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<p>Myocardial infarction (MI), one of the leading causes of global death, is associated with necrosis of myocardium due to blockage of oxygen supply towards heart. Clopidogrel (CLP) is an antiplatelet agent used in the treatment of MI. However, it belongs to Biopharmaceutics classification system (BCS) class II drugs with poor dissolution, reduced half-life and low bioavailability thereby resulting in reduced antiplatelet activity. This study aims to develop polymeric nanoparticles (PNPs) to address these limitations. CLP-PNPs were prepared by the nano precipitation technique and were statistically optimized by the Box-Behnken design. The PNPs were characterized in terms of particle size (P.S), zeta potential (Z.P), polydispersity index (PDI), and percentage entrapment efficiency (%EE). Moreover, Transmission electron microscopy (TEM), Fourier transformed infrared spectroscopy (FTIR) and x-ray diffraction (XRD) analyses were performed to investigate the surface morphology, chemical interaction and amorphous nature of the CLP-PNPs, respectively. Besides, in vitro release, pharmacokinetics and anti-platelet activity of the CLP-PNPs was examined and compared with CLP dispersion. The optimized CLP-PNPs demonstrated a P.S, of 214.15 ± 12.09&#xa0;nm, Z.P of + 16.9 ± 0.28 mV, PDI of 0.123 ± 0.05, and % EE of 86.15 ± 0.95%. Moreover, the optimized CLP-PNPs showed spherical morphology and uniform P.S. Furthermore, no major chemical interactions were found among the ingredients of CLP-PNPs and the crystalline CLP was changed to amorphous state in the lyophilized powder. The in vitro release data showed a sustained release profile of CLP from the CLP-PNPs, when compared with the CLP dispersion at pH 1.2, pH 6.8 and pH 7.4. However, the release was more pH dependent with minimal release at pH 1.2 and maximum at pH 7.4. Oral delivery of CLP-PNPs led to a significantly enhanced bioavailability (6.3-fold), in Sprague-Dawley rats. Additionally, CLP-PNPs exhibited a marked decrease in cardiac troponin T (cTn) level and serum myoglobin at different time intervals, after single oral dose, signifying an enhanced anti-platelet activity in MI induced rats as compared to CLP dispersion. The formulation was found stable up to 4 months. Overall, this study concluded that PNPs have the ability to sustain the drug release, improve the bioavailability and the antiplatelet activity of CLP when used in the treatment of MI.</p>

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Development of Clopidogrel Polymeric Nanoparticles with Sustained Release and Improved Bioavailability for the Treatment of Myocardial Infarction

  • 期刊论文

  • 发表日期：

    2026年1月30日

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  • Noshaba Saleem,
  • Ghazala Ishrat,
  • Sibgha Batool,
  • Abida Saleem,
  • Muhammad Mukhtiar,
  • Ali H. Alamri,
  • Ahmad S. Alqahtani,
  • Mohammed A. Alshahrani,
  • Mohammed A. Alshehri,
  • Fakhar ud Din

摘要

Myocardial infarction (MI), one of the leading causes of global death, is associated with necrosis of myocardium due to blockage of oxygen supply towards heart. Clopidogrel (CLP) is an antiplatelet agent used in the treatment of MI. However, it belongs to Biopharmaceutics classification system (BCS) class II drugs with poor dissolution, reduced half-life and low bioavailability thereby resulting in reduced antiplatelet activity. This study aims to develop polymeric nanoparticles (PNPs) to address these limitations. CLP-PNPs were prepared by the nano precipitation technique and were statistically optimized by the Box-Behnken design. The PNPs were characterized in terms of particle size (P.S), zeta potential (Z.P), polydispersity index (PDI), and percentage entrapment efficiency (%EE). Moreover, Transmission electron microscopy (TEM), Fourier transformed infrared spectroscopy (FTIR) and x-ray diffraction (XRD) analyses were performed to investigate the surface morphology, chemical interaction and amorphous nature of the CLP-PNPs, respectively. Besides, in vitro release, pharmacokinetics and anti-platelet activity of the CLP-PNPs was examined and compared with CLP dispersion. The optimized CLP-PNPs demonstrated a P.S, of 214.15 ± 12.09 nm, Z.P of + 16.9 ± 0.28 mV, PDI of 0.123 ± 0.05, and % EE of 86.15 ± 0.95%. Moreover, the optimized CLP-PNPs showed spherical morphology and uniform P.S. Furthermore, no major chemical interactions were found among the ingredients of CLP-PNPs and the crystalline CLP was changed to amorphous state in the lyophilized powder. The in vitro release data showed a sustained release profile of CLP from the CLP-PNPs, when compared with the CLP dispersion at pH 1.2, pH 6.8 and pH 7.4. However, the release was more pH dependent with minimal release at pH 1.2 and maximum at pH 7.4. Oral delivery of CLP-PNPs led to a significantly enhanced bioavailability (6.3-fold), in Sprague-Dawley rats. Additionally, CLP-PNPs exhibited a marked decrease in cardiac troponin T (cTn) level and serum myoglobin at different time intervals, after single oral dose, signifying an enhanced anti-platelet activity in MI induced rats as compared to CLP dispersion. The formulation was found stable up to 4 months. Overall, this study concluded that PNPs have the ability to sustain the drug release, improve the bioavailability and the antiplatelet activity of CLP when used in the treatment of MI.