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WO2009134053A2 - Pharmaceutical composition containing thiazide-based compound with controlled release and angiotensin-ii-receptor blocker - Google Patents

Pharmaceutical composition containing thiazide-based compound with controlled release and angiotensin-ii-receptor blocker Download PDF

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Publication number
WO2009134053A2
WO2009134053A2 PCT/KR2009/002219 KR2009002219W WO2009134053A2 WO 2009134053 A2 WO2009134053 A2 WO 2009134053A2 KR 2009002219 W KR2009002219 W KR 2009002219W WO 2009134053 A2 WO2009134053 A2 WO 2009134053A2
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Prior art keywords
release
cellulose
angiotensin
group
delayed
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PCT/KR2009/002219
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French (fr)
Korean (ko)
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WO2009134053A3 (en
Inventor
김성욱
전성수
조영관
구자성
이아람
손재운
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한올제약주식회사
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Publication of WO2009134053A2 publication Critical patent/WO2009134053A2/en
Publication of WO2009134053A3 publication Critical patent/WO2009134053A3/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

Definitions

  • composition comprising controlled release of chiazide-based compound and angiotensin ⁇ ⁇ ⁇ receptor blocker
  • the present invention relates to pharmaceutical compositions of thiazide-based compounds and angiotensin-II ′ receptor blockers and their complex formulation techniques.
  • pharmacological and pharmacological effects can be obtained by taking a controlled formulation of a controlled release rather than taking a single formulation of a chiazide-based compound and an angiotensin ⁇ ⁇ ⁇ receptor blocker at the same time.
  • the present invention relates to a formulation technology that maximizes the clinical anti-pressure effect and the prevention of complications and further reduces side effects.
  • anti-pressure therapy is not the only purpose to lower blood pressure.
  • the purpose of anti-pressure therapy is to prevent myocardial infarction, heart failure, stroke, and premature death, which can be easily merged with hypertension patients, and to prevent the worsening of the condition.
  • Hypertension has a wide variety of causes. Various causes cause hypertension in the same patient. Therefore, it is difficult to determine in advance what results would result from the use of a single antipressant (Journal of human hypertension 1995: 9: 9: S33-S36).
  • the combination formulation makes it very easy for the patient to adhere to the medication. As the elderly population grows, the time spent on prescription medication guidance can be cut in half.
  • Hydrochlorothiazide a representative diazide compound, is chemically named 6-chloro-3, 4—dihydro-2H-1, 2,4-benzothiadiazine-7-sulfonamide 1,1— It is a dioxide, a diuretic effect lasting 6 ⁇ 12 hours when administered orally as a hypertension treatment adjuvant, with a half-life of 5.6-14.8 hours per day.
  • thiazide compound diuretics include chlorothiazide and bendroflumezigit.
  • Angiotensin ⁇ ⁇ ⁇ receptor blockers block the binding of angiotensin receptors, one of the sources of vasoconstriction, and have been shown to be effective in lowering blood pressure in both myocardial systolic and diastolic and are frequently used in clinical trials.
  • the group of compounds being applied has reached about 10 species, including salts that are pharmaceutically usable.
  • they are used alone with patients with symptoms ranging from mild to moderate in hypertension, and with angiotensin converting enzyme inhibitors that have anti-hypertensive effects with similar mechanisms.
  • Angiotension 2 Receptor Antagonist An Overview , Am J Health ⁇ Syst Pharm 57 (13): 1231-1238, 2000].
  • angiotensin ⁇ receptor receptors The anti-pressure and renal protective action of the angiotensin ⁇ receptor receptors is described, for example, in J. Wagner et al. : Effects of ATI receptor blockade on blood pressure and the renin angiotensin system in spontaneously hypertensive rats of the stroke prone strain, Clin, Exp. Hyper t ens. , vol. 20 (1998), p. 205-221; M. Bohm et al. : Angiotensin— ⁇ —receptor blockade in TGR (mREN2) 27: Effects of renin ⁇ angiotensin ⁇ system gene expression and cardiovascular functions, J. Hyper tens., Vol. 13 (8) (1995), p. 891-899.
  • Kidney protective effects are described in the following publications: S. Andersen et al. Renoprotective effects of angiotensin— ⁇ —receptor blockade in type 1 diabetic patients with diabetic nephropathy, Kidney Int. , vol. 57 (2) (2000), p. 601-606; LM Ruilope: Renoprotection and renin-angiotensin system blockade in diabetes mellitus, Am. J. Hyper t ens. , vol. 10 (12PT2) Suppl. (1997), p. 325-331.
  • Hypertension regardless of the type of disease, blood pressure during the day is most The effect of the medication should be expressed early in the morning, when it is rising, and more preferably, the angiotensin and the angiotensin, which are directly responsible for the increase in sleep time and the increase in blood pressure, are synthesized. Diseases in which evening medications are recommended to maintain blood pressure lowering until early morning, when aldosterone synthesis peaks. Patterns of blood pressure response: Day and night variations; American Journal of Hypertension April 2001 . 14, No.
  • Combination preparations product name: Hyzaar, manufacturer: MSD; product name: Diovan HCT, manufacturer: Novartis, etc.
  • hydrochlorothiazide and angiotensin ⁇ ⁇ ⁇ receptor blocker as active ingredients as a ziazide compound diuretic are commercially available, and these are clinically known combinations It has been applied to many hypertensive patients due to the additional blood pressure lowering effect when administered. See Combination Therapy in the Management of Hypertension: Focus on Angiotension Receptor blocker Combined with Diuretics, J Clin Hyper tens.
  • angiotensin ⁇ ⁇ receptor blocker which is a diuretic
  • the angiotensin ⁇ ⁇ receptor blocker not only lowers the blood pressure but also reduces the total plasma volume through diuresis.
  • An additional hypotensive effect can be obtained, thereby increasing the hypertension, which is difficult to recover to normal blood pressure by administration of a single agent of angiotensin ⁇ ⁇ receptor blocker as well as mild hypertensive patients. It has also been found that significant anti-pressure effects can be obtained in patients.
  • hydrochlorothiazide a diazide compound
  • hydrochlorothiazide is a side effect of the diuretic effect of long-term use, and may cause hypokalemia due to excretion of potassium through the kidneys, causing hypokalemia.
  • Angiotensin ⁇ ⁇ receptor receptor is angiotensin By suppressing the production of potassium, the loss of potassium can be prevented.
  • Angiotensin ⁇ ⁇ ⁇ receptor blockers reduce the side effects of long-term administration of hydrochlorothiazit, a thiazide compound diuretic.
  • morning doses of these simultaneous combinations can overcome side effects such as sleep disorders caused by night urination and suburinal urine administration in the evening of hydrochlorothiazide, a thiazide compound diuretic.
  • the pharmacological effect of angiotensin ⁇ ⁇ ⁇ receptor blocker cannot be maintained until the morning of the highest risk time, and evening doses can maximize the pharmacological effect of angiotensin ⁇ ⁇ receptor blocker, but it is not effective in the administration of hydrochlorothiazide, a ziazide-based diuretic.
  • Side effects such as sleep disturbance caused by night urination and night urination are inevitable.
  • the eluted hydrochlorothiazide is eluted first to maintain diuretic effect until bedtime, resulting in a blood pressure lowering effect, penetrating into the blood vessel wall, accumulating and then vasodilating while minimizing sleep disturbance caused by urination at night during sleep.
  • the angiotensin _ ⁇ ⁇ receptor blocker is eluted at a different time, resulting in the sleep time and blood pressure rise, which is the synthesis of renin, a source that causes vasoconstriction.
  • the present invention not only shows the best pharmacological effect of each component through the functional combination of the ziazide compound and angiotensin ⁇ ⁇ ⁇ receptor blocker, but also maximizes the pharmacological effect while reducing side effects of each component when the two components are used together. It is the world's first design of a delayed-release functional combination that makes patient compliance easier. To date, no complex composition that controls the release properties in consideration of pharmacological mechanisms such as absorption, distribution, metabolism and excretion of thiazide-based compounds and angiotensin-II-receptor blockers has not been considered. Detailed description of the invention
  • the present inventors solved the maximization of the effect of the combination of the chiazide compound and angiotensin- ⁇ -receptor blocker from the pharmaceutical point of view, inducing the optimal pharmacological effect according to the absorption ability of the body, and the pharmacological effect of each drug.
  • the present invention has been completed by studying a combination composition that can overcome sleep disorders due to night urination, which is a limitation of the composition, and can increase the patient's medication swelling rate by rational administration once daily in the morning time.
  • a delayed-release compartment comprising an angiotensin ⁇ ⁇ ⁇ receptor blocker or a pharmaceutically acceptable salt thereof as an active ingredient, and a prior-release compartment comprising a thiazide compound or a pharmaceutically acceptable salt thereof as an active ingredient
  • Composite composition with controlled release to enable time difference dissolution characterized in that it comprises a;
  • composition according to the above (1) wherein the active ingredient included in the pre-release compartment releases at least 85% by weight within 1 hour after the start of release;
  • the angiotensin ⁇ _receptor blocker or the pharmaceutically acceptable salt thereof is substantially released after 4 hours from the start of dissolution of the thiazide compound or the pharmaceutically acceptable salt thereof.
  • angiotensin ⁇ -receptor blocker is losartan, valsartan, telmisartan, irbesartan, candesartan, emmesartan, eprosartan, and Selected from the group consisting of their isomers, wherein the ziazide compound is hydrochlorothiazit;
  • a combination composition characterized in that it is selected from the group consisting of chlorothiazide, bendroflumezigit, and their isomers;
  • the angiotensin ⁇ ⁇ 1 receptor blocker or a pharmaceutically acceptable salt thereof according to the above (6) is contained in the range of 5 to 600 mg in the composition, and the thiazide compound or pharmaceutically acceptable thereof A composite composition characterized in that the salt is contained in the range of 2.5 to 100 mg in the composition;
  • the co-composition is characterized in that the sex.compartment is a formulation comprising an osmotic pressure-controlling agent and a coating coated with a semipermeable membrane coating base, and a formulation selected from the group consisting of a kit comprising a delayed-release compartment and a prior-release compartment.
  • the sex.compartment is a formulation comprising an osmotic pressure-controlling agent and a coating coated with a semipermeable membrane coating base, and a formulation selected from the group consisting of a kit comprising a delayed-release compartment and a prior-release compartment.
  • the present invention controls the release of the angiotensin- ⁇ -receptor blocker and the active ingredient of the ziazide-based compound, respectively, to reduce side effects from the therapeutic side and to increase the patient's medication compliance by once-daily administration in the morning. Can be provided.
  • angiotensin ⁇ ⁇ receptor blocker a representative hypotensive agent
  • the above adjustment is preferably performed for a delay of 4 hours or more.
  • the ziazide-based compound with blood half-life of 12 hours or more is released first, the hypotensive action expressed by reducing the total plasma volume through diuresis is maintained until the next administration time, and urination, which can cause sleep disorders, It takes place during the day (am) time and is metabolized in vivo before angiotensin ⁇ ⁇ receptor blockers to prevent further loss of electrolytes that can be caused by co-administration.
  • Angiotensin- ⁇ -receptor blockers which are subsequently released and absorbed, are designed to maintain the blood pressure-lowering action from the evening of the synthesis of vasoconstrictor-inducing substances to the early morning of peak blood pressure, leading to the best therapeutic effect. It will have a blood pressure lowering effect in the time zone.
  • Table 2 The advantages of the composite compositions according to the invention over simple composites are shown in Table 2.
  • Beam 1 is a graph showing the dissolution patterns of hydrochlorothiazide monotherapy, losartan monotherapy, and Example 1.
  • FIG. 2 is a graph showing the dissolution patterns of Coza Plus (hydrochlorothiazide, Losartan simple complex) and Example 2) in the market.
  • Figure 3 is a graph showing the dissolution patterns of Examples 5-8.
  • Figure 4 is a graph showing the dissolution patterns of Examples 7, 9-11.
  • Fig. 5 is a graph showing the dissolution patterns of Koza Fullus F (hydrochlorothiazide, Losartan simple combination), a formulation of Example 15, which is commercially available.
  • Fig. 6 is a graph showing the dissolution patterns of the hydrochlorothiazide monotherapy, losartan monotherapy, and the preparation of Example 16.
  • Fig. 7 is a graph showing the dissolution profiles of hydrochlorothiazide monotherapy, valsartan monotherapy, and formulations containing irbesartan as active ingredients in the formulation of Example 20.
  • Fig. 8 is a graph of the dissolution profiles of a hydrochlorothiazide monotherapy, an irbesartan monotherapy, and an formulation containing irbesartan as an active ingredient in the preparation of Example 21.
  • 9 is a graph showing the dissolution patterns of the hydrochlorothiazide monotherapy, losartan monotherapy, and formulations of Examples 23 and 24.
  • 10 is a graph showing the dissolution patterns of the hydrochlorothiazide monotherapy, telmisartan monotherapy, and formulation of Example 27.
  • FIG. 8 is a graph showing the dissolution profiles of hydrochlorothiazide monotherapy, valsartan monotherapy, and formulations containing irbesartan as active ingredients in the formulation of Example 20.
  • FIG. 11 is a graph of the elution profile of a hydrochlorothiazide monotherapy, an iprosartan monotherapy, and an formulation having Irbesartan as an active ingredient in the formulation of Example 29.
  • FIG. 11 is a graph of the elution profile of a hydrochlorothiazide monotherapy, an iprosartan monotherapy, and an formulation having Irbesartan as an active ingredient in the formulation of Example 29.
  • Fig. 12 is a graph of the dissolution profiles of hydrochlorothiazide monotherapy, cantesartan cilexetil monotherapy, and formulations containing irbesartan as active ingredients in the preparation of Example 30.
  • FIG. 13 is a graph showing the dissolution patterns of the hydrochlorothiazide monotherapy, olmesartan medoxomil monotherapy, and the preparation of Example 31.
  • FIG. 13 is a graph showing the dissolution patterns of the hydrochlorothiazide monotherapy, olmesartan medoxomil monotherapy, and the preparation of Example 31.
  • Fig. 14 is a graph showing the dissolution patterns of the hydrochlorothiazide monotherapy, olmesartan medoxomil monotherapy, and the preparation of Example 37.
  • 17 is a graph comparing the average blood pressure between administration routes as a result of the clinical trial according to Experiment 15.
  • the present invention relates to a composite composition
  • a composite composition comprising a pharmaceutically acceptable carrier, a cyanide compound, and an angiotensin ⁇ receptor receptor as an active ingredient, a delayed-release compartment comprising an angiotensin ⁇ receptor receptor as an active ingredient, and It is characterized by a composite composition having controlled release properties comprising a pre-release compartment containing a zed compound as an active ingredient.
  • the present invention relates to a composite composition designed to control and release each drug at a specific rate by applying the so-called time difference dosing theory (Chronotherapy) principle of staggering the time of pharmacological action in each of the complex components.
  • Chronotherapy time difference dosing theory
  • the combination of Zide-based compound and angiotensin _11 ⁇ receptor blocker provides synergistic effect and reduces side effects, and it is easy to take the medicine for the patient with the convenience of taking 1 tablet once daily in the morning.
  • the present invention relates to a delayed-release complex composition comprising a thiazide-based compound of the new concept and an angiotensin ⁇ receptor receptor.
  • the thiazide compound is rapidly absorbed in the gastrointestinal tract immediately after administration and the angiotensin-?-Receptor blocker is released after a certain time and is absorbed in the small intestine. Specifically, when oral administration, the thiazide compound is released immediately and more than 853 ⁇ 4 of the drug is eluted within 1 hour, and the angiotensin® ⁇ ⁇ receptor blocker delays the release from the gastrointestinal tract and releases up to 4 hours after oral administration.
  • the angiotensin ⁇ ⁇ receptor blocker is delayed in the gastrointestinal tract to release a total of 4 after oral administration
  • the dissolution rate by time is adjusted to release no more than 30%.
  • the angiotensin ⁇ ⁇ ⁇ receptor blocker is controlled to release so that it is absorbed in the liver 2-4 hours later than the thiazide compound, and more preferably, angiotensin ⁇ after 4 hours from the start of dissolution of the thiazide compound ⁇ —controlled to substantially release the receptor blocker.
  • This complex formulated formulation is taken only once in the morning to have an even blood pressure control action, complication inhibition and side effects reduction for 24 hours.
  • the reason for taking the present invention composite composition of the present invention in the morning time is as follows.
  • the thiazide compound since the thiazide compound lasts 12 hours, but only once in the morning, seeps into the blood vessel wall and accumulates a certain amount for 12 hours. This amount of accumulation is insufficient to sustain diuresis for 24 hours, but is adequate to sustain vasodilator for 24 hours. This is why the current 12-hour continuous dose is administered only once a day. It can also overcome side effects such as night urination and sleep disorders caused by night urine.
  • angiotensin ⁇ receptor receptor blockers have a strong blood pressure-lowering effect during the evening from 4 pm to 12 pm during evening sleep. It has a pharmacological rhythm that keeps your blood pressure even. This is because aldosterone and angiotensin ⁇ ⁇ , which are the blood-releasing substances of the renin system, are mainly produced and operated in the night, and angiotensin ⁇ ⁇ receptor blocker inhibits the production of aldosterone and inhibits the action of angiotensin ⁇ . to be.
  • Losartan a representative drug of angiotensin receptor receptor blockers, enters the liver primarily when absorbed. Some of them are the active form of losartan molecules, which are directly spilled into the blood and reach the highest concentration in the blood within 1 hour. However, some of the other enzymes in the liver are caused by two enzymes called cytokine P450 2C7 and 3A4. The metabolism leads to higher activity losartan carboxylic acid, which leads to peak hyperemia levels 3-4 hours later. That is, the pharmacological action of losartan is the pharmacological action of losartan and losartan carboxylic acid complex which is losartan active metabolite.
  • Loss rate in blood is 600 mL / min for losartan and 50 mL / min for active metabolite, which shows a slower loss rate for active metabolite.
  • Treatment of patients with hypertension should maintain blood pressure evenly, especially 24 hours, and suppress heart sympathetic excess erythema 24 hours evenly. This can be achieved only by the present federal formulation formulation technology of the present invention.
  • the pharmaceutical composition comprising the thiazide compound of the present invention and angiotensin ⁇ _ receptor blocker will be described in detail.
  • the thiazide compound may be used as one or two or more combinations selected from hydrochlorothiazide, chlorothiazide, bendroflumezigit and pharmaceutically acceptable salts thereof, but is not limited to these types and is shown above.
  • hydrochlorothiazide or a pharmaceutically acceptable salt thereof can be used.
  • the thiazide compound in the composition is 2.5 to 100 nig, preferably 10 to 50 mg.
  • the dose of each drug is a daily dose based on an adult (an adult male weighing 65 to 75 kg).
  • hydrochloroziazite As a ziazide-based compound exhibiting the above-described blood pressure lowering effect, hydrochloroziazite is described as a specific example in the specification of the present invention, but the present invention is not limited thereto.
  • the angiotensin ⁇ ⁇ receptor receptor blocker included as an active ingredient of the composite composition of the present invention performs a blood pressure lowering action, specific examples thereof are losartan, valsartan, irbesartan, cantesartan, telmisartan, if And one or two or more combinations selected from losartan, olmesartan and pharmaceutically acceptable salts or isomers thereof.
  • the amount of angiotensin ⁇ ⁇ ⁇ receptor blocker in the composition is 5 to 600 mg, preferably . 5 to 300 mg.
  • the dose of each drug is a daily dose based on an adult (65-75 kg adult male).
  • the pharmaceutically acceptable salts mean salts commonly used in the pharmaceutical industry, for example, inorganic ions, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, made of calcium, potassium, sodium and magnesium, Inorganic acid salts, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, P-Truenesulfonic acid, naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, Oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glutonic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanic acid, Organic acid salts, methanesulfonic acid, ethanesulfonic
  • the anti-pressure (3) hydrochlorothiazide begins during the day when the action is diminished, penetrates into the blood vessel walls, accumulates in the lower blood pressure group, and becomes unsuitable for blood vessels and causes complications during sleep.
  • the risk of inadequate risk during the night time period (for post-weather and post-war concomitant seizures at 9 am) is also more effective for non-dippers than at the same time, as it reduces peak incidence at night.
  • novel compositions of the present invention are delayed-release compartments and thiazides consisting of angiotensin ⁇ ⁇ _receptor blockers, pharmaceutically acceptable salts thereof and the desired excipients so that they can be physically separated or partitioned to achieve different release rates of the two drugs.
  • the pre-release and delayed-release compartments presented above can be implemented in a variety of formulations. That is, the coating particles, granules, pellets or tablets obtained in this way can be coated by a conventional coating method comprising a release controlling substance selected from the group consisting of the delayed-release compartments presented above, multicomponent particles, granules,
  • the pellets can be layered in capsules or formulated into various tablets such as biphasic matrices, film coated tablets, multi-layer tablets nucleated tablets or osmotic nucleated tablets.
  • Such a pharmaceutical composition of the present invention is suitable for the prevention and treatment of kidney disease or for the treatment of cardiovascular diseases, and when taken in the morning time once a day between 6 am to 11 am exerts an effective effect.
  • Pre-release compartment refers to the compartment that is released earlier than the delayed-release compartment in the pharmaceutical formulation of the present invention, and includes ziazide-based drugs as pharmacologically active ingredients, and further includes a pharmaceutically acceptable additive as necessary. It may include.
  • the delayed-release compartment refers to a compartment in which the active ingredient is released after a certain time of release of the prior-release compartment active ingredient. Delayed-release compartments Angiotensin ⁇ ⁇ receptor blocker, an isomer thereof, or a pharmaceutically acceptable salt thereof, and 1) a release controlling substance or osmotic pressure control agent and a semipermeable membrane coating agent, as necessary, 2) pharmaceutically acceptable Possible additives may further be included.
  • the delayed-release compartment of the present invention uses a material selected from an enteric polymer, a water insoluble polymer, a hydrophobic compound, a hydrophilic polymer, and a combination of an osmotic semipermeable membrane coating base and an osmotic agent.
  • the release controlling substance of the delayed-release compartment may be used in an amount of 10 to 2,000 parts by weight based on 100 parts by weight of the active ingredient. If the amount is less than the above range, the delayed release property may not be obtained. Release is delayed and no significant clinical effect is obtained.
  • the enteric polymer is insoluble or stable under acidic conditions of less than pH 5, and refers to a polymer that is dissolved or decomposed under specific pH conditions of pH 5 or higher.
  • the enteric polymer which can be used in the present invention is at least one selected from the group consisting of an enteric cellulose derivative, an enteric acrylic acid copolymer, an enteric polymethacrylate copolymer, an enteric maleic acid copolymer and an enteric polyvinyl derivative.
  • Cellulose derivatives include hydroxypropylmethylcellulose acetate succinate, hypromellose phthalate (hydroxypropylmethylcellulose phthalate), hydroxymethylethylcellulose phthalate, celluloseacetate phthalate, cellullo Osacetate Succinate, Cellulose Acetate Maleate, Cellulose Benzoate Phthalate Cell Loss Propionate Phthalate, Methyl Cellulose Phthalate, Carboxymethylethyl Cellulose and Ethylhydroxyethyl Cellulose Phthalate, Methyl Hydrate rock From the agarose with ethyl selreul
  • At least one of the selected i-type enteric acrylic acid copolymers may be selected from the group consisting of styrene-acrylic acid copolymer, methyl acrylate-acrylic acid copolymer, methyl methacrylate acrylic acid copolymer (e.g.
  • enteric polymethacrylate copolymer is a poly (methyl methacrylate) copolymer (e.g., Eudragit L, Eudragit S) , Evonik, Germany), one or more selected from poly (ethyl methacrylate) copolymer (e.g.
  • the enteric maleic acid copolymer is vinyl acetate-maleic anhydride copolymer , Styrene maleic anhydride copolymer, styrene maleic acid monoester copolymer, vinyl methyl ether maleic acid At least one selected from an anhydride copolymer, an ethylene-maleic anhydride copolymer, a vinylbutyl ether-maleic anhydride copolymer, an acrylonitrile-methyl acrylate maleic anhydride copolymer, and a butyl-styrene-maleic anhydride copolymer
  • the enteric polyvinyl derivative is at least one selected from polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate and polyvinyl acetal phthalate.
  • the enteric polymer is preferably at least one selected from hydroxypropylmethyl cellulose phthalate or acrylic acid methacrylic acid copolymer.
  • the water insoluble polymer refers to a polymer that is not soluble in pharmaceutically acceptable water that controls the release of the drug.
  • the water-soluble polymers usable in the present invention include polyvinylacetates (eg, colicoat SR30D), water-insoluble polymethacrylate copolymers [eg, poly (ethylacrylate-methyl methacrylate) copolymers (eg, Eudra).
  • NE30D poly (ethyl acrylate- Methyl methacrylate—trimethylaminoethylmethacrylate chloride) copolymers (eg Eudragit RSP0), etc., ethyl cellulose, cellulose ester cellulose ether, cellulose acylate, cellulose dia At least one member selected from the group consisting of silates, cellulose triacylates, cellulose acetate, cellulose diacetate and cellulose triacetate.
  • the water-insoluble polymer is preferably one or more selected from ethyl cellulose, cellulose acetate, and polyvinylacetate.
  • the hydrophobic compound refers to a substance that does not dissolve in pharmaceutically acceptable water that controls the release of the drug.
  • the hydrophobic compounds usable in the present invention are selected from the group consisting of fatty acids and fatty acid esters, fatty acid alcohols, waxes, inorganic substances, and mixtures thereof, and the fatty acids and fatty acid esters are glyceryl palmitostearate, At least one selected from glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and slearinic acid, and the fatty acid alcohols are at least one selected from cetostearyl alcohol, cetyl alcohol and stearyl alcohol.
  • the wax is at least one selected from carnauba wax, beeswax, and microcrystalline wax
  • the inorganic material is selected from talc, precipitated carbonate, calcium hydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite and non-gum. It is one or more selected.
  • the hydrophobic compound is preferably carnauba wax.
  • the hydrophilic polymer refers to a polymeric material that is dissolved in pharmaceutically acceptable water that controls the release of the drug.
  • Hydrophilic polymers that can be used in the present invention Sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl polymers, and mixtures thereof, wherein the sugars are dextrins, polydextrins, At least one selected from dextran, pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose, and amylopectin;
  • the derivative is at least one selected from hydroxypropylcellose, hydroxypropylcelose, hydroxymethylcellose, hydroxyethylcellose, hydroxyethylcellose, methylcellose and carboxymethylcellose sodium.
  • Gum, locust bean gum, tragacanta, carrageenan, acacia gum The at least one protein selected from ruby gum, gellan gum, and xanthan gum is gelatin, casein, and zein at least one polyvinyl derivative selected from polyvinyl alcohol, polyvinyl pyridone, and polyvinyl acetal diethyl.
  • At least one hydrophilic polymethacrylate copolymer selected from aminoacetates may be a poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer (e.g.
  • the polyethylene derivative is at least one selected from polyethylene glycol, polyethylene oxide, and the carboxyvinyl polymer uses carbomer.
  • the hydrophilic polymer is preferably at least one selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyridone, and polyethylene glycol 6000.
  • the osmotic semipermeable membrane coating base is a pharmaceutically usable coating base, which is used in the coating layer of the pharmaceutical formulation to form a membrane which allows some components to pass but does not pass other components.
  • the semipermeable membrane coating base is, for example, polyvinyl acetate, polymethacrylate copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacyl And at least one selected from the group consisting of latex, cellulose acetate, cellulose diacetate, cellulose triacetate, and combinations thereof.
  • the semi-permeable coating agent is preferably at least one selected from ethyl cellulose and cellulose acetate.
  • Osmotic agents are selected from the group consisting of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, lithium sulfate, sodium sulfate, lithium sulfate, sodium sulfate and combinations thereof
  • the release control material is used alone or two or more, 5 to 10,000 parts by weight relative to 100 parts by weight of angiotensin ⁇ ⁇ ⁇ receptor blocker, preferably 20 to 5,000 parts by weight, most preferably 50 ⁇ 3,000 increments are used. At 5 parts by weight or less, it is difficult to have a delayed time, and at 10,000 parts by weight or more, no release of the drug occurs or the delay time exceeds 12 hours.
  • diluents As a pharmaceutically acceptable additive of the delayed-release compartment within the scope of not impairing the effects of the present invention, diluents, binders, disintegrants, lubricants, pH adjusting agents, stabilizers, coloring agents, flavoring agents, surfactants, etc. are suitable. Its content is preferably 100 to 30,000 parts by weight based on 100 parts by weight of the active ingredient.
  • a pharmaceutically acceptable diluent within the scope of not impairing the effects of the present invention sugar, starch, microcrystalline cellulose, lactose, glucose, manny, alginate alkaline earth metal salt, clay, polyethylene glycol and dicalcium phosphate, etc. of Can be used.
  • starch starch, microcrystalline cellulose, highly disperse silica, manny, lactose, polyethylene glycol, polyvinylpyridone, polyvinylpyridone copolymer, hydroxypropyl methylcellose, hydroxypropylcell Acetic acid, natural gum synthetic gum, gelatin and the like can be used.
  • Starch or modified starch such as sodium starch glycolate, potato starch or pregelatinized starch, clays such as bentonite, montmorillonite, veegum, and microcrystalline cellulose low-substituted hydroxypropyl cellulose as disintegrants Or crosslinked cells such as alginic acid and croscarmellose sodium, gums such as guar gum xanthan gum, crosslinked polymers such as crospovidone, and effervescent agents such as sodium bicarbonate and citric acid. It can be used in combination.
  • clays such as bentonite, montmorillonite, veegum, and microcrystalline cellulose low-substituted hydroxypropyl cellulose as disintegrants
  • crosslinked cells such as alginic acid and croscarmellose sodium
  • gums such as guar gum xanthan gum
  • crosslinked polymers such as crospovidone
  • effervescent agents such as sodium bicarbonate and citric acid. It
  • lubricants examples include talc, stearic acid, magnesium stearate, stearic acid calum, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostearate, and glyceryl palmi.
  • Tostearate colloidal silicon dioxide polyethylene glycol 4000 or a combination thereof may be used, and pharmaceutically acceptable additives may be selected and used as various additives selected from pH adjusting agents, stabilizers, surfactants, colorants, and flavoring agents.
  • microcrystalline cellulose pregelatinized starch, polyvinylpyridone copolymer, colloidal silicon dioxide, stearic acid magnesium and the like are used. It is not limited, and the above additives may contain a conventional range of dosages by the choice of those skilled in the art. Pharmaceutically, except for the active ingredient constituting the pre-release compartment
  • acceptable additives diluents, binders, disintegrants, lubricants, pH adjusting agents, stabilizers, coloring agents, flavoring agents, surfactants and the like are suitable, and the content thereof is preferably 100 to 30,000 parts by weight based on 100 parts by weight of the active ingredient.
  • Sugar, starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol and decalum phosphate may be used as a pharmaceutically acceptable diluent within the scope of not impairing the effects of the present invention. Can be.
  • Starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch as a disintegrating agent, clays such as bentonite, montmorillonite, veegum, microcrystalline cellulose and low-substituted hydroxypropyl and agarose or alginate in selreul, croscarmellose (croscarmellose) and a cross-linked selreul agarose acids such as sodium and gums such as guar gum, xanthan gum, cross-povidone (crospovidone), the cross-linked polymer such as, sodium bicarbonate, citric acid, etc. Can be used in combination.
  • clays such as bentonite, montmorillonite, veegum, microcrystalline cellulose and low-substituted hydroxypropyl and agarose or alginate in selreul, croscarmellose (croscarmellose) and a cross-linked selreul agarose acids
  • talc As lubricants, talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostearate, glyceryl palmi Tostearate, colloidal silicon dioxide, polyethylene glycol 4000, or a combination thereof may be used, and pharmaceutically acceptable additives may be selected as various additives selected from pH adjusters, stabilizer surfactants, and colorant flavors.
  • lactose lactose, microcrystalline cellulose, Corn starch, pregelatinized starch, polyvinylpyridone copolymer, sugar, hydroxypropylmethylcellose, hydroxypropylcellose, low-substituted hydroxypropylcellose, colloidal silicon dioxide, magnesium stearate, etc.
  • the scope of the present invention is used is not limited to the use of the additives, the additives may contain a conventional range of capacity by the choice of those skilled in the art.
  • the formulation may form a film-like coating layer on the outer surface of the tablet, if necessary. That is, the thiazide compound / angiotensin ⁇ ⁇ receptor blocker composite composition of the present invention can be used in the form of uncoated tablets without a coating layer, to form a coating layer on the surface of the tablet containing the active ingredient to be formulated into a coated tablet. In this case, there is an advantage of further securing the stability of the active ingredient.
  • the method of forming the coating layer can be appropriately selected by a person skilled in the art from the method of forming a film-like coating layer on the surface of the tablet layer using the above-described components, and can be applied to methods such as a fluidized bed coating method and a fan coating method. Can be. It is preferable to use a pan coating method.
  • the coating layer may be a coating agent, a coating aid or a combination thereof.
  • the coating layer may be used as a coating agent, such as cellulose derivatives, sugar derivatives, polyvinyl derivatives, waxes, fats, gelatin, and the like.
  • a coating agent such as cellulose derivatives, sugar derivatives, polyvinyl derivatives, waxes, fats, gelatin, and the like.
  • the polyethylene glycol, ethyl cellulose, glycerides, titanium oxide, diethyl phthalate and the like one or two or more kinds thereof may be used.
  • the coating layer is preferably included in the range of 0.5 to 15% by weight of the total weight of the tablet.
  • an angiotensin ⁇ ⁇ receptor blocker is used in one or two or more release control substances selected from enteric polymers, water insoluble polymers, hydrophobic compounds, hydrophilic polymers, osmotic semipermeable membrane coating bases and osmotic agents, and pharmaceutically. It is a step of obtaining a composition designed to enable delayed release in combination with conventional additives.
  • the second step is to use the particles, granules and pellets as they are obtained through the usual procedures for producing oral solids such as mixing, coalescing, drying and granulation from thiazide compounds and conventional pharmaceutically acceptable additives or It is a step of obtaining a composition designed to be capable of pre-release using particles, granules, pellets coated using a coating solution dissolved or suspended with a film coating agent.
  • the third step is to obtain a delayed-release oral combination using a composition designed to be delayed-release and a composition designed to be prior-release obtained in each of steps 1 and 2.
  • the particles, granules or pellets obtained in the first step may be used as is or in an enteric polymer, a water-insoluble polymer or a hydrophobic compound, a hydrophilic polymer, or an osmotic semipermeable membrane.
  • Tablets are prepared by coating with a release controlling substance comprising one or two or more selected from a coating base and an osmotic agent, then mixing with the granules prepared in the second step and tableting to a certain amount of weight.
  • the obtained tablet can be film-coated as necessary for the purpose of improving stability or properties.
  • a release controlling substance comprising particles, granules, pellets or tablets obtained in the first step comprising an enteric polymer, a water-insoluble polymer, a hydrophobic compound, a hydrophilic polymer, an osmotic semipermeable membrane coating base, and an osmotic agent.
  • the outer layer may be coated with a coating solution containing the drug obtained in the second step to prepare a film coated tablet. All. Multilayer Tablet Preparation
  • the particles, granules and pellets obtained in the first step may be used as they are or as an emission control material comprising at least one selected from an enteric polymer, a water insoluble polymer, a hydrophobic compound, a hydrophilic polymer, an osmotic semipermeable membrane coating base, and an osmotic agent.
  • the granules and pellets obtained in the second step may be added to prepare double tablets using a multilayer tablet press. If necessary, a triple layer or more multilayered tablets may be prepared or coated by adding an emission auxiliary layer to prepare a coated multilayer tablet.
  • the tablet obtained in the sieve step 1 is used as an inner core tablet, and the enteric polymer and the water insoluble Coating with a release control material comprising one or more selected from polymers, hydrophobic compounds, hydrophilic polymers, osmotic semipermeable membrane coating bases, and osmotic agents, and then using a nucleated tablet press with granules obtained in the second step.
  • Nucleated tablets can be prepared or coated to produce coated nucleated tablets. hemp.
  • the particles, granules and tablets obtained in the first step may be used as they are or as an emission control material comprising at least one selected from an enteric polymer, a water insoluble polymer, a hydrophobic compound, a hydrophilic polymer, an osmotic semipermeable membrane coating base, and an osmotic agent.
  • Coated and dried granules, pellets, tablets and granules and tablets obtained in the second step can be put into the capsule layer electrophoresis layered capsule to a certain size capsule by the effective amount of the footnote component. bar.
  • Angiotensin ⁇ ⁇ receptor blockers and release control substances or pharmaceutically acceptable additives are dissolved or suspended in water or organic solvents or mixed solvents, coated on sugar spherical granules, dried and, if necessary, enteric polymers, water insoluble polymers, hydrophobic
  • the release control material comprising one or two or more selected from a compound, a hydrophilic polymer, an osmotic semipermeable membrane coating base, and an osmotic agent is dissolved in water, an organic solvent or a mixed solvent, coated, dried, and then obtained in the second step.
  • Pellets coated with the coating liquid may be layered as they are on the capsule, or a capsule may be layered after film coating. Also, do the above.
  • Delayed-release granules, pellets, Tablets, pre-release granules, pellets, and tablets can be mixed with each other to produce delayed-release (pre-release) granules, granules-pellets, granules-tablets, pellets-granules, tablets-granules. four. Manufacture of kit
  • the angiotensin-containing receptor blocker preparation obtained in the first step and the zigzide compound-containing preparation obtained in the second step can be prepared as a kit that can be simultaneously layered on a foil, a blister or a bed.
  • the complex drug system of the present invention as described above is formulated with a compound containing an ziazide-based compound and angiotensin ⁇ ⁇ ⁇ receptor blocker as an active ingredient, and is administered only once a day in the morning hours to separately formulate each active ingredient.
  • Angiotensin® ⁇ ⁇ Receptor Blocker Delayed-Release Inner Core Tablets Angiotensin ⁇ ⁇ ⁇ Receptor Blocker Delayed-release inner core tablets were prepared in the following compositions and contents as shown in Table 4 with potassium losartan, microcrystalline cellulose, pregelatinized starch, polyvinylpyrrolidone copolymer, and colloidal silicon dioxide * 35. Sieve and mix for 5 minutes with a high-speed mixer to prepare a mixture. After adding magnesium stearate to the mixture, mix for 4 minutes, and use the rotary tableting machine (MRC-33: Sejong) to tablet the species mixture.
  • MRC-33 Sejong
  • the inner core tablet thus prepared was introduced into a high coater (SFC-30N: Sejong Machinery, South Korea), and hydroxypropylmethylcell was dissolved and dispersed in cellulose and acrylic acid methacrylic acid copolymer (acrylate) to be delayed as a coating solution. Ejective inner core tablets were prepared.
  • Preparation of the thiazide compound-releasing layer was carried out in a No. 35 sieve with hydrochlorothiazide, microcrystalline cellulose, lactose, corn starch, and low-substituted hydroxypropyl cellulose with the composition and contents shown in Table 4. Mix for minutes to prepare the mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution. Preferably fluid bed granulators are used. The fluid bed granulator used GPCG-l (Glatt, Germany).
  • the granulated material is dried in a fluidized bed dryer or a hot water dryer.
  • a fluid bed dryer Preferably use a fluid bed dryer.
  • Fluid bed granulation drier was used GPCG-l (Glatt, Germany).
  • the dry matter is established using an oscillator equipped with a No. 18 body. Add colloidal silicon dioxide to the formulation and mix with a double cone mixer. Magnesium stearate was added to the above mixture and finally mixed with a double cone mixer. 3) tableting and coating
  • nucleated tablet tableting machine (RUD-1: Kilian) to make the losartan inner core tablet as the inner core tablet and the composition containing the thiazide compound as the outer layer
  • hydroxypropylmethylcellose was separately prepared.
  • 2910, titanium oxide and talc were prepared by dissolving and dispersing a coating solution in 80% ethanol.
  • the above nucleated tablets were put into a high coater (SFC-30N: Sejong Machinery, Korea) and then coated with a coating solution to complete coating nucleated tablets.
  • SFC-30N Sejong Machinery, Korea
  • angiotensin ⁇ ⁇ receptor blocker delayed-release layer was prepared by sieving potassium losartan, microcrystalline cellulose, sodium starch glycolate, and lactose into a No. 35 sieve with a composition and content as shown in Table 6, followed by mixing for 5 minutes using a high speed mixer. Prepare the mixture. Separately, hydroxypropylcell is dissolved, dispersed in hydroxypropylcell, and cellulose phthalate (HP-50), which is combined, granulated and dried. The dried product was placed in a fluidized bed coater, and a solution of hydroxypropylcellulose phthalate (HP-55) and polyethylene glycol 6000 in 220 mg of ethane and 980 mg of methylene chloride was prepared.
  • Preparation of the thiazide-based compound pre-release layer was sieved through the hydrochloricitate, microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer, colloidal silicon dioxide with No. 35 in a composition and content as shown in Table 6. By mixing for 5 minutes to prepare a mixture. After the stearic acid magnesium was added to the mixture, the mixture was finally mixed with a double cone mixer for 4 minutes.
  • MRC-37T Sejong Tablet using a multi-layer tablet press
  • the pre-release layer composition containing the ziazide-based compound was placed in the primary powder feeder, and the delayed-release layer composition containing the angiotensin ⁇ ⁇ receptor receptor was placed in the secondary powder feeder, and the tableting was performed under conditions that minimize the infiltration of the layers. do.
  • hydroxypropylmethylcellose 2910, hydroxypropylcelose, hydroxypropylcellose, titanium oxide, and talc were prepared by dissolving and dispersing in 803 ⁇ 4 ethanol.
  • Example 23 Film Coated Tablet Preparation
  • potassium losartan, microcrystalline cellulose, sodium starch glycolate and lactose were sieved through a No. 35 sieve and mixed with a high speed mixer for 5 minutes to prepare a mixture.
  • hydroxypropylcell and hydroxypropylcell are dissolved in purified water and dissolved in purified water to combine, granulate and dry.
  • the dried material was placed in a fluidized bed coater, and a solution obtained by dissolving hydroxypropylcellulose phthalate (HP-55) and polyethylene glycol 6000 in 220 mg of ethane and 980 rag of methylene chloride was prepared. -1: Glatt, Germany) and coated. After the coating was completed, the colloidal silicon dioxide was added and mixed, followed by the addition of stearic acid magnesium, followed by mixing for 4 minutes to prepare angiotensin ⁇ receptor receptor delayed-release granules.
  • hydrochlorothiazide, hydroxyspecific propylmethylcellose 2910, hydroxypropylcelose, titanium oxide, and talc were dissolved and dispersed in 80% ethanol to form a pre-release coating solution containing a thiazide compound.
  • Film coated tablet preparation comprising angiotensin ⁇ receptor receptor delayed release layer and a pre-release layer of a cyanide compound
  • angiotensin ⁇ ⁇ ⁇ receptor blocker delayed-release granules of 1) were compressed into tablets using a rotary tablet press, tableting tablets were injected into a high coater (SFC-30N: Sejong Machinery, Korea) and then 2) ziazide System-based pre-release coating solution The coating was completed to prepare a delayed-release compartment in the form of a film-coated tablet including an angiotensin ⁇ ⁇ ⁇ receptor blocker delayed-release layer and a thiazide compound pre-release layer.
  • Example 24 Preparation of Capsules (Granules-Particles)
  • potassium losar, microcrystalline cellulose, sodium starch glycolate and lactose were sieved through a No. 35 sieve and mixed for 5 minutes using a high speed mixer to prepare a mixture.
  • hydroxypropylcell and hydroxypropylcell are dissolved in purified water and dissolved in purified water to combine, granulate and dry.
  • the dried product was placed in a fluidized bed coater, and a liquid obtained by dissolving hydrated propyl cellulose (HP-55) and polyethylene glycol 6000 in 220 mg of ethanol and 980 mg of methylene chloride was prepared. 1: Glatt, Germany) and coated. After the coating was completed, the colloidal silicon dioxide was added and mixed, followed by the addition of stearic acid magnesium, followed by mixing for 4 minutes to prepare angiotensin ⁇ receptor receptor delayed-release granules.
  • hydrochlorothiazide, microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer, colloidal silicon dioxide were sieved through a No. 35 sieve and mixed for 5 minutes with a high speed mixer to prepare a mixture.
  • irbesartan, lactose, croscarmellose sodium and sodium chloride were sieved through a No. 35 sieve and mixed for 5 minutes using a high speed mixer to prepare a mixture.
  • pregelatinized starch and poloxamer 188 were dissolved in purified water to form a binder, and then combined and dried.
  • the dried material was placed in a fluidized bed coater, and separately cellulose acetate (32% acetyl), cellulose acetate (39.8% acetyl), and hydroxypropylmethylcellose were dissolved in 220 mg of ethanol and 980 mg of methylene chloride, and Dispersed coating solution was prepared and the above granules were put in a fluidized bed granulation coater (GPCG- 1: Glatt, Germany) and coated.
  • Angiotensin ⁇ ⁇ ⁇ receptor blocker delayed-release granules were prepared by adding microcrystalline cells to the coating and adding colloidal silicon dioxide.
  • the zigzide compound hydrochlorothiazide and the excipient microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer, and colloidal silicon dioxide were sieved through a No. 35 sieve and mixed with a high speed mixer.
  • a biphasic matrix tablet was prepared with the composition and content shown in Table 7 according to the same biphasic matrix tablet manufacturing method as in Example 25.
  • Example 28 Preparation of Capsules (Pellets-Granules)
  • the sugar seeds were sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellose and losartan potassium were separately added to water and ethane.
  • the dissolved binder solution was sprayed to form pellets containing angiotensin® receptor blocker.
  • the granules were then sprayed with a solution of hydroxypropyl methylcellulose phthalate dissolved in 220 mg of ethane and 980 mg of methylene chloride to prepare angiotensin® receptor receptor blocker delayed-release pellets.
  • the thiazide compound pre-release layer is as shown in Table 8 Hydrochlorothiazide, microcrystalline cellulose, lactose, corn starch, low-substituted hydroxypropyl cellulose were added, sieved through a No. 35 sieve, and mixed in a double cone mixer for 5 minutes to prepare a mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution. Preferably fluid bed granulators are used. The fluid bed granulator used GPCG-l (Glatt, Germany).
  • the granulated material is dried in a fluidized bed dryer or a hot water dryer.
  • a fluid bed dryer is used.
  • Fluid bed granulation dryer was used GPCG-l (Glatt, Germany).
  • the dry matter is established using an oscillator equipped with a No. 18 body. Colloidal silicon dioxide is added to the formulation and mixed with a double cone mixer.
  • the sugar sphere was sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellose and iprosartan were separately added to water and ethanol.
  • the dissolved binder solution was sprayed to form pellets containing angiotensin ⁇ i receptor receptor blocker and dried. Again, 220 mg of ethane and methylene chloride with hydroxypropylmethylcelloseophthalate were added to the granules.
  • Angiotensin-? Receptor receptor blocker delayed-release pellets were prepared by spraying a solution dissolved in 980 mg.
  • the sugar seeds were sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcell was dissolved in water and ethanol. The solution was sprayed and dried to form a thiazide compound pre-release pellet.
  • GPCG 1 Glatt
  • sugar spheres were sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and then hydroxypropylmethylcellose and candesartan were dissolved separately in water and ethanol.
  • the binder solution was sprayed to form pellets containing angiotensin ⁇ i ⁇ receptor blocker and dried.
  • the back angiotensin eu ⁇ eu receptor blocker delayed-release pellets by spraying a liquid obtained by dissolving the ethane agarose phthalate with hydroxypropyl methylcellulose selreul in the granules through 220m g and 980 mg of methylene chloride was prepared.
  • the zigzide compound hydrochlorothiazide and the excipient microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer and colloidal silicon dioxide were sieved through a No. 35 sieve and mixed with a high speed mixer. Magnesium stearate was added to this mixture and finally mixed. The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare a thiazide compound-release tablet.
  • the angiotensin ⁇ ⁇ receptor blocker delayed-release granules were sieved with oligosarthan medoxomil microcrystalline cell as No. 35 and mixed with a high speed mixer as shown in Table 8. Colicoat SR30D was associated with the main component mixture. After the union is completed, the granules are granulated by using an oscillator in No. 18 and dried in a fluid bed dryer or a hot water dryer. Preferably a fluid bed dryer is used. Fluid bed granulation dryer was used GPCG-l (Glatt, Germany). When the drying was completed, it was reestablished as No. 20 sieve to prepare angiotensin ⁇ ⁇ receptor receptor delayed-release granules. 2) Preparation of Chiazide Compound Pre-Release Granules
  • the thiazide-based compound pre-release layer was sieved with hydrochlorothiazide, microcrystalline cellulose, lactose, corn starch, low-substituted hydroxypropyl cellulose, and sieved through a No. 35 sieve. Combine to produce the mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution. Preferably fluid bed granulators are used. The fluid bed granulator used GPCG-l (Glatt, Germany).
  • the granulated material is dried in a fluidized bed dryer or a hot water dryer.
  • a fluid bed dryer is used.
  • the fluid bed granule dryer used GPCG-1 (Glatt; Germany).
  • the dry matter is established using an oscillator equipped with a No. 18 body. Add colloidal silicon dioxide to the formulation and mix with a double cone mixer.
  • Angiotensin ⁇ ⁇ ⁇ Receptor blocker delayed-release granules were sieved through a No. 35 sieve with valsartan, microcrystalline cellulose, cross-linked polyvinylpyridone, and mixed in a double cone mixer for 5 minutes, as shown in Table 8, to prepare a mixture.
  • do. seperately Polyvinylpyridone is dissolved in purified water to prepare a binding solution.
  • the mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution.
  • fluid bed granulators are used.
  • the fluid bed granulator used GPCG - l (Glatt; Germany).
  • the granules are dried in a fluid bed dryer or a silver dryer.
  • a fluid bed dryer is used.
  • Fluid bed granulation dryer was used GPCG-l (Glatt, Germany).
  • the granules were sprayed with carnauba wax ethane dissolved in 220 mg of ethane and 980 mg of methylene chloride to prepare angiotensin ⁇ receptor blocker delayed-release granules.
  • sugar spheres were sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellose and hydrochlorothiazide were dissolved separately in water and ethane.
  • the binder solution was spray dried to form a thiazide compound pre-release pellet.
  • Angiotensin _ ⁇ receptor blocker delayed-release granules are shown in Table 8.
  • telmisartan, microcrystalline cellulose, and meglumine were added, sieved through a No. 35 sieve, and mixed in a double cone mixer for 5 minutes to prepare a mixture.
  • Solbi, polyvinylpyridone, and sodium hydroxide are dissolved in purified water to prepare a binding solution.
  • the mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution.
  • fluid bed granulators are used. Fluid bed granulator (GPCG-KGlatt, Germany) was used.
  • the granulated material is dried in a fluidized bed dryer or a hot water dryer.
  • a fluid bed dryer is used.
  • Fluid bed granulation drier was used GPCG-l (Glatt, Germany).
  • the granules were sprayed again with carnauba wax dissolved in 220 mg of ethanol and 980 mg of methylene chloride, thereby preparing angiotensin ⁇ ⁇ ⁇ receptor blocker delayed-release granules.
  • zigzide compound hydrochlorothiazide and excipient microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer, colloidal silicon dioxide were sieved through a No. 35 sieve and mixed with a high speed mixer. Magnesium stearate was added to this mixture and finally mixed. The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare a thiazide compound-release tablet.
  • angiotensin ⁇ ⁇ receptor blocker delayed-release tablets were sieved through Losartan potassium, microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer, and colloidal silicon dioxide with No. 35.
  • the mixture is prepared by mixing in a mixer for 5 minutes. After adding magnesium stearate to the mixture, mix for 4 minutes and tablet the final mixture using a rotary tablet press (MRC-33: Sejong).
  • the tablet thus prepared is put into a high coater (SFC-30N: Sejong Machinery, Korea).
  • the tablet was sprayed with a solution of polyethylene glycol 6000 and hydroxypropyl methylcellose phthalate in 220 mg of ethanol and 980 mg of methylene chloride to prepare an angiotensin receptor blocker delayed-release tablet.
  • the thiazide compound pre-release layer was sieved with hydrochlorothiazide, microcrystalline cellulose, lactose, corn starch, low-substituted hydroxypropyl cellulose and sieved through a No. 35 sieve, and then shaken for 5 minutes in a double cone mixer. Combine to produce the mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high speed granulator and granulated by adding a binder solution. Preferably fluid bed granulators are used. The fluid bed granulator used GPCG-l (Glatt, Germany).
  • the granules are dried in a fluid bed dryer or a silver dryer.
  • a fluid bed dryer is used.
  • Fluidized bed granulation dryers are available from GPCG-l (Glatt, Germany). Used.
  • the dry matter is established using an oscillator equipped with a No. 18 body. Colloidal silicon dioxide is added to the formulation and mixed with a double cone mixer.
  • Angiotensin ⁇ ⁇ receptor blocker delayed-release tablets were sieved through valsartan, microcrystalline cellulose, and crosslinked polyvinylpyridone as No. 35, and mixed for 5 minutes using a high-speed mixer to prepare a mixture. .
  • polyvinylpyridone is dissolved in purified water to prepare a binding solution.
  • the mixture is put into a fluidized bed granulator or a high speed granulator and granulated by adding a binder solution.
  • fluid bed granulators are used.
  • the fluid bed granulator used GPCG-l (Glatt, Germany). After the assembly is completed, the granulated material is dried in a fluidized bed dryer or a hot water dryer.
  • a fluid bed dryer is used.
  • GPCG-l (Glatt, Germany) was used for the evaporated granule dryer.
  • the dry matter is established using an oscillator equipped with a No. 18 body.
  • Magnesium stearate is added to the formulation and finally mixed with a double cone mixer.
  • the final mixture is compressed using a rotary tablet press (MRC-33: Sejong).
  • the tablet thus prepared is put into a high coater (SFC-30N: Sejong Machinery, Korea).
  • SFC-30N Sejong Machinery, Korea.
  • Angiotensin-? Receptor receptor blocker delayed-release tablets were prepared by spraying a solution of hydroxypropylmethylcelloose phthalate in 220 mg of ethanol and 980 mg of methylene chloride.
  • the sugar spheres were sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose and hydrochlorothiazide were dissolved separately in water and ethanol. The liquid was spray dried to form a thiazide compound pre-release pellet.
  • GPCG 1 Glatt
  • steps 1) and 2) were combined with a double cone mixer.
  • the mixture was placed in a powder feeder and filled using capsule bed electricity to complete the preparation of the controlled release formulation in capsule form.
  • Angiotensin ⁇ ⁇ ⁇ receptor blocker delayed-release tablets were sieved with telmisartan, microcrystalline cellulose, and meglumine as No. 35, and then mixed with a No. 35 sieve for 5 minutes in a double cone mixer to prepare a mixture. .
  • sorbetle, polyvinylpyridone, and sodium hydroxide are dissolved in purified water to prepare a binding solution.
  • the mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution.
  • fluid bed granulators are used. Fluid bed granulator (GPCG-KGlatt, Germany) was used.
  • Fluidized dryer or after assembly Dry the assembly in a hot water dryer.
  • a fluid bed dryer is used.
  • Fluid bed granulation dryer was used GPCG ⁇ l (GIatt, Germany).
  • the dry matter is established using an oscillator equipped with a No. 18 body.
  • Magnesium stearate is added to the formulation and finally mixed with a double cone mixer.
  • the final mixture is compressed using a rotary tablet press (MRC-33: Sejong).
  • the tablet thus prepared is put into a high coater (SFC-30N: Sejong Machinery, Korea).
  • angiotensin _ ⁇ ⁇ receptor blocker delayed-release tablet To the above tablets, a solution of ethylcellose and methacrylic acid co-polymer type C dissolved in 220 mg of ethanol and 980 mg of methylene chloride was sprayed to prepare angiotensin _ ⁇ ⁇ receptor blocker delayed-release tablet.
  • ziazide-based compound hydrochlorothiazide and excipient microcrystalline cellulose, pregelatinized starch, polyvinylpyridone co-polymer, and colloidal silicon dioxide were sieved through a No. 35 sieve and mixed with a high speed mixer. Stearic acid magnesium was added to this mixture for final mixing. The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare a thiazide compound-release tablet.
  • a rotary tableting machine (MRC-33: Sejong).
  • MRC-33 Sejong
  • ethylcellose was dispersed in purified water, and then coated with an inner core tablet using a high coater (SFC-30N, Sejong Machinery, Korea) to prepare an osmotic inner core tablet.
  • thiazide compound-release layer Preparation of the thiazide compound-release layer was carried out with hydrochlorothiazide, microcrystalline cellulose, lactose, corn starch, low-substituted hydroxylpropyl cellulose as shown in Table 9 and sieved through No. 35 sieve for 5 minutes in a double cone mixer. Are mixed to produce the mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution. Preferably fluid bed granulators are used. The fluid bed granulator used GPCG-l (Glatt, Germany).
  • fluid bed dryers Preferably fluid bed dryers are used. Fluid bed granulation drier was used GPCG-l (Glatt, Germany).
  • GPCG-l Gelatt, Germany.
  • the dry matter is established using an oscillator equipped with a No. 18 body. Add colloidal silicon dioxide to the formulation and mix with a double cone mixer. Magnesium stearate was added to the above mixture, and the final mixture was mixed with a debulcon mixer.
  • Osmotic nucleated tablets were prepared according to the composition and contents of Table 9 according to the same method for preparing the osmotic nucleated tablets as in Example 37.
  • Example 40 Blaster Packaging Kit
  • Example 15 The granules of Example 15, Step 1) and Example 15, Step 2) of Example 15 instead of mixing 1) angiotensin ⁇ i ⁇ receptor blocker delayed-release granules of Example 15 and 2) thiazide-based compound prior-release granules
  • the final composition of each process was compressed into tablets using a rotary tablet press (MRC-33: Sejong) and packaged for simultaneous use in a blister packaging container.
  • composition ratio (mg / t ablet)
  • Irbesi-Letan 150 Valsartan 80 Microcrystalline Cellulose 150 100 25 137 123 40 75 Sodium starch glycolate 8 8
  • Collicoat SR 30D (ingredient name: 30% suspension of polyvinyl acetate, bran 1: BASF) Table 71
  • the hydrochlorothiazide component of the nucleated tablet of the present invention was found to have almost the same elution characteristics as that of the control preparation dichroic tablet in the dissolution test, but the losartan component was very delayed in dissolution compared to the control agent Koza. You can check the speed.
  • the dissolution of the losartan component up to 120 minutes which is the artificial gastric juice section, was found to be within 10% of the nucleated tablet of losartan / hydrochlorothiazide of the present invention, but the control agent was about 60%.
  • the loss of losartan in the artificial serous section Elution was 100% in the total 150 minutes in the control agent, it was confirmed that much slower to about 2 in 240 minutes in the nucleated tablet functional combination of losartan / hydrochlorothiazide of the present invention.
  • the nucleated tablet formulation of losartan / hydrochlorothiazit of the present invention is different from the dissolution of the losartan monotherapy and the hydroclohozigit single agent, so that the initial release of losartan is much slower than hydrochlorothiazit. It is a pharmaceutical composition that is very effective in treating hypertension because it can be injected at the time when the secondary blood pressure lowering effect occurs. [Test Method of Thiazide-Based Compound Pre-Emission Layer]
  • Dissolution test basis Test method for 'hydrochlorothiazide purification' in USP 30: Apparatus 1 [Paddle method], 100 revolutions / minute
  • Test solution 0. IN—hydrochloric acid, 900 mL
  • Dissolution test basis Dissolution test method of General Test Method
  • Test Method Paddle Method, 50 Turns / Min
  • Test drug 0.1M hydrochloric acid solution, 750mL (artificial gas solution)
  • Experimental Example 2 Comparative Dissolution Profile Test The comparative dissolution test of the losartan / hydrochlorothiazide inner core tablet prepared in Example 2 and the composite control (coza plus tablet, MSD: losartan / hydrochlorothiazide composite) were carried out. . Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
  • hydrochlorothiazide component of the nucleated tablet of the present invention exhibited faster dissolution characteristics when compared to the control formulation Coza plus tablet when the dissolution test was carried out under the conditions of Experimental Example 1, but the hydrochlorothiazide elution of Coza plus tablet was the single agent or the present invention.
  • hydrochlorothiazide is affected by losartan, which has a slow elution rate in acid, because it is a simple complex without division. Elution rates are different from those of monoliths. In order to achieve the best effect of hydrochlorothiazide, it is necessary to show a fast dissolution rate similar to that of a single agent, not the delayed dissolution rate of a simple combination.
  • Losartan component can confirm a very delayed dissolution rate as in Experimental Example 1 compared to the control formulation Coza Plus.
  • the nucleated tablet formulation of losartan / hydrochlorothiazit of the present invention has a faster release rate of hydrochlorothiazit than Cozaplus, unlike the dissolution of the case of simultaneous administration of the losartan / hydrochlorothiazit simple combination without a compartment, which is a reference. Since the initial release is much slower than hydrochlorothiazide, it can be applied at the time when the second hypotensive effect of hydrochlorothiazide occurs, which is a very effective pharmaceutical composition for the treatment of hypertension.
  • Experimental Example 3 Comparative Dissolution Profile Test The comparative dissolution test of Examples 5 to 8 was performed. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
  • the nucleated tablet formulation of losartan / hydrochlorothiazide of the present invention can delay the initial release of losartan by an intended time by controlling the amount of ethylcell used in the coating. Therefore, losartan can be injected at the time when the second hypotensive effect of hydrochlorothiazide occurs. It is a very effective pharmaceutical composition for the treatment of hypertension.
  • Experimental Example 4 Comparative Dissolution Profile Test The comparative dissolution test of Examples 7 and 9 to 11 was performed. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
  • the nucleated tablet of the present invention has a delay time until the intended time of the lossartan component when polyvinylpyridone is present in the delayed release layer coated with ethylcellose. After it was confirmed that the release is relatively rapid. The dissolution of the losartan component was within 20% for a total of 240 minutes, and the losartan component was rapidly released as the amount of the polyvinylpyridone was increased.
  • the nucleated tablet formulation of losartan / hydrochlorothiazide of the present invention rapidly releases losartan after having a delay time until the intended time by controlling the amount of polyvinylpyrrolidone used in the delayed release layer coated with ethylcellose. You can. Therefore, losartan can be added at the time when the secondary blood pressure lowering effect of hydrochlorothiazide occurs, which is a very effective pharmaceutical composition for the treatment of hypertension.
  • Experimental Example 5 Comparative dissolution profile test The comparative dissolution test of the losartan / hydrochlorothiazide multilayer tablet and the composite control (coza plus F tablet, MSD: losartan / hydrochlorothiazide complex) prepared according to Example 15 was carried out. It was. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
  • Losartan component can confirm a very delayed dissolution rate as in Experimental Example 1 compared to the coza plus F tablets.
  • the multi-layered tablet formulation of losartan / hydrochlorothiazit of the present invention exhibits a faster release rate of hydrochlorothiazit than Coza plus F tablet, unlike the dissolution of co-administration of losartan / hydrochlorothiazide simple combination without a compartment. Since the initial release of losartan is much slower than hydrochlorothiazit, it can be applied at the time of the second hypotensive effect of hydrochlorothiazide, which is a very effective pharmaceutical composition for the treatment of hypertension.
  • Experimental Example 6 Comparative dissolution profile test Losartan / hydrochlorothiazide multilayer tablet prepared according to Example 16 and each component mono-control (coza-crystal, MSD: Losartan mono-I dichroic tablet, finite positive: hydrochlorothiazide Comparative dissolution test of a single agent) was performed.
  • the dissolution test method for each component is the same as in Experimental Example 1, and the nodules thereof are shown in FIG. 6.
  • the hydrochlorothiazide component of the multi-layered tablet of the present invention was almost equivalent to that of the control drug dichromatin tablet. It was confirmed that the dissolution characteristics, but the losartan component was confirmed to be very delayed dissolution rate compared to the control agent Koza.
  • the multi-layered tablet of losartan / hydrochlorothiazide of the present invention has a secondary blood pressure of hydrochlorothiazit because the initial release of losartan is much slower than that of hydrochlorothiazide, unlike the dissolution of co-administration of losartan monotherapy and hydrochlorothiazine monotherapy. It is a pharmaceutical composition that can be injected at the time of the lowering effect and is very effective in treating hypertension.
  • Experimental Example 7 Comparative dissolution profile test Valsartan / hydrochlorothiazide multilayer tablet prepared according to Example 20 and each component monotherapy control (dioban tablet, MSD: Valsartan monosaccharide I dichroic tablet, finite positive: hydrochlorothiazine monolith) A comparative dissolution test of was conducted. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG. According to FIG. 7, in the dissolution test under the conditions of Experimental Example 1, the hydrochlorothiazide component of the multi-layered tablet of the present invention was found to exhibit almost the same dissolution characteristics as that of the control, dichroic tablet, but the valsartan component was compared with the diovan, the control formulation.
  • the dissolution rate of the valsartan component in the artificial serous section was found to be much slower in the valsartan / hydrochlorothiazit of the present invention, about 20% in 240 minutes in total, compared to the control agent.
  • the multi-layered tablet formulation of valsartan / hydrochlorothiazide of the present invention has a secondary blood pressure lowering effect of hydrochlorothiazit because the initial release of valsartan is much slower than that of hydrochlorothiazide, unlike the dissolution of the valsartan monohydrochloride and the hydrochlorothiazide monotherapy simultaneously. Occurring It can be added at a point in time is a very effective pharmaceutical composition for treating hypertension.
  • Experimental Example 8 Comparative dissolution profile test ((X) mparative dissolution profile test) Irbesartan / hydrochlorothiazit multilayer tablets prepared according to Example 21 above and each component monoclonal control drug (Aprobel tablet, MSD: Irbesartan monosaccharide I Dike Rosin tablet, Yuhan Corporation: A comparative dissolution test of hydrochlorothiazide single agent) was performed. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
  • the hydrochlorothiazide component of the multi-layered tablet of the present invention was found to exhibit almost the same dissolution characteristics as that of the control, dichroic tablet, and the Irbesartan component was a control formulation. Compared with Diovan, we found very delayed dissolution rate. According to the dissolution test results of the irbesartan component, the dissolution rate of the irbesartan component in the artificial serous section was about 20% in 240 minutes in the multi-layered functional complex of irbesartan / hydrochlorothiazide of the present invention, unlike the control agent. It was confirmed that much slower.
  • the multi-layered tablet formulation of irbesartan / hydrochlorothiazide of the present invention is obtained when the irbesartan single agent and the hydrochlorothiazit single agent are simultaneously administered.
  • the initial release of irbesartan is much slower than hydrochlorothiazide, so it can be injected at the time of the secondary hypotensive effect of hydrochlorothiazide, which is a very effective pharmaceutical composition for the treatment of hypertension.
  • the film-coated tablets or capsules of losartan / hydrochlorothiazit of the present invention are different from the dissolution of the losartan monohydrochloride and the hydrochlorothiazine monoclonal drug, and thus the initial release of losartan is much slower than that of hydrochlorothiazide. It is a pharmaceutical composition that is very effective in treating hypertension because it can be injected at the time when the primary blood pressure lowering effect occurs.
  • Experimental Example 10 Comparative dissolution profile test Telmisartan / hydrochlorothiazit biphasic matrix tablets prepared according to Example 27 above, and each component of the single-agent reference drug (Micadis, Boehringer: I dichroic tablets, Yuhan Corporation: hydrochlorothiazide mono-)) was subjected to a comparative dissolution test. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
  • telmisartan / hydrochlorothiazit two-phase matrix tablet of the present invention is different from the dissolution of the telmisartan monohydrochloride and the hydrochlorothiazit monotherapy simultaneously, so that the initial release of telmisartan is much slower than that of the hydrochlorothiazit.
  • the hydrochlorothiazide component of the capsule (pelt-pellet) of the present invention was found to have almost the same dissolution characteristics as compared to the dichromat tablet, a control formulation, butyprosartan The component can identify a very delayed dissolution rate when compared to the control drug tebeten.
  • iprosartan / hydrochlorothiazide capsulicide pellet-pellet
  • the initial release of iprosartan is higher than that of hydrochlorothiazide.
  • hydrochlorothiazide because it is very slow It is a pharmaceutical composition that is very effective in the treatment of hypertension because it can be injected at the time when the hypotensive effect occurs.
  • the candesartan cilexetil / hydrochlorothiazit capsule (pellet-tablet) of the present invention has a very slow initial release of losartan, unlike the dissolution of the candesartan monotherapy and the hydrochlorothiazit monotherapy simultaneously. Therefore, it can be injected at the time when the secondary blood pressure lowering effect of hydrochlorothiazide is a very effective pharmaceutical composition for the treatment of hypertension.
  • Experimental Example 13 Comparative Dissolution Profile Test The emmesartan medoxomil / hydrochlorothiazide capsul agent (granule-granule) prepared according to Example 31 above and each component mono-control (olmetec tablet, Daewoong Pharma: A comparative dissolution test of olmesartan medoxomil single agent / dichroic tablet, Yuhan Corporation: hydrochlorothiazide single agent) was performed. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
  • the hydrochlorothiazide component of the capsulant (granule-granule) of the present invention was found to exhibit almost the same dissolution characteristics as compared to the dichromat tablet as a control formulation. Compared to Olmetec, a control formulation, very slow dissolution rates can be observed.
  • the olmesartan medoxomil / hydrochlorothiazit capsule (granule-granule) of the present invention has a very slow initial release of olmesartan, unlike the dissolution of the co-administration of losartan monotherapy and hydrochlorothiazit monotherapy. Therefore, it can be injected at the time when the secondary blood pressure lowering effect of hydrochlorothiazide is a very effective pharmaceutical composition for the treatment of hypertension.
  • Experimental Example 14 Comparative Dissolution Profile Test Losartan Potassium / Hydrochlorothiazit Osmotic Nucleus Tablets Prepared According to Example 37 and a Single-Component Reference (Coza Tablet, MSD: Losartan Potassium Monochloride I Dichroic Tablet) , Yuhan Corporation: A comparative dissolution test of hydrochlorothiazide single agent) was performed. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
  • the hydrochlorothiazide component of the osmotic nucleated tablet of the present invention was found to exhibit almost the same dissolution characteristics as that of the control, dichroic tablet, but the losartan component was controlled. Compared to co-crystal, the formulation, very slow dissolution rates can be identified.
  • the losartan potassium / hydrochlorothiazit osmotic nucleus tablet of the present invention has a secondary effect of hydrochlorothiazide because the initial release of losartan is much slower than that of hydrochlorothiazide, unlike the dissolution of the losartan monotherapy and the hydrochlorothiazit monotherapy simultaneously. It is a pharmaceutical composition that is very effective in the treatment of hypertension because it can be injected at the time of the hypotensive effect.
  • Experimental Example 15 Animal Study
  • This test is a rat model animal test. It is designed by dividing light condition and dark condition. The biorhythms of rats and humans are opposite, so when applied to humans, the time zone is reversed. > 1. In terms of blood pressure drop, systolic and diastolic blood pressures were lower than those of the screening group at 5 days.
  • the blood pressure level was lower in the hourly group compared to the concurrent group and the hourly group.
  • the hourly group showed the lowest blood pressure level in the morning (cancer) than in the evening (dark). .
  • the blood pressure drop effect of each time slot is as shown in Figs. 15-17.
  • the morning time difference group was confirmed to have the best blood pressure lowering effect among the four groups.
  • composition according to the present invention has an optimal blood pressure lowering effect during the time from the morning of the morning until the middle of the day after the administration of the average blood pressure, unlike the conventional simultaneous administration group.
  • the time-administrated case was administered for the purpose of lowering blood pressure than when the single agent of angiotensin _ receptor receptor and hydrochlorothiazide was administered simultaneously. It can be seen that the optimal effect of the clinical antihypertensive effect of angiotensin ⁇ ⁇ receptor blocker and hydrochlorothiazit is expressed.
  • Table 9 is a result of measuring the blood pressure and the pulse rate between the co-administered group of losartan and hydrochlorothiazide and the morning time difference group (cancer condition) according to the present invention.
  • the hypotensive action of losartan and hydrochlorothiazide is The mean time of systolic blood pressure drop was 5.83 ⁇ 4, mean diastolic pressure drop was 5.6%, and mean blood pressure drop was 9.9% in the time-difference group, which was provided by the test group.
  • the pulse rate increased to 0.08%, indicating no significant difference.
  • the delayed drug release of losartan administered for the purpose of lowering blood pressure with a time difference of 4 hours as intended by the present invention has an excellent blood pressure lowering effect compared to the time-administered group.
  • Table 13 is according to the administration time of losartan and hydrochlorothiazit It is the result of measuring blood pressure.
  • the mean systolic blood pressure lowering effect was 4.0%, and the average sin: gastric diastolic blood pressure was higher than the evening time difference group (dark condition).
  • the drop in blood pressure was 2.2%, mean blood pressure drop was 3.1%, and pulse rate was 7.0%.

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Abstract

The present invention relates to a pharmaceutical composition in which release of a thiazide-based compound and angiotensin-II-receptor blocker is controlled, and to a combination preparation technique for the same. More particularly, the present invention relates to a preparation technique capable of maximizing pharmacological and clinical blood pressure control effects and complication preventive effects and significantly reducing side effects by administrating a release-controlled combination preparation rather than administrating a single preparation of thiazide-based compound and a single preparation of angiotensin-II-receptor blocker at the same time.

Description

방출성 이 제어된 치아자이드계 화합물과 안지오텐신ᅳ Πᅳ수용체 차단제를 포함하는 약학적 조성물  Pharmaceutical composition comprising controlled release of chiazide-based compound and angiotensin ᅳ Π ᅳ receptor blocker
기술분야 Field of technology
본 발명은 치아자이드계 화합물과 안지오텐신 ~ IIᅳ수용체 차단제의 약학 조성물과 그 복합 제제화 기술에 관한 것이다.  The present invention relates to pharmaceutical compositions of thiazide-based compounds and angiotensin-II ′ receptor blockers and their complex formulation techniques.
보다 상세하게 설명한다면 , 치아자이드계 화합물 단일 제제와 안지오텐신ᅳ Π ᅳ수용체 차단제 단일 제제를 동시에 복용하는 경우보다 방출성이 제어된 복합 제제화하여 복용함으로써 약리학적 및. 임상학적 항압 효과와 합병증 예방 효과를 극대화 할 뿐 아니라 부작용을 더욱 감소시켜 주는 제제화 기술에 관한 발명이다. 배경기술  In more detail, pharmacological and pharmacological effects can be obtained by taking a controlled formulation of a controlled release rather than taking a single formulation of a chiazide-based compound and an angiotensin ᅳ π ᅳ receptor blocker at the same time. The present invention relates to a formulation technology that maximizes the clinical anti-pressure effect and the prevention of complications and further reduces side effects. Background
고혈압 치료의 문제점  Problems in treating high blood pressure
우수한 항압제가 많이 개발되어 처방되고 있다. 그럼에도 불구하고 고혈압 치료는 50% 법칙 (Rule)이 지배한다. 즉， 자기가 고혈압인 즐 아는 자가 50% 이다. 이 중 50¾ 즉, 25% 만이 치료를 받는다. 그러나 치료 환자의 50¾ 즉， 12. 5% 만이 제대로 된 치료롤 받고 있다는 의미다.  Many excellent anti-pressure drugs have been developed and prescribed. Nevertheless, the treatment of hypertension is ruled by the 50% rule. In other words, 50% of them enjoy high blood pressure. Only 50¾ of this, or 25%, is treated. However, only 50¾, or 12. 5% of the treated patients, are receiving proper care.
특히 항압 요법은 혈압만 내리는 것이 목적이 아니다. 고혈압 환자에게 합병되기 쉬운 심근 경색 , 심부전 , 뇌졸증， 조기 사망 등을 예방 해주고 그 병태의 악화를 막아 주어 건강 장수를 누리게 해 주는 것이 항압 요법의 목적인 것이다.  In particular, anti-pressure therapy is not the only purpose to lower blood pressure. The purpose of anti-pressure therapy is to prevent myocardial infarction, heart failure, stroke, and premature death, which can be easily merged with hypertension patients, and to prevent the worsening of the condition.
이러한 목적을 달성하기 위해서는 약물은 더욱 혁신되어야 한다.  To achieve this goal, drugs must be further innovated.
대체응지 (규칙 제 26조) 처방의의 처방 방법이 간편해야 한고， 환자의 복약 준수가 쉬워져야 한다. Alternative Response (Article 26) The prescribing method of the prescriber should be simple, and the patient should be easy to follow the medication.
복합제 조성물의 필요성 Necessity of the composite composition
지난 30년 동안 발표된 대단위 임상 (예: HOT, UKP0S 등)보고서에는 경증도 내지 중증도 고혈압 때부터 복합제로 치료함 로써 합병증 발병 및 악화를 예방하고 장수를 보장 받을 수 있다는 입증자료가 계속 증가해 왔다 (참조: 미국 고혈압 대책 위원회 고혈압 치료 지침 (JNC VI & VII), WH0- ISHC1999)).  Large clinical reports (e.g., HOT, UKP0S, etc.) published over the past 30 years have continued to increase the evidence that treatment with complications from mild to severe hypertension can prevent complications and exacerbations and ensure longevity. (See: American Committee on Hypertension Measures Hypertension Treatment Guidelines (JNC VI & VII), WH0-ISHC1999).
고혈압은 그 원인이 매우 다양하다. 다양한 원인이 동일한 환자에게 중복적으로 고혈압을 유발 시키고 있다. 따라서 단일 항압제를 사용하는 경우 어떤 결과가 나오는 지는 미리 판단하기 어렵다 (참조: Journal of human hypertension 1995： 9： S33-S36) .  Hypertension has a wide variety of causes. Various causes cause hypertension in the same patient. Therefore, it is difficult to determine in advance what results would result from the use of a single antipressant (Journal of human hypertension 1995: 9: 9: S33-S36).
때문에 항압제끼리의 복합 처방이 계속 증가되어 왔다. 특히 이러한 복합 처방 경향은 로사르탄， 발사르탄 등과 같은 안지오텐신ᅳ Πᅳ수용체 차단제 (ARB: Angiotensin Receptor Blockers)를 기초 약물로 하여 처방하기 시작한 이후 더욱 두드러지게 나타났다.  Therefore, the combination of anti-compressants has been increasing continuously. In particular, this combination prescription tendency became more prominent since the prescription of angiotensin Receptor Blockers (ARB) such as losartan and valsartan was started.
임상계 및 학계를 통해 매우 빈번하게 발표되어 온 고혈압 치료제 복합 처방의 필요성을 요약하면 다음과 같다 (참고: J. Hum. Hyper tens 1995： S33- In summary, the need for a combination of hypertension medications, which have been published very frequently in clinical and academia, is as follows (see J. Hum. Hyper tens 1995: S33-
S36). S36).
1) 동일 환자라 할지라도 다양한 원인이 중복되어 고혈압을 일으키고 있다.  1) Even in the same patient, a variety of causes are causing hypertension.
2) 단일 제제가 다양한 병태를 모두 다스릴 수 없음은 당연 하다.  2) It is natural that a single agent cannot control all of the various conditions.
3) 단일 제제의 효과는 처방환자의 50% 이하에게 유효 할뿐이다.  3) The effect of a single agent is only effective for up to 50% of prescription patients.
4) 복합 제제의 효과는 처방환자의 80%이상에게 유효하다. 5) 특히, 당뇨병 등 합병증을 지닌 자의 고혈압에 대해 단일 제제는 목적 하는 바의 항압 효과를 얻을 수 없을 뿐 아니라 합병증을 예방하기는 더욱 어렵다. 4) The effects of combination preparations are effective for over 80% of prescription patients. 5) In particular, for high blood pressure in people with complications such as diabetes, a single drug may not be able to achieve the desired antihypertensive effect, and it is more difficult to prevent complications.
6) 단일제의 저용량으로 듣지 않는 경우에 용량을 증가 시킨다는 것은 부작용만 증가시키는 경우가 많다. 오히려 복합제는 부작용을 줄여 줄 수가 있다.  6) In the case of low dose of single agent, increasing dose often increases only side effects. Rather, the combination can reduce side effects.
7) 복합 제제는 약리 작용을 달리하는 약효군 끼리를 복합함으로써 다양한 원인을 제거함과 동시에, 합병증을 예방하고 부작용을 상쇄 시킬 수가 있다. 따라서 고혈압을 처음부터 치료하는 경우에도 단일제로 시작하는 것보다 복합제로 시작하는 것이 최선의 치료법이라고 미국 심장학회 (American Heart Association)는 강조하고 있다.  7) Complex formulations can eliminate various causes, prevent complications and offset side effects by combining pharmacological groups with different pharmacological effects. Therefore, even when treating hypertension from the start, the American Heart Association emphasizes that starting with a combination is the best treatment, rather than starting with a single agent.
8) 특히， 합병증을 지닌 고혈압자는 합병증이 없는 고혈압자보다 혈압을 더 내려야 한다. 이러한 경우는 반드시 복합 처방이 필수적이다. 그럼에도 불구하고 단일 제제를 사용하는 경우 26%의 환자에게만 효과를 볼 수 있다. 복합 처방은 무려 74%의 환자에게 목표로 하는 혈압을 유지시켜 합병증의 악화를 예방 할 수 있다 (참조: HOT대단위 임상).  8) In particular, high blood pressure complications should lower blood pressure than high blood pressure without complications. In this case, a combination prescription is essential. Nevertheless, the use of a single formulation can only benefit 26% of patients. Combination regimens can help prevent complications by maintaining targeted blood pressure in as many as 74% of patients (see HOT large clinical trials).
9) 미국 FDA는 30년 전부터 이른바 고정 비율 복합 원리 (Fixed-dose Combination Therapy)에 의거 복합 제제의 필요성을 인정해 왔다. 약리 작용이 서로 다른 약물을 복합시킬 때는 단일 제제 각각을 단독으로 처방 할 때와 같은 동량씩을 복합시켜야 한다는 원리다. 이를 고정 비율 복합제라 하며， 단일 제제의 약효와 안전성이 이미 인정되어 있는 한， 그리고 처방의들에 의해 복합 처방이 실시되고 있는 한 이러한 복합제 조성물은 별도의 실험 없이 허가되고 있다.  9) The US FDA has recognized the need for a combination formulation for 30 years, based on the so-called Fixed-dose Combination Therapy. When combining drugs with different pharmacological actions, the principle is to combine the same amount as when each single drug is prescribed alone. This is called a fixed ratio combination, and as long as the efficacy and safety of a single formulation are already recognized, and as long as the combination is administered by the prescribing physician, such a combination composition is approved without separate experiment.
10) 고정 비율 복합 항압제는 보다 혈압 강하 작용이 우수하다는 것은 주지의 사실이다 . 10) Fixed-rate complex anti-pressure drugs are more effective in lowering blood pressure It is a well known fact.
11) 개개 성분의 용량을 증가 시키지 아니하므로， 개개 성분의 부작용 출현을 현저히 예방해 줄 수 있다.  11) Since it does not increase the dose of the individual components, it can significantly prevent the appearance of side effects of the individual components.
12) 혈압 강하제의 부작용은 상당수가 순환기계에 대한 부작용이다. 따라서 서로 다른 약리를 지닌 성분을 복합함으로써 서로의 부작용을 상쇄 시키는 경우가 많다 .  12) Many of the side effects of blood pressure lowering drugs are to the circulatory system. Therefore, the combination of ingredients with different pharmacology often cancel each other's side effects.
13) 복합 제제는 환자의 복약 준수를 매우 쉽 게 해 준다 . 노년 인구 증가에 따라 복약 지도에 소요되는 처방의의 시간 낭비를 반으로 줄여 줄 수가 있는 것이다 .  13) The combination formulation makes it very easy for the patient to adhere to the medication. As the elderly population grows, the time spent on prescription medication guidance can be cut in half.
14) 복합 제제는 순환기계 합병증의 발병위험 인자를 감소시켜 즐 수 있으므로 장기간의 예방 경비를 절감시켜 줄 수 있다.  14) Combined preparations can be used to reduce the risk of developing circulatory complications, thus reducing long-term preventive costs.
15) 단일 제제를 각각 유지하는 포장비용 절감과 고급 인력의 투약 조제 시간 절감은 엄 청난 액수에 달할 수 있다. 대표적 활성성분의 정보  15) The savings in packaging costs of maintaining a single formulation each and the time required to dispense medications for high-level personnel can be enormous. Representative Active Ingredient Information
본 발명의 복합제에 함유된 각 성분 특징 에 의한 복합처방의 합리성과 개개 성분의 약리작용은 다음 표 1과 같이 매우 이상적 이다 . The rationality and the pharmacological action of the individual components of the complex according to the characteristics of each component contained in the composite of the present invention is very ideal as shown in Table 1 below.
【표 1] [Table 1]
Figure imgf000007_0001
Figure imgf000007_0001
1) 치아자이드계 화합물 이뇨제의 대표적 약물인 히드로클로로치아짓과 이의 약학적 활용현황 1) Hydrochlorothiazide, a representative drug of diazide of chiazide compound, and its pharmaceutical application
대표적인 치아자이드계 화합물 이뇨제인 히드로클로로치아짓은 그 화학명이 6-클로로 -3， 4—디히드로 -2H-1, 2 ,4-벤조치아디아진 -7-술폰아미드 1,1— 이옥사이드이며, 고혈압치료보조제로 경구투여시 이뇨효과가 6~12시간에 걸쳐 지속되며 혈중 반감기가 5.6~14.8시간에 이르는 1일 1희 투여약물이다. Hydrochlorothiazide, a representative diazide compound, is chemically named 6-chloro-3, 4—dihydro-2H-1, 2,4-benzothiadiazine-7-sulfonamide 1,1— It is a dioxide, a diuretic effect lasting 6 ~ 12 hours when administered orally as a hypertension treatment adjuvant, with a half-life of 5.6-14.8 hours per day.
고혈압치료보조제로서 히드로클로로치아짓의 효과는 문헌 [참조: Pharmacological Properties of Combination: Therapies for Hyper t ens i on( Amer i canJourna 1 of Hypertension 1997； 10: 13S-16S) , Management of Hypertension: The Role of Combination Ther apy ( Amer i can Journal of Hypertension 1997； 10: 262S-271S) , Molecular sites for diuretic action(Bruce M. Hendry and J. Clive Elloy ； TIPS-November 1988 vol. 9)] 등에서 혈관확장 (이완)과 좌심방 압력 감소효과에 기인한 혈압강하효과와 이뇨촉진으로 전체혈중액량의 감소를 통한 2차적인 혈압강하효과 등으로 자세히 언급되어 있다.  The effect of hydrochlorothiazide as an adjuvant for hypertension has been described in Pharmacological Properties of Combination: Therapies for Hyper t ens i on (Amer i can Journa 1 of Hypertension 1997; 10: 13S-16S), Management of Hypertension: The Role of Combination Ther apy. (Amer i can Journal of Hypertension 1997; 10: 262S-271S), Molecular sites for diuretic action (Bruce M. Hendry and J. Clive Elloy; TIPS-November 1988 vol. 9), etc. It is mentioned in detail as the blood pressure lowering effect due to the reducing effect and the secondary blood pressure lowering effect through the reduction of the total blood fluid by diuretic promotion.
다른 치아자이드계 화합물 이뇨제로서는 클로로치아짓， 벤드로플루메치아짓등이 있다. 2) 안지오텐신ᅳ Πᅳ수용체 차단제와 이의 약학적 활용현황  Other thiazide compound diuretics include chlorothiazide and bendroflumezigit. 2) Angiotensin ᅳ Π ᅳ Receptor Blocker and its Pharmaceutical Utilization Status
안지오텐신ᅳ Πᅳ수용체 차단제는 혈관수축을 일으키는 근원물질 중 하나인 안지오텐신의 수용체와의 결합을 차단하여, 심근의 수축기와 확장기 모두에 있어서 혈압강하효과를 발휘하는 약물로 현재까지 밝혀져 있으며 빈번하게 임상에 적용되고 있는 일련의 화합물군이 약학적으로 활용 가능한 염을 포함하여 10여종에 이르고 있다. 또한， 이들은 고혈압과 관련된 제반 증상에 경증도부터 중둥도에 이르는 환자들에게 단독으로, 흑은 유사한 기전으로 항압효과를 보이는 안지오텐신 변환효소 억제제등과 함께 사용되고 있다 [참조: Angiotension 2 Receptor Antagonist： An Overview, Am J Health一 Syst Pharm 57(13)： 1231-1238, 2000] . 이러한 일련의 안지오텐신ᅳ Πᅳ수용체 차단제 중에서도 로사르탄， 발사르탄, 이르베사르탄， 칸테사르탄, 텔미사르탄, 이프로사르탄, 올메사르탄 등은 상용화되어 지난 수년간 고혈압치료 약물로서 급격한 성장을 보이고 있으며， 이와 함께 이들의 효과 역시 많은 임상시험을 통해 증명되고 있다 [참조: Pharmacologic, Pharmacokinetic, and Therapeutic Difference Among angiotensin— Π—receptor Antagonist: Pharmacotherapy 20(2): 130-139 2000] . 이러한 많은 임상시험 둥을 통해 밝혀진 바， 이들 안지오텐신ᅳ Πᅳ수용체 차단제들은 생체 내 대사경로와 반감기 등 약물동태학적인 차이에도 불구하고， 적정 투여량에서 심근 수축기와 확장기에 대한 혈압강하 효과는 동등하며， 동일 수용체 차단제로서 얻어지는 고혈압의 제반증상에 관련된 부가적인 심부전 예방 및 치료， 심근 경색 후 부정맥과 심부전 예방 치료， 당뇨병성 합병증 예방 치료， 신부전 예방 치료， 뇌졸중 예방 치료， 항 혈소판 작용, 동맥 경화 예방 작용， 알도스테론 유해 작용억제 대사 증후군 작용 완화, 순환기계 질환 연쇄적 악화예방 효과 역시 유사한 것으로 알려져 있다. Angiotensin ᅳ Π ᅳ receptor blockers block the binding of angiotensin receptors, one of the sources of vasoconstriction, and have been shown to be effective in lowering blood pressure in both myocardial systolic and diastolic and are frequently used in clinical trials. The group of compounds being applied has reached about 10 species, including salts that are pharmaceutically usable. In addition, they are used alone with patients with symptoms ranging from mild to moderate in hypertension, and with angiotensin converting enzyme inhibitors that have anti-hypertensive effects with similar mechanisms. [Angiotension 2 Receptor Antagonist ： An Overview , Am J Health 一 Syst Pharm 57 (13): 1231-1238, 2000]. Among these series of angiotensin receptor receptors, losartan, valsartan, irbesartan, cantesartan, telmisartan, iprosartan, olmesartan, etc. have been commercialized and showed rapid growth as a hypertensive drug in the last few years. In addition, their effectiveness has been demonstrated in many clinical trials [see Pharmacologic, Pharmacokinetic, and Therapeutic Difference Among angiotensin— Π—receptor Antagonist: Pharmacotherapy 20 (2): 130-139 2000]. Many of these studies have shown that these angiotensin Π ᅳ receptor blockers have equivalent blood pressure-lowering effects on myocardial systolic and diastolic at moderate doses, despite pharmacokinetic differences such as in vivo metabolic pathways and half-life. ， Additional heart failure prevention and treatment related to all symptoms of hypertension obtained as the same receptor blocker, Arrhythmia and heart failure prevention treatment after myocardial infarction, Diabetic complication prevention treatment, Kidney failure prevention treatment, Stroke prevention treatment, Antiplatelet action, Atherosclerosis prevention Aldosterone inhibitory effect metabolic syndrome alleviation, circulatory disease chain deterioration prevention effect is also known to be similar.
상기의 안지오텐신ᅳ Πᅳ수용체 차단제의 항압 및 신장 보호 작용은 예를 들어 다음 간행물 [참조: J. Wagner et al . ： Effects of ATI receptor blockade on blood pressure and the renin angiotensin system in spontaneously hypertensive rats of the stroke prone strain, Clin, Exp. Hyper t ens. , vol. 20(1998), p. 205-221 ； M. Bohm et al . ： angiotensin— Π—receptor blockade in TGR(mREN2)27: Effects of reninᅳ angiotensinᅳ system gene expression and cardiovascular functions, J. Hyper tens., vol. 13(8) (1995), p. 891-899]에 기술되어 있다.  The anti-pressure and renal protective action of the angiotensin ᅳ receptor receptors is described, for example, in J. Wagner et al. ： Effects of ATI receptor blockade on blood pressure and the renin angiotensin system in spontaneously hypertensive rats of the stroke prone strain, Clin, Exp. Hyper t ens. , vol. 20 (1998), p. 205-221; M. Bohm et al. : Angiotensin—Π—receptor blockade in TGR (mREN2) 27: Effects of renin ᅳ angiotensin ᅳ system gene expression and cardiovascular functions, J. Hyper tens., Vol. 13 (8) (1995), p. 891-899.
제 1의 임상시험에서 발견된 안지오텐신ᅳ Πᅳ수용체 차단제의 기타 신장 보호 효과가 다음 간행물 [참조: S. Andersen et al . Renoprotective effects of angiotensin— Π—receptor blockade in type 1 diabetic patients with diabetic nephropathy, Kidney Int. , vol. 57(2) (2000), p. 601-606 ； L. M. Ruilope: Renoprotection and renin-angiotensin system blockade in diabetes mellitus, Am. J. Hyper t ens. , vol. 10(12PT2)Suppl . (1997)， p. 325- 331]에 기재되어 있다. Others of Angiotensin ᅳ Π ᅳ Receptor Blockers Found in Phase I Clinical Trials Kidney protective effects are described in the following publications: S. Andersen et al. Renoprotective effects of angiotensin— Π—receptor blockade in type 1 diabetic patients with diabetic nephropathy, Kidney Int. , vol. 57 (2) (2000), p. 601-606; LM Ruilope: Renoprotection and renin-angiotensin system blockade in diabetes mellitus, Am. J. Hyper t ens. , vol. 10 (12PT2) Suppl. (1997), p. 325-331.
내피 이상에 대한 안지오텐신ᅳ Πᅳ수용체 차단제의 효과가 간행물 [참조： E. L. Schiffrin et al . ： Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan, Circulation, vol . 101(14) (2000) , p. 1653- 1659 ； R. M. Touyz et al . ： Angiotensin Π stimulates DNA and protein synthesis in vascular smooth muscle eel Is from human arteries: role of extracellular s i ngna 1—regulated kinases, J. Hypertension. , vol 17(7) (1999) , p. 907-916 ； E. L Schiffrin: Vascular remodelling and endothelial function in hypertensive patients: Effect of antihypertensive therapy, Scand . Cardiovasc. J. , vol. 32, Suppl. 47(1998), p. 15-21 ； Prasad: Acute and Chronic angiotensin-1 receptor reverses endothelial dysfunction in atherosclerosis, Circulation, vol. 101(2000)， p. 2349]에 기재되어 있다. 또한, 대한민국특허 공개 2000-0070046 에서는 안지오텐신 _1!ᅳ수용체 차단제 중 특히 로사르탄이 심부전증 환자의 사망률을 '감소시키고, 급발성 심장마비에 의한사망를의 감소와 예방효과가 있음이 언급되어 있다. 단순 복합처방의 문제점  The effects of angiotensin Π 차단 receptor blockers on endothelial abnormalities have been published in E. L. Schiffrin et al. : Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan, Circulation, vol. 101 (14) (2000), p. 1653-1659; R. M. Touyz et al. ： Angiotensin Π stimulates DNA and protein synthesis in vascular smooth muscle eel Is from human arteries: role of extracellular s i ngna 1—regulated kinases, J. Hypertension. , vol 17 (7) (1999), p. 907-916; E. L Schiffrin: Vascular remodelling and endothelial function in hypertensive patients: Effect of antihypertensive therapy, Scand. Cardiovasc. J., vol. 32, Suppl. 47 (1998), p. 15-21; Prasad: Acute and Chronic angiotensin-1 receptor reverses endothelial dysfunction in atherosclerosis, Circulation, vol. 101 (2000), p. 2349. In addition, Korean Patent Publication No. 2000-0070046 mentions that angiotensin _1! ᅳ receptor blocker, in particular, losartan 'reduces mortality in patients with heart failure, and reduces and prevents death by sudden heart attack. Problems of simple compound prescription
1) 고혈압은 질환의 특성상 그 유형에 관계없이, 하루 중 혈압이 가장 상승하는 시기인 이른 아침 시간에 복용약물의 효과가 발현되어야 하며, 더욱 바람직하게는 혈관수축을 유발하는 근원물질인 레닌 (renin)의 합성이 이루어지는 수면시간과 혈압상승에 직접적인 원인으로 작용하는 안지오텐신과 알도스테론의 합성이 최고조에 이르는 이른 아침까지의 혈압강하작용을 유지하기 위해, 저녁 시간대 약물의 복용이 권장되는 질환 [참조: Patterns of blood pressure response: Day and night variations ； American Journal of Hypertension April 2001ᅳ vol. 14, No. 4, Part 2, Preventing increase in early morning blood pressure, heart rate, and the rate-pressure product with control led onset extended release verapamil at bedtime versus enalapri 1 , losartan, and lacebo on rising ； American Heart journal October 2002]으로서， 이를 위해 치아자이드계 화합물 단일 제제와 안지오텐신- II-수용체 차단제 단일 제제를 동시에 복용하거나 단순히 복합한 복합제 조성물을 투여할 경우 이뇨제와의 병용투여로 기대되는 부가적인 혈압강하효과에도 불구하고, 야 (夜)뇨로 인한 수면장애와 함께 아연과 같은 특정 전해질의 부족이 심화될 수 있다 [참조: Demographic, Environmental, and Genetic Predictors of Metabolic side effects of Hydrochlorothiazide treatment in Hypertensive Subjects: American Journal of Hypertension 2005； 18： 1077-1083] . 1) Hypertension, regardless of the type of disease, blood pressure during the day is most The effect of the medication should be expressed early in the morning, when it is rising, and more preferably, the angiotensin and the angiotensin, which are directly responsible for the increase in sleep time and the increase in blood pressure, are synthesized. Diseases in which evening medications are recommended to maintain blood pressure lowering until early morning, when aldosterone synthesis peaks. Patterns of blood pressure response: Day and night variations; American Journal of Hypertension April 2001 . 14, No. 4, Part 2, Preventing increase in early morning blood pressure, heart rate, and the rate-pressure product with control led onset extended release verapamil at bedtime versus enalapri 1, losartan, and lacebo on rising; American Heart journal October 2002; In spite of the additional antihypertensive effects expected from co-administration with diuretics, the use of a single ziazide compound and a single angiotensin-II-receptor blocker at the same time, or simply a combination of complex compositions, Lack of specific electrolytes, such as zinc, may be intensified with sleep disturbances caused by urine. Demographic, Environmental, and Genetic Predictors of Metabolic side effects of Hydrochlorothiazide treatment in Hypertensive Subjects: American Journal of Hypertension 2005; 18:10 1077- 1083].
2) 이뇨제인 치아자이드계 화합물과 안지오텐신一 Πᅳ수용체 차단제의 단순 복합 제제를 야 (夜)뇨로 인한 수면장애를 피하기 위해, 오전 시간 중에 투여될 경우에는 수면 시간 증 합성되는 혈관수축유발물질의 합성을 억제할 수 없으며, 이로써 하루 중 혈압이 최고조에 이르는 이른 아침 시간대에 항압 효과를 얻을 수 없다. 선행기술의 예 2) Synthesis of vasoconstriction-inducing substance that is synthesized with increased sleep time when administered in the morning in order to avoid sleep disorders caused by night urination, with a simple combination preparation of a diuretic ziazide compound and angiotensin Π ᅳ receptor blocker It is not possible to suppress the anti-hypertensive effect in the early morning hours when blood pressure peaks during the day. Example of Prior Art
치아자이드계 화합물 이뇨제로서 히드로클로로치아짓과 안지오텐신ᅳ Πᅳ수용체 차단제를 활성성분으로 하는 복합 제제 (제품명 : Hyzaar, 제조원: MSD; 제품명: Diovan HCT, 제조원: Novartis 등)가 시판 중이며, 이들은 임상적으로 밝혀진 병용 투여 시의 부가적인 혈압강하효과를 장점으로 많은 고혈압환자에 적용되고 있으며， 문헌 [참조: Combination Therapy in the Management of Hypertension: Focus on Angiotension Receptor blocker Combined with Diuretics, J Clin Hyper tens. 2005； 7(2)： 96-101, Antihypertensive Efficacy of Angiotension Receptor Blocker in Combination with Hydrochlorothiazide: A Review of the Factorial Design Study, J CI in Hyper tens. 6(10)： 569-577, 2004, BP circardian profile, T/P ratio and Smoothness Index After Treatment with fixed combination Losartan 100/HCTZ 25 in Essential Hypertension (American Journal of Hypertension ； April 2002ᅳ vol. 15， No. 4, Part 2) , Losartan prevents the Diuretics-Induced Hypokalemia and Hyperuricemia in the patients with essential Hypertension (American Journal of Hypertension ； May 2005-vol . 18, No. 5, Part 2] 등에 두 가지 활성성분의 병용투여에 의한 항압 효과의 상승， 상가 작용과 그 유효성이 자세히 설명되어 있다.  Combination preparations (product name: Hyzaar, manufacturer: MSD; product name: Diovan HCT, manufacturer: Novartis, etc.) with hydrochlorothiazide and angiotensin ᅳ Π 차단 receptor blocker as active ingredients as a ziazide compound diuretic are commercially available, and these are clinically known combinations It has been applied to many hypertensive patients due to the additional blood pressure lowering effect when administered. See Combination Therapy in the Management of Hypertension: Focus on Angiotension Receptor blocker Combined with Diuretics, J Clin Hyper tens. 7 (2): 96-101, Antihypertensive Efficacy of Angiotension Receptor Blocker in Combination with Hydrochlorothiazide: A Review of the Factorial Design Study, J CI in Hyper tens. 6 (10): 569-577, 2004, BP circardian profile, T / P ratio and Smoothness Index After Treatment with fixed combination Losartan 100 / HCTZ 25 in Essential Hypertension (American Journal of Hypertension; April 2002 'vol. 15, No. 4, Part 2), Losartan prevents the Diuretics-Induced Hypokalemia and Hyperuricemia in the patients with essential Hypertension (American Journal of Hypertension; May 2005-vol. 18, No. 5, Part 2] Increasing the anti-pressure effect, the additive action and its effectiveness are described in detail.
상기의 문헌에 따르면 이뇨제인 치아자이드계 화합물과 안지오텐신ᅳ Πᅳ수용체 차단제를 동시 복용 복합 제제로 투여할 경우， 안지오텐신ᅳ Πᅳ수용체 차단제의 혈압강하 효과뿐 아니라， 이뇨를 통한 전체 혈장 용적을 감소시킴으로써 발현되는 부가적인 혈압강하 작용을 얻을 수 있으며 ,· 이로써 경증도의 고혈압 환자뿐 아니라, 안지오텐신ᅳ Πᅳ수용체 차단제 단일 제제의 투여로 정상 혈압으로 회복되기 힘든 증등도의 고혈압 환자의 경우에 있어서도 유의성 있는 항압 효과를 얻을 수 있는 것으로 밝혀져 있다 . According to the above literature, when a combination of a combination of a zigzide compound and angiotensin Π ᅳ receptor blocker, which is a diuretic, is administered, the angiotensin Π ᅳ receptor blocker not only lowers the blood pressure but also reduces the total plasma volume through diuresis. An additional hypotensive effect can be obtained, thereby increasing the hypertension, which is difficult to recover to normal blood pressure by administration of a single agent of angiotensin Π ᅳ receptor blocker as well as mild hypertensive patients. It has also been found that significant anti-pressure effects can be obtained in patients.
또한， 치아자이드계 화합물 이뇨제인 히드로클로로치아짓은 장기 복용 시 이뇨 작용에 따른 부작용으로 신장을 통해 정상이상으로 칼륨을 배설시켜 칼륨손실이 유발되어 저칼륨혈증을 보일 가능성 이 있으나， 안지오텐신ᅳ Π ᅳ수용체 차단제는 안지오텐신의 생성을 억제함으로써 칼륨의 손실을 방지해 줄 수 있다 . 안지오텐신ᅳ Π ᅳ수용체 차단제가 치아자이드계 화합물 이뇨제인 히드로클로로치아짓의 장기 투여에 따른 부작용을 감소시켜 주는 것 이다.  In addition, hydrochlorothiazide, a diazide compound, is a side effect of the diuretic effect of long-term use, and may cause hypokalemia due to excretion of potassium through the kidneys, causing hypokalemia. Angiotensin Π ᅳ receptor receptor is angiotensin By suppressing the production of potassium, the loss of potassium can be prevented. Angiotensin ᅳ π ᅳ receptor blockers reduce the side effects of long-term administration of hydrochlorothiazit, a thiazide compound diuretic.
하지만， 이들 동시 복용 단순 복합제의 아침 복용은 치아자이드계 화합물 이뇨제 인 히드로클로로치아짓의 저녁 에 투여 에 따른 야 (夜)뇨와 아 (夜)뇨로 인한 수면장애와 같은 부작용을 극복할 수는 있으나， 합병증 발생 최고 위험 시간대인 아침시간대까지 안지오텐신ᅳ Π ᅳ수용체 차단제의 약리 효과를 유지할 수 없으며 , 저녁 복용은 안지오텐신ᅳ Π ᅳ수용체 차단제의 약리 효과를 최대화 할 수 있으나， 치 아자이드계 화합물 이뇨제인 히드로클로로치아짓의 투여에 따른 야 (夜)뇨와 야 (夜)뇨로 인한 수면장애와 같은 부작용을 피할 수 없다 .  However, morning doses of these simultaneous combinations can overcome side effects such as sleep disorders caused by night urination and suburinal urine administration in the evening of hydrochlorothiazide, a thiazide compound diuretic. The pharmacological effect of angiotensin ᅳ π ᅳ receptor blocker cannot be maintained until the morning of the highest risk time, and evening doses can maximize the pharmacological effect of angiotensin ᅳ ΠΠreceptor blocker, but it is not effective in the administration of hydrochlorothiazide, a ziazide-based diuretic. Side effects such as sleep disturbance caused by night urination and night urination are inevitable.
국제공개공보 W0 06/063737은 안지오텐신ᅳ Π—수용체 차단제 , 또는 안지오텐신ᅳ Π—수용체 차단제 및 저용량의 히드로클로로치아짓의 약학적 조성물을 사용한 치료 시 혈압 감소가 층분하지 않은 환자에서 고혈압을 치료하기 위한 약학적 조성물로서， 텔미사르탄 약 80mg 및 히드로클로로치아짓 약 25n 또는 텔미사르탄 약 160nig 및 히드로클로로치 아짓 약 50mg을 포함하는 약학적 조성물에 관하여 언급하고 있다 . 이는 히드로클로로치 아짓과 텔미사르탄이 동시에 용출되는 단순 복합제에 관한 것으로 , 본 발명에서처 럼 먼저 용출된 히드로클로로치아짓을 먼저 용출되어 취침 전까지 이뇨작용을 지속시켜 혈압강하 효과를 나타내게 하고， 혈관 벽 속으로 침투해 들어가서 축적된 후 수면 중에 야간에 배뇨로 인한 수면장애를 최소화하면서도 혈관확장 작용을 발휘하여 야간의 혈압 강하 효과를 지속적으로 되도록 하며， 히드로클로로치아짓이 용출된 후 안지오텐신 _Πᅳ수용체 차단제를 시간차를 두고 용출케 하여 혈관수축을 유발하는 근원물질인 레닌 (renin)의 합성이 이루어지는 수면시간과 혈압상승에 직접적인 원인으로 작용하는 안지오텐신과 알도스테론의 합성이 최고조에 이르는 기상 이후 오전 9시까지의 혈압강하 효과를 유지하도록 설계된 것과는 개념이 전혀 다른 2성분의 단순 복합제로서， 논리적으로나 약리학적으 ¾ 혈압강하 효과 및 합병증 예방의 약효를 층분히 발휘하지 못하는 비합리적 제제로 사료된다. 현재 시판되고 있는 제제의 경우 모두 2성분의 단순 복합제이다. 이는 히드로클로로치아짓과 안지오텐신ᅳ Πᅳ수용체 차단제의 최고 약리효과에 대한 층분한 인식이 없었기 때문이다. 이러한 단순 복합제는 진보성 부족으로 인해 거절되고 있다. 한국 공개특허 제 2000-7002144호 역시 단순 복합제라 하여 한국 특허청으로부터 거절된 바 있다. International Publication No. W0 06/063737 discloses a pharmaceutical composition for treating high blood pressure in patients who do not have reduced blood pressure upon treatment with an angiotensin® Π—receptor blocker, or angiotensin ᅳ Π—receptor blocker and a low dose of hydrochlorothiazit. As such, reference is made to pharmaceutical compositions comprising about 80 mg of telmisartan and about 25 n of hydrochlorothiazide or about 160 nig of telmisartan and about 50 mg of hydrochlorothiazide. This relates to a simple combination in which both hydrochlorochizit and telmisartan are eluted simultaneously, as in the present invention. First, the eluted hydrochlorothiazide is eluted first to maintain diuretic effect until bedtime, resulting in a blood pressure lowering effect, penetrating into the blood vessel wall, accumulating and then vasodilating while minimizing sleep disturbance caused by urination at night during sleep. To keep the blood pressure lowering effect at night, and after hydrochlorothiazide is eluted, the angiotensin _Π ᅳ receptor blocker is eluted at a different time, resulting in the sleep time and blood pressure rise, which is the synthesis of renin, a source that causes vasoconstriction. It is a simple two-component combination that differs from the concept of angiotensin and aldosterone, which is a direct cause, designed to maintain the blood pressure lowering effect until 9 am after peak weather. Logically and pharmacologically, it prevents the blood pressure lowering effect and complications. Of It is considered as irrational agents do not sufficiently exert the effect layer. All formulations currently on the market are simple two-component combinations. This is due to the lack of awareness of the highest pharmacological effects of hydrochlorothiazide and angiotensin ᅳ π 차단 receptor blockers. These simple combinations are rejected due to lack of progress. Korean Laid-Open Patent No. 2000-7002144 was also rejected by the Korean Intellectual Property Office as a simple compound.
본 발명은 치아자이드계 화합물과 안지오텐신ᅳ Πᅳ수용체 차단제의 기능성 복합제를 통해 각 성분의 최고 약리 효과를 보이는 것뿐만 아니라 2성분을 함께 사용하였을 때 각 성분의 부작용을 줄임과 동시에 약리 효과를 극대화하였으며， 환자의 복약 준수를 보다 간편하게 한 지연방출 기능성 복합제 세계 최초로 고안한 것이다. 현재까지 치아자이드계 화합물과 안지오텐신 -II-수용체 차단제를 흡수， 분포， 대사, 배설 등의 약리 기전을 고려하여 방출성을 제어한복합조성물은 고려된 바가 전혀 없다. 발명의 상세한 설명 The present invention not only shows the best pharmacological effect of each component through the functional combination of the ziazide compound and angiotensin ᅳ Π ᅳ receptor blocker, but also maximizes the pharmacological effect while reducing side effects of each component when the two components are used together. It is the world's first design of a delayed-release functional combination that makes patient compliance easier. To date, no complex composition that controls the release properties in consideration of pharmacological mechanisms such as absorption, distribution, metabolism and excretion of thiazide-based compounds and angiotensin-II-receptor blockers has not been considered. Detailed description of the invention
기술적 과제 Technical challenge
이에 본 발명자들은 치아자이드계 화합물과 안지오텐신 -Π-수용체 차단제의 병용 투여시의 효과의 최대화를 약학적인 관점에서 해결하고， 체내 흡수 능력에 따른 최적의 약리효과를 유도하고, 각 약물의 약리효과를 발현하는 시간대에 약물을 투여하여 단일제제보다우수한 혈압강하효과를 가지는 1일 1회 복용 복합제 조성물로 저칼륨혈증의 개선 및 추가적인 혈압강하효과 등의 장점을 .유지하면서, 단순 병용 투여시나 동시 복용 단순 복합제 조성물의 한계점인 야 (夜)뇨로 인한 수면장애 등을 극복할 수 있으며, 아침 시간대의 1일 1회의 합리적인 투약으로 환자의 복약 순웅도를 상승시킬 수 있는 복합제 조성물을 연구하여 본 발명을 완성하였다.  Therefore, the present inventors solved the maximization of the effect of the combination of the chiazide compound and angiotensin-Π-receptor blocker from the pharmaceutical point of view, inducing the optimal pharmacological effect according to the absorption ability of the body, and the pharmacological effect of each drug. It is a single-dose combination composition that has a better blood pressure lowering effect than a single agent by administering the drug at the time of expression, while maintaining the advantages of improving hypokalemia and additional blood pressure-lowering effects, while using a simple concomitant or simultaneous combination The present invention has been completed by studying a combination composition that can overcome sleep disorders due to night urination, which is a limitation of the composition, and can increase the patient's medication swelling rate by rational administration once daily in the morning time.
기술적 해결방법 Technical solution
본 발명은，  The present invention,
(1) 안지오텐신 ᅳ Πᅳ수용체 차단제 또는 약학적으로 허용되는 그의 염을 활성성분으로 포함하는 지연방출성 구획과， 치아자이드계 화합물 또는 약학적으로 허용되는 그의 염을 활성성분으로 포함하는 선방출성 구획을 포함하는 것을 특징으로 하는 시간차 용출이 가능하도록 방출성이 조절된 복합제 조성물;  (1) a delayed-release compartment comprising an angiotensin 텐 Π 차단 receptor blocker or a pharmaceutically acceptable salt thereof as an active ingredient, and a prior-release compartment comprising a thiazide compound or a pharmaceutically acceptable salt thereof as an active ingredient Composite composition with controlled release to enable time difference dissolution, characterized in that it comprises a;
(2) 상기 (1)에 있어서， 상기 선방출성 구획에 포함되는 활성성분은 방출개시 후 1시간 이내에 85중량 % 이상이 방출되는 것을 특징으로 하는 방출성이 조절된 복합제 조성물;  (2) The composition according to the above (1), wherein the active ingredient included in the pre-release compartment releases at least 85% by weight within 1 hour after the start of release;
(3) 상기 (1)에 있어서， 상기 지연방출성 구획에 포함되는 활성성분은 상기 선방출성 구획에 포함되는 활성성분의 방출개시 후 4시간 이내에 40중량 % 이하가 방출되는 것을 특징으로 하는 방출성이 조절된 복합제 조성물; (3) The active ingredient according to (1), wherein the active ingredient included in the delayed-release compartment is 40% by weight within 4 hours after the start of release of the active ingredient included in the prior-release compartment. A composite composition with controlled release, characterized in that below is released;
(4) 상기 (1)에 있어서， 상기 안지오텐신ᅳ Π—수용체 차단제 또는 약학적으로 허용되는 그의 염이 상기 치아자이드계 화합물 또는 약학적으로 허용되는 그의 염보다 늦게 흡수될 수 있도록 2시간 내지 4시간 동안의 방출 지연시간을 갖는 방출성이 조절된 복합제 조성물;  (4) The method according to (1), wherein the angiotensin ᅳ —receptor blocker or pharmaceutically acceptable salt thereof is absorbed later than the thiazide compound or pharmaceutically acceptable salt thereof for 2 to 4 hours. A composite composition having controlled release properties having a release delay time of;
(5) 상기 (1)에 있어서, 상기 치아자이드계 화합물 또는 약학적으로 허용되는 그의 염의 용출 시작시로부터 4시간 후에 상기 안지오텐신ᅳ Π_수용체 차단제 또는 약학적으로 허용되는 그의 염이 실질적으로 방출되도록 방출성이 조절된 복합제 조성물;  (5) In the above (1), the angiotensin ᅳ _receptor blocker or the pharmaceutically acceptable salt thereof is substantially released after 4 hours from the start of dissolution of the thiazide compound or the pharmaceutically acceptable salt thereof. Composite compositions with controlled release;
(6) 상기 (1) 내지 (5)에 있어서 , 상기 안지오텐신ᅳ Π-수용체 차단제가 로사르탄， 발사르탄， 텔미사르탄， 이르베사르탄， 칸데사르탄, 을메사르탄， 에프로사르탄， 및 그들의 이성질체로 이루어진 군으로부터 선택되고, 상기 치아자이드계 화합물이 히드로클로로치아짓,. 클로로치아짓, 벤드로플루메치아짓， 및 그들의 이성질체로 이루어진 군으로부터 선택되는 것을 특징으로 하는 복합제 조성물;  (6) The above-mentioned (1) to (5), wherein the angiotensin ᅳ -receptor blocker is losartan, valsartan, telmisartan, irbesartan, candesartan, emmesartan, eprosartan, and Selected from the group consisting of their isomers, wherein the ziazide compound is hydrochlorothiazit; A combination composition, characterized in that it is selected from the group consisting of chlorothiazide, bendroflumezigit, and their isomers;
(7) '상기 (6)에 있어서， 상기 안지오텐신ᅳ Π一수용체 차단제 또는 약학적으로 허용되는 그의 염이 조성물 중 5 ~ 600 mg 범위로 함유되고, 상기 치아자이드계 화합물 또는 약학적으로 허용되는 그의 염이 조성물 중 2.5 ~ 100 mg범위로 함유되는 것을 특징으로ᅳ하는 복합제 조성물; 및 (7) ' The angiotensin ᅳ Π1 receptor blocker or a pharmaceutically acceptable salt thereof according to the above (6) is contained in the range of 5 to 600 mg in the composition, and the thiazide compound or pharmaceutically acceptable thereof A composite composition characterized in that the salt is contained in the range of 2.5 to 100 mg in the composition; And
(8) 상기 (1) 내지 (7)에 있어서， 2상의 메트릭스 형태의 단일정, 지연방출성 구획과 선방출성 구획이 각각 독립적으로 과립， 펠렛 또는 정제인 캡 제, 정제인 지연방출성 구획의 표면이 선방출성 구획으로 이루어진 필름코팅층에 의해 코팅되는 필름코팅정 지연방출성 구획과 선방출성 구획이 층을 이루는 다층정， 내핵정인 지연방출성 구획의 외층을 선방출성 구획이 구성하는 유핵정， 삼투성 내핵정인 지연방출성 구획의 외층을 선방출성 구획이 구성하는 삼투성 유핵정， 지연방출성 구획과 선방출성 구획 중 하나 이상의 외부에 코팅층을 추가로 포함하는 제형， 지연방출성.구획이 삼투압 조절제를 포함하며 반투과성막 코팅기제로 코팅된 제형， 및 지연방출성 구획과 선방출성 구획을 포함하는 키트 형태로 이루어진 군으로부터 선택된 제형인 것을 특징으로 하는 복합제 조성물을 특징적 양태로 한다. 유리한 효과 (8) The delayed-release compartment according to (1) to (7), wherein the single-phase, delayed-release compartment and the prior-release compartment in the biphasic matrix form are each independently granules, pellets, or tablets, which are caps and tablets. The outer layer of the film-coated tablet delayed-release compartment coated with the film-coating layer composed of the pre-release compartment and the delayed-release compartment, which is a multi-layered tablet and a core-resistant tablet in which the pre-release compartment forms a layer, Formulation further comprising a coating layer on the outside of one or more of the osmotic nucleus tablet, the delayed-release compartment and the prior-release compartment constituted by the prior-release compartment of the delayed-release compartment that constitutes the nucleated tablet and the osmotic inner core tablet. Characterized in that the co-composition is characterized in that the sex.compartment is a formulation comprising an osmotic pressure-controlling agent and a coating coated with a semipermeable membrane coating base, and a formulation selected from the group consisting of a kit comprising a delayed-release compartment and a prior-release compartment. Favorable effect
본 발명은 안지오텐신 -πᅳ수용체 차단제와 치아자이드계 화합물의 유효 성분의 방출을 각각 제어하여 치료학적 측면에서 부작용을 경감시키고 아침 시간대에 1일 1회 투여로 환자의 복약 순응도를 상승시키는 약물 송달 시스템을 제공할 수 있다.  The present invention controls the release of the angiotensin-π-receptor blocker and the active ingredient of the ziazide-based compound, respectively, to reduce side effects from the therapeutic side and to increase the patient's medication compliance by once-daily administration in the morning. Can be provided.
혈압강하제로서 대표적인 안지오텐신ᅳ Πᅳ수용체 차단제의 방출을 치아자이드계 화합물 투여 후 3~4시간. 이상, 바람직하게는 4시간 이상 지연되도록 조절한다. 그 시간 동안 혈중 반감기가 12시간 이상에 이르는 치아자이드계 화합물을 먼저 방출시키면， 이뇨를 통한 전체 혈장 용적을 감소시킴으로써 발현되는 혈압강하 작용은 다음 투여 시간까지 유지되며, 수면장애를 일으킬 수 있는 배뇨는 일과 (오전)시간 중에 이루어지고， 안지오텐신ᅳ Πᅳ수용체 차단제보다 먼저 생체 내 대사를 거쳐 , 병용투여 시 유발될 수 있는 전해질의 추가적인 소실을 방지할 수 있다. 뒤이어 방출되어 흡수된 안지오텐신—Π—수용체 차단제는， 혈관수축 유발물질의 합성이 이루어지는 저녁시간대부터 혈압상승이 최고조에 이르는 이른 아침시간대에 이르기까지 혈압강하작용이 유지되도록 하여 최상의 치료효과가 기대되는 특정 시간대에 혈압 강하 작용을 나타내게 된다. 단순 복합제보다 본 발명에 따르는 복합제 조성물이 우수한 점은 표 2에 나타냈다. The release of angiotensin Π ᅳ receptor blocker, a representative hypotensive agent, was observed for 3 to 4 hours after administration of the thiazide compound. The above adjustment is preferably performed for a delay of 4 hours or more. During that time, if the ziazide-based compound with blood half-life of 12 hours or more is released first, the hypotensive action expressed by reducing the total plasma volume through diuresis is maintained until the next administration time, and urination, which can cause sleep disorders, It takes place during the day (am) time and is metabolized in vivo before angiotensin Π ᅳ receptor blockers to prevent further loss of electrolytes that can be caused by co-administration. Angiotensin-Π-receptor blockers, which are subsequently released and absorbed, are designed to maintain the blood pressure-lowering action from the evening of the synthesis of vasoconstrictor-inducing substances to the early morning of peak blood pressure, leading to the best therapeutic effect. It will have a blood pressure lowering effect in the time zone. The advantages of the composite compositions according to the invention over simple composites are shown in Table 2.
【표 2】  Table 2
1) 혈압 강하 효과가 더욱 우수하다  1) The blood pressure lowering effect is more excellent
2) 부작용을 더욱 감소시킨다  2) further reduces side effects
3) 합병증 발생 위험 시간대에 최적의 효과를 나타낸다  3) Optimal effect at the time of risk of complications
4) 합병증 발생 위험도 높은 혈압 비하강군 고혈압자에게 최적이다  4) It is most suitable for hypertensive group who do not have high blood pressure.
5) 복약 지도 시간을 절약해주는 처방투약 정도 (正導)를 실현한다 도면의 간단한 설명  5) Realizing the amount of prescription medication that saves the time for taking medications.
보 1은 히드로클로로치아짓 단일제， 로사르탄 단일제, 실시예 1의 용출양상을 나타낸 그래프이다.  Beam 1 is a graph showing the dissolution patterns of hydrochlorothiazide monotherapy, losartan monotherapy, and Example 1.
도 2는 시관중인 코자 플러스 (히드로클로로치아짓， 로사르탄 단순 복합제)， 실시예 2)의 용출양상을 나타낸 그래프이다.  FIG. 2 is a graph showing the dissolution patterns of Coza Plus (hydrochlorothiazide, Losartan simple complex) and Example 2) in the market.
도 3은 실시예 5~8의 용출양상을 나타낸 그래프이다.  Figure 3 is a graph showing the dissolution patterns of Examples 5-8.
도 4는 실시예 7， 9~11의 용출양상을 나타낸 그래프이다.  Figure 4 is a graph showing the dissolution patterns of Examples 7, 9-11.
도 5는 시판증인 코자 풀러스에프 (히드로클로로치아짓, 로사르탄 단순 복합제)， 실시예 15의 제제의 용출양상을 나타낸 그래프이다.  Fig. 5 is a graph showing the dissolution patterns of Koza Fullus F (hydrochlorothiazide, Losartan simple combination), a formulation of Example 15, which is commercially available.
도 6은 히드로클로로치아짓 단일제, 로사르탄 단일제, 실시예 16의 제제의 용출양상을 나타낸그래프이다.  Fig. 6 is a graph showing the dissolution patterns of the hydrochlorothiazide monotherapy, losartan monotherapy, and the preparation of Example 16.
도 7은 히드로클로로치아짓 단일제， 발사르탄 단일제， 실시예 20의 제제에서 이르베사르탄을 활성성분으로 하는 제제의 용출양상 그래프이다. 도 8은 히드로클로로치아짓 단일제, 이르베사르탄 단일제, 실시예 21의 제제에서 이르베사르탄을 활성성분으로 하는 제제의 용출양상 그래프이다. 도 9는 히드로클로로치아짓 단일제， 로사르탄 단일제， 실시예 23， 24의 제제의 용출양상을 나타낸 그래프이다. 도 10은 히드로클로로치아짓 단일제， 텔미사르탄 단일제, 실시예 27의 제제의 용출양상을 나타낸 그래프이다. Fig. 7 is a graph showing the dissolution profiles of hydrochlorothiazide monotherapy, valsartan monotherapy, and formulations containing irbesartan as active ingredients in the formulation of Example 20. Fig. 8 is a graph of the dissolution profiles of a hydrochlorothiazide monotherapy, an irbesartan monotherapy, and an formulation containing irbesartan as an active ingredient in the preparation of Example 21. 9 is a graph showing the dissolution patterns of the hydrochlorothiazide monotherapy, losartan monotherapy, and formulations of Examples 23 and 24. 10 is a graph showing the dissolution patterns of the hydrochlorothiazide monotherapy, telmisartan monotherapy, and formulation of Example 27. FIG.
도 11은 히드로클로로치아짓 단일제， 이프로사르탄 단일제， 실시예 29의 제제에서 이르베사르탄을 활성성분으로하는 제제의 용출양상 그래프이다.  FIG. 11 is a graph of the elution profile of a hydrochlorothiazide monotherapy, an iprosartan monotherapy, and an formulation having Irbesartan as an active ingredient in the formulation of Example 29. FIG.
도 12은 히드로클로로치아짓 단일제， 칸테사르탄 실렉세틸 단일제, 실시예 30의 제제에서 이르베사르탄을 활성성분으로 하는 제제의 용출양상 그래프이다.  Fig. 12 is a graph of the dissolution profiles of hydrochlorothiazide monotherapy, cantesartan cilexetil monotherapy, and formulations containing irbesartan as active ingredients in the preparation of Example 30.
도 13는 히드로클로로치아짓 단일제， 올메사르탄 메독소밀 단일제, 실시예 31의 제제의 용출양상을 나타낸 그래프이다.  FIG. 13 is a graph showing the dissolution patterns of the hydrochlorothiazide monotherapy, olmesartan medoxomil monotherapy, and the preparation of Example 31. FIG.
도 14는 히드로클로로치아짓 단일제， 올메사르탄 메독소밀 단일제, 실시예 37의 제제의 용출양상을 나타낸 그래프이다.  Fig. 14 is a graph showing the dissolution patterns of the hydrochlorothiazide monotherapy, olmesartan medoxomil monotherapy, and the preparation of Example 37.
도 15은 실험예 15에 의한 임상시험결과로서 투여경로간 수축기 혈압을 비교한 그래프이다.  15 is a graph comparing systolic blood pressure between administration routes as a clinical test result according to Experiment 15.
도 16은 실험예 15에 의한 임상시험결과로서 투여경로간 이완기 혈압을 비교한그래프이다.  16 is a graph comparing diastolic blood pressure between administration routes as a clinical test result according to Experiment 15.
도 17는 실험예 15에 의한 임상시험결과로서 투여경로간 평균 혈압을 비교한그래프이다.  17 is a graph comparing the average blood pressure between administration routes as a result of the clinical trial according to Experiment 15.
발명의 실시를 위한 형태 Embodiment for Invention
본 발명은 약학적으로 허용 가능한 담체와 치아자이드계 화합물 및 안지오텐신ᅳ Πᅳ수용체 차단제를 활성성분으로 함유하는 복합 조성물에 있어서， 안지오텐신ᅳ Πᅳ수용체 차단제를 활성성분으로 하는 지연방출성 구획과, 치아자이드계 화합물을 활성성분으로 하는 선방출성 구획을 포함하여 이루어지는 방출성이 조절된 복합제 조성물을 그 특징으로 한다. 본 발명은 복합성분 각각의 체내 약리 작용 발현 시간에 시차를 두어 투약하는 이른바 시간차 투약 이론 (Chronotherapy) 원리를 적용하여 특정 속도로 각 약물을 제어 방출할 수 있도록 설계한 복합 조성물에 관한 발명으로서, 치아자이드계 화합물과 안지오텐신 _11ᅳ수용체 차단제의 병용 투여에 따른 약효의 상승효과를 얻음과 동시에 부작용을 감소시키며， 아침 시간대에 1일 1회 1정 복용의 편리성으로 환자의 복약이 용이한 효과를 나타내는 신개념의 치아자이드계 화합물과 안지오텐신ᅳ Πᅳ수용체 차단제를 포함하는 지연방출 복합 조성물에 관한 것이다. The present invention relates to a composite composition comprising a pharmaceutically acceptable carrier, a cyanide compound, and an angiotensin ᅳ receptor receptor as an active ingredient, a delayed-release compartment comprising an angiotensin ᅳ receptor receptor as an active ingredient, and It is characterized by a composite composition having controlled release properties comprising a pre-release compartment containing a zed compound as an active ingredient. The present invention relates to a composite composition designed to control and release each drug at a specific rate by applying the so-called time difference dosing theory (Chronotherapy) principle of staggering the time of pharmacological action in each of the complex components. The combination of Zide-based compound and angiotensin _11 ᅳ receptor blocker provides synergistic effect and reduces side effects, and it is easy to take the medicine for the patient with the convenience of taking 1 tablet once daily in the morning. The present invention relates to a delayed-release complex composition comprising a thiazide-based compound of the new concept and an angiotensin ᅳ receptor receptor.
이러한 본 발명의 복합 약물 시스템의 경우， 치아자이드계 화합물은 복용 즉시 빠른 속도로 위장관에서 흡수되고 안지오텐신 -Π-수용체 차단제는 일정 시ᅳ간 후부터 방출되어 소장에서 흡수된다. 구체적으로， 경구 투여 시 치아자이드계 화합물은 즉시 방출되어 1시간 이내 약물의 85¾ 이상이 용출되고, 안지오텐신ᅳ Πᅳ수용체 차단제는 위장에서 방출이 층분히 지연되어 경구 투여 후총 4 시간까지의 용출를이 40%를 넘지 않는 수준으로 방출 되도록 조절되고， 바람직하게는 치아자이드계 화합물은 1시간 이내에 약물의 90%이상 용출되고, 안지오텐신ᅳ Πᅳ수용체 차단제는 위장에서 방출이 층분히 지연되어 경구 투여 후 총 4 시간까지의 용출률이 30%를 넘지 않는 수준으로 방출 되도록 조절된다. 바람직하게는, 안지오텐신ᅳ πᅳ수용체 차단제는 치아자이드계 화합물 보다 2 ~ 4 시간 늦게 간에 흡수될 수 있도록 방출이 제어되고, 더욱 바람직하게는, 치아자이드계 화합물의 용출 시작 시로부터 4시간 이후 안지오텐신ᅳ Π—수용체 차단제가 실질적으로 방출되도록 제어된다.  In the combination drug system of the present invention, the thiazide compound is rapidly absorbed in the gastrointestinal tract immediately after administration and the angiotensin-?-Receptor blocker is released after a certain time and is absorbed in the small intestine. Specifically, when oral administration, the thiazide compound is released immediately and more than 85¾ of the drug is eluted within 1 hour, and the angiotensin® Π 체 receptor blocker delays the release from the gastrointestinal tract and releases up to 4 hours after oral administration. It is controlled to be released at a level not exceeding%, preferably the thiazide compound is eluted over 90% of the drug within 1 hour, the angiotensin Π ᅳ receptor blocker is delayed in the gastrointestinal tract to release a total of 4 after oral administration The dissolution rate by time is adjusted to release no more than 30%. Preferably, the angiotensin ᅳ π ᅳ receptor blocker is controlled to release so that it is absorbed in the liver 2-4 hours later than the thiazide compound, and more preferably, angiotensin ᅳ after 4 hours from the start of dissolution of the thiazide compound Π—controlled to substantially release the receptor blocker.
이렇게 복합 제제화 된 제제를 아침 식사 시 단 1회 복용케 하여 24시간 균등한 혈압 조절 작용과 합병증 억제 작용과 부작용 감소 작용을 발휘하게 한다. 특히 아침시간대에 본 발명의 지 연방출 복합제 조성물을 복용하게 하는 이유는 다음과 같다 . This complex formulated formulation is taken only once in the morning to have an even blood pressure control action, complication inhibition and side effects reduction for 24 hours. In particular, the reason for taking the present invention composite composition of the present invention in the morning time is as follows.
치아자이드계 화합물과 안지 ^텐신ᅳ Π ᅳ수용체 차단제는 다른 약물들과 마찬가지로 하루 24시간이 경과하는 과정에서 그 작용 양상이 생체 리듬 곡선 (Biorhythm)을 지니고 있다 [참조: J . Cl in. Hyper tens 5(1) : 17-23, 30, 2003] . ,  Chiazide-based compounds and Anji ^ tensin® receptor receptors, like other drugs, have a biorhythm curve in the course of 24 hours a day. Cl in. Hyper tens 5 (1): 17-23, 30, 2003]. ,
치아자이드계 화합물을 특히 아침시간대에 방출되게 하는 이유를 보다 상세하게 설명하자면 , 치아자이드계 화합물은 12시간 지속형 이지만 오전에 한번만 복용해도 혈관벽 속으로 스며들어 12시간 동안 일정량이 축적된다. 이 정도의 축적량으로서는 이뇨작용을 24시간 지속하기에는 모자라지만 혈관확장작용을 24시간 지속하기에는 적당한 량이다， 이 것 이 현재 12시간 지속형을 하루 한번 씩만 투약한 이유이다 . 또한 저녁 투여 에 따른 야 (夜)뇨와 야 (夜)뇨로 인한 수면 장애와 같은 부작용을 극복할 수 있다 .  To explain in more detail the reason for the release of the thiazide compound, particularly in the morning, the thiazide compound lasts 12 hours, but only once in the morning, seeps into the blood vessel wall and accumulates a certain amount for 12 hours. This amount of accumulation is insufficient to sustain diuresis for 24 hours, but is adequate to sustain vasodilator for 24 hours. This is why the current 12-hour continuous dose is administered only once a day. It can also overcome side effects such as night urination and sleep disorders caused by night urine.
안지오텐신一 Π ᅳ수용체 차단제를 .특히 저녁시간대에 방출되 게 하는 이유를 보다 상세하게 설명하자면， 안지오텐신ᅳ Π ᅳ수용체 차단제는 특히 저녁 투여 시 낮 4시부터 밤증 12시까지의 혈압 강하 작용이 강하여 저녁 수면 증 혈압을 균일하게 유지시 켜주는 약리리듬을 지니고 있다. 이는 레닌 (Renin)계의 혈압상승 물질인 알도스테론과 안지오텐신 ᅳ Π가 밤증에 주로 생성되어 작동하기 때문이 며 안지오텐신ᅳ Π ᅳ수용체 차단제는 바로 알도스테론의 생성을 억제하고 안지오텐신ᅳ Π의 작용을 억제하기 때문이다.  To explain in more detail why angiotensin receptor receptors are released during the evening, in particular, angiotensin Π receptor receptor blockers have a strong blood pressure-lowering effect during the evening from 4 pm to 12 pm during evening sleep. It has a pharmacological rhythm that keeps your blood pressure even. This is because aldosterone and angiotensin ᅳ Π, which are the blood-releasing substances of the renin system, are mainly produced and operated in the night, and angiotensin Π ᅳ receptor blocker inhibits the production of aldosterone and inhibits the action of angiotensin Π. to be.
안지오텐신ᅳ Π ᅳ수용체 차단제의 대표적 약물인 로사르탄은 흡수되면 일차로 간으로 들어간다 . 그 중 일부는 활성 형 자체 인 로사르탄 분자 그대로 혈증으로 유출되어 1시간 내에 혈중 최고 농도에 이르게 된다 . 그러나 나머지 일부는 간 내 효소 사이토크름 P450 2C7 와 3A4 라는 두 가지 효소에 의해 대사를 받아 더욱 활성 이 높은 로사르탄 카르복실산으로 변화된 후 3-4 시간 후에 최고 혈증 농도에 이르게 된다. 즉 , 로사르탄의 약리 작용은 로사르탄과 로사르탄 활성 대사체인 로사르탄 카르복실산 흔합체의 약리 작용이다. 경구 투여 용량의 약 14%가 간 내 효소에 의해 활성 형 대사체인 로사르탄 카르복실산의 형 태로 전환되며， 활성 형 대사체는 로사르탄의 40배에 해당하는 약리 작용을 나타낸다 . 혈중 소실 속도도 로사르탄이 600mL/min이고， 활성 형 대사체가 50mL/min 으로서 활성형 대사체가 더욱 느린 소실속도를 나타내어 지속적 인 작용 시간의 유지에 중요한 역할을 한다. Losartan, a representative drug of angiotensin receptor receptor blockers, enters the liver primarily when absorbed. Some of them are the active form of losartan molecules, which are directly spilled into the blood and reach the highest concentration in the blood within 1 hour. However, some of the other enzymes in the liver are caused by two enzymes called cytokine P450 2C7 and 3A4. The metabolism leads to higher activity losartan carboxylic acid, which leads to peak hyperemia levels 3-4 hours later. That is, the pharmacological action of losartan is the pharmacological action of losartan and losartan carboxylic acid complex which is losartan active metabolite. Approximately 14% of the oral dose is converted to the form of losartan carboxylic acid, an active metabolite, by an enzyme in the liver, and the active metabolite exhibits 40 times the pharmacological action of losartan. Loss rate in blood is 600 mL / min for losartan and 50 mL / min for active metabolite, which shows a slower loss rate for active metabolite.
고혈압 환자의 치료는 특히 혈압을 24시간 균등하게 유지시켜 주어 야 하고 심장의 교감계 과잉 홍분 상태를 24시간 균등하게 억제해주어야 한다. 이는 본 발명의 지 연방출 복합제 제제화 기술만이 그 목적을 달성할 수가 있다. 이하， 본 발명의 치아자이드계 화합물과 안지오텐신ᅳ Π _수용체 차단제를 포함하는 약학적 조성물을 구체적으로 설명한다 .  Treatment of patients with hypertension should maintain blood pressure evenly, especially 24 hours, and suppress heart sympathetic excess erythema 24 hours evenly. This can be achieved only by the present federal formulation formulation technology of the present invention. Hereinafter, the pharmaceutical composition comprising the thiazide compound of the present invention and angiotensin ᅳ _ receptor blocker will be described in detail.
상기 치아자이드계 화합물은 히드로클로로치아짓， 클로로치아짓， 벤드로플루메치아짓과 약학적으로 허용 가능한 그들의 염 중에서 선택된 1종 또는 2종 이상의 흔합물로 사용할 수 있으나， 이들의 종류에 한정하지 아니하고 상기 제시된 바와 같이 야뇨와 같은 부작용을 보이는 이뇨제 증에서 선택 사용 가능하다. 바람직하게는 히드로클로로치아짓 또는 그의 약학적으로 허용 가능한 염을 사용할 수 있다. 본 발명 에서 조성물 중 치아자이드계 화합물은 2.5 ~ 100 nig, 바람직하기로는 10 ~ 50 mg 이다. 상기 각 약물의 용량은 성 인 (체중 65 ~ 75kg의 성 인 남자)기준 1일 기준 용량이다.  The thiazide compound may be used as one or two or more combinations selected from hydrochlorothiazide, chlorothiazide, bendroflumezigit and pharmaceutically acceptable salts thereof, but is not limited to these types and is shown above. As can be used in diuretics with side effects such as nocturnal enuresis. Preferably hydrochlorothiazide or a pharmaceutically acceptable salt thereof can be used. In the present invention, the thiazide compound in the composition is 2.5 to 100 nig, preferably 10 to 50 mg. The dose of each drug is a daily dose based on an adult (an adult male weighing 65 to 75 kg).
상기한 혈압강하 효과를 나타내는 치 아자이드계 화합물로서 , 본 발명의 명세서에서는 히드로클로로치 아짓을 구체적 인 예로 들어 설명하지만， 본 발명 이 이로 한정되는 것은 아니다 . 또한， 본 발명의 복합 조성물의 활성 성분으로 포함되는 안지오텐신一 Π一수용체 차단제는 혈압 강하작용을 수행하며， 이의 구체적인 예로는 로사르탄, 발사르탄， 이르베사르탄， 칸테사르탄， 텔미사르탄, 이프로사르탄, 올메사르탄 및 약학적으로 허용 가능한 염 또는 이들의 이성질체 중에서 선택된 1종 또는 2종 이상의 흔합물을 들 수 있다. 본 발명의 명세서에서는 로사르탄을 구체적 예로 들어 설명하지만, 본 발명이 이로 한정되는 것은 아니다. 본 발명에서 조성물 중 안지오텐신 ᅳ Π ᅳ수용체 차단제의 사용량은 5 ~ 600 mg, 바람직하기로는. 5 ~ 300 mg이다. 상기 각 약물의 용량은 성인 (체중 65 ~ 75kg의 성인 남자)기준 1일 기준 용량이다. As a ziazide-based compound exhibiting the above-described blood pressure lowering effect, hydrochloroziazite is described as a specific example in the specification of the present invention, but the present invention is not limited thereto. In addition, the angiotensin 一 一 receptor receptor blocker included as an active ingredient of the composite composition of the present invention performs a blood pressure lowering action, specific examples thereof are losartan, valsartan, irbesartan, cantesartan, telmisartan, if And one or two or more combinations selected from losartan, olmesartan and pharmaceutically acceptable salts or isomers thereof. In the specification of the present invention, a losartan is described as a specific example, but the present invention is not limited thereto. In the present invention, the amount of angiotensin ᅳ Π ᅳ receptor blocker in the composition is 5 to 600 mg, preferably . 5 to 300 mg. The dose of each drug is a daily dose based on an adult (65-75 kg adult male).
본 발명에서， 약학적으로 허용 가능한 염은 의약업계에서 통상적으로 사용되는 염을 의미하며， 예를 들어 칼슘， 칼륨 , 나트륨 및 마그네슘 등으로 제조된 무기이온염， 염산， 질산, 인산， 브롬산， 요오드산， 과염소산， 주석산 및 황산 등으로 제조된 무기산염， 메탄설폰산， 에탄설폰산， 벤젠설폰산， P- 틀루엔술폰산， 나프탈렌설폰산,아세트산, 트리플루오로아세트산， 시트르산, 말레인산， 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산， 만데르산, 프로피온산, 구연산, 젖산, 글리콜산 ， 글루콘산， 갈락투론산， 글루탐산， 글루타르산, 글루쿠론산， 아스파르트산， 아스코르브산， 카본산, 바닐릭산， 하이드로 아이오딕산 등으로 제조된 유기산염， 메탄설폰산， 에탄설폰산， 벤젠설폰산， P-를루엔설폰산 및 나트탈렌설폰산 등으로 제조된 설폰산염 , 글리신 , 아르기닌， 라이신 등으로 제조된 아미노산염 및 트리메틸아민 , 트리에틸아민， 암모니아， 피리딘 , 피콜린 등으로 제조된 아민염 등이 있으나， 열거된 이들 염에 의해 본 발명에서 의미하는 염의 종류가 한정되는 것은 아니다. 단순 복합제와 비교한 본 발명의 기능성 복합제의 차별점과 이의 약리 효과의 우수성은 다음 표 3과 같다. In the present invention, the pharmaceutically acceptable salts mean salts commonly used in the pharmaceutical industry, for example, inorganic ions, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, made of calcium, potassium, sodium and magnesium, Inorganic acid salts, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, P-Truenesulfonic acid, naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, Oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glutonic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanic acid, Organic acid salts, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, P-ruluenesulfonic acid and nathalene sulfone made of hydroiodic acid Amino acid salts made from sulfonates, glycine, arginine, lysine, and the like, and amine salts made from trimethylamine, triethylamine, ammonia, pyridine, picoline, and the like, and the like. There is no limitation on the kind of salts. The superiority of the difference of the functional combination of the present invention and its pharmacological effect compared to the simple combination is shown in Table 3 below.
【표 3] [Table 3]
Figure imgf000025_0001
직위혈
Figure imgf000025_0001
Positional blood
후중험  Post-experience
5) 합병증 발생 (1) 아침 식사 (1) 식사 루 오전 9시에 위험 시간대 (오전 복용하면 복용하면 히드로클로로치아짓이 5시 -오전 11시 )에 시간대에 적정 먼저 용출흡수되 어 12시간은 대한 예방력과 농도 유지 어 려움 혈중 및 혈관벽으로부터의 시간차 투여 (2) 오전 7시경 과잉의 Na+ 이온을 배설시켜 항압 복용하면 로사르탄의 작용 5) Complications (1) Breakfast (1) Meal Lu at 9 am (when taken in the morning, hydrochlorothiazide is 5 am-11 am) at the appropriate time of dissolution and absorption. Difficult to maintain hyperconcentration Time difference administration from blood and blood vessel wall (2) Around 7 am Excessive Na + ions excreted and taking anti-pressure action of losartan
약효발현이 12시부터 (2) 이 러 한 이뇨작용은 발현하므로 항압 효과 취 침전까지 지속되어 수면 중 집중 시간대를 야간 배뇨로 인한 수면장애를 (2) As the diuretic effect is expressed from 12 o'clock, the diuretic effect is expressed, and the anti-pressure effect is maintained until sedimentation.
12시간으로 가정하여도 최소화 Minimize to 12 hours
24시 이후는 항압 (3) 히드로클로로치아짓은 작용이 감소되기 낮동안 아뇨작용을 발휘하면서 시작하여 혈압 혈관벽 속으로 침투해 들어가서 비하강군 고혈압자에 게 축적된 후 수면 중에는 혈관 부적합하고 합병증 확장 작용을 발휘하여 야간의 발생 최고 혈압을 감소시 켜 Non-dipper에 게 위험시간대 (기상 이후 적합하고 기상 후 합병 발작 오전 9시 )에 부적합 위험 시간대도 동시 투여군보다 유효  After 24 hours, the anti-pressure (3) hydrochlorothiazide begins during the day when the action is diminished, penetrates into the blood vessel walls, accumulates in the lower blood pressure group, and becomes unsuitable for blood vessels and causes complications during sleep. The risk of inadequate risk during the night time period (for post-weather and post-war concomitant seizures at 9 am) is also more effective for non-dippers than at the same time, as it reduces peak incidence at night.
6) 두 성분 상호 간 내에서의 상호 길항 작용 없음  6) No mutual antagonism within two components
작용 본 발명의 신규한 조성물은 물리적으로 분리되거나 구획되어 2개의 약물의 상이한 방출 속도를 얻을 수 있도록 안지오텐신ᅳ Π_수용체 차단제 , 이의 약학적으로 허용 가능한 염 및 원하는 부형제로 이루어지는 지연방출성 구획과 치아자이드계 화합물, 이의 약학적으로 허용 가능한 염 및 원하는 부형제로 이루어지는 선방출성 구획으로 이루어진다. Action The novel compositions of the present invention are delayed-release compartments and thiazides consisting of angiotensin ᅳ π_receptor blockers, pharmaceutically acceptable salts thereof and the desired excipients so that they can be physically separated or partitioned to achieve different release rates of the two drugs. Systemic compounds, their pharmaceutically acceptable salts and the desired excipients.
상기 제시된 선방출성 구획과 지연방출성 구획은 다양한 제형으로 구현 가능하다. 즉, 상기 제시된 지연방출성 구획으로 구성된 군으로부터 선택된 방출 제어 물질을 포함하는 통상의 코팅 방법에 의해 코팅될 수 있으며 이렇게 얻어진 코팅 입자, 과립, 펠렛 또는 정제 및 선방출성 구획의 다성분 입자， 과립， 펠렛을 캡술에 층진하거나 2상 메트릭스, 필름 코팅정， 다층정 유핵정 또는 삼투성 유핵정과 같은 다양한 정제로 제제화할 수 있다.  The pre-release and delayed-release compartments presented above can be implemented in a variety of formulations. That is, the coating particles, granules, pellets or tablets obtained in this way can be coated by a conventional coating method comprising a release controlling substance selected from the group consisting of the delayed-release compartments presented above, multicomponent particles, granules, The pellets can be layered in capsules or formulated into various tablets such as biphasic matrices, film coated tablets, multi-layer tablets nucleated tablets or osmotic nucleated tablets.
이러한 본 발명의 약학적 조성물은 신장질환 예방 및 치료용이나 심혈관 질환 치료용으로 적합하고, 아침 시간대에 1일 1회， 오전 6시 내지 11시 사이에 복용되는 경우, 유효한 효과를 발휘한다.  Such a pharmaceutical composition of the present invention is suitable for the prevention and treatment of kidney disease or for the treatment of cardiovascular diseases, and when taken in the morning time once a day between 6 am to 11 am exerts an effective effect.
1. 선 (先)방출성 구획 1. Pre-release block
선방출성 구획은 본 발명의 약제학적 제제에 있어서 지연방출성 구획에 비해 먼저 방출되는 구획을 의미하며， 약리학적 활성성분으로 치아자이드계 약물을 포함하며 필요에 따라 약제학적으로 허용 가능한 첨가제를 추가로 포함할 수 있다.  Pre-release compartment refers to the compartment that is released earlier than the delayed-release compartment in the pharmaceutical formulation of the present invention, and includes ziazide-based drugs as pharmacologically active ingredients, and further includes a pharmaceutically acceptable additive as necessary. It may include.
2. 지연방출성 구획 2. Delayed release block
본 발명에서 지연방출성 구획은 선방출성 구획 활성성분의 방출 일정 시간 후에 그 활성성분이 방출되는 구획을 의미한다. 지연방출성 구획은 약리학적 활성성분인 안지오텐신ᅳ Πᅳ수용체 차단제， 이의 이성질체 또는 그의 약제학적으로 허용되는 염 및 1) 방출제어물질 또는 삼투압 조절제 및 반투과성막 코팅기제를 포함하며, 필요에 따라， 2) 약제학적으로 허용 가능한 첨가제를 추가로 포함할 수 있다. 본 발명의 지연방출성 구획은 장용성 고분자， 수불용성 중합체， 소수성 화합물， 친수성 고분자， 및 삼투성 반투과성막 코팅기제와 삼투제의 조합 등 중에서 선택된 물질을 사용한다. 상기 지연방출성 구획의 방출제어 물질은 활성성분 100중량부에 대하여 10 ~ 2,000중량부 사용가능한테， 사용량이 상기 범위 미만이면 층분한 지연방출성을 얻을 수 없고, 사용량이 상기 범위를 초과하면 약물방출이 지연되어 유의성 있는 임상적 효과를 얻을 수 없다. In the present invention, the delayed-release compartment refers to a compartment in which the active ingredient is released after a certain time of release of the prior-release compartment active ingredient. Delayed-release compartments Angiotensin Π ᅳ receptor blocker, an isomer thereof, or a pharmaceutically acceptable salt thereof, and 1) a release controlling substance or osmotic pressure control agent and a semipermeable membrane coating agent, as necessary, 2) pharmaceutically acceptable Possible additives may further be included. The delayed-release compartment of the present invention uses a material selected from an enteric polymer, a water insoluble polymer, a hydrophobic compound, a hydrophilic polymer, and a combination of an osmotic semipermeable membrane coating base and an osmotic agent. The release controlling substance of the delayed-release compartment may be used in an amount of 10 to 2,000 parts by weight based on 100 parts by weight of the active ingredient. If the amount is less than the above range, the delayed release property may not be obtained. Release is delayed and no significant clinical effect is obtained.
상기 장용성 고분자는 pH 5 미만의 산성 조건하에서 불용성이거나 또는 안정한 것으로, pH 5 이상인 특정 pH 조건하에서 용해되거나 또는 분해되는 고분자를 말한다. 본 발명에서 사용가능한 장용성 고분자는 장용성 셀를로오스 유도체， 장용성 아크릴산계 공중합체， 장용성 폴리메하크릴레이트 공중합체， 장용성 말레인산계 공중합체 및 장용성 폴리비닐 유도체로 이루어진 군에서 선택된 1종이상이며， 상기 장용성 셀를로오스 유도체는 히드록시프로틸메틸셀를로오스 아세테이트숙시네이트 , 히프로멜로오스프탈레이트 (히드록시프로필메틸셀를로오스 프탈레이트)， 히드록시메틸에틸셀를로오스프탈레이트, 셀를로오스아세테이트프탈레이트， 셀를로오스아세테이트숙시네이트 , 셀를로오스아세테이트말레이트， 셀를로오스벤조에이트프탈레이트 셀를로오스프로피오네이트프탈레이트 , 메틸셀를로오스프탈레이트, 카르복시메틸에틸셀를로오스 및 에틸히드록시에틸셀를로오스프탈레이트, 메틸히드록시에틸셀를로오스 중에서 선택된 i종 이상이고 상기 장용성 아크릴산계 공중합체는 스티렌—아크릴산 공중합체， 아크릴산메틸-아크릴산 공중합체， 아크릴산메틸메타크릴산 공중합체 (예컨대， 아크릴-이즈)， 아크릴산부틸 -스티렌-아크릴산 공중합체， 및 아크릴산메틸-메타크릴산-아크릴산옥틸공중합체 중에서 선택된 1종 이상이며 상기 장용성 폴리메타크릴레이트 공중합체는 폴리 (메타크릴산 메틸 메타크릴레이트) 공중합체 (예컨대， 유드라짓 L, 유드라짓 S, 에보닉， 독일 ) , 플리 (메타크릴산 에틸아크릴레이트) 공중합체 (예컨대， 유드라짓 L100— 55) 증에서 선택된 1종 이상이며 , 상기 장용성 말레인산계 공중합체는 아세트산비닐-말레인산 무수물 공중합체 , 스티렌-말레인산 무수물 공중합체 , 스티 렌-말레인산모노에스테를 공중합체 , 비닐메틸에테르-말레인산 무수물 공중합체 , 에틸렌-말레인산 무수물 공중합체 , 비닐부틸에테르-말레인산 무수물 공중합체， 아크릴로니트릴-크릴산메틸 ᅳ 말레인산 무수물 공중합체 , 및 아크릴산부틸 -스티렌-말레인산 무수물 공중합체 중에서 선택된 1종 이상이고 상기 장용성 폴리비닐 유도체는 폴리비닐알콜프탈테이트， 폴리비닐아세탈프탈레이트 , 폴리비닐부틸레이트프탈레이트 및 폴리비닐아세트아세탈프탈레이트 중에서 선택된 1종 이상이다. 본 발명 제제에서， 장용성 고분자는 히드록시프로틸메틸셀를로오스 프탈레이트 또는 아크릴산 메타크릴산 공중합체 중에서 선택된 1종 이상이 바람직하다. 상기 수불용성 중합체는 약물의 방출을 제어하는 약제학적으로 허용가능한 물에 용해되지 않는 고분자를 말한다. 본 발명에서 사용가능한 수블용성 증합체는 폴리비닐아세테이트 (예컨대 , 콜리코트 SR30D) , 수불용성 폴리메타크릴레이트 공중합체 [예컨대 , 플리 (에틸아크릴레이트-메틸 메타크릴레이트) 공중합체 (예컨대 , 유드라짓 NE30D, 폴리 (에틸아크릴테이트- 메틸 메타크릴레이트—트리메틸아미노에틸메타크릴테이트 클로라이드)공중합체 (예컨대, 유드라짓 RSP0)등]， 에틸셀를로오스, 셀를로오스 에스테르 셀를로오스 에테르， 셀를로오스 아실레이트， 셀를로오스 디아실레이트, 셀를로오스 트리아실레이트， 셀를로오스 아세테이트, 셀를로오스 디아세테이트 및 셀를로오스 트리아세테이트로 이루어진 군에서 선택된 1 종 이상인 것이다. 본 발명의 제제에서 수불용성 중합체는 에틸셀를로오스， 셀를로오스 아세테이트， 폴리비닐아세테이트 중에서 선택된 1종 이상이 바람직하다. 상기 소수성 화합물은 약물의 방출을 제어하는 약제학적으로 허용가능한 물에 용해되지 않는 물질을 말한다. 본 발명에서 사용가능한 소수성 화합물은 지방산 및 지방산 에스테르류, 지방산 알코을류， 왁스류， 무기물질, 및 이들의 흔합물로 이루어진 군에서 선택된 것이며， 상기 지방산 및 지방산 에스테르류는 글리세릴 팔미토스테아레이트, 글리세릴 스테아레이트， 글리세릴 비헤네이트， 세틸 팔미테이트， 글리세릴 모노 올레이트 및 스레아린산 중에서 선택된 1종 이상이고 상기 지방산 알코을류는 세토스테아릴 알코올， 세틸알코올 및 스테아릴알코을 중에서 선택된 1종 이상이며 상기 왁스류는 카르나우바왁스, 밀납， 및 미결정왁스 중에서 선택된 1종 이상이고 상기 무기물질은 탈크, 침강탄산칼슴， 인산일수소칼슘， 산화아연， 산화티탄， 카올린， 벤토나이트， 몬모릴로나이트 및 비검 중에서 선택된 1종 이상이다. 본 발명의 제제에서 소수성 화합물은 카르나우바왁스가 바람직하다. 상기 친수성 고분자는 약물의 방출을 제어하는 약제학적으로 허용가능한 물에 용해되는 고분자 물질을 말한다. 본 발명에서 사용가능한 친수성 고분자는 당류， 셀를로오스 유도체， 검류， 단백질류， 폴리비닐 유도체， 친수성 폴리메타크릴레이트 공중합체， 폴리에틸렌 유도체， 카르복시비닐폴리머， 및 이들의 혼합물로 이루어진 군에서 선택된 것이며， 상기 당류는 덱스트린， 폴리덱스트린， 덱스트란， 펙틴 및 펙틴 유도체， 알긴산염， 폴리갈락투론산, 자일란， 아라비노자일란， 아라비노갈락탄， 전분， 히드록시프로필스타치， 아밀로오스, 및 아밀로펙틴 중에서 선택된 1종 이상이고 ； 상기 셀를로오스 유도체는 히드록시프로필셀를로오스, 히드록시프로필샐를로오스， 히드록시메틸셀를로오스, 히드록시에틸셀를로오스， 메틸셀를로오스 및 카르복시메틸셀를로오스 나트륨 중에서 선택된 1종 이상 상기 검류는 구아검， 로커스트 콩 검， 트라가칸타, 카라기난， 아카시아검， 아라비아검， 젤란검， 및 잔탄검 중에서 선택된 1종 이상 상기 단백질류는 젤라틴， 카제인, 및 제인 중에서 선택된 1종 이상 상기 플리비닐 유도체는 폴리비닐 알코올， 폴리비닐 피를리돈, 및 폴리비닐아세탈디에틸아미노아세테이트 중에서 선택된 1종 이상 상기 친수성 폴리메타크릴레이트 공중합체는 폴리 (부틸 메타크릴레이트 -(2- 디메틸아미노에틸)메타크릴레이트-메틸메타크릴레이트) 공중합체 (예컨대, 유드라짓 EIOO, 에보닉， 독일)， ，이고 상기 플리에틸렌 유도체는 폴리에틸렌 글리콜， 및 폴리에틸렌 옥사이드 증에서 선택된 1종 이상 및 상기 카르복시비닐폴리머는 카보머를 사용한다. 본 발명의 제제에서 친수성 고분자는 히드록시프로필셀를로오스, 히드록시프로필메틸셀를로오스， 폴리비닐 피를리돈， 폴리에틸렌 글리콜 6000중에서 선택된 1종 이상이 바람직하다. 삼투성 반투과성막 코팅기제는 약학적으로 사용가능한 코팅기제로서, 약학적 제제의 코팅층에 배합하여 일부 성분은 통과시키지만, 다른 성분은 통과시키지 않는 막을 형성하는데 사용하는 물질을 말한다. 본 발명에서 반투과성막 코팅기제는 예컨대 폴리비닐 아세테이트， 폴리메타크릴레이트 공중합체， 에틸셀를로오스， 셀를로오스 에스테르， 셀를로오스 에테르， 셀를로오스 아실레이트, 셀를로오스 디아실레이트, 셀를로오스 트리아실레이트， 셀를로오스 아세테이트, 셀를로오스 디아세테이트, 셀를로오스 트리아세테이트 및 이들의 흔합물로 이루어진 군에서 선택된 1종 이상을 들 수 있다. 본 발명의 제제에서 반투과성막 코팅기제는 에틸셀를로오스, 셀를로오스 아세테이트 증에서 선택된 1종 이상이 바람직하다. 삼투제는 황산마그네슘， 염화마그네슴， 염화나트륨, 염화리튬, 황산칼튬， 황산나트륨， 황산리튬, 황산나트륨 및 이들의 흔합물로 이루어진 군에서 선택된The enteric polymer is insoluble or stable under acidic conditions of less than pH 5, and refers to a polymer that is dissolved or decomposed under specific pH conditions of pH 5 or higher. The enteric polymer which can be used in the present invention is at least one selected from the group consisting of an enteric cellulose derivative, an enteric acrylic acid copolymer, an enteric polymethacrylate copolymer, an enteric maleic acid copolymer and an enteric polyvinyl derivative. Cellulose derivatives include hydroxypropylmethylcellulose acetate succinate, hypromellose phthalate (hydroxypropylmethylcellulose phthalate), hydroxymethylethylcellulose phthalate, celluloseacetate phthalate, cellullo Osacetate Succinate, Cellulose Acetate Maleate, Cellulose Benzoate Phthalate Cell Loss Propionate Phthalate, Methyl Cellulose Phthalate, Carboxymethylethyl Cellulose and Ethylhydroxyethyl Cellulose Phthalate, Methyl Hydrate rock From the agarose with ethyl selreul At least one of the selected i-type enteric acrylic acid copolymers may be selected from the group consisting of styrene-acrylic acid copolymer, methyl acrylate-acrylic acid copolymer, methyl methacrylate acrylic acid copolymer (e.g. acrylic-is), butyl acrylate-styrene-acrylic acid copolymer, and At least one selected from methyl acrylate-methacrylic acid-octyl acrylate copolymer, wherein the enteric polymethacrylate copolymer is a poly (methyl methacrylate) copolymer (e.g., Eudragit L, Eudragit S) , Evonik, Germany), one or more selected from poly (ethyl methacrylate) copolymer (e.g. Eudragit L100-55), the enteric maleic acid copolymer is vinyl acetate-maleic anhydride copolymer , Styrene maleic anhydride copolymer, styrene maleic acid monoester copolymer, vinyl methyl ether maleic acid At least one selected from an anhydride copolymer, an ethylene-maleic anhydride copolymer, a vinylbutyl ether-maleic anhydride copolymer, an acrylonitrile-methyl acrylate maleic anhydride copolymer, and a butyl-styrene-maleic anhydride copolymer The enteric polyvinyl derivative is at least one selected from polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate and polyvinyl acetal phthalate. In the preparation of the present invention, the enteric polymer is preferably at least one selected from hydroxypropylmethyl cellulose phthalate or acrylic acid methacrylic acid copolymer. The water insoluble polymer refers to a polymer that is not soluble in pharmaceutically acceptable water that controls the release of the drug. The water-soluble polymers usable in the present invention include polyvinylacetates (eg, colicoat SR30D), water-insoluble polymethacrylate copolymers [eg, poly (ethylacrylate-methyl methacrylate) copolymers (eg, Eudra). NE30D, poly (ethyl acrylate- Methyl methacrylate—trimethylaminoethylmethacrylate chloride) copolymers (eg Eudragit RSP0), etc., ethyl cellulose, cellulose ester cellulose ether, cellulose acylate, cellulose dia At least one member selected from the group consisting of silates, cellulose triacylates, cellulose acetate, cellulose diacetate and cellulose triacetate. In the preparation of the present invention, the water-insoluble polymer is preferably one or more selected from ethyl cellulose, cellulose acetate, and polyvinylacetate. The hydrophobic compound refers to a substance that does not dissolve in pharmaceutically acceptable water that controls the release of the drug. The hydrophobic compounds usable in the present invention are selected from the group consisting of fatty acids and fatty acid esters, fatty acid alcohols, waxes, inorganic substances, and mixtures thereof, and the fatty acids and fatty acid esters are glyceryl palmitostearate, At least one selected from glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and slearinic acid, and the fatty acid alcohols are at least one selected from cetostearyl alcohol, cetyl alcohol and stearyl alcohol. Wherein the wax is at least one selected from carnauba wax, beeswax, and microcrystalline wax, and the inorganic material is selected from talc, precipitated carbonate, calcium hydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite and non-gum. It is one or more selected. In the formulation of the present invention, the hydrophobic compound is preferably carnauba wax. The hydrophilic polymer refers to a polymeric material that is dissolved in pharmaceutically acceptable water that controls the release of the drug. Hydrophilic polymers that can be used in the present invention Sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl polymers, and mixtures thereof, wherein the sugars are dextrins, polydextrins, At least one selected from dextran, pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose, and amylopectin; The derivative is at least one selected from hydroxypropylcellose, hydroxypropylcelose, hydroxymethylcellose, hydroxyethylcellose, hydroxyethylcellose, methylcellose and carboxymethylcellose sodium. Gum, locust bean gum, tragacanta, carrageenan, acacia gum, The at least one protein selected from ruby gum, gellan gum, and xanthan gum is gelatin, casein, and zein at least one polyvinyl derivative selected from polyvinyl alcohol, polyvinyl pyridone, and polyvinyl acetal diethyl. At least one hydrophilic polymethacrylate copolymer selected from aminoacetates may be a poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer (e.g. Eudragit EIOO, Evo Nick, Germany), and the polyethylene derivative is at least one selected from polyethylene glycol, polyethylene oxide, and the carboxyvinyl polymer uses carbomer. In the preparation of the present invention, the hydrophilic polymer is preferably at least one selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyridone, and polyethylene glycol 6000. The osmotic semipermeable membrane coating base is a pharmaceutically usable coating base, which is used in the coating layer of the pharmaceutical formulation to form a membrane which allows some components to pass but does not pass other components. In the present invention The semipermeable membrane coating base is, for example, polyvinyl acetate, polymethacrylate copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacyl And at least one selected from the group consisting of latex, cellulose acetate, cellulose diacetate, cellulose triacetate, and combinations thereof. In the preparation of the present invention, the semi-permeable coating agent is preferably at least one selected from ethyl cellulose and cellulose acetate. Osmotic agents are selected from the group consisting of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, lithium sulfate, sodium sulfate, lithium sulfate, sodium sulfate and combinations thereof
1종 이상의 것이다. 바람직하게는 염화나트륨을 사용한다. 상기 방출제어 물질은 단독 또는 2종 이상을 사용되어， 안지오텐신ᅳ Πᅳ수용체 차단제 100중량부 대비 5~10，000 중량부를 사용하며， 바람직하게는 20~5， 000중량부， 가장 바람직하게는 50~3,000증량부를 사용된다. 5중량부 이하에서는 층분한 지연시간을 갖기 힘들고， 10, 000중량부 이상에서는 약물의 방출이 일어나지 않거나지연 시간이 12시간을 초과한다. It is one or more. Preferably sodium chloride is used. The release control material is used alone or two or more, 5 to 10,000 parts by weight relative to 100 parts by weight of angiotensin ᅳ π ᅳ receptor blocker, preferably 20 to 5,000 parts by weight, most preferably 50 ~ 3,000 increments are used. At 5 parts by weight or less, it is difficult to have a delayed time, and at 10,000 parts by weight or more, no release of the drug occurs or the delay time exceeds 12 hours.
본 발명의 효과를 해치지 않는 범위 안에서 상기 지연방출성 구획의 약학적으로 허용 가능한 첨가제로는， 회석제， 결합제， 붕해제， 윤활제 , pH 조절제， 안정화제, 착색제， 향료， 계면활성제 등이 적합하고， 이의 함량은 활성성분 100중량부에 대하여 100 ~ 30,000 중량부가 바람직하다. 본 발명의 효과를 해치지 않는 범위 안에서 약학적으로 허용 가능한 회석제로서 슈가， 전분, 미세결정성 셀를로오스， 유당， 포도당， 만니를, 알기네이트 알칼리토류금속염， 클레이, 폴리에틸렌글리콜 및 디칼슘 포스페이트 등을 사용할 수 있다. 결합제로서 전분， 미세결정성 셀를로오스, 고분산성 실리카, 만니를， 락토스, 폴리에틸렌글리콜, 폴리비닐피를리돈， 폴리비닐피를리돈 공중합체, 히드록시프로필 메틸셀를로오스， 히드록시프로필셀를로오스, 천연검 합성검 및 젤라틴 등을 사용할 수 있다 . 붕해제로서 전분글리콘산나트륨 옥수수 전분， 감자 전분 또는 전호화 전분 등의 전분 또는 변성전분과 벤토나이트， 몬모릴로나이트， 비검 (veegum) 등의 클레이와， 미결정셀를로오스 저치환도 히드록시프로필셀를로오스 또는 알긴산과 크로스카멜로스 (croscarmellose) 나트륨 등의 가교 셀를로오스류와， 구아검 잔탄검 등의 검류와， 크로스포비돈 (crospovidone) 등의 가교 중합체와， 중탄산 나트륨, 시트르산 등의 비등성 제제 등을 흔합사용할 수 있다. 윤활제로서는 탈크, 스테아린산， 스테아린산 마그네슘， 스테아린산 칼슴， 라우릴설페이트나트륨, 수소화식물성오일， 나트륨벤조에이트， 나트륨스테아릴푸마레이트， 글리세릴 베헤네이트， 글리세릴 모노레이트， 글리세릴모노스테아레이트, 글리세릴 팔미토스테아레이트 콜로이드성 이산화규소 폴리에틸렌글리콜 4000 또는 이들의 흔합물 등을 사용할 수 있고 이외에도 pH 조절제， 안정화제， 계면 활성제, 착색제， 향료 중에서 선택된 다양한 첨가제로서 약학적으로 허용 가능한 첨가제를 선택 사용할 수 있다. 이러한 첨가제로서 본 발명의 실시예에서는 미결정셀를로오스, 전호화 전분， 플리비닐피를리돈 공중합체, 콜로이드성 이산화규소， 스테아린산 마그네슴 등을 사용하고 있으나 본 발명의 범위가 상기 첨가제를 사용하는 것으로 한정되는 것은 아니며， 상기한 첨가제는 당업자의 선택에 의하여 통상의 범위의 용량을 함유할 수 있다. 상기 선방출성 구획을 구성하는 유효 활성성분을 제외한 약학적으로 허용 가능한 첨가제로는， 희석제, 결합제， 붕해제, 윤활제， pH조절제, 안정화제， 착색제， 향료, 계면활성제 등이 적합하고， 이의 함량은 활성성분 100중량부에 대하여 100 ~ 30,000중량부가 바람직하다. 본 발명의 효과를 해치지 않는 범위 안에서 약학적으로 허용 가능한 희석제로서 슈가， 전분, 미결정셀를로오스, 유당, 포도당， 만니틀， 알기네이트， 알칼리토류금속염, 클레이, 폴리에틸렌글리콜 및 디칼슴 포스페이트등을 사용할 수 있다. As a pharmaceutically acceptable additive of the delayed-release compartment within the scope of not impairing the effects of the present invention, diluents, binders, disintegrants, lubricants, pH adjusting agents, stabilizers, coloring agents, flavoring agents, surfactants, etc. are suitable. Its content is preferably 100 to 30,000 parts by weight based on 100 parts by weight of the active ingredient. As a pharmaceutically acceptable diluent within the scope of not impairing the effects of the present invention, sugar, starch, microcrystalline cellulose, lactose, glucose, manny, alginate alkaline earth metal salt, clay, polyethylene glycol and dicalcium phosphate, etc. of Can be used. As a binder, starch, microcrystalline cellulose, highly disperse silica, manny, lactose, polyethylene glycol, polyvinylpyridone, polyvinylpyridone copolymer, hydroxypropyl methylcellose, hydroxypropylcell Acetic acid, natural gum synthetic gum, gelatin and the like can be used. Starch or modified starch, such as sodium starch glycolate, potato starch or pregelatinized starch, clays such as bentonite, montmorillonite, veegum, and microcrystalline cellulose low-substituted hydroxypropyl cellulose as disintegrants Or crosslinked cells such as alginic acid and croscarmellose sodium, gums such as guar gum xanthan gum, crosslinked polymers such as crospovidone, and effervescent agents such as sodium bicarbonate and citric acid. It can be used in combination. Examples of lubricants include talc, stearic acid, magnesium stearate, stearic acid calum, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostearate, and glyceryl palmi. Tostearate colloidal silicon dioxide polyethylene glycol 4000 or a combination thereof may be used, and pharmaceutically acceptable additives may be selected and used as various additives selected from pH adjusting agents, stabilizers, surfactants, colorants, and flavoring agents. In the embodiment of the present invention as such additives, microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer, colloidal silicon dioxide, stearic acid magnesium and the like are used. It is not limited, and the above additives may contain a conventional range of dosages by the choice of those skilled in the art. Pharmaceutically, except for the active ingredient constituting the pre-release compartment As acceptable additives, diluents, binders, disintegrants, lubricants, pH adjusting agents, stabilizers, coloring agents, flavoring agents, surfactants and the like are suitable, and the content thereof is preferably 100 to 30,000 parts by weight based on 100 parts by weight of the active ingredient. Sugar, starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol and decalum phosphate may be used as a pharmaceutically acceptable diluent within the scope of not impairing the effects of the present invention. Can be.
결합제로서 전분, 미결정셀를로오스， 고분산성 실리카, 만니를, 유당, 플리에틸렌글리콜, 플리비닐피를리돈, 플리비닐피롤리돈 공중합체, 히드록시프로필 메틸셀를로오스， 히드록시프로필셀를로오스， 천연검， 합성검 및 젤라틴 등을 사용할 수 있다.  Starch, microcrystalline cellulose, highly dispersible silica, manny, lactose, polyethylene glycol, polyvinylpyridone, polyvinylpyrrolidone copolymer, hydroxypropyl methylcellose, hydroxypropylcelose , Natural gums, synthetic gums and gelatin can be used.
붕해제로서 전분글리콘산나트륨， 옥수수 전분， 감자 전분 또는 전호화 전분 등의 전분 또는 변성전분과, 벤토나이트， 몬모릴로나이트， 비검 (veegum) 등의 클레이와, 미결정셀를로오스， 저치환도 히드록시프로필셀를로오스 또는 알긴산과， 크로스카멜로스 (croscarmellose) 나트륨 등의 가교 셀를로오스류와, 구아검， 잔탄검 등의 검류와， 크로스포비돈 (crospovidone) ,등의 가교 중합체와， 중탄산나트륨， 시트르산 등의 비등성 제제 등을 흔합사용할 수 있다. Starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch as a disintegrating agent, clays such as bentonite, montmorillonite, veegum, microcrystalline cellulose and low-substituted hydroxypropyl and agarose or alginate in selreul, croscarmellose (croscarmellose) and a cross-linked selreul agarose acids such as sodium and gums such as guar gum, xanthan gum, cross-povidone (crospovidone), the cross-linked polymer such as, sodium bicarbonate, citric acid, etc. Can be used in combination.
윤활제로서는 탈크， 스테아린산， 스테아린산 마그네슘, 스테아린산 칼슘, 라우릴설페이트나트륨, 수소화식물성오일, 나트륨벤조에이트, 나트륨스테아릴푸마레이트， 글리세릴 베헤네이트, 글리세릴 모노레이트, 글리세릴모노스테아레이트， 글리세릴 팔미토스테아레이트, 콜로이드성 이산화규소， 폴리에틸렌글리콜 4000 또는 이들의 흔합물 등을 사용할 수 있고 이외에도 pH 조절제， 안정화제 계면 활성제， 착색제 향료 중에서 선택된 다양한 첨가제로서 약학적으로 허용 가능한 첨가제를 선택 사용할수 있다.  As lubricants, talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostearate, glyceryl palmi Tostearate, colloidal silicon dioxide, polyethylene glycol 4000, or a combination thereof may be used, and pharmaceutically acceptable additives may be selected as various additives selected from pH adjusters, stabilizer surfactants, and colorant flavors.
이러한 첨가제로서 본 발명의 실시예에서는 유당， 미결정셀를로오스, 옥수수 전분， 전호화전분， 폴리비닐피를리돈 공중합체 , 슈가， 히드록시프로필메틸셀를로오스， 히드록시프로필셀를로오스， 저치환도 히드록시프로필셀를로오스, 콜로이드성 이산화규소， 스테아린산 마그네슘 등을 사용하고 있으나 본 발명의 범위가 상기 첨가제를 사용하는 것으로 한정되는 것은 아니며, 상기한 첨가제는 당업자의 선택에 의하여 통상의 범위의 용량을 함유할 수 있다. In the embodiment of the present invention as such an additive, lactose, microcrystalline cellulose, Corn starch, pregelatinized starch, polyvinylpyridone copolymer, sugar, hydroxypropylmethylcellose, hydroxypropylcellose, low-substituted hydroxypropylcellose, colloidal silicon dioxide, magnesium stearate, etc. Although the scope of the present invention is used is not limited to the use of the additives, the additives may contain a conventional range of capacity by the choice of those skilled in the art.
상기 제제는 필요에 따라 상기 정제의 외면에 필름상의 코팅층을 형성시킬 수 있다. 즉, 본 발명의 치아자이드계 화합물 /안지오텐신一 Πᅳ수용체 차단제 복합 조성물은 코팅층이 없는 나정의 형태로도 사용 가능하며， 상기 유효성분을 함유하는 정제의 표면에 코팅층을 형성하여 코팅정으로 제제화할 경우 활성 성분의 안정성을 더욱 확보할 수 있는 이점이 있다. 코팅층을 형성하는 방법은 상기한 성분들을사용하여 정제층의 표면에 필름상의 코팅층을 형성할 수 있는 방법 중에서 당업자의 선택에 의하여 적절히 선택할수 있으며， 유동층 코팅법, 팬 코팅법 등의 방법을 적용할 수 있다. 바람직하기로는 팬 코팅법을사용하는 것이 좋다.  The formulation may form a film-like coating layer on the outer surface of the tablet, if necessary. That is, the thiazide compound / angiotensin 一 ᅳ receptor blocker composite composition of the present invention can be used in the form of uncoated tablets without a coating layer, to form a coating layer on the surface of the tablet containing the active ingredient to be formulated into a coated tablet. In this case, there is an advantage of further securing the stability of the active ingredient. The method of forming the coating layer can be appropriately selected by a person skilled in the art from the method of forming a film-like coating layer on the surface of the tablet layer using the above-described components, and can be applied to methods such as a fluidized bed coating method and a fan coating method. Can be. It is preferable to use a pan coating method.
상기 코팅층은 피막제， 피막 보조제 또는 이들의 흔합물을 사용할 수 있는데， 구체적으로 상기 코팅층은 피막제로서 셀를로오스 유도체, 당 유도체, 폴리비닐 유도체 , 왁스류, 지방류 및 젤라틴 등을 사용할 수 있고, 피막 보조제로서 폴리에틸렌글리콜， 에틸셀를로오스, 글리세라이드류， 산화티탄 및 디에틸프탈레이트 등 중에서 선택된 1종 또는 2종 이상의 흔합물을 사용할 수 있다.  The coating layer may be a coating agent, a coating aid or a combination thereof. Specifically, the coating layer may be used as a coating agent, such as cellulose derivatives, sugar derivatives, polyvinyl derivatives, waxes, fats, gelatin, and the like. As the polyethylene glycol, ethyl cellulose, glycerides, titanium oxide, diethyl phthalate and the like, one or two or more kinds thereof may be used.
이때， 코팅정으로 제형화할 경우 상기 코팅층은 정제 총 중량 중 0.5 ~ 15중량 % 범위로 포함되는 것이 좋다. 이하 본 발명의 치아자이드계 화합물과 안지오텐신ᅳ Πᅳ수용체 차단제의 효율적인 방출 시스템의 제조 방법을 각 단계별로 구체적으로 설명한다. At this time, when formulated as a coated tablet, the coating layer is preferably included in the range of 0.5 to 15% by weight of the total weight of the tablet. Hereinafter, a method for preparing an efficient release system of the thiazide compound and angiotensin ᅳ π ᅳ receptor blocker of the present invention will be described in detail for each step.
제 1 단계는， 안지오텐신ᅳ Πᅳ수용체 차단제를 장용성 고분자, 수불용성 중합체， 소수성 화합물， 친수성 고분자， 삼투성 반투과성막 코팅기제 및 삼투제 중에서 선택된 방출제어 물질 1종 또는 2종 이상 및 약학적으로 사용되는 통상의 첨가제와 흔합하여 지연방출이 가능하도록 설계된 조성물을 얻는 단계이다.  In the first step, an angiotensin Π ᅳ receptor blocker is used in one or two or more release control substances selected from enteric polymers, water insoluble polymers, hydrophobic compounds, hydrophilic polymers, osmotic semipermeable membrane coating bases and osmotic agents, and pharmaceutically. It is a step of obtaining a composition designed to enable delayed release in combination with conventional additives.
제 2 단계는, 치아자이드계 화합물과 약학적으로 허용되는 통상의 첨가제로부터 흔합, 연합, 건조 및 제립과 같은 경구 고형제를 생산하기 위한 통상의 과정을 통하여 얻어진 입자, 과립, 펠렛을 그대로 사용하거나 필름 코팅제와 함께 용해 또는 현탁 시킨 코팅액을 사용하여 코팅한 입자， 과립, 펠렛을 사용하여 선방출성이 가능하도록 설계된 조성물을 얻는 단계이다.  The second step is to use the particles, granules and pellets as they are obtained through the usual procedures for producing oral solids such as mixing, coalescing, drying and granulation from thiazide compounds and conventional pharmaceutically acceptable additives or It is a step of obtaining a composition designed to be capable of pre-release using particles, granules, pellets coated using a coating solution dissolved or suspended with a film coating agent.
제 3 단계는， 각 1 및 2단계에서 얻어진 지연방출이 가능하도록 설계된 조성물과 선방출이 가능하도록 설계된 조성물을 사용하여 지연방출성 경구투여 복합제를 얻는 단계이다.  The third step is to obtain a delayed-release oral combination using a composition designed to be delayed-release and a composition designed to be prior-release obtained in each of steps 1 and 2.
본 과정에 의하여 본 발명의 치아자이드계 화합물과 안지오텐신ᅳ Πᅳ수용체 차단제의 효율적인 방출을 나타내는 경구 투여 제제가 제조된다. 경구 투여 제제의 보다 상세한 제조 방법은 다음과 같으나， 이에 한정되는 것은 아니다. 가. 2상 메트릭스 정제의 제조  This procedure prepares oral dosage formulations that exhibit efficient release of the ziazide-based compounds of the invention and angiotensin ᅳ i receptor receptors. More detailed methods of preparing oral dosage forms are as follows, but are not limited thereto. end. Preparation of Two Phase Matrix Tablets
제 1단계에서 얻어진 입자， 과립 또는 펠렛을 그대로 또는 장용성 고분자, 수불용성 중합체ᅳ 소수성 화합물， 친수성 고분자， 삼투성 반투과성막 코팅 기제 및 삼투제 중에서 선택된 1종 또는 2종 이상을 포함하는 방출 제어 물질로 코팅 한 후 제 2단계에서 제조한 과립과 흔합하여 일정량의 무게로 타정하여 정제를 제조한다. 얻어진 정제를 안정성 또는 성상 개선의 목적으로 필요에 따라 필름 코팅을 할 수 있다 . 나. 필름 코팅 정의 제조 The particles, granules or pellets obtained in the first step may be used as is or in an enteric polymer, a water-insoluble polymer or a hydrophobic compound, a hydrophilic polymer, or an osmotic semipermeable membrane. Tablets are prepared by coating with a release controlling substance comprising one or two or more selected from a coating base and an osmotic agent, then mixing with the granules prepared in the second step and tableting to a certain amount of weight. The obtained tablet can be film-coated as necessary for the purpose of improving stability or properties. I. Film coating custom fabrication
제 1단계에서 얻어진 입자， 과립， 펠렛 또는 정제를 장용성 고분자， 수불용성 증합체 ᅳ 소수성 화합물， 친수성 고분자， 삼투성 반투과성막 코팅기제 및 삼투제 중에서 선택된 1종 또는 2종 이상올 포함하는 방출 제어 물질로 코팅하고 건조한 후 일정량으로 타정하여 정제를 제조하거나 코팅 정을 제조한 후， 외층에 제 2단계에서 얻은 약물을 포함하는 코팅 액으로 정제를 코팅하여 필름코팅정을 제조할 수 있다 . 다. 다층정의 제조  A release controlling substance comprising particles, granules, pellets or tablets obtained in the first step comprising an enteric polymer, a water-insoluble polymer, a hydrophobic compound, a hydrophilic polymer, an osmotic semipermeable membrane coating base, and an osmotic agent. After coating with dry and tableting to a certain amount to prepare a tablet or to prepare a coated tablet, the outer layer may be coated with a coating solution containing the drug obtained in the second step to prepare a film coated tablet. All. Multilayer Tablet Preparation
제 1단계에서 얻어진 입자， 과립 , 펠렛을 그대로 또는 장용성 고분자， 수불용성 중합체， 소수성 화합물 , 친수성 고분자, 삼투성 반투과성막 코팅기제 및 삼투제 중에서 선택된 1종 또는 2종 이상을 포함하는 방출 제어 물질로 코팅하고 건조한 후 제 2단계에서 얻어진 과립 ᅳ 펠펫을 추가하여 다층정 타정기를 이용하여 2중정으로 제조할 수 있다 . 필요에 따라 방출 보조층을 추가하여 3중 또는 그이상의 다층정을 제조하거나 코팅하여 코팅 다층정을 제조할 수 있다 . 라 . 유핵정  The particles, granules and pellets obtained in the first step may be used as they are or as an emission control material comprising at least one selected from an enteric polymer, a water insoluble polymer, a hydrophobic compound, a hydrophilic polymer, an osmotic semipermeable membrane coating base, and an osmotic agent. After coating and drying, the granules and pellets obtained in the second step may be added to prepare double tablets using a multilayer tablet press. If necessary, a triple layer or more multilayered tablets may be prepared or coated by adding an emission auxiliary layer to prepare a coated multilayer tablet. D. Nucleus
체 1단계에서 얻어진 정제를 내핵정으로 하고 장용성 고분자, 수불용성 중합체， 소수성 화합물, 친수성 고분자， 삼투성 반투과성막 코팅기제 및 삼투제 증에서 선택된 1종 또는 2종 이상을 포함하는 방출 제어 물질로 코팅한 후 제 2단계에서 얻은 과립과 함께 유핵정 타정기를 이용하여 유핵정을 제조하거나 코팅하여 코팅 유핵정을 제조할 수 있다. 마. 캡술제 (과립， 정제) The tablet obtained in the sieve step 1 is used as an inner core tablet, and the enteric polymer and the water insoluble Coating with a release control material comprising one or more selected from polymers, hydrophobic compounds, hydrophilic polymers, osmotic semipermeable membrane coating bases, and osmotic agents, and then using a nucleated tablet press with granules obtained in the second step. Nucleated tablets can be prepared or coated to produce coated nucleated tablets. hemp. Capsulants (granules, tablets)
제 1단계에서 얻어진 입자， 과립, 정제를 그대로 또는 장용성 고분자， 수불용성 중합체, 소수성 화합물, 친수성 고분자, 삼투성 반투과성막 코팅기제 및 삼투제 중에서 선택된 1종 또는 2종 이상을 포함하는 방출 제어 물질로 코팅하고 건조한 과립, 펠렛， 정제와 제 2단계에서 얻은 과립, 정제를 캡술층전기에 넣고 일정 크기의 캡술에 각주성분 유효량 해당량 만큼 층전하여 캡술제를 제조할 수 있다. 바. 캡술제 (펠렛)  The particles, granules and tablets obtained in the first step may be used as they are or as an emission control material comprising at least one selected from an enteric polymer, a water insoluble polymer, a hydrophobic compound, a hydrophilic polymer, an osmotic semipermeable membrane coating base, and an osmotic agent. Coated and dried granules, pellets, tablets and granules and tablets obtained in the second step can be put into the capsule layer electrophoresis layered capsule to a certain size capsule by the effective amount of the footnote component. bar. Capsulicide (pellets)
안지오텐신ᅳ Πᅳ수용체 차단제와 방출 제어 물질 또는 제제학적으로 허용 가능한 첨가제를 물 또는 유기용매 또는 흔합용매에 용해시키거나 현탁시켜 설탕 구형과립에 코팅， 건조 후 필요에 따라 장용성 고분자, 수불용성 중합체， 소수성 화합물, 친수성 고분자， 삼투성 반투과성막 코팅기제 및 삼투제 증에서 선택된 1종 또는 2종 이상을 포함하는 방출 제어 물질을 물 또는 유기용매 또는 흔합용매에 용해시킨 후 코팅, 건조한 후 제 2단계에서 얻은 코팅 액으로 코팅한 펠렛을 캡술에 그대로 층전하거나， 필름 코팅 후 층전하는 캡슬제를 제조할 수 있다. 또한, 위의 마. 바와 같은 제조방법으로 얻어진 지연방출성 과립, 펠렛， 정제와 선방출성 과립, 펠렛， 정제를 서로 흔합하여 지연방출성-선방출성 (과립-과립， 과립—펠렛, 과립-정제, 펠렛-과립, 정제-과립)의 형태로 제조 할 수 있다. 사. 키트의 제조 Angiotensin Π ᅳ receptor blockers and release control substances or pharmaceutically acceptable additives are dissolved or suspended in water or organic solvents or mixed solvents, coated on sugar spherical granules, dried and, if necessary, enteric polymers, water insoluble polymers, hydrophobic The release control material comprising one or two or more selected from a compound, a hydrophilic polymer, an osmotic semipermeable membrane coating base, and an osmotic agent is dissolved in water, an organic solvent or a mixed solvent, coated, dried, and then obtained in the second step. Pellets coated with the coating liquid may be layered as they are on the capsule, or a capsule may be layered after film coating. Also, do the above. Delayed-release granules, pellets, Tablets, pre-release granules, pellets, and tablets can be mixed with each other to produce delayed-release (pre-release) granules, granules-pellets, granules-tablets, pellets-granules, tablets-granules. four. Manufacture of kit
제 1단계에서 얻어진 안지오텐신— π_수용체 차단제 함유 제제와 제 2단계에서 얻어진 치아자이드계 화합물 함유 제제를 호일, 블러스터, 병 둥에 같이 층전하여 동시에 복용이 가능한 키트로 제조할수 있다. 상기와 같은 본 발명의 복합 약물 시스템은 치아자이드계 화합물과 안지오텐신ᅳ Πᅳ수용체 차단제를 유효 활성성분으로 포함하여 복합 제제화 되어 아침 시간대에 단 1일 1회씩 투여함으로써 각 유효 활성성분을 별도로 제제화하여 이를 동시에 복용케 하는 경우 보다 복약지도가 쉽고, 또한 부작용올 감소시킬 수 있으며, 각 약물이 가지는 혈압 강하 효과가 단독으로 가지는 효과보다 향상되어 나타나고， 두 약물을 동시에 투여하는 것 보다 향상된 효과를 나타낸다.  The angiotensin-containing receptor blocker preparation obtained in the first step and the zigzide compound-containing preparation obtained in the second step can be prepared as a kit that can be simultaneously layered on a foil, a blister or a bed. The complex drug system of the present invention as described above is formulated with a compound containing an ziazide-based compound and angiotensin ᅳ Π ᅳ receptor blocker as an active ingredient, and is administered only once a day in the morning hours to separately formulate each active ingredient. In the case of taking at the same time, it is easier to take the medication, and side effects can be reduced, and the blood pressure lowering effect of each drug appears to be higher than that of the single drug, and it shows an improved effect than the administration of two drugs simultaneously.
이러한 복합 약물 시스템을 이용하여 본 발명자들은 복합제 조성물 연구를 하였으며, 이러한 효과를 발휘 할 수 있음을 확인하였다. 이하， 본 발명을 실시예에 의거하여 구체적으로 설명하겠는바, 본 발명이 다음 실시예에 의하여 한정되는 것은 아니다. 실시예 1: 유핵정 제조  By using the combination drug system, the present inventors studied the combination composition, and confirmed that such an effect can be obtained. Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by the following Examples. Example 1 Preparation of Nucleated Tablets
1) 안지오텐신ᅳ Πᅳ수용체 차단제 지연방출형 내핵정의 제조 안지오텐신ᅳ Π ᅳ수용체 차단제 지연방출형 내핵정 제조는 표 4와 같은 조성과 함량으로 로사르탄 칼륨， 미결정셀를로오스， 전호화전분， 폴리비닐피롤리돈 공증합체 , 콜로이드성 이산화규소 * 35호체로 체과하고 고속흔합기로 5분간 흔합하여 흔합물을 제조한다. 흔합물에 스테아린산 마그네슘 투입 후 4분간 흔합하고， 종 흔합물을 로타리 타정기 (MRC-33 : 세종)를 사용하여 타정하며 이를 내핵정으로 한다. 이렇게 제조한 내핵정을 하이코터 (SFC-30N: 세종 기계 , 한국)에 투입하고 , 히드록시프로필메틸셀를로오스와 아크릴산 메타크릴산 공중합체 (아크릴리즈)를 용해 및 분산 시켜 코팅 액으로 하여 지연방출형 내핵정을 제조하였다. 1) Preparation of Angiotensin® Π ᅳ Receptor Blocker Delayed-Release Inner Core Tablets Angiotensin ᅳ Π ᅳ Receptor Blocker Delayed-release inner core tablets were prepared in the following compositions and contents as shown in Table 4 with potassium losartan, microcrystalline cellulose, pregelatinized starch, polyvinylpyrrolidone copolymer, and colloidal silicon dioxide * 35. Sieve and mix for 5 minutes with a high-speed mixer to prepare a mixture. After adding magnesium stearate to the mixture, mix for 4 minutes, and use the rotary tableting machine (MRC-33: Sejong) to tablet the species mixture. The inner core tablet thus prepared was introduced into a high coater (SFC-30N: Sejong Machinery, South Korea), and hydroxypropylmethylcell was dissolved and dispersed in cellulose and acrylic acid methacrylic acid copolymer (acrylate) to be delayed as a coating solution. Ejective inner core tablets were prepared.
2) 치아자이드계 화합물 선방출층의 제조 2) Preparation of Chiazide Compound Pre-Release Layer
치아자이드계 화합물 선방출층 제조는 표 4와 같은 조성과 함량으로 히드로클로로치아짓， 미결정셀를로오스， 유당， 옥수수전분 , 저치환도 히드록시프로필셀를로오스를 달아 35호체로 체과하고 더블콘믹서에서 5분간 흔합하여 흔합물을 제조한다. 따로 히드록시프로필셀를로오스를 정제수에 녹여 결합액을 제조한다. 상기 흔합물을 유동층과립기 또는 고속회전 조립기에 넣고 결합액을 가하여 조립한다. 바람직하게는 유동층 과립기를 사용한다. 유동층 과립기는 GPCG-l(Glatt , Germany)을 사용하였다. 조립이 완료된 후 유동층 건조기 또는 온수건조기에 조립물을 건조 시킨다. ■ 바람직하게는 유동층 건조기를 사용한다. 유동층 과립 건조기는 GPCG-l(Glatt , Germany)을 사용하였다. 건조가 완료되면 건조물을 18호체가 장착된 오실레이터를 사용하여 정립한다. 정 립물에 콜로이드성 이산화규소를 넣고 더블콘믹서로 흔합한다. 위의 흔합물에 스테아린산 마그네슘을 넣어 더블콘믹서로 최종 흔합하였다. 3) 타정 및 코팅 Preparation of the thiazide compound-releasing layer was carried out in a No. 35 sieve with hydrochlorothiazide, microcrystalline cellulose, lactose, corn starch, and low-substituted hydroxypropyl cellulose with the composition and contents shown in Table 4. Mix for minutes to prepare the mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution. Preferably fluid bed granulators are used. The fluid bed granulator used GPCG-l (Glatt, Germany). After the assembly is completed, the granulated material is dried in a fluidized bed dryer or a hot water dryer. ■ Preferably use a fluid bed dryer. Fluid bed granulation drier was used GPCG-l (Glatt, Germany). When drying is complete, the dry matter is established using an oscillator equipped with a No. 18 body. Add colloidal silicon dioxide to the formulation and mix with a double cone mixer. Magnesium stearate was added to the above mixture and finally mixed with a double cone mixer. 3) tableting and coating
유핵정 타정기 (RUD-1: Kilian)를 사용하여 로사르탄 내핵정을 내핵정으로 하고 치아자이드계 화합물을 포함하는 조성물을 외층으로 하여 유핵정 제조를 완료한후， 따로 히드록시프로필메틸셀를로오스 2910, 산화티탄， 탈크를 80% 에탄올에 용해 및 분산시킨 코팅액을 조제한다. 위의 유핵정을 하이코터 (SFC-30N: 세종 기계， 한국)에 투입한 후 코팅액으로 코팅하여 코팅 유핵정 제조를 완료하였다. 실시예 2내지 14: 유핵정 제조  Using a nucleated tablet tableting machine (RUD-1: Kilian) to make the losartan inner core tablet as the inner core tablet and the composition containing the thiazide compound as the outer layer, after completing the preparation of the nucleated tablet, hydroxypropylmethylcellose was separately prepared. 2910, titanium oxide and talc were prepared by dissolving and dispersing a coating solution in 80% ethanol. The above nucleated tablets were put into a high coater (SFC-30N: Sejong Machinery, Korea) and then coated with a coating solution to complete coating nucleated tablets. Examples 2-14: Nucleated Tablets Preparation
실시예 1과 동일한 유핵정의 제조 방법에 따라 표 4또는 5와 같은 조성과 함량으로 유핵정을 제조하였다. 실시예 15: 다층정 제조  Nucleated tablets were prepared in the same composition and content as Table 4 or 5, according to the same method as in Example 1. Example 15 Preparation of Multi-Layered Tablets
1) 안지오텐신ᅳ Πᅳ수용체 차단제 지연방출층의 제조  1) Preparation of Angiotensin® Π ᅳ Receptor Blocker Delayed-Release Layer
안지오텐신ᅳ Πᅳ수용체 차단제 지연방출층의 제조는 표 6과 같은 조성과 함량으로 로사르탄 칼륨， 미결정셀를로오스, 전분글리콘산나트륨, 유당을 35호체로 체과하고 고속흔합기로 5분간 혼합하여 흔합물을 제조한다. 따로 히드록시프로필셀를로오스와 히드록시프로필셀를로오스프탈레이트 (HP- 50)을 용해 및 분산시켜 결합액으로 하여 연합, 제립 및 건조한다. 건조물을 유동층 코팅기에 넣고, 따로 히드록시프로필셀를로오스프탈레이트 (HP-55)와 플리에틸렌 글리콜 6000을 에탄을 220mg 과 염화메틸렌 980 mg에 녹인 액을 조제하여 위의 조립물을 유동층 과립 코팅기 (GPCG-1: Glatt, Germany)에 넣고 코팅한다. 코팅 완료 후, 콜로이드성 이산화규소를 투입하고 흔합 한 뒤 스테아린산 마그네슘을 투입 후， 4분간 흔합하여 안지오텐신ᅳ Πᅳ수용체 차단제 지연방출층을 제조 하였다. Preparation of angiotensin Π ᅳ receptor blocker delayed-release layer was prepared by sieving potassium losartan, microcrystalline cellulose, sodium starch glycolate, and lactose into a No. 35 sieve with a composition and content as shown in Table 6, followed by mixing for 5 minutes using a high speed mixer. Prepare the mixture. Separately, hydroxypropylcell is dissolved, dispersed in hydroxypropylcell, and cellulose phthalate (HP-50), which is combined, granulated and dried. The dried product was placed in a fluidized bed coater, and a solution of hydroxypropylcellulose phthalate (HP-55) and polyethylene glycol 6000 in 220 mg of ethane and 980 mg of methylene chloride was prepared. -1: Glatt, Germany) and coated. After the coating was completed, the colloidal silicon dioxide was added and mixed, and then magnesium stearate was added and mixed for 4 minutes, followed by angiotensin ᅳ Π ᅳ receptor. A blocker delayed release layer was prepared.
2) 치아자이드계 화합물 선방출층의 제조 2) Preparation of Chiazide Compound Pre-Release Layer
치아자이드계 화합물 선방출층의 제조는 표 6과 같은 조성과 함량으로 히드로클로로치아짓 , 미결정셀를로오스, 전호화 전분， 폴리비닐피를리돈 공중합체， 콜로이드성 이산화규소를 35호체로 체과하고 고속흔합기로 5분간 흔합하여 흔합물을 제조한다. 흔합물에 스테아린산 마그네슴 투입 후 4분간 더블콘믹서로 최종 흔합하였다.  Preparation of the thiazide-based compound pre-release layer was sieved through the hydrochloricitate, microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer, colloidal silicon dioxide with No. 35 in a composition and content as shown in Table 6. By mixing for 5 minutes to prepare a mixture. After the stearic acid magnesium was added to the mixture, the mixture was finally mixed with a double cone mixer for 4 minutes.
3) 타정 및 코팅 3) tableting and coating
다층정 타정기 (MRC-37T: 세종)를 사용하여 타정한다. 치아자이드계 화합물을 포함하는 선방출층 조성물을 1차 분말공급기에 넣고， 안지오텐신ᅳ Π ᅳ수용체 차단제를 포함하는 지연방출층 조성물을 2차 분말 공급기에 넣어 층간의 흔입을 최소화할 수 있는 조건으로 타정한다. 따로 표 5에 나타낸 함량과 같이 히드록시프로필메틸셀를로오스 2910， 히드록시프로필셀를로오스 , 산화티탄, 탈크를 80¾ 에탄올에 용해 및 분산시킨 코팅 액을 조제한다. 위의 다층정을 하.이코터 (SFC-30N: 세종 기계 , 한국)에 투입한 후 코팅 액으로 코팅하여 코팅 다층정 형태의 지연방출성 구획의 제조를 완료하였다. 실시예 16 내지 22 : 다층정 제조  Tablet using a multi-layer tablet press (MRC-37T: Sejong). The pre-release layer composition containing the ziazide-based compound was placed in the primary powder feeder, and the delayed-release layer composition containing the angiotensin ᅳ Π receptor receptor was placed in the secondary powder feeder, and the tableting was performed under conditions that minimize the infiltration of the layers. do. Separately, as shown in Table 5, hydroxypropylmethylcellose 2910, hydroxypropylcelose, hydroxypropylcellose, titanium oxide, and talc were prepared by dissolving and dispersing in 80¾ ethanol. The multi-layered tablets above were put into a lower coater (SFC-30N: Sejong Machinery, Korea) and then coated with a coating solution to complete the preparation of the delayed-release compartment in the form of a coated multilayer tablet. Examples 16 to 22: Preparation of multi-layered tablets
실시예 15와 동일한 다층정의 제조 방법에 따라 표 6 또는 7과 같은 조성과 함량으로 다층정을 제조 하였다. 실시예 23: 필름코팅정 제조 According to the same method as in Example 15 to prepare a multilayer tablet was prepared a multilayer tablet with the composition and content shown in Table 6 or 7. Example 23: Film Coated Tablet Preparation
1) 안지오텐신ᅳ Πᅳ수용체 차단제 지연방출형 과립의 제조  1) Preparation of Angiotensin® Π ᅳ Receptor Blocker Delayed-Release Granules
표 7에 나타난 함량과 같이 로사르탄 칼륨, 미결정셀를로오스， 전분글리콘산나트륨， 유당을 35호체로 체과하고 고속흔합기로 5분간 흔합하여 흔합물을 제조한다. 따로 히드록시프로필셀를로오스와 히드록서프로필셀를로오스프탈레이트 (HP-50)을 정제수에 녹여 결합액으로 하여 연합， 제립 및 건조한다. 건조물을 유동층 코팅기에 넣고, 따로 히드록시프로필셀를로오스프탈레이트 (HP-55)와 플리에틸렌 글리콜 6000을 에탄을 220mg 과 염화메틸렌 980 rag에 녹인 액을 조제하여 위의 조립물을 유동층 과립 코팅기 (GPCG-1: Glatt, Germany)에 넣고 코팅한다. 코팅 완료 후， 콜로이드성 이산화규소를 투입하고 흔합 한 뒤 스테아린산 마그네슴을 투입 후, 4분간흔합하여 안지오텐신ᅳ Πᅳ수용체 차단제 지연방출형 과립을 제조한다.  As shown in Table 7, potassium losartan, microcrystalline cellulose, sodium starch glycolate and lactose were sieved through a No. 35 sieve and mixed with a high speed mixer for 5 minutes to prepare a mixture. Separately, hydroxypropylcell and hydroxypropylcell are dissolved in purified water and dissolved in purified water to combine, granulate and dry. The dried material was placed in a fluidized bed coater, and a solution obtained by dissolving hydroxypropylcellulose phthalate (HP-55) and polyethylene glycol 6000 in 220 mg of ethane and 980 rag of methylene chloride was prepared. -1: Glatt, Germany) and coated. After the coating was completed, the colloidal silicon dioxide was added and mixed, followed by the addition of stearic acid magnesium, followed by mixing for 4 minutes to prepare angiotensin ᅳ receptor receptor delayed-release granules.
2) 치아자이드계 화합물 선방출코팅액 제조 2) Preparation of Chiazide-Based Compounds
표 7에 나타난 함량과 같이 히드로클로로치아짓， 히드특시프로필메틸셀를로오스 2910, 히드록시프로필셀를로오스， 산화티탄, 탈크를 80% 에탄올에 용해 및 분산시켜 치아자이드계 화합물을 함유한 선방출 코팅액을 제조 한다.  As shown in Table 7, hydrochlorothiazide, hydroxyspecific propylmethylcellose 2910, hydroxypropylcelose, titanium oxide, and talc were dissolved and dispersed in 80% ethanol to form a pre-release coating solution containing a thiazide compound. Manufacture.
3) 안지오텐신ᅳ Πᅳ수용체 차단제 지연방출층과 치아자이드계 화합물 선방출층을 포함하는 필름코팅정 제조 3) Film coated tablet preparation comprising angiotensin ᅳ receptor receptor delayed release layer and a pre-release layer of a cyanide compound
1)의 안지오텐신ᅳ Π一수용체 차단제 지연방출형 과립을 로타리 타정기에서 타정한 후， 하이코터 코팅장치에 타정 정제를 하이코터 (SFC-30N: 세종 기계， 한국)에 투입한 후 2)의 치아자이드계 화합물 선방출 코팅액으로 코팅하여 안지오텐신ᅳ Π ᅳ수용체 차단제 지연방출층과 치아자이드계 화합물 선방출층을 포함하는 필름코팅정 형태의 지연방출성 구획의 제조를 완료하였다. 실시예 24: 캡슐제 제조 (과립-입자) After angiotensin ᅳ Π 一 receptor blocker delayed-release granules of 1) were compressed into tablets using a rotary tablet press, tableting tablets were injected into a high coater (SFC-30N: Sejong Machinery, Korea) and then 2) ziazide System-based pre-release coating solution The coating was completed to prepare a delayed-release compartment in the form of a film-coated tablet including an angiotensin ᅳ π ᅳ receptor blocker delayed-release layer and a thiazide compound pre-release layer. Example 24: Preparation of Capsules (Granules-Particles)
1) 안지오텐신ᅳ Π ᅳ수용체 차단제 지연방출형 과립의 제조  1) Preparation of Angiotensin ᅳ Π ᅳ Receptor Blocker Delayed-Release Granules
표 7에 나타난 함량과 같이 로사르탄 칼륨， 미결정셀를로오스， 전분글리콘산나트륨， 유당을 35호체로 체과하고 고속흔합기로 5분간 흔합하여 흔합물을 제조한다. 따로 히드록시프로필셀를로오스와 히드록시프로필셀를로오스프탈레이트 (HP— 50)을 정제수에 녹여 결합액으로 하여 연합, 제립 및 건조한다. 건조물을 유동층 코팅기에 넣고 , 따로 히드특시프로필셀를로오스프탈레이트 (HP-55)와 폴리에틸렌 글리콜 6000을 에탄올 220mg 과 염화메틸렌 980 mg에 녹인 액을 조제하여 위의 조립물을 유동층 과립 코팅기 (GPCG— 1 : Glatt , Germany)에 넣고 코팅한다. 코팅 완료 후, 콜로이드성 이산화규소를 투입하고 흔합 한 뒤 스테아린산 마그네슴을 투입 후, 4분간 흔합하여 안지오텐신ᅳ Π ᅳ수용체 차단제 지연방출형 과립을 제조한다.  As shown in Table 7, potassium losar, microcrystalline cellulose, sodium starch glycolate and lactose were sieved through a No. 35 sieve and mixed for 5 minutes using a high speed mixer to prepare a mixture. Separately, hydroxypropylcell and hydroxypropylcell are dissolved in purified water and dissolved in purified water to combine, granulate and dry. The dried product was placed in a fluidized bed coater, and a liquid obtained by dissolving hydrated propyl cellulose (HP-55) and polyethylene glycol 6000 in 220 mg of ethanol and 980 mg of methylene chloride was prepared. 1: Glatt, Germany) and coated. After the coating was completed, the colloidal silicon dioxide was added and mixed, followed by the addition of stearic acid magnesium, followed by mixing for 4 minutes to prepare angiotensin ᅳ receptor receptor delayed-release granules.
2) 치아자이드계 화합물 선방출층의 '제조 2) Manufacture of Chiazide-Based Compound
표 7에 나타난 함량과 같이 히드로클로로치아짓， 미결정셀를로오스， 전호화 전분 , 폴리비닐피를리돈 공중합체， 콜로이드성 이산화규소를 35호체로 체과하고 고속흔합기로 5분간 흔합하여 흔합물을 제조한다.  As shown in Table 7, hydrochlorothiazide, microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer, colloidal silicon dioxide were sieved through a No. 35 sieve and mixed for 5 minutes with a high speed mixer to prepare a mixture.
3) 흔합 및 캡술 층전 3) mixing and capsular layering
공정 1)과 2)의 최종 조성물을 더블콘믹서로 흔합한다. 흔합물에 스테아린산 마그네슘을 넣어 더블콘믹서로 최종 흔합한다. 최종 흔합된 흔합물을 분말공급기에 투입하고 캡술층전기를 이용하여 층전한다. 실시예 25: 2상 메트릭스 정제의 제조 The final compositions of steps 1) and 2) are mixed with a double cone mixer. Magnesium stearate is added to the mixture and finally mixed with a double cone mixer. Final mixed The mixture is placed in a powder feeder and layered using a capsul layered electric. Example 25 Preparation of Biphasic Matrix Tablets
1) 안지오텐신ᅳ Πᅳ수용체 차단제의 지연방출형 과립의 제조  1) Preparation of delayed-release granules of angiotensin ᅳ Π ᅳ receptor blocker
표 7에 나타난 함량과 같이 이르베사르탄， 유당, 크로스카멜로스 소듐, 염화나트륨을 35호체로 체과하고 고속흔합기로 5분간 흔합하여 흔합물을 제조하였다. 따로 전호화전분과 폴록사머 188을 정제수에 녹여 결합액으로 하여 연합 계립 및 건조하였다. 건조물을 유동층 코팅기에 넣고， 따로 셀를로오스아세테이트 (아세틸기 32%)， 셀를로오스아세테이트 (아세틸기 39. 8%), 히드록시프로필메틸셀를로오스를 에탄올 220mg 과 염화메틸렌 980 mg에 용해 및 분산 시킨 코팅액을 조제하여 위의 과립물을 유동층 과립 코팅기 (GPCG- 1: Glatt, Germany)에 넣고 코팅하였다. 코팅물에 미결정셀를로오스， 콜로이드성 이산화규소를 넣고 흔합하여 안지오텐신ᅳ Πᅳ수용체 차단제 지연방출 과립을 제조하였다.  As shown in Table 7, irbesartan, lactose, croscarmellose sodium and sodium chloride were sieved through a No. 35 sieve and mixed for 5 minutes using a high speed mixer to prepare a mixture. Separately, pregelatinized starch and poloxamer 188 were dissolved in purified water to form a binder, and then combined and dried. The dried material was placed in a fluidized bed coater, and separately cellulose acetate (32% acetyl), cellulose acetate (39.8% acetyl), and hydroxypropylmethylcellose were dissolved in 220 mg of ethanol and 980 mg of methylene chloride, and Dispersed coating solution was prepared and the above granules were put in a fluidized bed granulation coater (GPCG- 1: Glatt, Germany) and coated. Angiotensin ᅳ Π ᅳ receptor blocker delayed-release granules were prepared by adding microcrystalline cells to the coating and adding colloidal silicon dioxide.
2) 치아자이드계 화합물 선방출층 흔합물의 제조 2) Preparation of Chiazide Compound Pre-Release Layer Complex
표 7에 나타난 함량과 같이 치아자이드계 화합물인 히드로클로로치아짓과 부형제인 미결정셀를로오스， 전호화전분, 폴리비닐피를리돈 공중합체， 콜로이드성 이산화규소를 35호체로 체과 하고 고속흔합기로 흔합하였다.  As shown in Table 7, the zigzide compound hydrochlorothiazide and the excipient microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer, and colloidal silicon dioxide were sieved through a No. 35 sieve and mixed with a high speed mixer.
3) 타정 및 코팅 3) tableting and coating
위의 방법으로 제조된 1)의 안지오텐신ᅳ Πᅳ수용체 차단제 지연방출 과립과 치아자이드계 화합물인 히드로클로로치아짓 선방출 흔합물을 더블콘믹서에 넣고 흔합하였다. 이 흔합물에 스테아린산 마그네슴을 넣어 최종 흔합하였다. 최종 흔합물을 로타리 타정기 (MRC-33: 세종)를 사용하여 타정하였다. 따로 히드록시프로필메틸셀를로오스 2910, 히드록시프로필셀를로오스， 산화티탄， 탈크를 에탄올 64. 8mg과 정제수 16. 2mg에 용해 및 분산시킨 코팅액을 조제하여 위의 정제를 하이코터 (SFC-30N: 세종 기계， 한국)로서 필름 코팅 층을 형성하여 2상 메트릭스 정제를 제조하였다. 실시예 26 내지 27: 2상 메트릭스 정제의 제조 Angiotensin ᅳ Π ᅳ receptor blocker delayed-release granules of 1) prepared by the above method and a hydrochlorothiazide pre-release mixture, which is a thiazide compound, were prepared Place in a double cone mixer and mix. Stearic acid magnesium was added to this mixture for final mixing. The final mixture was compressed using a rotary tablet press (MRC-33: Sejong). Separately, a coating solution was prepared by dissolving and dispersing hydroxypropylmethylcellose 2910, hydroxypropylcellose, titanium oxide, and talc in 64.8 mg of ethanol and 16. 2 mg of purified water. : Sejong Machinery, South Korea) to form a film coating layer to prepare a two-phase matrix tablet. Examples 26-27 Preparation of Biphasic Matrix Tablets
실시예 25와 동일한 2상 메트릭스 정제의 제조 방법에 따라 표 7과 같은 조성과 함량으로 2상 메트릭스 정제를 제조하였다. 실시예 28: 캡슐제 제조 (펠렛-과립)  A biphasic matrix tablet was prepared with the composition and content shown in Table 7 according to the same biphasic matrix tablet manufacturing method as in Example 25. Example 28 Preparation of Capsules (Pellets-Granules)
1) 안지오텐신ᅳ Π—수용체 차단제 지연방출형 펠렛의 제조  1) Preparation of Angiotensin® Π—Receptor Blocker Delayed-Release Pellets
표 8에 나타난 함량과 같이 슈가 시드 (Sugar sphere)를 35호체로 체과하고 유동층 과립기 (GPCG 1: Glatt)에 투입한 뒤， 따로 물과 에탄을에 히드록시프로필메틸셀를로오스과 로사르탄 칼륨을 용해시킨 결합액을 분무하여 안지오텐신ᅳ Πᅳ수용체 차단제 함유 펠렛을 형성 , 건초하였다. 다시 상기의 과립에 히드록시프로필메틸셀를로오스프탈레이트를 에탄을 220mg과 염화메틸렌 980 mg에 녹인 액을 분무하여 안지오텐신ᅳ Πᅳ수용체 차단제 지연방출형 펠렛을 제조하였다.  As shown in Table 8, the sugar seeds were sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellose and losartan potassium were separately added to water and ethane. The dissolved binder solution was sprayed to form pellets containing angiotensin® receptor blocker. The granules were then sprayed with a solution of hydroxypropyl methylcellulose phthalate dissolved in 220 mg of ethane and 980 mg of methylene chloride to prepare angiotensin® receptor receptor blocker delayed-release pellets.
2) 치아자이드계 화합물 선방출형 과립의 제조 2) Preparation of Chiazide Compound Pre-Release Granules
치아자이드계 화합물 선방출층은 표 8에 나타난 함량과 같이 히드로클로로치아짓 , 미결정셀를로오스 , 유당 , 옥수수전분 , 저치환도 히드록시프로필셀를로오스를 달아 35호체로 체과하고 더블콘믹서에서 5분간 흔합하여 흔합물을 제조한다. 따로 히드록시프로필셀를로오스를 정제수에 녹여 결합액을 제조한다. 상기 흔합물을 유동층과립기 또는 고속회전 조립기에 넣고 결합액을 가하여 조립한다. 바람직하게는 유동층 과립기를 사용한다. 유동층 과립기는 GPCG-l(Glatt, Germany)을 사용하였다. 조립이 완료된 후 유동층 건조기 또는 온수건조기에 조립물을 건조 시킨다. 바람직하게는 유동층 건조기를 사용한다. 유동층 과립 건조기는 GPCG-l(Glatt, Germany)을 사용하였다. 건조가 완료되면 건조물을 18호체가 장착된 오실레이터를 사용하여 정립한다. 정립물에 콜로이드성 이산화규소를 넣고 더블콘믹서로 흔합한다. The thiazide compound pre-release layer is as shown in Table 8 Hydrochlorothiazide, microcrystalline cellulose, lactose, corn starch, low-substituted hydroxypropyl cellulose were added, sieved through a No. 35 sieve, and mixed in a double cone mixer for 5 minutes to prepare a mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution. Preferably fluid bed granulators are used. The fluid bed granulator used GPCG-l (Glatt, Germany). After the assembly is completed, the granulated material is dried in a fluidized bed dryer or a hot water dryer. Preferably a fluid bed dryer is used. Fluid bed granulation dryer was used GPCG-l (Glatt, Germany). When drying is complete, the dry matter is established using an oscillator equipped with a No. 18 body. Colloidal silicon dioxide is added to the formulation and mixed with a double cone mixer.
3) 흔합 및 캡슐 층전 3) mixing and capsule layering
공정 1)과 2)의 최종 조성물을 더블콘믹서로 흔합하였다. 흔합물에 스테아린산 마그네슴을 투입하고 더블콘믹서로 최종 흔합하였다. 최종 흔합된 흔합물을 분말 공급기에 투입하고 캡슐층전기를 이용하여 층전하여 캡슐형태의 제어 방출 제제의 제조를 완료하였다. 실시예 29: 캡술제 제조 (펠렛—펠렛)  The final compositions of steps 1) and 2) were combined with a double cone mixer. Magnesium stearate was added to the mixture and finally mixed with a double cone mixer. The final blended mixture was placed in a powder feeder and layered using a capsule bed electricity to complete the preparation of the controlled release formulation in capsule form. Example 29 Preparation of Capsulant (Pellets—Pellets)
1) 안지오텐신ᅳ Π—수용체 차단제 지연방출형 펠렛의 제조  1) Preparation of Angiotensin® Π—Receptor Blocker Delayed-Release Pellets
표 8에 나타난 함량과 같이 슈가 시드 (Sugar sphere)를 35호체로 체과하고 유동층 과립기 (GPCG 1: Glatt)에 투입한 뒤, 따로 물과 에탄올에 히드록시프로필메틸셀를로오스과 이프로사르탄을 용해시킨 결합액을 분무하여 안지오텐신ᅳ Πᅳ수용체 차단제 함유 펠렛을 형성 , 건조하였다. 다시 상기의 과립에 히드록시프로필메틸셀를로오스프탈레이트를 에탄을 220mg과 염화메틸렌 980 mg에 녹인 액을 분무하여 안지오텐신 -Πᅳ수용체 차단제 지연방출형 펠렛을 제조하였다. As shown in Table 8, the sugar sphere was sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellose and iprosartan were separately added to water and ethanol. The dissolved binder solution was sprayed to form pellets containing angiotensin ᅳ i receptor receptor blocker and dried. Again, 220 mg of ethane and methylene chloride with hydroxypropylmethylcelloseophthalate were added to the granules. Angiotensin-? Receptor receptor blocker delayed-release pellets were prepared by spraying a solution dissolved in 980 mg.
2) 치아자이드계 화합물 선방출형 펠렛의 제조 2) Preparation of Chiazide Compound Pre-Release Pellets
표 8에 나타난 함량과 같이 슈가 시드 (Sugar sphere)를 35호체로 체과하고 유동층 과립기 (GPCG 1： Glatt)에 투입한 뒤, 따로 물과 에탄올에 히드록시프로필메틸셀를로오스과 히드로클로로치아짓을 용해시킨 결합액을 분무， 건조하여 치아자이드계 화합물 선방출형 펠렛을 형성하였다.  As shown in Table 8, the sugar seeds were sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcell was dissolved in water and ethanol. The solution was sprayed and dried to form a thiazide compound pre-release pellet.
3) 흔합 및 캡슐 층전 3) mixing and capsule layering
공정 1)과 2)의 최종 조성물을 더블콘믹서로 흔합하였다. 흔합된 흔합물을 분말 공급기에 투입하고 캡슐층전기를 이용하여 층전하여 캡슐형태의 제어 방출 제제의 제조를 완료하였다. 실시예 30: 캡술제 제조 (펠렛-정제)  The final compositions of steps 1) and 2) were combined with a double cone mixer. The mixed mixture was placed in a powder feeder and layered using a capsule bed electricity to complete the preparation of the controlled release formulation in capsule form. Example 30 Capsule Preparation (Pellets-Tablets)
1) 안지오텐신一 Πᅳ수용체 차단제 지연방출형 펠렛의 제조  1) Preparation of Angiotensin 一 ᅳ Receptor Blocker Delayed-Release Pellets
표 8에 나타난 함량과 같이 슈가 시드 (Sugar sphere)를 35호체로 체과하고 유동층 과립기 (GPCG 1: Glatt)에 투입한 뒤， 따로 물과 에탄올에 히드록시프로필메틸셀를로오스과 칸데사르탄을 용해시킨 결합액을 분무하여 안지오텐신ᅳ Πᅳ수용체 차단제 함유 펠렛을 형성， 건조하였다. 다시 상기의 과립에 히드록시프로필메틸셀를로오스프탈레이트를 에탄을 220mg과 염화메틸렌 980 mg에 녹인 액을 분무하여 안지오텐신ᅳ Πᅳ수용체 차단제 지연방출형 펠렛을 제조하였다. 2) 치아자이드계 화합물 선방출형 정제의 제조 As shown in Table 8, sugar spheres were sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and then hydroxypropylmethylcellose and candesartan were dissolved separately in water and ethanol. The binder solution was sprayed to form pellets containing angiotensin ᅳ i ᅳ receptor blocker and dried. The back angiotensin eu Π eu receptor blocker delayed-release pellets by spraying a liquid obtained by dissolving the ethane agarose phthalate with hydroxypropyl methylcellulose selreul in the granules through 220m g and 980 mg of methylene chloride was prepared. 2) Preparation of Chiazide Compound Pre-Release Tablets
표 8에 나타난 함량과 같이 치아자이드계 화합물인 히드로클로로치아짓과 부형제인 미결정셀를로오스, 전호화전분， 폴리비닐피를리돈 공중합체， 콜로이드성 이산화규소를 35호체로 체과 하고 고속흔합기로 흔합하였다. 이 흔합물에 스테아린산 마그네슘을 넣어 최종 흔합하였다. 최종 흔합물을 로타리 타정기 (MRC-33: 세종)를 사용하여 타정하여 치아자이드계 화합물 선방출형 정제를 제조하였다.  As shown in Table 8, the zigzide compound hydrochlorothiazide and the excipient microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer and colloidal silicon dioxide were sieved through a No. 35 sieve and mixed with a high speed mixer. Magnesium stearate was added to this mixture and finally mixed. The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare a thiazide compound-release tablet.
3) 흔합 및 캡슐 층전 3) mixing and capsule layering
공정 1)과 2)의 최종 조성물을 더블콘믹서로 흔합하였다. 흔합된 흔합물을 분말 공급기에 투입하고 캡슐층전기를 이용하여 층전하여 캡슐형태의 제어 방출 제제의 제조를 완료하였다. 실시예 31: 캡술제 제조 (과립-과립)  The final compositions of steps 1) and 2) were combined with a double cone mixer. The mixed mixture was placed in a powder feeder and layered using a capsule bed electricity to complete the preparation of the controlled release formulation in capsule form. Example 31 Preparation of Capsulant (Granule-Granule)
1) 안지오텐신ᅳ Πᅳ수용체 차단제 지연방출형 과립의 제조  1) Preparation of Angiotensin® Π ᅳ Receptor Blocker Delayed-Release Granules
안지오텐신ᅳ Πᅳ수용체 차단제 지연방출형 과립은 표 8에 나타난 함량과 같이 올메사르탄 메독소밀 미결정셀를로오스를 35호체로 체과하고 고속흔합기로 흔합하였다. 콜리코트 SR30D를 주성분 흔합물과 함께 연합하였다. 연합이 끝나면 18호체로 오실레이터를 이용하여 제립하고 이를 유동층 건조기 또는 온수건조기에 조립물을 건조 시킨다. 바람직하게는 유동층 건조기를 사용한다. 유동층 과립 건조기는 GPCG-l(Glatt, Germany)을 사용하였다. 건조가 완료되면 다시 20호체로 정립하여 안지오텐신一 Πᅳ수용체 차단제 지연방출형 과립을 제조하였다. 2) 치아자이드계 화합물 선방출형 과립의 제조 The angiotensin Π ᅳ receptor blocker delayed-release granules were sieved with oligosarthan medoxomil microcrystalline cell as No. 35 and mixed with a high speed mixer as shown in Table 8. Colicoat SR30D was associated with the main component mixture. After the union is completed, the granules are granulated by using an oscillator in No. 18 and dried in a fluid bed dryer or a hot water dryer. Preferably a fluid bed dryer is used. Fluid bed granulation dryer was used GPCG-l (Glatt, Germany). When the drying was completed, it was reestablished as No. 20 sieve to prepare angiotensin 一 ᅳ receptor receptor delayed-release granules. 2) Preparation of Chiazide Compound Pre-Release Granules
치아자이드계 화합물 선방출층은 표 8에 나타난 함량과 같이 히드로클로로치아짓 , 미결정셀를로오스， 유당， 옥수수전분， 저치환도 히드록시프로필셀를로오스를 달아 35호체로 체과하고 더블콘믹서에서 5분간 흔합하여 흔합물을 제조한다. 따로 히드록시프로필셀를로오스를 정제수에 녹여 결합액을 제조한다. 상기 흔합물을 유동층과립기 또는 고속회전 조립기에 넣고 결합액을 가하여 조립한다. 바람직하게는 유동층 과립기를 사용한다. 유동층 과립기는 GPCG-l(Glatt , Germany)을 사용하였다. 조립이 완료된 후 유동층 건조기 또는 온수건조기에 조립물을 건조 시킨다. 바람직하게는 유동층 건조기를 사용한다. 유동층 과립 건조기는 GPCG-l(Glatt；， Germany)을 사용하였다. 건조가 완료되면 건조물을 18호체가 장착된 오실레이터를 사용하여 정 립한다. 정 립물에 콜로이드성 이산화규소를 넣고 더블콘믹서로 흔합한다.  As shown in Table 8, the thiazide-based compound pre-release layer was sieved with hydrochlorothiazide, microcrystalline cellulose, lactose, corn starch, low-substituted hydroxypropyl cellulose, and sieved through a No. 35 sieve. Combine to produce the mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution. Preferably fluid bed granulators are used. The fluid bed granulator used GPCG-l (Glatt, Germany). After the assembly is completed, the granulated material is dried in a fluidized bed dryer or a hot water dryer. Preferably a fluid bed dryer is used. The fluid bed granule dryer used GPCG-1 (Glatt; Germany). When drying is completed, the dry matter is established using an oscillator equipped with a No. 18 body. Add colloidal silicon dioxide to the formulation and mix with a double cone mixer.
3) 흔합 및 캡슐 층전 3) mixing and capsule layering
공정 1)과 2)의 최종 조성물을 더블콘믹서로 흔합하였다. 흔합물에 스테아린산 마그네슘을 투입하고 더블콘믹서로 최종 흔합하였다. 최종 흔합된 흔합물을 분말 공급기에 투입하고 캡술층전기를 이용하여 층전하여 캡술형태의 제어 방출 제제의 제조를 완료하였다. 실시 예 32: 캡술제 제조 (과립-펠렛)  The final compositions of steps 1) and 2) were combined with a double cone mixer. Magnesium stearate was added to the mixture and finally mixed with a double cone mixer. The final blended mixture was placed in a powder feeder and layered using a capsular bed electrolysis to complete the preparation of the controlled release formulation in capsular form. Example 32 Preparation of Capsulant (Granules-Pellets)
1) 안지오텐신ᅳ Π ᅳ수용체 차단제 지연방출형 과립의 제조  1) Preparation of Angiotensin ᅳ Π ᅳ Receptor Blocker Delayed-Release Granules
안지오텐신ᅳ Π ᅳ수용체 차단제 지연방출형 과립은 표 8에 나타난 함량과 같이 발사르탄， 미결정셀를로오스, 가교 폴리비닐피를리돈을 달아 35호체로 체과하고 더블콘믹서에서 5분간 흔합하여 흔합물을 제조한다. 따로 폴리비닐피를리돈을 정제수에 녹여 결합액을 제조한다. 상기 흔합물을 유동층과립기 또는 고속회전 조립기에 넣고 결합액을 가하여 조립한다. 바람직하게는 유동층 과립기를 사용한다. 유동층 과립기는 GPCG~l(Glatt；， Germany)을 사용하였다. 조립이 완료된 후 유동층 건조기 또는 은수건조기에 조립물을 건조 시킨다. 바람직하게는 유동층 건조기를 사용한다. 유동층 과립 건조기는 GPCG-l(Glatt, Germany)을 사용하였다. 건조가 완료되면 다시 상기의 과립에 카르나우바왁스를 에탄을 220mg 과 염화메틸렌 980 mg에 녹인 액을 분무하여 안지오텐신一 Πᅳ수용체 차단제 지연방출형 과립을 제조하였다. Angiotensin ᅳ Π ᅳ Receptor blocker delayed-release granules were sieved through a No. 35 sieve with valsartan, microcrystalline cellulose, cross-linked polyvinylpyridone, and mixed in a double cone mixer for 5 minutes, as shown in Table 8, to prepare a mixture. do. seperately Polyvinylpyridone is dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution. Preferably fluid bed granulators are used. The fluid bed granulator used GPCG - l (Glatt; Germany). After the assembly is completed, the granules are dried in a fluid bed dryer or a silver dryer. Preferably a fluid bed dryer is used. Fluid bed granulation dryer was used GPCG-l (Glatt, Germany). When the drying was completed again, the granules were sprayed with carnauba wax ethane dissolved in 220 mg of ethane and 980 mg of methylene chloride to prepare angiotensin Π receptor blocker delayed-release granules.
2) 치아자이드계 화합물 선방출형 펠렛의 제조 2) Preparation of Chiazide Compound Pre-Release Pellets
표 8에 나타난 함량과 같이 슈가 시드 (Sugar sphere)를 35호체로 체과하고 유동층 과립기 (GPCG 1: Glatt)에 투입한 뒤， 따로 물과 에탄을에 히드록시프로필메틸셀를로오스과 히드로클로로치아짓을 용해시킨 결합액을 분무 건조하여 치아자이드계 화합물 선방출형 펠렛을 형성하였다.  As shown in Table 8, sugar spheres were sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellose and hydrochlorothiazide were dissolved separately in water and ethane. The binder solution was spray dried to form a thiazide compound pre-release pellet.
3) 흔합 및 캡술 층전 3) mixing and capsular layering
공정 1)과 2)의 최종 조성물을 더블콘믹서로' 흔합하였다. 흔합물에 스테아린산 마그네슘을 투입하고 더블콘믹서로 최종 흔합하였다. 최종 흔합된 흔합물을 분말 공급기에 투입하고 캡술층전기를 이용하여 층전하여 캡슐형태의 제어 방출 제제의 제조를 완료하였다. 실시예 33: 캡슐제 제조 (과립-정제)  The final compositions of steps 1) and 2) were mixed with a double cone mixer. Magnesium stearate was added to the mixture and finally mixed with a double cone mixer. The final blended mixture was placed in a powder feeder and layered using a capsul layered electric charge to complete the preparation of the controlled release formulation in capsule form. Example 33 Preparation of Capsules (Granules-Tablets)
1) 안지오텐신ᅳ Πᅳ수용체 차단제 지연방출형 과립의 제조  1) Preparation of Angiotensin® Π ᅳ Receptor Blocker Delayed-Release Granules
안지오텐신 _Π 수용체 차단제 지연방출형 과립은 표 8에 나타난 함량과 같이 텔미사르탄, 미결정셀를로오스， 메글루민을 달아 35호체로 체과하고 더블콘믹서에서 5분간 흔합하여 흔합물을 제조한다. 따로 솔비를, 플리비닐피를리돈， 소듐 하이드록사이드를 정제수에 녹여 결합액을 제조한다. 상기 흔합물을 유동층과립기 또는 고속회전 조립기에 넣고 결합액을 가하여 조립한다. 바람직하게는 유동층 과립기를 사용한다. 유동층 과립기는 GPCG- KGlatt , Germany)을 사용하였다. 조립이 완료된 후 유동층 건조기 또는 온수건조기에 조립물을 건조 시킨다. 바람직하게는 유동층 건조기를 사용한다. 유동층 과립 건조기는 GPCG-l(Glatt , Germany)을 사용하였다. 건조가 완료되면 다시 상기의 과립에 카르나우바왁스를 에탄올 220mg 과 염화메틸렌 980 mg에 녹인 액을 분무하여 안지오텐신ᅳ Π ᅳ수용체 차단제 지연방출형 과립을 제조하였다. Angiotensin _Π receptor blocker delayed-release granules are shown in Table 8. As the content, telmisartan, microcrystalline cellulose, and meglumine were added, sieved through a No. 35 sieve, and mixed in a double cone mixer for 5 minutes to prepare a mixture. Separately, Solbi, polyvinylpyridone, and sodium hydroxide are dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution. Preferably fluid bed granulators are used. Fluid bed granulator (GPCG-KGlatt, Germany) was used. After the assembly is completed, the granulated material is dried in a fluidized bed dryer or a hot water dryer. Preferably a fluid bed dryer is used. Fluid bed granulation drier was used GPCG-l (Glatt, Germany). Upon completion of drying, the granules were sprayed again with carnauba wax dissolved in 220 mg of ethanol and 980 mg of methylene chloride, thereby preparing angiotensin ᅳ π ᅳ receptor blocker delayed-release granules.
2) 치아자이드계 화합물 선방출형 정제의 제조 2) Preparation of Chiazide Compound Pre-Release Tablets
표 8에 나타난 함량과 같이 치아자이드계 화합물인 히드로클로로치아짓과 부형제인 미결정셀를로오스 , 전호화전분， 폴리비닐피를리돈 공중합체 , 콜로이드성 이산화규소를 35호체로 체과 하고 고속흔합기로 흔합하였다. 이 흔합물에 스테아린산 마그네슘을 넣어 최종 흔합하였다. 최종 흔합물을 로타리 타정기 (MRC-33: 세종)를 사용하여 타정하여 치아자이드계 화합물 선방출형 정제를 제조하였다.  As shown in Table 8, zigzide compound hydrochlorothiazide and excipient microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer, colloidal silicon dioxide were sieved through a No. 35 sieve and mixed with a high speed mixer. Magnesium stearate was added to this mixture and finally mixed. The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare a thiazide compound-release tablet.
3) 흔합 및 캡술 층전 3) mixing and capsular layering
공정 1)과 2)의 최종 조성물을 더블콘믹서로 흔합하였다. 흔합된 흔합물을 분말 공급기에 투입하고 캡술층전기를 이용하여 층전하여 캡슐형태의 제어 방출 제제의 제조를 완료하였다. 실시예 34: 캡슐제 제조 (정제-과립 ) The final compositions of steps 1) and 2) were combined with a double cone mixer. The mixed mixture was placed in a powder feeder and layered using a capsul layered electric charge to complete the preparation of the controlled release formulation in capsule form. Example 34: Preparation of Capsules (Tablets-Granules)
1) 안지오텐신ᅳ Π ᅳ수용체 차단제 지연방출형 정제의 제조  1) Preparation of Angiotensin ᅳ ΠΠReceptor Blocker Delayed-Release Tablets
표 9에 나타난 함량과 같이 안지오텐신ᅳ Π ᅳ수용체 차단제 지연방출형 정제는 로사르탄 칼륨, 미결정셀를로오스, 전호화 전분， 폴리비닐피를리돈 공중합체 , 콜로이드성 이산화규소를 35호체로 체과하고 고속흔합기로 5분간 흔합하여 흔합물을 제조한다. 흔합물에 스테아린산 마그네슘 투입 후 4분간 흔합하고， 최종 흔합물을 로타리 타정기 (MRC-33: 세종)를 사용하여 타정한다. 이렇게 제조한 정제를 하이코터 (SFC-30N: 세종 기계， 한국)에 투입한다. 다시 상기의 정제에 폴리에틸렌글리콜 6000， 히드록시프로필메틸셀를로오스프탈레이트를 에탄올 220mg 과 염화메틸렌 980 mg에 녹인 액을 분무하여 안지오텐신 수용체 차단제 지연방출형 정제를 제조하였다.  As shown in Table 9, angiotensin ᅳ ΠΠreceptor blocker delayed-release tablets were sieved through Losartan potassium, microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer, and colloidal silicon dioxide with No. 35. The mixture is prepared by mixing in a mixer for 5 minutes. After adding magnesium stearate to the mixture, mix for 4 minutes and tablet the final mixture using a rotary tablet press (MRC-33: Sejong). The tablet thus prepared is put into a high coater (SFC-30N: Sejong Machinery, Korea). The tablet was sprayed with a solution of polyethylene glycol 6000 and hydroxypropyl methylcellose phthalate in 220 mg of ethanol and 980 mg of methylene chloride to prepare an angiotensin receptor blocker delayed-release tablet.
2) 치아자이드계 화합물 선방출형 과립의 제조 2) Preparation of Chiazide Compound Pre-Release Granules
치아자이드계 화합물 선방출층은 표 9에 나타난 함량과 같이 히드로클로로치아짓， 미결정셀를로오스， 유당, 옥수수전분, 저치환도 히드록시프로필셀를로오스를 달아 35호체로 체과하고 더블콘믹서에서 5분간 흔합하여 흔합물을 제조한다. 따로 히드록시프로필셀를로오스를 정제수에 녹여 결합액을 제조한다. 상기 흔합물을 유동층과립기 또는 고속희전 조립기에 넣고 결합액을 가하여 조립한다. 바람직하게는 유동층 과립기를 사용한다. 유동층 과립기는 GPCG-l(Glatt , Germany)을 사용하였다. 조립이 완료된 후 유동층 건조기 또는 은수건조기에 조립물을 건조 시킨다. 바람직하게는 유동층 건조기를 사용한다. 유동층 과립 건조기는 GPCG-l(Glatt , Germany)을 사용하였다. 건조가 완료되면 건조물을 18호체가 장착된 오실레이터를 사용하여 정립한다. 정립물에 콜로이드성 이산화규소를 넣고 더블콘믹서로 흔합한다. As shown in Table 9, the thiazide compound pre-release layer was sieved with hydrochlorothiazide, microcrystalline cellulose, lactose, corn starch, low-substituted hydroxypropyl cellulose and sieved through a No. 35 sieve, and then shaken for 5 minutes in a double cone mixer. Combine to produce the mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high speed granulator and granulated by adding a binder solution. Preferably fluid bed granulators are used. The fluid bed granulator used GPCG-l (Glatt, Germany). After the assembly is completed, the granules are dried in a fluid bed dryer or a silver dryer. Preferably a fluid bed dryer is used. Fluidized bed granulation dryers are available from GPCG-l (Glatt, Germany). Used. When drying is complete, the dry matter is established using an oscillator equipped with a No. 18 body. Colloidal silicon dioxide is added to the formulation and mixed with a double cone mixer.
3) 흔합 및 캡슬 층전 3) mixing and capping
공정 1)과 2)의 최종 조성물을 더블콘믹서로 흔합하였다. 흔합물에 스테아린산 마그네슘을 투입하고 더블콘믹서로 최종 흔합하였다. 최종 흔합된 흔합물을 분말 공급기에 투입하고 캡술층전기를 이용하여 층전하여 캡슐형태의 제어 방출 제제의 제조를 완료하였다. 실시예 35: 캡술제 제조 (정제-펠렛)  The final compositions of steps 1) and 2) were combined with a double cone mixer. Magnesium stearate was added to the mixture and finally mixed with a double cone mixer. The final blended mixture was placed in a powder feeder and layered using a capsul layered electric charge to complete the preparation of the controlled release formulation in capsule form. Example 35 Capsule Preparation (Tablet-Pellets)
1) 안지오텐신ᅳ Πᅳ수용체 차단제 지연방출형 정제의 제조  1) Preparation of Angiotensin® Π ᅳ Receptor Blocker Delayed-Release Tablets
안지오텐신ᅳ Πᅳ수용체 차단제 지연방출형 정제는 표 9에 나타난 함량과 같이 발사르탄， 미결정셀를로오스， 가교 폴리비닐피를리돈을 35호체로 체과하고 고속흔합기로 5분간 흔합하여 흔합물을 제조한다. 따로 플리비닐피를리돈을 정제수에 녹여 결합액을 제조한다. 상기 흔합물을 유동층과립기 또는 고속희전 조립기에 넣고 결합액을 가하여 조립한다. 바람직하게는 유동층 과립기를 사용한다. 유동층 과립기는 GPCG-l(Glatt, Germany)을 사용하였다. 조립이 완료된 후 유동층 건조기 또는 온수건조기에 조립물을 건조 시킨다. 바람직하게는 유동층 건조기를 사용한다. 유등층 과립 건조기는 GPCG-l(Glatt, Germany)을 사용하였다. 건조물을 18호체가 장착된 오실레이터를 사용하여 정립한다. 정립물에 스테아린산 마그네슘을 넣고 더블콘믹서로 최종 흔합한다. 최종 흔합물을 로타리 타정기 (MRC-33: 세종)를 사용하여 타정한다. 이렇게 제조한 정제를 하이코터 (SFC-30N: 세종 기계， 한국)에 투입한다. 다시 상기의 정제에 히드록시프로필셀를로오스， 히드록시프로필메틸셀를로오스프탈레이트를 에탄올 220mg 과 염화메틸렌 980 mg에 녹인 액을 분무하여 안지오텐신— Πᅳ수용체 차단제 지연방출형 정제를 제조하였다. Angiotensin Π ᅳ receptor blocker delayed-release tablets were sieved through valsartan, microcrystalline cellulose, and crosslinked polyvinylpyridone as No. 35, and mixed for 5 minutes using a high-speed mixer to prepare a mixture. . Separately, polyvinylpyridone is dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high speed granulator and granulated by adding a binder solution. Preferably fluid bed granulators are used. The fluid bed granulator used GPCG-l (Glatt, Germany). After the assembly is completed, the granulated material is dried in a fluidized bed dryer or a hot water dryer. Preferably a fluid bed dryer is used. GPCG-l (Glatt, Germany) was used for the evaporated granule dryer. The dry matter is established using an oscillator equipped with a No. 18 body. Magnesium stearate is added to the formulation and finally mixed with a double cone mixer. The final mixture is compressed using a rotary tablet press (MRC-33: Sejong). The tablet thus prepared is put into a high coater (SFC-30N: Sejong Machinery, Korea). Again hydroxypropyl cellulose in the above purification, Angiotensin-? Receptor receptor blocker delayed-release tablets were prepared by spraying a solution of hydroxypropylmethylcelloose phthalate in 220 mg of ethanol and 980 mg of methylene chloride.
2) 치아자이드계 화합물 선방출형 펠렛의 제조 2) Preparation of Chiazide Compound Pre-Release Pellets
표 9에 나타난 함량과 같이 슈가 시드 (Sugar sphere)를 35호체로 체과하고 유동층 과립기 (GPCG 1： Glatt)에 투입한 뒤， 따로 물과 에탄올에 히드록시프로필메틸셀를로오스과 히드로클로로치아짓을 용해시킨 결합액을 분무 건조하여 치아자이드계 화합물 선방출형 펠렛을 형성하였다.  As shown in Table 9, the sugar spheres were sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose and hydrochlorothiazide were dissolved separately in water and ethanol. The liquid was spray dried to form a thiazide compound pre-release pellet.
3) 흔합 및 캡술 층전 3) mixing and capsular layering
공정 1)과 2)의 최종 조성물을 더블콘믹서로 흔합하였다. 흔합물을 분말 공급기에 투입하고 캡슐층전기를 이용하여 충전하여 캡슐형태의 제어 방출 제제의 제조를 완료하였다.  The final compositions of steps 1) and 2) were combined with a double cone mixer. The mixture was placed in a powder feeder and filled using capsule bed electricity to complete the preparation of the controlled release formulation in capsule form.
실시예 36: 캡슐제 제조 (정제-정제) Example 36 Preparation of Capsules (Tablets-Tablets)
1) 안지오텐신ᅳ Πᅳ수용체 차단제 지연방출형 정제의 제조  1) Preparation of Angiotensin® Π ᅳ Receptor Blocker Delayed-Release Tablets
안지오텐신ᅳ Πᅳ수용체 차단제 지연방출형 정제는 표 9에 나타난 함량과 같이 텔미사르탄, 미결정셀를로오스， 메글루민을 달아 35호체로 체과하고 더블콘믹서에서 5분간 흔합하여 흔합물을 제조한다. 따로 솔비틀, 폴리비닐피를리돈， 소듐 하이드록사이드를 정제수에 녹여 결합액을 제조한다. 상기 흔합물을 유동층과립기 또는 고속회전 조립기에 넣고 결합액을 가하여 조립한다. 바람직하게는 유동층 과립기를 사용한다. 유동층 과립기는 GPCG- KGlatt, Germany)을 사용하였다. 조립이 완료된 후 유동층 건조기 또는 온수건조기에 조립물을 건조 시킨다. 바람직하게는 유동층 건조기를 사용한다. 유동층 과립 건조기는 GPCG~l(GIatt, Germany)을 사용하였다. 건조물을 18호체가 장착된 오실레이터를 사용하여 정립한다. 정립물에 스테아린산 마그네슘을 넣고 더블콘믹서로 최종 흔합한다. 최종 흔합물을 로타리 타정기 (MRC-33: 세종)를 사용하여 타정한다. 이렇게 제조한 정제를 하이코터 (SFC-30N: 세종 기계, 한국)에 투입한다. 다시 상기의 정제에 에틸셀를로오스， 메타크릴산 공증합체 type C를 에탄올 220mg 과 염화메틸렌 980 mg에 녹인 액을 분무하여 안지오텐신 _Πᅳ수용체 차단제 지연방출형 정제를 제조하였다. Angiotensin ᅳ Π ᅳ receptor blocker delayed-release tablets were sieved with telmisartan, microcrystalline cellulose, and meglumine as No. 35, and then mixed with a No. 35 sieve for 5 minutes in a double cone mixer to prepare a mixture. . Separately, sorbetle, polyvinylpyridone, and sodium hydroxide are dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution. Preferably fluid bed granulators are used. Fluid bed granulator (GPCG-KGlatt, Germany) was used. Fluidized dryer or after assembly Dry the assembly in a hot water dryer. Preferably a fluid bed dryer is used. Fluid bed granulation dryer was used GPCG ~ l (GIatt, Germany). The dry matter is established using an oscillator equipped with a No. 18 body. Magnesium stearate is added to the formulation and finally mixed with a double cone mixer. The final mixture is compressed using a rotary tablet press (MRC-33: Sejong). The tablet thus prepared is put into a high coater (SFC-30N: Sejong Machinery, Korea). To the above tablets, a solution of ethylcellose and methacrylic acid co-polymer type C dissolved in 220 mg of ethanol and 980 mg of methylene chloride was sprayed to prepare angiotensin _Π ᅳ receptor blocker delayed-release tablet.
2) 치아자이드계 화합물 선방출형 정제의 제조 2) Preparation of Chiazide Compound Pre-Release Tablets
표 9에 나타난 함량과 같이 치아자이드계 화합물인 히드로클로로치아짓과 부형제인 미결정셀를로오스， 전호화전분， 폴리비닐피를리돈 공증합체, 콜로이드성 이산화규소를 35호체로 체과 하고 고속흔합기로 흔합하였다. 이 흔합물에 스테아린산 마그네슴을 넣어 최종 흔합하였다. 최종 흔합물을 로타리 타정기 (MRC-33: 세종)를 사용하여 타정하여 치아자이드계 화합물 선방출형 정제를 제조하였다.  As shown in Table 9, ziazide-based compound hydrochlorothiazide and excipient microcrystalline cellulose, pregelatinized starch, polyvinylpyridone co-polymer, and colloidal silicon dioxide were sieved through a No. 35 sieve and mixed with a high speed mixer. Stearic acid magnesium was added to this mixture for final mixing. The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare a thiazide compound-release tablet.
3) 흔합 및 캡슐 층전 3) mixing and capsule layering
공정 1)과 2)의 최종 조성물을 더블콘믹서로 흔합하였다. 흔합된 흔합물을 분말 공급기에 투입하고 캡술층전기를 이용하여 층전하여 캡슐형태의 제어 방 제제의 제조를 완료하였다. 실시예 37: 삼투성 유핵정 제조 1) 안지오텐신ᅳ Π ᅳ수용체 차단제 지연방출형 삼투성 내핵정의 제조 안지오텐신ᅳ Π ᅳ수용체 차단제 지연방출형 내핵정 제조는 표 9에 나타난 함량과 같이 로사르탄 칼륨 , 미결정셀를로오스 염화나트륨을 35호체로 체과하고 고속흔합기로 5분간 흔합하여 흔합물을 제조한다. 흔합물에 스테아린산 마그네슴 투입 후 4분간 흔합하고， 최종 흔합물을 로타리 타정기 (MRC-33: 세종)를 사용하여 타정한다. 타정 후 삼투성 코팅기제로서 에틸셀를로오스를 정제수에 분산시킨 후 하이코터 (SFC-30N, 세종 기계， 한국)를 이용하여 내핵정에 코팅하여 삼투성 내핵정을 제조하였다. The final compositions of steps 1) and 2) were combined with a double cone mixer. The mixed mixture was placed in a powder feeder and layered using a capsul layered electric charge to complete the preparation of the capsule-type control room formulation. Example 37 Preparation of Osmotic Nucleated Tablets 1) Preparation of Angiotensin® Π ᅳ Receptor Blocker Delayed-Release Osmotic Inner Core Tablets Angiotensin® Π ᅳ Receptor Blocker Preparation of Delayed-Release Inner Core Tablets After mixing for 5 minutes with a high speed mixer to prepare a mixture. After stearic acid magnesium is added to the mixture, the mixture is mixed for 4 minutes, and the final mixture is compressed using a rotary tableting machine (MRC-33: Sejong). After tableting, as the osmotic coating base, ethylcellose was dispersed in purified water, and then coated with an inner core tablet using a high coater (SFC-30N, Sejong Machinery, Korea) to prepare an osmotic inner core tablet.
2) 치아자이드계 화합물 선방출층의 제조 2) Preparation of Chiazide Compound Pre-Release Layer
치아자이드계 화합물 선방출층 제조는 표 9에 나타난 함량과 같이 히드로클로로치아짓， 미결정셀를로오스， 유당, 옥수수전분， 저치환도 히드록서프로필셀를로오스를 달아 35호체로 체과하고 더블콘믹서에서 5분간 흔합하여 흔합물을 제조한다. 따로 히드록시프로필셀를로오스를 정제수에 녹여 결합액을 제조한다. 상기 흔합물을 유동층과립기 또는 고속회전 조립기에 넣고 결합액을 가하여 조립한다. 바람직하게는 유동층 과립기를 사용한다. 유동층 과립기는 GPCG-l(Glatt , Germany)을 사용하였다. 조립이 완료된 후 유동층 건조기 또는 온수건조기에 조립물을 건조 시킨다 . 바람직하게는 유동층 건조기를 사용한다 . 유동층 과립 건조기는 GPCG-l(Glatt , Germany)을 사용하였다. 건조가 완료되면 건조물을 18호체가 장착된 오실레이터를 사용하여 정 립한다. 정 립물에 콜로이드성 이산화규소를 넣고 더블콘믹서로 흔합한다. 위의 흔합물에 스테아린산 마그네슘을 넣어 더불콘믹서로 최종 흔합하였다.  Preparation of the thiazide compound-release layer was carried out with hydrochlorothiazide, microcrystalline cellulose, lactose, corn starch, low-substituted hydroxylpropyl cellulose as shown in Table 9 and sieved through No. 35 sieve for 5 minutes in a double cone mixer. Are mixed to produce the mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution. Preferably fluid bed granulators are used. The fluid bed granulator used GPCG-l (Glatt, Germany). After assembly is complete, dry the assembly in a fluid bed dryer or hot water dryer. Preferably fluid bed dryers are used. Fluid bed granulation drier was used GPCG-l (Glatt, Germany). When drying is completed, the dry matter is established using an oscillator equipped with a No. 18 body. Add colloidal silicon dioxide to the formulation and mix with a double cone mixer. Magnesium stearate was added to the above mixture, and the final mixture was mixed with a debulcon mixer.
3) 타정 및 코팅 유핵정 타정기 (RUD-1: Kilian)를 사용하여 안지오텐신ᅳ Πᅳ수용체 차단제 지연방출형 삼투성 내핵정으로 하고 치아자이드계 화합물을 포함하는 조성물을 외층으로 하여 유핵정 제조를 완료한 후, 따로 히드록시프로필메틸셀를로오스 2910, 산화티탄， 탈크를 80% 에탄을에 용해 및 분산시킨 코팅액을 조제한다. 위의 유핵정을 하이코터 (SFC-30N: 세종 기계, 한국)에 투입한 후 코팅액으로 코팅하여 코팅 삼투성 유핵정 제조를 완료하였다. 실시예 38 내지 39: 삼투성 유핵정 제조 3) tableting and coating Angiotensin ᅳ Π 정 receptor blocker delayed-release osmotic inner core tablet using a nucleated tablet tableting machine (RUD-1: Kilian) and a composition containing a cyanide compound as an outer layer were used to complete nucleated tablet separately. A coating solution obtained by dissolving and dispersing oxypropylmethylcellose 2910, titanium oxide, and talc in 80% ethane was prepared. The above nucleated tablet was added to a high coater (SFC-30N: Sejong Machinery, Korea) and then coated with a coating solution to complete the preparation of the coated osmotic nucleated tablet. Examples 38-39 Preparation of Osmotic Nucleated Tablets
실시예 37과 동일한 삼투성 유핵정의 제조 방법에 따라 표 9와 같은 조성과 함량으로 삼투성 유핵정을 제조하였다. 실시예 40: 블러스터 포장 키트  Osmotic nucleated tablets were prepared according to the composition and contents of Table 9 according to the same method for preparing the osmotic nucleated tablets as in Example 37. Example 40 Blaster Packaging Kit
실시예 15의 1) 안지오텐신ᅳ Πᅳ수용체 차단제 지연방출 과립과 2) 치아자이드계 화합물 선방출 과립을 흔합하여 타정하는 대신쎄 실시예 15의 공정 1)과 실시예 15의 공정 2)의 과립을 제조하여 각 공정의 최종 조성물을 각각 로타리 타정기 (MRC-33: 세종)를 사용하여 타정하고 블리스터 포장용기에 동시복용 가능하도록 포장하였다. The granules of Example 15, Step 1) and Example 15, Step 2) of Example 15 instead of mixing 1) angiotensin ᅳ i ᅳ receptor blocker delayed-release granules of Example 15 and 2) thiazide-based compound prior-release granules The final composition of each process was compressed into tablets using a rotary tablet press (MRC-33: Sejong) and packaged for simultaneous use in a blister packaging container.
【표 4】 Table 4
Figure imgf000058_0001
【표 5】'
Figure imgf000058_0001
[Table 5] '
Figure imgf000059_0001
【표 6】
Figure imgf000059_0001
Table 6
조성비 (mg/t ablet)  Composition ratio (mg / t ablet)
구성성분 실시 예  Component Example
15 16 17 18 19 20 21 로사르탄 칼륨 100 50 50 50 50  15 16 17 18 19 20 21 Losartan potassium 100 50 50 50 50
이르베시 -르탄 150 발사르탄 80 미 결정셀를로오스 150 100 25 137 123 40 75 전분글리콘산나트륨 8 8  Irbesi-Letan 150 Valsartan 80 Microcrystalline Cellulose 150 100 25 137 123 40 75 Sodium starch glycolate 8 8
히드록시프로필 8 4 5 8 15 셀를로오스  Hydroxypropyl 8 4 5 8 15 cellulose
지 G
연 유당 30 30 Lactose 30 30
방 가교 클리비 닐피를리돈 50 80 150 콜리코트 SR30D" 24 Anti-corrosion Crosslinked Clevy Nylpyridone 50 80 150 Collicoat SR30D "24
히드록시프로필메틸셀를로오스 2 4 3.2 6 히드록시프로 ¾메 ¾셀를로오스  Hydroxypropylmethylcellose 2 4 3.2 6 hydroxypro ¾me ¾cellose
프탈레이트 (ΗΡ-50) 10 10  Phthalate (ΗΡ-50) 10 10
히드록시프로필메틸셀를로오스  Hydroxypropylmethylcellose
프탈레이트 (HP— 55) 67.6 67.6 6  Phthalates (HP— 55) 67.6 67.6 6
폴리에틸렌 글리콜 6000 6.8 6.8  Polyethylene Glycol 6000 6.8 6.8
셀를로오스아세테 이 E  Cellulose Acetate E
(아세틸기 32%) 20 32 60 (Acetyl group 32%) 20 32 60
¾를로오스아세테이 E ( όᅡ세틸 ¾ Loose Acetate E (ό ᅡ Cetyl
기 39.8%) 20 ' 32 60 염화나트륨 25 40 75 콜로이드성 이산화규소 2 2 Group 39.8%) 20 '32 60 Sodium chloride 25 40 75 Colloidal silicon dioxide 22
스테아린산 마그네슘 1 1 3 3 3 4.8 9 히드로클로로치아짓 25 12.5 12.5 12.5 12.5 12.5 12.5 미결정 셀를로오스 275 51.5 51.5 51.5 51.5 51.5 51.5 전호화 전분 30 30 30 30 30 30 선 플리비닐피를리돈 공중합체 3 3 3 3 3 3 방 유당 ' 60 Magnesium Stearate 1 1 3 3 3 4.8 9 Hydrochlorothiazide 25 12.5 12.5 12.5 12.5 12.5 12.5 Microcrystalline Cellulose 275 51.5 51.5 51.5 51.5 51.5 51.5 Pregelatinized Starch 30 30 30 30 30 30 Sun Polyvinylpyridone Copolymer 3 3 3 3 3 three rooms of lactose, 60
은수 Φ;러부 · 90  Silver Φ; Rubu 90
히드록시프로필셀를로오스 12  Hydroxypropyl Cellulose 12
ᄌ 치환도히드록시프로필  ᄌ Substituted Hydroxypropyl
4를로오스 25  4Loose 25
콜로이드성 이산화규소 4.5 2 2 2 2 2 2 스테아린산 마그네슘 1 1 1 1 1 1 1 히드록시프로필메틸 ¾를로오스  Colloidal Silicon Dioxide 4.5 2 2 2 2 2 2 Magnesium Stearate 1 1 1 1 1 1 1 Hydroxypropylmethyl ¾
코 2910 20 13.25 13.24 13.24 13.24 14.7 24.5 팅 히드록시프로필셀를로오스 13.25 13.24 13.24 13.24 14.7 24.5 산화티탄 3 1.9 1.9 1.9 1.9 2.2 3.7 탈크 2 1.3 1.3 1.3 1.3 1.7 2.8 합계 900.9 409.1 329.68 329.68 329.68 453.3 755.5CO 2910 20 13.25 13.24 13.24 13.24 14.7 24.5 Ting hydroxypropylcelose 13.25 13.24 13.24 13.24 14.7 24.5 Titanium oxide 3 1.9 1.9 1.9 1.9 2.2 3.7 Talc 2 1.3 1.3 1.3 1.3 1.7 2.8 Total 900.9 409.1 329.68 329.68 329.68 453.3 755.5
1) 콜리코트 SR 30D (성분명 : 플리 비닐 아세테 이트 30% 현탁액， 겨 1조처 : 바스프사) 【표 71 1) Collicoat SR 30D (ingredient name: 30% suspension of polyvinyl acetate, bran 1: BASF) Table 71
Figure imgf000061_0001
【표 8】
Figure imgf000061_0001
Table 8
Figure imgf000062_0001
【표 9】
Figure imgf000062_0001
Table 9
Figure imgf000063_0001
실험예 1: 비교 용출시험 (comparative dissolution profile test) 상기 실시예 1에 따라 제조된 로사르탄 /히드로클로로치아짓 내핵정과 각 성분 단일제 대조약 (코자정, MSD: 로사르탄 단일제 I다이크로짇정， 유한양행: 히드로클로로치아짓 단일제)의 비교 용출시험을 실시하였다. 히드로클로로치아짓 성분 용출 시험의 경우 미국약전 (USP30)에 근거하여 용출시험을 진행하였고， 로사르탄 성분 용출시험의 경우 120분을 기점으로 용출액을 인공 위액에서 인공 장액으로 변경하여 총 480분간 용출시험을 진행하였다. 각 성분별 용출시험 방법은 아래와 같으며， 그 결과를 도 1과 같이 나타내었다.
Figure imgf000063_0001
Experimental Example 1: Comparative dissolution profile test Losartan / hydrochlorothiazide inner core tablet prepared according to Example 1 and each component mono-control (coza-crystal, MSD: Losartan monodisaccharide), Yuhan: hydrochlorothiazit Comparative dissolution test of a single agent) was performed. In the case of hydrochlorothiazide dissolution test, the dissolution test was conducted according to the USP30, and in the case of the Losartan dissolution test, the eluate was changed from artificial gastric fluid to artificial intestinal fluid for 120 minutes. . The dissolution test method for each component is as follows, and the results are shown in FIG.
도 1에 의하면 상기 용출 시험 시 본 발명의 유핵정 중 히드로클로로치아짓 성분은 대조 제제인 다이크로짇정과 비교하여 거의 동등한 용출특성을 나타내는 것으로 확인되었으나， 로사르탄 성분은 대조 제제인 코자와 비교할 때 매우 지연된 용출 속도를 확인 할 수 있다. 로사르탄 성분의 용출 시험 결과를 보면， 인공 위액 구간인 120분까지의 로사르탄 성분의 용출를은 본 발명의 로사르탄 /히드로클로로치아짓의 유핵정에서 10% 이내이나, 대조 제제는 약 60%임을 확인할 수 있었고, 이후 인공 장액 구간에서 로사르탄 성분의 . 용출를은 대조제제에서 총 150분에 100%이나， 본 발명의 로사르탄 /히드로클로로치아짓의 유핵정 기능성 복합제에서는 총 240분에 약 2 로 훨씬 느림을 확인할 수 있었다.  According to FIG. 1, the hydrochlorothiazide component of the nucleated tablet of the present invention was found to have almost the same elution characteristics as that of the control preparation dichroic tablet in the dissolution test, but the losartan component was very delayed in dissolution compared to the control agent Koza. You can check the speed. As a result of dissolution test of losartan component, the dissolution of the losartan component up to 120 minutes, which is the artificial gastric juice section, was found to be within 10% of the nucleated tablet of losartan / hydrochlorothiazide of the present invention, but the control agent was about 60%. , And the loss of losartan in the artificial serous section. Elution was 100% in the total 150 minutes in the control agent, it was confirmed that much slower to about 2 in 240 minutes in the nucleated tablet functional combination of losartan / hydrochlorothiazide of the present invention.
이처럼 본 발명의 로사르탄 /히드로클로로치아짓의 유핵정 제제는 대조약인 로사르탄 단일제와 히드로클로호치아짓 단일제를 동시 복용하였을 경우의 용출 양상과는 달리 로사르탄의 초기 방출이 히드로클로로치아짓보다 매우 느리기 때문에 히드로클로로치아짓의 2차적인 혈압강하효과가 발생하는 시점에 투입할수 있어 고혈압 치료에 매우 효과적인 약학조성물인 것이다. [치아자이드계 화합물 선방출층 시험방법] As described above, the nucleated tablet formulation of losartan / hydrochlorothiazit of the present invention is different from the dissolution of the losartan monotherapy and the hydroclohozigit single agent, so that the initial release of losartan is much slower than hydrochlorothiazit. It is a pharmaceutical composition that is very effective in treating hypertension because it can be injected at the time when the secondary blood pressure lowering effect occurs. [Test Method of Thiazide-Based Compound Pre-Emission Layer]
용출시험 근거: 미국약전 (USP 30)중의 '히드로클로로치아짓 정제'항 시험 방법: 장치 1 [패들법 (Paddle method)], 100회전 /분  Dissolution test basis: Test method for 'hydrochlorothiazide purification' in USP 30: Apparatus 1 [Paddle method], 100 revolutions / minute
시험액: 0. IN—염산， 900mL  Test solution: 0. IN—hydrochloric acid, 900 mL
분석방법 : 자외가시부흡광광도법  Analysis method: UV-visible absorption spectrophotometry
[안지오텐신 -II-수용체 지연방출층 시험방법] [Angiotensin-II-receptor delayed release layer test method]
용출시험 근거: 대한약전 제 8개정 중 일반시험법의 용출시험법  Dissolution test basis: Dissolution test method of General Test Method
시험 방법: 패들법, 50회전 /분  Test Method: Paddle Method, 50 Turns / Min
시험약: 0. 01M염산용액, 750mL (인공위액)  Test drug: 0.1M hydrochloric acid solution, 750mL (artificial gas solution)
pH 6. 8 인산완층액， 총 lOOOmL (인공장액)  pH 6. 8 Phosphoric Acid Complete Solution, Total lOOOmL (Phosphate)
분석 방법 : 자외가시부흡광광도법 · Analysis method: UV-visible spectrophotometry,
실험예 2: 비교 용출시험 (comparative dissolution profile test) 상기 실시예 2에 따라 제조된 로사르탄 /히드로클로로치아짓 내핵정과 복합제 대조약 (코자 플러스정， MSD: 로사르탄 /히드로클로로치아짓 복합제)의 비교 용출시험을 실시하였다. 각 성분별 용출시험 방법은 실험예 1과 같으며， 그 결과를 도 2와 같이 나타내었다. Experimental Example 2: Comparative Dissolution Profile Test The comparative dissolution test of the losartan / hydrochlorothiazide inner core tablet prepared in Example 2 and the composite control (coza plus tablet, MSD: losartan / hydrochlorothiazide composite) were carried out. . Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
도 2에 의하면 실험예 1의 ᅵ조건에서 용출 시험 시 본 발명의 유핵정 중 히드로클로로치아짓 성분은 대조 제제 코자플러스정과 비교하여 빠른 용출특성을 나타내는 것으로 확인되었으나, 코자플러스정의 히드로클로로치아짓 용출은 단일제나 본 발명의 유핵정과 달리 구획을 나누지 않은 단순 복합제이기 때문에 산에서 용출속도가 늦은 로사르탄의 영향을 받아 히드로클로로치아짓 단일제와 다른 용출 속도를 보인다. 히드로클로로치아짓의 최고 효과를 보이기 위해서는 단순 복합제의 지연된 용출 속도가 아닌 단일제와 유사한 빠른 용출 속도를 보여야 한다. 2 shows that the hydrochlorothiazide component of the nucleated tablet of the present invention exhibited faster dissolution characteristics when compared to the control formulation Coza plus tablet when the dissolution test was carried out under the conditions of Experimental Example 1, but the hydrochlorothiazide elution of Coza plus tablet was the single agent or the present invention. Unlike nucleated tablets, hydrochlorothiazide is affected by losartan, which has a slow elution rate in acid, because it is a simple complex without division. Elution rates are different from those of monoliths. In order to achieve the best effect of hydrochlorothiazide, it is necessary to show a fast dissolution rate similar to that of a single agent, not the delayed dissolution rate of a simple combination.
로사르탄 성분은 대조 제제인 코자플러스와 비교할 때 실험예 1과 같이 매우 지연된 용출 속도를 확인 할수 있다.  Losartan component can confirm a very delayed dissolution rate as in Experimental Example 1 compared to the control formulation Coza Plus.
이처럼 본 발명의 로사르탄 /히드로클로로치아짓의 유핵정 제제는 대조약인 구획을 나누지 않은 로사르탄 /히드로클로로치아짓 단순 복합제를 동시 복용하였을 경우의 용출 양상과는 달리 히드로클로로치아짓의 방출 속도가 코자플러스보다 빠르고， 로사르탄의 초기 방출이 히드로클로로치아짓보다 매우 느리기 때문에 히드로클로로치아짓의 2차적인 혈압강하효과가 발생하는 시점에 투입할 수 있어 고혈압 치료에 매우 효과적인 약학조성물인 것이다. 실험예 3: 비교 용줄시험 (comparative dissolution profile test) 상기 실시예 5 ~ 8의 비교 용출시험을 실시하였다. 각 성분별 용출시험 방법은 실험예 1과 같으며, 그 결과를 도 3과 같이 나타내었다.  As described above, the nucleated tablet formulation of losartan / hydrochlorothiazit of the present invention has a faster release rate of hydrochlorothiazit than Cozaplus, unlike the dissolution of the case of simultaneous administration of the losartan / hydrochlorothiazit simple combination without a compartment, which is a reference. Since the initial release is much slower than hydrochlorothiazide, it can be applied at the time when the second hypotensive effect of hydrochlorothiazide occurs, which is a very effective pharmaceutical composition for the treatment of hypertension. Experimental Example 3: Comparative Dissolution Profile Test The comparative dissolution test of Examples 5 to 8 was performed. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
도 3에 의하면 실험예 1의 조건에서 용출 시험 시 본 발명의 유핵정은 에틸셀를로오스의 사용량이 증가함에 따라 로사르탄 성분이 매우 지연된 용출 속도를 보임을 확인할 수 있었다. 에틸셀를로오스를 사용하여 코팅을 함으로써 실시예 .5 ~ 8에서 총 240분까지 20% 이내의 로사르탄 용출를을 확인할 수 있었다.  According to FIG. 3, in the dissolution test under the conditions of Experimental Example 1, it was confirmed that the losartan component showed a very delayed dissolution rate as the amount of ethylcellulose increased. By coating with ethyl cellulose, it was possible to confirm the loss of losartan within 20% up to 240 minutes in Example .5-8.
이처럼 본 발명의 로사르탄 /히드로클로로치아짓의 유핵정 제제는 에틸셀를로오스의 코팅 시 사용량을 조절함으로써 로사르탄의 초기 방출을 의도한 시간만큼 지연 방출시킬 수 있다. 따라서， 로사르탄을 히드로클로로치아짓의 2차적인 혈압강하효과가 발생하는 시점에 투입할수 있어 고혈압 치료에 매우 효과적인 약학조성물인 것이다. 실험예 4: 비교 용출시험 (comparative dissolution profile test) 상기 실시예 7， 9 ~ 11의 비교 용출시험을 실시하였다. 각 성분별 용출시험 방법은실험예 1과 같으며， 그 결과를 도 4과 같이 나타내었다. As described above, the nucleated tablet formulation of losartan / hydrochlorothiazide of the present invention can delay the initial release of losartan by an intended time by controlling the amount of ethylcell used in the coating. Therefore, losartan can be injected at the time when the second hypotensive effect of hydrochlorothiazide occurs. It is a very effective pharmaceutical composition for the treatment of hypertension. Experimental Example 4: Comparative Dissolution Profile Test The comparative dissolution test of Examples 7 and 9 to 11 was performed. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
도 4에 의하면 실험 예 1의 조건에서 용출 시험 시 본 발명의 유핵정은 에틸셀를로오스 코팅을 한 지연 방출층 내에 폴리비닐피를리돈이 있을 경우 로사르탄 성분이 의도한 시간까지 지연 시간을 가진 후 비교적 급격하게 방출되는 것을 확인할 수 있었다. 로사르탄 성분의 용출를은 총 240분까지 20% 이내이며, 플리비닐피를리돈의 사용량이 증가함에 따라 로사르탄 성분이 급격하게 방출되었다.  According to FIG. 4, in the dissolution test under the conditions of Experimental Example 1, the nucleated tablet of the present invention has a delay time until the intended time of the lossartan component when polyvinylpyridone is present in the delayed release layer coated with ethylcellose. After it was confirmed that the release is relatively rapid. The dissolution of the losartan component was within 20% for a total of 240 minutes, and the losartan component was rapidly released as the amount of the polyvinylpyridone was increased.
이처럼 본 발명의 로사르탄 /히드로클로로치아짓의 유핵정 제제는 에틸셀를로오스의 코팅을 한 지연 방출층 내의 플리비닐피롤리돈의 사용량을 조절함으로써 의도한 시간까지 지연 시간을 가진 후 급격하게 로사르탄을 방출시킬 수 있다. 따라서， 로사르탄을 히드로클로로치아짓의 2차적인 혈압강하효과가 발생하는 시점에 투입할 수 있어 고혈압 치료에 매우 효과적인 약학조성물인 것이다. 실험예 5: 비교 용출시험 (comparative dissolution profile test) 상기 실시예 15에 따라 제조된 로사르탄 /히드로클로로치아짓 다층정과 복합제 대조약 (코자 플러스에프정， MSD: 로사르탄 /히드로클로로치아짓 복합제)의 비교 용출시험을 실시하였다. 각성분별 용출시험 방법은 실험예 1과 같으며， 그 결과를 도 5과 같이 나타내었다. As described above, the nucleated tablet formulation of losartan / hydrochlorothiazide of the present invention rapidly releases losartan after having a delay time until the intended time by controlling the amount of polyvinylpyrrolidone used in the delayed release layer coated with ethylcellose. You can. Therefore, losartan can be added at the time when the secondary blood pressure lowering effect of hydrochlorothiazide occurs, which is a very effective pharmaceutical composition for the treatment of hypertension. Experimental Example 5: Comparative dissolution profile test The comparative dissolution test of the losartan / hydrochlorothiazide multilayer tablet and the composite control (coza plus F tablet, MSD: losartan / hydrochlorothiazide complex) prepared according to Example 15 was carried out. It was. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
도 5에 의하면 실험예 1의 조건에서 용출 시험 시 본 발명의 다층정 중 히드로클로로치아짓 성분은 대조 제제 코자플러스에프정과 비교하여 빠른 용출특성을 나타내는 것으로 확인되었으나， 코자플러스에프정의 히드로클로로치아짓 용출은 단일제나 본 발명의 다층정과 달리 구획을 나누지 않은 단순 복합제이기 때문에 산에서 용출속도가 늦은 로사르탄의 영향을 받아 히드로클로로치아짓 단일제와 다른 용출 속도를 보인다. 히드로클로로치아짓의 최고 효과를 보이기 위해서는 단순 복합제의 지연된 용출 속도가 아닌 단일제와 유사한 빠른 용출 속도를 보여야 한다. According to Figure 5 of the multilayer tablet of the present invention during the dissolution test in the conditions of Experimental Example 1 The hydrochlorothiazide component was found to exhibit faster dissolution characteristics compared to the coza plus F tablet of the control formulation.However, the hydrochlorothiazide elution of the coza plus F tablet was different from the single tablet or the multi-layered tablet of the present invention. Under the influence of letan, the dissolution rate is different from that of hydrochlorothiazide monolith. In order to achieve the best effect of hydrochlorothiazide, it is necessary to show a fast dissolution rate similar to that of a single agent, not the delayed dissolution rate of a simple combination.
로사르탄 성분은 대조 제제인 코자플러스에프정과 비교할 때 실험예 1과 같이 매우 지연된 용출속도를 확인 할수 있다.  Losartan component can confirm a very delayed dissolution rate as in Experimental Example 1 compared to the coza plus F tablets.
이처럼 본 발명의 로사르탄 /히드로클로로치아짓의 다층정 제제는 대조약인 구획을 나누지 않은 로사르탄 /히드로클로로치아짓 단순 복합제를 동시 복용하였을 경우의 용출 양상과는 달리 히드로클로로치아짓의 방출 속도가 코자플러스에프정 보다 빠르고， ' 로사르탄의 초기 방출이 히드로클로로치아짓보다 매우 느리기 때문에 히드로클로로치아짓의 2차적인 혈압강하효과가 발생하는 시점에 투입할 수 있어 고혈압 치료에 매우 효과적인 약학조성물인 것이다.  As described above, the multi-layered tablet formulation of losartan / hydrochlorothiazit of the present invention exhibits a faster release rate of hydrochlorothiazit than Coza plus F tablet, unlike the dissolution of co-administration of losartan / hydrochlorothiazide simple combination without a compartment. Since the initial release of losartan is much slower than hydrochlorothiazit, it can be applied at the time of the second hypotensive effect of hydrochlorothiazide, which is a very effective pharmaceutical composition for the treatment of hypertension.
실험예 6： 비교 용줄시험 (comparative dissolution profile test) 상기 실시예 16에 따라 제조된 로사르탄 /히드로클로로치아짓 다층정과 각 성분 단일제 대조약 (코자정， MSD: 로사르탄 단일제 I 다이크로짇정， 유한양행: 히드로클로로치아짓 단일제)의 비교 용출시험을 실시하였다. 각 성분별 용출시험 방법은 실험예 1과 같으며， 그 결괴：를 도 6와 같이 나타내었다. 도 6에 의하면 실험예 1의 조건에서 용출 시험 시 본 발명의 다층정 중 히드로클로로치아짓 성분은 대조 제제인 다이크로짇정과 비교하여 거의 동등한 용출특성을 나타내는 것으로 확인되었으나， 로사르탄 성분은 대조 제제인 코자와 비교할 때 매우 지연된 용출 속도를 확인 할수 있었다. Experimental Example 6: Comparative dissolution profile test Losartan / hydrochlorothiazide multilayer tablet prepared according to Example 16 and each component mono-control (coza-crystal, MSD: Losartan mono-I dichroic tablet, finite positive: hydrochlorothiazide Comparative dissolution test of a single agent) was performed. The dissolution test method for each component is the same as in Experimental Example 1, and the nodules thereof are shown in FIG. 6. According to FIG. 6, in the dissolution test under the conditions of Experimental Example 1, the hydrochlorothiazide component of the multi-layered tablet of the present invention was almost equivalent to that of the control drug dichromatin tablet. It was confirmed that the dissolution characteristics, but the losartan component was confirmed to be very delayed dissolution rate compared to the control agent Koza.
이처럼 본 발명의 로사르탄 /히드로클로로치아짓의 다층정 제제는 대조약인 로사르탄 단일제와 히드로클로로치아짓 단일제를 동시 복용하였을 경우의 용출 양상과는 달리 로사르탄의 초기 방출이 히드로클로로치아짓보다 매우 느리기 때문에 히드로클로로치아짓의 2차적인 혈압강하효과가 발생하는 시점에 투입할 수 있어 고혈압 치료에 매우 효과적인 약학조성물인 것이다. 실험예 7: 비교 용출시험 (comparative dissolution profile test) 상기 실시예 20에 따라 제조된 발사르탄 /히드로클로로치아짓 다층정과 각 성분 단일제 대조약 (디오반정, MSD: 발사르탄 단일제 I 다이크로짇정, 유한양행: 히드로클로로치아짓 단일제)의 비교 용출시험을 실시하였다. 각 성분별 용출시험 방법은 실험예 1과 같으며 , 그 결과를 도 7과 같이 나타내었다. 도 7에 의하면 실험예 1의 조건에서 용출 시험 시 본 발명의 다층정 중 히드로클로로치아짓 성분은 대조 제제인 다이크로짇정과 비교하여 거의 동등한 용출특성을 나타내는 것으로 확인되었으나, 발사르탄 성분은 대조 제제인 디오반과 비교할 때 매우 지연된 용출 속도를 확인 할 수 있었다. 발사르탄 성분의 용출 시험 결과를 보면， 인공 장액 구간에서 발사르탄 성분의 용출률은 대조제제와 달리 본 발명의 발사르탄 /히드로클로로치아짓의 다층정 기능성 복합제에서는 총 240분에 약 20%로 훨씬 느림을 확인할 수 있었다.  As described above, the multi-layered tablet of losartan / hydrochlorothiazide of the present invention has a secondary blood pressure of hydrochlorothiazit because the initial release of losartan is much slower than that of hydrochlorothiazide, unlike the dissolution of co-administration of losartan monotherapy and hydrochlorothiazine monotherapy. It is a pharmaceutical composition that can be injected at the time of the lowering effect and is very effective in treating hypertension. Experimental Example 7: Comparative dissolution profile test Valsartan / hydrochlorothiazide multilayer tablet prepared according to Example 20 and each component monotherapy control (dioban tablet, MSD: Valsartan monosaccharide I dichroic tablet, finite positive: hydrochlorothiazine monolith) A comparative dissolution test of was conducted. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG. According to FIG. 7, in the dissolution test under the conditions of Experimental Example 1, the hydrochlorothiazide component of the multi-layered tablet of the present invention was found to exhibit almost the same dissolution characteristics as that of the control, dichroic tablet, but the valsartan component was compared with the diovan, the control formulation. When the very delayed dissolution rate was confirmed. In the dissolution test results of the valsartan component, the dissolution rate of the valsartan component in the artificial serous section was found to be much slower in the valsartan / hydrochlorothiazit of the present invention, about 20% in 240 minutes in total, compared to the control agent.
이처럼 본 발명의 발사르탄 /히드로클로로치아짓의 다층정 제제는 대조약인 발사르탄 단일제와 히드로클로로치아짓 단일제를 동시 복용하였을 경우의 용출 양상과는 달리 발사르탄의 초기 방출이 히드로클로로치아짓보다 매우 느리기 때문에 히드로클로로치아짓의 2차적인 혈압강하효과가 발생하는 시점에 투입할수 있어 고혈압 치료에 매우 효과적인 약학 조성물인 것이다. 실험예 8: 비교 용출시험 ((X)mparative dissolution profile test) 상기 실시예 21에 따라 제조된 이르베사르탄 /히드로클로로치아짓 다층정과 각 성분 단일제 대조약 (아프로벨정， MSD: 이르베사르탄 단일제 I 다이크로짇정, 유한양행: 히드로클로로치아짓 단일제)의 비교 용출시험을 실시하였다. 각 성분별 용출시험 방법은 실험예 1과 같으며, 그 결과를 도 8과 같이 나타내었다. As described above, the multi-layered tablet formulation of valsartan / hydrochlorothiazide of the present invention has a secondary blood pressure lowering effect of hydrochlorothiazit because the initial release of valsartan is much slower than that of hydrochlorothiazide, unlike the dissolution of the valsartan monohydrochloride and the hydrochlorothiazide monotherapy simultaneously. Occurring It can be added at a point in time is a very effective pharmaceutical composition for treating hypertension. Experimental Example 8: Comparative dissolution profile test ((X) mparative dissolution profile test) Irbesartan / hydrochlorothiazit multilayer tablets prepared according to Example 21 above and each component monoclonal control drug (Aprobel tablet, MSD: Irbesartan monosaccharide I Dike Rosin tablet, Yuhan Corporation: A comparative dissolution test of hydrochlorothiazide single agent) was performed. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
도 8에 의하면 실험예 1의 조건에서 용출 시험 시 본 발명의 다층정 중 히드로클로로치아짓 성분은 대조 제제인 다이크로짇정과 비교하여 거의 동등한 용출특성을 나타내는 것으로 확인되었으나， 이르베사르탄 성분은 대조 제제인 디오반과 비교할 때 매우 지연된 용출 속도를 확인 할 수 있었다. 이르베사르탄 성분의 용출 시험 결과를 보면， 인공 장액 구간에서 이르베사르탄 성분의 용출률은 대조제제와 달리 본 발명의 이르베사르탄 /히드로클로로치아짓의 다층정 기능성 복합제에서는 총 240분에 약 20%로 훨씬 느림을 확인할 수 있었다.  According to FIG. 8, in the dissolution test under the conditions of Experimental Example 1, the hydrochlorothiazide component of the multi-layered tablet of the present invention was found to exhibit almost the same dissolution characteristics as that of the control, dichroic tablet, and the Irbesartan component was a control formulation. Compared with Diovan, we found very delayed dissolution rate. According to the dissolution test results of the irbesartan component, the dissolution rate of the irbesartan component in the artificial serous section was about 20% in 240 minutes in the multi-layered functional complex of irbesartan / hydrochlorothiazide of the present invention, unlike the control agent. It was confirmed that much slower.
이처럼 본 발명의 이르베사르탄 /히드로클로로치아짓의 다층정 제제는 대조약인 이르베사르탄 단일제와 히드로클로로치아짓 단일제를 동시 복용하였을 경우의 . 용출 양상과는 달리 이르베사르탄의 초기 방출이 히드로클로로치아짓보다 매우 느리기 때문에 히드로클로로치아짓의 2차적인 혈압강하효과가 발생하는 시점에 투입할 수 있어 고혈압 치료에 매우 효과적인 약학조성물인 것이다. 실험예 9： 비교 용출시험 (comparative dissolution profile test) 상기 실시예 23, 24에 따라 제조된 로사르탄 /히드로클로로치아짓 필름코팅정 또는 캅셀제이며 이와 각 성분 단일제 대조약 (코자정， MSD: 로사르탄 단일제 I 다이크로짇정， 유한양행: 히드로클로로치아짓 단일제)의 비교 용출시험을 실시하였다. 각 성분별 용출시험 방법은 실험예 1과 같으며, 그 결과를 도 9와 같이 나타내었다. As described above, the multi-layered tablet formulation of irbesartan / hydrochlorothiazide of the present invention is obtained when the irbesartan single agent and the hydrochlorothiazit single agent are simultaneously administered. Unlike the dissolution pattern, the initial release of irbesartan is much slower than hydrochlorothiazide, so it can be injected at the time of the secondary hypotensive effect of hydrochlorothiazide, which is a very effective pharmaceutical composition for the treatment of hypertension. Experimental Example 9 Comparative Dissolution Profile Test Comparative dissolution test of losartan / hydrochlorothiazide film-coated tablets or capsules prepared according to Examples 23 and 24, each of which is a control single agent (co-amethyst, MSD: losartan monohydrate I dichroic tablet, finite positive: hydrochlorothiazine monosaccharide) Was carried out. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
도 9에 의하면 실험예 1의 조건에서 용출 시험 시 본 발명의 필름코팅정 또는 캅셀제 중 히드로클로로치아짓 성분은 대조 제제인 다이크로짇정과 비교하여 거의 동등한 용출특성을 나타내는 것으로 확인되었으나， 로사르탄 성분은 대조 제제인 코자와 비교할 때 매우 지연된 용출 속도를 확인 할 수 있다. .  According to FIG. 9, in the dissolution test under the conditions of Experimental Example 1, the hydrochlorothiazide component of the film-coated tablet or capsule of the present invention was found to exhibit almost the same elution characteristics as that of the control, dichromat tablet, but the losartan component was the control formulation. Compared with encoder, we can see the very delayed dissolution rate. .
이처럼 본 발명의 로사르탄 /히드로클로로치아짓의 필름코팅정 또는 캅셀제제는 대조약인 로사르탄 단일제와 히드로클로로치아짓 단일제를 동시 복용하였을 경우의 용출 양상과는 달리 로사르탄의 초기 방출이 히드로클로로치아짓보다 매우 느리기 때문에 히드로클로로치아짓의 2차적인 혈압강하효과가 발생하는 시점에 투입할 수 있어 고혈압 치료에 매우 효과적인 약학조성물인 것이다. 실험예 10: 비교 용줄시험 (comparative dissolution profile test) 상기 실시예 27에 따라 제조된 텔미사르탄 /히드로클로로치아짓 2상 메트릭스 정제이며 이와 각 성분 단일제 대조약 (미카디스정, 베링거인게하임: 텔미사르탄 단일제 I 다이크로짇정, 유한양행: 히드로클로로치아짓 단일제)의 비교 용출시험을 실시하였다. 각 성분별 용출시험 방법은 실험예 1과 같으며, 그 결과를 도 10과 같이 나타내었다.  As described above, the film-coated tablets or capsules of losartan / hydrochlorothiazit of the present invention are different from the dissolution of the losartan monohydrochloride and the hydrochlorothiazine monoclonal drug, and thus the initial release of losartan is much slower than that of hydrochlorothiazide. It is a pharmaceutical composition that is very effective in treating hypertension because it can be injected at the time when the primary blood pressure lowering effect occurs. Experimental Example 10: Comparative dissolution profile test Telmisartan / hydrochlorothiazit biphasic matrix tablets prepared according to Example 27 above, and each component of the single-agent reference drug (Micadis, Boehringer: I dichroic tablets, Yuhan Corporation: hydrochlorothiazide mono-)) was subjected to a comparative dissolution test. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
도 10에 의하면 실험예 1의 조건에서 용출 시험 시 본 발명의 2상 메트릭스 히드로클로로치아짓 성분은 대조 제제인 다이크로짇정과 비교하여 거의 동등한 용출특성을 나타내는 것으로 확인되었으나, 텔미사르탄 성분은 대조 제제인 미카디스와 비교할 때 매우 지연된 용출 속도를 확인 할수 있다. 이처럼 본 발명의 텔미사르탄 /히드로클로로치아짓 2상 메트릭스 정제는 대조약인 텔미사르탄 단일제와 히드로클로로치아짓 단일제를 동시 복용하였을 경우의 용출 양상과는 달리 텔미사르탄의 초기 방출이 히드로클로로치아짓보다 매우 느리기 때문에 히드로클로로치아짓의 2차적인 혈압강하효과가 발생하는 시점에 투입할 수 있어 고혈압 치료에 매우 효과적인 약학조성물인 것이다. 실험예 11: 비교 용출시험 (comparative dissolution profile test) 상기 실시예 29에 따라 제조된 이프로사르탄 /히드로클로로치아짓 캡슬제 (펠렛-펠렛)이며 이와 각 성분 단일제 대조약 (테베텐정， 애보트: 이프로사르탄 단일제 I다이크로짇정, 유한양행: 히드로클로로치아짓 단일제)의 비교 용출시험을 실시하였다. 각 성분별 용출시험 방법은 실험예 1과 같으며, 그 결과를 도 11과 같이 나타내었다. 10 shows the two-phase of the present invention during the dissolution test under the conditions of Experimental Example 1 The matrix hydrochlorothiazide component was found to have almost the same elution characteristics as the control dichroic tablets, but the telmisartan component was found to be very delayed dissolution rate compared to the control agent Mikadis. As described above, the telmisartan / hydrochlorothiazit two-phase matrix tablet of the present invention is different from the dissolution of the telmisartan monohydrochloride and the hydrochlorothiazit monotherapy simultaneously, so that the initial release of telmisartan is much slower than that of the hydrochlorothiazit. It is a pharmaceutical composition that is very effective in treating hypertension because it can be injected at the time when the primary blood pressure lowering effect occurs. Experimental Example 11: Comparative Dissolution Profile Test Iprosartan / hydrochlorothiazide capsule (pellet-pellet) prepared according to Example 29, and a single-component control agent (tebeten tablet, Abbott: Iprosar) A comparative dissolution test of carbon single agent I dichromate tablet, Yuhan Corporation: hydrochlorothiazide single agent) was carried out. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
도 11에 의하면 실험예 1의 조건에서 용출 시험 시 본 발명의 캡슐제 (펠뼛-펠렛)중 히드로클로로치아짓 성분은 대조 제제인 다이크로짇정과 비교하여 거의 동등한 용출특성을 나타내는 것으로 확인되었으나， 이프로사르탄 성분은 대조 제제인 테베텐과 비교할 때 매우 지연된 용출 속도를 확인 할 수 있다.  According to FIG. 11, in the dissolution test under the conditions of Experimental Example 1, the hydrochlorothiazide component of the capsule (pelt-pellet) of the present invention was found to have almost the same dissolution characteristics as compared to the dichromat tablet, a control formulation, butyprosartan The component can identify a very delayed dissolution rate when compared to the control drug tebeten.
이처럼 본 발명의 이프로사르탄 /히드로클로로치아짓 캡술제 (펠렛- 펠렛)는 대조약인 이프로사르탄 단일제와 히드로클로로치아짓 단일제를 동시 복용하였을 경우의 용출 양상과는 달리 이프로사르탄의 초기 방출이 히드로클로로치아짓보다 매우 느리기 때문에 히드로클로로치아짓의 2차적인 혈압강하효과가 발생하는 시점에 투입할 수 있어 고혈압 치료에 매우 효과적인 약학조성물인 것이다. 실험예 12: 비교 용출시험 ((X)mparative dissolution profile test) 상기 실시예 30에 따라 제조된 칸테사르탄 실렉세틸 /히드로클로로치아짓 캡술제 (펠렛-정제)이며 이와 각 성분 단일제 대조약 (아타칸정， 아스트라제네카: 칸데사르탄 단일제 I 다이크로짇정， 유한양행: 히드로클로로치아짓 단일제)의 비교 용출시험을 실시하였다. 각 성분별 용출시험 방법은 실험예 1과 같으며， 그 결과를 도 12와 같이 나타내었다. As described above, unlike the dissolution of iprosartan / hydrochlorothiazide capsulicide (pellet-pellet) of the present invention, a combination of iprosartan monohydrochloride and hydrochlorothiazide monotherapy, the initial release of iprosartan is higher than that of hydrochlorothiazide. Secondary to hydrochlorothiazide because it is very slow It is a pharmaceutical composition that is very effective in the treatment of hypertension because it can be injected at the time when the hypotensive effect occurs. Experimental Example 12 Comparative Dissolution Profile Test ((X) mparative dissolution profile test) A cantesartan cilexetil / hydrochlorothiazit capsulant (pellet-tablet) prepared according to Example 30, and a single-component control agent (Atacan tablet, Astracan) Genca: candesartan monosaccharide I dichroic tablets, Yuhan Corporation: hydrochlorothiazit monolith), a comparative dissolution test was carried out. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
도 12에 의하면 실험예 1의 조건에서 용출 시험 시 본 발명의 캡술제 (펠렛-정제)중 히드로클로로치아짓 성분은 대조 제제인 다이크로짇정과 비교하여 거의 동등한 용출특성을 나타내는 것으로 확인되었으나， 칸데사르탄 성분은 대조 제제인 아타칸과 비교할 때 매우 지연된 용출 속도를 확인 할 수 있다.  According to FIG. 12, in the dissolution test under the conditions of Experimental Example 1, it was found that the hydrochlorothiazide component in the capsulant (pellet-tablet) of the present invention exhibited almost the same dissolution characteristics as compared to the diclotin tablet, which is a control formulation, and candesartan component. Compared to the control agent atacane, it is possible to confirm the very delayed dissolution rate.
이처럼 본 발명의 칸데사르탄 실렉세틸 /히드로클로로치아짓 캡술제 (펠렛-정제)는 대조약인 칸데사르탄 단일제와 히드로클로로치아짓 단일제를 동시 복용하였을 경우의 용출 양상과는 달리 로사르탄의 초기 방출이 히드로클로로치아짓보다 매우 느리기 때문에 히드로클로로치아짓의 2차적인 혈압강하효과가 발생하는 시점에 투입할 수 있어 고혈압 치료에 매우 효과적인 약학조성물인 것이다. 실험예 13: 비교 용출시험 (comparative dissolution profile test) 상기 실시예 31에 따라 제조된 을메사르탄 메독소밀 /히드로클로로치아짓 캡술제 (과립-과립)이며 이와 각 성분 단일제 대조약 (올메텍정, 대웅제약: 올메사르탄 메독소밀 단일제 / 다이크로짇정, 유한양행: 히드로클로로치아짓 단일제)의 비교 용출시험을 실시하였다. 각 성분별 용출시험 방법은 실험예 1과 같으며， 그 결과를 도 13와 같이 나타내었다. As described above, the candesartan cilexetil / hydrochlorothiazit capsule (pellet-tablet) of the present invention has a very slow initial release of losartan, unlike the dissolution of the candesartan monotherapy and the hydrochlorothiazit monotherapy simultaneously. Therefore, it can be injected at the time when the secondary blood pressure lowering effect of hydrochlorothiazide is a very effective pharmaceutical composition for the treatment of hypertension. Experimental Example 13: Comparative Dissolution Profile Test The emmesartan medoxomil / hydrochlorothiazide capsul agent (granule-granule) prepared according to Example 31 above and each component mono-control (olmetec tablet, Daewoong Pharma: A comparative dissolution test of olmesartan medoxomil single agent / dichroic tablet, Yuhan Corporation: hydrochlorothiazide single agent) was performed. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
도 13에 의하면 실험예 1의 조건에서 용출 시험 시 본 발명의 캡술제 (과립-과립) 중 히드로클로로치아짓 성분은 대조 제제인 다이크로짇정과 비교하여 거의 동등한 용출특성을 나타내는 것으로 확인되었으나， 을메사르탄 성분은 대조 제제인 올메텍과 비교할 때 매우 지연된 용출 속도를 확인 할 수 있다.  According to FIG. 13, in the dissolution test under the conditions of Experimental Example 1, the hydrochlorothiazide component of the capsulant (granule-granule) of the present invention was found to exhibit almost the same dissolution characteristics as compared to the dichromat tablet as a control formulation. Compared to Olmetec, a control formulation, very slow dissolution rates can be observed.
이처럼 본 발명의 올메사르탄 메독소밀 /히드로클로로치아짓 캡술제 (과립-과립)는 대조약인 로사르탄 단일제와 히드로클로로치아짓 단일제를 동시 복용하였을 경우의 용출 양상과는 달리 올메사르탄의 초기 방출이 히드로클로로치아짓보다 매우 느리기 때문에 히드로클로로치아짓의 2차적인 혈압강하효과가 발생하는 시점에 투입할 수 있어 고혈압 치료에 매우 효과적인 약학조성물인 것이다. 실험예 14： 비교 용출시험 (comparative dissolution profile test) 상기 실시예 37에 따라 제조된 로사르탄 칼륨 /히드로클로로치아짓 삼투성 유핵정과 각 성분 단일제 대조약 (코자정， MSD: 로사르탄 칼륨 단일제 I 다이크로짇정， 유한양행: 히드로클로로치아짓 단일제)의 비교 용출시험을 실시하였다. 각 성분별 용출시험 방법은실험예 1과 같으며, 그 결과를 도 14와 같이 나타내었다.  As described above, the olmesartan medoxomil / hydrochlorothiazit capsule (granule-granule) of the present invention has a very slow initial release of olmesartan, unlike the dissolution of the co-administration of losartan monotherapy and hydrochlorothiazit monotherapy. Therefore, it can be injected at the time when the secondary blood pressure lowering effect of hydrochlorothiazide is a very effective pharmaceutical composition for the treatment of hypertension. Experimental Example 14: Comparative Dissolution Profile Test Losartan Potassium / Hydrochlorothiazit Osmotic Nucleus Tablets Prepared According to Example 37 and a Single-Component Reference (Coza Tablet, MSD: Losartan Potassium Monochloride I Dichroic Tablet) , Yuhan Corporation: A comparative dissolution test of hydrochlorothiazide single agent) was performed. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
도 14에 의하면 실험예 1의 조건에서 용출 시험 시 본 발명의 삼투성 유핵정 중 히드로클로로치아짓 성분은 대조 제제인 다이크로짇정과 비교하여 거의 동등한 용출특성을 나타내는 것으로 확인되었으나, 로사르탄 성분은 대조 제제인 코자정과 비교할 때 매우지연된 용출 속도를 확인 할 수 있다. According to FIG. 14, in the dissolution test under the conditions of Experimental Example 1, the hydrochlorothiazide component of the osmotic nucleated tablet of the present invention was found to exhibit almost the same dissolution characteristics as that of the control, dichroic tablet, but the losartan component was controlled. Compared to co-crystal, the formulation, very slow dissolution rates can be identified.
이처럼 본 발명의 로사르탄 칼륨 /히드로클로로치아짓 삼투성 유핵정은 대조약인 로사르탄 단일제와 히드로클로로치아짓 단일제를 동시 복용하였을 경우의 용출 양상과는 달리 로사르탄의 초기 방출이 히드로클로로치아짓보다 매우 느리기 때문에 히드로클로로치아짓의 2차적인 혈압강하효과가 발생하는 시점에 투입할수 있어 고혈압 치료에 매우 효과적인 약학조성물인 것이다. 실험예 15: 동물 시험 (Animal Study)  As described above, the losartan potassium / hydrochlorothiazit osmotic nucleus tablet of the present invention has a secondary effect of hydrochlorothiazide because the initial release of losartan is much slower than that of hydrochlorothiazide, unlike the dissolution of the losartan monotherapy and the hydrochlorothiazit monotherapy simultaneously. It is a pharmaceutical composition that is very effective in the treatment of hypertension because it can be injected at the time of the hypotensive effect. Experimental Example 15: Animal Study
본 실험은 시판중인 대조약 (코자 플러스정， MSD: 로사르탄 /히드로클로로치아짓 복합제)의 방출시간과 유사하도록 히드로클로로치아짓과 로사르탄의 동시 . 투여군과 실험군으로서 본 발명의 실시예에 의하여 제공되는 조성물의 방출 시간과 같도록 히드로클로로치아짓과 로사르탄을 시간차 투여함으로써 본 발명에 의한 조성물로서의 효과를 확인하기 위한 동물시험을 표 7과 같이 실시하였다.  This experiment was performed simultaneously with hydrochlorothiazit and losartan to approximate the release time of a commercial control (Coza plus tablet, MSD: losartan / hydrochlorothiazide combination). As the administration group and the experimental group, an animal test for confirming the effect as the composition according to the present invention was administered as shown in Table 7 by timely administering hydrochlorothiazit and losartan in the same time as the release time of the composition provided by the Examples of the present invention.
또한， 본 실험은 최고의 항압효과를 보이기 위한 시간대별 투여도 확인할 수 있도록 시험 설계가 이루어졌다. In addition, this experiment was designed to confirm the time-phase administration to show the best anti-pressure effect.
【표 10】 Table 10
Figure imgf000076_0001
본 비교 동물 임상 결과 밝혀진 동물 임상결과의 약동학 /약력학은 표 11 및 도 15 ~ 17와 같다.
Figure imgf000076_0001
The pharmacokinetics / pharmacodynamics of the animal clinical results revealed in this comparative animal clinical results are shown in Table 11 and FIGS. 15 to 17.
【표 11]  Table 11
Figure imgf000077_0001
Figure imgf000077_0001
<본 시험은 쥐를 모델로 한 동물시험으로 명조건과 암조건으로 나누어 설계하였으며 , 쥐와 사람의 생체리듬은 정반대 이므로 사람에 게 적용 시 시간대를 반대로 적용함. > 1. 혈압 강하 면에서 수축기 혈압과 확장기 혈압은 스크리닝 군에 비해 5일째 낮은 혈압 수치를 나타내었다. <This test is a rat model animal test. It is designed by dividing light condition and dark condition. The biorhythms of rats and humans are opposite, so when applied to humans, the time zone is reversed. > 1. In terms of blood pressure drop, systolic and diastolic blood pressures were lower than those of the screening group at 5 days.
2. 혈압 강하 면에서 동시투여군과 시간차 투여군 비교 시， 시간차 투여군에서 가장 낮은 혈압 수치를 보였으며， 시간차 투여군증에서는 저녁투여 (명조건)보다 아침투여 (암조건)에서 가장낮은 혈압 수치를 나타내었다.  2. In terms of lowering blood pressure, the blood pressure level was lower in the hourly group compared to the concurrent group and the hourly group. The hourly group showed the lowest blood pressure level in the morning (cancer) than in the evening (dark). .
3. 시간대별 혈압 강하 효과는 도 15-17과 같다. 아침 시간차 투여군 (암조건)이 4그룹 중에서 가장 혈압강하 효과가 뛰어남을 확인하였다.  3. The blood pressure drop effect of each time slot is as shown in Figs. 15-17. The morning time difference group (cancer condition) was confirmed to have the best blood pressure lowering effect among the four groups.
4. 임상적 부작용 관찰에 의하면 저녁 투여군 (명조건)에서 야뇨의 증상을 ' 보였으며, 아침 투여군 (암조건)에서는 없었다. 아침 투여군 (암조건)에서는 아뇨로 인한 수면장애 문제가 발생하지 않을 것을 예상할 수 있다. 이로서， 본 발명에 의한 조성물이 통상적인 동시투여군과는 달리， 평균혈압이 최고조에 이르는 투여 익일 아침부터 한낮에 이르는 시간 동안의 최적의 혈압강하효과를 가지게 됨을 알수 있다. 4. There was, according to the clinical side effects were observed, and tinnitus in the evening yanyo group (light conditions), administered in the morning (dark conditions). In the morning dose group (cancer conditions) it can be expected that no sleep disorders will occur. Thus, it can be seen that the composition according to the present invention has an optimal blood pressure lowering effect during the time from the morning of the morning until the middle of the day after the administration of the average blood pressure, unlike the conventional simultaneous administration group.
본 발명에 의한 안지오텐신ᅳ Πᅳ수용체 차단제와 히드로클로로치아짓의 복합제 조성물과 같이 , 시간차투여한 경우가 안지오텐신ᅳ Π_수용체 차단제와 히드로클로로치아짓의 단일 제제 각각을 동시에 투여할 때의 경우보다 혈압 강하의 목적으로 투여된 안지오텐신ᅳ Πᅳ수용체 차단제와 히드로클로로치아짓의 임상적인 항압효과의 최적 효과가 발현되게 함을 알 수 있다.  As with the combination composition of the angiotensin ᅳ receptor receptor and hydrochlorothiazide according to the present invention, the time-administrated case was administered for the purpose of lowering blood pressure than when the single agent of angiotensin _ receptor receptor and hydrochlorothiazide was administered simultaneously. It can be seen that the optimal effect of the clinical antihypertensive effect of angiotensin Π ᅳ receptor blocker and hydrochlorothiazit is expressed.
한편， 표 9는 로사르탄과 히드로클로로치아짓의 동시투여군 및 본 발명에 따르는 아침 시간차 투여군 (암조건)간의 혈압 및 맥박수를 측정한 결과이다. 로사르탄과 히드로클로로치아짓에 의한 혈압강하작용은 본 발명에 의해 제공되는 시험군인 시간차투여군에서 동시투여군보다 평균좌위 수축기 혈압 강하 효과는 5.8¾， 평균 좌위 이완기 혈압강하 효과는 5.6%, 평균 혈압강하 효과는 9.9%로 전체적 혈압 강하효과가 유의적으로 증가됨을 관찰할 수 있었고， 맥박수는 0.08%로 증가로 유의적 차이는 없는 것으로 관찰할 수 있었다. On the other hand, Table 9 is a result of measuring the blood pressure and the pulse rate between the co-administered group of losartan and hydrochlorothiazide and the morning time difference group (cancer condition) according to the present invention. The hypotensive action of losartan and hydrochlorothiazide is The mean time of systolic blood pressure drop was 5.8¾, mean diastolic pressure drop was 5.6%, and mean blood pressure drop was 9.9% in the time-difference group, which was provided by the test group. The pulse rate increased to 0.08%, indicating no significant difference.
이로서 본 발명에 의해 의도된 바와 같이 4시간에 걸친 시간차를 두고 혈압 강하의 목적으로 투여된 로사르탄의 지연된 약물방출을 통하여 시간차 투여군어 동시 투여군에 비하여 우수한 혈압 강하효과를 가짐이 증명되었다. Thus, it was proved that the delayed drug release of losartan administered for the purpose of lowering blood pressure with a time difference of 4 hours as intended by the present invention has an excellent blood pressure lowering effect compared to the time-administered group.
【표 12] Table 12
Figure imgf000079_0001
Figure imgf000079_0001
<본 시험은 쥐를 모델로 한 동물시험으로 명조건과 암조건으로 나누어 설계하였으며, 쥐와 사람의 생체리듬은 정반대이므로 사람에게 적용 시 시간대를 반대로 적용함. > <This test is a rat model animal test. It is designed by dividing light condition and dark condition. The biorhythms of rats and humans are opposite to each other. >
한편， 표 13은 로사르탄과 히드로클로로치아짓의 투여 시간에 따른 혈압을 측정한 결과이다. 로사르탄와 히드로클로로치아짓에 의한 혈압강하작용이 본 발명에 의해 제공되는 시험군인 아침 시간차투여군 (암조건)에서 저녁 시간차투여군 (명조건)보다 평균좌위 수축기 혈압 강하 효과는 4.0%, 평균 죄:위 이완기 혈압강하 효과는 2.2%, 평균 혈압강하 효과는 3.1%, 맥박수는 7.0%로 전체적 혈압 강하효과가 유의적으로 증가됨을 관찰할 수 있었다. On the other hand, Table 13 is according to the administration time of losartan and hydrochlorothiazit It is the result of measuring blood pressure. In the morning time difference group (cancer condition), in which the blood pressure lowering effect of losartan and hydrochlorothiazide is provided by the present invention, the mean systolic blood pressure lowering effect was 4.0%, and the average sin: gastric diastolic blood pressure was higher than the evening time difference group (dark condition). The drop in blood pressure was 2.2%, mean blood pressure drop was 3.1%, and pulse rate was 7.0%.
이로서 본 발명에 의해 의도된 바와 같이 혈압 강하의 목적으로 투여된 로사르탄과 히드로클로로치아짓 복합제의 아침시간대 시간차 투여가 저녁 시간대 투여군 (명조건)에 비하여 우수한 혈압 강하효과를 가짐아증명되었다. 【표 13]  As a result of the present invention, it was proved that morning-time lag administration of losartan and hydrochlorothiazide combination administered for the purpose of lowering blood pressure had an excellent blood pressure-lowering effect as compared to the evening-time administration group (light condition). Table 13
Figure imgf000080_0001
Figure imgf000080_0001
<본 시험은 쥐를 모델로 한 동물시험으로 명조건과 암조건으로 나누어 설계하였으며， 쥐와 사람의 생체리듬은 정반대이므로 사람에게 적용 시 시간대를 반대로 적용함. > <This test is a model of animal model of rats. It is designed by dividing light condition and dark condition. The biorhythms of rats and humans are opposite to each other. >
¾론적으로 상기 임상시험을 통하여 본원발명에서 로사르탄으로 대표되는 안지오텐신ᅳ Πᅳ수용체 차단제와 히드로클로로치아짓으로 대표되는 치아자이드계 화합물의 복합제 조성물을 동시에 투여할 때보다는 시간차투여한 경우 또는 저녁 투여 (명조건)보다 아침 투여 (암조건)할 때의 경우， 혈압 강하의 목적으로 투여된 안지오텐신ᅳ Πᅳ수용체 차단제가 방출 시간 연장에 의해서 동일한 투여용량에서도 상승된 혈압강하 효과를 증명되었으며， 이로서 최적효과 발현을 예측됨을 알 수 있다. ¾ theory from the present invention to Losartan through the above clinical trials Blood pressure when administered in the morning or after the morning (dark condition) rather than the simultaneous administration of the combination composition of the representative angiotensin receptor receptor blocker and the chiazide compound represented by hydrochlorothiazide Angiotensin Π ᅳ receptor blockers administered for the purpose of lowering demonstrated an elevated blood pressure lowering effect even at the same dose by prolonging the release time, thereby predicting the optimum effect expression.
산업상 이용 가능성 Industrial availability
본 발명에 의해 제제화 된 복합 제제는  The composite formulation formulated by the present invention
1) 치아자이드계 화합물과 안지오텐신 _π~수용체 차단제의 단일 제제를 동시 복용함으로써 감소되는 약리학적 임상학적 치료 효과를 완벽하게 발휘 할수 있다.  1) Pharmacological and clinical therapeutic effects reduced by simultaneous administration of a single agent of thiazide-based compound and angiotensin _π ~ receptor blocker can be achieved.
2) 아침 식사 시간에 복용케 함으로써 24시간 균등하게 항압 작용과 합병증 예방 작용을 발휘케 할 수 있으며 특히 혈압상승이 최고조에 이르는 시기에 최고의 혈압강하작용을 나타낼 수 있다.  2) By taking it at breakfast time, it is possible to exert anti-pressure action and complication prevention effect evenly for 24 hours. In particular, it can show the best blood pressure lowering action at the peak of blood pressure rise.
3) 아침 시간 복용이라는 간단한 복약 준수 방법은 증가하는 수많은 노년층 환자에게 기대 이상의 공헌을 하게 될 것이며， 처방의에게 처방에 대한 소신과 복약 지도를 간편하게 해줄 수 있다.  3) Simple medication compliance measures, called morning medications, will make more contributions than expected to a growing number of older patients, and can make it easier for prescribing physicians to take prescriptions and take medication.
4) 심장 신장 뇌졸중 이라는 3대 합병증 예방에 최대 효과를 얻을 수 있는 복합 처방이므로 국민의 건강 장수에 막대한 기여를 할 것이다.  4) Since it is a complex prescription that can maximize the prevention of the three major complications such as heart kidney stroke, it will make a huge contribution to the longevity of people's health.
5) 당뇨병이 합병된 고혈압에 최우수 복합 처방이 될 것이다.  5) It will be the best combination prescription for hypertension with diabetes mellitus.
6) 증가 하는 노년층에게 필수 블가결한 최적 복합 제제가 될 것이다. 6) It will be an indispensable optimal combination formulation for the growing elderly.
7) 서로 다른 약리를 지닌 성분의 복합 제제이므로 부작용을 상쇄시켜 줄 뿐 아니라 순환기계 합병증의 발병 위험 인자를 감소시켜 즐 수 있으므로 장기간의 예방 경비를 절감시켜 즐 수 있다. 7) As it is a complex preparation of ingredients with different pharmacology, it can be enjoyed by not only canceling side effects but also reducing risk factors of circulatory complications. You can enjoy long-term prevention expenses.
8) 단일 제제를 각각 유지 하는 포장비용 절감과고급 인력의 투약 조제 시간 절감은 엄청난 액수에 달 할수 있다.  8) The savings in packaging costs for maintaining a single formulation each, and the time savings for high-quality personnel, can be enormous.
9) 바야흐로 싹이 트는 시간차 투여 이론 (Chronotherapy)을 어떻게 제제화 기술에 접목 시킬 것인가를 세계 약학계에 알려서 고정 비율 복합제 개발의 전성기를 개막 시킬 것이다.  9) It will open the heyday of the development of fixed-rate combinations by informing the world pharmacy how to incorporate the emerging sprouting theory of chronotherapy into formulation technology.

Claims

청구범위 Claim
1. 안지오텐신一 Πᅳ수용체 차단제 또는 약학적으로 허용되는 그의 염을 활성성분으로 포함하는 지연방출성 구획과, 치아자이드계 화합물 또는 약학적으로 허용되는 그의 염을 활성성분으로 포함하는 선방출성 구획을 포함하는 것을 특징으로 하는 시간차 용출이 가능하도록 방출성이 조절된 복합제 조성물. 1. A delayed-release compartment comprising an angiotensin 一 ᅳ receptor blocker or a pharmaceutically acceptable salt thereof as an active ingredient and a pre-release compartment comprising a thiazide compound or a pharmaceutically acceptable salt thereof as an active ingredient. Composite composition with controlled release to enable time difference dissolution, characterized in that it comprises.
2. 제 1항에 있어서， 상기 선방출성 구획에 포함되는 활성성분은 방출개시 후 1시간 이내에 85중량 ¾ 이상이 방출되는 것올 특징으로 하는 방출성이 조절된 복합제 조성물. 2. The composition of controlled release according to claim 1, wherein the active ingredient included in the pre-release compartment is released in an amount of 85 wt% or more within 1 hour after the start of release.
3. 제 1항에 있어서， 상기 지연방출성 구획에 포함되는 활성성분은 상기 선방출성 구획에 포함되는 활성성분의 방출개시 후 4 시간 이내에 40중량 ¾> 이하가 방출되는 것을 특징으로 하는 방출성이 조절된 복합제 조성물. 3. The active ingredient according to item 1, wherein the active ingredient included in the delayed-release compartment is released in less than 40 weight ¾> within 4 hours after the release of the active ingredient included in the prior-release compartment. Modified Co-Composition Composition.
4. 제 1 항에 있어서， 상기 안지오텐신— Π—수용체 차단제 또는 약학적으로 허용되는 그의 염이 상기 치아자이드계 화합물 또는 약학적으로 허용되는 그의 염보다 늦게 흡수될 수 있도록 2시간 내지 4시간 동안의 방출 지연시간을 갖는 방출성이 조절된 복합제 조성물. 4. The release according to 1, wherein the angiotensin —? — Receptor blocker or pharmaceutically acceptable salt thereof is released for 2 to 4 hours so that it can be absorbed later than the thiazide compound or pharmaceutically acceptable salt thereof A composite composition with controlled release having a delay time.
5. 제 1 항에 있어서, 상기 치아자이드계 화합물 또는 약학적으로 허용되는 그의 염의 용출 시작시로부터 4시간 후에 상기 안지오텐신ᅳ Πᅳ수용체 차단제 또는 약학적으로 허용되는 그의 염이 실질적으로 방출되도록 방출성이 조절된 복합제 조성물. 5. The method according to item 1, wherein after 4 hours from the start of dissolution of the thiazide compound or a pharmaceutically acceptable salt thereof, A composite composition wherein the release properties are adjusted such that the angiotensin ᅳ receptor receptor or pharmaceutically acceptable salt thereof is substantially released.
6. 제 1 항 내지 제 5 항 중 어느 한 항에 있어서， 상기 안지오텐신一 Πᅳ수용체 차단제가 로사르탄， 발사르탄， 텔미사르탄, 이르베사르탄, 칸데사르탄， 올메사르탄， 에프로사르탄， 및 그들의 이성질체로 이루어진 군으로부터 선택되는 것을 특징으로하는 복합제 조성물 6. The method according to any one of items 1 to 5, wherein the angiotensin Π ᅳ receptor blocker is losartan, valsartan, telmisartan, irbesartan, candesartan, olmesartan, eprosartan. , And a combination composition, characterized in that selected from the group consisting of their isomers
7. 제 6 항에 있어서, 상기 안지오텐신ᅳ Π—수용체 차단제 또는 약학적으로 허용되는 그의 염이 조성물 중 5 ~ 600 rag 범위로 함유되는 것을 특징으로하는 복합제 조성물, 7. The combination composition according to item 6, wherein the angiotensin ᅳ —receptor blocker or a pharmaceutically acceptable salt thereof is contained in the range of 5 to 600 rag in the composition,
8. 제 1 항 내지 제 5 항 중 어느 한 항에 있어서， 상기 치아자이드계 화합물이 히드로클로로치아짓, 클로로치아짓， 벤드로플루메치아짓, 및 그들의 이성질체로 이루어진 군으로부터 선택되는 것을 특징으로 하는 복합제 조성물. 8. The combination composition according to any one of items 1 to 5, wherein the thiazide compound is selected from the group consisting of hydrochlorothiazide, chlorothiazide, bendroflumezigit, and isomers thereof. .
9. 제 8 항에 있어서, 상기 치아자이드계 화합물 또는 약학적으로 허용되는 그의 염이 조성물 중 2.5 ~ 100 mg 범위로 함유되는 것을 특징으로 하는 복합제 조성물. 9. The combination composition according to item 8, wherein the thiazide compound or a pharmaceutically acceptable salt thereof is contained in the range of 2.5 to 100 mg in the composition.
10. 제 1 항 내지 제 5 항 중 어느 한 항에 있어서， 2상의 메트릭스 형태의 단일정， 지연방출성 구획과 선방출성 구획이 각각 독립적으로 과립， 펠렛 또는 정제인 캡술제, 정제인 지연방출성 구획의 표면이 선방출성 구획으로 이루어진 필름코팅층에 의해 코팅되는 필름코팅정， 지연방출성 구획과 선방출성 구획이 층을 이루는 다층정, 내핵정인 지연방출성 구획의 외층을 선방출성 구획이 구성하는 유핵정， 삼투성 내핵정인 지연방출성 구획의 외층을 선방출성 구획이 구성하는 삼투성 유핵정, 지연방출성 구획과 선방출성 구획 중 하나 이상의 외부에 코팅층을 추가로 포함하는 제형, 지연방출성 구획이 삼투압 조절제를 포함하며 반투과성막 코팅기제로 코팅된 제형， 및 지연방출성 구획과 선방출성 구획을 포함하는 키트 형태로 이루어진 군으로부터 선택된 제형인 것을 특징으로 하는 복합제 조성물. 10. The delayed-release according to any one of items 1 to 5, wherein the two-phase matrix form of the single tablet, the delayed-release compartment and the prior-release compartment are independently granules, pellets or tablets, a capsulant, and a tablet. Film coated tablets, delayed-release compartments and pre-release compartments whose surface is coated by a film coating layer consisting of a pre-release compartment Nucleated tablets constituted by prior-release compartments constitute the outer layers of the delayed-release compartments, which are layered multi-layered tablets and inner core tablets, osmotic nucleated tablets formed by the prior-release compartments, the outer layers of the delayed-release compartments, which are osmotic inner core tablets. A formulation further comprising a coating layer on the exterior of at least one of the sex and pre-release compartments, the delay-release compartment comprising an osmotic pressure regulator and coated with a semipermeable membrane coating base, and a kit comprising a delayed-release compartment and a pre-release compartment Combination composition, characterized in that the formulation is selected from the group consisting of.
11. 제 1 항 내지 제 5 항 중 어느 한 항에 있어서, 상기 지연방출성 구획이 장용성 고분자, 수불용성 중합체， 소수성 화합물, 친수성 고분자， 삼투성 반투과성막 코팅기제， 및 삼투제 증에서 선택된 방출제어 물질을 포함하는 것을 특징으로 하는 복합제 조성물. 11. The release control according to any one of items 1 to 5, wherein the delayed-release compartment is selected from an enteric polymer, a water insoluble polymer, a hydrophobic compound, a hydrophilic polymer, an osmotic semipermeable membrane coating base, and an osmotic agent. A composite composition comprising a substance.
12. 제 11 항에 있어서, 상기 장용성 고분자는 장용성 셀를로오스 유도체， 장용성 아크릴산계 공중합체， 장용성 폴리메타크릴레이트 공중합체, 장용성 말레인산계 공중합체 및 장용성 폴리비닐 유도체로 이루어진 군으로부터 선택된 1종또는 2종 이상의 흔합물인 것을 특징으로 하는 복합제 조성물. 12. The enteric polymer according to claim 11, wherein the enteric polymer is one selected from the group consisting of an enteric cellulose derivative, an enteric acrylic acid copolymer, an enteric polymethacrylate copolymer, an enteric maleic acid copolymer and an enteric polyvinyl derivative, or A composite composition, characterized in that two or more kinds of mixtures.
13. 제 12 항에 있어서， 상기 장용성 셀를로오스 유도체는 히드록시프로필메틸셀를로오스 아세테이트숙시네이트， 히프로멜로오스프탈레이트 (히드록시프로필메틸셀를로오스 프탈레이트)， 히드록시메틸에틸셀를로오스프탈레이트， 셀를로오스아세테이트프탈레이트， 셀를로오스아세테이트숙시네이트， 셀를로오스아세테이트말레이트 , 셀를로오스벤조에이트프괄레이트， 셀를로오스프로피오네이트프탈레이트， 메틸셀를로오스프탈레이트 , 카르복시메틸에틸셀를로오스， 에틸히드록시에틸셀를로오스프탈레이트， 및 메틸히드록시에틸셀를로오스로 이루어진 군으로부터 선택된 1종 이상이고; 상기 장용성 아크릴산계 공중합체는 스티렌-아크릴산 공중합체 , 아크릴산메틸-아크릴산 공중합체 , 아크릴산메틸메타크릴산 공중합체, 아크릴산부틸 -스티렌-아크릴산 공중합체, 및 아크릴산메틸-메타크릴산—아크릴산옥틸공중합체로 이루어진 군으로부터 선택된 1종 이상이며; 상기 장용성 폴리메타크릴레이트 공중합체는 폴리 (메타크릴산 메틸 메타크릴레이트) 공중합체, 및 폴리 (메타크릴산 에틸아크릴레이트) 공증합체로 이루어진 군으로부터 선택된 1종 이상이며; 상기 장용성 말레인산계 공중합체는 아세트산비닐-말레인산 무수물 공중합체 , 스티렌-말레인산 무수물 공증합체， 스티렌-말레인산모노에스테를 공증합체 ·, 비닐메틸에테르-말레인산 무수물 공중합체, 에틸렌-말레인산 무수물 공중합체， 비닐부틸에테르-말레인산 무수물 공중합체， 아크릴로니트릴-크릴산메틸 ·말레인산 무수물 공중합체 , 및 아크릴산부틸 -스티렌-말레인산 무수물 공중합체로 이루어진 군으로부터 선택된13. The enteric cellulose derivative according to claim 12, wherein the enteric cellulose derivatives are hydroxypropylmethylcellulose acetate succinate, hypromellose phthalate (hydroxypropylmethylcellose phthalate), hydroxymethylethylcellose phthalate , Cellulose acetate phthalate, Cellulose acetate succinate, Cellulose acetate maleate, Cellulose benzoate phthalate, Cellulose propionate phthalate At least one selected from the group consisting of methyl cellulose phthalate, carboxymethyl ethyl cellulose, ethyl hydroxyethyl cellulose phthalate, and methyl hydroxyethyl cellulose; 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-octyl acrylate copolymers. At least one selected from the group consisting of; The enteric polymethacrylate copolymer is at least one member selected from the group consisting of poly (methyl methacrylate) copolymers, and poly (ethyl methacrylate) co-polymers; The enteric maleic acid-based copolymer is a vinyl acetate-maleic anhydride copolymer, a styrene-maleic anhydride co-polymer, a styrene-maleic acid monoester co-polymer, a vinyl methyl ether-maleic anhydride copolymer, an ethylene-maleic anhydride copolymer, vinyl butyl An ether-maleic anhydride copolymer, an acrylonitrile-methyl methacrylate maleic anhydride copolymer, and a butyl acrylate-styrene-maleic anhydride copolymer
1종 이상이고; 상기 장용성 폴리비닐 유도체는 폴리비닐알콜프탈레이트， 폴리비닐아세탈프탈레이트， 폴리비닐부틸레이트프탈레이트 및 폴리비닐아세트아세탈프탈레이트로 이루어진 군으로부터 선택된 1종 이상인 것올 특징으로 하는 복합제 조성물. At least one; The enteric polyvinyl derivative is a composite composition, characterized in that at least one selected from the group consisting of polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate and polyvinyl acetal phthalate.
14. 제 11 항에 있어서, 상기 수불용성 중합체는 폴리비닐아세테이트， 수불용성 폴리메타크릴레이트 공중합체, 에틸셀를로오스， 셀를로오스 에스테르, 셀를로오스 에테르， 셀를로오스 아실레이트, 셀를로오스 디아실레이트， 셀를로오스 트리아실레이트, 셀를로오스 아세테이트, 셀를로오스 디아세테이트 및 셀를로오스 트리아세테이트로 이루어진 군으로부터 선택된 1종 또는 2 종 이상의 흔합물인 것을 특징으로 하는 복합제 조성물. 14. The water-insoluble polymer of claim 11, wherein the water-insoluble polymer is polyvinylacetate, water-insoluble polymethacrylate copolymer, ethylcellose, cellulose ester, cellulose ether, cellulose acylate, cellulose One or two selected from the group consisting of disylate, cellulose triacylate, cellulose acetate, cellulose diacetate, and cellulose triacetate It is a combination of the above, The composite composition characterized by the above-mentioned.
15. 제 11 항에 있어서， 상기 소수성 화합물은 지방산 및 지방산 에스테르류， 지방산 알코올류， 왁스류 및 무기물질로 이루어진 군으로부터 선택된 1종 또는 2종 이상의 흔합물인 것을 특징으로 하는 복합제 조성물. 15. The composition of claim 11, wherein the hydrophobic compound is one or two or more mixtures selected from the group consisting of fatty acids and fatty acid esters, fatty alcohols, waxes and inorganic substances.
16. 제 11 항에 있어서， 상기 지방산 및 지방산 에스테르류는 글리세릴 팔미토스테아레이트， 글리세릴 스테아레이트， 글리세될 비헤네이트, 세틸 팔미테이트， 글리세릴 모노 을레이트， 및 스레아린산으로 이루어진 군으로부터 선택된 ' 1종 이상이고; 상기 지방산 알코을류는 세토스테아릴 알코올， 세틸알코을 및 스테아릴알코올로 이루어진 군으로부터 선택된 1종 이상이며; 왁스류는 카르나우바왁스, 밀납 및 미결정왁스로 이루어진 군으로부터 선택된 1종 이상이고; 무기물질은 탈크， 침강탄산칼슴， 안산일수소칼슴， 산화아연， 산화티탄， 카올린， 벤토나이트， 몬모릴로나이트 및 비검으로 이루어진 군으로부터 선택된 1 종 이상인 것을 특징으로 하는 복합제 조성물. 16. The fatty acid and fatty acid esters according to item 11, wherein the fatty acid and fatty acid esters are selected from the group consisting of glyceryl palmitostearate, glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monoacrylate, and threric acid These "one or more, and; The fatty acid alcohols are at least one selected from the group consisting of cetostearyl alcohol, cetyl alcohol and stearyl alcohol; The wax is at least one selected from the group consisting of carnauba wax, beeswax and microcrystalline wax; The inorganic material is a combination composition, characterized in that at least one selected from the group consisting of talc, precipitated carbonate, calcium ansan, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite and non-gum.
17. 제 11 항에 있어서， 친수성 고분자는 당류， 셀를로오스 유도체, 검류， 단백질류, 폴리비닐 유도체， 친수성 폴리메타크릴레이트 공중합체， 폴리에틸렌 유도체 및 카르복시비닐폴리머로 이루어진 군으로부터 선택된 1종 또는 2종 이상의 흔합물인 것을 특징으로 하는 복합제 ¾성물. 17. The hydrophilic polymer according to item 11, wherein the hydrophilic polymer is one or two selected from the group consisting of sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, polyethylene derivatives and carboxyvinyl polymers. Compound ¾ composition, characterized in that the mixture of more than one species.
18. 제 17항에 있어서， 상기 당류는 덱스트린, 폴리덱스트린， 덱스트란, 펙틴 및 펙틴 유도체, 알긴산염， 폴리갈락투론산, 자일란, 아라비노자일란， 아라비노갈락탄， 전분， 히드록시프로필스타치， 아밀로오스, 및 아밀로펙틴으로 이루어진 군으로부터 선택된 1종 이상이고; 상기 셀를로오스 유도체는 히프로멜로오스， 히드록시프로필셀를로오스， 히드록시메틸셀를로오스， 히드록시에틸셀를로오스， 메틸셀를로오스， 및 카르복시메틸셀를로오스 나트륨으로 이루어진 군으로부터 선택된 1종 이상이며; 상기 검류는 구아검， 로커스트 콩 검， 트라가칸타， 카라기난， 아카시아검, 아라비아검， 젤란검， 및 잔탄검으로 이루어진 군으로부터 선택된 1종 이상이고; 상기 단백질류는 젤라틴, 카제인， 및 제인으로 이루어진 군으로부터 선택된 1종 이상이며; 상기 폴리비닐 유도체는 폴리비닐 알코을， 폴리비닐 피를리돈， 및 폴리비1 아세탈디에틸아미노아세테이트로 이루어진 군으로부터 선택된 1종 이상이고; 상기 친수성 폴리메타크릴레이트 공중합체는 폴리 (부틸 메타크릴레이트 -(2-디메틸아미노에틸 )메타크릴레이트-메틸메타크릴레이트) 공중합체, 및 폴리 (에틸 아크릴레이트 -메틸 메타크릴레이드- 트리에틸아미노에틸- 메타크릴레이트 클로라이드) 공중합체로 이루어진 군으로부터 선택된 1종 이상이며; 상기 폴리에틸렌 유도체는 폴리에틸렌 글리콜， 및 폴리에틸렌 옥사이드 중에서 선택된 1종 이상이고; 상기 카르복시비닐폴리머는 카보머로부터 선택된 1종 이상인 것을 특징으로 하는 복합제 조성물. ' 18. The saccharide according to the above 17, wherein the saccharide is dextrin, polydextrin, dextran, pectin and pectin derivative, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch. , With amylose, and amylopectin At least one selected from the group consisting of; The cellulose derivative is selected from the group consisting of hypromellose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, and carboxymethyl cellulose sodium. Species or more; The gum is at least one selected from the group consisting of guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, arabian gum, gellan gum, and xanthan gum; The protein is at least one selected from the group consisting of gelatin, casein, and zein; The polyvinyl derivative is at least one selected from the group consisting of polyvinyl alcohol, polyvinyl pyridone, and polybi 1 acetaldiethylaminoacetate; The hydrophilic polymethacrylate copolymers include poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer, and poly (ethyl acrylate-methyl methacrylate-triethylamino One or more selected from the group consisting of ethyl- methacrylate chloride) copolymers; The polyethylene derivative is at least one selected from polyethylene glycol, and polyethylene oxide; The carboxyvinyl polymer is a composite composition, characterized in that at least one selected from carbomer. '
19. 제 11 항에 있어서， 삼투성 반투과성막 코팅기제는 폴리비닐 아세테이트, 폴리메타크릴레이트 공중합체， 에틸셀를로오스, 셀를로오스 에스테르, 셀를로오스 에테르， 샐를로오스 아실레이트， 셀를로오스 디아실레이트， 셀를로오스 트리아실레이트, 셀를로오스 아세테이트， 셀를로오스 디아세테이트， 및 셀를로오스 트리아세테이트로 이루어진 군으로부터 선택된 1종또는 2종 이상의 흔합물인 것을 특징으로 하는 복합제 조성물. 19. The method of paragraph 11, wherein the osmotic semipermeable membrane coating base is polyvinyl acetate, polymethacrylate copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose A combination composition, characterized in that one or more mixtures selected from the group consisting of disylate, cellulose triacylate, cellulose acetate, cellulose diacetate, and cellulose triacetate.
20. 제 11 항에 있어서， 삼투제는 황산마그네슴， 염화마그네슴， 염화나트륨， 염화리튬， 황산칼륨， 황산나트륨, 황산리튬 및 황산나트륨으로 이루어 ¾ 군으로부터 선택된 1종 또는 2종 이상의 흔합물인 것을 특징으로 하는 복합제 조성물. 20. The osmotic agent according to item 11, wherein the osmotic agent is one or two or more mixtures selected from the group ¾ consisting of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate and sodium sulfate. The composite composition.
21. 제 1 항 내지 제 5 항 중 어느 한 항에 있어서， 1일 1회, 오전 6시 내지 11시 사이에 복용됨을 특징으로 하는 복합제 조성물. 21. The combination composition according to any one of items 1 to 5, which is taken once daily, between 6 am and 11 am.
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