WO2023234346A1 - Solid preparation and method for producing same - Google Patents

Abstract

The present invention addresses the problem of providing: a solid preparation obtained by blending an antacid and one or more types of compound selected from the group consisting of loxoprofen and a salt thereof, said preparation being a stable preparation in which a decrease in the loxoprofen content therein is suppressed; and a method for producing the same. The present invention provides a solid preparation which contains: one or more types of compound selected from the group consisting of loxoprofen and a salt thereof; a compound containing magnesium and/or aluminum; and a hydroxypropyl cellulose.

Description

Solid preparation and its manufacturing method

The present invention relates to a solid preparation and a method for producing the same. More specifically, the present invention relates to a stable solid formulation containing loxoprofen and/or a salt thereof, and a method for producing the same.

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 it also has strong antipyretic, analgesic, and antiinflammatory effects. It is known. 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 and/or its salts in combination with other active ingredients, loxoprofen is combined with specific sugars (lactose, sucrose, maltitol, fructose, xylitol, 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, as an oral solid composition that conceals the bitter taste of a bitter drug, low-substituted hydroxypropyl cellulose is used as a hydrophilic polymer, and water is added to the hydrophilic polymer so that water:hydrophilic polymer=1 to 10. : An oral solid obtained by adding a water-containing hydrophilic polymer in the range of 1, mixing it with (A) a drug that exhibits a bitter taste, granulating it, and then drying it until the moisture content is 7.5% by mass or less. A formulation has been reported (Patent Document 5).

Patent No. 4585220 Patent No. 6106727 Patent No. 5835865 Patent No. 6292744 Patent No. 5527921

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

The present inventors have focused on the fact that when a solid preparation containing loxoprofen and/or its salt and an antacid such as magnesium oxide is produced, the loxoprofen content decreases over time during storage. An object of the present invention is to provide a stable solid preparation containing loxoprofen and/or its salt and an antacid, in which a decrease in the content of loxoprofen in the preparation is suppressed, and a method for producing the same. .

The present inventors have made extensive studies to solve the above problems, and have found that by adding hydroxypropyl cellulose, a solid preparation containing loxoprofen and/or its salts and an antacid such as magnesium oxide can be obtained. They also found that the decrease in the content of loxoprofen was suppressed and an excellent formulation could be obtained, leading to the completion of the present invention.

That is, aspects of the present invention are as shown below.
(1) A solid preparation containing at least one member selected from the group consisting of loxoprofen and salts thereof, a compound containing at least one of magnesium and aluminum, and hydroxypropylcellulose.
(2) The solid preparation according to (1), wherein the hydroxypropylcellulose contains at least one of hydroxypropylcellulose and low-substituted hydroxypropylcellulose.
(3) The solid preparation according to (2), wherein the low-substituted hydroxypropyl cellulose has a particle diameter ratio D90/D50 of 1.5 to 3.0.
(4) The solid preparation according to (2) or (3), wherein the low-substituted hydroxypropyl cellulose has an average particle diameter of 30 to 60 μm.
(5) The solid preparation according to (2) or (3), wherein the proportion of hydroxypropoxy groups in the low-substituted hydroxypropyl cellulose is 7 to 16%.
(6) The compound containing at least one of magnesium and aluminum is one or more selected from the group consisting of magnesium oxide, magnesium aluminate metasilicate, and synthetic hydrotalcite, (1) The solid preparation according to any one of (5).
(7) The solid preparation according to any one of (1) to (6), further comprising one or more selected from the group consisting of crude drugs and their extracts, caffeine, and sedatives.
(8) The solid preparation according to any one of (1) to (7), further comprising a compound having an amino group.
(9) A method for producing a solid preparation containing at least one selected from the group consisting of loxoprofen and its salts, a compound containing at least one of magnesium and aluminum, and hydroxypropyl cellulose, comprising: Before granulating by adding at least one selected from the group consisting of loxoprofen and its salts and a compound containing at least one of magnesium and aluminum, water is added to hydroxypropyl cellulose to granulate it. A method for producing a solid preparation, comprising a first step of:
(10) The method for producing a solid preparation according to (9), wherein in the first step, the mass of the water is 0.4 times or more the mass of the hydroxypropyl cellulose.

According to the present invention, an excellent solid preparation in which a decrease in loxoprofen content is suppressed is provided, even if the solid preparation contains a mixture of loxoprofen and/or its salt and an antacid such as magnesium oxide.

The solid preparation of the present invention contains at least one member selected from the group consisting of loxoprofen and salts thereof, a compound containing at least one of magnesium and aluminum, and hydroxypropylcellulose.

The solid preparation of the present invention is a tablet, powder, granule, capsule, or pill as described in the Japanese Pharmacopoeia, 18th edition, and is preferably a granule or tablet. Most preferred are tablets. In addition, when testing the particle size of granules according to the 18th edition of the Japanese Pharmacopoeia, the amount that passes through a No. 18 (850 μm) sieve and remains on a No. 30 (500 μm) sieve is 10% of the total amount. The following may be referred to as fine granules.

Additionally, as an embodiment of the granules or tablets of the present invention, the preparation may be coated with a water-soluble polymer or the like. That is, examples include film-coated granules, film-coated tablets, and the like. Moreover, the solid preparation of the present invention may be sugar-coated.

Furthermore, when the solid preparation of the present invention is a tablet, in addition to a single-layer tablet as mainly shown in this specification, a multi-layer tablet formed by stacking two or three or more layers of powders or granules with different compositions and compression molding It can also be a lock. In addition, in the present invention, when the tablet is made into a multilayer tablet, loxoprofen and/or its salt, a compound containing at least one of magnesium and aluminum, and hydroxypropyl cellulose are contained in the same layer. .

The solid preparation of the present invention contains loxoprofen and/or a salt thereof.
In the present invention, "loxoprofen and/or its salt" means "at least one member selected from the group consisting of loxoprofen and its salt", and loxoprofen and/or its salt (including hydrated salt) (salt is Preferably, it is a pharmacologically acceptable salt), preferably loxoprofen sodium, and more preferably loxoprofen sodium dihydrate.
Loxoprofen and/or its salt used in the present invention is listed in the 18th edition Japanese Pharmacopoeia as loxoprofen sodium hydrate.

The content of loxoprofen and/or its salt contained in the solid preparation of the present invention is not limited, but as the amount of ingredients contained in the solid preparation per adult dosage unit (one dose), anhydrous The converted amount is preferably 10 to 180 mg, more preferably 30 to 120 mg, even more preferably 30 to 90 mg, and the number of administrations is 1 to 3 times a day.

When the solid preparation of the present invention is a tablet, the content of loxoprofen and/or its salt contained in the granules in the tablet is not particularly limited; ) is preferably 10 to 180 mg, more preferably 30 to 120 mg, even more preferably 30 to 90 mg, and may be 45 to 90 mg, in terms of anhydride equivalent. The frequency of administration is 1 to 3 times a day.

Loxoprofen and/or its salt contained in the tablet is not particularly limited, but is 1 to 80% by mass, preferably 2 to 50% by mass, and preferably 5 to 30% by mass, based on the mass of the entire solid preparation. %, and may be 5 to 20% by mass.

The solid preparation of the present invention contains a compound containing at least one of magnesium and aluminum.
Examples of compounds containing at least one of magnesium and aluminum include magnesium oxide, magnesium silicate, magnesium aluminate silicate, magnesium aluminum silicate, magnesium hydroxide, and co-precipitation of magnesium hydroxide/potassium aluminum sulfate. substance, magnesium carbonate, synthetic hydrotalcite, magnesium aluminate metasilicate, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium alumina hydroxide, aluminum hydroxide gel, aluminum hydroxide/sodium bicarbonate coprecipitation product, water Examples include aluminum oxide/magnesium carbonate mixed dry gel, aluminum hydroxide/magnesium carbonate/calcium carbonate coprecipitated product, bentonite, and the like. Among the above, the compound containing at least one of magnesium and aluminum is preferably one or more selected from the group consisting of magnesium oxide, magnesium aluminate metasilicate, and synthetic hydrotalcite. .

When using magnesium aluminate metasilicate in the present invention, those listed in the 18th edition of the Japanese Pharmacopoeia may be used, or those listed in the Encyclopedia of Pharmaceutical Additives may be used, and it is easy to use. available at.
Commercially available magnesium aluminate metasilicate is not particularly limited, but for example, there is Neusilin manufactured by Fuji Chemical Industry Co., Ltd.
The content ratio of magnesium aluminate metasilicate in the solid preparation of the present invention may be selected in consideration of the solid preparation's disintegration properties, drug dissolution properties, and function as an antacid, and is not particularly limited. may be 0.1 to 90% by weight, may be 1 to 90% by weight, preferably 5 to 80% by weight, based on the weight of .

When using magnesium oxide in the present invention, those listed in the Japanese Pharmacopoeia, 18th edition may be used, or those listed in the Encyclopedia of Pharmaceutical Additives may be used, which are easily available. It is.
Commercially available magnesium oxide is not particularly limited, but for example, magnesium oxide (light grade) manufactured by Tomita Pharmaceutical Co., Ltd., magnesium oxide (heavy grade) manufactured by Kyowa Chemical Industry, etc. may be used.
The content ratio of magnesium oxide in the solid preparation of the present invention may be selected by considering the disintegration property of the solid preparation, the dissolution property of the drug, and the function as an antacid, and is not particularly limited. As a standard, it may be 0.1 to 90% by weight, 1 to 90% by weight, preferably 5 to 80% by weight.

When using synthetic hydrotalcite in the present invention, those listed in the Japanese Non-Pharmaceutical Pharmaceutical Standards 2002 may be used, or those listed in the Encyclopedia of Pharmaceutical Additives may be used. available.
Commercially available synthetic hydrotalcites include, but are not particularly limited to, Alcamac (B grade) manufactured by Kyowa Chemical Industry Co., Ltd., Alcamac (L grade) manufactured by Kyowa Chemical Industry Co., Ltd., and Alcamac (L grade) manufactured by Kyowa Chemical Industry Co., Ltd. Alcamac (SH grade), Alcamac (SN grade) manufactured by Kyowa Chemical Industry Co., Ltd., etc. may also be used.
The content ratio of synthetic hydrotalcite in the solid preparation of the present invention may be selected in consideration of the solid preparation's disintegration properties, drug dissolution properties, and function as an antacid, and is not particularly limited. Based on the mass, it may be 0.1 to 90% by weight, 1 to 90% by weight, preferably 5 to 80% by weight.

The solid preparation of the present invention contains hydroxypropylcellulose.
As the hydroxypropylcellulose, it is preferable to use at least one of hydroxypropylcellulose and low-substituted hydroxypropylcellulose.

When hydroxypropyl cellulose is measured using a particle size distribution analyzer that uses laser diffraction and scattering (for example, Microtrac MT3000II series manufactured by Microtrac Bell Co., Ltd.), the 50% cumulative diameter of the obtained particle size distribution is D90/D50, which is the ratio of 90% integrated diameter, is preferably 1.5 to 3.0.

When hydroxypropyl cellulose is measured using a particle size distribution analyzer that uses laser diffraction and scattering (for example, Microtrac MT3000II series manufactured by Microtrac Bell Co., Ltd.), the average particle diameter (50% cumulative diameter) is , preferably 30 to 60 μm.

When hydroxypropylcelluloses are measured by the quantitative method described in the 18th edition Japanese Pharmacopoeia Manual, Low Substituted Hydroxypropylcellulose, the proportion of hydroxypropoxy groups is preferably 7 to 16%.

Hydroxypropylcellulose and low-substituted hydroxypropylcellulose may be those listed in the 18th edition of the Japanese Pharmacopoeia, or those listed in the Encyclopedia of Pharmaceutical Excipients, and are readily available. It is possible.
Commercially available hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose are not particularly limited, but include, for example, NISSO HPC (HPC-SL grade) manufactured by Nippon Soda Co., Ltd. and NISSO HPC (HPC-SSL grade) manufactured by Nippon Soda Co., Ltd. , NISSO HPC manufactured by Nippon Soda Co., Ltd. (HPC-L grade), NISSO HPC manufactured by Nippon Soda Co., Ltd. (HPC-H grade), KLUCEL ^TM manufactured by Ashland (ELF Pharm grade), KLUCEL TM manufactured by Ashland (EF Pharm grade), manufactured by Ashland KLUCELTM (LF Pharm grade), Shin-Etsu Chemical Co., Ltd. L-HPC ^TM (LH-21 grade), Shin-Etsu Chemical Co., Ltd. L-HPC ^TM (LH-22 grade), Shin-Etsu Chemical Co., Ltd. L-HPC ^TM (LH-11 grade), Shin-Etsu Chemical Co., Ltd. L-HPC ^TM (LH-B1 grade), Shin-Etsu Chemical Co., Ltd. L-HPC ^TM (LH-31 grade), Shin-Etsu Chemical Co., Ltd. L- HPC ^TM (LH-32 grade), L-HPC ^TM (NBD-22 grade) manufactured by Shin-Etsu Chemical Co., Ltd., L-HPC ^TM (NBD-21 grade) manufactured by Shin-Etsu Chemical Co., Ltd., L manufactured by Shin-Etsu Chemical Co., Ltd. -HPC ^TM (NBD-20 grade) or the like may also be used.
The content ratio of hydroxypropylcellulose in the solid preparation of the present invention may be selected in consideration of the solid preparation's disintegration property, drug dissolution property, and function as an antacid, and is not particularly limited. Based on the weight, it may be 1 to 80% by weight, may be 3 to 70% by weight, preferably 5 to 50% by weight.

The solid preparation of the present invention may preferably further contain one or more selected from the group consisting of crude drugs and their extracts, caffeine, and sedatives.
Examples of caffeine include caffeine hydrate, anhydrous caffeine, sodium benzoate caffeine, and citrate caffeine.
The content ratio of caffeine in the solid preparation of the present invention is not particularly limited, but may be, for example, 1 to 80% by mass, or 3 to 80% by mass, based on the mass of the entire solid preparation. It may be 5 to 70% by weight.

Examples of sedatives include allylisopropylacetylurea and bromovalerylurea.
The content of the sedative in the solid preparation of the present invention is not particularly limited, but may be, for example, 1 to 80% by mass, or 2 to 80% by mass, based on the mass of the entire solid preparation. , 2 to 70% by mass.

When using crude drugs, the types thereof are not particularly limited, but for example, ephedra, nandenjitsu, apricot, onji, licorice, bellflower, chazenshi, chazenso, seksan, senega, fritillary, fennel, japonica, japonica, and zebra. , Chamomile, Keihi, Gentian, Goou, Animal gall (including Yutan), Shajin, Gingerbread, Sojutsu, Clove, Chinpi, Byakujutsu, Jiryu, Chikusetsu carrot, Carrot, Akamegashiwa, Asenyaku, Inyoukaku, Corydalis, Scutellariae, Scutellariae, Valerian , caronin, kyounin, wolfberry, wolfberry, keigai, ketsumeishi, gennoshoko, kobushi, gomishi, saishin, sanshō, shion, zicoppi, peony, musk, shinii, senkyu, zenko, japonica, souhakuhi, soyou, taisan, touki, ipecac, Contains one or more ingredients selected from herbal medicines such as Bakumondo, Hange, Bangkouka, Hampi, Juniper, Bukryo, Botanpi, Borei, Rokujo, Bowie and their extracts (extracts, tinctures, dried extracts, etc.). can do.
The solid preparation of the present invention preferably contains at least one of licorice extract, peony extract, and valerian extract, and more preferably contains at least one of licorice extract and valerian extract.
The content ratio of the crude drug and its extract in the solid preparation of the present invention is not particularly limited, but for example, when each crude drug is an extract, it is 1 to 80% by mass based on the mass of the entire solid preparation, and 1 to 80% by mass. It may be 70% by weight, 1 to 60% by weight, or 1 to 50% by weight.

The herbal medicines used in the present invention, such as licorice, peony, and valerian, have been used medicinally since ancient times as single herbs or herbal medicines, and it is possible to use the herbal medicine powder or extracted components obtained according to the commonly used methods as they are. can. 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 extract components from crude drugs is not particularly limited, and any form such as 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 herbal medicine using an extraction solvent. As the extraction solvent, for example, water, a hydrophilic solvent, or a mixed solvent thereof is often used. Examples of the hydrophilic solvent 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; Examples include ethers such as dioxane and tetrahydrofuran; 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.
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.

When using "licorice" in the present invention, preferably, the licorice, licorice powder, licorice extract, and licorice crude extract listed in the 18th edition of the Japanese Pharmacopoeia can be used.
In addition, various types of licorice mentioned above and other than those mentioned above are 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, and are not particularly limited.
When commercially available licorice is used in a solid preparation, for example, licorice may be used in such a manner that the licorice content in the solid preparation is appropriate, taking into account the conversion ratio of the original herbal medicine.

There is no particular restriction on the content of licorice (licorice or licorice extract) in the solid preparation of the present invention, but preferably as the amount of the component contained in the solid preparation per daily dose, as the amount equivalent to the original drug. , 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, and the frequency of administration 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 dried licorice extract is not particularly limited, but is 0.1 to 80% by weight based on the weight of the entire solid preparation. Often it may be from 1 to 50% by weight, preferably from 5 to 40% by weight, more preferably from 10 to 30% by weight.

When "Valerian" is used in the present invention, Valerian root and Valerian powder listed in the 18th edition of the Japanese Pharmacopoeia can be preferably used as the "Valerian".
In addition, the above and other valerian plants are commercially available and can be easily obtained.
As commercially available valerian, for example, valerian powder or valerian extract (eg, soft extract, dry extract, etc.) can be used, and there is no particular limitation.
When using commercially available valerian in a solid preparation, valerian may be used so that the valerian content in the solid preparation is appropriate, taking into consideration the crude drug conversion ratio.

When using Valerian root (Valerian root or Valerian root extract) in the present invention, the content is not particularly limited, but for example, as the amount of the component contained in a solid preparation per daily dose, as the amount equivalent to the original drug. , may be 25 to 6000 mg, preferably 50 to 5000 mg, more preferably 100 to 4000 mg, still more preferably 200 mg to 3200 mg, and may be 400 to 1600 mg, and the frequency of administration is 1 to 3 times a day. It is.

For example, 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 from 1 to 50% by mass, and from 2 to 50% by mass, based on the mass of the entire solid preparation. It is preferably 40% by weight, more preferably 3 to 20% by weight.

When "peony" is used in the present invention, as "peony", peonies and peonies powder listed in the 18th edition of the Japanese Pharmacopoeia can be suitably used.
In addition, the above-mentioned peonies and other peonies other than those mentioned above are also commercially available and can be easily obtained.
As the commercially available peony, for example, peony powder or peony extract (including, for example, dried extract, soft extract, etc.) can be used, and there is no particular limitation.
When commercially available peonies are used in solid preparations, 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 drug.

When using peonies (peony or extracts thereof) in the present invention, the content is not particularly limited, but it is preferable to administer 100 to 5000 mg per day, and preferably 150 to 2000 mg per day in terms of the original drug. It is more preferable to administer 200 to 900 mg, and the administration frequency is 1 to 3 times a day.

In the solid preparation of the present invention, for example, when a dried peony extract is used, the content of the dried peony extract is not particularly limited, but may be 1 to 50% by mass based on the weight of the entire solid preparation, It is preferably 2 to 40% by weight, more preferably 3 to 20% by weight.

The solid preparation of the present invention may preferably further contain a compound having an amino group.
Compounds having an amino group are not particularly limited as long as they have an amino group, but examples include isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, histidine, tyrosine, cysteine, and asparagine. One or more components selected from acids, amino acids such as asparagine, serine, glutamic acid, glutamine, proline, glycine, alanine, and arginine, carbocysteine, tranexamic acid, or salts thereof, etc. may be blended.
The compound having an amino group contained in the solid preparation is not particularly limited, but may be 1 to 90% by weight, 2 to 80% by weight, 5 to 80% by weight, based on the weight of the entire solid preparation. It may be 60% by mass.
The amount of the compound having an amino group in the composition may be, for example, 100 to 1000 mg per dose, or 200 to 700 mg per dose, as the amount of the component contained in the solid preparation per daily dose. The frequency of administration may be 1 to 3 times per day.

Furthermore, the solid preparation of the present invention may also contain "hesperidins".
When using hesperidins in the present invention, mention may be made of 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 invention is not particularly limited, but may be 0 to 30% by weight, or 0.1 to 15% by weight, based on the weight of the entire solid preparation.
The amount of the compound containing hesperidin in the composition may be, for example, 10 to 500 mg per dose, or 20 to 300 mg per dose, as the amount of the component contained in the solid preparation per daily dose. The dosage may be 1 to 3 times per day.

The solid preparation of the present invention can be formulated according to conventional methods.
In the present invention, for example, granules containing loxoprofen and/or its salt, a compound containing at least one of magnesium and aluminum, and hydroxypropyl cellulose are produced, and the resulting granules include: A tablet may be manufactured by adding a final ingredient to form the outside of the granulated granules and compressing the mixture.

That is, the tablet can be produced by, for example, producing granules (at least one granule) containing loxoprofen and/or its salt, a compound containing at least one of magnesium and aluminum, and hydroxypropyl cellulose; It can be manufactured by a step of manufacturing a tablet by mixing the granulated granules and a desired additive (resulting powder component) 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) in the present invention is a part that constitutes the outside of the granule in the tablet, and may be a part configured to cover one granule in the tablet, for example. , it may be a portion configured to cover a plurality of 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. The tablet has granules in the tablet, and the granules contain loxoprofen and/or a salt thereof, a compound containing at least one of magnesium and aluminum, and at least one of hydroxypropylcelluloses. It may be

In the method for producing a solid preparation containing loxoprofen and/or a salt thereof, a compound containing at least one of magnesium and aluminum, and hydroxypropylcellulose according to the present invention, water and hydroxypropylcellulose are combined. It may also include a step of granulating (first step).
In the first step, the mass of water to be added should be more than 0.4 times the mass of hydroxypropyl cellulose, 0.5 times or more, 0.6 times or more, 0.7 times or more, 0.8 times or more. It may be 1.0 times or more or 1.0 times or more. The upper limit of the mass of hydroxypropyl cellulose relative to the mass of water is not particularly limited, but is generally 3 times or less.
By granulating water and hydroxypropylcellulose, and then granulating loxoprofen and/or its salt, and a compound containing at least one of magnesium and aluminum, hydroxypropylcellulose (especially low-substituted hydroxypropylcellulose) ) is incorporated with a compound containing loxoprofen and/or its salt and at least one of magnesium and aluminum, making it easier to achieve stabilization.

As an example, water is added to low-substituted hydroxypropyl cellulose and granulated, then loxoprofen and/or its salt and a compound containing at least one of magnesium and aluminum are added, and after granulation, necessary Add water accordingly and perform additional granulation. After the above granulation, other additives (for example, crude drug extract, croscarmellose sodium, hydroxypropyl cellulose, etc.) are added, water is added as necessary, and granulation is performed to produce granules. be able to. Tablets may be manufactured by mixing the final powder with the granules and then compressing the mixture using a tablet machine.

As another example, after adding a crude drug extract dispersed in water to low-substituted hydroxypropyl cellulose and granulating it, light silicic anhydride is added, and water is added and granulation is performed. After the above granulation, loxoprofen and/or its salt, a compound containing at least one of magnesium and aluminum, and optionally other additives (for example, crude drug extract, erythritol, partially pregelatinized starch, hydroxypropyl Granulated granules can be produced by adding cellulose (such as cellulose) and granulating it, then adding water as necessary and performing additional granulation. Tablets may be manufactured by mixing the final powder with the granules and then compressing the mixture using a tablet machine.

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, base materials, coating agents, 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, light anhydrous silicic acid, anhydrous calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate granules, monohydrogen phosphate, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granules, sodium hydrogen phosphate Hydrate, calcium dihydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate, potassium dihydrogen phosphate, crystalline cellulose, crystalline cellulose/carmellose sodium, crystalline cellulose (fine particles), crystalline cellulose (granules), Powdered cellulose, synthetic aluminum silicate, synthetic aluminum silicate/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, dextrin, corn starch, corn starch granules, trehalose, silicon dioxide, lactose hydrate, lactose granules, white sugar, potato starch, hydroxypropyl starch, partially pregelatinized 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, calcium sulfate, erythritol, glucose, fructose, etc. can.

Examples of binders include gum arabic, gum arabic powder, cold plum powder, gelatin, shellac, hydroxypropyl starch, hypromellose, pullulan, povidone, polyvinyl alcohol (completely saponified), polyvinyl alcohol (partially saponified), and methacrylic acid copolymer. One or more components selected from L, methacrylic acid copolymer LD, methacrylic acid copolymer S, butyl methacrylate/methyl methacrylate copolymer, methyl cellulose, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, etc. are blended. be able to.

Examples of the disintegrant include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, hydroxypropyl starch, partially pregelatinized starch, and the like.

Examples of disintegration aids include sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, light anhydrous silicic acid, crystalline cellulose, sodium bicarbonate, precipitated calcium carbonate, lactose hydrate, hydroxypropyl starch, and polysorbate. 40, polysorbate 60, 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 the fluidizing agent include hydrated silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, heavy silicic anhydride, magnesium alumina hydroxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, and phosphorus. One or more components selected from calcium oxyhydrogen granules and the like 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. Can be blended.

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

Examples of moisture-proofing agents include ethyl cellulose, olive oil, dry aluminum hydroxide gel, glycerin, magnesium silicate, light anhydrous silicic acid, hydrogenated oil, synthetic aluminum silicate, sucrose fatty acid ester, stearic acid, magnesium stearate, and purified One or more components selected from shellac, refined white sugar, talc, anhydrous neutral 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, light anhydrous silicic acid, 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, magnesium carbonate, 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 fat glyceryl (7E.O.), polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified product), macrogol 300, macro Gol 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, One type selected from DL-malic acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, L-leucine, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, etc. Alternatively, two or more types of components 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 antioxidants include ascorbic acid, L-ascorbic acid stearate, citric acid hydrate, soybean lecithin, natural vitamin E, natural vitamin E, tocopherol, tocopherol acetate, ascorbic acid palmitate, and sodium pyrosulfite. etc. can be mentioned.

As the filler, for example, RSS No. 1 raw rubber, starch acrylate 1000, hydrated silicon dioxide, titanium oxide, silicon dioxide, 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, licorice, licorice extract, licorice powder, xylitol, dipotassium glycyrrhizinate, disodium glycyrrhizinate, saccharin, sodium saccharin hydrate, and sucralose. , stevia extract, purified stevia extract, refined sucrose, fructose, sucrose, maltitol, D-mannitol, erythritol, etc. One or more components 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 1 selected from, 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. A species or two or more 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 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 be blended.

As a base, gum arabic powder, pregelatinized starch, ethyl cellulose, cacao butter, carnauba wax, carboxyvinyl polymer, carmellose, carmellose sodium, reduced maltose starch syrup, hydrated silicon dioxide, dry aluminum hydroxide gel, agar, agar powder, Xanthan gum, glycine, glycerin, glycerin fatty acid ester, light silicic anhydride, crystalline cellulose, hydrogenated oil, synthetic aluminum silicate, synthetic sodium magnesium silicate, titanium oxide, tartaric acid, sucrose fatty acid ester, silicone oil, stearic acid, stearic acid Magnesium, gelatin, D-sorbitol, talc, calcium carbonate, corn starch, lactic acid, ethyl lactate, calcium lactate hydrate, lactic acid/glycolic acid copolymer, concentrated glycerin, potato starch, hypromellose, pullulan, pectin, povidone, polysorbate 60, polysorbate 80, polyvinyl alcohol (partially saponified product), microcrystalline wax, macrogol 200, macrogol 300, macrogol 400, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macro Gol 6000NF, Macrogol 20000, D-mannitol, glyceryl monostearate, sorbitan monostearate, batyl monostearate, propylene glycol monostearate, polyethylene glycol monostearate, sodium lauryl sulfate, polyvinyl alcohol/acrylic acid/methacrylic One or more components selected from acid methyl copolymers and the like 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 methylcellulose acetate succinate, hydroxypropyl methylcellulose 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, methyl acrylate/methacrylic acid/methyl methacrylate copolymer, methyl cellulose, 2-methyl- Examples include 5-vinylpyridine methyl acrylate/methacrylic acid copolymer, aluminum monostearate, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, calcium sulfate, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, etc. can.

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, hypromellose, pullulan, povidone, polyvinyl alcohol (partially saponified), macrogol 1500, macrogol 4000, macrogol 6000, macrogol 6000NF, calcium hydrogen phosphate hydrate, calcium dihydrogen phosphate One or more components selected from hydrates, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymers, 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.

As a dispersant, 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, silicon Magnesium acid, light aluminum oxide, light silicic anhydride, crystalline cellulose, titanium oxide, sucrose fatty acid ester, stearic acid, magnesium stearate, D-sorbitol, soybean lecithin, dextrin, corn starch, lactose hydrate, concentrated glycerin, Potato starch, hydroxyethyl cellulose, hydroxypropyl starch, hypromellose, povidone, polyoxyethylene 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, methylcellulose, glyceryl monooleate, sorbitan monooleate, aluminum monostearate, glyceryl monostearate , sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, sodium lauryl sulfate and the like can be blended.

The antifoaming agent is selected from ethanol, glycerin fatty acid ester, dimethylpolysiloxane (for internal use), dimethylpolysiloxane/silicon dioxide mixture, sucrose fatty acid ester, silicone antifoaming agent, silicone oil, sorbitan fatty acid ester, polysorbate 80, etc. One or more types of components can be blended.

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

The solid preparation of the present invention can be suitably used for the purpose of suppressing fever, pain, and inflammation. The active ingredient loxoprofen and/or its salts have antipyretic, analgesic, and anti-inflammatory effects, so they can be used as antipyretic analgesics, especially for headaches, menstrual pain (menstrual pain), toothache, pain after tooth extraction, and sore throat. It is suitable for use as an analgesic for lower back pain, joint pain, muscle pain, stiff shoulder pain, 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).

The solid preparations of the present invention 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, etc.). , sublingual tablets, buccal tablets, adhesive tablets, gums, etc.), etc., as described in the 18th revised Japanese Pharmacopoeia, General Rules for Preparations, etc.
These compositions may further contain other active ingredients as necessary, such as antipyretic analgesics, antitussives and expectorants, antihistamines, antiinflammatory agents, anticholinergics, other vitamins, and xanthine derivatives according to the present invention. They may be blended as appropriate within a range that does not impair the properties of the ingredients, and if there is any contraindication to their blending, they may be formulated into a formulation by appropriately dividing the ingredients into granules.

Antipyretic analgesics include aspirin, aspirin aluminum, acetaminophen, ethenzamide, sazapirin, salicylamide, lactylphenetidine, ibuprofen, isopropylantipyrine, pranopfen, diclofenac sodium, mefenamic acid, indomethacin farnesil, acemethacin, etodolac, naproxen, meloxicam, One or more components selected from 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, difethenol hydrochloride, methdilazine hydrochloride, mebhydrozine napadisylate, promethazine methylene Examples include disalicylic acid and difetenol phosphate.

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

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, and iodine. Examples thereof include diphenylpiperidinomethyldioxolane, funnel root extract, funnel root total alkaloid citrate, and the like.

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, pantothenic acid. Sodium, biotin, mixture of equal amounts of potassium and magnesium aspartate, inositol hexanicotinate, ursodeoxycholic acid, L-cysteine, L-cysteine hydrochloride, orotin, gamma oryzanol, calcium glycerophosphate, calcium gluconate, glucnolactone, glucuronide. Examples include acid amide, sodium chondroitin sulfate, ginseng, yokuinin, and ioic acid.
Examples of xanthine derivatives (other xanthine derivatives) other than the above-mentioned caffeine include theophylline and theobromine.

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

The solid preparation of the present invention may be once packaged and stored airtight using SP packaging, PTP packaging, pouch packaging, stick packaging, bottle packaging, or the like. 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 a solid preparation and a packaging material for packaging the solid preparation.
Materials used for SP packaging, PTP packaging, stick packaging, and pillow packaging are not particularly limited, and examples include single-layer resins such as polyvinyl chloride film, polyvinylidene chloride film, polypropylene film, polyethylene terephthalate film, and polyethylene film. A film, a multilayer film made by combining these resin films, or a film made by adhering aluminum foil to these resin films can be used. Furthermore, the pharmaceutical product according to an embodiment of the present invention may use an environmentally friendly container (less environmentally friendly) as a packaging material, and at least a part of the packaging material may be environmentally friendly (less environmentally friendly). A material using a material (for example, recycled plastic, biomass plastic, biodegradable plastic) with low load may also be used.
Furthermore, in the pharmaceutical product according to one embodiment of the invention, glassine paper or vapor-deposited film may be used for at least a portion of the packaging material.

The packaging material for the solid preparation of the present invention is preferably, for example, a packaging made of a material that is not easily affected by moisture (a packaging formed 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 rise in moisture levels in solid preparations, storage stability of solid preparations, and stability of solid preparations after opening, we have used aluminum on both sides as a packaging material that is not easily affected by moisture (moisture-proof material). The used PTP packaging (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 the bottle packaging or pillow packaging.
As the gas barrier material, any known material may be used, and it is not particularly limited, but for example, it may be a laminate film having a functional barrier layer, etc., which may also serve as the moisture-proof material, or may be used in combination with the moisture-proof material. You may also use it.

In order to explain the present invention in more detail, comparative examples and examples are described below, but the present invention is not limited thereto.

Test Example 1: Storage stability test of tablets containing loxoprofen sodium hydrate and antacids1. Manufacture of Tablets The formulations (tablets) of Comparative Example 1 and Examples 1 to 5 used in the test were manufactured by the following method. In addition, the formulations (per 6 tablets) of Comparative Example 1 and Examples 1 to 5 are shown in Tables 1 and 2. The % appearing in Table 1 and the following tables means % by mass unless otherwise mentioned.

(Comparative example 1)
Loxoprofen sodium dihydrate (manufactured by KOLON LIFE SCIENCE, INC.), magnesium oxide (manufactured by Kyowa Chemical Co., Ltd.), and dried licorice extract (manufactured by Alps Yakuhin Kogyo Co., Ltd.) weighed according to the ratios in Table 1, and a portion Pregelatinized starch (manufactured by Asahi Kasei Corporation, PCS PC-10), croscarmellose sodium (manufactured by FMC International, AcDiSol Croscarmellose Sodium), and hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-SL) are granulated with high speed stirring. After mixing with a machine (model: FM-VG05, manufacturer: Powrec Co., Ltd.), purified water was added to granulate the mixture to obtain granules.
For the granulated granules, sodium stearyl fumarate (manufactured by Kimura Sangyo, PRUV) was mixed in a plastic bag as a final powder according to Table 1, and then pressed with a tablet machine (model: VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.). I got a tablet.

(Example 1)
Low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd., L-HPC NBD-022) weighed according to the ratio in Table 1 was put into a high-speed stirring granulator (model: FM-VG05, manufacturer: Powrec Co., Ltd.). After adding purified water and performing granulation 1, loxoprofen sodium dihydrate (manufactured by KOLON LIFE SCIENCE, INC.) and magnesium oxide (manufactured by Kyowa Chemical Co., Ltd.) were added, and purified water was added as necessary. Add and perform granulation 2. After granulation 2, licorice dried extract (manufactured by Alps Yakuhin Kogyo Co., Ltd.), croscarmellose sodium (manufactured by FMC International, AcDiSol Croscarmellose Sodium), and hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-SL) were added. By adding purified water as necessary and granulating it, it was made into granules.
After mixing the granulated granules with sodium stearyl fumarate (manufactured by Kimura Sangyo, PRUV) weighed according to the proportions shown in Table 1 as a final powder in a plastic bag, a tablet machine (model: VIRGO, manufactured by Kikusui Seisakusho Co., Ltd.) was used. ) to obtain tablets.

In Examples 2 to 5, tablets were obtained in the same manner as in Example 1, except that the compositions were changed to have the compositions shown in Tables 1 and 2. However, in Examples 4 and 5, D-mannitol (Granutol R, manufactured by Freund Sangyo Co., Ltd.) was added to the end to produce tablets.

2. Test method The tablets of Comparative Example 1 and Examples 1 to 5 were filled into glass bottles (3K standard bottles), closed with metal caps (Medicated No. 3), and left at 60°C for one month. After storage, the loxoprofen sodium content was measured by HPLC method, and the residual rate from before storage was calculated.

3. Test Results The loxoprofen sodium residual rate was as shown in Tables 1 and 2. In addition, "-" in Tables 1 to 4 means that the tablet does not contain the corresponding substance.
In addition, as an index of loxoprofen sodium residual rate in this test, evaluation was made using the criteria shown below.
A (excellent): Loxoprofen sodium residual rate is 95% or more B (fair): Loxoprofen sodium residual rate is less than 95%

As shown in Comparative Example 1, when loxoprofen sodium hydrate and magnesium oxide are mixed, the residual rate of loxoprofen sodium decreases, but as shown in Example 1, low-substituted hydroxypropyl added with purified water It was found that the decrease in the loxoprofen sodium content could be suppressed by adding loxoprofen sodium hydrate and magnesium oxide to cellulose granules and granulating them, and then adding other ingredients and granulating them.
As shown in Example 2, similar results were obtained even when the dried licorice extract was omitted.
Further, as shown in Examples 3 and 5, similar results could be obtained even when magnesium oxide was replaced with an antacid such as magnesium aluminate metasilicate or synthetic hydrotalcite.
Furthermore, as shown in Example 4, it was found that even when the grade of low-substituted hydroxypropyl cellulose was changed, the decrease in the loxoprofen sodium content could be suppressed.

<Examples 6 to 9>
The formulations (per 6 tablets) of Examples 6 to 9 are shown in Table 3.

(Example 6)
Low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd., L-HPC NBD-022) weighed according to the ratio in Table 3 was placed in a high-speed stirring granulator (model: FM-VG-25, manufacturer: Powrex Co., Ltd.). After adding valerian extract dispersed in purified water and performing granulation 1, add light anhydrous silicic acid (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd.), add purified water, and perform granulation 2. . After granulation 2, loxoprofen sodium dihydrate (manufactured by KOLON LIFE SCIENCE, INC.), magnesium oxide (manufactured by Kyowa Chemical Co., Ltd.), dried licorice extract (manufactured by Alps Yakuhin Kogyo Co., Ltd.), and erythritol (manufactured by Bussan Co., Ltd.) were added. Food Science Co., Ltd.), partially pregelatinized starch (Asahi Kasei Corporation, PCS PC-10), and hydroxypropyl cellulose (Nippon Soda Co., Ltd., HPC-SL fine powder) are added and granulated. It was made into granules.

Light silicic anhydride (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd.) and sodium stearyl fumarate (manufactured by Kimura Sangyo Co., Ltd., PRUV) weighed according to the ratio in Table 3 were added to the granulated granules as a final powder using a mixer (model: :TM-30S, Manufacturer: Showa Kagaku Kikai Kosakusho Co., Ltd.) and then compressed using a tablet machine (Model: Collect 19HUK, Manufacturer: Kikusui Seisakusho Co., Ltd.) to obtain tablets.

Tablets (uncoated tablets) prepared according to Table 3 were loaded into a film coating machine (model: HCT-MINI, manufacturer: Freund Sangyo Co., Ltd.), and polyvinyl alcohol (Gosenol EG-05P, manufactured by Mitsubishi Chemical Corporation) and hypromellose ( TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), titanium oxide (titanium oxide FG, manufactured by Freund Sangyo Co., Ltd.), sucrose fatty acid ester (Surf Hope SE PHARMA J-2203F), polyethylene glycol (manufactured by NOF Corporation, A film coating solution is prepared by mixing macrogol 6000P), iron sesquioxide (manufactured by Hesumi Kasei Co., Ltd.), and yellow iron sesquioxide (manufactured by Hesumi Kasei Co., Ltd.) in purified water. Next, the obtained coating liquid is applied to the tablet (uncoated tablet) in the desired amount using a film coating machine, and then carnauba wax (manufactured by Freund Sangyo Co., Ltd., carnauba wax 105) is added and polished to produce a film-coated tablet. do.

In Examples 7 to 9, film-coated tablets can be produced in the same manner as in Example 6, except that the composition was changed to have the composition shown in Table 3.

<Example 10>
The formulation (per 6 tablets) of Example 10 is shown in Table 4.
Low-substituted hydroxypropylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., L-HPC NBD-022) weighed according to the ratio in Table 4 was placed in a high-speed stirring granulator (model: FM-VG-400P, manufacturer: Powrec Co., Ltd.). After adding valerian extract dispersed in purified water and performing kneading 1, light anhydrous silicic acid (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd.) is added, purified water is added, and kneading 2 is performed. . After kneading 2, loxoprofen sodium dihydrate (manufactured by KOLON LIFE SCIENCE, INC.), magnesium oxide (manufactured by Kyowa Chemical Co., Ltd.), dried licorice extract (manufactured by Alps Yakuhin Kogyo Co., Ltd.), and erythritol (manufactured by Bussan Co., Ltd.) were added. Food Science Co., Ltd.), partially pregelatinized starch (Asahi Kasei Corporation, PCS PC-10), and hydroxypropyl cellulose (Nippon Soda Co., Ltd., HPC-SL fine powder) are added and granulated. It was made into granules.

To the granulated granules, light anhydrous silicic acid (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd.) and sodium stearyl fumarate (manufactured by Kimura Sangyo Co., Ltd., PRUV) weighed according to the ratio in Table 10 were added to the granules as a final powder using a mixer (model: :TM-1000S, Manufacturer: Showa Kagaku Kikai Kosakusho Co., Ltd.) and then compressed with a tablet machine (Model: AQUARIUS, Manufacturer: Kikusui Seisakusho Co., Ltd.) to obtain tablets.

In Example 10, a film-coated tablet can be produced in the same manner as in Example 6, except that the composition was changed to have the composition shown in Table 4.

The tablets of Example 10 were filled with PTP (polypropylene), further wrapped in polyethylene aluminum pillow packaging (combined packaging of PTP and polyethylene aluminum pillows), and left at 60°C for one month. After storage, the loxoprofen sodium content was measured by HPLC method, and the residual rate from before storage was calculated.
As a result, as shown in Example 10 (Table 4), good results were confirmed even when the tablets were filled with PTP (polypropylene) and stored in polyethylene aluminum pillow packaging.

<Formulation Examples 1 to 60>
The formulations (per 6 tablets) of Formulation Examples 1 to 60 are shown in Tables 5 to 12.
Tablets of Formulation Examples 1 to 60 can be prepared in the same manner as in Example 1, except that the compositions are changed to have the compositions shown in Tables 5 to 12.

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.

The solid preparation of the present invention can be used as an antipyretic analgesic, particularly 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, etc. 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 (10)

A solid preparation containing at least one member selected from the group consisting of loxoprofen and salts thereof, a compound containing at least one of magnesium and aluminum, and hydroxypropylcellulose.​ The solid preparation according to claim 1, wherein the hydroxypropylcellulose contains at least one of hydroxypropylcellulose and low-substituted hydroxypropylcellulose. The solid preparation according to claim 2, wherein the low-substituted hydroxypropyl cellulose has a particle diameter ratio D90/D50 of 1.5 to 3.0. The solid preparation according to claim 2 or 3, wherein the low-substituted hydroxypropyl cellulose has an average particle diameter of 30 to 60 μm. The solid preparation according to claim 2 or 3, wherein the proportion of hydroxypropoxy groups in the low-substituted hydroxypropylcellulose is 7 to 16%. According to claim 2 or 3, the compound containing at least one of magnesium and aluminum is one or more selected from the group consisting of magnesium oxide, magnesium aluminate metasilicate, and synthetic hydrotalcite. Solid formulation as described. The solid preparation according to claim 2 or 3, further comprising one or more selected from the group consisting of crude drugs and their extracts, caffeine, and sedatives. The solid preparation according to claim 2 or 3, further comprising a compound having an amino group. A method for producing a solid preparation containing at least one selected from the group consisting of loxoprofen and its salts, a compound containing at least one of magnesium and aluminum, and hydroxypropylcellulose, the method comprising: loxoprofen and its salts; A first method of adding water to hydroxypropylcellulose and granulating it before granulating it by adding at least one selected from the group consisting of salts and a compound containing at least one of magnesium and aluminum. A method for producing a solid dosage form, including the steps. The method for producing a solid preparation according to claim 9, wherein in the first step, the mass of the water is 0.4 times or more the mass of the hydroxypropyl cellulose.