 to 5, comprising performing one or more steps selected from crushing, sieving and grading on the obtained granules.

7. The method for manufacturing a solid dosage form according to any one of claims 1 to 6, wherein, The process includes shaping the resulting granules into granules, powders, capsules, pills, or tablets.

8. A tablet comprising the following ingredients A and B, Ingredient A: Selected from at least one of loxoprofen, its salts, and their hydrates. Component B: Selected from at least one of tranexamic acid and its salts; The tablet satisfies: (1) Hardness is above 30N (2) The dissolution rate at the 15-minute time point in the dissolution test is above 50%, and the standard deviation of the dissolution rate is below 3.0.

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