CN1517091A - 黄体酮制剂及制备方法 - Google Patents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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- A—HUMAN NECESSITIES
- 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
- 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
- A61K47/69—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 the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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Abstract
本发明的涉及一种黄体酮的制剂及制备方法,它由黄体酮的羟丙基-β-环糊精包合物组成,即由下述原料按重量比组成:黄体酮∶羟丙基-β-环糊精=1∶1-100;通过将溶于有机溶媒的黄体酮加入到含羟丙基-β-环糊精的水溶液中,搅拌或超声后,经除热原和除菌过滤,得到注射用粉针或水针。该制剂无油针的疼痛反应及过敏现象,稳定性高,临床使用非常方便。形成的包合物也可加入其他辅料,制成舌下片剂。
Description
所属技术领域
本发明涉及黄体酮制剂及制备方法,该制剂为孕激素药,主要用于激素替代疗法,用于妇女更年期综合症,不育症等孕激素缺乏病症。
背景技术
黄体酮为天然孕激素,具有调节激素平衡作用,黄体酮原料药及制剂美国药典USP 24版已收载,中国药典2000版二部也收载了黄体酮原料药及黄体酮注射液。黄体酮在临床上应用广泛,主要用于激素替代疗法,用于妇女更年期综合症,不育症等孕激素缺乏病症,黄体酮目前有多种剂型,包括油注射液,栓剂,胶囊剂等。
黄体酮为脂溶性物质,不溶于水,临床上只能制备成油溶液注射剂,该注射液注射时疼痛反应较大,易过敏,给临床使用带来不便。检索国内外文献,发现与本发明相关的文献有Macus E.在Jof Parenteral science and technology vol.43,No.5/1989 231-239发表的The Potential Use of Cyclodextrins in ParenteralFormulation与Cavalli R,在Iht J Pharm 1999 May 10;182(1):59-69发表的Solid lipid nanoparticles as carriersof hydrocortisone and progesterone complexes with beta-cyclodextrins。两篇文献均描述了黄体酮的羟丙基-β-环糊精包合物,但未说明其详细制备过程及比例,也没有涉及到黄体酮冻干粉针的制备方法和处方。检索专利文献,未发现相关的国内外专利。
本发明针对上述存在的问题而提供一种黄体酮制剂及制备方法,既利用黄体酮与羟丙基-β-环糊精包合,形成包合物,制备成粉针剂或水针剂,该粉针内溶物极易溶于水,无油针的疼痛反应及过敏现象,稳定性高,临床使用非常方便。
羟丙基-β-环糊精为β-环糊精的衍生物,具有筒状分子结构,分子量为1540,极易溶于水,包合量大,无溶血反应,毒性低,可应用于注射剂。黄体酮分子量较小,羟丙基-β-环糊精可以将其完全包合,经过试验,羟丙基-β-环糊精与黄体酮形成了包合物,包合物极易溶于水,达到10%以上。
本发明的技术方案如下:
它是由下述原料按重量比组成:
黄体酮∶羟丙基-β-环糊精=1∶1-100
本发明的制备方法为:
选择符合中国药典规定的黄体酮,将按上述重量比的黄体酮溶于适量的有机溶媒中,一般为甲醇、乙醇等,加入量(黄体酮的重量∶有机溶媒的体积)约为1∶1-5或更多范围内;将按上述重量比的羟丙基-β-环糊精(HPCD)溶于蒸馏水中,水加入量按HPCD计算(HPCD的重量∶水的体积),在1∶5-50范围内。将含HPCD的水溶液强烈搅拌,缓慢滴加黄体酮溶液,全部加完后,继续搅拌0.5-24小时,使用0.45μm微孔滤膜过滤,滤液在百级净化车间,经过超滤除热源和无菌过滤(0.22μm),按剂量规格分装,经冷冻干燥后,可制成冻干粉针。本发明的包合物,也可以经过超滤除热源和无菌过滤(0.22μm)后,经分装灌封后,直接制备成水针;该包合物也可加入适量的辅料,制备成栓剂,凝胶剂、片剂,胶囊等。
本发明的制剂也可以采用其它方法制备,如超声波法,即将上述含黄体酮溶液加到HPCD溶液后,置于超声波发生器中,如超声波清洗机,振荡机等中,进行超声振荡5-30分钟代替上述搅拌,也可得到包合物。进而制备成制剂。
本发明中的包合物中黄体酮与HPCD重量比为1∶1-100,其中以1∶10-30比例溶解度、包合率、含量、羟丙基-β-环糊精用量是最适宜的。而两者重量比为1∶1时,即有包合物形成,但此时包合率较低,药物损失较大,其中以1∶10包合率和含量及环糊精用量是最优化的,包合率可达95%以上。
按本发明得到的黄体酮制剂特征为含有黄体酮成分和羟丙基-β-环糊精化学成分的包合物,是水溶性的或以水为溶剂的。该包合物薄层色谱图谱,包括黄体酮,黄体酮包合物醇提取物,黄体酮包合物醚提取物样品,经展开后斑点显示,黄体酮与黄体酮包合物醇提取物斑点完全相同,而黄体酮包合物醚提取物不含有上述斑点成分,说明黄体酮与HPCD形成了包合物;
本发明优点在于提供了一种易溶于水的黄体酮的羟丙基-β-环糊精包合物,同时可提高其稳定性,提高其生物利用度,提供了可注射用的黄体酮冻干粉针和水针的制备方法。
本发明中的包合物主要通过如下方法证明,其一采用薄层色谱法测定其包合物是否形成。其方法为取黄体酮乙醇溶液(1→1ml),黄体酮包合物乙醇溶液(1→1ml),黄体酮包合物乙醚溶液(1→3ml)照薄层色谱法(中国药典2000年版二部附录VB)试验,吸取上述两种溶液各10μl,分别点于同一硅胶G薄层板上,以氯仿-乙酸乙酯(66∶33)为展开剂,展开后,凉干,置紫外光灯(254nm)下检视,结果,薄层色谱图显示黄体酮与黄体酮包合物乙醇溶液斑点完全一致,而黄体酮乙醚溶液无斑点,说明与HPCD形成了包合物。
其二,采用相溶解度法测定其包合物形成,其方法为取100mg黄体酮,加入至不同浓度的HPCD溶液中,搅拌24小时,0.45μm滤膜过滤,采用HPLC液相色谱法,以黄体酮为对照品,采用外标法测定其浓度,以黄体酮浓度对HPCD浓度做图,得溶解度曲线,曲线显示,随着HPCD的浓度加大,黄体酮浓度增高,证明形成了包合物。
实施例1
取黄体酮10g,溶于50ml乙醇中,取羟丙基-β-环糊精100g,溶于2000ml注射用水中,将黄体酮乙醇溶液逐滴加入HPCD溶液中,室温磁力搅拌3小时,使用0.45μm微孔滤膜过滤,冷冻,得白色疏松粉末,经薄层色谱证实,形成了黄体酮与羟丙基-β-环糊精包合物。液相色谱测定,包合率为95%,含量10%。
实施例2
取黄体酮1g,溶于5ml乙醇中,取羟丙基-β-环糊精100g,溶于500ml注射用水中,以下同例1,得白色疏松粉末,经薄层色谱证实,形成了黄体酮与羟丙基-β-环糊精包合物。液相色谱测定,包合率为99%,含量1%。
实施例3
取黄体酮10g,溶于50ml乙醇中,取羟丙基-β-环糊精20g,溶于100ml注射用水中,以下同例1,得白色疏松粉末,经薄层色谱证实,形成了黄体酮与羟丙基-β-环糊精包合物。液相色谱测定,包合率为58%。
实施例4
其它同例1,将磁力搅拌法改为超声振荡法,室温,振荡10分钟,将包合后溶液经0.45μm微孔滤膜过滤,滤液冷冻干燥,得白色疏松粉末,经薄层色谱证实,形成了包合物,经液相色谱测定,包合率为90%。
实施例5
自例1,包合后溶液经0.45μm微孔滤膜过滤后,采用超滤法,用载留分子量5000-10000的滤膜超滤,除热原之后,再经0.22μm滤膜过滤除菌,得到滤液在百级净化车间无菌分装约1000支或500支,冷冻干燥得到注射用黄体酮冻干粉针,每支含黄体酮10mg或20mg。
实施例6
自例1,包合后溶液经0.45μm微孔滤膜过滤后,采用超滤法,用载留分子量5000-10000的滤膜超滤,除热原之后,再经0.22μm滤膜过滤除菌,得到滤液在百级净化车间分装,分装约1000支或500支,每支含黄体酮10mg或20mg,无菌灌封,制备成黄体酮注射水针。
实施例7
将例5中超滤除热原方法改为活性炭法,其他同例5。
实施例8
自例5,将磁力搅拌法改为超声震荡10分钟,其他同例5。
实施例9
自例6,将磁力搅拌法改为超声震荡10分钟,其他同例6。
实施例10
将例1得到的包合物,加入适量的辅料,制成栓剂,舌下片剂和胶囊等。
Claims (6)
1、一种黄体酮的制剂,它是即由下述原料按重量比组成:黄体酮∶羟丙基-β-环糊精=1∶1-100;通过将溶于有机溶媒的黄体酮加入到含羟丙基-β-环糊精的水溶液中,搅拌后,形成易溶于水的黄体酮的羟丙基-β-环糊精包合物,经除热原和除菌过滤,得到注射用粉针或水针;所述的有机溶媒为乙醇,也可以是甲醇、丙酮。
2、按权利要求1所述的黄体酮的制剂,它是由下述原料按重量比组成:黄体酮∶羟丙基-β-环糊精=1∶10-30。
3、一种黄体酮的制剂的制备方法,它是由下述原料按重量比组成:黄体酮∶羟丙基-β-环糊精=1∶1-100;按上述重量比将黄体酮溶于1-5倍的有机溶媒中,按上述重量比将羟丙基-β-环糊精溶于5-50的蒸馏水中,将含羟丙基-β-环糊精的水溶液强烈搅拌,缓慢滴加黄体酮溶液,全部加完后,继续搅拌0.5-24小时,使用微孔滤膜过滤,除热原之后,再经滤膜过滤除菌,得到滤液在百级净化车间无菌分装,冷冻干燥得到注射用黄体酮冻干粉针;或得到的滤液无菌分装后,直接灌封,制备成水针。
4、按权利要求3所述的黄体酮的制剂的制备方法,也可以采用超声波法,即将上述含黄体酮溶液加到羟丙基-β-环糊精溶液后,置于超声波发生器中,进行超声振荡代替上述搅拌,也可得到黄体酮的注射用粉针或水针。
5、按权利要求1或2所述的黄体酮的制剂,将所述的黄体酮的羟丙基-β-环糊精包合物,加入辅料,制成速溶舌下片剂。
6、按权利要求1或2所述的黄体酮的制剂,将所述的黄体酮的羟丙基-β-环糊精包合物,加入辅料,制成片剂、胶囊。
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CN101152186B (zh) * | 2007-09-05 | 2011-07-06 | 杭州平和安康医药科技有限公司 | 黄体酮注射液及其制备方法 |
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