Preparation of apixaban-cyclodextrin – D-α-tocopheryl polyethylene glycol 1000 succinate supramolecular inclusion complex: Mechanistic and physicochemical assessment

Abstract

Apixaban (APX) is a poorly water-insoluble anticoagulant drug. To enhance the solubility and dissolution profile, the APX inclusion complex was prepared using beta cyclodextrin (βCD), methyl beta cyclodextrin (M βCD), and D-ɑ-tocopheryl polyethylene glycol succinate (TPGS). APX complexes were prepared and evaluated for molecular docking, infrared, differential scanning calorimetry, x-ray diffraction, flow property, saturation solubility, and dissolution study. The phase solubility study results displayed the higher stability constant values (Ks, 1:1) for APX: M βCD (817 M^-1) and APX: M βCD: TPGS (1979 M^-1) than the APX: βCD (651 M^-1) and APX: M βCD: TPGS (1463 M^-1). The computational docking between the APX and the target protein factor Xa inhibitor exhibited a docking score of -8.58 Kcal/mol. The receptors βCD (-6.77 Kcal/mol) and M βCD (-7.97 Kcal/mol) also displayed high docking scores. The ternary complex (F5, F6) displayed enhanced solubility and dissolution compared to the binary complex (F2, F3). The solid-state characterization confirms the formation of an amorphous complex after the inclusion of APX in cyclodextrin. From the findings, it can be concluded that the addition of water-soluble carriers to develop an inclusion complex could be a new way to enhance the solubility and dissolution profile of APX, which may also promote permeability as well as bioavailability.

Introduction

Apixaban (APX) (Fig. 1) is a potent oral anticoagulant that selectively inhibits coagulation factor (Xa). It is clinically indicated to prevent and treat venous thromboembolism, as well as to reduce the risk of stroke and systemic embolism in atrial fibrillation patients (Jain et al., 2017). It exhibits limited water solubility (28 µg/mL) and has a relatively low oral bioavailability of approximately 50% (Lee et al., 2023). The low bioavailability is mainly due to significant first-pass metabolism and restricted intestinal absorption (Granger et al., 2011). The drug is mostly absorbed in the small intestine, and its bioavailability can be improved by using different formulation methods that make it more soluble and permeable. There are different pharmaceutical formulations, including solid dispersion (Lee et al., 2023), inclusion complexes (Salman et al., 2023; Ismail et al., 2024), solid lipid nanoparticles (Ramadan et al., 2023), nanolipid carriers (Zaky et al., 2023), and co-crystals (Chen et al., 2016), that have been reported to improve the APX solubility and bioavailability. The developed solid dispersion and co-crystal significantly enhance 5.9-fold solubility in water (Lee et al., 2023) and about 2-2.5-fold enhancement in 0.1 M HCl (pH 1.0) and phosphate buffer of pH 6.8 (Chen et al., 2016). The APX inclusion complex was prepared by the kneading, spray drying, and solvent evaporation (SE) methods using βCD and hydroxypropyl beta cyclodextrin (HP βCD) as carriers (Salman et al., 2023). The developed inclusion complex depicted a significantly higher percentage of drug release (95%) over one hour compared to the free APX (60%). In another study, APX-βCD inclusion complexes were developed by the SE method (Ismail et al., 2024). The phase solubility results showed a three-fold increase in βCD solubility when compared to other CD types.

Cyclodextrins (CDs) are truncated conical shapes featuring an outside hydrophilic and an inside hydrophobic surface. The hydrophilic nature of its surface is attributed to primary hydroxyl groups at C-6 and secondary hydroxyl groups at C-2 and C-3 (Saha et al., 2016). The ether-like anomeric oxygen atoms and hydrophobic C3-H and C5-H atoms are oriented towards the inner region (Poulson et al., 2022). CDs are commonly utilized as host molecules to encapsulate hydrophobic guest molecules, resulting in the development of inclusion complexes (Liu et al., 2017; Rajamohan et al., 2024). The beta cyclodextrin (βCD, Fig. 2a) is the most commonly used CD due to its applicability in different dosage forms, high biocompatibility, and cavity dimension (∼6.0–6.5 Å), but its application is constrained by low water solubility (18.5 mg/mL) (Christoforides et al., 2022). The limited cavity space makes it less suitable for the high molecular weight drugs, bulky side chains, or rigid structures. Chemically modified CDs have drawn significant interest for enhancing their physicochemical properties (Christoforides et al., 2022; Fenyvesi et al., 2014). The methyl beta cyclodextrin (M βCD, Fig. 2b) adds flexibility to the cavity, helping accommodate larger or more hydrophobic drugs. The cavity size is approximately the same as native β CD, since methylation occurs on the hydroxyl groups outside the cavity and does not alter the core ring size. The substituted methyl group offers advantages such as improved solubility, lesser nephrotoxicity, and haemolytic activity (Varga et al., 2019). It has a higher aqueous solubility (>100 mM), better inclusion of large and poorly soluble drugs and forms more stable inclusion complexes. It has superior inclusion ability and water solubility because it can contain guest molecules in its cavity structure by forming inclusion complexes. It can also mask unpleasant tastes and protect the drug from degradation (Lu et al., 2019). The reduction of CDs quantities in the formation of the inclusion complex, while maintaining solubility, is important in delivery systems. The improvement in the complexation efficacy of cyclodextrins is limited, which requires the use of large quantities to solubilize the poorly water-soluble drugs. Loftsson and Brewster (1996) demonstrated that the addition of auxiliary substance enhances the solubilizing effect of cyclodextrins. The synergistic effect attributed to the formation of ternary complexes or co-complexes, as well as the enhanced physicochemical properties of complexed drugs due to their direct role in drug complexation (Jansook et al., 2009; da Silva et al., 2016).

Incorporating auxiliary substances into the binary complexes could facilitate the formation of ternary complexes (Srivalli et al., 2016). D-ɑ-tocopheryl polyethylene glycol succinate (TPGS) is a highly water-soluble non-ionic surfactant. It demonstrates P-glycoprotein inhibitory activity and is recognized for enhancing the solubility and absorption of hydrophobic drugs (Srivalli et al., 2012; Guo et al., 2013; Yan et al., 2021). The docking score enhances our understanding of the binding modes and affinities of Xa inhibitors to receptors. It also provides valuable research insights into the delivery systems. Factor Xa was identified as a highly susceptible target in the emerging class of antithrombotic drugs (Novichikhina et al., 2020). Thus, selected as the receptor for this study.

While APX-βCD inclusion complexes have been previously explored, the use of MβCD in combination with TPGS as an auxiliary substance for the development of binary and ternary APX complexes has not been systematically investigated. The present study aims to prepare and characterize APX-MβCD binary and ternary inclusion complexes using SE and freeze-drying (FD) methods.

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Materials

APX was procured from MSN laboratories, Telangana India. βCD (white powder, MW 1134.9, AR, ≥98%), M βCD (white powder, MW 1303, AR, ≥99.5%, degree of substitution <10%) and TPGS were procured from “Sigma Aldrich., Germany”. Ethanol and methanol were purchased from “Sigma Aldrich St Loius MA, USA”.

Preparation of apixaban-cyclodextrin – D-α-tocopheryl polyethylene glycol 1000 succinate supramolecular inclusion complex: Mechanistic and physicochemical assessment, Sadaf Jamal Gilania, Najla Altwaijry, Ahlam Mansour Sultan, Reem Basoudan, Reem Albesher, Kaneez Fatima, Journal of King Saud University –Science, https://jksus.org/preparation-of-apixaban-cyclodextrin-d-tocopheryl-polyethylene-glycol-1000-succinate-supramolecular-inclusion-complex-mechanistic-and-physicochemical-assessment/