CN1034105C - 鼻内用药的制剂的制备方法 - Google Patents
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Abstract
在磷脂如磷脂酰胆碱(卵磷脂)存在下,某些药物,尤其是药用活性多肽,经鼻内给药后可以增加全身吸收,最好将磷脂与植物油相混和。
Description
本发明涉及适用于鼻内给药的新药用制剂的制备方法。
虽然那些非侵袭式(non-invasive)给药法如口服法或直肠给药法对病人而言无疑是最方便的,但通常认为胃肠外给药是最有效的。尤其是在胃肠道中失活或吸收很差的药物,以及口服后易进行扩展的首次通过肝代谢效应的药物,通常进行胃肠外给药。
但是胃肠外给药有明显的不便之处,如需要无菌给药器具、反复注射会造成疼痛和刺激,以及潜在感染的危险。因此,人们寻找能阻止首次通过代谢效应而作用相当于胃肠外给药的另一种给药方式。其中,一种有希望的给药方式是通过鼻道给药。但是,正如其它非侵袭式给药法的情况一样,主要由于药物的化学性质,鼻内给药后药物的生物有效度大多无法预测。
例如,已知孕酮和萘心安由鼻腔吸收提供的血液浓度几乎相当于静脉给药。
现已知有分子量高达约1KD的药用活性剂的经鼻给药配方的实例。例如将活性麦角肽(ergopcptide)生物碱溶解到乙醇水溶液中作为气溶胶的配方(瑞士专利No.636,011);含有药用活性的胺和脂肪酸形成的盐的配方(加拿大专利No.988,852);以及将儿茶酚胺悬浮于脂肪酸(或酯)中并用聚氧乙烯乳化的配方(欧洲专利申请No.160,501)。
近几十年来,已经研制了各种各样的多肽药物(主要是合成的)。总的来讲,多肽药物因为在消化道中吸收不完全和消化不稳定,所以用胃肠外给药。也许正因如此,近年来多肽经鼻道给药方面的研究加强了。已经发现,虽然一些较小的多太(至多约10个氨基酸残基)配成简单的水溶液可在鼻内很好地吸收,但是较大的多肽通常的鼻内生物有效度既不完全又不稳定,随着分子量的增大更是如此(综述参见L.IIIum: Archiv for pharrnaci OgChemi 94(1987),127-135)。为了克服上述缺点(尤其当鼻内用药配方含较大的多肽时),人们设想,可以另外加入各种生物上适用的促进吸收剂或所谓的强化剂(enhancer)。
这方面可参考欧洲专利公告No.111,841,该专利公开了胆酸的促吸收作用;美国专利No.4,476,116公开了利用螯合剂(如EDTA)增加吸收的方法。
假如胰岛素经鼻腔吸收适当有效且稳定的话,与目前的肠胃外给药制剂相比,依赖胰岛素的糖尿病患者自然会非常乐于选用胰岛素经鼻用药的合适配方。已发明了许多增加吸收剂(主要是表面活性剂)用于上述配方。
英国专利No.1,527,605公开了离子型及非离子型的表面活性剂强化剂,如胆汁酸盐和聚氧乙烯高碳醇醚,另一方面,R.SaIzman等[NewEngland J.ofMed.312(1985),1078-1084]叙述了特定的聚氧乙烯高碳醇醚(即聚氧乙烯-9十二烷基醚)的应用。美国专利No.4,548,922公开了其它一些强化剂,例如牛磺二氢梭链孢酸的盐。
至今已知的强化剂的化学结构与那些已知的细胞膜组分的化学结构(包括鼻腔细胞膜的化学结构)大不相同。这一情况也许可以解释这些药物通常易于引起鼻内刺激,甚至造成鼻粘膜永久损伤(尤其在长期用药的情况下)。在这一背景下,与其它生理上存在的表面活性剂更相类似的强化剂如磷脂,是值得考虑的。然而根据英国专利NO.1,527,605(前已述及)公开的资料,一般长链卵磷脂混合物中的磷脂对于鼻用药配方中的胰岛素看不出有促进吸收的作用。
现已惊奇地发现,中等链长的磷脂酰胆碱和磷脂酰乙醇胺能够显著地促进药用活性化合物鼻内吸收,尤其可促进多肽的吸收,而且对鼻粘膜无刺激或损伤。在配方中将脂油(如植物油)与磷脂混和,则可进一步提高鼻内吸收效果。
首先,本发明提供了由药用活性剂和增加吸收系统所组成的鼻内用药制剂,这种增加吸收系统至少包括一种具有通式I的磷脂,其中R′和R″可以相同或不同,分别选自以下一组基团:氢,烷基,链烯基,烷基羰基,链烯基羰基,链二烯基羰基,链三烯基羰基或链四烯基羰基,这些基团的碳原子总数至多为14,条件是,R′和R″不都是氢,R表示亲水基团,可选自2-(三甲胺)乙基,2-氨基乙基,2-羧基-2-氨基乙基,2.3-二羟基丙基和五羟基环己基。这样就分别构成胆碱(卵磷脂)、乙醇胺、甘油、丝氨酸和肌醇的磷脂酰衍生物。在增加吸收系统中可以不加脂油,但是加入脂油和磷脂混合在一起更好。
其次,本发明提供了制备鼻内用药制剂的方法,该方法包括将至少一种具有通式I的磷脂(可以不加脂油,但加入脂油更好)和药用活性剂一起,以溶液或粉末状分散在液态或固态的稀释剂中,稀释剂中还可以有选择地加入辅助性的pH缓冲剂,防腐剂和渗透压调节剂。
式I化合物中较好的一个亚类是其中的R′和R″都是烷基羰基。其中更好的亚类是R为2-(三甲铵)乙基的化合物,这类化合物称为卵磷脂。另一个更为优选的式I化合物为,其中的R′和R″都代表烷基羰基并具有约4个碳原子,最好不超过12个碳原子。最优选的式I化合物的亚类是其中R′和R″都为壬基羰基。
本发明较好的制剂是含有两种式I磷脂的混合物的制剂。两种磷脂中之一,其中的R′和R″都是辛酰基、癸酰基或十二烷酰基,另一磷脂化合物,其中的R′和R″两个取代基之一为氢,另一为辛酰基、癸酰基或十二烷酰基(月桂酰)。
一些较好的式I化合物的实例为:
二辛酰基L-α-磷脂酰胆碱
二辛基-O-L-α-磷脂酰胆碱
二癸酰基L-α-磷脂酰胆碱
二癸基-O-L-α-磷脂酰胆碱
癸基-O-L-α-溶血磷脂酰胆碱
二(十二烷酰基)L-α-磷脂酰胆碱
十二烷酰基L-α-溶血磷脂酰胆碱
式I化合物有些是已知的,式I化合物可以用实质上已知的方法制备。
本发明中选择性地加到增加吸收系统中的脂油最好是植物油。其中豆油、花生油、椰子油、玉米油、橄榄油、葵花油或它们的混合物更好。本发明的另一优选的实施方案中,药用活性剂为多肽。多肽中较好的一类是胰岛素和胰岛素衍生物(例如通过化学或酶方法或重组DNA技术修饰过的胰岛素),或这些胰岛、胰岛素原和胰高血糖素的混合物。其它较好的多肽有甲状旁腺素、甲状旁腺素拮抗物、降钙素、后叶加压素、血管紧张肽原酶、催乳激素、生长激素、促甲状腺激素、促肾上腺皮质素、促肾上腺皮质素释放因子、促卵泡激素、促黄体激素、绒毛膜促性腺激素、前房肽(atrialpeptide)、干扰素、组织血纤维蛋白溶酶原激活因子、γ球蛋白、因子VII、因子VIII、生长激素释放激素、促黄体激素释放激素、生长激素释放抑制因子和胰腺分泌素。
本发明的制剂可以是液体,如适用于喷雾给药,或者是固体,如制成适用于鼻吸的粉剂。液体制剂,例如以水为溶剂的配方,通常包括辅助剂,如pH缓冲系统(最好是磷酸盐,柠檬酸盐或乙酸盐缓冲液),防腐剂和渗透压调节剂(如甘油或氯化钠)。粉剂则含有药用活性剂和增加吸收系统,它们与可鼻用的稀释粉末(或各种稀释粉末的混合物)混合。稀释粉末的例子有纤维素或其衍生物(如纤维素醚或羧甲基纤维素钠)、淀粉或部分降解的淀粉(如糊精、长链脂肪酸或其盐(如硬脂酸铝)、有机聚合物(如丙烯酸衍生物的聚合物)或无机载体(如滑石或硅藻土)。可以补充加入吸水聚合物,例如聚乙二醇或聚乙烯吡咯烷酮,以便改进粉剂鼻粘膜的粘附。
液体制剂最好以水作为稀释剂。这样的制剂可以通过将增加吸收系统分散到水介质中来制备。在水介质中含有药用活性剂和辅助剂。分散可以按应用于悬浮剂或乳化剂常用的方法来进行,例如可用超声处理。调水相到中性(即pH在约6.5~约8范围)可以在制备中任何一步进行。最好制备微乳剂,在微乳剂中,分散的颗粒或液滴的直径在10nm数量级,这样易于通过鼻粘膜。这样的微乳剂可以通过过滤灭菌。在本发明的最好配方中,式I磷脂和脂油的含量范围分别为该制剂的0.01~10%(W/V)和0.01~50%(W/V)。由于鼻粘膜上有肽酶和蛋白酶(参见R.E.Stratford andV.H.L.Lee:Int.Journ.pharmaceutics30(1986),73-82),因此在含有多肽的配方中掺入生物上适用的蛋白酶和肽酶抑制剂是合乎需要的。
本发明制剂中,药用活性剂的浓度显然取决于所选用的具体活化剂、活化剂的功效、鼻内给药和其它途经给药(如胃肠外注射)生物有效度的比较、以及与配方中预定单次剂量相联系的预定给药次数。熟练技术人员通常可从动物实验中获得上述药理数据,例如指标值(index value),如下文实例给出的对胰岛素制剂评价的数据。
以胰岛素为例,本发明制剂中的胰岛素浓度可为每毫升约5-1000国际单位(I.U.)的范围,最好为每毫升50-500I.U.。
本发明的胰岛素制剂最好含有牛、猪或人胰岛素。
制备本发明以水作稀释剂的胰岛素制剂的典型方法为:在酸(如盐酸)存在下,将胰岛素(如锌胰岛素晶体,例如英国专利NO.1,285,023公开的高纯级胰岛素)溶解于水中。再另外制备防腐剂水溶液,如苯酚、烷基苯酚(如甲苯酚)或对羟基苯甲酸甲酯的水溶液,该溶液还可以含有使溶液等渗的物质,如氯化钠或甘油。防腐剂溶液中还可以含有缓冲剂,如磷酸钠、柠檬酸钠、乙酸钠或Tris(三羟甲基氨基甲烷)和蛋白酶抑制剂。而后将所得防腐剂溶液与上述胰岛素酸性溶液混合,接着加入碱(例如氢氧化钠溶液)以调节pH值至中性。将式I磷脂(也可以是和脂油的混合物)制成溶液或乳剂(通过将其溶解或悬浮于水中而制得),然后将其加到胰岛素溶液中。如有必要,在与胰岛素溶液混和之前,将所有悬浮液用超声处理。如果需要的话,磷脂溶液或乳剂也可以含有缓冲剂和防腐剂。混合以后,可将胰岛素制剂的pH值再调至中性。最好再加水使所得胰岛素溶液的体积达到计算值。
本发明制剂可以在适用于鼻内给药并能调剂剂量的器具内使用。要求该器具有最佳计量精度并且其部件(如容器,阀门和调节器)适用于鼻给药制剂,且要能藉助于机械泵系统(例如定量喷雾器)或加压气溶胶系统。气溶胶系统要用推进剂,该推进剂应与配方不起化学反应。可以从气体,如碳氯化合物、碳氢化合物、氮气和氧化二氮以及这些气体的混合物中挑选合适的推进剂。
通过下面实例进一步叙述实施本发明的细节。但是,不应认为这些实例给本发明范围强加了各种限制。实例1-12中使用的胰岛素原料中,每毫克氮约含20~30微克锌。
豆油和花生油纯度分别符合U.S.PXXI和NF.XVI的纯化级。
实例1
将772毫克人胰岛素溶于40ml0.02M盐酸中,并加入1.6g无水甘油。然后加蒸馏水至体积为80ml。用0.2M氢氧化钠溶液调pH值至7.4。再将1.0g二癸酰基L-α-磷脂酰胆碱溶于2ml乙醇(96%)中,并用皮下注射器将其注入10ml蒸馏水中。形成的混浊液用高能超声发生器超声处理10分钟,然后将所得的胶体溶液在搅拌下加到胰岛素溶液中,并加蒸馏水至体积为100ml。将该制剂(每毫升含200国际单位胰岛素)调配到适合鼻内给药的喷雾器中,并向雄性新西兰白兔鼻腔喷入100微升,同时用类似的但不含二癸酰基L-α-磷脂酰胆碱的制剂对兔子进行测试。
每隔一定时间从兔子耳缘静脉采血样,用己糖激酶方法测定葡萄糖浓度。
试验结果如下:
相对于初始水平的血液葡萄糖百分数给药后时间(分钟) 0 30 60 90 120不含卵磷脂的胰岛素制剂 00 100 103 99 100含二癸酰基L-α-磷脂酰胆碱的胰岛素制剂 100 56 65 70 81
实例2
将100mg二癸酰基L-α-磷脂酰胆碱溶解在100mg豆油中,再将该溶液加到5m10.01MpH7.4的磷酸钠缓冲液中.
将该混合物超声乳化,再向该乳液中加入2ml(每毫升含400单位)胰岛素溶液,调pH值至7.4,并加蒸馏水至体积为10ml。
在对兔子鼻腔给予该制剂后,监测血液葡萄糖浓度120分钟。如果以单次血液葡萄糖值占初始的血糖百分数表示,则曲线上方的面积可以通过三角形法计算。于是可按下式计算指标:
指标=0.053×A/D
其中A是试验制剂测得的曲线上方的面积,D是所用试验制剂的剂量,因子0.053是从速效胰岛素制剂经皮下使用推导出的系数。
用这种方法测定,鼻用胰岛素乳剂的指标为24%。
另一种类似的但不含植物油配成的制剂,指标为12-15%。
实例3-12
实例3-6,8和12中的制剂按实例1所述方法类似的方式制备,而实例7和9-11中的制剂则按实例2的方法制备。下表中使用以下缩写符号:
磷脂酰胆碱:PC
二癸酰基磷脂酰胆碱:DDPC
二月桂基磷脂酰胆碱:DLPC
百分含量是指单位体积内的重量。所有制剂每毫升均含80国际单位胰岛素。
表中数据表明,含有中等链长的酰基或烷基磷脂酰胆碱具有良好的增加吸收的效果。
实例号 | 磷脂 | 植物油 | 指标 |
345 | 0.5%十二烷酰基溶血PC0.5%十四酰基溶血PC0.5%硬脂酰溶血PC | 无 | 10.9%3.8%0.8 |
6 | 0.5%DDPC+0.2%十二烷酰基溶血PC | 无 | 13.9% |
7 | 0.5%DDPC+0.2%十二烷酰基溶血PC | 花生油2% | 21.9% |
8 | 0.5%二癸基-O-PC | 无 | 21.9% |
9 | 0.5%二癸基-O-PC+0.5%DDPC | 花生油1% | 28.7% |
10 | 0.5%DDPC0.5%DLPC | 花生油1% | 18.9% |
11 | 0.5%DDPC0.5%二(十四酰基)PC | 花生油1% | 14.3% |
12 | 0.5%DDPC | 无 | 11% |
实例13
将100mg二癸酰基L-α-磷脂酰胆碱溶于100mg豆油中,将该溶液加到5ml0.01M含160mg甘油的磷酸钠缓冲液(pH为4)中,混合物经超声乳化后,向该乳剂中加入100mg胰高血糖素,并调pH至7.4,加水至体积为10ml。
该制剂经鼻施用于兔子后,从兔耳缘静脉采血样,用己糖激酶方法监测血样中的葡萄糖浓度。
下面是不同时间所测得的血液葡萄糖浓度:给药后时间(分钟) 0 15 30 60 120无强化剂系统的胰高血糖素 100 107 113 111 107有强化剂系统的胰高血糖素 100 144 178 188 163
Claims (11)
2.根据权利要求1的方法,其中R为2-(三甲铵)乙基
3.根据权利要求2的方法,其中R′和R″分别为含4-12个碳原子的烷基或烷基羰基,最好是烷基羰基。
4.根据权利要求3的方法,其中R′和R″分别代表壬基羰基。
5.根据权利要求2的方法,其中R′和R″二者之一为氢。
6.根据权利要求1的方法,其中增加吸收的系统还含有一种植物油,最好从下列一组植物油中选择:豆油、花生油、椰子油、玉米油、橄榄油和葵花油。
7.根据权利要求6的方法,其中植物油的含量范围为该制剂的0.1-10%(W/V)。
8.根据权利要求1-7之任一方法,其中的多肽是胰岛素或一种胰岛素衍生物,或其混合物。
9.根据权利要求8的方法,其中每毫升制剂中胰岛素的含量范围为50-500国际单位。
10.根据权利要求1-7之任一的方法,其中的多肽是胰高血糖素。
11.根据权利要求6的方法,该方法包括,将至少一种磷脂与一种植物油混合,与药用活性多肽一起以溶液或粉末状分散到一种液体或固体稀释剂中,该稀释剂可以有选择地包含辅助性的pH缓冲剂、防腐剂和渗透压调节剂。
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Application Number | Priority Date | Filing Date | Title |
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DK6042/86 | 1986-12-16 | ||
DK604286A DK604286D0 (da) | 1986-12-16 | 1986-12-16 | Praeparat |
DK3700/87 | 1987-07-16 | ||
DK370087A DK370087D0 (da) | 1987-07-16 | 1987-07-16 | Produkt med forbedrede egenskaber |
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CN1034105C true CN1034105C (zh) | 1997-02-26 |
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