The aim of this study was to develop hydrophobic ionic drug polymer complexes in order to provide sustained drug release from self-emulsifying drug delivery systems (SEDDS). Captopril (CTL) was used as an anionic model drug to form ionic complexes with the cationic polymers Eudragit RS, RL, and E. Complexes of polymer to CTL charge ratio 1:1, 2:1, and 4:1 were incorporated in two SEDDS, namely FA which was 40% Kolliphor RH 40, 20% Kolliphor EL, and 40% castor oil and FB, which was 40% Kolliphor RH 40, 30% glycerol, 15% Kolliphor EL, and 15% castor oil. Blank and complex loaded SEDDS were characterized regarding their droplet size, polydispersity index (PDI), and zeta potential. Resazurin assay was performed on Caco-2 cells to evaluate the biocompatibility of SEDDS. Release of CTL from SEDDS was determined in release medium containing 0.2 mg/mL of 5,5′-dithiobis(2-nitrobenzoic acid) (DNTB) allowing quantification of free drug released into solution via a thiol/disulfide exchange reaction between CTL and DNTB forming a yellow dye. The droplet size of SEDDS FA and SEDDS FB were in the range of 100 ± 20 nm and 40 ± 10 nm, respectively, with a PDI < 0.5. The zeta potential of SEDDS FA and SEDDS FB increased after the incorporation of complexes. Cell viability remained above 80% after incubation with SEDDS FA and SEDDS FB in a concentration of 1% and 3% for 4 h. Without any polymer, CTL was entirely released from both SEDDS within seconds. In contrast, the higher the cationic lipophilic polymer to CTL ratio in SEDDS, the more sustained was the release of CTL. Among the polymers which were evaluated, Eudragit RL provided the most sustained release. SEDDS FA containing Eudragit RL and CTL in a ratio of 1:1 released 64.78 ± 8.28% of CTL, whereas SEDDS FB containing the same complex showed a release of 91.85 ± 1.17% within 1 h. Due to the formation of lipophilic ionic polymer complexes a sustained drug release from oily droplets formed by SEDDS can be achieved. Taking into account that drugs are otherwise instantly released from SEDDS, results of this study might open the door for numerous additional applications of SEDDS for which a sustained drug release is essential.

Context: Overcoming the intestinal mucosal barrier can be a challenge in drug delivery. Nanoemulsions with negative zeta potentials can effectively permeate the mucus layer, but those with positive zeta potentials are better taken up by cells; a nanoemulsion with capricious zeta potential from negative to positive can achieve both good permeation and high uptake. Objective: This study aimed to develop dual-acting zeta-potential-amphoteric micelles enabling optimal muco-permeation and enhancement of cellular uptake. Methods: A micellar pre-concentrate was prepared from 15% Labrasol, 15% Kolliphor EL, 30% Kolliphor RH 40, and 40% dimethylsulfoxide. The micellar pre-concentrate was loaded with anionic stearic acid (SA), forming ionic complexes with cationic polymers at a ratio of 25:1 with Eudragit RS 100 and Eudragit RL 100. Blank micelles and those containing complexes were separately diluted in physiological buffers and examined for their droplet sizes, polydispersity indices (PDIs), zeta potentials, and cytotoxicity. The SA release from the micellar complexes was evaluated in 0.1 mM phosphate buffer (pH 6.8) containing 0.001% fluorescein, thereby enabling an instant decrease in fluorescence. Finally, the micelles were loaded with the model drug fluorescein diacetate (FDA) and evaluated for their muco-permeation behavior and cellular uptake. Results: The micellar dilutions formed micelles at the critical micelle concentration (CMC) of 312 µg/mL and showed a uniform average droplet size of 14.2 nm, with a PDI < 0.1. Micellar dilutions were non-cytotoxic when used at 1:100 in a physiological medium. Micelles loaded with ionic complexes achieved a sustained release of 95.5 ± 3.7% of the SA in 180 min. Moreover, the zeta potential of the complex-loaded micelles shifted from −5.4 to +1.8 mV, whereas the blank micelles showed a stabilized zeta potential of −10 mV. Furthermore, the negatively charged blank and complex-loaded micelles exhibited comparable muco-permeation, with an overall average of 58.2 ± 3.7% diffusion of FDA. The complex-loaded micellar droplets, however, provided a significantly higher cellular uptake of the model drug FDA (2.2-fold, p ≤ 0.01) Conclusion: Due to undergoing a shift in zeta potential, the modified micelles significantly enhanced cellular uptake while preserving mucus-permeating properties.

In this study, mucoactive self-emulsifying drug delivery systems (SEDDSs) based on sustained release of N-acetylcysteine (NAC) were developed for providing effective intestinal mucopermeation. Polymeric ionic complexes of NAC were formed with polyethyleneimine (PEI), Eudragit E 100, and Eudragit RS 100 and loaded into a novel SEDDS. The SEDDSs exhibited a stable average size of 75 ± 12 nm (polydispersity index (PDI) < 0.3) and showed a rise in the zeta potential from −17.31 mV to −7.72 mV. On Caco-2 cells, SEDDSs at 1–3% were non-cytotoxic. An average of 91.8 ± 5.4% NAC was released from SEDDSs containing Eudragit E 100 (p ≤ 0.05) and Eudragit RS 100 (p ≤ 0.001) complexes at a significantly slower rate within 80 min, whereas the SEDDS containing PEI released NAC in a matter of seconds. Similarly, the SEDDS complexes revealed a time-dependent reduction in mucus dynamic viscosity of 52.6 ± 19.9%. Consequently, as compared with a blank SEDDS, mucodiffusion revealed about 2- and 1.8-fold significantly greater mucopermeation of SEDDSs anchoring Eudragit E 100–NAC and RS 100–NAC complexes (p ≤ 0.05), respectively. The mucoactive SEDDSs, which steadily released NAC while permeating the mucus, were linked to a significantly increased mucopermeation in vitro as a result of optimal mucolytic targeting.

Aim: In this study, four fluorescein hydrophobic ionic complexes were formed with the cationic polymers Eudragit RS, Eudragit RL, Eudragit E, and polyethyleneimine (PEI) to provide fluorescein sustained release, sustained cellular uptake, and stability. Methods: Complexes were loaded in a self-emulsifying drug delivery system (SEDDS) composed of 40% Tween 80, 20% Kolliphor EL, 15% 2-n-Octyl-1-dodecanol, and 25% dipropylene glycol. SEDDS were investigated regarding their size, polydispersity index (PDI), zeta potential, and cytotoxicity. Fluorescein release from SEDDS was performed in phosphate buffer (pH 6.8 and pH 8) and the released fluorescein was evaluated for cellular uptake. Moreover, fluorescein from all of the SEDDS pre-concentrates was released at different time points to check its long-term stability over six months. Results: The average fluorescein load in SEDDS was 0.045%. SEDDS showed an average droplet size of 24.9 ± 1.6 nm with PDI ≤ 0.3. SEDDS complexes diluted 1:100 increased the zeta potential from -7.3 mV to +3.7 mV and provided > 85% cell viability. An 92.27 ± 3.18% fluorescein exhibited a few seconds of immediate release when used as control or PEI complex in SEDDS. On the contrary, Eudragit-fluorescein complexes in SEDDS showed sustained release of 87.01 ± 5.22% fluorescein in ≤ 70 min with 22.19 ± 14.56% and 59.27 ± 16.57% released at 10 min in pH 6.8 and pH 8 release media, respectively. Comparatively, the medium at pH 6.8 maintained a significantly improved sustained fluorescein release (p ≤ 0.001). Furthermore, Eudragit RS/RL compared to Eudragit E significantly exhibited a slower fluorescein release rate from SEDDS (p ≤ 0.01). The cellular uptake of the released fluorescein was 72.4 ± 8.2% for all SEDDS complexes after 3 h. Eudragit complexes compared to PEI complex in SEDDS significantly showed more sustained fluorescein cellular uptake at 1 h and 2 h (p ≤ 0.001). However, SEDDS complexes showed the longest fluorescein stability with PEI after six months, whereas fluorescein stability for SEDDS containing fluorescein as Eudragit complex and control showed 39.1% and 82.5% fluorescence decrease, respectively after three months. Conclusion: In the developed SEDDS, the presence of hydrophobic ionic complexes can significantly promote longer stability and sustained cellular uptake of fluorescein while releasing in a sustained manner.

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