KR20050001074A - A prolonged action tablet of felodipine and method of preparation thereof - Google Patents
A prolonged action tablet of felodipine and method of preparation thereof Download PDFInfo
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- A61K9/20—Pills, tablets, discs, rods
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Abstract
Description
본 발명은 펠로디핀의 지속성 정제 및 그 제조방법에 관한 것이다.The present invention relates to a persistent tablet of felodipine and a method for producing the same.
고혈압, 심장질환 등 순환기계 질환 치료제와 소염진통제 등은, 투여한 약물이 혈액 중에서 일정한 농도를 유지하도록 지속성 제제로 하는 것이 질병을 치료하는데 유리하다. 이러한 지속성 제제는 일반적으로 경구를 통하여 투여되는데, 위ㆍ장관을 거쳐서 서서히 약물이 방출되므로 환자의 편의성과 순응도를 높일 뿐만 아니라 부작용도 감소시킬 수 있는 장점이 있다. 특히 위ㆍ장관 유축과정에서 국소자극성이 있거나, 혈중 농도의 급속한 증가로 인한 부작용이 우려되는 약물의 경우 더욱 유리하다.In the treatment of circulatory disorders such as high blood pressure and heart disease, and anti-inflammatory drugs, it is advantageous to treat the disease so that the administered drug is used as a persistent agent to maintain a constant concentration in the blood. Such long-acting formulations are generally administered orally, and the drug is slowly released through the gastrointestinal tract and thus, there is an advantage that not only increases the convenience and compliance of the patient but also reduces side effects. In particular, it is more advantageous in the case of drugs that have local irritation during gastric and intestinal drainage process or are concerned about side effects due to rapid increase in blood concentration.
한편 칼슘 길항작용을 나타내어 고혈압, 협심증 등 순환기계 질환 치료제로 널리 사용되는 펠로디핀은 물에 대한 용해도가 매우 낮아서 정제 등과 같은 경구 제형으로 투여할 때 용출률을 높이지 못하는 경우 생체 이용율이 매우 낮다.Pelodipine, which is widely used as an agent for treating circulatory diseases such as hypertension and angina due to calcium antagonism, has a very low solubility in water, and thus bioavailability is very low when the dissolution rate cannot be increased when administered by oral dosage form such as tablets.
약물이 소화관액 또는 체액 중에 용해되는 것을 용출이라고 하며, 약물이 약효를 나타내기 위해서는 용출이 일어나서, 분자상태로 위ㆍ장관액 또는 혈액에 녹아서 흡수되어야 한다. 따라서 용출률은 약물의 생체내 효능을 나타내는데 중요한 역할을 하게 된다. 펠로디핀과 같이 난용성을 특징으로 하는 약물은 정제로부터 약물의 용출이 흡수율을 결정하는 중요한 요소가 되며 약효의 시작점, 강도, 적용시간 등을 결정하게 된다.The dissolution of the drug in the digestive tract or body fluid is called elution. In order for the drug to show its effect, elution occurs and must be absorbed by dissolving in gastric, intestinal fluid or blood in a molecular state. Therefore, dissolution rate plays an important role in indicating the in vivo efficacy of the drug. In the case of poorly soluble drugs such as pelodipine, the dissolution of the drug from the tablet becomes an important factor in determining the absorption rate, and determines the starting point, strength, and application time of the drug.
대한민국 특허 공고번호 제95-2147호에서는 매우 낮은 용해도를 특징으로 하는 펠로디핀 등의 디히드로피리딘 유도체를 갖는 약물에 비이온성 계면활성제를 가용화제로 첨가한 후 지속성 겔 시스템으로 방출을 조절하는 방법을 개시하고 있다.Korean Patent Publication No. 95-2147 discloses a method for controlling release with a persistent gel system after adding a nonionic surfactant as a solubilizer to a drug having a dihydropyridine derivative such as felodipine which is characterized by very low solubility. Doing.
또한 대한민국 특허 등록번호 제10-0315872호에서는 고체 분산체 등을 제조하여 단순 혼합하면 펠로디핀이 편재되어 함량균일성이 떨어지고 용출이 지연될 수 있어서 펠로디핀을 유기용매에 용해시킨 후 다시 폴리비닐피롤리돈을 용해시켜 결합액으로 하고, 셀룰로오스 중합체를 포함한 혼합물에 다시 연합해서 지속성 제제를 제조하는 방법을 개시하고 있다. 상기 방법은 제제화를 위해 여러 단계를 거쳐야 하므로 실제 생산공정에 적용하는 데 있어 비경제적이라는 단점이 있다.In addition, in Korean Patent Registration No. 10-0315872, if a solid dispersion or the like is prepared and simply mixed, felodipine may be ubiquitous and content uniformity may be lowered and elution may be delayed. Disclosed is a method of dissolving rolidone to form a binding liquid and reassociating with a mixture containing a cellulose polymer to prepare a sustained preparation. The method requires several steps for formulation, which is disadvantageous in that it is uneconomical for application in actual production processes.
본 발명은 비이온성 계면활성제 등 가용화제를 첨가하지 않을 뿐만 아니라 펠로디핀을 알코올 등의 유기 용매에 용해시키고 나서 다시 폴리비닐피롤리돈을 용해시켜 결합액으로 이용하는 복잡한 방법을 사용하지 않고도 제조될 수 있는 것으로서, 함량균일성을 가지며 장시간동안 지속적으로 펠로디핀을 용출시킬 수 있는 펠로디핀의 지속성 정제 및 그의 제조방법을 제공하고자 한다.The present invention can be prepared not only by adding a solubilizer such as a nonionic surfactant, but also by dissolving felodipine in an organic solvent such as alcohol, and then again dissolving polyvinylpyrrolidone to use as a binder solution. As it exists, it is intended to provide a persistent tablet of felodipine having a content uniformity and capable of eluting felodipine continuously for a long time, and a method for preparing the same.
본 발명의 펠로디핀의 지속성 정제는 정제 전체 조성에 대하여 펠로디핀 1~5중량%, 아크릴 중합체 5 ~ 15중량%, 셀룰로오스 중합체 35 ~ 55중량%, 지방 또는 지방족 알코올 2 ~ 8중량%, 폴리에틸렌글리콜 5~10중량% 및 첨가제를 포함한다.The sustained tablet of felodipine of the present invention is 1-5% by weight of felodipine, 5-15% by weight of acrylic polymer, 35-55% by weight of cellulose polymer, 2-8% by weight of fatty or aliphatic alcohol, polyethylene glycol 5-10% by weight and additives.
이와 같은 본 발명의 구성성분을 자세히 설명하면 다음과 같다.Referring to the components of the present invention in detail as follows.
본 발명의 지속성 정제에 포함되는 아크릴 중합체로는 제약용으로 허용 가능한 어떠한 아크릴 중합체라도 사용할 수 있다. 본 발명의 지속성 정제에 사용 가능한 아크릴 중합체로서는 바람직하게는 폴리메타크릴레이트류이다. 특히 폴리(에틸 아크릴레이트, 메틸 메타크릴레이트, 트리메틸암모니오에틸 메타크릴레이트 클로라이드) 1:2:0.2 [예를 들어, 상품명: 유드라짓(Eudragit) RL 100, RL PO 및 RL 30 D로 롬 아메리카 인코퍼레이티드(Rohm America Inc.)가 시판하고 있다] 및 폴리(에틸 아크릴레이트, 메틸 메타크릴레이트, 트리메틸암모니오에틸 메타크릴레이트 클로라이드) 1:2:0.1 [예를 들어, 상품명: 유드라짓 RS 100, RS PO 및 RS 30 D로 롬 아메리카 인코퍼레이티드가 시판하고 있다]이 바람직하며, 보다 바람직하게는 유드라짓 RS PO 이다. 이들은 단독으로 또는 조합하여 사용될 수 있다.As the acrylic polymer included in the persistent tablet of the present invention, any acrylic polymer acceptable for pharmaceutical use can be used. As the acrylic polymer which can be used for the persistent tablet of the present invention, polymethacrylates are preferable. In particular poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1: 2: 0.2 [for example, trade names Eudragit RL 100, RL PO and RL 30 D. Commercially available from Rohm America Inc.] and poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1: 2: 0.1 [for example, trade name: oil Rom America Incorporated is available in Dragit RS 100, RS PO and RS 30 D], more preferably Eudragit RS PO. These may be used alone or in combination.
상기 아크릴 중합체는 본 발명의 정제 전체 조성에 대하여, 5 ~ 15중량%로 포함된다. 본 발명의 아크릴 중합체가 5중량% 미만이면, 펠로디핀의 용출률을 제어할 수 없어서 속효성정과의 차이가 없어져 버리고, 15중량%를 초과하는 경우 펠로디핀의 용출률이 현저하게 낮아져서 생체 이용률이 낮아진다.The acrylic polymer is included in 5 to 15% by weight based on the total composition of the tablet of the present invention. If the acrylic polymer of the present invention is less than 5% by weight, the dissolution rate of felodipine can not be controlled, the difference with the fast-acting tablet disappears, and when it exceeds 15% by weight, the dissolution rate of felodipine is significantly lowered and the bioavailability is lowered.
본 발명의 지속성 정제에 포함되는 셀룰로오스 중합체로는 히드록시프로필메틸셀룰로오스[예를 들어, 신에추 케미칼사(Shin-Etsu Chemical Co., Ltd.)가 시판중인 상품명: 메톨로스(metolose)?] 및 히드록시프로필셀룰로오스[다우 케미칼사(Dow Chemical)가 시판 중인 상품명: 메토셀(methocel)?]로 이루어진 군 중에서 선택된 1종 이상의 성분을 사용할 수 있으며, 보다 바람직하게는 메톨로스 60SH-50이다.As the cellulose polymer included in the persistent tablet of the present invention, hydroxypropyl methyl cellulose (for example, Shin-Etsu Chemical Co., Ltd. is a commercially available product name: metolose?) And hydroxypropyl cellulose (trade name: Methocel sold by Dow Chemical Co., Ltd.) may be used, and at least one component selected from the group consisting of more preferably metolose 60SH-50.
상기 셀룰로오스 중합체는 본 발명의 정제 전체 조성에 대하여, 35 ~ 55중량%로 포함된다. 본 발명의 셀룰로오스 중합체가 35중량% 미만이면, 펠로디핀의 용출을 지속시키지 못하고, 55중량%를 초과하는 경우 연합ㆍ제립시 사용하는 알코올 양이 상당히 증가하여 정제를 압축하는 데 필요한 소성 유지에 어려움이 있다.The cellulose polymer is included at 35 to 55% by weight based on the total composition of the tablet of the present invention. If the cellulose polymer of the present invention is less than 35% by weight, elution of felodipine cannot be continued, and when it exceeds 55% by weight, the amount of alcohol used during association and granulation is increased significantly, which makes it difficult to maintain the plasticity required to compress the tablets. There is this.
본 발명의 지속성 정제에 포함되는 지방 또는 지방족 알코올로는 경화 피마자유, 세토스테아릴 알코올, 스테아릴 알코올 및 이들의 혼합물 등이 사용될 수 있다. 바람직하게는 경화 피마자유이다.Cured castor oil, cetostearyl alcohol, stearyl alcohol, mixtures thereof, and the like may be used as the fatty or aliphatic alcohol included in the persistent tablet of the present invention. Preferably it is hardened castor oil.
상기 지방 또는 지방족 알코올은 본 발명의 정제 전체 조성에 대하여, 2 ~ 8중량%로 포함된다.The fatty or aliphatic alcohol is contained in 2 to 8% by weight based on the total composition of the tablet of the present invention.
또한 본 발명의 조성에는 난용성 약물의 서방화기제에 흡상촉진을 목적으로 폴리에틸렌글리콜을 함유하는 바, 폴리에틸렌글리콜은 수분과 접촉시에 정제 내부로 유액을 끌어들여 난용성 약물의 방출을 도와주므로 최적의 용출률을 제공한다. 본 발명의 지속성 정제에서 폴리에틸렌글리콜은 분자량이 1,000 ~ 20,000 범위인 것을 사용하는 것이 바람직하고, 보다 바람직하게는 분자량이 6,000인 것이다.In addition, the composition of the present invention contains polyethylene glycol for the purpose of promoting wicking in the sustained release mechanism of poorly soluble drugs, and polyethylene glycol is optimal because it helps release the poorly soluble drug by drawing an emulsion into the tablet when in contact with water. Provides the dissolution rate of. In the sustained tablet of the present invention, polyethylene glycol is preferably used in the range of 1,000 to 20,000 molecular weight, more preferably 6,000 molecular weight.
상기 폴리에틸렌글리콜은 본 발명의 정제 전체 조성에 대하여 5 ~ 10중량%로포함된다. 폴리에틸렌글리콜을 상기 범위내에서 사용함으로써 본 발명의 펠로디핀의 지속성 정제의 적당한 용출율을 얻을 수 있다.The polyethylene glycol is included in 5 to 10% by weight based on the total composition of the tablet of the present invention. By using polyethylene glycol in the said range, the moderate dissolution rate of the persistent tablet of the felodipine of this invention can be obtained.
이외에도 본 발명의 지속성 정제의 조성에는 습식 과립법에 의한 정제 제조시, 통상적으로 사용되는 첨가제가 함유될 수 있다. 예로서는 유당, 옥수수전분, 인산칼슘, 미결정셀룰로오스 등의 부형제와 탈크, 스테아린산 마그네슘 등의 활택제가 있다. 이러한 첨가제는 정제 전체 조성 중에 20 ~ 40중량%의 범위로 포함되는 것이 바람직하다.In addition, the composition of the persistent tablet of the present invention may contain additives commonly used in the manufacture of tablets by wet granulation. Examples include excipients such as lactose, corn starch, calcium phosphate and microcrystalline cellulose, and lubricants such as talc and magnesium stearate. Such additives are preferably included in the range of 20 to 40% by weight in the overall composition of the tablet.
한편, 정제는 의약품을 일정한 형상으로 압축하여 만드는데, 압축을 하기 직전 상태를 제조하는 방법에 따라 직접 혼합법, 건식 과립법, 습식 과립법으로 나눈다. 본 발명의 정제는 상기의 구성성분을 사용하여 통상적인 습식 과립법에 의하여 제조하는 것이 바람직하다.On the other hand, tablets are made by compressing a medicine into a certain shape, which is divided into a direct mixing method, a dry granulation method, and a wet granulation method according to a method for producing a state immediately before compression. Tablets of the present invention are preferably prepared by conventional wet granulation using the above components.
본 발명의 펠로디핀의 지속성 정제는 난용성 약물인 펠로디핀과, 매트릭스 정제를 구성하는 부형제인 아크릴 중합체, 셀룰로오스 중합체 및 지방 또는 지방족 알코올, 흡상촉진제인 폴리에틸렌글리콜, 그리고 기타 첨가제를 혼합한 후 알코올을 사용하여 연합, 조립, 건조하고 정립한 후 활택제를 가하여 재혼합하여 압축 성형하는 일반적인 습식 과립법으로 매우 용이하게 제조할 수 있다. 이와 같이 제조된 본 발명의 펠로디핀의 지속성 정제는 장시간동안 일정한 용출률을 나타내게 된다.The sustained tablet of the felodipine of the present invention is a mixture of poorly soluble drug felodipine, acrylic polymers, cellulose polymers and fatty or aliphatic alcohols, polyethylene glycol as a stimulation accelerator, and other additives constituting the matrix tablet, and then alcohol It can be prepared very easily by the general wet granulation method of using, assembling, assembling, drying and sizing, remixing by adding a lubricant, and compression molding. The sustained tablet of felodipine of the present invention prepared as described above will exhibit a constant dissolution rate for a long time.
이하, 본 발명을 실시예를 통해 더욱 상세히 설명한다. 그러나 이러한 실시예가 본 발명의 범위를 제한하는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples do not limit the scope of the present invention.
실시예 1Example 1
하기의 조성을 갖는 펠로디핀의 지속성 정제를 다음 방법으로 제조하였다.A sustained tablet of felodipine having the following composition was prepared by the following method.
정제의 조성Composition of tablets
펠로디핀 5 g5 g of felodipine
유드라짓 RS P0 16 gEudragit RS P0 16 g
메톨로스 60SH-50 105 g105 g of metlosose 60SH-50
경화 피마자유 6 g6 g of hardened castor oil
유당 53 gLactose 53 g
폴리에틸렌글리콜 6000 14 gPolyethylene glycol 6000 14 g
탈크 3 gTalc 3 g
펠로디핀, 유드라짓 RS PO, 메톨로스 60SH-50, 폴리에틸렌글리콜 6000을 전질 균등하게 혼합한 후, 경화 피마자유를 에탄올에 용해시킨 액을 가하여 연합ㆍ제립하고, 적당한 온도에서 건조시켰다. 이 건조과립에 탈크를 가하여 재혼합한 후, 일정 중량으로 압축하여 정제를 제조하였다.Pelodipine, Eudragit RS PO, Metolos 60SH-50, and Polyethyleneglycol 6000 were mixed homogeneously, and the liquid which casted castor oil dissolved in ethanol was added, granulated, and dried at the suitable temperature. Talc was added to the dried granules to be remixed, and then compressed to a predetermined weight to prepare tablets.
실시예 2Example 2
정제의 조성Composition of tablets
펠로디핀 5 g5 g of felodipine
유드라짓 RS P0 16 gEudragit RS P0 16 g
메톨로스 60SH-50 105 g105 g of metlosose 60SH-50
세토스테아릴 알코올 6 g6 g of cetostearyl alcohol
유당 53 gLactose 53 g
폴리에틸렌글리콜 6000 14 gPolyethylene glycol 6000 14 g
탈크 3 gTalc 3 g
상기 조성으로 한 것을 제외하고, 상기 실시예 1에 기재된 방법과 동일하게 하여 정제를 제조하였다.A tablet was prepared in the same manner as in Example 1, except that the composition was used.
실시예 3Example 3
정제의 조성Composition of tablets
펠로디핀 5 g5 g of felodipine
유드라짓 RS PO 18 gEudragit RS PO 18 g
메톨로스 60SH-50 95 gMetolos 60SH-50 95 g
경화 피마자유 8 g8 g of hardened castor oil
유당 60 gLactose 60 g
폴리에틸렌글리콜 6000 12 gPolyethylene glycol 6000 12 g
탈크 4 g4 g of talc
상기 조성으로 한 것을 제외하고, 상기 실시예 1에 기재된 방법과 동일하게 하여 정제를 제조하였다.A tablet was prepared in the same manner as in Example 1, except that the composition was used.
실험예 1Experimental Example 1
상기 실시예 1 내지 3에서 제조된 본 발명의 지속성 정제를 사용하여 대한약전 일반시험법 용출시험법 제2법에 따라서 용출율을 실험하였다. 실시예 1 내지 3에서 제조된 본 발명의 지속성 정제 각 6정을 pH 6.5 완충액을 시험액으로 하여 100 rpm의 속도로 패들을 회전시켜 1시간, 4시간, 7시간 후 용출액 10 ml를 취하여 고속 액체크로마토그래피로 용출율을 측정하였다. 본 발명의 지속성 정제의 용출율을 표 1에 나타낸다. 비교예로서는 시판 중인 제제로서 아스트라제네카 (AstraZeneca)사의 스프렌딜(Splendil) 지속정을 사용하였다.The dissolution rate was tested in accordance with the Korean Pharmacopoeia General Test Method Dissolution Test Method 2 using the persistent tablets of the present invention prepared in Examples 1 to 3. Six tablets of the sustained tablet of the present invention prepared in Examples 1 to 3 using a pH 6.5 buffer solution as a test solution were rotated by paddle at a speed of 100 rpm to take 10 ml of the eluate after 1 hour, 4 hours, and 7 hours. The dissolution rate was measured by chromatography. The dissolution rate of the persistent tablet of the present invention is shown in Table 1. As a comparative example, Splendil sustained tablets of AstraZeneca were used as commercially available formulations.
실험예 2Experimental Example 2
실시예 1에서 제조된 본 발명의 지속성 정제 10정을 취하여 각각의 펠로디핀의 함량을 정량하였다. 그 결과는 다음과 같다.Ten tablets of the present invention prepared in Example 1 were taken to quantify the content of each felodipine. the results are as follow.
100.45%, 100.59%, 100.17%, 100.59%, 100.56%, 100.34%, 100.42%, 100.31%,100.76%, 100.23% 평균 100.44%100.45%, 100.59%, 100.17%, 100.59%, 100.56%, 100.34%, 100.42%, 100.31%, 100.76%, 100.23% Average 100.44%
상기 결과로부터 알 수 있는 바와 같이, 본 발명의 지속성 정제는 함량균일성에 있어서 매우 우수하였다.As can be seen from the above results, the persistent tablet of the present invention was very excellent in content uniformity.
본 발명에 의하여 비이온성 계면활성제를 가용화제로 첨가하지 않아도 될 뿐만 아니라, 펠로디핀을 폴리비닐피롤리돈과 같은 유기 용매에 용해시키는 복잡한 방법을 거치지 않고도 간편하게 일반적인 습식 과립법으로 지속성 용출효과를 나타내며 함량균일성이 높은 펠로디핀 지속성 정제를 제조할 수 있다.The present invention not only eliminates the addition of a nonionic surfactant as a solubilizer, but also provides a continuous dissolution effect by a simple wet granulation method without the complicated method of dissolving felodipine in an organic solvent such as polyvinylpyrrolidone. Pelodipine long-acting tablets with high uniformity can be prepared.
Claims (7)
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