(T1330-02-10) Development of a SMEDDS-Based Tablet for Sustained Release and Improved Solubility of Apixaban

Purpose: Apixaban is a BCS Class III drug with poor aqueous solubility (0.028 mg/mL) and limited intestinal permeability, leading to restricted oral absorption. In this study, a self-microemulsifying drug delivery system (SMEDDS) was developed to enhance the solubility of apixaban, and subsequently converted into a solid dosage form using a porous adsorbent. The optimized solid SMEDDS was further processed into a sustained-release tablet, designed to promote prolonged drug release and absorption, thereby improving the pharmacokinetic profile. This approach aims to enable a transition from twice-daily to once-daily dosing, ultimately improving patient compliance and therapeutic outcomes.

Methods: Based on solubility screening, castor oil, Labrasol®, and propylene glycol were selected as the oil phase, surfactant, and co-surfactant, respectively. Ternary phase diagrams were constructed to identify the self-emulsifying region. Liquid SMEDDS was then prepared and evaluated for their solubilization capacity, particle size, and polydispersity index (PDI). The SMEDDS was subsequently mixed with three different porous adsorbents to obtain solidified granules, which were analyzed using SEM, flowability tests, and in vitro dissolution studies. Tablets were formulated by incorporating binders, matrix-forming agents, and lubricants. The solid SMEDDS tablets were evaluated for friability and in vitro dissolution, and apixaban content was quantified using HPLC.

Results: First, the screening of surfactants was performed to identify suitable components for the SMEDDS formulation. Based on the solubility screening results, castor oil, Kolliphor® TPGS, and propylene glycol were selected as the oil phase, surfactant, and co-surfactant, respectively, due to their superior solubilizing capacity for apixaban. Using these components, ternary phase diagrams were constructed to evaluate the self-emulsification behavior of various formulations. Formulations containing 50–70% surfactant, 20–40% co-surfactant, and 5–15% oil formed clear and stable microemulsions, while those with higher oil content or insufficient surfactant levels exhibited turbidity and phase separation. These findings highlight the importance of optimizing component ratios for efficient self-emulsification, and the formulations within the optimal region were selected for further solubility evaluation and solidification processes. Second, the assessment of liquid SMEDDS focused on the evaluation of solubility, particle size, and polydispersity index (PDI). Among five SMEDDS formulations with excellent self-emulsifying properties, apixaban solubility was evaluated, and it was found that increasing the proportion of surfactant while keeping the oil content fixed at 10% led to improved solubility. Particle size and PDI analyses of the high-solubility formulations (LS1–LS3) revealed that LS2 exhibited the smallest droplet size (158.53 nm± 3.75) and the lowest PDI (9.57± 2.24), indicating the most uniform dispersion. Therefore, LS2 was selected for the dissolution study. Third, a screening of adsorbents was conducted to solidify the liquid SMEDDS. Three adsorbents—Aerosil® 200, Fujicalin®, and Neusilin® US2—were evaluated. Among them, Neusilin® US2, with its superior porosity, effectively absorbed the liquid formulation and maintained a uniform morphology without particle aggregation. In flowability assessments, granules prepared with Neusilin® US2 showed the best flow characteristics, with the 1:1 (SMEDDS:adsorbent) ratio exhibiting the highest flowability. However, under tablet compression, the 2:1 ratio demonstrated better tablet ability. Furthermore, in vitro dissolution studies revealed that granules containing Neusilin® US2 exhibited the fastest dissolution rate, indicating that it is the most suitable adsorbent for solid SMEDDS formulation. Finally, the evaluation of tablet properties confirmed the successful development of an optimized SMEDDS matrix tablet. The tablets demonstrated acceptable mechanical strength with a friability value of 0.71%, indicating suitability for further development. In vitro dissolution studies conducted in both distilled water and 0.05 M sodium phosphate buffer with 0.05% SLS revealed that the SMEDDS tablets significantly enhanced apixaban dissolution compared to the raw drug and achieved a sustained-release profile, highlighting their potential for once-daily oral administration.

Conclusion: A sustained-release SMEDDS tablet of apixaban was developed using lipid-based excipients and a hydrophilic matrix to improve solubility, permeability, and patient compliance. Dissolution tests showed prolonged drug release up to 14 hours, with comparable total release to Eliquis®. Enhanced absorption was likely due to lymphatic transport and P-gp inhibition by Kolliphor® TPGS. This approach supports dose reduction and improved bioavailability through once-daily administration.

(A) Solubility profile of apixaban in various oils, surfactants, and co-surfactants
(B) Ternary phase behavior of Kolliphor TPGS, Propylene glycol, and Castor oil

(A) Apixaban Solubilization in SMEDDS
(B) Apixaban Solubilization capacity in various SMEDDS formulation
(C) Particle size, PDI analysis of LS1, LS2 and LS3 (n=3)

(A) Dissolution behavior of apixaban from Eliquis, SMEDDS granule and tablet in DW (n=3)
(B) Dissolution behavior of apixaban from Eliquis, SMEDDS granule and tablet in 0.05M sodium phosphate buffer with 0.05% SLS solution (n=3)