环孢素A皮肤给药系统的设计与评价
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摘要
本文以增加难溶性的环状大分子环孢素A的皮肤吸收为主体思路，分别制备了微乳和微乳凝胶给药系统，综合运用物理促渗和化学促渗手段研究离体皮肤滞留与透过和大鼠在体药动学和组织分布的研究，对该药经皮渗透的体内外动力学行为及皮肤吸收机理进行了深入的研究和探讨。
研究结果证实，CysA的水溶解度为4.7μg/ml、熔点144℃、油水分配系数log P=3.0：CysA溶液的稳定性不受pH、离子、超声的影响，对热、光不稳定；CysA遇尼泊金乙脂发生降解，但对苯扎溴胺稳定。与对照组相比10％薄荷油、0.05％SLS和40％乙醇载药能够显著提高CysA在去角质层皮肤的滞留；促渗剂能减少CysA透过角质层进入表皮和真皮的时滞。
以微乳作为CysA皮肤给药的载体，分别以IPM为油相，AOT和Tween85分别为表面活性剂和助表面活性剂，双蒸水为水相，制备空白微乳。利用伪三元相图确定微乳形成的区域。利用粘度、电导、密度、折射率及表面张力等理化性质表征微乳结构，结果证明水含量在20％至30％时形成的微乳为双连续型。这一结果得到二维扩散排序谱获取的自扩散系数和低温DSC曲线中水信息的证实。实验证明，双连续型微乳载药大鼠皮肤各层滞留量和经皮渗透量大于O/W型和W/O型微乳，是皮肤外用制剂更具优势的载体。
微乳凝胶由于具有良好的亲油性和附着性，是外用亲脂性药物极具潜力的载体。将双连续微乳和明胶在相图指定的胶凝区域制备有机微乳凝胶(MBG)。
深入研究了决定MBG性质的动态粘弹性质，如屈服应力、弹性模量和损耗模量以及MBG组成对上述性质的影响规律，揭示了MBG的结构以及结构与性能间的关系，为确定具有适宜强度、粘弹性及附着力的MBG提供依据。另外还用“通道理论”从分子层面研究了MBG的导电性，证明MBG中存在油、水两个通道，指出了两个通道在药物传送过程中的重要作用。载药MBG研究表明，CysA在表皮和真皮中药物滞留量与载药量不呈线性关系，密闭条件下给药可以提高去角质层皮肤中CysA的含量，NMP有明显的促渗作用。
研究了物理促渗技术如电致孔和低频超声对CysA体外经皮渗透和皮肤滞留的影响。结果表明，强度0.8W/cm~2、超声30min药物的皮肤吸收最佳，CysA在表皮和真皮中的滞留是对照组的7倍；低频超声与Azone或SLS联用，可将CysA在皮肤中的滞留提高到25倍，显示两种促渗方法的协同效应。电致孔脉冲电压、脉冲时间和脉冲模式对药物皮肤吸收有影响，结果显示，大鼠表皮和真皮中CysA的滞留量随致孔电压的升高略有增加，随致孔时间的增加而增加。CysA是一个不电离的环状大分子，电场力对其经皮转运没有影响，这是致孔电压对大鼠去角质层中CysA滞留影响不大的原因。化学促渗剂与电致孔法联用对药物皮肤吸收有增强作用。但将电致孔、低频超声和化学促渗剂联合使用，未能取得更好的促渗效果。
以大鼠为模型动物，以HPLC方法为检测手段，进行了CysA皮肤给药系统的体内药动学及组织分布的研究。微乳和微乳凝胶经皮给药与市售CysA微乳(新山地明)灌胃相比，皮肤中药物的含量提高，而血液、肝、肾组织中药物的浓度低，表明双连续微乳及微乳凝胶皮肤给药具有良好的皮肤靶向性，这对于提高疗效、减小全身毒副作用具有十分重要意义。
皮肤刺激性实验表明连续使用微乳、低频超声及联合使用促渗剂，皮肤组织与对照组相比没有发生明显改变，提示这些用药方式是安全的；而微乳凝胶连续使用后，出现轻微的炎症浸润，其用药的安全性有待进一步研究。
Improving the dermal permeability of poorly water-soluble Cyclosporin A (CysA) was considered as main focus of this paper. The microemulsion and microemulsion based organogel (MBG) system were prepared, respectively. Combing the physical enhancing method and in vivo pharmacokinetic experiment of rat synthetically, the in vitro/in vivo derml permeation kinetic behavior of CysA and the relevant mechanism were deeply studied.
During the preformulation study, the drug solubility, oil/water partition coefficient and melting point were determined. The stability of CysA solution at various situations was investigated. It was showed that various pH, buffer solution and salt did not effect the stability of the drug, however, the addition of ethylparaben led to the highly degradation of CysA. At the same time, plastic could absorb the drug seriously. Besides, the solution of CysA was not stable under heat and light. Fortunately, the process of ultrasound did not affect the stability of the drug. CysA vehicle containing 40% ethanol showed significantly enhanced deposition of CysA into the stratum cornerm (SC) and deeper skin, as compared to other vehicles. Moreover, chemical enhancers shortened the lag time of the penetration of CysA into deeper skin. The present study suggests that the suspension of 40%ethanol containing 0.5% drug can more effectively enhance the topical delivery of CysA after skin pretreatment with 10%menthol or 0.05%SLS.
A novel microemulsion was prepared to increase the solubility and the in vitro dermal delivery of CysA. For the microemulsions, isopropyl myristate(IPM) was chosen as oil phase, Aersol-OT(AOT) as surfactants (S), Tween 85 as cosurfactant(CoS) and the double-distilled water as water phase. Pseudo-ternary phase diagrams were constructed to obtain the concentration range of each component for the microemulsion formation. The effects of structure and the concentration of surfactant and the loading of the drug on the topical delivery and permeation rate of CysA through rat skin were investigated.
Microemulsion type and structure were examined by measuring surface tension, density, viscometry, refractive index, electric conductivity, and the degree of agreement between the techniques was assessed. Results of conducting, viscosity, and surface tension measurement confirmed the transition to a bicontinuous structure. The increased transdermal delivery was found to be due mainly to water concentration and appeared to be dependent on the structure of the microemulsions.
Self-diffusion coefficients were determined by DOSY in order to investigate the influence of microemulsion structure with the equal drug concentration on their dermal delivery. The correlation between dermal permeation and structural characteristics of CysA microemulsion was investigated.
Basing on the optimized formulation, the different enhancers with different concentration were investigated and 3% Labrifil M1944 cs won the first. The content, viscosity, refractive index, conductivity of optimized microemlusion were studied and the results proved that test microemulsion was stable enough after storing more than 6 months at 40℃.
Gelatin-stabilised microemulsion-based organogels (MBG) was very useful for hydrophobic drugs because of their lipophilic nature in transdermal and topical delivery. MBG was rather different from that observed in aqueous gelatin solutions. The gelatin of the microemulsion did not take place however at all concentrations of gelatin and /or water. It was showed that different w_0, gelatin content and surfactant concentration might effect the formation of gels at MBG
The rheological properties such as the yield stresses, storage and loss moduli of the MBG samples increased and the network structures of the MBG became more compact with increasing the concentration of gelatin in the formulations. The conductivity of MBGs remained almost as high as the gelatin-free microemulsion. This suggested that the topology of MBGs was unaffected by the presence of even large amounts of gelatin. In other words, the behavior of the conductivity in all samples with gelatin belonged to the same universality class as that encountered in gelatine-free microemulsions. We can conclude that there are two kinds of channels in these systems, one kind is the channels of aqueous phase formed by AOT/gelatin/H_2O, the other kind is the channels of oil phase. The release characteristics of drug from MBG were studied according to drug concentration. As the concentration of drug increased, the release of drug from gel increased, showing concentration dependency. Percutaneous penetration studies using rat skin in vitro showed that the deposition of Cyclosporin A was significantly improved by MBG compared to the control. The MBG was stable in 20%ethanol containing CysA, whereas not stable under water, saline and ethanol.
Except the abovementioned methods, the physical enhancing method, such as electroporation and phonophoresis, were applied to improve the dermal permeation of CysA. Studies of intensity and exposure time acting on the deposition of CysA into deeper skin of in vitro sonophoresis were performed. Low-frequency ultrasound increased the amount of CysA retained in the skin only 7 times than the passive diffusion when the program was set at 0.8W/cm~2, 30min. Furthermore, we also tested the synergistic effect of ultrasound and other approaches such as chemical enhancers and electroporation on topical drug delivery of Cyclosporin A. We found that the efficacy of low-frequency ultrasound in enhancing topical delivery could be further increased by pretreatment of skin with chemical enhancers, such as laurocapram (Azone) and sodium lauryl sulfate (SLS). Electroporation increased the amount of Cyclosporin A retained in the skin only 3 times than the passive diffusion. Furthermore, we also tested the synergistic effect of electroporation and other approaches such as chemical enhancers and low-frequency ultrasound on topical drug delivery of Cyclosporin A. We found that the efficacy of electroporation in enhancing topical delivery can be further increased by pretreatment of skin with chemical enhancers, such as Azone and menthol. Meanwhile only a small amount was seen to across the full skin into the receiver compartment. Trimodality treatment comprising of pretreatment with Azone + ultrasound in combination followed by electroporation was not effective in enhancing the topical delivery of Cyclosporin A. The histopathological result did not reveal any lesions after application of low-frequency ultrasound or combination with ultrasound and enhancers. The stratum corneum and viable epidermis were of normal appearance.
Finally, we evaluated the therapeutic advantage of dermal administration of CysA in rat model. Local (subcutaneous and skin), systemic concentrations and organ distribution (liver and kidney) were evaluated serially following topical and oral application of the drug. In rat dermal applied with the microemulsion or MBG containing CysA, the deposition of the drug into skin and subcutaneous fat was much higher than the concentrations compared with oral administration. Systemic distribution in blood, liver and kidney was much lower following topical than following oral administration. With high local concentrations and minimal distribution to other organs via the circulation, topical applied microemulsion or MBG loaded with Cyclosporin A might deliver maximal therapeutic effect to local tissue while avoiding the side effects seen with systemic therapy. The histopathological findings revealed that the new microemulsion and MBG vehicle was a safe vehicle for topical drug delivery systems.
研究结果证实，CysA的水溶解度为4.7μg/ml、熔点144℃、油水分配系数log P=3.0：CysA溶液的稳定性不受pH、离子、超声的影响，对热、光不稳定；CysA遇尼泊金乙脂发生降解，但对苯扎溴胺稳定。与对照组相比10％薄荷油、0.05％SLS和40％乙醇载药能够显著提高CysA在去角质层皮肤的滞留；促渗剂能减少CysA透过角质层进入表皮和真皮的时滞。
以微乳作为CysA皮肤给药的载体，分别以IPM为油相，AOT和Tween85分别为表面活性剂和助表面活性剂，双蒸水为水相，制备空白微乳。利用伪三元相图确定微乳形成的区域。利用粘度、电导、密度、折射率及表面张力等理化性质表征微乳结构，结果证明水含量在20％至30％时形成的微乳为双连续型。这一结果得到二维扩散排序谱获取的自扩散系数和低温DSC曲线中水信息的证实。实验证明，双连续型微乳载药大鼠皮肤各层滞留量和经皮渗透量大于O/W型和W/O型微乳，是皮肤外用制剂更具优势的载体。
微乳凝胶由于具有良好的亲油性和附着性，是外用亲脂性药物极具潜力的载体。将双连续微乳和明胶在相图指定的胶凝区域制备有机微乳凝胶(MBG)。
深入研究了决定MBG性质的动态粘弹性质，如屈服应力、弹性模量和损耗模量以及MBG组成对上述性质的影响规律，揭示了MBG的结构以及结构与性能间的关系，为确定具有适宜强度、粘弹性及附着力的MBG提供依据。另外还用“通道理论”从分子层面研究了MBG的导电性，证明MBG中存在油、水两个通道，指出了两个通道在药物传送过程中的重要作用。载药MBG研究表明，CysA在表皮和真皮中药物滞留量与载药量不呈线性关系，密闭条件下给药可以提高去角质层皮肤中CysA的含量，NMP有明显的促渗作用。
研究了物理促渗技术如电致孔和低频超声对CysA体外经皮渗透和皮肤滞留的影响。结果表明，强度0.8W/cm~2、超声30min药物的皮肤吸收最佳，CysA在表皮和真皮中的滞留是对照组的7倍；低频超声与Azone或SLS联用，可将CysA在皮肤中的滞留提高到25倍，显示两种促渗方法的协同效应。电致孔脉冲电压、脉冲时间和脉冲模式对药物皮肤吸收有影响，结果显示，大鼠表皮和真皮中CysA的滞留量随致孔电压的升高略有增加，随致孔时间的增加而增加。CysA是一个不电离的环状大分子，电场力对其经皮转运没有影响，这是致孔电压对大鼠去角质层中CysA滞留影响不大的原因。化学促渗剂与电致孔法联用对药物皮肤吸收有增强作用。但将电致孔、低频超声和化学促渗剂联合使用，未能取得更好的促渗效果。
以大鼠为模型动物，以HPLC方法为检测手段，进行了CysA皮肤给药系统的体内药动学及组织分布的研究。微乳和微乳凝胶经皮给药与市售CysA微乳(新山地明)灌胃相比，皮肤中药物的含量提高，而血液、肝、肾组织中药物的浓度低，表明双连续微乳及微乳凝胶皮肤给药具有良好的皮肤靶向性，这对于提高疗效、减小全身毒副作用具有十分重要意义。
皮肤刺激性实验表明连续使用微乳、低频超声及联合使用促渗剂，皮肤组织与对照组相比没有发生明显改变，提示这些用药方式是安全的；而微乳凝胶连续使用后，出现轻微的炎症浸润，其用药的安全性有待进一步研究。
Improving the dermal permeability of poorly water-soluble Cyclosporin A (CysA) was considered as main focus of this paper. The microemulsion and microemulsion based organogel (MBG) system were prepared, respectively. Combing the physical enhancing method and in vivo pharmacokinetic experiment of rat synthetically, the in vitro/in vivo derml permeation kinetic behavior of CysA and the relevant mechanism were deeply studied.
During the preformulation study, the drug solubility, oil/water partition coefficient and melting point were determined. The stability of CysA solution at various situations was investigated. It was showed that various pH, buffer solution and salt did not effect the stability of the drug, however, the addition of ethylparaben led to the highly degradation of CysA. At the same time, plastic could absorb the drug seriously. Besides, the solution of CysA was not stable under heat and light. Fortunately, the process of ultrasound did not affect the stability of the drug. CysA vehicle containing 40% ethanol showed significantly enhanced deposition of CysA into the stratum cornerm (SC) and deeper skin, as compared to other vehicles. Moreover, chemical enhancers shortened the lag time of the penetration of CysA into deeper skin. The present study suggests that the suspension of 40%ethanol containing 0.5% drug can more effectively enhance the topical delivery of CysA after skin pretreatment with 10%menthol or 0.05%SLS.
A novel microemulsion was prepared to increase the solubility and the in vitro dermal delivery of CysA. For the microemulsions, isopropyl myristate(IPM) was chosen as oil phase, Aersol-OT(AOT) as surfactants (S), Tween 85 as cosurfactant(CoS) and the double-distilled water as water phase. Pseudo-ternary phase diagrams were constructed to obtain the concentration range of each component for the microemulsion formation. The effects of structure and the concentration of surfactant and the loading of the drug on the topical delivery and permeation rate of CysA through rat skin were investigated.
Microemulsion type and structure were examined by measuring surface tension, density, viscometry, refractive index, electric conductivity, and the degree of agreement between the techniques was assessed. Results of conducting, viscosity, and surface tension measurement confirmed the transition to a bicontinuous structure. The increased transdermal delivery was found to be due mainly to water concentration and appeared to be dependent on the structure of the microemulsions.
Self-diffusion coefficients were determined by DOSY in order to investigate the influence of microemulsion structure with the equal drug concentration on their dermal delivery. The correlation between dermal permeation and structural characteristics of CysA microemulsion was investigated.
Basing on the optimized formulation, the different enhancers with different concentration were investigated and 3% Labrifil M1944 cs won the first. The content, viscosity, refractive index, conductivity of optimized microemlusion were studied and the results proved that test microemulsion was stable enough after storing more than 6 months at 40℃.
Gelatin-stabilised microemulsion-based organogels (MBG) was very useful for hydrophobic drugs because of their lipophilic nature in transdermal and topical delivery. MBG was rather different from that observed in aqueous gelatin solutions. The gelatin of the microemulsion did not take place however at all concentrations of gelatin and /or water. It was showed that different w_0, gelatin content and surfactant concentration might effect the formation of gels at MBG
The rheological properties such as the yield stresses, storage and loss moduli of the MBG samples increased and the network structures of the MBG became more compact with increasing the concentration of gelatin in the formulations. The conductivity of MBGs remained almost as high as the gelatin-free microemulsion. This suggested that the topology of MBGs was unaffected by the presence of even large amounts of gelatin. In other words, the behavior of the conductivity in all samples with gelatin belonged to the same universality class as that encountered in gelatine-free microemulsions. We can conclude that there are two kinds of channels in these systems, one kind is the channels of aqueous phase formed by AOT/gelatin/H_2O, the other kind is the channels of oil phase. The release characteristics of drug from MBG were studied according to drug concentration. As the concentration of drug increased, the release of drug from gel increased, showing concentration dependency. Percutaneous penetration studies using rat skin in vitro showed that the deposition of Cyclosporin A was significantly improved by MBG compared to the control. The MBG was stable in 20%ethanol containing CysA, whereas not stable under water, saline and ethanol.
Except the abovementioned methods, the physical enhancing method, such as electroporation and phonophoresis, were applied to improve the dermal permeation of CysA. Studies of intensity and exposure time acting on the deposition of CysA into deeper skin of in vitro sonophoresis were performed. Low-frequency ultrasound increased the amount of CysA retained in the skin only 7 times than the passive diffusion when the program was set at 0.8W/cm~2, 30min. Furthermore, we also tested the synergistic effect of ultrasound and other approaches such as chemical enhancers and electroporation on topical drug delivery of Cyclosporin A. We found that the efficacy of low-frequency ultrasound in enhancing topical delivery could be further increased by pretreatment of skin with chemical enhancers, such as laurocapram (Azone) and sodium lauryl sulfate (SLS). Electroporation increased the amount of Cyclosporin A retained in the skin only 3 times than the passive diffusion. Furthermore, we also tested the synergistic effect of electroporation and other approaches such as chemical enhancers and low-frequency ultrasound on topical drug delivery of Cyclosporin A. We found that the efficacy of electroporation in enhancing topical delivery can be further increased by pretreatment of skin with chemical enhancers, such as Azone and menthol. Meanwhile only a small amount was seen to across the full skin into the receiver compartment. Trimodality treatment comprising of pretreatment with Azone + ultrasound in combination followed by electroporation was not effective in enhancing the topical delivery of Cyclosporin A. The histopathological result did not reveal any lesions after application of low-frequency ultrasound or combination with ultrasound and enhancers. The stratum corneum and viable epidermis were of normal appearance.
Finally, we evaluated the therapeutic advantage of dermal administration of CysA in rat model. Local (subcutaneous and skin), systemic concentrations and organ distribution (liver and kidney) were evaluated serially following topical and oral application of the drug. In rat dermal applied with the microemulsion or MBG containing CysA, the deposition of the drug into skin and subcutaneous fat was much higher than the concentrations compared with oral administration. Systemic distribution in blood, liver and kidney was much lower following topical than following oral administration. With high local concentrations and minimal distribution to other organs via the circulation, topical applied microemulsion or MBG loaded with Cyclosporin A might deliver maximal therapeutic effect to local tissue while avoiding the side effects seen with systemic therapy. The histopathological findings revealed that the new microemulsion and MBG vehicle was a safe vehicle for topical drug delivery systems.
引文
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