CN1149080C - 丙胺卡因及氟代烃气雾剂的制备 - Google Patents
丙胺卡因及氟代烃气雾剂的制备 Download PDFInfo
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Abstract
丙胺卡因碱,其液体或微小棒状晶体可溶于氟代烃推进剂中,产生一稳定的油状液体。该丙胺卡因碱可用于把其它通常不溶解的药物增溶溶解于氟代烃推进剂中。丙胺卡因碱与氟代烃推进剂的组合物可作为气雾剂喷洒,用于提供局部麻醉作用。
Description
本发明的技术领域
本发明普遍地与气雾剂的形成,包括氢氟化物推进剂和丙胺卡因碱有关。
背景技术
丙胺卡因是一种局部***,具有下列结构式:
丙胺卡因在英国专利839,943(1960年,属于阿斯特拉(Astra))中已有记载,并具有针状结晶,熔点37-38℃。其氢氯酸盐,分子式为C13H21ClN2O,经乙醇和异丙醚结晶,易溶于水。
局部***通过干扰可兴奋的膜例如神经细胞膜的电压门控的钠离子通道的开放而阻断神经脉冲。当足够数量的离子通道被阻断时,神经传导就在特定神经轴索的被麻醉部分中断了。这种减轻痛苦的机制与用止痛剂来减轻痛苦的机制有很大的不同。
麻醉剂在临床上的药效取决于其进入神经纤维的能力和其内在的阻断活性。神经鞘的渗透性、血管吸收和局部组织粘连等因素都是决定药效的重要因素。另外,注射的***液的用量、pH,以及缓冲能力也很重要。
局部麻醉剂传统上用针和注射器注入要作用的部位。绝大部分麻醉剂配方是麻醉剂盐酸盐的0.5-2%重量或体积浓度的水溶液。该溶液是用来注射扩散进入组织,神经周围,神经鞘内或硬膜外的空间。
将局部麻醉剂送到皮肤伤口依然是个问题,还主要是通过把局部麻醉剂的水溶液注射到伤口周围或伤口内而实现的。这种办法从机制上是有缺点的,因为穿刺时针本身可引起疼痛,而且***液的体积可引起作用位点(肌肉)牵张,这也引起疼痛。而且,象Parabens,乙醇,十六烷基氯化吡啶鎓,苯扎氯铵等诸如此类的防腐剂用在该水溶液中也可在伤口部位引起刺痛。
儿科急诊手册(Handbook of pediatric Emergencies,1994,Ed.Baldwin,Little,Brown and Company)中记载了一种局部用药配方:0.5%的盐酸丁卡因,肾上腺素1∶2000,和11.8%的盐酸卡因。该配方以将棉球在溶液中浸泡10-15分钟方式使用。这种使用方法和配方存在着局部***盐酸盐吸收慢的缺点,这就要求***液在用药部位放置很长时间,棉球直接用于受伤部位以及使用本药方前清洗伤口。另外,要获得深度的神经阻断,本办法还必须辅以注射局部***方。
为了阻断神经传导,局部麻醉要求***得到快速吸收。局部施用凝胶和流体在很多情况下证明是不成功的。例如,输尿管内传输的利多卡因凝胶在膀胱镜检查中并不比普通的润滑剂凝胶更有效(参见Stein etal.,Journal of Urology,June 1994,Vol.151,P1518-1521)。
用雾化的利多卡因盐酸盐的水溶液,借助于计量吸入器(MDI),配以氯氟化碳(CFC)推进剂及增溶剂和/或分散剂,把利多卡因以气雾剂的形式送到气管粘膜。然而,经验表明,这些配方存在着形成大液滴的缺点,这有碍于满意的吸人或者间接地传输到上呼吸道,包括喉和气管。另外,气雾剂配方中需要有有机溶剂和辅助剂也限制了活性药物的浓度,从而限制了非必需成分的剂量。而且,这些配方还没有用于局部麻醉,也不会成功用于局部麻醉,因为辅助剂和溶剂本身就是刺激物,将其用于敏感的粘膜和伤口时将引起疼痛。
氯氟化碳(CFC)推进剂已经广泛地用于气雾剂配方中;然而,CFC推进剂已经依国际条约被排除在外,由于它们可能的对臭氧层的负面影响。氟化烃(HFC)推进剂已经被广泛地研究作为CFCs的替代品。虽然HFCs在化学上与CFCs相似,HFCs还是有一些性质上的不同,这使得配制某些产品非常困难,特别是配制医学上和药学上用的气雾剂,其中能够提供控制量的药物,而且在某些情况下能够提供适于呼吸大小的微粒或液滴的能力是极其重要的。
本发明的概要
本发明的目的是提供新型的气雾剂配方,该配方包括:丙胺卡因,有或没有其它药物,溶于HFC推进剂,没有其它的有机溶剂和表面活性剂。
本发明的另一个目的是提供一种用丙胺卡因作HFC推进剂中的增溶剂的方法。
本发明的另一个目是提供一种新的丙胺卡因的组合物,其中丙胺卡因以液体或无定形与一种HFC推进剂组合。
按照本发明,发现,碱性形式的丙胺卡因可溶于HFC推进剂1,1,1,2-四氟乙烷和1,1,1,2,3,3,3-七氟丙烷。丙胺卡因以液态形式与HFC推进剂组合时,丙胺卡因是可溶的,以晶体与HFC推进剂组合时是不可溶的。液态的丙胺卡因碱与HFC推进剂组合形成一个稳定的具有油一致性的液体溶液。液态的丙胺卡因碱与HFC推进剂混和时,被认为是形成一个1∶1的分子离子复合物,从而使丙胺卡因留在溶液中并改变了这种复合的混和物的溶解性以致于混和物能完全相混或者可溶于丙胺卡因。丙胺卡因复合的HFC推进剂具有改良的物理特性:良好的溶解性,良好的悬浮特性,低的蒸汽压和高的粘度。在存在水或乙醇的情况下,丙胺卡因与HFC推进剂之间的缔合物或复合物被破坏,导致HFC推进剂的释放。丙胺卡因液体可以与其它药物,特别是其它***物组合,作为增溶剂,改进HFC推进剂的溶解性能以致于添加的局部麻醉剂在丙胺卡因/HFC溶液复合物中形成一个稳定的溶液。丙胺卡因液体/HFC复合物的油性可以作为从MDI配制气雾剂时的阀门润滑助剂;因此,克服或背离了传统的需另加阀门润滑剂的配方。丙胺卡因液体/HFC复合物也使制造某种颗粒状药物的稳定悬浮液成为可能(如β-***如沙丁胺醇等)。丙胺卡因/HFC复合物的液体性在局部麻醉处理方法学上具有优点,因为丙胺卡因可喷洒到一部位上,将该部位用液体包裹,这样由于丙胺卡因的液体性,也由于这个事实即丙胺卡因以液体可溶性碱形式存在,以及当复合物与膜上的水及病人皮肤表面的水作用时,复合的HFC推进剂能够迅速分解,相对于精细粉末,液体丙胺卡因能够被更加迅速地吸收。
本发明优选实施例的详细描述
液态的丙胺卡因碱可通过将丙胺卡因盐酸盐悬浮于乙酸乙酯中并以适当的碱水溶液如碳酸钠溶液洗涤直到所有的固体溶解掉为止而制得。乙酸乙酯可用标准的旋转蒸发方法或其它方法去掉。去掉乙酸乙酯后,丙胺卡因残液再溶解于一种低沸点溶剂如二氯甲烷中,以共沸蒸馏法除去乙酸乙酯。再用旋转蒸发器蒸去二氯甲烷,然后在高真空干燥丙胺卡因碱。
通过上述方法得到的丙胺卡因碱在室温下是液体,但是通过冷却或向液体中添加晶种很容易转变成通常的针状结晶。如上所述,丙胺卡因室温时通常为固体并具有针状结晶,熔点38℃。然而,所用的工艺条件使丙胺卡因在其正常熔点以下形成了液体的丙胺卡因碱。低熔点的固体在其熔点以下以液体形式存在,这不是一个不寻常的现象,但是,这种特性在丙胺卡因来说迄今为止是不为人知晓的。进一步冷却或添加晶种可使这些物质结晶,它们将保持固体状态直到达到它们预定的熔点。
从瑞典阿斯特拉药物公司得到的参照标准丙胺卡因碱样品被用于证实以上所述液体丙胺卡因碱的本性及纯度。用薄层凝胶色谱,红外(IR)光谱和核磁共振(NMR)成像证实:液体丙胺卡因碱与标准的丙胺卡因碱一样。
发现液体丙胺卡因碱易于溶解或吸收进入HFC推进剂1,1,1,2-四氟乙烷和1,1,1,2,3,3,3-七氟丙烷。液体丙胺卡因碱基与HFC推进剂组合,形成一个稳定的油状液体。
相反,通常的针状晶态的丙胺卡因碱不溶于HFC推进剂。晶体结构被认为阻止了丙胺卡因与HFC推进剂之间极性的/离子性的相互作用,从而晶体保持不溶解。
针状结晶被加热到38℃以上的温度时,就熔化了,产生的液体很容易溶解并吸收进HFC推进剂,形成一稳定的油状液体,只要没有针状结晶存在,丙胺卡因碱/HFC组合物在冷却到-82℃时都保持稳定;然而,向溶液保引入针状结晶晶种将引起丙胺卡因碱/HFC复合物的分解。
除了发现液体丙胺卡因碱易溶于HFCs外,还发现,微小棒状结晶的丙胺卡因碱与通常的针状结晶的丙胺卡因碱不同,易溶于HFC推进剂。微小棒状的丙胺卡因碱可通过沉淀及从过饱和溶液中过滤出来而得到。阿斯特拉药物公司提供的参考标准丙胺卡因样品是微小棒状结晶形的。丙胺卡因碱的微小棒状结晶与针状结晶在化学上是等同的,但在物理上是不等同的。
本发明的一个重要特在于制备与HFC推进剂配合的气雾剂时,可使用液体形式或微小棒状形式的丙胺卡因。把液体或微小棒状的丙胺卡因与HFC推进剂组合可生产一种稳定的复合物或缔合物,该复合物或缔合物为油状液体溶液,可用于MDIS或其它配方。该溶液是伤口部位或类似位置理想的局部***传送介质,其中,丙胺卡因以液体应用,吸收快,由于丙胺卡因以其脂溶性碱形式存在,丙胺卡因与作用位点的水和其它污物接触时,复合的HFC推进剂迅速分解,吸收作用得到增强。迅速的吸收使得应用时快速而有效的局部麻醉成为可能而不引起疼痛或不舒服。由于丙胺卡因碱以液体形式存在,喷洒它时,它能够形成一薄膜将需要麻醉的部位包裹。这样的部位包括外科手术期间暴露的气管粘膜,胃肠道,生殖-尿道,和所有的其表皮能够快速吸收局部***的伤口表面以及内脏器官表面。液体的油性改善了对应用表面的吸收同时保留了易于洗去的特点。
实施例1描述了液体丙胺卡因碱与HFC推进剂间复合物的形成。
实施例1
液体丙胺卡因碱,以油性液体存在,没有任何晶种,易于与氟代烃推进剂1,1,1,2-四氟乙烷(HFC-134a)和1,1,1,2,3,3,3-七氟丙烷(HFC-227)相混溶。同样,微小棒状结晶形的丙胺卡因碱易于与氟代烃推进剂1,1,1,2-四氟乙烷(HFC-134a)和1,1,1,2,3,3,3-七氟丙烷(HFC-227)相混溶。液体丙胺卡因碱或微小棒状丙胺卡因碱与HFC推进剂组合形成一稳定的液体溶液。
在配制某个特定的丙胺卡因/HFC溶液期间,将液体丙胺卡因置于一个4盎司的已知重量的玻璃瓶中。称瓶重以确定液体丙胺卡因碱的重量,然后以一连续阀把瓶子封口,以加压装罐机将HFC-134a加到瓶子中,再次称瓶重以确定加入的HFC-134a的重量,轻轻摇动瓶子以使液体丙胺卡因与HFC相互混和,混和物形成一清晰稳定的溶液,静置或冷却时,该溶液并不沉淀出丙胺卡因碱。打开阀门一短暂时间以释放HFC-134a蒸气,每隔一段时间称一次瓶重。每当各次的HFC-134a气体释放后,溶液都保持清晰稳定。这个过程持续进行直到所有的蒸气从瓶中释放出来。蒸气释放完以后的瓶子重量表明了一个1∶1重量比的丙胺卡因:HFC-134a残留物(产物依然在瓶中)。让瓶口开24小时同时称重量,发现HFC-134a慢慢地离开溶液直到瓶子重量表明只存在丙胺卡因碱为止。红外光谱证实回收的液体丙胺卡因碱并未因与HFC-134a的作用而改变。
把按上述方式制备的1∶1的丙胺卡因:HFC-134a混和物冷却到-82℃并未导致丙胺卡因从溶液中结晶出来,相反,丙胺卡因:HFC-134a形成了一种更加粘稠的溶液。从丙胺卡因通常具有38℃的熔点以及1∶1的溶液被高度浓缩来看,这个结果是令人吃惊的。这进一步暗示,液体丙胺卡因碱与HFC之间产生了某种形式的缔合物或复合物(例如离子性的)。将粘性油状物再温热到室温,丙胺卡因:HFC-134a仍然是液体。上述的冷却试验表明,液体丙胺卡因碱可用于通常用于MDI包装之类的冷罐装操作中而没有不良后果。
给1∶1的溶液接种丙胺卡因针状晶体导致丙胺卡因碱几天后从溶液中结晶出来。
发现液体丙胺卡因碱与HFC推进剂的缔合使得它可用作在HFC推进剂中增溶和/或分散其它药物的溶剂。特别地,丙胺卡因碱可用作其它局部***的增溶助剂,其中绝大部分在通常情况下不能溶于HFC推进剂。例如,丙胺卡因碱可与***普鲁卡因,***,氯普鲁卡因,丁卡因,甲哌卡因,利多卡因,布比卡因,依替卡因,罗哌卡因,和苯佐卡因一起用于HFC推进剂中。丙胺卡因可用在HFC气雾剂配方的制备中,该气雾剂配方用于吸入(鼻和/或口的),局部传输(如皮肤伤口,空的内脏和体腔传输),也可用于增溶,分散和/或与其它药物形成稳定的悬浮液,该药物包括如支气管扩张剂,消炎剂,止咳剂,血管作用药物,血管收缩剂,抗生素,多肽,类固醇,酶,抗组胺药,苯并二氮卓类,精神抑制药,镇静剂,维生素,激素,酶和受体抑制剂,拮抗剂,5-氨基乙酰丙酸和相似药剂,防腐剂和消毒剂等。
实施例2提供了几种不同的制备好的HFC气雾剂配方的组成。可以看到,丙胺卡因碱可在广泛的不同浓度下使用,其在气雾剂配方中的重量可在1-99%范围变化。最优选地,液体丙胺卡因碱占HFC气雾剂配方重量的1-60%。HFC推进剂可以占气雾剂配方重量的1-99%,最优选地,占气雾剂配方重量的60-95%。
如果有其它药物与丙胺卡因和HFC推进剂组合的话,该药物可占气雾剂配方重量的0.01-99%,最优选地,占气雾剂配方重量的0.01-10%。
实施例2
使用实施例1中的一般方法,制备了下列配方,它们都提供了稳定的溶液。
配方1
丙胺卡因碱 140mg 4.4% W/W
利多卡因碱 1260mg 40.0% W/W
HFC-134a 1760mg 55.6% W/W
配方2
丙胺卡因碱 340mg 15.5% W/W
利多卡因碱 1260mg 57.7% W/W
HFC-134a 580mg 26.6% W/W
配方3
丙胺卡因碱 520mg 34.9% W/W
利多卡因碱 1260mg 84.7% W/W
HFC-134a 175mg 11.7% W/W
配方4
丙胺卡因碱 411mg 33.4% W/W
利多卡因碱 476mg 38.6% W/W
HFC-134a 344mg 28.0% W/W
当冷却至-82℃时,配方1-4都有利多卡因碱的晶体析出、留下丙胺卡因和HFC-134a的粘稠油状溶液。重新温热,利多卡因晶体又回到溶液中。让瓶子敞开24小时以上时,HFC-134a蒸发了,局部麻醉剂冷却时就结晶出来。
配方5
苯佐卡因碱 322mg 3.7% W/W
HFC-134a 8283mg 没有溶液
配方6
丙胺卡因碱 184.6mg 56.2% W/W
苯佐卡因碱 12.7mg 3.8% W/W
HFC-134a 131.2mg 40.0% W/W
清澈的溶液
配方7
布比卡因碱 30.0mg 0.3% W/W
HFC-134a 10000mg 没有溶液
配方8
布比卡因碱 166.0mg 33.5% W/W
丙胺卡因碱 176.0mg 35.5% W/W
HFC-134a 153.0mg 31.0% W/W
清澈的溶液
配方4-8表明,一般不溶性麻醉剂(如苯佐卡因和布比卡因),当使用液体丙胺卡因碱:HFC-134a溶液时,可溶解于HFC推进剂中。当冷却到-82℃时,苯佐卡因与布比卡因从溶液中沉淀出来,重新温热后,苯佐卡因与布比卡因又溶解回到溶液中。
配方9
丁卡因碱 60mg 1.9% W/W
HFC-134a 3000mg 98.1% W/W
清澈的溶液
丁卡因的最大溶解度
配方10
丁卡因碱 150mg 5.8% W/W
丙胺卡因碱 178mg 6.9% W/W
HFC-134a 2250mg 87.3% W/W
配方9-10表明丙胺卡因可用于增加某些药物在HFC推进剂中的溶解度。
配方11
苯福林碱 6mg 0.12% W/W
HFC-134a 4890mg 没有溶液
配方12
苯福林碱 8mg 0.2% W/W
丙胺卡因碱 993mg 24.7% W/W
利多卡因碱 1009mg 25.1% W/W
HFC-134a 1110mg 50.0% W/W
这三种药物碱先一起加热溶解。该配方制得了一个稳定的苯福林悬浮液,设有观察到晶体生长的迹象。
配方13
苯福林碱 3mg 0.2% W/W
丙胺卡因碱 402mg 24.7% W/W
布比卡因碱 409mg 25.1% W/W
HFC-134a 814mg 50.0% W/W
该配方产生一个稳定的悬浮液。该配方中不要求预先加热混和碱化合物,但建议作为获得均一颗粒尺寸的苯福林悬浮液的手段。
配方11-13表明,用丙胺卡因作分散剂(与增溶剂相对)可形成一稳定的药物悬浮液。
虽然对本发明以优选的实施例的方式进行了叙述,掌握了该技术的人将会认识到在所附的权利要求书的精神和保护范围内的任何改动下,本发明仍然可以实施。
Claims (15)
1.一种组合物,包括:
一种氟代烃推进剂,选自由1,1,1,2-四氟乙烷和1,1,1,2,3,3,3-七氟丙烷及其组合组成的一组物质;和
溶解于所述的氟代烃推进剂中的丙胺卡因碱。
2.权利要求1所述的组合物还包括一种不同于丙胺卡因碱的麻醉剂,该麻醉剂溶解于所说的氟代烃推进剂中。
3.权利要求2所述的组合物,其特征在于,所说的麻醉剂选自由普鲁卡因,***,氯普鲁卡因,丁卡因,甲哌卡因,利多卡因,布比卡因,依替卡因,罗哌卡因和苯佐卡因组成的一组物质。
4.如权利要求1的组合物,由:
选自由1,1,1,2-四氟乙烷和1,1,1,2,3,3,3-七氟丙烷组成的一组物质的氟代烃推进剂;和
溶解于所说的氟代烃推进剂中的丙胺卡因碱组成。
5.一种把丙胺卡因碱溶解于氟代烃推进剂中的方法,包括下列步骤:
得到选自由液体和微小棒状组成的一组物理形态的丙胺卡因;和
把从所说的得到步骤中得到的丙胺卡因碱与选自由1,1,1,2-四氟乙烷和1,1,1,2,3,3,3-七氟丙烷组成的一组物质的氟代烃推进剂混和。
6.一种增加药物在氟代烃推进剂中的溶解度或把药物悬浮于氟代烃推进剂中的方法,包括下列步骤:
把丙胺卡因碱溶解于选自由1,1,1,2-四氟乙烷和1,1,1,2,3,3,3-七氟丙烷及其组合组成的一组物质的氟代烃推进剂中,所说的溶解步骤产生一个液体;和
通过选自由增溶和悬浮组成的一组办法,用所说的丙胺卡因碱作增溶剂或悬浮剂,把一种药物掺合到所说的液体中。
7.权利要求6所说的方法,其特征在于,溶解步骤和掺合步骤同时进行。
8.权利要求6所说的方法,其特征在于,所说的溶解步骤包括获得选自由液体和微小棒状组成的一组物理形态的丙胺卡因的步骤。
9.权利要求6所说的方法,其特征在于,所说的掺合步骤通过悬浮完成,其中所说的药物选自由支气管扩张剂,消炎药,止咳剂,血管作用药物,血管收缩剂,抗生素,多肽,类固醇,酶,抗组胺药,苯并二氮卓类,精神抑制剂,镇静剂,维生素,激素,酶和受体抑制剂,拮抗剂,5-氨基乙酰丙酸,防腐剂和消毒剂组成的一组物质。
10.权利要求9所说的方法,其特征在于,所说的药物是一种血管收缩剂。
11.权利要求10所说的方法,其特征在于,所说的血管收缩剂是苯福林。
12.权利要求6所说的方法,其特征在于,掺合步骤通过增溶作用完成,其中所说的药物是一种不同于丙胺卡因的麻醉剂。
13.权利要求12所说的方法,其特征在于,所说的麻醉剂从由普鲁卡因,***,氯普鲁卡因,丁卡因,甲哌卡因,利多卡因,布比卡因,依替卡因,罗哌卡因和苯佐卡因组成的一组物质中选出。
14.如权利要求1的组合物在制备麻醉病人用药物中的用途。
15.如权利要求14的用途,其中药物是气雾剂的形式。
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DE69420401T2 (de) * | 1993-03-29 | 2000-05-04 | Lynchris Pharmaceuticals, Ltd. | Anästhetikum in aerosolform auf der basis von lidocain |
US5453445A (en) * | 1994-05-02 | 1995-09-26 | Henry; Richard A. | Lidocaine-phenylephrine aerosol preparation |
-
1995
- 1995-05-05 US US08/435,812 patent/US5589156A/en not_active Expired - Lifetime
-
1996
- 1996-03-04 DK DK96902844T patent/DK0814793T3/da active
- 1996-03-04 DE DE69629109T patent/DE69629109T2/de not_active Expired - Lifetime
- 1996-03-04 PT PT96902844T patent/PT814793E/pt unknown
- 1996-03-04 AT AT96902844T patent/ATE245025T1/de active
- 1996-03-04 AU AU47113/96A patent/AU710600B2/en not_active Expired
- 1996-03-04 EP EP96902844A patent/EP0814793B1/en not_active Expired - Lifetime
- 1996-03-04 WO PCT/CA1996/000122 patent/WO1996029066A1/en active IP Right Grant
- 1996-03-04 ES ES96902844T patent/ES2203676T3/es not_active Expired - Lifetime
- 1996-03-04 CN CNB961926457A patent/CN1149080C/zh not_active Expired - Lifetime
- 1996-03-04 BR BR9607988-6A patent/BR9607988A/pt active IP Right Grant
- 1996-03-04 JP JP52792396A patent/JP4117707B2/ja not_active Expired - Lifetime
-
2014
- 2014-03-18 LU LU92402C patent/LU92402I2/fr unknown
Also Published As
Publication number | Publication date |
---|---|
AU710600B2 (en) | 1999-09-23 |
EP0814793B1 (en) | 2003-07-16 |
DE69629109T2 (de) | 2004-04-15 |
LU92402I2 (fr) | 2014-05-19 |
MX9707073A (es) | 1998-08-30 |
WO1996029066A1 (en) | 1996-09-26 |
CN1179103A (zh) | 1998-04-15 |
DE69629109D1 (de) | 2003-08-21 |
AU4711396A (en) | 1996-10-08 |
US5589156A (en) | 1996-12-31 |
JP4117707B2 (ja) | 2008-07-16 |
JPH11502202A (ja) | 1999-02-23 |
ES2203676T3 (es) | 2004-04-16 |
EP0814793A1 (en) | 1998-01-07 |
BR9607988A (pt) | 1999-11-30 |
DK0814793T3 (da) | 2003-12-01 |
ATE245025T1 (de) | 2003-08-15 |
PT814793E (pt) | 2003-12-31 |
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