Formulation and In Vivo Evaluation of Ticagrelor-Loaded Spanlastic Nanovesicles to Enhance Intestinal Absorption
Khalid K. Al-kinani, Hussein K. Alkufi, Salam Shanta TaherIntroduction:
Ticagrelor (TCG) is an effective P2Y12 receptor antagonist used to prevent atherothrombotic cardiovascular events; however, its poor solubility and limited permeability (BCS Class IV) restrict its oral bioavailability. Spanlastic Nanovesicles (SNVs), composed of nonionic surfactants and edge activators, offer a promising strategy to enhance drug solubility and permeability. This study aimed to develop and optimize TCG-loaded SNVs using the ethanol injection method, validate a sensitive HPLC method for TCG quantification, and evaluate the pharmacokinetic and antiplatelet performance of the optimized formulation in rats.
Method:
TCG-SNVs were prepared using the ethanol injection technique with a varying ratio of Span 60 and Tween 60. Formulations were characterized for Particle Size (PS), Polydispersity Index (PDI), and Encapsulation Efficiency (EE %). Morphology was examined by Transmission Electron Microscope (TEM). A reversed -phase HPLC method was validated for linearity, accuracy, precision, LOD, and LOQ. In vivo pharmacokinetic studies were conducted in Sprague-Dawley rats (10 mg /kg oral dose), and pharmacokinetic parameters (C max, Tmax, AUC, t 1/2) were determined. Inhibition of platelet aggregation was evaluated using a dual-channel aggregometer.
Results:
Among the tested formulations, SNV2 showed optimal characteristics with a particle size of 79.21 nm, PDI of 0.1213, and EE % of 86.87%. TEM confirmed spherical and uniformly distributed vesicles. The validated HPLC method demonstrated excellent linearity (100-800 ng/ml), high accuracy (mean recovery 99%), and acceptable precision (% RSD < 2%), with LOD and LOQ values of 8 ng/mL and 24.24 ng/mL in plasma, respectively. Pharmacokinetic analysis revealed significantly enhanced systemic exposure for SNV2 compared to the marketed product, with increased Cmax (9500 vs. 4500 ng/ml), AUC (115150 vs. 70107.5 ng/mL), reduced Tmax (4 vs. 8 hours), and a relative bioavailability improvement of 64.33%. Additionally, SNV2 demonstrated a greater reduction in ADP-induced platelet aggregation than the comparator formulation.
Discussion:
The improved pharmacokinetic and pharmacodynamic performance of SNV2 can be attributed to enhanced solubility, nanoscale size, high encapsulation efficiency, and improved intestinal permeability provided by the flexible spanlastic vesicles. The validated HPLC method ensures accurate and reliable quantification of TCG in plasma, supporting the robustness of the in vivo findings.
Conclusion:
TCG-loaded spanlastic nanovesicles prepared by the ethanol injection method significantly enhanced oral bioavailability and antiplatelet efficacy compared to the marketed formulation. The optimized SNV2 formulation represents a promising nanocarrier system for improving the therapeutic performance of ticagrelor and may offer potential clinical benefits in the management of cardiovascular diseases.