Construction And Evaluation Of Self-nanoemulsifying Drug Delivery System Of Rhubarb Anthraquinones

Objective: Rhubarb anthraquinones?RhA?were formulated in nanoemulsion based system with the aim of improving its solubility and oral bioavailability.Methods: 1.RhA loaded nanoemulsion?RhA-NE?was prepared using spontaneous nanoemulsification method.Solubility of RhA in oils,surfactants and co-surfactants was determined to select nanoemulsion components.Surfactants and co-surfactants were screened for their ability to emulsify selected oily phases.Pseudo-ternary phase diagrams were constructed to identify area of nanoemulsification.Influence of stabilizers and pH of the nanoemulsion system on zeta potential,mean droplet size,polydispersity,and rhubarb anthraquinones content change were assessed.A four-factors-five-levels central composite design?CCD?combined with response surface method?RSM?was carried out to attain optimal formulation.2.The optimal RhA-NE was evaluated by dynamic light scanning,transmission electron microscope,solubilizing capacity,encapsulation efficiency,drug loading and stability.The RhA content was determined by high performance liquid chromatography-diode array detection method.And in vitro drug release properties of RhA-NE and RhA suspension were also analyzed.3.RhA suspension and RhA-NE,separately used as reference drug and test drug,were orally administrated by Wistar rats at a single dosage of 15 mL/Kg?15 mg/Kg?.High performance liquid chromatography-fluorescence detection method was used to quantify RhA concentration in rat plasma.Data were dealed with a DAS 3.2.7 pharmacokinetic software and the pharmacokinetic parameters were analyzed by non-compartmental model method.Results: 1.Based on the application of CCD-RSM,RhA?5.1 mg per mL oil?,Capryol 90/ethyl oleate?19.5%,w/w?,cremophor RH 40?21.25%,w/w?,transcutol HP?21.25%,w/w?,oleic acid?1.50%,w/w?and distilled water?36.5%,w/w?was defined to achieve the optimized RhA-NE.2.The optimized RhA-NE can withstand the extensive dilution and did not show any phase separation or drug precipitation.The MDS and PDI of the optimized RhA-NE were 25.37 ± 0.55 nm and 0.136 ± 0.012,respectively.The mean ZP value was-17.6 ± 1.0 mV.A mean viscosity of 73.3 ± 1.4 cP was obtained at 25 ?,and a mean T% was 88.1 ± 1.9%.The entrapment efficiency of RhA in RhA–NE was about 98.091 ± 0.002 % and the drug loading was 0.101 ± 0.002 %.RhA content,MDS,PDI and ZP of RhA-NE were changed along with pH change.Except for RhA content,properties of RhA-NE were stable under high-light or high-temperature condition.The appearance and RhA contents were basically unchanged after 60 days storage at room temperature in brown bottle.52.51 ± 0.55% of RhA released from RhA-NE within 240 h,and the release profile was fitted to anomalous transport including diffusion and corrosion.3.The C_max and AUC_0-? of RhA in RhA-NE group were 1.20 times and 2.58 times of which in RhA suspension group.The CL_z/F of RhA in RhA-NE group was smaller than that of suspension,and MRT_0-? was extended 1.90 times.Compared to RhA suspension group,the T_max of rhein,emodin,physcion were all prolonged in RhA-NE group,the t_1/2z of RhA were all increased and the V_z/F of the rhein,emodin and chrysophanol in RhA-NE group was smaller,especially for the rhein.Conclusion: 1.The optimized self-nanoemulsification drug delivery system can enhance solubilization of RhA.RhA-NE possesses good properties of kinetic stability and relatively thermostability.It is adapted to storage in dark place at room temperature.The mechanism of RhA release from RhA-NE was anomalous transport.2.The oral bioavailability of RhA-NE was enhanced and MRT_0-? was prolonged compared to RhA suspension.