CN1116875C - 紫杉醇脂质组合物及其制备方法 - Google Patents
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Abstract
本发明公开了具有良好抗癌作用的紫杉醇脂质体制剂，其毒性小、病人耐受性好、水溶性及稳定性提高、相对成本较低；并公开了该制剂的可工业化实施的方法，用胆固醇及氨基酸作稳定剂，用甘露醇或葡萄糖作冻干保护剂，用异丙醇或乙醇作溶剂。
Description
本发明涉及通过改进配方使水溶性及稳定性增加的抗癌药物紫杉醇组合物冻干制剂及其制备方法。
紫杉醇是六十年代美国国立癌症研究所从数千种植物中筛选发现的抗癌药，治疗卵巢癌、乳腺癌及非小细胞肺癌。由于紫杉醇难溶于水及许多药用溶剂，目前国外及国内市售的紫杉醇注射剂均是用聚氧乙基代蓖麻油与无水乙醇的复合溶媒制备注射剂的。复合溶媒中的聚氧乙基代蓖麻油在体内降解时能释放组织胺，从而发生严重的过敏反应。美国布迈施贵宝公司在中国注册的紫杉醇注射剂(商品名为泰素)，其说明书中指出“为防止出现严重过敏反应，所有接受该药病人应预先给予皮质类固醇(如地塞米松)苯海拉明和H2受体拮抗剂(如西米替丁、雷尼替丁)”，还告之“注射前用生理盐水或5％葡萄糖稀释后会析出沉淀(结晶)，故还需接0.22μm微孔过滤器过滤，以保用药安全”。紫杉醇本身亦有血液学毒性、骨髓抑制、白细胞减少、血小板减少、贫血及其它毒性。这样就迫切需要改变紫杉醇的剂型，以增加其溶解度，提高其稳定性，避免由于上述复合溶媒带来的过敏反应及其它的毒副作用。从90年代初进行的紫杉醇脂质体的基础研究至目前临床前研究取得有实用价值的进展，实验表明紫杉醇脂质体制剂与注射剂相比，疗效相似，但毒性降低，耐受性提高。Sharma-A在《Int-J-Cancer》1997，71，103～107中报导用三种合成磷脂制成的紫杉醇脂质体(代号TTL)，其稳定性大于用单纯卵磷脂制成的紫杉醇脂质体(代号ETL)，但未说两者稳定性有多大差别，仅提到ETL制剂加水溶解后24小时稳定，并提及制备时所用于溶剂为苯或丁醇。苯作溶剂毒性很大。美国专利US Patent5,415,869(1995)中，提到用单纯卵磷脂制备紫杉醇脂质体制剂有聚集现象，故加入负电性物质或正电性物质，如磷脂酰甘油酯(PG)。该专利采用卵磷脂∶PG比例为9∶1或3∶7，用氯仿作溶剂时，紫杉醇脂质体不聚集，当比例为5∶5时就有紫杉醇结晶析出。PG在卵磷脂中含量极少，不易得到，国外也只有试剂规格的，价格昂贵，用氯仿作溶剂毒性太大。
本发明的目的是提供一种不含聚氧乙基代蓖麻油的紫杉醇脂质组合物冻干剂，具良好的水溶性，可直接溶于5％葡萄糖后静脉滴注。其毒性小、稳定性提高、相对成本较低。
本发明的目的还在于提供一种制备毒性小、具有良好水溶性、稳定性提高的紫杉醇脂质体制剂的可工业化实施的方法，用无毒溶媒及易得到的辅料替代有毒溶媒及昂贵的辅料。
本发明的技术方案是一种治疗癌症的紫杉醇脂质体制剂，其特征是以下述重量配比药物为原料：紫杉醇2～5份，磷脂20～200份，胆固醇2～30份，氨基酸0.4～4份，甘露醇或葡萄糖10～75份。
所述氨基酸可以是赖氨酸、苏氨酸或蛋氨酸。
所述磷脂是卵黄磷脂或大豆磷脂。
本发明技术方案还涉及一种治疗癌症的制剂的制备方法，其特征是以下述重量配比药物为原料：
紫杉醇2～5份，磷脂20～200份，胆固醇2～30份，氨基酸0.4～4份，甘露醇或葡萄糖10～75份。
将紫杉醇、磷脂、胆固醇按上述比例，溶于异丙醇或乙醇溶剂中，恒温除去溶剂，加入溶有按上述比例计算的氨基酸和甘露醇或葡萄糖的水溶液，使溶解，可用超声波或高压匀浆泵处理使粒径变小至0.1～5μm，分装入安瓿或西林瓶等容器内，冷冻干燥，即得白色块状的紫杉醇脂质体，封口或压盖时可通氮气、氦气或氩气。
所述氨基酸可以是赖氨酸、苏氨酸或蛋氨酸。
所述磷脂是卵黄磷脂或大豆磷脂。
所述恒温除去溶剂的温度是50～60℃。
本发明的有益效果表现在：
按本发明技术方案制备的紫杉醇脂质体制剂，抗癌疗效与市售紫杉醇注射液相似，参见表1。本发明采用单纯卵磷脂加胆固醇、氨基酸作稳定剂。氨基酸系两性物质，在一定pH条件下，如本技术方案条件下，可以产生带电性，从而防止聚集，且不会有紫杉醇结晶析出。比文献报导的加负电性物质如PG或带正电性物质，成本低，原料易得；比仅用单纯卵磷脂稳定，不会产生聚集现象，所得紫杉醇脂质体加水溶解后放置无结晶析出(表2)。本发明制备的紫杉醇脂质体制剂具有良好的水溶性，所得制剂中紫杉醇含量为4～8mg/ml，此浓度可适合于临床用药要求，可与市售紫杉醇注射液的相同量用于临床治疗。如按体表面积计算，每平方米175mg静脉滴注。
表1注射用紫杉醇脂质体与市售紫杉醇注射液对S-180的抑瘤作用
| 组别 | 剂量(mg/kg) | 动物数(只) | 瘤重(g) | 抑瘤率(％) | |
| 药前 | 药后 | ||||
| 紫杉醇脂质体紫杉醇脂质体紫杉醇脂质体紫杉醇注射液紫杉醇注射液对照 | 20.014.09.814.09.8 | 101010101010 | 10101010910 | 0.826±0.204**0.896±0.293**1.114±0.4250.860±0.177**1.180±0.2991.612±0.705 | 48.7944.4430.8946.6526.80 |
表2紫杉醇脂质体低温(2～10℃)稳定性试验数据
| 批号 | 时间(月) | 外观 | 显微镜检测 |
| №1 | 0 | 类白色疏松块状物 | 溶解后无结晶析出，不聚集 |
| 1 | 类白色疏松块状物 | 溶解后无结晶析出，不聚集 | |
| 6 | 类白色疏松块状物 | 溶解后无结晶析出，不聚集 | |
| 12 | 类白色疏松块状物 | 溶解后无结晶析出，不聚集 | |
| №2 | 0 | 类白色疏松块状物 | 溶解后无结晶析出，不聚集 |
| 1 | 类白色疏松块状物 | 溶解后无结晶析出，不聚集 | |
| 6 | 类白色疏松块状物 | 溶解后无结晶析出，不聚集 | |
| 12 | 类白色疏松块状物 | 溶解后无结晶析出，不聚集 |
实施例：
取注射用紫杉醇6.0g，精制卵磷脂72g及胆固醇10.8g置圆底烧瓶内，加适量乙醇至上述混合物中使完全溶解成澄明溶液，置恒温水浴(50℃)减压干燥成膜，加含赖氨酸1.4g的5％甘露醇溶液溶解膜，用超声波仪超声粉碎或高压匀浆泵进行匀浆，再用0.22μm滤膜过滤除菌，分装于安瓿内(或西林瓶)，使每瓶含紫杉醇30mg。进行冷冻干燥，通惰性气体封口即得白色块状紫杉醇脂质体制剂。
Claims (8)
1.一种治疗癌症的紫杉醇脂质体制剂，其特征是以下述重量配比药物为原料：紫杉醇2～5份，磷脂20～200份，胆固醇2～30份，氨基酸0.4～4份，甘露醇或葡萄糖10～75份。
2.根据权利要求1的紫杉醇脂质体制剂，其特征是所述氨基酸可以是赖氨酸、苏氨酸或蛋氨酸。
3.根据权利要求1的紫杉醇脂质体制剂，其特征是所述磷脂是卵磷脂或大豆磷脂。
4.一种治疗癌症的紫杉醇脂质体制剂的制备方法，其特征是以下重量配比药物为原料：
紫杉醇2～5份，磷脂20～200份，胆固醇2～30份，氨基酸0.4～4份，甘
露醇或葡萄糖10～75份；
将紫杉醇、磷脂、胆固醇按上述比例溶于异丙醇或乙醇中，恒温除去溶剂，加入溶有按上述比例计算的氨基酸和甘露醇或葡萄糖的水溶液，溶解后，分装入容器内，冷冻干燥，得紫杉醇脂质体制剂。
5.根据权利要求4的一种治疗癌症的紫杉醇脂质体制剂的制备方法，其特征是所述氨基酸可以是赖氨酸、苏氨酸或蛋氨酸。
6.根据权利要求4的一种治疗癌症的紫杉醇脂质体制剂的制备方法，其特征是所述磷脂是卵磷脂或大豆磷脂。
7.根据权利要求4的一种治疗癌症的紫杉醇脂质体制剂的制备方法，其特征是恒温除去溶剂的温度是50～60℃。
8.根据权利要求4，冷冻干燥后通入氮气、氦气或氩气。
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
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| CN00119039A CN1116875C (zh) | 2000-10-19 | 2000-10-19 | 紫杉醇脂质组合物及其制备方法 |
| PCT/CN2001/000309 WO2002032399A1 (fr) | 2000-10-19 | 2001-02-28 | Composition pharmaceutique pour le traitement du cancer combinant le taxol et un liposome ainsi que son procede de preparation |
| AU2001246338A AU2001246338A1 (en) | 2000-10-19 | 2001-02-28 | Taxol liposome composition for treatment of cancer and preparation thereof |
| DE60143168T DE60143168D1 (de) | 2000-10-19 | 2001-02-28 | Liposomzusammensetzungen, Paclitaxel enthaltend, zur Behandlung von Krebs und deren Zubereitung |
| RU2003114442/15A RU2264807C2 (ru) | 2000-10-19 | 2001-02-28 | Липосомальная композиция с паклитакселом для лечения рака и способ ее получения |
| EP01919099A EP1332755B1 (en) | 2000-10-19 | 2001-02-28 | Paclitaxel Liposome Composition For Treatment of Cancer and Preparation Thereof |
| AT01919099T ATE482688T1 (de) | 2000-10-19 | 2001-02-28 | Liposomzusammensetzungen, paclitaxel enthaltend, zur behandlung von krebs und deren zubereitung |
| JP2002535637A JP4890732B2 (ja) | 2000-10-19 | 2001-02-28 | 癌治療用パクリタキセル・リポソーム組成物およびその製造方法 |
| ES01919099T ES2353488T3 (es) | 2000-10-19 | 2001-02-28 | Composición de liposomas de paclitaxel para el tratamiento del cáncer, y su preparación. |
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| CN00119039A CN1116875C (zh) | 2000-10-19 | 2000-10-19 | 紫杉醇脂质组合物及其制备方法 |
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| EP (1) | EP1332755B1 (zh) |
| JP (1) | JP4890732B2 (zh) |
| CN (1) | CN1116875C (zh) |
| AT (1) | ATE482688T1 (zh) |
| AU (1) | AU2001246338A1 (zh) |
| DE (1) | DE60143168D1 (zh) |
| ES (1) | ES2353488T3 (zh) |
| RU (1) | RU2264807C2 (zh) |
| WO (1) | WO2002032399A1 (zh) |
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| US5891467A (en) * | 1997-01-31 | 1999-04-06 | Depotech Corporation | Method for utilizing neutral lipids to modify in vivo release from multivesicular liposomes |
-
2000
- 2000-10-19 CN CN00119039A patent/CN1116875C/zh not_active Expired - Lifetime
-
2001
- 2001-02-28 RU RU2003114442/15A patent/RU2264807C2/ru active
- 2001-02-28 WO PCT/CN2001/000309 patent/WO2002032399A1/zh not_active Ceased
- 2001-02-28 AU AU2001246338A patent/AU2001246338A1/en not_active Abandoned
- 2001-02-28 AT AT01919099T patent/ATE482688T1/de active
- 2001-02-28 EP EP01919099A patent/EP1332755B1/en not_active Expired - Lifetime
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100364525C (zh) * | 2006-04-12 | 2008-01-30 | 中国药科大学 | 含壳聚糖衍生物的多西他塞脂质体、冻干制剂及制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1332755A1 (en) | 2003-08-06 |
| ES2353488T3 (es) | 2011-03-02 |
| WO2002032399A1 (fr) | 2002-04-25 |
| AU2001246338A1 (en) | 2002-04-29 |
| EP1332755B1 (en) | 2010-09-29 |
| JP4890732B2 (ja) | 2012-03-07 |
| EP1332755A4 (en) | 2005-03-09 |
| JP2004516247A (ja) | 2004-06-03 |
| CN1291474A (zh) | 2001-04-18 |
| RU2264807C2 (ru) | 2005-11-27 |
| DE60143168D1 (de) | 2010-11-11 |
| ATE482688T1 (de) | 2010-10-15 |
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Address after: High road 210061 Jiangsu city of Nanjing province high tech Industrial Development Zone No. 28 Patentee after: NANJING LUYE PHARMACEUTICAL Co.,Ltd. Address before: High road 210061 Jiangsu city of Nanjing province high tech Industrial Development Zone No. 28 Patentee before: NANJING LVYE PHARMACEUTICAL CO.,LTD. |
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| CX01 | Expiry of patent term | ||
| CX01 | Expiry of patent term |
Granted publication date: 20030806 |