# Small Intestine-Targeted Long-Acting Oral Insulin Formulation Based on Engineered Milk Protein Nanoparticles

## TL;DR

Researchers developed an oral insulin formulation using engineered milk protein nanoparticles that effectively deliver insulin to the small intestine, offering a long-acting and safer alternative to injections.

## Contribution

A novel oral insulin formulation using casein-based nanoparticles with sodium caprate for improved bioavailability and prolonged action.

## Key findings

- The formulation achieved 18.1% insulin bioavailability in mice.
- Oral administration showed comparable efficacy to insulin injections but with a 6-hour longer duration of action.
- The formulation prevented hypoglycemia in fasted mice.

## Abstract

Insulin therapies remain essential for glycemic control
in diabetes
mellitus, yet conventional subcutaneous injection is associated with
poor patient compliance, risk of hypoglycemia, and other adverse effects.
Oral insulin formulations offer a promising alternative by improving
patient adherence and mimicking the endogenous insulin pathway. However,
their clinical trials, mostly in enteric capsules and tablets, have
yielded limited efficacy due to low insulin bioavailability. In this
study, we prepared an oral insulin formulation by coencapsulating
insulin and the permeation enhancer sodium caprate (C10) into milk protein casein-based nanocarriers (casNP). The casein
shell was optimized for stable loading of insulin/C10,
guided by ex vivo gut sac studies with different
C10 concentrations. Reported casNP/insulin/C10 exhibited excellent stability in simulated gastric fluid and enabled
insulin release in simulated jejunal fluid via trypsin-mediated casein
degradation. Oral administration in mice resulted in a stomach half-emptying
time of <15 min, small intestine delivery efficiency of 10.8 ±
1.7%, and insulin bioavailability of 18.1%, as measured in liver and
plasma. Oral casNP/insulin/C10 (50 IU/kg) exhibited a blood
sugar-lowering efficacy comparable to subcutaneously injected Insulin
Aspart (5 IU/kg), while extending the duration of action by approximately
6 h and preventing hypoglycemia in fasted mice. These findings demonstrate
that casNP/insulin/C10 is a promising oral insulin formulation
for managing diabetes.