CN87104229A - 阴道器 - Google Patents
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- A—HUMAN NECESSITIES
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- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
Abstract
本发明是关于治疗低雌激素妇女的包括17β-雌二醇和载体的组合材料的阴道器。此种阴道器能以大约0.5至25微克/24小时的释放量连续释放17β-雌二醇。
本发明还包括制作此种阴道器的方法和应用此种阴道器治疗低雌激素妇女的方法。
Description
本发明是关于阴道器，尤其是关于治疗低雌激素妇女的可在一段较长时间内释放出少量17β-雌二醇而又无不良副作用的阴道器。
17β-雌二醇通常用于治疗雌激素缺乏症。此种雌激素缺乏症是由于，例如卵巢切除手术、绝经、辐射诱发的卵巢衰渴、全垂体机能减退和卡尔曼氏（Kallman′s）综合症所引起的。
但是，口服17β-雌二醇的疗效是相当低的（1，2）。此外，由于肝门吸收（3）、肠代谢（4，5）和每次服药后循环雌激素时所产生的“浓药剂”的骤增（5），所以口服雌激素会影响肝蛋白。
阴道投药可避免由于口服雌激素疗法所带来的问题，而且从阴道可充分吸收类固醇。已经有人建议通过阴道器来对17β-雌二醇进行投药而且已经进行了充分的研究（6，7，8，9）。在这些研究工作中，其中有一项研究工作是由Englund等人（7）进行的，该研究论文公开了在体外具有释放量为200微克/24小时的阴道器，此释放量相当于妇女体内80-200微微克/毫升的血浆量。该论文最后作出结论，指出每日200微克的释放量太高，不能取代绝经后妇女所采用的口服疗法，因为此释放量超过了在育龄妇女卵泡期中所观察到的雌激素量。该论文认为每日释放50-100微克17β-雌二醇的阴道器可提供合适的剂量。
在Stumpf（6，9）和Veldhuls（8）的论文中，未讨论每日的释放量，但是，该文公开的血浆量为50-150微微克/毫升，此数量与Englund论文中所公开的数量大致相同。
与过去的研究工作和所作的建议相反，目前已经发现，释放相当少量的17β-雌二醇的阴道器就足以减轻或消除由于缺乏雌激素所引起的症状。这些症状可能是，例如，感到阴道干燥、瘙痒、交媾困难、排尿时刺痛、尿急和尿频。已经发现，如果根据本发明应用低剂量，可大大地减少诸如起斑点、突破性出血和停止服药即行出血等一类不良副作用。
根据本发明的阴道器的特征是，能以约0.5至25微克/24小时的释放量连续释放17β-雌二醇。
本发明还涉及在妇女阴道内固定放置一套含药阴道器以治疗低雌素妇女的方法，此种阴道器能以约0.5至25微克/24小时的释放量连续释放17β-雌二醇。
较好的释放量为1至10微克/24小时，而最适用的释放量为4至8微克/24小时。
从本发明的阴道器中连续地和基本上恒定地释放雌二醇的时间，基本上可包括从一日至一年的任何时间，该时间的长短则取决于几个因素。通常此时间是3或4个月。而较好的是至少在一个月内释放量基本上是恒定的。
本发明的阴道器可具有任何适用于阴道投药的形状。优选的阴道器形式是阴道环。
在阴道环（IVR）领域中，基本上有5种不同的设计。对于IVR的第一种设计来说，其中类固醇，如美国专利第3，545，397号中所述，是均匀地分散在整个惰性弹体中。
第二种IVR，包括一个惰性弹体环和包在此环外边的另一个浸有类固醇的惰性弹体环（参见，例如美国专利第4，012，496号）。
在第三种形式的IVR（称为Roseman IVR）中将一层含有类固醇的薄惰性弹体模压在一个中心惰性弹体上。
在第四种形式的IVR中，将一层含有类固醇的薄惰性弹体包在一个中心合成弹体的外面，然后再在外面包一层可变厚度的惰性弹体。在美国专利第4，292，965号中公开了此种形式的阴道环。
第五种形式的IVR，包括一个与类固醇混合的中心弹体和一层包在外面的惰性弹体。在避孕（Contraception）杂志1978年3月第17卷第3册第221-230页中叙述了此种形式的IVR。
本发明还包括制作治疗低雌激素妇女的阴道器的方法。此法包括将17β-雌二醇与载体组合的步骤，从而选择一定数量比例的17β-雌二醇和载体，使此种阴道器能以约0.5至25微克/24小时的释放量连续释放
17β-雌二醇，而较好的释放量约为1至10微克/24小时，最好的释放量约为4至8微克/24小时。
可从本技术领域中已知的多种多样材料中选择作为载体的弹体，而雌二醇的释放量则由菲克原理确定。所用弹体可选自，例如，RTV（室温硫化）型的两端接羟基的有机多分子硅醚，此种形式的有机多分子硅醚可在有固化催化剂存在和大气湿度条件下，在加入交联剂后，在室温下硬化为弹体。典型的固化催化剂是羧酸金属盐，较好的是锡盐，例如辛酸锡（二价）和2-乙基己酸锡（二价）。其他适用的弹体是双组份二甲基多分子硅醚组合物，此种组合物可在室温或稍为提高的温度下被铂催化，并能加入交联剂。
根据一项优选的实施方案，此种阴道器具有环状的形式，制作此种阴道环的方法是，首先将17β-雌二醇均匀地悬浮在一种医药上可接受的弹体中;用上述含17β-雌二醇的弹体制作环芯;然后再在此芯的外面包一层医药上可接受的弹体，随后再将制成的阴道器进行固化。
显然，固化温度和固化时间均可在较宽的范围内变动并取决于，例如，所用弹体的性质。阴道环芯和包在外面的未含药的弹体层可以用同一种弹体制成，但并非必须用同一种弹体制成。
固化温度可在室温和150℃之间变动，较好的是40-90℃。固化时间可在几秒和几日之间变动。但是，在实际情况中，优选的固化时间是少于1小时。
为了达到本发明的释放量，环芯直径与外层弹体管厚度的比值，较好的是在0.3至6之间变动，而最好的是在0.4至2之间。
下列实例进一步说明本发明。
实例1
将1份纯微粒17β-雌二醇与250份液态聚二甲基硅醚（382Silastic医用级弹体）混合。将此混合物用辛酸亚锡活化，然后再在压力下将此混合物注入双件式模具中，此双件式模具的外径为543毫米和内径为539毫米。将双件式模具中的混合物聚合，然后从模具中取出断面直径为2毫米的实心环。将厚度为3.5毫米的聚硅氧烷（382Silastic医用级弹体）管模压在此环的外面，从而制成第一套由2毫米的含药内环芯和3.5毫米的未含药的外层环管组成的阴道器。这些环能以8微克/24小时的释放量连续释放雌二醇150日。雌二醇的含量为1.91毫克/环1而SILASTIC的含量为11克。
实例2
用类似的方法制得第二套阴道环，但是能以约20微克/24小时的释放量连续释放雌二醇150日，此种环的不同之处在于，应用厚度1.5毫米的外层未含药的聚硅氧烷环管和直径为6毫米的环芯。在150日期间中释放量相当恒定，但是释放量的确会随时间的增加而稍为降低。此种阴道环的雌二醇含量为4.79毫克/环而silastic的含量为11克。
本文中所指的释放量是在体外的释放量，此释放量可根据避孕杂志1978年3月第225页（17卷，第3册）或避孕杂志1981年10月（24卷，第4册）或任何其他类似的方法进行测定。
因此，可以任何不同的方法制出任何不同形式或形状的含17β-雌二醇的阴道器。上述释放量测定步骤可用来确定所制出的阳道器是否符合本发明的释放量要求。
对9位绝经后妇女试验了为期三个月的释放量约为8微克/24小时的阴道环和对11位绝经后妇女试验了为期三个月的释放量约为20微克/24小时的阴道环。这些不同释放量的阴道环都很受欢迎，二组妇女的绝经后症状均已消失。
对以8微克/24小时释放量接受雌二醇投药的妇女，未观察到其他副作用。对以20微克/24小时释放量接受雌二醇投药的一位妇女，观额察到可忽略不计的出血量。
表1公开了根据试验者制得的两种不同形式的阴道环的17β-雌二醇体外释放量。
表2和3表明体内释放量以及体外和体内释放量之间的关系。
A＝含有4.79毫克雌二醇的环
B＝含有1.91毫克雌二醇的环
用E2释放量对时间作图，绘出释放曲线图，并计算出下列平均释放量：A型环：E220.3微克/24小时，使用时间为97或98日;E220.6微克/24小时，使用时间为92日;E220.0微克/24小时，使用时间为105日。B型环：E27.8微克/24小时，使用时间为93至99日。
参考文献
1. Botella-Llusia J 1973 Endocrinology of Women，
W.B.Saunders Co，Philadelphia，pp 32-33
2. Krantz JC，Carr CJ，LaDu BN 1969 The
Pharmacologic Principles of Medical Practice.
Williams & Wilkins Co，Baltimore，p 597
3. Utian WH 1980 Menopause in Modern Perspective：
A Guide to Clinical Practice，
Appleton-Century-Crofts，New York，pp 151-152
4. Ryan KJ，Engel LL 1953 The Interconversion of
estrone and estradiol by human tissue slices.
Endocrinol.52：287
5. Yen SSC，Martin PL，Burnier AM，Czekala NM，
Greaney MO，Callantine MR 1975 Circulating estra-
diol，estrone and gonadotropin levels following
the administration of orally active 17β-estra-
diol in postmenopausal women.J Clin Endocrinol
Metab 40：518
6. Stumpf et al 1982，Development of a vaginal ring
for achieving physiologic levels of
17β-estradiol in hypoestrogenic women，J Clin
Endocrinol Metab，54：208-210
7. Englund D.E.，1981，Pharmacokinetics and Phar-
macodynamic effects of vaginal oestradiol admi-
nistration from siiastic rings in postmenopausal
women，Maturitas，3：125-133
8. Veldhuls J.et al，1986，Endocrine impact of pure
estradiol replacement in postmenopausal women：
Alterations in anterior pituitary hormone release
and circulating sex steroid hormone con-
9. Stumpf.P.1986，Selecting constant serum estra-
estradiol levels achieved by vaginal rings，
Obstet.Gynecol.67：91-94，1986
Claims (10)
1、治疗低雌激素妇女的含有17β-雌二醇和载体的组合材料的阴道器，其特征在于所述的阴道器能以约0.5至25微克/24小时的释放量连续释17β-雌二醇。
2、根据权利要求1的阴道器，其特征在于释放量约为1至10微克/24小时，较好的是4至8微克/小时。
3、根据权利要求1的阴道器，其特征在于至少在一个月内，释放量基本上是恒定的。
4、根据权利要求1的阴道器，其中该阴道器具有环状的形式，此阴道环包括在其中有均匀悬浮的雌二醇的医药上可接受的弹体环芯和支承该环芯的外弹体层。
5、根据权利要求4阴道器，其中所述的环芯弹体是聚二甲基硅氧烷而外弹体层是聚硅氧烷管。
6、制作治疗低雌激素妇女的阴道器的方法，此法包括将17.β-雌二醇与载体组合的步骤，其特征在于选用一定数量比例的17β-雌二醇和载体，以使此种阴道器能以大约0.5至25微克/24小时的释放量连续释放17β-雌二醇。
7、根据权利要求6的方法，其特征在于该释放量约为1至10微克/小时，较好的是约为4至8微克/24小时。
8、根据权利要求6或7的方法，其特征在于至少在一个月内，释放量基本上是恒定的。
9、根据权利要求6至8中任何一项的方法，其特征在于：阴道环具有环状的形式;17β-雌二醇均匀地悬浮在医药上可接受的弹体中;用上述含17β-雌二醇的弹体制作环芯;在此环芯外面包一层医药上可接受的弹体;和将制得的阴道器进行固化。
10、根据权利要求6至9中任何一项的方法，其特征在于环芯直径与外层弹体管厚度的比值为0.3至6，较好的为0.4至2。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8602666A SE8602666D0 (sv) | 1986-06-16 | 1986-06-16 | Intravaginal devices |
| SE8602666-3 | 1986-06-16 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN87104229A true CN87104229A (zh) | 1987-12-30 |
| CN1034391C CN1034391C (zh) | 1997-04-02 |
Family
ID=20364821
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN87104229A Expired - Lifetime CN1034391C (zh) | 1986-06-16 | 1987-06-12 | 阴道器的制备方法 |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US4871543A (zh) |
| EP (1) | EP0253109B1 (zh) |
| JP (1) | JP2671953B2 (zh) |
| KR (1) | KR920005824B1 (zh) |
| CN (1) | CN1034391C (zh) |
| AT (1) | ATE68097T1 (zh) |
| AU (1) | AU599988B2 (zh) |
| CA (1) | CA1314482C (zh) |
| DE (1) | DE3773557D1 (zh) |
| DK (1) | DK175529B1 (zh) |
| ES (1) | ES2026481T3 (zh) |
| FI (1) | FI91709C (zh) |
| GR (1) | GR3003551T3 (zh) |
| HU (1) | HU205014B (zh) |
| IE (1) | IE60654B1 (zh) |
| IL (1) | IL82769A (zh) |
| NO (2) | NO172784C (zh) |
| NZ (1) | NZ220616A (zh) |
| PH (1) | PH26981A (zh) |
| PT (1) | PT85082B (zh) |
| SE (1) | SE8602666D0 (zh) |
| ZA (1) | ZA874174B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102098991B (zh) * | 2008-02-04 | 2014-10-22 | 特卫华妇女健康有限公司 | 包含孕酮的一体式阴道环以及其制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5188835A (en) * | 1986-06-16 | 1993-02-23 | Kabi Pharmacia Ab | Intravaginal devices |
| US5084277A (en) * | 1988-08-30 | 1992-01-28 | Greco John C | Vaginal progesterone tablet |
| FI93922C (fi) * | 1993-06-17 | 1995-06-26 | Leiras Oy | Vaikuttavaa ainetta luovuttava laite |
| FI95768C (fi) * | 1993-06-17 | 1996-03-25 | Leiras Oy | Emättimensisäinen antosysteemi |
| IL116433A (en) * | 1994-12-19 | 2002-02-10 | Galen Chemicals Ltd | INTRAVAGINAL DRUG DELIVERY DEVICES FOR THE ADMINISTRATION OF 17β-OESTRADIOL PRECURSORS |
| US5861431A (en) * | 1995-06-07 | 1999-01-19 | Iotek, Inc. | Incontinence treatment |
| US5816248A (en) * | 1996-03-29 | 1998-10-06 | Iotek, Inc. | Channeled vaginal insert and method for treating urogenital disorders |
| US5988169A (en) * | 1996-03-29 | 1999-11-23 | Iotek, Inc. | Vaginal insert and method for treating urogenital disorders |
| US6030375A (en) * | 1996-03-29 | 2000-02-29 | Iotek, Inc. | Compressible vaginal insert and method for treating urogenital disorders |
| US5891868A (en) * | 1997-11-21 | 1999-04-06 | Kaiser Foundation Health Plan, Inc. | Methods for treating postmenopausal women using ultra-low doses of estrogen |
| US20030219471A1 (en) * | 2002-03-11 | 2003-11-27 | Caubel Patrick Michel | Extended cycle estrogen and sulfatase inhibiting progestogen contraceptive regimens |
| DE60307602T2 (de) * | 2002-03-11 | 2007-10-04 | Janssen Pharmaceutica N.V. | Kontinuierliche sulfatase-hemmende progestogen enthaltende hormonsubstitutions-therapie |
| US20030225047A1 (en) * | 2002-03-11 | 2003-12-04 | Caubel Patrick Michel | Sulfatase inhibiting progestogen-only contraceptive regimens |
| AU2004233997C1 (en) * | 2003-04-29 | 2014-01-30 | Massachusetts Institiute Of Technology | Methods and devices for the sustained release of multiple drugs |
| US7816546B2 (en) * | 2003-06-30 | 2010-10-19 | Richter Gedeon Vegyeszeti Gyar Rt. | Process for the synthesis of high purity d-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-oxime |
| AU2020397648B2 (en) | 2019-12-06 | 2022-03-24 | Prathima Chowdary | Sustained release estrogen vaginal ring pessary for treatment of atrophy, cystitis and uterovaginal prolapse |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3920805A (en) * | 1971-12-09 | 1975-11-18 | Upjohn Co | Pharmaceutical devices and method |
| IN142428B (zh) * | 1974-07-05 | 1977-07-09 | Schering Ag | |
| US4155991A (en) * | 1974-10-18 | 1979-05-22 | Schering Aktiengesellschaft | Vaginal ring |
| DE2450107A1 (de) * | 1974-10-18 | 1976-04-29 | Schering Ag | Vaginalring |
| DE2611535A1 (de) * | 1976-03-16 | 1977-09-29 | Schering Ag | 6alpha-hydroxy-8alpha-oestradiole |
| JPS5845440B2 (ja) * | 1978-08-29 | 1983-10-08 | 呉羽化学工業株式会社 | プロスタグランジン誘導体とその製造方法及び薬剤 |
| US4292965A (en) * | 1978-12-29 | 1981-10-06 | The Population Council, Inc. | Intravaginal ring |
| US4250611A (en) * | 1979-04-19 | 1981-02-17 | Alza Corporation | Process for making drug delivery device with reservoir |
| US4402695A (en) * | 1980-01-21 | 1983-09-06 | Alza Corporation | Device for delivering agent in vagina |
| US4425339A (en) * | 1981-04-09 | 1984-01-10 | Syntex (U.S.A.) Inc. | Treatment of menopausal symptoms |
| GB2135189B (en) * | 1983-02-22 | 1986-07-09 | Joachim Georg Liehr | Estrogen deficiency conditioned with 2-fluoroestradiols |
| AU582540B2 (en) * | 1983-08-05 | 1989-04-06 | Pre Jay Holdings Ltd. | A method of hormonal treatment of perimenopausal, menopausal and post-menopausal disorders and multi-preparation pack therefor |
| US4596576A (en) * | 1984-10-12 | 1986-06-24 | Akzo N.V. | Release system for two or more active substances |
-
1986
- 1986-06-16 SE SE8602666A patent/SE8602666D0/xx unknown
-
1987
- 1987-05-26 IE IE137787A patent/IE60654B1/en not_active IP Right Cessation
- 1987-05-27 DE DE8787107710T patent/DE3773557D1/de not_active Expired - Lifetime
- 1987-05-27 EP EP87107710A patent/EP0253109B1/en not_active Expired - Lifetime
- 1987-05-27 ES ES198787107710T patent/ES2026481T3/es not_active Expired - Lifetime
- 1987-05-27 AT AT87107710T patent/ATE68097T1/de not_active IP Right Cessation
- 1987-06-03 CA CA000538695A patent/CA1314482C/en not_active Expired - Lifetime
- 1987-06-04 IL IL82769A patent/IL82769A/xx not_active IP Right Cessation
- 1987-06-09 NZ NZ220616A patent/NZ220616A/xx unknown
- 1987-06-10 PH PH35384A patent/PH26981A/en unknown
- 1987-06-10 ZA ZA874174A patent/ZA874174B/xx unknown
- 1987-06-12 US US07/060,833 patent/US4871543A/en not_active Expired - Lifetime
- 1987-06-12 FI FI872629A patent/FI91709C/fi not_active IP Right Cessation
- 1987-06-12 CN CN87104229A patent/CN1034391C/zh not_active Expired - Lifetime
- 1987-06-15 AU AU74222/87A patent/AU599988B2/en not_active Expired
- 1987-06-15 JP JP62148881A patent/JP2671953B2/ja not_active Expired - Lifetime
- 1987-06-15 HU HU872705A patent/HU205014B/hu unknown
- 1987-06-15 NO NO872489A patent/NO172784C/no unknown
- 1987-06-15 DK DK198703034A patent/DK175529B1/da not_active IP Right Cessation
- 1987-06-15 PT PT85082A patent/PT85082B/pt unknown
- 1987-06-16 KR KR1019870006101A patent/KR920005824B1/ko not_active IP Right Cessation
-
1992
- 1992-01-09 GR GR920400009T patent/GR3003551T3/el unknown
-
1997
- 1997-01-13 NO NO1997001C patent/NO1997001I1/no unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102098991B (zh) * | 2008-02-04 | 2014-10-22 | 特卫华妇女健康有限公司 | 包含孕酮的一体式阴道环以及其制备方法 |
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