Improved Stability and Antidiabetic Potential of Insulin Containing Folic Acid Functionalized Polymer Stabilized Multilayered Liposomes Following Oral Administration

Abstract

The present study reports the folic acid (FA) functionalized insulin loaded stable liposomes with improved bioavailability following oral administration. Liposomes were stabilized by alternating coating of negatively charged poly(acrylic acid) (PAA) and positively charged poly(allyl amine) hydrochloride (PAH) over liposomes. Furthermore, folic acid was appended as targeting ligand by synthesizing folic acid-poly(allyl amine) hydrochloride conjugate. The insulin entrapped within the freeze-dried formulation was found stable both chemically as well as conformationally and developed formulation exhibited excellent stability in simulated biological fluids. Caco-2 cell and ex vivo intestinal uptake studies revealed higher uptake of folic acid functionalized layersomes in comparison with their plain counterparts. In vivo pharmacodynamic and pharmacokinetic studies further revealed almost double hypoglycemia and approximately 20% relative bioavailability in comparison with subcutaneously administered standard insulin solution. Overall the proposed strategy is expected to contribute significantly in the field of designing ligand-anchored, polyelectrolyte-based stable systems in drug delivery.

Phytobioactive compound-based nanodelivery systems for the treatment of type 2 diabetes mellitus – current status

“…80 Folic acid-functionalized insulin-loaded liposomes were studied, and these showed enhanced bioavailability of insulin in the animal model through oral administration. 81 Although many antidiabetic phytobioactive compounds have been successfully studied for their oral bioavailability and their efficacy in reaching circulation systems, nanoliposomes loaded with phytobioactive compounds in antidiabetic animal models still have limited use.…”

Physicochemical and Formulation Developability Assessment for Therapeutic Peptide Delivery—A Primer

“…Due to their low permeability and slow oral absorption (2,3), peptides may have a significant residence time in the gastrointestinal (GI) tract. Therefore, it is recommended that oral peptide therapeutics be evaluated for chemical stability in biorelevant fluids (71)(72)(73).…”

“…To date, most research into oral peptide delivery has taken place in discovery and preclinical development. The characterization and stability testing for oral peptide formulations described in the scientific literature reflects the requirements in terms of duration and rigor for this stage of research and development (69,71,72,78). As more oral peptides move into clinical development, additional criteria will have to be established.…”

Novel drug delivery system: an immense hope for diabetics

“…While an array of investigations have been carried out, strategies to come up with the appropriate carrier systems for antidiabetic delivery are still being made to get widespread recognition in the global market. One such investigation was attempted by one of the authors (Agrawal et al, 2014). The proteolytic stability and antidiabetic potential of insulin were improved by developing folic acid functionalized, polymer stabilized multilayered liposomal carrier for oral administration.…”

“…Insulin and peptide surrogate Increased retention-time in lungs and hence reduced extra pulmonary sideeffects (Huang & Wang, 2006), Improved proteolytic stability in oral administration (Agrawal et al, 2014), Chemical responsive release (Karathanasis et al, 2006), Sustained release and transmucosal delivery (Jain et al, 2007a) Coating may often be non-uniform Entrapment efficiency is less compared to polymeric carrier systems Leakage is major cause of instability Sometime cholesterol which is used for bilayer arrangement, autoxidized and results in to leakage (Agrawal et al, 2014) Possible allergic reaction due to the presence of lipid (Agrawal et al, 2014;Zhang et al, 2014). Niosomes Insulin and peptide drugs Stabilized against enzymatic degradation in oral (Pardakhty et al, 2007) and vaginal delivery (Ning et al, 2005), Prolonged bioactivity for 6 h (Ning et al, 2005) Low entrapment efficiency (Pardakhty et al, 2007) Instability due to alteration in molecular arrangement of surfactants.…”