WO2004110448A1 - Medicinal composition containing benidipine hydrochloride - Google Patents

Medicinal composition containing benidipine hydrochloride Download PDF

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Publication number
WO2004110448A1
WO2004110448A1 PCT/JP2004/008821 JP2004008821W WO2004110448A1 WO 2004110448 A1 WO2004110448 A1 WO 2004110448A1 JP 2004008821 W JP2004008821 W JP 2004008821W WO 2004110448 A1 WO2004110448 A1 WO 2004110448A1
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WO
WIPO (PCT)
Prior art keywords
water
affinity
soluble
pharmaceutical composition
benidipine hydrochloride
Prior art date
Application number
PCT/JP2004/008821
Other languages
French (fr)
Japanese (ja)
Inventor
Tomohiko Goto
Eiji Hayakawa
Kazuhiko Takeshige
Original Assignee
Kyowa Hakko Kogyo 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 Kyowa Hakko Kogyo Co., Ltd. filed Critical Kyowa Hakko Kogyo Co., Ltd.
Priority to JP2005505044A priority Critical patent/JP3786287B2/en
Priority to KR1020057024145A priority patent/KR101060885B1/en
Publication of WO2004110448A1 publication Critical patent/WO2004110448A1/en

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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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a rapidly dissolving pharmaceutical composition containing venidipine hydrochloride and the like for promoting rapid absorption of the main drug, benidipine hydrochloride.
  • Bendidipine hydrochloride a dihydropyridine calcium antagonist
  • Benidipine hydrochloride is known to act on osteoblasts and osteoblasts, unlike other calcium antagonists such as difludipine and amlodipine, and to have an osteoprotective effect without impairing bone formation.
  • lipophosphatase which is widely known as an indicator of osteoblast activity, is increased, acts on bone metabolism, and stimulates osteoblast function.
  • Benidipine hydrochloride has a very low solubility in aqueous solvents, so it is not suitable for oral administration. It is necessary to devise such a method that the drug is rapidly eluted from the pharmaceutical composition in the gastrointestinal fluid. Disclosure of the invention
  • An object of the present invention is to provide a rapidly dissolving benidipine hydrochloride-containing pharmaceutical composition and the like for promoting rapid recovery of the main drug, benidipine hydrochloride.
  • the present invention relates to the following (1) to (20).
  • Vedidipine hydrochloride crystals having a volume average particle diameter of 1.0 to 50.0 m, or volume average particle diameters containing benzyldipine hydrochloride crystals and functional additives having water solubility or water affinity of 1,0 to 50.0 m
  • Benidipine hydrochloride crystals having a volume average particle diameter and a number average particle diameter of 4.5 to 30.0 ⁇ m, or a volume average particle diameter containing a benidivine hydrochloride crystal and a water-soluble or water-affinity functional additive 4.5
  • the weight ratio of the penididipine hydrochloride crystals to the water-soluble or water-affinity functional additive is The pharmaceutical composition according to the above (1) or (2), wherein the ratio is 1:99 to 99: 1.
  • the water-soluble or water-affinity functional additive has a water-solubility or water-affinity additive.
  • the pharmaceutical composition according to any one of the above-mentioned) to (3), which is a form.
  • water-soluble or water-affinity excipients may contain starches, starch derivatives, sugars, and sugars.
  • the water-soluble or water-affinity functional additive is a disintegrant.
  • the pharmaceutical composition according to any of (3).
  • the water-soluble or water-affinity functional additive is water-soluble or water-soluble.
  • the volume average particle size of the penidipine hydrochloride crystals is 1.0 to 50.0 m, or a functional additive having water-soluble or water-affinity crystals of benidipine hydrochloride.
  • the volume average particle diameter of the granules containing benidipine hydrochloride crystals and a functional additive having water solubility or water affinity is 1.0 to 50.0 ⁇ m.
  • the volume average particle size and number average size of the benidipine hydrochloride crystals should be 4.5 to 30.0 ⁇ m, or the benidipine hydrochloride crystals and water-soluble or water-soluble
  • the volume average particle diameter of the granule containing the benidipine hydrochloride crystal and the water-soluble or water-affinity functional additive is determined.
  • the water-soluble or water-affinity functional additives have water-solubility or water-affinity
  • excipients having water solubility or water affinity may contain starches, starch derivatives, sugars, sugars, etc.
  • Benidipine hydrochloride crystals and water-soluble or water-affinity functional additives The quick dissolution method according to any one of the above (11) to (15), wherein the functional additive having water solubility or water affinity in the contained powdery granules is a disintegrant.
  • the water-soluble or water-affinity functional additives have water-solubility or water-affinity
  • the pharmaceutical composition of the present invention preferably contains benidipine hydrochloride and exhibits a D30min value of about 40% to 100% (dissolution rate of benidipine hydrochloride at 30 minutes in a dissolution test).
  • the conditions for the dissolution test at this time are the same as the conditions for the dissolution test described in the test examples described below.
  • Water affinity refers to the property of attracting water molecules by some kind of interaction such as electrostatic interaction or hydrogen bonding.
  • the volume average particle diameter of the benidipine hydrochloride crystals in the present invention is L0-50.0-111, preferably 4.5-50.0 / m, more preferably 4.5-30.0111.
  • the powder of the present invention containing penidipine hydrochloride and a water-soluble or water-affinity functional additive has an adiabatic particle size of 1.0 to 50.0 in and 4.5 to 50.0 m. And more preferably 4.5 to 30.0 m.
  • the weight ratio with the functional additive having compatibility is preferably from 1:99 to 99: 1, more preferably from 1:50 to 1: 2, and even more preferably from 1:40 to 1: 1. : 4
  • the granular material containing the functional additive having the property is preferably a number average particle diameter of 1.0 to 50.0 ⁇ m, more preferably 4.5 to 30.0 // m, and a volume average particle diameter. More preferably, the difference in the number average particle diameter is 50% or less of the volume average particle diameter. Alternatively, the volume average particle diameter is preferably 12 to 50.0 m, regardless of the number average particle diameter. With these preferred average particle sizes, the quality of the pharmaceutical composition such as the stability of benidipine hydrochloride and the uniformity of the content of penidipine hydrochloride can be better maintained.
  • water-soluble or water-affinity functional additives examples include water-soluble or water-affinity excipients, disintegrants, and water-soluble or water-affinity binders.
  • water-soluble or water-compatible excipients include starches such as wheat starch, rice starch, corn starch, potato starch, modified starch, partially arsenic starch, starch derivatives such as hydroxypropyl starch, and lactose.
  • Sugars such as glucose, maltose and pullulan, sugar alcohols such as D-mannitol, sorbitol, erythritol, xylitol, lactitol, maltitol, celluloses such as crystalline cellulose, carmellose, carmellose sodium, croscar Cellulose such as sodium melose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, dexamethasylmethylcellulose Scan derivatives, dextrin and the like,
  • the amount of the excipient having a water-soluble or water affinity, a pharmaceutical composition from 40 to 95 mass% is preferred, more preferably 60 to 95 wt%.
  • Disintegrators include, for example, starches such as wheat starch, rice starch, corn starch, potato starch, starch derivatives such as oxystarch, partially arsenic starch, hydroxypropyl starch, celluloses such as crystalline cellulose, carmellose, carme Cellulose derivatives such as sodium cellulose, croscarmellose sodium, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose and carboxyethylmethylcellulose.
  • the amount of the disintegrant having the property is 1 to 10 mass in the pharmaceutical composition. /. And more preferably 2 to 5% by mass.
  • water-soluble or water-affinity binder examples include cellulosic substances such as crystalline cellulose, carmellose, carmellose sodium, croscarmellose sodium, and the like.
  • Cellulose derivatives such as methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxyethylmethylcellulose, polyvinyl alcohol, partially saponified polyvinyl alcohol, polyvinylpyrrolidone, etc.
  • the amount of the binder having water affinity to be used is preferably 0.1 to 10% by mass, more preferably 0.5 to 5% by mass in the pharmaceutical composition. /. It is.
  • the functional additive having water solubility or water affinity is contained in a pharmaceutical composition other than the granular material.
  • the amount of the water-soluble or water-affinity functional additive contained in the pharmaceutical composition other than the powdery granules is, for example, water-soluble or water-affinity excipients.
  • the total amount of the pharmaceutical composition in the granules and the pharmaceutical composition other than the granules is preferably 40 to 95% by mass, more preferably 60 to 95% by mass. It is preferable that the total amount of the pharmaceutical composition in the above-mentioned granular material and the pharmaceutical composition other than the above-mentioned granular material is 1 to 30% by mass, more preferably 2 to 15% by mass.
  • the excipient having water affinity it is preferable that the total amount of the pharmaceutical composition in the granular material and the pharmaceutical composition other than the granular material is 0.1 to 30% by mass. Preferably it is 0.5 to 15% by mass.
  • the pharmaceutical composition of the present invention contains, in addition to the above-mentioned water-soluble or water-affinity functional additives, other pharmaceutical additives generally used in the field of pharmaceuticals, such as lubricants, foaming agents, and sweeteners. Agents, fragrances, coloring agents and the like can also be added.
  • Lubricants include, for example, stearic acid, calcium stearate, magnesium stearate, polyoxyl 40 stearate, talc, ceanol, lab wax, caffeic anhydride, paraffin, boric acid, leucine, polyoxyethylene fatty acid ester, benzoic acid Acid sodium and the like.
  • the amount of the lubricant used is 0.01 to 1 mass in the pharmaceutical composition. /. And more preferably 0.01 to 0.5% by mass.
  • foaming agent examples include sodium hydrogen carbonate, sodium carbonate, calcium carbonate and the like.
  • sweetener examples include aspartame (registered trademark), saccharin, glycyrrhizin and the like.
  • flavors include lemon, orange, pine, mint, and menthol. It is.
  • coloring agent examples include yellow iron dioxide, iron sesquioxide, and evening pigment.
  • coating examples include sugar coating, film coating, polymer coating, and the like. The purpose of coating is, for example, by imparting flavor, gastric or enteric solubility, and oxidation or hydrolysis of a drug. Prevention of deterioration.
  • Coating agents used for coating for flavoring include, for example, methylcellulose, ethylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methyl methacrylate Butyl acrylate / dimethylaminoethyl methacrylate 'copolymer (E;), ethyl acrylate / methyl methacrylate / methyl methacrylate methacrylate-copolymer (RS) and the like.
  • Examples of the coating agent used for coating for imparting gastric solubility include methyl methacrylate 'butyl methacrylate' dimethylaminoethyl methacrylate copolymer (E), polyvinyl acetate yurujethylamino acetate (AEA) And so on.
  • Examples of coating agents used for coating for imparting enteric properties include methacrylic acid / methyl methacrylate / copolymer (L), methacrylic acid / ethyl acrylate / copolymer (LD), and acetic acid.
  • L methacrylic acid / methyl methacrylate / copolymer
  • LD methacrylic acid / ethyl acrylate / copolymer
  • acetic acid Cellulose, cellulose acetate fluorate, carboxymethyl cellulose, hydroxypropylmethylcellulose acetate succinate, hydroxyoxypropylmethyl cellulose monophthalate and the like can be mentioned.
  • the pulverizer used for pulverizing the benidipine hydrochloride crystals is not particularly limited, but a hammer mill, a jet mill or the like is preferably used.
  • Benidipi hydrochloride Can be processed to have a volume average particle size of 1.0 to 50.0 ⁇ m, preferably 4.5 to 50 ⁇ 0 ⁇ , more preferably 4.5 to 30.0 zm.
  • the number average particle diameter is preferably 1.0 to 50.0 zm, more preferably 4.5 to 30.0 ⁇ m, and further preferably the difference between the volume average particle diameter and the number average particle diameter is the volume average particle diameter. To 50% or less. Alternatively, it can be processed so that the volume average particle diameter is 12 to 50.0 zm, regardless of the number average particle diameter.
  • benidipine hydrochloride can be processed to have a volume average particle size of 1.0 to 5.0.0 mm by sieving, crystallization, spray drying, or the like.
  • the powder containing the benidipine hydrochloride crystal and the water-soluble or water-affinity functional additive is pulverized after adding the water-soluble or water-affinity functional additive to the benidipine hydrochloride crystal. It can be processed to have a volume average particle size of 1.0 to 50.0 ⁇ m, preferably 4.5 to 50.0 im, and more preferably 4.5 to 30.0 ⁇ m by sieving, crystallization, drying and the like.
  • the number average particle diameter; L 0 to 50.0, more preferably 4.5 to 30.0 im, still more preferably the volume average particle diameter and the number average Processing can be performed so that the difference in particle size is 50% or less of the volume average particle size.
  • processing can be performed so that the volume average particle diameter is 12 to 50.0 zm, regardless of the number average particle diameter.
  • benidipine hydrochloride crystals processed to have a volume average particle size of 1.0 to 50.0 m or powdered granules containing benidipine hydrochloride and a water-soluble or water-affinity functional additive may be added, if necessary.
  • Granulation is performed by adding the above-mentioned various pharmaceutical additives to obtain a granulated product.
  • the method of granulation is not particularly limited, but wet granulation is preferably used.
  • the granulator for example, a fluidized bed granulator, a tumbling stirring granulator, an extrusion granulator and the like are used.
  • vendidipine hydrochloride used in the pharmaceutical composition containing vendidipine hydrochloride of the present invention varies depending on the dose and the like, but is preferably 0.01 to 50% by mass, more preferably 0.01 to 30% by mass in the tablet.
  • the tableting machine used for the compression molding is not particularly limited, but it is preferable to use a mouthless tableting machine, and the compression molding pressure is preferably from 300 kg to 5000 kg.
  • the pharmaceutical composition may be coated for imparting flavor, gastric solubility or enteric solubility, etc., but this is done by coating the granulated product, that is, the raw granules before compression molding. And a method of coating tablets after compression molding.
  • the active ingredient benidipine hydrochloride crystals are attached together with a binder to lactose or the spherical granules of the crystal cell mouth and allowed to stand.
  • the granules are dried by a tray dryer, a fluidized bed dryer or the like to obtain elementary granules containing benidipine hydrochloride crystals.
  • the coating agent is mixed with a suitable solvent, for example, water, methanol, ethanol, 2-propanol, ethyl acetate, ethyl lactate, acetone, methylene chloride, 1,1,1-trichloromethane.
  • a suitable solvent for example, water, methanol, ethanol, 2-propanol, ethyl acetate, ethyl lactate, acetone, methylene chloride, 1,1,1-trichloromethane.
  • the coated powder is sprayed onto the elementary granules and coated with the coating agent solution dissolved or dispersed in ethane or the like or a mixed solvent of these, and dried with a standing-bed dryer or fluidized-bed dryer. Obtain granules.
  • the coating apparatus at this time is not particularly limited, but preferably a fluidized bed coating drying apparatus, a centrifugal fluidized granulation apparatus, a tumbling fluidized coating drying apparatus and the like are used.
  • the coating apparatus used for coating the tablets after compression molding is not particularly limited, but a drum-type film coating drying apparatus or a fluidized-bed coating apparatus is preferably used.
  • Immediate elution of venidipine hydrochloride from the pharmaceutical composition of the present invention can be achieved by adjusting the volume average particle diameter of the penidipine hydrochloride crystals to 1.0 50.0 m, preferably, in a pharmaceutical composition containing venidipine hydrochloride.
  • a pharmaceutical composition having an average particle size and a number average particle size of 4.5 to 30.0 m, or containing a benidipine hydrochloride crystal and a powder containing a water-soluble or water-affinity functional additive benidipine hydrochloride may be used.
  • the volume average particle diameter of the powder containing the crystals and the functional additive having water-solubility or water-miscibility is adjusted to 1.0 to 50.0 ⁇ m, preferably 4.5 to 50,0 zm.
  • a pharmaceutical composition containing benidipine hydrochloride by the above-mentioned method for producing a pharmaceutical composition of the present invention. Can be done.
  • Benidipine hydrochloride drug substance (lot P-010, manufactured by Kyowa Hakko, volume average particle diameter 65.0 ⁇ m, number average particle diameter 10.3 ⁇ m) 5000g was fed to a grinder sample mill (KIIWG-IF type, manufactured by Fuji Padal) This was subjected to a single milling treatment. Further, the obtained pulverized penidipine hydrochloride crystals were subjected to a single pulverization treatment by a jet mill pulverizer (PJM-100SP, manufactured by Nippon Pneumatic Industries, Ltd.) to obtain pulverized benidipine hydrochloride crystals.
  • PAM-100SP jet mill pulverizer
  • the average particle size of the pulverized benidipine hydrochloride crystals was measured by an image analyzer under a microscope (Olympus SP-500) by a wet method using a liquid noraffin suspension.
  • the pulverized penidipine hydrochloride crystals had a volume average particle diameter of 9.4111 and a number average particle diameter of 4.91.
  • the pulverized benzodipine hydrochloride crystals, lactose and potato starch are granulated by a fluidized bed granulator under spraying of an aqueous solution of polyvinyl alcohol, and magnesium stearate is added as a lubricant to a V-type mixer.
  • tablets were obtained by the following formulation and production method.
  • crushed benzodivine hydrochloride crystals, lactose and potato starch are granulated with a fluidized bed granulator while spraying an aqueous solution of polyvinyl alcohol, and magnesium stearate is mixed in a V-shape as a lubricant.
  • the mixture was mixed with a press to obtain granules for tableting.
  • a tablet having a tablet diameter of 7 mg and a tablet weight of 130 mg was obtained.
  • Benidipine hydrochloride drug substance (lot P-010, manufactured by Kyowa Hakko, volume average particle size 65,0 ⁇ 111, number average particle size 10.3 ⁇ m) was passed through a vibrating screen machine [100mesh (150 ⁇ m) sieve].
  • a vibrating screen machine [100mesh (150 ⁇ m) sieve].
  • the average particle size of the sieved benidipine hydrochloride crystals can be determined by a wet method using a fluid paraffin suspension under a microscope using an image analyzer (Olympus). SP-500).
  • the sieved benidipine hydrochloride crystals had a volume average average particle diameter of 26.3 m and a number average particle diameter of 6.6 / m.
  • the sieved venidipine hydrochloride crystals, lactose and potato starch are granulated in a fluidized bed granulator while spraying an aqueous solution of polyvinyl alcohol, and magnesium stearate is added as a lubricant to a V-type mixer.
  • Tablets were obtained using the drug substance of Benidipine hydrochloride (Lot P-010, manufactured by Kyowa Hakko, volume average particle diameter 65.0 m, number average particle diameter 10.3 ⁇ m) according to the following formulation and production method.
  • Benidipine hydrochloride drug substance (Lot P-010, manufactured by Kyowa Hakko, volume average particle diameter 65.0 Zffl, number average particle diameter 10.3 ⁇ ), lactose and potato starch are sprayed with an aqueous solution of polyvinyl alcohol, and the fluidized bed The mixture was granulated with a granulator, and magnesium stearate as a lubricant was further mixed with a V-type mixer to obtain granules for tableting. Using these granules for tableting, tablets having a tablet size of 7IM0 and a tablet weight of 130 mg were obtained.
  • Tablets were obtained using the drug substance of Benidipine hydrochloride (Lot P-005, manufactured by Kyowa Hakko, volume average particle size 147.1 zm, number average particle size 9.7 ⁇ ffl) according to the following formulation and manufacturing method.
  • Benidipine hydrochloride Lit P-005, manufactured by Kyowa Hakko, volume average particle size 147.1 zm, number average particle size 9.7 ⁇ ffl
  • Benidipine hydrochloride drug substance (Lot P-005, manufactured by Kyowa Hakko, volume average particle diameter 147.1 m, number average particle diameter 9.7 ⁇ m), lactose and potato starch are sprayed with an aqueous solution of polyvinyl alcohol into a fluidized bed granulator. Then, magnesium stearate as a lubricant was mixed with a V-type mixer to obtain granules for tableting. Using these granules for tableting, tablets having a tablet size of 7 nm0 and a tablet weight of 130 mg were obtained.
  • Table 1 shows the volume average particle size and the number average particle size of the benidipine hydrochloride crystals used in Examples 1, 2, and 3 and Comparative Examples 1 and 2.
  • Example 1 9.4 / in 4.9 jLLOi
  • Example 2 14.bj ⁇ 6.2 m
  • Example 3 26.3 m 6,6 im Comparative example 1 65.0 rn 10.3 m
  • Comparative Example 147.1 zm 9.7 ZJii Test Example: Dissolution Test
  • the dissolution test was performed according to the Japanese Pharmacopoeia Method 1 (rotating basket method) using 900 ml of the test solution [sodium lauryl sulfate PH6.8 sodium phosphate buffer solution (1500)] at 37 ° C. Performed at 50 rpm.
  • the eluate sampled 10, 20, 30, 45, and 60 minutes after the start of the test was subjected to high performance liquid chromatography [column: YMC A-301-1 (4.6 x 100 thighs), temperature; 40 ° moving bed: 0.05 mol / L aqueous solution of potassium dihydrogen phosphate / acetonitrile (55:45) + 1 aqueous ol / L aqueous solution of sodium lauryl sulfate], and evaluated as an elution profile.
  • Table 2 shows the dissolution test results of the tablets obtained in Examples 1, 2, and 3 and Comparative Examples 1 and 2. Table 2 Dissolution test results.
  • a medicinal composition containing benidipine hydrochloride and the like having a rapid dissolution property for promoting rapid absorption of the main drug, benidipine hydrochloride.

Abstract

A medicinal benidipine hydrochloride composition which has the property of enabling rapid dissolution for accelerating the rapid absorption of benidipine hydrochloride as the main drug. The composition is characterized by comprising benidipine hydrochloride crystals having a volume-average particle diameter of 1.0 to 50.0 μm or by comprising particles which have a volume-average particle diameter of 1.0 to 50.0 μm and comprise benidipine hydrochloride crystals and a functional additive having solubility in water or affinity for water.

Description

明 細 書  Specification
' 塩酸べニジピン含有医薬組成物  '' Pharmaceutical composition containing benidipine hydrochloride
枝術分野  Branch art
本発明は、主薬である塩酸べニジピンの速やかな吸収を促進するための、速やかな 溶出性を有する塩酸べ二ジピン含有医薬組成物等に関する。  The present invention relates to a rapidly dissolving pharmaceutical composition containing venidipine hydrochloride and the like for promoting rapid absorption of the main drug, benidipine hydrochloride.
背景技術  Background art
ジヒドロピリジン系カルシウム拮抗剤である塩酸べ二ジピンは高血圧症、腎実質性 高血圧症、狭心症等の治療薬として特に有用であり、安全性も高いとして汎用されて いる。また塩酸べニジピンは二フエジピンやアムロジピン等、他のカルシウム拮抗剤 とは異なり、造骨細胞および骨芽細胞に作用し、骨形成を損なうことなく、 骨保護作 用を示すことが知られており、さらに造骨活性の指標として広く知られているアル力 リホスファタ一ゼ活性を増加させ、骨代謝に作用し骨芽細胞機能を刺激していること が知られている。しかし前記のニフェジピンやアムロジピンではこれらの作用は知ら れていない [カルシフアイド 'ティシュー 'ィン夕ーナショナル（Calcif i ed Tissue International )N 1998年、 第 62卷、 p . 554-556 ]。加えてラヅトの骨粗しょう症モデ ルにおいても、塩酸べニジピンは、 骨量増加作用および骨強度の増加作用を示し、 さ らに骨量増加については X線検査によっても観察されている。すなわち塩酸べニジピ ンは骨代謝バランスのうち、 骨保護側に優位に働くことが示唆されているほ开薬と臨 床、 第 42卷、 第 11号別冊 (平成 5年 11月）、 p . 58 ( 2298 )- 66 ( 2306 ) ]。 これら一連の 塩酸べニジピンの骨保護作用は、 骨代謝に関与する副甲状腺ホルモン (PTH)等のカル シゥム代謝調節ホルモンを介した作用と考えられ、塩酸べニジピンの速やかな吸収と 速やかな代謝によ.り達成される血中 PTH の一過性の上昇が骨形成側に優位に働いて いることが示唆されている。 しかしながら、血中 PTHの長時間の上昇は、 骨代謝に悪 影響を及ぼすことが知られている。 Bendidipine hydrochloride, a dihydropyridine calcium antagonist, is particularly useful as a therapeutic agent for hypertension, renal parenchymal hypertension, angina pectoris, etc., and is widely used as having high safety. Benidipine hydrochloride is known to act on osteoblasts and osteoblasts, unlike other calcium antagonists such as difludipine and amlodipine, and to have an osteoprotective effect without impairing bone formation. Further, it is known that the activity of lipophosphatase, which is widely known as an indicator of osteoblast activity, is increased, acts on bone metabolism, and stimulates osteoblast function. However, these effects are not known for the aforementioned nifedipine or amlodipine [Calcifide 'Tissue' National, N 1998, Vol. 62, p. 554-556]. In addition, in a rat osteoporosis model, benidipine hydrochloride has an effect of increasing bone mass and bone strength, and an increase in bone mass has been observed by X-ray examination. In other words, Benidipine hydrochloride has been suggested to play a dominant role in the bone metabolic balance on the osteoprotective side, with chemotherapy and clinical trials, Vol. 42, No. 11, separate volume (Nov. 58 (2298) -66 (2306)]. The osteoprotective effects of these series of benidipine hydrochlorides are thought to be mediated by calcium metabolism regulating hormones such as parathyroid hormone (PTH), which are involved in bone metabolism. It has been suggested that the transient rise in blood PTH that is achieved is dominant on the osteogenic side. However, long-term increases in blood PTH are known to adversely affect bone metabolism.
以上の理由から、骨代謝への悪影響という副作用を回避するために、速やかな吸収 を促進するための、速やかな溶出性を有する塩酸べニジピン含有医薬組成物の開発が 望まれている。  For the above reasons, there is a need for the development of a rapidly dissolving benidipine hydrochloride-containing pharmaceutical composition that promotes rapid absorption to avoid the adverse effect of adversely affecting bone metabolism.
—方、 塩酸べニジピンの一般的な製剤例が知られている（特公平 2-51525号公報)。 また、塩酸べニジピンは、水性溶媒への溶解度が非常に低いために経口投与の場合に は消化管液中で薬物が医薬組成物から速やかに溶出するような工夫が必要である。 発明の開示 On the other hand, a general formulation example of benidipine hydrochloride is known (Japanese Patent Publication No. 2-51525). Benidipine hydrochloride has a very low solubility in aqueous solvents, so it is not suitable for oral administration. It is necessary to devise such a method that the drug is rapidly eluted from the pharmaceutical composition in the gastrointestinal fluid. Disclosure of the invention
本発明の目的は、主薬である塩酸べニジピンの速やかな咴収を促進するための、速 やかな溶出性を有する塩酸べニジピン含有医薬組成物等を提供することにある。  An object of the present invention is to provide a rapidly dissolving benidipine hydrochloride-containing pharmaceutical composition and the like for promoting rapid recovery of the main drug, benidipine hydrochloride.
本発明は、 下記の（1 )〜（20 )に関する。  The present invention relates to the following (1) to (20).
( 1 ) 体積平均粒子径 1.0〜50.0 mの塩酸べ二ジピン結晶、または塩酸べ二ジピン結 晶および水溶性もしくは水親和性を有する機能性添加剤を含有する体積平均粒子径 1 , 0〜50.0〃mの粉粒体を含有することを特徴とする塩酸べニジピン含有医薬組成物。 (1) Vedidipine hydrochloride crystals having a volume average particle diameter of 1.0 to 50.0 m, or volume average particle diameters containing benzyldipine hydrochloride crystals and functional additives having water solubility or water affinity of 1,0 to 50.0 m A pharmaceutical composition containing benidipine hydrochloride, characterized in that the composition comprises powder and granules of 〃m.
(2 ) 体積平均粒子径および個数平均粒子径が 4.5〜30.0〃mの塩酸べニジピン結晶、 または塩酸べニジビン結晶および水溶性もしくは水親和性を有する機能性添加剤を 含有する体積平均粒子径 4.5〜50.0^mの粉粒体を含有することを特徴とする塩酸べ ニジピン含有医薬組成物。 (2) Benidipine hydrochloride crystals having a volume average particle diameter and a number average particle diameter of 4.5 to 30.0 μm, or a volume average particle diameter containing a benidivine hydrochloride crystal and a water-soluble or water-affinity functional additive 4.5 A pharmaceutical composition containing benidipine hydrochloride, characterized in that the composition comprises powdery particles of up to 50.0 ^ m.
(3 ) 塩酸べニジビン結晶および水溶性もしくは水親和性を有する機能性添加剤を含 有する粉粒体において、塩酸ぺニジピン結晶と水溶性または水親和性を有する機能性 添加剤との重量比が 1 : 99〜99 : 1である前記（1 )または（2 )記載の医薬組成物。  (3) In the powder and granules containing benidivine hydrochloride crystals and the water-soluble or water-affinity functional additive, the weight ratio of the penididipine hydrochloride crystals to the water-soluble or water-affinity functional additive is The pharmaceutical composition according to the above (1) or (2), wherein the ratio is 1:99 to 99: 1.
(4 ) 塩酸べニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含 有する粉粒体において、水溶性または水親和性を有する機能性添加剤が水溶性または 水親和性を有する賦形剤である前記 ）〜（3 )のいずれかに記載の医薬組成物。  (4) In powders and granules containing benidipine hydrochloride crystals and a water-soluble or water-affinity functional additive, the water-soluble or water-affinity functional additive has a water-solubility or water-affinity additive. The pharmaceutical composition according to any one of the above-mentioned) to (3), which is a form.
(5 ) 塩酸べニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含 有する粉粒体において、水溶性または水親和性を有する賦形剤がデンプン類、デンプ ン誘導体、糖類、糖アルコール類、 セルロース類、 セルロース誘導体またはデキスト リンである前記（ 1 )〜（ 4 )のいずれかに記載の医薬組成物。  (5) In powders and granules containing benidipine hydrochloride crystals and water-soluble or water-affinitive functional additives, water-soluble or water-affinity excipients may contain starches, starch derivatives, sugars, and sugars. The pharmaceutical composition according to any one of the above (1) to (4), which is an alcohol, a cellulose, a cellulose derivative or dextrin.
(6 ) 塩酸べニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含 有する粉粒体において、水溶性または水親和性を有する機能性添加剤が崩壊剤である 前記 ( 1 )〜（ 3 )のいずれかに記載の医薬組成物。  (6) In a granule containing benidipine hydrochloride crystals and a water-soluble or water-affinity functional additive, the water-soluble or water-affinity functional additive is a disintegrant. The pharmaceutical composition according to any of (3).
(7 ) 崩壊剤がデンプン類、 デンプン誘導体、 セルロース類またはセルロース誘導体 である前記 ( 6 )記載の医薬組成物。  (7) The pharmaceutical composition according to the above (6), wherein the disintegrant is a starch, a starch derivative, a cellulose or a cellulose derivative.
(8 ) 塩酸べニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含 有する粉粒体において、水溶性または水親和性を有する機能性添加剤が水溶性または 水親和性を有する結合剤である前記 (1)〜(3)のいずれかに記載の医薬組成物。 (8) In a powder or granule containing benidipine hydrochloride crystals and a water-soluble or water-affinity functional additive, the water-soluble or water-affinity functional additive is water-soluble or water-soluble. The pharmaceutical composition according to any one of the above (1) to (3), which is a binder having water affinity.
(9) 水溶性または水親和性を有する結合剤がセルロース類、 セルロース誘導体、 ポ リビニルアルコール、部分けん化ポリビニルアルコールまたはポリビニルピロリドン である前記（ 8 )記載の医薬組成物。  (9) The pharmaceutical composition according to the above (8), wherein the binder having water solubility or affinity for water is cellulose, a cellulose derivative, polyvinyl alcohol, partially saponified polyvinyl alcohol or polyvinylpyrrolidone.
(10) コ一ティングされていることを特徴とする前記（1)〜（9)のいずれかに記載の 医薬組成物。 '  (10) The pharmaceutical composition according to any one of (1) to (9), which is coated. '
(11) 塩酸べニジピンを含有する医薬組成物において、塩酸ぺニジピン結晶の体積平 均粒子径を 1.0〜 50.0 mとする、 または塩酸べニジビン結晶および水溶性もしくは 水親和性を有する機能性添加剤を含有する粉粒体を含有する医薬組成物において、塩 酸べニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する 粉粒体の体積平均粒子径を 1.0〜50.0〃mとすることを特徴とする、 該医薬組成物か らの塩酸べ二ジピンの即溶出化方法。  (11) In a pharmaceutical composition containing benidipine hydrochloride, the volume average particle size of the penidipine hydrochloride crystals is 1.0 to 50.0 m, or a functional additive having water-soluble or water-affinity crystals of benidipine hydrochloride. In a pharmaceutical composition containing granules containing, the volume average particle diameter of the granules containing benidipine hydrochloride crystals and a functional additive having water solubility or water affinity is 1.0 to 50.0 μm. A method for rapidly eluting vedidipine hydrochloride from said pharmaceutical composition.
(12) 塩酸べニジピンを含有する医薬組成物において、塩酸べニジピン結晶の体積平 均粒子径および個数平均径を 4.5〜30.0〃mとする、 または塩酸べニジピン結晶およ び水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体を含有する医薬 組成物において、塩酸べニジピン結晶および水溶性もしくは水親和性を有する機能性 添加剤を含有する粉粒体の体積平均粒子径を 4.5〜50.0〃mとすることを特徴とする、 該医薬組成物からの塩酸べニジピンの即溶出化方法。  (12) In a pharmaceutical composition containing benidipine hydrochloride, the volume average particle size and number average size of the benidipine hydrochloride crystals should be 4.5 to 30.0 μm, or the benidipine hydrochloride crystals and water-soluble or water-soluble In a pharmaceutical composition containing a granule containing a functional additive having a property, the volume average particle diameter of the granule containing the benidipine hydrochloride crystal and the water-soluble or water-affinity functional additive is determined. A method for rapidly eluting benidipine hydrochloride from the pharmaceutical composition, wherein the diameter is 4.5 to 50.0 μm.
(13) 塩酸べニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を 含有する粉粒体において、塩酸べニジピン結晶と水溶性または水親和性を有する機能 性添加剤との重量比が 1： 99〜99： 1である前記（11 )または（12 )記載の即溶出化方法。 (13) In the powder containing benidipine hydrochloride crystals and a water-soluble or water-affinity functional additive, the weight ratio of the benidipine hydrochloride crystals to the water-soluble or water-affinity functional additive is reduced. The rapid elution method according to the above (11) or (12), wherein the ratio is 1:99 to 99: 1.
(14) 塩酸ぺニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を 含有する粉粒体において、水溶性または水親和性を有する機能性添加剤が水溶性また は水親和性を有する賦形剤である前記（11)〜（13)のいずれかに記載の即溶出化方法。(14) In powders containing penidipine hydrochloride crystals and water-soluble or water-affinitive functional additives, the water-soluble or water-affinity functional additives have water-solubility or water-affinity The rapid elution method according to any one of the above (11) to (13), which is an excipient.
(15) 塩酸ぺニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を 含有する粉粒体において、水溶性または水親和性を有する賦形剤がデンプン類、デン プン誘導体、糖類、糖アルコール類、 セルロース類、 セルロース誘導体またはデキス トリンである前記 (11)~(14)のいずれかに記載の即溶出化方法。 (15) In powders containing penidipine hydrochloride crystals and functional additives having water solubility or water affinity, excipients having water solubility or water affinity may contain starches, starch derivatives, sugars, sugars, etc. The rapid elution method according to any one of the above (11) to (14), which is an alcohol, a cellulose, a cellulose derivative or dextrin.
(16) 塩酸べニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を 含有する粉粒体において、水溶性または水親和性を有する機能性添加剤が崩壊剤であ る前記 (11)〜(15)のいずれかに記載の即溶出化方法。 (16) Benidipine hydrochloride crystals and water-soluble or water-affinity functional additives The quick dissolution method according to any one of the above (11) to (15), wherein the functional additive having water solubility or water affinity in the contained powdery granules is a disintegrant.
(17) 崩壊剤がデンプン類、デンプン誘導体、セルロース類またはセルロース誘導体 である前記（16)記載の即溶出化方法。  (17) The rapid elution method according to the above (16), wherein the disintegrant is a starch, a starch derivative, a cellulose or a cellulose derivative.
(18) 塩酸べニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を 含有する粉粒体において、水溶性または水親和性を有する機能性添加剤が水溶性また は水親和性を有する結合剤である前記 (11)〜 5)のいずれかに記載の即溶出化方法。 (18) In powders and granules containing benidipine hydrochloride crystals and water-soluble or water-affinity functional additives, the water-soluble or water-affinity functional additives have water-solubility or water-affinity The rapid elution method according to any one of the above (11) to 5), which is a binder.
(19) 水溶性または水親和性を有する結合剤がセル口一ス類、セルロース誘導体、ポ リビニルアルコール、部分けん化ポリビニルアルコールまたはポリビニルピロリドン である前記 (18)記載の即溶出化方法。 . (19) The rapid elution method according to the above (18), wherein the binder having water solubility or affinity for water is a cell mouth, a cellulose derivative, polyvinyl alcohol, partially saponified polyvinyl alcohol or polyvinyl pyrrolidone. .
(20) 医薬組成物がコ一ティングされている医薬組成物である前記（11 )〜（19)のい ずれかに記載の即溶出化方法。 本発明の医薬組成物は、 塩酸べニジピンを含有し、 約 40%〜100%の D30min値 (溶出 試験における 30分の時点での塩酸べニジピンの溶出率）を示すことが好ましい。なお この際の溶出試験の条件は、後記の試験例に記載の溶出試験における条件と同じであ る。  (20) The rapid elution method according to any one of the above (11) to (19), wherein the pharmaceutical composition is a coated pharmaceutical composition. The pharmaceutical composition of the present invention preferably contains benidipine hydrochloride and exhibits a D30min value of about 40% to 100% (dissolution rate of benidipine hydrochloride at 30 minutes in a dissolution test). The conditions for the dissolution test at this time are the same as the conditions for the dissolution test described in the test examples described below.
水親和性とは、静電相互作用や水素結合等の何らかの相互作用により、水分子と引 き合う性質をいう。  Water affinity refers to the property of attracting water molecules by some kind of interaction such as electrostatic interaction or hydrogen bonding.
本発明における塩酸べニジピン結晶の体積平均粒子径は、 L0〜50.0 〃111であり、 4.5〜50.0 /m あるのが好ましく、 4.5〜30.0 111でぁるのがょり好ましぃ。 また本 発明における塩酸ぺニジピンおよび水溶性または水親和性を有する機能性添加剤を 含有する粉粒体のィ *1貴平均粒子径は、 1.0〜50.0 inであり、 4.5〜50.0 mであるの が好ましく、 4.5〜30.0 mであるのがより好ましい。 塩酸べニジピンおよび水溶性 または水親和性を有する機能性添加剤を含有する粉粒体を含有することを特徴とす る塩酸べニジピン含有医薬組成物において、塩酸べニジピン結晶と水溶性または水親 和性を有する機能性添加剤との重量比は 1： 99〜99： 1であるのが好ましく、 より好ま しくは 1： 50〜1： 2であり、 さらに好ましぐは 1： 40〜1： 4である。  The volume average particle diameter of the benidipine hydrochloride crystals in the present invention is L0-50.0-111, preferably 4.5-50.0 / m, more preferably 4.5-30.0111. The powder of the present invention containing penidipine hydrochloride and a water-soluble or water-affinity functional additive has an adiabatic particle size of 1.0 to 50.0 in and 4.5 to 50.0 m. And more preferably 4.5 to 30.0 m. A medicinal composition containing benidipine hydrochloride and a granule containing a functional additive having a water-soluble or water-affinitive property, comprising a benidipine hydrochloride crystal and a water-soluble or hydrophile. The weight ratio with the functional additive having compatibility is preferably from 1:99 to 99: 1, more preferably from 1:50 to 1: 2, and even more preferably from 1:40 to 1: 1. : 4
また、該塩酸べニジピン結晶、ならびに塩酸べニジピンおよび水溶性または水親和 性を有する機能性添加剤を含有する粉粒体は、それそれ個数平均粒子径 1.0〜50.0〃 mであることが好ましく、 4.5〜30.0//mであることがより好ましく、体積平均粒子径 と個数平均 子径の差が、体積平均粒子径に対して 50%以下の値であることがより好 ましい。 または、 個数平均粒子径に関わらず、 体積平均粒子径が 12〜50.0 mである のが好ましい。 これらの好ましい平均粒子径においては、 塩酸べニジピンの安定性、 塩酸ぺニジピンの含量均一性等の医薬組成物の品質をよりよく保つことができる。 水溶性または水親和性を有する機能性添加剤としては、例えば水溶性または水親和 性を有する賦形剤、 崩壊剤、 水溶性または水親和性を有する結合剤等があげられる。 水溶性または水親和性を有する賦形剤としては、例えばコムギデンプン、 コメデン プン、 トウモロコシデンプン、 バレイショデンプン等のデンプン類、 化デンプン、 部分ひ化デンプン、 ヒドロキシプロピルデンプン等のデンプン誘導体、 ラクト一ス、 グルコース、 マルト一ス、 プルラン等の糖類、 D-マンニトール、 ソルビトール、 エリ スリ トール、 キシリ トール、 ラクチトール、 マルチトール等の糖アルコール類、 結晶 セルロース等のセルロース類、 カルメロース、 カルメロ一スナトリウム、 クロスカル メロ一スナトリウム、 メチルセルロース、 ェチルセルロース、 ヒドロキシプロピルセ ルロース、 ヒドロキシプロピルメチルセルロース、 ヒドロキシェチルセルロース、 力 ルボキシェチルメチルセルロース等のセルロース誘導体、デキストリン等があげられ、 水溶性または水親和性を有する賦形剤の使用量としては、医薬組成物中 40〜95質量％ が好ましく、 さらに好ましくは 60〜95質量％である。 The benidipine hydrochloride crystals, and the benidipine hydrochloride and water-soluble or The granular material containing the functional additive having the property is preferably a number average particle diameter of 1.0 to 50.0 μm, more preferably 4.5 to 30.0 // m, and a volume average particle diameter. More preferably, the difference in the number average particle diameter is 50% or less of the volume average particle diameter. Alternatively, the volume average particle diameter is preferably 12 to 50.0 m, regardless of the number average particle diameter. With these preferred average particle sizes, the quality of the pharmaceutical composition such as the stability of benidipine hydrochloride and the uniformity of the content of penidipine hydrochloride can be better maintained. Examples of the water-soluble or water-affinity functional additives include water-soluble or water-affinity excipients, disintegrants, and water-soluble or water-affinity binders. Examples of the water-soluble or water-compatible excipients include starches such as wheat starch, rice starch, corn starch, potato starch, modified starch, partially arsenic starch, starch derivatives such as hydroxypropyl starch, and lactose. Sugars such as glucose, maltose and pullulan, sugar alcohols such as D-mannitol, sorbitol, erythritol, xylitol, lactitol, maltitol, celluloses such as crystalline cellulose, carmellose, carmellose sodium, croscar Cellulose such as sodium melose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, dexamethasylmethylcellulose Scan derivatives, dextrin and the like, The amount of the excipient having a water-soluble or water affinity, a pharmaceutical composition from 40 to 95 mass% is preferred, more preferably 60 to 95 wt%.
崩壊剤としては、 例えばコムギデンプン、 コメデンプン、 トウモロコシデンプン、 バレイショデンプン等のデンプン類、 化デンプン、 部分ひ化デンプン、 ヒドロキシ プロピルデンプン等のデンプン誘導体、結晶セルロース等のセルロース類、 カルメロ —ス、カルメロースナトリウム、クロスカルメロースナトリウム、メチルセルロース、 ェチルセルロース、 ヒドロキシプロピルセルロース、 ヒドロキシプロピルメチルセル ロース、 ヒドロキシェチルセルロース、 カルボキシェチルメチルセルロース等のセル 口ース誘導体等があげられ、水溶性または水親和性を有する崩壊剤の使用量としては、 医薬組成物中 1〜10質量。/。が好ましく、 さらに好ましくは 2〜5質量 %である。  Disintegrators include, for example, starches such as wheat starch, rice starch, corn starch, potato starch, starch derivatives such as oxystarch, partially arsenic starch, hydroxypropyl starch, celluloses such as crystalline cellulose, carmellose, carme Cellulose derivatives such as sodium cellulose, croscarmellose sodium, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose and carboxyethylmethylcellulose. The amount of the disintegrant having the property is 1 to 10 mass in the pharmaceutical composition. /. And more preferably 2 to 5% by mass.
水溶性または水親和性を有する結合剤としては、例えば結晶セルロース等のセル口 ース類、 カルメロ一ス、 カルメロ一スナトリウム、 クロスカルメロースナトリウム、 メチルセル口一ス、 ェチルセルロース、 ヒドロキシプロピルセルロース、 ヒドロキシ プロピルメチルセルロース、 ヒドロキシェチルセルロース、 カルボキシェチルメチル セルロース等のセルロース誘導体、ポリビニルアルコール、部分けん化ポリビニルァ ルコール、ポリビニルピロリドン等があげられ、水溶性または水親和性を有する結合 剤の使用量としては、医薬組成物中 0.1〜10質量％が好ましく、さらに好ましくは 0. 5 〜 5質量。/。である。 Examples of the water-soluble or water-affinity binder include cellulosic substances such as crystalline cellulose, carmellose, carmellose sodium, croscarmellose sodium, and the like. Cellulose derivatives such as methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxyethylmethylcellulose, polyvinyl alcohol, partially saponified polyvinyl alcohol, polyvinylpyrrolidone, etc. The amount of the binder having water affinity to be used is preferably 0.1 to 10% by mass, more preferably 0.5 to 5% by mass in the pharmaceutical composition. /. It is.
本発明の医薬組成物においては、前記水溶性または水親和性を有する機能性添加剤 が、前記粉粒体以外の医薬組成物中に含有されていることが好ましい。前記粉粒体以 外の医薬組成物中に含有される水溶性または水親和性を有する機能性添加剤の量と しては、例えば水溶性または水親和性を有する賦形剤では、前記粉粒体中と、前記粉 粒体以外の医薬組成物中とで合わせて医薬組成物の 40〜95 質量％であるのが好まし く、 さらに好ましくは 60~95質量 %であり、 崩壊剤では、前記粉粒体中と、前記粉粒 体以外の医薬組成物中とで合わせて医薬組成物の 1〜30質量 %であるのが好ましく、 さらに好ましくは 2〜15質量 ° /。であり、 水親和性を有する賦形剤では、 前記粉粒体中 と、 前記粉粒体以外の医薬組成物中とで合わせて医薬組成物の 0.1〜30質量％である のが好ましく、 さらに好ましくは 0.5〜15質量％である。  In the pharmaceutical composition of the present invention, it is preferable that the functional additive having water solubility or water affinity is contained in a pharmaceutical composition other than the granular material. The amount of the water-soluble or water-affinity functional additive contained in the pharmaceutical composition other than the powdery granules is, for example, water-soluble or water-affinity excipients, The total amount of the pharmaceutical composition in the granules and the pharmaceutical composition other than the granules is preferably 40 to 95% by mass, more preferably 60 to 95% by mass. It is preferable that the total amount of the pharmaceutical composition in the above-mentioned granular material and the pharmaceutical composition other than the above-mentioned granular material is 1 to 30% by mass, more preferably 2 to 15% by mass. In the excipient having water affinity, it is preferable that the total amount of the pharmaceutical composition in the granular material and the pharmaceutical composition other than the granular material is 0.1 to 30% by mass. Preferably it is 0.5 to 15% by mass.
本発明の医薬組成物には、前記の水溶性または水親和性を有する機能性添加剤に加 え、製剤の分野で一般に用いられる他の製剤用添加物、例えば滑沢剤、発泡剤、 甘味 剤、 香料、 着色剤等を加えることもできる。  The pharmaceutical composition of the present invention contains, in addition to the above-mentioned water-soluble or water-affinity functional additives, other pharmaceutical additives generally used in the field of pharmaceuticals, such as lubricants, foaming agents, and sweeteners. Agents, fragrances, coloring agents and the like can also be added.
滑沢剤としては、例えばステアリン酸、 ステアリン酸カルシウム、ステアリン酸マ グネシゥム、ステアリン酸ポリオキシル 40、 タルク、セ夕ノール、 ラブリワックス、 無水ケィ酸、 パラフィン、 ホウ酸、 ロイシン、 ポリオキシエチレン脂肪酸エステル、 安息香酸ナトリウム等があげられる。 滑沢剤の使用量としては、 医薬組成物中 0.01 〜1質量。/。が好ましく、 さらに好ましくは 0.01〜0 , 5質量％である。  Lubricants include, for example, stearic acid, calcium stearate, magnesium stearate, polyoxyl 40 stearate, talc, ceanol, lab wax, caffeic anhydride, paraffin, boric acid, leucine, polyoxyethylene fatty acid ester, benzoic acid Acid sodium and the like. The amount of the lubricant used is 0.01 to 1 mass in the pharmaceutical composition. /. And more preferably 0.01 to 0.5% by mass.
発泡剤としては、例えば炭酸水素ナトリウム、炭酸ナトリウム、炭酸カルシウム等 があげられる。  Examples of the foaming agent include sodium hydrogen carbonate, sodium carbonate, calcium carbonate and the like.
甘味剤としては、例えばアスパルテーム（登録商標)、 サッカリン、 グリチルリチン 等があげられる。  Examples of the sweetener include aspartame (registered trademark), saccharin, glycyrrhizin and the like.
香料としては、 例えばレモン、 オレンジ、 パイン、 ミント、 メントール等があげら れる。 Examples of flavors include lemon, orange, pine, mint, and menthol. It is.
着色剤どしては、例えば黄色 Ξ二酸化鉄、三二酸化鉄、夕ール色素等があげられる。 コーティングとしては、例えば糖衣、 フィルムコ一ティング、 ポリマ一コーティン グ等があげられ、 コ一ティングを行う目的としては、例えば矯味、 胃溶性または腸溶 性の付与、 薬物の酸化や加水分解等による変質防止等があげられる。  Examples of the coloring agent include yellow iron dioxide, iron sesquioxide, and evening pigment. Examples of the coating include sugar coating, film coating, polymer coating, and the like. The purpose of coating is, for example, by imparting flavor, gastric or enteric solubility, and oxidation or hydrolysis of a drug. Prevention of deterioration.
矯味のためのコ一ティングに用いられるコ一ティング剤としては、例えばメチルセ ルロース、 ェチルセルロース、 ヒドロキシェチルメチルセル口一ス、 ヒドロキシプロ ピルメチルセルロース、 ヒドロキシプロピルセルロース、メ夕クリル酸メチル 'メタ クリル酸プチル ·メタクリル酸ジメチルアミノエチル 'コポリマー (E；)、 ァクリル酸 ェチル ·メ夕クリル酸メチル ·メ夕クリル酸塩化トリメチルアンモニゥムェチル · コポリマ一 (RS )等があげられる。  Coating agents used for coating for flavoring include, for example, methylcellulose, ethylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methyl methacrylate Butyl acrylate / dimethylaminoethyl methacrylate 'copolymer (E;), ethyl acrylate / methyl methacrylate / methyl methacrylate methacrylate-copolymer (RS) and the like.
胃溶性の付与のためのコーティングに用いられるコーティング剤としては、例えば メタクリル酸メチル 'メタクリル酸プチル 'メタクリル酸ジメチルァミノェチル · コポリマ一 (E)、ポリビニルァセ夕一ルジェチルァミノアセテート（AEA)等があげられ る。  Examples of the coating agent used for coating for imparting gastric solubility include methyl methacrylate 'butyl methacrylate' dimethylaminoethyl methacrylate copolymer (E), polyvinyl acetate yurujethylamino acetate (AEA) And so on.
腸溶性の付与のためのコ一ティングに用いられるコーティング剤としては、例えば メタグリル酸 ·メ夕クリル酸メチル .コポリマ一 (L )、 メ夕クリル酸 'ァクリル酸ェ チル ·コポリマー (LD )、 酢酸セルロース、 酢酸フ夕ル酸セルロース、 カルボキシメチ ルェチルセルロース、ヒドロキシプロピルメチルセルロースアセテートサクシネート、 ヒド Oキシプロピルメチルセルロ一スフタレ一ト等があげられる。  Examples of coating agents used for coating for imparting enteric properties include methacrylic acid / methyl methacrylate / copolymer (L), methacrylic acid / ethyl acrylate / copolymer (LD), and acetic acid. Cellulose, cellulose acetate fluorate, carboxymethyl cellulose, hydroxypropylmethylcellulose acetate succinate, hydroxyoxypropylmethyl cellulose monophthalate and the like can be mentioned.
なお前記の矯味または胃溶性もしくは腸溶性の付与のためのコーティングに用い られるコーティング剤によってコーティングすることにより、同時に薬物の酸化や加 水分解等による変質防止等の目的を達成することが可能な場合もある。  In the case where it is possible to simultaneously achieve the purpose of preventing deterioration due to oxidation or hydrolytic decomposition of the drug by coating with the coating agent used for coating for imparting the above-mentioned taste or imparting gastric or enteric properties. There is also.
次に、本発明の塩酸べニジビン含有医薬組成物の好ましい製造法について、錠剤を 例に説明する。なお、本発明の塩酸ぺニジピン含有医薬組成物の形態としては、錠剤 の他、 顆粒剤、 散剤、 丸剤等があげられる。  Next, a preferred method for producing the pharmaceutical composition containing benidivine hydrochloride of the present invention will be described using tablets as an example. Examples of the form of the pharmaceutical composition containing penidipine hydrochloride of the present invention include tablets, granules, powders, and pills.
( 1 )塩酸べ二ジピン結晶の粉砕および造粒工程 (1) Pulverization and granulation process of benzodipine hydrochloride crystals
塩酸べニジピン結晶の粉碎に用いられる粉砕機は特に限定されないが、好ましくは ハンマ一ミル、 ジェヅトミル等が用いられる。 この粉碎工程において、 塩酸べニジピ ンを体積平均粒子径 1.0〜50.0〃m、 好ましくは 4.5〜50 · 0〃πι、 より好ましくは 4. 5 〜30.0 zmとなるよう加工することができる。 The pulverizer used for pulverizing the benidipine hydrochloride crystals is not particularly limited, but a hammer mill, a jet mill or the like is preferably used. In this milling process, Benidipi hydrochloride Can be processed to have a volume average particle size of 1.0 to 50.0 μm, preferably 4.5 to 50 · 0〃πι, more preferably 4.5 to 30.0 zm.
また、 前記粉砕工程において、 好ましくは個数平均粒子径 1.0~50.0 zm、 より好 ましくは 4.5〜30.0〃mとし、 さらに好ましくは体積平均粒子径と個数平均粒子径の 差が、体積平均粒子径に対して 50%以下の値となるよう加工することができる。 また は、個数平均粒子径に関わらず、体積平均粒子径が 12〜50.0 zmとなるよう加工する ことができる。  In the pulverizing step, the number average particle diameter is preferably 1.0 to 50.0 zm, more preferably 4.5 to 30.0 μm, and further preferably the difference between the volume average particle diameter and the number average particle diameter is the volume average particle diameter. To 50% or less. Alternatively, it can be processed so that the volume average particle diameter is 12 to 50.0 zm, regardless of the number average particle diameter.
また粉砕の代わりに、篩過、 晶析、 スプレ一ドライ等によって塩酸べニジピンを体 積平均粒子径 1.0〜5.0.0 ΠΙとなるように加工することもできる。  Instead of grinding, benidipine hydrochloride can be processed to have a volume average particle size of 1.0 to 5.0.0 mm by sieving, crystallization, spray drying, or the like.
塩酸べニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有 する粉粒体は、塩酸べニジピン結晶に前記の水溶性もしくは水親和性を有する機能性 添加剤を加えた後に粉砕、篩過、 晶析、 スズレ一ドライ等によって体積平均粒子径 1.0〜50.0〃m、好ましくは 4.5〜50.0 im、 より好ましくは 4. 5〜30.0〃mとなるよう 加工することができる。  The powder containing the benidipine hydrochloride crystal and the water-soluble or water-affinity functional additive is pulverized after adding the water-soluble or water-affinity functional additive to the benidipine hydrochloride crystal. It can be processed to have a volume average particle size of 1.0 to 50.0 μm, preferably 4.5 to 50.0 im, and more preferably 4.5 to 30.0 μm by sieving, crystallization, drying and the like.
また、 前記粉碎、 篩過、 晶析、 スプレードライ等によって、 好ましくは個数平均粒 子径； L 0〜50.0 より好ましくは 4. 5〜30.0 imとし、 さらに好ましくは体積平 均粒子径と個数平均粒子径の差が、体積平均粒子径に対して 50%以下の値となるよう 加工することができる。 または、 個数平均粒子径に関わらず、 体積平均粒子径が 12 〜50.0 zmとなるよう加工することができる。  Further, by the above-mentioned pulverization, sieving, crystallization, spray-drying and the like, preferably the number average particle diameter; L 0 to 50.0, more preferably 4.5 to 30.0 im, still more preferably the volume average particle diameter and the number average Processing can be performed so that the difference in particle size is 50% or less of the volume average particle size. Alternatively, processing can be performed so that the volume average particle diameter is 12 to 50.0 zm, regardless of the number average particle diameter.
続いて、 体積平均粒子径 1.0〜50.0 mとなるよう加工された塩酸べニジピン結晶 または塩酸べ二ジピンぉよび水溶性もしくは水親和性を有する機能性添加剤を含有 する粉粒体に、必要により前記の各種製剤用添加物を加えて造粒を行い、造粒物を得 る。造粒の方法としては、特に種類を問わないが、好ましくは湿式造粒が用いられる。 造粒機としては、例えば流動層造粒機、転動攪拌造粒機、押し出し造粒機等が用いら れる。  Subsequently, benidipine hydrochloride crystals processed to have a volume average particle size of 1.0 to 50.0 m or powdered granules containing benidipine hydrochloride and a water-soluble or water-affinity functional additive may be added, if necessary. Granulation is performed by adding the above-mentioned various pharmaceutical additives to obtain a granulated product. The method of granulation is not particularly limited, but wet granulation is preferably used. As the granulator, for example, a fluidized bed granulator, a tumbling stirring granulator, an extrusion granulator and the like are used.
本発明の塩酸べ二ジピン含有医薬組成物における塩酸べ二ジピンの使用量として は、 投与量等により異なるが、錠剤中 0.01〜50質量％が好ましく、 さらに好ましくは 0.01〜30質量％である。  The amount of vendidipine hydrochloride used in the pharmaceutical composition containing vendidipine hydrochloride of the present invention varies depending on the dose and the like, but is preferably 0.01 to 50% by mass, more preferably 0.01 to 30% by mass in the tablet.
( 2 )塩酸べ二ジピンを含有する錠剤の製造工程 前記 (1 )で得られた造粒物を乾燥後、 滑沢剤を加えて混合し圧縮成形する。 このと き、 前記の各種製剤用添加物を加えることもできる。 (2) Manufacturing process of tablets containing venidipine hydrochloride After drying the granulated product obtained in the above (1), a lubricant is added, mixed and compression molded. At this time, the above-mentioned additives for various preparations can be added.
圧縮成形に用いる打錠機は、特に限定されないが、 口一夕リー打錠機を用いるのが 好ましく、 圧縮成形圧力は、 300 kg〜5000 kgであることが好ましい。  The tableting machine used for the compression molding is not particularly limited, but it is preferable to use a mouthless tableting machine, and the compression molding pressure is preferably from 300 kg to 5000 kg.
また、矯味、 胃溶性または腸溶性の付与等のために、 医薬組成物にコ一テ ングを 行うこともできるが、これには造粒物即ち圧縮成形前の素顆粒にコ一ティングを行う 方法と、 圧縮成形後の錠剤にコーティングを行う方法等があげられる。  The pharmaceutical composition may be coated for imparting flavor, gastric solubility or enteric solubility, etc., but this is done by coating the granulated product, that is, the raw granules before compression molding. And a method of coating tablets after compression molding.
圧縮成形前の素顆粒にコ一ティングを行う方法としては、例えばコーティング装置 中で、ラクトースまたは結晶セル口一スの球形顆粒に結合剤とともに活性成分である 塩酸べニジピン結晶を付着させ、静置棚式乾燥機、流動層乾燥機等で乾燥して、塩酸 ベニジピン結晶を含有した素顆粒を得る。さらに、 コ一ティング装置中で、 コ一ティ ング剤を適当な溶媒、 例えば水、 メタノール、 エタノール、 2-プロパノール、 酢酸ェ チル、 乳酸ェチル、 アセトン、塩化メチレン、 1，1 , 1-トリクロ口エタン等またはこれ らの混合溶媒等で溶解または分散させたコーティング剤液を素顆粒にスプレーして コーティングし、静置棚式乾燥機または流動層乾燥機等で乾燥して、コーティングさ れた粉粒体を得る。 この時のコーティング装置は、 特に限定されるものではないが、 好ましくは流動層コ一ティング乾燥装置、遠心流動造粒装置、転動流動コ一ティング 乾燥装置等が用いられる。  As a method of coating the elementary granules before compression molding, for example, in a coating apparatus, the active ingredient benidipine hydrochloride crystals are attached together with a binder to lactose or the spherical granules of the crystal cell mouth and allowed to stand. The granules are dried by a tray dryer, a fluidized bed dryer or the like to obtain elementary granules containing benidipine hydrochloride crystals. Further, in a coating apparatus, the coating agent is mixed with a suitable solvent, for example, water, methanol, ethanol, 2-propanol, ethyl acetate, ethyl lactate, acetone, methylene chloride, 1,1,1-trichloromethane. The coated powder is sprayed onto the elementary granules and coated with the coating agent solution dissolved or dispersed in ethane or the like or a mixed solvent of these, and dried with a standing-bed dryer or fluidized-bed dryer. Obtain granules. The coating apparatus at this time is not particularly limited, but preferably a fluidized bed coating drying apparatus, a centrifugal fluidized granulation apparatus, a tumbling fluidized coating drying apparatus and the like are used.
また、圧縮成形後の錠剤にコ一ティングを行う際のコーティング装置は、特に限定 されるものではないが、好ましくはドラム式フィルムコ一ティング乾燥装置または流 動層コ一ティング装置が用いられる。  The coating apparatus used for coating the tablets after compression molding is not particularly limited, but a drum-type film coating drying apparatus or a fluidized-bed coating apparatus is preferably used.
本発明の医薬組成物からの塩酸べ二ジピンの即溶出化は、塩酸べ二ジピンを含有す る医薬組成物において、 塩酸ぺニジピン結晶の体積平均粒子径を 1.0 50.0 m、 好 ましくは体積平均粒子径および個数平均粒子径を 4.5~30.0 mとする、 または塩酸 ベニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する粉 粒体を含有する医薬組成物において、塩酸べニジピン結晶および水溶性もしくは水親 和性を有する機能性添加剤を含有する粉粒体の体積平均粒子径を 1.0〜50.0〃m、 好 ましくは 4.5〜50 , 0 zmとすることにより行うことができ、 例えば、 上記した本発明 の医薬組成物の製造法により塩酸べニジピン含有医薬組成物を製造することによつ て行うことができる。 Immediate elution of venidipine hydrochloride from the pharmaceutical composition of the present invention can be achieved by adjusting the volume average particle diameter of the penidipine hydrochloride crystals to 1.0 50.0 m, preferably, in a pharmaceutical composition containing venidipine hydrochloride. In a pharmaceutical composition having an average particle size and a number average particle size of 4.5 to 30.0 m, or containing a benidipine hydrochloride crystal and a powder containing a water-soluble or water-affinity functional additive, benidipine hydrochloride may be used. The volume average particle diameter of the powder containing the crystals and the functional additive having water-solubility or water-miscibility is adjusted to 1.0 to 50.0 μm, preferably 4.5 to 50,0 zm. For example, by producing a pharmaceutical composition containing benidipine hydrochloride by the above-mentioned method for producing a pharmaceutical composition of the present invention. Can be done.
次に本発明を実施例でさらに詳しく説明するが、本発明はこれらに限定されるも のではない。  Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.
発明 実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
実施例 1 Example 1
(塩酸ぺニジピン原薬の粉碎）  (Crushing of the drug substance of penidipine hydrochloride)
塩酸べニジピン原薬 (ロット P- 010、協和発酵製、体積平均粒子径 65.0^m、個数平 均粒子径 10.3〃m)5000gを粉砕機サンプルミル (KIIWG- IF型、 不二パゥダル製）によ る 1回粉碎処理に付した。さらに、得られた粉砕された塩酸ぺニジピン結晶をジェヅ トミル粉砕機 (PJM-100SP、日本ニューマチック工業社製）による 1回粉碎処理に付し、 粉砕された塩酸べニジピン結晶を得た。粉碎された塩酸べニジピン結晶の平均粒子径 は、 流動ノ ラフィン懸濁による湿式法で顕微鏡下イメージアナライザ一（ォリンパス SP - 500型）にて測定した。 その結果、 粉砕された塩酸ぺニジピン結晶は、 体積平均粒 子径 9.4 111、 個数平均粒子径 4.9 Π1であった。  Benidipine hydrochloride drug substance (lot P-010, manufactured by Kyowa Hakko, volume average particle diameter 65.0 ^ m, number average particle diameter 10.3〃m) 5000g was fed to a grinder sample mill (KIIWG-IF type, manufactured by Fuji Padal) This was subjected to a single milling treatment. Further, the obtained pulverized penidipine hydrochloride crystals were subjected to a single pulverization treatment by a jet mill pulverizer (PJM-100SP, manufactured by Nippon Pneumatic Industries, Ltd.) to obtain pulverized benidipine hydrochloride crystals. The average particle size of the pulverized benidipine hydrochloride crystals was measured by an image analyzer under a microscope (Olympus SP-500) by a wet method using a liquid noraffin suspension. As a result, the pulverized penidipine hydrochloride crystals had a volume average particle diameter of 9.4111 and a number average particle diameter of 4.91.
(粉碎された塩酸べ二ジピン結晶を用 ^、た錠剤製造） (Use crushed venedipine hydrochloride crystals ^, tablets)
上記の粉碎された塩酸べニジピン結晶を用いて、 以下の処方および製造法により、 餘剤を得た。  Using the pulverized benidipine hydrochloride crystals described above, the following formulation and production method were used to obtain an ointment.
(錠剤処方） (Tablet prescription)
粉砕された塩酸べニジピン結晶 4, ,33 kg  Crushed benidipine hydrochloride crystals 4, 33 kg
ラクト一ス 68. ,69 kg  Lactose 68., 69 kg
バレイショデンプン 41, ,38 kg  Potato starch 41,, 38 kg
ポリビニルアルコール 4, ,2 kg  Polyvinyl alcohol 4,2 kg
ステアリン酸マグネシウム 1, 4 kg  Magnesium stearate 1, 4 kg
120, ,0 kg  120,, 0 kg
(錠剤製造法）  (Tablet manufacturing method)
粉砕された塩酸べ二ジピン結晶、ラクトースおよびバレイショデンプンをポリビニ ルアルコールの水溶液を噴霧下、流動層造粒機にて造粒し、 さらに、滑沢剤としてス テアリン酸マグネシウムを V型混合機にて混合し、打錠用顆粒を得た。この打錠用顆 粒を用いて、 錠剤径 7腿 、 錠剤重量 130mgの錠剤を得た。 実施例 The pulverized benzodipine hydrochloride crystals, lactose and potato starch are granulated by a fluidized bed granulator under spraying of an aqueous solution of polyvinyl alcohol, and magnesium stearate is added as a lubricant to a V-type mixer. To obtain tableting granules. A tablet having a tablet diameter of 7 thighs and a tablet weight of 130 mg was obtained using the tableting granules. Example
(塩酸ぺニジピン原薬の粉碎） ' ■ 塩酸べニジピン原薬（ロット P- 010、協和発酵製、体積平均粒子径 65.0〃m、個数平 均粒子径 10,3〃m)500.0gを粉砕機サンプルミル (KIIWG - IF型、 不二パウダノレ製）によ る 1回粉砕処理に付し、粉砕された塩酸べニジピン結晶を得た。粉砕された塩酸べ二 ジピン結晶の平均粒子径は、流動パラフィン懸濁による湿式法で顕微鏡下ィメージァ ナライザ一 (ォリンパス SP- 500型）にて測定した。 その結果、 粉碎された塩酸ぺニジ ピン結晶は、 体積平均粒子径 14.5〃m、 個数平均粒子径 6.2〃ιηであった。  (Crushing of the drug substance of nidipine hydrochloride) '' ■ Milling 500.0 g of drug substance of benidipine hydrochloride (Lot P-010, manufactured by Kyowa Hakko Co., Ltd., volume average particle diameter 65.0〃m, number average particle diameter 10,3〃m) The sample was subjected to a single pulverization treatment using a sample mill (KIIWG-IF type, manufactured by Fuji Powder Nore) to obtain pulverized benidipine hydrochloride crystals. The average particle size of the pulverized benzodipine hydrochloride crystals was measured by a wet method using a liquid paraffin suspension with an image analyzer (Olympus SP-500) under a microscope. As a result, the pulverized penidipine hydrochloride crystals had a volume average particle diameter of 14.5 μm and a number average particle diameter of 6.2 μιη.
(粉砕された塩酸べ二ジピン結晶を用いた錠剤製造） (Tablet production using pulverized benzodipine hydrochloride crystals)
上記の粉砕された塩酸べニジピン結晶を用いて、 以下の処方および製造法により、 錠剤を得た。  Using the pulverized benidipine hydrochloride crystals, tablets were obtained by the following formulation and production method.
(錠剤処方） (Tablet prescription)
粉砕された塩酸ぺニジピン結晶 .33 k  Crushed penidipine hydrochloride crystal .33 k
ラクト一ス 68, ,69 kg  Lactose 68,, 69 kg
バレイショデンプン 41, ,38 kg  Potato starch 41,, 38 kg
ポリビニルアルコール 4, .2 kg  Polyvinyl alcohol 4.2 kg
ステアリン酸マグネシゥム 1, ,4 kg  Magnesium stearate 1,, 4 kg
120, ,0 kg  120,, 0 kg
(錠剤製造法）  (Tablet manufacturing method)
粉碎された塩酸べ二ジビン結晶、ラクト一スおよびバレイショデンプンをポリビニ ルアルコールの水溶液を噴霧下、流動層造粒機にて造粒し、 さらに、滑沢剤としてス テアリン酸マグネシウムを V型混合機にて混合し、打錠用顆粒を得た。この打錠用顆 粒を用いて、 錠剤径 7卿 、 錠剤重量 130mgの錠剤を得た。  The crushed benzodivine hydrochloride crystals, lactose and potato starch are granulated with a fluidized bed granulator while spraying an aqueous solution of polyvinyl alcohol, and magnesium stearate is mixed in a V-shape as a lubricant. The mixture was mixed with a press to obtain granules for tableting. Using the granules for tableting, a tablet having a tablet diameter of 7 mg and a tablet weight of 130 mg was obtained.
実施例 3 Example 3
(塩酸べニジピン原薬の篩過）  (Sieving of the drug substance of benidipine hydrochloride)
塩酸べニジピン原薬（ロット P- 010、協和発酵製、体積平均粒子径 65,0^111、個数平 均粒子径 10.3〃m)5000gを振動フルィ機 [100mesh(150〃m)篩過]にて処理し、 篩過さ れた塩酸べニジピン結晶を得た。篩過された塩酸べニジピン結晶の平均粒子径は、流 動パラフィン懸濁による湿式法で顕微鏡下ィメ一ジアナライザ一（ォリンパス SP - 500型）にて測定した。その結果、 篩過された塩酸べニジピン結晶は、 体積平均平 均粒子径 26.3 m、 個数平均粒子径 6.6 /mであった。 5000g of Benidipine hydrochloride drug substance (lot P-010, manufactured by Kyowa Hakko, volume average particle size 65,0 ^ 111, number average particle size 10.3〃m) was passed through a vibrating screen machine [100mesh (150〃m) sieve]. To obtain sieved benidipine hydrochloride crystals. The average particle size of the sieved benidipine hydrochloride crystals can be determined by a wet method using a fluid paraffin suspension under a microscope using an image analyzer (Olympus). SP-500). As a result, the sieved benidipine hydrochloride crystals had a volume average average particle diameter of 26.3 m and a number average particle diameter of 6.6 / m.
(篩過された塩酸べ二ジピン結晶を用いた錠剤製造 ) (Tablet production using sieved venidipine hydrochloride crystals)
上記の篩過された塩酸べニジピン結晶を用いて、 以下の処方および製造法により、 錠剤を得た。  Using the above-mentioned sieved benidipine hydrochloride crystals, tablets were obtained by the following formulation and production method.
(錠剤処方） (Tablet prescription)
篩過された塩酸べ二ジピン結晶 4, .33 k  Screened benidipine hydrochloride crystals 4.33 k
ラクト一ス 68, ,69 kg  Lactose 68,, 69 kg
バレイショデンプン 41, ,38 kg  Potato starch 41,, 38 kg
ポリビニルアルコール 4, ,2 kg  Polyvinyl alcohol 4,2 kg
ステアリン酸マグネシウム L ,4 kg  Magnesium stearate L, 4 kg
120, .0 kg  120, .0 kg
(錠剤製造法）  (Tablet manufacturing method)
篩過された塩酸べ二ジピン結晶、ラクトースおよびバレイショデンプンをポリビニ ルアルコールの水溶液を噴霧下、流動層造粒機にて造粒し、さらに滑沢剤としてステ ァリン酸マグネシウムを V型混合機にて混合し、打錠用顆粒を得た。この打錠用顆粒 を用いて、 錠剤径 7mm 、 錠剤重量 130mgの錠剤を得た。  The sieved venidipine hydrochloride crystals, lactose and potato starch are granulated in a fluidized bed granulator while spraying an aqueous solution of polyvinyl alcohol, and magnesium stearate is added as a lubricant to a V-type mixer. To obtain tableting granules. A tablet having a tablet diameter of 7 mm and a tablet weight of 130 mg was obtained using the tableting granules.
比較例 1 Comparative Example 1
(未粉砕または未篩過塩酸べ二ジピン結晶を用いた錠剤製造） ，  (Tablet production using unmilled or unsieved perdihydrochloride crystals),
塩酸べニジピン原薬（ロット P-010、協和発酵製、体積平均粒子径 65.0 m、個数平 均粒子径 10.3〃m)を用いて、 以下の処方および製造法により、 錠剤を得た。  Tablets were obtained using the drug substance of Benidipine hydrochloride (Lot P-010, manufactured by Kyowa Hakko, volume average particle diameter 65.0 m, number average particle diameter 10.3 μm) according to the following formulation and production method.
(錠剤処方） (Tablet prescription)
塩酸べニジピン原薬 4, ,33 kg  Benidipine hydrochloride API 4,, 33 kg
ラクトース 68, ,69 kg  Lactose 68,, 69 kg
バレイショデンプン 41, ,38 kg  Potato starch 41,, 38 kg
ポリビニルアルコール 4, ,2 kg  Polyvinyl alcohol 4,2 kg
ステアリン酸マグネシウム 1, ,4 kg  Magnesium stearate 1,, 4 kg
120, .0 kg  120, .0 kg
錠剤製造法） 塩酸べニジピン原薬（ロット P-010、,協和発酵製、体積平均粒子径 65.0 Zffl、個数平 均粒子径 10.3〃ιη)、 ラクト一スおよびバレイショデンプンをポリビニルアルコール の水溶液を噴霧下、流動層造粒機にて造粒し、さらに滑沢剤としてステアリン酸マグ ネシゥムを V型混合機にて混合し、打錠用顆粒を得た。 この打錠用顆粒を用いて、錠 剤径 7IM0、 錠剤重量 130mgの錠剤を得た。 Tablet manufacturing method) Benidipine hydrochloride drug substance (Lot P-010, manufactured by Kyowa Hakko, volume average particle diameter 65.0 Zffl, number average particle diameter 10.3〃ιη), lactose and potato starch are sprayed with an aqueous solution of polyvinyl alcohol, and the fluidized bed The mixture was granulated with a granulator, and magnesium stearate as a lubricant was further mixed with a V-type mixer to obtain granules for tableting. Using these granules for tableting, tablets having a tablet size of 7IM0 and a tablet weight of 130 mg were obtained.
比較例 Comparative example
(未粉砕または未篩過塩酸べニジピン結晶を用レヽた錠剤製造）  (Tablet production using unmilled or unsieved benidipine hydrochloride crystals)
塩酸べニジピン原薬（ロット P-005、 協和発酵製、 体積平均粒子径 147.1 zm、 個数 平均粒子径 9.7〃ffl)を用いて、 以下の処方および製造法により、 錠剤を得た。  Tablets were obtained using the drug substance of Benidipine hydrochloride (Lot P-005, manufactured by Kyowa Hakko, volume average particle size 147.1 zm, number average particle size 9.7〃ffl) according to the following formulation and manufacturing method.
(錠剤処方） (Tablet prescription)
塩酸べニジピン原薬 4 .33 kg  Benidipine hydrochloride API 4.33 kg
ラク'トース 68, ,69 kg  Lak 'tose 68,, 69 kg
バレイショデンプン 41, ,38 kg  Potato starch 41,, 38 kg
ポリビニルアルコール 4, ,2 kg  Polyvinyl alcohol 4,2 kg
ステアリン酸マグネシゥム 1. ,4 kg  Magnesium stearate 1., 4 kg
(錠剤製造法  (Tablet manufacturing method
塩酸べニジピン原薬（ロット P-005、 協和発酵製、 体積平均粒子径 147.1 m、 個数 平均粒子径 9.7〃m)、 ラクトースおよびバレイショデンプンをポリビニルアルコール の水溶液を噴霧下、流動層造粒機にて造粒し、さらに滑沢剤としてステアリン酸マグ ネシゥムを V型混合機にて混合し、打錠用顆粒を得た。 この打錠用顆粒を用いて、錠 剤径 7nim0、 錠剤重量 130mgの錠剤を得た。  Benidipine hydrochloride drug substance (Lot P-005, manufactured by Kyowa Hakko, volume average particle diameter 147.1 m, number average particle diameter 9.7 〃m), lactose and potato starch are sprayed with an aqueous solution of polyvinyl alcohol into a fluidized bed granulator. Then, magnesium stearate as a lubricant was mixed with a V-type mixer to obtain granules for tableting. Using these granules for tableting, tablets having a tablet size of 7 nm0 and a tablet weight of 130 mg were obtained.
実施例 1、 2、 3および比較例 1、 2で用いた塩酸べニジピン結晶の体積平均粒子径 および個数平均粒子径を表 1に示した。  Table 1 shows the volume average particle size and the number average particle size of the benidipine hydrochloride crystals used in Examples 1, 2, and 3 and Comparative Examples 1 and 2.
表 1 塩酸べニジピン結晶の平均粒子径  Table 1 Average particle size of benidipine hydrochloride crystals
体積平均粒子径 個数平均粒子径  Volume average particle size Number average particle size
実施例 1 9.4 /in 4.9 jLLOi 実施例 2 14. b j ^ 6.2 m 実施例 3 26.3 m 6,6 im 比較例 1 65.0 rn 10.3 m 比較例 147.1 zm 9.7 ZJii 試験例:溶出試験 Example 1 9.4 / in 4.9 jLLOi Example 2 14.bj ^ 6.2 m Example 3 26.3 m 6,6 im Comparative example 1 65.0 rn 10.3 m Comparative Example 147.1 zm 9.7 ZJii Test Example: Dissolution Test
溶出試験は日局第 1法 (回転バスケット法）に従い、 試験液 [ラウリル硫酸ナトリウ ムの PH6.8リン酸ナトリゥム緩衝液溶液（1 500 ) ] 900mlを用いて行い、操作条件は、 37°C、 50rpmで実施した。 試験開始 10、 20、 30、 45、 60分後にサンプリングされた 溶出液を高速液体クロマトグラフィー法 [カラム： YMC A- 301-1 (4. 6 X 100腿)、 温 度； 40° 移動層： 0.05mol/L リン酸二水素カリウム水溶液/ァセトニトリル混液 (55 : 45 ) + 1匪 ol/Lラウリル硫酸ナトリゥム水溶液]により定量し、溶出プロフアイル として評価じた。  The dissolution test was performed according to the Japanese Pharmacopoeia Method 1 (rotating basket method) using 900 ml of the test solution [sodium lauryl sulfate PH6.8 sodium phosphate buffer solution (1500)] at 37 ° C. Performed at 50 rpm. The eluate sampled 10, 20, 30, 45, and 60 minutes after the start of the test was subjected to high performance liquid chromatography [column: YMC A-301-1 (4.6 x 100 thighs), temperature; 40 ° moving bed: 0.05 mol / L aqueous solution of potassium dihydrogen phosphate / acetonitrile (55:45) + 1 aqueous ol / L aqueous solution of sodium lauryl sulfate], and evaluated as an elution profile.
実施例 1、 2、 3および比較例 1、 2で得られた錠剤の溶出試験結果を表 2に示した。 表 2 溶出試験結果 .  Table 2 shows the dissolution test results of the tablets obtained in Examples 1, 2, and 3 and Comparative Examples 1 and 2. Table 2 Dissolution test results.
Figure imgf000015_0001
比較例 1および 2で得られた錠剤では、 塩酸ぺニジピンの溶出遅延が観察された。 一方、 粉砕された塩酸べニジピン結晶を用いて製造された錠剤 (実施例 1、 2 )および 籂過された塩酸べニジビン結晶を用いて製造された錠剤 (実施例 3 )では、速やかな塩 酸べ二ジピンの溶出が観察された。
Figure imgf000015_0001
In the tablets obtained in Comparative Examples 1 and 2, the dissolution delay of penidipine hydrochloride was observed. On the other hand, the tablets manufactured using the crushed benidipine hydrochloride crystals (Examples 1 and 2) and the tablets manufactured using the filtered benidivine hydrochloride crystals (Example 3) showed rapid hydrochloride. Elution of venidipine was observed.
産業上の利用可能性  Industrial applicability
本発明により、主薬である塩酸べニジピンの速やかな吸収を促進するための、速や かな溶出性を有する塩酸べニジピン含有医薬組成物等が提供される。  According to the present invention, there is provided a medicinal composition containing benidipine hydrochloride and the like having a rapid dissolution property for promoting rapid absorption of the main drug, benidipine hydrochloride.

Claims

請求の範囲 The scope of the claims
1. 体積平均粒子径 1 .0〜50.0〃mの塩酸べニジピン結晶、 または塩酸べニジピン 結晶および水溶性もしくは水親和性を有する機能性添加剤を含有する体積平均粒子 径 1.0〜50.0 imの粉粒体を含有することを特徴とする塩酸べニジビン含有医薬組成 物。  1. A powder having a volume average particle diameter of 1.0 to 50.0 im containing benidipine hydrochloride crystals having a volume average particle diameter of 1.0 to 50.0 m or a functional additive having water solubility or affinity with water. A pharmaceutical composition containing benidivine hydrochloride, characterized by containing granules.
. 体積平均粒子径および個数平均粒子径が 4. 5〜30.0〃mの塩酸べニジピン結晶、 または塩酸べニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を 含有する体積平均粒子径 4.5〜50.0 mの粉粒体を含有することを特徴とする塩酸べ ニジピン含有医薬組成物。  A volume-average particle size of 4.5 to 30.0〃m, including a benidipine hydrochloride crystal or a benidipine hydrochloride crystal and a water-soluble or water-affinity functional additive 4.5. A pharmaceutical composition containing benidipine hydrochloride, characterized in that it contains powders of up to 50.0 m.
3. 塩酸べニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を 含有する粉粒体において、塩酸べニジピン結晶と水溶性または水親和性を有する機能 性添加剤との重量比が 1 : 99〜99 : 1である請求の範囲 1または 2記載の医薬組成物。  3. In a powder or granule containing benidipine hydrochloride crystals and a water-soluble or water-affinity functional additive, the weight ratio of the benidipine hydrochloride crystals to the water-soluble or water-affinity functional additive is 1 3. The pharmaceutical composition according to claim 1 or 2, wherein the composition is 99 to 99: 1.
4. 塩酸べニジビン結晶および水溶性もしくは水親和性を有する機能性添加剤を 含有する粉粒体において、水溶性または水親和性を有する機能性添加剤が水溶性また は水親和性を有する賦形剤である請求の範囲 1〜3のいずれかに記載の医薬組成物。  4. In powders containing benidivine hydrochloride crystals and water-soluble or water-affinity functional additives, the water-soluble or water-affinity functional additives have a water-solubility or water-affinity additive. The pharmaceutical composition according to any one of claims 1 to 3, which is a form.
5. 塩酸べニジビン結晶および水溶性もしくは水親和性を有する機能性添加剤を 含有する粉粒体において、水溶性または水親和性を有する賦形剤がデンプン類、デン プン誘導体、糖類、糖アルコール類、 セルロース類、 セルロース誘導体またはデキス トリンである請求の範囲 1~4のいずれかに記載の医薬組成物。  5. In granules containing benidivine hydrochloride crystals and water-soluble or water-affinity functional additives, water-soluble or water-affinity excipients are used as starches, starch derivatives, sugars, sugar alcohols. 5. The pharmaceutical composition according to any one of claims 1 to 4, which is a cellulose, a cellulose, a cellulose derivative or dextrin.
6. 塩酸べニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を 含有する粉粒体において、水溶性または水親和性を有する機能性添加剤が崩壊剤であ る請求の範囲 1〜3のいずれかに記載の医薬組成物。  6. In the powder containing benidipine hydrochloride crystals and a functional additive having water solubility or water affinity, the functional additive having water solubility or water affinity is a disintegrant. 4. The pharmaceutical composition according to any one of 3.
7. 崩壌剤がデンプン類、デンプン誘導体、セルロース類またはセルロース誘導体 である請求の範囲 6記載の医薬組成物。  7. The pharmaceutical composition according to claim 6, wherein the disintegrant is a starch, a starch derivative, a cellulose or a cellulose derivative.
8. 塩酸ぺニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を 含有する粉粒体において、水溶性または水親和性を有する機能性添加剤が水溶性また は水親和性を有する結合剤である請求の範囲 1〜3のいずれかに記載の医薬組成物。  8. In powders containing penidipine hydrochloride crystals and water-soluble or water-affinity functional additives, water-soluble or water-affinity functional additives are bound by water-solubility or water-affinity The pharmaceutical composition according to any one of claims 1 to 3, which is an agent.
9. 水溶性または水親和性を有する結合剤がセルロース類、セルロース誘導体、ポ リビニルアルコール、部分けん化ポリビニルアルコールまたはポリビニルピロリ ドン である請求の範囲 8記載の医薬組成物。 9. When the binder having water solubility or affinity for water is celluloses, cellulose derivatives, polyvinyl alcohol, partially saponified polyvinyl alcohol or polyvinyl pyrrolidone. 9. The pharmaceutical composition according to claim 8, which is:
10. コ一ティングされていることを特徴とする請求の範囲 1〜9 のいずれかに記 載の医薬組成物。  10. The pharmaceutical composition according to any one of claims 1 to 9, which is coated.
11. 塩酸べニジピンを含有する医薬組成物において、 塩酸べニジピン結晶の体積 平均粒子径を 1.0〜50.0〃fflとする、 または塩酸べニジピン結晶および水溶性もしく は水親和性を有する機能性添加剤を含有する粉粒体を含有する医薬組成物において、 塩酸べニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を含有す る粉粒体の体積平均粒子径を 1.0〜50.0 mとすることを特徴とする、 該医薬組成物 からの塩酸べ二ジピンの即溶出化方法。  11. In a pharmaceutical composition containing benidipine hydrochloride, the volume average particle size of the benidipine hydrochloride crystals should be 1.0 to 50.0〃ffl, or a functional additive with water-soluble or water-affinity benidipine hydrochloride crystals In a pharmaceutical composition containing a granule containing the agent, the volume average particle diameter of the granule containing benidipine hydrochloride crystals and a functional additive having water solubility or affinity for water is 1.0 to 50.0 m. A method for immediately eluting venidipine hydrochloride from the pharmaceutical composition.
12. 塩酸べニジピンを含有する医薬組成物において、 塩酸べニジピン結晶の体積 平均粒子径および個数平均径を 4.5〜30.0 imとする、 または塩酸べニジピン結晶お よび水溶性もしくは水親和性を有する機能性添加剤を含有する粉粒体を含有する医 薬組成物において、塩酸べニジピン結晶および水溶性もしくは水親和性を有する機能 性添加剤を含有する粉粒体の体積平均粒子径を 4.5〜50.0〃mとすることを特徴とす る、 該医薬組成物からの塩酸べニジピンの即溶出化方法。  12. In a pharmaceutical composition containing benidipine hydrochloride, the volume average particle diameter and the number average diameter of the benidipine hydrochloride crystals are set to 4.5 to 30.0 im, or the function has water-soluble or water-affinity benidipine hydrochloride crystals. In a pharmaceutical composition containing a granular material containing a functional additive, the volume average particle diameter of the granular material containing a benidipine hydrochloride crystal and a functional additive having water solubility or affinity for water is 4.5 to 50.0. A method for immediately eluting benidipine hydrochloride from the pharmaceutical composition, characterized in that the composition has a diameter of 〃m.
13. 塩酸べニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を 含有する医薬組成物において、塩酸べニジピン結晶と水溶性または水親和性を有する 機能性添加剤との重量比が 1:99〜99:1である請求の範囲 11または 12記載の即溶出 化方法。 '  13. In a pharmaceutical composition containing benidipine hydrochloride crystals and a water-soluble or water-affinity functional additive, the weight ratio of the benidipine hydrochloride crystals to the water-soluble or water-affinity functional additive is 1 13. The immediate elution method according to claim 11 or 12, wherein the ratio is from 99 to 99: 1. '
14. 塩酸べニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤を 含有する医薬組成物において、水溶性または水親和性を有する機能性添加剤が水溶性 または水親和性を有する賦形剤である請求の範囲 11〜13のいずれかに記載の即溶出 化方法。  14. In a pharmaceutical composition containing a benidipine hydrochloride crystal and a water-soluble or water-affinity functional additive, the water-soluble or water-affinity functional additive has a water-soluble or water-affinity excipient. 14. The rapid elution method according to any one of claims 11 to 13, which is an agent.
15. 水溶性または水親和性を有する賦形剤がデンプン類、デンプン誘導体、糖類、 糖アルコール類、セルロース類、セルロース誘導体またはデキストリンである請求の 範囲 11〜14のいずれかに記載の即溶出化方法。  15. Immediate elution according to any one of claims 11 to 14, wherein the water-soluble or water-compatible excipient is starch, starch derivative, sugar, sugar alcohol, cellulose, cellulose derivative or dextrin. Method.
16. 塩酸べニジピン結晶および水溶性もしぐは水親和性を有する機能性添加剤を 含有する医薬組成物において、水溶性または水親和性を有する機能性添加剤が崩壊剤 である請求の範囲 11〜15のいずれかに記載の即溶出化方法。 16. In a pharmaceutical composition containing a benidipine hydrochloride crystal and a water-soluble mogus or water-soluble functional additive, the water-soluble or water-compatible functional additive is a disintegrant. 15. The method for immediate elution according to any one of items 15 to 15.
17. 崩壊剤がデンプン類、 デンプン誘導体、 セルロース類またはセルロース誘導 体である請求の範囲 16記載の即溶出化方法。 。 17. The method according to claim 16, wherein the disintegrant is a starch, a starch derivative, a cellulose or a cellulose derivative. .
18 . 塩酸べニジピン結晶および水溶性もしくは水親和性を有する機能性添加剤'を 含有する医薬組成物において、水溶性または水親和性を有する機能性添加剤が水溶性 または水親和性を有する結合剤である請求の範囲 11〜15のいずれかに記載の即溶出 化方法。  18. In a pharmaceutical composition containing a benidipine hydrochloride crystal and a water-soluble or water-affinity functional additive, the water-soluble or water-affinity functional additive has a water-soluble or water-affinity binding. 16. The method for immediate elution according to any one of claims 11 to 15, which is an agent.
19 . 水溶性または水親和性を有する結合剤がセルロース類、 セルロース誘導体、 ポリビニルアルコール、部分けん化ポリビニルアルコールまたはポリビニルピロリド ンである請求の範囲 18記載の即溶出化方法。 .  19. The rapid elution method according to claim 18, wherein the binder having water solubility or affinity for water is cellulose, a cellulose derivative, polyvinyl alcohol, partially saponified polyvinyl alcohol, or polyvinyl pyrrolidone. .
20 . 医薬組成物がコーティングされている医薬組成物である請求の範囲 11〜19 のいずれかに記載の即溶出化方法。  20. The rapid elution method according to any one of claims 11 to 19, wherein the pharmaceutical composition is a coated pharmaceutical composition.
PCT/JP2004/008821 2003-06-17 2004-06-17 Medicinal composition containing benidipine hydrochloride WO2004110448A1 (en)

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