Strategic approach to developing a self-microemulsifying drug delivery system to enhance antiplatelet activity and bioavailability of ticagrelor

Abstract

Background

Ticagrelor (TCG) is used to inhibit platelet aggregation in patients with acute coronary syndrome, but its poor solubility and low bioavailability limit its in vivo efficacy. The purpose of this study was to manufacture an optimized TCG-loaded self-microemulsifying drug delivery system (SMEDDS) to enhance the oral bioavailability and antiplatelet activity of TCG.

Materials and methods

Solubility and emulsification tests were conducted to determine the most suitable oils, surfactants, and cosurfactants. Scheffé’s mixture design was applied to optimize the percentage of each component applied in the SMEDDS formulation to achieve optimal physical characteristics, ie, high solubility of TCG in SMEDDS, small droplet size, low precipitation, and high transmittance.

Results

The optimized TCG-loaded SMEDDS (TCG-SM) formulation composed of 10.0% Capmul MCM (oil), 53.8% Cremophor EL (surfactant), and 36.2% Transcutol P (cosurfactant) significantly improving the dissolution of TCG in various media compared with TCG in Brilinta^® (commercial product). TCG-SM exhibited higher cellular uptake and permeability in Caco-2 cells than raw TCG suspension. In pharmacokinetic studies in rats, TCG-SM exhibited higher oral bioavailability with 5.7 and 6.4 times higher area under the concentration–time curve and maximum plasma concentration, respectively, than a raw TCG suspension. Antiplatelet activity studies exhibited that the TCG-SM formulation showed significantly improved inhibition of platelet aggregation compared with raw TCG at the same dose of TCG. And, a 10 mg/kg dose of raw TCG suspension and a 5 mg/kg dose of TCG-SM had a similar area under the inhibitory curve (907.0%±408.8% and 907.8%±200.5%⋅hours, respectively) for antiplatelet activity.

Conclusion

These results suggest that the developed TCG-SM could be successfully used as an efficient method to achieve the enhanced antiplatelet activity and bioavailability of TCG.

Keywords:

• ticagrelor
• SMEDDS
• optimization
• bioavailability
• platelet aggregation
• antiplatelet activity

Supplementary material

Figure S1 (A) Apical-basolateral (A–B) transport of TCG across Caco-2 cell monolayer for 180 minutes. (B) Basolateral-apical (B–A) transport of TCG across Caco-2 cell monolayer for 180 minutes.

Notes: Values are expressed as mean ± SD (n=4).

Abbreviations: TCG, ticagrelor; TCG-CE, ticagrelor-loaded Cremophor EL; TCG-SM, ticagrelor-loaded self-microemulsifying drug delivery system.

Table S1 The classification standards of emulsification grade

Table S2 Coefficient equations of responses according to the level of factors

Table S3 The experimental composition and observed responses through Scheffé’s mixture design

Acknowledgments

This work was supported by the Basic Science Research Program (2016R1A2B4011294) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology. The sample excipients of Gattefossé Co. and ABITEC Corporations were from the kind support of Masung & Co., Ltd. We would like to thank DW Yeom for fruitful discussions about the design of experiments study.

Disclosure

Mr Gi-Ho Son and Mr Ki-Hyun Bang are employed by Korea United Pharmaceutical Co. Ltd., Sejong, Republic of Korea. Mr Sung-Hoon Jeon is employed by SamA Pharmaceutical Co. Ltd., Suwon, Republic of Korea. The authors did not receive grants/funds from these affiliations for this study. The authors report no other conflicts of interest in this work.