Ionic liquids for oral insulin delivery

Abstract

With the rise in diabetes mellitus cases worldwide and lack of patient adherence to glycemia management using injectable insulin, there is an urgent need for the development of efficient oral insulin formulations. However, the gastrointestinal tract presents a formidable barrier to oral delivery of biologics. Here we report the development of a highly effective oral insulin formulation using choline and geranate (CAGE) ionic liquid. CAGE significantly enhanced paracellular transport of insulin, while protecting it from enzymatic degradation and by interacting with the mucus layer resulting in its thinning. In vivo, insulin-CAGE demonstrated exceptional pharmacokinetic and pharmacodynamic outcome after jejunal administration in rats. Low insulin doses (3-10 U/kg) brought about a significant decrease in blood glucose levels, which were sustained for longer periods (up to 12 hours), unlike s.c. injected insulin. When 10 U/kg insulin-CAGE was orally delivered in enterically coated capsules using an oral gavage, a sustained decrease in blood glucose of up to 45% was observed. The formulation exhibited high biocompatibility and was stable for 2 months at room temperature and for at least 4 months under refrigeration. Taken together, the results indicate that CAGE is a promising oral delivery vehicle and should be further explored for oral delivery of insulin and other biologics that are currently marketed as injectables.

From Farm to Pharmacy: Strawberry-Enabled Oral Delivery of Protein Drugs

“…Area above the curve calculations showing that pharmacodynamic activity of intestinal insulin at the highest pelargonidin dose (80 mg/kg) is approximately double that of subcutaneous insulin (Fig 4d and Table 1). This performance outpaces other promising, recently reported strategies for oral insulin delivery, including ionic liquid (28) and anionic nanoparticles (29), which achieve between 60% and 100% relative bioactivity.…”

“…(30) and anionic nanoparticle permeation enhancers (29) in healthy animals have achieved 7% and 29% relative insulin bioactivity, whereas this system produces 140% of the pharmacodynamic potency per insulin molecule (Table 1). It is also notable that the hypoglycemic effect here is achieved using only a 1 U/kg oral insulin dose, as opposed to the 10-100 U/kg doses that other oral delivery systems have necessitated (28)(29)(30).…”

Unique stabilizing mechanism provided by biocompatible choline-based ionic liquids for inhibiting dissociation of inactivated foot-and-mouth disease virus particles

“…For instance, the biocompatible ILs based on the choline cation enhance the thermostability of enzymes, interleukin-2 (IL-2), monoclonal antibodies (mAbs), and insulin. [16][17][18][19] Imidazoliumbased ionic liquids [Bmim][Br] was found to inhibit aggregation of insulin. 20 Ammonium-based protic ionic liquid triethylammonium dihydrogen phosphate (TEAP) can act as a stabilizer and refolding additive for Succinylated Con A.…”

“…Choline has been recognized by the Food and Drug Administration as generally regarded as safe ingredients. 19 Choline-based ILs are also regarded with good biocompatibility and safety. 19 To evaluate stability of FMDV, the differential scanning uorimetry (DSF) technology was employed for thermal stability analysis.…”

“…19 Choline-based ILs are also regarded with good biocompatibility and safety. 19 To evaluate stability of FMDV, the differential scanning uorimetry (DSF) technology was employed for thermal stability analysis. Dissociation of 146S into 12S was detected and quantied by highperformance size-exclusion chromatography (HPSEC).…”