The Preparation Of A Transdermal Delivery System Based On THCA354 Gels And Its Pharmacokinetics Characters

Dermatitis-eczema skin disease is a common type of clinical delayed-type allergic disease.The incidence of the disease was significantly rising in recent years.The main drugs for the treatment of the disease make severe adverse reactions and undesirable side effects.Therefore a new drug which is well effect on dermatitis and less side effect is badly needed on clinical.In early drug screening study of our team,By drawing from the structural characteristics and physiological activity of polyphenols cinnamic acid and polyphenol diphenylethylene,and through analyzing the structure-activity relationship,we screened the best one by anti-inflammatory pharmacodynamics experiment,to synthesized a new type of polyphenols acrylic acid derivatives which is(E)-phenenthyl-3-(3,5-dihydroxy-4-isopropyl phenyl)acrylate(THCA354).So the objective of this paper is to predicte the percutaneous penetration performance of the drug through investigated the main physico-chemical properties of THCA354;and screened out optimal formulation of THCA354 gels through orthogonal and pharmacodynamics experiments,then study the pharmacodynamics of the gels;and explore the pharmacokinetic of THCA354 gels by microdialysis technology and HPLC-MS analysis method,explore the gels concentration-effect relationship in vivo and in vitro of animals in order to developing a novel NSAIDs topical preparations for curing dermatitis-eczema.Method:1.According to ChP2015,we study the main physico-chemical parameters of THCA354,such as the appearance,melting point,oil-water partition coefficient and solubility,and investigate the relationship between the p H and solubility,In order to predict whether THCA354 can be made into transdermal drug delivery preparation.2.With the results of THCA354’s preformulation study and L9(34)orthogonal experiments,we screened the optimal formulation by evaluating the anti-inflammatory effect of nine groups of THCA354 gels induced by 12-O-tetradecano ylphorbol-13-acetate(TPA),arachidonic acid and evaluating the anti-allergic effect of THCA354 gels induced by DNFB.and developed THCA354 creams on this basis.3.Evaluated the anti-inflammatory effect of THCA354 gels and creams on 12-O-tetradecanoylphorbol-13-acetate(TPA)and arachidonic acid induced ear edema in mice in vivo,and we study the anti-itching effect of THCA354 gels and creams on scratching behavior induced by Compound 48/80,In order to evaluate the influence of THCA354 on anti-allergic,a mouse model of allegic contact dermatitis by DNFB was used.And at the same time we study concentration-response relationship.4.Investigated the influence factors of microdialysis recovery rate in vitro and determine the recovery rate in vitro and in vivo,and es Tablelished method of microdialysis and HPLC-MS detection technology.Then we study the pharmacokinetic of THCA354 gels by detect the drug concentration in rat dermis,and combined with in vitro pharmacodynamics research results,to clarify THCA354 the concentration-effect-time relationship of the target skin.Results:Traits and physico-chemical parameters studies proved that THCA354 was a yellowish osteoporosis,odourless,tasteless powder crystal.Its melting point was 164.80 ℃,and it was easy be solubled in methanol,ethanol,acetone and ethyl acetate,solubled in propylene glycol and difficult to be solubled in water,and solubility increased with the increase of the p H of solvent between p H5.0 to 9.0,lg P was 1.857,the preformulation studies shown that THCA354 is suiTablele for transdermal drug delivery preparation for the treatment of dermatitis-eczema.We screened out optimal formulation of THCA354 gels by L9(34)orthogonal and pharmacodynamic experiments through evaluating the anti-inflammatory effect of THCA354 gels on 12-O-tetradecanoyl phorbol-13-acetate(TPA),arachidonic acid and evaluating the anti-allergic effect of THCA354 gels on DNFB.In the end,the combination of 5.00%THCA354,2.00% Carbomer,5.00% propylene glycol and 5.00% glycerinum is the optimal formulation.Then we designed THCA354 cream based on the optimal formulation gels.Pharmacodynamics experiment stduies indicated that the optimal formulation of THCA354 gels(5.00%)and creams(5.00%)could significantly suppressed acute,subacute,and chronic inflammation which is induced by TPA and arachidonic acid.and there is a dose response relationship Within a certain range between10 to 40 mg dose;and low,medium(10 and 20 mg)dose of gels and cream preparation has inhibitory effect on the pruritus induced by C48/80;The optimal formulation of THCA354 gels and cream could also significantly suppress allergic,and is a dose response relationship Within a certain range between 6 to 48 mg.The recovery of THCA354 microdialysis experiments showed that the recovery of THCA354 decreases as the flow rate increased,THCA354 recovery was independent of concentration over the concentration range and the drug concentration of the perfusion.The recovery rate is consistent by gain and loss method.in vitro recovery of THCA354 was 22.51±0.69% by gain method,and 21.12±2.88% by loss method,in vivo recovery of THCA354 was 12.04±1.21% by loss method and we rediction the in vivo recovery by gain is 12.83%,and the recovery was s Tablele over the 6h study period.We establelished method of microdialysis and HPLC-MS detection technology for THCA354 concentration in rat dermis,the recovery rate and precision are all conform to the requirements of the determination of drugs in vivo,it can be used for the determination of the microdialysis sample.Through the HPLC-MS method,we determined the THCA354 concentration in dialysate in different times,the results show that THCA354 can be detected in the dermis after the treatment of 280 min,and went Cmax(72.00±69.47)ng/mL in 440~460 min,and could not be detected in 600 min,and the drug stay within the dermis about 320 min,it shown that the drug retained in the dermis for a long time.Conclusions:The results of preformulation study proved that THCA354 is suitablele for the preparation of transdermal drug delivery preparation.We screened out the optimal THCA354 gels process prescription according to the orthogonal design experiment and pharmacodynamic experiment.It further proved that THCA354 gels and cream had significant effect of anti-inflammatory,anti-allergic and anti-itch through the pharmacodynamics experiment.And there was a certain drug concentration and drug retained in the dermis for a long time,it achieved the purpose of drug local drug delivery for local action.The study of this paper will provide experimental basis for its development into clinical topical therapies for dermatitis eczema skin disease.