Intestinal-absorption enhancers to improve the oral delivery of poorly permeable drug compounds have been studied since the
1960s. The approaches taken to increase absorption of these types of compounds have varied considerably in the years since
Windsor et al. demonstrated that ethylenediaminetetraacetic acid increased absorption of heparin in rats and dogs (1). Strategies
have included using surface-active agents, such as surfactants, steroidal detergents, acylcarnitines, and alkanoylcholines,
liposomes, mucoadhesive polymers, prodrug modification, nano- and microparticles, modifications of known bacterial intestinal
toxins, n-acetylated a-amino acids and n-acetylated non-a-amino acids, ultrasound, iontophoresis, and bioadhesive intestinal patches.
Several factors have inhibited the commercial development of technologies to improve bioavailability. Concerns include toxicity,
the preservation of epithelial barrier function, inter- and intra-subject variability, and the ability to deliver adequate
therapeutic levels over a sustained period. Other concerns are the requirement for large amounts of expensive active payloads,
the lack of reliable and predictive animal models, and the inability to incorporate the enhancer technology into practical,
stable, and reproducible solid-dose formulations amenable to commercial scale manufacturing.
Oral absorption enhancement technology
GIPET (a registered trademark of Merrion Pharmaceuticals) is an oral-absorption-enhancement technology platform that has advanced
to clinical evaluation. This enhancer system has increased the oral bioavailability of several types of low-permeability compounds
safely in man. Although absorption-enhancement technology focuses primarily on low-permeability drugs, it also can improve
the bioavailability of some moderately permeable drug compounds, thus resulting in lower intra- and inter-subject variation
and improved pharmacokinetic (PK) profiles.
Significant technical hurdles exist when formulating with enhancer systems. Co-release of the promoter and the active compound
at appropriate relative concentrations adjacent to the epithelium of the small intestine is necessary to generate sufficiently
mixed micelles to increase absorption. The GIPET technology consists of three formats containing surface-active materials
to achieve absorption in the small intestine. The first format, GIPET I, is an enteric-coated tablet consisting of the surface-active
materials in powder form combined with a drug in select ratios by weight. The second, GIPET II, consists of microemulsions
of oil and surfactant with a drug in an enteric-coated gel capsule (hard or soft). The third format, GIPET III, consists of
a mixture of fatty-acid derivatives in an enteric-coated gel capsule. All three GIPET platforms have been tested in humans.
The in vivo results for all three formats show that the technology platform is suitable for oral delivery of a wide range of molecule
Barriers to intestinal absorption. There are many gastrointestinal (GI) tract barriers to the absorption of small hydrophilic and macromolecules, including
peptides and proteins. These barriers include the low pH in the stomach and the enzymatic milieu of the stomach and small
intestine, both of which may result in the degradation of the compound before it reaches the wall of the GI tract. If the
compound survives these conditions, it moves to the diffusion barriers of the mucus gel layer, consisting of an unstirred
water layer and a layer produced by a mixture of sloughed-off epithelial cells and GI fluids.
The diffusion barriers discriminate on the basis of lipophilicity and charge. Once through these diffusion barriers, the compound
must pass through the epithelial cell layer lining the gut wall. The tight junctions (TJ) between cells of this layer form
a barrier to the uncontrolled absorption of noxious luminal xenobiotics (i.e., the gate function), and maintain epithelial
polarity (i.e., the fence function). The pore radius of the TJ (ranging from 3 to 11å depending on the region of the GI tract)
prevents the passage of molecules with molecular weights in excess of approximately 500 Da. Small hydrophilic molecules may
alternatively pass through the cell monolayer via carrier-mediated transporters on the apical membrane as an alternative to low-capacity paracellular flux via tight junctions. Only relatively lipophilic molecules diffuse through the cell membrane to pass transcellularly into the
systemic circulation. Transcellular migration across the intestinal epithelial monolayer does not represent an unrestricted
passageway for a molecule because it faces potential metabolism within the cell (i.e., primary metabolism by Cytochrome P450),
or it may be ejected back out to the luminal surface by efflux pumps, including the permeability glycoprotein (P-glycoprotein)
and breast-cancer-resistant proteins. Absorption via the small-intestine blood supply means that the drug will go to the liver via the hepatic portal vein, where it may be metabolized (i.e., the first-pass effect) and eliminated from the body. Overcoming
these barriers requires specialized technology to produce safe and effective oral delivery.