Oral Insulin Formulation Research Articles

Nanomedicine and its potential in diabetes research and practice

Nanomedicine involves measurement and therapy at the level of 1-100 nm. Although the science is still in its infancy, it has major potential applications in diabetes. These include solving needs such as non-invasive glucose monitoring using implanted nanosensors, with key techniques being fluorescence resonance energy transfer (FRET) and fluorescence lifetime sensing, as well as new nano-encapsulation technologies for sensors such as layer-by-layer (LBL) films. The latter might also achieve better insulin delivery in diabetes by both improved islet encapsulation and oral insulin formulations. An 'artificial nanopancreas' could be an alternative closed-loop insulin delivery system. Other applications of nanomedicine include targeted molecular imaging in vivo (e.g. tissue complications) using quantum dots (QDs) or gold nanoparticles, and single-molecule detection for the study of molecular diversity in diabetes pathology.

Confocal microscopic analysis of transport mechanisms of insulin across the cell monolayer

Development of oral insulin formulations would significantly improve the quality of life of patients suffering from diabetes. Complexation hydrogels developed in our laboratory, are one of the most promising classes of materials for use in targeted oral delivery of proteins. Results from confocal microscopy analysis of insulin transport in Caco-2 cells indicated that the primary route of transport was the paracellular pathway and that the transcellular component of the transport was insignificant.

In vitro and in vivo evaluation of a novel oral insulin formulation

To develop a stable self-emulsifying formulation for oral delivery of insulin. Caco-2 cell line and diabetic beagles were used as in vitro and in vivo models to study the absorption mechanism and the hypoglycemic efficacy of the formulation. In addition, various physicochemical parameters of the formulation such as droplet size, insulin encapsulation efficiency and stability were evaluated. This formulation enabled changes in barrier properties of Caco-2 monolayers, as referred by transepithelial electrical resistance (TEER) and apparent permeability coefficients (P(app)) of the paracellular marker ranitidine (20-fold greater than control) but not transcellular marker propranolol, suggesting that the opening of tight junctions was involved. In diabetic beagle dogs, the bioavailability of this formulation was up to 15.2% at a dose of 2.5 IU/kg in comparison with the hypoglycemic effect of native insulin (0.5 IU/kg) delivered by subcutaneous injection. This formulation, recently approved by the China State Food and Drug Administration to enter clinical trials, was stable, degradation-protected and absorption-enhanced, and provided a promising formulation for oral insulin delivery.

Novel delivery system based on complexation hydrogels as delivery vehicles for insulin–transferrin conjugates

A variety of approaches have been investigated to address the problems associated with oral insulin delivery, but the bioavailability of oral insulin is still low. Insulin is rapidly degraded by the enzymes in the GI tract and is not transported across the epithelial barrier easily. The oral insulin formulation developed in this work makes use of complexation hydrogels for oral delivery of insulin bioconjugates. The insulin bioconjugates synthesized in this work consist of insulin bound to transferrin molecule which can be uptaken by the epithelial cells. The conjugates can increase the permeability of insulin across the epithelial barrier by receptor-mediated transcytosis. The transferrin in the conjugate is also shown to stabilize insulin in the presence of intestinal enzymes. Use of complexation hydrogels for delivery of insulin–transferrin conjugate may greatly increase the bioavailability of oral insulin. This is because, the complexation hydrogels are known to exhibit characteristics that make them ideal candidates for oral protein delivery. They can also inhibit the degradation of insulin in the GI tract. Thus, combination of these two approaches may provide an innovative platform for oral insulin delivery.

An oral insulin formulation, 'Oralin'*, significantly improves glucose control in patients with type??2 diabetes mellitus,

An oral insulin formulation, 'Oralin'*, significantly improves glucose control in patients with type??2 diabetes mellitus,

Self-assembled "nanocubicle" as a carrier for peroral insulin delivery.

A patient with (insulin-dependent) diabetes mellitus receives at least one subcutaneous insulin injection a day to maintain low serum glucose concentrations. Since patients' compliance with such dosage regimens is too low, the development of an oral formula is clearly attractive. We present the development of a liquid formula that can be easily dispersed in water to produce particles named "nanocubicles" which efficiently encapsulate insulin. Fasted streptozotocin-induced diabetic rats were administered orally with particles encapsulating insulin, and particles without insulin or soluble insulin in water. Groups of rats were also injected soluble insulin in PBS for control. Blood glucose concentration and insulin concentration were measured 1, 2, 3, 4 and 6 h after the administration of the insulin formulas. In vitro experiments show that the particles can be taken up by the Caco-2 cells at a high ratio. The serum glucose concentration was controlled for more than 6 h after oral insulin administration but returned to the basal concentration in 3 h when 1 IU/kg of insulin was injected intravenously. Our biocompatible and stable oral insulin formulation is easy to prepare and produces reproducible hypoglycaemic effects, therefore we anticipate clinical acceptance and utilization of this form of insulin therapy.

Oral Administration of Insulin in Solid Form to Nondiabetic and Diabetic Dogs

It was previously demonstrated that a biologically active insulin could cross the mucosal membrane in the gut by using surface active substances. In this report we describe studies in which insulin administered orally, in a solid formulation, was effectively absorbed in the canine model. The insulin was mixed with cholate and soybean trypsin inhibitor. It was delivered orally, as enterocoated microtablets, to nondiabetic and diabetic (pancreatectomized) dogs in a fasting state. The time interval between the administration of the drug and the beginning of a decrease in the plasma glucose levels was 60–140 min. This decrease reached a minimum level of 20–40 % of the initial values and lasted for more than 90 min following administration of the drug. In this model a pronounced increment in plasma insulin levels was shown prior to the drop of plasma glucose concentrations. It is concluded that with this novel oral insulin formulation a beneficial biological effect can be achieved in the treatment of diabetes.

Vancomycin and insulin used as models for oral delivery of peptides

Targeted administration of vancomycin HCl and porcine insulin to different sections of the gastrointestinal tract of rats indicated that the lower small intestine (ileum) and the colon were more favorable sites for peptide absorption. Intact absorption of vancomycin without absorption enhancement or enzyme inhibition at an absolute bioavailability of 5% was observed. Insulin is not absorbed in the lower gastrointestinal tract without absorption enhancer or enzyme inhibition coadministration. However, appreciable absorption of insulin was observed by decreased glucose levels and increased plasma insulin levels following administration to the colon of nondiabetic rats with 1% sodium glycocholate (SGC) and 1% disodium ethylenediaminetetraacetic acid (Na 2EDTA) or aprotinin. A significant increase in absorption was observed following rectal administration of the same formulation. Formulation development was undertaken to target release utilizing Eudragit® S100 enteric coating and decrease gastrointestinal transit time comparing two bioadhesive polymers (chitosan and Carbopol® 934). Salicylate microspheres incorporated in enteric and nonenteric formulations with chitosan or Carbomer (Carbopol® 934) were tested for sustained delivery in the lower gastrointestinal tract using rat and dog animal models. Optimized formulations were designed for porcine insulin which were then tested in the nondiabetic dog model for bioavailability and pharmacological response. Microspheres of triglyceride mixtures and low-melting fat composition were prepared using a spinning disk method and subsequently incorporated in two-part gelatin capsules containing Carbopol® 934 or incorporated in chitosan film prior to placement in two-part gelatin capsules. Improved bioavailability for the enteric coated oral insulin formulation was observed in the dog model with prolonged decrease in plasma glucose.