Abstract
Oral delivery of macromolecular drugs is the most patient-preferred route of administration because it is painless and convenient. Over the past 30years, significant attention has been paid to oral protein delivery in adults. Unfortunately, there is an outstanding need for similar efforts in infants, a patient population with distinct intestinal physiology and treatment needs. Here, we assess the intestinal permeability of neonatal and infant mice to determine the feasibility of orally delivering peptide and protein drugs without permeation enhancers or other assistance. Using the non-everted gut sac model, we found that macromolecular permeability depended on molecular size, mouse age, and intestinal tissue type using model dextrans. For example, the apparent permeability of 70kDa FITC-Dextran (FD70) in infant small intestinal tissue was 2-5-fold higher than in adult tissue. As mice aged, the expression of barrier-forming and pore-forming tight junction proteins increased and decreased, respectively. The in vivo oral absorption of 4kDa FITC-Dextran (FD4) and FD70 was significantly higher in younger mice, and there was a fourfold increase in oral absorption of the 80kDa protein lactoferrin compared to adults. Oral gavage of insulin (5IU/kg) reduced blood glucose levels in infants by >20% at 2 and 3h but had no effect in adults. Oral insulin had 35% and <1% of the pharmacodynamic effect of a 1IU/kg subcutaneous dose in infants and adults, as measured by area above the curve. These data indicate that the uniquely leaky nature of the infantile intestine may support the oral delivery of biologics without the need for traditional oral delivery technology.
Highlights
Oral drug delivery is attractive to patients due to its ease, and there has been great success in formulating small molecule drugs [1]
This observation was based on the oral absorption of FITC-Dextran 4 kDa (FD4)
To better understand the intestinal permeability of larger macromolecules as a function of age, we assessed the permeability of four FITC-Dextrans: 4 kDa, 10 kDa (FD10), 70 kDa (FD70), and 150 kDa (FD150) in the non-everted gut sac model in mice
Summary
Oral drug delivery is attractive to patients due to its ease, and there has been great success in formulating small molecule drugs [1]. Because injections are often inconvenient, painful, and cause noncompliance, significant research has focused on the development of oral formulations for biologic drugs in adults [3]. The key challenge preventing oral peptide and protein delivery is low intestinal permeability. The barrier function of the intestine is governed by intercellular protein complexes called tight junctions that restrict the paracellular passage of molecules larger than ~600 Da [7]. In adults, this has necessitated the incorporation of permeation enhancers into oral biologic formulations to transiently dilate the paracellular space [8,9,10]. While oral peptide delivery in adults requires permeation enhancers, pediatric oral biologic delivery may be possible without them
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