The use of charge-coupled polymeric microparticles and micromagnets for modulating the bioavailability of orally delivered macromolecules

Abstract

Protein drugs have low bioavailability after oral administration, which is due in part to fast transit of the drugs or drug delivery vehicles through the gastrointestinal tract. Increasing the time that the drugs spend in the intestine after dosing would allow for greater absorption and increased bioavailability. We developed a formulation strategy that can be used to prolong intestinal retention of drug delivery vehicles without substantial alterations to current polymeric encapsulation strategies. A model drug, insulin, was encapsulated in negatively-charged poly(lactic-co-glycolic acid) (PLGA) microparticles, and the microparticles were subsequently mixed with positively-charged micromagnets, whose size will prevent them from being absorbed. Stable complexes formed through electrostatic interaction. The complexes were effectively immobilized in vitro in a model of the mouse small intestine by application of an external magnetic field. Mice that were gavaged with radio-labeled complexes and fitted with a magnetic belt retained 32.5% of the 125 I-insulin in the small intestine compared with 5.4% for the control group 6 hours after administration (p=0.005). Furthermore, mice similarly gavaged with complexes encapsulating insulin (120 Units/kg) exhibited long-term glucose reduction in the groups with magnetic belts. The corresponding bioavailability of insulin was 5.11% compared with 0.87% for the control group (p=0.007).• Correspondence to Robert Langer (Office

Biodistribution, pharmacodynamics and pharmacokinetics of insulin analogues in a rat model: Oral delivery using pH-Responsive nanoparticles vs. subcutaneous injection

“…The relative bioavailability (BA R ) of test NPs after oral administration was calculated using the following formula [24].…”

Nanolayer encapsulation of insulin- chitosan complexes improves efficiency of oral insulin delivery

“…Blood samples were collected from the tail veins of mice before administering the drug and at different time intervals after dosing for measurement of the blood glucose concentration (Accu-Chek Aviva; Roche Diagnostics, Mannheim, Germany). The relative pharmacological activity of insulin after oral administration was calculated by comparing the area under the curve of the glucose level profile of the experiment group with that of direct ip administration, as recommended by Teply et al 18 We assessed the pharmacodynamic properties of the oral insulin formulations by an ip glucose tolerance test, using fasted (overnight) diabetic animals. Weight-matched, nondiabetic male ICR mice were used as the controls.…”

Peptide and Protein Interaction with Membrane Systems

“…A well characterized, medium-length peptaibiotic is GAIV, whose sequence is nOct -Aib 1 -Gly 2 -Leu 3 -Aib 4 -Gly 5 -Gly 6 -Leu 7 -Aib 8 -Gly 9 -Ile 10 -Lol, where nOct is n-octanoyl, and Lol is leucinol. This 10-mer peptide was isolated from Trichoderma longibrachiatum in 1992 [6] and since then it was studied both in solution and in model membranes by a number of physico-chemical techniques [108] including NMR [6,54], X-ray crystallography [137], EPR [88-90, 114, 130, 131] fluorescence [45,86,126,[140][141][142] electrochemistry [10,123], and molecular dynamics (MD) simulations [17]. Its 3D-structure is helical, with a flexible hinge in the central part, formed by two consecutive Gly residues [6,137,138,141].…”

“…For this reason, different models were proposed to explain its pore-forming activity, including the SMH mechanism [38,54,90] and a carrier function [88,89]. However, several evidences would favor a barrel-stave structure for its pores, just like Alm.…”

“…The most promising approaches are represented by emulsions, micro-and nanoparticles, and liposomes [35,51,54].…”