(T0930-07-39) Improving the Solubility of Apixaban and Preparation Sustained-Release Tablets Through a Solidified Self-Microemulsifying Drug Delivery System

Purpose: In this study, we developed tablets using Self-Microemulsifying Drug Delivery System (SMEDDS) technology to improve the solubility and bioavailability of apixaban. SMEDDS is a technology that improves the solubility and bioavailability of poorly soluble drugs by combining surfactants, co-surfactants, oils, and drugs in optimal ratios. After preparing liquid SMEDDS, it was solidified with an adsorbent and then prepared in tablet form. In vitro studies were performed to evaluate the prepared formulations.

Methods: For formulation development, the solubility of apixaban in various oils, surfactants, and cosurfactants was evaluated. Castor oil, Labrasol®, and propylene glycol were selected based on their solubility results. Ternary phase diagrams were then created to identify self-microemulsifying formulations. To prepare the SMEDDS, oil, surfactant, and cosurfactant were mixed and then apixaban was added. The mixture was treated using a vortexer and sonicator. The formulation was diluted and particle size and polydispersity index were measured using dynamic light scattering. Liquid SMEDDS was adsorbed using a solid adsorbent to form granules, dried at 60°C, and then tablets were completed by compression. Dissolution studies were performed using the USP II paddle method in a sodium phosphate buffer containing SLS. Samples were analyzed for apixaban concentration by HPLC.

Results: 1) Apixaban solubility study and Ternary phase diagram - Solubility test results, Castor oil (251.00 μg/mL), Labrasol® (440.69 μg/mL), and propylene glycol (177.0 μg/mL) were selected for the SMEDDS formulation. Sodium lauryl sulfate (SLS) was excluded due to toxicity concerns despite its high solubility (5100.6 μg/mL). Ternary phase diagram showed that SMEDDS formulations contain less than 20% castor oil, less than 30% Labrasol®, and more than 60% propylene glycol, resulting in a translucent appearance. 2) Solubilization capacity and Particle size and polydispersity index - In this study, the S1 formulation with 40% Labrasol® as a surfactant and 50% propylene glycol as a co-surfactant exhibited the highest solubility. Similarly, formulations like S4 (50% Labrasol®, 40% propylene glycol) and S2 (20% Labrasol®, 20% Kolliphor® ELP, 50% co-surfactant) also demonstrated high solubility. Generally, formulations using only Labrasol® as a surfactant showed excellent solubility. Formulations with higher proportions of propylene glycol showed increased solubility. Particle size analysis was conducted on formulations S1 and S4. S2 exhibited significant deviations, so particle size analysis was not performed. Particle size and polydispersity index analysis showed that both S1 and S4 dispersed in water had average diameter sizes. Specifically, the particle size of S1 was 272.1 nm, demonstrating good dispersion characteristics in water, whereas S4 had a particle size of 342.6 nm, showing poor dispersion characteristics compared to S1. 3) Dissolution study - Examination of the dissolution profiles of apixaban from SMEDDS tablets and Eliquis in DW, 0.05 M sodium phosphate buffer, and 0.05 M sodium phosphate buffer containing SLS showed that in all cases, SMEDDS tablets and Eliquis exhibited higher dissolution rates than the raw apixaban material. SMEDDS tablets demonstrated a high dissolution rate across various dissolution test solutions, effectively addressing the low solubility of apixaban. Furthermore, apixaban was formulated into a sustained-release formulation that releases slowly over 14 hrs using a matrix and filler. This approach can potentially enhance medication compliance compared to the immediate-release version of Eliquis.

Conclusion: Studies have shown that SMEDDS tablets significantly improve the solubility and bioavailability of apixaban. Compared to Eliquis, which is an immediate-release tablet, SMEDDS tablets have the advantage of being able to be released continuously for more than 14 hrs by mixing matrix and filler. In conclusion, SMEDDS technology can improve solubility and bioavailability, and patient compliance can be improved by preparing in sustained release form.

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Acknowledgements: This work was supported by the Mid-Career Researcher Program (No. NRF-2021R1A2C2008834) and the Basic Research Infrastructure Support Program (University-Centered Labs-2018R1A6A1A03023718) through the National Research Foundation of Korea (NRF) funded by the Korean government (MSIT).

Figure 1.
(A) Apixaban solubility in various oils, surfactants, and co-surfactants
(B) Ternary phase diagram of Labrasol®, propylene glycol, castor oil

Figure 2.
(A) Solubilization capacity in various SMEDDS formulation
(B) Particle size and PDI analysis of S1 and S4 (n=3)

Figure 3.
(A) Dissolution profiles of apixaban of Eliquis and SMEDDS tablet in water (n=3),
(B) Dissolution profiles of apixaban of Eliquis and SMEDDS tablet in 0.05M sodium phosphate buffer (n=3),
(C) Dissolution profiles of apixaban of Eliquis and SMEDDS tablet in 0.05M sodium phosphate buffer with 0.05% SLS solution (n=3)