JP2021091616A - Pharmaceutical preparation, solid pharmaceutical preparation and tablet - Google Patents

Abstract

To provide a pharmaceutical preparation that can prevent a decrease in the content of meloxicam or a salt thereof even when an antacid is used together.SOLUTION: A pharmaceutical preparation contains at least one selected from meloxicam and a pharmaceutically acceptable salt thereof (A), ab aluminum-containing antacid (B), and at least one selected from organic carboxylic acid and a pharmaceutically acceptable salt thereof (C). The mass ratio represented by (C) component/(B) component is preferably 0.001-2.5.SELECTED DRAWING: None

Description

The present invention relates to pharmaceutical preparations, solid pharmaceutical preparations and tablets.

Non-steroidal anti-inflammatory drugs (NSAIDs) and the like are widely used as antipyretic analgesic components in pharmaceutical preparations such as antipyretic analgesics. Among NSAIDs, meloxicam or a salt thereof is known as an analgesic component that exhibits an analgesic effect for a long period of time.
Meloxicam or its salt is known to have gastric disorders as a side effect. Pharmaceutical preparations containing antacids are known to suppress gastric disorders.
For example, Patent Document 1 discloses a formulation comprising a combination of meloxicam or a salt thereof and an antacid (antacid).

International Publication No. 2005/004915

However, when a compound containing aluminum is used as an antacid, there is a problem that the content of meloxicam or a salt thereof is lowered.
Therefore, an object of the present invention is a pharmaceutical preparation capable of suppressing a decrease in the content of meloxicam or a salt thereof even if an antacid is also used.

The present invention has the following aspects.
<1> At least one (A) selected from meloxicam and its pharmaceutically acceptable salt, and
An antacid (B) containing aluminum and
At least one (C) selected from organic carboxylic acids and salts thereof, and
A pharmaceutical preparation containing.
<2> The pharmaceutical preparation according to <1>, wherein the mass ratio represented by the component (C) / component (B) is 0.001 to 2.5.

<3> A group of particles (α1) containing at least one (A) selected from meloxicam and a pharmaceutically acceptable salt thereof, and substantially free of an aluminum-containing antacid (B). When,
It has a group (β1) of particles containing the component (B) and substantially not containing the component (A).
A solid pharmaceutical preparation in which at least one of the group of particles (α1) and the group of particles (β1) is a group of granulated particles.
<4> At least one of the group of particles (α1) and the group of particles (β1) is a group of granulated particles further containing at least one (C) selected from an organic carboxylic acid and a salt thereof. The solid pharmaceutical preparation according to <3>.
<5> The solid pharmaceutical preparation according to <4>, wherein the mass ratio represented by the component (C) / component (B) is 0.001 to 2.5.

<6> A layer (α2) containing at least one selected from meloxicam and a pharmaceutically acceptable salt thereof (A) and substantially free of an aluminum-containing antacid (B).
A layer (β2) containing the component (B) and substantially not containing the component (A).
Have, tablets.
<7> The tablet according to <6>, wherein at least one layer of the layer (α2) and the layer (β2) further contains at least one (C) selected from an organic carboxylic acid and a salt thereof.
<8>
The tablet according to <7>, wherein the mass ratio represented by the component (C) / the component (B) is 0.001 to 2.5.

According to the pharmaceutical preparation of the present invention, even if an antacid containing aluminum is used together, a decrease in the content of meloxicam or a salt thereof can be suppressed.

The pharmaceutical preparation of the present invention comprises at least one (A) ((A) component) selected from meloxicam and a pharmaceutically acceptable salt thereof, and an antacid (B) ((B) component) containing aluminum. And contains.
The dosage form of the pharmaceutical preparation may be an oral preparation or a parenteral preparation. The oral preparation may be a solid pharmaceutical preparation such as tablets (film-coated tablets, orally disintegrating tablets, etc.), capsules, microcapsules, granules, fine granules, powders, etc., emulsions, self-emulsifying preparations, syrups, etc. It may be a liquid preparation such as an agent, a jelly agent, an inhalant, or a semi-solid pharmaceutical preparation. Parenteral preparations include, for example, ointments, suppositories, injections (emulsifying, suspending, non-aqueous), solid injections that are emulsified or suspended at the time of use, infusion preparations, transdermal absorbents, and the like. Examples include external preparations.
The pharmaceutical preparation of the present invention is administered to a patient regardless of whether it is oral, intravenous, intraarterial, inhalation, rectal, intravaginal or external use. Among them, the oral preparation is preferable, and tablets, capsules and the like are more preferable. The tablet may be a single-layer tablet or a multi-layer tablet having two or more layers. Further, the tablet may be an uncoated tablet or a coated tablet. The capsule may be, for example, a tablet encapsulated in a soft capsule or a microcapsule.

When the pharmaceutical preparation of the present invention is a tablet, the effect of the present invention does not change significantly depending on the shape of the tablet. The size of the tablet is not particularly limited in terms of the effect of the present invention, but the diameter φ of the tablet is preferably, for example, 6 to 14 mm from the viewpoint of ease of handling and swallowability of the tablet.
From the viewpoint of ease of handling and swallowing of the tablet, the shape of the tablet is preferably a shape having a columnar portion and a bulging portion that bulges from the upper and lower end faces of the columnar portion. Examples of the tablet having a columnar portion and a bulging portion include R tablets (standard R tablets, sugar-coated R tablets, etc.), two-stage R tablets, Sumi square flat tablets, Sumi round flat tablets, and the like. The bulges of these tablets may be vertically asymmetric, but are preferably vertically symmetrical.

When the pharmaceutical product is a granule, a fine particle or a powder, the average particle size of the pharmaceutical product is preferably 10 to 700 μm, more preferably 50 to 500 μm. The average particle size is a weight average particle size (D50) measured according to a laser diffraction type particle size distribution measurement method.

(First Embodiment)
<Pharmaceutical product>
The pharmaceutical preparation according to the first embodiment of the present invention will be described.
The pharmaceutical preparation of the present embodiment contains (A) component, (B) component, and at least one (C) ((C) component) selected from an organic carboxylic acid and a salt thereof.
Examples of the pharmaceutical preparation of the present embodiment include single-layer tablets, pills, granules obtained by granulating the components (A) to (C) together, powder-mixed powders and fine granules, and liquid preparations. Further, as the pharmaceutical preparation of the present embodiment, a multi-layer tablet having a layer having both the components (A) to (C) can be mentioned. That is, the pharmaceutical preparation of the present embodiment is a dosage form in which the components (A) to (C) coexist.

≪ (A) component ≫
The components (A) are meloxicam (chemical name: 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide) and At least one selected from the pharmaceutically acceptable salts. Pharmaceutically acceptable salts of meloxicam include, for example, those described in European Patent No. 2,482B1, US Pat. No. 4,233,299 and WO 99/49867. Can be mentioned. Acceptable salts include sodium salts, potassium salts, ammonium salts, meglumin salts, tris salts and the like.
The component (A) may be used alone or in combination of two or more.

The content of the component (A) in the pharmaceutical preparation is preferably such that the amount of the component (A) per dose is 0.5 to 70 mg, more preferably 2 to 50 mg, and further preferably 2.5 to 20 mg. Preferably, 5 to 15 mg is particularly preferred. When the content of the component (A) is at least the above lower limit value, the pharmacological effect of the pharmaceutical preparation can be further enhanced. When the content of the component (A) is not more than the above upper limit value, an obstacle during tablet production (for example, adhesion of a pharmaceutical preparation to a tablet or punch of a tableting machine) is unlikely to occur. Further, when the content of the component (A) is not more than the above upper limit value, gastric disorders can be further reduced.
When the pharmaceutical preparation is a tablet, the content of the following component (A) may be contained in one tablet or may be the total amount of tablets to be taken at one time.

When the pharmaceutical preparation is a tablet or a capsule, the content of the component (A) per tablet (or capsule) is appropriately determined in consideration of the number of tablets (or the number of capsules) per dose.

The content ratio of the component (A) in the pharmaceutical product is, for example, preferably 0.1 to 20% by mass, more preferably 0.5 to 10% by mass, and 1.0 to 5 to the total mass of the pharmaceutical product. .0% by mass is more preferable. When the content ratio of the component (A) is equal to or higher than the above lower limit value, the pharmacological effect of the pharmaceutical preparation can be further enhanced. When the content ratio of the component (A) is not more than the above upper limit value, an obstacle during tablet production (for example, adhesion of a pharmaceutical preparation to a tablet or punch of a tableting machine) is unlikely to occur. Further, when the content ratio of the component (A) is not more than the above upper limit value, gastric disorders can be further reduced.

≪ (B) component ≫
The component (B) is an antacid containing aluminum. By containing the component (B), the pharmaceutical preparation of the present embodiment can reduce the gastric disorder caused by the component (A).
The component (B) is a so-called aluminum-based antacid, which is an alkaline compound having aluminum in its molecule. In addition to aluminum, the component (B) may contain alkali metals such as sodium and potassium, and metal atoms such as magnesium and silicon. The content of aluminum with respect to the total mass of the component (B) is 1% by mass or more. From the viewpoint of remarkable effect on the subject of the present invention, the content of aluminum with respect to the total mass of the component (B) is preferably 10% by mass or more. The content of aluminum in the component (B) is a value obtained by the mass ratio calculated from the chemical formula.

The components (B) include dry aluminum hydroxide gel, magnesium aluminometasilicate, synthetic hydrotalcite, synthetic aluminum silicate, dihydroxyaluminum aminoacetic acid, aluminum hydroxide gel, aluminum hydroxide-magnesium hydroxide co-dry gel, and water. Examples thereof include aluminum oxide-sodium bicarbonate co-precipitate, aluminum hydroxide-calcium carbonate-magnesium carbonate co-precipitate, magnesium hydroxide-aluminum potassium sulfate co-precipitate, magnesium aluminosilicate, magnesium aluminum hydroxide and the like. Among them, as the component (B), dry aluminum hydroxide gel, magnesium aluminate aluminate, synthetic hydrotalcite, synthetic aluminum silicate, and dihydroxyaluminum aminoacetic acid are preferable.
These components (B) may be used alone or in combination of two or more.

The content of the component (B) in the pharmaceutical preparation is preferably such that the amount of the component (B) per dose is 40 to 1500 mg, more preferably 60 to 800 mg, and 200 to 500 mg. Is even more preferable. When the content of the component (B) is at least the above lower limit value, the stomach disorder caused by the component (A) can be further reduced. When the content of the component (B) is not more than the above upper limit value, the decrease in the content of the component (A) can be suppressed more satisfactorily.
The amount of the main component (B) per dose is shown below. When the pharmaceutical preparation is a tablet, the content of the following component (B) may be contained in one tablet or may be the total amount of tablets to be taken at one time.

When the component (B) is a dry aluminum hydroxide gel, the amount of the component (B) per dose is preferably 40 to 1000 mg, more preferably 100 to 800 mg, still more preferably 200 to 500 mg.

When the component (B) is magnesium aluminate metasilicate, the amount of the component (B) per dose is preferably 60 to 1500 mg, more preferably 150 to 800 mg, still more preferably 250 to 500 mg.

When the component (B) is synthetic hydrotalcite, the amount of the component (B) per dose is preferably 100 to 1000 mg, more preferably 200 to 600 mg, still more preferably 300 to 400 mg.

When the component (B) is synthetic aluminum silicate, the amount of the component (B) per dose is preferably 100 to 1000 mg, more preferably 180 to 700 mg, still more preferably 250 to 400 mg.

When the component (B) is dihydroxyaluminum acetic acid, the amount of the component (B) per dose is preferably 40 to 1500 mg, more preferably 100 to 600 mg, still more preferably 150 to 400 mg.

The content ratio of the component (B) in the pharmaceutical preparation is preferably 10 to 85% by mass, more preferably 20 to 80% by mass. When the content ratio of the component (B) is equal to or higher than the above lower limit value, the gastric disorder caused by the component (A) can be further reduced. When the content ratio of the component (B) is not more than the above upper limit value, the decrease in the content of the component (A) can be suppressed more satisfactorily.

≪ (C) component ≫
The pharmaceutical preparation contains at least one (C) ((C) component) selected from an organic carboxylic acid and a salt thereof. By containing the component (C), the pharmaceutical preparation of the present embodiment can suppress a decrease in the content of the component (A).

Examples of the component (C) include monovalent or polyvalent carboxylic acids, hydroxycarboxylic acids, aminocarboxylic acids and the like. Examples of the carboxylic acid of the monovalent or polyunsaturated carboxylic acid include acetic acid, butyric acid, succinic acid, maleic acid and fumaric acid. Examples of the hydroxycarboxylic acid include lactic acid, citric acid, malic acid, tartaric acid and the like. Examples of the aminocarboxylic acid include ethylenediaminetetraacetic acid (EDTA), ethylenediaminediacetic acid (EDDA), diethylenetriamine pentaacetic acid (DTPA), N- (2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA) and the like.
Examples of the salt of the component (C) include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium, and ammonium salts.
Among these components (C), malic acid, citric acid, fumaric acid, maleic acid, ethylenediaminetetraacetic acid (EDTA) and salts thereof are preferable.
These components (C) may be used alone or in combination of two or more.

As for the lower limit of the component (C) in the pharmaceutical preparation, the amount of the component (C) per dose is preferably 1 mg or more, more preferably 2 mg or more, still more preferably 3 mg or more. An amount of 4 mg or more is particularly preferable, and an amount of 5 mg or more is most preferable. When the content of the component (C) is at least the above lower limit value, the component (C) is uniformly distributed in the pharmaceutical preparation, and the decrease in the content of the component (A) can be suppressed more satisfactorily.
The upper limit of the component (C) in the pharmaceutical preparation is preferably an amount of the component (C) per dose of 250 mg or less, more preferably 150 mg or less, still more preferably 100 mg or less. The amount of 90 mg or less is particularly preferable, the amount of 75 mg or less is more preferable, the amount of 50 mg or less is more preferably more preferable, the amount of 25 mg or less is even more preferable, and the amount of 20 mg or less is most preferable. .. When the content of the component (C) is not more than the above upper limit value, the disintegration of the tablet after ingestion can be accelerated when the pharmaceutical preparation is made into a tablet.
The preferable range of the content of the component (C) in the pharmaceutical preparation per dose is preferably 1 to 250 mg, more preferably 1 to 100 mg, further preferably 3 to 50 mg, and most preferably 5 to 20 mg. The content in one tablet is preferably 0.2 to 250 mg, more preferably 1 to 50 mg.
When the pharmaceutical product is a tablet, the content of the above component (C) may be contained in one tablet or may be the total amount of tablets to be taken at one time.

The content ratio of the component (C) in the pharmaceutical preparation is preferably 0.1 to 30% by mass, more preferably 0.3 to 15% by mass. When the content ratio of the component (C) is equal to or higher than the above lower limit value, the decrease in the content of the component (A) can be further suppressed. When the content ratio of the component (C) is not more than the above upper limit value, the disintegration of the tablet after ingestion can be accelerated when the pharmaceutical preparation is made into a tablet.

In the pharmaceutical preparation, the lower limit of the mass ratio (C / B ratio) represented by the component (C) / component (B) is preferably 0.001 or more, more preferably 0.00375 or more, and 0.01 or more. More preferred. The upper limit of the C / B ratio is preferably 2.5 or less, more preferably 0.5 or less, and even more preferably 0.1 or less. When the C / B ratio is equal to or higher than the above lower limit, the stability of the component (A) with time is good. When the C / B ratio is not more than the above upper limit, the disintegration of the tablet after taking the drug can be accelerated when the pharmaceutical preparation is made into a tablet.

In the pharmaceutical preparation, the lower limit of the mass ratio (C / A ratio) represented by the component (C) / component (A) is preferably 0.1 or more, more preferably 0.3 or more, and 0.5 or more. More preferred. The upper limit of the C / A ratio is preferably 25 or less, more preferably 7.5 or less, and even more preferably 2.0 or less. When the C / A ratio is at least the above lower limit, the stability of the component (A) over time becomes good, and the hardness can be further increased when the pharmaceutical preparation is made into tablets. When the C / A ratio is not more than the above upper limit, the elution of the component (A) can be further enhanced.

≪Arbitrary ingredient≫
If necessary, the pharmaceutical preparation may further contain components (arbitrary components) other than the components (A) to (C) as long as the effects of the present invention are not impaired.
Examples of the optional component include a physiologically active component, an additive (however, excluding the components (A) to (C)) and the like.

Examples of bioactive components include antipyretic and analgesic components (excluding component (A)) (for example, pyroxycam, ampyroxicam, serocoxib, lofecoxib, thialamide, loxoprofen Na, etenzamid, sulpyrine, acetaminophen, acetylsalicylic acid, etc.) , Analgesic and hypnotic components (eg, allylisopropylacetylurea, bromvalerylurea, etc.), antihistamine components (eg, isotipendyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, dipheterol hydrochloride, triprolidine hydrochloride, triperenamine hydrochloride, tonzilamine hydrochloride, phenetazine hydrochloride, hydrochloric acid Metodilazine, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline theocrate, mebuhydroline napadisylate, promethazine methylene disalicylate, carbinoxamine maleate, dl-chlorpheniramine maleate Lamine, dipheterol phosphate, etc.), central excitatory components (eg, sodium benzoate, caffeine, anhydrous caffeine, etc.), antitussive and sputum components (codein phosphate, dextrometholphan hydrobromide, dimemorphan phosphorus, etc.) Acid salt, tipepidin hibenzate, methoxyphenamine hydrochloride, trimetquinol hydrochloride, carbocysteine, acetylcysteine, ethylcysteine, dl-methylephedrine, bromuhexin hydrochloride, therapeptase, lysozyme chloride, ambroxol, theophylline, aminophilin ), Vitamin components (eg, Vitamin B ₁ and its derivatives and their salts, Vitamin B ₂ and its derivatives and their salts, Vitamin B ₆ and its derivatives and their salts, Vitamin B ₁₂ and its derivatives and their salts , Vitamin C and its derivatives and their salts, Vitamin D and its derivatives and their salts, Vitamin E and its derivatives and their salts, hesperidin and its derivatives and their salts, etc.), Analgesics (Iresen, Engosaku, Ogon, etc.) Gaihaku, Kanzo, Kikyo, Shakuyaku, Senega, etc.), etc.), etc., which are listed in the 17th Amendment of the Japanese Pharmacy Law, Articles of Pharmaceuticals, "Raw Drugs, etc."). These physiologically active ingredients may be used alone or in combination of two or more.
The content of the physiologically active ingredient in the pharmaceutical product is not particularly limited, but is preferably 1 to 40% by mass, more preferably 3 to 30% by mass, based on the total mass of the pharmaceutical product.

Examples of additives include binders, excipients, disintegrants, lubricants, flavors, pigments, bases, sweeteners, acidulants and the like.
Examples of the binder include sucrose, gelatin, gum arabic powder, polyvinylpyrrolidone, pullulan, dextrin and the like.
Examples of the excipient include crystalline cellulose, lactose (hydrate), cornstarch, powdered sugar, mannitol, L-cysteine and the like.
Examples of the disintegrant include low-degree-of-substitution hydroxypropyl cellulose, crospovidone, croscarmellose sodium and the like.
Examples of the lubricant include magnesium stearate, stearyl sodium fumarate, sucrose fatty acid ester, and light anhydrous silicic acid.
Examples of the fragrance include menthol, limonene, vegetable essential oil (mentha oil, mint oil, lychee oil, orange oil, lemon oil, etc.) and the like.
Examples of the pigment include iron sesquioxide and the like.
Examples of the base include water, ethanol and the like.
Examples of the sweetener include sodium saccharin, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, sucralose and the like.
Examples of the acidulant include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid and salts thereof. Citric acid, tartaric acid, malic acid, succinic acid, fumaric acid, lactic acid and salts thereof are contained in the component (C), but may be appropriately used as an acidulant.
These additives may be used alone or in combination of two or more.
The content of the additive in the pharmaceutical product is not particularly limited, but is preferably 1 to 80% by mass, more preferably 10 to 70% by mass, based on the total mass of the pharmaceutical product.
The total of the components (A) to (C) and the optional components does not exceed 100% by mass.

<Manufacturing method>
The method for producing the pharmaceutical preparation of the present embodiment is not particularly limited as long as the components (A) to (C) can coexist.
When the pharmaceutical preparation is a single-layer tablet, a production method in which the components (A) to (C) and, if necessary, an arbitrary component are powder-mixed and the obtained powder mixture is tableted can be mentioned.
Further, for example, the components (A) to (C) and, if necessary, an arbitrary component are powder-mixed, and the obtained powder mixture is granulated to form a group of granulated particles, which is used as a granule. The method can be mentioned. The obtained particle group may be encapsulated to form a capsule, or the obtained particle group may be tableted to form a tablet.

Hereinafter, a method for granulating the granules will be described.
Examples of the granulation method include a dry granulation method and a wet granulation method. Examples of the wet granulation method include a fluidized bed granulation method, a stirring granulation method, a rolling granulation method, and an extrusion granulation method.
As the granulation method, a wet granulation method is preferable from the viewpoint of manufacturability. Among them, the fluidized bed granulation method and the stirring granulation method are preferable from the viewpoints of efficient contact of the components (A) to (C), operability, and productivity.
Granulation conditions can be appropriately selected according to the granulation method. For example, when granulating by the fluidized bed granulation method, granulation can be performed at an air supply temperature of 60 to 100 ° C. and an air supply air volume of 1.0 to 4.0 m ³ / min. When granulation is performed by the stirring granulation method, granulation can be performed at a chopper rotation speed of 500 to 3000 rpm and an agitator rotation speed of 100 to 500 rpm.

Granulation may be performed while spraying a liquid that does not cause any problem in production. Examples of such a liquid include water, ethanol and the like.
Generally, in the wet granulation method, granulation is performed while spraying a binder solution in which a binder such as a water-soluble polymer or a water-insoluble acrylic acid polymer is dispersed or dissolved in water. Also in the granulation step of this embodiment, granulation may be performed while spraying the binding liquid. In this case, the particles (x) constituting the obtained particle group (X) contain a binder.
When the binder contains a water-soluble polymer, the particles (x) preferably have a low content of the binder from the viewpoint of maintaining good disintegration property. Specifically, the spray amount of the binding liquid is preferably an amount in which the content of the water-soluble polymer is 5% by mass or less with respect to the total mass of the particles (x).

After granulation, the obtained granulated particles are dried for the purpose of adjusting the water content, if necessary.
The drying method is not particularly limited, but it is preferable to dry the shelves using a dryer such as a fluidized bed granulator or a box-type ventilation type dryer.
The drying conditions can be appropriately selected according to the drying method. For example, when drying is performed using a fluidized bed granulator, it can be dried at an air supply temperature of 60 to 100 ° C., a drying time of 10 to 90 minutes, and an air supply air volume of 1.0 to 4.0 m ³ / min. .. When drying is performed using a box-type ventilation type dryer, it can be dried at a drying temperature of 40 to 90 ° C. and a drying time of 15 to 130 minutes.

Although the manufacturing method of the embodiment having the powder mixing step and the granulation step has been described above, the manufacturing method of the particle group (X) is not limited to the manufacturing method of this aspect.
For example, the particle swarm (X) may be produced by a production method having a granulation step and not a powder mixing step. In this case, in the granulation step, each component to be granulated (components (A) to (C), etc.) may be brought into contact with each other in a solid state such as powder, or in a state of being dissolved or dispersed in a liquid medium. You may make contact.

When the granulation step is performed without going through the powder mixing step, the order of charging the components (A) to (C) into the granulator is not particularly limited as long as there is no problem in manufacturing. For example, the component (A) may be charged and granulated, then the component (B) and (C) may be charged into the granulator and further granulated, and the components (A) and (B) may be further granulated. The input order may be reversed. It is preferable that the components (A) to (C) are simultaneously or in advance in the granulator to perform granulation in that the particles (x) tend to be more uniform and the process can be avoided. ..

When the pharmaceutical preparation is a liquid preparation, a production method in which the components (A) to (C) and, if necessary, an arbitrary component are dispersed in water or the like as a dispersion medium can be mentioned.

<How to use>
The method of using the pharmaceutical preparation of the present embodiment is appropriately determined according to the dosage form. That is, the pharmaceutical preparation is orally ingested so that the components (A) to (C) have a desired dose.

Since the pharmaceutical preparation of the present embodiment has both the component (A) and the component (B), it is possible to reduce the gastric disorder caused by the component (A) while exerting the medicinal effect of the component (A). Here, when the component (A) coexists with the component (B), the content of the component (A) decreases with time. However, according to the pharmaceutical preparation of the present embodiment, since the component (C) is contained, even if the component (A) and the component (B) coexist, the decrease in the content of the component (A) can be suppressed.

Dosage form (single layer tablet, capsule, microcapsule, granule, fine granule, powder, emulsion, self-emulsifying preparation, syrup, jelly, inhalation) in which the component (A) and the component (B) coexist Agents, etc.) raises the subject of the present invention. Therefore, according to the pharmaceutical preparation of the present embodiment, the presence of the component (C) in the coexistence of the component (A) and the component (B) causes the component (A) to be contained in any dosage form. The decrease in quantity can be suppressed.

(Second embodiment)
The solid pharmaceutical preparation of the present embodiment contains a group of particles (α1) containing the component (A) and substantially not containing the component (B), and the component (B), and substantially contains the component (A). It has a group of particles (β1) that does not contain. At least one of the group of particles (α1) and the group of particles (β1) is granulated particles.
In addition, "substantially not contained" means that it is not contained at all or is contained to the extent that the influence of each component does not occur.

<Group of particles (α1)>
The group of particles (α1) is a group of particles containing the component (A) and substantially not containing the component (B). When the group of particles (β1) described later is a group of granulated particles, the group of particles (α1) may be a group of granulated particles or a group of particles in which the particles of the component (A) are independently present. .. When the group of particles (β1) described later is not a granulated particle, the group of particles (α1) is a group of granulated particles.
The type, content and content ratio of the component (A) are the same as those in the first embodiment.
The content of the component (B) with respect to the total mass of the group of particles (α1) is, for example, preferably 5% by mass or less, more preferably 3% by mass or less, and further preferably 0% by mass.

The group of particles (α1) may be a group of granulated particles containing the component (C). When the particle group (α1) contains the component (C), the decrease in the content of the component (A) in the solid pharmaceutical preparation can be better suppressed.
The type of the component (C) is the same as that of the first embodiment.
The content of the component (C) in the solid pharmaceutical preparation in the present embodiment is preferably 1 to 250 mg per dose, more preferably 3 to 50 mg. The content ratio of the component (C) in the solid pharmaceutical preparation is preferably 0.1 to 30% by mass, more preferably 0.3 to 15% by mass. The reason why the content and the content ratio are preferable is the same as in the first embodiment.

In the particle group (α1), the lower limit of the mass ratio (C / A ratio) represented by the component (C) / component (A) is preferably 0.1 or more, more preferably 0.3 or more, and 0. .5 or more is more preferable. The upper limit of the C / A ratio is preferably 25 or less, more preferably 7.5 or less, and even more preferably 3 or less. When the C / A ratio is equal to or higher than the above lower limit, the stability of the component (A) with time becomes better, and the hardness can be further increased when the solid pharmaceutical preparation is made into tablets. When the C / A ratio is not more than the above upper limit, the elution property of the component (A) can be further enhanced.

The group of particles (α1) may contain an arbitrary component other than the component (A) and the component (C).
Examples of the optional component include the same components as those in the first embodiment.

When the group of particles (α1) is a group of granulated particles, the method for producing the group of particles (α1) is a powder mixture of the component (A) and, if necessary, the component (C) or an optional component. , A manufacturing method for granulating this. Examples of the granulation method include the same granulation method as in the first embodiment.

When the group of particles (α1) is a group of granulated particles, the average particle size of the group of particles (α1) is preferably 10 to 700 μm, more preferably 50 to 500 μm. When the average particle size is equal to or more than the above lower limit, the ratio of the surface area to the volume is small, and even if the granulated particles constituting the particle group (α1) come into contact with the particles constituting the particle group (β1), The influence of the component (B) on the component (A) in the particle group (α1) is small. Therefore, the decrease in the content of the component (A) can be suppressed more satisfactorily. When the average particle size is not more than the above upper limit value, the elution of the component (A) can be enhanced when the solid pharmaceutical preparation is made into a tablet.
When the group of particles (α1) is not a group of granulated particles but a group of particles in which the particles of the component (A) are independently present, the average particle size is preferably 5 to 500 μm, preferably 20 to 350 μm. preferable. The reason why the average particle size is preferable is the same as when the group of particles (α1) is a group of granulated particles.
The average particle size can be measured by a low tap method or a laser diffraction / scattering method. The average particle size measured by the low-tap method corresponds to the particle size at which the cumulative frequency is 50% by mass on a mass basis.

<Group of particles (β1)>
The particle group (β1) is a particle group containing the component (B) and substantially not containing the component (A). When the group of particles (α1) is a group of granulated particles, the group of particles (β1) may be a group of granulated particles or a group of particles in which the particles of the component (B) exist independently. When the group of particles (α1) is not granulated particles, the group of particles (β1) is a group of granulated particles.
The type, content and content ratio of the component (B) are the same as those in the first embodiment.
The content of the component (A) with respect to the total mass of the group of particles (β1) is, for example, preferably 5% by mass or less, more preferably 3% by mass or less, still more preferably 0% by mass.

The group of particles (β1) may be a group of granulated particles containing the component (C). When the particle group (β1) contains the component (C), the decrease in the content of the component (A) in the solid pharmaceutical preparation can be better suppressed.
The type of the component (C) is the same as that of the first embodiment.
The content of the component (C) in the solid pharmaceutical preparation in the present embodiment is preferably 1 to 250 mg per dose, more preferably 3 to 50 mg. The content ratio of the component (C) in the solid pharmaceutical preparation is preferably 0.1 to 30% by mass, more preferably 0.3 to 15% by mass. The reason why the content and the content ratio are preferable is the same as in the first embodiment.

In the particle group (β1), the lower limit of the mass ratio (C / B ratio) represented by the component (C) / component (B) is preferably 0.001 or more, more preferably 0.00375 or more, and 0. 0.01 or more is more preferable. The upper limit of the C / B ratio is preferably 2.5 or less, more preferably 0.5 or less, and even more preferably 0.1 or less. When the C / B ratio is equal to or higher than the above lower limit, the stability of the component (A) with time is good. When the C / B ratio is not more than the above upper limit, when the solid pharmaceutical preparation is made into a tablet, the disintegration of the tablet after taking the tablet can be accelerated.

Further, in the solid pharmaceutical preparation, the lower limit of the C / B ratio is preferably 0.001 or more, more preferably 0.00375 or more, still more preferably 0.01 or more. The upper limit of the C / B ratio is preferably 2.5 or less, more preferably 0.5 or less, and even more preferably 0.1 or less. When the C / B ratio is equal to or higher than the above lower limit, the stability of the component (A) with time is good. When the C / B ratio is not more than the above upper limit, when the solid pharmaceutical preparation is made into a tablet, the disintegration of the tablet after taking the tablet can be accelerated.

The group of particles (β1) may contain any component other than the component (B) and the component (C).
Examples of the optional component include the same components as those in the first embodiment.

When the group of particles (β1) is a group of granulated particles, the method for producing the group of particles (β1) is to prepare a powder mixture of the component (B) and, if necessary, the component (C) or an optional component. A manufacturing method for granulating this can be mentioned. Examples of the granulation method include the same granulation method as in the first embodiment.

When the group of particles (β1) is a group of granulated particles, the average particle size of the group of particles (β1) is preferably 10 to 700 μm, more preferably 50 to 500 μm. When the average particle size is equal to or more than the above lower limit, the ratio of the surface area to the volume is small, and even if the granulated particles constituting the particle group (β1) come into contact with the particles constituting the particle group (α1), The influence of the component (B) on the component (A) in the particle group (α1) is small. Therefore, the decrease in the content of the component (A) can be suppressed more satisfactorily. When the average particle size is not more than the above upper limit value, the uniformity of the preparation becomes better when the solid pharmaceutical preparation is made into tablets.
When the group of particles (β1) is not a group of granulated particles but a group of particles in which the particles of the component (B) are independently present, the average particle size is preferably 5 to 500 μm, preferably 20 to 350 μm. preferable. The reason why the average particle size is preferable is the same as when the group of particles (β1) is a group of granulated particles.
The method for measuring the average particle size of the particle group (β1) is the same as the method for measuring the average particle size of the particle group (α1).

<Arbitrary particle group>
The solid pharmaceutical preparation of the present embodiment may have a group of other particles (arbitrary particle group) in addition to the group of particles (α1) and the group of particles (β1). Examples of the arbitrary particle group include a particle group containing the component (C) and substantially not containing the component (A) and the component (B). That is, the component (C) may be present in the solid pharmaceutical preparation as a particle group different from the particle group (α1) and the particle group (β1).

<Manufacturing method>
In the method for producing a solid pharmaceutical preparation of the present embodiment, a group of particles (α1) and a group of particles (β1) are powder-mixed, and this is used as a granule. Alternatively, the obtained granules may be used as capsules. Further, for example, the obtained granules may be tableted to form a tablet containing a group of particles (α1) and a group of particles (β1) in the same layer.

According to the solid pharmaceutical preparation of the present embodiment, since at least one of the particle group (α1) and the particle group (β1) is a group of granulated particles, the component (A) and the component (B) are in direct contact with each other. There are few opportunities to do it. Therefore, it is possible to suppress a decrease in the content of the component (A). The solid pharmaceutical preparation of the present embodiment is not particularly limited as long as at least one of the component (A) and the component (B) is contained in the group of granulated particles, but it suppresses a decrease in the content of the component (A). It is preferable to use the group of particles (α1) as granulated particles because the dose per dose can be reduced.

The dosage form in which the component (A) and the component (B) coexist (single-layer tablets, capsules, microcapsules, granules, fine granules, powders, inhalants, etc.) poses the problems of the present invention. Therefore, according to the pharmaceutical preparation of the present embodiment, by making the particles containing the component (A) and the component (B) independent of each other, the content of the component (A) can be reduced in any dosage form. Can be suppressed.

(Third embodiment)
The tablet of the present embodiment contains a layer (α2) containing the component (A) and substantially not containing the component (B), and a layer containing the component (B) and substantially not containing the component (A). It is a multi-layer tablet having (β2).

<Layer (α2)>
The layer (α2) is a layer containing the component (A) and substantially not containing the component (B).
The type, content and content ratio of the component (A) are the same as those in the first embodiment.
The content of the component (B) with respect to the total mass of the layer (α2) is, for example, preferably 5% by mass or less, more preferably 3% by mass or less, and further preferably 0% by mass.

The layer (α2) may contain the component (C). When the layer (α2) contains the component (C), it is possible to better suppress the decrease in the content of the component (A) in the tablet.
The type of the component (C) is the same as that of the first embodiment.
The content of the component (C) in the tablet in the present embodiment is preferably 1 to 250 mg per dose, more preferably 3 to 50 mg. The content ratio of the component (C) in the tablet is preferably 0.1 to 30% by mass, more preferably 0.3 to 15% by mass. The reason why the content and the content ratio are preferable is the same as in the first embodiment.

In the layer (α2), the lower limit of the mass ratio (C / A ratio) represented by the component (C) / component (A) is preferably 0.1 or more, more preferably 0.3 or more, and 0.5. The above is more preferable. The upper limit of the C / A ratio is preferably 25 or less, more preferably 7.5 or less, and even more preferably 2 or less. When the C / A ratio is equal to or higher than the above lower limit, the hardness of the tablet can be further increased. When the C / A ratio is not more than the above upper limit, the elution property of the component (A) can be further enhanced.

The layer (α2) may contain any component other than the component (A) and the component (C).
Examples of the optional component include the same components as those in the first embodiment.

<Layer (β2)>
The layer (β2) is a group of granulated particles containing the component (B) and substantially not containing the component (A).
The type, content and content ratio of the component (B) are the same as those in the first embodiment.
The content of the component (A) with respect to the total mass of the layer (β2) is, for example, preferably 5% by mass or less, more preferably 3% by mass or less, and further preferably 0% by mass.

The layer (β2) may contain the component (C). When the layer (β2) contains the component (C), it is possible to better suppress the decrease in the content of the component (A) in the tablet.
The type of the component (C) is the same as that of the first embodiment.
The content of the component (C) in the tablet in the present embodiment is preferably 1 to 250 mg per dose, more preferably 3 to 50 mg. The content ratio of the component (C) in the tablet is preferably 0.1 to 30% by mass, more preferably 0.3 to 15% by mass. The reason why the content and the content ratio are preferable is the same as in the first embodiment.

In the layer (β2), the lower limit of the mass ratio (C / B ratio) represented by the component (C) / component (B) is preferably 0.001 or more, more preferably 0.00375 or more, and 0.01. The above is more preferable. The upper limit of the C / B ratio is preferably 2.5 or less, more preferably 0.5 or less, and even more preferably 0.1 or less. When the C / B ratio is equal to or higher than the above lower limit, the stability of the component (A) with time is good. If the C / B ratio is not more than the above upper limit, the disintegration of the tablet after taking the tablet can be accelerated.

Further, in the tablet, the lower limit of the C / B ratio is preferably 0.001 or more, more preferably 0.00375 or more, and further preferably 0.01 or more. The upper limit of the C / B ratio is preferably 2.5 or less, more preferably 0.5 or less, and even more preferably 0.1 or less. When the C / B ratio is equal to or higher than the above lower limit, the stability of the component (A) with time is good. If the C / B ratio is not more than the above upper limit, the disintegration of the tablet after taking the tablet can be accelerated.

The layer (β2) may contain an optional component other than the component (B) and the component (C).
Examples of the optional component include the same components as those in the first embodiment.

<Manufacturing method>
As a method for producing a tablet of the present embodiment, a production method based on a conventionally known production method can be exemplified.
For example, the following manufacturing method can be exemplified. The powder that is the raw material of the layer (β2) is put into the mortar of the tableting machine, and this is temporarily compressed. Next, the powder that is the raw material of the layer (α2) is put into the mortar, and the powder that is the raw material of the layer (α2) is placed on the temporarily compressed powder. Next, a pestle is inserted into the mortar to obtain a double-layered tablet having a layer (β2) in the lower layer and a layer (α2) in the upper layer. Further, the surface of the uncoated tablet may be coated to serve as a coating agent. Further, an arbitrary layer may be provided between the layer (α2) and the layer (β2) to form a three-layer tablet.
The order of the raw materials to be put into the mortar is not particularly limited.

According to the tablet of the present embodiment, since the component (A) and the component (B) are contained in different layers, the contact point between the two is limited to the boundary between them. Therefore, the component (A) is less affected by the component (B), and the decrease in the content of the component (A) is suppressed.

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to the following description.

(Raw materials used)
<Ingredient (A)>
-A-1: Meloxicam (trade name: meloxicam, manufactured by SUN Pharma).

<Ingredient (B)>
-B-1: Dry aluminum hydroxide gel (trade name: S-100, standard: Nihon Bureau, manufactured by Kyowa Chemical Industry Co., Ltd.).
-B-2: Magnesium aluminate metasilicate (trade name: Neucillin UFL-2, standard: external regulations, Fuji Chemical Industries, Ltd.).
-B-3: Synthetic hydrotalcite (trade name: Alcamac SN, standard: external regulations, manufactured by Kyowa Chemical Industry Co., Ltd.).
-B-4: Synthetic aluminum silicate (manufactured by Yoshida Pharmaceutical Company Ltd.).
-B-5: Dihydroxyaluminum aminoacetic acid (trade name: glycineal, standard: external regulation, manufactured by Kyowa Chemical Industry Co., Ltd.).

<Ingredient (C)>
-C-1: Citric acid (manufactured by Fuso Pharmaceutical Co., Ltd.).
-C-2: Malic acid (DL-malic acid, manufactured by Wako Pure Chemical Industries, Ltd.).
-C-3: EDTA (trade name: Doujin N001 2Na, manufactured by Dojin Chemical Laboratory Co., Ltd.).

<Arbitrary ingredient>
-Crystalline cellulose (grade: PH-302, standard: Nihon Bureau, manufactured by Asahi Kasei Corporation).
-Magnesium stearate (standard: Nihon Bureau, manufactured by Taihei Kagaku Sangyo Co., Ltd.).
-Lactose hydrate (trade name: Pharmatose200M, standard: Nihon Bureau, manufactured by DMV).
-Hydroxypropyl cellulose (trade name: HPC-L, standard: Nippon Soda Co., Ltd.).

(Evaluation method)
<Residual rate>
The tablets of each example were packaged in PTP (press-through pack, blister part: VSL-4601N, manufactured by Sumitomo Bakelite Co., Ltd.), and the package was stored at 55 ° C. and 80% RH for 6 weeks.
The content (Ax) of the component (A) in the tablet immediately before the start of storage and the content (Ay) of the component (A) in the tablet after storage were measured, and the component (A) remained in the following formula (1). The rate was calculated. The content of meloxicam was measured by UV using a spectrophotometer (UV-2700, manufactured by Shimadzu Corporation) based on the quantification method of meloxicam tablets listed in USP.

Residual rate (mass%) = Ay ÷ Ax × 100 ・ ・ ・ (1)

(Examples 1-1 to 1-17, Comparative Examples 1-1 to 1-5)
According to the compounding ratios shown in Tables 1 and 2, the components (A) to (C) and the optional components were powder-mixed in a plastic bag to obtain 2000 g of a powder mixture.
The obtained powder mixture was tableted with LIBRA2 (manufactured by Kikusui Seisakusho Co., Ltd.) so as to have the mass of one tablet shown in the table to obtain tablets (standard R tablets) of each example. The pestle used for locking was φ8.5 mm, and the hardness was 2 kgf to 30 kgf.
For the obtained tablets, the residual rate of the component (A) was evaluated, and the results are shown in the table.

As shown in Tables 1 and 2, in all of Examples 1-1 to 1-17 to which the present invention was applied, the residual ratio of the component (A) was 84% by mass or more.
The residual ratio of the component (A) of Comparative Examples 1-1 to 1-5 lacking the component (C) was 73% by mass or less.

(Examples 2-1 to 2-4)
Based on the compounding ratio shown in Table 3, the raw material powder of the particle group (α1) (excluding hydroxypropyl cellulose) was powder-mixed in a plastic bag to obtain 3000 g of a powder mixture. .. The obtained powder mixture was put into a fluidized bed granulator (“FLO-5” manufactured by Freund Industries, Ltd.), and while spraying 4% by mass of a binding liquid (hydroxypropyl cellulose aqueous solution), fluidized bed granulation was performed. Was done. The granulation conditions were an air supply temperature of 60 ° C. and an air supply air volume of 2.0 m ³ / min. The fluidized bed granulation is completed by spraying the binder so that the content of hydroxypropyl cellulose in the particle group (α1) becomes the value shown in the table in terms of solid matter, and the particle group (α1) of each example is completed. ) Was obtained as a group of granulated particles. Subsequently, the group of particles (α1) was dried using the same fluidized bed granulator at an air supply temperature of 70 ° C. and an air supply air volume of 1.5 m ^{3 / min for 20 minutes.} A group of particles (β1), crystalline cellulose and magnesium stearate were added to the obtained group of particles (α1) according to the compounding ratio shown in the table, and the powder was mixed in a plastic bag. This powder mixture was tableted with LIBRA2 (manufactured by Kikusui Seisakusho Co., Ltd.) so as to have the mass of one tablet shown in the table to obtain tablets (standard R tablets) of each example. The pestle used for locking was φ8.5 mm, and the hardness was 2 kgf to 30 kgf.
The residual rate of the obtained tablets was evaluated, and the results are shown in the table.

(Comparative Example 2-1)
Tablets were obtained in the same manner as in Example 2-1 except that the component (A), the component (B), crystalline cellulose, and magnesium stearate were powder-mixed to obtain a powder mixture.
For the obtained tablets, the residual rate of the component (A) was evaluated, and the results are shown in the table.

As shown in Table 3, in all of Examples 2-1 to 2-4 to which the present invention was applied, the residual ratio of the component (A) was 81% by mass or more. The residual ratio of the component (A) of Comparative Example 2-1 in which the powder mixture containing the component (A) and the component (B), which was not a group of granulated particles, was tableted was 77% by mass.

(Examples 3-1 to 3-3)
Based on the compounding ratio shown in Table 4, the raw material powder of the layer (α2) was powder-mixed in a plastic bag to obtain 3000 g of a powder mixture (α2). Further, the raw material powder of the layer (β2) was powder-mixed in a plastic bag to obtain 3000 g of a powder mixture (β2).
The powder mixture (α2) and the powder mixture (β2) are tableted with LIBRA2 (manufactured by Kikusui Seisakusho Co., Ltd.) so as to have the mass of one tablet shown in the table, and the tablets (standard R tablets) of each example are obtained. Obtained. The pestle used for locking was φ8.5 mm, and the hardness was 2 kgf to 30 kgf. Further, at the time of tableting, the powder mixture (β2) was first put into the mortar and a temporary compression operation was performed.
For the obtained tablets, the residual rate of the component (A) was evaluated, and the results are shown in the table.

As shown in Table 4, the residual ratio of the component (A) of Examples 3-1 to 3-3 to which the present invention was applied was 97% by mass or more.

Claims (8)

At least one selected from meloxicam and its pharmaceutically acceptable salt (A) and
An antacid (B) containing aluminum and
At least one (C) selected from organic carboxylic acids and salts thereof, and
A pharmaceutical preparation containing. The pharmaceutical preparation according to claim 1, wherein the mass ratio represented by the component (C) / the component (B) is 0.001 to 2.5. A group of particles (α1) containing at least one (A) selected from meloxicam and a pharmaceutically acceptable salt thereof, and substantially free of an aluminum-containing antacid (B).
It has a group (β1) of particles containing the component (B) and substantially not containing the component (A).
A solid pharmaceutical preparation in which at least one of the group of particles (α1) and the group of particles (β1) is a group of granulated particles. 3. Claim 3 in which at least one of the group of particles (α1) and the group of particles (β1) is a group of granulated particles further containing at least one (C) selected from an organic carboxylic acid and a salt thereof. The solid pharmaceutical preparation according to. The solid pharmaceutical preparation according to claim 4, wherein the mass ratio represented by the component (C) / the component (B) is 0.001 to 2.5. A layer (α2) containing at least one (A) selected from meloxicam and a pharmaceutically acceptable salt thereof and substantially free of an aluminum-containing antacid (B).
A layer (β2) containing the component (B) and substantially not containing the component (A).
Have, tablets. The tablet according to claim 6, wherein at least one of the layer (α2) and the layer (β2) further contains at least one (C) selected from an organic carboxylic acid and a salt thereof. The tablet according to claim 7, wherein the mass ratio represented by the component (C) / the component (B) is 0.001 to 2.5.