KR880001765B1 - 마이크로 캅셀의 제조방법 - Google Patents
마이크로 캅셀의 제조방법 Download PDFInfo
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- KR880001765B1 KR880001765B1 KR1019810003746A KR810003746A KR880001765B1 KR 880001765 B1 KR880001765 B1 KR 880001765B1 KR 1019810003746 A KR1019810003746 A KR 1019810003746A KR 810003746 A KR810003746 A KR 810003746A KR 880001765 B1 KR880001765 B1 KR 880001765B1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- 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
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- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S424/00—Drug, bio-affecting and body treating compositions
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Abstract
내용 없음.
Description
본 발명은 마이크로캅셀, 특히 생물학적 활성제제를 함유하는 마이크로캅셀의 제조방법에 관한 것이다.
어떤 형태의 화합물을 마이크로캅셀 형태로 캅셀화시킬 수 있는 여러가지 방법이 공지되어 있다. 이러한 방법에서는 캅셀화시킬 물질을 일반적으로 벽(wall)형성 물질을 함유하는 용매에 분산시킨다. 공정의 단일 단계에서는 용매를 마이크로캅셀로부터 제거한 다음 마이크로캅셀 생성물을 수득한다. 통상적인 선행 마이크로캅셀화 방법의 예는 미합중국 특허 제3,737,337호에 언급되어 있는데 여기에는 용매중의 벽 또는 막(shell)을 형성하는 중합체 물질의 용액을 제조하는 방법이 기술되어 있다. 이 용매는 물에만 부분적으로 용해된다. 고체 또는 충전 물질을 중합체 함유 용액에 용해시키거나 분산시킨후, 충전 물질을 함유하는 용액을 유기용매와 혼화되지 않는 액체 수용액에 분산시켜 마이크로캅셀로부터 용매를 제거한다. 단일 단계로서 물질을 함유하는 마이크로캅셀로부터 용매를 제거시킬 수 있는 또 다른 방법의 한예가 미합중국 특허 제3,523,906호에 기술되어 있다. 이 방법에서는 캅셀화할 물질을 물과 혼화될 수 없는 용매에 용해된 중합체 물질 용액에 유화시킨 다음 이 유제를 친수성 콜로이드를 함유하는 수용액에 유화시킨다. 마이크로캅셀로부터 용매를 제거하는 과정은 단일 단계로 증발시켜 생성물을 수득한다. 미합중국 특허 제3,691,090호에 기술되어 있는 또 다른 한 방법도 수용성 매질내에서 바람직하게는 감압하에서 유기 용매를 수용성 매체의 마이크로캅셀 분산액으로부터 단일 단계로 증발시킨다. 미합중국 특허 제3,891,570호의 방법은 상기와 비슷한 방법으로서 다가알콜 매질내의 마이크로캅셀의 분산액으로부터의 용매는 마이크로캅셀을 감압하에 두거나 가열시킴으로써 마이크로캅셀로부터 증발된다. 한 단계로 용매를 제거시키는 방법의 또다른 예가 미합중국 특허 제3,960,757호에 기술되어 있다.
통상적인 캅셀화 기술의 난점은 특히, 이를 프로게스테론(progesterone) 또는 노르게스티메이트(norge-stimate)와 같은 약제의 마이크로캅셀화에 사용할 경우 약제의 충진이 제한적인 요소라는 것이다. 마이크로캅셀화할 제제 및 부형제의 물리적 및 화학적 특성에 따라, 대단히 많이 충진된 마이크로캅셀을 제조하고자 시도한 결과 제제결정이 마이크로캅셀 외부로 돌출되거나 공정매질내에서 증대되는 것과 같은 불완전한 마이크로캅셀화가 야기된다. 그러므로, 계속 특성이 개선되고 질이 높은 미세입자를 제조하는 기술이 필요하다.
따라서, 본 발명의 목적은 물질 충진 정도가 개선되고 질이 개량된 활성제제를 함유하는 마이크로캅셀을 제조하는 기술을 제공하는 것이다.
간단히, 본 발명의 목적은 (a) 활성제제를 용매에 용해시키거나 분산시키고 벽형성 물질을 상기 용매에 용해시킨 다음, (b) 벽형성 물질 및 상기 활성제제를 함유하는 상기 용매를 연속상 처리 매질(continuous-phase processing medium)내에 분산시키고, (c) 상기 단계(b)의 분산액으로부터 상기 용매의 일부를 증발시켜서 현탁액내에 상기 활성제제가 함유된 마이크로캅셀을 형성시킨 다음 (d) 상기 마이크로캅셀에 잔존하는 용매를 추출시킴을 특징으로 하여 활성제제가 함유된 마이크로캅셀을 제조하는 방법에 의해 성취될 수 있다.
개량된 특성을 갖는 마이크로캅셀을 수득하기 위한 본 발명의 주요점은 제조시 단일 공정단계가 아닌 별개의 2단계로 유체매질에 현탁된 마이크로캅셀로부터 용매를 제거시킨다는 것이다. 2단계 용매제거 기술로써 개량된 질 및 다량의 활성제를 함유하는 마이크로캅셀 생성물을 제조할 수 있다. 통상적인 방법을 능가하는 본 방법의 잇점은 본 2단계 용매제거 기술이 단일 단계로 용매를 제거하는 기술로 제조한 통산적인 마이크로캅셀 생성물과 비교하여 활성제제 함유량이 대단히 높고 품질이 대단히 우수한 마이크로캅셀 생성물을 생성시킬 수 있다는 점이다.
마이크로캅셀에 혼입될 수 있는 물질을 용매에 용해시킨다. 본 마이크로캅셀내에 혼입시킬 수 있는 적절한 활성제제에는 농약, 향료, 경화제, 염료, 산화제 및 생물학적 활성제제가 포함된다. 용매에 분산시키거나 용해되는 활성제제 량은 중요하지 않으나, 벽형성 물질에 비해 활성제제의 양이 너무 많은 경우 마이크로캅셀이 형성되지 않으므로, 이때 벽형성 물질에 대한 활성제제의 비율은 중요하다. 특히 벽형성 물질과 혼합된 활성제제의 량은 벽형성 물질 20중량부에 대해 활성제제 약 80중량부 이하가 사용된다. 마이크로캅셀내의 활성제제의 함량이 너무 낮아 마이크로캅셀의 실질적인 유용성이 없는 경유를 제외하고는, 활성제제의 벽형성 물질과의 혼합비에 대한 하한선은 없다. 그러나 용액을 더 희석시키면 시킬수록 주어진 량의 활성제제를 함유하는 마이크로캅셀 생성물을 제조하기 위해서 결국 제거해야 하는 용매의 량은 더 많이 존재한다. 보통 5 내지 30중량%의 활성제제를 용매에 용해시키거나 현탁시킨다.
활성제제를 함유하는 용액의 제조에 사용되는 용매는 클로로포름, 메틸렌 클로라이드, 메틸클로로포름 등과 같은 할로겐화 지방족 탄화수소 ; 방향족 탄화수소 화합물 ; 할로겐화 방향족 탄화수소 화합물, 테트라하이드로푸란 등과 같은 환형 에테르, 알콜, 물, 아세톤 등을 함유하는 여러가지 일반적인 유기용매로부터 선택될 수 있다. 상기 용매는 벽물질을 용해시킬 수 있어야 하며, 활성제에 대해 화학적으로 불활성이어야 하며, 연속상 처리 매질과 혼화되지 않아야 하며, 연속상 처리 매질 보다 낮은 비점을 가져야 한다. 용매에 용해할 벽 물질의 량은 용매내의 중합체의 용해도 및 생성되는 중합체 용액의 점도에 따라 좌우된다. 점성은 마이크로캅셀의 최종 크기를 결정한다. 상기 용매의 혼합물은 활성제제에 대한 적절한 용매로서 사용될 수도 있다.
단순 증발 기술로 제조하기 쉬운 저비점 용매를 사용하는 것이 바람직하다.
활성제제를 함유하는 용액에 마이크로캅셀내의 활성제제를 에워싸며 봉입시킬 수 있는 벽형성 물질을 가한다. 용액에 첨가되는 벽형성 물질의 량은 용액이 연속상 처리 매질내의 분산될 때 마이크로캅셀이 신속히 형성되게 하는 량이다. 활성제제 및 벽형성 물질을 용매에 가한후 연속상 처리 매질내에 용매를 분산시켜야 한다. 보통 5 내지 35중량%의 벽형성 물질을 용매내에 용해시킨다.
적절한 벽형성 물질에는 폴리스티렌, 에틸 셀룰로우즈, 셀룰로우즈 아세테이트, 하이드록시프로필메틸 셀룰로우즈 프탈레이트, 디부틸아미노 하이드록시프로필에테르, 폴리비닐 부티랄, 폴리비닐 포르말, 폴리(메트)아크릴산 에스테르, 폴리비닐아세탈-디에틸아미노 아세테이트, 2-메틸-5-비닐피리딘 메타크릴레이트-메타크릴산 공중합체, 폴리카보네이트, 폴리에스테르, 폴리프로필렌, 비닐-클로라이드-비닐아세테이트 공중합체, 폴리삭카라이드, 글리세롤 디스테아레이트 등이 포함된다. 중합체 벽형성 물질의 바람직한 그룹에는 폴리락티드, 폴리글리콜리드, 폴리카프로락톤 및 이들의 공중합체를 포함하여 지방족 폴리에스테르와 같은 미생물로 분해될 수 있는 물질이다.
활성제제 및 벽형성 물질을 함유하는 용매상을 제조한 다음, 활성제제를 함유하는 벽형성 물질의 마이크로 소적은 활성제제와 벽형성 물질을 함유하는 용액을 연속상 처리 매질에 분산시켜 생성시킬 수 있다. 연속상 처리 매질은 용매와 혼화되지 않아야 하며 용매보다 더 높은 비점을 가져야 한다. 대개의 경우에 처리 매질은 물인 반면, 비수용성 연속상 처리 매질은 크실렌 또는 톨루엔과 같은 유기액체, 실리콘 오일과 같은 합성유, 땅콩유를 포함하는 식물유와 같은 천연유이다. 보통 계면활성제제(유화제)를 연속상 처리 매질에 첨가하여 마이크로캅셀이 응집되는 것을 막고 유제내의 용매 마이크로 소적의 크기를 조절한다. 예로써 물을 연속상 처리 매질로 사용할 경우, 바람직한 계면활성제는 1 내지 10% 농도의 폴리(비닐알콜)(PVA)이다. 분산액은 콜로이드 밀, 균질기 등과 같은 장치로 연속상 처리 매질을 기계적으로 교반시켜 형성시킬 수 있다. 유제는 활성제제 벽형성 물질 용액의 소적을 연속상 처리매질에 첨가시켜 형성시킬 수 있다. 분산 단계의 바람직한 태양에서 유기용매 용액을 폴리비닐 알콜을 함유하는 수용액에 분산시킨다. 유제를 형성하는 동안 온도는 특별히 중요하지 않으나 마이크로캅셀의 크기 및 질을 좌우한다. 또한, 사용된 용매 및 연속상처리 매질에 따라서, 온도를 너무나 낮게 해서는 않되며 또는 용매 및 처리 매질을 고형화하거나 처리 매질을 실용상 지나치게 점성으로 또는 고점성으로 하여 매질을 증발시키거나 액체처리 매질을 유지시켜서는 않된다. 더우기 매질의 온도를 너무 상승시켜 마이크로캅셀내에 혼입되어 있는 특정 활성제의 안정성이 역효과를 받지 않도록 한다. 따라서, 안정한 조작 조건이 유지되는 온도에서 분산공정을 수행할 수 있다.
형성된 분산액은 안정된 유제이며, 이 분산액으로부터 유기용매 불혼화성 유체내의 마이크로 소적의 유기 용매를 용매 제거 공정의 첫 단계에서 제거한다. 가열, 감압 또는 이들의 복합 방법과 같은 통상적인 기술을 사용해 용매를 쉽게 제거시킬 수 있다. 마이크로 소적의 용매를 증발시키기 위해 사용되는 온도는 중요하지 않으나 온도가 너무 높아 마이크로캅셀의 제조에 사용되는 온도에 민감한 물질을 분해시켜서도 않되며 너무나 빠른 속도로 용매가 증발되어 벽형성 물질에 결함이 생기게 해서도 않된다. 일반적으로 10 내지 90%, 바람직하게는 40 내지 60%의 용매가 첫번째 용매 제거 단계에서 제거된다.
첫번째 용매 제거 단계를 거친후, 용매 불혼화성 유체매질내에 분산된 마이크로캅셀을 어떤 통상적인 분리 방법을 사용해 유체매질로부터 분리시킨다. 예로써, 유체를 마이크로캅셀로부터 경사분리시킬 수 있거나 마이크로캅셀 유체 현탁액을 여과시킬 수 있다. 경우에 따라 여러가지 분리기술을 혼용할 수 있다.
연속상 처리매질로부터 마이크로캅셀을 분리시킨 다음, 마이크로캅셀내에 존재하는 잔류용매를 추출시켜 제거한다. 이러한 두번째 단계에서, 마이크로캅셀은 계면활성제 존재 또는 부재하에 제 1 단계에서 사용된 것과 동일한 연속상 처리 매질 또는 다른 액체에 현탁시킬 수 있다. 추출매질은 마이크로캅셀로부터 용매를 추출시키며 마이크로캅셀을 용해시키지는 않는다. 추출하는 동안, 용해된 용매를 함유하는 추출매질을 제거하고 새로운 추출매질로 대체해야 한다. 이 과정은 연속적 논리로 행하는 것이 바람직하며, 여기서 추출매질 보충속도는 중요하다. 만일 이 속도가 너무 느리면, 제제 결정은 마이크로캅셀로부터 돌출되거나 추출매질내에서 증대된다. 명백히, 주어진 공정에 대한 추출매질 보충속도는 다양하며, 이는 공정을 수행할 때 용이하게 결정할 수 있으므로 속도에 대한 정확한 한계를 미리 결정할 필요는 없다. 잔류 용매를 마이크로캅셀로부터 제거시킨후 마이크로캅셀을 공기에 노출시키거나 또는 진공건조, 데시켄트상에서의 건조 등과 같은 통상적인 건조기술로 건조시킬 수 있다.
본 발명의 마이크로캅셀 생성물은 때때로 불규칙적으로 형성되지만 보통 구형 형태 입자를 형성한다. 마이크로캅셀은 초 마이크론 내지 밀리메타 크기의 직경으로 크기가 다양할 수 있다. 초 마이크론 내지 250㎛직경은 표준 시린지 및 바늘로 마이크로캅셀을 투여할 약제에 바람직하다. 마이크로캅셀은 그 안에 혼입된 물질의 형태에 따라 다양하게 사용할 수 있다. 본 마이크로캅셀은 여러가지 생물학적 활성제제를 인체 및 동물에 투여함에 있어서 특히 유용하다. 예를 들면 피임제가 함유된 본 마이크로캅셀은 산아 조절용으로 주사 또는 자궁 경관을 통해 여성 생식기관으로 투여할 수 있다. 적합한 피임제에는 디에틸 스틸베스토롤, 17-β-에스트라디올, 에스토론, 에티닐 에스트라디올, 메스트란올 등과 같은 에스트로겐 ; 노르에틴드론, 노르게스트릴, 에티노디올 디아세테이트, 린에스트렌올, 메드록시프로게스테론 아세테이트, 디메티스테론, 메게스트롤 아세테이트, 클로르마딘온 아세테이트, 노르게스티메이트, 노르에티스테론, 에티스테론, 멜렌게스트롤, 노르에티노드렐 등과 같은 프로게스틴 ; 노닐펜옥시폴리옥시에틸렌글리콜, 벤제토늄 클로라이드, 클로린단올 등과 같은 살정자 화합물이다. 본 발명 마이크로캅셀내에 혼입할 수 있는 기타 생물학적으로 활성이 있는 제제는 수산화알루미늄, 탄산칼슘, 탄산마그네슘, 탄산나트륨 등과 같은 위장 치료제 ; 비-스테로이드성 불임증 치료제 ; 부교감 신경자극 흥분제 ; 정신치료제 ; 클로로프로마진 염산, 클로즈아핀, 메소리드아진, 메티아핀, 레제르핀, 티오리드아진 등과 같은 정신병 치료제 ; 클로르디아제프옥사이드, 디아제팜, 메르프로바메이트, 템아제팜 등과 같은 신경안정제 ; 비(鼻) 충혈제거제 ; 코데인, 페노바르비탈, 나트륨 펜토바르비탈, 나트륨 세코바르비탈 등과 같은 진정-최면제 ; 테스토스테론 및 테스토스테론 프로피오네이트와 같은 기타 스테로이드 ; 설폰 아미드 ; 교감신경 흥분제 ; 왁찐 ; 비타민 및 필수아미노산, 필수지방 등과 같은 영양소 ; 4-아미노퀴놀린, 8-아미노퀴놀린, 피리메트아민 등과 같은 항말라리아제 ; 마진돌, 펜테르민 등과 같은 편두통치료제 ; L-도파와 같은 파킨슨씨병 치료제 ; 아트로핀, 메트스코폴아민 브로마이드 등과 같은 항경련제 ; 담즙 요법제, 소화제, 효소 등과 같은 항경련성 및 항콜린제 ; 덱스트로메토르판, 노스카핀 등과 같은 진해제 ; 기관지 확장제 ; 고혈압치료 화합물, 라우볼피아 알칼로이드,관상 혈관확장제, 니트로글리세린, 유기 질산염, 펜타에리트리토테트라니트레이트 등과 같은 심장혈관계 약제 ; 염화칼륨과 같은 전해질 대체물 ; 카페인 함유 또는 불함유 에르고트아민, 수소화 에르고트알칼로이드, 디하이드로에르고크리스틴 메탄 설페이트, 디하이드로 에르고코르닌 메탄설포네이트, 디하이드로에르고크로이프틴 메탄설포네이트 및 이의 혼합물과 같은 에르고트 알칼로이드 ; 아트로핀 설페이트, 벨라도나, 히오신 하이드로브로마이드 등과 같은 알칼로이드 ; 진통제 ; 코데인, 디하이드로코디에논, 메페리딘, 모르핀 등과 같은 진통제 ; 살리실레이트, 아스피린, 아세트아미노펜, α-프로폭시펜 등과 같은 비-마약, 세팔로스포린, 클로란페니칼, 겐타마이신, 가나마이신 A, 가나마이신 B, 페니실린, 암피실린, 스트렙토마이신 A, 안티마이신 A, 클로로팜테니올, 메트로미다졸, 옥시테트라사이클린 페니실린 G, 테트라사이클린 등과 같은 항생제 ; 항암제 ; 메페니토인, 페노바르비탈, 트리메타디온 과 같은 항경련제 ; 티에틸페라진과 같은 진토제 ; 클로로핀아진, 디멘하이드리네이트, 디펜하이드라민, 페르펜아진, 트리펠렌아민 등과 같은 항히스타민제 ; 호르몬제, 하이드로코티손, 프레드니솔론, 프레드니손, 비-호르몬제, 알로푸리놀, 아스피린, 인도메타신, 페닐부타존 등과 같은 소염제 ; 프로스타글란딘 ; 티오데파, 클로람부실, 사이클로포스파미드, 멜파란, 니트로겐, 머스타드, 메토트렉세이트 등과 같은 항종양제 ; 나이제리아 고노르헤아(Neisseria gonorrhea), 마이코박테리움 튜베르쿨로시스(Mycobacterium tuberculosis), 헤르페스 바이러스(Herpers virus : humonis type 1 및 2), 칸디다 알비칸스(Candida albicans), 칸디다 크로피칼리스(Candida tropicalis), 트리코모나스 바기날리스(Trichomonas vaginalis), 헤모필루스 바기날리스(Haemophilus vaginalis), 그룹 B스트렙토코커스 에콜리(Streptococcus ecoli), 마이크로플라스마 호미니스(Microplasma hominis), 헤모필루스 더크레이(Hemophilus ducreyi), 그라눌로마 인구이날레(Granuloma inguinale), 림포파티아 베네레움(Lymphopathia venereum), 트레포네마 팔리둠(Treponema pallidum), 브루셀라 아보르투스(Brucella abortus), 브루셀라 멜리텐시스(brucella Melitensis), 브루셀라 수이스(Brucella suis), 브루셀라 카니스(Brucella canis), 캄필로 박터 페투스(Campylobacter fetus), 캄필로박터 페트스 인데스티날리스(Campylobacter fetus intestinalis), 렙토스피라 포모나(Leptospira pomona), 리스테리아 모노사이토게네스(Listeria monocytogenes), 브루셀라 오비스(Brucella ovis), 에퀸 헤르페스 바이러스 1(Equine herpes virus 1), 에퀸 아르테리티스 바이러스 (Equine arteritis virus), IBR-IBR 바이러스(IBR-IBR virus), BVD-MB 바이러스(BVD-MB virus), 클라미디아 시타시 (Chlamydia psittaci), 트리코모나스 포에투스(Trichomonas foetus), 톡소플라스마 곤디(Toxoplasma gondii), 에스케리키아 콜리(Escherichia coli), 악티노바실러스 에퀼리(Actinobacillus equuli), 살모넬라 아보르투스 오비스(Salmonella abortus ovis), 살모넬라 아보르투스 에퀴(Salmonella abortus equi), 슈도모나스 아에루기노사(Pseudomonas aeruginosa), 코리네박테리움 에퀴(Corynebacter-ium equi), 코리네박테리움 피오게네스(Corynebacterium pyogenes), 악티노바실러스 세미니스(Actinobaccilus seminis), 마이코플라스마 보비게니탈리움(Mycoplasma bovigenitalium), 아스페르길루스 푸미가투스(Aspergillus fumigatus), 아브시디아 라모사(Absidia ramosa), 트리파노소마 에퀴페르둠(Trypanosoma equiperdum), 바베시아 카발리(Babesia caballi), 클로스트리디움 테타니(Clostridium tetani), 등과 같은 미생물의 항원, 상기 미생물에 대해 반작용을 하는 항체, 리보뉴클리아제, 뉴라미디나제, 트립신, 글리코겐 포스포릴라제, 스페름 락트산 탈수소 효소, 스페름 하이알루로니다제, 아데노신-트리포스파타제, 알칼리성 포스파타제, 알칼리성 포스파타제 에스테라제, 아미노 펩티다제, 트립신 키모트립신, 아밀라제, 무라미다제, 선체성 단백질 분해효소, 디에스테라제, 글루탐산 탈수소효소, 석신산 탈수소효소, β-글리코포스파타제, 리파제, 아데노신트리포스파타제, α-펩테이트 γ-글루타밀로 트랜스펩티다제, 스테롤-3-β-올-탈수소효소, DPN-디-아프로라제와 같은 효소이다.
다음 실시예는 본 발명을 설명하기 위한 것이며 달리 언급이 없는 한 이로써 제한하는 것은 아니다.
[실시예 1]
2.5g의 프로게스테론 및 10g의 폴리(DL-락티드)를 38g의 메틸렌 콜로라이드에 용해시킨다. 유기용액을 120g의 5% 수용성 폴리(비닐알콜)에 마이크로소적으로서 분산시킨다. 분산액은 유기용액을 200ml들이 수지용기에 든 교반된 수용성 폴리(비닐알콜) 용액에 가하여 수득할 수 있다. 유제의 교반은 공지된 장치(Teflon turbine impeller driven by Fisher stedi-speed moter)를 사용할 수 있다.
적절한 수중유 유제를 제조한 후 유제의 압력을 계속 감압시켜 기포가 형성될 때까지 유지시킨다. 용매 증발 단계는 40 내지 60%의 메틸렌 클로라이드가 제거될 때까지 계속한다. 마이크로캅셀 현탄액은 10분동안 41G에서 원심분리시킨다. 상층액을 경사 분리시킨 다음 마이크로캅셀을 50 내지 100ml의 탈이온수로 재현탁시키고 이 현탁액의 절반을 미세(4 내지 5.5㎛) 프릿 유리 깔대기에 붓는다. 흡입시켜 마이크로캅셀을 천천히 여과시킨다. 여과시키는 동안 천천히 교반하면서 계속 탈이온수를 첨가하여 마이크로캅셀을 현탁 액내에 유지시킨다. 마이크로캅셀은 약 400 내지 500ml의 탈이온수가 사용될 때까지 상기 방법으로 세척한다. 이 세척 단계는 마이크로캅셀내에 잔존하는 잔류 메틸렌 클로라이드를 추출시키며 마이크로캅셀을 경화시킨다.
마지막 10ml의 물이 제거되는 동안 마이크로캅셀이 형성된다. 약 1분동안 마이크로캅셀 케이크로부터 물을 배출시킨 후 마이크로캅셀 케이크를 주걱을 사용하여 조그마한 조각으로 붕괴시킨다. 여과 깔때기에 흡입시키는 동안 마이크로캅셀을 깔대기내에서 30분동안 계속 교반시킨다.마이크로캅셀을 적당히 건조시킨 다음 즉시 낙타털 솔을 사용하여 250㎛ 스테인레이스강 체에 통과시킨다. 체질은 마이크로캅셀의 건조를 돕는다. 250㎛체를 통과한 마이크로캅셀을 더 적은 크기의 체에 통과시키거나 일야 방치하여 건조시킬 수 있다. 최종 생성물은 폴리(DL-락티드) 중의 20%의 프로게스테론을 함유하는 자유 유동성 구형입자로 구성되어 있다.
[실시예 2]
3g의 노르게스티메이트 및 3g의 폴리(락티드-공(CO)-글리콜리드를 1g이 메틸렌 클로라이드에 용해시킨다. 유기용액을 58g의 5중량%의 수용성 폴리(비닐알콜)에 마이크로소적으로 분산시킨다. 유제는 유기용액을 수지용기에 교반된 수용성 폴리(비닐알콜) 용액에 첨가시켜 수득할 수 있다. 유제의 교반은 공지된 장치(Teflon turbine impeller driven by a fisher steadi-speed moter)를 사용할 수 있다.
적절한 수중유 유제를 제조한 후, 유제의 압력을 계속 감압시켜 기포가 형성될 때까지 유지시킨다. 용매증발 단계는 40 내지 60%의 메틸렌 클로라이드가 제거될 때까지 계속한다. 마이크로캅셀 현탁액은 3분동안 27G에서 원심분리시킨다. 상층액을 경사분리시킨 다음 마이크로캅셀을 50 내지 100ml의 탈이온수로 재현탁 시킨후 미세(4 내지 5.5㎛) 프릿 유리 깔때기에 붓는다. 흡입시켜 마이크로캅셀을 천천히 여과시킨다. 여과시키는 동안 천천히 교반하면서 탈이온수를 계속 첨가하여 마이크로캅셀을 현탁액내에 유지시킨다. 약 2000ml의 탈이온수가 사용될 때까지 마이크로캅셀을 상기 방법으로 세척한다. 이 세척 단계는 마이크로캅셀내에 잔존하는 잔류 메틸렌 클로라이드를 추출시키며 마이크로캅셀을 경화시킨다.
마지막 10ml의 물이 제거되는 동안 마이크로캅셀이 형성된다. 약 1분동안 마이크로캅셀 케이크로부터 물을 배출시킨후 케이크를 주걱을 사용하여 조그만한 조각으로 붕괴시킨다. 여과 깔대기에 흡입시키는 동안 마이크로캅셀을 깔대기에서 30분동안 계속 교반시킨다. 마이크로캅셀을 적당히 건조시킨 다음 즉시 낙타털 솔을 사용하여 250㎛ 스테인레스강 체에 통과시킨다. 최종 생성물은 폴리(락티드-공-글리콜리드) 중의 50중량%의 노르게스티메이트를 함유하는 자유 유동성 구형입자로 구성되어 있다.
본 발명을 충분히 서술하였으므로, 본 명세서에 기술된 바와 같은 본 발명의 목적 및 범주를 벗어나지 않는 범위내에서 변화 및 변형시킬 수 있다는 것은 당해분야의 숙련가들에 명백할 것이다.
Claims (17)
- (a) 농약, 향료, 경화제, 염료, 산화제 및 생물학적 활성제제중에서 선택된 활성제제를 용매(이는 벽물질을 용해시킬 수 있고, 활성제제에 대해 화학적으로 불활성이며, 연속상처리 매질에 비혼화성이고, 연속상처리 매질보다 낮은 비점을 갖는 물질이다)에 용해시키거나 분산시킨 후, 폴리스티렌, 에틸셀룰로우즈, 셀룰로우즈 아세테이트, 하이드록시프로필 메틸 셀룰로우즈 프탈레이트, 디부틸아미노 하이드록시프로필 에테르, 폴리비닐 부티랄, 폴리비닐 포르말, 폴리(메트)아크릴산 에스테르, 폴리비닐 아세탈-디에틸아미노 아세테이트, 2-메틸-5-비닐 피리딘 메타크릴레이트-메타크릴산 공중합체, 폴리카보네이트, 폴리에스테르, 폴리프로필렌, 비닐클로라이드-비닐 아세테이트 공중합체, 폴리삭카라이드, 글리세롤 디스테아레이트 중에서 선택된 벽형성 물질을 상기 용액에 용해시키고 ; (b) 상기 활성제제 및 벽형성 물질을 함유하는 상기 용매를 물, 유기액체, 합성유 및 천연유중에서 선택된 연속상 처리매질(이는 용매에 비혼화성이며 용매보다 비점이 높은 액상매질이다)에 분산시키고 ; (c) 단계(b)의 분산액으로부터 용매의 일부를 증발시켜 현탁액내에 상기 활성제제를 함유하는 마이크로캅셀을 형성시키고, (d) 상기 마이크로캅셀로부터 잔류 용매를 추출시킴을 특징으로 하여, 활성제제가 충진된 마이크로캅셀을 제조하는 방법.
- 제 1 항에 있어서, 단계(c)에서 형성된 마이크로캅셀을 상기 연속상 처리매질로부터 분리시킨후 단계(d)에서 용매를 완전히 제거시키는 방법.
- 제 1 항에 있어서, 연속상 처리매질이 물, 크실렌, 톨루엔, 합성유 또는 천연유인 방법.
- 제 3 항에 있어서, 연속상 처리매질이 계면활성제를 추가로 함유하는 방법.
- 제 4 항에 있어서, 연속상 형성 매질이 1 내지 10%의 폴리비닐알콜을 함유하는 물인 방법.
- 제 1 항에 있어서, 단계(b)의 유체 생성물이 안정한 유중수 유제 또는 수중유 유제인 방법.
- 제 1 항에 있어서, 용매가 할로겐화된 지방족 화합물, 할로겐화된 방향족 탄화수소 화합물, 방향족 탄화수소 화합물, 사이클릭 에테르, 알콜, 물 및 아세톤으로 구성된 그룹중에서 선택된 물질인 방법.
- 제 7 항에 있어서, 용매가 메틸렌 클로라이드인 방법.
- 제 1 항에 있어서, 분산액상의 압력을 감소시켜 용매를 분산액으로부터 증발시키는 방법.
- 제 1 항에 있어서, 단계(c)에서 10 내지 90중량%의 용매를 마이크로캅셀로부터 증발시키는 방법.
- 제 1 항에 있어서, 단계(d)의 마이크로캅셀을 계면활성제를 함유하는 물로 세척한 후 진공 여과시켜 마이크로캅셀로부터 잔류 용매를 제거하는 방법.
- 제11항에 있어서, 세척한 마이크로캅셀을 진공하에 둔 다음 마이크로캅셀을 체에 통과시켜 건조시키는 방법.
- 제 1 항에 있어서, 폴리에스테르가 폴리락티드, 폴리글리콜리드 또는 폴리카프로락톤 또는 이들의 공중합체인 방법.
- 제 1 항에 있어서, 활성제제가 에스트로겐, 프로게스틴, 위장치료제, 비-스테로이드성 불임증 치료제, 부교감 신경자극 흥분제, 정신치료제, 신경안정제, 비(鼻) 충혈제거제, 진정-최면제, 비-에스트로겐 및 비-프로게스테이션 스테로이드, 설폰 아미드, 교감신경 흥분제, 왁찐, 비타민, 영양소, 항말라리아제 화합물, 편두통 치료제, 파킨슨씨병 치료제, 항경련제, 항콜린제, 진해제, 기관지 확장제, 심장혈관계 약제, 전해질 대체물, 에르고트 알칼로이드, 진통제, 비-마약, 항생제, 항암제, 항경련제, 진토재, 항히스타민제, 소염제, 프로스타글란딘, 항종양제, 항원 및 항체로 구성된 그룹중에서 선택된 생물학적 활성제제인 방법.
- 제 1 항에 있어서, 5 내지 30중량%의 활성제제를 용매에 용해시키거나 분산시키는 방법.
- 제 1 항에 있어서, 5 내지 35중량%의 벽형성 물질을 용매에 용해시키는 방법.
- 제 1 항에 있어서, 용매중의 벽형성 물질에 대한 활성제제의 중량비가 20중량%의 벽형성 물질에 대해 약 80중량% 이하의 활성제제인 방법.
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US06/194,127 US4389330A (en) | 1980-10-06 | 1980-10-06 | Microencapsulation process |
US194127 | 1980-10-06 | ||
US194,127 | 1980-10-06 |
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KR830007069A KR830007069A (ko) | 1983-10-14 |
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- 1981-10-05 KR KR1019810003746A patent/KR880001765B1/ko active
- 1981-10-05 NZ NZ198554A patent/NZ198554A/en unknown
- 1981-10-05 IT IT8124303A patent/IT1215625B/it active
- 1981-10-06 SE SE8105897A patent/SE453798B/sv not_active IP Right Cessation
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