WO2019240310A1 - Complex formulation comprising aceclofenac and esomeprazole and method of preparing same - Google Patents

Complex formulation comprising aceclofenac and esomeprazole and method of preparing same Download PDF

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Publication number
WO2019240310A1
WO2019240310A1 PCT/KR2018/006720 KR2018006720W WO2019240310A1 WO 2019240310 A1 WO2019240310 A1 WO 2019240310A1 KR 2018006720 W KR2018006720 W KR 2018006720W WO 2019240310 A1 WO2019240310 A1 WO 2019240310A1
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layer
active ingredient
tablet
aceclofenac
coating
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PCT/KR2018/006720
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French (fr)
Korean (ko)
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최연웅
장재상
이남송
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한국유나이티드제약 주식회사
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Publication of WO2019240310A1 publication Critical patent/WO2019240310A1/en

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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
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/435—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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to an anti-inflammatory analgesic agent aceclofenac and gastric acid secretion agent Someprazole two effective ingredients to minimize side effects and improve the convenience of the drug formulations and a preparation method thereof.
  • Nonsteroidal anti-inflammatory drugs are nonsteroidal anti-inflammatory drugs (NSAIDs), which are mainly used for symptoms such as rheumatoid arthritis, ankylosing spondylitis and osteoarthritis (degenerative arthritis).
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • Aceclofenac has a short duration of 0.5 ⁇ 2 hours in nonsteroidal anti-inflammatory analgesic drugs, and its effect lasts about 4 hours. Therefore, it is used for acute pain such as postoperative pain and toothache.
  • the present applicant has developed a bilayer tablet consisting of an immediate release layer for expressing the fast analgesic effect of aceclofenac and a sustained release layer for maintaining the anti-inflammatory analgesic effect for a long time (Korean Patent No. 1234254). Has released a new improved drug.
  • Clanza CR tablet is a double-layer tablet structure of the immediate release layer and the sustained release layer that maintains the anti-inflammatory analgesic effect for a long time. By improving the patient's ease of taking it.
  • aceclofenac may cause side effects such as gastrointestinal disorders, gastric pain, gastritis and reflux esophagitis in long-term prescription, which are general side effects of nonsteroidal analgesics.
  • side effects such as gastrointestinal disorders, gastric pain, gastritis and reflux esophagitis in long-term prescription, which are general side effects of nonsteroidal analgesics.
  • side effects such as gastrointestinal disorders, gastric pain, gastritis and reflux esophagitis in long-term prescription, which are general side effects of nonsteroidal analgesics.
  • side effects such as gastrointestinal disorders, gastric pain, gastritis and reflux esophagitis in long-term prescription, which are general side effects of nonsteroidal analgesics.
  • non-steroidal analgesics In the United States, there are 70,000 cases of gastrointestinal side effects caused by non-steroidal analgesics and about 7,000 deaths from gastrointestinal side effects.
  • NSAIDs inhibit the action of cyclooxygenase enzymes, which induce the synthesis of prostaglandins that are involved in gastric acid secretion of gastric mucosa. Excessive secretion of gastric acid in the gastrointestinal tract continues to occur, such as non-ulcer dyspepsia, peptic ulcer, Solinger syndrome, and reflux esophagitis.
  • PPI Proton Pump Inhibitors
  • the present inventors have invented a complex formulation of aceclofenac and eomeprazole.
  • a capsule, a two-layer tablet, a coated tablet, a nucleated tablet, and the like are known as a single-part composite formulation using two active ingredients.
  • the formulations have the following problems.
  • the tablets or granules are filled into the soft capsules, and the sufficient active ingredient content to exhibit pharmacological activity was not obtained due to the limitation of the capsule size.
  • the active ingredient of esomeprazole can be dissolved in a coating liquid and coated on a tablet containing aceclofenac, but the yield is low in the preliminary preparation step and the coating liquid manufacturing step due to the coating, which exceeds 20-40% of the active ingredient. It should be put in, and the content was not uniform problem appeared.
  • Nucleated tablets are prepared by the tableting method of the core-shell structure, and have the advantage of uniformly adjusting the content and relatively easy to separate coating, but the size of the shell portion is exponentially proportional to the active ingredient content and size of the core. Will increase. Therefore, in order to achieve an excellent pharmacological effect while preparing an effective amount of aceclofenac and esomeprazole in order to prevent side effects, there is a problem that the formulation size becomes very large so that oral administration is difficult.
  • the preparation of the aceclofenac and esomeprazole combination formulations according to the present invention is not preferable due to technical and economic factors. Accordingly, the present inventors have studied and invented a multi-layered tablet formulation having excellent long-term stability while exhibiting excellent pharmacological effects, including an inert layer and a protective coating layer, which prevent the interaction and stability deterioration between two components.
  • the present invention is an oral administration co-formulation comprising aceclofenac and eomeprazole, a multi-layered tablet formulation overcoming the disadvantages of conventional formulations by forming an inert layer, characterized by having excellent pharmacological effects and long-term stability.
  • the present invention comprises a first active ingredient layer containing aceclofenac or a pharmaceutically acceptable salt thereof; A second active ingredient layer containing esomeprazole or a pharmaceutically acceptable salt thereof; And it provides an oral administration multi-layered tablet combination comprising an inert layer containing no active ingredient.
  • the inactive layer is formed between the first active ingredient layer and the second active ingredient layer, and prevents the modification of the active ingredient due to physical contact between the first active ingredient layer and the second active ingredient side, the present multilayer Tablet formulations have superior long-term stability compared to other conventional formulations containing similar active ingredients.
  • the formulation according to the present invention is a three-layer tablet consisting of a first active ingredient layer, an inactive layer and a second active ingredient layer. It is important to adjust the weight ratio of each layer preferably in order to ensure stability in the three-layer tableting, the total weight of the first active ingredient layer is 80 to 120% by weight relative to the total weight of the inactive layer, When the total weight of the active ingredient layer is 80 to 120% by weight, the tableting property was good, and the hardness and stability in long-term storage were also excellent.
  • the first active ingredient layer of the multi-layered tablet composite preparation of the present invention comprises 40 to 60 wt% of aceclofenac and its pharmaceutically acceptable salts based on the total weight of the first active ingredient layer, and the second active ingredient layer Silver, based on the total weight of the second active ingredient layer may comprise 5 to 20% by weight of esomeprazole and its pharmaceutically acceptable salts.
  • the amount of the active ingredient is less than the range, the pharmacological activity by aceclofenac or the side effect prevention effect by esomeprazole may be reduced, when the content exceeds the above range, side effects of gastrointestinal diseases or indigestion may occur.
  • the second active ingredient layer may include 5 to 20 wt% stabilizer, 6 to 10 wt% binder, and 1 to 5 wt% disintegrant based on the total weight of the second active ingredient layer.
  • Multi-layered tablet composite preparation according to the present invention comprises a binder in order to improve granule flowability during tableting by wet granulation method.
  • the binder is in the above range, the flowability is most favorable.
  • the binder is less than the above range, the flowability is poor, and when the binder is exceeded, the release effect after oral administration may be reduced.
  • the disintegrant is to prevent the release inhibition that may occur as a binder is optimized according to the content of the binder. Therefore, the release effect may be lowered if the disintegrant is less than the above range, the stability of the tablet may be lowered if it exceeds the above range.
  • the stabilizer is intended to prevent the destabilization of the relatively unstable second active ingredient, if less than the above-mentioned range, long-term preservation is inferior, and even if more than the above range does not appear to have a significant effect, the economy is inferior.
  • the stabilizer may include one or two selected from the group consisting of L-arginine, calcium hydrogen phosphate dihydrate, and the active ingredient included in the second active ingredient layer is vulnerable to acids. Since it has a relatively good stability when using calcium hydrogen phosphate dihydrate that can act as a relatively alkalizing agent.
  • the active ingredient of the second active ingredient layer may include esomeprazole or a pharmaceutically acceptable salt thereof, and in particular, the use of esopeprazole magnesium trihydrate exhibits excellent effects and facilitates supply of materials. Preferred for production in large quantities.
  • the total weight of the inactive layer is preferably 150 to 300mg, the weight of each active ingredient layer is adjusted according to the weight of the inactive layer, the smaller the weight of the inactive layer, the smaller the size of the entire formulation, so Will increase.
  • the weight of the inactive layer is preferably at least 150 mg or more.
  • the total weight of the inert layer exceeds 300mg, the dosage form is too large, and the convenience of medication is lowered, and the economical efficiency is lowered because the input amount of the material is increased and the tableting process is lengthened.
  • the inert layer may include one or two selected from the group consisting of microcrystalline cellulose, hydroxypropyl methyl cellulose, by mixing a relatively small amount of hydroxypropyl methyl cellulose rather than using microcrystalline cellulose alone When used, a more preferable effect is obtained.
  • the inactive layer may include 80 to 99% by weight of microcrystalline cellulose and 1 to 20% by weight of hydroxypropylmethylcellulose based on the total weight of the inactive layer.
  • the orally administered multi-layered tablet complex preparations include a first coating layer formed by coating a coating solution containing a non-acidic coating agent on the oral-administered multi-layered tablet composite formulation; And a second coating layer formed by coating a coating solution containing a moisture barrier coating base on the first coating layer. Since the active ingredient of the second active ingredient layer is easily denatured by an acid, the first coating layer which is in direct contact with the multi-layered tablet complex preparation is made of a non-acidic coating base. On the coating layer may be formed a second coating layer made of a moisture barrier coating base to prevent the penetration of moisture.
  • the non-acidic coating base of the first coating layer may include hydroxypropylmethylcellulose, and corresponds to a sub-coating that blocks the contact between the second coating layer and the tablet so that the moisture barrier coating base component does not affect the tablet. do.
  • the moisture barrier coating base of the second coating layer may be selected from commercially known coating bases, but it is preferable to use a coating base containing no stearic acid component.
  • a coating base containing no stearic acid component As a result of the applicant's experiment, when the coating base containing stearic acid is used in the second coating layer, the tablet is partially blacked and the flexible material is generated despite the first coating layer blocking the contact between the tablet and the second coating layer. Was observed.
  • the moisture barrier coating base includes polyvinyl alcohol and hydroxypropyl methyl cellulose as the main component, and preferably includes one or two polymer substances as the main component.
  • the multi-layered tablet complex preparation according to the present invention comprises a first active ingredient layer containing aceclobenac or a pharmaceutically acceptable salt thereof, a second active ingredient layer and an active ingredient containing esomeprazole or a pharmaceutically acceptable salt thereof.
  • an inert layer that does not contain, due to the structure in which the first active ingredient layer and the second active ingredient layer are separated from each other by the inactive layer it is possible to prevent denaturation and decrease in content due to physical contact between the active ingredients. have.
  • by further forming a coating layer to block external moisture on the outside of the tablet it is characterized by ensuring long-term stability.
  • the first active ingredient layer according to the present invention is aceclofenac, an excipient microcrystalline cellulose and a disintegrant croscarmellose sodium 10-20 minutes in a speed mixer, and then mixed several times with the addition of the fed solution Can be prepared.
  • the association is postmixed with lubricant, disintegrant.
  • the postmixed mixture is mixed in a drum mixer to prepare final granules of the first active ingredient layer.
  • the second active ingredient layer according to the present invention contains an active ingredient, e. Smefra or a pharmaceutically acceptable salt thereof, and after mixing someprazole magnesium, an excipient microcrystalline cellulose, and a stabilizer, several times while adding an association solution Mix over to prepare the union.
  • an active ingredient e. Smefra or a pharmaceutically acceptable salt thereof
  • the association is dried in a dryer.
  • the dry matter is mixed with a lubricant and then mixed with a binder and a disintegrant.
  • the post-mixture prepares the final granules of the second active ingredient layer.
  • the inert layer according to the present invention is prepared by adding the fed solution to the excipient microcrystalline cellulose.
  • the union is dried to produce the final granules.
  • the first active ingredient layer granules, the second active ingredient layer granules and the granules of the inactive layer are compressed while applying pressure.
  • the tableted uncoated tablet is separated using a tablet debranching, and then coated with the three-layer uncoated tablet with a coating base containing glycerin using a coater.
  • the primary coating tablet is coated with a waterproof coating base such as a coating base including polyvinyl alcohol using a coating machine to prepare a coated triple layer composite formulation.
  • a waterproof coating base such as a coating base including polyvinyl alcohol

Abstract

The present invention relates to a complex formulation which comprises two active ingredients, Aceclofenac, an anti-inflammatory painkiller, and Esomeprazole, a proton-pump inhibitor, thereby minimizing the side effects caused by Aceclofenac while improving medication adherence and stability, and to a method of preparing same. A multilayered tablet complex formulation according to the present invention comprises a first active ingredient layer containing Aceclofenac or a pharmaceutically acceptable salt thereof, a second active ingredient layer containing Esomeprazole or a pharmaceutically acceptable salt thereof, and an inert layer not containing any active ingredient, wherein the structure in which the first active ingredient layer and the second active ingredient layer are separated from each other by the inert layer can prevent degradation and content loss attributable to the respective active ingredients being in physical contact with each other. Furthermore, the multilayered tablet complex formulation may further include a coating layer blocking external moisture on the outside of a tablet, thereby exhibiting excellent long-term stability.

Description

아세클로페낙과 에스오메프라졸을 포함하는 복합제제 및 그 제조방법Complex preparation containing aceclofenac and eomeprazole and preparation method thereof
본 발명은 소염진통제인 아세클로페낙과 위산분비 억제제인 에스오메프라졸 두 가지 유효성분을 함유하여 부작용을 최소화 시키고 복약편의성을 개선한 복합제제 및 그 제조방법에 관한 것이다.The present invention relates to an anti-inflammatory analgesic agent aceclofenac and gastric acid secretion agent Someprazole two effective ingredients to minimize side effects and improve the convenience of the drug formulations and a preparation method thereof.
비스테로이드성 소염 진통제(NSAIDs, 아세클로페낙(Aceclofenac)은 비스테로이드성 소염 진통제(NSAIDs, Non-steroidal anti-inflammatory drugs)로서 류마티스관절염, 강직척추염, 골관절염(퇴행관절염) 등의 증상에 주로 사용된다. 특히 아세클로페낙은 비스테로이드성 소염 진통제 계열 약물 중에서도 진통효과 발현시간이 0.5 내지 2 시간으로 짧은 편이며, 작용 효과가 4시간 정도 지속되므로, 수술 후 통증, 치통 등 급성 통증의 완화에도 사용되는 등 적용 영역이 넓어 시장성이 우수하다.Nonsteroidal anti-inflammatory drugs (NSAIDs, Aceclofenac) are nonsteroidal anti-inflammatory drugs (NSAIDs), which are mainly used for symptoms such as rheumatoid arthritis, ankylosing spondylitis and osteoarthritis (degenerative arthritis). Aceclofenac has a short duration of 0.5 ~ 2 hours in nonsteroidal anti-inflammatory analgesic drugs, and its effect lasts about 4 hours. Therefore, it is used for acute pain such as postoperative pain and toothache. Wide marketability
한편 본 출원인은 아세클로페낙의 빠른 진통효과 발현을 위한 속방층과 소염진통효과를 오랫동안 유지시키기 위한 서방층으로 구성된 이중층 정제를 개발하여(한국등록특허 제1234254호) “클란자 CR정”이라는 상품명으로 아세클로페낙의 개량신약을 출시한바 있다. 클란자CR정은 소염진통제에서 가장 중요시되는 빠른 진통 효과를 나타나기 위한 속방층과 소염진통 효과를 오랫동안 유지시키는 서방층의 이중층 정제 구조인데, 기존 1일 2회 용법의 아세클로페낙 제제를 1일 1회 용법으로 개선시켜 환자의 복용 편의성 향상시킨 것이다.On the other hand, the present applicant has developed a bilayer tablet consisting of an immediate release layer for expressing the fast analgesic effect of aceclofenac and a sustained release layer for maintaining the anti-inflammatory analgesic effect for a long time (Korean Patent No. 1234254). Has released a new improved drug. Clanza CR tablet is a double-layer tablet structure of the immediate release layer and the sustained release layer that maintains the anti-inflammatory analgesic effect for a long time. By improving the patient's ease of taking it.
그러나, 아세클로페낙은 장기 처방 시 위장관 장애, 위통, 위염, 역류성 식도염 등의 부작용이 발생할 수 있으며, 이는 비스테로이드성 진통제의 일반적인 부작용에 해당한다. 이와 관련하여 미국에서는 비스테로이드성 진통제의 위장관 부작용으로 인해 연간 7만 건의 환자가 발생하며, 위장관 부작용에 의한 사망자는 약 7천명에 달할 것이라는 조사 결과가 발표된 바 있다.However, aceclofenac may cause side effects such as gastrointestinal disorders, gastric pain, gastritis and reflux esophagitis in long-term prescription, which are general side effects of nonsteroidal analgesics. In the United States, there are 70,000 cases of gastrointestinal side effects caused by non-steroidal analgesics and about 7,000 deaths from gastrointestinal side effects.
비스테로이드성 소염진통제는 사이클로옥시게나아제 효소의 작용을 억제하는데, 상기 사이클로옥시게나아제 효소는 위점막 위산 분비에 관여하는 프로스타글란딘의 합성을 유도하는 것으로서, 비스테로이드성 소염진통제를 장기간 복용하는 경우, 위장관내에 위산이 과다하게 분비되는 상태가 지속되어 비궤양성 소화불량, 소화성 궤양, 졸링거 증후군, 역류성 식도염 등 발생하게 되는 것이다.NSAIDs inhibit the action of cyclooxygenase enzymes, which induce the synthesis of prostaglandins that are involved in gastric acid secretion of gastric mucosa. Excessive secretion of gastric acid in the gastrointestinal tract continues to occur, such as non-ulcer dyspepsia, peptic ulcer, Solinger syndrome, and reflux esophagitis.
따라서, 비스테로이드성 소염진통제의 장기 복용에 따른 부작용을 방지하기 위해서는 위산 분비의 급격한 증가를 원천적으로 차단하는 위산분비억제제(PPI, Proton Pump Inhibitors)를 병용 투여하는 것이 바람직하다. 현재 널리 사용되고 있는 프로톤펌프억제제(PPI)로는 오메프라졸, 란소프라졸, 라베프라졸, 판토프라졸, 에스오메프라졸 등이 있다. 이 중에서도 44명 환자를 대상으로 상기 유효성분의 표준용량을 투여해 위내 pH에서 24시간 동안 미치는 영향을 관찰한 결과 에스오메프라졸이 다른 프로톤펌프억제제에 비해 위 내 산도 조절에 효과적이라는 연구결과(AM J Gastroenterol 2003:98: 2016-20)가 있다. Therefore, in order to prevent the side effects of long-term administration of nonsteroidal anti-inflammatory drugs, it is preferable to co-administer PPI (Proton Pump Inhibitors) to block the rapid increase in gastric acid secretion. Proton pump inhibitors (PPI), which are widely used at present, include omeprazole, lansoprazole, rabeprazole, pantoprazole, and omeprazole. Among 44 patients, the standard dose of the active ingredient was observed for 24 hours at pH in the stomach, and the results showed that esomeprazole was more effective in controlling gastric acidity than other proton pump inhibitors (AM J Gastroenterol 2003: 98: 2016-20).
따라서, 비스테로이드성 소염진통제의 효과를 극대화하면서도, 그로 인한 부작용을 방지하기 위하여, 본 출원인들은 아세클로페낙과 에스오메프라졸의 복합 제형을 발명하게 되었다. Therefore, in order to maximize the effect of nonsteroidal anti-inflammatory drugs, and to prevent the side effects, the present inventors have invented a complex formulation of aceclofenac and eomeprazole.
두 가지 유효성분에 의한 복합제 단일제형으로는 일반적으로 캡슐제, 이층정제, 코팅정, 유핵정 등이 알려져 있으나, 본 출원인이 실험을 거듭한 결과 상기 제형들은 다음과 같은 문제점이 있는 것으로 나타났다.In general, a capsule, a two-layer tablet, a coated tablet, a nucleated tablet, and the like are known as a single-part composite formulation using two active ingredients. However, as a result of repeated experiments by the applicant, the formulations have the following problems.
캡슐제의 경우, 연질 캡슐 내부에 정제 또는 과립을 충전하게 되는데, 캡슐 크기의 제한으로 약리활성을 나타내기 충분한 유효성분 함량을 확보할 수 없었다.In the case of capsules, the tablets or granules are filled into the soft capsules, and the sufficient active ingredient content to exhibit pharmacological activity was not obtained due to the limitation of the capsule size.
이층정제의 경우, 아세클로페낙과 에스오메프라졸 유효성분의 상호작용으로 인하여, 유효성분을 포함한 각 층이 접촉하는 부분을 중심으로 유효성분이 급속히 변성되는 현상이 나타났다. 각 층을 보호층 성분으로 코팅하여도 타정 시 충격으로 인해 코팅층을 붕괴되어 의도하는 결과를 얻을 수 없었다.In the case of bilayer tablets, due to the interaction between aceclofenac and esomeprazole active ingredient, the active ingredient was rapidly denatured around the contact portion of each layer including the active ingredient. Even when each layer was coated with a protective layer component, the coating layer collapsed due to the impact during tableting, and thus the intended result was not obtained.
코팅정의 경우, 에스오메프라졸의 유효성분을 코팅액에 용해시켜 아세클로페낙을 포함하는 정제에 코팅시키는 제형이 가능하나, 코팅으로 인한 사전 준비단계 및 코팅액 제조단계에서 수율이 낮아 유효성분을 20~40% 이상 초과 투입하여야 하며, 함량도 균일하지 못한 문제가 나타났다.In the case of coated tablets, the active ingredient of esomeprazole can be dissolved in a coating liquid and coated on a tablet containing aceclofenac, but the yield is low in the preliminary preparation step and the coating liquid manufacturing step due to the coating, which exceeds 20-40% of the active ingredient. It should be put in, and the content was not uniform problem appeared.
유핵정은 코어-쉘 구조의 타정 방식으로 제조하는 제형으로서 함량을 균일하게 조절 가능하고 분리코팅이 비교적 용이하다는 장점이 있으나, 코어의 유효성분 함량 및 크기에 비례하여 쉘 부분의 크기가 기하급수적으로 늘어나게 된다. 따라서, 우수한 약리 효과를 달성하면서도 부작용을 방지하기 위해 유효한 함량의 아세클로페낙과 에스오메프라졸을 포함하여 제조하는 경우, 경구 투여가 어려울 정도로 제형 크기가 매우 커지는 문제가 있었다.Nucleated tablets are prepared by the tableting method of the core-shell structure, and have the advantage of uniformly adjusting the content and relatively easy to separate coating, but the size of the shell portion is exponentially proportional to the active ingredient content and size of the core. Will increase. Therefore, in order to achieve an excellent pharmacological effect while preparing an effective amount of aceclofenac and esomeprazole in order to prevent side effects, there is a problem that the formulation size becomes very large so that oral administration is difficult.
종래의 복합제 제형으로는 본 발명에 의한 아세클로페낙과 에스오메프라졸 복합제제를 제조하는 것이 기술적·경제적 요인으로 바람직하지 못한 것으로 나타났다. 따라서, 본 출원인은 연구를 거듭하여, 두 성분 간의 상호작용 및 안정성 저하 현상을 방지하는 비활성층과 보호코팅층을 포함하여, 우수한 약리효과를 발현하면서도 장기 안정성이 우수한 다층정 제형을 발명하였다.In the conventional combination formulation, it was found that the preparation of the aceclofenac and esomeprazole combination formulations according to the present invention is not preferable due to technical and economic factors. Accordingly, the present inventors have studied and invented a multi-layered tablet formulation having excellent long-term stability while exhibiting excellent pharmacological effects, including an inert layer and a protective coating layer, which prevent the interaction and stability deterioration between two components.
본 발명은 아세클로페낙과 에스오메프라졸을 포함하는 경구 투여 복합제제로서, 비활성층을 형성하여 종래 제형에 의한 단점을 극복한 다층정 제형으로, 우수한 약리 효과 및 장기 안정성을 가지는 것을 특징으로 한다.The present invention is an oral administration co-formulation comprising aceclofenac and eomeprazole, a multi-layered tablet formulation overcoming the disadvantages of conventional formulations by forming an inert layer, characterized by having excellent pharmacological effects and long-term stability.
본 발명은 아세클로페낙 또는 이의 약학적으로 허용가능한 염을 함유하는 제1유효성분층; 에스오메프라졸 또는 이의 약학적으로 허용가능한 염을 함유하는 제2유효성분층; 및 유효성분을 함유하지 않는 비활성층을 포함하는 경구 투여 다층정 복합제제를 제공한다. 상기 비활성층은 상기 제1유효성분층과 상기 제2유효성분층 사이에 형성되며, 상기 제1유효성분층과 제2유효성분 측의 물리적인 접촉으로 인한 유효성분의 변성을 방지하여, 본 다층정 제형은 유사한 유효성분을 포함하는 종래의 타 제형에 비하여 월등한 장기 안정성을 가진다.The present invention comprises a first active ingredient layer containing aceclofenac or a pharmaceutically acceptable salt thereof; A second active ingredient layer containing esomeprazole or a pharmaceutically acceptable salt thereof; And it provides an oral administration multi-layered tablet combination comprising an inert layer containing no active ingredient. The inactive layer is formed between the first active ingredient layer and the second active ingredient layer, and prevents the modification of the active ingredient due to physical contact between the first active ingredient layer and the second active ingredient side, the present multilayer Tablet formulations have superior long-term stability compared to other conventional formulations containing similar active ingredients.
상기한 바와 같이 본 발명에 의한 제형은 제1유효성분층, 비활성층 및 제2유효성분층으로 이루어진 3층정이다. 3층정 타정시 안정성을 확보하기 위해서는 각 층의 중량 비율을 바람직하게 조정하는 것이 중요한데, 상기 비활성층의 총 중량에 대하여, 상기 제1유효성분층의 총 중량이 80 내지 120중량%이고, 상기 제2유효성분층의 총 중량이 80 내지 120중량%인 경우, 타정성이 양호하였으며, 경도 및 장기 보존 시 안정성 또한 우수한 것으로 나타났다.As described above, the formulation according to the present invention is a three-layer tablet consisting of a first active ingredient layer, an inactive layer and a second active ingredient layer. It is important to adjust the weight ratio of each layer preferably in order to ensure stability in the three-layer tableting, the total weight of the first active ingredient layer is 80 to 120% by weight relative to the total weight of the inactive layer, When the total weight of the active ingredient layer is 80 to 120% by weight, the tableting property was good, and the hardness and stability in long-term storage were also excellent.
본 발명의 다층정 복합제제의 제1유효성분층은, 제1유효성분층의 총 중량을 기준으로 아세클로페낙 및 이의 약학적으로 허용가능한 염을 40 내지 60 중량% 포함하고, 상기 제2유효성분층은, 제2유효성분층의 총 중량을 기준으로 에스오메프라졸 및 이의 약학적으로 허용가능한 염을 5 내지 20중량% 포함할 수 있다.The first active ingredient layer of the multi-layered tablet composite preparation of the present invention comprises 40 to 60 wt% of aceclofenac and its pharmaceutically acceptable salts based on the total weight of the first active ingredient layer, and the second active ingredient layer Silver, based on the total weight of the second active ingredient layer may comprise 5 to 20% by weight of esomeprazole and its pharmaceutically acceptable salts.
상기 유효성분의 함량 범위 미만인 경우, 아세클로페낙에 의한 약리 활성 또는 에스오메프라졸에 의한 부작용 방지 효과가 저하될 수 있으며, 상기 함량 범위를 초과하는 경우, 위장관 질환이나 소화불량의 부작용이 발생할 수 있다.When the amount of the active ingredient is less than the range, the pharmacological activity by aceclofenac or the side effect prevention effect by esomeprazole may be reduced, when the content exceeds the above range, side effects of gastrointestinal diseases or indigestion may occur.
더욱 구체적으로 상기 제2유효성분층은, 제2유효성분층의 총 중량을 기준으로, 안정화제 5 내지 20 중량%, 결합제 6 내지 10중량%, 붕해제 1 내지 5중량% 포함할 수 있다.More specifically, the second active ingredient layer may include 5 to 20 wt% stabilizer, 6 to 10 wt% binder, and 1 to 5 wt% disintegrant based on the total weight of the second active ingredient layer.
본 발명에 의한 다층정 복합제제는 습식과립방법으로 타정 시 과립 흐름성을 양호하게 하기 위하여 결합제를 포함한다. 결합제는 상기 범위일 때 흐름성이 가장 양호하게 나타나며, 상기 범위 미만인 경우 흐름성이 나빠지고, 상기 범위를 초과하는 경우 경구 투여 후 방출 효과가 저하될 수 있다. Multi-layered tablet composite preparation according to the present invention comprises a binder in order to improve granule flowability during tableting by wet granulation method. When the binder is in the above range, the flowability is most favorable. When the binder is less than the above range, the flowability is poor, and when the binder is exceeded, the release effect after oral administration may be reduced.
상기 붕해제는 결합제로 발생할 수 있는 방출 억제를 방지하기 위한 것으로 결합제의 함량에 따라 최적화된 것이다. 따라서, 붕해제가 상기 범위 미만일 경우 방출 효과가 저하될 수 있으며, 상기 범위를 초과하는 경우에는 정제의 안정성이 떨어질 수 있다.The disintegrant is to prevent the release inhibition that may occur as a binder is optimized according to the content of the binder. Therefore, the release effect may be lowered if the disintegrant is less than the above range, the stability of the tablet may be lowered if it exceeds the above range.
상기 안정화제는 상대적으로 불안정한 제2유효성분의 변성을 방지하여 위한 것으로서 상기 범위 미만인 경우 장기 보존성이 떨어지며, 상기 범위를 초과하여 더 포함하여도 유의미한 효과는 나타나지 않으므로 경제성이 떨어지게 된다.The stabilizer is intended to prevent the destabilization of the relatively unstable second active ingredient, if less than the above-mentioned range, long-term preservation is inferior, and even if more than the above range does not appear to have a significant effect, the economy is inferior.
상기 안정화제는 L-아르기닌(L-arginine), 인산수소칼슘이수화물로 이루어진 군에서 선택된 1종 또는 2종을 포함하는 것이 사용될 수 있는데, 제2유효성분층에 포함된 유효성분이 산에 취약한 특성을 가지므로, 상대적으로 알칼리화제로 작용할 수 있는 인산수소칼슘이수화물을 사용할 경우 더욱 우수한 안정성을 가진다.The stabilizer may include one or two selected from the group consisting of L-arginine, calcium hydrogen phosphate dihydrate, and the active ingredient included in the second active ingredient layer is vulnerable to acids. Since it has a relatively good stability when using calcium hydrogen phosphate dihydrate that can act as a relatively alkalizing agent.
한편, 상기 제2유효성분층의 유효성분은 에스오메프라졸 또는 이의 약학적으로 허용가능한 염을 포함할 수 있으나, 특히 에스오페프라졸 마그네슘 삼수화물을 사용하는 것이 우수한 효과를 나타내면서도 재료 수급이 용이하여 대량으로 제조하기에 바람직하다.Meanwhile, the active ingredient of the second active ingredient layer may include esomeprazole or a pharmaceutically acceptable salt thereof, and in particular, the use of esopeprazole magnesium trihydrate exhibits excellent effects and facilitates supply of materials. Preferred for production in large quantities.
또한, 상기 비활성층의 총 중량은 150 내지 300mg인 것이 바람직한데, 비활성층의 중량에 따라 각 유효성분층의 중량이 조절되므로, 비활성층의 중량이 적을 수록 전체 제형의 크기가 작아져 복약편의성이 증가하게 된다. 그러나, 비활성층 총 중량이 150mg 미만인 경우 본 발명에 의한 삼층정 타정 시 비활성층이 붕괴되는 문제가 발생할 수 있다. 따라서, 비활성층의 중량은 최소 150mg 이상인 것이 바람직하다. 또한 비활성층 총 중량이 300mg을 초과하는 경우에는 제형이 지나치게 커져 복약편의성이 저하되며, 재료의 투입량이 늘고 타정 공정도 길어지므로 경제성이 떨어진다. In addition, the total weight of the inactive layer is preferably 150 to 300mg, the weight of each active ingredient layer is adjusted according to the weight of the inactive layer, the smaller the weight of the inactive layer, the smaller the size of the entire formulation, so Will increase. However, when the total weight of the inert layer is less than 150 mg, a problem may occur that the inactive layer collapses when tableting tablets according to the present invention. Therefore, the weight of the inactive layer is preferably at least 150 mg or more. In addition, when the total weight of the inert layer exceeds 300mg, the dosage form is too large, and the convenience of medication is lowered, and the economical efficiency is lowered because the input amount of the material is increased and the tableting process is lengthened.
한편, 상기 비활성층은 미결정셀룰로오스, 하이드록시프로필메틸셀룰로오스로 이루어진 군으로부터 선택된 1종 또는 2종을 포함할 수 있는데, 미결정셀룰로오스를 단독으로 사용하는 것보다 하이드록시프로필메틸셀룰로오스를 상대적으로 소량 혼합하여 사용하는 경우 더욱 바람직한 효과가 나타난다. 이에 따라 상기 비활성층은 비활성층 총 중량을 기준으로 미결정셀룰로오스 80 내지 99 중량%, 하이드록시프로필메틸셀룰로오스 1 ~ 20% 중량%를 포함할 수 있다.On the other hand, the inert layer may include one or two selected from the group consisting of microcrystalline cellulose, hydroxypropyl methyl cellulose, by mixing a relatively small amount of hydroxypropyl methyl cellulose rather than using microcrystalline cellulose alone When used, a more preferable effect is obtained. Accordingly, the inactive layer may include 80 to 99% by weight of microcrystalline cellulose and 1 to 20% by weight of hydroxypropylmethylcellulose based on the total weight of the inactive layer.
한편, 상기 경구 투여 다층정 복합제제는 비산성(non-acidic) 코팅기제를 함유하는 코팅액을 상기 경구 투여 다층정 복합제제 상에 코팅하여 형성된 제1코팅층; 및 수분차단성 코팅기제를 함유하는 코팅액을 상기 제1코팅층 상에 코팅하여 형성된 제2코팅층;을 추가로 포함할 수 있다. 상기 제2유효성분층의 유효성분은 산에 의하여 쉽게 변성되는 성질을 갖고 있으므로, 상기 다층정 복합제제와 직접 접촉하는 제1코팅층은 비산성(non-acidic) 성분의 코팅기제로 이루어지며, 제1코팅층 상에는 수분의 침투를 방지하는 수분차단성 코팅기제로 이루어진 제2코팅층이 형성될 수 있다.On the other hand, the orally administered multi-layered tablet complex preparations include a first coating layer formed by coating a coating solution containing a non-acidic coating agent on the oral-administered multi-layered tablet composite formulation; And a second coating layer formed by coating a coating solution containing a moisture barrier coating base on the first coating layer. Since the active ingredient of the second active ingredient layer is easily denatured by an acid, the first coating layer which is in direct contact with the multi-layered tablet complex preparation is made of a non-acidic coating base. On the coating layer may be formed a second coating layer made of a moisture barrier coating base to prevent the penetration of moisture.
상기 제1코팅층의 비산성 코팅기제는 하이드록시프로필메틸셀룰로오스를 포함하는 것이 사용될 수 있으며, 수분 차단성 코팅기제 성분이 정제에 영향을 미치지 않도록 제2코팅층과 정제의 접촉을 차단하는 서브코팅에 해당한다. The non-acidic coating base of the first coating layer may include hydroxypropylmethylcellulose, and corresponds to a sub-coating that blocks the contact between the second coating layer and the tablet so that the moisture barrier coating base component does not affect the tablet. do.
한편 상기 제2코팅층의 수분차단성 코팅기제는 시판되는 공지된 코팅기제에서 선택하여 사용할 수도 있으나, 스테아르산 성분은 포함하지 않는 코팅기제를 사용하는 것이 바람직하다. 본 출원인이 실험한 결과, 스테아르산을 포함하는 코팅기제를 제2코팅층에 사용하는 경우 정제와 제2코팅층의 접촉을 차단하는 제1코팅층에도 불구하고 정제의 성상이 일부 흑변하면서 유연물질이 발생하는 것이 관찰되었다.Meanwhile, the moisture barrier coating base of the second coating layer may be selected from commercially known coating bases, but it is preferable to use a coating base containing no stearic acid component. As a result of the applicant's experiment, when the coating base containing stearic acid is used in the second coating layer, the tablet is partially blacked and the flexible material is generated despite the first coating layer blocking the contact between the tablet and the second coating layer. Was observed.
상기 수분차단성 코팅기제는 주성분으로 폴리비닐알코올 및 하이드록시프로필메틸셀룰로오스로 이루어진 군에서 1종 또는 2종의 고분자 물질을 주성분으로 포함하는 것이 수분차단성이 우수하게 나타나 바람직하다.The moisture barrier coating base includes polyvinyl alcohol and hydroxypropyl methyl cellulose as the main component, and preferably includes one or two polymer substances as the main component.
본 발명에 의한 다층정 복합제제는 아세클로베낙 또는 이의 약학적으로 허용가능한 염을 함유하는 제1유효성분 층, 에스오메프라졸 또는 이의 약학적으로 허용가능한 염을 함유하는 제2유효성분층 및 유효성분을 함유하지 않는 비활성층을 포함하는 것으로서, 상기 제1유효성분층과 제2유효성분층이 비활성층에 의하여 상호 분리된 구조로 인하여 각 유효성분 간의 물리적 접촉에 의한 변성 및 함량 저하를 방지할 수 있다. 또한, 외부의 수분을 차단하는 코팅층을 정제 외부에 추가로 형성함으로써, 장기 안정성을 확보하는 것을 특징으로 한다.The multi-layered tablet complex preparation according to the present invention comprises a first active ingredient layer containing aceclobenac or a pharmaceutically acceptable salt thereof, a second active ingredient layer and an active ingredient containing esomeprazole or a pharmaceutically acceptable salt thereof. By including an inert layer that does not contain, due to the structure in which the first active ingredient layer and the second active ingredient layer are separated from each other by the inactive layer it is possible to prevent denaturation and decrease in content due to physical contact between the active ingredients. have. In addition, by further forming a coating layer to block external moisture on the outside of the tablet, it is characterized by ensuring long-term stability.
이하, 본 발명에 의한 복합제 및 그 제조방법에 관하여, 구체적으로 설명한다. 이하에서 기재하는 구체적인 사항이나 도면의 내용은 본 발명의 실시형태를 예시하는 것에 불과하므로, 본 발명은 이러한 기재 사항이나 내용에 한정되는 것으로 이해되어서는 아니 될 것이다.EMBODIMENT OF THE INVENTION Hereinafter, the composite agent by this invention and its manufacturing method are demonstrated concretely. The specific matters and the contents of the drawings described below are merely illustrative of embodiments of the present invention, and therefore, the present invention should not be understood as being limited to such descriptions and contents.
이하 상기한 방법에 따른 본 발명에 따른 제형의 바람직한 일 제조 방법에 대하여 보다 구체적으로 설명한다.Hereinafter, a preferred method for preparing a formulation according to the present invention according to the above-described method will be described in more detail.
제1유효성분층의 제조Preparation of the first active ingredient layer
본 발명에 따른 제1유효성분층은 유효성분인 아세클로페낙과 부형제 미결정셀룰로오스 및 붕해제 크로스카르멜로오스나트륨을 스피드 혼합기에서 10 내지 20분간 혼합한 후, 연합액을 첨가하면서 수회에 걸쳐 혼합하여 연합물을 제조할 수 있다. The first active ingredient layer according to the present invention is aceclofenac, an excipient microcrystalline cellulose and a disintegrant croscarmellose sodium 10-20 minutes in a speed mixer, and then mixed several times with the addition of the fed solution Can be prepared.
상기 연합물을 활택제, 붕해제와 후혼합한다.The association is postmixed with lubricant, disintegrant.
상기 후혼합물을 드럼혼합기에서 혼합하여 제1유효성분층의 최종 과립을 제조한다. The postmixed mixture is mixed in a drum mixer to prepare final granules of the first active ingredient layer.
제2유효성분층의 제조Preparation of Second Active Ingredient Layer
본 발명에 따른 제2유효성분층은 유효성분인 에스오메프라 또는 이의 약학적으로 허용가능한 염을 함유하며, 에스오메프라졸마그네슘과 부형제 미결정셀룰로오스 및 안정제를 혼합한 후, 연합액을 첨가하면서 수 회에 걸쳐 혼합하여 연합물을 제조한다. The second active ingredient layer according to the present invention contains an active ingredient, e. Smefra or a pharmaceutically acceptable salt thereof, and after mixing someprazole magnesium, an excipient microcrystalline cellulose, and a stabilizer, several times while adding an association solution Mix over to prepare the union.
상기 연합물을 건조기에서건조시킨다.The association is dried in a dryer.
상기 건조물을 활택제와 혼합한 후 결합제및 붕해제와 후혼합한다. The dry matter is mixed with a lubricant and then mixed with a binder and a disintegrant.
상기 후혼합물을 제2유효성분층의 최종 과립을 제조한다. The post-mixture prepares the final granules of the second active ingredient layer.
비활성층의 제조Preparation of Inactive Layer
본 발명에 따른 비활성층은 부형제 미결정셀룰로오스에 연합액을 첨가하여 연합물을 제조한다. The inert layer according to the present invention is prepared by adding the fed solution to the excipient microcrystalline cellulose.
상기 연합물을 건조시켜 최종 과립을 제조한다.The union is dried to produce the final granules.
3층정 타정3-layer tablet tablet
상기 제1유효성분층 과립과, 제2유효성분층 과립 및 비활성층의 과립을압력을 가하면서 타정한다.The first active ingredient layer granules, the second active ingredient layer granules and the granules of the inactive layer are compressed while applying pressure.
제1코팅층(서브코팅) 형성First coating layer (sub coating) formation
상기 타정된 나정을 정제탈분기를 이용하여 탈분한 후, 코팅기를 사용하여글리세린을 포함하는 코팅기제로 상기 삼층정 나정을 코팅한다.The tableted uncoated tablet is separated using a tablet debranching, and then coated with the three-layer uncoated tablet with a coating base containing glycerin using a coater.
제2코팅층(본코팅) 형성Second coating layer (main coating) formation
상기 1차코팅정을 코팅기를 사용하여 폴리비닐알코올포함하는 코팅기제등의 방수성 코팅기제로 코팅하여, 코팅된 삼층정 복합제제를 제조한다.The primary coating tablet is coated with a waterproof coating base such as a coating base including polyvinyl alcohol using a coating machine to prepare a coated triple layer composite formulation.

Claims (3)

  1. 아세클로페낙 또는 이의 약학적으로 허용가능한 염을 함유하는 제1유효성분층;A first active ingredient layer containing aceclofenac or a pharmaceutically acceptable salt thereof;
    에스오메프라졸 또는 이의 약학적으로 허용가능한 염을 함유하는 제2유효성분층; 및A second active ingredient layer containing esomeprazole or a pharmaceutically acceptable salt thereof; And
    유효성분을 함유하지 않는 비활성층을 포함하며,Including an inert layer containing no active ingredient,
    상기 비활성층은 상기 제1유효성분층과 상기 제2유효성분층 사이에 형성되는 것인 경구 투여 다층정 복합제제.The inactive layer is an orally administered multi-layered tablet complex preparation is formed between the first active ingredient layer and the second active ingredient layer.
  2. (a) 아세클로페낙 또는 이의 약학적으로 허용가능한 염을 함유하는 제1유효성분층 과립을 제조하는 단계;(a) preparing a first active ingredient layer granule containing aceclofenac or a pharmaceutically acceptable salt thereof;
    (b) 에스오메프라졸 또는 이의 약학적으로 허용가능한 염을 함유하는 제2유효성분층 과립을 제조하는 단계;(b) preparing a second active ingredient layer granule containing esomeprazole or a pharmaceutically acceptable salt thereof;
    (c) 유효성분을 함유하지 않는 비활성층 과립을 제조하는 단계;(c) preparing inert layer granules containing no active ingredient;
    (d) 제1유효성분층 과립을 충진 및 타정하여 제1유효성분층 정제를 제조하는 단계;(d) filling and tableting the first active ingredient layer granules to produce a first active ingredient layer tablet;
    (e) 제1유효성분층 정제 위에 비활성층 과립을 충진 및 타정하여 이층정 정제를 제조하는 단계;(e) filling and tableting inert layer granules on the first active ingredient layer tablet to prepare a bilayer tablet;
    (f) 상기 이층정 정제 위에 제2유효성분층 과립을 충진 및 타정하여 삼층정 정제를 제조하는 단계;를 포함하는 경구 투여 다층정 복합제제의 제조방법.(f) filling and tableting a second active ingredient layer granule on the bilayer tablet to prepare a three-layer tablet.
  3. 제2항에 있어서,The method of claim 2,
    상기 (a) 내지 (f)단계에,In the step (a) to (f),
    (g) 상기 삼층정 정제 상에 하이드록시프로필메틸셀룰로오스를 포함하는 코팅액으로 제1코팅층을 형성하는 단계;(g) forming a first coating layer with a coating liquid containing hydroxypropylmethylcellulose on the three-layer tablet;
    (h) 상기 제1코팅층 상에 폴리비닐알코올 및 하이드록시프로필메틸셀룰로오스로 이루어진 군에서 선택된 1종 또는 2종의 성분을 포함하는 코팅액으로 제2코팅층을 형성하는 단계;를 추가로 포함하는 경구 투여 다층정 복합제제의 제조방법.(h) forming a second coating layer with a coating liquid comprising one or two components selected from the group consisting of polyvinyl alcohol and hydroxypropylmethyl cellulose on the first coating layer; oral administration further comprising Method for producing a multilayer tablet composite formulation.
PCT/KR2018/006720 2018-06-14 2018-06-14 Complex formulation comprising aceclofenac and esomeprazole and method of preparing same WO2019240310A1 (en)

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Publication number Priority date Publication date Assignee Title
KR100483870B1 (en) * 1996-01-08 2005-09-30 아스트라제네카 악티에볼라그 Oral Pharmaceutical Dosage Forms Comprising a Proton Pump Inhibitor and a NSAID
US20050249811A1 (en) * 2001-06-01 2005-11-10 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
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KR20150114657A (en) * 2014-04-02 2015-10-13 일양약품주식회사 Pharmaceutical compositions and a method for manufacturing containing Ilaprazole and nonsteroidal anti-inflammatory drug or pharmaceutically acceptable salt
KR20160020625A (en) * 2014-08-13 2016-02-24 영남대학교 산학협력단 Immediate release oral composition comprising non-steroidal anti-inflammatory drug and proton pump inhibitor, and method for preparing the same

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100483870B1 (en) * 1996-01-08 2005-09-30 아스트라제네카 악티에볼라그 Oral Pharmaceutical Dosage Forms Comprising a Proton Pump Inhibitor and a NSAID
US20050249811A1 (en) * 2001-06-01 2005-11-10 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
KR20130115593A (en) * 2012-04-12 2013-10-22 한미약품 주식회사 Pharmaceutical composite formulation comprising non-steroidal anti-inflammatory drug and proton pump inhibitor, and method for preparing the same
KR20150114657A (en) * 2014-04-02 2015-10-13 일양약품주식회사 Pharmaceutical compositions and a method for manufacturing containing Ilaprazole and nonsteroidal anti-inflammatory drug or pharmaceutically acceptable salt
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