CN101028266B - 含有米力农的肺部给药制剂 - Google Patents
含有米力农的肺部给药制剂 Download PDFInfo
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- CN101028266B CN101028266B CN200610044407A CN200610044407A CN101028266B CN 101028266 B CN101028266 B CN 101028266B CN 200610044407 A CN200610044407 A CN 200610044407A CN 200610044407 A CN200610044407 A CN 200610044407A CN 101028266 B CN101028266 B CN 101028266B
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- Prior art keywords
- milrinone
- pulmonary
- group
- pharmaceutical composition
- lecithin
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Abstract
肺动脉高压由于发病隐匿、病情进展迅速、至今没有十分有效的治疗手段,预后不良,死亡率较高。对肺动脉高压的治疗也是肺源性心脏病治疗的中心环节。本发明通过药理实验证实,米力农通过肺部给药,显著降低了给药剂量,同时对野百合碱或低氧引起的肺动脉高压取得了极为显著的疗效,显著优于灌胃给药的效果。米力农肺部给药制剂如气雾剂、喷雾剂、粉雾剂、微球制剂或脂质体制剂使用方便,直接到达肺部,具有十分明显的速效作用与定位作用。
Description
所属技术领域
本发明属于西药的新型给药技术。
背景技术
肺动脉高压(PH)是一种发病率很低的疾病,但由于发病隐匿、病情进展迅速、至今没有十分有效的治疗手段,预后不良,死亡率较高。近年来对PH的研究取得了多方面的进展,但这一领域的研究中尚有一些关键问题需要解决。
造成肺动脉高压的原因很多,包括原发性和继发性等情况。肺动脉高压的治疗除一般性治疗如病因治疗、减肥、瓣膜外科手术和治疗伴发疾病(心力衰竭和高血压等)之外,还包括以下一些特异性的药物治疗措施。
钙离子拮抗剂:如氨氯地平,但仅对10%的肺动脉高压病例治疗有效。
前列环素:前列环素很早就用于肺动脉高压的治疗。目前开发成功的新的前列环素制剂依前列醇,已经成为治疗肺动脉高压的“金方法”,尤其适用于原发性肺动脉高压,效果显著,对于其他原因引起者效果一般。但依前列醇的临床应用还存在一些问题,除必须中心导管给药和留置导管外,还有一些药物不良反应,如不可处理的腹泻、下颌疼痛、血小板减少、系统性高血压、脸红等。此外,该药的价格亦非常昂贵。
内皮素受体阻滞剂:如波生坦,其改善肺动脉高压的能力不如依前列醇,且亦有一些不良反应,如30%的患者出现肝毒性、贫血等。
米力农是一种磷酸二脂酶III(PDEIII)抑制剂,作为一种非儿茶酚胺、非洋地黄类的正性肌力药,在治疗充血性心力衰竭(CHF)和扩张血管等方面发挥了越来越重要的作用。在美国等多国,静脉注射米力农已被广泛用于改善心力衰竭病人的心脏功能。磷酸二脂酶(PDE)是一组广泛存在于心血管系统,具有反应特异性和作用底物特异性的酶。PDE通过催化环核苷酸(例如环磷酸腺苷,cAMP)的水解而终止其作用。PDE抑制剂通过抑制PDE的功能而提高细胞内环核苷酸的浓度,以第二信使产生血流动力学效应。心肌中有几种PDE,包括一种钙调节蛋白激活型PDE,一种环磷酸鸟苷(cGMP)激动型PDE,一种cAMP抑制型PDE(即PDEIII)。米力农是一种PDEIII抑制剂,通过与PDEIII的特定部位结合而抑制此酶,促使心肌cAMP水解减慢,cAMP浓度提高,继而激活蛋白激酶,使更多钙通道开放,Ca2+进入心肌细胞内增多,产生正性变力作用。血管平滑肌的PDEIII受抑制后引起cAMP积聚,平滑肌细胞Ca2+外流增加,引起动静脉血管松弛扩张。
在临床使用的过程中,发现米力农注射液对肺动脉高压具有一定的疗效。近几年来有文献报道,使用米力农注射液对心脏移植患者手术过程中或手术后出现的肺动脉高压有一定的预防治疗作用。
吸入给药是近几年来发展起来的一中较为简单有效的给药途径.肺部具有巨大的吸收面积,肺上皮细胞极薄并具有良好的通透性,对于一些大分子也具有透过性,下呼吸道的的清除作用较缓慢,大分子在肺内较长的滞留时间可以增大其在肺泡中的吸收,不用促透剂,大分子药物就能够被吸收进入血流,通过吸入给药也能发挥全身作用.巨大的吸收面积、丰富的毛细血管和极小的跨粘膜距离,决定了肺部给药的吸收迅速,而且吸收后的药物直接进入血液循环,无肝脏首过效应.
呼吸道上皮细胞为类脂细胞。分子量小于1000的药物、脂溶性药物容易被吸收,而且本发明的药物为脂溶性药物,因此,通过肺部给药可达到吸收速度快、生物利用度高的目的。
发明内容
我们鲁南制药集团股份有限公司紧跟米力农临床应用的前沿,创造性地提出将我公司生产的米力农注射液改变给药途径做成肺部给药制剂,用于肺动脉高压的治疗。我们将米力农制备成肺部给药制剂以便于患者用药,并进行了初步的动物试验,取得了理想的效果。本发明通过药理实验证实,米力农通过肺部给药,在显著降低给药剂量的情况下(与灌胃给药相比较),对野百合碱或低氧引起的肺动脉高压有着极为显著的疗效,而且其降低肺动脉压力和预防右心肥厚的效果要显著优于灌胃给药组。米力农肺部给药制剂如气雾剂、喷雾剂、粉雾剂、微球制剂或脂质体制剂使用方便,直接到达肺部,具有十分明显的速效作用与定位作用。
我们根据米力农原料药的理化性质特点,将其制备成气雾剂、喷雾剂、粉雾剂、微球制剂或脂质体制剂,在气雾剂或喷雾剂的制备过程中,我们发现乙醇、聚乙二醇、异丙醇、丙二醇、甘油、油醇、乙酸乙酯、丙酮、维生素C、芳香油、尼泊金甲酯、尼泊金丙酯、聚山梨酯、月桂醇硫酸钠、卵磷脂或其衍生物、肉豆蔻异丙酯、矿物油、烷基苯氧基乙醇、脂肪酸山梨坦、三乙醇胺硬脂酸酯、三氯一氟甲烷、二氯二氟甲烷、二氯四氟乙烷、三氟一氟乙烷、七氟丙烷、一氯二氟乙烷、二氟乙烷、一氟二氟甲烷、异丁烷、丙烷、正丁烷或二甲醚等辅料具有较好的效果。在粉雾剂的制备过程中,我们发现乳糖、葡聚糖、甘露醇、木糖醇、阿拉伯胶、硬脂酸镁或胶体二氧化硅等辅料效果较好。在微球的制备过程中,我们发现明胶、阿拉伯胶、海藻酸盐、壳聚糖、蛋白类、淀粉、葡聚糖、羧甲基纤维素、纤维醋酸酯、乙基纤维素、甲基纤维素、羧丙甲纤维素、聚脂、聚合酸酐或水凝胶材料等辅料效果较好。在脂质体的制备过程中,我们发现豆磷脂、胆固醇、脑磷脂、胆固醇乙酰脂、β-谷固醇、牛胆酸钠、蛋磷脂酰胆碱、合成二棕榈-L-α-磷脂酰胆碱、合成磷脂酰丝氨酸、磷脂酰肌醇、神经鞘磷脂、鞘髓磷脂、二鲸蜡磷酸酯或二肉豆蔻酰卵磷脂等辅料效果较好。
具体实施方式
实施例1
米力农肺部给药制剂对野百合碱(MCT)诱发大鼠肺动脉高压的治疗作用
试验目的:利用测定大鼠右心室和肺动脉血压来考察米力农肺部给药制剂对野百合碱(MCT)诱发肺心病肺动脉高压的作用。
受试药物:硝苯地平,米力农。
组别设置:正常对照组、肺动脉高压模型组、硝苯地平组、米力农灌胃给药组,米力农肺部给药组。硝苯地平组灌胃给予硝苯地平20mg·kg-1·d-1。米力农灌胃给药组给予米力农10mg·kg-1·d-1,米力农肺部给药制剂分别设高、中、低剂量组,通过超声雾化方式给药,根据推算,高、中、低剂量组的米力农给药量大约依次为1000μg·kg-1·d-1、400μg·kg-1·d-1和160μg·kg-1·d-1。
操作步骤:
根据文献复制野百合碱所致的慢性肺动脉高压大鼠模型。选用体重180-220g的雄性SD大鼠70只,按体重随即分为正常对照组、肺动脉高压模型组、普通口服制剂组、米力农灌胃给药组和米力农肺部给药制剂组。除正常对照组外,其余各组大鼠每只均按60mg·kg-1·d-1皮下注射野百合碱一次,常规饲养大鼠,一周后即可得到慢性肺动脉高压大鼠。
正常对照组和肺动脉高压模型组连续灌胃给予生理盐水21d。普通制剂组灌胃给予硝苯地平,剂量为20mg·kg-1·d-1,连续给药21d。米力农灌胃给药组灌胃给予米力农,10mg·kg-1·d-1,连续给药21d。米力农肺部给药组用生理盐水分别配制成2.0mg·ml-1、0.8mg·ml-1、0.32mg·ml-1、的米力农溶液,每天雾化吸入5min,连续21d。
将大鼠用10%乌拉坦(1ml/100g体重)腹腔注射麻醉。仰卧固定在解剖台上进行气管插管术,将小动物呼吸机直接与气管相连,调整控制呼吸频率60次/min,吸入峰压0.9kPa,呼出末压0.25kPa,然后沿胸骨正中打开胸腔,用充满肝素化生理盐水的7号针头从右心室上角插入右心室和肺动脉,肉眼可以直接看到针头的位置。针头的另一端用导管与压力换能器相连并将压力变化记录在记录以上。用水银血压计对记录仪进行校正。
大鼠肺动脉压直接测定:用小动物人工呼吸机与大鼠气管,模拟生理条件下的呼吸通气量,然后打开胸腔,用充满肝素化的生理盐水的7号针头插入右心室和肺动脉,通过压力换能器与生理记录仪相连,直接观察和记录大鼠右心室压和肺动脉压力。
处死大鼠后,分离心脏以及右心室自由壁,称右心室自由壁(RV)重和左心室加室间隔(LV+S)重,计算右心肥厚指数(RV/LV+S)。
实验结果:
研究表明选用SD大鼠应用MCT造成肺动脉高压模型效果确切,米力农肺部给药制剂确有降低肺动脉高压大鼠的右心室压和肺动脉压的作用。米力农肺部给药显著地降低了肺动脉高压大鼠的RV/LV+S比值,提示该肺部给药具有有效地减轻MCT引起的大鼠右心室肥大的作用。阳性对照药硝苯地平也能有效地减小RV/LV+S比值,但其作用效果要明显低于米力农肺部给药。米力农肺部给药治疗MCT引起肺动脉高压也取得了意想不到的效果,且呈明显的剂量依赖性。具体实验结果见表1。
表1.米力农肺部给药制剂对野百合碱(MCT)诱发大鼠肺动脉高压的治疗作用
△与模型对照组相比P<0.05,△△与模型对照组相比P<0.01.
▲与硝苯地平相比P<0.05,▲▲与硝苯地平相比P<0.01.
★与米力农灌胃组相比P<0.05,★★与米力农灌胃组相比P<0.01.
实施例2
米力农肺部给药对大鼠低氧性肺动脉高压的治疗作用
试验目的:观察米力农肺部给药对低氧性肺动脉高压的治疗作用。
受试药物:米力农,硝苯地平。
组别设置:正常对照组、低氧性肺动脉高压模型组、阳性药对照组、米力农灌胃给药组、米力农肺部给药的高、中、低剂量组。阳性药对照组灌胃给予硝苯地平20mg·kg-1·d-1。米力农灌胃给药组灌胃给予米力农10mg·kg-1·d-1,米力农肺部给药的高、中、低剂量组,经过粗略推算,米力农给药量大约依次为1000μg·kg-1·d-1、400μg·kg-1·d-1和160μg·kg-1·d-1。
操作步骤:
1.缺氧性肺动脉高压大鼠模型的建立:
将健康SD大鼠70只,雌雄均有,体重150-200g,按体重随即分为正常对照组(A)、肺动脉高压模型组(B)、米力农肺部给药制剂溶剂组(C)、普通口服制剂组(D)、米力农灌胃给药组(E)和米力农肺部给药制剂组(F-H),每组10只。除正常对照组外,造模开始将大鼠置于常压缺氧舱内,用测氧仪动态监测,使舱内保持10%O2,90%N2,箱内的水蒸气分别用钠石灰、无水氯化钙吸收,每天缺氧8小时,每周6天,连续3周。各组大鼠均自由饮水和摄食,并分别于每周第1天和第4天缺氧后予温水擦洗尾部并常规消毒,经尾静脉缓慢注射0.6%FeCI3(0.2ml/100g),正常对照组同时经尾静脉注入等体积生理盐水。
同时C-H组大鼠每次缺氧前进行以下操作:C组大鼠每天超声雾化吸入米力农肺部给药制剂溶剂,每天5min。D组和E组分别灌胃给予硝苯地平(20mg·kg-1·d-1)和米力农(10mg·kg-1·d-1),连续7天。对F-H组大鼠每天超声雾化器给予相应制剂,米力农肺部给药制剂剂量分别为(相当于原料药)1000μg·kg-1·d-1、400μg·kg-1·d-1、160μg·kg-1·d-1。
2.制备大鼠肺动脉导管:
取长度约15cmPV21管,在其末端1cm处用火焰加热。待导管遇热开始软化时,使其末端在重力作用下逐渐弯曲,形成半径为3mm左右的圆滑弧型。该PV21导管末端的弧度应尽量与右室壁和肺动脉所形成的弧度相似。弧度过大或过小,插管均易在右心室内形成折返,而不易进入肺动脉。插管制备成后,在距离末端3~4cm处做标记,作为插管时判断导管位置之用。
3.肺动脉插管:
戊巴比妥钠45mg/kg麻醉大鼠。仰位固定于手术板上,正中切开颈部皮肤,钝性分离皮下组织及肌层,剥离颈动脉及右颈外静脉。将与压力换能器连接并充满肝素盐水的PE250管插入颈动脉。压力换能器通过载波放大器与多导生理记录仪相连。所记录压力代表系统循环血压。将上述制备的肺动脉插管内充满肝素盐水,插入右侧颈外静脉。插入过程中,保持PV21导管的弧向下方,并根据插管的标记判断到达心脏部位时,将插管左旋并向前推进。此时密切观察生理记录仪显示屏。当压力基线上升并出现肺动脉波形时,立即将PV21导管固定,并开始描记肺动脉高压。如果插管失败,可将导管回拉1cm左右,再次向前推进,直到出现肺动脉压波形。插管过程中,大鼠由于麻醉可出现分泌物阻塞气道现象,此时可进行气管插管,吸出分泌物。呼吸道通畅后,再行肺动脉插管。插管时,应注意观察主动脉压波形。若反复刺激会出现心率失常,应停止操作,当其恢复后,再继续进行。
4.右心肥厚指数的测量:
肺动脉压力检测完毕后,开胸取出心脏。将心脏分离为右心室自由壁(RV)和左心室加室间隔(LV+S),用滤纸吸除血液并分别称重,计算右心肥厚指数。
右心肥厚指数=RV/(LV+S)
5.实验结果
结果表明,选用SD大鼠应用常压低氧肺动脉高压模型造模成功。经方差分析,米力农肺部给药各个剂量组大鼠右心肥厚指数、右心室压以及肺动脉压与模型组相比较有显著性差异(P<0.01),米力农肺部给药治疗低氧引起肺动脉高压存在明显的剂量依赖性,而且肺部给药高剂量组的效果要显著优于硝苯地平组。具体的实验结果见表2。
表2 米力农肺部给药对大鼠低氧性肺动脉高压的治疗作用
△与模型对照组相比P<0.05,△△与模型对照组相比P<0.01.
▲与硝苯地平相比P<0.05,▲▲与硝苯地平相比P<0.01.
★与米力农灌胃组相比P<0.05,★★与米力农灌胃组相比P<0.01.
实施例3
米力农气雾剂
1.处方:
米力农 175-800g
月桂醇硫酸钠 20g
脂肪酸山梨坦80 35g
纯化水 1400ml
聚山梨酯80 30g
甘油 250ml
二氯二氟甲烷 适量
2.制备工艺:
将米力农与乳化剂等混合均匀,在搅拌条件下加水乳化,分装于耐压容器中,安装阀门系统后每瓶压入5.5g二氯二氟甲烷,即得。
实施例4
米力农喷雾剂
处方及制备工艺:米力农100-1000g、聚山梨酯80适量、水适量制成1000瓶将米力农用适当方法制成细粉,加入表面活性剂混合均匀,再加入到含防腐剂和增粘剂的水溶液中,分散均匀即得。
实施例5
米力农粉雾剂
处方及制备工艺:将米力农20g用适当方法制成极细的粉末,与20g乳糖充分混合均匀,分装到空心胶囊中,使每粒含米力农20mg,平均分装于耐压容器中,安装阀门系统后即得。
实施例6
米力农微球
处方及制备工艺:取含有3g卡波姆与乙基纤维素混合物的无水乙醇溶液50ml,混悬入0.5~2.0g米力农后,加入到含司盘8010g的400ml轻质液体石蜡中,室温条件下,600r·min-1搅拌蒸发16h。砂芯漏斗抽滤,收集微球,石油醚洗涤(50ml×3),室温真空干燥24h。根据不同需要,以50目不锈钢筛筛分得到米力农微球制剂,分装于耐压容器中,安装阀门系统后即得。
实施例7
米力农脂质体
处方及制备工艺:300-1000ml米力农(4mg/ml)液,300mg/ml卵磷脂乙醇液450g,二氯二氟甲烷混合成有机相,与4000ml 5%乙醇液的水相充分混合均匀,分装于耐压容器中,安装阀门系统后即得。
以上实施例所制备的米力农肺部给药制剂均经动物实验证明对肺动脉高压模型大鼠有理想的治疗效果.
Claims (5)
1.一种含有米力农用于治疗肺动脉高压的药物组合物,其特征在于,它是气雾剂、喷雾剂、粉雾剂、微球制剂或脂质体制剂。
2.如权利要求1所述的药物组合物,其特征在于,所述气雾剂或喷雾剂含有下列辅料中的一种或多种:乙醇、聚乙二醇、异丙醇、丙二醇、甘油、油醇、乙酸乙酯、丙酮、维生素C、芳香油、尼泊金甲酯、尼泊金丙酯、聚山梨酯、月桂醇硫酸钠、卵磷脂、肉豆蔻异丙酯、矿物油、烷基苯氧基乙醇、脂肪酸山梨坦、三乙醇胺硬脂酸酯、三氯一氟甲烷、二氯二氟甲烷、二氯四氟乙烷、三氟一氟乙烷、七氟丙烷、一氯二氟乙烷、二氟乙烷、一氟二氟甲烷、异丁烷、丙烷、正丁烷或二甲醚。
3.如权利要求1所述的药物组合物,其特征在于,所述粉雾剂含有下列辅料:乳糖、葡聚糖、甘露醇、木糖醇、阿拉伯胶、硬脂酸镁或胶体二氧化硅。
4.如权利要求1所述的药物组合物,其特征在于,所述微球制剂含有下列辅料:明胶、阿拉伯胶、海藻酸盐、壳聚糖、蛋白类、淀粉、葡聚糖、羧甲基纤维素盐、纤维醋法酯、乙基纤维素、甲基纤维素、羧丙甲纤维素、聚脂、聚合酸酐或水凝胶材料。
5.如权利要求1所述的药物组合物,其特征在于,所述脂质体制剂含有下列辅料:豆磷脂、胆固醇、脑磷脂、胆固醇乙酰脂、β-谷固醇、牛胆酸钠、蛋磷脂酰胆碱、合成二棕榈-L-α-磷脂酰胆碱、合成磷脂酰丝氨酸、磷脂酰肌醇、神经鞘磷脂、鞘髓磷脂、二鲸蜡磷酸酯或二肉豆蔻酰卵磷脂。
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