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.
Oral absorption enhancement technologyGIPET (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 classes.
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.