CN112315946A - 一种灯盏花素吸入剂及其制备方法 - Google Patents
一种灯盏花素吸入剂及其制备方法 Download PDFInfo
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Abstract
本发明涉及医药技术领域,具体涉及一种灯盏花素吸入剂及其制备方法,包括灯盏花素的纳米制剂和吸入装置;所述灯盏花素吸入剂的体外沉积率不小于30%。本发明提供的灯盏花素吸入剂,通过采用包括灯盏花素的纳米制剂与吸入装置的灯盏花素吸入剂,将灯盏花素吸入剂的体外沉积率提升至不小于30%,能够显著提升灯盏花素应用于肺部给药的疗效,降低给药剂量,相比于现有的常规剂型,明显提升抑制炎症反应的程度和抑制肺水肿的程度,有效减少肺部急性损伤、推迟或减弱呼吸窘迫的出现,缓解重型和危重型患者症状,有利于患者治愈,减少死亡。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种灯盏花素吸入剂及其制备方法。
背景技术
急性肺损伤(acute lung injury,ALI)/急性呼吸窘迫综合征(ARDS)是一种临床常见危重症,病死率极高,严重威胁重症患者的生命。据统计,有超过10%的ALI患者需进入重症监护病房治疗,病死率高达32%-55%,近年来还有逐步增高的趋势,明显增加了社会与经济负担,可与胸部肿瘤、AIDS、支气管哮喘或心肌梗死等相提并论。ALS/ARDS的基本病理生理改变是肺泡上皮细胞和肺毛细血管内皮通透性增加所致的非心源性肺水肿,由于肺泡水肿、肺泡塌陷导致严重通气/血流比例失调,特别是肺内分流明显增加,从而产生严重的低氧血症,导致急性低氧性呼吸功能不全或衰竭。临床上表现为进行性低氧血症和呼吸窘迫,肺部影像学表现为非均一性的渗出性病变。
多种危险因素可诱发ALI/ARDS,主要包括(1)直接肺损伤因素:严重肺部感染、胃内容物吸入、肺挫伤、吸入有毒气体、淹溺、氧中毒等;(2)间接肺损伤因素:严重感染、严重非胸部创伤、急性重症胰腺炎、大量输血、体外循环、弥漫性血管内凝血等,参见《急性肺损伤/急性呼吸窘迫综合征诊断与治疗指南(2006)》。
严重病毒感染会引起急性肺损伤或者急性呼吸窘迫综合征,例如2019新型冠状病毒(COVID-19病毒)感染,新型冠状病毒感染主要累及肺,患者的肺脏有不同程度的实变,主要引起深部气道和肺泡损伤为特征的炎性反应,伴随大量黏稠的分泌物从肺泡内溢出,引起肺水肿和细胞凋亡,加速肺损伤,临床表现为呼吸困难、胸闷、气短,出现急性肺损伤、呼吸窘迫等严重症状,影像学检查会发现肺部有磨玻璃一样的肺间质的改变。
目前仍缺乏有效的治疗急性肺损伤的药物和方法。
肺部给药系统是指药物经特殊给药系统直接进入呼吸道发挥局部或全身治疗作用的给药系统,目前肺部给药系统有气雾剂、喷雾剂、粉雾剂或干粉吸入剂。
灯盏花素(Breviscapine)是灯盏花的主要活性成分,具有改善心脑血循环、增加脑血流量、降低血管阻力和抗血小板凝集等作用,也有研究表明其具有一定的抗肺间质纤维化作用。临床上主要用于心脑血管疾病,如闭塞性脑血管所致后遗症、瘫痪、冠心病、心绞痛等,对于急性肺损伤也有一定的疗效。但是因其难溶于水,口服吸收差,生物利用度低,所以大大限制了其临床应用。
目前,国内外上市的灯盏花素制剂主要有片剂和胶囊剂,生物利用度低,为此,张永昕等在《灯盏花素固体脂质纳米粒的制备》一文中公开了灯盏花素固体脂质体及其的制备方法,并通过处方和工艺优化,显著提高了灯盏花素的包封率和生物利用度,然而当将其应用于肺部给药时,仍然存在给药量大、疗效差的问题,无法代替现有的药物使用。
发明内容
因此,本发明要解决的技术问题在于克服现有技术中的灯盏花素用于急性肺损伤时存在给药量大、疗效差的缺陷,从而提供一种灯盏花素吸入剂及其制备方法。
一种灯盏花素吸入剂,包括含有灯盏花素的纳米制剂和吸入装置。所述灯盏花素吸入剂的体外沉积率不小于30%。
可选地,所述灯盏花素吸入剂的体外沉积率不小于50%,优选地,所述灯盏花素吸入剂的体外沉积率为65%-80%,更优选地,所述灯盏花素吸入剂的体外沉积率为72%-77%。
可选地,所述含有灯盏花素纳米制剂为灯盏花素固体脂质纳米粒、灯盏花素纳米脂质体、灯盏花素纳米乳中的任一种或者上述任一种与助悬剂、水混合形成的灯盏花素混悬液。
可选地,所述灯盏花素吸入剂选自粉雾剂、气雾剂或雾化吸入剂中的任一种。
可选地,当灯盏花素为粉雾剂或者雾化吸入剂时,所述灯盏花素吸入剂还包括载体;
当所述灯盏花素吸入剂为粉雾剂时,所述载体选自葡萄糖、乳糖、蔗糖、海藻糖、甘露醇、山梨醇和木糖醇中的至少一种;
当所述灯盏花素吸入剂为雾化吸入剂时,所述载体为乙醇与含枸橼酸的水溶液形成的混合液或者吐温80与含枸橼酸的水溶液形成的混合液,优选地,所述载体为乙醇与含枸橼酸的水溶液形成的混合液,更优选地,所述载体中,乙醇、枸橼酸和水的体积比为(30-50):(2-6):(44-68)。
可选地,当所述灯盏花素吸入剂为粉雾剂时,所述纳米制剂与载体的质量比为100:(5-15);
当所述灯盏花素吸入剂为雾化吸入剂时,所述纳米制剂与载体的质量比为(1.0-4.0):100。
可选地,所述灯盏花素固体脂质纳米粒包括如下重量份的原料,灯盏花素0.5-2份、磷脂3-10份、稳定剂8-20份、乳化剂0.2-2份、水溶液20-84份;
和/或,所述灯盏花素纳米脂质体包括如下重量份的原料,灯盏花素0.5-2.5份、磷脂8-30份、稳定剂0.3-2份、乳化剂0.2-2份、水溶液17-78.5份;
和/或,所述灯盏花素纳米乳包括如下重量份的原料,灯盏花素0.1-1份、油脂5-15份、乳化剂20-30份、助乳化剂2-8份、水溶液50-72.9份;
和/或,所述灯盏花素混悬液包括如下重量份的原料,包括如下重量份的原料,灯盏花素固体脂质纳米粒或灯盏花素纳米脂质体或灯盏花素纳米乳0.1-0.5份、助悬剂0.01-0.05份、水溶液50-100份。
可选地,所述磷脂选自大豆卵磷脂、蛋黄卵磷脂、二硬脂酰磷脂酰胆碱、二棕榈酰磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱中的至少一种;
所述稳定剂选自单硬脂酸甘油酯、三硬脂酸甘油酯、胆固醇、二鲸蜡磷酸酯、豆甾醇、谷甾醇、神经酰胺、油酸、油酸钠、单油酸甘油酯、辛酸甘油酯、癸酸甘油酯、辛癸酸甘油酯和中的至少一种;
所述乳化剂选自泊洛沙姆、吐温80、胆酸、胆酸钠、脱氧胆酸钠、脂肪酸山梨坦80、聚乙二醇1000维生素E琥珀酸酯、聚氧乙烯氢化蓖麻油、丙二醇和无水乙醇中的至少一种。
可选地,所述水溶液为水、生理盐水、葡萄糖水溶液、磷酸盐缓冲液中的至少一种。
可选地,所述助悬剂选自微晶纤维素、卡波姆、黄原胶、壳聚糖和羧甲基纤维素钠中的至少一种;优选地,所述助悬剂包括卡波姆和黄原胶,所述卡波姆与黄原胶的质量比为1:5-5:1。
可选地,所述灯盏花素混悬液还包括1-2重量份的增溶剂或5-15重量份的防腐剂。
可选地,所述增溶剂为乙醇或者甘油,所述防腐剂为对羟基苯甲酸乙酯或者对羟基苯甲酸甲酯;
和/或,所述助悬剂包括卡波姆和黄原胶,所述卡波姆与黄原胶的质量比为1:5-5:1。
可选地,所述油脂为丙二醇单辛酸酯、辛酸癸酸聚乙二醇甘油酯、聚氧乙烯蓖麻油、油酸乙酯中的至少一种;
所述助乳化剂为无水乙醇、丙二醇和聚乙二醇中的至少一种。
优选地,按照重量份数计,所述灯盏花素固体脂质纳米粒包括,灯盏花素0.5份、大豆卵磷脂3.6份、三硬脂酸甘油酯8.5份、泊洛沙姆0.4份、水20份。
优选地,按照重量份数计,所述灯盏花素纳米脂质体包括,灯盏花素0.5份、蛋黄卵磷脂8份、胆固醇0.35份、聚乙二醇1000维生素E琥珀酸酯0.3份、磷酸盐缓冲液17.2份。
优选地,按照重量份数计,所述灯盏花素纳米乳包括,灯盏花素1份、油酸乙酯10份、聚氧乙烯氢化蓖麻油20份、无水乙醇3.16份,水65份。
优选地,按照重量份数计,所述纳米混悬液包括,灯盏花素纳米冻干脂质体0.5份、卡波姆0.02份、黄原胶0.02份、对羟基苯甲酸乙酯10份、无水乙醇1.58份、水100份。
本发明还提供了一种灯盏花素吸入剂的制备方法,包括如下步骤:
将含有灯盏花素的纳米制剂装入吸入装置中,制得所述灯盏花素吸入剂。
可选地,可将灯盏花素吸入剂的纳米制剂与药学上可接受的辅料或载体混合制备所述灯盏花素吸入剂。
本发明所述的灯盏花素吸入剂的纳米制剂可与药学上可接受的辅料或载体混合分别制成粉雾剂、气雾剂或雾化吸入剂;或者是直接制得粉雾剂、气雾剂或雾化吸入剂。
本发明还提供了一种灯盏花素固体脂质纳米粒的制备方法,包括如下步骤:
将灯盏花素、磷脂和稳定剂混合,加热,得到油相;将乳化剂与水溶液混合,加热,得到水相,将油相加入水相中,搅拌,探头超声,即得。
可选地,所述探头超声的功率为400-600W,时间为5-10min。
本发明还提供了一种灯盏花素纳米脂质体的制备方法,包括如下步骤:
将灯盏花素、磷脂、稳定剂和乳化剂,加入有机溶剂溶解,得到油相;将油相加入水溶液中,得到混悬液,去除有机溶剂,即得。
可选地,所述有机溶剂选自乙醇、乙醚中的任一种。
可选地,可将纳米脂质体冻干后再加入分散剂得到纳米脂质体的混悬液。
优选地,所述分散剂为油酸乙酯;冻干前加入冻干保护剂。所述冻干保护剂可以但不局限于采用含5wt%甘氨酸、5wt%甘露醇的水溶液。
本发明还提供了一种灯盏花素纳米乳的制备方法,包括如下步骤:取油脂、乳化剂、助乳化剂混合,加入灯盏花素得到油相;取油相在搅拌下加入水,即得。
本发明还提供了一种灯盏花素混悬液吸入剂的制备方法,包括如下步骤:将助悬剂与水混合,得到含助悬剂的水溶液;将灯盏花素纳米脂质体或灯盏花素纳米乳或灯盏花素固体脂质纳米粒加入含助悬剂的水溶液中,分散均匀,即得。
可选地,所述灯盏花素混悬液吸入剂的制备方法,包括如下步骤:将防腐剂溶于增溶剂中,加入水混合,加入卡波姆,使其充分溶胀,加入黄原胶继续搅拌使其完全溶解,即得含助悬剂的水溶液;向含助悬剂的水溶液中加入灯盏花素纳米冻干脂质体搅拌,过滤膜,即得。
本发明中的吸入装置可以采用本领域常规装置,例如雾化器、干粉吸入装置、气雾瓶等,其中,气雾瓶为含有抛射剂的耐压容器,例如玻璃容器或者金属容器等。
本发明技术方案,具有如下优点:
1.本发明提供的灯盏花素吸入剂,通过采用包括灯盏花素的纳米制剂与吸入装置的灯盏花素吸入剂,将灯盏花素吸入剂的体外沉积率提升至不小于30%,能够显著提升灯盏花素应用于肺部给药的疗效,降低给药剂量,相比于现有的常规剂型,明显提升抑制炎症反应的程度和抑制肺水肿的程度,有效减少肺部急性损伤、推迟或减弱呼吸窘迫的出现,缓解重型和危重型患者症状,有利于患者治愈,减少死亡。
2.本发明提供的灯盏花素吸入剂,所述灯盏花素吸入剂的体外沉积率不小于50%,优选地,所述灯盏花素吸入剂的体外沉积率为65%-80%,通过进一步提升灯盏花素吸入剂的体外沉积率,可以进一步提升灯盏花素吸入剂的疗效。
3.本发明提供的灯盏花素吸入剂,采用灯盏花素固体脂质纳米粒、灯盏花素纳米脂质体、灯盏花素纳米乳中的任一种或者上述任一种与助悬剂、水混合形成的灯盏花素混悬液作为含灯盏花素的纳米制剂,能够显著提升灯盏花素吸入剂的体外沉积率,提高对急性肺损伤的疗效。
4.本发明提供的灯盏花素吸入剂,当灯盏花素吸入剂为粉雾剂时,通过采用选自葡萄糖、乳糖、蔗糖、海藻糖、甘露醇、山梨醇和木糖醇中的至少一种为载体加入粉雾剂中,能够显著提升灯盏花素吸入剂的体外沉积率,尤其是采用乳糖时,体外沉积率提升至72.1%,从而显著地提升灯盏花素应用于肺部给药的疗效,降低给药剂量。
5.本发明提供的灯盏花素吸入剂,当灯盏花素吸入剂为雾化吸入剂时,采用特定的载体,即乙醇与含枸橼酸的水溶液形成的混合液或者吐温80与含枸橼酸的水溶液形成的混合液,能够显著提升灯盏花素肺部给药系统的体外沉积率至48.4%-73.6%,提高对急性肺损伤的疗效;优选地,所述载体为乙醇与含枸橼酸的水溶液形成的混合液,更优选地,所述载体中,乙醇、枸橼酸和水的体积比为(30-50):(2-6):(44-68);能够更加显著地提升灯盏花素肺部给药系统的体外沉积率,从而更加显著地提升灯盏花素应用于肺部给药的疗效,降低给药剂量。
6.本发明提供的灯盏花素吸入剂,对于灯盏花素固体脂质纳米粒、灯盏花素纳米脂质体、灯盏花素纳米乳以及灯盏花素混悬液,采用特定的原料组成与配比能够显著提升灯盏花素吸入剂的体外沉积率,显著地提升灯盏花素应用于肺部给药的疗效,降低给药剂量。
7.本发明提供的灯盏花素吸入剂,对于灯盏花素固体脂质纳米粒,通过控制探头超声时间为5-10min,或者控制泊洛沙姆的用量为1wt%-2wt%,能够更加显著提升灯盏花素吸入剂的体外沉积率,从而更加显著地提升灯盏花素应用于肺部给药的疗效,降低给药剂量。
8.本发明提供的灯盏花素吸入剂,对于灯盏花素纳米脂质体,通过采用冻干工艺得到固体脂质体,能够更加显著提升灯盏花素吸入剂的体外沉积率,体外沉积率提升至77%,从而显著地提升灯盏花素应用于肺部给药的疗效,降低给药剂量。
9.本发明提供的灯盏花素吸入剂,对于灯盏花素混悬液通过采用特定的助悬剂,即选自微晶纤维素、卡波姆、黄原胶、壳聚糖和羧甲基纤维素钠中的至少一种;能够更加显著提升灯盏花素吸入剂的体外沉积率,优选地,所述助悬剂包括卡波姆和黄原胶,所述卡波姆与黄原胶的质量比为1:5-5:1,将体外沉积率提升至66.3%左右,从而更加显著地提升灯盏花素应用于肺部给药的疗效,降低给药剂量。
10.本发明提供的灯盏花素吸入剂的制备方法,包括如下步骤:将含有灯盏花素的纳米制剂转入吸入装置中,制得所述灯盏花素吸入剂。首先制备得到含有灯盏花素的纳米制剂来保证其生物利用度,然后制得所述吸入剂,通过该方法制得的灯盏花素吸入剂具有较高的体外沉积率,可提高对急性肺损伤的疗效。
11.本发明提供的灯盏花素吸入剂的制备方法,通过将含有灯盏花素的纳米制剂与合适的载体混合,然后制备所述灯盏花素吸入剂。可保证制得的灯盏花素吸入剂在肺部沉积(1-3μm可到达肺泡),显著提升灯盏花素吸入剂的体外沉积率,然后再缓慢释放出药物,提高对急性肺损伤的疗效。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案,下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施方式,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1是本发明实施例1制得的灯盏花素吸入剂的扫描电镜图;
图2是本发明实施例5制得的灯盏花素吸入剂的扫描电镜图;
图3是本发明实施例7制得的灯盏花素吸入剂的扫描电镜图。
具体实施方式
提供下述实施例是为了更好地进一步理解本发明,并不局限于所述最佳实施方式,不对本发明的内容和保护范围构成限制,任何人在本发明的启示下或是将本发明与其他现有技术的特征进行组合而得出的任何与本发明相同或相近似的产品,均落在本发明的保护范围之内。
实施例中未注明具体实验步骤或条件者,按照本领域内的文献所描述的常规实验步骤的操作或条件即可进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规试剂产品。
本发明所述的灯盏花素纳米制剂(灯盏花素固体脂质纳米粒、灯盏花素纳米脂质体、灯盏花素纳米乳和灯盏花素混悬液)的制备方法并不局限于实施例中提供的方法,现有的灯盏花素纳米制剂的制备方法均可。
本发明实施例中采用的灯盏花素(原料药)的纯度≥98%(HPLC)。
各实施例中灯盏花素含量测定采用如下方法:
将被测样品(实施例7的灯盏花素纳米乳,实施例9的灯盏花素纳米脂质体的混悬液)分别冻干,将冻干后的样品以及实施例5的灯盏花素纳米冻干脂质体、实施例1中所述药物粉末分别用纯水配置成样品浓度0.5g/mL的水溶液;备用;
分别取1ml上述水溶液置于超滤离心管(Millipore,截留分子量10kDa)中4000rpm离心30min,滤液用HPLC检测,即得灯盏花素的游离量M1(mg);
分别取1ml上述水溶液,然后分别加入10倍量甲醇和二氯甲烷的混合溶剂(10:1,v/v)混合均匀,并涡旋萃取5min,涡旋萃取后的上层液用0.45μm滤膜过滤后用HPLC检测,即得灯盏花素的总量M2(mg);
上述被测样品中灯盏花素的含量(mg/g)=(M2-M1)mg/0.5g;
HPLC条件:
仪器Agilent1200VWD,色谱柱ZORBAX-C18柱(4.6x 250mm,5μm),流动相为甲醇-0.1%磷酸(体积比35:65)等度洗脱,流速为1.00ml/min,柱温35℃,检测波长335nm。
实施例1粉雾剂
本实施例提供了一种灯盏花素粉雾型吸入剂,包括含灯盏花素的纳米制剂和吸入装置,本实施例的含灯盏花素的纳米制剂为灯盏花素固体脂质纳米粒,配方如下表1所示:
表1灯盏花素固体脂质纳米粒的配方
组分 | 灯盏花素 | 稳定剂 | 磷脂 | 乳化剂 | 水溶液 |
名称 | 灯盏花素 | 三硬脂酸甘油酯 | 大豆卵磷脂 | 泊洛沙姆188 | 水 |
质量 | 0.4g | 8.5g | 3.6g | 0.4g | 20g |
本实施例还提供了上述灯盏花素粉雾型吸入剂的制备方法,包括如下步骤:
灯盏花素固体脂质纳米粒的制备:
按上表质量称取各原料备用,然后将灯盏花素、磷脂和稳定剂混合,然后加热至80℃,300rpm搅拌均匀得油相;
乳化剂与20g水溶液混合并加热至80℃,得水相;
将油相平分为5份,然后分5次加入水相,并保持80℃不变,溶液呈透明状,油相加入完毕后,在800rpm搅拌1h,400W下探头超声6min,即得所述灯盏花素固体脂质纳米粒。采用马尔文激光粒度仪测定所述灯盏花素固体脂质纳米粒的平均粒径为131nm、电位为-7.95mV;
灯盏花素粉雾型吸入剂的制备:
将2g乳糖与18g水溶液(水)混合并降温至0℃,得载体水溶液;然后在800rpm搅拌状态下将上述灯盏花素固体脂质纳米粒加入上述的载体水溶液中,所得混合溶液带有蓝色乳光;将其进行喷雾干燥得到药物粉末(经检测,灯盏花素含量17.18mg/g),将药物粉末装入干粉吸入装置(本实施例中采用美国杜拉Spiros)中,即得所述灯盏花素粉雾型吸入剂。图1是本实施例制得的灯盏花素吸入剂的扫描电镜图,由图1可知,本实施例制得的灯盏花素粉雾型吸入剂具有纳米粒径;
其中喷雾干燥过程中,进口温度为120℃,干燥风速0.7m3/min,雾化压力190KPa,供液速度4mL/min;干燥时间为20min。
实施例2粉雾剂
本实施例提供了一种灯盏花素粉雾型吸入剂,与实施例1的区别仅在于本实施例灯盏花素粉雾型吸入剂的配方中载体乳糖的量为0(没有添加载体),且在灯盏花素粉雾型吸入剂的制备方法中,将乳化剂与40g水溶液(水)混合,直接将所述灯盏花素固体脂质纳米粒进行喷雾干燥,其余均与实施例1相同。
实施例3粉雾剂
本实施例提供了一种灯盏花素粉雾型吸入剂,与实施例1的区别仅在于灯盏花素粉雾型吸入剂的制备方法中探头超声的时间,本实施例探头超声的时间为15min,其余原料组成和制备方法均与实施例1相同。
实施例4粉雾剂
本实施例提供了一种灯盏花素粉雾型吸入剂,与实施例1的区别仅在于灯盏花素粉雾型吸入剂的配方中泊洛沙姆188的质量不同,本实施例中泊洛沙姆188的质量为0.2g,其余原料组成和制备方法均与实施例1相同。
实施例5气雾剂
本实施例提供了一种灯盏花素气雾型吸入剂,包括含灯盏花素的纳米制剂和吸入装置,本实施例的含灯盏花素的纳米制剂为灯盏花素纳米脂质体,配方如下表2所示:
表2灯盏花素纳米脂质体的配方
组分 | 灯盏花素 | 稳定剂 | 磷脂 | 乳化剂 | 辅料 | 水溶液 |
名称 | 灯盏花素 | 胆固醇 | EPC | TPGS | 甘露醇 | pH6.5的磷酸盐缓冲液 |
质量 | 0.6g | 0.35g | 8g | 0.3g | 2% | 17.2g |
注:TPGS即为聚乙二醇1000维生素E琥珀酸脂,EPC为蛋黄卵磷脂,2%指的是辅料的质量为水溶液质量的2wt%。
本实施例还提供了上述灯盏花素气雾型吸入剂的制备方法,包括如下步骤:
灯盏花素纳米脂质体的制备:
按上表质量称取各原料,然后将灯盏花素、磷脂、稳定剂和乳化剂加入25mL无水乙醇中,超声使其完全溶解,得油相;
将甘露醇与pH6.5的磷酸盐缓冲液混合,得含2wt%甘露醇的磷酸盐缓冲液,为水相;其中pH6.5的磷酸盐缓冲液是按中国药典2015版中pH6.5的磷酸盐缓冲液的制备方法制得的(取磷酸二氢钾0.136g,加0.1mol/L氢氧化钠溶液3ml(约12mg),溶解后用水稀释至20ml,制得pH6.5的磷酸盐缓冲液的质量约为17.2g);
搅拌状态下,以1mL/min的速度将油相加入上述21g水相中,加入完毕后,继续搅拌30min混合均匀,然后在40℃水浴中去除有机溶剂,即得所述灯盏花素纳米脂质体。采用马尔文激光粒度仪测定其平均粒径为101nm,电位为-7.75mV。
灯盏花素纳米冻干脂质体的制备:
向上述的灯盏花素纳米脂质体中加入冻干保护剂(占灯盏花素纳米脂质体5wt%甘氨酸和占灯盏花素纳米脂质体5wt%甘露醇),-80℃预冻2h后成为固体,然后在-40℃冻干2h,-20℃冻干3h,0℃冻干3h;之后10℃过夜,即得。总冻干时间为24h。
灯盏花素气雾型吸入剂的制备:
称取上述灯盏花素纳米冻干脂质体100mg(经检测,灯盏花素含量37mg/g),加入0.5g分散剂(本实施例采用油酸乙酯)混合均匀,然后转移至气雾瓶(本实施例中采用德国百瑞Pari Chamber储雾罐)中,加上定量阀盖,封口,瓶内压入25g抛射剂(本实施例采用四氟乙烷),混匀,室温水浴超声分散1min,即得。图2是本实施例制得的灯盏花素吸入剂的扫描电镜图,由图2可知,本实施例制得的灯盏花素气雾型吸入剂具有纳米粒径。
实施例6气雾剂
本实施例提供了灯盏花素气雾型吸入剂,与实施例5的区别在于没有灯盏花素纳米冻干脂质体的制备步骤、且没有添加分散剂,而直接采用灯盏花素纳米脂质体制备灯盏花素气雾型吸入剂,具体地,
本实施例的灯盏花素肺部给药系统的制备方法,包括如下步骤:取灯盏花素纳米脂质体300mg,转至玻璃气雾瓶中,加上定量阀盖,封口,瓶内压入25g载体(抛射剂),混匀,室温水浴超声分散1min,即得。
实施例7雾化吸入剂
本实施例提供了一种灯盏花素雾化吸入剂,包括含灯盏花素的纳米制剂和吸入装置,本实施例的含灯盏花素的纳米制剂为灯盏花素纳米乳,配方如下表3所示:
表3灯盏花素纳米乳的配方
本实施例还提供了上述灯盏花素雾化吸入剂的制备方法,包括如下步骤:
灯盏花素纳米乳的制备:
取油脂、乳化剂、助乳化剂混合,室温下搅拌均匀,加入灯盏花素继续搅拌至完全溶解,得油相;
在搅拌状态下,向上述的油相中缓慢加入水,即得。采用马尔文激光粒度仪测定其平均粒径为142nm,电位为15.31mV。
灯盏花素雾化吸入剂的制备:
雾化液(载体)的制备:将100mL水和4mL枸橼酸混合后,加入40mL乙醇,混匀,即得。
灯盏花素雾化吸入剂的制备:
取上述灯盏花素纳米乳1g(经检测,灯盏花素含量10.75mg/g)与10g雾化液混合均匀,然后装入医用雾化器(本实施例中采用欧姆龙网式雾化器)中,即得灯盏花素雾化吸入剂(灯盏花素水雾剂)。图3是本实施例制得的灯盏花素吸入剂的扫描电镜图,由图3可知,本实施例制得的灯盏花素雾化吸入剂具有纳米粒径。
实施例8雾化吸入剂
本实施例提供了一种灯盏花素雾化吸入剂,与实施例7的区别仅在于雾化液的组成不同,而灯盏花素纳米乳的配方、雾化液与灯盏花素纳米乳的质量及灯盏花素雾化吸入剂的制备方法均与实施例7相同。其中,本实施例采用的雾化液的组成包括吐温80、水和枸橼酸,其制备方法为,取100mL水与4mL枸橼酸混合后,加入15g吐温80混合均匀,即得。
实施例9雾化吸入剂
本实施例提供了一种灯盏花素雾化吸入剂,包括含灯盏花素的纳米制剂和吸入装置,本实施例的含灯盏花素的纳米制剂为灯盏花素纳米脂质体的混悬液,配方如下表4所示:
表4灯盏花素纳米脂质体的混悬液的配方
本实施例还提供了上述灯盏花素雾化吸入剂的制备方法,包括如下步骤:
灯盏花素纳米脂质体的混悬液的制备:
取防腐剂溶解于增溶剂中,加入水,搅拌下混合均匀,加入卡波姆,使其充分溶胀,加入黄原胶继续搅拌使其完全溶解,即得含助悬剂的水溶液;
向含助悬剂的水溶液中加入实施例5制备的灯盏花素纳米冻干脂质体过夜搅拌至完全溶解,过0.22μm滤膜,即得灯盏花素纳米脂质体的混悬液。
灯盏花素雾化吸入剂的制备:
将上述的灯盏花素纳米脂质体的混悬液(经检测,灯盏花素含量3.09mg/g)注入雾化吸入器(本实施例采用勃林格殷格翰公司生产的Respimat吸入器)中,即得所述灯盏花素雾化吸入剂。
实施例10雾化吸入剂
本实施例提供了一种灯盏花素雾化吸入剂,与实施例9的区别仅在于黄原胶的质量为0,在制备含助悬剂的水溶液时未加入黄原胶,其他原料组成和制备方法均相同。
实施例11雾化吸入剂
本实施例提供了一种灯盏花素雾化吸入剂,与实施例9的区别仅在于将黄原胶替换为0.02g壳聚糖,在制备制备含助悬剂的水溶液时加入壳聚糖,其他原料组成和制备方法均相同。
实施例12雾化吸入剂
本实施例提供了一种灯盏花素雾化吸入剂,与实施例9的区别仅在于将黄原胶替换为0.02g羧甲基纤维素钠,在制备制备含助悬剂的水溶液时加入羧甲基纤维素钠,其他原料组成和制备方法均相同。
实验例1
将上述各实施例制得的灯盏花素雾化吸入剂,分别按照《中国药典》2020版的规定(通则0951),采用双级玻璃碰撞器(TSI)测定其体外沉积率(微细粒子剂量),每个吸入剂平行测定三次,取平均值,结果如下表5所示。
表5平均体外沉积率结果表
结果见上表所示,实施例1-4制得的粉雾剂相比,实施例1的体外沉积率明显提升;实施例5-6制得的气雾剂相比,实施例5的体外沉积率明显提升;实施例7-8制得的雾化吸入剂相比,实施例7的体外沉积率明显提升,实施例9-12制得的雾化吸入剂相比,实施例9的体外沉积率最高,实施例11次之,实施例12更次之,实施例10最差。
实验例2
1、受试药物、试剂和仪器
受试药物:按照上述实施例1、5、7和9中的方法分别制备得到灯盏花素吸入剂;灯盏花素片剂购自云南植物药业有限公司公司,规格20mg/片。
脂多糖(LPS),含量>97%,规格500mg,购自sigma公司;醋酸地塞米松片,规格0.74mg×100片,购自广东华南药业集团有限公司;Mouse IL-1βELISA试剂盒和Mouse IL-6ELISA试剂盒购自碧云天生物技术有限公司,Mouse TNF-αELISA试剂盒购自Biovision公司,Mouse Myeloperoxidase(MPO)ELISA试剂盒购自艾恩斯生物科技有限公司。主要仪器包括气体麻醉机,离心机,电子天平,BIO-RAD酶标仪等,均为市购。
2、药物溶液的配制:
灯盏花素片剂药物溶液:采用质量百分数为0.5%的CMC-Na(羧甲基纤维素钠)的水溶液将灯盏花素片(研磨后)配制成浓度为0.1mg/mL的灯盏花素溶液,备用。
LPS溶液:称取LPS,采用生理盐水配制成LPS浓度为0.5mg/mL的LPS溶液。
地塞米松溶液:采用质量百分数为0.5%的CMC-Na的水溶液将醋酸地塞米松片(研磨后)配制成浓度为0.1mg/mL的地塞米松溶液,备用。
各组受试药物溶液:按照实施例1的方法制备灯盏花素固体脂质纳米粒并按照实施例1的方法进行喷雾干燥得到的药物粉末,取药物粉末加入生理盐水中制得浓度为5mg/mL(以灯盏花素计)的受试药物溶液1;按照实施例5的方法制备,在注入吸收装置前经与分散剂混合均匀的液体药物,取液体药物加入生理盐水中制得浓度为5mg/mL(以灯盏花素计)的受试药物溶液2;按照实施例7的方法制备得到灯盏花素纳米乳并按照实施例7的方法加入雾化液混合均匀,得到受试药物3;按照实施例9的方法制备得到的灯盏花素纳米脂质体的混悬液,即为受试药物溶液4。
3、动物分组、造模及给药
ICR小鼠,SPF级,6-8周龄,雄性80只,体重18-22g。小鼠采用异氟烷诱导麻醉后绑定于斜面操作台上,随机分为空白对照小鼠和模型组,模型组用小鼠气管内雾化装置进行气管内喷雾给予浓度为0.5mg/mL的LPS溶液造成小鼠急性肺损伤,以LPS质量计,每kg小鼠体重的给药量为5mg的LPS;空白对照小鼠(10只)用相同方法喷雾给予生理盐水5mg/kg动物体重。
将模型组小鼠随机分组,每组10只,分别为模型对照组、地塞米松阳性药组、灯盏花素片剂组和试验组1-4;另外10只空白小鼠作为空白对照组。造模当日为第一日,造模后动物称重开始给药,每天1次,连续3天,其中空白对照组和模型对照组灌胃给予生理盐水5mg/kg动物体重;阳性药组灌胃给予浓度为0.1mg/mL的地塞米松溶液,以地塞米松的质量计,每kg小鼠体重给予地塞米松的质量均为5mg;灯盏花素片剂组灌胃给予浓度为0.1mg/mL的灯盏花素溶液,以灯盏花素的质量计,每kg小鼠体重给予灯盏花素的质量为5mg;试验组1-4分别给予上述制得的受试药物溶液1-4;每kg小鼠体重给予灯盏花素的质量为5mg(分3-4次缓慢注入)。
试验组1给予受试药物溶液1,试验组2给予受试药物溶液2,试验组3给予得到受试药物3,试验组4给予受试药物溶液4,均从气管内注入。
4、实验内容
造模72小时后,将动物安乐死,采集小鼠外周血,分离血清,零下80度冻存;采集双侧肺脏,称重(湿重);用1mL注射器吸取0.5mL生理盐水从肺静脉灌洗肺脏(反复抽吸3次),收集双肺肺泡灌洗液,分离上清液,零下80度冻存;灌洗后肺脏用滤纸吸干,称重(干重)。
取各组处理后小鼠的血清分别采用Mouse IL-1βELISA试剂盒、Mouse IL-6ELISA试剂盒、Mouse TNF-αELISA试剂盒和MPO ELISA试剂盒结合酶标仪,参照各个试剂盒说明书记载的步骤,分别测定血清中炎性因子IL-1β、IL-6、TNF-α、MPO的含量。
取各组处理后小鼠的灌洗上清液分别采用Mouse IL-1βELISA试剂盒、Mouse IL-6ELISA试剂盒和Mouse TNF-αELISA试剂盒结合酶标仪,参照各个试剂盒说明书记载的步骤,分别测定血清中炎性因子IL-1β、IL-6、TNF-α的含量。
5、数据统计和分析
采用Excel对数据进行录入和统计分析。
6、实验结果
表6肺脏湿重/干重比(n=10,平均值±SD)
注:**表示与模型对照组相比,P<0.01(t-test检验);***表示与模型对照组相比,P<0.001(t-test检验)
表7肺泡灌洗液上清液中炎性因子(n=10,平均值±SD)
组别编号 | TNF-α | IL-6 | IL-1β |
空白对照组 | 97.3±9.0 | 49.4±3.7 | 113.5±20.3 |
模型对照组 | 1495.0±247.0 | 1269.6±202.6 | 1075.9±145.0 |
灯盏花素片剂药物溶液 | 1062.1±137.8** | 933.2±104.2** | 791.2±160.1** |
试验组1 | 762.3±152.1*** | 673.6±134.5*** | 586.5±142.1*** |
试验组2 | 675.1±143.2*** | 622.5±186.0*** | 529.3±187.8*** |
试验组3 | 559.5±130.7*** | 544.0±182.5*** | 471.9±142.2*** |
试验组4 | 839.2±229.8*** | 661.7±102.1*** | 652.7±203.3*** |
阳性药组 | 827.8±139.7*** | 728.1±85.7*** | 636.1±114.8*** |
注:**表示与模型对照组相比,P<0.01(t-test检验);***表示与模型对照组相比,P<0.001(t-test检验)
表8血清中炎性因子(n=10,平均值±SD)
组别编号 | TNF-α | IL-6 | IL-1β | MPO |
空白对照组 | 1.4±0.3 | 0.7±0.1 | 19.1±2.3 | 0.7±0.1 |
模型对照组 | 13.8±2.4 | 2.5±0.6 | 207.1±40.3 | 6.7±1.2 |
灯盏花素片剂药物溶液 | 8.1±0.8** | 1.5±0.3** | 121.3±17.9** | 4.0±1.0** |
试验组1 | 4.6±0.8*** | 0.8±0.2*** | 62.3±18.4*** | 2.4±0.8*** |
试验组2 | 4.3±0.9*** | 0.7±0.3*** | 52.2±15.1*** | 1.9±0.7*** |
试验组3 | 3.8±0.5*** | 0.6±0.3*** | 41±19.1*** | 1.6±0.4*** |
试验组4 | 6.4±1.4*** | 1.3±0.3*** | 93.9±24.6*** | 3.1±1.3*** |
阳性药组 | 5.1±0.6*** | 1±0.3*** | 75.7±10.7*** | 2.8±0.5*** |
注:**表示与模型对照组相比,P<0.01(t-test检验);***表示与模型对照组相比,P<0.001(t-test检验)
由表6-8可知:造模后,相比于空白对照组,模型对照组小鼠中血清和灌洗上清液各炎性因子均有显著升高,肺脏湿重与干重之比显著升高,表明造模成功;各试验组给药3天后与模型对照组相比,各化合物组能显著降低促炎细胞因子(IL-1β、IL-6、TNF-α、MPO)的产生(与模型对照组相比P<0.01或P<0.001),显著降低肺脏湿重与干重之比(与模型对照组相比P<0.01或P<0.001),具有统计学意义。
7、实验结论
本发明提供的灯盏花素纳米吸入剂能够明显抑制炎症反应,抑制炎性因子的释放,降低肺泡灌洗液和血清中的炎性因子含量,同时还能够明显抑制肺水肿,减少肺积液的产生,降低肺脏湿重,抑制急性肺损伤导致的肺脏湿重与干重比的升高程度,从而起到在抗炎的同时抑制肺部水肿的作用,且具有质量低、疗效显著的优点,可以作为潜在的预防或者治疗急性肺损伤的药物。
显然,上述实施例仅仅是为清楚地说明所作的举例,而并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (10)
1.一种灯盏花素吸入剂,其特征在于,包括含有灯盏花素的纳米制剂和吸入装置;所述灯盏花素吸入剂的体外沉积率不小于30%。
2.根据权利要求1所述的灯盏花素吸入剂,其特征在于,所述灯盏花素吸入剂的体外沉积率不小于50%,优选地,所述灯盏花素吸入剂的体外沉积率为65%-80%,更优选地,所述灯盏花素吸入剂的体外沉积率为72%-77%。
3.根据权利要求1或2所述的灯盏花素吸入剂,其特征在于,所述含有灯盏花素的纳米制剂为灯盏花素固体脂质纳米粒、灯盏花素纳米脂质体、灯盏花素纳米乳中的任一种或者上述任一种与助悬剂、水混合形成的灯盏花素混悬液。
4.根据权利要求1-3任一项所述的灯盏花素吸入剂,其特征在于,所述灯盏花素吸入剂选自粉雾剂、气雾剂或雾化吸入剂中的任一种。
5.根据权利要求4所述的灯盏花素吸入剂,其特征在于,当灯盏花素为粉雾剂或者雾化吸入剂时,所述灯盏花素吸入剂还包括载体;
当所述灯盏花素吸入剂为粉雾剂时,所述载体选自葡萄糖、乳糖、蔗糖、海藻糖、甘露醇、山梨醇和木糖醇中的至少一种;
当所述灯盏花素吸入剂为雾化吸入剂时,所述载体为乙醇与含枸橼酸的水溶液形成的混合液或者吐温80与含枸橼酸的水溶液形成的混合液,优选地,所述载体为乙醇与含枸橼酸的水溶液形成的混合液,更优选地,所述载体中,乙醇、枸橼酸和水的体积比为30-50:2-6:44-68。
6.根据权利要求3所述的灯盏花素吸入剂,其特征在于,所述灯盏花素固体脂质纳米粒包括如下重量份的原料,灯盏花素0.5-2份、磷脂3-10份、稳定剂8-20份、乳化剂0.2-2份、水溶液20-84份;
和/或,所述灯盏花素纳米脂质体包括如下重量份的原料,灯盏花素0.5-2.5份、磷脂8-30份、稳定剂0.3-2份、乳化剂0.2-2份、水溶液17-78.5份;
和/或,所述灯盏花素纳米乳包括如下重量份的原料,灯盏花素0.1-1份、油脂5-15份、乳化剂20-30份、助乳化剂2-8份、水溶液50-72.9份;
和/或,所述灯盏花素混悬液包括如下重量份的原料,包括如下重量份的原料,灯盏花素固体脂质纳米粒或灯盏花素纳米脂质体或灯盏花素纳米乳0.1-0.5份、助悬剂0.01-0.05份、水溶液50-100份。
7.根据权利要求6所述的灯盏花素吸入剂,其特征在于,所述助悬剂选自微晶纤维素、卡波姆、黄原胶、壳聚糖和羧甲基纤维素钠中的至少一种;优选地,所述助悬剂包括卡波姆和黄原胶,所述卡波姆与黄原胶的质量比为1:5-5:1。
8.根据权利要求6或7所述的灯盏花素吸入剂,其特征在于,所述灯盏花素混悬液还包括1-2重量份的增溶剂或5-15重量份的防腐剂。
9.根据权利要求5所述的灯盏花素吸入剂,其特征在于,
当所述灯盏花素吸入剂为粉雾剂时,所述纳米制剂与载体的质量比为100:5-15;
当所述灯盏花素吸入剂为雾化吸入剂时,所述纳米制剂与载体的质量比为(1.0-4.0):100。
10.一种灯盏花素吸入剂的制备方法,其特征在于,包括如下步骤:
将含有灯盏花素的纳米制剂装入吸入装置中,制得灯盏花素吸入剂。
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CN1876004A (zh) * | 2005-06-10 | 2006-12-13 | 浙江中医学院 | 一种治疗脑血管病的药物 |
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