KR20220166205A - Pharmaceutical composite formulation and method of preparing pharmaceutical composite formulation - Google Patents
Pharmaceutical composite formulation and method of preparing pharmaceutical composite formulation Download PDFInfo
- Publication number
- KR20220166205A KR20220166205A KR1020220069822A KR20220069822A KR20220166205A KR 20220166205 A KR20220166205 A KR 20220166205A KR 1020220069822 A KR1020220069822 A KR 1020220069822A KR 20220069822 A KR20220069822 A KR 20220069822A KR 20220166205 A KR20220166205 A KR 20220166205A
- Authority
- KR
- South Korea
- Prior art keywords
- layer
- hydrate
- pharmaceutically acceptable
- pharmaceutical combination
- acceptable salt
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
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- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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Abstract
Description
본 발명은 약학적 복합 제제 및 제조 방법에 관한 것으로, 보다 구체적으로는 피마살탄을 유효성분으로 포함하는 약학적 복합 제제 및 제조 방법에 관한 것이다.The present invention relates to a pharmaceutical complex preparation and a preparation method, and more particularly, to a pharmaceutical combination preparation containing fimasartan as an active ingredient and a preparation method.
고혈압은 혈압 그 자체를 치료하는 것보다 혈압을 정상 범위로 유지시켜 생명을 위협하는 뇌졸중, 심부전증, 심근경색 등의 관상동맥질환, 신부전과 같은 심혈관계 합병증을 예방하는 것이 중요하므로, 꾸준히 일정 압 이하로 혈압을 조절하는 것이 중요하다. 혈압 치료제는 장기간 복용할 것이 요구되므로 치료 약물의 선택에 있어서도 신중을 기하여야 한다. 따라서, 장기간에 걸친 일정한 혈압 유지를 위해서 한가지 약물을 선택하기보다는 다른 메커니즘을 가진 약물을 병용하고 병용투여로 단일 약물의 사용량을 줄임으로써, 장기간의 약물 복용에 의해 발생할 수 있는 부작용을 감소시킬 필요가 있다.For hypertension, it is important to prevent life-threatening stroke, heart failure, coronary artery disease such as myocardial infarction, and cardiovascular complications such as renal failure by maintaining blood pressure within the normal range rather than treating the blood pressure itself. It is important to control blood pressure with Since antihypertensive drugs require long-term administration, care must be taken in the selection of therapeutic drugs. Therefore, it is necessary to reduce the side effects that may occur from long-term drug use by combining drugs with different mechanisms and reducing the amount of single drug through combined administration, rather than selecting one drug to maintain constant blood pressure over a long period of time. there is.
고혈압을 포함한 심혈관계 질환 등의 치료를 보다 효과적으로 하기 위해 위와 같이 서로 다른 작용 기전을 가진 복합 제제를 고려할 수 있으나, 이 경우, 각 성분의 상호 간섭으로 인해 각 활성성분의 용출에 영향을 주는 문제가 발생할 수 있다. In order to more effectively treat cardiovascular diseases, including hypertension, complex preparations with different mechanisms of action can be considered, but in this case, there is a problem affecting the dissolution of each active ingredient due to mutual interference of each ingredient. can happen
고혈압 및 기타 의학적 징후를 치료하기 위해 개발된 안지오텐신 II 수용체 길항제 (Angiotensin II Receptor Blocker, ARB) 계열의 혈압강하제로 알려져 있는 피마살탄 (한국등록특허 10-1058284)은 2-n-부틸-5-디메틸아미노티오카르본일메틸-6-메틸-3-[[2'-(1H-테트라졸-5-일)비페닐-4-일]메틸]피리미딘-4(3H)-온으로, 분자 화학적으로 기술된 비펩타이드이며, 실험식은 C27H30N7OS이고, 분자량은 501.65이다. Fimasartan (Korean Patent No. 10-1058284), known as an angiotensin II Receptor Blocker (ARB) family of antihypertensive drugs developed to treat hypertension and other medical indications, is a 2-n-butyl-5-dimethyl Aminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one, molecularly chemically It is the described non-peptide, the empirical formula is C 27 H 30 N 7 O S , and the molecular weight is 501.65.
피마살탄 단일 제제로 품목허가를 받아 시판되고 있는 카나브®는 낮은 pH (예를 들어, pH 1.2 내지 pH 1.4)에서 용해도가 낮은데 이를 다른 약리학적 활성 성분과의 복합 제제로 하면 단일 제제에서 나타내는 용출률보다 더 낮은 용출률을 나타낼 수도 있는 문제점이 있다. Kanarb ® , marketed as a single formulation of Fimasartan, has low solubility at low pH (e.g., pH 1.2 to pH 1.4). There is a problem that may indicate a lower dissolution rate.
고혈압 치료를 위해 칼슘채널차단제인 암로디핀과 ARB계열의 약물과의 복합제가 활발히 연구되고 있고, ARB 계열의 약물과 이뇨제인 히드로클로로티아지드 또는 2종 이상의 ARB 계열의 약물의 배합 치료와 관련하여 많은 연구들이 진행되고 있다. 이들 2성분 복합 제제에서 ARB 계열의 약물로서 피마살탄을 포함하면서도 유효성, 안전성 등이 확인된 복합제들이 허가 및 판매 중이다. 피마살탄 기반의 허가 및 판매 중인 복합 제제로는, 피마살탄과 암로디핀을 복합화한 듀카브® 정, 피마살탄과 로수바스타틴을 복합화한 투베로® 정 등이 있다.For the treatment of hypertension, a combination of amlodipine, a calcium channel blocker, and an ARB-type drug is being actively studied, and many studies have been conducted on the combination treatment of an ARB-type drug and a diuretic, hydrochlorothiazide, or two or more ARB-type drugs. are in progress Among these two-component combination preparations, combination preparations containing fimasartan as an ARB-type drug and having confirmed efficacy and safety are being licensed and sold. Fimasartan-based combined preparations include Ducarb ® tablets in which fimasartan and amlodipine are combined, and Tubero ® tablets in which fimasartan and rosuvastatin are combined.
질환의 효과적인 치료, 복약 편의성 증진을 위해서는 계속하여 이러한 피마살탄과 새로운 성분의 약물을 복합화한 2성분 복합 제제, 나아가 이미 다양한 조합의 3성분, 4성분 등의 복합 제제의 개발이 요구되고 있지만, 피마살탄에 새로운 성분의 약물을 복합화하거나, 이미 유효성이 확인된 2성분 복합 제제라 하더라도 제3의 성분으로서 다른 약물을 추가로 복합화하는 경우, 또 다른 상호 작용으로 인해 피마살탄의 용출률이 저하될 수 있다.In order to effectively treat diseases and improve medication convenience, development of two-component complex formulations in which fimasartan and new drugs are combined, as well as complex formulations of three or four components in various combinations are required. In the case of compounding a new drug with Sartan or additionally compounding another drug as a third component even in a two-component combination formulation for which effectiveness has already been confirmed, the dissolution rate of fimasartan may be lowered due to another interaction. .
본 발명의 일 목적은 우수한 용출 특성 및 약리 효과를 나타내면서 복약 편의성이 향상된 2 이상의 유효성분을 포함하는 약학적 복합 제제를 제공하는 것이다.One object of the present invention is to provide a pharmaceutical combination formulation containing two or more active ingredients with improved medication convenience while exhibiting excellent dissolution characteristics and pharmacological effects.
본 발명의 다른 목적은 상기 약학적 복합 제제의 제조 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing the pharmaceutical combination formulation.
본 발명의 일 목적을 위한 약학적 복합 제제는 유효성분으로서 피마살탄, 이의 약학적으로 허용 가능한 염, 이의 용매화물 또는 이의 수화물 및 첨가제를 포함하는 제1 층; 및 적어도 1 이상의 유효성분 및 첨가제를 포함하는 제2 층을 포함하고, 상기 제1 층과 제2 층의 붕해 시간의 차이가 1분 30초 이상 7분 미만이다.A pharmaceutical complex preparation for one purpose of the present invention includes a first layer comprising fimasartan, a pharmaceutically acceptable salt thereof, a solvate thereof or a hydrate thereof, and an excipient as an active ingredient; and a second layer comprising at least one active ingredient and an additive, wherein a difference in disintegration time between the first layer and the second layer is greater than 1 minute and 30 seconds and less than 7 minutes.
본 발명에서, "붕해 시간"은 고형 제제가 시험액 중에서 완전히 붕해되는데 걸리는 시간을 의미한다. 붕해 시간은 대한 약전 붕해시험법에 따라 측정된다. 상기 붕해 시간을 정의하는 시험액은 물일 수 있다.In the present invention, "disintegration time" means the time required for the solid preparation to completely disintegrate in the test solution. Disintegration time is measured according to the disintegration test method of the Korean Pharmacopoeia. The test liquid defining the disintegration time may be water.
일 실시예에서, 상기 제1 층과 제2 층의 붕해 시간의 차이는 1분 30초 이상 6분 40초 이하일 수 있다.In one embodiment, the difference in disintegration time between the first layer and the second layer may be 1 minute 30 seconds or more and 6 minutes 40 seconds or less.
일 실시예에서, 상기 제1 층의 붕해 시간은 2분 이상 7분 15초 미만일 수 있다. 이때, 상기 제2 층의 붕해 시간은 15초 이상 30초 이하일 수 있다.In one embodiment, the disintegration time of the first layer may be greater than 2 minutes and less than 7 minutes and 15 seconds. At this time, the disintegration time of the second layer may be 15 seconds or more and 30 seconds or less.
일 실시예에서, 상기 제1 층의 붕해 시간은 2분 이상 7분 이하일 수 있다. 이때, 상기 제2 층의 붕해 시간은 15초 이상 30초 이하일 수 있다.In one embodiment, the disintegration time of the first layer may be 2 minutes or more and 7 minutes or less. At this time, the disintegration time of the second layer may be 15 seconds or more and 30 seconds or less.
본 발명의 복합 제제에서, 제1 층과 제2 층의 붕해 시간 차이가 1분 30초 이상 7분 미만임에 의해서 유효성분이 우수한 용출 특성을 나타내는 복합 제제를 제공할 수 있다. 제1 층과 제2 층의 붕해 시간의 차이를 1 분 30초 이상 7분 미만인 조건 하에서 제2 층의 유효성분에 의해 제1 층의 피마살탄이 간섭을 받지 않고 피마살탄의 우수한 최종 용출률을 구현할 수 있다. 또한, 본 발명에 따른 복합 제제의 제1 층과 제2 층의 붕해 시간 차이는 제2 층의 유효성분의 용출 결과에는 영향을 미치지 않는다. 따라서, 본 발명의 복합 제제는 우수한 용출 및 약리 효과를 나타내면서, 향상된 복약 편의성을 갖는다.In the combination preparation of the present invention, the difference in disintegration time between the first layer and the second layer is 1 minute 30 seconds or more and less than 7 minutes, thereby providing a combination preparation showing excellent dissolution characteristics of active ingredients. Fimasartan of the first layer is not interfered with by the active ingredient of the second layer under the condition that the difference in disintegration time between the first layer and the second layer is 1 minute 30 seconds or more and less than 7 minutes, and an excellent final dissolution rate of fimasartan can be realized. can In addition, the difference in disintegration time between the first layer and the second layer of the complex preparation according to the present invention does not affect the dissolution result of the active ingredient in the second layer. Therefore, the combined preparation of the present invention exhibits excellent dissolution and pharmacological effects, and has improved medication convenience.
일 실시예에서, 상기 약학적 복합 제제 단위제형 당 상기 제1 층의 유효성분의 함유량은 30 mg 내지 70 mg일 수 있다. 예를 들어, 상기 약학적 복합 제제 단위제형 당 상기 제1 층의 유효성분의 함유량은 30 mg 내지 40 mg이거나, 60 mg 내지 70 mg일 수 있다. 일 실시예에서, 상기 약학적 복합 제제 단위제형 당, 피마사르탄칼륨삼수화물로서 30 mg 내지 70 mg, 30 mg 내지 40 mg 또는 60 mg 내지 70 mg을 포함할 수 있다. 예를 들어, 상기 약학적 복합 제제 단위제형 당, 피마사르탄칼륨으로서 30 mg 또는 60 mg을 포함할 수 있다.In one embodiment, the content of the active ingredient of the first layer per unit dosage form of the pharmaceutical combination formulation may be 30 mg to 70 mg. For example, the content of the active ingredient of the first layer per unit dosage form of the pharmaceutical combination formulation may be 30 mg to 40 mg or 60 mg to 70 mg. In one embodiment, 30 mg to 70 mg, 30 mg to 40 mg, or 60 mg to 70 mg of fimasartan potassium trihydrate may be included per unit dosage form of the pharmaceutical combination formulation. For example, 30 mg or 60 mg of fimasartan potassium may be included per unit dosage form of the pharmaceutical combination formulation.
본 발명에 따른 피마살탄은 하기 화학식 1로 표시되는 화합물일 수 있다.Fimasartan according to the present invention may be a compound represented by Formula 1 below.
<화학식 1><Formula 1>
본 발명에 따른 피마살탄의 약학적으로 허용 가능한 염은 의약업계에서 통상적으로 사용되는 염을 의미하며, 특별히 제한되지 않는다. 예를 들어, 약학적으로 허용 가능한 염은 칼슘, 칼륨, 나트륨, 또는 마그네슘 등으로 제조된 무기이온염; 염산, 질산, 인산, 브롬산, 요오드산, 과염소산, 타르타르산, 또는 황산 등으로 제조된 무기산염; 아세트산, 트리플루오로아세트산, 시트르산, 말레인산, 숙신산, 옥살산, 벤조산, 푸마르산, 만데르산, 프로피온산, 젖산, 글리콜산, 글루콘산, 갈락투론산, 글루탐산, 글루타르산, 글루쿠론산, 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 하이드로아이오딕산, 만델산, 뮤크산, 질산, 파모산, 판토텐산, 또는 숙신산 등으로 제조된 유기산염; 메탄설폰산, 에탄설폰산, 벤젠설폰산, p-톨루엔설폰산, 캄포르설폰산, 또는 나프탈렌설폰산 등으로 제조된 설폰산염; 글리신, 아르기닌, 또는 라이신 등으로 제조된 아미노산염; 또는 트리메틸아민, 트리에틸아민, 암모니아, 피리딘, 또는 피콜린 등으로 제조된 아민염 등을 포함할 수 있다.The pharmaceutically acceptable salt of fimasartan according to the present invention means a salt commonly used in the pharmaceutical industry, and is not particularly limited. For example, pharmaceutically acceptable salts are inorganic ion salts prepared with calcium, potassium, sodium, or magnesium; inorganic acid salts prepared with hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid, tartaric acid, or sulfuric acid; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, organic acid salts prepared from ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, mandelic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, or succinic acid; sulfonic acid salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, or naphthalenesulfonic acid; amino acid salts prepared with glycine, arginine, or lysine; or an amine salt prepared with trimethylamine, triethylamine, ammonia, pyridine, or picoline.
본 발명에 따른 피마살탄 또는 이의 약학적으로 허용 가능한 염의 수화물은 일수화물, 이수화물, 삼수화물, 사수화물, 오수화물 등일 수 있다.The hydrate of fimasartan or a pharmaceutically acceptable salt thereof according to the present invention may be a monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate or the like.
본 발명의 피마살탄 또는 이의 약학적으로 허용 가능한 염의 용매화물은 분자간 힘으로 결합되는 화학양론적 또는 비화학양론적 양의 용매를 포함할 수 있다.The solvate of fimasartan or a pharmaceutically acceptable salt thereof according to the present invention may contain a stoichiometric or non-stoichiometric amount of solvent bound by intermolecular forces.
상기 제1 층은 피마살탄칼륨 삼수화물을 포함할 수 있다.The first layer may include fimasartan potassium trihydrate.
상기 제1 층의 첨가제는 부형제, 결합제, 붕해제, 활택제, 코팅제 등을 포함할 수 있다. 이외에도 계면활성제, 유화제, 착색제, 향료 중에서 선택되는 약제학적으로 허용 가능한 다양한 첨가제를 사용하여 본 발명의 약학적 복합 제제로 제제화할 수 있고, 상기 첨가제는 선택에 의하여 통상 범위의 용량을 함유하여 제제화될 수 있다.Additives of the first layer may include excipients, binders, disintegrants, lubricants, coating agents, and the like. In addition, the pharmaceutical combination formulation of the present invention may be formulated using various pharmaceutically acceptable additives selected from surfactants, emulsifiers, colorants, and flavoring agents, and the additives may be formulated containing a dose within the usual range by selection. can
부형제는 미결정셀룰로오스, 규소화미결정셀룰로오스, 만니톨, 수크로오스, 락토오스, 소르비톨, 자일리톨, 글루코오스, 침강탄산칼슘 또는 이들 중 2 이상의 조합을 포함할 수 있다.The excipient may include microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, sucrose, lactose, sorbitol, xylitol, glucose, precipitated calcium carbonate, or a combination of two or more thereof.
결합제는 포도당 시럽, 폴리비닐피롤리돈, 폴리에틸렌글리콜6000, 메틸셀룰로오스, 카르복시메틸셀룰로오스나트륨, 에틸셀룰로오스, 히드록시에틸셀룰로오스, 히드록시프로필셀룰로오스, 히드록시프로필메틸셀룰로오스, 메틸셀룰로오스, 젤라틴, 포비돈, 전분, 예비 젤라틴화된 전분(전호화전분) 또는 이들 중 2 이상의 조합을 포함할 수 있다.Binders are glucose syrup, polyvinylpyrrolidone, polyethylene glycol 6000, methylcellulose, carboxymethylcellulose sodium, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, gelatin, povidone, starch , pregelatinized starch (pregelatinized starch), or a combination of two or more of these.
붕해제는 전분글리콜산나트륨, 옥수수전분, 감자전분, 또는 전젤라틴화전분(전호화전분) 등의 전분 또는 변성전분; 벤토나이트, 몬모릴로나이트, 또는 비검(veegum) 등의 클레이; 저치환도 히드록시프로필셀룰로오스 등의 셀룰로오스; 크로스카멜로오스나트륨 등의 가교 셀룰로오스류; 구아검, 잔탄검 등의 검류; 크로스포비돈 등의 가교 중합체; 중탄산나트륨, 시트르산 등의 비등성 제제 또는 이들 중 2 이상의 조합을 포함할 수 있다.The disintegrant may be starch or modified starch such as sodium starch glycolate, corn starch, potato starch, or pregelatinized starch (pregelatinized starch); clays such as bentonite, montmorillonite, or veegum; cellulose such as low-substituted hydroxypropyl cellulose; cross-linked celluloses such as croscarmellose sodium; gums such as guar gum and xanthan gum; crosslinked polymers such as crospovidone; effervescent agents such as sodium bicarbonate, citric acid, or a combination of two or more thereof.
활택제는 스테아르산칼슘, 글리세릴 모노스테아레이트, 글리세릴 팔미토스테아레이트, 스테아르산마그네슘, 라우릴황산나트륨, 스테아릴푸마르산나트륨, 스테아르산아연, 스테아르산, 경화된 식물성 오일, 폴리에틸렌글리콜, 벤조산나트륨, 탈크 또는 이들 중 2 이상의 조합을 포함할 수 있다.Lubricant: calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate , talc, or a combination of two or more thereof.
코팅제는 폴리비닐알콜, 히드록시프로필메틸셀룰로오스, 메틸셀룰로오스, 에틸셀룰로오스, 폴리비닐아세테이트, 폴리에틸렌글리콜, 이산화티탄, 산화철 등이나 상품명 오파드라이® 또는 이들 중 2 이상의 조합을 포함할 수 있다.The coating agent may include polyvinyl alcohol, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, polyvinyl acetate, polyethylene glycol, titanium dioxide, iron oxide, or the like, trade name Opadry® , or a combination of two or more thereof.
일 실시예에서, 상기 제1 층의 첨가제는 크로스카멜로오스나트륨, 크로스포비돈, 전분글리콜산나트륨, 전호화전분 및 저치환도 히드록시프로필셀룰로오스로 이루어진 군으로부터 선택된 적어도 어느 하나를 포함할 수 있다.In one embodiment, the additive of the first layer may include at least one selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized starch, and low-substituted hydroxypropyl cellulose.
일 실시예에서, 상기 제1 층은 피마살탄, 이의 약학적으로 허용 가능한 염, 이의 용매화물 또는 이의 수화물과 제1 붕해제를 포함하는 피마살탄 과립과, 제2 붕해제를 포함할 수 있다. 상기 제1 및 제2 붕해제들은 서로 동일하거나 다를 수 있다. 상기 제1 및 제2 붕해제는 각각 독립적으로 크로스카멜로오스나트륨, 크로스포비돈, 전분글리콜산나트륨, 전호화전분 및 저치환도 히드록시프로필셀룰로오스로 이루어진 군으로부터 선택된 적어도 어느 하나일 수 있다.In one embodiment, the first layer may include fimasartan granules including fimasartan, a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof, and a first disintegrant, and a second disintegrant. The first and second disintegrants may be the same as or different from each other. The first and second disintegrants may each independently be at least one selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized starch, and low-substituted hydroxypropyl cellulose.
일 실시예에서, 상기 제1 층의 유효성분의 용출률은 30% 이상 70% 이하일 수 있다.In one embodiment, the dissolution rate of the active ingredient of the first layer may be 30% or more and 70% or less.
일 실시예에서, 상기 제1 층의 유효성분의 용출률은 34% 이상 65% 이하일 수 있고, 구체적으로, 34.6% 이상 64.6% 이하일 수 있다. 이때, 상기 용출률은 pH 1.2 시험액에서의 최종 용출률을 의미할 수 있다.In one embodiment, the dissolution rate of the active ingredient of the first layer may be 34% or more and 65% or less, specifically, 34.6% or more and 64.6% or less. At this time, the dissolution rate may mean the final dissolution rate in the pH 1.2 test solution.
상기 제2 층의 유효성분은 칼슘채널차단제, HMG-CoA 환원효소 억제제, 또는 이뇨제 등을 포함할 수 있고, 이들은 각각 단독으로 또는 2 이상이 조합되어 사용될 수 있다.The active ingredient of the second layer may include a calcium channel blocker, an HMG-CoA reductase inhibitor, or a diuretic, each of which may be used alone or in combination of two or more.
상기 칼슘채널차단제는 니페디핀, 니모디핀, 닐바디핀, 마니디핀, 바르니디핀, 니트렌디핀, 베니디핀, 니카르디핀, 레르카니디핀, 암로디핀, 니솔디핀, 에포니디핀, 실니디핀, 아젤니디핀, 펠로디핀, 아라니디핀 또는 프라니디핀 등을 들 수 있고, 이들의 약제학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물을 포함할 수 있으며, 이들은 각각 단독으로 또는 2 이상이 조합되어 사용될 수 있다. The calcium channel blocker is nifedipine, nimodipine, nilvadipine, manidipine, barnidipine, nitrendipine, benidipine, nicardipine, lercanidipine, amlodipine, nisoldipine, eponidipine, cilnidipine, azelnidipine , felodipine, aranidipine, or franidipine, and the like, and may include pharmaceutically acceptable salts thereof, hydrates thereof, or solvates thereof, each of which may be used alone or in combination of two or more thereof. can be used
이때의 칼슘채널차단제의 약제학적으로 허용 가능한 염, 수화물 및 용매화물 각각은 피마살탄의 염, 수화물 및 용매화물 각각에서 설명한 것과 실질적으로 동일하므로, 중복되는 설명은 생략한다.Since each of the pharmaceutically acceptable salts, hydrates and solvates of the calcium channel blocker is substantially the same as that described for each of the salts, hydrates and solvates of fimasartan, duplicate descriptions will be omitted.
상기 HMG-CoA 환원효소 억제제의 예로서는, 로수바스타틴, 아토바스타틴, 피타바스타틴, 프라바스타틴, 심바스타틴 또는 로바스타틴 등을 들 수 있고, 이들의 약제학적으로 허용 가능한 염, 이들의 수화물 또는 이들의 용매화물을 포함할 수 있으며, 이들은 각각 단독으로 또는 2 이상이 조합되어 사용될 수 있다. Examples of the HMG-CoA reductase inhibitor include rosuvastatin, atorvastatin, pitavastatin, pravastatin, simvastatin, or lovastatin, and pharmaceutically acceptable salts thereof, hydrates thereof, or solvates thereof. It may include, and these may be used individually or in combination of two or more.
이때의 HMG-CoA 환원효소 억제제의 약제학적으로 허용 가능한 염, 수화물 및 용매화물 각각은 피마살탄의 염, 수화물 및 용매화물 각각에서 설명한 것과 실질적으로 동일하므로, 중복되는 설명은 생략한다.Since each of the pharmaceutically acceptable salt, hydrate and solvate of the HMG-CoA reductase inhibitor at this time is substantially the same as the salt, hydrate and solvate of fimasartan, duplicate descriptions will be omitted.
상기 이뇨제는 클로로티아지드, 히드로클로로티아지드, 클로르탈리돈, 인다파미드 등을 포함할 수 있다.The diuretic may include chlorothiazide, hydrochlorothiazide, chlorthalidone, indapamide, and the like.
일 실시예에서, 상기 제2 층의 유효성분은 암로디핀, 이의 약제학적으로 허용 가능한 염 또는 이의 수화물; 아토바스타틴, 이의 약제학적으로 허용 가능한 염 또는 이의 수화물; 및 히드로클로로티아지드, 이의 약제학적으로 허용 가능한 염 또는 이의 수화물로 이루어진 군으로부터 선택된 적어도 어느 하나를 포함할 수 있다.In one embodiment, the active ingredient of the second layer is amlodipine, a pharmaceutically acceptable salt or hydrate thereof; atorvastatin, a pharmaceutically acceptable salt thereof or a hydrate thereof; And it may include at least one selected from the group consisting of hydrochlorothiazide, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
일 실시예에서, 상기 제2 층의 유효성분은 암로디핀, 이의 약제학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물을 포함할 수 있다.In one embodiment, the active ingredient of the second layer may include amlodipine, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.
일 실시예에서, 상기 제2 층의 유효성분은 암로디핀, 이의 약제학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물; 및 히드로클로로티아지드를 포함할 수 있다.In one embodiment, the active ingredient of the second layer is amlodipine, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof; and hydrochlorothiazide.
상기 제2 층은 암로디핀 베실산염 및 히드로클로로티아지드를 포함할 수 있다.The second layer may include amlodipine besylate and hydrochlorothiazide.
일 실시예에서, 상기 제2 층의 유효성분은 HMG-CoA 환원효소 억제제로서 아토바스타틴, 이의 약제학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물을 포함할 수 있다.In one embodiment, the active ingredient of the second layer may include atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof as an HMG-CoA reductase inhibitor.
일 실시예에서, 상기 약학적 복합 제제 단위제형 당, 상기 제2 층의 유효성분으로서 암로디핀 베실산염을 6 내지 14 mg 포함할 수 있다. 또는, 상기 약학적 복합 제제 단위제형 당, 상기 제2 층의 유효성분은 암로디핀으로서 5 mg 내지 10 mg을 포함할 수 있다.In one embodiment, 6 to 14 mg of amlodipine besylate may be included as an active ingredient of the second layer per unit dosage form of the pharmaceutical combination formulation. Alternatively, the active ingredient of the second layer may include 5 mg to 10 mg of amlodipine per unit dosage form of the pharmaceutical combination formulation.
예를 들어, 상기 약학적 복합 제제 단위제형 당, 상기 제2 층의 유효성분으로서 히드로클로로티아지드를 12.5 mg 내지 25 mg 포함할 수 있다.For example, 12.5 mg to 25 mg of hydrochlorothiazide as an active ingredient of the second layer may be included per unit dosage form of the pharmaceutical combination formulation.
예를 들어, 상기 약학적 복합 제제 단위제형 당, 상기 제2 층의 유효성분은 아토바스타틴칼슘 삼수화물을 10 내지 50 mg 포함할 수 있다. 또는, 상기 약학적 복합 제제 단위제형 당, 아토바스타틴으로서 10 내지 40 mg을 포함할 수 있다.For example, the active ingredient of the second layer may include 10 to 50 mg of atorvastatin calcium trihydrate per unit dosage form of the pharmaceutical combination formulation. Alternatively, it may contain 10 to 40 mg as atorvastatin per unit dosage form of the pharmaceutical combination formulation.
상기 제2 층의 첨가제는 부형제, 결합제, 붕해제, 활택제, 코팅제 등을 포함할 수 있다. 상기 제2 층의 첨가제는 상기 제1 층의 첨가제에서 설명한 것과 실질적으로 동일하므로, 중복되는 설명은 생략한다. 상기 제2 층에 포함되는 첨가제는, 상기 제1 층에 포함되는 첨가제와 동일하거나 서로 다를 수 있다.Additives of the second layer may include excipients, binders, disintegrants, lubricants, coating agents, and the like. Since the additives of the second layer are substantially the same as those described in the additives of the first layer, overlapping descriptions are omitted. Additives included in the second layer may be the same as or different from additives included in the first layer.
일 실시예에서, 상기 제2 층은 암로디핀, 이의 약제학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물, 히드로클로로티아지드, 미결정셀룰로오스, 전호화전분, 히드록시프로필셀룰로오스, 전분글리콜산나트륨 및 스테아르산마그네슘을 포함할 수 있다.In one embodiment, the second layer is amlodipine, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, hydrochlorothiazide, microcrystalline cellulose, pregelatinized starch, hydroxypropyl cellulose, sodium starch glycolate and stearate. May contain magnesium acid.
일 실시예에서, 상기 제2 층은 아토바스타틴, 이의 약제학적으로 허용 가능한 염, 이의 수화물 또는 이의 용매화물, 침강탄산칼슘, 유당수화물, 미결정셀룰로오스, 폴리소르베이트80, 크로스카멜로오스나트륨, 히드록시프로필셀룰로오스 및 스테아르산마그네슘을 포함할 수 있다.In one embodiment, the second layer is atorvastatin, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, precipitated calcium carbonate, lactose hydrate, microcrystalline cellulose, polysorbate 80, croscarmellose sodium, hydrogel. hydroxypropylcellulose and magnesium stearate.
본 발명의 일 목적을 위한 약학적 복합 제제는 유효성분으로서 피마살탄, 이의 약학적으로 허용 가능한 염, 이의 용매화물 또는 이의 수화물 및 첨가제를 포함하는 제1 층; 및 암로디핀, 이의 약제학적으로 허용 가능한 염 또는 이의 수화물, 히드로클로로티아지드, 이의 약제학적으로 허용 가능한 염 또는 이의 수화물 및 첨가제를 포함하는 제2 층을 포함하고, 상기 제1 층과 제2 층의 붕해 시간의 차이가 1분 30초 이상 7분 미만이다.A pharmaceutical complex preparation for one purpose of the present invention includes a first layer comprising fimasartan, a pharmaceutically acceptable salt thereof, a solvate thereof or a hydrate thereof, and an excipient as an active ingredient; and a second layer comprising amlodipine, a pharmaceutically acceptable salt thereof or a hydrate thereof, hydrochlorothiazide, a pharmaceutically acceptable salt thereof or a hydrate thereof, and an additive, wherein the first layer and the second layer The difference in disintegration time is 1 minute 30 seconds or more and less than 7 minutes.
본 발명의 일 목적을 위한 약학적 복합 제제는 유효성분으로서 피마살탄, 이의 약학적으로 허용 가능한 염, 이의 용매화물 또는 이의 수화물 및 첨가제를 포함하는 제1 층; 및 아토바스타틴, 이의 약제학적으로 허용 가능한 염 또는 이의 수화물 및 첨가제를 포함하는 제2 층을 포함하고, 상기 제1 층과 제2 층의 붕해 시간의 차이가 1분 30초 이상 7분 미만이다.A pharmaceutical complex preparation for one purpose of the present invention includes a first layer comprising fimasartan, a pharmaceutically acceptable salt thereof, a solvate thereof or a hydrate thereof, and an excipient as an active ingredient; and a second layer comprising atorvastatin, a pharmaceutically acceptable salt thereof or a hydrate thereof, and an additive, wherein a difference in disintegration time between the first layer and the second layer is greater than or equal to 1 minute 30 seconds and less than 7 minutes. .
본 발명에 따른 약학적 복합 제제는 고형 제제일 수 있으며, 정제의 형태일 수 있다. 이때, 정제란, 모든 모양 및 크기의 압축된 제약 투여 형태를 포함하는 것을 의미하고, 본 발명에 따른 약학적 복합 제제는 이층정제를 포함할 수 있다. 이층정제란 구획을 분리하여 각 성분이 혼재되지 않고 각 층에 독립적으로 존재하는 복합 제제를 의미한다. 이층정제는 코팅될 수 있고, 약학적 복합 제제는 코팅층을 포함할 수 있다.The pharmaceutical combination preparation according to the present invention may be a solid preparation or may be in the form of a tablet. At this time, the tablet means to include compressed pharmaceutical dosage forms of all shapes and sizes, and the pharmaceutical combination preparation according to the present invention may include a two-layer tablet. A two-layer tablet refers to a complex preparation in which the compartments are separated so that each component exists independently in each layer without being mixed. The bi-layer tablet may be coated, and the pharmaceutical combination preparation may include a coating layer.
본 발명에 따른 약학적 복합 제제의 제조 방법은,The method for preparing a pharmaceutical combination formulation according to the present invention,
(a) 피마살탄, 이의 약학적으로 허용 가능한 염, 이의 수화물, 또는 이의 용매화물 및 첨가제를 혼합하여 제1 혼합물을 제조하는 단계;(a) preparing a first mixture by mixing fimasartan, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, and an additive;
(b) 적어도 1 이상의 유효성분 및 첨가제를 혼합하여 제2 혼합물을 제조하는 단계; 및(b) preparing a second mixture by mixing at least one active ingredient and an additive; and
(c) 상기 제1 혼합물과 상기 제2 혼합물을 타정하여 복합 제제를 제조하는 단계를 포함하고,(c) preparing a composite formulation by tableting the first mixture and the second mixture,
상기 복합 제제는 상기 제1 혼합물을 포함하는 제1 층과 상기 제2 혼합물을 포함하는 제2 층을 포함하고, 상기 제1 층과 상기 제2 층의 붕해 시간의 차이가 1분 30초 이상 7분 미만이다.The complex formulation includes a first layer containing the first mixture and a second layer containing the second mixture, and the difference in disintegration time between the first layer and the second layer is 1 minute 30 seconds or more 7 less than a minute
이층정제는 코팅될 수 있다. 코팅 방법으로는 통상의 방법을 사용할 수 있으며, 그 예로 팬 코팅법, 유도층 코팅법 또는 압축 코팅법 등을 들 수 있다.Bi-layer tablets may be coated. Conventional methods may be used as the coating method, and examples thereof include a pan coating method, an induction layer coating method, and a compression coating method.
상기 제2 혼합물의 유효성분은 HMG-CoA 환원효소 억제제, 칼슘채널차단제 또는 이뇨제 등을 포함할 수 있고, 이들은 각각 단독으로 또는 2 이상이 조합되어 사용될 수 있다.The active ingredient of the second mixture may include an HMG-CoA reductase inhibitor, a calcium channel blocker or a diuretic, and these may be used alone or in combination of two or more.
상기 제1 혼합물은 피마살탄, 이의 약학적으로 허용 가능한 염, 이의 용매화물 또는 이의 수화물과 제1 붕해제를 포함하는 피마살탄 과립과, 제2 붕해제를 포함할 수 있다. 상기 제1 및 제2 붕해제들은 서로 동일하거나 다를 수 있다.The first mixture may include fimasartan granules including fimasartan, a pharmaceutically acceptable salt thereof, a solvate thereof or a hydrate thereof, and a first disintegrant, and a second disintegrant. The first and second disintegrants may be the same as or different from each other.
상기 제1 혼합물을 제조하는 단계는 피마살탄, 이의 약학적으로 허용 가능한 염, 이의 용매화물 또는 이의 수화물과 제1 붕해제를 포함하는 피마살탄 과립을 제조하는 단계; 및 상기 피마살탄 과립과 제2 붕해제를 혼합하는 단계를 포함할 수 있다. 상기 제2 붕해제와 함께 다른 첨가제가 더 혼합될 수 있다. 상기 제1 및 제2 붕해제는 각각 독립적으로 크로스카멜로오스나트륨, 크로스포비돈, 전분글리콜산나트륨, 전호화전분 및 저치환도 히드록시프로필셀룰로오스로 이루어진 군으로부터 선택된 적어도 어느 하나일 수 있다.The preparing of the first mixture may include preparing fimasartan granules comprising fimasartan, a pharmaceutically acceptable salt thereof, a solvate thereof or a hydrate thereof, and a first disintegrant; and mixing the fimasartan granules with a second disintegrant. Other additives may be further mixed with the second disintegrant. The first and second disintegrants may each independently be at least one selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized starch, and low-substituted hydroxypropyl cellulose.
본 발명의 약학적 복합 제제 및 제조 방법에 따르면, 복합 제제의 제1 층과 제2 층의 붕해 시간 차이의 제어를 통해 유효성분이 우수한 용출 특성을 나타내는 복합 제제를 제공할 수 있다. 제1 층과 제2 층의 붕해 시간의 차이를 1 분 30초 이상 7분 미만인 조건 하에서 제2 층의 유효성분에 의해 제1 층의 피마살탄이 간섭을 받지 않고 피마살탄의 우수한 최종 용출률을 구현할 수 있다. 또한, 본 발명에 따른 복합 제제의 제1 층과 제2 층의 붕해 시간 차이는 제2 층의 유효성분의 용출 결과에는 영향을 미치지 않는다. 따라서, 본 발명의 복합 제제는 우수한 용출 및 약리 효과를 나타내면서, 향상된 복약 편의성을 갖는다.According to the pharmaceutical combination formulation and preparation method of the present invention, a combination formulation exhibiting excellent dissolution characteristics of active ingredients can be provided by controlling the difference in disintegration time between the first layer and the second layer of the combination formulation. Fimasartan of the first layer is not interfered with by the active ingredient of the second layer under the condition that the difference in disintegration time between the first layer and the second layer is 1 minute 30 seconds or more and less than 7 minutes, and an excellent final dissolution rate of fimasartan can be realized. can In addition, the difference in disintegration time between the first layer and the second layer of the complex preparation according to the present invention does not affect the dissolution result of the active ingredient in the second layer. Therefore, the combined preparation of the present invention exhibits excellent dissolution and pharmacological effects, and has improved medication convenience.
이하, 본 발명의 실시예에 대해 상세히 설명한다. 다르게 정의되지 않는 한, 기술적이거나 과학적인 용어를 포함해서 여기서 사용되는 모든 용어들은 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 가지고 있다. 일반적으로 사용되는 사전에 정의되어 있는 것과 같은 용어들은 관련 기술의 문맥 상 가지는 의미와 일치하는 의미를 가지는 것으로 해석되어야 하며, 본 출원에서 명백하게 정의하지 않는 한, 이상적이거나 과도하게 형식적인 의미로 해석되지 않는다.Hereinafter, embodiments of the present invention will be described in detail. Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related art, and unless explicitly defined in the present application, they should not be interpreted in an ideal or excessively formal meaning. don't
제조예 1(1) 내지 1(37) - 피마살탄을 유효성분으로 포함하는 과립의 제조Preparation Examples 1 (1) to 1 (37) - Preparation of granules containing fimasartan as an active ingredient
제조예 1(1) 내지 1(37) 각각에서는 단위제형당 제1 층에 포함되는 각 성분이 하기 표 1과 같은 분량(mg/tablet)이 되도록 정하여 피마살탄 과립을 제조하였다. 단위제형당 제1 층을 구성하는 성분 전체의 분량은 제조예 1(1) 내지 1(34)를 이용한 경우 150 mg/tablet이고, 제조예 1(35) 내지 1(37)을 이용한 경우 75 mg/tablet이다.In each of Preparation Examples 1(1) to 1(37), fimasartan granules were prepared by determining the amount (mg/tablet) of each component included in the first layer per unit dosage form as shown in Table 1 below. The amount of all components constituting the first layer per unit dosage form is 150 mg/tablet in the case of using Preparation Examples 1(1) to 1(34), and 75 mg in the case of using Preparation Examples 1(35) to 1(37) /tablet.
구체적으로, 피마살탄칼륨삼수화물, 유당수화물, 미결정셀룰로오스 및 제1 붕해제를 약 5분간 혼합한 후, 유동층과립기 (Fluid Bed Granulator)에 넣고 약 2분간 혼합하였다. 이와 별도로, 정제수에 히드록시프로필셀룰로오스를 넣고 결합액을 제조하였다.Specifically, after mixing fimasartan potassium trihydrate, lactose hydrate, microcrystalline cellulose, and the first disintegrant for about 5 minutes, they were placed in a fluid bed granulator and mixed for about 2 minutes. Separately, a binder solution was prepared by adding hydroxypropyl cellulose to purified water.
제조된 결합액을 유동층과립기를 이용하여 습식과립화 한 후 건조하였고, 정립기를 사용하여 상기 건조된 과립을 정립하였으며, 상기 정립물에 제2 붕해제를 넣고 Bin 타입 혼합기에서 약 10분간 혼합한 후, 추가로 스테아르산마그네슘을 더하고 약 5분간 혼합하여 제조예 1(1) 내지 1(37)에 따른 각각의 피마살탄 과립을 제조하였다.The prepared binder solution was wet-granulated using a fluid bed granulator and then dried, and the dried granules were sized using a sizing machine, and a second disintegrant was added to the sized material, and mixed in a Bin type mixer for about 10 minutes. , Magnesium stearate was further added and mixed for about 5 minutes to prepare respective fimasartan granules according to Preparation Examples 1(1) to 1(37).
하기 표 1에서, 제1 및 제2 붕해제들의 기재 중 CCS는 크로스카멜로오스나트륨을, CP는 크로스포비돈을, 그리고 SSG는 전분글리콜산나트륨을 의미하고, L-HPC는 저치환도 히드록시프로필셀룰로오스를 의미한다.In Table 1 below, in the description of the first and second disintegrants, CCS means croscarmellose sodium, CP means crospovidone, SSG means sodium starch glycolate, and L-HPC means low-substituted hydroxypropyl means cellulose.
[표 1][Table 1]
제조예 2(1) 및 (2) - 암로디핀 및 히드로클로로티아지드를 유효성분으로 포함하는 과립의 제조Preparation Example 2 (1) and (2) - Preparation of granules containing amlodipine and hydrochlorothiazide as active ingredients
제조예 2에서는 단위제형당 제2 층에 포함되는 각 성분이 하기 표 2 및 표 3과 같은 분량(mg/tablet)이 되도록 정하여 암로디핀/히드로클로로티아지드 과립 (1) 및 (2)를 제조하였다.In Preparation Example 2, amlodipine/hydrochlorothiazide granules (1) and (2) were prepared by determining the amount (mg/tablet) of each component included in the second layer per unit dosage form as shown in Tables 2 and 3 below. .
구체적으로, 암로디핀 베실산염, 히드로클로로티아지드, 미결정셀룰로오스, 전호화전분 및 전분글리콜산나트륨을 5분간 혼합한 후, 상기 혼합물을 고속과립기 (High shear mixer)에 넣고 5분간 혼합하였다.Specifically, after mixing amlodipine besylate, hydrochlorothiazide, microcrystalline cellulose, pregelatinized starch, and sodium starch glycolate for 5 minutes, the mixture was put into a high shear mixer and mixed for 5 minutes.
이와 별도로, 정제수에 히드록시프로필셀룰로오스를 넣고 결합액을 제조하였다.Separately, a binder solution was prepared by adding hydroxypropyl cellulose to purified water.
제조된 결합액을 상기 제조된 혼합물과 고속과립기를 이용하여 습식과립화 한 후 건조하였고, 정립기를 사용하여 상기 건조된 과립을 정립하였으며, 상기 정립물에 스테아르산마그네슘을 더하고 약 5분간 혼합하여 암로디핀/히드로클로로티아지드 과립 (1) 및 (2)를 각각 제조하였다.The prepared binder solution was wet-granulated using the above-prepared mixture and a high-speed granulator, then dried, and the dried granules were sized using a sizing machine. Magnesium stearate was added to the sized product and mixed for about 5 minutes to obtain amlodipine. / Hydrochlorothiazide granules (1) and (2) were prepared, respectively.
[표 2][Table 2]
[표 3][Table 3]
제조예 3 - 아토바스타틴을 유효성분으로 포함하는 과립의 제조Preparation Example 3 - Preparation of granules containing atorvastatin as an active ingredient
아토바스타틴칼슘 삼수화물, 침강탄산칼슘, 유당수화물, 미결정셀룰로오스 및 폴리소르베이트80을 약 10분간 혼합한 후, 상기 혼합물을 고속과립기 (High shear mixer)에 넣고 약 3분간 혼합하였다.After mixing atorvastatin calcium trihydrate, precipitated calcium carbonate, lactose hydrate, microcrystalline cellulose, and polysorbate 80 for about 10 minutes, the mixture was put into a high shear mixer and mixed for about 3 minutes.
이와 별도로, 정제수에 히드록시프로필셀룰로오스를 넣고 결합액을 제조하였다.Separately, a binder solution was prepared by adding hydroxypropyl cellulose to purified water.
제조된 결합액을 상기 제조된 혼합물과 고속과립기를 이용하여 습식과립화 한 후 건조하였고, 정립기를 사용하여 상기 건조된 과립을 정립하였으며, 상기 정립물에 크로스카멜로오스나트륨을 넣고 Bin 타입 혼합기에서 약 5분간 혼합한 후, 추가로 스테아르산마그네슘을 더하고 약 5분간 혼합하여 아토바스타틴 과립을 제조하였다.The prepared binder solution was wet-granulated using the above-prepared mixture and a high-speed granulator, and then dried, and the dried granules were sized using a sizing machine, and croscarmellose sodium was added to the sized product, and about After mixing for 5 minutes, magnesium stearate was further added and mixed for about 5 minutes to prepare atorvastatin granules.
제조예 3에서는 단위제형당 제2 층에 포함되는 각 성분이 하기 표 4와 같은 분량(mg/tablet)이 되도록 정하여 아토바스타틴 과립을 제조하였다.In Preparation Example 3, atorvastatin granules were prepared by determining the amount (mg/tablet) of each component included in the second layer per unit dosage form as shown in Table 4 below.
[표 4][Table 4]
실시예 1 - 이층정제의 제조Example 1 - Preparation of a bi-layer tablet
제조예 1(3)에 따라 얻어진 피마살탄 과립과 제조예 2(1)에 따라 얻어진 암로디핀/히드로클로로티아지드 과립 (1) 각각을 이용하여 다층정 타정기 (Korsch)의 펀치 다이에 넣고 5 ~ 15 kN의 타정압으로 타정하여 경도가 5 ~ 20 kp가 되도록 이층정제를 제조하였다. 이층정제에 포함된 성분들의 단위제형 당 함량은 표 1 및 표 2와 같다.Each of the fimasartan granules obtained in Preparation Example 1(3) and the amlodipine/hydrochlorothiazide granules (1) obtained in Preparation Example 2(1) were put into a punch die of a multi-layer tablet tableting machine (Korsch) and then 5 to 15 A two-layer tablet was prepared to have a hardness of 5 to 20 kp by tableting at a tableting pressure of kN. The contents per unit dosage form of the ingredients included in the two-layer tablet are shown in Tables 1 and 2.
실시예 2 내지 24 - 이층정제의 제조Examples 2 to 24 - Preparation of bi-layer tablets
제조예 1(4) 내지 1(25) 및 1(31)에 따라 얻어진 피마살탄 과립과 제조예 2(1)에 따라 얻어진 암로디핀/히드로클로로티아지드 과립 (1)을 이용하여 이층정제들을 각각 준비하였다. 이층정제들에 포함된 성분들의 단위제형 당 함량은 표 1 및 표 2와 같다.Two-layer tablets were prepared using the fimasartan granules obtained according to Preparation Examples 1(4) to 1(25) and 1(31) and the amlodipine/hydrochlorothiazide granules (1) obtained according to Preparation Example 2(1), respectively. did The contents per unit dosage form of the ingredients included in the double-layer tablets are shown in Tables 1 and 2.
실시예 25 - 이층정제의 제조Example 25 - Preparation of a bi-layer tablet
제조예 1(37)에 따라 얻어진 피마살탄 과립과 제조예 2(2)에 따라 얻어진 암로디핀/히드로클로로티아지드 과립 (2)를 이용하여 이층정제를 제조하였다. 이층정제에 포함된 성분들의 단위제형 당 함량은 표 1 및 표 3과 같다.A bilayer tablet was prepared using the fimasartan granules obtained according to Preparation Example 1 (37) and the amlodipine/hydrochlorothiazide granules (2) obtained according to Preparation Example 2 (2). The contents per unit dosage form of the ingredients included in the two-layer tablet are shown in Tables 1 and 3.
실시예 26 - 이층정제의 제조Example 26 - Preparation of a bi-layer tablet
제조예 1(4)에 따라 얻어진 피마살탄 과립과 제조예 3에 따라 얻어진 아토바스타틴 과립을 이용하여 이층정제를 준비하였다. 이층정제에 포함된 성분들의 단위제형 당 함량은 표 1 및 표 4와 같다.A two-layer tablet was prepared using the fimasartan granules obtained according to Preparation Example 1(4) and the atorvastatin granules obtained according to Preparation Example 3. The contents per unit dosage form of the ingredients included in the two-layer tablet are shown in Tables 1 and 4.
비교예 1 내지 10 - 이층정제의 제조Comparative Examples 1 to 10 - Preparation of bilayer tablets
제조예 1(1), 1(2), 1(26) 내지 1(30) 및 1(32) 내지 1(34)에 따라 얻어진 피마살탄 과립 각각을 이용하여 이층정제를 준비하였다. 이층정제들에 포함된 성분들의 단위제형 당 함량은 표 1 및 표 2와 같다.Two-layer tablets were prepared using each of the fimasartan granules obtained according to Preparation Examples 1(1), 1(2), 1(26) to 1(30) and 1(32) to 1(34). The contents per unit dosage form of the ingredients included in the double-layer tablets are shown in Tables 1 and 2.
비교예 11 및 12 - 이층정제의 제조Comparative Examples 11 and 12 - Preparation of bi-layer tablets
제조예 1(35) 및 제조예 1(36)에 따라 얻어진 피마살탄 과립 각각과 제조예 2(2)에 따라 얻어진 암로디핀/히드로클로로티아지드 과립 (2)를 이용하여 이층정제를 제조하였다. 이층정제들에 포함된 성분들의 단위제형 당 함량은 표 1 및 표 3과 같다.A bi-layer tablet was prepared using each of the fimasartan granules obtained in Preparation Examples 1 (35) and 1 (36) and the amlodipine/hydrochlorothiazide granules (2) obtained in Preparation Example 2 (2). The contents per unit dosage form of the ingredients included in the two-layer tablets are shown in Tables 1 and 3.
비교예 13 - 이층정제의 제조Comparative Example 13 - Preparation of a bi-layer tablet
제조예 1(29)에 따라 얻어진 피마살탄 과립과 제조예 3에 따라 얻어진 아토바스타틴 과립을 이용하여 이층정제를 준비하였다. 이층정제들에 포함된 성분들의 단위제형 당 함량은 표 1 및 표 4와 같다.A two-layer tablet was prepared using the fimasartan granules obtained according to Preparation Example 1 (29) and the atorvastatin granules obtained according to Preparation Example 3. The contents per unit dosage form of the ingredients included in the double-layer tablets are shown in Tables 1 and 4.
시험예 - 붕해 시험Test Example - Disintegration Test
실시예 1 내지 26 및 비교예 1 내지 13에 따른 이층정제에 대해서 붕해시험을 진행하였다. 붕해시험은 대한약전 일반시험법에 기재된 붕해시험법(시험액: 물, 보조판: 사용하지 않음)에 따라서 붕해 시간을 측정하였다. 그 결과 제1 층 및 제2 층 각각의 붕해 시간 및 이들의 붕해 시간의 차이를 하기 표 5에 나타낸다.A disintegration test was conducted on the two-layer tablets according to Examples 1 to 26 and Comparative Examples 1 to 13. In the disintegration test, the disintegration time was measured according to the disintegration test method described in the General Test Methods of the Korean Pharmacopoeia (test solution: water, auxiliary plate: not used). As a result, the disintegration time of each of the first layer and the second layer and the difference between the disintegration times thereof are shown in Table 5 below.
제1 층의 붕해 시간 및 제2 층의 붕해 시간은 붕해시험 대상의 샘플에서 제1 층 및 제2 층이 각각 모두 붕해되었을 때의 시간을 의미한다.The disintegration time of the first layer and the disintegration time of the second layer refer to the time when both the first layer and the second layer are disintegrated, respectively, in the sample to be tested for disintegration.
[표 5][Table 5]
특성 평가 - 유효성분의 용출률 실험Characteristic evaluation - active ingredient dissolution rate test
실시예 1 내지 26에 따른 이층정제들 각각을 이용하여 대한 약전 일반시험법에 기재된 용출시험법에 따라서 용출을 평가하였다.Dissolution was evaluated according to the dissolution test method described in the General Test Methods of the Korean Pharmacopoeia using each of the two-layer tablets according to Examples 1 to 26.
- 용출시험액 : 1액 (pH 1.2), 900 mL- Dissolution test solution: 1 liquid (pH 1.2), 900 mL
- 시험온도 : 37±0.5℃- Test temperature: 37±0.5℃
- 시험방법 : 대한약전 용출시험법 제 2법 (패들법), 분당 50 회전- Test method: Korean Pharmacopoeia Dissolution test method 2 (paddle method), 50 revolutions per minute
- 용출시험장치 : LABINDIA DS14000 SMART- Dissolution tester: LABINDIA DS14000 SMART
- 샘플 채취시간 : 5, 10, 15, 30, 60분- Sample collection time: 5, 10, 15, 30, 60 minutes
- 샘플 채취량 : 10 mL- Sample collection amount: 10 mL
- 필터 : 0.45 um 실린지 필터- Filter: 0.45 um syringe filter
실험 결과 1 - 피마살탄의 최종 용출률Experiment Result 1 - Final dissolution rate of Fimasartan
실시예 1 내지 26에 따른 이층정제들 각각에서의 피마살탄의 최종 용출률은 용출 시험액에서 1 시간동안 측정하였고, 그 결과를 하기 표 6에 나타낸다.The final dissolution rate of fimasartan in each of the two-layer tablets according to Examples 1 to 26 was measured in the dissolution test solution for 1 hour, and the results are shown in Table 6 below.
[표 6][Table 6]
표 6을 참조하면, 실시예 1 내지 26 각각에서의 피마살탄의 최종 용출률은 모두 30% 내지 70% 범위 내에 포함된 것을 확인할 수 있다. 특히, 3 이상의 유효성분을 포함하면서 피마살탄의 최종 용출률이 45% 내지 55%인 복합 제제, 구체적으로 49% 내지 50%인 복합 제제와 비교할 때, 이보다 더 우수하거나 실질적으로 동등한 범위 내에 포함된다.Referring to Table 6, it can be seen that the final dissolution rates of fimasartan in each of Examples 1 to 26 were all within the range of 30% to 70%. In particular, when compared to a combination formulation containing three or more active ingredients and having a final dissolution rate of fimasartan of 45% to 55%, specifically 49% to 50%, it is included within a range that is superior to or substantially equivalent to the combination formulation.
반면, 비교예 3 내지 10 및 13에서의 최종 용출률은 최대 20.8%에 불과한, 현저히 낮은 수준임을 확인할 수 있다. 또한, 비교예 1, 2, 11 및 12의 용출률은 매우 높은 것을 확인할 수 있지만, 이 정도의 지나치게 높은 피마살탄의 용출률은 안전성 문제로 이어지고 피마살탄의 최종 용출률이 45% 내지 55%, 구체적으로 49% 내지 50%인 복합 제제와 비교할 때 약리학적으로도 다른 제제에 해당하므로 적합하지 않다. On the other hand, it can be seen that the final dissolution rate in Comparative Examples 3 to 10 and 13 is at a remarkably low level, only up to 20.8%. In addition, it can be seen that the dissolution rates of Comparative Examples 1, 2, 11, and 12 are very high, but such an excessively high dissolution rate of fimasartan leads to safety problems, and the final dissolution rate of fimasartan is 45% to 55%, specifically 49%. Compared to a combination formulation of % to 50%, it is not suitable because it corresponds to a different formulation pharmacologically.
3 이상의 유효성분을 포함하면서 피마살탄의 최종 용출률이 45% 내지 55%, 구체적으로 49% 내지 50%인 복합 제제를 기준으로 하는 경우에, 의약품 동등성시험 기준(제2020-91호, 2020.09.22, 제7조 제2항 및 제3항)을 참조하면, 표 6의 실시예 1 내지 26의 용출시험 결과는 비교 용출시험 결과로서, 3 이상의 유효성분을 포함하면서 피마살탄의 최종 용출률이 45% 내지 55%, 구체적으로 49% 내지 50%인 복합 제제 대비 생물학적 동등성이 입증되었다고 볼 수 있거나 생물학적 동등성시험을 면제받을 수 있는 근거가 되는 반면, 동등 기준을 벗어난 비교예 1 내지 13에 따른 제제들은 결국 피마살탄의 최종 용출률이 45% 내지 55%, 구체적으로 49% 내지 50%인 복합 제제와 약리학적으로 동등하지 않은, 의약품으로서 부적합한 제제에 해당한다.In the case of a composite formulation containing three or more active ingredients and having a final dissolution rate of fimasartan of 45% to 55%, specifically 49% to 50%, the drug equivalence test standard (No. 2020-91, 2020.09.22) , Article 7, paragraphs 2 and 3), the dissolution test results of Examples 1 to 26 in Table 6 are comparative dissolution test results, and the final dissolution rate of fimasartan was 45% while containing three or more active ingredients. to 55%, specifically 49% to 50%, bioequivalence compared to composite formulations can be considered proven or is a basis for exemption from bioequivalence testing, whereas formulations according to Comparative Examples 1 to 13 that deviate from equivalence standards eventually It corresponds to a preparation that is not pharmacologically equivalent to a combination preparation in which the final dissolution rate of fimasartan is 45% to 55%, specifically 49% to 50%, and is unsuitable as a pharmaceutical.
표 6을 통해서, 복합 제제에서 피마살탄의 최종 용출률은 제1 층의 붕해 시간에 의존하는 것이 아니라는 점을 확인할 수 있고, 제1 층과 제2 층의 붕해 시간의 차이를 1 분 30초 이상 7분 미만인 조건 하에서 제2 층의 유효성분에 의해 제1 층의 피마살탄이 간섭을 받지 않고 피마살탄의 우수한 최종 용출률을 구현할 수 있음이 확인된다.Through Table 6, it can be confirmed that the final dissolution rate of fimasartan in the composite formulation does not depend on the disintegration time of the first layer, and the difference between the disintegration time of the first layer and the second layer is 1 minute 30 seconds or more 7 It was confirmed that an excellent final dissolution rate of fimasartan could be realized without the fimasartan of the first layer being interfered with by the active ingredient of the second layer under the condition of less than 10 minutes.
실험 결과 2 - 제2 층의 유효성분들의 용출률Experiment Result 2 - Dissolution rate of active ingredients in the second layer
또한, 용출률 실험 결과에서, 실시예 25의 이층정제에서 암로디핀의 최종 용출률은 90%이고 히드로클로로티아지드의 최종 용출률은 93.5%인 것을 확인할 수 있다. 이와 같이, 본 발명에 따른 복합 제제의 제2 층의 유효성분들 역시도 우수한 용출 특성을 나타내는 것을 확인할 수 있다. 비교예 11 및 12 각각에서의 제2 층의 유효성분들의 최종 용출률 또한 실시예들과 유사한 수준으로 나타내는 것을 확인하였다. 즉, 본 발명에 따른 복합 제제의 제1 층과 제2 층의 붕해 시간 차이는 제2 층의 유효성분의 용출 결과에는 영향을 미치지 않음을 확인할 수 있다.In addition, from the dissolution rate test results, it can be seen that the final dissolution rate of amlodipine in the two-layer tablet of Example 25 was 90% and the final dissolution rate of hydrochlorothiazide was 93.5%. As such, it can be confirmed that the active ingredients of the second layer of the complex formulation according to the present invention also exhibit excellent dissolution characteristics. It was confirmed that the final dissolution rate of the active ingredients of the second layer in each of Comparative Examples 11 and 12 was similar to that of Examples. That is, it can be confirmed that the difference in disintegration time between the first layer and the second layer of the complex formulation according to the present invention does not affect the dissolution result of the active ingredient in the second layer.
특성평가 - 가속 조건 하의 안정성Characterization - Stability under accelerated conditions
실시예 2에 따른 이층정제를 오파드라이 (Colorcon) 9.0 mg을 사용하여 코팅정을 제조하였고, 코팅정 표면에 카르나우바납 0.025 mg을 사용하여 광택 처리하였다. 이때 얻어진 정제를 40±2℃ 및 상대습도 75±5% 조건에서 보관하여 전/후의 각 유효성분의 함량을 측정하여 함량 변화를 비교하였다. 또한, 액체 크로마토그래피(HPLC)을 이용하여 자외선 흡수 분광법으로 분석하여 유연물질을 측정하였다. 그 결과를 하기 표 7에 나타낸다. Coated tablets were prepared using 9.0 mg of Opadry (Colorcon) for the double-layer tablet according to Example 2, and the surface of the coated tablets was polished using 0.025 mg of carnauba wax. At this time, the obtained tablets were stored at 40 ± 2 ° C and relative humidity of 75 ± 5%, and the content of each active ingredient before / after was measured to compare the content change. In addition, related substances were measured by analyzing by ultraviolet absorption spectroscopy using liquid chromatography (HPLC). The results are shown in Table 7 below.
[표 7][Table 7]
(ACB = 4-amino-6-chloro-1,3-benzenedisulfonamide)(ACB = 4-amino-6-chloro-1,3-benzenedisulfonamide)
표 7을 참조하면, 본 발명의 실시예 2에 따른 이층정제는 3개월 및 6개월이 경과한 시점에서도 각 성분의 함량이 유지되고, 유연물질의 발생 또한 거의 없는 것을 확인할 수 있다. 즉, 본 발명의 실시예 2에 따른 이층정제는 열 및 수분에 대하여 안정적인 것을 확인할 수 있다.Referring to Table 7, it can be seen that in the two-layer tablet according to Example 2 of the present invention, the content of each component is maintained even after 3 months and 6 months have elapsed, and related substances are hardly generated. That is, it can be confirmed that the two-layer tablet according to Example 2 of the present invention is stable against heat and moisture.
상기에서는 본 발명의 바람직한 실시예를 참조하여 설명하였지만, 해당 기술 분야의 숙련된 당업자는 하기의 특허 청구 범위에 기재된 본 발명의 사상 및 영역으로부터 벗어나지 않는 범위 내에서 본 발명을 다양하게 수정 및 변경시킬 수 있음을 이해할 수 있을 것이다.Although the above has been described with reference to preferred embodiments of the present invention, those skilled in the art can variously modify and change the present invention without departing from the spirit and scope of the present invention described in the claims below. You will understand that you can.
Claims (14)
적어도 1 이상의 유효성분 및 첨가제를 포함하는 제2 층을 포함하고,
상기 제1 층과 제2 층의 붕해 시간의 차이가 1분 30초 이상 7분 미만인,
약학적 복합 제제.A first layer containing fimasartan, a pharmaceutically acceptable salt thereof, a solvate thereof or a hydrate thereof, and an additive as an active ingredient; and
A second layer comprising at least one active ingredient and an additive;
The difference between the disintegration time of the first layer and the second layer is 1 minute 30 seconds or more and less than 7 minutes,
Pharmaceutical combination preparation.
상기 제2 층의 유효성분은 칼슘채널차단제 및 이뇨제를 포함하는 것인,
약학적 복합 제제.According to claim 1,
The active ingredient of the second layer comprises a calcium channel blocker and a diuretic,
Pharmaceutical combination preparation.
상기 제2 층의 유효성분은 HMG-CoA 환원효소 억제제를 포함하는 것인,
약학적 복합 제제.According to claim 1,
The active ingredient of the second layer includes an HMG-CoA reductase inhibitor,
Pharmaceutical combination preparation.
상기 제2 층의 유효성분은
암로디핀, 이의 약제학적으로 허용 가능한 염 또는 이의 수화물;
아토바스타틴, 이의 약제학적으로 허용 가능한 염 또는 이의 수화물; 및
히드로클로로티아지드, 이의 약제학적으로 허용 가능한 염 또는 이의 수화물로 이루어진 군으로부터 선택된 적어도 어느 하나를 포함하는 것인,
약학적 복합 제제.According to claim 1,
The active ingredient of the second layer is
amlodipine, a pharmaceutically acceptable salt thereof or a hydrate thereof;
atorvastatin, a pharmaceutically acceptable salt thereof or a hydrate thereof; and
It contains at least one selected from the group consisting of hydrochlorothiazide, a pharmaceutically acceptable salt thereof, or a hydrate thereof,
Pharmaceutical combination preparation.
상기 제1 층의 첨가제는
붕해제, 결합제, 부형제, 활택제, 코팅제 및 이들의 혼합물 중 적어도 어느 하나를 포함하는 것인,
약학적 복합 제제.According to claim 1,
The additive of the first layer is
Which includes at least one of a disintegrant, a binder, an excipient, a lubricant, a coating agent, and mixtures thereof,
Pharmaceutical combination preparation.
상기 제1 층의 첨가제는
크로스카멜로오스나트륨, 크로스포비돈, 전분글리콜산나트륨, 전호화전분 및 저치환도 히드록시프로필셀룰로오스로 이루어진 군으로부터 선택된 적어도 어느 하나를 포함하는 것인,
약학적 복합 제제.According to claim 1,
The additive of the first layer is
Containing at least one selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized starch and low-substituted hydroxypropyl cellulose,
Pharmaceutical combination preparation.
상기 제1 층의 붕해 시간은 2분 이상 7분 15초 미만이고,
상기 제2 층의 붕해 시간은 15초 이상 30초 이하인 것인,
약학적 복합 제제.According to claim 1,
The disintegration time of the first layer is 2 minutes or more and less than 7 minutes 15 seconds,
The disintegration time of the second layer is 15 seconds or more and 30 seconds or less,
Pharmaceutical combination preparation.
암로디핀, 이의 약제학적으로 허용 가능한 염 또는 이의 수화물, 히드로클로로티아지드, 이의 약제학적으로 허용 가능한 염 또는 이의 수화물 및 첨가제를 포함하는 제2 층을 포함하고,
상기 제1 층과 제2 층의 붕해 시간의 차이가 1분 30초 이상 7분 미만인,
약학적 복합 제제.A first layer containing fimasartan, a pharmaceutically acceptable salt thereof, a solvate thereof or a hydrate thereof, and an additive as an active ingredient; and
a second layer comprising amlodipine, a pharmaceutically acceptable salt thereof or a hydrate thereof, hydrochlorothiazide, a pharmaceutically acceptable salt or hydrate thereof, and an additive;
The difference between the disintegration time of the first layer and the second layer is 1 minute 30 seconds or more and less than 7 minutes,
Pharmaceutical combination preparation.
아토바스타틴, 이의 약제학적으로 허용 가능한 염 또는 이의 수화물 및 첨가제를 포함하는 제2 층을 포함하고,
상기 제1 층과 제2 층의 붕해 시간의 차이가 1분 30초 이상 7분 미만인,
약학적 복합 제제.A first layer containing fimasartan, a pharmaceutically acceptable salt thereof, a solvate thereof or a hydrate thereof, and an additive as an active ingredient; and
a second layer comprising atorvastatin, a pharmaceutically acceptable salt thereof or a hydrate thereof, and an additive;
The difference between the disintegration time of the first layer and the second layer is 1 minute 30 seconds or more and less than 7 minutes,
Pharmaceutical combination preparation.
(b) 적어도 1 이상의 유효성분 및 첨가제를 혼합하여 제2 혼합물을 제조하는 단계; 및
(c) 상기 제1 혼합물과 상기 제2 혼합물을 타정하여 복합 제제를 제조하는 단계를 포함하고,
상기 복합 제제는 상기 제1 혼합물을 포함하는 제1 층과 상기 제2 혼합물을 포함하는 제2 층을 포함하며,
상기 제1 층과 상기 제2 층의 붕해 시간의 차이가 1분 30초 이상 7분 미만인 것인,
약학적 복합 제제의 제조 방법.(a) preparing a first mixture by mixing fimasartan, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof, and an additive;
(b) preparing a second mixture by mixing at least one active ingredient and an additive; and
(c) preparing a composite formulation by tableting the first mixture and the second mixture,
The combined formulation includes a first layer containing the first mixture and a second layer containing the second mixture,
The difference between the disintegration time of the first layer and the second layer is 1 minute 30 seconds or more and less than 7 minutes,
A method for preparing a pharmaceutical combination formulation.
상기 제2 층은 암로디핀 베실산염 및 히드로클로로티아지드를 포함하는,
약학적 복합 제제.According to claim 8
The second layer comprises amlodipine besylate and hydrochlorothiazide,
Pharmaceutical combination preparation.
상기 제1 층은 피마살탄칼륨 삼수화물을 포함하는, 약학적 복합 제제.According to claim 8
Wherein the first layer comprises fimasartan potassium trihydrate.
상기 제1 층의 첨가제는
크로스카멜로오스나트륨, 크로스포비돈, 전분글리콜산나트륨, 전호화전분 및 저치환도 히드록시프로필셀룰로오스로 이루어진 군으로부터 선택된 적어도 어느 하나를 포함하는 것인,
약학적 복합 제제.According to claim 8,
The additive of the first layer is
Containing at least one selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, pregelatinized starch and low-substituted hydroxypropyl cellulose,
Pharmaceutical combination preparation.
상기 제1 층의 붕해 시간은 2분 이상 7분 15초 미만이고,
상기 제2 층의 붕해 시간은 15초 이상 30초 이하인 것인,
약학적 복합 제제.According to claim 8,
The disintegration time of the first layer is 2 minutes or more and less than 7 minutes 15 seconds,
The disintegration time of the second layer is 15 seconds or more and 30 seconds or less,
Pharmaceutical combination preparation.
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