CN1798549B - 稳定的气雾剂分散体 - Google Patents
稳定的气雾剂分散体 Download PDFInfo
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- CN1798549B CN1798549B CN2004800150751A CN200480015075A CN1798549B CN 1798549 B CN1798549 B CN 1798549B CN 2004800150751 A CN2004800150751 A CN 2004800150751A CN 200480015075 A CN200480015075 A CN 200480015075A CN 1798549 B CN1798549 B CN 1798549B
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- nanoparticle
- stable pharmaceutical
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- pharmaceutical dispersions
- medicine
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- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
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- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/0095—Preparation of aerosols
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B82B1/00—Nanostructures formed by manipulation of individual atoms or molecules, or limited collections of atoms or molecules as discrete units
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K23/00—Use of substances as emulsifying, wetting, dispersing, or foam-producing agents
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K23/00—Use of substances as emulsifying, wetting, dispersing, or foam-producing agents
- C09K23/38—Alcohols, e.g. oxidation products of paraffins
Abstract
本发明涉及用于给药的稳定的含纳米粒子的分散体。该分散体包括赋形剂纳米粒子、含药物的分散相和含抛射剂的连续相。
Description
发明背景
本发明涉及用于从气雾剂中施用药物的气雾剂分散体。
药物从基于抛射剂的气雾剂中以各种形式递送,如定量吸入器(MDI)、局部喷雾器和搅打器(whip),其中MDI最为常见。因为MDI是在二十世纪五十年代中期引入的,所以吸入成为向哮喘患者的气道局部施用支气管扩张药和甾族化合物最广泛使用的途径。与口服支气管扩张药相比,通过MDI吸入提供了迅速的起效作用和很低的全身副反应发生率。
药物气雾剂取决于其制造过程中所使用的抛射剂体系的抛射力。常规地,抛射剂系统由全氟化合物、氢氟烷(HFA)、或氯氟碳化合物(CFC)的混合物组成,选择它们来提供所需的蒸汽压和悬浮稳定性。虽然这些体系可以用来递送溶解的药物,但典型地以细微粒形式包括所选的生物活性剂,从而在液化的抛射剂中提供分散体。为了使这些体系中的聚集问题最小化或防止聚集问题,通常用表面活性剂涂覆生物活性剂的表面,协助使用气雾剂抛射剂润湿粒子。以这种方式使用表面活性剂来维持基本上均匀的分散体,这被称为“稳定”悬浮液。在一些分散体中,可能不希望使用表面活性剂。向活生物体稳定并有效地递送治疗活性的化合物(也就是药物),这通常受到在药物的实际化学特性和药理学活性之外许多参素的影响。
药物气雾剂可能是通过口腔或鼻腔吸入向肺部系统引入药物的有效方式,但是有许多控制药物气雾剂组成的参素影响它们的性能。这些参素的相对重要性会因所用剂型的类型(例如定量吸入器或MDI、干粉吸入器、雾化吸入器)和所递送药物的类型而变化,但通常会包括以下因素如:剂型中药物的浓度、向生物体递送的气雾剂粒度、组合物的理化稳定性、以及递送到肺部系统的粒子被身体吸收的能力。
为了获得某些需要的性质或可接受的性质平衡,有时需要在药物气雾剂组合物中包括各种赋形剂。已提出许多不同的赋形剂用于药物气雾剂,以溶解药物、改善药物的悬浮质量、增加发射粒子的尺寸等。但是,许多提出的赋形剂尽管能提供一种或多种益处,但具有的缺陷在其他方面使它们不适于使用,例如毒性问题、有限的抛射剂溶解度、与其它产品组分的有害相互作用、或者被广泛利用的能力有限。
更具体地,在任何已知的抛射剂中的大多数药物悬浮液倾向于讯速聚集。如果不能控制悬浮材料的粒度而发生聚集,气雾剂容器的阀孔就会堵塞,使分配装置不起作用,或者如果使用了计量阀门,定量就可能不准确。这种有害的聚集或絮凝会导致不正确的剂量,这会导致不希望的结果,在高效低剂量药物的情况下,尤其如此。此外,这种讯速的粒子聚集还会导致悬浮液的快速乳化或沉降。通常,在就要使用之前通过剧烈摇动MDI装置来解决所致的相分离。但是,患者的顺从性难以控制,并且许多市售悬浮液是如此不稳定,从而在摇动和使用之间即使有轻微的延迟也会影响剂量的均匀度。
因此,一直需要新型有效的赋形剂,其可用于药物气雾剂,尤其是使用氢氟碳化合物抛射剂如HFC-134a和HFC-227的加压药物气雾剂。虽然在过去十年中进行了研究投入,但是在现今,配制适于满足严格的功能和治疗要求的不含CFC的加压定量吸入器仍然是很重要的。
发明概述
一方面,本发明提供了稳定的药物分散体,该分散体包括:含药物的分散固体相和含抛射剂和赋形剂纳米粒子的连续液体相。
另一方面,本发明提供了通过呼吸道治疗哺乳动物的方法,该方法包括以下步骤:向所述哺乳动物的呼吸道施用有效量的本发明药物分散体。
另一方面,本发明提供了一种定量吸入器,该定量吸入器包括有计量阀门的气雾剂容器、和放置在该容器内的本发明的稳定药物分散体。
另一方面,本发明提供了制备气雾剂分散体的方法,该方法包括以下步骤:提供气雾剂容器,将本发明的药物分散体加入到所述容器中。
另一方面,本发明提供了稳定药物分散体的方法,该方法包括以下步骤:向分散体中添加有效量的赋形剂纳米粒子,该分散体包括:含药物的分散固体相和含抛射剂的连续液体相。
另一方面,本发明提供了稳定的药物分散体,该分散体基本上由含药物的分散固体相和含抛射剂和赋形剂纳米粒子的连续液体相组成。
附图简述
图1显示了实施例13-16的摇动-延迟递药(SDMD)试验结果。
图2显示了实施例17-19的SDMD试验结果。
图3显示了实施例20的SDMD试验结果。
发明详述
本发明的分散体是稳定的分散体,它以气雾剂的形式在使用时间段内提供可重复的药物剂量,而基本不需要搅拌分散体,或者以最小的能量输入就能轻易地再分散。通过向分散体中加入有效量的赋形剂纳米粒子,使含药物和抛射剂的分散体变得稳定。“有效量”的赋形剂纳米粒子是指该量能使药物粒子的聚集最小化并形成稳定的分散体,在使用时间段内基本不需要搅拌分散体就能保持分散,或者以最小的能量输入就能轻易地再分散。不期望被任何理论所限制,据信,纳米粒子能在空间上抑制分散相的聚集,而不是通过粒子电荷来抑制分散粒子的聚集。用于本发明分散体的赋形剂纳米粒子看起来可溶于分散体的连续相中,在本发明的分散体中不会沉淀、絮凝等。此外,与常规的悬浮助剂相比,赋形剂纳米粒子基本上不会与药物粒子表面缔合,在低浓度时是有效的悬浮助剂。本发明的稳定分散体可以含有少于0.001wt%的表面活性剂、表面活化剂、常规乳化剂、洗涤剂、和/或保护胶体。
用于本文时,“分散体”是指分布在整个液体连续相中的固体,其在使用时间段内不会分离。
用于本文时,“分离”是指液体分散体中的固体粒子逐渐沉淀或乳化,形成具有显著不同浓度的固体粒子和连续液体相的不同层。
用于本文时,“分散稳定性”用于描述分散体的分离趋势。对于具有良好分散稳定性的分散体,粒子在连续相中保持近似均匀的分布。对分散稳定性差的分散体,粒子在连续相中不能保持近似均匀的分布,可能会分离。
用于本文时,“赋形剂”泛指除主要活性药物部分之外的任何惰性添加剂,用于改善气雾剂分散体剂型的一些方面。
用于本文时,“气雾剂分散体”是指药物分散体,它包括药物和在压力下能将药物递送给患者的抛射剂。
用于本文时,“纳米粒子”是指有机或无机的粒子或分子及其组合,它们看起来可溶于连续相中,其中每个粒子在连续相中具有纳米级尺寸,在连续相中占据或提供了小于100纳米的空间排阻区。
本发明的稳定分散体包括表面改性的无机纳米粒子、表面改性的有机纳米粒子、和/或具有未改性表面的立体有机分子(纳米粒子)。“立体有机分子”是指具有可以纳米直径尺度描述的排阻体积并且由共价键合的有机单元组成的单个分子(例如聚合物)。“立体有机分子”不包括可溶于连续相的线型聚合物。在一个实施方案中,它们基本上由与纳米粒子内部或芯中存在的部分相同的表面上的部分组成。希望纳米粒子是分散于整个连续相中的单独的未缔合的(也就是未聚集的)纳米粒子,希望它们不会不可逆地相互缔合,并且不会与分散的药物缔合。术语“与……缔合”包括:例如共价键合、氢键合、静电吸引、色散力、和疏水作用。
选择纳米粒子,以使由此形成的组合物不会产生一定程度的干扰组合物的所需性质的粒子附聚或聚集。表面改性的有机或无机纳米粒子的表面基团能改变纳米粒子的“溶解度”或“润湿性”特性。选择表面基团,以使粒子与包括连续相组分的连续相相容。未改性的纳米粒子无需另外的表面改性就与连续相相容。
评价纳米粒子和连续相的相容性的一种方法包括,确定所得组合物是否能形成稳定的分散体。不相容的纳米粒子不能在预期的有效浓度时改善悬浮质量。对于透明的连续相,评价纳米粒子与透明连续相的相容性的一种有用方法包括以下步骤:将纳米粒子和连续相混合,观察纳米粒子是否看起来溶于连续相中,以致所得分散体是透明或者半透明的。
对于表面改性的纳米粒子,表面改性纳米粒子中无机或有机粒子组分的性质会阻止表面改性的粒子真正地溶于连续相中,也就是表面改性的纳米粒子会分散在连续相中。但是,表面基团与连续相的相容性会使表面改性的纳米粒子看起来溶于连续相中。随着表面改性纳米粒子的尺寸增加,连续相的混浊度通常也增加。选择优选的表面改性纳米粒子,使得它们不会从连续相中沉淀出来。评价连续相和表面改性或未改性纳米粒子的相容性的其他步骤包括:在随后引入要被分散在连续相中的药物粒子后,确定组合物是否形成稳定的分散体。
也可以基于表面基团和连续相的溶解度参数选择合适的表面基团。希望表面基团或衍生出该表面基团的试剂的溶解度参数与连续相的溶解度参数相似。例如,当连续相疏水时,本领域技术人员可以从多种疏水性表面基团中选择,以获得与疏水性连续相相容的表面改性粒子。类似地,当连续相亲水时,本领域技术人员可以从亲水性表面基团中选择,当连续相是氢氟碳化合物时,本领域技术人员可以从多种相容的表面基团中选择。纳米粒子还可以包括至少两种不同的表面基团,它们一起提供溶解度参数与连续相溶解度参数相似的纳米粒子。表面改性的纳米粒子不是两亲的。
可以选择表面基团,以提供统计学平均的、被无规地表面改性的粒子。
如果需要,在纳米粒子表面上的表面基团含量足以提供表面改性的纳米粒子,该表面改性的纳米粒子能随后被分散在连续相中,而不会聚集。希望表面基团的含量足以在纳米粒子的表面形成单层,并希望是连续的单层。
表面改性基团可以源自表面改性剂。示意性地,表面改性剂可以用式A-B表示,其中A基团能结合到粒子表面,B基团为相容性基团(不与连续相反应)或相容性基团的连接基团。选择相容性基团,使粒子相对地增加极性、相对地减少极性、或相对地没有极性。
合适的表面改性剂种类包括:例如硅烷、有机酸、有机碱、醇、及其组合。
有用的硅烷例子包括有机硅烷,其包括例如:烷基氯硅烷,烷氧基硅烷如甲基三甲氧基硅烷、甲基三乙氧基硅烷、乙基三甲氧基硅烷、乙基三乙氧基硅烷、正丙基三甲氧基硅烷、正丙基三乙氧基硅烷、异丙基三甲氧基硅烷、异丙基三乙氧基硅烷、丁基三甲氧基硅烷、丁基三乙氧基硅烷、己基三甲氧基硅烷、辛基三甲氧基硅烷、3-巯基丙基三甲氧基硅烷、正辛基三乙氧基硅烷、苯基三乙氧基硅烷、聚三乙氧基硅烷、乙烯基三甲氧基硅烷、乙烯基二甲基乙氧基硅烷、乙烯基甲基二乙酸基硅烷、乙烯基甲基二乙氧基硅烷、乙烯基三乙酸基硅烷、乙烯基三乙氧基硅烷、乙烯基三异丙氧基硅烷、乙烯基三甲氧基硅烷、乙烯基三苯氧基硅烷、乙烯基三(叔丁氧基)硅烷、乙烯基三(异丁氧基)硅烷、乙烯基三(异丙烯氧基)硅烷和乙烯基三(2-甲氧基乙氧基)硅烷;三烷氧基芳基硅烷;异辛基三甲氧基-硅烷;N-(3-三乙氧基甲硅烷基丙基)甲氧基乙氧基乙氧基乙基氨基甲酸酯;N-(3-三乙氧基甲硅烷基丙基)甲氧基乙氧基乙氧基乙基氨基甲酸酯;硅烷官能化的(甲基)丙烯酸酯,包括:例如3-(甲基丙烯酰氧基)丙基三甲氧基硅烷、3-丙烯酰氧基丙基三甲氧基硅烷、3-(甲基丙烯酰氧基)丙基三乙氧基硅烷、3-(甲基丙烯酰氧基)丙基甲基二甲氧基硅烷、3-(丙烯酰氧基丙基)甲基二甲氧基硅烷、3-(甲基丙烯酰氧基)丙基二甲基乙氧基硅烷、3-(甲基丙烯酰氧基)甲基三乙氧基硅烷、3-(甲基丙烯酰氧基)甲基三甲氧基硅烷、3-(甲基丙烯酰氧基)丙基二甲基乙氧基硅烷、3-(甲基丙烯酰氧基)丙烯基三甲氧基硅烷、和3-(甲基丙烯酰氧基)丙基三甲氧基硅烷;聚二烷基硅氧烷,包括例如聚二甲基硅氧烷;芳基硅烷,包括例如取代和未取代的芳基硅烷;烷基硅烷,包括例如取代和未取代的烷基硅烷,包括例如甲氧基和羟基取代的烷基硅烷、及其组合。
用硅烷官能化的(甲基)丙烯酸酯表面改性二氧化硅的方法描述于例如:美国专利号4,491,508和4,455,205(Olsen等人);美国专利号4,478,876和4,486,504(Chung);和美国专利号5,258,225(Katsamberis)中。
有用的有机酸表面改性剂包括例如:碳的含氧酸(如羧酸)、硫和磷的含氧酸、及其组合。
具有羧酸官能度的极性表面改性剂的代表性例子包括CH3O(CH2CH2O)2CH2COOH(下文称为MEEAA)和化学结构为CH3OCH2CH2OCH2COOH的2-(2-甲氧基乙氧基)乙酸(下文称为MEAA)、酸官能化的聚乙二醇(PEG)如单(聚乙二醇)琥珀酸酯和用乙酸、丙酸或丁酸单基取代的聚乙二醇。这些聚合物或它们的衍生物可以按美国专利号5,672,662中所述制备,或者从商业购买。
具有羧酸官能度的非极性表面改性剂的代表性例子包括:辛酸、十二烷酸和油酸。
含磷的酸的合适例子包括:膦酸,其包括例如:辛基膦酸、月桂基膦酸、癸基膦酸、十二烷基膦酸、十八烷基膦酸、和磷酸盐或磷酸取代的聚乙二醇。
有用的有机碱表面改性剂包括例如:烷基胺,其包括例如:辛胺、癸胺、十二烷胺和十八烷胺、或胺官能化的聚乙二醇。
其它有用的非硅烷表面改性剂的例子包括:丙烯酸、甲基丙烯酸、丙烯酸-β-羧基乙酯、琥珀酸-单-2-(甲基丙烯酰氧基乙基)酯、及其组合。给纳米粒子提供极性特性和反应性的有用的表面改性剂是琥珀酸单(甲基丙烯酰氧基聚乙二醇)酯。
合适的表面改性醇包括例如:脂族醇,其包括例如十八醇、十二醇、月桂醇和糠醇;脂环醇,其包括例如环己醇;和芳香醇,其包括例如苯酚和苯甲醇;聚乙二醇、单甲基聚乙二醇、及其组合。
可以使用各种方法来改性纳米粒子的表面,包括例如向纳米粒子(例如为粉末或胶态分散体的形式)中添加表面改性剂,使表面改性剂与纳米粒子反应。本领域技术人员会认识到,在本发明的范围内,使纳米粒子与相容性基团结合在一起的多个合成顺序是可行的并且是可以预期的,例如,反应性基团/连接基团可以与纳米粒子反应,然后与相容性基团反应。或者,反应性基团/连接基团可以与相容性基团反应,然后与纳米粒子反应。其它有用的表面改性方法描述于例如美国专利号2,801,185和4,522,958中。
纳米粒子主要是有机的或无机的、或其组合。合适的无机纳米粒子的例子包括:二氧化硅和金属氧化物纳米粒子,其包括:氧化锆、二氧化钛、铈土、氧化铝、氧化铁、氧化钒、氧化锑、氧化锡、氧化铝/二氧化硅、磷酸钙、磷酸钙,如羟基-磷灰石、及其组合,还包括组合材料,如材料的混合物或者环绕着中心无机或有机芯的材料层。合适的有机纳米粒子的例子包括:巴尔敏斯特富勒烯(buckminsterFullerene)(富勒烯(fullerene))、树枝状聚合物(dendrimer)、不溶于抛射剂的糖,如乳糖、海藻糖、葡萄糖或蔗糖;氨基酸、和线型或支化聚合物或超支化的“星形”聚合物,如具有多种端基的4臂、6臂、或8臂的聚乙二醇(购自Aldrich Chemical Company,Milwaukee,WI,或Shearwater Corporation,Huntsville,AL)、及其组合。
富勒烯的具体例子包括C60、C70、C82、和C84。树枝状聚合物的具体例子包括第2至10代(G2-G10)的聚酰胺型胺(PAMAM)树枝状聚合物(购自Aldrich Chemical Company)。
本领域技术人员会理解,上述纳米粒子可以直接使用或经表面改性使用,并且可以以任何组合使用。应该对不溶性纳米粒子(如无机物、糖如海藻糖或乳糖、或某些树枝状聚合物)进行适当的表面改性,使它们在连续相中是可以润湿的。也可以使用改性来控制空间排阻区的体积。表面改性的非限制性方法包括:吸附、与“表面”发生离子或共价的化学反应、或用反应性部分包封或涂覆纳米粒子,从而产生能增加粒子在连续相中的“溶解度”的壳。如果吸附是改性纳米粒子表面的主要方法,则被吸附的种类应由本领域技术人员选择,以避免大量脱附和随的药物表面改性。
当纳米粒子存在于含HFA的连续相中时,希望纳米粒子表面由多种醚、酯、或酰胺部分组成。对于还包含共溶剂(例如乙醇)或二甲醚、丙烷、丁烷、或其掺混物的连续相,纳米粒子的表面性质可以更疏水。合意的纳米粒子表面由已知的生物相容性材料如聚乙二醇、或源自交酯或己内酯的聚酯组成。
目前市售的PAMAM树枝状聚合物具有伯胺、羟基、羧酸钠盐、混合的胺/羟基、和C12表面官能团。本领域技术人员会认识到,这些树枝状聚合物可以直接使用,或者如果需要,被改性以使表面与连续相相容。
有用的氧化锆纳米粒子包括在粒子表面上吸附油酸和丙烯酸组合的氧化锆纳米粒子。
有用的二氧化硅纳米粒子包括用硅烷表面改性剂进行表面改性的二氧化硅纳米粒子,其包括:例如丙烯酰氧基丙基三甲氧基硅烷、3-甲基丙烯酰氧基丙基三甲氧基硅烷、3-巯基丙基三甲氧基硅烷、正辛基三甲氧基硅烷、异辛基三甲氧基硅烷、及其组合。二氧化硅纳米粒子可以用许多表面改性剂处理,其包括:例如醇、有机硅烷,包括例如烷基三氯硅烷、三烷氧基硅烷、三烷氧基(烷基)硅烷、及其组合,和有机钛酸盐,及其混合物。
有用的表面改性的氧化铁粒子包括用衍生自甲硅烷基或氰基的长链烃或醚(如聚乙二醇)改性的氧化铁粒子。对磷酸钙有用的表面改性基团包括基于以下的离子键:1)酰基或烷基酸如羧酸盐、磷酸盐或硫酸盐-任选地和大于一价的金属阳离子,或2)烷基或胺,以及衍生物。
在含HFA的连续相中,有用的表面改性剂包括:具有上述官能度的聚酯或酯,例如含醇、酸、或胺官能度的单官能PEG。
对巴尔敏斯特富勒烯(富勒烯)和聚酰胺型胺(PAMAM)树枝状聚合物有用的表面改性基团包括直链或支化烷基,范围为至少C3至不大于C30,可以是C3至C30之间的任意大小或范围。
不论纳米粒子是否经过表面改性,其平均粒径小于约100nm;在其它实施方案中,平均粒径不大于约50nm、40nm、30nm、20nm、15nm、10nm、或5nm;在其它实施方案中,平均粒径为约3nm至约50nm;在其它实施方案中,平均粒径为约3nm至约20nm;在其它实施方案中,平均粒径为约5nm至约10nm。如果纳米粒子聚集,则聚集粒子的最大横截面尺寸在所有这些优选范围内。
纳米粒子可以是胶态分散体的形式。有用的市售未改性二氧化硅的例子包括纳米尺寸的胶态二氧化硅,以商品名NALCO 1040、1050、1060、2326、2327、和2329胶态二氧化硅从Nalco Chemical Co.,Naperville,IL购得。
有用的金属氧化物胶态分散体包括:胶体氧化锆,其合适的例子描述于美国专利号5,037,579;胶态二氧化钛,其有用的例子描述于在1998年7月30日提交的PCT公开号WO 00/06495,发明名称为“用于制备透明金属氧化物胶体和陶瓷聚合体的纳米尺寸的金属氧化物粒子”(Nanosize Metal Oxide Particles for Producing Transparent MetalOxide Colloids and Ceramers)(Arney等人)。
在本发明的分散体中,以使药物粒子聚集最小化的有效量使用纳米粒子。纳米粒子通常的含量为0.005wt%至0.5wt%,可以以0.001wt%和0.5wt%之间的任何量或范围存在。在其它实施方案中,本发明的分散体包含小于0.5wt%、0.4wt%、0.3wt%、或0.2wt%的纳米粒子。本领域技术人员会认识到,所需的有效量取决于抛射剂的类型、纳米粒子的表面官能度和粒度、药物的浓度和类型、以及其它赋形剂的存在。可以使用本文描述的不同纳米粒子类型的组合。
本发明可以用于被制成气雾剂分散体的任何药物。其它合适药物的非限制性例子包括:抗过敏药、镇痛药、支气管扩张药、抗组胺药、治疗用蛋白质和肽、镇咳药、抗心绞痛制剂、抗生素、抗炎制剂、利尿药、激素、或磺胺类药如血管收缩胺、酶、生物碱或甾族化合物,可以使用的这些具体例子或药物的组合是:异丙肾上腺素、去氧肾上腺素、苯丙醇胺、高血糖素、肾上腺素红、胰蛋白酶、肾上腺素、麻黄碱、那可丁、可待因、阿托品、肝素、吗啡、二氢吗啡酮、双氢吗啡、麦角胺、东莨菪碱、美沙吡林、维生素B12、特布他林、利米特罗、沙丁胺醇、异丙肾上腺素、非诺特罗、氧托溴铵、瑞普特罗、布地奈德、氟尼缩松、环索奈德、福莫特罗、丙酸氟替卡松、沙美特罗、丙卡特罗、异丙托铵、曲安奈德、替泼尼旦、糠酸莫米松、秋水仙碱、吡布特罗、丙酸倍氯米松、奥西那林、芬太尼、海洛因、和地尔硫。其它的是抗生素如新霉素、头孢菌素、链霉素、青霉素、普鲁卡因青霉素、四环素、氯四环素和羟四环素;促肾上腺皮质激素和肾上腺皮质激素,如可的松、氢化可的松、醋酸氢化可的松和泼尼松龙;抗过敏化合物如色甘酸二钠、和奈多罗米;蛋白质和肽分子如胰岛素、喷他脒、降钙素、阿米洛利、干扰素、LHRH类似物、IDNA聚合酶(IDNAase)、肝素等。如果使用,上面示例的药物可以作为游离碱使用,或者作为本领域已知的一种或多种盐使用。疫苗也可以从这种方法中获益。
上面示例的药物可以作为游离碱使用,或者作为本领域已知的一种或多种盐使用。对游离碱或盐的选择受分散体中药物的物理稳定性的影响。可以使用上述药物的下列盐:乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、酒石酸氢盐、溴化物、乙二胺四乙酸钙、樟磺酸盐、碳酸盐、氯化物、柠檬酸盐、二盐酸盐、乙二胺四乙酸盐、乙二磺酸盐、依托酸盐、乙磺酸盐、富马酸盐、fluceptate、葡糖酸盐、谷氨酸盐、乙醇酰基阿散酸盐(glycollylarsanilate)、己基雷琐辛酸盐(hexylresorcinate)、氢溴酸盐、盐酸盐、羟萘酸盐、碘化物、羟乙磺酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐、甲基硫酸盐、粘液酸盐、萘磺酸盐、硝酸盐、扑姆酸盐(恩波酸盐)、泛酸盐、磷酸盐、二磷酸盐、聚半乳糖醛酸盐、水杨酸盐、硬脂酸盐、碱式乙酸盐、琥珀酸盐、硫酸盐、鞣酸盐、酒石酸盐、和三乙基碘化物(triethiodide)。
也可以使用阳离子盐。合适的阳离子盐包括碱金属盐如钠盐和钾盐、和铵盐以及本领域已知的可药用胺盐,例如甘氨酸、乙二胺、胆碱、二乙醇胺、三乙醇胺、十八烷胺、二乙胺、三乙胺、1-氨基-2-丙醇-氨基-2-(羟基甲基)丙烷-1,3-二醇和1-(3,4-二羟基苯基)-2异丙基氨基乙醇。
为了药用,希望药物粉末的粒度在直径上应该不大于100微米,因为更大的粒子会堵塞容器的阀门或孔。在另一个实施方案中,粒度在直径上应该小于25微米。由于生理学的原因,希望细碎的固体粉末粒度在直径上应该小于约25微米,在另一个实施方案中小于约10微米。希望用于吸入治疗的粉末粒度小于约5微米。
本发明的药物分散体含有以治疗有效量的分散在分散体中的药物。“治疗有效量”是指该量足以产生治疗效果,例如支气管扩张或抗病毒活性。该量会因本领域技术人员已知的因素而改变,例如具体药物的药理学活性、被治疗的病症、给药频率、治疗部位、以及共同施用的任何其它治疗剂的存在。药物的浓度取决于期望的剂量,但通常在0.01wt%至15wt%;0.01wt%至10wt%;0.01wt%至5wt%;0.01wt%至4wt%;0.01wt%至3wt%;或0.01wt%至2wt%的范围内,可以以0.001wt%至15wt%之间的任何量或范围存在。
合适的抛射剂包括例如:氯氟碳化合物(CFC),如三氯氟甲烷(也称为抛射剂11)、二氯二氟甲烷(也称为抛射剂12)、和1,2-二氯-1,1,2,2-四氯乙烷(也称为抛射剂114);氢氯氟碳化合物;氢氟碳化合物(HFC),如1,1,1,2-四氟乙烷(也称为抛射剂134a、HFC-134a、或HFA-134a)和1,1,1,2,3,3,3-七氟丙烷(也称为抛射剂227、HFC-227、或HFA-227);二氧化碳、二甲醚、丁烷、丙烷、或其混合物。在其它实施方案中,抛射剂包括氯氟碳化合物、氢氯氟碳化合物、氢氟碳化合物、或其混合物。在其它实施方案中,氢氟碳化合物被用作抛射剂。在其它实施方案中,HFC-227和/或HFC-134a被用作抛射剂。
在本发明的分散体中,抛射剂的含量占分散体的至少70wt%,通常为约85wt%至99.99wt%。
合适的佐剂包括:醇如乙醇、异丙醇、丙醇;烃如丙烷、丁烷、异丁烷、戊烷、异戊烷、新戊烷;其它抛射剂如通常称作抛射剂11、12、114、113、142b、152a 124的那些;二甲醚;表面活性剂如氟化和未氟化的表面活性剂;羧酸;和聚乙氧基化物。在使用量下,佐剂应当与抛射剂和所有共佐剂是易混的。
可以将本发明的分散体填充进配有计量阀门的常规气雾剂容器中,以常规方式分配。
实施例
制备表面改性的纳米粒子
制备PEG改性的二氧化硅纳米粒子(PEG-纳米SiO2)
按如下制备PEG改性的二氧化硅纳米粒子(PEG-纳米SiO2):在玻璃容器中,将525克(g)平均粒度为5nm、表面积为约600平方米/克(NALCO 2326,Nalco Chemical Co.,Naperville,IL)的氨稳定的胶态二氧化硅(15%固体)和46.3g聚乙氧基化三烷氧基硅烷(SILQUEST A1230,购自Crompton Chemicals,Middlebury,CT)以及203.5g蒸馏水混合。将容器密封,在80℃烘箱中放置16小时。将所得沉淀组合物蒸发干燥。向干燥粒子中添加甲苯,溶液与乙酸酐回流,以盖住(cap)任何未反应的-OH基团。用旋转式蒸发器除去甲苯,获得白色粉末。
制备PEG改性的氧化铁纳米粒子(PEG-纳米Fe2O3)
按如下制备胶态的水解氧化铁纳米粒子:在快速搅拌下,将1L1.875M碳酸氢铵溶液滴加到2L 0.375M九水合硝酸铁溶液中。加入完成后,通过使去离子水缓慢通过渗析管(长度约1米,1000MWCOSpectra/Por(Spectrum Laboratories,Inc.,Savannah,GA))而用去离子水渗析溶液,该渗析管浸在搅拌的水解硝酸铁溶液中。用约5当量体积的去离子水渗析后,在剩余的渗析过程中,将胶态的水解氧化铁纳米粒子溶液加热到约65℃。用另外7当量体积的去离子水继续渗析。
将100g胶态的水解氧化铁纳米粒子与0.71g 2-[2-(2-甲氧基乙氧基)乙氧基]乙酸组合,振摇使混合,在80℃烘箱中放置约18小时。将所得沉淀组合物在150℃烘箱中干燥,回收PEG改性的氧化铁纳米粒子(PEG-纳米Fe2O3),其为红棕色固体。
制备乙酰化星形-PEG-有机纳米粒子(PEG-纳米星形聚合物)
在80℃下,在容器内,将聚(环氧乙烷)(4臂或6臂,羟基封端(Aldrich Chemical Company)添加到过量乙酸酐中。在氮气下,将容器中的混合物搅拌24小时,然后在真空下除去过量的乙酸酐。IR分析显示没有羟基存在。
制备异辛基取代的二氧化硅纳米粒子(IO-纳米SiO2)
按美国专利公开号2002/0128336中所述制备异辛基取代的二氧化硅纳米粒子(IO-纳米SiO2)。
制备PEG改性的PAMAM树枝状聚合物
按如下制备表面改性的PAMAM(第2代)树枝状聚合物(PAMAMG-2):
合成MPEG-N-羟基琥珀酰亚胺酯
将100g单官能聚乙二醇(Polyglykol M,1100MW,购自Clariant,Sulzbach am Taunus,Germany,以后称为MPEG 1100)在甲苯中共沸干燥24小时,然后在50℃下,在持续搅拌下加入2摩尔过量的金属钠(4.2g)。将温度升到75℃,使反应再进行24小时。将反应物冷却到室温,除去所有未反应的钠,再冷却到10℃。加入溴乙酸叔丁酯(30mL,2.25摩尔过量,Aldrich Chemical Company),在将温度逐渐升到室温的同时,在持续搅拌下使反应再进行48小时。真空过滤反应物,除去NaBr盐,在旋转式蒸发器上汽提除去甲苯。将M-PEG 1100叔丁酯产物溶于300mL二氯甲烷中,用净化水(3×400mL)萃取。有机相用硫酸钠干燥,过滤,在旋转式蒸发器上汽提除去溶剂。在高真空下,在110℃蒸馏分离所有残余的挥发物。在50℃下,用2.25g一水合氢氧化锂的175mL净化水溶液将产物水解48小时。用HCl将反应物酸化至pH3.0,用二氯甲烷(4×300mL)萃取。有机相用硫酸钠干燥,过滤,在旋转式蒸发器上汽提除去溶剂,获得12g M-PEG 1100酸,将其溶于150mL四氢呋喃中,加入2摩尔过量的2.6g N-羟基琥珀酰亚胺(Aldrich ChemicalCompany),同时加入2.6g 1,3-二环己基碳二亚胺(1.1摩尔过量,AldrichChemical Company)。在持续搅拌下使反应在0℃下进行24小时。然后将所得混合物真空过滤,除去源自1,3-二环己基碳二亚胺的尿素,然后在旋转式蒸发器上除去THF。
乙酰化PAMAM G-2MPEG 1100衍生物(PAMAM G-2MPEG1100)
在0℃下,将0.5g STARBURST PAMAM G-2(Aldrich ChemicalCompany)溶于100mL N,N-二甲基甲酰胺中,添加5.4g MPEG 1100-N-羟基琥珀酰亚胺酯。在持续搅拌下使反应进行2小时。一旦暖热到室温,就添加100mL甲苯。用净化水(5×300mL)和1.0 NaOH(5×200mL)漂洗所得溶液。在旋转式蒸发器上汽提除去甲苯,在高真空下干燥产物。
为了盖住任何未反应的末端氨基,将产物再溶于50mL甲苯中,用过量的乙酸酐处理。在80℃经过2小时后,将溶液稍微冷却,添加50mL乙醇。然后在旋转式蒸发器上汽提除去所有溶剂,在高真空下干燥乙酰化PAMAM G-2MPEG 1100衍生物。
乙酰化PAMAM G-2MPEG 2000衍生物(PAMAM G-2MPEG2000)
用与上述制备乙酰化PAMAM G-2MPEG 1100衍生物相同的方法制备PAMAM G-2MPEG 2000衍生物,除了使用0.16g STARBURSTPAMAM G-2树枝状聚合物(Aldrich Chemical Company)和1.5g MPEG2000丙酸琥珀酰亚胺酯(MPEG-SPA,购自Nektar,San Carlos,CA)作为起始反应物。
乙酰化PAMAM G-4MPEG 1100衍生物(PAMAM G-4MPEG1100)
如上面合成乙酰化PAMAM G-2MPEG 1100衍生物所述,用5.0gMPEG 1100-N-羟基琥珀酰亚胺酯处理0.4g STARBURST PAMAMG-4(第4代)树枝状聚合物(Aldrich Chemical Company)。反应两小时后,添加另外的4.0g MPEG-N-羟基琥珀酰亚胺酯,为了使反应的完成程度更高,使反应继续进行另外两小时。
制备分散体
按如下制备受试分散体:称取赋形剂(如果有的话)、药物、和乙醇的量,加入到MDI罐中,然后将连续阀门拧到(crimp)罐上。迫使已知量的抛射剂通过连续阀门进入罐中。为了充分减少分散体的挥发性,将罐置于干冰上使之冷却,从而可以从罐上除去连续阀门,将计量阀门拧到罐上。在试验前使每个分散体暖热并稳定至少12小时。
悬浮质量摇动试验
用悬浮质量摇动试验评价实施例1-12和22-29以及比较例A-D的MDI分散体的物理稳定性。按照表2和3所示,将适量的药物、纳米粒子分散剂、抛射剂、乙醇和任何赋形剂置于有封盖(polyseal cap)的玻璃瓶中。将每个瓶摇动30秒。然后将瓶静置20分钟。20分钟后,目视观察瓶中的悬浮性质并记录。按表1所示的等级系统对分散体评级。
表1
悬浮质量的视觉等级
悬浮质量的视觉等级 | 对悬浮液的描述 |
1 | 在摇动过程中形成聚集体 |
2 | 摇动终止后立即开始絮凝 |
3 | 摇动终止后1-5秒开始絮凝 |
4 | 摇动终止后5-30秒开始絮凝 |
5 | 摇动终止后超过30秒开始絮凝 |
6 | 10分钟后未观察到絮凝 |
摇动-延迟递药
摇动-延迟递药(SDMD)试验用于评价在摇动和再填充定量体积之间的延迟对下一次剂量的影响。为了进行SDMD试验,准备MDI:将MDI向排气罩开启四次,在每次开启前立即摇动MDI。准备好MDI后,在再一次向排气罩开启之前,将MDI摇动并以竖立状态放置指定量的时间。然后向Unit Spray Collection Apparatus(单元喷雾收集装置)(USCA-美国药典,<621>部分,1996)开启MDI。通过USCA装置的抽取流速为30Lpm。在USCA的壁上或USCA中的过滤器上收集从MDI发射的剂量。按如下测定USCA壁上和过滤器上沉积的药量:用合适的溶剂漂洗这些组分以溶解药物,然后用合适的HPLC方法分析溶液。以摇动延迟时间为0、30和60秒进行试验。
实施例1-21和比较例A-G用表面改性无机纳米粒子制备的MDI
制备包括药物和表面改性无机纳米粒子分散体的剂型,对实施例1-21和比较例A-D进行上述悬浮质量摇动试验。试验结果示于下面表2中。比较例不含纳米粒子分散剂。结果显示,向MDI剂型中加入少量无机纳米粒子分散体而产生的剂型在悬浮质量摇动试验中保持分散。
对实施例13-20和比较例E、F、和G进行上述摇动延迟递药试验。这些试验的结果示于图1-3中。除非另有说明,所有实施例中估算的药物粒度质量中值为2.5微米。图1显示,与不含纳米粒子分散剂的MDI剂型(比较例E)相比,加入表面改性的纳米粒子(PEG-纳米Fe2O3或PEG-纳米SiO2)稳定了含硫酸沙丁胺醇的MDI剂型(实施例13-16)。将所加纳米粒子分散剂的量从0.25%减少到0.03%对剂型的稳定性影响很小。图2显示,在摇动延迟递药试验30秒后,与对照组相比,加入甚至更少量的纳米粒子分散剂(在实施例17-19中为0.01%至0.001%)对稳定MDI剂型仍有效果。图3显示,纳米粒子分散剂对稳定其中药物粒度质量中值很小的MDI剂型特别有效。
实施例22-28用表面改性有机纳米粒子配制的MDI
实施例22-28的分散体和视觉试验结果示于下表3中。对这些实施例,表2中的比较例A-D是相应的参照物。所有实施例中,估算的药物粒度质量中值为2.5微米。
在不背离本发明范围和精神的情况下,本发明的预期修改和替换对本领域技术人员是显而易见的。本发明不应被本申请为说明性目的所提出的实施方案所限制。
Claims (16)
1.一种稳定的药物分散体,包括:
含药物的分散固体相;和
含抛射剂和经表面改性的赋形剂纳米粒子的连续液体相,其中所述纳米粒子的平均粒径小于100nm,
其中经表面改性的赋形剂纳米粒子选自PEG-改性的二氧化硅纳米粒子、乙酰化星形-PEG-有机纳米粒子、PEG改性的树枝状聚合物、异辛基取代的二氧化硅纳米粒子、PEG改性的氧化铁纳米粒子和包括4臂、6臂、或8臂的聚环氧乙烷的星形聚合物。
2.如权利要求1所述的稳定的药物分散体,其中赋形剂纳米粒子被PEG表面改性。
3.如权利要求1所述的稳定的药物分散体,其中抛射剂包括:氯氟碳化合物、氢氯氟碳化合物、氢氟碳化合物、或其混合物。
4.如权利要求1所述的稳定的药物分散体,其中抛射剂包括:三氯氟甲烷;二氯二氟甲烷;1,2-二氯-1,1,2,2-四氟乙烷;1,1,1,2-四氟乙烷;1,1,1,2,3,3,3-七氟丙烷;二氧化碳;二甲醚;丁烷;丙烷;或其混合物。
5.如权利要求1所述的稳定的药物分散体,其中抛射剂包括:1,1,1,2-四氟乙烷、1,1,1,2,3,3,3-七氟丙烷、或其组合。
6.如权利要求1所述的稳定的药物分散体,其中药物选自:抗过敏药、镇痛药、支气管扩张药、抗组胺药、治疗用蛋白质和肽、镇咳药、抗心绞痛制剂、抗生素、抗炎制剂、利尿药、激素、和磺胺类药。
7.如权利要求6所述的稳定的药物分散体,其中所述激素选自促肾上腺皮质激素和肾上腺皮质激素。
8.如权利要求1所述的稳定的药物分散体,其中所述分散体含有小于0.001wt%的表面活性剂。
9.如权利要求1所述的稳定的药物分散体,其中所述纳米粒子的平均粒径小于50nm。
10.如权利要求1所述的稳定的药物分散体,其中所述纳米粒子的平均粒径小于20nm。
11.如权利要求1所述的稳定的药物分散体,其中所述纳米粒子的平均粒径小于10nm。
12.如权利要求1所述的稳定的药物分散体,其中所述纳米粒子的含量为0.001wt%至0.5wt%。
13.如权利要求1所述的稳定的药物分散体,其中药物选自:异丙肾上腺素、去氧肾上腺素、苯丙醇胺、高血糖素、肾上腺素红、胰蛋白酶、肾上腺素、麻黄碱、那可丁、可待因、阿托品、肝素、吗啡、二氢吗啡酮、双氢吗啡、麦角胺、东莨菪碱、美沙吡林、维生素B12、特布他林、利米特罗、沙丁胺醇、异丙肾上腺素、非诺特罗、氧托溴铵、瑞普特罗、布地奈德、氟尼缩松、环索奈德、福莫特罗、丙酸氟替卡松、沙美特罗、丙卡特罗、异丙托铵、曲安奈德、替泼尼旦、糠酸莫米松、秋水仙碱、吡布特罗、丙酸倍氯米松、奥西那林、芬太尼、海洛因、地尔硫新霉素、头孢菌素、链霉素、青霉素、普鲁卡因青霉素、四环素、氯四环素、羟四环素可的松、氢化可的松、醋酸氢化可的松和泼尼松龙、色甘酸二钠、奈多罗米、胰岛素、喷他脒、降钙素、阿米洛利、干扰素、IDNA聚合酶、肝素、及其组合。
14.药物在用于制备权利要求1的通过呼吸道治疗哺乳动物的药物分散体中的用途。
15.一种定量吸入器,包括:
具有计量阀门的气雾剂容器;和
放置在该容器内的权利要求1的稳定的药物分散体。
16.一种制备气雾剂分散体的方法,包括以下步骤:
提供气雾剂容器;和
向所述容器中投入权利要求1的药物分散体。
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US10/449,443 | 2003-05-30 | ||
US10/449,443 US7459146B2 (en) | 2003-05-30 | 2003-05-30 | Stabilized aerosol dispersions |
PCT/US2004/010847 WO2004108118A1 (en) | 2003-05-30 | 2004-04-08 | Stabilized aerosol dispersions |
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CN1798549A CN1798549A (zh) | 2006-07-05 |
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US (1) | US7459146B2 (zh) |
EP (1) | EP1628645A1 (zh) |
JP (1) | JP4680894B2 (zh) |
KR (1) | KR20060038938A (zh) |
CN (1) | CN1798549B (zh) |
WO (1) | WO2004108118A1 (zh) |
Families Citing this family (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060257324A1 (en) * | 2000-05-22 | 2006-11-16 | Chiesi Farmaceutici S.P.A. | Pharmaceutical solution formulations for pressurised metered dose inhalers |
US7459146B2 (en) * | 2003-05-30 | 2008-12-02 | 3M Innovative Properties Company | Stabilized aerosol dispersions |
US20040242729A1 (en) * | 2003-05-30 | 2004-12-02 | 3M Innovative Properties Company | Stabilized particle dispersions containing surface-modified inorganic nanoparticles |
US7109247B2 (en) * | 2003-05-30 | 2006-09-19 | 3M Innovative Properties Company | Stabilized particle dispersions containing nanoparticles |
DE102004053310A1 (de) * | 2004-11-04 | 2006-05-11 | Wacker Chemie Ag | Mikrowellenaktive Siliconelastomere |
EP1700825A1 (de) * | 2004-12-23 | 2006-09-13 | Degussa AG | Oberflächenmodifizierte, strukturmodifizierte Titandioxide |
AU2006278571B2 (en) * | 2005-08-05 | 2011-11-24 | 3M Innovative Properties Company | Compositions exhibiting improved flowability |
US8367734B1 (en) | 2005-08-11 | 2013-02-05 | Amphastar Pharmaceuticals Inc. | Stable epinephrine suspension formulation with high inhalation delivery efficiency |
US20070292688A1 (en) * | 2005-08-18 | 2007-12-20 | Eastman Kodak Company | Silylamine modified nanoparticulate carriers |
US20070099883A1 (en) * | 2005-10-07 | 2007-05-03 | Cheryl Lynn Calis | Anhydrous mometasone furoate formulation |
US7767736B2 (en) * | 2005-12-05 | 2010-08-03 | 3M Innovative Properties Company | Flame retardant polymer composition |
DE102006000691A1 (de) * | 2006-01-02 | 2007-07-05 | Henkel Kgaa | Aerosol-Reiniger mit korrosionsinhibierender Wirkung |
US20100119697A1 (en) * | 2006-05-10 | 2010-05-13 | 3M Innovative Properties Company | Compositions and coatings containing fluorescent, inorganic nanoparticles |
CN101108166B (zh) * | 2006-07-19 | 2011-07-27 | 鲁明华 | 定量纳米气雾剂及其制备方法 |
WO2008087909A1 (ja) * | 2007-01-16 | 2008-07-24 | Sumitomo Bakelite Company, Ltd. | 医療用粒子、及び分析用粒子、並びにそれらの製造方法 |
DE102007008663A1 (de) * | 2007-02-20 | 2008-08-21 | Merck Patent Gmbh | Bindemittel |
EP2137533A2 (en) * | 2007-04-19 | 2009-12-30 | 3M Innovative Properties Company | Uses of water-dispersible silica nanoparticles for attaching biomolecules |
EP2140264A1 (en) * | 2007-04-19 | 2010-01-06 | 3M Innovative Properties Company | Methods of use of solid support material for binding biomolecules |
JP5349838B2 (ja) * | 2007-11-30 | 2013-11-20 | 和光純薬工業株式会社 | smallRNAの取得用担体、取得方法及び取得用試薬 |
CN102089317B (zh) * | 2008-05-08 | 2016-10-19 | 3M创新有限公司 | 制备纳米粒子的方法 |
KR100961280B1 (ko) * | 2008-05-21 | 2010-06-03 | 한국생명공학연구원 | 형광특성이 향상된 풀러렌-실리카 나노입자, 이의 제조방법및 이의 용도 |
US11337962B2 (en) | 2009-09-25 | 2022-05-24 | Upsher-Smith Laboratories, Llc | Formulations comprising triptan compounds |
DK2480197T3 (en) | 2009-09-25 | 2016-01-25 | Reddys Lab Ltd Dr | Compositions containing triptanforbindelser |
CN102416179B (zh) | 2010-09-28 | 2014-05-07 | 益得生物科技股份有限公司 | 用于哮喘的吸入性复方组合物 |
CN103328038A (zh) | 2010-12-01 | 2013-09-25 | 史拜诺莫度雷森公司 | 向神经解剖结构直接递送药剂 |
EP3319907B1 (de) | 2015-07-10 | 2020-08-05 | Evonik Operations GmbH | Sio2 enthaltende dispersion mit hoher salzstabilität |
US10723628B2 (en) | 2015-07-10 | 2020-07-28 | Evonik Operations Gmbh | SiO2 containing dispersion with high salt stability |
US10920084B2 (en) | 2015-07-10 | 2021-02-16 | Evonik Operations Gmbh | Metal oxide-containing dispersion with high salt stability |
CN108291137B (zh) | 2015-10-26 | 2021-01-12 | 赢创运营有限公司 | 使用二氧化硅流体获得矿物油的方法 |
SG11202100580UA (en) | 2018-07-23 | 2021-02-25 | Trevi Therapeutics Inc | Treatment of chronic cough, breathlessness and dyspnea |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0478456A1 (fr) * | 1990-09-26 | 1992-04-01 | Sandoz Ltd | Composition antifongique sous forme de spray sec |
WO2002030394A2 (en) * | 2000-10-09 | 2002-04-18 | 3M Innovative Properties Company | Medicinal aerosol formulations |
Family Cites Families (54)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE837243C (de) | 1944-09-30 | 1952-04-21 | Bayer Ag | Schwebemittel fuer waessrige Suspensionen |
US2801185A (en) | 1952-05-16 | 1957-07-30 | Du Pont | Silica hydrosol powder |
DE1467023A1 (de) * | 1964-02-28 | 1969-01-23 | Degussa | Verfahren zur Inkorporierung von Wasser in feinst verteilter Kieselsaeure |
US4680173A (en) * | 1977-04-28 | 1987-07-14 | Norman D. Burger | Aerosol dispensing system |
US4478876A (en) | 1980-12-18 | 1984-10-23 | General Electric Company | Process of coating a substrate with an abrasion resistant ultraviolet curable composition |
US4455205A (en) | 1981-06-01 | 1984-06-19 | General Electric Company | UV Curable polysiloxane from colloidal silica, methacryloyl silane, diacrylate, resorcinol monobenzoate and photoinitiator |
US4491508A (en) | 1981-06-01 | 1985-01-01 | General Electric Company | Method of preparing curable coating composition from alcohol, colloidal silica, silylacrylate and multiacrylate monomer |
US4486504A (en) | 1982-03-19 | 1984-12-04 | General Electric Company | Solventless, ultraviolet radiation-curable silicone coating compositions |
US4522958A (en) | 1983-09-06 | 1985-06-11 | Ppg Industries, Inc. | High-solids coating composition for improved rheology control containing chemically modified inorganic microparticles |
DE3333639A1 (de) * | 1983-09-17 | 1985-03-28 | Dynamit Nobel Ag | Zubereitung von nitroestern fuer die koronartherapie |
US5776434A (en) | 1988-12-06 | 1998-07-07 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
US5225183A (en) | 1988-12-06 | 1993-07-06 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
US5439670A (en) | 1989-11-28 | 1995-08-08 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
US5037579A (en) | 1990-02-12 | 1991-08-06 | Nalco Chemical Company | Hydrothermal process for producing zirconia sol |
US5258225A (en) | 1990-02-16 | 1993-11-02 | General Electric Company | Acrylic coated thermoplastic substrate |
US5145684A (en) * | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
US5182097A (en) | 1991-02-14 | 1993-01-26 | Virginia Commonwealth University | Formulations for delivery of drugs by metered dose inhalers with reduced or no chlorofluorocarbon content |
FR2677544B1 (fr) * | 1991-06-14 | 1993-09-24 | Oreal | Composition cosmetique contenant un melange de nanopigments d'oxydes metalliques et de pigments melaniques. |
DE4120760A1 (de) * | 1991-06-24 | 1993-03-04 | 3 M Medica Gmbh | Traegersysteme fuer arzneimittel |
IL104068A (en) | 1991-12-12 | 1998-10-30 | Glaxo Group Ltd | Pharmaceutical preparations in a spray without surfactant containing 1, 1, 1, 2 tetrafluoroethane or 1,1,2,3,3 petafluor N propane as propellant |
CA2125666C (en) | 1991-12-12 | 2002-07-16 | Rachel Ann Akehurst | Medicaments |
ES2079210T3 (es) | 1991-12-12 | 1996-01-01 | Glaxo Group Ltd | Formulacion farmaceutica de aerosol. |
FR2698002B1 (fr) * | 1992-11-13 | 1995-01-13 | Oreal | Composition cosmétique de maquillage contenant un fullerène ou un mélange de fullerènes comme agent pigmentant. |
IL108416A (en) * | 1993-01-25 | 1998-10-30 | Sonus Pharma Inc | Colloids with phase difference as contrast ultrasound agents |
US5492688A (en) | 1993-04-28 | 1996-02-20 | The Center For Innovative Technology | Metered dose inhaler fomulations which include the ozone-friendly propellant HFC 134a and a pharmaceutically acceptable suspending, solubilizing, wetting, emulsifying or lubricating agent |
EP0731688B1 (en) | 1993-12-02 | 2003-03-05 | Abbott Laboratories | Aerosol drug formulations for use with non-cfc propellants |
US5508023A (en) | 1994-04-11 | 1996-04-16 | The Center For Innovative Technology | Pharmaceutically acceptable agents for solubilizing, wetting, emulsifying, or lubricating in metered dose inhaler formulations which use HFC-227 propellant |
IT1275955B1 (it) * | 1995-03-22 | 1997-10-24 | Dompe Spa | Formulazioni farmaceutiche in forma di gel tissotropico |
US5672662A (en) | 1995-07-07 | 1997-09-30 | Shearwater Polymers, Inc. | Poly(ethylene glycol) and related polymers monosubstituted with propionic or butanoic acids and functional derivatives thereof for biotechnical applications |
FR2746302B1 (fr) * | 1996-03-20 | 1998-12-24 | Oreal | Compositions cosmetiques comprenant des nanopigments |
US6054488A (en) | 1996-06-11 | 2000-04-25 | 3M Innovative Properties Company | Medicinal aerosol formulations of formoterol |
FR2759582A1 (fr) * | 1997-02-14 | 1998-08-21 | Oreal | Composition deodorante |
US6309623B1 (en) | 1997-09-29 | 2001-10-30 | Inhale Therapeutic Systems, Inc. | Stabilized preparations for use in metered dose inhalers |
DE19811790A1 (de) * | 1998-03-18 | 1999-09-23 | Bayer Ag | Nanopartikel enthaltende transparente Lackbindemittel mit verbesserter Verkratzungsbeständigkeit, ein Verfahren zur Herstellung sowie deren Verwendung |
FR2781373B1 (fr) * | 1998-07-07 | 2001-09-21 | Pf Medicament | Formulations thixotropes pour le remplissage de gelules |
JP4279465B2 (ja) | 1998-07-30 | 2009-06-17 | スリーエム カンパニー | 透明な金属酸化物のコロイド及びセラマーを製造するためのナノサイズ金属酸化物の粒子 |
US6319513B1 (en) * | 1998-08-24 | 2001-11-20 | The Procter & Gamble Company | Oral liquid mucoadhesive compounds |
US7521068B2 (en) * | 1998-11-12 | 2009-04-21 | Elan Pharma International Ltd. | Dry powder aerosols of nanoparticulate drugs |
US6258896B1 (en) * | 1998-12-18 | 2001-07-10 | 3M Innovative Properties Company | Dendritic polymer dispersants for hydrophobic particles in water-based systems |
WO2000045878A2 (de) * | 1999-02-03 | 2000-08-10 | Max-Delbrück-Centrum für Molekulare Medizin | Druckluftinhalator zur pulmonalen applikation liposomalen pulver-aerosols sowie dafür geeignete pulver-aerosole |
US6238798B1 (en) * | 1999-02-22 | 2001-05-29 | 3M Innovative Properties Company | Ceramer composition and composite comprising free radically curable fluorochemical component |
ES2293913T3 (es) | 1999-07-20 | 2008-04-01 | THE PROCTER & GAMBLE COMPANY | Particulas de aceite encapsulado mejoradas. |
AU776770B2 (en) | 1999-12-03 | 2004-09-23 | Kuraray Co., Ltd. | Dental or oralogic composition |
FR2808704B1 (fr) * | 2000-05-10 | 2002-08-16 | Rhodia Chimie Sa | Agents tensioactifs formes par des particules minerales de dimension nanometrique de surface modifiee |
MXPA02001323A (es) | 2000-05-10 | 2004-07-16 | Alliance Pharma | Microgranulos con base fosfolipida para la liberacion de farmaco. |
US20040081627A1 (en) * | 2000-10-09 | 2004-04-29 | Jinks Phillip A | Medicinal aerosol formulations |
US6467897B1 (en) | 2001-01-08 | 2002-10-22 | 3M Innovative Properties Company | Energy curable inks and other compositions incorporating surface modified, nanometer-sized particles |
US6586483B2 (en) | 2001-01-08 | 2003-07-01 | 3M Innovative Properties Company | Foam including surface-modified nanoparticles |
JP4293735B2 (ja) * | 2001-01-19 | 2009-07-08 | 三栄源エフ・エフ・アイ株式会社 | フラーレン誘導体およびそれからなる組成物 |
FR2830450B1 (fr) | 2001-10-09 | 2004-02-06 | Univ Pasteur | Utilisation de dendrimeres dans une composition ophtalmique |
US7129277B2 (en) * | 2002-12-31 | 2006-10-31 | 3M Innovative Properties Company | Emulsions including surface-modified inorganic nanoparticles |
US7001580B2 (en) * | 2002-12-31 | 2006-02-21 | 3M Innovative Properties Company | Emulsions including surface-modified organic molecules |
US7459146B2 (en) * | 2003-05-30 | 2008-12-02 | 3M Innovative Properties Company | Stabilized aerosol dispersions |
US7109247B2 (en) * | 2003-05-30 | 2006-09-19 | 3M Innovative Properties Company | Stabilized particle dispersions containing nanoparticles |
-
2003
- 2003-05-30 US US10/449,443 patent/US7459146B2/en not_active Expired - Fee Related
-
2004
- 2004-04-08 JP JP2006509816A patent/JP4680894B2/ja not_active Expired - Fee Related
- 2004-04-08 KR KR1020057022771A patent/KR20060038938A/ko not_active Application Discontinuation
- 2004-04-08 WO PCT/US2004/010847 patent/WO2004108118A1/en active Application Filing
- 2004-04-08 CN CN2004800150751A patent/CN1798549B/zh not_active Expired - Fee Related
- 2004-04-08 EP EP04749884A patent/EP1628645A1/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0478456A1 (fr) * | 1990-09-26 | 1992-04-01 | Sandoz Ltd | Composition antifongique sous forme de spray sec |
WO2002030394A2 (en) * | 2000-10-09 | 2002-04-18 | 3M Innovative Properties Company | Medicinal aerosol formulations |
Non-Patent Citations (2)
Title |
---|
KIBBE AH ET AL.Handbook of Pharmaceutical Excipients 3.AMERICAN PHARMACEUTICALASSOCIATION/PHARMACEUTICAL PRESS,2000,143-145. |
KIBBE AH ET AL.Handbook of Pharmaceutical Excipients 3.AMERICAN PHARMACEUTICALASSOCIATION/PHARMACEUTICAL PRESS,2000,143-145. * |
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EP1628645A1 (en) | 2006-03-01 |
US20040241101A1 (en) | 2004-12-02 |
JP4680894B2 (ja) | 2011-05-11 |
US7459146B2 (en) | 2008-12-02 |
WO2004108118A1 (en) | 2004-12-16 |
CN1798549A (zh) | 2006-07-05 |
JP2006526624A (ja) | 2006-11-24 |
KR20060038938A (ko) | 2006-05-04 |
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