CN1087938C - 东莨菪碱膏药 - Google Patents
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Abstract
本发明描述了膏药形式的含东莨菪碱的透皮治疗系统，其含活性物质的各层包含作为基底聚合物的丙烯酸或甲基丙烯酸衍生物的共聚物和浓度为在总的赋形剂配方中为饱和溶解度的50-100%，更好的是60-100%的东莨菪碱。
Description
东莨菪碱是一种已知在市售硬膏剂系统中通过透皮给药、具有全身性作用的物质。东莨菪碱是一种所谓的止吐剂，宜用于防止例如因旅途中平衡不断的被动改变而引起的恶心和呕吐。
透皮给药在治疗上的优点在于，活性物质通过透皮系统以一种受控的方式缓慢地提供。所以，有可能一方面符合东莨菪碱较窄的治疗窗(TW)，另一方面达到治疗血浆水平而不必担心因过量而引起副作用。美国专利3,797,494描述了市售系统的结构。它主要由背衬层、活性物质贮留层、微孔膜、也包含活性物质的皮肤粘合层和在使用前去除的保护膜构成。贮留层和皮肤粘合层由分子量不同的聚异丁烯和矿物油的混合物组成。活性物质分散在所述混合物中呈粘性液体。在此基础上构成的其含活性物质的组成部分具有一定的缺点。在某些情况下会发生自发结晶而影响膏药中活性物质的生物利用度。美国专利4,832,953详细说明了这种不稳定性。该专利描述了一种通过对包装后的膏药进行后继的热处理来防止结晶的方法。根据此专利的说明，发生结晶的主要是东莨菪碱水合物。
在其生产后某个不能预言的时刻，在某些很难确定的条件下，包含于某一给药剂型中的活性物质发生凝聚状态的改变，从而影响其生物利用度，这是相当不利的。
基于这样的技术现状，本发明的目的是提供适用于活性物质东莨菪碱的另一种聚合物配方，该配方没有上述专利所述的重大缺点。
在权利要求1的前序部分所述的这种透皮治疗系统中，根据本发明，膏药含活性物质的各层包含作为基底聚合物的丙烯酸或甲基丙烯酸衍生物的共聚物和一定浓度的东莨菪碱，此浓度相当于总赋形剂配方中饱和溶解度的50-100％，饱和溶解度的60-100％更好。
从属权利要求提供了本发明的其它实施方案。
根据文献资料，东莨菪碱是一种粘性液体。但是，专业人士难以理解的是分子量为303.35的、相对极性的物质在其稳定的聚集状态下会是液体。但是在适当条件下会使东莨菪碱结晶。由此获得熔点约为68℃的白色固体物质。因此，活性物质以一种不稳定的改性状态存在于已有技术的膏药中。所以，很可能结晶的不是东莨菪碱的水合物，而是发生了东莨菪碱本身的液-固相转化。因为与晶体东莨菪碱相比，液态东莨菪碱代表了具有高能量的改性形式，根据本领域熟练技术人员已知的理论，东莨菪碱溶解在聚合物本身之中的浓度高于饱和浓度。所以，结晶不仅可能发生在活性物质分散部分，也可能发生于聚合物本身。
本发明较好地提供了一种新的包含东莨菪碱的基底聚合物配方，它避免了已知的关系到膏药疗效的缺点。根据本发明，使用的聚合物中包含了完全溶解形式的东莨菪碱，其浓度低于或至多等于饱和浓度，这一点较好地避免了活性物质东莨菪碱的不稳定性及其在膏药中的结晶。为此，这些聚合物必须对东莨菪碱具有比本领域已知配方高的溶解能力。具自粘性的以聚丙烯酸及其衍生物为基础的共聚物已被证明是合适的聚合物。在这类聚合物中，根据共聚物的确切组成和添加的助剂的量及种类，东莨菪碱的溶解度在约10至20％(w/w)之间。该溶解度已不仅是足以在约2.5cm2大小、透皮系统常规厚度的膏药中放置例如防止旅途不适的、三天治疗所需的活性物质。这些聚丙烯酸酯粘合剂的有关粘合力、内聚力和溶解能力等性能可通过选择生产用的单体和选择可由聚合反应条件预先确定的分子量来改变。根据本发明，最重要的是对东莨菪碱的溶解能力。由于东莨菪碱是一种相对具极性的物质，那些聚丙烯酸酯粘合剂以具有极性官能团的为宜。通常存在于聚丙烯酸酯粘合剂中的这类基团的实例包括羧基、羟基和氨基。可将这类基团引入粘合剂的合适单体包括例如甲基丙烯酸、丙烯酸、二元醇与丙烯酸和甲基丙烯酸的半酯，以及两种酸与氨基醇的酯。
聚丙烯酸酯粘合剂与许多低分子量物质是可配伍的。可根据该化合物而添加这些物质来改善给定的聚丙烯酸酯粘合剂的溶解能力。实际上，即，极性基团数量不足的聚丙烯酸酯粘合剂必须添加相对具极性的非活性成份，而极性基团过量的聚丙烯酸酯粘合剂必须添加相对非极性的非活性成份。由于活性物质的热力学活度不取决于绝对浓度而取决于实际浓度与饱和浓度之比，所以后一种可能性对于通过降低东莨菪碱的溶解度，从而在对活性物质有过大的溶解度的聚丙烯酸酯粘合剂中节省活性物质是十分重要的。由此可见，根据本发明，以10-30％(重量)为东莨菪碱在粘合剂或粘合剂/非活性物质混合物中的最佳饱和溶解度。
由于东莨菪碱是相对具极性的物质，较好的是利用添加液态烃来降低饱和溶解度。已证明，二辛基环己烷尤其适合。作为提高饱和溶解度的更强极性的物质，主要可使用脂肪酸、脂肪醇、聚乙二醇或聚丙二醇、甘油衍生物和泛醇。已证明，尤其适合的是脂肪酸，例如油酸。
基于这些粘合剂或粘合剂/助剂配方，可制造出所谓透皮骨架系统和膜系统，这些系统在重要的人体皮肤体外渗透实验中被证明与市售的竞争性产品是生物等效的。图1和图2中显示了这种透皮系统的结构。从结构上说，最简单的透皮系统是骨架系统。它由对活性物质和助剂基本上不可透过的背衬层(1.3)，含活性物质的自粘性聚合物配方(1.2)和需在使用前去除的保护膜(1.1)构成。适合用作背衬层和保护膜的材料对本领域熟练技术人员来说是众所周知的。实际上一般可使用以聚乙二醇对苯二甲酸酯为基础的膜，保护膜还需至少在其与粘合剂接触的一侧硅化以便于从膏药上去除。如果聚合物配方的压敏粘合力过低，可以另外添加面向皮肤的压敏粘合剂层(这里未显示)。一种膜系统由背衬层(2.5)，活性物质贮留层(2.4)，膜(2.3)，皮肤接触层(2.2)和需在使用前去除的保护层(2.1)构成。活性物质贮留层和皮肤接触层可具有相同或不同的组成。根据本发明，重要的只是至少贮留层是以聚丙烯酸酯粘合剂为基础的，而且对东莨菪碱具有10-30％(重量)的溶解能力。合适的膜材料也是本领域熟练技术人员众所周知的。已证明，以乙烯和乙酸乙烯酯的共聚物为基础的膜尤其适合与本发明的聚丙烯酸酯粘合剂组合。透过此膜的活性物质流量可通过乙酸乙烯酯含量和膜的厚度来调控。乙酸乙烯酯含量越高、厚度越薄，膜对东莨菪碱的透过性越高。已证明，适合的膜具有至少4％的乙酸乙烯酯，厚度在50至100μm之间。对大小不超过5cm2的膏药来说，厚50μm、含9-20％乙酸乙烯酯的膜尤其适合。
表1和图1中显示了使用本发明骨架系统的渗透实验结果。实验使用Franz渗透池和人体皮肤(乳房修复手术中的女性前胸皮肤)进行。
表2和图2显示了使用本发明膜系统的结果。
表1
实施例1和2骨架系统的渗透性测定
| 配方 | 以下时间后透过皮肤的东莨菪碱的累计量(μg/cm2)(n的平均值＝3) | |||
| 16h | 24h | 40h | 48h | |
| 比较组 | 115.8 | 185.1 | 297.4 | 350.7 |
| 实施例1 | 118.1 | 208.0 | 349.2 | 403.0 |
| 实施例2 | 120.3 | 203.4 | 320.2 | 410.3 |
表2
实施例3和4膜系统的渗透性测定
这些渗透性实验的结果清楚地表明，本发明的膏药与比较样品同样有效，但没有它们的缺点。由于活性物质的浓度不超过饱和溶解度，所以没有重结晶的危险。而且，聚丙烯酸酯配方因其理化特性而对东莨菪碱水合物具有足够的溶解能力，能防止因实际存在于粘合剂中的水量而发生重结晶，所以，几乎不可能形成东莨菪碱水合物晶体。
| 配方 | 以下时间后透过皮肤的东莨菪碱的累计量(μg/cm2)(n的平均值＝3) | |||
| 16h | 24h | 40h | 48h | |
| 比较组 | 115.8 | 185.1 | 297.4 | 350.7 |
| 实施例1 | 129.9 | 209.6 | 311.7 | 350.0 |
| 实施例2 | 135.4 | 215.3 | 330.8 | 360.4 |
实施例
实施例1
27g 聚丙烯酸酯粘合剂(Durotak 901-1051，固体含量52％)
3.4g 油酸
0.12g 乙酰丙酮铝
4.0g 东莨菪碱
3.7g 乙醇
仔细混合以上物质，在一层硅化的聚酯膜上涂成200μm厚的膜。含溶剂的膜在50℃干燥30分钟，覆盖以23μm厚的一层聚酯膜。由总的层合片冲切出单张膏药系统(面积：2.5cm2)。
实施例2
27g 聚丙烯酸酯粘合剂(Durotak 901-1051，固体含量52％)
3.4g 油醇
0.12g 乙酰丙酮铝
3.0g 东莨菪碱
3.7g 乙醇
仔细混合以上物质，在一层硅化的聚酯膜上涂成200μm厚的膜。含溶剂的膜在50℃干燥30分钟，覆盖以23μm厚的一层聚酯膜。由总的层合片冲切出单张膏药系统(面积：2.5cm2)。
实施例3
73.6g 聚丙烯酸酯粘合剂(Durotak 901-1051，固体含量52％)
9g 油酸
0.38g 乙酰丙酮铝
12.0g 东莨菪碱
17g 乙醇
仔细混合以上物质，将其用于涂布加工。
a.生产皮肤粘合层
将以上物质在一层硅化的聚酯膜上涂成50μm厚的膜。含溶剂的膜在50℃干燥30分钟，覆盖以一层50μm厚、由含9％乙酸乙烯酯的乙烯-乙酸乙烯酯共聚物构成的膜。
b.生产贮留层
在第二涂布步骤中，将相同的物质在另一硅化的聚酯膜上涂布成150μm厚的膜；去除溶剂后，以23μm厚的聚酯膜覆盖。
c.生产总的层合片
从聚酯膜上剥下按照b制造的贮留层，将其层合到按照a制造的皮肤粘合层膜上。
由总的层合片冲切出大小为2.5cm2的膏药系统。
实施例473.6g 聚丙烯酸酯粘合剂(Durotak 901-1051，固体含量52％)9g 油醇0.38g 乙酰丙酮铝9.0g 东莨菪碱17g 乙醇仔细混合以上物质，将其用于涂布加工。其它步骤与实施例3相同。
Claims (10)
1.一种多层结构的膏药形式的透皮治疗系统，由背衬层、压敏胶粘性活性物质贮留层、视需要而定用于调控活性物质流量的膜、可选择的附加的皮肤粘合层和可去除的保护膜构成，而且包含活性物质东莨菪碱，其特征在于，膏药的含活性物质层包含作为基底聚合物的丙烯酸或甲基丙烯酸衍生物的含极性基团的共聚物，这些共聚物本身或其与极性助剂的混合物对东莨菪碱具有10-30％(重量)的溶解能力，并在总的赋形剂配方中含浓度为饱和溶解度50-100％的东莨菪碱。
2.根据权利要求1所述的透皮治疗系统，含活性物质层的总制剂中含相当于饱和溶解度60-100％的东莨菪碱。
3.根据权利要求1所述的透皮治疗系统，其特征在于，它是骨架系统。
4.根据权利要求1所述的透皮治疗系统，其特征在于，它是膜系统。
5.根据权利要求1所述的透皮治疗系统，其特征在于，膜包含乙烯和乙酸乙烯酯的共聚物。
6.根据权利要求1所述的透皮治疗系统，其特征在于，膜包含至少4％乙酸乙烯酯。
7.根据权利要求1所述的透皮治疗系统，其特征在于，膏药的含活性物质层包含用于降低对东莨菪碱的饱和溶解度的烃。
8.根据权利要求7所述的透皮治疗系统，其中所述的烃是二辛基环己烷。
9.根据权利要求1所述的透皮治疗系统，其特征在于，膏药的含活性物质层包含用于提高对东莨菪碱饱和溶解度的脂肪酸或脂肪醇。
10.根据权利要求9所述的透皮治疗系统，其中所述的脂肪酸或脂肪醇是油酸或油醇。
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| DEP4433004.9 | 1994-09-16 | ||
| DE4433004 | 1994-09-16 | ||
| DE4438989A DE4438989C2 (de) | 1994-09-16 | 1994-10-31 | Scopolaminpflaster |
| DEP4438989.2 | 1994-10-31 |
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| DE19738643C2 (de) * | 1997-09-04 | 2001-10-04 | Lohmann Therapie Syst Lts | Transdermales therapeutisches System mit dem Wirkstoff Scopolaminbase und Verfahren zu seiner Herstellung |
| US6087341A (en) * | 1998-02-12 | 2000-07-11 | The Board Of Trustees Of The Leland Standford Junior University | Introduction of nucleic acid into skin cells by topical application |
| US20020119187A1 (en) * | 2000-09-29 | 2002-08-29 | Cantor Adam S. | Composition for the transdermal delivery of fentanyl |
| US20050208117A1 (en) * | 2001-03-16 | 2005-09-22 | Venkatraman Subramanian S | Transdermal administration of fentanyl and analogs thereof |
| CA2440884C (en) * | 2001-03-16 | 2012-05-22 | Alza Corporation | Transdermal patch for administering fentanyl |
| DE10141650C1 (de) * | 2001-08-24 | 2002-11-28 | Lohmann Therapie Syst Lts | Transdermales Therapeutisches System mit Fentanyl bzw. verwandten Substanzen |
| RU2349315C9 (ru) * | 2003-04-14 | 2010-02-27 | Лтс Ломанн Терапи-Системе Аг | Терапевтический пластырь с полисилоксановой матрицей, содержащей капсаицин |
| CA2522184A1 (en) * | 2003-04-17 | 2004-11-04 | The Trustees Of Columbia University In The City Of New York | Desmoglein 4 is a novel gene involved in hair growth |
| AU2005238034A1 (en) * | 2004-04-23 | 2005-11-10 | The Trustees Of Columbia University In The City Of New York | Inhibition of hairless protein mRNA |
| FR2884143B1 (fr) * | 2005-04-08 | 2007-06-22 | Millet Innovation Sa | Timbre dermique rechargeable |
| US20070010550A1 (en) * | 2005-07-08 | 2007-01-11 | The Board Of Regents Of The University Of Texas | Scopolamine to Reduce or Eliminate Hot Flashes, Night Sweats, and Insomnia |
| CA2643037C (en) * | 2006-02-27 | 2014-08-05 | Noven Pharmaceuticals, Inc. | Compositions and methods for delivery of amino-functional drugs |
| DE102006028987A1 (de) * | 2006-06-24 | 2007-12-27 | Lts Lohmann Therapie-Systeme Ag | Ultraschallverstärktes transdermales therapeutisches System |
| JP5687901B2 (ja) * | 2007-10-15 | 2015-03-25 | アルザ・コーポレーシヨン | 日に１回の取り替えによるフェンタニルの経皮投与 |
| CN102764342B (zh) * | 2012-07-17 | 2013-12-04 | 陈鼎汉 | 治疗褥疮、糖尿病伤口、烫伤的药膏 |
| AU2020240797B2 (en) * | 2019-03-19 | 2024-12-19 | Nobelpharma Co., Ltd. | Pharmaceutical composition having excellent drug absorption into the living body and excellent chemical stability |
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| EP0387693A2 (de) * | 1989-03-15 | 1990-09-19 | LTS LOHMANN THERAPIE-SYSTEME GmbH & CO.KG | Transdermales System mit gestufter Wirkstoffabgabe und Verwendung für die lokale oder systemische, kosmetische Wirkstoffverabreichung |
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| US5310559A (en) * | 1982-09-01 | 1994-05-10 | Hercon Laboratories Corporation | Device for controlled release and delivery to mammalian tissue of pharmacologically active agents incorporating a rate controlling member which comprises an alkylene-alkyl acrylate copolymer |
| US4832953A (en) * | 1987-08-13 | 1989-05-23 | Alza Corporation | Method for preventing the formation of a crystalline hydrate in a dispersion of a liquid in a monaqueous matrix |
| US5474783A (en) * | 1988-03-04 | 1995-12-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
| EP0356382B1 (de) * | 1988-08-02 | 1994-02-16 | Ciba-Geigy Ag | Mehrschichtiges Pflaster |
| US5176917A (en) * | 1989-03-15 | 1993-01-05 | Lts Lohmann | Transdermal system exhibiting graduated drug release and its use for the local or systemic administration of active substances |
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| EP0387693A2 (de) * | 1989-03-15 | 1990-09-19 | LTS LOHMANN THERAPIE-SYSTEME GmbH & CO.KG | Transdermales System mit gestufter Wirkstoffabgabe und Verwendung für die lokale oder systemische, kosmetische Wirkstoffverabreichung |
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| Publication number | Publication date |
|---|---|
| NO312496B1 (no) | 2002-05-21 |
| CN1158084A (zh) | 1997-08-27 |
| CA2200189C (en) | 2008-06-17 |
| CA2200189A1 (en) | 1996-03-21 |
| SK282640B6 (sk) | 2002-10-08 |
| JPH10505825A (ja) | 1998-06-09 |
| MY112477A (en) | 2001-06-30 |
| IL115189A0 (en) | 1995-12-31 |
| HUT77383A (hu) | 1998-04-28 |
| PL182158B1 (pl) | 2001-11-30 |
| MX9701968A (es) | 1998-02-28 |
| IL115189A (en) | 1999-12-22 |
| JP4466977B2 (ja) | 2010-05-26 |
| ES2219665T3 (es) | 2004-12-01 |
| DE59510883D1 (de) | 2004-04-29 |
| CZ289313B6 (cs) | 2001-12-12 |
| EP0781134A1 (de) | 1997-07-02 |
| ATE262333T1 (de) | 2004-04-15 |
| NO971203D0 (no) | 1997-03-14 |
| NO971203L (no) | 1997-03-14 |
| CZ75797A3 (en) | 1997-07-16 |
| EP0781134B9 (de) | 2004-09-29 |
| US5714162A (en) | 1998-02-03 |
| AU695698B2 (en) | 1998-08-20 |
| NZ292921A (en) | 1998-09-24 |
| FI118885B (fi) | 2008-04-30 |
| FI971097A0 (fi) | 1997-03-14 |
| FI971097L (fi) | 1997-03-14 |
| AU3523195A (en) | 1996-03-29 |
| WO1996008251A1 (de) | 1996-03-21 |
| EP0781134B1 (de) | 2004-03-24 |
| SK33897A3 (en) | 1997-09-10 |
| PL319259A1 (en) | 1997-08-04 |
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