Design and Optimization of Rivaroxaban-Cyclodextrin-Polymer Triple Complex Formulation with Improved Solubility

Drug Des Devel Ther. 2022 Dec 16:16:4279-4289. doi: 10.2147/DDDT.S389884. eCollection 2022.

Abstract

Purpose: This study aimed to ensure the convenience of administration and reproducibility of efficacy, regardless of the meal, by improving the solubility of rivaroxaban (RIV).

Methods: RIV is a non-vitamin K antagonist oral anticoagulants that exhibits a coagulation effect by directly inhibiting coagulation factor Xa. However, RIV has a very low solubility; therefore, it must be administered with a meal at high doses. We used a drug- hydroxypropyl-beta-cyclodextrin (CD)-water-soluble polymer triple complex (R-C-P complex) to solubilize RIV. Using Minitab, we evaluated the effect of each factor on RIV solubility and developed an optimal R-C-P complex formulation. The amount of CD, amount of polymer, and polymer type were set as the independent variables X1, X2, and X3, respectively. RIV solubility (Y1) and dissolution rate for 45 min in pH 4.5 medium (Y2) and pH 1.2 medium (Y3) were set as response variables.

Results: The most efficient RIV solubilization effect was obtained from the composition using CD and HPMC 2208, and physicochemical properties and dissolution parameters were analyzed. RIV in the R-C-P complex was present in an amorphous form and showed high solubility. Unlike commercial products, it showed a 100% dissolution rate. The R-C-P complex formulation secured high RIV solubility and 100% release regardless of pH.

Conclusion: The results imply that high-dose RIV can be administered regardless of the meal, reducing the risk of changing the drug effect due to the patient's administration mistake.

Keywords: design of experiment; drug-cyclodextrin-polymer triple complex; rivaroxaban; solubilization.

MeSH terms

  • 2-Hydroxypropyl-beta-cyclodextrin
  • Cyclodextrins* / chemistry
  • Humans
  • Pharmaceutical Preparations
  • Polymers
  • Reproducibility of Results
  • Rivaroxaban*
  • Solubility

Substances

  • Rivaroxaban
  • Cyclodextrins
  • Pharmaceutical Preparations
  • 2-Hydroxypropyl-beta-cyclodextrin
  • Polymers

Grants and funding

This study was supported by a National Research Foundation of Korea grant provided by the Korean government (NRF-2021R1A2C4002746 and 2017R1A5A2015541). This research was supported by “Regional Innovation Strategy (RIS)” through the National Research Foundation of Korea(NRF) funded by the Ministry of Education(MOE)(2021RIS-001).