CN1088432A - 具由抗真菌药和聚合物包膜的核的微球 - Google Patents
具由抗真菌药和聚合物包膜的核的微球 Download PDFInfo
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Abstract
本发明涉及含25—30目核、亲水聚合物和抗真
菌剂包膜及包封层的微球;涉及含微球的药物剂型和
制备该微球的方法。
Description
本发明涉及在水性介质中低溶解度的抗真菌剂的新组合物,涉及该组合物的制备方法和含该新组合物的口服药物剂型。
开发吡咯类抗真菌剂如:伊曲康唑(itraconazole)和萨泼康唑(saperconazole)的有效的药用组合物相当大地受到这样的事实的阻碍,即所述的抗真菌剂极微溶解于水。该化合物的溶解度和生物利用率能通过与环糊精或其衍生物形成复合物而增大,正如WO 85/02767和美国专利第4764604中所述。然而,对口服有好的生物利用率的抗真菌制剂仍有很大的需求。
伊曲康唑,即(±)-顺式-4-[4-[4-[4-[[2-(2,4-二氯苯基)-2-(1H-1,2,4-三唑-1-基甲基)-1,3-二氧戊环-4-基]甲氧基]苯基]-1-哌嗪基]苯基]-2,4-二氢-2-(1-甲基丙基)-3H-1,2,4-三唑-3-酮是一个经口服、非肠道和局部使用的广谱抗真菌化合物,并公开在美国专利第4267179上。它的二氟类似物萨泼康唑,即(±)-顺式-4-[4-[4-[4-[[2-(2,4-二氟苯基)-2-(1H-1,2,4-三唑-1-基甲基)-1,3-二氧戊环-4-基]甲氧基]苯基]-1-哌嗪基]苯基]-2,4-二氢-2-(1-甲氧基丙基)-3H-1,2,4-三唑-3-酮具有增进的抗曲霉(Aspergillus spp.)活性,并在美国专利第491613.4上公开。
已出乎意外地发现:将溶解性很差的抗真菌剂混在亲水性聚合物中,并将这个混合物作为包膜涂在许多小球外面,制成具良好生物利用率的组合物。该组合物很容易制备,且适宜于制成适合口服的药物剂型。
具体来讲,本发明涉及微球(bead)。该微球含有(a)中央圆形或球形的核,(b)亲水聚合物和抗真菌剂的包膜和(c)包封聚合物层(seal-coating polymer layer);其特征在于:该核具约600-700微米(25-30目)的直径。
按占微球的总重量计算,由25-30目核可获得的微球大约含有:(a)20-60%的核成分;(b)25-50%的亲水聚合物;(c)10-25%的抗真菌剂;以及(d)2-5%的包封聚合物。
核具体的大小是十分重要的。一方面,如果核太大,则可供药物包膜层的表面积较小,导致形成较厚的包膜层。这个问题的解决方法就是在制备过程中需要强化干燥手段以减少包膜层中的残留溶剂。该强干燥条件反过来可以影响药物从微球溶出。所以,在制备过程中要很好地控制该条件。另一方面,小核会提供较大的总表面供包膜,导致形成较簿的包膜层。因此,可使用不太强的干燥手段来减少残留溶剂。但是,核太小例如30-35目的核的缺点在于:在包膜过程中易聚集。所以,25-30目是核的最佳大小,这时,核既不会聚集,也不需要强的干燥手段。
适合用作本发明微球中的核的材料是多种多样的,但条件是:该材料是药学上能接受的,并有合适尺寸(约25-30目)和坚固程度。这类材料的例子有聚合物,如塑料树脂;无机物质如硅石、玻璃、羟基磷灰石和无机盐类(氯化钠或氯化钾,碳酸钙或碳酸镁)等;有机物如:活性碳、有机酸(柠檬酸、富马酸、酒石酸、抗坏血酸和其它酸)和糖类及它们的衍生物。特别适合的材料是糖类,如:单糖、寡糖、多糖和它们的衍生物,如:葡萄糖、鼠李糖、半乳糖、乳糖、蔗糖、甘露糖醇、山梨醇、糊精、麦芽糖糊精、纤维素、羧甲基纤维素钠、淀粉(玉米、水稻、土豆、小麦和木薯)等糖类。
适合用作本发明微球核的最好的材料是25-30目的糖球(NFXVII,p1989),它们含67.5%-91.5%(W/W)的蔗糖,其余是淀粉,也可以是糊精。这些成分在药学上属于惰性或中性的。
药物包膜层最好含亲水性聚合物,如:羟丙基甲基纤维素(Methocel
,Pharmacoat
),异丁烯酸(Eudragit E
),羟丙基纤维素(Klucel
),或聚乙烯吡咯烷酮。优先选用低粘度、即约5mPa.s的羟丙基甲基纤维素,例如,羟丙基甲基纤维素2910为5mPa.s。优选的在该药物包膜层作为药物的抗真菌剂是亲脂的吡咯类抗真菌剂,特别是伊曲康唑和萨泼康唑。当所用药物与聚合物的重量比为约1∶1-1∶2、最好约1∶1.5时,可获得最佳的溶解效果。在药物包膜层中,药物成分是以固体分散体、还是以溶液状态存在可被示差扫描量热法所证实。
用在药物包膜外面的包封聚合物层是为了防止微球间的粘连,而这种粘连将产生伴随降低溶解速度和生物利用率的不好的作用。最好是用聚乙二醇(PEG)薄层、尤其是聚乙二醇20000薄层作包封聚合物层。
优选的微球大约含:(a)26-38%的糖;(b)32-33%的羟丙基甲基纤维素2910,粘度为5mPa.s;(c)21-22%的伊曲康唑或萨泼康唑;和(d)3-4%的聚乙二醇20000。
此外,本发明微球还可以含各种添加剂,如增厚剂、润滑剂、表面活性剂、防腐剂、配位剂和螯合剂、电解质或其它活性成分,如抗炎剂、抗菌剂、消毒剂或维生素。
本发明微球能方便地制成各种药物剂型。合适的剂型含抗真菌有效量的上述微球。最好是将该微球按一定量装在硬胶囊内,例如,每个胶囊含50或100毫克的活性成分。例如0号硬胶囊适合装入含20-25重量%的伊曲康唑或萨泼康唑的微球,相当于约100毫克的活性成分。
本发明微球宜按下述方法来制备。将适当量的抗真菌剂和亲水聚合物溶解在合适的溶剂系统中,得到药物包膜溶液。合适的溶剂系统包括二氯甲烷和醇的混合物,最好是乙醇,它可以用例如丁酮来变性。该混合物应该至少含50重量%的二氯甲烷作为溶解药物成分的溶剂。由于羟丙基甲基纤维素不能完全溶于二氯甲烷中,所以,必须加入至少10%的醇。最好是在该包膜溶液中使用相对较低比例的二氯甲烷/醇,如:二氯甲烷/乙醇之比为75/25(W/W)-55/45(W/W),约60/40(W/W)为佳。在药物包膜溶液中,固体物质,即抗真菌剂和亲水聚合物的含量可以在7-10%(W/W)范围内,以约8%为佳。
25-30目核的药物包膜过程宜在配有沃斯特底部喷雾隔板(spray insert)(如18英寸沃斯特隔板)的流化床成粒机(如Glatt WSG-30型)中完成。显然,过程参数将决定于所用设备。
喷雾速度应该仔细地调整。过低的喷雾速度能造成部分药物包膜溶液的喷雾干燥,导致产品损失。过高的喷雾速度将造成过湿随后聚集。由于聚集现象是最严重的问题,所以,开始时可以使用较低的喷雾速度,在包膜过程中增加喷雾速度,微球便逐渐变大。
使用药物包膜溶液所依靠的雾化空气压也影响包膜效果。低的雾化空气压导致形成较大的液滴并使聚集倾向增加。可以想象得到,高的雾化空气压能带来药物溶液的喷雾干燥的风险,但已发现这不成问题。因而,可将雾化空气压调整到近最大水平。
流化空气量能通过操作该设备的废气阀来控制,而且,应该调整到保证最佳的微球循环为标准。过低的空气量将引起微球不能充分流化;过高的空气量,由于在设备中形成气流对流,干扰微球循环。我们已获得本过程的最佳条件,即打开废气阀到约为它的最大位置的50%,然后随着包膜过程进行,逐渐打开到约为最大值的60%。
利用约50-55℃范围内的入口空气温度有利于包膜过程进行。更高的温度可以加速该过程,但有缺点,即溶剂蒸发太快,使包膜液不能均匀地涂在微球的表面,导致形成多孔的药物包膜层。随着带包膜的微球的总体积增加,药物的溶解度可以显著下降到不能接受的水平。显然,最佳的操作温度将进一步取决于使用的设备、核及抗真菌剂的性质、每批容量、溶剂和喷雾速度。
控制最佳包膜效果的参数将在下文的实施例中详述。在那些条件下进行包膜操作可以得到重复性非常好的结果。
为了减少药物包膜层中的残留溶剂,可方便地将药物包膜的核在任何合适的干燥设备中干燥。使用真空转筒干燥机在下述条件下能获得良好的效果:干燥温度约为60℃-90℃,以约80℃为佳;减压范围约在150-400毫巴(15-40kPa),以200-300毫巴(20-30kPa)为佳;干燥时间至少为24小时,以约36小时为佳。真空转筒干燥机宜以最低速度转动,如每分钟2-3转。干燥以后,药物包膜的核可以过筛。
将包封聚合物层在配有沃斯特底部喷雾隔板的流化床成粒机中涂到药物包膜的核上。将适当量的包封聚合物溶在合适的溶剂系统中可制得包封溶液。所述溶剂系统可以是例如二氯甲烷和醇类的混合物,以乙醇为佳,乙醇可以例如用丁酮变性。所用二氯甲烷/醇之比例与用在药物包膜过程的比例类似,因此可在约75/25-55/45(W/W)范围内,以约60/40(W/W)为佳。在包封喷雾溶液中包封聚合物的含量可以在7-12%(W/W)范围内,以约10%为佳。在包封过程中,搅拌包封喷雾液有利。控制这最后一步操作的参数基本上与药物包膜过程中所用的参数类似。适合的条件在下文的实施例中将详述。
在涂完包封聚合物层后,需要进一步干燥。在喷雾完成后,操作由参数控制的设备,约需5到15分钟,就能容易地将多余溶剂除去。
药物包膜过程和包封过程最好都在惰性气体、如氮气中进行。包衣设备最好安在地上,并配备合适的含高效冷凝系统的溶剂回收系统。
可将经药物包膜并包封的微球用标准的自动化胶囊灌装机装在硬胶囊内。适合的接地和去电离设备能有利地防止静电荷出现。
胶囊的灌装速度可以影响重量分布,应该予以监测。当在约最大速度的75%-85%的速度下操作该设备时,可以获得良好效果,而在许多情况下,操作按全速进行。
使用以上所述的过程参数,可以得到方便的、可重复的制备微球的生产方法,所述微球包含25-30目核,由抗真菌剂和亲水聚合物组成的药物包膜层和薄的包封聚合物层。药代动力学研究表明:如此获得的微球具有极好的溶解度和生物利用率性质。
实施例
a)伊曲康唑喷雾溶液
将二氯甲烷(375Kg)和变性乙醇(250Kg)通过过滤器(5μ)充入一个伊诺克斯容器(inox vessel)中。在搅拌下,加入伊曲康唑(21.74Kg)和羟丙基甲基纤维素2910(粘度5mPa.s)(32.61Kg)。待完全溶解后停止搅拌(使用同一方法可获得合适的萨泼康唑喷雾溶液)。
b)包封喷雾溶液
搅拌下将二氯甲烷(21.13Kg)和聚乙二醇20000(Macrogol 20000)(3.913Kg)充入一个伊诺克斯容器中。加入变性乙醇(14.09Kg),搅拌到溶液均匀为止。
c)药物包膜过程
在配有18英寸沃斯特(底部喷雾)隔板的流化床成粒机(Glatt,WSG 30型)中装入25-30目(600-700μm)的糖球(41.74Kg)。将该糖球用50-55℃的干燥空气加热。流化空气量按下述方法控制:开始时,把废气阀开到约为其最大值的50%,到喷雾过程结束时,升至最大值的60%。然后,将预先制备好的伊曲康唑喷雾溶液喷到在该设备中运动的糖球上。在喷该溶液时,最初的释放速度约600-700克/分钟,雾化空气压约为3.5公斤/平方厘米(0.343Mpa)。在喷雾液释出约30%后,将释放速度增加到700-800克/分钟。
当喷雾过程完成后,将带包膜的微球进一步用50-55℃的干燥空气干燥约10分钟。然后,将带包膜的微球在该设备中用20-25℃的干燥空气冷却约10-20分钟。将带包膜的微球从该设备中倒出并收集起来。
d)中间干燥
为使带包膜微球上残留溶剂水平达到最低限度,所以,要经过干燥一步。将带包膜的微球导入真空转筒式干燥机中,在约80℃和约200-300mbar(20-30kPa)的温度和压力下,至少干燥24小时,最好是约36小时。转筒式干燥器以最低转速(2-3rpm)运行。将干燥好的带包膜微球用筛子(Sweco S24C;筛目宽度1.14mm)过筛。
e)包封过程
将干燥好的带包膜微球再一次导入配有沃斯特隔板的流化床成粒机中,并用50-55℃的干燥空气加热。然后将预先制备好的包封喷雾溶液喷到在该设备中运动的带包膜的微球上。以约400-500克/分的释放速度喷洒该溶液,雾化空气压约为2.5巴(0.25MPa)。当喷雾过程结束后,将该微球进一步用50-55℃的干燥空气干燥10分钟,然后将带包膜的微球在该设备中用20-25℃的干燥空气冷却约5-15分钟。将该微球从该设备中移出,储存于适当的容器中。
f)装胶囊
用标准自动化胶囊灌装机(如GFK-500型,Hoffliger and Karg.德国)将药物包膜的微球装入硬胶囊(0号)中。为了获得具最佳重量分布的胶囊,将装胶囊速度降低至约为其最大速度的75-85%。每粒胶囊含约460毫克的微球,相当于约100毫克的伊曲康唑。使用上述的过程参数,可获含100毫克伊曲康唑的硬胶囊。该胶囊满足各项要求,尤其是溶解技术规范的要求。用含萨泼康唑的喷雾溶液按上述同样方法操作,可得到含100毫克萨泼康唑的硬胶囊。
Claims (10)
1、包含a)中央圆形或球形的核,b)亲水聚合物和抗真菌剂的包膜,及c)包封聚合物层的微球;其特征在于所述核的直径约为600-700微米(25-30目)。
2、按照权利要求1的微球,所述微球按占微球的总重量计算,含有:
a)20-60%的核材料,
b)25-50%的亲水聚合物,
c)10-25%的抗真菌剂,及
d)2-5%的包封聚合物。
3、按照权利要求2的微球,其中,核材料是25-30目的糖球,亲水聚合物是羟丙基甲基纤维素及抗真菌剂是伊曲康唑或萨泼康唑。
4、按照权利要求3的微球,其中,抗真菌剂与亲水聚合物的重量比约为1∶1-1∶2。
5、按照权利要求2的微球,其中,包封聚合物是聚乙二醇。
6、按照权利要求2的微球,它大约含有:
a)26-38%的糖,
b)32-33%羟丙基甲基纤维素2910,粘度为5mPa.s,
c)21-22%的伊曲康唑或萨泼康唑,及
d)3-4%的聚乙二醇20000。
7、含抗真菌有效量的权利要求1-6中任一权项要求的微球的药物剂型。
8、按照权利要求7的剂型,其中,该剂型是含以权利要求1-6中任一权项要求的微球形式的抗真菌剂伊曲康唑或萨泼康唑的硬胶囊。
9、按照权利要求1-6中任一权项要求的微球的制备方法,其特征在于:
a)在配有沃斯特(底部喷雾)隔板的流化床成粒机中,通过喷洒溶在由二氯甲烷和乙醇组成的有机溶剂中的抗真菌剂和亲水聚合物的溶液给25-30目核包膜;
b)在真空转筒干燥器中干燥所得的带包膜的核;
c)在配有沃斯特(底部喷雾)隔板的流化床成粒机中,通过喷洒溶在由二氯甲烷和乙醇组成的有机溶剂中的聚合物包封溶液,包封该干燥的核。
10、用权利要求9的方法可获得的药物包膜的微球。
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EP92202664 | 1992-09-03 | ||
EP92202664.6 | 1992-09-03 |
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CN1088432A true CN1088432A (zh) | 1994-06-29 |
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1996
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1998
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1813753B (zh) * | 2000-02-29 | 2010-04-07 | 布里斯托尔-迈尔斯斯奎布公司 | 低剂量艾替开韦制剂及其应用 |
US9549946B2 (en) | 2002-11-26 | 2017-01-24 | The University Of Chicago | Materials and methods for preventing and treating microbe-mediated epithelial disorders |
CN101283984B (zh) * | 2007-04-12 | 2010-05-26 | 永胜药品工业股份有限公司 | 高生物使用率的经杀真菌剂和聚合物涂覆的核心微粒状物 |
CN104507480A (zh) * | 2012-06-21 | 2015-04-08 | 梅恩医药国际有限公司 | 伊曲康唑组合物和剂型及其使用方法 |
CN103948911A (zh) * | 2014-04-23 | 2014-07-30 | 深圳市健元医药科技有限公司 | 一种棘白菌素类抗真菌药物缓释微球制剂及其制备方法 |
CN103948911B (zh) * | 2014-04-23 | 2016-04-20 | 深圳市健元医药科技有限公司 | 一种棘白菌素类抗真菌药物缓释微球制剂及其制备方法 |
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