CN87102641A - 阴道栓的生产方法 - Google Patents
阴道栓的生产方法 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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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
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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Abstract
一种生产阴道栓的方法。此法包括将一种羟基值少于50的硬脂肪加热熔化,然后与硫酸脱氢表雄甾酮的药用盐混合,将混合物模铸,并冷却成型。这种阴道栓可用于改善孕妇分娩前的状况,其特点是稳定性好。
Description
本发明涉及一种生产阴道栓的方法。更具体蒂说,本发明涉及一种生产含药用脱氢表雄甾酮硫酸盐(下简称DHAS)的阴道栓的方法。
DHAS的药用盐具有促进在晚期姙娠时子宫颈成熟的活性,还能增强子宫平滑肌对催产素的反应性。在日本,临床上常选用它的钠盐注射液作为分娩前指征的治疗药(美国专利U.S.P.No4,005,200和No4,061,744)。
本发明的目的在于提供一种生产阴道栓的方法,这种阴道栓适于阴道内给药,给药较简便且稳定性较好。
本发明人对可能作为这种含药用DHAS盐阴道栓基质的各种亲脂和亲水化合物进行了探索性评价。结果表明,采用羟基值少于50的硬脂肪为基质制造的阴道栓,其稳定性好,且对孕妇的分娩前状况有明显改善。本发明就是以上述的发现为依据。本发明的特点是采用羟基值少于50的硬脂肪作为栓剂基质。这里所指的“硬脂肪”是指含8~18碳原子的直链饱和脂肪酸的单甘油酯、双甘油酯和三甘油酯的混合物。这类混合物的例子在文献中均有叙述,例如:马丁代尔大药典:第28版,1067页(Martindale The Extra Pharmacopoeia 28th edition editedby.James,EF.Reynotds,P1067,The Pharmaceufcial Press,London,1982)和日本药向方外标准,1986.10.1第1239页(Standards of Ingredients of Drugs not in the Japanese Pharmacopoeia,edited by Pharmaceutical Affairs Bureau,Ministry of Health and Welfare in Japan P1239 Oct.1.1986,Yakugyo Jiho Co.,Ltd.Tokyo,Japan)。在本发明中,采用的就是这种羟基值少于50的硬脂肪。这种羟基值少于50的硬脂肪容易获得,市售的商品有Dynamit Nobel公司生产的Witepsol H-35,H-5,H-15和W-35,日本油脂(Nippon Oil & Fats)公司生产的Nissan Pharmasol B-115。用羟基值高于50的硬脂肪制造的任何阴道栓,其稳定性都较低,且在贮存和运输时会变色。此外DHAS药用盐会降解主要生成DHA。
上述的DHAS药用盐可以是各种DHAS的金属盐如钠盐,钾盐,锂盐,镁盐等。还可以是铵盐。
本发明提出的方法如下所述:将羟基值少于50的硬脂肪加热熔化,然后与DHAS的药用盐均匀混合,混合物按预先规定的数量注入模型内,经冷却即得本发明的阴道栓。
DHAS的药用盐最好用结晶粉末,平均粒径在3~20微米之间,若平均粒径大于20微米,则DHAS盐不易均匀地分散于硬脂肪中,这样在各个栓剂之间,甚至在每个栓剂内DHAS的含量都会有差异。
上述硬脂肪与上述DHAS药用盐的比例,一般为每1~20份重量硬脂肪含一份盐。
按照本发明方法制得的阴道栓,可给予姙娠第37~39周的孕妇,剂量通常为100~1500毫克DHAS药用盐,每日1~3次。
按照本发明方法可保证获得稳定性好的阴道栓。当采用亲水基质或羟基值大于50的硬脂肪时,在温度为35℃的贮存条件下,DHAS药用盐会部分地分解成DHA,同时栓剂会变色。对比之下,按本发明方法制成的阴道栓在类似情况下不会分解,也不会变色,这将在下述的试验实施例1中看到。
此外,按本发明方法制得的阴道栓能明显地加速子宫颈成熟(试验实施例2),并且毒性低(试验实施3)。因此,根据本发明方法制得的阴道栓,可用作为改善孕妇分娩前状况的药物。
显然,本发明的生产方法可用于制造稳定性好,并且对孕妇分娩前状况有明显改善作用的阴道栓。
下述的试验例是试图说明根据本发明方法制得的阴道的用途。
试验实施例1
稳定性试验
1.样品
将按本发明方法制得的6个阴道栓(每个含DHAS双水合物钠盐)和5个不同的对照栓剂作为样品。每个样品中DHAS双水合物钠盐与基质的重量比均为1∶9(例6除外,其比例为2∶8)。
例1的阴道栓(基质:羟基值为2.3的硬脂肪)
例2的阴道栓(基质:羟基值为3.0的硬脂肪)
例3的阴道栓(基质:羟基值为11.6的硬脂肪)
例4的阴道栓(基质:羟基值为12.3的硬脂肪)
例5的阴道栓(基质:羟基值为46.0的硬脂肪)
例6的阴道栓(基质:羟基值为11.6的硬脂肪)
对照例1的阴道栓(基质:羟基值为53.5的硬脂肪)
对照例2的阴道栓(基质:羟基值为54.3的硬脂肪)
对照例3的阴道栓(基质:羟基值为64.1的硬脂肪)
对照例4的阴道栓(基质:亲水性基质=4∶5(重量/重量)
Macrogol 4000和Macrogol 1540的混合物)
对照例5的阴道栓(基质:亲水性基质=聚氧乙烯-聚氧丙烯二醇)。
2.方法
将每10只栓试验样品在制备后立即置入温度为35℃的保温箱中,贮存2和6个月后,观察每只样品的外观及检查DHAS钠盐的分解产物(DHA)。分解产物的检测采用薄层色谱法。每批阴道栓随机取出3个样品,在加入60毫升乙醇后,将混合物在约50℃加热并剧烈搅拌,然后于水浴中冷却30分钟。离心分离,取出上层清液按10微升一份,点样于硅胶板上(硅胶60F254,0.25毫米厚,Merck出品)。色谱是用混合溶媒(氯仿∶甲醇∶水=75∶22∶3,体积/体积)展开距理约10厘米。待硅胶板在空气中干燥后,均匀喷上浓硫酸∶乙醇(1∶1体积/体积),并于80℃加热5分钟。DHAS的钠盐及其分解产物均显斑点。根据上述条件,DHAS钠盐在Rf约0.2处为紫红色斑点,分解产物DHA在Rf约0.73处为浅红色斑点。
3.结果
上述试验结果列于表1
按本发明方法,用羟基值少于50的硬脂肪制得的阴道栓没有变色,且甚至在贮存较长时间后,没有发现分解产物。
另一方面,用羟基值大于50的硬脂肪制得的阴道栓,在放置过程中会变色。用薄层色谱对这些栓剂分析时,发现在Rf约0.73处有一浅红色斑点,证实此分解物为DHA。
表1
稳定性试验
阴道栓 2个月 6个月
样品 栓剂基质 颜色 分解产物 颜色 分解产物
例1 羟基值=2.3的硬脂肪 白色 无 白色 无
例2 羟基值=3.0的硬脂肪 白色 无 白色 无
例3 羟基值=11.6的硬脂肪 白色 无 白色 无
例4 羟基值=12.3的硬脂肪 白色 无 白色 无
例5 羟基值=46.0的硬脂肪 白色 无 白色 无
例6* 羟基值=11.6的硬脂肪 白色 无 白色 无
对照例1 羟基值=53.5的硬脂肪 浅棕黄色 有 棕黄色 有
对照例2 羟基值=54.3的硬脂肪 浅棕黄色 有 棕黄色 有
对照例3 羟基值=64.1的硬脂肪 浅棕黄色 有 棕黄色 有
对照例4 Macrogol 4000和1540 白色 无 棕黄色 有
(4∶5)
对照例5 聚氧乙烯-聚氧丙烯 棕黄色 有 棕黄色 有
*DHAS双水合物钠盐与基质的重量比,在此例中为2∶8;所有其它例子的比例为1∶9。
试验例2
子宫颈伸展性试验
1.样品
按本发明方法制得的阴道栓(阴道栓的组分与例6的相同,制成直径为4毫米的园柱)
2.试验动物
初产的雌性韦斯泰(Wistar)大鼠(13周龄,每组6只动物)
3.方法
从姙娠第12日开始,每天一次阴道内给予大鼠100毫克样品,连续5天。对照组大鼠每天给一次与试验药中所用的同样的基质(Witopsol H-15,Dyramit Nobel公司出品),剂量100毫克。在姙娠第17天,将大鼠断头处死,分离出子宫颈。在离宫颈和阴道穹窿连接处3毫米的地方将子宫颈剖割开,用这段子宫颈测定它的伸展性。将二根钢棒平行地分别插入离体子宫颈的两个子宫颈管内。将其中一根钢棒按预定的速度牵拉。因作用于宫颈张力的变化而引起子宫颈的伸展,可通过与另一根钢棒连接的力位移换能器(Nihon Kohden有限公司出品)记录在笔录示波器上(Nihon Kohden有限公司出品)。以子宫颈伸展的长度为横轴,张力为纵轴作图。
4.结果
表2表示在所用张力为5~25克时,子宫颈伸展的长度。
表2
伸展长度(毫米)
平均±标准误差
用本发明方法制得的 1.8±0.29*
阴道栓处理的大鼠
对照组 1.0±0.19
*P<0.05(t-试验)
虽然,用本发明方法制得的阴道栓,有利于子宫颈的伸展。换句话说,用本发明方法制得的阴道栓能提高子宫颈的伸展性和促进它的成熟。
试验例3
急性毒性试验
1.样品
将羟基值为11.6的硬脂肪(Witepsol H-15 Dyramit Nobel有限公司出品)加热熔化,然后加入同样重量的DHAS双水合物钠盐(平均粒径为7微米)。彻底混合后,将混合物注入模型内,冷却后即得直径3或4毫米的园柱形栓剂。
2.动物试验
雌性SD大鼠(6周龄,体重149~168克,每组5只动物)
雌性ICR小鼠(6周龄,体重24.7~27.1克每组5只动物)
3.方法
采用上述栓剂,阴道内给予大、小鼠剂量为500毫克/公斤的DHAS双水合物钠盐。大小鼠均可自由摄取食物和水。给予大鼠的栓剂直径为4毫米,给予小鼠的直径为3毫米。
4.结果
给药后,对动物观察14天,未发现死亡或全身情况的改变。
拟用下述的例子和对照例更详尽地对本发明加以说明。
实施例1
于不锈钢烧杯内,加入900克羟基值为2.3的硬脂肪(Witepsol H-35,Dynamit Nobel有限公司出品),于40~42℃熔化后,加入100克粉碎的DHAS双水合物钠盐(平均粒径为7微米),混合均匀。混合物于37~38℃注入纺锤形模子内,每份1克。冷却后即得每粒含100毫克DHAS双水合物钠盐的阴道栓。
实施例2~5
重复实施例1的条件,但分别用羟基值为3.0,11.6,12.3和46.0的硬脂肪代替羟基值为2.3的硬脂肪。所得的阴道栓每粒含100毫克DHAS双水合物钠盐。
硬脂肪
日本油脂有限公司(Nippon Oil & Fat Co.,Ltd)实
(Dynamit Nobel Co.)
实施例6
按实施例1的方法,将800克羟基值为11.6的硬脂肪(Witepsol H-15,Dynamit Nobel公司出品)和200克DHAS双水合物钠盐(平均粒径为5微米)均匀混合,然后以每份一克的量注入模内,冷却后即得每粒含200毫克DHAS双水合物钠盐的阴道栓。
对照例1~3
重复实施例1的条件,但分别用羟基值为53.5,54.3或64.1的硬脂肪代替羟基值为2.3的硬脂肪。所得的阴道栓每粒含100毫克DHAS双水合物钠盐。
硬脂肪
对照例1 Witepsol S-55(OH值=53.5)(Dynamit Nobel Co)
对照例2 Nissan Pharmasol T-115(OH值=54.3)
日本油脂有限公司(Nippon Oil & Fats Co.,Ltd)
(Dynamit Nobel Co.)
对照例4
将400克Macrogol 4000和500克Macrogot 1540放入不锈钢烧杯内,于50~60℃熔化后,加入粉碎的DHAS双水合物钠盐(平均粒径为7微米)100克,混合好,混合物以每份1克的数量注入纺锤形模子内,冷却后即得每粒含100毫克DHAS双水合物钠盐的阴道栓。
对照例5
将900克聚氧乙烯-聚氧丙烯二醇(Unilub 70DP-950B,日本油脂有限公司Nippon Oil & Fats Co.,Ltd)放入不锈钢烧杯内,于55~60℃熔化后,加入100克粉碎的DHAS双水合物钠盐(平均粒径为7微米),混合好后,以每份1克的数量注入纺锤形模子内,冷却后即得每粒含100毫克DHAS双水合物钠盐的阴道栓。
Claims (1)
1、一种生产阴道栓的方法。此法包括将一种羟基值少于50的硬脂肪加热熔化,然后与硫酸脱氢表雄甾酮的药用盐混合,将混合物模铸并冷却成形。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP61250157A JPS63104924A (ja) | 1986-10-20 | 1986-10-20 | 膣坐剤 |
JP250157/86 | 1986-10-20 |
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CN87102641A true CN87102641A (zh) | 1988-05-04 |
CN1025591C CN1025591C (zh) | 1994-08-10 |
Family
ID=17203671
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CN87102641A Expired - Fee Related CN1025591C (zh) | 1986-10-20 | 1987-04-09 | 阴道栓的生产方法 |
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US (1) | US4789669A (zh) |
EP (1) | EP0264524B1 (zh) |
JP (1) | JPS63104924A (zh) |
KR (1) | KR900005822B1 (zh) |
CN (1) | CN1025591C (zh) |
AT (1) | ATE64097T1 (zh) |
DE (1) | DE3770571D1 (zh) |
ES (1) | ES2022181B3 (zh) |
GR (1) | GR3002053T3 (zh) |
PT (1) | PT84515B (zh) |
Cited By (1)
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CN1084612C (zh) * | 1993-12-03 | 2002-05-15 | 莱弗实验有限公司 | 杀病毒、杀菌以及杀精子的阴道栓 |
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JPH02178228A (ja) * | 1988-12-27 | 1990-07-11 | Lion Corp | 坐剤組成物 |
JP2546808B2 (ja) * | 1989-01-23 | 1996-10-23 | 鐘紡株式会社 | 膣坐剤 |
US5246704A (en) * | 1989-01-23 | 1993-09-21 | Kanebo, Ltd. | Vaginal suppository |
US5232700A (en) * | 1990-11-14 | 1993-08-03 | The Administrators Of The Tulane Educational Fund | Methods of prophylaxis and treatment of herpes simplex lesions utilizing piracetam as the active ingredient |
JP3467628B2 (ja) * | 1991-05-24 | 2003-11-17 | 岩城製薬株式会社 | 坐剤用基剤 |
ES2227523T3 (es) * | 1993-01-19 | 2005-04-01 | Endorecherche Inc. | Usos terapeuticos y sistemas de suministro de deshidroepiandrosterona. |
US6383431B1 (en) * | 1997-04-04 | 2002-05-07 | The Procter & Gamble Company | Method of modifying a nonwoven fibrous web for use as component of a disposable absorbent article |
US7405207B2 (en) * | 2002-06-17 | 2008-07-29 | Epigenesis Pharmaceuticals, Inc. | Nebulizer formulations of dehydroepiandrosterone and methods of treating asthma or chronic obstructive pulmonary disease using compositions thereof |
CA2489124A1 (en) * | 2002-06-17 | 2004-12-02 | Epigenesis Pharmaceuticals Llc | Nebulizer formulations of dehydroepiandrosterone and methods of treating asthma or chronic obstructive pulmonary disease using compositions thereof |
NZ554619A (en) | 2004-10-20 | 2011-01-28 | Endorech Inc | Sex steroid precursors alone or in combination with a selective estrogen receptor modulator and/or with estrogens and/or a type 5 CGMP phosphodiesterase inhibitor for the prevention and treatment of vaginal dryness and sexual dysfunction in postmenopausal women |
US20070172508A1 (en) * | 2006-01-26 | 2007-07-26 | Paul Zupkas | Transluminal drug delivery methods and devices |
US20080145268A1 (en) * | 2006-12-15 | 2008-06-19 | Martin Stephanie M | Deodorizing container that includes an anthraquinone ink |
US20080145269A1 (en) * | 2006-12-15 | 2008-06-19 | Martin Stephanie M | Deodorizing container that includes a modified nanoparticle ink |
US8268806B2 (en) | 2007-08-10 | 2012-09-18 | Endorecherche, Inc. | Pharmaceutical compositions |
US20100087402A1 (en) * | 2008-09-29 | 2010-04-08 | Vivus, Inc. | Methods and compositions for the treatment of estrogen-dependent hyperproliferative uterine disorders |
AU2012228213B2 (en) * | 2011-03-17 | 2015-08-06 | Sonia Pharma Gmbh | Treatment of vaginal atrophy as novel indication for myrrh |
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US4005200A (en) * | 1975-07-17 | 1977-01-25 | Kanebo, Ltd. | Method for improving the maturity of the parturient canal and the sensitivity to oxytocin |
SE439586B (sv) * | 1975-09-05 | 1985-06-24 | Kanebo Ltd | Sett att framstella ett stabilt farmaceutiskt torrpreparat av ett alkalimetallsalt av dehydroepiandrosteronsulfat |
US4496556A (en) * | 1982-08-16 | 1985-01-29 | Norman Orentreich | Topical applications for preventing dry skin |
CA1207231A (en) * | 1982-08-24 | 1986-07-08 | Hans W. Zulliger | Medicated suppository |
-
1986
- 1986-10-20 JP JP61250157A patent/JPS63104924A/ja active Granted
-
1987
- 1987-03-09 EP EP87103351A patent/EP0264524B1/en not_active Expired - Lifetime
- 1987-03-09 AT AT87103351T patent/ATE64097T1/de not_active IP Right Cessation
- 1987-03-09 ES ES87103351T patent/ES2022181B3/es not_active Expired - Lifetime
- 1987-03-09 DE DE8787103351T patent/DE3770571D1/de not_active Expired - Fee Related
- 1987-03-10 US US07/024,204 patent/US4789669A/en not_active Expired - Fee Related
- 1987-03-18 PT PT84515A patent/PT84515B/pt not_active IP Right Cessation
- 1987-04-09 CN CN87102641A patent/CN1025591C/zh not_active Expired - Fee Related
- 1987-07-02 KR KR1019870007061A patent/KR900005822B1/ko not_active IP Right Cessation
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1084612C (zh) * | 1993-12-03 | 2002-05-15 | 莱弗实验有限公司 | 杀病毒、杀菌以及杀精子的阴道栓 |
Also Published As
Publication number | Publication date |
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DE3770571D1 (de) | 1991-07-11 |
JPH0517884B2 (zh) | 1993-03-10 |
EP0264524B1 (en) | 1991-06-05 |
ES2022181B3 (es) | 1991-12-01 |
GR3002053T3 (en) | 1992-12-30 |
JPS63104924A (ja) | 1988-05-10 |
KR900005822B1 (ko) | 1990-08-13 |
PT84515B (pt) | 1990-07-31 |
US4789669A (en) | 1988-12-06 |
KR880004799A (ko) | 1988-06-27 |
ATE64097T1 (de) | 1991-06-15 |
PT84515A (en) | 1987-04-01 |
CN1025591C (zh) | 1994-08-10 |
EP0264524A1 (en) | 1988-04-27 |
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