KR20130008496A - Oral pharmaceutical composition for sustained release containing guanfacine - Google Patents
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Abstract
본 발명은 구안파신 2 중량%에 희석제로서 유당 55～65 중량%와 중성 수팽윤성 방출 제어용 고분자로서 하이드록시프로필메틸셀룰로스 13～17 중량%, 음이온성 수팽윤성 방출 제어용 고분자로서 폴리아크릴산나트륨 13～17 중량%, 붕해제로서 크로스카멜로스나트륨 3～5 중량%, 결합제로서 폴리비닐피롤리돈 2～4 중량% 및 윤활제로서 스테아르산마그네슘 0.8～1.2 중량%를 혼합시켜 과립화시킨 후 타정시켜 제조된 구안파신 서방성 정제 조성물에 관한 것이다.The present invention relates to 2% by weight of guanfacin, 55-65% by weight of lactose as a diluent, 13-17% by weight of hydroxypropylmethylcellulose as a polymer for controlling neutral water swellability, and 13-17% of polyacrylic acid as a polymer for controlling anionic water swellability. Prepared by granulation after mixing by weight, 3 to 5% by weight of croscarmellose sodium as disintegrant, 2 to 4% by weight of polyvinylpyrrolidone as binder and 0.8 to 1.2% by weight of magnesium stearate as lubricant Guanpacin sustained-release tablet composition.
Description
본 발명은 구안파신(guanfacine)을 활성 성분으로 함유하는 경구용 서방성 약제학적 조성물에 관한 것이다. 더욱 상세하게는 주의력 결핍 과잉행동장애(ADHD)의 치료에 사용되는 구안파신의 경구용 서방성 정제의 약제학적 조성물에 관한 것이다.
The present invention relates to an oral sustained release pharmaceutical composition containing guanfacine as an active ingredient. More particularly, the present invention relates to pharmaceutical compositions of oral sustained release tablets of guanpacin used for the treatment of attention deficit hyperactivity disorder (ADHD).
N-(디아미노메틸리덴)-2-(2,6-디클로로페닐)아세트아미드의 화학명을 지닌 하기 식 Ⅰ로 나타나는 구안파신 또는 그의 염산염은 선택적 알파2 A-아드레날린 수용체 효용제로 알려져 있으며 수축기 및 이완기 혈압을 감소시키는 항 고혈압제로 사용되어 왔다. 그러나 최근 항 고혈압제로서의 의약용도 이외에 주의력 결핍 과잉행동장애(ADHD)의 치료제로서 FDA로부터 승인 받고 임상에 적용되고 있다.
N - (diamino-methylidene) -2- (2,6-dichlorophenyl) Development and pasin or its hydrochloride represented by the following formula having the chemical name Ⅰ acetamide is selective alpha 2 A - adrenoceptor known utility agent, and systolic and diastolic It has been used as an antihypertensive agent to reduce blood pressure. Recently, however, the drug has been approved by the FDA and applied in clinical practice as a treatment for attention deficit hyperactivity disorder (ADHD) in addition to its use as an antihypertensive drug.
주의력 결핍/과잉행동 장애(ADHD)는 아동기에 많이 나타나는 장애로 지속적으로 주의력이 부족하여 산만하고 과다활동 충동성을 보이는 상태를 말한다. 이러한 증상들을 치료하지 않고 방치할 경우 아동기 내내 여러 방면에서 어려움이 지속되고 일부의 경우 청소년기와 성인기가 되어서도 증상이 남게 된다.
Attention deficit / hyperactivity disorder (ADHD) is a condition characterized by many disturbances in childhood characterized by distracted and hyperactivity impulsivity due to lack of continuous attention. If left untreated, the symptoms persist in many ways throughout childhood, and in some cases, symptoms remain in adolescence and adulthood.
그러나 이 질환의 정확한 원인은 현재까지 알려진 바가 없으나 뇌영상 촬영에서 정상인에 비해 활동과 주의집중을 조절하는 부위의 뇌 활성이 떨어지는 소견이 관찰되며 이 부위의 구조적 차이도 발견되고 있다.
However, the exact cause of the disease has not been known to date, but in brain imaging, there is a decrease in the activity of the brain, which controls activity and attention, compared to normal people, and structural differences are found.
ADHD에는 약물치료가 효과적이다. 약물 치료를 통해 80% 정도가 분명한 호전을 보이는데 집중력 기억력 학습능력이 전반적으로 좋아진다. 이러한 ADHD의 효과적 약물로서 최근 구안파신이 각광받고 있다.
Medication is effective for ADHD. About 80% of the medications show a clear improvement, which improves concentration, memory, and learning. Guanfasin has recently been in the spotlight as an effective drug of ADHD.
구안파신은 물에 대한 용해성이 높고 생체 이용률 역시 우수한 약물로 알려져 있고 신장을 통해 쉽게 배출된다. 그러나 구안파신은 응집성 및 결정구조와 관련된 인자 때문에 그 제제화가 통상적인 정제 또는 캡슐제와 같은 경구용 제제로 제형화시킬 때에는 적정한 입도를 지닌 구안파신 미세 분말을 균질하게 분산시켜 부형제와 적절한 조건하에서 경구용 제제로 제형화시켜야 하는 어려움이 있었던 것이다.
Guanfacin is known for its high solubility in water and good bioavailability and is easily released through the kidneys. However, due to factors related to cohesiveness and crystal structure, guanfacin is orally administered under excipients and appropriate conditions by homogeneously dispersing the fine granules of guanfacin with appropriate particle size when formulated into oral preparations such as tablets or capsules. There was a difficulty in formulating a formulation.
한편으로는 구안파신은 소아 또는 청소년에게 경구 투여하는 약물이므로 용법 용량을 개선시켜 1일 1회 투여 용량으로의 경구 투여 제형이 요구되며 따라서 인체 내에서 지속적 방출 특성을 지닌 서방성 정제 형태의 경구 투여 형태의 개발이 요구되어왔던 것이다.
On the other hand, since guanfacin is a drug administered orally to children or adolescents, an oral dosage form is required in a once-daily dosage by improving the dosage. Therefore, oral administration in the form of sustained-release tablets with sustained release characteristics in the human body is required. Form development has been required.
따라서 본 발명자들은 구안파신의 적절한 입도를 조절하여 균질하게 분산시킨 후 적절한 부형제로 과립화시킨 정제형 경구 투여 제형을 개발하던 중, 구안파신에 희석제로 유당, 중성 수팽윤성 방출 제어용 고분자로서 하이드록시프로필메틸셀룰로스(HPMC), 음이온성 수팽윤성 방출 제어용 고분자로서 폴리아크릴산나트륨, 붕해제로 크로스카멜로스나트륨, 결합제로 폴리비닐피롤리돈, 윤활제로 스테아르산마그네슘을 사용할 때 최적의 지속적 방출 특성을 지닌 구안파신 서방성 정제를 제조할 수 있음을 발명함으로써 본 발명을 완성하게 된 것이다
Therefore, the present inventors are developing a tablet-type oral dosage form which is homogeneously dispersed by controlling the proper particle size of guanfacin and then granulated with an appropriate excipient, and hydroxypropyl as a polymer for controlling lactose and neutral water swellable release as a diluent in guanfacin. Methyl cellulose (HPMC), an anionic water swellable polymer for controlling the release of sodium polyacrylate, croscarmellose sodium as a disintegrant, polyvinylpyrrolidone as a binder, and magnesium stearate as a lubricant. The present invention has been completed by inventing the facin sustained release tablet.
따라서 본 발명이 해결하고자 하는 과제는 구안파신의 적절한 입도를 조절하여 균질하게 분산시킨 후 적절한 부형제로 과립화시킨 정제형 경구 투여 제형을 개발코자 한 것이다. 구안파신에 희석제로 유당, 중성 수팽윤성 방출 제어용 고분자로서 하이드록시프로필메틸셀룰로스(HPMC), 음이온성 수팽윤성 방출 제어용 고분자로서 폴리아크릴산나트륨, 붕해제로 크로스카멜로스나트륨, 결합제로 폴리비닐피롤리돈, 윤활제로 스테아르산마그네슘을 사용함으로써 최적의 지속적 방출 특성을 지닌 구안파신 서방성 정제를 개발코자 한 것이다.
Therefore, the problem to be solved by the present invention is to develop a tablet oral dosage form which is homogeneously dispersed by controlling the proper particle size of guanpacin and then granulated with an appropriate excipient. Lactose as a diluent to guanfacine, hydroxypropylmethylcellulose (HPMC) as a polymer for controlling the control of neutral water swellability, sodium polyacrylate as a polymer for controlling anionic water swellability, sodium croscarmellose as disintegrant, polyvinylpyrrolidone as a binder In order to develop a sustained release tablet of guanfacin with optimal sustained release properties, magnesium stearate is used as a lubricant.
본 발명의 목적은 구안파신 2 중량%에 희석제로서 유당 55～65 중량%와 중성 수팽윤성 방출 제어용 고분자로서 하이드록시프로필메틸셀룰로스 13～17 중량%, 음이온성 수팽윤성 방출 제어용 고분자로서 폴리아크릴산나트륨 13～17 중량%, 붕해제로서 크로스카멜로스나트륨 3～5 중량%, 결합제로서 폴리비닐피롤리돈 2～4 중량% 및 윤활제로서 스테아르산마그네슘 0.8～1.2 중량%를 혼합시켜 과립화시킨 후 타정시켜 제조된 구안파신 서방성 정제 조성물을 제공하는 것이다.
The object of the present invention is 2% by weight of guanfacin, 55-65% by weight of lactose as a diluent and 13-17% by weight of hydroxypropylmethylcellulose as a polymer for controlling neutral water swellability, and sodium polyacrylate 13 as a polymer for controlling anionic water swellability. ˜17% by weight, 3-5% by weight of croscarmellose sodium as disintegrant, 2-4% by weight of polyvinylpyrrolidone as binder and 0.8-1.2% by weight of magnesium stearate as lubricant, followed by granulation It is to provide a prepared guanfasin sustained-release tablet composition.
이때 유효 활성성분인 구안파신의 함량은 0.5～4mg 임을 특징으로 한다.
At this time, the content of guanfasin active ingredient is characterized in that 0.5 ~ 4mg.
본 발명의 또다른 목적은 ⅰ) 구안파신 2 중량%에 희석제로서 유당 55～65 중량%와 중성 수팽윤성 방출 제어용 고분자로서 하이드록시프로필메틸셀룰로스 13～17 중량%, 음이온성 수팽윤성 방출 제어용 고분자로서 폴리아크릴산나트륨 13～17 중량%, 붕해제로서 크로스카멜로스나트륨 3～5 중량%, 결합제로서 폴리비닐피롤리돈 2～4 중량% 및 윤활제로서 스테아르산마그네슘 0.8～1.2 중량%를 혼합시켜 혼합물의 입도를 500㎛ 이하로 세분말화시킨 후 과립화시키는 단계; 및 ⅱ) 건조된 과립화 혼합물을 정제로 압착 타정시키는 단계;로 이루어진 구안파신 서방성 정제 조성물의 제조 방법을 제공하는 것이다.
Another object of the present invention is iii) 55% to 65% by weight of lactose as a diluent in guanfasin and 13 to 17% by weight of hydroxypropylmethylcellulose as a polymer for controlling neutral water swellable release, and a polymer for controlling anionic water swellable release. 13 to 17% by weight of sodium polyacrylate, 3 to 5% by weight of croscarmellose sodium as disintegrant, 2 to 4% by weight of polyvinylpyrrolidone as binder and 0.8 to 1.2% by weight of magnesium stearate as lubricant Granulating the particle size to 500 μm or less and then granulating it; And ii) compressing the dried granulation mixture into a tablet; to provide a method for producing a guanfacin sustained-release tablet composition consisting of.
본 발명의 또다른 목적은 상기 구안파신 서방성 정제 조성물을 주의력 결핍 과잉행동장애(ADHD) 치료제로서 사용하는 방법을 제공하는 것이다.
It is another object of the present invention to provide a method of using the guanpacin sustained release tablet composition as a therapeutic agent for attention deficit hyperactivity disorder (ADHD).
본 발명의 효과는 구안파신의 적절한 입도를 조절하여 균질하게 분산시킨 후 적절한 부형제로 과립화시킨 정제형 경구 투여 제형을 제공하는 것이다. 구안파신에 희석제로 유당, 중성 수팽윤성 방출 제어용 고분자로서 하이드록시프로필메틸셀룰로스(HPMC), 음이온성 수팽윤성 방출 제어용 고분자로서 폴리아크릴산나트륨, 붕해제로 크로스카멜로스나트륨, 결합제로 폴리비닐피롤리돈, 윤활제로 스테아르산마그네슘을 사용함으로써 최적의 지속적 방출 특성을 지닌 구안파신 서방성 정제를 제공하는 것이다.
The effect of the present invention is to provide a tablet oral dosage form which is homogeneously dispersed by controlling the proper particle size of guanpacin and then granulated with an appropriate excipient. Lactose as a diluent to guanfacine, hydroxypropylmethylcellulose (HPMC) as a polymer for controlling the control of neutral water swellability, sodium polyacrylate as a polymer for controlling anionic water swellability, sodium croscarmellose as disintegrant, polyvinylpyrrolidone as a binder By using magnesium stearate as a lubricant, Guanfasin sustained-release tablets with optimal sustained release properties are provided.
도 1은 제조실시예 1, 제조비교예 1, 3, 4, 5에서 제조된 정제의 시간 변화에 따른 용출율을 나타내는 그래프이다.1 is a graph showing the dissolution rate according to the time change of the tablets prepared in Preparation Example 1, Preparation Comparative Examples 1, 3, 4, 5.
본 발명은 구안파신 2 중량%에 희석제로서 유당 55～65 중량%와 중성 수팽윤성 방출 제어용 고분자로서 하이드록시프로필메틸셀룰로스 13～17 중량%, 음이온성 수팽윤성 방출 제어용 고분자로서 폴리아크릴산나트륨 13～17 중량%, 붕해제로서 크로스카멜로스나트륨 3～5 중량%, 결합제로서 폴리비닐피롤리돈 2～4 중량% 및 윤활제로서 스테아르산마그네슘 0.8～1.2 중량%를 혼합시켜 과립화시킨 후 타정시켜 제조된 구안파신 서방성 정제 조성물에 관한 것이다.
The present invention relates to 2% by weight of guanfacin, from 55 to 65% by weight of lactose as a diluent, and 13 to 17% by weight of hydroxypropylmethylcellulose as a polymer for controlling neutral water swellability, and to 13 to 17% of sodium polyacrylate as a polymer for controlling anionic water swellability. Prepared by granulation after mixing by weight, 3 to 5% by weight of croscarmellose sodium as disintegrant, 2 to 4% by weight of polyvinylpyrrolidone as binder and 0.8 to 1.2% by weight of magnesium stearate as lubricant Guanpacin sustained-release tablet composition.
상기 구안파신 서방성 정제 조성물에 사용되는 희석제로서는 유당 44～50 중량%를 사용하였다. 이러한 희석제는 담체 물질로서 함유되는 것이다. 상기한 희석제를 사용할 때 구안파신의 방출 속도, 안정성, 유동성 및 건조 특성이 최대로 유지된다.
As the diluent used in the guanfacin sustained-release tablet composition, lactose 44-50% by weight was used. Such diluents are those which are contained as carrier materials. When using the diluents described above, the release rate, stability, flowability and drying properties of guanpacin are maintained to the maximum.
희석제로 사용되는 유당의 경우 락토오즈, 무수락토오즈, 락토오즈 1 수화물, 분무 건조된 락토오즈 등을 사용할 수 있다.
In the case of lactose used as a diluent, lactose, anhydrous lactose, lactose monohydrate, spray dried lactose and the like can be used.
또한 방출 제어용 고분자로서 중성 수팽윤성 방출 제어용 고분자 하이드록시프로필메틸셀룰로스 13～17 중량%와 음이온성 수팽윤성 방출 제어용 고분자 폴리아크릴산나트륨 13～17 중량%를 사용한다. 이는 상기 2종의 방출 제어용 고분자를 매트릭스 형태로 혼합시켜 구안파신의 방출을 제어하여 서방성 정제로 제조하기 위한 것이다.
As the release controlling polymer, 13 to 17% by weight of the neutral water swellable release controlling polymer hydroxypropylmethylcellulose and 13 to 17% by weight of the anionic water swellable release controlling polymer sodium polyacrylate are used. This is to prepare a sustained-release tablet by controlling the release of guanpacin by mixing the two release control polymers in the form of a matrix.
일반적으로 중성 수팽윤성 중합체는 알킬셀룰로오스 하이드록시알킬셀룰로오스 카르복시알킬셀룰로오스 에스테르 기타 천연 반합성 또는 합성 디사카라이드 올리고사카라이드 및 폴리사카라이드 등을 사용할 수 있으나 본 발명에서는 하이드록시프로필메틸셀룰로오스(HPMC)를 사용한다. 이때 사용되는 HPMC의 경우 바람직한 점도는 60,000 cps 내지 120,000 cps 정도이고 점도가 120,000 cps를 초과하면 약물과의 균일한 혼합이 어려워진다.
In general, the neutral water swellable polymer may be alkyl cellulose hydroxyalkyl cellulose carboxyalkyl cellulose ester and other natural semi-synthetic or synthetic disaccharide oligosaccharides and polysaccharides, but in the present invention hydroxypropyl methyl cellulose (HPMC) is used do. In the case of HPMC used, the preferred viscosity is about 60,000 cps to 120,000 cps, and if the viscosity exceeds 120,000 cps, uniform mixing with the drug becomes difficult.
또한 음이온성 수팽윤성 중합체는 아크릴산중합체 메타크릴산공중합체 알긴산염 키틴유도체 등을 사용할 수 있으나 본 발명에서는 아크릴산중합체 중 폴리아크릴산나트륨을 사용한다.
In addition, the anionic water swellable polymer may be an acrylic acid methacrylic acid copolymer alginate chitin derivative or the like, but in the present invention, sodium polyacrylate is used in the acrylic acid polymer.
한편 구안파신 서방성 정제 조성물에 사용되는 붕해제로서는 크로스카멜로스나트륨 3～5 중량%를 사용하고 크로스카멜로스나트륨은 우수한 과립 내 붕해 능력을 부여한다.
On the other hand, 3 to 5% by weight of croscarmellose sodium is used as the disintegrant used in the guanfacin sustained-release tablet composition, and croscarmellose sodium gives excellent disintegration ability in granules.
또한 구안파신 서방성 정제 조성물에 사용되는 결합제로서 폴리비닐피롤리돈 2～4 중량%를 사용하고 이러한 결합제는 정제화되는 분말에 충분한 응집성을 부여함으로써 윤활, 압축 및 포장과 같은 각종 정제 제형화 조작을 용이하게 한다. 또한 폴리비닐피롤리돈은 과립화 분말 혼합물에 응집성을 제공하여 과립을 형성하는데 필요한 결합을 촉진시킨다. 폴리비닐피롤리돈을 함유하여 과립화시켜 제조된 본 발명의 서방성 정제 조성물은 상대적으로 우수한 생체 이용률을 나타내는 것이다.
In addition, 2 to 4% by weight of polyvinylpyrrolidone is used as the binder used in the guanfacin sustained-release tablet composition, and the binder imparts sufficient cohesiveness to the powder to be tableted to perform various tablet formulation operations such as lubrication, compression, and packaging. To facilitate. Polyvinylpyrrolidone also provides cohesiveness to the granulated powder mixture to promote the binding necessary to form granules. The sustained release tablet compositions of the present invention prepared by granulation containing polyvinylpyrrolidone exhibit relatively good bioavailability.
또한 구안파신 서방성 정제 조성물에 사용되는 윤활제로서 스테아르산마그네슘 0.8～1.2 중량%를 사용한다. 스테아르산마그네슘은 정제 제형의 압축시 타정 압축 장치와 과립 혼합물간의 마찰력을 감소시켜 바람직한 형상으로 정제 제형을 제조할 수 있게 한다.
In addition, magnesium stearate 0.8-1.2% by weight is used as a lubricant used in the guanfacin sustained-release tablet composition. Magnesium stearate reduces the friction between the tableting compression device and the granule mixture upon compression of the tablet formulation, allowing the preparation of the tablet formulation in the desired shape.
본 발명의 서방성 정제 조성물 내의 유효 활성성분인 구안파신의 함량은 0.5～4mg 임을 특징으로 한다. 이는 통상 ADHD 치료시 1일 투여 함량이 4mg 이하임을 감안한 것으로 본 발명의 서방성 정제 조성물은 바람직하게는 1일 1회 투여하나 필요시 1일 2회 투여가 가능한 것이다.
The content of guanfasin, the active ingredient in the sustained-release tablet composition of the present invention is characterized in that 0.5 ~ 4mg. This is generally considered that the daily dosage content of 4 mg or less in the treatment of ADHD, the sustained-release tablet composition of the present invention is preferably administered once a day, but can be administered twice a day if necessary.
한편 본 발명의 정제 제형의 제조 방법을 살펴보면 다음과 같다.
On the other hand look at the manufacturing method of the tablet formulation of the present invention.
첫 번째 단계는 구안파신 30 중량%에 희석제로서 유당 44～50 중량%, 중성 수팽윤성 방출 제어용 고분자로서 하이드록시프로필메틸셀룰로스 13～17 중량%, 음이온성 수팽윤성 방출 제어용 고분자로서 폴리아크릴산나트륨 13～17 중량%, 붕해제로서 크로스카멜로스나트륨 3～5 중량%, 결합제로서 폴리비닐피롤리돈 2～4 중량% 및 윤활제로서 스테아르산마그네슘 0.8～1.2 중량%를 혼합시켜 혼합물의 입도를 500㎛ 이하로 조절시킨 후 과립화시키는 단계이다.
The first step is 30-50% by weight of guanfacin, 44-50% by weight of lactose as a diluent, 13-17% by weight of hydroxypropylmethylcellulose as a neutral water swellable release control polymer, and 13 ~ 17% by weight of polyacrylate as an anionic water-swellable release control polymer. 17% by weight, 3-5% by weight of croscarmellose sodium as disintegrant, 2-4% by weight of polyvinylpyrrolidone as binder, and 0.8-1.2% by weight of magnesium stearate as lubricant were mixed to obtain a particle size of 500 µm or less. It is granulation after adjusting to.
또한 두 번째 단계는 건조된 과립화 혼합물을 정제로 압착 타정시키는 단계이다. 이때 건조는 예를 들면 오븐 또는 유동층 건조기에서 건조됨으로써 건조 과립이 형성된다. 건조된 과립을 압착시켜 정제로 타정시키며 적당한 형태의 압착 장치 또는 타정 장치를 사용하여 정제로 압착 타정시키는 것이다.
The second step is also compression compression of the dried granulation mixture into tablets. At this time, the drying is for example dried in an oven or a fluid bed dryer to form dry granules. The dried granules are compressed and compressed into tablets and compressed into tablets using a compression device or tableting device of a suitable type.
이하 본 발명을 실시예 및 비교예를 통해 더욱 상세히 설명한다.
Hereinafter, the present invention will be described in more detail with reference to examples and comparative examples.
(제조실시예 1) 본 발명의 서방성 정제 조성물의 제조
Preparation Example 1 Preparation of a Sustained Release Tablet Composition of the Present Invention
구안파신 2 중량%에 희석제로서 유당 60 중량%, 중성 수팽윤성 방출 제어용 고분자로서 하이드록시프로필메틸셀룰로스 15 중량%, 음이온성 수팽윤성 방출 제어용 고분자로서 폴리아크릴산나트륨 15 중량%, 붕해제로서 크로스카멜로스나트륨 4 중량%, 결합제로서 폴리비닐피롤리돈 3 중량% 및 윤활제로서 스테아르산마그네슘 1.0 중량%를 혼합시켜 과립화시킨 후 타정시켜 제조된 구안파신 서방성 정제 조성물을 제조한다.
60% by weight of lactose as a diluent, 2% by weight of guanfacin, 15% by weight of hydroxypropylmethylcellulose as a neutral water-swellable release controlling polymer, 15% by weight of sodium polyacrylate as anionic water-swellable release controlling polymer, croscarmellose as a disintegrant Guanpacin sustained-release tablet compositions prepared by granulating by mixing 4% by weight of sodium, 3% by weight of polyvinylpyrrolidone as a binder, and 1.0% by weight of magnesium stearate as lubricants are then granulated and compressed into tablets.
(제조실시예 2) 본 발명의 서방성 정제 조성물의 제조
Preparation Example 2 Preparation of Sustained Release Tablet Composition of the Present Invention
구안파신 2 중량%에 희석제로서 유당 58 중량%, 중성 수팽윤성 방출 제어용 고분자로서 하이드록시프로필메틸셀룰로스 16 중량%, 음이온성 수팽윤성 방출 제어용 고분자로서 폴리아크릴산나트륨 16 중량%, 붕해제로서 크로스카멜로스나트륨 4 중량%, 결합제로서 폴리비닐피롤리돈 3 중량% 및 윤활제로서 스테아르산마그네슘 1.0 중량%를 혼합시켜 과립화시킨 후 타정시켜 제조된 구안파신 서방성 정제 조성물을 제조한다.
58% by weight of lactose as a diluent, 2% by weight of guanfacin, 16% by weight of hydroxypropylmethylcellulose as a neutral water-swellable release controlling polymer, 16% by weight of sodium polyacrylate as anionic water-swellable release controlling polymer, croscarmellose as a disintegrant Guanpacin sustained-release tablet compositions prepared by granulating by mixing 4% by weight of sodium, 3% by weight of polyvinylpyrrolidone as a binder, and 1.0% by weight of magnesium stearate as lubricants are then granulated and compressed into tablets.
(제조실시예 3) 본 발명의 서방성 정제 조성물의 제조
Preparation Example 3 Preparation of Sustained Release Tablet Composition of the Present Invention
구안파신 2 중량%에 희석제로서 유당 62 중량%, 중성 수팽윤성 방출 제어용 고분자로서 하이드록시프로필메틸셀룰로스 14 중량%, 음이온성 수팽윤성 방출 제어용 고분자로서 폴리아크릴산나트륨 14 중량%, 붕해제로서 크로스카멜로스나트륨 4 중량%, 결합제로서 폴리비닐피롤리돈 3 중량% 및 윤활제로서 스테아르산마그네슘 1.0 중량%를 혼합시켜 과립화시킨 후 타정시켜 제조된 구안파신 서방성 정제 조성물을 제조한다.
62% by weight of lactose as a diluent, 14% by weight of hydroxypropylmethylcellulose as a neutral water swellable release control polymer, 14% by weight of sodium polyacrylate as an anionic water swellable release control polymer, croscarmellose as a disintegrant Guanpacin sustained-release tablet compositions prepared by granulating by mixing 4% by weight of sodium, 3% by weight of polyvinylpyrrolidone as a binder, and 1.0% by weight of magnesium stearate as lubricants are then granulated and compressed into tablets.
(제조비교예 1) 유당의 함량 초과 및 HPMC 불포함
(Comparative Example 1) Excess lactose content and HPMC not included
구안파신 2 중량%에 희석제로서 유당 75 중량%, 방출 제어용 고분자로서 폴리아크릴산나트륨 15 중량%, 붕해제로서 크로스카멜로스나트륨 4 중량%, 결합제로서 폴리비닐피롤리돈 3 중량% 및 윤활제로서 스테아르산마그네슘 1.0 중량%를 혼합시켜 과립화시킨 후 타정시켜 제조된 구안파신 서방성 정제 조성물을 제조한다.
2% by weight of guanfacin, 75% by weight lactose as diluent, 15% by weight sodium polyacrylate as release control polymer, 4% by weight of croscarmellose sodium as disintegrant, 3% by weight polyvinylpyrrolidone as binder and stearic acid as lubricant Guanpacin sustained-release tablet compositions prepared by mixing and granulating 1.0% by weight of magnesium are then prepared.
(제조비교예 2) 유당의 함량 초과 및 폴리아크릴산나트륨 불포함
(Comparative Example 2) Excess lactose content and no sodium polyacrylate
구안파신 2 중량%에 희석제로서 유당 75 중량%, 방출 제어용 고분자로서 HPMC 15 중량%, 붕해제로서 크로스카멜로스나트륨 4 중량%, 결합제로서 폴리비닐피롤리돈 3 중량% 및 윤활제로서 스테아르산마그네슘 1.0 중량%를 혼합시켜 과립화시킨 후 타정시켜 제조된 구안파신 서방성 정제 조성물을 제조한다.
Guanfasin 2% by weight of lactose 75% by weight of diluent,
(제조비교예 3) 유당의 함량 초과 및 HPMC 불포함 및 붕해제 미첨가
(Comparative Example 3) Excess lactose content and no HPMC and no disintegrant
구안파신 2 중량%에 희석제로서 유당 79 중량%, 방출 제어용 고분자로서 폴리아크릴산나트륨 15 중량%, 결합제로서 폴리비닐피롤리돈 3 중량% 및 윤활제로서 스테아르산마그네슘 1.0 중량%를 혼합시켜 과립화시킨 후 타정시켜 제조된 구안파신 서방성 정제 조성물을 제조한다.
Granulated by mixing 2% by weight of guanfasin with 79% by weight of lactose as a diluent, 15% by weight of sodium polyacrylate as a release controlling polymer, 3% by weight of polyvinylpyrrolidone as a binder and 1.0% by weight of magnesium stearate as a lubricant. Guanpacin sustained-release tablet compositions prepared by tableting are prepared.
(제조비교예 4) 유당의 함량 초과, 폴리아크릴산나트륨 불포함 및 결합제 미첨가
(Comparative Example 4) Excess lactose content, no sodium polyacrylate and no binder
구안파신 2 중량%에 희석제로서 유당 78 중량%, 방출 제어용 고분자로서 HPMC 15 중량%, 붕해제로서 크로스카멜로스나트륨 4 중량% 및 윤활제로서 스테아르산마그네슘 1.0 중량%를 혼합시켜 과립화시킨 후 타정시켜 제조된 구안파신 서방성 정제 조성물을 제조한다.
2% by weight of guanfasin, 78% by weight of lactose as a diluent, 15% by weight of HPMC as a release controlling polymer, 4% by weight of croscarmellose as a disintegrating agent and 1.0% by weight of magnesium stearate as a lubricant are granulated and tableted. The prepared guanfacin sustained-release tablet composition is prepared.
(제조비교예 5) 유당 함량 초과, 폴리아크릴산나트륨 불포함 및 윤활제 미첨가
(Comparative Example 5) Excess lactose content, no sodium polyacrylate and no lubricant
구안파신 2 중량%에 희석제로서 유당 76 중량%, 방출 제어용 고분자로서 HPMC 15 중량%, 붕해제로서 크로스카멜로스나트륨 4 중량% 및 결합제로서 폴리비닐피롤리돈 3 중량%를 혼합시켜 과립화시킨 후 타정시켜 제조된 구안파신 서방성 정제 조성물을 제조한다.
Granulated by mixing 2% by weight of guanfasin, 76% by weight lactose as a diluent, 15% by weight HPMC as a release control polymer, 4% by weight of croscarmellose sodium as a disintegrant and 3% by weight of polyvinylpyrrolidone as a binder. Guanpacin sustained-release tablet compositions prepared by tableting are prepared.
(실시예 1) 용출 시험
Example 1 Dissolution Test
제조실시예 1, 제조비교예 1, 3, 4 및 5에서 제조한 정제를 대한약전 제8 개정판 패들 방법으로 다음과 같은 조건 하에서 용출 시험을 실시하고 유효 활성성분인 구안파신의 용출율을 시간 경과에 따라 측정하였다.
The tablets prepared in Preparation Example 1, Comparative Examples 1, 3, 4, and 5 were subjected to dissolution test under the following conditions using the paddle method of the Korean Pharmacopoeia, and the dissolution rate of guanfasin, an active ingredient, was determined over time. Measured accordingly.
용출시험액 : 대한약전 붕해시험법 제 2액(pH 6.8), 900ml, 37±0.5℃Dissolution test solution: Korea Pharmacopoeia Disintegration Test Method 2 (pH 6.8), 900ml, 37 ± 0.5 ℃
용출방법 : 대한약전 용출시험 제 2법(패들법), 분당 50 회전
Dissolution Method: Method 2, Paddle Method, KEPA, 50 revolutions per minute
상기 용출시험에서 시간마다 획득한 검액으로부터 활성성분의 용출율을 분석하였다. 시료채취는 시료채취 시간마다 용출액을 취해 0.45㎛ 필터로 여과하여 검액으로 하고 용출액을 취한 후에는 새로운 용출액을 동량 보정해주었다. 용출율 분석은 HPLC를 사용하여 분석하였으며 시간의 경과에 따른 용출율 시험 결과를 도 1에 나타내었다.
The dissolution rate of the active ingredient was analyzed from the sample solution obtained every hour in the dissolution test. Sampling was performed by taking the eluate at each sampling time and filtering with 0.45㎛ filter to make the sample solution. After taking the eluate, the new eluate was equally corrected. Dissolution rate analysis was performed using HPLC and the results of dissolution rate test over time are shown in FIG. 1.
도 1에 나타난 바와 같이 본 발명 제조실시예 1에서 제조된 구안파신 서방성 정제 조성물의 경우 10시간 이후에는 90% 이상의 안정적인 용출을 나타내었으나 제조비교에 1에서 제조된 정제 조성물의 경우 제조실시예 1에서 제조된 구안파신 서방성 정제 조성물보다 측정 시간별로 5~10% 정도 감소한 용출율을 나타내었으며 제조비교예 3, 제조비교예 4, 제조비교예 5에서 제조된 정제 조성물의 경우 제조비교예 1에서 제조된 정제 조성물보다도 시간별로 5~20% 정도 감소한 용출율을 나타내었다.
As shown in FIG. 1, the guanfacin sustained-release tablet composition prepared in Preparation Example 1 of the present invention showed stable elution of 90% or more after 10 hours, but the preparation composition of Preparation Example 1 in Comparative Example 1 The dissolution rate was reduced by about 5 to 10% by measurement time compared to the guanfasin sustained-release tablet composition prepared in the preparation of Comparative Example 3, Preparation Example 4, Preparation Comparative Example 5 prepared in Comparative Preparation Example 1 The dissolution rate was reduced by about 5 to 20% over time than the purified tablet composition.
이와 같은 용출 곡선을 통해 본 발명의 제조실시예 1에서 제조된 구안파신 서방성 정제 조성물이 신속한 시간 내에 충분히 용출되며 지속적인 용출 패턴을 나타내는 것이 확인되었다.
Through this dissolution curve, it was confirmed that the guanfacin sustained-release tablet composition prepared in Preparation Example 1 of the present invention was sufficiently eluted in a short time and showed a continuous dissolution pattern.
(실시예 2) 안정성시험
Example 2 Stability Test
제조실시예 1 및 제조비교예 1, 2, 3 및 4에서 제조한 정제를 PTP포장 후 가속조건인 40℃, 상대습도 75%에서 6개월 간 보관하여 고속액체크로마토그래피에 의해 구안파신의 함량을 측정하고 그 결과를 표 1에 나타내었다.
The tablets prepared in Preparation Example 1 and Comparative Examples 1, 2, 3 and 4 were stored for 6 months at 40 ° C. and 75% RH after accelerating PTP, and the contents of guanfacin were determined by high-performance liquid chromatography. It measured and the result is shown in Table 1.
상기 표 1에 나타난 바와 같이 본 발명 제조실시예 1에서 제조된 구안파신 서방성 정제 조성물은 가속조건 하에서 6개월 동안 경시 변화를 관찰한 결과 매우 안정적인 정제 제형임을 확인할 수 있었다.
As shown in Table 1, the guanfasin sustained-release tablet composition prepared in Preparation Example 1 of the present invention was observed to change over time for 6 months under accelerated conditions, it was confirmed that the tablet formulation is very stable.
그러나 제조비교예 1에서 제조된 구안파신 서방성 정제 조성물은 6개월 후 함량이 92.4%로서 기준에는 적합한 것이었으나 경시 변화에 따른 함량 감소가 상당히 이루어진 것을 알 수 있었다. 또한 제조비교에 2, 3, 4에서 제조된 구안파신 서방성 정제 조성물의 경우 6개월 후 함량이 기준인 90%에 미치지 못하는 것으로 경시 변화에 따른 함량 감소로 인해 적합하지 않은 정제 제형임을 확인하였다.However, Guanpasin sustained-release tablet composition prepared in Comparative Preparation Example 1 was 62.4 months after the content was 92.4%, which was suitable for the standard, but it was found that the content decrease was significantly changed with time. In addition, the Guanpasin sustained-release tablet composition prepared in 2, 3, 4 compared to the manufacturing comparison after 6 months, the content was found to be not suitable tablet formulation due to the decrease in content over time.
Claims (4)
55% to 65% by weight of lactose as a diluent, 13 to 17% by weight of hydroxypropylmethylcellulose as a polymer for controlling neutral water swellability, 13 to 17% by weight of sodium polyacrylate as a polymer for controlling anionic water swellability, Guanpacin sustained-release prepared by granulating by mixing 3 to 5% by weight of croscarmellose sodium as disintegrant, 2 to 4% by weight of polyvinylpyrrolidone as binder and 0.8 to 1.2% by weight of magnesium stearate as lubricant. Sex tablet compositions
According to claim 1, Guanpasin sustained-release tablet composition, characterized in that the content of guanfasin active ingredient is 0.5 ~ 4mg.
ⅱ) 건조된 과립화 혼합물을 정제로 압착 타정시키는 단계;
로 이루어진 구안파신 서방성 정제 조성물의 제조 방법
I) 55% to 65% by weight of lactose as a diluent, 13 to 17% by weight of hydroxypropylmethylcellulose as a polymer for controlling neutral water swellability, and 13 to 17% by weight of sodium polyacrylate as a polymer for controlling anionic water swellability. %, 3 to 5% by weight of croscarmellose sodium as disintegrant, 2 to 4% by weight of polyvinylpyrrolidone as binder, and 0.8 to 1.2% by weight of magnesium stearate as lubricant, Granulating and then granulating; And
Ii) compressing the dried granulation mixture with a tablet;
Method for preparing guanpacin sustained-release tablet composition consisting of
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