KR19990066978A - 경구 또는 직장 투여용 다층 고상 제형의 제조방법 - Google Patents
경구 또는 직장 투여용 다층 고상 제형의 제조방법 Download PDFInfo
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- KR19990066978A KR19990066978A KR1019980702911A KR19980702911A KR19990066978A KR 19990066978 A KR19990066978 A KR 19990066978A KR 1019980702911 A KR1019980702911 A KR 1019980702911A KR 19980702911 A KR19980702911 A KR 19980702911A KR 19990066978 A KR19990066978 A KR 19990066978A
- Authority
- KR
- South Korea
- Prior art keywords
- active ingredient
- formulation
- ibuprofen
- oral
- molding
- Prior art date
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Abstract
본 발명은 각 조성물이 생리학적 환경에서 가용성 또는 팽윤성인 열가소성의, 약리학상 허용가능한 고분자 결합제를 포함하고 조성물 중 1개 이상이 제약학적 활성 성분을 함유하는 2개 이상의 조성물을 공압출시키고, 공압출된 다층 물질을 원하는 제형으로 조형시킴을 포함하는 경구 또는 직장 투여용 다층 고상 제형의 제조 방법에 관한 것이다.
Description
본 발명은 경구 또는 직장 투여용의 다층 고상 제형의 제조 방법 및 본 발명에 따른 방법으로 수득가능한 제형에 관한 것이다.
몇 개의 층으로 이루어지는 제형, 예를 들면 코팅가능한 적층 또는 다층 정제는 예를 들어, 서로 배합 금지의 활성 성분을 조합하기 위하여 또는 제어 방출형 제형의 경우 투여량의 초기 및 지속 방출이 일어나도록 하기 위하여 점점 더 많이 사용되고 있다. 이러한 유형의 제형은 통상의 방법으로 제조된다. 적층 정제는 건성 코팅에 의해 제조하고, 다층 정제는 두 개 이상의 과립층을 압축함으로써 제조한다. 이를 위해 특수한 기계가 필요한데, 이 기계는 그의 작동 방법 면에서 두 개 이상의 충전 및 압축 지점이 필요한 통상의 회전식 기계와 비슷하다. 따라서 이런 통상적인 방법은 복잡하고 비용이 많이 든다.
전통적인 다단식, 뱃치식 정제 제조 방법보다 훨씬 더 간단한 정제 제조 방법이 일찍이 알려졌다. 이 방법은 고분자 결합제 중에 활성 성분을 취하고, 활성 성분을 함유하는 중합체 용융물을 압출시키고, 압출기로부터 압출되는 압출물을 적당한 방법 (예를 들어, 유럽 특허 공개 제240 904호 및 제240 906호 참조)으로 조형하는 것을 포함한다.
공압출법은 플라스틱 공학 기술에서 알려져 있고, 다수의 압출기로부터의 용융 스트림을 각종 열가소성 물질의 특정 층 구조가 만들어지도록 주형 내에서 조합하는 것을 포함한다. 제약 산업에서 공압출법의 사용은 주로 포장 필름의 제조에 한정되어 있다. 또한, 어류용 의약품 및 이식제 형태의 중합체 캡슐 및 코팅된 활성 성분의 제조가 알려져 있다.
국제 특허 공개 제89/12442호는 어류의 약물 치료를 위한 제형을 기재하고 있다. 일반적으로, 물고기에게는 먹이를 통해 약을 투여하는데 즉, 약을 먹이와 혼합한다. 이런 형태의 문제점은 약의 맛 때문에 물고기가 약-함유 먹이를 먹지 않는다는 것이다. 그 결과는 오랜 기간 동안 물에 남아 있는 약-함유 먹이의 상당 부분이 쓰이지 않고 남아서 가라앉게 된다는 것이었다. 이것은 약이 바람직하지 않게 물로 방출되어 자연히 물을 오염시키게 된다.
이런 문제를 해결하기 위하여, 국제 특허 제89/12442호는 공압출법으로 제조되며, 내부 챔버를 둘러싸고 있는 외층으로 구성되는 제형을 제안하였다. 외층은 물고기가 먹을 수 있는 제형을 만들기 위하여 적당한 동물성 또는 식물성 물질을 함유하는 녹말 유도체로 구성된다. 또한, 물 및 내부 챔버에 포함된 활성 성분이 외부층을 투과할 수 없다. 내부 챔버는 점성 현탁액 중의 활성 성분을 포함하며, 이는 챔버의 일부만을 채운다. 이로써 상기 제형이 물에서 가라앉지 않고 뜨는데 필수적인 부력을 주는 공기 공간을 상기 제형이 갖게 된다.
미국 특허 제5,283,187호는 활성 성분으로서 반투과성 중합체 막내에 봉합된 세포 현탁액을 포함하는 이식제를 기재하고 있다. 적당한 수혼화성 유기 용매 중의 상기 중합체 용액과 세포 현탁액의 공압출에 의해 이식제를 제조한다. 상기 중합체는 압출 중에 응집하며 홈이 있는 망상 구조를 형성하는 중합체를 선택해야만 막이 반투과성이 된다.
유럽 특허 공개 제303 306호는 10 g/10 분이 넘는 용융 흐름 지수 및 20 중량% 이상의 비닐 아세테이트 함량을 갖는 에틸렌/비닐 아세테이트 공중합체로 이루어진 코어 (core)를 갖는 원통형 이식제를 기재하고 있다. 코어는 마찬가지로 에틸렌/비닐 아세테이트 공중합체로 구성된 두께 50 내지 250 ㎛의 막으로 둘러싼다. 그러나, 이 중합체는 10 g/10 분 미만의 용융 흐름 지수 및 20 중량% 미만의 비닐 아세테이트 함량을 갖는다. 이 막은 코어에 포함된 활성 성분, 예컨대 피임약의 방출을 제어하는데, 피암약의 경우 2년 이상의 주기에 걸쳐 15 내지 30 ㎍의 일일 투여량으로 방출하는 방법으로 제어한다. 이 이식제는 두 개의 중합체 층의 공압출에 의해 제조된다.
상기 언급된 이식제는 비경구식으로, 예를 들어 피하에 투여된다. 이 이식제의 외층은 체액에 녹지 않도록 고안되었고, 따라서 간단한 방법으로 체내에서 다시 제거할 수 있다.
경구 또는 직장으로 투여가 가능하며, 필요한 활성 성분 방출 특성의 특별한 조절을 위해 사용되는 제형이 충족시켜야 하는 요건은 이식제의 요건과는 매우 다르다. 이런 유형의 제형은 이식제에 비해 상대적으로 빠르게 특정 방식으로 특정 장소에 활성 성분을 방출하고, 편리하게 체액에 용해되는 용도에 사용된다.
본 발명의 목적은 경구 또는 직장으로 투여할 수 있는 고상 제형 및 이런 제형을 간단하고 쉬운 방법으로 제조할 수 있고, 필요 방출 특성이 보장되는 제조 방법을 제공하는 것이다.
본 발명자들은 조성물 중 1개 이상이 제약학적 활성 성분을 함유하는, 약리학상 허용가능한 열가소성 중합체를 포함하는 2개의 조성물을 공압출시킴으로써 수득가능한 다층 고상 제형으로 상기 목적을 달성할 수 있음을 발견하였다.
따라서, 본 발명은 각 조성물이 생리적인 환경에서 가용성 또는 팽윤성인 열가소성의, 생리학상 허용가능한 고분자 결합제를 포함하며, 1개 이상의 조성물에 제약학적 활성 성분이 포함되는 2개 이상의 조성물을 공압출하고, 공압출된 다층 물질을 특정 제형으로 조형하는 것을 포함하는 경구 또는 직장 투여용 다층 고상 제형의 제조 방법 및 이 방법으로 수득가능한 제형에 관한 것이다.
도 1은 성형 롤을 사용하여 정제를 공압출 및 조형하는 도식적인 단면도를 나타낸다.
도 2는 핀치 장치로 정제를 조형하는 도식적인 단면도를 나타낸다.
경구 및 직장 투여용 고상 제형에는 구체적으로는 정제, 제피 정제, 파스틸 (pastilles) 및 펠렛 (pellets), 및 좌약이 포함된다.
본 발명에 따라 제조된 제형은 외층이 막이 아니라 체액 중에 가용성 및(또는) 팽윤성이고, 적당한 경우 보호층 또는 접착층이 되도록 고안되는 것이 바람직하다.
본 발명에 따라 제조될 수 있는 제형은 2 또는 3개의 층을 포함하는 것이 바람직하다. 이들은 개방 또는 밀봉 형태, 특히 개방 또는 밀봉형 다층 정제가 될 수 있다.
층 중의 1개 이상이 1종 이상의 제약학적 활성 성분을 함유한다. 또한, 다른 층에 다른 활성 성분을 함유시키는 것도 가능하다. 이 방법은 서로 배합 금지된 두 개의 활성 성분을 가공할 수 있거나, 또는 활성 성분의 방출 특성을 제어할 수 있다는 잇점을 갖는다. 예를 들면, 외층 중 하나가 활성 성분을 함유함으로써 초기 투여를, 내층이 활성 성분을 함유함으로써 지속 투여를 제공하는 것이 가능하다.
층 두께는 원하는 방출 특성에 따라 선택할 수 있다. 층 두께를 증가시키면 활성 성분의 방출이 더욱 지연되는데 즉, 효과가 더 오랫 동안 지속된다.
본 발명에 속한 제형은 소위 결장을 표적으로 하여 작용하는데 특히 적당하다. 이런 목적을 위하여, 활성 성분의 방출은 적당한 물질의 선택에 의해 시간-, pH- 또는 효소-의존 방법으로 조절할 수 있다. 시간-의존성 제어는 예를 들어, 층 두께 및(또는) 빠르거나 느린 용해 물질에 의해 가능하다. 예를 들어, 폴리비닐피롤리돈은 비교적 빠르게 용해하고, 에틸셀룰로오즈, 폴리아크릴레이트 또는 폴리메타크릴레이트 (Eudragit RL, RS)는 비교적 느리게 용해한다.
pH-의존성 제어는 위액에서는 가용성이고(이거나) (예로서 폴리비닐피롤리돈) 위액에서는 녹지 않고 장액에서 녹는 물질 (예로서 셀룰로오즈 프탈레이트, 폴리아크릴레이트 또는 메타크릴레이트 (Eudragit L 30 D 또는 S))을 사용함으로써 가능하다.
효소-의존성 제어는 예를 들어, 갈락토만난스 (galactomannans)와 같은 장내 효소에 노출될 경우에만 활성 성분을 방출하는 물질을 사용함으로써 가능하다.
본 발명의 제형은, 각 조성물이 열가소성의, 약리학상 허용가능한 1 종 이상의 고분자 결합제, 적당한 경우에는 1 종 이상의 제약학적 활성 성분 및 1 종 이상의 통상적인 보조제를 포함하며, 1 종 이상 성분의 용융 및 연화로 인해 페이스트상 또는 점성상이 되어 (열가소성), 따라서 압출이 가능하게 되는 둘 이상의 별도의 조성물 (혼합물)로부터 출발하여 제조한다. 이 조성물의 유리 전이 온도는 이 조성물에 존재하는 모든 성분들의 분해 온도보다 낮다. 바람직하게는, 결합제는 생리적인 환경 중에 가용성 또는 팽윤성이어야 한다. 적당한 결합제의 예로는 폴리비닐피롤리돈 (PVP), N-비닐피롤리돈 (NVP) 및 비닐 에스테르류, 특히 비닐 아세테이트의 공중합체, 비닐 아세테이트 및 크로톤산의 공중합체, 부분 가수분해된 폴리비닐 아세테이트, 폴리비닐 알콜, 폴리(히드록시알킬 아크릴레이트류), 폴리(히드록시알킬 메타크릴레이트류), 폴리아크릴레이트 및 폴리메타크릴레이트류 (Eudragit 형), 메틸 메타크릴레이트 및 아크릴산의 공중합체, 셀룰로오즈 에스테르류, 셀룰로오즈 에테르류, 특히 메틸셀룰로오즈 및 에틸셀룰로오즈, 히드록시알킬셀룰로오즈류, 특히 히드록시프로필셀룰로오즈, 히드록시알킬알킬셀룰로오즈류, 특히 히드록시프로필에틸셀룰로오즈, 셀룰로오즈 프탈레이트류, 특히 셀룰로오즈 아세테이트 프탈레이트 및 히드록시프로필메틸셀룰로오즈 프탈레이트, 녹말, 녹말 유도체 (예를 들면, 말토덱스트린), 당 알콜류, 예를 들면 만니톨 또는 팔라티노즈 및 만난스, 특히 갈락토만난스가 있다. 상기 중합체의 K 값 (H. Fikentsher, Cellulose-Chemie 13 (1932), 58-64 및 71-74에 따름)은 10 내지 100, 바람직하게는 12 내지 70, 특히 12 내지 35이고, PVP는 바람직하게는 12 내지 35, 특히 12 내지 17이다.
활성 성분을 수용하기 위한 바람직한 결합제로는 폴리비닐피롤리돈, N-비닐피롤리돈 및 비닐 에스테르의 공중합체, 및 히드록시알킬 아크릴레이트가 있다.
활성 성분을 함유하지 않는 층용의 바람직한 결합제로는 수성 매질 중에 또는 pH<5에서 불용성인 결합제, 구체적으로는 히드록시알킬셀룰로오즈, 알킬셀룰로오즈, 히드록시알킬알킬셀룰로오즈, 폴리아크릴레이트, 셀룰로오즈 프탈레이트, 폴리라크티드 및 갈락토만난스가 있다.
고분자 결합제는 모든 성분의 전체 혼합물 중에서 50 내지 180, 바람직하게는 60 내지 130 ℃ 범위에서 연화 또는 용융되어 조성물의 압출이 가능해야 한다. 따라서, 혼합물의 유리 전이 온도는 180 ℃ 미만, 바람직하게는 130 ℃미만이어야 한다. 필요하다면, 고분자 결합제는 통상적인 약리학상 허용가능한 가소화 보조제, 예를 들면, 장쇄 알콜류, 에틸렌 글리콜, 프로필렌 글리콜, 글리세롤, 트리메틸올프로판, 트리에틸렌 글리콜, 당 알콜류 (예를 들어, 부탄디올류, 펜타에리트리톨과 같은 펜탄올류 또는 헥산올류), 폴리에틸렌 글리콜류, 폴리플로필렌 글리콜류, 폴리에틸렌/프로필렌 글리콜류, 실리콘류, 방향족 카르복실산 에스테르류 (예를 들어, 디알킬 프탈레이트류, 트리멜리트산 에스테르류, 벤조산 에스테르류, 테레프탈산 에스테르류) 또는 지방족 디카르복실산 에스테르류 (예를 들어, 디알킬 아디페이트류, 세바크산 에스테르류, 아젤라산 에스테르류, 시트르산 및 타르타르산 에스테르류), 글리세롤 모노-, 디- 또는 트리아세테이트 또는 나트륨 디에틸 술포숙시네이트와 같은 지방산 에스테르류에 의해 감소된다. 일반적으로, 가소화제 농도는 특정 층을 이루는 조성물의 총 중량의 0.5 내지 15, 바람직하게는 0.5 내지 5 %이다. 혼합물이 가소화제를 포함하지 않는 것이 바람직하다.
제약학적 보조제의 총량은 중합체 중량의 100 % 까지일 수 있으며, 통상적인 제약학적 보조제의 예로는,
특히 특정 층을 이루는 조성물 총 중량의 0.02 내지 50, 바람직하게는 0.20 내지 20 % 농도의 증량제 또는 부피 증가제, 예를 들면 실리케이트류 또는 규조토, 산화 마그네슘, 산화 알루미늄, 산화 티타늄, 스테아르산 또는 그의 염류 (예를 들면, 마그네슘 또는 칼슘 염), 메틸셀룰로오즈, 나트륨 카르복시메틸셀룰로오즈, 탈크, 자당, 유당, 곡물 또는 옥수수 녹말, 감자 소백분, 폴리비닐 알콜,
특정 층을 이루는 조성물 총 중량의 0.1 내지 5, 바람직하게는 0.1 내지 3 % 농도의 윤활제, 예를 들면 알루미늄 및 칼슘 스테아레이트류, 탈크 및 실리콘류,
특정 층을 이루는 조성물 총 중량의 0.001 내지 10, 바람직하게는 0.5 내지 3 % 농도의 염료류, 예를 들면 아조염료, 유기 또는 무기 안료, 또는 무기 안료를 갖는 천연 염료가 있으며,
동물성 또는 식물성 지방, 특히 수소화된 형태의 지방 및 실온에서 고체인 유동제가 있다. 이런 지방은 50 ℃ 이상의 융점을 갖는 것이 바람직하다. C12, C14, C16및 C18지방산의 트리글리세리드가 바람직하다. 카르나우바 왁스와 같은 왁스도 또한 사용할 수 있다. 이런 지방과 왁스를 이롭게는 단독으로 또는 모노- 및(또는) 디글리세리드 또는 포스파티드, 특히 레시틴과 함께 혼합할 수 있다. 모노- 및 디글리세리드는 바람직하게 상기 언급된 지방산 형태에서 유도된다. 지방, 왁스, 모노 및 디글리세리드 및(또는) 레시틴의 총량은 특정 층을 이루는 조성물 총 중량의 0.1 내지 30, 바람직하게는 0.1 내지 5 %이다.
또한 보조 물질로 산화 방지제, 광 안정화제, 히드로과산화물 파괴제, 라디칼 포획제, 미생물 공격에 대한 안정화제와 같은 안정화제가 있다.
또한, 습윤화제, 보존제, 붕해제, 흡착제 및 이형제 및 발포제가 있다 (예를 들어, H. Sucker 외, Pharmazeutische Technologie, Thieme-Verlag, Stuttgart 1978 참조).
또한 본 발명의 목적을 위한 보조 물질은 제약학적 활성 성분을 갖는 고체 용액을 제조하기 위한 물질을 의미한다. 이런 보조 물질의 예로는 펜타에리트리톨 및 펜타에리트리톨 테트라아세테이트, 산화 폴리에틸렌 및 산화 폴리프로필렌과 같은 중합체 및 그의 블록 공중합체 (폴록사머 (Poloxamers)), 레시틴과 같은 포스파티드류, 비닐 피롤리돈의 단독 중합체 및 공중합체, 폴리옥시에틸렌 40 스테아레이트와 같은 계면 활성제류, 및 시트르산 및 숙신산, 담즙산, 스테롤 및 문헌 [J.L. Ford, Pharm. Acta Helv.61, 69-88 (1986)]에 기재된 다른 것들이 있다.
적당한 보조 물질의 유일한 필요 조건은 적당한 온도 안정화이다.
본 발명의 목적을 위한 제약학적 활성 성분은 공정 조건하에서 분해되지 않는 한은 제약학적 효과와 최소의 부작용을 갖는 모든 물질을 의미한다. 투여량 당 활성 성분의 양 및 농도는 효능 및 방출 속도에 따라 넓은 범위내에서 달라질 수 있다. 활성 성분이 필요한 효과를 달성하기에 충분해야 한다는 것이 유일한 조건이다. 따라서, 활성 성분 농도는 0.1 내지 95, 바람직하게는 20 내지 80, 특히 30 내지 70 중량%의 범위가 될 수 있다. 또한 이부프로펜/카페인과 같은 활성 성분의 조합도 사용할 수 있다. 본 발명의 목적을 위한 활성 성분으로는 비타민류 및 무기물류, 및 농작물 처치제 및 살충제도 있다. 비타민류로는 A군의 비타민, B군의 비타민, 및 비타민 C, D군, E군, F군, H군, I 및 J군, K군 및 P군의 비타민을 포함한다. B군의 비타민은 B1, B2, B6및 B12, 및 니코틴산 및 니코틴아미드 외에, 아데닌, 콜린, 판토텐산, 비오틴, 아데닐산, 폴산, 오로트산, 판감산, 카르니틴, p-아미노벤조산, 미오-이노시톨 및 리포산과 같은 비타민 B 성질을 갖는 화합물을 의미한다. 또한 본 발명의 목적을 위한 활성 성분은 치료상의 펩티드도 포함한다.
본 발명에 따른 방법은, 예를 들어
아세부톨올, 아세틸시스테인, 아세틸살리실산, 아시클로버, 알프라졸람, 알파칼시돌, 알란토인, 알로푸리놀, 암브록솔, 아미카신, 아미로리드, 아미노아세트산, 아미오다론, 아미트립틸린, 암로디핀, 암옥시실린, 암피실린, 아스코르브산, 아스파르탐, 아스테미졸, 아테놀올, 베클로메타손, 벤제라지드, 벤잘코늄 염산염, 벤조카인, 벤조산, 베타메타손, 베자피브레이트, 비오틴, 비페리덴, 비소프롤올, 브로마제팜, 브롬헥신, 브로모크립틴, 부데조니드, 부펙사마크, 부플로메딜, 부스피론, 카페인, 캄포르, 캅토프릴, 카르바마제핀, 카르비도파, 카르보플라틴, 세파클로르, 세팔렉신, 세파트록실, 세파졸린, 세픽심, 세포탁심, 세프타지딤, 세프트리악손, 세푸록심, 셀레길린, 클로르암페니콜, 클로로헥시딘, 클로르페니르아민, 클로르탈리돈, 콜린, 시클로스포린, 실라스타틴, 시메티딘, 시프로플록사킨, 시사프리드, 시스플라틴, 클라리트로미신, 클라불란산, 클로미프라민, 클로나제팜, 클로니딘, 클로트리마졸, 코데인, 콜레스티라민, 크로모클릭산, 시아노코발아민, 시프로테론, 데소게스트렐, 덱사메타손, 덱스판테놀, 덱스트로메토르판, 덱스트로프로폭시펜, 디아제팜, 디클로페낙, 디곡신, 디히드로코데인, 디히드로에르고타민, 디히드로에르고톡신, 딜티아젬, 디펜히드라민, 디피리다몰, 디피론, 디조피라미드, 돔페리돈, 도파민, 독시시클린, 에날라프릴, 에페드린, 에피네프린, 에르고칼시페롤, 에르고타민, 에리트로미신, 에스트라디올, 에티닐에스트라디올, 에토포시드, 유칼립투스 글로불루스, 파모티딘, 펠로디핀, 페노피브레이트, 페노테롤, 펜타닐, 팔라빈 모노뉴클레오티드, 플루코나졸, 플루나리진, 플루오로우라실, 플루옥세틴, 플루르비프로펜, 푸로세미드, 칼로파밀, 겜피브로질, 겐타미신, 깅고 빌로바, 글리벤클아미드, 글리피지드, 클로자핀, 글리시르히자 글라브라, 그리세오풀빈, 구아이페네신, 할로페리돌, 헤파린, 히알루론산, 히드로클로로티아지드, 히드로코돈, 히드로코르티존, 히드로모르폰, 이프라트로퓸 히드록시드, 이부프로펜, 이미페넴, 인도메타신, 이오헥솔, 이오파미돌, 이소소르비드 디니트레이트, 이소소르비드 모노니트레이트, 이소트레티노인, 케토티펜, 케토코나졸, 케토프로펜, 케노로락, 라베탈올, 락툴로즈, 레시틴, 레보카르니틴, 레보도파, 레보글루타미드, 레보노르게스트렐, 레보티록신, 리도카인, 리파제, 이미프라민, 리시노프릴, 로페라미드, 로라제팜, 로바스타틴, 메드록시프로게스테론, 멘톨, 멘토트렉세이트, 메틸도파, 메틸프레드니솔론, 메토클로프라미드, 메토프롤올, 미코나졸, 미다졸람, 미노시클린, 미녹시딜, 미소프로스톨, 모르핀, 멀티비타민 혼합물 또는 조합물 및 무기염류, N-메틸에페드린, 나프티드로푸릴, 나프록센, 네오미신, 니카르디핀, 니세르골린, 니코틴아미드, 니코틴, 니코틴산, 니페디핀, 니모디핀, 니트라제팜, 니트렌디핀, 니자티딘, 노레티스테론, 노르플록사신, 노르게스트렐, 노르트립티린, 니스타틴, 오플록사신, 오메프라졸, 온단세트론, 판크레아틴, 판테놀, 판토텐산, 파라세타몰, 페니실린 G, 페니실린 V, 페노바르비탈, 펜톡시필린, 페녹시메틸페닐실린, 페닐에프린, 페닐프로판올아민, 페니토인, 피록시캄, 폴리믹신 B, 포비돈 요오딘, 프라바스타틴, 프라제팜, 프라조신, 프레드니솔론, 프레드니존, 브로모크립틴, 프로파페논, 프로프라놀올, 프록시필린, 슈도에페드린, 피리독신, 퀴니딘, 라미프릴, 라니티딘, 레세르핀, 레티놀, 리보플라빈, 리팜피신, 루포시드, 사카린, 살부타몰, 살카토닌, 살리실산, 심바스타틴, 소마토트로핀, 소탈올, 스피로놀락톤, 수크랄페이트, 술박탐, 술파메톡사졸, 술파자라진, 술피리드, 타목시펜, 테가푸르, 테프레논, 테라조신, 테르부탈린, 테르페나딘, 테트라시클린, 테오필린, 티아민, 티클로피딘, 티몰올, 트라넥삼산, 트레티노인, 트리암시놀론 아세토니드, 트리암테렌, 트리메토프림, 트록세루틴, 우라실, 발프로산, 반코미신, 베라파밀, 비타민 E, 폴린산, 지도부딘과 같은 활성 성분의 가공에 적당하다.
바람직한 활성 성분으로는 이부프로펜 (라세미체, 거울상 이성질체 또는 농축 거울상 이성질체), 케토프로펜, 플루르비프로펜, 아세틸살리실산, 베라파밀, 파라세타몰, 니페디핀 또는 카프토프릴이 있다.
특별히 고체 용액의 형성이 있을 수 있다. "고체 용액"이란 용어는 앞서 인용한 문헌의 숙련자에게 잘 알려져 있다. 중합체 중의 제약 활성 성분의 고체 용액에서, 활성 성분은 중합체 중의 분자 분산액 형태로 존재한다.
공압출 전에, 제형의 각 층을 이루는 조성물을 따로 따로 제조해야 한다. 이를 위해서는, 하류 기어 펌프가 있는 별도의 압출기 또는 용융물 용기에서 용매 없이 출발 성분을 가공한다. 단독으로 또는 건조 혼합물로 연속해서 (예를 들어, 시차 계량 공급 장치를 통해) 성분을 공급한다. 그리고 나서, 압출기 또는 용융기에서 조성물을 혼합 및(또는) 연화 또는 용융시킨다. 특정 온도에 민감한 활성 성분을 혼입시키기 원한다면, 이 혼합물을 편의상 조성물의 연화 또는 용융 후에 첨가하고, 압출기에서 또는 혼련기 또는 혼합 반응조에서 종단 및 횡단 혼합에 의해 혼입시키고, 조성물과 균질화한다. 압출기, 특히 혼합 부를 갖는 이축 압출기 또는 일축 압출기는 이 압출기가 특정 물질에 대한 최적의 조건하에서 작동 가능하므로 조성물의 제조에 특히 편리하다. 예를 들어, 매 층마다 다른 가공 온도를 선택할 수 있다.
각각의 압출기 또는 다른 장치로부터의 용융 또는 가소성 조성물을 조인트 공압출 다이로 통과시켜서 압출한다. 공압출 다이의 형상은 원하는 제형에 따라 결정된다. 예를 들면, 슬롯 다이 (slot die)라고 불리는 편평한 다이 간격을 갖는 다이 및 환상 슬릿을 갖는 다이가 적합하다. 또한 다이 디자인은 사용된 고분자 결합제 및 목적하는 제형에 따라 결정된다.
공압출 다이의 아래에서 원하는 제형으로 조형한다. 공압출 다이 및 조형 형태에 따라 각종 형상을 제조할 수 있다. 예를 들어, 특히 둘 또는 세 개의 층을 갖는 개방형 다층 정제는 슬롯 다이의 압출물로부터, 펀칭 또는 커팅에 의해, 예를 들면 백열 와이어를 사용하여 제조할 수 있다. 대안적으로, 개방형 다층 정제는 환상 슬릿을 갖는 다이를 경유하여, 압출 후 즉시 압출물을 커팅 또는 차핑하거나, 또는 바람직하게는 적어도 일부를 냉각시킨 후 압출물을 커팅 또는 차핑함으로써 제조할 수 있다.
밀봉형 제형, 즉 활성 성분을 함유하는 층이 활성 성분이 없는 층으로 완전히 둘러싸인 제형은 특히 환형 슬릿을 갖는 다이를 사용하여 하기의 실시예에서 설명되는 예를 들어 도 1 및 2에 도시된 적당한 핀치 장치로 압출물을 가공함으로써 얻어진다. 이것과 관련하여, 다층 정제의 내층은 외층이 냉각된 후에도 핀치 장치에 유입될 때 여전히 가소성이어서 변형 가능한 것이 이롭다. 이런 방식으로 특히 정제, 바람직하게는 구상 정제, 제피 정제, 파스틸 및 펠렛을 제조하는 것이 가능하다.
다층 제형은 후속 단계에서 통상적인 방법으로 구형으로 만들고(거나) 코팅을 할 수 있다. 원형은 롤, 벨트 및 프레스에 의해, 코팅은 코팅 팬 또는 유동층 장치로 처리함으로써 수행하는 것이 바람직하다.
따라서, 본 발명에 의한 방법으로 특히 간단하고 쉬운 방법으로 경구 및 직장 투여용 고상 제형을 제조하는 것이 가능하다. 덧붙여서, 본 발명의 방법은 제형 및 그의 구조의 선택 및 고분자 결합제의 선택에 따라 원하는 방출 특성을 광범위하게 조정할 수 있는 가능성을 제공한다.
다음의 실시예들은 본 발명을 설명하며, 본 발명을 한정하는 것은 아니다.
<실시예 1>
히드록시프로필셀룰로오즈 (크루셀 (Klucel) F) 10 kg/h를 연속적으로 계량하고 이축 압출기 (ZSK 25형)를 통해 용융시킨다 . 이와 동시에, 활성 성분으로 이부프로펜 30 중량%를 함유하는 폴리비닐피롤리돈 (PVP) 30 kg/h를 또 다른 이축 압출기 (ZSK 30)에서 제조한다. 하기 조건하에서, 압출물을 환형 슬릿을 갖는 동심 공압출 다이를 통해 압출시켜 활성 성분을 함유하는 PVP 코어 및 크루셀 피층으로 구성되는 압출물을 제조한다.
ZSK 30 압출기: | ZSK 25 압출기: |
1 구간: 43 ℃ | 1 구간: 70 ℃ |
2 구간: 57 ℃ | 2 구간: 120 ℃ |
3 구간: 120 ℃ | 3 구간: 110 ℃ |
4 구간: 100 ℃ | 4 구간: 100 ℃ |
5 구간: 100 ℃ | 5 구간: 100 ℃ |
헤드 : 100 ℃ | 헤드 : 110 ℃ |
다이 : 100 ℃ | 다이 : 100 ℃ |
그 후, 이 압출물을 도 1 및 2에 도시된 핀치 장치에 의해 밀봉형 구상 정제로 분리한다. 도 1에서, (1)은 공압출 다이를 나타낸다. 다이로부터 압출되는 압출물 (2) (각 층은 도면에 제시되지 않음)를 두 개의 역방향-회전 성형롤 (3)을 갖는 압연 장치로 통과시킨다. 성형롤은 바 (6)으로 분리되어 있는 오목부 (5)를 갖는다. 성형롤 (3) 사이의 간격은 그들이 바 (6) 중의 하나의 바가 일직선으로 서로 접촉하거나, 극히 작은 간격만이 있도록 선택한다. 오목부 (5)의 모양은 이런 식으로 각종 제형의 제조가 가능하도록 광범위하게 선택할 수 있다.
공압출 다이 (1)로부터 압출되는 압출물 (2)는 오목부 (5)에 수용되고, 바 (6)에 의해 각각의 제형으로 분리된다. 도 1에서 도시된 장치를 사용하여, 아직 가는 줄 (8)로 연결되어 있는 구상 정제 (4)가 이런 방법으로 얻어진다.
별법으로, 도 2에서 도시된 장치로 핀칭시킬 수 있다. 공압출 다이로부터 압출되는 압출 생성물 (2)를 서로 마주보고 있고, 압출물 (2)를 밀봉하는 두 개의 핀치 바 (7)이 구비된 장치로 통과시킨다. 핀치 바 (7)은 압출물 (2)에 대해 수직으로 이동시킬 수 있고 (도 2에 화살표로 나타냄), 도 1의 압연 장치 롤 (3)에서의 오목부와 비슷한 서로 마주하는 오목부를 갖는다. 제조된 제형을 분리시키기 위해, 핀치 바 (7)을 그들이 서로 접촉하거나 단지 매우 작은 간격만이 남을 때까지 압출물 (2)를 향해 이동시킨다. 이로써 각각의 제형이 가는 줄 (8)로 여전히 연결되어 있지만, 제형이 분리되게 된다. 마찬가지로, 밀봉형 구상 정제도 도 2에서 도시된 장치를 사용하여 얻어진다. 얻어진 구상 정제의 플래시는 통상적인 방법, 예를 들어 회전팬으로 끊을 수 있다.
얻어진 구상 정제의 클루셀 외부 피층은 PVP 코어에 분산되어 있는 활성 성분이 더 느리게 방출되게 한다.
<실시예 2>
코어에 이부프로펜 및 외층에 카페인을 함유하는 정제가 실시예 1에서 설명한 방법에 의해 5 %의 카페인을 함유하는 히드록시프로필셀룰로오즈와 함께 실시예 1에서 설명된 재료를 사용하여 얻어진다.
<실시예 3>
히드록시프로필셀룰로오즈 및 에틸셀룰로오즈의 혼합물 10 kg/h를 8:1의 중량비로 연속하여 계량하고, 이축 압출기 (ZSK 25형)에서 용융시킨다 . 이와 동시에, 활성 성분으로 파라세타몰 40 중량%를 함유하는 폴리비닐피롤리돈 15 kg/h를 제2의 이축 압출기 (ZSK 30)에서 제조한다. 활성 성분으로 파라세타몰 40 중량%를 함유하는 히드록시프로필셀룰로오즈 용융물 15 kg/h을 제3의 압출물에 기어 펌프로 이송한다.
이들 압출물을 동심 환형 공압출 다이로 압출시켜 낮은 방출 속도의 히드록시프로필셀룰로오즈, 높은 방출 속도의 폴리비닐피롤리돈의 외층 및 히드록시프로필셀룰로오즈/에틸셀룰로오즈 피층으로 구성된 압출물을 제조하였다 (압출 조건은 실시예 1에서 설명됨).
도 1 또는 도 2에서 도시된 핀치 장치에 의해 압출물을 각각의 밀봉형 정제로 분리시킨다.
활성 성분 방출의 속도를 얻어진 다층 정제에 의해 환자 컴플라이언스를 증가시키도록 최적으로 제어할 수 있다.
<실시예 4>
활성 성분으로 니페디핀 30 중량%를 함유하는 폴리비닐피롤리돈 15 kg/h를 이축 압출기 (ZSK 30형)에서 제조한다. 이와 동시에, 활성 성분으로 니페디핀 40 중량%를 함유하는 히드록시프로필셀룰로오즈 용융물 15 kg/h를 또 다른 압출물에 기어 펌프로 이송한다.
높은 방출 속도를 갖는 폴리비닐피롤리돈 층으로 양쪽이 둘러싸이고 낮은 방출 속도를 갖는 히드록시프로필셀룰로오즈 층으로 구성된 샌드위치 구조를 갖는 조성물을 만들기 위해 슬롯 다이 (3개의 슬롯)를 통해 두 개의 압출물을 압출시킨다 (압출 조건은 실시예 1에서 설명됨).
압출물을 펀칭 장치에 의해 개방형 다층 정제로 분리시킨다.
이후 단계에서, 얻어진 개방형 다층 정제를 코팅팬에서 아크릴산 공중합체로 코팅할 수 있다.
활성 성분 방출의 속도를 다층 정제의 샌드위치 구조에 의해 환자 컴플라이언스를 증가시키도록 최적으로 제어할 수 있다.
<실시예 5>
실시예 1에서 설명한 방법에 의해 실시예 1에서 설명한 물질을 사용하여 압출물을 제조하고, 적당한 냉각 절단 장치에 의해 개방형 다층 정제로 분리시킨다. 클루셀 외부 피층은 PVP 코어에 분산되어 있는 활성 성분이 더 느리게 방출되게 한다.
<실시예 6>
실시예 3에서 설명된 물질을 사용하여 실시예 3에서 설명된 방법에 의해 낮은 방출 속도의 히드록시프로필셀룰로오즈 코어, 높은 방출 속도의 폴리비닐피롤리돈의 가장자리층 및 히드록시프로필셀룰로오즈/에틸셀룰로오즈의 외층으로 구성된 압출물을 제조하였다. 이 압출물을 냉각 절단 장치에 의해 각각의 개방형 다층 정제로 분리시킨다.
활성 성분 방출의 속도를 다층 정제의 배열에 의해 환자 컴플라이언스를 증가시키도록 최적으로 제어할 수 있다.
<실시예 7>
폴리라크티드 10 kg/h를 연속적으로 계량하고, 이축 압출기 (ZSK 25형)를 통해 용융시킨다. 이와 동시에, 활성 성분으로 이부프로펜 40 중량%를 함유하는 폴리비닐피롤리돈 30 kg/h을 또 다른 이축 압출기 (ZSK 30형)에서 제조한다. 이들 두 압출물을 환형 공압출 다이를 통해 압출시켜 활성 성분을 함유하는 PVP 코어 및 폴리라크티드 피층으로 구성된 압출물을 제조하였다 (압출 조건은 실시예 1에서 설명됨).
이 압출물을 냉각 절단 장치에 의해 각각의 개방형 다층 정제로 분리시킨다.
폴리라크티드 피층은 가수분해에 안정하고, 효소적으로 및 가수분해에 의해 분해를 할 수 있어서 활성 성분을 코어 매트릭스로부터 방출할 수 있다.
<실시예 8>
만니톨 40 중량% 및 베라파밀 30 중량%를 갖는 비닐피롤리돈/비닐아세테이트 (6:4) 공중합체 (30 중량%) 10 kg/h를 이축 압출기 (ZSK 25)에서 용융시킨다. 이와 동시에, 활성 성분으로 베라파밀 30 중량%를 함유하는 히드록시프로필셀룰로오즈 30 kg/h를 또 다른 이축 압출기 (ZSK 30)에서 제조한다. 이들 두 압출물을 실시예 1의 특정 조건하에서 환형 공압출 다이를 통해 압출시킨다. 도 2에 도시된 장치를 사용하여 실시예 1에서 설명한 방법에 의해 정제를 조형한다. 이 정제는 활성 성분을 함유하는 히드록시프로필셀룰로오즈 코어 및 비닐피롤리돈/비닐 아세테이트 공중합체/만니톨 피층으로 구성된다.
<실시예 9>
비타민 A 및 E를 갖는 히드록시프로필셀룰로오즈 코어 (낮은 치환 정도를 갖는 히드록시프로필셀룰로오즈, LH 31형) 및 비타민 C를 갖는 히드록시프로필셀룰로오즈 피층 (클루셀 F)을 갖는 정제를 실시예 2에서 설명된 방법에 의해 제조한다.
Claims (10)
- 각 조성물이 생리학적 환경 중에 가용성 또는 팽윤성인 열가소성의, 약리학상 허용가능한 고분자 결합제를 포함하고 조성물 중 1개 이상이 제약학적 활성 성분을 함유하는 2개 이상의 조성물을 공압출시키고, 공압출된 다층 물질을 원하는 제형으로 조형시킴을 포함하는 경구 또는 직장 투여용 다층 고상 제형의 제조 방법.
- 제1항에 있어서, 활성 성분을 함유하지 않는 층용의 고분자 결합제가 히드록시알킬셀룰로오즈류, 알킬셀룰로오즈류, 히드록시알킬알킬셀룰로오즈류, 셀룰로오즈 프탈레이트류, 폴리아크릴레이트류, 갈락토만난스류 및 폴리라크티드류 중에서 선택되는 방법.
- 제1항 또는 제2항에 있어서, 활성 성분을 함유하는 층용의 고분자 결합제가 폴리비닐피롤리돈류, N-비닐피롤리돈 및 비닐 에스테르류의 공중합체 및 히드록시알킬아크릴레이트류 중에서 선택되는 방법.
- 제1항 내지 제3항 중 어느 한 항에 있어서, 이부프로펜, 케토프로펜, 플루르비프로펜, 아세틸살리실산, 베라파밀, 파라세타몰, 니페디핀, 카페인, 카프토프릴 및 비타민 또는 2 종 이상의 상기 활성 성분의 혼합물 중에서 선택된 활성 성분을 사용하는 방법.
- 제1항 내지 제4항 중 어느 한 항에 있어서, 밀봉형 제형을 제조하기 위해 공압출은 동심 환형 공압출 다이를 이용하여 수행되고, 조형은 성형 압연 장치로 또는 열간 절단법 또는 냉간 절단법에 의해 수행되는 방법.
- 제1항 내지 제4항 중 어느 한 항에 있어서, 개방형 제형, 특히 개방형 다층 정제를 제조하기 위해, 공압출은 슬롯 다이를 이용하여 수행되고, 조형은 펀칭에 의해 수행되는 방법.
- 제5항 또는 제6항에 있어서, 히드록시프로필셀룰로오즈를 외층용의 고분자 결합제로 사용하고, 폴리비닐피롤리돈을 내층 및 코어용의 고분자 결합제로 사용하는 방법.
- 제5항 내지 제7항 중 어느 한 항에 있어서, 이부프로펜만을, 또는 이부프로펜 또는 비타민 A 및 E가 코어에 위치하고, 카페인 또는 비타민 C가 외층에 위치하는 이부프로펜/카페인 또는 비타민 A, C, E를 활성 성분으로 사용하는 방법.
- 제1항 내지 제8항 중 어느 한 항에 있어서, 이후 단계에서 다층 제형을 구상으로 만들고(거나) 코팅시키는 방법.
- 제1항 내지 제9항 중 어느 한 항의 방법에 의해 수득가능한 경구 또는 직장 투여용의 다층 고상 제형.
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DE19539361A DE19539361A1 (de) | 1995-10-23 | 1995-10-23 | Verfahren zur Herstellung von mehrschichtigen, festen Arzneiformen zur oralen oder rektalen Verabreichung |
DE19539361.9 | 1995-10-23 | ||
PCT/EP1996/004601 WO1997015293A2 (de) | 1995-10-23 | 1996-10-23 | Verfahren zur herstellung von mehrschichtigen, festen arzneiformen zur oralen oder rektalen verabreichung |
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IT1252185B (it) * | 1991-12-11 | 1995-06-05 | Therapicon Srl | Preparazioni farmaceutiche a liberazione programmata |
DE19629753A1 (de) * | 1996-07-23 | 1998-01-29 | Basf Ag | Verfahren zur Herstellung von festen Arzneiformen |
IT1297886B1 (it) * | 1997-02-28 | 1999-12-20 | Carmine Antropoli | Nifedipina per uso topico |
DE19710213A1 (de) * | 1997-03-12 | 1998-09-17 | Basf Ag | Verfahren zur Herstellung von festen Kombinationsarzneiformen |
EP0998270B1 (de) * | 1997-07-09 | 2005-01-12 | Swiss Caps Rechte und Lizenzen AG | Verfahren und vorrichtung zum herstellen einer mehrschichtigen, physiologisch verträglichen darreichungsform |
FR2766088B1 (fr) * | 1997-07-17 | 2001-01-05 | Dow Corning Sa | Dispositifs a liberation controlee d'un agent pharmaceutique, leur fabrication par co-extrusion et article intermediaire |
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1995
- 1995-10-23 DE DE19539361A patent/DE19539361A1/de not_active Withdrawn
-
1996
- 1996-10-16 IN IN1824MA1996 patent/IN182500B/en unknown
- 1996-10-22 ZA ZA9608849A patent/ZA968849B/xx unknown
- 1996-10-22 HR HR960483A patent/HRP960483B1/xx not_active IP Right Cessation
- 1996-10-23 CA CA002232356A patent/CA2232356C/en not_active Expired - Fee Related
- 1996-10-23 ES ES96937214T patent/ES2175139T3/es not_active Expired - Lifetime
- 1996-10-23 PL PL96327395A patent/PL327395A1/xx unknown
- 1996-10-23 DE DE59609104T patent/DE59609104D1/de not_active Expired - Lifetime
- 1996-10-23 HU HU9802996A patent/HUP9802996A3/hu unknown
- 1996-10-23 CZ CZ19981242A patent/CZ289689B6/cs not_active IP Right Cessation
- 1996-10-23 PT PT96937214T patent/PT857062E/pt unknown
- 1996-10-23 AT AT96937214T patent/ATE216224T1/de not_active IP Right Cessation
- 1996-10-23 JP JP9516274A patent/JPH11513697A/ja active Pending
- 1996-10-23 EP EP96937214A patent/EP0857062B1/de not_active Expired - Lifetime
- 1996-10-23 US US09/051,544 patent/US6120802A/en not_active Expired - Lifetime
- 1996-10-23 KR KR1019980702911A patent/KR19990066978A/ko not_active Application Discontinuation
- 1996-10-23 WO PCT/EP1996/004601 patent/WO1997015293A2/de not_active Application Discontinuation
- 1996-10-23 CN CN96197791A patent/CN1092955C/zh not_active Expired - Fee Related
- 1996-10-23 AU AU74912/96A patent/AU706859B2/en not_active Ceased
- 1996-10-23 DK DK96937214T patent/DK0857062T3/da active
-
1998
- 1998-03-10 BG BG102313A patent/BG102313A/xx unknown
- 1998-03-19 MX MX9802153A patent/MX9802153A/es not_active IP Right Cessation
- 1998-04-22 NO NO981793A patent/NO981793D0/no not_active Application Discontinuation
Cited By (1)
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KR100697093B1 (ko) * | 2005-05-09 | 2007-03-20 | 주식회사 대웅제약 | 비타민 c 및 감기 치료제를 함유하는 이중정 제형 및 그의제조방법 |
Also Published As
Publication number | Publication date |
---|---|
DE59609104D1 (de) | 2002-05-23 |
HRP960483A2 (en) | 1997-12-31 |
AU7491296A (en) | 1997-05-15 |
HRP960483B1 (en) | 2002-02-28 |
US6120802A (en) | 2000-09-19 |
PL327395A1 (en) | 1998-12-07 |
ES2175139T3 (es) | 2002-11-16 |
PT857062E (pt) | 2002-09-30 |
WO1997015293A2 (de) | 1997-05-01 |
HUP9802996A2 (hu) | 2000-06-28 |
EP0857062B1 (de) | 2002-04-17 |
BG102313A (en) | 1998-10-30 |
CA2232356A1 (en) | 1997-05-01 |
ZA968849B (en) | 1998-04-22 |
CA2232356C (en) | 2005-08-23 |
NO981793L (no) | 1998-04-22 |
DE19539361A1 (de) | 1997-04-24 |
CN1200033A (zh) | 1998-11-25 |
HUP9802996A3 (en) | 2000-08-28 |
AU706859B2 (en) | 1999-06-24 |
IN182500B (ko) | 1999-04-17 |
JPH11513697A (ja) | 1999-11-24 |
WO1997015293A3 (de) | 1997-08-14 |
MX9802153A (es) | 1998-08-30 |
ATE216224T1 (de) | 2002-05-15 |
DK0857062T3 (da) | 2002-07-15 |
NO981793D0 (no) | 1998-04-22 |
CN1092955C (zh) | 2002-10-23 |
CZ124298A3 (cs) | 1998-07-15 |
CZ289689B6 (cs) | 2002-03-13 |
EP0857062A2 (de) | 1998-08-12 |
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