Intestinal Permeation Enhancement for Poorly Absorbed Drugs: Matching Mechanism of Action with Biological Assessment

摘要

Use of permeation enhancers for oral delivery of macromolecules has a history dating back nearly 50 years. After a lull in the late 1990s, permeation enhancers are now providing convincing human clinical efficacy and safety data with selected cargoes. While any of the most advanced enhancers in clinical development are recognized as safe for human consumption due to their presence in foodstuffs and use as excipients, this does not however necessarily mean that they are safe in oral dosage forms specifically designed to promote absorption. It is somewhat ironic that the enhancer-based platforms that appear most advanced for oral delivery are relatively simple solid-dose formulations, whose mechanism of promotion in higher non-reductionist models appears multi-faceted. At the relevant doses required for efficacy, they can have relatively non-specific effects on the epithelium in vivo. In addition, assumptions over potential toxicity of enhancers have hampered the research area despite a myriad of human data showing little evidence of bystander pathogen absorption. In fact, there is evidence that some promoters are no more damaging to the intestinal epithelium than several food substances, established drug formulations and normal bowel residents, such as bile salts. Furthermore, the intestinal epithelium has a remarkable capacity to repair superficial mucosal injury (1), which may allow at least a degree of repeat dosing. The fact that an oro-buccal formulation of insulin containing micelles and bile salt-type excipients was recently approved by the FDA for selected Type II diabetic patients (2) offers encouragement to the intestinal delivery field. It is recognized however, that there are significant differences in the challenges for regional intestinal delivery, along with a potentially higher safety bar.This presentation will review key data from my group on the medium chain fatty acid enhancer, sodium caprate (C_(10)). 1 will describe how our experiments (3) and those of others (4) using Caco-2 monolayers as well as rodent and human intestinal mucosae mounted in Ussing chambers deciphered how= the agent reversibly opens epithelial tight junctions in vitro by intracellular mechanisms at low concentrations. Next, rat intestinal instillations and perfusion data will be discussed in respect of efficacy and histopathology, along with the discovery that the concentrations required for efficacy (50-150 mM) are related in part to surfactant-like transcellular effects at that are well above the critical micellar concentration (CMC). This led us to re-examinethe received wisdom that the CMC for C_(10) was 13 mM, when we discovered that such a conclusion was highly method- and buffer-dependent. Using laser imaging, we found evidence of vesicle formation at high mM concentrations; such data suggested that specific tight junction effects that might account for delivering macromolecules in vivo could not be correct. In the rat intestinal instillation model, we showed that superficial mucosal injury induced by C_(10) was reversible within 30 minutes and that these effects were correlated with bioactive delivery — similar data to that published by Joe Robinson's lab in respect of delivering phenol red with a non-specific surfactant (5). The major difference was that C_(10) seems to reverse more quickly at both the level of damage and concomitant delivery.Finally, recent clinical data from Merrion Pharmaceuticals (Dublin, Ireland) and ISIS Pharma (Carlsbad, CA) based on enteric coated solid-dose formulations containing C_(10) improved oral absorption of bisphosphonates and anti-sense oligonucleotides, respectively. This suggests that reasonable oral bioavailability with acceptable safety profiles may eventually be attained in man for selected bioactives (3).