JP3906485B1 - Drug package - Google Patents

Abstract

Disclosed is a drug packaging capable of minimizing quality degradation such as delay in disintegration during storage of capsules containing pranlukast hydrate packaged in a plastic sheet and minimizing capsule cracking. Provide the body.
A capsule 2 filled with a composition containing pranlukast hydrate PTP-packaged in a sheet 1 and a desiccant 3 are encapsulated and hermetically packaged with a film 4. The drug packaging body in which the relative humidity of the internal atmosphere measured using a thermohygrometer is adjusted to 10% to 45% at a temperature of 25 ° C.
[Selection] Figure 1

Description

  The present invention relates to a drug package for capsules containing pranlukast hydrate.

  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-packaged or PTP-packaged preparations are provided on the market as drug packs that are further sealed in a sealed body such as an aluminum film bag in order to avoid the influence of outside air and light.

  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. It has been reported that solid preparations containing pranlukast hydrate, particularly in the case of capsules, undergo dissolution changes in one week when stored in a non-packaging state at a temperature of 25 ° C. and a relative humidity of 75% (non- Patent Document 1). Furthermore, even when the capsule is in a PTP packaged state, the decay rate and dissolution of the capsule may change due to an increase in the moisture content and humidity of the outside air.

  So far, a drug package in which a tablet containing perindopril erbumine 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 a change in elution, moisture contained in a sealed body made of a moisture-proof film and a desiccant together with a PTP package. The capsule sometimes cracked due to the decrease in the thickness. Therefore, as described above, after the Pranlukast hydrate capsule is packaged in PTP and then simply sealed in a sealed body or simply sealed in a sealed body together with a desiccant, the relative humidity of the atmosphere in the packaged body Therefore, there was a problem that the capsule disintegration delay, elution delay and capsule breakage could not be prevented. Regarding this problem, there is no description or suggestion on adjusting the relative humidity of the internal atmosphere of the drug package.

JP-A-61-050977 Japanese Patent Laid-Open No. 11-206850 Stability information of tablets and capsules without packaging, revised version 3 (Japan Hospital, Pharmaceutical Journal)

  The object of the present invention is to minimize degradation of quality such as delay in disintegration during storage of capsules containing pranlukast hydrate packaged in a plastic sheet, and to minimize capsule cracking. It is to provide a drug package that can be used.

  The present inventors consider that it is effective to adjust the relative humidity in the drug package in order to achieve the above object, and contain pranlukast hydrate PTP-packed with a plastic sheet. For a drug package encapsulated with a desiccant and sealed with a film, the amount of the desiccant and the moisture content of the composition and capsule film in the capsule The combination was studied earnestly. As a result, surprisingly, the relative humidity of the internal atmosphere was adjusted so that the disintegration of the capsules and the cracking of the capsules could be suppressed by certain combinations of these elements. The present inventors have found that a drug package can be provided and completed the present invention.

That is, the present invention
[1] A capsule filled with a composition containing pranlukast hydrate PTP-packed with a sheet and a desiccant are encapsulated and hermetically packaged with a film at a temperature of 25 ° C. , A drug package in which the relative humidity of the internal atmosphere measured using a thermohygrometer is adjusted to 10% to 45%,
[2] The drug package according to [1], further containing a moisturizing agent,
[3] The drug package according to [1], wherein the sheet is a plastic sheet or an aluminum sheet,
[4] The drug package according to the above [1], wherein the capsule is a capsule containing 112.5 mg or 225 mg of pranlukast hydrate per capsule,
[5] The drug package according to [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,
[6] The drug package according to the above [1], wherein the water content of the 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] A composition comprising pranlukast hydrate contains 30 to 60 parts by weight of lactose and 7.5 parts by weight of polyethylene glycol with respect to 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,
[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 [11], wherein the weight of the desiccant to be encapsulated is 0.7 parts by weight to 17 parts by weight per 100 parts by weight of a capsule.
[16] The drug package according to the above [11], wherein the weight of the desiccant to be encapsulated is 1 to 15 parts by weight per 100 parts by weight of the total capsule.
[17] The drug package according to [1], which is a pillow package of an aluminum film,
[18] (I) a capsule filled with a composition comprising pranlukast hydrate having all the following characteristics (a) to (e), PTP-packed with a plastic sheet: , (II) 0.7 to 17 parts by weight of a desiccant having a moisture absorption rate of 20% to 35% at a temperature of 25 ° C. and a relative humidity of 50% per 100 parts by weight of a capsule. (III) 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 10% to 45%:
(A) 112.5 mg or 225 mg pranlukast hydrate per capsule,
(B) Contains 130 mg to 400 mg of composition per capsule,
(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] A composition comprising pranlukast hydrate is a composition comprising pranlukast hydrate, a saccharide, a water-soluble polymer and a lubricant, wherein the desiccant is silica gel. Or the drug package according to [18] above, which is a desiccant containing calcium chloride,
[20] A capsule containing 112.5 mg of pranlukast hydrate per capsule, wherein the composition comprising pranlukast hydrate is pranlukast hydrate 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 100 parts by weight. 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 a total capsule. 19] The drug package according to the above,
[21] Pranlukast hydrate adjusted to have all of the following characteristics (a) to (e), which is PTP-packed with a plastic sheet in a drug package hermetically packaged with a film Capsules filled with a composition containing the above, and a sheet-like desiccant containing calcium chloride, and 0.7 parts by weight of the sheet-like desiccant per 100 parts by weight of the total capsule weight By adjusting to contain 17 parts by weight and enclosing together, the relative humidity of the internal atmosphere of the drug package measured using a thermohygrometer at a temperature of 25 ° C. is adjusted to about 10% to about 45%. Method:
(A) 112.5 mg or 225 mg pranlukast hydrate per capsule,
(B) Contains 130 mg to 400 mg of composition per capsule,
(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.

  In the drug package of the present invention, there are capsules filled with a composition containing pranlukast hydrate PTP-packaged with a plastic sheet, and a desiccant having a certain moisture absorption rate. By appropriately encapsulating, the relative humidity of the internal atmosphere of the drug package is adjusted to a preferred range, and the capsules formed by filling the composition that is susceptible to moisture are delayed in disintegration during storage, abnormal (for example, The effect which suppresses a crack, a chip, etc.) is produced.

  In the present invention, a capsule filled with a composition containing pranlukast hydrate is packaged in a sheet, and the drug package includes a capsule packaged in this sheet and a desiccant. It may contain a moisturizing agent as necessary, and the whole is hermetically packaged with a film. That is, the drug package of the present invention contains a capsule packaged with the above sheet and a desiccant, and may contain a moisturizing agent if necessary, and is hermetically packaged with a film. It is a drug package.

  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 pharmaceuticals, and examples thereof include a plastic sheet and an aluminum sheet. Preferably, it is a plastic sheet.

  In the present invention, examples of the plastic sheet include a polyvinyl chloride sheet, a polyvinylidene chloride (PVDC) sheet, a vinylidene chloride sheet, a polychlorotrifluoroethylene sheet, an unstretched polypropylene (CPP or IPP) sheet, a cyclic polyolefin sheet, and a polyethylene sheet. Non-stretched nylon (CNy) sheet, biaxially stretched nylon (ONy) sheet, biaxially stretched polypropylene (OPP) sheet, hard vinyl chloride sheet, polyethylene terephthalate sheet, polyacrylonitrile copolymer (PAN) sheet, polyvinyl alcohol ( PVA) sheet, polyester (PET) sheet, ethylene-vinyl acetate copolymer (EVA) sheet, ionomer (IO) sheet, polyamide (PA or Ny) sheet, ethylene vinyl Alcohol copolymer (EVOH) sheet, a polycarbonate (PC) sheet 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.

As the plastic sheet used in the present invention is preferably one having about 0.5g ^/ m 2 · 24hr~ about 5.0g ^/ m 2 · 24hr of moisture permeability (water vapor permeability). Examples of the plastic sheet having such a preferable moisture permeability include a hard vinyl chloride sheet, a composite sheet combining hard vinyl chloride and polyvinylidene chloride, an unstretched polypropylene sheet, and the like. However, it is not limited to these.

  The above-mentioned moisture permeability means the amount of water vapor that passes through a sheet of 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. For example, it is preferable to carry out in accordance with a method generally known as a method for measuring the moisture permeability of a packaging material such as a plastic sheet or a sheet, particularly the cup method (JIS Z0208).

  The plastic sheet does not need to be a flat sheet. For example, a sheet in which recesses are formed can be used to provide a space for storing capsules one by one.

  In the present invention, when the capsule is packaged in a sheet, the sheet and another film-like material may be appropriately combined, and the capsule may be encapsulated between the two and used. For example, one or more selected from film-form materials used as ordinary packaging materials such as vapor-deposited films deposited with inorganic substances such as aluminum, silicon oxide, aluminum oxide, paper, aluminum film, cellophane film, For the purpose of protecting the contents, it can be combined with the above sheet as appropriate and used in combination. Examples of the method for laminating the above sheet and other film-like materials include dry lamination, extrusion coating / lamination, wet lamination, hot melt lamination, coextrusion lamination, non-solvent lamination, thermal lamination and the like.

In the present invention, SP (strip package) packaging, PTP (press through package) packaging, blister packaging may be used as a form of packaging capsules filled with a composition containing pranlukast hydrate or the like. (Blister pack). PTP packaging is preferable.
As the PTP packaging used in the present invention, for example, a combination of hard vinyl chloride and an aluminum film and bonding and molding by a known method is preferable.

  In the present invention, the composition containing pranlukast hydrate (hereinafter sometimes abbreviated as the composition of the present invention) is preferably (1) containing pranlukast hydrate, Is a composition containing (2) a saccharide and (3) a water-soluble polymer, and (4) an additive (preparation base) generally used in producing a capsule. is there. Here, as additives (formulation bases), for example, excipients, binders, lubricants, stabilizing agents, disintegrating agents, 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 for the composition of the present invention. It can mix | blend suitably and can be used. As the additive, a lubricant is preferable.

Pranlukast hydrate used in the composition of the present invention is represented by the following formula (A)
4-oxo-8- [4- (4-phenylbutoxy) benzoylamino] -2- (tetrazol-5-yl) -4H-1-benzopyran 1/2 hydrate represented by the formula: The production of pranlukast hydrate can be performed, for example, according to the method described in JP-A No. 61-050977.

  Examples of the saccharide in the composition of the present invention include 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, rice starch and the like. Lactose, sucrose, mannitol and the like are preferable. More preferably, it is lactose.

  Examples of the water-soluble polymer in the composition of the present invention include celluloses (eg, hydroxymethylcellulose, hydroxymethylethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMCP). ), Hydroxypropyl methylcellulose acetate succinate (HPMCAS), etc.), synthetic polymers (eg, polyethylene glycol (eg, macrogol 4000, etc.), polyvinylpyrrolidone, polyvinyl alcohol, etc.), gelatin and the like. Preferred are polyethylene glycol, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and the like. More preferably, it is polyethylene glycol.

  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, rice starch, etc.), microcrystalline 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, Examples thereof include magnesium aluminate metasilicate.

  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.

  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, citric acid, calcium citrate, sodium citrate, glycine, glycerin, 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, dibutylhydroxytoluene Dimethylpolysiloxane, calcium bromide, tartaric acid, calcium hydroxide, sodium hydroxide, magnesium hydroxide, stearic acid, cetanol, gelatin, D-sorbitol, talc, ammonium carbonate, potassium carbonate, sodium bicarbonate, 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 (polyvinylpyrrolidone), polyvinyl alcohol (partially saponified product), polyvinylidene Alcohol and dibutyl ether mixture, maleic acid, malonic acid, D-mannitol, anhydrous citric acid, anhydrous sodium citrate, anhydrous sodium acetate, anhydrous maleic acid, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, aluminum metasilicate Magnesium sulfate, sodium metasulfobenzoate, sodium metaphosphate, methylcellulose, methyl vinyl ether / maleic anhydride copolymer, potassium iodide, sodium iodide, sodium lauryl sulfate, zinc sulfate, potassium aluminum sulfate, potassium sulfate, magnesium sulfate, phosphorus Examples include acids, potassium dihydrogen phosphate, and calcium dihydrogen phosphate.

  Examples of the disintegrant include low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, hydroxypropyl starch, corn starch, and calcium calcium glycolate.

  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, polyoxyethylene hydrogenated castor oil, monostearic acid Examples include sorbitan and sodium lauryl sulfate.

As a fragrance | flavor, lemon oil, orange oil, menthol, brackish oil etc. are mentioned, for example.
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.
Examples of solubilizers include glutamic acid and aspartic acid.
Examples of the coating agent include sucrose, gelatin, hydroxypropylcellulose, hydroxymethylcellulose phthalate and the like.

  In addition to the exemplified applications, the additives described above may be used for other purposes (for example, excipients, binders, lubricants, stabilizers, disintegrating agents, taste-masking agents, surfactants, fragrances, and coloring agents. , Antioxidants, masking agents, antistatic agents, fluidizing agents, wetting agents, elution aids, solubilizing aids, coating agents, etc.), they may be used for that purpose. In addition to the above, additives such as those described in publicly known documents such as “Pharmaceutical Additives Dictionary” published by Yakuji Nippo 2005 (edited by Japan Pharmaceutical Additives Association) may be used.

  The composition of the present invention comprises (1) pranlukast hydrate, (2) saccharide, (3) water-soluble polymer, and (4) additives (formulations) generally used in producing capsules. It is preferable that the composition contains a base. The combination of (1) to (4) includes (1) pranlukast hydrate, (2) one or more saccharides selected from the group consisting of lactose, sucrose and mannitol, (3) polyethylene glycol, A combination of one or more water-soluble polymers selected from the group consisting of methylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, and (4) a lubricant is preferred, (1) pranlukast hydrate, (2) A combination of lactose, (3) polyethylene glycol and (4) magnesium stearate is more preferred.

  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. More preferably about 30 parts by weight to about 60 parts by weight. Further, 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.

  In the composition of the present invention, the weight ratio of 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 1.0 parts by weight. To about 4.5 parts by weight.

  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, more preferably about 150 mg to about 380 mg per capsule.

The form of the composition of the present invention is preferably a granulated product. Examples of the granulated product include granulation methods for commonly used pharmaceutical preparations, for example, granulation described in “Granulation Handbook” (edited by Japan Powder Industrial Technology Association, Ohmsha, 1991). It is not particularly limited as long as it is a granulated product produced by the method, for example, wet granulated product, dry granulated product, rolling granulated product, spray dried granulated product, extruded granulated product, fluidized bed granulated product. , Stirring granulation, compression granulation, melt granulation, crushed granulation, coating granulation, liquid phase granulation, vacuum freeze granulation 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 a stirred granulated product, a stirred fluidized bed granulated product, a stirred rolling fluidized bed granulated product, and the like.

When the composition of the present invention is a spray-dried granulated product, the weight percentage of pranlukast hydrate in 100% by weight of the spray-dried granulated product is preferably about 50% to about 98%, more preferably About 55% to about 90%, particularly preferably 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%. % To about 80%.

  The capsule in the present invention is not particularly limited as long as it is a capsule filled with the composition of the present invention, and may be the same as a capsule generally used as a pharmaceutical product. Capsules include hard capsules, soft capsules and the like.

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

  The above capsule film usually contains a capsule base and a plasticizer. If necessary, for example, a fragrance (for example, mint oil, cinnamon oil, strawberry or other fruit essence or flavor), an antiseptic ( For example, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, etc.), pigment (for example, yellow No. 4, yellow No. 5, red No. 3, blue No. 1, copper chlorofin etc.), opacifying agent (eg, titanium dioxide) , Bengala, iron sesquioxide, etc.), lubricants (eg, magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol, sodium lauryl sulfate, etc.), solubility regulators (eg, , Cellulose acetate phthalate, hydroxypropyl methylcellulose Alkali metal salt, alkali metal salt of hydroxymethylcellulose acetate succinate, alkali metal alginate, alkali metal polyacrylate, methylcellulose, carboxymethylcellulose, casein, collagen, agar powder, polyvinyl alcohol, pectin, etc.) Also good.

  In the present invention, the capsule base used for the capsule film may be any substance that can be used as the capsule film base. For example, protein (eg, gelatin, gelatin hydrolyzate, collagen, collagen hydrolyzate, casein), polysaccharide (eg, starch, amylose, polygalacturonic acid, agar, carrageenan, gum arabic, gellan gum, xanthan gum, pectin, Alginic acid, pullulan, etc.), celluloses (eg, hydroxymethylcellulose, hydroxymethylethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetates Succinate (HPMCAS), etc.), biodegradable plastics (eg, polylactic acid, polyhydroxy) Butyric acid, polyglutamic acid, etc.), hydrogenated fats (e.g., medium chain fatty acid triglyceride and diglyceride (e.g., butter, margarine, shortening, cocoa butter, etc.) and the like) and the like. These capsule bases may be used in appropriate combination of two or more. In the present invention, among these capsule bases, protein, particularly gelatin is preferable.

  The plasticizer used for the capsule film may be any substance that can be used as the plasticizer for the capsule film. For example, sugar (eg, sucrose, sucrose, water candy, etc.), sugar alcohol (eg, sorbitol, xylitol, mannitol, etc.), polyhydric alcohol (eg, glycerin, ethylene glycol, polyethylene glycol, propylene glycol, etc.), etc. It is done. Of these, polyhydric alcohols, particularly polyethylene glycol, are preferred.

  In the present invention, the content of pranlukast hydrate contained in the capsule is preferably about 112.5 mg to about 450 mg per capsule, more preferably 112.5 mg, 225 mg or 450 mg, still more preferably Is 112.5 mg or 225 mg, particularly preferably 112.5 mg. The size of the capsule is preferably No. 1, 2, 3, or 4 capsules, and the weight of empty capsules per capsule is preferably about 30 mg to about 90 mg. For example, No. 2 capsule or No. 3 capsule containing 225 mg of pranlukast hydrate or No. 3 capsule or No. 4 capsule containing 112.5 mg is preferable from the viewpoint of patient compliance.

  Therefore, in the capsule of the present invention, the total weight of one capsule is preferably the sum of the weight of the composition to be filled and the weight of the empty capsule, and is preferably about 160 mg to about 490 mg, preferably about 180 mg to about 470 mg is more preferred.

  In the present invention, the desiccant is not particularly limited as long as it is generally used during storage of pharmaceuticals. Examples of such a desiccant include aluminum oxide, calcium, calcium chloride, calcium hydride, and calcium oxide. , Calcium sulfate, copper sulfate, lithium aluminum hydride, magnesium, magnesium oxide, magnesium perchlorate, magnesium sulfate, synthetic zeolite (eg, molecular sieve), natural zeolite, diphosphorus pentoxide, potassium carbonate, potassium hydroxide, Examples include silica gel, silica alumina gel, sodium, sodium hydroxide, sodium sulfate, magnesium aluminate silicate, activated carbon and the like. You may use these in combination of 2 or more types as needed.

  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, vinyl acetate-maleic anhydride copolymer, isobutylene-maleic anhydride copolymer, acrylic acid- Examples include methacrylic acid copolymers, polyvinyl alcohol, polyethylene oxide, polypropylene oxide, polyvinyl pyrrolidone, sulfonated polystyrene, polyvinyl pyridine, polyacrylamide, and polymethacrylamide.

  Examples of the desiccant used in the present invention include granules, films, plates or sheets, and granules filled in a breathable bag (for example, dryer (trade name) , Yamajin Corporation; silica gel), ID F (trade name, ID Corporation; calcium chloride) 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 the desiccant is formed into a sheet, for example, the desiccant is blended into a suitable support, plastic for molding, etc., and the desiccant is kneaded into the plastic and molded into a sheet, or pulp material. For example, a method of impregnating a solution containing a substance that is a raw material of the desiccant and molding the solution may be used. As the sheet-like desiccant, an ID sheet (trade name, IDY Co., Ltd .; calcium chloride), high sheet dry (trade name, Marutani Kako Co., Ltd .; silica gel), high dry pack (trade name, Marutani Kako Co., Ltd .; Silica gel). Preferably, an ID sheet is used.

  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 a desiccant containing calcium chloride or silica gel. A sheet-like desiccant containing calcium chloride is more preferred, and a sheet-like desiccant containing about 10% by weight to about 30% by weight of calcium chloride is particularly preferred. Examples of the sheet-like desiccant containing about 10 wt% to about 30 wt% of calcium chloride include an ID sheet (trade name, ID Co., Ltd.).

  When a 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, and about 1 part by weight to about 15 parts by weight with respect to 100 parts by weight of one capsule. It is more preferable to use about 1.5 parts by weight to about 11 parts by weight.

For example, in the drug package of the present invention, 14 capsules containing 112.5 mg of pranlukast hydrate and PTP-wrapped per sheet with a plastic sheet are encapsulated in 10 sheets per drug package. In this case, about 0.22 g is equivalent to about 0.7 part by weight to about 17 parts by weight of “desiccant containing calcium chloride or silica gel” with respect to 100 parts by weight of one capsule. It is preferable to encapsulate about 5.5 g of “sheet-like desiccant containing calcium chloride” or “desiccant containing granular silica gel” at the same time. In addition, about 0.32 g to about 4.8 g of “a desiccant containing calcium chloride or silica gel” corresponding to about 1 part by weight to about 15 parts by weight relative to 100 parts by weight of one capsule. It is more preferable to enclose “sheet-like desiccant containing calcium chloride” or “desiccant containing granular silica gel” at the same time, and about 1.5 parts by weight to about 11 parts by weight with respect to 100 parts by weight of one capsule. In addition, about 0.48 g to about 3.4 g of “sheet-like desiccant containing calcium chloride” or “desiccant containing granular silica gel” are encapsulated at the same time. Particularly preferred is about 3.1 to about 9.3 parts by weight of “desiccant containing calcium chloride or silica gel” with respect to 100 parts by weight of the total weight of one capsule. As an equivalent, it is especially preferred to encapsulate about 1g~ about 3g "sheet drying agent comprises calcium chloride" or "desiccant comprising particulate silica gel" at the same time. Here, the weight when the “sheet 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.

  A moisturizing agent can be encapsulated in the drug package of the present invention in combination with the above desiccant. In the present invention, the humectant means a substance having water absorption, moisture absorption and moisture release functions, and a function capable of maintaining a constant humidity, that is, a function of adjusting to equilibrium humidity, and is also referred to as a humidity control agent. . Examples of such a humectant include hydrated ethylene glycol-containing sheets, dry keep (trade name, Sasaki Chemical Co., Ltd.), and the like.

  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 refers to a capsule (hereinafter also referred to as “PTP package”) filled with the composition of the present invention enclosed in a drug package and packaged in PTP with a sheet. , Meaning the atmosphere in which the 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.

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 about 10% to about 40%, more preferably about 17% to about 40%, and particularly preferably 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 capsule 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.

The relative humidity can be measured by a known method. For example, a method described in Examples (for example, a method using a thermohygrometer (THARMO RECORDER RS-12; ESPEC)) or a water activity measuring apparatus (eg, AQUALAB CX-3TE; Decagon, etc.), Moisture permeability test equipment (example: L80-5005; Risshi, GTR-WV; GTR Tech Co., Ltd.), thermogravimetry measuring equipment (example: TGA-50 / 50H; Shimadzu Corporation, etc.), water vapor permeability measurement The relative humidity can be measured using a combination of devices (eg, PERMATRAN-W (R) 3/61; MOCON, etc.).
[Relative humidity measurement method]
The method for measuring relative humidity using the above-described water activity measuring apparatus is as follows.
<Measurement of water activity value of pranlukast hydrate-containing capsule>
Pranlukast hydrate-containing capsules and desiccant (for example, ID sheet etc.) PTP-wrapped using PVC are put together in a sample cup, and using a water activity measuring device (AQUALAB CX-3TE: Decagon) The water activity (Aw; Water Acitvity) value in the sealed sample cup is measured. The obtained Aw value is converted into Equilibrium relative humidity (ERH).

  Examples of the drug package of the present invention include a drug package as shown in FIG. The drug package shown in FIG. 1 includes 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) made of a film and hermetically packaged.

  The film used for the exterior material may be any film-like material that can be sealed, and is not particularly limited. 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 polyvinylidene chloride film, a high-density polyethylene laminated paper, a polyvinylidene chloride laminated paper, and preferably an aluminum film. Examples of the form of the exterior material include cans, bottles, bags (for example, cartoner 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).

  The drug package of the present invention is preferably an aluminum film package using an aluminum film as an exterior material, more preferably an aluminum film pillow package. The aluminum film package can be produced by a known method, for example, by encapsulating a PTP package and a desiccant in a bag made of an aluminum film and heat-sealing.

In addition, the space volume inside the drug package of the present invention is preferably about 60 to 80 cm ^{3 and} more preferably about 65 to 75 cm ³ when calculated by excluding the volume of the PTP package and the desiccant.

  In the present invention, the above-mentioned relative humidity of the internal atmosphere is “adjusted” means that the relative humidity reaches a steady state after about 6 hours after the preparation of the drug package of the present invention, as in Examples below. Means that the value remains within a predetermined range for at least about 6 months.

  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 not particularly limited as long as it is a substance that constitutes the drug package of the present invention, and preferred examples include the composition of the present invention, the capsule film constituting the capsule, and the like. In the present invention, the water content of the composition comprising pranlukast hydrate or the like is preferably about 1% to about 2.7%, and about 1.2% to about 2.5%. More preferably. The moisture content of the capsule film is preferably about 8% to about 17%, more preferably about 9% to about 16%. 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, in particular, a water content measurement method listed in the Japanese Pharmacopoeia, in particular, a water content measurement method (Karl Fischer method) listed in the 15th revision Japanese Pharmacopoeia. .

  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 the composition and capsule film By appropriately combining the water content, the relative humidity of the internal atmosphere of the drug package can be adjusted to a certain range. The drug package of the present invention in which the relative humidity of the internal atmosphere is adjusted in such a manner is that the capsule filled with the composition of the present invention has a decay delay, elution delay, abnormalities (eg, cracks, chips, etc.) during storage. ), Wind and deliquescence can be suppressed.

  In the present invention, “disintegration delay” means that the dissolution 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, the elution of pranlukast hydrate is achieved by the disintegration of the composition of the present invention, which is the content in the capsule, and by subdividing into small particles and increasing the surface area. It is believed to be reliable and absorbed quickly from the digestive tract wall.

  In the present invention, the degree of “disintegration delay” is determined by subjecting a capsule filled with the composition of the present invention to the disintegration test after being stored for an arbitrary period of time inside and outside the drug package and outside the PTP package. This can be confirmed by comparing with the test results. 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 internal solid preparations such as tablets and capsules. It is preferable to carry out in accordance with the law, especially the disintegration test method listed in the 15th revision Japanese Pharmacopoeia.

  In the present invention, “elution delay” means that the bioavailability (bioavailability) after in vivo administration is changed by delaying the elution rate of pranlukast hydrate. As will be apparent to those skilled in the art, the elution rate of the active ingredient in a capsule defines the 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 there will be side effects.

  In the present invention, the degree of “elution delay” is determined by subjecting a capsule filled with the composition of the present invention to an elution test after storing it for an arbitrary period of time inside and outside the drug package and outside the PTP package. This can be confirmed by comparing the test results. The dissolution test can be performed by a known method. For example, the dissolution test can be performed according to a method generally known as a dissolution test method for internal solid preparations such as tablets and capsules. 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) It is preferable to carry out according to the above.

  The conditions for storage 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 referred to as an accelerated test or a severe test. As such, it may be at high temperature and / or high humidity. By making the conditions of high temperature and / or high humidity, the result of long-term storage at room temperature can be obtained in a shorter period of time.

  The cause of the above-mentioned “delay delay” and “elution delay” is generally a composition containing an active ingredient or a formulation base (for example, in a capsule) over time by storing a drug, particularly a capsule. It is considered that some change (for example, change in moisture content, etc.) occurs in the capsule film if any.

  In the present invention, “abnormality” of a capsule means that a certain change (for example, a decrease in the strength of the capsule film) occurs over time during storage, resulting in a planluca such as cracking or chipping. This means that the capsule function of protecting the composition containing the strike hydrate is impaired. Specifically, when the capsule is cracked or chipped, not only the composition containing pranlukast hydrate flows out, but also the internal volume of the composition or the The condition changes and the capsule's ability to retain a certain amount of pranlukast hydrate and its quality will be impaired.

  The above-mentioned “abnormality” of the capsule is the case where the capsule filled with the composition of the present invention is stored inside and outside the drug package and outside of the PTP package for an arbitrary period, and then subjected to a crack load test, and cracks with respect to the total number of specimens. It can be confirmed by comparing the cracking rate calculated by the number of specimens 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 or the like to the capsule, and for example, can be performed by a falling weight impact test or the like as shown in Examples below.

The drug package of the present invention has the purpose of the present invention, that is, the disintegration delay, elution delay, abnormality (for example, cracking, chipping, etc.), storage, deliquescence, etc. of the capsule filled with the composition of the present invention. In order to achieve this, it is preferable to combine the elements constituting the drug package of the present invention described above into specific combinations as shown below. That is, (I) a capsule filled with a composition containing pranlukast hydrate having all the following characteristics (a) to (e), which is PTP-packaged with a plastic sheet; II) A desiccant having a moisture absorption of about 20% to about 35% at a temperature of 25 ° C. and a relative humidity of 50% of about 0.7 parts by weight to about 17 parts by weight per 100 parts by weight of one capsule. Is packaged in a hermetically sealed form with (III) 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%. Preferably there is.
(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) the weight of empty capsules per capsule is from about 30 mg to about 90 mg;
(D) the moisture content of the composition is from about 1% to about 2.7%;
(E) The moisture content of the capsule film is about 8% to about 17%.

More preferably, as a combination of components in the drug package of the present invention, (I) Pranlukast hydrate having all the above-mentioned characteristics (a) to (e), which is PTP-packaged with a plastic sheet, Capsules filled with a composition comprising a saccharide, a water-soluble polymer and a lubricant, and (II) about 0.7 parts by weight to about 17 parts by weight per 100 parts by weight of one capsule per capsule And a desiccant containing silica gel or calcium chloride, (III) hermetically packaged with a film, and at a temperature of 25 ° C., the relative humidity of the internal atmosphere measured with a thermohygrometer is about 10% to A drug package adjusted to about 45%. Particularly preferably, (I) a capsule filled with a composition containing pranlukast hydrate having the following characteristics (i) to (vi), which is PTP packaged with a plastic sheet: And (II) about 1 to about 15 parts by weight of a sheet-like desiccant containing calcium chloride per 100 parts by weight of one capsule, and (III) hermetically packaged with a film. Thus, a drug package in which the relative humidity of the internal atmosphere measured with a thermohygrometer is adjusted to about 10% to about 45% at a temperature of 25 ° C. can be mentioned.
(I) contains about 112.5 mg pranlukast hydrate per capsule;
(Ii) from about 130 mg to about 400 mg of composition per capsule;
(Iii) the composition comprises from about 30 to about 60 parts by weight of lactose, from about 7.5 to about 15 parts by weight of polyethylene glycol per 100 parts by weight of pranlukast hydrate, and stearic acid A composition comprising about 1 to about 4.5 parts by weight of magnesium,
(Iv) the weight of empty capsules per capsule is from about 30 mg to about 90 mg;
(V) the moisture content of the composition is from about 1% to about 2.7%;
(Vi) The moisture content of the capsule film is about 8% to about 17%.

[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, dysmenorrhea It is useful as a prophylactic and / or therapeutic drug for various diseases such as infectious diseases.
[toxicity]
Pranlukast hydrate in the present invention has low toxicity and is sufficiently safe for use as a medicine.

EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.
In the following description, the packaging operation for producing the PTP package or drug package is performed at ordinary temperature (about 18 to 28 ° C.) and normal humidity (about 30 to 70%) under normal conditions obvious to those skilled in the art. This was done according to the law.
In each test example, during the storage period of 6 months, the temperature and relative humidity of each test section were kept constant, and the relative humidity was measured by a thermohygrometer (THERMO RECORDER RS-12: manufactured by ESPEC). It measured using.

[Formulation example]: Production of capsule containing pranlukast hydrate (112.5 mg) According to the method described in JP-A-61-050977, pranlukast hydrate is added to a polyethylene glycol aqueous solution. A spray-dried granulated product was obtained by spraying a suspension of (40 kg) and lactose (18.7 kg) with a spray dryer. No. 3 capsules (Capsugel Japan Co., Ltd.) containing a mixture of the resulting granulated product and magnesium stearate (as appropriate) as the contents so that the content of pranlukast hydrate is 112.5 mg per capsule. By filling according to a conventional method, a capsule containing pranlukast hydrate having the following composition was obtained.
<Composition (per capsule)>
・ Pranlukast hydrate (112.5mg)
・ Lactose (52.65mg)
・ Polyethylene glycol (Macrogol 4000) (11.25mg)
・ Magnesium stearate (3.6mg)
・ Empty Capsule 3 (49.0mg)

[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 hard vinyl chloride sheet (Sumilite (registered trademark) VSS-1104; Sumitomo Bakelite Co., Ltd., hereinafter abbreviated as PVC) having a thickness of 200 μm. To PTP package (PTP package 1).
Similarly, as a plastic sheet, a composite sheet (VSL-4501; Sumitomo Bakelite Co., Ltd., hereinafter abbreviated as PVC / PVDC) combining hard vinyl chloride and vinylidene chloride having a thickness of 250 μm was used for PTP packaging (PTP packaging). Body 2).
Similarly, PTP packaging was performed using unstretched polypropylene (NS-3451; Sumitomo Bakelite Co., Ltd., hereinafter abbreviated as CPP) as a plastic sheet (PTP package 3).
Each PTP package was manufactured by laminating each plastic sheet and an aluminum film by a conventional method and encapsulating 14 capsules per sheet.

[Examples 1 to 7 and Comparative Example 1]
PTP package 1 obtained in the above PTP package production example and calcium chloride-impregnated sheet-like desiccant (ID sheet; IDY Co., Ltd.) or bag-like desiccant containing granular silica gel (Dryan; Yamanin Pharmaceutical Co., Ltd.) Was placed in an aluminum film bag (about 110 mm × about 200 mm) and hermetically packaged to produce a drug package having the structure shown in Table 1 below. Here, in the case of a sheet-like desiccant containing calcium chloride, the weight of the desiccant means a weight including the weight of the sheet-like pulp material impregnated with calcium chloride.

Each of the following tests was performed using the drug package obtained in the above Examples or Comparative Examples, the capsule (no packaging) or the PTP package (no aluminum film bag) obtained in the formulation example as a sample.
In interpreting the test results, the relative humidity when capsules (no packaging) and PTP packaging (no aluminum film bag) were used for each test was determined by using the capsule or PTP packaging in the aluminum film bag. It was considered to show the same value as the relative humidity of the internal atmosphere of the sealed drug package.

[Test Example 1: Measurement of moisture content of capsule]
Samples of capsules (no wrapping) and PTP wrapping body 1 (no aluminum film wrapping) obtained in the formulation examples were stored for 6 months under a temperature of 25 ° C. and a relative humidity of 22% or 75%. At the start (initial), after 2 months, 4 months and 6 months, according to the moisture measurement method (Karl Fischer method) described in the 15th revision Japanese Pharmacopoeia, the capsule film and the contents filled in the capsule (composition) The water content was measured for each of three samples, and the average value was calculated. The results are shown in Table 2.

  From the above results, when stored under the condition of relative humidity of 22%, the moisture content of the contents is 2 months, 4 months, and 6 months after the capsule is in either the unpacked state or the PTP packaged state. Although it hardly changed, it was found that the moisture content of the capsule film was lower than the initial one. On the other hand, when stored under conditions of a relative humidity of 75%, the moisture content of the capsule film and contents increased after 2 months, 4 months and 6 months.

  Next, for the samples of Examples 2 and 3, at the start 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, the 15th revised Japanese Pharmacopoeia According to the described moisture measurement method (Karl Fischer method), the moisture content of the contents (composition) filled in the capsule was measured for each of three samples, and the average value was calculated. The results are shown in Table 3.

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, either of the two desiccants is used. Even in the drug package composed of the combination, the water content of the contents was not increased. Moreover, when the moisture content of the content was measured on the same conditions about the drug packaging body manufactured in Example 1 and Examples 4-7, the substantially same value as said result was shown. 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.
In addition, when measuring the moisture content of the contents under the same conditions for the 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, The value was almost the same as the above result. From this, it was found that the moisture content of the contents was not affected by the difference in the plastic sheet used for the PTP package.

[Test Example 2: Measurement of capsule disintegration time]
Samples of capsules (no wrapping) and PTP wrapping body 1 (no aluminum film wrapping) obtained in the formulation examples were stored for 6 months under a temperature of 25 ° C. and a relative humidity of 22% or 75%. At the start (initial stage), 2 months, 4 months and 6 months later, the disintegration time was examined according to the disintegration test method (capsule) described in the 15th revision Japanese Pharmacopoeia. The test was performed with 6 specimens each, and all the specimens were disintegrated within 20 minutes and the contents were completely dissolved. The results are shown in Table 4.

  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 the storage period of 6 months under the condition of a temperature of 25 ° C. and a relative humidity of 75% (initial), 2 After 4 months and 6 months, the disintegration time was examined in the same manner as above. The results are shown in Table 5.

  In addition, when the disintegration test was performed under the same conditions for the drug packages produced in Examples 1, 5 and 7, the disintegration in all the examples was disintegrated within 20 minutes at all the above points in the storage period. And since the contents were completely dissolved, it was compatible.

  As shown by the above results, when stored under conditions of a temperature of 25 ° C. and a relative humidity of 75%, the PTP package 1 was stored as described above or was stored as a drug package without a desiccant as in Comparative Example 1. Unlike sometimes incompatible after 4 and 6 months, the two desiccants and the amount of desiccant (about 1.52 parts by weight as the amount of desiccant relative to 100 parts by weight of one capsule total weight) In the drug package composed of any combination with (about 10.3 parts by weight), the extension of the disintegration time was suppressed and it was suitable at all time points.

  When the results of Test Example 1 and Test Example 2 are taken together, when stored under the condition of a relative humidity of 75%, in the case of no packaging, PTP packaging (without aluminum film packaging) or Comparative Example 1, Test Example 1 It was clarified that the disintegration time observed in Test Example 2 was prolonged as the contents and the moisture content of the capsule film increased in Example 1, and the internal atmosphere of the drug package was about 75%. It was suggested that the capsule disintegration delay occurs when the above is reached. On the other hand, in the drug packaging body of the example, the moisture content of the content is within a preferable range (water content of the composition: about 1%) by enclosing a certain amount of an appropriate desiccant together and hermetically packaging with a film. (About 2.7%, water content of capsule film: about 8% to about 17%)), it is considered that the decay delay was suppressed.

[Test Example 3: Measurement of capsule strength]
For samples of capsules (unwrapped) obtained in the formulation example, after 2 months, 4 months and 6 months in a storage period of 6 months under conditions of a temperature of 25 ° C. and a relative humidity of 22% or 75%, the following The strength of the capsule was measured according to the falling weight impact test method. Moreover, it measured by the same method after 7 days and 37 days in the storage period of 37 days on the conditions of temperature 25 degreeC relative humidity 7%. The results are summarized in Table 6.
<Falling weight impact test>
(1) A capsule was placed sideways in the center of the pedestal of the falling weight impact test apparatus. A metal weight of 100 g was fixed to the upper part of the cylinder with a stopper so that the height was 80 mm from the pedestal.
(2) The cylinder was placed on the pedestal, the hook of the stopper was pushed in and removed, and the weight was naturally dropped onto the capsule body and the cap part.
(3) Each of the 50 samples was subjected to the test, and the presence or absence of cracks or chipping in the capsule was confirmed. The ratio of capsules that caused either cracking or chipping in all capsules was calculated as the cracking rate.

From the above results, under the condition 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 is 75%. Below, since the cracking rate of the capsules after storage for 2 months, 4 months, and 6 months in an unwrapped state was 0% at any time point, it was suitable under any conditions. On the other hand, it was found that the cracking rate of the capsule rapidly increased under a drying condition of a temperature of 25 ° C. and a relative humidity of 7%, which was incompatible.
Therefore, it became clear that the strength of the capsules decreased when the moisture content of the capsule film was less than or equal to 22% relative humidity at 25 ° C. in Test Example 1. Further, it was suggested that the relative humidity of the internal atmosphere of the drug package should be adjusted to exceed at least 7% because the capsule cracking rate increases in an atmosphere with a relative humidity of about 7% or less.

[Test Example 4: Measurement of relative humidity inside capsule aluminum film package]
In the drug package manufactured in Examples 1, 5 and 7 described above, a thermohygrometer (THERMO RECORDER RS-12: ESPEC) was sealed in an aluminum film bag (110 mm × 200 mm) at the time of hermetically sealed. Heat-sealed by the method. The drug package containing the heat-sealed thermo-hygrometer is allowed to stand at room temperature for 48 hours, and then left for 24 hours in an environment at a temperature of 25 ° C. and a relative humidity of 60%, and the relative humidity of the internal atmosphere of the drug package is adjusted. 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.

  For 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 within the range of about 10 to 23%. I found out. 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%.

  From the above results, the amount of the desiccant was defined as “sheet desiccant containing calcium chloride” or “desiccant containing granular silica gel” and about 1.5 parts by weight to about 11 parts per 100 parts by weight of the total weight of one capsule. When used in the range of parts by weight, it was found that the relative humidity at a temperature of 25 ° C. in the film package was adjusted to about 10% to about 40%.

  When the results of Test Examples 1 to 3 are taken together, the water content of the composition and capsule film of the drug packaging bodies of Examples 1 to 7 is about 1% to about 2.7% and about 8%, respectively. Since it was in the range of ˜17%, neither disintegration delay nor capsule cracking occurred. Furthermore, considering Test Example 4 together, the internal atmosphere of the drug package is adjusted to about 10 to about 40% by adjusting the moisture content of the composition and capsule film as described above. It turns out that it is adjusted.

  Therefore, capsules filled with a composition containing pranlukast hydrate PTP-packaged in a plastic sheet, and the amount of the desiccant is set to “sheet desiccant containing calcium chloride” or “granular silica gel”. The composition of the capsule and the water content of the capsule film can be obtained by adjusting the content to about 1.5 parts by weight to about 11 parts by weight per 100 parts by weight of the total capsule weight. It has been found that the relative humidity of the internal atmosphere of the drug package is adjusted to about 10% to about 40% because the rate is adjusted to the optimal range.

  According to the present invention, there is provided a drug package in which quality deterioration such as disintegration delay during storage of capsules containing pranlukast hydrate packaged in PTP and abnormalities such as capsule cracking are suppressed to a minimum. Can be provided.

It is a schematic diagram which illustrates the structure of the drug packaging body of this invention.

Explanation of symbols

1: Plastic sheet 2: Capsule 3: Desiccant 4: Exterior material (film)

Claims (3)

(I) a capsule filled with a composition containing pranlukast hydrate having all the following characteristics (a) to (e), PTP-packed with a plastic sheet: ) 0.7 to 17 parts by weight of a desiccant having a moisture absorption rate of 20% to 35% at a temperature of 25 ° C. and a relative humidity of 50% is encapsulated per 100 parts by weight of a capsule. 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) 112.5 mg or 225 mg pranlukast hydrate per capsule,
(B) Contains 130 mg to 400 mg of composition per capsule,
(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%. The composition comprising pranlukast hydrate is a composition comprising pranlukast hydrate, a saccharide, a water-soluble polymer and a lubricant, and the desiccant is silica gel or calcium chloride. drug package according to claim 1, wherein a drying agent comprising a. The capsule contains 112.5 mg of pranlukast hydrate per capsule, and the composition containing pranlukast hydrate contains 100 parts by weight of pranlukast hydrate. 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, drying agent is a sheet-like desiccant containing calcium chloride, the sheet-like drying agent is 1 total weight per 100 parts by weight of the capsule, according to claim 2, wherein the encapsulated at a ratio of 1 part by weight to 15 parts by weight Drug package.