Solid pharmaceutical preparations

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

[Technical field]

[0001] The present invention relates to pharmaceutical formulations, solid pharmaceutical formulations and tablets. [Background technology]

[0002] In pharmaceutical preparations such as antipyretics and analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used as antipyretic and analgesic ingredients. Among NSAIDs, meloxicam or a salt thereof is known as an analgesic ingredient that exhibits an analgesic effect for a long period of time. Meloxicam or a salt thereof is known to have a side effect of causing stomach disorders, and pharmaceutical preparations containing antacids to suppress stomach disorders are known. For example, Patent Document 1 discloses a formulation comprising a combination of meloxicam or a salt thereof and an antacid (antacid agent). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2005 / 004915 Summary of the Invention [Problem to be solved by the invention]

[0004] However, when a compound containing aluminum is used as an antacid, there is a problem that the content of meloxicam or a salt thereof decreases. Therefore, an object of the present invention is to provide a pharmaceutical preparation which can suppress a decrease in the content of meloxicam or a salt thereof even when an antacid is concomitantly contained therein. [Means for solving the problem]

[0005] The present invention has the following aspects. <1> At least one (A) selected from meloxicam and a pharma- ceutical acceptable salt thereof; an antacid containing aluminum (B); At least one selected from organic carboxylic acids and salts thereof (C); A pharmaceutical formulation comprising: <2> The mass ratio of the component (C) to the component (B) is 0.001 to 2.5. <1> 2. The pharmaceutical formulation according to claim 1 .

[0006] <3> A group of particles (α1) containing at least one kind (A) selected from meloxicam and a pharma- ceutically acceptable salt thereof and substantially not containing an antacid (B) containing aluminum; and a group (β1) of particles containing the component (B) and substantially not containing the component (A), At least one of the particle group (α1) and the particle group (β1) is a group of granulated particles. <4> At least one of the particle group (α1) and the particle group (β1) is a group of granulated particles further containing at least one kind (C) selected from an organic carboxylic acid and a salt thereof. <3> 2. The solid pharmaceutical formulation according to claim 1 . <5> The mass ratio of the component (C) to the component (B) is 0.001 to 2.5. <4> 2. The solid pharmaceutical formulation according to claim 1 .

[0007] <6> A layer (α2) containing at least one selected from meloxicam and a pharma- ceutically acceptable salt thereof (A) and substantially not containing an antacid containing aluminum (B); A layer (β2) containing the component (B) and substantially not containing the component (A); A tablet having the formula: <7> At least one of the layer (α2) and the layer (β2) further contains at least one kind (C) selected from an organic carboxylic acid and a salt thereof. <6> The tablet described in. <8> The mass ratio of the component (C) to the component (B) is 0.001 to 2.5. <7> The tablet described in. Effect of the Invention

[0008] According to the pharmaceutical preparation of the present invention, even when an antacid containing aluminum is used concomitantly, a decrease in the content of meloxicam or a salt thereof can be suppressed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The pharmaceutical preparation of the present invention contains at least one member (A) selected from meloxicam and a pharma- ceutical acceptable salt thereof (component (A)), and an antacid (B) containing aluminum (component (B)). 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 a tablet (film-coated tablet, orally disintegrating tablet, etc.), a capsule, a microcapsule, a granule, a fine granule, or a powder, or a liquid preparation or semi-solid pharmaceutical preparation such as an emulsion, a self-emulsifying preparation, a syrup, a jelly, or an inhalant. Examples of the parenteral preparation include ointments, suppositories, injections (emulsions, suspensions, non-aqueous), solid injections that are emulsified or suspended when used, infusion preparations, external preparations such as transdermal absorbents, etc. The pharmaceutical preparation of the present invention is administered to a patient by oral, intravenous, intraarterial, inhalation, rectal, vaginal or external administration, and among them, oral preparations are preferred, and tablets, capsules and the like are more preferred. The tablets may be single-layer tablets or multi-layer tablets of two or more layers. The tablets may be plain tablets or coated tablets. The capsules may be tablets enclosed in soft capsules or microcapsules.

[0010] 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 in terms of ease of handling and swallowing of the tablet. From the viewpoint of ease of handling and swallowability, the shape of the tablet is preferably a shape having a cylindrical portion and a bulging portion bulging from the upper and lower end faces of the cylindrical portion. Examples of the tablet having the cylindrical portion and the 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, etc. The bulging portions of these tablets may be asymmetrical from top to bottom, but are preferably symmetrical from top to bottom.

[0011] When the pharmaceutical preparation is in the form of granules, fine granules or powder, the average particle size of the pharmaceutical preparation is preferably 10 to 700 μm, more preferably 50 to 500 μm. The average particle size is the weight-average particle size (D50) measured according to a laser diffraction particle size distribution measurement method.

[0012] First Embodiment <Pharmaceutical preparations> The pharmaceutical preparation according to the first embodiment of the present invention will be described. The pharmaceutical preparation of the present embodiment contains in combination a component (A), a component (B), and at least one compound (C) selected from an organic carboxylic acid and a salt thereof (component (C)). The pharmaceutical preparation of this embodiment may be a single-layer tablet, a pill, a granule prepared by granulating the components (A) to (C) together, a powder or fine granule prepared by mixing powders, a liquid preparation, etc. The pharmaceutical preparation of this embodiment may be a multi-layer tablet having a layer containing the components (A) to (C) together. That is, the pharmaceutical preparation of this embodiment is a dosage form in which the components (A) to (C) coexist.

[0013] Component (A) The component (A) is at least one selected from meloxicam (chemical name: 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide) and its pharma- ceutical acceptable salts. Examples of the pharma-ceutical acceptable salts of meloxicam include those described in European Patent No. 2,482B1, U.S. Patent No. 4,233,299, and International Publication No. 99 / 49867. Examples of the acceptable salts include sodium salts, potassium salts, ammonium salts, meglumine salts, and tris salts. The component (A) may be used alone or in combination of two or more types.

[0014] The content of the (A) component in the pharmaceutical preparation is preferably an amount such that the amount of the (A) component per dose is 0.5 to 70 mg, more preferably 2 to 50 mg, even more preferably 2.5 to 20 mg, and particularly preferably 5 to 15 mg. If the content of the (A) component is equal to or greater than the above lower limit, the pharmacological effect of the pharmaceutical preparation can be further enhanced. If the content of the (A) component is equal to or less than the above upper limit, problems during tablet production (for example, adhesion of the pharmaceutical preparation to the disks and punches of a tablet press) are less likely to occur. In addition, if the content of the (A) component is equal to or less than the above upper limit, stomach problems 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 the tablets taken at one time.

[0015] When the pharmaceutical preparation is a tablet or capsule, the content of component (A) per tablet (or capsule) is appropriately determined taking into consideration the number of tablets (or capsules) per dose.

[0016] The content of the (A) component in the pharmaceutical preparation is, for example, preferably 0.1 to 20% by mass, more preferably 0.5 to 10% by mass, and even more preferably 1.0 to 5.0% by mass, based on the total mass of the pharmaceutical preparation. If the content of the (A) component is equal to or higher than the above lower limit, the pharmacological effect of the pharmaceutical preparation can be further improved. If the content of the (A) component is equal to or lower than the above upper limit, problems during tablet production (for example, adhesion of the pharmaceutical preparation to the disks and punches of a tablet press) are less likely to occur. In addition, if the content of the (A) component is equal to or lower than the above upper limit, stomach problems can be further reduced.

[0017] ≪(B) Component≫ Component (B) is an antacid containing aluminum. By containing component (B), the pharmaceutical preparation of this embodiment can reduce stomach damage caused by component (A). Component (B) is a so-called aluminum-based antacid, and is an alkaline compound having aluminum in the molecule. Component (B) may contain, in addition to aluminum, alkali metals such as sodium and potassium, and metal atoms such as magnesium and silicon. The aluminum content relative to the total mass of component (B) is 1 mass% or more. In view of the remarkable effect on the problem of the present invention, the aluminum content relative to the total mass of component (B) is preferably 10 mass% or more. The aluminum content in component (B) is a value determined by the mass ratio calculated from the chemical formula.

[0018] Examples of component (B) include dried aluminum hydroxide gel, magnesium aluminometasilicate, synthetic hydrotalcite, synthetic aluminum silicate, dihydroxyaluminum aminoacetic acid, aluminum hydroxide gel, aluminum hydroxide-magnesium carbonate co-dried gel, aluminum hydroxide-sodium bicarbonate co-precipitate, aluminum hydroxide-calcium carbonate-magnesium carbonate co-precipitate, magnesium hydroxide-aluminum potassium sulfate co-precipitate, magnesium aluminosilicate, magnesium aluminum hydroxide, etc. Among these, preferred examples of component (B) are dried aluminum hydroxide gel, magnesium aluminometasilicate, synthetic hydrotalcite, synthetic aluminum silicate, and dihydroxyaluminum aminoacetic acid. These components (B) may be used alone or in combination of two or more.

[0019] The content of the (B) component in the pharmaceutical preparation is preferably 40 to 1500 mg, more preferably 60 to 800 mg, and even more preferably 200 to 500 mg per dose of the (B) component. If the content of the (B) component is equal to or greater than the lower limit, gastric disorders caused by the (A) component can be more effectively alleviated. If the content of the (B) component is equal to or less than the upper limit, the decrease in the content of the (A) component can be more effectively prevented. The amount of the main (B) component per dose is shown below. When the pharmaceutical preparation is a tablet, the content of the (B) component described below may be contained in one tablet, or may be the total amount of the number of tablets taken at one time.

[0020] When component (B) is a dry aluminum hydroxide gel, the amount of component (B) per dose is preferably 40 to 1000 mg, more preferably 100 to 800 mg, and even more preferably 200 to 500 mg.

[0021] When component (B) is magnesium aluminometasilicate, the amount of component (B) per dose is preferably 60 to 1500 mg, more preferably 150 to 800 mg, and even more preferably 250 to 500 mg.

[0022] 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, and even more preferably 300 to 400 mg.

[0023] When component (B) is synthetic aluminum silicate, the amount of component (B) per dose is preferably 100 to 1000 mg, more preferably 180 to 700 mg, and even more preferably 250 to 400 mg.

[0024] When component (B) is dihydroxyaluminum acetate, the amount of component (B) per dose is preferably 40 to 1500 mg, more preferably 100 to 600 mg, and even more preferably 150 to 400 mg.

[0025] The content of component (B) in the pharmaceutical preparation is preferably 10 to 85% by mass, more preferably 20 to 80% by mass. If the content of component (B) is equal to or higher than the lower limit, gastric disorders caused by component (A) can be more effectively reduced. If the content of component (B) is equal to or lower than the upper limit, a decrease in the content of component (A) can be more effectively prevented.

[0026] ≪(C) Component≫ The pharmaceutical preparation contains at least one kind (C) selected from organic carboxylic acids and salts thereof (component (C)). By containing component (C), the pharmaceutical preparation of the present embodiment can suppress a decrease in the content of component (A).

[0027] Examples of the (C) component include mono- or polycarboxylic acids, hydroxycarboxylic acids, and aminocarboxylic acids. Examples of the mono- or polycarboxylic acids include acetic acid, butyric acid, succinic acid, maleic acid, and fumaric acid. Examples of the hydroxycarboxylic acids include lactic acid, citric acid, malic acid, and tartaric acid. Examples of the aminocarboxylic acids include ethylenediaminetetraacetic acid (EDTA), ethylenediaminediacetic acid (EDDA), diethylenetriaminepentaacetic acid (DTPA), and N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA). Examples of salts of component (C) include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium, and ammonium salts. Of these components (C), malic acid, citric acid, fumaric acid, maleic acid, ethylenediaminetetraacetic acid (EDTA), and salts thereof are preferred. These components (C) may be used alone or in combination of two or more.

[0028] The lower limit of the component (C) in the pharmaceutical preparation is preferably an amount that results in the amount of component (C) per dose of 1 mg or more, more preferably an amount that results in ... The upper limit of the amount of the component (C) in the pharmaceutical preparation is preferably 250 mg or less, more preferably 150 mg or less, even more preferably 100 mg or less, particularly preferably 90 mg or less, more preferably 75 mg or less, even more preferably 50 mg or less, even more preferably 25 mg or less, and most preferably 20 mg or less. If the content of the component (C) is equal to or less than the upper limit, the disintegration of the tablet after administration can be accelerated when the pharmaceutical preparation is made into a tablet. The preferred range of the content of component (C) in the pharmaceutical preparation per dose is preferably 1 to 250 mg, more preferably 1 to 100 mg, even more preferably 3 to 50 mg, and most preferably 5 to 20 mg. The content in one tablet is preferably 0.2 to 250 mg, and more preferably 1 to 50 mg. When the pharmaceutical preparation is a tablet, the content of the above component (C) may be contained in one tablet, or may be the total amount of the tablets taken at one time.

[0029] The content of component (C) in the pharmaceutical preparation is preferably 0.1 to 30% by mass, more preferably 0.3 to 15% by mass. If the content of component (C) is equal to or higher than the lower limit, the decrease in the content of component (A) can be further suppressed. If the content of component (C) is equal to or lower than the upper limit, the disintegration of the tablet after taking the pharmaceutical preparation can be accelerated.

[0030] In the pharmaceutical preparation, the lower limit of the mass ratio (C / B ratio) represented by the (C) component / (B) component is preferably 0.001 or more, more preferably 0.00375 or more, and even 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. If the C / B ratio is above the lower limit, the stability of the (A) component over time is good. If the C / B ratio is below the upper limit, when the pharmaceutical preparation is made into a tablet, the disintegration of the tablet after taking it can be accelerated.

[0031] In the pharmaceutical preparation, the lower limit of the mass ratio (C / A ratio) represented by the (C) component / (A) component is preferably 0.1 or more, more preferably 0.3 or more, and even more preferably 0.5 or more. 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. If the C / A ratio is above the lower limit, the stability of the (A) component over time is good, and when the pharmaceutical preparation is made into a tablet, the hardness can be further increased. If the C / A ratio is below the upper limit, the dissolution property of the (A) component can be further increased.

[0032] ≪Optional ingredients≫ The pharmaceutical preparation may further contain other components (optional components) other than the components (A) to (C) as necessary, to the extent that the effects of the present invention are not impaired. The optional components include physiologically active components and additives (excluding components (A) to (C)).

[0033] Examples of physiologically active ingredients include antipyretic and analgesic ingredients (excluding ingredient (A)) (e.g., piroxicam, ampiroxicam, cerocoxib, rofecoxib, tiaramide, loxoprofen sodium, ethenzamide, sulpyrine, acetaminophen, acetylsalicylic acid, etc.), sedative and hypnotic ingredients (e.g., allylisopropylacetylurea, bromvalerylurea, etc.), antihistamine ingredients (e.g., isothipendyl hydrochloride, hydrochloride, Diphenylpyraline, diphenhydramine hydrochloride, difeterol hydrochloride, triprolidine hydrochloride, tripelennamine hydrochloride, thonzylamine hydrochloride, fenethazine hydrochloride, methdilazine hydrochloride, diphenhydramine salicylate, carbinoxamine diphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teoclate, mebhydroline napadisilate, promethazine methylenedisalicyl salts, carbinoxamine maleate, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, difeterol phosphate, etc.), central stimulants (e.g., sodium caffeine benzoate, caffeine, anhydrous caffeine, etc.), antitussive and expectorant ingredients (codeine phosphate, dextromethorphan hydrobromide, dimemorphan phosphate, tipepidine hibenzate, methoxyphenamine hydrochloride, trimetoquinol hydrochloride, carbocysteine, acetylcysteine, ethylcysteine, dl-methylephedrine, bromhexine hydrochloride, serrapeptase, lysozyme chloride, ambroxol, theophylline, aminophylline), vitamin ingredients (e.g., vitamin B1 and its derivatives and their salts, vitamin B2 and its derivatives and their salts, vitamin B6 and its derivatives and their salts, vitamin B 12and 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.), herbal medicines (Irei Sen, Corydalis Root, Scutellaria Root, Gaihaku, Licorice, Platycodon Root, Peony Root, Senega, etc., ingredients listed in the "Herbal Medicines, etc." Articles on Drugs in the 17th Revised Japanese Pharmacopoeia), 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 preparation 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 preparation.

[0034] Examples of the additives include binders, excipients, disintegrants, lubricants, flavors, colorants, bases, sweeteners, and acidulants. Examples of binders include sucrose, gelatin, powdered gum arabic, polyvinylpyrrolidone, pullulan, and dextrin. Examples of excipients include crystalline cellulose, lactose (hydrate), corn starch, powdered sugar, mannitol, and L-cysteine. Disintegrants include low-substituted hydroxypropylcellulose, crospovidone, croscarmellose sodium and the like. Examples of the lubricant include magnesium stearate, sodium stearyl fumarate, sucrose fatty acid esters, light anhydrous silicic acid, and the like. Examples of the fragrance include menthol, limonene, and plant essential oils (peppermint oil, mint oil, lychee oil, orange oil, lemon oil, etc.). The pigment may be ferric oxide or the like. The base includes water, ethanol, and the like. Sweeteners include sodium saccharin, aspartame, stevia, dipotassium glycyrrhizinate, acesulfame potassium, thaumatin, and sucralose. 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 included in component (C), but may be used as an acidulant as appropriate. These additives may be used alone or in combination of two or more. The content of the additive in the pharmaceutical preparation 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 preparation. The total amount of the components (A) to (C) and any optional components does not exceed 100 mass %.

[0035] <Manufacturing method> The method for producing the pharmaceutical formulation 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, the preparation method includes powder-mixing the components (A) to (C) and, if necessary, any optional components, and compressing the resulting powder mixture into tablets. In addition, for example, the components (A) to (C) and any optional components as required are powder-mixed, the resulting powder mixture is granulated to form a group of granulated particles, and the resulting group of particles is made into a granule. The resulting group of particles may be encapsulated to form a capsule, or the resulting group of particles may be compressed to form a tablet.

[0036] The granulation method for the granules will be described below. Examples of the granulation method include a dry granulation method, a wet granulation method, etc. Examples of the wet granulation method include a fluidized bed granulation method, an agitation granulation method, a rolling granulation method, an extrusion granulation method, etc. As the granulation method, wet granulation is preferred from the viewpoint of manufacturability, and among them, fluidized bed granulation and agitation granulation are preferred from the viewpoints of efficient contact of components (A) to (C), operability, and productivity. Granulation conditions can be appropriately selected depending on the granulation method. For example, when granulation is performed by a fluidized bed granulation method, the supply air temperature is 60 to 100°C, and the supply air volume is 1.0 to 4.0 m 3When granulation is performed by the stirring granulation method, the chopper rotation speed can be set to 500 to 3000 rpm and the agitator rotation speed to 100 to 500 rpm.

[0037] Granulation may be carried out while spraying a liquid that does not cause problems in manufacturing, such as water, ethanol, etc. In general, in wet granulation, granulation is performed while spraying a binder liquid in which a binder such as a water-soluble polymer or a water-insoluble acrylic acid polymer is dispersed or dissolved in water. In the granulation step of this embodiment, granulation may be performed while spraying a binder 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 binder content of the particles (x) is preferably small in order to maintain good disintegrability. Specifically, the amount of the binder solution to be sprayed is preferably an amount such that the content of the water-soluble polymer is 5% by mass or less relative to the total mass of the particles (x).

[0038] After granulation, the resulting granulated particles are dried, if necessary, for the purpose of adjusting the moisture content, etc. The drying method is not particularly limited, but shelf drying using a dryer such as a fluidized bed granulator or a box-type ventilation dryer is preferred. Drying conditions can be appropriately selected depending on the drying method. For example, when drying is performed using a fluidized bed granulator, the intake air temperature is 60 to 100°C, the drying time is 10 to 90 minutes, and the intake air volume is 1.0 to 4.0 m 3 When drying is performed using a box-type ventilation dryer, the drying temperature is 40 to 90°C and the drying time is 15 to 130 minutes.

[0039] Although the manufacturing method 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 this embodiment. For example, the particle group (X) may be produced by a production method having a granulation step but not having a powder mixing step. In this case, in the granulation step, the components to be granulated (e.g., components (A) to (C)) may be contacted in a solid state such as powder, or in a state dissolved or dispersed in a liquid medium.

[0040] When the granulation step is performed without going through the powder mixing step, the order of feeding the components (A) to (C) into the granulator is not particularly limited as long as it does not cause any problems in production. For example, the component (A) may be fed and granulated, and then the components (B) and (C) may be fed into the granulator and further granulated, or the order of feeding the components (A) and (B) may be reversed. In terms of making the particles (x) more uniform and avoiding the process from becoming complicated, it is preferable to feed the components (A) to (C) into the granulator simultaneously or in advance to perform granulation.

[0041] When the pharmaceutical preparation is a liquid preparation, the preparation may be produced by dispersing the components (A) to (C) and, if necessary, any optional components in water or the like serving as a dispersion medium.

[0042] <How to use> The method of using the pharmaceutical preparation of this embodiment is appropriately determined depending on the dosage form. That is, the pharmaceutical preparation is taken orally or the like so that the components (A) to (C) are administered in the desired amounts.

[0043] According to the pharmaceutical preparation of this embodiment, since the (A) component and the (B) component are both present, the (A) component's efficacy can be exerted while reducing the stomach disorder caused by the (A) component. Here, when the (A) component coexists with the (B) component, the content of the (A) component decreases over time. However, according to the pharmaceutical preparation of this embodiment, since the (C) component is contained, even when the (A) component and the (B) component coexist, the decrease in the (A) component's content can be suppressed.

[0044] The problem of the present invention arises in dosage forms in which the components (A) and (B) coexist (single-layer tablets, capsules, microcapsules, granules, fine granules, powders, emulsions, self-emulsifying preparations, syrups, jellies, inhalants, etc.). Therefore, according to the pharmaceutical preparation of this embodiment, the presence of the component (C) in the coexistence of the components (A) and (B) makes it possible to suppress a decrease in the content of the component (A) in any dosage form.

[0045] Second Embodiment The solid pharmaceutical formulation of this embodiment has a particle group (α1) containing component (A) and substantially no component (B), and a particle group (β1) containing component (B) and substantially no component (A). At least one of the particle group (α1) and the particle group (β1) is a granulated particle. The term "substantially free of" means that each component is not contained at all or is contained to such an extent that it does not have an effect on the other components.

[0046] <Particle group (α1)> The particle group (α1) is a group of particles that contains the component (A) and does not substantially contain the component (B). When the particle group (β1) described later is a group of granulated particles, the particle group (α1) may be a group of granulated particles or a group of particles in which particles of the component (A) exist independently. When the particle group (β1) described later is not a granulated particle, the particle group (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) relative to the total mass of the particle group (α1) is, for example, preferably 5 mass % or less, more preferably 3 mass % or less, and even more preferably 0 mass %.

[0047] The particle group (α1) may be a group of granulated particles containing the component (C). By containing the component (C) in the particle group (α1), the decrease in the content of the component (A) in the solid pharmaceutical preparation can be suppressed more effectively. The type of component (C) is the same as in the first embodiment. The content of the component (C) in the solid pharmaceutical formulation in this 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 formulation is preferably 0.1 to 30 mass %, more preferably 0.3 to 15 mass %. The reasons why the above content and content ratio are preferable are the same as those in the first embodiment.

[0048] In the particle group (α1), the lower limit of the mass ratio (C / A ratio) represented by the (C) component / (A) component is preferably 0.1 or more, more preferably 0.3 or more, and even more preferably 0.5 or more. 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. If the C / A ratio is above the lower limit, the stability of the (A) component over time is improved, and when the solid pharmaceutical preparation is made into a tablet, the hardness can be increased. If the C / A ratio is below the upper limit, the dissolution property of the (A) component can be increased.

[0049] The particle group (α1) may contain an optional component other than the component (A) and the component (C). Optional components include the same components as in the first embodiment.

[0050] When the particle group (α1) is a group of granulated particles, the particle group (α1) can be produced by a method of preparing a powder mixture of the (A) component and, if necessary, the (C) component or an optional component, and granulating the mixture. The granulation method can be the same as that of the first embodiment.

[0051] When the particle group (α1) is a group of granulated particles, the average particle diameter of the particle group (α1) is preferably 10 to 700 μm, more preferably 50 to 500 μm. If the average particle diameter is equal to or greater than the lower limit, the ratio of surface area to 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 effect 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 effectively. If the average particle diameter is equal to or less than the upper limit, the dissolution of the component (A) can be improved when the solid pharmaceutical preparation is made into a tablet. When the particle group (α1) is not a group of granulated particles but a group of particles in which the particles of component (A) exist independently, the average particle size is preferably 5 to 500 μm, more preferably 20 to 350 μm. The reason why the average particle size is preferable is the same as when the particle group (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.

[0052] <Group of particles (β1)> The particle group (β1) is a particle group that contains the component (B) and does not substantially contain the component (A). When the particle group (α1) is a group of granulated particles, the particle group (β1) may be a group of granulated particles, or may be a group of particles in which particles of the component (B) exist independently. When the particle group (α1) is not a group of granulated particles, the particle group (β1) is a group of granulated particles. The type, content and content ratio of the (B) component are the same as those in the first embodiment. The content of the component (A) relative to the total mass of the particle group (β1) is, for example, preferably 5 mass % or less, more preferably 3 mass % or less, and even more preferably 0 mass %.

[0053] The particle group (β1) may be a group of granulated particles containing the component (C). By containing the component (C) in the particle group (β1), the decrease in the content of the component (A) in the solid pharmaceutical preparation can be suppressed more effectively. The type of component (C) is the same as in the first embodiment. The content of the component (C) in the solid pharmaceutical formulation in this 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 formulation is preferably 0.1 to 30 mass %, more preferably 0.3 to 15 mass %. The reasons why the above content and content ratio are preferable are the same as those in the first embodiment.

[0054] In the particle group (β1), the lower limit of the mass ratio (C / B ratio) represented by the (C) component / (B) component is preferably 0.001 or more, more preferably 0.00375 or more, and even 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. If the C / B ratio is above the lower limit, the stability of the (A) component over time is good. If the C / B ratio is below the upper limit, when the solid pharmaceutical preparation is made into a tablet, the disintegration of the tablet after taking it can be accelerated.

[0055] In addition, 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, and even 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. If the C / B ratio is above the lower limit, the stability over time of the (A) component is good. If the C / B ratio is below the upper limit, when the solid pharmaceutical preparation is made into a tablet, the disintegration of the tablet after taking it can be accelerated.

[0056] The particle group (β1) may contain an optional component other than the components (B) and (C). Optional components include the same components as in the first embodiment.

[0057] When the particle group (β1) is a group of granulated particles, the particle group (β1) can be produced by a method of preparing a powder mixture of the (B) component and, if necessary, the (C) component or an optional component, and granulating the mixture. The granulation method can be the same as that of the first embodiment.

[0058] When the particle group (β1) is a group of granulated particles, the average particle size of the particle group (β1) is preferably 10 to 700 μm, more preferably 50 to 500 μm. If the average particle size is equal to or greater than the lower limit, the ratio of surface area to 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 effect 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 effectively. If the average particle size is equal to or less than the upper limit, the uniformity of the solid pharmaceutical preparation becomes better when the solid pharmaceutical preparation is made into a tablet. When the particle group (β1) is not a group of granulated particles but a group of particles in which the particles of component (B) exist independently, the average particle size is preferably 5 to 500 μm, more preferably 20 to 350 μm. The reason why the average particle size is preferable is the same as when the particle group (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).

[0059] <Arbitrary particle group> The solid pharmaceutical formulation of this embodiment may have other particle groups (arbitrary particle groups) in addition to the particle groups (α1) and (β1). The arbitrary particle groups include, for example, particle groups that contain the (C) component and do not substantially contain the (A) component and the (B) component. That is, the (C) component may be present in the solid pharmaceutical formulation as a particle group different from the particle groups (α1) and (β1).

[0060] <Manufacturing method> In the method for producing a solid pharmaceutical formulation of the present embodiment, the particle group (α1) and the particle group (β1) are powder-mixed to form a granule. Alternatively, the obtained granule may be made into a capsule. In addition, for example, the obtained granule may be compressed into a tablet containing the particle group (α1) and the particle group (β1) in the same layer.

[0061] According to the solid pharmaceutical formulation of this embodiment, at least one of the particle group (α1) and the particle group (β1) is a group of granulated particles, so that the (A) component and the (B) component have little chance of direct contact with each other. Therefore, the decrease in the content of the (A) component can be suppressed. The solid pharmaceutical formulation of this embodiment is not particularly limited as long as at least one of the (A) component and the (B) component is included in the group of granulated particles, but it is preferable that the particle group (α1) is a granulated particle because the decrease in the content of the (A) component can be suppressed and the dosage per administration can be reduced.

[0062] The problem of the present invention arises in dosage forms in which component (A) and component (B) coexist (single-layer tablets, capsules, microcapsules, granules, fine granules, powders, inhalants, etc.). Therefore, according to the pharmaceutical preparation of this embodiment, by separating particles each containing component (A) and component (B), it is possible to suppress a decrease in the content of component (A) in any dosage form.

[0063] Third embodiment The tablet of this embodiment is a multi-layer tablet having a layer (α2) containing component (A) and substantially no component (B), and a layer (β2) containing component (B) and substantially no component (A).

[0064] <Layer(α2)> The layer (α2) contains the component (A) and is a layer that does not substantially contain 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) relative to the total mass of the layer (α2) is, for example, preferably 5 mass % or less, more preferably 3 mass % or less, and even more preferably 0 mass %.

[0065] The layer (α2) may contain the component (C). When the layer (α2) contains the component (C), a decrease in the content of the component (A) in the tablet can be more effectively suppressed. The type of component (C) is the same as in the first embodiment. The content of component (C) in the tablet in this embodiment is preferably 1 to 250 mg per dose, more preferably 3 to 50 mg. The content ratio of component (C) in the tablet is preferably 0.1 to 30 mass %, more preferably 0.3 to 15 mass %. The reasons why the above content and content ratio are preferable are the same as those in the first embodiment.

[0066] In layer (α2), the lower limit of the mass ratio (C / A ratio) of component (C) to component (A) is preferably 0.1 or more, more preferably 0.3 or more, and even more preferably 0.5 or more. 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. If the C / A ratio is equal to or more than the lower limit, the tablet hardness can be further increased. If the C / A ratio is equal to or less than the upper limit, the dissolution property of component (A) can be further increased.

[0067] The layer (α2) may contain any component other than the component (A) and the component (C). Optional components include the same components as in the first embodiment.

[0068] <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 (B) component are the same as those in the first embodiment. The content of the component (A) relative to the total mass of the layer (β2) is, for example, preferably 5 mass % or less, more preferably 3 mass % or less, and even more preferably 0 mass %.

[0069] The layer (β2) may contain the component (C). When the layer (β2) contains the component (C), a decrease in the content of the component (A) in the tablet can be more effectively suppressed. The type of component (C) is the same as in the first embodiment. The content of component (C) in the tablet in this embodiment is preferably 1 to 250 mg per dose, more preferably 3 to 50 mg. The content ratio of component (C) in the tablet is preferably 0.1 to 30 mass %, more preferably 0.3 to 15 mass %. The reasons why the above content and content ratio are preferable are the same as those in the first embodiment.

[0070] In layer (β2), the lower limit of the mass ratio (C / B ratio) represented by the (C) component / (B) component is preferably 0.001 or more, more preferably 0.00375 or more, and even 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. If the C / B ratio is above the lower limit, the stability of the (A) component over time is good. If the C / B ratio is below the upper limit, the disintegration of the tablet after administration can be accelerated.

[0071] In addition, the lower limit of the C / B ratio in the tablet is preferably 0.001 or more, more preferably 0.00375 or more, and even 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. If the C / B ratio is above the lower limit, the stability of the (A) component over time is good. If the C / B ratio is below the upper limit, the disintegration of the tablet after administration can be accelerated.

[0072] The layer (β2) may contain any component other than the components (B) and (C). Optional components include the same components as in the first embodiment.

[0073] <Manufacturing method> The method for producing the tablet of this embodiment can be, for example, a production method based on a conventionally known production method. For example, the following manufacturing method can be exemplified. The powder that will be the raw material of the layer (β2) is put into the mortar of a tablet press and pre-compressed. Next, the powder that will be the raw material of the layer (α2) is put into the mortar, and the powder that will be the raw material of the layer (α2) is placed on the pre-compressed powder. Next, a pestle is inserted into the mortar to obtain a plain tablet of a two-layer tablet having a layer (β2) as a lower layer and a layer (α2) as an upper layer. Furthermore, a coating may be applied to the surface of the plain tablet as a coating agent. Also, an arbitrary layer may be provided between the layer (α2) and the layer (β2) to make a three-layer tablet. The order in which the raw materials are charged into the mortar is not particularly limited.

[0074] In the tablet of this embodiment, the components (A) and (B) are contained in different layers, and therefore the contact point between the two is limited to the boundary between the two components. Therefore, the component (A) is less susceptible to the influence of the component (B), and the decrease in the content of the component (A) is suppressed. EXAMPLES

[0075] The present invention will be described in detail below with reference to examples, but the present invention is not limited to the following description.

[0076] (Raw materials used) <Component (A)> A-1: Meloxicam (trade name: Meloxicam, manufactured by SUN Pharma).

[0077] <(B) component> B-1: Dried aluminum hydroxide gel (product name: S-100, specification: Japanese Pharmacopoeia, manufactured by Kyowa Chemical Industry Co., Ltd.). B-2: Magnesium aluminometasilicate (product name: Neusilin UFL-2, standard: extra-governmental regulation, Fuji Chemical Industry Co., Ltd.). B-3: Synthetic hydrotalcite (product name: Arcamac SN, standard: extra-official regulation, manufactured by Kyowa Chemical Industry Co., Ltd.). · B-4: Synthetic aluminum silicate (manufactured by Yoshida Pharmaceutical Co., Ltd.). B-5: Dihydroxyaluminum aminoacetic acid (product name: Glycinal, specification: extra-official regulation, manufactured by Kyowa Chemical Industry Co., Ltd.).

[0078] <(C) component> 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 (Product name: Doujin N001 2Na, manufactured by Dojindo Chemical Research Institute Co., Ltd.).

[0079] <Optional ingredients> -Crystalline cellulose (Grade: PH-302, Standard: Japanese Pharmacopoeia, manufactured by Asahi Kasei Corporation). Magnesium stearate (Standard: Japanese Pharmacopoeia, manufactured by Taihei Chemical Industry Co., Ltd.). ·Lactose hydrate (product name: Pharmatose 200M, specifications: Japan Bureau, manufactured by DMV). - Hydroxypropyl cellulose (product name: HPC-L, standard: Japanese Pharmacopoeia, manufactured by Nippon Soda Co., Ltd.).

[0080] (Evaluation method) <Survival rate> The tablets of each example were packaged in a PTP (press-through pack, blister part: VSL-4601N, manufactured by Sumitomo Bakelite Co., Ltd.), and the packaged product was stored under conditions of 55° C. and 80% RH for 6 weeks. The content (Ax) of component (A) in the tablet immediately before the start of storage and the content (Ay) of component (A) in the tablet after storage were measured, and the residual rate of component (A) was calculated using the following formula (1). The content of meloxicam was measured by UV using a spectrophotometer (UV-2700, Shimadzu Corporation) based on the quantitative method for meloxicam tablets listed in the USP.

[0081] Survival rate (mass%)=Ay÷Ax×100 (1)

[0082] (Examples 1-1 to 1-17, Comparative Examples 1-1 to 1-5) According to the blending ratios shown in Tables 1 and 2, components (A) to (C) and optional components were powder-mixed in a plastic bag to obtain 2000 g of a powder mixture. The obtained powder mixture was compressed into tablets using LIBRA2 (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets (standard R tablets) for each example, with a punch having a diameter of 8.5 mm and a hardness of 2 kgf to 30 kgf. The remaining rate of component (A) in the obtained tablets was evaluated, and the results are shown in the table.

[0083] [Table 1]

[0084] [Table 2]

[0085] As shown in Tables 1 and 2, in all of Examples 1-1 to 1-17 in which the present invention was applied, the residual ratio of component (A) was 84 mass % or more. The residual ratio of component (A) in Comparative Examples 1-1 to 1-5, which lacked component (C), was 73 mass % or less.

[0086] (Examples 2-1 to 2-4) Based on the blending ratio shown in Table 3, the raw powders of particle group (α1) (excluding hydroxypropyl cellulose) were powder-mixed in a plastic bag to obtain 3,000 g of a powder mixture. The obtained powder mixture was placed in a fluidized bed granulator (Freund Corporation, "FLO-5"), and fluidized bed granulation was carried out while spraying 4% by mass of a binding liquid (aqueous solution of hydroxypropyl cellulose). The granulation conditions were an inlet air temperature of 60°C and an inlet air volume of 2.0 m. 3 The binder liquid was sprayed so that the content of hydroxypropyl cellulose in the particle group (α1) was the value shown in the table in terms of solid matter, and the fluidized bed granulation was completed, and the particle group (α1) of each example was obtained as a granulated particle group. Next, using the same fluidized bed granulator, the supply air temperature was 70°C and the supply air volume was 1.5 m 3The particle group (α1) was dried at 10 ... The residual rate of the obtained tablets was evaluated, and the results are shown in the table.

[0087] (Comparative Example 2-1) Tablets were obtained in the same manner as in Example 2-1, except that component (A), component (B), microcrystalline cellulose, and magnesium stearate were powder-mixed to obtain a powder mixture. The remaining rate of component (A) in the obtained tablets was evaluated, and the results are shown in the table.

[0088] [Table 3]

[0089] As shown in Table 3, in Examples 2-1 to 2-4 in which the present invention was applied, the residual ratio of component (A) was 81% by mass or more in all cases. In Comparative Example 2-1 in which a powder mixture containing component (A) and component (B) that were not a group of granulated particles was compressed into tablets, the residual ratio of component (A) was 77% by mass.

[0090] (Examples 3-1 to 3-3) Based on the blending ratio shown in Table 4, the raw material powders for layer (α2) were powder-mixed in a plastic bag to obtain 3000 g of a powder mixture (α2). Also, the raw material powders for layer (β2) were powder-mixed in a plastic bag to obtain 3000 g of a powder mixture (β2). The powder mixture (α2) and the powder mixture (β2) were compressed with LIBRA2 (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets (standard R tablets) for each example, with the weight of one tablet shown in the table. The punch used for compression was φ8.5 mm, and the hardness was set to 2 kgf to 30 kgf. In addition, when compressing, the powder mixture (β2) was first put into the mortar and a temporary compression operation was performed. The remaining rate of component (A) in the obtained tablets was evaluated, and the results are shown in the table.

[0091] [Table 4]

[0092] As shown in Table 4, the residual ratio of component (A) in Examples 3-1 to 3-3 in which the present invention was applied was 97% by mass or more.

Claims

1. At least one member (A) selected from meloxicam and a pharma- ceutical acceptable salt thereof; an antacid containing aluminum (B); (C) at least one selected from organic carboxylic acids and salts thereof; A pharmaceutical formulation comprising:

2. The pharmaceutical formulation according to claim 1, wherein the mass ratio of the component (C) to the component (B) is 0.001 to 2.

5.

3. A group of particles (α1) containing at least one kind (A) selected from meloxicam and a pharma- ceutically acceptable salt thereof and substantially not containing an antacid (B) containing aluminum; and a group (β1) of particles containing the component (B) and substantially not containing the component (A), At least one of the particle group (α1) and the particle group (β1) is a group of granulated particles.

4. 4. The solid pharmaceutical formulation according to claim 3, wherein at least one of the particle group (α1) and the particle group (β1) is a group of granulated particles further containing at least one kind (C) selected from an organic carboxylic acid and a salt thereof.

5. The solid pharmaceutical formulation according to claim 4, wherein the mass ratio of the component (C) to the component (B) is 0.001 to 2.

5.

6. A layer (α2) containing at least one selected from meloxicam and a pharma- ceutically acceptable salt thereof (A) and substantially not containing an antacid containing aluminum (B); A layer (β2) containing the component (B) and substantially not containing the component (A); A tablet having the formula:

7. The tablet according to claim 6, further comprising at least one (C) selected from organic carboxylic acids and salts thereof in at least one of the layer (α2) and the layer (β2).

8. The tablet according to claim 7, wherein the mass ratio of the (C) component to the (B) component is 0.001 to 2.5.