CN1335766A - 一种制备用于吸入给药的药物颗粒悬浮体的方法 - Google Patents
一种制备用于吸入给药的药物颗粒悬浮体的方法 Download PDFInfo
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- CN1335766A CN1335766A CN99812934A CN99812934A CN1335766A CN 1335766 A CN1335766 A CN 1335766A CN 99812934 A CN99812934 A CN 99812934A CN 99812934 A CN99812934 A CN 99812934A CN 1335766 A CN1335766 A CN 1335766A
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Abstract
本发明涉及一种制备用于吸入给药的药物颗粒悬浮体的方法,它提供一种均匀分散在载体中的、有优化颗粒大小和分布的颗粒。该方法—它也适用于制备灭菌悬浮体—包括步骤:在一个能提供高能涡动的涡轮乳化器中均化和微米化,任选随后在一个高压均化器中再进行处理。本发明的另一方面涉及一种通过伽玛照射制备微米化的灭菌的二丙酸倍氯米松的方法。
Description
通过吸入法给药的方法已采用许多年了,并且是治疗那些空气供应受限的疾病如哮喘和慢性支气管炎的主要措施。
此外,众多吸入制剂已上市了多年,作为局部治疗鼻炎和/或鼻窦炎的类固醇消炎药、减充血剂和抗过敏剂。
吸入式给药比之全身式给药的一个优越之处在于,它能将药物直接传递到作用点,从而避免全身性给药的副作用。该给药方式可以取得更迅速的临床疗效和高的治疗指数。
在不同类的、通过吸入式给药来治疗呼吸道疾病的药物中,糖皮质类固醇如二丙酸倍氯米松(BDP)、地塞米松、9-去氟肤轻松、布地奈德、丙酸氟替卡松特别重要。它们可以以细分散的即微米化的粉末形式、配制成在含任何必要的表面活性剂和/或助溶剂的水相中的悬浮体形式给药,当打算以气悬体喷雾剂的计量量形式给药时,它们也应含有一种低沸点驱动剂。
给药形式的有效性取决于在作用点位上颗粒的适宜沉积量。确定将到达病人呼吸道深处的可吸入药物的比例的一个最重要参数是从装置中产生的颗粒大小。为了保证有效地渗入到支气管和小泡中并由此保证高的可呼吸分率,颗粒的平均气动直径(MMAD)应低于5-6微米(μm)。对于鼻道给药,则需要高效一些MMAD的颗粒。
为了正确给药和因此达到治疗效果的其它重要特征是在悬浮体中颗粒大小的分布和均匀分散性。
所说参数控制不好将有利于松散附聚物(凝乳)形成或,若凝乳变得密实和熔合,则悬浮的颗粒的饼块将易于损害产物的可再悬浮性,并在装填容器和应用过程中不利于提供均匀的剂量。
本发明的一个目的是提供一种方法,用于制备一种用在气动吸入式药物制剂中的颗粒悬浮体,所说颗粒有优化的颗粒大小和分布,以适合于得到具有高治疗效率的组合物。
在本发明的第一个实施方案中,方法这样进行:使用一种涡轮乳化器,并任选接着用一种高压均化器处理。
因此,所说方法包括一个第一步骤,其中一个构成载体的水溶液在一个涡轮乳化器装置中分散。一个适于该处理的典型涡轮乳化器包括一个容器,它装备有磁力搅拌和一个用于均化悬浮体的高能涡轮系统。该装置也可装配有一个加热用蒸汽外套以及一个真空系统。
载体任选含有润滑剂,表面活性剂,增粘剂,防腐剂、稳定化剂、等渗剂和/或缓冲剂,且可任选是灭菌了的。在第二步中,将一种或多种微米化的活性成分-由常规研磨所得-加入该水相中、并通过施加很高的速度(2000-3000,优选2500-2600 r.p.m)约15-20分钟而分散在同一涡轮乳化器容器中。已发现,为了防止在储存时发生附聚,所说的条件对于有效地分散微米化了的有效成分颗粒是必须的。此外,已令人惊异地发现,在处理过程中,颗粒经历进一步的温和研磨,它降低有较大直径的晶体的尺寸,由此消除具有较高颗粒尺寸分布的部分。
任选地,该方法可在负压下操作,以便使悬浮体撇去浮渣。
在本发明的一个更优选的实施方案中,分散在水相中的药物要经历一个另外的高压均化处理,以便进一步降低悬浮颗粒的平均大小。用于该处理的一种典型的设备,如Microfluidizer,包括一个能提供高达1500巴压力的高压泵和一或多个交互作用室。在处理过程中,样品作为一种物流引入,然后在操作压力下受迫通过交互作用室,在此处,该物流被加速到极高的速度并经历三种主要的力:i)剪切力(颗粒相互滑过,撕扯);ii)冲击力(碰撞、破碎作用);iii)空化作用力(环绕的液相的空穴或气泡的坍塌;速度变化增大,压力变化减小)。
固体颗粒大小的下降程度和所产生的颗粒分布曲线可通过控制以下变量而优化:i)交互作用室的类型和尺寸;ii)操作压力;iii)处理时间和物料进行的循环圈数。
处理的效果还取决于经受处理的成分的理化特性。根据其晶格的硬度,要求不同的压力和处理时间,以获得所需的结果。
对类固醇而言,已经发现,可以如此束紧颗粒分布曲线,以使至少90%的颗粒的平均直径低于或等于5μm,这可通过保持操作压力在500-1000巴来实现。特别地,用于传导到肺部的经优化的颗粒是通过使用带有尖锐的边缘的交互作用室并保持操作压力为600-800巴而得到的。要避免在更高的压力下过度处理,因为它将导致颗粒大小的生长和凝乳的生成。可通过使悬浮体仅通过一个处理循环并因此只经历很短的时间而获得所说令人惊异的结果,这使得本发明方法从工业角度看非常方便和有吸引力。
本发明方法在室温下有效地进行,这对不耐热的分子如类固醇而言就具有很显著的优点。另一方面,在处理过程中,温度并不显著增加。此外,所说的具体压力范围被证明是适合于降低已悬浮了的活性成分的颗粒尺寸的,同时不要求显著增加表面活性剂的量。一个一般的知识是,随着微米化,活性成分的总表面积增加,这有时对改变悬浮体的配方是需要的。因此必须将颗粒的破碎控制在所选用的组成所允许的程度之内。
在按本发明的处理的末尾,将得到一种颗粒,其颗粒大小分布被控制在很好地限定的参数范围之内,且被悬浮的颗粒有好的分散。得到的配制物是物理上稳定的,并在储存至少一年后易于再悬浮。
为了防止悬浮体粘度增加和防止在储存期间生成松散的附聚物——这在使用前将使病人产生疑惑,本发明方法可有利地在600-700巴下、并采用与前一个串接的另一个交互作用室来操作。
高压均化的最广泛应用涉及颜料、涂料、喷墨打印墨水和陶瓷粉末的固-液分散体。
WO96/14925涉及硬的、非屈服的颗粒的分散体,它用于磁记录介质如声乐带、视频带或计算机盘。
在现有技术中可找到在药物组合物中的应用例子,但还未见到处理类固醇的例子。
EP768114要求了所说装置在环境温度下处理气悬体制剂中的应用,该制剂含有低沸点组成如氢氟碳烷(HFA)。在550-620巴下、但经重复的处理循环之后获得了均化。示例3的活性成分、例如异丙托溴铵和沙丁罗尔硫酸盐(Sulbuterol sulfate)的微米化仅在很高的压力(约1400巴)下实现。
EP726088还公开了一种方法,包括在高压下使物料通过多个小孔往返循环,以得到均匀分散的制剂,它含有待用于压缩的气悬体吸入药剂的液化的推进剂。
Illig等人(药物工艺(Pharm Tech)1996年10月)在一个旨在描述Microfluidizer加工法相对于常规研磨处理法的优点的研究中,应用了该技术来生产具有下降的颗粒大小的、磺酸盐化了的、不透射线的材料的悬浮体。
Calvor等人(药物开发工艺(Pharm Dev Technol)3,297-305,1998)公开了一种高压均化方法,以生产聚合物的纳米级颗粒制剂(小于1μm,并优选为5-7nm)。
按照本发明方法制备的悬浮体可被分隔在适宜的容器、例如用于喷雾的多剂量-或优选单剂量系统中,它用所谓“吹制、装填和封口”工艺(″blow,fill and seal″technology):预先形成或制成,或封装在泵或用于鼻吸给药的系统中。
两个步骤—它们分别涉及涡轮乳化器和高压均化器—均可在不与大气接触的情况下进行,并因此适应在无菌环境下操作。
该方法的所用步骤均可以工业规模进行。
能够有利地得自于这种处理的分散体的类型是:i)得自一种微米化灭菌活性成分的灭菌悬浮体;ii)得自一种微米化非灭菌活性成分的悬浮体。
本发明方法也可有利地用于:iii)得自一种以非微米化的粉末形式存在的非灭菌成分的悬浮体;iv)作为用湿蒸汽处理本体悬浮体后得到的灭菌制剂。
事实上已更令人惊异地发现,具有所需颗粒大小分布的颗粒也可通过使含非微米化的活性成分的悬浮体经受高压均化处理而得到。尤其是,通过施加一种低于前面所称压力的操作压力,可得到适用于鼻道给药的颗粒。所说处理也可能在在热灭菌处理后、其性能发生了不利的变化的情况出现后有效地用于恢复所需的颗粒大小分布。所说热灭菌处理方法可能会导致附聚物的生成,它们难于被解附聚成为适于给药的细颗粒。
能被有利地用于按本发明方法制备悬浮体的药物包括这些类固醇,它们通常通过吸入法来给药,以治疗呼吸道疾病,如二丙酸倍氯米松、9-去氟肤轻松、糖酸莫米松、曲氨奈德、地塞米松、丙酸氟替卡松、布地奈德和它的差向异构体。可将活性成分分散在一种水溶液中或在一种高沸点有机溶剂如醇类中而制得相应的制剂。根据所得的颗粒大小和颗粒分布,它们既可用于肺部给药,又可用于鼻道给药。
此外,按本发明方法得到的颗粒适合为干燥的,可任选在压缩的剂量化的气悬体吸入器中稳定化。有机溶剂中的悬浮体可直接分配到容器中以用于压缩的气悬体。
如上报道的,按本发明的方法适应于在灭菌条件下操作。由于对用于喷雾的药物制剂灭菌要求提得越来越多,则提供作为灭菌的单剂量制剂形式给药的类固醇的含水悬浮体是很有利的。所说制剂可避免使用抗微生物剂或防腐剂,后者被广泛报道为对呼吸道过敏和刺激的起因,并因此引起咳嗽或支气管痉挛。
因此本发明的第二个目的是提供一种制备颗粒制剂的方法,该制剂将用于气悬体吸入法的含水悬浮体,所说颗粒由灭菌微米化的活性成分组成,并具有优化了的颗粒大小分布的特性,以能够得到高的治疗效率。
所说方法包括下列步骤:i)在一种合适的涡轮乳化器中制备一种水溶液,它构成载体且任选含润湿剂、表面活性剂、增粘剂、稳定化剂、等渗剂和/或缓冲物质;ii)在同一容器中对该含水基质灭菌;iii)在一种灭菌的环境下加入一种或多种活性的灭菌的微米化了的成分;iv)通过使用同一涡轮乳化器而分散所有成分。
得到的悬浮体可在无菌条件下直接分装在塑性单剂量容器中,容器经预成型和通过适当处理灭菌了,或通过采用“吹制、装填和封口”工艺无菌生产。
包装前,悬浮体可任选经历另一次高压均化处理,它仍然在灭菌条件下进行。
本发明的第三个目的是用于制备治疗上可接受的、微米化的BDP的方法,BDP是经伽玛射线照射灭菌了的。
使用伽玛照射来使类固醇灭菌已在文献中报道。但是,有关数据仅涉及粉末、溶液、悬浮体、霜剂或软膏形式的药物;此外,即使在最有利的情况下,常常观察到含量下降,这不符合现行的、用于药物制剂或用于药物制剂的产物的ICH(国际大会协调规则)要求。
Hayes R.等人在药物药理学期刊32(增刊),48页,1980中对比了粉末BDP与其在甲醇或丙二醇于现行用于霜剂的溶剂中的溶液中的稳定性。采用的钴60(60Co)的剂量为1-4Mrad作为伽玛照射源。结论为,粉末形式的BDP在照射后马上稳定了,而其溶液迅速降解。
Bussey DM等人在J Parent Sci Technol 37,51-54,1983中、Kane MP等人在J Pharm Sci72,30-35,1983中报道了通过60Co作为照射源灭菌了的皮质类固醇粉末的降解数据。降解百分数随具体活性成分而变化,在泼尼松时为最低0.2%/Mrad,最高为氢化可的松琥珀酸钠时的1.4%/Mrad。照射后的降解引起C17侧链的损失和在C11位醇基团的氧化。微米化的类固醇的灭菌由Illum L等人报道于ArchPharm Chemi Sci Ed.2,167-74,1974中。经历了两个不同照射剂量(4.5和15Mrad)的活性成分显示了不同的降解度,即对乙酸氢化可的松和泼尼松低于1%,对氢化可的松、泼尼松龙和泼松松龙水合物则约为2.4%。
WO99/25359公开了一种粉化形式的糖皮质类固醇、优选布地奈德的灭菌方法,其中采用的温度(100-130℃)显著低于被认为是其它物质灭菌所需的温度。
PT-A-69652公开了使用环氧乙烯和二氧化碳的、微米化的糖皮质类固醇的冷灭菌。具体的例子是Prednacinolone、地塞米松、泼尼松龙和它们的盐、酯和氟代衍生物。未报道BDP的灭菌。此外,该技术要求消去残余的环氧乙烷,这耗时且困难。考虑到现行的严格政策要求,该方法将不适宜于生产治疗上可接受的糖皮质类固醇。
总之,灭菌方法,尤其是伽玛射线照射法,以前并未应用到微米化的二丙酸倍氯米松(BDP)上。此外,微米化的、经照射的产品的相应悬浮体在储存期间的稳定性从未被研究清楚过,降解过程可能确实会由于药物经照射后储积的能量并经较长储藏时间后而发生。
现已令人惊异地发现,在特定条件下、经2-9KGy伽玛照射的BDP微米化物质将保持化学稳定。与WO99/25359中报道过的布地奈德的情况相反,相比于未照射过的产物,没有观察到显著的化学降解。按本发明方法灭菌的BDP微米化物质未经历过其晶体特性的变化,如由DSC(示差扫描量热计)、TGA(热重分析)、XRD(X-射线衍射)、IR(红外谱)所证实,也未发生颗粒大小改变,如Malvern分析所示。同样,在长期和加速储存条件下,相应的悬浮体也证明是物理和化学稳定的。
该方法对在由适宜材料、优选聚乙烯制成的容器中并在由氮气置换了空气、优在真空条件下包装的产品进行处理;该容器则被封装于由隔氧材料如Polikem或Co-Pack制成的袋中。
现已发现,在照射时氧的存在将剧烈地影响产物的稳定性,因为产物对氧化性过程变得更为敏感。容器的体积与微米化的粉末的量之比应该保持尽可能地低,且必要地等于或低于7∶l/w/v。
按照国际标准组织规程ISO-11137-2B,本发明方法能有效地保证的灭菌保质水平为至少为10-6(优选10-7,且它提供一种满足欧洲药典标准(Ph.Eur.)的无菌材料。
本发明方法提供了解决制备用作喷雾剂的微米化BDP无菌悬浮体时存在的技术问题的途径。直接对最终制剂进行的现有技术的灭菌方法确实不适用于此;由于悬浮的颗粒的不可过滤性,无菌过滤法不适用;而湿蒸汽(高压釜处理)涉及一定的热量,只有热稳定的类固醇才能忍受它。例如BDP悬浮体-它经历了在类似于在US3,962,430中报道的条件下的湿蒸汽处理-将发生活性成分含量显著下降(约8-9%)的现象,产生相应显著增加的降解产物(约(10-11%)。
用于该方法的BDP原料的生物负担小于100CFU/每克(群落生成单位),优选小于10CFU/克,并以微米化的粉末形式、优选以其MMAD小于10μm、优选小于5μm的颗粒形式使用。
用于吸入的相应制剂可有利地用于治疗鼻和肺的任何过敏条件和/或发炎状况,例如用于治疗医院和家庭病房中的气喘及治疗支气管肺的发育异常。
下列实施例对本发明进行进一步说明。实施例1:伽玛照射对微米化的BDP灭菌
约600克微米化的BDP储存在一个经氮置换空气的20升聚乙烯容器中,该容器又用两个Polikem袋密封。该产物在2-9KGy下用伽玛照射。此后,BDP纯度和有关物质的量用HPLC测定。对经历了2KGy剂量的批料,由Malvern分析法和TGA分别求取了颗粒尺寸和重量损失,其间与未照射的产物对比。
按照欧洲药典中报道的直接培养方法,使所有批料均经历灭菌度试验。每0.5克照射过的粉末样品用以下活体ATCC微生物培养:360UFC金黄色葡萄球菌、400UFC枯草杆菌、350UFC产芽胞棱状芽胞杆菌、330UFC白色念珠菌。在加入1%聚山梨醇酯80后,将培养介质温育14天。与未照射的产物对比,测定微生物群落密度。
结果列于表1中。表1求取 未照射的 照射的BDP 射的BDP 照射的BDP
2KGy 3.17KGy 9.08KGy重量损失(%,TGA) 0.12 0.13 - -纯度(%) 99.7 99.6 99.6 99.3有关物质(%) 0.3 0.4 0.4 0.7颗粒尺寸分布(μm,Malvern)d(0.1) 0.49 0.48d(0.5) 1.91 1.81d(0.9) 5.98 5.73
结果表明,在经过伽玛照射后,BDP是稳定的。仅在9.08KGy照射后观察到了化学降解的少量增加。但是,相应的批料满足纯度规格。
经历2KGy照射后的批料的颗粒大小未受影响。未观察到水的吸收。所有批料均满足欧洲药典的灭菌要求。
实施例2通过涡轮乳化器、由经2KGy剂量伽玛照射灭菌(实施例1)后的微米化BDP出发,制备灭菌的悬浮体组分 组成
总 每个药剂单位灭菌的微米化BDP 40.0g (0.8mg)聚山梨醇酯(Tween)20 100.0g (2.0mg)脱水山梨醇单月桂酸酯 20.0g (0.4mg)氯化钠 900.0g (18.0mg)无菌水加入至 100.01 (2.0ml)
灭菌悬浮液的制备包括一个第一步,其中,含水基质在一个置于层流罩之下的涡轮乳化器Tecninox 100L中、在一个控制污染的环境中制备。在用灭菌水注入设备中后,加入氯化钠和表面活性剂,然后在磁性高能涡轮搅拌下,制剂被混合至表面活性剂被均匀分散。
该制剂然后在装有加热蒸汽外套的涡轮乳化器中,在121℃下灭菌20分钟。
将该制剂冷却至35℃后,将灭菌的活性成分加到灭菌的含水基质中,仍然处于层流罩之下:首先将活性成分仅经磁力搅拌而分散,然后借助涡轮系统、在2600r.p.m.下分散15-20分钟。
然后将涡轮乳化器通过一个无菌管连接到配给设备的一个储池,它置于在控制污染的环境中的层流罩之下;最后,对每个经β-照射预灭菌后的单剂量给药容器配给2.15ml悬浮体。实施例3:按实施例2得到的制剂的颗粒大小分析
由实施例2所述方法得到的悬浮颗粒的颗粒大小分布由Malvern光散射分析法分析。监测的参数是10%、50%和90%颗粒的体积平均直径(μm),分别表示为d(0.1)、d(0.5)和d(0.9),且它们是在假设颗粒本身具有等价于球形的几何形状的前提下求取的。
在加速条件下(40℃、75%相对湿度)作6个月储存之后、和在长期条件(25℃、60%相对湿度)下作6和12个月储存后,分析样品。结果列于表2中。表2:
储存时间(月) 数据 悬浮体
(μm)
0 d(0.1) 0.76
d(0.5) 3.01
d(0.9) 9.42
6 d(0.1) 0.78
(40℃,75%相对湿度) d(0.5) 3.05
d(0.9) 8.03
6 d(0.1) 0.79
(25℃,60%相对湿度) d(0.5) 3.17
d(0.9) 9.62
12 d(0.1) 0.78
(25℃,60%相对湿度) d(0.5) 3.5
d(0.9) 9.78
结果证实,悬浮的BDP微米化颗粒在悬浮体中经历了伽玛照射后,储存后保持其颗粒大小不变。实施例4:多级液体冲击器分析
用实施例2的方法得到的灭菌悬浮体的喷雾行为用多级液体冲击器(M.S.L.I.)分析,采用如USP/NF中所述的设备和步骤。使用常规喷雾器(Micron-Medel)喷雾5分钟。所说试验能评价制剂的呼吸剂量,该剂量对应于细颗粒剂量(颗粒大小低于6.8μm的颗粒数量)和极细颗粒剂量(颗粒大小低于3μm的颗粒数量)的总和。
表3列出了两次求取的平均值结果。按实施例2得到的两个不同制剂与一种市售的制剂作了对比。表3
剂量(μg) | 参比 | 制剂1 | 制剂2 |
细剂量 | 30.5 | 104.0 | 128.5 |
极细剂量 | 12.0 | 78.0 | 83.0 |
结果显示了,按实施例2得到的制剂中细-和极细颗粒的剂量有急剧增加,证实用涡轮乳化器处理改进了颗粒的大小分布和可分散性特征。此外,该结果证明,伽玛照射并未不利地影响喷雾化性能。实施例5:由伽玛照射的微米化BDP制得的灭菌悬浮体的化学稳定性
通过使用实施例2中描述的方法得到的制剂被配给在事先经β-照射灭菌了的聚丙烯单剂量容器中,并在加速和长期条件下储存后按ICH指南进行试验。活性成分的化学稳定性结果列于表4和5中。BDP的和它的主要降解产物(倍氯米松-17-丙酸酯、倍氯米松-21-丙酸酯和倍氯米松)的评价由HPLC进行。表4:在加速条件(40℃、75%R.H.)下储存后的制剂的化学稳定性
时间(月) BDP评价 降解产物* pH
(g/100ml) (%w/w)
0 0.0388 1)0.16
(100%) 2)0.18 4.7
3)<LOD
3 0.0395 1)0.13
(101.8%) 2)0.16 3.7
3)<LOD
6 0.0396 1)0.12
(102.1%) 2)0.15 3.7
3)<LOD(*)降解的:1)倍氯米松-17-丙酸酯;2)倍氯米松-21-丙酸酯;3)倍氯米松LOD:检测极限;n.d.:未检测。表5:在长期条件(25℃,60%R.H.)下储存后的制剂的化学稳定性
时间(月) BDP评价 降解产物* pH
(g/100ml) (%w/w)
0 0.0388 1)0.16
(100%) 2)0.18 4.7
3)<LOD
3 0.0396 1)0.15
(102.1%) 2)0.17 4.0
3)<LOD
6 0.0390 1)0.15
(100.5%) 2)0.16 4.0
3)<LOD
9 0.0375 1)0.12
(96.6%) 2)0.16 3.8
3)<LOD
12 0.0413 1)0.13
(106.4%) 2)0.17 4.0
3)<LOD(*)降解的:1)倍氯米松-17-丙酸酯;2)倍氯米松-21-丙酸酯;3)倍氯米松LOD:检测极限;n.d.:未检测。
表4和表5结果证实,按本发明方法制得的制剂的特征在两种条件下保持未变。既未观察到含量下降,也未观察到降解产物的增加。pH值的略微增加可归因于制剂中缺乏缓冲物质。
按欧洲药典,该制剂也证明是灭菌的。实施例6:由未灭菌的微米化BDP起始、随后进行高压均化而得的悬
浮体的表征
一种按实施例2配制的BDP悬浮体在涡轮乳化器中、由非灭菌的微米化活性成分起始制备。得到的产物然后转移到高压均化器的主交互作用室,并在增压下经历一轮处理。由Malvern光散射和多级液体冲击器分析法分别求取颗粒大小和喷雾性能。结果列于表6和7中,未经过高压均化的悬浮体也对比列出。表6:在一个100升涡轮乳化器中制得的BDP悬浮体的Malvern分析
结果
压力 d(0.1) d(0.5) d(0.9)
μm μm μm
500巴 0.84 3.53 8.73
800巴 0.85 2.48 5.421000巴 0.82 2.43 5.07对比剂 0.92 2.77 7.63
该分析数据表明,从操作压力为500巴开始,颗粒大小和颗粒分布范围降低。表7:在一个10升涡轮乳化器中制备的BDP悬浮体的Malvern和
M.S.L.I.分析
压力 d(0.1) d(0.5) d(0.9) 细剂量 极细剂量
μm μm μm μg μg590-610巴 0.58 1.37 2.88 - -700-720巴 0.59 1.37 2.80 - -800-820巴 0.59 1.36 2.80 160.7 112.3890-910巴 0.58 1.36 2.76 - -1000-1020巴 0.57 1.34 2.72 - -参比物 0.58 2.11 6.95 89 57
用均化器处理的悬浮体显示了颗粒大小和分布范围的显著降低。
此外,用高压均化器处理的悬浮体由其细-和极细颗粒的剂量而显示了显著改进了的喷雾性能。实施例7:由未灭菌的微米化BDP出发、并经600巴下的高压均化处
理后得到的悬浮体的稳定性
如实施例2报道,制备一种具有如下组成的BDP悬浮体,它由非灭菌的微米化活性成分起始制备。
组分 总量 每个药物单元的组成
微米化的BDP 40.0g (0,8mg)聚山梨醇酯(Tween)20 100.0g (3.0mg)脱水山梨糖醇单月桂酸酯 20.0g (0.4mg)
氯化钠 900.0g (18.0mg)灭菌水,加到 100.0升 (2.0ml)
将该悬浮体转移到高压均化器的主交互作用室中,并在600巴下经历一轮处理。该均化器还装有另一个与前一交互作用室串接的交互作用室。得到的产物配给到由β-照射预先灭菌的聚丙烯单剂量容器中,并在长期条件(25℃、60%R.H.)下储存。储存一年后,悬浮的颗粒的大小由Malvern光散射分析法求取。结果列于表8中。表8
储存时间(月) Malvern数据 BDP悬浮体
(μm)
0 d(0.1) 0.71
d(0.5) 1.96
d(0.9) 4.05
12 d(0.1) 0.78
d(0.5) 2.02
d(0.9) 4.06
在储存中颗粒大小不改变,证实了制剂的物理稳定性。此外,在手摇动后悬浮体易于再悬浮,且没有观察到附聚物生成。实施例8:由非灭菌、非微米化BDP出发、并经历高压均化而得到的
悬浮体的颗粒大小表征
一种如实施例2配制的BDP悬浮体在一个涡轮乳化器中、由非灭菌的、非微米化的活性成分出发、并经历如实施例6所述的处理而制得。如前所述求定了颗粒大小和喷雾性能。
结果列于表9中。表9
压力 d(0.1) d(0.5) d(0.9)
μm μm μm
150巴 0.81 3.16 9.93
300巴 0.72 2.67 8.50
500巴 0.70 2.09 5.49
参比物 1.40 16.84 108.05
表8中所列结果也证明,对由非微米化的产物出发制得的悬浮体进行高压均化处理,显著地降低了颗粒大小和束紧了颗粒分布范围。
Claims (13)
1.制备用作气悬体吸入剂的药物制剂的颗粒悬浮体的方法,包括以下步骤:
a)在一种能提供高能涡动的涡轮乳化器中制备一种活性成分的、优选微米化的活性成分的悬浮体;
b)使得到的悬浮体任选在一个高压均化器中经历另一个处理。
2.按权利要求1的方法,其特征在于:
a)借助一个合适的涡轮乳化器,将一种或多种活性成分分散在一种构成载体的、任选地通过加热或过滤而灭菌并任选含有润湿剂、增粘剂、防腐剂、稳定化剂、等渗剂和/或缓冲物质的水溶液中;
b)在一个高压均化器中,使得到的悬浮体进一步经历一个均化和微米化步骤;
c)将悬浮体分装于适合的容器中。
3.按权利要求1或2的方法,其中,在灭菌条件下、由一种灭菌的微米化活性成分出发进行制备。
4.按权利要求1-3的方法,其中,由非微米化、非灭菌的粉末形式的活性成分出发制得的悬浮体再进行高压均化处理。
5.按权利要求1-4的方法,其中,微米化的活性成分是一种皮质类固醇。
6.按权利要求1-5的方法,其中,微米化的活性成分已经过伽玛射线照射灭菌。
7.按权利要求1-6的方法,其中,微米化的活性成分是二丙酸倍氯米松。
8.按权利要求1-7的方法,其中,至少90%的颗粒的体积直径低于或等于5μm。
9.按权利要求1-9的方法,其中,高压均化处理在500—1000巴、优选在600-800巴下进行。
10.治疗上可接受的微米化二丙酸倍氯米松,按欧洲药典它是无菌的。
11.对微米化的二丙酸倍氯米松进行灭菌的方法,包括在2-9KGy下进行伽玛照射。
12.按权利要求10-11的BDP在制备用于处理鼻和肺的过敏-和/或发炎状态的药物中的应用。
13.按权利要求12的应用,所说药物用于处理支气管肺的发育异常。
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