CN1088195C - 脂类分散液及其制备方法 - Google Patents
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Abstract
本发明公开了一种用作测定脂类含量的标准溶液的含水分溶液,这种分散液具有与血清脂类相似的分散形式和颗粒尺寸。可如下制备此分散液:首先将胆固醇、磷脂、胆汁酸或胆酸盐以及中性类脂和/或胆甾醇酯加入到有机溶剂中,其次从制得的混合物中蒸发掉有机溶剂,并且使得到的类似薄膜的混合物用温度被加热到比卵磷脂的相变温度高的水或缓冲剂溶胀,然后利用一个物理剪切力来分散溶液。由此,可容易地得到一种含有浓度约少于1000mg/dl的胆固醇、相当稳定并可保存一段较长时间的溶液。
Description
技术领域
本发明一种用作测定脂类含量的标准溶液的水分散液以及这种分散液的制备方法。
背景技术
目前,业已迅速广泛地利用一种近期开发出的酶促测定法来测定体液中的脂类含量,尤其是测定胆固醇的含量,并且这种脂类测定方法在临床诊断领域中用得愈来愈多。因此,需要一种合适的用于测定脂类含量的标准溶液。然而,脂类本质上难溶于水,于是,专门使用那些溶于有机溶剂的脂类标准溶液。因此,这些标准溶液中的脂类在存在状态和流动性方面与体液(例如血清)中的脂类不同。这会导致标准溶液与作为样品的体液(例如血清)之间在反应性上具有较大差异,从而使测定值发生偏差。
因此,业已使用来源于人或动物的血清或提纯脂蛋白胆固醇作为标准溶液。例如,在日本专利公开文本No.56-101555中描述了这种纯化脂蛋白胆固醇的方法。然而,在使用血清的方法中,要得到廉价的血清是困难的,同时,未知杂质可能会影响测定值。用于纯化脂蛋白的方法还具有操作复杂的问题。
为了改善这些缺陷,业已使用那些用表面活性剂加溶于水的脂类作为标准溶液。然而,需要大量的表面活性剂来使脂类加溶于水。因此,利用此方法制备的溶液的粘度高,并且有时处理起来困难。
为了解决这个问题,建议采用表面活性剂和脂类的混合物,其中表面活性剂和脂类的HLB值不同(例如参见日本公开专利文本No.57-84356)。然而,对于利用此方法得到的溶液,在上述的酶促测定方法中,溶液中存在的表面活性剂有时会抑制酶促反应。由于脂类的分散形式与血清中的不同,因此按照此测定方法,这种溶液有时不适于用作标准溶液。
如上所述,业已研究出各种利用一个简单的操作过程即可稳定溶解或分散脂类的方法。
然而,如上所述脂类的这种分散形式明显不同于血清中的分散形式的事实,有时会造成问题,即阻碍将此溶液用作校正仪器的标准溶液。考虑到这一点,还是利用了用表面活性剂分散脂类的方法。然而,当可以使用表面活性剂时还有一个问题即是:不能稳定地分散生理上产生的较高浓度的胆固醇。
为了解决上述这些问题,本发明的发明人进行了深入的研究。结果,发现一种分散液表现出作为胆固醇标准溶液的极好特性,如下制备这种分散液:首先将胆固醇、卵磷脂、一种表面活性剂以及一种中性类脂和/或一种胆甾醇酯按一特定的浓度比范围加入到有机溶剂中,其次从制得的混合物中蒸发掉有机溶剂,然后使得到的类似薄膜的混合物用温度被加热到比卵磷脂的相变温度高的水或缓冲液溶胀,最后利用超声辐射分散此溶液而得到这种分散液。
发明简介
本发明提供了一种脂类分散液,包括以下组分:一种胆汁酸或其盐、用作脂类的一种磷脂、胆固醇以及从胆甾醇脂和中性类脂构成的组合中选择的至少一种组分,还有作为分散介质的水或一种含水溶剂,其中胆汁酸或其盐以及脂类被分散在水或含水溶剂中。
本发明还提供了一种制备脂类分散液的方法,包括如下步骤:首先将胆汁酸或其盐以及脂类溶于有机溶剂中,然后将有机溶剂从得到的溶液中蒸发掉,最后将水或含水溶剂加入到所含的残留的固体中,以便施加一个物理剪切力。
施加物理剪切力的步骤最好是在脱氧的气氛下进行的。
另外,蒸发有机溶剂的步骤最好是在胆汁酸或其盐以及脂类能溶于有机溶剂的温度下进行。
脂类包括一种磷脂、胆固醇以及从胆甾醇酯和中性类脂构成的组合中选择的至少一种组分。
在本发明的一个实施例中,优选的是:将胆固醇亚油酸酯用作胆固醇和胆甾醇酯,将卵磷酯用作磷脂,将牛磺脱氧胆酸钠用作胆酸盐,以及将三硬脂酸甘油酯用作中性类脂。并且较为可取的是:胆固醇以及胆甾醇酯的总和与卵磷脂的重量比为1∶1至1∶4,胆酸盐与卵磷脂的重量比为1∶1至1∶20,中性类脂与卵磷脂的重量比为1∶10至1∶5,以及当卵磷脂最后分散于水或缓冲剂中时卵磷脂的浓度不超过1000mg/dl。
利用上述方法制备的胆固醇标准溶液具有与在血清脂类相似的分散形式和粒度,并且能提供一种胆固醇和胆甾醇酯的总浓度约少于1000mg/dl的分散液。如此制备的胆固醇分散液相当稳定并且能贮存一段长的时间。
从以下结合附图所进行的详细描述中将更好地理解和体会本发明(关于构成和内容)以及本发明的其它目的和性质,同时所附的权利要求书中特别阐明了本发明的这些新颖特性。
具体实施方式
下面的例子进一步详细说明了本发明,但不能认为是对本发明范围的限制。例1
将60mg胆固醇、90mg用作磷脂的卵磷脂、18mg用作中性类脂的三硬脂酸甘油酯以及4.5mg用作胆酸盐的胆酸钠溶解于1ml用作有机溶剂的2-丙醇中。其次将得到的溶液倒入用旋转蒸发器旋转的玻璃容器(例如试管)中,然后在减压下蒸发2-丙醇。这样,在玻璃容器的内壁上形成了一层胆固醇、卵磷脂、三硬脂酸甘油酯和胆酸钠的均匀混合物薄膜。
蒸发2-丙醇以便形成薄膜的步骤是通过向上述溶液中喷入惰性气体(例如氮或氩)进行的,而不是利用旋转蒸发器的真空蒸发。利用这种方式,通过在减压的气氛下蒸发溶剂可阻止在形成薄膜的步骤中磷脂和中性类脂的氧化。
将温度被加热到比卵磷脂的相变温度高的水或用作含水溶剂的磷酸盐缓冲剂加入到玻璃容器中,所述薄膜在玻璃容器的内壁上形成并被溶胀。然后,用一超声压碎机辐射超声波,以便施加一个物理剪切力,并且上述的薄膜被分散在水或磷酸盐缓冲剂中。被分散的脂类颗粒的直径取决于超声波的输出和辐射时间。最后,可得到直径大约为50nm的脂类颗粒。
在上述施加物理剪切力以便分散薄膜的过程中,还可利用法兰西压碎机取代超声压碎机。
在此例中,用作表面活性剂的胆酸钠也可溶于2-丙醇中,从而它能均匀地包含在薄膜中。当胆酸钠不加入2-丙醇溶液中而是在溶胀和分散薄膜的步骤中加入时,不能得到具有理想的颗粒尺寸的溶液。例2
将15mg胆固醇、90mg用作磷脂的卵磷脂、45mg用作胆甾醇酯的胆固醇亚油酸酯和4.5mg用作胆汁酸的脱氧胆酸溶于1ml用作有机溶剂的2-丙醇中。通过将得到的溶液倒入玻璃容器(例如试管)中并用与例1中所述相同方式使溶液分散到水或含水溶剂中而得到的含有酯型胆固醇(例如胆固醇亚油酸酯)的胆固醇标准溶液。例3
将15mg胆固醇、90mg用作磷脂的卵磷脂、45mg用作胆甾醇酯的胆固醇亚油酸酯、18mg用作中性类脂的三硬脂酸甘油酯和4.5mg用作胆酸盐的牛磺脱氧胆酸钠溶于1ml用作有机溶剂的2-丙醇中。将得到的溶液倒入用旋转蒸发器旋转的玻璃容器(例如试管)中,然后,在减压下蒸发2-丙醇。这样,在玻璃容器的内壁上形成一层胆固醇、卵磷脂、三硬脂酸甘油酯和胆酸钠的均匀混合物薄膜。
蒸发溶剂时必需将玻璃容器加热到大约60℃,从而形成一个薄膜。当温度大约在室温时,上述溶液迅速形成白色沉淀。形成薄膜时的温度必须是胆固醇、磷脂、胆甾醇脂、中性类脂和胆酸盐这些溶质都不会沉积和沉淀的温度。因此,必需注意到形成薄膜的最佳温度随溶质的组成以及量的不同而变化的事实。
通过将水或缓冲溶液加到利用上述方法形成的薄膜中并用与例1中所述相同的方式进行分散可得到含有酯型胆固醇(例如胆固醇亚油酸酯)和中性类脂(例如三硬脂酸甘油酯)的胆固醇标准溶液。
至于利用此方法得到的胆固醇标准溶液的脂类颗粒形式,是:具有强疏水性的酯型胆固醇和中性类脂存在于颗粒的中心部分,而磷脂和胆固醇及其存在于外部的亲水性侧链形成脂类颗粒的表面,以便覆盖酯型胆固醇和中性类脂。这种形式与血液中脂类的形式类似。
在上述的例子中,卵磷脂用作磷脂,胆固醇亚油酸酯用作胆甾醇脂,三硬脂酸甘油酯(一种甘油三酯)用作中性类脂,胆酸钠和牛磺脱氧胆酸钠用作酸盐,牛磺脱氧胆酸作用胆汁酸,但是它们并不局限于此。
对于磷脂,例如可单独或组合使用卵磷脂、磷脂酰丝氨酸、磷脂酰甘油、磷脂酰肌醇、磷脂酸、鞘磷脂和溶血卵磷脂。
对于胆汁酸或胆酸盐,例如可单独或组合使用胆酸、牛磺脱氧胆酸、牛磺胆酸、脱氧胆酸、甘氨胆酸、甘氨脱氧胆酸及其钠盐。
对于中性类脂,例如可使用组分脂肪酸有大约9-17个碳原子的甘油三酯(例如三硬脂酸甘油酸、三软脂酸甘油酯等)。对于胆甾醇脂,例如可使用那些具有脂肪侧链并且其烃族具有18个或少于18个碳原子的胆甾醇酯。
即使用胆汁酸取代应用胆酸盐的例子中的胆酸盐和用胆酸盐取代应用胆汁酸的例子中的胆汁酸,也不会破坏本发明的效果。
对于用于溶解脂类以形成薄膜的有机溶剂,可使用2-丙醇,但是也可使用能溶解磷脂、胆固醇、胆汁酸或胆酸盐、胆甾醇酯和中性类脂的任何有机溶剂,例如醇(如2-丙醇、乙醇、甲醇等)、***、异丙醚、氯仿、二氯甲烷等。
如上所述,按照本发明,可容易地得到具有与血清脂类相似的分散形式和颗粒尺寸的分散液,并且这种分散液的胆固醇和胆甾醇脂的总浓度高,例如大约少于100mg/dl。另外,如此制备的胆固醇分散液相当稳定并能在室温下保存一段长的时间。
虽然此处利用优选的实施例对本发明进行了描述,但是应该理解这些公开内容不能认为是对本发明的限定。在阅读了上述的公开内容之后,各种变型和改进毫无疑问对于本发明所属的领域中的普通技术人员来说都是显而易见的。因此,应该认为所附的权利要求书覆盖了本发明的实际精髓和范围内的所有变型和改进。
Claims (6)
1.一种标准胆固醇分散液,包括一种胆汁酸或其盐、一种磷脂、胆固醇和从胆甾醇酯和中性类脂构成的组合中选择的至少一种成分,以及用作分散介质的水或含水溶剂,所述胆汁酸或其盐以及所述脂类被分散在所述水或含水溶剂中。
2.根据权利要求1所述的标准胆固醇分散液,其特征在于磷脂是卵磷脂,并且胆固醇及胆甾醇酯的总和与卵磷脂的重量比为1∶1至1∶4,胆酸盐与卵磷脂的重量比为1∶1至1∶20,中性类脂与卵磷脂的重量比为1∶10至1∶5,并且卵磷脂的浓度不超过1,000mg/dl。
3.一种制备标准胆固醇分散液的方法,包括如下步骤:首先将胆汗酸或其盐以及脂类溶于有机溶剂中,其中所述脂类包括磷脂、胆固醇以及从胆甾醇酯和中性类脂构成的组合中选择的至少一种组分;在胆汁酸或其盐以及脂类可溶于有机溶剂的温度下,从得到的溶液中蒸发掉有机溶剂;将水或含水溶剂加到所含的残余的固体中,以便施加一个物理剪切力。
4.根据权利要求3所述的制备标准胆固醇分散液的方法,其特征在于施加物理剪切力的步骤是辐射超声波的步骤。
5.根据权利要求3所述的制备标准胆固醇分散液的方法,其特征在于蒸发有机溶剂的步骤是在脱氧的气氛下进行的。
6.根据权利要求3所述的制备标准胆固醇分散液的方法,其中胆固醇及胆甾醇酯的总和与磷脂的重量比为1∶1至1∶4,胆酸盐与磷脂的重量比为1∶1至1∶20,中性类脂与磷脂的重量比为1∶10至1∶5。
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EP (1) | EP0744621B1 (zh) |
CN (1) | CN1088195C (zh) |
DE (1) | DE69632100T2 (zh) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
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DE10228680A1 (de) * | 2002-06-27 | 2004-01-22 | Holden Development Limited, Tortola | Grundlage für transdermale Formulierungen (PTF) |
TR201802446T4 (tr) * | 2004-05-19 | 2018-03-21 | Los Angeles Biomedical Res Inst Harbor Ucla Medical Ct | Sodyum deoksikolat içeren enjeksiyonluk bileşim. |
US7754230B2 (en) * | 2004-05-19 | 2010-07-13 | The Regents Of The University Of California | Methods and related compositions for reduction of fat |
US20060127468A1 (en) * | 2004-05-19 | 2006-06-15 | Kolodney Michael S | Methods and related compositions for reduction of fat and skin tightening |
TWI467702B (zh) * | 2005-03-28 | 2015-01-01 | Semiconductor Energy Lab | 記憶裝置和其製造方法 |
GB0522942D0 (en) | 2005-11-10 | 2005-12-21 | Leigh Steven | Dissolution composition |
WO2008040799A2 (en) * | 2006-10-06 | 2008-04-10 | Boehringer Ingelheim International Gmbh | Process for preparing instant forms of aqueous mixed micellar solutions as physiological buffer systems for use in the analysis of in vitro release |
CN101762709B (zh) * | 2008-12-19 | 2013-06-12 | 深圳迈瑞生物医疗电子股份有限公司 | 一种胆固醇水质定标液及其制备方法 |
US8101593B2 (en) | 2009-03-03 | 2012-01-24 | Kythera Biopharmaceuticals, Inc. | Formulations of deoxycholic acid and salts thereof |
WO2012112940A1 (en) | 2011-02-18 | 2012-08-23 | Kythera Biopharmaceuticals, Inc. | Treatment of submental fat |
US8653058B2 (en) | 2011-04-05 | 2014-02-18 | Kythera Biopharmaceuticals, Inc. | Compositions comprising deoxycholic acid and salts thereof suitable for use in treating fat deposits |
BR112014029188B1 (pt) * | 2012-05-31 | 2020-02-11 | Terumo Kabushiki Kaisha | Veículo sensível ao ph e método de preparação do mesmo, e droga sensível ao ph e composição medicamentosa sensível ao ph contendo o veículo, e método de cultura usando o mesmo |
WO2014182940A1 (en) * | 2013-05-08 | 2014-11-13 | Northeastern University | Mucus strengthening formulations to alter mucus barrier properties |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
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US2062782A (en) * | 1936-01-10 | 1936-12-01 | Albert K Epstein | Treatment of lecithin |
US2362013A (en) * | 1940-05-07 | 1944-11-07 | Winthrop Chem Co Inc | Stable colloidal solutions containing lecithin and cholesterol and process of preparing same |
US3361680A (en) * | 1963-05-13 | 1968-01-02 | Sun Oil Co | Use of ultrasonic vibrations to disperse a liquid in another liquid |
DE1692566A1 (de) * | 1967-04-18 | 1971-08-05 | Unilever Nv | Verfahren zur Herstellung von partiell hydrolysierten Pflanzenphosphatiden mit verbesserter Emulgierwirkung |
US4115313A (en) * | 1974-10-08 | 1978-09-19 | Irving Lyon | Bile acid emulsions |
IT1202370B (it) * | 1976-07-12 | 1989-02-09 | Hoffmann La Roche | Soluzioni inietabili in cui l'atti vita' emolitica degli agenti di formazione di micelle naturali e' evitata mediante l'aggiunta di lipoidi e relativi prodotti |
DE2839433A1 (de) * | 1978-09-11 | 1980-03-20 | Merck Patent Gmbh | Waessrige lipid-standardloesung und verfahren zu ihrer herstellung |
US4200551A (en) * | 1978-11-27 | 1980-04-29 | A. E. Staley Manufacturing Company | Cold-water-dispersible lecithin concentrates |
DE2904305C2 (de) * | 1979-02-05 | 1981-07-02 | Boehringer Mannheim Gmbh, 6800 Mannheim | Reagens zur Lipasebestimmung und Verfahren zu seiner Herstellung |
US4290774A (en) * | 1980-01-07 | 1981-09-22 | Miles Laboratories, Inc. | Purification of lipoprotein cholesterol for use as a cholesterol reference material |
US4409326A (en) * | 1980-07-10 | 1983-10-11 | Modrovich Ivan Endre | Stabilized enzymatic solutions and method for determining total cholesterol in human serum |
JPS5784356A (en) * | 1980-11-13 | 1982-05-26 | Toyobo Co Ltd | Water soluble standard solution for measurement of fatty substance |
US4485054A (en) * | 1982-10-04 | 1984-11-27 | Lipoderm Pharmaceuticals Limited | Method of encapsulating biologically active materials in multilamellar lipid vesicles (MLV) |
-
1996
- 1996-05-02 US US08/641,765 patent/US5759445A/en not_active Ceased
- 1996-05-21 EP EP96303580A patent/EP0744621B1/en not_active Expired - Lifetime
- 1996-05-21 DE DE69632100T patent/DE69632100T2/de not_active Expired - Fee Related
- 1996-05-24 CN CN96111024.4A patent/CN1088195C/zh not_active Expired - Fee Related
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1999
- 1999-06-07 US US09/327,019 patent/USRE37002E/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
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USRE37002E (en) | 2000-12-26 |
EP0744621B1 (en) | 2004-04-07 |
US5759445A (en) | 1998-06-02 |
EP0744621A2 (en) | 1996-11-27 |
CN1146018A (zh) | 1997-03-26 |
DE69632100D1 (de) | 2004-05-13 |
EP0744621A3 (en) | 1998-06-10 |
DE69632100T2 (de) | 2005-04-28 |
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