CN1078461C - 有结合水添加剂的雌二醇－透皮治疗体系 - Google Patents
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Abstract
一种透皮治疗体系，包含活性物质雌二醇，并有对活性物质和潮气不渗透的背层、含活性物质的基质；以及，需要时，有覆盖于基质的可除去的保护层的层状结构；其特征在于，基质包括最大含1wt%水或基本无水的甘油。
Description
本发明涉及透皮治疗体系，它包含活性物质雌二醇，并有对活性物质和潮气不渗透的背层、含活性物质的基质，以及，需要时，有覆盖于基质的可除去的保护层的层状结构。
在一些疾病的治疗中，市场上引入透皮治疗体系(TTS)迄今已有一段时间了。
含活性物质雌二醇的透皮治疗体系作为更年期疾病的治疗剂已有市售，近来也可治疗骨质疏松症；它们在治疗中确属有效。
以下术语“雌二醇”被理解成无水17-β-雌二醇。
现有技术系统的一个缺点是活性物质通过皮肤渗透能力不足。虽然在设计透皮治疗体系时已使用了一些制剂学的措施(如使用多层系统，使用控制膜，改变活性物质的浓度，改变基础聚合物之类)，但超越某些限度，所谓的“饱和流量”，渗透能力便不能再增加。来自固体的活性物质(细小分散相)经皮渗透原则上不可进一步增加的发现，在Higuchi的开创性著作中也曾提及(如，T.Higuchi，霜剂和软膏剂经皮吸收过程的物理化学分析(Physical ChemicalAnalysis of percutaneous absorption process from creams and ointments，J.Soc.Cosmetic Chem.11，85-97页1990))。
在EP0421454中揭示的系统，包括加入“结晶抑制剂”和粘性树脂的丙烯酸型聚合物中的雌二醇。它也含有溶胀剂以防止粘附力的过早流失。
另外，对于许多活性物质，在生产透皮治疗体系时可加入所谓的“吸收增加剂”。这些通常是促进人体皮肤吸收性质的液体混合物；基于这样的原因，它们可让活性物质从足够小的透皮治疗体系—表面被吸收。
易于挥发的增加剂，如用于活性物质雌二醇的乙醇特别涉及由透皮治疗体系粘合层极度软化所产生的问题，它们也需要系统提供另外大空间，这使透皮治疗体系过厚而不便采用。
加入较难挥发的，但大部份是活性较差的增加剂(如，甘油酯、环酰胺、按油醇)也可生产在一层或数层中包括活性物质和促进吸附组份的基质系统，但是，这些透皮治疗体系的粘附力不足是其缺点。
美国专利4863738代表了许多例子中的一个，提出了活性物质雌二醇与特定的增加剂(在该发明中是甘油单油酸酯)以任意的浓度用于任选的透皮治疗体系的基质。
但是，即使这类现有技术的透皮治疗体系也没有令人满意的疗效。理由或是因皮肤对所选的增加剂难能耐受，或是因由于通过皮肤流量的不足，系统仍有不可接受的大表面。
另一个增加活性物质流过皮肤的(理论)可能方法是将比相应的饱和溶解度更多的活性物质的分子分散物(即没有结晶)溶于透皮治疗体系。通过皮肤的通透率随着这些系统的过饱和程度而有了相同程度的增加。但是，这些物理状态是热动力学上不稳定的，因此这些剂型是不可储存的。至少在数月或数年内，活性物质会不可预见地自发沉淀，结果通过皮肤的流量会逐渐减少到饱和的流量水平；根据起始浓度，这会损失大部份的最初治疗活性。
在储存时发生该过程是由于雌二醇的特定的理化性质。
在室温和正常的相对空气湿度(20-60％相对湿度)下，雌二醇不是以两个已知的无水变体(I和II)之一存在，而是半水合物(Busetti，ActaCryst.1972，B28，560)。由于层状结构通过氢键稳定，且由于结晶化合物的扩散紧密性，水合物可在短时间里热处理到约170℃而不会分解(Kuhnert-Brandestatter和Winkler(1976)Scientia Pharmaceutica 44(3)，177-190)。但是，通过微细化而扩展晶体表面，雌二醇半水合物会在约120℃已可定量地转化为无水形式。根据自己的观察，若慢慢地加热(0.2-1K/分钟)，对于特别细的物质，加热到约90℃即已发生该转化。
另一方面，随着水蒸气分压减少，雌二醇在一些聚合物中，特别在聚丙烯酸酯中有更高的溶解度。根据Fick定理，在更高的浓度但其它tswr相同会增加通过皮肤的扩散流量；基于这个理由，这类浓度的增加在经皮吸收中极为有用。但是，雌二醇—半水合物所引入的水已足以使雌二醇—半水合物从溶液中逐渐地重结晶出来(Kuhnert-Brandstatter和Winker(1976)Scientia Pharmaceutica44(3)，177-190)。在结晶期间，从系统到皮肤的流量速度随着浓度的下降而明显地减少。
因此，通过将浓度精确地调节到雌二醇无水物饱和溶解度以下(DE-PS 4237 453)或通过使用部分不溶解的、分散的雌二醇—无水物(DE-PS 42 23 360)可得到药效令人满意的溶液，这样的透皮治疗体系是已知的。考虑到这一最新的技术进展，甚至可以说重要的是在生产和储存雌二醇透皮治疗体系时保持足够低的湿度以避免溶解不良的雌二醇—半水合物大面积沉淀。
为了这个目的，原则上可用低水蒸气渗透率的包装。但是，由于当今的透皮治疗体系中仅含少量雌二醇，极少量湿度足以导致雌二醇—半水合物的沉淀。如在透皮治疗体系中存在2毫克溶解状态的雌二醇(无水物)，仅66.1微克水(根据分子量比率计算)会导致完全沉淀。因此，在数年的储存期间，使用常规的包装极难排除这样少量潮气的进入。
因此，本发明的一个目的是提供一种含有雌二醇的透皮治疗体系，它包括长期防止雌二醇半水合物沉淀的保护物，所述保护物掺入含活性物质层的本身，它防止结晶成雌二醇—半水合物。
甘油是极性很大的化合物，可以任何比例与水混溶。无水甘油极能吸湿，可在某些条件下用作脱水剂。实验显示，它的无水形式能从雌二醇—半水合物中除去结晶水。就此而言，术语“无水”或“基本无水”被理解成水含量≤1％。若在室温下将雌二醇—半水合物在无水甘油中搅拌24小时，半水合物的平板形结晶转化为细针状。这些针状晶体或为无水雌二醇，或为雌二醇—甘油—溶剂合物。只需向用于该试验的甘油加入2％水即可防止该反应。这清楚地表明与无水甘油反应所生成的东西不含有任何水。
本发明上述透皮治疗体系的技术方案可以不同的方法来实施。最简单的形式是单层基质系统，它的基质同时具有压敏粘合功能，而使特殊的粘合层成为多余。分散于基质的甘油保证储存期间平衡一潮气的含量，它低至足以不产生雌二醇—半水合物的沉淀。优选的是包含于基质的雌二醇以无水结晶的分散物形式存在。
若该层的粘合力不足或该层不可直接与皮肤接触，则基质可层压到特殊的皮肤粘合层上。
若将几乎对雌二醇不通透的膜放在包括雌二醇和能结合水的分散甘油的这类基质和粘合层之间，则可通过该膏药而不是通过皮肤来控制活性物质的释放。除了广泛使用的丙烯酸共聚物适合与雌二醇共用外，其它聚合物也可用作基质材料，如聚异丁烯、聚乙烯乙酸酯和共聚物、合成橡胶、苯乙烯和异丙烯或苯乙烯和丁二烯的嵌段聚合物和聚硅氧烷。优选的是，基质的基础材料或数层基质中一层的基础材料是丙烯酸酯共聚物，所述丙烯酸酯共聚物对于雌二醇结晶的溶解度为0.4-3.0wt％。
在任何情况下，本发明的透皮治疗体系的特征是有分散的、基本无水的甘油存在。就此而言，该系统甘油的准确用量必须：一方面，该系统中的甘油溶解度是过量的，它以独立相存在，分散于小液滴中，另一方面，在该系统中与潮气结合的总能力是足够的。加入2％被认为是最小值；上限值可根据机械与力学值确定，如基质的流动性能、粘合力和加工性能。一般来说，加入量的比例为10-50％(重量)，较好的是10-35％(重量)。
实施例
实施例1
2.0克微细化的17-β-雌二醇与
2.75克无水甘油
25克丙烯酸酯共聚物溶液(固体含量42％)和
5.9克松香—甘油酯衍生物(Hercules的氢化松香酯5E)混合，
接着涂覆在100微米聚硅氧烷化聚酯膜上，使涂覆重量达120克/米2。将涂层在25℃、50℃、80℃和95℃下干燥，每次干燥10分钟。在辊压下将10微米聚酯膜马上施加(层压)到干燥层上，避免形成空气气泡。
用软填料冲头冲下16厘米2透皮治疗体系，马上装入防潮、热封的袋中。
实施例2
2.0克微细化的17-β-雌二醇，
60.0克Cariflex TR 1107(苯乙烯—异丙烯嵌段聚合物)，
120.0克氢化松香酯5E(松香衍生物的热塑性酯胶)，
50.0克粘稠石蜡
50.0克无水甘油
在130℃可抽真空的捏合机中熔融，在10小时内捏合而使外部均匀。
熔融物被冷却到120℃；接着在连续涂覆流水线上涂覆在100微米聚硅氧烷化聚酯膜上，使涂覆重量达200克/米2。
继而在辊压下将15微米厚聚酯膜马上施加(层压)到仍为热的层上，避免形成空气气泡。
用软填料冲头冲下16厘米2透皮治疗体系。
Claims (5)
1.一种透皮治疗体系，包括活性物质雌二醇，并有对活性物质和潮气不渗透的背层、含活性物质的基质，以及，需要时，有覆盖于基质的可除去的保护层的层状结构，其特征在于，基质包括10-35wt％甘油，所述甘油的水含量≤1％。
2.根据权利要求1所述的透皮治疗体系，其特征在于基质由数层构成，至少一层包括水含量≤1％的甘油。
3.根据权利要求2所述的透皮治疗体系，其特征在于基质的基础材料或数层基质中一层的基础材料是丙烯酸酯共聚物。
4.根据权利要求3所述的透皮治疗体系，其特征在于丙烯酸酯共聚物对于雌二醇结晶的溶解度为0.4-3.0wt％。
5.根据权利要求1，2，3或4所述的透皮治疗体系，其特征在于，包含于基质的雌二醇以无水结晶的分散物形式存在。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4429667A DE4429667C2 (de) | 1994-08-20 | 1994-08-20 | Estradiol-TTS mit wasserbindenden Zusätzen und Verfahren zu seiner Herstellung |
| DEP4429667.3 | 1994-08-20 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1155835A CN1155835A (zh) | 1997-07-30 |
| CN1078461C true CN1078461C (zh) | 2002-01-30 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95194677A Expired - Fee Related CN1078461C (zh) | 1994-08-20 | 1995-08-12 | 有结合水添加剂的雌二醇－透皮治疗体系 |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US5902602A (zh) |
| EP (1) | EP0776199B1 (zh) |
| JP (1) | JP3825799B2 (zh) |
| KR (1) | KR100401136B1 (zh) |
| CN (1) | CN1078461C (zh) |
| AT (1) | ATE185067T1 (zh) |
| AU (1) | AU695970B2 (zh) |
| CZ (1) | CZ289397B6 (zh) |
| DE (2) | DE4429667C2 (zh) |
| DK (1) | DK0776199T3 (zh) |
| ES (1) | ES2139932T3 (zh) |
| FI (1) | FI118720B (zh) |
| GR (1) | GR3032218T3 (zh) |
| HU (1) | HU226959B1 (zh) |
| IL (1) | IL114949A (zh) |
| MX (1) | MX9701302A (zh) |
| NO (1) | NO313984B1 (zh) |
| NZ (1) | NZ291813A (zh) |
| PL (1) | PL180965B1 (zh) |
| SK (1) | SK281626B6 (zh) |
| WO (1) | WO1996005814A1 (zh) |
| ZA (1) | ZA956925B (zh) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5698217A (en) * | 1995-05-31 | 1997-12-16 | Minnesota Mining And Manufacturing Company | Transdermal drug delivery device containing a desiccant |
| DE19600347A1 (de) * | 1996-01-08 | 1997-07-10 | Lohmann Therapie Syst Lts | Hauthaftende pharmazeutische Zubereitung, insbesondere TTS zur Abgabe von 17-beta-Estradiol an den menschlichen Organismus |
| DE19713141A1 (de) * | 1996-03-29 | 1997-10-30 | Labtec Gmbh | Transdermales System mit Melatonin |
| DE19827732A1 (de) * | 1998-06-22 | 1999-12-23 | Rottapharm Bv | Transdermales System vom Matrix-Typ zur Abgabe von Wirkstoffen mit einer hohen Abgaberate von Steroid-Hormonen und die Verwendung eines derartigen Systems zur Hormonersatztherapie |
| US10493049B2 (en) | 2016-02-10 | 2019-12-03 | Niracle LLC | Applicator-based transdermal drug delivery system for administration of drugs in combination with topical formulations |
| EP4308088B1 (en) | 2021-11-08 | 2025-03-12 | Weiyong Li | Transdermal drug delivery system for delivering a drug to a patient |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4855294A (en) * | 1988-09-06 | 1989-08-08 | Theratech, Inc. | Method for reducing skin irritation associated with drug/penetration enhancer compositions |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE12731T1 (de) * | 1979-01-11 | 1985-05-15 | Key Pharma | Polymere diffusionsmatrix und verfahren zu deren herstellung. |
| US4438139A (en) * | 1979-08-14 | 1984-03-20 | Key Pharmaceuticals, Inc. | Polymeric diffusion matrix containing estrogens |
| CA1163559A (en) * | 1980-07-09 | 1984-03-13 | Alec D. Keith | Polymeric diffusion matrix for administration of drugs |
| DE3333240A1 (de) * | 1983-09-12 | 1985-03-28 | Schering AG, 1000 Berlin und 4709 Bergkamen | Mittel zur transdermalen applikation von arzneimittelwirkstoffen |
| ZA853488B (en) * | 1984-05-10 | 1986-12-30 | American Home Prod | Transdermal dosage form |
| US4810499A (en) * | 1984-10-01 | 1989-03-07 | Biotek, Inc. | Transdermal drug delivery system and method |
| US4788062A (en) * | 1987-02-26 | 1988-11-29 | Alza Corporation | Transdermal administration of progesterone, estradiol esters, and mixtures thereof |
| US4816258A (en) * | 1987-02-26 | 1989-03-28 | Alza Corporation | Transdermal contraceptive formulations |
| US4764379A (en) * | 1987-08-24 | 1988-08-16 | Alza Corporation | Transdermal drug delivery device with dual permeation enhancers |
| US4863738A (en) * | 1987-11-23 | 1989-09-05 | Alza Corporation | Skin permeation enhancer compositions using glycerol monooleate |
| DD279818A1 (de) * | 1989-02-06 | 1990-06-20 | Jenapharm Veb | Verfahren zur herstellung eines medizinischen pflasters |
| DE3933460A1 (de) * | 1989-10-06 | 1991-04-18 | Lohmann Therapie Syst Lts | Oestrogenhaltiges wirkstoffpflaster |
| AR246186A1 (es) * | 1989-11-17 | 1994-07-29 | Beta Pharm Co | Procedimiento para fabricar un dispositivo para administrar estradiol por via transdermica. |
| DE4210165A1 (de) * | 1991-07-30 | 1993-02-04 | Schering Ag | Transdermale therapeutische systeme |
| US5518734A (en) * | 1991-09-25 | 1996-05-21 | Beta Pharmaceuticals Co. | Transdermal delivery system for estradiol and process for manufacturing said device |
| DE4210711A1 (de) * | 1991-10-31 | 1993-05-06 | Schering Ag Berlin Und Bergkamen, 1000 Berlin, De | Transdermale therapeutische systeme mit kristallisationsinhibitoren |
| WO1993025168A1 (en) * | 1992-06-11 | 1993-12-23 | Theratech, Inc. | The use of glycerin in moderating transdermal drug delivery |
| DE59405277D1 (de) * | 1993-04-20 | 1998-03-26 | Hexal Ag | Wirkstoffplaster |
-
1994
- 1994-08-20 DE DE4429667A patent/DE4429667C2/de not_active Expired - Fee Related
-
1995
- 1995-08-12 DE DE59506962T patent/DE59506962D1/de not_active Expired - Lifetime
- 1995-08-12 ES ES95929856T patent/ES2139932T3/es not_active Expired - Lifetime
- 1995-08-12 CZ CZ1997509A patent/CZ289397B6/cs not_active IP Right Cessation
- 1995-08-12 AT AT95929856T patent/ATE185067T1/de active
- 1995-08-12 WO PCT/EP1995/003201 patent/WO1996005814A1/de active IP Right Grant
- 1995-08-12 EP EP95929856A patent/EP0776199B1/de not_active Expired - Lifetime
- 1995-08-12 NZ NZ291813A patent/NZ291813A/en not_active IP Right Cessation
- 1995-08-12 MX MX9701302A patent/MX9701302A/es unknown
- 1995-08-12 US US08/632,490 patent/US5902602A/en not_active Expired - Lifetime
- 1995-08-12 HU HU9701729A patent/HU226959B1/hu not_active IP Right Cessation
- 1995-08-12 CN CN95194677A patent/CN1078461C/zh not_active Expired - Fee Related
- 1995-08-12 JP JP50775496A patent/JP3825799B2/ja not_active Expired - Lifetime
- 1995-08-12 AU AU33449/95A patent/AU695970B2/en not_active Ceased
- 1995-08-12 KR KR1019970701108A patent/KR100401136B1/ko not_active Expired - Fee Related
- 1995-08-12 SK SK220-97A patent/SK281626B6/sk not_active IP Right Cessation
- 1995-08-12 DK DK95929856T patent/DK0776199T3/da active
- 1995-08-12 PL PL95319013A patent/PL180965B1/pl not_active IP Right Cessation
- 1995-08-15 IL IL11494995A patent/IL114949A/en not_active IP Right Cessation
- 1995-08-18 ZA ZA956925A patent/ZA956925B/xx unknown
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1997
- 1997-01-28 NO NO19970360A patent/NO313984B1/no not_active IP Right Cessation
- 1997-02-19 FI FI970701A patent/FI118720B/fi not_active IP Right Cessation
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- 1999-12-22 GR GR990403305T patent/GR3032218T3/el unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4855294A (en) * | 1988-09-06 | 1989-08-08 | Theratech, Inc. | Method for reducing skin irritation associated with drug/penetration enhancer compositions |
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