Design And Evaluation Of Cyclosporin A Dermal Delivery System

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 w₀, gelatin content and surfactant concentration might effect the formation of gels at MBGThe 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/H₂O, 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/cm², 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.