JP4742679B2 - Composition for solid preparation - Google Patents

Description

  The present invention relates to a composition for solid preparations containing pranlukast hydrate, water-soluble celluloses and saccharides.

  Pranlukast hydrate is known as a leukotriene (LT) antagonist (see Patent Document 1) and is marketed as a therapeutic agent for bronchial asthma and allergic rhinitis. In order for pranlukast hydrate to exhibit an effective therapeutic effect for bronchial asthma and allergic rhinitis, it requires a very high dose. It is required to take 4 capsules. Taking such a relatively large No. 3 capsule two capsules at a time can be problematic for patients who have difficulty swallowing, especially children and elderly patients, and is not a preferred dosage form. Therefore, it has been desired to reduce the size of the preparation in order to improve patient compliance. However, since pranlukast hydrate has very strong adhesiveness, it is difficult to produce a solid preparation suitable for taking by ordinary methods, and in order to produce a small preparation that solves various problems. Requires special formulation methods. For example, as a method for reducing adhesion, a method for reducing adhesion by spray-drying pranlukast hydrate together with sugars is known (see Patent Document 2). However, this method has problems in the preparation process, the quality of the obtained preparation (elution stability, disintegration, uneven color of tablets, etc.), and the production of a high content solid preparation.

JP-A-61-050977 Japanese Patent No. 2958863

  Accordingly, an object of the present invention is to provide a novel composition for solid preparations containing pranlukast hydrate that can be made into a small preparation with improved patient compliance.

  In view of the above problems, the present inventors have conducted intensive studies, and as a result, polyethylene glycol, which is an additive (binder) contained in a capsule (trade name: onon capsule) containing the current pranlukast hydrate. Surprisingly, by changing the water content to water-soluble celluloses (for example, hydroxypropylmethylcellulose, etc.) It has been found that a granulated product can be produced and the resulting solid preparation can be miniaturized. Furthermore, by using the obtained granulated material, a solid preparation having a high content of pranlukast hydrate was also successfully obtained. In the solid preparation (particularly tablet) thus obtained, it has been found that the dissolution rate is improved and the dissolution stability over time is improved, and the tableting moldability and the disintegration rate are also improved. The present invention has been completed.

The resulting solid preparations (especially tablets) are found to be extremely useful for providing pharmaceutical products with excellent in vivo absorption and stability over time, without adhesion between tablets and uneven color. It was done. That is, the present invention provides (1) a composition for solid preparations characterized by containing pranlukast hydrate, sugars and water-soluble celluloses,
(2) The composition according to item (1), wherein the water-soluble cellulose is hydroxypropylmethylcellulose;
(3) The composition according to item (2), which is a spray-dried granulated product,
(4) The composition according to item (2), wherein the pranlukast hydrate is 0.70 to 0.98 parts by weight with respect to 1 part by weight of the composition;
(5) The composition according to item (4), wherein the pranlukast hydrate is 0.75 to 0.87 parts by weight,
(6) As described in (2) above, 0.05 to 0.30 parts by weight of saccharide and 0.002 to 0.050 parts by weight of hydroxypropylmethylcellulose with respect to 1 part by weight of pranlukast hydrate Composition,
(7) A tablet containing the composition according to (2) above,
(8) a capsule containing the composition according to item (2),
(9) The tablet according to the above item (7), containing 112.5 mg of pranlukast hydrate in one tablet,
(10) The tablet according to the above item (7), containing 225 mg of pranlukast hydrate in one tablet,
(11) The tablet according to item (7), wherein the pranlukast hydrate is 0.50 to 0.90 parts by weight with respect to 1 part by weight of one tablet,
(12) The tablet according to the above (11), wherein the pranlukast hydrate is 0.55 to 0.70 parts by weight,
(13) The tablet according to (9) above, wherein the volume of one tablet is 100 to 175 mm ³ ;
(14) The tablet according to item (10), wherein the volume of one tablet is 200 to 350 mm ³ ;
(15) The tablet according to the above (9), wherein the weight of one tablet is 125 to 225 mg,
(16) The tablet according to the above (10), wherein the weight of one tablet is 250 to 450 mg,
(17) The tablet according to (9) above, which is a circular tablet having a diameter of 7 to 8 mm and a thickness of 2 to 4 mm,
(18) The tablet according to the above item (10), which is a caplet tablet having a major axis of 13 to 14 mm, a minor axis of 6 to 7 mm, and a thickness of 4 to 5 mm;
(19) The capsule according to (8) above, wherein 225 mg of pranlukast hydrate is contained in one capsule.
(20) The capsule according to the above item (8), wherein the pranlukast hydrate is 0.50 to 0.90 parts by weight per 1 part by weight of the capsule,
(21) The capsule according to the above (20), wherein the capsule is No. 2 capsule or No. 3 capsule;
(22) A spray-dried granulated product containing 0.20 to 0.25 parts by weight of saccharide and 0.004 to 0.009 parts by weight of hydroxypropylmethylcellulose with respect to 1 part by weight of pranlukast hydrate. A tablet containing 112.5 mg or 225 mg of pranlukast hydrate in one tablet, and 0.5 to 0.70 wt.% Of pranlukast hydrate per 1 part by weight of one tablet Pranlukast hydrate high content tablets, characterized in that
(23) A composition for solid preparation, comprising pranlukast hydrate and water-soluble celluloses,
(24) The tablet according to item (7), which is sealed and packaged,
(25) The capsule according to the above item (7), which is sealed and packaged,
(26) A composition for producing a high-content solid preparation with reduced adhesion cohesiveness, comprising pranlukast hydrate, saccharides and water-soluble celluloses,
(27) The composition according to item (26), wherein the water-soluble cellulose is hydroxypropylmethylcellulose;
(28) The composition according to item (27), which is a spray-dried granulated product,
(29) 1 part by weight of pranlukast hydrate is 0.05 to 0.30 part by weight of saccharide and 0.002 to 0.050 part by weight of hydroxypropylmethylcellulose, and 1 part by weight of the composition In contrast, pranlukast hydrate high content composition with reduced adhesion, characterized in that pranlukast hydrate is 0.75 to 0.87 parts by weight,
(30) A tablet comprising the composition described in (28) above,
(31) A capsule comprising the composition described in (28) above,
(32) A method for producing a high-content preparation containing pranlukast hydrate, characterized by using hydroxypropylmethylcellulose;
(33) A method for increasing the content of a preparation containing pranlukast hydrate, characterized by using hydroxypropylmethylcellulose;
(34) A method for reducing the adhesion and cohesiveness of a granulated product containing pranlukast hydrate characterized by using hydroxypropylmethylcellulose and (35) pranlukast water characterized by using hydroxypropylmethylcellulose The present invention relates to a method for producing a small solid preparation comprising a granulated product containing a Japanese product.

  The pranlukast hydrate used in the present invention has the formula (A)

4-oxo-8- [4- (4-phenylbutoxy) benzoylamino] -2- (tetrazol-5-yl) -4H-1-benzopyran 1/2 hydrate represented by formula (1). The production of pranlukast hydrate can be carried out, for example, according to the method described in JP-A 61-050977.

  The water-soluble celluloses used in the present invention are those in which hydrogen bonds are lost by substituting some of the hydrogen atoms of the hydroxyl groups of cellulose with methyl groups, ethyl groups, propyl groups, hydroxypropyl groups or hydroxyethyl groups. Water-soluble polymer. For example, hydroxymethylcellulose, hydroxymethylethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS) and the like can be mentioned. . Any water-soluble cellulose is preferable, but hydroxypropylmethylcellulose is particularly preferable.

The methoxy group content of hydroxypropylmethylcellulose used in the present invention is preferably about 19 to 30% by weight, the hydroxypropoxy group content is preferably about 4 to 12% by weight, and the viscosity is preferably about 2.5 to 17.5 mm ² / s. Examples of hydroxypropylmethylcellulose that can be suitably used include hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose 2910, hydroxypropylmethylcellulose 2208, and the like. Kogyo Co., Ltd.), Methocel K, Methocel E (Dow Chemical Co., Ltd.), Marporose (Matsumoto Yushi Seiyaku Co., Ltd.) and the like. Examples of Tc-5 include Tc-5E, Tc-5Ew, Tc-5R, Tc-5Rw, Tc-5Mw, Tc-5S, and the like.

  Examples of the saccharide in the present invention include glucose, fructose, maltose, lactose, isomerized lactose, reduced lactose, sucrose, D-mannitol, erythritol, maltitol, xylitol, palatinose, trehalose, sorbitol, corn starch, potato starch, wheat Starch, rice starch and the like can be mentioned, and lactose is preferable.

  In the present invention, the composition for solid preparation represents a granulated product for producing tablets and / or capsules containing a high content of pranlukast hydrate, in other words, “high content solid preparation” “Composition for manufacture”.

  Moreover, the composition for solid preparation of the present invention may further contain an additive (formulation base) generally used in producing a solid preparation, for example, an excipient, a binder, One or two types of lubricants, disintegrating agents, flavoring agents, flavoring agents, surfactants, fragrances, coloring agents, antioxidants, masking agents, antistatic agents, fluidizing agents, wetting agents, elution aids, etc. As described above, they can be appropriately blended and used.

  The composition for solid preparation of the present invention is used, for example, as a solid preparation such as powder, granule, tablet, capsule or the like, or dissolved / suspended at the time of taking the solid preparation as a solution or suspension at the time of taking It can be used as a preparation (for example, dry syrup). Preferable preparation forms include tablets or capsules.

  Methods for formulating the composition for solid preparations of the present invention are known, for example, pranlukast hydrate, water-soluble celluloses (for example, hydroxypropylmethylcellulose, etc.), saccharides, and other additives as required Or a known granulation method (for example, extrusion granulation method, mixed stirring granulation method, high speed mixed stirring granulation method, fluidized bed granulation method, tumbling stirred fluidized bed granulation method, rolling rolling Granulate, dry (compressed) granulation, crushing granulation, spray-drying granulation, etc.) Can be manufactured. Moreover, a tablet and a capsule can be manufactured by adding the granule, powder, or granule obtained previously and other additives as needed, and tableting or capsule-filling. Moreover, a tablet may be coat | covered using the film coating base which is accept | permitted pharmacologically as needed and does not prevent the effect of this invention.

  Any additive (carrier) may be added as long as the effects of the present invention are not disturbed or the effects of the present invention are minimized.

  Other additives include, for example, excipients, binders, disintegrants, flavoring agents, surfactants, fragrances, lubricants, coloring agents, antioxidants, masking agents, antistatic agents, fluidizing agents, Wetting agents, flavoring agents, elution aids and the like can be mentioned, and one or more selected from these may be used in appropriate combination.

  Examples of the excipient include sugars (eg, glucose, fructose, maltose, lactose, isomerized lactose, reduced lactose, sucrose, D-mannitol, erythritol, maltitol, xylitol, palatinose, trehalose, sorbitol, corn starch, potato Starch, wheat starch, rice starch, etc.), crystalline cellulose, anhydrous silicic acid, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate and the like. Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, sodium carboxymethylcellulose, partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, gum arabic powder, gelatin and the like. Can be mentioned. Examples of the disintegrant include low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, hydroxypropyl starch, and corn starch. Examples of the corrigent include sucrose, D-sorbitol, xylitol, citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, sodium saccharin, dipotassium glycyrrhizin, sodium glutamate, 5′-sodium inosinate, 5 '-Sodium guanylate and the like can be mentioned. Examples of the surfactant include polysorbate (for example, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, etc.), polyoxyethylene / polyoxypropylene copolymer, sodium lauryl sulfate, and the like. As a fragrance | flavor, lemon oil, orange oil, menthol, brackish oil etc. are mentioned, for example. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol and the like. Examples of the colorant include titanium oxide, food yellow No. 5, food blue No. 2, iron sesquioxide, yellow iron sesquioxide, and the like. Examples of the antioxidant include sodium ascorbate, L-cysteine, sodium sulfite, vitamin E and the like. Examples of the concealing agent include titanium oxide. Examples of the antistatic agent include talc and titanium oxide. Examples of the fluidizing agent include light anhydrous silicic acid, talc, hydrous silicon dioxide and the like. Examples of the wetting agent include polysorbate 80, sodium laurate sulfate, sucrose fatty acid ester, polyethylene glycol, hydroxypropyl cellulose (HPC), and the like. Examples of the dissolution aid include dry methacrylic acid copolymer LD, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, and the like.

  As the granulated product of the composition for solid preparation of the present invention, spray-dried granulated product is preferable. The spray-drying granulation method for obtaining a spray-dried granulated product is a method for obtaining a fine granulated particle by spraying and atomizing a liquid substance in an air stream, drying or coagulating it, and gelling. It is possible to improve surface physical properties, improve the shape of the powder and the powder surface, and the like. Further, compared with other granulation methods, it becomes porous, so that wettability is improved by capillary action, and particles having a smooth surface can be obtained. Furthermore, since the drying time is as short as several seconds to several tens of seconds and the product temperature does not rise above the exhaust temperature, there is little heat effect. Therefore, it is a preferred granulation method for pranlukast hydrate having very strong adhesion and water repellency.

  The amount of pranlukast hydrate in 1 part by weight of the composition for solid preparations of the present invention is preferably about 0.70 to 0.98 parts by weight, more preferably about 0.75 to 0.90 parts by weight, particularly preferably. Is about 0.75 to 0.87 parts by weight.

  In addition, the saccharide in 1 part by weight of the spray-dried granulated product of the solid composition of the present invention is preferably about 0.25 part by weight or less, more preferably about 0.05 to 0.20 part by weight, particularly preferably about 0. .15 to 0.20 parts by weight.

  In the composition for solid preparation of the present invention, the weight ratio of saccharide to 1 part by weight of pranlukast hydrate is preferably about 0.05 to 0.30 part by weight, more preferably about 0.10. 0.25 parts by weight, particularly preferably about 0.2 to 0.25 parts by weight.

  In the composition for solid preparation of the present invention, the weight ratio of the water-soluble cellulose to 1 part by weight of pranlukast hydrate is preferably about 0.002 to 0.050 part by weight, more preferably about The amount is 0.004 to 0.030 parts by weight, particularly preferably about 0.004 to 0.009 parts by weight.

  When the composition for solid preparation of the present invention is used as a tablet or capsule, the content of pranlukast hydrate in the preparation varies depending on age, body weight, symptom, therapeutic effect, administration method, treatment time, etc. It is preferable to manufacture so that the desired effect of invention may be acquired. For example, the dose of pranlukast hydrate per adult is preferably about 25 to 2500 mg, more preferably about 112.5 to 450 mg, and further preferably about 225 to 450 mg.

As a tablet containing the composition for solid preparations of the present invention, a tablet having a shape and a size that does not give a burden to a patient to be taken is preferable. For example, a round tablet, a deformed tablet (for example, caplet tablet etc.), etc. are mentioned. In the case of a round tablet, the diameter is preferably about 7 to 9 mm and the thickness is preferably about 2 to 4 mm. In the case of a caplet tablet, the major axis is about 13 ˜15 mm, the minor axis is preferably about 5 to 7 mm, and the thickness is preferably about 4 to 5 mm. The shape of the tablet is not particularly limited, but is preferably cylindrical and has a curvature surface.
In addition, the content of pranlukast hydrate contained in the tablet is preferably about 112.5 to 450 mg, more preferably about 112.5 mg or about 225 mg per tablet.

  In the tablet of the present invention, that is, the high-content tablet, the content of pranlukast hydrate is preferably about 0.50 to 0.90 parts by weight, more preferably about 0 to 1 part by weight of one tablet. .50 to 0.80 parts by weight, particularly preferably about 0.55 to 0.70 parts by weight.

  The weight of a tablet containing about 112.5 mg of pranlukast hydrate is preferably about 125 to 225 mg, more preferably about 140 to 225 mg, and particularly preferably about 160 to 205 mg.

  The weight of one tablet containing about 225 mg of pranlukast hydrate is preferably about 250 to 450 mg, more preferably about 280 to 450 mg, and particularly preferably about 320 to 410 mg.

The volume of one tablet containing about 112.5 mg of pranlukast hydrate is preferably about 100 to 175 mm ³ , more preferably about 110 to 175 mm ³ , and particularly preferably about 125 to 160 mm ³ . is there.

The volume of one tablet containing 225 mg of pranlukast hydrate is preferably about 200 to 350 mm ³ , more preferably about 220 to 350 mm ³ , and particularly preferably about 250 to 320 mm ³ .

  The content of pranlukast hydrate contained in the capsule containing the solid composition of the present invention is preferably about 225 to 450 mg, more preferably 225 mg or 450 mg per capsule. As the size of the capsule, No. 1, No. 2, No. 3, or No. 4 capsule is preferable. For example, No. 2 capsule or No. 3 capsule containing 225 mg of pranlukast hydrate or No. 4 capsule containing 112.5 mg of pranlukast hydrate is preferable from the viewpoint of patient compliance. .

  In the capsule in the present invention, that is, the high content capsule, the content of pranlukast hydrate is preferably about 0.50 to 0.90 parts by weight per 1 part by weight of one capsule.

  The tablet hardness containing the solid composition of the present invention is preferably 8.0 to 14.6 kg. For example, the major axis is 13 to 15 mm and the minor axis is 5 to 7 mm. The tablet hardness is 10.0 to 14.6 kg. Caplet tablets, preferably round tablets with a tablet hardness of 8.0 to 12.0 kg and a diameter of 7 to 9 mm.

  It has been reported that when a capsule containing pranlukast hydrate is left unpacked, the dissolution property becomes unstable in one week (“Stability information of tablets and capsules in the unpacked state” ", Revised 3rd edition, Pharmaceutical Journal, Feb. 5, 2003, p.136). If the dissolution property becomes unstable, the bioavailability changes after administration in vivo, and there is a possibility that the medicinal effect may be insufficient or may have side effects. It has been clarified that elution with time is stable by using the pharmaceutical composition.

  In the present invention, the dissolution over time is stable because the preparation (eg, tablet, capsule, etc.) produced using the composition for solid preparation of the present invention is subjected to, for example, an accelerated test (40 ° C. 75 % RH) and a severe test (60 ° C.), it means that dissolution delay and acceleration are less likely to occur as compared to the preparation before the test.

  After the tablet and / or capsule of the present invention is produced as described above, it is optionally packaged as desired. Such packaging may be, for example, non-unit packaging that is not individually packaged (for example, bulk packaging). For example, sealed packaging such as so-called heat sealing that seals pharmaceuticals with a heat-adhesive film is used. preferable. The sealed packaging in the present invention includes, for example, packaging using a pharmacopoeia-defined “airtight container” or “sealed container”. The heat seal includes PTP (Press Through Pack) packaging, SP (Strip Package) packaging, and the like, and PTP packaging is particularly preferable. Examples of the material for the PTP packaging include PVC (polyvinyl chloride), PVDC (polyvinylidene chloride) -coated PVC (polyvinyl chloride), PP (polypropylene), and polypropylene-based multilayers. PTP packaging is preferably used in combination with aluminum packaging. Further, after the capsule of the present invention is subjected to PTP packaging or SP packaging, a certain amount thereof may be secondarily packaged with polyethylene or aluminum foil (so-called pillow packaging).

  The preparation of the present invention is characterized in that it reduces adhesion cohesion based on the physical properties of pranlukast hydrate, and tensile rupture force is used as a parameter reflecting the adhesion cohesion.

The tensile breaking force in the preparation of the present invention with reduced adhesiveness is preferably about 10.0 g or less, more preferably about 0.1 to 8.0 g.
[Application to pharmaceutical products]
Since the preparation of the present invention contains pranlukast hydrate as an active ingredient, respiratory diseases such as bronchial asthma, sinusitis, COPD (chronic obstructive pulmonary disease), Meniere's disease, migraine, cough, menstrual difficulty It is useful as a prophylactic and / or therapeutic drug for various diseases such as infectious diseases.
[toxicity]
The preparation containing pranlukast hydrate provided by the present invention has low toxicity and is sufficiently safe for use as a medicine.

  By using water-soluble celluloses (for example, hydroxypropylmethylcellulose and the like), the adhesiveness can be reduced even if the amount of saccharide is reduced, so that it is possible to produce a small preparation (especially a tablet). In addition, the present invention has solved various problems in the formulation process, further improves the dissolution rate and stabilizes dissolution over time, and dramatically improves the moldability in formulation. That is, the preparation of the present invention is a high-content solid preparation containing pranlukast hydrate that solves various problems.

EXAMPLES Hereinafter, although an Example explains this invention in full detail, it is for understanding this invention well and this invention is not limited to these.
Formulation Example 1
Tc-5Rw (3 g; Shin-Etsu Chemical Co., Ltd.) was dissolved in purified water (1027 mL), and lactose (100 g; NZMP) and pranlukast hydrate (450 g) were added to form a suspension. This suspension is spray-dried with a spray dryer (air supply (inlet) temperature: 180 ° C., exhaust temperature: 100 to 110 ° C., liquid feed rate: 30 to 40 g / min, atomizer rotational speed: 12000 rpm), and pranlukast A hydrate spray-dried product was obtained. This was sieved with a 0.5 mm sieve to obtain a spray-dried granulated product (SD product) (450 g). Low-substituted hydroxypropylcellulose (L-HPC) (3 g; Shin-Etsu Chemical Co., Ltd.) and magnesium stearate (1.2 g; Taihei Chemical Industry Co., Ltd.) were added to the obtained SD product (55.8 g).・ Mixed to obtain a powder for tableting. This tableting powder was tableted with a tableting machine (Okada Seiko, Tab-ALL) under the conditions of a heel diameter of 7.5 mm and a tableting pressure of 750 kgf. The following prescription is a diameter of 7.5 mm and a thickness of 3 Tablet 1 containing 75.7% by weight of 1 mm pranlukast hydrate was produced.
Formulation of tablet 1 of the present invention (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 112.5mg
Lactose 25.0mg
Tc-5Rw 0.8mg
Additive L-HPC 7.4 mg
Magnesium stearate 3.0mg
148.7 mg total
Formulation Example 2
By performing the same operation as in Formulation Example 1, tablet 2 containing 84.0% by weight of pranlukast hydrate having a diameter of 7.5 mm and a thickness of 2.9 mm, which is the following formulation, was produced.
Formulation of tablet 2 of the present invention (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 112.5mg
Lactose 11.3mg
Tc-5Rw 0.8mg
Additive L-HPC 6.7mg
Magnesium stearate 2.7mg
134.0 mg total
Formulation Example 3
By performing the same operation as in Formulation Example 1, tablet 3 containing 74.7% by weight of pranlukast hydrate having a diameter of 7.5 mm and a thickness of 3.2 mm, which is the following formulation, was produced.
Formulation of tablet 3 of the present invention (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 112.5mg
Lactose 25.0mg
Tc-5Rw 2.5mg
Additive L-HPC 7.5mg
Magnesium stearate 3.0mg
150.5mg total
Formulation Example 4
Tc-5Rw (5.4 g; Shin-Etsu Chemical Co., Ltd.) was dissolved in purified water (1848.6 mL), and lactose (180 g; NZMP) and pranlukast hydrate (810 g) were added and suspended. Liquid. Spray suspension (supply air (inlet) temperature: 180 ° C., exhaust temperature: 100 to 110 ° C., liquid feed rate: 30 to 40 g / min, atomizer rotation speed: 10000 rpm, Okawahara Chemical Industries under the following conditions It was spray-dried with L-8), and a spray-dried product of pranlukast hydrate was obtained. This was sieved with a 0.5 mm sieve to obtain a spray-dried granulated product (SD product) (826.2 g). The obtained SD product (760 g) was mixed with lactose for direct compression (super tab) (155 g; NZMP), dried methacrylic acid copolymer LD (Eudragit L100-55) (50 g; Laem), croscarmellose sodium (Ac-Di). -Sol) (25 g; Asahi Kasei Co., Ltd.) and magnesium stearate (10 g; Taihei Chemical Industry Co., Ltd.) were mixed for 30 minutes in a Bole container mixer (manufactured by Kotobuki Kogyo Co., Ltd., MC-2.5). Got the end. This powder for tableting was tableted with a tableting machine (manufactured by Kikusui Seisakusho, Virgo) under the conditions of a diameter of 8 mm and a tableting pressure of 1000 kgf. Tablet 4 containing 61.8% of pranlukast hydrate having a diameter of 41 mm and a tablet hardness of 9.4 kg was produced.
Formulation of tablet 4 of the present invention (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 112.5mg
Lactose 25.0mg
Tc-5Rw 0.8mg
Additive Eudragit L100-55 9.1 mg
Super Tab 28.2mg
Ac-Di-Sol 4.5mg
Magnesium stearate 1.8mg
Total 181.9mg
Formulation Example 5
Tc-5Rw (5.4 g; Shin-Etsu Chemical Co., Ltd.) was dissolved in purified water (1848.6 mL), and lactose (180 g; NZMP) and pranlukast hydrate (810 g) were added and suspended. Liquid. Spray suspension (supply air (inlet) temperature: 180 ° C., exhaust temperature: 100 to 110 ° C., liquid feeding speed: 30 to 40 g / min, atomizer rotation speed: 10,000 rpm, manufactured by Okawara Kako Co., Ltd., A spray-dried product of pranlukast hydrate was obtained by spray drying in L-8). This was sieved with a 0.5 mm sieve to obtain a spray-dried granulated product (SD product) (843.2 g). The obtained SD product (760 g) was used for direct compression lactose (supertab) (150 g; NZMP), dry methacrylic acid copolymer LD (Eudragit L100-55) (50 g; Reem), Tc-5Rw (30.0 g; For tableting, Shin-Etsu Chemical Co., Ltd.) and magnesium stearate (10 g; Taihei Chemical Industry Co., Ltd.) were mixed for 30 minutes in a Boule container mixer (manufactured by Kotobuki Industry Co., Ltd., MC-2.5). I got the end. This powder for tableting was tableted with a tableting machine (Virgo, manufactured by Kikusui Seisakusho Co., Ltd.) under the conditions of a wrinkle diameter of 14 mm, a short diameter of 6 mm, and a tableting pressure of 800 kgf. A caplet tablet (Tablet 5) containing 61.8% pranlukast hydrate having a thickness of 6 mm, a thickness of 4.86 mm and a tablet hardness of 13.8 kg was produced.
Formulation of tablet 5 of the present invention (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 225.0mg
Lactose 50.0mg
Tc-5Rw 1.5mg
Additive Eudragit L100-55 18.2mg
Super Tab 54.6mg
Tc-5Rw 10.9mg
Magnesium stearate 3.6mg
363.8mg total
Formulation Example 6
Tc-5Rw (1.2 kg; Shin-Etsu Chemical Co., Ltd.) was dissolved in purified water (221.2 kg), and lactose (40 kg; NZMP) and pranlukast hydrate (180 kg) were added and suspended. Liquid. Spray suspension (supply air (inlet) temperature: 190 ° C., exhaust temperature: 85 ± 5 ° C., liquid feeding speed: 100 kg / hour, atomizer rotation speed: 16000 ± 100 rpm, manufactured by Okawara Kako Co., Ltd., Spray-dried with ODA-27) to obtain a spray-dried product of pranlukast hydrate. This was sieved with a 0.85 mm sieve to obtain a spray-dried granulated product (SD product) (212.3 kg). The obtained SD product (47.005 kg) was directly mixed with lactose (super tab) (9.574 kg; NZMP), dried methacrylic acid copolymer LD (Eudragit L100-55) (1.53 kg; Rohm), Croscalme Loose sodium (Kickolate ND-2HS) (1.53 kg; Nichirin Chemical Industry Co., Ltd.), light anhydrous silicic acid (Adsolider 101) (0.52 kg; Freund Sangyo Co., Ltd.) and magnesium stearate (1.04 kg; Taihei Chemical Industry Co., Ltd.) was mixed for 30 minutes with a Boule Container Mixer (manufactured by Kotobuki Industries Co., Ltd., MC-150) to obtain a tableting powder. This tableting powder was tableted with a tableting machine (manufactured by Hata Seiko Co., Ltd., HT-X20) under the conditions of a wrinkle diameter of 14 mm, a short diameter of 6 mm, and a tableting pressure of 900 kgf. A caplet tablet (tablet 6) containing 62.5% of pranlukast hydrate having a size of 6 mm, a thickness of 4.26 mm, and a tablet hardness of 12.64 kg was produced.
Formulation of tablet 6 of the present invention (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 225.0mg
Lactose 50.0mg
Tc-5Rw 1.5mg
Additive Eudragit L100-55 9.0mg
Super Tab 56.5mg
Kikkolate ND-2HS 9.0mg
ADSOLIDER 101 3.0mg
Magnesium stearate 6.0mg
360.0mg total
Formulation Example 7
Tc-5Rw (1.2 kg; Shin-Etsu Chemical Co., Ltd.) was dissolved in purified water (221.2 kg), and lactose (40 kg; NZMP) and pranlukast hydrate (180 kg) were added and suspended. Liquid. Spray suspension (supply air (inlet) temperature: 190 ° C., exhaust temperature: 85 ± 5 ° C., liquid feeding speed: 100 kg / hour, atomizer rotation speed: 16000 ± 100 rpm, manufactured by Okawara Kako Co., Ltd., Spray-dried with ODA-27) to obtain a spray-dried product of pranlukast hydrate. This was sieved with a 0.85 mm sieve to obtain a spray-dried granulated product (SD product) (212.3 kg). The obtained SD product (47.005 kg) was directly mixed with lactose (super tab) (9.574 kg; NZMP), dried methacrylic acid copolymer LD (Eudragit L100-55) (1.53 kg; Rohm), Croscalme Loose sodium (Kickolate ND-2HS) (1.53 kg; Nichirin Chemical Industry Co., Ltd.), light anhydrous silicic acid (Adsolider 101) (0.52 kg; Freund Sangyo Co., Ltd.) and magnesium stearate (1.04 kg; Taihei Chemical Industry Co., Ltd.) was mixed for 30 minutes with a Boule Container Mixer (manufactured by Kotobuki Industries Co., Ltd., MC-150) to obtain a tableting powder. This powder for tableting was tableted with a tableting machine (manufactured by Hata Seiko Co., Ltd., HT-X20) under the conditions of a punch diameter of 8.0 mm and a tableting pressure of 700 kgf, and the following prescription was 8.0 mm. A round tablet (Tablet 7) containing 62.5% of pranlukast hydrate having a thickness of 3.47 mm and a tablet hardness of 9.99 kg was produced.
Formulation of tablet 7 of the present invention (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 112.5mg
Lactose 25.0mg
Tc-5Rw 0.75mg
Additive Eudragit L100-55 4.5mg
Super tub 28.25mg
Kikkolate ND-2HS 4.5mg
Adsolider 101 1.5mg
Magnesium stearate 3.0mg
180.0mg total
Comparative Example 1
By using polyethylene glycol (PEG) instead of Tc-5Rw and performing the same operation as in Formulation Example 1, the following formulation, pranlukast hydrate having a diameter of 7.5 mm and a thickness of 3.78 mm, was obtained. Comparative tablet 1 containing 59.3% by weight was produced.
Formulation of comparative tablet 1 (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 112.5mg
Lactose 52.7mg
PEG 11.3mg
Additive L-HPC 9.5 mg
Magnesium stearate 3.8mg
189.8mg total
Comparative Example 2
By using polyethylene glycol (PEG) instead of Tc-5Rw and not using lactose, the same procedure as in Formulation Example 1 was performed, whereby the following prescription was 7.5 mm in diameter and 2.91 mm in thickness. Comparative tablet 2 containing 84.5% by weight of pranlukast hydrate was produced.
Formulation of comparative tablet 2 (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 112.5mg
PEG 11.3mg
Additive L-HPC 6.7mg
Magnesium stearate 2.7mg
Total 133.1mg
Comparative Example 3
By using polyethylene glycol (PEG) instead of Tc-5Rw and not using lactose, the same procedure as in Formulation Example 1 was performed, whereby the following prescription was 7.5 mm in diameter and 2.75 mm in thickness. Comparative tablet 3 containing 92.4% by weight of pranlukast hydrate was produced.
Formulation of comparative tablet 3 (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 112.5mg
PEG 0.8mg
Additive L-HPC 6.1 mg
Magnesium stearate 2.4mg
Total 121.8mg
Comparative Example 4
By using polyethylene glycol (PEG) instead of Tc-5Rw and performing the same operation as in Formulation Example 1, the following formulation, pranlukast hydrate having a diameter of 7.5 mm and a thickness of 3.20 mm, was obtained. Comparative tablet 4 containing 75.7% by weight was produced.
Formulation of comparative tablet 4 (in 1 tablet)
Ingredients of spray-dried granule Pranlukast hydrate 112.5mg
Lactose 25.0mg
PEG 0.8mg
Additive L-HPC 7.4 mg
Magnesium stearate 3.0mg
148.7 mg total
Evaluation of Adhesiveness of Spray-Dried Granulated Product (SD Product) The tensile breaking force of the SD product produced in Formulation Examples 1 to 3 and Comparative Examples 1 to 4 was measured by Agrobot (trade name). The measurement conditions of the Ag robot are: cell inner diameter 25 mm, cell temperature 25 ° C., spring wire diameter 1.0 mm, compression speed 0.1 mm / second, maximum compression force 200 kgf, compression holding time 60 seconds, tensile speed 0.04 mm / second, The tensile sampling time was 20 seconds. The results are shown in Table 1. Note that * cannot be measured because it is greater than the measurement limit value.

  As is clear from the above results, the SD product, which is a preparation of the present invention with a reduced saccharide content, shows a marked reduction in adhesion during compression compared to the SD product used in the comparative example. Therefore, by using the solid composition of the present invention, it is possible to simultaneously increase the content of pranlukast hydrate and suppress tableting troubles associated with sticking to the punch during tableting. Became clear.

That is, it is clear that the preparation of the present invention has a tensile breaking force of 10.0 g or less, and the adhesion and aggregation properties are reduced as compared with the preparation of the comparative example.
Dissolution evaluation 1
The tablets produced in Formulation Examples 1 to 3 and Comparative Examples 1 to 4 were subjected to a dissolution test in 0.5% polysorbate 80 phosphate buffer (pH 6.8). The test was conducted in accordance with the 14th revised Japanese Pharmacopoeia General Test Method 66 Dissolution Test Method / Second Method (50 rpm). The test solution used was a solution obtained by adding 0.5% polysorbate 80 to a phosphate buffer solution (1 → 2) having a pH of 6.8. The sampled liquid was measured by the absorbance method (measurement wavelength: 350 nm), and the elution rate after 30 minutes and after 60 minutes was calculated.
Dissolution evaluation 2 (time stability test)
The tablets produced in Formulation Examples 1 to 3 and Comparative Examples 1 to 4 are packed in a glass bottle, and this is either (i) in a thermostatic chamber at 60 ° C. in a sealed state or (ii) 40 ° C. and 75% relative humidity in an opened state. Stored in the lower temperature and humidity chamber. After storage for 16 days, each tablet was collected, and the dissolution rate was measured in the same manner as in the dissolution evaluation 1. The results of dissolution tests 1 and 2 are shown in Table 2 below.

  As is clear from the above results, the preparation of the present invention generally has an improved dissolution rate as compared with the comparative preparation. In addition, as is apparent from the comparison preparation after storage, changes such as delay and acceleration of dissolution rate are observed. In contrast, in most of the preparations of the present invention, fluctuations in dissolution rate are very small, indicating that the preparations are excellent in ability to control dissolution and storage stability of quality.

It can be said that the dissolution property is stable if the dissolution property is ± 12% or less after 60 minutes as compared with the numerical value in dissolution property evaluation 1 and the dissolution rate is 85% or more after 60 minutes.
The tablets produced in Formulation Examples 1 to 3 and Comparative Examples 1 to 4 for disintegration evaluation were stored for 16 days in a constant temperature and humidity chamber at 40 ° C. and a relative humidity of 75%, or in a constant temperature chamber at 60 ° C. A comparison was made. The disintegration time is measured according to the Japanese Pharmacopoeia General Test Method 58 Disintegration Test Method using water, the first solution (pH 1.2), and the second solution (pH 6.8) as the test solution. Was done. Table 3 shows the results of tablets stored under conditions of 40 ° C. and 75% relative humidity, and Table 4 shows the results of tablets stored under conditions of 60 ° C. Note that the rate of change (%) is, for example, the rate of increase (+) when the decay time is higher after storage than before storage, and the rate of decrease (−) when the time after storage is lower than before storage. means.

As is apparent from Tables 3 and 4 above, the preparation of the present invention is generally improved or has the same level of disintegration as the comparative preparation, and the rate of change in disintegration before and after storage (stability) ), It is clear that the disintegration stability of the preparation of the present invention is excellent even under accelerated test conditions (40 ° C. 75% RH), severe test conditions (60 ° C.), and both conditions. .
Tablet moldability test The tablet hardness, tablet diameter, and tablet thickness of the tablets produced in Formulation Examples 1 and 2 and Comparative Examples 1 to 4 were measured using a WHT-2 tablet measuring device (Pharma Test Co., Ltd.). The tensile strength was calculated according to 1. With the tensile strength of the tablet of Comparative Example 1 as 100, the relative tensile strength of the other tablets was measured. The results are shown in Table 5.
Formula 1: Tensile strength = (2 × tablet hardness) / (circumference ratio × tablet diameter × tablet thickness) [kg / mm ² ]

  As is apparent from the above, it can be seen that when the PEG is changed to Tc-5Rw, the tensile strength is maintained or improved even if the lactose content is reduced.

By using the solid composition of the present invention, the adhesiveness can be reduced even if the saccharide content is reduced, so that a stable quality preparation and a small preparation with improved patient compliance can be provided.

Claims (8)

A tablet obtained by granulating a composition containing pranlukast hydrate, saccharides and hydroxypropylmethylcellulose, and compressing the resulting granulated product with other additives as necessary. , with respect to 1 part by weight of the content of hydroxypropyl methylcellulose in the granulated product in pranlukast hydrate, 0.004 to 0.030 part by weight der is, in one tablet, pranlukast hydrate 112 .5mg or 225mg you containing tablets.   The tablet according to claim 1, wherein the content of the saccharide in the granulated product is 0.10 to 0.25 parts by weight with respect to 1 part by weight of pranlukast hydrate.   The tablet according to claim 1 or 2, wherein the content of hydroxypropylmethylcellulose in the granulated product is 0.004 to 0.009 parts by weight with respect to 1 part by weight of pranlukast hydrate. In one tablet, pranlukast hydrate containing 112.5 mg, the content of hydroxyaldehyde methylcellulose granules in the relative pranlukast hydrate 1 part by weight, 0.007 parts by weight or 0. 022 parts by weight of der Ru claim 1 or 2 tablet according. One tablet contains 225 mg of pranlukast hydrate, and the content of hydroxypropylmethylcellulose in the granulated product is 0.007 parts by weight or 0.022 parts by weight with respect to 1 part by weight of pranlukast hydrate. der Ru claim 1 or 2 tablet according.   The tablet according to any one of claims 1 to 3, wherein the pranlukast hydrate is 0.50 to 0.90 parts by weight with respect to 1 part by weight of the tablet.   The tablet according to claim 6, wherein the pranlukast hydrate is 0.55 to 0.70 parts by weight.   It is obtained by granulating a composition containing 0.10 to 0.25 parts by weight of saccharide and 0.004 to 0.009 parts by weight of hydroxypropylmethylcellulose with respect to 1 part by weight of pranlukast hydrate. A tablet obtained by compressing the granulated product with other additives as necessary, containing 112.5 mg or 225 mg of pranlukast hydrate in one tablet, and 1 part by weight of the tablet On the other hand, a pranlukast hydrate high-content tablet characterized in that pranlukast hydrate is 0.55 to 0.70 parts by weight.