CN102292072A - 用微粒包衣载体的方法 - Google Patents
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- CN102292072A CN102292072A CN2010800056187A CN201080005618A CN102292072A CN 102292072 A CN102292072 A CN 102292072A CN 2010800056187 A CN2010800056187 A CN 2010800056187A CN 201080005618 A CN201080005618 A CN 201080005618A CN 102292072 A CN102292072 A CN 102292072A
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Abstract
本发明公开了用药物微粒包衣载体的方法。例如，包衣载体可以在单步方法中获得，此方法需要从包含API的溶液微滴中蒸发溶剂来获得干微粒，然后将其包衣在载体上。
Description
与相关申请的交叉引用
本申请主张2009年1月26日提交的U.S.临时专利申请序列号61/147,287的权利，其全部内容通过引用并入本文。
技术领域
本发明涉及用微粒包衣载体的方法。
背景技术
已知在现有技术中有数种用颗粒包衣载体的方法。一个代表性的方法是通过使用流化床作为载体来进行。当一定质量的固体颗粒物质(通常在贮存容器中)被放置在合适的条件下而产生固/液混合物，而表现为流体时，则形成流化床。这通常是通过在颗粒介质中导入加压流体而完成的。结果使得该介质具有许多普通流体的性质和特征。
根据现有技术中已知的一个方法，通常使用Wurster装置将悬浮液的液滴喷射到流化床上。该Wurster装置通常包括一个容器，该容器中具有向上延伸的圆柱形隔板(partition)，且在其下端具有穿孔的板或筛网以界定用于颗粒的底壁。该隔板置于穿孔板之上。所述圆柱形隔板之内的区域界定所述容器的上升床(upbed)，而该隔板之外的区域界定该容器的沉降床(downbed)。所述穿孔的板包括大穿孔区域以及更大比例的穿孔开放区域，空气通过它以增加的速度流入上升床，还包括具有较小比例开放区域的穿孔区域，空气通过它以减小的速度流入沉降床。上升床区域中的较高速度的空气输送颗粒通过穿孔板并进入上升床区域，所述颗粒用于从向上延伸的喷嘴喷出的包衣液的包衣、分层和干燥。然后该颗粒在隔板之上的扩张室中与较低流速的空气相会。当空气速度不足以支撑产物时，颗粒落入沉降床区域并再次进入较高速度的空气中，如此完成在上升床区域包衣和在沉降床区域干燥的一次循环。各种型号的Wurster装置和方法在U.S.专利号2,648,609、2,799,241、3,089,824、3,196,827、3,207,824和3,253,944中公开。
在制药行业中，API(活性药学成分)通常沉积在载体上引入患者体内。载体是用于通过增加混合物的均匀性和避免API颗粒聚集来改善剂型性能的物质。在制药行业许多物质已知适合作为载体，例如：微晶纤维素，乳糖和甘露糖醇。本领域技术人员通常根据其粒度分布和溶解性质来选择载体。
Wurster装置包衣方法使得载体被一层具有大尺寸范围的API晶体包衣。该层的生成是由于溶剂蒸发前液滴粘附到载体颗粒上所致。在此方法中，API颗粒悬浮在分散液中。如果API颗粒非常小，则它们可能聚集，悬浮液不会均匀。在许多情况下，API颗粒在悬浮液中不稳定，在悬浮液配制后应立刻进行加工。
此外，可能容易理解Wurster装置的方法不适合用于利用API溶液微滴或空气悬浮干燥的微粒来包衣载体颗粒，因为微粒或微滴与载体颗粒碰撞的概率较低。在这种情况下，微粒可能会经由过滤系统逸出，原料将会损失。
为配制合适的作为用于经吸入器递送的干粉治疗药剂，发明人已作出许多尝试。典型地，在如多糖或柠檬酸的特定辅料的存在下，通过干燥活性药剂来制造制剂，以提高在干燥过程中或存储时的稳定性。
CA-A-2136704公开了通过喷雾干燥药用物质如胰岛素(还有许多其他药物)和载体而获得的产品。WO-A-9735562公开了喷雾干燥胰岛素和多糖的溶液。WO-A-9524183主要涉及包含胰岛素和载体材料的干粉，所述载体材料通常为糖，其为通过喷雾干燥得到的无定形粉末微粒的形式。WO95/23613公开了喷雾干燥的DNase制剂。US 6,926,908公开了喷雾干燥的高浓度治疗药剂。
现有技术需要用API微粒来包衣载体的方法，其中，所述API微粒悬浮在空气中或由微滴形成。
附图概述
图1是用纳米雾化API包衣的纤维素的SEM图像。
发明概述
在一个实施方式中，本发明提供包括下述步骤的方法：
a.提供含API和溶剂的溶液的微滴；
b.从所述微滴中蒸发溶剂而获得干微粒；和
c.将所述微粒与静态载体床或周期性搅动载体床接触以获得用微粒包衣的载体。
发明详述
本发明包括用微粒对静态或周期性搅动载体床进行包衣的方法。
在优选实施方式中，本发明提供用微粒包衣的载体，其中，所述微粒可以从所述载体分离。
通过上述制备方法获得的载体，被优选一般呈圆形、且优选尺寸范围相对狭窄的微粒所包衣。使用圆形微粒是重要的，例如，在吸入药剂产品行业中，因为相对较小的、圆的颗粒更容易流通过呼吸道系统，因此可改善API的利用度。
圆形的微粒还提供微粒与载体的最小接触，从而改善API从沉积于其上的载体分离的能力，并使其更好程度地作用于靶点。
任何API都可以用于本发明的实施。例如包括多西他赛，其他细胞毒性药物，利哌利酮(risperidone)，倍氯美松(beclomethasone)，氟替卡松(fluticasone)，布地萘德(budesonide)，其他类固醇药物，沙丁胺醇(salbutamol)，特布他林(terbutaline)，异丙托品(ipratropium)，氧托品(oxitropium)，福莫特罗(formoterol)，沙美特罗(salmeterol)，缬沙坦(valsartan)，依折麦布(ezetimibe)，帕潘立酮(paliperidone)，阿瑞吡坦(aprepitant)，他克莫司(tacrolimus)，西罗莫司(sirolimus)，依维莫司(everolimus)和噻托溴铵(tiotropium)。
本文记载的“静态载体床”为一层载体颗粒如乳糖或微晶纤维素，其静置于支撑筛网上。
本文记载的“周期性搅动载体床”为静态载体床，其通过合适的搅拌器搅动以均质化粉末并暴露新的载体颗粒于包衣工艺。
本文记载的“SEM”为扫描电子显微镜，用来观察微小范围内的颗粒和结构。这种显微镜通过用高能量电子束以光栅扫描模式扫描样品表面进行成像。
在具体实施例中，本发明的方法包括以下步骤：
a.提供含至少一种API和溶剂的溶液的微滴；
b.从微滴中蒸发溶剂以获得微粒；和
c.将微粒与静态载体床或周期性搅动载体床接触以获得用微粒包衣的载体。
优选地，通过喷雾器获得微滴。喷雾器是从液体、溶液或悬浮液制造小液滴喷雾的装置。已知有许多类型的喷雾器，它们的生成液滴大小和运行机制不同。射流喷雾器通过将液滴与空气射流共喷射来生成液滴。转盘喷雾器通过在转盘上产生液体层来生成液滴。超声波喷雾器通过超声波振动的方式将液体分散成液滴。纳米喷雾器通过在膜上形成超薄液体层，并透过膜喷射雾化气体，将薄液体层破碎成亚微液滴来生成液滴。喷雾器在性能和参数如液滴大小，液滴速度和载气中的液滴浓度上不同。
一些喷雾器可以用于制备微滴，例如US专利号6,899,322中记载的超声波喷雾器(SonoteK，http://www.sonozap.com/Ultrasonic_Atomizer.html)和Nano-Sol纳米喷雾器(http://www.nanosol-il.com/prods.html)。喷雾器使用气体，通常为氮气或二氧化碳气体，作为喷雾和输送气体(所述气体产生微滴然后将其转运到目标)，以便微滴从被气体包围的喷雾器上脱离。
获得的微滴优选平均直径为约1-15微米，优选1-3微米。优选地，用于获得微滴的溶液为API完全溶解在适当的溶剂或表面活性剂中的溶液。API与溶剂或表面活性剂的比例优选在约1％至约30％之间，人们可以调整API与溶剂或表面活性剂的比例以获得不同大小或不同密度的微滴和颗粒。溶液可以包含其他成分，如另外的API，防腐剂，稳定剂，着色剂等。
优选的表面活性剂选自聚乙烯醇(PVA)，聚山梨酯80(聚氧乙烯(20)失水山梨糖醇单油酸酯)，聚山梨酯20(聚氧乙烯(20)失水山梨糖醇单月桂酸酯)，泊洛沙姆188，聚氧乙烯化35蓖麻油(cremophor EL)，聚氧乙烯40氢化蓖麻油或它们的混合物。
为了引导气流和微滴(或微粒，如果已经发生自然蒸发)经管道流向含有静态载体的容器，优选对载体床的下降气流一侧施加真空。真空吸力优选正好高到足以克服床上方的压力降并提供分层的气流。优选地，管道设计为使气流和微滴/颗粒以分层流动的方式流动，由此将粘附在管道和容器壁上的颗粒数量减少到最低限度。
由于各个微滴的表面面部比较大，故可自发地实现获得微粒的微滴的蒸发。这也可以通过，例如加热气流和微滴流向含有静态床的容器所经过的管道的方式来实现。任选地，载体床置于其中的容器也可以被加热以辅助蒸发。典型地，沿管长的一部分的约40-100℃的温度将足以蒸发微滴的溶剂。
优选在到达静态或周期性搅动载体置于其中的容器时，溶剂已经从微滴中部分蒸发而获得潮湿的微粒；更优选溶剂已经完全从微滴中蒸发而获得干燥的微粒。本领域技术人员会确定适当的蒸发条件以便可以控制微粒中的水含量。在某些情况下，潮湿的颗粒将使得微粒更好地粘附到载体上。
优选获得的微粒呈圆形。这至少部分通过在与载体接触前从微滴蒸发溶剂来实现。干微粒的平均直径优选为约100nm至约10,000nm，优选约200-5,000nm，更优选约500-5,000nm，最优选约500-1,000nm。
优选静态载体为制药行业中已知适合的辅料。适合载体的例子有：微晶纤维素(如Avicel 101)，乳糖和甘露糖醇。典型地，根据沉积于其上的API并根据给药途径来选择载体。载体颗粒的粒度分布可能会影响沉积的效率和跨床的压力降。有已知的方法来控制和操纵载体颗粒的大小，如过筛和研磨。
典型地，载体位于筛网上的容器中，以确保载体颗粒不因真空而从容器逸出。筛网可由不锈钢，聚酯，特氟隆等制成。本领域技术人员会根据所需载体颗粒的大小选择合适的具有一定大小的孔的筛网，以使筛网可允许通过喷雾和输送气体而无载体颗粒的逸出。例如，当使用Avicel 101时，发现孔的大小优选为约50至约100微米。
静态载体床典型地每15分钟利用搅动器搅动，以使载体的新的表面暴露并被干微粒包衣。这有助于改善干微粒沉积的效率和一致性。
典型地，一旦气流和微滴/颗粒到达容器，输送气体(如氮气)则容易因真空而从载体床和筛网内的空隙离开容器。而干微粒则因为载体是作为阻止微粒从容器逸出的过滤器，而沉积在载体上。
在优选的实施方式中，本方法是在单步中进行的。本文记载的“单步方法”，是指下述方法，在此方法中微粒在被输送气体运载时被干燥并被包衣到载体上。例如，微粒被干燥然后在另一个步骤中与载体混合的方法则不包括在术语“单步方法”的范围内。
由此参照特别优选的实施方式和说明性实施例来描述本发明，本领域技术人员能够理解不脱离说明书中所公开的本发明的主旨和范围的对所描述和说明的本发明的变更。记载的实施例用于帮助理解本发明，但并不意味，也不应被理解为，以任何方式限制其范围。若无相反的陈述，上述特定实施方式的任何组合都与本发明一致并被本发明所包含。
实施例
实施例中使用的纳米喷雾器由NanoSol公司生产，使用4个喷雾组分。实验使用缬沙坦API进行。缬沙坦的多晶型已记载于WO 04083192A1，其制备方法已公开在WO 20040094391中，这两者都通过引用并入本文。应容易地理解实施例可应用于不同的API。本发明在溶剂和溶质的选择上不包含任何固有的限制。
实施例1-用缬沙坦API对纤维素喷雾包衣
2％缬沙坦在溶剂(乙醇)中的溶液通过纳米喷雾器喷雾生成平均大小为约1-10微米的微滴。氮气用作喷雾和输送气体。载体为Avicel 101，用75μm筛网过筛以除去细颗粒。过筛的目的是为了减小床体上的压力降。床收集装置为改进的过滤—干燥器(GL filtration LTD公司生产的model filterlab 80)。改进包括将真空泵连接到容器底部，以去除氮和向床体引导悬浮颗粒和微滴流。仪器的第二个改进为去除烧结金属过滤介质，并以聚酯制成的支撑网来代替。
设计连接喷雾器和收集容器的管道以保持悬浮颗粒和微滴的分层流动。因此，管道壁上颗粒的沉积是最小的。加热元件被安装在管道的一个区段，以辅助乙醇蒸发。
纳米喷雾—包衣时床上的压力降增加，其在约20分钟内从30毫巴上升至219毫巴。发现通过搅动该床，压力降恢复到其原始值。在本实施例中，进行6次循环，喷雾总时间为131分钟。
不同的喷雾时间后：一次为46分钟后，另一次为131分钟后，两次取样分析缬沙坦的含量。并通过SEM观察样品。
从SEM照片(见图1)上可以观察到圆形的API颗粒(约100nm至约10000nm)沉积在载体上。通过实验分析可知，整个过程中API重量百分比(基于API和载体的总重量)被提升了：46分钟喷雾后为4.21％，131分钟后为9.95％。
Claims (20)
1.单步方法，其包括以下步骤：
提供输送气体，该输送气体运载包含API和溶剂的溶液的微滴；
从所述微滴中蒸发所述溶剂以获得由所述输送气体运载的包含所述API的干微粒；和
将载体用由所述输送气体运载的包含所述API的干微粒进行包衣。
2.权利要求1所述的方法，其中所述API选自：多西他赛，利哌利酮，倍氯美松，氟替卡松，布地萘德，沙丁胺醇，特布他林，异丙托品，氧托品，福莫特罗，沙美特罗，缬沙坦，依折麦布，帕潘立酮，阿瑞吡坦，他克莫司，西罗莫司，依维莫司和噻托溴铵。
3.权利要求1所述的方法，其中所述载体选自：微晶纤维素，乳糖和甘露糖醇。
4.权利要求1所述的方法，其中所述微滴的平均直径为约1至约15微米。
5.权利要求1所述的方法，其中所述干微粒的平均直径为约100nm至约10,000nm。
6.权利要求5所述的方法，其中所述干微粒的平均直径为约500nm至约5,000nm。
7.权利要求6所述的方法，其中所述干微粒的平均直径为约200nm至约5,000nm。
8.权利要求7所述的方法，其中所述干微粒的平均直径为约500nm至约1,000nm。
9.权利要求1所述的方法，其中所述包衣步骤包括将所述干微粒与载体床接触以获得用微粒包衣的载体。
10.权利要求9所述的方法，其中所述载体床为静态载体床或周期性搅动载体床。
11.权利要求1所述的方法，其中所述溶剂为乙醇。
12.单步方法，其包括以下步骤：
提供输送气体，该输送气体运载API和溶剂的溶液的微滴；
从所述微滴中蒸发所述溶剂以获得由所述输送气体运载的所述API的干微粒；和
将载体用由所述输送气体运载的所述API的干微粒进行包衣。
13.权利要求12所述的方法，其中所述载体选自：微晶纤维素，乳糖和甘露糖醇。
14.权利要求12所述的方法，其中所述微滴的平均直径为约1至约15微米。
15.权利要求12所述的方法，其中所述干微粒的平均直径为约100nm至约10,000nm。
16.权利要求15所述的方法，其中所述干微粒的平均直径为约500nm至约5,000nm。
17.权利要求16所述的方法，其中所述干微粒的平均直径为约200nm至约5,000nm。
18.权利要求17所述的方法，其中所述干微粒的平均直径为约500nm至约1,000nm。
19.权利要求12所述的方法，其中所述包衣步骤包括将所述干微粒与载体床接触以获得用微粒包衣的载体。
20.单步方法，其包括以下步骤：
提供输送气体，该输送气体运载基本上由API和溶剂组成的溶液微滴；
从所述微滴中蒸发所述溶剂以获得由所述输送气体运载的基本上由所述API组成的干微粒；和
将载体用由所述输送气体运载的基本上由所述API组成的干微粒进行包衣。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| US14728709P | 2009-01-26 | 2009-01-26 | |
| US61/147287 | 2009-01-26 | ||
| PCT/US2010/022045 WO2010085780A1 (en) | 2009-01-26 | 2010-01-26 | Processes for coating a carrier with microparticles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102292072A true CN102292072A (zh) | 2011-12-21 |
Family
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| CN2010800056187A Pending CN102292072A (zh) | 2009-01-26 | 2010-01-26 | 用微粒包衣载体的方法 |
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| US (2) | US8889213B2 (zh) |
| EP (1) | EP2389162A1 (zh) |
| JP (1) | JP5643229B2 (zh) |
| KR (1) | KR20110104120A (zh) |
| CN (1) | CN102292072A (zh) |
| CA (1) | CA2750711C (zh) |
| IL (1) | IL214221A0 (zh) |
| WO (1) | WO2010085780A1 (zh) |
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-
2010
- 2010-01-26 KR KR1020117018893A patent/KR20110104120A/ko not_active Ceased
- 2010-01-26 EP EP10701607A patent/EP2389162A1/en not_active Withdrawn
- 2010-01-26 CA CA2750711A patent/CA2750711C/en not_active Expired - Fee Related
- 2010-01-26 JP JP2011548201A patent/JP5643229B2/ja not_active Expired - Fee Related
- 2010-01-26 CN CN2010800056187A patent/CN102292072A/zh active Pending
- 2010-01-26 US US12/693,602 patent/US8889213B2/en not_active Expired - Fee Related
- 2010-01-26 WO PCT/US2010/022045 patent/WO2010085780A1/en active Application Filing
-
2011
- 2011-07-20 IL IL214221A patent/IL214221A0/en unknown
-
2014
- 2014-05-27 US US14/288,014 patent/US20140272100A1/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102593471A (zh) * | 2012-03-06 | 2012-07-18 | 中国科学院长春应用化学研究所 | 质子交换膜燃料电池电极和质子交换膜燃料电池的制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| US8889213B2 (en) | 2014-11-18 |
| CA2750711C (en) | 2015-07-07 |
| EP2389162A1 (en) | 2011-11-30 |
| KR20110104120A (ko) | 2011-09-21 |
| WO2010085780A1 (en) | 2010-07-29 |
| JP2012515798A (ja) | 2012-07-12 |
| US20140272100A1 (en) | 2014-09-18 |
| JP5643229B2 (ja) | 2014-12-17 |
| IL214221A0 (en) | 2011-08-31 |
| US20100189878A1 (en) | 2010-07-29 |
| CA2750711A1 (en) | 2010-07-29 |
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