Enhanced oral bioavailability of insulin-loaded solid lipid nanoparticles: pharmacokinetic bioavailability of insulin-loaded solid lipid nanoparticles in diabetic rats

Abstract

Objective: Insulin is a hormone used in the treatment of diabetes mellitus. Multiple injections of insulin every day may causes pain, allergic reactions at injection site, which lead to low patient compliance. The aim of this work was to develop and evaluate an efficient solid lipid nanoparticle (SLN) carrier for oral delivery of insulin. Methods: SLNs were prepared by double emulsion solvent evaporation (w/o/w) technique, employing glyceryltrimyristate (Dynasan 114) as lipid phase and soy lecithin and polyvinyl alcohol as primary and secondary emulsifier, respectively, and evaluated in vitro for particle size, polydispersity index (PDI) and drug entrapment. Results: Among the eight different developed formulae (F1-F8), F7 showed an average particle size (99 nm), PDI (0.021), high entrapment of drug (56.5%). The optimized formulation (F7) was further evaluated by FT-IR, DSC, XRD, in vitro release, permeation, stability, bioavailability and pharmacological studies. Insulin-loaded SLNs showed better protection from gastrointestinal environment as evident from the relative bioavailability, which was enhanced five times as compared to the insulin solution. A significant enhancement of relative bioavailability of insulin was observed, i.e. approximately five times of pure insulin solution when loaded in SLN (8.26% versus 1.7% only).

Evaluation of inhaled recombinant human insulin dry powders: pharmacokinetics, pharmacodynamics and 14-day inhalation

“…In the present study, PK‐PD modelling and non‐compartmental analysis demonstrated that the pharmacokinetic and pharmacodynamic properties of inhaled rh‐insulin microparticles were significantly improved in the presence of PS or PHT. The relative pharmacokinetic bioavailability F (%) and pharmacodynamic availability PA (%) in PS and PHT‐loaded rh‐insulin dry powders were enhanced compared with previously reported inhaled insulin . Generally, rh‐insulin has low bioavailability mostly due to its early degradation before absorption, inactivation and digestion by widely distributed insulin‐degrading enzymes (proteolytic enzymes), poor permeability across mucosal epithelium, high molecular weight and lack of lipophilicity .…”

“…The relative pharmacokinetic bioavailability F (%) and pharmacodynamic availability PA (%) in PS and PHT-loaded rhinsulin dry powders were enhanced compared with previously reported inhaled insulin. [5,28,30] Generally, rh-insulin Data represent mean AE SEM (n = 5). T min , time to reach the minimum serum glucose concentration; C min (%), the percentage minimum serum glucose concentration; AAC 0-360 min , area above the curve of reduced serum glucose concentrations; PA, the relative pharmacological availability; k in , the apparent zero-order rate constant for the production of serum glucose, k out , the first-order rate constant for the utilization of serum glucose, IC 50 , the rh-insulin concentration that produces 50% of maximal inhibition on serum glucose production.…”

“…Although continuous insulin infusion provides an alternative for intensive therapy regimes, multiple daily s.c. injections of insulin remain the most common route because of the safety concern with the use of continuous s.c. insulin infusion in hospital . Therefore, non‐invasive or alternative route of insulin administration such as nasal, oral or pulmonary have been widely investigated, among which pulmonary delivery of insulin still receive most attention …”

“…[4] Therefore, non-invasive or alternative route of insulin administration such as nasal, oral or pulmonary have been widely investigated, among which pulmonary delivery of insulin still receive most attention. [5][6][7] The superior physiological function and anatomic structure of pulmonary provides a unique absorption environment for protein or peptide drugs. [8,9] With a molecular weight of 5808, recombinant human insulin (rh-insulin) is able to cross the alveolus epithelium and enter systemic circulation as solution or dry powders.…”

Formation of multimeric antibodies for self-delivery of active monomers

“…Proteins and peptides, such as insulin, growth hormones, antibodies and enzymes, are being routinely used for therapeutic purposes (Szlachcic et al, 2011;Ansari et al, 2016). However, in contrast to these advances in protein production and purification techniques, the mode of administration of proteins to patients has remained principally unchanged, based almost solely on injections of the proteins in their native conformation (Narayanaswamy et al, 2016).…”