CN1069693C - 烷氧基化脂肪纯化的方法 - Google Patents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/56—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
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- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11C—FATTY ACIDS FROM FATS, OILS OR WAXES; CANDLES; FATS, OILS OR FATTY ACIDS BY CHEMICAL MODIFICATION OF FATS, OILS, OR FATTY ACIDS OBTAINED THEREFROM
- C11C3/00—Fats, oils, or fatty acids by chemical modification of fats, oils, or fatty acids obtained therefrom
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Abstract
通过用固体物质处理以纯化烷氧基化脂肪的方法，其中氧化铝和硅酸盐的混合物用作固体物质。
Description
本发明涉及通过用固体物质处理以纯化烷氧基化脂肪的方法，通过该方法可获得的烷氧基化脂肪，及其应用。
烷氧基化脂肪具有广泛的用途。重要性正在增加的用途为用作溶剂组分以制备不溶于水的活性物质(特别是药)的溶液。在某些情况下用药时药必须存在于稳定的溶液中，如注入药时。
EP 645 145 A公开了由抗肿瘤活性物质和溶剂的溶液组成的药物配方，该溶剂包含烷氧基化脂肪作为共溶剂或增溶剂。通过加入酸或盐或通过用氧化铝处理烷氧基化脂肪，特别是由于羧化物含量降至特定水平的事实，而使该药物配方稳定。
WO 94/12030公开了可通过加入特定的酸而稳定的如EP 645 145中描述的药物配方，在此例中最终的pH值必须低于8.1。
然而，这些先前技术药物配方的组分仍经常不符合相对于最终配方的稳定性的这类组分应符合的要求。
本发明的目标是提供可用于纯化烷氧基化脂肪的方法，以使其更适用于药物配方。
我们已发现通过用固体物质处理纯化烷氧基化脂肪的方法可实现这个目标，其中氧化铝和硅酸盐的混合物用作固体物质。
根据本发明的方法不仅可能降低杂质含量，而且也可能减少水含量和降低pH值。
令人惊讶地，根据本发明的方法也降低了烷氧基化脂肪的粘度，其结果是得到可更好控制的产品。如果起始物质的粘度范围在700-850mPa·s，根据本发明纯化的产品粘度在600-750mPa·s的范围，即每一情况中降低100mPa·s。另外，也可实现催化剂残余物的降低。
根据本发明的方法的优选实施方案包括将烷氧基化脂肪与氧化铝和硅酸盐(吸附剂)混合并搅拌，然后滤除固体物质。令人惊奇的是仅通过混合组分就实现了期望的纯化效果，此处升高温度是适当的。烷氧基化脂肪的处理优选通过与吸附剂混合并于15-180℃搅拌而进行，优选在30-100℃，特别是40-80℃。反应期间压力可减至10-800mbar。该反应也可在保护气(如N2)下进行。反应时间优选1至12h。优选加入占全部混合物重量0.5-15％(重量)特别是1-10％(重量)的吸附剂。也可额外加入0-3％(重量)的助滤剂，如硅藻土(kieselguhr)。
优选使用的硅酸盐为碱金属和/或碱土金属硅酸盐，特别是硅酸镁或硅酸钙或硅酸铝及漂白土。可作为例子提及的商业产品为Ambosol，Tonsil FF或Magnesol。
通常，氧化铝和硅酸盐的混合物是通过机械混合两个组分，如在反应器中，而得到的。
该方法的优选实施方案进一步包括在用固体物质处理之前、期间或之后加入酸。纯化的最终产品可以被酸化至pH＜7，例如用短链(1-3个碳原子)有机酸，如乙酸。然而，其它酸，如柠檬酸或无机酸也是合适的。EP 645 145指出了可能的酸。此外，酸性盐，例如氨基酸的铵盐，如甘氨酸盐酸盐，也可用于酸化。
本发明也涉及通过根据本发明的方法制备的纯化的烷氧基化脂肪，及根据本发明制备的烷氧基化脂肪用于药物制剂的生产。
根据本发明的方法纯化的烷氧基化脂肪，例如乙氧基化脂肪酸，特别是乙氧基化蓖麻油，是申请者以专利商标名CremophorEL出售的。然而，如EP 645 145 A中提及的其它脂肪也可用根据本发明的方法纯化。
特别地，用根据本发明纯化并在需要时酸化的烷氧基化脂肪制备的药物制剂是那些含有不溶于水的活性物质者。制剂通常也包括另一个溶剂组分，如醇，特别是乙醇，在此情况下烷氧基化脂肪对醇的比例可以为30∶70-70∶30。
特别地，预期的活性物质为不溶于水的活性物质，特别是抗肿瘤活性物质，例如paclitaxel(紫杉酚)。关于其它可能的活性物质(如替尼泊甙，喜树碱及其衍生物)，确切的参考文献见EP 645 145 A。
实施例
实施例1
使用了具有如下分析数据的乙氧基化蓖麻油(CremophorEL)：
-pH7.0
-粘度：750mPa·s
-Karl-Fischer水含量约2.5％
-游离脂肪酸含量0.1-0.5％
2500kg 100％的纯CremophorEL于氮气下加热至50℃，加入75kg硅酸镁(来自Hoechst的Ambosol 500)，75kg酸性氧化铝和5.25kg硅藻土(来自Lehmann & Voss的Hyflow＝硅藻土助滤剂(流动煅烧的白色淡水硅藻))。混合物在50-55℃下搅拌3.5h。然后滤除吸附剂。过滤器的孔径为10μm-20μm。
实施例2
方法为实施例1的方法，但用碱性氧化铝代替酸性氧化铝。
结果：
| 吸附剂 | H2O含量(％) | 游离脂肪酸含量(％) | |
| 1 | 3％硅酸镁/3％酸性氧化铝1) | 0.15 | 0.03 |
| 2 | 5％硅酸镁(sic)/2)5％碱性氧化铝 | 0.49 | 0.02 |
实施例1中得到的产物的pH为5.9，也就是，即使没有另外酸化由于pH的降低也达到了稳定效果(于浓度为10％的水溶液中测量pH)。
粘度为650mPa·s
为了比较，进行了如下实验：
| 吸附剂 | H2O含量(％) | 脂肪酸含量(％) | |
| 3 | 3％硅酸镁(sic) | 0.69 | 0.11 |
| 4 | 5％硅酸镁 | 0.16 | 0.11 |
| 5 | 3％酸性氧化铝1) | 0.24 | 0.06 |
1)活性酸性氧化铝90，Merck活度标准1
2)Al2O3 W 200强碱性
结果表明分别单独使用氧化铝或硅酸盐不能获得期望的结果，特别是低的脂肪酸含量。然而，根据本发明，共同使用吸附剂则以令人惊讶的方式产生协同效应，因此得到的产物有助于适用作药物制剂。
Claims (8)
1.通过用固体物质处理以纯化烷氧基化脂肪的方法，其中氧化铝和硅酸盐的混合物用作固体物质，处理温度为15-180℃。
2.如权利要求1中所要求的方法，其中碱金属或/和碱土金属硅酸盐用作硅酸盐。
3.如权利要求1中所要求的方法，其中处理包括将烷氧基化脂肪与氧化铝和硅酸盐混合并搅拌，随后滤除固体物质。
4.如权利要求3中所要求的方法，其中使用占全部混合物重量0.5-15％的固体物质。
5.如权利要求3中所要求的方法，其中在处理中另外加入0-3％(重量)的助滤剂。
6.如权利要求1中所要求的方法，其中在处理之前、期间或之后加入酸。
7.通过如权利要求1-6任何一项中所要求的方法可获得的纯化的烷氧基化脂肪，具有0.03％或更小的游离脂肪酸含量。
8.通过如权利要求7中所要求的方法纯化的烷氧基化脂肪在药物制剂生产中的应用。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19536165.2 | 1995-09-28 | ||
| DE19536165A DE19536165A1 (de) | 1995-09-28 | 1995-09-28 | Verfahren zur Reinigung von alkoxylierten Fetten |
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| Publication Number | Publication Date |
|---|---|
| CN1198183A CN1198183A (zh) | 1998-11-04 |
| CN1069693C true CN1069693C (zh) | 2001-08-15 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN96197265A Expired - Lifetime CN1069693C (zh) | 1995-09-28 | 1996-09-20 | 烷氧基化脂肪纯化的方法 |
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| Country | Link |
|---|---|
| US (1) | US6096911A (zh) |
| EP (1) | EP0871691B1 (zh) |
| JP (1) | JP3865778B2 (zh) |
| KR (1) | KR100426294B1 (zh) |
| CN (1) | CN1069693C (zh) |
| AU (1) | AU725017B2 (zh) |
| CA (1) | CA2230952C (zh) |
| DE (2) | DE19536165A1 (zh) |
| EA (1) | EA000506B1 (zh) |
| HU (1) | HU224334B1 (zh) |
| IL (1) | IL123565A (zh) |
| NZ (1) | NZ319571A (zh) |
| WO (1) | WO1997012017A1 (zh) |
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| US6388112B1 (en) | 1998-10-20 | 2002-05-14 | Ben Venue Laboratories, Inc. | Process for purification of solvents useful in the preparation of pharmaceutical compositions |
| CZ294371B6 (cs) * | 2002-06-10 | 2004-12-15 | Pliva - Lachema, A. S. | Stabilizovaná farmaceutická kompozice na bázi polyoxyethylovaného ricinového oleje a způsob její přípravy |
| ATE437654T1 (de) * | 2003-05-19 | 2009-08-15 | Ebewe Pharma Gmbh Nfg Kg | Verfahren zur herstellung einer stabilen injizierbaren formulierung von paclitaxel |
| WO2013062117A1 (ja) * | 2011-10-27 | 2013-05-02 | Asaoka Keiichiro | 油分離方法、その方法に用いられる油水分離剤及び油分離装置 |
| BR112014026713A2 (pt) * | 2012-04-26 | 2017-07-18 | The Dallas Group Of America | purificação de óleos e gorduras comestíveis não refinados com silicato de magnésio e ácidos orgânicos |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1096673A (zh) * | 1992-11-27 | 1994-12-28 | 福丁有限公司 | 注射用药物组合物 |
| CN1107367A (zh) * | 1993-09-29 | 1995-08-30 | 布里斯托尔-米尔斯·斯奎布公司 | 稳定的药物组合物和稳定化溶剂 |
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| JPS5820152A (ja) * | 1981-07-27 | 1983-02-05 | Hakugen:Kk | 食用油用酸化防止剤 |
| US4735815A (en) * | 1986-08-13 | 1988-04-05 | Harshaw/Filtrol | Treatment of impure frying oils |
| US4701438A (en) * | 1986-08-13 | 1987-10-20 | Kaiser Aluminum & Chemical Corporation | Treating compositions for used frying oils |
| JPH0199518A (ja) * | 1987-10-14 | 1989-04-18 | Nippon Light Metal Co Ltd | 油漉し用濾過材 |
| EP0835657B1 (en) * | 1992-11-27 | 2004-08-25 | Mayne Pharma (USA) Inc. | Stable injectable paclitaxel composition |
-
1995
- 1995-09-28 DE DE19536165A patent/DE19536165A1/de not_active Withdrawn
-
1996
- 1996-09-20 DE DE59610386T patent/DE59610386D1/de not_active Expired - Lifetime
- 1996-09-20 CA CA002230952A patent/CA2230952C/en not_active Expired - Fee Related
- 1996-09-20 EP EP96933342A patent/EP0871691B1/de not_active Expired - Lifetime
- 1996-09-20 US US09/043,502 patent/US6096911A/en not_active Expired - Lifetime
- 1996-09-20 KR KR10-1998-0702290A patent/KR100426294B1/ko not_active IP Right Cessation
- 1996-09-20 NZ NZ319571A patent/NZ319571A/xx unknown
- 1996-09-20 AU AU72120/96A patent/AU725017B2/en not_active Ceased
- 1996-09-20 JP JP51312597A patent/JP3865778B2/ja not_active Expired - Lifetime
- 1996-09-20 CN CN96197265A patent/CN1069693C/zh not_active Expired - Lifetime
- 1996-09-20 EA EA199800332A patent/EA000506B1/ru not_active IP Right Cessation
- 1996-09-20 WO PCT/EP1996/004116 patent/WO1997012017A1/de active IP Right Grant
- 1996-09-20 IL IL12356596A patent/IL123565A/xx not_active IP Right Cessation
- 1996-09-20 HU HU9903775A patent/HU224334B1/hu not_active IP Right Cessation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1096673A (zh) * | 1992-11-27 | 1994-12-28 | 福丁有限公司 | 注射用药物组合物 |
| CN1107367A (zh) * | 1993-09-29 | 1995-08-30 | 布里斯托尔-米尔斯·斯奎布公司 | 稳定的药物组合物和稳定化溶剂 |
Also Published As
| Publication number | Publication date |
|---|---|
| NZ319571A (en) | 2000-01-28 |
| US6096911A (en) | 2000-08-01 |
| AU7212096A (en) | 1997-04-17 |
| CA2230952C (en) | 2007-05-29 |
| EA000506B1 (ru) | 1999-10-28 |
| EA199800332A1 (ru) | 1998-10-29 |
| CN1198183A (zh) | 1998-11-04 |
| WO1997012017A1 (de) | 1997-04-03 |
| HUP9903775A3 (en) | 2001-01-29 |
| DE19536165A1 (de) | 1997-04-03 |
| JP2000501123A (ja) | 2000-02-02 |
| DE59610386D1 (de) | 2003-05-28 |
| KR100426294B1 (ko) | 2004-05-17 |
| IL123565A (en) | 2000-08-31 |
| AU725017B2 (en) | 2000-10-05 |
| CA2230952A1 (en) | 1997-04-03 |
| EP0871691B1 (de) | 2003-04-23 |
| KR19990063822A (ko) | 1999-07-26 |
| HUP9903775A2 (hu) | 2000-03-28 |
| JP3865778B2 (ja) | 2007-01-10 |
| EP0871691A1 (de) | 1998-10-21 |
| IL123565A0 (en) | 1998-10-30 |
| HU224334B1 (hu) | 2005-08-29 |
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