CN101193624A - 通过短期加热和快速干燥制备基于不良水溶性的活性物质的固溶体 - Google Patents
通过短期加热和快速干燥制备基于不良水溶性的活性物质的固溶体 Download PDFInfo
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- CN101193624A CN101193624A CNA2006800205768A CN200680020576A CN101193624A CN 101193624 A CN101193624 A CN 101193624A CN A2006800205768 A CNA2006800205768 A CN A2006800205768A CN 200680020576 A CN200680020576 A CN 200680020576A CN 101193624 A CN101193624 A CN 101193624A
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Abstract
本发明涉及一种由不良溶解性物质制备以分子级别分散于助剂基质中的粉末或颗粒化固溶体的方法,该方法在于:雾化含有不良溶解性活性物质和和基质助剂的溶液,在基质助剂存在下将不良溶解性物质的水悬浮体加热至高于其在常压下的沸点的温度,使不良溶解性的活性物质转化成溶液,通过雾化和干燥固结化含有所述不良溶解性物质和基质助剂的溶液,其中喷雾溶液在引入到雾化装置之前具有90~350℃的温度。
Description
本发明涉及一种制备微溶性活性成分的固溶体的方法,通过所述方法获得的粉末形式的产物,及其在剂型中的应用。
微溶于含水介质的活性成分非常难配制,因为它几乎不可能开发成生物可生物利用的剂型。最有前景的方法之一是形成活性成分以分子分散体的形式掺入其中的固溶体。该形式经常导致明显更高的生物利用度。因为在聚合物已经溶解后,活性成分以溶解形式为人体或植物所用。
术语“固溶体”经常不正确地用于文献中,因为固态结晶物质的掺入也称作固溶体。然而严格来讲,这些是固态分散体。在本文中,固溶体是指真正的分子分散体。
已经描述了各种据说适于制备固溶体的物质,还尤其是聚合物如聚乙烯基吡咯烷酮、纤维素酯、糖、糖醇、淀粉和天然多糖。
所述固溶体的制备仍然是相当复杂的方法。
下述方法可以使用:
1、在高温下使活性成分和聚合物熔融并挤出。该方法的不足是高温作用于活性成分达几分钟,此外产生大的成形制品,且为了可压片,必须将所述成形制品费力地研磨粉碎。而且,所述成形制品通常不具有多孔性,以至可压缩性非常差。片剂经常显示低的耐破碎性和高的易碎性。只有具有特定最小孔隙率的产物才可容易地被压缩。另一个因素是,除了热应力外,剪切力也在熔体挤出过程中作用并可导致活性成分分解。
2、将活性成分和聚合物溶解在可溶解二者的有机溶剂中,并蒸发溶剂或喷雾干燥。该方法自身的不足是它必须大规模地使用有机溶剂,该溶剂对于环境是危险的且是爆炸性的,而且有机溶剂的使用使得成本较高。此外,经常难以发现能够溶解亲水性聚合物和亲脂性药用物质两者的溶剂。
3、在含水聚合物溶液中分散活性成分,例如通过湿法研磨和喷雾干燥。如果在此情形下活性成分不溶于水,则不会形成固溶体而仅形成固态分散体,后者远不具有像分子溶液那样的性质,尤其是不具有生物利用性。
US 5876760描述了一种由普仑司特、糖类、如果合适的话水溶性的聚合物和表面活性剂组成的喷雾干燥的粉末。活性成分悬浮在赋形剂的水溶液中,后者在常规的条件下干燥分散。活性成分在最终产物中呈结晶形式。
US 6197781公开了一种活性成分溶解在溶剂中并在20~80℃的温度下与载体一起喷雾干燥的含雷帕霉素的制剂,所述的载体可由聚氧乙烯-聚氧丙烯嵌段共聚物、聚乙烯基吡咯烷酮、微晶纤维素和水溶性的蔗糖组成。在该情形下使用大量的有机溶剂,溶液的温度在喷雾干燥前明显低于100℃。
WO 99/56751描述了通过将帕罗西汀盐、优选其盐酸盐与水和聚合物混合并然后在25~100℃、优选60℃下干燥制备的无定形帕罗西汀制剂。该帕罗西汀盐甚至在低温下也溶于水,因此固溶体的制备并不代表特殊的问题。WO 01/30349同样涉及将无定形帕罗西汀盐在聚乙烯基吡咯烷酮和另外的酸中的加工。制备发生在15~40℃的温度。
WO 03/000294涉及不良水溶性的药用物质在具有增强溶解度的聚合物的基质中的固态分散体。例如描述了通过使用有机溶剂或者通过熔融工艺的制备。
DE 19951617涉及具有呈两种不同物理形式的活性成分的药物剂型。在该情形中,活性成分部分呈微粒形式且部分呈溶解形式。制备可以常规的方法使用有机溶剂进行。固溶体的制备优选通过熔体挤出进行。
US 2001/0007678和US 2003/0082239描述了通过熔体挤出并然后研磨制备的具有水溶性聚合物的伊曲康唑的固态分散体。这些制剂具有前面已知的不足,例如不良的压片性。
描述在US 2002/0009494中的固态分散体通过将微溶性的药用物质与乙酸琥珀酸羟丙基甲基纤维素一起溶解在有机溶剂中并喷雾干燥制备。通常需要大量的溶剂以制备部分制剂。
US 2002/0031547公开了在有机溶剂中用形成凝胶的水溶性聚合物溶解药用物质并干燥。然后用碱金属盐和弱酸或强酸混合该制剂并制成片剂。形成凝胶的聚合物是纤维素醚。由于形成凝胶聚合物减慢了崩解和片剂中活性成分的释放,因此并不令人吃惊的是,需要其它添加剂提高崩解速率。
WO 01/47492描述了基本上不溶的药用物质与具有酸性官能团的聚合物的固态分散体。该药用物质呈微粒形式,以及有机溶剂、尤其是二氯甲烷用于制备中。
WO 2002051385同样描述了使用有机溶剂制备固溶体。所用的聚合物是纤维素衍生物和聚乙烯基吡咯烷酮。其它的赋形剂是润湿剂。
使用有机溶剂的其它固溶体描述在WO 2001068092、EP 1027886、EP 102787、EP 102788、US 2001/0053778、WO 03/000235、WO 2001068092、WO 2003000226、US 2001/0053791中。
US 2003/0104068和US 2003/082236公开了具有小于2μm尺寸的活性成分颗粒的掺入。由于其微粒状态,真实意义上并不涉及固溶体。
DE 4329446描述了一种其中在保护性胶体存在下在高于活性成分的熔点下制备活性成分在水中或水与有机溶剂的混合物中的熔融乳液并喷雾干燥该乳液的方法。在该情形下其结果得到胶状的活性成分颗粒而非固溶体。
本发明的目的是找到一种避免有机溶剂、不涉及活性成分的大的热应力、直接提供具有良好的压片性和流动性的产品并容易进行的方法。
因此,已经发现一种通过雾化微溶性物质和基质赋形剂的溶液而制备微溶性物质的粉末形式的固溶体的方法,其中该微溶性物质在赋形剂基质中呈分子分散体形式,所述方法包括在0.08~20MPa的压力下、在基质赋形剂存在下将微溶性物质的水悬浮体加热至>90℃至350℃,使该微溶性物质溶解,并随后通过雾化和干燥将其转化为粉末形式,其中当喷雾溶液进料到雾化装置时该喷雾溶液的温度>90至350℃。
根据本发明,固溶体指的是活性成分在赋形剂基质中呈分子分散体形式的状态。在该状态,通过X-射线衍射法检测到无活性成分的结晶部分。由于结晶部分在X-射线衍射法中的检测极限是3%重量,因此表述“无结晶部分”是指存在小于3%重量的结晶部分。分子分散体的状态可通过差示扫描量热法(DSC)法确定。在分子分散体的情形下,在活性成分的熔融区域没有观察到熔融峰。该方法的检测极限是1%重量。
微溶性物质在本发明的上下文中是指其在至少一种下述介质中于室温(20℃)下的饱和溶解度小于1%重量的物质:水,0.1M盐酸水溶液,pH7.2的磷酸盐缓冲液,0.9%重量的氯化钠水溶液。
根据本发明合适的微溶性物质是大量的活性成分和活性物质、尤其是药用或化妆品用活性成分,用于营养补充品或食品组合物或食品添加剂的活性成分。
在本发明上下文中微溶性物质的实例是:
吡罗昔康(piroxicam)、克霉唑(clotrimazole)、卡马西平(carbamazepine)、17-β-雌二醇(17-beta-estradiol)、磺胺噻唑(sulfathiazole)、非诺贝特(fenofibrate)、苯坐卡因(benzocaine)、利多卡因(lidocaine)、二甲茚定(dimethindene)、比哌立登(biperiden)、比沙可啶(bisacodyl)、氯碘羟嗪(clioquinol)、氟哌利多(droperidol)、氟哌啶醇(haloperidol)、硝苯地平(nifedipine)、尼群地平(nitrendipine)、四环素(tetracycline)、苯妥英(phenytoin)、格拉非宁(glafenine)、夫洛非宁(floctafenine)、吲哚美辛(indometacin)、右酮洛芬(ketoprofen)、右布洛芬(ibuprofen)、双嘧达莫(dipyridamole)、Mefenaminsure、胺碘酮(amiodarone)、非洛地平(felodipine)、伊曲康唑(itraconazole)、酮康唑(ketoconazole)、danazole、呋塞米(furosemide)、甲苯磺丁脲(tolbutamide)、利托那韦(ritonavir)、洛匹那韦(lopinavir)、萘普生(naproxen)、螺内酯(spironolactone)、普罗帕酮(propafenone)、孕酮(progesterone)、紫杉醇(paclitaxel)、泰索帝(docetaxel)、茶碱(theophylline)、氢化可的松(hydrocortisone)、β-胡萝卜素、维生素A、生育酚乙酸酯、核黄素、维生素Q10、维生素D、维生素K、戒酒硫(disulfiram)、尼莫地平(nimodipine)、chlorthiazide、氯磺丙脲(chlorpropamide)、乙双香豆素(dicoumarol)、氯霉素(chloramphenicol)、地高辛(digoxin)、氯尼达明(lonidamine)、苯噻啶(pizotifen)、阿托伐醌(atovaquone)、氨曾奈韦(amprenavir)、贝卡瑞特(bexarotene)、calcitrol、氯法齐明(clofazimine)、度骨化醇(doxercalciferol)、屈大麻酚(dronabinol)、Durasteride、Etoposid、Loratadin、Risperidon、Saquinavir、Sirolimus、Valproicsure、两性霉素(amphotericin)、Alprostadil、卡氯芥(carmustine)、利眠宁(chlordiazepoxide)、fenoldopam、美法仑(melphalan)、Methocarbamil、土霉素(oxytetracycline)、泰索帝(docetaxel)、伏维斯腾特(fulvestrant)、丙泊酚(propofol)、伏利康唑(voriconazole)、齐普拉西酮(ziprasidone)、醋酸亮丙瑞林(leuprolide acetate)、Viadur、戊柔比星(valrubicin)、曲马朵(tramadol)、赛利可喜(celecoxib)、依托度酸(etodolac)、Refocoxib、奥沙普泰(oxaprozin)、来氟米特(lefiunomide)、双氯芬酸(diclofenac)、萘丁美酮(nabumetone)、右布洛芬(ibuprofen)、Flurbiprofen、四氢大麻酚(tetrahydrocannabinol)、辣椒素(capsaicin)、酮咯酸(ketorolac)、阿苯达唑(albendazole)、伊维菌素(ivermectin)、胺碘酮(amiodarone)、齐留通(zileuton)、扎鲁司特(zafirlukast)、沙丁胺醇(albuterol)、蒙鲁司特(montelukast)、阿齐霉素(azithromycin)、环丙沙星(ciprofloxacin)、克拉霉素(clarithromycin)、地红霉素(dirithromycin)、利福布汀(rifabutin)、Rifapentin、曲伐沙星(trovafioxacin)、巴氯芬(baciofen)、Ritanovir、沙奎那韦(saquinavir)、那非那韦(nelfinavir)、依法韦仑(efavirenz)、双香豆素(dicoumarol)、Tirofiran、西洛他唑(cilostazol)、Ticlidopin、Ciopidrogel、Oprevelkin、帕罗西汀(paroxetine)、舍曲林(sertraline)、文拉法辛(venlafaxine)、安非他酮(bupropion)、氯米帕明(clomipramine)、米格列醇(miglitol)、瑞格列奈(repaglinide)、Glymeprid、吡格列酮(pioglitazone)、罗格列酮(rosiglitazone)、曲格列酮(troglitazone)、格列本脲(glyburide)、格列吡嗪(glipizide)、格列本脲(glibenciamide)、Fosphenytion、噻加宾(tiagabine)、扎吡酯(topiramat)、拉莫三嗪(lamotrigin)、氮己烯酸(vigabatrin)、两性霉素B(amphotericin B)、布替萘芬(butenafine)、Terbinafin、伊曲康唑(itraconazole)、Flucanazol、咪康唑(miconazole)、酮康唑(ketoconazole)、甲硝唑(metronidazole)、灰黄霉素(griseofulvin)、呋喃妥英(nitrofurantoin)、利生普利(lisinopril)、Benezepril、硝苯地平(nifedipine)、Nilsolidipin、替米沙坦(telmisartan)、依贝沙坦(irbesartan)、Eposartan、缬沙坦(valsartan)、Candesartan、米诺地尔(minoxidil)、特拉唑嗪(terazosin)、氯氟菲醇(halofantrine)、甲氟喹(mefloquine)、二氢麦角胺(dihydroergotamine)、麦角胺(ergotamine)、夫罗曲坦(frovatriptan)、苯噻啶(pizotifen)、舒马普坦(sumatriptan)、佐米曲坦(zolmitriptan)、那拉曲坦(naratiptan)、利扎曲坦(rizatriptan)、Aminogluthemid、白消胺(busulphan)、奥环孢素(cyclosporin)、米托蒽醌(mitoxantrone)、伊利替康(irinotecan)、依托泊苷(etoposide)、替尼泊苷(teniposide)、紫杉醇、他克莫司(tacrolimus)、Sirolimius、他莫西芬(tamoxifen)、Camptothecan、拓扑替康(topotecan)、Nilutanid、Bicalutanid、Toremifen、阿托伐醌(atovaquone)、甲硝唑(metronidazole)、呋喃唑酮(furazolidone)、帕立骨化醇(paricalcitol)、苯佐那酯(benzonatate)、咪达唑仑(midazolam)、唑吡坦(zolpidem)、Gabapentin、佐匹克隆(zopiclone)、地高辛(digoxin)、氯地米松(beclomethasone)、布地奈德(budesonide)、倍他米松(betamethasone)、泼尼松(prednisolone)、西沙必利(cisapride)、甲氰咪呱(cimetidine)、洛哌丁胺(loperamide)、法莫替丁(famotidine)、Lanosprazol、雷贝拉唑(rabeprazole)、尼扎替丁(nizatidine)、奥美拉唑(omeprazole)、Citrizin、桂利嗪(cinnarizine)、Dexchlopheniramin、氯雷他定(loratadine)、氯马斯汀(clemastine)、非索那汀(fexofenadine)、氯苯那敏(chlorpheniramine)、Acutretin、他扎罗汀(tazarotene)、Calciprotien、骨化三醇(calcitriol)、贝卡罗汀(targretin)、骨化醇(ergocalciferol)、胆骨化醇(cholecalciferol)、异维A酸(isotretinoin)、维A酸(tretinoin)、骨化二醇(caleifediol)、非诺贝特(fenofibrate)、普罗布考(probucol)、吉非贝齐(gemfibrozil)、色伐他汀(cerivistatin)、普伐他汀(pravastatin)、辛伐他汀(simvastatin)、氟伐他汀(fluvastatin)、阿托伐他汀(atorvastatin)、替扎尼定(tizanidine)、单曲林(dantrolene)、硝酸异山梨酯(isosorbide dinatrate)、双氢速甾醇(dihydrotachysterol)、必需脂肪酸、可待因(codeine)、芬太尼(fentanyl)、美沙酮(methadone)、纳布啡(nalbuphine)、喷他佐辛(pentazocine)、氯米芬(clomiphene)、Danazol、Dihydroepiandrosteron、甲羟孕酮(medroxyprogesterone)、孕酮(progesterone)、利美索龙(rimexolone)、醋酸megesterol(megesterol acetate)、雌二醇(estradiol)、非那雄胺(finasteride)、Mefepriston、L-thryroxine、Tamsulosin、甲氧沙林(methoxsalen)、他克林(tacrine)、多奈哌齐(donepezil)、雷洛昔芬(raloxifene)、Vertoporfin、西布曲明(sibutramine)、溴吡斯的明(pyridostigmine),以及它们的异构体、衍生物、盐或混合物。
通过本发明方法制备的固溶体可具有下述定量组成:
(i)1~50%重量的至少一种活性成分,
(ii)10~99%重量的至少一种水溶性基质赋形剂,
(iii)0~30%重量的一种或多种表面活性剂,
(iv)0~30%重量的助增溶剂,
(v)0~50%重量的其它赋形剂,
其中组分(i)~(v)的量总计100%重量。
合适的构成基质的赋形剂原则上是所有能够与活性成分形成固溶体的物质。
合适的实例是下述结构分类的水溶性聚合物:
聚乙烯基吡咯烷酮、乙烯基吡咯烷酮-乙酸乙烯酯共聚物、聚乙烯基己内酰胺、聚乙烯基甲酰胺、聚乙烯基乙酰胺、聚丙烯酸酯、聚甲基丙烯酸酯、聚丙烯酰胺、聚乙烯亚胺、聚乙烯基胺、羟基烷基纤维素、烷基羟基烷基纤维素、羧烷基纤维素、乙酸琥珀酸烷基羟基烷基纤维素、乙酸邻苯二甲酸烷基羟基烷基纤维素、邻苯二甲酸烷基羟基烷基纤维素、乙酸邻苯二甲酸纤维素、淀粉、羟烷基淀粉、羧烷基淀粉、改性淀粉、琥珀酸辛烯酯-淀粉,葡聚糖,聚氧乙烯-聚氧丙烯嵌段共聚物,聚环氧乙烷、聚环氧丙烷,聚氨基酸。
然而也可以使用低分子量的载体:糖如蔗糖、葡萄糖、麦芽糖、木糖、果糖、核糖、阿拉伯糖、半乳糖、海藻糖;糖醇如山梨糖醇、甘露醇、木糖醇、赤藓醇、Palatinit、麦芽糖醇、乳糖醇;脲;烟酰胺;氨基酸;环糊精。
优选物质是具有酰胺结构的那些,因为它们能够溶解高浓度的活性成分。
优选使用的聚合物基质赋形剂是聚乙烯基吡咯烷酮、N-乙烯基吡咯烷酮与乙酸乙烯酯的共聚物。还优选使用甲基丙烯酸烷基酯或丙烯酸烷基酯。
聚合物以1%重量水溶液的Fikentscher K值可为5~120,优选10~95。
脲是特别合适的低分子量基质赋形剂。
基质赋形剂(ii)的使用量优选为30~90%重量。
此外可以使用进一步改善溶解度的增溶剂。合适的增溶剂是表面活性剂,其通常具有大于10的HLB(HLB:亲水亲油平衡值)。所述的增溶剂描述在:Fiedler,Lexikon der Hilfsstoffe,Editio Cantor Verlag Aulendorf,第5版,第117-121页。
下述已经证实特别合适:
脂肪酸的碱金属盐或铵盐、磺化或硫酸化脂肪酸的碱金属盐或铵盐、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇、聚氧乙烯甘油脂肪酸酯、聚氧乙烯甘油脂肪醇、聚氧乙烯脱水山梨糖醇脂肪酸酯、乙氧基化蓖麻油、乙氧基化氢化蓖麻油、乙氧基化12-羟基硬脂酸、Poloxamere或其混合物。
所述的表面活性剂(iii)的使用量优选为1~20%重量。
还已经证实有利的是,在特定情形下使用具有HLB小于10的助增溶剂(iv),因为由此会促进固溶体的形成和稳定性。这些物质同样描述在:Fiedler,Lexikon der Hilfsstoffe,Editio Cantor Verlag Aulendorf、第5版,第115-117页。
例如,可采用下述物质:
聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇、聚氧乙烯甘油脂肪酸酯、聚氧乙烯甘油脂肪醇、甘油脂肪酸酯、甘油脂肪醇、脱水山梨糖醇脂肪酸酯。
还可能可取的是,使用至多10%重量的有机溶剂作为额外的增溶剂。合适的有机溶剂是乙醇、异丙醇或丙酮。然而,优选免除使用有机溶剂。
某些活性成分、增溶剂和助增溶剂具有相当大的增塑效果,即它们明显降低聚合物的玻璃化转变温度,因而有时候使得很难喷雾干燥。在这些情形下,已经证实使用吸附剂非常有利。该吸附剂吸收液体或半固体活性成分聚合物溶液,因而制得可满意使用的固态制剂。可应用的吸附剂的实例是下述物质:硅石、疏水硅石、碱金属或碱土金属的硅酸盐、碱土金属/铝的硅酸盐、交联的聚乙烯基吡咯烷酮、纤维素、淀粉、交联的羧甲基淀粉钠、交联的羧甲基纤维素钠。
吸附剂通常在加热步骤之前悬浮在喷雾溶液中,然后干燥。然而,也可将一部分以粉末形式吹入喷雾塔。
为了实现特定的特性,还可以额外使用其它的赋形剂(v):增塑剂,抗氧化剂,防腐剂,色料,增香剂和增味剂,填料,抗粘剂,促进崩解的赋形剂(崩解剂),缓释剂。这些类型的赋形剂优选存在量为0.1~20%重量。
根据本发明,首先通过加热制备包含活性成分和基质赋形剂和如果合适的话,其它成分(iii)~(v)的含水溶液。水优选用作唯一的溶剂。
下述方法原则上也可以用于制备所述溶液:
方法A:制备包含呈悬浮形式的活性成分和呈溶解形式的基质赋形剂以及如果合适的话,其它成分的水悬浮体。这可通过首先将基质赋形剂溶解在水中并将活性成分悬浮在该溶液中,或者通过将基质赋形剂添加到活性成分的水悬浮体中进行。将以此方式获得的悬浮体然后在合适的装置中加热,直至活性成分已经溶解。
方法B:如方法A所述,制备包含呈溶解形式的基质赋形剂的活性成分的水悬浮体,并将该悬浮体通过与热水流或蒸汽流混合而加热,直至活性成分已经溶解。
方法C:在方法B的轻微变型中,也可以将基质赋形剂—只要它们是热稳定的-溶解在热水流中,并与活性成分在水中的悬浮体混合。
不考虑所选的方法,适用下列内容:
小颗粒尺寸有利于活性成分分散在水或者聚合物水溶液中,因为它首先促进分散,其次该溶解过程在升高的温度下更快。如果放置粗的活性成分,则它也可能在悬浮体加热之前在聚合物溶液中减小尺寸或者研磨。为了减小尺寸,可以使用例如高压均化器、转子-定子设备、球磨机或胶体磨。然而,原则上也可以首先将如上所述的活性成分放进水中,然后才添加聚合物。
水悬浮体的加热在合适的装置中连续进行。
该加热可在例如任何合适的热交换器中进行,其中称作热交换器的装置通常是其中为了实现加热将热量通过传热剂传输到其它介质的那些。
在间接热交换中,传热介质和待加热的介质通过热交换表面隔开。适于作为传热介质的是热油、热蒸气或过热水或其它通常的热气或热液体。该传热介质可逆流通入待加热的水悬浮体。其它可行方式也可以是将待加热的介质连续地通过静态的传热介质。
在直接的热交换中,如根据本发明在方法B)或C)中所进行的那样,使两种介质接触。合适的直接热交换剂因此是作为传热剂的过热的水或蒸汽。
活性成分悬浮体的加热可通常使用可以实现快速加热速率的所有方法进行。因而电加热、感应加热或微波加热也是可以的。
为了将活性成分溶解在水中,将水悬浮体加热到高于混合物在大气压下的沸点的温度。关于此可选择的温度是>90℃至350℃、优选110~300℃、特别优选120~250℃。
为了避免起始材料上的热应力,不考虑使用所述方法中的哪一种,在>90℃下加热的停留时间保持在秒钟级别。含活性成分的介质在用于加热的装置中的停留时间优选小于180秒,特别优选小于60秒,非常特别优选小于15秒。为了实现活性成分的完全溶解,通常选择最小0.5秒的保留时间。
溶液的固体含量通常为1~70%重量,优选3~60%重量,特别优选5~40%重量。
活性成分、基质赋形剂和如果合适的话,其它成分的热的和加压的水溶液在通过装置后直接进入雾化装置。该雾化可通过喷嘴进行,在此情形下原则上单个或多个流体喷嘴是合适的,或者通过转盘进行。制剂的雾化在干燥塔中优选通过单个流体喷嘴在10~250巴的压力下进行。然而也可使用多个流体喷嘴,尤其是两个流体喷嘴,在此情形下雾化气体的压力可为0.15~10MPa。
干燥气体的塔入口温度为50~200℃,优选为70~180℃。合适的干燥气体是空气或惰性气体如氮气、氩气或氦气。塔的出口温度为40~120℃。干燥气体在干燥塔中可并流或逆流通入液滴,优选并流通入。
除了简单的喷雾干燥外,也可以用内部和/或外部流化床(如FSD技术,来自Niro)进行附聚喷雾干燥,在此情形下,在喷雾干燥中形成的颗粒附聚成更大的结构体。
通常可以使用溶液在其中雾化的所有干燥技术,包括流化床喷雾造粒。
如果喷雾干燥的颗粒具有一定的粘附倾向,用非常细的颗粒固体涂粉是适宜的。在此情形下,该细颗粒固体作为粉尘引入到喷雾塔中,因而确保不发生粘结或附聚。这里已经证实胶态硅石非常合适。然而,也可以使用其它的物质,例如疏水硅石、碱金属或碱土金属的硅酸盐、碱土金属/铝的硅酸盐、交联的聚乙烯基吡咯烷酮、纤维素、淀粉、交联的羧甲基淀粉钠或交联的羧甲基纤维素钠。
在通过本发明的方法A制备固溶体的实施方案中,因此将药用物质分散在聚合物的水溶液中,并在合适的装置中将悬浮体加热到大于90℃的温度,以使得活性成分晶体溶解。含活性成分的聚合物溶液的加热应当尽可能快地进行,以为了将药用物质的热应力降至最低。为此目的,如上所述优选以几秒的停留时间将含活性成分的悬浮体连续通过合适的装置。随后将该加热和加压的活性成分溶液雾化并干燥。喷雾溶液的温度在雾化之前不久,即在引入到雾化装置之前>90至350℃,优选110~300℃和特别优选120~250℃。喷雾溶液的压力在此情形下为0.08~20MPa,优选1~15MPa。
在本发明的优选实施方案中,含活性成分的聚合物溶液可通过位于110~500℃、优选130~300℃温度的热油浴中的细管泵送。这可以进行快速传热。含活性成分的聚合物溶液的温度通过改变油浴温度和流动速率而调节。在通过该细管之后,立即将热的加压溶液通过喷嘴进行雾化并用热的干燥气体干燥。水的蒸发导致喷雾液滴的骤然冷却和干燥。
该类型的工序例如在图1中示意性地进行了描述。在此情形下,在装有搅拌器的容器1中制备活性成分在基质赋形剂的水溶液中的悬浮体,然后将该悬浮体连续地在盘管中泵送通过装有加热传热介质的加热器2a的热交换器2,然后在喷雾塔4中通过喷嘴3将溶液雾化并干燥,以及收集所得的微粒固溶体5。
在本发明的其它实施方案中,可以选择下述方法工序B。当微溶性物质的热应力需要进一步最小化时,特别推荐该工序。将微溶性物质在室温下或在活性成分不会分解的稍微升高的温度下悬浮在聚合物溶液中。将该悬浮体进料至混合池,在该池中悬浮体与过热的水或蒸汽湍流混合。所述水或蒸汽的温度应为110~500℃,优选150~400℃,特别优选180℃~300℃。水或蒸汽的高温以及湍流混合导致活性成分在聚合物溶液中的悬浮体在极短时间内被加热到大于100℃的温度,且活性成分溶解。在通过混合池之后立即进行在喷嘴中的雾化和喷雾干燥。待喷雾溶液的温度通过两股液体流的温度及其混合比例进行控制。水或蒸汽流的更高温度和水或蒸汽流对活性成分/聚合物悬浮体的更大比例增加待喷雾的活性成分溶液的温度。在混合池中的停留时间取决于两股液体流的流动速率和混合单元的几何构造。活性成分在聚合物溶液中的悬浮体通常在秒钟级别的时间内达到希望的温度。活性成分的热应力也取决于混合后多迅速地喷雾干燥。混合池和喷嘴之间的距离因此应当适当地小。最小停留时间必须使得溶解活性成分晶体,并取决于活性成分特定的溶解速率、溶液或悬浮体的温度和颗粒尺寸。活性成分在高温下的总停留时间可通过流动速率、混合池的几何构造以及到喷嘴的距离的长度进行调节。总停留时间通常小于30秒,优选小于15秒,特别优选小于5秒。
如果活性成分的溶解速率高,也可获得小于1秒的时间。
体积流动可在9∶1~1∶9的比例范围内变动。混合池的几何构造也可广泛改变。由简单的T-片至具有高度湍流的非常精细的混合单元。料流汇合在一起的角度可为5~180℃。在特别的实施方案中,可通过注射器喷嘴将一种料流注入到其它料流中。
其它的赋形剂如增溶剂通常引入到含活性成分的料流中,但它们原则上也可经由热水相进料。
该类型的工序在图2中示意性地进行了描述。在此情形下,在装有搅拌器的容器6中制备在基质赋形剂溶液中的活性成分悬浮体,并将其连续地泵送至混合池8中。通过带有加热器7b的热交换器7a将水由容器7中连续地泵出,并同样作为过热的水或蒸汽泵进混合池8中。活性成分的加热和溶解在混合池8中通过两股料流的连续混合进行。然后将热溶液通过喷嘴9在喷雾塔10中雾化,并收集微粒固溶体11。
通过本发明方法制备的粉末由于它的多孔性具有非常良好的压片性能。通常获得25~500μm的平均颗粒尺寸。
根据本发明制备的制剂的优点是:高浓度的活性成分呈固态分子溶液形式,使得该固溶体在含水介质中快速溶解且该活性成分在含水介质中在过饱和区域长时间保持。由此获得大的生物学效果。
本发明的制剂具有比以前公开的制备方法明显更好优异压片性。所得片剂具有高的耐破碎性和非常低的易碎性。本发明的制剂通常可直接压片。
活性成分的释放可通过添加缓释剂适当地控制。因此理想地可以制备微溶性活性成分的真正可再现释放的缓释形式。
实施例
实施例1
茶碱在聚维酮中的固溶体
将10.0kg的Kollidon 30溶解在40.0kg的软化水中。将5.0kg的精细研磨的茶碱在激烈搅拌下悬浮在该聚合物溶液中。通过位于155℃温度的油浴中、直径为10mm的细盘管泵送该溶液进行简短加热,在此过程中,溶液的温度升至150℃。流动速率为800~1000ml/min,其用高压泵设定。管中的压力为10.45MPa。将该热溶液在喷雾干燥器中通过具有0.6mm直径的单流体喷嘴在100巴的压力下雾化。设置出口空气温度为95℃,入口空气温度为145℃。获得干燥的自由流动的粉末。
实施例2
卡马西平在聚维酮中的固溶体
将10.0kg的Kollidon 30溶解在40.0kg的软化水中。将5.0kg的精细研磨的卡马西平在激烈搅拌下悬浮在该聚合物溶液中。通过位于130℃温度的油浴中、直径为10mm的细盘管泵送该溶液进行简短加热,在此过程中,溶液的温度升至125℃。流动速率在9MPa的压力下为700~800ml/min,其通过高压泵调节。将该热溶液在FSD喷雾干燥器中通过0.7mm直径的单流体喷嘴在90巴的压力下雾化并附聚。设置出口空气温度为96℃,入口空气温度为145℃。获得具有优异流动性能的干燥粉末。
实施例3
磺胺噻唑在共聚维酮中的固溶体
将10.0kg的Kollidon VA 64和1.0kg的甘露醇溶解在40.0kg的软化水中。将5.0kg的精细研磨的磺胺噻唑在激烈搅拌下悬浮在该聚合物溶液中。通过位于130℃温度的油浴中、直径为10mm的细盘管泵送该溶液进行简短加热,在此过程中,溶液的温度升至116℃。流动速率在9.1MPa的压力下为600~800ml/min,这通过高压泵调节。将该热溶液在喷雾干燥器中通过0.6mm直径的单流体喷嘴在90巴的压力下雾化。设置出口空气温度为55℃,入口空气温度为115℃。获得干燥的自由流动的粉末。
实施例4
吡罗昔康在1∶1共聚维酮/聚维酮中的固溶体
将4.5kg的Kollidon VA 64、5.0kg的Kollidon 30、0.25kg的烟酰胺和0.5kg的十二烷基硫酸钠溶解在40.0kg的软化水中。将3.0kg的精细研磨的吡罗昔康在激烈搅拌下悬浮在该聚合物溶液中。通过位于200℃温度的油浴中、直径为10mm的细盘管泵送该溶液进行简短加热,在此过程中,溶液的温度升至160℃。流动速率在9.1MPa的压力下为600~700ml/min,这通过高压泵调节。将该热溶液在喷雾干燥器中通过0.6mm直径的单流体喷嘴在90巴的压力下雾化。设置出口空气温度为70℃,入口空气温度为125℃。获得干燥的自由流动的粉末。
实施例5
克霉唑在聚维酮K 17中的固溶体
将10.0kg的Kollidon 17 PF、0.3kg的Lutrol F 68(poloxamer 188)和0.3kg的硬脂酸钠溶解在40.0kg的软化水中。将2.0kg的精细研磨的克霉唑在激烈搅拌下悬浮在该聚合物溶液中。通过位于135℃温度的油浴中、直径为10mm的细盘管泵送该溶液进行简短加热,在此过程中,溶液的温度升至115℃。将该热溶液在喷雾流化床干燥器中用双流体喷嘴雾化。设置出口空气温度为65℃,入口空气温度为100℃。获得干燥的、比较精细的、非常自由流动的粉末。
实施例6
桂利嗪在聚维酮中的固溶体
将10.0kg的Kollidon 30和0.5kg的Cremophor RH40(氢化蓖麻油与45mol的环氧乙烷的反应产物)溶解在40.0kg的软化水中。将2.5kg的桂利嗪在激烈搅拌下悬浮在该聚合物溶液中,然后用Ultra-turrax处理15分钟而均化。将该细颗粒悬浮体的料流在热交换器中加热到60℃,并通过T-片与加热到280℃的水蒸汽合并。含活性成分的料流对热水流的比例为1∶2。喷嘴上游的热溶液的温度为195℃且在此温度下的停留时间为2.5秒。将该热溶液在喷雾干燥器中通过0.6mm直径的单流体喷嘴在100巴的压力下雾化。设置出口空气温度为95℃,入口空气温度为145℃。获得干燥的、自由流动的粉末。
实施例7
酮康唑在聚维酮/聚乙烯基己内酰胺中的固溶体
将8.0kg的Kollidon 30、K值为30的2.0kg聚乙烯基己内酰胺和0.2kg的聚山梨酯80和0.1kg的棕榈酸抗坏血酸酯溶解在40.0kg的软化水中。将2.0kg的酮康唑在激烈搅拌下悬浮在该聚合物溶液中,然后用Ultra-turrax处理15分钟而均化。将该细颗粒悬浮体的料流在热交换器中加热到50℃,并在混合池中与加热到240℃的水流合并。含活性成分的料流对热水流的比例为1∶5。喷嘴上游的热溶液的温度为200℃且在此温度下的停留时间为2.0秒。将该热溶液在喷雾干燥器中通过0.6mm直径的单流体喷嘴在100巴的压力下雾化。设置出口空气温度为95℃,入口空气温度为145℃。获得干燥的、自由流动的粉末。
实施例8
吲哚美辛在聚维酮中的固溶体
将10.0kg的Kollidon 30、0.2kg的聚乙二醇6000和0.2kg的Cremophor RH 40溶解在40.0kg的软化水中。将2.0kg的吲哚美辛在激烈搅拌下悬浮在该聚合物溶液中,然后用Ultra-turrax处理15分钟而均化。将该细颗粒悬浮体的料流在热交换器中加热到50℃,并在混合池中与加热到280℃的水流合并。含活性成分的料流对热水流的比例为1∶1。喷嘴上游的热溶液的温度为158℃且在此温度下的停留时间为1.5秒。该热溶液在喷雾干燥器中通过0.6mm直径的单流体喷嘴在100巴的压力下雾化。同时,将Aerosil 200作为粉尘经由单独的喷嘴引入到塔中,溶液中的固体对Aerosil的比例为99∶1。设置出口空气温度为82℃,入口空气温度为143℃。获得干燥的、自由流动的粉末。
实施例9
β-胡萝卜素在聚维酮中的固溶体
将8.0kg的Kollidon 25、1.5kg的Cremophor RH 40、0.5kg的尿素、0.1kg的棕榈酸抗坏血酸酯和0.05kg的丁基羟基甲苯溶解在30.0kg的无氧气的软化水中。将1.0kg的β-胡萝卜素在激烈搅拌下悬浮在该聚合物溶液中,然后用Ultra-turrax处理15分钟而均化。将该细颗粒悬浮体的料流在热交换器中加热到70℃,并在混合池中与加热到230℃的水流合并。含活性成分的料流对热水流的比例为1∶3。喷嘴上游的热溶液的温度为190℃且在此温度下的停留时间为3.0秒。将该热溶液在喷雾干燥器中通过0.7mm直径的单流体喷嘴在100巴的压力下雾化。设置出口空气温度为69℃,入口空气温度为120℃。获得干燥的、自由流动的粉末。
实施例10
茶碱在尿素中的固溶体
将10.0kg的尿素溶解在40.0kg的软化水中。将3.0kg精细研磨的茶碱在激烈搅拌下悬浮在该聚合物溶液中。通过位于155℃温度的油浴中、直径为3mm的细盘管泵送该溶液进行简短加热,在此过程中,溶液的温度升至150℃。流动速率为500~600ml/mi,这使用高压泵设定。将该热溶液在喷雾干燥器中通过0.5mm直径的单流体喷嘴在100巴压力下雾化。设置出口空气温度为77℃,入口空气温度为125℃。获得干燥的、自由流动的粉末。
对比例1
茶碱在聚维酮中的固态分散体
将10.0kg的Kollidon 30溶解在40.0kg的软化水中。将5.0kg的茶碱在激烈搅拌下悬浮在该聚合物溶液中。将该悬浮体在喷雾干燥器中通过0.5mm直径的单流体喷嘴在100巴压力下雾化。设置出口空气温度为90℃,入口空气温度为160℃。获得干燥的、自由流动的粉末。
对比例2
卡马西平在聚维酮中的固态分散体
将10.0kg的Kollidon 30溶解在40.0kg的软化水中。将5.0kg的卡马西平在激烈搅拌下悬浮在该聚合物溶液中。将该悬浮体在FSD喷雾干燥器中通过双流体喷嘴雾化并附聚。设置出口空气温度为88℃,入口空气温度为155℃。获得干燥粉末。
表1
实施例 | 显微镜评价 | DSC研究 | X-射线衍射学 |
实施例1茶碱 | 无晶体 | 在270~274℃无活性成分峰 | 无定形 |
实施例2卡马西平 | 无晶体 | 在191℃无活性成分峰 | 无定形 |
实施例3磺胺噻唑 | 无晶体 | 在202℃无活性成分峰 | 无定形 |
实施例4吡罗昔康 | 无晶体 | 在205℃无活性成分峰 | 无定形 |
实施例5克霉唑 | 无晶体 | 在148℃无活性成分峰 | 无定形 |
实施例6桂利嗪 | 无晶体 | 无活性成分峰 | 无定形 |
实施例7酮康唑 | 无晶体 | 在146℃无活性成分峰 | 无定形 |
实施例8吲哚美辛 | 无晶体 | 在155℃无活性成分峰 | 无定形 |
实施例9β-胡萝卜素 | 无晶体 | 无活性成分峰 | 无定形 |
实施例10茶碱 | 无晶体 | 在270~274℃无活性成分峰 | 无定形 |
对比例1 | 晶体 | 在270~274℃有活性成分峰 | 有结晶部分 |
对比例2 | 晶体 | 在191℃有活性成分峰 | 有结晶部分 |
实施例11
茶碱片剂
将2.1kg来自实施例1的茶碱固溶体与1.5kg的LudipressLCE(93%乳糖、3.5%聚维酮、3.5%交聚维酮的共加工产物)、0.03kg的胶态硅石(Aerosil 200,得自Degussa)、0.15kg的交聚维酮(Kollidon CL,得自BASF)和0.03kg的硬脂酸镁在Turbula混合器中混合10分钟,并使用Korsch PH 106型旋转压片机在18kN的压缩力下压缩成片剂。该片剂具有10mm的直径和331mg的重量。
也类似地使用来自对比例1的粉末和纯的茶碱晶体压缩得到片剂。在USP 2004桨式装置中测定片剂的耐压碎性和活性成分的释放。
产物 | 耐压碎性 | 15分钟后的释放,% | 30分钟后的释放,% |
实施例1 | 225 | 62 | 99 |
对比例1 | 174 | 42 | 80 |
茶碱晶体 | 140 | 34 | 78 |
实施例14
卡马西平胶囊
将180g来自实施例2的卡马西平固溶体与100g的磷酸氢钙、1.5g的Aerosil 200和20g的Kollidon CL在Turbula混合器中混合10分钟,并以301.5mg的量封装成明胶胶囊。
也类似地使用来自对比例2的粉末和纯的卡马西平晶体制备胶囊。
在USP 2004桨式装置中测定胶囊的活性成分的释放。
产物 | 15分钟后的释放,% | 30分钟后的释放,% |
实施例2 | 55 | 101 |
对比例2 | 35 | 66 |
卡马西平晶体 | 22 | 53 |
Claims (28)
1.一种通过雾化活性成分和基质赋形剂的溶液而制备微溶性物质的粉末或颗粒形式的固溶体的方法,其包括在基质赋形剂存在下将微溶性物质的水悬浮体加热至高于在大气压下的沸点的温度,使该微溶性物质溶解,并随后通过雾化和干燥将微溶性物质和基质赋形剂的溶液转化为固体形式,其中喷雾溶液在进料到喷雾装置之前其温度为90~350℃。
2.根据权利要求1的方法,其中喷雾溶液在雾化之前其温度为110~300℃,且所述活性成分呈溶解形式。
3.根据权利要求1的方法,其中喷雾溶液在雾化之前其温度为120~250℃,且所述活性成分呈溶解形式。
4.根据权利要求1~3任一项的方法,其中活性成分在高于90℃的温度下的停留时间小于180秒。
5.根据权利要求1~3任一项的方法,其中活性成分在高于90℃的温度下的停留时间小于60秒。
6.根据权利要求1~3任一项的方法,其中活性成分在高于90℃的温度下的停留时间小于15秒。
7.根据权利要求1~6任一项的方法,其中微溶性物质在赋形剂基质中的浓度为1~50%重量,优选大于10%,特别优选大于20%。
8.根据权利要求1~7任一项的方法,其中微溶性物质在赋形剂基质中的浓度为10~50%重量。
9.根据权利要求1~8任一项的方法,其中微溶性物质在赋形剂基质中的浓度为20~50%重量。
10.根据权利要求1~9任一项的方法,其中使用具有酰胺基的基质赋形剂来形成固溶体。
11.根据权利要求1~10任一项的方法,其中用于形成固溶体的基质赋形剂是如下物质的均聚物或共聚物:N-乙烯基吡咯烷酮、N-乙烯基己内酰胺、N-乙烯基甲酰胺或N-乙烯基乙酰胺。
12.根据权利要求1~11任一项的方法,其中固溶体额外包含HLB大于10的表面活性剂作为增溶剂。
13.根据权利要求1~12任一项的方法,其中固溶体额外包含HLB小于10的助增溶剂。
14.根据权利要求1~13任一项的方法,其中喷雾溶液包含吸附剂。
15.根据权利要求1~14任一项的方法,其中活性成分的悬浮体通过热交换器加热。
16.根据权利要求1~15任一项的方法,其中活性成分的悬浮体的加热通过与热的液体流或热的蒸汽流混合进行。
17.根据权利要求16的方法,其中活性成分的悬浮体对热的液体流的比例为9∶1~1∶9。
18.根据权利要求16或17的方法,其中活性成分的悬浮体对热的液体流的比例为7∶3~3∶7。
19.根据权利要求16~18任一项的方法,其中热的液体或蒸汽流的温度为110~500℃。
20.根据权利要求16~19任一项的方法,其中热的液体或蒸汽流的温度为150~400℃。
21.根据权利要求16~20任一项的方法,其中热的液体或蒸汽流的温度为180~300℃.
22.根据权利要求1~21任一项的方法,其中将雾化干燥或流化床喷雾造粒的方法用于干燥。
23.根据权利要求1~22任一项的方法,其中将吸附剂或隔离剂在雾化干燥过程中吹入喷雾塔中。
24.根据权利要求1~23任一项的方法,其中微溶性活性成分是药用物质、维生素、类胡萝卜素或营养品。
25.一种根据权利要求1~24任一项的方法制备的粉末或颗粒形式的固溶体。
26.根据权利要求25的粉末或颗粒,其包含a)1~50%重量的活性成分,b)10~99%重量的水溶性基质赋形剂,c)0~30%重量的增溶剂,d)0~30%重量的助增溶剂和e)0~50%重量的其它常规赋形剂。
27.根据权利要求25或26的粉末或颗粒用于制备药物剂形、食品或营养补充品的用途。
28.一种包含根据权利要求25或26的粉末或颗粒的药物剂形、食品或营养补充品。
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