Abstract
The application of permeation enhancers (PEs) to improve transport of poorly absorbed active pharmaceutical ingredients across the intestinal epithelium is a widely tested approach. Several hundred compounds have been shown to alter the epithelial barrier, and although the research emphasis has broadened to encompass a role for nanoparticle approaches, PEs represent a key constituent of conventional oral formulations that have progressed to clinical testing. In this review, we highlight promising PEs in early development, summarize the current state of the art, and highlight challenges to the translation of PE-based delivery systems into safe and effective oral dosage forms for patients.
Highlights
Since the early 1990s, the pharmaceutical industry has gradually reduced attrition related to non-optimal pharmacokinetics (PK) and low bioavailability (BA) of drugs in development [1]
Low permeability might be acceptable if a safe and consistent therapeutic effect can be achieved with a molecule that has a long t1/2, even in the context of high variability in BA, otherwise poorly permeable drugs are typically formulated in injectable dosage forms or in dosage forms using other routes of delivery with higher membrane permeability than the intestine, such as the nasal route
While there is no evidence to date that oral permeation enhancers (PEs)-macromolecule dosage forms cause infections in clinical trials, it is important to mention that if this is true risk, potential clinical manifestations range from asymptomatic infection to diarrhea, to more serious infections depending on the micro-organism and host genetic variability [120]
Summary
Since the early 1990s, the pharmaceutical industry has gradually reduced attrition related to non-optimal pharmacokinetics (PK) and low bioavailability (BA) of drugs in development [1]. Proprietary formulations that attempt to improve oral absorption of macromolecules in humans usually include permeation enhancers (PEs) Failure of these PE-based formulations to translate into commercial products has led academic investigators to prioritize development of more technologically advanced drug delivery systems rather than address impediments to translation of PEs. Several hundred compounds have been shown to alter permeability in oral, nasal, buccal, pulmonary, vaginal, and corneal delivery models. At low test concentrations in reductionist cell and tissue based delivery models, transcellular perturbants (i) activate plasma membrane receptors and enzymes, (ii) modulate intracellular mediators, (iii) selectively remove TJ proteins from fluidic regions of the membrane, and (iv) initiate repair mechanisms related to opening of TJs [20] In some cases, these actions are uncoupled from membrane perturbation [21]. It remains to be seen if CPPs will eventually advance to clinical testing in oral delivery of anti-diabetic peptides [33]
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