CN1232539C - 有机药物与倍他环糊精衍生物的配合物及其制备方法 - Google Patents
有机药物与倍他环糊精衍生物的配合物及其制备方法 Download PDFInfo
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Abstract
有机药物与β-环糊精衍生物的配合物及其制备方法,以羟丙基β-环糊精(HP-β-CD)为代表的β-CD的衍生物为主体,以有机药物分子或其他有机分子为客体,以在水的存在下为必要条件,经过识别和组装,生成稳定的弱键(非键)结合的水溶性配位化合物(或称配合物、超分子化合物),该制品极易或易溶于水,溶解速度快,具有无限稀释稳定性。
Description
技术领域
本发明涉及一种有机药物与β-环糊精衍生物的配合物及其制备方法。
背景技术
药物在水中溶解度在X%数量级以下时,药物制剂的开发及生物利用度将受到限制和影响,而在药典、基本药物名录中难溶、不溶于水的大约占三分之一强,增加其水中溶解度以提高药效意义重大。利用β-环糊精(β-CD)或其衍生物与药物的配合作用增加药物的水溶性,是经多年和广泛研究的方法。但β-CD本身的低溶解度限制了它的应用,特别是β-CD经静脉注射,可引起血中尿素氮增加,经肾小管吸收时,因其水溶性低会结晶出来,造成组织坏死现象。因此特别是以羟丙基β-环糊精(HP-β-CD)为代表的β-CD的衍生物以安全剂量大、与血液相溶性好、不改变药效、增加药物的水溶性、稳定性等特点,可用于制备静脉注射、口服等各种剂型,因而被认为是比较有前途的药物载体材料。
总结多年来的文献制备方法的特点大致是:1、采用较高浓度的HP-β-CD水溶液(如>40%),利用基于cmc临界胶束浓度的增溶作用,溶解难溶的药物;2、采用机械的搅拌、超声破碎等方法使固体药物高度分散以加速其溶解;3、采用适宜的酸、碱表面活性剂、潜溶剂助溶和增加稳定性;4、通过结晶、共沉淀法从饱和溶液中析出沉淀,再进行喷雾干燥或冷冻干燥;5、工艺周期长,须在洁净或较低温度下数十小时或数日处理药物。2000年进行临床试验的依曲康唑注射液是第一个进入临床试验的依曲康唑-羟丙基-β-环糊精包合复合物静脉输注液体制剂,但在其配方中使用了相当量的酸和潜溶剂等以增加制剂的稳定性,它的药物与羟丙基-β-环糊精的质量比为1∶40。波谱学杂志第17卷第3期2000年六月报道的氟哌酸-羟丙基β-环糊精固体包合物的制备及其性质的研究一文,就是采用较高浓度的HP-β-CD水溶液,采用机械搅拌,在洁净或较低温度下数十小时或数日处理药物,利用共沉淀法,再通过干燥制得氟哌酸-羟丙基-β-环糊精固体粉末状包合物。
上述方法制备的包合物,在一定程度上提高了药物的溶解性,但该固体粉末状包合物加水溶解时常不能全部溶解,或溶液再加水稀释时析出不溶物,其特点是对稀释和再溶解的不稳定、不可逆。究其原因,是组成的不稳定性,该固体粉末是一种包合复合物,而没有形成超分子化学意义上的组成稳定的配位化合物。
发明内容
本发明的目的就是要提供一种有机药物与β-环糊精衍生物配合物及其制备方法,该方法制备的配合物组成稳定,是超分子化学意义上的配位化合物,该制品极易或易溶于水,溶解速度快,具有无限稀释稳定性。
本发明的方法是按照分子间相互作用的原理,以羟丙基-β-环糊精(HP-β-CD)为代表的β-CD的衍生物为主体,以有机药物分子或其它有机分子为客体,以在水存在下为必要条件,经过识别和组装,生成稳定的弱键(非键)结合的配位化合物(或称配合物、超分子化合物),有机药物与β-环糊精衍生物形成稳定的、易溶于水的配合物,其二者分子比或质量比具有一个临界值,其临界值是通过单元试验或制备饱和溶液的方法来确定的。
本发明工艺周期短,一般只需3~4小时,具体流程如下:
①此步药物溶液等可分别超滤除菌,脱色脱热原。
②此步可将干燥的疏松体在反应器中粉碎为所需粒度的多孔颗粒或粉末。
该产品具有多种用途:
1、可通过转溶制备溶液或冻干粉、块;
2、加入有关辅料制备各种片剂、颗粒剂、胶囊、糖浆等口服、腔道药剂;
3、制成粉雾化吸入药剂;
4、制成滴眼,滴鼻,含漱,气雾,直肠,冲、洗的药用溶液;
5、制成用于人以外的畜、禽、农作物、植物的病虫防治和激素,营养添加物等;
6、用于化工,如酶制剂、催化剂等其他有关用途。
具体实施方式:
本发明以药典、基本药物名录中各类代表药物50余例,与羟丙基、羟乙基、磺烷基、乙醚基、甲基、乙基的β-CD取代物制备配合物为例,说明该方法的普遍适用和有效性。
1、抗疟药:倍半萜内酯类青蒿素及其衍生物
青蒿素(Artemisinin),青蒿琥酯(Artesunate),蒿乙醚(Artemoter)等。
临界值:分子比3~9。
2、大环内酯类抗生素
红霉素(Erythromycin),麦迪霉素(Medicamycin),罗红霉素(Roxithromycin),阿齐霉素(Azithromycin),甲红霉素(Clarithromycin)等。
临界值:分子比6~18。
3、唑类抗真菌药
依曲康唑(Itraconazole),酮康唑(Ketoconazole),咪康唑(Miconazole),克霉唑(Clotrimazole)等。
临界值:分子比3~18。
4、生物碱镇痛药
高乌甲素(Lappaconitine),罗通定(Rotundine)等。
5、氮卓类等抗焦虑及镇静安眠药
地西泮(Diazepam),劳拉西泮(Lorazepam),艾司唑仑(Estazolam),谷维素(Oryzanol),唑吡坦(Zolpidem)等。
临界值:分子比3~6。
6、抗肿瘤药
他莫西芬(Tamoxifen),紫杉醇(Paclitexel,Taxol)[*],白消安(Busulfan),依托泊苷(Etoposide)等。
临界值:分子比2~100,质量比9~180。
[*]Taxol因HP-β-CD的用量过大超过安全剂量,无临床价值。
7、甾体化合物
泼尼松(Prednisone),睾酮(Tostesterone),普拉睾酮(Prasterone),螺内酯(Spironolactone)等。
临界值:分子比3~10。
8、磺胺类及增效剂
磺胺甲噁唑(SMZ),磺胺异噁唑(Sulfafurazol),磺胺嘧啶(SD),及增效剂甲氧苄啶(TMP)等。
9、镇咳祛痰药
二氧丙嗪(Dioxopromethazine),溴己新(Bromohexamine)。
临界值:分子比2~12。
10、抗菌药
安比西林(Ampicilline),环丙沙星(Ciprofloxacin),呋喃唑酮(Furazolidone),诺氟沙星(Norfloxacin),甲硝唑(Metromdazole),替硝唑(Tinidazole)[*]等。
[*]替硝唑与β-CD的衍生物制备的配合物易氧化变色。
11、解热、抗炎、镇痛药
对乙基氨基酚(Paracetamol),吡罗昔康(Proxicam),布洛芬(Ibuprofen)等。
临界值:分子比大于3。
12、循环系统药物
尼莫地平(Nimodipine),尼群地平(Nitrendipine),桂利嗪(Cinnarizine),吗多明(Molsidomine)以及他汀类降血脂药。
临界值:分子比2~50。
13、其他
法莫替丁(Famotidine),西布曲明(Sibutramine),西地那非(Sildenafil,伟哥),格列齐特(Gliclazide),地芬尼多(Difenidol),咖啡因(Caffeine),酮替芬(Ketotifen),硫辛酸(Lipoicacid),硫辛酰胺(Thioctamide),薄荷脑(Menthol),龙脑(Bomeol),樟脑(Camphor)等。
碱性有机化合物的盐也可与HP-β-CD形成水溶性更强的配合物,其临界值与碱性有机化合物不同。
以上50余种药物分别与羟丙基、羟乙基、磺烷基、乙醚基、甲基、乙基的β-CD取代物制备的配合物,经加水溶解时均极易溶于水或易溶于水,且溶解速度快,溶液再加水稀释时其配合物具有无限稀释稳定性。
特别重要的文献和本发明的实验结果都表明:药物和HP-β-CD及β-CD的多种衍生物制备的配合物一般不影响药效,常增强药效;不增加毒、副作用,常降低毒、副作用;改变剂型和改变给药途径时,增强药效的结果更明显。例如青蒿素类和HP-β-CD的配合物杀灭疟原虫的药效试验,感染伯式疟原虫小鼠杀灭疟原虫的实验结果列于下表:
青蒿素(Artemisinin),青蒿琥酯(Artesunate),它们的HP-β-CD配合物表示为药物-HP-β-CD。
二种青蒿素类与HP-β-CD的配合物与原药药效比较表
品名 | 给药途径 | 药效(杀虫) | ED90比较口服/静注 | |
ED50 | ED90 | |||
青蒿素青蒿素-HP-β-CD | 口服静注 | 195 | 4923 | 2.131 |
青蒿琥酯青蒿琥酯-HP-β-CD | 口服静注 | 9.964.32 | 25.1313.37 | 1.881 |
由上可见:药效分别提高2.13和1.88倍,而副作用未见明显增加。
又如盐酸西布曲明-HP-β-CD配合物(易溶于水)制成口腔速溶片(Rapiddissolving tablet in mauth),做动物试验(狗)与口服胶囊剂比较,口腔速溶片的生物利用度较胶囊高约1倍以上。
本发明的优点在于:
1、工艺较现有技术简单,周期短,一般只需3~4小时;
2、不加入酸、碱表面活性剂、潜溶剂,增强了药效,减少了副作用;
3、用水或有机溶剂将有机药物溶解,然后转换为水溶液,通过分子组装,生成配合物并制成疏松的多孔性固体,从而极易或易溶于水,溶解速度快,具有无限稀释稳定性;
4、通过单元试验或制备饱和溶液的方法来确定有机药物与β-环糊精衍生物的临界值,按临界值配比制备,使配合物组成稳定。
Claims (6)
1、制备有机药物与β-环糊精衍生物配合物的方法,其特征在于,以选自羟丙基、羟乙基、磺烷基、乙醚基、甲基、乙基中任一种或多种取代基取代β-环糊精而形成的β-环糊精衍生物为主体,以有机药物分子为客体,在水的存在下进行反应,形成稳定的非键或弱键结合的水溶性配合物,
其流程为:
在洁净环境下
a.在有机药物中加入水或亲水性有机溶剂,在30~100℃的温度下加热至有机药物完全溶解,获得有机药物溶液;
b.在a步骤得到的溶液中加入临界值的β-环糊精衍生物的溶液,该临界值为可使有机药物与之形成稳定的配位化合物的摩尔比或质量比,再在30~100℃的温度下加热浓缩并减压干燥至含水量<1%,以使溶剂转换为水溶液,获得由有机药物与β-环糊精衍生物形成的稳定而且无菌的水溶性配位化合物。
2、根据权利要求1所述的制备有机药物与β-环糊精衍生物配合物的方法,其特征在于:a步骤中加入的溶剂是亲水性有机溶剂。
3、根据权利要求1所述的制备有机药物与β-环糊精衍生物配合物的方法,其特征在于:在形成稳定而且无菌的水溶性配合物时使用的温度范围是60~75℃。
4、根据权利要求1所述的制备有机药物与β-环糊精衍生物配合物的方法,其特征在于:有机药物与β-环糊精衍生物的临界值是通过单元试验或制备饱和溶液的方法来确定的。
5、根据权利要求1所述的制备有机药物与β-环糊精衍生物配合物的方法,其特征在于:a步骤中所述有机药物选自以下药物:
a、抗疟药倍半萜内酯类青蒿素,包括青蒿素,青蒿琥酯,蒿乙醚;临界摩尔比为3~9;
b、大环内酯类抗生素,包括红霉素,麦迪霉素,罗红霉素,阿齐霉素,甲红霉素;临界摩尔比为6~18;
c、唑类抗真菌药,包括依曲康唑,酮康唑,咪康唑,克霉唑;临界摩尔比为3~18;
d、氮卓类抗焦虑及镇静安眠药,包括地西泮,劳拉西泮,艾司唑仑,谷维素,唑吡坦;临界摩尔比为3~6;
e、抗肿瘤药,包括他莫昔芬,紫杉醇,白消安,依托泊苷;临界摩尔比为2~100,质量比为9~180;
f、甾体化合物,包括泼尼松,睾酮,普拉睾酮,螺内酯;临界摩尔比为3~10;
g、磺胺类及增效剂,包括磺胺甲噁唑,磺胺异噁唑,磺胺嘧啶,及增效剂甲氧苄啶;临界摩尔比为2~5;
h、镇咳祛痰药,包括二氧丙嗪,溴己新;临界摩尔比为2~12;
i、解热、抗炎、镇痛药,包括对乙基氨基酚,吡罗昔康,布洛芬,临界摩尔比大于3;
j、循环系统药物,包括尼莫地平,尼群地平,桂利嗪,吗多明以及他汀类降血脂药;临界摩尔比为2~50。
6、根据权利要求1所述的制备有机药物与β-环糊精衍生物配合物的方法,其特征在于:该配合物经过加热真空膨化和干燥制得多孔无菌颗粒或粉末。
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CNB021167664A CN1232539C (zh) | 2002-05-10 | 2002-05-10 | 有机药物与倍他环糊精衍生物的配合物及其制备方法 |
PCT/CN2003/000337 WO2003095498A1 (fr) | 2002-05-10 | 2003-05-09 | Complexe d'agents therapeutiques organiques et de derives de beta-cyclodextrine et son procede de preparation |
JP2004503512A JP2005530866A (ja) | 2002-05-10 | 2003-05-09 | 有機医薬とβ−シクロデキストリン誘導体との複合体、およびその調製方法 |
CNB038106299A CN100467494C (zh) | 2002-05-10 | 2003-05-09 | 有机药物与β-环糊精衍生物配合物及其制备方法 |
CA002484835A CA2484835A1 (en) | 2002-05-10 | 2003-05-09 | Complex of organic medicines and beta-cyclodextrin derivatives and its preparing process |
AU2003242083A AU2003242083A1 (en) | 2002-05-10 | 2003-05-09 | Complex of organic medicines and beta-cyclodextrin derivatives and its preparing process |
EP03729798A EP1514877A4 (en) | 2002-05-10 | 2003-05-09 | COMPLEX OF ORGANIC THERAPEUTIC AGENTS AND BETA-CYCLODEXTRIN DERIVATIVES AND PROCESS FOR PREPARING THE SAME |
KR10-2004-7018140A KR20050013548A (ko) | 2002-05-10 | 2003-05-09 | 유기 약제 및 베타-시클로덱스트린 유도체의 복합체 및 그제조 방법 |
US10/514,184 US20050215520A1 (en) | 2002-05-10 | 2003-05-09 | Complex of organic medicines and beta-cyclodextrin derivatives and its preparing process |
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