The aim of this study was to evaluate biodegradable cationic surfactants based on lysine. Methods: Lysine was esterified with cholesterol, oleyl alcohol and 1-decanol resulting in cholesteryl lysinate (CL), oleyl lysinate (OL) and decyl lysinate (DL). Esters were investigated regarding their log D noctanol/water , critical micelle concentration (CMC) and biodegradability. Hemolytic potential of CL, OL, DL and the already established hexadecyl lysinate (HL) was determined and complexes with insulin (INS) were formed by hydrophobic ion pairing (HIP). Lipophilic characteristics of ion-pairs were examined by analyzing their log P n-butanol/water. Results: Successful synthesis of CL, OL and DL was confirmed by IR, NMR and MS. Log D analysis revealed amphiphilic properties for the esters and a CMC of 0.01 mM, 2.0 mM and 6.0 mM was found for CL, OL and DL, respectively. Biodegradability was proven, as over 99% of OL and DL were degraded by isolated enzymes within 30 min and after 3 h 97% of CL was cleaved by membrane bound enzymes. OL as well as DL displayed no hemolytic effect and for CL cytotoxicity was significantly reduced in comparison to HL. INS/CL complex exhibited highest lipophilicity. Conclusion: Cholesterol-amino acid based surfactants seem to be promising agents for HIP.

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The present work aimed to form hydrophobic ion pairs (HIPs) of a small molecule remaining inside the oily droplets of SEDDS to a high extent. HIPs of ethacridine and various surfactants classified by functional groups of phosphates, sulfates, and sulfonates were formed and precipitation efficiency, log D n‑octanol/water, and solubility in different excipients were investigated. Most lipophilic HIPs were incorporated into SEDDS and evaluated regarding drug release. Docusate HIPs showed the highest increase in lipophilicity with a precipitation efficiency of 100%, a log D n‑octanol/water of 2.66 and a solubility of 132 mg/mL in n-octanol, 123 mg/mL in oleyl alcohol, and 40 mg/mL in medium chain triglycerides. Docusate HIPs were incorporated into three SEDDS of increasing lipophilicity (F1 < F2 < F3) based on medium chain triglycerides, oleyl alcohol, Kolliphor EL, and Tween 80 (F1: 1 + 5 + 2 + 2; F2: 3 + 3 + 2 + 2; F3: 5 + 1 + 4 + 0). Highest achievable payloads ranged from 74.49 mg/mL (F3) to 97.13 mg/mL (F1) and log DSEDDS/RM increased by at least 7.5 units (4.99, F1). Drug release studies via the diffusion membrane method confirmed minor release of docusate HIPs from all SEDDS (<2.7% within 4 h). In conclusion, highly lipophilic HIPs remain inside the oily phase of SEDDS and likely reach the absorption membrane in intact form.

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