CN102933235A - 氟醚(Fluran)复合物 - Google Patents
氟醚(Fluran)复合物 Download PDFInfo
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- 150000002170 ethers Chemical class 0.000 title abstract description 4
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- DPYMFVXJLLWWEU-UHFFFAOYSA-N desflurane Chemical compound FC(F)OC(F)C(F)(F)F DPYMFVXJLLWWEU-UHFFFAOYSA-N 0.000 claims description 2
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- 239000003814 drug Substances 0.000 claims description 2
- 229960000305 enflurane Drugs 0.000 claims description 2
- JPGQOUSTVILISH-UHFFFAOYSA-N enflurane Chemical compound FC(F)OC(F)(F)C(F)Cl JPGQOUSTVILISH-UHFFFAOYSA-N 0.000 claims description 2
- 229960002725 isoflurane Drugs 0.000 claims description 2
- RFKMCNOHBTXSMU-UHFFFAOYSA-N methoxyflurane Chemical compound COC(F)(F)C(Cl)Cl RFKMCNOHBTXSMU-UHFFFAOYSA-N 0.000 claims description 2
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- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
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- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
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- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
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Abstract
本发明的主题是α-环糊精和一种氟醚的复合物，其特征在于复合物总重量的至少3重量％的氟醚含量。
Description
本发明涉及氟醚复合物及其作为麻醉剂的制剂。
氟醚是在麻醉学中用于维持或导入麻醉
的药物，并且在现有技术中通过吸入被吸收。吸入麻醉剂作为气体或借助于汽化器气化的液体经呼吸面罩、喉罩或气管内导管来施加。
氟醚具有低沸点和高蒸气压。它是多卤代醚。氟醚是亲脂性物质，其麻醉效果尤其被解释为来源于与细胞膜的组成部分的亲脂性的非特异性相互作用。
本发明的目的在于提供氟醚制剂，所述氟醚制剂允许以不同于通过吸入的途径来施加。
本发明的主题是α-环糊精和氟醚的复合物，其中氟醚含量至少为复合物总质量的3重量％。
本发明已认识到，可以令人吃惊地制备氟醚与α-环糊精的复合物，所述复合物能够形成用于口服给药或静脉内给药的麻醉剂制剂的基础，且能够具有3或更高重量％的高的氟含量。
环糊精通常具有圆环形状，并有相应成形的空腔。氟醚作为客体分子进入所述空腔，由此得到可在水溶液中配制的极度亲酯的氟醚的复合物，该复合物能够将氟醚提供到预先设定的药物作用位置。
α-环糊精有6个吡喃葡糖单位，其中每个吡喃葡糖单位拥有三个OH基团，它们可以任选被取代(例如甲基化)。
根据本发明的复合物的氟醚含量优选为至少5重量％，更优选至少7重量％，更优选至少8重量％，更优选8-12重量％。可将所述值任意组合成为根据本发明的范围。
氟醚是多氟化醚，且优选选自七氟醚、安氟醚、异氟醚、地氟醚和甲氧氟烷。七氟醚为特别优选的。
根据本发明，该复合物可以具有5-15重量％，优选7-13重量％的水含量(残余水含量)。
此外，本发明的主题是用作药品应用的根据本发明的复合物。
本发明的另一主题是用于口服或静脉内给药的配制的麻醉剂，所述麻醉剂包含根据本发明的复合物。
此外，本发明的主题是用于制备根据本发明的复合物的方法，其具有以下步骤：
a)制备α-环糊精的水溶液，
b)将氟醚加入该水溶液中，
c)分离析出的复合物。
根据本发明，在第一步中制备α-环糊精的水溶液。优选在悬浮液中没有未溶解的环糊精残留的完全溶解。优选的在水溶液中的α-环糊精的浓度是5-30重量％，优选5-20重量％，更优选5-15重量％。如果使用未取代的α-环糊精，其上限为14.5重量％(未取代的α-环糊精在水中的溶解度)。取代的，特别是(部分)甲基化的α-甲基环糊精在水中能够具有更高的溶解度。
α-环糊精在水中的溶解优选在室温下进行。将氟醚添加到溶解的α-环糊精中。形成复合物，可将该复合物从水溶液中结晶析出并分离。
在本发明范围内，如果氟醚以1∶0.5-1∶2，优选1∶0.8-1∶1.2的与α-环糊精的摩尔比加入，则是优选的。尤其可以将氟醚与α-环糊精等摩尔加入。
在析出的复合物中，发现氟醚与环糊精的摩尔比约在1∶1.5-1∶6的范围。优选1∶1.5-1∶2的范围。与析出的复合物中的氟醚与环糊精的摩尔比相比较，在制备时则优选使用一摩尔过量的氟醚。
根据本发明，优选在加入氟醚后冷却到例如5-10℃的温度，以促进复合物的析出，并从而提高产率。
以下将说明实施例和比较例。
1.使用的材料
-纯净水(Millipor Q品质的水)
-α-环糊精
-β-环糊精
-2-羟基丙基-β-环糊精
-甲基-β-环糊精(RAMEB)
-七氟醚
所有的环糊精采购于Cyclo Lab Cyclodextrin Research&Development Laborotory Ltd.，匈牙利。七氟醚采购于Abbott GmbH，Wiesbaden，威斯巴登。
2.测定所制备的复合物的七氟醚含量
通过气相色谱法确定复合物中七氟醚的含量。气相色谱的条件如下：
气相色谱：Shimadzu GC-17A
检测器：注射器：火焰离子化检测器(FID)Shimadzu AoC-5000 autoinjector
软件：Shimadzu Class-VP 7.4版
气体：
载体：氦气(99.999％)
其他气体：氮气(99.999％)
合成空气(99.999％)
氢气(Whatman氢气发生器)
柱子：Rtx624(30mx0.32mmx1.8mm)(Restek)
温度程序：
注射器温度：220℃
检测器温度：220℃
分流比：100∶1
速度：30厘米/秒
注射程序如下：在60℃预热10分钟之后，将250微升蒸气样品在70℃下注入气相色谱仪。
样品准备
比较溶液：将1毫升蒸馏水与250微升DMF放入样品瓶中。
校准溶液：在2毫升玻璃瓶中称入100毫克七氟醚并添加DMF直至标线处作为原液。
取不同量的原液(20、65、110、155和200微升)分别用DMF定容到200微升，并与1毫升蒸馏水加入顶空样品瓶中(19.5毫升)。
样品溶液：将50毫克的样本复合物与1毫升蒸馏水和200微升DMF加入顶空样品瓶(19.5毫升)中。此外，将1毫升母液(得自环糊精与七氟醚络合除去析出的复合物后的上清液)与200微升DMF加到顶空样品瓶(19.5毫升)中。
实施例1
本实施例描述了七氟醚的α-环糊精(α-CD)复合物的制备过程。
在圆底烧瓶中，将45.25克(0.0465摩尔)α-CD在持续搅拌和室温条件下溶解在500毫升的水中。在α-CD完全溶解后，在室温条件下将6毫升(0.0465摩尔)七氟醚加入该溶液。白色的沉淀物析出并将其用冰水冷却至5-10℃。在该温度下搅拌4小时，然后将瓶子保存在冰箱中过夜。随后，将析出的七氟醚/α-环糊精复合物晶体过滤并在真空中用五氧化二磷干燥。
实施例2
本实施例展示了合适的环糊精的选择对复合物形成的影响。为了便于比较，这里使用了β-环糊精(β-CD)，羟基丙基-β-环糊精(HP-β-CD)以及RAMEB。这些对比例不是根据本发明的。
将4种环糊精分别制成1毫升的水溶液。在该水溶液中环糊精的浓度如下所示：
α-CD：10重量％
β-CD：2重量％
HP-β-CD：10重量％
RAMEB：10重量％
基于各环糊精的摩尔含量计，将七氟醚以1∶1的摩尔比加入这些溶液中。
在HP-β-CD和RAMEB的情况中得到均匀的溶液，复合物无析出。
在α-CD和β-CD的情况中形成了白色沉淀。
在下一步中分别制备了100毫升的α-CD(9.05重量％)和β-CD(1.78重量％)的水溶。再次以1∶1的摩尔比加入七氟醚。如实施例1中所述一般进一步制取所析出的白色沉淀物的。
析出的复合物的七氟醚含量通过气相色谱法来测定。结果在下表1中给出。
| α-CD | β-CD | |
| CD浓度(％) | 9.05 | 1.78 |
| 湿质量(克) | 10.00 | 0.97 |
| 干质量(克) | 6.57 | 0.83 |
| 产率(％) | 72.6 | 46.6 |
| 七氟醚含量(％) | 9.2 | 1.8 |
| 摩尔比七氟醚/CD | 1∶1.8 | 1∶8.6 |
该表显示了，α-CD适合形成高浓度七氟醚复合物，而β-CD只能实现复合物中相对较低的七氟醚浓度。
实施例3
在该实施例中改变了用α-CD制备七氟醚复合物的制备条件。结果显示在表2中。
在实施例3.1中使用了较少比例的水，因此α-CD不能完全被溶解。人们认识到，在这种制备条件下降低了复合物的七氟醚含量。
实施例3.4显示了另外一个具有低水含量的实验。人们认识到，这里也得到高产率，但复合物中七氟醚含量为5.7重量％比实施例1中低。
实施例2.2和2.3使用了较高的水含量。这里，在起始溶液中设定了不同的七氟醚/α-环糊精摩尔比(在实施例3.2中1∶1，实施例3.3中1∶2)。在这两种情况中都在复合物中得到了较高的七氟醚含量。如表中可看出，相较于复合物中的摩尔比明显过量使用的七氟醚提高了产率(实施例2.2)。
实施例4
从上面的实验得出，如果制备9％的α-环糊精水溶液且加入的七氟醚与溶解的α-CD的摩尔比为1∶1，则将得到良好的产率和在复合物中得到较高的七氟醚含量。下表3表明，在这些条件下可以可靠地重复复合物的制备。在三次试验中，产生了很大程度相同或可比较的结果。
Claims (11)
1.α-环糊精和一种氟醚的复合物，其特征在于，占复合物总重量最少3重量％的氟醚含量。
2.根据权利要求1的复合物，其特征在于，氟醚含量为至少5重量％，优选至少7重量％，更优选至少8重量％，更优选8-12重量％。
3.根据权利要求1或2的复合物，其特征在于，所述氟醚选自七氟醚、安氟醚、异氟醚、地氟醚和甲氧氟烷。
4.根据权利要求1至3之一的复合物，其特征在于，所述复合物具有5-15重量％，优选7-13重量％的水含量。
5.根据权利要求1至4之一的作为药物使用的复合物。
6.用于口服或静脉内给药的配制的麻醉剂，其特征在于，所述麻醉剂具有根据权利要求1至4之一的复合物。
7.用于制备根据权利要求1至4之一的复合物的方法，其特征在于下述步骤：
b.制备α-环糊精的水溶液，
c.将氟醚加到该水溶液中，
d.分离析出的复合物。
8.根据权利要求7的方法，其特征在于，在a)步骤中制得的水溶液中α-环糊精的浓度为5-30重量％，优选5-20重量％，更优选5-15重量％。
9.根据权利要求7或8的方法，其特征在于，在b)步骤中以1∶0.5-1∶2，优选1∶0.8-1∶1.2的与α-环糊精的比例加入氟醚。
10.根据权利要求7至9之一的方法，其特征在于，在b)步骤中的氟醚的加入在室温下进行。
11.根据权利要求7至10之一的方法，其特征在于，在加入氟醚后冷却，优选冷却到5-10℃之间的温度。
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| CN1424112A (zh) * | 2002-12-17 | 2003-06-18 | 上海医药工业研究院 | 难溶性药物的水溶性包合物及其制备方法 |
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| CN1454085A (zh) * | 2000-06-21 | 2003-11-05 | 印度血清及疫苗有限公司 | 透明水性麻醉组合物 |
| CN1424112A (zh) * | 2002-12-17 | 2003-06-18 | 上海医药工业研究院 | 难溶性药物的水溶性包合物及其制备方法 |
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