CN116350586B - 一种尼莫地平胶束注射液及其制备方法 - Google Patents
一种尼莫地平胶束注射液及其制备方法 Download PDFInfo
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- CN116350586B CN116350586B CN202310439077.8A CN202310439077A CN116350586B CN 116350586 B CN116350586 B CN 116350586B CN 202310439077 A CN202310439077 A CN 202310439077A CN 116350586 B CN116350586 B CN 116350586B
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- nimodipine
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Abstract
本发明属于医药领域,提供了一种尼莫地平胶束注射液及其制备方法,具体是一种用于静脉滴注的高浓度尼莫地平胶束注射液,其由活性成分尼莫地平与辅料磷脂、胆酸或其盐、表面修饰材料、等渗调节剂、pH调节剂和注射用水组成。该注射剂不仅极大提高了尼莫地平的溶解度,而且选用生理相容性辅料磷脂与胆酸、安全性好的胶束体系增溶,采用创新的薄膜分散‑水化工艺,处方中摒弃乙醇作增溶剂,从而显著提高用药的安全性。该注射剂可直接用注射液稀释,配伍溶液24h稳定性良好,不需要输液泵特殊设备和次级护理,提高用药安全性和依从性。
Description
技术领域
本发明属于医药领域,提供了一种尼莫地平胶束注射液及其制备方法。
背景技术
尼莫地平为光学异构体的混合物,其化学名称为2,6-二甲基-4-(3-硝基苯基)-1,4-二氢-3,5-吡啶二甲酸-2-甲氧乙基-(1-甲乙基)酯,其分子式:C21H26N2O7,分子量418.4,结构式如下:
尼莫地平是一种吡啶二羧酸二甲酯,是一种精细结晶的黄色物质,熔点为125~126℃,溶于乙醇、氯仿、乙酸乙酯和聚乙二醇,但不溶于水。尼莫地平在中性和酸性介质中稳定,对碱敏感。它具有热稳定性和非吸湿性,但对光敏感度适中,尤其是在溶液中;尼莫地平1%(w/v)溶液的pH值为6~6.8。
尼莫地平为第二代1,4-二氢吡啶类钙拮抗剂,具有高度亲脂性,容易穿透血脑屏障。动物试验中,尼莫地平可与L-型Ca2+通道高亲和力和高特异性结合,进而抑制Ca2+跨膜内流。据推断尼莫地平可改善因神经细胞Ca2+离子内流增加而引发的病理状态的稳定性和机能能力,如脑缺血。因其易渗透血脑屏障,具有选择性扩张脑血管、显著逆转基底动脉和脊髓前动脉痉挛的作用,临床上用于治疗高血压、中风、偏头痛、蛛网膜下腔出血及其它脑出血疾病,是目前脑血管病治疗的首选药物,特别对老年性痴呆具有较高的临床应用价值。尼莫地平为治疗缺血性脑损伤一线治疗药物。
原研药注射液由德国拜尔公司研制,于1985年4月上市,规格为50ml:10mg。尼莫地平已有多个产品进入2018版国家基药目录(片剂、胶囊:20mg、30mg)、2021版国家医保目录(甲类:口服常释剂型,乙类:注射剂)。目前尼莫地平在国内获批生产的剂型有普通片剂、胶囊剂、注射剂及口服溶液等。尽管尼莫地平具有良好的生物学效应,但其临床性能受到其低口服生物利用度(低至10%)和低水溶性(3.86μg/mL)的限制。因此,静脉给药是尼莫地平疗效的替代途径。为了达到足够的尼莫地平浓度,上市制剂通过用约40%的溶剂混合物溶解尼莫地平,即由23.7%(v/v)乙醇和17%(v/v)聚乙二醇400组成溶剂混合物。然而这种浓度在临床上应用时有许多明显的缺点:大量乙醇对酗酒或酒精代谢受损的人以及孕妇或哺乳期妇女有害。此外高浓度的乙醇可能会在注射部位引起疼痛和刺激。由于尼莫地平必须以1~2mg/h的速度慢速滴注,否则病人无法耐受其副作用,即10mg药物所需滴注时间一般需要至少5h,使用时需与配伍溶液(0.9%氯化钠注射液、5%葡萄糖注射液等)混合滴注或用特殊的三通输液器与注射液同时滴注,混合液直接输入病人体内;静脉注射最长连续输注长达三周。同时尼莫地平在乙醇溶解,在水中不溶解,尼莫地平输液为含乙醇的非水溶性制剂,当与其他输液配伍后,均可析出结晶,含量下降,降低药物疗效,也给病人带来一定程度的危险。
专利文献CN20181146629公开了一种尼莫地平注射液组合物及其制备方法,处方中采用了高比例的大豆油、中链脂肪油或大豆油和中链脂肪油混合物。因此,商业化生产时对乳化水平和技术工艺相应标准提高。另外,大豆油等不饱和脂肪酸中不饱和双键化学性质不稳定,杂质降解影响用药安全。因而,要求产品中过氧化值、甲氧基苯胺值及游离脂肪酸等指标的质量标准控制相应更严格。
专利文献CN1732936A公开了尼莫地平乳注射液及制备方法,在制备过程中加入了适量的苯甲醇从而提高了尼莫地平在乳剂中的溶解度及制剂的稳定性,使尼莫地平乳剂的浓度相对较高。苯甲醇具有消毒防腐、局部麻醉作用,在注射剂中用于抑菌剂、止痛剂,且具有溶血作用。儿童用于肌内注射的注射液含有苯甲醇时可引起臀肌挛缩症。《中国药典》2020年版附录注射剂项下对静脉注射剂添加抑菌剂有严格限定。
专利文献CN112137956A公开了一种尼莫地平缓释乳注射液的制备方法,处方中使用吐温80。目前含吐温80的药物静脉注射剂的临床不良反应多,可引起溶血反应、急性超敏反应、外周神经毒性、抑制P-糖蛋白活性、内在抗肿瘤效应、肝毒性等。因此,要慎用含吐温80的静脉注射剂。
专利文献CN101485632A公开了尼莫地平脂质微球注射液及其制备方法,但是脂质微球制剂,工艺复杂,成本高,长期存储脂质微球的包裹容易破坏产生泄露,带来临床风险,且粒径较大,静脉注射风险高。
专利文献CN105796490B公开了一种含氨基酸的尼莫地平注射液组合物及其制备方法,采用了乙醇和聚乙二醇增溶制备注射剂。
专利文献CN114886850A公开了尼莫地平制剂及治疗病症的方法,处方中使用表面活性剂聚山梨酯80和有机溶剂乙醇增溶剂。
上述两篇现有技术均存在如下缺点:大量乙醇对酗酒或酒精代谢受损的人以及孕妇或哺乳期妇女有害。此外高浓度的乙醇可能会在注射部位引起疼痛和刺激。
专利文献CN101088503A公开了尼莫地平冻干粉针剂及其制备方法,配方中使用吐温80、聚乙二醇400、丙二醇和乙醇等。丙二醇临床不良反应临床报道多,限制了其在临床上的应用。
专利文献CN102525917B一种尼莫地平胶束注射剂及其制备方法,配方中采用了活性炭,且热压灭菌后含量显著降低,不符合中国药典及进口注册标准。活性炭作为注射剂中常用吸附剂,起到了相应的吸附热原作用。但是,活性炭原材料与生产工艺的多样性、活化机理的不确定性、质量控制的局限性,以及由此而导致引入杂质和不溶性微粒的可能性,都会给活性炭在注射剂中的应用带来风险。因活性炭原材料来源和生产工艺多样,导致其可能含有不同的元素杂质;部分元素杂质具有毒性,包括神经毒性和肾毒性等。注射剂控制热原方式多种多样,进口注射剂品种基本不再使用活性炭。因此,最大化减少活性炭在注射剂生产中引入的风险是必然趋势。
专利CN114796110A公开了一种不含乙醇的难溶性药物浓缩液以及由其制备的胶束溶液,针对难溶性药物尼莫地平,处方中采用蛋黄卵磷脂、15-羟基硬脂酸聚乙二醇酯、丙二醇,其中15-羟基硬脂酸聚乙二醇酯的重量百分比高达46%、丙二醇重量百分比高达51%。15-羟基硬脂酸聚乙二醇酯为人工合成辅料,用量大,安全性低;高浓度的丙二醇注射可引发疼痛和刺激,浓度更高可致人体溶血。处方中摒弃乙醇但仍然使用有机溶剂,且有机溶剂本身具有毒副作用,其在注射剂中的使用更加严格。
因此能否提供一种更为安全,且尼莫地平浓度较高的注射液,成为本领域亟待解决的技术问题。
发明内容
针对上述技术存在的不足,本发明的发明人提供了一种用于静脉滴注的高浓度尼莫地平胶束注射液及其制备方法,其由活性成分尼莫地平与辅料磷脂、胆酸或其盐、表面修饰材料、等渗调节剂、pH调节剂和注射用水组成。该注射剂不仅极大提高了尼莫地平的溶解度,而且选用生理相容性辅料磷脂与胆酸、安全性好的胶束体系增溶,采用创新的薄膜分散-水化工艺,处方中摒弃乙醇作增溶剂,从而显著提高用药的安全性。该注射剂可直接用注射液稀释,配伍溶液24h稳定性良好,不需要输液泵特殊设备和次级护理,提高用药安全性和依从性。
本发明的主要发明构思在于提供了一种针对尼莫地平而言更为理想的载体,基于尼莫地平的生理相容性和溶解能力,磷脂酰胆碱(PC)-胆盐(BS)混合胶束(MM)制剂是静脉内施用难溶性药物的有吸引力的候选者,这种将水溶性表面活性剂与水不溶性磷脂结合的简单方法可得到各向同性清澈的溶液。高浓度胆汁中存在的胆盐可以在很大程度上溶解磷脂酰胆碱,形成一种透明的混合胶束溶液,进而可以溶解水溶性差的物质。通过溶解的磷脂,可以中和磷脂酰胆碱的溶血作用,最重要的是,磷脂酰胆碱(PC)-胆盐(BS)混合胶束(MM)制剂已被证明在局部和全身耐受性良好,给药后没有胚胎毒性,不存在致畸或致突变作用。在没有毒理学溶剂混合物的情况下,磷脂酰胆碱(PC)-胆盐(BS)混合胶束(MM)制剂可以减少刺激并提高患者的依从性。因此,磷脂酰胆碱(PC)-胆盐(BS)混合胶束(MM)制剂是静脉内施用尼莫地平的理想药物载体。综合上述思路,本申请最终基于磷脂-胆盐混合胶束体系,摒弃有机溶剂增溶方案,开发磷脂、胆盐和表面修饰材料的创新组方设计,构建新型的纳米胶束增溶体系,实现对尼莫地平的有效增溶,突破尼莫地平注射液改良的“卡脖子”技术难题。
具体的,本申请的技术方案如下:
一种尼莫地平胶束注射液,包含活性成分尼莫地平,磷脂,胆酸或其盐,表面修饰材料,等渗调节剂,pH调节剂和注射用水;各组分的比例如下:
注射液中活性成分尼莫地平浓度为0.1mg/ml~4mg/ml,进一步优选为0.5mg/ml~2.5mg/ml;除此之外,尼莫地平与磷脂的重量比为0.5~20:100,胆酸或其盐与磷脂的重量比为0.1~10:1,表面修饰材料与尼莫地平的重量比为0~10:1,等渗调节剂和磷脂的重量比为0.1~5:1;pH调节剂的用量根据最终注射液的pH确定;
上述尼莫地平胶束注射液的体积规格为1ml~10ml,优选地为5ml,且被包含在安瓿瓶中。
优选的,所述磷脂包含但不限于大豆磷脂、蛋黄磷脂、氢化大豆磷脂(HSPC)、氢化蛋黄磷脂(HEPC),二棕榈酰磷脂酰胆碱(DPPC)、二棕榈酰磷脂酰乙醇胺(DPPE)、二硬脂酰磷脂酰胆碱(DSPC)、二月桂酰磷脂酰胆碱(DLPC)、二油酰磷脂酰乙醇胺(DOPE)、二硬脂酰磷脂酰乙醇胺(DSPE)、二油酰磷脂酰胆碱(DOPC)中的一种;其中优选大豆磷脂。
优选的所述胆酸为甘氨胆酸、脱氧胆酸、甘氨鹅脱氧胆酸,牛磺胆酸及牛磺鹅脱氧胆酸或其盐的一种或几种的混合物;其中优选甘氨胆酸或甘氨胆酸钠。
优选的所述表面修饰材料为15-羟基硬脂酸聚乙二醇酯、聚氧乙烯聚氧丙烯共聚物、聚氧乙烯脱水山梨醇脂肪酸酯类、聚氧乙烯蓖麻油衍生物、聚乙二醇维生素E琥珀酸酯、聚乙二醇-二硬脂酰磷脂酰胆碱中的任意一种或多种按照任意比例组成;其中优选为15-羟基硬脂酸聚乙二醇酯(HS 15或/>HS 15)、聚氧乙烯聚氧丙烯共聚物(泊洛沙姆188)、聚氧乙烯脱水山梨醇脂肪酸酯类(聚山梨酯80)。
优选的所述等渗调节剂为蔗糖、海藻糖、葡萄糖、乳糖、果糖、甘露醇、葡聚糖、山梨醇、右旋糖酐、甘氨酸、羟乙基淀粉、聚乙烯吡咯烷酮、聚乙烯酮等中的任意一种或多种按照任意比例组合物;其中优选蔗糖。
优选的所述生理药效学上可接受的pH调节剂中的酸选自冰醋酸、甲酸、三氟乙酸、磷酸、枸橼酸、酒石酸、草酸、苹果酸、丙氨酸、盐酸、亮氨酸、异亮氨酸、苹果酸、缬氨酸、色氨酸、马来酸、富马酸、乳酸、苯丙氨酸、甲硫氨酸和琥珀酸中的任意一种或多种按照任意比例组成,其中优选为枸橼酸;pH调节剂中的碱为氢氧化钠、碳酸酸钠、碳酸氢钠、氢氧化钾、氢氧化胆碱、精氨酸、赖氨酸、组氨酸、二乙胺、三乙胺、葡甲胺、枸橼酸钠、酒石酸钠、乳酸钠、磷酸钠、磷酸氢二钠中的任意一种或多种按照任意比例组合物,其中优选为氢氧化钠。
除此之外,发明人还提供了上述尼莫地平胶束注射液的制备方法,制备方法为薄膜分散法,其具体过程如下:
步骤(1):称取组方中尼莫地平、磷脂、胆酸或其盐、表面修饰材料,溶于适量有机溶剂中;
步骤(2):将步骤(1)所得的溶液转移至旋转蒸发仪,水浴温度30~70℃,开启真空除去有机溶剂,得疏松薄膜;
步骤(3):称取组方中等渗调节剂,稀释于注射用水;若步骤(1)辅料为胆酸,则加入与胆酸摩尔比为1:1的pH调节剂中的碱,充保护气体,得稳定剂溶液;将其完全转移至步骤(2)所得疏松薄膜中,搅拌使其水化完全,pH调节剂调节溶液pH,热处理,放冷即得尼莫地平胶束溶液;
步骤(4):将步骤(3)所得溶液用注射用水定容,充保护气体,除菌过滤,分装至安瓿瓶熔封,热压灭菌,即得尼莫地平胶束注射液。
在某些优选的实施方案中,本发明部分涉及尼莫地平胶束注射液中,胆酸或其盐与磷脂的比例为0.5~2:1;表面修饰材料与尼莫地平重量比0~10:1,并且作为优选的实施方式之一,优选地为0.1:1。
上述薄膜分散法有机溶剂为甲醇、乙醇、乙酸乙酯、异丙醇中的任意一种或多种按照任意比例组合物,有机溶剂用量为所制备注射液体积的2%~8%,所述的保护气体为氮气、氦气、二氧化碳和氩气中的任意一种。
优选的所述的有机溶剂为甲醇和乙醇混合溶剂,甲醇和乙醇的优选比例为4:1。
步骤(3)中所述的热处理为90~100℃,时间为20~30min;步骤(3)和(4)所述的保护气体为氮气,通入保护气体的时间为0.5~2小时,其中步骤(4)需控制溶解氧残留范围5~10ppm。
步骤(4)中获得的纳米胶束注射液规格为0.1mg/ml~4mg/ml,进一步优选为0.5mg/ml~2.5mg/ml。
上述步骤(4)最终获得的胶束注射液的pH值为5.0~8.5,优选的pH值为5.5~7.5;所述胶束注射液的Z-Average为2~10nm;所述胶束注射液的Zeta电位为-20mV~-50mV;所述胶束注射液的透光率大于90%。
具体应用时,可与本发明所提供的尼莫地平胶束注射液的配伍稀释注射液包括但不限于0.9%氯化钠注射液、5%葡萄糖、乳酸钠林格氏液、含镁乳酸钠林格氏液、右旋糖酐40溶液、6%的聚氧-2-羟乙基淀粉、5%人血白蛋白或血液,并且作为优选的实施方式之一,优选0.9%氯化钠注射液或5%葡萄糖。将其稀释至浓度为0.02mg/ml~0.04mg/ml时,仍然为澄清透明溶液且未见尼莫地平的析出结晶。
本发明上述提供的尼莫地平胶束注射液可作为治疗诸如但不限于各种原因的蛛网膜下腔出血后脑血管痉挛和急性脑血管病恢复期的血液循环改善、与高压氧治疗一起治疗弥漫性脑损伤、协助颅神经损伤后的恢复、治疗频繁偏头痛及偏头痛预防、外周性眩晕和梅尼埃病、减少全身麻醉下老年患者术后谵妄的发生、耐药性癫痫、性高潮头痛和与沐浴有关的头痛。
与现有技术相比,本发明具有以下有益效果:
(1)本发明制备的尼莫地平胶束注射液,可选择性添加含聚乙二醇链的辅料作胶束表面修饰材料,具体可以是15-羟基硬脂酸聚乙二醇酯(SolutolHS 15或KolliphorHS15)、聚氧乙烯聚氧丙烯共聚物(泊洛沙姆188)、聚氧乙烯脱水山梨醇脂肪酸酯类(聚山梨酯80)或聚乙二醇2000-二硬脂酸磷脂酰乙醇胺(PEG2000-DSPE),聚氧乙烯蓖麻油(CremophorELP或Kolliphor ELP),聚乙二醇维生素E琥珀酸酯(TPGS 1000);当选择添加时其用量少,重量百分比可低至整个体系的0.02%,构建新型的纳米胶束增溶体系,可显著提高混合胶束的物理和化学稳定性,提高载药量,并大大提高尼莫地平的水溶性和稳定性,经过低温循环试验、冻融试验和配伍稳定性实验,均无晶体析出。显著提高在0.9%氯化钠注射液等电解质溶液的稳定性,从而可以采用电解质注射液做输液,方便临床应用。
(2)本发明制备的尼莫地平胶束注射液,尼莫地平注射浓缩制剂针剂浓度高达4mg/ml,解决尼莫地平注射液溶解度差的卡脖子问题,且相对于市售注射剂0.2mg/ml,具有更高的临床价值。
(3)本发明制备的尼莫地平胶束注射液,制备过程中增加热处理步骤,显著提高了注射液的物理和化学稳定性,过滤后药液于25℃放置48h,外观、含量、有关物质、粒径等均无显著变化,为下一步灌装、熔封等步骤提供了充足的时间,有利于放大生产。
(4)本发明制备的尼莫地平胶束注射液,可耐受热压灭菌,灭菌前后注射液性状、pH、粒径、含量、有关物质等指标均无显著变化,符合2020年版药典要求,极大提高无菌保障性。
(5)本发明制备的尼莫地平胶束注射液,处方中摒弃乙醇增溶剂,不含有机溶剂,降低了过敏性、酒精中毒或酒精代谢受损、疼痛和炎症等,显著提高临床用药安全性
(6)本发明所述的制备工艺易于放大,且采用创新的薄膜分散-水化工艺,显著降低了无水乙醇等有机溶剂的用量,工艺中摒弃活性炭的使用,从而有利于放大生产。而现有技术中的胶束专利采用无水乙醇或丙二醇,安全性低,使用量大,增大了放大生产难度;脂肪乳、脂质体等其他复杂注射剂型,处方工艺复杂,不利于工艺放大,质量控制难度大,稳定性差。
附图说明
图1显示了实施例1采用薄膜分散法制备的尼莫地平混合胶束注射液外观形态图。
图2显示了实施例5采用薄膜分散法制备的尼莫地平胶束注射液有关物质测定高效液相色谱图。
图3、图4显示了实施例7采用薄膜分散法制备的尼莫地平胶束注射液粒径分布图。
图5显示了实验例8中实施例7采用薄膜分散法制备的尼莫地平胶束注射液配伍稳定性考察(0.9%氯化钠注射液)时所测含量变化曲线(0.02mg/ml和0.04mg/ml)。
图6显示了实验例8中实施例7采用薄膜分散法制备的尼莫地平胶束注射液配伍稳定性考察(5%葡萄糖注射液)时所测含量变化曲线(0.02mg/ml和0.04mg/ml)。
图7为实验例8中原研注射液(尼膜同,Nimotop)的配伍稳定性考察(0.9%氯化钠注射液)时所测含量变化曲线(0.02mg/ml和0.04mg/ml)。
图8为实验例8中原研注射液(尼膜同,Nimotop)的配伍稳定性考察(5%葡萄糖注射液)时所测含量变化曲线(0.02mg/ml和0.04mg/ml)。
具体实施方式
以下通过实施例形式的具体实施方式,对本发明的上述内容做进一步的详细说明,但不应将此理解为本发明上述主题的范围仅限于以下的实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围,除特殊说明外,下述实施例中均采用常规现有技术完成。
实施例1尼莫地平胶束注射液的制备
每支含尼莫地平10mg,25支尼莫地平胶束注射液的组成为:
制备工艺:
(1)按照所述处方量称取尼莫地平、大豆卵磷脂、甘氨胆酸溶于甲醇、乙醇中,搅拌分散均匀,得澄明液体;
(2)将步骤(1)中所得澄明溶液用旋转蒸发仪旋蒸去除甲醇、乙醇,形成薄膜;
(3)按上述处方称取蔗糖、氢氧化钠、枸橼酸、枸橼酸钠,溶解于100ml注射用水中,得澄明溶液,充保护气氮气,加至上述薄膜中水化完全得澄明液体,油浴100℃热处理30min,放冷至室温,0.1mol/L氢氧化钠溶液调节pH值至6.5,注射用水定容至125ml,得到尼莫地平混合胶束溶液;
(4)除菌过滤,分装至安瓿瓶,熔封,121℃、15min热压灭菌,即得尼莫地平混合胶束注射液。
如图1所示同批次注射液澄清透明、淡黄绿色。混合胶束溶液Z-Average为2.577nm,PDI为0.239,Zeta电位为-30.0mV。
实施例2
每支含尼莫地平10mg,25支尼莫地平胶束注射液的组成为:
制备工艺:
步骤(1)(2)同实施例1。
(3)按上述处方称取蔗糖、氢氧化钠,溶解于100ml注射用水中,得澄明溶液,充保护气氮气,加至上述薄膜中,水化完全得澄明液体,0.1mol/L氢氧化钠溶液调节pH值至6.5,注射用水定容至125ml,得到尼莫地平混合胶束溶液;
(4)除菌过滤,分装至安瓿瓶,熔封,121℃、12min热压灭菌,即得尼莫地平混合胶束注射液。
该注射液澄清透明、淡黄绿色。混合胶束溶液Z-Average为5.105nm,PDI为0.350,Zeta电位为-43.9mV。
实施例3
每支含尼莫地平10mg,20支尼莫地平胶束注射液的组成为:
制备工艺:
步骤(1)(2)同实施例1。
(3)按上述处方称取蔗糖溶解于80ml注射用水中,得澄明溶液,充保护气氮气,加至上述薄膜中,水化完全得澄明液体,油浴80℃热处理30min,放冷至室温。0.1mol/L氢氧化钠溶液调节pH值至6.0,注射用水定容至100ml,得到尼莫地平混合胶束溶液。
(4)除菌过滤,分装至安瓿瓶,熔封,121℃、12min热压灭菌,得尼莫地平混合胶束注射液。
该注射液澄清透明、淡黄绿色。混合胶束溶液Z-Average为2.639nm,PDI为0.301,Zeta电位为-30.5mV。
实施例4
每支含尼莫地平10mg,20支尼莫地平胶束注射液的组成为:
制备工艺:
步骤(1)(2)同实施例1。
(3)按上述处方称取蔗糖、氢氧化钠溶解于80ml注射用水中,得澄明溶液,充保护气氮气,加至上述薄膜中,水化完全后,油浴100℃热处理60min,放冷至室温。0.1mol/L枸橼酸溶液调节pH值至6.0,注射用水定容至100ml,得到尼莫地平混合胶束溶液。
(4)除菌过滤,分装至安瓿瓶,熔封,121℃、12min热压灭菌,得尼莫地平混合胶束注射液。
该注射液澄清透明、淡黄绿色。混合胶束溶液Z-Average为5.698nm,PDI为0.310,Zeta电位为-29.7mV。
实施例5
每支含尼莫地平10mg,20支尼莫地平胶束注射液的组成为:
制备工艺:
(1)按照所述配比称取尼莫地平、大豆卵磷脂、甘氨胆酸、泊洛沙姆188溶于甲醇、乙醇中,搅拌分散均匀,得澄明液体;
(2)将步骤(1)中所得澄明溶液用旋转蒸发仪旋蒸去除甲醇、乙醇,形成薄膜;
(3)按上述处方称取蔗糖、氢氧化钠、枸橼酸溶解于80ml注射用水中,加至上述薄膜中,水化完全后得澄明溶液,油浴100℃热处理30min,放冷至室温。0.1mol/L枸橼酸溶液调节pH值至6.5,注射用水定容至100ml,得到尼莫地平混合胶束溶液。
(4)除菌过滤,分装至安瓿瓶,熔封,121℃、12min热压灭菌,得尼莫地平混合胶束注射液。
该注射液澄清透明、淡黄绿色。如图3、图4所示,混合胶束溶液Z-Average为2.734nm,PDI为0.255,Zeta电位为-28.8mV。
实施例6
每支含尼莫地平10mg,20支尼莫地平胶束注射液的组成为:
制备工艺:
(1)按照所述配比称取尼莫地平、大豆卵磷脂、甘氨胆酸、SolutolHS 15溶于甲醇、乙醇中,搅拌分散均匀,得澄明液体;
(2)将步骤(1)中所得澄明溶液用旋转蒸发仪旋蒸去除甲醇、乙醇,形成薄膜;
(3)按上述处方称取蔗糖、氢氧化钠、枸橼酸、枸橼酸钠溶解于80ml注射用水中,得澄明溶液,充保护气氮气10min,加至上述薄膜中,水化完全后,0.1mol/L氢氧化钠溶液调节pH值至6.5,注射用水定容至100ml,得到尼莫地平混合胶束溶液。
(4)除菌过滤,分装至安瓿瓶,熔封,121℃、15min热压灭菌,得尼莫地平混合胶束注射液。
该注射液澄清透明、淡黄绿色。混合胶束溶液Z-Average为9.860nm,PDI为0.357,Zeta电位为-26.9mV。
实施例7
每支含尼莫地平10mg,20支尼莫地平胶束注射液的组成为:
制备工艺:
(1)按照所述配比称取尼莫地平、大豆卵磷脂、甘氨胆酸、SolutolHS 15溶于甲醇、乙醇中,搅拌分散均匀,得澄明液体;
(2)将步骤(1)中所得澄明溶液用旋转蒸发仪旋蒸去除甲醇、乙醇,形成薄膜;
(3)按上述处方称取蔗糖、氢氧化钠、枸橼酸溶解于80ml注射用水中,得澄明溶液,充保护气氮气30min,加至上述薄膜中,水化完全后,油浴100℃热处理30min,放冷至室温。0.1mol/L氢氧化钠溶液调节pH值至6.5,注射用水定容至100ml,得到尼莫地平混合胶束溶液。
(4)除菌过滤,分装至安瓿瓶,熔封,121℃、15min热压灭菌,得尼莫地平混合胶束注射液。
该注射液澄清透明、淡黄绿色。混合胶束溶液Z-Average为2.834nm,PDI为0.201,Zeta电位为-34.7mV。
实施例8
每支含尼莫地平10mg,20支尼莫地平胶束注射液的组成为:
制备工艺:
(1)按照所述配比称取尼莫地平、大豆卵磷脂、甘氨胆酸、SolutolHS 15溶于甲醇、乙醇中,搅拌分散均匀,得澄明液体;
(2)将步骤(1)中所得澄明溶液用旋转蒸发仪旋蒸去除甲醇、乙醇,形成薄膜;
(3)按上述处方称取蔗糖、氢氧化钠、枸橼酸溶解于80ml注射用水中,得澄明溶液,充保护气氮气60min,加至上述薄膜中,水化完全后,油浴100℃热处理30min,放冷至室温。0.1mol/L枸橼酸溶液调节pH值至6.5,注射用水定容至100ml,得到尼莫地平混合胶束溶液。
(4)除菌过滤,分装至安瓿瓶,熔封,121℃、15min热压灭菌,得尼莫地平混合胶束注射液。
该注射液澄清透明、淡黄绿色。混合胶束溶液Z-Average为3.325nm,PDI为0.315,Zeta电位为-37.6mV。
实施例9
每支含尼莫地平10mg,20支尼莫地平胶束注射液的组成为:
制备工艺:
(1)按照所述配比称取尼莫地平、蛋黄卵磷脂、牛黄胆酸、SolutolHS 15溶于甲醇、乙醇中,搅拌分散均匀,得澄明液体;
(2)将步骤(1)中所得澄明溶液用旋转蒸发仪旋蒸去除甲醇、乙醇,直至除尽且形成薄膜;
(3)按上述处方称取蔗糖、氢氧化钠溶解于80ml注射用水中,得澄明溶液,充保护气氮气60min,加至上述薄膜中,水化完全后,油浴100℃热处理30min,放冷至室温。0.1mol/L枸橼酸溶液调节pH值至5.5,注射用水定容至100ml,得到尼莫地平混合胶束溶液。
(4)除菌过滤,分装至安瓿瓶,熔封,121℃、15min热压灭菌,得尼莫地平混合胶束注射液。
该注射液澄清透明、淡黄绿色。混合胶束溶液Z-Average为3.325nm,PDI为0.315,Zeta电位为-37.6mV。
实施例10
每支含尼莫地平10mg,20支尼莫地平胶束注射液的组成为:
制备工艺:
(1)按照所述配比称取尼莫地平、氢化大豆磷脂、甘氨胆酸、泊洛沙姆188溶于甲醇、乙醇中,搅拌分散均匀,得澄明液体;
(2)将步骤(1)中所得澄明溶液置旋转蒸发仪旋蒸去除甲醇、乙醇,直至除尽且形成薄膜;
(3)按上述处方称取蔗糖、氢氧化钠溶解于60ml注射用水中,得澄明溶液,充保护气氮气30min,加至上述薄膜中,水化完全后,油浴100℃热处理30min,放冷至室温。0.1mol/L氢氧化钠溶液调节pH值至6.5,注射用水定容至80ml,得到尼莫地平混合胶束溶液。
(4)除菌过滤,分装至安瓿瓶,熔封,121℃、15min热压灭菌,得尼莫地平混合胶束注射液。
该注射液澄清透明、淡黄绿色。混合胶束溶液Z-Average为2.679nm,PDI为0.371,Zeta电位为-29.1mV。
实施例11
每支含尼莫地平10mg,20支尼莫地平胶束注射液的组成为:
制备工艺:
(1)按照所述配比称取尼莫地平、大豆卵磷脂、甘氨胆酸、SolutolHS 15溶于甲醇、乙醇中,搅拌分散均匀,得澄明液体;
(2)将步骤(1)中所得澄明溶液置旋转蒸发仪旋蒸去除甲醇、乙醇,直至除尽且形成薄膜;
(3)按上述处方称取蔗糖、氢氧化钠溶解于80ml注射用水中,得澄明溶液,充保护气氮气30min,加至上述薄膜中,水化完全后,油浴100℃热处理30min,放冷至室温。0.1mol/L氢氧化钠溶液调节pH值至7.0,注射用水定容至100ml,得到尼莫地平混合胶束溶液。
(4)除菌过滤,分装至安瓿瓶,熔封,121℃、15min热压灭菌,得尼莫地平混合胶束注射液。
该注射液澄清透明、淡黄绿色。混合胶束溶液Z-Average为3.517nm,PDI为0.392,Zeta电位为-34.2mV。
实施例12
每支含尼莫地平10mg,20支尼莫地平胶束注射液的组成为:
制备工艺:
(1)按照所述配比称取尼莫地平、大豆卵磷脂、甘氨胆酸、聚山梨酯80溶于甲醇、乙醇中,搅拌分散均匀,得澄明液体;
(2)将步骤(1)中所得澄明溶液用旋转蒸发仪旋蒸去除甲醇、乙醇,直至除尽且形成薄膜;
(3)按上述处方称取甘露醇、氢氧化钠溶解于80ml注射用水中,得澄明溶液,充保护气氮气,加至上述薄膜中,水化完全后,油浴100℃热处理30min,放冷至室温。0.1mol/L枸橼酸溶液调节pH值至6.5,注射用水定容至100ml,得到尼莫地平混合胶束溶液。
(4)除菌过滤,分装至安瓿瓶,熔封,121℃、12min热压灭菌,得尼莫地平混合胶束注射液。
该注射液澄清透明、淡黄绿色。混合胶束溶液Z-Average为2.267nm,PDI为0.321,Zeta电位为-31.5mV。
实施例13
每支含尼莫地平10mg,20支尼莫地平胶束注射液的组成为:
制备工艺:
(1)按照上述处方称取尼莫地平、大豆卵磷脂、甘氨胆酸、聚乙二醇1000维生素E琥珀酸酯(TPGS1000)溶于甲醇、乙醇中,搅拌分散均匀,得澄明液体;
(2)将步骤(1)中所得澄明溶液用旋转蒸发仪旋蒸去除甲醇、乙醇,直至除尽且形成薄膜;
(3)按上述处方称取海藻糖、氢氧化钠溶解于80ml注射用水中,得澄明溶液,充保护气氮气,加至上述薄膜中,水化完全后,油浴100℃热处理30min,放冷至室温。0.1mol/L枸橼酸溶液调节pH值至6.0,注射用水定容至100ml,得到尼莫地平混合胶束溶液。
(4)除菌过滤,分装至安瓿瓶,熔封,121℃、12min热压灭菌,得尼莫地平混合胶束注射液。
该注射液澄清透明、淡黄绿色。混合胶束溶液Z-Average为2.627nm,PDI为0.291,Zeta电位为-35.1mV。
上述实施例经过实验验证,可优选应用实施例5-13,最优选为实施例5-8。
对比例1
根据专利CN 102525917B中实施例1,制备尼莫地平胶束注射液,步骤如下:
称取50mg的蛋黄卵磷脂、50mg的甘氨胆酸钠、1.25mg的尼莫地平置于50ml圆底烧瓶中,加入10ml乙醇,溶解,超声分散均匀。在水浴温度40℃下旋蒸去除乙醇,直至无醇味,形成一层透明薄膜,再用2.5ml的注射用水分散,得到含药混合胶束的分散体溶液。加入0.05%注射级活性炭搅拌15min后,12000rpm/min离心分离5min,用0.22μm微孔滤膜过滤,取滤液,分装,热压灭菌121℃下灭菌15min,得到尼莫地平混合胶束注射液。
对比例2
根据专利CN 102525917B中实施例2,制备尼莫地平胶束注射液,步骤如下:
称取50mg的蛋黄卵磷脂、50mg的甘氨胆酸钠、1mg的尼莫地平置于50ml圆底烧瓶中,加入10ml乙醇,溶解,超声分散均匀。再旋蒸除去乙醇,水浴温度35℃,旋至无醇味,形成一层透明薄膜,再用2.5ml的注射用水分散,得到含药混合胶束的分散体溶液。加入0.05%注射级活性炭搅拌15min后,12000rpm/min离心分离5min,然后用0.22μm微孔滤膜过滤,取滤液,分装,热压灭菌121℃下灭菌15min,得到尼莫地平混合胶束注射液。
实验例1载药量、含量、有关物质、残留溶剂的测定方法
1、载药量=(处方中溶解的尼莫地平的量)/{加入的总辅料的量(磷脂+胆盐+尼莫地平)}。
2、含量测定方法
色谱条件:用十八烷基硅烷键合硅胶为填充剂;以甲醇-乙腈-水(35∶38:27)为流动相;检测波长为235nm;进样体积10μl,柱温40℃。
对照品溶液:称取尼莫地平20mg,置20ml容量瓶中,加入甲醇溶解并稀释至刻度,摇匀,用溶剂(甲醇-乙腈-水,35∶38:27)稀释10倍,摇匀即得。
供试品溶液:精密量取有关物质项下供试品溶液2ml,置20ml量瓶中,用溶剂(甲醇-乙腈-水,35∶38:27)稀释至刻度,摇匀。
3、有关物质测试方法
色谱条件:用十八烷基硅烷键合硅胶为填充剂;以甲醇-水(40∶60)为流动相A,乙腈-水(90∶10)为流动相B;检测波长为235nm;进样体积10μl,柱温40℃。按表1进行梯度洗脱。
表1尼莫地平胶束注射液有关物质方法梯度洗脱表
供试品溶液:精密量取本品1ml,置10ml量瓶中,用甲醇稀释至刻度,摇匀。
4、残留溶剂测定方法:
(1)色谱条件:以6%氰丙基苯基-94%二甲基聚硅氧烷(或极性相近)为固定液的毛细管柱(推荐使用Agilent DB-624,0.53mm×30m,3μm或效能相当的色谱柱);起始温度为40℃,维持8分钟,以每分钟10℃的速率升温至180℃,维持5min;进样口温度为200℃;检测器为火焰离子化检测器,检测器温度为300℃;柱流量为每分钟2ml;分流比为10:1;顶空平衡温度为80℃;定量环温度为90℃;平衡时间为30分钟。
***适用性要求:对照品溶液色谱图中,甲醇、乙醇依次出峰,各色谱峰之间的分离度均应符合要求。
(2)溶液的制备
供试品溶液:取本品约100mg,精密称定,置20ml顶空瓶中,精密加入超纯水2ml,振摇,密封。
对照品溶液:分别取甲醇、乙醇各适量,精密称定,用超纯水定量稀释制成每1ml中各约含150μg、250μg的混合溶液,精密量取该溶液2ml,置20ml顶空瓶中,密封。
按照上述载药量、含量、有关物质、残留溶剂测定方法检测实施例1-13、对比例1-2,结果见表2;实施例5所制备胶束注射液灭菌后有关物质色谱图如图2所示。由表2结果可见,实施例制备的胶束注射液载药量明显高于对比例;实施例制备的胶束注射液热压灭菌前后含量无明显变化,且有关物质符合药典及进口注册标准;对比例1-2制备的注射液灭菌前后含量下降显著,有关物质超出标准,故实施例1-13有显著优势。
表2尼莫地平胶束注射液载药量、含量、有关物质等检测结果
实验例2考察添加表面修饰材料的影响
本发明制备的尼莫地平胶束注射液,处方中添加表面修饰材料,构建新型的纳米胶束增溶体系,可显著提高混合胶束的物理和化学稳定性,提高载药量,并大大提高尼莫地平的水溶性和稳定性。
由实验例1载药量结果可知,实施例1-4处方中未添加表面修饰材料,其载药量均大于对比例,实施例5-11均添加不同处方量的表面修饰材料,其载药量均大于实施例1-4,添加表面修饰材料能提高载药量。
通过对比实施例2(未添加)和实施例6(添加),两者均未进行热处理,过滤后样品于25℃下放置48h,通过观察性状(有无晶体析出)判断物理稳定性。结果如下表所示,实施例2放置6h析出,实施例6制备的注射液于25℃放置12h无析出,能显著提高胶束注射液的物理稳定性。
表3物理稳定性考察结果
实验例3考察热处理对稳定性影响
本发明制备的尼莫地平胶束注射液,制备过程中增加热处理步骤,设计实施例2、3、4、5、7进行考察,并与对比例进行对比,过滤后样品于25℃下放置48h,通过观察性状(有无晶体析出)判断物理稳定性。
由表4中结果可知,对比例1-2过滤后样品25℃放置4h均有晶体析出;实施例2放置6h后有晶体析出,优于对比例;实施例3放置8h有晶体析出;实施例4、5和7于25℃下放置36h性状未发生改变,实施例5和7放置48h仍未析出;
按照实验例1中含量、有关物质方法检测,由下表5中结果可知,pH、含量、有关物质等均无显著变化。
综合上述实验结果,本发明制备的尼莫地平胶束注射液,制备过程中增加热处理步骤显著提高了注射液的物理稳定性,过滤后溶液于25℃放置48h,外观、含量、有关物质、粒度等均无显著变化。
表4热处理考察结果
表5尼莫地平胶束注射液含量、有关物质、粒度等检测结果
实验例4考察充保护气体对胶束注射液的影响
对比实施例5-8,由表6结果可知充保护气体必要性,且充保护气体时间维持0.5-1h,尼莫地平混合胶束注射剂水化溶液采用氮气作保护气,能降低有关物质(关键杂质Ⅰ)的水平,提高尼莫地平注射剂的物理和化学稳定性。
表6有关物质测试结果
实验例5灭菌条件的考察
考察热压灭菌条件选择对尼莫地平胶束注射液含量影响,分别选用121℃/12min或121℃/15min对制备的胶束注射液进行热压灭菌,采用实施例6中含量检测方法,结果见表7。由表7可见灭菌前后含量结果无显著变化,综合考虑辅料稳定性等因素,故选用热压灭菌121℃/12min。
表7不同灭菌条件自制样品含量测试结果
实验例6低温循环试验
取实施例5制备的尼莫地平胶束注射液进行低温循环试验,试验应包含3次循环,每次循环于2-8℃下放置2天,然后在40℃下放置2天,每轮结束后均取样检测,按照实验例1中含量、有关物质方法检测,结果见表8。
由表8结果可知,3轮结束后,无析出现象;pH值、澄清度与颜色、粒径、电位、含量、有关物质等与0天相比均无显著变化,自制胶束注射液可耐受低温循环试验。
表8低温循环试验结果
实验例7冻融试验
取实施例4制备的尼莫地平胶束注射液进行冻融试验,试验应包含3次循环,每次循环于-10--20℃下放置2天,然后在40℃下放置2天,每轮结束后均取样检测,按照实验例1中含量、有关物质方法检测,结果见表9。
由表9结果可知,3轮循环结束后,观察性状,无析出现象;pH值、澄清度与颜色、粒度、电位、含量、有关物质等与0天相比均无显著变化,自制胶束注射液可耐受冻融试验。
表9冻融试验结果
实验例8配伍稳定性
取实施例7制备的尼莫地平胶束注射液及原研注射液分别用0.9%氯化钠注射液、5%葡萄糖注射液稀释至浓度为0.04mg/ml或0.02mg/ml,室温(25℃)下放置24h,考察临床使用条件下的稳定性。结合实验例1中含量、有关物质分析检测方法,对稀释稳定性进行考察,结果见表10,表11,含量变化曲线见附图5-8。
由表10,表11结果可知,自制品(实施例7)24h内观察无析出现象,含量、有关物质(杂质Ⅰ及总杂)无显著变化,且不溶性微粒无显著增加。
表10实施例7配伍溶液含量测定结果
表11原研注射液配伍溶液含量测定结果
结论:原研注射液稀释于0.9%氯化钠注射液或5%葡萄糖注射液,含量波动显著,尤其是稀释于0.9%氯化钠注射液放置1h后波动异常,分析原因为配伍溶液有结晶析出,进样采集到析出晶体导致含量测试异常,无需考察后续稳定性。相对于原研品注射液,自制样品的配伍溶液放置24h无析出现象,且含量无显著变化,稳定性好。
实验例9影响因素试验
取实施例8制备的尼莫地平胶束注射液,分别置于高温40℃、光照条件(光照强度4500lx,紫外200W·h/m2)下进行影响因素考察,于30天取样,按照实验例1中含量、有关物质方法检测,结果见表12。由表12结果可知,自制注射液分别于高温40℃、光照条件下放置30天,其性状、pH值、澄清度与颜色、粒度、电位、含量、有关物质均无显著变化,均符合药典标准。
表12影响因素试验结果
实验例10加速试验和长期试验
实例11、12、13中尼莫地平混合胶束注射液在下列条件下进行稳定性研究,记录外观、性状、pH及Zeta电位变化,并根据上文实施例6测定尼莫地平含量、有关物质,结果见表13。
其中,对比例灭菌后含量降低6%左右,总杂超出药典中标准,故未进行稳定性考察。
长期试验:25℃±2℃/60%RH±5%RH;加速试验:40℃±2℃/75%RH±5%RH。
表13尼莫地平胶束注射液稳定性考察结果
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结论:由上表可知,实施例11-13尼莫地平胶束注射液在长期稳定性、加速稳定性的条件下放置6个月,外观、pH、电位、含量、有关物质(杂质Ⅰ、总杂)等指标均无显著变化。以上结果表明,实施例11-13尼莫地平胶束注射液稳定性能良好。尼莫地平胶束注射液设计贮存条件为2-8℃保存,根据加速稳定性实验结果,尼莫地平胶束注射液的有效期暂定2年。
对于本领域的普通技术人员而言,具体实施例只是对本发明进行了示例性描述,显然本发明具体实现并不受上述方式的限制,只要采用了本发明的方法构思和技术方案进行的各种非实质性的改进,或未经改进将本发明的构思和技术方案直接应用于其它场合的,均在本发明的保护范围之内。
Claims (8)
1.一种尼莫地平胶束注射液,其特征在于:包含活性成分尼莫地平,磷脂,胆酸或其盐,表面修饰材料,等渗调节剂,pH调节剂和注射用水;其中各组分的比例如下:
注射液中活性成分尼莫地平浓度为0.1mg/ml~4mg/ml;除此之外,尼莫地平与磷脂的重量比为0.5~20:100,胆酸或其盐与磷脂的重量比为0.1~10:1,表面修饰材料与尼莫地平的重量比为0.1~10:1,等渗调节剂和磷脂的重量比为0.1~5:1;
其制备方法为薄膜分散法,其具体过程如下:
步骤(1):称取组方中尼莫地平、磷脂、胆酸或其盐、表面修饰材料,溶于适量有机溶剂中;
步骤(2):将步骤(1)所得的溶液转移至旋转蒸发仪,水浴温度30~70℃,开启真空除去有机溶剂,得疏松薄膜;
步骤(3):称取组方中等渗调节剂,稀释于注射用水;若步骤(1)辅料为胆酸,则加入与胆酸摩尔比为1:1的pH调节剂中的碱,充保护气体,得稳定剂溶液;将其完全转移至步骤(2)所得疏松薄膜中,搅拌使其水化完全,pH调节剂调节溶液pH,热处理,放冷即得尼莫地平胶束溶液;
所述的热处理为90~100℃,时间为20~30min;
步骤(4):将步骤(3)所得溶液用注射用水定容,充保护气体,除菌过滤,分装至安瓿瓶熔封,热压灭菌,即得尼莫地平胶束注射液;
所述表面修饰材料为15 - 羟基硬脂酸聚乙二醇酯、聚氧乙烯聚氧丙烯共聚物、聚氧乙烯脱水山梨醇脂肪酸酯类、聚氧乙烯蓖麻油衍生物、聚乙二醇维生素E琥珀酸酯、聚乙二醇-二硬脂酰磷脂酰胆碱中的任意一种或多种按照任意比例组成。
2.根据权利要求1所述尼莫地平胶束注射液,其特征在于:所述磷脂选自大豆磷脂、蛋黄磷脂、氢化大豆磷脂、氢化蛋黄磷脂,二棕榈酰磷脂酰胆碱、二棕榈酰磷脂酰乙醇胺、二硬脂酰磷脂酰胆碱、二月桂酰磷脂酰胆碱、二油酰磷脂酰乙醇胺、二硬脂酰磷脂酰乙醇胺、二油酰磷脂酰胆碱中的一种。
3.根据权利要求1所述尼莫地平胶束注射液,其特征在于:所述胆酸或其盐为甘氨胆酸、脱氧胆酸、甘氨鹅脱氧胆酸,牛磺胆酸及牛磺鹅脱氧胆酸或其盐中的一种或几种的混合物。
4.根据权利要求1所述尼莫地平胶束注射液,其特征在于:所述等渗调节剂为蔗糖、海藻糖、葡萄糖、乳糖、果糖、甘露醇、葡聚糖、山梨醇、右旋糖酐、甘氨酸、羟乙基淀粉、聚乙烯吡咯烷酮、聚乙烯酮中的任意一种或多种按照任意比例组合物;
所述生理药效学上可接受的pH调节剂中的酸选自冰醋酸、甲酸、三氟乙酸、磷酸、枸橼酸、酒石酸、草酸、苹果酸、丙氨酸、盐酸、亮氨酸、异亮氨酸、苹果酸、缬氨酸、色氨酸、马来酸、富马酸、乳酸、苯丙氨酸、甲硫氨酸和琥珀酸中的任意一种或多种按照任意比例组成;pH调节剂中的碱为氢氧化钠、碳酸酸钠、碳酸氢钠、氢氧化钾、氢氧化胆碱、精氨酸、赖氨酸、组氨酸、二乙胺、三乙胺、葡甲胺、枸橼酸钠、酒石酸钠、乳酸钠、磷酸钠、磷酸氢二钠中的任意一种或多种按照任意比例组合物。
5.根据权利要求1-4中任一一项所述尼莫地平胶束注射液,其特征在于:
所述磷脂选自大豆磷脂,所述胆酸或其盐选自甘氨胆酸或甘氨胆酸钠;所述表面修饰材料为15-羟基硬脂酸聚乙二醇酯、聚氧乙烯聚氧丙烯共聚物、聚氧乙烯脱水山梨醇脂肪酸酯类中的一种,所述等渗调节剂为蔗糖,所述pH调节剂中的酸选自枸橼酸,pH调节剂中的碱为氢氧化钠。
6.权利要求1所述尼莫地平胶束注射液的制备方法,其特征在于:制备方法为薄膜分散法,其具体过程如下:
步骤(1):称取组方中尼莫地平、磷脂、胆酸或其盐、表面修饰材料,溶于适量有机溶剂中;
步骤(2):将步骤(1)所得的溶液转移至旋转蒸发仪,水浴温度30~70℃,开启真空除去有机溶剂,得疏松薄膜;
步骤(3):称取组方中等渗调节剂,稀释于注射用水;若步骤(1)辅料为胆酸,则加入与胆酸摩尔比为1:1的pH调节剂中的碱,充保护气体,得稳定剂溶液;将其完全转移至步骤(2)所得疏松薄膜中,搅拌使其水化完全,pH调节剂调节溶液pH,热处理,放冷即得尼莫地平胶束溶液;
所述的热处理为90~100℃,时间为20~30min;
步骤(4):将步骤(3)所得溶液用注射用水定容,充保护气体,除菌过滤,分装至安瓿瓶熔封,热压灭菌,即得尼莫地平胶束注射液。
7.根据权利要求6所述尼莫地平胶束注射液的制备方法,其特征在于:
上述薄膜分散法中有机溶剂为甲醇、乙醇、乙酸乙酯、异丙醇中的任意一种或多种按照任意比例组合物,有机溶剂用量为所制备注射液体积的2%~8%,所述的保护气体为氮气、氦气、二氧化碳和氩气中的任意一种;步骤(3)和(4)中所述的保护气体为氮气,通入保护气体的时间均为0.5~2小时,步骤(4)需控制溶解氧残留范围5~10ppm;步骤(4)中获得的纳米胶束注射液中尼莫地平的浓度为0.1mg/ml~4mg/ml。
8.权利要求1所述尼莫地平胶束注射液在制备预防和治疗动脉瘤性蛛网膜下腔出血后脑血管痉挛引起的缺血性神经损伤药物中的应用。
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