Preparation And Evaluation Of Bioadhesive Solid Dispersion Based On Coaxial-electrospray Technology

A bioadhesive core-shell structured drug delivery system was established based on electrostatic spray technology in this article.Solid dispersion and bioadhesive materials were combined to resolve the low solubility and poor bioavailability problems of Ticagrelo which is biopharmaceuticals classification system（BCS）class IV drug.Meanwhile,this research will lay a foundation for the development of insoluble and refractory drug delivery system.Part Ⅰ:ReviewsThis part introduced the principle and development of electrostatic spray technology,including the uniaxial and coaxial electrostatic spray technology.The influence factors of the electrostatic spray technology such as surface tension,liquid viscosity,carrier molecular weight,solution conductivity,electric field voltage,solution flow rate,receiving distance and inner diameter of the needle were also presented in detail.Then solid dispersion and bioadhesive materials were reviewed detailly.Finally,the physicochemical properties and pharmacokinetics of Ticagrelo were introduced.Part Ⅱ:Pre-formulation studyIn this section,an UV spectrophotometry analytical method with good specificity and high sensitivity was established to determine in vitro samples of Ticagrelor.The results showed that the blank excipients had no interference with the detection of Ticagrelor.The linear relationship was good in the range of 1²5μg/mL.The intra-day and inter-day precision were less than 3%,and the recovery was 98%-102%.The stability of the sample in 72 h was good.The logP value of Ticagrelor in the n-octanol-water system was 1.65,indicating that Ticagrelor has good liposolubility and poor water solubility.The absorption of Ticagrelor in duodenum,jejunum and ileum segment of rats was investigated,the results showed that the absorption of drug in each intestinal segment was small,and jejunum was the best absorption site for Ticagrelor.Part Ⅲ:Preparation and in vitro evaluation of Ticagrelor solid dispersion（T-SD）prepared by uniaxial electrostatic spray technologyIn this part,the morphology,yield and in vitro dissolution of Ticagrelor were taken as indexes to optimize T-SD preparation process with uniaxial electrostatic spray method.The optimized formulation and parameter were as following:Ticagrelor:poloxamer 188=1:3,flow rate=0.15mm/min,receiving distance=18 cm,positive voltage=18 kV,needle inner diameter=0.5 mm.The results of scanning electron microscopy（SEM）showed that T-SD had spherical and granular appearance,and the average particle size was about 760 nm.The results of DSC showed that Ticagrelor was mainly present as an amorphous form in the solid dispersion.The in vitro release results showed that the cumulative dissolution of T-SD at 5 min was about 60%,which was 50%higher than that of the crude drug.The dissolution of the T-SD was 90%at 90 min,indicating that in vitro dissolution was significantly improved up to 40%higher than that of the crude drug.Part Ⅳ:Preparation and in vitro evaluation of core-shell structured Ticagrelor bioadhesive solid dispersion（T-BSD）prepared by coaxial electrostatic spray technologyIn this part,T-BSD was successfully prepared by coaxial electrostatic spray technology.The adhesion,dissolution and encapsulation efficiency of the sample were used as indexes to investigate the types of the bioadhesive materials,the amount of addition and process parameters.Finally,the Carbomer 940 was chosen as shell material.The optimal parameters were as follows:positive voltage=18 kV,negative voltage=2KV,distance=18 cm,coaxial nozzle=18G/21G,shell solution flow rate=0.1 mm/min,the nuclear layer solution flow rate=0.15 mm/min.SEM showed that T-BSD had normal round appearance,and the particle size was about 1μm.At the same time,Shell structure was obviously observed by laser confocal microscopy（LSCM）.The in vitro dissolution rate of T-BSD was lower than that of T-SD,but it was higher compared with the crude drug.The release mechanism of T-BSD in pH1.0 HCI medium containing 0.01%Tween 80 was Fickian diffusion.The results of bioadhesion tests showed that the adhesion effect of T-BSD in each intestinal segment was greatly improved compared with T-SD.Part Ⅴ:Pharmacokinetic study of T-BSD and T-SD in SD ratsIn this part,the in vivo analytical methods were established to determine the content of Ticagrelor in rat’s blood samples by high performance liquid chromatography（HPLC）.The blank plasma had no interference with drug detection.The analytical method had high recovery rate,specificity and precision,which met the research requirements of the in vivo sample methodology.The pharmacokinetic studies in SD rats of Ticagrelor bulk drug,T-SD and T-BSD were carried out.In vivo pharmacokinetic parameters were calculated by DAS software,the results showed that the half-life(t_1/2)of Ticagrelor bulk drug,T-SD and T-BSD was 11.21h,9.28h and 12.09h,respectively.Average residence time（MRT）was respectively 8.618 h,7.277 h and 9.441 h,and T_max was respectively 1 h,2 h and 4 h.The results indicated that T-BSD could prolong the drug residence time in vivo.The C_max of the bulk drug was 367.32 ng/mL,the C_max of T-SD increased to 868.32ng/mL,and the C_maxax of T-BSD was 846.27 ng/mL.The results showed that the homotaxial and coaxial electrostatic spray preparations all could improve the solubility of Ticagrelor.The relative bioavailability of T-SD and TB-SD was respectively 219.4%and 430.4%,which indicated that both T-SD and T-BSD could significantly improve the in vivo absorption of Ticagrelor.