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Formulation and Delivery - Chemical

(M1530-08-54) Compatibility Assessment of Ready-to-Fill Delayed Release Capsules with Self-Nanoemulsifying Drug Delivery Systems (SNEDDS)

Monday, November 10, 2025
3:30 PM - 4:30 PM CT
Purpose: Lipid-based formulations, such as self-nanoemulsifying drug delivery systems (SNEDDS), have shown promise in enhancing the oral solubility of poorly water- soluble drugs. These formulations are liquid or semisolid and are usually filled into soft capsules (1). Grüne et al. and Koehl et al have shown that non-functionalized capsules, whether based on HPMC or gelatin, are compatible with a wide range of SNEDDS formulations, thereby serving as viable alternative carrier for SNEDDS (2, 3). The combination of pre-functionalized hard capsules with the SNEDDS technology has not yet been investigated. In this study, two surrogate SNEDDS formulations, comprising an oil, surfactant, and a co-solvent, were filled into ready-to-fill functionalized hard capsules. This approach aimed to evaluate the compatibility of the SNEDDS formulations, assess the enteric functionality of the capsules, and analyze their performance in releasing the SNEDDS formulations within the targeted particle size range.

Methods: SNEDDS formulations of celecoxib and fenofibrate were prepared as outlined by Schmied et al (4). The celecoxib formulation consisted of celecoxib (9.09%), d-TPGS (6.24%), Gelucire 44/14 (4.55%), Tween 80 (49.85%) and Miglyol 812 (30.27%) and the fenofibrate formulation of fenofibrate (5.21%), d-TPGS (11.06%), Tween 80 (55.29%), Brij 35 (9.48%) and Miglyol 812 (18.96%), respectively. For manufacturing of the SNEEDS all ingredients were weighed together in a glass flask and stirred for 1h at 50°C on a magnetic stirrer until an isotropic solution was obtained. The resulting nanoemulsions, after dispersion in various media, had to have a droplet size < 50 nm.
Disintegration was performed with 500 mg SNEEDS formulation filled in size 0 uncoated capsules (HPMC capsule; GoCaps) or size 0 ready-to-fill delayed release capsules (EUDRACAP® enteric and EUDRACAP® colon; Evonik) by using a USP conform disintegration tester (PTZ Auto 4 Pharmatest). Disintegration was studied for 2h in 0.1N HCl (pH 1.0), followed by 30 min phosphate buffer saline Ph. Eur. (pH 6.8), and 120 min phosphate buffer Ph. Eur. (pH 7.2) depending on the functionality of the capsule. All experiments were performed in a media volume of 750 mL at 37 ± 0.5 °C with six capsules.
Dynamic light scattering (DLS) was measured using a Zetasizer Nano ZS (Malvern Panalytical) to investigate the droplet size of the SNEDDS formulations after emulsification in various media either by magnetic stirrer or disintegrator. For magnetic stirring, an aliquot of 300 µL SNEDDS was added to 500 mL media (0.1N HCl, PBS pH 6.8 or phosphate buffer pH 7.2) and stirred for 60 min at 37°. After emulsification, 1 mL was withdrawn and measured at 25°C in automatic mode with water as dispersant (viscosity: 0.8872 cP; RI: 1.330) for size calculation. For the disintegrator, an aliquot of 1 mL was taken after complete disintegration, centrifuged for 8 min at 7,700 g and analyzed as described previously.

Results: To assess the capability of the SNEDDS formulations in generating a stable and translucent nanoemulsion, the SNEDDS were added to various media, specifically to 0.1N HCl and PBS at pH 6.8. Following emulsification, all samples resulted in a translucent nanoemulsion. The particle size analysis revealed that the fenofibrate SNEDDS formulation exhibited a size range of 20-22 nm, while the celecoxib SNEDDS formulation measured between 27-31 nm (Figure 1 and 2; red and green line), both formulations were within the target size range of less than 50 nm. Therefore, these formulations were subsequently filled into HPMC and ready-to-fill delayed-release capsules for disintegration studies. Table 1 shows the mean disintegration time of six capsules. HPMC capsules disintegrated in the first medium (0.1N HCl) within 5 and 7 min, respectively. In contrast, the delayed-release capsules EUDRACAP® enteric and colon, demonstrated resistance in the acidic stage for two hours. The liquid SNEDDS formulation was released only in the second medium (PBS pH 6.8) for EUDRACAP® enteric capsules, and in the third medium (phosphate buffer pH 7.2) for EUDRACAP® colon capsules, respectively. Finally, the particle size distribution following disintegration was analyzed. As illustrated in Figures 1 and 2, the presence of the pigment TiO2 within the HPMC capsules affected the DLS measurements, resulting in a primary peak within the range of 100 to 1,000 nm (blue line). To mitigate this interference, samples were centrifuged to remove the solid components as thoroughly as possible. All capsule types successfully released the SNEDDS formulation within the targeted size range of less than 50 nm, as represented by the black, magenta, and pink lines.

Conclusion: This study highlights the successful integration of pre-functionalized hard capsules with the SNEDDS technology, demonstrating their compatibility and effectiveness in maintaining enteric functionality. The formulations released within the targeted particle size range of less than 50 nm, indicating their potential for oral solubility enhancement. Combining the SNEDDS technology with pre-functionalized capsules may result in a higher drug efficiency and less adverse effects by delivering the SNEDDS to the optimal target region in the GI tract.

Table 1: Mean disintegration time of n=6 capsules. The value in the cells represents the disintegration time in the defined media. (n.d. = not disintegrated)

Figure 1: Size distribution (by intensity) for celecoxib loaded SNEDDS formulations in pure media and after disintegration testing. Disintegration samples were centrifuged for 8 min at 7,700 g.

Figure 2: Size distribution (by intensity) for fenofibrate loaded SNEDDS formulations in pure media and after disintegration testing. Disintegration samples were centrifuged for 8 min at 7,700 g.