CN1259902C - 制造紫杉醇和白蛋白的纳米颗粒的方法 - Google Patents
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Abstract
一种制备有抗肿瘤性质的紫杉醇和白蛋白的纳米颗粒的方法，用此方法，将通过向白蛋白与氯仿的水溶液中加入粉末状紫杉醇得到的混合物进行高压均质处理。
Description
技术领域
本发明涉及制备紫杉醇和白蛋白的纳米颗粒的方法，能用于获得抗肿瘤组合物。
背景技术
紫杉醇是在文献中已知的天然物质，具有重要的抗肿瘤活性：它的弱水溶性使其难于对人给药，由于此原因，已开发了多种能使其可注射的系统。
根据这些系统中的一个，紫杉醇与生物相容性且有很强的与紫杉醇结合能力的人血清白蛋白(HSA)联合，并通过已知的超声波、高压匀质化和微流化技术形成可注射乳剂(Allemann等，Eur.J.Pharm.Biopharm.39(5)，173-191(1993))。
基于这些要素，并通过使用上述超声波、高压匀化技术，美国VivoRx药物公司已开发了含有紫杉醇和HSA的制剂CAPXOL(R)。
在US 5439686、US 5498421、US 5560933和相应的WO94/18954中，VivoRx要求保护用超声波技术制备的紫杉醇和HSA的微粒，得到平均粒径(MPS)＜10微米的颗粒。在这些专利中记载的制备方法不能用于工业化规模，并且如此得到的微粒有太高的MPS，这使其不适于和不能用于对病人给药。
VivoRx很清楚这一点，因此它在US 5916596和US 6096331及WO 98/14174和WO 99/00113中记载并要求保护通过用无菌0.9％NaCl水溶液重制紫杉醇和HSA的冷冻干燥粉末而得到的无菌纳米乳剂，其MPS＜0.2微米。如引证的专利所述的，这些用高压匀化方法得到的纳米乳剂据称有高的稳定性，此处术语“稳定性”的意义既表示MPS不随时间改变，也表示不出现纳米颗粒沉淀(US 6096331，实施例11)。
按前述VivoRx专利的教导(见US 5916596的实施例1、5和6)，先分别制备紫杉醇的溶液和含有HSA的水溶液，然后将这些相混合在一起，并在室温(0℃和+44℃之间)将这样得到的混合物在9000至40000psi之间的高压下进行匀质化处理。
蒸发除去溶剂并通过无菌滤器(0.22微米)过滤后，将混合物在-20℃和-80℃之间冷冻，并最终在+20℃和+35℃之间的温度下加热冻干，产生具有抗肿瘤性质的能用于制备可注射制剂的粉末。
必须如此制备两个分离的相(一个含有紫杉醇，另一个含有HSA)，然后在其高压匀质化之前混合在一起。这需要使用至少两个分别的反应器和用相应的混合制备两个分别的溶液，所有都要在无菌条件下完成，包括高的设施成本、完成混合操作的时间很长，并需要溶剂的旋转蒸发(在匀质化处理结束时)，随后通过无菌滤器过滤，结果总产率较低。
发明内容
因此本发明的主要目的是提供一种制备紫杉醇和HSA的纳米颗粒的无菌冷冻干燥粉末的方法，它需要使用单一反应器形成将进行匀质化处理的含有紫杉醇和HSA的液体混合物，并可以在非常短的时间内，以低于现有技术的成本完成。
通过下面的方法达到了这一目的和进一步的目的，在该方法中，将温度为0℃至40℃之间的含有紫杉醇和白蛋白的水性混合物，在9000至40000psi之间的高压下经过匀质化处理，产生纳米乳剂，它在-20℃和-80℃之间冷冻，并最终在+20℃和+35℃之间的温度下加热冻干，其中所述的水性混合物是在无菌条件下通过将所述白蛋白溶解在无菌水中达到2％-3％(W/V)浓度，然后向此白蛋白溶液中加入2％-4％(V/V)的氯仿，然后加入占溶液中白蛋白重量5.4％-20.0％的无菌粉末状的紫杉醇而得到的。加入液体混合物中的无菌粉末状紫杉醇的量优选为白蛋白重量的5.6％至19.4％之间。
重要的是注意到：在此方法中使用无菌粉末状的紫杉醇不仅大大简化了流程本身，并且此方法与现有技术相比，还使在匀化处理前完成各种组分的混合所需的时间大大缩短，而也能得到更好的最终产率，并简化了为得到所需的无菌冷冻干燥粉末所遵循的条件。
通过按前述方式操作，得到了用紫杉醇和HSA的纳米颗粒的混合物形成的粉末，它完全类似或等同于用前述在先申请记载的用更复杂、费力和昂贵的方法能得到的粉末。
从这些混合物，当使用在US 5916596推荐的压力范围内的Avestin匀质器加工时，得到pH＝6.7的纳米乳剂，当它在如所述专利所报道的旋转蒸发器中蒸发时，产生MPS约为0.2微米(在蒸发后MPS的增加＞0.02微米)的纳米乳剂，它在其可注射的生理溶液的制剂中不稳定(MPS的增加约为0.05微米，在约12小时内倾向于沉积)，并难于过滤通过0.22微米滤器进行灭菌，这些滤器易于阻塞并使紫杉醇的产率降低到非常低的值(降至或低于30％)。
当按US 5916596和US 6096331报道的冷冻干燥并重制后，用如上所述的本发明的方法和按在先专利的方法制备的产品的稳定性(按US 6096331实施例11的教导评价)是能接受的，但从未超过24小时。
已令人惊奇地发现，如果在含有HS A的液体混合物中加入至少一种其量足以使粉末状纳米颗粒的重制可注射水性混合物的pH达到5.4和5.8之间(优选使pH达到5.5和5.7之间)的生物相容性酸(在向其中加入粉末状的紫杉醇之前)，可注射形态的冷冻干燥并重制混合物的稳定性大大增加，超过24小时。
加入上述酸或类似物质形成了本发明的一部分。
优选地，所述酸选自盐酸、柠檬酸、磷酸、醋酸、生物相容性有机或无机酸，但柠檬酸是最优选的一种。
具体实施方式
为阐明本发明的特征，现在描述它的一些非限定性的实施例，一些用生理pH的液体混合物，一些用酸酸化以突出使用酸所产生的差异。
实施例1
制备pH6.7的制剂
以无菌软化水将符合FDA规范的可注射的209％(w/v)HSA水溶液(pH＝6.9±0.5)稀释到3％(w/v)。
在高能振荡下将41.4ml所述溶液与1.25ml无菌氯仿，并与73.6mg(溶液中白蛋白重量的5.9％)粉末状无菌紫杉醇(效价＞99％)混合，然后将混合物在高压匀化器内(适当地灭菌)处理直至得到纳米乳剂(MPS约0.2微米)，将其真空蒸发以除去溶剂，在无菌条件下冷冻并冻干48小时。
得到的含有4.60％(W/W)紫杉醇的粉末，与0.9％NaCl水溶液重制形成紫杉醇浓度为2mg/ml的溶液。得到的制剂具有0.486微米的MPS，pH＝6.7，稳定性＜12小时。
得到的产品与用US 5916596实施例1的方法制备的产品有同样的特性。
实施例2
制备pH6.7的制剂
以无菌软化水将符合FDA规范的可注射的25％(w/v)HSA水溶液(pH＝6.9±0.5)稀释到2％(w/v)。
将49.0ml所述溶液与1.0ml无菌氯仿，并与72.5mg(白蛋白重量的7.4％)粉末状无菌紫杉醇(效价＞99％)混合，然后将混合物在高压匀化器内(适当地灭菌)处理直至得到纳米乳剂(MPS约0.2微米)，将其真空蒸发以除去溶剂，通过无菌滤器过滤(0.2微米)，在无菌条件下冷冻并冻干48小时。
得到的含有0.60％(W/W)紫杉醇的粉末，与0.9％NaCl水溶液重制形成紫杉醇浓度为2mg/ml的溶液。得到的制剂具有0.25微米的MPS，pH＝6.7，稳定性＜12小时。
实施例3
制备pH6.7的制剂
以无菌软化水将符合FDA规范的可注射的20％(w/v)HSA水溶液(pH＝6.9±0.5)稀释到3％(w/v)。
将46.7ml所述溶液与1.40ml无菌氯仿，并与108.5mg(白蛋白的7.7％)粉末状无菌紫杉醇(效价＞99％)混合，然后将混合物在高压匀化器内(适当地灭菌)处理直至得到纳米乳剂(MPS约0.2微米)，将其真空蒸发以除去溶剂，通过无菌滤器过滤(0.2微米)，在无菌条件下冷冻并冻干48小时。
得到的含有0.77％(W/W)紫杉醇的粉末，与0.9％NaCl水溶液重制形成紫杉醇浓度为2mg/ml的溶液。得到的制剂具有0.12微米的MPS，pH＝6.7，稳定性＜12小时。
如已在说明书的开始部分说明的，过滤导致紫杉醇相当大的损失(冷冻干燥粉末含有0.55％紫杉醇而非实施例2的5.2％)。这使将得到的制剂的MPS＜0.2微米。
实施例4
制备pH6.7的制剂
以无菌软化水将符合FDA规范的可注射的25％(w/v)HSA水溶液(pH＝6.9±0.5)稀释到3％(w/v)。
将29.1ml所述溶液与0.90ml无菌氯仿，并与67.0mg(白蛋白的7.7％)粉末状无菌紫杉醇(效价＞99％)混合，然后将混合物在高压匀化器内(适当地灭菌)处理直至得到纳米乳剂(MPS约0.2微米)，将其真空蒸发以除去溶剂，通过无菌滤器过滤(0.2微米)，在无菌条件下冷冻并冻干48小时。
得到含有0.70％(W/W)紫杉醇的粉末再与0.9％NaCl水溶液重制形成紫杉醇浓度为1.5mg/ml的溶液。得到的制剂具有0.25微米的MPS，pH＝6.7，稳定性＜12小时。
得到的产品与用US 5916596实施例5的方法制备的产品有同样的特性。
实施例5
制备pH6.7的制剂
以无菌软化水将符合FDA规范的可注射的20％(w/v)HSA水溶液(pH＝6.9±0.5)稀释到2.5％(w/v)，并用氯仿预饱和(1％V/V)。
将48.5ml所述溶液与1.0ml无菌氯仿，并与75mg(白蛋白的6.2％)粉末状无菌紫杉醇(效价＞99％)混合，然后将混合物在高压匀化器内(适当地灭菌)处理直至得到纳米乳剂(MPS约0.2微米)，将其真空蒸发以除去溶剂，通过无菌滤器过滤(0.2微米)，在无菌条件下冷冻并冻干48小时。
得到含有0.70％(W/W)紫杉醇的粉末，再与0.9％NaCl水溶液重制形成紫杉醇浓度为2.2mg/ml的溶液。得到的制剂具有0.18微米的MPS，pH＝6.7，稳定性＜12小时。
在实施例3结束时进行的观察在此情况下也得到验证。
实施例6
制备pH＝5.6的制剂
以无菌软化水将FDA规范的可注射的25％(w/v)HSA水溶液(pH＝6.9±0.5)稀释到3％(w/v)，用1MHCl将pH调节到5.6，HCl与白蛋白中的一些碱性基团成盐。
将57ml预先灭菌的所述溶液在强力搅拌下与1.40ml无菌氯仿，并与108mg(白蛋白重量的6.3％)粉末状无菌紫杉醇(效价＞99％)混合至少30分钟。
将混合物在匀化器内(适当地灭菌)在高压(9000-40000psi)下处理直至得到纳米乳剂(MPS＜0.2微米)，在无菌条件下将其快速冷冻到-80℃并冻干55小时，同时升温至+30℃。
将得到含有4.83％(W/W)紫杉醇和4％(w/w)水的粉末，与0.9％NaCl水溶液重制形成紫杉醇浓度为2mg/ml的溶液。得到的制剂具有0.175微米的MPS，pH＝5.6，稳定性＞24小时。
用磷酸代替盐酸得到相同的结果。
实施例7
制备pH＝5.4的制剂
以无菌软化水将符合FDA规范的可注射的25％(w/v)HSA水溶液稀释到3％(w/v)，用柠檬酸将pH调节到5.4，柠檬酸与白蛋白中的一些碱性基团成盐。
将50ml预先灭菌的所述溶液在强力搅拌下与1.23ml无菌氯仿，并与98mg(白蛋白的6.5％)粉末状无菌紫杉醇(效价＞99％)混合至少40分钟。
将混合物在匀化器内(适当地灭菌)在高压(9000-40000psi)下处理直至得到纳米乳剂(MPS＜0.2微米)，在无菌条件下将其快速冷冻到-30℃并冻干57小时，同时升温至+35℃。
将得到的含有4.80％(W/W)紫杉醇和3.8％(w/w)水的粉末，与0.9％NaCl水溶液重制形成紫杉醇浓度为2mg/ml的溶液。得到的制剂具有0.19微米的MPS，pH＝5.4，稳定性＞24小时。
用醋酸代替柠檬酸得到相同的结果。
实施例8
制备pH＝5.5的制剂
以无菌软化水将FDA规范的可注射的25％(w/v)HSA水溶液稀释到3％(w/v)，用无菌柠檬酸将pH调节到5.5，柠檬酸与白蛋白中的一些碱性基团成盐。
将37ml所述溶液在强力搅拌下与0.91ml无菌氯仿，并与71mg(白蛋白的6.4％)粉末状无菌紫杉醇(效价＞99％)混合至少40分钟，然后将混合物冷却到5-8℃。
将混合物在匀化器内(适当地灭菌)在高压(9000-40000psi)下处理直至得到纳米乳剂(MPS＜0.2微米)，在无菌条件下将其快速冷冻到-80℃并冻干58小时，同时升温至+30℃。
将得到的含有4.70％(W/W)紫杉醇和4.5％(w/w)水的粉末，与0.9％NaCl水溶液重制形成紫杉醇浓度为2mg/ml的溶液。得到的制剂具有0.185微米的MPS，pH＝5.5，稳定性＞24小时。
实施例9
制备pH＝5.5的制剂
以无菌软化水将符合FDA规范的可注射的20％(w/v)HSA水溶液(pH＝6.9±0.5)稀释到3％(w/v)，用柠檬酸将pH调节到5.5，柠檬酸与白蛋白中的一些碱性基团成盐。
将110ml所述溶液与4.10ml无菌氯仿，并与639mg(白蛋白的19.4％)粉末状无菌紫杉醇(效价＞99％)混合，然后将混合物在高压匀化器内(适当地灭菌)处理直至得到纳米乳剂(MPS约0.2微米)，将其通过无菌滤器过滤(0.2微米)，真空蒸发以除去溶剂，在无菌条件下冷冻并冻干48小时。
将得到的含有10.8％(W/W)紫杉醇的粉末，与0.9％NaCl水溶液重制形成紫杉醇浓度为2mg/ml的溶液。得到的制剂具有0.15微米的MPS，稳定性＞24小时。
Claims (7)
1.一种制备由紫杉醇和人血清白蛋白的纳米颗粒构成的无菌冷冻干燥粉末的方法，该方法包括将含有紫杉醇和白蛋白的水性混合物在0℃-40℃之间的温度，9000至40000psi之间的高压下经过均质化处理，得到纳米乳剂，它在-20℃至-80℃之间的温度下冷冻，最后经过加热到+20℃至35℃之间的温度而冻干，该方法的特征在于所述水性混合物是这样获得的：在无菌条件下，通过将2％至3％(W/V)所述白蛋白溶解在无菌水中，然后向所述白蛋白溶液中加入2％至4％(V/V)的无菌氯仿，再加入占溶液中白蛋白重量5.4％至20.0％(W/W)的无菌粉末状的紫杉醇。
2.根据权利要求1所述的方法，其特征在于加入所述白蛋白溶液中的无菌粉末状的紫杉醇的量在白蛋白重量的5.6％至19.4％(W/W)之间。
3.根据权利要求1或2所述的方法，其特征在于在加入紫杉醇之前，向所述白蛋白溶液中加入至少一种生物相容性酸，其量足以使粉末状纳米颗粒重制形成的水性可注射混合物的pH达到5.4-5.8之间。
4.根据权利要求3所述的方法，其特征在于所述酸的量是使所述重制形成的水溶液的pH达到5.5至5.7之间的量。
5.根据权利要求3或4所述的方法，其特征在于所述的酸选自生物相容性有机酸和无机酸。
6.根据权利要求5所述的方法，其特征在于所述的酸是盐酸、柠檬酸、磷酸或醋酸。
7.根据权利要求6所述的方法，其特征在于所述的酸是柠檬酸。
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2002
- 2002-03-29 IT IT2002MI000681A patent/ITMI20020681A1/it unknown
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2003
- 2003-03-03 EP EP03004629A patent/EP1348431A1/en not_active Withdrawn
- 2003-03-05 AU AU2003200920A patent/AU2003200920A1/en not_active Abandoned
- 2003-03-05 IL IL15476203A patent/IL154762A0/xx unknown
- 2003-03-07 NZ NZ524605A patent/NZ524605A/en not_active IP Right Cessation
- 2003-03-10 US US10/383,639 patent/US20030185894A1/en not_active Abandoned
- 2003-03-13 ZA ZA200302040A patent/ZA200302040B/xx unknown
- 2003-03-14 JP JP2003070028A patent/JP4794115B2/ja not_active Expired - Lifetime
- 2003-03-24 MX MXPA03002543A patent/MXPA03002543A/es unknown
- 2003-03-26 BR BR0300846-0A patent/BR0300846A/pt not_active Application Discontinuation
- 2003-03-27 KR KR10-2003-0019242A patent/KR20030078722A/ko not_active Application Discontinuation
- 2003-03-28 RU RU2003108821/15A patent/RU2003108821A/ru not_active Application Discontinuation
- 2003-03-28 CA CA002423915A patent/CA2423915A1/en not_active Abandoned
- 2003-03-28 NO NO20031448A patent/NO334407B1/no not_active IP Right Cessation
- 2003-03-28 CN CNB031083617A patent/CN1259902C/zh not_active Expired - Lifetime
- 2003-03-28 CN CNA2006100770064A patent/CN1911446A/zh active Pending
-
2006
- 2006-01-17 US US11/334,004 patent/US20060121119A1/en not_active Abandoned
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2011
- 2011-03-01 JP JP2011043799A patent/JP2011132253A/ja not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109793728A (zh) * | 2013-01-11 | 2019-05-24 | 阿布拉科斯生物科学有限公司 | 治疗胰腺癌的方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP4794115B2 (ja) | 2011-10-19 |
| CA2423915A1 (en) | 2003-09-29 |
| CN1448128A (zh) | 2003-10-15 |
| US20030185894A1 (en) | 2003-10-02 |
| ITMI20020681A1 (it) | 2003-09-29 |
| EP1348431A1 (en) | 2003-10-01 |
| ITMI20020681A0 (it) | 2002-03-29 |
| NO20031448D0 (no) | 2003-03-28 |
| NZ524605A (en) | 2004-03-26 |
| JP2011132253A (ja) | 2011-07-07 |
| BR0300846A (pt) | 2004-08-17 |
| JP2003300878A (ja) | 2003-10-21 |
| RU2003108821A (ru) | 2004-11-10 |
| KR20030078722A (ko) | 2003-10-08 |
| AU2003200920A1 (en) | 2003-10-16 |
| US20060121119A1 (en) | 2006-06-08 |
| IL154762A0 (en) | 2003-10-31 |
| CN1911446A (zh) | 2007-02-14 |
| MXPA03002543A (es) | 2005-08-26 |
| NO334407B1 (no) | 2014-02-24 |
| ZA200302040B (en) | 2003-09-17 |
| NO20031448L (no) | 2003-09-30 |
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