Development Of Quercetin Microemulsion In Situ Gel

Quercetin(Q),is a five-hydroxyl flavonoid compound,which has many pharmacological effects such as anti-cancer,anti-alzheimer’s disease(AD),anti-oxidation,anti-bacterial,antiinflammatory,and promoting wound healing,some literature studies have shown that quercetin can treat gastric ulcer,vulvovaginal candidiasis,diabetic foot and other skin and mucosal diseases through anti-inflammatory,antioxidant,and promoting wound healing.Oral ulcer is a common oral mucosal disease in clinical practice with high recurrence rate and poor clinical treatment effect,and the etiology is still unclear until now,but a large number of research results have shown that most inflammatory factors are involved in the formation of oral ulcer.At present,the drugs commonly used for the clinical treatment of oral ulcer include antibacterials,anti-inflammatory drugs,and glucocorticoids,etc.,which are mainly chemically synthesized drugs with certain side effects,moreover,the marketed preparations for oral ulcer topical administration such as powders and sprays are easily diluted and washed by saliva,resulting in low local drug concentration,short residence time,difficulty in accurate administration,and poor therapeutic effect.Therefore,this topic considers developing the natural extract-quercetin,which has various pharmacological effects such as antiinflammatory,antioxidant,promoting wound healing,into a microemulsion in situ gel preparation,which can stay at the site of administration for a long time after local administration,relieving patient pain and improving patient compliance.However,quercetin has extremely low water solubility(the solubility is about 1 μg/mL),which greatly restricts the development of its preparations.Microemulsion is a transparent or slightly opalescent colloidal dispersion system,which is spontaneously formed,it can be formed by simple stirring and mixing,and the preparation process is simple,so we consider it as the carrier of quercetin to improve the solubility of quercetin,and then use the deacetylated gellan gum(DGG)or a mixed solution with Pluronic 407(Pluronic F127,F127)as the gel matrix to prepare an ion/temperature-sensitive in situ gel,which prolongs its residence time on the oral mucosa,thereby achieving the effect of treating oral ulcers.In this project,the quercetin microemulsion in situ gel preparation was used for the treatment of oral mucosal diseases for the first time,and the feasibility of its use in the treatment of oral ulcers was verified,which laid the foundation for the development of external preparations for the treatment of oral mucosal diseases.In this study,the composition of the microemulsion formulation was firstly determined,The oil phase component was determined by equilibrium solubility and compatibility test.Then,the composition of mixed emulsifier and the approximate range of three phases in the microemulsion prescription was determined by compariing the area of the microemulsion in the pseudo-ternary phase diagram.The simple grid method was used to optimize the formulation with particle size and drug content as indicators,the formulation was finally determined as:the oil phase was propylene glycol monocaprylate(Capryol 90),the emulsifier S was Tween 80-polyoxyethylene castor oil(Cremphor EL,EL)(1:1,w/w),and the coemulsifier So was 1,2-propanediol-diethylene glycol monoethyl ether(Transcutol HP,HP)(1:1,w/w),and the oil phase:mixed emulsifier Smix(S:S0 was 2:1(w/w)):water in a ratio of 21.7:48.3:30(w/w).Through the single factor investigation of drug addition order,preparation dosage,stirring time,stirring speed and temperature,the preparation process was determined as follows:at room temperature,quercetin,oil phase and mixed emulsifier were stirred and mixed until the quercetin was dissolved,and then stirred with water at 400 r/min for 30min.The in situ gel matrix was determined to be a mixed aqueous solution(1:1,v/v)of 0.4%DGG+10%F127(1:1,v/v)by the investigation of gelation,adhesion time,adhesion force and in vitro release indexes.The final prescription of quercetin microemulsion in situ gel preparation was 0.4%DGG+10%F127 mixed aqueous solution(1:1,v/v)and microemulsion ratio of 2:1(V/V).In order to investigate the in vitro mucosal penetration of the determined microemulsion in situ gel preparation,the pH6.8 phosphate buffer(containing 1%Tween80)was used as the receiving medium(simulating artificial saliva),and the franz diffusion cell(simulating mucosal penetration)was used as the test device,the porcine esophagus mucosa was used to simulate oral mucosa for in vitro mucosal permeability test.The results showed that the in vitro mucosal penetration was 0.44 μg/cm2 at 12h,which was low and suitable for topical administration.To ensure the safety of the preparation,multiple administration mucosal irritation test was carried out on the buccal mucosa of rats.Preliminary findings showed that the quercetin microemulsion in situ gel had no irritation to buccal mucosa of rats,and was safe.Then,a preliminary pharmacodynamic evaluation was carried out on the rat oral ulcer model established by glacial acetic acid burning method.The results showed that the ulcer area was significantly reduced in the quercetin microemulsion in situ gel group after administration for 7 days,and the ulcer healing time was about 10 days,there was no significant difference compared with the watermelon frost group,while the difference was significant(P<0.05)compared with the model group,indicating that the quercetin microemulsion in situ gel had a certain effect on the treatment of oral ulcer.