KR101220829B1 - Sustained-release tablet containing trimebutine - Google Patents
Sustained-release tablet containing trimebutine Download PDFInfo
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- KR101220829B1 KR101220829B1 KR1020100069014A KR20100069014A KR101220829B1 KR 101220829 B1 KR101220829 B1 KR 101220829B1 KR 1020100069014 A KR1020100069014 A KR 1020100069014A KR 20100069014 A KR20100069014 A KR 20100069014A KR 101220829 B1 KR101220829 B1 KR 101220829B1
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- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 26
- LORDFXWUHHSAQU-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid [2-(dimethylamino)-2-phenylbutyl] ester Chemical compound C=1C=CC=CC=1C(CC)(N(C)C)COC(=O)C1=CC(OC)=C(OC)C(OC)=C1 LORDFXWUHHSAQU-UHFFFAOYSA-N 0.000 title description 3
- 229960005345 trimebutine Drugs 0.000 title description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 23
- 239000004480 active ingredient Substances 0.000 claims abstract description 9
- 238000013268 sustained release Methods 0.000 claims abstract description 8
- 239000012730 sustained-release form Substances 0.000 claims abstract description 8
- 239000010410 layer Substances 0.000 claims description 60
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 39
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 27
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 24
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 24
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 22
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 22
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 22
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 22
- 239000011976 maleic acid Substances 0.000 claims description 22
- 239000003826 tablet Substances 0.000 claims description 22
- 229960003943 hypromellose Drugs 0.000 claims description 21
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 12
- 239000001530 fumaric acid Substances 0.000 claims description 12
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 12
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 12
- 235000019359 magnesium stearate Nutrition 0.000 claims description 12
- 239000003086 colorant Substances 0.000 claims description 8
- 239000007888 film coating Substances 0.000 claims description 8
- 238000009501 film coating Methods 0.000 claims description 8
- 239000004793 Polystyrene Substances 0.000 claims description 3
- 229920002223 polystyrene Polymers 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 9
- 238000004090 dissolution Methods 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000007922 dissolution test Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000013065 commercial product Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000004513 sizing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 229920003156 Eudragit® RL PO Polymers 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- YYRMJZQKEFZXMX-UHFFFAOYSA-L calcium bis(dihydrogenphosphate) Chemical compound [Ca+2].OP(O)([O-])=O.OP(O)([O-])=O YYRMJZQKEFZXMX-UHFFFAOYSA-L 0.000 description 1
- 229940062672 calcium dihydrogen phosphate Drugs 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000019691 monocalcium phosphate Nutrition 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—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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- Life Sciences & Earth Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Emergency Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
Abstract
본 발명은 트리메부틴 함유 서방성 정제에 관한 것으로서, 좀더 상세하게는 서로 인접한 상층부와 하층부의 이층 구조로 이루어지며, 상기 상층부와 하층부에는 각각 유효성분과 친수성 서방기제인 폴리에칠렌옥시드가 포함되어 있어서, 제조과정에서 경도저하 또는 타정장애와 같은 문제점이 발생하지 않고, 나아가 용출패턴이 매우 우수한 트리메부틴 함유 서방성 정제에 관한 것이다. The present invention relates to a trimebutin-containing sustained-release tablet, and more specifically, it consists of a two-layer structure of the upper layer and the lower layer adjacent to each other, wherein the upper layer and the lower layer include an active ingredient and a hydrophilic sustained-release polyethylene oxide, respectively, There is no problem such as hardness decrease or tableting disorder in the process, and further relates to a trimebutin-containing sustained-release tablet having an excellent dissolution pattern.
Description
본 발명은 트리메부틴 함유 서방성 정제에 관한 것으로서, 좀더 상세하게는 서로 인접한 상층부와 하층부의 이층 구조로 이루어지며, 상기 상층부와 하층부에는 각각 유효성분과 친수성 서방기제인 폴리에칠렌옥시드가 포함되어 있어서, 제조과정에서 경도저하 또는 타정장애와 같은 문제점이 발생하지 않고, 나아가 용출패턴이 매우 우수한 트리메부틴 함유 서방성 정제에 관한 것이다.
The present invention relates to a trimebutin-containing sustained-release tablet, and more specifically, it consists of a two-layer structure of the upper layer and the lower layer adjacent to each other, wherein the upper layer and the lower layer include an active ingredient and a hydrophilic sustained-release polyethylene oxide, respectively, There is no problem such as hardness decrease or tableting disorder in the process, and further relates to a trimebutin-containing sustained-release tablet having an excellent dissolution pattern.
트리메부틴(Trimebutine), 즉 3, 4, 5-트리메톡시 벤조산 2-(디메틸아미노)-2-페닐부틸 에스테르(3, 4, 5-trimethoxy benzoic acid-2-dimethyl amino-2-phenybutyl ester) 및 그의 말레이트염은 소화에 관여하는 말초 엔세팔린성(Encephalinergic) 수용체에 작용하는 공지의 약물이다. Trimebutine, i.e. 3, 4, 5-trimethoxy benzoic acid 2- (dimethylamino) -2-phenylbutyl ester (3, 4, 5-trimethoxy benzoic acid-2-dimethyl amino-2-phenybutyl ester ) And its malate salts are known drugs that act on peripheral Encephalinergic receptors involved in digestion.
이러한 트리메부틴은 그 자체나 말레인산과의 염 형태로서, 복통이나 소화불량, 구역, 구토와 같은 소화기능 이상이나, 과민성 대장증후군 및 변비나 설사와 같은 비감염성 위장관 장애의 치료에 사용되며, 정제, 주사제, 좌약 형태 및 경구 투여용 현탁액으로 제조, 판매되고 있다.
This trimebuterine is itself or in the form of a salt with maleic acid, and is used for the treatment of digestive problems such as abdominal pain, indigestion, nausea and vomiting, or irritable bowel syndrome and non-infectious gastrointestinal disorders such as constipation or diarrhea. , In the form of injections, suppositories, and suspensions for oral administration.
종래에 알려진 트리메부틴의 서방성 정제에 대한 기술들을 살펴보면, 예컨대, 국내 등록특허 제0539642호(등록일자; 2005.12.22)에는 30~60 중량%의 트리메부틴 말레에이트와, 코어를 제조하는데 적절한 캐리어 및 유효성분의 방출을 향상시키는 캐리어를 함유하는 코어, 그리고 코어의 붕해 및 유효성분의 조기방출을 방지하는데 충분히 효과적인 수용성 임시 코팅을 포함하는 경구 투여용 트리메부틴 말레에이트 정제가 소개되어 있다.Looking at conventionally known techniques for sustained-release tablets of trimebuterin, for example, in Korean Patent No. 0939642 (registration date; Dec. 22, 2005), 30-60% by weight of trimebuterin maleate, and to prepare a core Trimebutin maleate tablets for oral administration are introduced that include a core containing a carrier that enhances the release of an appropriate carrier and active ingredient, and a water-soluble temporary coating that is sufficiently effective to prevent disintegration of the core and premature release of the active ingredient. .
또한, 국내 등록특허 제0483716호(등록일자; 2005.04.08)에는 트리메부틴 또는 말레인산 트리메부틴 30～60 중량%와 유당 20～40 중량%, 인산일수소칼슘 0.1～10 중량%, 포비돈 K-30 0.1～10 중량%, 활택제, 부형제 및 서방화제로 유드라짓 RL-PO 5～25 중량%를 함유한 트리메부틴 또는 말레인산트리메부틴의 서방성 정제 조성물이 소개되어 있다.
In addition, Korean Patent No. 0483716 (registration date; 2005.04.08) has 30-60% by weight of trimebuterin or maleic acid trimerbutin, 20-40% by weight lactose, 0.1-10% by weight of calcium dihydrogen phosphate, povidone K A sustained-release tablet composition of trimebuterine or trimebuterine maleate containing 0.1-30% by weight of -30 and 5-25% of Eudragit RL-PO by lubricant, excipient and sustained-release agent is introduced.
그러나 상기와 같은 종래의 트리메부틴 함유 서방성 정제들은 과량의 서방화 기제를 과량으로 정제 하나의 무게가 700mg이 넘기 때문에 이를 환자들이 복용하기에는 너무 크다는 불편함이 있었다. However, such conventional trimebutin-containing sustained-release tablets have an inconvenience of being too large for patients to take since the weight of one tablet in excess of an excess sustained release mechanism is over 700 mg.
또한, 정제 타정시에 스티킹(sticking)과 같은 타정 장애가 발생하거나 타정된 정제의 경도가 너무 낮은 경우도 종종 발생하게 되는데, 이처럼 서방성 정제가 낮은 경도를 갖게 되면, 유효성분의 방출패턴이 과방출을 일으키는 등의 문제점을 야기하는 원인이 된다.
In addition, tableting disorders such as sticking occurs during tablet tableting or when the hardness of the tablet is too low. Often, when the sustained-release tablet has a low hardness, the release pattern of the active ingredient is excessive. This can cause problems such as causing an outflow.
이에 본 발명의 목적은 트리메부틴 또는 그 염류를 포함하는 서방성 정제에 있어서, 종래 기술의 문제점인 경도저하 및 타정장애와 같은 문제점을 해결함으로써 전반적인 제조공정이 간편하고 용이하며, 나아가 생체이용률은 종래의 정제와 동일하면서도 보다 안정적인 방출패턴을 나타내는 트리메부틴 함유 서방성 정제를 제공하는 것이다.Accordingly, an object of the present invention is to solve the problems such as hardness decrease and tableting disorder, which are problems of the prior art in sustained-release tablets containing trimebuterin or salts thereof, the overall manufacturing process is simple and easy, and further, the bioavailability is It is to provide a trimebutin-containing sustained-release tablet which is the same as a conventional tablet but exhibits a more stable release pattern.
본 발명이 해결하고자 하는 과제들을 보다 구체적으로 정리해 보면 다음과 같다.The problems to be solved by the present invention are summarized as follows.
첫째, 정제 하나의 무게가 500mg을 넘지 않도록 설계하여 환자들의 복용 편의성을 향상시키고자 한다.First, the weight of one tablet is designed not to exceed 500mg to improve the convenience of patients taking.
둘째, 친수성 서방기제인 폴리에칠렌옥시드를 사용하여 보다 새롭고 안전한 방출지연 효과를 얻고자 한다.Second, it is intended to obtain a new and safe release delay effect by using a hydrophilic sustained release polyethylene oxide.
셋째, 상층부와 하층부로 이루어진 이층 구조로서, 방출속도를 보다 안전하고 완벽하게 제어할 수 있는 서방출 정제를 구현하고자 한다.Third, as a two-layer structure consisting of the upper layer and the lower layer, it is intended to implement a slow release tablet that can more safely and completely control the release rate.
넷째, 타정 과정에서 나타나는 스티킹(sticking)이나 경도저하 등의 문제점을 해결하고자 한다.Fourth, to solve the problems such as sticking (sticking) or hardness decrease in the tableting process.
다섯째, 유효성분의 방출속도가 일정한 0차 반응속도를 유지하며, 동시에 생체 이용률은 적어도 기존 시판품과 동일하거나 기존 시판품 보다 우수한 서방성 정제를 구현하고자 한다.
Fifth, the release rate of the active ingredient is to maintain a constant zero-order reaction rate, while at the same time the bioavailability is to implement a sustained-release tablet at least the same as the conventional commercial product or superior to the conventional commercial product.
상기 과제를 달성하기 위하여 본 발명에 따른 트리메부틴 함유 서방성 정제는, 서로 인접한 상층부와 하층부 및 이들을 감싸는 필름코팅층으로 이루어지되 1정 중에 유효성분으로서 말레인산 트리메부틴 300mg을 포함하고 1정의 중량이 480~500mg 이며, 상기 상층부에는 말레인산트리메부틴 100~110 중량부와 폴리에칠렌옥시드 12~30 중량부, 히프로멜로오스 6~20 중량부가 포함되어 있고, 상기 하층부에는 말레인산 트리메부틴 190~200 중량부와 폴리에칠렌옥시드 25~55 중량부, 히프로멜로오스 10~35 중량부가 포함되어 있는 것을 특징으로 한다.In order to achieve the above object, the trimebutin-containing sustained-release tablet according to the present invention is composed of an upper layer and a lower layer adjacent to each other and a film coating layer surrounding them, and includes 300 mg of maleic acid trimerbutin as an active ingredient in one tablet and has a weight of one tablet. 480-500 mg, the upper layer contains 100 to 110 parts by weight of trimeric acid maleate, 12 to 30 parts by weight of polyethylene oxide, and 6 to 20 parts by weight of hypromellose, and the lower layer contains 190 to 200 maleic acid trimerbutin. It is characterized in that the weight part, 25 to 55 parts by weight of polyethylene oxide, 10 to 35 parts by weight of hypromellose is included.
또한, 본 발명에 따른 트리메부틴 함유 서방성 정제는, 말레인산트리메부틴 105mg, 히프로멜로오스 6.25~18.25 mg, 폴리에틸렌옥시드 15~27mg, 푸마르산 22.75mg, 히드록시프로필셀룰로오스 1.75mg, 스테아린산 마그네슘 7mg, 착색제 1mg으로 이루어진 상층부와; 말레인산트리메부틴 195mg, 히프로멜로오스 11.75~33.75mg, 폴리에틸렌옥시드 28~50mg, 푸마르산 42.25mg, 히드록시프로필셀룰로오스 3.25mg, 스테아린산마그네슘 13mg으로 이루어진 하층부와; 상기 상층부와 하층부를 함께 둘러싸는 필름코팅층; 으로 이루어진 것을 특징으로 한다.
In addition, the trimetabutin-containing sustained-release tablet according to the present invention is 105 mg of maleic acid trimebuterin, 6.25-18.25 mg of hypromellose, 15-27 mg of polyethylene oxide, 22.75 mg of fumaric acid, 1.75 mg of hydroxypropyl cellulose, magnesium stearate An upper layer composed of 7 mg and 1 mg of a coloring agent; Lower layer consisting of 195 mg of maleic acid trimebutin, 11.75 to 33.75 mg of hypromellose, 28 to 50 mg of polyethylene oxide, 42.25 mg of fumaric acid, 3.25 mg of hydroxypropyl cellulose, and 13 mg of magnesium stearate; A film coating layer surrounding the upper and lower layers together; Characterized in that consisting of.
본 발명에 따른 트리메부틴 함유 서방성 정제는 1일 2회 투여만으로도 1일 3회 또는 그 이상 투여해야 하는 기존 시판 정제와 동일한 약리효과를 나타내며, 동시에 정제 하나의 무게가 500mg 이하로 감소되어 있어서 환자들의 복약 순응도가 높은 효과가 있다. The trimebutin-containing sustained-release tablet according to the present invention exhibits the same pharmacological effect as conventional commercial tablets to be administered three or more times a day, even if administered twice a day, and at the same time, the weight of one tablet is reduced to 500 mg or less. Patients have high drug compliance.
또한, 종래에 트리메부틴 함유 정제를 제조하는 과정에서 나타나는 경도저하나 타정장애 등의 문제점을 해결함으로써 전반적인 제조공정이 용이하고, 특히 대량 생산에 적합한 효과가 있다.
In addition, the overall manufacturing process is easy by solving problems such as low hardness and tableting disorders that appear in the process of manufacturing a trimebuterin-containing tablet in the prior art, in particular, there is an effect suitable for mass production.
도 1은 본 발명에 따른 서방성 정제의 실물 사진이고,
도 2는 본 발명에 따른 서방성 정제에 대한 증류수에서의 용출 프로파일을 나타낸 그래프이다.1 is a real picture of the sustained-release tablet according to the invention,
Figure 2 is a graph showing the elution profile in distilled water for slow release tablets according to the present invention.
이하, 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.
본 발명에 따른 트리메부틴 함유 서방성 정제는 1정 중에 유효성분으로서 말레인산 트리메부틴 300mg을 포함하고, 전체 중량이 480~500mg 이며, 서로 인접한 상층부와 하층부 및 이들을 감싸는 필름코팅층으로 이루어진다.The trimebutin-containing sustained-release tablet according to the present invention contains 300 mg of maleic acid trimerbutin as an active ingredient in one tablet, and has a total weight of 480 to 500 mg, and includes an upper layer and a lower layer adjacent to each other and a film coating layer surrounding them.
그리고 상층부에는 상층부에는 말레인산트리메부틴 100~110 중량부와 폴리에칠렌옥시드 12~30 중량부, 히프로멜로오스 6~20 중량부가 포함되어 있고, 상기 하층부에는 말레인산 트리메부틴 190~200 중량부와 폴리에칠렌옥시드 25~55 중량부, 히프로멜로오스 10~35 중량부가 포함되어 있다. And in the upper part, the upper part contains 100 to 110 parts by weight of trimerbutane maleic acid, 12 to 30 parts by weight of polyethylene oxide, 6 to 20 parts by weight of hypromellose, and the lower layer is 190 to 200 parts by weight of maleic acid trimerbutin and 25 to 55 parts by weight of polyethylene oxide and 10 to 35 parts by weight of hypromellose are included.
본 발명에서‘히프로멜로스’는 ‘히드록시프로필메틸셀룰로오스’의 약칭이다. In the present invention, "hypromellose" is an abbreviation of "hydroxypropyl methyl cellulose."
상기 필름코팅층은 통상적인 코팅층과 동일한 것으로서, 히프로멜로오스와 폴리에틸렌글리콜로 이루어진다. 상기 필름코팅층의 중량은 상층부 및 하층부 중량에 대하여 2~3% 정도 되도록 도포하는 것이 바람직하다.
The film coating layer is the same as a conventional coating layer, it is made of hypromellose and polyethylene glycol. The weight of the film coating layer is preferably applied so as to about 2 to 3% with respect to the weight of the upper and lower layers.
본 발명에서 서방성 기제로 사용되는 폴리에칠렌옥시드(Polyethylene oxide)는 친수성 물질로서, 종래에 알려진 서방성 기제에 비하여 소량으로도 점도를 크게 향상시킬 수 있기 때문에 정제의 크기를 소형화 하는데 큰 역할을 한다. 또한, 스티킹(sticking)과 같은 타정장애를 줄이고, 정제의 경도를 향상시키는 매우 특징적인 기능을 가지고 있다. Polyethylene oxide (polyethylene oxide) used as a sustained release base in the present invention is a hydrophilic material, and can play a significant role in miniaturizing the tablet size because it can significantly improve the viscosity even in a small amount compared to conventionally known sustained release bases. . It also has a very characteristic function of reducing tableting disorders such as sticking and improving the hardness of tablets.
상기 폴리에칠렌옥시드로는 컬러콘(Colorcon)사가 판매중인 POLYOX(상품명)를 사용할 수 있고, 분자량에 따라 각각 서로 다른 점도를 갖는데, 본 발명에서는 분자량이 300,000 내지 7,000,000인 것을 사용하는 것이 바람직하다. The polyethylene oxide may be used POLYOX (trade name) sold by Colorcon (Colorcon), each having a different viscosity depending on the molecular weight, in the present invention, it is preferable to use a molecular weight of 300,000 to 7,000,000.
만일 분자량이 7,000,000 이상인 폴리에칠렌옥시드를 사용하면, 본 발명에서 얻고자 하는 용출패턴을 구현할 수 없고, 반대로 분자량이 300,000 미만인 폴리에칠렌옥시드를 사용하면, 원하는 점도를 얻기 위해 보다 많은 양의 폴리에칠렌옥시드를 사용해야 하기 때문에 결과적으로 정제 자체가 크기가 커지게 되어 종래의 트리메부틴 서방성 정제와 마찬가지로 환자의 복용에 불편을 초래할 수도 있다.
If a molecular weight of more than 7,000,000 polystyrene oxide is used, the elution pattern to be obtained in the present invention cannot be realized. On the contrary, if a molecular weight of less than 300,000 polypropylene oxide is used, a higher amount of polyethylene oxide may be used to obtain a desired viscosity. As a result, the tablet itself becomes larger in size, which may cause inconvenience to the patient as with conventional trimebuterine sustained release tablets.
본 발명에서는 상층부와 하층부의 이중층 구조를 형성하기 위하여 다층 타정기를 이용하여 타정한다. 이때, 상층부와 하층부 중 적어도 어느 한쪽에는 도 1에서 보는 바와 같이 착색제를 첨가하여 상층부와 하층부가 육안으로 쉽게 구별되도록 구성하는 것이 바람직하다. In the present invention, in order to form a double layer structure of the upper layer portion and the lower layer portion is compressed using a multilayer tablet press. In this case, it is preferable to configure the upper layer and the lower layer to be easily distinguished by the naked eye by adding a colorant to at least one of the upper and lower layers as shown in FIG. 1.
이처럼 본 발명에 따른 서방성 정제는 상층부와 하층부의 이중층 구조로 형성되어 있어서 종래의 단일층 구조에 비하여 약물 방출을 좀더 안전하고 효과적으로 제어할 수 있다. As described above, the sustained-release tablet according to the present invention is formed in a double layer structure of the upper layer and the lower layer, and thus can more safely and effectively control drug release as compared to the conventional single layer structure.
또한, 상층부와 하층부의 색상을 서로 다르게 구성함으로써, 의사나 약사 또는 환자들에게 보다 우수한 심미감을 제공할 수 있다.
In addition, by differently configuring the color of the upper and lower layers, it is possible to provide a better aesthetic feeling to the doctor, pharmacist or patients.
이하, 본 발명에 대한 실시예를 들어보면 다음과 같다.Hereinafter, examples of the present invention will be described.
[실시예 1]Example 1
1) 상층부 조성물의 제조 : 상기 표 1에서 상층부의 조성비율에 따라 말레인산트리메부틴과 히프로멜로오스, 푸마르산을 혼합한 후, 여기에 히드록시프로필셀룰로오스와 착색제를 녹여 만든 결합제를 첨가하여 과립 공정 후 건조한다. 이어 정립 공정 후 폴리에칠렌옥시드를 혼합하고, 다시 스테아르산마그네슘을 첨가, 혼합하여 상층부 조성물을 제조한다.
1) Preparation of the upper layer composition: After mixing the maleic acid trimerbutin, hypromellose, and fumaric acid according to the composition ratio of the upper layer in Table 1, by adding a binder made by dissolving the hydroxypropyl cellulose and the colorant to the granulation process After drying. Next, after the sizing process, the polyethylene oxide is mixed, and magnesium stearate is further added and mixed to prepare an upper layer composition.
2) 하층부 조성물의 제조 : 상기 표 1에서 하층부의 조성비율에 따라 말레인산트리메부틴과 히프로멜로오스, 푸마르산을 혼합한 후, 여기에 히드록시프로필셀룰로오스를 녹여 만든 결합제를 첨가하여 과립공정 후 건조한다. 이어 정립 공정 후 폴리에칠렌옥시드를 혼합하고, 다시 스테아르산마그네슘을 첨가, 혼합하여 상층부 조성물을 제조한다.
2) Preparation of the lower layer composition: After mixing the maleic acid trimerbutin, hypromellose, and fumaric acid according to the composition ratio of the lower layer in Table 1, and added to the binder made by dissolving hydroxypropyl cellulose to dry after granulation process do. Next, after the sizing process, the polyethylene oxide is mixed, and magnesium stearate is further added and mixed to prepare an upper layer composition.
3) 타정 및 코팅 : 다층 타정기로 상기 상층부 조성물과 하층부 조성물을 타정하여 상층부와 하층부를 형성하고, 여기에 통상적인 방법으로 히프로멜로오스와 폴리에틸렌글리콜을 도포하여 필름코팅층을 형성함으로써 정제 하나의 중량이 500 mg인 서방성 정제를 제조하였다.3) Tableting and coating: Tableting the upper layer composition and the lower layer composition with a multi-layer tablet press to form an upper layer and a lower layer, and by applying a hypromellose and polyethylene glycol in a conventional manner to form a film coating layer by weight of one tablet This 500 mg sustained release tablet was prepared.
[실시예 2] [Example 2]
상기 실시예 1과 동일한 방법으로 하되, 상층부와 하층부를 다음 표 2와 같은 조성비율로 구성하여 트리메부틴 함유 서방성 정제를 제조한다.In the same manner as in Example 1, the upper layer and the lower layer is composed of a composition ratio as shown in Table 2 below to prepare a trimebutin-containing sustained-release tablet.
[실시예 3] [Example 3]
상기 실시예 1과 동일한 방법으로 하되, 상층부와 하층부를 다음 표 2와 같은 조성비율로 구성하여 트리메부틴 함유 서방성 정제를 제조한다.In the same manner as in Example 1, the upper layer and the lower layer is composed of a composition ratio as shown in Table 2 below to prepare a trimebutin-containing sustained-release tablet.
[용출시험]Dissolution Test
상기 실시예 1 내지 실시예 3 에 따라 제조된 서방성 정제에 대하여 증류수 내에서 50rpm-패들 시험법으로 용출시험을 실시하고, 그 결과를 도 2에 그래프로 나타내었다.For the sustained release tablets prepared according to Examples 1 to 3 above, a dissolution test was carried out in 50 rpm paddle test in distilled water, and the results are shown graphically in FIG. 2.
첨부 도 2에서 보는 바와 같이, 본 발명에 따른 말레인산 함유 서방성 정제는 용출시험 후 8시간 동안 0차 반응속도를 유지하면서 매우 이상적인 방출패턴을 나타낸다는 것을 알 수 있다.As shown in FIG. 2, it can be seen that the maleic acid-containing sustained-release tablet according to the present invention exhibits a very ideal release pattern while maintaining a zero-order reaction rate for 8 hours after the dissolution test.
Claims (4)
상기 상층부에는 말레인산트리메부틴 100~110 중량부와 분자량이 300,000 내지 7,000,000인 폴리에칠렌옥시드 12~30 중량부, 히프로멜로오스 6~20 중량부가 포함되어 있고,
상기 하층부에는 말레인산 트리메부틴 190~200 중량부와 분자량이 300,000 내지 7,000,000인 폴리에칠렌옥시드 25~55 중량부, 히프로멜로오스 10~35 중량부가 포함되어 있는 것을 특징으로 하는 트리메부틴 함유 서방성 정제.
Consisting of the upper and lower layers adjacent to each other and the film coating layer surrounding them, which contains 300 mg of maleic acid trimethbutin as an active ingredient in one tablet, and the weight of one tablet is 480-500 mg,
The upper layer includes 100 to 110 parts by weight of trimerbutane maleate, 12 to 30 parts by weight of polystyrene oxide having a molecular weight of 300,000 to 7,000,000, 6 to 20 parts by weight of hypromellose,
The lower layer contains trimebutin-containing sustained-release, characterized in that 190 to 200 parts by weight of maleic acid trimerbutin, 25 to 55 parts by weight of polystyrene oxide having a molecular weight of 300,000 to 7,000,000, and 10 to 35 parts by weight of hypromellose. refine.
2. The sustained-release tablet containing trimebbutin according to claim 1, wherein at least one of the upper layer and the lower layer contains a colorant.
말레인산트리메부틴 195mg, 히프로멜로오스 11.75~33.75mg, 분자량이 300,000 내지 7,000,000인 폴리에틸렌옥시드 28~50mg, 푸마르산 42.25mg, 히드록시프로필셀룰로오스 3.25mg, 스테아린산마그네슘 13mg으로 이루어진 하층부와;
상기 상층부와 하층부를 함께 둘러싸는 필름코팅층; 으로 이루어진 것을 특징으로 하는 트리메부틴 함유 서방성 정제Upper layer consisting of 105 mg of maleic acid trimebuterin, 6.25-18.25 mg of hypromellose, 15-27 mg of polyethylene oxide having a molecular weight of 300,000 to 7,000,000, 22.75 mg of fumaric acid, 1.75 mg of hydroxypropyl cellulose, 7 mg of magnesium stearate, and 1 mg of a coloring agent;
A lower layer consisting of 195 mg of maleic acid trimebutin, 11.75 to 33.75 mg of hypromellose, 28 to 50 mg of polyethylene oxide having a molecular weight of 300,000 to 7,000,000, 42.25 mg of fumaric acid, 3.25 mg of hydroxypropyl cellulose, and 13 mg of magnesium stearate;
A film coating layer surrounding the upper and lower layers together; Trimebutin-containing sustained-release tablet, characterized in that consisting of
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| RU2536254C1 (en) * | 2013-11-26 | 2014-12-20 | Общество С Ограниченной Ответственностью "Валента-Интеллект" | Retard tablets of trimebutine |
| KR101679140B1 (en) | 2015-03-10 | 2016-11-25 | 경희대학교 산학협력단 | Palladium ion-specific DNA aptamer and a method for selecting the same |
| RU2706166C2 (en) * | 2017-11-20 | 2019-11-14 | Общество С Ограниченной Ответственностью "Валента - Интеллект" | Novel polymorphic forms of trimebutine maleate, method for production and use thereof |
| RU2770300C2 (en) * | 2019-10-17 | 2022-04-15 | Общество С Ограниченной Ответственностью "Валента - Интеллект" | New polymorphic forms of trimebutine maleate, method for production and application |
| RU2770301C2 (en) * | 2019-10-17 | 2022-04-15 | Общество С Ограниченной Ответственностью "Валента - Интеллект" | New polymorphic forms of trimebutine maleate, method for production and application |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005232185A (en) * | 2003-03-06 | 2005-09-02 | Astellas Pharma Inc | Medicinal composition for regulating release and process for producing the same |
| KR20100037737A (en) * | 2008-10-02 | 2010-04-12 | 한국유나이티드제약 주식회사 | Trimebutine slow -releasing tablet having improved releasing rate and convenience for internal use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2752162B1 (en) * | 1996-08-07 | 1998-11-06 | Jouveinal Lab | TRIMEBUTINE FILM MALEATE TABLET |
| KR100483716B1 (en) * | 2002-06-26 | 2005-04-18 | 한국유나이티드제약 주식회사 | Formulation of Trimebutine Sustained-release Tablets and its Manufacturing Method |
| JP5774853B2 (en) * | 2008-01-25 | 2015-09-09 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | Pharmaceutical dosage form |
| KR101048487B1 (en) * | 2008-08-19 | 2011-07-11 | 한국콜마 주식회사 | Trimebutin Maleic Acid |
-
2010
- 2010-07-16 KR KR1020100069014A patent/KR101220829B1/en active Active
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2011
- 2011-03-18 EA EA201390014A patent/EA023139B1/en unknown
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005232185A (en) * | 2003-03-06 | 2005-09-02 | Astellas Pharma Inc | Medicinal composition for regulating release and process for producing the same |
| KR20100037737A (en) * | 2008-10-02 | 2010-04-12 | 한국유나이티드제약 주식회사 | Trimebutine slow -releasing tablet having improved releasing rate and convenience for internal use |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2012008675A1 (en) | 2012-01-19 |
| EA201390014A1 (en) | 2013-12-30 |
| KR20120008262A (en) | 2012-01-30 |
| EA023139B1 (en) | 2016-04-29 |
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