KR19980702193A - 고형 활성 화합물 제제 - Google Patents
고형 활성 화합물 제제 Download PDFInfo
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- KR19980702193A KR19980702193A KR1019970705588A KR19970705588A KR19980702193A KR 19980702193 A KR19980702193 A KR 19980702193A KR 1019970705588 A KR1019970705588 A KR 1019970705588A KR 19970705588 A KR19970705588 A KR 19970705588A KR 19980702193 A KR19980702193 A KR 19980702193A
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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Abstract
본 발명은 A) 하나 이상의 활성 화합물, B) B1) 10 내지 90 중량%의 열가소적으로 가공될 수 있는 수용성 중합체, 및 B2) 10 내지 90 중량%의 저치환된 히드록시프로필셀룰로오스의 혼합물, 및 C) 제제 총량을 기준으로 0 내지 50 중량%의 통상의 제약학적 보조제를 용융 압출시켜 수득될 수 있는 고형 제제에 관한 것이다.
Description
본 발명은
A) 하나 이상의 활성 화합물,
B) B1) 10 내지 90 중량%의 하나 이상의 열가소적으로 가공될 수 있는 수용성 중합체, 및 B2) 10 내지 90 중량%의 저치환된 수불용성 히드록시프로필셀룰로오스의 혼합물, 및
C) 제제 총량을 기준으로 0 내지 50 중량%의 하나 이상의 제약학적 보조제를 함께 용융 압출시켜 수득될 수 있는 고형 제제에 관한 것이다.
더욱이, 본 발명은 상기 제제의 제조 방법 및 그의 약제로서의 용도에 관한 것이다.
용융 압출시켜 제조되는 활성 화합물 함유 제제는 공지되어 있다.
수용성 중합체, 바람직하게는 비닐피롤리돈의 공중합체의 활성 화합물 함유 용융물의 압출에 대해 유럽 특허 공개 제 240 904호 및 유럽 특허 공개 제 240 906호에 기재되어 있다.
일본 특허 공개 제 58-192817호 및 일본 특허 공개 제 58-79915호에는 결합제로서 히드록시프로필셀룰로오스와 같은 열가소성 중합체 기재의 활성 화합물 함유 제제의 용융 압출에 대해 기재되어 있다.
셀룰로우스와 프로필렌 옥시드를 부분적으로 에스테르화시켜 제조된 저치환 히드록시프로필셀룰로우스 (L-HPC)는 물에 불용성이지만, 물과의 접촉시 팽윤된다. 이같은 팽윤으로 인해, L-HPC는 정제의 분해를 촉진시키는 분해제로 사용된다. 또한, L-HPC는 정제 경도를 증가시키기 위한 정제의 결합제로 사용될 수 있다.
가와시마 (Kawashima) 등의 문헌 [Chem. Pharm. Bull.41(1933), 1827-31]에는 정제화를 위한 과립에서 L-HPC의 용도가 주로 L-HPC의 입경에 좌우되고, 한편 활성 화합물 방출 프로파일은 압축시의 압축력에 의해 결정적인 영향을 받는 것으로 기재되어 있다.
그러나, 치환도가 높은 히드록시프로필셀룰로우스와는 달리 L-HPC는 열가소적 가공성을 나타내지 않는다.
본 발명의 목적은 중합체-활성 화합물의 용융 압출에 의해 제조될 수 있고 활성 화합물의 방출도를 특정하게 조정할 수 있는 활성 화합물 제제를 발견하는 것이다.
본 발명자들은 상기 목적이 처음에 정의된 제제, 그의 제조 방법 및 그의 약제로서의 용도에 의해 달성될 수 있음을 알게 되었다.
성분 A)로 적합한 활성 화합물은 용융 압출 시의 가공 조건하에서 분해되지 않는 화합물이다.
적합한 활성 화합물은 예컨대, 아세부톨롤, 아세틸시스테인, 아세틸살리실산, 아시클로비르, 알프라졸람, 알부민, 알파칼시돌, 알란토인, 알로푸리놀, 암브록솔, 아미카신, 아밀로리드, 아미노아세트산, 아미오다론, 아미트립틸린, 암로디핀, 아목시실린, 암피실린, 아스코르브산, 아스파르탐, 아스테미졸, 아테놀롤, 베클로메타손, 벤세라지드, 벤즈알코늄 히드록시드, 벤조카인, 벤조산, 베타메타손, 벤자피브레이트, 비오틴, 비페리덴, 비소프롤롤, 브로마제팜, 브롬헥신, 브로모크립틴, 뷰데소니드, 부펙사막, 부플로메딜, 부스피론, 카페인, 캠퍼, 카프토프릴, 카르밤아제핀, 카르비도파, 카르보플라틴, 세파클로, 세팔렉신, 세파드록실, 세파졸린, 세픽심, 세포탁심, 세프타지딘, 세프트리악존, 세푸록심 악세틸, 클로람페니콜, 클로르헥시딘, 클로르페니라민, 클로르탈리돈, 콜린, 시클로스포린, 실라스타틴, 시메티딘, 시프로프록사신, 시사프리드, 시스플라틴, 클라리트로마이신, 클라불란산, 클로미프라민, 클로나제팜, 클로니딘, 클로트리마졸, 클로자핀, 코데인, 콜레스티라민, 크로모글릭산, 시아노코발라민, 시프로테론, 데소게스트렐, 덱사메타손, 덱스판테놀, 덱스트로메토판, 덱스트로프로폭시펜, 디아제팜, 디클로페낙, 디곡신, 디히드로코데인, 디히드로에르고타민, 딜티아젬, 디펜히드라민, 디피리다몰, 디피론, 디소피라미드, 돔페리돈, 도파민, 에날라프릴, 엡헤드린, 에피네프린, 에르고칼시페롤, 에르고타민, 에리트로마이신, 에스트라디올, 에티닐에스트라디올, 에토포시드, 유칼립투스 글로불루스, 파모티딘, 페로디핀, 페노프브레이트, 페노테롤, 펜타닐, 플라빈 모노뉴클레오티드, 플루코나졸, 플루나리진, 플루오로우라실, 풀루옥세틴, 플루르비프로펜, 폴린산, 푸로세미드, 겜피브로질, 겜타마이신, 긴코 빌로바, 글리벤클라미드, 글리피지드, 글리시르히자 글라브라, 구아이페네신, 할로페리돌, 헤파린, 히알루론산, 히드로클로로티아지드, 히드로코돈, 히드로코르티손, 히드로모르폰, 이프라트로퓸 히드록시드, 이부프로펜, 이미페넴, 인도메타신, 이오헥솔, 이오파미돌, 이소소르비드 디니트레이트, 이소소르비드 모노니트레이트, 이소트레티노인, 테토티펜, 케토코나졸, 케토프로펜, 테토롤락, 라베탈롤, 락툴로스, 레시틴, 레보카르니틴, 레보도파, 레보글루타미드, 레보노르게스트렐, 레보티록신, 리도카인, 리파제, 리시노프릴, 로페라미드, 로라제팜, 로바스타틴, 메드록시프로게스테론, 멘톨, 메토트렉세이트, 메틸도파, 메틸프레드니솔론, 메토클로프라미드, 메토프롤롤, 미코나졸, 미다졸람, 미노시클린, 미녹시딜, 미소프로스톨, 모르핀, 멀티비타민 및, 미네랄, 니스타틴, N-메틸페드린, 나프티드로푸릴, 나프록센, 네오마이신, 니카르디핀, 니세르골린, 니코틴아미드, 니코틴, 니코틴산, 니페디핀, 니모디핀, 니트렌디핀, 니자티딘, 노레티스테론, 노르프록사신, 노르게스트렐, 노르트립틸린, 오플록사신, 오메프라졸, 온단세트론, 판크레아틴, 판테놀, 판토텐산, 파라세타몰, 페니실린 G, 페니실린 V, 페노바르비탈, 펜톡시필린, 페닐레프린, 페닐프로파놀아민, 페니토인, 피록시캄, 폴리믹 B, 포비돈-요오드, 프라바스타틴, 프라조신, 프레드니솔론, 프로파페논, 프로프라놀롤, 슈도에페드린, 피리독신, 퀴니딘, 라미프릴, 라니티딘, 레세르핀, 레티놀, 리보플라빈, 리팜피신, 루토시드, 사카린, 살부타몰, 살카토닌, 살리실산, 셀레길린, 심바스타틴, 소마트로핀, 소탈롤, 아피로놀락톤, 수크랄페이트, 술박탐, 술팜톡사졸, 술피리드, 타목시펜, 테가푸르, 테프레논, 테라조신, 테르부탈린, 테르페나딘, 테오필린, 티아민, 티클로피딘, 티몰롤, 트라넥삼산, 트레티노인, 트리암시놀론 아세토니드, 트리암테렌, 트리메토프림, 트록세루틴, 우라실, 발프로산, 반코마이신, 베라파밀, 비타민 E, 지도부딘이다.
더욱이, 적합한 활성 화합물은 비타민 C, β-카로텐 및 다른 카로테노이드 또는 작물 보호제와 같은 비타민이다.
활성 화합물은 바람직하게는 고용체 형태, 즉 매트릭스 중에 분자 분산되어 분포되는 형태, 또는 고체 분산액의 형태로 존재한다.
총 제제 중의 활성 화합물 성분 A)의 양은 활성도 및 방출 속도에 따라 넓은 범위에서 변할 수 있다. 즉, 활성 화합물 함량은 총 제제를 기준으로 0.1 내지 90 중량%, 바람직하게는 0.5 내지 60 중량%이다. 하나의 조건은 제제가 열가소적으로 가공될 수 있다는 점이다.
중합성 성분 B)로서, 본 발명에 따른 제제는 B1) 10 내지 90 중량%, 바람직하게는 20 내지 80 중량%의 수용성인 열가소성 중합체, 및 B2) 10 내지 90 중량%, 바람직하게는 20 내지 80 중량%의 수불용성인 저치환된 히드록시프로필셀룰로오스의 혼합물을 포함하고, 정량치는 B1) 및 B2)의 총량을 기준으로 한다.
언급할만한 수용성 중합체 B1)은 메틸셀룰루오스와 같은 알킬셀룰로오스, 히드록시메틸-, 히드록시에틸-, 히드록시프로필- 및 히드록시부틸셀룰로오스와 같은 히드록시알킬셀룰로오스, 히드록시에틸메틸- 및 히드록시프로필메틸셀룰로오스와 같은 히드록시알킬알킬셀룰로오스, 폴리비닐피롤리돈, 50 중량% 이하의 비닐 아세테이트를 함유한 N-비닐피롤리돈과 비닐 아세테이트의 공중합체, 카르복시메틸셀룰로오스와 같은 카르복시알킬셀룰로오스, 알기닌산과 같은 폴리사카리드 및 그의 알칼리 금속 및 암모늄염, 및 수용성 중합체의 혼합물이다.
성분 B1)은 물질이 압출성이 되도록 50 내지 180 ℃, 바람직하게는 60 내지 150 ℃의 범위에서 모든 성분의 전체 혼합물 중에서 연화되거나 용융되어야 한다.
수용성이란 0.5 g 이상, 바람직하게는 2 g 이상의 중합체가 20 ℃에서 100 g의 물에서 콜로이드 형태로라도 용해되어야함을 의미한다.
바람직하게는, 사용된 중합체 성분 A)는 몰 치환도가 3.0 내지 4.4인 히드록시프로필셀룰로오스이다.
본 발명에 따르면, 성분 B2)는 몰 치환도가 0.5 내지 2, 바람직하게는 1.5 내지 1.8인 저치환 히드록시프로필셀룰로오스, 미국 약전 NF XVII 및 일본 약전 JP XI에 기재된 저치환 히드록시프로필셀룰로우스 (L-HPC)이고, 이같은 형태의 L-HPC는 수불용성이지만, 수중에서 팽윤될 수 있고, 열가소성은 아니다.
상술한 범위 내에서, 사용된 성분 B2)의 양은 바람직하게는 필요한 활성 화합물 방출 속도에 좌우된다. 고속 방출의 경우, 보다 소량, 예컨대 5 내지 30 중량%가 바람직하다. 활성 화합물의 방출이 지체될 필요가 있다면, 30 내지 90 중량%의 B2)를 사용하는 것이 바람직하다.
본 발명에 따르면, 사용된 L-HPC의 입경이 결정적이지는 않다.
성분 C)로서, 본 발명에 따른 제제는 충전제, 윤활제, 성형 방출제, 흐름 조절제, 가소제, 착색제 및 안정화제와 같은 통상의 제약 보조제를 약 50 중량% 이하로 포함할 수 있다. 이들 양 및 하기 양은 각각 제제의 총량 (100%)을 기준으로 한다.
언급할만한 충전제는 예컨대, 마그네슘, 알루미늄, 규소 및 티탄의 산화물, 및 락토스, 만니톨, 소르비톨, 크실리톨, 펜타에리트리톨 및 그의 유도체로, 충전제의 양은 약 0.02 내지 50 중량%, 바람직하게는 0.2 내지 20 중량%이다.
언급할만한 흐름 조절제는 예컨대, C12-, C14-, C16- 및 C18-지방산과 같은 장쇄 지방산의 모노-, 디- 및 트리글리세리드, 카르노바 왁스와 같은 왁스 및 레시틴으로, 사용량은 약 0.1 내지 30 중량%, 바람직하게는 0.1 내지 5 중량%이다.
언급할만한 가소제는 예컨대 폴리에틸렌 글리콜, 폴리프로필렌 글리콜 및 폴리에틸렌 프로필렌 글리콜과 같은 저분자량 폴리알킬렌 옥시드, 프로필렌 글리콜, 글리세롤, 펜타에리트리톨 및 소르비톨과 같은 다가 알코올, 및 소듐 디에틸술포숙시네이트, 글리세롤의 모노-, 디- 및 트리아세테이트 및 폴리에틸렌 글리콜 스테아르산 에스테르이다. 이 경우, 가소제의 양은 약 0.5 내지 15 중량%, 바람직하게는 0.5 내지 5 중량%이다.
언급할만한 윤활제는 예컨대, 알루미늄 또는 칼슘의 스테아레이트 및 활석 및 실리콘이고, 그 양은 약 0.1 내지 5 중량%, 바람직하게는 약 0.1 내지 3 중량%이다.
언급할만한 안정화제는 예컨대, 광안정화제, 산화방지제, 라디칼 스캐빈져, 및 미생물 공격에 대한 안정화제로, 그 양은 바람직하게는 약 0.01 내지 0.05 중량%이다.
본 발명에 따른 제제를 제조하기 위해, 활성 화합물 성분은 물리적 혼합물의 형태로 중합체 B와 직접 융합되거나 기존재하는 중합체 용융물과 혼합된다.
그렇지 않으면, 성분 A)와 용융물을 공지된 방법으로 압출기, 바람직하게는 단일- 또는 이중-스크류 압출기 중에서 50 내지 200 ℃에서 혼합시킨다. 본 발명에 따른 제제를 제조하기 위한 활성 화합물 함유 중합체 용융물을 예컨대, 유럽 특허 공개 제 240 906호에 기재된 방법 및 독일 특허 공개 제 38 30 355호에 개시된 가공 방법에 따라 압출물을 캘린더링키고, 압출물을 회전 나이프로 성형 가능한 고체 표면을 갖는 동일한 부피로 나누고, 통상의 정제화기에서 정제로 압축시켜 성형시켰다.
보조제를 활성 화합물과 중합체 B의 용융물 또는 용액과 혼합시킬 수 있다. 또한, 보조제는 활성 화합물과 함께 중합체 용융물로 혼입될 수 있다. 또한, 보조제, 활성 화합물 및 중합체 B의 혼합물을 직접 융합시킬 수 있다. 일반적으로, 보조제, 활성 화합물 및 중합체 B의 물리적 혼합물을 융합시킨다.
본 발명에 따른 제제는 약제로 사용되고 정제, 펠렛제, 과립제 또는 캡슐제의 형태로 사용될 수 있다. 바람직하게는, 활성 화합물의 방출이 지연되는 제약 형태는 본 발명에 따른 제조를 사용하여 제조된다.
필요한 경우, 고체 약제형은 통상의 코팅제와 함께 제공되어 (코팅된 정제) 외형 및 (또는) 미각을 향상시킬 수 있고 또는 활성 화합물의 방출을 더욱 지연시킬 수 있다. 활성 화합물의 방출이 지연되도록 정제가 경구 투여된다면, 정제가 공지된 방법 중 하나의 방법에 따라 밀폐된 셀 다공형으로 제조되어 위 내에 퍼져서 더 오랫동안 잔류하게 된다.
본 발명에 의해 간단하게 본 발명에 따른 고형 약제형의 활성 화합물 방출 프로파일을 특히, 활성 화합물의 방출이 지연되는 고형 약제형의 제조시에 특정하게 조정할 수 있다.
실시예 1 내지 3
표에 실린 양으로 활성 화합물, 중합체 B1) 및 B2)를 혼합시키고, 이중-스크류 압출기 (ZSK 30, Werner Pfleiderer)로 도입시키고 5 종의 온도 영역에서 압출시켰다. 각각 온도 영역 (배치 1-5)의 온도를 각각 표 I에 나타내었다. 압출기 노즐 립을 통해 나타나는 용융 압출물을 나이프 롤 과립기를 사용하여 공기 냉각 열을 환원시켜 펠렛화시켰다.
활성 화합물의 방출을 USP XXI, 미국 약전에 따른 패들법에 의해 측정하였다. 이같은 시험관내 방법을 사용하여 활성 화합물을 함유한 성형된 물품 (예컨대, 정제, 펠렛제 등)의 용액의 속도를 측정하였다.
이를 행하기 위해, pH가 6.8인 포스페이트 완충액을 37℃에서 1ℓ 둥근 바닥 용기 중의 0.1 중량%의 소듐 라우릴 술페이트로 온도 조절하고 300 g의 입자 크기가 1.25 내지 1.60 mm인 펠렛을 부가하였다. 펠렛으로부터의 활성 화합물 방출을 각 경우 UV 분광기로 패들 회전 속도 100 rpm에서 1, 2, 3, 4, 5, 6, 7 및 8 시간 후측정하였다.
상기 시험 결과를 하기 표 II에 나타낸다.
| 실시예 | 니페디핀 중량% | 중합체 B1)1)중량% | 중합체 B2)2)중량% | 온도 배치 1 - 5 |
| 1 | 20 | 50 | 30 | 700,120,110,100,100 |
| 2 | 20 | 40 | 40 | 60,120,120,110,120 |
| 3 | 20 | 30 | 50 | 60,120,120,120,130 |
| 1)몰치환도가 3.0 내지 4.4인 히드록시프로필셀룰로우스 (Klucel EF, Hercules, 미국)2)몰치환도가 1.5 내지 1.8인 히드록시프로필셀룰로우스 (LH 31, Shin-Etsu Chemical Comp. Ltd., 일본) |
| 실시예 | 하기 시간 경과후 방출 % | |||||||
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | |
| 1 | 32 | 70 | 91 | 99 | 100 | 100 | 100 | 100 |
| 2 | 31 | 60 | 77 | 89 | 96 | 100 | 100 | 100 |
| 3 | 24 | 43 | 57 | 69 | 75 | 81 | 87 | 91 |
Claims (6)
- A) 하나 이상의 활성 화합물,B) B1) 10 내지 90 중량%의 하나 이상의 열가소적으로 가공될 수 있는 수용성 중합체, 및 B2) 10 내지 90 중량%의 저치환된 수불용성 히드록시프로필셀룰로오스의 혼합물, 및C) 제제 총량을 기준으로 0 내지 50 중량%의 하나 이상의 제약학적 보조제를 함께 용융 압출시켜 수득될 수 있는 고형 제제.
- 제1항에 있어서, 성분 B2)로서 몰 치환도가 1.5 내지 1.8인 히드록시프로필셀룰로오스를 포함하는 제제.
- 제1 또는 2항에 있어서, 성분 B1)으로서 수용성 히드록시프로필셀룰로오스를 포함하는 제제.
- 활성 화합물 A)를 중합성 성분 B) 및 적합하게는 보조제 C)와 가공시켜 용융물을 얻고, 용융물을 압출시키고, 추가로 성형 가공시키는 것으로 이루어진, 제1 내지 3항 중 어느 한 항에 따른 제제의 제조 방법.
- 제1 내지 3항 중 어느 한 항에 따른 제제의 약제로서의 용도.
- 제1 내지 3항 중 어느 한 항에 따른 제제로부터 제조된 고형 약제형.
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| DE19504832A DE19504832A1 (de) | 1995-02-14 | 1995-02-14 | Feste Wirkstoff-Zubereitungen |
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| JPS5879915A (ja) * | 1981-11-09 | 1983-05-13 | Nippon Soda Co Ltd | 棒状薬剤の製造方法 |
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1995
- 1995-02-14 DE DE19504832A patent/DE19504832A1/de not_active Withdrawn
-
1996
- 1996-02-01 SK SK1043-97A patent/SK104397A3/sk unknown
- 1996-02-01 DE DE59609451T patent/DE59609451D1/de not_active Expired - Lifetime
- 1996-02-01 KR KR1019970705588A patent/KR19980702193A/ko not_active Application Discontinuation
- 1996-02-01 HU HU9702424A patent/HUP9702424A3/hu unknown
- 1996-02-01 PL PL96321755A patent/PL321755A1/xx unknown
- 1996-02-01 CN CNB961919280A patent/CN1177584C/zh not_active Expired - Lifetime
- 1996-02-01 NZ NZ302243A patent/NZ302243A/xx unknown
- 1996-02-01 DK DK96903958T patent/DK0809488T3/da active
- 1996-02-01 WO PCT/EP1996/000417 patent/WO1996025151A1/de active IP Right Grant
- 1996-02-01 JP JP52461596A patent/JP4049810B2/ja not_active Expired - Fee Related
- 1996-02-01 AT AT96903958T patent/ATE220541T1/de active
- 1996-02-01 US US08/875,514 patent/US5939099A/en not_active Expired - Lifetime
- 1996-02-01 BR BR9606957A patent/BR9606957A/pt not_active Application Discontinuation
- 1996-02-01 CZ CZ972394A patent/CZ239497A3/cs unknown
- 1996-02-01 PT PT96903958T patent/PT809488E/pt unknown
- 1996-02-01 AU AU47860/96A patent/AU4786096A/en not_active Abandoned
- 1996-02-01 ES ES96903958T patent/ES2180738T3/es not_active Expired - Lifetime
- 1996-02-01 EP EP96903958A patent/EP0809488B1/de not_active Expired - Lifetime
- 1996-02-01 CA CA002211033A patent/CA2211033C/en not_active Expired - Lifetime
- 1996-02-01 TR TR97/00786T patent/TR199700786T1/xx unknown
- 1996-02-12 IL IL11711296A patent/IL117112A0/xx unknown
- 1996-02-13 ZA ZA9601137A patent/ZA961137B/xx unknown
-
1997
- 1997-07-17 BG BG101781A patent/BG101781A/xx unknown
- 1997-08-13 NO NO973730A patent/NO973730L/no unknown
- 1997-08-13 FI FI973320A patent/FI973320A/fi unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100464749B1 (ko) * | 1999-01-18 | 2005-01-07 | 신에쓰 가가꾸 고교 가부시끼가이샤 | 저치환도 히드록시프로필 셀룰로오즈 |
| KR20010029723A (ko) * | 1999-05-18 | 2001-04-16 | 카나가와 치히로 | 저치환도 히드록시프로필셀룰로오스 및 고형 제제 |
| KR20160015234A (ko) * | 2013-06-03 | 2016-02-12 | 신에쓰 가가꾸 고교 가부시끼가이샤 | 가열 용융 압출용 조성물 및 이것을 사용한 가열 용융 압출 성형물의 제조 방법 |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2211033A1 (en) | 1996-08-22 |
| NZ302243A (en) | 1999-01-28 |
| CN1174503A (zh) | 1998-02-25 |
| HUP9702424A3 (en) | 2001-03-28 |
| ATE220541T1 (de) | 2002-08-15 |
| CN1177584C (zh) | 2004-12-01 |
| BR9606957A (pt) | 1997-10-28 |
| DK0809488T3 (da) | 2002-09-02 |
| ZA961137B (en) | 1997-09-16 |
| WO1996025151A1 (de) | 1996-08-22 |
| DE19504832A1 (de) | 1996-08-22 |
| DE59609451D1 (de) | 2002-08-22 |
| US5939099A (en) | 1999-08-17 |
| JPH10513477A (ja) | 1998-12-22 |
| SK104397A3 (en) | 1998-04-08 |
| BG101781A (en) | 1998-03-31 |
| PL321755A1 (en) | 1997-12-22 |
| PT809488E (pt) | 2002-11-29 |
| IL117112A0 (en) | 1996-06-18 |
| FI973320A0 (fi) | 1997-08-13 |
| EP0809488B1 (de) | 2002-07-17 |
| NO973730D0 (no) | 1997-08-13 |
| AU4786096A (en) | 1996-09-04 |
| TR199700786T1 (xx) | 1998-02-21 |
| ES2180738T3 (es) | 2003-02-16 |
| JP4049810B2 (ja) | 2008-02-20 |
| EP0809488A1 (de) | 1997-12-03 |
| FI973320A (fi) | 1997-10-13 |
| CA2211033C (en) | 2005-04-26 |
| NO973730L (no) | 1997-08-13 |
| HUP9702424A2 (hu) | 1998-06-29 |
| CZ239497A3 (cs) | 1998-01-14 |
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