Preparation and Characterization of Clopidogrel Bisulfate-Hydroxypropyl-β-Cyclodextrin Mixed Inclusion Complex for Improved Intestinal Solubility and Anti-Thrombotic Efficacy

The study aimed to increase the intestinal solubility and absorption of orally bioavailable clopidogrel-bisulfate (CPB) by complexing with hydroxypropyl-β-cyclodextrin (HCD) to form a binary inclusion complex that was stabilized by Tween 80 (T80) resulting into mixed inclusion complex. The results of phase solubility studies and molecular docking of CPB with β-cyclodextrin (β-CD) and HCD suggested higher solubility and binding energy of the stable CPB: HCD complex in the presence of T80 as compared to the CPB: β-CD complex.

Highlights

• CPB: HP-β-CD: T80 inclusion complex was successfully prepared using kneading method.
• Molecular docking and spectral attributes confirmed inclusion complex formation.
• CPB: HP-β-CD: T80 mixed inclusion complex showed chemical stability at alkaline pH.
• Prepared soft gelatin capsule showed improved solubility and anticoagulant activity.

The D-Optimal mixture design was used to optimize the formulation containing the CPB: HCD: T80 mixed inclusion complex. The results suggest the enhanced stability of the CPB: HCD inclusion complex in the presence of T80. The spectral attributes confirmed the inclusion complexation and pointed out the central position of CPB in a hydrophilic cavity of HCD. Further, the prepared soft gelatin capsule successfully confirmed the importance of obliterating the intestinal precipitation associated problem of CPB through an in-vitro release study. The anticoagulant activity in rabbits confirmed that soft gelatin capsules showed 1.2 folds and 1.3 folds increase in clotting time, 1.2 fold and 1.5 folds increase in bleeding time when compared to marketed formulation and pure drug, respectively. Conclusively, soft gelatin capsules exhibit the potential to enhance the oral bioavailability of CPB, leading to reduction of the dose and dose-related side effects.

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Akashdeep Singh, Radhika Sharma, Saurav Chaudhary, Vikas Rana, Preparation and Characterization of Clopidogrel Bisulfate-Hydroxypropyl-β-Cyclodextrin Mixed Inclusion Complex for Improved Intestinal Solubility and Anti-Thrombotic Efficacy, Journal of Pharmaceutical Sciences, 2022, ISSN 0022-3549,
https://doi.org/10.1016/j.xphs.2022.07.005.