KR101125087B1 - Durg package - Google Patents

Abstract

SUMMARY OF THE INVENTION An object of the present invention is to provide a drug package that can minimize the deterioration of quality such as decay delay during storage of capsules containing franlukast hydrate packaged with a plastic sheet and to minimize the fragmentation of capsules. Is to provide.

The present invention is made of a capsule (2) filled with a composition made up of franc lucaste hydrate PTP packaged into a sheet (1), and a desiccant (3) is sealed and sealed with a film (4) The present invention relates to a drug package having a relative humidity of 10% to 45% of internal air measured using a thermo-hygrometer at a temperature of 25 ° C.

Francacast hydrate, capsules, decay delay, drug package

Description

Drug package {DURG PACKAGE}

TECHNICAL FIELD This invention relates to the drug package of the capsule which consists of franlukast hydrate.

As a package form when sealing solid preparations, such as a tablet and a capsule agent with a plastic sheet, etc., SP (strip package) packaging, PTP (press through package) packaging, etc. are generally used. And these SP packaging or PTP packaged formulations are provided on the market as a drug package which encapsulated again in the sealing body, such as an aluminum film bag, in order to avoid the influence of outside air or light.

On the other hand, Franlukast hydrate is known as a leukotriene (LT) antagonist (see Japanese Patent Application Laid-Open No. 61-050977), and is also clinically applied as a treatment for bronchial asthma or allergic rhinitis. It has been reported that solid preparations containing franlukast hydrate, especially in the case of capsules, remain unpacked at a temperature of 25 ° C. and a relative humidity of 75% for one week to elution changes (in the unpacked state of tablets and capsules). Revision of Stability Information, 3rd edition (see Japan Hospital, Pharmaceutical Journal). In addition, even in the state which PTP packaged, this capsule agent may change the retardation speed | rate and elution by the rise of moisture, humidity, etc. which it contains.

Until now, the tablet which uses perindopril erbumin as an active ingredient, and the drug package which enclosed the desiccant together in the sealing body are disclosed (refer Unexamined-Japanese-Patent No. 11-206850). However, in the case of the capsules of franlukast hydrate, in order to prevent the delay of disintegration rate or the change of dissolution, the capsules are divided by the decrease of the moisture contained in the sealed body made of moisture-proof film such as PTP package. There was a thing. Therefore, as described above, simply encapsulating the capsules of franlukast hydrate in PTP and then simply encapsulating the encapsulating agent or encapsulating the encapsulating agent such as a desiccant does not control the relative humidity of the atmosphere within the encapsulation, thus delaying the collapse of the encapsulating agent. There has been a problem such as preventing elution delay or breaking of capsules. There is neither description nor suggestion in this document regarding the adjustment of the relative humidity of the internal air of the drug package in this regard.

[Initiation of invention]

[Problem to Solve Invention]

SUMMARY OF THE INVENTION An object of the present invention is to provide a drug package that can minimize the deterioration of quality, such as decay delay in the storage of capsules containing franlukast hydrate packed in a plastic sheet, and minimize the fragmentation of capsules. Is to provide.

[Means for solving the problem]

In order to achieve the above object, the present inventors believe that it is effective to control the relative humidity in the drug package, so that the capsules filled with the composition containing the franlukast hydrate, PTP-packed with a plastic sheet, are filled with a drying agent. About the drug package enclosed and sealed by the film, the combination of the quantity of a desiccant, the composition in the said capsule agent, and the moisture content of a capsule film was examined carefully. As a result, it is surprisingly possible to provide a drug package in which the relative humidity of the internal air is controlled by suppressing the collapse delay and the fragmentation of the capsule during the storage of the capsule by using a specific combination of these elements. It was found and completed the present invention.

That is, the present invention,

1. A capsule filled with a composition comprising franlukast hydrate PTP-packed with a sheet, and a desiccant are sealed and sealed with a film, and the inside air measured using a hygrometer at a temperature of 25 ° C. Drug package with relative humidity adjusted from 10% to 45%,

2. The drug package according to the above 1, wherein the moisturizing agent is also enclosed;

3. The drug package according to item 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 franlukast hydrate per capsule,

5. The drug package according to item 1, wherein the capsule is a capsule containing 130 mg to 400 mg of composition 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 franlukast hydrate is 1% to 2.7%,

7. The drug package according to item 1 above, wherein the water content of the capsule film in the capsule is 8% to 17%.

8. The drug package according to the above 1, wherein the composition comprising franlukast hydrate is also a composition comprising a sugar, a water soluble polymer and a lubricant.

9. The drug package according to item 8, wherein the sugar is lactose, the water-soluble polymer is polyethylene glycol, and the lubricant is magnesium stearate,

10. The composition according to the above 9, wherein the composition containing franlukast hydrate comprises 30 parts by weight to 60 parts by weight of lactose and 100 parts by weight of polyethylene glycol and 7.5 parts by weight to 15 parts by weight of polyethylene glycol. And a drug package comprising a composition comprising 1.0 parts by weight to 4.5 parts by weight of magnesium stearate,

11. The drug package according to item 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 item 11, wherein the desiccant is silica gel or calcium chloride,

13. The drug package according to item 11, wherein the desiccant is a sheet-shaped desiccant,

14. The drug package according to item 13, wherein the sheet-shaped desiccant is a sheet-shaped desiccant containing calcium chloride,

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

16. The drug package according to 11 above, wherein the weight of the desiccant encapsulated per 100 parts by weight of the total capsule of capsule is 1 part by weight to 15 parts by weight,

17. The drug package according to the above 1, which is a pillow package of an aluminum film;

18. (I) a capsule filled with a composition consisting of franlukast hydrate having all of the following properties (a) to (e) or (f) to (j), PTP-packed with a plastic sheet, (II) 0.7 to 17 parts by weight per 100 parts by weight of the total capsule of the capsule is filled with a desiccant having a moisture absorption of 20% to 35% at a temperature of 25 ° C. and a relative humidity of 50%, and is sealed with a film (III). The drug package is packaged and adjusted to a relative humidity of 10% to 45% of the internal air measured using a thermo-hygrometer at a temperature of 25 ° C:
(a) contains 112.5 mg of franlukast hydrate per capsule,
(b) from 130 mg to 400 mg of composition per capsule,
(c) the weight of the empty capsule per capsule is 30 mg to 90 mg,
(d) the moisture content of the composition is 1% to 2.7%,
(e) the water content of the capsule film is 8% to 17%,
(f) contains 225 mg of franlukast hydrate per capsule,
(g) from 230 mg to 450 mg of composition per capsule,
(h) the weight of the empty capsule per capsule is 30 mg to 90 mg,
(i) the moisture content of the composition is 1% to 2.7%,
(j) The water content of the capsule film is 8% to 17%.

delete

delete

delete

delete

delete

19. The composition according to the above 18, wherein the composition comprising franlukast hydrate is a composition containing franlukast hydrate, sugars, water-soluble polymers and lubricants, and the drying agent is a desiccant comprising silica gel or calcium chloride. Medication package,

20. The composition according to the above 19, wherein the capsule is a capsule containing 112.5 mg of franlukast hydrate per capsule, and wherein the composition comprising franlukast hydrate contains 30 parts by weight of lactose per 100 parts by weight of franlukast hydrate. 60 parts by weight, polyethylene glycol containing 7.5 parts by weight to 15 parts by weight, 1.0 parts by weight to 4.5 parts by weight of magnesium stearate, the composition is a sheet-like drying agent containing calcium chloride, the sheet-like drying agent Drug package, characterized in that the encapsulated in a ratio of 1 to 15 parts by weight per 100 parts by weight of one capsule,

21. A capsule filled with a composition comprising franlukast hydrate, which is adjusted to have all of the properties of (a) to (e) below, PTP packaged with a plastic sheet in a drug-packed package sealed with a film. And the sheet-shaped desiccant containing calcium chloride is adjusted to be contained so as to contain 0.7 to 17 parts by weight of the sheet-shaped desiccant per 100 parts by weight of the total weight of the capsule made of the capsule, at a temperature of 25 ° C of the drug package. Adjusting the relative humidity of the internal air measured using a thermo-hygrometer to about 10% to about 45%;

(a) contains 112.5 mg or 225 mg of franlukast hydrate per capsule,

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

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

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

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

Etc.

[Effects of the Invention]

In the drug package according to the present invention, a capsule filled with a composition comprising franlukast hydrate PTP-packed with a plastic sheet therein and a desiccant having a constant moisture absorption are appropriately sealed so that the relative air of the drug package is sealed. Humidity is adjusted to a preferable range, and it brings about the effect of suppressing collapse delay, abnormality (for example, splitting, distortion, etc.) at the time of the storage of the capsule made by filling the said composition which is easy to be influenced by moisture.

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

[Description of the code]

1: plastic sheet

2: capsule

3: drying agent

4: Exterior materials (film)

BEST MODE FOR CARRYING OUT THE INVENTION [

In the present invention, a capsule filled with a composition comprising franlukast hydrate is packaged into a sheet, and the drug package may include a capsule packed with this sheet, a desiccant, and may contain a moisturizing agent if necessary. All of them are sealed and packaged with a film. That is, the drug package of the present invention is a drug package formed by encapsulating a capsule and a desiccant packed with the sheet, and a moisturizing agent may be enclosed as necessary, and sealed by film.

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

In the present invention, as the plastic sheet, for example, polyvinyl chloride sheet, polyvinylidene chloride (PVDC) sheet, vinylidene chloride sheet, polychlorotrifluoroethylene sheet, unstretched polypropylene (CPP or IPP) sheet, cyclic polyolefin Sheet, polyethylene sheet, unstretched 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 air A coalescence (EVOH) sheet, a polycarbonate (PC) sheet, a polystyrene (PS) sheet, etc. are mentioned. You may use these plastic sheets as a composite sheet which combined two or more types suitably.

As the plastic sheet used in the present invention, one having a water vapor transmission rate (water vapor transmission rate) of about 0.5 g / m ² to 24 hr to about 5.0 g / m ^{2 to} 24 hr is preferable. Examples of the plastic sheet having such a 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, and particularly, a hard vinyl chloride sheet is preferable. However, it is not limited to these.

The moisture permeability refers to the amount of water vapor passing through the sheet of unit area at a given time under conditions of a predetermined temperature and humidity, and the measurement can be performed by a known method. For example, it is generally preferable to carry out according to the method known as a moisture permeability measurement method of packaging materials, such as a plastic sheet and a sheet, especially the cup method (JIS # Z0208).

It is not necessary to be a flat sheet as a plastic sheet, For example, the sheet | seat in which the recessed part was shape | molded can be used in order to provide the space for accommodating a capsule agent one by one.

In the present invention, when the capsule is packaged in a sheet, the sheet and the other film-like material may be appropriately combined, and the capsule may be nested so as to contain the capsule. For example, one or two or more kinds of film-like materials used as conventional packaging materials such as vapor deposition films, paper, aluminum films, and cellophane films, on which inorganic materials such as aluminum, silicon oxide, and aluminum oxide are deposited, may be selected. It can be used by laminating | combining suitably with the said sheet for the purpose of protecting, etc. Dry lamination, extrusion coating lamination, wet lamination, hot melt lamination, co-extrusion molding lamination, non-sorbent lamination, thermal lamination, etc. are mentioned as a method of laminating | stacking said sheet | seat and another film-like material.

In the present invention, as a form of packaging a capsule filled with a composition containing franlukast hydrate or the like in a sheet, an SP (strip package) package, a PTP (press through package) package, a blister pack, etc. may be mentioned. Can be. Preferably it is a PTP package.

As the PTP package used in the present invention, for example, a hard vinyl chloride and an aluminum film are combined to be superimposed and molded by a known method.

In the present invention, a composition comprising franlukast hydrate (hereinafter sometimes abbreviated as the composition of the present invention) means (1) franlukast hydrate, and preferably (2) sugars and ( 3) It is a composition which contains a water-soluble polymer, and may contain the additive (formulation base) generally used when manufacturing a capsule agent (4). As the additive (formulation base), for example, excipients, binders, lubricants, stabilizers, disintegrants, copulation agents, surfactants, fragrances, coloring agents, antioxidants, masking agents, antistatic agents, glidants, wetting agents, Elution adjuvant, a dissolution adjuvant, a coating agent, etc. can be mentioned, One or two or more types can be selected from these, and can be mix | blended suitably for the composition of this invention, and can be used. As said additive, a lubricant is preferable.

With lanlukast hydrate used for the composition of this invention, following formula (A)

4-oxo-8- [4- (4-phenol) benzoylamino] -2- (tetrazol-5-yl) -4H-1-benzopyran 1/2 hydrate is shown. The production of franlukast hydrate can be carried out according to the method described in, for example, Japanese Patent Laid-Open No. 61-050977.

Examples of the sugars in the composition of the present invention include lactose, mannitol, white sugar, dextrin, dextran, trehalose, pullulan, glucose, fructose, maltose, isomerized lactose, reduced lactose, sucrose, erythritol, maltitol, xylitol and pallatino. Sodium starch, sorbitol, corn starch, potato starch, wheat starch, rice starch and the like. Preferred are lactose, white sugar, mannitol and the like. More preferably lactose.

As a water-soluble polymer in the composition of this invention, celluloses (for example, hydroxymethyl cellulose, hydroxymethyl ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC)) , Hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), etc., synthetic polymers (e.g. polyethylene glycol (e.g., macrogol 4000, etc.), polyvinylpyrrolidone, Polyvinyl alcohol, etc.), gelatin, etc. are mentioned. Preferably, they are polyethylene glycol, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose. More preferably, it is polyethylene glycol.

Excipients as additives are, for example, sugars (e.g. lactose, mannitol, white sugar, dextrin, dextran, trehalose, pullulan, glucose, fructose, maltose, isomerized lactose, reducing lactose, sucrose, erythritol, maltitol, xylitol, palatinose) Sorbitol, corn starch, potato starch, wheat starch, rice starch and the like), microcrystalline cellulose, silicic anhydride, calcium phosphate anhydrous, precipitated calcium carbonate, calcium silicate and the like.

As the binder, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone (polyvinylpyrrolidone), methyl cellulose, polyvinyl alcohol, carboxymethyl cellulose sodium, partially α starch, α starch, sodium alginate, pullul Column, gum arabic, gelatin, magnesium aluminate silicate, and the like.

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

As a stabilizing agent, for example, adipic acid, ascorbic acid, L-aspartic acid, albumin, benzoic acid, ethanol, ethylenediamine, zinc chloride, calcium chloride, sodium chloride, benzalkonium chloride, benzetonium chloride, magnesium chloride, hydrochloric acid, hydrochloric acid Arginine, Cysteine Hydrochloride, Lidine Hydrochloride, Carmellose Calcium, Carmellose Sodium, Dihydrochloric Acid, Citric Acid, Calcium Citrate, Sodium Citrate, Glycine, Glycerin, Crystalline Cellulose, Cured Oil, Sesame Oil, Sodium Chondroitin Sulfate, Acetic Acid, Zinc Acetate Tocopherol acetate, sodium acetate, sodium salicylate, phenyl salicylate, zinc oxide, magnesium oxide, diisopropanolamine, diethanolamine, dibutyl hydroxytoluene, dimethylpolyshirokisan, calcium bromide, tartaric acid, calcium hydroxide, sodium hydroxide , Magnesium hydroxide, stearic acid, cetanol, gelatin, D-sorbitol, talc, ammonium carbonate, potassium carbonate, carbonate Sodium, sodium carbonate, magnesium carbonate, thioglycolic acid, sodium thioglycolate, sodium thiosulfate, dextrin, tocopherol, lactic acid, sodium lactate, lactose, urea, concentrated glycerin, white sugar, microcrystalline cellulose, hydroxypropyl cellulose, Hydroquinone, glacial acetic acid, glucose, fumaric acid, monosodium fumarate, sodium propionate, propylene glycol, benzyl alcohol, povidone (polyvinylpyrrolidone), polyvinyl alcohol (partial saponified), polyvinyl alcohol dibutyl ether mixture, maleic acid , Malonic acid, D-mannitol, citric anhydride, sodium citrate anhydrous, sodium acetate anhydride, maleic anhydride, sodium monohydrogen phosphate, sodium dihydrogen phosphate, magnesium aluminate metasilicate, sodium metasulfobenzoate, sodium metaphosphate, Methyl cellulose, methyl vinyl ether-maleic anhydride copolymer, potassium iodide, sodium iodide, sodium lauryl sulfate, sulfuric acid Zinc, potassium aluminum sulfate, potassium sulfate, magnesium sulfate, phosphoric acid, potassium dihydrogen phosphate, calcium dihydrogen phosphate and the like.

As a disintegrating agent, for example, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, hydroxypropyl starch, corn starch, cellulose glycolic acid Calcium etc. are mentioned.

Examples of copulating agents include sucrose, D-sorbitol, xylitol, citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, tomate, sodium saccharin, glycyridine dipotassium, sodium glutamate, and 5'-inosinic acid. Sodium, 5′-sodium guanylate, and the like.

As surfactant, For example, polysorbate (for example, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, etc.), a polyoxyethylene polyoxypropylene copolymer, Polyoxyethylene hardened castor oil, sorbitan monostearate, sodium lauryl sulfate, etc. are mentioned.

As a fragrance, lemon oil, orange oil, menthol, peppermint oil etc. are mentioned, for example.

As a coloring agent, titanium oxide, edible yellow No. 5, edible blue No. 2, iron trioxide, yellow iron trioxide, etc. are mentioned, for example.

As antioxidant, sodium ascorbate, L-cysteine, sodium sulfite, vitamin E etc. are mentioned, for example.

As a concealing agent, titanium oxide etc. are mentioned, for example.

Talc, titanium oxide, etc. are mentioned as an antistatic agent, for example.

Examples of the fluidizing agent include hard silicic anhydride, talc, hydrous silicon dioxide and the like.

Examples of the humectant include polysorbate 80, sodium lauryl sulfate, sucrose fatty acid ester, polyethylene glycol, hydroxypropyl cellulose (HPC), and the like.

Examples of the elution aid include dry methacrylic acid copolymer-LD, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, and the like.

Examples of the dissolution aid include glutamic acid and aspartic acid.

Examples of the coating agent include white sugar, gelatin, hydroxypropyl cellulose, hydroxymethyl cellulose phthalate, and the like.

In addition, the additives described above may be used for purposes other than the exemplified uses (e.g., excipients, binders, lubricants, stabilizers, disintegrants, copulating agents, surfactants, flavoring agents, coloring agents, antioxidants, masking agents, antistatic agents). , Fluidizing agents, wetting agents, dissolution aids, dissolution aids, coating agents, and the like). In addition to the above, additives described in well-known literature, for example, Pharmacy Daily, 2005, published in "Pharmaceutical Additives Dictionary" (edited by Japan Pharmaceutical Additives Association), may be used.

It is preferable that the composition of this invention contains the composition (1) franlukast hydrate, (2) saccharide, (3) water soluble polymer, and (4) the additive (agent base) generally used when manufacturing a capsule agent. . The combination of the above (1) to (4) includes (1) franlukast hydrate, (2) at least one sugar selected from the group consisting of lactose, white sugar and mannitol, (3) polyethylene glycol, methyl cellulose, hydroxypropyl A combination of at least one water-soluble polymer selected from the group consisting of cellulose and hydroxypropylmethylcellulose, and (4) glidants is preferred, (1) franlukast hydrate, (2) lactose, (3) polyethylene glycol and (4) A combination of magnesium stearate is more preferable.

In the composition of the present invention, the weight ratio of saccharides to 100 parts by weight of lanukast 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, and more preferably. Preferably from about 30 parts by weight to about 60 parts by weight. In addition, the weight ratio of the water-soluble polymer to 100 parts by weight of lanlukast hydrate is preferably about 5 parts by weight to about 20 parts by weight, and more preferably about 7.5 parts by weight to about 15 parts by weight.

In the composition of the present invention, the weight ratio of the lubricant to 100 parts by weight of lanukast hydrate is preferably about 0.5 part by weight to about 5 parts by weight, more preferably about 1.0 part by weight to about 4.5 parts by weight.

In the present invention, the weight of the composition of the present invention filled with a capsule agent is preferably about 130 mg to about 400 mg, more preferably about 150 mg to about 380 mg per capsule.

As a form of the composition of this invention, a granulated material is preferable. As the granulated product, if it is a granulated product manufactured by a method of assembling commonly used pharmaceutical preparations, for example, an assembly method described in "Assembly Handbook" (Japanese Powder Industry Technology Association, Omsa, 1991), etc. Although not particularly limited, for example, wet granules, dry granules, rolling granules, spray dried granules, extrusion granules, fluidized bed granules, stirred granules, compressed granules, molten granules, crushed granules, coatings Granulated material, liquid granulated material, vacuum freezing granulated material, etc. are mentioned. Among them, preferred are rolling granules, spray dried granules, extruded granules, fluidized bed granules, stirred granules and the like. More preferably, it is a spray dried granulated body, a stirred granulated body, etc.

In addition, the stirred granules include stirred granules, stirred fluidized bed granules, stirred electric fluidized bed granules, and the like.

When the composition of the present invention is a spray dried granule, it is preferably about 50% to about 98%, more preferably about 55% to about 90% by weight of franlukast hydrate in 100% by weight of the spray dried granule. %, Particularly preferably from about 60% to about 80%.

When the composition of the present invention is a stirred granule, it is preferably about 30% to about 98%, more preferably about 50% to about 80% by weight of franlukast hydrate in 100% by weight of the stirred granule. .

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 the capsule commonly used as a medicine. Capsules include hard capsules, soft capsules and the like.

The capsule agent in this invention is a capsule agent containing franlukast hydrate, and is a formulation which filled the capsule film (empty capsule) with the fixed amount of the composition of this invention by the conventional method. As a capsule film, any of a hard capsule and a soft capsule may be sufficient.

The capsule film usually contains a capsule base and a plasticizer. If necessary, for example, fragrance (for example, peppermint oil, cinnamon oil, strawberry and other fruit essences and flavors), and preservative (for example, parahydroxybenzoic acid). Ethyl, parahydroxybenzoate, etc.), pigments (e.g. yellow 4, yellow 5, red 3, blue 1, copper chloropine, etc.), opacifying agents (e.g. titanium dioxide, bengal, trioxide) Iron, etc., glidants (e.g. magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol, sodium lauryl sulfate), solubility modifiers (e.g. cellulose acetate phthalate, hydroxy) Alkali metal salts of propylmethylcellulose, alkali metal salts of hydroxymethylcellulose acetate succinate, alginate alkali salts, polya Rilsan may also include an alkali metal salt, methyl cellulose, carboxymethyl cellulose, casein, collagen, agar powder, polyvinyl alcohol, pectin, etc.), and the like.

The capsule base used in the capsule film in the present invention may be any substance as long as it is a substance that can be used as the base of the capsule film. For example, proteins (e.g. gelatin, gelatin hydrolysates, collagen, collagen hydrolysates, casein, etc.), polysaccharides (e.g. starch, amylose, polygalacturonic acid, agar, carrageenan, gum arabic, gellan gum, xanthan gum , Pectin, alginic acid, pullulan, etc., celluloses (for example, hydroxymethylcellulose, hydroxymethylethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC) ), Hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS, etc.), biodegradable plastics (e.g. polylactic acid, polyhydroxybutyric acid, polyglutamic acid, etc.), hardened fats and oils ( For example, triglyceride and diglyceride of medium chain fatty acid (for example, butter, margarine, shortening, cacao butter, etc.) etc. are mentioned. have. You may use these capsule bases in combination of 2 or more types as appropriate. In this invention, a protein, especially gelatin is preferable among these capsule bases.

In addition, the plasticizer used for a capsule film may be any substance as long as it is a substance that can be used as a plasticizer for the capsule film. For example, sugars (e.g. sucrose, white sugar, starch syrup), sugar alcohols (e.g. sorbitol, xylitol, mannitol, etc.), polyhydric alcohols (e.g. glycerin, ethylene glycol, polyethylene glycol, propylene Glycol etc.) etc. are mentioned. Especially, polyhydric alcohol, especially polyethylene glycol is preferable.

In the present invention, the content of franlukast 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 112.5 mg or 225 mg, Especially preferably, it is 112.5 mg. As the size of the capsule, No. 1, No. 2, No. 3 or No. 4 capsule is preferable, and the weight of the empty capsule per capsule is preferably about 30 mg to about 90 mg. For example, the No. 2 capsule or the No. 3 capsule containing 225 mg of franlukast hydrate, or the No. 3 or No. 4 capsule containing 112.5 mg, and the like are preferable from the viewpoint of compliance of the intake patient.

Therefore, in the capsule of the present invention, the total weight of one capsule is obtained by adding the weight of the composition to be filled and the weight of the empty capsule, so that about 160 mg to about 490 mg is preferable, and about 180 mg to about 470 mg are more preferable.

In the present invention, the desiccant is not particularly limited as long as it is generally used in the storage of medicines. Examples of such desiccant include aluminum oxide, calcium, calcium chloride, calcium hydride, calcium oxide, calcium sulfate, copper sulfate and lithium aluminum hydride. , Magnesium, magnesium oxide, magnesium perchlorate, magnesium sulfate, synthetic zeolites (e.g. molecular filters, etc.), natural zeolites, diphosphate pentoxide, potassium carbonate, potassium hydroxide, silica gel, silica alumina gel, sodium, sodium hydroxide, sodium sulfate, Magnesium aluminate, activated carbon, etc. are mentioned. You may use these in combination of 2 or more types as needed.

In addition to the desiccants listed above, an absorbent comprising a polymer polymer as a component is also included in the category of the desiccant in the present invention. Such absorbents are not particularly limited, but examples thereof include vinyl acetate (meth) acrylic acid ester copolymers, Vinyl acetate-maleic anhydride copolymer, isobutylene-maleic anhydride copolymer, acrylic acid-methacrylic acid copolymer, polyvinyl alcohol, polyethylene oxide, polypropylene oxide, polyvinylpyrrolidone, sulfonated polystyrene, Polyvinylpyridine, polyacrylamide, polymethacrylamide, and the like.

As a form of the drying agent used for this invention, what was shape | molded in granular form, film form, plate form, or sheet form, for example, and the granular thing filled in the air permeable bag (for example, dry yarn ( Although a brand name, Yamani Corporation, silica gel, IDF (brand name, ID Corporation, calcium chloride), etc. are mentioned, The form is not specifically limited.

In the present invention, a desiccant molded into a sheet shape (also referred to as a "sheet-shaped desiccant") is preferably used. When the desiccant is molded into a sheet shape, for example, a desiccant is blended into a suitable support, a molding plastic, etc., and the desiccant is poured into the plastic to form a sheet, or a solution containing a substance which is a raw material of the desiccant in the pulp material. The method of impregnation and shaping | molding, etc. are mentioned. As a sheet-shaped desiccant, an ID sheet (brand name, Kabushiki Kaisha); high sheet dry (brand name, Marutani Kakouki Co., Ltd., silica gel), high dry pack (brand name, Marutani Kakoki Kabushiki Kaisha; silica gel) Etc. can be mentioned. Preferably an ID sheet is mentioned.

As a desiccant used in the present invention, a desiccant having a moisture absorption of about 20% to about 35% at a temperature of 25 ° C. and a relative humidity of 50% is preferable. As such a desiccant, Preferably, the desiccant containing a silica gel, a silica alumina gel, calcium chloride, a pentoxide, synthetic zeolite, a natural zeolite, etc. is mentioned, More preferably, a desiccant containing calcium chloride or a silica gel is mentioned. And the like, and more preferably, a sheet-shaped desiccant containing calcium chloride, and particularly preferably a sheet-shaped desiccant containing about 10% by weight to about 30% by weight of calcium chloride. As a sheet-form desiccant containing about 10 weight%-about 30 weight% of calcium chloride, ID sheet (brand name, ID of a company) is mentioned, for example.

When using a desiccant in the present invention, it is preferable to use about 0.7 part by weight to about 17 parts by weight, more preferably about 1 part by weight to about 15 parts by weight, based on 100 parts by weight of the total weight of one capsule. It is particularly preferable to use from about 1.5 parts by weight to about 11 parts by weight.

For example, in the drug package of the present invention, when a capsule containing 112.5 mg of franlukast hydrate is packed in a plastic sheet with 14 PTPs per sheet, the total weight of one capsule of the capsule is 10. About 0.2 parts by weight to about 17 parts by weight of "drying agent containing calcium chloride or silica gel", based on 100 parts by weight, containing about 0.22 g to about 5.5 g of "sheet-shaped drying agent containing calcium chloride" or "granular silica gel." It is preferable to enclose the "drying agent" at the same time. Also, from about 1 part by weight to about 15 parts by weight of the "drying agent comprising calcium chloride or silica gel" based on 100 parts by weight of the total weight of one capsule, about 0.32 g to about 4.8 g of "sheet-shaped drying agent containing calcium chloride" Or it is more preferable to enclose a "drying agent containing granular silica gel" simultaneously, and it is equivalent to about 1.5 weight part-about 11 weight part "drying agent containing calcium chloride or a silica gel" with respect to 100 weight part of total weight of 1 capsule. It is particularly preferable to simultaneously enclose 0.48 g to about 3.4 g of "sheet-shaped desiccant containing calcium chloride" or "drying agent containing granular silica gel", and from about 3.1 part by weight to about 9.3 based on 100 parts by weight of the total weight of one capsule About 1 g to about 3 g of "calcium chloride," corresponding to parts by weight of the "drying agent containing calcium chloride or silica gel." Encapsulating the sheet-like drying agent "or drying agent" comprising a "particulate silica gel while it is particularly preferred to include. The weight in the case of using the "sheet-like desiccant containing calcium chloride" here means the weight also including the weight of the sheet-like pulp material impregnated with calcium chloride.

Moreover, about 0.5 mm-about 3 mm are preferable as thickness of "the sheet-shaped drying agent containing calcium chloride."

In the drug package of the present invention, a moisturizing agent can be enclosed in combination with the above-mentioned drying agent. In the present invention, the moisturizing agent means a substance having a function of absorbing, absorbing moisture, and moisture-proof and maintaining a constant humidity, that is, adjusting to equilibrium humidity, and is also called a moisturizing agent. Examples of such moisturizing agents include hydrous ethylene glycol-containing sheets and dry keeps (trade name, Sasaki Kagaku Yakuhin Co., Ltd.).

In the drug package of the present invention, it is important to control the relative humidity of the internal air to a certain range. In the present invention, the internal air means an atmosphere in which a capsule agent (hereinafter sometimes referred to as a "PTP package") filled with the composition of the present invention packed in a PTP package in a drug package and filled with a desiccant is placed. . Since the relative humidity of the internal air is in equilibrium with the relative humidity in the PTP package, it can be considered that it is equivalent to the relative humidity of the environment where the capsule is in contact with the PTP package.

In the present invention, the relative humidity of the internal air is adjusted to about 10% to about 45%. The relative humidity of the internal air 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 air is less than about 10%, serious abnormalities (for example, cleavage, crushing, etc.) occur in the capsule. In addition, when the relative humidity of the internal air exceeds about 45%, there is a collapse delay, dissolution delay, etc. of the capsule, such as impaired function as a medicine.

Here, the relative humidity of the internal air means a relative humidity measured using a thermo-hygrometer at a temperature of 25 ° C.

The relative humidity can be measured by a known method. For example, the method described in the following examples (for example, a method using a thermo-hygrometer (THARMO® RECORDER® RS-12; ESPEC), etc.), or a water activity measuring device (for example, AQUALAB® CX-3TE; Decagon) Moisture permeability test apparatus (e.g. L80-5005; Rishisa, GTR-WV; GTR Tech Co., Ltd.), thermogravimetric measuring device (e.g. TGA-50 / 50H; Shimatsu Seisakusho, etc.), water vapor transmission rate The relative humidity can be measured using a combination of a measuring device (eg, PERMATRAN-W (R) 3/61; MOCON Co., Ltd.) or the like.

[Relative humidity measurement method]

The method of measuring relative humidity using the above-described water activity measuring device is as shown below.

<Measurement of water activity value of francaste hydrate-containing capsule>

The above-mentioned sample sealed by using a water activity measuring device (AQUALAB® CX-3TE: Decagon Co., Ltd.) was placed in a sample cup together with a PTP-packed franlukast hydrate-containing capsule and a desiccant (for example, an ID sheet) using PVC. The water activity (Aw; Water Acitvity) value in a cup is measured. The obtained Aw value is converted into equilibrium relative humidity (ERH).

As a drug package of this invention, the drug package as shown in FIG. 1 is mentioned, for example. The drug package shown in FIG. 1 is encapsulated in a capsule (2) and a desiccant (3) filled with a composition containing a fluorolukast hydrate PTP-packed with a plastic sheet (1) in a packaging material (4). It is hermetically packed.

The film to be used for the exterior material may be a film-like material that can be sealed, and is not particularly limited, but preferably has a property capable of preventing the inflow and outflow of gas such as water vapor. As such a film, an aluminum film, a high density polyethylene film, a polyvinylidene chloride film, a high density polyethylene laminate paper, a polyvinylidene chloride laminate paper, etc. are mentioned, For example, Preferably, it is an aluminum film. Examples of the form of the packaging material include cans, bottles, and bags (for example, cartoner packaging, shrink packaging, pillow packaging, etc.), but bags are preferable. In addition, when the shape of the exterior material is a bag, a bag with a zipper (for example, a single zipper, a double zipper, etc.) may be used.

The drug package of the present invention is preferably an aluminum film package using an aluminum film as a packaging material, more preferably a pillow package of an aluminum film. An aluminum film package can be manufactured by sealing a well-known method, for example, a PTP package and a desiccant, in the bag etc. which consist of aluminum films, and performing heat sealing (heat adhesion) etc., for example.

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

In the present invention, the relative humidity of the internal air is "controlled" that the relative humidity reaches a steady state after about 6 hours after the drug package of the present invention is manufactured, as in the following example, at least about 6 thereafter. It means that the value is kept within a predetermined range for months.

In the present invention, the moisture content means the amount of water contained in the test substance, that is, the water content. The test substance is not particularly limited as long as it is a substance constituting the drug package of the present invention. Preferably, the composition of the present invention, a capsule coating constituting the capsule, etc. may be mentioned. In the present invention, the water content of the composition containing franlukast hydrate and the like is preferably about 1% to about 2.7%, more preferably about 1.2% to about 2.5%. The water content of the capsule coating 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 well-known method. For example, it can be measured according to a method known as a water measurement method of a medicine, in particular, a water measurement method contained in the Japanese Pharmacy Defense Agency, and in particular, a water measurement method (Karl Fisher's Method) contained in the 15th Amendment of Japan Pharmacy Defense Agency.

In the present invention, the pharmaceutical package is prepared by appropriately combining the capsules filled with the composition of the present invention, which is PTP-packed with the sheet, the amount of the desiccant having a constant hygroscopicity, and the moisture content of the composition and the capsule film, which are encapsulated in the drug package. The relative humidity of the internal air can be adjusted within a certain range. Thus, the drug package of the present invention, in which the relative humidity of the internal air is adjusted, has a disintegration delay, elution delay, abnormality (e.g., splitting, crushing, etc.) during storage of the capsule agent filled with the composition of the present invention, Wind seas, deliquescence, etc. can be suppressed.

In the present invention, the "collapse delay" means that the dissolution rate of the franlukast hydrate is delayed by prolonging the disintegration time of the contents of the capsule in the present invention. As will be apparent to those skilled in the art, the composition of the present invention, which is the contents in the capsule, is broken down, subdivided into small particle shapes, and the surface area is increased.

In the present invention, the degree of "collapse delay" can be confirmed by disintegrating the capsules filled with the composition of the present invention for a certain period of time in the drug package and outside the PTP package, and then comparing them with the test results in the initial state. Can be. The disintegration test can be carried out by a known method. For example, the disintegration test can be carried out according to a method known as a disintegration test method for a solid preparation such as tablets or capsules. It is preferable to carry out according to the collapse test method etc. which are contained in the Japanese Pharmacy.

In the present invention, "dissolution delay" means that the bioavailability after in vivo administration changes due to a delay in the elution rate of franlukast hydrate. As is clear to those skilled in the art, the dissolution rate of the active ingredient in the capsule agent defines the bioavailability of the capsule agent, so that the bioavailability after in vivo administration changes due to elution delay, resulting in insufficient drug expression or accompanying side effects. I think there is concern.

In the present invention, the degree of "dissolution delay" is to compare the test results in the initial state by performing the dissolution test after storing the capsule formed by filling the composition of the present invention in the drug package and the PTP package for a certain period of time. You can check it. The dissolution test can be carried out by a known method, for example, generally according to the method known as the dissolution test method for the content of solid preparations such as tablets and capsules, but the dissolution test method listed in the Japanese Pharmacy, among others, is revised. It is preferable to carry out according to the dissolution test method listed in the Japanese Pharmacy, for example, according to the first method (rotating basket method), the second method (paddle method), the third method (Flow-Through-Cell Method), etc. desirable.

The conditions for preservation for confirming the degree of "dissolution delay" are not particularly limited, but may be, for example, room temperature so as to be usually carried out by a person skilled in the art, and even under conditions of high temperature and / or high humidity as generally referred to as accelerated test or harsh test. do. By setting it as conditions of high temperature and / or high humidity, the result of long term storage at room temperature can be obtained more in a short time.

As a cause of the above-mentioned "collapse delay" or "dissolution delay", generally, a change in the composition and preparation base (for example, capsule coating, etc., if a capsule is produced) containing an active ingredient over time by preserving drugs, especially capsules. It is thought that it is because (for example, a change in moisture content) occurs.

In the present invention, the term "idea" of a capsule agent is a preservation of a certain amount of change (for example, a decrease in the strength of the capsule film, etc.) of the capsule agent over time by preservation. It means that it will be in the state which impairs the function of the capsule agent which protects the composition to make. Specifically, when the capsule is broken, crushed, etc., the composition containing the franlukast hydrate not only flows out, but also the content or state of the composition changes due to the inflow and outflow of moisture, the outflow and inflow of gas, etc. The ability of the capsules to retain is impaired.

The above-described "capacity" of the capsules is obtained by dividing the capsules filled with the composition of the present invention in a drug package and a PTP package for a predetermined period of time, and then performing a split load test to calculate the number of divided samples for the total number of samples. It can confirm by comparing a ratio and a split rate for every storage period. The split load test may be performed by, for example, a method of evaluating strength by applying a constant impact, load, or the like to a capsule, and may be, for example, a fall impact test or the like as shown in Examples described later. .

The drug package of the present invention suppresses disintegration delay, elution delay, abnormality (e.g., splitting, crushing, etc.), wind-sealing, decontamination, etc. in the object of the present invention, i. In order to achieve this, it is preferable to make the above-mentioned elements constituting the drug package of the present invention have a specific combination as shown below. That is, the total weight of the capsules filled with the composition which consists of (I) PRAN packaged with the plastic sheet, and containing the composition containing the franc hydrate which has all the following characteristics (a)-(e), and (II) capsules 1 capsule total weight 100 About 0.7 parts by weight to about 17 parts by weight of a desiccant having a moisture absorption of about 20% to about 35% at a temperature of 25 ° C. and a relative humidity of 50% is encapsulated, and (III) is sealed and packaged with a film. It is preferable that the drug package is adjusted to about 10% to about 45% relative humidity of the internal air measured using a thermo-hygrometer at a temperature of 25 ° C.

(a) comprising about 112.5 mg or about 225 mg of franlukast hydrate per capsule,

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

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

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

(e) The water content of the capsule coating is about 8% to about 17%.

As the combination of the components in the drug package of the present invention, franlukast hydrates, sugars, all of which have all the characteristics of (a) to (e) described above, PTP packaged with (I) plastic sheets, A capsule filled with a composition comprising a water-soluble polymer and a lubricant, and (II) a drying agent containing silica gel or calcium chloride, from about 0.7 parts by weight to about 17 parts by weight per 100 parts by weight of the total capsule of (II) capsule, (III) The drug package is formed by sealing the film, and the relative humidity of the internal air measured using a thermo-hygrometer at a temperature of 25 ° C. is adjusted to about 10% to about 45%. Particularly preferably, (I) a capsule filled with a composition containing franlukast hydrate having all of the following properties (i) to (iii) PTP-packed with a plastic sheet, and (II) capsule 1 capsule About 1 part by weight to about 15 parts by weight of the sheet-like desiccant containing calcium chloride is encapsulated and sealed by a film (III), and measured by using a thermo-hygrometer at a temperature of 25 ° C. Drug packaging in which the relative humidity of the air is adjusted from about 10% to about 45%.

(Iii) about 112.5 mg of franlukast hydrate per capsule,

(Ii) from about 130 mg to about 400 mg of a composition per capsule,

(Iii) the composition comprises about 30 parts by weight to about 60 parts by weight of lactose per 100 parts by weight of lanlukast hydrate, about 7.5 parts by weight to about 15 parts by weight of polyethylene glycol, and about 1 part by weight of magnesium stearate To about 4.5 parts by weight of the composition,

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

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

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

[Application to pharmaceutical products]

The composition of the present invention is to contain a variety of lanukast hydrate as an active ingredient, such as bronchial asthma, allergic rhinitis, sinusitis, chronic obstructive pulmonary disease, Meniere disease, exudative otitis media, migraine, dysmenorrhea It is useful as a prophylactic and / or therapeutic drug of a disease, etc.

[toxicity]

Franlukast hydrate in the present invention is low toxicity and sufficiently safe for use as a medicament.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.

In addition, in the following, the packaging work for the production of PTP package or drug package was carried out according to a general method 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%).

In each test example, the temperature and relative humidity of each test fixture were kept constant during the six month storage period, and the relative humidity was measured using a thermohygrometer (THERMO® RECORDER® RS-12: manufactured by ESPEC).

[Formulation example]: Production of franlukast hydrate (112.5 mg) -containing capsule

Spray dried granules were obtained by spraying a suspension of franlukast hydrate (40 kg) and lactose (18.7 kg) in an aqueous polyethylene glycol solution according to the method described in Japanese Patent Application Laid-Open No. 61-050977. Using the mixture of the obtained granulated product and magnesium stearate (suitable) as the contents, the content of franlukast hydrate was 112.5 mg per capsule, and No. 3 capsule (caps gel-Jepan Kabushiki Kaisha or Kuori Kapus Co., Ltd.) was incorporated. The capsules containing franc lucastt hydrate which are the following compositions were obtained by filling in the General method).

<Composition (per one capsule)>

Franlukast hydrate (112.5 mg)

Lactose (52.65 mg)

Polyethylene glycol (macrogol 4000) (11.25mg)

Magnesium Stearate (3.6 mg)

Empty capsule 3 (49.0mg)

[PTP package production example]

As a plastic sheet used for PTP packaging about the lanukast hydrate-containing capsule produced in the above formulation example, a hard vinyl chloride sheet having a thickness of 200 μm (Sumilite (registered trademark) VSS-1104; Sumitomo Bakelite Co., Ltd., abbreviated as PVC) PTP was packaged using (PTP package 1).

Similarly, PTP packaging was carried out using a composite sheet (VSL-4501; Sumitomo Bakelite Co., Ltd., abbreviated below as PVC / PVDC) using a combination of hard vinyl chloride and vinylidene chloride having a thickness of 250 µm as a plastic sheet (PTP package 2).

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

In addition, any PTP package was produced by overlapping each plastic sheet and an aluminum film by a general method and encapsulating 14 capsules per sheet.

[Examples 1 to 7 and Comparative Example 1]

PTP package 1 and calcium chloride impregnated sheet-form desiccant (ID sheet; ID) or granular silica gel which were obtained by the said PTP package manufacture example, or dry-type desiccant (Dryyan; Yamani Yakuhin Co., Ltd.), The drug package of the structure shown in following Table 1 was manufactured by sealing in an aluminum film bag (about 110 mm x about 200 mm), and packaging it. Here, the weight of the desiccant means a weight including the weight of the sheet-like pulp material impregnated with calcium chloride in the case of the sheet-shaped desiccant containing calcium chloride.

Drug packaging PTP Package
(Plastic sheet) Number of capsules per 1 drug package drier
(weight) Amount of desiccant to 100 parts by weight of total weight of one capsule of capsule Example 1 PTP Package 1
(PVC) 56 Calcium chloride impregnated sheet (1.3 g) 10.3 parts by weight Example 2 〃 140 Calcium chloride impregnated sheet (3 g) 9.3 parts by weight Example 3 〃 140 Granular Silica Gel (3g) 9.3 parts by weight Example 4 〃 140 Granular Silica Gel (2g) 6.2 parts by weight Example 5 〃 56 Calcium chloride impregnated sheet (0.44 g) 3.46 parts by weight Example 6 〃 140 Granular Silica Gel (1g) 3.1 parts by weight Example 7 〃 56 Calcium chloride impregnated sheet (0.19 g) 1.52 parts by weight Comparative Example 1 〃 140 none 0 parts by weight

The following tests were performed using the drug package obtained in the said Example or the comparative example, the capsule agent (unpackaged) obtained by the formulation example, or the PTP package (without aluminum film bag) as a sample.

In the analysis of test results, the relative humidity when a capsule (unpackaged) and a PTP package (without an aluminum film bag) are used for each test is measured in a drug package in which the capsule or the PTP package is placed in an aluminum film bag and sealed. It was considered to have the same value as the relative humidity of the internal air of the sieve.

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

Initiation of preservation in the shelf life of 6 months under conditions of 25% or 22% or 75% of the temperature of the capsules (unpackaged) and PTP package 1 (no aluminum film package) obtained in the formulation example (initial stage) ), 2, 4, and 6 months later, the water content of the capsule film and the contents (composition) filled in the capsule was measured according to the water measurement method (Kar Fisher method) described in the 15th Amendment of Japan, and the average value was calculated. It was. The results are shown in Table 2.

Preservation condition
(25 ℃) Sample Moisture content (%) Early 2 months later 4 months later 6 months later film contents film contents film contents film contents Relative Humidity 22% Capsule (unpacking) 12.1 1.92 10.5 1.93 11.2 1.97 10.9 1.93 PTP Package 1
(PVC) 〃 〃 10.4 2.01 11.1 1.97 10.6 1.95 Relative Humidity 75% Capsule (unpacking) 〃 〃 17.8 3.00 18.7 3.09 19.2 2.96 PTP Package 1
(PVC) 〃 〃 17.1 2.78 17.7 3.04 18.7 2.89

From the above results, when stored under the conditions of 22% relative humidity, the moisture content of the capsules in the unpacked state and PTP-packed state remained almost unchanged after 2 months, 4 months and 6 months, but the water content of the capsule film was It turned out that it was degraded. On the other hand, when stored under the conditions of 75% relative humidity, after 2 months, 4 months, and 6 months, the capsule film and the water content of the contents were higher than the initial stage.

Next, with respect to the samples of Examples 2 and 3, the water measurement method described in the 15th revised Japanese Pharmacy Defense Initiation (Initial) and 6 months later in the storage period of 6 months under the conditions of 25 ° C and 75% relative humidity. According to the Karl Fischer method, the water 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.

Sample % Moisture content of contents (Early) 6 months later Example 2 1.61 1.46 Example 3 〃 1.48

Storage condition: temperature 25 ℃, relative humidity 75%

As shown in the above results, when stored under the conditions of a temperature of 25 ° C. and a relative humidity of 75%, a drug package composed of any combination of two kinds of desiccants, unlike the result obtained when the PTP package 1 was stored as it is. Also in the sieve, there was no increase in the moisture content of the contents. In addition, the moisture content of the contents of the drug package prepared in Example 1 and Examples 4 to 7 was measured under the same conditions, and showed almost the same value as the above result. On the other hand, the water content of the contents of the drug package of Comparative Example 1 was measured under the same conditions, and the water content of the contents increased.

In addition, the water content of the contents was measured under the same conditions with respect to 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. Almost the same value as. From this, it was found that the water content of the contents was not affected by the difference in the plastic sheet used for the PTP package.

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

Initiation of preservation in a shelf life of 6 months under conditions of 25 ° C, 22% or 75% relative humidity of the capsules (unpacked) and PTP package 1 (no aluminum film package) obtained in the formulation example ( After the initial), 2 months, 4 months and 6 months, the disintegration time was examined according to the disintegration test method (capsules) described in the 15th Amendment of Japan Pharmacopoeia. The test was made into six specimens, all collapsed within 20 minutes, and the contents completely dissolved were made suitable, and the others were not suitable. The results are shown in Table 4.

Preservation condition
(25 ℃) Sample Moisture content (%) Early 2 months later 4 months later 6 months later Relative Humidity 22% Capsule (unpacking) 5 ~ 6 6 ~ 7 5 ~ 7 5 ~ 7 PTP Package 1
(PVC) 〃 5 ~ 7 6 ~ 7 5 ~ 7 Relative Humidity 75% Capsule (unpacking) 〃 7-11 incongruity# incongruity# PTP Package 1
(PVC) 〃 7-8 incongruity# incongruity#

#: Insoluble lumps of contents remain

Next, the storage start time (initial stage) and two months in the storage period of 6 months under the conditions of the temperature of 25 degreeC, 75% of a relative humidity with respect to the sample of Examples 2-4, 6 and Comparative Example 1 shown in Table 5 below. After 4 months and 6 months, the disintegration time was examined in the same manner as above. The results are shown in Table 5.

Sample Moisture content (%) Early 2 months later 4 months later 6 months later Example 2 6 ~ 8 8 ~ 11 8 ~ 10 7-9 Example 3 〃 9 ~ 11 5-9 7-9 Example 4 3 to 4 17-20 6-12 9-14 Example 6 〃 5 to 10 5 ~ 7 9-13 Comparative Example 1 〃 15 incongruity* -

*: 2 samples remain in 6 samples at 20 minutes of test

Further, the drug packages prepared in Examples 1, 5, and 7 were subjected to the disintegration test under the same conditions. In all of the examples, the disintegration test was carried out within 20 minutes at all the above points in the storage period, and the contents were completely destroyed. As it melt | dissolved, it was suitable.

As shown in the above results, when stored under the conditions of a temperature of 25 ° C. and a relative humidity of 75%, the PTP package 1 as described above or when stored as a drug package without a desiccant as in Comparative Example 1 was 4 months and 6 months. The drug package consisting of any combination of two kinds of desiccant and the amount of desiccant (about 1.52 parts by weight to about 10.3 parts by weight as the amount of desiccant relative to 100 parts by weight of the total weight of one capsule of capsule) Even in this case, the extension of the collapse time was suppressed, making it suitable at all time points.

The results of Test Example 1 and Example 2 are summarized to show the contents and capsules of the unpacked, PTP package (no aluminum film package), or the contents observed in Test Example 1 in Comparative Example 1 when stored under the conditions of 75% relative humidity. As the water content of the film increased, it became apparent that the extension of the disintegration time observed in Test Example 2 occurred, suggesting that the capsule disintegration delay occurred when the internal air of the drug package became about 75% or more. On the other hand, in the drug package of the embodiment, a certain amount of a suitable desiccant is sealed together and sealed and packed with a film, so that the moisture content of the contents is in a preferred range (water content of the composition: from about 1% to about 2.7%, and moisture content of the capsule film: from about 8%). About 17%), the collapse delay is thought to be suppressed.

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

The following fall impact test method after two months, four months, and six months in a shelf life of 6 months under conditions of 25 ° C, 22% or 75% relative humidity of the capsule (unpackaged) sample obtained in the formulation example. The strength of the capsule was measured accordingly. In addition, it measured by the same method also after 7 days and 37 days in the 37-day storage period on condition of the temperature of 25 degreeC, and 7% of a relative humidity. The results are summarized in Table 6.

<Falling impact test>

(1) In the center of the circle | round | yen of the stand of the fall impact test apparatus, the capsule agent was put together. A 100 g metal weight was fixed on the top of the cylinder with a metal fixture so as to have a height of 80 mm from the base.

(2) The cylinder was attached to the pedestal, the hook of the metal fixture was pushed off, and the weight was naturally dropped on the body and cap part made of a capsule.

(3) Each 50 specimens were tested for the presence of fragmentation and distortion of the capsules. The ratio of the capsule agent which caused either division or crushing in all the capsule agents was computed as a split ratio.

Preservation condition (25 ℃) Sample Split number / 50 7 days later 37 days later 2 months later 4 months later 6 months later Relative Humidity 7% Capsule (unpacking) One 9 - - - Relative Humidity 22% Capsule (unpacking) - - One 8 9 Relative Humidity 75% Capsule (unpacking) - - 0 0 0

From the above results, the fragmentation rate of the capsules after storage for 2 months, 4 months and 6 months in an unpacked state under a condition of 25 ° C and a relative humidity of 22% is within a suitable range, and remains unpacked under a condition of 75% relative humidity. Since the cleavage rate of the capsule agent after 2 months, 4 months, and 6 months of storage was 0% at any point, it was suitable under any conditions. On the other hand, it was found that under the conditions of drying at a temperature of 25 ° C. and a relative humidity of 7%, the fragmentation rate of the capsules rapidly increased and was inadequate.

Therefore, it became clear that the intensity | strength of a capsule agent falls when it became below the moisture content of the capsule film in 22% of the relative humidity 22% of the temperature of 25 degreeC of the test example. In addition, it was suggested that the relative humidity of the capsule air should be adjusted to be at least 7% because the fragmentation rate of the capsule increases in an atmosphere having a relative humidity of about 7% or less.

 [Test Example 4: Relative Humidity Measurement in Aluminum Film Package Made in Capsule]

In the drug package prepared in Examples 1, 5 and 7, the thermo-hygrometer (THERMO® RECORDER® RS-12: ESPEC Co., Ltd.) was enclosed in an aluminum film bag (110 mm x 200 mm) at the time of sealing packaging. By heat-sealing. The drug package containing the heat-sealed hygrometer is allowed to stand at room temperature for 48 hours, then at 25 ° C. and 60% relative humidity for 24 hours, and the relative humidity of the internal air of the drug package. Was monitored.

Table 7 shows the results of measuring the relative humidity of the internal air at a temperature of 25 ° C. and the relative humidity reaching a steady state.

Sample Relative humidity Example 1 37% RH Example 5 23% RH Example 7 10% RH

In addition, the relative humidity of the internal air of each drug package in the same method and conditions as described above for the drug package of Examples 2, 3 and 4, the relative humidity is in the range of about 10 to 23% I could see that. In addition, the relative humidity of the internal air of the drug package was similarly monitored for the drug package of Example 6, and it was found that the relative humidity was in the range of about 23 to 37%.

From the above results, when the amount of the desiccant is used in the 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 as a "sheet-shaped desiccant containing calcium chloride" or "drying agent containing granular silica gel", It was found that the relative humidity at a temperature of 25 ° C. was adjusted to about 10% to about 40%.

The results of Test Examples 1 to 3 collectively indicate that the water content of the composition and the capsule coating was in the range of about 1% to about 2.7% and about 8% to 17%, respectively, for the drug package of Examples 1 to 7. No delay and splitting of the capsules occurred. In addition, in consideration of Test Example 4, it can be seen that the air inside the drug package is controlled to about 10 to about 40% by being adjusted within the range of the moisture content of the composition and the capsule coating as described above.

Therefore, the total weight of one capsule as a capsule material filled with the composition containing the franc lucast hydrate PTP-packed with the plastic sheet, and the quantity of a desiccant as "sheet-type desiccant containing calcium chloride" or "drying agent containing granular silica gel". If the amount is adjusted in a range of about 1.5 parts by weight to about 11 parts by weight per 100 parts by weight, the relative humidity of the internal air of the drug package is about 10% to about 40 since the composition of the capsule and the moisture content of the capsule film are adjusted to a suitable range. It can be seen that it is adjusted to%.

According to the present invention, it is possible to provide a drug package in which quality deterioration such as disintegration delay at the time of storage of a capsule containing PTP-packed lanucast hydrate, and abnormality such as fragmentation of the capsule are minimized.

Claims (19)

delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete (I) a capsule filled with a composition comprising franlukast hydrate having all of the following properties (a) to (e) or (f) to (j), PTP packaged with a plastic sheet, and (II) ) 0.7 parts by weight to 17 parts by weight per 100 parts by weight of the total capsule of the capsule, a desiccant having a moisture absorption of 20% to 35% at a temperature of 25 ° C. and a relative humidity of 50% is encapsulated, and (III) sealed and packed with a film. A drug package having a relative humidity of 10% to 45% of internal air measured using a thermo-hygrometer at a temperature of 25 ° C .: (a) contains 112.5 mg of franlukast hydrate per capsule, (b) from 130 mg to 400 mg of composition per capsule, (c) the weight of the empty capsule per capsule is 30 mg to 90 mg, (d) the moisture content of the composition is 1% to 2.7%, (e) the water content of the capsule film is 8% to 17%, (f) contains 225 mg of franlukast hydrate per capsule, (g) from 230 mg to 450 mg of composition per capsule, (h) the weight of the empty capsule per capsule is 30 mg to 90 mg, (i) the moisture content of the composition is 1% to 2.7%, (j) The water content of the capsule film is 8% to 17%. 17. A composition according to claim 16, wherein the composition comprising franlukast hydrate is a composition containing franlukast hydrate, sugars, water-soluble polymers and lubricants, and the desiccant is a desiccant comprising silica gel or calcium chloride. Drug package. 18. The capsule according to claim 17, wherein the capsule comprises 112.5 mg of franlukast hydrate per capsule, wherein the composition comprising franlukast hydrate comprises 30 parts by weight to 60 parts by weight of lactose per 100 parts by weight of franlukast hydrate. It is a composition comprising a weight part, 7.5 to 15 parts by weight of polyethylene glycol, 1.0 to 4.5 parts by weight of magnesium stearate, the drying agent is a sheet-like drying agent containing calcium chloride, the sheet-like drying agent is 1 A drug package is encapsulated in a proportion of 1 to 15 parts by weight per 100 parts by weight of the capsule. delete

Images