Classifications

• • 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
  • A61K9/20—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
  • 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
  • A61K31/435—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
• • 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
  • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• • 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
  • 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
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• • 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
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
• • 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
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • 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
  • A61K9/2004—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
  • 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
• • 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 composition containing olmesartan medoxomil and amlodipine.
• Angiotensin II receptor antagonists and calcium channel antagonists are presently widely used as drugs to treat or prevent hypertension, heart disease, or the like.
• Angiotensin II receptor antagonists which are renin-angiotensin inhibitors, are particularly effective against renin-dependent hypertension, and they demonstrate a protective action against cardiovascular or renal damage.
• Calcium channel antagonists have a natriuretic action in addition to a vasodilating action, and they are also effective against body fluid retention (renin-independent) hypertension.
• an angiotensin II receptor antagonist and a calcium channel antagonist would yield a calcium channel antagonist action and a secondary natriuretic action in vascular smooth muscles due to the calcium channel antagonist in addition to the inhibitory effect on the renin-angiotensin system due to the angiotensin II receptor antagonist, which would make it possible to inhibit multiple hypertension factors simultaneously, and that this combination would demonstrate stable and sufficient therapeutic or preventative effects against hypertension, regardless of the cause of the disease.
• Thiazide diuretics are also widely used as drugs to treat or prevent hypertension, heart disease, or the like. Their diuretic effect makes thiazide diuretics effective for the treatment of hypertension. It is therefore expected that the combined use of an angiotensin II receptor antagonist and a thiazide diuretic would make it possible to inhibit multiple hypertension factors simultaneously due to the diuretic action of the thiazide diuretic in addition to the inhibitory effect on the renin-angiotensin system due to the angiotensin II receptor antagonist, and that this combination would demonstrate stable and sufficient therapeutic or preventative effects against hypertension, regardless of the cause of the disease.
• Olmesartan medoxomil is marketed as Olmetec (registered trademark) tablets or Benicar(R), and these contain 5 mg, 10 mg, 20 mg, or 40 mg of olmesartan medoxomil as active ingredient and low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, lactose, and magnesium stearate as excipients.
• amlodipine 3-Ethyl-5-methyl-( ⁇ )-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate (called amlodipine hereinafter) is a well-known compound which is an excellent calcium channel antagonist and is useful as a drug for treating or preventing hypertension, heart disease, and the like.
• Amlodipine is marketed as Norvasc (registered trademark) tablets, and it contains 3.47 mg or 6.93 mg of amlodipine besylate as active ingredient (2.5 mg or 5 mg of amlodipine) and microcrystalline cellulose, anhydrous calcium hydrogen phosphate, carboxymethyl starch sodium, magnesium stearate, hypromellose, titanium oxide, talc, and carnauba wax as excipients.
• hydrochlorothiazide 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide
• Drugs which combine olmesartan medoxomil and amlodipine (pamphlet of International Patent Publication WO 2004/067003) and drugs which combine olmesartan medoxomil and hydrochlorothiazide (pamphlet of International Patent Publication WO 2002/041890) are known in the prior art, but there is no known solid dosage form such as that of the present invention containing olmesartan medoxomil and amlodipine having improved dissolution properties as a result of the further inclusion of excipients containing calcium.
• solid dosage form such as that of the present invention containing olmesartan medoxomil, amlodipine and hydrochlorothiazide having improved dissolution properties as a result of the further inclusion of excipients containing calcium.
• Patent Document 1 Japanese Patent 2082519 (U.S. Pat. No. 5,616,599)
• Patent Document 2 Japanese Patent 1401088 (U.S. Pat. No. 4,572,909)
• Patent Document 3 U.S. Pat. No. 3,025,292
• Patent Document 4 Pamphlet of International Patent Publication WO 2004/067003
• Patent Document 5 Pamphlet of International Patent Publication WO 2002/041890
• the problem of the present invention is to provide a pharmaceutical composition with improved dissolution properties containing (A) olmesartan medoxomil and (B) amlodipine as active ingredients and (C) a calcium-containing excipient.
• olmesartan medoxomil which is an angiotensin II receptor antagonist
• amlodipine which is a calcium channel antagonist
• the present invention provides a pharmaceutical composition (in particular, a composition for preventing or treating hypertension) containing (A) olmesartan medoxomil and (B) amlodipine as active ingredients and (C) a calcium-containing excipient; a method of using olmesartan medoxomil and amlodipine to produce the pharmaceutical composition described above (in particular, a composition for preventing or treating hypertension); a method of preventing or treating diseases (hypertension, in particular) by administering the above pharmaceutical composition containing pharmacologically effective doses of olmesartan medoxomil and amlodipine to warm-blooded animals (humans, in particular); and a method of improving the dissolution properties of a pharmaceutical composition (in particular, a composition for treating or preventing hypertension) containing olmesartan medoxomil and amlodipine by including a calcium-containing excipient.
• the pharmaceutical composition described above may also include hydrochlorothiazide as an
• the present invention provides:
• composition containing (A) olmesartan medoxomil and (B) amlodipine as active ingredients and (C) a calcium-containing excipient;
• component (C) is one or more types of compounds selected from carmellose calcium, calcium silicate, calcium hydrogen phosphate, calcium carbonate, calcium sulfate dihydrate, calcium ascorbate, calcium chloride, and calcium stearate;
• component (C) is carmellose calcium
• (6) a pharmaceutical composition according to (4), wherein the drug product is a powder, fine granules, a granule, a capsule, or a tablet;
• the active ingredients of the pharmaceutical composition of the present invention are olmesartan medoxomil and amlodipine. Hydrochlorothiazide may also be added as an active ingredient of the pharmaceutical composition of the present invention.
• Olmesartan medoxomil which is one of the active ingredients of the pharmaceutical composition of the present invention, can easily be manufactured in accordance with the method described in Japanese Patent 2082519 (U.S. Pat. No. 5,616,599) or the like.
• Amlodipine which is another active ingredient of the pharmaceutical composition of the present invention, can easily be manufactured in accordance with the method described in Japanese Patent 1401088 (U.S. Pat. No. 4,572,909) or the like.
• Amlodipine can form pharmacologically acceptable salts, and these salts are also included in the present invention.
• the pharmacologically acceptable salts may be either acid-addition salts or base-addition salts. Examples include besylate, hydrochlorides, hydrobromides, fumarates, citrates, tartrates, maleates, camsilates, lactates, mesylates, nicotinates, and gluconates, and although the present invention is not limited to these, besylates are preferred.
• Hydrochlorothiazide which is another active ingredient of the pharmaceutical composition of the present invention, can easily be manufactured in accordance with the method described in U.S. Pat. No. 3,025,292.
• Hydrochlorothiazide includes pharmacologically acceptable salts, examples of which include hydrohalic acid salts such as hydrofluorides, hydrochlorides, hydrobromides, and hydriodides; nitrates; perchlorates; sulfates; phosphates; C1-C4 alkane sulfonates which may be substituted with halogens such as methanesulfonates, trifluoromethanesulfonates, and ethanesulfonates; C6-C10 arylsulfonates which may be substituted with C1-C4 alkyls such as benzenesulfonates and p-toluenesulfonates; C1-C6 fatty acid salts such as acetates, mal
• the “calcium-containing excipient” in the pharmaceutical composition of the present invention is a pharmacologically acceptable excipient containing calcium, and calcium may be included in any excipient such as a filler, a lubricant, a binder, a disintegrant, an emulsifying agent, a stabilizer, a sweetening or flavoring agent, or a diluent.
• examples include carmellose calcium (made by Gotoku Chemical Co., Ltd., ECG-505 or the like), calcium silicate, calcium hydrogen phosphate, calcium carbonate, calcium sulfate dihydrate, calcium ascorbate, calcium chloride, and calcium stearate, and carmellose calcium is preferred.
• the amount of calcium present in the pharmaceutical composition is preferably at least 0.08% of the formula weight, more preferably within the range of 0.08-30 weight %, even more preferably within the range of 0.08-4 weight %, and most preferably within the range of 0.2-4 weight %.
• the calcium-containing excipient may be contained uniformly throughout the entire drug product or in a specific part of the drug product. If a film coating layer is provided, the calcium-containing excipient may be included in the film coating layer.
• the pharmaceutical composition of the present invention may further contain additional appropriate pharmaceutically acceptable excipients such as fillers, lubricants, binders, disintegrants, emulsifying agents, stabilizers, sweetening and flavoring agents, or diluents as necessary.
• excipients such as fillers, lubricants, binders, disintegrants, emulsifying agents, stabilizers, sweetening and flavoring agents, or diluents as necessary.
• fillers examples include organic fillers including sugar derivatives such as lactose, sucrose, glucose, mannitol, or sorbitol; starch derivatives such as corn starch, potato starch, ⁇ -starch, or dextrin; cellulose derivatives such as microcrystalline cellulose; gum arabic; dextran; or pullulan; and inorganic fillers including silicic acid salt derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, or magnesium aluminometasilicate; phosphoric acid salts such as calcium hydrogen phosphate; carbonic acid salts such as calcium carbonate; or sulfuric acid salts such as calcium sulfate.
• sugar derivatives such as lactose, sucrose, glucose, mannitol, or sorbitol
• starch derivatives such as corn starch, potato starch, ⁇ -starch, or dextrin
• cellulose derivatives such as microcrystalline cellulose
• gum arabic dextran
• pullulan
• lubricants examples include stearic acid; stearic acid metal salts such as, calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as beeswax or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium stearyl fumarate; sodium benzoate; D,L-leucine; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid or silicic acid hydrate; or the starch derivatives described above.
• binder examples include hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, macrogol, or similar compounds as those of the fillers described above.
• disintegrants examples include cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, or croscarmellose sodium; crospovidone; or chemically modified starches or celluloses such as carboxymethyl starch or carboxymethyl starch sodium.
• emulsifying agents examples include colloidal clays such as bentonite or veegum; metal hydrides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationic surfactants such as benzalkonium chloride; or nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, or sucrose fatty acid esters.
• colloidal clays such as bentonite or veegum
• metal hydrides such as magnesium hydroxide or aluminum hydroxide
• anionic surfactants such as sodium lauryl sulfate or calcium stearate
• cationic surfactants such as benzalkonium chloride
• nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, or sucrose fatty acid esters.
• stabilizers examples include parahydroxybenozoic acid esters such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol, or phenyl ethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; or sorbic acid.
• sweetening and flavoring agents examples include sweetening agents such as saccharin sodium or aspartame; acidulants such as citric acid, malic acid, or tartaric acid; and flavoring agents such as menthol, lemon, or orange.
• diotyl examples include lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinylpyrrolidone, magnesium aluminometasilicate, or mixtures thereof.
• olmesartan medoxomil (B) amlodipine, and (C) the calcium-containing excipient may be separate formulations or may be a combination product in which they are uniformly mixed (single formulation). Also in cases in which hydrochlorothiazide is further included in the pharmaceutical composition of the present invention, they may be separate formulations or a combination drug product in which they are uniformly mixed (single formulation), although the composition is preferably a combination product.
• the pharmaceutical composition of the present invention is preferably a solid dosage form, examples of which include tablets (including sublingual tablets and orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, fine granules, powder, pills, chewable drugs, and troches. It is preferably a powder, fine granules, a granule, a capsule, or a tablet, more preferably a tablet, and even more preferably a tablet in which (A), (B), and (C) are uniformly combined. It is most preferably a tablet in which (A), (B), (C), and hydrochlorothiazide are uniformly combined.
• a tablet of the present invention is obtained, for example, by granulating, drying, and screening the main drugs together with a filler, a binder, a disintegrant or the like, adding and mixing a lubricant or the like, and compacting it into a tablet, according to commonly known methods.
• granulation can be performed by means of wet granulation, dry granulation, or hot melt granulation; specifically, it is performed using a high-shear granulator, a fluid bed granulator, an extruder, or a roller compactor. After granulation, operations such as drying and screening may be performed as necessary.
• the mixture of the main drugs and a filler, a binder, a disintegrant, a lubricant, or the like may also be tableted directly.
• the tablet of the present invention may be provided with at least one layer of a film coating.
• Coating is performed using a film coating machine, for example, and examples of film coating agents include sugar-coating agent, aqueous film coating agent, enteric film coating agent, and sustained release film coating agent.
• Sucrose is used as a sugar-coating agent, and one or more types selected from talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone, pullulan, and the like may also be used in combination.
• aqueous film coating agents examples include cellulose derivatives such as hydroxypropyl cellulose, hypromellose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, and sodium carboxymethylcellulose; synthetic polymers such as polyvinylacetal diethylaminoacetate, aminoalkylmethacrylate copolymers, polyvinylpyrrolidone, polyvinyl alcohol, and polyvinyl alcohol copolymers; and polysaccharides such as pullulan.
• cellulose derivatives such as hydroxypropyl cellulose, hypromellose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, and sodium carboxymethylcellulose
• synthetic polymers such as polyvinylacetal diethylaminoacetate, aminoalkylmethacrylate copolymers, polyvinylpyrrolidone, polyvinyl alcohol, and polyvinyl alcohol copolymers
• polysaccharides such as pullulan.
• enteric film coating agents examples include cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, and cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S; and natural substances such as shellac.
• sustained release film coating agents include cellulose derivatives such as ethyl cellulose; and acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS or an ethyl acrylate/methyl methacrylate/copolymer dispersion.
• Two or more types of the coating agents described above may also be mixed at an appropriate ratio and used.
• appropriate pharmacologically acceptable excipients such as plasticizers, fillers, lubricants, masking agents, colorants, and preservatives may also be included as necessary.
• the dissolution properties of the pharmaceutical composition of the present invention are measured in accordance with Dissolution Test method 2 (Paddle Method) of the General Tests, Processes and Apparatus of the Japanese Pharmacopoeia.
• Dissolution Test method 2 Phase Method of the General Tests, Processes and Apparatus of the Japanese Pharmacopoeia.
• JP Japanese Pharmacopoeia
• JP-2 Japanese Pharmacopoeia 2 nd fluid for disintegration test
• JP-2 pH 6.8
• This is filtered using a membrane filter with a pore size of 0.45 ⁇ m, and the dissolution rate of olmesartan medoxomil is calculated by assaying the filtrate using high-performance liquid chromatography.
• the dose and dose ratio of olmesartan medoxomil and amlodipine, which are active ingredients of the pharmaceutical composition of the present invention, can be changed based on various conditions such as the activity of each drug and the patient's symptoms, age, and weight.
• the doses differ depending on factors such as symptoms and age, but if administered orally, they can be administered at a daily adult dose of 5-80 mg (preferably 10-40 mg) of olmesartan medoxomil and 2.5-20 mg (preferably 5-10 mg) of amlodipine (as free form base) 1-6 times per day (preferably once daily) based on the patient's symptoms.
• the doses differ depending on factors such as symptoms and age, but if administered orally, they can be administered at a daily adult dose of 5-80 mg (preferably 10-40 mg) of olmesartan medoxomil, 2.5-20 mg (preferably 5-10 mg) of amlodipine (as free form base), and 5-50 mg (preferably 12.5-25 mg) of hydrochlorothiazide (as free form base) 1-6 times per day (preferably once daily) based on the patient's symptoms.
• the ratio of the doses of olmesartan medoxomil and amlodipine, which are active ingredients of the pharmaceutical composition of the present invention may also vary widely, the dose ratio of olmesartan medoxomil and amlodipine may be, for example, within the range of 1:50 to 50:1 (weight ratio) and is preferably within the range of 1:10 to 10:1.
• the most preferred mode is a tablet containing 40 mg/10 mg, 40 mg/5 mg, 20 mg/10 mg, 20 mg/5 mg, 10 mg/10 mg, or 10 mg/5 mg of olmesartan medoxomil/azelnidipine.
• the dose ratio of olmesartan medoxomil, amlodipine, and hydrochlorothiazide may be, for example, within the range of 1:50:1-50 to 50:1:1-50 (weight ratio) and is preferably within the range of 1:10:1-10 and 10:1:1-10.
• the most preferred mode is a tablet containing 40 mg/10 mg/12.5 mg, 40 mg/5 mg/12.5 mg, 40 mg/5 mg/25 mg, 40 mg/10 mg/25 mg, 20 mg/10 mg/12.5 mg, or 20 mg/5 mg/12.5 mg of olmesartan medoxomil/azelnidipine/hydrochlorothiazide.
• the pharmaceutical composition of the present invention is effective for the prevention or treatment of, for example, hypertension or diseases originating from hypertension (more specifically, hypertension, heart disease [angina pectoris, myocardial infarction, arrhythmia, heart failure, or cardiac hypertrophy], kidney disease [diabetic kidney disease, glomerular nephritis, or nephrosclerosis], or cerebrovascular disease [cerebral infarction or cerebral hemorrhage]).
• hypertension or diseases originating from hypertension more specifically, hypertension, heart disease [angina pectoris, myocardial infarction, arrhythmia, heart failure, or cardiac hypertrophy], kidney disease [diabetic kidney disease, glomerular nephritis, or nephrosclerosis], or cerebrovascular disease [cerebral infarction or cerebral hemorrhage]).
• a filler (D-mannitol (made by Merck, Parteck M100)) and a disintegrant (carmellose (made by Gotoku Chemical Co., Ltd., NS-300)) were added to olmesartan medoxomil or amlodipine besylate or a combination of both, and in cases in which calcium was added, calcium carbonate was added and mixed using a pestle, in a mortar. After this was sieved, it was remixed, and a lubricant (magnesium stearate) was then added and mixed. The resulting mixture was compacted using a hydraulic press with a ⁇ 9 mm convex with two radius punch, and tablets of formulations 1 through 6 (Table 1) were obtained.
• JP 2 nd fluid for disintegration test prepared by dissolving 40.83 g of potassium dihydrogen phosphate and 5.6 g of sodium hydroxide in 6 L of purified water, and dissolution tests were performed under the following conditions.
• Dissolution medium JP 2 nd fluid for disintegration test
• volume of dissolution medium 900 mL
• test solution was sampled and filtered using a Mirex-LH (PTFE membrane, 0.45 ⁇ m, made by the Millipore Co.). Two mL from the initial stage was discarded, and the next 10 mL was collected in a test tube. This was transferred to a volumetric flask in which 2 mL of an internal standard solution was placed in advance to form a total of 10 mL, and this was used as a measurement specimen.
• Mirex-LH PTFE membrane, 0.45 ⁇ m, made by the Millipore Co.
• the dissolution percent of olmesartan medoxomil was low in drug products combined with amlodipine besylate, but the dissolution percent of olmesartan medoxomil recovered when calcium was added to the drug products.
• a filler (D-mannitol (made by Merck, Parteck M100)), a disintegrant (carmellose calcium (made by Gotoku Chemical Co., Ltd., ECG-505) carmellose (made by Gotoku Chemical Co., Ltd., NS-300)), low-substituted hydroxypropyl cellulose (L-HPC) (made by Shin-Etsu Chemical Co., Ltd., LH-21), croscarmellose sodium (made by FMC Biopolymer, Ac-Di-Sol), carboxymethyl starch sodium (made by JRS Pharma, Explotab), and crospovidone (made by BASF, Kollidon CL) were added to olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide and mixed using a pestle, in a mortar.
• a disintegrant carmellose calcium (made by Gotoku Chemical Co., Ltd., ECG-505) carmellose (made by Gotoku Chemical Co., Ltd
• Tests were performed using the same method as in (Test Example 1).
• a filler (D-mannitol (made by Merck, Parteck M100)), a disintegrant (carmellose (made by Gotoku Chemical Co., Ltd., NS-300)), and a partially pregelatinized starch (made by Colorcon, Starch1500) were added to olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide and mixed using a pestle, in a mortar. After this was sieved, it was remixed, and a lubricant (magnesium stearate) was then added and mixed. The resulting mixture was compacted using a hydraulic press with a ⁇ 9 mm convex with two radius punch, and tablets of formulation 14 and 15 (Table 5) were obtained.
• Tests were performed with the same method as in (Test Example 1) using JP 2 nd fluid for disintegration test and solutions prepared by dissolving 3, 30, and 60 mg of calcium chloride in 900 mL of JP 2 nd fluid for disintegration test as test solutions. Formulations 14 and 15 were used as test formulation.
• a filler (D-mannitol (made by Merck, Parteck M100)) and a disintegrant (carmellose calcium (made by Gotoku Chemical Co., Ltd., ECG-505)) were added to olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide and mixed for 15 min with a container blender. After this was sieved with a screening mill, it was remixed for 15 min with a container blender to obtain a mixed powder.
• Tests were performed using the same method as in (Test Example 1).
• a filler (D-mannitol (made by Merck, Parteck M100)), a disintegrant (carmellose (made by Gotoku Chemical Co., Ltd., NS-300)) and calcium-containing excipients (calcium silicate, calcium hydrogen phosphate, calcium carbonate, calcium sulfate dihydrate, calcium ascorbate, and calcium chloride) were added to olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide and mixed using a pestle, in a mortar. After this was sieved, it was remixed, and a lubricant (magnesium stearate and calcium stearate) was then added and mixed. The resulting mixture was compacted using a hydraulic press with a ⁇ 9 mm convex with two radius punch, and tablets of formulations 20 through 27 (Table 9) were obtained.
• a filler (D-mannitol (made by Merck, Parteck M100)), a disintegrant (carmellose (made by Gotoku Chemical Co., Ltd., NS-300)) and magnesium-containing excipients (magnesium aluminometasilicate, magnesium hydroxide, magnesium oxide, and magnesium carbonate) were added to olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide and mixed using a pestle, in a mortar. After this was sieved, it was remixed, and lubricants (magnesium stearate and calcium stearate) were then added and mixed. The resulting mixture was compacted using a hydraulic press with a ⁇ 9 mm convex with two radius punch, and tablets of formulations 28 through 31 (Table 10) were obtained.
• Tests were performed using the same method as in (Test Example 1).
• a filler (D-mannitol (made by Merck, Parteck M100)), a disintegrant (partially pregelatinized starch (made by Colorcon, Starch1500)), low-substituted hydroxypropyl cellulose (L-HPC) (made by Shin-Etsu Chemical Co., Ltd., LH-21), croscarmellose sodium (made by FMC Biopolymer, Ac-Di-Sol), and carboxymethyl starch sodium (made by JRS Pharma, Explotab) were added to olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide and mixed using a pestle, in a mortar after adding calcium carbonate as a calcium excipient.
• Tests were performed using the same method as in (Test Example 1).
• Formulation 1 Formulation 2
• Formulation 3 Formulation 4
• Formulation 5 Formulation 6
• Olmesartan 95.2 — 64.5 87.7 — 90.0 medoxomil dissolution rate (%)
• Amlodipine — 82.5 90.8 — 95.1 96.5 besylate dissolution rate (%)
• Formulation Formulation Ingredient 14 15 Olmesartan medoxomil 40 40 Amlodipine besylate 13.888 13.888 Hydrochlorothiazide 25 25 D-mannitol 157.512 112.512 Carmellose 60 — Partially pregelatinized starch — 105 Magnesium stearate 3.6 3.6 Total 300 300
• a pharmaceutical composition with improved dissolution properties containing (A) olmesartan medoxomil and (B) amlodipine as active ingredients and (C) a calcium-containing excipient can be obtained.

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