FI76493B - Mikroinkapslingsfoerfarande. - Google Patents
Mikroinkapslingsfoerfarande. Download PDFInfo
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- FI76493B FI76493B FI813077A FI813077A FI76493B FI 76493 B FI76493 B FI 76493B FI 813077 A FI813077 A FI 813077A FI 813077 A FI813077 A FI 813077A FI 76493 B FI76493 B FI 76493B
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- microcapsules
- solvent
- active
- active substance
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- 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
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Description
1 76493
Mikrokapselointimenetelmä Tämä keksintö koskee mikrokapselien valmistusmenetelmää. Tarkemmin sanottuna tämä keksintö koskee biologisesti aktiivista ainetta sisältävien mikrokapselien valmistusmenetelmää.
Ennestään tunnetaan lukuisia menetelmiä, joilla haluttu tuote voidaan kapseloida mikrokapselien sisään. Menetelmissä kapseloitava materiaali tavallisesti dispergoidaan liuottimeen, joka sisältää seinänmuodostajamateriaalin. Liuotin poistetaan mikrokapseleista yhdessä prosessivaiheessa ja näin saadaan mikrokapselituote. Tavanomaisesta ennestään tunnetusta mikrokapselointimenetelmästä on esimerkkinä US-patentti 3 737 337, jossa tehdään seinänmuodostaja- tai kuorenmuodostajapolymeerin liuos liuottimeen. Liuotin liukenee veteen vain osittain. Kiinteä aine tai ydinaine liuotetaan tai dispergoidaan polymeeripitoiseen liuokseen ja sen jälkeen ydinainepitoinen liuos dispergoidaan yhdessä vaiheessa vesipitoiseen nesteeseen, joka ei sekoitu orgaaniseen liuottimeen, koska tällöin liuotin saadaan poistetuksi mikrokapseleista. Vielä toisesta menetelmästä, jossa liuotin poistetaan yhdessä vaiheessa aktiivista ainetta sisältävistä mikrokapseleista, on esimerkkinä US-patentti 3 523 906. Tässä menetelmässä kapseloitava materiaali emulgoidaan liuokseen, joka sisältää polymeerin liuottimessa, joka on veteen-sekoittumatonta, ja sen jälkeen emulsio emulgoidaan vesi-liuokseen, joka sisältää hydrofiilisen kolloidin. Sitten liuotin poistetaan mikrokapseleista yhdellä haihdutuksella ja näin saadaan tuote. Vielä eräässä menetelmässä, joka on esitetty US-patentissa 3 691 090 orgaaninen liuotin haihdutetaan yhdessä vaiheessa vesipitoiseen väliaineeseen tehdystä mikrokapselidispersiosta mielellään alipaineessa. Vastaavasti selostetaan US-patentissa 3 891 570 menetelmää, jossa mikrokapselien polyhydriseen alkoholivällaineeseen tehdystä dispersiosta haihdutetaan liuotin mikrokapseleista lämmön 2 76493 avulla tai kohdistamalla mikrokapeeleihin alipaine. Vielä eräs yksivaiheinen liuottimenpoistomenetelmä on kuvattu US-patentissa 3 960 757.
Tavanomaisissa kapselointimenetelmissä, varsinkin haluttaessa mikrokapseloida Jokin farmaseuttinen aine, kuten progesteroni tai norgestimaatti, lääkkeiden lisäys muodostaa rajoittavana tekijänä ongelman. Riippuen laimentimen ja kapseloitavan aineen fysikaalisista ja kemiallisista ominaisuuksista johtaa kapseloitavan aineen liian suuri pitoisuus epätäydelliseen kapseloitumiseen eli kiteet tunkeutuvat ulos kapseleista tai niiden pitoisuus väliaineessa lisääntyy. Näin ollen on jatkuvasti olemassa tarve löytää sellainen mikrohiukkasten valmistusmenetelmä, jolla saavutetaan paremmat ominaisuudet ja korkeampi laatu.
Näin ollen tämän keksinnön yhtenä tarkoituksena on tarjota menetelmä, jolla voidaan valmistaa mikrokapseleita, joiden sisältämät materiaalimäärät ja laatu ovat entistä paremmat.
Lyhyesti sanottuna tämä ja muut tämän keksinnön tarkoitukset, jotka ilmenevät tarkemmin jäljempänä olevasta selostuksesta, saavutetaan valmistamalla aktiivista ainetta sisältävät mik-rokapsslit siten, että <a) vaikuttava aine liuotetaan tai dispergoidaan liuottimeen ja kuorenmuodostaja-aine liuotetaan tähän liuottimeen, (b> liuotin, joka sisältää aktiivisen aineen ja kuorenmuodostaja-aineen, dispergoidaan jatkuvafaasi-seen prosessointiväliaineeseen, <c) 10-90 paino-% liuottimes-ta haihdutetaan pois dispersiosta ja näin muodostuu aktiivista ainetta sisältävien mikrokapeelien suspensio, ja <d) loput liuottimesta uutetaan mikrokapeeleista.
Tämän keksinnön mukaisessa menetelmässä, jolla voidaan valmistaa ominaisuuksiltaan entistä parempia mikrokapseleita, on keskeisenä piirteenä ee, että valmistuksen aikana neste- 3 76493 mäiseen väliaineeseen suspendoituneista mikrokapseleista poistetaan liuotin kahdessa erillisessä vaiheessa eikä ainoastaan yhdessä prosessivaiheessa. Kaksivaiheinen poisto-tekniikka johtaa parempilaatuiseen mikrokapselituotteeseen, jonka sisältämä aktiivisen aineen pitoisuus on entistä korkeampi. Tämän keksinnön mukaisen menetelmän etu tavanomaisiin menetelmiin verrattuna on se, että kaksivaiheisella liuottimenpoistotekniikalla saadaan mikrokapselituote, jolla on odottamattoman suuri aktiivisen aineen pitoisuus ja yllättävän hyvä laatu verrattuna tavanomaisiin mikrokapse-leihin, jotka on valmistettu poistamalla liuotin ainoastaan yhdessä vaiheessa.
Mikrokapseleihin sisällytettävä aine liuotetaan liuottimeen. Sopivia aktiivisia aineita, jotka voidaan sisällyttää tässä tarkoitettuihin mikrokapseleihin ovat mm. maatalouskemikaalit, parfyymit, vulkanoimisaineet, väriaineet, hapetus-aineet ja biologisesti aktiiviset aineet. Liuottimeen liuotetun tai dispergoidun aktiivisen aineen määrä ei sinänsä ole kriittinen tekijä, mutta aktiivisen aineen määrän suhde kuorenmuodostaja-aineen määrään on tärkeä sikäli, että mik-rokapseleita ei muodostu, jos aktiivisen aineen määrän suhde kuorenmuodostaja-aineen määrään on liian suuri. Käytännössä voi aktiivisen aineen ja kuorenmuodostaja-aineen määrien yhdistelmä olla sellainen, että se sisältää korkeintaan 80 paino-osaa aktiivista ainetta ja 20 paino-osaa kuorenmuo-dostaja-ainetta. Kuorenmuodostaja-aineen kanssa yhdistettävällä aktiivisen aineen määrällä ei ole alarajaa, mutta hyvin pienen määrän aktiivista ainetta sisältävät mikrokapse-lit eivät ole käyttökelpoisia. On kuitenkin selvää, että liuoksen ollessa laimeata on läsnä suuri määrä liuotinta, joka sitten pitää poistaa, jotta saataisiin mikrokapselituote, joka sisältää tietyn määrän aktiivista ainetta. Liuottimeen liuotetaan tai suspendoidaan tavallisesti 5-30 paino-% aktiivista ainetta.
Liuotin, johon aktiivinen aine liuotetaan, voidaan valita 4 76493 useista tavallisista orgaanisista liuottimista, joita ovat mm. halogenoidut hiilivedyt kuten kloroformi, metyleeniklo-ridi, metyylikloroformi tms., aromaattiset hiilivedyt, halogenoidut aromaattiset hiilivedyt, sykliset eetterit kuten tetrahydrofuraani tms., alkoholit, vesi, asetoni tms. Liuotin pitää valita niin, että se liuottaa kuorenmuodostaja-aineen, se on kemiallisesti inertti aktiivisen aineen suhteen, se ei sekoitu jatkuvafaasiseen prosessointiväliainee-seen ja sen kiehumispisteen pitäisi olla alempana kuin jat-kuvafaasisen prosessointiväliaineen kiehumispiste. Liuotti-meen liuotettavan kuorenmuodostaja-aineen määrä riippuu polymeerin liukenevuudesta liuottimeen ja saadun polymeeri-liuoksen viskositeetista. Viskositeetti on suhteessa mikro-kapselien lopulliseen kokoon. Edellä mainittujen liuottimien seoksia voidaan myös käyttää aktiivisen aineen liuottimina. On edullista käyttää matalalla kiehuvia liuottimia, sillä ne on helpompi aikanaan poistaa yksinkertaisilla haihdutusmenetelmillä.
Aktiivista ainetta sisältävään liuokseen lisätään kuoren-muodostaja-aine, joka ympäröi ja sulkee aktiivisen aineen mikrokapseleihin. Liuokseen lisätään sellainen määrä kuo-renmuodostaja-ainetta, että mikrokapselit muodostuvat helposti, kun liuos dispergoidaan jatkuvafaasiseen prosessoin-tiväliaineeseen. Sekä aktiivisen aineen että kuorenmuodostaja-aineen pitäisi olla liuenneessa muodossa, ennenkuin liuotin dispergoidaan jatkuvafaasiseen prosessointiväliai-neeseen.
Sopivia kuorenmuodostaja-aineita ovat mm. polystyreeni, etyyliselluloosa, selluloosa-asetaatti, hydroksipropyyli-metyyliselluloosaftalaatti, selluloosa-asetaatti, dibutyyli-aminohydroksipropyylieetteri, polyvinyylibutyraali, polyvi-nyyliformaali, poly(met)akryylihapon esteri, polyvinyyliase-taatti-dietyyliaminoasetaatti, 2-metyyli-5-vinyylipyri-diinimetakrylaatti-metakryylihapon sekapolymeeri, polykar-bonaatti, polyesterit, polypropyleeni, vinyylikloridi-vi-nyyliasetaattisekapolymeeri, polysakkaridit, glyserolidi- 5 76493 stearaatti tms. Etusijalle asetettavia polymeerisiä kuo-renmuodostaja-aineita ovat sellaiset, jotka hajoavat biologisesti, kuten alifaattiset polyesterit, mm. polylakti-di, polyglykolidi, polykaprolaktoni ja näiden sekapolymee-rit.
Aktiivisen aineen ja kuorenmuodostaja-aineen sisältävän liuotinfaasin valmistuksen jälkeen muodostetaan mikropisa-roita kuorenmuodostaja-aineesta, joka sisältää aktiivisen aineen, dispergoimalla jatkuvafaasiseen prosessointiväli-aineeseen liuos, joka sisältää aktiivisen aineen ja kuorenmuodostaja-aineen. Jatkuvafaasisen prosessointiväliaineen pitää olla sellaista, ettei liuotin sekoitu siihen, ja sillä pitää olla korkeampi kiehumispiste kuin liuottimena. Prosessointiväliaine on usein vesi, mutta sopivia muita jat-kuvafaasisia prosessointiliuottimia ovat mm. orgaaniset nesteet, kuten ksyleeni tai tolueeni, synteettiset öljyt, kuten silikoniöljy, ja luonnonöljyt, kuten kasviöljyt, mm. maapähkinäöljy. Jatkuvafaasiseen prosessointiväliaineeseen lisätään tavallisesti pinta-aktiivista ainetta (emulgointi-ainetta) estämään mikrokapselien agglomeroitumista ja säätelemään emulsion sisältämien mikropisaroiden kokoa. Kun jatkuvafaasisena prosessointiaineena käytetään vettä, on poly(vinyylialkoholi) (PVA) hyvä pinta-aktiivinen aine, kun sitä käytetään väkevyytenä 1-10 %. Dispersio voidaan saada aikaan sekoittamalla jatkuvafaasista prosessointiväliainet-ta mekaanisesti esim. kolloidimyllyssä, homogenisaattorissa tms. Emulsio voidaan aikaansaada myös lisäämällä jatkuvafaasiseen prosessointiväliaineeseen pieninä pisaroina liuosta, joka sisältää aktiivista ainetta ja kuorenmuodostaja-ainetta. Edullisessa dispergointivaiheen toteutustavassa orgaaninen liuos dispergoidaan vesiliuokseen, joka sisältää polyvinyylialkoholia. Emulgointilämpötila ei ole varsin kriittinen, mutta se voi vaikuttaa mikrokapselien kokoon ja laatuun. Riippuen liuottimesta ja käytetystä jatkuvafaa-sisesta prosessointiväliaineesta ei lämpötila saa olla matala, jotteivät liuotin ja prosessointiväliaine kiinteydy tai 6 76493 prosessointiväliaine tule liian viskoosiksi käytännön tarkoituksia ajatellen# eikä se saa olla liian korkea, jottei prosessointiväliaine haihdu tai nestemäinen olomuoto muutu. Eikä väliaineen lämpötila saa olla liian korkea mikrokapse-leihin sisällytettävän aktiivisen aineen vahingoittumisen vuoksi. Niinpä dispergointi voidaan suorittaa missä tahansa lämpötilassa, jossa operaatio-olosuhteet pysyvät stabiileina.
Muodostunut dispersio on stabiili emulsio, ja ensimmäisessä liuottimenpoistovaiheessa poistetaan orgaaninen liuotin dispersion mikropisaroista, jotka ovat orgaaniseen liuotti-meen sekoittumattomassa nesteessä. Liuotin voidaan helposti poistaa tavallisilla menetelmillä, kuten kuumentamalla, käyttämällä alipainetta tai näiden yhdistelmää. Lämpötila, jota käytetään liuottimen haihduttamisessa mikropisaroista, ei ole kriittinen, mutta sen ei pitäisi olla niin korkea, että mikrokapselien sisältämä mahdollinen lämpöherkkä materiaali vahingoittuu, eikä sen myöskään pitäisi olla niin korkea, että nopeasti haihtuva liuotin vahingoittaa kuorenmuodostaja-materiaalia. Ensimmäisessä liuottimenpoistovaiheessa poistetaan yleensä 10-90 %, mielellään 40-60 % liuottimesta.
Ensimmäisen liuottimenpoistovaiheen jälkeen liuottimeen sekoittumattomaan nesteeseen dispergoituneet mikrokapselit erotetaan nesteestä jollakin tavallisella erotusmenetelmällä. Neste voidaan esim. dekantoida mikrokapseleista tai mikro-kapseli-nestesuspensio voidaan suodattaa. Myös muita erotusmenetelmiä tai niiden yhdistelmiä voidaan käyttää.
Sen jälkeen kun mikrokapselit on poistettu jatkuvafaasises-ta prosessointiväliaineesta, loput mikrokapselien sisältämästä liuottimesta uutetaan pois. Tässä toisessa vaiheessa mikrokapselit voidaan suspendoida ensimmäisessä vaiheessa käytettyyn jatkuvafaasiseen prosessointiväliaineeseen, joka haluttaessa voi sisältää pinta-aktiivista ainetta, tai 7 76493 johonkin muuhun nesteeseen. Uuttoaine uuttaa liuottimen mikrokapseleista, mutta ei liuota mikrokapseleita. Uuton aikana pitää uuttoaine ja siihen liuennut liuotin poistaa ja korvata tuoreella uuttoaineella. Tämä on parasta tehdä jatkuvatoimisesti, jolloin uuttoaineen korvaus on kriittinen tekijä. Jos nopeus on liian pieni, aktiivisen aineen kiteet tunkeutuvat ulos mikrokapseleista tai kasvavat uut-toaineessa. On selvää, että uuttoaineen korvausnopeus vaih-telee prosessista riippuen ja se voidaan määrittää toteutuksen yhteydessä, joten mitään tarkkoja nopeusarvoja ei tässä yhteydessä voida antaa. Kun loput liuottimesta on poistettu mikrokapseleista, ne kuivataan esim. ilmakuivauk-sella tai muilla tavallisilla menetelmillä, kuten vakuumi-kuivauksella tai kuivausaineella.
Tämän keksinnön mukainen mikrokapselituote muodostuu taval-lisesesti pallomaisista hiukkasista, mutta joskus voivat mikrokapselit olla muodoltaan epäsäännöllisiä. Mikrokapse-lien halkaisija voi vaihdella submikronista millimetriin. Submikronin ja 250 ^um välillä olevat halkaisijat ovat edullisia farmaseuttisissa valmisteissa, sillä tällöin mikrokapselit voidaan antaa tavallisilla ruiskuilla tai neuloilla. Mikrokapseleita voidaan käyttää mitä erilaisimpiin tarkoituksiin niihin sisällytetyn aineen laadusta riippuen. Nyt kyseessä olevat mikrokapselit ovat erityisen käyttökelpoisia haluttaessa antaa ihmisille tai eläimille erilaisia biologisesti aktiivisia aineita. Esimerkiksi, jos nämä mikrokapselit sisältävät ehkäisyainetta, ne voidaan antaa ruiskeina tai kohdunkaulan kautta suvunjatkamiseli-miin syntyvyydensäännöstelytarkoituksessa. Sopivia ehkäisy-aineita ovat mm. estrogeenit kuten dietyylistilbestroli, 17-beta-estradioli, estroni, etinyyliestradioli, mestra-noli tms.; progestiinit kuten noretindroni, norgestryyli, etynodiolidiasetaatti, lynestrenoli, medroksiprogesteroni-asetaatti, dimetisteroni, megestroliasetaatti, kloorimadi-noniasetaatti, norgestimaatti, noretisteroni, etisteroni, melengestroli, noretynodrel tms. ja spermisidiset yhdisteet 8 76493 kuten nonyylifenoksipolyoksietyleeniglykoli, bentsetonium-kloridi/ klorindanoli tms. Muita biologisesti aktiivisia aineita, jotka voidaan sisällyttää nyt kyseessä oleviin mikrokapseleihin ovat mm. ruuansulatuskanavaan kohdistuvat hoitoaineet kuten alumiinihydroksidi, kalsiumkarbonaatti, magnesiumkarbonaatti, natriumkarbonaatti tms; ei-steroidi-set ehkäisyaineet; parasympatomimeettiset aineet; psykoterapeuttiset aineet; voimakkaat rauhoittavat aineet kuten kloropromatsiini HC1, klotsapiini, mesoridatsiini, metia-piini, reserpiini, tioridatsiini tms.; lievemmät rauhoittavat aineet kuten klooridiatsepalenidi, diatsepaami, meproba-maatti, tematsepaami tms; nenän verekkyyttä vähentävät aineet; sedatiivis-hypnoottiset aineet kuten kodeiini, fe-nobarbitaali, natriumpentobarbitaali, natriumsekobarbitaali tms.; muut steroidit kuten testosteroni ja testosteronipro-pionaatti; sulfonamidit; sympatomimeettiset aineet; rokotteet; vitamiinit ja ravintoaineet kuten välttämättömät aminohapot, välttämättömät rasvat tms.; malariaa hillitsevät aineet kuten 4-aminokinoliinit, 8-aminokinoliinit, pyrimeta-miini tms.; migreeniä hillitsevät aineet kuten matsindoli, fentermiini tms.; Parkinsonin tautia hillitsevät aineet kuten L-dopa; kouristuksia hillitsevät aineet kuten atropii-ni, metskopolamiinibromidi tms.; antispasmodit ja antikolin-ergit kuten sapenhoitoaineet, ruuansulatusaineet, entsyymit tms.; yskää hillitsevät aineet kuten dekstrometrofaani, noskapiini tms; keuhkoputkenlaajennusaineet; sydänverisuonia laajentavat aineet kuten verenpaineenalennusaineet, Rauwolfia-alkaloidit, sepelvaltimoiden laajennusaineet, nitroglyseriini, orgaaniset nitraatit, pentaerytritotetra-nitraatti tms.; korvaavat elektrolyytit kuten natriumklori-di; ergotalkaloidit kuten ergotamiini kofeiinin kanssa tai ilman sitä, hydratut ergotalkaloidit, dihydroergokristiini-metaanisulfaatti, dihydroergokorniinimetaanisulfaatti, dihydroergokroyptiini-metaanlsulfaatti. ja näiden yhdistelmät; alkaloidit kuten atropiinisulfaatti, belladonna, hyoskiinihydrobromidi tms.; kivunpoistoaineet; narkoottiset aineet kuten kodeiini, dihydrodienoni, meperidiini, mor 9 76493 fiini tms.; ei-narkoottiset aineet kuten salisylaatit, aspiriini/ asetminöfen, d-propoksifeeni tms.; antibiootit kuten kefalosporiinit/ kloramfenikoli, gentamisiini, kana-mysiini A, kanamysiini B, penisilliinit, ampisilliini, streptomysiini A, antimysiini A, klooripamtenioli, metromidat-soli, oksitetrasykliini, penisilliini G, tetrasykliinit tms.; syöpälääkkeet, antikonvulsantit kuten mefenytoiini, fenobarbitaali, trimetadioni; oksentamista hillitsevät aineet kuten tietyylipiperatsiini; antihistamiinit kuten kloorifinatsiini, dimenhydrinaatti, difenhydramiini, per-fenatsiini, tripelennamiini tms.; tulehduksia hillitsevät aineet kuten hormonaaliset aineet, hydrokortisoni, pred-nisoloni, prednisoni, ei-hormonaaliset aineet, allopurino-li, aspiriini, indömetasiini, fenyylibutetsoni tms.; prosta-glandiinit; sytotoksiäet lääkkeet kuten tiotepa, kloram-busiili, syklofosfamidi, melfalaani, typpisinappi, meto-treksaatti tms.; ja sellaisten mikro-organismien antigeenit kuin Neisseria gonorrhea, Mycobacterium tuberculosisis, Herpes virus (humonis, tyypit 1 ja 2), Candida albicans, Candida tropicalis, Trichomonas vaginalis, Haemophilus vaginalis, Group B streptococcus ecoli, Microplasma homi-nis, Hemophilus ducreyi, Granuloma inguinale, Lymphopathia venereum, Treponema pallidum, Brucella abortus, Brucella melitensis, Brucella suis, Brucella canis, Campylobacter fetus, Campylobacter fetus intestinalis, Leptospira pomona, Listeria monocytogenes, Brucella ovis, Equine herpes virus 1, Equine arteritis virus, IBR-IBP virus, BVD-MB virus, Chlamydia psittaci, Trichomonas foetus. Toxoplasma gondii, Escherichia coli, Actinobacillus equuli, Salmonella abortus ovis, Salmonella abortus equi, Pseudomonas aeruginosa, Corynebacterium equi, Corynebacterium pyogenes, Actinobacillus seminis, Mycoplasma bovigenitalium, Aspergillus fumigatus, Absidia ramosa, Trypanosoma equiperdum, Babesia caballi, Clostridium tetani tms.; edellä mainittujen mikro-organismien vasta-aineet ja entsyymit kuten ribonuk-leaasi, neuramidaasi, trypsiind, glykogeenifosforylaasi, 10 76493 sperman laktinen dehydrogenaasi, sperman hyaluronidaasi, adenosiinitrifosfataasi, alkalinen fosfataasi, aikaiinen fosfataasiesteraasi, aminopeptidaasi, trypsiini, kymotryp-siini, amylaasi, muramidaasi, akrosomaaliproteinaasi, diesteraasi, glutamiinihapon dehydrogenaasi, raeripihkaha-pon dehydrogenaasi, beta-glykofosfataasi, lipaasi, ATP-aasi, alfa-peptaatti-gamma-glutamoyylitranspeptidaasi, steroli-3-beta-olidehydrogenaasi, DPN-di-aproaasi.
Edellä olevan keksinnön yleiskuvauksen jälkeen selostetaan seuraavien esimerkkien avulla keksinnön mukaisen menetelmän toteutustapoja yksityiskohtaisemmin, mutta tarkoitus ei ole rajoittaa keksintöä, ellei näin erityisesti mainita.
Esimerkki 1 2,5 g progesteronia ja 10 g poly(DL-laktidia) liuotettiin 38 g:aan metyleenikloridia. Orgaaninen liuos dispergoitiin mikropisaroina 120 g:aan poly(vinyylialkoholin) 5 %:sta vesiliuosta. Dispersio valmistettiin lisäämällä orgaaninen liuos 200 ml:n hartsikattilassa olevaan polyvinyylialkoho-lin vesiliuokseen. Emulsion sekoituksessa käytettiin Fisher Stedi-Speed-moottorilla varustettua teflonista turbiinisi ipira tästä.
Kun oli saatu aikaan stabiili Ö1jy-vedessä-anulsio , emulsion yllä oleva, paipetta laskettiin tasaisesti ja lopuksi se jätettiin tasolle, jossa se oli juuri vaahtoamispisteen yläpuolella. Liuottimen haihdutusta jatkettiin, kunnes 40-60 % metyleenikloridista oli poistunut. Mikrokapselisuspensiota sentrifugoitiin nopeudella 41G 10 minuutin ajan. Emäliuos dekantoitiin pois ja mikrokapselit suspendoitiin uudestaan 50-100 mitään tislattua vettä ja puolet tästä suspensiosta kaadettiin hienolla huokoslasisuodattimella (4-5,5 ^um) varustettuun lasisuppiloon. Imu kytkettiin päälle ja mikro-kapselit suodatettiin hitaasti. Suodatuksen aikana mikro-kapselit pidettiin suspensiossa sekoittamalla niitä hitaasti ja lisäämällä tislattua vettä jatkuvasti. Mikrokapse- 11 76493 leita pestiin tällä tavalla, kunnes 400-500 ml tislattua vettä oli käytetty. Tällä pesuvaiheella saatiin uutetuksi jäljelle jäänyt metyleenikloridi mikrokapseleista ja samalla mikrokapselit kovettuivat.
Mikrokapselien annettiin painua pohjaan samalla, kun viimeinen 10 ml:n vesimäärä poistettiin. Kun vettä oli valunut pois mikrokapselikakusta noin 1 minuutin ajan, kakku rikottiin spaattelilla pienemmiksi osiksi. Suodatussuppi-lossa pidettiin imu päällä samalla, kun mikrokapseleita sekoitettiin jatkuvasti suppilossa vielä 30 min. Nyt mikro-kapselit olivat riittävän kuivia niin että ne voitiin heti seuloa 250 ^um ruostumattoman terässeulan läpi käyttämällä apuna kamelinkarvaharjaa. Seulominen edisti mikrokapselien kuivumista. 250 ^um seulonnan jälkeen mikrokapselit voitiin helposti seuloa pienempireikäisten seulojen läpi tai ne voitiin jättää yön ajaksi kuivumaan. Lopputuote muodostui vapaasti valuvista pallomaisista hiukkasista, jotka sisälsivät 20 paino-% progesteronia poly(DL-laktidissa).
Esimerkki 2 3 g norgestimaattia ja 3 g poly(laktidikoglykolidia) liuotettiin 18 g:aan metyleenikloridia. Orgaaninen liuos dis-pergoitiin mikropisaroina 58 g saan polyvinyylialkoholin 5 %:sta vesiliuosta. Emulsio valmistettiin lisäämällä orgaaninen liuos hartsikattilassa olevaan polyvinyylialkoholin vesiliuokseen. Emulsion sekoituksessa käytettiin Fisher Stedi-Speed-moottorilla varustettua teflonista tur-biinisiipiratasta.
Kun oli saatu stabiili öljy-vedessä-emulsio, emulsion yllä olevaa painetta laskettiin tasaisesti ja lopuksi se jätettiin tasolle, jossa se oli juuri vaahtoamispisteen yläpuolella. Liuottimen haihdutusta jatkettiin, kunnes 40-60 % metyleenikloridista oli haihtunut. Mikrokapselisuspensiota sentrifugoitiin nopeudella 27G 3 min. Sitten emäliuos dekan-toitiin pois ja mikrokapselit suspendoitiin 50-100 ml:aan !2 76493 tislattua vettä ja suspensio kaadettiin hienolla huokos-lasisuodattimella (4-5,5 ^um) varustetun lasisuppilon läpi. Imu kytkettiin päälle ja mikrokapselit suodatettiin hitaasti. Suodatuksen aikana mikrokapselit pidettiin suspensiossa sekoittamalla niitä hitaasti ja lisäämällä tislattua vettä jatkuvasti. Mikrokapseleita pestiin tällä tavalla, kunnes 2000 ml tislattua vettä oli käytetty. Tällä pesuvaiheella saatiin uutetuksi jäljelle jäänyt metyleeni-kloridi mikrokapseleista ja samalla mikrokapselit kovettuivat.
Mikrokapselien annettiin painua pohjaan samalla, kun viimeinen 10 ml:n vesimäärä poistettiin. Kun vesi oli valunut pois mikrokapseleista noin 1 minuutin ajan, kakku rikottiin spaattelilla pienemmiksi osiksi. Suodatussuppilossa pidettiin imu päällä samalla, kun mikrokapseleita sekoitettiin jatkuvasti suppilossa vielä 30 min. Nyt mikrokapselit olivat riittävän kuivia niin että ne voitiin heti seuloa ruostumattoman terässeulan läpi käyttämällä apuna kamelin-karvaharjaa. Lopputuote muodostui vapaasti valuvista pallomaisista hiukkasista, jotka sisälsivät 50 paino-% norges-timaattia poly(laktidikoglykolidissä).
Tämä keksintö on näin tullut täysin selostetuksi, mutta on selvää, että alaan perehtyneet pystyvät löytämään useita muunnoksia silti poikkeamatta tämän keksinnön hengestä tai sen kattamasta alasta.
Claims (12)
13 76493 Pat«nttlvaatimuln«t
1. Menetelmä aktiivista ainetta sisältävien mikrokapse-lien valmistamiseksi, jossa menetelmässä <a> liuotetaan tai dispergoidaan aktiivinen aine liuotti- meen ja kuorenmuodostaja-aine liuotetaan tähän liuottimeen; <b> liuotin, joka sisältää aktiivisen aineen ja kuoren- muodostaja-aineen dispergoidaan jatkuvafaasiseen prosessointi väliaineeseen, tunnettu siitä, että (c) 10-90 paino-% liuottimesta haihdutetaan pois dispersiosta, jolloin muodostuu aktiivista ainetta sisältävien mik-rokapselien suspensio; ja (d) loput liuottimesta uutetaan mikrokapseleista.
2. Patenttivaatimuksen 1 mukainen menetelmä, tunnettu siitä, että vaiheessa Cc) muodostuneet mikrokapselit erotetaan jatkuvafaasisesta prosessointiväliaineesta ennenkuin liuotin poistetaan täydellisesti vaiheessa Cd).
3. Patenttivaatimuksen 1 mukainen menetelmä, tunnettu siitä, että jatkuvafaasisena prosessointivällaineena käytetään vettä ja mahdollisesti pinta-aktiivista ainetta.
4. Patenttivaatimuksen 1 mukainen menetelmä, tunnettu siitä, että jatkuvafaasinen prosessointiväliaine on vesi, joka sisältää 1-10 X polyvinyylialkoholia.
5. Patenttivaatimuksen 1 mukainen menetelmä, tunnettu siitä, että vaiheen (b> dispergointi tuottaa stabiilin vesi-öljyssä-emulsion tai öljy-vedessä-emulsion.
6. Patenttivaatimuksen 1 mukainen menetelmä, tunnettu siitä, että liuotin on metyleenikloridi. 1« 76493
7. Patenttivaatimuksen 1 mukainen menetelmä, tunnettu siitä, että liuotin haihdutetaan dispersiosta alentamalla dispersion yllä olevaa painetta. Θ. Patenttivaatimuksen 1 mukainen menetelmä, tunnettu siitä, että loput liuottimesta poistetaan mikrokapseleista vaiheessa <d> pesemällä mikrokapselit pinta-aktiivista ainetta sisältävällä vedellä vakuumisuodattamalla.
9. Patenttivaatimuksen 8 mukainen menetelmä, tunnettu siitä, että mikrokapselit kuivataan kohdistamalla niihin vakuutti ja sen jälkeen seulomalla ne.
10. Patenttivaatimuksen 1 mukainen menetelmä, tunnettu siitä, että 5-30 paino-X aktiivista ainetta liuotetaan tai dispergoidaan liuottimeen.
11. Patenttivaatimuksen 1 mukainen menetelmä, tunnettu siitä, että 5-35 paino-X kuorenmuodostaja-ainetta liuotetaan liuottimeen.
12. Patenttivaatimuksen 1 mukainen menetelmä, tunnettu siitä, että aktiivisen aineen ja kuorenmuodostaja-aineen välinen painosuhde liuottimessa on noin 80 paino-X aktiivista ainetta : 20 paino-X kuorenmuodostaja-ainetta.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US19412780 | 1980-10-06 | ||
| US06/194,127 US4389330A (en) | 1980-10-06 | 1980-10-06 | Microencapsulation process |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI813077L FI813077L (fi) | 1982-04-07 |
| FI76493B true FI76493B (fi) | 1988-07-29 |
| FI76493C FI76493C (fi) | 1988-11-10 |
Family
ID=22716397
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI813077A FI76493C (fi) | 1980-10-06 | 1981-10-05 | Mikroinkapslingsfoerfarande. |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US4389330A (fi) |
| JP (1) | JPS5793912A (fi) |
| KR (1) | KR880001765B1 (fi) |
| AT (1) | AT384557B (fi) |
| AU (1) | AU543059B2 (fi) |
| BE (1) | BE890638A (fi) |
| CA (1) | CA1142810A (fi) |
| CH (1) | CH648494A5 (fi) |
| DE (1) | DE3136606C2 (fi) |
| DK (1) | DK156374C (fi) |
| ES (1) | ES505709A0 (fi) |
| FI (1) | FI76493C (fi) |
| FR (1) | FR2491351A1 (fi) |
| GB (1) | GB2088314B (fi) |
| HU (1) | HU184884B (fi) |
| IE (1) | IE51822B1 (fi) |
| IL (1) | IL63814A (fi) |
| IT (1) | IT1215625B (fi) |
| NL (1) | NL8104507A (fi) |
| NO (1) | NO152964C (fi) |
| NZ (1) | NZ198554A (fi) |
| SE (1) | SE453798B (fi) |
| YU (1) | YU43774B (fi) |
| ZA (1) | ZA815441B (fi) |
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| IT631615A (fi) * | 1960-02-26 | |||
| US3576758A (en) * | 1966-10-17 | 1971-04-27 | Ncr Co | Treatment of polypeptide-containing hydrophilic polymeric capsule wall material with uranium and vanadium compounds |
| US3657144A (en) * | 1967-06-05 | 1972-04-18 | Ncr Co | Encapsulation process |
| US3732172A (en) * | 1968-02-28 | 1973-05-08 | Ncr Co | Process for making minute capsules and prefabricated system useful therein |
| BE744162A (fr) * | 1969-01-16 | 1970-06-15 | Fuji Photo Film Co Ltd | Procede d'encapsulage |
| US3773919A (en) * | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
| DE2010116A1 (de) * | 1970-03-04 | 1971-09-16 | Farbenfabriken Bayer Ag, 5090 Leverkusen | Verfahren zur Herstellung von Mikrogranulaten |
| GB1413186A (en) * | 1973-06-27 | 1975-11-12 | Toyo Jozo Kk | Process for encapsulation of medicaments |
| US4205060A (en) * | 1978-12-20 | 1980-05-27 | Pennwalt Corporation | Microcapsules containing medicament-polymer salt having a water-insoluble polymer sheath, their production and their use |
-
1980
- 1980-10-06 US US06/194,127 patent/US4389330A/en not_active Expired - Lifetime
-
1981
- 1981-08-07 ZA ZA815441A patent/ZA815441B/xx unknown
- 1981-08-25 DK DK376381A patent/DK156374C/da active
- 1981-09-02 NO NO812977A patent/NO152964C/no unknown
- 1981-09-13 IL IL63814A patent/IL63814A/xx not_active IP Right Cessation
- 1981-09-14 YU YU2207/81A patent/YU43774B/xx unknown
- 1981-09-15 DE DE3136606A patent/DE3136606C2/de not_active Expired - Fee Related
- 1981-09-16 AT AT0399481A patent/AT384557B/de not_active IP Right Cessation
- 1981-09-17 CA CA000386136A patent/CA1142810A/en not_active Expired
- 1981-09-18 HU HU812707A patent/HU184884B/hu not_active IP Right Cessation
- 1981-09-23 ES ES505709A patent/ES505709A0/es active Granted
- 1981-09-24 FR FR8118058A patent/FR2491351A1/fr active Granted
- 1981-10-01 AU AU75942/81A patent/AU543059B2/en not_active Ceased
- 1981-10-01 GB GB8129694A patent/GB2088314B/en not_active Expired
- 1981-10-03 NL NL8104507A patent/NL8104507A/nl unknown
- 1981-10-05 NZ NZ198554A patent/NZ198554A/en unknown
- 1981-10-05 IE IE2327/81A patent/IE51822B1/en not_active IP Right Cessation
- 1981-10-05 BE BE0/206176A patent/BE890638A/fr not_active IP Right Cessation
- 1981-10-05 KR KR1019810003746A patent/KR880001765B1/ko active
- 1981-10-05 IT IT8124303A patent/IT1215625B/it active
- 1981-10-05 JP JP56158593A patent/JPS5793912A/ja active Granted
- 1981-10-05 FI FI813077A patent/FI76493C/fi not_active IP Right Cessation
- 1981-10-05 CH CH6384/81A patent/CH648494A5/de not_active IP Right Cessation
- 1981-10-06 SE SE8105897A patent/SE453798B/sv not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM | Patent lapsed | ||
| MM | Patent lapsed |
Owner name: STOLLE RESEARCH & DEVELOPMENT CORP. |