壳聚糖修饰盐酸利多卡因柔性脂质体研究
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摘要
目的：透皮给药系统(Transdermal drug delivery system,TDDS)可使药物以一定的速率通过皮肤,经毛细血管吸收进入体循环而产生全身或局部治疗作用,具有可产生持久、恒定和可控的血药浓度,避免肝脏的首过效应和胃肠道因素的干扰与降解作用,提高药物的生物利用度。透皮给药系统用于局部麻醉具有操作简单、无痛、无损伤、减少患者对疼痛恐惧感等优点,尤其适用于一些不宜采用局部浸润麻醉和需要长时间镇痛的情况,具有广阔的临床应用前景。
盐酸利多卡因(Lidocaine hydrochloride, LID)为酰胺类局部麻醉药,作用较强,具有起效快,黏膜穿透、扩散性强、作用时间长等特点,是一种较理想的局部麻醉剂。目前,国内盐酸利多卡因主要的应用剂型是注射剂和胶浆剂,但盐酸利多卡因的注射剂及胶浆剂均不能满足皮肤局部麻醉的临床应用要求,注射剂应用不便且浸润麻醉给患者带来疼痛和心理恐惧,而胶浆剂则仅适用于粘膜局部麻醉。
本课题旨在以盐酸利多卡因为模型药物,以壳聚糖修饰传递体/类脂质体为载体,研究一种无痛、无损伤、给药方便易行,能够渗透完整皮肤达到真皮层的浅表镇痛剂,其功效在于能够实现无针管理,在较短时间及可发生应用效应,且能长时间保持药物效果,对浅表皮肤各种小手术起到镇痛的作用的新型透皮给药制剂,为临床应用提供实验数据及理论基础。
方法：以盐酸利多卡因为模型药物,卵磷脂和表面活性剂为膜材,制备盐酸利多卡因传递体,以粒径、Zeta电位、包封率为指标,单因素分析考察表面活性剂类型及含量、药物含量、壳聚糖含量对壳聚糖修饰传递体粒径和包封率的影响,采用正交分析优化处方,确定最佳处方组成。
以盐酸利多卡因为模型药物,非离子表面活性剂表面活性剂为膜材,添加适量乙醇改良处方,制备盐酸利多卡因类脂质体,以粒径、Zeta电位、包封率为指标,单因素分析考察非离子表面活性剂类型、药物含量、壳聚糖含量和胆固醇含量对壳聚糖修饰类脂质体粒径和包封率的影响,采用正交分析优化处方,确定最佳处方组成。
采用透射电镜、粒度分析仪对壳聚糖修饰的传递体/类脂质体进行表征,研究了传递体/类脂质体经壳聚糖修饰后脂质膜变形性,并评价了室温和4℃储存条件下,壳聚糖修饰传递体/类脂质体稳定性。
采用改良的Franz扩散池,以透析膜和离体鼠皮为皮肤模型,建立了壳聚糖修饰传递体/类脂质体体外透皮实验方法,考察传递体/类脂质体经壳聚糖修饰后,体外释药及透皮速率变化。以SD大鼠为在体透皮实验模型,考察了壳聚糖修饰传递体/类脂质体在体透皮应用效果,并建立福尔马林致痛模型,验证壳聚糖修饰传递体/类脂质体实际镇痛效果。将壳聚糖修饰传递体/类脂质体作用于新西兰大白兔去毛皮肤表面,考察其对新西兰大白兔的皮肤急性毒性和皮肤刺激性,评价壳聚糖修饰传递体/类脂质体透皮给药制剂安全性。
结果：壳聚糖修饰传递体单因素分析结果表明,传递体处方成分中加入表面活性剂,对粒径无显著影响,Zeta电位降低；当表面活性剂为15%(w/w)时,SDC与卵磷脂作为膜质材料制备的LID传递体包封率最高。传递体经壳聚糖修饰后,粒径增大,zeta电位由负值转变为正值,药物含量固定时,传递体包封率随壳聚糖含量的增加而减小。正交分析优化处方,结果表明,壳聚糖含量为0.3%(w/v),Tween60含量为15%(w/w),脂质和药物比为3：1,磷脂与胆固醇比为1：1时壳聚糖修饰传递体处方最优。
壳聚糖修饰类脂质体单因素分析结果表明,类脂质体处方成分中加入适量乙醇,粒径变小,包封率增大。Span20、Span60、Tween20、 Tween60四种非离子表面活性剂制备的类脂质体包封率分别为49.7%、65.2%、51.5%和78.9%,Twee60作为膜材制备的类脂质体包封率最高。增加胆固醇含量,类脂质体包封率增加,当脂质与胆固醇质量比为1：1,得到的类脂质体包封率达到最高,继续增加胆固醇含量,包封率反而降低。类脂质体经壳聚糖修饰后,粒径增大,Zeta电位由负值转变为正值,药物含量固定时,类脂质体包封率随壳聚糖含量的增加而减小。正交分析优化处方,结果表明,壳聚糖含量为0.3%(w/v),LID含量为0.5mg/ml,脂质和药物比为3：1,乙醇含量为20%时壳聚糖修饰类脂质体处方最优。
透射电镜结果表明,传递体/类脂质体经壳聚糖修饰后,在脂质体外面形成一层保护层,两种壳聚糖修饰脂质体均为完整圆球形或椭圆球形。壳聚糖修饰的传递体/类脂质体变形性有所降低,稳定性增强,在4。C储存条件下,脂质体粒径、包封率无显著变化,性质稳定。
体外释放实验表明,壳聚糖修饰传递体/类脂质体释药分为突释和缓释两部分,与传递体/类脂质体相比,显著减慢药物释放,达到缓释作用：体内、外透皮实验结果表明,壳聚糖修饰传递体/类脂质体能显著提高药物透皮速率,增加药物皮肤滞留量。
建立福尔马林致痛模型,当福尔马林浓度为0.025%时,对大鼠致痛效果好,为合适的致痛浓度,壳聚糖修饰传递体/类脂质能显著减少大鼠舔掌、缩腿时间,与生理盐水对照组相比差异显著,结果表明,壳聚糖修饰传递体/类脂质体具有良好的镇痛效果。壳聚糖修饰传递体/类脂质体对皮肤无急性毒性和皮肤刺激性,使用安全。
结论：本研究成功制备了壳聚糖修饰传递体/类脂质,两种壳聚糖修饰柔性脂质体安全、无毒,能够渗透完整皮肤达到真皮层,具有良好的镇痛作用,能够在较短时间发生效应,且能长时间缓慢释放药物,延长镇痛时间。本课题研制的壳聚糖修饰传递体/类脂质体为透皮给药系统提供了一种新剂型,具有很高的临床实用价值。
Objective:Transdermal drug delivery systems (TDDS) has made important contributions to medical practices and has several advantages including eliminating first-pass hepatic metabolism, providing release of drug for sustained time, avoiding painful and improving patient compliance. TDDS have so many advantage such as easy to operation, painless, no damage, no pain and reduce the phobia of patients used for local anesthesia, especially suitable to some local anesthesia unfavorable for local infiltrating anesthesia and some local anesthesia which need a long analgesia time. TDDS as drug carrier local anesthesia has wide prospect of clinical application.
Local anesthetic agents (LID) as analgesic with strong fast effect-acting and mucous membrane penetration, can eliminate pain in a circumscribed area of the body and minimize patients'phobia. It is a kind of ideal local anesthetic. However, the main pharmaceutics of LID is injection and gel in clinic, injection is inconvenience and can bring pain and psychological fear to patients, and gel only used for mucous membrane, both of them are all can not meet the requirement of local anesthetic for skin.
In this research, LID as model drug, we used CH modified transfersome and noisome, In order to avail a new a new pharmaceutics for skin small surgery application which painless, no damage, convenient, reduce pain and psychological fear to patients, we used CH to modify transfersome and niosome. These new pharmaceutics we obtained can penetrate skin and reach the dermis superficial in a short time and can delay release the drug. As painkillers for small surgery, the data of CH coated transfersome (CCT) and CH coated noisome (CCN) can provide a basis theoretical for clinic.
Method:In this study, an effective transdermal delivery system for local anaesthetic was developed with lidocaine hydrochloride (LI D) as model drug. Transfersome composed of soya lecithin with sur factant as edge activator, was prepared by rotary evaporation sonicat ion method. We studied the influence of surfactant, drug and CH to the size, Zeta potential and encapsulation efficiency of CCT and d etermined the prescription composition.
LID as model drug, niosome composed of non-ionic surfactant was prepared by rotary evaporation sonication method. We studied the influence of non-ionic surfactant, drug, cholesterol and CH to the size, Zeta potential and encapsulation efficiency of CCT and determined the prescription composition.
The morphology, vesicles size, polydispersity index (PI) and zeta potential of CCT and CCN were analyzed by TEM and dynamic light scattering (DLS). The deformation and stability at the room temperature and4℃of CCT and CCN also be studied.
In vitro release and In vitro permeation study of LID from different vesicular formulations were determined using a Franz diffusion cells with cellulose membrane and the skin of the rats. The flux and drug deposition of CCT and CCN were studied. The painkiller effect of CCT and CCN were studied by formalin pain model and the security of CCT and CCN were test on rabbits.
Result:The factor analysis results show that add the surface the Zeta potential reduce and it is no effect to the vesicles size. When the content of SDC surface was15%(w/w), we get the highest EE%. Chitosan (CH)(0.1-0.5%, w/v) coated transfersome by electrostatic attraction of negative transfersome and positive CH. CH coating changed the transfersome surface charge and increased the vesicle size. EE% decreased with the increase of CH content. Results show that the CH content is0.3%(w/v), SDC content is15%(w/w), the ratio of lipid and drugs is3:1, phospholipids and cholesterol ratio is1:1are the best prescription of CCT.
The factor analysis results show that ethanol can reduce the noisome size and increase the EE%. The encapsulation rate of noisome which prepared with Span20, Span60, Tween20and Tween60were49.7%,65.2%,51.5%and78.9%. The EE%of niosome increasing with the content of cholesterol, the highest EE%was on the ratio of lipid and cholesterol at1:1. Chitosan (CH)(0.1-0.5%, w/v) coated niosome by electrostatic attraction of negative transfersome and positive CH. CH coating changed the niosome surface charge and increased the vesicle size. EE%decreased with the increase of CH content. Results show that the CH content is0.3%(w/v), LID content is0.5mg/ml, the ratio of lipid and drugs is3:1, ethanol content is20%are the best prescription of CCN.
The morphology, vesicles size, polydispersity index (PI) and zeta potential were analyzed by TEM and dynamic light scattering (DLS). Results show that CCT and CCN are all homogenous spherical in shape and there is a shell after coated by CH. After coated, the deformation of transfersome and noisome reduce. CH coated elastic vesicles demonstrated an improved physicochemical stability at4℃in a3month storage period. CCT and CCN displayed a prolonged drug release profile in vitro release study. The in vitro permeation study showed that CCT and CCN were able to give a statistically significant improvement of skin permeation of LID in comparison with elastic vesicle (transfersome and niosome) and CH solution. CCT and CCN significantly reduced pain compared with elastic vesicles (transfersome and niosome) and CH solution.
Conclusion The research had successfully prepared CCT and CCN which have excellent painkiller effective. These pharmaceutics safe, non-toxic, can penetrate the skin reach the dermis. CCT and CCN might be a potential TDDS for local anaesthetic.
盐酸利多卡因(Lidocaine hydrochloride, LID)为酰胺类局部麻醉药,作用较强,具有起效快,黏膜穿透、扩散性强、作用时间长等特点,是一种较理想的局部麻醉剂。目前,国内盐酸利多卡因主要的应用剂型是注射剂和胶浆剂,但盐酸利多卡因的注射剂及胶浆剂均不能满足皮肤局部麻醉的临床应用要求,注射剂应用不便且浸润麻醉给患者带来疼痛和心理恐惧,而胶浆剂则仅适用于粘膜局部麻醉。
本课题旨在以盐酸利多卡因为模型药物,以壳聚糖修饰传递体/类脂质体为载体,研究一种无痛、无损伤、给药方便易行,能够渗透完整皮肤达到真皮层的浅表镇痛剂,其功效在于能够实现无针管理,在较短时间及可发生应用效应,且能长时间保持药物效果,对浅表皮肤各种小手术起到镇痛的作用的新型透皮给药制剂,为临床应用提供实验数据及理论基础。
方法：以盐酸利多卡因为模型药物,卵磷脂和表面活性剂为膜材,制备盐酸利多卡因传递体,以粒径、Zeta电位、包封率为指标,单因素分析考察表面活性剂类型及含量、药物含量、壳聚糖含量对壳聚糖修饰传递体粒径和包封率的影响,采用正交分析优化处方,确定最佳处方组成。
以盐酸利多卡因为模型药物,非离子表面活性剂表面活性剂为膜材,添加适量乙醇改良处方,制备盐酸利多卡因类脂质体,以粒径、Zeta电位、包封率为指标,单因素分析考察非离子表面活性剂类型、药物含量、壳聚糖含量和胆固醇含量对壳聚糖修饰类脂质体粒径和包封率的影响,采用正交分析优化处方,确定最佳处方组成。
采用透射电镜、粒度分析仪对壳聚糖修饰的传递体/类脂质体进行表征,研究了传递体/类脂质体经壳聚糖修饰后脂质膜变形性,并评价了室温和4℃储存条件下,壳聚糖修饰传递体/类脂质体稳定性。
采用改良的Franz扩散池,以透析膜和离体鼠皮为皮肤模型,建立了壳聚糖修饰传递体/类脂质体体外透皮实验方法,考察传递体/类脂质体经壳聚糖修饰后,体外释药及透皮速率变化。以SD大鼠为在体透皮实验模型,考察了壳聚糖修饰传递体/类脂质体在体透皮应用效果,并建立福尔马林致痛模型,验证壳聚糖修饰传递体/类脂质体实际镇痛效果。将壳聚糖修饰传递体/类脂质体作用于新西兰大白兔去毛皮肤表面,考察其对新西兰大白兔的皮肤急性毒性和皮肤刺激性,评价壳聚糖修饰传递体/类脂质体透皮给药制剂安全性。
结果：壳聚糖修饰传递体单因素分析结果表明,传递体处方成分中加入表面活性剂,对粒径无显著影响,Zeta电位降低；当表面活性剂为15%(w/w)时,SDC与卵磷脂作为膜质材料制备的LID传递体包封率最高。传递体经壳聚糖修饰后,粒径增大,zeta电位由负值转变为正值,药物含量固定时,传递体包封率随壳聚糖含量的增加而减小。正交分析优化处方,结果表明,壳聚糖含量为0.3%(w/v),Tween60含量为15%(w/w),脂质和药物比为3：1,磷脂与胆固醇比为1：1时壳聚糖修饰传递体处方最优。
壳聚糖修饰类脂质体单因素分析结果表明,类脂质体处方成分中加入适量乙醇,粒径变小,包封率增大。Span20、Span60、Tween20、 Tween60四种非离子表面活性剂制备的类脂质体包封率分别为49.7%、65.2%、51.5%和78.9%,Twee60作为膜材制备的类脂质体包封率最高。增加胆固醇含量,类脂质体包封率增加,当脂质与胆固醇质量比为1：1,得到的类脂质体包封率达到最高,继续增加胆固醇含量,包封率反而降低。类脂质体经壳聚糖修饰后,粒径增大,Zeta电位由负值转变为正值,药物含量固定时,类脂质体包封率随壳聚糖含量的增加而减小。正交分析优化处方,结果表明,壳聚糖含量为0.3%(w/v),LID含量为0.5mg/ml,脂质和药物比为3：1,乙醇含量为20%时壳聚糖修饰类脂质体处方最优。
透射电镜结果表明,传递体/类脂质体经壳聚糖修饰后,在脂质体外面形成一层保护层,两种壳聚糖修饰脂质体均为完整圆球形或椭圆球形。壳聚糖修饰的传递体/类脂质体变形性有所降低,稳定性增强,在4。C储存条件下,脂质体粒径、包封率无显著变化,性质稳定。
体外释放实验表明,壳聚糖修饰传递体/类脂质体释药分为突释和缓释两部分,与传递体/类脂质体相比,显著减慢药物释放,达到缓释作用：体内、外透皮实验结果表明,壳聚糖修饰传递体/类脂质体能显著提高药物透皮速率,增加药物皮肤滞留量。
建立福尔马林致痛模型,当福尔马林浓度为0.025%时,对大鼠致痛效果好,为合适的致痛浓度,壳聚糖修饰传递体/类脂质能显著减少大鼠舔掌、缩腿时间,与生理盐水对照组相比差异显著,结果表明,壳聚糖修饰传递体/类脂质体具有良好的镇痛效果。壳聚糖修饰传递体/类脂质体对皮肤无急性毒性和皮肤刺激性,使用安全。
结论：本研究成功制备了壳聚糖修饰传递体/类脂质,两种壳聚糖修饰柔性脂质体安全、无毒,能够渗透完整皮肤达到真皮层,具有良好的镇痛作用,能够在较短时间发生效应,且能长时间缓慢释放药物,延长镇痛时间。本课题研制的壳聚糖修饰传递体/类脂质体为透皮给药系统提供了一种新剂型,具有很高的临床实用价值。
Objective:Transdermal drug delivery systems (TDDS) has made important contributions to medical practices and has several advantages including eliminating first-pass hepatic metabolism, providing release of drug for sustained time, avoiding painful and improving patient compliance. TDDS have so many advantage such as easy to operation, painless, no damage, no pain and reduce the phobia of patients used for local anesthesia, especially suitable to some local anesthesia unfavorable for local infiltrating anesthesia and some local anesthesia which need a long analgesia time. TDDS as drug carrier local anesthesia has wide prospect of clinical application.
Local anesthetic agents (LID) as analgesic with strong fast effect-acting and mucous membrane penetration, can eliminate pain in a circumscribed area of the body and minimize patients'phobia. It is a kind of ideal local anesthetic. However, the main pharmaceutics of LID is injection and gel in clinic, injection is inconvenience and can bring pain and psychological fear to patients, and gel only used for mucous membrane, both of them are all can not meet the requirement of local anesthetic for skin.
In this research, LID as model drug, we used CH modified transfersome and noisome, In order to avail a new a new pharmaceutics for skin small surgery application which painless, no damage, convenient, reduce pain and psychological fear to patients, we used CH to modify transfersome and niosome. These new pharmaceutics we obtained can penetrate skin and reach the dermis superficial in a short time and can delay release the drug. As painkillers for small surgery, the data of CH coated transfersome (CCT) and CH coated noisome (CCN) can provide a basis theoretical for clinic.
Method:In this study, an effective transdermal delivery system for local anaesthetic was developed with lidocaine hydrochloride (LI D) as model drug. Transfersome composed of soya lecithin with sur factant as edge activator, was prepared by rotary evaporation sonicat ion method. We studied the influence of surfactant, drug and CH to the size, Zeta potential and encapsulation efficiency of CCT and d etermined the prescription composition.
LID as model drug, niosome composed of non-ionic surfactant was prepared by rotary evaporation sonication method. We studied the influence of non-ionic surfactant, drug, cholesterol and CH to the size, Zeta potential and encapsulation efficiency of CCT and determined the prescription composition.
The morphology, vesicles size, polydispersity index (PI) and zeta potential of CCT and CCN were analyzed by TEM and dynamic light scattering (DLS). The deformation and stability at the room temperature and4℃of CCT and CCN also be studied.
In vitro release and In vitro permeation study of LID from different vesicular formulations were determined using a Franz diffusion cells with cellulose membrane and the skin of the rats. The flux and drug deposition of CCT and CCN were studied. The painkiller effect of CCT and CCN were studied by formalin pain model and the security of CCT and CCN were test on rabbits.
Result:The factor analysis results show that add the surface the Zeta potential reduce and it is no effect to the vesicles size. When the content of SDC surface was15%(w/w), we get the highest EE%. Chitosan (CH)(0.1-0.5%, w/v) coated transfersome by electrostatic attraction of negative transfersome and positive CH. CH coating changed the transfersome surface charge and increased the vesicle size. EE% decreased with the increase of CH content. Results show that the CH content is0.3%(w/v), SDC content is15%(w/w), the ratio of lipid and drugs is3:1, phospholipids and cholesterol ratio is1:1are the best prescription of CCT.
The factor analysis results show that ethanol can reduce the noisome size and increase the EE%. The encapsulation rate of noisome which prepared with Span20, Span60, Tween20and Tween60were49.7%,65.2%,51.5%and78.9%. The EE%of niosome increasing with the content of cholesterol, the highest EE%was on the ratio of lipid and cholesterol at1:1. Chitosan (CH)(0.1-0.5%, w/v) coated niosome by electrostatic attraction of negative transfersome and positive CH. CH coating changed the niosome surface charge and increased the vesicle size. EE%decreased with the increase of CH content. Results show that the CH content is0.3%(w/v), LID content is0.5mg/ml, the ratio of lipid and drugs is3:1, ethanol content is20%are the best prescription of CCN.
The morphology, vesicles size, polydispersity index (PI) and zeta potential were analyzed by TEM and dynamic light scattering (DLS). Results show that CCT and CCN are all homogenous spherical in shape and there is a shell after coated by CH. After coated, the deformation of transfersome and noisome reduce. CH coated elastic vesicles demonstrated an improved physicochemical stability at4℃in a3month storage period. CCT and CCN displayed a prolonged drug release profile in vitro release study. The in vitro permeation study showed that CCT and CCN were able to give a statistically significant improvement of skin permeation of LID in comparison with elastic vesicle (transfersome and niosome) and CH solution. CCT and CCN significantly reduced pain compared with elastic vesicles (transfersome and niosome) and CH solution.
Conclusion The research had successfully prepared CCT and CCN which have excellent painkiller effective. These pharmaceutics safe, non-toxic, can penetrate the skin reach the dermis. CCT and CCN might be a potential TDDS for local anaesthetic.
引文
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