WO2014058047A1 - Procédé de production de préparation pharmaceutique contenant un inhibiteur calcique / antagoniste du récepteur d'angiotensine ii - Google Patents

Procédé de production de préparation pharmaceutique contenant un inhibiteur calcique / antagoniste du récepteur d'angiotensine ii Download PDF

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Publication number
WO2014058047A1
WO2014058047A1 PCT/JP2013/077730 JP2013077730W WO2014058047A1 WO 2014058047 A1 WO2014058047 A1 WO 2014058047A1 JP 2013077730 W JP2013077730 W JP 2013077730W WO 2014058047 A1 WO2014058047 A1 WO 2014058047A1
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Prior art keywords
angiotensin
antagonist
receptor antagonist
calcium antagonist
water
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PCT/JP2013/077730
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English (en)
Japanese (ja)
Inventor
一郎 原
友紀子 田中
祐幸 樋口
晶子 寺本
智也 小野下
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味の素株式会社
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Priority to JP2014540903A priority Critical patent/JP5790965B2/ja
Priority to KR1020167023724A priority patent/KR101931489B1/ko
Priority to KR1020157012315A priority patent/KR101778050B1/ko
Publication of WO2014058047A1 publication Critical patent/WO2014058047A1/fr

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    • 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
    • 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
    • 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
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a method for producing a pharmaceutical preparation containing a calcium antagonist and an angiotensin II receptor antagonist as active ingredients.
  • High blood pressure refers to a state in which blood pressure is continuously higher than the normal range. High blood pressure is one of lifestyle-related diseases, and arteriosclerosis, ischemic heart disease, stroke, etc. may develop if the hypertensive state persists.
  • blood pressure control using antihypertensive drugs is widely used for the treatment of hypertensive patients.
  • antihypertensive drugs calcium antagonists (CCB), angiotensin exchange enzyme inhibitors, angiotensin II receptor antagonists (ARB) and the like are generally used.
  • CB Calcium antagonists
  • ARB Angiotensin II receptor antagonist
  • ARB suppresses the physiological action of angiotensin II produced in the renin-angiotensin system and having a strong pressor action by specifically antagonizing the angiotensin II receptor, and has a hypotensive action. It is known to play.
  • calcium antagonists and angiotensin II receptor antagonists have antihypertensive effects by different mechanisms. Therefore, for hypertensive patients whose symptoms do not improve much with single-agent administration, it has been attempted to use a calcium antagonist and an angiotensin II receptor antagonist together for the purpose of enhancing the therapeutic effect (patent) Reference 1).
  • both the calcium antagonist and the angiotensin II receptor antagonist drug substance have low solubility in water, and there is a problem that it takes time until the drug substance is administered even if the drug substance is administered.
  • cilnidipine one of the calcium antagonists
  • valsartan one of the angiotensin II receptor antagonists
  • the solubility is about 0.17 mg / mL. Therefore, the calcium antagonist preparation and the angiotensin II receptor antagonist preparation currently on the market have been devised to increase the elution rate.
  • the commercial calcium antagonist preparation and the angiotensin II receptor antagonist preparation improve the dissolution rate by different methods, respectively, both dissolution profiles should be realized with one pharmaceutical preparation (compound). Is difficult.
  • the present invention has been made in view of the above problems, and a method for producing a pharmaceutical preparation (compound) capable of realizing an elution profile close to the elution profile of each of a commercially available calcium antagonist preparation and an angiotensin II receptor antagonist preparation
  • the purpose is to provide.
  • the present invention employs the following configuration.
  • a method for producing a pharmaceutical preparation comprising a calcium antagonist and an angiotensin II receptor antagonist as active ingredients, wherein the calcium antagonist and the angiotensin II receptor antagonist are granulated together or separately without using water.
  • the manufacturing method of the pharmaceutical formulation characterized by including the granulation process to do.
  • the manufacturing method as described in said (1) using an organic solvent in the said granulation process.
  • the calcium antagonist is granulated together with the angiotensin II receptor antagonist without using water to obtain granules containing the calcium antagonist and the angiotensin II receptor antagonist (1) or The manufacturing method as described in (2).
  • the angiotensin II receptor antagonist is mixed and granulated without using water, The production method according to (3) above, wherein a granule containing a calcium antagonist and an angiotensin II receptor antagonist is obtained by granulating a calcium antagonist together with an angiotensin II receptor antagonist without using water.
  • a calcium antagonist and an angiotensin II receptor antagonist are separately granulated without using water to obtain a calcium antagonist-containing granule and an angiotensin II receptor antagonist-containing granule, (1) or the manufacturing method as described in (2).
  • the calcium antagonist comprises a 1,4-dihydropyridine derivative.
  • the 1,4-dihydropyridine derivative is at least one selected from the group consisting of cilnidipine, amlodipine, nilvadipine, nifedipine, azelnidipine, nisoldipine, nicardipine, nimodipine, nitrendipine and manidipine as described in (7) above Production method.
  • the angiotensin II receptor antagonist is at least one selected from the group consisting of valsartan, candesartan, irbesartan, losartan, telmisartan, olmesartan, irbesartan, and eprosartan.
  • the manufacturing method in any one.
  • (10) Any of the above (2) to (9), wherein the organic solvent is at least one selected from the group consisting of dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, acetone, and diethyl ether The manufacturing method as described in.
  • the pharmaceutical preparation produced by the method of the present invention can realize an elution profile close to the elution profile of each of the commercially available calcium antagonist preparation and angiotensin II receptor antagonist preparation.
  • the method for producing a pharmaceutical preparation of the present invention is a method for producing a pharmaceutical preparation comprising a calcium antagonist and an angiotensin II receptor antagonist as active ingredients, wherein the calcium antagonist and the angiotensin II receptor antagonist are added without using water. It includes a granulation step of granulating together or separately.
  • the pharmaceutical preparation obtained by the production method of the present invention preferably has at least a calcium antagonist in the form of a solid dispersion.
  • the calcium antagonist and angiotensin II receptor antagonist may be in the form of a solid dispersion.
  • the “solid dispersion” means a solid in which a drug is dispersed in a monomolecular form in an inert carrier.
  • the drug is present in the carrier in an amorphous state.
  • any polymer compound can be used without particular limitation, and examples thereof include polymer compounds such as a binder, a suspending agent, and a surfactant.
  • Suspending agents include gum arabic, xanthan gum, sodium alginate and the like.
  • the surfactant include polyoxyethylene hydrogenated castor oil, sodium lauryl sulfate, polyoxyethylene-polyoxypropylene glycol and the like.
  • the solid dispersion can be obtained, for example, by granulating using a solution in which a drug and a carrier component are dissolved in an organic solvent and then drying.
  • the production method of the present invention includes a step of granulating a calcium antagonist and an angiotensin II receptor antagonist together or separately without using water (granulation step). Therefore, in the present invention, the calcium antagonist and the angiotensin II receptor antagonist are granulated without dissolving in water. In the granulation step, it is preferable to granulate the calcium antagonist and the angiotensin II receptor antagonist together or separately using an organic solvent without using water. Furthermore, it is preferable to perform the granulation using a disintegrant together with a calcium antagonist and / or an angiotensin II receptor antagonist.
  • a fluidized bed granulator is used to convert the calcium antagonist into an angiotensin II receptor antagonist without using water.
  • the method of granulating by spraying can be mentioned.
  • the spraying is preferably performed by spraying a solution obtained by dissolving a calcium antagonist in an organic solvent onto an angiotensin II receptor antagonist.
  • the particles may be sized using a sizing machine and dried using a fluidized bed dryer.
  • the calcium antagonist is granulated without using water (preferably using an organic solvent) and calcium antagonist.
  • An example is a method in which an angiotensin II receptor antagonist is mixed and granulated without using the water after obtaining the drug-containing granule. After granulation, for example, the particles may be sized using a sizing machine and dried using a fluidized bed dryer. By the said method, the granule containing a calcium antagonist and an angiotensin II receptor antagonist can be obtained.
  • Examples of a method for granulating a mixture of an angiotensin II receptor antagonist and a calcium antagonist-containing granule include a granulation method using a dry granulator.
  • a granule containing a calcium antagonist and an angiotensin II receptor antagonist is obtained in a form in which an angiotensin II receptor antagonist is present so as to cover part or all of the granule containing a calcium antagonist. be able to.
  • a disintegrant is present both in the granule containing the calcium antagonist and on the outside of the granule.
  • the calcium antagonist is granulated without using water, and an angiotensin II receptor antagonist is separately added to water.
  • the method of granulating without using can be mentioned.
  • the particles may be sized using a sizing machine and dried using a fluidized bed dryer. According to the above method, a mixture containing calcium antagonist-containing granules and angiotensin II receptor antagonist-containing granules can be obtained.
  • a calcium antagonist is a drug that exhibits a blood pressure lowering action by suppressing the uptake of Ca 2+ into cells via ion channels and attenuating the contraction of smooth muscle.
  • the calcium antagonist used in the present invention preferably contains a 1,4-dihydropyridine derivative.
  • the 1,4-dihydropyridine derivative is preferably at least one selected from the group consisting of cilnidipine, amlodipine, nilvadipine, nifedipine, azelnidipine, nisoldipine, nicardipine, nimodipine, nitrendipine and manidipine.
  • cilnidipine (chemical name: ( ⁇ ) -2-methoxyethyl 3-phenyl-2 (E) -propenyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5 -Pyridined carbon box) is particularly preferred.
  • Silnidipine is a known compound as an L / N-type calcium antagonist that inhibits both L-type and N-type calcium channels, and can be produced by a known production method. It is also possible to obtain the formulation on the market. Furthermore, cilnidipine can be obtained from the preparation by extraction or the like.
  • the calcium antagonist may be a pharmacologically acceptable salt, hydrate, or solvate as necessary.
  • pharmacologically acceptable salts include salts with inorganic acids (hydrochlorides, hydrobromides, phosphates, sulfates, etc.), salts with organic acids (acetates, succinates, Maleate, fumarate, malate, tartrate, etc.).
  • an appropriate optically active form thereof may be used as necessary.
  • the calcium antagonist is preferably contained in an amount of 0.1 to 10% by mass, more preferably 0.5 to 5% by mass with respect to 100% by mass of the pharmaceutical preparation.
  • An angiotensin II receptor antagonist is a drug that exhibits an action of lowering blood pressure by antagonizing angiotensin II, which is a pressor substance, and preventing angiotensin II from binding to the angiotensin II receptor.
  • angiotensin II receptor antagonists include valsartan, candesartan, irbesartan, losartan, telmisartan, olmesartan, irbesartan, and eprosartan.
  • the angiotensin II receptor antagonist may be a pharmacologically acceptable salt, hydrate, or solvate as necessary.
  • pharmacologically acceptable salts include salts with inorganic acids (hydrochlorides, hydrobromides, phosphates, sulfates, etc.), salts with organic acids (acetates, succinates, Maleate, fumarate, malate, tartrate, etc.).
  • an appropriate optically active substance thereof may be used as necessary.
  • An angiotensin II receptor antagonist may be used individually by 1 type, and may be used in combination of 2 or more type.
  • the angiotensin II receptor antagonist is preferably contained in an amount of 5 to 50% by mass and more preferably 10 to 40% by mass with respect to 100% by mass of the pharmaceutical preparation.
  • the mass ratio of the calcium antagonist to the angiotensin II receptor antagonist is preferably in the range of 1: 1 to 1:32, and more preferably in the range of 1: 4 to 1:16. .
  • Organic solvent examples include dichloromethane, dichloroethane, chloroform, methanol, ethanol, propanol, isopropanol, acetone, and diethyl ether.
  • An organic solvent may be used individually by 1 type, and may be used in combination of 2 or more type.
  • the amount of the organic solvent is not particularly limited as long as the calcium antagonist or the calcium antagonist and the angiotensin II receptor antagonist can be granulated, and may be appropriately adjusted according to the granulation method.
  • ⁇ Disintegrant> In the production method of the present invention, it is preferable to use a disintegrant in the granulation step, and granulation is performed using a mixture obtained by mixing the disintegrant with a calcium antagonist and / or an angiotensin II receptor antagonist. It is more preferable. Moreover, it is preferable to perform granulation by dissolving a disintegrant in an organic solvent together with a calcium antagonist and / or an angiotensin II receptor antagonist.
  • croscarmellose sodium, low-substituted hydroxypropylcellulose, carboxymethyl starch sodium, carmellose, carmellose calcium, carmellose sodium, crospovidone, low-substituted carboxymethyl starch sodium and pregelatinized starch are preferred, More preferred are croscarmellose sodium, low-substituted hydroxypropylcellulose, carmellose, carmellose sodium, crospovidone and low-substituted carboxymethyl starch sodium, croscarmellose sodium and low-substituted hydroxypropylcellulose are more preferred, and croscarmellose. Loose sodium is particularly preferred.
  • a disintegrating agent may be used individually by 1 type, and may be used in combination of 2 or more type.
  • the disintegrant is preferably contained in an amount of 5% by mass or more based on 100% by mass of the pharmaceutical preparation, more preferably in the range of 5 to 35% by mass, and in the range of 6 to 30% by mass. Even more preferred.
  • the disintegrant is preferably contained in the range of 1 to 15% by mass, and more preferably in the range of 1 to 10% by mass.
  • the pharmaceutical preparation of the present invention may contain a binder.
  • Various binders can be used and are not particularly limited, and examples thereof include water-soluble polymers. Among these, hydroxypropylcellulose, hypromellose phthalate, methylcellulose, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, cellulose acetate phthalate, hydroxypropylcellulose, Hypromellose phthalate is more preferred.
  • the binder is preferably contained in an amount of 1 to 90% by mass, more preferably 3 to 40% by mass, and even more preferably 5 to 20% by mass with respect to 100% by mass of the pharmaceutical preparation.
  • the binder When a binder is used, the binder is preferably contained in a granule containing a calcium antagonist.
  • a lubricant, an excipient, a fluidizing agent and the like may be added to the calcium antagonist and / or the angiotensin II receptor antagonist.
  • excipients can be used, and are not particularly limited.
  • sugars such as lactose hydrate, sucrose, glucose, reduced maltose, mannitol, sorbitol, corn starch
  • examples include potato starch, partially pregelatinized starch, starches such as dextrin and pullulan and derivatives thereof, celluloses such as crystalline cellulose and microcrystalline cellulose, macrogol, and one or a mixture of two or more of magnesium aluminate metasilicate.
  • lactose hydrate, mannitol, partially pregelatinized starch, and crystalline cellulose are preferable, and lactose hydrate and crystalline cellulose are more preferable.
  • One type of excipient may be used alone, or two or more types may be used in combination.
  • the excipient is preferably contained in an amount of 1 to 40% by mass, more preferably 1 to 30% by mass, relative to 100% by mass of the pharmaceutical preparation.
  • the manufacturing method of the pharmaceutical formulation of this invention may include the process of compression-molding the granule obtained at the granulation process.
  • the compression molding may be performed using a known method.
  • magnesium stearate, talc, stearic acid, calcium stearate or magnesium carbonate may be added and mixed, and compression molding may be performed with a tableting machine.
  • the shape of the tablet obtained by compression molding is not particularly limited. For example, round shape, oval shape (any oval shape except for a perfect circle: oval shape, oval shape, oval barrel shape, oval shape, etc.), rhombus, triangle, etc. .
  • the shape of the dividing line may be any of a flat groove type, a U-shaped groove type, and a V-shaped groove type.
  • the tablet is elliptical, it is preferably formed along the minor axis.
  • the method for producing a pharmaceutical preparation of the present invention may further include a step of performing a coating treatment after the compression molding step.
  • the coating agent used for the coating treatment include hypromellose and tuna gogol 6000.
  • a conventionally known method may be used.
  • a coating solution obtained by dissolving a coating agent in a solvent such as water is used as a pharmaceutical preparation using a pan coding device, a drum type coating device, a fluid coating device, or the like. What is necessary is just to coat the surface.
  • coloring agents such as yellow ferric oxide, ferric oxide, black iron oxide, titanium oxide, edible blue No. 1, edible yellow No. 4, and edible red No. 2 may be added to the coating liquid. Good. By adding these colorants, the photostability of the calcium antagonist can be improved.
  • the pharmaceutical preparation obtained by the method of the present invention is preferably a solid preparation, more preferably in the form of a tablet, capsule, fine granule or granule, and particularly preferably in the form of a tablet.
  • the dissolution test based on the paddle method it is preferable that 75% by mass or more of the angiotensin II receptor antagonist is dissolved in water 15 minutes after the start of the test. Similarly, in the dissolution test based on the paddle method, it is preferable that 85% by mass or more of the angiotensin II receptor antagonist is dissolved in water 30 minutes after the start of the test.
  • the dissolution rate is within the above range, dissolution profiles close to the dissolution profiles of the commercially available calcium antagonist preparation and angiotensin II receptor antagonist preparation can be achieved. Therefore, it is possible to obtain a pharmaceutical preparation (combination agent) that exhibits the same effect as when two kinds of preparations are administered in combination.
  • the pharmaceutical preparation obtained by the production method of the present invention has an antihypertensive action, it is useful as an antihypertensive agent for treating hypertensive patients.
  • Examples of the administration target of the pharmaceutical preparation obtained by the production method of the present invention include mammals such as mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, and humans. In particular, humans are preferable as administration subjects.
  • Example 1 Magnesium aluminate metasilicate (22.4 kg), crystalline cellulose (6.41 kg), lactose hydrate (4.86 kg) and croscarmellose sodium (5.10 kg) were placed in a stirring granulator and mixed. Thereafter, a binder solution in which cilnidipine (2.04 kg), macrogol 400 (1.43 kg) and hydroxypropylcellulose (8.16 kg) are dissolved in methanol (28.3 kg) and dichloromethane (8.5 kg) is added and granulated. did. After granulation, the mixture was sized (screen: 1.6 mm) with a sizing machine (Comil) and dried for 90 minutes at an exhaust temperature of 60 ° C.
  • Comil a sizing machine
  • the above cilnidipine granules (2966.4 g), valsartan (969.6 kg), crystalline cellulose (936 g), croscarmellose sodium (960 g), hydrous silicon dioxide (96 g) and magnesium stearate (24 g) Mix for 20 minutes to obtain a mixed powder.
  • the obtained mixed powder is made into flakes by dry granulation (roll pressure: 6 Mpa), sized (screen: 1.6 mm) with a sizing machine (Comil), and granulates containing cilnidipine / valsartan with the formulation shown in Table 2 are obtained. Obtained.
  • Magnesium stearate was added to and mixed with the silnidipine / valsartan blended granule obtained above so as to have the formulation shown in Table 3, and the tablets having the formulation shown in Table 3 were obtained by compression molding with a tableting machine. .
  • Valsartan (400 g), crystalline cellulose (340 g) and croscarmellose sodium (400 g) are put into a fluid bed granulator, and a combined solution in which hydroxypropyl cellulose (100 g) is dissolved in methanol (280 g) and dichloromethane (1120 g) is sprayed. (Spray speed 70 g / mL, exhaust temperature 30 ° C.) to obtain valsartan granules having the formulation shown in Table 4.
  • the valsartan granule obtained above, the cilnidipine granule obtained in Example 1 and magnesium stearate were added and mixed so as to have the formulation shown in Table 5, and compression-molded with a tableting machine to show in Table 5.
  • a prescription tablet was obtained.
  • Valsartan (200 g), crystalline cellulose (550 g), croscarmellose sodium (275 g), lactose hydrate (90 g) were placed in a fluidized bed granulator, cilnidipine (25 g) in methanol (1120 g) and dichloromethane (280 g), A binding solution in which hydroxypropylcellulose (100 g) was dissolved was sprayed (spray rate 70 g / mL, exhaust temperature 30 ° C.) to obtain granules containing cilnidipine / valsartan having the formulation shown in Table 6.
  • Tablets with the formulation shown in Table 7 were obtained by adding and mixing magnesium stearate to the granildipine / valsartan combination granule obtained above so as to have the formulation shown in Table 7 and compression molding with a tableting machine.
  • Table 8 shows valsartan (40 g), cilnidipine (5 g), crystalline cellulose (123 g), croscarmellose sodium (80 g) and magnesium stearate (2 g) added and mixed, and compression molded with a tableting machine. A prescription tablet was obtained. (The ratio of cilnidipine contained in the tablet: 2.0%, the ratio of valsartan: 16.0%, the total disintegrant: 32.0%) For valsartan, a drug substance having a particle diameter D90 of 20 ⁇ m or less was used.
  • Valsartan (484.8 g), crystalline cellulose (378 g), croscarmellose sodium (480 g) and hydroxypropylcellulose (150 g) were placed in a stirring granulator, and water (2100 g) was added for granulation. After granulation, it is sized (screen: 1.6 mm) with a sizing machine (Comil) and dried for 45 minutes at an exhaust temperature of 60 ° C. or less using a fluidized bed dryer to obtain valsartan granules with the formulation shown in Table 9. It was.
  • the valsartan granule obtained above, the cilnidipine granule obtained in Example 1 and magnesium stearate were added and mixed so as to have the formulation shown in Table 9, and compression-molded with a tableting machine and shown in Table 10 A prescription tablet was obtained.
  • Example 1 The particle size of valsartan in the tablets of Examples 1 to 3 and Comparative Examples 1 to 3 was measured.
  • 50 mg of valsartan was dispersed in a dispersion solution (silicon oil: n-heptane containing 0.2% span 85/60: 40 v / v), and then the particle size was measured using Malvern Particle size analyzer. D90 was calculated.
  • Test Example 3 About the dissolution test of valsartan, according to the dissolution test method (paddle method) described in the 16th revised Japanese Pharmacopoeia section, the test was performed using 50 mL per minute and 900 mL of water as a test solution. Test solutions 15 and 30 minutes after the start of the test were collected and tested by liquid chromatography to calculate the elution rate of cilnidipine. For Examples 1 and 2 and Comparative Example 1, one tablet was used, and for Example 3 and Comparative Example 2, two tablets were used.
  • Test Example 4 For the dissolution test of cilnidipine, in accordance with the dissolution test method (paddle method) described in the 16th revised Japanese Pharmacopoeia section, dissolution at 50 rpm, 0.1 w / v% polysorbate 80 was added as a test solution. The test was conducted using 900 mL of the second test liquid. Test solutions 7 and 90 minutes after the start of the test were collected and tested by liquid chromatography to calculate the elution rate of cilnidipine. For Examples 1 and 2 and Comparative Example 1, one tablet was used, and for Example 3 and Comparative Example 2, two tablets were used.
  • the dissolution rate of the tablets prepared in Examples 1 to 3 and Comparative Examples 1 to 3 was confirmed according to Test Examples 3 and 4. The results are listed in Table 12.
  • the dissolution rate of Atelec (registered trademark) tablets, which are commercial formulations of cilnidipine, and Dioban (registered trademark) tablets, which are commercial formulations of valsartan is the reference value. What satisfy
  • the pharmaceutical preparation produced by the method of the present invention can increase the elution rate of the calcium antagonist, and can realize elution profiles close to the elution profiles of the commercially available calcium antagonist preparation and angiotensin II receptor antagonist preparation, respectively. Therefore, it is very useful industrially.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un procédé de production d'une préparation pharmaceutique contenant un inhibiteur calcique et un antagoniste de récepteur d'angiotensine II en tant que composants actifs, ledit procédé étant caractérisé en ce qu'il comprend une étape de granulation consistant à granuler l'antagoniste du calcium et l'antagoniste du récepteur de l'angiotensine II conjointement ou séparément, sans utiliser d'eau. Une préparation pharmaceutique produite par le procédé peut avoir un profil d'élution proche du profil d'élution d'une préparation d'inhibiteur calcique disponible dans le commerce et du profil d'élution d'une préparation d'antagoniste de récepteur d'angiotensine II disponible dans le commerce.
PCT/JP2013/077730 2012-10-12 2013-10-11 Procédé de production de préparation pharmaceutique contenant un inhibiteur calcique / antagoniste du récepteur d'angiotensine ii WO2014058047A1 (fr)

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JP2014540903A JP5790965B2 (ja) 2012-10-12 2013-10-11 カルシウム拮抗薬／アンジオテンシンｉｉ受容体拮抗薬含有医薬製剤の製造方法
KR1020167023724A KR101931489B1 (ko) 2012-10-12 2013-10-11 칼슘 길항약／안지오텐신 ｉｉ 수용체 길항약 함유 의약 제제의 제조 방법
KR1020157012315A KR101778050B1 (ko) 2012-10-12 2013-10-11 칼슘 길항약／안지오텐신 ｉｉ 수용체 길항약 함유 의약 제제의 제조 방법

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JP2012-226984 2012-10-12
JP2012226984 2012-10-12

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015007116A (ja) * 2012-10-12 2015-01-15 味の素株式会社 カルシウム拮抗薬／アンジオテンシンｉｉ受容体拮抗薬含有医薬製剤
JP2021192797A (ja) * 2015-11-30 2021-12-23 大原薬品工業株式会社 医薬品包装箱を利用した、配合錠の両面印字情報の提供方法

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6843498B2 (ja) * 2015-10-14 2021-03-17 Ｅａファーマ株式会社 錠剤、固体分散体顆粒及びその製造方法
JP2017210435A (ja) * 2016-05-25 2017-11-30 ダイト株式会社 イルベサルタン及びアムロジピンベシル酸塩配合錠の製造方法
KR101769293B1 (ko) * 2016-09-30 2017-08-30 주식회사 종근당 칸데사르탄 및 암로디핀을 포함하는 단일층으로 이루어진 복합제

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0892071A (ja) * 1994-09-27 1996-04-09 Morishita Roussel Kk 重炭酸透析用剤
JPH10504295A (ja) * 1994-08-17 1998-04-28 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー 医薬処方
JP2004002348A (ja) * 2002-03-27 2004-01-08 Bayer Yakuhin Ltd 小型化されたニフェジピン有核錠剤
JP2008044871A (ja) * 2006-08-11 2008-02-28 Ajinomoto Co Inc 心血管疾患予防・治療剤
JP2009504744A (ja) * 2005-08-17 2009-02-05 ノバルティス アクチエンゲゼルシャフト バルサルタンとアムロジピンの固体投与形態およびその製造方法
JP2009542709A (ja) * 2006-06-27 2009-12-03 ノバルティス アクチエンゲゼルシャフト バルサルタン、アムロジピンおよびヒドロクロロチアジドの固体投与量剤形およびその製造法
WO2010137855A2 (fr) * 2009-05-27 2010-12-02 Dasan Medichem Co., Ltd. Comprimé multicouches comprenant une couche effervescente
JP2011500505A (ja) * 2006-09-15 2011-01-06 第一三共株式会社 オルメサルタンメドキソミル及びアムロジピンの固形製剤
JP2012509918A (ja) * 2008-11-27 2012-04-26 バイエル・ファルマ・アクチェンゲゼルシャフト ニフェジピンまたはニソルジピンおよびアンジオテンシンｉｉアンタゴニストおよび／または利尿剤を含む医薬投与形

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100530546B1 (ko) * 2001-07-27 2005-11-23 아스텔라스세이야쿠 가부시키가이샤 구강내에서 신속하게 붕괴되는 정제용 서방성 미립자가함유된 조성물 및 그의 제조 방법
ES2404939T3 (es) * 2005-06-27 2013-05-29 Daiichi Sankyo Company, Limited Preparación farmacéutica que contiene un antagonista del receptor de la angiotensina II y un bloqueador de los canales de calcio
WO2007001065A2 (fr) * 2005-06-27 2007-01-04 Daiichi Sankyo Company, Limited Methode pour preparer un produit medicamenteux se presentant sous forme de granules humides
WO2008016171A1 (fr) * 2006-08-04 2008-02-07 Ajinomoto Co., Inc. Agent prophylactique/thérapeutique destiné à un dysfonctionnement rénal
KR20100016093A (ko) * 2007-03-30 2010-02-12 아지노모토 가부시키가이샤 고체 분산체 제제

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10504295A (ja) * 1994-08-17 1998-04-28 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー 医薬処方
JPH0892071A (ja) * 1994-09-27 1996-04-09 Morishita Roussel Kk 重炭酸透析用剤
JP2004002348A (ja) * 2002-03-27 2004-01-08 Bayer Yakuhin Ltd 小型化されたニフェジピン有核錠剤
JP2009504744A (ja) * 2005-08-17 2009-02-05 ノバルティス アクチエンゲゼルシャフト バルサルタンとアムロジピンの固体投与形態およびその製造方法
JP2009542709A (ja) * 2006-06-27 2009-12-03 ノバルティス アクチエンゲゼルシャフト バルサルタン、アムロジピンおよびヒドロクロロチアジドの固体投与量剤形およびその製造法
JP2008044871A (ja) * 2006-08-11 2008-02-28 Ajinomoto Co Inc 心血管疾患予防・治療剤
JP2011500505A (ja) * 2006-09-15 2011-01-06 第一三共株式会社 オルメサルタンメドキソミル及びアムロジピンの固形製剤
JP2012509918A (ja) * 2008-11-27 2012-04-26 バイエル・ファルマ・アクチェンゲゼルシャフト ニフェジピンまたはニソルジピンおよびアンジオテンシンｉｉアンタゴニストおよび／または利尿剤を含む医薬投与形
WO2010137855A2 (fr) * 2009-05-27 2010-12-02 Dasan Medichem Co., Ltd. Comprimé multicouches comprenant une couche effervescente

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015007116A (ja) * 2012-10-12 2015-01-15 味の素株式会社 カルシウム拮抗薬／アンジオテンシンｉｉ受容体拮抗薬含有医薬製剤
JP2021192797A (ja) * 2015-11-30 2021-12-23 大原薬品工業株式会社 医薬品包装箱を利用した、配合錠の両面印字情報の提供方法
JP7334218B2 (ja) 2015-11-30 2023-08-28 大原薬品工業株式会社 医薬品包装箱を利用した、配合錠の両面印字情報の提供方法

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KR20160105543A (ko) 2016-09-06
JP5790965B2 (ja) 2015-10-07
KR20150065887A (ko) 2015-06-15
KR101931489B1 (ko) 2018-12-24
KR101778050B1 (ko) 2017-09-13
JP2015003915A (ja) 2015-01-08
JP6302802B2 (ja) 2018-03-28
TW201427720A (zh) 2014-07-16
JPWO2014058047A1 (ja) 2016-09-05

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