Oral colon delivery of insulin with the aid of functional adjuvants☆,☆☆
Graphical abstract
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.
References (220)
- et al.
Cell biology and active transport processes in the colon
Adv. Drug Deliv. Rev.
(1991) The transit of dosage forms through the colon
Int. J. Pharm.
(2010)Physiology of the colorectal barrier
Adv. Drug Deliv. Rev.
(1997)- et al.
Regulation of intestinal epithelial function: a link between opportunities for macromolecular drug delivery and inflammatory bowel disease
Adv. Drug Deliv. Rev.
(2005) New oral delivery systems for treatment of inflammatory bowel disease
Adv. Drug Deliv. Rev.
(2005)- et al.
Topical delivery of therapeutic agents in the treatment of inflammatory bowel disease
Adv. Drug Deliv. Rev.
(2005) - et al.
In vivo pharmacokinetics in human volunteers: oral administered guar gum-based colon-targeted 5-fluorouracil tablets
Eur. J. Pharm. Sci.
(2003) - et al.
Colonic drug delivery of 5-fluorouracil: an in vitro evaluation
Int. J. Pharm.
(2004) - et al.
Mechanisms of antibiotic resistance and delivery strategies to prevent its emergence
J. Drug Deliv. Sci. Technol.
(2010) Colon-specific drug delivery
Adv. Drug Deliv. Rev.
(1991)
Microbially triggered drug delivery to the colon
Eur. J. Pharm. Sci.
Studies on lactulose formulations for colon-specific drug delivery
Int. J. Pharm.
Scintigraphic evaluation of a novel Colon-Targeted Delivery System (CODES™) in healthy volunteers
J. Pharm. Sci.
An in vitro investigation into the suitability of pH-dependent polymers for colonic targeting
Int. J. Pharm.
An in vivo investigation into the suitability of pH dependent polymers for colonic targeting
Int. J. Pharm.
Pharmaceutical design of a novel colon-targeted delivery system using two-layer-coated tablets of three different pharmaceutical formulations, supported by clinical evidence in humans
J. Control. Release
New preparation method of intestinal pressure-controlled colon delivery capsules by coating machine and evaluation in beagle dogs
J. Control. Release
Evaluation of intestinal pressure-controlled colon delivery capsule containing caffeine as a model drug in human volunteers
J. Control. Release
The design and evaluation of controlled release systems for the gastrointestinal tract
J. Control. Release
Preparation of enteric coated timed-release press-coated tablets and evaluation of their function by in vitro and in vivo tests for colon targeting
Int. J. Pharm.
In vitro and in vivo evaluation of an oral system for time and/or site-specific drug delivery
J. Control. Release
Different HPMC viscosity grades as coating agents for an oral time and/or site-controlled delivery system: a study on process parameters and in vitro performances
Eur. J. Pharm. Sci.
Different HPMC viscosity grades as coating agents for an oral time and/or site-controlled delivery system: an investigation into the mechanisms governing drug release
J. Pharm. Sci.
Enteric coated timed release systems for colonic targeting
Int. J. Pharm.
Scintigraphic evaluation of a new capsule-type colon specific drug delivery system in healthy volunteers
J. Pharm. Sci.
In vivo drug release behavior in dogs from a new colon-targeted delivery system
J. Control. Release
Evaluation of colonic absorbability of drugs in dogs using a novel colon-targeted delivery capsule (CTDC)
J. Control. Release
A pulsatile drug delivery system based on rupturable coated hard gelatin capsules
J. Control. Release
Formulation parameters affecting the performance of coated gelatin capsules with pulsatile release profiles
Int. J. Pharm.
Development of pulsatile release tablets with swelling and rupturable layers
J. Control. Release
In vivo performance of time-controlled explosion system (TES) in GI physiology regulated dogs
Int. J. Pharm.
A new multiparticulate delayed release system. Part I: Dissolution properties and release mechanism
J. Control. Release
An organic acid-induced sigmoidal release system for oral controlled-release preparations. 2. Permeability enhancement of Eudragit RS coating led by the physicochemical interactions with organic acid
J. Pharm. Sci.
The tolerability of multiple oral doses of Pulsincap™ capsules in healthy volunteers
J. Control. Release
Modulation of active pharmaceutical material release from a novel ‘tablet in capsule system’ containing an effervescent blend
J. Control. Release
Time and pH dependent colon specific, pulsatile delivery of theophylline for nocturnal asthma
Int. J. Pharm.
Role of the mucous/glycocalyx layers in insulin permeation across the rat ileal membrane
Int. J. Pharm.
The colon as a site for drug delivery
J. Control. Release
Structural requirements for intestinal absorption of peptide drugs
J. Control. Release
Past, present, and future technologies for oral delivery of therapeutic proteins
J. Pharm. Sci.
Transmembrane transport of peptide type compounds: prospects for oral delivery
J. Control. Release
Current strategies used to enhance the paracellular transport of therapeutic polypeptides across the intestinal epithelium
Int. J. Pharm.
The intestinal peptide carrier: a potential transport system for small peptide derived drugs
Adv. Drug Deliv. Rev.
Enhancement of polypeptide and protein absorption by macromolecular carriers via endocytosis and transcytosis
Adv. Drug Deliv. Rev.
In vitro permeability of peptidomimetic drugs: the role of polarized efflux pathways as additional barriers to absorption
Adv. Drug Deliv. Rev.
Intestinal secretion of drugs. The role of P-glycoprotein and related drug efflux systems in limiting oral drug absorption
Adv. Drug Deliv. Rev.
Protease inhibitors and penetration enhancers as approaches to modify peptide absorption
J. Control. Release
Oral colon-specific drug delivery: design strategies
S.T.P. Pharma Pratiques
Time-controlled oral delivery systems for colon targeting
Expert Opin. Drug Deliv.
The colon as a possible target for orally administered peptide and protein drugs
Crit. Rev. Ther. Drug Carrier Syst.
Cited by (0)
- ☆
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”.