Enhanced oral absorption of insulin: hydrophobic ion pairing and a self-microemulsifying drug delivery system using a D-optimal mixture design

The lipophilicity of a peptide drug can be considerably increased by hydrophobic ion pairing with amphiphilic counterions for successful incorporation into lipid-based formulations. Herein, to enhance the oral absorption of insulin (INS), a self-microemulsifying drug delivery system (SMEDDS) formulation was developed. Prior to optimization, INS was complexed with sodium n-octadecyl sulfate (SOS) to increase the loading into the SMEDDS. The INS–SOS complex was characterized via scanning electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and its dissociation behavior. The SMEDDS was optimized using a D-optimal mixture design with three independent variables including Capmul MCM (X₁, 9.31%), Labrasol (X₂, 49.77%), and Tetraglycol (X₃, 40.92%) and three response variables including droplet size (Y₁, 115.2 nm), INS stability (Y₂, 46.75%), and INS leakage (Y₃, 17.67%). The desirability function was 0.766, indicating excellent agreement between the predicted and experimental values. The stability of INS-SOS against gastrointestinal enzymes was noticeably improved in the SMEDDS, and the majority of INS remained in oil droplets during release. Following oral administration in diabetic rats, the optimized SMEDDS resulted in pharmacological availabilities of 3.23% (50 IU/kg) and 2.13% (100 IU/kg). Thus, the optimized SMEDDS is a good candidate for the practical development of oral delivery of peptide drugs such as INS.

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Materials

Human recombinant INS, α-chymotrypsin, bile salts, Brij L4, lipase from porcine pancreas, n-octanol, pepsin, Tetraglycol, trypsin, sodium deoxycholate (SDC), sodium docusate (DOC), sodium oleate (OLE), and Tween 20 were obtained from Sigma–Aldrich Chemical Co. (St. Louis, MO, USA). Capmul MCM was purchased from Abitec Co. (Janesville, WI, USA). Capryol 90, Labrasol, Plurol Oleique CC 497, and Transcutol P were supplied by Gattefosse (Saint-Priest, France). Cremophor EL was purchased from BASF (Ludwigshafen, Germany). SOS was obtained from Acros Organics (NJ, USA). All other chemicals and reagents were purchased from commercial sources and were of analytical grade.