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: SMEDDS; antiplatelet activity; bioavailability; optimization; platelet aggregation; ticagrelor.

Figure 1

Solubility of ticagrelor in various excipients. Notes: (A) Oils. (B) Surfactants and cosurfactants. Values are expressed as mean ± SD (n=3).

Figure 2

Pseudoternary phase diagram. Notes: (A) Capmul MCM, Cremophor EL, and Transcutol P. (B) Capmul MCM, Tween 20, and Transcutol P. Green line, red line, and blue line indicate compositions forming microemulsion of the grade A, grade B, and grade C, respectively.

Figure 3

Three-dimensional surface plots of responses. Notes: (A) Y₁: Solubility of TCG in SMEDDS. (B) Y₂: Precipitation. (C) Y₃: Droplet size. (D) Y₄: Transmittance.

Figure 4

(A) Desirability plot using numerical optimization. (B) Transmission electron microscopy images and an electrophoretic laser scattering measurement of optimized ticagrelor-loaded self-microemulsifying drug delivery system in corresponding distilled water. Scale bar 200 nm.

Figure 5

Dissolution profile of Brilinta^®, TCG-CE, and TCG-SM in (A) pH 1.2 media, (B) pH 4.0 media, (C) pH 6.8 media, and (D) distilled water. Notes: Values are expressed as mean ± SD (n=3). Abbreviations: TCG-SM, ticagrelor-loaded self-microemulsifying drug delivery system; TCG-CE, ticagrelor-loaded Cremophor EL.

Figure 6

(A) Cell viability of Caco-2 as a function of TCG corresponding concentration for raw TCG solution, blank-CE, TCG-CE, blank-SM, and TCG-SM. (B) Caco-2 cellular uptake of TCG treated with raw TCG solution, TCG-CE, and TCG-SM after incubation for 4 hours. (C) P_app of raw TCG solution, TCG-CE, and TCG-SM across Caco-2 cell monolayer. Notes: (A) Values are expressed as mean ± SD (n=4). (B) Values are expressed as mean ± SD (n=4). *P<0.05 vs raw TCG solution, ^#P<0.05 vs TCG-CE. (C) Values are expressed as mean ± SD (n=4). *P<0.05 vs raw TCG solution, ^#P<0.05 vs TCG-CE. Abbreviations: blank-CE, Cremophor EL without ticagrelor; blank-SM, self-microemulsifying drug delivery system without ticagrelor; CE, Cremophor EL; P_app, apparent permeability coefficients; SM, self-microemulsifying drug delivery system; TCG-CE, ticagrelor-loaded Cremophor EL; TCG-SM, ticagrelor-loaded self-microemulsifying drug delivery system; TCG, ticagrelor.

Figure 7

Mean plasma concentration–time profiles of TCG in rats after oral administration of raw TCG suspension, TCG-CE, and TCG-SM at a dose equivalent to 10 mg/kg of TCG. Note: Values are expressed as mean ± SD (n=11). Abbreviations: TCG, ticagrelor; TCG-CE, ticagrelor-loaded Cremophor EL; TCG-SM, ticagrelor-loaded self-microemulsifying drug delivery system.

Figure 8

In vitro concentration–response curves for TCG inhibitory actions on ADP-induced platelet aggregations of raw TCG suspension and TCG-SM. Notes: EC₅₀ was defined as the concentration of the drug that inhibits platelet aggregation to 50%. Values are expressed as mean ± SEM (n=3). Abbreviations: EC₅₀, 50% effective concentration; SEM, standard error of mean; TCG, ticagrelor; TCG-SM, ticagrelor-loaded self-microemulsifying drug delivery system.

Figure 9

(A) Ex vivo antiplatelet activity evaluation of raw TCG suspension and TCG-SM according to dose of 2, 5, and 10 mg/kg. (B) Dose–response curve for ADP-induced platelet aggregation in TCG according to time-points (2, 5, and 10 hours) after oral administration of raw TCG suspension and TCG-SM. Notes: (A) Values are expressed as mean ± SEM (n=9). (B) ED₅₀ was defined as the dose of the drug that inhibits platelet aggregation to 50%. Values are expressed as mean ± SEM (n=9). Abbreviations: ED₅₀, 50% effective dose; SEM, standard error of mean; TCG, ticagrelor; TCG-SM, ticagrelor-loaded self-microemulsifying drug delivery system.

Figure 10

Main design and result for the development of TCG-SM. Abbreviations: BCS, Biopharmaceutical Classification System; blank-CE, Cremophor EL without ticagrelor; blank-SM, self-microemulsifying drug delivery system without ticagrelor; CE, Cremophor EL; TCG, ticagrelor; TCG-SM, ticagrelor-loaded self-microemulsifying drug delivery system.