CN1321628C - 湿磨方法 - Google Patents
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- B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
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- A61K9/1605—Excipients; Inactive ingredients
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Abstract
本发明提供了一种药物物质的微细制剂的制备方法,该方法包括在具有至少一个室和搅拌装置的研磨机中湿磨药物物质的混悬液,所述的室和/或所述的搅拌装置包括尼龙,其中所述尼龙含有一种或多种内部润滑剂,得到药物物质的微细制剂,其中研磨介质的污染和过程污染的水平均得到降低。
Description
本发明涉及研磨领域。更具体地说,本发明涉及可以用于制备药物物质的亚微颗粒的新型研磨方法。
药物物质的一个重要标准是获得良好的生物利用度,它是在通常通过口服途径给药后使药物物质吸收收入血流中的程度。已知各种因素会影响药物物质的生物利用度。例如,低生物利用度通常是低水溶性的结果。因此,在给药后,难溶于水的药物物质倾向于从胃肠道中消除,此后被吸收入血流中。
确定低水溶性的一种方式是应用可选择的更为强力的溶剂,诸如DMSO。尽管这类溶剂适合于药理学研究,但是它们几乎不适合于一般临床应用。众所周知颗粒药物的溶出率可能与药物的颗粒大小成反比,即溶解率随表面积的增加而增加。因此,提高难溶性药物的生物利用度的可选择的策略是将它们制成微细组合物。减小药物颗粒大小的许多方法在本领域中是公知的。
气流动力粉碎(超微粉碎)的两种这类方法是反向喷射(流化床型)或螺旋喷射(薄饼型)。这些方法因将不利的污染物从研磨物质中引入药物的危害降低而是有利的,其中所研磨的物质的大小因颗粒-颗粒碰撞而得到减小。然而,可通过这两种方法之一获得的最小颗粒大小的直径在2-5微米的范围。还将干磨法(诸如锤式研磨法)用于减小药物颗粒大小且由此增加药物的溶解性。然而,可获得的最小颗粒大小的直径约为30微米。尽管这些颗粒大小适合于片剂和其它剂型,但是分散的精细程度不足以显著提高难溶药物的溶出率。
用于微细制剂的另一种方法是湿磨法。常规的湿磨方法包括使粗药物物质的液体混悬液经过诸如分散研磨机这样的机械装置以便减小药物物质的大小。分散研磨机的一个实例是介质研磨机,诸如珠磨机。湿珠研磨法包括制备未研磨的粗药物物质的混悬液的步骤。然后使这种分散液通过含马达驱动搅棒和一定量研磨珠的研磨室以便产生精细研磨的混悬液。将筛用于将所述的珠保留在研磨室内,同时使每一研磨室内的产物流出。可以将管线上的混合器用于生产线以便粉碎研磨/未研磨的聚集物。
使用再循环法使大部分湿珠研磨物通过一个研磨室,其中将一种玻珠大小用于获得必不可少的大小减小。这是一种漆、墨水和陶瓷加工的确定方法,其中在湿磨过程中将一定量的能量[以kW/小时计]施加给产物以便满足目标颗粒大小。用于湿磨法的研磨机通常应用例如碳化钨这样的硬质陶瓷或不锈钢以便形成研磨室和搅拌棒且常用的研磨介质包括新开发的钇稳定的具有达到钻石硬度的氧化锆珠或基于聚苯乙烯或其它类似聚合物的相对较软的研磨介质。
因研磨介质和研磨室对产物的污染是湿磨法中常遇到的难题。在大批量(>10Kg)中,为了使颗粒大小小于1微米,研磨介质污染水平(锆和钇+形成不锈钢的元素,例如铁、钒等)可以增加到250ppm以上。这类水平的污染在制备药物过程中显然不能被接受。避免这种难题的一种方式是使用基于聚苯乙烯的研磨珠。然而,这种方式具有对大批量(即>20Kg)的加工时间可以为几天的缺陷。另一种方法是用聚氨基甲酸酯(Netzsch FeinmahltechnikGmbH)涂敷湿珠的研磨表面。然而,实际上已经发现涂敷了聚氨基甲酸酯的研磨组分具有极短的有效期限,它易被湿磨法中所用的研磨介质破坏。
美国专利US5,145,684和欧洲专利申请EP-A-0499299中公开了一种湿磨法以便生产含有以足量吸附在表面上而将有效平均颗粒大小(D95-D99)维持在约400nm以下的表面改性剂的结晶药物物质颗粒。认为作为稳定的混悬液的这种颗粒组合物为难溶于水的化合物提供了改善的生物利用度。然而,该方法本身持续时间极长,通常超过24小时且会经历来自研磨介质和研磨组分的高污染水平。因此,在EP-A-0499299中,将来自玻璃研磨珠的硅氧烷污染水平在湿研磨的达那唑含水淤浆中测定为10ppm、36ppm和71ppm(分别为实施例3、4和5)。它分别等于在相同干制剂中的38ppm、102ppm和182ppm的水平。
WO99/30687(SmithKline Beecham)中特别公开了包括苯并吡喃化合物(诸如反式-6-乙酰基-4S-(4-氟苯甲酰基氨基)-3,4-二氢-2,2-二甲基-2H-1-苯并吡喃-3R-醇和顺式-6-乙酰基-4S-(3-氯-4-氟苯甲酰基氨基)-3,4-二氢-2,2-二甲基-2H-1-苯并吡喃-3S-醇)的颗粒形式的组合物,它具有一定的颗粒大小分布,使得体积平均直径的中位值在350-700nm的范围。作为适合于制备这些组合物的WO99/30687中所述的一种方法包括在珠磨机中湿磨含水分散液,其中研磨室内衬有诸如尼龙这样的耐磨聚合物物质或由它构成。将这类方法描述为具有减少来自研磨物质的污染的优点。WO99/30687中的实施例描述了具有来自钇稳定的锆粉研磨珠的污染水平的研磨制剂:就锆而言<200ppn;而就钇而言<20ppm。
因此,本发明的一个目的是提供适合于制备微细药物组合物的改进的湿磨方法,其中产品的污染得到降低而没有防碍加工速度。
已经令人意外地发现使用至少某些研磨表面由包括一种或多种内部润滑剂的尼龙(聚酰胺)制成的研磨机的湿磨方法不仅可以导致研磨的产物具有显著降低的来自研磨介质的污染水平,而且还消除了来自所有研磨室组分物质的污染,但不会防碍加工效率。
因此,本发明在第一个方面中提供了药物物质的微细制剂的制备方法,该方法包括在具有至少一个室和搅拌装置的研磨机中湿磨药物物质的混悬液,所述的室和/或所述的搅拌装置包括含有润滑的尼龙。
本发明的方法使用在诸如分散研磨机这样的研磨机中进行的湿磨步骤以便产生药物物质的微细颗粒混悬液。可以使用诸如Lachman等在TheTheory and Practice of Industrial Pharmacy,第2章,“研磨”,45页(1986)中所述的那些常规湿磨方法来实施本发明。用于湿磨方法的药物物质混悬液一般是粗药物物质溶于液体介质所得到的混悬液。所谓“混悬液”指的是所述药物物质基本上不溶于所述液体介质。可以使用适宜的含水介质。粗药物物质可以通过商购获得或可以通过本领域中公知的技术来制备。使用本发明的方法可以使粗药物制剂的平均颗粒大小达到1mm直径。这有利于避免对药物物质预处理的需要。
含水介质中适宜含有一种或多种药物上可接受的水溶性载体,它们适合于空间稳定和在研磨成药物组合物后例如通过喷雾干燥进一步加工药物物质。最适于空间稳定和喷雾干燥的药物上可接受的赋形剂是:表面活性剂,诸如伯洛沙姆、十二烷基硫酸钠和聚山梨醇酯类等;稳定剂,诸如纤维素,例如羟丙基甲基纤维素;和载体,诸如碳水化合物,例如甘露糖醇。
在进行研磨的含水介质中,药物物质的含量可以约为1%-约40%w/v。
诸如羟丙基甲基纤维素(HPMC)这样的主要稳定剂的量可以在所研磨组合物的约0.1-约5%w/v范围内改变。载体的量可以在1-10%w/v内改变。
适用于本发明的研磨机包括诸如球磨机、磨碎机、振动研磨机这样的分散研磨机和诸如砂磨机和珠磨机这样的介质研磨机。这些分散研磨机在本领域中是众所周知的。适用于本发明的分散研磨机包括至少一个研磨室单元,它确定了一个内室和在该内室中带有用于搅拌所研磨的物质和研磨介质的装置。分散研磨机可以包括单研磨室单元或者包括多个研磨室单元。在后一种情况中,所述的研磨室可以按顺序排列,使得在研磨过程中药物物质的液体混悬液经流体连接件依次通过一个、几个或全部的室。在每种情况中,可以通过分散研磨机以单程方式或通过经研磨机使药物物质再循环所需数量的次数即多程法来加工所述的药物物质。优选单程法。下文涉及的“室”和“多室”包括所谓的选自研磨机中总室数量中的一个室或一个以上的室。
就介质研磨机而言,搅拌可以由以可移动方式安装在研磨室内、例如在外部电机驱动的旋转轴上的搅棒、针、圆盘等来完成。适用于本发明方法介质研磨机的研磨剂可以是诸如砂或珠这样的介质,但就制备精细磨碎的药物物质而言,建议使用珠。
“尼龙”指的是聚酰胺且包括Nylon6、Nylon6,6、Nylon4,6、Nylon11和Nylon12。优选高分子量尼龙。用于本发明的合适的高分子量尼龙包括具有重均分子量大于约30,000Da的尼龙。有利的是高分子量尼龙具有的重均分子量大于约100,000Da。
所谓“含有润滑剂的尼龙”(lubricated nylon)指的是含有诸如增塑润滑剂这样的润滑剂的尼龙,所述的润滑剂分布在所述的尼龙中。合适的润滑剂包括:低分子量烃类润滑剂,诸如邻苯二甲酸酯类,例如邻苯二甲酸二己酯、邻苯二甲酸二异辛酯、邻苯二甲酸二异壬酯和己二酸二异壬酯;和高分子量增塑剂,诸如石油蜡。润滑剂可以是液体或固体形式,例如油或蜡类或其组合。
为了获得本发明的优点,关注的是在研磨过程中至少接触药物物质和研磨介质的室的表面和/或搅拌装置的表面由含有润滑剂的尼龙制成。因此,所述的室和/或搅拌装置可以完全由含有润滑剂的尼龙模制或它们可以由混有含有润滑剂的尼龙的常用材料制成或涂敷了全部或部分含有润滑剂的尼龙层。
在本发明该方面的优选实施方案中,所述分散研磨机中的室和搅拌装置包括含有润滑剂的尼龙。因此,在研磨过程中至少接触药物物质和研磨介质的室的表面和搅拌装置的表面由含有润滑剂的尼龙制成。
含有润滑剂的尼龙可以有利地包括一种或多种液体或固体润滑剂或液体和固体润滑剂的组合。当这种尼龙包括液体和固体润滑剂的组合时获得了特别良好的效果。有利的是该尼龙可以含有1、2、3、4、5或6种不同的润滑剂。
优选所述的含有润滑剂的尼龙(诸如高分子量含有润滑剂的尼龙)具有下列特征中的至少一种且优选具有下列全部特征:
·在23℃下的肖氏D硬度为70-90,更优选80-85;
·在23℃下的抗压强度为650-810kg/cm2或80-120N/mm2,更优选85-100N/mm2;
·在23℃下的弯曲强度为700-1270kg/cm2;
·摩擦系数(钢上的样品)≤0.5、更优选≤0.3、更优选≤0.2、最优选≤0.1。(摩擦系数一般在0.08-0.4的范围内);
·在23℃下的拉伸强度为710-920kg/cm2或≥35N/mm2,更优选40-100N/mm2,最优选60-90N/mm2;
·拉伸中击为650-1100焦耳/cm2;
·在55m(分钟)-1.MPa的测试条件下的磨耗减量≤1mg/km,优选≤0.7mg/km,更优选≤0.4mg/km,最优选≤0.1mg/km。
具有这些特征的特定商购产品包括高分子量尼龙NylubeTM、OilonTM和Natural6TM,它们均商购自上述的Nylacast Ltd.。特别优选的含有润滑剂的尼龙是商购自Nylacast的NylubeTM,它含有固体润滑剂且具有下列特征:
·在23℃下的肖氏D硬度为80-84(ASTM D638);
·在23℃下的抗压强度为650-800kg/cm2(BS303);
·在23℃下的弯曲强度为700-1200kg/cm2(BS303);
·摩擦系数为0.08-0.10(钢上的尼龙);
·在23℃下的拉伸强度为710-890kg/cm2(ASTM D638);
·拉伸冲击为650-1050焦耳/cm2(ASTM D676);
·在55m(分钟)-1.MPa的测试条件下的磨耗减量≤0.1mg/km。
特别优选的类型NylubeTM是在55m(分钟)-1.MPa的测试条件下一般具有0.02mg/km磨耗减量的Nylube CF016TM。
特别优选的含有润滑剂的尼龙是商购自Nylacast的OilonTM,它含有液体润滑剂且具有下列特征:
·在23℃下的肖氏D硬度为80-85(ASTM D638);
·在23℃下的抗压强度为670-810kg/cm2(BS303);
·在23℃下的弯曲强度为770-1200kg/cm2(BS303);
·摩擦系数为0.13-0.14(钢上的尼龙);
·在23℃下的拉伸强度为720-900kg/cm2(ASTM D638);
·拉伸冲击为660-1100焦耳/cm2(ASTM D676);
·在55m(分钟)-1.MPa的测试条件下的磨耗减量≤0.1mg/km。
另一种优选的含有润滑剂的尼龙是商购自美国Cast Nylons的Nyloil-FG。
由于在很高的加载量时磨耗减量几乎可以忽略不计,所以在本发明的方法中特别优选使用Nylacast的Nylube CF016TM。
优选用于本发明方法的分散研磨机是珠磨机。合适的珠磨机是得自Nylacast Ltd.,Leicester,UK的AP0010研磨机。由诸如Dena systems BK Ltd.,Barnsley,UK或Drais,GmbH,Mannheim,Germany这样的其它公司制造的珠磨机也可以用于湿磨药物物质。
在这种实施方案中,搅拌装置适合包括搅棒、针或圆盘或它们的任意组合。有利的搅拌装置是一个或多个旋转搅棒。珠可以由聚苯乙烯、玻璃、用氧化镁稳定的氧化锆、用钇稳定的氧化锆、用铯稳定的氧化锆、硅酸锆、氧化锆-氧化铝、不锈钢、钛或铝制成。特别适用于本发明该的珠是由用钇稳定的氧化锆制成的珠。诸如上面所列的适用于本发明该实施方案的珠可以以不同尺寸获得。一般来说,可以使用具有平均直径约达5mm的球形珠,不过,当所述的珠具有小于2mm、优选约0.1-约1.25mm的平均直径时获得了良好的效果。
在本发明的该方面中,优选使用包括多个研磨室的研磨机。这些室应如上所述以液力连接方式彼此连接。例如,珠磨机可以包括2-10个研磨室,所选择的研磨室的确切数量应使加工时间最优化且取决于药物物质的粗混悬液中药物颗粒和所得研磨制剂中所需的药物颗粒的大小。选择可变的珠加载量和/或电机速度以便使研磨过程最优化。
在分散研磨机是带有多个研磨室的珠磨机的本发明实施方案中,如果第一个研磨室内的研磨珠的平均直径小于第二个研磨室内的研磨珠的平均直径则获得了附加的优点,其中第二个研磨室在第一个研磨室的上游。例如,第一个研磨室内的研磨珠的平均直径可以大于后续研磨室内的珠的平均直径。在一个特别优选的实施方案中,所述珠的平均直径在研磨室内依次减小,即各研磨室中含有相似平均大小或小于前面研磨室内的珠。这样能够获得较小颗粒大小的药物物质而不会增加来自研磨介质或室的污染水平。
在分散研磨机是带有多个研磨室的珠磨机的本发明实施方案中,可以使所述的药物物质在所有的室中循环。另一方面,通过分离一个或多个研磨室,可以将药物物质通过其中循环的研磨室的数量减少至该珠磨机中总研磨室数量的一个或几个。在进行进一步加工前所述的药物物质可以通过该珠磨机一次或许多次而与药物物质通过其中循环的研磨室的数量无关。换句话说,可以以单程方式或多程方式湿磨所述的药物物质。在多程方法中,药物物质通过其中循环的研磨室的数量和/或顺序可以根据循环的不同而改变。优选所述的药物物质按次序通过所有的室仅一次。这种单程法提供了加工时间减少和药物物质与研磨珠和室表面接触最少的优点,由此减少了污染。
本发明的方法可以包括干燥所述药物物质的其它步骤。所谓“干燥”指的是除去该方法中使用的任何的水或其它液体载体以便将所述的药物物质保持在液体混悬液或溶液中。这种干燥步骤可以是本领域中公知的任意干燥方法,包括冷冻干燥、喷雾制粒或喷雾干燥。在这些方法中,特别优选喷雾干燥。所有这些技术在本领域中均是众所周知的。最适宜使用诸如Mobile Minor Spray Dryer[Niro,Denmark]这样的喷雾干燥机或诸如由Glatt,Germany制造的那些流化床干燥机对磨碎的组合物进行喷雾干燥/流化床制粒。
本发明在第二个方面中提供可通过本发明第一个方面的方法获得的药物物质的微细制剂。在本发明的该方面中,该制剂的有效平均颗粒大小(D95-D99)一般小于约3000nm,诸如在400nm-约2500nm的范围。该制剂的有效平均颗粒大小通常在450-1200nm的范围。混悬液制剂的颗粒大小分布可以通过诸如激光衍射或光子相关波谱法等许多的分析技术来测定。例如,可以将得自Malvern Instruments Ltd.,Malvern,England的Malvern激光衍射装置Master Sizer S Model S4700用于分析微细混悬液的特征或可以将也得自Malvern Instruments Ltd.,Malvem,England的诸如Malvem Zetasizer5000这样的光子相关能波谱仪用于分析微细混悬液的特征。此外,可以使用具有足够的灵敏度和拆分纳米颗粒的任意其它颗粒大小技术。
在本发明的该方面中,例如喷雾干燥粉末的固体(干燥的)药物制剂中的研磨介质的污染水平一般≤20ppm、更一般地≤10ppm、最一般地≤5ppm。就在含有0.1-10%w/w的稳定剂的含水淤浆中所含浓度为1-30%w/w的湿磨药物制剂而言,这些污染水平一般等于8-0.2ppm、更一般的情况为4-0.1ppm且最一般的情况为2-0.05ppm。
本发明令人意外的优点在于使用本发明研磨法制备的药物制剂不含来自研磨机组分的可检测到的污染水平(定量水平为0.1ppm)。已经研究了来自研磨过程的总污染水平且来自研磨机中聚合物组分的污染水平令人意外地基本上低于0.1ppm,由此总过程污染一般≤20ppm、优选≤10ppm、更优选≤5ppm。
在本发明的该方面中,所述的药物物质例如可以是萘丁美酮或反式-6-乙酰基-4S-(4-氟苯甲酰基氨基)-3,4-二氢-2,2-二甲基-2H-1-苯并吡喃-3R-醇。
本发明在第三个方面中提供了包括按照本发明方法制备的药物物质的微细制剂的药物组合物。通过混合制备组合物且由此它们适合于口服或非肠道给药。该组合物可以是片剂、胶囊、再溶解粉剂或栓剂的形式。优选口服给药用的组合物。
用于口服给药的片剂和胶囊通常以单位剂量存在且含有诸如粘合剂、填充剂和稀释剂(压片助剂或压制助剂)、润滑剂、崩解剂、着色剂、调味剂和湿润剂这样的常用赋形剂。可以按照本领域中众所周知的技术给片剂包衣。
可以通过混合、填充、压片等常规方法来制备固体口服组合物。可以使用反复混合操作使活性剂分布在使用大量填充剂的那些组合物中。这类操作当然是本领域中众所周知的。
口服制剂还包括诸如片剂或丸剂、珠或颗粒这样的常用控释制剂,它们带有缓释包衣层或肠溶包衣层,或者例如通过包含成胶聚合物或形成基质的蜡类而改进以控制活性化合物释放。
在该组合物中有利的是包括湿润剂以便有利于本发明化合物的均匀分布。
本发明的组合物优选适合于口服给药。该组合物优选以单位剂量存在。优选将这类组合物每天给药1-2次。优选的单位剂型包括片剂或胶囊。可以通过诸如掺合、填充和压制这样常规的混合方法来配制本发明的组合物。用于本发明的合适的药物上可接受的载体包括稀释剂、填充剂、粘合剂和崩解剂。
为了更好地理解本发明和解释它们如何实施,现在通过实施例并参照附图来解释,其中:
附图1是可以按照本发明优选实施方案使用的分散研磨机。
附图2是可供选择的研磨机的排列。
参照附图1,本发明的研磨机包括两个研磨室(1,2),它们各自带有由电机(5)驱动的搅棒(3)。室(1,2)和搅棒(3,4)由Nylube CF016模制而成。第一个室通过导管(9,11)以液力连接方式与储蓄器(7)和第二个室(2)连接。每一导管(9,11)安装有一个管线上的混合器(13,15)。连接储蓄器和第一室的导管(9)上还安装有诸如气泵(16)这样的合适的泵,该泵的能量足以将液体介质泵入到整个研磨机周围。所述的储蓄器中含有混合装置(17),该装置在应用中可维粗药物物质(18)的液体混悬液。每一研磨室(1,2)内含有一定量的由筛(19,21)截留的钇稳定的氧化锆珠(未显示)。出口导管(23)使第二个研磨室(2)与连接储蓄器(7)的再循环导管(24)连接。再循环导管(24)中含有龙头(25)。安装接收储蓄器(27)以收集磨碎成纳米的药物混悬液(29)。
在应用中,储蓄器(7)中加入了液体介质中的粗药物物质(18)且由混合装置(17)维持成混悬液形式。粗药物物质的混悬液由气泵(16)沿导管(9)经第一个管线内混合器(13)泵出,该步骤可以从所述混悬液中除去聚集物。超细分散液然后进入第一个研磨室(1)。在第一个研磨室中,搅棒(3)的混合作用在它被电机(5)驱动时和珠(未显示)一起将粗药物混悬液研磨预设定的期限,该期限通过操作泵(16)来控制。这部分研磨的分散液随后被泵出而通过另一个管线内混合器(15)和第二个研磨室(2),此后通过出口导管(23)离开第二个研磨室。然后这种研磨成纳米的药物物质混悬液(29)通过再循环导管(24)再循环回第一个储蓄器(7),或如果龙头(25)开启,则所述的研磨成纳米的药物物质混悬液(29)排入接收的储蓄器(27)中。
在另一种可供选择的研磨机排列中,串联排列等数量的研磨室(31)和气泵(16)(参见附图2)。
下列实施例用来解释本发明。这些实施例并不用来限定如上所述和如下文要求保护的本发明范围。
实施例
实施例1
使200Kg批量的包括20%w/w6-乙酰基-3,4-二氢-2,2-二甲基-反式(+)-4-(4-氟苯甲酰基氨基)-2H-1-苯并[b]吡喃-3R-醇(制备方法参见WO92/22293的实施例20)、1.5%w/w羟丙基甲基纤维素、0.2%w/w十二烷基硫酸钠和5.0%w/w甘露糖醇的含水混悬液通过Dena DS-1P5珠磨机。在单程配置中使用5个8L的由Nylacast Nylube制造的研磨室,其中各室中含有85%(体积)的钇稳定的氧化锆珠(来自Tosoh,Japan)。使用下列珠的大小:1-5个室中3个室分别含有1.0mm、0.8mm、0.65mm的珠和2个室含有0.4mm的珠。以2.9L/分钟加工该批量,产物在研磨机中的存在时间为5分钟且批量加工时间为70分钟。在加工过程中的室压在2-3巴[28-42psi]之间改变。产率超过85%。随后将精细研磨的混悬液进行喷雾干燥。
在喷雾干燥的粉末中研磨介质的污染水平<3ppm锆(Zr)且<1ppm钇(Y)。
未加工的药物的颗粒大小约为1mm且产物具有如折射率校正的激光衍射测定的0.5微米的平均颗粒大小。
实施例2
使200Kg批量的含有30%w/w 4-(6’-甲氧基-2’-萘基)-丁-2-酮(萘丁美酮,制备方法参见美国专利US 4,420,639)、w/w十二烷基硫酸钠、3%w/w羟丙基甲基纤维素和4%w/w甘露糖醇的含水混悬液通过Dena DS-1P5珠磨机。在单程配置中使用5个8L的由Nylacast Nylube制造的研磨室,其中各室中含有70%(体积)的钇稳定的氧化锆珠(来自Tosoh,Japan)。使用下列珠的大小:1-5个室中3个室分别含有1.0mm、0.8mm、0.65mm的珠和2个室含有0.4mm的珠。以1.5L/分钟加工该批量,产物在研磨机中的存在时间为10分钟且批量加工时间为21/4小时。在加工过程中的室压在2-3巴[28-42psi]之间改变。产率超过85%。随后将精细研磨的混悬液进行喷雾干燥。
在喷雾干燥的粉末中研磨介质的污染水平<3ppm锆(Zr)且<1ppm钇(Y)。
未加工的药物的颗粒大小约为1mm且产物具有如激光衍射测定的0.9微米的平均颗粒大小。
使用剧烈提取方法来对可能存在来自由Rubber And Plastic ResearchAssociation(Shawbury,UK)的基于聚合物的研磨机组分的产品污染进行研究并通过气相色谱法、高压液相色谱法和质谱法进行分析。所述组分包括尼龙研磨室和搅棒、PTFE、Viton和EPDM O-环和PEEK填充的PTFE孔隙分离器。尽管可以鉴定可提取的物质,但是对喷雾干燥的粉末进行的分析发现没有产物携带任何的研磨机组分物质。对可提取的各物质的定量极限为40ppb且检测极限为20ppb。在喷雾干燥产品中提取物质的总量小于0.1ppm。
Claims (14)
1.药物物质的微细制剂的制备方法,该方法包括在具有至少一个含有研磨介质的室和搅拌装置的研磨机中湿磨药物物质的混悬液,其中在研磨过程中至少接触药物物质和研磨介质的室的表面和搅拌装置的表面由含有润滑剂的尼龙制成;和研磨后,干燥所述的药物物质,由此,固体干燥的药物制剂中的研磨介质的污染水平≤20ppm。
2.如权利要求1中所述的方法,其中所述的含有润滑剂的尼龙含有一种或多种固体润滑剂。
3.如上述任意权利要求中所述的方法,其中所述的含有润滑剂的尼龙含有一种或多种液体润滑剂。
4.如上述任意权利要求中所述的方法,其中所述的含有润滑剂的尼龙含有一种以上的润滑剂。
5.如上述任意权利要求中所述的方法,其中所述的含有润滑剂的尼龙具有的摩擦系数≤0.35。
6.如上述任意权利要求中所述的方法,其中所述的含有润滑剂的尼龙是NylubeTM、OilonTM或Nyloil-FGTM。
7.可通过权利要求1-6中任意一项所述方法获得的药物物质的微细制剂。
8.权利要求7的微细制剂,其中研磨介质的污染水平≤10ppm。
9.权利要求7的微细制剂,其中研磨介质的污染水平≤5ppm。
10.权利要求7的微细制剂,其中过程污染的总水平≤20ppm。
11.权利要求7的微细制剂,其中过程污染的总水平≤10ppm。
12.权利要求7的微细制剂,其中过程污染的总水平≤5ppm。
13.包括如权利要求7-12中任意一项所述的药物物质的微细制剂的药物组合物。
14.如权利要求7-12中任意一项所述的微细制剂或如权利要求13中所述的组合物,其中所述的药物物质是萘丁关酮或反式-6-乙酰基-4S-(4-氟苯甲酰基氨基)-3,4-二氢-2,2-二甲基-2H-1-苯并吡喃-3R-醇。
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