CN1234346C - 用于气溶胶化的妥布霉素的最佳制剂 - Google Patents
用于气溶胶化的妥布霉素的最佳制剂 Download PDFInfo
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Abstract
本发明提供了一种以无添加剂的等渗溶液的形式经气溶胶化释放的妥布霉素制剂,该溶液的pH已最佳化以确保在室温下的合适货架期。所述制剂可以有益地用于治疗和预防急性和慢性支气管内感染,特别是因绿脓假单胞菌引起且伴随诸如囊性纤维化的肺病。
Description
发明领域
本发明涉及通过气溶胶化释放的妥布霉素制剂。
本发明提供了一种以无添加剂的等渗溶液的形式经气溶胶化释放的妥布霉素制剂,该溶液的pH已最佳化以确保在室温下的合适货架期。
所述制剂可以有益地用于治疗和预防急性和慢性支气管内感染,特别是因绿脓假单胞菌引起且伴随如囊性纤维化的肺病。
发明背景
尽管加压计量吸入器(MDI)和干粉吸入器(DPI)是最常用的吸入药物释放系统,但是雾化器已越来越普遍地用于治疗呼吸道梗塞,特别是患哮喘的婴幼儿和患严重哮喘或慢性呼吸道梗塞的患者。雾化器使用超声或加压气体将液体,经常是水溶液或悬液的药物产生可吸入大小范围(1-5μm)的气溶胶小滴。它们与MDI和DPI相比的益处在于药物可以在正常呼吸期间经口罩或面罩吸入。因此,可以使用它们向难以使用其它设备进行的患者,如小孩释放气溶胶化的药物。
几种治疗有用的药物可以通过雾化器释放,它们包括β2-激动剂、皮质类固醇、抗胆碱能药、抗变态反应药、粘液溶解药和抗生素。已尝试用气溶胶化抗生素治疗的主要临床情况是治疗患囊性纤维化(CF)的患者。
CF是一种普通遗传疾病,特征在于炎症和进行性肺组织破坏。CF患者内肺衰弱与特别是因绿脓假单胞菌引起的支气管内感染导致产生的脓性痰累积有关。前者是CF患者发病和死亡的主要原因。
妥布霉素是一种特异性地抗绿脓假单胞菌活性的氨基葡糖苷抗生素。它较差地渗透到支气管内分泌物(痰)内,需要大静脉内剂量以在感染位置获得有效浓度。这些高剂量使得患者处于肾中毒和耳中毒影响的危险。通过气溶胶给药直接向下呼吸道释放妥布霉素受到欢迎,这是由于它在感染位置产生高浓度的抗生素。鉴于有限地吸收进入循环,气溶胶释放妥布霉素应伴随最小的全身性毒性。这样将能够开发出一种更安全、长期的治疗。
在这一点上,由于其治疗剂量相当大,因此由于不能将妥布霉素配制成MDI或DPI,使得雾化极其方便。
文献中报道的临床研究显示与患CF的患者从气溶胶化妥布霉素获益相反的结果。这些研究中的变异性可能部分由于患者群、治疗特征、雾化器、制剂及其给药方式之间的差异。而且,已通过临时使用可商购获得的注射液进行了大多数研究。这些制品通常含有抗氧化剂和防腐剂,已知它们可以引起反常反应如支气管痉挛和咳嗽(Nikolaizik等人Eur J Pediatr 1996,155,608-611;The Lancet,1988年7月23日,202)。
由于所有这些原因,需要标准化步骤以及将给药到CF患者的诸如妥布霉素的抗生素气溶胶加以改进。
因此,考虑了概括的所有问题之后,非常有益地提供了一种妥布霉素制剂,可以经气溶胶化的治疗有用浓度释放到支气管内空间,它:i)能够使用喷射和超声雾化器在相当短的时间内有效地雾化;ii)能够产生为患者充分耐受的气溶胶;iii)能够产生可以有效地到达治疗目标区域的气溶胶颗粒;iv)摆脱了可以产生不希望的副作用的物质(防腐剂和其它物质);v)能够保证尽可能长的货架期,特别是在室温下的货架期。
因此,为了获得妥布霉素气溶胶给药用的最佳制剂,需要小心调整以下参数:
·剂量/体积比。气溶胶释放用的制剂应含有以最小可能体积的溶液配制的最小但有效量的妥布霉素。事实上,体积最小,雾化时间最短。短的雾化时间依次是患者依从性的重要决定因素并且在医院使工作人员所花时间较少。配备时间的含义(McCallion等人Int J Pharm1996,130,1-11)。
·摩尔渗透压浓度。众所周知,吸入治疗的副反应可以因药物溶液的摩尔渗透压浓度过低或过高引起。相反,等渗溶液除去了反常支气管收缩和咳嗽的危险(The Lancet,1988,op.cit.;Mann等人Br MedJ 1984,289,469)。摩尔渗透压浓度还影响雾化器在输出速率和粒径分布(vide ultra)方面的性能。
·雾化之后的粒径分布。临床气溶胶的功效取决于其渗透到呼吸道的能力。为了渗透到周围区域,要求气溶胶大小为0.8-5μm,为了肺泡沉积,大小优选为约3μm。呼出的主要是小于0.5μm的颗粒。除了治疗目的之外,在药物副作用方面,气溶胶颗粒的大小也是重要的。沉积在上呼吸道中的较大小滴事实上通过粘膜纤毛的清除过程从气管-支气管快速除去,同时药物具有可被全身性吸收的影响和潜在的副作用。几个专家(Newman等人Thorax 1988,43,318-322;Smaldone等人J Aerosol med,1988,1,113-126;Thomas等人Eur Respir J 1991,4,616-622)建议由于渗透到周围呼吸道特别理想,因此必需特别注意抗生素治疗CF时的气溶胶化药物的小滴大小。
·制剂的pH。可以接受的制剂的一个重要要求是其适合销售、分配、贮藏和使用的合适的货架期。通常,妥布霉素静脉内溶液含有苯酚或其它防腐剂以及抗氧化剂以保持效能并使可导致溶液变色的降解产物的形成最小化。然而,正如已指出的,所述物质可能在患有诸如CF的肺病的患者内诱导不希望的反应。妥布霉素的稳定性严格地取决于pH。因此,其制剂的pH需要仔细调整,以便在没有防腐剂和/或抗氧化剂的情况下使降解产物形成慢或者防止其形成;以诸如尽可能防止变色的方式调整pH也是有益的,尽管颜色的深度不是氧化程度的可靠的指示剂。特别优选在环境贮藏条件(室温,并且在这种情况下避光)下提供合适货架期的制剂,这是由于现有技术的制剂室温下的稳定性相当不令人满意。使用期间,按照EP 734249制备并且以商品名Tobi销售的制剂在室温下的确仅能保持28天。
发明目的
本发明的目的是提供一种制剂,它能够通过适合充分耐受的雾化给药并将妥布霉素有效地释放到支气管内空间,用于治疗绿脓假单胞菌和/或伴随诸如CF的肺病的其它易感菌感染。
具体地说,本发明的目的是提供一种制剂,为通过雾化给药的水溶液形式,其中为了保证患者较好地依从性、最大耐受和功效以及室温下尽可能长的货架期,已将妥布霉素浓度、张力和pH最佳化。
根据本发明,提供了一种制剂,在pH为4.0-5.5且摩尔渗透压浓度为250-450mOsm/l(约等于mOsm/kg)的氯化钠水溶液中妥布霉素占7.5%w/v。
在本发明的一个优选实施方式中,制剂含有在4ml半盐水溶液(0.45%氯化钠)中的300mg妥布霉素硫酸盐,以便其摩尔渗透压浓度在280-350mOsm/l并且pH为5.2。
在现有技术中,已提出了几种吸入用的妥布霉素制剂用于治疗患CF和绿脓假单胞菌感染的患者。
大多数可商购获得的妥布霉素注射液当临时用于吸入时可引起显著的支气管梗塞,这是由于它们不是不含防腐剂的,而是含有抗氧化剂如EDTA钠和/或偏重亚硫酸钠以及诸如苯酚的防腐剂。
Wall等人(The Lancet,1983年6月11日,1325)报道了通过手持雾化器每天2次吸入80mg妥布霉素和1g替卡西林之后的临床研究结果。在其自身允许下,该方案的一个缺陷是吸入所需的时间(约30分钟)。
Ramsey等人(New Eng J Med 1993,328,1740-1746)进行了广泛研究以评价气溶胶化妥布霉素的安全性和功效。为了达到目标浓度(≥400μg/g痰),它们使用600mg无防腐剂的妥布霉素硫酸盐(溶解在30ml半强度生理盐水中,pH调整至6.85-7.05)。所用的超声雾化器(DeVilbiss)需要较大体积。除了吸入需要的时间长之外,pH也不是最佳。从稳定性的角度,已知在接近中性的pH下,妥布霉素尽管相对水解非常稳定,但是快速氧化(Brandl等人Drug Dev Ind Pharm 1992,18,1423-1436)。Common Compendia(Martindale,Physician DeskReference)建议事实上保持妥布霉素溶液在3.0-6.5的pH下。
EP 734249要求保护一种制剂,它含有200mg-400mg溶解在约5ml含有0.225%氯化钠(1/4标准盐水-NS-)的溶液中,且pH为5.5-6.5的氨基葡糖苷。根据本发明人,该制剂含有以最小可能体积的生理可接受的溶液配制的最小但有效量氨基葡糖苷,它具有一盐度:经过调整能够产生为患者充分接受的氨基葡糖苷,但是防止了出现继发性不希望的作用如支气管痉挛和咳嗽(第4页第51-55行)。含1/4NS和60mg妥布霉素/ml 1/4NS(等于6%w/v)的优选妥布霉素制剂的pH为约6.0,并且摩尔渗透压浓度在165-190mOsm/l的范围内。根据本发明人,该摩尔渗透压浓度范围在给药于囊性纤维化患者的气溶胶的安全范围内,并且四分之一标准盐水,即含有0.225%氯化钠和60mg/ml妥布霉素的盐水的另一优点是,与以0.9%正常盐水溶液配制的妥布霉素相比,该制品更有效地通过超声雾化器雾化(第5页第50-54行)。本发明人陈述,更浓的溶液(与60mg/ml相比)将增加该溶液的摩尔渗透压浓度,从而使用喷射和超声雾化器都将降低制剂的输出。另外,较小体积的更浓溶液由于雾化器的典型静区体积(1ml):这意味着由于雾化器不完全工作,因此最后1ml溶液被浪费,因此也是不利的(第6页第35-38行)。从贮藏和更长货架期的角度,发现要求保护的pH范围最佳(第7页第2-3行),但是事实上,能够获得5℃下完全稳定的溶液和室温下持续6个月的有效稳定的溶液;而且要求保护的制剂在袋中贮藏(这样避光)获得的颜色保持在可接受的范围内,但是没有数据提到在袋之外的行为。
要求pH在5.5-6.5之间,这是由于根据本发明人的观点,pH小于4.5的任何气溶胶经常在易感个体内诱导支气管痉挛,并且pH在4.5-5.5之间的气溶胶偶尔引起该问题(第5页第58行-第6页第1行)。Le Brun等人Int J Pharm 1999,189,205-214公开了一种吸入用的10%w/v妥布霉素溶液,pH为7.5。同样的专家(Int J Pharm 1999,189,215-225),在旨在开发高浓度溶液的另一研究中,研究了范围在5-30%w/v的几种妥布霉素溶液的气溶胶化性能。在该文章中公开的所有溶液具有接近中性的pH并呈现远离等渗值(282mOsm/l)的摩尔渗透压浓度。
在前述文献中没有一个公开了本发明的制剂的特征,并且没有一个教导公开过本发明解决该问题的整个方案,从而提供一种以较小体积经气溶胶释放并且张力接近生理值的浓溶液。
使用相对于现有技术中报道为最佳化的更浓溶液(7.5%相对6.0%w/v)能够使用体积较小的小瓶,这样依次能够减少雾化的时间。尽管一些雾化器确实具有1ml的静区体积,其它雾化器具有较小的(0.5ml或更小),所以使用4ml的小瓶的浪费仅为约10%或更少。
根据本发明,制剂的摩尔渗透压浓度在认为是等渗的溶液的范围内,而EP 734249和Ramsey等人的制剂都具有一摩尔渗透压浓度,即165-190mOsm/l,认为是低渗的典型溶液(Derbracher等人Atemwegs und Lung 1994,20,381-382)。尽管现有技术的制剂最终是安全的,但是仅等渗溶液可以完全防止反常支气管收缩的危险。而且,在该实施例2中报道的结果显示,与EP 734249中所述的相反,摩尔渗透压浓度在要求保护的范围内的制剂尽管其浓度高,但是仍然被有效地雾化。
就贮藏和室温的货架期而言,发现pH在4.0-5.5之间,优选5.2是最佳的。长期稳定性研究显示,本发明制剂中的妥布霉素稳定高达9个月。而且,就所有该期间而言,其颜色没有显著的变化,并且即使不在铝箔袋内贮藏,也保持在可接受的范围内。
根据本发明的另一实施方式,还提供了这种制剂的制备方法,所述方法包括步骤:
i)制备含有0.45%w/v氯化钠的水溶液;
ii)用浓强酸调整其pH;
iii)加入活性组份并混合至完全溶解;
iv)再次调整pH至所需值;
v)将该溶液填充至适当容器中,优选通过过滤预杀菌。
本发明的气溶胶制剂指的是一种7.5%w/v氨基葡糖苷家族的抗生素,优选妥布霉素及其盐的水溶液,用于治疗因革兰氏阳性和阴性菌引起的肺感染、肺病如囊性纤维化、用绿脓假单胞菌感染的非-CF支气管扩张和其它慢性肺病,特别是在恶化阶段,诸如支气管扩张、COPD和支气管性哮喘。
该制剂的摩尔渗透压浓度应在250-450mOsm/l,优选260-400,甚至更优选280-350mOsm/l的范围内;它可以使用任何生理可接受的盐或非挥发性化合物调整;优选妥布霉素溶解在0.45%w/v氯化钠水溶液中。
使用任何浓强酸,优选硫酸可以调整pH,并且应在4.0-5.5,优选5.0-5.4的范围内。
本发明的制剂可以分布于合适容器如2或4ml的多剂量小瓶或预杀菌的单位剂量小瓶中,这取决于治疗指征;另外,小瓶可以使用“吹、填充和密封”工艺无菌地填充。该填充优选在惰性环境下进行。这些溶液制剂可以有益地通过过滤杀菌。
通过以下实施例描述本发明。
实施例1
在pH5.2下制备7.5%w/v妥布霉素溶液和稳定性研究
组成指的是1单位剂量小瓶(2ml)
组成 | 量 |
妥布霉素氯化钠硫酸2N氢氧化钠1M*纯净水 | 150mg9mg适量至pH5.2±0.2适量至pH5.2±0.2适量至2ml |
*仅仅在需要时加入
将氯化钠溶解在401纯净水中(混合15分钟,保证NaCl完全溶解)。然后,将301硫酸(2N H2SO4)加入到该盐水溶液中;在该操作期间,监控溶液温度。当溶液温度为约25-30℃时,吹入N2获得溶解的O2小于1mg/l的值。之后,加入妥布霉素并混合至完全溶解(不少于15分钟),同时将温度保持在25-30℃以下。检查pH值,并且如果需要的话加入2N硫酸或1M氢氧化钠溶液以获得5.2±0.2的pH值。当溶液温度在25℃±2℃时,加入纯净水达到最终体积。将最终溶液混合15分钟。再次检查pH值,并且如果需要的话,加入2N硫酸或1M氢氧化钠溶液以获得5.2±0.2的pH。将该溶液通过一0.45μm尼龙过滤器过滤,并经两个0.2μm尼龙过滤器过滤。
在氮气净化下将该溶液分配于2ml聚乙烯无色单位剂量小瓶中。
在长期(25℃,60%R.H.)和加速条件(40℃,75%R.H.)[R.H.=相对湿度]下评价小瓶的稳定性。结果分别报道于表1和2。通过HPLC进行妥布霉素及其主要相关物质(降解产物)的分析。还测定残余氧、pH和摩尔渗透压浓度。使用凝固点降低渗透压力计测定摩尔渗透压浓度。
本发明的制剂在室温下最终稳定至少9个月,并且在加速条件下稳定6个月。在这两种条件下pH和摩尔渗透压浓度基本保持不变。在室温下,本发明制剂的颜色变化不显著,并且即使不在铝箔袋中贮藏也保持在可接受的范围内。
表1-在长期条件(25℃,60%R.H.)下的稳定性
分析 | 技术控制 | 化学控制 | ||||
溶液外观 | 氧mg/l | 摩尔渗透压浓度mOsm/l | 妥布霉素mg/ml(%) | pH | 相关物质% | |
说明范围t=0t=3个月t=6个月t=9个月 | 澄清的浅黄色溶液澄清的浅黄色溶液澄清的浅黄色溶液澄清的浅黄色溶液澄清的浅黄色溶液 | (a)2.82.93.02.8 | 260-350321314304293 | 67.5-82.575.8(100)76.6(101.1)75.4(99.5)76.5(100.9) | 4.5-5.55.25.25.05.1 | (a)6.396.355.846.27 |
(a)未确定
表2-实施例1的溶液-在加速条件(40℃,75%R.H.)下的稳定性
分析 | 技术控制 | 化学控制 | ||||
溶液外观 | 氧mg/l | 摩尔渗透压浓度mOsm/l | 妥布霉素mg/ml(%) | pH | 相关物质% | |
说明范围t=0t=1个月t=3个月t=6个月 | 澄清的浅黄色溶液澄清的浅黄色溶液澄清的浅黄色溶液澄清的黄色溶液澄清的黄色溶液 | (a)2.82.72.83.2 | 260-350321n.d.311292 | 67.5-82.575.8(100)78.3(103.3)75.3(99.3)77.1(101.7) | 4.5-5.55.25.15.14.7 | (a)6.396.425.486.17 |
(a)未确定(n.d.)未测出
实施例2
使用市售喷射雾化器(PARI-BOY),雾化时间是5分钟,评价实施例1的吸入用溶液的雾化效率,以雾化的活性组份的百分比表示。还通过Malvern分析表征通过雾化溶液产生的小滴的大小分布,其分别包括10%、50%和90%小滴的直径(μm)表示。
为了比较起见,将按照EP 734249的优选实施方式的教导制得的制剂(即含有60mg活性成分/ml的0.225%氯化钠水溶液并且pH为约6)雾化。将两种制剂都填充在2ml单位剂量小瓶中。以两个测定的平均值将结果报告于表3。
表3
摩尔渗透压浓度(mom/l) | Malvern分析(μm) | 效率(%) | |||
实施例1的制剂EP734249的制剂 | 295222 | 10%1.611.78 | 50%6.266.24 | 90%13.4613.46 | 47.442.2 |
结果显示将摩尔渗透压浓度接近等渗的实施例1的制剂有效地雾化。
通过雾化制得的小滴的大小分布反而实际上相同。
Claims (7)
1、一种气溶胶制剂,包含75mg/ml溶解在0.45%w/v氯化钠水溶液中的妥布霉素,其中pH在4.0-5.5之间,并且摩尔渗透压浓度在250-450mOsm/l的范围内。
2、如权利要求1的气溶胶制剂,其中所述pH在5.0-5.4范围内。
3、如权利要求1的气溶胶制剂,其中所述摩尔渗透压浓度在260-400mOsm/L之间。
4、如权利要求1-3任一项的气溶胶制剂,其中pH是5.2,并且摩尔渗透压浓度在280-350mOsm/l之间。
5、一种如权利要求1的气溶胶制剂的制备方法,所述方法包括步骤:
i)制备含有0.45%w/v氯化钠的水溶液;
ii)用浓强酸调节其pH;
iii)加入活性组份并混合至完全溶解;
iv)再次调节pH至所需值;
v)将该溶液填充至适当容器中。
6、如权利要求5的方法,其中所述浓强酸是硫酸。
7、如权利要求5或6的方法,其中所述水溶液经由过滤预除菌。
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EP01116071A EP1273292B1 (en) | 2001-07-02 | 2001-07-02 | Optimised formulation of tobramycin for aerosolization |
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US20050083693A1 (en) * | 2003-10-21 | 2005-04-21 | Timothy Garrett | Flag illumination fixture |
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2001
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- 2001-07-02 EP EP01116071A patent/EP1273292B1/en not_active Expired - Lifetime
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2002
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- 2002-06-29 EG EG2002060744A patent/EG24019A/xx active
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2003
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- 2003-12-19 BG BG108475A patent/BG66328B1/bg unknown
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2004
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- 2005-02-03 HK HK05100912A patent/HK1068784A1/xx not_active IP Right Cessation
- 2005-03-18 US US11/083,139 patent/US7696178B2/en not_active Expired - Lifetime
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2009
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