WO2007060802A1 - Preparation pharmaceutique solide et composition de preparation pharmaceutique - Google Patents

Preparation pharmaceutique solide et composition de preparation pharmaceutique Download PDF

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Publication number
WO2007060802A1
WO2007060802A1 PCT/JP2006/321101 JP2006321101W WO2007060802A1 WO 2007060802 A1 WO2007060802 A1 WO 2007060802A1 JP 2006321101 W JP2006321101 W JP 2006321101W WO 2007060802 A1 WO2007060802 A1 WO 2007060802A1
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WO
WIPO (PCT)
Prior art keywords
weight
granulated product
pharmaceutical composition
capsule
pranlukast hydrate
Prior art date
Application number
PCT/JP2006/321101
Other languages
English (en)
Japanese (ja)
Inventor
Masanobu Yamamoto
Kimihito Torii
Nobutaka Abe
Takehiko Horio
Yuri Matsuura
Original Assignee
Ono Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ono Pharmaceutical Co., Ltd. filed Critical Ono Pharmaceutical Co., Ltd.
Publication of WO2007060802A1 publication Critical patent/WO2007060802A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention comprises pranlukast hydrate, a cellulosic disintegrant and an excipient, which dissolves rapidly, exhibits stable dissolution, and has little change in dissolution rate over time.
  • the present invention relates to a granulated product suitable for solid preparations!
  • Pranlukast hydrate is known as a leukotrien antagonist (see Patent Document 1), and a capsule (trade name: ononcapsell) or dry syrup containing pranlukast hydrate as an active ingredient (Product name: Onon Dry Syrup) is listed.
  • Pranlukast hydrate-containing preparations are very useful as treatments for bronchial asthma and allergic rhinitis.
  • pranlukast hydrate Due to the relationship between the properties of cellulose and cellulose, there is a concern about the further increase (deterioration) in the adhesion (aggregation) of granulating powder (granulated material), and the formulation of pranlukast hydrate with improved dissolution is It was considered very difficult.
  • Patent Document 1 Japanese Patent Application Laid-Open No. 61-050977 (Claims)
  • Patent Document 2 JP-A-2005-187406 (Claims, Examples)
  • Patent Document 3 Japanese Patent No. 2958863 (paragraph [0004])
  • Non-Patent Document 1 Tablet 'Capsule Stability Information in Unwrapped State Revised 3rd Edition (Japan Hospital, Pharmaceutical Journal) (page 136)
  • An object of the present invention is to provide a granulated material containing a stable pranlukast hydrate, in which the active ingredient is rapidly eluted and hardly changes in the dissolution rate even when stored in an unwrapped state. It is to provide a pharmaceutical composition.
  • the inventors of the present invention prepared a granulated product by combining pranlukast hydrate with a specific cellulose-based disintegrant and an excipient.
  • the elution property of pranlukast hydrate can be improved by making the content of the cellulose-based disintegrant with respect to pranlukast hydrate a specific value in the granulated product. I found that it can be improved.
  • the present inventors have found that the granulated product found above and a pharmaceutical composition containing the same exhibit stable dissolution and little change in dissolution rate over time, thereby completing the present invention. .
  • the rotating speed of the stirring blade is 50-500rpm
  • the amount of added water is 20 to 45% by weight when the charged amount is 100% by weight.
  • a pharmaceutical composition comprising pranlukast hydrate, a cellulosic disintegrant and an excipient, which dissolves quickly, exhibits stable dissolution, and has little change in dissolution rate over time.
  • the cellulosic disintegrant is at least one selected from the group consisting of crystalline cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, and low-substituted hydroxypropylcellulose.
  • a granule comprising the pharmaceutical composition according to [12] above
  • the elution of the pranlukast hydrate which is an active ingredient without deteriorating the adhesion and aggregation properties, is improved by granulating using specific celluloses as a disintegrant.
  • a granulated product can be provided. Therefore, the granulated tanned pharmaceutical composition containing the pranlukast hydrate, cellulose disintegrant and excipient of the present invention is suitable for the production of a solid preparation, and the solid preparation (tablet , Capsules, etc.), the active ingredient elutes quickly, and even if stored in an unwrapped state, the dissolution change is unlikely to occur. Therefore, it is possible to provide a solid preparation containing pranlukast hydrate having a stable quality.
  • FIG. 1 is a graph showing the results of dissolution tests of Formulation Examples 1 to 3.
  • the granulated product of the present invention is a granulated product comprising pranlukast hydrate, a cellulosic disintegrant, and an excipient.
  • a granulated product such as a powder or a granule with little change in dissolution rate over time.
  • the pranlukast hydrate used in the present invention has the formula (A)
  • the cellulose-based disintegrant used in the present invention includes crystalline cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium or carboxymethylcellulose. These can be used by appropriately blending one or more thereof. Preferably, low-substituted hydroxypropylcellulose or croscarmellose sodium is used. More preferred is low-substituted hydroxypropylcellulose.
  • the low-substituted hydroxypropyl cellulose (L-HPC) used in the present invention is distinguished from ordinary hydroxypropyl cellulose (HPC), and the hydroxypropoxyl group content in hydroxypropyl cellulose is about 5 to 16% by weight.
  • the low-substituted hydroxypropyl cellulose is about 7 to 9.9 parts by weight, which is preferably about 7 to 13 parts by weight of the low-substituted hydroxypropyl cellulose. Particularly preferred.
  • L-HPC examples include low-substituted hydroxypropyl cellulose having a hydroxypropoxyl group content of about 7 to 9.9 parts by weight in hydroxypropylcellulose, such as LH-22 (Shin-Etsu Chemical Co., Ltd.). Co., Ltd., average particle size of about 40 / ⁇ ⁇ ), LH-32 (Shin-Etsu Chemical Co., Ltd., average particle size of about 25 ⁇ m), and mixtures thereof. These are commercially available.
  • LH-21 manufactured by Shin-Etsu Chemical Co., Ltd., average particle diameter of about 40 m
  • LH-31 manufactured by Shin-Etsu Chemical Co., Ltd., average particle size of about 25 m
  • LH--11 manufactured by Shin-Etsu Chemical Co., Ltd., average particle size of about 50; ⁇ ⁇
  • LH-B1 Shin-Etsu Chemical
  • LH-B1 Shin-Etsu Chemical
  • LH-20 (manufactured by Shin-Etsu Chemical Co., Ltd., average particle size of about 40) is used as a low-substituted hydroxypropyl cellulose having a hydroxypropoxyl group content in hydroxypropyl cellulose of about 13.0 to 16.0 weight.
  • LH-30 (manufactured by Shin-Etsu Chemical Co., Ltd., average particle size of about 25 ⁇ m), and mixtures thereof, etc., which are commercially available.
  • Normal hydroxypropyl cellulose is hydroxypropyl cellulose having a hydroxypropoxyl group content of about 53.4-77.5 parts by weight in hydroxypropyl cellulose.
  • Examples of the excipient used in the present invention include saccharides, starches, crystalline cellulose, anhydrous calcium acid, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, and the like. It can mix
  • saccharides are used.
  • Examples of the saccharide include glucose, fructose, maltose, lactose, sucrose, isomerized lactose, reduced lactose, sucrose, mannitol, erythritol, maltitol, xylitol, palatinose, trehalose, sorbitol and the like. Lactose, sucrose or mannitol is preferred, and lactose is more preferred.
  • Examples of starches include corn starch, potato starch, wheat starch, and rice starch.
  • the method for producing the granulated product of the present invention is in accordance with a known method, for example, pranlukast hydrate, cellulosic disintegrant, excipient, and, if necessary, other additives are mixed.
  • known granulation methods for example, extrusion granulation method, stirring granulation method, mixed stirring granulation method, high speed mixing stirring granulation method, kneading high speed stirring granulation method, fluidized bed granulation method, rolling stirring
  • drying, sizing, classification, etc. as necessary Can be manufactured.
  • stirring granulation method including mixed stirring granulation method, high speed mixed stirring granulation method, kneading high speed stirring granulation method), fluidized bed granulation method, rolling
  • the stirring fluidized bed granulation method or the spray drying granulation method is preferable, and the stirring granulation method is particularly preferable.
  • the granulated product of the present invention comprises, in addition to pranlukast hydrate, a cellulosic disintegrant and an excipient, an additive generally used in producing a granulated product or a pharmaceutical composition.
  • an additive generally used in producing a granulated product or a pharmaceutical composition for example, binders, lubricants, flavoring agents, flavoring agents, surfactants, fragrances, coloring agents, antioxidants, masking agents, antistatic agents, wetting agents.
  • one or more elution aids, fluidizing agents and the like can be appropriately blended and used.
  • it may contain a disintegrant other than the above-mentioned cellulose-based disintegrant, and one or more of them can be appropriately blended and used as desired.
  • binder examples include water-soluble celluloses, povidone, polybulurpyrrolidone, polybulal alcohol, sodium carboxymethylcellulose, partially alpha-denified starch, alpha-gelatinized starch, sodium alginate, pullulan, gum arabic powder, Examples include gelatin.
  • Water-soluble celluloses are water-soluble celluloses that have lost hydrogen bonds by substituting part of the hydrogen atoms of the hydroxyl group of cellulose with methyl, ethyl, propyl, hydroxypropyl, or hydroxyethyl groups. Is a molecule.
  • hydroxymethylenoresenorelose hydroxyethinoremethinoresolerose, methinoresenorelose, hydroxychetylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate ( HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), and the like, and one or more of these may be used as appropriate.
  • HPMC hydroxypropylmethylcellulose
  • HPMCP hydroxypropylmethylcellulose phthalate
  • HPPMCAS hydroxypropylmethylcellulose acetate succinate
  • water-soluble celluloses V and deviation are also preferred! /, But hydroxypropylmethylcellulose or hydroxypropylcellulose (HPC) is particularly preferred.
  • Examples of the corrigent include sucrose, D-sorbitol, xylitol, citrate, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, saccharin sodium, glycyrrhizin dipotassium, sodium glutamate, -Sodium inosinate, 5,-Sodium guarate, etc.
  • Examples of the surfactant include polysorbate (for example, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, etc.), polyoxyethylene 'polyoxypropylene copolymer, sodium lauryl sulfate, and the like. Can be mentioned.
  • Examples of the fragrances include lemon oil, orange oil, menthol and brackish oil.
  • Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, and polyethylene dallicol.
  • Examples of the colorant include titanium oxide, edible yellow No. 5, edible blue No. 2, iron sesquioxide, yellow sesquioxide, and iron oxide.
  • Examples of the antioxidant include sodium ascorbate, L-cysteine, sodium sulfite, vitamin E and the like.
  • Examples of the concealing agent include titanium oxide.
  • antistatic agent examples include talc and titanium oxide.
  • wetting agent examples include polysorbate 80, sodium laurate sulfate, sucrose fatty acid ester, polyethylene glycol, hydroxypropyl cellulose (HPC), and the like.
  • dissolution aid examples include dry methacrylic acid copolymer LD, hydroxypropyl methylenocellulose acetate succinate, hydroxypropinoremethylol cellulose phthalate, and the like.
  • Examples of the fluidizing agent include light caustic anhydride, talc, hydrous silicon dioxide and the like.
  • Disintegrants other than the above-described cellulose-based disintegrants include adipic acid, alginic acid, sodium alginate, alpha-monoized starch, sodium carboxymethyl starch, hydrous oxalic acid, licorice powder, and kanteng powder.
  • Guar gum calcium citrate, glycerin fatty acid ester, croscarmellose sodium, crospovidone, light anhydrous silicate, synthetic aluminum silicate, wheat starch, rice starch, cellulose acetate phthalate, dioctyl sodium sulfosuccin Sucrose fatty acid ester, magnesium hydroxide alumina, calcium stearate, polyoxyl 40 stearate, refined white sugar, sorbitan sesquioleate gelatin, sorbitan fatty acid ester, talc, sodium bicarbonate, charcoal
  • Magnesium acid precipitated calcium carbonate, sodium carboxymethyl starch with low degree of substitution, dextrin, sodium dehydroacetate, corn starch, tragacanth powder, honey, potato starch, partially pregelatinized starch, monosodium fumarate, povidone, polyoxyethylene cured Castor Oil 60, Polyoxyethylene (105) Polyoxypropylene (5) Glycol, Polyoxyethylene (160) Polyoxypropy
  • the pharmaceutical composition means a composition comprising pranlukast hydrate, a cellulosic disintegrant, and an excipient.
  • the pharmaceutical composition in the present invention is a composition obtained by mixing the granulated product, which may be the granulated product itself, and one or more of the other additives as described above.
  • the granulated product or the pharmaceutical composition of the present invention can be suitably used for the production of a solid preparation. That is, the granulated product or the pharmaceutical composition obtained by the above method is filled or tableted by a known method, for example, “capsule filled with granulated product”, “tablet granulated product” Can be manufactured as “tablets”, “capsules filled with the pharmaceutical composition”, and “tablets formed by compressing the pharmaceutical composition”. It can also be used as a granule or powder as it is. Furthermore, tablets, powders or granules can be used as a dissolving Z suspension type preparation (for example, dry syrup) for use as a solution or suspension when taken.
  • a dissolving Z suspension type preparation for example, dry syrup
  • Capsule formed by filling granulated product "tablet formed by compressing granulated product”, “capsule filled with pharmaceutical composition”, “formulation composition”
  • the granulated product is mixed with other additives such as a lubricant as necessary, and then tableted or filled into capsules.
  • the capsule skin of the capsule filled with the granulated product or the pharmaceutical composition of the present invention may be any conventional skin, such as gelatin or polyethylene glycol. Examples include blended gelatin, hydroxypropylmethylcellulose, pullulan and the like.
  • the tablet may be coated with a film coating base that is pharmaceutically acceptable as necessary and does not interfere with the effects of the present invention.
  • the dry syrup agent the granulated product obtained by the above-mentioned method can be used as it is as a dry syrup agent, and if desired, a commonly used bitterness improving agent (flavoring agent) can be added and used.
  • a commonly used bitterness improving agent flavoring agent
  • a dry syrup that can be taken suspended in water can be provided.
  • a capsule formed by filling the granulated product of the present invention, a capsule filled with the pharmaceutical composition of the present invention, or the granulated product of the present invention As the solid preparation in the present invention, a capsule formed by filling the granulated product of the present invention, a capsule filled with the pharmaceutical composition of the present invention, or the granulated product of the present invention.
  • a tablet formed by tableting or a tablet formed by compressing the pharmaceutical composition of the present invention is preferred, more preferably a capsule filled with the granulated product of the present invention, and the pharmaceutical composition of the present invention.
  • Examples of other additives that may be added in the process of producing capsules filled with a granulated product, a tanned pharmaceutical composition, or tablets formed by tableting include, for example, excipients, Disintegrants, binders, fluidizers, flavoring agents, surfactants, fragrances, lubricants, coloring agents, antioxidants, masking agents, antistatic agents, wetting agents, flavoring agents, dissolution aids, etc. One or more selected from these may be appropriately blended and used.
  • Excipients disintegrants, binders, fluidizing agents, flavoring agents, surfactants, fragrances, lubricants, coloring agents, antioxidants, masking agents, antistatic agents, wetting agents, flavoring agents, elution aids As mentioned above, those mentioned above can be mentioned.
  • the content of pranlukast hydrate in the granulated product according to the present invention is preferably about 50 to about 98% by weight when the granulated product or the pharmaceutical composition is 100 parts by weight. More preferred is about 60 to about 90 parts by weight, and particularly preferred is about 60 to about 80 parts by weight.
  • the weight ratio of the cellulosic disintegrant to 1 part by weight of pranlukast hydrate is preferably about 0.02-0. 2 parts by weight, more preferably about 0.02 to about 0.15 parts by weight, particularly preferably about 0.07 to about 0.15 parts by weight, and particularly preferably about 0.07 parts by weight. To about 0.13 parts by weight.
  • the weight ratio of the excipient to 1 part by weight of pranlukast hydrate is about 0.05 to about 0. 8 parts by weight, more preferred Or about 0.1 to about 0.6 parts by weight, particularly preferably about 0.15 to about 0.35 parts by weight.
  • the weight ratio of the binder to 1 part by weight of pranlukast hydrate is preferably about 0.01 to about 0.00. 3 parts by weight, more preferably about 0.01 to about 0.1 part by weight, and particularly preferably about 0.01 to about 0.04 part by weight.
  • the content of pranlukast hydrate in the solid preparation of the present invention varies depending on age, body weight, symptom, therapeutic effect, administration method, treatment time, dosage form, etc., but the desired effect of the present invention is obtained. It is preferable to set so that For adults, the dose of pranlukast hydrate per day is preferably about 25 to 2500 mg, more preferably about 112.5 to 450 mg. Specifically, about 50 mg, about 70 mg, about 100 mg, about 112.5 mg, about 140 mg, about 200 mg, about 225 mg, about 280 mg or about 450 mg are preferred.
  • the content of pranlukast hydrate in one capsule or one tablet is preferably about 112.5 mg. Or about 225 mg, more preferably about 112.5 mg.
  • the granulated product or pharmaceutical composition of the present invention in order to administer the granulated product or pharmaceutical composition of the present invention to children, it is preferably used as a powder, a condyle granule or a dry syrup.
  • the daily dose of pranlukast hydrate per kg body weight of the pediatric patient is preferably about 2 mg to about 10 mg, more preferably about 5 mg to about 8 mg, and more preferably about 7 mg.
  • it is preferable to administer pranlukast hydrate from about 50 mg to about 1 OO mg per day, more preferably about 50 mg or about 1 OO mg. .
  • the dissolution rate is determined based on the 14th revised Japanese Pharmacopoeia General Test Method.
  • the dissolution rate of pranlukast hydrate is calculated by conducting a dissolution test according to Method 2 (Paddle Method: 50 rpm). Specifically, 1.0% polysorbate 80-containing disintegration test solution 2 (pH 6.8, 900 mL) was selected as the test solution, a dissolution test was performed using a sinker, and the resulting sample solution was measured by the absorbance method (measurement wavelength 350 nm ) And the elution rate of pranlukast hydrate can be calculated.
  • the term “elutes quickly” means a capsule formed by filling the granulated product or pharmaceutical composition of the present invention, the granulated product or the pharmaceutical composition. Or, it means that pranlukast hydrate contained in tablets formed by tableting the granulated product or pharmaceutical composition dissolves quickly.For example, in the above dissolution test, dissolution 30 minutes after the start of the test. The index is that the power is 0% or more.
  • the “stable dissolution” means, for example, the granulated product or pharmaceutical composition of the present invention, the granulated product or It indicates that a capsule formed by filling a pharmaceutical composition or a tablet formed by tableting the granulated product or the pharmaceutical composition shows uniform solubility.
  • the granulated product or the pharmaceutical composition of the present invention the capsule filled with the granulated product or the pharmaceutical composition, or the tablet formed by compressing the granulated product or the pharmaceutical composition.
  • the dissolution rate at 30 minutes after the start of the test is 40% or more, and the dissolution rate at 120 minutes after the start of the test is 70% or more, preferably 80% or more after 90 minutes from the start of the test. Use as an indicator. Preferably, “stable dissolution” is indicated.
  • the dissolution rate after 30 minutes from the start of the test is 60% or more, and the dissolution rate after 120 minutes from the start of the test is 85% or more.
  • the change in dissolution rate with time is small means the granulated product or pharmaceutical composition of the present invention and the granulated product. Furthermore, the dissolution rate changes even after the capsules filled with the pharmaceutical composition or the tablets formed by squeezing the granulated product and the pharmaceutical composition are stored for a certain period of time under warming and Z or humidification conditions. Or no change in dissolution rate. For example, the granulated product or pharmaceutical composition of the present invention stored in a non-packed state at a temperature of 25 ° C.
  • the difference in dissolution rate was preferably 30% or less, preferably compared with that before storage. Is 20% or less, more preferably 15% or less.
  • the difference in dissolution rate is the dissolution rate measured at a given measurement time before storage in C (%) and the same after storage for 2 weeks.
  • the lower index is preferably 20% or less, more preferably 15% or less.
  • the average tensile breaking strength of the granulated product can be employed.
  • the average tensile breaking strength of the granulated product of the present invention is preferably about 300 to about 600 g, more preferably about 300 to about 450 g, and particularly preferably about 350 to about 450 g. If the average tensile rupture force of the granulated product is less than 300 g, the adhesion / aggregation property is small, but the elution property tends to decrease, which is not preferable. On the other hand, if it exceeds 600 g, adhesion and cohesiveness increase, which may cause problems in the production and use of the granulated product.
  • the average tensile rupture force is calculated by a compression property / adhesion property measuring device (trade name: TAG Robot, manufactured by Hosokawa Micron Corporation).
  • adhesion 'aggregation between particles is caused by the following forces. 1) intermolecular force between solid particles, 2) binding force on the particle surface, 3) electrostatic charge force, 4) surface tension due to interparticle liquid cross-linking, binding force due to capillary negative pressure, 5) binding force due to binder, 6) High temperature • Bonding due to melting of particles under high pressure.
  • the Tag Robot (trade name) is a device that can perform stable measurements in the high-pressure and dense areas handled by powder mixing and granulation operations, which were difficult to measure with existing devices.
  • Numberer 1 It is defined by the particle diameter Xp, the powder layer structure (spatial ratio ⁇ , coordination number k), and interparticle adhesion force H, and is one of the indices indicating adhesion. .
  • the average particle size of the granulated product of the present invention is about 200 to about 450 ⁇ m, more preferably about 250 to about 370 ⁇ m, and particularly preferably about 300 to 370 ⁇ m. .
  • the average particle diameter of the granulated product means the cumulative 50% average particle diameter (weight-based average diameter) of the powder particles.
  • the average particle size in the present invention is, for example, a dry type V, and an ultrasonic vibration type fully automatic particle size distribution measuring device (Robot Shifter, manufactured by Seishin Enterprise), which is a separate measuring device, with a set step force of 6 steps. , 24, 32, 60, 100, 150, and 200 can be used.
  • the bulk density of the granulated product of the present invention is preferably about 0.4 to about 0.65 gZmL, more preferably about 0.53 to about 0.59 gZmL.
  • the “bulk density of the granulated product” means a value (loose bulk density) obtained by dividing the “weight of the granulated product” by the “volume when the granulated product is put in a container”. For example, a sample of about 30 g is accurately weighed, placed in a dry graduated cylinder without being compacted, read to the smallest unit of the scale, and the weight of the granulated product divided by the final bulk volume of the granulated product is bulky. It can be measured by the density method.
  • the rotation speed of the stirring blade is preferably 50 to 500 rpm, more preferably 100 to 350 rpm, and particularly preferably 250 to 350 rpm.
  • Stirring time is preferably 1 to: more preferably 1 to 5 minutes, more preferably 1 to 3 minutes.
  • the stirring time in the present invention is a time during which the granulating liquid is added to the granulating powder and the granulating powder is stirred in a wet state.
  • the granulation liquid water (purified water), hydrous ethanol, absolute ethanol, a mixture thereof, or the like can be used, or a binder or the like can be dissolved or suspended in these.
  • the amount of water added is preferably about 20 to about 45% by weight, preferably about 20 to about 35% by weight, and more preferably about 24 to about 30% by weight when the charged amount is 100% by weight. It is.
  • the amount charged is pranlukast hydrate and cellulose before starting stirring. It means the total weight of the system disintegrant, excipient, and other additives added as necessary.
  • the agitation granulator includes a vertical granulator (manufactured by Baurec Co., Ltd.), a kneading high speed agitation granulator SPG (manufactured by Dalton), a flow jet duller-ureter FJG (manufactured by Okawara Seisakusho), Dalton), Bole Baguille Meter VMA (manufactured by Kotobuki Kogyo), high-speed agitating mixing granulator NMG (manufactured by Nara Machinery Co., Ltd.), high-speed mixer (manufactured by Fukae Bautech), Diosna agitating and mixing granulator (manufactured by mutual) ), New Speed-Idar (manufactured by Seida Okada), etc.
  • the granulated or non-granulated pharmaceutical composition of the present invention contains pranlukast hydrate as an active ingredient, so that respiratory respiration such as bronchial asthma, allergic rhinitis, sinusitis, COPD (chronic obstructive pulmonary disease), etc. It is useful as a preventive and Z or therapeutic agent for various diseases such as organ disease, Meniere's disease, exudative otitis media, migraine, cough, and dysmenorrhea.
  • the granulated product or pharmaceutical composition containing pranlukast hydrate provided by the present invention has low toxicity and is sufficiently safe for use as a medicine.
  • Pranlukast hydrate (787.5g) and lactose (175. Og; LACTOSE NEW ZEALAND) in the container of the stirring granulator (FM—VG—10P type Vertical Caldera-Yureter, manufactured by Parek Co., Ltd.)
  • FM—VG—10P type Vertical Caldera-Yureter manufactured by Parek Co., Ltd.
  • L—HPC Low-substituted hydroxypropyl cellulose
  • T-5EW manufactured by Co., Ltd.
  • This dried product is sieved using a standard sieve (aperture: 1.OOmm), and granulated granulated pranlukast hydrate (VG product, average particle size 351.6 m, loose bulk density 0.56 g / mL). Obtained.
  • VG product granulated granulated pranlukast hydrate
  • 400. Og bag mixing was performed to obtain a powder for capsule filling.
  • This powdered powder is filled into No. 3 capsules using a capsule filling machine (LIQFILsuper40, Qualikibusu Co., Ltd.), and cellulose disintegrant is added to about 0.089 parts per 1 part by weight of pranlukast hydrate.
  • Capsule 1 having the following formulation and containing about 0.22 parts by weight of excipient and excipient was produced.
  • Capsule 2 having the following formulation was produced, which did not contain a cellulose-based disintegrant and contained about 0.22 parts by weight of excipients per 1 part by weight of pranlukast hydrate.
  • the average particle size of the granulated product was 380.
  • the loose bulk density was 0.61 gz mL.
  • Purified cast is used in an amount of about 26% by weight of purified water, and the amount of excipients and other agents used is changed as appropriate.
  • a capsule 5 containing about 0.089 parts by weight of a loin disintegrant and about 0.31 parts by weight of a saccharide was prepared.
  • the average particle size of the granulated product is 294.9 ⁇ m, The bulk density was 0.57 gZmL.
  • the tensile breaking force was measured with a Hogagawa Micron Co., Ltd. tag robot (trade name; model AGR-2).
  • the measurement conditions of the flag robot are as follows:
  • L-HPC parts by weight means parts by weight of L HPC in the case of 1 part by weight of pranlukast hydrate in the granulated product.
  • the capsules produced in Formulation Examples 1 to 3 were subjected to a dissolution test in the second disintegration test solution (pH 6.8) containing 1.0% polysorbate 80.
  • the test was conducted using a sinker in accordance with the 14th revised Japanese Pharmacopoeia general test method, dissolution test method method 2 (paddle method: 50 rpm).
  • the test solution was a solution prepared by adding 1.0% polysorbate 80 to the second disintegration test solution (pH 6.8).
  • the sampled solution was measured by the absorbance method (measurement wavelength: 350 nm), and the elution rate was calculated. The results are shown in Table 2 and FIG.
  • formulation example 1 is about 73% 30 minutes after the start of the disintegration test
  • the dissolution rate was about 93% after 120 minutes, and the dissolution rate was clearly improved as compared with Formulation Example 2 and Formulation Example 3.
  • Capsule 1 manufactured in Formulation Example 1 was unwrapped and kept at 25 ° C and 75% relative humidity After storing in a humidity chamber for 2 weeks, the dissolution rate was measured in the same manner as in the above dissolution evaluation 1. Table 3 shows the difference (%) relative to the dissolution rate before storage.
  • Capsule 1 produced in Formulation Example 1 has a difference in elution rate (decrease) compared to before storage even after storage in a non-packaging state for a certain period under humidified conditions. However, it was clarified that it was a formulation with little change in dissolution rate over time.
  • the dissolution rate in the capsules produced in Formulation Examples 1, 4 and 5 was calculated by conducting a dissolution test similar to the above-described dissolution evaluation 1. The results are shown in Table 4.
  • Preliminary hydroxypropyl methylcellulose (157.5 g; Shin-Etsu Chemical “TC-5EW” manufactured by Kogyo Co., Ltd. was dissolved in purified water (2092.5 g) to obtain a binding solution.
  • Pranlukast hydrate 750. Og
  • lactose (166.7 g; LACTOSE NEW ZE ALAND
  • FM-VG-10P type vertical caldera-ureter manufactured by Norec Co., Ltd.
  • This wet product was dried using a fluidized bed granulator (STREA-1, manufactured by Baurec Co., Ltd.) at a supply air temperature of 85 ° C until the exhaust heat temperature reached 40 ° C.
  • This dried product was sieved using a standard sieve (aperture: 1.00 mm) to obtain a granulated product (VG product) of pranlukast hydrate.
  • VG product granulated product
  • L—HPC low-substituted hydroxypropyl cellulose
  • the active ingredient dissolves quickly and exhibits stable dissolution. It does not affect the overall availability. Therefore, it is possible to provide biologically equivalent and stable quality preparations.

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Abstract

La présente invention concerne une préparation pharmaceutique solide et une composition de préparation pharmaceutique contenant du pranlukast hydraté stable qui est élué rapidement et dont le taux d'élution n'est pas susceptible de changer même si la préparation ou composition est conservée dans un état non emballé. Une substance granulée selon l’invention contient de 0,02 à 0,15 partie en poids d'hydroxypropylcellulose à faible substitution et de 0,1 à 0,6 partie en poids d'un ou de plusieurs excipients choisis parmi le lactose, le sucre doux blanc et le mannitol par rapport à 1 partie en poids du pranlukast hydraté, est rapidement éluée, présente une aptitude à l'élution stable et son taux d'élution varie faiblement au cours du temps.
PCT/JP2006/321101 2005-11-24 2006-10-24 Preparation pharmaceutique solide et composition de preparation pharmaceutique WO2007060802A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014012954A1 (fr) 2012-07-18 2014-01-23 Takeda Gmbh Traitement de l'asthme sévère partiellement régulé ou non régulé
JP2015010085A (ja) * 2013-07-02 2015-01-19 三菱瓦斯化学株式会社 ピロロキノリンキノン類を含む分散液
WO2015110394A1 (fr) 2014-01-22 2015-07-30 Takeda Gmbh Traitement de l'asthme grave partiellement contrôlé ou non contrôlé avec un inhibiteur de pde4 (et en combinaison avec un modificateur des leucotriènes)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102363727B1 (ko) * 2015-06-01 2022-02-16 삼아제약 주식회사 생체이용률이 개선된 프란루카스트 함유 고형 제제의 조성물 및 그 제조방법

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003097102A1 (fr) * 2002-05-22 2003-11-27 Shionogi & Co., Ltd. Preparation pharmaceutique dans laquelle la propriete de dissolution d'un medicament faiblement soluble dans l'eau est amelioree
JP2005139086A (ja) * 2003-11-04 2005-06-02 Ono Pharmaceut Co Ltd 速崩壊製剤
JP2005139085A (ja) * 2003-11-04 2005-06-02 Ono Pharmaceut Co Ltd 顆粒
JP2005187106A (ja) * 2003-12-24 2005-07-14 Nisca Corp シート供給装置及びこれを用いた画像読取装置並びに重送原稿検出方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003097102A1 (fr) * 2002-05-22 2003-11-27 Shionogi & Co., Ltd. Preparation pharmaceutique dans laquelle la propriete de dissolution d'un medicament faiblement soluble dans l'eau est amelioree
JP2005139086A (ja) * 2003-11-04 2005-06-02 Ono Pharmaceut Co Ltd 速崩壊製剤
JP2005139085A (ja) * 2003-11-04 2005-06-02 Ono Pharmaceut Co Ltd 顆粒
JP2005187106A (ja) * 2003-12-24 2005-07-14 Nisca Corp シート供給装置及びこれを用いた画像読取装置並びに重送原稿検出方法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014012954A1 (fr) 2012-07-18 2014-01-23 Takeda Gmbh Traitement de l'asthme sévère partiellement régulé ou non régulé
JP2015010085A (ja) * 2013-07-02 2015-01-19 三菱瓦斯化学株式会社 ピロロキノリンキノン類を含む分散液
WO2015110394A1 (fr) 2014-01-22 2015-07-30 Takeda Gmbh Traitement de l'asthme grave partiellement contrôlé ou non contrôlé avec un inhibiteur de pde4 (et en combinaison avec un modificateur des leucotriènes)

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