WO2011028016A2 - Pharmaceutical preparation comprising beta-adrenergic blockers and angiotensin ii receptor blockers - Google Patents

Pharmaceutical preparation comprising beta-adrenergic blockers and angiotensin ii receptor blockers Download PDF

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Publication number
WO2011028016A2
WO2011028016A2 PCT/KR2010/005918 KR2010005918W WO2011028016A2 WO 2011028016 A2 WO2011028016 A2 WO 2011028016A2 KR 2010005918 W KR2010005918 W KR 2010005918W WO 2011028016 A2 WO2011028016 A2 WO 2011028016A2
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Prior art keywords
cellulose
release
delayed
copolymer
tablet
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PCT/KR2010/005918
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French (fr)
Korean (ko)
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WO2011028016A3 (en
Inventor
김성욱
전성수
구자성
김진욱
이나영
Original Assignee
한올바이오파마주식회사
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Publication of WO2011028016A2 publication Critical patent/WO2011028016A2/en
Publication of WO2011028016A3 publication Critical patent/WO2011028016A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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

  • compositions comprising beta adrenergic blockers and angiotensin-2 receptor antagonists
  • the present invention relates to a pharmaceutical formulation containing a metha adrenergic blocker and an angiotensin-2 receptor antagonist as an active ingredient, each component is released at a time difference.
  • Hypertension is a symptom caused by multiple causes. Therefore, it is difficult to determine in advance what will be the consequences of using a single antipressant [Journal of hypertension 1995: 9: S33-S36]. For this reason, a combination of anticoagulants has been on the rise for more effective treatments.
  • JNC Joint Nat ional Committee
  • US Patent Publication No. 2005—0004194 discloses a combination of angiotensin converting enzyme inhibitors and angiotensin-2 receptor antagonists for treating cardiovascular diseases by reducing side effects and enhancing effects on patients with myocardial infarction.
  • Korean Patent Publication No. 2004 ⁇ 0078140 discloses an antihypertensive complex preparation of valsartan and calcium channel blocker, which is an angiotensin-2 receptor antagonist.
  • a simple combination of beta adrenergic blocker and angiotensin-2 receptor antagonist Administration of the agent may affect pharmacokinetics, such as peak blood concentration (Cmax) and area under the blood plasma curve (AUC).
  • Cmax peak blood concentration
  • AUC area under the blood plasma curve
  • a type of angiotensin-2 receptor antagonist, navibble does not affect losartan's pharmacokinetics, but losartan is The peak blood concentration (Cmax) and the area under the blood curve (AUC) were reduced (Cl inical Pharmacology Review).
  • the inventors of the present invention have attempted to develop a formulation that does not affect the pharmacokinetic properties such as absorption, dash, distribution, and excretion of each component, as well as combining effective components for the target disease.
  • the problem to be solved by the present invention is to provide an agent that exhibits an equal anti-pressure action and prevent complications, and reduces side effects due to drug interactions.
  • the present invention provides a pharmaceutical formulation comprising a prior release compartment comprising a beta adrenergic blocker as a pharmacologically active ingredient, and a delayed release compartment comprising an angiotensin-2 receptor antagonist as a pharmacologically active ingredient.
  • the angiotensin-2 receptor antagonist of the formulation-delayed-releasing compartment of the present invention is preferably 1 hour to 8 hours after the delayed time period, preferably 1 to 8 hours after the release of the beta adrenergic blocker. Can be released later.
  • the formulation of the present invention may be delayed to within 20% of the total amount of angiotensin-2 receptor antagonist released within 2 hours after the release of the beta adrenergic blocker. .
  • the formulation of the present invention may include 0.1-350 parts by weight of an angiotensin ⁇ 2 receptor antagonist based on 1 part by weight of the beta adrenergic blocker.
  • Pre-release compartment refers to the compartment in which the active ingredient is released earlier than the delayed-release compartment in the pharmaceutical formulation of the present invention, and in addition to the pharmacologically active ingredient, It may further include a pharmaceutically acceptable additive.
  • the pharmacologically active component of the prior-release compartment is a beta-adrenergic blocker, and the beta-adrenergic blocker blocks the excitability of the sympathetic nervous system due to the adrenergic stimulation of ⁇ receptors present in the cardiovascular and smooth muscle, hypertension, Drugs used to treat a variety of heart diseases, including angina and deep vein, for example, alprenole, acebuto, amosulal, arotinol, athenol, befunol, betaxol, Bevan roll, Bisoph, Boffindol, Bucumol, Buffet roll, Bupral, Bunitrol, Buffandol roll, Bhuttopil, Carazole, Catheters, Carvedil, Selelyph, Cetamolol chloranol Dilole, epanol, indenol, labetatal, levobunol, mepindol, metipranol, metopelol, morphol,
  • Naviball is preferable, and Naviball hydrochloride is more preferable.
  • the beta adrenergic blocker may comprise 1 to 1400 mg of the formulation, preferably 2 to 300 mg. The dose is based on a daily adult (weight 65-75kg adult male).
  • Naviball is the fourth-generation beta adrenergic blocker, not only has all the benefits of the first, second and third generation beta-adrenergic blockers, but also produces NO, which expands peripheral blood vessels.
  • stage I side effects such as sexual function degeneration, lipid increased, diabetes Ill Chemistry, limb coldness which shows the effect on expansion Dextrocardia heart failure.
  • it is suitable for elderly patients with systolic hypertension, those with heart failure, elderly diabetic hypertension, elderly hyperlipidemic hypertension, and hypertension combined with heart failure.
  • Naviball can obtain an effective therapeutic effect by combining angiotensin-2 receptor antagonist with hypertension in severely ill patients such as heart failure and myocardial infarction.
  • the formulation of the present invention is a pharmacologically used additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, stabilizers, pH adjusting agents, dissolution aids, etc. within the scope of not impairing the effects of the present invention. It may be formulated further using within a range that does not interfere with the release of the active ingredient.
  • the diluent is starch, microcrystalline salose, lactose, glucose, manny, alginate, alkaline earth metal salt, clay, polyethylene glycol, dicalcium phosphate, or A mixture or the like can be used.
  • the binder may contain starch, microcrystalline cellulose, highly dispersible silica, manny, sucrose, lactose, polyethylene glycol, pulley vinylpyridone, hydroxypropylmethylcellulose, hydroxypropylcelose, Natural gums, synthetic gums, polyvinylpyrrolidone copolymers, povidone, gelatin, or a combination thereof can be used.
  • the disintegrating agent may be a starch or modified starch such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch (pregelatinized starch); Clay such as bentonite, montmorillonite, or veegum; Cellulose such as microcrystalline cellulose, hydroxypropyl salose or carboxymethyl cellulose; Algins such as alginic acid natcom or alginic acid; Crosslinked cells such as sodium croscarmel lose; Guar gum; Gums such as xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyridone (crospovidone); Effervescent preparations such as sodium bicarbonate, citric acid, or a combination thereof can be used.
  • Clay such as bentonite, montmorillonite, or veegum
  • Cellulose such as microcrystalline cellulose, hydroxypropyl salose or carboxymethyl cellulose
  • Algins such as alginic acid natcom or al
  • the lubricant includes talc, stearic acid, magnesium stearate, calarate stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl Monostearate, glyceryl palmitostearate, polyethylene glycol, or a combination thereof may be used.
  • the stabilizer may be a salt of an alkali metal, a salt of an alkaline earth metal, an alkalizing agent, an ascorbic acid, citric acid, butylated hydroxy anisole, butylated hydroxy aluene, a tocopherol derivative, Calcium carbonate, sodium carbonate, sodium hydrogen carbonate, magnesium oxide, magnesium carbonate, sodium citrate and the like can be used.
  • the pH adjusting agent may be used as an acidifying agent such as chemistry, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid and / or basicizing agents such as precipitated calcium carbonate, aqueous ammonia, meglumine and the like.
  • the dissolution aid may be polyoxyethylene sorbitan fatty acid ester such as sodium lauryl sulfate, polysorbate, sodium docuate, or the like.
  • a pharmaceutically acceptable additive may be selected and used to formulate the formulation of the present invention.
  • the range of additives usable in the present invention is not limited to the use of the above additives, and the above additives may be formulated to contain a range of dosages by selection.
  • the delayed-release compartment has a predetermined time of release of the active ingredient of the prior-release compartment. After which the active ingredient is released.
  • Delayed-release compartments include (1) pharmacologically active ingredients and (2—1) release control substances or (2-2) osmotic pressure regulators and semipermeable membrane coating agents, and as needed, (3) It may further comprise acceptable additives.
  • the pharmacologically active component of the delayed-release compartment is an angiotensin-2 receptor antagonist, which blocks angiotensin 2, one of the sources of blood vessel contraction, to bind to the ATI receptor in the angiotensin receptor.
  • angiotensin-2 receptor antagonist which blocks angiotensin 2, one of the sources of blood vessel contraction, to bind to the ATI receptor in the angiotensin receptor.
  • drugs that lower blood pressure in both diastolic phases for example losartan, valsartan, telmisartan, irbesartan, candesartan, olmesartan, eprosartan and their isomers.
  • It is selected from pharmaceutically acceptable salts and prodrugs thereof, and may contain 1 to 1500 mg of the preparation, preferably 10 to 800 mg.
  • the dose is based on a daily adult (65-75 kg adult male).
  • the prodrug is preferably emmesartan medoc rough.
  • the delayed-release compartment in the pharmaceutical formulation of the present invention includes a release controlling substance
  • the release controlling substance of the present formulation includes, for example, an enteric polymer, a water insoluble polymer, a hydrophobic compound, a hydrophilic polymer, and these It is at least one selected from a mixture of, preferably at least one selected from a soluble polymer and an enteric polymer.
  • 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 angiotensin-2 receptor antagonist. Excessive weight delayed drug release may result in a significant clinical effect.
  • the enteric polymer is insoluble or stable under acidic conditions.
  • enteric polymers usable in the present invention are enteric cellulose derivatives, enteric acrylic acid copolymers, enteric polymethacrylate copolymers, enteric maleic acid copolymers, enteric polyvinyl derivatives, and combinations thereof. It is one or more selected.
  • enteric cellulose derivatives are hydroxypropylmethylcelloselooseacetate succinate (or hypromelloseacetatesuccinate), hydroxypropylmethylcelloseloose phthalate (or hypromellose). Osphthalate), hydroxymethylethyl cell, cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate Nate, Salose Acetate Maleate, Cellulose Benzoate Phthalate, Cellulose Spropionate Phthalate, Methyl Cellulose Phthalate, Carboxymethylethyl Saloose, Ethylhydroxyethyl Cellulose Phthalate, Methyl At least one selected from hydroxyethyl cellose and a mixture thereof;
  • the enteric acrylic acid copolymer may include styrene-acrylic acid copolymer, methyl acrylate-acrylic acid copolymer, methyl methacrylate acrylic acid copolymer, butyl acrylate-styrene-acryl
  • the enteric maleic acid-based copolymers include vinyl acetate-maleic anhydride copolymer, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer,.
  • the enteric pulley vinyl derivative is preferably at least one selected from polyvinyl alcohol phthalate, polyvinylacetate phthalate, polyvinylbutyrate phthalate, polyvinylacetacetal phthalate, and mixtures thereof. More preferred examples of the enteric polymer are at least one selected from hydroxypropylmethylsal phthalate and methyl methacrylate copolymer.
  • 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 may be easily dissolved at a pH of less than 5 when the content is less than 0.1 parts by weight. 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 soluble polymer refers to a polymer that is insoluble in pharmaceutically acceptable water that controls the release of the drug.
  • Soluble polymers usable in the present invention include polyvinyl acetate, soluble soluble methacrylate copolymers (e.g. poly (ethyl acrylate, methyl methacrylate) co-polymers (e.g. Eudragit NE30D), poly ( Ethyl acrylate, methyl methacrylate, trimethylaminoethyl methacrylate chloride) copolymers (e.g.
  • Eudragit RS, RL etc., ethyl cellulose, sealulose ester, cellulose ether, Cellulose Acylate, Cellulose Disylate, Cellulose Triacylate, Cellulose Acetate, Cellulose Diacetate, Cellulose Triacetate And at least one selected from the group consisting of a mixture thereof, and more preferably polyvinylacetate, ethyl salose, poly (ethyl acrylate, methyl methacrylate, and trimethylaminoethyl methacrylate. Chloride) copolymer, and cellulose acetate.
  • the water-soluble 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. In case of more than 30 parts by weight, excessive elution may be 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 acid alcohols, waxes, inorganic substances, and mixtures thereof.
  • the fatty acids and fatty acid esters may be selected from glyceryl palmitostearate, glyceryl stearate, glyceryl distearate, glyceryl bihenate, cetyl palmitate, glyceryl monoacrylate, stearic acid and mixtures thereof.
  • the fatty acid alcohols are at least one selected from cetostearyl alcohol, cetyl alcohol, stearyl alcohol, and mixtures thereof;
  • the waxes are selected from carnauba wax, beeswax, microcrystalline wax, and mixtures thereof.
  • the inorganic material is selected from talc, precipitated carbonated carbon, monohydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, non-gum and mixtures thereof.
  • 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 dissolution may be delayed.
  • the hydrophilic polymer refers to a polymer material dissolved in pharmaceutically acceptable water that controls the release of the drug.
  • hydrophilic polymers usable in the present invention include sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl copolymers, and mixtures thereof. At least one selected from the group consisting of.
  • the sugars include dextrin, plydextrin, textlan, pectin and pectin derivatives, alginates, polygalacturonic acids, xylans, arabinoxylans, arabinogal lactans, starches, hydroxypropylstarches, amylose, amylopectin, and these At least one selected from the complications of;
  • the cellulose derivatives include hydroxypropylmethylcellose (or hypromellose), hydroxypropylsalose, hydroxymethylcellose, At least one selected from hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, natcom, hydroxypropyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose, and combinations thereof ego ;
  • the gum is at least one selected from guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, arabic gum, gellan gum, xanthan gum, and combinations thereof
  • the polyethylene derivative is at least one selected from polyethylene glycol, polyethylene oxide and mixtures thereof;
  • the carboxyvinyl copolymer is a carbomer.
  • Preferred examples of the hydrophilic polymer are selected from polyvinyl pyridone, hydroxypropyl cellulose, hypromellose, and poly (ethyl acrylate-methyl methacrylate-triethyl aminoethyl-methacrylate chloride) copolymer 1 or more types.
  • the hydrophilic polymer is 0.05 parts by weight to 30 parts by weight with respect to 1 parts by weight of the active ingredient, preferably 0 . May contain from 5 to 20 parts by weight, and 0.05 parts by weight, and the case is concerned with not control the release rate of less than, there is there fear of excessive output is delayed for the case of exceeding 30 parts by weight.
  • the delayed-release compartment of the present invention includes an osmotic pressure control agent and may be coated with a semipermeable membrane coater.
  • 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 regulator may be included in an amount of 0.01 parts by weight to 10 parts by weight, preferably 0.05 parts by weight and 0.5 parts by weight, based on 1 part by weight of the active ingredient. It may be difficult to obtain a delayed delayed release property less than 0.01 parts by weight, and drug release may be delayed above 10 parts by weight to obtain a significant clinical effect.
  • the semi-permeable membrane coating base is a substance blended into the coating layer of the pharmaceutical formulation, and is used to form a film that allows some components to pass but does not pass other components. Say a substance.
  • the semipermeable membrane coating base may use the above-mentioned water-insoluble polymer.
  • the semi-permeable membrane coating base includes, for example, pulley vinyl acetate, polymethacrylate copolymer, pulley (ethyl acrylate, methyl methacrylate) copolymer, poly (ethyl acrylate), methyl methacrylate, Trimethylaminoethyl methacrylate chloride) Copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cell And at least one selected from the group consisting of rose acetate, cellulose diacetate, cellulose triacetate, and combinations thereof.
  • the semi-permeable membrane coating base may be included in an amount of 0.01 parts by weight to 10 parts by weight, preferably 05 parts by weight to 1.25 parts by weight, with respect to 1 part by weight of the active ingredient.
  • the amount is 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 formulation of the present invention is a diluent other than those referred to 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 binders, disintegrating agents, lubricants, pH adjusting agents, antifoaming agents, dissolution aids and the like can be formulated by further using within a range not departing from the nature of delayed release.
  • the pharmaceutical preparations of the present invention may be prepared in various formulations, and may be formulated, for example, in tablets, powders, granules, or capsules, such as uncoated tablets, coated tablets, multilayer tablets, or nucleated tablets. .
  • the formulations of the present invention are tablets which are selectively mixed with additives such as granules constituting the pre-release compartment and granules constituting the delayed-release compartment and the like, and have a pre-release compartment and a delayed-release compartment in a single tablet.
  • the active ingredients in the compartments may be eluted separately to give their 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 is a film coating consisting of a film consisting of a tablet consisting of a delayed-release compartment and a pre-release compartment enclosing the outside of the tablet It may be in a tableting form, and as the film coating layer is dissolved, the active component of the film coating layer is eluted first.
  • the pharmaceutical preparation of the present invention is obtained by mixing pharmaceutical additives in granules constituting the delayed-release compartment and the prior-release compartment, and tableting in two or three tablets using a multiple tableting machine.
  • the delayed-release compartment and the prior-release compartment may be in the form of a multilayered multi-layered tablet in which a layer is formed.
  • This formulation is a tablet for oral administration which is formulated to enable pre-release and delayed release in layers.
  • the pharmaceutical preparation 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 tableting. Then, the surface of the tablet is coated with a semipermeable membrane coating agent to make it an inner core.
  • the granules constituting the pre-release compartment are mixed with pharmaceutical additives and then compressed into tablets as an outer layer to have a delayed-release inner core, and the surface of the inner core is surrounded by a prior release layer.
  • the pharmaceutical formulation of the present invention may be in the form of a capsule, granules, pellets, or tablets consisting of delayed-release compartments, and granules, granules, granules, tablets, or tablets of prior-release compartments.
  • Tablets consisting of delayed-release compartments 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 hydroxypropylmethyl cellulose, or a combination 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 may comprise (3) a prior-release compartment (b) a delayed-release compartment and (C) may consist of a container for stratifying the pre-release compartment and the sustained release compartment.
  • the kit produces particles, granules, pellets, or tablets that constitute the prior release compartment, and separately prepares the particles, granules, pellets, or tablets that constitute the delayed release compartment, such as foils, blisters, bottles, and the like. It can be prepared in a form that can be filled and taken simultaneously.
  • the formulation of the present invention may further form a coating layer on the outside of the delayed-release compartment and / or the prior-release compartment. That is, for the purpose of controlling release or stabilizing the product on the surface of particles, granules, pellets, or tablets, which consist of a sustained-release compartment and / or a prior-release compartment. It can be coated.
  • the formulation according to the present invention is also provided in a state such as uncoated tablets without additional coating, but if necessary, a coating layer is formed on the outside of the formulation to further form a coating tablet. It may be a formulation. By forming the coating layer, it is possible to further secure the stability of the seed, the active ingredient.
  • the coating layer may be appropriately selected by a person skilled in the art from a method of forming a film-like coating layer on the surface of the tablet layer, and a method such as a fluidized bed coating method or a fan coating method may be applied.
  • a method such as a fluidized bed coating method or a fan coating method may be applied.
  • the pan coating method can be applied.
  • the coating layer may be formed by using a coating agent, a coating aid, or a combination thereof.
  • the coating agent may be formed by cellulose such as hydroxypropyl methyl salose, hydroxy propyl cellulose, or the like.
  • Derivatives, sugar derivatives, polyvinyl derivatives, waxes, fats, gelatins, or mixtures thereof, and the like, and coating aids include 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. If less than 0.5% by weight, it may be difficult to secure stability depending on the product's protection and formulation, and if it exceeds 15% by weight, there is a risk of affecting the release pattern of the active ingredient.
  • the formulation of the present invention may be administered for evening administration once a day between 5 to 11 o'clock in the evening to exhibit an anti-pressure action and a complication prevention effect evenly for 24 hours.
  • the -2 receptor antagonist effectively lowers blood pressure after dawn, resulting in an even 24 hour anti-hypertensive action and complication prevention.
  • the blood pressure can be maintained evenly during the risk of complications (new morning to morning time). It is useful for hypertensive patients with complications that must be suppressed.
  • the formulation of the present invention is useful for suppressing non-dipper type hypertension, which is a type of high blood pressure that does not lower blood pressure during sleep.
  • the non-dipper type hypertension is present in the elderly, diabetics, cardiac hypertrophy and other complications such as stroke.
  • the agent of the present invention is taken in the evening hours, which is useful for suppressing sleep syndrome blood pressure.
  • the formulations of the present invention release angiotensin-2 receptor antagonists and beta adrenergic blockers by first releasing the beta adrenergic blockers that are relatively soluble in acid and delaying the release of angiotensin-2 receptor antagonists with low solubility in acid.
  • Angiotensin-2 receptor antagonist with low solubility throughout the gastrointestinal tract which is acidic, does not dissociate from the formulation due to solidification in the stomach, or temporarily cured black due to low solubility. This can avoid phenomena affecting the release and absorption of subsequently released drug.
  • the beta adrenergic blocker Since the beta adrenergic blocker first enters the liver and is activated by the cytokine P450 enzyme in the liver, the angiotensin-2 receptor antagonist passes through the liver, thus the beta adrenergic blocker and the angiotensin-2 receptor antagonist. It blocks the metabolic interactions that can occur in the liver, reducing the side effects of drug interactions.
  • the -2 receptor antagonist effectively lowers blood pressure after dawn, resulting in an even 24 hour anti-hypertensive action and complication prevention.
  • the present invention provides a method for treating cardiovascular disease, comprising the step of administering the agent of the present invention to a mammal including a human.
  • the therapeutic method of administering the agent of the present invention once daily, especially in the evening (17 to 23 o'clock), can exert anti-pressure action and prevent complications evenly for 24 hours, thereby treating cardiovascular diseases. .
  • the cardiovascular disease is meant to include hypertension, or high blood pressure complications.
  • the pharmaceutical formulation of the present invention may be prepared by any suitable method in the art, for example
  • Chronotherapeut i cs 2003, Peter Redfern, PhP
  • Remington's Pharmaceutical Science Remington's Pharmaceutical Science (Recent Edition, Mack Publ i shing Company, Easton PA), etc. It may be prepared by a method comprising the following steps specifically.
  • the active ingredient of the delayed-release compartment is administered with one or two or more release control substances selected from enteric polymers, water insoluble polymers, hydrophobic compounds, and hydrophilic polymers, and conventional additives used in pharmaceutical preparations.
  • release control substances selected from enteric polymers, water insoluble polymers, hydrophobic compounds, and hydrophilic polymers, and conventional additives used in pharmaceutical preparations.
  • the second step is a conventional method for producing oral solids by mixing, associating, drying, granulating or coating, and tableting by administering the active ingredient of the prior release compartment and a conventionally acceptable pharmaceutically acceptable additive. It is a step of obtaining the pre-release granules or tablets obtained through the process.
  • the granular black tablets obtained in the first and second steps are mixed with pharmaceutical excipients, and then compressed or compressed into layers 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 will be described in more detail as follows, but is not limited thereto. [87] [A] Preparation of Two-Phase Matrix Tablets
  • the mixture is 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 properties.
  • 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 and further coated with black to prepare tablets.
  • a release control material By dissolving and dispersing in the film coating solution of the coating on the tablet outer layer can be prepared orally administered film coating tablet containing the active ingredient in the C film coating.
  • the granules obtained in the first step and additionally coated or dried with the release control material and the granules obtained in the second step may be prepared in a double tablet using a tablet press.
  • Coated multilayer tablets may be prepared by formulating or coating triple or more multilayered tablets by adding a release aid layer as required by the formulation design or need.
  • [93] [D] Preparation of Nucleated Tablets 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 be coated as they are or additionally to the inner core, followed by the nucleated tablet together with the fruit obtained in the second step.
  • a tableted nucleated tablet may be prepared by tableting with a tableting machine to prepare a nucleated tablet in the form of a pre-emission layer surrounded by the surface of the inner core or by further coating.
  • the granules obtained in step 1 are additionally coated as is or with a release control substance, and the dried granules or tablets and the granules or tablets obtained in the second step are placed in a capsular bed electric converter and the effective amount of each principal component is applied to a constant sized capsule.
  • the amount can be layered to produce a capsule.
  • Capsule preparations can be prepared by layering into capsules with a capsular layer pendulum after mixing with release control pellets containing the active ingredient of the release compartment.
  • the human dosage of the preparation 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, adult beta adrenergic blocker and angiotensin- As a total amount of the two receptor antagonists, 2.0 to 2200 mg can be administered per day, and preferably 10.0 to 1900 mg per day can be used to exert anti-pressure action and prevent complications.
  • the formulation of the present invention is formulated to conform to the theory of drug metabolic enzyme interactions and the principle of time difference administration by enabling time difference dissolution between two components of angiotensin-2 receptor antagonist and beta adrenergic blocker.
  • Drug movement Compared to when released in the city can increase the efficacy and reduce side effects.
  • the formulation of the present invention is administered in a time-phase manner in the expression of pharmacological action in each of the components
  • Chronotherapy is a drug delivery system designed to achieve the most ideal effect when absorbed into the body by controlling the controlled release from the body by applying the principle and the Xenobiotics principle of the drug.
  • the pharmaceutical preparation of the present invention exhibits an equal anti-pressure action and prevents complications, and is particularly useful for maintaining hypertension with complications, and for suppressing blood pressure during sleep. It does not affect the release and absorption of each drug and reduces the side effects of drug interactions.
  • Example 1 is a graph showing the dissolution rate of Naviball and Losartan in the formulation of Example 2.
  • Figure 2 is a graph showing the elution of Naviball and Losartan in the formulations of Examples 3, 4 and 5.
  • Example 3 is a graph showing the dissolution of nebivolol and valsartan in the formulation of Example 17.
  • Figure 4 is a graph showing the elution of Naviball and Valsartan in the formulations of Examples 15, 16, and 18.
  • Figure 5 is a graph showing the dissolution rate of Navible and telmisartan in the formulation of Example 27.
  • Fig. 6 is a graph showing the dissolution rate of Naviball and eprosartan in the formulation of Example 28.
  • Example 7 is a graph showing the dissolution rate of carvedil and olmesartan in the formulation of Example 36.
  • the granules were again coated with a solution of cellulose acetate (CA-320S / CA-398NF10, Eastman Chemical Company, USA) and hydroxypropylmethylcellose in a mixture of ethanol and methylene chloride. .
  • colloidal silicon dioxide and stearic acid magnesium are added and mixed to form a rotary tableting machine equipped with a 10.0 mm diameter bias (MRC-33, Sejong Pharmatech). Tableting in Korea).
  • hydroxypropylmethyl cellulose 2910, polyethylene glycol 6000, and titanium oxide were separately dissolved and dispersed in purified water and ethanol mixed solvent as described in the following Table 1 to prepare a coating solution.
  • the tablets were put in a high coater (SFC-30F, Sejong Pharmatech, Korea) and then coated with a coating solution.
  • Example 2 In the same method as in Example 1 (2), the colloidal silicon dioxide and magnesium stearate were added to the Losartan potassium salt non-release granules prepared in the same manner as in Example 1, and In combination, a losartan potassium salt delayed-release layer is prepared.
  • Naviball hydrochloride (Cadi la, India), sodium lauryl sulfate, lactose (Parmatose, DMV Pharma, The Netherlands), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA) Weighed and appled with No. 35 sieve and mixed for 15 minutes in a double cone mixer (Dasan Pharmatech, Korea) to prepare a mixture. Separately, hydroxypropylcellose (HPC-L, Nippon soda, Japan) was dissolved in purified water to prepare a binding solution. The mixture was put into a fluidized bed granulator (GPCG-1: Glatt, Germany) and granulated by addition of a binder solution.
  • GPCG-1 fluidized bed granulator
  • the losartan potassium salt branched granules prepared in the above (2) were stacked in the middle layer (second layer), and the naviball hydrochloride of Example 3 (1) was divided into one layer and three layers.
  • the rotary multi-layer tablet press tablet machine MRC-37T, Sejong Pharmatech, Korea
  • Tableting it was coated in the same manner as the coating method of Example 1 (3).
  • Nucleating tablets were prepared by using a nucleating tableting machine (RUD-I, Ki li an, Deukil) as a core of losartan potassium salt as the inner core, and tableting with hydrochloric acid navigable as the outer layer. After the tableting of the above, separately coated in the same manner as the coating method of Example 1 (3) as shown in the following Table 1 to prepare a nucleated tablet.
  • ROD-I nucleating tableting machine
  • Example 4 Prepared in the same manner as in Example 4 (1) with the ingredients and contents shown in Table 1, tableting the hydrophobic navigating # granules using a rotary tableting machine (MRC-33, Sejong Pharmatech, Korea) After preparing Losartan potassium salt delayed-release granules in the same manner as in Example 4 (2), the tablets were compressed using a rotary tablet press (MRC-33, Sejong Pharmatech, Korea). After the tableting, two tablets were layered in a capsule capsule device (SF-40N, Sejong Pharmatech, Korea) in No. 1 capsule to prepare a capsule.
  • MRC-33 rotary tableting machine
  • MRC-33 Sejong Pharmatech, Korea
  • SF-40N Sejong Pharmatech, Korea
  • Naviball hydrochloride (Cadi la, India), sodium lauryl sulfate, lactose (Parmatose, DMV Pharma, The Netherlands), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA), cross Sodium camelos was weighed and appled into No. 35 sieve, and the mixture was prepared for 15 minutes in a double cone mixer (Dasan Pharmatech, Korea). Separately, the binder solution was prepared by dissolving hydroxyipropyl cellulose (HPC-L, Nippon soda, Japan) in purified water. The mixture was placed in a fluidized bed granulator (GPCG-1: Glatt, Germany), and the binder solution was added to assemble and dried. The dried product was sized using an F-type sizer equipped with No. 20 sieve, and then stearic acid magnesium was added thereto, followed by final mixing to prepare granules of hydrochloric acid.
  • HPC-L hydroxyipropyl cellulose
  • GPCG-1 Glat
  • the granules were coated with a solution in which phthalic acid hydroxypropylmethylsalose was dissolved in a mixed solvent of ethanol and methylene chloride. After completion of coating, stearic acid magnesium is added The final mixing was carried out to prepare a losartan potassium salt delayed-release granule mixture.
  • ⁇ i6i> Preparation of releasing Pel3 ⁇ 4 from Naviv hydrochloric acid was carried out by adding Sugar seed to a fluidized bed granulator (GPCG 1 Glatt, Germany), and then adding hydroxypropyl salulose (HPC) to a mixture of water and ethanol. -L, Nippon soda, Japan), hydroxypropylmethylcellose, Naviball hydrochloride, and a binder solution in which sodium lauryl sulfate was dissolved or suspended were sprayed to form pellets to produce a rapid release pellet of Naviball hydrochloride. It was.
  • HPC hydroxypropyl salulose
  • sucrose sucrose sphere
  • GPCG 1 Glatt, Germany fluidized bed granulator
  • hydroxypropylmethylsal was added separately to a mixed solvent of water and ethane.
  • Loose and losartan potassium salt were dissolved or sprayed with suspension binder to form pellets and dried.
  • the granules were then sprayed with a solution of phthalic acid special propylmethylcellose in ethane and a methylene chloride mixed solvent to prepare a delayed release of losartan potassium salt of 3 ⁇ 43 ⁇ 4.
  • Example 4 With the ingredients and contents shown in Table 2, to prepare a pre-release pellet of hydrochloric acid Naviball in the same manner as in Example (1) of the above Example 8, the losartan potassium salt delayed-release layer purification was carried out in Example 4 (2). Delayed-release tablets were prepared in the same manner as above), and each tablet and pellets were prepared by layering a capsule capsule layer 0 into a capsule No. 0.
  • Eudragit L30D-55 (Eudragit L30D-55, Evonik, Germany), talc, triethyl citrate (Citrof lex 2, Morimura, Japan) was dissolved and dispersed in purified water to prepare a secondary coating solution.
  • the tablet is administered to a high coater (SFC-30F, Sejong Pharmatech, Korea), and after the first coating (hydroxypropyl methylcell release coating), the second coating (Yudra L30D-55 coating solution) to prepare a losartan potassium salt inner core tablet.
  • Nucleated-tablet tablets were prepared in the same manner as the tableting and coating method of Example 4 (3).
  • microcrystalline cellulose, croscarmellose sodium, and colloidal silicon dioxide were added and mixed, and then stearic acid was added to the granules and finally mixed with a rotary tableting machine (ffiC-33, Sejong Pharmatech, Korea). Then, tablets were coated with a coating solution in which hydroxypropylmethylcellose 2910, polyethylene glycol 6000, and titanium oxide were dissolved and dispersed in ethanol and purified water, thereby preparing Naviball hydrochloride tablets.
  • Each tablet having the coating of (1) and (2) completed is one PTP (Press Through).
  • the packaging kit was packaged in a packaging container (Wider-VII, Bucheon Machine, Korea) to produce the packaging kit.
  • the losartan potassium salt-derived uncoated tablet of (2) was administered to a high coater (Src-30F, Sejong Pharmatech, Korea), and the hydrochloric acid navigator of (1) was coated with a coating solution. After drug coating was completed, it was coated in the same manner as in Example 1 (3) separately as shown in the following Table 2.
  • Naviball hydrochloric acid pre-release granules were prepared in the same manner as in Example 4 (1) with the ingredients and contents shown in Table 2.
  • Nucleated tablets were prepared in the same manner as the tableting and coating method of Example 4 (3).
  • Example 2 In the same manner as in Example 1 (1) with the ingredients and contents shown in Table 3, the nebivolol linear release granules were prepared.
  • the granules were again coated with a solution of cellulose acetate (CA-320S / CA-398NF10, Eastman Chemical Company, USA) and hydroxypropylmethylsalose in a mixture of ethanol and methylene chloride.
  • cellulose acetate CA-320S / CA-398NF10, Eastman Chemical Company, USA
  • hydroxypropylmethylsalose in a mixture of ethanol and methylene chloride.
  • colloidal silicon dioxide and stearic acid magnesium are added and mixed to form a rotary tableting machine (MRC-33, three species with a 10.0 mm diameter bias). Tableting in Pharmatech, Korea). Tablet-finished tablets were coated in the same manner as in Example 1 (3).
  • Example 2 (1) with hydrochloric acid Guinea bolreul prior-release layer in the same manner as the ingredients and contents shown in Table 3 were prepared.
  • valsartan, microcrystalline salose, lactose, and croissant The mixture was prepared by apologies of scaramel sodium (Vivasoi, JRS, Germany) with No. 35 sieve and mixing for 15 minutes with a double cone mixer (Dasan Pharmatech, Korea). Separately, hydroxypropylcellose (HPC-L, Nippon soda, Japan) was dissolved in purified water to prepare a defect solution. The mixture was placed in a fluidized bed granulator (GPCG-1: Glatt, Germany), granulated by adding a binder solution, and granules were formed and dried. Separately, the granules were again coated with a solution of Eudragit RS (Eudragit RS, Evonik, Germany) ⁇ triethyl citrate in a mixture of ethanol and methylene chloride.
  • Eudragit RS Eudragit RS, Evonik, Germany
  • colloidal silicon dioxide and magnesium stearate are added thereto, followed by final mixing to prepare a valsartan delayed-release layer.
  • Example 3 In the same manner as in Example 3 (1) using the ingredients and contents shown in Table 3, the nebivolol pre-release layer was prepared.
  • the granules were again coated with a solution in which hydroxypropylmethyl salose and cellulose acetate were dissolved in a mixed solvent of ethanol and methylene chloride. Colloidal silicon dioxide and magnesium stearate were added thereto, followed by final mixing to prepare a valsartan delayed-release layer.
  • the valsartan fed federal granule mixture prepared in (2) was stacked in a thick layer (second layer), and (1) the nebivolol pre-release granules were divided into one and three layers to form a rotary multilayer tablet.
  • a thick layer second layer
  • tableting Coating was carried out in the same manner as in Example 1 (3).
  • Croscarmellose sodium and colloidal silicon dioxide were mixed with the mixture, and magnesium stearate was added to the final mixture, followed by compression using a rotary tableting machine.
  • a high coater SFC-30F, Sejong Pharmatech, Korea
  • a nucleated tablet was prepared by using a nucleated tableting machine (RUD-b Ki l ian, Germany) as a inner nuclear tablet and navigating hydrochloric acid with a pre-release layer as an outer layer. After the above-mentioned tableting, it was separately coated in the same manner as in Example 1 (3) to the content shown in Table 3 to prepare a nucleated tablet.
  • Example 5 It was prepared in the same manner as in Example 5 (1) with the ingredients and contents shown in Table 3, except that the hydrochloric acid navib was pre-release granules were compressed using a rotary tableting machine (MRC-33, Sejong Pharmatech, Korea).
  • the capsules were prepared by layering the tablets (1) and (2) on the capsule of No. 1 with a capsule layer device.
  • Example 19> Preparation of valsartan capsules (granules + tablets) with Naviball hydrochloric acid (233) Preparation of Prerelease Granules for Hydrochloric Acid Naviball
  • Naviball hydrochloride prepared in the same manner as in Example 7 (1) with the ingredients and contents shown in Table 3 to prepare a pre-release layer granules.
  • valsartan, microcrystalline cellulose, lactose and croscarmellose sodium were appled with No. 35 sieve and mixed for 15 minutes with a double cone mixer to prepare a mixture.
  • the hydrophilic propylcellose HPC-L, Nippon soda, Japan
  • the mixture was placed in a fluidized bed granulator (GPCG-1: Glatt, Dukil) and granulated by the addition of a binder solution to form granules and dried.
  • the granules were then coated with a solution in which phthalic acid hydroxypropylmethylcellose was dissolved in a mixed solvent of ethanol and methylene chloride. After completion of the coating, stearic acid magnesium was added to the final mixture to prepare a valsartan delayed-release granule mixture.
  • pellets are formed by spraying hydroxypropylcellulose, hydroxypropylmethylsalose, valsartan dissolved or suspended binder solution in a mixture of water and ethanol. And dried.
  • valsartan delayed-release pellets were prepared by spraying Eudragit RUEudragit RL, Evonik, Germany) and triethyl citrate in ethane and a mixed solvent of methylene chloride.
  • the pellets of (1) and (2) were mixed and layered with a capsule filling machine in capsule 0 to prepare a capsule.
  • Example 9 (1) In the same manner as in Example 9 (1), with the ingredients and contents shown in Table 4, a pre-release pellet was produced by navigating hydrochloric acid in the same manner as in Example 9 (1), and the delayed release of valsartan was delayed in the same manner as in Example 17 (2). Release tablets were prepared, and capsules were prepared by layering tablets and pellets into capsule 0 with a capsule layering machine.
  • the ingredients and contents shown in Table 4 were apples of valsartan, microcrystalline cellulose, lactose, and manny with No. 35 sieves, followed by mixing for 5 minutes with a double cone eater (Dasan Pharmatech, Korea) to prepare a mixture. Separately, hydroxypropylcell was dissolved in purified water to prepare a binding solution. After administering the above mixture to a fluidized bed granulator or a high speed mixer, the binder was sprayed to prepare granules. The granules were dried in a fluidized bed drier, and then mixed with crosslinked pulley vinylpyridone in the granules, mixed with magnesium stearate, and finally mixed with a tablet press using a rotary tablet machine.
  • hydroxypropylmethylcellose was dissolved in 80% ethane, and acrylic acid (Acryl-EZE, Colorcon, USA) was dissolved in purified water to prepare a coating solution.
  • acrylic acid Acryl-EZE, Colorcon, USA
  • the tablets are coated with a high coater (SFC-30F, Sejong Pharmatech, Korea) and the primary coating (hydroxypropyl methylcellose coating solution), and then the inner core was coated with a secondary coating (acrylic coating solution) to prepare a valsartan inner core tablet.
  • a nucleated tablet was manufactured by the same method as the tableting and coating method of Example 4 (3).
  • ⁇ 268> a rotary tableting machine for the nebulol hydrochloride pre-release granules and valsartan delayed-release granules, respectively
  • Tablets that have been compressed are coated with hydroxypropyl methylcellose 2910, polyethylene glycol 6000, and titanium oxide in a coating solution in which ethane and ethane were dissolved and dispersed in purified water.
  • Each coated tablet was prepared according to the manufacturing method of the packaging kit of Example 11 (3).
  • valsartan, microcrystalline shellulose, sodium chloride, crocarmellose sodium, and colloidal silicon oxide were apologized as No. 35 and mixed with a double cone mixer (Dasanpa Matek, Korea). Then, crosslinked polyvinylpyridone was added and mixed, and then stearic acid magnesium was added and finally mixed. The final mixture was compressed using a rotary tablet press (MRC-33: Sejong Pharmatech, Korea).
  • Naviball hydrochloric acid pre-release granules were prepared in the same manner as in Example 5 (1).
  • a nucleated tablet was prepared according to the tableting and coating method of Example 4 (3).
  • Nucleated tablets were prepared by tableting and coating in the same manner as in Example 4 (3), using the ingredients and contents shown in Table 5.
  • Carvedyl (Cad a, India), sodium lauryl sulfate, lactose (Parmatose, DMV Prma, The Netherlands), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA) according to the ingredients and contents shown in Table 5 was weighed and appled into a No. 35 sieve and mixed for 15 minutes in a double cone mixer (Dasan Pharmatech, Korea) to prepare a mixture.
  • hydroxypropylcellose HPC-L, Nippon soda, Japan
  • HPC-L hydroxypropylcellose
  • the mixture was placed in a fluidized bed and granulator (GPCG-1: Glatt, Dukil), and granulated and dried by adding a binder solution.
  • the dried material was sized using an F-type sizer equipped with No. 20 body, mixed with crosslinked polyvinylpyrrolidone and colloidal silicon dioxide, and stearic acid magnesium was added to the mixture.
  • carvedil was prepared as a pre-release granule.
  • hypromellose acetate succinate HPMC-AS, Shi net su, Japan
  • triethyl citrate were dissolved in 80% ethanol and then sprayed on the granules formed above to coat the granules and then dried.
  • Magnesium stearate was added to the granules, followed by mixing to prepare irbesartan delayed-release granules. (313) layered capsules
  • the capsules were prepared by layering the succinic acid metope with the first-release granules and the Irbesartan branch fed granules in cap No. 0 capsules with a capsul layered pendulum.
  • hydroxypropylmethylsalose 2910 was dissolved in 80% ethanol, and acrylic acid (Aery® EZE, Co. con, USA) was dissolved in purified water to prepare a coating solution.
  • the tablet is administered to a high coater (SFC-30F, Sejong Pharmatech, Korea) and the first coating (hydroxypropyl methyl cellulose coating solution), and then the second coating (acrylic coating)
  • the inner core was coated with the liquid) to prepare telmisartan inner core tablets.
  • Example 35 Candesartan cilexetil capsules (tablets + tablets) prepared with carvedil
  • Carvedil-pre-release granules prepared in the same manner as in Example 34 (1) were compressed using a rotary tableting machine (MRC-33, Sejong Pharmatech, Korea) using the ingredients and contents shown in Table 6.
  • MRC-33 rotary tableting machine
  • Table 6 Preparation of candesartan cilexetil delayed-release tablets
  • the tablets prepared in (1) and (2) were layered on the first capsule with a capsul layering device to prepare a capsulant.
  • Carvedil-pre-release tablets were prepared by the same method as described in Example 35 (1), using the ingredients and contents shown in Table 6.
  • the tablet was coated with a coating solution in which hydroxypropyl methylcellose 2910, polyethylene glycol 6000, and titanium oxide were dissolved and dispersed in ethanol and purified water to prepare carvedyl-based coated tablets.
  • Each of the coated tablets was packaged in one press-pack pack in a packing machine (Wider-VII, Bucheon Machine, Korea) to prepare a packaging kit for simultaneous use.
  • the granules were again coated with a solution of phthalate hydroxypropylmethylcellose in ethane and a methylene chloride mixed solvent.
  • colloidal silicon dioxide was added and mixed, and stearic acid magnesium was added to the mixture, followed by final mixing to prepare a mixture for a delayed-release layer of potassium potassium salt.
  • the composite prepared in (2) was stacked in an intermediate layer (second layer), and the composite prepared in Example 37 (1) was divided into one and three layers to form a rotary multi-layer tablet press machine (MRC-37T, Into each other granule inlet of Sejong Pharmatech, Korea) and tableting, and then coated in the same manner as in Example 1 (3).
  • MRC-37T rotary multi-layer tablet press machine
  • Example 2 the tablets of Example 2 were prepared with Naviball hydrochloride in the dissolution test under the following conditions.
  • the components showed almost the same elution characteristics as the control formulation, Vystol ic.
  • Losartan component can be found to be very late dissolution compared to the cozaar (Cozaar) control.
  • the dissolution of Losartan by 20 hours was less than 20%, and the dissolution of the control formulation was slower (about 75%).
  • the losartan potassium salt of the delayed-release compartment of the present invention has a very slow initial release unlike the dissolution of the single losartanium salt, which is a reference drug. After several hours, Losartan is eluted and the blood pressure can be controlled during the morning so that the blood pressure can be maintained evenly for 24 hours.
  • Test method Paddle method, 50 revolutions / minute
  • Test solution 0.01N hydrochloric acid solution, 1000 mL (0-2 hours),
  • Test method Paddle method, 50 revolutions / minute
  • the nav balls are eluted first, and then Rosasartan is eluted after a certain time.
  • the formulations prepared in Examples 3, 4 and 5 can be seen that when the oral administration in the evening, the Naviball is eluted first to control the blood pressure during the night time, and after a few hours, Rosatan is eluted to control the blood pressure during the morning time. .
  • a comparative dissolution test was carried out using the tablets obtained in Example 17 and the treat- ment Vicelic (Forest labs: Bystolic, Naviball hydrochloride monolith) and Valsartan (Novartis: Diovan, Valsartan monolithic).
  • the dissolution test was performed by changing the eluate from pHl.2-hydrochloric acid solution (acidic environment) to pH 6.8 phosphate buffer (phosphate solution).
  • the valsartan dissolution test method is as follows, and the results are shown in FIG. 3 (the number of test subjects is 12 each). Naviball component dissolution test is the same as in Experiment 1.
  • Example 17 the tablets of Example 17 were found to exhibit almost equivalent elution characteristics when compared to Vystolic, which is a control agent, during the dissolution test under the following conditions. A very late dissolution can be seen when comparing with the control product, Diovan.
  • the overbalsartan nucleated tablet elution test of Example 17 hydrochloric acid hydrochloride the dissolution rate of the valsartan component up to 2 hours was less than 103 ⁇ 4, which is slower than that of the control formulation (about 30%).
  • Test solution pH 1.2 hydrochloric acid solution, lOOOraL (0-2 hours)
  • the dissolution test was performed by changing the eluate from pH 1.2 hydrochloric acid solution (acidic environment) to pH 6.8 (phosphate solution) complete solution for 2 hours.
  • the dissolution test method for each component is as follows, and the results are shown in FIGS. 5, 6, and 7 (the test population is 12 each).
  • the extraction test for the components of the nav ball is the same as in Experiment 1.
  • telmisartan, eprosartanmesylate, and olmesartanme toxin density had an emission pattern as intended.
  • Test method Paddle method, 50 revolutions / minute
  • Test solution 0.1 N hydrochloric acid solution, 1,000 mL (0-2 hours) ,
  • Test method Paddle method, 75 revolutions / minute
  • Test solution pH 1.2 hydrochloric acid solution, lOOOraL (0-2 hours)
  • Test method Paddle method, 75 revolutions / minute ⁇ 416>
  • Test solution pH 1.2 hydrochloric acid solution, lOOOmL (0 ⁇ 2 hours)
  • Test method Paddle method, 50 revolutions / minute
  • Test solution pH 1.2 hydrochloric acid solution, lOOOOmL (0 ⁇ 2 hours)
  • the present invention provides a pharmaceutical formulation comprising a prior release compartment comprising a beta adrenergic blocker as a pharmacologically active ingredient, and a delayed release compartment comprising an angiotensin-2 receptor antagonist as a pharmacologically active ingredient.
  • the formulation shows an equal anti-pressure action and prevents complications, and in particular, it can maintain blood pressure evenly during the period of risk of complications, and is useful for patients with high blood pressure who have complications and those who need sleep pressure control. There is an advantage in that it is effective in reducing the side effects of the industrial use.

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Abstract

The present invention relates to a pharmaceutical preparation comprising: an immediate-release compartment including beta-adrenergic blockers as pharmacologically active ingredients; and an extended-release compartment including angiotensin II receptor blockers as pharmacologically active ingredients. The preparation of the present invention exhibits uniform anti-tension effects and effects of preventing complications, and particularly, maintains the blood pressure at a constant level in the dangerous time period in which complications might occur, and thus can be effectively used for a hypertension patient suffering from complications and for a patient requiring the blood pressure thereof to be inhibited during sleep, and effectively reduces side effects caused by the interaction between drugs.

Description

【명세서】  【Specification】
【발명의 명칭】  [Name of invention]
베타 아드레날린 차단제와 안지오텐신— 2 수용체 길항제를 포함하는 약제학적 제제  Pharmaceutical formulations comprising beta adrenergic blockers and angiotensin-2 receptor antagonists
【기슬분야】  【Field of Energy】
<1> 본 발명은 볘타 아드레날린 차단제와 안지오텐신 -2 수용체 길항제를 유효성분 으로 함유하며， 각각의 성분이 시간차를 두고 방출하는 약제학적 제제에 관한 것이 다.  <1> The present invention relates to a pharmaceutical formulation containing a metha adrenergic blocker and an angiotensin-2 receptor antagonist as an active ingredient, each component is released at a time difference.
【배경기술】  Background Art
<2> 고혈압은 매우 다양한 원인에 의해 증복적으로 유발되는 증상이다. 따라서 단 일 항압제를 사용하는 경우 어떤 결과가 나오는 지는 미리 판단하기 어렵다 [Journal of hypertension 1995： 9: S33-S36] . 이 러한 이유로 보다 효과적인 치료를 위학여 항압제들의 복합 처방이 계속 증가하여 왔다.  <2> Hypertension is a symptom caused by multiple causes. Therefore, it is difficult to determine in advance what will be the consequences of using a single antipressant [Journal of hypertension 1995: 9: S33-S36]. For this reason, a combination of anticoagulants has been on the rise for more effective treatments.
<3> 지난 30년 동안 발표된 대단위 임상 (예 : Hypertension Optimal Treatment ,Large clinical trials (eg Hypertension Optimal Treatment, published over the last 30 years)
United Kingdom Prospect ive Diabetes Study 등) 보고서에도 경증 내지 증등증 고혈 압때부터 복합 처방으로 치료함으로써 합병증 발병 및 악화를 예방하고 장수를 보장 받을 수 있다는 입증자료가 계속 증가해 왔다 [미국 고혈압 대책 위원회 고혈압 치료 지침 , JNC(Joint Nat ional Committee) Report 6 and 7, World Health Organization- Internat ional Society of Hypertension (1999)] . In the United Kingdom Prospect ive Diabetes Study, etc., reports have continued to increase the evidence that long-term hypertension can lead to complications and prevent complications and ensure longevity. , Joint Nat ional Committee (JNC) Report 6 and 7, World Health Organization-Internat ional Society of Hypertension (1999).
<4> 미국 공개특허 제 2005— 0004194호에는 심근 경색 환자에 대해 부작용을 줄이 고 효과를 높여 심혈관 질환을 치료하기 위한 안지오텐신 전환효소 저해제와 안지오 텐신 -2 수용체 길항제의 복합처방이 개시되어 있고， 대한민국 공개특허 제 2004ᅳ 0078140호에는 안지오텐신 -2 수용체 길항제인 발사르탄과 칼슘 채널 차단제의 항 고 혈압 복합제제가 개시되어 있다.  US Patent Publication No. 2005—0004194 discloses a combination of angiotensin converting enzyme inhibitors and angiotensin-2 receptor antagonists for treating cardiovascular diseases by reducing side effects and enhancing effects on patients with myocardial infarction. , Korean Patent Publication No. 2004 ᅳ 0078140 discloses an antihypertensive complex preparation of valsartan and calcium channel blocker, which is an angiotensin-2 receptor antagonist.
<5> 국제공개공보 W003/097099에는 안지오텐신 -2 수용체 차단제 및 베타수용체 차 단제 각각의 단위 제형을 동시에 투여하는 단순 병용 요법 이 심근경색증 후 환자의 심혈관 질환의 치료에 효과적 임이 개시되어 있다.  International Publication No. W003 / 097099 discloses that a simple combination therapy in which unit dosage forms of angiotensin-2 receptor blockers and beta receptor blockers are simultaneously administered is effective for the treatment of cardiovascular disease in patients after myocardial infarction.
<6> 그러나 이종약물대사학 (Xenobiot ics) 이론에 따르면 , 2종 이상의 약물이 경구 투여되는 경우， 간내 동일한 약물효소계에 의하여 대사되는 과정에서 상호길항하게 되어 , 원약의 효과를 완전히 발휘할 수 없거나， 오히려 감소되는 등의 부작용이 발생 할 수 있다 (The new Engl and journal of medicine 2003： 349： 484-85)  However, according to the theory of Xenobiot ics, when two or more drugs are administered orally, they are mutually antagonized in the process of metabolism by the same drug-enzyme system in the liver, so that the effects of the original drugs cannot be fully exhibited. Rather, side effects such as diminishing can occur (The new Engl and journal of medicine 2003: 349: 484-85).
<7> 또한, 베타 아드레날린 차단제와 안지오텐신— 2 수용체 길항제의 단순 복합제 제를 투여시 , 최고혈증농도 (Cmax)와 혈증농도 곡선하면적 (AUC)과 같은 약물동력학 (Pharmacokinet ics)에 영향을 줄 수 있다. 베타 아드레날린 차단제의 일종인 네비볼 를과 안지오텐신 -2 수용체 길항제의 일종인 로사르탄 동시투여시， 네비블를은 로사르 탄의 약물동력학 (Pharmacokinet ics)에 영향을 주지 않지만, 로사르탄은 네비볼를에 의해 최고혈중농도 (Cmax)와 혈중농도 곡선하면적 (AUC)이 감소되었다 (Cl inical Pharmacology Review) . <7> A simple combination of beta adrenergic blocker and angiotensin-2 receptor antagonist Administration of the agent may affect pharmacokinetics, such as peak blood concentration (Cmax) and area under the blood plasma curve (AUC). In coadministration of beta adrenergic blocker navigol and losartan, a type of angiotensin-2 receptor antagonist, navibble does not affect losartan's pharmacokinetics, but losartan is The peak blood concentration (Cmax) and the area under the blood curve (AUC) were reduced (Cl inical Pharmacology Review).
<s> 이에， 본 발명자들은 대상질환에 효과적인 성분을 복합하는 것뿐만 아니라， 각각의 성분의 흡수， 대시 ·, 분포， 배설과 같은 약물동력학적 성질에 영향을 주지 않 는 제제를 개발하고자 하였다.  <s> Accordingly, the inventors of the present invention have attempted to develop a formulation that does not affect the pharmacokinetic properties such as absorption, dash, distribution, and excretion of each component, as well as combining effective components for the target disease.
【발명의 상세한 설명】  [Detailed Description of the Invention]
【기술적 과제】  [Technical problem]
<9> 본 발명 이 해결하고자 하는 과제는 균등한 항압작용과 합병증 예방 작용을 나 타내며， 약물간 상호작용에 따른 부작용을 감소시켜 주는 제제를 제공하는 것이다. 【기술적 해결방법】  The problem to be solved by the present invention is to provide an agent that exhibits an equal anti-pressure action and prevent complications, and reduces side effects due to drug interactions. Technical Solution
<10> 본 발명은 약리학적 활성성분으로 베타 아드레날린 차단제를 포함하는 선방출 성 구획 , 및 약리학적 활성성분으로 안지오텐신 -2 수용체 길항제를 포함하는 지연 방 출성 구획을 포함하는 약제학적 제제를 제공한다.  The present invention provides a pharmaceutical formulation comprising a prior release compartment comprising a beta adrenergic blocker as a pharmacologically active ingredient, and a delayed release compartment comprising an angiotensin-2 receptor antagonist as a pharmacologically active ingredient.
<ιι> 본 발명의 제제 중 선방출성 구획의 베타 아드레날린 차단제는 방출개시 후<ιι> Beta-adrenergic blockers of the prior-release compartment in the formulations of the present invention after release
1시간 이내에 베타 아드레날린 차단제 총량의 85%이상이 방출되어， 원하는 약효를 신 속하게 발생할 수 있다. Within 1 hour, more than 85% of the total amount of beta adrenergic blocker is released, which can quickly produce the desired effect.
<12> 본 발명의 제제 증 지연방출성 구획의 안지오텐신 -2 수용체 길항제는 지연시 간 경과 후， 바람직하게는 베타 아드레날린 차단제의 방출 1시간 내지 8시간 후 , 보 다 바람직하게는 1시간 내지 6시간 후에 방출될 수 있다. <12> The angiotensin-2 receptor antagonist of the formulation-delayed-releasing compartment of the present invention is preferably 1 hour to 8 hours after the delayed time period, preferably 1 to 8 hours after the release of the beta adrenergic blocker. Can be released later.
<13> 본 발명 제제는 베타 아드레날린 차단제의 방출개시 후 2시간 이내에 방출되 는 안지오텐신 -2 수용체 길항제의 방출량이 안지오텐신— 2 수용체 길항제 총량의 20% 이내로 지연되어 원하는 약효를 지연시간 경과 후 발생할 수 있다. <13> The formulation of the present invention may be delayed to within 20% of the total amount of angiotensin-2 receptor antagonist released within 2 hours after the release of the beta adrenergic blocker. .
<14> 또한, 본 발명의 제제는 상기 베타 아드레날린 차단제 1중량부에 대하여 안 지오텐신ᅳ 2 수용체 길항제를 0.1-350증량부 포함할 수 있다. In addition, the formulation of the present invention may include 0.1-350 parts by weight of an angiotensin ᅳ 2 receptor antagonist based on 1 part by weight of the beta adrenergic blocker.
<15> 본 발명 제제의 각 구획을 보다 상세히 설명하면 다음과 같다. Each compartment of the formulation of the present invention will be described in more detail as follows.
<16> 1. 선 (先)방출성 구획  <16> 1. Prerelease compartments
<17> 선방출성 구획은 본 발명의 약제학적 제제에 있어서 지연방출성 구획에 비해 먼저 활성성분이 방출되는 구획을 의미하며 , 약리학적 활성성분 외에 필요에 따라 약 제학적으로 허용 가능한 첨가제를 추가로 포함할 수 있다. <17> Pre-release compartment refers to the compartment in which the active ingredient is released earlier than the delayed-release compartment in the pharmaceutical formulation of the present invention, and in addition to the pharmacologically active ingredient, It may further include a pharmaceutically acceptable additive.
<18> (1) 약리학적 활성성분  (18) Pharmacologically active ingredients
<19> 선방출성 구획의 약리학적 활성성분은 베타아드레날린 차단제로， 상기 베타 아드레날린차단제는 심 혈관 및 평활근에 많이 존재하는 β 수용체가 아드레날린에 의 한 자극으로 교감신경계가 흥분되는 것을 차단하여 , 고혈압， 협심증 , 심부정맥을 포 함하는 여러가지 심장질환을 치료하는 데 사용되는 약물을 외미하며 , 예를 들어 알프 레놀를， 아세부토를， 아모술랄를， 아로티놀를, 아테놀를, 베푸놀를， 베탁솔를， 베반 롤를 , 비소프를를, 보핀돌를, 부쿠몰를 , 뷔페를롤， 부푸랄를 , 부니트롤를， 부프란돌 롤， 부토필를틀， 카라졸를， 카테을를 , 카르베딜를， 셀릴프를를, 세타몰롤 클로라놀 를， 딜레발를, 에파놀롤， 인데놀를 , 라베탈를， 레보부놀를, 메핀돌를， 메티프라놀를， 메토프를롤, 모프를롤， 나돌를, 나독솔를, 네비볼를 , 니프라딜를， 옥스프레놀를, 퍼 부틀롤 , 핀돌를， 프택를를 , 프로네탈를， 프로프라놀를 , 소탈롤 , 수피날를 , 탈린돌 , 테르타틀를， 틸리솔를， 티몰를， 를리프를를， 지베놀를， 이들의 이성질체 ᅳ 및 이들의 약학적으로 허용 가능한 염 등에서 선택된 것으로， 네비볼를이 바람직하며 염산 네비 볼를이 더욱 바람직하다. 상기 베타아드레날린 차단제는 제제 중 1 ~ 1400mg 포함할 수 있고 , 바람직하게는 2 ~ 300mg을 포함한다. 상기 용량은 1일 성인 (체중 65~75kg 성 인남자) 기준의 용량이다.  The pharmacologically active component of the prior-release compartment is a beta-adrenergic blocker, and the beta-adrenergic blocker blocks the excitability of the sympathetic nervous system due to the adrenergic stimulation of β receptors present in the cardiovascular and smooth muscle, hypertension, Drugs used to treat a variety of heart diseases, including angina and deep vein, for example, alprenole, acebuto, amosulal, arotinol, athenol, befunol, betaxol, Bevan roll, Bisoph, Boffindol, Bucumol, Buffet roll, Bupral, Bunitrol, Buffandol roll, Bhuttopil, Carazole, Catheters, Carvedil, Selelyph, Cetamolol chloranol Dilole, epanol, indenol, labetatal, levobunol, mepindol, metipranol, metopelol, morphol, nadol, nadoxol, navigator Ball, nipradil, oxprenol, fur bootol, pindol, pact, pronetal, propranol, sotalol, supinal, tallindol, tertattle, tilisol, thymol, lelip, Gibenol is selected from the isomers thereof, pharmaceutically acceptable salts thereof, and the like. Naviball is preferable, and Naviball hydrochloride is more preferable. The beta adrenergic blocker may comprise 1 to 1400 mg of the formulation, preferably 2 to 300 mg. The dose is based on a daily adult (weight 65-75kg adult male).
<20> 네비볼를은 제 4세대 베타 아드레날린 차단제로， 1, 2， 3세대 베타 아드레날 린 차단제가 갖는 모든 장점을 가질 뿐만 아니라， NO를 생성시켜 말초 혈관을 확장시 켜 주므로， 다른 베타 아드레날린 차'단제가 갖는 성기능 퇴화， 지질증가, 당뇨병 악 화， 사지 냉감 등의 부작용이 없으며 , 우심 확장성 심부전에도 효과를 나타낸다. 특 히 노인성 수축기 고혈압자로서 심부전을 지닌 자, 노인성 당뇨병성 고혈압자, 노인 성 고지질성 고혈압자， 심부전을 겸 한 고혈압자에게 적합하다. Naviball is the fourth-generation beta adrenergic blocker, not only has all the benefits of the first, second and third generation beta-adrenergic blockers, but also produces NO, which expands peripheral blood vessels. There is no difference "stage I side effects such as sexual function degeneration, lipid increased, diabetes Ill Chemistry, limb coldness which shows the effect on expansion Dextrocardia heart failure. In particular, it is suitable for elderly patients with systolic hypertension, those with heart failure, elderly diabetic hypertension, elderly hyperlipidemic hypertension, and hypertension combined with heart failure.
<21> 따라서， 네비볼를은 심부전 , 심근 경색 등 중증 질환자의 고혈압에 안지오텐 신 -2 수용체 길항제를 복합함으로써 , 유효한 치료효과를 얻을 수 있다.  Therefore, Naviball can obtain an effective therapeutic effect by combining angiotensin-2 receptor antagonist with hypertension in severely ill patients such as heart failure and myocardial infarction.
<22> (2) 약제학적으로 허용가능한 첨가제  (2) pharmaceutically acceptable additives
<23> 본 발명의 제제는 본 발명의 효과를 해치지 않는 범위에서 약학적으로 허용 가능한 회석제， 결합제， 붕해제 , 윤활제， 안정화제 , pH 조절제 , 용해보조제 등의 통 상적으로 사용되는 첨가제를 약리학적 활성성분의 방출을 방해하지 않는 범위 내에서 추가로 사용하여 제제화할 수 있다 .  <23> The formulation of the present invention is a pharmacologically used additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, stabilizers, pH adjusting agents, dissolution aids, etc. within the scope of not impairing the effects of the present invention. It may be formulated further using within a range that does not interfere with the release of the active ingredient.
<24> 상기 회석제는 전분 , 미세결정 샐를로오스 , 유당， 포도당 , 만니를， 알기네이 트， 알칼리토금속류염 , 클레이， 폴리에틸렌글리콜 , 디칼슘포스페이트 , 또는 이들의 흔합물 등을 사용할 수 있다. The diluent is starch, microcrystalline salose, lactose, glucose, manny, alginate, alkaline earth metal salt, clay, polyethylene glycol, dicalcium phosphate, or A mixture or the like can be used.
<25> 상기 결합제는 전분， 미세결정 셀를로오스， 고분산성 실리카, 만니를， 자당, 유당, 폴리에틸렌글리콜， 풀리비닐피를리돈 , 히드록시프로필메틸셀를로오스, 히드록 시프로필셀를로오스， 천연검 , 합성검 , 폴리비닐피롤리돈 공중합체 , 포비돈, 젤라틴， 또는 이들의 흔합물 등을 사용할 수 있다. The binder may contain starch, microcrystalline cellulose, highly dispersible silica, manny, sucrose, lactose, polyethylene glycol, pulley vinylpyridone, hydroxypropylmethylcellulose, hydroxypropylcelose, Natural gums, synthetic gums, polyvinylpyrrolidone copolymers, povidone, gelatin, or a combination thereof can be used.
<26> 상기 붕해제는 나트륨전분글리콜레이트， 옥수수전분 , 감자전분 또는 전젤라틴 화전분 (전호화전분) 등의 전분 또는 변성전분 ; 벤토나이트， 몬모릴로나이트， 또는 비 검 (veegum) 등의 클레이 ; 미결정셀를로오스， 히드록시프로필샐를로오스 또는 카르복 시메틸셀를로오스 등의 셀를로오스류; 알긴산나트콤 또는 알긴산 등의 알긴류 ; 크로 스카멜로스 (croscarmel lose)나트륨 등의 가교 셀를로오스류 ; 구아검 ; 잔탄검 등의 검 류; 가교 폴리비닐피를리돈 (crospovidone) 등의 가교 중합체 ; 증탄산나트륨， 시트르 산 등의 비등성 제제 , 또는 이들의 흔합물을 사용할 수 있다 . The disintegrating agent may be a starch or modified starch such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch (pregelatinized starch); Clay such as bentonite, montmorillonite, or veegum; Cellulose such as microcrystalline cellulose, hydroxypropyl salose or carboxymethyl cellulose; Algins such as alginic acid natcom or alginic acid; Crosslinked cells such as sodium croscarmel lose; Guar gum; Gums such as xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyridone (crospovidone); Effervescent preparations such as sodium bicarbonate, citric acid, or a combination thereof can be used.
<27> 상기 윤활제는 탈크， 스테아르산， 스테아르산 마그네슘, 스테아르산 칼슴 , 라 우릴황산나트륨， 수소화식물성오일， 나트륨벤조에 이트， 나트륨스테아릴푸마레이트 , 글리세릴 베헤네이트， 글리세릴 모노레이트， 글리세릴모노스테아레이트, 글리세릴 팔 미토스테아레이트， 폴리에틸렌글리콜 또는 이들의 흔합물 등을 사용할 수 있다. <28> 상기 안정화제는 알칼리금속의 염， 알칼리토금속의 염， 또는 이들의 흔합물인 알칼리화제， 아스코르빈산 , 구연산，부틸레이티드히드록시 아니솔，부틸레이티드히드 록시 를루엔 , 토코페롤 유도체， 탄산칼슘, 탄산나트륨, 탄산수소나트륨， 산화마그네 슴， 탄산마그네슴 , 구연산나트륨 등을 사용할 수 있다.  The lubricant includes talc, stearic acid, magnesium stearate, calarate stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl Monostearate, glyceryl palmitostearate, polyethylene glycol, or a combination thereof may be used. The stabilizer may be a salt of an alkali metal, a salt of an alkaline earth metal, an alkalizing agent, an ascorbic acid, citric acid, butylated hydroxy anisole, butylated hydroxy aluene, a tocopherol derivative, Calcium carbonate, sodium carbonate, sodium hydrogen carbonate, magnesium oxide, magnesium carbonate, sodium citrate and the like can be used.
<29> 상기 pH 조절제는 초학， 아디프산， 아스코르브산, 사과산, 숙신산, 주석산， 푸마르산 , 구연산과 같은 산성화제 및 /또는 침강 탄산 칼슘 , 암모니아수 , 메글루민과 같은 염기성화제 등을 사용할 수 있다. The pH adjusting agent may be used as an acidifying agent such as chemistry, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid and / or basicizing agents such as precipitated calcium carbonate, aqueous ammonia, meglumine and the like. .
<30> 상기 용해보조제는 라우릴황산나트륨, 폴리소르베이트 등의 폴리옥시에틸렌 소르비탄 지방산 에스테르， 도큐세이트 나트륨 등을 사용할 수 있다. The dissolution aid may be polyoxyethylene sorbitan fatty acid ester such as sodium lauryl sulfate, polysorbate, sodium docuate, or the like.
<31> 이외에도 착색제， 향료 중에서 선택된 다양한 첨가제로서 약학적으로 허용 가 능한 첨가제를 선택 사용하여 본 발명의 제제를 제제화할 수 있다. In addition to the various additives selected from colorants and fragrances, a pharmaceutically acceptable additive may be selected and used to formulate the formulation of the present invention.
<32> 본 발명에서 사용가능한 첨가제의 범위가 상기 첨가제를 사용하는 것으로 한 정되는 것은 아니며 , 상기한 첨가제는 선택에 의하여 통상 범위의 용량을 함유하여 제제화할 수 있다. The range of additives usable in the present invention is not limited to the use of the above additives, and the above additives may be formulated to contain a range of dosages by selection.
<33> 2. 지연 방출성 구획 2. Delayed release compartment
<34> 본 발명에서 지연 방출성 구획은 선방출성 구획 활성성분의 방출 일정 시간 후에 그 활성성분이 방출되는 구획을 의미한다. 지연 방출성 구획은 (1)약리학적 활 성성분 및 (2—1)방출제어물질 또는 (2-2)삼투압 조절제 및 반투과성막 코팅기제를 포 함하며， 필요에 따라， (3) 약제학적으로 허용 가능한 첨가제를 추가로 포함할 수 있 다. In the present invention, the delayed-release compartment has a predetermined time of release of the active ingredient of the prior-release compartment. After which the active ingredient is released. Delayed-release compartments include (1) pharmacologically active ingredients and (2—1) release control substances or (2-2) osmotic pressure regulators and semipermeable membrane coating agents, and as needed, (3) It may further comprise acceptable additives.
<35> (1) 약리학적 활성성분  (1) Pharmacologically active ingredients
<36> 지연방출성 구획의 약리학적 활성성분은 안지오텐신 -2 수용체 길항제로, 혈 관수축을 일으키는 근원물질 중 하나인 안지오텐신 2가 안지오텐신 수용체 중 ATI 수 용체와 결합하는 것을 차단하여 , 심근의 수축기와 확장기 모두에 있어 혈압강하효과 를 발휘하는 약물을 의미하며 , 예를 들어 로사르탄, 발사르탄, 텔미사르탄, 이르베사 르탄, 칸데사르탄 , 올메사르탄, 에프로사르탄 등과 이들의 이성질체， 이들의 약학적 으로 허용 가능한 염 및 이들의 프로드럭 중에서 선택된 것으로 , 제제 증 1 ~ 1500mg 포함할 수 있고， 바람직하게는 10~ 800mg을 포함한다 . 상기 용량은 1일 성인 (체중 65~75kg 성인남자) 기준의 용량이다. 상기 프로드럭은 바람직하게는 을메사르탄 메독 소밀이다.  The pharmacologically active component of the delayed-release compartment is an angiotensin-2 receptor antagonist, which blocks angiotensin 2, one of the sources of blood vessel contraction, to bind to the ATI receptor in the angiotensin receptor. Refers to drugs that lower blood pressure in both diastolic phases, for example losartan, valsartan, telmisartan, irbesartan, candesartan, olmesartan, eprosartan and their isomers, It is selected from pharmaceutically acceptable salts and prodrugs thereof, and may contain 1 to 1500 mg of the preparation, preferably 10 to 800 mg. The dose is based on a daily adult (65-75 kg adult male). The prodrug is preferably emmesartan medoc rough.
<37> (2-1) 방출제어물질 (2-1) Release Control Substances
<38> 본 발명의 약제학적 제제 중 지연방출성 구획은 방출제어물질을 포함하며， 본 발명 제제의 방출제어 물질은 예를 들어， 장용성 고분자, 수불용성 중합체， 소수 성 화합물， 친수성 고분자， 및 이들의 흔합물 중에서 선택된 하나 이상으로， 바람직 하게는 수블용성 중합체 및 장용성 고분자 중에서 선택된 하나 이상이다. 상기 제제 의 방출제어물질은 안지오텐신 -2 수용체 길항제 1 중량부에 대하여 0.1 ~ 100 중량 부 , 바람직하게는 1~50중량부이며 , 0.1중량부 미만일 경우 층분한 지연시간을 갖기 어려을 염려가 있고， 100중량부 초과시 약물방출이 과도하게 지연되어 유의청 있는 임상적 효과를 얻기 어려을 수 있다.  The delayed-release compartment in the pharmaceutical formulation of the present invention includes a release controlling substance, and the release controlling substance of the present formulation includes, for example, an enteric polymer, a water insoluble polymer, a hydrophobic compound, a hydrophilic polymer, and these It is at least one selected from a mixture of, preferably at least one selected from a soluble polymer and an enteric polymer. 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 angiotensin-2 receptor antagonist. Excessive weight delayed drug release may result in a significant clinical effect.
<39> 상기 장용성 고분자는 산성 조건하에서 불용성이거나 또는 안정한 것으로, pH The enteric polymer is insoluble or stable under acidic conditions.
5 이상인 특정 pH 조건하에서 용해되거나 또는 분해되는 고분자를 말한다 . 본 발명에 서 사용가능한 장용성 고분자는 장용성 셀를로오스 유도체 , 장용성 아크릴산계 공중 합체， 장용성 폴리메타크릴레이트 공중합체 , 장용성 말레인산계 공중합체， 장용성 폴 리비닐 유도체， 및 이들의 흔합물로 이루어진 군에서 선택된 1종 이상이다. It refers to a polymer that is dissolved or decomposed under specific pH conditions of 5 or more. The enteric polymers usable in the present invention are enteric cellulose derivatives, enteric acrylic acid copolymers, enteric polymethacrylate copolymers, enteric maleic acid copolymers, enteric polyvinyl derivatives, and combinations thereof. It is one or more selected.
<40> 여기서 , 장용성 셀를로오스 유도체는 히드록시프로필메틸셀를로오스아세테이 트숙시네이트 (또는 히프로멜로오스아세테이트숙시네이트이라 함)， 히드록시프로필메 틸셀를로오스프탈레이트 (또는 히프로멜로오스프탈레이트이라 함)， 히드록시메틸에틸 셀를로오스프탈레이트， 셀를로오스아세테이트프탈레이트 , 셀를로오스아세테이트숙시 네이트， 샐를로오스아세테이트말레이트， 셀를로오스벤조에이트프탈테이트 , 셀를로오 스프로피오네이트프탈레이트， 메틸셀를로오스프탈레이트， 카르복시메틸에틸샐를로오 스, 에틸히드록시에틸셀를로오스프탈레이트 , 메틸히드록시에틸셀를로오스 및 이들의 흔합물 중에서 선택된 1종 이상이고 ; 상기 장용성 아크릴산계 공중합체는 스티 렌-아 크릴산 공중합체， 아크릴산메틸-아크릴산 공중합체， 아크릴산메틸메타크릴산 공중합 체，아크 ¾산부틸—스티 렌-아크릴산 공증합체 , 아크릴산메틸—메타크릴산-아크릴산옥틸 공중합체 및 이들의 혼합물 중에서 선택된 1종 이상이고 ; 상기 장용성 풀리메타크릴 레이트 공중합체는 폴리 (메타크릴산-메틸메타크릴레이트) 공중합체 (예컨대，유드라짓Wherein the enteric cellulose derivatives are hydroxypropylmethylcelloselooseacetate succinate (or hypromelloseacetatesuccinate), hydroxypropylmethylcelloseloose phthalate (or hypromellose). Osphthalate), hydroxymethylethyl cell, cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate Nate, Salose Acetate Maleate, Cellulose Benzoate Phthalate, Cellulose Spropionate Phthalate, Methyl Cellulose Phthalate, Carboxymethylethyl Saloose, Ethylhydroxyethyl Cellulose Phthalate, Methyl At least one selected from hydroxyethyl cellose and a mixture thereof; The enteric acrylic acid copolymer may include styrene-acrylic acid copolymer, methyl acrylate-acrylic acid copolymer, methyl methacrylate acrylic acid copolymer, butyl acrylate-styrene-acrylic acid copolymer, methyl acrylate-methacrylic acid- At least one selected from octyl acrylate copolymers and mixtures thereof; The enteric pulley methacrylate copolymer is a poly (methacrylate-methylmethacrylate) copolymer (e.g. Eudragit
L 100, 유드라짓 S, 에보닉 , 득일)， 폴리 (메타크릴산 · 에틸아크릴레이트)공중합체 (예 컨대， 유드라짓 L 100-55, 에보닉， 독일， 아크릴이즈， Colorcon, 미국) 및 이들의L 100, Eudragit S, Evonik, Ind.), Poly (methacrylic acid ethyl acrylate) copolymer (e.g. Eudragit L 100-55, Evonik, Germany, Acrylic, Colorcon, USA) And their
. 흔합물 중에서 선택된 1종 이상이고 ; 상기 장용성 말레인산계 공중합체는 아세트산비 닐-말레인산 무수물 공중합체， 스티 렌-말레인산 무수물 공중합체 , 스티 렌 -말레인산모 노에스테르 공중합체 , . 비닐메틸에 테르-말레인산 무수물 공중합체 , 에틸렌-말레인산 무수물 공증합체， 비닐부틸에 테르-말레인산 무수물 공증합체 , 아크릴로니트릴-아크릴 산메틸 · 말레인산 무수물 공증합체， 아크릴산부틸 -스티 렌-말레인산 무수물 공증합체 및 이들의 흔합물 중에서 선택된 1종 이상이며 ; 상기 장용성 풀리비닐 유도체는 폴리 비닐알콜프탈레이트，폴리비닐아세테이트프탈레이트，플리비닐부티 레이트프탈레이트 , 플리비닐아세트아세탈프탈레이트 및 이들의 흔합물 중에서 선택된 1종 이상이 바람직 하다. 상기 장용성 고분자로 더욱 바람직한 예는 히드록시프로필메틸샐를로오스 프탈 레이트 및 아크릴산메틸메타크릴산 공중합체 증에서 선택된 하나 이상이다. . At least one selected from the complexes; The enteric maleic acid-based copolymers include vinyl acetate-maleic anhydride copolymer, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer,. Vinylmethyl ether-maleic anhydride copolymer, ethylene-maleic anhydride copolymer, vinyl butyl ether-maleic anhydride copolymer, acrylonitrile-methyl acrylate maleic anhydride copolymer, butyl styrene-maleic anhydride copolymer And at least one selected from these mixtures; The enteric pulley vinyl derivative is preferably at least one selected from polyvinyl alcohol phthalate, polyvinylacetate phthalate, polyvinylbutyrate phthalate, polyvinylacetacetal phthalate, and mixtures thereof. More preferred examples of the enteric polymer are at least one selected from hydroxypropylmethylsal phthalate and methyl methacrylate copolymer.
<4i> 여기서 , 장용성 고분자는 활성성분 1 증량부에 대해서 0.1 중량부 ~ 20 증량 부 , 바람직하게는 0.5 중량부 ~ 10 중량부로 포함될 수 있으며， 0.1 중량부 미만시 pH 5 미만에서 쉽게 용해될 염려가 있고 , 20 중량부 초과시 불필요하게 제제 총중량 이 커지거나 과도하게 용출이 지연될 염려가 있다.  <4i> wherein 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 may be easily dissolved at a pH of less than 5 when the content is less than 0.1 parts by weight. 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.
<42> 상기 수블용성 중합체는 약물의 방출을 제어하는 약제학적으로 허용가능한 물에 용해되지 않는 고분자를 말한다. 본 발명에서 사용가능한 수블용성 중합체는 폴 리비닐 아세테이트 , 수블용성 풀리메타크릴레이트 공중합체{예 : 폴리 (에틸아크릴레이 트，메틸 메타크릴레이트) 공증합체 (예컨대， 유드라짓 NE30D) , 폴리 (에틸아크릴레이 트，메틸 메타크릴레이트,트리메틸아미노에틸메타크릴레이트 클로라이드)공중합체 (예 컨대， 유드라짓 RS, RL) 등}， 에틸샐를로오스， 씰를로오스 에스테르， 셀를로오스 에 테르 , 셀를로오스 아실레이트， 셀를로오스 디아실레이트， 셀를로오스 트리아실레이 트， 셀를로오스 아세테이트， 셀를로오스 디아세테이트, 셀를로오스 트리아세테이트 및 이들의 흔합물로 이루어진 군에서 선택된 1종 이상이 바람직하며 , 더욱 바람직하 게는 폴리비닐아세테이트 , 에틸샐를로오스 , 폴리 (에 틸아크릴레이트 ,메틸 메타크릴레 이트，트리메틸아미노에틸메타크릴레이트 클로라이드)공중합체 , 및 셀를로오스 아세테 이트 중에서 선택된 하나 이상이다. 여기서， 수블용성 중합체는 활성성분 1 중량부에 대해서 0.1 중량부 ~ 30 중량부, 바람직하게는 0.5 중량부 ~ 20 중량부로 포함될 수 있으며， 0.1 중량부 미만인 경우에는 약물의 방출이 제어되지 않을 염려기" 있고， 30 중량부 초과인 경우에는 과도하게 용출이 지연될 염 려가 있다. The soluble polymer refers to a polymer that is insoluble in pharmaceutically acceptable water that controls the release of the drug. Soluble polymers usable in the present invention include polyvinyl acetate, soluble soluble methacrylate copolymers (e.g. poly (ethyl acrylate, methyl methacrylate) co-polymers (e.g. Eudragit NE30D), poly ( Ethyl acrylate, methyl methacrylate, trimethylaminoethyl methacrylate chloride) copolymers (e.g. Eudragit RS, RL), etc., ethyl cellulose, sealulose ester, cellulose ether, Cellulose Acylate, Cellulose Disylate, Cellulose Triacylate, Cellulose Acetate, Cellulose Diacetate, Cellulose Triacetate And at least one selected from the group consisting of a mixture thereof, and more preferably polyvinylacetate, ethyl salose, poly (ethyl acrylate, methyl methacrylate, and trimethylaminoethyl methacrylate. Chloride) copolymer, and cellulose acetate. Here, the water-soluble 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. In case of more than 30 parts by weight, excessive elution may be delayed.
<43> 상기 소수성 화합물은 약물의 방출을 제어하는 약제학적으로 허용가능한 물 에 용해되지 않는 물질을 말한다. 본 발명에서 사용가능한 소수성 화합물은 예를 들 어， 지방산 및 지방산 에스테르류 , 지방산 알코을류， 왁스류， 무기물질 , 및 이들의 흔합물로 이루어진 군에서 선택된 1종 이상이다. 상기 지방산 및 지방산 에스테르류 는 글리세릴 팔미토스테아레이트, 글리세릴 스테아테이트， 글리세릴 디스테아레이트, 글리세릴 비헤네이트 , 세틸 팔미테이트， 글리세릴 모노 을레이트, 스테아르산 및 이 들의 흔합물 중에서 선택된 1종 이상이고 ; 상기 지방산 알코올류는 세토스테아릴 알 코을， 세틸알코올， 스테아릴알코을 및 이들의 흔합물 증에서 선택된 1종 이상이고 ; 상기 왁스류는 카르나우바왁스, 밀납， 미결정왁스， 및 이들의 흔합물 증에서 선택된 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 acid alcohols, waxes, inorganic substances, and mixtures thereof. The fatty acids and fatty acid esters may be selected from glyceryl palmitostearate, glyceryl stearate, glyceryl distearate, glyceryl bihenate, cetyl palmitate, glyceryl monoacrylate, stearic acid and mixtures thereof. Species or more; The fatty acid alcohols are at least one selected from cetostearyl alcohol, cetyl alcohol, stearyl alcohol, and mixtures thereof; The waxes are selected from carnauba wax, beeswax, microcrystalline wax, and mixtures thereof.
1종 이상이며 ; 상기 무기물질은 탈크, 침강탄산칼슴， 인산일수소칼슴, 산화아연， 산 화티탄， 카올린 , 벤토나이트， 몬모릴로나이트, 비검 및 이들의 혼합물 중에서 선택된1 or more types; The inorganic material is selected from talc, precipitated carbonated carbon, monohydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, non-gum and mixtures thereof.
1종 이상인 것이 바람직하다. 상기 소수성 화합물의 더욱 바람직한 예는 카르나우바 왁스이다 . 여기서 , 소수성 화합물은 활성성분 1 증량부에 대해서 0.1 중량부 ~ 20 중 량부， 바람직하게는 0.5 중량부 ~ 10 중량부로 포함될 수 있으며 , 0.1 중량부 미만인 경우에는 약물의 방출이 제어되지 않을 염려가 있고， 20 중량부 초과인 경우에는 과 도하게 용출이 지 연될 염려가 있다. It is preferable that it is 1 or more types. A more preferred example of the hydrophobic compound is carnauba wax. Here, 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 dissolution may be delayed.
<44> 상기 친수성 고분자는 약물의 방출을 제어하는 약제학적으로 허용가능한 물에 용해되는 고분자 물질을 말한다. 본 발명 에서 사용가능한 친수성 고분자의 예는 당 류， 셀를로오스 유도체， 검류， 단백질류, 폴리비닐 유도체 , 친수성 폴리메타크릴레이 트 공중합체， 폴리에틸렌 유도체， 카르복시비닐공중합체， 및 이들의 흔합물로 이루어 진 군에서 선택된 1종 이상이다. 상기 당류는 덱스트린 , 플리덱스트린， 텍스트란， 펙 틴 및 펙틴 유도체 , 알긴산염， 폴리갈락투론산， 자일란 , 아라비노자일란， 아라비노갈 락탄 , 전분， 히드록시프로필스타치 , 아밀로오스， 아밀로펙틴， 및 이들의 흔합물 증에 서 선택된 1종 이상이고; 상기 샐를로오스 유도체는 히드록시프로필메틸셀를로오스 ( 또는 히프로멜로오스라 함) , 히드록시프로필샐를로오스 , 히드록시메틸셀를로오스， 히 드록시에틸셀를로오스， 메틸셀를로오스 , 카르복시메틸셀를로오스 나트콤 , 히드록시프 로필 메틸샐를로오스 아세테이트 숙시네이트, 히드록시에틸메틸셀를로오스, 및 이들 의 흔합물 중에서 선택된 1종 이상이고 ; 상기 검류는 구아검， 로커스트 콩 검 , 트라 가칸타， 카라기난, 아카시아검， 아라비아검， 젤란검 , 잔탄검 , 및 이들의 흔합물 중에 서 선택된 1종 이상이고 ; 상기 단백질류는 젤라틴 , 카제인， 제인， 및 이들의 흔합물 중에서 선택된 1종 이상이고; 상기 폴리비닐 유도체는 풀리비닐 알코올, 폴리비닐 피 를리돈, 폴리비닐아세탈디에틸아미노아세테이트， 및 이들의 흔합물 중에서 선택된 1 종 이상이고 ; 상기 친수성 폴리메타크릴레이트 공중합체는 폴리 (부틸 메타크릴레이 트， (2-디메틸아미노에틸)메타크릴레이트-메틸메타크릴레이트) 공중합체 (예컨대 , 유 드라짓 E, 에보닉 , 독일)， 폴리 (메타크릴산-메틸메타크릴레이트) 공중합체， 폴리 (메 타크 ¾산-에틸아크릴레이트) 공증합체 및 이들의 흔합물 증에서 선택된 1종 이상이 고; 상기 폴리에틸렌 유도체는 폴리에틸렌 글리콜， 폴리에틸렌 옥사이드 및 이들의 혼합물 중에서 선택된 1종 이상이며 ; 상기 카르복시비닐공증합체는 카보머 인 것이 바 람직하다. 상기 친수성 고분자의 바람직한 예는 폴리비닐 피를리돈 , 히드록시프로필 셀를로오스, 히프로멜로오스，폴리 (에틸 아크릴레이트 -메틸 메타크릴레이트-트리에틸 아미노에틸- 메타크릴레이트 클로라이드) 공중합체 중에서 선택된 1종 이상이다.The hydrophilic polymer refers to a polymer material dissolved in pharmaceutically acceptable water that controls the release of the drug. Examples of hydrophilic polymers usable in the present invention include sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl copolymers, and mixtures thereof. At least one selected from the group consisting of. The sugars include dextrin, plydextrin, textlan, pectin and pectin derivatives, alginates, polygalacturonic acids, xylans, arabinoxylans, arabinogal lactans, starches, hydroxypropylstarches, amylose, amylopectin, and these At least one selected from the complications of; The cellulose derivatives include hydroxypropylmethylcellose (or hypromellose), hydroxypropylsalose, hydroxymethylcellose, At least one selected from hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, natcom, hydroxypropyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose, and combinations thereof ego ; The gum is at least one selected from guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, arabic gum, gellan gum, xanthan gum, and combinations thereof; The protein is at least one selected from gelatin, casein, zein, and combinations thereof; The polyvinyl derivative is at least one selected from pulley vinyl alcohol, polyvinyl pyridone, polyvinyl acetal diethylamino acetate, and combinations thereof; The hydrophilic polymethacrylate copolymer may be a poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer (e.g. Eudragit E, Evonik, Germany), poly At least one selected from (methacrylic acid-methyl methacrylate) copolymers, poly (methacrylic acid-ethyl acrylate) co-polymers, and mixtures thereof; The polyethylene derivative is at least one selected from polyethylene glycol, polyethylene oxide and mixtures thereof; Preferably, the carboxyvinyl copolymer is a carbomer. Preferred examples of the hydrophilic polymer are selected from polyvinyl pyridone, hydroxypropyl cellulose, hypromellose, and poly (ethyl acrylate-methyl methacrylate-triethyl aminoethyl-methacrylate chloride) copolymer 1 or more types.
<45> 여기서， 친수성 고분자는 활성성분 1 증량부에 대해서 0.05 증량부 ~ 30 증 량부 , 바람직하게는 0.5~20 중량부로 포함될 수 있으며， 0.05 중량부 미만인 경우에 는 방출속도가 조절되지 않을 염려가 있고， 30 중량부 초과인 경우에는 과도하게 용 출이 지연될 염려가 있다. Here, the hydrophilic polymer is 0.05 parts by weight to 30 parts by weight with respect to 1 parts by weight of the active ingredient, preferably 0 . May contain from 5 to 20 parts by weight, and 0.05 parts by weight, and the case is concerned with not control the release rate of less than, there is there fear of excessive output is delayed for the case of exceeding 30 parts by weight.
<46> (2-2) 삼투압 조절제 및 반투과성막 코팅기제  (2-2) Osmotic pressure regulator and semipermeable membrane coating base
<47> 본 발명의 지연방출성 구획은 삼투압 조절제를 포함하며， 반투과성막 코팅기 제로 코팅된 형태일 수 있다.  The delayed-release compartment of the present invention includes an osmotic pressure control agent and may be coated with a semipermeable membrane coater.
<48> 상기 삼투압조절제는 황산마그네슘， 염화마그네슴, 염화나트륨， 염화리튬, 황 산칼륨， 황산리튬， 황산나트륨 및 이들의 혼합물로 이루어진 군에서 선택된 1종 이상 이 바람직하다 . 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.
<49> 여기서 , 삼투압 조절제는 활성성분 1 중량부에 대해서 0.01 중량부 ~ 10 중량 부， 바람직하게는 0.05 중량부 0.5 중량부로 포함될 수 있다. 0.01 중량부 미만에서 층분한 지연방출성을 얻기 어려을 염 려가 있고， 10 중량부 초과에서 약물방출이 지연 되어 유의성 있는 임상적 효과를 얻기 어려을 염려가 있다.  Here, the osmotic pressure regulator may be included in an amount of 0.01 parts by weight to 10 parts by weight, preferably 0.05 parts by weight and 0.5 parts by weight, based on 1 part by weight of the active ingredient. It may be difficult to obtain a delayed delayed release property less than 0.01 parts by weight, and drug release may be delayed above 10 parts by weight to obtain a significant clinical effect.
<50> 상기 반투과성막 코팅기제는 약제학적 제제의 코팅층에 배합되는 물질로서， 일부 성분은 통과시키지만 다른 성분은 통과시키지 않는 막을 형성하는테 사용되는 물질을 말한다. 본 발명에서 반투과성막 코팅기제는 상기 언급된 수불용성 중합체를 사용할 수 있다. The semi-permeable membrane coating base is a substance blended into the coating layer of the pharmaceutical formulation, and is used to form a film that allows some components to pass but does not pass other components. Say a substance. In the present invention, the semipermeable membrane coating base may use the above-mentioned water-insoluble polymer.
<51> 본 발명에서 반투과성막 코팅기제는 예컨대 풀리비닐 아세테이트， 폴리메타크 릴레이트 공중합체 , 풀리 (에틸아크릴레이트 , 메틸 메타크릴레이트) 공중합체 , 폴리 ( 에틸아크¾레이트， 메틸 메타크릴레이트, 트리메틸아미노에틸메타크릴레이트 클로라 이드)공증합체 , 에틸셀를로오스， 셀를로오스 에스테르, 셀를로오스 에테르, 셀를로오 스 아실레이트， 샐를로오스 디아실레이트, 셀를로오스 트리아실레이트， 셀를로오스 아세테이트， 셀를로오스 디아세테이트, 셀를로오스 트리아세테 이트 및 이들의 흔합물 로 이루어진 군에서 선택된 1종 이상을 들 수 있다 .  In the present invention, the semi-permeable membrane coating base includes, for example, pulley vinyl acetate, polymethacrylate copolymer, pulley (ethyl acrylate, methyl methacrylate) copolymer, poly (ethyl acrylate), methyl methacrylate, Trimethylaminoethyl methacrylate chloride) Copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cell And at least one selected from the group consisting of rose acetate, cellulose diacetate, cellulose triacetate, and combinations thereof.
<52> 여기서 , 반투과성막 코팅 기제는 활성성분 1 증량부에 대해서 0.01 중량부 ~ 10 중량부， 바람직하게는 으 05 중량부 ~ 1.25 중량부로 포함될 수 있으며 , 0.01 중량부 미만인 경우에는 층분한 지 연 시간을 갖기 어려을 염려가 있고， 10 증량부 초과인 경 우에는 약물의 방출이 일어나지 않거나 지연시간이 길어지는 문제점이 있다.  Here, the semi-permeable membrane coating base may be included in an amount of 0.01 parts by weight to 10 parts by weight, preferably 05 parts by weight to 1.25 parts by weight, with respect to 1 part by weight of the active ingredient. There is a concern that it may be difficult to have time, and when the amount is 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.
<53> (3) 약제학적으로 허용가능한 첨가제  (3) pharmaceutically acceptable additives
<54> 본 발명의 제제는 본 발명의 효과를 해치지 않는 범위 안에서 약학적으로 허 용 가능한 (2-1) 방출제어물질 및 (2-2) 삼투압 조절제 및 반투과성막 코팅기제로 언 급한 것 이외의 회석제 결합제 , 붕해제， 윤활제， pH 조절제， 소포제， 용해보조제 등 의 통상적으로 사용되는 첨가제를 지연방출성의 성격을 벗어나지 않는 범위 내에서 추가로 사용하여 제제화할 수 있다.  <54> The formulation of the present invention is a diluent other than those referred to 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 binders, disintegrating agents, lubricants, pH adjusting agents, antifoaming agents, dissolution aids and the like can be formulated by further using within a range not departing from the nature of delayed release.
<55> 상기 첨가제에 관한 상세한 내용은 상기 선방출성 구획에서 상술한 내용과 동 일하다. ■ Details of the additives are the same as those described above in the above-release compartment. ■
<56> 본 발명의 약제학적 제제는 다양한 제형으로 제조할 수 있으며 , 예를 들어 나정， 코팅정， 다층정， 또는 유핵정 등의 정제， 분말제 , 과립제 , 또는 캡슬제 등으로 제형화할 수 있다. The pharmaceutical preparations of the present invention may be prepared in various formulations, and may be formulated, for example, in tablets, powders, granules, or capsules, such as uncoated tablets, coated tablets, multilayer tablets, or nucleated tablets. .
<57> 본 발명의 제제는 선방출성 구획을 이루는 과립 등과 지연방출성 구획을 이 루는 과립 등에 선택적으로 첨가제를 후흔합하여 타정한 것으로 단일 정제 내에 선방 출성 구획과 지연방출성 구획을 갖게 되어 각각의 구획의 활성성분이 별도로 용출하 게 되어 각각의 약효를 나타내게 되는 나정 형태일 수 있다 .  The formulations of the present invention are tablets which are selectively mixed with additives such as granules constituting the pre-release compartment and granules constituting the delayed-release compartment and the like, and have a pre-release compartment and a delayed-release compartment in a single tablet. The active ingredients in the compartments may be eluted separately to give their respective effects.
<58> 본 발명의 제제는 지연방출성 구획 및 선방출성 구획 이 균일하게 흔합된 후 타정하여 얻어지는 2상의 매트릭스 정제 형 태일 수 있다.  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.
<59> 또한， 본 발명의 약제학적 제제는 지연방출성 구획으로 이루어진 정제와 상기 정제의 외부를 들러싸는 선방출성 구획으로 이투어진 필름코팅층으로 구성된 필름코 팅정 형 태일 수 있으며， 필름코팅층이 용해됨에 따라 필름코팅층의 활성성분이 먼저 용출되게 된다. In addition, the pharmaceutical formulation of the present invention is a film coating consisting of a film consisting of a tablet consisting of a delayed-release compartment and a pre-release compartment enclosing the outside of the tablet It may be in a tableting form, and as the film coating layer is dissolved, the active component of the film coating layer is eluted first.
<60> 또한， 본 발명의 약제학적 제제는 지연방출성 구획과 선방출성 구획을 구성하 는 과립물에 약제학적 인 첨가제를 흔합하고, 다중 타정기를 사용하여 2증정 혹은 3증 정으로 타정하여 얻어진， 지연방출성 구획과 선방출성 구획 이 층을 이루는 다층구조 의 다층정 형태일 수 있다. 이 제제는 층별로 선방출과 지연방출이 가능하도록 제제 화된 경구 투여용 정제이다.  In addition, the pharmaceutical preparation of the present invention is obtained by mixing pharmaceutical additives in granules constituting the delayed-release compartment and the prior-release compartment, and tableting in two or three tablets using a multiple tableting machine. In addition, the delayed-release compartment and the prior-release compartment may be in the form of a multilayered multi-layered tablet in which a layer is formed. This formulation is a tablet for oral administration which is formulated to enable pre-release and delayed release in layers.
<61> 또한， 본 발명의 약제학적제제는 지연방출성 구획으로 이루어진 내핵정과 상 기 내핵정의 외면을 둘러싸고 있는 선방출성 구획으로 이루어진 외층으로 구성된 유 핵정 형태일 수 있다. 상기 유핵정은 삼투성 유핵정 일 수 있으며， 상기 삼투성 유핵 정은 지연방출을 위해 삼투압조절제를 정제의 내부에 함유하게 하여 타정한 후, 반투 과성막 코팅기제로 정제의 표면을 코팅하여 이를 내핵으로 하고， 선방출성 구획을 구 성하는 과립물을 약제학적인 첨가제와 흔합한 뒤 외층으로 하여 타정함으로써 지연방 출성의 내핵을 갖고 상기 내핵의 표면을 선방출층이 둘러싼 형태의 제형이다. In addition, the pharmaceutical preparation 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 tableting. Then, the surface of the tablet is coated with a semipermeable membrane coating agent to make it an inner core. ， The granules constituting the pre-release compartment are mixed with pharmaceutical additives and then compressed into tablets as an outer layer to have a delayed-release inner core, and the surface of the inner core is surrounded by a prior release layer.
<62> 본 발명의 약제학적 제제는 지연방출성 구획으로 이루어진 입자, 과립 , 펠렛， 또는 정제와, 선방출성 구획으로 이루어진 입자ᅳ 과립， ¾¾ ᅳ 또는 정제를 포함하는 캡술제 형 태일 수 있다.  The pharmaceutical formulation of the present invention may be in the form of a capsule, granules, pellets, or tablets consisting of delayed-release compartments, and granules, granules, granules, tablets, or tablets of prior-release compartments.
<63> 상기 캡슐제의 지연방출성 구획으로 이루어진 정제는 삼투압 조절제를 정제 내부에 포함하고， 정제의 표면에 반투과성막 코팅기제를 갖는 삼투성 코팅정일 수 있 다. Tablets consisting of delayed-release compartments 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.
<64> 상기 캡슐제의 기제는 젤라틴， 숙시네이트 젤라틴 , 또는 히드록시프로필메틸 셀를로오스, 그 흔합물 중에서 선택된 하나일 수 있다.  The base of the capsule may be one selected from gelatin, succinate gelatin, or hydroxypropylmethyl cellulose, or a combination thereof.
<65> 또한 본 발명의 약제학적 제제는 지연방출성 구획 , 및 선방출성 구획을 포함 하는 키트 형 태 일 수 있으며 , 구체적으로, 상기 키트는 ( 3) 선방출성 구획 (b) 지연방 출성 구획 및 ( C)상기 선방출성 구획 및 지 연방출성 구획을 층진하기 위한 용기로 이 루어진 것 일 수 있다. 상기 키트는 선방출성 구획을 구성하는 입자, 과립， 펠렛 , 또 는 정제를 제조하고， 지연방출성 구획을 구성하는 입자， 과립， 펠렛 또는 정제를 별 도로 제조하여， 호일 , 블리스터 , 병 등에 같이 충진하여 동시 에 복용이 가능한 형 태 로 제조할 수 있다.  In addition, 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, specifically, the kit may comprise (3) a prior-release compartment (b) a delayed-release compartment and (C) may consist of a container for stratifying the pre-release compartment and the sustained release compartment. The kit produces particles, granules, pellets, or tablets that constitute the prior release compartment, and separately prepares the particles, granules, pellets, or tablets that constitute the delayed release compartment, such as foils, blisters, bottles, and the like. It can be prepared in a form that can be filled and taken simultaneously.
<66> 본 발명의 제제는 지연방출성 구획 및 /또는 선방출성 구획의 외부에 코팅층을 추가로 형성할 수 있다. 즉 지 연방출성 구획 및 /또는 선방출성 구획으로 이루어진 입 자, 과립 , 펠¾ , 또는 정제 등의 표면에 방출제어 또는 제제 안정을 위한 목적으로 코팅을 할 수 있다. The formulation of the present invention may further form a coating layer on the outside of the delayed-release compartment and / or the prior-release compartment. That is, for the purpose of controlling release or stabilizing the product on the surface of particles, granules, pellets, or tablets, which consist of a sustained-release compartment and / or a prior-release compartment. It can be coated.
<67> 또한, 본 발명에 따른 제제는, 추가의 코팅이 없는 나정 등의 상태로도 제공 되지만, 필요에 따라 상기 제제의 외부에 코팅층을 형성시켜 , 코팅충을 추가로 포함 하는 코팅정 형 태의 제제일 수 있다. 코팅층을 형성함으로씨 , 활성성분의 안정성을 더욱 확보할 수 있다.  In addition, the formulation according to the present invention is also provided in a state such as uncoated tablets without additional coating, but if necessary, a coating layer is formed on the outside of the formulation to further form a coating tablet. It may be a formulation. By forming the coating layer, it is possible to further secure the stability of the seed, the active ingredient.
<68> 코팅층을 형성하는 방법은 정제층의 표면에 필름상의 코팅층을 형성할 수 있 는 방법 중에서 당업자의 선택에 의하여 적절히 선택할 수 있으며， 유동층 코팅법， 팬 코팅법 등의 방법을 적용할 수 있으며 , 바람직하게는 팬 코팅법을 적용할 수 있 다. ᅳ  The coating layer may be appropriately selected by a person skilled in the art from a method of forming a film-like coating layer on the surface of the tablet layer, and a method such as a fluidized bed coating method or a fan coating method may be applied. Preferably, the pan coating method can be applied. ᅳ
<69> 코팅층은 피막제 , 피막 보조제 또는 이들의 흔합물을 사용하여 형성할 수 있 으며， 예를 들어， 피막제는 히드록시프로필메틸샐를로오스， 히드특시프로필셀를로오 스 등과 같은 셀를로오스 유도체， 당 유도체， 폴리비닐 유도체 , 왁스류 , 지방류， 젤 라틴， 또는 이들의 흔합물 등을 사용할 수 있고， 피막 보조제는 폴리에 틸렌글리콜， 에틸셀를로오스， 글리세라이드류，산화티탄， 탈크 , 디에틸프탈테이트， 트리에틸 시트 레이트 또는 이들의 흔합물 등을 사용할 수 있다 .  The coating layer may be formed by using a coating agent, a coating aid, or a combination thereof. For example, the coating agent may be formed by cellulose such as hydroxypropyl methyl salose, hydroxy propyl cellulose, or the like. Derivatives, sugar derivatives, polyvinyl derivatives, waxes, fats, gelatins, or mixtures thereof, and the like, and coating aids include polyethylene glycol, ethyl cellulose, glycerides, titanium oxide, talc, Diethyl phthalate, triethyl citrate, or a mixture thereof.
<70> 코팅층은 정제 총 중량에 대하여 0.5~15 중량퍼센트 (% w/w) 범위로 포함될 수 있다 . 0.5중량 % 미만인 경우 제품의 보호와 제형에 따라 안정성의 확보가 어려을 수 있으며， 15중량 ¾ 초과하는 경우에는 활성성분의 방출양상에 영향을 미칠 우려가 있다.  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. If less than 0.5% by weight, it may be difficult to secure stability depending on the product's protection and formulation, and if it exceeds 15% by weight, there is a risk of affecting the release pattern of the active ingredient.
<71>  <71>
<72> 본 발명의 제제는 저녁투여용으로， 1일 1회 저녁 5시 내지 11시 사이에 투 여하여 24시간 균등하게 항압작용과 합병증 예방 작용을 발휘할 수 있다.  The formulation of the present invention may be administered for evening administration once a day between 5 to 11 o'clock in the evening to exhibit an anti-pressure action and a complication prevention effect evenly for 24 hours.
<73> 본 발명의 제제를 저녁시간대에 한번 복용하여도 , 선방출 되는 베타 아드레날 린 차단제에 의하여 새벽까지 혈압을 효과적으로 강하하고 , 지연방출되는 안지오텐신 Even when the preparation of the present invention is taken once in the evening, angiotensin which effectively lowers blood pressure until dawn and is delayed by beta-adrenergic blocker released beforehand
-2 수용체 길항제에 의해 새벽 이후의 혈압을 효과적으로 강하하게 되어 24시간 균등 한 항압작용과 합병증 예방 작용을 발휘하게 된다. The -2 receptor antagonist effectively lowers blood pressure after dawn, resulting in an even 24 hour anti-hypertensive action and complication prevention.
<74> 본 발명의 제제를 저녁시간대에 투여함으로써 , 특히 합병증 발생 위험시간 (새 벽부터 오전 시간)대에 혈압을 균둥하게 유지시켜 즐 수 있으므로 , 심장의 교감계 과 잉 흥분 상태를 24시간 균등하게 억제해 주어야 하는 합병증을 지닌 고혈압환자에게 유용하다. 또한, 일반 고혈압 환자와 달리 수면 중 혈압이 저하되지 않는 유형의 고 혈압인 Non-dipper형 고혈압의 억제에 본 발명의 제제는 유용하다. 상기 Non— dipper 형 고혈압은 노인， 당뇨병자， 심장비대자 등에서 나타나며， 뇌졸중과 같은 합병증 위 험이 높은 고혈압으로, 본 발명의 제제를 저녁시간대에 복용하여 수면 증 혈압억제에 유용하다. By administering the preparation of the present invention in the evening, the blood pressure can be maintained evenly during the risk of complications (new morning to morning time). It is useful for hypertensive patients with complications that must be suppressed. In addition, unlike general hypertension patients, the formulation of the present invention is useful for suppressing non-dipper type hypertension, which is a type of high blood pressure that does not lower blood pressure during sleep. The non-dipper type hypertension is present in the elderly, diabetics, cardiac hypertrophy and other complications such as stroke. With high blood pressure, the agent of the present invention is taken in the evening hours, which is useful for suppressing sleep syndrome blood pressure.
<75> 본 발명의 제제는 상대적으로 산성에서 용해가 유리한 베타 아드레날린 차단 제를 먼저 방출시키고ᅳ 산성에서 낮은 용해도를 갖는 안지오텐신— 2 수용체 길항제의 방출을 지연시킴으로써， 안지오텐신 -2 수용체 길항제와 베타 아드레날린 차단제를 함 깨 포함하는 조성물 투여시 산성환경인 위장관계 전반에서 낮은 용해도를 갖는 안지 오텐신 -2 수용체 길항제가 위 내에서 고형화되어 제형으로부터 해리되지 않거나, 낮 은 용해도로 인한 일시 적 인 경화 흑은 고화가 진행되어 이후에 방출되는 약물의 방출 과 흡수에 영향을 미치는 현상을 피할 수 있다.  The formulations of the present invention release angiotensin-2 receptor antagonists and beta adrenergic blockers by first releasing the beta adrenergic blockers that are relatively soluble in acid and delaying the release of angiotensin-2 receptor antagonists with low solubility in acid. Angiotensin-2 receptor antagonist with low solubility throughout the gastrointestinal tract, which is acidic, does not dissociate from the formulation due to solidification in the stomach, or temporarily cured black due to low solubility. This can avoid phenomena affecting the release and absorption of subsequently released drug.
<76> 본 발명의 제제는 베타 아드레날린 차단제가 먼저 간에 유입되어 간에서 사이 토크름 P450 효소에 의해 활성화되고 난 후， 안지오텐신 -2 수용체 길항제가 간을 통 과하게 되므로 베타 아드레날린 차단제와 안지오텐신 -2 수용체 길항제 간에 발생할 수 있는 대사적인 상호작용을 차단하게 되어 약물간 상호작용에 따른 부작용을 감소 시켜 ^다.  Since the beta adrenergic blocker first enters the liver and is activated by the cytokine P450 enzyme in the liver, the angiotensin-2 receptor antagonist passes through the liver, thus the beta adrenergic blocker and the angiotensin-2 receptor antagonist. It blocks the metabolic interactions that can occur in the liver, reducing the side effects of drug interactions.
<77> 본 발명의 제제를 저녁시간대에 한번 복용하여도 , 선방출 되는 떼타 아드레날 린 차단제에 의하여 새벽까지 혈압을 효과적으로 강하하고 , 지연방출되는 안지오텐신 <77> Even if the preparation of the present invention is taken once in the evening, angiotensin that effectively lowers blood pressure until dawn and is delayed by the early release terta adrenaline blocker
-2 수용체 길항제에 의해 새벽 이후의 혈압을 효과적으로 강하하게 되어 24시간 균등 한 항압작용과 합병증 예방 작용을 발휘하게 된다. The -2 receptor antagonist effectively lowers blood pressure after dawn, resulting in an even 24 hour anti-hypertensive action and complication prevention.
<78> 또한， 본 발명은 본 발명의 제제를 인간을 포함하는 포유류에게 투여하는 단 계를 포함하는 심 혈관계 질환 치료방법을 제공한다.  In addition, the present invention provides a method for treating cardiovascular disease, comprising the step of administering the agent of the present invention to a mammal including a human.
<79> 본 발명의 제제를 하루에 한번 특히 저녁시간대 (17 ~ 23시 )에 투여하는 치료 방법에 의해， 24시간 균등하게 항압작용과 합병증 예방 작용을 발휘할 수 있으므로 , 심혈관계 질환을 치료할 수 있다.  The therapeutic method of administering the agent of the present invention once daily, especially in the evening (17 to 23 o'clock), can exert anti-pressure action and prevent complications evenly for 24 hours, thereby treating cardiovascular diseases. .
<80> 상기 심혈관계 질환은 고혈압， 또는 고혈압 합병증 등을 포함하는 의미 이다. The cardiovascular disease is meant to include hypertension, or high blood pressure complications.
<81> 본 발명의 약제학적 제제는 당 분야의 적절한 방법으로， 예를 들어<81> The pharmaceutical formulation of the present invention may be prepared by any suitable method in the art, for example
Chronotherapeut i cs (2003 , Peter Redfern, PhP) , Remington' s Pharmaceutical Science (최근판， Mack Publ i shing Company, Easton PA) 등에 개시되어 있는 방법을 참조하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화 할 수 있으며， 구체적 으로 이하의 단계를 포함하는 방법에 의해 제조될 수 있다. With reference to methods disclosed in Chronotherapeut i cs (2003, Peter Redfern, PhP), Remington's Pharmaceutical Science (Recent Edition, Mack Publ i shing Company, Easton PA), etc. It may be prepared by a method comprising the following steps specifically.
<82> 제 1 단계는 지연방출성 구획의 활성성분을 장용성 고분자, 수불용성 중합체 , 소수성 화합물， 친수성 고분자 중에서 선택된 방출제어물질 1종 또는 2종 이상과 약 제학적으로 사용되는 통상의 첨가제를 투여하여 흔합， 연합， 건조， 제립 또는 코팅 , 및 타정을 통해 지연방출성 과립 또는 정제를 얻거나， 상기 활성성분을 삼투압조절제 와 약제학적으로 사용되는 통상의 첨가제를 투여하여 흔합， 연합, 건조， 제립 또는 타정한 후 반투과성막 코팅기제로 코팅하여 지 연방출성 과립 또는 정제를 얻는 단계 이다. In the first step, the active ingredient of the delayed-release compartment is administered with one or two or more release control substances selected from enteric polymers, water insoluble polymers, hydrophobic compounds, and hydrophilic polymers, and conventional additives used in pharmaceutical preparations. Mixing, associating, drying, granulating or coating And delayed-release granules or tablets through tableting, or by administering osmotic pressure-controlling agents and conventional additives used in pharmaceuticals, and then mixing, coalescing, drying, granulating or tableting and coating with a semi-permeable membrane coating base. It is the step of obtaining the oleaginous granules or tablets.
<83> 제 2 단계는 선방출성 구획의 활성성분과 약제학적으로 허용되는 통상의 첨가 제를 투여하여 흔합， 연합， 건조， 제립 혹은 코팅 , 및 타정을 통해 경구 고형제를 생 산하기 위한 통상의 과정을 통하여 얻어진 선방출성 과립 또는 정제를 얻는 단계이 다.  The second step is a conventional method for producing oral solids by mixing, associating, drying, granulating or coating, and tableting by administering the active ingredient of the prior release compartment and a conventionally acceptable pharmaceutically acceptable additive. It is a step of obtaining the pre-release granules or tablets obtained through the process.
<84> 제 3 단계는 상기 제 1 단계 및 제 2 단계에서 얻어진 각각의 과립 흑은 정제 를 약제학적인 부형제와 흔합하여 타정 또는 층전하여 경구 투여용 제제를 얻는 단계 이다.  In the third step, the granular black tablets obtained in the first and second steps are mixed with pharmaceutical excipients, and then compressed or compressed into layers to obtain a preparation for oral administration.
<85> 상기 제 1 단계와 상기 제 2 단계는 순서를 바꾸거나, 동시에 실시할 수 있 다.  The first step and the second step may be reversed or executed simultaneously.
<86> 상기 과정에 의하여 본 발명의 약제학적 제제가 제조될 수 있으며， 제 3단계의 제제화 방법을 보다 상세하게 설명하면 다음과 같으나, 이에 한정되는 것은 아니다. <87> [A] 2상의 매트릭스 정제의 제조  The pharmaceutical formulation of the present invention may be prepared by the above process, and the formulation method of the third step will be described in more detail as follows, but is not limited thereto. [87] [A] Preparation of Two-Phase Matrix Tablets
<88> 제 1 단계에서 얻어진 입자 또는 과립을 그대로 또는 방출제어물질로 추가 코 팅한 후 , 제 2 단계에서 제조한 과립과 혼합하여 일정량의 무게로 타정하여 정제를 제조한다. 얻어진 정제를 안정성 또는 성상 개선의 목적으로 필요에 따라 필름 코팅 을 할 수 있다.  After further coating the particles or granules obtained in the first step as it is or with a release control material, the mixture is 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 properties.
<89> [B] 활성성분을 함유한 필름코팅정의 제조  [89] [B] Preparation of Film Coated Tablet Containing Active Ingredient
<90> 제 1 단계에서 얻어진 코팅정 또는 과립을 그대로 또는 방출제어물질로 추가 코팅하고 건조한 후 일정량으로 타정하여 그대로 흑은 추가로 코팅하여 정제를 제조 한 후, 별도로 선방출성 구획의 활성성분을 수용성의 필름코팅용액에 용해 , 분산시켜 정제 외층에 코팅함으로씨 필름코팅에 활성성분을 함유한 경구투여형 필름코팅정제 를 제조할 수 있다.  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 and further coated with black to prepare tablets. By dissolving and dispersing in the film coating solution of the coating on the tablet outer layer can be prepared orally administered film coating tablet containing the active ingredient in the C film coating.
<91> [C] 다층정의 제조  [91] [C] Preparation of Multi-Layered Tablets
<92> 제 1 단계에서 얻어진 과립을 그대로 또는 방출제어물질로 추가 코팅하고 건 조하여 얻은 과립과 제 2 단계에서 얻어진 과립을 타정기를 이용하여 2중정으로 제조 할 수 있다. 제형설계 또는 필요에 따라 방출 보조층을 추가하여 3증 또는 그 이상의 다층정을 제조하거나 코팅하여 코팅 다층정을 제조할 수 있다.  The granules obtained in the first step and additionally coated or dried with the release control material and the granules obtained in the second step may be prepared in a double tablet using a tablet press. Coated multilayer tablets may be prepared by formulating or coating triple or more multilayered tablets by adding a release aid layer as required by the formulation design or need.
<93> [D] 유핵정의 제조 <94> 제 1 단계에서 얻어진 코팅정 또는 과립을 그대로 또는 방출제어물질로 추가 코팅하고 건조한 후 일정량으로 타정하여 그대로 혹은 추가로 코팅을 하여 내핵으로 한 후， 제 2 단계에서 얻은 과림과 함께 유핵정타정기로 타정하여 내핵의 표면을 선 방출층이 들러싼 형 태의 유핵정을 제조하거나 추가 코팅하여 코팅 유핵정을 제조할 수 있다. [93] [D] Preparation of Nucleated Tablets 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 be coated as they are or additionally to the inner core, followed by the nucleated tablet together with the fruit obtained in the second step. A tableted nucleated tablet may be prepared by tableting with a tableting machine to prepare a nucleated tablet in the form of a pre-emission layer surrounded by the surface of the inner core or by further coating.
<95> [E] 캡술제 (과립 또는 정제 함유)의 제조  [95] Preparation of [E] Capsulant (Containing Granules or Tablets)
<96> 계 1 단계에서 얻어진 과립을 그대로 또는 방출제어물질로 추가 코팅하고 건 조한 과립 또는 정제와, 제 2 단계에서 얻은 과립 또는 정제를 캡슬층전기에 넣고 일 정 크기의 캡슬에 각 주성분 유효량 해당 량만큼 층전하여 캡슐제를 제조할 수 있다. The granules obtained in step 1 are additionally coated as is or with a release control substance, and the dried granules or tablets and the granules or tablets obtained in the second step are placed in a capsular bed electric converter and the effective amount of each principal component is applied to a constant sized capsule. The amount can be layered to produce a capsule.
<97> [F] 캡술제 (펠벳 )의 제조 [97] [F] Preparation of Capsulant (Pelvet)
<98> (1) 지연방출성 구획의 활성성분과 방출제어물질， 필요에 따라 약제학적으로 허용 가능한 첨가제를 물， 유기용매 , 또는 흔합용매에 용해시키거나 현탁시켜 설탕 구형과립에 코팅 , 건조 후 필요에 따라 방출제어물질 단독 또는 2종 이상을 사용하여 물， 유기용매 , 또는 혼합용매에 용해시킨 후 코팅 , 건조한 후 제 2 단계에서 얻은 과 립 또는 제 3 단계에서 얻은 정제와 흔합 후 캡술충진기로 캡슐에 층전하여 캡술제를 제조할 수 있다.  (1) Dissolve or suspend the active ingredient in the delayed-release compartment, the release-controlling substance and, if necessary, a pharmaceutically acceptable additive in water, an organic solvent, or a mixed solvent, and then coating the spherical granules with sugar and drying them. If necessary, dissolve in water, organic solvent, or mixed solvent using release control material alone or two or more, and then coating, drying, and mixing with granules obtained in the second step or tablets obtained in the third step. Capsules can be prepared by layering into capsules.
<99> (2) 선방출성 구획의 활성성분과 제제학적으로 허용 가능한 첨가제를 물， 유 기용매， 또는 흔합용매에 용해시키거나 현탁시켜 설탕 구형과립에 코팅， 건조 후 상 기 (1)의 지연방출성 구획의 활성성분을 함유한 방출제어 펠렛과 흔합 후 캡술층진기 로 캡술에 층전하여 캡술제를 제조할 수 있다.  (2) coating the spherical granules with sugar by dissolving or suspending the active ingredient and the pharmaceutically acceptable additive in the pre-release compartment in water, an organic solvent or a mixed solvent, and delaying the above (1). Capsule preparations can be prepared by layering into capsules with a capsular layer pendulum after mixing with release control pellets containing the active ingredient of the release compartment.
<ioo> [G] 키트의 제조  <ioo> Preparation of [G] Kits
<ιοι> 제 1 단계에서 얻어진 지 연방출성 구획의 제제 (안지오텐신 -2 수용체 길항제 ) 와， 제 2 단계에서 얻은 선방출성 구획의 제제 (베타 아드레날린 차단제 )를 호일 , 블 리스터 , 병 등에 같이 층전하여 동시에 복용이 가능한 키트로 제조할 수 있다.  <ιοι> Layered preparation of the sustained-release compartment preparation (angiotensin-2 receptor antagonist) obtained in the first stage and the prior-release compartment preparation (beta adrenergic blocker) obtained in the second stage together with foil, blister, bottle, etc. Can be prepared in a dosage kit.
<102> 본 발명 제제의 인체 투여량은 체내에서 활성성분의 흡수도, 불활성화율 및 배설속도, 환자의 연령， 성별 및 상태 등에 따라 적절히 선택되나， 일반적으로는 성 인에게 베타 아드레날린 차단제와 안지오텐신 -2 수용체 길항제의 합계량으로 , 1일 2.0 ~ 2200 mg 투여할 수 있으며 , 바람직하게는 1일 10.0 ~ 1900mg을 투여하여 항압 작용과 합병증 예방 작용을 발휘토록 할 수 있다.  <102> The human dosage of the preparation 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, adult beta adrenergic blocker and angiotensin- As a total amount of the two receptor antagonists, 2.0 to 2200 mg can be administered per day, and preferably 10.0 to 1900 mg per day can be used to exert anti-pressure action and prevent complications.
<103> 본 발명의 제제는 안지오텐신 -2 수용체 길항제와 베타 아드레날린 차단제 두 성분 간의 시간차 용출을 가능하게 함으로써， 약물 대사 효소 상호 작용 이론과 시간 차 투약 원리에 적합하도록 제제화한 것으로， 두 성분을 동시에 복용하여 , 약물이 동 시에 방출되는 경우에 비해 약효를 증가시키고 부작용을 감소시킬 수 있다. <104> 즉 , 본 발명의 제제는 성분 각각의 체내 약리 작용 발현에 시간차 투약 The formulation of the present invention is formulated to conform to the theory of drug metabolic enzyme interactions and the principle of time difference administration by enabling time difference dissolution between two components of angiotensin-2 receptor antagonist and beta adrenergic blocker. Drug movement Compared to when released in the city can increase the efficacy and reduce side effects. In other words, the formulation of the present invention is administered in a time-phase manner in the expression of pharmacological action in each of the components
(Chronotherapy)원리와 약물의 체내 대사 (Xenobiot ics)원리를 적용하여 특정 속도로 체내에서 제어 방출하여 체내 흡수시 가장 이상적인 효과를 나타낼 수 있도록 설계된 약물 송달 시스템이다.  Chronotherapy is a drug delivery system designed to achieve the most ideal effect when absorbed into the body by controlling the controlled release from the body by applying the principle and the Xenobiotics principle of the drug.
【유리한 효과】  Advantageous Effects
<105> 본 발명의 약제학적 제제는 균등한 항압작용과 합병증 예방 작용을 나타내며 , 특히 합병증 발생 위험시간대에 혈압을 균등하게 유지시켜 즐 수 있어 합병증을 지닌 고혈압 환자， 수면 중 혈압억제 등에 유용하고， 각각의 약물의 방출과 흡수에 영향을 미치지 아니하며， 약물간 상호작용에 따른 부작용을 감소시켜 준다.  The pharmaceutical preparation of the present invention exhibits an equal anti-pressure action and prevents complications, and is particularly useful for maintaining hypertension with complications, and for suppressing blood pressure during sleep. It does not affect the release and absorption of each drug and reduces the side effects of drug interactions.
【도면의 간단한 설명】  [Brief Description of Drawings]
<106> 도 1은 실시 예 2의 제제에서 네비볼를과 로사르탄의 용출률을 나타낸 그래프이 다.  1 is a graph showing the dissolution rate of Naviball and Losartan in the formulation of Example 2.
<107> 도 2는 실시 예 3， 4, 5의 제제에서 네비볼를과 로사르탄의 용출를을 나타낸 그 래프이다.  Figure 2 is a graph showing the elution of Naviball and Losartan in the formulations of Examples 3, 4 and 5.
<108> 도 3은 실시 예 17의 제제에서 네비볼롤과 발사르탄의 용출를을 나타낸 그래프 이다.  3 is a graph showing the dissolution of nebivolol and valsartan in the formulation of Example 17.
<109> 도 4는 실시 예 15， 16， 18의 제제에서 네비볼를과 발사르탄의 용출를을 나타낸 그래프이다.  Figure 4 is a graph showing the elution of Naviball and Valsartan in the formulations of Examples 15, 16, and 18.
<ιιο> 도 5는 실시예 27의 제제에서 네비블를과 텔미사르탄의 용출률을 나타낸 그래 프이다.  <ιιο> Figure 5 is a graph showing the dissolution rate of Navible and telmisartan in the formulation of Example 27.
<πΐ> 도 6은 실시 예 28의 제제에서 네비볼를과 에프로사르탄의 용출률을 나타낸 그 래프이다.  Fig. 6 is a graph showing the dissolution rate of Naviball and eprosartan in the formulation of Example 28.
<112> 도 7은 실시 예 36의 제제에서 카르베딜를과 올메사르탄의 용출률을 나타낸 그 래프이다 .  7 is a graph showing the dissolution rate of carvedil and olmesartan in the formulation of Example 36.
【발명의 실시를 위한 형태】  [Form for implementation of invention]
<113> 본 발명의 이해를 돕기 위하여 실시 예를 제시한다. 하기의 실시 예는 본 발명 을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐 , 실시 예에 의해 본 발명의 내용이 한정되는 것은 아니다.  Examples are provided for better understanding of the present invention. The following examples are merely provided to more easily understand the present invention, but are not limited to the contents of the present invention by the examples.
<114> <실시 예 1> 염산 네비볼를 - 로사르탄 칼륨염 2상 매트릭스 정제 제조  Example 1 Preparation of Naviball Hydrochloride-Losartan Potassium Salt Two-Phase Matrix Tablet
<115> (1) 네비볼를 선방출성 과립의 제조  (1) Preparation of Pre-Release Granules in Naviball
<ιΐ6> 표 1에 나타난 성분 및 함량으로 염산 네비블를 (Cadi la, 인도) , 라우릴 황산 나트륨, 유당 (Parmatose, DMV Pharma, 네덜란드)， 미결정셀를로오스 (AvicelPH, FMC Biopolymer , 미국)를 칭량하여 35 호체로 사과하고 더블콘믹서 (다산파마텍， 한국)에 서 15분간 흔합하여 흔합물을 제조하였다. 별도로 히드록시프로필셀를로오스 (HPC-L, Nippon soda, 일본)를 정제수에 녹여 결합액을 제조하였다. 상기 흔합물을 유동충과 립기 (GPCG-1 ： Glatt , 독일 )에 넣고 결합액을 가하여 조립하였다. 조립물의 건조가 완료된 후， 20호채가 장착된 F형 정 립기 (KYK-60 ： 보성기계， 한국)를 사용하여 정 립 하여， 과립을 제조하였다. <ιΐ6> Naviable hydrochloric acid (Cadi la, India), lauryl sulfate with the ingredients and contents shown in Table 1 Sodium, lactose (Parmatose, DMV Pharma, Netherlands) and microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA) were weighed and apologies with No. 35 and mixed for 15 minutes in a double cone mixer (Dasan Pharmatech, Korea). Prepared. Separately, hydroxypropylcellose (HPC-L, Nippon soda, Japan) was dissolved in purified water to prepare a binding solution. The mixture was put into a fluidized bed granulator (GPCG-1: Glatt, Germany) and granulated by adding a binder solution. After drying of the granulated material, granules were prepared by sizing using an F-type sizer (KYK-60: Bosung Machine, Korea) equipped with No. 20 housing.
<117> (2) 로사르탄 칼륨염의 지연방출성 과립 제조 (2) Preparation of delayed-release granules of losartan potassium salt
<118> 표 1에 나타난 성분 및 함량으로, 로사르탄 칼륨염 (동우， 한국)， 미결정샐를 로오스， 크로스 카멜로스 나트륨 (Vivasol , JRS, 독일)을 35호체로 사과하고 더불콘믹 서 (다산파마텍， 한국)로 15분간 흔합하여 흔합물을 제조하였다. 별도로 히드록시프 로필샐를로오스 (HPC-L, Nippon soda, 일본)를 정제수에 녹여 결합액으로 하였다. 상 기의 흔합물을 유동층과립기 (GPCG— 1 ： Glatt , 독일 )에 넣고 결합액을 가하여 조립하 여 과립을 형성 , 건조하였다. 별도로 에탄올과 염화메틸렌 흔합용매에 셀를로오스아 세테이트 (CA-320S/CA-398NF10, Eastman Chemical Company, 미국)， 히드록시프로필메 틸셀를로오스를 용해시킨 용액으로 다시 상기의 과립을 코팅하였다.  <118> With the ingredients and contents shown in Table 1, apples of losartan potassium salt (Dongwoo, Korea), microcrystalline salose, loose, croscarmellose sodium (Vivasol, JRS, Germany) were identified as No. 35 and debulconic mixer (Dasan Pharmatech). , Korea) was mixed for 15 minutes to prepare a mixture. Separately, hydroxypropylsalose (HPC-L, Nippon soda, Japan) was dissolved in purified water to prepare a binding solution. The mixture was placed in a fluidized bed granulator (GPCG-1: Glatt, Germany), granulated by adding a binder solution, and granulated to form granules. Separately, the granules were again coated with a solution of cellulose acetate (CA-320S / CA-398NF10, Eastman Chemical Company, USA) and hydroxypropylmethylcellose in a mixture of ethanol and methylene chloride. .
<119> (3) 타정 및 코팅  (119) tableting and coating
<120> 상기 (1) , (2)의 두 과립물을 흔합한 후， 콜로이드성 이산화규소와 스테아르 산 마그네슴을 투입 및 흔합하여 직경 10.0隱편치가 장착된 로타리 타정기 (MRC-33, 세종파마텍， 한국)에서 타정하였다.  After mixing two granules of (1) and (2) above, colloidal silicon dioxide and stearic acid magnesium are added and mixed to form a rotary tableting machine equipped with a 10.0 mm diameter bias (MRC-33, Sejong Pharmatech). Tableting in Korea).
<121> 상기의 타정 후， 별도로 다음 표 1에 나타낸 함량과 같이 히드록시프로필메틸 셀를로오스 2910， 폴리에틸렌글리콜 6000， 산화티탄을 정제수와 에탄올 흔합용매에 용해 및 분산시켜 코팅 액을 조제하였다. 상기의 정제을 하이코터 (SFC-30F, 세종파마 텍 , 한국)에 투입한 후 코팅 액으로 정제를 코팅하였다.  After the above-mentioned tableting, hydroxypropylmethyl cellulose 2910, polyethylene glycol 6000, and titanium oxide were separately dissolved and dispersed in purified water and ethanol mixed solvent as described in the following Table 1 to prepare a coating solution. The tablets were put in a high coater (SFC-30F, Sejong Pharmatech, Korea) and then coated with a coating solution.
<122> <실시 예 2> 염산 네비블롤 - 로사르탄 칼륨염 이중정제 제조  <Example 2> Preparation of Naviblo Hydrochloride-Losartan Potassium Salt Double Tablet
<123> (1) 염산 네비볼를 선방출성 구획의 제조  (1) Preparation of a Pre-Released Compartment in Naviball Hydrochloric Acid
<124> 표 1에 나타난 성분과 함량으로 염산 네비볼를 (Cadi la, 인도)ᅳ 라우릴 황산 나트륨， 유당 (Parmatose, DMV Pharma, 네덜란드) , 미결정셀를로오스 (AvicelPH, FMC Biopolymer, 미국)를 칭량하여 35 호체로 사과하고 더블콘믹서 (다산파마텍， 한국)에 서 15분간 흔합하여 흔합물을 제조하였다. 별도로 히드록시프로필셀를로오스 (HPOL, Nippon soda, 일본)를 정제수에 녹여 결합액을 제조하였다. 상기 혼합물을 유동층과 립기 (GPCG-1 ： Glatt , 독일 )에 넣고 결합액을 가하여 조립하였다. 조립물의 건조가 완료된 후 , 20호체가 장착된 F형 정 립기를 사용하여 정 립 하였다. 정 립물에 전분글리 콘산나트륨과 콜로이드성 이산화규소 및 스테아르산 마그네슘을 투입한 후 , 최종 흔 합하여 염산 네비볼를 선방출층을 제조한다. <124> Weigh Naviball hydrochloride (Cadi la, India) ᅳ sodium lauryl sulfate, lactose (Parmatose, DMV Pharma, Netherlands) and microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA) using the ingredients and contents shown in Table 1. The apples in No. 35 sieve and mixed for 15 minutes in a double cone mixer (Dasan Pharmatech, Korea) to prepare a mixture. Separately, hydroxypropylcellose (HPOL, Nippon soda, Japan) was dissolved in purified water to prepare a binding solution. The mixture was put into a fluidized bed granulator (GPCG-1: Glatt, Germany) and granulated by adding a binder solution. The dryness of the assembly After completion, it was established using the F-type sizer equipped with No. 20 body. Sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate were added to the sieved material, followed by final mixing to prepare a pre-release layer of navigable hydrochloride.
<125> (2) 로사르탄 칼륨염 지 연방출성 구획의 제조 (2) Preparation of Losartan Potassium Salt Lipid Release Block
<126> 표 1에 나타난 성분과 함량으로 상기 실시 예 1의 (2)에서와 동일한 방법으로 제조한 로사르탄 칼륨염 지 연방출성 과립에 콜로이드성 이산화규소 및 스테아르산 마 그네슘을 투입하고, 최종 흔합하여 로사르탄 칼륨염 지연방출층을 제조한다.  In the same method as in Example 1 (2), the colloidal silicon dioxide and magnesium stearate were added to the Losartan potassium salt non-release granules prepared in the same manner as in Example 1, and In combination, a losartan potassium salt delayed-release layer is prepared.
<127> (3) 타정 및 코팅  (127) tableting and coating
<128> 제조된 염산 네비볼를 선방출층과 로사르탄 칼륨염 지연방출층을 직경 10讓 편치가 장착된 로타리 다층정 타정기 (MRC-37T, 세종파마텍， 한국)의 다른 과립 주입 구에 각각 넣고 타정한 후， 타정이 완료된 정제를 상기 실시 예 1 (3)의 코팅방법과 동일하게 코팅하였다 .  <128> Naviball hydrochloric acid prepared in each of the pre-release layer and the losartan potassium salt delayed-release layer in a granule injection hole of the rotary multi-layer tablet press (MRC-37T, Sejong Pharmatech, Korea) equipped with a 10 讓 diameter biased tablet After the tableting was completed, the tablets were coated in the same manner as in the coating method of Example 1 (3).
<129> <실시예 3> 염산 네비블를 ᅳ 로사르탄 칼륨염 다층정제 제조  <Example 3> Losartan potassium salt multi-layer tablets prepared by navigating hydrochloric acid
<130> (1) 염산 네비볼를 선방출층의 제조  (1) Preparation of Pre-Release Layer of Hydrochloric Acid Naviball
<131> 표 1에 나타난 성분과 함량으로 , 염산 네비볼를 (Cadi la, 인도) , 라우릴 황산 나트륨， 유당 (Parmatose, DMV Pharma, 네덜란드)， 미결정셀를로오스 (AvicelPH, FMC Biopolymer , 미국)를 칭량하여 35 호체로 사과하고 더블콘믹서 (다산파마텍， 한국)에 서 15분간 흔합하여 흔합물을 제조하였다. 별도로 히드록시프로필셀를로오스 (HPC-L, Nippon soda, 일본)를 정제수에 녹여 결합액을 제조하였다 . 상기 흔합물을 유동층과 립기 (GPCG— 1 ： Glatt , 독일 )에 넣고 결합액을 가하여 조립하였다. 조립물의 건조가 완료된 후, 20호체가 장착된 F형 정 립기를 사용하여 정 립 하였다. 정 립물에 전분글리 콘산나트륨과 콜로이드성 이산화규소 및 스테아르산 마그네슘을 투입한 후, 최종 흔 합하여 염산 네비볼를 선방출층을 제조하였다.  Naviball hydrochloride (Cadi la, India), sodium lauryl sulfate, lactose (Parmatose, DMV Pharma, The Netherlands), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA) Weighed and appled with No. 35 sieve and mixed for 15 minutes in a double cone mixer (Dasan Pharmatech, Korea) to prepare a mixture. Separately, hydroxypropylcellose (HPC-L, Nippon soda, Japan) was dissolved in purified water to prepare a binding solution. The mixture was put into a fluidized bed granulator (GPCG-1: Glatt, Germany) and granulated by addition of a binder solution. After the drying of the granules was completed, it was established using the F-type sizer equipped with No. 20 body. Sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate were added to the sieved material, followed by final mixing, to prepare a pre-release layer of navigable hydrochloride.
<132> (2) 로사르탄 칼륨염 지 연방출층의 제조  (2) Preparation of Losartan Potassium Salt Exhaust Layer
<133> 표 1에 나타난 성분과 함량으로, 상기 실시 예 2 (2)의 로사르탄 칼륨염 지연 방출층과 동일한 방법으로 제조하였다.  The ingredients and contents shown in Table 1 were prepared in the same manner as the losartan potassium salt delayed-release layer of Example 2 (2).
<134> (3) 타정 및 코팅  (134) tableting and coating
<135> 상기 (2)에서 제조한 로사르탄 칼륨염 지 연방출 과립을 중간층 (2번째층)으로 쌓고， 실시 예 3 (1)의 염산 네비볼를 속방출 과립을 1층 및 3층으로 분할하여 로타리 다층정 타정기 (MRC-37T, 세종파마텍， 한국)의 다른 과립 주입구에 각각 넣고 타정한 후 , 상기 실시 예 1 (3)의 코팅방법과 동일하게 코팅하였다 .  The losartan potassium salt branched granules prepared in the above (2) were stacked in the middle layer (second layer), and the naviball hydrochloride of Example 3 (1) was divided into one layer and three layers. Into each other granule inlet of the rotary multi-layer tablet press tablet machine (MRC-37T, Sejong Pharmatech, Korea) and tableting, it was coated in the same manner as the coating method of Example 1 (3).
<136> <실시예 4> 염산 네비볼를 - 로사르탄 칼륨염 유핵정제 제조 <137> (1) 염산 네비볼를 선방출성 구획의 제조 <Example 4> Preparation of nucleated hydrochloric acid-losartan potassium salt nucleated tablet (1) Preparation of a Pre-Releasable Compartment in Naviball Hydrochloric Acid
<138> 표 1에 나타난 성분과 함량으로 염산 네비볼를 (Cadi la, 인도) , 유당  Naviball hydrochloric acid (Cadi la, India), lactose, according to the components and contents shown in Table 1
(Parmatose, DMV Pharma, 네덜란드) , 미결정셀를로오스 (AviceiPH, FMC Biopolymer, 미국)， 전젤라틴화전분을 칭량하여 35 호체로 사과하고 더블콘믹서 (다산파마텍 , 한 국)에서 15분간 흔합하여 흔합물을 제조하였다. 별도로 히드록시프로필셀를로오스 (HPC-L, Nippon soda, 일본)를 정제수에 녹여 결합액을 제조하였다. 상기 흔합물을 유동층과립기 (GPCG-1 ： Glatt , 독일 )에 넣고 결합액을 가하여 조립하였다. 조립물의 건조가 완료된 후, 20호체가 장착된 F형 정 립기를 사용하여 정 립 하였다. 정 립물에 라우릴 황산 나트륨， 크로스카멜로스나트륨， 콜로이드성 이산화규소 및 스테아르산 마그네슘을 투입한 후， 최종 흔합하여 염산 네비볼를 선방출층을 제조하였다.  (Parmatose, DMV Pharma, Netherlands), microcrystalline cellulose (AviceiPH, FMC Biopolymer, USA), pregelatinized starch were weighed and apologized to No. 35 and mixed for 15 minutes in a double cone mixer (Dasan Pharmatech, Korea). The mixture was prepared. Separately, hydroxypropylcellose (HPC-L, Nippon soda, Japan) was dissolved in purified water to prepare a binding solution. The mixture was put into a fluidized bed granulator (GPCG-1: Glatt, Germany) and granulated by the addition of a binder solution. After the drying of the granules was completed, it was established using the F-type sizer equipped with No. 20 body. Sodium lauryl sulfate, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate were added to the sieved material, and the final mixture was mixed with Naviball hydrochloride to prepare a pre-release layer.
<139> (2) 로사르탄 칼륨염의 지 연방출성 구획의 제조  (2) Preparation of Sterile Release Blocks of Losartan Potassium Salt
<140> 표 1에 나타난 성분 및 함량으로， 로사르탄 칼륨염， 전젤라틴화전분， 미결정 셀를로오스， 크로스 카멜로스 나트륨 (Vivasol , JRS, 독일) , 가교폴리비닐피를리돈 , 콜로이드성 이산화규소를 35호체로 사과하고 더블콘믹서 (다산파마텍， 한국)로 15분간 흔합하여 흔합물을 제조하였다. 흔합물에 코포비돈 (Kol l idon VA64, BASF, 독일 )을 투 입후 혼합하고， 스테아르산 마그네슘을 투입하여 최종흔합한 후 , 로타리 타정기를 사 용하여 타정하였다. 별도로 아크릴이즈를 정제수에 분산시킨 후， 하이코터 (SFC-30F, 세종파마텍 , 한국)를 이용하여 상기의 정제에 코팅하여 로사르탄 칼륨염 지연방출층 내핵정을 제조하였다 .  <140> Ingredients and contents shown in Table 1, potassium potassium salt, pregelatinized starch, microcrystalline cellulose, croscarmellose sodium (Vivasol, JRS, Germany), crosslinked polyvinylpyridone, colloidal silicon dioxide Was apples in No. 35 sieve and mixed with a double cone mixer (Dasan Pharmatech, Korea) for 15 minutes to prepare a mixture. Copovidone (Kol l idon VA64, BASF, Germany) was added to the mixture, mixed, and finally mixed with magnesium stearate, followed by compression using a rotary tablet press. Separately, after dispersing acrylamide in purified water, and coated on the tablets using a high coater (SFC-30F, Sejong Pharmatech, Korea) to prepare a losartan potassium salt delayed-release layer inner core tablet.
<141> (3) 타정 및 코팅  (141) tableting and coating
<142> 유핵정타정기 (RUD-I , Ki li an, 득일 )를 사용하여 로사르탄 칼륨염 핵정을 내핵 으로 하고 , 염산 네비블를 선방출층을 외층으로 하여 함깨 타정하여 유핵정을 제조하 였다. 상기의 타정 후, 별도로 다음 표 1에 나타낸 함량과 같이 상기 실시 예 1 (3)의 코팅방법과 동일하게 코팅하여 유핵정 정제를 제조하였다.  Nucleating tablets were prepared by using a nucleating tableting machine (RUD-I, Ki li an, Deukil) as a core of losartan potassium salt as the inner core, and tableting with hydrochloric acid navigable as the outer layer. After the tableting of the above, separately coated in the same manner as the coating method of Example 1 (3) as shown in the following Table 1 to prepare a nucleated tablet.
<143> <실시 예 5> 염산 네비볼를 - 로사르탄 칼륨염 캡슬제 (정제 + 정제)의 제조 Example 5 Preparation of Naviball Hydrochloride-Losartan Potassium Salt Capsule (Tablet + Tablet)
<144> 표 1에 나타난 성분 및 함량으로 상기 실시 예 4 (1)과 동일한 방법으로 제조하되， 염 산 네비볼를 선방 #성 과립을 로타리 타정기 (MRC-33, 세종파마텍 , 한국)를 이용하여 타정하고 , 상기 실시 예 4 (2)와 동일한 방법으로 로사르탄 칼륨염 지연방출형 과립을 제조한 후, 로타리 타정기 (MRC-33, 세종파마텍， 한국)를 이용하여 타정하였다. 상기 의 타정 후， 두 정제를 1호 캡슐에 캡슬층진기 (SF-40N, 세종파마텍 , 한국)로 층진하 여 캡술제를 제조하였다. <144> Prepared in the same manner as in Example 4 (1) with the ingredients and contents shown in Table 1, tableting the hydrophobic navigating # granules using a rotary tableting machine (MRC-33, Sejong Pharmatech, Korea) After preparing Losartan potassium salt delayed-release granules in the same manner as in Example 4 (2), the tablets were compressed using a rotary tablet press (MRC-33, Sejong Pharmatech, Korea). After the tableting, two tablets were layered in a capsule capsule device (SF-40N, Sejong Pharmatech, Korea) in No. 1 capsule to prepare a capsule.
<145> <실시 예 6> 염산 네비블를-로사르탄 칼륨염 캡슐제 (과립 + 정제 )의 제조 <146> (1) 염산 네비볼를 선방출 과립 제조 Example 6 Preparation of Naviable Hydrochloric Acid-Losartan Potassium Salt Capsules (Granules + Tablets) (146) (1) Preparation of Prerelease Granules for Hydrochloric Acid Naviball
<147> 표 1에 나타난 성분 및 함량으로 염산 네비볼를 (Cadi la, 인도)， 라우릴 황산 나트륨 , 유당 (Parmatose, DMV Pharma, 네덜란드) , 미결정셀를로오스 (AvicelPH, FMC Biopolymer, 미국)， 크로스카멜로스나트륨을 칭량하여 35 호체로 사과하고 더블콘믹 서 (다산파마텍， 한국)에서 15분간 흔함하여 흔합물을 제조하였다. 별도로 히드특시 프로필셀를로오스 (HPC-L, Nippon soda, 일본)를 정제수에 녹여 결합액을 제조하였다. 상기 흔합물을 유동층과립기 (GPCG-1 ： Glatt , 독일 )에 넣고 결합액을 가하여 조립， 건조하였다. 건조물을 20호체가 장착된 F형 정 립기를 사용하여 정 립하고 , 스테아르산 마그네슴을 투입한 후， 최종흔합하여 염산 네비블를 선방출 과립을 제조하였다 . Naviball hydrochloride (Cadi la, India), sodium lauryl sulfate, lactose (Parmatose, DMV Pharma, The Netherlands), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA), cross Sodium camelos was weighed and appled into No. 35 sieve, and the mixture was prepared for 15 minutes in a double cone mixer (Dasan Pharmatech, Korea). Separately, the binder solution was prepared by dissolving hydroxyipropyl cellulose (HPC-L, Nippon soda, Japan) in purified water. The mixture was placed in a fluidized bed granulator (GPCG-1: Glatt, Germany), and the binder solution was added to assemble and dried. The dried product was sized using an F-type sizer equipped with No. 20 sieve, and then stearic acid magnesium was added thereto, followed by final mixing to prepare granules of hydrochloric acid.
<148> (2) 로사르탄 칼륨염 지 연방출 정제의 제조 (2) Preparation of Losartan Potassium Salt Extracted Tablets
<149> 표 1에 나타난 성분 및 함량으로 , 로사르탄 칼륨염， 전젤라틴화전분， 미결정 셀를로오스， 크로스 카멜로스 나트륨， 가교풀리비닐피를리돈, 콜로이드성 이산화규소 를 35호체로 사과하고 더블콘믹서 (다산파마텍， 한국)로 15분간 흔합하여 흔합물을 제 조하였다. 흔합물에 코포비돈 (Kol l idon VA64, BASF, 독일)을 투입하여 흔합하고 스 테아르산 마그네슴을 투입하여 최종흔합한 후， 로타리 타정기를 사용하여 타정하였 다. 별도로 에탄올과 염화메틸렌 흔합용매에 프탈산히드록시프로필메틸셀를로오스를 용해시킨 코팅 액을 제조한 후ᅤ 상기의 정제를 코팅하였다. As shown in Table 1, apples of losartan potassium salt, pregelatinized starch, microcrystalline cellulose, croscarmellose sodium, cross-linked polyvinylpyridone and colloidal silicon dioxide were used as apples. The mixture was mixed for 15 minutes with a mixer (Dasan Pharmatech, Korea). Copovidone (Kol l idon VA64, BASF, Germany) was added to the mixture, mixed with the stearic acid magnesium and finally mixed, and then compressed using a tablet press. A separate coating to prepare a reaction solution to dissolve the agarose in hydroxypropylmethylcellulose phthalate in ethanol and methylene chloride selreul heunhap solvent was then coating the tablet of yae.
<150> (3) 캡슐 층진  <150> (3) layered capsule
<151> 상기의 (1)과 (2)를 동일한 캡슐 (0호 캡술)에 캡술층진기로 층진하여 염산 네비볼를 로사르탄 칼륨염 캡슐제 (과립 + 정제 )를 제조하였다.  (1) and (2) above were layered in the same capsule (No. 0 capsule) with a capsul layered layer to prepare a sorbitan hydrochloric acid losartan potassium salt capsule (granule + tablet).
<152> <실시예 7> 염산 네비볼를 로사르탄 칼륨염 캡슬제 (과립 + 과립 )의 제조<Example 7> Preparation of losartan potassium salt capsule (granule + granules)
<153> (1) 염산 네비볼를 선방출 과립의 제조 (1) Preparation of Granules Pre-Released Naviball Hydrochloric Acid
<154> 표 1에 나타난 성분 및 함량으로 상기 실시 예 6(1)의 염산 네비볼롤 과립과 동일한 방법으로 제조하였다.  The ingredients and contents shown in Table 1 were prepared in the same manner as the hydrochloride nebivolol granules of Example 6 (1).
<155> (2) 로사르탄 칼륨염 지연방출 과립의 제조  (2) Preparation of Losartan Potassium Salt Delayed-Release Granules
<156> 표 1에 나타난 성분 및 함량으로， 로사르탄 칼륨염 , 미결정셀를로오스， 크로 스 카멜로스 나트륨을 35호체로 사과하고 더블콘믹서 (다산파마텍， 한국)로 15분간 흔 합하여 흔합물을 제조하였다. 별도로 히드록시프로필샐를로오스 (HPC-L, Nippon soda, 일본)를 정제수에 녹여 결합액으로 하였다. 상기의 흔합물을 유동층과립기 (GPCG-1 ： Glatt , 독일)에 넣고 결합액을 가하여 조립하여 과립을 형성， 건조하였다. 다시 에탄올과 염화메틸렌 흔합용매에 프탈산히드록시프로필메틸샐를로오스를 용해시 킨 용액으로 상기의 과립을 코팅하였다. 코팅 완료 후， 스테아르산 마그네슴을 투입 하여 최종흔합하여 로사르탄 칼륨염 지연방출 과립 흔합물을 제조하였다.<156> With the ingredients and contents shown in Table 1, acetonitrile potassium salt, microcrystalline cellulose, and croscarmellose sodium were apologized with No. 35, and mixed with a double cone mixer (Dasan Pharmatech, Korea) for 15 minutes. Prepared. Separately, hydroxypropylsalose (HPC-L, Nippon soda, Japan) was dissolved in purified water to prepare a binding solution. The mixture was placed in a fluidized bed granulator (GPCG-1: Glatt, Germany), granulated by adding a binder solution, and granulated to form granules. Again, the granules were coated with a solution in which phthalic acid hydroxypropylmethylsalose was dissolved in a mixed solvent of ethanol and methylene chloride. After completion of coating, stearic acid magnesium is added The final mixing was carried out to prepare a losartan potassium salt delayed-release granule mixture.
<157> (3) 캡슐 층진 (3) layered capsules
<158> 상기의 (1)과 (2)를 0호 캡슐에 캡슐충진기로 충진하여 캡술제를 제조하였다.  (1) and (2) above were filled into capsule 0 using a capsule filling machine to prepare a capsulant.
<159> <실시 예 8> 염산 네비볼를 - 로사르탄 칼륨염 캡슐제 (펠 ¾+펠¾)의 제조Example 8 Preparation of Naviball Hydrochloride-Losartan Potassium Salt Capsule (Pel ¾ + Pel¾)
<160> (1) 염산 네비볼를 선방출성 펠렛의 제조 (1) Preparation of Pelvic Pellets by Naviball Hydrochloric Acid
<i6i> 염산 네비불를 선방출성 펠¾의 제조는 슈가 시드 (Sugar sphere)를 유동층 과 립기 (GPCG 1 Glatt , 독일 )에 투입한 뒤 , 따로 물과 에탄올 흔합액에 히드록시프로필 샐를로오스 (HPC-L, Nippon soda, 일본)， 히드록시프로필메틸셀를로오스， 염산 네비볼 를， 라우릴 황산 나트륨을 용해 또는 현탁시킨 결합액을 분무하여 펠렛을 형성 건조 하여 염산 네비볼를 속방출성 펠렛을 제조하였다.  <i6i> Preparation of releasing Pel¾ from Naviv hydrochloric acid was carried out by adding Sugar seed to a fluidized bed granulator (GPCG 1 Glatt, Germany), and then adding hydroxypropyl salulose (HPC) to a mixture of water and ethanol. -L, Nippon soda, Japan), hydroxypropylmethylcellose, Naviball hydrochloride, and a binder solution in which sodium lauryl sulfate was dissolved or suspended were sprayed to form pellets to produce a rapid release pellet of Naviball hydrochloride. It was.
<162> . (2) 로사르탄 칼륨염 지 연방출 펠렛의 제조  <162>. (2) Preparation of Losartan Potassium Salt Extraction Pellets
<163> 로사르탄 칼륨염 지 연방출 펠렛의 제조는 슈가 시드 (Sugar sphere)를 유동층 과립기 (GPCG 1 Glatt , 독일 )에 투입한 뒤， 따로 물과 에탄을 흔합용매에 히드록시프 로필메틸샐를로오스와 로사르탄 칼륨염을 용해 또는 현탁 결합액을 분무하여 펠렛을 형성하고， 건조하였다. 다시 상기의 과립에 프탈산히드특시프로필메틸셀를로오스를 에탄을과 염화메틸렌 흔합용매에 녹인 액을 분무하여 로사르탄 칼륨염 지연방출 ¾¾ 을 제조하였다.  In the preparation of Losartan potassium salt fed-out pellets, sucrose (Sugar sphere) was added to a fluidized bed granulator (GPCG 1 Glatt, Germany), and then hydroxypropylmethylsal was added separately to a mixed solvent of water and ethane. Loose and losartan potassium salt were dissolved or sprayed with suspension binder to form pellets and dried. The granules were then sprayed with a solution of phthalic acid special propylmethylcellose in ethane and a methylene chloride mixed solvent to prepare a delayed release of losartan potassium salt of ¾¾.
<164> (4) 캡술 충진  (164) Capsule Filling
<165> 상기의 (1)과 (2)를 0호 캡슐에 캡슐층진기로 충진하여 캡슐제를 제조하였 다.  (1) and (2) above were filled into No. 0 capsules with a capsule layered device to prepare a capsule.
<166> <실시예 9> 염산 네비볼를 - 로사르탄 칼륨염 캡술제 제조 (정제， 펠렛) Example 9 Preparation of Naviball Hydrochloride with Losartan Potassium Salt Capsule (Tablet, Pellets)
<167> 표 2에 나타난 성분 및 함량으로 , 상기 실시예 8의 (1)과 동일한 방법으로 염 산 네비볼를 선방출성 펠렛을 제조하고， 로사르탄 칼륨염 지연방출층 정제는 상기 실 시예 4(2)와 동일한 방법으로 지연방출 정제를 제조하여， 각각의 정제와 펠¾을 0호 캡슐에 캡술층진기로 층진하여 제조하였다. With the ingredients and contents shown in Table 2, to prepare a pre-release pellet of hydrochloric acid Naviball in the same manner as in Example (1) of the above Example 8, the losartan potassium salt delayed-release layer purification was carried out in Example 4 (2). Delayed-release tablets were prepared in the same manner as above), and each tablet and pellets were prepared by layering a capsule capsule layer 0 into a capsule No. 0.
<168> <실시 예 10> 염산 네비볼를-로사르탄 칼륨염 유핵정 정제의 제조  Example 10 Preparation of Naviball Hydrochloride-Losartan Potassium Salt Nucleated Tablets
<169> (1) 염산 네비볼를 선방출성 구획의 제조  (1) Preparation of Pre-Releasable Compartments of Naviball Hydrochloric Acid
<170> 표 2에 나타난 성분 및 함량으로， 염산 네비블롤， 유당， 라우릴 황산 나트륨, 미결정셀를로오스 전분글리콘산나트륨을 칭량하여 35 호체로 사과하고 더블콘믹서 ( 다산파마텍 , 한국)에서 20분간 흔합하여 흔합물을 제조하였다. 흔합 완료 후 스테아 르산 마그네슘을 투입 후 4분간 흔합하여 염산 네비볼를 선방출성 흔합물을 제조하였 다 . <171> (2) 로사르탄 칼륨염 지연방출성 과립 제조 <170> With the ingredients and contents shown in Table 2, weighing Naviblo hydrochloride, lactose, sodium lauryl sulfate and microcrystalline sodium sodium starch glycolate were weighed and apologized as No. 35 and in a double cone mixer (Dasan Pharmatech, Korea). The mixture was prepared by mixing for 20 minutes. After completion of the mixture, magnesium stearate was added, followed by mixing for 4 minutes to prepare a naviball hydrochloride prior-release mixture. (171) Losartan Potassium Salt Delayed-Release Granules Preparation
<172> 표 2에 나타난 성분 및 함량으로， 로사르탄 칼륨염 , 미결정셀를로오스, 전젤 라틴화전분을 35호체로 사과하고 더블콘믹서 (다산파마텍， 한국)로 5분간 흔합하여 흔 합물을 제조하였다. 다시 상기의 흔합물에 크로스카멜로스나트륨과 콜로이드성 이산 화규소를 투입하여 흔합하고, 스테아르산 마그네슘 투입 후 최종 흔합하여 로타리 타 정기를 사용하여 타정하였다. 별도로 히드록시프로필메칠셀를로오스를 80% 에탄을에 녹여 1차 코팅 액을 제조하였고, 유드라짓 L30D-55(Eudragit L30D-55, 에보닉 , 독일 )， 탈크， 트리에틸시트레이트 (Citrof lex 2, Morimura, 일본) 를 정제수에 용해 및 분산 시켜 2차 코팅 액을 제조하였다. 코팅 액 제조가 완료된 후， 상기 정제를 하이코터 (SFC-30F, 세종파마텍， 한국)에 투여하고 1차 코팅 (히드록시프로필메칠셀를로오스 코 팅 액 )을 한 후， 2차 코팅 (유드라짓 L30D-55 코팅 액 )하여 , 로사르탄 칼륨염 내핵정을 제조하였다.  <172> With the ingredients and contents shown in Table 2, apples of losartan potassium salt, microcrystalline cellulose and whole gel latin starch were subjected to apples with No. 35, and mixed with a double cone mixer (Dasan Pharmatech, Korea) for 5 minutes to prepare a mixture. It was. Again, the mixture was mixed with sodium croscarmellose and colloidal silicon dioxide, mixed with magnesium stearate, and finally mixed with a tablet press using a rotary tableting machine. Separately, hydroxypropylmethylcellose was dissolved in 80% ethane to prepare a primary coating solution. Eudragit L30D-55 (Eudragit L30D-55, Evonik, Germany), talc, triethyl citrate (Citrof lex 2, Morimura, Japan) was dissolved and dispersed in purified water to prepare a secondary coating solution. After the preparation of the coating solution is completed, the tablet is administered to a high coater (SFC-30F, Sejong Pharmatech, Korea), and after the first coating (hydroxypropyl methylcell release coating), the second coating (Yudra L30D-55 coating solution) to prepare a losartan potassium salt inner core tablet.
<173> (3) 타정 및 코팅  (1) Tableting and Coating
<174> 상기 실시 예 4 (3)의 타정 및 코팅 방법과 동일한 방법으로 유핵정 정제를 제조하였다.  Nucleated-tablet tablets were prepared in the same manner as the tableting and coating method of Example 4 (3).
<175> <실시 예 11〉 염산 네비볼롤 - 로사르탄 칼륨염 블리스터 포장 키트의 제조 Example 11 Preparation of Navivolol Hydrochloride-Losartan Potassium Salt Blister Packaging Kit
<176> (1) 염산 네비볼롤 선방출성 정제 제조 (1) Preparation of Nebivolol Pre-Releasable Tablet for Hydrochloric Acid
<177> 표 2에 나타난 성분 및 함량으로， 염산 네비볼를， 라우릴황산나트륨， 유당， 전분글리콘산나트륨을 칭량하여 35호체로 사과하고， 더블콘믹서 (다산파마텍， 한국)에 서 흔합하여 흔합물을 제조하였다 . 별도로 히드특시프로필셀를로오스를 정제수에 녹 여 결합액으로 하였다. 위의 흔합물을 유동층 과립기에 투여한 후， 결합액을 분무하 여 과립을 제조， 건조하였다. 다시 상기의 과립에 미결정셀를로오스 , 크로스카멜로스 나트륨, 콜로이드성 이산화규소를 넣고 흔합한 후, 스테아르산 마그네슴을 투입 및 최종혼합하여 로타리 타정기 (ffiC-33, 세종파마텍， 한국)로 타정한 후, 히드록시프로 필메틸셀를로오스 2910， 플리에틸렌글리콜 6000， 및 산화티탄을 에탄올 및 정제수에 용해 및 분산시킨 코팅 액으로 정제를 코팅하여 염산 네비볼를 선방출성 정제를 제조 하였다 .  <177> Weighing Naviball hydrochloride, sodium lauryl sulfate, lactose, sodium starch glycolate with apples No. 35 with ingredients and contents shown in Table 2, and mixed in a double cone mixer (Dasan Pharmatech, Korea) The mixture was prepared. Separately, hydroxypropylcellose was dissolved in purified water to obtain a binding solution. After administering the above mixture to a fluidized bed granulator, the binder was sprayed to prepare granules and dried. Into the granules, microcrystalline cellulose, croscarmellose sodium, and colloidal silicon dioxide were added and mixed, and then stearic acid was added to the granules and finally mixed with a rotary tableting machine (ffiC-33, Sejong Pharmatech, Korea). Then, tablets were coated with a coating solution in which hydroxypropylmethylcellose 2910, polyethylene glycol 6000, and titanium oxide were dissolved and dispersed in ethanol and purified water, thereby preparing Naviball hydrochloride tablets.
<178> (2) 로사르탄 칼륨염의 지연방출 정제 제조  (2) Preparation of delayed-release tablets of losartan potassium salt
<179> 표 2에 나타난 성분 및 함량으로， 로사르탄 칼륨염과 전젤라틴화전분 , 유당， 미결정셀를로오스, 가교폴리비닐피를리돈 , 콜로이드성 이산화규소를 35호체로 사과하 고 더블콘믹서 (다산파마텍， 한국)로 15분간 흔합하여 흔합물을 제조하였다. 상기 흔 합물에 스테아르산 마그네슘을 투입하고 최종 흔합하여 로타리 타정기로 타정하였다. 별도로 콜리코트 SR30D(Kon icoat SR30D, BASF, 독일) , 트리에틸시트레이트를 정제 수에 용해 및 분산시켜 얻은 코팅 액으로 타정 이 완료된 정제를 코팅하여 로사르탄 칼 륨염 지연방출 정제를 제조하였다. <179> With the ingredients and contents shown in Table 2, apples of losartan potassium salt, pregelatinized starch, lactose, microcrystalline cellulose, cross-linked polyvinylpyridone and colloidal silicon dioxide were identified as No. 35 and double cone mixer. (Dasan Pharmatech, Korea) was mixed for 15 minutes to prepare a mixture. Magnesium stearate was added to the mixture and the final mixture was compressed into tablets using a rotary tablet press. Separately, tablets prepared by tableting were coated with a coating solution obtained by dissolving and dispersing Colicoat SR30D (Kon icoat SR30D, BASF, Germany) and triethyl citrate in purified water, thereby preparing Losartan calcium salt delayed-release tablets.
<180> (3) 포장 키트 제조 (3) Manufacture of Packaging Kits
<isi> 상기 (1)， (2)의 코팅 이 완료된 각각의 정제는 하나의 PTP(Press Through <isi> Each tablet having the coating of (1) and (2) completed is one PTP (Press Through).
Pack)포장용기에 포장기 (Wider-VII , 부천기계， 한국)로 포장하여 동시복용이 가능한 포장키트를 제조하였다. Pack) The packaging kit was packaged in a packaging container (Wider-VII, Bucheon Machine, Korea) to produce the packaging kit.
<182> <실시 예 12> 염산 네비볼롤 - 로사르탄 칼륨염 함유 필름코팅정와 제조 Example 12 Preparation of Nebivolol Hydrochloride-Losartan Potassium Salt-Containing Film-Coated Tablets
<183> (1) 염산 네비볼를 코팅 액의 제조 <183> (1) Preparation of Coating Solution for Naviball Hydrochloric Acid
<184> 표 2에 나타난 성분 및 함량으로， 염산 네비볼를 , 라우릴황산나트륨, 콜로이 드성 이산화규소 (Aerosi l 200, 에보닉 , 독일 ) 및 히드록시프로필셀를로오스를 정제수 와 에탄올 흔합액에 용해 또는 현탁시 켜 염산 네비불를 코팅 액을 제조하였다  In the ingredients and contents shown in Table 2, chlorine hydrochloride, sodium lauryl sulfate, colloidal silicon dioxide (Aerosi l 200, Evonik, Germany) and hydroxypropylcellose were dissolved in purified water and ethanol mixture, or The suspension was prepared by coating a hydrochloric acid navigator.
<185> (2) 로사르탄 칼륨염 지연방출 나정 제조  (2) Preparation of Losartan Potassium Salt Delayed-Release Uncoated Tablets
<186> 표 2에 나타난 성분 및 함량으로 , 로사르탄 칼륨염과 전젤라틴화전분， 미결정 셀를로오스 , 가교플리비닐피를리돈， 콜로이드성 이산화규소를 35호체로 사과하고 더 블콘믹서 (다산파마텍 , 한국)로 15분간 흔합하여 혼합물을 제조하였다. 다시 상기의 과립에 카보머 (Cabopol 71G, 루브리졸， 미국)를 분말상태로 투입하여 10분간 흔합한 후， 일정한 크기로 체과하였다. 체과 후 스테아르산 마그네슘 투입하고 최종 흔합하 여 로사르탄 칼륨염 지연방출 과립을 제조한 후， 로타리 타정기 (MRC-33, 세종파마텍 한국)를 사용하여 지름 7匪로 타정하여 나정을 제조하였다.  In Table 2, apples of losartan potassium salt, pregelatinized starch, microcrystalline cellulose, cross-linked polyvinylpyridone and colloidal silicon dioxide were identified as No. 35 and the blecon mixer (Dasan Pharmatech) was used. , Korea) was mixed for 15 minutes to prepare a mixture. Carbomer (Cabopol 71G, Lubrizol, USA) was added to the granules in a powder state, mixed for 10 minutes, and sieved to a constant size. After sieving, magnesium stearate was added and finally mixed to prepare Losartan potassium salt delayed-release granules, and then tableted to a diameter of 7 mm using a rotary tablet press (MRC-33, Sejong Pharmatech Korea) to prepare uncoated tablets.
<187> (3) 코팅  (187) (3) coating
<iss> 상기 (2)의 로사르탄 칼륨염 지 연방출성 나정을 하이코터 (Src-30F, 세종파마 텍， 한국)에 투여하고 (1)의 염산 네비볼를 코팅 액으로 코팅하였다. 약물 코팅완료 후， 별도로 다음 표 2에 나타낸 함량과 같이 상기 실시 예 1 (3)과 동일한 방법으로 코팅하였다.  <iss> The losartan potassium salt-derived uncoated tablet of (2) was administered to a high coater (Src-30F, Sejong Pharmatech, Korea), and the hydrochloric acid navigator of (1) was coated with a coating solution. After drug coating was completed, it was coated in the same manner as in Example 1 (3) separately as shown in the following Table 2.
<189> <실시 예 13> 염산 네비볼를 로사르탄 칼륨염 삼투성 유핵정의 제조  Example 13 Preparation of Losartan Potassium Salt Osmotic Nucleated Tablet with Naviball Hydrochloride
<190> (1) 로사르탄 칼륨염 지 연방출 구획의 제조 (내핵 )  (190) (1) Preparation of Losartan Potassium Salt Extraction Section (Inner Core)
<191> 표 2의 성분 및 함량으로， 로사르탄 칼륨염 , 미결정 샐를로오스， 염화나트륨, 전젤라틴화전분， 크로스카멜로스나트륨， 콜로이드성 이산화규소를 35호체로 사과하고 더블콘믹서 (다산파마텍， 한국)로 흔합한 후 여기에 코포비돈을 투입하여 흔합한 후， 스테아르산 마그네슘을 넣어 최종적으로 흔합하였다. 상기 최종 흔합물을 로타리 타 정기 (MRC-33: 세종)를 사용하여 타정하였다. 타정 후 삼투성 코팅기제로서 에 칠셀를 로오스를 90% 에탄올에 분산시킨 후 하이코터 (SFC-30F, 세종파마텍 , 한국)를 이용하 여 정제에 코팅하여 삼투성 핵정을 제조하였다. <191> In the ingredients and contents of Table 2, apples of losartan potassium salt, microcrystalline salose, sodium chloride, pregelatinized starch, croscarmellose sodium, and colloidal silicon dioxide were identified as No. 35 and double cone mixer (Dasan Pharmatech, Korea), and copovidone was added to the mixture, followed by mixing with magnesium stearate for final mixing. The final mixture was compressed using a rotary tablet press (MRC-33: Sejong). After tableting, apply chillel to osmotic coating base. After dispersing the loose in 90% ethanol, using a high coater (SFC-30F, Sejong Pharmatech, Korea) was coated on the tablet to prepare an osmotic core tablet.
<192> (2) 염산 네비블를 선방출성 과립의 제조 (2) Preparation of Prerelease Granules with Hydrochloric Acid Navible
<193> 표 2의 성분 및 함량으로， 실시 예 4 (1)과 동일한 방법으로 염산 네비볼를 선 방출성 과립을 제조하였다.  Naviball hydrochloric acid pre-release granules were prepared in the same manner as in Example 4 (1) with the ingredients and contents shown in Table 2.
<194> (3) 타정 및 코팅 (194) tableting and coating
<195> 상기 실시 예 4 (3)의 타정 및 코팅 방법과 동일한 방법으로 유핵정 정제를 제조하였다.  Nucleated tablets were prepared in the same manner as the tableting and coating method of Example 4 (3).
<196> <실시 예 14> 염산 네비볼를 - 발사르탄 2상 매트릭스 정제 제조  Example 14 Preparation of Naviball Hydrochloride-Valsartan Two-Phase Matrix Tablet
<197> (1) 염산 네비볼를 선방출성 구획의 제조  (1) Preparation of Sun-Released Compartments in Naviball Hydrochloric Acid
<198> 표 3에 나타난 성분 및 함량으로 상기 실시 예 1 (1) 과 동일한 방법으로 염산 네비볼롤 선방출성 과립을 제조하였다.  In the same manner as in Example 1 (1) with the ingredients and contents shown in Table 3, the nebivolol linear release granules were prepared.
<199> (2) 발사르탄의 지연방출성 과립 제조  (2) Preparation of delayed-release granules of valsartan
<2oo> 표 3에 나타난 성분 및 함량으로， 발사르탄 (Ranboxy, 인도) , 미결정셀를로오 스 , 유당， 만니를, 크로스카멜로스나트륨을 35호체로 사과하고 더블콘믹서 (다산파마 텍 , 한국)로 15분간 흔합하여 흔합물을 제조하였다. 별도로 히드록시프로필셀를로오 스 (HPC-L, Nippon soda, 일본)를 정제수에 녹여 결합액으로 하였다 . 상기의 흔합물 을 유동층과립기 (GPCG-1 ： Glatt , 독일 )에 넣고 결합액을 가하여 조립하여 과립을 형 성， 건조하였다 . 별도로 에탄올과 염화메틸렌 흔합용매에 샐를로오스아세테이트 (CA- 320S/CA-398NF10, Eastman Chemical Company, 미국)， 히드록시프로필메틸샐를로오스 를 용해시킨 용액으로 다시 상기의 과립을 코팅하였다.  <2oo> Apple and valsartan (Ranboxy, India), microcrystalline cellulose, lactose, manny and croscarmellose sodium were identified as No. 35 and the double cone mixer (Dasan Pharmatech, Korea). The mixture was prepared by mixing for 15 minutes. Separately, hydroxypropylcellose (HPC-L, Nippon soda, Japan) was dissolved in purified water to obtain a binding solution. The mixture was placed in a fluidized bed granulator (GPCG-1: Glatt, Germany), granulated by adding a binder solution, and granules were formed and dried. Separately, the granules were again coated with a solution of cellulose acetate (CA-320S / CA-398NF10, Eastman Chemical Company, USA) and hydroxypropylmethylsalose in a mixture of ethanol and methylene chloride.
<201> (3) 타정 및 코팅  (201) tableting and coating
<202> 상기 (1)， (2)의 두 과립물을 흔합한 후， 콜로이드성 이산화규소와 스테아르산 마그네슴을 투입 및 흔합하여 직경 10.0 mm편치가 장착된 로타리 타정기 (MRC-33, 세 종파마텍， 한국)에서 타정하였다. 타정이 완료된 정제를 상기 실시 예 1 (3)과 동일한 방법으로 코팅하였다.  After mixing two granules of (1) and (2) above, colloidal silicon dioxide and stearic acid magnesium are added and mixed to form a rotary tableting machine (MRC-33, three species with a 10.0 mm diameter bias). Tableting in Pharmatech, Korea). Tablet-finished tablets were coated in the same manner as in Example 1 (3).
<203> <실시 예 15> 염산 네비볼를 - 발사르탄 이중정제 제조  Example 15 Preparation of Naviball Hydrochloride-Valsartan Double Tablet
<204> (1) 염산 네비볼롤 선방출성 구획의 제조  (1) Preparation of Nebivolol Prior Release Section Hydrochloric Acid
<205> ' 표 3에 나타난 성분 및 함량으로 상기 실시 예 2 (1) 와 동일한 방법으로 염산 네비볼를 선방출층을 제조하였다. <205>, the Example 2 (1) with hydrochloric acid Guinea bolreul prior-release layer in the same manner as the ingredients and contents shown in Table 3 were prepared.
<206> (2) 발사르탄 지 연방출성 구획의 제조  (206) Manufacture of Valsartan federally released compartments
<207> 표 3에 나타난 성분 및 함량으로, 발사르탄， 미결정샐를로오스， 유당, 크로 스 카멜로스 나트륨 (Vivasoi , JRS, 독일 )을 35호체로 사과하고 더블콘믹서 (다산파마 텍， 한국)로 15분간 흔합하여 흔합물을 제조하였다. 별도로 히드록시프로필셀를로오 스 (HPC-L, Nippon soda, 일본)를 정제수에 녹여 결함액으로 하였다. 상기의 흔합물 을 유동층과립기 (GPCG-1 ： Glatt , 독일)에 넣고 결합액을 가하여 조립하여 과립을 형 성， 건조하였다. 별도로 에탄올과 염화메틸렌 흔합용매에 유드라짓 RS (Eudragit RS, 에보닉， 독일 )ᅳ 트리에틸시트레이트를 용해시킨 용액으로 다시 상기의 과립을 코팅하 였다. As ingredients and contents shown in Table 3, valsartan, microcrystalline salose, lactose, and croissant The mixture was prepared by apologies of scaramel sodium (Vivasoi, JRS, Germany) with No. 35 sieve and mixing for 15 minutes with a double cone mixer (Dasan Pharmatech, Korea). Separately, hydroxypropylcellose (HPC-L, Nippon soda, Japan) was dissolved in purified water to prepare a defect solution. The mixture was placed in a fluidized bed granulator (GPCG-1: Glatt, Germany), granulated by adding a binder solution, and granules were formed and dried. Separately, the granules were again coated with a solution of Eudragit RS (Eudragit RS, Evonik, Germany) ᅳ triethyl citrate in a mixture of ethanol and methylene chloride.
<208> 여기에 콜로이드성 이산화규소 및 스테아르산 마그네슘을 투입하고, 최종 흔 합하여 발사르탄 지연방출층을 제조한다.  Colloidal silicon dioxide and magnesium stearate are added thereto, followed by final mixing to prepare a valsartan delayed-release layer.
<209> (3) 타정 및 코팅 (209) tableting and coating
<2io> 제조된 염산 네비블를 선방출층과 로사르탄 칼륨염 지연방출층을 직경 10mm 편치가 장착된 로타리 다층정 타정기 (MRC-37T, 세종파마텍， 한국)의 다른 과립 주입 구에 각각 넣고 타정한 후, 타정이 완료된 정제를 상기 실시 예 1 (3)과 동일한 방법 으로 코팅하였다, <2io> The prepared hydrochloric acid navigator was put into the granulation inlet of the rotary multi-layer tablet press (MRC-37T, Sejong Pharmatech, Korea) equipped with a 10-mm diameter pre-release layer and a losartan potassium salt delayed-release layer. After the tableting was completed, the same coating as in Example 1 ( 3 ),
<2ΐ ι> <실시 예 16> 염산 네비볼롤 - 로사르탄 칼륨염 다층정제 제조  <2ΐ ι> <Example 16> Preparation of nebivolol hydrochloride-Losartan potassium salt multilayer tablet
<212> (1) 염산 네비볼를 선방출성 구획의 제조  (1) Preparation of a Negative Hydrochloric Acid Block
<213> 표 3에 나타난 성분 및 함량으로 상기 실시예 3 (1)과 동일한 방법으로 염산 네비볼롤 선방출층을 제조하였다  In the same manner as in Example 3 (1) using the ingredients and contents shown in Table 3, the nebivolol pre-release layer was prepared.
<214> (2) 발사르탄 지 연방출성 구획의 제조  (2) Preparation of Valsartan federally released compartments.
<215> 표 3에 나타난 성분 및 함량으로， 발사르탄, 미결정셀를로오스，유당, 크로 스 카델로스 나트륨 (Vivasol , JRS, 독일)을 35호체로 사과하고 더블콘믹서 (다산파마 텍， 한국)로 15분간 흔합하여 흔합물을 제조하였다. 별도로 히드록시프로필셀를로오 스 (HPC-L, Nippon soda, 일본)를 정제수에 녹여 결합액으로 하였다. 상기의 흔합물 을 유동층과립기 (GPCG-1 ： Glatt , 독일 )에 넣고 결합액을 가하여 조립하여 과립을 형 성， 건조하였다. 별도로 에탄올과 염화메틸렌 혼합용매에 히드록시프로필메틸샐를로 오스와 셀롤로오스아세테이트를 용해시킨 용액으로 다시 상기의 과립을 코팅하였다. 여기에 콜로이드성 이산화규소 및 스테아르산 마그네슘을 투입하고， 최종 혼합하여 발사르탄 지연방출층을 제조한다.  <215> With the ingredients and contents shown in Table 3, apple valsartan, microcrystalline cellulose, lactose, and cross cardello sodium (Vivasol, JRS, Germany) were identified as No. 35 and a double cone mixer (Dasan Pharmatech, Korea). The mixture was prepared by mixing for 15 minutes. Separately, hydroxypropylcellose (HPC-L, Nippon soda, Japan) was dissolved in purified water to prepare a binding solution. The mixture was placed in a fluidized bed granulator (GPCG-1: Glatt, Germany), granulated by adding a binder solution, and granules were formed and dried. Separately, the granules were again coated with a solution in which hydroxypropylmethyl salose and cellulose acetate were dissolved in a mixed solvent of ethanol and methylene chloride. Colloidal silicon dioxide and magnesium stearate were added thereto, followed by final mixing to prepare a valsartan delayed-release layer.
<216> (3) 타정 및 코팅 (216) tableting and coating
<217> (2)에서 제조한 발사르탄 지 연방출 과립 흔합물을 증간층 (2번째층)으로 쌓고， 상기 (1) 염산 네비볼롤 선방출 과립을 1층 및 3층으로 분할하여 로타리 다층정 타정 기 (MRC-37T, 세종파마텍 , 한국)의 다른 과립 주입구에 각각 넣고 타정한 후, 상기 실 시 예 1 (3)과 동일한 방법으로 코팅하였다. The valsartan fed federal granule mixture prepared in (2) was stacked in a thick layer (second layer), and (1) the nebivolol pre-release granules were divided into one and three layers to form a rotary multilayer tablet. Into the other granule inlet of the machine (MRC-37T, Sejong Pharmatech, Korea) and tableting Coating was carried out in the same manner as in Example 1 (3).
<218> <실시예 17> 염산 네비블를 - 발사르탄 유핵정제 제조  Example 17 Preparation of Hydrochloric Acid Navi-Valsartan Nucleic Acid Tablet
<219> (1) 염산 네비블를 선방출성 구획의 제조  (1) Preparation of Prerelease Releasing Hydrochloric Acid Navible
<220> 표 3에 나타난 성분 및 함량으로 상기 실시 예 4 (1) 과 동일한 방법으로 염 산 네비볼를 선방출층을 제조하였다  In the same manner as in Example 4 (1), the pre-release layer of hydrochloric acid navig was prepared using the ingredients and contents shown in Table 3.
<221> (2) 발사르탄의 지연방출성 구획의 제조  (2) Preparation of delayed-release compartments of valsartan
<222> 표 3에 나타난 성분 및 함량으로， 발사르탄과 미결정셀를로오스, 유당, 만니 를을 35호체로 사과하고 더블콘믹서 (다산파마텍 , 한국)로 15분간 흔합하여 흔합물을 제조하였다. 별도로 히드록시프로필샐를로오스 (HPC-L, Nippon soda, 일본)를 정제수 에 녹여 결합액으로 하였다. 상기의 흔합물을 유동층과립기 (GPCG— 1 ： Glatt , 독일 ) 에 넣고 결합액을 가하여 조립하여 과립을 형성， 건조하였다. 흔합물에 크로스카멜 로스나트륨 및 콜로이드성 이산화규소를 흔합하고， 스테아르산 마그네슘을 투입하여 최종흔합한 후， 로타리 타정기를 사용하여 타정하였다. 별도로 아크릴이즈를 정제수 에 분산시킨 후， 하이코터 (SFC-30F, 세종파마텍， 한국)를 이용하여 상기의 정제에 코 팅하여 발사르탄 지연방출층 내핵정을 제조하였다.  With the ingredients and contents shown in Table 3, apples of valsartan, microcrystalline cellulose, lactose and manny were collected into No. 35 sieves, and mixed with a double cone mixer (Dasan Pharmatech, Korea) for 15 minutes to prepare a mixture. Separately, hydroxypropylsalose (HPC-L, Nippon soda, Japan) was dissolved in purified water to prepare a binding solution. The above mixture was placed in a fluidized bed granulator (GPCG-1: Glatt, Germany), granulated by adding a binder solution, and granulated to form granules. Croscarmellose sodium and colloidal silicon dioxide were mixed with the mixture, and magnesium stearate was added to the final mixture, followed by compression using a rotary tableting machine. Separately, after dispersing acrylamide in purified water, coating the above tablets using a high coater (SFC-30F, Sejong Pharmatech, Korea) to prepare a valsartan delayed-release layer inner core tablet.
<223> (3) 타정 및 코팅  (223) tableting and coating
<224> 유핵정타정기 (RUD-ᄂ Ki l ian, 독일)를 사용하여 발사르탄 핵정을 내핵정으로 하고 염산 네비볼를 선방출층을 외층으로 하여 함깨 타정하여 유핵정을 제조하였다. 상기의 타정 후, 별도로 다음 표 3에 나타낸 함량으로 , 상기 실시예 1 (3)과 동일한 방법으로 코팅하여 유핵정 정제를 제조하였다.  A nucleated tablet was prepared by using a nucleated tableting machine (RUD-b Ki l ian, Germany) as a inner nuclear tablet and navigating hydrochloric acid with a pre-release layer as an outer layer. After the above-mentioned tableting, it was separately coated in the same manner as in Example 1 (3) to the content shown in Table 3 to prepare a nucleated tablet.
<225> <실시예 18> 염산 네비블를 - 발사르탄 캡술제 (정제 + 정제 )의 제조  Example 18 Preparation of Naviable Hydrochloride-Valsartan Capsul (Tablet + Tablet)
<226> (1) 염산 네비블를 선방출 정제의 제조 (226) Preparation of Prerelease Tablets with Hydrochloric Acid Navible
<227> 표 3에 나타난 성분 및 함량으로 상기 실시 예 5 (1) 와 동일한 방법으로 제조 하되 , 염산 네비볼를 선방출성 과립을 로타리 타정기 (MRC-33, 세종파마텍 , 한국)를 이용하여 타정하였다.  It was prepared in the same manner as in Example 5 (1) with the ingredients and contents shown in Table 3, except that the hydrochloric acid navib was pre-release granules were compressed using a rotary tableting machine (MRC-33, Sejong Pharmatech, Korea).
<228> (2) 발사르탄 지연방출 정제의 제조  (2) Preparation of Valsartan Delayed-Release Tablet
<229> 표 3에 나타난 성분 및 함량으로 상기 실시 예 17 (2)와 동일한 방법으로 발 사르한 지연방출형 과립을 제조한 후， 로타리 타정기 (MRC-33, 세종파마텍， 한국)를 이용하여 타정하였다 .  <229> After preparing the delayed-release granules sprayed in the same manner as in Example 17 (2) with the ingredients and contents shown in Table 3, tableting using a rotary tableting machine (MRC-33, Sejong Pharmatech, Korea) It was.
<230> (3) 캡슐충전  (230) Capsule Filling
<231> 상기 (1) , (2) 정제를 1호 캡슬에 캡슐층진기로 층진하여 캡슐제를 제조하였다. <232> <실시 예 19> 염산 네비볼를一발사르탄 캡슐제 (과립 + 정제 )의 제조 <233> (1) 염산 네비볼를 선방출 과립 제조 The capsules were prepared by layering the tablets (1) and (2) on the capsule of No. 1 with a capsule layer device. <Example 19> Preparation of valsartan capsules (granules + tablets) with Naviball hydrochloric acid (233) Preparation of Prerelease Granules for Hydrochloric Acid Naviball
<234> 표 3에 나타난 성분 및 함량으로 상기 실시예 6 (1)과 동일한 방법으로 염산 네비블를 선방출 과립을 제조하였다.  In the same manner as in Example 6 (1) above with the ingredients and contents shown in Table 3, pre-release granules of hydrochloric acid Navible were prepared.
<235> (2) 발사르탄 지 연방출 정제의 제조 (235) Preparation of Valsartan Federated Tablets
<236> 표 3에 나타난 성분 및 함량으로, 발사르탄， 미결정 셀를로오스， 유당, 만니 틀을 35호체로 사과하고 더블콘믹서 (다산파마텍 , 한국)로 15분간 흔합하여 흔합물을 제조하였다. 별도로 히드록시프로필셀를로오스 (HPC-L, Nippon soda, 일본)를 정제수 에 녹여 결합액으로 하였다. 상기의 흔합물을 유동층과립기 (GPCG— 1 ： Glatt , 독일 ) 에 넣고 결합액을 가하여 조립하여 과립을 형성， 건조하였다.. 흔합물에 크로스카멜 로스나트륨 및 콜로이드성 이산화규소를 혼합하고， 스테아르산 마그네슘을 투입하여 최종흔합한 후 , 로타리 타정기를 사용하여 타정하였다. 별도로 정제수에 유드라짓 L30D-55 (Eudragit L30D-55, 에보닉 , 독일)， 트리에틸세트레이트， 탈크를 용해 및 분 산시킨 코팅 액을 제조한 후， 상기의 정제를 코팅하였다.  With the ingredients and contents shown in Table 3, valsartan, microcrystalline cellulose, lactose, and mantle were appled with No. 35 sieve and mixed for 15 minutes with a double cone mixer (Dasan Pharmatech, Korea) to prepare a mixture. Separately, hydroxypropylcellose (HPC-L, Nippon soda, Japan) was dissolved in purified water to obtain a binding solution. The above mixture was placed in a fluidized bed granulator (GPCG— 1: Glatt, Germany), and granulated by adding a binder solution to form granules and dried. The mixture was mixed with croscarmellose sodium and colloidal silicon dioxide, and then stearized. After final mixing with magnesium acid, the tablets were compressed using a rotary tablet press. Separately, purified tablets were prepared by dissolving and dispersing Eudragit L30D-55 (Eudragit L30D-55, Evonik, Germany), triethylcetate, and talc in purified water.
<237> (3) 캡술 충진  (237) (3) capsul filling
<238> 상기의 (1)과 (2)를 동일한 캡슬 (0호 캡술)에 캡슐층진기로 층진하여 염산 네비불를 발사르탄 캡슐제 (과립 + 정제 )를 제조하였다 .  (1) and (2) above were layered in the same capsule (No. 0 capsule) with a capsule layered device to prepare valsartan capsules (granules + tablets) with navigable hydrochloride.
<239> <실시 예 20> 염산 네비볼를 발사르탄 캡슬제 (과립 + 과립 )의 제조  Example 20 Preparation of Valsartan Capsules (Granules + Granules)
<240> (1) 염산 네비볼를 선방출 과립의 제조  (1) Preparation of Granules Pre-Released Naviball Hydrochloric Acid
<241> 표 3에 나타난 성분 및 함량으로 상기 실시예 7 (1)과 동일한 방법으로 제조 한 염산 네비볼를 선방출층 과립을 제조하였다.  Naviball hydrochloride prepared in the same manner as in Example 7 (1) with the ingredients and contents shown in Table 3 to prepare a pre-release layer granules.
<242> (2) 발사르탄 지연방출 과립의 제조  (2) Preparation of Valsartan Delayed-Release Granules
<243> 표 3에 나타난 성분 및 함량으로， 발사르탄, 미결정셀를로오스, 유당, 크로스 카멜로스 나트륨을 35호체로 사과하고 더블콘믹서로 15분간 흔합하여 혼합물을 제조 하였다. 별도로 히드특시프로필셀를로오스 (HPC-L, Nippon soda, 일본)를 정제수에 녹여 결합액으로 하였다. 상기의 혼합물을 유동층과립기 (GPCG-1 ： Glatt , 득일 )에 넣고 결합액을 가하여 조립하여 과립을 형성， 건조하였다. 다시 에탄올과 염화메틸렌 흔합용매에 프탈산히드록시프로필메틸셀를로오스를 용해시킨 용액으로 상기의 과립을 코팅하였다 . 코팅 완료 후， 스테아르산 마그네슴을 투입하여 최종흔합하여 발사르탄 지연방출 과립 혼합물을 제조하였다.  With the ingredients and contents shown in Table 3, valsartan, microcrystalline cellulose, lactose and croscarmellose sodium were appled with No. 35 sieve and mixed for 15 minutes with a double cone mixer to prepare a mixture. Separately, the hydrophilic propylcellose (HPC-L, Nippon soda, Japan) was dissolved in purified water to prepare a binding solution. The mixture was placed in a fluidized bed granulator (GPCG-1: Glatt, Dukil) and granulated by the addition of a binder solution to form granules and dried. The granules were then coated with a solution in which phthalic acid hydroxypropylmethylcellose was dissolved in a mixed solvent of ethanol and methylene chloride. After completion of the coating, stearic acid magnesium was added to the final mixture to prepare a valsartan delayed-release granule mixture.
<244> (3) 캡술 충진  (244) Capsule Filling
<245> 상기의 (1)과 (2)를 0호 캡술에 캡술층진기로 층진하여 캡술제를 제조하였다.  (1) and (2) above were layered with a capsul layered device on the cap capsule of No. 0 to prepare a capsulant.
<246> <실시 예 21> 염산 네비볼를 - 발사르탄 캡슬제 (펠렛 +펠렛)의 제조 <247> (1) 염산 네비볼를 선방출성 펠렛의 제조 Example 21 Preparation of Naviball Hydrochloride-Valsartan Capsule (Pellets + Pellets) (247) Preparation of Prerelease Pellets for Naviball Hydrochloric Acid
<248> 표 4에 나타난 성분 및 함량으로 , 상기 실시예 8 (1)과 동일한 방법으로 염산 네비볼를 선방출성 펠렛을 제조하였다.  With the ingredients and contents shown in Table 4, a pre-release pellet was prepared in Naviball hydrochloric acid in the same manner as in Example 8 (1).
<249> (2) 발사르탄 지연방출 팰¾의 제조 (2) Preparation of Valsartan Delayed-Release Pal¾
<250> 발사르탄 지연방출 펠¾의 제조는 슈가 시드 (Sugar sphere)를 유동층 과립기  Preparation of Valsartan Delayed-Release Pel¾ Using a Sugar Seed Fluidized Bed Granulator
(GPCG 1， Glatt , 독일 )에 투입한 뒤 따로 물과 에탄올 흔합용매에 히드록시프로필셀 를로오스， 히드록시프로필메틸샐를로오스, 발사르탄을 용해 또는 현탁한 결합액을 분 무하여 펠렛을 형성하고, 건조하였다. 다시 상기의 과립에 유드라짓 RUEudragit RL, 에보닉 , 독일 ) , 트리에 틸시트레이트를 에탄을과 염화메틸렌 흔합용매에 녹인 액을 분 무하여 발사르탄 지연방출 펠렛을 제조하였다.  (GPCG 1, Glatt, Germany), and then pellets are formed by spraying hydroxypropylcellulose, hydroxypropylmethylsalose, valsartan dissolved or suspended binder solution in a mixture of water and ethanol. And dried. Again, valsartan delayed-release pellets were prepared by spraying Eudragit RUEudragit RL, Evonik, Germany) and triethyl citrate in ethane and a mixed solvent of methylene chloride.
<251> (3) 캡술층진  <251> (3) Capsular layered
<252> 상기 (1) , (2)의 펠렛을 흔합하여 0호 캡슬에 캡슐충진기로 층진하여 캡슬제 를 제조하였다.  The pellets of (1) and (2) were mixed and layered with a capsule filling machine in capsule 0 to prepare a capsule.
<253> <실시 예 22> 염산 네비볼를 - 발사르탄 캡슬제 제조 (정제， 펠렛 )  <Example 22> Preparation of Naviball hydrochloric acid-Valsartan capsule (tablet, pellet)
<254> 표 4에 나타난 성분 및 함량으로， 상기 실시예 9 (1)과 동일한 방식으로 염산 네비볼를 선방출성 펠벳을 제조하고, 발사르탄 지연방출 정제는 상기 실시 예 17 (2) 와 동일한 방법으로 지연방출 정제를 제조하여， 정제와 펠¾을 0호 캡슐에 캡술층진 기로 층진하여 캡슐제를 제조하였다.  In the same manner as in Example 9 (1), with the ingredients and contents shown in Table 4, a pre-release pellet was produced by navigating hydrochloric acid in the same manner as in Example 9 (1), and the delayed release of valsartan was delayed in the same manner as in Example 17 (2). Release tablets were prepared, and capsules were prepared by layering tablets and pellets into capsule 0 with a capsule layering machine.
<255> <실시예 23> 염산 네비볼를-발사르탄 유핵정 정제의 제조  Example 23 Preparation of Naviball Hydrochloride-Valsartan Nucleated Tablets
<256> (1) 염산 네비볼를 선방출성 구획의 제조  (1) Preparation of a compartment for pre-release hydrochloric acid navigator
<257> 표 4에 나타난 성분 및 함량으로 상기 실시 예 10 (1)과 동일한 방법으로 염산 네비불를 선방출성 과립을 제조하였다ᅳ  In the same manner as in Example 10 (1) above with the ingredients and contents shown in Table 4, aviable hydrochloride pre-release granules were prepared.
<258> (2) 발사르탄 지연방출성 구획 제조 (2) Preparation of Valsartan Delayed-Release Compartment
<259> 표 4에 나타난 성분 및 함량으로 발사르탄， 미결정셀롤로오스， 유당， 만니를 을 35호체로 사과하고 더블콘먹서 (다산파마텍， 한국)로 5분간 흔합하여 흔합물을 제 조하였다. 별도로 히드록시프로필셀를로오스를 정제수에 녹여 결합액으로 하였다. 위 의 흔합물을 유동층 과립기 또는 고속혼합기에 투여한 후, 결합액을 분무하며 과립을 제조하였다. 완료된 과립을 유동층 건조기에서 건조한 후, 다시 상기의 과립에 가교 풀리비닐피를리돈을 투입하여 흔합하고 , 스테아르산 마그네슘 투입 후 최종 흔합하여 로타리 타정기를 사용하여 타정하였다. 별도로 히드록시프로필메틸셀를로오스를 80% 에탄을에 녹이고 , 아크릴이즈 (Acryl-EZE, Colorcon, 미국)를 정제수에 녹여 코팅 액을 제조하였다. 코팅 액 제조가 완료된 후 , 상기 정제를 하이코터 (SFC-30F, 세종파마텍 , 한국)에 투여하고 1차 코팅 (히드록시프로필메틸셀를로오스 코팅 액 )을 한 후 , 2차 코 팅 (아크릴이즈 코팅액 )으로 내핵을 코팅하여， 발사르탄 내핵정을 제조하였다. The ingredients and contents shown in Table 4 were apples of valsartan, microcrystalline cellulose, lactose, and manny with No. 35 sieves, followed by mixing for 5 minutes with a double cone eater (Dasan Pharmatech, Korea) to prepare a mixture. Separately, hydroxypropylcell was dissolved in purified water to prepare a binding solution. After administering the above mixture to a fluidized bed granulator or a high speed mixer, the binder was sprayed to prepare granules. The granules were dried in a fluidized bed drier, and then mixed with crosslinked pulley vinylpyridone in the granules, mixed with magnesium stearate, and finally mixed with a tablet press using a rotary tablet machine. Separately, hydroxypropylmethylcellose was dissolved in 80% ethane, and acrylic acid (Acryl-EZE, Colorcon, USA) was dissolved in purified water to prepare a coating solution. After the preparation of the coating solution is completed, the tablets are coated with a high coater (SFC-30F, Sejong Pharmatech, Korea) and the primary coating (hydroxypropyl methylcellose coating solution), and then the inner core was coated with a secondary coating (acrylic coating solution) to prepare a valsartan inner core tablet.
<260> (3) 타정 및 코팅 (260) tableting and coating
<261> 상기 실시 예 4 (3)의 타정 및 코팅 방법과 동일한 방법으로 유핵정 정제를 제조하였다.  A nucleated tablet was manufactured by the same method as the tableting and coating method of Example 4 (3).
<262> <실시예 24> 염산 네비볼를 - 발사르탄 블리스터 포장 키트의 제조  Example 24 Preparation of Hydrochloric Acid Naviball-Valsartan Blister Packaging Kit
<263> (1) 염산 네비볼를 과립 제조  (263) (1) Naviball hydrochloric acid granules
<264> 표 4 에 나타난 성분 및 함량으로, 상기 실시 예 11 (1)과 동일한 방법으로 염 산 네비블를 선방출성 과립을 제조하였다.  In the same manner as in Example 11 (1), the pre-release granules of hydrochloric acid Navible were prepared by using the ingredients and contents shown in Table 4.
^65> (2) 발사르탄의 지연방출 과립 제조 ^ 65> (2) Preparation of delayed-release granules of valsartan
<266> 표 4에 나타난 성분 및 함량으로， 발사르탄， 미결정셀를로오스, 유당, 가교플 리비닐피를리돈， 콜로이드성 이산화규소를 35호체로 사과하고 더블콘믹서 (다산파마 텍 , 한국)로 15분간 흔합하여 흔합물을 제조하였다. 다시 상기의 과립에 카보머 (Cabopol 71G, 루브리졸， 미국)를 분말상태로 투입하여 10분간 흔합한 후， 일정한 크 기로 체과하였다 . 체과 후 스테아르산 마그네슴을 투입하고 4분간 흔합하여 염산 발 사르탄 지 연방출 과립을 제조하였다.  <266> With the ingredients and contents shown in Table 4, valsartan, microcrystalline cellulose, lactose, cross-linked polyvinylpyridone, and colloidal silicon dioxide were apologized as No. 35 and a double cone mixer (Dasan Pharmatech, Korea). The mixture was prepared by mixing for 15 minutes. Carbomer (Cabopol 71G, Lubrizol, USA) was added to the granules in a powder state, mixed for 10 minutes, and then sieved to a constant size. After sieving, stearic acid magnesium was added thereto and mixed for 4 minutes to prepare Valsartan hydrochloride granules.
<267> (3) 타정 및 코팅 후 포장 키트 제조 (2) Preparation of Packaging Kit after Tableting and Coating
<268> 염산 네비볼롤 선방출 과립과 발사르탄 지연방출 과립을 각각 로타리 타정기  <268> a rotary tableting machine for the nebulol hydrochloride pre-release granules and valsartan delayed-release granules, respectively
(MRC— 33， 세종파마텍， 한국)로 타정하였다. 타정 이 완료된 정제를 히드록시프로필메 틸셀를로오스 2910， 폴리에 틸렌글리콜 6000， 및 산화티탄을 에탄을 및 정제수에 용해 및 분산시킨 코팅 액으로 각각의 정제를 코팅하였다. 코팅이 완료된 각각의 정제는 상 기 실시 예 11(3)의 포장키트 제조법에 따라 제조하였다.  (MRC— 33, Sejong Pharmatech, Korea). Tablets that have been compressed are coated with hydroxypropyl methylcellose 2910, polyethylene glycol 6000, and titanium oxide in a coating solution in which ethane and ethane were dissolved and dispersed in purified water. Each coated tablet was prepared according to the manufacturing method of the packaging kit of Example 11 (3).
<269> <실시예 25〉염산 네비볼를 - 발사르탄 함유 필름코팅정의 제조  <Example 25> Preparation of valsartan-containing film coated tablets with hydrochloric acid navigable ball
<270> (1) 염산 네비볼를 코팅 액의 제조  (1) Preparation of Coating Solution for Naviball Hydrochloric Acid
<271> 표 4에 나타난 성분 및 함량으로, 상기 실시 예 12 (1)과 동일한 방법으로 염 산 네비볼를 코팅 액을 제조하였다 .  With the ingredients and contents shown in Table 4, a coating solution of hydrochloric acid Naviball was prepared in the same manner as in Example 12 (1).
<272> (2) 발사르탄 지 연방출성 나정의 제조  (272) Preparation of Valsartan Fiesar Uncoated Tablets
<273> 표 4에 나타난 성분 및 함량으로 ᅤ 발사르탄과 미결정셀를로오스， 유당， 만니 를, 가교풀리비닐피를리돈 , 콜로이드성 이산화규소를 35호체로 사과하고 더블콘믹서 ( 다산파마텍 , 한국)로 15분간 흔합하여 흔합물을 제조하였다. 다시 상기의 과립에 카 보머 (Cabopol 71G, 루브리졸， 미국)를 분말상태로 투입하여 10분간 흔합한 후, 일 정한 크기로 체과하였다. 체과 후 스테아르산 마그네슴 투입하고 4분간 흔합하여 염 산 발사르탄 지연방출 혼합물을 제조하였다. 상기 최종 흔합물을 로타리 타정기 (MRC- 33， 세종파마텍 , 한국)를 사용하여 지름 7隱로 타정하여 나정을 제조하였다. <273> The ingredients and contents shown in Table 4 apologize with valsartan, microcrystalline cellulose, lactose, manny , cross-linked polyvinylpyridone, and colloidal silicon dioxide with No. 35 and double cone mixer (Dasan Pharmatech, Korea). The mixture was prepared by mixing for 15 minutes. Carbomer (Cabopol 71G, Lubrizol, USA) was added to the granules in a powder state, mixed for 10 minutes, and then sieved to a predetermined size. After sieving, stearic acid magnesium was added and mixed for 4 minutes. An acid valsartan delayed release mixture was prepared. The final mixture was compressed into tablets with a diameter of 7 mm using a rotary tablet press (MRC-33, Sejong Pharmatech, Korea) to prepare uncoated tablets.
<274> (3) 코팅  (274) (3) coating
<275> 표 4에 나타난 성분 및 함량으로, 상기 실시 예 12 (3)과 동일한 방법으로 코 팅하였다.  The ingredients and contents shown in Table 4 were coated in the same manner as in Example 12 (3).
<276> <실시 예 26> 염산 네비불를 - 발사르탄 삼투성 유핵정의 제조  Example 26 Preparation of Naval Fire Hydrochloride-Valsartan Osmotic Nucleated Tablets
<277> (1) 발사르탄 지연방출성 구획의 제조 (내핵 )  (1) Preparation of Valsartan delayed-release compartment (inner core)
<278> 표 4의 성분 및 함량으로， 발사르탄과 미결정 셸를로오스 및 염화나트륨， 크 로스카멜로스나트륨， 콜로이드성이산화규소을 35호체로 사과하고 더블콘믹서 (다산파 마텍， 한국)로 흔합하였다. 여기에 가교폴리비닐피를리돈을 투입하여 혼합한 후， 스 테아르산 마그네슴을 넣어 최종적으로 흔합하였다. 상기 최종 흔합물을 로타리 타정 기 (MRC-33: 세종파마텍 , 한국)를 사용하여 타정하였다. 타정 후 삼투성 코팅기제로서 에틸샐를로오스를 정제수와 에탄올 흔합용액에 분산시 ¾ 후 하이코터 (SFC-30F, 세종 파마텍 , 한국)를 이용하여 내핵에 코팅하여 삼투성 핵정을 제조하였다.  In the ingredients and contents of Table 4, valsartan, microcrystalline shellulose, sodium chloride, crocarmellose sodium, and colloidal silicon oxide were apologized as No. 35 and mixed with a double cone mixer (Dasanpa Matek, Korea). Then, crosslinked polyvinylpyridone was added and mixed, and then stearic acid magnesium was added and finally mixed. The final mixture was compressed using a rotary tablet press (MRC-33: Sejong Pharmatech, Korea). After tableting, when the ethyl salose was dispersed in purified water and ethanol mixed solution as an osmotic coating base, ¾ was coated on the inner core using a high coater (SFC-30F, Sejong Pharmatech, Korea) to prepare an osmotic core tablet.
<279> (2) 염산 네비블를 선방출성 과립의 제조  (2) Preparation of Prerelease Granules with Hydrochloric Acid Navible
<280> 표 4의 성분 및 함량으로 , 실시 예 5 (1)과 동일한 방법으로 염산 네비볼를 선 방출성 과립을 제조하였다.  Naviball hydrochloric acid pre-release granules were prepared in the same manner as in Example 5 (1).
<281> (3) 타정 및 코팅  (3) Tableting and coating
<282> 상기 실시예 4 (3)의 타정 및 코팅 방법에 따라 유핵정 정제를 제조하였다. A nucleated tablet was prepared according to the tableting and coating method of Example 4 (3).
<283> <실시예 27> 염산 네비볼를 - 텔미사르탄 유핵정의 제조 Example 27 Preparation of Naviball Hydrochloride-Telmisartan Nucleated Tablets
<284> (1) 염산 네비블를 선방출성 구획의 제조  (1) Preparation of Prerelease Releasing Hydrochloric Acid Navible
<285> 표 5에 나타난 성분 및 함량으로， 상기 실시예 4(1)과 동일한 방법으로 염산 네비볼를 선방출층을 제조하였다.  With the ingredients and contents shown in Table 5, in the same manner as in Example 4 (1), a pre-release layer of hydrochloric acid Naviball was prepared.
<286> (2) 텔미사르탄 지연방출성 구획의 제조 (2) preparation of telmisartan delayed-release compartment
<287> 표 5에 나타난 성분 및 함량으로, 텔미사르탄, 미결정셀를로오스를 35호체로 사과하고 더블콘믹서 (다산파마텍 , 한국)로 15분간 흔합하여 흔합물을 제조하였다 . 별도로 히드록시프로필셀를로오스 (HPC-L, Nippon soda, 일본)와 수산화나트륨을 정제 수에 녹여 결합액으로 하였다. 상기의 흔합물을 유동층과립기 (GPCG-1 ： Glatt , 독 일 )에 넣고 결합액을 가하여 조립하여 과립을 형성， 건조하였다. 다시 에탄올과 염화 메틸렌 흔합용매에 프탈산히드록시프로필메틸샐를로오스를 용해시킨 용액으로 상기의 과립을 코팅하였다. 코팅 완료 후, 크로스 카멜로스 나트륨을 넣고 흔합한 뒤 스테아 르산 마그네슴을 투입하여 최종흔합하여 텔미사르탄 지연방출층을 제조하였다 <288> (3) 타정 및 코팅 <287> With the ingredients and contents shown in Table 5, Telmisartan and microcrystalline cellulose were apples as No. 35, and the mixture was mixed with a double cone mixer (Dasan Pharmatech, Korea) for 15 minutes to prepare a mixture. Separately, hydroxypropylcelose (HPC-L, Nippon soda, Japan) and sodium hydroxide were dissolved in purified water to obtain a binding solution. The above mixture was placed in a fluidized bed granulator (GPCG-1: Glatt, German) and granulated by adding a binder solution to form granules and dried. The granules were then coated with a solution of phthalic acid hydroxypropylmethylsalose in ethanol and methylene chloride mixed solvent. After the completion of the coating, the croscarmellose sodium was added and mixed, followed by the addition of stearic acid magnesium and finally mixed to prepare a telmisartan delayed-release layer. (288) tableting and coating
<289> 표 5에 나타난 성분 및 함량으로， 상기 실시예 4 (3)과 동일한 방법으로 타정 및 코팅하여 유핵정을 제조하였다.  Nucleated tablets were prepared by tableting and coating in the same manner as in Example 4 (3), using the ingredients and contents shown in Table 5.
<290> <실시 예 28> 염산 네비블를 - 에프로사르탄 메실산염 이중정 제조  Example 28 Preparation of Hydrochloric Acid Navible-Eprosartan Mesylate Double Tablet
<291> 표 5에 나타난 성분 및 함량으로, 로사르탄 칼륨염 대신 에프로사르탄 메실산 염을 사용하는 것을 제의하고는 상기 실시 예 2와 동일한 방법으로 제조하였다.  The ingredients and contents shown in Table 5 were prepared in the same manner as in Example 2, except that eprosartan mesylic acid salt was used instead of losartan potassium salt.
<292> <실시예 29> 염산 네비볼를 - 칸데사르탄 실렉세틸 다층정 제조  <292> <Example 29> Naviball hydrochloric acid-Candesartan cilexetil multi-layer tablets prepared
<293> 표 5에 나타난 성분 및 함량으로 , 로사르탄 칼륨염 대신 칸데사르탄 실렉세틸  Candesartan cilexetil instead of losartan potassium salt as the ingredients and contents shown in Table 5.
(Ranbaxy, India)을 사용하는 것을 제외하고는 상기 실시 예 3과 동일한 방법으로 제 조하였다.  It was prepared in the same manner as in Example 3 except for using (Ranbaxy, India).
<294> <실시 예 30> 카르베딜를 - 칸데사르탄 실렉세틸 유핵정 제조  Example 30 Preparation of Carvedil-Candesartan Silexetil Nucleated Tablets
<295> (1) 카르베딜를 선방출성 구획의 제조  (1) Preparation of Carbedyl Pre-Release Compartments
<296> 표 5에 나타난 성분 및 함량으로 카르베딜를 (Cad a, 인도)， 라우릴 황산 나 트륨, 유당 (Parmatose , DMV P arma , 네덜란드)， 미결정셀를로오스 (AvicelPH, FMC Biopolymer , 미국)를 칭량하여 35 호체로 사과하고 더블콘믹서 (다산파마텍， 한국)에 서 15분간 흔합하여 혼합물을 제조하였다. 별도로 히드록시프로필셀를로오스 (HPC-L, Nippon soda , 일본)를 정제수에 녹여 결합액을 제조하였다. 상기 흔합물을 유동층과 립기 (GPCG-1 ： Glatt , 득일 )에 넣고 결합액을 가하여 조립 , 건조하였다. 건조물을 20 호체가 장착된 F형 정 립기를 사용하여 정 립하고， 가교폴리비닐피롤리돈과 콜로이드성 이산화규소를 투입하여 흔합하고， 이 흔합물에 스테아르산 마그네슴을 투입한 후, 최 종흔합하여 카르베딜를 선방출 과립을 제조하였다  Carvedyl (Cad a, India), sodium lauryl sulfate, lactose (Parmatose, DMV Prma, The Netherlands), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA) according to the ingredients and contents shown in Table 5 Was weighed and appled into a No. 35 sieve and mixed for 15 minutes in a double cone mixer (Dasan Pharmatech, Korea) to prepare a mixture. Separately, hydroxypropylcellose (HPC-L, Nippon soda, Japan) was dissolved in purified water to prepare a binding solution. The mixture was placed in a fluidized bed and granulator (GPCG-1: Glatt, Dukil), and granulated and dried by adding a binder solution. The dried material was sized using an F-type sizer equipped with No. 20 body, mixed with crosslinked polyvinylpyrrolidone and colloidal silicon dioxide, and stearic acid magnesium was added to the mixture. Combined, carvedil was prepared as a pre-release granule.
<297> (2) 칸데사르탄 실렉세틸 지연방출 내핵정 제조  (2) Preparation of Candesartan Silexetil Delayed-Release Inner Core Tablets
<298> 표 5에 나타난 성분 및 함량으로， 칸데사르탄 실렉세틸과 미결정셀를로오스, 유당， 크로스 카멜로스 나트콤 (Vivasol , JRS, 독일)， 콜로이드성 이산화규소를 35호 체로 사과하고 더블콘믹서 (다산파마텍， 한국)로 15분간 혼합하여 흔합물을 제조하였 다ᅳ 흔합물에 스테아르산 마그네슘을 투입하여 최종흔합한 후, 로타리 타정기를 사용 하여 타정하였다 . 별도로 아크릴이츠를 정제수에 분산시킨 후， 하이코터 (SFO30F , 세 종파마텍 , 한국)를 이용하여 상기의 정제에 코팅하여 칸데사르탄 실렉세틸지 연방출 내핵정을 제조하였다.  <298> Candesartan cilexetil and microcrystalline cellulose, lactose, croscarmellose natcom (Vivasol, JRS, Germany) and colloidal silicon dioxide were used as the ingredients and contents shown in Table 5. The mixture was prepared by mixing with a mixer (Dasan Pharmatech, Korea) for 15 minutes. Magnesium stearate was added to the mixture for final mixing, followed by compression using a rotary tableting machine. After separately dispersing acrylates in purified water, using a high coater (SFO30F, Sejong Pharmatech, Korea) was coated on the tablets to prepare a cored tablet of candesartan cilexetil paper.
<299> (3) 타정 및 코팅  (2) Tableting and coating
<300> 표 5에 나타난 성분 및 함량으로 , 상기 실시 예 4(3)와 등일한 방법으로 타정 및 코팅하여 유핵정을 제조하였다 . <30i> <실시 예 31> 염산 네비볼를 - 올메사르탄 메독소밀 캡술제 (정제 +과립 ) 제조Nucleated tablets were prepared by tableting and coating in the same manner as in Example 4 (3), using the ingredients and contents shown in Table 5. Example 31 Preparation of Naviball Hydrochloride-Olmesartan Medoxomil Capsule (Tablet + Granule)
<302> (1) 염산 네비볼를 선방출성 과립의 제조 (1) Preparation of Prerelease Granules for Hydrochloric Acid Naviball
<303> 표 5에 나타난 성분 및 함량으로, 상기 실시 예 4 (1)와 동일한 방법으로 제조하였다. The ingredients and contents shown in Table 5 were prepared in the same manner as in Example 4 (1).
<304> (2) 을메사르탄 메독소밀 지연방출성 정제의 제조 (2) Preparation of emmesartan medoxomill delayed-release tablet
<305> 표 5에 나타난 성분 및 함량으로 , 올메사르탄 메독소밀， 미결정셀를로오스， 유당, 크로스 카멜로스 나트륨 (Vivasol , JRS, 독일 )을 35호체로 사과하고 더블콘믹서 (다산파마텍， 한국)로 15분간 혼합하여 흔합물을 제조하였다. 흔합물에 스테아르산 마그네슴을 투밉하여 최종흔합한 후 , 로타리 타정기를 사용하여 타정하였다 . 별도로 아크릴이즈를 정제수에 분산시 킨 후， 하이코터 (SFC-30F, 세종파마텍， 한국)를 이용하 여 상기의 정제에 코팅하여 올메사르탄 메독소밀 지연방출 정제를 제조하였다.  <305> In the ingredients and contents shown in Table 5, olmesartan medoxomil, microcrystalline cellulose, lactose, croscarmellose sodium (Vivasol, JRS, Germany) were apologized with No. 35 and a double cone mixer (Dasan Pharmatech, Korea). ) Was mixed for 15 minutes to prepare a mixture. The final mixture was mixed with 2 Mg stearic acid in the mixture and then compressed using a rotary tableting machine. Separately, after dispersing acrylase in purified water, and coated on the tablets using a high coater (SFC-30F, Sejong Pharmatech, Korea) to prepare an olmesartan delayed-release tablet.
<306> (3) 타정 및 캡술 층진 (3) tableting and capsul stratum
<307> 상기 실시 예 5의 방법으로 타정 및 캡술 층진하였다.  Tableting and capsulation layered by the method of Example 5.
<308> <실시예 32> 숙신산 메토프를를 - 이르베사르탄 캡술제 (과립 + 과립 ) 제조 <Example 32> Preparation of succinic acid metope-irbesartan capsulant (granules + granules)
<309> ( 1) 숙신산 메토프를롤 선방출성 과립의 제조 (1) Preparation of succinic acid metoprolol pre-release granules
<3io> 표 5에 나타난 성분 및 함량으로 숙신산 메토프를를 (Dr Reddy, 인도) , 라우릴 황산 나트륨， 미결정셀를로오스 (Avicel PH101, FMC Biopolymer , 미국)， 크로스카멜로 스나트륨을 칭량하여 35 호체로 사과하고 더블콘믹서 (다산파마텍， 한국)에서 15분간 흔합하여 흔합물을 제조하였다. 별도로 히드록시프로필샐를로오스 (HPC-L, Nippon soda, 일본)를 정제수에 녹여 결합액을 제조하였다 . 상기 흔합물을 유동층과립기 (GPCG-1 ： Glatt , 독일 )에 넣고 결합액을 가하여 조립， 건조하였다. 건조물을 20호체 가 장착된 F형 정 립기를 사용하여 정 립하고, 스테아르산 마그네슘을 투입한 후, 최종 흔합하여 숙신산 메토프를를 선방출성 과립을 제조하였다. .  <3io> Weighing succinate metope (Dr Reddy, India), sodium lauryl sulfate, microcrystalline cellulose (Avicel PH101, FMC Biopolymer, USA), croscarmellose sodium using the ingredients and contents shown in Table 5. Sieve apples and mixed for 15 minutes in a double cone mixer (Dasan Pharmatech, Korea) to prepare a mixture. Separately, hydroxypropylsalose (HPC-L, Nippon soda, Japan) was dissolved in purified water to prepare a binding solution. The mixture was placed in a fluidized bed granulator (GPCG-1: Glatt, Germany), and the binder solution was added to assemble and dried. The dried product was sized using a No. 20 sieve equipped with an F-type granulator, and magnesium stearate was added thereto, followed by final mixing to prepare linear granules containing succinic acid metope. .
<311> (2) 이르베사르탄 지연방출성 과립의 제조  (2) Preparation of Irbesartan Delayed-Release Granules
<312> 표 5에 나타난 성분 및 함량으로， 이르베사르탄, 미결정샐를로오스， 유당, 크 로스 카멜로스 나트륨을 35호체로 사과하고 더블콘믹서 (다산파마텍 , 한국)로 15분간 흔합하여 흔합물을 제조하였다. 별도로 히드록시프로필샐를로오스 (HPC-L, Nippon soda, 일본)를 정제수에 녹여 결합액으로 하였다. 상기의 혼합물을 유동층과립기 (GPCG-1 ： Glatt , 독일 )에 넣고 결합액을 가하여 조립하여 과립을 형성하였다. 따로 히프로멜로오스아세테이트숙시네이트 (HPMC-AS, Shi net su, 일본)，트리에틸시트레이트 를 80% 에탄올에 용해시킨 후 위에서 형성된 과립에 분무하여 과립을 코팅한 다음 건 조 하였다. 상기 과립물에 스테아르산마그네슘을 투입한 뒤 흔합하여 이르베사르탄 지연방출성 과립을 제조하였다. <313> (3) 캡슐 층진 <312> With the ingredients and contents shown in Table 5, apples Irbesartan, microcrystalline salose, lactose, and croscarmellose sodium with No. 35 were mixed and mixed with a double cone mixer (Dasan Pharmatech, Korea) for 15 minutes. The mixture was prepared. Separately, hydroxypropylsalose (HPC-L, Nippon soda, Japan) was dissolved in purified water to prepare a binding solution. The mixture was placed in a fluidized bed granulator (GPCG-1: Glatt, Germany) and granulated by adding a binder solution to form granules. Separately, hypromellose acetate succinate (HPMC-AS, Shi net su, Japan) and triethyl citrate were dissolved in 80% ethanol and then sprayed on the granules formed above to coat the granules and then dried. Magnesium stearate was added to the granules, followed by mixing to prepare irbesartan delayed-release granules. (313) layered capsules
<314> 상기 숙신산 메토프를틀 선방출성 과립과 이르베사르탄 지 연방출 과립을 0호 캡슐에 캡술층진기로 층진하여 캡슐제를 제조하였다.  The capsules were prepared by layering the succinic acid metope with the first-release granules and the Irbesartan branch fed granules in cap No. 0 capsules with a capsul layered pendulum.
<315> <실시예 33> 숙신산 메토프를를―로사르탄 캡술제 (펠렛 +펠렛 ) 제조  Example 33 Preparation of Succinic Acid Metope-Rosartan Capsulant (Pellets + Pellets)
<316> 표 6에 나타난 성분 및 함량으로, 네비블를 대신 숙신산 메토프를를을 사용하 고， 발사르탄 대신 로사르탄을 사용한 것을 제외하고는 상기 실시 예 21과 동일한 방 법으로 제조하였다.  The ingredients and contents shown in Table 6 were prepared in the same manner as in Example 21, except that succinic acid metope was used instead of Navible, and losartan was used instead of valsartan.
<317> <실시 예 34> 카르베딜를 - 텔미사르탄 유핵정의 제조  Example 34 Preparation of Carvedil-Telmisartan Nucleated Tablets
<318> (1) 카르베딜를 선방출성 구획의 제조  (1) Preparation of Carbedyl Pre-Release Compartments
<319> 표 6에 나타난 성분 및 함량으로 상기 실시 예 30(1)과 동일한 방법으로 제조 하였다 .  The ingredients and contents shown in Table 6 were prepared in the same manner as in Example 30 (1).
<320> (2) 텔미사르탄 지연방출 내핵정의 제조  (2) Preparation of telmisartan delayed-release inner core tablet
<321> 표 6에 나타난 성분 및 함량으로， 텔미사르탄， 미결정셀를로오스를 35호체로 사과하고 더블콘믹서 (다산파마텍， 한국)로 15분간 흔합하여 흔합물을 제조하였다. 별도로 히드록시프로필셀를로오스 (HPC-L, Nippon soda, 일본)와 수산화나트륨을 정제 수에 녹여 결합액으로 하였다. 상기의 흔합물을 유동층과립기 (GPCG-1 ： Glatt , 독 일)에 넣고 결합액을 가하여 조립하여 과립을 형성， 건조하였다. 다시 상기의 과립에 크로스카멜로스 나트륨을 투입하여 혼합하고 , 스테아르산 마그네슴 투입 후 최종 흔 합하여 로타리 타정기를 사용하여 타정하였다 . 별도로 히드록시프로필메틸샐를로오스 2910을 80% 에탄올에 녹이고， 아크릴이즈 (Aery卜 EZE, Co lor con, 미국)를 정제수에 녹 여 코팅 액을 제조하였다. 코팅 액 제조가 완료된 후, 상기 정제를 하이코터 (SFC-30F, 세종파마텍， 한국)에 투여하고 1차 코팅 (히드록시프로필메칠셀를로오스 코팅 액 )을 한 후， 2차 코팅 (아크릴이즈 코팅 액 )으로 내핵을 코팅하예 텔미사르탄 내핵정을 제조하 였다.  <32> With the ingredients and contents shown in Table 6, Telmisartan and microcrystalline cellulose were apples as No. 35, and the mixture was mixed with a double cone mixer (Dasan Pharmatech, Korea) for 15 minutes to prepare a mixture. Separately, hydroxypropylcell was dissolved in purified water (HPC-L, Nippon soda, Japan) and sodium hydroxide to obtain a binding solution. The above mixture was placed in a fluidized bed granulator (GPCG-1: Glatt, German) and granulated by adding a binder solution to form granules and dried. Again, the above granules were mixed with sodium croscarmellose, mixed with stearic acid, and finally mixed using a rotary tableting machine. Separately, hydroxypropylmethylsalose 2910 was dissolved in 80% ethanol, and acrylic acid (Aery® EZE, Co. con, USA) was dissolved in purified water to prepare a coating solution. After the preparation of the coating solution is completed, the tablet is administered to a high coater (SFC-30F, Sejong Pharmatech, Korea) and the first coating (hydroxypropyl methyl cellulose coating solution), and then the second coating (acrylic coating) The inner core was coated with the liquid) to prepare telmisartan inner core tablets.
<322> (3) 타정 및 코팅  (3) tableting and coating
<323> 표 6에 나타난 성분 및 함량으로， 상기 실시 예 4 (3)와 동일한 방법으로 타정 및 코팅하여 유핵정을 제조하였다.  With the ingredients and contents shown in Table 6, tableting and coating were carried out in the same manner as in Example 4 (3) to prepare a nucleated tablet.
<324> <실시 예 35> 카르베딜를 ᅳ 칸데사르탄 실렉세틸 캡슐제 (정제 +정제 ) 제조<Example 35> Candesartan cilexetil capsules (tablets + tablets) prepared with carvedil
<325> (1) 카르베딜를 선방출성 정제의 제조 (1) Preparation of Prerelease Tablets with Carvedil
<326> 표 6에 나타난 성분 및 함량으로 상기 실시 예 34 (1)과 동일한 방법으로 제조 한， 카르베딜를 선방출성 과립을 로타리 타정기 (MRC-33, 세종파마텍 , 한국)를 이용하 여 타정하였다. <327> (2) 칸데사르탄 실렉세틸 지연방출성 정제의 제조 Carvedil-pre-release granules prepared in the same manner as in Example 34 (1) were compressed using a rotary tableting machine (MRC-33, Sejong Pharmatech, Korea) using the ingredients and contents shown in Table 6. (2) Preparation of candesartan cilexetil delayed-release tablets
<328> 표 6에 나타난 성분 및 함량으로， 칸데사르탄 실렉세틸， 미결정샐를로오스 , 유당, 크로스 카멜로스 나트륨 (Vivasol , JRS, 독일 )， 콜로이드성 이산화규소를 35호 체로 사과하고 더블콘믹서 (다산파마텍 , 한국)로 15분간 흔합하여 흔합물을 제조하였 다. 혼합물에 스테아르산 마그네슘을 투입하여 최종흔합한 후， 로타리 타정기를 사용 하여 타정하였다. 별도로 아크릴이즈 (Acryl-EZE, Co lor con, 미국)를 정제수에 분산시 켜 코팅 액을 제조한 후 하이코터를 이용하여 상기의 정제에 코팅하여 칸데사르탄 실 렉세틸 지연방출 정계를 제조하였다 .  <328> With the ingredients and contents shown in Table 6, candesartan cilexetil, microcrystalline salose, lactose, croscarmellose sodium (Vivasol, JRS, Germany) and colloidal silicon dioxide were appled with a No. 35 sieve and a double cone mixer (Dasan Pharmatech, Korea) was mixed for 15 minutes to prepare a mixture. Magnesium stearate was added to the mixture, followed by final mixing, followed by compression using a rotary tableting machine. Separately, the acrylic solution (Acryl-EZE, Co., USA) was dispersed in purified water to prepare a coating solution, and then coated on the tablet using a high coater to prepare candesartan cilexetil delayed-release system.
<329> (3) 캡술층진 <329> (3) capsul strata
<330> (1) , (2)에서 제조한 정제를 1호 캡슬에 캡술층진기로 층진하여 캡술제를 제 조하였다.  The tablets prepared in (1) and (2) were layered on the first capsule with a capsul layering device to prepare a capsulant.
<331> <실시 예 36> 카르베딜를 - 올메사르탄 메독소밀 키트제의 제조  Example 36 Preparation of Carvedil-Olmesartan Medoxomil Kit
<332> (1) 카르베딜를 선방출성 구획의 제조  (1) Preparation of Carbedyl Pre-Release Compartments
<333> 표 6에 나타난 성분 및 함량으로， 상기 실시 예 35 (1)과 동일한 방법으로 하 여 카르베딜를 선방출성 정제를 제조하였다. 상기 정제에 히드록시프로필메틸셀를로 오스 2910， 폴리에틸렌글리콜 6000 및 산화티탄을 에탄올 및 정제수에 용해 및 분산 시킨 코팅 액으로 정제를 코팅하여 카르베딜를 선방출 코팅정제를 제조하였다  Carvedil-pre-release tablets were prepared by the same method as described in Example 35 (1), using the ingredients and contents shown in Table 6. The tablet was coated with a coating solution in which hydroxypropyl methylcellose 2910, polyethylene glycol 6000, and titanium oxide were dissolved and dispersed in ethanol and purified water to prepare carvedyl-based coated tablets.
<334> (2) 올메사르탄 메독소밀 지 연방출성 구획의 제조  (334) Preparation of Olmesartan Medozomil Mill Flea Block
<335> 표 6에 나타난 성분 및 함량으로， 올메사르탄 메독소밀， 미결정샐를로오스， 유당, 가교폴리비닐피를리돈， 콜로이드성 이산화규소를 35호체로 사과하고 더블콘믹 서 (다산파마텍 , 한국)로 15분간 흔합하여 흔합물을 제조하였다. 흔합물에 스테아르산 마그네슘 을 투입하여 최종흔합한 후， 로타리 타정기를 사용하여 타정하였다. 별도로 아크릴이즈를 정제수에 분산시켜 코팅 액을 제조한 후 하이코터를 이용하여 상기의 정 제에 코팅하여 을메사르탄 메독소밀 지연방출 정제를 제조하였다.  <335> According to the ingredients and contents shown in Table 6, olmesartan medoxomil, microcrystalline salose, lactose, crosslinked polyvinylpyridone, and colloidal silicon dioxide were apologized with No. 35, and the double conmixer (Dasan Pharmatech, Korea ) Was mixed for 15 minutes to prepare a mixture. Magnesium stearate was added to the mixture for final mixing, followed by compression using a rotary tablet press. Separately, acrylic is dispersed in purified water to prepare a coating solution, and then coated on the tablet using a high coater to prepare Emesartan Medoxomil delayed-release tablet.
<336> (3) 포장 키트 제조 (3) Manufacture of packaging kits
<337> 코팅 이 완료된 각각의 정제는 하나의 PTP(Press Through Pack) 포장용기에 포장기 (Wider-VII , 부천기계， 한국)로 포장하여 동시복용이 가능한 포장키트를 제조 하였다.  Each of the coated tablets was packaged in one press-pack pack in a packing machine (Wider-VII, Bucheon Machine, Korea) to prepare a packaging kit for simultaneous use.
<338> <실시 예 37> 아테놀롤 - 로사르탄 다층정제의 제조  Example 37 Preparation of Athenolol-Losartan Multilayer Tablet
<339> (1) 아테놀롤 선방출층의 제조  (1) Preparation of Atenolol Pre-Release Layer
<340> 표 6에 나타난 성분 및 함량으로， 아테놀를， 미결정샐를로오스， 히드톡시프 로필셀를로오스, 전분글리콘산나트륨을 칭량하여 35 호체로 사과하고 더블콘믹서 (다 산파마텍， 한국)에서 15분간 혼합하여 흔합물을 제조하였다. 상기 흔합물에 스테아르 산 마그네슘을 투입 후 최종흔합하여 아테놀를 선방출층용 흔합물을 제조하였다.<340> With the ingredients and contents shown in Table 6, athenol, microcrystalline salose, hydroxypropyl cellulose, sodium starch glycolate were weighed and appled with No. 35 sieve, and a double cone mixer (C The mixture was prepared by mixing for 15 minutes in San Pharmatech, Korea). Magnesium stearate was added to the mixture, followed by final mixing to prepare a mixture of athenol for the prior release layer.
<341> (2) 로사르탄 칼륨염 지 연방출층의 제조 (2) Preparation of Losartan Potassium Salt Exhaust Layer
<342> 표 6에 나타난 성분 및 함량으로, 로사르탄 칼륨염 (동우， 한국)， 미결정셀를로 오스 , 크로스 카멜로스 나트륨 (Vivasol , JRS, 독일 )을 35호체로 사과하고 더블콘믹서 (다산파마텍 한국)로 15분간 흔합하여 흔합물을 제조하였다. 별도로 히드록시프로 필샐를로오스 (HPC-L, Nippon soda, 일본)를 정제수에 녹여 결합액으로 하였다 . 상기 의 흔합물을 유동층과립기 (GPCG-1 ： Glatt , 독일)에 넣고 결합액을 가하여 조립하여 과립올 형성， 건조하였다 . 별도로 에탄을과 염화메틸렌 흔합용매에 프탈산히드록시프 로필메틸셀를로오스를 용해시킨 용액으로 다시 상기의 과립을 코팅하였다. 여기에 콜 로이드성 이산화규소를 투입하여 흔합하고 , 이 흔합물에 다시 스테아르산 마그네슴을 투입한 후 최종 흔합하여 로사르탄 칼륨염 지연방출층용 흔합물을 제조하였다. <342> In the ingredients and contents shown in Table 6, losartan potassium salt (Dongwoo, Korea), microcrystalline cellulose, croscarmellose sodium (Vivasol, JRS, Germany) were cited as No. 35 and double cone mixer (Dasan Pharmatech). Korea) for 15 minutes to prepare a mixture. Separately, hydroxypropylsalose (HPC-L, Nippon soda, Japan) was dissolved in purified water to prepare a binding solution. The above mixture was placed in a fluidized bed granulator (GPCG-1: Glatt, Germany), granulated by adding a binder solution, and granules were formed and dried. Separately, the granules were again coated with a solution of phthalate hydroxypropylmethylcellose in ethane and a methylene chloride mixed solvent. To this, colloidal silicon dioxide was added and mixed, and stearic acid magnesium was added to the mixture, followed by final mixing to prepare a mixture for a delayed-release layer of potassium potassium salt.
<343> (3) 타정 및 코팅 (3) Tableting and coating
<344> (2)에서 제조한 흔합물을 중간층 (2번째층)으로 쌓고， 실시 예 37 (1)에서 제조 한 흔합물을 1층 및 3층으로 분할하여 로타리 다층정 타정기 (MRC-37T, 세종파마텍 , 한국)의 다른 과립 주입구에 각각 넣고 타정한 후, 상기 실시 예 1 (3)과 동일한 방법 으로 코팅하였다 .  The composite prepared in (2) was stacked in an intermediate layer (second layer), and the composite prepared in Example 37 (1) was divided into one and three layers to form a rotary multi-layer tablet press machine (MRC-37T, Into each other granule inlet of Sejong Pharmatech, Korea) and tableting, and then coated in the same manner as in Example 1 (3).
<345> <실시 예 38> 아테놀를 - 칸데사르탄 실롁세틸 삼투성 유핵정의 제조  Example 38 Preparation of Athenol-Candesartan Silcecetyl Osmotic Nucleated Tablets
<346> (1) 아테놀롤 선방출성 구획의 제조  (1) preparation of atenolol pre-release compartments
<347> 표 6에 나타난 성분 및 함량으로， 상기 실시 예 37 (1)과 동일한 방법으 S 제 조하였다.  The ingredients and contents shown in Table 6 were prepared in the same manner as in Example 37 (1).
<348> (2) 칸데사르탄 실렉세틸 지연방출성 구획의 제조  (2) Preparation of candesartan cilexetil delayed-release compartments
<349> 표 6에 나타난 성분 및 함량으로， 발사르탄 대신 칸데사르탄 실렉세틸을 사 용하는 것을 제외하고는 상기 실시예 26 (1)와 동일한 방법으로 제조하였다.  With the ingredients and contents shown in Table 6, it was prepared in the same manner as in Example 26 (1) except for using candesartan cilexetil instead of valsartan.
<350> (3) 타정 및 코팅  (3) tableting and coating
<351> 표 6에 나타난 성분 및 함량으로， 상기 실시 예 4 (3)의 타정 및 코팅 방법에 따라 유핵정 정제를 제조하였다 . <352> [표 1] Nucleated tablets were prepared according to the tableting and coating method of Example 4 (3), using the ingredients and contents shown in Table 6. Table 1
Figure imgf000037_0001
Figure imgf000037_0001
1) ¾리(메 ^크릴산 .쎄릴아크쾰례이旦) 증 l, colorcon, 미국 1) Lime (Methacrylic Acid .Serryl Arc Kol-Ye-Yeong) increase l, colorcon, USA
<353> <354> [표 2] <353> Table 2
Figure imgf000038_0001
Figure imgf000038_0001
1) 풀리비 닐아세테이트 27%, 포비 2.7%, 소디움라우렬설페이트 0,3%, ¾ 정제수 70%, BASF, 독¾ 2} 폴리 (메타크럴산 크릴레이트) ■증합처 I 30% aquous dispersion, 에보닉 , 독일 1) Pullibi Niacetate 27%, Pobi 2.7%, Sodium Lausulfate 0,3%, ¾ purified water 70%, BASF, poison ¾ 2} Poly (methacrylate) acrylate ■ I 30% aquous dispersion, Evonik, Germany
<355> ' 조성삐 (mg/단우 1제제) <355>' Composition Bee (mg / Danwoo 1 formulation)
구성성분 실 시 에  In the case of ingredient
14 15 16 17 18 19 20 영산 네비볼를 5.45 10.9 10.9 5.45 5.45 21.8 5.45 라우월 ¾산나트 1· 0.1 0.2 0.2 0.1 0.1 0.4 0.1 미결정셸 ■로오스 40 40 23 35 12.5 12.5 12.5 히 e록시^：로 셸클로오人 2.5 2.5 4.6 9.6 2 2 2 유당 60.95 99.95 161 290 60 60 60 전¾라틴확전분 - - - 96 20 - - 전분 ■리€■산나트 · - 13.S 13.8 - - - - 크로-*、카¾로ᅳ八나 ^름 - - - 25 0.6 0.6 0.614 15 16 17 18 19 20 Youngsan Naviball 5.45 10.9 10.9 5.45 5.45 21.8 5.45 Lauwall ¾San Nat 1 · 0.1 0.2 0.2 0.1 0.1 0.4 0.1 Microcrystalline Shell ■ Loos 40 40 23 35 12.5 12.5 12.5 Chlorine 2.5 2.5 4.6 9.6 2 2 2 Lactose 60.95 99.95 161 290 60 60 60 Starch Latin Proliferated Starch---96 20--Starch ■ Li € ■ Sanat ·-13.S 13.8----Cro- * 카-카-25 0.6 0.6 0.6
¾르이드성 이산화규소 - 1.15 1.15 2.4 0.5 - - 스테아르산마그 Li|슘 - 2 2 4.S 1 1 1 정제수 (휘발성) 60 60 60 60 60 60 60 합계 109 170.5 216.65 468.35 102.15 93.3 81.65¾ fluoride silicon dioxide-1.15 1.15 2.4 0.5--Magnesium stearate Li | 2 2 4.S 1 1 1 Purified water (volatile) 60 60 60 60 60 60 60 Total 109 170.5 216.65 468.35 102.15 93.3 81.65
¾사르탄 80 80 80 80 80 80 80 미결정셀틀로오스 10 20 20 1Q 20 20 10 히 록人 로필셸콜로오人 2 2 2 2 2 2 2 유당 30 50 50 30 30 30 20 만니통 20 ᅳ - 20 20 20 - 크로스카¾로스나 름 6 10 10 10 10 10 5 콜로0|드성 이산화규소 1 1 1 1 1 - 스테아르산마그네승 - 1 1 1 1 1 0.5 프랄산히드록시프로필 ¾Sartan 80 80 80 80 80 80 80 Microcrystalline Cellulose 10 20 20 1Q 20 20 10 Hi Lok Lofil Shell Colo 2 2 2 2 2 2 2 Lactose 30 50 50 30 30 30 20 Manitong 20 ᅳ-20 20 20-Crosscar ¾ Loss 6 10 10 10 10 10 5 Colo-de-silicon dioxide 1 1 1 1 1-Magnesium stearate-1 1 1 1 1 0.5 Hydroxypropyl phthalate
- - - ᅳ - - 15 메릴셸를로오  ---ᅳ--15 Merrill Shello
유드라 RS13 - 16 - - - - 셸 ■로오스아세테이트 320S 60 - 80 ᅳ - - 셸물로오스아세테이트 398NF10 30 - 50 - - - - 히드록시프로필 릴셸률로오스 3 - 3 - - - - 아크릴이쯔 3 - - - 10 15 - - 유드라 ¾ L30D-5531 - - - - 35 - 랄크 - - - - 5 - 트리에럴시트레이트 - 2 - - - 1 - 정제수 (후ᅵ발성) 20 20 20 20/40 20/40 60 20 에탄을 (휘발성) 200 200 200 - - - 90 염화메월런 K후 1발성) 200 200 200 - - ᅳ 90 합계 241 182 297 164 179 205 13Z5 콥로이드성 이산화규소 1.5 - - - - - ᅳ 스터1아르산마그네슘 3 L " - - ᅳ - - 히드록사프로필 Eudra RS 13-16 ----Shell ■ Loose Acetate 320S 60-80 ᅳ--Shellulose Acetate 398NF10 30-50----Hydroxypropyl Ryl Shell Rate 3-3----Acrylic Tsu 3 ---10 15--Eudra ¾ L30D-55 31 ----35-Ralph----5-Trial citrate-2---1-Purified water (post talk) 20 20 20 20/40 20/40 60 20 Ethane (volatile) 200 200 200---90 1 ammonium after Wall chloride K 200) 200 200 200--ᅳ 90 Total 241 182 297 164 179 205 13Z5 Cobboid silicon dioxide 1.5- ----ᅳ sterone magnesium arsenate 3 L " -----hydroxyxapropyl
7 10.5 10.5 10.5 - - - 메 ¾셸툴로오스 2910  7 10.5 10.5 10.5---Me ¾Shellulose 2910
산회—E1탄 2 3 3 3 - - 풀리 ¾롄글리클 6000 0.65 1 1 1 ᅳ ᅳ - Mountain Ash—E1 bullet 2 3 3 3--Pulley ¾Lianglyckle 6000 0.65 1 1 1 ᅳ ᅳ-
011탄을 (휘발성) 80 120 120 120 ᅳ ᅳ - 정제수 (후 1발성) 20 30 30 30 - - - 총합 ~ 364.15 367 528.15 646.S5 281.15 303.3 214.15) 폴리 (애릴아크¾산.메릴매타크릴산，트리메럴앙모니오에릴 nil타크럴산 ·로라 01드)공증^제 1：2：0.2, 에보닉, 옥일011 charcoal (volatile) 80 120 120 120 ᅳ 정제-purified water (after 1 ignition) 20 30 30 30---total ~ 364.15 367 528.15 646.S5 281.15 303.3 214.15) poly (arylic acid, merylmethacrylic acid, Trimmer anmony o'eryl nil tacrochloric acid Laura 01) notary ^ agent 1: 2: 0.2, ebony, jade
) 폴리 크럴산 쥘아크 ¾레이트) 공중합제, colorcon, 미국) Polychloric Acid Hydroxyl Copolymer), colorcon, USA
) 풀리 (메타크럴산 릴아크릴레이트) 공중합제 30% aquous dispersion, 0j|보닉, 독일 <358> [표 4] ) Pulley (methacrylate acrylate) Copolymer 30% aquous dispersion, 0j | Bonic, Germany TABLE 4
Figure imgf000040_0001
Figure imgf000040_0001
1) 폴리 (에릴아크릴산 릴메타크럴산,트리메 ^암 S니오 0!|릴 메타크릴산晉로라이드)공증합체 1:2:0.1, 이ᅵ보닉，독일 1) Poly (Erylacrylic acid methacrylate, Trime ^ amnio S! 0! | Reel methacrylic acid fluoride) co-polymer 1: 2: 0.1, Bonic, Germany
2) 풀리 (0||타크럴산 .에뛸 01·크럴레 01트) 공중 T제, colorcon, 미국 2) Pulley (0 || Taclar Mountain .Etrol 01 · Claret 01) Aerial T Festival, colorcon, USA
<360> <361> [표 5] <360> Table 5
Figure imgf000041_0001
Figure imgf000041_0001
1) 폴리 (메 타크럴산 '에릴 01·크퀼레이트) 공중합제， colorcon, 미국 1) Poly (methacrylic acid 'Eryl 01.Cquilate) copolymer, colorcon, USA
<362> <363> [표 6] <362> TABLE 6
Figure imgf000042_0001
Figure imgf000042_0001
： L)풀리 (에럴 산.메릴메타크릴산,트리매뭡앙모니오에털 메타크^산클로 ¾oi드)공중합제 1:2:0.1,이 1보닉,독일 ¾ ■리 (대|타크렬산.에틸아크릴리ᅵ이트) 쭝합체， colorcon,미국 ： L) Pulley (Eral acid. Meryl methacrylic acid, trimethylamine anmonio- eryta meta-sanchloro ¾oi) Copolymer 1: 2: 0.1, yibonic, Germany ¾ ■ Li (large | tatric acid.ethyl Acrylate), Colorcon, USA
<365>  <365>
<366> <실험예 1>용출 양상시험 (dissolution profile test) <367> 상기 실시 예 2에서 얻은 정제와 대조약으로 코자 (Merck ： Cozaar , 로사르탄 칼륨염 단일제 )와 바이스를릭 (Forest labs : Bystol ic ， 염산 네비볼를 단일제 )을 사 용하여 비교 용출시험을 실시하였다. 로사르탄 칼륨염 성분 제제의 경우 2시간을 기 점으로 용출액을 pH 1.2-염산용액 (산성환경 )에서 pH 6.8(인공장액 )완층액으로 변경하 여 용출시험을 진행하였다. 각 성분별 용출시험 방법은 아래와 같으며 , 그 결과를 도 1에 나타내었다 (시험 개체수는 각각 12개 ) . Experimental Example 1 Dissolution profile test <367> Comparative dissolution test was conducted using Coza (Merck: Cozaar, Losartan Potassium Salt Single Agent) and Vicelic (Forest labs: Bystol ic, Naviball hydrochloride single agent) as the tablet and the control agent obtained in Example 2. It was. In the case of the losartan potassium salt component dissolution test, the eluate was changed from pH 1.2-hydrochloric acid solution (acidic environment) to pH 6.8 (phosphate solution) complete solution. The dissolution test method for each component is as follows, and the results are shown in FIG. 1 (the number of test subjects is 12 each).
<368> 도 1에 의하면 실시 예 2의 정제는 하기 조건에서 용출 시험시 염산 네비볼를 According to FIG. 1, the tablets of Example 2 were prepared with Naviball hydrochloride in the dissolution test under the following conditions.
® ―  ® ―
성분은 대조 제제인 바이스를릭 (Bystol ic )과 비교하여 거의 동등한 용출특성을 나타  The components showed almost the same elution characteristics as the control formulation, Vystol ic.
• ⑨ • ⑨
내는 것으로 확인되었으며， 로사르탄 성분은 대조 제제인 코자 (Cozaar )와 비교할 때 매우 늦어진 용출을 확인할 수 있다. 실시 예 2의 네비볼를과 로사르탄 이중정의 용출시험 결과， 2 시간까지 로사르탄의 용출를이 20% 이내로서 , 대조 제제의 용출를 ( 약 75%) 보다 느리다.  Losartan component can be found to be very late dissolution compared to the cozaar (Cozaar) control. As a result of the elution test of Naviball and Losartan double tablets of Example 2, the dissolution of Losartan by 20 hours was less than 20%, and the dissolution of the control formulation was slower (about 75%).
<369> 이처 럼 본 발명의 지연방출 구획의 로사르탄 칼륨염은 대조약인 로사르탄 칼 륨염 단일제의 용출양상과는 달리 초기 방출이 매우 느리기 때문에 저녁에 경구 투여 시 네비볼를이 먼저 용출되어 밤 시간 동안 혈압을 조절하고 몇 시간 후에 로사르탄 이 용출되어 아침 시간 동안의 혈압을 조절할 수 있으므로 24시간 균등하게 혈압을 유지시켜 줄 수 있다.  As described above, the losartan potassium salt of the delayed-release compartment of the present invention has a very slow initial release unlike the dissolution of the single losartanium salt, which is a reference drug. After several hours, Losartan is eluted and the blood pressure can be controlled during the morning so that the blood pressure can be maintained evenly for 24 hours.
<370> [염산 네비볼를 시험방법 ]  [Test Method of Hydrochloric Acid Naviball]
<37i> 시험 방법 ： 패들법 (Paddle method) , 50 회전 /분  <37i> Test method: Paddle method, 50 revolutions / minute
<372> 시험액 ： 0.01N 염산용액 , 1000 mL (0~2시간) ,  <372> Test solution: 0.01N hydrochloric acid solution, 1000 mL (0-2 hours),
<373> 분석방법 ： 자외가시부흡광광도법 (검출파장 = 최 대 282 nm)  <373> Analysis method: Ultraviolet-visible absorption spectrophotometry (detection wavelength = maximum 282 nm)
<374> [로사르탄 칼륨염 시험방법 ]  [374] Test Method of Potassium Salt of Losartan
<375> 시험 방법 ： 패들법 (Paddle method) , 50회전 /분  <375> Test method: Paddle method, 50 revolutions / minute
<376> 시험액 ： 0.01N염산용액， 1000 mL (0~2시간)，  <376> Test solution: 0.01 N hydrochloric acid solution, 1000 mL (0-2 hours)
<377> pH 6.8인공장액 , 1000 mL (2시간 이후)  <377> Plant solution with pH 6.8, 1000 mL (after 2 hours)
<378> 분석방법 ： 자외가시부흡광광도법 (검출파장 = 254 nra)  <378> Analysis method: Ultraviolet-visible absorption spectrophotometry (detection wavelength = 254 nra)
<379> <실험예 2> 용출 양상 시험 (dissolut ion prof i le test)  <Experimental Example 2> Dissolut ion prof i le test
<380> 실시예 3, 4, 5에서 얻은 여러 제형의 제제를 실험예 1의 시험방법에 따라 실 시하여 , 그 결과를 도 2에 나타내었다 (시험 개체수는 각각 12개임 ) .  Formulations of various formulations obtained in Examples 3, 4 and 5 were carried out according to the test method of Experimental Example 1, and the results are shown in FIG.
<381> 도 1과 도 2의 결과에서 보는 바와 같이 네비볼를이 먼저 용출되고, 일정 시 간 경과 후 로사르탄이 용출되는 것을 확인할 수 있다. 따라서 본 발명의 목적대로 실시예 3， 4, 5에서 제조된 제제는 저녁에 경구투여 시 네비볼를이 먼저 용출되어 밤시간동안 혈압을조절하고 몇 시간후에 로사르탄이 용출되어 아침 시간동안의 혈압을조절할수 있음을 알수 있다. As shown in the results of FIGS. 1 and 2, it can be seen that the nav balls are eluted first, and then Rosasartan is eluted after a certain time. Thus for the purposes of the present invention The formulations prepared in Examples 3, 4 and 5 can be seen that when the oral administration in the evening, the Naviball is eluted first to control the blood pressure during the night time, and after a few hours, Rosatan is eluted to control the blood pressure during the morning time. .
<382> <실험예 3>용출 양상시험 (dissolution profile test) <Experiment 3> Dissolution profile test
<383> 실시예 17에서 얻은정제와대조약바이스를릭 (Forest labs: Bystolic ， 염산 네비볼를단일제)과발사르탄 (Novartis ： Diovan ， 발사르탄단일제)을사용하여 비 교용출시험을실시하였다. 발사르탄성분 제제의 경우， 2시간을기점으로용출액을 pHl.2 -염산용액 (산성환경)에서 pH 6.8인산염 완충액 (인공장액)으로변경하여 용출 시험을진행하였다. 발사르탄성분용출시험 방법은 아래와 같으며， 그결과를도 3 에 나타내었다 (시험 개체수는각각 12개). 네비볼를성분용출시험은실험예 1과동 일하다.  A comparative dissolution test was carried out using the tablets obtained in Example 17 and the treat- ment Vicelic (Forest labs: Bystolic, Naviball hydrochloride monolith) and Valsartan (Novartis: Diovan, Valsartan monolithic). In the case of the valsartan component formulation, the dissolution test was performed by changing the eluate from pHl.2-hydrochloric acid solution (acidic environment) to pH 6.8 phosphate buffer (phosphate solution). The valsartan dissolution test method is as follows, and the results are shown in FIG. 3 (the number of test subjects is 12 each). Naviball component dissolution test is the same as in Experiment 1.
<384> 도 3에 의하면실시예 17의 정제는하기 조건에서 용출시험시 염산네비볼를 성분은대조제제인 바이스를릭 (Bystolic )과비교하여 거의 동등한용출특성을나타 내는것으로확인되었으며， 발사르탄성분은대조제제인디오반 (Diovan )과비교할 때 매우늦어진 용출을확인할수 있다. 실시예 17의 염산네비볼를과발사르탄유핵 정 용출시험 결과, 2시간까지의 발사르탄성분의 용출률이 10¾ 이내로서 대조 제제 의 용출를 (약 30%)보다느리다.  According to FIG. 3, the tablets of Example 17 were found to exhibit almost equivalent elution characteristics when compared to Vystolic, which is a control agent, during the dissolution test under the following conditions. A very late dissolution can be seen when comparing with the control product, Diovan. As a result of the overbalsartan nucleated tablet elution test of Example 17 hydrochloric acid hydrochloride, the dissolution rate of the valsartan component up to 2 hours was less than 10¾, which is slower than that of the control formulation (about 30%).
<385> [발사르탄시험방법 ]  <385> [Valsartan Test Method]
<386> 시험 방법 ： 패들법 (Paddle method), 50희전 /분  <386> Test method ： Paddle method (50 paddles per minute)
<387> 시험액 ： pH 1.2 염산용액， lOOOraL (0~2시간)  <387> Test solution: pH 1.2 hydrochloric acid solution, lOOOraL (0-2 hours)
<388> pH 6.8완충액 (인산염 용액)， 1000 mL (2시간 이후)  PH 6.8 buffer (phosphate solution), 1000 mL (after 2 hours)
<389> 분석방법 ： 자외가시부흠광광도법 (검출파장 =최대 270， 최소 250 nm) <389> Analysis method ： UV-visible spectrophotometry (detection wavelength = maximum 270, minimum 250 nm)
<390> <실험예 4>용출 양상시험 (dissolution profile test) Experimental Example 4 Dissolution profile test
<39i> 실시예 15, 16, 18에서 얻은여러 제형의 제제를실험예 3의 발사르탄용출방 법에 따라실시하여, 그 결과를도 4에 나타내었다 (시험 개체수는각각 12개임). <392> 도 4의 결과에서 보는바와같이 일정 시간경과후 발사르탄이 용출되는 것 을확인할수 있다. 따라서 본 발명의 목적대로실시예 15， 16, 18에서 제조된 제제 는저녁에 경구투여 시 네비볼롤이 먼저 용출되어 밤시간동안혈압을조절하고몇 시간후에 발사르탄이 용출되어 아침 시간동안의 혈.압을조절할수 있음을 알수 있 다.  The formulations of the various formulations obtained in Examples 15, 16, and 18 were subjected to the valsartan elution method of Experimental Example 3, and the results are shown in FIG. 4 (the number of test individuals was 12 each). As shown in the result of FIG. 4, it can be seen that valsartan is eluted after a certain period of time. Therefore, the preparations prepared in Examples 15, 16, and 18 according to the purpose of the present invention, when the oral administration in the evening, the nebivolol is eluted first to control the blood pressure during the night time, and after a few hours valsartan is eluted, the blood. Can be adjusted.
<393> <실험예 5>용출 양상시험 (dissolution profile test) <394> 실시 예 27， 28, 36에서 얻은여러 제형의 정제, 키트제와대조약바이스를릭Experimental Example 5 Dissolution profile test <394> Tablets of various formulations obtained in Examples 27, 28 and 36
(Forest labs: Bystolic ， 염산 네비볼를 단일제), 텔미사르탄 (Boehringer ingelheim: Micardis, 텔미사르탄단일제)ᅳ에프로사르탄메실산염 (Abbott： Teveten(Forest labs: Bystolic, Naviball hydrochloric acid mono), telmisartan (Boehringer ingelheim: Micardis, telmisartan monochloride) ᅳ eprosartan mesylate (Abbott: Teveten
®, 에프로사르탄메실산염 단일정), 을메사르탄메독소밀 (대웅제약: Olmetec®, 올메 사르탄메독소밀단일정)， 카르베딜를 (종근당: 딜라트렌， 카르베딜를단일정)을사용 하여 비교용출시험을실시하였다. ® , Eprosartan mesylate monolith), Emesartan medoxomil (Daewoong Pharm .: Olmetec ® , Olmesartan methoxomil singlet schedule), carvedil (seeds per day: dilatrene, carvedil singlet) Comparative dissolution test was performed.
<395> 텔미사르탄， 에프로사르탄메실산염 , 올메사르탄메독소밀성분제제의 경우 <395> In case of telmisartan, eprosartan mesylate, or olmesartan medoxo
2시간을기점으로용출액을 pH 1.2 염산용액 (산성환경)에서 pH 6.8(인공장액)완층액 으로 변경하여 용출시험을 진행하였다. 각 성분별 용출시험 방법은 아래와 같으며， 그결과를도 5, 6， 7에 나타내었다 (시험 개체수는각각 12개임). 네비볼를성분용 출시험은실험예 1과동일하다. The dissolution test was performed by changing the eluate from pH 1.2 hydrochloric acid solution (acidic environment) to pH 6.8 (phosphate solution) complete solution for 2 hours. The dissolution test method for each component is as follows, and the results are shown in FIGS. 5, 6, and 7 (the test population is 12 each). The extraction test for the components of the nav ball is the same as in Experiment 1.
<396> 도 5， 6, 7의 결과로부터 텔미사르탄과에프로사르탄메실산염 , 올메사르탄메 독소밀도 의도한 대로 방출패턴을 가짐을 확인하였다. 5, 6 and 7, it was confirmed that telmisartan, eprosartanmesylate, and olmesartanme toxin density had an emission pattern as intended.
<397>  <397>
<398> [카르베딜를시험방법 ]  <398> [Test Method of Carvedyl]
<399> 시험 방법 ： 패들법 (Paddle method), 50회전 /분  <399> Test method: Paddle method, 50 revolutions / minute
<400> 시험액 ： 0.1 N염산용액, 1,000 mL (0~2시간)，  Test solution ： 0.1 N hydrochloric acid solution, 1,000 mL (0-2 hours) ，
<40i> pH 6.8 인공장액， 1,000 mL (2시간 이후)  <40i> pH 6.8 artificial intestine, 1,000 mL (after 2 hours)
<402> 분석방법 ： 자외가시부흡광광도법 (검출파장 =최대 240 nm)  Analysis method: ultraviolet visible absorption spectroscopy (detection wavelength = maximum 240 nm)
<403>  <403>
<404> [텔미사르탄시험방법 ]  <404> [Telmisartan Test Method]
<405> 시험 방법 ： 패들법 (Paddle method), 75회전 /분  Test method: Paddle method, 75 revolutions / minute
<406> 시험액 ： pH 1.2 염산용액, lOOOraL (0~2시간)  Test solution ： pH 1.2 hydrochloric acid solution, lOOOraL (0-2 hours)
<407> pH 6.8완층액 (인산염 용액)， 1000 mL (2시간 이후)  PH 6.8 complete solution (phosphate solution), 1000 mL (after 2 hours)
<408> 분석방법 ： 고속액체크로마토그래프법  Analysis method: high speed liquid chromatography method
<409> 검출파장 ： 271 nm  <409> Detection wavelength: 271 nm
<4io> 이동상 ： 물 (0.05몰 인산이수소칼륨 )/아세토나이트릴 = 60：40  <4io> Mobile phase: Water (0.05 mol potassium dihydrogen phosphate) / acetonitrile = 60:40
<4ΐι> 컬럼 ： 안지름 4.6 mm, 길이 250讓의 스테인레스관에 옥타데실실릴화한 겔 <4ΐι> column: Gel octadecylylated in a stainless steel tube of inner diameter 4.6 mm and length 250 mm
<412> 유속 ： 1 mL/분 Flow rate ： 1 mL / min
<413>  <413>
<414> [에프로사르탄메실산염 시험방법]  [414] [Test Method of Eprosartan Mesylate]
<415> 시험 방법 ： 패들법 (Paddle method), 75회전 /분 <416> 시험액 ： pH 1.2 염산용액， lOOOmL (0~2시간) <415> Test method: Paddle method, 75 revolutions / minute <416> Test solution ： pH 1.2 hydrochloric acid solution, lOOOmL (0 ~ 2 hours)
<4i7> pH=7.5 완충액 (인산염 용액 ) , 1000 mL (2시간 이후)  <4i7> pH = 7.5 buffer (phosphate solution), 1000 mL (after 2 hours)
<418> 분석방법 ： 고속액체크로마토그래프법  Analysis method ： High speed liquid chromatography method
<419> 검출 파장 ： 235 nm  <419> Detection wavelength: 235 nm
<420> 이동상 ： 물 (0.1몰 아세트산 암모늄 )/아세토나이트릴 = 50 :50  Mobile phase: water (0.1 mol ammonium acetate) / acetonitrile = 50:50
<42i> 컬럼 ： 안지름 4.6 ram, 길이 750 mm의 스테인레스관에 옥타데실실릴화한 겔 <42i> Column ： A gel octadecylated into a stainless steel tube having a diameter of 4.6 ram and a length of 750 mm.
<422> 유속 ： 2 mL/분 Flow rate ： 2 mL / min
<423>  <423>
<424> [을메사르탄 메독소밀 시험방법 ]  [Memesartan Methosome Mill Test Method]
<425> 시험 방법 ： 패들법 (Paddle method) , 50 회전 /분  Test method: Paddle method, 50 revolutions / minute
<426> 시험액 : pH 1.2 염산용액， lOOOmL (0~2시간)  <426> Test solution: pH 1.2 hydrochloric acid solution, lOOOOmL (0 ~ 2 hours)
<427> pH=6.8 완충액， 1000 mL (2시간 이후)  PH = 6.8 buffer, 1000 mL (after 2 hours)
<428> 분석방법 ： 고속액체크로마토그래프법  Analysis method ： High speed liquid chromatography method
<429> 검출 파장 ： 215 nm  <429> detection wavelength: 215 nm
<430> 이동상 ： 물 (0. 트리플투오로아세트산) /아세토나이트릴 (0.1% 트리플루오로 아세트산 ) = 30 :70  Mobile phase: water (0. triple toroacetic acid) / acetonitrile (0.1% trifluoro acetic acid) = 30:70
<431> 컬럼 ： 안지름 4.6 ram, 길이 250 画의 스테인레스관에 옥타데실실릴화한 겔 Column: octadecylsilylated gel in stainless steel pipe of inner diameter of 4.6 ram and length of 250 mm 3
<432> 유속 ： 1 mL/분 Flow rate ： 1 mL / min
【산업상 이용가능성】 Industrial Applicability
본 발명은 약리학적 활성성분으로 베타 아드레날린 차단제를 포함하는 선방출 성 구획， 및 약리학적 활성성분으로 안지오텐신 -2 수용체 길항제를 포함하는 지연방 출성 구획을 포함하는 약제학적 제제를 제공하며 , 본 발명의 제제는 균등한 항압작용 과 합병증 예방 작용을 나타내며 , 특히 합병증 발생 위험시간대에 혈압을 균등하게 유지시켜 줄 수 있어， 합병증을 지닌 고혈압 환자, 수면 증 혈압억제가 필요한 환자 등에 유용하고 , 약물간 상호작용에 따른 부작용 감소에 효과적이라는 장점이 있어 산 업상 이용가능성이 있다.  The present invention provides a pharmaceutical formulation comprising a prior release compartment comprising a beta adrenergic blocker as a pharmacologically active ingredient, and a delayed release compartment comprising an angiotensin-2 receptor antagonist as a pharmacologically active ingredient. The formulation shows an equal anti-pressure action and prevents complications, and in particular, it can maintain blood pressure evenly during the period of risk of complications, and is useful for patients with high blood pressure who have complications and those who need sleep pressure control. There is an advantage in that it is effective in reducing the side effects of the industrial use.

Claims

【청구의 범위】 [Range of request]
【청구항 1】  [Claim 1]
약리학적 활성성분으로 베타 아드레날린 차단제를 포함하는 선방출성 구획 ᅳ 및 약리학적 활성성분으로 안지오텐신 -2 수용체 길항제를 포함하는 지연 방출성 구획 을 포함하는 약제학적 제제  Pharmaceutical formulation comprising a prior release compartment 베타 comprising beta adrenergic blocker as a pharmacologically active ingredient and a delayed release compartment comprising angiotensin-2 receptor antagonist as a pharmacologically active ingredient
【청구항 2]  [Claim 2]
제 1 항에 있어서， 상기 선방출성 구획의 베타 아드레날린 차단제는 베타 아 드레날린 차단제 방출개시 후 1 시간 이내에 총량의 85% 이상이 방출되는 것인 약제 학적 제제 .  The pharmaceutical formulation of claim 1, wherein the beta adrenergic blocker in the prior release compartment releases at least 85% of the total amount within 1 hour after initiation of the beta adrenergic blocker release.
【청구항 3]  [Claim 3]
제 1 항에 있어서， 상기 안지오텐신 -2수용체 길항제는 베타 아드레날린 차단 제 방출 후 1시간 내지 8시간 이후에 방출되는 것인 약제학적 제제 .  The pharmaceutical formulation of claim 1, wherein the angiotensin-2 receptor antagonist is released 1 hour to 8 hours after beta adrenergic blocker release.
【청구항 4]  [Claim 4]
제 3 항에 있어서 , 상기 제제는 베타 아드레날린 차단제 방출 개시 후 2시간 이내에 제제 중 안지오텐신ᅳ2수용체 길항제 총량의 20% 이내가 방출되는 것인 약제학 적 제제 .  The pharmaceutical formulation of claim 3, wherein the formulation releases within 20% of the total amount of angiotensin ᅳ 2 receptor antagonist in the formulation within 2 hours after initiation of the beta adrenergic blocker release.
【청구항 5]  [Claim 5]
제 1 항 내지 제 4항 중 어느 한 항에 있어서， 상기 베타 아드테날린 차단제는 알프레놀를， 아세부토를, 아모술랄롤， 아로티놀를， 아테놀를, 베푸놀를， 베탁솔를, 베반를를, 비소프를를， 보핀돌를, 부쿠몰를， 뷔페를를, 부푸랄를， 부니트를를， 부프 란돌를， 부토필를를， 카라졸를, 카테올를, 카르베딜를， 셀릴프를를， 세타몰를， 클로 라놀를, 딜레발를, 에파놀를， 인데놀를, 라베탈를, 레보부놀를， 메핀돌를， 메티프라 놀를, 메토프를를， 모프를를, 나돌롤， 나독솔를， 네비볼롤， 니프라딜를， 옥스프레놀 를, 퍼부를를， 핀돌를, 프택를를ᅳ 프로네탈를, 프로프라놀를， 소탈를， 수피날를， 탈 린돌， 테르타를를 , 틸리솔를, 티몰를, 를리프를를ᅳ 지베놀를， 이들의 이성질체， 및 이들의 약학적으로 허용 가능한 염으로 이루어진 군에서 선택된 것인 약제학적 제제 . The method of claim 1, wherein the beta atheliner blocker comprises alpreol, acebuto, amosulolol, arotinol, athenol, befunol, betaxol, bevan, bisov For boffindol, for bucumol, for buffet, for bufural, for bonit, for buffrandol, for butophyll, carazole, catol, carvedil, selylp, cetamol, chloranol, dilbal, epa Gnoll, Indenol, Lavetal, Levobunol, Mepindol, Methifra Gnoll, Metope, Morph, Nadolol, Nadoxol, Navivolol, Nipradil, Oxprenol, Perbu, Pindol, It is composed of protecol, propranols, phthalates, supinal, tallindol, terta, tilisol, thymol, levifed givenol, isomers thereof, and pharmaceutically acceptable salts thereof. Pharmaceutical agents selected from the group of genes.
【청구항 6] [Claim 6]
제 1 항 내지 제 4항 중 어느 한 항에 있어서， 상기 안지오텐신 -2수용체 길항 제는 로사르탄, 발사르탄， 텔미사르탄, 이르베사르탄, 칸데사르탄, 을메사르탄, 에프 로사르탄， 이들의 이성질제， 약학적으로 허용 가능한 염 , 및 이들의 프로드럭으로 이 루어진 군에서 선택된 것인 약제학적 제제 .  The method according to any one of claims 1 to 4, wherein the angiotensin-2 receptor antagonist is losartan, valsartan, telmisartan, irbesartan, candesartan, emmesartan, frosatartan, A pharmaceutical formulation selected from the group consisting of isomers, pharmaceutically acceptable salts, and their prodrugs.
【청구항 7] 제 i 항 내지 제 4항 증 어느 한 항에 있어서， 상기 베타아드레날린차단제 1 중량부에 대하여， 안지오텐신 -2 수용체 길항제는 0.1 ~ 350 중량부인 약제학적 제제 . [Claim 7] The pharmaceutical preparation according to any one of claims i to 4, wherein the angiotensin-2 receptor antagonist is 0.1 to 350 parts by weight based on 1 part by weight of the beta adrenergic blocker.
【청구항 8】 [Claim 8]
제 1항 내지 제 4항 중 어느 한 항에 있어서 , 상기 지연방출성 구획은 활성성 분 외에 장용성 고분자， 수불용성 증합체， 소수성 화합물, 친수성 고분자 및 이들의 흔합물 중에서 선택된 1종 이상의 방출제어물질을 추가로 포함하는 약제학적 제제 .  The method according to any one of claims 1 to 4, wherein the delayed-release compartment comprises at least one release controlling substance selected from an enteric polymer, a water-insoluble polymer, a hydrophobic compound, a hydrophilic polymer, and a mixture thereof in addition to the active component. Pharmaceutical formulations further comprising:
【청구항 9] [Claim 9]
제 8 항에 있어서， 상기 방출제어물질은 안지오텐신 -2 수용체 길항제 1중량부 에 대하여 0.1 ~ 100 중량부로 포함되는 것인 약제학적 제제 .  The pharmaceutical formulation of claim 8, wherein the release controlling substance is included in an amount of 0.1 to 100 parts by weight based on 1 part by weight of the angiotensin-2 receptor antagonist.
【청구항 10]  [Claim 10]
제 8 항에 있어서， 상기 장용성 고분자는 장용성 셀를로오스 유도체 장용성 아크릴산계 공중합체， 장용성 폴리메타크릴레이트 공중합체， 장용성 말레인산계 공중 합체 , 장용성 폴리비닐 유도체， 및 이들의 흔합물로 이루어진 군에서 선택된 1종 이 상인 약제학적 제제 .  The enteric polymer according to claim 8, wherein the enteric polymer is selected from the group consisting of enteric cellulose derivatives, enteric acrylic acid copolymers, enteric polymethacrylate copolymers, enteric maleic acid copolymers, enteric polyvinyl derivatives, and mixtures thereof. One or more pharmaceutical agents.
【청구항 111  [Claim 111]
제 10 항에 있어서， 상기 장용성 셀를로오스 유도체는 히드록시프로필메틸셀 를로오스아세테이트숙시네이트， 히드록시프로필메틸셀를로오스프탈레이트， 히드록시 메틸에틸셀를로오스프탈레이트， 셀를로오스아세테이트프탈레이트, 셀를로오스아세테 이트숙시네이트， 셀를로오스아세테이트말레이트 , 셀를로오스벤조에이트프탈레이트， 셀를로오스프로피오네이트프탈레이트， 메틸셀를로오스프탈레이트， 카르복시메틸에틸 셀를로오스，에틸히드톡시에틸셀를로오스프탈레이트, 메틸히드록시에틸셀를로오스 및 이들의 흔합물 중에서 선택된 1종 이상이고 ; 상기 장용성 아크릴산계 공중합체는 스 티렌-아크릴산 공중합체， 아크릴산메틸—아크릴산 공중합체 , 아크릴산메틸메타크릴산 공중합체，아크릴산부틸-스티렌-아크릴산 공중합체 , 아크릴산메틸-메타크릴산-아크릴 산옥틸공중합체 및 이들의 흔합물 중에서 선택된 1종 이상이고; 상기 장용성 폴리메 타크릴레이트 공중합체는 폴리 (메타크릴산-메틸메타크릴레이트) 공중합체，폴리 (메타 크릴산 . 에틸아크릴레이트)공증합체 및 이들의 흔합물 중에서 선택된 1종이상이고; 상기 장용성 말레인산계 공중합체는 아세트산비닐-말레인산 무수물 공중합체， 스티렌 -말레인산 무수물 공중합체 , 스티렌-말레인산모노에스테르 공증합체 , 비닐메틸에테르 -말레인산 무수물 공중합체 , 에틸렌-말레인산 무수물 공중합체 , 비닐부틸에테르 -말레 인산 무수물 공중합체， 아크릴로니트릴-아크릴산메틸 · 말레인산 무수물 공중합체， 아 크릴산부틸-스티렌—말레인산 무수물 공중합체 및 이들의 흔합물 중에서 선택된 1종 이상이며 ; 상기 장용성 플리비닐 유도체는 폴리비닐알콜프탈레이트, 플리비닐아세테 이트프탈레이트 , 폴리비닐부티 레이트프탈레이트，폴리비닐아세트아세탈프탈레이트 및 이들의 흔합물 중에서 선택된 1종 이상인 약제학적 제제 . The method of claim 10, wherein the enteric cellulose derivative is selected from the group consisting of hydroxypropyl methyl cell, cellulose acetate succinate, hydroxypropyl methyl cell, cellulose phthalate, hydroxy methyl ethyl cell, cellulose phthalate, cellulose acetate phthalate, and a cell. Loose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethylethyl cellulose, ethyl hydroxyethyl cellulose At least one selected from phthalate, methyl hydroxyethyl cellulose and a mixture thereof; The enteric acrylic acid copolymers include styrene-acrylic acid copolymers, methyl acrylate-acrylic acid copolymers, methyl methacrylate acrylic acid copolymers, butyl acrylate-styrene-acrylic acid copolymers, and methyl acrylate-methacrylic acid acrylic acid octyl copolymers. And at least one selected from the combinations thereof; The enteric polymethacrylate copolymer is at least one selected from a poly (methacrylate-methylmethacrylate) copolymer, a poly (methacrylate.ethylacrylate) copolymer and a mixture thereof; 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- 1 type selected from maleic anhydride copolymers, acrylonitrile-methyl acrylate, maleic anhydride copolymers, butyl acrylate-styrene-maleic anhydride copolymers and mixtures thereof Above; The enteric polyvinyl derivative is at least one selected from polyvinyl alcohol phthalate, polyvinylacetate phthalate, polyvinyl butyrate phthalate, polyvinylacetacetal phthalate, and combinations thereof.
【청구항 12]  [Claim 12]
제 8 항에 있어서， 상기 수블용성 중합체는 폴리비닐 아세테이트, 수불용성 폴리메타크릴레이트 공중합체， 에틸셀를로오스, 셀를로오스 에스테르， 셀를로오스 에 테르， 셀를로오스 아실레이트， 셀를로오스 디아실레이트， 셀를로오스 트리아실레이 트， 셀를로오스 아세테이트， 셀를로오스 디아세테이트， 셀를로오스 트리아세테이트 및 이들의 흔합물로 이루어진 군에서 선택된 1종 이상인 약제학적 제제 .  The method of claim 8, wherein the water-soluble polymer is polyvinyl acetate, water-insoluble polymethacrylate copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dia A pharmaceutical agent selected from the group consisting of silates, cellulose triacylates, cellulose acetate, cellulose diacetate, cellulose triacetate and combinations thereof.
【청구항 13】  [Claim 13]
제 8 항에 있어서， 상기 소수성 화합물은 지방산 및 지방산 에스테르류， 지방 산 알코올류， 왁스류， 무기물질 및 이들의 흔합물 중에서 선택된 1종 이상인 약제학 적 제제 .  The pharmaceutical preparation according to claim 8, wherein the hydrophobic compound is at least one selected from fatty acids and fatty acid esters, fatty acid alcohols, waxes, inorganic substances and combinations thereof.
【청구항 14】  [Claim 14]
제 13 항에 있어서， 상기 지방산 및 지방산 에스테르류는 글리세릴 괄미토스 테아레이트， 글리세릴 스테아레이트， 글리세릴 디스테아레이트， 글리세릴 비헤네이 트， 세틸 팔미테이트， 글리세릴 모노 을레이트， 스테아르산 및 이들의 흔합물 중에서 선택된 1종 이상이고; 상기 지방산 알코올류는 세토스테아릴 알코을， 세틸알코올， 스 테아릴알코을 및 이들의 흔합물 증에서 선택된 1종 이상이고 ; 상기 왁스류는 카르나 우바왁스， 밀납， 미결정왁스 및 이들의 흔합물 중에서 선택된 1종 이상이며 ; 상기 무 기물질은 탈크， 침강탄산칼슘， 인산일수소칼슘，산화아연，산화티탄， 카을린 , 벤토나 이트， 몬모릴로나이트, 비검 및 이들의 흔합물 중에서 선택된 1종 이상인 약제학적 제제 .  The method according to claim 13, wherein the fatty acids and fatty acid esters are glyceryl bumpitostearate, glyceryl stearate, glyceryl distearate, glyceryl bihenate, cetyl palmitate, glyceryl monoacrylate, stearic acid and At least one selected from their mixtures; The 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 substance is at least one selected from talc, precipitated calcium carbonate, calcium dihydrogen phosphate, zinc oxide, titanium oxide, chlorine, bentonite, montmorillonite, non-gum and combinations thereof.
【청구항 15]  [Claim 15]
제 8 항에 있어서， 상기 친수성 고분자는 당류， 셀를로오스 유도체 , 검류， 단 백질류， 폴리비닐 유도체， 친수성 폴리메타크릴레이트 공중합체， 폴리에틸렌 유도체， 카르복시비닐공중합체 및 이들의 흔합물 중에서 선택된 1종 이상인 약제학적 제제 .  The method according to claim 8, wherein the hydrophilic polymer is selected from sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl copolymers, and mixtures thereof. Pharmaceutical formulations of more than one species.
【청구항 16】 [Claim 16]
제 15 항에 있어세 상기 당류는 덱스트린， 폴리덱스트린 , 덱스트란， 펙틴 및 펙틴 유도체， 알긴산염 , 폴리갈락투론산, 자일란， 아라비노자일란, 아라비노갈락탄, 전분, 히드록시프로필스타치， 아밀로오스, 아밀로펙틴 및 이들의 흔합물 증에서 선택 된 1종 이상이고 ; 상기 셀를로오스 유도체는 히드록시프로필메틸셀를로오스， 히드록 시프로필셀를로오스, 히드록시메틸셀를로오스， 히드록시에틸셀를로오스, 메틸셀를로 오스, 카르복시메틸셀를로오스 나트륨, 히드록시프로필 메틸셀를로오스 아세테이트 숙시네이트， 히드록시에틸메틸셀를로오스 및 이들의 흔합물 중에서 선택된 1종 이상 이고; 상기 검류는구아검 , 로커스트콩검 , 트라가칸타, 카라기난, 아카시아검 , 아라 비아검， 젤란검， 잔탄검 및 이들의 흔합물중에서 선택된 1종 이상이고; 상기 단백질 류는 젤라틴, 카제인, 제인 및 이들의 흔합물 중에서 선택 1종 이상이고; 상기 폴리 비닐 유도체는폴리비닐 알코올, 폴리비닐 피를리돈， 폴리비닐아세탈디에틸아미노아 세테이트 및 이들의 흔합물 중에서 선택된 1종 이상이고; 상기 친수성 폴리메타크릴 레이트공중합체는풀리 (부틸 메타크릴레이트, (2-디메틸아미노에틸)메타크릴레이트_ 메틸메타크릴레이트) 공중합체， 플리 (메타크릴산-메틸메타크릴레이트) 공중합체， 폴 리 (메타크릴산-에틸아크릴레이트) 공중합체， 및 이들의 흔합물중에서 선택된 1종 이 상이고상기 폴리에틸렌유도체는폴리에틸렌글리콜， 폴리에틸렌옥사이드및 이들의 흔합물 증에서 선택된 1종 이상이며; 상기 카르복시비닐 공중합체는 카보머인 것인 약제학적 제제. According to claim 15, wherein the sugar is dextrin, polydextrin, dextran, pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch, amylose At least one selected from amylopectin and their complications; The cellulose derivative is hydroxypropyl methyl cellulose, hydroxy Cipropyl Cellulose, Hydroxymethyl Cellulose, Hydroxyethyl Cellulose, Methyl Cellulose, Carboxymethyl Cellulose Sodium, Hydroxypropyl Methyl Cellulose Acetate Succinate, Hydroxyethylmethyl Cellulose And at least one selected from a combination thereof; The gum is at least one selected from guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, aravia gum, gellan gum, xanthan gum and combinations thereof; The protein is at least one selected from gelatin, casein, zein and combinations thereof; The polyvinyl derivative is at least one selected from polyvinyl alcohol, polyvinyl pyridone, polyvinylacetal diethylamino acetate, and combinations thereof; The hydrophilic polymethacrylate copolymer is a pulley (butyl methacrylate, (2-dimethylaminoethyl) methacrylate_ methyl methacrylate) copolymer, poly (methacrylate-methyl methacrylate) copolymer, poly At least one selected from li (methacrylic acid-ethyl acrylate) copolymer, and mixtures thereof, and the polyethylene derivative is at least one selected from polyethylene glycol, polyethylene oxide, and a mixture thereof; The carboxyvinyl copolymer is a carbomer.
【청구항 17]  [Claim 17]
제 1항 내지 제 4항 중 어느한항에 있어서, 상기 약제학적 제제는하기 형 태 중에서 선택된 것인 약제학적 제제:  The pharmaceutical formulation according to any one of claims 1 to 4, wherein the pharmaceutical formulation is selected from the following forms:
지연방출성 구획 및 선방출성 구획이 균일하게 흔합된 후 타정하여 얻어지는 2상의 매트릭스 정제 형태，  2-phase matrix tablet form obtained by tableting after delayed-release compartment and pre-release compartment uniformly mixed,
지연방출성 구획으로 이루어진 정제와상기 정제의 외부를들러싸는선방출성 구획으로 이루어진 필름코팅층으로 구성된 필름코팅정 형태，  Film-coated tablet form consisting of a film coating layer consisting of a tablet consisting of a delayed-release compartment and a pre-release compartment surrounding the outside of the tablet,
지연방출성 구획과 선방출성 구획이 층을 이루는 다층정 형태,  A multi-layered tablet in which the delayed-release compartment and the prior-release compartment are layered,
지연방출성 구획으로 이루어진 내핵정과， 상기 내핵정의 외면을둘러싸고 있 는선방출성 구획으로 이루어진 외층으로구성된 유핵정 형태,  Nucleated tablet form consisting of an inner core consisting of a delayed-release compartment, and an outer layer consisting of a pre-release compartment surrounding the outer surface of the inner core,
지연방출성 구획으로 이루어진 입자, 과립, 펠뻣, 또는 정제와， 선방출성 구 획으로 이루어진 입자, 과립, 펠렛， 또는정제를 포함하는 캡술제 형태，  Capsular forms comprising particles, granules, pellets or tablets consisting of delayed-release compartments and particles, granules, pellets or tablets of prior-release compartments,
지연방출성 구획은 삼투압조절제를포함하며 반투과성막코팅기제로코팅된 형태;  Delayed-release compartments include osmotic pressure-controlling agents and are coated with a semipermeable membrane coating base;
지연방출성 구획, 또는선방출성 구획 중 하나 이상의 외부에 코팅층을 추가 로포함하는 형태;  A form further comprising a coating layer on the outside of at least one of the delayed-release compartment or the prior-release compartment;
제제의 외부에 코팅층을 추가로 포함하는코팅정 형태; 및  Coated tablet form further comprising a coating layer on the outside of the formulation; And
지연방출성 구획, 및 선방출성 구획을 포함하는 키트 형태. A kit form comprising a delayed release compartment and a prior release compartment.
【청구항 18】 [Claim 18]
제 17항에 있어서， 상기 유핵정은 삼투성 유핵정인 약제학적 제제.  The pharmaceutical formulation of claim 17, wherein the nucleated tablet is an osmotic nucleated tablet.
【청구항 19】  [Claim 19]
제 17항에 있어서， 상기 삼투압조절제는황산마그네슴, 염화마그네슘， 염화 나트륨, 염화리튬, 황산칼륨, 황산리튬， 황산나트륨, 및 이들의 흔합물로 이루어진 군에서 선택된 1종 이상인 것인 약제학적 제제.  18. The pharmaceutical formulation of claim 17, wherein the osmotic pressure regulator is at least one selected from the group consisting of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, lithium sulfate, sodium sulfate, and combinations thereof.
【청구항 20]  [Claim 20]
제 17항에 있어서, 상기 반투과성막 코팅기제는 폴리비닐 아세테이트, 폴리 메타크릴레이트 공중합체， 폴리 (에틸아크릴레이트， 메틸 메타크릴레이트) 공중합체， 플리 (에틸아크릴레이트， 메틸메타크릴레이트， 트리메틸아미노에틸메타크릴레이트클 로라이드)공중합체， 에틸셀를로오스， 셀를로오스에스테르, 셀를로오스에테르， 셀를 로오스아실레이트 , 셀를로오스디아실레이트， 셀를로오스트리아실레이트, 셀를로오 스아세테이트, 셀를로오스디아세테이트 셀를로오스트리아세테이트， 및 이들의 흔 합물로 이루어진 군에서 선택된 1종 이상인 것인 약제학적 제제.  18. The method of claim 17, wherein the semipermeable membrane coating base is polyvinyl acetate, poly methacrylate copolymer, poly (ethyl acrylate, methyl methacrylate) copolymer, poly (ethyl acrylate, methyl methacrylate, trimethylamino Ethyl methacrylate chloride) copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose australate, cellulose acetate , Cellulose cellulose diacetate, cellulose uroacetate, and combinations thereof.
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