CN115227654A - 一种卡巴他赛脂质体冻干粉组合物及其制备方法 - Google Patents
一种卡巴他赛脂质体冻干粉组合物及其制备方法 Download PDFInfo
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- CN115227654A CN115227654A CN202210404983.XA CN202210404983A CN115227654A CN 115227654 A CN115227654 A CN 115227654A CN 202210404983 A CN202210404983 A CN 202210404983A CN 115227654 A CN115227654 A CN 115227654A
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Abstract
本申请属于医药制剂领域,具体涉及一种卡巴他赛脂质体冻干粉组合物及其制备方法。该药物组合物包括卡巴他赛或其药学上可接受的盐、维生素E琥珀酸聚乙二醇酯、磷脂、胆固醇及冻干保护剂。该药物组合物不使用吐温‑80、制备工艺简单,以实现降低卡巴他赛注射液的毒性,简化药液配制过程,同时提高卡巴他赛制剂的载药量,降低临床用药剂量。
Description
技术领域
本发明属于医药制剂领域,具体涉及一种卡巴他赛脂质体冻干粉组合物及其制备方法。
背景技术
卡巴他赛是一种半合成紫杉烷类化合物,作为微管抑制剂,能与微管蛋白结合,促使微管双聚体装配成微管,阻止其去多聚化过程,抑制微管分解使细胞阻滞于G2和M期,从而抑制癌细胞的有丝分裂和增殖。与其他紫杉烷类药物(多西他赛和紫杉醇)相比,卡巴他赛对P糖蛋白的亲和力低,发生药物耐受性的机率低,可用于治疗多药耐药性肿瘤。此外,卡巴他赛通过血脑屏障的能力强于多西他赛和紫杉醇,对多西他赛不敏感的肿瘤模型也显示出广谱的体内抗肿瘤活性。2010年6月,美国FDA批准Sanofi-Aventis公司研发的卡巴他赛与泼尼松联合用于治疗经多西他赛治疗过的激素难治性转移性前列腺癌。
卡巴他赛亲脂性强,几乎不溶于水,上市的卡巴他赛制剂仅有法国赛诺菲公司研制的卡巴他赛注射液(商品名为Jevtan),研究表明,卡巴他赛的原研注射液存在如下缺陷:1)处方中溶媒的毒性和致敏性:API水溶性差,处方使用100%的吐温-80作溶剂进行改善,但研究发现吐温-80诱导的短暂适中的超敏反应与其体液滞留有关,且其有轻微的溶血性,因此,实际临床使用时前,需使用抗组胺类药物和非甾体抗炎药物进行预处理,即使经前述处理后,患者仍有可能出现不同程度的过敏反应,需随时进行观察;2)原研注射液稳定性较差:该注射液先将药物溶解于吐温-80中,临床使用前,用13%乙醇稀释至10mg/mL,而在给药前,进一步用5%葡萄糖或生理盐水稀释至临床使用浓度,稀释后注射液需在4小时内使用,否则将会产生沉淀,另外,卡巴他赛吐温-80溶液在低温15℃以下易析出,存在用药方面的安全隐患;3)临床剂量准确性较差:临床使用前需进行两步稀释,且装量比较小,不同护士在配药时剂量存在差异,影响疗效和安全性。
CN102068407A公开了一种卡巴他赛注射液及其制备方法,该方法制备的卡巴他赛注射液是一支西林瓶包装的药物溶液,然而,其制备过程仍然采用乙醇为溶剂、吐温-80为增溶剂,只不过减少了稀释步骤,因此,仍然存在上述上市产品中所存在的不足。
CN103768018A公开了一种卡巴他赛脂质体注射剂及其制备方法,该脂质体包括卡巴他赛、磷脂、胆固醇、甘露醇或葡萄糖,该技术方案解决了原研普通注射液配方中含有吐温-80的过敏风险,并提高了药物在动物体内的暴露量,但是所得脂质体成品质量可控性较差,分散在脂质体磷脂双分子层中的卡巴他赛容易受到载药量、温度等因素的影响而在体系中析出,成品放置12个月前后含量变化较大,载药量较低,制备方法繁琐,尚无法进行工业化大生产。
CN103974703A公开了一种卡巴他赛制剂及其制备方法,包含卡巴他赛、增溶剂、生育酚聚乙二醇琥珀酸酯(TPGS)、一种或多种水溶助长剂、任选存在的一种或多种pKa为约3至约6的试剂、以及任选存在的一种或多种抗氧化剂,所得制剂含大量的抗氧化剂、增溶剂、水溶性助长剂、pKa为约3至约6的酸或缓冲剂,本身就能引发安全性问题,加上卡巴他赛分子中含较多酯键使之稳定性差,在浓缩状态下更易水解。
CN104306333A公开了一种卡巴他赛脂质微球注射液及其制备方法,处方组成包含了表面活性剂(吐温类)和两亲性聚氨基酸,临床使用中仍有可能产生过敏、溶血等不良反应。
CN104473873A公开了一种卡巴他赛长循环脂质体注射液及其制备方法,包括卡巴他赛或其药学上可接受的盐、生育酚聚乙二醇琥珀酸酯、二硬脂酰磷脂酰乙醇胺-聚乙二醇-马来酰亚胺和磷脂。该脂质体处方中不含胆固醇,会降低所得脂质体制剂的体内外稳定性,进而影响机体的疗效。
CN104856973A公开了卡巴他赛胶束载药系统,该系统除了载体材料本身安全性存在问题外,胶束制剂在体内的不稳定性是该系统临床应用的另一大障碍。
CN105030701A公开了一种注射用卡巴他赛组合物和一种注射用卡巴他赛稀释液及其制备方法,注射用卡巴他赛组合物中的主要成份为卡巴他赛丙酮化物,辅料为牛磺酸、乙醇溶液,稀释剂为聚山梨酯-80、乙醇,因此,所得组合物仍存在上市品中所存在的不足之处。
CN105380906A一种卡巴他赛肿瘤靶向脂质体注射剂及其制备方法,该注射剂通过如下方法制备而成:将卡巴他赛、磷脂、胆固醇、叶酸-聚乙二醇-双硬脂酰磷脂酰乙醇胺溶于有机溶剂中,减压蒸发除去有机溶剂,放置于真空干燥箱中,除尽有机溶剂,加入含有冻干保护剂的磷酸盐缓冲液形成混悬剂,匀化,整粒,冷冻干燥即可。所得脂质体注射剂粒径偏大,载药量较低。
CN107158395A公开了一种卡巴他赛磷脂组合物,该组合物包括卡巴他赛脂质复合物、磷脂和胆固醇,尚未解决卡巴他赛药物不稳定、临床使用前配制步骤繁琐的技术问题,所得制剂包封率较低,处方中使用大量有机溶剂,制备工艺复杂,制备时需将所制备的磷脂复合物两次溶于有机溶剂,并进行两次蒸馏以除去有机溶剂,此外,所得组合物的载药量也有待于提高。
CN107137353A公开了一种注射用卡巴他赛脂质体剂型,包含卡巴他赛、磷脂、胆固醇、冻干保护剂、水性介质、稳定剂,可通过探头超声分散、高速分散机分散、高压均质机分散等方法制备而成,载药量较低。
CN110302160A公开了一种卡巴他赛前药脂质体,包含卡巴他赛、卵磷脂、胆固醇和DSPE-PEG2k,所得卡巴他赛前药脂质体的成品粒径偏大,PDI较大。
现有技术中,为提高卡巴他赛的药效,多将API与辅料做成可靶向机体特定部位的脂质体,但脂质体稳定性差,长期贮存中脂质体易聚集,脂质体进入体内后包封的药物因温差可导致API快速泄露,此外,脂质体处方中还含有表面活性剂,存在用药安全性问题,脂质体制备方法复杂,难以实现工业化生产,制得的脂质体粒径难以控制,分布不均匀,包封率低、载药量低、稳定性差。因此,如何选择脂质体的辅料种类、比例及筛选制备工艺,从而提供一种能解决上述技术问题的卡巴他赛新剂型,为临床提供配制方便快捷、载药量高、稳定性好的产品,具有重要的现实意义。
发明内容
鉴于现有技术的缺陷,本发明的目的在于提供一种卡巴他赛脂质体冻干粉组合物,该组合物不使用吐温-80、制备工艺简单,以实现降低卡巴他赛注射液的毒性,简化药液配制过程,同时提高卡巴他赛制剂的载药量,降低临床用药剂量。
本发明的技术方案为:一种卡巴他赛脂质体冻干粉组合物,所述组合物包含卡巴他赛或其药学上可接受的盐、维生素E琥珀酸聚乙二醇酯、磷脂、胆固醇及冻干保护剂,其中维生素E琥珀酸聚乙二醇酯又称为TPGS。
优选地,所述组合物中,卡巴他赛与TPGS的重量比为1:0.1~5;进一步优选地,卡巴他赛与TPGS的重量比为1:1~3。
优选地,所述组合物中,TPGS中的聚乙二醇的分子量为400~4000。
优选地,所述组合物中,卡巴他赛与磷脂的重量比为1:1~20;进一步优选地,卡巴他赛与磷脂的重量比为1:10~20。
优选地,所述组合物中,磷脂选自大豆卵磷脂(SPC)、蛋黄卵磷脂(EPC)、氢化大豆磷脂(HSPC)、二硬脂酰磷脂酰胆碱(DSPC)、二棕榈酰磷脂酰胆碱(DPPC)、磷脂酰甘油(DSPG)中的一种或几种;进一步优选地,磷脂选自大豆卵磷脂(SPC)、蛋黄卵磷脂(EPC)、氢化大豆磷脂(HSPC)中的一种或几种。
优选地,所述组合物中,卡巴他赛与胆固醇的重量比为1:0.1~5;进一步优选地,卡巴他赛与胆固醇的重量比为1:0.5~2。
优选地,所述组合物中,卡巴他赛与冻干保护剂的重量比为1:10~100;进一步优选地,卡巴他赛与冻干保护剂的重量比为1:45~70。
优选地,所述组合物中,冻干保护剂选自蔗糖、氨基酸、葡萄糖、甘露醇、乳糖、海藻糖中的一种或几种;进一步优选地,冻干保护剂选自蔗糖、氨基酸或葡萄糖中的一种或几种。
优选地,所述组合物含有如下重量份的组份:卡巴他赛为1份,TPGS为0.1~5份,磷脂为1~20份,胆固醇为0.1~5份,冻干保护剂为10~100份。
进一步优选地,所述组合物含有如下重量份的组份:卡巴他赛为1份,TPGS为1~3份,磷脂为10~20份,胆固醇为0.5~2份,冻干保护剂为45~70份。
本发明还提供了一种卡巴他赛脂质体冻干粉组合物的制备方法:将卡巴他赛或其药学上可接受的盐、维生素E琥珀酸聚乙二醇酯、磷脂和胆固醇溶于有机溶剂中,旋转蒸发除去有机溶剂,加入冻干保护剂的水溶液水化后形成脂质体混悬液,然后在10000~30000psi压力下经双层聚碳酸酯膜高压匀质或挤出,过滤、分装、冷冻干燥即得卡巴他赛脂质体冻干粉组合物。
优选地,所述组合物的制备方法中,有机溶剂选自氯仿、甲醇、乙醇、丙酮中一种或几种。
优选地,所述组合物的制备方法中,双层聚碳酸酯膜的孔径为0.05~0.8μm。
本发明所述组合物,可以在现有处方的基础上,添加适量的抗氧化剂或/和稳定剂,进一步提高组合物稳定性等性质。
本发明的优势在于:
(1)本发明将卡巴他赛包封于柔性脂质中,双亲性分子TPGS提供了PEG基团,能保护脂质体不被网状内皮系统中的巨噬细胞吞噬,延长在血液循环中的时间显著改善了卡巴他赛的药动学行为,并且,TPGS作为高效的P-gp糖蛋白抑制剂,克服多药耐药,从而提高卡巴他赛的治疗效果;
(2)本发明所述卡巴他赛脂质体冻干粉组合物,不使用吐温-80,处方中所用有机溶剂的用量低于现有技术中记载的处方量,并可最终在旋转蒸发条件下将其除去,降低有机溶剂刺激的风险,用药安全性更好;
(3)本发明所述卡巴他赛脂质体冻干粉组合物,制备工艺简单,适合大规模生产;
(4)本发明所得卡巴他赛脂质体冻干粉组合物,包封率高于95%,载药量高,粒径分布均匀;
(5)本发明所得卡巴他赛脂质体冻干粉组合物,稳定性较好,临床使用简便,卡巴他赛脂质体注射剂在加入注射用水后重新分散后,能以任意比例溶于输液稀释给药,大大简化了临床使用;所得脂质体中的药物持续释放,延长了在血液中的循环时间,提高了药物有效成分的利用率。
具体实施方式
下面列举具体实施方式对本发明予以进一步说明,但不以任何方式限制本发明的范围,本领域技术人员根据本发明的基本思想,可以做出各种修改或改进,但是只要不脱离本发明的基本思想,均在本发明的范围之内。
实施例1
(一)处方
(二)制备工艺:
取处方量物料至10L圆底烧瓶,加入乙醇300mL溶解,在65℃下减压干燥除去有机溶剂,使其在圆底烧瓶壁形成脂膜,加入3L含9wt%蔗糖的水溶液,在室温(10~30℃)下搅拌水化,使脂膜脱落,形成脂质体混悬液;将水化后的脂质体混悬液依次经双层孔径为0.2μm、0.08μm的聚碳酸酯膜挤出各2次,将所得脂质体溶液过滤除菌后分装至西林瓶中,冷冻干燥得到卡巴他赛脂质体冻干粉组合物。
实施例2
(一)处方
(二)制备工艺:
取处方量物料至10L圆底烧瓶,加入氯仿300mL溶解,在50℃下减压干燥除去有机溶剂,使其在圆底烧瓶壁形成脂膜,加入3L含14wt%精氨酸的水溶液,在室温(10~30℃)下搅拌水化,使脂膜脱落,形成脂质体混悬液;将水化后的脂质体混悬液依次经双层孔径为0.1μm、0.05μm的聚碳酸酯膜挤出各2次,将所得脂质体溶液过滤除菌后分装至西林瓶中,冷冻干燥得到卡巴他赛脂质体冻干粉组合物。
实施例3
(一)处方
(二)制备工艺:
取处方量物料至10L圆底烧瓶,加入甲醇400mL溶解,在50℃下减压干燥除去有机溶剂,使其在圆底烧瓶壁形成脂膜,加入3L含12wt%葡萄糖的水溶液,在室温(10~30℃)下搅拌水化,使脂膜脱落,形成脂质体混悬液;将水化后的脂质体混悬液依次经双层孔径为0.2μm、0.05μm的聚碳酸酯膜挤出各2次,将所得脂质体溶液过滤除菌后分装至西林瓶中,冷冻干燥得到卡巴他赛脂质体冻干粉组合物。
实施例4
(一)处方
(二)制备工艺:
取处方量物料至10L圆底烧瓶,加入丙酮200mL溶解,在35℃下减压干燥除去有机溶剂,使其在圆底烧瓶壁形成脂膜,加入3L含2wt%甘露醇的水溶液,在室温(10~30℃)下搅拌水化,使脂膜脱落,形成脂质体混悬液;将水化后的脂质体混悬液依次经双层孔径为0.4μm、0.1μm的聚碳酸酯膜挤出各2次,将所得脂质体溶液过滤除菌后分装至西林瓶中,冷冻干燥得到卡巴他赛脂质体冻干粉组合物。
实施例5
(一)处方
(二)制备工艺:
取处方量物料至10L圆底烧瓶,加入乙醇300mL溶解,在50℃下减压干燥除去有机溶剂,使其在圆底烧瓶壁形成脂膜,加入3L含20wt%冻干保护剂(乳糖和海藻糖)的水溶液,在室温(10~30℃)下搅拌水化,使脂膜脱落,形成脂质体混悬液;将水化后的脂质体混悬液依次经双层孔径为0.8μm、0.08μm的聚碳酸酯膜挤出各2次,将所得脂质体溶液过滤除菌后分装至西林瓶中,冷冻干燥得到卡巴他赛脂质体冻干粉组合物。
实施例6
(一)处方
(二)制备工艺:
取处方量物料至10L圆底烧瓶,加入甲醇400mL溶解,在50℃下减压干燥除去有机溶剂,使其在圆底烧瓶壁形成脂膜,加入3L含12wt%葡萄糖的水溶液,在室温(10~30℃)下搅拌水化,使脂膜脱落,形成脂质体混悬液;将水化后的脂质体混悬液依次经双层孔径为0.2μm、0.05μm的聚碳酸酯膜挤出各2次,将所得脂质体溶液过滤除菌后分装至西林瓶中,冷冻干燥得到卡巴他赛脂质体冻干粉组合物。
实施例7
(一)处方
(二)制备工艺:
取处方量物料至10L圆底烧瓶,加入甲醇300mL溶解,在50℃下减压干燥除去有机溶剂,使其在圆底烧瓶壁形成脂膜,加入3L含12wt%葡萄糖的水溶液,在室温(10~30℃)下搅拌水化,使脂膜脱落,形成脂质体混悬液;将水化后的脂质体混悬液依次经双层孔径为0.2μm、0.05μm的聚碳酸酯膜挤出各2次,将所得脂质体溶液过滤除菌后分装至西林瓶中,冷冻干燥得到卡巴他赛脂质体冻干粉组合物。
实施例8
(一)处方
(二)制备工艺:
取处方量物料至10L圆底烧瓶,加入乙醇300mL溶解,在65℃下减压干燥除去有机溶剂,使其在圆底烧瓶壁形成脂膜,加入3L含9wt%蔗糖的水溶液,在室温(10~30℃)下搅拌水化,使脂膜脱落,形成脂质体混悬液;将水化后的脂质体混悬液依次经双层孔径为0.2μm、0.08μm的聚碳酸酯膜挤出各2次,将所得脂质体溶液过滤除菌后分装至西林瓶中,冷冻干燥得到卡巴他赛脂质体冻干粉组合物。
实施例9
(一)处方
(二)制备工艺:
取处方量物料至10L圆底烧瓶,加入乙醇400mL溶解,在65℃下减压干燥除去有机溶剂,使其在圆底烧瓶壁形成脂膜,加入3L含1.6wt%蔗糖的水溶液,在室温(10~30℃)下搅拌水化,使脂膜脱落,形成脂质体混悬液;将水化后的脂质体混悬液依次经双层孔径为1μm、0.4μm的聚碳酸酯膜挤出各2次,将所得脂质体溶液过滤除菌后分装至西林瓶中,冷冻干燥得到卡巴他赛脂质体冻干粉组合物。
实施例10
(一)处方
(二)制备工艺:
取处方量物料至10L圆底烧瓶,加入乙醇300mL溶解,在65℃下减压干燥除去有机溶剂,使其在圆底烧瓶壁形成脂膜,加入3L含21wt%蔗糖的水溶液,在室温(10~30℃)下搅拌水化,使脂膜脱落,形成脂质体混悬液;将水化后的脂质体混悬液依次经双层孔径为0.8μm、0.08μm的聚碳酸酯膜挤出各2次,将所得脂质体溶液过滤除菌后分装至西林瓶中,冷冻干燥得到卡巴他赛脂质体冻干粉组合物。
实施例11
(一)处方
(二)制备工艺:
取处方量物料至10L圆底烧瓶,加入乙醇300mL溶解,在65℃下减压干燥除去有机溶剂,使其在圆底烧瓶壁形成脂膜,加入3L含9wt%蔗糖的水溶液,在室温(10~30℃)下搅拌水化,使脂膜脱落,形成脂质体混悬液;将水化后的脂质体混悬液依次经双层孔径为3μm、1μm的聚碳酸酯膜挤出各2次,将所得脂质体溶液过滤除菌后分装至西林瓶中,冷冻干燥得到卡巴他赛脂质体冻干粉组合物。
对比实施例1
称取60mg卡巴他赛、300mg二硬脂酰磷脂酰甘油(DSPG)加入10mL氯仿:甲醇(9:1,v/v)中于60℃搅拌0.5h,至溶液澄清透明,旋转蒸发得卡巴他赛脂质复合物;取上述卡巴他赛脂质复合物、1200mg氢化大豆磷脂(HSPC)、120mg胆固醇,用40mL氯仿:甲醇(9:1,v/v)溶液溶解,经喷雾干燥(入口温度:45℃)得白色颗粒,加入30mL含10wt%蔗糖的水溶液水化,然后在20000psi压力下高压均质5次,即得卡巴他赛磷脂组合物,分装至西林瓶中,冷冻干燥即得卡巴他赛磷脂组合物冻干粉。
对比实施例2
(一)处方
(二)制备工艺:
将处方量的卡巴他赛、糖原质、TPGS1000、α-硫辛酸、柠檬酸和PEG 400,混合均匀,经0.22μm滤膜过滤,分装于西林瓶中,得卡巴他赛胶束。
对比实施例3
称取处方量的大豆磷脂1000mg、胆固醇50mg、卡巴他赛28mg,用二氯甲烷550ml于30℃水浴搅拌下使溶解,后旋转蒸发,使磷脂的二氯甲烷溶液在壁上成膜;30℃减压除去二氯甲烷后加入同温度水性介质0.1mol/L的柠檬酸盐(pH值6.6)溶液100ml,30℃水浴中水化,取出脂质体放入烧杯中;冷却至室温后,于高速分散机中10000rpm分散5min,加入4%葡萄糖冻干保护剂,依次经0.45μm、0.22μm滤膜过滤,分装于西林瓶中,冷冻干燥,即得。
验证实施例
1、外观、粒径和电位的测定
外观:应为白色至淡黄色疏松饼状物,表面平整美观,无裂纹。
粒径和电位:仪器为Zeta size动态光散射粒度仪,型号为Nanozs型,厂家为Malvern;参数设置为波长632.8nm、角度173°、温度25℃、平衡2min、介质为9wt%蔗糖溶液;样品制备:分别取各上述实施例所得的卡巴他赛制剂,用纯化水复溶,取30μL复溶后的样品,稀释至1mL,用粒度分析仪测定粒径,结果如表1所示。
表1卡巴他赛制剂的外观和粒径的测定结果
本发明的实施例1~11所得卡巴他赛制剂的粒径均在80~120nm之间,粒径分布的数值小于0.3,粒径分布均匀;实施例1~5所得卡巴他赛脂质体冻干粉组合物的粒径均在80~100nm之间,粒径分布的数值小于0.1;对比实施例1所得脂质体,为淡黄色非疏松饼状物,对比实施例2~3所得脂质体,粒径分布不均匀。
2、含量、包封率、载药量和复溶时间的测定
含量的测定:
仪器:高效液相色谱仪型号:Thermo 3000
测试方法:HPLC法
色谱条件:色谱柱:Ultimate XB-C18(4.6×250mm,5μm);流动相:甲醇:水=80:20(V:V);
检测波长:230nm;流速:1mL/min;进样体积:20μL;柱温:30.0±5℃;
样品制备:分别取上述实施例所得的卡巴他赛制剂,加定量注射用水使其充分溶解,精密量取样品溶液1mL,置10mL容量瓶中,加入甲醇稀释至刻度,摇匀。稀释样品经孔径为0.22μm的微孔滤膜过滤,进样;
结果:本品含量为标示量的99.05%。
包封率的测定:分别取上述实施例所得的卡巴他赛制剂,加定量注射用水使其充分溶解。精密移取2mL脂质体溶液至超滤离心管,离心力设置为7000×g,离心时间为10min,离心温度为25℃。离心后精密量取下部离心液1mL,置10mL容量瓶中,加入甲醇超声3min破乳并稀释至刻度,摇匀。稀释样品经孔径为0.22μm的微孔滤膜过滤,按上述“含量”测定色谱条件进样,HPLC法测定,峰面积记为A。另取卡巴他赛脂质体冻干粉,加定量注射用水使其充分溶解。精密量取样品1mL,置10mL容量瓶中,后续处理方法同前,峰面积记为A0。依照以下公式计算包封率:包封率%=A/A0×100%。
载药量的测定:分别取上述实施例所得的卡巴他赛制剂,加定量注射用水使其充分溶解。精密移取2mL脂质体溶液至超滤离心管,离心力设置为7000×g,离心时间为10min,离心温度为25℃。离心后精密量取下部离心液1mL,置10mL容量瓶中,加入甲醇超声3min破乳并稀释至刻度,摇匀。稀释样品经孔径为0.22μm的微孔滤膜过滤,按上述“含量”测定色谱条件进样,HPLC法测定,浓度为C1。根据以下公式计算载药量:载药量=10C1/(10C1+M)×100%。M为处方中每瓶辅料(不含冻干保护剂)的质量。结果如表2所示。
复溶时间:分别取上述实施例所得的卡巴他赛制剂,加定量注射用水、5%葡萄糖注射液或0.9%氯化钠注射液轻摇复溶,记录复溶时间。
表2卡巴他赛制剂的含量、包封率和载药量的测定结果
样品 | 含量(%) | 包封率(%) | 载药量(%) | 复溶时间(s) |
实施例1 | 99.79 | 98.12 | 7.8 | 10.5 |
实施例2 | 99.87 | 98.46 | 5.1 | 11.1 |
实施例3 | 99.85 | 98.75 | 4.3 | 11.6 |
实施例4 | 99.68 | 97.76 | 9.3 | 12.4 |
实施例5 | 99.72 | 97.98 | 8.0 | 11.8 |
实施例6 | 99.48 | 97.61 | 4.2 | 13.5 |
实施例7 | 99.13 | 98.08 | 3.3 | 16.2 |
实施例8 | 98.75 | 97.16 | 3.2 | 18.7 |
实施例9 | 95.48 | 93.75 | 2.0 | 25.3 |
实施例10 | 94.65 | 95.13 | 2.1 | 26.9 |
实施例11 | 99.66 | 97.83 | 4.8 | 20.4 |
对比实施例1 | 90.12 | 86.20 | 1.9 | 300.5 |
对比实施例2 | 88.24 | 62.11 | 1.2 | 405.8 |
对比实施例3 | 99.01 | 93.55 | 1.5 | 380.5 |
3、取上述实施例1所得的卡巴他赛制剂进行体外释放度和配伍稳定性的测定
体外释放度:取卡巴他赛脂质体冻干粉组合物,加入定量注射用水复溶,利用流通池溶出仪进行实验,取1mL样品溶液置透析袋(MW=3500~5000)中,将装入透析袋的样品置于溶出杯中进行实验,溶出条件为:温度37℃,流速8mL/min,开环模式,不补液。释放介质是100mL含0.5%吐温80的PBS缓冲液,分别于0.5h、1.0h、2.0h、4.0h、6.0h、8.0h、12.0h、24.0h、36.0h和48.0h时取1mL透析液,按上述“含量”测定HPLC法进样,作释放度曲线,结果如表3所示。
表3卡巴他赛制剂的体外释放度的测定结果
时间(h) | 0.5 | 1.0 | 2.0 | 4.0 | 6.0 | 8.0 |
释放率(%) | 5.69 | 8.09 | 11.33 | 13.88 | 15.68 | 16.35 |
时间(h) | 12.0 | 18.0 | 24.0 | 36.0 | 48.0 | |
释放率(%) | 17.03 | 18.55 | 19.06 | 19.59 | 19.66 |
结果表明,脂质体中药物的释放有明显的缓释效果,本发明脂质体缓释效果好。
配伍稳定性:取卡巴他赛脂质体冻干粉组合物,加定量注射用水、5%葡萄糖注射液或0.9%氯化钠注射液复溶,考察室温放置24小时的稳定性,使用纳米粒径分析仪测试粒径,结果如表4所示。
表4卡巴他赛制剂的配伍稳定性的测定结果
注:PDI,即Polydispersity Index
结果表明,本发明所得卡巴他赛脂质体冻干粉组合物,配伍稳定性良好。
Claims (10)
1.一种卡巴他赛脂质体冻干粉组合物,其特征在于,所述组合物包含卡巴他赛或其药学上可接受的盐、维生素E琥珀酸聚乙二醇酯、磷脂、胆固醇及冻干保护剂,其中,维生素E琥珀酸聚乙二醇酯又称为TPGS。
2.如权利要求1所述的组合物,其特征在于,所述组合物中,卡巴他赛与TPGS的重量比为1:0.1~5。
3.如权利要求1所述的组合物,其特征在于,所述组合物中,卡巴他赛与磷脂的重量比为1:1~20。
4.如权利要求1所述的组合物,其特征在于,所述组合物中,磷脂选自大豆卵磷脂、蛋黄卵磷脂、氢化大豆磷脂、二硬脂酰磷脂酰胆碱、二棕榈酰磷脂酰胆碱、磷脂酰甘油中的一种或几种。
5.如权利要求1所述的组合物,其特征在于,所述组合物中,卡巴他赛与胆固醇的重量比为1:0.1~5。
6.如权利要求1所述的组合物,其特征在于,所述组合物中,卡巴他赛与冻干保护剂的重量比为1:10~100。
7.如权利要求1所述的组合物,其特征在于,所述组合物中,冻干保护剂选自蔗糖、氨基酸、葡萄糖、甘露醇、乳糖、海藻糖中的一种或几种。
8.如权利要求1~7任一项所述的组合物,其特征在于,所述组合物中,含有如下重量份的组份:卡巴他赛为1份,TPGS为0.1~5份,磷脂为1~20份,胆固醇为0.1~5份,冻干保护剂为10~100份。
9.一种如权利要求1所述的卡巴他赛脂质体冻干粉组合物的制备方法,其特征在于,将卡巴他赛或其药学上可接受的盐、维生素E琥珀酸聚乙二醇酯、磷脂和胆固醇溶于有机溶剂中,旋转蒸发除去有机溶剂,加入冻干保护剂的水溶液水化后形成脂质体混悬液,然后在10000~30000psi压力下经双层聚碳酸酯膜高压匀质或挤出,过滤、分装、冷冻干燥即得卡巴他赛脂质体冻干粉组合物。
10.如权利要求9所述的制备方法,其特征在于,所述组合物的制备方法中,双层聚碳酸酯膜的孔径为0.05~0.8μm。
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