Solid Self-Microemulsifying Drug Delivery System for Improved Oral Bioavailability of Relugolix: Preparation and Evaluation

Abstract

Purpose: To improve the oral absorption of relugolix (RLGL), which has low oral bioavailability due to its low solubility and being a substrate of P-glycoprotein (P-gp). A solid self-microemulsifying drug delivery system of relugolix (RLGL-S-SMEDDS) was prepared and evaluated in vitro and in vivo.

Methods: The composition of the solid self-microemulsifying drug delivery system (S-SMEDDS) was selected by solubility study and pseudo-ternary phase diagram, and further optimized by Design-Expert optimization design. The optimized RLGL-S-SMEDDS were evaluated in terms of particle size, zeta potential, morphology analysis, thermodynamic stability, drug release, flow properties, transporter pathways in Caco-2 cells, the influence of excipients on the intestinal transporters, transport within Caco-2 cell monolayers and transport in lymphocyte. In vivo pharmacokinetic study and toxicological study were also conducted.

Results: The optimum formulation for self-microemulsifying drug delivery system (SMEDDS) consists of Ethyl Oleate (26% of the weight), Solutol HS15 (49% of the weight), Transcutol HP (25% of the weight) and loaded relugolix (4.8 mg/g). The S-SMEDDS was then formed by adsorbing 2.4 g of SMEDDS onto 1 g of hydrophilic-200 silica. In phosphate buffered saline (PBS) (pH 6.8) release medium containing 1% tween 80, the vitro release studies showed 86% cumulative drug release for RLGL-S-SMEDDS and 3.6% cumulative drug release for RLGL suspensions. In vitro cellular uptake experiments revealed that the uptake of RLGL-S-SMEDDS by Caco-2 cells was three times higher than that of free RLGL, and that S-SMEDDS can enhance the drug absorption through lymphatic absorption and inhibition of intestinal transporter. In vivo pharmacokinetic evaluation demonstrated that the oral bioavailability of RLGL-S-SMEDDS was 1.9 times higher than that of RLGL-suspensions. There was no apparent cardiac, hepatic, splenic, pulmonary or renal toxicity on the surface discovered by pathological analysis after oral administration.

Conclusion: It is evident that S-SMEDDS may be a safe and effective method to improve oral absorption of drugs with low oral bioavailability.

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Materials

Relugolix was from Takeda Pharmaceutical Industry Co., Ltd. (99%, Tokyo, Japan). Isopropyl myristate, ethanol, ethyl oleate, PEG 400 and Tween 80 were purchased from Aladdin Biochem Tech. Co., Ltd. (Shanghai, China). Transcutol HP (Gattefosse, France), Solutol HS15 and Kolliphor P188 (BASF Ltd., Shanghai, China) were obtained as gift samples. Hydrophilic-200 silica and Sylysiak 320 were purchased from Yien Chemical Technology Co., Ltd. (Shanghai, China). Triton X-100, Dulbecco’s modified Eagle’s medium (DMEM), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and trypsin were purchased from Beijing Solarbio Sci&tech. Co., Ltd. (Beijing, China). Corning Matrigel Matrix were purchased from Corning Life Sciences (Wujiang) Co., Ltd. (Jiangsu, China). All the other chemicals and reagents were of analytical or HPLC grade and obtained from commercial sources.

Li ZL, Deng GX, Fang CZ, Zhao YQ, Yuan J, Chen L, Zhong HJ, Guo F. Solid Self-Microemulsifying Drug Delivery System for Improved Oral Bioavailability of Relugolix: Preparation and Evaluation. Int J Nanomedicine. 2025;20:1065-1082, https://doi.org/10.2147/IJN.S497099

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