CN1170360A - 具有粘性贴面和剥离密封圆片的经皮输送系统 - Google Patents
具有粘性贴面和剥离密封圆片的经皮输送系统 Download PDFInfo
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- CN1170360A CN1170360A CN95196946A CN95196946A CN1170360A CN 1170360 A CN1170360 A CN 1170360A CN 95196946 A CN95196946 A CN 95196946A CN 95196946 A CN95196946 A CN 95196946A CN 1170360 A CN1170360 A CN 1170360A
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Abstract
一种用于向个体的皮肤或粘膜施用活性剂的装置(10),包括一个层状复合体,其组成为一个粘性贴面(26),一个位于该粘性贴面中部下面的背层(14),一个可透过活性剂的膜(16),由所述背层和膜形成一个储池(12),其中盛有一种活性剂配方,在所述可透过活性剂的膜下面有一个剥离密封圆片(20),在所述剥离密封圆片、可透过活性剂的膜和背层周围有一个热密封(22),可活动释放衬垫(24)位于暴露的贴面和剥离密封圆片下面。所述粘性层位于活性剂通向皮肤或粘膜的通路的上方及其周围,并通过多重热封密防止被储池内成分降解。剥离密封圆片可防止盛有活性剂的储池的泄露,而释放衬垫可在使用前防止所述粘合剂暴露于环境中。
Description
本发明属于经皮和经粘膜施用活性剂(药物)的领域。更具体地讲,本发明涉及一种用于实现上述用药的装置,该装置有一个盛活性剂的储池和一个用于将该装置固定于皮肤或粘膜上的粘性层。粘性层位于活性剂通向皮肤或粘膜的通路的上方及周围,并通过多重热密封防止被储池成分降解。一个剥离密封圆片能防止盛有活性剂的储池的泄露,而一个释放衬垫能在使用之前防止所述粘性剂暴露于环境中。
在许多专利中都披露了通过皮肤或粘膜施用药物的装置。这些装置通常分为两类:基质系统和液体储池系统。两种系统均为层状复合体,即:从底部至顶部有一个可剥离的释放衬垫,一个用于将所述装置固定在皮肤上的压敏粘性层,一个含有药物的层和一个可透过药物的背层。在基质类系统中,药物分散于一种固体或半固体载体中。在储池类系统中,药物通常在液体溶液中,该溶液盛在通常形成于所述背层与可透过药物的膜层之间的有壁容器中。
业已披露了若干种储池型系统。Kwiatek等的美国专利US4,710,191涉及一种储池型装置,它包括一个可剥离的热密封的释放衬垫层,其位于储池及背层超过储池部分的下面。在另一个实施方案中,还包括一个位于背层和储池之间的微孔膜。
Chang等的美国专利US4,829,224披露了一种具有一个储池的装置,该储池是由背层和一个可透过药物的膜层形成。在储池的周围有一个由粘性材料制成的环形层。在膜的下面有一个可剥离的衬垫层。在整个组件下面有一个第二可剥离层——释放衬垫。第一热密封连接背层和膜,并环绕所述储池。第二热密封与第一热密封同心,连接背层和释放层。当释放衬垫被除去时,该第二热密封被破坏。该装置可包括一个位于膜及背层部分下面的内层衬层。该内层衬垫随着除去释放层而被除去,以便暴露所述膜。
Chang等的美国专利US4,983,395涉及另一种装置,该装置由一个背层和一个膜层形成一个储池。一个可剥离的内层位于储池及背层和膜层的位于储池外面部分的下面。一个粘性层位于所述内层及背层和膜层的其余部分的下面。在粘性层下面有一个可剥离的释放衬垫。一个第一热密封在储池的周围连接背层和膜层。一个第二热密封位于第一热密封下面并连接所述膜和内层衬垫。在使用中,将释放衬垫和内层衬垫剥去,以便露出膜层和粘性层的下表面,然后将该装置贴在皮肤或粘膜上。
本发明是一种用于经皮或经粘膜进行药物输送的改进装置,其中,在盛药物的储池下面有一个闭合的剥离密封层,用于防止药物在使用之前释放。一个释放衬垫贴在剥离密封层及粘性贴面的暴露部分的上面。这样,释放衬垫就不必是闭合的了,并可选自很多种可以吸入并具有可拉伸的弹性性质的材料。这种装置价廉,而且易于制造。
此外,在本发明的装置中,只有该装置的与储池连接的中央部分是闭合的,留下该装置在所述中央部分的周围的那部分为非闭合的或适于吸入的。
本发明涉及一种用于向个体的皮肤或粘膜施用活性剂的装置,它包括一个层状复合体,包括
(a)一个粘性贴面,有一个中央部分和一个周围部分;
(b)一个背层,位于所述粘性贴面中央部分的下面;
(c)一个可以透过活性剂的膜,位于背层下面,背层和膜形成
(d)位于二者之间的储池,储池中盛有一种活性剂;
(e)一个剥离密封圆片,位于可透过活性剂的膜的下面;
(f)一个位于所述剥离密封圆片、可透过活性剂的膜和背层周围的热密封;和
(g)一个活动释放衬垫,位于粘性贴面周围部分及剥离密封圆片的下面。
图1是本发明装置的一种实施方案的放大剖视图。
图2A和2B是本发明装置的另一种实施方案的放大俯视图。
图3是本发明另一种实施方案的放大截面图。
图4是图3实施方案的放大视图,表示该装置的拆卸状态。
图5是比较keterolac三羟甲基氨基甲烷的计算的释放动力学和基于例23中所述试验的实验累积释放动力学的曲线。
图1表示一种用于向皮肤或粘膜施用一种活性剂配方的装置,总体上用10表示。装置10为一种层状复合体。在上背层14与下面的可透过药物的膜层16之间形成一个药物储池12。在膜层16下面有一个剥离密封圆片20。背层14、膜层16和剥离密封圆片20三层的周围22热密封在一起,膜层16与背层14热密封在一起,剥离密封圆片20与膜层16热密封在一起。一个释放衬垫24位于剥离密封圆片20下面并超出热密封22的外围。一个粘性层26贴在背层14及释放衬热24超出热密封22周围的部分上。最上面的贴面层30贴在粘性层26上面。在该实施方案中,在将该装置贴在皮肤上之前将释放衬垫连同剥离密封圆片一起除掉。
图2A和2B表示本发明装置的另一种实施方案,其中,有一个垂片32延伸通过热密封22,以便能轻易除去剥离密封圆片20。垂片32既可像在图2A中所示那样通过热密封22延伸一个较短的长度,又可像在图2B中所示那样延伸至装置10的周围34。
图3和4表示本发明层状复合体的另一种实施方案,总体上用40表示。图3和4的装置与图1装置的区别在于,在剥离密封圆片与第一粘性层的周围部分的下面有一个第二粘性层。更具体地讲,装置40(从上表面到下表面)由一个非闭合的贴面层42、一个第一粘性层44、一个背层46、一个含有可经皮用药的溶液或凝胶配方的药物储池48、一个可透过药物的膜层50、一个剥离密封圆片52、一个第二粘性层54和一个释放衬垫层56组成。如图所示,背层膜、储池、膜和剥离密封圆片“顺序布置”,而且,其面积小于贴面、两个粘性层和释放衬垫的面积。后者周向超出前者的整个外围。背层膜、膜及剥离密封圆片在其整个外围60处热密封在一起。
在使用时,将释放衬垫层、第二粘性层的位于剥离密封圆片下面的部分和剥离密封圆片同该组件的其余部分分离。分离或拆散的结构如图4所示。就此而言,释放层与第二粘性层之间、第二粘性层与第一粘性层和剥离密封圆片之间、以及剥离密封圆片与膜之间的相对粘合强度是这样的:当除去释放衬垫时,第二粘性层的中央部分和剥离密封圆片被一起除去。将除去的释放层亚结构丢弃。将带有药物储池的亚结构贴在皮肤上,由第二粘性层的周围环形部分将该亚结构固定在皮肤或粘膜上。当其这样贴于皮肤上时,药物储池通过膜与皮肤之间形成扩散性联系。换句话说,药物可自由地经膜扩散至皮肤。
该装置的背层14或46可由单层膜或多层膜组成。但无论哪种形式,其内表面都必须能够热密封至膜层16或50上。组成背层的一层或几层膜不能透过储池中所盛的药物配方成分。也可以用于本发明的、在经皮输送装置中用作背层的材料的例子有:聚乙烯、聚丙烯、聚氯乙烯、聚对苯二甲酸乙二醇酯、乙烯乙酸乙烯酯共聚物及其组合。背层可以包括一层或几层金属层和/或一层或几层纤维层。背层最好是闭合的。
本文中用于表述该装置的主要活性成分的“活性剂”或“药物”,是指能对该装置的配戴者产生治疗、预防或其它有益药理学和/或生理学作用的生物活性化合物或这些化合物的混合物。可用于本发明装置的药物类型的例子有抗炎药物、止痛药、抗关节炎药、镇痉药、抗抑郁药、抗精神病药、安定药、抗焦虑药、麻醉拮抗剂、抗震颤麻痹剂、胆碱能拮抗剂、抗癌药、免疫抑制剂、抗病毒剂、抗生物剂、食欲抑制剂、止吐药、抗胆碱能剂、抗组胺剂、抗偏头痛剂、心肌动脉、脑或外周血管扩张剂、激素剂、避孕剂、抗凝剂、利尿剂、抗过敏剂、心血管药物等。上述类型的合适药物本身能够透过皮肤或通过用一种经皮吸收增强剂对皮肤进行处理而使其能够通过皮肤。由于该装置的大小受患者接受程度的限制,优选药物为那些在血液中能以低浓度起作用的药物。具体药物的例子有类固醇,如雌二醇、孕酮、18-甲炔诺酮、左旋18-甲炔诺酮、炔诺酮、乙酸甲氧基孕酮、3-Ketodesogestel、睾酮及其酯,硝基化合物,如硝化甘油和硝酸异山梨醇、烟碱、氯苯那敏、特非那定、反2-[3-(吡咯烷基)对甲苯丙烯基]吡啶、皮质醇,Oxicam衍生物,如吡氧噻嗪、酮丙酸,粘多糖酶,如硫基粘多糖酶,叔丁啡,芬太尼,纳洛酮,可待因,二氢麦角胺,苯噻啶,舒喘宁,叔丁喘宁,前列腺素,如米索前列醇和恩前列素,奥美拉唑,丙咪嗪,苯甲酰胺,如甲氧氯普胺,莨菪胺,肽类,如生长释放因子和抑生长素,可乐定,二氢吡啶,如利心平,戊脉安,麻黄碱,心得静,美多心胺,螺内酯,尼卡地平氢氯化物,1,25-二羟胆骨化醇,噻嗪类,如氢氯噻嗪,氟桂嗪,sydononimines,如吗导敏,硫酸多糖,如肝素组分,以及上述化合物与可以药用的酸或碱形成的盐。
除上述药物外,根据皮肤对药物的通透性,可在储池中含有一种经皮吸收增强剂,以提高药物透过皮肤的能力并共同施用于皮肤上。经皮吸收增强剂的例子披露于以下文献中:美国专利US3,989,816,US4,863,970,US4,316,893,US4,405,616,US4,060,084和US4,379,454,以及J.Pharm.Sci(1975)64:901-924 。储池中所盛配方还包括溶剂、胶凝剂、稳定剂、抗刺激剂及其它添加剂。
膜层16或50可透过药物。膜层可以是由本身能透过储池中的待施用于皮肤或粘膜上的成分的材料制成的“致密”膜,或是由多孔膜制成,其孔中填充有可透过药物的材料,包括药物储池配方本身,必要时该配方中可含有增强剂。对于致密膜来说,所述成分溶于所述材料中,并经该材料扩散至皮肤。对于微孔材料来说,所述成分经微孔扩散至皮肤。所述膜可以是或不是一种速率控制部件,这要取决于具体涉及的药物、皮肤对药物的透过性和产生治疗效果所需的输送速度。用于制造致密膜的材料的例子见美国专利US.3,598,122和US4,650,484。用于制造微孔膜的材料的例子见美国专利US3,797,494和US4,031,894。
粘性层26、44和54是由压敏外科用粘合剂组成,如常用于将经皮药物输送装置、绷带或其它敷料固定在皮肤上的粘合剂。上述粘合剂的例子有聚异丁烯(PIB)、天然橡胶粘合剂、丙烯酸酯和异丁烯酸酯粘合剂及硅氧烷粘合剂。优选可吸入的非封闭性粘合剂,如丙烯酸酯/异丁烯酸酯和硅氧烷粘合剂。
剥离密封圆片20或52可以由一层或多层组成。该圆片应当(1)不能透过储池配方中经膜扩散的药物成分,(2)可以与膜层进行热密封,和(3)本身可剥离,或通过诸如硅氧烷或碳氟化物处理或用一种密封不亲合层进行表面处理的技术使得其变得可剥离。合适的剥离密封圆片包括由Berte k 4418 Peelable Seal、Total HealthcarePackaging TPC-0812或TPC-0760和UCB Medical Industries LR4/25制成的圆片。
释放衬垫24或56也可类似地由一层或多层组成。然而,与剥离密封圆片不同,释放衬垫不必是不可透过药物配方的成分的,由剥离密封圆片阻止所述成分从储池中释出。因此,合适的衬垫可以由诸如聚酯、低密度聚乙烯(LDPE)、高密度聚乙烯(HDPE)、聚丙烯、聚苯乙烯、聚酰胺、尼龙、聚氯乙烯和特种纸制成,并包括AkrosilBiorelease衬垫、Scotchpat 1022释放衬垫、Adhesives ResearchAR5MS、涂在HDPE上的Custom Coating和Laminating 7000或涂在聚对苯二甲酸乙二醇酯(PET)上的6020。
贴面层30或42覆盖粘性层26或44,它可由诸如聚烯烃、聚亚胺酯、尼龙、聚酯、乙烯、乙酸塔夫绸或其它弹性织物或无纺织物或膜制成。贴面材料最好是非闭合的(可吸入的)。
该装置的相应部分可以用药物配制、经皮装置和分层技术领域的已知方法进行配制和组装。该装置的形状并不重要,可以直接组装预成型的装置,或由大片的层状复合体冲切,切割或其它方式成型。
下面的实施例对本发明做进一步说明。这些实施例并非要以任何方式限定本发明的范围。
实施例
例1
用一把10mil隙的铸刀将一种医用级压敏丙烯酸粘合剂MA-31(Adhesives Research,Glen Rock,PA)涂在低剥离强度的硅烷化释放衬垫上。将粘性溶剂在80℃下蒸15分钟,以形成0.002英寸的最终干粘合剂厚度。然后将贴面材料Volara Foam 15EO(Voltek,Division of Sekisui America Corp,Lawrence MA)层压在所述干粘性膜上,形成贴面粘性层。该贴面粘性层被用于生产工艺的下述后续步骤中。
将15mg/ml睾酮溶于含有50.0/15.0/30.0/2.5/2.5%(v/v)乙醇/水/甘油/单油酸甘油酯/月桂酸甲酯的溶液中,制成一种凝胶化睾酮配方。所得溶液用3.0%(w/v)的Carbopol 1342凝胶化。通过加2N NaOH将所得凝胶的pH调至4.5~5.0。
带有剥离密封圆片的贴面片按如下方法制造:将CoTran 9711微孔膜(3M,St.Paul,MN)放置在LR4/25剥离密封圆片膜(UCBMedical Industries,Bloomfield,CT)上。将0.9g睾酮配方分配到微孔膜上。对背层膜(Scotchpak 1012,3M,St.Paul MN)进行预压,形成一个平的、体积约为1.0cc的圆形杯。将预压背层膜放置在凝胶上,使背层膜上的压痕正对凝胶压痕。然后在370°F的温度下以30psi的压力用0.4秒的停留时间将背层膜热密封到微孔膜/剥离密封膜层上。采用内径为1.22英寸、热密封宽度为0.03英寸的圆形热密封型片。形成一个活性表面为7.5cm2的含凝胶的储池。该热密封步骤能同时在微孔膜与背层膜之间形成永久性储池密封,在微孔膜与剥离密封圆片膜之间形成可剥离的密封。然后从该热密封层上冲切出直径为3.5cm和总面积为9.6cm2的中间含药物的储池系统。
将上述储池系统层压到事先制备好的贴面贴性层上,方法是:将保护性释放衬垫从贴面粘合剂除去;将冲切储池系统放置在粘合剂上,使背层膜接触粘合剂;重新把释放衬垫层压在暴露的粘合剂上;最后从该叠层上冲切出实际的贴面粘性经皮输送系统。用于上述作业的冲切模的直径为5.5cm,从而能冲切出最终表面积为23.8cm2的经皮输送系统,包括周边粘性部分。该系统在用于皮肤之前分两步启动:首先将覆盖粘合剂的释放衬垫除去,然后再除去保护储池的可剥离的圆片膜。
例2
采用例1的方法制备带有粘性贴面的经皮系统,所不同的是,所用粘合剂是医用级丙烯酸粘合剂,Gelva 737(Monsanto,St.Louis,MO)。
例3
采用例1的方法制备带有粘性贴面的经皮系统,所不同的是,所用粘合剂是医用级PIB粘合剂MA-24(Adhesives Research,GlenRock,PA)。
例4
采用例1的方法制备带有粘性贴面的经皮系统,所不同的是,使用硅氧烷基粘合剂,BIO PSA X7-2920(Dow Corning,Midland,MI)。所用释放衬垫为与所述硅氧烷粘合剂相容的Akrosil BioRe-lease衬垫(Menasha,WI)。
例5
采用例1的方法制备带有粘性贴面的经皮系统,所不同的是,所采用的粘合剂是一种(丙烯酸共聚物)粘合剂TSR Adhesive(SekisuiChemical Company,Osaka,Japan)。
例6
采用与例1相同的方法制备带有一个粘性贴面的经皮系统,所不同的是,剥离密封圆片膜是多层PET/LDPE/Foil/Primacor 3440/LLDPE/Heat Seal Film弹性包装材料,TPC-0812(Tolas HealthcarePackaging,Feasterville,PA)。
例7
采用与例1相同的方法制备带有一个粘性贴面的经皮系统,所不同的是,剥离密封圆片膜是Peelable Foil Film材料,一种PET/粘合剂/Foil/粘合剂/LLDPE/Heat Seal Film多层材料(Technipaq,Crystal Lake,IL)。
例8
采用与例1相同的方法制备带有一个粘性贴面的经皮系统,所不同的是,贴面材料是一种压纹聚亚胺酯弹性膜。
例9
采用与例1相同的方法制备带有一个粘性贴面的经皮系统,所不同的是,贴面材料是100%的无纺聚酯织物。
例10
采用与例1相同的方法制备带有一个粘性贴面的经皮系统,所不同的是,所述贴面材料是纺粘尼龙膜。
例11
采用与例1相同的方法制备带有一个粘性贴面的经皮系统,所不同的是,所述贴面材料是机织乙酸塔夫绸膜。
例12
将经商业渠道获得的由Calgon Vestal Laboratories出售的一种规格为4英寸×4英寸的伤口敷料,MitraflexPlus用作粘性贴面。
将60mg/ml ketorolac三羟甲基氨基甲烷溶于一种含有55.28/33.17/10.0/1.55%(v/v)异丙醇/水/甘油/豆蒄酸异丙酯中,制成凝胶化ketorolac三羟甲基氨基甲烷。用5.0%(w/v)NatrosolPlus330CS将所得溶液凝胶化,通过加入2N HCl将所得凝胶调至5.1±(0.2)。该凝胶中还含有0.1%(w/v)的丁酸化羟基甲苯作为抗氧化剂。
具有剥离密封圆片的贴面膜片是按以下方法制成的:将一片CoTran 9710微孔膜放置在一个LR4/25剥离密封圆片膜上,将3.44g ketorolac三羟甲基氨基甲烷配方分配到该微孔膜上。对背层膜进行预压,以形成一个平的圆形杯。将预压背层膜放置在凝胶上,以使背层膜上的压痕正对凝胶的凹部。然后在370°F下以30psi的压力和0.4秒的停留时间将背层膜与微孔膜/剥离密封膜层热密封在一起。将一个Oval热密封模用于制备活性表面为30cm2的含凝胶的储池。该热密封步骤能同时产生微孔膜与背层膜之间的永久性储池和微孔膜与剥离密封圆片膜之间的可剥离密封。然后,以42.55cm2的总表面积从热密封的叠层上冲切出该中间含药物的储池系统。
以下述方式将上述储池系统层压到MitraflexPlus贴面粘性层上:从伤口敷料上除去保护性释放衬垫;将冲切储池系统放置在粘合剂上,使背层膜接触粘合剂;和再次把释放衬垫层压到暴露的粘合剂上,以获得实际的贴面粘性经皮输送系统。在用于皮肤处理之前,分两步启动该系统:首先除去覆盖该粘合剂的释放衬垫,接着再除去保护储池的可剥离的圆片膜。
例13
采用例12的方法制备带有一个粘性贴面的经皮系统,所不同的是,所采用的贴面粘性层是按例1方法生产的。经皮输送系统的终表面积为63cm2。
例14
采用例13的方法制备带有一个粘性贴面的经皮系统,所不同的是,使用的粘合剂是医用级PIB粘合剂,MA-24(Adhesives Re-search,Glen Rock,PA)。
例15
采用例13所述方法制备带有一个粘性贴面的经皮系统,所不同的是,使用硅氧烷基粘合剂,BIO PSA X7-2920(Dow Corning,Mid-land,MI)。所使用的释放衬垫是Akrosil BioRelease衬垫(Menasha,WI),它与上述硅氧烷粘合剂是相容的。
例16
用例13所述方法制备带有一个粘性贴面的经皮系统,所不同的是,使用的粘合剂是丙烯酸共聚物粘合剂,TSR Adhesive(SekisuiChemical Company,OSaka,Japan)。
例17
用例13所述方法制备带有一个粘性贴面的经皮系统,所不同的是,剥离密封圆片膜是多层PET/LDPE/Foil/Primacor3440/LLDPE/Heat Seal膜弹性包装材料,TPC-0812(Tolas HealthcarePackaging,Feasterville,PA)。
例18
采用与例13相同的方法制备带有一个粘性贴面的经皮系统,所不同的是,剥离密封圆片膜是一种Peelable Foil Film,一种多层DET/粘合剂/Foil/粘合剂/LLDPE/Heat Seal Film(Technipaq,Crys-tal Lake,IL)。
例19
采用例13的方法制备带有一种粘性贴面的经皮系统,所不同的是贴面材料是一种压纹聚亚胺酯弹性膜。
例20
用例13所述方法制备带有一个粘性贴面的经皮系统,所不同的是,贴面材料是100%的无纺聚酯织物。
例21
用例13所述方法制备带有一个粘性贴面的中间药物-C的经皮系统,所不同的是,贴面材料是纺粘尼龙膜。
例22
用例13所述方法制备带有一个粘性贴面的经皮系统,所不同的是,贴面材料是机纺乙酸塔夫稠膜。
例23
按例12方法制备ketorolac三羟甲基氨基甲烷凝胶配方。评价凝胶的体外皮肤流通性能。
用改性的Franz扩散细胞进行体外人尸体皮肤流通研究,将该细胞放入校准的水浴中,将皮肤的表面温度维持在32℃。用Klig-man和Christopher(Arch,Dermatol.88,702-705,1963)的方法从完整厚度的人尸体表皮上分离上表膜。以60℃的温度对完整厚度的皮肤进行60秒的处理。从真皮上轻轻剥离角质层和上皮。将真皮膜放在0.65cm2的表面扩散细胞上,使表皮侧朝向容纳室并夹持定位。然后向容纳室中加注含有0.02%叠氮钠作为抑菌剂的水溶液。将细胞置于校准的循环水浴中,将皮肤的表面温度维持在32±1℃,并将皮肤水合过夜。次日晨,将75μl凝胶化ketorolac配方转移到通过将一个Teflon洗器放置在角质层表面所形成的腔中,通过将一个包埋背层膜夹持在Teflon洗器组件上对所述腔体进行包埋。在实验中,其中放有一根磁棒的容纳腔由放置在水浴下面的磁力搅拌器连续搅拌。在预定的时间段上收集容纳腔中的全部内容物,用表1的方法进行HPLC法药物定量分析。重新向容纳腔中填充新的受体介质,小心消除皮肤/溶液介面上的一切气泡。由浓度—时间曲线计算出第24小时时的平均稳态流通,间隔流通和每单位面积的累积输送。由片状活性面(30cm2)通过倍乘体外累积输送量(μg/cm2/24h)推算出体内输送量。
表I
体外表皮流通
HPLC法
将按例12方法制备的贴面贴在24个健康成年志愿者(12个男性,12个女性)的胸部。以预定的时间间隔收集血浆样品进行ketorolac定量分析。在每一研究中,在除去贴面之后,将使用过的贴面放在100ml甲醇中抽提,并用在表II中所述的HPLC方法分析药物含量。原始贴面药物含量及最终贴面药物含量之间的差值为释放出的ke-torolac,基于贴面耗竭分析结果。
柱 Partisphere C-18(100mm)流速 1.0ml/分波长 314nm注入体积 10μl保留时间 2.0±0.3分流动相 60/40/0.5(%v/v)乙腈/H2O/冰酯酸pH~3.0 |
表II
贴面含量分析
HPLC法
表III中比较了基于贴面耗竭分析的体内累积释放量与基于体外皮肤流通量结果的30cm2贴面的推算药物释放量。推算的药物释放量是由平均体外累积输送量(μg/cm2/24h)乘以贴面的作用面积(30cm2)而得出的。平均体内剂量是由起始贴面药物含量与残余贴面药物含量的差求出。在体内,30cm2贴面的释放量为(46.4±17.5)mg ke-torolac三羟甲基氨基甲烷/日,能很好地符合预测值53.7mg/日。图5表示,按照Wagner和Nelson的方法(J.Pham.Sci.610-611,1963)的方法计算出的平均体内累积输入动力学极符合体外累计输入动力学。
柱 Zorbax RX-C85μm,15cm×4.6mm流速 1.0ml/分波长 314nm注入体积 10μl保留时间 5.2±0.2分流动相 60/40/1(%v/v)乙腈/H2O/冰醋酸pH~3.0 |
表III
推测的和观察到的贴面系统的体内性能
贴面系统 | Ketorolac三羟甲基氨基甲烷的推测剂量(mg/天/) | Ketorolac三羟甲基氨基甲烷的体内剂量(mg/day) |
30cm2贴面 | 53.7 | 46.4±17.5(24个对象) |
例24
采用例1的方法制备带有一个粘性贴面的经皮系统,所不同的是,用于冲切该经皮输送系统的液体储池部分的模具使得剥离密封圆片垂片可及释放衬垫的边缘,如图2B所示。该延长的垂片使得成品系统仅需一个步骤即被启用,而不是像在例1中那样需两个步骤。在该一步法中,用一只手的拇指和食指抓住释放衬垫和剥离密封圆片的延长的垂片,用另一只手抓住背层膜。将剥离密封圆片和释放衬垫从背层膜上拉下来,以便启用该系统。
例25
用10mil隙的铸刀将医用级的压敏粘合剂MA-31(AdhesiveResearch,Glen Rock,PA)涂在高剥离强度、硅氧烷化的释放衬垫上。将粘性溶剂在80℃下蒸发15分钟,形成0.0015英寸的最终干燥粘合剂厚度。然后,将一种低强度加工用2mil高密度聚乙烯硅烷化衬垫层压到干燥粘合剂膜上,形成初级粘性层。将该初级粘性层和按例1方法制成的贴面粘性层用于下述生产方法的后期阶段中。
按例1方法制造中间含药物的储池,所不同的是,睾酮凝胶的重量为1.8g,活性表面为15cm2,总表面积为18.4cm2。以下述方式将储池系统层压到所述初级粘性层上:除去加工用衬垫,将中切储池放置在粘性材料中间,让剥离密封圆片膜接触粘性材料。将保护性衬垫从贴面粘性层上除去,将贴面粘合剂层压到初级粘性/储池系统上,使得贴面粘合剂与中间含药物的储池的背层膜接触,而且初级粘性层的粘合面延伸超过中间含药物的储池。从该叠层结构上冲切下成品贴面粘性经皮输送系统,使该系统的总表面积为33cm2。
该系统的启用是通过一个步骤进行的,即将高剥离强度衬垫从贴面粘合剂上撕拉下来。剥离密封圆片仍然连接在衬垫上,而暴露出储池部分。
例26
采用例25所述方法制备带有一个粘性贴面的经皮系统,所不同的是,用于初级粘性层和贴面粘性层的粘合剂是医用级聚异丁烯(PIB)粘合剂MA-24(Adhesives Research,Glen Rock,PA)。
例27
采用与例25相同的方法制备带有一个粘性贴面的经皮系统,所不同的是,用于初级粘性层和贴面粘性层的粘合剂是硅氧烷基粘合剂,BIO PSA X7-2920(Dow Corning,Midland,MI)。
对化学领域、经皮药物输送、药理学及相关领域技术人员来说,对上述方法加以改进以实现本发明是显而易见的事情,均落入由以下权利要求所限定的范围内。
Claims (12)
1、一种用于向个体的皮肤或粘膜施用活性剂的装置,包括一种层状复合体,其组成为:
(a)一个粘性贴面,有一个中央部分和一个周围部分;
(b)一个背层,位于所述粘性贴面中央部分的下面;
(c)一个可以透过活性剂的膜,位于背层下面,背层和膜形成
(d)位于二者之间的储池,储池中盛有一种活性剂配方;
(e)一个剥离密封圆片,位于可透过活性剂的膜的下面;
(f)一个位于所述剥离密封圆片、可透过活性剂的膜和背层周围的热密封;和
(g)一个活动释放衬垫,位于粘性贴面周围部分及剥离密封圆片下面。
2.如权利要求1的装置,其中所述粘合剂是由选自聚异丁烯、天然橡胶、丙烯酸酯、异丁烯酸酯和硅氧烷的材料制成。
3.如权利要求1的装置,其中所述背层包括至少一个不可透过的膜层。
4.如权利要求1的装置,其中所述膜选自微孔膜和致密膜。
5.如权利要求1的装置,其中所述剥离密封圆片由至少一层构成。
6.如权利要求1的装置,还包括一种透皮的吸收增强剂。
7.如权利要求1的装置,其中,所述配方还包括一种选自溶剂、胶凝剂、稳定剂和抗刺激剂的材料。
8.如权利要求1的装置,包括一个粘性层,它位于粘性贴面周围部分及剥离密封圆片的下面,并且覆盖释放衬垫。
9.如权利要求1的装置,其中所述粘性贴面是非闭合的,而背层是闭合的。
10.一种用于向个体的皮肤或粘膜施用活性剂的装置,包括一种层状覆合体,其组成为
(a)一个粘性贴面,有一个中央部分和一个周围部分;
(b)一个背层,位于所述粘性贴面中央部分的下面;
(c)一个可以透过活性剂的膜,由背层和膜形成
(d)位于二者之间的储池,储池中盛有一种活性剂配方;
(e)一个剥离密封圆片,位于可透过活性剂的膜的下面;
(f)一个位于所述剥离密封圆片、可透过活性剂的膜和背层周围的热密封;和
(g)一个活动释放衬垫,位于粘性贴面周围部分及剥离密封圆片的下面;和
(h)一个在所述剥离密封圆片上的垂片,用于辅助除去所述圆片。
11.如权利要求10的装置,包括一个粘性层,它位于所述粘性贴面周围部分和剥离密封圆片的下面,并且覆盖释放层。
12.如权利要求10的装置,其中所述粘性贴面是非闭合的,而背层是闭合的。
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ES8608895A1 (es) * | 1984-08-17 | 1986-07-16 | Allpack Ind Lohnverpackung | Parche adhesivo farmaceutico y procedimiento para su fabri- cacion |
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WO1993023019A1 (en) * | 1992-05-11 | 1993-11-25 | Sri International | Transdermal drug delivery systems and related compositions and methods of use |
-
1995
- 1995-12-08 EP EP95943869A patent/EP0799029A1/en not_active Withdrawn
- 1995-12-08 CN CN95196946A patent/CN1170360A/zh active Pending
- 1995-12-08 JP JP8519931A patent/JPH10511353A/ja not_active Withdrawn
- 1995-12-08 AU AU45233/96A patent/AU695170B2/en not_active Ceased
- 1995-12-08 CA CA002208132A patent/CA2208132A1/en not_active Abandoned
- 1995-12-08 WO PCT/US1995/016498 patent/WO1996019205A1/en not_active Application Discontinuation
- 1995-12-11 TW TW084113258A patent/TW438607B/zh not_active IP Right Cessation
- 1995-12-19 ZA ZA9510786A patent/ZA9510786B/xx unknown
-
1996
- 1996-04-26 US US08/638,440 patent/US5662925A/en not_active Expired - Lifetime
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107427473A (zh) * | 2015-03-13 | 2017-12-01 | 绿叶制药股份公司 | 具有包含两个黏合剂层的覆盖层的透皮治疗系统 |
CN107427473B (zh) * | 2015-03-13 | 2021-07-06 | 绿叶制药股份公司 | 具有包含两个黏合剂层的覆盖层的透皮治疗系统 |
CN106853271A (zh) * | 2015-12-08 | 2017-06-16 | 株式会社乐派司 | 微结构体的制造方法 |
CN106853271B (zh) * | 2015-12-08 | 2020-01-14 | 株式会社乐派司 | 微结构体的制造方法 |
CN112334100A (zh) * | 2018-06-22 | 2021-02-05 | 维塔尔康奈克特公司 | 粘合覆盖物 |
CN112334100B (zh) * | 2018-06-22 | 2023-06-09 | 维塔尔康奈克特公司 | 粘合覆盖物 |
Also Published As
Publication number | Publication date |
---|---|
CA2208132A1 (en) | 1996-06-27 |
US5662925A (en) | 1997-09-02 |
WO1996019205A1 (en) | 1996-06-27 |
ZA9510786B (en) | 1996-06-20 |
EP0799029A1 (en) | 1997-10-08 |
AU695170B2 (en) | 1998-08-06 |
AU4523396A (en) | 1996-07-10 |
JPH10511353A (ja) | 1998-11-04 |
MX9704291A (es) | 1997-09-30 |
TW438607B (en) | 2001-06-07 |
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