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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• • 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
  • A61K47/38—Cellulose; Derivatives thereof
• • 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
  • A61K31/41—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
  • A61K31/4164—1,3-Diazoles
  • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• • 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
  • A61K31/4164—1,3-Diazoles
  • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
• • 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
  • 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
  • A61K47/02—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
  • A61K9/14—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
• • 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
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
• • 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 pharmaceutical preparation comprising 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 drugs lack the storage stability, and calcium antagonists have the problem that the degradation of light proceeds with time.
• angiotensin II receptor antagonists have a problem that the elution rate is extremely reduced when stored under high temperature conditions. Therefore, the calcium antagonist preparation is required to be stored under light-shielding conditions, and the angiotensin II receptor antagonist preparation is required to be stored with attention to temperature.
• both drugs are simply used in combination, the above disadvantages are not a significant problem because both drugs need to be stored separately in different ways.
• both drugs since both drugs cannot be stored separately, the problem cannot be solved like a concomitant drug. Therefore, it must always be stored with attention to both temperature and light.
• both the calcium antagonist and the angiotensin II receptor antagonist drug substance have low water solubility, and there is a problem that it takes time until the drug substance is administered even if the drug substance is administered.
• cilnidipine which is one of calcium antagonists
• valsartan which is one of angiotensin II receptor antagonists
• the calcium antagonist preparation and the angiotensin II receptor antagonist preparation currently on the market have been devised to increase the elution rate.
• 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 an object of the present invention is to provide a pharmaceutical preparation in which the storage stability of an angiotensin II receptor antagonist is enhanced, thereby reducing the storage conditions. Furthermore, it aims at providing the pharmaceutical formulation (formulation) which can implement
• the present invention employs the following configuration.
• a disintegrating agent is present so as to cover a part or all of the granules together with the angiotensin II receptor antagonist.
• the disintegrant is at least one selected from the group consisting of croscarmellose sodium, croscarmellose calcium, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, crospovidone and pregelatinized starch
• the calcium antagonist is at least one selected from the group consisting of cilnidipine, amlodipine, nilvadipine, nifedipine, azelnidipine, nisoldipine, nicardipine, nimodipine, nitrendipine and manidipine.
• the pharmaceutical formulation in any one.
• 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 pharmaceutical formulation in any one of.
• Formulation. (12) The pharmaceutical preparation according to the above (11), wherein the ratio of the colorant is in the range of 0.1 to 5 parts by mass with respect to 100 parts by mass of the coating film.
• the pharmaceutical preparation of the present invention can improve the storage stability of an angiotensin II receptor antagonist. Moreover, this pharmaceutical formulation can implement
• the pharmaceutical preparation of the present invention comprises a calcium antagonist and angiotensin II receptor antagonist as active ingredients and 5% by mass or more of a disintegrant, and at least the calcium antagonist is in the form of a solid dispersion.
• the pharmaceutical preparation of the present invention preferably contains a granule containing a calcium antagonist and an angiotensin II receptor antagonist, and an angiotensin II receptor antagonist so as to cover part or all of the granule containing a calcium antagonist. More preferably the drug is present.
• Such pharmaceutical preparations include, for example, granules, fine granules, and one or more calcium antagonist-containing granules and an angiotensin II receptor antagonist, which are surrounded by an angiotensin II receptor antagonist.
• Tablets obtained by tableting a mixture with the angiotensin II receptor antagonist is present so as to cover a part or all of the granule containing the calcium antagonist, and at least the calcium antagonist is in the form of a solid dispersion.
• An angiotensin II receptor antagonist together with the calcium 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. Within the solid dispersion, the drug is present in the carrier in an amorphous state.
• the inert carrier 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. Examples of 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.
• Calcium antagonists are drugs that have a blood pressure lowering action by suppressing the uptake of Ca 2+ into cells via ion channels and attenuating smooth muscle contraction.
• the calcium antagonist used in the present invention is preferably a 1,4-dihydropyridine derivative, and is at least one selected from the group consisting of cilnidipine, amlodipine, nilvadipine, nifedipine, azelnidipine, nisoldipine, nicardipine, nimodipine, nitrendipine and manidipine. More preferably.
• 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.
• 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.
• Examples of 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.
• the angiotensin II receptor antagonist include valsartan, candesartan, losartan, telmisartan, olmesartan, irbesartan, eprosartan, and the like.
• 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. .
• the disintegrant means an additive that gets wet when taken or put in water, and disintegrates the preparation.
• croscarmellose sodium, croscarmellose calcium, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, crospovidone and pregelatinized starch are preferable, croscarmellose sodium, low Substituted hydroxypropylcellulose, sodium carboxymethyl starch and crospovidone are more preferred, croscarmellose sodium, low substituted hydroxypropylcellulose are even more preferred, and croscarmellose 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 contained in a total of 5% by mass or more with respect to 100% by mass of the pharmaceutical preparation, preferably 5 to 35% by mass, and more preferably 6 to 30% by mass.
• the disintegrant is preferably included in the granule together with the calcium antagonist. Moreover, it is preferable that a disintegrating agent exists so that a part or all of the said granule may be covered with an angiotensin II receptor antagonist.
• the disintegrant contained in the granule containing the calcium antagonist (first disintegrant) and the disintegrant present along with the angiotensin II receptor antagonist (second disintegrant) were the same disintegrant.
• different types of disintegrants may be used. Only one of the first disintegrant and the second disintegrant may be included in the pharmaceutical preparation, but both the first disintegrant and the second disintegrant are included in the pharmaceutical preparation. Preferably it is.
• the first disintegrant is preferably contained in an amount of 1 to 15% by mass, more preferably 1 to 10% by mass with respect to 100% by mass of the pharmaceutical preparation.
• the second disintegrant is preferably contained in an amount of 1 to 30% by mass and more preferably 2 to 25% by mass with respect to 100% by mass of the pharmaceutical preparation.
• 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. When a binder is used, the binder is preferably contained in a granule containing a calcium antagonist.
• the pharmaceutical preparation of the present invention may contain a lubricant.
• Various lubricants can be used, and are not particularly limited. Examples thereof include magnesium stearate, stearic acid, calcium stearate, and magnesium carbonate.
• the lubricant is preferably contained in an amount of 0.5 to 2% by mass relative to 100% by mass of the pharmaceutical preparation.
• the lubricant is preferably present so as to cover part or all of the granule together with the angiotensin II receptor antagonist.
• the pharmaceutical preparation of the present invention may contain an excipient.
• excipients can be used, and are not particularly limited.
• sugars such as lactose hydrate, sucrose, glucose, reduced maltose, mannitol, sorbitol, corn starch, potato starch, Examples thereof include starches such as partially pregelatinized starch, 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 (first excipient) contained in the granule containing the calcium antagonist and the angiotensin II receptor antagonist are covered with a part or all of the granule.
• the excipient (second excipient) present in this manner may be the same or different. Only one of the first excipient and the second excipient may be contained in the pharmaceutical preparation.
• the first excipient is preferably contained in an amount of 1 to 40% by mass, more preferably 1 to 30% by mass with respect to 100% by mass of the pharmaceutical preparation.
• the second excipient is preferably contained in an amount of 1 to 40% by mass, more preferably 5 to 30% by mass with respect to 100% by mass of the pharmaceutical preparation.
• the pharmaceutical preparation of the present invention may contain a fluidizing agent.
• Various fluidizing agents can be used, and are not particularly limited. Examples thereof include hydrous silicon dioxide, light silicic anhydride, and talc. Of these, hydrous silicon dioxide is more preferable.
• the fluidizing agent is preferably contained in an amount of 1 to 10% by mass, more preferably 1 to 5% by mass with respect to 100% by mass of the pharmaceutical preparation. When a fluidizing agent is used, the fluidizing agent is preferably present so as to cover part or all of the granule together with the angiotensin II receptor antagonist.
• the pharmaceutical formulation of this invention has a coating film on the surface.
• the mass ratio of the coating film may be adjusted according to the purpose, but is preferably 1 to 10% by mass, more preferably 3 to 8% by mass with respect to 100% by mass of the pharmaceutical preparation.
• the coating film can be formed on the surface of a pharmaceutical preparation, for example, by applying a coating solution obtained by dissolving a coating agent in water using a pan coding device, a drum type coating device, a fluid coating device, or the like.
• a coating solution obtained by dissolving a coating agent in water using a pan coding device, a drum type coating device, a fluid coating device, or the like.
• the coating agent include hypromellose and tuna gogol 6000.
• the coating film preferably contains an iron oxide-based colorant such as yellow iron sesquioxide, iron sesquioxide, and black iron oxide.
• the said coloring agent may be used individually by 1 type, and may be used in combination of 2 or more type.
• the colorant is preferably contained in a proportion of 0.1 to 5 parts by mass, more preferably 0.25 to 1 part by mass with respect to 100 parts by mass of the coating film.
• the coating film may further contain other colorant such as titanium oxide in addition to the iron oxide colorant.
• titanium oxide is included, the titanium oxide is preferably included in an amount of 5 to 25 parts by mass, and more preferably 10 to 20 parts by mass with respect to 100 parts by mass of the coating film.
• the pharmaceutical preparation 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 shape of the tablet is not particularly limited, and examples thereof include a round shape, an oval shape (any oval shape except for a perfect circle: an oval shape, an oval shape, an oval shape, an oval shape, etc.), a rhombus, a triangle, and the like.
• 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 pharmaceutical preparation of the present invention is preferably such that 48 to 78% by mass of the calcium antagonist is dissolved in water 15 minutes after the start of the test. Similarly, in a dissolution test based on the paddle method, it is preferable that 75% by mass or more of the calcium antagonist is dissolved in water 90 minutes after the start of the test. Further, in 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.
• dissolution rate When 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 formulation of this invention can be manufactured by a conventionally well-known method in the said field
• it can be produced by a dry granulation method, a wet granulation method, a direct tableting method or the like. More specifically, for example, it is manufactured by granulating a calcium antagonist, mixing an angiotensin II receptor antagonist into the obtained granule containing granule, granulating by dry granulation method, and then tableting can do.
• the pharmaceutical preparation 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 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 The silnidipine granules shown in Table 1 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol).
• the uncoated tablets obtained above were coated with the formulation shown in Table 3 using a pan-type coating machine to obtain film-coated tablets.
• Example 2 The silnidipine granules shown in Table 1 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol). By mixing the ingredients shown in Table 4 into the obtained cilnidipine granules, dry granulation, sizing, and tableting, an uncoated tablet of the cilnidipine / valsartan compound was obtained (disintegrant addition amount: 52.5 mg / tablet, 21% per uncoated tablet). The obtained uncoated tablets were coated with the formulation shown in Table 3 using a pan-type coating machine to obtain film-coated tablets.
• an organic solvent diichloromethane and methanol
• Example 3 The silnidipine granules shown in Table 1 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol). By mixing the ingredients shown in Table 5 into the obtained cilnidipine granules, dry granulation, sizing, and tableting, an uncoated tablet of the cilnidipine / valsartan compound was obtained (disintegrant addition amount: 12.5 mg / tablet, 29% per uncoated tablet). The obtained uncoated tablets were coated with the formulation shown in Table 3 using a pan-type coating machine to obtain film-coated tablets.
• Test Example 1 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 dissolution rate of valsartan.
• Test Example 2 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 15 and 90 minutes after the start of the test were collected and tested by liquid chromatography to calculate the elution rate of cilnidipine.
• Test Example 3 The sample was stored for one month in an airtight state at a temperature of 60 ° C., and the dissolution rate was calculated according to Test Example 1.
• the dissolution rate (%) of Examples 1 to 3 and Comparative Example 1 was calculated according to Test Examples 1 and 2.
• the target values were set in consideration of the dissolution rate of Atelec (registered trademark) tablets, which are commercial preparations of cilnidipine, and Dioban (registered trademark) tablets, which are commercial preparations of valsartan, and the dissolution rates of cilnidipine and valsartan are all target values. Those satisfying the criteria were evaluated as ⁇ , and those not satisfying at least one were evaluated as ⁇ .
• both cilnidipine and valsartan showed target dissolution rates, confirming that they were preparations having the target dissolution rate.
• Comparative Example 1 was not a preparation having a target dissolution rate without showing a target dissolution rate.
• Example 1 The stability was confirmed according to Test Example 3 using Example 1, Example 2, and Diovan Tablets 40 mg (commercially available product). As a result, the preparations of the formulations of Example 1 and Example 2 maintained a high dissolution rate even after storage.
• Example 4 The silnidipine granules shown in Table 10 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol).
• the uncoated tablets obtained above were coated with the formulation shown in Table 12 using a pan-type coating machine to obtain film-coated tablets.
• the proportion of cilnidipine contained in the tablet 1.9%, the proportion of valsartan: 15.2%, the proportion of the first disintegrant: 4.8%, the proportion of the second disintegrant: 7.6% ( Disintegrant total: 12.4%).
• Example 5 The silnidipine granules shown in Table 14 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol).
• the uncoated tablets obtained above were coated with the formulation shown in Table 16 using a pan-type coating machine to obtain film-coated tablets.
• the proportion of cilnidipine contained in the tablet 1.9%, the proportion of valsartan: 15.5%, the proportion of the first disintegrant: 4.8%, the proportion of the second disintegrant: 15.4% ( Disintegrant total: 20.2%).
• Example 6 The silnidipine granules shown in Table 14 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol). The obtained cilnidipine granules were mixed with the components shown in Table 15, dry granulation, sizing, and tableting to obtain plain tablets of the cilnidipine / valsartan compound. The obtained uncoated tablets were coated with the formulation shown in Table 17 using a pan-type coating machine to obtain film-coated tablets.
• the proportion of cilnidipine contained in the tablet 1.9%, the proportion of valsartan: 15.5%, the proportion of the first disintegrant: 4.8%, the proportion of the second disintegrant: 15.4% ( Disintegrant total: 20.2%).
• Example 7 The silnidipine granules shown in Table 14 were obtained by stirring granulation using an organic solvent (dichloromethane and methanol). The ingredients shown in Table 15 were mixed into the obtained cilnidipine granules, dry granulation, sizing and tableting to obtain plain tablets of the cilnidipine / valsartan compounding agent. The obtained uncoated tablets were coated with the formulation shown in Table 18 using a pan-type coating machine to obtain film-coated tablets.
• the proportion of cilnidipine contained in the tablet 1.9%, the proportion of valsartan: 15.5%, the proportion of the first disintegrant: 4.8%, the proportion of the second disintegrant: 15.4% ( Disintegrant total: 20.2%).
• the proportion of cilnidipine contained in the tablet 1.9%, the proportion of valsartan: 15.5%, the proportion of the first disintegrant: 4.8%, the proportion of the second disintegrant: 15.4% ( Disintegrant total: 20.2%).
• the pharmaceutical preparation of the present invention can improve the storage stability of an angiotensin II receptor antagonist. Moreover, this pharmaceutical formulation can implement

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