Oral Self-microemulsifying Drug Delivery System Of Relugolix

The solubility of relugolix in water is extremely low,and it is the substrate of Pglycoprotein.After oral administration,the bioavailability of relugolix is only 12%.In order to improve the oral bioavailability of relugolix,the self-microemulsifying drug delivery system(SMEDDS)was prepared and evaluated in vitro and in vivo.The oil phase,surfactant,and cosurfactant were initially selected through solubility and compatibility experiments.Pseudoternary phase diagrams were drawn to determine the range of surfactant and co-surfactant ratios,and finally the prescription was optimized to minimize the surfactant concentration by star point design-effect surface method.The optimal formulation for self-microemulsifying drug delivery system consisted of ethyl oleate(26% w/w),Solutol HS 15(49% w/w),Transcutol HP(25% w/w),and loading of Relugolix(4.8 mg/g).Pharmacological evaluation showed that the SMEDDS were dispersed in water with particle size about 25.27 ± 0.26 nm,the potential was about-8 m V,uniform distribution.Transmission electron microscopy results showed a sphere-like morphology.SMEDDS has high dilution resistance and no significant effect of p H,and good thermodynamic stability.Preparation of RLGL-S-SMEDDS by solid adsorption method,and the SMEDDS was used as a solubilizing carrier for the drug.Hydrophilic-200 silica was screened as the best solid carrier by maximum adsorption and in vitro release.Pharmacological properties examination shows the particle size and PDI of S-SMEDDS were similar to those of SMEDDS after dispersion in water;SEM results showed that SMEDDS was adsorbed in silica voids;XRD results showed that SMEDSS was successfully adsorbed and existed in Hydrophilic-200 silica in an amorphous state.The powderological properties showed that RLGL-S-SMEDDS has good flowability and compressibility.In vitro release showed that the cumulative drug release of RLGL-S-SMEDDS was 86%and that of RLGL powder was 3.6% in phosphate buffered solution(PBS)(p H 6.8)release medium containing 1% Tween 80.The results of the preliminary safety evaluation showed that the toxicity of RLGL,S-SMEDDS,Transcutol HP and Solutol HS 15 in Caco-2 cells was greater than 90%at concentrations of 0.1-20 μg/m L using the MTT method.By fluorescence inverted microscopy and flow cytometric uptake experiments,the results showed that the uptake of COU-S-SMEDDS was three times higher than the uptake of free COU.Flow cytometric uptake experiments by co-incubation with cellular efflux protein inhibitors showed that efflux from Caco-2 cells involves the P-gp and MRP-2 pathways.Flow cytometric uptake experiments by co-incubation with the prescribed components showed that the prescribed surfactant Solutol HS15 was effective in inhibiting intestinal transporters to increase drug uptake.Cell transport was used Caco-2 cell monolayer model and the results showed that the transport of COU-S-SMEDDS was increased compared with that of free COU due to the inhibition of exoproteins by Solutol HS 15.A monolayer model of M cells was established to examine lymphatic transport,and the results showed that the formulation enhances drug uptake through lymphatic uptake.In vivo pharmacokinetic evaluation showed that the blood concentration(Cmax)in the RLGL-S-SMEDDS group being 3.2 times higher than that of RLGL suspension,and the area under the concentration time curve(AUC0-∞)in the RLGL-S-SMEDDS group being 1.9 times higher than that of RLGL suspension.This effectively improved the oral bioavailability of RLGL.Histological stained sections were used to observe the organism conditions after oral administration.The histological staining of the animal organs after oral administration showed that RLGL-S-SMEDDS has good biosafety.In summary,constructed a oral solid self microemulsifying drug delivery system for relugolix,which has been demonstrated through in vitro and in vivo evaluations to improve the bioavailability of RLGL-S-SMEDDS with low toxicity and side effects.