Transdermal Drug Delivery System Of Martrine And It Different Parts Pharmacokinetics In Rats

Matrine is the major active pharmaceutical ingredient from the dried roots of traditional Chinese herb named Sphora flavescents Ait（Kushen） or Spohora alopecuroides（Kudouzi）, which have been extensively used in China for the treatment of chronic hepatitis and liver fibrosis, et al. Commonly used formulations are injections or oral capsules. Injection administration is inconvenience and has local pain, while oral administration has obvious gastrointestinal reaction. Matrine have suitable characteristics for transdermal delivery systems. In this study, firstly screening matrine patch prescription in vitro, then using microdialysis sampling technique to study pharmacokinetics in rat liver, blood, skin and plasma after transdermal administration, and compared with iv administration.The results of formulation screening showed that oily azone and peppermint oil has good penetration effect, and propandiol has no obvious penetration effect to matrine. The optimal formulation of matrine patch contained 6 mg·cm-2 drug, 12 % azone, 16 % peppermint oil. The accumulative permeation amount of the optimal formulation was（5698.583±387.94） μg·cm-2 in 12 h. The permeation rate of matrinewas（470.41±16.79） μg·cm-2·h-1.Matrine analysis was performed on a Diamonsil C18 column（4.6 mm × 150 mm, 5 μm）, with a mobile phase consisting acetonitrile-0.1% phosphoric acid（adjusted to p H 7.6-7.7 with triethylamine）（35:65 in microdialysate and 30:70 in plasma）, a flow rate of 1.0 ml·min-1, a detection wavelength of 220 nm, a column temperature at 35 ℃, and an injection volume of 20 μL. The result showed good linear correlation over the range of 0.10 25.00 μg · m L-1 in microdialysate and 0.32 81.80 μg · m L-1 in plasma（r=1, n=5）, respectively. The intra- and inter-day precision over these ranges were not more than 6.95% in microdialysate and 10.75 % in plasma, respectively. The average accuracy was in the range of 94.7 105.9 % in microdialysate and 98.6¹07.9 % in plasma, respectively. The method is accurate, simple, sensitive and specific for determination of matrine in rat microdialysate and plasma.The results of probe recovery of matrine showed that the recovery was independent of the drug concentration（Matrine: 2.5, 5.0, 10.0 μg·m L-1） and inversely proportional to perfusion velocity（1.0, 2.0, 3.0 μL·min-1）. At the same flow velocity, the recovery measured by in vitro positive dialysis was basically consistent with that measured by retrodialysis. The positive dialysis recoveries of concentric cannula probe and linear probe were（ 41.57±0.92） % ^76.91±1.38 % and（ 44.69±1.24） % ^82.11±3.13 % in vitro,while were（ 12.26±0.32） % ^39.22±1.86 % and（ 6.39±0.66） % ^18.72±1.79 % in vivo. For the pharmacokinetics of matrine the in vitro positive dialysis was able to achieve a more accurate result in a more convenient way, therefore, its recovery could be applied to the pharmacokinetic studies.The pharmacokinetic results of matrine iv administration showed that the AUC and Cmax of matrine with a trend as follows: plasma>blood microdialysis>liver microdialysis. The reason is that drug permeate into blood firstly and then entered into liver, and the drug concentration obtained from blood microdialysis is free drug concentration while the plasma concentration is composed with free and protein-bound drug concentration. At low（10 mg·kg-1）, medium（20 mg·kg-1） and high dosages（40 mg·kg-1）, the Cmax of blood and plasma was increased with the dosage. The Cmax of liver at low dosage dosage was no significant difference to that of medium, while there was a multiple relationship between the C max of liver at medium dosage and that of high dosage, and the every AUC of medium-and high-dosage increased multiply as well.In regard to the pharmacokinetics of matrine transdermal administration, the AUC of matrine showed a trend as follows: subcutaneous microdialysis> plasma > blood microdialysis> liver microdialysis, and the AUC in blood microdialysate were about 50% compared with those in plasma, which suggested that free matrine concentration was about 50% of total plasma concentration. Compared with the iv administration pharmacokinetics of matrine（40 mg·kg-1）, low dosage patch group showed the AUC of patch was twice as large as that of iv injection, and similar Cmax and 3 times MRT（0-t）, which implied that low dose group can achieve the effect of iv administration and maintain a long time and slow controlled release. The drug concentration in vivo has a multiple relationship of administration area basically. The higher concentration in subcutaneous tissue suggested that skin t have drug storage effect.The result showed that the optimal formulation of matrine patch had good transdermal penetration. The matrine patch can release drug stably and maintain the drug concentration at a certain level. The study provided a basis for the development of new formulations.