| lObjectiveSinomenine and tripterygium wilfordii polyglycosidium treatment therapeutic effect on rheumatoid arthritis(RA)significantly,currently listed mainly tablets(such as sinomenine hydrochloride sustained release tablets,tripterygium polyglycosidium tablet etc.),in order to convenient administration,improve patient compliance and reduce the toxic side effects,this paper intends to combined the extract of tripterygium wilfordii polyglycosidium(TWPE)and sinomenine made into topical gel,in order to through compatibility and change the route of administration efficiency attenuated.On the one hand,sinomenine and tripterygium glycosides has the same pharmacological effects and treatment of RA are similar effects,compatibility can reduce both dosage,reduce toxicity,and synergistic effect;on the other hand,local percutaneous to route of administration,only a small amount of drugs through the skin absorption into the blood circulation,to avoid systemic adverse reaction caused by oral medication.Therefore,the development of shuangteng gel is explored,which lays the foundation for the treatment of RA safe and effective topical preparation.2Methods and Results2.1 Sinomenine,TWPE proportion determinedSinomenine and TWPE was made gel for transdermal administration,through anti-inflammatory and analgesic test,screening of sinomenine and TWPE optimum ratio is 1:1,and the results show that the combination of sinomenine and TWPE compared to single drug has synergistic effect in analgesic effect and in the aspect of anti-inflammation,only with sinomenine alone has significant differences,and TWPE difference is not obvious.2.2 Studies on the pre-formulationThe main active constituents of sinomenine and triptolide were determined the solubility and oil/water partition coefficient.The results show that the sinomenine hydrophilic is relatively large,the solubility decreased with increasing pH of medium;triptolide is a lipid soluble drug,the pH of the medium had no significant effect on the solubility of triptolide.The oil/water partition coefficient of sinomenine was 0.16(logP=-0.80),which increases with increasing pH value is raised;the oil/water partition coefficient of triptolide was 2.68(logP=0.43),the distribution coefficient pH of the solution less affected.2.3 Shuangteng gel forming process researchThe appearance,viscosity,stability,drug percutaneous penetration etc.as index and the gel matrix,pH adjusting agent,drug loading,moisturizing agents were investigated.Using the orthogonal experiment design of penetration enhancers were screened and further optimized prescription.The results showed that the best penetration enhancers was 5%azone;the optimal prescription of shuangteng gel was 1%Cp940,15%glycerol,10%ethanol,2%drugs,5%azone,0.1%ethylparaben,0.1%sodium bisulfite,1%triethanolamine,amount of water.2.4 Quality evaluation of shuangteng gelWe checked on the appearance of shuangteng gel and detennined the pH value of shuangteng gel,the methods of HPLC was established for the determination of preparation.Shuangteng gel prepared yellow opaque semisolid,uniform fine,consistency is appropriate,easy to spread;viscosity between 2000-2500mpa·s;pH value was about 7.2;content of sinomenine was 6.62±0.30mg/g,the content of triptolide was 42.43±2.29?g/g,total two terpenc lactone content of 158.20±4.23?g/g.The factors affecting the test indicated that the shuangteng gel placed in low temperature and dark environment.Franz diffusion cell was used,rat abdominal skin as permeation barrier,the shuangteng gel,ointment and gel paste in vitro percutaneous penneability test were studied.Results of the shuangteng gel transdermal drug rate is far greater than the ointment and gel paste,with significant difference(P<0.01).Franz diffusion cell was used,with a semipenneable membrane for the barrier,shuangteng gel and suspension of release test in vitro were studied.The results showed that the release rule of sinomenine and triptolide in the gel with the zero order release kinetics model was the best fitting effect;the release rate of shuangteng suspension of drug is far greater than shuangteng gel,indicating the formation of a sink condition,dialysis membrane does not limit the release of drug,this method can be used to evaluate shuagnteng gel in vitro release rule.In vitro transdermal of shuangteng gel correlation with the in vitro release studies found that in vitro release rate of the drug greater than the rate of in vitro percutaneous,which shows skin is a rate limiting barrier shuangteng gel,the gel belongs to the skin-controlled transdermal drug delivery systems.2.5 Shuangteng gel in rats skin pharmacokinetics studyFor the linear probe in vivo recovery were studied,the results show that,with the increase of perfusion flow,probe in vivo recovery decreased;effects of probe in vivo recovery was not affected by drug concentration.And probe in vivo recovery stability were investigated,the results of the probe within 14h in vivo recovery was good stability.Using the microdialysis technique to study the drug concentration process of dynamic change in rat abdominal skin after giving shuangteng gel,and the relative cumulative Q uptake of the time for the linear regression of t,the results showed that the sinomenine and triptolide of shuangteng gel Q-t showed a good linear relationship(R>0.99),indicating that shuangteng gel in vivo transdermal process in accordance with the Fick diffusion law,belongs to the zero order process.Non compartmental model fitting to the skin drug concentration and time using PKSolver 2.0 software.The results of sinomenine,triptolide half-life were 60.545,221.514 min respectively;the peak concentrations were 178.73,2.05?g/mL respectively;the peak time were 580,420min respectively.Suggest that triptolide and sinomenine on the skin has reached peak concentration,that play the efficacy component is different in different time periods,triptolide first reached the peak concentration,produce effect,and keep the concentration for a period of time in the skin,then with sinomenine together play effect,synergistic effect.3ConclusionsIn this paper,shuangteng gel made good spread and easy washing.The prescription and the preparation process is reasonable and feasible,stable,placed in the cold dark environment.Shuangteng gel percutaneous absorption is better than the ointment and gel paste.Provides preparation choose new developed for treatment of RA. |
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