WO2007069378A1 - Drug package - Google Patents

Abstract

It is intended to provide a drug package by which deterioration (for example, delayed disintegration) in storing a pranlukast hydrate-containing capsule wrapped in a plastic sheet can be minimized and the breakage of the capsule can be minimized too. A drug package wherein a capsule (2) having a composition containing pranlukast hydrate enclosed therein, which is PTP-packaged on a sheet (1), and a desiccating agent (3) are hermetically sealed in a film (4) and the relative humidity of the internal atmosphere thereof measured by using a thermohygrometer at a temperature of 25oC is regulated to 10% to 45%.

Description

 Drug package

 Technical field

 TECHNICAL FIELD [0001] The present invention relates to a drug package for capsules containing pranlukast hydrate.

 [0002] SP (strip package) packaging, PTP (press through package) packaging, and the like are generally used as packaging forms when a solid preparation such as a tablet or capsule is sealed with a plastic sheet or the like. These SP-packed or PTP-packed preparations are provided to the market as drug packs that are further sealed in sealed bodies such as aluminum film bags to avoid the effects of outside air and light! .

 [0003] On the other hand, pranlukast hydrate is known as a leukotriene (LT) antagonist (see Patent Document 1), and is actually applied clinically as a therapeutic agent for bronchial asthma and allergic rhinitis. Solid formulations containing pranlukast hydrate have been reported to undergo dissolution changes in one week when stored unwrapped at a temperature of 25 ° C and a relative humidity of 75%, especially in the case of capsules ( Non-patent document 1). Furthermore, even when the capsule is in a PTP-encapsulated state, the decay rate and elution may change due to an increase in the moisture content and humidity of the outside air.

[0004] So far, a drug package in which a tablet containing perindopril elpmin as an active ingredient and a desiccant are both enclosed in a sealed body has been disclosed (see Patent Document 2). However, in the case of pranlukast hydrate capsules, in order to prevent a delay in disintegration rate and changes in dissolution, a desiccant is contained together with a PTP package in a moisture-proof film-tight seal. The capsule may be broken due to a decrease in moisture. Therefore, as described above, pranlukast hydrate capsules after PTP packaging are simply sealed in a sealed body or simply sealed in a sealed body with a desiccant. Since the humidity could not be adjusted, there were problems such as delay in disintegration of the capsule, delay in dissolution, and failure to prevent cracking of the force capsule. With regard to this problem, the internal atmosphere of the drug package Regarding the adjustment of the relative humidity of the atmosphere, there is no description or suggestion in the above literature.

 Patent Document 1: Japanese Patent Application Laid-Open No. 61-050977

 Patent Document 2: JP-A-11-206850

 Non-Patent Document 1: Tablet 'Capsule Stability Information in Non-Packaging State Revised 3rd Edition (Japan Hospital, Pharmaceutical Journal)

 Disclosure of the invention

 Problems to be solved by the invention

[0006] The object of the present invention is to minimize degradation such as delay in disintegration during storage of capsules containing pranlukast hydrate packaged in a plastic sheet, and minimize cracking of capsules. The object is to provide a drug package that can be suppressed to a low level.

 Means for solving the problem

[0007] In order to achieve the above-mentioned object, the present inventors consider that it is effective to adjust the relative humidity in the drug package, and pranlukast hydrate packaged in PTP with a plastic sheet. Capsules filled with a composition comprising a desiccant and encapsulated with a desiccant and hermetically sealed with a film, the amount of the desiccant, and the composition and capsule film in the capsule The combination of the moisture content of each was studied earnestly. as a result

Surprisingly, drugs with controlled relative humidity of the internal atmosphere that can suppress the decay delay and capsule cracking during storage of these capsules by combining them with certain factors. The present inventors have found that a package can be provided and have completed the present invention.

That is, the present invention provides:

 [1] Capsules filled with a composition containing pranlukast hydrate PTP-packed with a sheet and a desiccant are enclosed, and sealed in a film at a temperature of 25 A drug package in which the relative humidity of the internal atmosphere measured using a thermo-hygrometer is adjusted to 10% to 45% at ° C.

 [2] The drug package according to [1], further containing a humectant,

[3] The drug packaging according to [1], wherein the sheet is a plastic sheet or an aluminum sheet. body,

 [4] Capsenore strength A drug package according to the above [1], which is a capsule containing 112.5 mg or 225 mg of pranlukast hydrate per capsenore,

 [5] The drug package according to the above [1], wherein the capsule is a capsenole containing 130 mg to 400 mg of thread and composition per capsenole, and the weight of the empty capsule per capsule is 30 mg to 90 mg. Body,

 [6] The drug package according to [1], wherein the moisture content of the yarn and composition comprising pranlukast hydrate is 1% to 2.7%,

 [7] The drug package according to [1], wherein the moisture content of the capsule film in the capsule is 8% to 17%,

 [8] The drug package according to [1], wherein the composition comprising pranlukast hydrate is a composition further containing a saccharide, a water-soluble polymer, and a lubricant,

 [9] The drug package according to [8], wherein the saccharide is lactose, the water-soluble polymer is polyethylene glycol, and the lubricant is magnesium stearate,

 [10] Strength of composition comprising pranlukast hydrate 30 parts by weight to 60 parts by weight of lactose and 7.5 parts by weight of polyethylene glycol per 100 parts by weight of pranlukast hydrate The drug package according to [9] above, which is a composition comprising 15 parts by weight and 1.0 part by weight to 4.5 parts by weight of magnesium stearate,

 [11] The drug package according to [1], wherein the desiccant is a desiccant having a moisture absorption rate of 20% to 35% at a temperature of 25 ° C. and a relative humidity of 50%.

 [12] The drug package according to [11], wherein the desiccant is silica gel or calcium chloride salt,

 [13] The drug package according to [11], wherein the desiccant is a sheet desiccant,

 [14] The drug package according to [13], wherein the sheet-like desiccant is a sheet-like desiccant containing calcium chloride.

 [15] The drug package according to the above [11], wherein the weight of the desiccant encapsulated is 0.7 to 17 parts by weight per 100 parts by weight of the total capsule weight

[16] Capsule Weight of desiccant encapsulated per 100 parts by weight of total capsule The drug package according to [11], wherein is 1 to 15 parts by weight,

 [17] The drug package according to [1], which is a pillow package of an aluminum film,

 [18] (I) Capsule filled with a composition containing pranlukast hydrate, having all of the following characteristics (a) to (e), PTP-packed with a plastic sheet (II) capsules 0.7 to 17 parts by weight per 100 parts by weight of total capsule 1 temperature 2

A desiccant having a moisture absorption rate of 20% to 35% at 5 ° C and a relative humidity of 50%.

(III) Drug package that is hermetically packaged with a film, and the relative humidity of the internal atmosphere measured at 25 ° C using a thermo-hygrometer is adjusted to 10% to 45%:

 (a) 12.5 mg or 225 mg pranlukast hydrate per capsule,

(b) 130 mg to 400 mg of thread and composition per capsenore,

 (c) The weight of empty capsules per capsule is 30 mg to 90 mg,

 (d) the moisture content of the composition is 1% to 2.7%,

 (e) the moisture content of the capsule film is 8% to 17%,

 [19] Composition power comprising pranlukast hydrate A composition comprising pranlukast hydrate, sugar, water-soluble polymer and lubricant, and the desiccant is silica gel or Is a drug package according to the above [18], which is a desiccant containing calcium chloride

[20] Capsule strength A capsule containing 112.5 mg of pranlukast hydrate per capsule. A composition containing pranlukast hydrate. Pranlukast hydrate 100 weight A composition comprising 30 to 60 parts by weight of lactose, 7.5 to 15 parts by weight of polyethylene glycol, and 1.0 to 4.5 parts by weight of magnesium stearate per part, The desiccant is a sheet-like desiccant containing calcium chloride, and the sheet-like desiccant is enclosed at a ratio of 1 to 15 parts by weight per 100 parts by weight of the total weight of one capsule [19 ] Drug packaging body according to the description,

[21] Pranlukast, which is adjusted to have all of the following characteristics (a) to (e), which is packaged in a plastic sheet and PTP in a drug package hermetically sealed with a film. A capsule filled with a composition containing a hydrate, and a sheet-like desiccant containing calcium chloride salt, and the amount of the sheet-like desiccant is 0 per 100 parts by weight of one capsule. Adjusting to contain 7 parts by weight to 17 parts by weight and encapsulating the drug package To adjust the relative humidity of the internal atmosphere, measured using a thermohygrometer at 25 ° C, to about 10% to about 45%:

 (a) 12.5 mg or 225 mg pranlukast hydrate per capsule,

(b) 130 mg to 400 mg of thread and composition per capsenore,

 (c) The weight of empty capsules per capsule is 30 mg to 90 mg,

 (d) the moisture content of the composition is 1% to 2.7%,

 (e) the moisture content of the capsule film is 8% to 17%,

 Etc.

 The invention's effect

 [0009] In the drug package of the present invention, a capsule filled with a composition containing pranlukast hydrate PTP-wrapped with a plastic sheet inside, and a certain moisture absorption rate. By appropriately encapsulating the desiccant, the relative humidity of the internal atmosphere of the drug package is adjusted to a preferable range, and the disintegration delay during storage of the capsule filled with the composition that is easily affected by moisture, It has the effect of suppressing abnormalities (eg cracks, chips, etc.).

 Brief Description of Drawings

FIG. 1 is a schematic view illustrating the configuration of a drug package of the present invention.

 Explanation of symbols

 [0011] 1: Plastic sheet

 2: Capsule

 3: Desiccant

 4: Exterior material (film)

 BEST MODE FOR CARRYING OUT THE INVENTION

[0012] In the present invention, a capsule filled with a composition containing pranlukast hydrate is packaged in a sheet, and a drug package is a capsule packaged in this sheet. All of them, including a desiccant and optionally containing a moisturizing agent, are hermetically sealed in a film. That is, the drug package of the present invention is the above sheet. A drug package in which a capsule packaged in (1) and a desiccant are encapsulated and sealed in a film that may contain a moisturizing agent if necessary.

 [0013] In the present invention, the sheet used for packaging the capsule is not particularly limited as long as it is a sheet capable of packaging a pharmaceutical, and examples thereof include a plastic sheet and an aluminum sheet. Preferably, it is a plastic sheet.

 [0014] In the present invention, the plastic sheet may be, for example, a polychlorinated cellulose sheet, a polychlorinated vinylidene (PVDC) sheet, a polyvinylidene chloride sheet, a polychlorinated trifluoroethylene sheet, Stretched polypropylene (CPP or IPP) sheet, cyclic polyolefin sheet, polyethylene sheet, non-stretched nylon (CNy) sheet, biaxially stretched nylon (ONy) sheet, biaxially stretched polypropylene (OPP) sheet, rigid chloride bull sheet, polyethylene terf Tara sheet, Polyacrylonitrile copolymer (PAN) sheet, Polybulal alcohol (PVA) sheet, Polyester (PET) sheet, Ethylene acetate acetate copolymer (EVA) sheet, Ionomer (IO) sheet, Polyamide (PA or Ny) sheet, ethylene 'bulcoalcohol copolymer (EVOH) sheet, polycarbonate (PC) Over preparative and polystyrene (PS) seat, and the like. These plastic sheets may be used as a composite sheet in which two or more kinds are appropriately combined.

[0015] The plastic sheet used in the present invention preferably has a moisture permeability (water vapor permeability) of about 0.5 gZm ² '24 hr to about 5. OgZ m ² '24 hr. Examples of the plastic sheet having such preferred moisture permeability include hard salt vinyl sheet, composite sheet combining hard vinyl chloride and polysalt vinylidene, and unstretched polypropylene sheet. A hard salt vinyl sheet is preferred, but is not limited thereto.

 [0016] The above-mentioned moisture permeability means the amount of water vapor that passes through a sheet of a unit area in a certain time under the conditions of a predetermined temperature and humidity, and the measurement can be performed by a known method. The For example, it is preferable to carry out according to a method generally known as a method for measuring moisture permeability of a packaging material such as a plastic sheet or a sheet, particularly the cup method (JIS Z0208).

[0017] As the plastic sheet, it is not necessary to be a flat sheet. For example, a sheet in which a concave portion for providing a space for storing capsules one by one is used. Can do.

 [0018] In the present invention, when the capsule is packaged in a sheet, the sheet and another film-like material are appropriately combined, and the capsule is sandwiched between the two and used. Also good. For example, one or more kinds of film-like materials used as ordinary packaging materials such as vapor-deposited films deposited with inorganic substances such as aluminum, silicon oxide, and aluminum oxide, paper, aluminum films, and cellophane films Can be selected and combined with the above sheet for the purpose of protecting the contents and used together. As a method of laminating the above sheet and other film-like materials, dry lamination, extrusion coating, lamination, wet lamination, hot melt lamination, co-extrusion lamination, non-solvent lamination, thermal Lamination etc. are mentioned.

 [0019] In the present invention, the capsule packaged with a composition containing pranlukast hydrate or the like is packaged in a sheet as SP (strip package) packaging, PTP (press throu gh package), blister pack and the like. PTP packaging is preferable.

 As the PTP packaging used in the present invention, for example, a combination of a hard salt cellulose and an aluminum film and bonding and molding by a known method is preferable.

 [0020] In the present invention, the composition containing pranlukast hydrate (hereinafter sometimes abbreviated as the composition of the present invention) refers to (1) pranlukast water. Containing a hydrate, preferably (2) a saccharide and (3) a water-soluble polymer, and (4) an additive (formulation base) generally used in the manufacture of capsules. It is a composition that may be present. Here, as additives (formulation base), for example, excipients, binders, lubricants, stabilizers, disintegrators, corrigents, surfactants, fragrances, colorants, antioxidants , Hiding agents, antistatic agents, fluidizing agents, wetting agents, elution aids, solubilizing aids, coating agents, etc., and one or more of these can be selected and the composition of the present invention. It can be blended and used as appropriate. As the additive, a lubricant is preferable.

 [0021] The pranlukast hydrate used in the composition of the present invention is represented by the following formula (A):

で示される 4—ォキソ—8— [4— (4—フエ-ルブトキシ）ベンゾィルァミノ]— 2— (テト ラゾールー 5—ィル） -4H- 1一べンゾピラン 1Z2水和物である。プランルカスト水 和物の製造は、例えば、特開昭 61— 050977号明細書記載の方法に準じて行うこと ができる。 [Chemical 1]

4-oxo-8- [4- (4-Ferbutoxy) benzoylamino]-2— (tetrazol-5-yl) -4H-1 monobenzopyran 1Z2 hydrate represented by The production of pranlukast hydrate can be carried out, for example, according to the method described in JP-A 61-050977.

 [0022] Examples of the saccharide in the composition of the present invention include lactose, mannitol, sucrose, dextrin, dextran, trehalose, pullulan, glucose, fructose, maltose, isomeric lactose, reduced lactose, sucrose, erythritol, and maltitol. , Xylitol, palatinose, sorbitol, corn starch, potato starch, wheat starch, rice starch and the like. Lactose, sucrose, mannitol and the like are preferable. More preferably, it is lactose.

 [0023] Examples of the water-soluble polymer in the composition of the present invention include celluloses (for example, hydroxymethylenoresenorelose, hydroxymethinoretinorelose, methinoresenorelose, hydroxyethylcellulose, hydroxypropylcellulose (HPC), hydroxy Propylmethyl cellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), etc., synthetic polymers (eg, polyethylene glycol (eg, Macrogol 4000), Polybulurpyrrolidone, polybulal alcohol, etc.), gelatin and the like. Polyethylene glycol mononole, methinoresenorelose, hydroxypropinoresenorerose, hydroxypropinoremethinocellulose and the like are preferable. More preferably, it is polyethylene glycol.

[0024] Examples of excipients as additives include saccharides (eg, lactose, mannitol, sucrose, dextrin, dextran, trehalose, pullulan, glucose, fructose, maltose, isomerized lactose, reduced lactose, sucrose. , Erythritol, maltitol, xylitol, palatinose, sorbitol, corn starch, potato starch, wheat starch, and rice starch), microcrystalline cellulose, anhydrous carboxylic acid, anhydrous calcium phosphate, precipitated calcium carbonate And calcium silicate.

 [0025] Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone (polybulurpyrrolidone), methylcellulose, polybulal alcohol, sodium carboxymethylcellulose, partially pregelatinized starch, pregelatinized starch, sodium alginate, Examples include pullulan, gum arabic powder, gelatin, and magnesium aluminate metasilicate.

 [0026] Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol and the like. Preferably, it is magnesium stearate.

[0027] Examples of the stabilizing agent include adipic acid, ascorbic acid, L-aspartic acid, albumin, benzoic acid, ethanol, ethylenediamine, zinc chloride, calcium chloride, sodium chloride, benzalkonium chloride, benzethonium chloride, Magnesium chloride, hydrochloric acid, arginine hydrochloride, cysteine hydrochloride, lysine hydrochloride, carmellose calcium, carmellose sodium, dilute hydrochloric acid, citrate, calcium citrate, sodium citrate, glycine, dalyserin, crystalline cellulose, hydrogenated oil, sesame oil, chondroitin sulfate , Acetic acid, zinc acetate, tocopherol acetate, sodium acetate, sodium salicylate, phenyl salicylate, zinc oxide, magnesium oxide, diisopropanolamine, diethanolamine, dibutylhydroxy Ruene, dimethylpolysiloxane, calcium bromide, tartaric acid, hydroxylating power Lucium, sodium hydroxide, magnesium hydroxide, stearic acid, cetanol, gelatin, D-sorbitol, talc, ammonium carbonate, potassium carbonate, hydrogen carbonate Sodium, sodium carbonate, magnesium carbonate, thioglycolic acid, sodium thioglycolate, sodium thiosulfate, dextrin, tocopherol, lactic acid, sodium lactate solution, lactose, urea, concentrated glycerin, sucrose, microcrystalline cellulose, hydroxypropylcellulose, hydroquinone , Glacial acetic acid, glucose, fumaric acid, monosodium fumarate, sodium propionate, propylene glycol, benzyl alcohol, povidone (polybulurpyrrolidone), polybullic alcohol (partially saponified product) Polybutyl alcohol 'dibutyl ether mixture, maleic acid, malonic acid, D-manntol, anhydrous citrate, anhydrous sodium citrate, anhydrous sodium acetate, maleic anhydride, anhydrous monohydrogen phosphate, anhydrous dihydrogen phosphate sodium, Magnesium aluminate metasilicate, sodium metasulfobenzoate, sodium metaphosphate, methylcellulose, methyl butyl ether 'maleic anhydride copolymer, potassium iodide, sodium iodide, sodium lauryl sulfate, zinc sulfate, potassium aluminum sulfate, potassium sulfate, Examples thereof include magnesium sulfate, phosphoric acid, potassium dihydrogen phosphate, and calcium dihydrogen phosphate.

 [0028] Examples of the disintegrant include low-substituted hydroxypropylcellulose, carmellose, strength rumellose calcium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, hydroxypropyl starch, corn starch, and fibrin glycoprotein. Examples thereof include calcium oxalate.

 [0029] Examples of the corrigent include sucrose, D-sorbitol, xylitol, citrate, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, saccharin sodium, glycyrrhizin dipotassium, sodium glutamate, 5 ' — Sodium inosinate, 5′-sodium guarate, and the like.

 [0030] Examples of the surfactant include polysorbate (for example, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, etc.), polyoxyethylene 'polyoxypropylene copolymer, polyoxyethylene hydrogenated castor oil, Examples include sorbitan monostearate and sodium lauryl sulfate.

 [0031] Examples of the fragrances include lemon oil, orange oil, menthol, and brackish oil. Examples of the colorant include titanium oxide, edible yellow No. 5, edible blue No. 2, iron sesquioxide, yellow sesquioxide. Iron etc. are mentioned.

 Examples of the antioxidant include sodium ascorbate, L-cystine, sodium sulfite, vitamin E and the like.

[0032] 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 caustic anhydride, talc, hydrous silicon dioxide, and the like.

Examples of wetting agents include polysorbate 80, sodium laurate sulfate, sucrose fat Acid esters, polyethylene glycol, hydroxypropyl cellulose (HPC), and the like.

 [0033] Examples of the dissolution aid include dry methacrylic acid copolymer LD, hydroxypropyl methylenocellulose acetate succinate, and hydroxypropinoremethylol cellulose phthalate.

 Examples of solubilizers include glutamic acid and aspartic acid.

 Examples of the coating agent include sucrose, gelatin, hydroxypropylcellulose, and hydroxymethylcellulose phthalate.

 [0034] In addition to the exemplified uses, the additives described above may be used for other purposes (for example, excipients, binders, lubricants, stabilizers, disintegrators, corrigents, surfactants, perfumes). , Coloring agents, antioxidants, masking agents, antistatic agents, fluidizing agents, wetting agents, elution aids, solubilizing agents, coating agents, etc.), they may be used in their applications. In addition to the above, other known additives such as those described in Yakuji Nippo 2005 “Pharmaceutical Additives Dictionary” (edited by Japan Pharmaceutical Additives Association) may be used. .

 [0035] The composition of the present invention is generally used in producing (1) pranlukast hydrate, (2) saccharides, (3) water-soluble polymers, and (4) capsules. It is preferable that the composition contains an additive (formulation base). The combinations of (1) to (4) include (1) one or more sugars selected from the group consisting of pranlukast hydrate, (2) lactose, sucrose and mantolka, (3) polyethylene Glycol, methylcellulose, hydroxypropylcellulose and one or more water-soluble polymers selected from the group consisting of hydroxypropylmethylcellulose and (4) a combination of lubricants are preferred (1) pranlukast hydration A combination of (2) lactose, (3) polyethylene glycol and (4) magnesium stearate.

[0036] In the composition of the present invention, the weight ratio of saccharide to 100 parts by weight of pranlukast hydrate is preferably about 20 parts by weight to about 70 parts by weight, more preferably about 25 parts by weight to about 65 parts by weight. Parts by weight, more preferably about 30 parts by weight to about 60 parts by weight. The weight ratio of the water-soluble polymer to 100 parts by weight of pranlukast hydrate is preferably about 5 parts by weight to about 20 parts by weight, more preferably about 7.5 parts by weight to about 15 parts by weight. It is. [0037] In the composition of the present invention, the weight ratio of the lubricant to 100 parts by weight of pranlukast hydrate is preferably about 0.5 parts by weight to about 5 parts by weight, more preferably about 1 part. 0 parts by weight to about 4.5 parts by weight.

 [0038] In the present invention, the weight of the composition of the present invention filled in the capsule is preferably about 130 mg to about 400 mg force S, more preferably about 150 mg to about 380 mg force per capsule.

 [0039] The form of the composition of the present invention is preferably a granulated product. The granulated product is described in a granulation method of a commonly used pharmaceutical preparation, for example, “Granulation Nond Book” (edited by the Japan Powder Industrial Technology Association, Ohm, 1991). It is not particularly limited as long as it is a granulated product produced by a granulation method or the like. For example, wet granulated product, dry granulated product, rolling granulated product, spray dried granulated product, extruded granulated product, fluidized bed granulated product. Granules, agitation granulations, compression granulations, melt granulations, crushed granulations, coating granulations, liquid phase granulations, vacuum freeze granulations and the like. Among them, preferred are rolling granulated products, spray dried granulated products, extruded granulated products, fluidized bed granulated products, stirred granulated products, and the like. More preferred are spray-dried granules, stirred granules, and the like.

 The stirred granulated product includes stirred granulated product, stirred fluidized bed granulated product, stirred rolling fluidized bed granulated product and the like.

 [0040] When the composition of the present invention is a spray-dried granule, the weight percentage of pranlukast hydrate in 100% by weight of the spray-dried granule is preferably about 50% to about 98%. More preferably from about 55% to about 90%, particularly preferably from about 60% to about 80%.

 When the composition of the present invention is a stirred granulated product, the weight percentage of pranlukast hydrate in 100% by weight of the stirred granulated product is preferably about 30% to about 98%, more preferably about 50%. ~ 80%.

 [0041] The capsule in the present invention is not particularly limited as long as it is filled with the composition of the present invention, and may be the same as those generally used as pharmaceuticals. Capsules include hard capsules, soft capsules and the like.

[0042] The capsule in the present invention is a capsule containing pranlukast hydrate, and a certain amount of the composition of the present invention is added to the capsule film (empty capsule) according to a conventional method. The formulation filled in The capsule film may be a hard capsule or a soft capsule.

 [0043] The above-mentioned capsule film usually contains a capsule base and a plasticizer. If necessary, for example, a fragrance (for example, heart force oil, cinnamon oil, strawberry or other fruit essence or flavor). Etc.), preservatives (eg paraethyl hydroxybenzoate, propyl parahydroxybenzoate, etc.), dyes (eg yellow 4, yellow 5, red 3, blue 1, copper black fins, etc.), opaque (For example, titanium dioxide, bengara, ferric sesquioxide), lubricant (for example, magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol, lauryl sulfate) Sodium, etc.), solubility regulators (eg cellulose acetate phthalate, hydroxypropylmethyl) Alkali metal salt of cellulose, Alkali metal salt of hydroxymethyl cellulose acetate succinate, Alginate alkali salt, Polyacrylic acid Alkaline metal salt, Methylcellulose, Carboxymethylcellulose, Casein, Collagen, Agar powder, Polybulu alcohol, Pectin Etc.) may be included.

In the present invention, the capsule base used for the capsule film may be any substance that can be used as the base of the capsule film. For example, proteins (eg, gelatin, gelatin hydrolyzate, collagen, collagen hydrolyzate, casein, etc.), polysaccharides (eg starch, amylose, polygalataturonic acid, agar, carrageenan, gum arabic, dielan gum, xanthan gum, pectin) , Alginic acid, pullulan, etc.), cellulose (eg, hydroxymethylcellulose, hydroxymethylethylcellulose, methinoresenorelose, hydroxyethinoresenorelose, hydroxypropenoresenorelose (HP C), hydroxypropyl methylcellulose (HPMC) , Hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), etc.), biodegradable plastics (eg, polylactic acid, polyhydroxybutyric acid, polyg) And the like (eg, butter, margarine, shortening, cacao butter, etc.)) and the like. These capsule bases may be used in appropriate combination of two or more. In the present invention, among these capsule bases, proteins, particularly gelatin, are preferable. [0045] The plasticizer used for the capsule film may be any material that can be used as a plasticizer for the capsule film. For example, sugar (eg, sucrose, sucrose, starch, etc.), sugar alcohol (eg, sorbitol, xylitol, mannitol, etc.), polyhydric alcohol (eg, glycerin, ethylene glycol, polyethylene glycol, polypropylene glycol, etc.) ) And the like. Of these, polyhydric alcohols, particularly polyethylene glycol, are preferred.

 [0046] In the present invention, the content of pranlukast hydrate contained in the capsule is preferably about 112.5 mg to about 450 mg, more preferably 112.5 mg per capsule. 22 5mg or ί or 450mg, more preferably ί or 112. 5mg or ί or 225mg, especially 112.5mg. Also, as the size of capsules, No. 1, 2, 3, or 4 capsules are preferred. The weight of empty capsules per capsule is preferably about 30 mg to about 90 mg. For example, No. 2 capsules or No. 3 capsules containing 225 mg of pranlukast hydrate, or No. 3 capsules or No. 4 capsules containing 112.5 mg are preferable from the viewpoint of patient compliance.

 [0047] Therefore, in the capsule of the present invention, the total weight of one capsule is calculated by adding the weight of the composition to be filled and the weight of the empty capsule. Therefore, about 160 mg to about 490 mg is preferable. About 180mg to about 470mg force is preferred!

 [0048] In the present invention, the desiccant is not particularly limited as long as it is generally used at the time of storage of pharmaceuticals. Examples of such desiccant include acid aluminum, strength aluminum, calcium chloride, Calcium hydride, calcium oxide, calcium sulfate, copper sulfate, lithium aluminum hydride, magnesium, magnesium oxide, magnesium perchlorate, magnesium sulfate, synthetic zeolite (for example, molecular sieve), natural zeolite, diphosphorus pentoxide , Potassium carbonate, potassium hydroxide, silica gel, silica alumina gel, sodium, sodium hydroxide, sodium sulfate, magnesium aluminate, activated carbon and the like. These may be used in an appropriate combination of two or more as required.

[0049] In addition to the desiccants listed above, water-absorbing agents containing a high molecular polymer as a constituent component are also included in the category of desiccants in the present invention. Such a water absorbing agent is not particularly limited. For example, vinyl acetate- (meth) acrylic acid ester copolymer, butyl acetate maleic anhydride copolymer, isobutylene maleic anhydride copolymer, acrylic acid-methacrylic acid copolymer, polybutyl alcohol, polyethylene oxide, polypropylene Examples include oxide, polypyrrole pyrrolidone, sulfonated polystyrene, polybutyrpyridine, polyacrylamide, and polymethacrylamide.

 [0050] As the form of the desiccant used in the present invention, for example, granular, film-shaped, plate-shaped or sheet-shaped, and granular products filled in a breathable bag (for example, Examples thereof include dridan (trade name, Yamajin Corporation; silica gel), ID F (trade name, ID Corporation; salty calcium), and the like, but the form is not particularly limited.

 In the present invention, a desiccant formed into a sheet (also referred to as “sheet desiccant”) is preferably used. When molding the desiccant into a sheet, for example, a method of blending the desiccant into an appropriate support, molding plastic, etc., and kneading the desiccant into the plastic to form into a sheet, or pulp material And a method of impregnating with a solution containing a substance as a raw material of the desiccant. Sheet desiccants include ID sheets (trade name, IDY Co., Ltd .; salty calcium), high sheet dry (trade name, Marutani Kako Co., Ltd .; silica gel), and high dry pack (trade name, Marutani). Koki Co., Ltd .; silica gel). Preferably, an ID sheet is used.

 [0052] The desiccant used in the present invention is preferably a desiccant having a moisture absorption rate of about 20% to about 35% at a temperature of 25 ° C and a relative humidity of 50%. Such a desiccant is preferably a desiccant containing, for example, silica gel, silica alumina gel, calcium chloride, diphosphorus pentoxide, synthetic zeolite or natural zeolite, and more preferably calcium chloride or Examples thereof include a desiccant containing silica gel, more preferably a sheet-like desiccant containing salty calcium, and particularly preferably a sheet-like drying containing about 10% to 30% by weight of salty calcium. Agents. Examples of the sheet-like desiccant containing about 10% to about 30% by weight of calcium chloride include an ID sheet (trade name, ID Co., Ltd.).

[0053] When the desiccant is used in the present invention, it is preferable to use about 0.7 parts by weight to about 17 parts by weight of the desiccant with respect to 100 parts by weight of the total weight of one capsule. About 15 [0054] For example, in the drug package of the present invention, 14 capsules each containing 122.5 mg of pranlukast hydrate in a plastic sheet are PTP-wrapped per sheet, and the drug package 1 When 10 capsules are encapsulated, the total weight of 100 capsules per capsule is about 0.7 to about 17 parts by weight of “desiccant containing calcium chloride or silica gel”. Correspondingly, it is preferred to simultaneously encapsulate about 0.22 g to about 5.5 g of “sheet desiccant containing calcium chloride” or “desiccant containing granular silica gel”. Furthermore, from about 1 part to about 15 parts by weight of “a desiccant containing calcium chloride or silica gel” with respect to 100 parts by weight of one capsule, about 0.32 g to about 4. It is more preferable to enclose 8 g of “sheet-like desiccant containing salty calcium” or “desiccant containing granular silica gel” at the same time. About 1.5 parts by weight per 100 parts by weight of one capsule About 0.48 g to about 3.4 g of “sheet-like desiccant containing salty calcium” or “granular” as equivalent to about 11 parts by weight of “desiccant containing salty calcium or silica gel” It is particularly preferred to encapsulate the `` desiccant containing silica gel '' at the same time. About 3.1 parts by weight to about 9.3 parts by weight of `` calcium chloride or silica gel is included with respect to 100 parts by weight of one cab cell The equivalent of "desiccant" is about lg to about 3g It is especially preferred that drying agent "at the same time encapsulating comprising a sheet-like drying agent" or "granular silica gel containing Shioi匕 Cal Shiumu. Here, the weight when the “sheet-like desiccant containing calcium chloride” is used means the weight including the weight of the sheet-like pulp material impregnated with calcium chloride.

 The thickness of the “sheet-like desiccant containing calcium chloride” is preferably about 0.5 mm to about 3 mm.

[0055] In the drug package of the present invention, a humectant can be encapsulated in combination with the above desiccant. In the present invention, the humectant means a substance having a water absorption, moisture absorption and moisture release function, and a function capable of maintaining a constant humidity, that is, a function of adjusting to an equilibrium humidity. Say. Examples of such a humectant include hydrated ethylene glycol-containing sheets, dry keep (trade name, Sasaki Chemical Co., Ltd.), and the like. [0056] In the drug package of the present invention, it is important that the relative humidity of the internal atmosphere is adjusted within a certain range. In the present invention, the internal atmosphere is a capsule filled with the composition of the present invention PTP-packed with a sheet enclosed in a drug package (hereinafter sometimes referred to as “PTP package”). And an atmosphere in which a desiccant is placed. Since the relative humidity of the internal atmosphere is in equilibrium with the relative humidity in the PTP package, it is considered to be equivalent to the relative humidity of the environment in which the capsule is in contact with the PTP package.

 [0057] In the present invention, the relative humidity of the internal atmosphere is adjusted to about 10% to about 45%. The relative humidity of the internal atmosphere is preferably from about 17% to about 40%, more preferably from about 10% to about 40%, particularly preferably from about 20% to about 35%.

 When the relative humidity of the internal atmosphere is less than about 10%, serious abnormalities (for example, cracking, chipping, etc.) occur in the capsule. In addition, when the relative humidity of the internal atmosphere exceeds about 45%, the capsules may have a disintegration delay, a dissolution delay, or the like that impairs the function as a pharmaceutical product.

 Here, the relative humidity of the internal atmosphere means a relative humidity measured using a thermohygrometer at a temperature of 25 ° C.

 [0058] The relative humidity can be measured by a known method. For example, the method described in the examples below (for example, a method using a thermo-hygrometer (THARMO RECORDER RS-12; ESPEC), etc.) or a water activity measuring device (eg, AQUALAB CX-3TE; Decagon, etc.) , Moisture permeability test equipment (ex. L80-5005; Ritsushi Co., Ltd., GTR-WV; GTR Tech Co., Ltd.), thermogravimetry equipment (ex. TGA-50Z50H; Shimadzu Corporation etc.), water vapor permeability The relative humidity can be measured using a combination of measuring devices (eg, PERMATRAN-W (R) 3/61; MOCON, etc.).

 [Relative humidity measurement method]

 The relative humidity measurement method using the above-described water activity measuring apparatus is as follows.

 <Measurement of water activity of capsule containing pranlukast hydrate>

Pranlukast hydrate-containing capsules and desiccants (for example, ID sheets, etc.) that are PTP-packaged using PVC are placed in a sample cup, and a water activity measuring device (AQUAL Measure the water activity (Aw; Water Acitvity) value in the sealed sample cup using AB CX-3TE. The obtained Aw value is converted to ERH (equil ibrium relative humidity).

 [0059] Examples of the drug package of the present invention include a drug package as shown in FIG. The drug package shown in Fig. 1 is composed of a capsule (2) and a desiccant (3) filled with a composition containing pranlukast hydrate PTP-packaged with a plastic sheet (1). It is enclosed in a packaging material (4) that is film-powered and sealed and packaged.

 [0060] The film used for the exterior material is not particularly limited as long as it is a film-like material that can be sealed. However, a film having a property capable of preventing the inflow and outflow of gas such as water vapor is preferable. Examples of such a film include an aluminum film, a high-density polyethylene film, a polyvinyl chloride film, a high-density polyethylene laminate paper, a polyvinylidene chloride laminate paper, and preferably an aluminum film. Examples of the form of the exterior material include cans, bottles, bags (for example, car toner packaging, shrink packaging, pillow packaging, etc.), and bags are preferred. Furthermore, when the form of the exterior material is a bag, it may be a bag having a chuck (for example, a single chuck or a double chuck).

 [0061] The drug package of the present invention is preferably an aluminum film package using an aluminum film as an exterior material, and more preferably an aluminum film pillow package. The aluminum film package can be manufactured by a known method, for example, by encapsulating a PTP package and a desiccant in a bag or the like that also contains aluminum film and heat-sealing.

[0062] In addition, as the space volume inside the drug package of the present invention, when calculated excluding the volume of the PTP package and the desiccant, about 60 to 80 cm ³ is preferable, and about 65 to 75 cm ³ is more preferable. Good.

 [0063] In the present invention, the relative humidity of the internal atmosphere described above is "adjusted" when the relative humidity is about 6 hours after the preparation of the drug package of the present invention as shown in the Examples below. It means that the steady state is reached and then the value is kept within the prescribed range for at least about 6 months.

[0064] In the present invention, the water content means the amount of water contained in the test substance, that is, the water content. Here, the test substance is a substance that constitutes the drug package of the present invention. Although not limited to this, Preferably, the composition of the present invention, the capsule membrane constituting the capsule, and the like are mentioned. In the present invention, the water content of the composition comprising pranlukast hydrate or the like is preferably about 1% to about 2.7%, preferably about 1.2% to about 2.5%. It is more preferable that it is. More preferably, the moisture content of the capsule film is about 9% to about 16%, preferably about 8% to about 17%. The water content of these test substances can be measured by a known method. For example, it can be measured according to a method known for water content measurement of pharmaceuticals, especially the water content measurement method listed in the Japanese Pharmacopoeia, in particular, the water content measurement method (Karl Fischer method) listed in the 15th revision Japanese Pharmacopoeia. .

 [0065] In the present invention, a capsule filled with the composition of the present invention enclosed in a drug package and PTP-packed with a sheet, an amount of a desiccant having a certain moisture absorption rate, and a composition The relative humidity of the internal atmosphere of the drug package can be adjusted within a certain range by appropriately combining the moisture content of the capsule film. The drug package of the present invention in which the relative humidity of the internal atmosphere is adjusted in this manner is a disintegration delay, elution delay, abnormality (for example, cracking, chipping) during storage of a capsule filled with the composition of the present invention. Etc.), and wind and deliquescence can be suppressed.

 [0066] In the present invention, "disintegration delay" means that the elution rate of pranlukast hydrate is delayed by extending the disintegration time of the contents of the capsule in the present invention. As will be apparent to those skilled in the art, elution of pranlukast hydrate occurs when the composition of the present invention, which is the content in the capsule, is disintegrated and subdivided into small particles to increase the surface area. It is considered that gastrointestinal wall force is absorbed quickly.

 [0067] In the present invention, the degree of "disintegration delay" is determined in the disintegration test after the capsule filled with the composition of the present invention is stored for an arbitrary period inside and outside the drug package and outside the PTP package. This can be confirmed by comparing with the test results in the initial state. The disintegration test can be performed by a known method. For example, the disintegration test can be performed according to a method generally known as a disintegration test method for solid preparations for internal use such as tablets and capsules. It is preferable to carry out the test according to the test method, especially the disintegration test method listed in the 15th revision of the Japanese Pharmacopoeia.

In the present invention, “elution delay” means that the elution rate of pranlukast hydrate is delayed. This means that bioavailability changes after in vivo administration. As is apparent to those skilled in the art, the elution rate of the active ingredient in the capsule defines the bioavailability (bioavailability) of the capsule, so that bioavailability after in vivo administration changes due to delayed elution. However, it is considered that there is a possibility that the medicinal effect will be insufficient or that there will be side effects.

 [0069] In the present invention, the degree of "elution delay" is determined in the dissolution test after the capsule filled with the composition of the present invention is stored for an arbitrary period inside and outside the drug package and outside the PTP package. This can be confirmed by comparing the test results in the initial state. The dissolution test can be performed by a known method. For example, the dissolution test method listed in the Japanese Pharmacopoeia can be performed according to a method generally known as a dissolution test method for internal solid preparations such as tablets and capsules. In particular, it is preferable to follow the dissolution test method listed in the 14th revised Japanese Pharmacopoeia. For example, the first method (rotating basket method), the second method (paddle method), the third method (flow-through cell method) ) And the like.

 [0070] Storage conditions for confirming the degree of "elution delay" are not particularly limited. For example, it may be room temperature as is usually performed by those skilled in the art, and is generally an accelerated test or a severe test. It may be at high temperature and Z or high humidity conditions. By using high temperature and Z or high humidity conditions, the result of long-term storage at room temperature can be obtained in a shorter period of time.

 [0071] The cause of the occurrence of the above-mentioned "disintegration delay" and "elution delay" is generally a composition or formulation base containing an active ingredient over time by storing a drug, particularly a capsule agent (for example, For example, in the case of a capsule, it is considered that some kind of change (for example, change in moisture content, etc.) is generated in the capsule film.

[0072] In the present invention, the "abnormality" of the capsule means that a certain change (for example, a decrease in the strength of the capsule film, etc.) occurs in the capsule agent over time due to storage, resulting in cracking. This means that the capsule function of protecting the composition containing pranlukast hydrate such as chipping is impaired. Specifically, when the capsule is cracked, chipped, etc., the content of the composition is increased by the inflow and outflow of moisture and the inflow and outflow of gas just by flowing out the yarn and composition containing pranlukast hydrate. Or the state changes and a certain amount of bra The function of the capsule to maintain Nurukast hydrate and its quality will be impaired.

 [0073] The above-mentioned "abnormality" of the capsule is obtained by storing the capsule filled with the composition of the present invention inside and outside the drug package and outside the PTP package for an arbitrary period, and then subjecting it to a crack load test. This can be confirmed by comparing the cracking rate calculated by the number of cracked specimens against the number and the cracking rate for each storage period. The crack load test can be performed by, for example, a method of evaluating the strength by applying a certain impact, load, etc. to the capsule, and can be performed, for example, by a falling weight impact test as shown in Examples below. .

 [0074] The drug package of the present invention has the object of the present invention, that is, the disintegration delay, elution delay, abnormality (for example, cracking, chipping, etc.) during storage of the capsule filled with the composition of the present invention, In order to achieve suppression of deliquescence and the like, it is preferable that the elements constituting the above-described drug package of the present invention be a specific combination as shown below. That is, (I) a capsule filled with a composition comprising Pranlukast hydrate having the following characteristics (a) to (e) packed in PTP with a plastic sheet: (II) Capsules A total weight of one capsule of about 0.7 to about 17 parts by weight, with a moisture absorption of about 20% to about 35% at a temperature of 25 ° C and a relative humidity of 50%. (III) The film is hermetically sealed with a film, and at a temperature of 25 ° C, the relative humidity of the internal atmosphere measured with a thermohygrometer is adjusted to about 10% to about 45%. The drug package is preferred.

 (a) Contains about 112.5 mg or about 225 mg of pranlukast hydrate per capsule

(b) about 130 mg to about 400 mg of composition per capsule,

 (c) per capsule, the weight of the empty capsule is about 30 mg to about 90 mg,

 (d) the moisture content of the yarn composition is about 1% to about 2.7%;

 (e) The moisture content of the capsule film is about 8% to about 17%.

[0075] More preferably, the combination of the constituent elements in the drug package of the present invention is (P) pranlukast having all the above-mentioned characteristics (a) to (e), which is PTP-packed with a plastic sheet. Filled with a composition containing hydrate, saccharide, water-soluble polymer and lubricant Capsules and (II) a desiccant containing about 0.7 to about 17 parts by weight of silica gel or calcium chloride per 100 parts by weight of the total capsule weight, and (III) An example is a drug package that is hermetically packaged with a film and has a relative humidity of about 10% to about 45% measured at 25 ° C using a thermohygrometer. Particularly preferably, (I) a composition containing pranlukast hydrate, which has all of the following characteristics (i) to (vi) and is packed in PTP with a plastic sheet, is filled. And (II) a capsule-like sheet-like desiccant containing about 1 to about 15 parts by weight per 100 parts by weight of the total capsule weight, and (III) An example is a drug package that is hermetically packaged with a film, and at a temperature of 25 ° C, the relative humidity of the internal atmosphere measured with a thermohygrometer is adjusted to about 10% to about 45%.

 (i) Contains about 112.5 mg of pranlukast hydrate per capsule,

 (ii) about 130 mg to about 400 mg of thread and composition per capsenore;

 (iii) the composition comprises from about 30 to about 60 parts by weight lactose, from about 7.5 to about 15 parts by weight polyethylene glycol per 100 parts by weight pranlukast hydrate, and stearin A yarn composition comprising about 1 part by weight to about 4.5 parts by weight of magnesium acid,

 (iv) the weight of the empty capsule per capsenore is about 30 mg to about 90 mg;

 (V) the water content power of the composition is about 1% to about 2.7%,

 (vi) The moisture content of the capsule film is about 8% to about 17%.

[0076] [Application to pharmaceutical products]

 Since the composition of the present invention contains pranlukast hydrate as an active ingredient, bronchial asthma, allergic rhinitis, sinusitis, chronic obstructive pulmonary disease, Meniere's disease, exudative otitis media, migraine, It is useful as a preventive and Z or therapeutic agent for various diseases such as dysmenorrhea.

 [Toxicity]

 Pranlukast hydrate in the present invention has low toxicity and is sufficiently safe for use as a medicine.

 Example

[0077] Hereinafter, the ability to specifically explain the present invention through examples, the present invention is not limited to these. It is not something.

 In the following, the packaging operation for the production of the PTP package or drug package is apparent to those skilled in the art under the environment of normal temperature (about 18 to 28 ° C) and normal humidity (about 30 to 70%). This was done according to the usual method.

 In each test example, during the storage period of 6 months, the temperature and relative humidity of each test section are kept constant, and the relative humidity is measured by a thermo-hygrometer (THERMO RECORDER

RS-12: manufactured by ESPEC).

[0078] [Formulation example]: Production of capsule containing pranlukast hydrate (112.5 mg)

 According to the method described in JP-A 61-050977, a suspension of pranlukast hydrate (40 kg) and lactose (18.7 kg) in a polyethylene glycol aqueous solution is sprayed with a spray dryer. Spray-dried granulated material was obtained by spraying. The mixture of the resulting granulated product and magnesium stearate (as appropriate) is used as the content, and the content of pranlukast hydrate is 112.5 mg per capsule, and the number 3 capsule (forced gel) · Capsules containing pranlukast hydrate having the following composition were obtained by filling in a conventional method (made by Japan Co., Ltd. or Qualicabus Co., Ltd.).

 <Composition (per capsenolet)>

 • Pranlukast hydrate (112.5 mg)

 'Lactose (52. 65mg)

 • Polyethylene glycol (Macrogol 4000) (11. 25mg)

 'Magnesium stearate (3.6 mg)

 , Empty capsule 3 (49. Omg)

[0079] [Example of PTP package production]

 About the capsule containing pranlukast hydrate produced in the above formulation example As a plastic sheet used for PTP packaging, a 200 μm-thick hard chloride bule sheet (Sumilite (registered trademark) VSS-1104; Sumitomo Bakelite Co., Ltd., PTP packaged using abbreviated PVC) (PTP package 1).

Similarly, a composite sheet consisting of a hard salty bulb and a salty vinylidene with a thickness of 250 m (VSL—4501; Sumitomo Bakelite Co., Ltd., hereinafter referred to as PVCZP) Abbreviated as VDC. ) Was used for PTP packaging (PTP package 2).

 Similarly, PTP packaging was performed using unstretched polypropylene (NS-3451; Sumitomo Beta Light Co., Ltd., hereinafter abbreviated as CPP) as a plastic sheet (PTP package 3).

 Each PTP package was manufactured by pasting each plastic sheet and aluminum film in a conventional manner and encapsulating 14 capsules per sheet.

[0080] [Examples 1 to 7 and Comparative Example 1]

 PTP package 1 obtained in the above PTP package production example and calcium chloride impregnated sheet desiccant (ID sheet; IDY Co., Ltd.) or a bag-shaped desiccant containing granular silica gel (Dry Yarn; Yamanin Pharmaceutical Co., Ltd.) Were packaged in an aluminum film bag (about 110 mm x about 200 mm) and hermetically packaged to produce a drug package having the structure shown in Table 1 below. Here, the weight of the desiccant means the weight including the weight of the sheet-like pulp material impregnated with salty calcium, in the case of a sheet-like desiccant containing salty calcium.

[0081] [Table 1]

Using the drug package obtained in the above examples or comparative examples, the capsule obtained in the formulation example (no packaging) or the PTP package (no aluminum film bag) as samples, the following tests Went.

 When interpreting the test results, the relative humidity when capsules (no packaging) and PTP packaging (without aluminum film bags) are used for each test is the relative humidity of the capsule or PTP packaging with aluminum film. The drug package sealed in a bag was considered to exhibit the same value as the relative humidity of the internal atmosphere.

 [0083] [Test Example 1: Measurement of moisture content of capsule]

 6 months shelf life at 25 ° C and relative humidity of 22% or 75% for samples of capsules (no packaging) and PTP packaging 1 (without aluminum film packaging) obtained in the formulation example At the start of storage (initial), after 2 months, 4 months and 6 months, according to the moisture measurement method (Karl Fischer method) described in the 15th revised Japanese Pharmacopoeia (Karl Fischer method) The water content of the composition was measured for 3 samples, and the average value was calculated for each sample. The results are shown in Table 2.

 [0084] [Table 2]

 [0085] From the above results, when stored at a relative humidity of 22%, the contents of the capsules in either unwrapped or PTP packaged state after 2 months, 4 months, and 6 months It was found that the moisture content of the capsule film was lower than that of the initial stage, although the moisture content of the capsule film was hardly changed. On the other hand, when stored at a relative humidity of 75%, the moisture content of the capsule film and contents increased after 2 months, 4 months, and 6 months.

[0086] Next, with respect to the samples of Examples 2 and 3, the fifteenth amendment was made at the beginning of storage in the storage period of 6 months under the condition of a temperature of 25 ° C and a relative humidity of 75% (initial) and after 6 months. Fill the capsule according to the moisture measurement method (Karl Fischer method) described in the Japanese Pharmacopoeia. The moisture content of the contents (composition) was measured for 3 samples each, and the average value was calculated for each sample. The results are shown in Table 3.

 [Table 3] Storage conditions: Temperature 25. C, relative humidity 75%

 [0088] As shown in the above results, when stored under the conditions of a temperature of 25 ° C and a relative humidity of 75%, unlike the results of storing the PTP package 1 as described above, there are two types of Even though the drug package consisted of a combination of V and deviation with the desiccant !, there was no power increase in the water content of the contents. Further, when the moisture content of the contents of the drug package manufactured in Example 1 and Examples 4 to 7 was measured under the same conditions, it showed almost the same value as the above result. On the other hand, when the moisture content of the contents of the drug package of Comparative Example 1 was measured under the same conditions, the moisture content of the contents increased.

 Note that the moisture content of the contents was measured under the same conditions for a drug package manufactured in the same manner except that PTP package 2 or 3 was used instead of PTP package 1 in Examples 2 and 3 above. The value was almost the same as the above result. This proved that the moisture content of the contents was not affected by the difference in the plastic sheet used in the PTP package.

 [0089] [Test Example 2: Measurement of disintegration time of capsule]

 6 months shelf life at 25 ° C and relative humidity of 22% or 75% for samples of capsules (no packaging) and PTP packaging 1 (without aluminum film packaging) obtained in the formulation example Disintegration time was examined according to the disintegration test method (capsule) described in the 15th revised Japanese pharmacopoeia at the start of storage (initial stage) in 2 months, 4 months and 6 months later. The test was performed on 6 specimens each, and all the samples were disintegrated within 20 minutes and the contents were completely dissolved. The results are shown in Table 4.

[0090] [Table 4] Storage conditions Sample Disintegration time (min)

 (25 ° C)

 Initial 2 months later 4 months later 6 months later

 Capsule

 5-6 6-7 5-7 5-7

 (No packaging)

 Relative humidity

 22% PTP packaging 1

 II 5-7 6-7 5-7

 (PVC)

 Capsule II 7 ~ 1 1 Nonconforming # Nonconforming # (No packaging)

 Relative humidity

 75% PTP packaging 1

 II 7-8 Nonconforming # Nonconforming #

 (PVC)

 #: Insoluble lumps remain

[0091] Next, for the samples of Examples 2 to 4, 6 and Comparative Example 1 shown in Table 5 below, at the start of storage in a storage period of 6 months under the condition of a temperature of 25 ° C and a relative humidity of 75% (Initial), disintegration time was examined after 2 months, 4 months and 6 months in the same manner as above. The results are shown in Table 5.

 [0092] [Table 5]

 *: 2 out of 6 samples remain at 20 minutes after the start of the test

 [0093] Further, when the disintegration test was carried out under the same conditions for the drug packages produced in Examples 5 and 7, in all the examples, the total number was within 20 minutes at all the points in the storage period. It was compatible because it collapsed and the contents were completely dissolved.

[0094] As shown in the above results, when stored under the condition of a temperature of 25 ° C and a relative humidity of 75%, the PTP package 1 described above remains as it is, or the desiccant is not present as in Comparative Example 1. Unlike the case where it was incompatible after 4 and 6 months when stored as a drug package, the amount of desiccant was 2 types of desiccant and the amount of desiccant (the amount of desiccant relative to 100 parts by weight of one capsule) The drug package consisting of any combination of about 1.52 parts by weight to about 10.3 parts by weight) was able to suppress the disintegration time extension and became compatible at all time points. [0095] When the results of Test Example 1 and Test Example 2 above are taken together, when stored under conditions of a relative humidity of 75%, no packaging, PTP packaging (without aluminum film packaging), or Comparative Example 1, As the water content of the contents and capsule film observed in Test Example 1 increased, it became clear that the disintegration time observed in Test Example 2 was prolonged, and the internal atmosphere of the drug package was changed. It was suggested that the capsule disintegration was delayed at about 75% or more. On the other hand, in the drug package of the example, the moisture content of the contents is within a preferable range by sealing together with a certain amount of an appropriate desiccant and hermetically packaging with a film (the moisture content of the composition: about 1% to about 2.7%, and the moisture content of the capsule film was adjusted to about 8% to about 17%.

 [0096] [Test Example 3: Measurement of capsule strength]

 Samples of capsules (unwrapped) obtained in the formulation examples are 2 months, 4 months and 6 months in a 6 month storage period at a temperature of 25 ° C and a relative humidity of 22% or 75%. After a month, the strength of the capsule was measured according to the following falling weight impact test method. Measurements were also made in the same way after 7 and 37 days in a 37-day storage period at a temperature of 25 ° C and a relative humidity of 7%. The results are summarized in Table 6.

 <Falling weight impact test>

 (1) The capsule was placed sideways in the center of the pedestal of the falling weight impact test apparatus. An lOOg metal weight was fixed to the top of the cylinder with a stopper so that it was 80 mm above the pedestal.

 (2) The cylinder was placed on the pedestal, the hook of the fastener was pushed in and removed, and the weight was allowed to fall naturally onto the capsule body and cap.

 (3) Each of the 50 samples was subjected to the test, and the capsules were checked for cracks and chipping. The ratio of capsules that produced cracks, chipping! /, Or misalignment in the full-strength plastics was calculated as the cracking rate.

[0097] [Table 6] Storage conditions Sample Number of cracks 50

 (25 ° C) 7 days later 3 hours later 2 months later 4 months later 6 months later Relative humidity capsule

 1 9---7% (no packaging)

 Relative humidity Capsule ― ― 1 8 9 22% (No packaging)

 Relative humidity capsule

 0 0 0

 75% (no packaging)

[0098] From the above results, under the conditions of a temperature of 25 ° C and a relative humidity of 22%, the cracking rate of the capsules after storage for 2 months, 4 months and 6 months in the unwrapped state is within the applicable range, and the relative humidity Under the 75% condition, the cracking rate of the capsules after storage for 2 months, 4 months, and 6 months in the unwrapped state was 0% at any time point. On the other hand, it was found that the cracking rate of the capsule rapidly increased under dry conditions at a temperature of 25 ° C and a relative humidity of 7%.

 Therefore, it became apparent that the strength of the capsules decreased when the water content of the capsule film was below the moisture content of Test Example 1 at a temperature of 25 ° C. and a relative humidity of 22%. It was also suggested that the relative humidity of the internal atmosphere of the drug package should be adjusted to exceed at least 7%, since the capsule cracking ratio increases in an atmosphere with a relative humidity of about 7% or less.

 [0099] [Test Example 4: Relative humidity measurement inside capsule aluminum film package]

 In the drug package manufactured in Examples 1, 5 and 7 described above, the thermo-hygrometer (THERMO RECORDER RS-12: ESPEC) was sealed in an aluminum film bag (110 mm X 200 mm) during hermetically sealed packaging. Heat-sealed by a conventional method. The drug package containing the heat-sealed thermo-hygrometer is allowed to stand at room temperature for 48 hours, and then allowed to stand for 24 hours in an environment at a temperature of 25 ° C and a relative humidity of 60%. The humidity was monitored.

 Table 7 shows the results of measuring the relative humidity of the internal atmosphere when the temperature reached 25 ° C and the relative humidity reached a steady state.

[0100] [Table 7] Sample relative humidity

 Example 1 37% RH

 Example 5 23% RH

 Example 7 10% RH

[0101] Further, regarding the drug packages of Examples 2, 3 and 4, when the relative humidity of the internal atmosphere of each drug package was monitored by the same method and the same conditions as described above, the relative humidity was about 10 to 23%. The power was within the range. Furthermore, when the relative humidity of the internal atmosphere of the drug package was similarly monitored for the drug package of Example 6, it was found that the relative humidity was in the range of about 23 to 37%.

 [0102] From the above results, the amount of the desiccant was defined as “sheet-like desiccant containing calcium chloride” or “desiccant containing granular silica gel”. When used in the range of 5 parts by weight to about 11 parts by weight, the relative humidity at a temperature of 25 ° C in the film package was adjusted to about 10% to about 40%.

 [0103] When the results of Test Examples 1 to 3 are taken together, the moisture content of the composition and the capsule film of the drug packages of Examples 1 to 7 is about 1% to about 2.7% and Since it was in the range of about 8% to 17%, neither disintegration delay nor capsule cracking occurred. Furthermore, considering Test Example 4 together, the internal atmosphere of the drug package is about 10 to about 40% by adjusting the moisture content of the composition and the capsule film as described above. The power to be adjusted to.

 [0104] Accordingly, a capsule filled with a composition containing pranlukast hydrate PTP-packed with a plastic sheet, and the amount of the desiccant is "sheet-like dry containing salty calcium" Composition "or" desiccant containing granular silica gel "by adjusting the content within a range of about 1.5 parts by weight to about 11 parts by weight per 100 parts by weight of the total weight of one capsule and encapsulating them together It was found that the relative humidity of the internal atmosphere of the drug package is adjusted to about 10% to about 40% because the moisture content of the product and capsule film is adjusted to the optimum range.

 Industrial applicability

[0105] According to the present invention, a capsule containing PTP-packed pranlukast hydrate is preserved. It is possible to provide a drug package in which deterioration in quality such as disintegration delay at the time of existence and abnormalities such as capsule breakage are minimized.

Claims

The scope of the claims  [I] Capsules filled with a composition containing pranlukast hydrate PTP-packed with a sheet and a desiccant are enclosed, sealed in a film, and a temperature of 25 ° In C, a drug package in which the relative humidity of the internal atmosphere measured with a thermohygrometer is adjusted to 10% to 45%.  [2] The pharmaceutical package according to claim 1, wherein the sheet is a plastic sheet or an aluminum sheet.  [3] The drug package according to claim 1, which is a capsule containing 112.5 mg or 225 mg of pranlukast hydrate per capsenore. [4] The drug package according to claim 1, wherein the capsule is a capsule containing a composition of 130 mg to 400 mg per capsule, and the weight of the empty capsule per capsule is 30 mg to 90 mg. body. 5. The drug package according to claim 1, wherein the water content of the composition comprising pranlukast hydrate is 1% to 2.7%. 6. The drug package according to claim 1, wherein the water content of the capsule film in the capsule is 8% to 17%.  7. The drug package according to claim 1, wherein the composition comprising pranlukast hydrate is a composition further comprising a saccharide, a water-soluble polymer and a lubricant.  8. The drug package according to claim 7, wherein the saccharide is lactose, the water-soluble polymer is polyethylene glycol, and the lubricant is magnesium stearate.  [9] Compositional power comprising pranlukast hydrate 30 parts by weight to 60 parts by weight of lactose and 7.5 parts by weight of polyethylene glycol to 15 parts by weight per 100 parts by weight of pranlukast hydrate 9. The drug package according to claim 8, which is a composition comprising parts by weight and containing 1.0 to 4.5 parts by weight of magnesium stearate.  10. The drug package according to claim 1, wherein the desiccant is a desiccant having a moisture absorption rate of 20% to 35% at a temperature of 25 ° C. and a relative humidity of 50%. [II] The drug package according to claim 10, wherein the desiccant is silica gel or calcium chloride salt. 12. The drug package according to claim 10, wherein the desiccant is a sheet desiccant. 13. The drug package according to claim 12, wherein the sheet-like desiccant is a sheet-like desiccant containing sodium chloride calcium.  [14] Capsule The weight of the desiccant encapsulated per 100 parts by weight of the total capsule is 0.  The drug package according to claim 10, which is 7 to 17 parts by weight.  15. The drug package according to claim 10, wherein the weight of the desiccant to be encapsulated is 1 part by weight to 15 parts by weight per 100 parts by weight of the total capsule weight.  [16] (I) Filled with a composition containing pranlukast hydrate, which has the following characteristics (a) to (e), PTP-packed with a plastic sheet: Capsule and (ii) Capsules with a total moisture content of 0.7 to 17 parts by weight per 100 parts by weight of capsules at a temperature of 25 ° C and a relative humidity of 50%. (III) Drug whose internal humidity measured at 25 ° C using a thermohygrometer is adjusted to 10% to 45%. Package:  (a) 12.5 mg or 225 mg pranlukast hydrate per capsule, (b) 130 mg to 400 mg of thread and composition per capsenore,  (c) The weight of empty capsules per capsule is 30 mg to 90 mg,  (d) the moisture content of the composition is 1% to 2.7%,  (e) The moisture content of the capsule film is 8% to 17%.  [17] Composition power comprising pranlukast hydrate A composition comprising pranlukast hydrate, sugar, water-soluble polymer and lubricant, wherein the desiccant is silica gel or salt 17. The drug package according to claim 16, which is a desiccant containing calcium. [18] Capsule strength Capsules containing 112.5 mg of pranlukast hydrate per capsule, comprising pranlukast hydrate Pranlukast hydrate 100 wt. A composition containing 30 to 60 parts by weight of lactose, 7.5 to 15 parts by weight of polyethylene glycol, and 1.0 to 4.5 parts by weight of magnesium stearate per part. The desiccant is a sheet-like desiccant containing calcium chloride, and the sheet-like desiccant is encapsulated at a ratio of 1 to 15 parts by weight per 100 parts by weight of the total weight of one capsule. A drug package according to claim 17, wherein Pranlukast hydrate, adjusted to have all of the following characteristics (a) to (e), packaged in a plastic sheet in a drug package sealed with a film, and PTP packed in a plastic sheet And a sheet-like desiccant containing calcium salt calcium, and 0.7 parts of the sheet-like desiccant per 100 parts by weight of the total weight of one capsule. The relative humidity of the internal atmosphere measured by using a thermohygrometer at a temperature of 25 ° C of the drug package is adjusted to about 10% to about 45% by adjusting to contain 17 parts by weight to 17 parts by weight and enclosing them together. To adjust to%:  (a) 12.5 mg or 225 mg pranlukast hydrate per capsule, (b) 130 mg to 400 mg of thread and composition per capsenore,  (c) The weight of empty capsules per capsule is 30 mg to 90 mg,  (d) the moisture content of the composition is 1% to 2.7%,  (e) The moisture content of the capsule film is 8% to 17%.