Physicochemical, pharmacokinetic and pharmacodynamic analyses of amphiphilic cyclodextrin-based nanoparticles designed to enhance intestinal delivery of insulin

Abstract

Due to excellent efficacy, low toxicity, and well-defined selectivity, development of new injectable peptides is increasing. However, the translation of these drugs into products for effective oral delivery has been restricted due to poor oral bioavailability. Nanoparticle (NP) formulations have potential to overcome the barriers to oral peptide delivery through protecting the payload and increasing bioavailability. This study describes the rational design, optimization and evaluation of a cyclodextrin-based NP entrapping insulin glulisine for intestinal administration. A cationic amphiphilic cyclodextrin (click propyl-amine cyclodextrin (CD)) was selected as the primary complexing agent for NP development. Following NP synthesis, in vitro characterization was performed. The insulin glulisine NPs exhibited an average size of 109 ± 9 nm, low polydispersity index (0.272) negative zeta potential (-25 ± 3 mV), high association efficiency (71.4 ± 3.37%) and an insulin loading of 10.2%. In addition, the NPs exhibited colloidal stability in intestinal-biorelevant media (SIF, supplemented-SIF 1% (w/v) and FaSSIF-V2) for up to 4 h. Proteolysis studies indicated that the NPs conferred protection to the entrapped insulin relative to free insulin. In vivo rat jejunal instillation studies demonstrated that the NPs mediated systemic insulin absorption, accompanied by a decrease in blood glucose levels. The relative bioavailability of the instilled insulin (50 IU/kg) from the NP was 5.5% compared to subcutaneous administration of insulin solution (1 IU/kg). The pharmacodynamic and pharmacokinetic data indicate that this cyclodextrin-based formulation may have potential for further research as an oral insulin dosage form.

<p>Overcoming Multiple Absorption Barrier for Insulin Oral Delivery Using Multifunctional Nanoparticles Based on Chitosan Derivatives and Hyaluronic Acid</p>

“…We then placed samples upon a shaking table set to 100 r/min and set to run for a pre-specified time. 4 In addition, 400 μL of sample was collected from SGF or SIF at predetermined time points and placed into a quartz cell. The corresponding values for the spectrum were recorded at 20°C by the use of a Chirascan spectrophotometer (Chirascan, Applied Photophysics, Surrey, UK).…”

“…Based upon determinations of the best stability of HA-DCDA-CS-r8-INS NPs in the preparation process, enzyme stability was further assessed by circular dichroism (CD). 4 CD spectrums for the insulin group were significantly changed in simulations of gastric fluid (SGF) treatments and demonstrated that the secondary structure was obviously destroyed (Figure 5B and C). Compared with the insulin solution, the degradation of insulin in the nanobased preparation was almost negligent.…”

“…These secretions consequently allow insulin to enter the liver through the hepatic portal vein thereafter entering peripheral tissues, ultimately resulting in beneficial reductions in concentration-based blood sugar and hypoglycemia risk across the entire circulatory system. 4 Therefore, oral forms are possibly ideal means for insulin delivery and have become an optimal choice for many patients. 5 However, challenges exist despite some of the unique advantages of orally applied insulin.…”

Macrocyclic Amphiphiles for Drug Delivery

“…al. reported amphiphilic CD21 ‐based NPs for enhancing the intestinal delivery of insulin glulisine, a rapid‐acting insulin analogue for anti‐diabete. After encapsulating insulin glulisine, the obtained NPs shown average diameter of 109 nm and insulin glulisine loading of 10.2 %.…”

“…Percentage of the initial blood glucose levels following instilled to the jejunum by insulin glulisine solution, insulin glulisine NPs, and PBS, and subcutaneous administration of insulin glulisine solution. Reprinted with permission from Ref [53]. Copyright 2018 from Elsevier.…”