JP2023178261A - solid preparation - Google Patents

Abstract

To provide a technique that stably blends loxoprofen, its salt or their hydrates and Paeonia lactiflora in pharmaceutical compositions.SOLUTION: A solid preparation includes a component (A): at least one selected from the group consisting of loxoprofen, its salt and their hydrates, a component (B): at least one selected from the group consisting of Paeonia lactiflora and its extract, a component (C): magnesium oxide, and a component (E): at least one selected from the group consisting of anhydrous caffeine, caffeine hydrate, and sodium caffeine benzoate. In the solid preparation, the water content is 3 mass% or less relative to the total mass of the solid preparation.SELECTED DRAWING: None

Description

The present invention relates to solid formulations.

Loxoprofen, a propionic acid-based nonsteroidal antipyretic, analgesic, and antiinflammatory drug (hereinafter referred to as "NSAIDs"), exhibits the same inhibitory effect on prostaglandin biosynthesis as other NSAIDs, but has strong antipyretic, analgesic, and antiinflammatory effects. It is known to have an effect. Loxoprofen is a prodrug that is absorbed from the gastrointestinal tract after oral administration as an unchanged form with weak gastric mucosal stimulating effect and becomes active in the body, so it is characterized by less gastric mucosal damage compared to other NSAIDs. This is also known (for example, see Non-Patent Document 1).

As a technique for further suppressing gastric mucosal disorders by orally administering loxoprofen or its salts in combination with other active ingredients, loxoprofen is combined with specific sugars (lactose, sucrose, maltitol, fructose, xylitol, trehalose, or lactitol). (see Patent Document 1), an antacid (magnesium oxide) (see Patent Document 2), an anti-plasmin drug tranexamic acid (see Patent Document 3), etc. have been disclosed. There is.

Additionally, it has been disclosed that loxoprofen sodium or its hydrate has high hygroscopicity and is difficult to formulate into stable formulations and to form into formulations with excellent storage stability after formulation. (Patent Document 4).

On the other hand, since herbal medicines absorb moisture and are sticky, they tend to adhere to manufacturing equipment during the manufacturing stage of the preparation, resulting in a significant decrease in productivity and a low content due to loss of the component in the process. In addition, the high hygroscopicity of herbal medicines is thought to be one of the causes of discoloration, which not only changes the appearance of the preparation over time, but also causes a decrease in the content of active ingredients and poor disintegration and dissolution performance. Easy to occur. As a method to improve stickiness when producing a composition using herbal medicines that easily absorb moisture, a method has been reported in which an inorganic substance, crystalline cellulose, and croscarmellose sodium are blended in a certain ratio (Patent Document 5) . In addition, technology has been reported regarding tablets containing crude drug powder that are compact and contain high concentration crude drug powder, and have a strength that prevents wear and tear during packaging and transportation, and a method for manufacturing the same (Patent Document 6).

Japanese Patent Application Publication No. 2005-139165 JP 2016-27058 Publication Japanese Patent Application Publication No. 2010-83882 Japanese Patent Application Publication No. 2014-58491 Japanese Patent Application Publication No. 2012-1474 Japanese Patent Application Publication No. 2006-28171

Pharmacology and Treatment Vol. 16 No. 2 1988 p. 611-619

However, the change over time of a solid preparation containing loxoprofen, a salt thereof, or a hydrate thereof and peony has not been known.

Therefore, the present inventor investigated and found that when a solid preparation containing loxoprofen, a salt thereof, or a hydrate thereof and peony was formulated, the amount of paeoniflorin, an indicator component of peony, decreased over time during storage. It has been newly discovered that there is a concern that the content may decrease.

Therefore, the present invention provides a technique for stably blending loxoprofen, a salt thereof, or a hydrate thereof and peony into a pharmaceutical composition.

As a result of intensive studies by the present inventors to solve the above problems, we found that loxoprofen, its salts or their hydrates, peonies, magnesium oxide, anhydrous caffeine, caffeine hydrate, and caffeine sodium benzoate. The present inventors have discovered that the storage stability of a pharmaceutical composition can be improved by incorporating one or more selected from the group consisting of:

That is, aspects of the present invention are as shown below.
[1] A solid preparation containing the following components (A) to (C) and (E), in which the content of water in the solid preparation is 3% by mass or less based on the entire solid preparation, Solid formulation.
(A) One or more types selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof (B) One or more types selected from the group consisting of peonies and extracts thereof (C) Magnesium oxide (E) Anhydrous caffeine , caffeine hydrate, and one or more selected from the group consisting of caffeine sodium benzoate [2] The solid preparation according to [1], wherein the component (B) contains paeoniflorin.
[3] The mass ratio ((B)/(E)) of the content of the component (B) to the content of the component (E) in the solid preparation is 0.01 or more and 500 or less, [1] Or the solid preparation according to [2].
[4] Component (D): The solid preparation according to any one of [1] to [3], further comprising light silicic anhydride.
[5] Component (F): The solid preparation according to any one of [1] to [4], further comprising a compound having an amino group.
[6] A stabilizer for a pharmaceutical composition containing the following components (A) to (C) and (E).
(A) One or more types selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof (B) One or more types selected from the group consisting of peonies and extracts thereof (C) Magnesium oxide (E) Anhydrous caffeine , caffeine hydrate, and caffeine sodium benzoate [7] The stabilizer according to [6], wherein the component (B) contains paeoniflorin.
[8] The mass ratio ((B)/(E)) of the content of the component (B) to the content of the component (E) in the stabilizer is 0.01 or more and 500 or less, [6 ] or the stabilizer according to [7].
[9] Component (D): The stabilizer according to any one of [6] to [8], further comprising light anhydrous silicic acid.
[10] Component (F): The stabilizer according to any one of [6] to [9], further comprising a compound having an amino group.
[11] A method for stabilizing a pharmaceutical composition, which comprises incorporating the following component (E) into a pharmaceutical composition containing the following components (A) to (C).
(A) One or more types selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof (B) One or more types selected from the group consisting of peonies and extracts thereof (C) Magnesium oxide (E) Anhydrous caffeine , caffeine hydrate, and one or more selected from the group consisting of caffeine sodium benzoate

According to the present invention, loxoprofen, a salt thereof, or a hydrate thereof and peony can be stably blended into a pharmaceutical composition.

Embodiments of the present invention will be described below. In this embodiment, the composition may contain each component alone or in combination of two or more.
In this specification, "~" indicating a numerical range represents the above or below, and includes both ends of the numerical value.

(Solid preparation)
In this embodiment, the solid preparation contains the following components (A) to (C) and (E). Further, the content of water in the solid preparation is 3% by mass or less based on the entire solid preparation.
(A) One or more types selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof (B) One or more types selected from the group consisting of peonies and extracts thereof (C) Magnesium oxide (E) Anhydrous caffeine , caffeine hydrate, and one or more selected from the group consisting of caffeine sodium benzoate.The solid preparation is specifically a pharmaceutical composition.
Each component will be explained below.

<Component (A)>
Component (A) is one or more selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof.
In the present embodiment, "loxoprofen, a salt thereof, and a hydrate thereof" specifically refers to loxoprofen or a salt thereof (including a hydrated salt), and preferably loxoprofen sodium and a hydrate thereof. More preferably, it is at least one selected from the group consisting of loxoprofen sodium dihydrate.
In this embodiment, loxoprofen sodium dihydrate is listed as loxoprofen sodium hydrate in the 18th edition of the Japanese Pharmacopoeia.

The content of component (A) contained in the solid preparation is not limited, but it is preferably the amount of the component contained in the solid preparation per adult dosage unit (one dose) in terms of anhydride. The dose is 10 to 180 mg, more preferably 30 to 120 mg, even more preferably 30 to 90 mg, and the frequency of administration is preferably 1 to 3 times a day.

In this embodiment, when the solid preparation is a tablet obtained by compressing a powder, granulated granules, or a mixture of powder and granulated granules, the components contained in the granulated granules or powder ( The content of A) is not limited, but as the amount of the ingredient contained in the tablet per adult dosage unit (single dose), it is preferably 10 to 180 mg, more preferably 30 to 180 mg in terms of anhydride. The dose is 120 mg, more preferably 30 to 90 mg, and may be 60 to 90 mg, and in this case as well, the frequency of administration is preferably 1 to 3 times a day.

The amount of component (A) contained in the solid preparation is not limited, but is 1 to 80 parts by weight, preferably 2 to 50 parts by weight, and preferably 5 to 30 parts by weight, per 100 parts by weight of the solid preparation. It is more preferable that the amount is 7 to 20 parts by mass.

<Component (B)>
Component (B) is one or more selected from the group consisting of peonies and extracts thereof. Component (B) specifically includes paeoniflorin. Moreover, from the viewpoint of stably obtaining the desired effect, component (B) preferably contains paeoniflorin.

In this embodiment, component (B) and other herbal medicines when the solid preparation further contains a herbal medicine other than component (B) such as licorice are all used medicinally as single ingredients or herbal medicines since ancient times. The herbal medicine powders or extract components obtained according to commonly used methods can be used as they are. As for the form of crude drug powder or extracted components, ordinary commercially available products or processed products thereof can be used. As the herbal medicine powder, for example, a powder (fine powder) obtained by finely pulverizing a dried chopped product may be used. Further, the form of the extracted component from the crude drug is not limited, and any form such as a dry extract, extract powder, soft extract, liquid extract, ethanol or a tincture containing ethanol and water can be used. Preferred herbal medicines include extract components that have a high degree of freedom in formulation, such as soft extracts and dried extract powders.

The extracted component can be obtained by a conventional method, for example, by extracting the active component having antibacterial activity from the crude drug using an extraction solvent. As the extraction solvent, for example, water, a hydrophilic solvent, or a mixed solvent thereof is often used. Examples of hydrophilic solvents include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, s-butanol, and t-butanol; cellosolves such as methyl cellosolve and ethyl cellosolve; ketones such as acetone; and dioxane. , ethers such as tetrahydrofuran; and nitrogen-containing solvents such as pyridine, morpholine, acetonitrile, N,N-dimethylformamide, dimethylacetamide, and N-methylpyrrolidone. These hydrophilic solvents may be used alone or as a mixed solvent of two or more.

As the "peony", those listed in the 18th edition of the Japanese Pharmacopoeia can be preferably used.
Peonies other than those mentioned above are also commercially available and can be easily obtained.
Commercially available peonies include, for example, peony powder and peony extract (including, for example, dry extracts and soft extracts), but are not limited thereto.
When commercially available peonies are used in oral pharmaceutical compositions, peonies may be used so that the content of peonies in the solid preparation is appropriate, taking into account the conversion ratio of the original herbal medicine.

There is no limitation on the content of component (B) in the solid preparation, but it is preferable to administer 100 to 5000 mg, more preferably 150 to 2000 mg, and more preferably 200 to 900 mg per day in terms of the original herbal medicine as peony. It is even more preferable to administer the drug, and the administration frequency is preferably 1 to 3 times a day.

For example, when using a dried peony extract in a solid preparation, the content of the dried peony extract is not limited, but may be 1 to 50% by mass, based on the weight of the entire solid preparation, and may be 2 to 40% by mass. %, more preferably 3 to 20% by mass.

<Component (C)>
Component (C) is magnesium oxide.
As component (C), those listed in the 18th edition of the Japanese Pharmacopoeia may be used and are easily 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 ratio of magnesium oxide in the solid preparation may be selected in consideration of the solid preparation's disintegration properties, drug dissolution properties, and function as an antacid, and is not limited to 0% based on the mass of the entire solid preparation. 80% by weight, 0.1 to 70% by weight, preferably 1 to 25% by weight.

<Component (E)>
Component (E) is one or more selected from the group consisting of anhydrous caffeine, caffeine hydrate, and caffeine sodium benzoate. These are listed in the 18th revised Japanese Pharmacopoeia.

The content of component (E) in the solid preparation is not limited, but is preferably an amount of 10 to 1000 mg, more preferably 50 to 500 mg, and more preferably 100 to 1000 mg of anhydrous caffeine per day. Even more preferably, the amount administered is 250 mg.

The amount of component (E) contained in the solid preparation is not limited, but is 1 to 80 parts by weight, preferably 2 to 50 parts by weight, and preferably 5 to 30 parts by weight, per 100 parts by weight of the solid preparation. It is more preferable that there be.

Although the mass ratio of the content of component (B) to the content of component (E) in the solid preparation ((B)/(E)) is not limited, it is preferable from the viewpoint of improving tableting suitability during preparation of the preparation. is 0.01 or more, more preferably 0.1 or more, still more preferably 0.2 or more.
Further, from the viewpoint of improving granulation suitability during preparation of the preparation, the mass ratio ((B)/(E)) is preferably 500 or less, more preferably 50 or less, and even more preferably 5 or less.

From the viewpoint of improving the storage stability of the solid preparation, it is also preferable that the mass ratio ((B)/(E)) is 0.01 to 0.5.
Further, from the viewpoint of improving granulation suitability during preparation of the preparation, it is also preferable that the mass ratio ((B)/(E)) is 1 to 500.

The mass ratio of the content of component (E) in the solid preparation to the amount of component (B) equivalent to the crude drug equivalent is not limited, but from the viewpoint of improving the storage stability of the solid preparation, it is preferably 0.1 or more, More preferably it is 0.2 or more, still more preferably 0.4 or more.
Further, from the viewpoint of improving granulation suitability during preparation of the preparation, the mass ratio of the content of component (E) in the solid preparation to the amount of component (B) equivalent to the crude drug is preferably 500 or less, more preferably It is 100 or less, more preferably 10 or less.

The solid preparation may include a core amorphous (co-amorphous) formed from component (E) and paeoniflorin.

<Water>
In this embodiment, the content of water in the solid preparation is not limited, but from the viewpoint of improving the storage stability of the solid preparation, the content of water is 3% by mass or less, preferably 2.5% by mass based on the entire solid preparation. The content is more preferably 2% by mass or less, and even more preferably 1.5% by mass or less.
Further, the content of water in the solid preparation is specifically 0% by mass or more, and the solid preparation may not contain water or may contain water at the above concentration or less.

In this embodiment, the solid preparation may further contain components other than components (A) to (C) and (E). Examples of such components are listed below.

<Component (D)>
From the viewpoint of improving storage stability, the solid preparation preferably further contains component (D): light silicic anhydride.
Light anhydrous silicic acid is a known compound described in the 18th edition of the Japanese Pharmacopoeia, and examples of commercially available products include the Aerosil series manufactured by Nippon Aerosil Co., Ltd., Ad Solider 101 manufactured by Freund Sangyo Co., Ltd., and Fuji Silysia Chemical Co., Ltd. Examples include the Silicia series manufactured by the company.

The specific surface area of component (D) is not limited, but from the viewpoint of improving the storage stability of solid preparations, it is, for example, 1.5 x 10 ² m ² /g or more, preferably 1.7 x 10 ² m ² /g. g or more, and preferably 2.5×10 ² m ² /g or more.
Further, from the viewpoint of improving uniform dispersibility during preparation of the preparation, the specific surface area of component (D) is preferably 1.0 x 10 ³ m ² /g or less, more preferably 8.0 x 10 ² m ² /g or less, more preferably 3.5×10 ² m ² /g or less.
Here, the specific surface area of component (D) is specifically measured by the BET multipoint method (see General Test Method 3.02 "Specific Surface Area Measuring Method" of the 18th edition of the Japanese Pharmacopoeia). .

The content ratio of component (D) in the solid preparation is not limited, but from the viewpoint of improving the storage stability of the solid preparation, it may be 0.1 to 95% by mass, based on the mass of the entire solid preparation, and may be 0.1 to 95% by mass, based on the mass of the entire solid preparation. It may be 5 to 70% by mass, it may be 0.8 to 50% by mass, it may be 1 to 30% by mass, it is preferably 1 to 20% by mass, and it is preferably 2 to 15% by mass. % is more preferable.

When the solid preparation is a tablet obtained by compressing granules, component (D) may be contained in the granules, may be contained in the rear end (outside of the granules), It may be contained in both the granule and the final part (outside of the granule), but from the viewpoint of improving the storage stability of the solid preparation, it must be contained at least in the component (B) and the preparation without intervening between them. is preferred.

The mass ratio of the content of component (B) to the content of component (D) in the solid preparation ((B)/(D)) is not limited, but it can be used to improve granulation suitability and tableting suitability during preparation. From this point of view, it is preferably 0.02 or more, more preferably 0.1 or more, even more preferably 0.2 or more.
Further, from the viewpoint of improving the storage stability of the solid preparation, the mass ratio ((B)/(D)) is preferably 1000 or less, more preferably 100 or less, and still more preferably 50 or less.

The mass ratio of the content of component (D) in the solid preparation to the amount of component (B) equivalent to the crude drug equivalent is not limited, but from the viewpoint of improving granulation suitability and tableting suitability during preparation of the preparation, it is preferably 0. The number is 2 or more, more preferably 1 or more, even more preferably 2 or more.
Furthermore, from the viewpoint of improving the storage stability of the solid preparation, the mass ratio of the content of component (D) in the solid preparation to the amount of component (B) equivalent to the original drug is preferably 1000 or less, more preferably 2000 or less. It is preferably 100 or less.

<Antacid>
In this embodiment, the solid preparation may further contain an antacid other than component (C).
Examples of antacids other than component (C) include alkaline earth metals and/or earth metal basic inorganic compounds such as magnesium silicate, magnesium aluminate silicate, magnesium aluminum silicate, magnesium hydroxide, Co-precipitated product of magnesium hydroxide and potassium aluminum sulfate, magnesium carbonate, synthetic hydrotalcite, magnesium aluminate metasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium alumina hydroxide, aluminum hydroxide gel, hydroxide Aluminum/sodium bicarbonate coprecipitation product, aluminum hydroxide/magnesium carbonate mixed dry gel, aluminum hydroxide/magnesium carbonate/calcium carbonate coprecipitation product, bentonite, calcium silicate, calcium carbonate, precipitated calcium carbonate, hydrogen phosphate Inorganic salts of metals selected from magnesium, aluminum, and calcium, such as calcium and anhydrous calcium hydrogen phosphate, etc., and alkali metal basic inorganic compounds include, for example, dry sodium carbonate, sodium hydroxide, and hydrogen carbonate. Examples include inorganic salts of metals selected from sodium and potassium, such as sodium, sodium carbonate hydrate, sodium hydrogen phosphate hydrate, anhydrous sodium monohydrogen phosphate, potassium hydroxide, potassium hydrogen carbonate, potassium carbonate, etc. Other examples include bolei and glycine, and one or more components selected from these may be blended. Among these, one or more selected from the group consisting of magnesium aluminate metasilicate, synthetic aluminum silicate, precipitated calcium carbonate, and glycine are preferred.

When using magnesium aluminate metasilicate as an antacid, those listed in the 18th edition of the Japanese Pharmacopoeia may be used and are easily available.
Commercially available magnesium aluminate metasilicate includes, but is not limited to, Neusilin manufactured by Fuji Chemical Industry Co., Ltd., for example.
The content ratio of magnesium aluminate metasilicate in the solid preparation may be selected in consideration of the solid preparation's disintegration properties, drug dissolution properties, and function as an antacid, and is not limited, but is based on the mass of the entire solid preparation. The total amount with component (C) may be more than 0 to 80% by weight, may be 0.1 to 70% by weight, and preferably 1 to 50% by weight.

The total content of component (C) and other antacids in the solid preparation may be selected in consideration of the disintegration properties of the solid preparation, the dissolution properties of the drug, and the function as an antacid, but is not limited to the following: Based on the weight of the entire solid preparation, it may be more than 0 to 80% by weight, may be 0.1 to 70% by weight, and preferably 1 to 50% by weight.

<Licorice and its extract>
In this embodiment, the solid preparation may further include one or more selected from the group consisting of licorice and extracts thereof.
Licorice is traditionally used as an anti-inflammatory agent, cold medicine, antipyretic analgesic, antitussive expectorant, gastrointestinal medicine, anthelmintic medicine, oral medicine for rhinitis, throat freshener, stomach refreshing medicine, vitamin-containing health medicine, sweetener, It may be used as a flavoring, coloring, flavoring, perfuming, or excipient.

In this embodiment, when using "licorice", those listed in the 18th edition of the Japanese Pharmacopoeia can be preferably used.
Licorice other than those mentioned above are also commercially available and can be easily obtained.
Commercially available licorice extracts include, for example, extracts using water or 30% ethanol aqueous solution as extraction solvents. , products with various crude drug conversion ratios are on sale. In addition to these licorice extracts, licorice extracts, licorice extracts, and the like may be used as appropriate, without limitation.
When using commercially available licorice in an oral pharmaceutical composition, for example, licorice may be used in such a way that the licorice content in the solid preparation is appropriate, taking into account the conversion ratio of the original herbal medicine.

In the present embodiment, there is no restriction on the content of licorice (licorice or licorice extract) in the solid preparation, but it is preferable as the amount of the component contained in the solid preparation per daily dose, as the amount equivalent to the original drug. is 10 mg to 10 g, more preferably 150 mg to 5 g, even more preferably 500 mg to 3000 mg, and may be 500 mg to 1500 mg. The frequency of administration is preferably 1 to 3 times a day.

For example, when dry licorice extract is used in a solid preparation, the content of the dried licorice extract is not limited, but may be 0.1 to 80% by mass, based on the weight of the entire solid preparation, and may be 1 to 80% by mass. It may be 50% by weight, preferably 5-40% by weight, more preferably 10-30% by weight.

<Partially pregelatinized starch>
In this embodiment, the solid preparation preferably further contains partially pregelatinized starch from the viewpoint of improving granulation suitability during preparation and dissolution of the solid preparation.
Partially pregelatinized starch is, for example, a starch obtained by partially pregelatinizing wheat starch, corn starch, or potato starch, and is listed in the Pharmaceutical Excipients Standard 2018 and is easily available.

The content of partially pregelatinized starch in a solid preparation is not limited, but for example, in the case of tablets, it may be 1 to 1000 mg, preferably 2 to 500 mg per tablet.
The content ratio of partially pregelatinized starch in the solid preparation is not limited, but from the viewpoint of shortening the disintegration time of the solid preparation and improving drug dissolution from the solid preparation, the content ratio is 0.1 to 0.1 based on the mass of the entire solid preparation. It may be 95% by weight, 1 to 80% by weight, preferably 2 to 70% by weight, more preferably 5 to 40% by weight.

In addition, when the solid preparation is a tablet obtained by compressing granules, partially pregelatinized starch may be contained in the granules or in the rear end (outside of the granules). , may be contained in both the granules and the final powder (outside of the granules), but from the viewpoint of improving granulation suitability during drug production and dissolution of solid preparations, it is included at least in the granules. It is preferable.

<Component (F)>
The solid preparation of the present embodiment may preferably further contain component (F): a compound having an amino group, from the viewpoint of further imparting a desired effect to the solid preparation. Here, the component (F) is specifically a component other than the above-mentioned components.
Component (F) is not limited as long as it is a compound having an amino group, but examples include isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, histidine, tyrosine, cysteine, aspartic acid, One or more components selected from amino acids such as asparagine, serine, glutamic acid, glutamine, proline, glycine, alanine, and arginine, carbocisteine, tranexamic acid, or salts thereof, etc. may be blended.
Component (F) contained in the solid preparation is not limited, but may be 1 to 90% by weight, 2 to 80% by weight, 5 to 60% by weight, based on the weight of the entire solid preparation. It may be %.
The blending amount of component (F) may be, for example, 100 to 1000 mg per dose, or 120 to 700 mg per dose, as the amount of the component contained in the solid preparation per daily dose. The number of times is preferably 1 to 3 times a day.

<Hesperidins>
Further, the solid preparation of this embodiment may include "hesperidins".
When hesperidins are used in this embodiment, examples thereof include hesperidin and hesperidin derivatives such as glycosylhesperidin. Hesperidin is also called vitamin P and is listed in the Japanese Pharmaceutical Standards 2002 and the like.
The content of hesperidin in the solid preparation of the present embodiment is not limited, but may be 0 to 30% by mass, or more than 0 to 30% by mass, and 0.1 to 15% by mass, based on the mass of the entire solid preparation. It may be.
The amount of the compound containing hesperidin in the composition may be, for example, 1 to 500 mg per dose, and 5 to 300 mg per dose, as the amount of the component contained in the solid preparation per daily dose. The administration frequency is preferably 1 to 3 times a day.

<Manufacturing method>
In the present embodiment, the method for producing a solid preparation includes, for example, a step of blending components (A) to (C) and (E) and other components as appropriate.
Solid preparations can be formulated according to conventional methods depending on the dosage form.

For example, when the solid preparation is a tablet, the tablet is manufactured by manufacturing a mixture containing components (A) to (C) and (E) and other components as appropriate, and compressing the resulting mixture. good.
More specifically, granules containing components (A) to (C) and (E) and other components as appropriate are produced, and an external part of the granules is formed on the obtained granules. Tablets may be manufactured by adding a final ingredient and compressing.
That is, tablets are produced, for example, by a step of manufacturing granules (at least one granule) containing components (A) to (C) and (E) and other components as appropriate; It can be manufactured by a process of manufacturing tablets by mixing the additives (sub-pending ingredients) and compressing the mixture. Furthermore, the components placed outside the granules may optionally be in the form of granules.

The latter component (outside of the granule) is a part that constitutes the outside of the granule in the tablet, and for example, it may be a part configured to cover one granule in the tablet, It may be a portion configured to cover the granules. In addition, it may be a region that covers at least one granule in the tablet and a region that constitutes the outer surface of the tablet.
In this embodiment, the tablet has granules in the tablet, and components (A) to (C) and (E) may be contained in the granules.

The moisture value (moisture content) of the granulated granules may be such that the water content in the solid preparation (in the final preparation) is 3% by mass or less, for example, 5% by mass or less, and 3% by mass. It is more preferably at most 2% by mass, even more preferably at most 2% by mass. This makes it possible to more stably suppress a decrease in the content of loxoprofen, and to obtain tablets with even better long-term stability.

For formulation, known methods and additives can be used as appropriate. Additives may be added as appropriate within a range that does not impair the effects of the present invention.
Additives include pharmaceutically acceptable carriers, such as excipients, binders, disintegrants, disintegration aids, lubricants, flow agents, brightening agents, foaming agents, moisture-proofing agents, surfactants, Stabilizers, emulsifiers, antioxidants, fillers, preservatives, sweeteners, flavoring agents, cooling agents, fragrances, fragrances, colorants, bases, coatings, sugar coating agents, plasticizers, dispersants, and Preparation additives that can be used in conventionally known solid preparations, such as antifoaming agents, can be used for the above purpose.

Examples of excipients include candy powder, gum arabic, gum arabic powder, cacao butter, caramel, sodium carboxymethyl starch, hydrated silicon dioxide, anhydrous amorphous silicon oxide, xylitol, magnesium aluminate silicate, calcium silicate, Magnesium silicate, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, monohydrogen phosphate, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granules, sodium hydrogen phosphate hydrate, phosphorus Calcium dihydrogen acid hydrate, sodium dihydrogen phosphate hydrate, crystalline cellulose, crystalline cellulose/carmellose sodium, crystalline cellulose (fine particles), crystalline cellulose (granules), powdered cellulose, synthetic aluminum silicate, synthetic silicic acid Aluminum, hydroxypropyl starch, crystalline cellulose, wheat starch, rice flour, rice starch, heavy silicic anhydride, refined white sugar, refined white sugar spherical granules, gelatin, D-sorbitol, calcium carbonate, magnesium carbonate, precipitated calcium carbonate, low degree of substitution Hydroxypropyl cellulose, dextrin, corn starch, corn starch granules, trehalose, silicon dioxide (excluding light anhydrous silicic acid), lactose hydrate, lactose granules, white sugar, potato starch, hydroxypropyl starch, powdered sugar , powdered candy, powdered reduced maltose starch syrup, powdered cellulose, pectin, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, maltitol, D-mannitol, magnesium aluminate metasilicate, calcium sulfate, erythritol, glucose, Examples include fructose.

Examples of binders include gum arabic, gum arabic powder, 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., or one or more components selected from can be blended.

Examples of the disintegrant include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and hydroxypropyl starch.

Examples of disintegration aids include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, polysorbate 40, polysorbate 60, Examples include polysorbate 80, macrogol 1500, macrogol 4000, and the like.

Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, polyethylene glycol, hydrogenated oil, and sodium stearyl fumarate.

Examples of fluidizing agents include hydrous silicon dioxide, synthetic aluminum silicate, heavy silicic anhydride, magnesium alumina hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, and calcium hydrogen phosphate granules. One or more components selected from the following can be blended.

As the brightening agent, 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. are blended. can do.

As the blowing agent, one or more components selected from, for example, dry sodium carbonate, tartaric acid, potassium hydrogen tartrate, sodium hydrogen carbonate, anhydrous citric acid, etc. can be blended.

Examples of moisture-proofing agents include ethyl cellulose, olive oil, dry aluminum hydroxide gel, glycerin, magnesium silicate, hydrogenated oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, refined shellac, refined white sugar, One or more components selected from 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. can be blended. .

Examples of the surfactant include sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan monolaurate. Oxyethylene 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, macrogol 400, sorbitan monooleate , glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, sodium lauryl sulfate, and the like can be blended.

Examples of the stabilizer include adipic acid, L-aspartic acid, sodium L-aspartate, DL-alanine, L-alanine, L-arginine, L-arginine hydrochloride, sodium alginate, propylene glycol alginate ester, benzoic acid. , sodium benzoate, ethylenediamine, calcium edetate disodium, sodium edetate, edetate tetrasodium, edetate tetrasodium 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, hydrated silicon dioxide, dry sodium carbonate, glycine, glycerin, glycerin fatty acid ester, calcium gluconate water sodium gluconate, magnesium gluconate, potassium L-glutamate, sodium L-glutamate, L-lysine L-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 hydrolyzate, sorbitan fatty acid ester, taurine, talc, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium carbonate hydrate, carbonic acid Magnesium, 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 hydrogenation 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, glyceryl monostearate, medicinal charcoal, magnesium sulfate hydrate, DL-malic acid, One or more components selected from sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, etc. can be blended.

Examples of emulsifiers include glycerin fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyglycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, Examples include polyethylene glycol fatty acid ester, hydrogenated soybean phospholipid, and the like.

Examples of the antioxidant include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soybean lecithin, natural vitamin E, tocopherol, tocopherol acetate, ascorbic acid palmitate, sodium pyrosulfite, and the like. Can be done.

As the filler, for example, RSS No. 1 raw rubber, starch acrylate 1000, hydrated silicon dioxide, titanium oxide, silicon dioxide (excluding light anhydrous silicic acid), calcium monohydrogen phosphate, and the like.

Examples of the preservative include benzoic acid, sodium benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, methyl paraoxybenzoate, dehydroacetic acid, sodium dehydroacetate, sorbic acid, phenoxyethanol, and the like.

Examples of sweeteners include aspartame, acesulfame potassium, amacha, amacha powder, reduced maltose starch syrup, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, sodium saccharin hydrate, sucralose, stevia extract, purified stevia extract. , refined sucrose, fructose, sucrose, maltitol, D-mannitol, erythritol, and the like can be blended.

Examples of flavoring agents include sodium chloride, orange, orange oil, cacao powder, fructose, caramel, xylitol, calcium citrate, citric acid hydrate, sodium citrate hydrate, L-glutamic acid, sodium L-glutamate, Grapefruit extract, brown sugar, saccharin, sodium saccharin hydrate, tartaric acid, D-tartaric acid, potassium hydrogen tartrate, DL-sodium tartrate, sucralose, stevia extract, purified stevia extract, aspergillus, D-sorbitol, tannic acid, trehalose hydrate A kind selected from the group consisting of 100% polyester, fructooligosaccharide, 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. Alternatively, two or more types of components can be blended.

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

Examples of flavoring agents include 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. One or more selected components can be blended.

Examples of aromatic agents include fennel powder, fennel 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, Examples include vanillin, bergamot oil, d-borneol, dl-borneol, dl-menthol, l-menthol, eucalyptus oil, rose water, rose oil, and the like.

Examples of colorants include yellow iron oxide, yellow iron sesquioxide, orange essence, brown iron oxide, carbon black, caramel, β-carotene, gold leaf, black iron oxide, titanium oxide, iron sesquioxide, dizuazo yellow, and edible iron oxide. 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, Iron Sesquioxide/Glycerin Suspension Contains one or more ingredients selected from liquid, sodium copper chlorophyllin, copper chlorophyll, phenol red, malachite green, methylene blue, medicinal charcoal, riboflavin, riboflavin butyrate, sodium riboflavin phosphate, green tea powder, rose oil, etc. can do.

Examples of the base include gum arabic powder, pregelatinized starch (excluding the above partially pregelatinized starch), ethyl cellulose, cacao butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose starch syrup, and hydrated silicon dioxide. , dry aluminum hydroxide gel, agar, agar powder, xanthan gum, glycine, glycerin, glycerin fatty acid ester, crystalline cellulose, hydrogenated 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, 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, glyceryl monostearate, sorbitan monostearate, batyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, lauryl One or more components selected from sodium sulfate, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, etc. can be blended.

Examples of coating agents include ethyl acrylate/methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, gum arabic, gum arabic powder, ethyl cellulose, ethyl cellulose aqueous dispersion, carnauba wax, carboxyvinyl polymer, Gold leaf, silver leaf, triethyl citrate, glycerin, glycerin fatty acid ester, hydrogenated oil, titanium oxide, sucrose fatty acid ester, stearyl alcohol, stearic acid, magnesium stearate, purified gelatin, purified shellac, gelatin, D-sorbitol, talc, carbonic acid Calcium, magnesium carbonate, medium gold leaf, precipitated calcium carbonate, concentrated glycerin, white shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose 2910, titanium oxide, macrogol 400 mixture, hypromellose, fumaric acid, stearic acid, Polyvinyl acetal diethylaminoacetate/hydroxypropyl methylcellulose 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 aluminate metasilicate, methyl acrylate/methacrylate/methyl Methacrylate copolymer, methylcellulose, 2-methyl-5-vinylpyridine methyl acrylate/methacrylic acid copolymer, aluminum monostearate, glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol/acrylic acid/methacrylate Examples include acid methyl copolymers.

Examples of sugar coating agents include gum arabic, gum arabic powder, ethyl cellulose, carnauba wax, carmellose sodium, titanium oxide, stearic acid, polyoxyl stearate 40, purified gelatin, purified shellac, refined white sugar, gelatin, shellac, talc, precipitated carbonic acid. Calcium, white shellac, white sugar, hydroxypropylcellulose, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, calcium hydrogen phosphate hydrate, phosphorus One or more components selected from calcium acid dihydrogen hydrate, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, etc. can be blended.

Examples of the plasticizer include triethyl citrate, glycerin, glycerin fatty acid ester, D-sorbitol, medium chain fatty acid triglyceride, triacetin, concentrated glycerin, castor oil, polyoxyethylene hydrogenated castor oil 60, propylene glycol, polyoxyethylene (105 ) Polyoxypropylene (5) selected from glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, glyceryl monostearate, isopropyl linoleate, liquid paraffin, etc. One or more types of components can be blended.

Examples of dispersants include aminoalkyl methacrylate polymer RS, gum arabic, gum arabic powder, 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 hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil oil 60, polysorbate 20, polysorbate 60, polysorbate 80, microcrystalline wax, macrogol 300, macrogol 4000, macrogol 6000, macrogol 6000NF, anhydrous sodium citrate, magnesium aluminate metasilicate, methylcellulose, glycerin monooleate, One or more components selected from sorbitan monooleate, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate, etc. can be blended.

Examples of antifoaming agents include one or more selected from ethanol, glycerin fatty acid ester, dimethylpolysiloxane (for internal use), sucrose fatty acid ester, silicone antifoaming agent, silicone oil, sorbitan fatty acid ester, polysorbate 80, etc. The following ingredients can be blended.

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

In addition, the solid preparation may further contain other active ingredients as necessary, such as antipyretic analgesics, antitussives and expectorants, antihistamines, antiinflammatory agents, anticholinergics, other vitamins, xanthine derivatives, and sedatives. may be blended as appropriate within a range that does not impair the effects of the present invention, and if there is any contraindication to their blending, they may be divided into granules as appropriate to formulate a formulation.

Examples of antipyretic analgesics include aspirin, aspirin aluminum, acetaminophen, ethenzamide, sazapirin, salicylamide, lactylphenetidine, ibuprofen, isopropylantipyrine, pranopfen, diclofenac sodium, mefenamic acid, indomethacin farnesil, acemethacin, etodolac, naproxen, One or more components selected from meloxicam, celecoxib, sodium salicylate, tialamide hydrochloride, etc. can be blended.

Antitussive and expectorant agents include, for example, codeine, codeine phosphate hydrate, dihydrocodeine, dihydrocodeine phosphate, dibnate sodium, dimemorphan phosphate, tipepidine citrate, tipepidine hibenzate, dextromethorphan, dextrose. Lomethorphan hydrobromide hydrate, dextromethorphan phenolphthalin salt, allocramide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, pentoxyverine citrate, noscapine, noscapine hydrochloride, trimethoquinol Hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, l-methylephedrine hydrochloride, dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, guaifenesin, potassium guaiacolsulfonate, potassium cresolsulfonate, L- Examples include 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, and carbinoxamine maleate. salt, d-chlorpheniramine maleate, dl-chlorpheniramine maleate, ketotifen fumarate, diphenylpyraline hydrochloride, diphenylpyraline theocurate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, Triprolidine hydrochloride, tripelenamine hydrochloride, tonzilamine hydrochloride, fexofenadine, phenetazine hydrochloride, promethazine hydrochloride, promethazine, mequitazine, methdilazine hydrochloride, loratadine, isopentyl hydrochloride, difeterol hydrochloride, methdilazine hydrochloride, mebhydroline napadisylate, promethazine methylene Examples include disalicylic acid and difeterol phosphate.

Examples of anti-inflammatory agents include glycyrrhizic acid, derivatives thereof, salts thereof (eg, dipotassium glycyrrhizinate, monoammonium glycyrrhizinate, etc.), tranexamic acid (component (F)), and the like.

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, and isopropamide iodide. , iodized diphenylpiperidinomethyldioxolane, funnel extract, funnel root, funnel root total alkaloid citrate, and the like.

Examples of vitamins include vitamin A, vitamin C, vitamin B1, vitamin B2, vitamin B5, vitamin B6, vitamin B12, vitamin P, vitamin E, nicotinic acid, nicotinamide, panthenol, calcium pantothenate, and pantothenic acid. Sodium, biotin, potassium/magnesium aspartate mixture in equal proportions, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine hydrochloride, orotin, gamma oryzanol, calcium glycerophosphate, calcium gluconate, glucnolactone, glucuronic acid Examples include amide, sodium chondroitin sulfate, ginseng, yokuinin, and ioic acid.

Examples of xanthine derivatives include caffeine citrate.
Examples of sedatives include allylisopropylacetylurea and bromovalerylurea.

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

Solid preparations can be suitably used for the purpose of suppressing fever, pain, and inflammation. Since the active ingredient loxoprofen or its salt has antipyretic, analgesic, and anti-inflammatory effects, it can be used as an antipyretic analgesic for headaches, menstrual pain (menstrual pain), toothache, pain after tooth extraction, and sore throat. Suitable for use as an analgesic for pain, lower back pain, joint pain, muscle pain, stiff shoulders, ear pain, bruise pain, fracture pain, sprain pain, trauma pain, etc., and as a fever reliever for chills and fever, and as a cold treatment agent. It can be suitably used for the purpose of alleviating cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, fever, chills, headache, sneezing, joint pain, muscle pain).

<Dosage form>
Solid preparations include, for example, preparations for oral administration (including tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets, etc.), preparations for oral administration (oral tablets, troches, tongue tablets, etc.). (including sub-tablets, buccal tablets, adhesive tablets, gums, etc.), etc.), etc.), etc.), etc.), etc., as described in the 18th edition of the Japanese Pharmacopoeia, General Rules for Preparations, etc.

In addition, examples of the dosage forms of solid preparations include capsules, pills, granules, fine granules, powders, and tablets. These solid preparations may be coated with sugar coating, film coating, etc. by a known method, if necessary. 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 packaging container in which the solid preparation according to the present embodiment is housed. By making it into a package, for example, the convenience of using the solid preparation can be improved.

<Packaging form>
Regarding the packaging form of the solid preparation, it may be once packaged and stored airtight using SP packaging (Strip Package), PTP packaging (Press Through Package), stick packaging, bottle packaging, pouch packaging, etc. That is, the solid preparation may be housed in an airtight package. Furthermore, they may be wrapped in pillows or stored in a box or the like.
In other words, the pharmaceutical according to one embodiment of the present invention may include the solid preparation according to the above embodiment and a packaging material for packaging the solid preparation.
Materials used for SP packaging, PTP packaging, stick packaging, and pillow packaging are not limited, and examples include single-layer resin films such as polyvinyl chloride film, polyvinylidene chloride film, polypropylene film, polyethylene terephthalate film, and polyethylene film. Alternatively, a multilayer film made by combining these resin films, or a film made by adhering aluminum foil to these resin films can be used.

The packaging material for the solid preparation is preferably, for example, a packaging made of a material that is not easily affected by moisture (a packaging made of at least one of a moisture-proof material and a gas barrier material).
For example, as packaging made of a material that is less affected by moisture (moisture-proof material), PTP (polypropylene) + polyethylene aluminum pillow packaging (combination packaging of PTP and polyethylene aluminum pillows) may be used. In addition, in consideration of suppressing the increase in moisture content in tablets, storage stability of tablets, stability of tablets after opening, etc., we use PTP packaging that uses aluminum on both sides as a packaging material that is not easily affected by moisture (moisture-proof material). (Al-Al packaging) may also be used.
In addition, if hygroscopicity is a concern, a desiccant or the like may be stored at the same time in a packaging container such as a bottle packaging or a pillow packaging.
As the gas barrier material, any known material may be used, and it is not limited to, for example, a laminate film having a functional barrier layer may be used, and it may also serve as the moisture-proof material, or may be used in conjunction with the moisture-proof material. , may be used.

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

(Stabilizer and stabilization method)
In this embodiment, the stabilizer of the pharmaceutical composition contains the above-mentioned components (A) to (C) and (E), and preferably further contains the above-mentioned component (D).
Furthermore, in this embodiment, the method for stabilizing a pharmaceutical composition includes incorporating the above-mentioned component (E) into a pharmaceutical composition containing the above-mentioned components (A) to (C), and preferably the above-mentioned pharmaceutical composition. It includes further containing the above-mentioned component (D) in the composition.
Here, the pharmaceutical composition is specifically the above-mentioned solid preparation, and the above-mentioned configuration can be used as appropriate. For example, for components (A) to (C) and (E) and other components constituting the pharmaceutical composition, the configurations described above in the solid preparation section can be used as appropriate.

In this embodiment, by incorporating components (A) to (C) and (E) together into a pharmaceutical composition such as a solid preparation, the storage stability of the pharmaceutical composition can be improved. More specifically, it is possible to suitably suppress a decrease in the residual rate of component (B) in the pharmaceutical composition or its constituent components, such as paeoniflorin, after storage. Although the reason for this is not necessarily clear, it is presumed that a core amorphous form of component (E) and paeoniflorin is formed in the pharmaceutical composition such as a solid preparation. Here, the presence or absence of core amorphous formation between component (E) and paeoniflorin can be specifically confirmed by obtaining a diffraction pattern of the solid preparation using an X-ray diffraction method.

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

<Test Example 1> Confirmation of the residual rate of paeoniflorin After preparing the tablets of each example shown in Tables 1 and 2, place them in a glass bottle and store them at 60°C with a tightly stopper for 2 weeks, and then measure the residual rate of paeoniflorin (PFL). The storage stability of the tablets was evaluated.

Details of the components listed in Tables 1 and 2 are as follows.
Loxoprofen sodium hydrate: KOLON LIFE SCIENCE, INC. Manufactured by Anhydrous Caffeine: Manufactured by Shizuoka Caffeine Industries Co., Ltd. Magnesium oxide: Japanese Pharmacopoeia Magnesium Oxide Heavy, manufactured by Kyowa Chemical Industry Co., Ltd. Licorice Dried Extract: Manufactured by Alps Yakuhin Kogyo Co., Ltd. Peony Dried Extract: Peony Dry Extract-Q, Japan Powdered Yakuhin Co., Ltd. Manufactured (extract: herbal medicine = 7:1)
Lactose hydrate: PHARMATOSE Lactose 200M, partially pregelatinized starch manufactured by DMV international: PCS PC-10, light silicic anhydride manufactured by Asahi Kasei Corporation: Aerosil 200, specific surface area 200 m ² /g (175-225 m ² /g), Nippon Aerosil Croscarmellose sodium: AcDiSol, DuPont carmellose calcium: ECG-505, Gotoku Pharmaceutical Co., Ltd. Calcium stearate: Taihei Kagaku Sangyo Co., Ltd.

(Example 1)
According to the ratios in Table 1, loxoprofen sodium hydrate, anhydrous caffeine, magnesium oxide, dried licorice extract, dried peony extract, lactose hydrate, partially pregelatinized starch, light anhydrous silicic acid, carmellose sodium was placed in a fluidized bed granulation dryer (manufactured by Powrex, FD-MP-01) and sprayed with purified water to form granules.
For the granulated granules, carmellose calcium weighed according to the ratio in Table 1 and calcium stearate were mixed in a plastic bag as a final powder, and then tableted with a tablet machine (manufactured by Kikusui Seisakusho Co., Ltd., VIRGO) to form tablets. I got it. Table 1 shows the amounts (mg) of the ingredients in the six tablets, along with the tablet mass per tablet.

(Examples 2-4, Comparative Examples 1-9)
Tablets of each example were manufactured in accordance with Example 1, except that the formulation of the granulation part was changed to the contents of Table 1 or Table 2.

(Measurement of moisture content)
The water content was determined by measuring the loss on drying (%) of the tablets obtained in each example. Specifically, using a halogen moisture meter (manufactured by Mettler Toledo, HX204), the loss on drying when heated at 80° C. until the mass fluctuation became 1 mg/50 seconds was measured as the moisture value.
The measurement results are also shown in Tables 1 and 2.

(Measurement of PFL residual rate)
The determination of paeoniflorin in each tablet before and after storage was performed three times for each sample using high-performance liquid chromatography (HPLC) as appropriate, based on the liquid chromatography method of the 18th edition of the Japanese Pharmacopoeia. The ratio of the average value of content after storage to the average value of content was calculated and used as the residual rate of paeoniflorin in the tablet.
The measurement results are also shown in Tables 1 and 2.

From Tables 1 and 2, in each Example, the decrease in the residual rate of PFL after storage was effectively suppressed compared to the Comparative Example, and tablets with excellent storage stability were obtained.

<Formulation Examples 1 to 16>
The formulations (per 6 tablets, mg/day) of Formulation Examples 1 to 16 are shown in Tables 3 and 4.
For Formulation Examples 1 to 16, tablets can be produced according to the method of Example 1, except that the compositions are changed to have the compositions shown in Tables 3 and 4. Moreover, the tablet can have a water content of 3% by mass or less. The coating was applied using a conventional method.

Although preferred embodiments and examples of the present invention have been described above, the present invention is not limited thereto. Additions, omissions, substitutions, and other changes to the configuration are possible without departing from the spirit of the invention.

In the present invention, solid preparations are extremely useful in terms of quality since they have excellent storage stability.
The solid preparation is used as an antipyretic analgesic, specifically for headaches, menstrual pain (menstrual pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, muscle pain, stiff shoulders, earache, bruise pain, It is suitable for pain relief from fracture pain, sprain pain, trauma pain, etc., and for alleviating fever during chills and fever.It is also used as a cold treatment for various cold symptoms (runny nose, stuffy nose, cough, phlegm, sore throat, etc.). It is suitable for alleviating symptoms (fever, chills, headache, sneezing, joint pain, muscle pain).

Claims (11)

A solid preparation containing the following components (A) to (C) and (E), wherein the content of water in the solid preparation is 3% by mass or less based on the entire solid preparation.
(A) One or more types selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof (B) One or more types selected from the group consisting of peonies and extracts thereof (C) Magnesium oxide (E) Anhydrous caffeine , caffeine hydrate, and one or more selected from the group consisting of caffeine sodium benzoate The solid preparation according to claim 1, wherein the component (B) contains paeoniflorin. Claim 1 or 2, wherein the mass ratio ((B)/(E)) of the content of the component (B) to the content of the component (E) in the solid preparation is 0.01 or more and 500 or less. Solid formulation as described. Component (D): The solid preparation according to claim 1 or 2, further comprising light silicic anhydride. Component (F): The solid preparation according to claim 1 or 2, further comprising a compound having an amino group. A stabilizer for a pharmaceutical composition containing the following components (A) to (C) and (E).
(A) One or more types selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof (B) One or more types selected from the group consisting of peonies and extracts thereof (C) Magnesium oxide (E) Anhydrous caffeine , caffeine hydrate, and one or more selected from the group consisting of caffeine sodium benzoate The stabilizer according to claim 6, wherein the component (B) comprises paeoniflorin. Claim 6 or 7, wherein the mass ratio ((B)/(E)) of the content of the component (B) to the content of the component (E) in the stabilizer is 0.01 or more and 500 or less. Stabilizers as described in . Component (D): The stabilizer according to claim 6 or 7, further comprising light silicic anhydride. Component (F): The stabilizer according to claim 6 or 7, further comprising a compound having an amino group. A method for stabilizing a pharmaceutical composition, which comprises incorporating the following component (E) into a pharmaceutical composition containing the following components (A) to (C).
(A) One or more types selected from the group consisting of loxoprofen, salts thereof, and hydrates thereof (B) One or more types selected from the group consisting of peonies and extracts thereof (C) Magnesium oxide (E) Anhydrous caffeine , caffeine hydrate, and one or more selected from the group consisting of caffeine sodium benzoate