CN103429233B - 含有加兰他敏或其盐的经皮输送系统 - Google Patents
含有加兰他敏或其盐的经皮输送系统 Download PDFInfo
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- CN103429233B CN103429233B CN201280009262.3A CN201280009262A CN103429233B CN 103429233 B CN103429233 B CN 103429233B CN 201280009262 A CN201280009262 A CN 201280009262A CN 103429233 B CN103429233 B CN 103429233B
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- galantamine
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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Abstract
本发明提供了一种经皮输送系统，其包含作为活性成份的加兰他敏或其医药上可接受的盐，以及含药物的基质层，此层包含作为黏着剂的苯乙烯-丁二烯-苯乙烯共聚物或苯乙烯-异戊二烯-苯乙烯共聚物。
Description
技术领域
本发明是关于一种经皮输送系统，其包含加兰他敏(GALANTAMINE)或其盐作为活性成份，更明确的是有关一种经皮输送系统，其包含有含药物的基质层，其基质是以苯乙烯-丁二烯-苯乙烯共聚物或苯乙烯-异戊二烯-苯乙烯共聚物作为黏着剂形成。
背景技术
爱滋海默症(Alzheimer'sdisease)是最常见的一种痴呆形式。此症是一种以丧失心智能力为特征的神经性疾病，严重性足以妨碍日常生活的正常活动。爱滋海默症通常发生在老年，特点是诸如记忆、推理及规画等认知功能的减退。患者自症状开始出现起的中位数存活时间约为8年(Coyle,J.,Kershaw,P.,2001.Galantamine,acholinesteraseinhibitorthatallostericallymodulatesnicotinicreceptors:effectsonthecourseofAlzheimersdisease.Biol.Psychiatry.49,289-299)。加兰他敏是一种第三生物碱且为可逆、竞争型乙酰胆碱酯酶抑制剂(Zarotsky,V.,Sramek,J.J.,Cutler,N.R.,2001.Galantaminehydrobromide:anagentforAlzheimer'sdisease.Am.J.Health-Syst.Pharm.60,446-452)。加兰他敏对于爱滋海默症的症状治疗有效且耐受性佳；且改善患者的认知、全脑功能及日常生活活动(Scott,L.J.,Goa,K.L.,2000.Galantamine:areviewofitsuseinAlzheimer'sdisease.Drugs.60,1095-1122;Corey-Bloom,J.,2003.Galantamine:areviewofitsuseinAlzheimer'sdiseaseandvasculardementia.Int.J.Clin.Pract.57,219-223)。
目前，市面上可取得的加兰他敏为锭剂及/或口服溶液。加兰他敏经口投药后有如腹痛、恶心及腹泻的副作用。因此，加兰他敏的另一种投药方式可能有助于治疗的成功。
经皮药物输送系统(TDDS)的优势是使肠胃副作用减至最少，最常见的副作用诸如恶心及呕吐，甚至会导致治疗中断。TDDS提供的优点有诸如产生持续且受控制的血中药物浓度，增进生物可利用性且绕过首程代谢。尽管TDDS具有此等优点，其用途仍因皮肤最外层-角质层-而受限。虽然此层仅有20至25微米厚，但其提供针对许多化合物的渗透障壁且具有针对治疗性TDDS的主要问题(Thomas,B.J.,Finnin,F.C.,2004.Thetransdermalrevolution.DrugDiscov.Today.9,697-703.Walters,K.A.,Walker,M.,Olejnik,O.,1987.Non-ionicsurfactanteffectsonhairlessmouseskinpermeabilitycharacteristics.j.Pharm.Pharmacol.40,525-529)。
可采用各种方法来克服皮肤的不渗透性。在此等方法中，最常在TDDS中采用化学促进剂，以帮助所投予的药物的通透性(Williams,A.C.,Barry,B.W.,2004.Permeationenhancers.Adv.DrugDeliver.Rev.56,603-618)。众所周知化学促进剂的促进性质视药物及其他调配组份的物化性质而定。在以基质为主的TDDS中，尤其是黏着剂包药物(DIA)型，感压性黏着剂(PSA，以下称为“黏着剂”)兼具有对皮肤黏着性及作为调合物基底的两项功能。在选择适当的黏着剂之前必需考虑药物、黏着剂及促进剂之间的兼容性以及黏着剂性质。
美国专利编号5,700,480已揭示一种经皮输送系统，其包含一储存层，此层含有加兰他敏、塑化剂及作为黏着剂的聚丙烯酸酯(例如，丙烯酸酯共聚物/甲基丙烯酸酯共聚物)。美国专利编号5,700,480的经皮输送系统显示极低的通透性，即，约2.7μg/cm2/hr。为解决该项问题并提高载药量，美国专利公告编号2007/0104771A1已揭示一种经皮输送系统，其包含药物储存器，此储存器含有具有极性官能单体组份的丙烯酸酯、大于10重量%的加兰他敏及用以在大于4.5μg/cm2/hr的通量下输送加兰他敏的渗透促进剂。然而，美国专利公告编号2007/0104771A1的经皮输送系统具有其通量仍低的缺点，即，最高11.35μg/cm2/hr(表2)。
发明内容
本发明提供一种经皮药物输送系统，其包含作为活性成份的加兰他敏或其盐，其可抑制加兰他敏或其盐的结晶，借此不仅保持治疗有效血中浓度历经至少24小时，亦提供高度皮肤通透率。
即，本发明提供一种经皮输送系统，其含有加兰他敏或其医药上可接受的盐，其连续显现多于24小时的皮肤通透率。
根据本发明的一方面，提供一种经皮输送系统，其包含含药物的基质层，此层包含加作为活性成份的兰他敏或其医药上可接受的盐；及作为黏着剂的苯乙烯-丁二烯-苯乙烯共聚物或苯乙烯-异戊二烯-苯乙烯共聚物。
本发明具体实施例中，经皮输送系统可由背衬层、含药物的基质层及脱离层组成。
在本发明经皮输送系统中，加兰他敏或其医药上可接受的盐可存在量的范围以含药物的基质层的总重计为0.5至20重量%，较佳为10至20重量%。而且，黏着剂可存在量的范围以含药物的基质层的总重计为70至95重量%。
本发明经皮输送系统可进一步包含一或多种通透促进剂，选自由以下组成的群：丙二醇月桂酸酯、月桂醇、三乙酸甘油酯、肉豆蔻酸异丙酯、桉油酚、聚环氧乙烷月桂醚、聚乙二醇油酰甘油酯及辛酸根基己酰基聚乙二醇甘油酯。较佳，该通透促进剂可为聚环氧乙烷月桂醚。该通透促进剂可存在量的范围以该含药物的基质层的总重计为0.5至10重量%，较佳为约5重量%的量。
在本发明经皮输送系统中，含药物的基质层可具有50μm至100μm--较佳50μm至80μm范围内的厚度。
本发明经皮输送系统包含通过使用苯乙烯-丁二烯-苯乙烯共聚物或苯乙烯-异戊二烯-苯乙烯共聚物作为黏着剂所制得的基质，其抑制基质中加兰他敏或其盐的结晶，因而可使血液浓度稳定的保持治疗有效浓度至少24小时。尤其，本发明经皮输送系统可提供高皮肤通透率，例如最大值38μg/cm2/hr。
附图说明
图1显示通过评估黏着剂类型对在15%w/w载药量下的加兰他敏渗透跨经无毛小鼠皮肤的影响所得结果。数值表示成平均值±标准偏差。(n=3)
图2显示通过评估丙烯酸黏着剂中官能基对于在15%w/w载药量下的加兰他敏渗透性的影响所得结果。数值表示成平均值±标准偏差。(n=3)
图3显示使用具有羟基官能基的丙烯酸系黏着剂在15%w/w的载药量下制备的新鲜及结晶贴片之间进行比较所得结果(Duro-87-2510)。数值表示成平均值±标准偏差。(n=3)
图4显示通过在80μm干燥基质厚度下评估在SBS基质中的载药量对于加兰他敏渗透跨经无毛小鼠皮肤的效果所得到的结果。数值表示成平均值±标准偏差。(n=3)
图5显示通过评估在促进剂存在下载药量对于加兰他敏于SBS基质中渗透的影响所得到的结果。数值表示成平均值±标准偏差。(n=3)
图6显示通过评估SBS基质干燥厚度在15%载药量下历经48小时对于加兰他敏渗透的影响而得到的结果。数值表示成平均值±标准偏差。(n=3)
具体实施方式
本发明提供一种经皮输送系统，其包含含药物的基质层，此层包含作为活性成份的加兰他敏或其医药上可接受的盐；及作为黏着剂的苯乙烯-丁二烯-苯乙烯共聚物或苯乙烯-异戊二烯-苯乙烯共聚物。
为了解决现有使用丙烯酸系黏着剂的经皮输送系统对皮肤通透性低的问题，本发明者针对黏着剂特征、药物浓度、基质厚度、渗透促进剂等进行各种研究。本发明发现低通透率是因为加兰他敏中的第三胺基与黏着剂中羧基官能基之间相互作用；及因为其中使用丙烯酸黏着剂的基质中的加兰他敏结晶。而且，本发明者发现当使用特定黏着剂(即，苯乙烯-丁二烯-苯乙烯共聚物或苯乙烯-异戊二烯-苯乙烯共聚物)设计含药物的基质层时，加兰他敏与黏着剂之间的相互作用连同加兰他敏的结晶受到有效的抑制，因而可达成高的皮肤通透性。
黏着剂，即，苯乙烯-丁二烯-苯乙烯共聚物或苯乙烯-异戊二烯-苯乙烯共聚物，不仅执行黏着功能，而亦形成药物基底或底质。黏着剂可存在量的范围为70至95重量%，较佳为80至90重量%的范围，但不受限于此。
在本发明经皮输送系统中，加兰他敏或其医药上可接受的盐(例如，HBr盐)可使用足以得到治疗有效血液浓度的量，例如用量范围以该含药物的基质层的总重计为0.5至20重量%，较佳为10至20重量%，更佳为10至15重量%，特佳为约15重量%。若加兰他敏或其医药上可接受的盐的量低于0.5重量%，则用以得到所需药物疗效的经皮输送系统的尺寸(即，面积)可能变成超大，因而降低患者的服药顺从性。同样，若加兰他敏或其医药上可接受的盐的量大于20重量%，含药物的基质层中可能形成药物结晶，导致黏着力降低或药物通透率降低。
而且，本发明经皮输送系统可包含渗透促进剂。该渗透促进剂可存在量的范围以该含药物的基质层的总重计为0.5至10重量%，较佳为约5重量%，唯其量是随着渗透促进剂的种类而改变。若渗透促进剂的量低于0.5重量%，可能难以得到充分的通透性增进效果。此外，若渗透促进剂的量大于10重量%，则通透性增进效果无法明显增加。使用过量的渗透促进剂可能造成对皮肤的黏着力降低；或因内聚力减弱而造成冷流。
该渗透促进剂可为选自由以下组成的群的一种或多种：丙二醇月桂酸酯[例如FCC]、月桂醇、三乙酸甘油酯、肉豆蔻酸异丙酯、桉油酚、聚环氧乙烷月桂醚[例如，BrijTM30,BrijTM52等)、聚乙二醇油酰甘油酯(或聚乙二醇-8甘油亚油酸酯)[例如，2609等]及辛酸根基己酰基聚乙二醇甘油酯(或聚乙二醇-8甘油辛酸酯/癸酸酯)[例如，等]。其中，可优选的使用聚环氧乙烷月桂醚。
在本发明经皮输送系统中，含药物的基质层可具有50μm至100μm--较佳50μm至80μm范围内的厚度。
本发明具体实施例中，提供一种经皮输送系统，其包含厚度约80μm的含药物基质层，该含药物基质系由约15重量%的加兰他敏、约5重量%的聚环氧乙烷月桂醚及其余量的苯乙烯-丁二烯-苯乙烯共聚物所组成。
本发明经皮输送系统可由背衬层、含药物的基质层及脱离层所组成。由背衬层、含药物的基质层及脱离层所组成的本发明经皮输送系统可通过在脱离层上形成含药物的基质层且随的在该层上形成背衬层而制备。就脱离层而言，可使用经皮输送系统领域中所使用的脱离衬垫或其层积物。例如，可使用由聚乙烯、聚酯、聚氯乙烯、聚偏二氯乙烯等制得而涂覆有聚硅氧树脂或氯化物树脂的薄膜、纸或其层积物。而且，可使用经皮药物输送系统领域所常用的不吸收药物且可弯曲的材料作为背衬层(亦称为“背衬膜”)。例如，可使用聚烯烃、聚醚、多层乙烯乙酸乙烯酯薄膜、聚酯、聚胺基甲酸乙酯等。本发明经皮输送系统可例如通过将加兰他敏或其医药上可接受的盐溶于适当的溶剂(例如氯仿等)中；与苯乙烯-丁二烯-苯乙烯共聚物或苯乙烯-异戊二烯-苯乙烯共聚物(及若需要则使用的渗透促进剂)混合；将形成的混合物铸造于涂覆有例如聚硅氧的脱离衬垫上，之后将混合物干燥；及随之于其上层积背衬层。
现在，参考以下实施例进一步详细描述本发明。这些实施例仅供说明，而不限制本发明范围。
1.材料及方法
(1)材料
FCC、月桂醇、三乙酸甘油酯、肉豆蔻酸异丙酯、桉油酚、聚环氧乙烷月桂醚(例如BrijTM30,BrijTM52等)、聚乙二醇油酰甘油酯(例如2609CS等]及辛酸根基己酰基聚乙二醇甘油酯(例如等)。
加兰他敏购自IvaxPharmaceuticals(Opava-Komarot,CzechRepublic)。聚乙二醇-8甘油辛酸酯/癸酸酯得自Gattefosse(Gennevillers,France)。聚乙二醇-8甘油亚油酸酯(2609)购自MasungCo.(Seoul,Korea)。油酸、丙二醇及山梨醇酐单油酸酯(80)购自JunseiChemical(Tokyo,Japan)。肉豆蔻酸异丙酯(IPM)及PEG-20杏仁甘油酯(A40)得自Croda(Parsippany,NJ,USA)。桉油酚、月桂醇及30购自SigmaChemical(St.Louis,MO,USA)。丙烯酸、聚异丁烯(PIB)及苯乙烯-丁二烯-苯乙烯共聚物(SBS)黏着剂在有机溶剂中的溶液得自NationalStarchandChemicalCompany(Bridgewater,NJ,USA)。聚硅氧黏着剂溶液(7-4302)得自DowCorning(Midland,MI,USA)。所有其他化学品皆为试剂级或以上，都在不进一步纯化下使用。
(2)方法
<1>含加兰他敏的黏着剂基质的制备
药物溶液是借着将加兰他敏溶于氯仿而制备且与促进剂及黏着剂混合。形成的混合物铸于脱离衬垫上。于室温固化10分钟，之后于80℃干燥20分钟，以移除残留的有机溶剂。移除溶剂后，干燥薄膜与聚酯背衬膜(9728，3M，USA)层积。
<2>皮肤膜制备
自6至8周大的无毛小鼠身上切下全厚皮肤。小鼠在以二乙醚麻醉的情况下人道处死。以剪刀及手术刀谨慎的取出皮下脂肪、组织及血管。仅使用无孔洞或任何其他缺陷的皮肤。为进行体外皮肤渗透研究。将皮肤切成约6cm2的小片。
<3>体外经皮渗透实验
使用修正版Franz扩散池研究加兰他敏自该经皮输送系统跨经无毛小鼠皮肤的体外经皮渗透特性。使用流通式扩散池系统且温度保持在37℃。接收池开口的表面积为2cm2，而其体积为5.5mL。接收池装满磷酸盐缓冲剂溶液(pH6.0)，培养基藉涂覆铁弗龙的磁性搅拌棒于500rpm搅拌。切下的皮肤装置于各接收池上。将O形环及接收池盖放置于各片皮肤顶部。此等组份随后夹住。每4小时收集试样历经24小时，且通过高效液相色谱层析检测(HPLC)。
<4>分析方法
加兰他敏使用先前记录的方法进行分析(Ang,C.,Fen,H.E.,Sub,H.E.,2006.PharmacokineticsofgalantamineHbrinplasmaandbrainofmice.Chin.J.Pharm.37,55-61)，只有轻度修正。使用由以下组成的HPLC系统(ShimadzuScientificInstruments,MD)：UV侦测器(SPD-10A)、C18管柱(4.6×100mm,5μm,Gemini)、泵(LC-10AD)及自动注射器(SIL-10A)。UV侦测器的波长为230nm；管柱温度保持于30℃；流速为1mL/min；且注射体积为30μL。移动相是由含有0.2%三乙基胺的甲醇/水组成，用磷酸(35/65,v/v)调至pH6.4。
<5>数据演算
渗透数据是通过针对流通式扩散池系统(Choi,H-K.,Angello,J.,1994.TheMathematicalanalysisandoptimizationofaflowthroughdiffusioncellsystem.Pharm.Res.11,595-599)发展的方法分析。
2.结果与讨论：
(1)黏着剂效应
设计TDDS时，选择适当的黏着剂基质相当重要。众所周知黏着剂的物化性质可明显影响跨经皮肤的药物通量(Subedi,R.K.,Jang,J.H.,Kim,Jae-II,Park,Y.J.,Choi,H.-K.,2010.Formulationandevaluationoftransdermalpatchcontainingsibutramine.J.Kor.Pharm.Sci.40,33-38)。黏着剂基质对加兰他敏的渗透的影响是使用丙烯酸、丙烯酸橡胶混杂物、SBS、溶剂及PIB基质进行研究。所筛选的物化性质列于表1。
<表1>研究中所使用的物化性质
含有丙烯酸、丙烯酸橡胶混杂物、SBS、聚硅氧及PIB基质的贴片在15%w/w载药量下筛选。加兰他敏由丙烯酸黏着剂渗透的速率最高，接着为SBS、丙烯酸橡胶混杂物、聚硅氧及PIB(参见图1)。丙烯酸黏着剂中不同官能基对于加兰他敏的渗透性的影响亦进行研究(参见图2)。由含有具羟基官能基的丙烯酸黏着剂的基质观察到加兰他敏的最高渗透(87-2510)。由含有具羧基官能基的丙烯酸黏着剂观察到加兰他敏的最低渗透(87-2979)。此可能因为加兰他敏中的第三胺基与87-2979中-COOH基团相互作用。此类药物聚合物相互作用的机率被广泛的记录(Kim,J.H.,ChoY.-J.,Choi,H.-K.,2000.Effectofvehiclesandpressuresensitiveadhesivesonthepermeationoftacrineacrosshairlessmouseskin.Int.J.Pharm.196,105-113;Morimoto,Y.,Kokubo,T.,Sugibayashi,K.,1992.Diffusionofdruginacrylictypepressuresensitiveadhesivematrix.II.Influenceofinteraction.J.Control.Release.18,113-121;Subedi,R.K.,Jang,J.H.,Kim,Jae-II,Park,Y.J.,Choi,H.-K.,2010.Formulationandevaluationoftransdermalpatchcontainingsibutramine.J.Kor.Pharm.Sci.40,33-38)。
出手意料的是当贴片储存室温下时，发现所有基质(SBS除外)皆在一周内发展出结晶。虽然最高通量是得自在具有羟基官能基的丙烯酸基质中制备的新鲜试样，但贴片中药物结晶确实造成药物通量的明显降低(参见图3)。考虑载药能力、适当的渗透率及良好黏着性，决定SBS基质最优异。
(2)加兰他敏浓度对皮肤渗透性的效应
图4显示在SBS基质中的载药量对于加兰他敏渗透跨经无毛小鼠皮肤的效果。当载药量自2.5增至15%w/w聚合物重量时，渗透率亦成比例的增加。在加兰他敏于贴片中的浓度与平均累积通量之间的相关系数R2=0.998。在载药量为20%w/w时，在72小时内观察基质中的结晶。加兰他敏在SBS基质中高于15%w/w浓度下可能超饱和，造成基质中药物的再结晶。载药量的进一步增加未能使渗透明显增加。为将载药量优化，亦研究于促进剂存在下载药量对加兰他敏通量的影响。图5显示12.5%w/w至20%w/w的载药量于5%v/w30存在下的影响。加兰他敏的渗透性大幅增高至15%w/w的载药量。然而，超过15%w/w的载药量，通量保持几乎定值，在20%w/w的载药量时甚至降低。此通量降低可能是因为基质中加兰他敏结晶。因此，决定最优异的载药量为15%w/w。
(3)基质厚度的效应
基质层厚度是发展以基质为主的TDDS中重要参数之一。较厚基质可在相对长的施用时间下将较高量药物输送到皮肤(Furuishi,T.,Io,T.,Fukami,T.,Suzuki,T.,Tomono,K.,2008.Formulationandinvitroevaluationofpentazocinetransdermaldeliverysystem.Biol.Pharm.Bull.31,1439-1443)。因为有较高量的药物可自贴片渗透。然而，较厚基质亦具有导致冷流的较高倾向(Wokovich,A.M.,Prodduturi,S.,Doub,W.H.,Hussain,A.S.,Buhse,L.F.,2006.Transdermaldeliverysystem(TDDS)adhesionasacriticalsafety,efficacyandqualityattribute.Eur.J.Pharm.Biopharm.64,1-8)。因此，在负载加兰他敏的贴片中研究厚度的影响，以评估渗透性以及黏着特征。在24小时研究期间，不可能与不同厚度基质的渗透特征作出区隔。将该研究延长到48小时，较厚黏着基质显示较佳且较固定的特性走势(参见图6)。尤其，较薄基质(40μm)显示下降的渗透特性走势。所制备贴片的黏着剂也可藉图钉测试(thumbtacktest)手动的评估。结果，发现高于50μm的基质厚度具有充足的黏着力。基质厚度超过80μm时，通量无法明显增加且所得到的特性走势几乎相同。如前文所述，可能不期望较厚的基质，因可能在施加于皮肤上时造成冷流。因此，考虑黏着及潜在冷流的下，决定基质厚度较佳为50μm至80μm，最佳是80μm。
(4)渗透促进剂的效应
渗透促进剂可逆的降低角质层的渗透障壁。渗透促进剂亦可作为塑化剂，增加药物在基质中的移动性。评估各种渗透促进剂(5%v/w)在SBS基质中而载药量为15%w/w的效应。其结果列示于表2。
<表2>
*增进比=使用渗透促进剂时的通量/无渗透促进剂时的通量
在所筛选的渗透促进剂中，A40、丙二醇、聚乙二醇(PEG)400、及甘油无法增进加兰他敏的渗透。而FCC、月桂醇、三乙酸甘油酯、肉豆蔻酸异丙酯(IPM)、桉油酚、30、2609及明显增进加兰他敏的渗透性。其中，30及FCC显示相对较高的加兰他敏增进比。显示最高增进比的30对加兰他敏的皮肤渗透性的增进效果是在不同浓度下评估(聚合物重量的25至10%v/w)，15%w/w的载药量。观察到随着渗透促进剂浓度的增加，加兰他敏渗透的倾向增加(参见图7)。当30的水平自2.5增至5%v/w时，观察到渗透特性走势明显增加。然而，超过5%v/w的30浓度时，渗透性的增加不明显。此外，观察到含有多于5%v/w的30的贴片的黏着性明显降低。因此，考虑渗透性及黏着性，决定贴片中30最佳水平是约5%v/w。
3.结论
根据前述研究，可自优化调配物得到8μg/cm2/h的通量。例如，该经皮输送系统包含有含药物的而厚度约80μm的基质层，该含药物基质是由约15重量%的加兰他敏、约5重量%的聚环氧乙烷月桂醚及其余量的苯乙烯-丁二烯-苯乙烯共聚物组成。因此，认为甚至是小于9cm2的贴片尺寸，亦可输送8mg加兰他敏/日。
Claims (4)
1.一种避免结晶、增加载药量及通透量的加兰他敏经皮输送系统，其包含含药物的基质层，此层包含作为活性成份的加兰他敏或其医药上可接受的盐、作为黏着剂的苯乙烯-丁二烯-苯乙烯共聚物及作为渗透促进剂的聚环氧乙烷月桂醚，其中加兰他敏或其医药上可接受的盐的存在量以该含药物的基质层的总重计为15重量％，该黏着剂的存在量以该含药物的基质层的总重计为80重量％，及该渗透促进剂的存在量以该含药物的基质层的总重计为5重量％。
2.如权利要求1所述的加兰他敏经皮输送系统，其中该经皮输送系统是由背衬层、含药物的基质层及脱离层所组成。
3.如权利要求1或2所述的加兰他敏经皮输送系统，其中该含药物的基质层的厚度范围为50μm至100μm。
4.如权利要求1或2所述的加兰他敏经皮输送系统，其中该含药物的基质层的厚度范围为50μm至80μm。
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| JP6285820B2 (ja) * | 2014-08-07 | 2018-02-28 | 久光製薬株式会社 | ガランタミン含有経皮吸収製剤 |
| US20180008612A1 (en) * | 2016-07-11 | 2018-01-11 | Taho Pharmaceuticals Ltd. | Transdermal delivery system containing galantamine or salts thereof |
| CN106265678B (zh) * | 2016-07-18 | 2019-06-04 | 陕西省中医医院 | 一种用于治疗面瘫的膏药及其制备方法 |
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| DE19906977C1 (de) * | 1999-02-19 | 2000-06-15 | Lohmann Therapie Syst Lts | Desoxypeganin-TTS und seine Verwendung |
| US20050074487A1 (en) * | 1999-12-16 | 2005-04-07 | Tsung-Min Hsu | Transdermal and topical administration of drugs using basic permeation enhancers |
| PT1895994E (pt) * | 2005-05-13 | 2010-12-03 | Alza Corp | Sistema de administração de medicamentos de camada múltipla com barreira contra o fluxo de material do reservatório |
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| US5932238A (en) * | 1990-03-29 | 1999-08-03 | Lts Lohmann Therapie-Systeme Gmbh & Co. | Galanthamine containing transdermal applicator for the treatment of alcoholism |
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| CN101312717A (zh) * | 2005-12-01 | 2008-11-26 | 诺瓦提斯公司 | 透皮治疗系统 |
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