WO2025041817A1 - Solid preparation and medicine - Google Patents

Abstract

This solid preparation contains component (A): at least one substance selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof, and component (B): at least one substance selected from the group consisting of tranexamic acid and salts thereof, and is such that in an X-ray diffraction pattern measured using Cu-Kα rays, there is no peak in at least three of the following five ranges of diffraction angle 2θ: 7.3 ± 0.1, 11.0 ± 0.1, 19.1 ± 0.1, 22.2 ± 0.1, and 24.8 ± 0.1.

Description

Solid Dosage Forms and Pharmaceuticals

The present invention relates to solid preparations and pharmaceuticals.

Currently, preparations containing multiple medicinal ingredients are widely used for general cold medicines and antipyretics and analgesics. For example, general cold medicines are known to contain many ingredients, such as antipyretics, antitussives, expectorants, and rhinitis medications. These drugs are widely sold as over-the-counter medicines, and from the standpoint of efficacy and safety, they need to have excellent stability as a formulation.

Lofexoprofen sodium or its hydrate is widely used in clinical practice as a nonsteroidal antipyretic analgesic. In addition, tranexamic acid is used as an active ingredient in general cold medicines as an anti-inflammatory agent to suppress inflammation.

The combined use of loxoprofen sodium or its hydrate with tranexamic acid and pharmaceutical compositions combining these have already been reported (see Patent Document 1), but this document does not include any description of the compounding changes of loxoprofen sodium or its hydrate with tranexamic acid, and therefore the stability of preparations combining loxoprofen sodium or its hydrate with tranexamic acid is unknown.

JP 2010-83882 A

However, as a result of the inventor's investigations, it was found that there is room for improvement in terms of storage stability in the formulation described in Patent Document 1 above.

The inventors further investigated and found that in a solid preparation containing component (A) at least one selected from the group consisting of loxoprofen, its salts, and hydrates thereof, and component (B) at least one selected from the group consisting of tranexamic acid and its salts, by appropriately controlling the X-ray diffraction pattern, it is possible to suppress a decrease in the content ratio of component (A) during storage and improve storage stability, thereby completing the present invention.

According to one aspect of the present invention, there is provided the following solid formulation.
1. A solid formulation containing the following components (A) and (B):
(A) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof; (B) at least one selected from the group consisting of tranexamic acid and a salt thereof. A solid formulation, which does not have peaks in at least three or more of the five ranges of diffraction angles 2θ of 7.3±0.1, 11.0±0.1, 19.1±0.1, 22.2±0.1, and 24.8±0.1 in an X-ray diffraction pattern of the solid formulation measured using Cu-Kα radiation.
2. The solid formulation according to 1.,
A solid preparation, wherein an X-ray diffraction pattern of the solid preparation measured using Cu-Kα radiation has a peak in at least one of three ranges of diffraction angle 2θ: 18.2±0.3, 20.5±0.3, and 21.9±0.3.
3. The solid formulation according to 1. or 2.,
A solid preparation, in which an X-ray diffraction pattern of the solid preparation measured using Cu-Kα radiation has a peak in at least one of the four ranges of diffraction angle 2θ of 6.8±0.1, 18.2±0.1, 20.5±0.1, and 21.9±0.1.
4. The solid formulation according to any one of 1 to 3,
A solid formulation, in which the mass ratio of the component (B) to the mass of the component (A) in the solid formulation is 0.1 or more and 10 or less.
5. The solid formulation according to any one of 1 to 4,
A solid formulation, wherein when measurement is performed at 80°C, the moisture content is defined as the loss on drying in the solid formulation at the time when the mass loss per 50 seconds becomes less than 1 mg, and the moisture content is 2.5 mass% or less.
6. The solid formulation according to any one of 1 to 5,
The solid preparation is in the form of granules, powder, capsules, pills, or tablets.
7. The solid formulation according to any one of 1. to 5.
Pharmaceuticals in the form of granules, powders, capsules, pills, or tablets.

The present invention provides a solid formulation with excellent storage stability.

The solid formulation of this embodiment will be described.

(Solid preparations)
The solid preparation of the present embodiment contains the following components (A) and (B):
(A) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof; (B) at least one selected from the group consisting of tranexamic acid and a salt thereof. The solid preparation is configured so that in an X-ray diffraction pattern measured using Cu-Kα radiation, it does not have peaks in at least three or more of the five ranges of diffraction angles 2θ of 7.3±0.1, 11.0±0.1, 19.1±0.1, 22.2±0.1, and 24.8±0.1.

According to the findings of the present inventors, it has been found that by mixing raw ingredients containing ingredients (A) and (B) and wet granulating them, followed by drying, it is possible to suppress the decrease in the content ratio of ingredient (A) during storage, as compared to solid preparation P1, which is prepared without wet granulating the raw ingredients and then drying. This results in a solid preparation with excellent storage stability.

Analysis of the crystal structure of the solid preparation showed that the X-ray diffraction pattern of the solid preparation of this embodiment was different from that of the solid preparation P1, indicating that the crystal structure was different. Note that the solid preparation P2, which was prepared by simply physically mixing the raw materials, also showed the same X-ray diffraction pattern as the solid preparation P1.
Although the detailed mechanism is unclear, it is speculated that, although component (A) is stable on its own, in a mixed state containing components (A) and (B), the content of component (A) decreases due to reaction with moisture contained inside or outside during the manufacturing process.
In contrast, it is believed that the solid preparation of the present embodiment has moisture removed by the above-mentioned drying treatment, and the crystal structure is stabilized even in a mixed state containing component (A) and component (B).

Here, the X-ray diffraction patterns of the solid preparations P1 and P2 had peaks in each of the five ranges of diffraction angle 2θ of 7.3±0.1, 11.0±0.1, 19.1±0.1, 22.2±0.1, and 24.8±0.1.
In contrast, the solid preparation of this embodiment has the above-mentioned characteristic peaks fluctuating in the X-ray diffraction patterns of solid preparations P1 and P2, and does not have peaks in at least three or more of the five ranges, preferably does not have peaks in four or more, and more preferably does not have peaks in five or more, thereby making it possible to suppress a decrease in the content ratio of component (A) in the solid preparation during storage.

In another embodiment, the X-ray diffraction pattern of the solid formulation of this embodiment may have a peak in at least one of the three ranges of diffraction angle 2θ of 18.2±0.3, 20.5±0.3, and 21.9±0.3, or may have peaks in two of these ranges. In addition, this peak may exist at least in the range of diffraction angle 2θ of 18.2±0.3. This makes it possible to suppress a decrease in the content ratio of component (A) in the solid formulation even after storage under harsh storage conditions.

In another embodiment, the X-ray diffraction pattern of the solid formulation of this embodiment may have a peak in at least one of the four ranges of diffraction angle 2θ of 6.8±0.1, 18.2±0.1, 20.5±0.1, and 21.9±0.1. This peak may be present at least in the range of diffraction angle 2θ of 6.8±0.1 or 20.5±0.1. This makes it possible to suppress a decrease in the content ratio of component (A) in the solid formulation even after storage under harsh storage conditions.

In this embodiment, for example, it is possible to control the above-mentioned X-ray diffraction pattern by appropriately selecting the type and amount of each component contained in the solid formulation, the preparation method of the solid formulation, etc. Among these, for example, mixing raw material components including component (A) and component (B) and wet granulating them, followed by a predetermined drying process, etc., can be cited as an element for making the above-mentioned X-ray diffraction pattern have a peak at a desired position.

Specific examples of the form of the solid preparation include granules, powders, capsules, tablets, and pills, as described in the 18th Revised Japanese Pharmacopoeia. The "solid preparation" of the present invention is preferably a granule, powder, capsule, or tablet, and more preferably a tablet.

The above-mentioned granules or tablets may be preferably coated with a water-soluble polymer or coated with sugar. That is, preferred embodiments of the granules and tablets include film-coated granules, film-coated tablets, and sugar-coated tablets.
In addition, preferred embodiments of the above tablets include multi-layer tablets in which powders or granules having different compositions are stacked and compressed into two or more layers.

The solid preparation preferably has a mixed phase in which components (A) and (B) are in contact with each other. In the mixed phase, the dispersion state of components (A) and (B) is not particularly limited, but each may be uniformly dispersed. The solid preparation may have a separate phase in which components (A) and (B) are not substantially in contact with each other, but may not have such a separate phase.

In addition, since the solid preparation of the present embodiment has an excellent antipyretic effect, it is suitable for use as a cold medicine such as a general cold medicine or an antipyretic analgesic. For example, by adding various ingredients, it can be administered to patients having various cold symptoms, particularly fever, chills, headache, sore throat, runny nose, stuffy nose, cough, phlegm, joint pain, muscle pain, sneezing, etc., to relieve these symptoms.
The solid preparation can be used, for example, as an oral solid preparation from the viewpoint of ease of ingestion.

<Component (A)>
The component (A) contains at least one member selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof.
The at least one member selected from the group consisting of rofecoxib, its salts, and their hydrates includes one or more members selected from the group consisting of rofecoxib, rofecoxib sodium, rofecoxib sodium monohydrate, and rofecoxib sodium dihydrate.
Lofecoxib sodium dihydrate is listed in the 18th Edition of the Japanese Pharmacopoeia as lofecoxib sodium hydrate.

The amount of component (A) contained in the solid preparation is not limited, but is 1 to 80 parts by mass, preferably 2 to 50 parts by mass, more preferably 5 to 30 parts by mass, and may be 7 to 20 parts by mass per 100 parts by mass of the solid preparation.
The content of component (A) contained in the solid preparation is not limited, but the amount of the component contained in the solid preparation per one dosage unit (single dosage) for adults is preferably 10 to 180 mg, more preferably 30 to 120 mg, and even more preferably 30 to 90 mg, calculated as an anhydrous amount, and the frequency of administration is preferably once to three times per day.
In this embodiment, when the solid preparation is a tablet obtained by compressing a powder, granulated granules, or a mixture of the powder and granulated granules, the content of component (A) contained in the granulated granules or powder in the solid preparation is not limited, but the amount of the component contained in a tablet per dosage unit (single dosage) for adults is preferably 10 to 180 mg, more preferably 30 to 120 mg, even more preferably 30 to 90 mg, or may be 60 to 90 mg, in terms of anhydrous equivalent, and in this case too, the number of administrations is preferably 1 to 3 times a day.

<Component (B)>
Component (B) is at least one member selected from the group consisting of tranexamic acid and salts thereof.
Component (B) is a known compound and can be produced by known methods or can be a commercially available product. Tranexamic acid is listed in the 18th edition of the Japanese Pharmacopoeia.

In addition, the content of component (B) is not limited, but from the viewpoint of improving the antipyretic effect, it is preferably 10% by mass or more, and more preferably 12.5% by mass or more, based on 100% by mass of the solid preparation.
Furthermore, from the viewpoint of obtaining more preferable properties of the preparation, the content of component (B) is preferably 40% by mass or less, and more preferably 36% by mass or less, based on 100% by mass of the solid preparation, although this is not limited thereto.
The amount of component (B) may be, for example, 100 to 1000 mg per administration, or 120 to 700 mg per administration, in terms of the amount of the component contained in the solid preparation per daily dose, and the frequency of administration is preferably 1 to 3 times a day.

In the solid preparation, the mass of component (B)/mass of component (A) is, for example, 0.1 to 10, preferably 0.5 to 10, and more preferably 1 to 10. This allows a balance between storage stability and other efficacies such as an antipyretic effect.

Measurements are carried out at 80° C., and the loss on drying (% by mass) in the solid preparation at the time when the mass loss per 50 seconds becomes less than 1 mg is regarded as the water content.
The water content of the solid preparation is, for example, 2.5% by mass or less, preferably 1.5% by mass or less, more preferably 1.0% by mass or less, which can suppress a decrease in the content of component (A) in the solid preparation even after storage under harsh storage conditions.

In this embodiment, the solid preparation may further contain components other than the components (A) and (B).
The solid preparation of the present invention may be used as a material (intermediate material) composed of components (A) and (B), and may further contain components other than components (A) and (B).
Examples of such ingredients are given below.

<Antacids>
In this embodiment, the solid preparation may preferably further contain an antacid from the viewpoint of suppressing damage to the gastric mucosa.

Antacids include, for example, alkaline earth metal and/or earth metal basic inorganic compounds such as magnesium oxide, magnesium silicate, magnesium aluminosilicate, magnesium aluminum silicate, magnesium hydroxide, co-precipitation product of magnesium hydroxide and aluminum potassium sulfate, magnesium carbonate, synthetic hydrotalcite, magnesium aluminometasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium alumina hydroxide, aluminum hydroxide gel, co-precipitation product of aluminum hydroxide and sodium hydrogen carbonate, mixed dried gel of aluminum hydroxide and magnesium carbonate, co-precipitation product of aluminum hydroxide, magnesium carbonate and calcium carbonate. Examples of the basic inorganic compounds include inorganic salts of metals selected from magnesium, aluminum, and calcium, such as calcium carbonate, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate. Examples of the basic inorganic compounds of alkali metals include inorganic salts of metals selected from sodium and potassium, such as dry sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous sodium monohydrogen phosphate, potassium hydroxide, potassium hydrogen carbonate, and potassium carbonate. Other examples include borax and glycine, and one or more components selected from these can be blended. Among these, one or more components selected from the group consisting of magnesium oxide, magnesium aluminometasilicate, synthetic aluminum silicate, precipitated calcium carbonate, and glycine are preferred.

When magnesium oxide is used as an antacid, the one listed in the 18th revised Japanese Pharmacopoeia may be used, and is readily available.
Commercially available magnesium oxide is not limited, but for example, magnesium oxide (light grade) manufactured by Tomita Pharmaceutical Co., Ltd., magnesium oxide (heavy grade) manufactured by Kyowa Chemical Industry Co., Ltd., etc. may be used.
The content of magnesium oxide in the solid preparation may be selected taking into consideration the disintegration property of the solid preparation, the dissolution property of the drug, and the function as an antacid, and is not limited thereto, and may be 0 to 80 mass% or more than 0 to 80 mass%, may be 0.1 to 70 mass%, and is preferably 1 to 25 mass%, based on the mass of the entire solid preparation.

When magnesium aluminometasilicate is used, one listed in the 18th revised edition of the Japanese Pharmacopoeia may be used, and is readily available.
Commercially available magnesium aluminometasilicate includes, but is not limited to, Neusilin manufactured by Fuji Chemical Industry Co., Ltd.
The content of magnesium aluminometasilicate in the solid preparation is not limited and may be selected taking into consideration the disintegration property of the solid preparation, the dissolution property of the drug, and the function as an antacid agent, and may be 0 to 80 mass% or more than 0 to 80 mass%, may be 0.1 to 70 mass%, and is preferably 1 to 50 mass%, based on the mass of the entire solid preparation.

<Herbal medicines (herbal medicine ingredients)>
The solid preparation of the present invention may contain herbal medicines.
The herbal medicines used in the present invention are not particularly limited, but include, for example, Ephedra, Nandina, Scutellaria, Onji, Licorice, Platycodon, Coptis, Coptis, Garlic, Senega, Fritillaria, Fennel, Phellodendron Bark, Coptis Rhizome, Zedoary, Chamomile, Cinnamon Bark, Gentiana, Bezoar, Animal Gall (including Yutang), Shajin, Ginger, Atractylodes Root, Clove, Tangerine Peel, Atractylodes Root, Dioscorea Root, Carrot, Mallotus Japonicus, Acacia Root, Corydalis Root, Scutellaria Root, and Valerian. It is possible to blend one or more ingredients selected from herbal medicines such as U, Calonin, Kyonin, Lycium Root, Lycium Bark, Chinese Cabbage, Cassia Root, Gennoshoko, Magnolia Root, Gomizushi, Saishin, Zanthoxylum, Aster Root, Jikoppi, Peony Root, Musk, Xinjiang, Cnidium Root, Zenko, Swertia Root, Sohakuhi, Feng Shui, Taisan, Touki, Ipecac, Bakumondou, Pinellia Root, Japanese Bean, Japanese Pear, Angelica Root, Poria Cocos, Peony Pepper, Borei, Rokujo, Bowi, and extracts thereof (extracts, tinctures, dried extracts, etc.).
The solid preparation of the present invention preferably contains at least one of licorice extract, peony extract, and valerian extract.
The content ratio of the herbal medicines in the solid preparation of the present invention is not particularly limited, but for example, when each herbal medicine is an extract, it is 1 to 80 mass %, optionally 1 to 50 mass %, optionally 1 to 40 mass %, or optionally 1 to 30 mass %, based on the mass of the entire solid preparation.

The herbal medicines used in the present invention, such as licorice, peony, and valerian, have been used for medicinal purposes since ancient times, either as a single ingredient or as a traditional Chinese medicine, and the herbal powder or extract obtained according to the conventional method can be used as is. The form of the herbal powder or extract can be a normal commercially available product or a processed product thereof. For example, a dried, chopped, processed product can be further pulverized into a powder (fine powder) to be used as a dry powder. The form of the extract from the herbal medicine is not particularly limited, and any form can be used, such as a dried extract, extract powder, soft extract, liquid extract, or tincture containing ethanol or ethanol and water. Preferred herbal medicines include extract components that have a high degree of freedom in formulation, such as soft extracts and dried extract powders.

The extract component can be obtained by a conventional method, for example, by extracting an active ingredient having an antibacterial action from the herbal medicine using an extraction solvent. As the extraction solvent, for example, water, a hydrophilic solvent, or a mixed solvent thereof is often used. The hydrophilic solvent includes, for example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, s-butanol, t-butanol, etc.; cellosolves such as methyl cellosolve, ethyl cellosolve, etc.; ketones such as acetone, etc.; ethers such as dioxane, tetrahydrofuran, etc.; nitrogen-containing solvents such as pyridine, morpholine, acetonitrile, N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, etc. These hydrophilic solvents may be used alone or as a mixed solvent of two or more kinds.
Licorice may be used as in the past as an anti-inflammatory agent, cold medicine, antipyretic analgesic, cough suppressant, expectorant, gastrointestinal medicine, anthelmintic, internal medicine for rhinitis, throat freshener, stomach freshener, vitamin-containing health supplement, sweetener, flavoring agent, colorant, flavoring agent, perfume, or excipient.

When "licorice" is used in the present invention, it is preferable to use the one listed in the 18th revised Japanese Pharmacopoeia.
Licorice other than those mentioned above is also commercially available and can be easily obtained.
Commercially available licorice extracts include those that use water or a 30% ethanol aqueous solution as an extraction solvent, and are sold with various raw drug equivalent ratios depending on the type of extract, such as licorice extract, licorice dry extract, licorice soft extract, licorice liquid extract, etc. In addition to these licorice extracts, licorice extracts, licorice extract liquids, etc. may also be used appropriately and are not particularly limited.
When using commercially available licorice in an oral pharmaceutical composition, licorice may be used so that the licorice content in the tablet is appropriate, taking into consideration, for example, the ratio of the original herbal medicine.

There are no particular limitations on the amount of licorice (licorice or licorice extract) contained in the solid preparation of the present invention, but the amount of the ingredient contained in a tablet per daily dose, calculated as the amount of raw herbal medicine, is preferably 10 mg to 10 g, more preferably 150 mg to 5 g, and even more preferably 500 mg to 3000 mg, and may be 500 mg to 1500 mg, and the number of doses is 1 to 3 times a day.

In the solid preparation of the present invention, for example, when dry licorice extract is used, the content of the dry licorice extract is not particularly limited, but may be 0.1 to 80% by mass, 1 to 50% by mass, preferably 5 to 40% by mass, and more preferably 10 to 30% by mass, based on the total mass of the tablet.

When "Valeriana officinalis" is used in the present invention, the "Valeriana officinalis" that can be used is preferably that listed in the 18th revised Japanese Pharmacopoeia.
Other valerian plants besides those mentioned above are also available commercially and are easily available.
As commercially available valerian, for example, valerian powder or valerian extract (for example, soft extract or dry extract) can be used, and is not particularly limited.
When using commercially available valerian in an oral pharmaceutical composition, valerian may be used so that the valerian content in the tablet is appropriate, taking into consideration the ratio of the original herbal medicine.

When "Valeriana (Valeriana or Valeriana extract)" is used in the present invention, the content is not particularly limited, but for example, the amount of the ingredient contained in a tablet per daily dose, calculated as the amount of raw herbal medicine, may be 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 may be 60 to 450 mg, and the number of doses is 1 to 3 times a day.

When valerian extract is used in the solid preparation of the present invention, the content of valerian extract is not particularly limited, but may be 1 to 50% by mass, preferably 2 to 40% by mass, and more preferably 3 to 20% by mass, based on the mass of the entire tablet.

When "peony" is used in the present invention, the "peony" that can be used is preferably that listed in the 18th revised Japanese Pharmacopoeia.
Other peonies than those mentioned above are also available commercially and are easily available.
As commercially available peonies, for example, peony powder and peony extract (including, for example, dried extract and soft extract) can be used, and are not particularly limited.
When using commercially available peony root in an oral pharmaceutical composition, peony root may be used so that the peony root content in the tablet is appropriate, taking into consideration the raw herbal drug conversion ratio.

When "peony (peony or extract thereof)" is used in the present invention, the content is not particularly limited, but it is preferable to administer 100 to 5000 mg per day, more preferably 150 to 2000 mg, and particularly preferably 200 to 900 mg, calculated as the raw herb of peony, and the number of administrations is 1 to 3 times per day.

When using, for example, dried peony extract in the solid preparation of the present invention, the content of the dried peony extract is not particularly limited, but may 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.

(Method of manufacturing solid preparations)
An example of a method for producing a solid formulation of the present embodiment includes a wet granulation step of adding water to raw material components including component (A) and component (B), mixing the mixture, and granulating the mixture, and a drying step of drying the granulated product obtained after the wet granulation step.
The drying step is not particularly limited, but may be, for example, a heating temperature of 30 to 100° C., preferably 60 to 90° C. The heating time may be, for example, 0.01 to 24 hours, preferably 0.1 to 6 hours.
The environmental conditions during the drying process may be, for example, atmospheric pressure.
In addition, other medicinal ingredients may be mixed with the raw ingredients in the wet granulation step according to a conventional method, as long as it does not affect the present invention, and additives may also be added if necessary.
For example, when the solid preparation is a tablet, the components (A) and (B) and other appropriate components are mixed and wet granulated, the granules are dried, and the final powder components are added to the resulting granules so as to form the outer granules, followed by tableting to produce tablets.
That is, the tablet can be produced by, for example, a process of producing a granulated granule (at least one granulated granule) containing the component (A) and the component (B) and other components as appropriate; and a process of producing a tablet by mixing the granulated granule with a desired additive (final component) and compressing the mixture into a tablet. In addition, the component to be placed outside the granule may be optionally in the form of a granule.

The final component (outside of granulated granule) is a portion that constitutes the outside of the granulated granule in the tablet, and may be, for example, a portion that is configured to cover one granulated granule in the tablet, or may be a portion that is configured to cover multiple granulated granules. Also, it may be a portion that covers at least one granulated granule in the tablet and also constitutes the outer surface of the tablet.
In one embodiment of the present invention, the solid preparation may be used as a material (intermediate material) composed of components (A) and (B), or a solid preparation (material/intermediate material) composed of components (A) and (B) may be produced and further contain components other than components (A) and (B).
That is, the solid preparation of the present invention contains a solid preparation composed of components (A) and (B) as an intermediate material, and may be in the form of granules, powders, capsules, pills, or tablets and used as 0016.
In other words, the pharmaceutical product in one embodiment of the present invention may be in the form of granules, powder, capsules, pills, or tablets, including the solid formulation of the present invention.

As a method for storing solid preparations, it is preferable to store the prepared solid preparations in a sealed storage container such as a glass bottle or a PTP. As severe storage conditions, an external environmental temperature of 30°C or higher and/or an external environmental humidity of 60% RH or higher may be adopted.

The formulation can be prepared by using known methods and additives as appropriate. The additives may be added as appropriate within the range that does not impair the effects of the present invention.
Examples of additives include pharma- ceutically acceptable carriers, such as excipients, binders, disintegrants, disintegration aids, lubricants, fluidizing agents, glossing agents, foaming agents, moisture-proofing agents, surfactants, stabilizers, emulsifiers, antioxidants, fillers, preservatives, sweeteners, flavoring agents, refreshing agents, flavorings, fragrances, coloring agents, bases, coating agents, sugar-coating agents, plasticizers, dispersants, and antifoaming agents, and formulation additives that can be used in conventionally known solid preparations can be used for the above-mentioned purposes. These may be used alone or in combination of two or more kinds.

Examples of excipients include candy powder, gum arabic, powdered gum arabic, cocoa butter, caramel, sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon oxide, xylitol, magnesium aluminosilicate, calcium silicate, magnesium silicate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, calcium monohydrogen phosphate, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granules, sodium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate, crystalline cellulose, crystalline cellulose-carmellose sodium, crystalline cellulose (fine particles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate-hydroxypropyl starch Examples of the sugars that can be used include crystalline cellulose, wheat starch, rice flour, rice starch, heavy anhydrous silicic acid, refined sucrose, refined sucrose spherical 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, sucrose, potato starch, hydroxypropyl starch, powdered sugar, powdered candy, powdered reduced maltose syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D-mannitol, magnesium aluminometasilicate, calcium sulfate, erythritol, glucose, fructose, etc. These may be used alone or in combination of two or more.

As a binder, for example, one or more components selected from gum arabic, powdered gum arabic, cold plum powder, gelatin, shellac, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (completely 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. can be blended.

Examples of disintegrants include carboxymethylethylcellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropyl starch, etc. These may be used alone or in combination of two or more.

Disintegration aids include, for example, sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 1500, macrogol 4000, etc.

Lubricants include, for example, magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, glycerin fatty acid esters, polyethylene glycol, hardened oils, sodium stearyl fumarate, etc.

The fluidizing agent may be one or more components selected from the group consisting of synthetic aluminum silicate, heavy anhydrous silicic acid, magnesium alumina hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, calcium hydrogen phosphate granules, etc.

The glossing agent may be, for example, one or more components selected from carnauba wax, white beeswax, refined shellac, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, beeswax, etc.

The foaming agent may be, for example, one or more components selected from dry sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium hydrogen carbonate, anhydrous citric acid, etc.

As the moisture-proofing agent, for example, 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, refined shellac, refined white sugar, talc, neutral anhydrous sodium sulfate, precipitated calcium carbonate, a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylamino acetate, hydroxypropyl methylcellulose 2910, polyvinyl acetal diethylamino acetate, etc. can be blended.

The surfactant may be one or more components selected from, for example, sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbit 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, macrogol 400, sorbitan monooleate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, sodium lauryl sulfate, etc.

Stabilizers include, for example, adipic acid, 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 edetate, sodium edetate, tetrasodium edetate, tetrasodium edetate tetrahydrate, zinc chloride, ammonium chloride, calcium chloride hydrate, cetylpyridinium chloride, ferric chloride, sodium chloride, magnesium chloride, cysteine hydrochloride, L-histidine hydrochloride, cocoa butter, carboxyvinyl polymer, carmellose calcium, carmellose, Sodium sulphate, hydrated silicon dioxide, dried sodium carbonate, glycine, glycerin, glycerin fatty acid ester, calcium gluconate hydrate, sodium gluconate, magnesium gluconate, potassium L-glutamate, sodium L-glutamate, L-lysine glutamate, crystalline sodium dihydrogen phosphate, sodium chondroitin sulfate, zinc oxide, L-cystine, L-cysteine, tartaric acid, sucrose fatty acid ester, stearic acid, purified gelatin, purified soybean lecithin, gelatin, gelatin hydrolysate, sorbitan fatty acid ester, taurine, talc, calcium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate hydrate, magnesium carbonate Netium, natural vitamin E, tocopherol, tocopherol acetate, lactose, concentrated glycerin, povidone, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene hydrogenated 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 glyceryl ( 7E.O.), polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 4000, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methylcellulose, l-menthol, glycerin monostearate, medicinal 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., can be blended with one or more ingredients selected from the following.

Examples of emulsifiers include glycerin fatty acid esters, propylene glycol fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyglycerin fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene sorbit fatty acid esters, polyethylene glycol fatty acid esters, and hydrogenated soybean phospholipids.

Examples of antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soy lecithin, natural vitamin E, tocopherol, tocopherol acetate, ascorbic palmitate, sodium pyrosulfite, etc.

Fillers include, for example, RSS No. 1 raw rubber, starch acrylate 1000, hydrous silicon dioxide, titanium oxide, silicon dioxide, calcium hydrogen phosphate, etc.

Examples of preservatives include benzoic acid, sodium benzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, dehydroacetic acid, sodium dehydroacetate, sorbic acid, and phenoxyethanol.

Sweetening agents that can be blended include, for example, one or more ingredients selected from aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose syrup, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, refined stevia extract, refined white sugar, fructose, white sugar, maltitol, D-mannitol, erythritol, etc.

As flavoring agents, for example, one or more ingredients selected from sodium chloride, orange, orange oil, cacao powder, fructose, caramel, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, L-sodium glutamate, grapefruit extract, brown sugar, saccharin, saccharin sodium hydrate, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, sucralose, stevia extract, refined stevia extract, Swertia japonica, 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, DL-sodium malate, lemon oil, rose oil, etc. can be blended.

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

Flavors that can be blended include, for example, one or more ingredients selected from orange flavor, guarana extract, sweet orange, strawberry, brown sugar flavor, strawberry flavor, cherry flavor, banana powder flavor, peach essence, fruit essence, peppermint, melon powder flavor, l-menthol, peppermint oil, etc.

Examples of fragrances include fennel powder, fennel oil, ethyl vanillin, d-camphor, dl-camphor, spearmint oil, turpentine oil, pineapple powder flavor 51357, pineapple powder flavor 59492, peppermint water, peppermint oil, vanilla powder flavor 54286, vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, rose oil, etc.

Colorants that can be used include, for example, one or more of the following: yellow iron oxide, yellow iron oxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, gold leaf, black iron oxide, titanium oxide, iron oxide, diaz azo yellow, food blue No. 1, food yellow No. 4, food yellow No. 5, food blue No. 2 aluminum lake, food yellow No. 4 aluminum lake, food red No. 2, food red No. 3, food red No. 102, ferric oxide/glycerin suspension, sodium copper chlorophyllin, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, riboflavin sodium phosphate, green tea powder, rose oil, etc.

Examples of bases include powdered acacia, pregelatinized starch, partially pregelatinized starch, ethyl cellulose, cacao butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose syrup, hydrated silicon dioxide, dried aluminum hydroxide gel, agar, powdered agar, xanthan gum, glycine, glycerin, glycerin fatty acid ester, light anhydrous silicic acid, crystalline cellulose, hardened oil, synthetic aluminum silicate, synthetic sodium magnesium silicate, titanium oxide, tartaric acid, sucrose fatty acid ester, 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 glycerin, potato starch, hyd. It can contain one or more ingredients selected from the group consisting of hydroxypropyl cellulose, hypromellose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified), microcrystalline wax, macrogol 200, macrogol 300, macrogol 400, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, D-mannitol, glycerin monostearate, sorbitan monostearate, batyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, and polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer.

Examples of coating agents include ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, powdered gum arabic, ethyl cellulose, ethyl cellulose aqueous dispersion, carnauba wax, carboxyvinyl polymer, gold leaf, silver leaf, triethyl citrate, glycerin, glycerin fatty acid ester, hardened oil, titanium oxide, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, refined gelatin, refined shellac, gelatin, D-sorbitol, talc, calcium carbonate, magnesium carbonate, medium gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, mixture of hydroxypropyl methylcellulose 2910, titanium oxide, and macrogol 400, hypromellose, fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, hydo Examples of the copolymer include dimethyl ether 2910 mixture, pullulan, polysorbate 80, polyvinyl acetal diethylaminoacetate, povidone, polyvinyl alcohol (partially saponified), macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 6000NF, macrogol 20000, macrogol 35000, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, magnesium aluminometasilicate, methyl acrylate-methacrylic acid-methyl methacrylate copolymer, methyl cellulose, 2-methyl-5-vinylpyridine methyl acrylate-methacrylic acid copolymer, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

The sugar-coating agent may be one or more components selected from the group consisting of gum arabic, powdered gum arabic, ethyl cellulose, carnauba wax, carmellose sodium, titanium oxide, stearic acid, polyoxyl 40 stearate, refined gelatin, refined shellac, refined white sugar, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, white sugar, hydroxypropyl cellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000 NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate hydrate, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc.

The plasticizer may be one or more components selected from the group consisting of triethyl citrate, glycerin, glycerin fatty acid esters, D-sorbitol, medium-chain triglycerides, triacetin, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000 NF, glycerin monostearate, isopropyl linoleate, and liquid paraffin.

Dispersants include, for example, aminoalkyl methacrylate polymer RS, gum arabic, powdered gum arabic, carboxyvinyl polymer, sodium carboxymethyl starch, agar powder, citric acid hydrate, sodium citrate hydrate, glycerin, glycerin fatty acid ester, magnesium silicate, light aluminum oxide, crystalline cellulose, titanium oxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, low-substituted hydroxypropyl cellulose, dextrin, corn starch, lactose hydrate, concentrated glycerin, potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hypromellose, povidone, polyoxyethylene cellulose, hydroxypropyl ... One or more components selected from ethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, macrogol 300, macrogol 4000, macrogol 6000, macrogol 6000NF, anhydrous sodium citrate, magnesium aluminometasilicate, methylcellulose, glycerin monooleate, sorbitan monooleate, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, etc. may be blended.

The defoaming agent may be one or more components selected from, for example, ethanol, glycerin fatty acid ester, dimethylpolysiloxane (for internal use), dimethylpolysiloxane/silicon dioxide mixture, sucrose fatty acid ester, silicon defoamer, silicon oil, sorbitan fatty acid ester, polysorbate 80, etc.

These additives are not limited to those listed above, and one of these may be used, or two or more may be used in combination.

In addition, the solid preparation may further contain medicinal ingredients other than the ingredients (A) and (B), such as antipyretics, analgesics, cough suppressants, expectorants, antihistamines, anti-inflammatory agents, anticholinergic agents, other vitamins, xanthine derivatives, and sedatives, as necessary, within the range that does not impair the effects of the present invention. If there are any contraindications for the inclusion of these ingredients, the solid preparation may be formulated by dividing them into granules, etc., as appropriate.

As an antipyretic analgesic, for example, one or more components selected from aspirin, aluminum aspirin, acetaminophen, ethenzamide, sazapirin, salicylamide, lactylphenetidine, ibuprofen, isopropylantipyrine, planopfen, diclofenac sodium, mefenamic acid, indomethacin farnesyl, acemetacin, etodolac, naproxen, meloxicam, celecoxib, sodium salicylate, and tiaramide hydrochloride can be blended.

Examples of antitussives and expectorants include codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, dibunate sodium, dimemorfan phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan, dextromethorphan hydrobromide hydrate, dextromethorphan phenolphthaline salt, alloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, pentoxyverine citrate, and nosca These include vincristine, noscapine hydrochloride, trimetoquinol hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, L-carbocysteine, ambroxol hydrochloride, bromhexine hydrochloride, and L-ethylcysteine hydrochloride.

Examples of antihistamines include azelastine hydrochloride, alimemazine tartrate, ebastine, epinastine hydrochloride, emedastine fumarate, oxatomide, olopatadine hydrochloride, carbinoxamine, clemastine fumarate, diphenyl disulfonate, carbinoxamine maleate, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, dif These include phenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, triprolidine hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fexofenadine, fenethazine hydrochloride, promethazine hydrochloride, promethazine, mequitazine, methdilazine hydrochloride, loratadine, isopentyl hydrochloride, difeterol hydrochloride, methdilazine hydrochloride, mebhydroline napadisalicylate, promethazine methylenedisalicylate, difeterol phosphate, etc.

Examples of anti-inflammatory agents include glycyrrhizinic acid and its derivatives, as well as their salts (e.g., dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.).

Examples of anticholinergic agents include scopolamine hydrobromide, Datura extract, methylscopolamine bromide, methyl-l-hyoscyamine bromide, pirenzepine hydrochloride, butylscopolamine bromide, belladonna alkaloids, belladonna extract, belladonna total alkaloids, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, Scolytsum extract, Scolytsum root, and Scolytsum root total alkaloid citrate.

Examples of vitamins include vitamin A, vitamin C, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin P, vitamin E, hesperidin, nicotinic acid, nicotinamide, panthenol, calcium pantothenate, sodium pantothenate, biotin, an equal mixture of potassium and magnesium aspartate, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine hydrochloride, orotin, gamma oryzanol, calcium glycerophosphate, calcium gluconate, gluconolactone, glucuronic acid amide, sodium chondroitin sulfate, carrot, coix seed, and iodine.

Examples of xanthine derivatives include caffeine hydrate, anhydrous caffeine, sodium caffeine benzoate, and caffeine citrate.
Sedatives include, for example, allylisopropylacetylurea and bromvalerylurea.

These additives are not limited to those listed above, and one of these may be used, or two or more may be used in combination.

The solid preparation can be suitably used for the purpose of suppressing fever, pain, and inflammation. At least one selected from the group consisting of the active ingredient loxoprofen, its salts, and their hydrates has antipyretic, analgesic, and anti-inflammatory effects, and therefore can be suitably used as an antipyretic and analgesic agent, specifically for the purpose of relieving pain from headaches, menstrual pain (period pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, muscle pain, stiff shoulder pain, ear pain, bruise pain, bone fracture pain, sprain pain, and trauma pain, and for reducing fever during chills and fever, and can also be suitably used as a cold treatment agent for the purpose of relieving various cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

(Dosage form)
The solid preparation may be in the dosage form described in the General Provisions for Preparations of the Japanese Pharmacopoeia, 18th Edition, etc., such as preparations for oral administration (including tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.) and preparations for oral application (including oral tablets, troches, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.).

The dosage form of the solid preparation may be, for example, a capsule, a pill, a granule, a fine granule, a powder, or a tablet. If necessary, these solid preparations may be coated with sugar coating, film coating, or the like by a known method. The dosage form of the solid preparation is preferably a plain tablet, a film-coated tablet, a sugar-coated tablet, a granule, a fine granule, or a capsule, and more preferably a granule, a plain tablet, a film-coated tablet, or a sugar-coated tablet.

(Package)
The package is a package in which the solid preparation of the present embodiment is accommodated in a packaging container. By forming the package, for example, the convenience of using the solid preparation can be improved.

(Packaging format)
Regarding the packaging form of the solid preparation, it may be packaged once and stored airtight in a strip package (SP package), a press through package (PTP package), a stick package, a bottle package, a pouch package, or the like. That is, the solid preparation may be contained in an airtight package. Furthermore, it may be packaged in a pillowcase, or may be stored in a box or the like.
In other words, a pharmaceutical product according to one embodiment of the present invention may include a solid formulation according to the above embodiment and a packaging material for packaging the solid formulation.
Materials used for SP packaging, PTP packaging, stick packaging, and pillow packaging are not limited, and examples of materials that can be used include single-layer resin films such as polyvinyl chloride film, polyvinylidene chloride film, polypropylene film, polyethylene terephthalate film, and polyethylene film, multi-layer films combining these resin films, and these resin films with aluminum foil attached.

The packaging material for the solid preparation is preferably a packaging material that is not easily affected by moisture (a packaging material formed from at least one of a moisture-proof material and a gas barrier material), for example.
For example, as packaging made of a material that is less susceptible to moisture (moisture-proof material), PTP (polypropylene) + polyethylene aluminum pillow packaging (combined packaging of PTP and polyethylene aluminum pillow) may be used. In addition, in consideration of suppression of an increase in the moisture content of the tablet, storage stability of the tablet, and stability of the tablet after opening, PTP packaging using aluminum on both sides (Al-Al packaging) may be used as packaging made of a material that is less susceptible to moisture (moisture-proof material).
If moisture absorption is a concern, a desiccant or the like may be stored in the packaging container, such as a bottle or pillowcase.
The gas barrier material may be any known material, and is not limited thereto. For example, it may be a laminate film having a functional barrier layer, which may also serve as the moisture-proof material or may be used in combination with the moisture-proof material.

Furthermore, packaging containers may be environmentally friendly. For example, environmentally friendly materials such as recycled plastics, biomass plastics, and biodegradable plastics may be used for part or all of the packaging material.

The above describes the embodiments of the present invention, but these are merely examples of the present invention, and various configurations other than those described above can be adopted. Furthermore, the present invention is not limited to the above-described embodiments, and modifications and improvements within the scope of the present invention are included.

The present invention will be described in detail below with reference to examples, but the present invention is not limited to the description of these examples.

<Manufacture of solid dosage forms>
(Comparative Example 1)
10.0 g of loxoprofen sodium hydrate (KOLON) and 30.0 g of tranexamic acid (AMI) were physically mixed in a mortar to obtain a physical mixture (Solid Preparation P2 above). The obtained physical mixture was sealed in a glass bottle and stored for one month under an external environment of 40° C. and 75% RH.

(Comparative Example 2)
10.0 g of loxoprofen sodium hydrate (KOLON) and 30.0 g of tranexamic acid (AMI) were mixed, 2.0 g of water was added, and the mixture was kneaded in a mortar to obtain granules (above solid preparation P1). The obtained granules were stored in a sealed glass bottle under an external environment of 60° C. for one month.

Example 1
10.0 g of loxoprofen sodium hydrate (KOLON) and 30.0 g of tranexamic acid (AMI) were mixed, 2.0 g of water was added, and the mixture was kneaded in a mortar and dried at 80° C. for 1 hour to obtain granules. The obtained granules were stored in a sealed glass bottle under an external environment of 40° C. and 75% RH for 1 month.

Example 2
10.0 g of loxoprofen sodium hydrate (KOLON) and 30.0 g of tranexamic acid (AMI) were mixed, 2.0 g of water was added, and the mixture was kneaded in a mortar and dried at 80° C. for 1 hour to obtain granules. The obtained granules were stored in a sealed glass bottle under an external environment of 60° C. for 1 month.

Example 3
4.0 g of loxoprofen sodium hydrate (KOLON), 12.0 g of tranexamic acid (AMI), 20.0 g of crystalline cellulose (Asahi Kasei), and 4.0 g of croscarmellose sodium (FMC) were mixed, 4.0 g of water was added, and the mixture was kneaded in a mortar and dried at 80° C. for 1 hour to obtain granules. The obtained granules were stored in a sealed glass bottle under an external environment of 40° C. and 75% RH for 1 month.

Example 4
4.0 g of loxoprofen sodium hydrate (KOLON), 12.0 g of tranexamic acid (AMI), 20.0 g of D-mannitol (Butsusan Food Science), and 4.0 g of croscarmellose sodium (FMC) were mixed, 4.0 g of water was added, and the mixture was kneaded in a mortar and dried at 80° C. for 1 hour to obtain granules. The obtained granules were stored in a sealed glass bottle under an external environment of 40° C. and 75% RH for 1 month.

<X-ray diffraction pattern>
For the samples (solid preparations) after storage obtained in each Example and Comparative Example, the X-ray diffraction patterns were measured under the following measurement conditions using a powder X-ray diffractometer (product name: Empyrean, manufactured by PANalytical Corporation).
In the measured X-ray diffraction pattern, first, it was confirmed whether the peak exists in the range of the diffraction angle 2θ of 7.3 ± 0.1, 11.0 ± 0.1, 19.1 ± 0.1, 22.2 ± 0.1, 24.8 ± 0.1. Second, it was confirmed whether the peak exists in the range of the diffraction angle 2θ of 6.8 ± 0.1, 18.2 ± 0.1, 20.5 ± 0.1, 21.9 ± 0.1, and third, it was confirmed whether the peak exists in the range of the diffraction angle 2θ of 18.2 ± 0.3, 20.5 ± 0.3, 21.9 ± 0.3. The results are shown in Table 1. In Table 1, when a peak exists in the second range, it is represented by a numerical value without parentheses, when a peak does not exist in the second range and a peak exists in the third range, it is represented by a numerical value with parentheses, and when neither exists, it is represented by -.
(Measurement conditions)
X-ray source: Cu-Kα ray (λ=1.54Å)
Method: Reflection method Measurement temperature: Room temperature Output setting: 45 kV, 40 mA
Measurement range: 5° to 40°
Scan speed: 0.075°/sec, continuous scan measurement step: 0.013°
Scan axis: 2θ-θ
Sample preparation: An appropriate amount of specimen was taken with a spatula, placed on a non-reflective sample holder, and flattened with medical paper.

<Loss on drying (LOD)>
The samples obtained in each Example and Comparative Example immediately before storage were measured at 80° C. using a halogen moisture meter (Mettler Toledo, HX204), and the moisture value was calculated as the loss on drying (mass%) from the total amount of mass loss at the point when the mass loss per 50 seconds became less than 1 mg. The results are shown in Table 1.

The following evaluations were carried out on the obtained samples (solid preparations) after storage.

<Storage stability: Measurement of LOX residual rate>
For the samples (solid preparations) obtained in each Example and Comparative Example, the content of loxoprofen sodium hydrate (referred to as "LOX") was measured three times before and after storage using high performance liquid chromatography (HPLC) as appropriate based on the liquid chromatography method of the 18th Edition of the Japanese Pharmacopoeia.
When the average value of the LOX content before storage was W1 and the average value of the LOX content after storage was W2, the LOX residual rate was calculated from the formula: (W2/W1)×100%. The results are shown in Table 1.

The solid preparations of Examples 1 to 4 showed LOX residual rates close to 100% compared to Comparative Examples 1 and 2, and therefore were able to suppress the decrease in the content ratio of component (A) in the solid preparation during storage (compositional fluctuation), demonstrating excellent storage stability.

The above describes preferred embodiments and examples of the present invention, but the present invention is not limited to these. Additions, omissions, substitutions, and other modifications to the configuration are possible without departing from the spirit of the present invention.

In the present invention, the solid preparation has excellent storage stability and is therefore extremely useful in terms of quality.
The solid preparation is preferably used as an antipyretic and analgesic agent, specifically for relieving pain such as headache, menstrual pain (period pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, muscle pain, stiff shoulder pain, earache, bruise pain, fracture pain, sprain pain, and pain from trauma, and for reducing fever during chills and fever, and is also preferably used as a cold treatment agent for relieving various cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, and muscle pain).

This application claims priority based on Japanese Patent Application No. 2023-135752, filed on August 23, 2023, the entire disclosure of which is incorporated herein by reference.

Claims (7)

A solid formulation comprising the following components (A) and (B):
(A) at least one selected from the group consisting of loxoprofen, a salt thereof, and a hydrate thereof; (B) at least one selected from the group consisting of tranexamic acid and a salt thereof. A solid formulation, which does not have peaks in at least three or more of the five ranges of diffraction angles 2θ of 7.3±0.1, 11.0±0.1, 19.1±0.1, 22.2±0.1, and 24.8±0.1 in an X-ray diffraction pattern of the solid formulation measured using Cu-Kα radiation. The solid formulation according to claim 1,
A solid preparation, wherein an X-ray diffraction pattern of the solid preparation measured using Cu-Kα radiation has a peak in at least one of three ranges of diffraction angle 2θ: 18.2±0.3, 20.5±0.3, and 21.9±0.3. The solid formulation according to claim 1 or 2,
A solid preparation, in which an X-ray diffraction pattern of the solid preparation measured using Cu-Kα radiation has a peak in at least one of the four ranges of diffraction angle 2θ of 6.8±0.1, 18.2±0.1, 20.5±0.1, and 21.9±0.1. The solid preparation according to any one of claims 1 to 3,
A solid formulation, in which the mass ratio of the component (B) to the mass of the component (A) in the solid formulation is 0.1 or more and 10 or less. The solid preparation according to any one of claims 1 to 4,
A solid formulation, wherein when measurement is performed at 80°C, the moisture content is defined as the loss on drying in the solid formulation at the time when the mass loss per 50 seconds becomes less than 1 mg, and the moisture content is 2.5 mass% or less. The solid preparation according to any one of claims 1 to 5,
The solid preparation is in the form of granules, powder, capsules, pills, or tablets. The solid formulation according to any one of claims 1 to 5,
Pharmaceuticals in the form of granules, powders, capsules, pills, or tablets.