KR100196256B1 - 서방성 약물 제형 - Google Patents
서방성 약물 제형 Download PDFInfo
- Publication number
- KR100196256B1 KR100196256B1 KR1019920702558A KR920702558A KR100196256B1 KR 100196256 B1 KR100196256 B1 KR 100196256B1 KR 1019920702558 A KR1019920702558 A KR 1019920702558A KR 920702558 A KR920702558 A KR 920702558A KR 100196256 B1 KR100196256 B1 KR 100196256B1
- Authority
- KR
- South Korea
- Prior art keywords
- membrane
- drug
- consisting essentially
- colon
- formulation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
약 5.0보다 큰 pH에서 실질적으로 가용성인 pH의존성 중합체로 필수적으로 구성된 제1막 및 위장액 중에서 실질적으로 불용성이지만 위장액에 대해 투과성이도록하는 하나 이상의 중합체로 필수적으로 구성된 제2막으로 둘러싸인 약제(아미노 살리실산 작용기를 갖지 않으며, 장에서 국소 작용을 하는 항-염증성 및 항열소성 약제, 만성 장 염증 또는 자극의 국소치료용 코르티코스테로이드, 및 페퍼민트 오일은 포함하지 않는다)의 코어로 필수적으로 구성되고 각 단위의 입자 크기가 약 5mm 이하인 많은 다수 용량 단위(multidose unit)로 필수적으로 이루어짐을 특징으로하는, 표유동물의 소장 및 결장으로 약제를 전달하기 위한 표적된 약제 방출 제형물을 제공한다. 이 제형물은 약제의 약 10%만이 위로 방출되고 약제의 모든 잔류 부분은 소장 및/또는 결장에서 약 ½시간 내지 약 8시간 동안 방출됨을 특징으로 한다.
Description
본 발명은 서방성 약물 제형(controlled reaease drug formulation) 및 장에서, 특히 소장 및/또는 결장에서 약리학적 작용을 수행해야 하는 약물의 표적되고(targeted) 조절된 방출을 수득하는 방법에 관한 것이다.
미합중국 특허 제4,503,030호는 반투과성 및 pH 의존성 막(여기서, 이러한 막에 있는 구멍은 핵이 외부와 접촉하도록 한다)으로 덮혀있는 약물을 함유하는 코어(core)로 이루어진, 삼투적으로 방출되는 정제에 관해 언급하고 있다. 위에서, 정제는 온전하게 유지되며 방출은 막에 있는 구멍을 통해 일어나는 반면, 장에서는 막이 완전히 붕해된다.
미합중국 특허 제4,432,966호는 결장에서 붕해되는 정제의 제조에 대해 기술하고 있다. 이것은 정제 코어를 2개의 층으로 피복함으로써 달성된다.
제1층은 pH 비의존성 중합체 및 미정질 셀룰로오즈로 이루어지며 제2 층은 pH 의존성 중합체로 이루어진다. pH 비의존성 중합체와 미정질 셀룰로오즈가 함께 존재하는 것은 결장에서 정제가 붕해되는 것을 보장하기 위해 필수적인데, 이는 미정질 셀룰로오즈가 결장에 존재하는 특이 효소 및 세균에 의해 분해되기 때문이다.
방출이 지속되거나 지연되는 약제학적 제제가 EP-A-239661, EP-A-148811, EP-A-212745, WO 85/03437, EP-A-277925, EP-A-342522 및 WO 87/01588에 기술되어 있다. 이들 인용문헌은 하기 중에서 선택된 형태의 피복된 약물 코어에 대해 기술하고 있다: 다양한 크기의 과립, 결정, 논파렐(non pareil) 또는 슈크로오즈 약물 피복된 코어, 및 구형 과립, 또는 단일의 큰 정제. 그러나, 이들 문헌에는 약물이 각각 실질적으로 동일한 크기의 다수의 미니정제의 형태인 표적되거나 지속된 방출 제형은 기술되어 있지 않다.
본 발명은 단일 용량 형태(monodose form) 대신 다용량 형태(multidose form)이고, 다양한 크기의 미소캡슐 또는 유사 캡슐 대신에 실질적으로 크기가 동일한 미니정제(minltablet)에 관한 것이므로 상기 인용문헌에 비해 여러가지 이점을 갖는다.
다용량 형태는 넓은 영역의 위장관으로 확산되므로 고농도의 약물로 인한 점막의 자극 문제를 피하고 감소시켜주며 동일한 약물에 대한 흡수도를 향상시키는 것으로 공지되어 있다.
더우기, 본 발명에서, 피복된 입자들이 장에서 적당한 pH에 도달하는 경우 pH 의존성 막은 용해되는 반면, pH 비의존성 막은 온전하게 유지되어 약물의 용해를 지연시키는데, 이때의 시간은 약 30분 내지 약 8시간으로 다양할 수 있으며, 결과적으로 약물의 작용은 소장 및/또는 결장으로 연장된다.
본 발명에 따라, 약 5.0을 초과하는 pH에서 사실상 가용성인, 메타크릴산 및 메타크릴산 메틸 또는 에틸 에스테르계 음이온성 공중합체, 셀룰로오즈 아세테이트 프탈레이트, 하이드록시프로필메틸셀룰로오즈 프탈레이트, 폴리비닐 아세테이트 프탈레이트, 쉘락, 하이드록시프로필메틸셀룰로오즈 아세테이트석시네이트, 카복시메틸셀룰로오즈, 셀룰로오즈 아세테이트 트리멜리테이트 및 말레산과 프탈산 유도체와의 공중합체로부터 선택된 pH 의존성 중합체로 필수적으로 이루어진 제1 막 및 위장액에서 사실상 불용성이지만 위장액에 대해 투과성인, 4급 암모늄 그룹의 함량이 적은 아크릴산 및 메타크릴산 에스테르로 부터 형성된 공중합체, 평균 분자량이 800,000인 에틸 아크릴레이트 및 메틸 메타크릴레이트계 중성 공중합체, 에틸셀룰로오즈, 폴리에틸렌, 폴리실록산 및 이들의 혼합물로부터 선택된 하나 이상의 중합체로 필수적으로 이루어진, 제2 막으로 둘러싸인 약물(아미노살리실산 작용성 그룹을 갖지 않으며, 장에서 국소작용을 하는 소염제 및 항염증제, 만성 장 염증 또는 자극의 국소 치료용 코르티코스테로이드, 및 페퍼민트 오일은 포함하지 않는다)의 코어로 필수적으로 이루어진, 약 5mm 이하의 실질적으로 동일한 입자 크기를 갖는 다수의 미니정제로 필수적으로 이루어짐을 특징으로 하는, 포유동물의 소장 및/또는 결장으로 약물을 전달하기 위한 표적된 약물 방출 제형이 제공된다. 상기 제형은 위에서(또는 약 4.5 미만의 pH에서) 약물의 약 10% 이하가 방출되고 실질적으로 약물의 모든 잔류 부분은 장 및/또는 결장에서(또는 pH 5 이상인 자극된 위장 매질중에서) 약 30분 내지 약 8시간 동안 방출되도록 하는 용해 속도에 의해 추가로 특징지워질 수 있다. 방출은 자극된 위액에서 3시간 후에 약물의 약 11% 이하가 방출되고 약 6시간 후에 약물의 약 75% 이하가 방출됨에 의해 추가로 특징지워질 수 있다. 또 다른 양태에서, 용해가 소장에서 일어나는 경우, 위에서는 10% 이하가 방출되면서 실질적으로 모든 방출(90%)이 pH 6.8에서 1 내지 1½시간 내에 일어나는 것이 바람직하다.
전형적인 pH 값은 위에서는 1 내지 3.5이고, 십이지장에서는 5 내지 6이고, 공장에서는 6 내지 7이고, 회장에서는 7 내지 8이다.
본 발명은 장, 특히 결장에서 작용하는 약물 뿐만 아니라 위액에 의해 파괴되거나, 예를 들어, 췌장성 프로테아제 및 회장의 세균성 프로테아제와 같은 효소에 의해 불활성화되는 약물에 적합하다. 다음의 약물이 예로서 인용되지만 이들로 제한되지는 않는다: 페니실린 G, 칼시토닌, 헤파린, 페리틴, 수크랄페이트, 메베베린 하이드로클로라이드, 아카르보오즈, 디메티콘 및 시메티콘, 면역글로불린, 구충제, 살원생동물제, 국소 및 일반 작용성 장 항감염제 및 항진균제. 본 발명에서는 하기는 제외된다: 아미노살리실산 작용성 그룹을 갖는 약물, 장에서 국소 작용을 하는 소염제 및 항염증제, 만성 장 염증 또는 자극의 국소 치료용 코르티코스테로이드 및 페퍼민트 오일.
장, 특히 결장의 몇몇 질환에 대해서는 약물을 약리학적 작용을 수행하게될 장소로 온전하게 수송하는 것이 중요하다.
이것은 약물을 pH 의존성 용해도를 갖는 막, 특히 5.0을 초과하는 pH에서 가용성인 막으로 피복시켜 뒤, 및 장의 처음 일부에서는 약물이 온전하게 유지되는 반면, 장에서 pH가 5.0을 초과하는 경우, 용해되어 약물을 방출시키도록 함으로써 달성된다. 그러나 다양한 약물을 위해서, 점막과의 접촉 또는 이의 흡수가 모든 결장을 따라 일어나는 것이 중요하므로 효과가 시간상 지연되어 약물이 pH 의존성 막으로만 피복된 경우에 일어나는 바와 같이 처음 관 부위에서만 나타나지 않도록 방출을 지연시키는 것이 필요하다.
본 발명에 이르러, pH 의존성 용해도를 갖는 막 및 위장액에서 불용성이지만 위장액에 대해 투과성인 막을 독립적으로 적용시켜, 약물의 용해를 지연시키고, 방출을 느리게 하므로써 소장 또는 결장 또는 이들 둘 다에까지 약물의 작용이 수반될 수 있도록 한다는 것이 밝혀졌다. 사실상 약물이 Eudragit S 막(7을 초과하는 pH에서 용해된다)으로 피복되는 경우(실시예 1 참조), pH 6.2 이하의 완충액에서는 방출이 매우 낮지만(처음 3시간), pH가 7.2로 증가하면 약물의 급속한 용해가 일어난다.
위장액에서 불용성이지만 위장액에 대해 투과성인 에틸셀룰로오즈의 제2 막을 Eudragit 막에 적용시킴으로써 약물의 방출을 지연시키고 추가의 3시간 동안 효과를 연장시킬 수 있다.
지연성 막이 적용된 후, pH 의존성 막이 적용되는 경우(실시예 2 참조), 동일한 결과가 수득되는 반면, 막을 구성하는 2가지 형태의 중합체가 혼합되는 경우(실시예 3 참조), 지연된 효과는 수득되지 않는다. 대신에, 이때의 방출은 pH 의존성 중합체만을 적용시킴에 의해서 수득되는 것과 매우 유사하다.
더우기, 약물은 pH 의존성 중합체의 적합한 선택이 이루어짐으로써 소장 또는 결장에 표적될 수 있다. 예를 들어, 5.5를 초과하는 pH에서 가용성인 Eudragit L30D를 pH 의존성 막으로서 사용하는 경우, 이것은 십이지장에서 용해된 다음, pH 비의존성 막이 공장 또는 공장과 회장 또는 소장과 결장(코어에 적용된 pH 비의존성 막의 투과도 및 양에 의존적임)에 까지 약물의 방출을 지연시킨다. 이와 반대로, 7보다 큰 pH에서 가용성인 Eudragit S를 pH 의존성 막으로서 사용하는 경우, 이것은 회장에서만 용해되므로 pH 비의존성 막이 결장에 까지 약물의 방출을 연장시킬 것이다.
그러므로, 본 발명의 독특한 특성은 주어진 pH에서 가용성인 막 및 불용성이지만 투과성인 막의 무순적인 연속적 적용으로 이루어진다.
따라서, 장의 특정 관에 표적된 약물의 방출 및 상기 방출의 연장은 남은 장관의 전체를 따라 효과적이도록 이루어진다.
[제1막으로 피복하기 위한 방법에 대한 설명]
본 발명은 나중에 기술되는 바와 같이 피복되는 매우 작은 크기의 정제(또한 미니 정제라 함)형태의 약물인 다용량 형태에 적용된다. 상기 피복된 약물은 캡슐, 단일 용량 사쉐이(sachet), 급속히 붕해되는 정제 또는 경구 투여용으로 적합한 기타 약제학적 형태로 제형화된다.
미니 정제로 구성되는 다용량 형태의 단일 유니트의 크기는 0.1 내지 3.5mm로 다양할 수 있지만, 5mm를 초과해서는 안된다.
사실상, 단일 유니트가 작을수록 위장관에서의 분산도는 넓으며, 더우기, 5mm을 초과하는 유니트는 위 전체에 보유되는 반면, 5mm보다 작은 유니트는 액체와 유사한 방식으로 위를 휠씬 급속히 통과한다.
이러한 현상은 문헌[참조: S. S. Davis The Design and Evaluation of the Control led Release Systems for the Gastrointestinal Tract publ ished in the Journal of Controlled Release, 2(1985) 27-38]에 기술되어 있다.
약물은 종종 미세한 분말 형태이기 때문에, 이들은 일반적으로 공지된 건조 또는 습윤 기술(압축)에 의해 과립화하여 목적 입자 크기를 수득한다.
그러나, 과립형태의 약물에 대해 언급하고 있는 하기될 설명은 미니 정제에 대해서도 또한 타당한 것으로 고려되어야만 한다.
과립화된 약물을 Wurster 삽입부재가 장착된 UNI Glatt 유동층 컨테이너에 넣고, 유기용매 또는 유기 용매의 혼합물 또는 유기용매와 물과의 혼합물 또는 용액 분산액 또는 수성 유제에 용해되는 pH 의존성 중합체와 함께 분무기를 통해 분무함으로써 피 복시 킨다.
또한, 가소제를 가하는 것이 편리하다. pH 의존성 막을 구성하는 중합체의 형태중에서, 다음이 예로서 인용되지만 이들로 제한된지는 않는다: 메타크릴산 및 메타크릴산 메틸 또는 에틸 에스테르의 음이온성 공중합체(예: Eudragit L, S, L30D, L100-55), 셀룰로오즈 아세티이트 프탈레이트, 하이드록시프로필메틸셀룰로오즈 프탈레이트(예: HP 50), 폴리비닐아세테이트 프탈레이트, 쉘락, 하이드록시프로필메틸-셀룰로오즈아세테이트 석시네이트(예: AS-L), 카복시메틸셀룰로오즈, 셀룰로오즈 아세테이트 트리멜리테이트 및 말레산과 프탈산 유도체와의 공중합체.
가소제 중에서 폴리에틸렌 글리콜, 디부틸 프탈레이트, 디에틸 프탈레이트, 시트르산 에스테르가 인용되며, 보조제 중에서 활석, 이산화규소, 이산화티탄, 마그네슘 스테아레이트가 예로써 인용되지만 이들로 제한되지는 않는다.
피복된 과립은, 예를 들어, 열기(약 50℃)로 약 30분 동안 건조시킨다.
[제2막 피복 방법에 대한 설명]
pH 의존성 막으로 피복된 과립은 그다음에 유사한 기술을 사용하여 제2pH 비의존성 막으로 피복한다. 또한, 이러한 경우에, 유기용액 또는 수용액 또는 수성 분산액/유제를 사용할 수 있고 상기 지시된 형태의 가소제 및 보조제를 가하는 것이 편리하다.
pH 비의존성 막을 구성하는 중합체의 형태중에서 예로써 하기가 인용되지만 이들로 제한되지는 않는다: 4급 암모늄 그룹의 함량이 적은 아크릴산 및 메타크릴산 에스테르의 공중합체, 평균 분자량이 800,000인 에틸 아크릴레이트 및 메틸메타크릴레이트계 중성 공중합체(Eudragit RS/RL/NE), 에틸셀룰로오즈, 폴리에틸렌, 폴리실록산 단독, 또는 이들 서로간의 혼합물, 또는 수용성 pH 비의존성 중합체, 예를 들어, 하이드록시프로필메틸셀룰로오즈, 하이드록시프로필셀룰로오즈, 하이드록시에틸셀룰로오즈, 메틸셀룰로오즈, 폴리비닐피롤리돈과의 혼합물.
상기 막으로 피복된 과립을, 예를 들어, 열기(약 50℃)를 사용하여 약 30분동안 건조시킨다.
이미 언급한 바와 같이 또한 2개의 막을 사용한 피복은 기술된 것과 반대의 순서로 행할 수 있다.
본 발명은 실시예 1, 2 및 3으로 예시된다. 실시예 4는 본 발명에 따른 피복된 미니정제의 제조를 설명한다.
800g의 메베베린 하이드로클로라이드를 하이드록시프로필 메틸셀룰로오즈를 사용하여 710 내지 1300μ의 입자크기로 과립화하고 Wurster 삽입부재가 장착된 UNI Glatt 유동층 컨테이너에 넣는다.
상기 과립을 분무기를 사용하여 하기 조성이 함유된 현탁액을 분무함으로써 제1 막인 Eudragit S로 피복한다: 468g의 메틸렌 클로라이드, 156g의 이소프로필알콜, 55.6g의 Eudragit S, 5.5g의 디부틸 프탈레이트 및 28g의 활석.
피복된 과립을 열기(약 50 ℃)를 사용하여 30분 동안 건조시킨 후, 다음 서열의 인공액, 즉 0.1N HCl(2시간), pH 6.2 완충액(1시간), 및 pH 7.2 완충액(하기되는 시간)을 이용하여 USP 기기 2(패들)로 방출을 측정한다.
하기 결과가 수득된다:
그 다음에, 제2 막인 에틸셀룰로오즈를 용액, 즉 199g의 메틸렌 클로라이드. 44g의 에틸 알콜, 4.3g의 에틸셀룰로오즈, 8.6g의 하이드록시프로필메틸셀룰로오즈 및 1.5g의 디아세틸화된 모노글리세라이드를 분무함으로서 상기 Eudragit S 피복된 과립 700g에 적용시키고 최종적으로 50℃의 공기를 사용하여 약 30분 동안 건조시킨다. 상기 2개의 막으로 피복된 과립을 상기 기술한 바와 같이 다시 분석하여 하기 결과를 수득한다:
[실시예 2]
700g의 칼시토닌을 결합제로서 락토오즈 및 하이드록시프로필메틸셀룰로오즈를 사용하여 710 내지 1300μ의 입자크기로 과립화하고 Wurster 삽입부재가 장착된 UNI Glatt 컨테이너에 넣는다.
상기 과립을 분무기를 사용하여 하기 조성이 함유된 용액을 분무함으로써 제1 막인 에틸셀룰로오즈/하이드록시프로필메틸셀룰로오즈로 피복한다. 200g의 메틸렌 클로라이드, 45g의 에틸 알콜, 6.4g의 에틸셀룰로오즈, 6.4g의 하이드록시프로필메틸셀룰로오즈 및 1.4g의 디아세틸화된 모노글리세라이드.
피복된 과릴을 열기(약 50℃)를 사용하여 30분 동안 건조시킨 , 다음 서열의 인공액, 즉 0.1N HCI(2시간), pH 6.2 완충액(1시간), 및 pH 7.2 완충액(하기되는 시간)을 이용하여 USP 기기 2(패들)로 방출을 측정한다.
하기 결과가 수득된다:
그 다음에. 제2 막인 Eudragit S 막을 현탁액. 즉 134g의 메틸렌 클로라이드, 65g의 이소프로필 알콜, 23g의 Eudragit S, 2.3g의 디부틸 프탈레이트 및 11.5g의 활석을 분무함으로서 상기 피복된 과립에 적용시키고 최종적으로 50 ℃의 공기를 사용하여 약 30분 동안 건조시킨다.
상기 2개의 막으로 피복된 과립을 상기 기술한 바와 같이 다시 분석하여 하기 결과를 수득한다.
[실시예 3]
800g의 메베베린 하이드로클로라이드를 하이드록시프로필메틸셀룰로오즈를 사용하여 710 내지 1300㎛의 입자 크기로 과립화하고 Wurster 삽입부재가 장착된 UNI Glatt 유동층 컨테이너에 넣는다.
상기 과립을 분무기를 사용하여 하기 조성이 함유된 현탁액을 분무함으로써 에틸셀룰로오즈 하이드록시프로필메틸셀룰로오즈/Eudragit S막으로 피복한다: 836g의 메틸렌 클로라이드, 418g의 이소프로필 알콜, 5.8g의 에틸셀룰로오즈, 11.8g의 하이드록시프로필메틸셀룰로오즈, 58.7g의 Eudragit S, 3.7g의 디부틸 프탈레이트 및 29g의 활석.
피복된 과립을 열기(약 45 ℃)를 사용하여 30분 동안 건조시킨 후. 다음 서열의 인공액, 즉 0.1N HCI(2시간), pH 6.2 완충액(1시간), 및 pH 7.2 완충액(하기되는 시간)을 이용하여 USP 기기 2(패들)로 방출을 측정한다.
하기 결과가 수득된다:
[실시예 4]
위액에 의해 파괴되는 단백질인 페리틴의 매우 작은 정제를 제조한다. 이들은 직경이 2.0mm이고 두께가 2.2mm이며 하기 조성을 갖는다:
이러한 페리틴 미니정제 2.2kg을 Wurster 삽입부재가 장착된 Yersaglatt 컨테이너(유동층 피복기)에 넣는다.
이들을 하기 조성의 현탁액을 분무하여 에틸셀룰로오즈 수성 분산액(AquacoatR/FMC) 및 하이드록시프로필 메틸셀룰로오즈의 막으로 피복시킨다:
피복된 미니. 정제를 열기(약 60 ℃)를 사용하여 30분 동안 건조시킨 후, pH 6.8의 완충액 중에서 USP 기기 2(패들)로 방출을 측정한다. 하기 결과가 수득된다:
그 다음에, 하기 조성을 갖는 수성 아크릴계 수지 분산액(Eudragit L3OD)을 상기 피복된 미니 정제에 적용시킨다:
이중 피복된 미니정제를 약 50 ℃의 공기로 약 30분 동안 건조시키고, 다음 서열의 인공액, 즉 0.1N HCl(60분), pH 4.5 완충액(60분) 및 pH 6.8 완충액을 사용하여 USP 기기 2(패들)로 방출을 분석한다.
하기 결과가 수득된다:
상기 실시예는 pH 6.8에서 1 내지 1½ 시간에 걸쳐 실질적으로 모든 방출이 일어나는 소장을 표적하는 제형을 설명한 것이다.
Claims (3)
- 약 5.0을 초과하는 pH에서 사실상 가용성인, 메타크릴산 및 메타크릴산 메틸 또는 에틸 에스테르계 음이온성 공중합체, 셀룰로오즈 아세테이트 프탈레이트, 하이드록시프로필메틸셀룰로오즈 프탈레이트, 폴리비닐 아세테이트 프탈레이트, 쉘락, 하이드록시프로필메틸셀룰로오즈 아세테이트 석시네이트, 카복시메틸셀룰로오즈, 셀룰로오즈 아세테이트 트리멜리테이트 및 말레산과 프탈산 유도체와의 공중합체로부터 선택된 pH 의존성 중합체로 필수적으로 이루어진 제1막 및 위장액에서 사실상 불용성이지만 위장액에 대해 투과성인, 4급 암모늄 그룹의 함량이 적은 아크릴산 및 메타크릴산 에스테르로부터 형성된 공중합체, 평균 분자량이 800,000인 에틸 아크릴레이트 및 메틸 메타크릴레이트계 중성 공중합체, 에틸셀룰로오즈, 폴리에틸렌, 폴리실록산 및 이들의 혼합물로부터 선택된 하나 이상의 중합체로 필수적으로 이루어진, 제1막의 내부 또는 외부에 있는 제2막으로 둘러싸인, 칼시토닌 및 페리틴으로부터 선택된 약물의 코어로 필수적으로 이루어진 약 5mm 이하의 실질적으로 동일한 입자 크기를 갖는 다수의 미니정제로 필수적으로 이루어짐을 특징으로 하는, 포유동물의 소장 및/또는 결장으로 약물을 전달하기 위한 표적된 약물 방출 제형.
- 제1항에 있어서, 하이드록시프로필메틸셀룰로오즈, 하이드록시프로필셀룰로오즈, 하이드록시에틸셀룰로오즈, 메틸셀룰로오즈, 폴리비닐피롤리돈 및 이들의 혼합물로부터 선탁된 pH 비의존성 수용성 중합체를 추가로 포함하는 제형.
- 제1항 또는 제2항에 있어서, 미니정제의 입자 크기가 0.1 내지 5.0mm인 제형.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT20054A/90 | 1990-04-14 | ||
| IT02005490A IT1246382B (it) | 1990-04-17 | 1990-04-17 | Metodo per la cessione mirata e controllata di farmaci nell'intestino e particolarmente nel colon |
| PCT/EP1991/000688 WO1991016042A1 (en) | 1990-04-17 | 1991-04-09 | Controlled release drug formulation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR930700077A KR930700077A (ko) | 1993-03-13 |
| KR100196256B1 true KR100196256B1 (ko) | 1999-06-15 |
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| Application Number | Title | Priority Date | Filing Date |
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| KR1019920702558A Expired - Fee Related KR100196256B1 (ko) | 1990-04-17 | 1991-04-09 | 서방성 약물 제형 |
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| US (1) | US5900252A (ko) |
| EP (2) | EP0453001A1 (ko) |
| JP (2) | JP3194974B2 (ko) |
| KR (1) | KR100196256B1 (ko) |
| AT (1) | ATE144138T1 (ko) |
| AU (1) | AU654277B2 (ko) |
| CA (2) | CA2035155A1 (ko) |
| DE (1) | DE69122751T2 (ko) |
| DK (1) | DK0524989T3 (ko) |
| ES (1) | ES2093097T3 (ko) |
| GR (1) | GR3021847T3 (ko) |
| IE (1) | IE911271A1 (ko) |
| IT (1) | IT1246382B (ko) |
| NZ (1) | NZ237823A (ko) |
| PT (1) | PT97370B (ko) |
| RU (1) | RU2111743C1 (ko) |
| SG (1) | SG46584A1 (ko) |
| TW (1) | TW223022B (ko) |
| WO (1) | WO1991016042A1 (ko) |
| ZA (1) | ZA912792B (ko) |
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| US6764697B1 (en) | 1991-06-27 | 2004-07-20 | Alza Corporation | System for delaying drug delivery up to seven hours |
| US5160742A (en) * | 1991-12-31 | 1992-11-03 | Abbott Laboratories | System for delivering an active substance for sustained release |
| IT1260505B (it) * | 1992-06-01 | 1996-04-09 | Poli Ind Chimica Spa | Sistemi farmaceutici orali a cessione ritardata per il rilascio specifico nel colon |
| FR2692484B1 (fr) * | 1992-06-22 | 1995-06-30 | Gouchet Franck | Nouvelle forme galenique de 4-asa a liberation controlee. |
| WO1995016451A1 (fr) * | 1992-06-22 | 1995-06-22 | Franck Arno Gouchet | Comprimes a liberation controlee de 4-asa |
| CA2141582C (en) * | 1992-08-05 | 2003-09-30 | Angelo Mario Morella | Pelletised pharmaceutical composition |
| AU670958B2 (en) * | 1992-08-05 | 1996-08-08 | Mayne Pharma International Pty Ltd | Pelletised pharmaceutical composition |
| US5358502A (en) | 1993-02-25 | 1994-10-25 | Pfizer Inc | PH-triggered osmotic bursting delivery devices |
| US5914132A (en) * | 1993-02-26 | 1999-06-22 | The Procter & Gamble Company | Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery |
| IT1265092B1 (it) * | 1993-05-31 | 1996-10-30 | Giuliani Spa | Preparato per uso come integratore alimentare, o dietetico,a rilascio mirato nel colon |
| DE4332394A1 (de) * | 1993-09-23 | 1995-03-30 | Falk Pharma Gmbh | Budesonid-Pellets mit kontrolliertem Freigabeprofil und Verfahren zu ihrer Herstellung |
| US5523095A (en) * | 1993-12-15 | 1996-06-04 | Eastman Chemical Company | Controlled release matrix system using cellulose acetate/polyvinylpyrrolidone blends |
| US5536505A (en) * | 1993-12-15 | 1996-07-16 | Eastman Chemical Company | Controlled release matrix system using cellulose acetate/poly-2-ethyl-2-oxazoline blends |
| CN1072964C (zh) | 1994-04-22 | 2001-10-17 | 山之内制药株式会社 | 结肠特异性释药系统 |
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| RU2111743C1 (ru) | 1998-05-27 |
| US5900252A (en) | 1999-05-04 |
| EP0453001A1 (en) | 1991-10-23 |
| SG46584A1 (en) | 1998-02-20 |
| PT97370A (pt) | 1992-01-31 |
| EP0524989A1 (en) | 1993-02-03 |
| NZ237823A (en) | 1992-09-25 |
| ZA912792B (en) | 1992-12-30 |
| IT1246382B (it) | 1994-11-18 |
| IE911271A1 (en) | 1991-10-23 |
| AU7679891A (en) | 1991-11-11 |
| EP0524989B1 (en) | 1996-10-16 |
| DE69122751T2 (de) | 1997-02-13 |
| ATE144138T1 (de) | 1996-11-15 |
| WO1991016042A1 (en) | 1991-10-31 |
| IT9020054A1 (ko) | 1991-10-17 |
| CA2035155A1 (en) | 1991-10-18 |
| IT9020054A0 (it) | 1990-04-17 |
| CA2040471A1 (en) | 1991-10-18 |
| JPH05506217A (ja) | 1993-09-16 |
| KR930700077A (ko) | 1993-03-13 |
| GR3021847T3 (en) | 1997-02-28 |
| DK0524989T3 (da) | 1996-11-18 |
| JPH04224517A (ja) | 1992-08-13 |
| TW223022B (ko) | 1994-05-01 |
| ES2093097T3 (es) | 1996-12-16 |
| AU654277B2 (en) | 1994-11-03 |
| DE69122751D1 (de) | 1996-11-21 |
| PT97370B (pt) | 1998-08-31 |
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