KR101156054B1 - A stable and control-released pharmaceutical composition comprising eperisone - Google Patents
A stable and control-released pharmaceutical composition comprising eperisone Download PDFInfo
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Abstract
Description
본 발명은 제제의 장기 보관 안정성은 물론, 장관 내 장기 체류해야 하는 서방성 제제 특성상 위장관 내 극한 환경에서의 안정성 개선과 함께 속효성 및 지효성을 필요로 하는 약물의 치료 특성상 이중방출 특성을 나타내는 에페리손 함유 서방성 의약조성물에 관한 것이다.
The present invention is a long-term storage stability of the formulation, as well as the long-term retention in the intestinal tract due to the nature of the drug in the extreme properties of the gastrointestinal tract and improved efficacy in the extreme environment of the drug that requires fast release and sustained release eferison containing a double-release property A sustained release pharmaceutical composition.
일반적으로, 에페리손(Eperisone)은 오래전부터 근골격계 질환에 수반하는 동통성 근육연축을 비롯한 신경계 질환에 의한 경직성 마비의 치료에 사용되는 약물이며, 그 화학구조는 아래와 같다.In general, Eperisone (Eperisone) is a drug that has been used for the treatment of stiff paralysis due to long-term musculoskeletal disorders, including painful muscle spasms and nervous system diseases, the chemical structure is as follows.
에페리손(Eperisone)
Eperisone
상기 약물은 알칼리 환경에서 피페리딘 링으로 쉽게 분해되어 매우 불안정한 특성이 있었음에도 불구하고 지금까지 이들의 안정성을 개선하고자 하는 연구가 매우 미흡한 실정이었다. 그 결과, 시판중인 제품의 경우에도 제조 직후나 장기 보관 중, 심지어 보관개시 후 1, 2개월 내에 불순물 함량이 1 ~ 2% 이상까지 증가되는 등 매우 불안정하여 제조 후 일정기간 경과 후에는 목적하는 약효가 반감되는 등의 문제가 있었다. Although the drugs were easily decomposed into piperidine rings in an alkaline environment and had very unstable properties, studies to improve their stability have been very insufficient until now. As a result, even in the case of commercially available products, the content of impurities is very unstable, such as an increase in impurities content of 1 to 2% or more within 1 or 2 months immediately after manufacture, during long-term storage, or even after storage. There was a problem such as being halved.
게다가, 상기 약물을 위장관 내에서 장시간 머무르며 약물을 서서히 방출하도록 하는 1일 1회의 서방성 제제로 개발하는 경우, 상기 약물은 반감기 및 혈중 내 소실 시간이 짧을 뿐만 아니라, 약물의 흡수부위가 장관 상부이고, 상술한 바와 같이 장관 내 알칼리 환경에서 매우 불안정한 특성 등의 문제가 있어 장기간 보관을 위한 제제 자체의 안정성 개선은 물론 장관 내 장기 체류 중 장내 극한 환경에서의 안정성 개선을 위한 노력도 함께 요구되는 실정이었다. In addition, when the drug is developed as a once-release sustained release formulation that keeps the drug in the gastrointestinal tract for a long time and releases the drug slowly, the drug has a short half-life and a short time in blood loss, and the absorption portion of the drug is in the upper intestinal tract. As described above, there is a problem of very unstable characteristics in the alkaline environment of the intestine, and therefore, efforts to improve the stability of the formulation itself for long-term storage as well as to improve the stability in the intestinal extreme environment during long-term intestine are required. .
또한, 상기 약물은 반감기 및 혈중 내 소실시간이 짧아 서방성으로의 제제화가 어려워 지금까지도 복용법이 주로 1일 3회로 되어 있다. 따라서, 환자들은 복용법을 준수하기 어려웠고 그 결과 복용 순응도가 떨어져 환자의 치료효과가 반감되는 문제점이 있어 왔으며, 또한 최근 이들 약물과 보통 함께 복용하는 비스테로이드성 소염진통제(NSAIDs) 계열 약물들이 1일 1회 용법으로 개발되는 사례가 많아졌음에도 불구하고 상기와 같은 문제점으로 이들 약물은 여전히 1일 3회 제제밖에 없어 복용법상 상호 불균일로 인한 문제점도 있어왔다. In addition, the drug has a short half-life and a short loss time in blood, making it difficult to formulate into sustained release. Up to now, the drug is mainly used three times a day. As a result, patients have been difficult to comply with the dosage regimen, and as a result, their compliance has been reduced, and the treatment effects of patients have been halved. Also, recently, NSAIDs-based drugs usually taken together with these drugs are daily 1 Despite the increasing number of cases developed by the use of the above-mentioned problems, these drugs still have only three formulations per day, there has been a problem due to mutual unevenness in the dosage method.
따라서, 상기와 같은 1일 3회 용법에 따른 불편을 개선하고자 하는 많은 노력들이 있었으며, 그와 같은 예로 왁스 매트릭스를 제조하는 방법[미국특허 제 5,700,410호], 서방성 캡슐을 이용하는 방법[미국특허 제5,498,422호], 하이드로겔을 이용하는 방법[미국특허 제6,500,455호], 유핵정과 피복층 사이에 지연방출 코팅층을 두는 방법[한국특허 제574213호], 팽창성 막으로 코팅하는 방법[한국 공개특허 제1989-0004685호], 소수성 유기화합물 및 수불용성 중합체 필름으로 코팅하는 방법[국제공개 WO2000/24423], 서방성 기재로 유드라짓(Eudragit)을 이용하는 방법[미국특허 제2005/0196451호], 위-체류 약물 시스템을 이용하는 방법[미국특허 제2010/0249423호], 그리고 특히 친수성 중합체, 소수성 중합체, 셀룰로오스 유도체, 천연 검, 수불용성 중합체, 스테아르산 등의 지연 방출제를 이용하여 서방성 제제를 개발하려는 등 많은 노력이 있어왔다[참조: WO2010/103544]. Therefore, a lot of efforts have been made to improve the inconvenience caused by the above-mentioned three times daily use method, such as a method of manufacturing a wax matrix [US Patent No. 5,700,410], a method using a sustained-release capsule [US Patent No. 5,498,422], a method using a hydrogel [US Pat. No. 6,500,455], a method of placing a delayed-release coating layer between a nucleated tablet and a coating layer [Korean Patent No. 574213], and a method of coating with an expandable membrane [Korean Patent No. 1989- 0004685], a method of coating with a hydrophobic organic compound and a water-insoluble polymer film [WO 2000/24423], a method of using Eudragit as a sustained-release substrate [US Patent No. 2005/0196451], stomach-retention Methods of using drug systems [US Pat. No. 2010/0249423], and especially delayed release of hydrophilic polymers, hydrophobic polymers, cellulose derivatives, natural gums, water insoluble polymers, stearic acid and the like Use the There have been many efforts to develop sustained-release preparations [See: WO2010 / 103544].
그러나, 이러한 종래의 방법들은 모두 본 발명의 에페리손과 같은 약물 특성상 필요로 하는 초기 약효 발현속도가 빠르면서 효과는 지속적으로 발휘되어야 하는 이중방출 특성을 맞출 수 없는 문제점이 있어 왔다. However, all of these conventional methods have a problem that can not meet the dual release characteristics that the effect is to be continuously exerted while the initial drug expression rate required by the characteristics of the drug, such as the eferison of the present invention.
이에, 제제의 장기 보관안정성 개선은 물론 제제 복용시 서방성 제제의 특성상 장관 내의 극한 환경에서 장기 체류 중의 안정성 개선과 본 제품의 이중 방출 특성을 살리고 복용편리성 개선을 통한 환자들의 복약 순응도를 높일 필요성도 함께 요구되던 실정이었다.
Therefore, it is necessary to improve the long-term storage stability of the formulation, as well as to improve the compliance with the medications by improving the stability during long-term stay in the extreme environment in the intestinal tract and the dual release characteristics of the product, and the convenience of taking it. Was also required.
본 발명의 발명자들은 상기와 같은 문제점을 해결하고자 예의 노력한 결과, 특정 범위의 지연방출제와 함께 카보머, 시트르산 등의 특정 종류의 산성화제를 포함시켜 제제 전체를 pH 5.6 이하 범위로 제제화 함으로써, 속효성 및 지효성을 필요로 하는 약물의 치료 특성상 이중방출 특성은 물론, 제제의 안정성과 장관 내에서 장시간 체류해야 하는 서방성 제제의 특성상 pH 변화에도 주성분 분해를 억제하고 용출특성도 변화하지 않음을 확인하여 본 발명을 완성하였다.
The inventors of the present invention intensively tried to solve the above problems, as a result of formulating the entire formulation to a pH of 5.6 or less by including a specific type of acidifying agent, such as carbomer, citric acid, with a specific range of delayed release agent, In addition, due to the therapeutic properties of drugs requiring sustained release, as well as the stability of the preparations and the sustained release of the extended-dose preparations that must be retained for a long time in the intestinal tract, the main component degradation is suppressed and the dissolution properties do not change. The invention was completed.
본 발명은 산성화제를 포함하는 안정한 에페리손 함유 서방성 의약조성물을 에페리손 함유 서방성 의약조성물에 관한 것으로, 이러한 산성화제로는 산성 pH 조절제 또는 물에 현탁, 용해, 팽윤 또는 혼화(miscible)되었을 때 pH 5.0 이하를 나타내는 부형제 중에서 선택된 것이 바람직하다. 여기서, 상기 산성화제나 pH 5.0 이하를 나타내는 부형제는 상술한 바와 같이 제제 내의 환경을 pH 5.6 이하로 낮추기 위해 첨가되며, 이들의 첨가로 인해 주성분인 에페리손 성분 자체를 안정화시킬 수 있을 뿐만 아니라, 위장관 내 장기 체류 중에도 산과 알칼리 환경 모두에서 유의성 있는 용출패턴을 유지함은 물론, 장관 내 알칼리와의 접촉에 따른 주성분의 분해도 막아 장관 체류 중 약물 흡수과정에서의 주성분 안정성도 함께 유지시킬 수 있도록 도움을 준다. The present invention relates to a stable ephericone-containing sustained-release pharmaceutical composition comprising an acidifying agent, wherein the acidifying agent is suspended, dissolved, swelled or miscible in an acidic pH adjusting agent or water. Preference is given to those selected from excipients which exhibit a pH of 5.0 or less. Here, the acidifying agent or an excipient exhibiting a pH of 5.0 or less is added to lower the environment in the formulation to pH 5.6 or less as described above, and the addition thereof can not only stabilize the main component eferison component itself, but also in the gastrointestinal tract. In addition to maintaining significant dissolution patterns in both acid and alkali environments during long-term stays, it also helps to maintain the main component stability during the absorption of the drug during intestinal retention by preventing degradation of the main component due to contact with alkali in the intestine.
따라서, 상기 산성화제의 함량은 종류에 따라 상이하지만, 상기 조성물의 0.5%(W/V) 수성용액의 산도를 pH 0.5 ~ pH 5.6 범위에 들도록 조절할 수 있는 양이 바람직하다. 보다 구체적으로 산성 pH 조절제는 알긴산(Alginic acid), 아세트산(Acetic acid), 포름산(Formic acid), 아디프산(Adipic acid), 에데트산(Edetic acid), 푸마르산(Fumaric acid), 젖산(Lactic acid), 말산(Malic acid), 말레산(Maleic acid), 팔미트산(Palmitic acid), 프로피온산(Propionic acid), 소르빈산(Sorbic acid), 스테아르산(Stearic acid), 주석산(Tartaric acid), 아스코르빈산(Ascorbic acid), 에리소르빈산(Erythorbic Acid), 시트르산(Citric acid), 옥살산(Oxalic acid), 숙신산(Succinic acid), 톨루엔설폰산, 메탄설폰산, 질산, 염산, 인산, 황산 중에서 선택된 1종 이상을 포함하는 것이 바람직하며, 특히 시트르산이 가장 바람직하다. Therefore, the content of the acidifying agent is different depending on the type, but the amount that can be adjusted so that the acidity of the 0.5% (W / V) aqueous solution of the composition is in the range of pH 0.5 ~ pH 5.6. More specifically, acidic pH regulators include alginic acid, acetic acid, formic acid, adipic acid, edetic acid, fumaric acid, and lactic acid. ), Malic acid, maleic acid, maleic acid, palmitic acid, propionic acid, sorbic acid, stearic acid, tartaric acid, ascorbic acid One selected from ascorbic acid, erythorbic acid, citric acid, oxalic acid, oxalic acid, succinic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, hydrochloric acid, phosphoric acid, and sulfuric acid It is preferable to contain the above, and citric acid is especially preferable.
또한, pH 5.0 이하를 나타내는 부형제로는 물에 현탁, 용해, 팽윤 또는 혼화(miscible)되었을 때 pH 5.0 이하를 나타내는 모든 부형제가 바람직하나, 보다 구체적으로는 카보머(Carbomer), 폴리카르보필(Polycarbophil) 및 폴리덱스트로스(Polydextrose) 중에서 선택된 1종 이상이 가장 바람직하다. In addition, as an excipient having a pH of 5.0 or less, all excipients having a pH of 5.0 or less when suspended, dissolved, swelled or miscible in water are preferable. More specifically, a carbomer or a polycarbophil And at least one selected from Polydextrose is most preferred.
또한, 본 발명은 조성물 전체를 0.5%(W/V) 수성용액으로 제조했을 때의 산도가 pH 0.5 ~ 5.6 범위가 바람직하며, 특히 pH 4.5 이하가 보다 바람직하다. 왜냐하면, pH 0.5 미만이면 너무 강한 산 특성으로 인해 복용시 구강 및 식도 점막의 손상에 영향을 미칠 수 있기 때문에 바람직하지 않은 반면, pH 5.6을 넘어 알칼리화 되면 조성물의 안정성이 현저히 떨어지게 되고, 약물 투여시 장관에서 알칼리 환경으로의 급변에 따른 알칼리와의 접촉으로 인한 주성분의 분해를 차단할 수 없게 되기 때문이다. 이때, 바람직한 에페리손은 에페리손 염산염이며, 함량은 150 ~ 300mg/day이다. In the present invention, the acidity when the whole composition is prepared with 0.5% (W / V) aqueous solution is preferably in the range of pH 0.5 to 5.6, more preferably pH 4.5 or less. This is undesirable because a pH of less than 0.5 may adversely affect the oral and esophageal mucosa at the time of taking due to too strong acidic properties, whereas alkalizing above pH 5.6 will significantly reduce the stability of the composition, and the intestinal tract at the time of drug administration. This is because it is impossible to block decomposition of the main component due to contact with alkali caused by sudden change in the alkaline environment. At this time, the preferred eferison is eferison hydrochloride, and the content is 150 to 300 mg / day.
그리고, 본 발명은 속효성 및 지효성을 필요로 하는 약물의 치료특성상 이중방출 특성의 서방성 제제를 포함한다. 여기서 “서방성”이라 함은 용출 초기 60분내 전체 함량의 30중량% 이상, 6시간 내 75중량% 미만, 그리고 24시간내 90중량% 이상 용출되는 범위를 나타낸다. 일반적으로, 이와 같은 이중 방출패턴은 진통제처럼 복용 초기 약효가 빨리 발휘되도록 한 다음 이후에는 약효가 지속적으로 유지되게끔 할 필요가 있는 약물에 적용된다. In addition, the present invention includes a sustained release formulation having a dual release property in terms of therapeutic properties of drugs requiring fast and sustained release. The term "sustained release" herein refers to a range in which more than 30% by weight of the total content in the initial 60 minutes of dissolution, less than 75% by weight in 6 hours, and 90% or more by weight in 24 hours. In general, this dual release pattern is applied to drugs that need to be activated early, such as painkillers, and then continue to be effective afterwards.
따라서, 본 발명에서도 방출초기부터 약물의 방출율이 일직선으로 나타나는 일반적인 서방제제와는 달리, 복용초기 신속한 근이완 및 진통효과를 보기 위해 이중 방출패턴의 제제가 반드시 필요하며, 그 시간대별 함량을 조절하는 것은 매우 중요한 일이다. 즉, 본 발명에서 초기 약물의 방출속도가 60분내 전체 함량의 30중량% 보다 너무 낮게 되면 환자가 목적하는 초기의 빠른 약효를 얻을 수 없게 되고 50중량%를 초과하게 되면 복용 초기 도즈 덤핑 등의 문제로 환자가 위험해지는 문제가 있을 수 있으며, 또한 6시간 내 75중량% 이상 용출되면 역시 초기 과량의 용출로 인해 부작용이 발생할 우려가 있어 바람직하지 않을 뿐만 아니라 지속적인 효과도 나타낼 수 없는 등 약물의 시간대별 방출함량을 조절하는 것은 본 발명의 목적을 달성하는데 매우 중요한 요소이다. Therefore, in the present invention, unlike the general sustained-release preparations in which the release rate of the drug is straight from the beginning of the release, the preparation of the double release pattern is necessary to see the rapid muscle relaxation and analgesic effect at the beginning of the dose, and the content of each time zone is controlled. It is very important. That is, in the present invention, if the release rate of the initial drug is too lower than 30% by weight of the total content within 60 minutes, the patient cannot obtain the desired initial fast efficacy, and if it exceeds 50% by weight, problems such as initial dose dosing dumping As a result, the patient may be at risk, and if more than 75% by weight is eluted within 6 hours, there may be side effects due to the initial excessive dissolution, which may not be desirable and may not have a lasting effect. Controlling the release content is a very important factor in achieving the object of the present invention.
또한, 본 발명은 상기와 같은 이중방출 특성의 서방성 제제를 만들기 위해 주성분인 염산에페리손 1 중량부에 대하여 지연방출제 0.05 ~ 3중량부를 포함할 수 있으며, 특히 지연방출제 0.1 ~ 2.5중량부를 포함하는 것이 바람직하다. 왜냐하면, 본 발명에서와 같은 약물 특성상 환자로 하여금 신속한 근이완 효과 및 진통효과에 대한 만족은 물론 안전성을 확보하기 위한 특정 시간대별 방출 함량을 조절하는 것은 매우 중요한 것이어서, 지연방출제의 함량이 너무 낮으면 목적하는 약물의 초기 용출속도가 너무 빨라 도즈 덤핑(Dose Dumping)이 나타나 환자가 위험해지는 문제점이 있어 바람직하지 않게 되고, 지연방출제 함량이 너무 높으면 초기 용출속도가 너무 늦게 되어 초기 약효발현속도가 빨라야 하는 환자의 만족도를 맞출 수가 없게 되기 때문이다. In addition, the present invention may include 0.05 to 3 parts by weight of the delayed release agent with respect to 1 part by weight of eferison hydrochloride as a main component in order to make a sustained release formulation of the double-release properties as described above, in particular 0.1 to 2.5 parts by weight of the delayed release agent It is preferable to include a part. Because, in the nature of the drug as in the present invention, it is very important for the patient to control the release content according to specific time periods to ensure the safety as well as the rapid muscle relaxation effect and analgesic effect, so that the content of the delayed release agent is too low. If the initial drug dissolution rate is too fast, dose dumping appears, which causes the patient to be in danger, which is not desirable. If the delayed release agent content is too high, the initial dissolution rate is too slow, and the initial drug expression rate is increased. This is because the patient's satisfaction, which must be fast, cannot be met.
이때, 지연방출제는 셀룰로오스 유도체로서, 메틸셀룰로오스, 에틸셀룰로오스, 하이드록시프로필메틸셀룰로오스, 하이드록시프로필셀룰로오스, 하이드록시에틸셀룰로오스, 카르복시메틸셀룰로오스 등; 친수성 중합체로는 폴리사카라이드, 폴리아크릴레이트, 하이드로겔, 폴리비닐알콜, 폴리비닐피롤리돈, 카보폴, 폴리에틸렌 옥사이드, 마그네슘알루미늄실리케이트, 전분 유도체, 또는 이들의 혼합물; 소수성 중합체로는 아크릴산과 메타크릴산에스터의 공중합체(상품명; '유드라짓'), 폴리에틸렌, 폴리아미드, 폴리비닐클로라이드, 폴리비닐아세테이트, 폴리비닐알콜, 또는 이들이 혼합물; 비수용성 중합체로서 폴리아크릴산, 아크릴 수지, 아크릴 라텍스 분산물, 셀룰로오스아세테이트 프탈레이트, 폴리비닐아세테이트 프탈레이트, 하이드록시프로필메틸셀룰로오스 프탈레이트, 또는 이들의 혼합물들 중에서 1종 이상 선택 사용한다. At this time, the delayed-release agent is a cellulose derivative, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose and the like; Hydrophilic polymers include polysaccharides, polyacrylates, hydrogels, polyvinyl alcohols, polyvinylpyrrolidones, carbopol, polyethylene oxides, magnesium aluminum silicates, starch derivatives, or mixtures thereof; Hydrophobic polymers include copolymers of acrylic acid and methacrylic acid esters (trade name: Eudragit), polyethylene, polyamides, polyvinylchloride, polyvinylacetate, polyvinyl alcohol, or mixtures thereof; At least one selected from among polyacrylic acid, acrylic resin, acrylic latex dispersion, cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, or mixtures thereof is used as the water-insoluble polymer.
또한, 상기 지연방출제 가운데에는 친수성 중합체 및 소수성 중합체의 혼합물이 바람직하고, 초기 방출속도나 효과 발현 지속 정도에 따라 그 비율을 조절할 수 있으며, 특히 이들 혼합물 중에는 폴리비닐피롤리돈 : 폴리비닐아세테이트가 2 : 8 중량부로 혼합된 것(상품명; '콜리돈에스알')이 가장 바람직하다. 그리고, 본 발명은 조성물 전체의 비중이 pH 1 수용액에서 0.5 ~ 1.2 g/ml 범위인 것을 포함하며, 더욱 바람직하기로는 0.6 ~ 1.2 g/ml, 가장 바람직하기로는 0.8 ~ 1.2g/ml 범위를 포함한다. Among the delayed release agents, a mixture of a hydrophilic polymer and a hydrophobic polymer is preferable, and the ratio can be adjusted according to the initial release rate or the duration of effect expression. Particularly, in these mixtures, polyvinylpyrrolidone: polyvinylacetate is used. 2: 8 parts by weight of the mixture (trade name: 'collidone RS') is most preferred. In addition, the present invention includes a specific gravity of the composition as a whole range of 0.5 to 1.2 g / ml in an aqueous solution of pH 1, more preferably 0.6 to 1.2 g / ml, most preferably contains 0.8 to 1.2 g / ml do.
상기에서 살핀 바와 같이 본 발명의 서방성 제제는 일반 1일 3회 제제와는 달리 1일 1회 복용만으로도 일반 제제와 동일한 효과를 나타내야 되기 때문에 위장관에서 지속적인 방출이 필요하다. 그런데, 에페리손은 장관 환경인 알칼리에 매우 불안정한 특성이 있고, 또한 약물의 흡수부위도 주로 위장관 상부에 위치하고 있어 가급적이면 산성 환경인 위에 오랜 동안 체류시킬 필요가 있다. As described above, the sustained-release preparation of the present invention is required to have a sustained release from the gastrointestinal tract, because unlike the general three-day preparation, it should have the same effect as the general preparation only once a day. By the way, Eperisone is very unstable to alkali, which is an intestinal environment, and also the absorption part of the drug is mainly located in the upper gastrointestinal tract, so it is necessary to stay for a long time in an acidic environment if possible.
따라서, 통상의 플로팅(Floating) 시스템이나 위부착 시스템, 팽윤 시스템 등의 위 체류 시스템을 이용할 수 있으며, 특히 이들 전체 제제의 비중을 위액의 비중과 유사하거나 낮은 범위로 조절하는 것이 바람직하며, 구체적으로 조성물 전체의 비중 범위는 0.5 ~ 1.2 g/ml가 바람직하다. 왜냐하면, 전체 조성물 비중이 1.2 g/ml를 초과하여 너무 높으면 위액보다 비중이 높게 되어 위의 하부로 가라앉게 되고, 그 결과 위에 체류한 채 계속하여 약물을 방출하고자 하는 목적을 달성할 수 없게 되는 문제점이 있는 반면, 조성물의 비중이 0.5 g/ml 보다 낮게 되면 위액의 상부에만 위치하게 되어 제제의 한 면에서만 약물이 방출되게 되어 방출량이 적게 되는 문제점이 있게 된다. Therefore, it is possible to use a gastric retention system such as a conventional floating system, gastric adhesion system, swelling system, and in particular, it is preferable to adjust the specific gravity of these whole preparations to a range similar to or lower than that of gastric juice. As for the specific gravity range of the whole composition, 0.5-1.2 g / ml is preferable. Because, if the total composition specific gravity is too high exceeding 1.2 g / ml, the specific gravity is higher than the gastric juice to sink to the lower part of the stomach, and as a result, it is impossible to achieve the purpose of continuing to release the drug while staying on the stomach On the other hand, if the specific gravity of the composition is lower than 0.5 g / ml is located only in the upper portion of the gastric juice has a problem that the drug is released only on one side of the formulation is less release.
또한, 본 발명은 통상의 위 체류 시스템으로써 제제 내에 중탄산나트륨를 비롯한 공지된 모든 가스 발생제를 포함하며, 이때 가스 발생제는 주성분의 안정성을 위해 주성분과의 접촉을 피할 수 있도록 서방상과는 별도의 외부상에 위치시키는 것이 바람직하며, 특히 서방상의 용출이 저해되지 않도록 정제 등의 한 면에만 접촉하는 것이 바람직하다. 이때 조성물의 pH는 가스발생제가 포함된 층을 제외한 약물층만의 pH가 0.5 내지 5.6이 되도록 조정하는 것이 필요하다. In addition, the present invention includes all known gas generators, including sodium bicarbonate, in the formulation as a conventional gastric retention system, wherein the gas generator is separate from the sustained phase to avoid contact with the main component for stability of the main component. It is preferable to locate in an external phase, and it is preferable to contact only one side of a tablet etc. especially in order not to inhibit elution of a slow release phase. At this time, the pH of the composition needs to be adjusted so that the pH of only the drug layer except for the layer containing the gas generator is 0.5 to 5.6.
또한, 본 발명은 비스테로이드성 소염진통제(NSAID)계 약물을 추가적으로 포함할 수 있는데, 구체적으로는 아세클로페낙, 디클로페낙, 멜록시캄, 나프록센, 이부프로펜, 덱시부프로펜, 록소프로펜, 잘토프로펜, 펠비낙, 케토프로펜, 에토돌락, 나부메톤, 셀레콕시브, 니메설리드 등에서 선택할 수 있다. 이와 같이 추가적으로 비스테로이드성 소염진통제를 함께 제제화하면, 두 약물간의 상승효과를 통해 소염작용은 물론 진통효과까지 함께 얻을 수 있는 장점은 물론 환자로 하여금 복용편리성을 증가시켜 약물 순응도를 높일 수 있게 된다. In addition, the present invention may further include nonsteroidal anti-inflammatory drugs (NSAID) -based drugs, specifically, aceclofenac, diclofenac, meloxycamp, naproxen, ibuprofen, dexibuprofen, roxofene, zaltoprofen , Felbinac, ketoprofen, etodolak, nabumetone, celecoxib, nimesulide and the like. In this way, if the nonsteroidal anti-inflammatory drugs are formulated together, the anti-inflammatory effect and the analgesic effect can be obtained through the synergistic effect between the two drugs, and the patient can increase the convenience of taking the drug and increase the drug compliance. .
마지막으로 본 발명은 과립, 비드, 펠렛, 2상 이상을 포함하는 정제 형태나 캡슐, 다층, 코팅, 유핵, 매트릭스 형태 등의 일반 제제, 또는 위 또는 위장관상부에서 서방출되도록 조절한 모든 제제를 포함한다. 이상에서 살핀 바와 같이, 본 발명은 에페리손과 함께 산성화제, 지연방출제를 함께 포함시켜 제제화 할 수 있는데, 통상의 직타법이나 습식법, 건식법 등을 통해 제조할 수 있다.
Finally, the present invention includes granules, beads, pellets, tablets or capsules containing two or more phases, general formulations such as multilayers, coatings, nucleus, matrix, or all formulations controlled to be sustained in the stomach or gastrointestinal tract. do. As described above, the present invention can be formulated by including an acidifying agent and a delayed-release agent together with the eferison, it can be prepared through a conventional direct method, wet method, dry method and the like.
본 발명은 에페리손 함유 의약조성물에 관한 것으로서, 본 발명은 카보머, 시트르산 등의 특정 종류의 산성화제를 포함시켜 pH 5.6 이하 범위로 제제화함으로써, 제제의 제조 직후나 장기 보관중 산성화제가 포함되지 않은 제제나 종래 시판 제제에 비하여 20배 이상 안정성을 월등히 개선할 수 있었을 뿐만 아니라, 서방성 제제 특성상 장관에 장기 체류 중의 극한 환경에서도 용출특성의 변화 없이 주성분의 분해를 억제할 수 있는 효과가 있다. 또한, 본 발명은 특정 범위의 지연방출제를 조절함으로써 속효성 및 지효성을 필요로 하는 본 발명 약물의 특성을 잘 살릴 수 있는 이중방출 특성의 서방성 제제를 구현할 수 있는 효과가 있다.
The present invention relates to a pharmaceutical composition containing eferisone, the present invention is formulated to a pH of 5.6 or less by including a specific type of acidifying agent such as carbomer, citric acid, so that the acidifying agent is not included immediately after the preparation of the preparation or during long-term storage In addition to being able to significantly improve stability over 20 times compared to formulations and commercially available formulations, the sustained release formulation has the effect of suppressing decomposition of the main component without changing the dissolution properties even in the extreme conditions of long-term residence in the intestine. In addition, the present invention has the effect of realizing a sustained release formulation of a double-release property that can make good use of the properties of the drug of the present invention that requires fast and sustained release by controlling a delayed release agent in a specific range.
도 1은 본 발명에 따른 의약조성물로 제조된 정제에 대한 용출율 시험결과를 나타낸 그래프이다.1 is a graph showing the dissolution rate test results for the tablet prepared with the pharmaceutical composition according to the present invention.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.
Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples.
염산에페리손 75.0g, 미결정셀룰로오스 40.0g, 콜리돈에스알(상품명) 72.5g, 카보머 5.0g 및 시트르산 4.0g을 달아 비닐백에 넣고 10분간 혼합하였다. 추가로 콜로이드성 이산화규소 1.5g 및 스테아르산 마그네슘 2.0g을 달아 50메쉬(mesh) 체에 여과한 후 투입하여 3분간 혼합하여 최종혼합물로 하였다. 상기 혼합물을 타정기에서 압축하여 정제로 제조하였다. 정제는 1정당 400mg으로 하여 염산 에페리손으로써 150mg이 함유되도록 하였다.
75.0 g of eferisone hydrochloride, 40.0 g of microcrystalline cellulose, 72.5 g of collidone R (trade name), 5.0 g of carbomer, and 4.0 g of citric acid were weighed into a plastic bag and mixed for 10 minutes. In addition, 1.5 g of colloidal silicon dioxide and 2.0 g of magnesium stearate were weighed, filtered through a 50 mesh sieve, and mixed for 3 minutes to prepare a final mixture. The mixture was compressed into tablet presses to make tablets. The tablets were made up to 400 mg per tablet so as to contain 150 mg of eferisone hydrochloride.
염산에페리손 75.0g, 미결정셀룰로오스 55.0g, 콜리돈에스알(상품명) 50.0g 및 카보머 15.0g을 달아 비닐백에 넣고 10분간 혼합하였다. 추가로 콜로이드성 이산화규소 3.0g 및 스테아르산 마그네슘 2.0g을 달아 50메쉬 체에 여과한 후 투입하여 3분간 혼합하여 최종혼합물로 하였다. 상기 혼합물을 타정기에서 압축하여 정제로 제조하였다. 정제는 1정당 400mg으로 하여 염산에페리손으로써 150mg이 함유되도록 하였다.
75.0 g of eferisone hydrochloride, 55.0 g of microcrystalline cellulose, 50.0 g of collidone R (trade name) and 15.0 g of carbomer were weighed and mixed in a plastic bag for 10 minutes. In addition, 3.0 g of colloidal silicon dioxide and 2.0 g of magnesium stearate were added, filtered through a 50 mesh sieve, and then mixed for 3 minutes to obtain a final mixture. The mixture was compressed into tablet presses to make tablets. The tablets were made up to 400 mg per tablet to contain 150 mg of eferisone hydrochloride.
염산에페리손 300.0g, 미결정셀룰로오스 368.0g, 히드록시프로필 메칠셀룰로오스 100.0g, 카보머 4.0g 및 시트르산 16.0g을 달아 스피드믹서(기산기계, KM-5)에 넣고 아지테이터 100rpm으로 회전하여 3분간 혼합하였다. 추가로 물을 넣어 아지테이터 100rpm, 초파 1500rpm으로 회전하여 3분간 회전하여 과립물이 형성되도록 하였다. 형성된 과립물을 오븐에서 50℃ 조건으로 2시간 동안 건조한 후 오실레이터(Oscillator, ERWEKA사 AR-402)에서 20메쉬(표준 규격 KSA5101-1)를 이용하여 분쇄 및 정립하여 과립물을 제조하였다. 추가로 콜로이드성 이산화규소 4.0g 및 스테아르산마그네슘 8.0g을 달아 50메쉬 체에 여과한 후 투입하여 비닐백에서 3분간 혼합하여 최종혼합물로 하였다. 상기 혼합물을 타정기에서 압축하여 정제로 제조하였다. 정제는 1정당 400mg으로 하여 염산에페리손으로써 150mg이 함유되도록 하였다.
Add 300.0 g of Ephericone hydrochloride, 368.0 g of microcrystalline cellulose, 100.0 g of hydroxypropyl methylcellulose, 4.0 g of carbomer, and 16.0 g of citric acid, and place it in a speed mixer (KIS-5, KM-5). Mixed. Further water was added to rotate the agitator 100rpm, microwave 1500rpm to rotate for 3 minutes to form granules. The granules thus formed were dried in an oven at 50 ° C. for 2 hours, and then ground and granulated using 20 mesh (standard standard KSA5101-1) in an oscillator (Oscillator, AR-402, ERWEKA) to prepare granules. In addition, 4.0 g of colloidal silicon dioxide and 8.0 g of magnesium stearate were added, filtered through a 50 mesh sieve, and then mixed for 3 minutes in a plastic bag to obtain a final mixture. The mixture was compressed into tablet presses to make tablets. The tablets were made up to 400 mg per tablet to contain 150 mg of eferisone hydrochloride.
염산에페리손 300.0g, 미결정셀룰로오스 399.0g, 구연산 30.0g 및 유드라짓(상품명) RS PO 24.0g을 달아 스피드믹서(기산기계, KM-5)에 넣고 아지테이터 100rpm으로 회전하여 3분간 혼합하였다. 추가로 에탄올을 넣어 아지테이터 100rpm, 초파 1500rpm으로 회전하여 3분간 회전하여 과립물이 형성되도록 하였다. 형성된 과립물을 오븐에서 50℃ 조건으로 1시간 동안 건조한 후 오실레이터(Oscillator, ERWEKA사 AR-402)에서 20메쉬(표준 규격 KSA5101-1)를 이용하여 분쇄 및 정립하여 과립물을 제조하였다. 추가로 스테아르산 마그네슘 7.0g을 달아 50메쉬 체에 여과한 후 투입하여 비닐백에서 3분간 혼합하여 최종혼합물로 하였다. 상기 혼합물을 타정기에서 압축하여 정제로 제조하였다. 정제는 1정당 380mg으로 하여 염산에페리손으로써 150mg이 함유되도록 하였다.
300.0 g of Ephericone hydrochloride, 399.0 g of microcrystalline cellulose, 30.0 g of citric acid, and 24.0 g of Eudragit (trade name) were added to a speed mixer (KM-5), and the mixture was spun at 100 rpm and mixed for 3 minutes. . In addition, ethanol was added to rotate the agitator 100rpm, microwave 1500rpm to rotate for 3 minutes to form a granule. The granules thus formed were dried in an oven at 50 ° C. for 1 hour, and then ground and granulated using an oscillator (Oscillator, ERWEKA AR-402) using 20 mesh (standard standard KSA5101-1) to prepare granules. In addition, 7.0g of magnesium stearate was added, filtered through a 50 mesh sieve, and mixed for 3 minutes in a plastic bag to obtain a final mixture. The mixture was compressed into tablet presses to make tablets. The tablet was 380 mg per tablet so that 150 mg of eferison hydrochloride was contained.
염산에페리손 150.0g, 미결정셀룰로오스 33.8g, 콜리돈에스알(상품명) 110.0g, 카보머 12.0g 및 구연산 8.0g을 달아 비닐백에 넣고 10분간 혼합하였다. 추가로 콜로이드성이산화규소 3.0g 및 스테아르산 마그네슘 3.2g을 달아 50메쉬 체에 여과한 후 투입하여 3분간 혼합하여 약물층 혼합물로 하였다. 이와 별도로 미결정셀룰로오스 22.8g, 콜리돈에스알 80.0g, 카포머 6.0g, 구연산 5.0g 및 중탄산나트륨 15.0g을 달아 비닐백에 넣고 10분간 혼합한 후 스테아르산마그네슘 1.2g을 달아 50메쉬체에 여과한 후 투입하여 3분간 혼합하여 부유층 혼합물로 하였다. 약물층 320mg 및 부유층 130mg이 각 층에 포함되도록 이층정 타정기에서 압축하여 정제로 제조하였다. 정제는 1정당 450mg으로 하여 염산에페리손 150mg이 함유되도록 하였다.
150.0 g of eferisone hydrochloride, 33.8 g of microcrystalline cellulose, 110.0 g of collidone RS (trade name), 12.0 g of carbomer, and 8.0 g of citric acid were weighed and mixed in a plastic bag for 10 minutes. In addition, 3.0 g of colloidal silicon oxide and 3.2 g of magnesium stearate were added, filtered through a 50 mesh sieve, and then mixed for 3 minutes to obtain a drug layer mixture. Separately, 22.8 g of microcrystalline cellulose, 80.0 g of collidone R, 6.0 g of capper, 5.0 g of citric acid, and 15.0 g of sodium bicarbonate were weighed and mixed in a plastic bag for 10 minutes. Then, the mixture was added and mixed for 3 minutes to prepare a floating layer mixture. The drug layer 320mg and the floating layer 130mg was compressed into a two-layer tablet press so that each layer was prepared as a tablet. The tablets were made up to 450 mg per tablet to contain 150 mg of eferisone hydrochloride.
[비교예 1] Comparative Example 1
염산에페리손 75.0g, 미결정셀룰로오스 21.5g 및 콜리돈에스알(상품명) 100.0g을 달아 비닐백에 넣고 10분간 혼합하였다. 추가로 콜로이드성 이산화규소 1.5g 및 스테아르산 마그네슘 2.0g을 달아 50메쉬 체에 여과한 후 투입하여 3분간 혼합하여 최종혼합물로 하였다. 상기 혼합물을 타정기에서 압축하여 정제로 제조하였다. 정제는 1정당 400mg으로 하여 염산에페리손으로써 150mg이 함유되도록 하였다.
75.0 g of eferisone hydrochloride, 21.5 g of microcrystalline cellulose, and 100.0 g of collidone R (trade name) were weighed and mixed in a plastic bag for 10 minutes. In addition, 1.5 g of colloidal silicon dioxide and 2.0 g of magnesium stearate were added, filtered through a 50 mesh sieve, and then mixed for 3 minutes to obtain a final mixture. The mixture was compressed into tablet presses to make tablets. The tablets were made up to 400 mg per tablet to contain 150 mg of eferisone hydrochloride.
[비교예 2] Comparative Example 2
염산에페리손 300.0g, 미결정셀룰로오스 429.0g 및 유드라짓(상품명) RS PO 24.0g을 달아 스피드믹서(기산기계, KM-5)에 넣고 아지테이터 100rpm으로 회전하여 3분간 혼합하였다. 추가로 에탄올을 넣어 아지테이터 100rpm, 초파 1500rpm으로 회전하여 3분간 회전하여 과립물이 형성되도록 하였다. 형성된 과립물을 오븐에서 50℃ 조건으로 1시간 동안 건조한 후 오실레이터(Oscillator, ERWEKA사 AR-402)에서 20메쉬(표준 규격 KSA5101-1)를 이용하여 분쇄 및 정립하여 과립물을 제조하였다. 300.0 g of eferisone hydrochloride, 429.0 g of microcrystalline cellulose, and 24.0 g of Eudragit (trade name) RS PO were added to a speed mixer (KM-5, KM-5), and the mixture was spun at 100 rpm and mixed for 3 minutes. In addition, ethanol was added to rotate the agitator 100rpm, microwave 1500rpm to rotate for 3 minutes to form a granule. The granules thus formed were dried in an oven at 50 ° C. for 1 hour, and then ground and granulated using an oscillator (Oscillator, ERWEKA AR-402) using 20 mesh (standard standard KSA5101-1) to prepare granules.
추가로 스테아르산마그네슘 7.0g을 달아 50메쉬 체에 여과한 후 투입하여 비닐백에서 3분간 혼합하여 최종혼합물로 하였다. 상기 혼합물을 타정기에서 압축하여 정제로 제조하였다. 정제는 1정당 380mg으로 하여 염산에페리손으로써 150mg이 함유되도록 하였다.
In addition, 7.0 g of magnesium stearate was added, filtered through a 50 mesh sieve, and then mixed for 3 minutes in a plastic bag to obtain a final mixture. The mixture was compressed into tablet presses to make tablets. The tablet was 380 mg per tablet so that 150 mg of eferison hydrochloride was contained.
[실험예 1] Experimental Example 1
각 실시예 및 비교예에서 제조된 정제를 유발에서 분쇄하여 고운 가루로 한 후 1정 분량을 달아 100mL 정제수에 넣어 10분간 교반하여 완전히 혼합하도록 하였다. 각 용액의 pH를 pH 미터(Denver사, UB-5)를 이용하여 측정하였다.
The tablets prepared in Examples and Comparative Examples were ground in a mortar to make a fine powder, weighed in 1 tablet, and placed in 100 mL purified water for 10 minutes to be thoroughly mixed. The pH of each solution was measured using a pH meter (Denver, UB-5).
실험결과 구연산 또는 카보머 등의 산성화제를 첨가한 경우의 pH는 5.6 이하로 나타났으며, 그렇지 않은 경우의 비교예는 모두 6.0 이상의 pH를 나타내었다. 실시예 5의 경우 전체 정제의 pH는 약 6.69로 높게 나타났으나 이는 부유층에 함유된 중탄산나트륨에 의한 것으로 보이며, 이의 영향을 배제하기 위해 약물층만의 pH를 측정하였을 때는 4.38로 낮게 나타남을 확인하였다.
As a result of the experiment, the pH of the case of adding an acidifying agent such as citric acid or carbomer was found to be 5.6 or less, and all of the comparative examples otherwise showed a pH of 6.0 or more. In the case of Example 5, the pH of the whole tablet was about 6.69, but this was probably due to sodium bicarbonate contained in the suspended layer, and the pH of the drug layer alone was measured to be low as 4.38 to exclude the effect. .
[실험예 2] [Example 2]
각 실시예 및 비교예에서 제조된 정제를 HDPE 재질의 병에 넣어 마개를 한 후 온도 40℃, 상대습도 75%의 항온 항습기에 보관한 후 8주 동안 불순물의 생성 정도를 비교하였다. 불순물 측정은 각 정제를 0.1% 과염소산을 함유한 60% 메탄올 용액에 넣어 초음파 처리를 통해 충분히 녹인 후 0.45um 멤브레인 필터로 여과하여 액체 크로마토그래프법에 따라 시험하였다.
The tablets prepared in each Example and Comparative Example were put in a bottle made of HDPE, and capped, and then stored in a constant temperature and humidity chamber at a temperature of 40 ° C. and a relative humidity of 75%, and then the degree of generation of impurities was compared for 8 weeks. Impurity measurement was tested according to the liquid chromatograph method by dissolving each tablet in a 60% methanol solution containing 0.1% perchloric acid, solubilized sufficiently by sonication, and filtered through a 0.45um membrane filter.
Storage period
[실험예 3] [Example 3]
상기 실시예 1 및 비교예 1의 정제 각 1정을 pH6.8 완충액 100mL에 넣어 37℃에서 6시간 동안 방치하였다. 이후 0.1% 과염소산을 함유한 60% 메탄올 900mL를 추가로 넣어 초음파 처리를 통해 충분히 녹인 후 0.45um 멤브레인 필터로 여과하여 액체 크로마토그래프법에 따라 시험하여 불순물의 생성 정도를 비교하였다.
Each tablet of Example 1 and Comparative Example 1 was put in 100 mL of pH6.8 buffer and left at 37 ° C. for 6 hours. Thereafter, 900 mL of 60% methanol containing 0.1% perchloric acid was further added, and then sufficiently dissolved by sonication, filtered through a 0.45 um membrane filter, and tested according to a liquid chromatograph method.
이상에서 살핀 바와 같이, 기존 에페리손 제제는 1일 3회 복용하는 즉시 방출 제제로 제조되어 시판되고 있으며, 이러한 제제는 30분에서 1시간 사이에 붕해가 완료되기 때문에 위에서 머무르는 동안 신속히 붕해되어 약물의 흡수가 이루어지게 된다. 그러나 본 발명에서와 같은 서방성 제제는 위에서 체류하는 시간 뿐 아니라 소장을 통과하는 시간 동안에도 정제의 붕해가 완전히 이루어지지 않아 정제 내에 약물을 계속 함유한 상태로 이동하게 된다. As described above, the conventional epherisone preparation is commercially prepared and released as an immediate release formulation three times daily, and since such disintegration is completed within 30 minutes to 1 hour, it disintegrates rapidly during the stay in the stomach, Absorption is achieved. However, the sustained-release preparation as in the present invention does not completely disintegrate during the time of staying in the stomach as well as the time of passing through the small intestine, so that the drug continues to contain the drug in the tablet.
본 발명에서도 위에서 체류하는 동안 주성분인 에페리손은 약 30 내지 40% 가량만이 방출되고, 남은 양은 붕해되지 않은 정제 내에 남아 소장을 통과하면서 서서히 방출되는 양상을 나타내게 된다. 이 경우 정제 내에 남아있는 에페리손은 소장의 높은 pH에 의해 빠르게 분해되기 시작한다. In the present invention, while only about 30 to 40% of the main component of the erythrosine is released during the stomach, the remaining amount is gradually released while passing through the small intestine while remaining in the undisintegrated tablet. In this case, the eferisons remaining in the tablets begin to degrade rapidly by the high pH of the small intestine.
따라서 에페리손을 함유한 서방제의 경우 소장의 높은 pH에서도 안정함을 유지하기 위한 정제 내의 내부 환경의 pH를 낮게 유지할 필요가 있었으며, 본 발명자들은 이에 정제 내에 산성화제를 첨가함으로써 pH6.8 완충액의 환경에서 에페리손의 분해산물이 현저히 낮게 생성됨을 확인할 수 있었다.
Therefore, it was necessary to keep the pH of the internal environment in the tablet low to maintain stability even at high pH of the small intestine in the case of the sustained-release agent containing eperisone. In the environment it was confirmed that the degradation products of eferison is produced significantly lower.
[실험예 4] [Example 4]
상기 실시예의 정제 각 1정을 37℃, pH 1.2 완충액에 넣어 패들법으로 50rpm의 조건에서 용출시험을 진행하였다. 각 시점에서 5mL를 채취하여 멤브레인 필터로 여과한 후 액체 크로마토그래프법으로 유효성분의 용출율을 측정하고, 그 결과를 다음 표 4 및 첨부 도 1에 나타내었다.
Each tablet of the tablet of Example 1 was put in a buffer of pH 1.2 at 37 ℃, the dissolution test was carried out at 50rpm conditions by the paddle method. 5mL was collected at each time point, filtered through a membrane filter, and the elution rate of the active ingredient was measured by liquid chromatography, and the results are shown in Table 4 and the accompanying FIG. 1.
상기 결과와 같이 초기 1시간까지는 평균 분당 0.51~0.56%의 방출속도를 나타내며 신속하게 30%이상의 약물을 한 시간 동안 방출하였다. 이는 기존 시판의약품인 즉시방출제제 1정에 해당하는 양으로써 신속한 효과발현을 위해 필요한 양이라고 할 수 있다. 이후 6시간까지는 평균 분당 0.11~0.12%의 속도로 방출이 진행되어 장시간에 걸쳐 안정한 형태의 약물방출 구조를 나타내고 있음을 확인할 수 있었다. 결과적으로, 본 발명에 따라 구성된 서방제제는 이중방출패턴을 나타냄을 확인하였으며, 이는 초기 신속한 효과와 더불어 약물의 복용횟수를 줄이면서도 지속적인 치료 효과를 나타낼 수 있다. As shown in the above results, the release rate was 0.51 to 0.56% per minute until the first hour, and more than 30% of the drug was rapidly released for one hour. This amount is equivalent to one tablet of the existing commercial drug immediate release agent, which can be said to be necessary for rapid effect expression. After 6 hours, the release progressed at an average rate of 0.11 to 0.12% per minute, indicating that the drug release structure was stable over a long period of time. As a result, it was confirmed that the sustained release formulation according to the present invention exhibits a double release pattern, which may exhibit a continuous therapeutic effect while reducing the number of times of taking the drug with an initial rapid effect.
Claims (7)
An acidic pH adjusting agent or an acidifying agent selected from the group consisting of an excipient exhibiting a pH of 5.0 or less when suspended, dissolved, swelled, or mixed in water, and has an acidity of 0.5 to 5.6 when prepared in a 0.5% (W / V) aqueous solution. Stable ephericone-containing sustained-release pharmaceutical composition, characterized in that.
According to claim 1, wherein the excipient exhibiting a pH of 5.0 or less, stable eferison containing sustained-release pharmaceutical composition, characterized in that at least one selected from the group consisting of carbomer, polycarbophil and polydextrose.
The pharmaceutical composition of claim 1, wherein the pharmaceutical composition additionally contains 0.05 to 3 parts by weight of a delayed release agent based on 1 part by weight of eferison hydrochloride, wherein the delayed release agent is methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxy. Propyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose; Polysaccharides, polyacrylates, hydrogels, polyvinyl alcohols, polyvinylpyrrolidones, carbopol, polyethylene oxides, magnesium aluminum silicates, starch derivatives; Copolymers of acrylic acid and methacrylic acid esters, polyethylene, polyamides, polyvinylchlorides, polyvinylacetates, polyvinyl alcohols; A stable ephericone-containing sustained-release pharmaceutical composition, characterized in that it is at least one selected from the group consisting of polyacrylic acid, acrylic resin, acrylic latex dispersion, cellulose acetate phthalate, polyvinylacetate phthalate, and hydroxypropylmethylcellulose phthalate.
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KR1020110106388A KR101156054B1 (en) | 2011-09-05 | 2011-10-18 | A stable and control-released pharmaceutical composition comprising eperisone |
CN201280051152.3A CN103889455B (en) | 2011-10-18 | 2012-03-28 | Stabilize Eperisone medical component and the sustained release preparation containing above-mentioned constituent |
BR112014009506A BR112014009506B1 (en) | 2011-10-18 | 2012-03-28 | stabilized sustained-release preparation containing eperisone |
MX2014004652A MX346661B (en) | 2011-09-05 | 2012-03-28 | Stabilized eperisone medical composition, and sustained-release preparation containing same. |
PCT/KR2012/002288 WO2013058450A1 (en) | 2011-10-18 | 2012-03-28 | Stabilized eperisone medical composition, and sustained-release preparation containing same |
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Cited By (7)
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WO2013105819A1 (en) * | 2012-01-13 | 2013-07-18 | Hanmi Pharm. Co., Ltd. | Stable pharmaceutical composition comprising eperisone or a pharmaceutically acceptable salt thereof and an acidifying agent |
WO2014157852A1 (en) * | 2013-03-29 | 2014-10-02 | 초당약품공업 주식회사 | Sustained-release medicinal composition containing eperisone as active ingredient |
WO2014157851A1 (en) * | 2013-03-29 | 2014-10-02 | 초당약품공업 주식회사 | Eperisone pharmaceutical composition having improved preservability and ph stability |
KR101760278B1 (en) | 2016-08-29 | 2017-07-21 | 초당약품공업 주식회사 | Process for preparing sustained release microsphere including eperisone as active ingredient |
KR101799321B1 (en) | 2016-08-29 | 2017-11-20 | 초당약품공업 주식회사 | The complex formulation of eperisone sustained release microsphere and aceclofenac |
KR20200117138A (en) | 2019-04-03 | 2020-10-14 | 위더스제약주식회사 | Eperisone-containing pharmaceutical having improved storage-stability |
KR20210088285A (en) * | 2020-01-06 | 2021-07-14 | (주)휴온스 | Pharmaceutical formulation containing methylergometrine maleate with improved stability and method preparing the same |
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KR101230178B1 (en) | 2010-06-10 | 2013-02-06 | 주식회사 네비팜 | A composition for treating or preventing osteoporosis and a method of preparing the same |
WO2018044020A1 (en) * | 2016-08-29 | 2018-03-08 | 초당약품공업 주식회사 | Method for preparing eperisone sustained release microsphere, and composite preparation of eperisone sustained release microsphere and aceclofenac |
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WO2013105819A1 (en) * | 2012-01-13 | 2013-07-18 | Hanmi Pharm. Co., Ltd. | Stable pharmaceutical composition comprising eperisone or a pharmaceutically acceptable salt thereof and an acidifying agent |
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WO2014157851A1 (en) * | 2013-03-29 | 2014-10-02 | 초당약품공업 주식회사 | Eperisone pharmaceutical composition having improved preservability and ph stability |
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KR101760278B1 (en) | 2016-08-29 | 2017-07-21 | 초당약품공업 주식회사 | Process for preparing sustained release microsphere including eperisone as active ingredient |
KR101799321B1 (en) | 2016-08-29 | 2017-11-20 | 초당약품공업 주식회사 | The complex formulation of eperisone sustained release microsphere and aceclofenac |
KR20200117138A (en) | 2019-04-03 | 2020-10-14 | 위더스제약주식회사 | Eperisone-containing pharmaceutical having improved storage-stability |
KR20210088285A (en) * | 2020-01-06 | 2021-07-14 | (주)휴온스 | Pharmaceutical formulation containing methylergometrine maleate with improved stability and method preparing the same |
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