KR100602235B1 - The Manufacturing Method Of The Pharmaceutical compositions of Controlled release - Google Patents

The Manufacturing Method Of The Pharmaceutical compositions of Controlled release Download PDF

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KR100602235B1
KR100602235B1 KR1020020039747A KR20020039747A KR100602235B1 KR 100602235 B1 KR100602235 B1 KR 100602235B1 KR 1020020039747 A KR1020020039747 A KR 1020020039747A KR 20020039747 A KR20020039747 A KR 20020039747A KR 100602235 B1 KR100602235 B1 KR 100602235B1
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장시영
최재승
박성배
김용철
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한국맥널티 주식회사
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Abstract

본 발명은 염산슈도에페드린 및 염산세티리진을 함유하는, 경구적으로 투여 가능한 방출제어형 구형과립의 제조방법에 관한 것이다. 즉 불활성의 코어에 서방출성 약물층과 서방출성 코팅 제어막을 입힌 다음 그 위에 속방출성 약물층을 고착시킨 구형과립을 제조하는 방법 및 이를 함유하는 약제학적 조성물에 관한 것이다. 본 발명은 서방출성 약물층에 염산슈도에페드린을 함유하고, 속방출성 약물층에 염산슈도에페드린 및 염산세티리진을 함유하며, 복용 후 속방출성 약물층의 약물들은 신속하게 방출되어 약효를 발현하고 서방출성 약물층의 약물은 위장관내 pH 변화와 상관없이 지속적으로 약물을 방출하는 것을 특징으로 한다.The present invention relates to a method for preparing orally administrable controlled release spherical granules containing pseudoephedrine hydrochloride and cetirizine hydrochloride. That is, the present invention relates to a method for producing a spherical granule having a slow-release drug layer and a sustained-release coating control film coated on an inert core, and then a fast-release drug layer fixed thereon, and a pharmaceutical composition containing the same. The present invention contains pseudoephedrine hydrochloride in the sustained-release drug layer, and pseudoephedrine hydrochloride and cetirizine hydrochloride in the rapid-release drug layer, and the drugs in the rapid-release drug layer rapidly release after administration to express the drug and sustained release. The drug in the drug layer is characterized by a continuous release of the drug regardless of the change in pH in the gastrointestinal tract.

염산슈도에페드린, 염산세티리진, 구형과립Pseudoephedrine hydrochloride, cetirizine hydrochloride, spherical granules

Description

방출제어형 약제학적 조성물의 제조방법 {The Manufacturing Method Of The Pharmaceutical compositions of Controlled release}The manufacturing method of the pharmaceutical compositions of controlled release

도 1은, 본 발명의 제제예 1과 시판제제에 대한 염산슈도에페드린의 용출시험 결과를 나타낸 그래프이다.BRIEF DESCRIPTION OF THE DRAWINGS The graph which shows the dissolution test result of pseudoephedrine hydrochloride in the preparation example 1 of this invention and a commercial preparation.

본 발명은 염산슈도에페드린 및 염산세티리진을 함유한 제제로 속방성으로 염산슈도에페드린과 염산세티리진을 함유하고 따로 서방성의 염산슈도에페드린 약물층을 가진 약제학적 제제로서 단일 제제에 두 약물을 모두 포함하며, 서방성 약물층의 약물 방출이 위장관내 pH 변화와 무관하게 이루어지는 것을 그 특징으로 한다.The present invention is a pharmaceutical formulation containing pseudoephedrine hydrochloride and cetirizine hydrochloride, which contains immediate release of pseudoephedrine hydrochloride and cetirizine hydrochloride, and has a sustained-release suedephedrine hydrochloride drug layer, which includes both drugs in a single formulation. Drug release of the drug layer is characterized in that it is independent of pH changes in the gastrointestinal tract.

슈도에페드린(C10H15NO, MW=165.2)은 에페드린의 광학이성체로 에페드린과 유사한 작용을 하지만 진정작용은 상대적으로 작다. 슈도에페드린의 염으로는 염산슈도에페드린(C10H15NO?HCl, MW=201.7)과 황산슈도에페드린((C10H15NO)2?H2SO4, MW=428.5)이 의약품으로 사용되고 있다. 슈도에페드린 및 그 염은 SYMPATHOMIMETIC AGENT로 일반적으로 알러지성 비염에 기인하는 비울혈의 개선을 위해 항히스타민제와 함께 처방된다. 반감기는 5~7시간 정도이고 산성뇨에서 소실속도가 증가하여 반감기가 짧아진다. 또한 MAO 대사를 거치지 않고 대부분이 비대사체로, 일부 간대사를 받은 대사체와 함께 뇨중으로 배설된다. 하루 3-4회 경구 복용하는 제제가 일반적으로 장시간 유효농도의 유지가 가능한 항히스타민제는 통상의 방법으로 방출되고, 슈도에페드린 등의 비울혈완화제는 제어방출을 통해 1일 2회 내지는 1일 1회로 투여하는 것이 이상적이며 환자의 순응도에서 유리한 점이 있다.Pseudoephedrine (C10H15NO, MW = 165.2) is an optical isomer of ephedrine, which acts similar to ephedrine but has a relatively small sedation. As a salt of pseudoephedrine, pseudoephedrine hydrochloride (C10H15NO? HCl, MW = 201.7) and pseudoephedrine sulfate ((C10H15NO) 2? H2SO4, MW = 428.5) are used as medicines. Pseudoephedrine and its salts are SYMPATHOMIMETIC AGENT, which are usually prescribed with antihistamines for the improvement of nasal congestion due to allergic rhinitis. The half-life is about 5-7 hours and the half-life is shortened due to the increase of the disappearance rate in acidic urine. It is also excreted in urine together with metabolites that have undergone some hepatic metabolism, mostly without metabolism, without undergoing MAO metabolism. Antihistamines, which can be administered orally 3-4 times a day in general, can maintain their effective concentration for a long time, and are released in a conventional manner, and non-depressants such as pseudoephedrine are administered twice a day or once a day through controlled release. Ideally, there is an advantage in patient compliance.

염산세티리진(C21H25ClN2O3?2HCl, MW=461.8)은 피페라진계의 2세대 H1-리셉터 길항약으로서 진정작용이 작고, 항무스카린 효과가 미미하다. 경구로 투여할 경우 위장관내에서 신속하게 흡수되어 1시간 이내에 최대혈중농도에 도달하고, 반감기는 약 11시간이며 주로 요중으로 배설된다. 일반적으로 10mg을 1일 1회 또는 5mg을 1일 2회 투여한다.Cetirizine hydrochloride (C21H25ClN2O3-2HCl, MW = 461.8) is a piperazine-based second-generation H1-receptor antagonist with small sedation and minimal antimuscarinic effects. When taken orally, it is rapidly absorbed in the gastrointestinal tract, reaching a maximum blood concentration within 1 hour, with a half-life of about 11 hours, mainly excreted in the urine. Generally, 10 mg is administered once a day or 5 mg is administered twice a day.

백당으로 만든 구형입자에 염산슈도에페드린을 서방성약물층과 속방성약물층으로 나누어 코팅하여 펠렛을 제조하고, 따로 염산세티리진을 속붕해성 정제로 만든 다음 공캅셀에 충전한 제품이 상품명 씨러스캅셀 로 시판되고 있다. 그러나 이렇게 펠렛과 정제를 하나의 공캅셀에 충전하는 경우 특수한 충전기가 필요하고 제조공정이 길어지는 단점이 있다.The pellets are prepared by coating susceptible hydrochloride with suede hydrochloride into a sustained-release drug layer and a rapid-release drug layer, and separately preparing cetirizine hydrochloride as a fast disintegrating tablet and filling it into a blank capsule. It is commercially available. However, when the pellets and tablets are filled in one empty capsule, a special charger is required and the manufacturing process is long.

약물을 서방출시술은 크게 정제나 미세구체를 코팅하여 코팅막이 점차 파괴되며 약물이 방출되는 코팅형과 약물과 왁스 또는 고분자 물질을 함께 혼화하여 만 든 매트릭스형이 있다. 이중에서 미세구체에 약물을 입힌 다음 고분자 물질로 코팅하여 펠렛으로 만드는 방법은 Multiple unit으로 투여되므로 단일제제로 투여되는 경우에 비해 약물 방출을 정교하게 조절할 수 있고, 음식물의 영향이나 제제의 손상에 비교적 안정적인 장점이 있다. Sustained release of the drug is largely coated with tablets or microspheres, the coating film is gradually destroyed, there is a coating form in which the drug is released and a matrix made by mixing the drug and wax or polymer material together. Among them, the method of coating the microspheres and coating them with a polymer material to form pellets is administered in multiple units, so that the drug release can be precisely controlled compared to the case of a single agent, and relatively stable to food effects or damage to the preparation. There is an advantage.

약물이 약효를 발현하기 위해서는 유효혈중농도를 유지해야 하는데 이를 위해서는 하나의 제제에 서방출성 약물저장부 이외에 속방출성 약물저장부를 함께 설계하면 초기에 신속하게 유효혈중농도에 도달한 다음 지속적으로 유효혈중농도를 유지하는 장점이 있다. 특히 비충혈개선제나 알러지성 비염에 사용되는 항히스타민제와 같은 약물들은 신속한 증상 완화와 지속적인 증상 개선을 위해 위와 같은 제제로 설계할 필요성이 있다. 이와 같이 서방출성 약물저장부와 속방출성 약물저장부를 한 제제에 포함시키고자 하는 선행기술로는 다음과 같은 것들이 있다.In order for the drug to express its efficacy, it is necessary to maintain the effective blood concentration. For this purpose, if one drug is designed together with the slow-release drug storage in addition to the slow-release drug storage, the effective blood concentration is rapidly reached and then continuously There is an advantage of maintaining the concentration. In particular, drugs such as anti-hyperstatin and antihistamines used for allergic rhinitis need to be designed with such preparations for rapid symptom relief and continuous improvement of symptoms. As described above, there are the following prior arts for including the sustained release drug storage unit and the rapid release drug storage unit in one formulation.

미합중국 공개특허 제 4,996,061호의 다중 압축법으로 타정하여 2개의 약물층으로 이루어진 정제를 제조하는 방법으로, 한 층은 울혈완화효과를 가진 약물과 수용성의 비이온성 셀룰로오스에테르를 기타의 첨가제와 함께 제조하고, 다른 층은 음이온성 계면활성제를 함유하는 것을 특징으로 하는 방법, 미합중국 공개특허 제 4,792,452호의 pH 의존성인 아르기닌산의 염과 pH 비의존성인 친수콜로이드겔화제를 결합제 및 첨가제로 사용하여 위장관내의 pH 변화에 의해 약물의 방출이 가능하도록 한 방법, 미합중국 공개특허 제 6,267,986호의 두층으로 이루어진 정제를 제조하면서 한층은 황산슈도에페드린을 잔탄검, 아르기닌산 나트륨 등의 친수성 고분 자와 2가의 금속이온과의 가교에 의해 제어방출하고, 다른 한층은 로라타딘을 함유한 층으로 약물이 신속하게 방출되는 방법, 대한민국 공개특허 87-8583의 트리아세트산셀룰로오스와 히드록시프로필셀룰로오스로 이루어진 격실 안에 슈도에페드린과 브롬페니라민을 넣고 삼투압에 의해 작은 구멍을 통해 약물이 방출되는 방법, 대한민국 공개특허 특2000-0076269의 폴리아크릴산 또는 셀룰로오스와 알칼리 또는 알칼리성 토금속 수산화물과의 서방출을 원하는 약물을 포함한 매트릭스층을 제조하고 속방출을 원하는 약물층을 고착시켜 다층 정제화하는 방법, 미합중국 공개특허 제 5,859,060호, 제 5,998,478호 및 제 6,099,860호의 슈도에페드린을 친수성 고분자인 히드록시프로필메칠셀룰로오스 등과 타정하여 핵정으로 하고, 그 외층에 나프록센과 슈도에페드린을 함께 코팅하는 방법, 미합중국 공개특허 제 5,895,663호의 염산슈도에페드린을 고점도의 히드록시프로필메칠셀룰로오스(Methocel K100LV, DOW) 및 미결정셀룰로오스와 함께 타정하여 제어방출하는 방법, 미합중국 공개특허 제 6,171,618 호의 염산슈도에페드린을 유당, 에칠셀룰로오스. 포비돈 등과 함께 습식과립법으로 과립화한 것을 타정하여 핵정으로 하고 그 위에 에칠셀룰로오스로 코팅하여 서방출성 약물층으로 한 다음 속방출성의 염산슈도에페드린 및 염산세티리진을 코팅하는 방법으로서 염산세티리진이 분자량 100 이하의 알콜류와 함께 있을 경우 에스테르화 반응에 의해 안정성이 문제가 되는 것을 고분자알콜류(예, 폴리에칠렌글리콜 3350등)를 사용함으로써 개선한 방법, 미합중국 공개특허 제 5,807,579호의 에칠셀룰로오스와 슈도에페드린으로 서방출성 펠렛을 제조하고 이 펠렛을 중탄산나트륨, 셀룰로오스 및 약물과 함께 타정하여 속방출성 약물층으로 만드는 방법, 미합중국 공개특허 제 5,681,582호의 고점도의 히드록시프로필메칠셀룰로오스와 염산슈도에페드린을 함께 서방출성 약물층으로 한 다음 에칠셀룰로오스로 서방층코팅막을 입히고, 속방출성 약물층에 염산슈도에페드린과 아스테미졸을 저점도의 히드록시프로필메칠셀룰로오스와 함께 제조한 제제 방법, 미합중국 공개특허 제 6,251,427호의 백당으로 만든 미세구형과립에 황산슈도에페드린을 입히고 그 위에 에칠셀룰로오스나 폴리아크릴레이트(상품명:유드라짓RS)로 코팅하여 서방성 펠렛을 제조하고, 따로 미세구형과립에 황산슈도에페드린과 로라타딘을 코팅하여 속방성 펠렛을 제조한 다음 이들을 공캅셀에 충전하는 방법에 대하여 소개하고 있다.A method of preparing tablets consisting of two drug layers by compression using multiple compression methods of US Patent No. 4,996,061, one layer of the drug having a congestion-releasing effect and a water-soluble nonionic cellulose ether together with other additives, Another layer is characterized by containing anionic surfactants, by pH changes in the gastrointestinal tract using salts of arginic acid, pH-dependent, and hydrophilic colloid gelling agents, pH-independent of US Pat. No. 4,792,452, as binders and additives. A method that allows the release of the drug, a tablet consisting of two layers of U.S. Patent No. 6,267,986, is further controlled by the crosslinking of pseudoephedrine sulfate by crosslinking hydrophilic polymers such as xanthan gum and sodium arginate with divalent metal ions. The other layer is a loratadine-containing layer. Method of releasing crab, Method of releasing drug through small pore by osmotic pressure by putting pseudoephedrine and brompheniramine in a compartment consisting of triacetic acid cellulose and hydroxypropyl cellulose of Korean Patent Application Publication No. 87-8583, Korea Patent Publication No. 2000-0076269 A method of preparing a matrix layer comprising a drug for the sustained release of polyacrylic acid or cellulose and an alkali or alkaline earth metal hydroxide of the compound, and fixing the drug layer for rapid release, thereby multi-layer tableting, U.S. Patent Nos. 5,859,060,5,998,478 and A method of coating the pseudoephedrine of No. 6,099,860 with a hydrophilic polymer, such as hydroxypropylmethylcellulose, to make a nucleus tablet, and coating naproxen and pseudoephedrine together on the outer layer. Seven cellulose (Methocel K100LV, DOW) and a method of microcrystalline cellulose and a release control with the other appointed, U.S. Patent Publication No. 6,171,618 a lactose favor pseudoephedrine hydrochloride, echil cellulose. Tablets granulated by wet granulation with povidone and the like to be nuclear tablets, coated with ethyl cellulose on them to form a sustained release drug layer, followed by rapid release of pseudoephedrine hydrochloride and cetirizine hydrochloride. In case of coexisting with the following alcohols, the stability problem by the esterification reaction was improved by using polymer alcohols (e.g., polyethylene glycol 3350, etc.). The sustained-release pellet was prepared by using ethyl cellulose and pseudoephedrine of U.S. Patent No. 5,807,579. Method of preparing and pelletizing the pellet together with sodium bicarbonate, cellulose and drug to form a fast-release drug layer. The high-viscosity hydroxypropylmethylcellulose of U.S. Patent No. 5,681,582 and sudoephedrine hydrochloride together are sustained-release drug layer, followed by ethyl With cellulose A method of preparing a sustained-layer coating film and preparing a rapid-release drug layer with pseudoephedrine hydrochloride and asemizol in combination with low-viscosity hydroxypropylmethylcellulose, and suedephedrine sulfate in micro-spherical granules made of white sugar of U.S. Patent No. 6,251,427. Coated with ethyl cellulose or polyacrylate (trade name: Eudragit RS), to prepare sustained-release pellets. Separately, microspheres are coated with pseudoephedrine and loratadine to prepare immediate-release pellets. How to charge is introduced.

그러나 이상의 어느 방법에서도 염산슈도에페드린과 염산세티리진을 함께 코팅하여 서방출성 약물층과 속방출성 약물층을 같은 펠렛에 제조하는 방법에 대하여 소개한 예가 없다. 서방출성 약물층과 속방출성 약물층을 단일 펠렛안에 코팅하여 제조하는 경우, 서방성펠렛과 속방성펠렛을 따로 제조하여 혼합하는 경우보다 제조공정이 쉽고, 제조원가가 감소되는 장점이 있으며 펠렛의 혼화성에 유리한 장점이 있다. However, none of the above-described methods has been introduced in which a method of producing a sustained-release drug layer and a rapid-release drug layer by coating both pseudoephedrine hydrochloride and cetirizine hydrochloride together on the same pellet. When the sustained-release drug layer and the rapid-release drug layer are manufactured by coating in a single pellet, the manufacturing process is easier and the manufacturing cost is reduced than when the sustained-release pellet and the rapid-release pellet are separately prepared and mixed. There is an advantage to Mars.

한편, 경구로 투여된 제제는 위장관을 거치며 약물이 방출되고, 방출된 약물은 위장점막을 통해 흡수가 이루어진다. 위장관을 지나는 동안 제제는 산성영역인 위와 염기성영역인 소장을 지나게 된다. 따라서, 8시간 이상의 서방출성 제제를 설계할 때, 위장관 내의 pH 변화와 상관없이 약물을 방출시킬 필요가 있다. 이러한 목적으로 사용되는 고분자로는 에칠셀룰로오스와 폴리메타크릴레이트가 대표적이 다.On the other hand, orally administered formulations are released through the gastrointestinal tract, the released drug is absorbed through the gastrointestinal mucosa. While passing through the gastrointestinal tract, the preparation passes through the acidic stomach and the basic small intestine. Therefore, when designing sustained release formulations of 8 hours or more, it is necessary to release the drug regardless of the pH change in the gastrointestinal tract. Examples of the polymer used for this purpose are ethyl cellulose and polymethacrylate.

본 발명의 목적은 단일 펠렛안에 서방출성 약물층으로 염산슈도에페드린을 함유하고 속방출성 약물층으로 염산슈도에페드린과 염산세티리진을 함유하는 제제를 제조하되 서방출성 약물층은 소화관내의 pH 변화에 상관없이 약물을 방출되는 방출제어형 약제학적 조성물의 제조방법을 제공하는 것이다.An object of the present invention is to prepare a formulation containing sudoephedrine hydrochloride as a sustained release drug layer in a single pellet and sudoephedrine hydrochloride and cetirizine hydrochloride as a rapid release drug layer, regardless of the pH change in the digestive tract. To provide a method for preparing a controlled release pharmaceutical composition to release the drug.

본 발명의 구성은 다음과 같다.The configuration of the present invention is as follows.

1) 불활성 코어 : 백당, 셀룰로오스 등의 불활성 물질로 이루어진 코어1) Inert core: core made of inert substance such as sugar, cellulose

2) 서방출성 약물층 : 하나 이상의 활성물질로 구성되고 약물 유효농도를 유지시키기 위해 서서히 방출되는 약물 저장부2) Sustained-release drug layer: drug storage consisting of one or more active substances and slowly released to maintain drug effective concentration

3) 서방출 제어 코팅막 : 서방출성 약물층으로부터 pH와 무관하게 약물의 방출이 이루어지도록 제어하는 고분자의 코팅막3) Sustained release control coating film: Polymeric coating film that controls the release of drug from the sustained release drug layer regardless of pH

4) 속방출성 약물층 : 하나 이상의 활성물질로 구성되고 제제의 투여 직후 신속하게 약물이 방출되어 유효농도에 이르도록 하는 약물저장부4) Rapid-release drug layer: drug storage unit consisting of one or more active substances and promptly released the drug to reach the effective concentration

본 발명을 다음의 실시예 및 실험예를 통해 더욱 상세하게 설명하지만, 본 발명이 이에 한정되는 것은 아니다.The present invention will be described in more detail with reference to the following examples and experimental examples, but the present invention is not limited thereto.

[실시예 1] 염산슈도에페드린 서방약물층 코어의 제조Example 1 Preparation of Sudoephedrine Hydrochloride Sustained Release Drug Layer Core

표1의 조성에 따라 염산슈도에페드린 및 포비돈 K-30을 에탄올/정제수 혼합액에 넣어 녹이고 경질무수규산을 넣어 분산시킨 다음 100호체로 여과하여 코팅액으로 하였다. 원심구형 과립기에 백당과립을 넣고 위의 코팅액을 교반하면서 원심구형과립기에서 분당 30 ㎖의 속도로 분무하여 건조하며, 송입공기의 온도는 75℃, 송출공기의 온도는 40±2℃, 분사압력은 2 kg/cm2, 회전속도는 120 rpm으로 하여 구형과립을 제조하였다. 제조된 과립은 760 mmHg, 50℃로 16시간 동안 감압건조하였다. According to the composition of Table 1, pseudoephedrine hydrochloride and povidone K-30 were dissolved in an ethanol / purified water mixture, dissolved with hard silicic acid, and then filtered through No. 100 to obtain a coating solution. Put the white sugar granules in the centrifugal granulator and spray the above coating solution with 30 ml per minute in a centrifugal spherical granulator and dry them.The temperature of the inlet air is 75 ℃, the temperature of the outlet air is 40 ± 2 ℃, and the spray pressure. Spherical granules were prepared at 2 kg / cm2 and a rotation speed of 120 rpm. The granules thus prepared were dried under reduced pressure at 760 mmHg, 50 ° C. for 16 hours.

[표1] 염산슈도에페드린 서방약물층 코어의 조성 비율[Table 1] Composition ratio of sudoephedrine hydrochloride sustained-release drug layer core

원료  Raw material mg/구형과립 mg / spherical granules 백당과립  White sugar granule 100.0 100.0 염산슈도에페드린  Hydrochloric acid pseudoephedrine 90.0 90.0 포비돈 K-30  Povidone K-30 1.607 1.607 경질무수규산  Light anhydrous silicic acid 0.230 0.230 에탄올  ethanol 150.0 150.0 정제수  Purified water 100.0 100.0

[실시예 2 ~ 실시예 7][Example 2 to Example 7]

실시예 1에서 제조한 서방약물층 코어을 가지고 표 2의 조성으로 코팅액을 제조하여 100호체로 여과하여 코팅액으로 하였다. 원심구형 과립기에 서방약물층 코어를 넣고 코팅액을 교반하면서 원심구형과립기에서 분당 25 ㎖의 속도로 분무하여 건조하며, 송입공기의 온도는 80℃, 송출공기의 온도는 40±2℃, 분사압력은 2.5 kg/cm2, 회전속도는 120 rpm으로 하여 구형과립을 제조하였다. 제조된 과립은 760 mmHg, 50℃로 16시간 동안 감압건조하였다. The coating solution was prepared in the composition of Table 2 with the sustained release drug layer core prepared in Example 1, and filtered through No. 100 to obtain a coating solution. Insert the sustained-release drug layer core into the centrifugal spherical granulator and spray the solution at 25 ml / min in a centrifugal spherical granulator while stirring the coating solution. The temperature of the inlet air is 80 ℃, the temperature of the outlet air is 40 ± 2 ℃, and the spray pressure. Silver 2.5 kg / cm2, the rotation speed was 120 rpm to make a spherical granules. The granules thus prepared were dried under reduced pressure at 760 mmHg, 50 ° C. for 16 hours.

[표2] 염산슈도에페드린 서방출성 구형과립(mg/구형과립)Table 2 Pseudohydrophedrine hydrochloride sustained-release spherical granules (mg / spherical granules)

실시예2  Example 2 실시예3 Example 3 실시예4 Example 4 실시예5 Example 5 실시예6 Example 6 실시예7 Example 7 염산슈도에페드린코어Hydrochloric acid pseudoephedrine core 191.837191.837 191.837191.837 191.837191.837 191.837191.837 191.837191.837 191.837191.837 에칠셀룰로오스Ethyl Cellulose 6.1396.139 12.27812.278 15.34715.347 13.42913.429 16.78616.786 20.14320.143 디에칠프탈레이트Diethylphthalate -- -- -- 2.0142.014 2.5182.518 3.0213.021 탈크Talc 1.5351.535 3.0693.069 3.8373.837 3.7413.741 4.6764.676 5.6115.611 에탄올ethanol 60.060.0 120.0120.0 150.0150.0 150.0150.0 187.5187.5 225.0225.0 메칠렌클로라이드Methylene chloride 60.060.0 120.0120.0 150.0150.0 150.0150.0 187.5187.5 225.0225.0

[실험예 1] 염산슈도에페드린 서방출성 구형과립의 용출실험Experimental Example 1 Dissolution Test of Sudoephedrine Hydrochloride-releasing Spherical Granules

실시예 2 ~ 실시예 7의 염산슈도에페드린 서방출성 구형과립을 염산슈도에페드린으 로서 100mg에 해당하는 양을 취해 약전 용출시험법 제2법에 따라 pH 1.2 염산완충액 500 mL에서 교반속도 125rpm으로 용출시험을 실시하였으며 그 결과는 표 3과 같다.100 mg of the pseudo-ephedrine sustained-release spherical granules of Examples 2 to 7 were used as pseudoephedrine hydrochloride, and the dissolution test was carried out at a stirring speed of 125 rpm at 500 mL of pH 1.2 hydrochloric acid buffer solution according to the second method of the Pharmacopoeia Dissolution Test Method. The results are shown in Table 3.

염산슈도에페드린의 HPLC 분석조건HPLC analysis conditions of pseudoephedrine hydrochloride

칼럼 : KROMASIL KR100-5C18 (250×4.6mm)Column: KROMASIL KR100-5C18 (250 × 4.6mm)

이동상 : 정제수 800mL 및 아세토니트릴 200mL 혼합액에 헵탄설폰산나트륨 200mg을 넣어 녹이고 1M-황산으로 pH 2.5로 맞춘다.Mobile phase: Dissolve 200 mg of heptane sulfonate in 800 mL of purified water and 200 mL of acetonitrile and adjust to pH 2.5 with 1 M sulfuric acid.

유속 : 1.0mL/minFlow rate: 1.0mL / min

파장 : 210nmWavelength: 210nm

주입량 : 20㎕Injection amount: 20µl

[표3] 염산슈도에페드린 서방출성 구형과립의 용출률(%)Table 3: Dissolution rate of Pseudo-Ephedrine sustained-release spherical granules (%)

시간(분)  Minutes 실시예2 Example 2 실시예3 Example 3 실시예4 Example 4 실시예5 Example 5 실시예6 Example 6 실시예7 Example 7 00 00 00 00 00 00 00 1515 49.049.0 4.34.3 1.11.1 7.97.9 4.14.1 2.62.6 3030 60.360.3 17.517.5 8.78.7 21.221.2 10.410.4 5.15.1 6060 70.370.3 33.433.4 26.726.7 44.144.1 26.526.5 19.419.4 120120 76.976.9 46.346.3 42.842.8 63.463.4 50.050.0 44.144.1 240240 78.978.9 57.857.8 57.057.0 79.279.2 72.972.9 66.366.3 360360 81.381.3 63.563.5 64.064.0 86.686.6 83.883.8 77.977.9 480480 81.481.4 65.865.8 70.970.9 91.491.4 87.287.2 82.882.8

[제제예 1] 염산슈도에페드린 및 염산세티리진 복합제제의 제조Preparation Example 1 Preparation of Pseudohydrophedrine Hydrochloride and Cetirizine Hydrochloride

실시예 6 및 7의 염산슈도에페드린 서방출성 구형과립을 코어로 하여 표 4의 조성으로 원심구형 과립기에 서방출성 구형과립을 넣고 코팅액을 교반하면서 원심구형과립기에서 분당 25 ㎖의 속도로 분무하여 건조하며, 송입공기의 온도는 85℃, 송출공기의 온도는 50±2℃, 분사압력은 3 kg/cm2, 회전속도는 120 rpm으로 하여 구형과립을 제조하였다. 제조된 과립은 760 mmHg, 50℃로 16시간 동안 감압건조하였다. 제조된 구형과립 100g을 달아 스테아린산마그네슘 0.5g과 혼화한 다음 염산슈도에페드린으로서 120mg에 해당하는 양을 취하여 1호 캅셀에 충전하였다.The sustained-release spherical granules were prepared in the centrifugal spherical granulator according to the composition of Table 4, using pseudoephedrine hydrochloride sustained-release spherical granules of Examples 6 and 7, sprayed at a rate of 25 ml / min in a centrifugal spherical granulator while stirring the coating solution. , Spherical granules were prepared at a temperature of inlet air of 85 ° C., a temperature of outgoing air of 50 ± 2 ° C., an injection pressure of 3 kg / cm 2, and a rotational speed of 120 rpm. The granules thus prepared were dried under reduced pressure at 760 mmHg, 50 ° C. for 16 hours. 100 g of the spherical granules prepared were mixed with 0.5 g of magnesium stearate, and then charged in capsule No. 1 with an amount corresponding to 120 mg as pseudoephedrine hydrochloride.

[표4] 속방출성 약물층의 조성 비율[Table 4] Composition ratio of fast-release drug layer

원료Raw material mg/구형과립mg / spherical granules 염산슈도에페드린 서방출성 구형과립Pseudohydroephrine hydrochloride-releasing spherical granules 220.613220.613 염산슈도에페드린Hydrochloric acid pseudoephedrine 30.030.0 염산세티리진Cetirizine hydrochloride 5.05.0 포비돈 K-30Povidone K-30 1.51.5 경질무수규산Light anhydrous silicic acid 0.180.18 크로스포비돈Crospovidone 12.012.0 옥수수전분Corn starch 11.3211.32 에탄올ethanol 180180 정제수Purified water 120120

[실험예 2] 염산슈도에페드린 및 염산세티리진 함유 캅셀의 용출시험Experimental Example 2 Dissolution Test of Pseudohydrophedrine Hydrochloride and Cetirizine Hydrochloride-Containing Capsules

제제예 1의 캅셀 제제를 가지고 약전 용출시험법 제2법에 따라 pH 1.2 염산완충액 500 mL, pH 4.0 초산완충액 500mL 및 pH 7.4 인산완충액 500mL에서 교반속도 125rpm으로 용출시험을 실시하였으며 그 결과는 표5 및 표6과 같다.Using the capsule formulation of Formulation Example 1, dissolution test was performed at a stirring speed of 125 rpm in 500 mL of pH 1.2 hydrochloric acid buffer solution, 500 mL of pH 4.0 acetic acid buffer solution, and 500 mL of pH 7.4 phosphate buffer solution according to Method 2 of the Pharmacopoeia Elution Test. And Table 6.

염산세티리진의 HPLC 분석조건 HPLC analysis conditions for cetirizine hydrochloride

칼럼 : KROMASIL KR100-5C18 (250×4.6mm)Column: KROMASIL KR100-5C18 (250 × 4.6mm)

이동상 : 정제수 600mL 및 아세토니트릴 400mL 혼합액에 헵탄설폰산나트륨 200mg을 넣어 녹이고 1M-황산으로 pH 2.5로 맞춘다.Mobile phase: Dissolve 200 mg of heptane sulfonate in 600 mL of purified water and 400 mL of acetonitrile and adjust to pH 2.5 with 1M sulfuric acid.

유속 : 1.2mL/minFlow rate: 1.2mL / min

파장 : 230nmWavelength: 230nm

주입량 : 20㎕Injection amount: 20µl

[표5] 제제예 1의 염산슈도에페드린의 용출률(%)TABLE 5 Dissolution rate of Pseudoephedrine hydrochloride of Formulation Example 1 (%)

시간(분)Minutes pH 1.2 완충액pH 1.2 buffer pH 4.0 완충액pH 4.0 buffer pH 7.4 완충액pH 7.4 buffer 00 00 00 00 1515 29.7±0.36*29.7 ± 0.36 * 26.5±0.1226.5 ± 0.12 27.8±1.4527.8 ± 1.45 3030 31.1±0.0231.1 ± 0.02 30.7±0.3530.7 ± 0.35 29.5±0.7829.5 ± 0.78 6060 35.1±0.4535.1 ± 0.45 34.8±0.5634.8 ± 0.56 33.5±1.1333.5 ± 1.13 120120 50.0±1.3750.0 ± 1.37 48.8±1.2648.8 ± 1.26 48.1±1.0248.1 ± 1.02 240240 70.5±2.3570.5 ± 2.35 67.2±1.5867.2 ± 1.58 66.8±1.3566.8 ± 1.35 360360 82.5±2.5582.5 ± 2.55 79.5±2.4279.5 ± 2.42 78.8±1.6978.8 ± 1.69 480480 92.1±0.0592.1 ± 0.05 91.7±1.1291.7 ± 1.12 90.5±2.2190.5 ± 2.21

(* ; 검체수 3, 평균±표준편차) (*; Sample number 3, mean ± standard deviation)

[표6] 제제예 1의 염산세티리진의 용출률(%)TABLE 6 Dissolution rate of cetirizine hydrochloride of Formulation Example 1 (%)

시city pH 1.2 완충액pH 1.2 buffer pH 4.0 완충액pH 4.0 buffer pH 7.4 완충액pH 7.4 buffer 00 00 00 00 1515 98.2±0.04*98.2 ± 0.04 * 97.1±0.0297.1 ± 0.02 96.8±0.3196.8 ± 0.31 3030 98.3±0.1698.3 ± 0.16 97.6±0.0597.6 ± 0.05 97.2±0.5197.2 ± 0.51 4545 98.5±0.2598.5 ± 0.25 98.5±0.7798.5 ± 0.77 97.8±0.0597.8 ± 0.05 6060 99.0±0.1799.0 ± 0.17 98.8±0.2298.8 ± 0.22 98.2±0.4898.2 ± 0.48

(* ; 검체수 3, 평균±표준편차) (*; Sample number 3, mean ± standard deviation)

상기 실시예 및 제제예에서 단일 구형과립에 속방출성 약물층에 염산세티리진 및 염산슈도에페드린을 함유하고 서방출성 약물층에 염산슈도에페드린을 함유하여 신속하게 염산세티리진 및 염산슈도에페드린을 방출시킨 다음, pH에 상관없이 염산슈도에페드린을 지속적으로 방출시키는 구형과립의 제조가 가능하다
In the above Examples and Formulations, cetirizine hydrochloride and pseudoephedrine hydrochloride were rapidly released by containing cetirizine hydrochloride and pseudoephedrine hydrochloride in the immediate-release drug layer in a single spherical granule, and pseudoephedrine hydrochloride in the sustained release drug layer, followed by pH Irrespective of which spherical granules can be produced to continuously release pseudoephedrine hydrochloride.

Claims (8)

염산슈도에페드린 및 포비돈 K-30을 에탄올/정제수 혼합액에 넣어 녹이고 경질무수규산을 넣어 분산시킨 다음 100호체로 여과하여 코팅액으로 하고, 원심구형 과립기에 백당과립을 넣고 상기 코팅액을 교반하면서 원심구형과립기에 의해 제조되는 불활성코어와 염산슈도에페드린의 혼합에 의한 서방출성 약물층 코어 제조단계; Pseudohydrophedrine hydrochloride and povidone K-30 were dissolved in an ethanol / purified water mixture, dissolved and dispersed with light anhydrous silicic acid. The mixture was filtered through No. 100 sieve to form a coating solution. Preparing a sustained release drug layer core by mixing a prepared inert core with pseudoephedrine hydrochloride; 상기 서방출성 약물층 코어를 원심구형 과립기에 넣고, 염산슈도에페드린코어, 에칠셀룰로오스, 디에칠프탈레이트, 탈크, 에탄올 및 메칠렌클로라이드로 이루어진 코팅액을 교반하면서 원심구형과립기에서 분무하여 건조하는 서방출성 약물층 제어 코팅막 형성단계;The sustained-release drug layer core is placed in a centrifugal spherical granulator, and a sustained-release drug layer sprayed and dried in a centrifugal spherical granulator while stirring a coating liquid consisting of pseudoephedrine core hydrochloride, ethyl cellulose, diethphthalate, talc, ethanol and methylene chloride. Forming a control coating film; 상기 코팅된 서방출성 구형과립을 코어로 하여 염산슈도에페드린, 연산세티리진, 포비돈 K-30, 경질무수규산, 크로스포비돈, 옥수수전분, 에탄올 및 정제수로 이루어지는 속방출성 약물층을 교반하면서 원심구형과립기에서 분무하고 건조하여 구형과립으로 제조하는 혼합단계; 로 이루어지는 것을 특징으로 하는 방출제어형 약제학적 조성물의 제조방법.Centrifugal spherical granulator while stirring the fast-release drug layer consisting of pseudoephedrine hydrochloride, ocecetirizine, povidone K-30, light anhydrous silicic acid, crospovidone, corn starch, ethanol and purified water as the core Spraying and drying to prepare a spherical granules; Method for producing a controlled release pharmaceutical composition, characterized in that consisting of. 제1항에 있어서, 상기 서방출성 약물층 코어 제조단계는 상기 원심구형과립기에서 분당 30 ㎖의 속도로 분무하여 건조하며, 송입공기의 온도는 75℃, 송출공기의 온도는 40±2℃, 분사압력은 2 kg/cm2, 회전속도는 120 rpm으로 하여 구형과립을 제조하였다. 제조된 과립은 760 mmHg, 50℃로 16시간 동안 감압건조하는 것을 특징으로 하는 방출제어형 약제학적 조성물의 제조방법.The method of claim 1, wherein the sustained-release drug layer core manufacturing step is sprayed and dried at a rate of 30 ml per minute in the centrifugal spherical granulator, the temperature of the feed air is 75 ℃, the temperature of the discharge air is 40 ± 2 ℃, Spherical granules were prepared at a spray pressure of 2 kg / cm 2 and a rotation speed of 120 rpm. The prepared granules are dried at 760 mmHg, 50 ° C. under reduced pressure for 16 hours. 제1항에 있어서, 상기 서방출성 약물층 제어 코팅막 형성단계의 상기 원심구형과립기에서 분당 25 ㎖의 속도로 분무하여 건조하며, 송입공기의 온도는 80℃, 송출공기의 온도는 40±2℃, 분사압력은 2.5 kg/cm2, 회전속도는 120 rpm으로 하여 구형과립을 제조하였다. 제조된 과립은 760 mmHg, 50℃로 16시간 동안 감압건조하여 서방출성 약물층 제어 코팅막을 형성시키는 것을 특징으로 하는 방출제어형 약제학적 조성물의 제조방법.The method of claim 1, wherein in the centrifugal spherical granulator of the sustained-release drug layer control coating film forming step is sprayed and dried at a rate of 25 ml per minute, the temperature of the charge air is 80 ℃, the temperature of the discharge air is 40 ± 2 ℃ , Spherical granules were prepared at a spray pressure of 2.5 kg / cm 2 and a rotation speed of 120 rpm. The prepared granules are dried under reduced pressure at 760 mmHg, 50 ° C. for 16 hours to form a sustained release drug layer controlled coating film. 제1항에 있어서, 상기 혼합단계의 상기 원심구형과립기에서 분당 25 ㎖의 속도로 분무하여 건조하며, 송입공기의 온도는 85℃, 송출공기의 온도는 50±2℃, 분사압력은 3 kg/cm2, 회전속도는 120 rpm으로 하여 구형과립을 제조하고, 상기 제조된 과립은 760 mmHg, 50℃로 16시간 동안 감압건조하는 것을 특징으로 하는 방출제어형 약제학적 조성물의 제조방법.The method of claim 1, wherein the centrifugal granulator of the mixing step is dried by spraying at a rate of 25 ml per minute, the temperature of the feed air is 85 ℃, the temperature of the discharge air is 50 ± 2 ℃, the injection pressure 3 kg / cm2, the rotation speed is 120 rpm to produce spherical granules, the granules are 760 mmHg, 50 ℃ to produce a controlled release pharmaceutical composition, characterized in that the drying for 16 hours at 50 ℃. 삭제delete 삭제delete 삭제delete 삭제delete
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