CN1173702C - 含有糖皮质激素的可药用吸入粉末及消毒该粉末的方法 - Google Patents
含有糖皮质激素的可药用吸入粉末及消毒该粉末的方法 Download PDFInfo
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- CN1173702C CN1173702C CNB988131099A CN98813109A CN1173702C CN 1173702 C CN1173702 C CN 1173702C CN B988131099 A CNB988131099 A CN B988131099A CN 98813109 A CN98813109 A CN 98813109A CN 1173702 C CN1173702 C CN 1173702C
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- Prior art keywords
- glucocorticoid
- budesonide
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- spore
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Abstract
本发明提供了对粉末形式的糖皮质激素、无菌糖皮质激素、含有糖皮质激素的无菌配方进行消毒的方法,以及将它们用于治疗鼻或肺的过敏性和/或炎症疾病。
Description
发明领域
本发明涉及对粉末形式的糖皮质激素、无菌糖皮质激素、含有糖皮质激素的无菌配方进行消毒的方法,以及将它们用于治疗鼻或肺的过敏性和/或炎症疾病。
发明背景
过去人们已经提出各种方法用于消毒糖皮质激素。PT-A-69652公布用环氧乙烷和二氧化碳的混合物对研磨得极细的糖皮质激素进行低温灭菌。依PT-A-69652所述,粉末形式的甾类化合物在温度高于60℃时不稳定。糖皮质激素的具体的例子有prednacindone、地塞米松(dexamethasone)和强的松龙(prednisolone),以及它们的盐、酯和氟的衍生物,包括地塞米松醋酸盐、地塞米松磷酸盐、强的松龙特戊酸酯和9-α氟强的松龙。然而环氧乙烷有毒,当将它用于消毒糖皮质激素时,发现它的残留量超过制药规范,制药规范所要求的环氧乙烷的残留量很低。因此,人们发现这种方法不适于生产治疗可接受的糖皮质激素和含有糖皮质激素的配方。
US-A-3962430公布了生产无菌等渗的医药制剂溶液的方法,它包括将药剂在100℃时加入到饱和的氯化钠水溶液中,然后将混合物在100-130℃加热。该方法不适合用于吸入用途的细粉末状糖皮质激素的悬浮液,因为其中涉及的水、加热和冷却步骤对颗粒的大小产生了不利的影响。实际上,它可导致在细颗粒之间形成桥,从而产生大而坚硬的聚合体,这种聚合体不会在施用时分解成所需的细颗粒。
设想的可选的方法是干热灭菌。根据欧洲药典(EuropeanPharmacopoeia,1996,第283-284页),常规的加热灭菌方法是在180℃持续30分钟或最低在160℃持续2小时。根据北欧药典(Pharmacopoeia Nordica,1964,第16页),这种灭菌可以在140℃持续3小时。然而在这些方法所采用的温度下,糖皮质激素会出现明显的降解,而且表面结构易发生变化。
已知的还可采用β-或γ-射线进行灭菌。实际上,Illum和Moeller在Arch.Pharm.Chemi.Sci.,Ed.2,1974,第167-174页中建议使用这种射线来消毒糖皮质激素。然而当将这种射线用于消毒一定细碎程度的,如微粉状的糖皮质激素时,它们明显被降解了。
Andaris Ltd.的专利WO-A-96/09814涉及到一种水溶性物质(其平均颗粒大小为1至10微米)经喷雾干燥制成的颗粒。该发明的目的是生产均匀的、可再生的颗粒,用于干粉吸入器。优选的水溶性物质是天然或重组形式的人体蛋白或它的一个片段,如,人血清白蛋白(HSA)、α-1抗胰蛋白酶或醇脱氢酶。另外也生产了活性物质和载体的结合物,如,布地奈德(budesonide)和乳糖。该发明只是大概地陈述说如此生产的微颗粒可以是无菌的,但并没有指出如何能实现,也没有给出任何无菌的证据。
Astra AB的专利WO-A-96/32095涉及到将吸入用化合物溶于溶剂中,以制备适于吸入的颗粒的方法。据介绍,如此获得的含该可吸入化合物的溶液以小滴形式存在,或以喷流形式注入易与溶剂混合且处于激发态的抗溶剂中。用该方法生产的布地奈德的物质平均直径(massmedian diameter,MMD)小于10微米。在WO-A-96/32095中没有关于灭菌或无菌颗粒的信息。
Instytut Farmaceutyczny的专利WO-A-92/11280涉及这样一种方法:通过一种缩合反应,接着从乙醇中结晶出该缩合反应的粗产物,以制得(22R)布地奈德非对映异构体。将所得到的21-醋酸布地奈德(22R)进行水解,并将如此获得的产物从乙酸乙酯中结晶出来。(22S)布地奈德非对映异构体的含量为1%或更少。在WO-A-92/11280中没有关于灭菌或无菌颗粒的信息。
我们也发现对糖皮质激素的药剂配方(尤其是悬浊液,如,水悬浊液)进行终末灭菌的尝试都被证明不令人满意。这种悬浊液不能采用通常可采用的过滤除菌的方法来进行灭菌,因为大多数糖皮质激素的颗粒会滞留在滤器中。我们也证明对含该产品的玻璃瓶进行湿热灭菌,如蒸气处理,会导致颗粒大小不可接受的改变。
已知有各种细粉末状的糖皮质激素的水悬浊液,如含布地奈德的产品,即所谓的Pulmicort雾状悬浊液(Pulmicort是瑞典Astra AB的商标)。在WO-A-95/31964中也可了解氟替卡松(fluticasone)丙酸盐的类似配方。
因此,需要有一种新的方法用于糖皮质激素(及含有它们的配方)的灭菌。
奇怪的是,目前我们发现,糖皮质激素干粉的有效灭菌可以在比其它物质加热灭菌所必需的温度低得多的温度下进行。这种无菌糖皮质激素可被用于制备含有它们的无菌配方。
发明详述
本发明提供了消毒糖皮质激素的方法,这种方法包括在温度为100至130℃时加热粉末状的糖皮质激素。该法优选的温度为110至120℃,更优选的,在110℃;优选的时间最长可达约24小时,更优选的,最长可达10小时,如,从1至10小时。本方法可在大气条件下方便地进行,例如,可在空气中进行,但也可以在惰性气体环境中,如在氩气或氮气环境中,进行。
令人惊奇的是,我们发现当将这种方法用于糖皮质激素布地奈德时,杀灭的孢子数比用于对照物硬脂酸钙时多得多。当用于糖皮质激素罗氟奈德时所取得的效果更好。
我们认为(但我们并不想被这一解释所局限),糖皮质激素可以在如此出乎意料的低温下被灭菌,这一事实提示,当与加热处理一起应用时,糖皮质激素可以在杀灭孢子中提供某种协同效应。
本发明中使用的糖皮质激素,优选的是一种抗炎症的糖皮质激素,如,用于鼻或口腔吸入。本发明中可能用到的糖皮质激素的例子包括倍氟美松(betamethasone)、氟替卡松(如,以丙酸盐的形式)、布地奈德、替泼尼旦(tipredane)、地塞米松、倍氯米松(beclomethasone)(如,以二丙酸盐的形式)、强的松龙(prednisolone)、氟轻松(fluocinolone)、曲安奈德(triamcinolone)(如以乙酰胺的形式)、莫比松(momethasone)(如,以糠酸盐的形式)、罗氟奈德(如,以棕榈酸盐的形式)、二氟美松(flumethasone)、氟尼缩松(flunisolide)、西氟奈德(ciclesonide)、地夫可特(deflazacort)、可的伐唑(cortivazol)、16α,17α-亚丁基二氧-6α,9α-二氟-11β,21-二羟基-孕-1,4-二烯-3,20-二酮;6α,9α-二氟-11β-羟基-16α,17α-亚丁基二氧-17β-甲硫基-雄-4-烯-3-酮;16α,17α-亚丁基二氧-6α,9α-二氟-11β-羟基-3-氧-雄-1,4-二烯-17β-硫代羧酸S-甲酯;9α-氯-6α-氟-11β-羟基-16α-甲基-3-氧-17α-丙酸基-雄-1,4-二烯-17α-羧酸甲酯;6α,9α-二氟-11β-羟基-16α-甲基-3-氧-17α-丙酸基-雄-1,4-二烯-17β-硫代羧酸S-(2-氧-四氢呋喃-3-基)酯;可选择的是它们纯的同分异构体形式(如果存在这些形式)及/或它们的酯、缩醛或盐的形式(如果可被采用)。合适的是使用莫比松糠酸盐、倍氯米松二丙酸盐或氟替卡松丙酸盐,或者是具不对称缩醛结构,即包括:16α,17α-亚丁基二氧的糖皮质激素,如布地奈德、罗氟奈德或罗氟奈德棕榈酸盐。优选的是使用布地奈德、罗氟奈德或罗氟奈德棕榈酸盐,最优选的是布地奈德。
优选的是使用细碎状的糖皮质激素,如微粉化的粉末,优选的是其物质平均直径小于10微米的细碎颗粒的形式,更优选的是小于5微米。此外,糖皮质激素可以是一种极其细碎的形式,如,其物质平均直径小于1.0微米。细碎状的颗粒可以通过已知的传统方法,如通过研磨或通过直接沉淀,进行制备。关于微粉化的信息可以从如“TheTheory and Practice of Industrial Pharmacy”,Lachman,Libermann和Klang,2nd Ed.,1976,Lea & Febiger,Philadelphia,USA中找到。
消毒所用的温度、时间、批量大小和消毒方式是互相依赖的。因此,通常本发明的方法中采用的温度越高,消毒糖皮质激素所需的时间就越短。本方法优选的时间是持续8小时以内,如,1至8小时,当温度高于约110℃时,更优选的是4小时以内。在温度为约120℃时,本方法优选的是持续4小时以内,如,从1至4小时,更优选的是2小时以内,如,从1至2小时。
在温度为从约110℃到130℃下,批量为50克的糖皮质激素可适当加热1至4小时。如果需要的话,可采用分批量消毒,如4×50克。
本方法的采用可以使抗热孢子的数目减少log 4以上。适当地使用本发明的方法可以使抗热孢子的数目降低log 6。优选地使用本发明的方法可以使抗热孢子的数目减少log 6以上,更优选地使用本发明的方法可使抗热孢子的数目减少log 7以上。
鉴定灭菌方法效率的一种不同的方法是使用D值。D值,也称为DT值,指的是在一定温度下(以℃表示),减少(“杀灭”)90%或1log周期(即残留1/10)的标准化孢子群所需的时间(以分钟表示)。
使用本发明的方法,可使在预先选定的温度T条件下(T的范围为从100至130℃)的D值小于约240分钟。适当地使用本发明的方法,可使D值在预先选定的温度T条件下,小于大约150分钟。优选地使用本发明的方法,可使D值在预先选定的温度T条件下,小于大约90分钟。更优选地使用本法,可使D值小于30分钟。合适的温度为100、110、120或130℃。
本灭菌法理想地以这样一种方式进行:在灭菌时,一堆糖皮质激素的所有部分均可达到所要求的温度,并在所要求的时间内保持所要求的温度。
本方法可以分批的或连续的方式进行,优选的是分批的方式。
本方法中所使用的合适的糖皮质激素原料(微粉形式),是相当干燥的,即含水量低于1%(w/w)。本方法中的优选原料的含水量低于0.5%(w/w),更优选的原料的含水量低于0.3%(w/w)。
本方法中合适的糖皮质激素原料的每克生物负载(bioburden)少于50菌落形成单位(colony forming units,CFU)。本方法中优选的糖皮质激素原料的生物负载少于10CFU/克,更优选的是少于1CFU/克。
根据本发明,进一步提供了一种无菌糖皮质激素(如,布地奈德),具合适的干燥度,且优选的是微粉形式,如,其物质平均直径小于10微米,更优选的是小于5微米。
我们所用的术语“无菌的”一词指的是一项产品符合美国药典23/NF18,1995,第1686-1690页及第1963-1975页中的无菌标准,并提供了治疗上可接受的糖皮质激素及含有它们的配方。对最终产品无菌度的进一步规定包括欧洲药典(Ph,Eur.1998,Chapter 2.6.1及5.1.1)、英国药典(BP 1993,Appendix XVI A,p.A 180及AppendixXVIII A,p.A 184)和日本药典(JP,13th ed.,第69-71及181-182页)。治疗上可接受的优选的糖皮质激素及含有它们的配方业已采用一种方法生产出来,该法能确保达到美国药典23/NF18,1995,第1686-1690及1963-1975页中所述的无菌度。
本发明中的糖皮质激素的药效及理化性质/它的化学纯度和物理形式与制备它的原料将基本保持一致,即由本灭菌方法引起的降解,特别是化学降解,将是有限的。
本发明中的糖皮质激素优选的重量纯度至少为98.5%,更优选的重量纯度至少为99%,最优选的重量纯度至少为99.2%。
本发明进一步提供了一种无菌糖皮质激素,优选的是一种抗炎症的糖皮质激素,更优选的是布地奈德、罗氟奈德或罗氟奈德棕榈酸盐,最优选的是布地奈德,用于治疗鼻或肺的过敏性和/或炎症疾病,如,慢性阻塞性肺部疾病(COPD)、鼻炎或哮喘。本发明也提供了这种无菌糖皮质激素在制造治疗这类疾病的药剂(尤其是无菌药剂)中的应用,优选的是抗炎症的糖皮质激素,更优选的是布地奈德。
本发明进一步提供了含有一种糖皮质激素水悬液的无菌药剂配方,其中优选的糖皮质激素是无菌微粉状的糖皮质激素,如布地奈德。
本发明还提供了一种含有一种糖皮质激素及一种或多种治疗上可接受的添加剂、稀释剂或载体的无菌药剂配方。这些添加剂的例子包括表面活性剂、pH调节剂、螯合剂、使悬浮液等渗的试剂和增稠剂。
为使糖皮质激素颗粒能够有效地分散到悬浮液中,可有选择性地使用表面活性剂,例如,可以与卵磷脂相结合。本发明配方中的表面活性剂也起到稳定剂的功能。合适的表面活性剂的例子包括烷芳基聚醚醇型的非离子表面活性剂,尤其是TyloxapolTM-一种4-(1,1,3,3-四甲基丁基)酚与环氧乙烷和甲醛的聚合体。此外适合的表面活性剂包括山梨聚糖的衍生物,如聚氧乙烯山梨聚糖脂肪酸酯,优选的是聚山梨醇和TweenTM族,更优选的是聚山梨醇80或聚氧乙烯20山梨聚糖单油酸(TweenTM 80)。适合的表面活性剂还包括聚氧乙烯醚,尤其是聚氧乙烯烷基醚,优选的是五乙烯乙二醇单n-十二醚或C12E5。此外适合的表面活性剂包括聚羟亚烃(Poloxamers)、聚氧乙烯蓖麻油衍生物、聚乙烯醇和聚氧化乙烯的嵌段共聚物、聚氧化丙烯氧、聚氧化丁烯和聚乙烯乙二醇(PEGs),或者是这些表面活性剂任意的混合物。此外适合的表面活性剂包括聚乙烯乙二醇衍生物,尤其是聚乙烯乙二醇660羟基硬脂酸盐或SolutolTM HS 15、聚维酮、聚乙烯吡咯烷酮(PVP)和聚乙烯乙二醇(PEGs)。
表面活性剂在配方中的浓度为约0.002至2%w/w。我们推荐聚氧乙烯山梨聚糖脂肪酸酯的浓度为约0.005至0.5%w/w,聚羟亚烃的浓度为约0.01至2%w/w,聚氧乙烯烷基酯或聚氧乙烯蓖麻油衍生物在配方中的浓度为约0.01至1.0%w/w。
混悬液的pH值可根据需要进行调整。合适的pH调节剂的例子有弱的有机酸(如柠檬酸)、强的无机酸(如氢氯酸)和强碱试剂(如NaOH)。换句话说,混悬液系统pH值的调节可以通过对缓冲液的酸和盐形式(如柠檬酸、柠檬酸钠、醋酸、醋酸钠和磷酸钠)的用量进行平衡来实现。对于用来吸入的配方,我们优选其pH值范围为从约3.5至约6.0,更优选的从4.0至5.0,最优选的从4.2至4.8。
我们也推荐配方中含有一种合适的螯合剂,如乙二胺四乙酸(EDTA)二钠。螯合剂在配方中的浓度可为约0.005至0.1%w/w。
可以加入使悬浊液等渗的试剂,例如右旋糖、甘油、D-甘露醇、氯化钠、氯化钾和溴化钠。
为得到凝聚或生成沉淀的趋势最小的稳定的悬浊液,配方中须含有一种增稠剂。增稠剂的例子包括纤维素衍生物、合适的纤维素醚或微晶纤维素。优选的纤维素醚包括乙基纤维素、乙基甲基纤维素、羟基乙基纤维素、羟基乙基甲基纤维素、羟基乙基乙基纤维素、甲基纤维素、羟基甲基纤维素、羟基丙基纤维素、羟基丙基甲基纤维素和羧甲基纤维素(CMC),例如,它们的钠盐。合适的增稠剂还包括环糊精和糊精。合适的增稠剂进一步包括黄原酸胶(xanthan gum)、胍尔豆胶(guar gum)和卡波姆(carbomer)。本发明配方中优选的增稠剂有聚维酮(povidone)、聚乙烯吡咯烷酮(polyvinylpyrrolidone,PVP)和聚乙烯乙二醇(PEG)。
增稠剂在配方中的浓度为约0.1至3.0%w/w。配方中微晶纤维素和钠羧甲基纤维素(CMC)优选的浓度约0.5至2.5%,黄原酸胶约0.3至3%,卡波姆约0.1至2%,胍尔豆胶约0.3至2%以及羟基丙基甲基纤维素约0.5至3.0%w/w。
悬浊液中的活性组分,如布地奈德,是以小颗粒的形式存在的,至少90%的小颗粒的物质平均直径小于20微米,合适的至少80%小于10微米,优选的至少70%小于7微米,最优选的至少60%小于4微米。
我们推荐糖皮质激素在悬浊液中的含量为约0.05至20mg/ml。更优选的糖皮质激素在悬浊液中的含量为0.08至10mg/ml,最优选的,糖皮质激素的含量为0.1至5mg/ml。
依据本方法灭菌的含有糖皮质激素(如微粉化的布地奈德、罗氟奈德或罗氟奈德棕榈酸盐)的无菌药剂配方,可以通过混合无菌糖皮质激素和任何合适的添加剂如表面活性剂、pH调节剂或螯合剂、使混悬液等渗的试剂或增稠剂来制得。所有组分,除了糖皮质激素,均可通过将其水悬浊液过滤除菌制得。如此获得的无菌悬浊液可以保存在超压力的无菌惰性气体(如氮气或氩气)环境中。而且须在无菌条件下,例如使用吹气/填充/密封系统,将其装入事先已灭菌的容器中,以最终制得一种无菌药剂产品。
本发明还提供了一种用于治疗鼻或肺的炎症疾病的方法,包括给患有此类疾病的哺乳动物(尤其是人类)施用有效剂量的一种无菌糖皮质激素或一种含有无菌糖皮质激素的无菌配方,优选的是含有依照本发明所制造的无菌糖皮质激素的无菌配方。具体地说,本发明提供了一种用于治疗慢性阻塞性肺部疾病(COPD)、鼻炎、哮喘或其它过敏性及/或炎症疾病的方法,包括给患有此类疾病的哺乳动物(尤其是人类)施用有效剂量的一种无菌糖皮质激素或一种含有无菌糖皮质激素的无菌配方,优选的是含有依照本发明所制造的无菌糖皮质激素的无菌配方。
实施例
参照以下实施例对本发明进行说明,这些实施例并不是用来限制本发明。
实施例1
进行一些实验以确定加热处理对微粉化布地奈德样品的化学纯度及物理形式的影响。
表1显示用干消毒器,Lytzen model CB 1200,加热处理9份批量为50克微粉化的布地奈德(在下面的表1中的样品编号为2-10)。样品1没有接受这种处理并被用作对照样品。在处理之后,对样品的化学及物理性质进行分析。
表1
编号 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
温度/℃ | - | 100 | 100 | 100 | 110 | 110 | 110 | 120 | 120 | 120 |
时间/小时 | 0 | 4 | 6 | 10 | 2 | 4 | 10 | 1 | 2 | 4 |
大小/微米 | 2.0 | 2.2 | 2.2 | 2.2 | 2.2 | 2.2 | 2.3 | 2.2 | 2.2 | 2.3 |
大小范围(10-90%)/微米 | 2.6 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 |
差位异构体A/%重量比 | 48.8 | 48.8 | 48.7 | 48.7 | 48.7 | 48.8 | 48.7 | 48.7 | 48.7 | 48.7 |
布地奈德含量/%重量比 | 99.4 | 99.3 | 99.3 | 99.2 | 99.2 | 99.3 | 98.9 | 99.2 | 99.2 | 99.0 |
已知的异质类固醇总量 | 0.13 | 0.14 | 0.16 | 0.15 | 0.16 | 0.15 | 0.18 | 0.14 | 0.15 | 0.17 |
未知的异质类固醇总量 | 0.04 | 0.04 | 0.05 | 0.05 | 0.04 | 0.08 | 0.18 | 0.04 | 0.07 | 0.16 |
加热处理之后,布地奈德的Brunauer、Emett和Teller(BET)表面值(通过Micrometrics Gemini 2375装置测得;也可见BritishStandard 4359(1969)第1部分)或每种样品相对于样品1的X-射线衍射图样均没有改变。每种样品的颗粒大小用物质平均直径(MMD)来衡量(使用一种Coulter计数器)。
实施例2
将布地奈德与硬脂酸钙的灭菌效果进行比较。
给布地奈德样品0.5克和硬脂酸钙样品0.5克分别接种含1.5×107孢子数的0.1毫升Steris枯草芽孢杆菌(globigii)(Lot#LG 126B)的孢子悬浊液。采用与实施例1相同的技术,将每种样品在一Baxter恒温烘箱(Constant Tempearture Oven)中110℃加热3小时10分。测量样品中的孢子数,所得结果示于以下的表2中。
表2
化合物 | (加热)之前 | (加热)之后 |
硬脂酸钙 | 1.5×107孢子 | 3.3×106孢子 |
布地奈德 | 1.5×107孢子 | <10孢子 |
加热处理使得经过接种的布地奈德样品中的孢子数的对数减少达6.2以上,而经过接种的硬脂酸钙样品中孢子数的对数减少小于0.7。
实施例3
采用一些试验以评估各种天然微生物的耐热性能。
在120毫升末端开口的聚丙烯容器中,每0.5克布地奈德粉末样品各接种约102-103可繁殖的ATCC微生物。每一样品均在110℃下加热3小时10分。在加热处理前后分别测定样品中微生物的数目,所得结果如表3所示。
表3
微生物 | 加热之前 | 加热之后 |
大肠埃希氏菌 | 450 | 0 |
枯草芽孢杆菌ATCC 6633 | 300 | 0 |
伤寒沙门氏菌 | 270 | 0 |
C.albicans | 780 | 0 |
A.niger | 260 | 0 |
M.luteus | 300 | 0 |
S.epidermidis | 240 | 0 |
C.sporogenes | 160 | 0 |
Ps.Aeruginosa | 350 | 0 |
枯草芽孢杆菌ATCC 6633 | 1.2×105 | 11 |
1).经在10°稀释的玻片上进行革兰氏染色鉴定,发现一种特异的菌种。
从表3显而易见,在110℃下对糖皮质激素进行3小时10分的加热处理是一种对各种各样的微生物进行灭菌的有效方法。
实施例4
用实施例2中的方法进行灭菌并符合美国药典23/NF18,1995无菌标准的含有微粉状布地奈德的配方可以通过混合以下组分来制得:
表4
微粉化布地奈德 0.125mg
乙二胺四乙酸二钠 0.1mg
氯化钠 8.5mg
聚山梨醇酯80 0.2mg
无水柠檬酸 0.28mg
柠檬酸钠 0.5mg
纯净水 加至1ml
所有组分,除布地奈德外,通过将它们的水溶液作无菌过滤制得,并在无菌条件下,将最终得到的悬浊液以合适的体积(约2毫升),装入预先灭菌的5毫升容器中,以制得一种无菌产品。
最终制得的悬浊液可以保存在过压的无菌氮气环境中,并可以使用充气/灌注/密封系统装入容器中。
实施例5
可通过混合以下组分制备含有由实施例2的方法灭菌的微粉末状布地奈德无菌制剂。
表5
布地奈德微粉 2-3mg
乙二胺四乙酸二钠 0.1mg
氯化钠 8.5mg
稳定剂 0.02-2mg
无水柠檬酸 0.28mg
柠檬酸钠 0.5mg
纯净水 加至1ml
所有组分,除布地奈德外,通过将它们的水溶液作无菌过滤制得,在无菌条件下,将最终得到的悬浊液以合适体积(约2毫升),装入预先灭菌的5毫升容器中以制得一种无菌产品。
最终制得的悬浊液可以保存在过压的无菌氮气环境中,并可以使用充气/灌注/密封系统装入容器中。
实施例6
将大约2毫升枯草杆菌(Bacillus subtilis)的孢子悬浊液接种到5克布地奈德微粉中。
混合布地奈德和孢子悬浊液,并在55℃下持续干燥约3小时。经接种并干燥后的布地萘德与20-40克未经接种的布地奈德微粉混合。
在一台Heraeus ST 5060加热装置中,将该样品每5克一份分别在100℃、110℃或120℃进行加热处理。在不同的加热时间后从各个加热温度中分别取出1克样品。每份这种样品均转移到10毫升pH7.2的稀释介质中。合适的稀释液的组成是0.1%的蛋白胨水溶液。根据美国药典23/NF18,1995,第1681-1686页,特别是第1684页中所述的平板浇灌技术来计数每克样品的孢子数。
在加热处理之前计数在80℃下加热10分钟(用以杀灭营养细胞)的样品中的孢子数。
结果如表6所示,其中DT值是在特定温度下(以℃表示),使孢子数目在加热处理之后减少log 1所需的时间(以分钟表示)。
表6
在100℃下加热
80℃ | 在100℃下加热的时间 | |||
10分钟 | 15分钟 | 45分钟 | 75分钟 | |
孢子数/克 | 6.5×106 | 4.8×103 | 7.1×102 | 1.7×102 |
log孢子/g | 6.81 | 3.68 | 2.85 | 2.23 |
D100=41.5分钟;相关系数=-0.0996
这意味着在100℃下,为使孢子数减少log 6,须加热6×41.5分钟。
在110℃下加热
80℃ | 在110℃下加热的时间 | |||
10分钟 | 5分钟 | 15分钟 | 20分钟 | |
孢子数/克 | 2×106 | 2.08×104 | 9.25×102 | 3.55×102 |
log孢子数/克 | 6.20 | 4.32 | 2.97 | 2.55 |
D110=8.3分钟;相关系数=-0.995
这意味着在110℃下,为使孢子数降低log 6,须加热6×8.3分钟。
表6(续)
在120℃下加热
80℃ | 在120℃下加热的时间 | |||
10分钟 | 4分钟 | 6分钟 | 8分钟 | |
孢子数/克 | 1.5×106 | 1.9×102 | 5.5×101 | 2×101 |
log孢子数/克 | 6.19 | 2.28 | 1.74 | 1.30 |
D120=4.1分钟;相关系数=-0.998
这意味着在120℃下,为使孢子数降低log 6,须加热6×4.1分钟。
实施例7
用与实施例6中所用的不同的一种孢子悬浊液,接种1克微粉状的布地奈德、泼尼松龙和倍氯米松二丙酸盐及0.5克的罗氟奈德。
在110℃下加热处理这些样品。加热不同时间后取出样品。根据美国药典23/NF18,1995,第1681-1686页,特别是第1684页中所述的平板浇灌技术来计数孢子的数目。
根据加热处理前后的孢子数目,可以计算孢子数目的对数减少及十进法减少时间(即在特定温度下使微生物数目减少一个对数所需的时间)。
结果如表7所示。
表7
在110℃下加热
糖皮质激素 | D110值(分钟) |
布地奈德 | 41 |
罗氟奈德 | 9.8 |
倍氯米松二丙酸盐 | 72.7 |
泼尼松龙 | 73.8 |
表7清楚地显示本方法对减少含有糖皮质激素的样品中的孢子数目十分有效。本方法对布地奈德和罗氟奈德尤其有效。事实上,对1.0克罗氟奈德样品全部进行分析,显示在一个很短的周期时间内(≥5分钟,110℃下)即把孢子全部杀灭,在这种情况下,D110值就无法计算。
对照实施例8
照射
对在塑料容器中储存的约3克粉末状布地奈德物质进行照射。将该物质暴露于2.5至25kGy的β-射线和8至32kGy的γ-射线中。暴露之后,采用液相层析测定布地奈德的含量及相关物质的量。布地奈德的化学稳定性被认为是研究中最关键的参数。
表8
照射灭菌过程中微粉状布地奈德物质的稳定性
暴露强度(kGy) | 参照品i) | β2.5 | β5 | β10 | β17 | β25 | γ7.8 | γ31.9 |
布地奈德含量(%) | 99.5-99.8 | 99.1 | 98.9 | 98.9 | 98.8 | 98.8 | 97.9 | 95.0 |
相关物质已知的异质类固醇总量已知的异质类固醇总量 | 0.13-0.150.03-0.04 | 0.190.19 | 0.190.24 | 0.180.26 | 0.200.36 | 0.210.43 | 0.340.68 | 0.511.8 |
i)在不同的天数进行分析,而且每次都对参照品进行分析。
从表8的结果可以看出在暴露于β-及γ-射线的样品中,布地奈德含量减少。发现了几种新的降解产物,特别是在经γ-照射的样品中。另外,经β-及γ-照射的样品的质量平衡都很差。当暴露于β-或γ-射线中时,布地奈德含量减少0.5-4.6个百分点。
可以得出结论,由于发生了显著的化学降解,用β-或γ-射线对粉末状的布地奈德进行灭菌是不令人满意的。
Claims (15)
1.消毒粉末的方法,所述粉末包含糖皮质激素或其酯,缩醛或盐,经从100至130℃之间的温度灭菌加热处理1-8小时,且其中所述糖皮质激素,或其酯,缩醛或盐包含一种不对称缩醛结构,其中的不对称缩醛结构包含16α,17α-亚丁基二氧,其中糖皮质激素粉末的物质平均直径小于10微米。
2.权利要求1的方法,其中糖皮质激素是一种抗炎症的糖皮质激素。
3.权利要求1的方法,其中糖皮质激素,或其酯,缩醛或盐选自:布地奈德、罗氟奈德以及罗氟奈德棕榈酸盐。
4.根据权利要求1的方法,其中糖皮质激素的加热温度是从110至120℃。
5.根据权利要求1的方法,其中糖皮质激素在120℃的温度下加热不超过4小时。
6.根据权利要求1的方法,其中糖皮质激素在120℃的温度下加热不超过2小时。
7.根据权利要求1的方法,其中在加热处理之前,糖皮质激素的含水量低于1%w/w。
8.根据权利要求1的方法,其特征在于该方法在惰性气体中进行。
9.根据权利要求1的方法,其特征在于,借助于加热处理,粉末中耐热孢子数目的减少量大于1og6。
10.根据权利要求1的方法,其特征在于,粉末中的孢子数减少90%所需的时间,在100至130℃时小于240分钟。
11.根据权利要求1的方法,其特征在于,糖皮质激素在110至130℃时加热小于4小时。
12.根据权利要求1的方法,其中在加热处理之前,糖皮质激素的含水量低于0.5%w/w。
13.根据权利要求1的方法,其中糖皮质激素粉末的物质平均直径小于5微米。
14.根据权利要求1的方法,其特征在于,借助于加热处理,粉末中耐热孢子数目的减少量大于log7。
15.根据权利要求1的方法,其特征在于,粉末中的孢子数减少90%所需的时间,在100至130℃时小于90分钟。
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Cited By (2)
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CN107510687A (zh) * | 2017-08-18 | 2017-12-26 | 南京海纳医药科技股份有限公司 | 一种供雾化用含有福莫特罗和布地奈德的吸入混悬液及其制备方法 |
CN107510687B (zh) * | 2017-08-18 | 2020-07-03 | 南京海纳医药科技股份有限公司 | 一种供雾化用含有福莫特罗和布地奈德的吸入混悬液及其制备方法 |
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