CN1036836C - 制备含有孕二烯酮的透皮治疗系统的方法 - Google Patents
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Abstract
本发明是关于制备含有孕二烯酮的透皮治疗系统的方法,治疗系统中还可任选含有一种或两种雌激素,还可含有助透剂。
Description
本发明是关于制备含有孕二烯酮的透皮治疗系统的方法,此系统中还可含有雌激素和/或助透剂。
孕二烯酮(13-乙基-17β-羟基-18,19-二去甲-17α-孕-4,15-二)烯-3-酮),为分子式如下的化合物:它是皆知的具有特别强的孕激素样作用的药理活性物质,它在与雌激素样作用的化合物合用时,被用来制备口服避孕药(Femovan_)。
现已发现,孕二烯酮,必要时与一种或多种雌激素合用,可很好地用于制备含活性物质或活性物质的混合物的药剂。
透皮用药具有众所周知的优点,它可在一个长的时间内使有效物质均匀地释放,通常在另外情况下,例如只有口服可以达到。这种特性在一系列内分泌疾病中被有效地利用了。一般情况下,难溶水的甾类激素,例如孕激素,制成透皮系统是相当困难的,在治疗中该透皮系统保证有足够的有效物质透入皮肤。
现已发现,当药剂含有熟知的甾类激素,透皮给药只是在一定条件下才有可能时,借助本发明的药剂,可意外地能使治疗上有足够量的均匀透入速度的甾类激素透过皮肤。(EP-A 137278和EP-A 275716)
适合本发明药剂的雌激素是,例如雌二醇、雌三醇、乙炔基雌二醇及其酯类,(EP-A 163596),如雌二醇-二丙酸酯,雌二醇-二己酸酯和雌二醇-二癸酸醋。按本发明的复方制剂,除含有孕二烯酮外,主要含有1至3,特别是1至2个的雌激素。
为了制备药物制剂,将有效物质或有效物质的混合物溶解或悬浮在一种合适的挥发性的溶剂和/或助透剂中。得到的溶液和悬浮液与常规的赋料例如:赋形剂和杀菌药混合,必要时消毒后装入普通容器。另一方面也可以将溶液或悬浮液与乳化剂和水进一步加工成洗剂或软膏。还可以加入压缩气体,装入普通的计量容器中,制成气雾剂。
适宜的挥发性溶剂,例如:低碳醇、酮或低碳羧酸酯,如乙醇、异丙醇、丙酮,或乙酸乙酯,极性醚,如四氢呋喃,低碳烃,如环己烷或气油,或卤代碳氢化合物,如二氯甲烷、三氯甲烷、三氯三氟甲烷、三氯氟甲烷、不言而喻,这些溶剂的混合物也是适用的。
适宜的助透剂 有醇,如1,2-丙二醇或苯甲醇,含有8到18个碳原子的饱和和不饱和脂肪醇,如月桂醇或十六烷醇,碳氢化合物,如矿物油,含有8到18个碳原子的饱和和不饱和脂肪酸,如硬脂酸或油酸,通式如下的脂肪酸酯:
CH3-(CH2)n-COOR
式中
n表示8到18的数值
R表示最多是6个碳原子的烷基。
或通式如下的二羧酸二酯:
R'OCO(CH2)mCOOR'
式中
m表示4到8的数值
每个R'都表示至多为6个碳原子的烷基。
适用于本发明药剂的脂肪酸酯 有月桂酸、肉豆蔻酸、硬脂酸和棕榈酸,以及这些酸的甲酯、乙酯、丙酯、异丙酯、丁酯、仲一丁酯、异丁酯。特别优越的酯是肉豆蔻酸酯类,如甲酯,尤其是异丙酯。适宜的二羧酸二酯 有己二酸二异丙酯,己二酸二异丁酯和癸二酸酯。无需说,助透剂的混合物也适用于本发明药剂的制备。
有效物质或有效物质的混合物在溶剂中溶解或悬浮的浓度,通常孕二烯酮含量最好在0.01到25%(重量)之间,雌激素的浓度当然与所用有效物质的性质和一次用药的剂量有关,在个别情况下,还必须由专业人员进行常规预试验,例如确定本发明选用的药剂的有效物质的血浆浓度。例如参见“Weiner K1inische Wochen-schrift”93,1981,601-604或美国专利4,719,054号。通常按本发明药剂的有效物质浓度为0.01到25%(重量)的雌激素。在配方制剂中孕二烯酮与雌激素的重量比为5∶1到1∶10。
本发明药剂经皮吸收速度的测定,可用放射性标记的 类激素进行。
Frisch从无毛老鼠的腹部取下无脂肪皮肤,将其装在弗朗茨氏扩散池内,扩散池内含有等渗聚乙烯乙二醇-(MG400)-溶液或PH值为7的磷酸盐缓冲液作为收集液。然后,在皮肤上加2微升测试溶液,在24、48、72小时用液闪计数器测定收集液中类激素的含量。
百分之二的孕二烯酮(重量)在肉豆蔻酸异丙酯(试验A)和石蜡(试验B)的溶液进行了测定。
下表1列出了试验的结果:
表1
在每平方厘米的皮肤表面孕二烯酮的经皮流出ng数和小时
时间间隔 试验A 试验B
经皮流出量 经皮流出量00-24h 546 75524-48h 379 24548-72h 287 100
此外,还应指出,在非放射标记的孕二烯酮溶解在1,2-丙二醇(试验C)或肉豆蔻酸异丙酯中(试验D),绝经后妇女能充分的经皮吸收。
测试中,0.4mg孕二烯酮每次都溶解在200微升的适当的介质中,测定48小时透过10平方厘米的皮肤表面的药量。
下表2列出了该试验的结果,
表2
在每平方厘米皮肤表面上孕二烯酮的经皮流过的ng数和小时
稳态血浆含有量 经皮流出量ng/cm2/std
pg/ml 在24-48小时内试验C 250 43试验D 337 57如果将有效物质或它的混合物加到透皮治疗系统(TTS)中,就可使设置的有效物质或它的混合物的剂量更加均匀的应用。适宜的透皮治疗系统是常规用的有效物质的经皮给药(YieW,Chien:“经皮控制的全身给药”Marce1Dekker,Inc.,New York Based,1987;Dr.Richard Baker:“1934-1984透皮药物转运专利的分析”和“最近透皮转运专利(1984-1986年)的分析”和Enhancers“膜技术与研究”1030 HamiltonCourt Menlo Park CA94025(415)328-2228)。
例如,人们应用的这种透皮治疗系统,是由如下几方面组成的:
a)一层不能渗透覆盖层,
一种含有粘附于此覆盖层的孕二烯酮,必要时或
含有孕二烯酮和雌激素和所希望的助透剂的可透入的药物组分层,这种药物层本身是粘性的,或由一种皮肤粘合剂覆盖或包封,该皮肤粘合剂也可含有助透剂。
一层可剥落的保护层,或者
b)一层不能渗透的覆盖层,
一种含有处在覆盖层表面或覆盖层中的孕二烯酮,必要时或含有雌激素和所希望的助透剂的药物贮存层,
一层能渗透这种组合物的聚合物层,
一种必要时含有助透剂的,能够渗透增强药剂的皮肤粘合剂层
一层可剥落的保护层。
根据上述a的透皮治疗系统提供了一种简单的基质体系,可用下例说明。
含有1-25%(重量)的有效物质或有效物质的混合物的溶液或悬浮液,含有0-40%(重量)的助透剂,含30-70%(重量)的医用粘合剂,加入挥发性适度的溶剂成100%(重量),涂布在平坦的不渗透的覆盖层上,干燥后再赋予其一层可剥落的保护层。
若用医用基质时,系统干燥后,不能或不能充分地粘合在皮肤上,因此,在涂布可剥落的保护层之前,要用一种皮肤粘合剂将系统覆复或包封住。
适用的溶剂和助透剂是已提及的液体。适于作为医用粘合剂的有,如聚丙烯酸酯、有机硅、聚氨酯以及天然的或合成橡胶。其它的基质还有纤维素醚、聚乙烯化合物或硅酸盐。
通常用于透皮治疗系统的所有薄膜都适用于作为保护层,有些薄膜是有机硅化合物或氟聚合物涂层。
这个系统的覆盖层用10至100um厚的聚乙烯或聚酯薄膜,对这些薄膜进行了染色或金属镀膜。药剂层厚度最好为20到500um。将有效物质最好涂布在5至100cm2的表面。
上述b的透皮治疗系统的制备实例如下。
将不能渗透的薄膜加热和/或拉伸使其变形,形成一个可容纳0.1到3毫升液体的隆起小包,将助透剂中含1-50%(重量)的有效物质或其混合物的溶液或悬浮液装满该隆起包内。含有效物质的溶液或悬浮液也可加入最多为10%(重量)的基质使其增稠。
已热接或粘合上的可渗透聚合物层作为皮肤上的盖层,在它的上面有可渗透的皮肤粘合剂层和可剥落的保护层。
上面已提到,该系统使用了助透剂。可渗透的聚合物层是20到200um厚的纤维素酯类、纤维素醚类、有机硅或聚烯烃化合物薄膜。通过改变聚合物层可使有效物质或它的混合物的扩散速度能在很宽的范围内变化。
上述a的透皮治疗系统中已叙述了用相同的材料作为粘合层和保护层。
这样,可通过简便的改变各种参数制成的透皮治疗系统,其有效物质或它的混合物有不同释放速度。最后是贮存,可用铝箔包装。
上面已提到本发明的透皮用药可以是洗剂、软膏或气雾剂。配制要在良好的条件下进行,以免包藏物混入。
透皮用的乳状凝胶是由有效物质或它的混合物、助透剂、乳化剂(这里可用亲水亲脂性的助透剂作为乳化剂)和必要时加基质组成。典型的配方是含有0.1-25%(重量)的有效物质或它的混合物,0-10%(重量)的乳化剂,0-5%(重量)的基质,0-5%(重量)的助透剂,加水到百分之百。用常规方法将药剂乳化,必要时加入常用的抗氧剂、防腐剂等。
将活性物质或其混合物溶解或悬浮于溶剂,如水、低碳醇或其混合物,必要时加入助透剂和增稠基质,可得到均相凝胶。
这种凝胶的典型配方是含有0.01-25%(重量)的有效物质或它的混合物,1-20%(重量)的基质,0-40%(重量)的助透剂,加溶剂到100%(重量)。
必要时这个凝胶也可以加入抗氧剂、防腐剂等。
典型的配方实例如下:
1~25%(重量)的有效物质或有效物质的混合物,0~20%(重量)的基质,0~60%(重量)的助透剂,加溶剂和必要时加膨化剂到100%,若用压缩气包装,就不要加膨化剂。
按本发明制成的含孕二烯酮的透皮用药可用来治疗与已知的含高效孕激素口服制剂相同的疾病。此外,也发现本发明的含有雌激素的药剂也可用采阻止受孕。本发明的药剂对需要用较高剂量的有效物质和长时期治疗如数月至数年的疾病具有特别的优点,它显著地降低了用药频率,达到明显均匀的血药浓度。此外,它的优点还有对胃肠没有副作用,并且,在含有雌激素的复合制剂的情况下,肝脏的首过效应也会使雌激素的含量降低,这个优点使得本发明的不含雌激素的治疗药特别适用于治疗子宫内膜异位,与孕激素有关的良性的乳腺瘤或月经前的综合症。
雌激素顺序地或连续地与孕二烯酮合用,进行透皮给药有特殊的优点,例如治疗更年期疾病、预防骨质疏松,调整循环系统和稳定循环系统。
本发明的透皮药剂的给药方式与其他透皮组合物的给药方式相似。因此,当单独使用孕二烯酮时,可通过身体各部位皮肤给药,但最好通过臀部、胸前部和胸侧部、大腿和臂前部皮肤给药。当孕二烯酮与雌激素同时给药或与雌激素联合使用分别给药时,可通过身体各部位皮肤透皮给药,但最好通过臀部、胸前部和胸侧部、大腿和臂前部皮肤给药。无论透皮组合物的形式如何,例如无论是普通的透皮膏药或软膏,还是洗剂或喷雾剂,合适的给药部位基本是一样的。可利用常规方法确定对一定疾病状态的给药次数,基本与常规的孕二烯酮和/或雌激素的给药次数相同。
勿须进一步详述,可认为,本领域技术人员可充分利用本发明。下述的最佳实施例只是说明本发明而不是对本发明的限制。
在上述和下述的实例中,所有的温度都是未经校正的摄氏温度而且除非另有说明,所有的份数和百分数均指重量而言。
在说明书上文和下文中引用的专利和出版物以及德国相关申请P38 36 862 5(1988年10月27日申请)和P39 10 587,4(1989年3月29日申请)均作为参考文献引用。
下面所述的实施例是用来进一步解释本发明。这里使用了如下的商业产品:
厂家3M的聚酯薄膜,厚度0.074毫米(Skotch Pak_1009),厂家Ce1anese的聚丙烯薄膜(Celgard_2500),厂家3M的衬里薄膜Skotchpak_1022和1360,厂家3M的穿透粘合剂9871,厂家Henke1 KG的牌号为Si he11o_J6610-21的聚丙烯酸酯—粘合剂,厂家DowCorning的牌号为X-7-2960的有机硅粘合剂,和厂家Hercules的牌号为Klucel_HXF的羟丙基纤维素。
实施例1
向62.4克50%的有机硅粘合剂在汽油中的溶液依次地加入
0.8克孕二烯酮
8.0克1.2-丙二醇在搅拌下使溶解或者悬浮(因为粘合剂是浑浊的,不能明确地确定是否是完全的溶液),驱气后,用涂布设备将溶液/悬浮液涂于聚酯膜上,待挥发性溶剂挥发后形成一层均匀的薄膜,每平方米约40克固体涂层。然后,粘合上用氟聚合物敷盖的聚酯衬里。用一个冲切机将所得到的层压物分割成10平方厘米一块的药贴,并用铝箔包装。这个药贴在揭下衬里—薄膜后就可贴在皮肤上。
含量测定表明药贴含有均匀分布的平均0.08mg/cm2有效物质。此外,药贴更具有在32℃水中超过30个小时的体外释放性能的特性。根据线性关系和一个典型的基质释放过程计算出孕二烯酮的释放速度为0.4ug/cm2/h。
实施例2
在170克50%的聚丙烯酸酯—粘合剂于丙酮/汽油的溶液中依次加入:
5.0克孕二烯酮和
10.0克肉豆蔻酸异丙酯在搅拌下使其溶解或悬浮,驱气后,用涂布设备将溶液/悬浮液涂在聚酯薄膜上,待挥发性溶液挥发后,形成一层均匀的薄膜,每平方米含100克固体涂料,然后,与硅酮化的无有效物质的衬里—薄膜粘合。用冲切机将所得到的层压物分割成10平方厘米一块的药贴,并用铝箔包装。这个药贴在将衬里—薄膜揭掉后就可贴在皮肤上。
孕二烯酮的平均含量是0.5mg/cm2,平均释放速度是0.3ug/cm2/h。
实施例3
在112克50%的聚丙烯酸酯—粘合剂于丙酮/汽油的溶液中依次加入
3.5克雌二醇
3.5克孕二烯酮
7.0克含有10%的1-十二烷醇的1,2-丙二醇搅拌下使其溶解或悬浮,驱气后,用涂布设备,将溶液/悬浮液涂在聚酯薄膜上,待挥发性溶剂挥发后形成一层均匀的薄膜,每平方米含70克固体涂料,然后,与硅酮化的无有效物质的衬里—薄膜粘合。用冲切机将所得到的层压物分割成10平方厘米一块的药贴,并用铝箔包装。这个药贴在将衬里薄膜揭掉后就可贴在皮肤上。
雌二醇和孕二烯酮的含量同样都是0.35mg/cm2。
将膏药放在32℃水中离体测试48小时,雌二醇的释放速度达到0.6ug/cm2/h,比孕二烯酮高,孕二烯酮的释放速度是0.4ug/cm2/h。
实施例4
将直径为7.4厘米的聚酯薄膜拉伸和加热,使它变形,形成一个10cm2的圆突面,其中加入1ml的悬浮液。悬浮液含有:
2.5mg雌二醇和
2.5mg孕二烯酮溶剂是含10%月桂酸的1,2-丙二醇。将聚丙烯膜或纤维素醋酸酯丁酸酯薄膜热封在圆包周围。按每单位时间的压力进行热封的温度在70℃和100℃之间,将皮肤粘合剂薄膜加在渗透聚合物层上。将药贴装上衬里,并用铝箔包装。
这个药贴中的两种有效物质在32℃的水中的离体释放具有相同的数据。在0.02~0.08ug/cm2/h之间。
实施例5
在76,78克乙醇(96%(体积))或异丙醇中依次溶解
0.2克雌二醇
0.02克孕二烯酮
10.0克1,2-丙二醇和
10.0克肉豆蔻酸异丙酯再加入3克羟丙基纤维素溶液并驱除空气,在2小时膨润以后,将凝胶填入具有三层内护涂层的铝管中。
含量测定表明,可得到在凝胶中的有效物质呈均匀的分布,为理论值的95%~105%。
实施例6
20.00克的孕二烯酮在1000克的肉豆蔻酸异丙酯中溶解、无菌过滤,并在无菌条件下落入5ml的药瓶中。
Claims (3)
1.一种制备含孕二烯酮的透皮治疗系统的方法,该透皮治疗系统由
一层不能渗透的覆盖层,
一种粘附于此覆盖层上的、含孕二烯酮的药物层,和
一层可剥落的保护层组成,包括:
将由1-25%的孕二烯酮、30-70重量%的医用粘合剂、用一种合适的易挥发溶剂加至100重量%组成的溶液或悬浮液涂布到一平坦的不能渗透的覆盖层上,在干燥之后施加一层可剥落的保护层。
2.权利要求1的方法,还加入雌激素。
3.权利要求1或2的方法,还加入至多40重量%的助透剂。
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DE3836862A DE3836862A1 (de) | 1988-10-27 | 1988-10-27 | Mittel zur transdermalen applikation von steroidhormonen |
DEP3836862.5 | 1988-10-27 | ||
DE19893910578 DE3910578A1 (de) | 1989-03-29 | 1989-03-29 | Mittel zur transdermalen applikation enthaltend gestoden |
DEP3910578.4 | 1989-03-29 |
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CN96109379A Expired - Lifetime CN1069829C (zh) | 1988-10-27 | 1996-07-30 | 含有孕二烯酮的透皮应用的药剂 |
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Families Citing this family (67)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2083404C (en) * | 1990-06-01 | 2001-02-20 | Alfred Moo-Young | Therapeutically effective topical application of st1435 |
US5320850A (en) * | 1990-10-29 | 1994-06-14 | Alza Corporation | Transdermal delivery of the gestogen ST-1435 and devices therefor |
EP0555360A1 (en) * | 1990-10-29 | 1993-08-18 | Alza Corporation | Transdermal contraceptive formulations, methods and devices |
US5512292A (en) * | 1990-10-29 | 1996-04-30 | Alza Corporation | Transdermal contraceptive formulations methods and devices |
US5198223A (en) * | 1990-10-29 | 1993-03-30 | Alza Corporation | Transdermal formulations, methods and devices |
DE4210165A1 (de) * | 1991-07-30 | 1993-02-04 | Schering Ag | Transdermale therapeutische systeme |
RU2119337C1 (ru) * | 1992-03-21 | 1998-09-27 | Энтек Гезельшафт фюр Эндокринологише Технологи мбХ | Трансдермальный препарат продленного действия с антиостеопоротической активностью |
JP2960832B2 (ja) * | 1992-05-08 | 1999-10-12 | ペルマテック テクノロジー アクチェンゲゼルシャフト | エストラジオールの投与システム |
DE4329242A1 (de) * | 1993-08-26 | 1995-03-02 | Schering Ag | Mittel zur transdermalen Applikation enthaltend Gestodenester |
JPH09510697A (ja) * | 1994-01-27 | 1997-10-28 | シエーリング アクチエンゲゼルシヤフト | 14α,17α−エタノエストラ−1,3,5(10)−トリエン−3,17β−ジオールを含有する経皮投与のための薬剤 |
JPH0827003A (ja) * | 1994-07-22 | 1996-01-30 | Sekisui Chem Co Ltd | 経皮吸収製剤 |
US6024974A (en) * | 1995-01-06 | 2000-02-15 | Noven Pharmaceuticals, Inc. | Composition and methods for transdermal delivery of acid labile drugs |
IL116539A (en) * | 1995-01-06 | 2002-02-10 | Noven Pharma | Preparations given through the skin of unstable anti-acid drugs |
IT1283102B1 (it) * | 1996-06-06 | 1998-04-07 | Permatec Nv | Composizione terapeutica per la somministrazione transdermica di un principio attivo estrogeno o progestinico o di loro miscele |
KR100215027B1 (ko) * | 1997-01-27 | 1999-08-16 | 성재갑 | 스테로이드계 약물의 경피흡수투여용 조성물 및 이를 포함하는 경피흡수투여용 제형 |
DE19739916C2 (de) * | 1997-09-11 | 2001-09-13 | Hesch Rolf Dieter | Verwendung einer Kombination aus einem Gestagen und einem Estrogen zur kontinuierlichen Ovulationshemmung und ggf. gleichzeitigen Behandlung und/oder Prophylaxe von Tumoren der Brustdrüsen |
IT1294748B1 (it) | 1997-09-17 | 1999-04-12 | Permatec Tech Ag | Formulazione per un dispositivo transdermico |
FR2772270B1 (fr) * | 1997-12-15 | 2002-06-07 | Besins Iscovesco Lab | Utilisation d'un oestrogene pour le traitement de la depression postnatale |
AU1728099A (en) | 1997-12-22 | 1999-07-12 | Alza Corporation | Monoglyceride and ethyl palmitate permeation enhancer compositions |
IL147247A0 (en) * | 1999-07-02 | 2002-08-14 | Lohmann Therapie Syst Lts | Microreservoir system based on polysiloxanes and ambiphilic solvents |
DE10019171A1 (de) * | 2000-04-07 | 2001-10-18 | Schering Ag | Zusammensetzungen zur Verwendung als Penetrationsverstärker in transdermalen Formulierungen für hoch lipophile Wirkstoffe |
US20030139384A1 (en) * | 2000-08-30 | 2003-07-24 | Dudley Robert E. | Method for treating erectile dysfunction and increasing libido in men |
US6503894B1 (en) | 2000-08-30 | 2003-01-07 | Unimed Pharmaceuticals, Inc. | Pharmaceutical composition and method for treating hypogonadism |
DE10107663B4 (de) * | 2001-02-19 | 2004-09-09 | Lts Lohmann Therapie-Systeme Ag | Testosteronhaltiges transdermales therapeutisches System, Verfahren zu seiner Herstellung und seine Verwendung |
FR2848112B1 (fr) * | 2002-12-10 | 2007-02-16 | Besins Int Belgique | Composition pharmaceutique pour administration transdermique ou transmuqueuse comprenant au moins un progestatif et/ou au moins un oestrogene, son procede de preparation et ses utilisations |
FR2851470B1 (fr) | 2003-02-20 | 2007-11-16 | Besins Int Belgique | Composition pharmaceutique pour administration transdermique ou transmuqueuse |
EP1594483B1 (de) | 2003-02-21 | 2006-07-19 | Schering AG | Uv-stabiles transdermales pflaster |
US7858607B2 (en) * | 2003-03-14 | 2010-12-28 | Mamchur Stephen A | System for use by compounding pharmacists to produce hormone replacement medicine customized for each consumer |
US7879357B2 (en) * | 2003-04-28 | 2011-02-01 | Bayer Schering Pharma Ag | Pharmaceutical composition in the form of a hydrogel for transdermal administration of active ingredients |
JO2492B1 (en) * | 2003-04-28 | 2009-10-05 | شيرينج ايه جي | A pharmaceutical formula in the form of aqueous gel for the skin use of its active ingredients |
US20050036953A1 (en) * | 2003-08-13 | 2005-02-17 | Moshe Arkin | Topical compositions of ammonium lactate |
US20050037040A1 (en) * | 2003-08-13 | 2005-02-17 | Moshe Arkin | Topical compositions of urea and ammonium lactate |
US20050042182A1 (en) * | 2003-08-13 | 2005-02-24 | Moshe Arkin | Topical compositions of urea |
US20050042268A1 (en) * | 2003-07-16 | 2005-02-24 | Chaim Aschkenasy | Pharmaceutical composition and method for transdermal drug delivery |
US20050020552A1 (en) * | 2003-07-16 | 2005-01-27 | Chaim Aschkenasy | Pharmaceutical composition and method for transdermal drug delivery |
US20050025833A1 (en) * | 2003-07-16 | 2005-02-03 | Chaim Aschkenasy | Pharmaceutical composition and method for transdermal drug delivery |
US20050129756A1 (en) * | 2003-12-10 | 2005-06-16 | Hans-Peter Podhaisky | UV-stable, liquid or semisolid transdermal pharmaceutical preparation with light sensitive active ingredient |
US8668925B2 (en) | 2003-12-12 | 2014-03-11 | Bayer Intellectual Property Gmbh | Transdermal delivery of hormones without the need of penetration enhancers |
MXPA06006682A (es) * | 2003-12-12 | 2006-08-11 | Schering Ag | Hormonas de administracion transdermica que no necesitan potenciadores de penetracion. |
UA89766C2 (en) * | 2003-12-12 | 2010-03-10 | Байер Шеринг Фарма Акциенгезельшафт | Transdermal delivery system of gestodene |
US7105263B2 (en) * | 2003-12-30 | 2006-09-12 | Samsung Electronics Company | Dry toner comprising encapsulated pigment, methods and uses |
US20050222106A1 (en) * | 2004-04-01 | 2005-10-06 | Stefan Bracht | Drospirenone-containing preparations for transdermal use |
GB0409498D0 (en) * | 2004-04-28 | 2004-06-02 | Hunter Fleming Ltd | Transdermal steroid formulation |
US20060008432A1 (en) * | 2004-07-07 | 2006-01-12 | Sebastiano Scarampi | Gilsonite derived pharmaceutical delivery compositions and methods: nail applications |
US8962013B2 (en) | 2005-05-02 | 2015-02-24 | Bayer Intellectual Property Gmbh | Multi-layered transdermal system with triazine UV absorber |
US20110086086A1 (en) * | 2005-07-26 | 2011-04-14 | Pfizer Inc | Transdermal system for varenicline |
SI2450041T1 (sl) | 2005-10-12 | 2019-02-28 | Unimed Pharmaceuticals, Llc | Izboljšan testosteronski gel za uporabo pri zdravljenju hipogonadizma |
EP2613772B1 (en) | 2010-09-06 | 2016-12-14 | Bayer Intellectual Property GmbH | Low-dose transdermal patches with high drug release |
DE102010040299A1 (de) | 2010-09-06 | 2012-03-08 | Bayer Schering Pharma Aktiengesellschaft | Transdermale therapeutische Systeme mit kristallisationsinhibierender Schutzfolie (Release Liner) |
CN101973239B (zh) * | 2010-09-15 | 2012-02-29 | 中北大学 | 车用轮胎主动防护装置 |
US9301920B2 (en) | 2012-06-18 | 2016-04-05 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
PT2782584T (pt) | 2011-11-23 | 2021-09-02 | Therapeuticsmd Inc | Preparações e terapias de substituição para hormonoterapias naturais combinadas |
US20150196640A1 (en) | 2012-06-18 | 2015-07-16 | Therapeuticsmd, Inc. | Progesterone formulations having a desirable pk profile |
US10806697B2 (en) | 2012-12-21 | 2020-10-20 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US20130338122A1 (en) | 2012-06-18 | 2013-12-19 | Therapeuticsmd, Inc. | Transdermal hormone replacement therapies |
US10806740B2 (en) | 2012-06-18 | 2020-10-20 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US11246875B2 (en) | 2012-12-21 | 2022-02-15 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10471072B2 (en) | 2012-12-21 | 2019-11-12 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11266661B2 (en) | 2012-12-21 | 2022-03-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US9180091B2 (en) | 2012-12-21 | 2015-11-10 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
US10568891B2 (en) | 2012-12-21 | 2020-02-25 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10537581B2 (en) | 2012-12-21 | 2020-01-21 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
MX2016014281A (es) | 2014-05-22 | 2017-02-22 | Therapeuticsmd Inc | Formulaciones y terapias de reemplazo de combinación de hormonas naturales. |
US10328087B2 (en) | 2015-07-23 | 2019-06-25 | Therapeuticsmd, Inc. | Formulations for solubilizing hormones |
KR20180126582A (ko) | 2016-04-01 | 2018-11-27 | 쎄러퓨틱스엠디, 인코퍼레이티드 | 스테로이드 호르몬 약제학적 조성물 |
US10286077B2 (en) | 2016-04-01 | 2019-05-14 | Therapeuticsmd, Inc. | Steroid hormone compositions in medium chain oils |
US11633405B2 (en) | 2020-02-07 | 2023-04-25 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical formulations |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3333240A1 (de) * | 1983-09-12 | 1985-03-28 | Schering AG, 1000 Berlin und 4709 Bergkamen | Mittel zur transdermalen applikation von arzneimittelwirkstoffen |
FI83087C (fi) | 1984-05-16 | 1991-05-27 | Schering Ag | Foerfarande foer framstaellning av terapeutiskt anvaendbara estriol-3,17-diestrar. |
EP0186019B1 (de) * | 1984-12-22 | 1993-10-06 | Schwarz Pharma Ag | Wirkstoffpflaster |
DE3511587A1 (de) * | 1985-03-27 | 1986-10-02 | Schering AG, Berlin und Bergkamen, 1000 Berlin | Glykoester des estradiols und estriols |
CN1021196C (zh) * | 1986-12-29 | 1993-06-16 | 新泽西州州立大学(鲁杰斯) | 透皮雌激素/孕激素药剂单元、系统及方法 |
US4788062A (en) * | 1987-02-26 | 1988-11-29 | Alza Corporation | Transdermal administration of progesterone, estradiol esters, and mixtures thereof |
CH674618A5 (zh) * | 1987-04-02 | 1990-06-29 | Ciba Geigy Ag | |
US5422119A (en) * | 1987-09-24 | 1995-06-06 | Jencap Research Ltd. | Transdermal hormone replacement therapy |
FR2717688B1 (fr) * | 1994-03-28 | 1996-07-05 | Lhd Lab Hygiene Dietetique | Système matriciel transdermique d'administration d'un oestrogène et/ou un progestatif à base d'EVA. |
FR2717689B1 (fr) * | 1994-03-28 | 1996-07-05 | Lhd Lab Hygiene Dietetique | Système matriciel transdermique d'administration d'un oestrogène et/ou un progestatif à base de copolymère styrène-isoprène-styrène. |
-
1989
- 1989-10-11 EP EP89118855A patent/EP0370220B1/de not_active Expired - Lifetime
- 1989-10-11 WO PCT/EP1989/001200 patent/WO1990004397A1/de active IP Right Grant
- 1989-10-11 EP EP93250189A patent/EP0573133A1/de not_active Withdrawn
- 1989-10-11 ES ES89118855T patent/ES2081823T3/es not_active Expired - Lifetime
- 1989-10-11 AT AT89912449T patent/ATE132751T1/de not_active IP Right Cessation
- 1989-10-11 HU HU896546A patent/HU210549B/hu unknown
- 1989-10-11 JP JP51155389A patent/JP3238389B2/ja not_active Expired - Fee Related
- 1989-10-11 DE DE58909570T patent/DE58909570D1/de not_active Expired - Lifetime
- 1989-10-11 EP EP89912449A patent/EP0394429B1/de not_active Expired - Lifetime
- 1989-10-16 IL IL9200789A patent/IL92007A/en not_active IP Right Cessation
- 1989-10-16 MX MX017971A patent/MX173621B/es unknown
- 1989-10-20 IE IE970562A patent/IE970562A1/en not_active IP Right Cessation
- 1989-10-20 IE IE337689A patent/IE81077B1/en not_active IP Right Cessation
- 1989-10-25 CN CN89108149A patent/CN1036836C/zh not_active Expired - Lifetime
- 1989-10-25 AU AU43747/89A patent/AU4374789A/en not_active Abandoned
- 1989-10-26 KR KR1019890015580A patent/KR0137463B1/ko not_active IP Right Cessation
- 1989-10-26 CA CA002001618A patent/CA2001618C/en not_active Expired - Lifetime
- 1989-10-27 PT PT92131A patent/PT92131B/pt not_active IP Right Cessation
-
1990
- 1990-06-06 DK DK199001385A patent/DK175804B1/da not_active IP Right Cessation
- 1990-06-21 BG BG092281A patent/BG92281A/bg unknown
- 1990-06-26 NO NO902840A patent/NO180567C/no unknown
- 1990-06-26 FI FI903213A patent/FI100456B/fi active IP Right Grant
-
1992
- 1992-12-09 AU AU30011/92A patent/AU3001192A/en not_active Abandoned
-
1995
- 1995-03-13 US US08/403,137 patent/US5788984A/en not_active Expired - Lifetime
- 1995-04-26 NO NO951592A patent/NO951592D0/no unknown
- 1995-06-08 AU AU20596/95A patent/AU2059695A/en not_active Abandoned
-
1996
- 1996-02-22 GR GR960400488T patent/GR3019079T3/el unknown
- 1996-07-30 CN CN96109379A patent/CN1069829C/zh not_active Expired - Lifetime
-
1998
- 1998-07-21 AU AU77416/98A patent/AU714979B2/en not_active Expired
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