JP7163015B2 - oral solid composition - Google Patents

Description

TECHNICAL FIELD The present invention relates to an oral solid composition, and more particularly to an oral solid composition containing a basic compound to accelerate the effect expression of naproxen.

Naproxen is a propionic acid-based non-steroidal anti-inflammatory analgesic, and has anti-inflammatory, analgesic and antipyretic effects by inhibiting the biosynthesis of prostaglandins that cause fever and inflammation. However, when naproxen is made into a solid formulation and orally administered, it is known that it takes time for the effects of antipyretic analgesia and the like to appear after taking it, because naproxen is a drug that is difficult to dissolve in water.

In order to overcome this drawback of slow onset of efficacy of naproxen in oral solid formulations, attempts have been made to accelerate the dissolution of naproxen. A technique of combining micron mannitol has been reported (Patent Document 1). However, in this technique, mannitol must be spray-dried in advance, and mannitol must be adjusted to a specific particle size as described above during spray-drying, so the manufacturing process is complicated and time-consuming. there were.

Japanese Patent Application Laid-Open No. 2003-192582

Accordingly, an object of the present invention is to provide an oral solid composition which can improve the poor solubility of naproxen by a simple means and which can be expected to exhibit a rapid effect.

The inventors of the present invention have conducted intensive research to solve the above problems, and obtained the knowledge that naproxen is rapidly dissolved in water by combining naproxen with a basic compound. It has been found that an oral solid composition with rapid effect expression can be obtained. In particular, when a basic compound containing a monovalent to trivalent metal is used as the basic compound, it has been found that rapid and sustained solubility can be obtained. In addition, the present inventors have found that an oral solid composition with good disintegration and immediate effect can be obtained by further blending a cellulose-based water-swellable polymer, even in the case of a solid preparation, and completed the present invention. .

That is, the present invention is an oral solid composition characterized by containing naproxen or a salt thereof and a basic compound.

The present invention also provides the oral solid composition, wherein the basic compound is one or more selected from basic compounds containing monovalent to trivalent metals and amine-based basic compounds.

Furthermore, the present invention is the oral solid composition further comprising a cellulosic water-swellable polymer.

INDUSTRIAL APPLICABILITY According to the oral solid composition of the present invention, naproxen can be rapidly dissolved, so that an oral solid composition having excellent immediate anti-inflammatory, analgesic and antipyretic effects can be provided. In addition, when a basic compound containing a monovalent to trivalent metal is used as the basic substance, it is possible to provide an oral solid composition excellent in rapid and sustained solubility. Furthermore, by further blending a cellulose-based water-swellable polymer, even when it is made into a solid preparation, disintegration in the oral cavity or the like upon oral ingestion is enhanced, and more rapid efficacy can be obtained.

The oral solid composition of the present invention contains naproxen or a salt thereof and a basic compound (hereinafter referred to as "the composition of the present invention").

Naproxen used in the composition of the present invention is a compound known to have anti-inflammatory, analgesic, and antipyretic effects, and its chemical name is (2S)-2-(6-methoxynaphthalen-2-yl)propanoic acid ( (2S)-2-(6-Methoxynaphthalen-2-yl)propanoic acid) _, whose molecular formula is _C14H14O3 and molecular weight is _230.26 .

Naproxen or a salt thereof used in the composition of the present invention includes free naproxen and pharmaceutically acceptable salts thereof such as sodium salt, potassium salt, ammonium salt, meglumine salt, tris salt and salts of basic amino acids. etc. As naproxen or a salt thereof used in the composition of the present invention, it is preferable to use free naproxen as it is.

The amount of naproxen or a salt thereof (hereinafter simply referred to as "naproxen") in the composition of the present invention may be appropriately determined depending on the sex, age, symptoms, etc. of the recipient. For example, it is preferable that the composition of the present invention is formulated so that the daily dosage for an adult is usually 10-1200 mg, preferably 15-600 mg, more preferably 20-400 mg. The content of naproxen relative to the total mass of the composition of the present invention is, for example, preferably 1 to 99% by mass (hereinafter referred to as "%"), more preferably 5 to 95%.

On the other hand, examples of the basic compound used in the composition of the present invention include basic compounds containing monovalent to trivalent metals, amine-based basic compounds, and the like. Basic compounds containing monovalent to trivalent metals are not particularly limited, but examples include potassium hydrogen carbonate, sodium hydrogen carbonate, calcium silicate, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium carbonate, magnesium hydroxide, Magnesium oxide, magnesium silicate, synthetic hydrotalcite, magnesium aluminometasilicate, synthetic aluminum silicate, dried aluminum hydroxide gel, aluminum hydroxide gel, aluminum hydroxide-sodium bicarbonate coprecipitate, aluminum hydroxide-carbonic acid Basic inorganic compounds containing monovalent to trivalent metals such as magnesium mixed dried gel, aluminum hydroxide/magnesium carbonate/calcium carbonate coprecipitate, magnesium hydroxide/aluminum potassium sulfate coprecipitate, sodium citrate, Basic organic compounds containing monovalent to trivalent metals such as aldioxa, sucralfate, and dihydroxyaluminum aminoacetate can be mentioned.

The amine-based basic compound is not particularly limited, and examples thereof include glycinal and arginine.

The basic compound in the composition of the present invention can be used singly or in combination of two or more kinds, and preferable examples thereof include potassium hydrogen carbonate, sodium hydrogen carbonate, calcium silicate, precipitated calcium carbonate, Anhydrous calcium hydrogen phosphate, magnesium carbonate, magnesium hydroxide, magnesium oxide, magnesium silicate, synthetic hydrotalcite, magnesium aluminometasilicate, synthetic aluminum silicate, dry aluminum hydroxide gel, aluminum hydroxide gel, sodium citrate , aldioxa, and basic compounds containing monovalent to trivalent metals such as sucralfate. Rapid and sustained solubility can be obtained by using a basic compound containing a monovalent to trivalent metal.

The content ratio of naproxen and the basic compound in the composition of the present invention is not particularly limited, and may be determined according to the blending amount of naproxen. 001 to 100 parts by mass, more preferably 0.01 to 50 parts by mass, and even more preferably 0.1 to 30 parts by mass.

Moreover, it is desirable that the composition of the present invention further contains a cellulose-based water-swellable polymer. By blending the cellulose-based water-swellable polymer, the disintegration property in the oral cavity or the like when orally administered is improved, and the solubility of naproxen can be further increased.

Examples of the cellulose-based water-swellable polymer include low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, crystalline cellulose, pregelatinized starch, sodium carboxymethylstarch, and the like. be done. Among these, low-substituted hydroxypropyl cellulose is preferred.

When low-substituted hydroxypropyl cellulose is used as the cellulosic water-swellable polymer, the hydroxypropoxy group content is 5.0 to 16.0 from the standpoint of ease of processing into an oral solid composition with excellent shape and particle size. It is preferably 0% by mass, more preferably 7.0 to 13.0% by mass. Examples of such low-substituted hydroxypropyl cellulose include LH-11 (10.0 to 12.9% by mass of hydroxypropoxy groups) and LH-21 (10.0 to 12% by mass of hydroxypropoxy groups) manufactured by Shin-Etsu Chemical Co., Ltd. .9% by mass) LH-22 (7.0 to 9.9% by mass of hydroxypropoxy group) LH-31 (10.0 to 12.9% by mass of hydroxypropoxy group), LH-32 (7.0% by mass of hydroxypropoxy group ~9.9% by mass), LH-B1 (hydroxypropoxy group 10.0 to 12.9% by mass), NBD-020 (hydroxypropoxy group 13.0 to 15.9% by mass), NBD-021 (hydroxypropoxy 10.0 to 12.9% by mass of groups) and NBD-022 (7.0 to 9.9% by mass of hydroxypropoxy groups). Furthermore, the average particle size of the low-substituted hydroxypropyl cellulose is preferably about 60 µm or less, more preferably 55 µm or less.

In the composition of the present invention, the blending amount of the cellulose-based water-swellable polymer is not particularly limited.

In addition to the above ingredients, the composition of the present invention may include other active pharmaceutical ingredients, such as anti-inflammatory/antipyretic analgesics other than naproxen, antihistamines, antiallergics, antitussive expectorants, central nervous system stimulants, Vitamins, crude drugs, etc. may be added.

Examples of anti-inflammatory/antipyretic analgesics other than naproxen include aspirin, aspirin aluminum, acetaminophen, ethenzamide, sazapyrin, salicylamide, loxoprofen, lactylphenetidine, isopropylantipyrine, glycyrrhizin, ammonium glycyrrhizinate, potassium glycyrrhizinate, Examples thereof include glycyrrhizic acid such as dipotassium glycyrrhizinate, analogues thereof or salts thereof, and tranexamic acid. These may use 1 type(s) or 2 or more types.

Examples of antihistamines and antiallergic agents include azelastine hydrochloride, alimemazine tartrate, isothipendyl hydrochloride, iproheptine hydrochloride, epinastine hydrochloride, ebastine, emedastine fumarate, oxatomide, and carbinoxamin diphenyl. Disulfonate, carpinoxamine maleate, clemastine fumarate, chlorpheniramine maleate, d-chlorpheniramine maleate, difererol hydrochloride, difererol phosphate, carbinoxamine diphenyldisulfonate, diphenylpyraline hydrochloride, diphenylpyraline teocrate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, cetirizine hydrochloride, triprolidine hydrochloride hydrate, tripelennamine hydrochloride, tonjilamine hydrochloride, fexofenadine, phenetazine hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, bepotastine besilate, homochlorcyclidine hydrochloride, mequitazine, methdilazine hydrochloride, mebhydroline napadisilate, levocetirizine hydrochloride and the like. These may use 1 type(s) or 2 or more types.

Furthermore, the above antitussive expectorants include ambroxol hydrochloride, aloclamide hydrochloride, tipepidine citrate, cloperastine hydrochloride, cloperastine fendizoate, codeine phosphate hydrate, dihydrocodeine phosphate hydrate, dibunate Sodium, Tipepidine Hibenzate, Dextromethorphan Hydrobromide, Dextromethorphan Phenolphthalate, Pentoxyberic Citrate, Dimemorphan Phosphate, Noscapine, Noscapine Hydrochloride Hydrate, dl-Methyl Ephedrine hydrochloride, dl-methylephedrine saccharin salt, guaifenesin, potassium guaiacol sulfonate, potassium cresol sulfonate, bromhexine hydrochloride, L-carbocysteine, L-ethylcysteine hydrochloride, belladonna total alkaloids, isopropamide iodide, eprazinone hydrochloride, etc. is mentioned. These may use 1 type(s) or 2 or more types.

Furthermore, the central nervous system stimulants include sodium caffeine benzoate, anhydrous caffeine, and caffeine hydrate. These may be added singly or in combination of two or more.

Examples of the vitamins include vitamin _B1 and derivatives thereof and salts thereof, vitamin B2 and derivatives thereof and salts thereof, vitamin _C and derivatives thereof and salts thereof, hesperidin and derivatives thereof and salts thereof, and the like. In addition, the above crude drugs include, for example, Ephedra, Nantenjitsu, Touhi, Onji, Glycyrrhiza, Bellflower, Shazenshii, Shazensou, Sekisan, Senega, Fritillaria, Fennel, Phellodendron bark, Japanese coptis, Kajutsu, Chamomile, Cinnamon, Gentian, Chinese gourd, beast Bile, Shajin, Ginger, Sojutsu, Clove, Chimpi, Byakujutsu, Jiryu, Chikusetsu Ginseng, Ginseng, Kakkonto, Kakkonto Kakikyo, Keishito, Kososan, Saikokeishito, Shosaikoto, Shoseiryuto , Bakumondoto, Hangekobokuto, and Maoto. These may be added singly or in combination of two or more.

In addition, the composition of the present invention may optionally contain formulation additives that can be contained in ordinary oral solid compositions.

Formulation additives include commonly used excipients, binders, disintegrants, and lubricants, as well as various carriers, stabilizers, surfactants, plasticizers, lubricants, and softeners. Solubilizing agent, reducing agent, buffering agent, sweetening agent, base, adsorbent, flavoring agent, suspending agent, antioxidant, brightening agent, coating agent, shell, wetting agent, moisture control agent, filler, antifoaming agent, cooling agent, coloring agent, flavoring agent, fragrance, sugar coating agent, tonicity agent, softening agent, emulsifier, thickening agent, thickening agent, foaming agent, pH adjuster , diluents, dispersants, disintegration aids, disintegration extenders, fragrances, moisture-proof agents, preservatives, preservatives, fluidizers, antistatic agents, bulking agents, moisturizing agents, wetting agents, etc. . Examples of these additives include the PFSB Notification No. 1204 No. 1 (Pharmaceutical Affairs Administrative Law), Pharmaceutical Excipients Dictionary 2007 (edited by the Japan Pharmaceutical Excipients Association, Yakuji Nippo), and the 8th Edition Food Additives Official Code (Japan Food Additives Association).

Excipients among the pharmaceutical additives include, for example, lactose, sugar alcohols, light anhydrous silicic acid, and titanium oxide. One or more of these excipients can be used.

Examples of the binder include gelatin, gum arabic powder, hypromellose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, polyvinyl alcohol/polyethylene glycol/graft copolymer, pullulan, dextrin, and methacrylic acid. Examples thereof include acrylic acid derivatives such as copolymers, shellac, and carboxyvinyl polymers. One or more of these binders can be used.

Examples of disintegrants include crospovidone, cross-linked insoluble polyvinylpyrrolidone, and the like. One or more of these disintegrants can be used.

Examples of the lubricant include talc, stearic acid, magnesium stearate, sucrose fatty acid esters, polyethylene glycol and the like. One or more of these lubricants can be used.

The composition of the present invention can be prepared by blending naproxen and a basic compound, or these and a cellulose-based water-swellable polymer with other active pharmaceutical ingredients and formulation additives according to a conventional method, if necessary. It is prepared by making a formulation. Examples of this solid preparation include internal solid preparations such as powder preparations, granules, and tablets. It can also be used as a formulation or the like.

In the production of the composition of the present invention, as a method of mixing each component, for example, a mortar, a mechanomill (MM-20N type, manufactured by Okada Seiko Co., Ltd.), a high-speed stirring granulator (manufactured by Powrex Co., Ltd.), or the like is used. and mixing method. The mixing conditions are not particularly limited as long as they can be uniformly mixed, and can be appropriately selected according to the types and amounts of the components used for mixing.

In addition, the composition of the present invention can be further kneaded and granulated by adding a kneading liquid to the above mixed powder. The amount of the kneading liquid added at this time is preferably about 0.05 to 10 times the mass of the mixed powder. Purified water, ethanol, or the like can be used as the kneading liquid, and among these, purified water is preferable. Equipment used for kneading includes, for example, a mortar, a mechanomill (MM-20N type, manufactured by Okada Seiko Co., Ltd.), a high-speed stirring granulator (manufactured by Powrex Co., Ltd.), and the like. The kneading conditions are not particularly limited as long as uniform kneading can be achieved, and can be appropriately selected depending on the types and amounts of the components used for kneading.

Furthermore, granulation is carried out by using an extrusion granulator such as a cylindrical granulator, a rotary granulator, a screw extrusion granulator, a pellet mill type granulator, etc. be able to. The obtained granules can be dried as they are or after being spheroidized by a spheronizer such as Marumerizer (manufactured by Fuji Paudal Co., Ltd.). As the apparatus used for drying, for example, a box type dryer (manufactured by Espec Co., Ltd.), a fluidized bed dryer (manufactured by Freund Sangyo Co., Ltd.) or the like is used, and drying is preferably performed under conditions of 40 to 90 ° C. . As a guideline for completing the drying, for example, an infrared moisture meter FD-800 (manufactured by Ketsuto Kagaku Kenkyusho Co., Ltd.) may be used to dry until the moisture content reaches 2% or less. After drying the granules, if necessary, the granules may be sized using a stainless screen or the like.

Since naproxen is rapidly dissolved in the composition of the present invention thus obtained, the effect of naproxen appears immediately after administration of naproxen. Therefore, the composition of the present invention can be used, for example, as an antipyretic, an analgesic, an anti-inflammatory agent, and particularly for applications where rapid anti-inflammatory and analgesic effects of naproxen are required.

EXAMPLES Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1
Solubility test:
Powder formulation (1)
1 g of naproxen and 1 g of the basic substance listed in Table 1 were mixed in a mortar to prepare a powder formulation. The dissolution rate of naproxen in the resulting powder formulation was measured by the following dissolution test method. The dissolution rate was also measured for naproxen having the same particle size as a comparative product. These results are shown in Table 1 together.

From the above results, it was confirmed that naproxen dissolved faster in the combination of naproxen and the basic substance listed in Table 1 than in naproxen alone (comparative product). It was also confirmed that when magnesium carbonate or magnesium oxide was used as the basic substance, the elution rate of naproxen after 30 minutes was extremely high.

<Elution test method>
According to Japanese Pharmacopoeia Dissolution Test Method 2, each powder formulation containing 20 mg of naproxen was added to 900 mL of purified water, and a dissolution test was performed under the conditions of a paddle rotation speed of 50 rpm and a temperature of 37±0.5°C. The elution amount of naproxen was measured by liquid chromatography, and the elution rate was calculated from this elution amount.

Example 2
Solubility test:
Powder formulation (2)
15 g of naproxen, 15 g of the basic substance listed in Table 2, and 15 g of low-substituted hydroxypropyl cellulose (11.1% by mass of hydroxypropoxy group; manufactured by Shin-Etsu Chemical Co., Ltd.; the same applies hereinafter) were added to Mechanomil (MM-20N type, manufactured by Okada Seiko Co., Ltd.), and mixed for 3 minutes at a spindle rotation speed of 900 rpm to produce a powder formulation. The dissolution rate of this powder formulation was measured by the same method as above. As a comparative product, the same naproxen powder as in Example 1 was used. The results are also shown in Table 2.

From the above results, when calcium silicate is used when low-substituted hydroxypropyl cellulose is blended, the elution rate of naproxen after 30 minutes is higher than when low-substituted hydroxypropyl cellulose of Example 1 is not blended. was confirmed. It was also confirmed that when magnesium oxide and magnesium carbonate were used, the dissolution rate of naproxen after 5 minutes was extremely high.

Example 3
Solubility test:
Granules (1)
14.0 g of naproxen, 14.0 g of the basic substances listed in Table 3, and 14.0 g of low-substituted hydroxypropyl cellulose were treated with Mechanomill (MM-20N type, manufactured by Okada Seiko Co., Ltd.) at a spindle speed of 900 rpm for 3 Mix for a minute. To this mixed powder, 56 g of purified water was added as a kneading liquid, and the mixture was kneaded for 3 minutes with a Mechanomill at a spindle speed of 900 rpm. After extruding this kneaded product with a stainless screen, it was dried with a box dryer (manufactured by Espec Co., Ltd.) until the moisture content was 2% or less to obtain a granulated product (the moisture content of the granulated product was measured by infrared Measured with a moisture meter FD-800 (manufactured by Kett Science Laboratory Co., Ltd., 60° C., 10 minutes; hereinafter the same).

The resulting granules are sieved through a 26-mesh stainless screen, and the granules that have passed through it are further sieved through a 150-mesh stainless screen. A 600 μm sized granule was obtained. The dissolution rate of the sized granules was measured by the same method as above. The results are also shown in Table 3.

From the above results, in the case of granule preparation, when potassium hydrogen carbonate or sodium hydrogen carbonate is used as a basic substance, the dissolution rate after 5 minutes is extremely high, and the dissolution rate is also high after 15 minutes and 30 minutes. confirmed to be maintained.

Example 4
Film-coated tablet (1):
According to the formulation shown in Table 4, each weighed component was put into a high-speed stirring granulator (VG-10 type, manufactured by Powrex) and mixed for 3 minutes. Next, an appropriate amount of purified water was added to each of the mixed powders corresponding to Formulations 1 to 5, and the mixture was kneaded for 3 minutes with a high-speed stirring granulator (VG-10 type, manufactured by Powrex Corporation). Next, the kneaded product was granulated using an extrusion granulator (Model TDG-80, manufactured by Dalton). Further, the obtained extruded granules are put into a fluidized bed dryer (FLO-2 type, manufactured by Freund Corporation), dried until the water content in the granules becomes 2% or less, and then comiled to align. Granulation was performed to obtain granules.

Next, 140 g of crystalline cellulose and 10 g of magnesium stearate were added to 900 g of each of the obtained granules and mixed with a V-type mixer (TCV-5 type, manufactured by Tokuju Kosakusho Co., Ltd.) to obtain 1050 g of tableting powder. . Next, tableting was performed using a rotary tableting machine (Model VIRG0512, manufactured by Kikusui Seisakusho) to produce uncoated tablets with a naproxen content of 100 mg, a diameter of 9.5 mm and a tablet weight of 350 mg.

Next, after dissolving 120 g of hypromellose and 20 g of polyethylene glycol in purified water, 10 g of talc and 10 g of titanium oxide were dispersed to prepare 2000 g of a film coating liquid having a solid concentration of 8%. Then, 500 g of the uncoated tablet was put into a coating machine (HC-LABO type, manufactured by Freund Corporation) and coated by spraying the prepared film coating liquid to obtain a white film-coated tablet with a tablet weight of 360 mg.

Example 5
Film-coated tablet (2):
According to the formulation shown in Table 5, each weighed component was put into a high-speed stirring granulator (VG-10 type, manufactured by Powrex) and mixed for 3 minutes. Next, an appropriate amount of purified water was added to each of the mixed powders corresponding to Formulations 6 to 10, and kneaded and granulated for 3 minutes with a high-speed stirring granulator (VG-10 type, manufactured by Powrex). Next, the obtained granules are put into a fluidized bed dryer (FLO-2 type, manufactured by Freund Corporation) and dried until the water content is 2% or less, and then sieved with a combil to obtain granules. got

Next, 140 g of crystalline cellulose and 10 g of magnesium stearate were added to 900 g of each of the obtained granules and mixed with a V-type mixer (TCV-5 type, manufactured by Tokuju Kosakusho Co., Ltd.) to obtain 1050 g of tableting powder. . Next, tableting was performed using a rotary tableting machine (Model VIRG0512, manufactured by Kikusui Seisakusho) to produce uncoated tablets with a naproxen content of 100 mg, a diameter of 9.5 mm and a tablet weight of 350 mg.

Next, after dissolving 120 g of hypromellose and 20 g of polyethylene glycol in purified water, 10 g of talc and 10 g of titanium oxide were dispersed to prepare 2000 g of a film coating liquid having a solid concentration of 8%. Then, 500 g of the uncoated tablet was put into a coating machine (HC-LABO type, manufactured by Freund Corporation) and coated by spraying the prepared film coating liquid to obtain a white film-coated tablet with a tablet weight of 360 mg.

Example 6
Granules (2):
According to the formulation shown in Table 6, each weighed component was put into a high-speed stirring granulator (VG-10 type, manufactured by Powrex) and mixed for 3 minutes. Next, an appropriate amount of purified water was added to each of the mixed powders corresponding to Formulations 11 to 15, and the mixture was kneaded for 3 minutes with a high-speed stirring granulator (VG-10 model, manufactured by Powrex Corporation). Next, the kneaded product was granulated using an extrusion granulator (Model TDG-80, manufactured by Dalton). Further, the obtained extruded granules are put into a fluidized bed dryer (FLO-2 type, manufactured by Freund Corporation), dried until the water content in the granules becomes 2% or less, and then comiled to align. Granulation was performed to obtain granules.

Next, 10 g of aspartame, 10 g of acesulfame potassium, and 4 g of magnesium stearate were added to 800 g of each of the obtained granules, and mixed with a V-type mixer (TCV-5 type, manufactured by Tokuju Kosakusho Co., Ltd.) to obtain granule powder for filling. 824 g was obtained. Next, aluminum heat-seal packaging was performed to obtain granules with a naproxen content of 100 mg and a packaging weight of 1236 mg.

Example 7
Granules (3):
According to the formulation shown in Table 7, each weighed component was added to a high-speed stirring granulator (VG-10 type, manufactured by Powrex) and mixed for 3 minutes. Next, an appropriate amount of purified water was added to each of the mixed powders corresponding to Formulations 16 to 20, and the mixture was kneaded for 3 minutes with a high-speed stirring granulator (VG-10 type, manufactured by Powrex Corporation). Next, the obtained kneaded granules are put into a fluidized bed dryer (FLO-2 type, manufactured by Freund Corporation) and dried until the water content in the granules becomes 2% or less. The granules were obtained by sizing.

Next, 10 g of aspartame, 10 g of acesulfame potassium, and 4 g of magnesium stearate were added to 800 g of each of the obtained granules, and mixed with a V-type mixer (TCV-5 type, manufactured by Tokuju Kosakusho Co., Ltd.) to obtain granule powder for filling. 824 g was obtained. Next, aluminum heat-seal packaging was performed to obtain granules with a naproxen content of 100 mg and a packaging weight of 1236 mg.

Example 8
Hard capsule (1):
According to the formulation shown in Table 8, each weighed component was put into a high-speed stirring granulator (VG-10 type, manufactured by Powrex) and mixed for 3 minutes. Next, an appropriate amount of purified water was added to each of the mixed powders corresponding to Formulations 21 to 26, and the mixture was kneaded for 3 minutes with a high-speed stirring granulator (VG-10 model, manufactured by Powrex Corporation). Next, the kneaded product was granulated using an extrusion granulator (Model TDG-80, manufactured by Dalton). Further, the obtained extruded granules are put into a fluidized bed dryer (FLO-2 type, manufactured by Freund Corporation), dried until the water content in the granules becomes 2% or less, and then comiled to align. Granulation was performed to obtain granules.

Next, 840 g of each granule obtained was added with 8.4 g of magnesium stearate and mixed with a V-type mixer (Type TCV-5, manufactured by Tokuju Kosakusho Co., Ltd.) to obtain 848.4 g of granule powder for filling. rice field. Next, No. 1 gelatin capsules were filled using a capsule filling machine (Liqufil-5 type, manufactured by Qualicaps) to obtain hard capsules containing 100 mg of naproxen and 303 mg of substance per capsule.

Example 9
Hard capsule (2):
According to the formulation shown in Table 9, each weighed component was put into a high-speed stirring granulator (VG-10 type, manufactured by Powrex) and mixed for 3 minutes. Next, an appropriate amount of purified water was added to each of the mixed powders corresponding to formulations 27 to 32, and the mixture was kneaded for 3 minutes with a high-speed stirring granulator (VG-10 model, manufactured by Powrex Corporation). Next, the obtained kneaded granules are put into a fluidized bed dryer (FLO-2 type, manufactured by Freund Corporation) and dried until the water content in the granules becomes 2% or less. The granules were obtained by sizing.

Next, 840 g of each granule obtained was added with 8.4 g of magnesium stearate and mixed with a V-type mixer (Type TCV-5, manufactured by Tokuju Kosakusho Co., Ltd.) to obtain 848.4 g of granule powder for filling. rice field. Next, No. 1 gelatin capsules were filled using a capsule filling machine (Liqufil-5 type, manufactured by Qualicaps) to obtain hard capsules containing 100 mg of naproxen and 303 mg of substance per capsule.

Example 10
Granules (4)
15.0 g of naproxen, 15.0 g of sodium bicarbonate, and 15.0 g of various water-swellable polymers shown in Table 10 are placed in Mechanomill (MM-20N type, manufactured by Okada Seiko Co., Ltd.) and mixed for 3 minutes at a spindle speed of 900 rpm. did. To this mixed powder, 60 g of purified water was added as a kneading liquid, and the mixture was kneaded for 3 minutes with a Mechanomill at a spindle speed of 900 rpm. This kneaded material was extruded through a stainless screen, and then dried with a box-type dryer (manufactured by Espec Co., Ltd.) until the moisture content became 2% or less to obtain a granulated material.

The resulting granules are sieved through a 26-mesh stainless screen, and the granules that have passed through it are further sieved through a 150-mesh stainless screen. A 600 μm sized granule was obtained. The sieved granules were measured for dissolution rate up to 30 minutes by the following method. Table 11 shows the results.

< Elution test >
According to Japanese Pharmacopoeia Dissolution Test Method 2, put each granule preparation containing 100 mg of naproxen in 900 mL of pH 4.0 buffer, and dissolve under the conditions of paddle rotation speed of 50 rpm and temperature of 37.0 ± 0.5°C. did the test. The elution amount of naproxen was measured by liquid chromatography, and the elution rate was calculated from this elution amount.

Example 11
Granules (5):
15.0 g of naproxen, the amounts of sodium hydrogencarbonate and low-substituted hydroxypropyl cellulose shown in Table 12 were placed in Mechanomill (Model MM-20N, manufactured by Okada Seiko Co., Ltd.) and mixed at a spindle speed of 900 rpm for 3 minutes. To this mixed powder, 50 to 60 g of purified water was added as a kneading liquid, and the mixture was kneaded for 3 minutes with a Mechanomill at a spindle speed of 900 rpm.

This kneaded material was extruded through a stainless screen, and then dried with a box-type dryer (manufactured by Espec Co., Ltd.) until the moisture content became 2% or less to obtain a granulated material. The resulting granules are sieved through a 26-mesh stainless screen, and the granules that have passed through it are further sieved through a 150-mesh stainless screen. A 600 μm sized granule was obtained. About this sized granule, the dissolution rate up to 30 minutes was measured by the dissolution test of Example 12. The results are shown in Table 13.

Example 12
Film-coated tablets:
According to a conventional method, granules were obtained using the ingredients described in the granule section in Table 14 and an appropriate amount of purified water. Next, the compounding ingredients described in the tablet addition section were added to the granules, and tablets of 360 mg per tablet were compressed according to a conventional method.

On the other hand, each solid component described in the coating part of Table 14 was dispersed/suspended in an appropriate amount of purified water to prepare a coating liquid. Using this coating liquid, the uncoated tablets were coated according to a conventional method and dried to obtain a film coating agent of 370 mg per tablet.

The obtained film coating agent (containing 100 mg of naproxen) was placed in 900 ml of pH 4.0 buffer solution, and a solubility test was conducted according to Method 2 of Dissolution Test Method of Japanese Pharmacopoeia (37° C., 50 rpm). As a control, the same amount of naproxen bulk powder was used. The results are shown in Table 15.

The composition of the present invention uses a combination of naproxen and a basic compound to improve the sparing solubility of naproxen. Furthermore, when a cellulose-based water-swellable polymer is added to this, the disintegration of the formulation can also be enhanced. Therefore, the present invention can provide an oral solid composition having immediate anti-inflammatory, antipyretic, and analgesic effects, and can be widely used in the field of pharmaceuticals.

Claims (6)

An oral solid composition comprising naproxen, a basic compound and a cellulosic water-swellable polymer,
The basic compound is at least one selected from the group consisting of potassium hydrogen carbonate, sodium hydrogen carbonate, sodium citrate, calcium silicate, magnesium carbonate, magnesium hydroxide, magnesium oxide, synthetic aluminum silicate and dry aluminum hydroxide gel. be,
An oral solid composition, excluding those containing thaumatin or arginine, characterized in that: 2. The oral solid composition according to claim 1, wherein the blending ratio of naproxen and basic compound is 0.001 to 100 parts of basic compound per 1 part by mass of naproxen. 3. The oral solid composition according to claim 1, which contains 1 to 99% by mass of the cellulose-based water-swellable polymer. The cellulosic water-swellable polymer was selected from the group consisting of low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, microcrystalline cellulose, pregelatinized starch and sodium carboxymethylstarch. 4. The oral solid composition according to any one of claims 1 to 3, which is one or more. The oral solid composition according to any one of claims 1 to 4, which is a powder formulation, granules or tablets. The oral solid composition according to any one of claims 1 to 5, which is an antipyretic, analgesic or antiphlogistic.