Oral colon delivery of insulin with the aid of functional adjuvants,☆☆

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Abstract

Oral colon delivery is currently considered of importance not only for the treatment of local pathologies, such as primarily inflammatory bowel disease (IBD), but also as a means of accomplishing systemic therapeutic goals. Although the large bowel fails to be ideally suited for absorption processes, it may indeed offer a number of advantages over the small intestine, including a long transit time, lower levels of peptidases and higher responsiveness to permeation enhancers. Accordingly, it has been under extensive investigation as a possible strategy to improve the oral bioavailability of peptide and protein drugs. Because of a strong underlying rationale, most of these studies have focused on insulin. In the present review, the impact of key anatomical and physiological characteristics of the colon on its viability as a protein release site is discussed. Moreover, the main formulation approaches to oral colon targeting are outlined along with the design features and performance of insulin-based devices.

Introduction

In the area of oral delivery, a growing attention has been focused over the past few decades on the design and manufacturing of advanced formulations intended for release of bioactive compounds to selected regions of the gastrointestinal (GI) tract. By controlling the site of drug liberation throughout the gut, it would be possible to limit the tolerability issues associated with treatments that mainly affect specific GI districts, enhance the bioavailability of drugs that show regional differences in their stability and/or permeability profiles or, alternatively, improve the therapeutic outcome in the management of widespread local pathologies (e.g. phlogosis, ulcers, microbial infections, motility disorders).

In particular, colon delivery appears to be related to a range of either potential or fulfilled interesting applications [1], [2]. Indeed, besides its long-lasting exploitation for the topical treatment of intestinal pathologic conditions, such as primarily IBD, it is extensively investigated as a means of achieving therapeutic levels of systemically-acting drugs in the general circulation. This specifically relates to the pursuit of an improved oral bioavailability for degradable and poorly permeable macromolecules of high current relevance and therapeutic value. Among them, insulin is perhaps the most prominent example.

In the present article, the potential of the large bowel as a site for release is preliminarily outlined along with the main targeting approaches that are described in the literature. Subsequently, the rationale behind colonic delivery of insulin is discussed, and an overview of oral delivery devices intended for positioned release of the hormone to the large intestine is provided. Their key design characteristics and the relevant impact on performance are commented. Particular interest is focused on formulations that not only are conceived to protect the conveyed drug molecule and promote its absorption from the colonic environment, but also possess intrinsic mechanisms enabling targeted release. Finally, in vitro, ex vivo and, when available, in vivo results from animal studies are reported.

Section snippets

Brief outline of the anatomy and physiology of the colon

The colon is the portion of intestine that starts from the caecum at the ileocaecal valve and ends with the rectum. It comprises the ascending (right), transverse, descending (left) and sigmoid branches. In the adult, it is approximately 150 cm long and 7 cm wide. The colonic wall is formed from overlapping layers, i.e. the mucosa, submucosa, muscularis externa, including a continuous layer of circular fibers and three bands of longitudinal fibers (teniae coli), and the serosa [3], [4]. The

Rationale behind oral colon delivery

Due to the inherent anatomical characteristics and physiological role, the colon has long been considered unsuitable for absorption of substrates other than water or small inorganic ions and, consequently, not viable as a release site for systemically-acting drugs. However, it has been representing an elective GI region for targeted delivery of locally-acting molecules. Currently, the benefits resulting from selective release of steroidal and non-steroidal anti-inflammatory drugs into the large

Formulation strategies for oral colon delivery

For the purpose of colon delivery, a vast array of formulations have been attempted and described in the literature as potentially effective targeting strategies. These generally rely on selected physiological parameters exhibiting typical variation patterns along the GI tract that would be perceived by dosage forms, such as the composition of the microflora, pH of fluids, intra-luminal pressure and transit or residence times within particular segments of the gut. According to which of the

Biochemical and biophysical absorption barriers

Like the entire GI tract, the large bowel poses powerful biochemical and biophysical barriers that act synergistically to hinder the absorption of peptide and protein compounds in their native form. In the colon lumen, biochemical barriers include residual soluble proteases of pancreatic origin and enzymes derived from sloughed enterocytes as well as produced by the resident micro-organisms [76], [77], [78]. Microbial peptidases perform prevailing extracellular activities. They may either be

Insulin and diabetes mellitus

Insulin is a polypeptide hormone (MW 5808 Da) formed from A (21 amino acids) and B (30 amino acids) chains interconnected by two disulfide bridges, which help stabilize its globular three-dimensional conformation with prevailing polar exterior and hidden hydrophobic residues [133]. A further disulfide bridge is present within A chain. Insulin shows a marked tendency to self-association into soluble dimers and hexamers [134]. The latter, consisting of three dimers arranged around two divalent

Oral systems for colon delivery of insulin

Oral delivery systems intended for colonic release of insulin were devised according to microflora-, pH- and time-dependent strategies (Table 1).

Conclusions

Over the past three decades, the feasibility of biotechnological insulin production has considerably intensified the efforts towards the identification and development of alternative administration modes that may at least partly replace the poorly convenient and non-fully satisfactory parenteral route currently in use. Although especially attractive, oral dosing is hindered by powerful biochemical and biophysical barriers that have not thoroughly been overcome to date. In order to increase the

Acknowledgements

The technical assistance of Mr. Paolo Tosoncin is gratefully acknowledged.

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    In memory of Professor Maria Edvige Sangalli.

    ☆☆

    This review is part of the Advanced Drug Delivery Reviews theme issue on “Advances in Oral Drug Delivery: Improved Bioavailability of Poorly Absorbed Drugs by Tissue and Cellular Optimization”.

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