CN116459224A - 一种丁苯酞纳米脂质体冻干粉针剂及其制备方法 - Google Patents
一种丁苯酞纳米脂质体冻干粉针剂及其制备方法 Download PDFInfo
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- CN116459224A CN116459224A CN202310539599.5A CN202310539599A CN116459224A CN 116459224 A CN116459224 A CN 116459224A CN 202310539599 A CN202310539599 A CN 202310539599A CN 116459224 A CN116459224 A CN 116459224A
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- Prior art keywords
- butylphthalide
- injection
- liposome
- freeze
- acid
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- 229950005197 butylphthalide Drugs 0.000 title claims abstract description 138
- 239000007924 injection Substances 0.000 title claims abstract description 117
- 238000002347 injection Methods 0.000 title claims abstract description 117
- 239000002502 liposome Substances 0.000 title claims abstract description 104
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- 238000000034 method Methods 0.000 claims abstract description 47
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Landscapes
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Abstract
本发明涉及医药领域,具体涉及一种纳米脂质体及其制备方法。特别地,本发明涉及一种治疗急性缺血性脑卒中的丁苯酞纳米脂质体粉针剂及其制备方法。该纳米脂质体主要是由丁苯酞或左旋丁苯酞、磷脂、胆固醇、长循环材料、负电荷材料、保护剂及pH调节剂组成。本发明采用薄膜分散法及混合腔制备法制备丁苯酞纳米脂质体,混合腔技术更易于实现线性放大,更适合放大生产规模。本发明采用脂质体包合增溶,完全摒弃磺丁基‑β‑环糊精及其他类型环糊精的使用,降低毒副作用,提高治疗指数提高了用药安全性。冻干粉针剂稳定性高,便于储存及运输。且本发明的丁苯酞纳米脂质体冻干粉针剂制备工艺简单,易于放大,因此具有极高的产业化应用价值。
Description
技术领域
本发明涉及医药领域,具体涉及一种丁苯酞纳米脂质体冻干粉针剂及其制备方法领域。
背景技术
缺血性脑卒中是各类病因所致脑部血液供应障碍,导致脑组织缺血、缺氧性坏死,出现相应神经功能缺损,是人类三大致死病因之一。据全球疾病负担研究估计,随着我国人口老龄化的日益加剧,中国已成为卒中终生风险最高和疾病负担最重的国家,发病率高达39.3%。
丁苯酞具有独特的双重作用机制,既能重构微循环,增加缺血去灌注,从而保护血管结构完整、恢复血管管径、增加缺血区血流量及周围微血管数量,又能保护线粒体,减少细胞死亡,双重狙击来对抗脑卒中,已被推荐为急性脑梗死早期治疗安全、有效的药物。
丁苯酞是一种有机物,又称芹菜甲素,属简单苯酞类,为油状液体,有芹菜香味,可溶于甲醇、乙醇、二甲基亚砜等有机溶剂,难溶于水,是中国研究和开发的用于治疗缺血性脑卒中的药物。可抗脑缺血和抗老年痴呆。化学名称为:3-正丁基-1(3H)-异苯并呋喃酮(dl-3-n-butylphthalide,NBP),分子式:C12H14O2,分子量:190.24,结构式见图1:
图1 丁苯酞化学结构式
最早上市的丁苯酞相关产品为丁苯酞软胶囊,除已上市丁苯酞软胶囊外,专利CN110856712B公开了一种由丁苯酞自微乳组合物制备成的软胶囊,但以上丁苯酞软胶囊均属口服剂型,肝脏首过效应大,生物利用度低,给药剂量大,起效缓慢,而且急性缺血性脑卒中患者神经功能缺损的改善,需要注射剂发挥急救疗效。
由于丁苯酞是油状液体,所以给静脉给药带来很大困难。专利CN1166693C公布了丁苯酞环糊精或环糊精衍生物包合物及其制备方法和用途,用该方法制备的丁苯酞氯化钠注射液,已应用于临床,但该方法采用HP-β-CD包合技术增溶,HP-β-CD:药物=33:1(质量比)。环糊精类辅料分子量大,通过肾小球过滤作用排泄,环糊精用量大易造成肾脏蓄积毒性,该产品说明书已明确要求:肌酐清除率<30 ml/min的患者慎用本品,因此给患者的带来一定的安全问题并限制了临床患者的使用,使得丁苯酞注射液不能满足临床需求。
专利CN113662908A公开了一种稳定的丁苯酞小水针及其制备方法,但该方法依旧采用大量磺丁基倍他环糊精钠包合的增溶方式,丁苯酞与磺丁基倍他环糊精钠的重量比为1:(30~35)。专利CN112386571A公开了一种稳定的丁苯酞氯化钠注射液,虽然降低了磺丁基倍他环糊精钠的使用量,但优选地丁苯酞与磺丁基倍他环糊精钠的摩尔比为1:(1.60~2.20),更优选为1.77,即丁苯酞与磺丁基倍他环糊精钠的质量比为1:(18~25),磺丁基倍他环糊精钠的用量仍较多,未解决根本问题。专利CN110548004A、专利CN107970208B公开了一种丁苯酞注射液,由丁苯酞或其衍生物、表面活性剂及注射用水组成,通过加入一种或几种表面活性剂联用的方式来实现增溶目的,合成的表面活性剂用量较大,存在溶血性,过敏性等安全风险。
专利CN100367951C公开了一种丁苯酞静脉乳剂,由丁苯酞、大豆油、乳化剂、等渗剂和注射用水组成,采用两步乳化分散法制备。但该静脉乳剂存在主药浓度大、粒径大且范围分布范围广及乳剂稳定性差的弊端,而且处方工艺复杂,生产成本高。
脂质体(liposome)是一种人工膜,在水中磷脂分子亲水头部插入水中,脂质体疏水尾部伸向空气,搅动后形成双层脂分子的球形脂质体,直径为25~1000 nm不等。脂质体利用其可以和细胞膜融合的特点可作为药物载体,将药物送入细胞内部。纳米脂质体注射液属于纳米制剂,能增加药物透过血脑屏障的能力,具有脑靶向特点。可将药物有效地靶向输送、浓集于脑病变部位,减少用药剂量和用药次数,提高药物稳定性,降低毒副作用,提高治疗指数。目前已有多种脂质体类药物上市,比如盐酸多柔比星脂质体注射液、榄香烯脂质体注射液、注射用紫杉醇脂质体等。
目前尚未有丁苯酞或左旋丁苯酞关于脂质体增溶的相关研究报道。虽然已有纳米脂质体制备的相关技术启示,但不同的活性物质,所需要的处方及制备工艺都是不同的,所以说对处方的摸索及制备工艺的优化是制备丁苯酞或左旋丁苯酞纳米脂质体的关键。
纳米脂质体的制备方法包括薄膜分散法、超声波分散法、逆相蒸发法、注入法、冷冻干燥法等。常用的为薄膜分散法,该制备方法简单易操作,但该方法制备纳米脂质体还需均匀粒径的操作步骤,且该制备方法更适合小试和中试阶段,因此,经典薄膜分散法存在着制约工业化放大生产的技术瓶颈,严重限制了丁苯酞改良型注射剂产业化的进程。
冻干制剂具有稳定性高、便于运输及储存、使用方便的特点,且含水量低,不易被氧化。冻干块疏松多孔、易于水化分散形成溶液。脂质体载药与普通制剂相比具有靶向性好,长效等优点。
发明内容
丁苯酞是难溶于水的油状液体,本发明将该药物制备成纳米脂质体注射剂,目的是解决丁苯酞难溶性问题,克服已上市丁苯酞氯化钠注射液及在研的丁苯酞注射液存在的肾脏蓄积毒性、溶血性、过敏性等安全缺陷。
本发明所要解决的技术问题是提供一种安全性高、稳定性好的丁苯酞纳米脂质体注射剂及其制备工艺。本发明首次采用纳米脂质体为药物载体,制备包含丁苯酞或左旋丁苯酞的注射剂。本发明完全摒弃环糊精包合或通过添加其他表面活性剂增溶的手段,在不改变药物临床有效性的前提下,显著提高了安全性及稳定性:冻干粉针剂具有良好的稳定性及复溶性能。本发明的制备工艺更易于实现线性放大,适合放大生产规模。由此提供了以下发明:
本发明提供了一种丁苯酞纳米脂质体冻干粉针剂,包含丁苯酞或左旋丁苯酞、磷脂、胆固醇、长循环材料、负电荷材料、保护剂、pH调节剂及注射用水。所述纳米脂质体注射剂中,丁苯酞或左旋丁苯酞与磷脂、胆固醇的重量比为1:(0.5~15.0):(0.5~5.0),丁苯酞或左旋丁苯酞与长循环材料、负电荷材料的重量比为1:(0.3~5.0):(0.02~3.0),丁苯酞或左旋丁苯酞与保护剂的重量比为1:(4~70)。
在某些实施方案中,所述磷脂为大豆卵磷脂、蛋黄磷脂、氢化大豆卵磷脂、氢化蛋黄磷脂、合成磷脂中的一种或几种,其中优选大豆卵磷脂,注射级。
在某些实施方案中,所述长循环材料为神经节苷脂和唾液酸衍生物(GM1)、二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)、聚乙二醇1000维生素E琥珀酸酯(TPGS)中的一种或几种,其中优选聚乙二醇1000维生素E琥珀酸酯(TPGS)。
在某些实施方案中,所述负电荷材料为蛋黄卵磷脂酰甘油、四肉豆蔻酰心磷脂、维生素E琥珀酸酯(VES)、胆固醇琥珀酸酯、脱氧胆酸钠、胆固醇硫酸钠、油酸钠、甲氧基聚乙二醇磷脂(MPEG-DSPE)等中的一种或几种组成的混合物,其中优选油酸钠。
在某些实施方案中,所述保护剂为甘露醇、山梨醇、葡萄糖、甘氨酸、氯化钠、蔗糖、海藻糖、麦芽糖、葡聚糖、乳糖、右旋糖酐、羟乙基淀粉、聚维酮中的任意一种或多种按照任意比例组成的混合物,其中优选蔗糖与氯化钠组成的混合溶液。
在某些实施方案中,所述pH调节剂中的酸选自盐酸、醋酸、硝酸、硫酸、磷酸、柠檬酸、苹果酸、马来酸、富马酸、乳酸、酒石酸和琥珀酸等无机酸或有机酸,其中优选为盐酸;pH调节剂中的碱,优选为氢氧化钠。
在某些实施方案中,所述的丁苯酞纳米脂质体,部分处方中含有抗氧化剂的使用,比如硫脲、亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、硫代硫酸钠、叔丁基对羟基茴香醚、二丁基苯酚、没食子酸丙酯、抗坏血酸棕榈酸酯、生育酚、维生素C、金属络合剂等。
所述脂质体为类球状实体;
所述脂质体溶液的pH为4.50~8.00;
所述脂质体的平均粒径为60-130 nm;
所述脂质体的包封率大于85%。
一方面,本发明提供了两种制备所述丁苯酞纳米脂质体注射剂的工艺:“薄膜分散法”,改良的乙醇注入法即“混合腔制备法”。
(1)“薄膜分散法”包括以下步骤:
步骤1:按所述配比,称取丁苯酞或左旋丁苯酞、磷脂、胆固醇、长循环材料、负电荷材料于圆底烧瓶中,加入有机溶剂,超声搅拌,得到澄清透亮溶液1;
步骤2:将步骤1所得溶液1置旋转蒸发仪上,水浴、减压,除去有机溶剂,得到疏松薄膜;
步骤3:按所述配比,称取保护剂于烧杯中,加入注射用水,搅拌溶解,得澄清透亮溶液2;
步骤4:将步骤2所得薄膜用溶液2水化,得泛白均一液体,定容,用高压均质机(Avestin C3高压均质机)均质、用脂质体滤膜挤出器(AE-100,加拿大ATS公司)挤出,即得透明泛蓝的光丁苯酞纳米脂质体溶液;
步骤5:将步骤4所得丁苯酞纳米脂质体溶液除菌过滤,分装至冻干西林瓶,充保护气体,半压塞,冷冻干燥,充保护气体,压塞,出箱,轧盖,即得丁苯酞纳米脂质体冻干粉针剂。
(2)改良的乙醇注入法即“混合腔制备法”,包括以下步骤:
步骤1:按所述配比,称取丁苯酞或左旋丁苯酞、磷脂、胆固醇、长循环材料、负电荷材料于圆底烧瓶中,加入有机溶剂,超声搅拌,得到澄清透亮溶液1(油相);
步骤2:按所述配比,称取保护剂于烧杯中,加入注射用水,搅拌溶解,得澄清透亮溶液2(水相);
步骤3:将溶液1和溶液2通过蠕动泵系统混合,并用注射用水稀释一倍,待水相与油相混合充分得到脂质体初乳时,将脂质体初乳进行超滤除去有机溶剂,得到脂质体中间体,
步骤4:将步骤3所得脂质体中间体定容,然后通过脂质体滤膜挤出器进行整粒,得到丁苯酞纳米脂质体溶液;
步骤5:将步骤4所得丁苯酞纳米脂质体溶液除菌过滤,分装至冻干西林瓶,充保护气体,半压塞,冷冻干燥,充保护气体,压塞,出箱,轧盖,即得丁苯酞纳米脂质体冻干粉针剂。
在某些实施例中,步骤1中所述的有机溶剂选自甲醇、乙醇、乙腈、二甲基亚砜、异丙醇等一种或几种按照任意比例组成的混合物,其中优选为无水乙醇;
在某些实施例中,步骤5中所述的保护气体为氮气、二氧化碳和氩气中的任意一种或多种,其中优选为氮气,通入保护气体的时间为1~2 h,残留氧的浓度控制在5~10 ppm;
在某些实施方案中,所述冷冻干燥的步骤具体包括:(1)预冻 将半压塞的样品放入冻干箱,开启循环泵隔板制冷,设定1 h隔板温度达到-30~-50℃,保温3~6 h。(2)升华干燥 设定1h后样品温度达到-25~-15℃,保温26~40 h,真空度为10~20 Pa,在该段进行升华干燥。(3)解析干燥 设定2 h后样品温度达到20~30℃,保温2~6 h,真空度为5~15 Pa,在该段进行解析干燥。
本发明的丁苯酞纳米脂质体冻干粉针剂为白色疏松块状,用注射用水或生理盐水或5%葡萄糖注射液复溶后,再用0.9%氯化钠注射液或5%葡萄糖注射液稀释后静脉滴注给药。
本发明所述磷脂、胆固醇、长循环材料、负电荷材料、保护剂、pH调节剂的不同种类及用量均可对丁苯酞纳米脂质体注射剂的平均粒径、Zeta电位、载药量、包封率及稳定性有重要影响,本发明根据差示扫描量热仪检测到的DSC曲线初步确定其一次干燥温度及时间,所得样品塌陷,含水量为4.7%±0.82%,根据冻干样品的外观形态及水分对冻干程序进行优化,得到上述冻干程序,按照优化后的冻干程序冷冻干燥得到的丁苯酞脂质体冻干粉针剂为米白色均一疏松冻干块,用卡尔费休法测定其水分为1.30%±0.96%,符合药典要求。冻干粉针剂冻干前后平均粒径、Zeta电位、pH、含量、包封率均无明显变化;改变磷脂、长循环材料、负电荷材料、保护剂、pH调节剂的种类或用量,所制备的丁苯酞纳米脂质体注射剂粒径变大或变小、包封率及稳定性有明显差异。
本发明技术方案与现有技术相比,具有以下有益效果:
1.本发明制备的丁苯酞纳米脂质体注射剂以脂质体为载体,将难溶于水的丁苯酞或左旋丁苯酞包在脂质体内部,完全摒弃磺丁基倍他环糊精、羟丙基倍他环糊精及其他合成表面活性剂的使用,降低了肾脏蓄积毒性、溶血性、过敏性,提高临床用药安全性。
2. 本发明制备的丁苯酞纳米脂质体冻干粉针剂,具有高载药量、高包封率、高稳定性的特点。
3. 经典的薄膜分散法,相对来说对仪器设备依赖度低,但该方法所制备的脂质体一般粒径偏大、不均匀,需要用高压均质机均质及挤出器挤出以均匀、缩小粒径。本发明在经典乙醇注入法的基础上进行创新,建立了“混合腔制备法”。该方法基于经典乙醇注入法的原理,借鉴微流控技术的特点,采用梯度将油相与水相进行一步混合制备纳米脂质体。该法只需一步混合便可以将药物磷脂溶液转变为粒径大小适宜、粒度分布集中、载药量高的纳米脂质体粒子,其生产流程近似于普通注射粉针剂的工艺流程,工艺简便,所制得的脂质体的粒径大小、粒度分布、载药量、包封率等指标不受生产规模限制,对解决小试-中试-生产难以线性放大的难题、实现脂质体的产业化具有很大的效益。
附图说明
图1显示了创新的“混合腔制备法”工艺流程。
图2显示了实施例1中,采用“经典薄膜分散法”制备的丁苯酞脂质体冻干粉针剂的性状外观。
图3显示了实施例1中,采用“经典薄膜分散法”制备的丁苯酞脂质体冻干粉针剂复溶后的性状外观。
图4显示了丁苯酞脂质体溶液的DSC曲线。
图5显示了实施例1中,采用“经典薄膜分散法”制备的丁苯酞脂质体冻干粉针剂复溶后经甲醇破坏后的含量测定的高效液相色谱图(图5A)与对照品的高效液相色谱图(图5B)。
图6显示了实施例1中,采用“经典薄膜分散法”制备的丁苯酞脂质体冻干粉针剂复溶后用马尔文激光粒度仪(Malvern Zetasizer Nano ZS90)测定样品的粒径分布图。
图7显示了实施例6中,采用“混合腔制备法”制备的丁苯酞脂质体冻干粉针剂复溶后用马尔文激光粒度仪(Malvern Zetasizer Nano ZS90)测定样品的粒径分布图。
图8显示了实施例1中,采用“经典薄膜分散法”制备的丁苯酞脂质体冻干粉针剂复溶后用马尔文激光粒度仪(Malvern Zetasizer Nano ZS90)测定样品的电位布图。
图9显示了实施例1中,采用“经典薄膜分散法”制备的丁苯酞脂质体冻干粉针剂复溶后用透射电镜拍的微观形态,可以看到丁苯酞脂质体为球状或类球状,有明显的双层膜结构。
具体实施方式
下面结合具体实施例来进一步描述本发明,本发明的优点和特点将会随着描述而更为清楚。但应理解的是所述实施例仅是范例性的,不对本发明的范围构成任何限制。本领域技术人员更应理解的是,在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换,但这些修改或替换均落入本发明的保护范围。
实施例1丁苯酞纳米脂质体冻干粉针剂的制备
每瓶含丁苯酞25 mg,100支丁苯酞纳米脂质体冻干粉针剂的组成。
处方:
丁苯酞 2.5g
大豆卵磷脂(Lipoid S100) 25g
胆固醇(日本精化株式会社,注射级) 2.5g
聚乙二醇1000维生素E琥珀酸酯(法国PMC ISOCHEM公司,注射级) 2.5g
油酸钠 0.1g
蔗糖(德国MERCK公司,注射级) 125g
氯化钠 11.25g
无水乙醇 200mL
注射用水 定容至1250mL
制备工艺(经典薄膜分散法)
(1)按所述配比,称取丁苯酞、大豆卵磷脂、胆固醇、聚乙二醇1000维生素E琥珀酸酯、油酸钠于圆底烧瓶中,加入无水乙醇,超声搅拌,得到澄清透亮溶液1;
(2)将步骤(1)所得溶液1置旋转蒸发仪上,45℃水浴、减压,除去无水乙醇,得到疏松薄膜;
(3)按所述配比,称取蔗糖、氯化钠于烧杯中,加入1000 mL注射用水,搅拌溶解,得澄清透亮溶液2;
(4)将步骤(2)所得薄膜用溶液2水化2 h,得泛白均一液体,用注射用水定容至1250 mL,用高压均质机(Avestin C3 高压均质机)均质,再用脂质体滤膜挤出器(AE-100,加拿大ATS公司)挤出,孔径200 nm的聚碳酸酯膜挤出3次,再用孔径80 nm的聚碳酸酯膜挤出3次,即得丁苯酞纳米脂质体溶液;
(5)将步骤(4)所得丁苯酞纳米脂质体溶液除菌过滤,分装至冻干西林瓶,12.5mL/支,充氮气1.5 h,半压塞,冷冻干燥,其中冷冻干燥的步骤为:a)预冻 将半压塞的样品放入冻干箱,开启循环泵隔板制冷,设定1 h隔板温度达到-40℃,保温4 h;b)升华干燥 设定1 h后样品温度达到-20℃,保温40 h,真空度为13 Pa,在该段进行升华干燥;c)解析干燥设定2 h后样品温度达到25℃,保温6 h,真空度为5 Pa,在该段进行解析干燥。冷冻干燥结束后往冻干腔内充氮气,压塞,出箱,轧盖,即得丁苯酞纳米脂质体冻干粉针剂。
实施例2丁苯酞纳米脂质体冻干粉针剂的制备
每瓶含丁苯酞25 mg,100支丁苯酞纳米脂质体冻干粉针剂的组成。
处方:
丁苯酞 2.5g
蛋黄磷脂(Lipoid E100) 25g
胆固醇(日本精化株式会社,注射级) 2.5g
二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000 2.5g
油酸钠 0.1g
葡萄糖(德国MERCK公司,注射级) 62.5g
乙醇 250mL
注射用水 定容至1250mL
制备工艺(经典薄膜分散法)
具体制备方法参照实施例1。
实施例3丁苯酞纳米脂质体冻干粉针剂的制备
每瓶含丁苯酞25 mg,100支丁苯酞纳米脂质体冻干粉针剂的组成。
处方:
丁苯酞 2.5g
氢化大豆卵磷脂 (Lipoid SPC-3) 25g
胆固醇(日本精化株式会社,注射级) 2.5g
聚乙二醇1000维生素E琥珀酸酯(法国PMC ISOCHEM公司,注射级) 2.5g
油酸 2.5g
甘露醇 62.5g
无水甲醇 200mL
0.5mol/L氢氧化钠溶液 适量
注射用水 定容至1250mL
制备工艺(经典薄膜分散法)
具体制备方法参照实施例1。
实施例4左旋丁苯酞纳米脂质体冻干粉针剂的制备
每瓶含左旋丁苯酞25 mg,100支丁苯酞纳米脂质体冻干粉针剂的组成。
处方:
左旋丁苯酞 2.5g
二棕榈酰磷脂 17.5g
胆固醇(日本精化株式会社,注射级) 1.75g
聚乙二醇1000维生素E琥珀酸酯(法国PMC ISOCHEM公司,注射级) 2.5g
油酸钠 0.1g
维生素E 2.5g
乳糖 125g
甲醇 150mL
注射用水 定容至1250mL
制备工艺(经典薄膜分散法)
具体制备方法参照实施例1。
实施例5左旋丁苯酞纳米脂质体冻干粉针剂的制备
每瓶含左旋丁苯酞25 mg,100支丁苯酞纳米脂质体冻干粉针剂的组成。
处方:
左旋丁苯酞 2.5g
大豆卵磷脂(Lipoid S100) 30g
胆固醇(日本精化株式会社,注射级) 2.75g
聚乙二醇1000维生素E琥珀酸酯(法国PMC ISOCHEM公司,注射级) 3.0g
甲氧基聚乙二醇磷脂 0.5g
蔗糖 100g
无水乙醇 100mL
注射用水 定容至1000mL
制备工艺(经典薄膜分散法)
具体制备方法参照实施例1。
实施例6丁苯酞纳米脂质体冻干粉针剂的制备
每瓶含丁苯酞25 mg,100支丁苯酞纳米脂质体冻干粉针剂的组成。
处方:
丁苯酞 2.5g
大豆卵磷脂(Lipoid S100) 27.5g
胆固醇(日本精化株式会社,注射级) 3.0g
聚乙二醇1000维生素E琥珀酸酯(法国PMC ISOCHEM公司,注射级) 2.75g
维生素E琥珀酸酯 0.5g
蔗糖(德国MERCK公司,注射级) 125g
氯化钠 11.25g
无水乙醇 200mL
注射用水 定容至1250mL
制备工艺(混合腔制备法)
(1)按所述配比,称取丁苯酞、大豆卵磷脂、胆固醇、聚乙二醇1000维生素E琥珀酸酯、维生素E琥珀酸酯于烧杯中,加入无水乙醇,用保鲜膜或封口膜将烧杯封口,超声搅拌,得到澄清透亮溶液1(油相);
(2)按所述配比,称取蔗糖和氯化钠于烧杯中,加入800 mL注射用水,搅拌溶解,得澄清透亮溶液2(水相);
(3)将溶液1和溶液2通过蠕动泵系统混合,且油相注入速度为100mL/min,水相注入速度为500 mL/min,混合速度为300 rpm/s,混合时间为10 min,混合完成后加入400mL注射用水进行稀释,待水相与油相混合充分得到脂质体初乳时,将脂质体初乳超滤8次除去有机溶剂,得到脂质体中间体,
步骤4:将步骤3所得脂质体中间体定容,然后通过脂质体滤膜挤出器进行整粒,得到丁苯酞纳米脂质体溶液;
步骤5:将步骤4所得丁苯酞纳米脂质体溶液除菌过滤,分装至冻干西林瓶,12.5mL/瓶,充保护气体,半压塞,冷冻干燥,充保护气体,压塞,出箱,轧盖,即得丁苯酞纳米脂质体冻干粉针剂。
实施例7丁苯酞纳米脂质体冻干粉针剂的制备
每瓶含丁苯酞25 mg,100支丁苯酞纳米脂质体冻干粉针剂的组成。
处方:
丁苯酞 2.5g
大豆卵磷脂(上海太伟) 30g
胆固醇(日本精化株式会社,注射级) 2.5g
二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000 2.75g
维生素E琥珀酸酯 0.5g
蔗糖(德国MERCK公司,注射级) 100g
无水乙醇 250mL
注射用水 定容至1000mL
制备工艺(混合腔制备法)
具体制备方法参照实施例6。
实施例8丁苯酞纳米脂质体冻干粉针剂的制备
每瓶含丁苯酞25 mg,100支丁苯酞纳米脂质体冻干粉针剂的组成。
处方:
丁苯酞 2.5g
大豆卵磷脂(上海太伟) 30g
胆固醇(日本精化株式会社,注射级) 2.5g
聚乙二醇1000维生素E琥珀酸酯(法国PMC ISOCHEM公司,注射级) 2.75g
甲氧基聚乙二醇磷脂 0.5g
右旋糖酐70 62.5g
无水乙醇 300mL
注射用水 定容至1250mL
制备工艺(混合腔制备法)
具体制备方法参照实施例6。
实施例9左旋丁苯酞纳米脂质体冻干粉针剂的制备
每瓶含左旋丁苯酞25 mg,100支丁苯酞纳米脂质体冻干粉针剂的组成。
处方:
左旋丁苯酞 2.5g
氢化大豆卵磷脂 37.5g
胆固醇(日本精化株式会社,注射级) 7.5g
聚乙二醇1000维生素E琥珀酸酯(法国PMC ISOCHEM公司,注射级) 3g
胆固醇琥珀酸酯 0.3g
乳糖 62.5g
无水乙醇 250mL
注射用水 定容至1250mL
制备工艺(混合腔制备法)
具体制备方法参照实施例6。
实施例10左旋丁苯酞纳米脂质体冻干粉针剂的制备
每瓶含左旋丁苯酞25 mg,100支丁苯酞纳米脂质体冻干粉针剂的组成。
处方:
左旋丁苯酞 2.5g
氢化蛋黄磷脂 37.5g
胆固醇(日本精化株式会社,注射级) 7.5g
聚乙二醇1000维生素E琥珀酸酯(法国PMC ISOCHEM公司,注射级) 3g
胆固醇硫酸钠 0.1g
葡聚糖 62.5g
无水乙醇 400mL
注射用水 定容至1250mL
制备工艺(混合腔制备法)
具体制备方法参照实施例6。
实验例1样品包封率测定方法
(1) 超滤离心法
取1mL脂质体溶液于50 mL容量瓶中,用蒸馏水定容,取稀释后的脂质体0.5 mL于100 kD的Amicon® Ultra离心式过滤器中,3000 r/min低温离心30min,称取离心管离心前后的重量,取滤液,0.22 μm尼龙滤膜过滤, 取续滤液, HPLC法测峰面积,计算滤液中的药物含量,计算包封率(EE);将拦截在离心管中的脂质体于低温离心机中,3000 r/min,离心20 min,将反甩下来的脂质体用甲醇破坏、定容,用0.22 μm尼龙滤头过滤,取续滤液,HPLC法测峰面积,计算脂质体中的药物含量,计算包封率(EE)。
(其中Ma为投药量,Mf为游离药物量。)
(2) 透析法
透析袋前处理:将透析袋(USA进口,分子截留量14000)置于1 mmol·L-1的EDTA与2% NaHCO3溶液中煮沸20 min,冷却至室温后,用蒸馏水将透析袋里外冲洗干净,用蒸馏水将透析袋里外冲洗干净,再用蒸馏水加以煮沸10min,冷却至室温后将透析袋浸泡于70%的乙醇溶液中进行保存,使用前需用蒸馏水将透析袋里外加以清洗。
取复溶后脂质体溶液5 mL分别置于透析袋中, 两端用夹子卡紧, 分别置再250mL生理盐水中, 室温下磁力搅拌8 h, 使游离药物透析出来。取2 mL释放介质,取出的样品用0.22 μm尼龙滤膜过滤,HPLC检测药物含量,计算包封率(EE)。
实验例2样品含量测定方法
(1)色谱条件与系统适用性试验
用十八烷基硅烷键合硅胶为填充剂;以甲醇-水(70:30)为流动相;检测波长为254nm;进样体积20 μl;柱温35℃,流速:1 ml/min,理论板数按丁苯酞峰计算应不低于1500。
(2)测定法
精密量取本品2 ml,置50 ml容量瓶中,加甲醇超声破乳并定容,摇匀,作为供试品溶液;另精密称取丁苯酞原料适量于量瓶中,加甲醇溶解并稀释,制成每1 ml含100 µg的溶液,作为对照品溶液。取供试品溶液与对照品溶液各20 µl,分别注入液相色谱仪,记录色谱图,按外标法以峰面积计算,即得。
实验例3样品加速稳定性
对实施例1-10制备的样品在(25℃±2℃,RH 60%±5%)放置下,进行稳定性实验考察,结果见表1。
表1实施例1~10丁苯酞纳米脂质体冻干粉针剂加速稳定性实验
结果表明,本发明丁苯酞纳米脂质体冻干粉针剂稳定性好,短暂偏离储存温度对产品质量影响不大,暂定有效期为两年(2~8℃储存条件)。
实验例4样品复溶稳定性实验
对实施例1~10制备的样品,用注射用水复溶后于温度25℃±2℃,相对湿度60%±5%的条件下考察其稳定性,结果见表2。
表2实施例1~10丁苯酞纳米脂质体冻干粉针剂复溶稳定性实验(25℃±2℃,RH60%±5%)
结果表明,本发明提供的丁苯酞纳米脂质体冻干粉针剂复溶后25℃±2℃,相对湿度60%±5%及5℃±3℃条件下12小时内稳定,符合临床用药需求。
实验例5样品稀释稳定性实验
对实施例1~10制备的样品注射用水复溶后,使用100 ml 0.9%氯化钠注射液稀释后考察其临床使用条件下的稳定性,结果见表3。
表3实施例1~10丁苯酞纳米脂质体冻干粉针剂稀释稳定性实验(0.9%氯化钠注射液)
对实施例9~11制备的样品注射用水复溶后,使用100ml 5%注射液稀释后考察其临床使用条件下的稳定性,结果见表4。
表4实施例1~10丁苯酞纳米脂质体冻干粉针剂稀释稳定性实验(5%葡萄糖注射液)
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结果表明,本发明提供的丁苯酞纳米脂质体冻干粉针剂用0.9%氯化钠注射液及5%葡萄糖注射液稀释后在临床使用条件下12小时内稳定,满足临床用药需要。
Claims (10)
1.一种丁苯酞纳米脂质体冻干粉针剂,其特征在于包含丁苯酞或左旋丁苯酞、磷脂、胆固醇、长循环材料、负电荷材料、保护剂及pH调节剂,丁苯酞或左旋丁苯酞与磷脂、胆固醇的质量比为1:(0.5~15):(0.5~5.0),丁苯酞或左旋丁苯酞与长循环材料、负电荷材料的重量比为1:(0.3~5.0):(0.02~3.0),丁苯酞或左旋丁苯酞与保护剂的重量比为1:(4~70)。
2.根据权利要求1所述的一种丁苯酞纳米脂质体冻干粉针剂,其特征在于,所述磷脂为大豆卵磷脂、蛋黄磷脂、氢化大豆卵磷脂、氢化蛋黄磷脂、合成磷脂中的一种或几种,其中优选大豆卵磷脂,注射级。
3.根据权利要求1所述的一种丁苯酞纳米脂质体冻干粉针剂,其特征在于,所述的长循环材料为神经节苷脂和唾液酸衍生物(GM1)、二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)、聚乙二醇1000维生素E琥珀酸酯(TPGS)中的一种或几种,其中优选聚乙二醇1000维生素E琥珀酸酯(TPGS)。
4.根据权利要求1所述的一种丁苯酞纳米脂质体冻干粉针剂,其特征在于,所述的负电荷材料为蛋黄卵磷脂酰甘油、四肉豆蔻酰心磷脂、维生素E琥珀酸酯(VES)、胆固醇琥珀酸酯、脱氧胆酸钠、胆固醇硫酸钠、油酸钠、甲氧基聚乙二醇磷脂(MPEG-DSPE)等中的一种或几种组成的混合物,其中优选油酸钠。
5.根据权利要求1所述的一种丁苯酞纳米脂质体冻干粉针剂,其特征在于,所述的保护剂为甘露醇、山梨醇、葡萄糖、甘氨酸、氯化钠、蔗糖、海藻糖、麦芽糖、葡聚糖、乳糖、右旋糖酐、羟乙基淀粉、聚维酮中的任意一种或多种按照任意比例组成的混合物,其中优选蔗糖与氯化钠组成的混合物。
6.根据权利要求1所述的一种丁苯酞纳米脂质体冻干粉针剂,其特征在于,所述的pH调节剂中的酸选自盐酸、醋酸、硝酸、硫酸、磷酸、柠檬酸、苹果酸、马来酸、富马酸、乳酸、酒石酸和琥珀酸等无机酸或有机酸,其中优选为盐酸;pH调节剂中的碱,优选为氢氧化钠。
7.根据权利要求1-6任一所述的丁苯酞纳米脂质体冻干粉针剂,其制备方式采用“改良的乙醇注入法”,称为“混合腔制备法”,包括以下步骤:
步骤1:按配比,称取丁苯酞或左旋丁苯酞、磷脂、胆固醇、长循环材料、负电荷材料于圆底烧瓶中,加入有机溶剂,超声搅拌,得到澄清透亮溶液1(油相);
步骤2:按配比,称取保护剂于烧杯中,加入注射用水,搅拌溶解,得澄清透亮溶液2(水相);
步骤3:将溶液1和溶液2通过蠕动泵系统混合,并用注射用水稀释一倍,待水相与油相混合充分得到脂质体初乳时,将脂质体初乳进行超滤除去有机溶剂,得到脂质体中间体,
步骤4:将步骤3所得脂质体中间体定容,然后通过脂质体滤膜挤出器进行整粒,得到丁苯酞纳米脂质体溶液;
步骤5:将步骤4所得丁苯酞纳米脂质体溶液除菌过滤,分装至冻干西林瓶,充保护气体,半压塞,冷冻干燥,充保护气体,压塞,出箱,轧盖,即得丁苯酞纳米脂质体冻干粉针剂。
8.根据照权利要求7所述的丁苯酞纳米脂质体冻干粉针剂,其特征在于:
步骤1中,所述的有机溶剂选自甲醇、乙醇、乙腈、二甲基亚砜、异丙醇等一种或几种按照任意比例组成的混合物,其中优选为无水乙醇;
步骤5中,所述的保护气体为氮气、二氧化碳和氩气中的任意一种或多种,其中优选为氮气,通入保护气体的时间为1~2小时,残留氧的浓度控制在5~10 ppm。
9.根据照权利要求7所述的丁苯酞纳米脂质体冻干粉针剂,其特征在于:所述冷冻干燥的步骤具体包括:
(1)预冻 将半压塞的样品放入冻干箱,开启循环泵隔板制冷,设定1h隔板温度达到-30~-50℃,保温3~6 h;
(2)升华干燥 设定1h后样品温度达到-25~-15℃,保温26~40 h,真空度为10~20 Pa,在该段进行升华干燥;
(3)解析干燥 设定2 h后样品温度达到20~30℃,保温2~6 h,真空度为5~15 Pa,在该段进行解析干燥。
10.如权利要求1-6所述丁苯酞纳米脂质体冻干粉针剂在治疗缺血性脑卒中的应用。
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