WO2010008244A2 - Préparation pharmaceutique - Google Patents

Préparation pharmaceutique Download PDF

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Publication number
WO2010008244A2
WO2010008244A2 PCT/KR2009/003969 KR2009003969W WO2010008244A2 WO 2010008244 A2 WO2010008244 A2 WO 2010008244A2 KR 2009003969 W KR2009003969 W KR 2009003969W WO 2010008244 A2 WO2010008244 A2 WO 2010008244A2
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Prior art keywords
cellulose
release
pharmaceutical formulation
copolymer
mixtures
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PCT/KR2009/003969
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English (en)
Korean (ko)
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WO2010008244A3 (fr
Inventor
김성욱
전성수
구자성
김병하
이나영
Original Assignee
한올제약주식회사
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Publication of WO2010008244A2 publication Critical patent/WO2010008244A2/fr
Publication of WO2010008244A3 publication Critical patent/WO2010008244A3/fr

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    • 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
    • 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
    • A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • 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 containing an angiotensin-2 receptor antagonist and a beta adrenergic blocker as an active ingredient, each of which is released over time.
  • Hypertension is a condition that is caused by multiple causes. Therefore, it is difficult to determine in advance what results would result from the use of a single anticompressant [Journal of hypertension 1995: 9: S33-S36]. For this reason, a combination of anti-pressure agents has been increasing for more effective treatment.
  • US Patent Publication No. 2005-0004194 discloses a combination of angiotensin converting enzyme inhibitor and angiotensin-2 receptor antagonist for treating cardiovascular disease by reducing side effects and enhancing the effects on patients with myocardial infarction.
  • Korean Patent Laid-Open Publication No. 2004-0078140 discloses an antihypertensive complex preparation of valsartan and calcium channel blocker, which is an angiotensin-2 receptor antagonist.
  • WO 03/097099 discloses that simple combination therapy in which unit dosage forms of angiotensin-2 receptor blocker and beta receptor blocker are simultaneously administered is effective for the treatment of cardiovascular disease in patients after myocardial infarction.
  • the present inventors have completed the present invention as a result of research to develop a complex formulation for cardiovascular diseases such as hypertension.
  • the problem to be solved by the present invention is to show an equal anti-pressure action and prevent complications, in particular, it is possible to maintain the blood pressure evenly in the dangerous time period of complications, it is useful for patients with hypertension with complications, blood pressure control during sleep, etc. It is intended to provide an agent that reduces the side effects of interaction.
  • the present invention provides a pharmaceutical formulation comprising a prior release compartment comprising an angiotensin-2 receptor antagonist as a pharmacologically active ingredient, and a delayed release compartment comprising a beta adrenergic blocker as a pharmacologically active ingredient.
  • the angiotensin-2 receptor antagonist which is the active ingredient of the pre-release compartment, is prerelease, and preferably, at least 85% of the total amount of the angiotensin-2 receptor antagonist is released within 1 hour after the release of the angiotensin-2 receptor antagonist. Therefore, the desired effect can be generated quickly.
  • the beta adrenergic blocker of the delayed-release compartment in the formulations of the invention is released after a delay, ie 1 to 8 hours after release of the angiotensin-2 receptor antagonist, preferably 1 to 6 hours.
  • the release amount of the beta adrenergic blocker released within 2 hours after the release of the angiotensin-2 receptor antagonist is within 0-10% of the total amount of the beta adrenergic blocker. Can be.
  • the formulation of the present invention may comprise 0.1 to 350 parts by weight of the angiotensin-2 receptor antagonist based on 1 part by weight of the adrenergic blocker.
  • Pre-release compartment refers to the compartment in which the active ingredient is first released in comparison with the delayed-release compartment in the pharmaceutical formulation of the present invention, and may further include a pharmaceutically acceptable additive as necessary in addition to the pharmacologically active ingredient. .
  • the pharmacologically active component of the prior-release compartment is an angiotensin 2 receptor antagonist, and the angiotensin-2 receptor antagonist blocks angiotensin 2, one of the sources of vasoconstriction, with the AT1 receptor in the angiotensin receptor.
  • It is a drug that exerts a blood pressure-lowering effect on both myocardial systolic and diastolic phases, such as losartan, valsartan, telmisartan, irbesartan, candesartan, olmesartan, and / or eprosartan.
  • Isomers of and pharmaceutically acceptable salts thereof may be selected, and may include 1 to 800 mg of the formulation, and preferably 15 to 370 mg. The dose is based on a daily adult (65-75 kg adult male).
  • formulations of the present invention do not interfere with the release of pharmacologically active ingredients from commonly used additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, pH adjusters, dissolution aids and the like without departing from the effect of the present invention. It can be formulated using further within the range which does not.
  • the diluent may be starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, dicalcium phosphate, or a mixture thereof.
  • the binder is starch, microcrystalline cellulose, highly dispersible silica, mannitol, sucrose, lactose, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, natural gum, synthetic gum, polyvinylpyrrolidone Copolymers, povidone, gelatin, mixtures thereof, and the like.
  • the disintegrant may be a starch or modified starch such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch (starch starch); Clay such as bentonite, montmorillonite, or veegum; Celluloses such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algins such as sodium alginate or alginic acid; Crosslinked celluloses such as croscarmellose sodium; Gums such as guar gum and xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Effervescent agents such as sodium bicarbonate, citric acid, or mixtures thereof can be used.
  • starch starch such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch (starch starch); Clay such as bentonite, montmorillonite, or veegum; Celluloses such as microcrystalline cellulose, hydroxypropyl
  • the lubricant is talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostearate, Glyceryl palmitostearate, polyethylene glycol, and / or mixtures thereof, and the like.
  • the stabilizer may be ascorbic acid, citric acid, butylated hydroxy anisole, butylated hydroxy toluene, and / or tocopherol derivatives.
  • an alkalizing agent which is a salt of an alkali metal, a salt of an alkaline earth metal, or a mixture thereof, may be used.
  • calcium carbonate, sodium carbonate, sodium hydrogen carbonate, magnesium oxide, magnesium carbonate, and / or sodium citrate Etc. can be used.
  • the pH adjusting agent may be an acidifying agent such as acetic acid, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid, and a basicizing agent such as precipitated calcium carbonate, aqueous ammonia, and meglumine.
  • an acidifying agent such as acetic acid, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid, and a basicizing agent such as precipitated calcium carbonate, aqueous ammonia, and meglumine.
  • the dissolution aid may be used polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, sodium docusate and the like.
  • a pharmaceutically acceptable additive may be selected and used in the preparation of the present invention as various additives selected from colorants and fragrances.
  • the range of additives usable in the present invention is not limited to the use of such additives, and the above additives may be formulated to contain a range of dosages, usually by selection.
  • the delayed-release compartment refers to a compartment in which the active ingredient is released after a certain time of release of the prior-release compartment active ingredient.
  • the delayed-release compartment comprises (1) a pharmacologically active ingredient and (2-1) release controlling substance or (2-2) an osmotic pressure regulator and a semipermeable membrane coating base, and (3) a pharmaceutically acceptable It may further include an additive.
  • the pharmacologically active component of the delayed-release compartment is beta adrenergic antagonist, and the beta adrenergic blocker blocks the excitability of the sympathetic nervous system due to the stimulation of the adrenergic beta receptors in the cardiovascular and smooth muscle, resulting in hypertension
  • beta adrenergic blocker is alprenolol, acebutorol, amosulolol, arotinol, atenolol, befunolol, betaxolol, bevan Tolol, Bisoprolol, Boffindolol, Bucumolol, Buffololol, Bufuralol, Bunitrolol, Bufrandolol, Butopylolol, Carazolol, Caterolol, Carvedilol, Celylprolol, Cetamolol, Chlor
  • Nebivolol is a fourth-generation beta adrenergic blocker that not only has all the benefits of first-, second- and third-generation beta-adrenergic blockers, but also produces NO, which dilates peripheral blood vessels. It has no side effects such as increase, worsening of diabetes mellitus, cold limbs, and effects on right heart dilatation heart failure. It is particularly suitable for elderly systolic hypertensives, those with heart failure, elderly diabetic hypertension, elderly hyperlipidemic hypertension, and hypertension combined with heart failure.
  • nebivolol can obtain an effective therapeutic effect by combining angiotensin-2 receptor antagonist with hypertension of severe diseases such as heart failure and myocardial infarction.
  • the delayed-release compartment in the pharmaceutical formulation of the present invention comprises a release controlling substance, wherein the release controlling substance of the present formulation is selected from, for example, enteric polymers, water insoluble polymers, hydrophobic compounds, hydrophilic polymers, and mixtures thereof. At least one, preferably at least one selected from water-insoluble polymers and enteric polymers.
  • the release controlling substance of the formulation is 0.1 to 100 parts by weight, preferably 1 to 50 parts by weight, with respect to 1 part by weight of the beta adrenergic blocker, and when it is less than 0.1 parts by weight, it is difficult to have a sufficient delay time. Drug release may be excessively delayed, making it difficult to obtain significant clinical effects.
  • the enteric polymer is insoluble or stable under acidic conditions, and refers to a polymer that is dissolved or decomposed under specific pH conditions of pH 5 or more.
  • the enteric polymer usable in the present invention is at least one selected from the group consisting of an enteric cellulose derivative, an enteric acrylic acid copolymer, an enteric polymethacrylate copolymer, an enteric maleic acid copolymer, an enteric polyvinyl derivative, and a mixture thereof. .
  • the enteric cellulose derivative may be hydroxypropylmethylcellulose acetate succinate (or hypromellose acetate succinate), hydroxypropylmethyl cellulose phthalate (or hypromellose phthalate), hydroxymethylethyl cellulose phthalate , Cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethylethyl cellulose, ethyl hydroxyethyl cellulose phthalate, methyl hydroxyethyl cellulose and their At least one selected from a mixture;
  • the enteric acrylic acid copolymers include styrene-acrylic acid copolymers, methyl acrylate-acrylic acid copolymers, methyl methacrylate acrylates, butyl acrylate-styrene-acrylic acid copolymers, methyl acrylate-methacrylic acid-o
  • the enteric maleic acid copolymer is vinyl acetate-maleic anhydride copolymer, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinyl methyl ether-maleic anhydride copolymer, ethylene-maleic anhydride copolymer, vinyl butyl ether- At least one selected from maleic anhydride copolymer, acrylonitrile-methyl acrylate maleic anhydride copolymer, butyl styrene-maleic-maleic anhydride copolymer and mixtures thereof;
  • the enteric polyvinyl derivative is preferably at least one selected from polyvinyl alcohol phthalate, polyvin
  • the enteric polymer may be included in an amount of 0.1 parts by weight to 20 parts by weight, preferably 0.5 parts by weight to 10 parts by weight with respect to 1 part by weight of the active ingredient, and less than 0.1 parts by weight may be easily dissolved at a pH of less than 5, If the amount exceeds 20 parts by weight, the total weight of the preparation may be unnecessarily increased or the elution may be excessively delayed.
  • the water insoluble polymer refers to a polymer that is not soluble in pharmaceutically acceptable water that controls the release of the drug.
  • the water-insoluble polymers usable in the present invention are polyvinyl acetate, water-insoluble polymethacrylate copolymers (e.g. poly (ethylacrylate, methyl methacrylate) copolymers (eg Eudragit NE30D), poly (ethylacrylic) Latex, methyl methacrylate, trimethylaminoethyl methacrylate chloride) copolymer (e.g.
  • Eudragit RS, RL), etc. ⁇ ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose tri At least one selected from the group consisting of acylate, cellulose acetate, cellulose diacetate, cellulose triacetate and mixtures thereof is preferred, and more preferably polyvinylacetate, ethyl cellulose, poly (ethyl acrylate, methyl methacrylate).
  • Trimethylaminoethyl methacrylate Bit chloride is at least one selected from a copolymer, and cellulose acetate.
  • the water-insoluble polymer may be included in an amount of 0.1 parts by weight to 30 parts by weight, preferably 0.5 parts by weight to 20 parts by weight, and less than 0.1 parts by weight based on 1 part by weight of the active ingredient. If the content is more than 30 parts by weight, the dissolution may be excessively delayed.
  • the hydrophobic compound refers to a substance that does not dissolve in pharmaceutically acceptable water that controls the release of the drug.
  • the hydrophobic compound usable in the present invention is, for example, at least one selected from the group consisting of fatty acids and fatty acid esters, fatty alcohols, waxes, inorganic substances, and mixtures thereof.
  • fatty acids and fatty acid esters are selected from glyceryl palmitostearate, glyceryl stearate, glyceryl distearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate, stearic acid and mixtures thereof Species or more;
  • Fatty acid alcohols are at least one selected from cetostearyl alcohol, cetyl alcohol, stearyl alcohol and mixtures thereof;
  • the waxes are at least one selected from carnauba wax, beeswax, microcrystalline wax, and mixtures thereof;
  • the inorganic material is preferably at least one selected from talc, precipitated calcium carbonate, calcium dihydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, bum and mixtures thereof.
  • a more preferred example of the hydrophobic compound is carnauba wax.
  • the hydrophobic compound may be included in an amount of 0.1 parts by weight to 20 parts by weight, preferably 0.5 parts by weight to 10 parts by weight with respect to 1 part by weight of the active ingredient, and when less than 0.1 parts by weight, the release of the drug may not be controlled. In case of more than 20 parts by weight, excessive elution may be delayed.
  • the hydrophilic polymer refers to a polymeric material that is dissolved in pharmaceutically acceptable water that controls the release of the drug.
  • hydrophilic polymers usable in the present invention include 1 selected from the group consisting of sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl copolymers, and mixtures thereof. More than species.
  • sugars are dextrins, polydextrins, dextran, pectin and pectin derivatives, alginates, polygalacturonic acids, xylans, arabinoxylans, arabinogalactan, starch, hydroxypropylstarches, amylose, amylopectin, and their At least one selected from mixtures;
  • Cellulose derivatives include hydroxypropylmethylcellulose (or hypromellose), hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose sodium, hydroxypropyl methylcellulose acetate succinate, At least one selected from hydroxyethyl methyl cellulose, and mixtures thereof;
  • the gum is at least one selected from guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, arabic gum, gellan gum, xanthan gum, and mixtures thereof;
  • Proteins may be at least one selected from gelatin,
  • hydrophilic polymer are selected from polyvinyl pyrrolidone, hydroxypropyl cellulose, hypromellose, and poly (ethyl acrylate-methyl methacrylate-triethylaminoethyl- methacrylate chloride) copolymer. More than species.
  • the hydrophilic polymer may be included in an amount of 0.05 parts by weight to 30 parts by weight, preferably 0.5 to 20 parts by weight with respect to 1 part by weight of the active ingredient, and when it is less than 0.05 parts by weight, the release rate may not be controlled. If the excess is excessive, there is a fear that excessive dissolution is delayed.
  • the delayed-release compartment of the present invention includes an osmotic pressure regulator and may be a compartment coated with a semipermeable membrane coating base.
  • the osmotic pressure regulator is preferably at least one selected from the group consisting of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, lithium sulfate, sodium sulfate and mixtures thereof.
  • the osmotic pressure control agent may be included in an amount of 0.01 parts by weight to 10 parts by weight, preferably 0.05 parts by weight to 0.5 parts by weight with respect to 1 part by weight of the active ingredient, and there is a concern that it is difficult to obtain sufficient time difference release property at less than 0.01 parts by weight, Drug release may be delayed at more than 10 parts by weight, making it difficult to obtain a significant clinical effect.
  • the semi-permeable membrane coating base is a substance to be blended into the coating layer of the pharmaceutical formulation, and refers to a substance used to form a membrane that allows some components to pass but does not pass other components.
  • the semipermeable membrane coating base may use the above-mentioned water-insoluble polymer.
  • the semipermeable membrane coating base in the present invention is, for example, polyvinyl acetate, polymethacrylate copolymer, poly (ethylacrylate, methyl methacrylate) copolymer, poly (ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate Late chloride) copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate and mixtures thereof The above is mentioned.
  • the semi-permeable membrane coating base may be included in an amount of 0.01 parts by weight to 10 parts by weight, preferably 0.05 parts by weight to 1.25 parts by weight, with respect to 1 part by weight of the active ingredient, and when it is less than 0.01 parts by weight, it may be difficult to have a sufficient delay time. And, if more than 10 parts by weight there is a problem that the release of the drug does not occur or the delay time is long.
  • the formulations of the present invention are diluents, binders, and borates other than those mentioned as pharmaceutically acceptable (2-1) release controlling substances and (2-2) osmotic pressure regulators and semipermeable membrane coating agents within the scope of not impairing the effects of the present invention.
  • Commonly used additives such as release, lubricants, pH adjusters, antifoams, dissolution aids and the like can be formulated further using within a range not departing from the nature of delayed release.
  • the pharmaceutical preparations of the present invention can be prepared in a variety of formulations and can be formulated, for example, in tablets, powders, granules, capsules, and the like, such as uncoated tablets, coated tablets, multilayer tablets, or nucleated tablets.
  • the formulation of the present invention is a tabletting by selectively mixing additives such as granules constituting the pre-release compartment and granules constituting the delayed-release compartment and the like to have a pre-release compartment and a delayed-release compartment in a single tablet, and thus the active ingredient of each compartment.
  • additives such as granules constituting the pre-release compartment and granules constituting the delayed-release compartment and the like to have a pre-release compartment and a delayed-release compartment in a single tablet, and thus the active ingredient of each compartment.
  • This may be in the form of uncoated tablets will be eluted separately to show the respective effects.
  • the formulation of the present invention may be in the form of a two-phase matrix tablet obtained by tableting after the delayed-release compartment and the prior-release compartment are uniformly mixed.
  • the pharmaceutical formulation of the present invention may be in the form of a film coated tablet consisting of a tablet consisting of a delayed-release compartment and a film coating layer consisting of a pre-release compartment surrounding the outside of the tablet, the film coating layer of the film coating layer as it is dissolved
  • the active ingredient is eluted first.
  • the pharmaceutical formulation of the present invention is a delayed-release compartment, obtained by mixing the pharmaceutical additives in the granules constituting the delayed-release compartment and the prior-release compartment, and tableting in a double or triple tablet using a multiple tableting machine and
  • the pre-emitting compartments may be in the form of a multi-layered tablet with a layered structure.
  • This formulation is a tablet for oral administration which is formulated to enable pre-release and delayed release in layers.
  • the pharmaceutical formulation of the present invention may be in the form of a nucleus tablet consisting of an inner layer consisting of a delayed-release compartment and an outer layer consisting of a prior-release compartment surrounding the outer surface of the inner core tablet.
  • the nucleated tablet may be an osmotic nucleated tablet, and the osmotic nucleated tablet contains an osmotic pressure-controlling agent inside the tablet for delayed release, followed by compression, and then coated the surface of the tablet with a semipermeable membrane coating agent to form an inner core.
  • compositions of the present invention may be in the form of capsules comprising particles, granules, pellets, or tablets consisting of delayed-release compartments, and particles, granules, pellets, or tablets consisting of prior release compartments.
  • the tablet consisting of the delayed-release compartment of the capsule may include an osmotic pressure-controlling agent within the tablet and an osmotic coated tablet having a semipermeable membrane coating base on the surface of the tablet.
  • the base of the capsule may be one selected from gelatin, succinate gelatin, or hydroxypropylmethylcellulose, or a mixture thereof.
  • the pharmaceutical formulation of the present invention may be in the form of a kit comprising a delayed-release compartment, and a prior-release compartment
  • the kit comprises (a) a prior-release compartment (b) a delayed-release compartment and (c) the It may consist of a container for filling the pre-release compartment and the delayed-release compartment.
  • the kit prepares the particles, granules, pellets, or tablets constituting the prerelease compartment, and separately prepares the granules, pellets, or tablets constituting the delayed release compartment, and fills them together with foil, blisters, bottles, and the like. It can be prepared in a form that can be taken at the same time.
  • the formulations of the present invention may further form a coating layer on the exterior of the delayed release compartment and / or the prior release compartment.
  • the surface of the particles, granules, pellets, or tablets consisting of delayed-release compartments and / or pre-release compartments may be coated for the purpose of release control or formulation stability.
  • the formulation according to the present invention is also provided in a state such as uncoated tablets without additional coating, but may be in the form of a coated tablet containing a coating layer further by forming a coating layer on the outside of the formulation, if necessary. .
  • a coating layer By forming the coating layer, it is possible to further ensure the stability of the active ingredient.
  • the method of forming the coating layer may be appropriately selected by a person skilled in the art from the method of forming a film-like coating layer on the surface of the tablet layer, a method such as a fluidized bed coating method, a fan coating method may be applied, and preferably Fan coating can be applied.
  • the coating layer may be formed by using a coating agent, a coating aid, or a mixture thereof.
  • the coating agent may be a cellulose derivative such as hydroxypropylmethylcellulose, hydroxypropylcellulose, sugar derivatives, polyvinyl derivatives, waxes, or fatty acids. , Gelatin, or a mixture thereof, and the like, and a coating aid may be polyethylene glycol, ethyl cellulose, glycerides, titanium oxide, talc, diethyl phthalate, triethyl citrate or a mixture thereof.
  • the coating layer may be included in the range of 0.5 to 15% by weight (% w / w) based on the total weight of the tablet.
  • the formulation of the present invention can be administered once a day between 5 to 11 o'clock in the evening, and can exert anti-pressure action and complication prevention evenly for 24 hours.
  • Beta adrenergic blockers are known to have strong antitumor activity after dawn [N EnglJ Med 2003; 348; 2377-8, Chronology International 2006; 23 (4): 813-829], angiotensin-2 receptor antagonists are known to have strong blood pressure lowering effects from midnight to dawn [J. Hypertens, 2005; 23: 1913-1922, Hypertension, 2003; 42: 283-290, Chronobiol. Int. 2005; 22: 755-776], even when the preparation of the present invention is taken once in the evening, the blood pressure is effectively lowered until dawn by an angiotensin-2 receptor antagonist, which is released, and the blood pressure after dawn by a beta-adrenergic blocker delayed release. It effectively lowers the 24 hours even anti-pressure action and prevent complications.
  • the preparation of the present invention By administering the preparation of the present invention in the evening time, blood pressure can be maintained evenly in the time of risk of complications (from dawn to morning time). Therefore, the sympathetic hyper-excited state of the heart should be suppressed evenly for 24 hours. It is useful for patients with high blood pressure with complications.
  • the formulation of the present invention is useful for suppressing non-dipper type hypertension, a type of hypertension in which blood pressure does not decrease during sleep.
  • the non-dipper type hypertension is present in the elderly, diabetics, cardiac hypertrophy, and high blood pressure with a high risk of complications such as stroke, and is useful for suppressing blood pressure during sleep by taking the preparation of the present invention in the evening.
  • the agent of the present invention is an angiotensin-2 receptor antagonist
  • the agent of the present invention is an angiotensin-2 receptor antagonist
  • is first introduced into the liver is activated by the cytochrome P450 enzyme in the liver, after the beta adrenergic blocker passes through the liver between the beta adrenergic blocker and the angiotensin-2 receptor antagonist Blocks metabolic interactions that may occur, reducing side effects of drug interactions.
  • the present invention also provides a method for treating cardiovascular disease, comprising administering the agent of the present invention to a mammal including a human.
  • cardiovascular diseases can be treated.
  • the cardiovascular disease is meant to include hypertension, or high blood pressure complications.
  • compositions of the present invention may be prepared by any suitable method in the art, for example, with reference to methods disclosed in Chronotherapeutics (2003, Peter Redfern, PhP), Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA, and the like. It can be formulated preferably according to a disease or a component, and can be manufactured by the method containing the following steps specifically ,.
  • the active ingredient of the delayed-release compartment is mixed with, or combined with, one or two release controlling substances selected from an enteric polymer, a water insoluble polymer, a hydrophobic compound, and a hydrophilic polymer, and a conventional additive used in pharmaceuticals.
  • Delayed-release granules or tablets are obtained through drying, granulation or coating, and tableting, or the active ingredient is semipermeable after mixing, associating, drying, granulating or tableting by administering an osmotic agent and a conventional additive which is used pharmaceutically. It is a step of obtaining delayed-release granules or tablets by coating with a membrane coating base.
  • the second step involves the administration of the active ingredient of the prior-release compartment and the conventionally acceptable pharmaceutically acceptable additives to produce the oral solids through mixing, coalescing, drying, granulating or coating, and tableting to produce oral solids. Obtaining extruded granules or tablets.
  • the granules or tablets obtained in the first step and the second step are mixed with pharmaceutical excipients, tableted or filled to obtain a preparation for oral administration.
  • the first step and the second step may be reversed or executed simultaneously.
  • the pharmaceutical formulation of the present invention may be prepared by the above process, and the formulation method of the third step is described in more detail as follows, but is not limited thereto.
  • the particles or granules obtained in the first step are further coated as they are or with a release controlling material, and then mixed with the granules prepared in the second step and compressed into a certain amount of weight to prepare a tablet.
  • the obtained tablet can be film coated as necessary for the purpose of improving stability or property.
  • the coated tablets or granules obtained in the first step are additionally coated as they are or with a release control material, dried, and then compressed into a predetermined amount to prepare tablets as they are or additionally coated, and then the active ingredients of the pre-release compartments are separately coated with a water-soluble film coating solution.
  • the tablet outer layer obtained in step 1 can be used to prepare an orally administered film coating tablet containing the active ingredient in a film coating.
  • the granules obtained in the first step as they are or are additionally coated and dried with a release controlling substance and the granules obtained in the second step can be prepared in double tablets using a tablet press.
  • Coated multi-layered tablets can be prepared by formulating or coating triple or more multi-layered tablets by adding a release aid layer as needed, or by formulation.
  • the coated tablet or granules obtained in the first step are additionally coated as it is or with a release control material, dried, and then compressed into a predetermined amount to be coated as it is or additionally to the inner core, followed by a nucleated tableting machine together with the granules obtained in the second step.
  • the coated nucleated tablet may be prepared by preparing or coating a nucleated tablet having a form in which a pre-release layer is enclosed on the surface of the inner core.
  • the granules obtained in the first step are additionally coated as is or with a release controlling substance, and the dried granules or tablets and the granules or tablets obtained in the second step are placed in a capsule charger and filled into capsules of a predetermined size by an effective amount of each active ingredient in an appropriate amount.
  • Capsules may be prepared by mixing the release control pellets containing the ingredients and filling the capsules with a capsule filling machine.
  • the delayed-release compartment preparation (beta-adrenergic blocker-containing formulation) obtained in the first stage and the prior-release compartment preparation (angiotensin-2 receptor antagonist-containing formulation) obtained in the second stage are filled together with a foil, blister, bottle, etc. It can be made into a kit that can be taken at the same time.
  • the human dosage of the formulation of the present invention is appropriately selected depending on the absorption rate, inactivation rate and excretion rate of the active ingredient in the body, the age, sex and condition of the patient, but in general, the beta adrenergic blocker and angiotensin-2 receptor antagonist in adults In a total amount, 2.0 to 2200 mg per day, preferably 42 to 1900 mg per day can be exerted anti-pressure action and prevent complications.
  • the formulation of the present invention is formulated to be compatible with the theory of drug metabolic enzyme interactions and the principle of time difference administration by allowing time difference dissolution between two components of angiotensin-2 receptor antagonist and beta adrenergic blocker. It can increase the efficacy and reduce the side effects compared with the simultaneous release.
  • the formulation of the present invention applies the principle of chronotherapy and the principle of Xenobiotics of the drug to the expression of pharmacological action of each of the complex components to control release in the body at a specific rate to achieve the most ideal effect upon absorption in the body.
  • the pharmaceutical preparation of the present invention exhibits an equal anti-pressure action and prevents complications, and is particularly useful for hypertension patients with complications, suppressing blood pressure during sleep, and the like. Reduces the side effects of action.
  • Example 1 is a graph showing the dissolution rate of valsartan and nebivolol in the valsartan-hydrochloride nebivolol-containing formulation of Example 2 compared with the reference drug.
  • FIG. 3 is a graph showing the dissolution rate of losartan and nebivolol hydrochloride in the losartan-hydrochloride nebivolol-containing preparation of Example 14 compared with the reference drug.
  • 5 is a graph showing the dissolution rate of losartan in the formulations of Examples 21, 22, 23, and 24 compared with the reference drug.
  • Example 6 is a graph showing the dissolution rate of candesartan cilexetil and atenolol in the candesartan cilexetil-atenolol-containing formulation of Example 34 in comparison with the reference drug.
  • Example 7 is a graph showing the dissolution rate of eprosartan and carvedilol in the eprosartan-carvedilol-containing formulation of Example 36 in comparison with the reference drug.
  • Example 8 is a graph showing the dissolution rate of telmisartan and carvedilol in the telmisartan-carvedilol-containing formulation of Example 37 compared with the reference drug.
  • Example 9 is a graph showing the dissolution rate of losartan and metoprolol in the losartan-metoprolol-containing formulation of Example 39, compared with the reference drug.
  • Valsartan (Ranbaxy, India), lactose (Parmatose, DMV Pharma, Netherlands), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA), poloxamer 188 (Lutrol-F68, BASF, Germany), starch Sodium glyconate (Primojel, DMV Pharma, The Netherlands) was weighed and inconvenienced as No. 35. Separately, hydroxypropyl cellulose (HPC-L, Nippon soda, Japan) was dissolved in purified water to prepare a binding solution. The mixture was put into a fluid bed granulator GPCG-1 (Glatt, Germany) and granulated by the addition of a binder solution. The fluid bed dryer assembly was dried after assembly was complete.
  • the dried product was sized using an F-type sizer (KYK-60, Korea Medi, Korea) equipped with a No. 20 body, thereby preparing Valsartan pre-release granules.
  • hydrochloric acid nebivolol (Cadila, India), microcrystalline cellulose, sodium lauryl sulfate (Texapon K12P, Cognis Corp, USA), crosslinked polyvinylpyrrolidone (Crospovidone, BASF, Germany) No. 35
  • the apples were sieved, and hydroxypropyl cellulose (HPC-L, Nippon soda, Japan) was separately dissolved in purified water to obtain a binding solution.
  • Fluidized bed granulators and fluidized bed drying are the same as those of valsartan pre-release granules.
  • the dried material was placed in a fluidized bed coater and separately cellulose acetate (acetal group 32%) (Eastman Chemical Company, USA), cellulose acetate (acetal group 39.8%) (Eastman Chemical Company, USA), and hydroxypropylmethylcellulose in ethanol and methylene chloride The melted solution was prepared to coat the granulated product.
  • the product temperature is maintained at 34 ⁇ 38 °C, when the coating is complete, while drying and surface work for about 1 hour while maintaining the product temperature 40 °C, to produce a nebivolol delayed-release granules hydrochloric acid.
  • magnesium stearate was added thereto, and then mixed for 4 minutes and compressed into tablets using a rotary tablet press (MRC-33: Sejong Pharmatech, Korea) equipped with a 10.0 mm diameter punch. .
  • Tablets that have been tableted are prepared by dissolving and dispersing hydroxypropylmethylcellulose 2910 (Shin-etsu, Japan), polyethylene glycol 6000 (BASF, Germany), and titanium oxide (Tioside Americas, USA) in ethanol and purified water. By coating.
  • magnesium stearate was added to the delayed-release layer granules of (2) nebivolol hydrochloride of Example 1, and finally mixed to prepare a delayed-release layer of nebivolol hydrochloride.
  • magnesium stearate was added to the (1) valsartan pre-release granules of Example 1, and finally mixed to prepare a valsartan pre-release layer.
  • the prepared Navivolol delayed-release layer and valsartan pre-release layer were put into different granule inlet holes of a rotary multi-layer tablet tablet press (MRC-37T: Sejong Pharmatech, Korea) equipped with a 10 mm diameter puncher, and then tableted. Hydroxypropylmethylcellulose 2910, polyethylene glycol 6000, and titanium oxide were coated using a coating solution prepared by dissolving and dispersing in ethanol and purified water.
  • the tablets were put into different granules, and tableted, the tablets were tableted with hydroxypropylmethylcellulose 2910, polyethylene glycol 6000, and titanium oxide in a coating solution prepared by dissolving and dispersing ethanol in purified water.
  • Example 1 (2) After the magnesium stearate was added to the granules of delayed-release layer of nebivolol hydrochloride prepared by the method of Example 1 (2), the final mixture was rotary with a 6 mm diameter punch.
  • MRC-33 Sejong Pharmatech, Korea
  • Magnesium stearate was added to the mixture, and the mixture was compressed into tablets.
  • the tablets having been tableted are coated with a coating solution prepared by dissolving and dispersing hydroxypropylmethylcellulose 2910, polyethylene glycol 6000, and titanium oxide in ethanol and purified water to prepare a coated tablet.
  • Valsartan pre-release granules were prepared according to the method of Example 2, except that the components and contents shown in Table 1 do not include lactose.
  • the nebivolol delayed-release layer of Example 2 above It prepared by the same method as the preparation.
  • the valsartan pre-release granules were compressed in a rotary tablet press equipped with a 6 mm diameter punch, and the hydrochloride nebivolol delayed-release granules were compressed in a rotary tablet press equipped with a 5 mm diameter punch (MRC-33: Sejong Pharmatech, Korea). Tableting was completed two tablets were filled capsule No. 1 capsule (SF-40N, Sejong Pharmatech, Korea) into No. 1 capsule (HPMC hard capsule, Seoheung capsule, Korea) to prepare a capsule.
  • the nebivolol delayed-release tablet hydrochloride was prepared according to the preparation method of delayed-release tablet hydrochloride in Example 5, and the valsartan pre-release granules were prepared according to the preparation method of Example 2 (1). After the preparation, each tablet and granules were filled in the same capsule (No. 0 capsule) with a capsule charger to prepare a nebivolol valsartan hydrochloride (tablet + granules).
  • the capsules were prepared by filling the No. 0 capsules with Navivolol delayed-release granules and valsartan granules prepared in the same manner as in Example 2 with a capsule charger.
  • sugar seeds were added to a fluidized bed granulator (GPCG 1: Glatt), and then poloxamer and hydroxypropyl cellulose (HPC-L, Nippon) were mixed separately with purified water and ethanol. soda, Japan) and valsartan were sprayed to form a pellet containing valsartan by spraying a binder solution in which valsartan was dissolved or suspended to prepare valsartan pre-release pellets.
  • GPCG 1 Glatt
  • HPC-L hydroxypropyl cellulose
  • sugar seeds were added to a fluidized bed granulator (GPCG 1: Glatt), and then hydroxypropylmethylcellulose, sodium lauryl sulfate, and nebivolol hydrochloric acid were separately mixed with purified water and ethanol.
  • the binder solution dissolved or suspended was sprayed to form a nebivolol-containing pellet, and dried.
  • the granules were sprayed with phthalic hydroxypropylmethylcellulose in a mixture of ethanol and methylene chloride to prepare nebivolol delayed-release pellets.
  • Capsules were prepared by mixing two pellets prepared in the above (1) and (2) and filling the capsule No. 0 with a capsule charger.
  • valsartan pre-release pellets were prepared in the same manner as in Example (1), and the nebivolol delayed-release tablet of hydrochloric acid was prepared by the method of Example 2 (2).
  • Magnesium stearate was added to the delayed-release layer granules of the ball roll, and the final mixture was compressed into tablets and pellets by tableting with a rotary tablet press (MRC-33: Sejong Pharmatech, Korea) equipped with a 6 mm diameter punch.
  • the capsules were filled in capsule No. 0 with a capsule charger to prepare a capsule.
  • valsartan, lactose, poloxamer, microcrystalline cellulose, sodium starch glycolate were weighed and appled into No. 35 sieve and mixed for 20 minutes in a double cone mixer to prepare a mixture.
  • hydroxypropyl methyl cellulose was dissolved in 80% ethanol, and acrylic acid (Acryl-eze, Colorcon, USA) was dispersed in purified water to prepare a coating solution. After the preparation of the coating solution was completed, the granules were administered to the fluidized bed coater and subjected to the first coating (hydroxypropylmethylcellulose coating solution), followed by a second coating (acrylic coating solution).
  • magnesium stearate was added thereto, mixed for 4 minutes, and compressed using a rotary tablet press (MRC-33: Sejong Pharmatech, Korea) equipped with a 12.0 mm diameter punch. Tablet-finished tablets were coated with a coating solution in which hydroxypropylmethylcellulose 2910, polyethylene glycol 6000, and titanium oxide were dissolved and dispersed in ethanol and purified water.
  • valsartan lactose, poloxamer 188, microcrystalline cellulose, sodium starch glycolate, starch gelatinized starch (Starch 1500G, Colorcon, USA) and weigh apples in No. 35 with the ingredients and contents shown in Table 2.
  • the mixture was prepared by mixing for 20 minutes at. After completion of mixing, magnesium stearate was added and mixed for 4 minutes to prepare valsartan pre-release granules.
  • nebivolol hydrochloride, microcrystalline cellulose, sodium lauryl sulfate was appled with No. 35 sieve, and mixed for 5 minutes with a double cone mixer to prepare a mixture.
  • hydroxypropyl cellulose was dissolved in purified water to obtain a binding solution.
  • the above mixture was administered to a fluidized bed granulator (GPCG-1, Glatt, Germany), followed by spraying the binding solution to prepare granules.
  • the granules were dried in a fluidized bed dryer (GPCC-1, Glatt, Germany), and then carbomer 71G (carboxyvinyl polymer, lubrizol) was added to the granules in a powder state and mixed for 10 minutes. I passed. After sieving, magnesium stearate was added and mixed for 4 minutes to prepare nebivolol delayed-release granules.
  • GPCC-1 fluidized bed dryer
  • Valsartan pre-release granules are compressed into a rotary tablet press (MRC-33: Sejong Pharmatech, Korea) equipped with a 6 mm diameter punch.Navivolol delayed-release granules hydrochloric acid rotary tablets (RC-30: Sejong Pharmatech, equipped with a 5 mm diameter punch) Korea). Tablet-finished tablets were coated with a coating solution in which hydroxypropylmethylcellulose 2910, polyethylene glycol 6000, and titanium oxide were dissolved and dispersed in ethanol and purified water. Each coated tablet was packaged in a single press through pack (PTP) packaging container with a packaging machine (WiderVII, Bucheon machine, Korea) to prepare a packaging kit for simultaneous use.
  • PTP press through pack
  • nebivolol hydrochloride, microcrystalline cellulose and sodium lauryl sulfate were appled in a No. 35 sieve, mixed in a double cone mixer, and then poured into a fluidized bed granulator (GPCG 1: Glatt), and separately hydroxypropyl cellulose. After spraying the binder solution dissolved in water to form granules, drying was completed. Carbomer 71G was added to the granules in a powder state and mixed for 10 minutes. Magnesium stearate was added thereto and mixed with a final double cone mixer, and the final mixture was rotary tablet press (MRC-33: Sejong Pharmatech, Korea). Uncoated tablet was prepared by tableting with a 7 mm diameter punch.
  • the valsartan coating solution was prepared by dissolving valsartan, colloidal silicon oxide, poloxamer, and hydroxypropylmethylcellulose in a mixture of ethanol and methylene chloride with the components and contents shown in Table 2.
  • Hydrochloric acid nebivolol uncoated tablets were administered to a high coater (SFC-30F Sejong Machinery, Korea) and coated with valsartan coating solution. After the drug coating was completed, hydroxypropylmethylcellulose 2910, polyethylene glycol 6000, and titanium oxide were coated using a coating solution dissolved and dispersed in ethanol and purified water.
  • Valsartan pre-release granules were prepared in the same manner as in Example 11 (1), with the components and contents shown in Table 2.
  • nucleated tablet tableting machine Kilian
  • hydrochloric acid nebivolol osmotic nuclear tablets and valsartan pre-release granules as outer layers, tablets were made with a 12 mm diameter punch and then a high coater ) To form a film coating layer to prepare a nucleated tablet. Tablets having been tableted were coated with a coating solution in which hydroxypropylmethylcellulose 2910, polyethylene glycol 6000, and titanium oxide were dissolved and dispersed in ethanol and purified water.
  • Example 2 (2) Prepared in the same manner as in Example 2 (2), except that Eudragit RL was used instead of cellulose acetate (acetal group 32%) and cellulose acetate (39.8%) with the ingredients and contents shown in Table 3. It was.
  • apple nebivolol hydrochloride, microcrystalline cellulose and sodium lauryl sulfate were appled in a No. 35 sieve, mixed in a double cone mixer, and then put into a fluidized bed granulator (GPCG 1: Glatt), and separately hydroxypropyl cellulose.
  • GPCG 1 Glatt
  • Carbomer 71G was added to the granules in a powder state and mixed for 10 minutes.
  • Magnesium stearate was added thereto and mixed in a final double cone mixer, and the final mixture was mixed with a rotary tablet press (MRC-33: Sejong Pharmatech).
  • the uncoated tablet thus prepared was coated with a coating solution in which phthalic acid hydroxypropylmethylcellulose (Shin-etsu, Japan) was dissolved in a mixed solvent of methylene chloride and ethanol to prepare a core tablet.
  • phthalic acid hydroxypropylmethylcellulose Shin-etsu, Japan
  • telmisartan (Ranbaxy, India) was used instead of mbvalsartan.
  • Example 5 The ingredients and contents shown in Table 5 were prepared according to the method of Example 1 (2), except that Eudragit RS was used instead of cellulose acetate (acetal group 32%) and cellulose acetate (39.8% acetal group). .
  • sugar seeds were added to a fluidized bed granulator (GPCG 1: Glatt), and then poloxamer, sodium hydroxide, hydroxypropylmethylcellulose and candee were mixed with purified water and ethanol.
  • GPCG 1 Glatt
  • poloxamer, sodium hydroxide, hydroxypropylmethylcellulose and candee were mixed with purified water and ethanol.
  • cellulose acetate (acetal group 32%) (Eastman Chemical Company, USA) and cellulose acetate (acetal group 39.8%) (Eastman Chemical Company, USA) are dissolved in a mixed solvent of ethanol and methylene chloride After the preparation, the tablet was coated with a high coater (SFC-30F, Sejong Machinery, Korea) to prepare an osmotic tablet.
  • a high coater SFC-30F, Sejong Machinery, Korea
  • the candesartan cilexetil pre-release pellet and atenolol delayed-release tablets were filled into capsule 0 using a capsule charger to prepare a capsule.
  • Athenolol, microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA), sodium lauryl sulfate, hydroxypropyl cellulose, carbomer 71G, and crosslinked vinylpyrrolidone were weighed into the ingredients and contents shown in Table 6.
  • the mixture was prepared by mixing for 20 minutes in a cone mixer. Magnesium stearate was added to the mixture for final mixing, followed by compression with a 5 mm diameter punch using a rotary tablet press (Sejong Pharmatech-30: Sejong).
  • candesartan cilexetil, colloidal silicon oxide, poloxamer, and hydroxypropyl cellulose were dissolved in a mixture of ethanol and methylene chloride to prepare a candesartan cilexetil coating solution.
  • Atenolol delayed-release tablets were administered to a high coater (SFC-30F Sejong Machinery, Korea) and coated with the candesartan cilexetil coating solution of (2). After the drug coating was completed, hydroxypropylmethylcellulose 2910, polyethylene glycol 6000, and titanium oxide were coated with a coating solution dissolved and dispersed in ethanol and purified water.
  • Carvedilol delayed-release granules were prepared in the same manner as the method of preparing granules of delayed-release layer granules of (2) nebivolol hydrochloride of Example 1, except that carvedilol was used instead of nebivolol hydrochloride in the ingredients and contents shown in Table 6. Prepared.
  • the carvedilol delayed-release layer granules prepared in (2) were compressed into tablets with a rotary tablet press (MRC-33: Sejong Pharmatech, Korea) equipped with a 5 mm diameter punch to prepare an inner core, followed by a 12 mm punch equipped oil. It was compressed with the eprosartan fast-release granules of (1) in a nuclear tablet press (RUD-I Killian, Germany). Tablets are finished tablets hydroxypropyl methyl cellulose 2910, polyethylene glycol 6000, titanium oxide was dissolved and dispersed in ethanol and purified water coating the tablet with a coating solution to prepare a nucleated tablet.
  • MRC-33 Sejong Pharmatech, Korea
  • Example 6 The ingredients and contents shown in Table 6 were prepared according to the method of Example 36 (1), except that candesartan cilexetil (Ranbaxy, India) was used instead of eprosartan.
  • Comparative dissolution tests were performed using valsartan (Novartis: Diovan, Valsartan monolith) and nebivolol (Forest labs: Bystolic, nebivolol monolith) as the tablets and the control agent obtained in Example 2.
  • the dissolution test was performed by changing the elution solution from 0.1 N-hydrochloric acid solution (acidic environment) to pH 6.8 (phosphate solution).
  • phosphate buffer was used.
  • the dissolution test method for each component is as follows, and the results are shown in FIG. 1 (the number of test samples is 12 pieces each).
  • the tablet of Example 2 was found to have almost the same elution characteristics as the valsartan component in the dissolution test under the following conditions, compared to the control agent Diovan, and the nebivolol component was compared with the control agent Bystolic. Very slow elution rates can be seen.
  • the nebivolol / valsartan double tablets of Example 2 had a dissolution rate of all of the nebivolol components up to 2 hours within 10%, much slower than the dissolution rate of the control formulation (about 99%).
  • the tablets of the nebivolol / valsartan of the present invention are unlikely to be metabolized in the liver before the valsartan because the initial release of the nebivolol is much slower than the valsartan, in contrast to the control drug nevivolol single agent.
  • Dissolution test basis Dissolution test method of General Test Method
  • Test method Paddle method, 50 revolutions / minute
  • Test solution 0.1 N hydrochloric acid solution, 500 mL (0-2 hours),
  • Test method Paddle method, 50 revolutions / minute
  • Formulations of various formulations obtained in Examples 2, 3, 4, and 5 were carried out according to the nebivolol comparative elution method of Experimental Example 1, and the results are shown in FIG. 2 (the number of test samples was 12 each).
  • the preparation prepared in Examples 2 to 5 for the purpose of the present invention can control the blood pressure during the day time of nebivolol delayed eluting during oral administration during the evening.
  • the formulation of the present invention can be developed in all formulations of the examples.
  • Example 14 Using the tablets prepared in Example 14 and the control agent Losartan (Merck: Cozaar, Losartan single agent) and nebivolol (Forest labs: Bystolic, Nebivolol single agent) according to the comparative test method of Navivolol of Experimental Example 1 Losartan comparative dissolution test method was carried out as follows, each result is shown in Figure 3 (the number of test samples each 12).
  • FIG. 3 is a result of comparative dissolution test of the tablet of Example 14, a combination agent of losartan and nebivolol, which is an angiotensin-2 receptor antagonist drug, and a control drug of losartan and nebivolol.
  • the drug began to elute 2 hours after the start and it was confirmed that more than 80% eluted within 1 hour.
  • Dissolution test basis 'Losartan Potassium tablet' in Dissolution Methods for Drug Products (FDA)
  • Test method Paddle method, 50 revolutions / minute
  • Test liquid water (degassing), 900 mL
  • Figure 4 shows the comparative dissolution test results of the formulations of Examples 21, 22, 23, 24 and the nebivolol control, the nebivolol is 1 hour after starting the drug dissolution 2 hours after the start of the dissolution test intended by the present invention It was confirmed that more than 80% eluted within.
  • Example 34 A comparative dissolution test was conducted using the tablet prepared in Example 34 and the control agent candesartan (Astrazeneca: Atacand, candesartan mono) and atenolol (modern drugs: Hyundai tenolmin tablet, atenolol mono). It was.
  • the dissolution test was performed by changing the eluate from 0.1 N hydrochloric acid solution (acidic environment) to pH 6.8 (phosphate) solution.
  • the dissolution test method for each component is as follows, and the results are shown in FIG. 6 (the number of test samples is 12 each).
  • Example 34 the tablet of Example 34 was confirmed that the candesartan component in the dissolution test under the following conditions compared to the control agent atacane (Astrageneca: Atacand, Candesartan single agent), but almost the same elution characteristics, The norol component can be seen that the initial drug release is delayed when comparing the dissolution results with the control agent Hyundaitenolmin.
  • the atenolol / candesartan tablet of the present invention is unlikely to be metabolized in the liver prior to candesartan because the initial release of atenolol is much slower than candesartan, unlike the atenolol monotherapy, which is a reference drug.
  • Dissolution test basis Dissolution test method of General Test Method
  • Test method Paddle method, 50 revolutions / minute
  • Test solution 0.1 N hydrochloric acid solution, 500 mL (0-2 hours),
  • Dissolution test basis 'Candesartan Cilexetil tablet' in Dissolution Methods for Drug Products (FDA)
  • Test method Paddle method, 50 revolutions / minute
  • Formulations of the various formulations obtained in Examples 36, 37 and 39 and the control agent eprosartan (Abbott: Teveten, eprosartan monolith), carvedilol (common root: dilatrene, carvedilol monolith), telme Comparative dissolution tests were carried out using Sartan (Boehringer ingelheim: Micardis, Telmisartan mono), Metoprolol (Astrazeneca: Toprol-XL, Metoprolol sustained-release tablet mono).
  • the dissolution test was performed by changing the eluate from 0.1 N hydrochloric acid solution (acid environment) to pH 6.8 (phosphate solution).
  • the dissolution test method for each component is as follows, and the results are shown in FIGS. 7, 8, and 9 (the test population is 12 each).
  • carvedilol and metoprolol which are adrenergic beta receptor blocker-based drugs other than nebivolol, also have an intended release pattern.
  • Dissolution test basis Dissolution test method of General Test Method
  • Test method Paddle method, 50 revolutions / minute
  • Test solution 0.1 N hydrochloric acid solution, 500 mL (0-2 hours),
  • Test method Paddle method, 50 revolutions / minute
  • Test solution 0.1 N hydrochloric acid solution, 500 mL (0-2 hours),
  • Dissolution test basis 'Eprosartan Mesylate / Hydrochlorothiazide tablet' in Dissolution Methods for Drug Products (FDA)
  • Test method Paddle method, 75 revolutions / minute
  • Dissolution test basis 'Telmisartan tablet' in Dissolution Methods for Drug Products (FDA)
  • Test method Paddle method, 75 revolutions / minute
  • the formulation of the present invention exhibits an equal anti-pressure action and prevents complications, and is particularly useful for hypertension patients with complications, suppressing blood pressure during sleep, and for drug interactions. Reduce side effects.

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Abstract

La présente invention concerne une préparation pharmaceutique comprenant un compartiment à libération précoce, contenant un antagoniste du récepteur de l'angiotensine 2 en tant qu'ingrédient pharmacologiquement actif, et un compartiment à libération retardée, contenant en tant qu'ingrédient pharmacologiquement actif un bêta-bloquant qui bloque l'action de l'adrénaline. La préparation de la présente invention permet de maintenir une pression à un niveau constant et d'éviter les complications. La préparation permet, en particulier, de maintenir la pression sanguine à un niveau constant pendant une période à risque de complications. Ainsi, la préparation a l'avantage de pouvoir être utilisée par des patients souffrant d'hypertension ayant entraîné des complications ou des patients nécessitant une diminution de pression sanguine pendant leur sommeil, etc., et de réduire les effets indésirables liés aux interactions médicamenteuses.
PCT/KR2009/003969 2008-07-18 2009-07-17 Préparation pharmaceutique WO2010008244A2 (fr)

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KR20070078625A (ko) * 2006-01-27 2007-08-01 씨제이 주식회사 멀티플 유닛 타입 서방성 경구 제제 및 그 제조방법
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WO2017048033A1 (fr) * 2015-09-15 2017-03-23 Chong Kun Dang Pharmaceutical Corp. Préparation d'un mélange de produits pharmaceutiques
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