CN109985248B - 甲氨蝶呤经皮给药局部控释制剂及其制备方法和应用 - Google Patents
甲氨蝶呤经皮给药局部控释制剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了甲氨蝶呤经皮给药局部控释制剂及其制备方法和应用,该制剂为介孔二氧化硅负载甲氨蝶呤后,表面包裹一层聚多巴胺或聚甲基多巴。所采用的介孔二氧化硅生物相容性良好,比表面积大,载药量高,并通过聚多巴胺在碱性条件下聚合,将药物包裹在介孔二氧化硅内,酸性条件下降解释放甲氨蝶呤,达到药物可控释放的目的。该制剂在外表面包裹一层黑色的聚多巴胺也能确保甲氨蝶呤的光稳定性,在药剂保存和管理过程中更方便。同时研究发现,聚甲基多巴表现出具有与聚多巴胺相似的“门控”作用,智能递送药物。
Description
技术领域
本发明涉及药物控制释放领域,具体是一种甲氨蝶呤经皮给药局部控释制剂及其制备方法和应用,利用介孔二氧化硅负载甲氨蝶呤,聚多巴胺或甲基多巴包裹后,提高甲氨蝶呤光稳定性,实现甲氨蝶呤的可控释放。
背景技术
类风湿性关节炎(rheumatoid arthritis,RA)是一种以关节滑膜炎症为主、累及全身的自身免疫性疾病。甲氨蝶呤(MTX)作为目前治疗类风湿性关节炎的首选核心药物,可调节患者的异常免疫,显著减少软骨破坏和骨质侵蚀,控制骨病变加重,阻止或延缓关节破坏,减少残疾,在控制病程进展的治疗中具有重要地位。但由于长期大量服用药物可引起全身并发症,易导致股骨头坏死,高血压,体重增加等副作用,从而大大限制了其临床应用。关节腔内注射可使药物主要集中于受损关节部位,降低全身毒副作用,但需反复给药,患者适应性差。同时,甲氨蝶呤具有光不稳定性,因此需要在制备和保存过程中对其避光保存。减少甲氨蝶呤的摄入量并提高甲氨蝶呤制剂的稳定性,有利于降低药物的毒副作用,提高临床应用过程中的患者适应性。
发明内容
本发明要解决的问题是,甲氨蝶呤制剂因光照导致的含量下降及类似物生成,长期大量服用导致的患者不良反应,有效降低患者的用药剂量。
本发明利用多巴胺或甲基多巴在碱性条件下聚合形成聚多巴胺或聚甲基多巴包裹在介孔材料表面阻碍甲氨蝶呤的释放,提高甲氨蝶呤的光稳定性,降低甲氨蝶呤的毒副作用,提高患者适应性。当聚合物包裹的介孔材料到达偏酸性的骨关节炎症组织时,聚合物降解,甲氨蝶呤从介孔材料中释放出来,从而有效提高甲氨蝶呤在病变部位的药物浓度。
本发明解决其技术问题所采用的技术方案是:
甲氨蝶呤经皮给药局部控释制剂,该制剂为介孔二氧化硅负载甲氨蝶呤后,表面包裹一层聚多巴胺或聚甲基多巴。制剂的组成为孔径为7nm的mSiO2包封率和载药率分别为96.8%和48.4%,聚多巴胺与负载甲氨蝶呤的介孔二氧化硅的质量比为1:1-1:2.
制备方法是,将甲氨蝶呤和介孔二氧化硅分散于pH7.4的磷酸盐缓冲液中,使甲氨蝶呤吸附于介孔二氧化硅的孔道内,采用多巴胺或甲基多巴在pH8.5的缓冲溶液中在介孔二氧化硅表面聚合,制备得到光稳定性良好的甲氨蝶呤经皮局部给药控释制剂。
所采用的介孔二氧化硅生物相容性好,结构均一,载药量和负载率高。
聚合物在关节炎症组织或肿瘤组织偏酸性的环境附近降解释放甲氨蝶呤,达到控释的目的。该制剂具有提高甲氨蝶呤光稳定性与控制释放的双重作用。
进一步的详细的制备过程如下:
(1)将24mL十六烷基三甲基氯化铵(CTAC)、36mL水、0.18g三乙醇胺(TEA)依次加入到100mL烧瓶中,80℃恒温磁力搅拌1h;
(2)逐滴加入配制好的4mL正硅酸乙酯(TEOS)和1mL环乙烷混合液并在60℃慢速搅拌12h;
(3)反应完成后用0.6%的硝酸铵乙醇溶液在60℃水浴中洗涤三次,每次6h;
(4)反应完成后用无水乙醇除去硝酸铵,冻干,得到介孔二氧化硅(mSiO2);
(5)将5mg MTX在50ul二甲基亚砜(DMSO)中充分溶解,加入5mg mSiO2,加入1ml pH=7.4的PBS溶液中充分分散,室温条件下摇床震荡24h,离心去除上清,收集底部沉淀的MTX-mSiO2;
(6)将多巴胺或甲基多巴与MTX-mSiO2按照质量比为1:1-1:2分散在pH=8.5的PBS溶液中,避光搅拌1h-24h,离心,加10ml pH=8.5的PBS冲洗未聚合的部分,得到甲氨蝶呤经皮给药局部控释制剂。
甲氨蝶呤经皮给药局部控释制剂的应用,用于控制甲氨蝶呤智能释放。甲氨蝶呤在正常组织中不释放,到达关节炎症组织或肿瘤组织细胞偏酸性的微环境智能释放。
将甲氨蝶呤控释制剂置于不同pH值得缓冲该溶液中,在预设的时间点取样,通过定量分析溶液中甲氨蝶呤的浓度,结果表明该制剂具有较好的提高甲氨蝶呤稳定性的功能和控释功能。实验动物在体药效学研究表明该制剂有效的降低的甲氨蝶呤的用药剂量,具有良好的缓释性能。
本发明的有益效果是:制备了一种甲氨蝶呤控释制剂,同时较好的提高的甲氨蝶呤的光稳定性。该甲氨蝶呤经皮给药控释制剂是通过将甲氨蝶呤负载于介孔二氧化硅内,并在其表面包裹一层聚多巴胺,所采用的介孔二氧化硅生物相容性良好,比表面积大,载药量高,并通过聚多巴胺在碱性条件下聚合,将药物包裹在介孔二氧化硅内,酸性条件下降解释放甲氨蝶呤,达到药物可控释放的目的。该制剂在外表面包裹一层黑色的聚多巴胺也能确保甲氨蝶呤的光稳定性,在药剂保存和管理过程中更方便。同时研究发现,聚甲基多巴表现出具有与聚多巴胺相似的“门控”作用,智能递送药物。
附图说明
图1a为实施例所得的介孔二氧化硅透射电镜扫描成像图;
图1b为实施例所得的介孔二氧化硅动态光散射粒径分布图;
图1c为实施例所得的介孔二氧化硅氮气吸附解吸等温线曲线;
图1d为实施例所得的介孔二氧化硅孔径分布曲线;
图2为实施例所得的甲氨蝶呤标准曲线;
图3a为实施例不同pH值条件下甲氨蝶呤稳定性;
图3b为实施例不同光照时间条件下甲氨蝶呤稳定性;
图3c为实施例不同温度条件下甲氨蝶呤稳定性;
图4为实施例所得的MTX-mSiO2在pH=5.0、6.5、7.4的累积释放率;
图5a为实施例DA与MTX-mSiO2不同含量配比反应后DA的包覆效果,其中各个编号的试剂瓶中:①5mg MTX-mSiO2+5mg DA;②5mg MTX-mSiO2+10mg DA;③5mg MTX-mSiO2+5mgDA;④5mg MTX-mSiO2+10mg DA;
图5b为图5a中②的透射电镜扫描成像;
图6为DA聚合反应时间对MTX释放的影响;
图7为不同pH条件下甲氨蝶呤从MTX-mSiO2@PDA中释放情况的比较;
图8为甲氨蝶呤经皮透过药量-时间曲线;
图9为不同pH条件下MTX-mSiO2@PDA中甲氨蝶呤经皮透过药量-时间曲线;
图10a为空白对照组小鼠足趾肿胀程度;
图10b为模型组小鼠足趾肿胀程度;
图11为不同给药方式对小鼠足趾肿胀程度的影响;
图12a为正常小鼠足趾侧面X光片扫描图;
图12b为MTX-mSiO2@PDA给药组小鼠足趾侧面X光片扫描图;
图12c为PBS组小鼠足趾侧面X光片扫描图;
图12d为腹腔注射组小鼠足趾侧面X光片扫描图;
图12e为正常小鼠足趾正面X光片扫描图;
图12f为MTX-mSiO2@PDA给药组小鼠足趾正面X光片扫描图;
图12g为PBS组小鼠足趾正面X光片扫描图;
图12h为腹腔注射组小鼠足趾正面X光片扫描图。
具体实施方式
下面通过实施例对本发明作进一步说明,其目的在于更好的理解本发明的内容,应当理解,本发明的内容不应局限于实施例的范围,本发明的保护范围由所附权利要求书的范围确定。
实施例1介孔二氧化硅的制备
将24mL十六烷基三甲基氯化铵(CTAC)、36mL水、0.18g三乙醇胺(TEA)依次加入到100mL烧瓶中,80℃恒温磁力搅拌1h。逐滴加入配制好的4mL正硅酸乙酯(TEOS)和1mL环乙烷混合液并在60℃慢速搅拌12h。反应完成后用0.6%的硝酸铵乙醇溶液在60℃水浴中洗涤三次,每次6h。反应完成后用无水乙醇除去硝酸铵,冻干,得到介孔二氧化硅。介孔二氧化硅表征图如图1a和图1b、图1c、图1d。
实施例2.甲氨蝶呤含量测定方法
(1)色谱条件
采用岛津LC-6AD进行甲氨蝶呤含量检测,色谱柱:Thermo ODS-2 C18(150mm×4.6mm,5μm),流动相为乙腈:水=17:83(0.1%三氟乙酸),检测波长:302nm,流速:1ml/min,进样量20μl。色谱柱:SinoPak C18 5μm。柱尺寸:4.6mm*200mm。
(2)绘制标准曲线
用蒸馏水梯度稀释之前配好的110μg/ml的MTX标准溶液,分别制成2.2μg/ml,5.5μg/ml,11μg/ml,22μg/ml,55μg/ml和110μg/ml的溶液,每个浓度进样一次,每次进样量20μl。以峰面积为纵坐标,标准溶液浓度为横坐标,进行线性回归。
(3)样品处理方法
用高效液相色谱法测定不同浓度甲氨蝶呤,按照在HPLC上测得相应的浓度,作出甲氨蝶呤的标准曲线方程:y=66653x+123622,R2=0.9993,如图2,证明甲氨蝶呤在5.5-220μg/ml范围内线性关系良好。将各待测样品用0.22μm滤膜过滤后,高效液相色谱仪按(1)中色谱条件进样检测MTX含量。
实施例3.甲氨蝶呤稳定性研究
比较光照时间、不同pH值(5.5,7.4,8.5,9.0)、温度(25℃,40℃,80℃)对甲氨蝶呤稳定性的影响。
(1)光照稳定性:取6个小离心管,标记后用移液枪向其中加入(110μg/ml,pH7.4)甲氨蝶呤溶液各1ml,将避光组用锡箔纸完全包裹以达到避光条件。两组同时放置于日光下,并分别于6h、24h、48h、96h、144h取样。
(2)温度稳定性:取9个小离心管,标记后用移液枪向其中加入(110μg/ml,pH7.4)甲氨蝶呤溶液各1ml,分别避光保存于不同温度(25℃,40℃,80℃),并于6h、24h、48h、72h、96h取样。
(3)pH稳定性:取12个小离心管,标记后用移液枪向其中加入预先配制好的不同pH值(110μg/ml,pH=5.5,7.4,8.5,9.0)甲氨蝶呤溶液各1ml,放于室温避光条件下并分别于6h、24h、48h、72h、96h取样。
结果表明pH5.5-9.0范围内,甲氨蝶呤144h内可以保持较高的稳定性,如图3a。图3b表明pH7.4,室温条件下,日光照射48h,甲氨蝶呤具有较高的稳定性,96h开始甲氨蝶呤浓度明显下降,降为初始值的40%以下,且随着时间的延长稳定性呈逐渐下降的趋势,该结果表明在制备甲氨蝶呤制剂的过程中应注意避光操作。图3c考察了pH7.4,避光条件下不同温度对甲氨蝶呤稳定性的影响,从图中可以观察到,80℃时甲氨蝶呤可稳定存在48h,48h后甲氨蝶呤稳定性呈明显下降趋势,96h时下降为初始浓度的40%左右。
实施例4.MTX-mSiO2@PDA控释给药系统的构建及甲氨蝶呤释放实验
(1)甲氨蝶呤负载实验
将5mg MTX在50ul二甲基亚砜(DMSO)中充分溶解,加入5mg mSiO2,加入1ml pH=7.4的PBS溶液中充分分散,室温条件下摇床震荡24h,离心去除上清,收集底部沉淀的MTX-mSiO2,再次用PBS(pH=7.4)冲洗两次,洗去材料表面残留的MTX,并计算负载率和包封率。
首先对介孔二氧化硅负载甲氨蝶呤过程不同pH条件下的载药量和包封率进行考察,表1中可以看出在本实验条件下pH值对甲氨蝶呤的载药量和包封率影响没有显著性差异。
表1不同pH值介孔二氧化硅负载情况
比较不同pH条件下甲氨蝶呤从介孔二氧化硅中的释放情况发现,在释放实验的前2h,甲氨蝶呤在介孔二氧化硅中突释效果明显,2h后为缓慢释放,且随着pH值的增加,甲氨蝶呤的突释效应和累积释放率均呈增加趋势,如图4。推测该现象可能与MTX的理化性质有关,由于MTX分子中含有两个羧基,因此当释放液pH增大时,溶液中的H+含量越少,甲氨蝶呤与溶液中电荷斥力作用越弱,甲氨蝶呤更容易从介孔二氧化硅中释放出来,所以pH越高累积释放量越大,并重新与溶液呈现吸附平衡状态,不再释放。由于人体中正常细胞内外pH值为7.4,炎症细胞外为6.5,炎症细胞内为5.0,该结果说明在炎症细胞内部甲氨蝶呤可以起到更好的缓释效果。本研究通过多巴胺聚合包裹介孔二氧化硅,保证甲氨蝶呤在pH7.4的正常细胞组织中不释放或仅有少量释放。
(2)MTX-mSiO2@PDA控释给药系统的构建
将DA与MTX-mSiO2=1:1比例分散在pH=8.5的PBS溶液中,避光搅拌不同时间(1h,6h,24h)。离心,加10ml pH=8.5的PBS冲洗未聚合的DA,得到MTX-mSiO2@PDA。比较不同聚合时间对聚多巴胺形成的影响。
研究发现多巴胺(DA)与MTX-mSiO2含量配比不同导致DA聚合效果不同,本研究将DA与MTX-mSiO2按不同比例分散在pH8.5的Tris缓冲液中,避光搅拌1h。离心,加少量pH8.5的Tris缓冲液洗去未聚合的DA,得到MTX-mSiO2@PDA。图5a所示为反应后DA的包覆效果,从图中可以发现5mg MTX-mSiO2+10mg DA组包覆效果最好。透射电镜扫描成像显示多巴胺成功聚合成聚多巴胺(PDA),均匀的包覆在介孔二氧化硅表面,如图5b。由于多巴胺(DA)包覆厚度随聚合反应时间而增加,本研究通过改变多巴胺聚合反应时间,比较不同厚度聚多巴胺对甲氨蝶呤释放的影响,发现随着聚合反应时间延长,PDA厚度增加,甲氨蝶呤从介孔二氧化硅中释放过程“突释”效果明显改善,如图6,因此确定PDA包覆时间为24h。
(3)甲氨蝶呤释放实验
将MTX-mSiO2和MTX-mSiO2@PDA两组载药纳米颗粒分别进行释放实验,将纳米颗粒分散于1ml不同pH值的PBS释放溶液中(pH=5.0,6.5,7.4),常温摇床震荡,分别于0h、0.5h、2h、4h、8h、24h、48h离心,取200μl释放液,同时补充相同pH值空白释放液。释放结束后MTX-mSiO2组用DMSO溶解出48h内未释放的MTX,MTX-mSiO2@PDA组先加入50μl盐酸,将材料表面PDA充分溶解,后用DMSO溶解出48h内未释放的MTX。通过高效液相色谱法测定MTX含量,计算不同时间药物的释放率。公式如下:
对甲氨蝶呤在不同pH条件下从MTX-mSiO2@PDA给药系统中的释放情况进行研究。发现甲氨蝶呤从MTX-mSiO2@PDA给药系统中的累积释放速率随释放介质pH值得减小而显著增加,在pH5.5时甲氨蝶呤48h累积释放速率约为pH7.4时的2倍,如图7。该结果说明聚多巴胺在酸性条件下降解较快,该给药系统可以有效避免在经皮输送过程中甲氨蝶呤从介孔二氧化硅中的“突释”,同时在关节炎症组织的可控释放。
实施例4.体外透皮实验
(1)实验动物
SD大鼠,体重200±20g,由中国人民解放军军事科学院提供,实验期间将其饲养在标准的鼠笼里,正常供应水和食物。
(2)体外透皮实验
处死大鼠后,剥离大鼠腹部皮肤用于体外透皮实验。将皮肤固定于改良Franz立式透皮扩散池,对甲氨蝶呤经皮动力学参数进行测定,供给液为甲氨蝶呤饱和溶液,接收液为含20%乙醇的水溶液或供给液侧为MTX-mSiO2@PDA,接收液侧为不同pH值的磷酸盐缓冲液。分别于不同时间(1h、3h、6h、9h、12h)取样0.3ml,同时补充相同体积的空白接收介质。取样结束后将样品置于-20℃冰箱内保存待测。
甲氨蝶呤体外经皮渗透实验可以看出角质层显示出了较强的屏障作用,剥离角质层后,甲氨蝶呤在去角质层皮肤中的时间延迟明显下降,药物在0.9h即可达到稳态,同时全皮、去角质层皮肤、角质层的扩散系数分别为8.29×10-8cm2/s、3.06×10-7cm2/s、4.62×10- 8cm2/s,扩散系数较大,说明甲氨蝶呤较易透过皮肤。甲氨蝶呤在去角质皮肤24h累积透过量约为全皮累积透过量的5倍,进一步说明角质层对甲氨蝶呤的经皮渗透的主要屏障,如图8。
表2甲氨蝶呤经皮渗透动力学参数
因此设计pH敏感甲氨蝶呤控释给药系统(MTX-mSiO2@PDA),可有效减少药物在角质层中的驻留,合理有效控制药物在关节组织的释放,减少患者在用药过程中的不良反应。比较不同pH条件下,MTX-mSiO2@PDA中甲氨蝶呤经皮透过药量-时间曲线。从图9可以看出,随着pH值得下降,甲氨蝶呤从MTX-mSiO2@PDA释放量显著增加,说明PDA具有明显的pH敏感性,pH值下降,介孔二氧化硅表面的PDA降解,甲氨蝶呤从介孔材料中快速释放。MTX-mSiO2@PDA具有较好的控制甲氨蝶呤释放的作用。
实施例5.在体药效学研究
(1)建立DBA/1小鼠胶原诱发类风湿性关节炎(CIA)模型
所有小鼠随机分为两组:正常组(n=6)、模型组(n=18),适应性喂养24h。将牛ΙΙ型胶原(CΙΙ)与弗氏完全佐剂(CFA)等体积混合乳化制成CΙΙ胶原乳剂。无菌条件下以每只0.1mg的剂量在小鼠尾根部皮注射,首次免疫当日记为1d。在21d,将CΙΙ与弗氏不完全佐剂(IFA)等体积混合乳化,再次注射于小鼠尾根部皮下,剂量同前。对照组在1d及21d分别注射等体积完全及不完全佐剂[21]。监测关节炎发生率。发现小鼠首次免疫28d开始发病,35d后发病率达91.7%,足趾肿胀厚度为初始值的122%,图10a和图10b所示空白对照组(正常组)与模型组小鼠足趾肿胀程度差异,模型组小鼠足趾肿胀程度与对照组相比差异极为显著(P<0.01)。
(2)在体药效学评价
对构建的甲氨蝶呤控释给药系统MTX-mSiO2@PDA与甲氨蝶呤腹腔注射组进行药效学结果比较。将10mg MTX-SiO2@PDA溶于5ml的PBS(pH=7.4)溶液中制成MTX-SiO2@PDA悬浊液。超声5min后取其中0.05ml悬浊液与0.2ml凝胶中制备成卡波姆混合药液,每只小鼠在病患处涂抹50μl上述含药凝胶。另一组腹腔注射MTX(35μg/g)。空白组用0.05ml含PBS(pH=7.4)的卡波姆凝胶涂抹小鼠病患处。每周进行两次实验并监测小鼠脚掌厚度,试验持续4周。对构建的甲氨蝶呤控释给药系统MTX-mSiO2@PDA与甲氨蝶呤腹腔注射组进行药效学结果比较。通过不同给药方式对小鼠组织肿胀程度的影响发现,MTX-mSiO2@PDA组与MTX腹腔注射给药组均可以减轻小鼠足趾肿胀程度,与空白对照组相比具有显著性差异。MTX-mSiO2@PDA与腹腔注射组相比起效较慢,腹腔注射组第3天起足趾肿胀程度即开始减轻,MTX-mSiO2@PDA组则从给药第六天起足趾肿胀程度开始减轻,如图11。27天后MTX-mSiO2@PDA与腹腔注射组小鼠足趾厚度降低为初始值的70%,基本恢复到正常水平。但与MTX腹腔注射组相比,MTX-mSiO2@PDA组实验偏差较小,分析可能是MTX-mSiO2@PDA较MTX腹腔注射给药血药浓度波动较小所致。
最后一次实验每组取一只处死后小鼠足趾进行X光片扫描对足趾关节部位进行病理学指标评价。采用Skyscan1174型Micro CT的Scaner软件对各样本进行扫描。电压50kV,电流800μA,以12μm扫描分辨率、1304×1024视野大小进行扫描。以足跟骨底端为基线,向足趾方向取5.0mm*5.0mm*6.0mm的区域为三维重建兴趣区域(ROI),用N-Recon软件进行三维图像重建,用CT-AN软件进行三维分析。
图12a-图12h为各个实验小鼠足趾X光片扫描图。正常小鼠足趾部(图12a和图12e)骨表面光滑,表面积较小(127.28mm2),建模后小鼠足趾部骨表面呈现粗糙结构,严重的呈现骨关节明显变形(图12c和图12g)其中PBS组小鼠足趾部骨表面积最大(218.87mm2),MTX-mSiO2@PDA组和MTX腹腔注射组小鼠足趾部骨表面积分别为182.77mm2和176.38mm2,与PBS组相比较好的控制了病情的发展。
Claims (4)
1.甲氨蝶呤经皮给药局部控释制剂,其特征在于,该制剂为介孔二氧化硅负载甲氨蝶呤后,表面包裹一层聚多巴胺或聚甲基多巴。
2.甲氨蝶呤经皮给药局部控释制剂的制备方法,包括以下步骤:
将甲氨蝶呤和介孔二氧化硅分散于pH 7.4的磷酸盐缓冲液中,使甲氨蝶呤吸附于介孔二氧化硅的孔道内,采用多巴胺或甲基多巴在pH8.5的缓冲溶液中在介孔二氧化硅表面聚合,制备得到甲氨蝶呤经皮局部给药控释制剂。
3.根据权利要求2所述的甲氨蝶呤经皮给药局部控释制剂的制备方法,原料按照以下比例配置,包括以下步骤:
(1)将24 mL十六烷基三甲基氯化铵(CTAC)、36 mL水、0.18 g三乙醇胺(TEA)依次加入到100 mL烧瓶中, 80℃ 恒温磁力搅拌1 h;
(2)逐滴加入配制好的4 mL正硅酸乙酯(TEOS)和1 mL环乙烷混合液并在60℃ 慢速搅拌12 h;
(3)反应完成后用0.6 %的硝酸铵乙醇溶液在60℃ 水浴中洗涤三次,每次6 h;
(4)反应完成后用无水乙醇除去硝酸铵,冻干,得到介孔二氧化硅(mSiO2);
(5)将5 mg MTX在50 ul 二甲基亚砜(DMSO)中充分溶解,加入5 mg mSiO2,加入1ml pH=7.4的PBS溶液中充分分散,室温条件下摇床震荡24 h,离心去除上清,收集底部沉淀的MTX- mSiO2;
(6)将多巴胺或甲基多巴与 MTX - mSiO2按照质量比为1:1-1:2分散在pH=8.5的PBS溶液中,避光搅拌1 h-24 h,离心,加10ml pH=8.5的PBS冲洗未聚合的部分,得到甲氨蝶呤经皮给药局部控释制剂。
4.根据权利要求1所述的甲氨蝶呤经皮给药局部控释制剂的应用,其特征在于,用于制备控制甲氨蝶呤智能释放的药物。
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