CN1731984A - 通过在冷表面上冰冻得到的药物粒子 - Google Patents
通过在冷表面上冰冻得到的药物粒子 Download PDFInfo
- Publication number
- CN1731984A CN1731984A CNA038258234A CN03825823A CN1731984A CN 1731984 A CN1731984 A CN 1731984A CN A038258234 A CNA038258234 A CN A038258234A CN 03825823 A CN03825823 A CN 03825823A CN 1731984 A CN1731984 A CN 1731984A
- Authority
- CN
- China
- Prior art keywords
- solution
- cold
- organic solvent
- particle
- butanols
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Abstract
本发明涉及一种制备微米级或次微米级药物粒子的方法,它包括将含有水难溶性药物和至少一种可冻结的有机溶剂的溶液与冷表面接触以便冻结该溶液;除去有机溶剂。还公开了所得到的粒子和能用于实施本发明方法的设备的几个实施方案。
Description
技术领域
本发明涉及通过在冷表面上冰冻制备的粒子,特别是通过在冷固体表面上冰冻制备的水难溶性药品粒子。
背景技术
一个药物终产品理想的特性是具有高的生物利用度和短的溶解时间。生物利用度是一个术语,意指在对机体给药之后,药品(或药物)进入靶组织的程度。差的生物利用度是药物组合物,特别是含有难溶于水的活性组分的药物组合物研发中遇到的一个重要问题。例如,水难溶性药物经口服给药后,在被吸收进入血液循环之前就从胃肠道代谢消除。
众所周知,粒化药物的溶解速率随其表面积的增加而增加,即减小药粒的大小。所以,人们已经尝试了对药物组合物的药物颗粒粒度和粒度范围进行控制。例如,如美国专利No.5145684所述,使用湿磨技术,。然而,这种湿磨技术会产生与研磨介质污染有关的问题。此外,药物暴露于过度的机械剪切或极端高温下,可能引起药物改变或由于活性成份分解而导致的活性丧失,,或者由于重结晶(recrystallyzation)过程导致活性丧失,即,各种结晶的多晶型物的形成或药物(至少是一部分)由晶状转化成无定型态,如Florence等,Effect of Particle Size Reduction on Digoxin Crystal Properties,Journalof Pharmaceutics and Pharmacology,Vol.26,No.6,479-480(1974),以及R.Suryanarayanan和A.G.Mitchell,Evaluation of Two Concepts ofCrystallinity Using Calcium Gluceptate as a Model Compound,International Journal of Pharmaceutics,Vol.24,1-17(1985)所述。此外,湿磨技术常常引起一部分较大颗粒的出现,从而影响颗粒彻底溶解的时间。
其它减小粒度的工作包括如美国专利No.3,309,777和5,780,295所述的。‘777和‘295专利所描述了工艺包括气化生物学悬浮液,然后通过撞击气溶胶粒子将它们收集在冷收集表面之上,从而使每一个粒子外包围一层纯水冰层。接着从冷表面取出这种冻结的气溶胶粒子并干燥。‘777和‘295专利告诉我们在生物学悬浮液中使用原生水(primarily water)的方法,但是,当采用水难溶性药物时这种方法是不适宜的。‘777专利和‘295专利都未解决水难溶性药物进行该操作时遇到的问题。
美国专利No.3,932,943和WO 02/060411描述了以修饰颗粒结构为目所作的努力:通过将那些物质喷雾进入低温液体而得到冰冻物质。然而,这些参考文献所描述的技术在从低温液体回收颗粒、低温液体的处理和环境等方面存在问题。
美国专利Nos.3,313,032和5,727,333描述了由溶液干燥物质的方法。然而,这些专利都没有改善水难溶性药物生物利用度和溶解速率的需要。
提供稳定的微米或次微米粒度级的水难溶性药物组合物会是有益的,这种组合物具有改善的生物利用度,但不具有与以上鉴别的
现有技术相关的问题。
发明内容
首先,本发明涉及一种用于制备微米级或次微米组药物粒子的方法,包括将含有水难溶性药物和至少一种可冻结的有机溶剂的溶液与冷表面接触以冻结该溶液;除去有机溶剂。
其次,本发明涉及由一种方法生产的药物粒子,这种方法包括:含有难溶性药物和至少一种可冻结的有机溶剂的溶液与冷表面接触以便冻结该溶液;除去有机溶剂。
另外,本发明涉及一种制备药物粒子的设备,它包括:具有第一侧面和相对第二侧面的冷固体表面;位于冷表面第一侧面近端的加料装置(application means),这种加料装置用于含有难溶性药物和至少一种可冻结的有机溶剂的溶液施加至冷表面的第一侧面以便冻结该溶液;位于冷表面第二侧面近端的冷却装置,该装置用于冷却冷表面;接近冷表面的清除装置,用于从冷表面的第一侧面除去冻结的溶液;由冻结溶液清除有机溶剂用的溶剂清除装置;和由冷表面转移冻结溶液至溶剂清除装置用的装置。
本发明具有能够加工水难溶性药物,从而改善那些药物溶解速率和生物利用度的优点。此外,与以上现有技术描述的那些方法相比,本发明允许在最终药物制剂中提高药物载量。此外,由于避免固-液分离步骤和/或液-液分离步骤或与处理低温液体相关的步骤,本发明某些方面允许所得药物粒子更易于加工。
附图说明
图1是适用于本发明的设备的一项实施方案的平面图。
图2是适用于本发明的设备的一项供选择实施方案的平面图。
图3是适用于本发明的设备的一项供选择实施方案的侧视图。
发明效果图1说明了能用于实施本发明的设备的第一实施方案10。溶液首先施加至冷表面。这种溶液包括难溶性药物和至少一种可冻结的有机溶剂。在本文使用时,术语“水难溶性”意指具有小于约10mg/ml水溶解度的那些药物。本发明特别适用于具有小于1mg/ml甚至低至500ng/ml溶解度的那些药物。
优选地,药物基本上是纯的形式并且在至少一种液体介质中是可分散的。优选的包括经口服给药的药物,包括,例如:止痛药、抗炎药、驱肠虫药、抗心律失常药、抗生素(包括青霉素)、抗凝药、抗抑郁药、抗糖尿病药、镇癫痫药、抗组胺药、抗高血压药、抗毒蕈碱药、抗分枝杆菌药、抗肿瘤药、免疫抑制药、抗甲状腺药、抗病毒药、抗焦虑镇静药(催眠药和精神抑制药)、收敛药、β-肾上腺素能受体阻断剂、血液制品和代用品、强心(cardiacinotropic)药、造影剂、皮质甾类、咳嗽抑制药(祛痰剂和粘液溶解剂)、诊断剂、诊断显影剂、利尿剂、多巴胺制剂(抗帕金森氏病剂)、凝血药、免疫(immuriological)药、血脂调节药、肌肉松弛药、拟副交感神经药、甲状旁腺降钙素和双膦酸盐、***素、放射性药物、性激素(包括类固醇)、抗过敏药、刺激剂和厌食药、拟交感神经药、甲状腺制剂、vasidilator和黄嘌呤。这些类别的药物和每个类别包含种类的清单的描述见于Martindale,The Extra Pharmacopoeia,第29版,ThePharmaceutical Press,London,1989,它的公开通过本参考特此并入。
溶液还包括至少一种可冻结的有机溶剂。这种有机溶剂必须能够溶解该水难溶性药。优选地,这种药物在有机溶剂中具有约0.1至约90重量百分比的溶解度。特别适合的有机溶剂选自能够在相对高的温度冻结且具有相对接近于冰点的沸点的那些。优选地,这种有机溶剂具有小于约100℃的冰点,更优选小于约75℃。优选地,这种有机溶剂选自醇、醚、卤化碳、烃、卤代烃、芳香烃、酯、乙酸酯、有机酸、胺、酮、砜、腈、碳酸酯、醛或它们的组合。具体适合的有机溶剂的例子包括乙醇、异丁醇、甲醇、n-丁醇、异丙醇、n-戊醇、n-庚醇、仲-辛醇、环戊醇、n-辛醇、苄醇、乙二醇、环庚醇、n-癸醇、环辛醇、环己醇、t-丁醇、t-戊醇、五氟苯酚、甲基丁炔醇、六氟异丙醇、2,2,2-三氟乙醇、n-己醇、1,3,4-硝基甲酚、乙酸甲酯、乙酸异丁酯、乙酸n-丙酯、乙酸乙酯、乙酸异戊酯、乙酸n-丁酯、乙酸异丙酯、乙酸n-戊酯、乙酸n-辛酯、乙酸仲丁酯、甲苯、乙苯、间-二甲苯、邻-二甲苯、对-二甲苯、混合的二甲苯、苯、环己烷、环庚烷(cycoheptane)、1,2,4,5-四甲苯、环丙烷、乙二醛、乙醛、三甲基乙醛、二甲基甲酰胺、β-甲基吡啶、吡啶、吗啉、哌嗪、3,5-二氯吡啶、吡嗪、乙二胺、噁唑、二乙胺、三乙胺、甲胺、碳酸二甲酯、二碳酸二-t-丁酯、甲酸甲酯、甲酸异丁酯、甲酸异戊酯、甲酸n-丙酯、甲酸乙酯、甲酸n-戊酯,和草酸二甲酯、二***、甲基-t-丁基醚、二异丙基醚、1,4-二噁烷、四氢呋喃、1,3,5-三噁烷、p-二噁烷、二甲醚、对-二氯苯、五氟甲苯、六氟甲苯、1,2,4,5-四氟苯、1,3,5-三氟苯、氯仿、二氯甲烷、四氯化碳、1,2-二氟-1,1,2,2-四氯乙烷、1,1,1-三氯-2,2,2-三氟乙烷、二氟乙烯、1,1,1-三氯乙烷、2,2-二氯丙烷、1,1,2-三氯-1,2,2-三氟乙烷、二氯乙烯、全氟环丁烷、反-二氯乙烯、1-溴-1-氯-2,2,2-三氟乙烷,和全氟癸烷、反-1,2-12,-二氯乙烯、n-己烷、n-庚烷、n-辛烷、n-癸烷、2,2,3,3-四甲基丁烷、双环(2.2.1)庚-2-烯、2,3,4-三甲基-1-戊烯、2,5-二甲基-2,4-己二烯、四硝基甲烷、顺-1,3,5-己三烯、新戊烷、2,2,3-三甲基丁烷、二甲基乙炔、联乙炔、丙酮、甲基乙基酮、甲基异-丁基酮、甲基丁基酮、环戊酮、甲基-t-丁基酮、二异丁基酮、二乙基酮、二丙基酮、环己酮、甲基庚基酮、乙腈、反丁烯二乙腈(fumaronitrile)、甲酸、冰醋酸、羟基乙酸、丙酸、三氟乙酸、二甲基亚砜或它们的组合。使用组合溶剂时,溶剂比例不是决定性的,取决于希望达到的溶液冰点以及溶于该组合溶剂的具体药物所希望达到的溶解水平。
更优选地,可冻结的有机溶剂选自二氯甲烷、环戊醇、t-戊醇、对-二甲苯、t-丁醇、乙腈、四氢呋喃、环己烷、三氟乙醇、羟基乙酸、乙酸、环己酮、甲基t-丁基酮、二乙基酮,和它们的组合。最优选地,可冻结的溶剂选自通常被认为是药学上可接受的。任选地,这种溶液进一步包括至少一种稳定剂。非此即彼地,任选的稳定剂在溶液冻结之后加入。这种稳定剂用于抑制晶体生长和抑制药物粒子聚集及附聚。一种或多种稳定剂的选择将取决于药物分子。通常,聚合稳定剂是优选的。粒子稳定剂的例子包括磷脂、表面活性剂、聚合表面活性剂、胞囊(vesicles)、聚合物,包括共聚物和均聚物及生物聚合物、和/或分散助剂。适合的表面活性剂包括明胶、酪蛋白、卵磷酯、磷酯、***树胶、胆固醇、西黄蓍胶、脂肪酸和脂肪酸盐、苯扎氯铵、甘油单和二脂肪酸酯和醚、十八十六醇混合物、聚西托醇(cetomacrogol)1000、聚氧化乙烯蓖麻油衍生物、聚氧化乙烯脱水山梨醇脂肪酸酯,例如商业上可得到的吐温系列(Tween)、聚乙二醇、聚(环氧乙烷/环氧丙烷)共聚物,例如商业上可得到的Poloxomers或普罗尼克类(Pluronics)、聚氧化乙烯脂肪酸醚,例如商业上可得到的Brijs,聚氧化乙烯脂肪酸酯、脱水山梨醇脂肪酸酯,例如商业上可得到的司盘类(Spans)、胶态二氧化硅、磷酸盐、十二烷基硫酸钠、羧甲基纤维素钙、羧甲基纤维素钠、甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、非晶纤维素、硅酸镁铝、三乙醇胺、聚乙烯醇(PVA)、月桂基硫酸钠、聚乙烯吡咯烷酮(PVP)、聚(丙烯酸)和其它阴离子、阳离子、两性离子和非离子表面活性剂。在American Pharmaceutical Association和ThePharmaceutical Society of Great Britain,the Pharmaceutical Press 1986年共同出版的《药物辅料手册》(Handbook of PharmaceuticalExcipients)中,详细描述了其它适合的稳定剂,该手册通过参考并入本文。这样的稳定剂是商业上可得到的和/或可通过本领域已知技术制备。
通常地,加入溶液的稳定剂的数量将取决于药物的剂型和药物类型。优选地,稳定剂以小于90%的浓度加入溶液,更优选小于70%,更为优选的是小于50%。
如果使用稳定剂,即使水对于溶解水难性药物无效,也可任选地加入溶液以有助于溶解稳定剂。。
在一项实施方案中,稳定剂特征是表面活性剂。本文适合采用的表面活性剂可由本领域熟练人员迅速确定,包括各种非离子、阴离子、阳离子和两性离子表面活性剂,或者这些表面活性剂的混合物。优选的表面活性剂能够显著减少不连续相中油滴聚结趋势。非离子表面活性剂的例子包括聚亚烷基二醇醚和脂肪醇、脂肪胺或脂肪酸与环氧乙烷或环氧丙烷的缩合产物;不同分子量和水解程度的聚乙烯醇;聚乙烯吡咯烷酮;和Brij,吐温,和司盘系列表面活性剂。阴离子表面活性剂包括烷基芳磺酸盐,硫酸盐化聚乙二醇醚和磺基琥珀酸醚。阳离子表面活性剂包括季铵化合物和脂肪胺。
冷固体表面包括第一侧面和相对的第二侧面。溶液通过位于冷固体表面近端的加料装置施加至冷固体表面。在图1所示实施方案中,喷雾器11是将溶液施加至冷表面用装置。喷雾器11可以是标准的、商业上可得到的喷雾器或者是专门设计的喷雾器。可以使用将溶液施加至冷表面的任何装置,例如利用重力、压力差、电荷和/或温差的装置。可供选择地,如图2所示的滴管21可用于以滴加方式将溶液加至冷表面,还可以使用滚筒、刷子或其它毛细管作用加料器。此外,可用真空将溶液吸引到冷表面上。也可使用其它类型的本领域熟练人员已知的加料装置。
在图1和2所示的实施方案中,冷固体表面包括圆筒12,它能在低温下保持不变和旋转。然而,可以使用任何固体表面,没有必要要求表面是曲线或者能移动。还可使用固体平面或不能旋转的曲面,只要这种表面是固态且能耐受极低温度,从而能够大体上冻结刚接触的溶液。固体表面的例子包括但不限于滚筒、带、盘等。
溶液施加至冷表面的速率应当是充分的,以便溶液在接触固体表面后不久就能大体上冻结。优选地,溶液接触冷表面后在小于一分钟内大体上冻结。更优选地,溶液施加至冷表面,接触冷表面后在小于一秒钟内大体上冻结。溶液施加至表面在冷表面上形成的溶液薄膜层厚度应该满足在刚接触数秒内冻结。优选地,加料速率产生厚度小于5毫米的膜,更优选地,小于约1mm,甚至小于约0.2mm,极优选小于约0.05mm。如果溶液薄膜不足以在接触冷表面数秒内大体上冻结,那么就是溶液施加太快了。
用于冷表面的材料可以是任何能够冷却至希望温度的材料。优选地,构造材料能够良好热传递。特别适合用于冷表面材料的例子包括金属,金属合金,玻璃,和陶瓷。
溶液在施加至冷表面之前的温度不是关键。
本发明包括位于冷固体表面第二侧面近端的冷却装置,这种冷却装置用于冷却表面。冷却固体表面可采用任何适当的装置,这些装置包括利用低温固体、低温气体、低温液体或者能够达到低温的传热流体。低温固体定义为在水冰点之下升华的物质,例如,二氧化碳。低温气体意指在水冰点以下是气体的物质,例如,氮气。低温液体是在水冰点以下是液体的物质,例如,液氮。在如图1和2所示的实施方案中,圆筒12内的孔13用于在圆筒12内侧放置干冰冷却圆筒12表面。在图3所示的实施方案中,低温传热剂33,例如氮或液体二氧化碳,用来与冷表面直接或间接接触,冷却表面。还可使用其它本领域熟练人员已知的冷却表面的装置。
冷表面应当冷却到的温度将取决于溶液中使用的有机溶剂或溶剂类。在溶液和冷固体表面接触之前,冷固体表面温度应当冷却至低于可冻结的有机溶剂冰点之下,这样就确保溶液刚一接触固体表面就大体上冻结。可冻结有机溶剂冰点和冷表面温度之间的差异会影响溶液冻结速率。
本文使用时,术语“冻结的溶液”定义为水难溶性药物粒子和,任选地,一种或多种赋形剂,悬浮于冻结的有机溶剂基质内。一旦溶液在接触冷表面之后便在数秒内大体上冻结,形成这样的冻结溶液。
优选地,冷表面冷却至低于有机溶剂冰点至少5℃的温度,更优选的是低于有机溶剂冰点至少30℃,甚至低于有机溶剂冰点至少50℃,极优选低于有机溶剂冰点至少75℃。令人期望地,在实施本发明工艺的整个时间周期内,冷表面保持在低温。
本发明还包括从冷表面清除冻结溶液的装置。如图1和2所示,转移冻结溶液用装置的一个例子包括刀片部件14,它剥落冷表面冻结溶液,然后使冻结溶液在重力作用下转移到收集面或者直接进行下一步加工。振动、压力、刷子或鼓风机或其它利用压差的方法都可用于从冷表面清除冻结溶液。此外,在冷表面上无粘性涂敷会使冻结溶液自动清除。
图1和2还显示用来收集从圆筒12清除的冻结溶液的成品盘16,另一个盘17作为冷却成品盘16用的可选装置。通过冷却成品盘,溶液保持冻结直到准备进行下一步加工。
对于本发明来说,转移冻结溶液至后面加工步骤的装置可能也是必须的。在如图1-2所示那些实施例中,冻结溶液在重力作用下进入随后的加工步骤。在其它实施例中,传送机可用于转移冻结溶液。
溶剂清除装置用于从冻结溶液除去有机溶剂,从而产生所制备的药物粒子。合适的溶剂清除方法包括升华和蒸发。升华技术的例子包括但不限于冷冻干燥和常压冷冻干燥,这些是溶剂清除领域熟练人员已知的。蒸发技术的例子包括但不限于蒸馏技术和喷雾干燥技术,这些也是溶剂清除领域熟练人员已知的。为了采用这样的蒸发技术,就要求冻结溶液首先能够分散在与有机溶剂可混合但不能溶解药物的液体中,例如,水。
通过光散射技术测量,粒子分散于水中之后所得药物粒子平均体积平均粒度是0.05微米至150微米。更优选地,平均体积平均粒度是50微米或更小,甚至25微米或更小,极优选5微米或更小,最优选1微米或更小。
所得的药物粒子相对于未采用本发明加工的颗粒,具有高的表面积。有益地,高表面积能有助于加快溶解时间。优选地,采用本领域熟练人员已知的BET技术测量时,根据本发明制备的粒子具有至少2m2/g的表面积,更优选至少5m2/g的表面积,甚至至少10m2/g。
这种药物粒子可与任何药学上接受的载体混合,形成能够适合口服给药的药物制剂。本发明的组合物还可包括任选的赋形剂,例如本领域熟练人员已知的标准填充剂、粘合剂或崩解剂。
与采用本发明加工之前的药物相比,所得的药物粒子在体外显示增加的溶解速率。优选地,采用本领域熟练人员已知的标准体外溶解方法测量时,采用本发明加工的药物粒子显示至少1.5倍于未加工药物溶解速率的体外溶解速率,更优选至少5倍于未加药物溶解速率,还优选至少10倍于未加工药物溶解速率。例如,在2分钟内,如果未加工药物溶解20%,采用本发明加工的粒子会溶解至少30%。
令人惊奇地,尽管本发明包括快速冷冻,所得的药物粒子实际上是充分结晶的。
通过以下实施例进一步阐明本发明,这些实施例是本发明的纯粹示范。除非另外说明,所有份数和百分比是以重量计。
实施例
材料
环孢菌素A是购自POLI Industria Chimica S.P.A的药物。
达那唑是购自Spectrum Chemical Co.,&Diosynth Co.的药物。
酮康唑、酮洛芬、萘普生、硝苯地平、***、曲安奈德(triamcinalone acetonide)、卡马西平和醋酸氢化可的松是购自Spectrum Chemical Co.的药物。
普罗尼克F-127,是购自Sigma Chemical Co.的稳定剂。
普罗尼克F-108,Pluronic F-88是购自BASF Co.的稳定剂。
普罗尼克F-68,聚乙烯吡咯烷酮(PVP,10K,29K,55K)、司盘40,、司盘60,、和聚乙二醇(PEG,10K)是购自Aldrich Chemical Co.的稳定剂。
对-二甲苯、t-戊醇、1,3,5-三噁烷,、仲-乙酸丁酯和环戊醇是购自Aldrich Chemical Co.的溶剂。
t-丁醇、丙腈、丙酮、四氢呋喃和乙酸乙酯是购自Fisher ScientificCo.的溶剂。
分析方法
粒度分析。在分散于水中之后,采用贝克曼库特氏计数器,对大量原料药粉末和实施例1-60制备的粉末进行分析。
USP溶出度测定装置法2。采用以下方法得到的溶解本文还称为“体外溶解”。采用的溶解介质随药物而变,并且说明如下。溶解介质加热至37℃并脱气。每次实验利用三个容器进行溶解。根据本发明制备的11至12mg药物粒子加至每个容器以便溶解分析。溶解样品自动过滤进入含有0.1mL乙腈的实验试管,用涡流混合器混合,过滤并由HPLC分析。在2,5,10,15,20,30,60,和120分钟采样,在60分钟时,搅拌速度提高至200rpm,以确保在120分钟左右完全溶解。120分钟记录是无限时间记录,无限时间用于计算效力。测量原样原料药粉和根据本发明实施例1-60制备的药物粒子的溶解时间。实施例1-60使用的各种药物溶解介质如下:
对于萘普生、卡马西平(Carbamazapine)&酮洛芬:溶解介质是含有5.0wt.%氯化钠的去离子水。
对于达那唑:溶解介质是含有0.75wt.%SLS,1.21wt.%三(羟甲基)氨基甲烷的去离子水,且调节至pH为9。。
对于环孢菌素A:溶解介质是含有0.1wt.%SLS的去离子水。
对于酮康唑:溶解介质是含有0.5wt.%SLS的去离子水。
对于硝苯地平:溶解介质是含有0.3wt.%SLS和3.0wt.%氯化钠的去离子水。
对于***&曲安奈德:溶解介质是含有10wt.%氯化钠的去离子水。
对于醋酸氢化可的松:溶解介质是含有0.3wt.%氯化钠十二烷基硫酸酸钠(SDS)的去离子水。
结晶度百分比。通过X-射线衍生法采用布鲁克(Bruker)D-8自动化衍射计。
常压冷冻干燥(ATMFD)。ATMFD是以下实施例中采用的溶剂清除方法。传热流体经热交换器循环夹套循环,即用于冷却干燥气体,然后至ATMFD单元夹套。冷却了的氮气流经ATMFD单元底部,以从药物升华出溶剂并流化固体。ATMFD单元和氮气温度缓慢加热至室温。这种工艺ATMFD部分结束之后,由旋风器或ATMFD单元收集固体。
冷冻干燥。冷冻干燥是用于以下一些实施例的供选择的溶剂清除方法。制备的冻结溶液转移至以干冰冷却的瓶中。在冷却了的容器内加工过的固体置于Virtis冷冻干燥机上并在近似100毫托真空干燥约12-24小时。
对于实施例1-60的每一个,溶液采用表A所列材料制备。
表A
实施例 | 药物 | Wt%药物 | 溶剂 | Wt%溶剂 | 稳定剂 | Wt%稳定剂 |
1 | 达那唑((瓶) | 1.44 | t-丁醇 | 95.68 | 普罗尼克F-127.&PVP(10k)(50/50)wt.%比 | 2.88 |
2 | 酮康唑(喷雾) | 1.22 | t-丁醇 | 97.56 | 普罗尼克F-127 | 1.22 |
3 | 达那唑(喷雾) | 2.13 | t-丁醇 | 95.74 | 普罗尼克F-127 | 2.13 |
4 | 卡马西平 | 1.92 | t-丁醇 | 96.16 | 普罗尼克F-127 | 1.92 |
5 | 卡马西平 | 0.50 | 对-二甲苯 | 99.00 | 普罗尼克F-127 | 0.50 |
6 | 卡马西平 | 1.92 | t-丁醇 | 96.16 | 普罗尼克F-127 | 1.92 |
7 | 卡马西平 | 0.95 | t-丁醇 | 98.10 | 普罗尼克F-88 | 0.95 |
8 | 卡马西平 | 0.95 | t-丁醇 | 98.08 | PVP(10k) | 0.97 |
9 | 卡马西平 | 1.00 | t-丁醇 | 98.00 | 普罗尼克F-127.&PVP(10k)(50/50)wt.%比 | 1.00 |
10 | 环孢菌素A | 1.92 | t-丁醇 | 96.16 | 普罗尼克F-127 | 1.92 |
11 | 环孢菌素A | 1.92 | t-丁醇 | 96.16 | 普罗尼克F-127 | 1.92 |
12 | 达那唑 | 2.83 | t-丁醇 | 94.34 | 普罗尼克F-127 | 2.83 |
13 | 达那唑 | 3.70 | t-丁醇 | 92.60 | 普罗尼克F-127 | 3.70 |
14 | 达那唑 | 4.55 | t-丁醇 | 90.90 | 普罗尼克F-127 | 4.55 |
15 | 达那唑 | 1.61 | t-丁醇 | 96.78 | 普罗尼克F-127 | 1.61 |
16 | 达那唑 | 1.47 | t-丁醇 | 98.04 | 普罗尼克F-108.&PVP(55k)(50/50)wt.%比 | 0.49 |
17 | 达那唑 | 0.93 | t-丁醇 | 98.08 | PVP(10k) | 0.99 |
18 | 达那唑 | 0.90 | t-丁醇 | 98.14 | PVP(29k) | 0.96 |
19 | 达那唑 | 0.98 | t-丁醇 | 98.04 | PVP(55k) | 0.98 |
20 | 达那唑 | 1.04 | t-丁醇 | 97.93 | PEG(10k) | 1.03 |
21 | 醋酸氢化可的松 | 1.00 | t-丁醇 | 98.00 | 普罗尼克F-127 | 1.00 |
22 | 醋酸氢化可的松 | 0.97 | t-丁醇 | 98.03 | 普罗尼克F-127,&PEG(10k)(50/50)wt.%比 | 1.00 |
23 | 醋酸氢化可的松 | 0.92 | t-丁醇 | 98.17 | 普罗尼克F-68 | 0.91 |
24 | 醋酸氢化可的松 | 0.95 | t-丁醇 | 98.11 | PEG(10k) | 0.94 |
25 | 酮康唑 | 1.17 | t-丁醇 | 97.66 | 普罗尼克F-127 | 1.17 |
26 | 酮康唑 | 0.98 | t-丁醇 | 98.04 | 普罗尼克F-127 | 0.98 |
27 | 酮洛芬 | 1.92 | t-丁醇 | 96.16 | 普罗尼克F-127 | 1.92 |
28 | 酮洛芬 | 1.92 | t-丁醇 | 96.16 | 普罗尼克F-127 | 1.92 |
29 | 酮洛芬 | 1.00 | t-丁醇 | 97.93 | 普罗尼克F-88 | 1.07 |
30 | 萘普生 | 1.61 | t-丁醇 | 96.78 | 普罗尼克F-127 | 1.61 |
31 | 萘普生 | 1.61 | t-丁醇 | 96.78 | 普罗尼克F-127 | 1.61 |
32 | 萘普生 | 1.00 | t-丁醇,&t-戊醇(60/40)wt.%比 | 98.00 | 普罗尼克F-127 | 1.00 |
33 | 萘普生 | 1.60 | t-丁醇 | 98.00 | 普罗尼克F-127.&PEG(29k)(50/50)wt.%比 | 0.40 |
34 | 萘普生 | 1.40 | 对-二甲苯,&1,3,5-三噁烷(80/20)wt.%比 | 98.00 | 普罗尼克F-127 | 0.60 |
35 | 萘普生 | 9.94 | t-丁醇 | 80.10 | 普罗尼克F-127 | 9.96 |
36 | 萘普生 | 1.00 | t-丁醇,&环戊醇(80/20)wt.%比 | 97.99 | 普罗尼克F-127 | 1.01 |
37 | 萘普生 | 1.67 | t-丁醇(还加入去离子水以参与溶解稳定剂)。(50/50)wt.%比 | 96.67 | 普罗尼克F-127 | 1.66 |
38 | 萘普生 | 1.00 | t-丁醇,&乙腈(90/10)wt.%比 | 98.00 | 普罗尼克F-127 | 1.00 |
39 | 萘普生 | 13.73 | t-丁醇,&丙酮(90/10)wt.%比 | 80.38 | 普罗尼克F-127 | 5.89 |
40 | 萘普生 | 1.00 | t-丁醇,&乙酸乙酯(90/10)wt.%比 | 98.00 | 普罗尼克F-127 | 1.00 |
41 | 萘普生 | 1.00 | t-丁醇,&仲-乙酸丁酯(90/10)wt.%比 | 98.00 | 普罗尼克F-127 | 1.00 |
42 | 萘普生 | 1.00 | t-丁醇,&1,3,5-三噁烷(50/50)wt.%比 | 98.00 | 普罗尼克F-127 | 1.00 |
43 | 萘普生 | 4.11 | 对-二甲苯 | 94.13 | 普罗尼克F-127 | 1.76 |
44 | 萘普生 | 0.95 | t-丁醇 | 98.11 | 司盘40 | 0.94 |
45 | 萘普生 | 0.94 | t-丁醇 | 98.10 | 普罗尼克F-127,&SPAN40(50/50)wt.%比 | 0.96 |
46 | 萘普生 | 1.00 | t-丁醇 | 98.01 | 司盘60 | 0.99 |
47 | 萘普生 | 0.98 | t-丁醇 | 98.01 | 普罗尼克F-127,&SPAN 60(50/50)wt.%比 | 1.01 |
48 | 硝苯地平 | 1.92 | t-丁醇 | 96.16 | 普罗尼克F-127 | 1.92 |
49 | 硝苯地平 | 1.92 | t-丁醇 | 96.16 | 普罗尼克F-127 | 1.92 |
50 | 硝苯地平 | 0.95 | t-丁醇 | 98.06 | 普罗尼克F-108,&PVP(55k)(50/50)wt.%比 | 0.99 |
51 | *** | 0.89 | t-丁醇 | 98.22 | 普罗尼克F-127 | 0.89 |
52 | *** | 0.89 | t-丁醇 | 98.22 | 普罗尼克F-127 | 0.89 |
53 | *** | 0.94 | t-丁醇 | 98.07 | 普罗尼克F-108 | 0.99 |
54 | 曲安奈德 | 1.92 | t-丁醇 | 96.16 | 普罗尼克F-127 | 1.92 |
55 | 曲安奈德 | 1.92 | t-丁醇 | 96.16 | 普罗尼克F-127 | 1.92 |
56 | 曲安奈德 | 0.76 | t-丁醇 | 98.47 | PVP(10k) | 0.77 |
57 | 萘普生 | 2.50 | t-丁醇 | 94.99 | 普罗尼克F-127 | 2.51 |
58 | 萘普生 | 5.83 | t-丁醇 | 91.67 | 普罗尼克F-127 | 2.50 |
59 | 萘普生 | 5.93 | 乙腈 | 91.41 | 普罗尼克F-127 | 2.66 |
60 | 萘普生 | 3.67 | 四氢呋喃,(还加入去离子水以参与溶解稳定剂)。(68/32)wt.%比 | 94.73 | 普罗尼克F-127 | 1.60 |
实施例1
125-mL冷冻干燥瓶在干冰7—丙酮浴中冷却至-78℃。制备的溶液缓慢用滴管吸取至冷却的冷冻干燥瓶内。冷冻干燥瓶内冻结的固体接着置于冷冻干燥单元上并令其冻干,直至彻底干燥,产生0.9g易流动的白色粉末。在加工之前和之后测定的粒度分析结果和溶解时间如表B所示。
实施例2和3
使用图1所示的设备。圆筒12以干冰冷却至-78℃。溶液喷在圆筒12上持续约10分钟。所得的冻结固体通过使用刀片部件14除去,并收集在冷却的成品收集盘16中。收集的物质用手转移至溶剂清除单元。在实施本发明的工艺之前和之后测定的粒度分析结果和溶解时间如表B所示。
实施例4至56
使用图2所示的设备。圆筒12以干冰冷却至-78℃。溶液采用加料漏斗滴在圆筒12上持续约10分钟。所得的冻结固体通过使用刀片部件14除去,并收集在冷却的成品收集盘16中。接着收集的物质用手转移至溶剂清除步骤。在实施本发明的工艺之前和之后测定的粒度分析结果和溶解时间如表B所示。
实施例57至60
使用图2所示的设备。圆筒12以干冰冷却至-78℃。溶液采用加料漏斗滴在圆筒12上持续约10分钟。所得的冻结固体通过使用刀片部件14除去,并收集在冷却的成品收集盘16中。收集的产品分散在去离子水中。然后直接取分散的固体/水/溶剂浆至溶剂清除步骤。在实施本发明的工艺之前和之后测定的粒度分析结果和溶解时间如表B所示。
表B
实施例 | 药物 | 干燥方法 | 原料药的PSA*(微米) | 已加工药物的PSA*(微米) | 原料药2分钟后的溶解(wt%) | 已加工药物2分钟后的溶解(wt%) | %结晶度 |
1 | 达那唑(瓶) | 冷冻干燥 | 24.86 | 0.301 | 56.42 | 97.1 | - |
2 | 酮康唑(喷雾) | ATMFD | 13.5 | 7.334 | 26.1 | 100.77 | - |
3 | 达那唑(喷雾) | ATMFD | 24.86 | 23.47 | 56.42 | 103.3 | - |
4 | 卡马西平 | ATMFD | 391.4 | 30.07 | 4.83 | 74.62 | 79.2 |
5 | 卡马西平 | ATMFD | 391.4 | 22.58 | 4.83 | 77.30 | - |
6 | 卡马两平 | 冷冻干燥 | 391.4 | 54.13 | 4.83 | 48.23 | - |
7 | 卡马两平 | 冷冻干燥 | 391.4 | 103.10 | 4.83 | 77.52 | - |
8 | 卡马西平 | 冷冻干燥 | 391.4 | 92.43 | 4.83 | 65.37 | - |
9 | 卡马西平 | 冷冻干燥 | 391.4 | 74.26 | 4.83 | 77.50 | - |
10 | 环孢菌素A | ATMFD | 53.89 | 38.02 | 3.39 | 86.4 | 无定形的 |
11 | 环孢菌素A | 冷冻干燥 | 53.89 | 22.04 | 3.39 | 26.02 | - |
12 | 达那唑 | ATMFD | 24.86 | 17.60 | 56.42 | 100.17 | 70.4 |
13 | 达那唑 | ATMFD | 24.86 | 43.29 | 56.42 | 99.22 | - |
14 | 达那唑 | ATMFD | 24.86 | 34.54 | 56.42 | 104.15 | - |
15 | 达那唑 | 冷冻干燥 | 24.86 | 15.47 | 56.42 | 99.75 | - |
16 | 达那唑 | 冷冻干燥 | 24.86 | 7.011 | 56.42 | 97.55 | - |
17 | 达那唑 | 冷冻干燥 | 24.86 | 4.377 | 56.42 | 101.41 | - |
18 | 达那唑 | 冷冻干燥 | 24.86 | 108.50 | 56.42 | 103.01 | - |
19 | 达那唑 | 冷冻干燥 | 24.86 | 20.80 | 56.42 | 89.52 | - |
20 | 达那唑 | 冷冻干燥 | 24.86 | 16.53 | 56.42 | 93.31 | - |
21 | 醋酸氢化可的松 | ATMFD | 17.07 | 7.447 | 21.16 | 97.46 | 91.2 |
22 | 醋酸氢化可的松 | 冷冻干燥 | 17.07 | 3.949 | 21.16 | 100.49 | - |
23 | 醋酸氢化可的松 | 冷冻干燥 | 17.07 | 9.740 | 21.16 | 94.65 | - |
24 | 醋酸氢化可的松 | 冷冻干燥 | 17.07 | 27.94 | 21.16 | 91.10 | - |
25 | 酮康唑 | ATMFD | 13.50 | 11.64 | 26.10 | 98.85 | 94.6 |
26 | 酮康唑 | 冷冻干燥 | 13.50 | 76.66 | 26.10 | 78.8 | - |
27 | 酮洛芬 | ATMFD | 42.73 | 27.60 | 2.81 | 92.39 | 74.7 |
28 | 酮洛芬 | 冷冻干燥 | 42.73 | 82.93 | 2.81 | 57.06 | - |
29 | 酮洛芬 | 冷冻干燥 | 42.73 | 91.82 | 2.81 | 72.70 | - |
30 | 萘普生 | ATMFD | 24.07 | 13.28 | 2.81 | 64.05 | - |
31 | 萘普生 | 冷冻干燥 | 24.07 | 2.193 | 0.29 | 71.57 | 90.5 |
32 | 萘普生 | 冷冻干燥 | 24.07 | 0.847 | 0.29 | 99.96 | - |
33 | 萘普生 | 冷冻干燥 | 24.07 | 0.859 | 0.29 | 70.23 | - |
34 | 萘普生 | 冷冻干燥 | 24.07 | 9.858 | 0.29 | 76.77 | - |
35 | 萘普生 | 冷冻干燥 | 24.07 | 1.272 | 0.29 | 65.77 | - |
36 | 萘普生 | 冷冻干燥 | 24.07 | 56.33 | 0.29 | 94.77 | - |
37 | 萘普生 | 冷冻干燥 | 24.07 | 84.76 | 0.29 | 70.69 | - |
38 | 萘普生 | 冷冻干燥 | 24.07 | 10.76 | 0.29 | 70.54 | - |
39 | 萘普生 | 冷冻干燥 | 24.07 | 18.24 | 0.29 | 76.43 | - |
40 | 萘普生 | 冷冻干燥 | 24.07 | 44.04 | 0.29 | 88.77 | - |
41 | 萘普生 | 冷冻干燥 | 24.07 | 33.80 | 0.29 | 87.16 | - |
42 | 萘普生 | 冷冻干燥 | 24.07 | 0.807 | 0.29 | 74.17 | - |
43 | 萘普生 | 冷冻干燥 | 24.07 | 1.114 | 0.29 | 78.46 | - |
44 | 萘普生 | 冷冻干燥 | 24.07 | 118.40 | 0.29 | 37.34 | - |
45 | 萘普生 | 冷冻干燥 | 24.07 | 79.69 | 0.29 | 44.31 | - |
46 | 萘普生 | 冷冻干燥 | 24.07 | 74.51 | 0.29 | 34.71 | - |
47 | 萘普生 | 冷冻干燥 | 24.07 | 67.90 | 0.29 | 40.82 | - |
48 | 硝苯地平 | ATMFD | 244.9 | 39.53 | 4.70 | 83.34 | 77.9 |
49 | 硝苯地平 | 冷冻干燥 | 244.9 | 16.45 | 4.70 | 56.65 | - |
50 | 硝苯地平 | 冷冻干燥 | 244.9 | 19.13 | 4.70 | 76.75 | - |
51 | *** | ATMFD | 3.263 | 15.30 | 0.97 | 81.42 | 81.7 |
52 | *** | 冷冻干燥 | 3.263 | 11.52 | 0.97 | 89.19 | - |
53 | *** | 冷冻干燥 | 3.263 | 14.31 | 0.97 | 80.24 | - |
54 | 曲安奈德 | ATMFD | 7.707 | 11.60 | 5.38 | 47.56 | 38.2 |
55 | 曲安奈德 | 冷冻干燥 | 7.707 | 9.176 | 5.38 | 51.90 | - |
56 | 曲安奈德 | 冷冻干燥 | 7.707 | 15.08 | 5.38 | 32.31 | - |
57 | 萘普生 | 冷冻干燥 | 24.07 | 3.622 | 0.29 | 63.20 | - |
58 | 萘普生 | 冷冻干燥 | 24.07 | 3.282 | 0.29 | 59.84 | - |
59 | 萘普生 | 冷冻干燥 | 24.07 | 6.477 | 0.29 | 70.23 | - |
60 | 萘普生 | 冷冻干燥 | 24.07 | 10.59 | 0.29 | 82.22 | - |
*PSA意指“粒度分析”。
Claims (19)
1.一种制备微米级或次微米级药物粒子的方法,包括:
(a)将含有水难溶性药物和至少一种可冻结的有机溶剂的溶液与冷表面接触,使溶液冻结;和
(b)除去有机溶剂。
2.根据权利要求1的方法,其中步骤(a)的冷表面的温度低于可冻结的有机溶剂的冰点。
3.根据权利要求1的方法,其中步骤(a)的冷表面低于5℃。
4.根据权利要求1的方法,其中还包括冷却该冷表面的步骤。
5.根据权利要求4的方法,其中采用低温固体、低温气体、低温液体或能够达到低温的传热流体冷却冷表面。
6.根据权利要求1的方法,其中可冻结的有机溶剂选自醇、醚、烃、卤代烃、芳香烃、酯、乙酸酯、有机酸、胺、酮、砜、腈、碳酸酯或它们的组合。
7.根据权利要求1的方法,其中溶液还进一步包括水。
8.根据权利要求1的方法,其中在粒子分散于水中之后该粒子平均体积平均粒度是0.05微米至150微米。
9.根据权利要求1的方法,其中所得到的粒子具有至少2m2/g的表面积。
10.根据权利要求1的方法,其中所得到的药物粒子显示至少2倍于未加工药物溶解速率的体外溶解速率。
11.根据权利要求1的方法,其中溶液还包括至少一种稳定剂。
12.根据权利要求11的方法,其中稳定剂选自磷脂、表面活性剂、聚合表面活性剂、胞囊、聚合物、包括共聚物和均聚物及生物聚合物、分散助剂或它们的组合。
13.根据权利要求1的方法,其中步骤(b)采用升华或蒸发进行。
14.一种药物制剂,包括:
根据权利要求1的方法制备的药物粒子;和
药学上可接受的载体。
15.由一种以下方法制备的药物粒子,该方法包括:
(a)含有水难溶性药物和至少一种可冻结的有机溶剂的溶液与冷表面接触,以致于冻结该溶液;和
(b)除去有机溶剂。
16.根据权利要求15的药物粒子,其中在粒子分散于水中之后该粒子平均体积平均粒度是0.05微米至150微米。
17.根据权利要求15的药物粒子,其中所得到的药物粒子显示至少2倍于未加工药物溶解速率的体外溶解速率。
18.一种药物制剂,包括:
根据权利要求15的药物粒子;和
药学上可接受的载体。
19.一种制备药物粒子的设备,包括:
(a)具有第一侧面和相对第二侧面的冷固体表面;
(b)位于冷固体表面第一侧面近端的加料装置,这种加料装置适于允许含有水难溶性药物和至少一种可冻结的有机溶剂的溶液施加至冷固体表面的第一侧面以便冻结该溶液;
(c)位于冷固体表面第二侧面近端的冷却装置,这种冷却装置适于冷却冷固体表面;
(d)接近冷表面的清除装置,以便从冷表面的第一侧面除去冻结溶液;
(e)由冻结溶液中清除有机溶剂用的溶剂清除装置;和
(f)由(b)转移冻结溶液至溶剂清除装置(d)用的装置。
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US (2) | US9175906B2 (zh) |
EP (1) | EP1589948A1 (zh) |
JP (1) | JP4933732B2 (zh) |
KR (1) | KR20050096936A (zh) |
CN (1) | CN1731984A (zh) |
AU (1) | AU2003296893A1 (zh) |
CA (1) | CA2513006A1 (zh) |
WO (1) | WO2004064808A1 (zh) |
Cited By (5)
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CN101618019B (zh) * | 2008-07-01 | 2011-08-03 | 上海通用药业股份有限公司 | 一种醋酸曲安奈德微粒及其制备方法和药物组合物 |
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WO2020088479A1 (zh) * | 2018-10-30 | 2020-05-07 | 中国科学院化学研究所 | 一种利用水溶液制备单晶或无定型物的方法 |
WO2020088481A1 (zh) * | 2018-10-30 | 2020-05-07 | 中国科学院化学研究所 | 一种制备药物或药物中间体单晶或无定型物的方法 |
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-
2003
- 2003-08-12 AU AU2003296893A patent/AU2003296893A1/en not_active Abandoned
- 2003-08-12 CN CNA038258234A patent/CN1731984A/zh active Pending
- 2003-08-12 JP JP2004566896A patent/JP4933732B2/ja not_active Expired - Lifetime
- 2003-08-12 EP EP03815476A patent/EP1589948A1/en not_active Withdrawn
- 2003-08-12 CA CA002513006A patent/CA2513006A1/en not_active Abandoned
- 2003-08-12 US US10/639,361 patent/US9175906B2/en active Active
- 2003-08-12 KR KR1020057013059A patent/KR20050096936A/ko not_active Application Discontinuation
- 2003-08-12 WO PCT/US2003/025338 patent/WO2004064808A1/en active Application Filing
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CN101618019B (zh) * | 2008-07-01 | 2011-08-03 | 上海通用药业股份有限公司 | 一种醋酸曲安奈德微粒及其制备方法和药物组合物 |
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CN102348948B (zh) * | 2009-03-11 | 2014-12-10 | 鲍利葛股份公司 | 干燥微纤维化纤维素的方法 |
WO2020088479A1 (zh) * | 2018-10-30 | 2020-05-07 | 中国科学院化学研究所 | 一种利用水溶液制备单晶或无定型物的方法 |
WO2020088481A1 (zh) * | 2018-10-30 | 2020-05-07 | 中国科学院化学研究所 | 一种制备药物或药物中间体单晶或无定型物的方法 |
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Also Published As
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WO2004064808A1 (en) | 2004-08-05 |
CA2513006A1 (en) | 2004-08-05 |
JP2006514076A (ja) | 2006-04-27 |
US20040137070A1 (en) | 2004-07-15 |
AU2003296893A1 (en) | 2004-08-13 |
US9175906B2 (en) | 2015-11-03 |
JP4933732B2 (ja) | 2012-05-16 |
US20160074328A1 (en) | 2016-03-17 |
KR20050096936A (ko) | 2005-10-06 |
EP1589948A1 (en) | 2005-11-02 |
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