Absorption-Enhancing Mechanisms of Capryol 90, a Novel Absorption Enhancer, for Improving the Intestinal Absorption of Poorly Absorbed Drugs: Contributions to Trans- or Para-Cellular Pathways.

PURPOSE: We have previously reported that Capryol 90 improves the intestinal absorption of insulin, a peptide drug, without causing serious damage to the intestinal epithelium. However, the effects of Capryol 90 and its related formulations on the intestinal absorption of other drugs, and their absorption-enhancing mechanisms are still unclear. The aim of this study is to evaluate the effects of Capryol 90 and its related formulations on the intestinal absorption of drugs and elucidate their absorption-enhancing mechanisms. METHODS: The intestinal absorption of 5(6)-carboxyfluorescein, fluorescein isothiocyanate-dextrans, and alendronate was evaluated using an in situ closed loop method. Brush border membrane vesicles (BBMVs) were labeled with fluorescent probes, and the fluidity of membrane was evaluated by a fluorescence depolarization method. The expression levels of tight junction (TJ) proteins were measured using a Western blot method and immunofluorescence staining. RESULTS: Among the tested excipients, Capryol 90 significantly improved the small and large intestinal absorption of drugs. In mechanistic studies, Capryol 90 increased the membrane fluidity of lipid bilayers in BBMVs. Additionally, Capryol 90 decreased the expression levels of TJ-associated proteins, namely claudin-4, occludin, and ZO-1. CONCLUSIONS: Capryol 90 is an effective absorption enhancer for improving the intestinal absorption of poorly absorbed drugs via both transcellular and paracellular pathways.

Approaches to improve intestinal and transmucosal absorption of peptide and protein drugs.

The oral bioavailability of hydrophilic and macromolecular drugs is generally poor owing to their poor membrane permeability. For example, peptide and protein drugs are poorly absorbed because of their low stability and poor membrane permeability in the gastrointestinal tract. Consequently, these drugs can be clinically administered only via injection. However, such frequent administration of injections subjects the patients to considerable pain, along with increasing the possibility of serious side effects. Several approaches have been examined to overcome the delivery problems associated with the poorly absorbed drugs. These include (1) use of additives such as absorption enhancers and protease inhibitors, (2) modification of the chemical structure of drugs to produce prodrugs and analogs, (3) application of dosage forms to entrap these poorly absorbed drugs, and (4) development of novel and alternative administration methods (apart from oral and parenteral administration). We examined these approaches and demonstrated their effectiveness in improving intestinal and transmucosal absorption of several poorly absorbed drugs. These approaches may provide useful and basic information to improve the intestinal and transmucosal absorption of poorly absorbed drugs including peptide and protein drugs.

Enhanced Intestinal Absorption of Insulin by Capryol 90, a Novel Absorption Enhancer in Rats: Implications in Oral Insulin Delivery.

Labrasol® is a self-emulsifying excipient that contains saturated polyglycolysed C6-C14 glycerides and this additive is known to improve the intestinal absorption of poorly absorbed drugs after oral administration. However, the effects of formulations similar to Labrasol® on the intestinal absorption of poorly absorbed drugs have not been characterized. In this study, we used insulin as a model peptide drug and examined the absorption-enhancing effects of Labrasol® and its related formulations for insulin absorption in rats. The co-administration of Labrasol-related formulations with insulin reduced the blood glucose levels. Among these formulations, Capryol 90 was the most effective additive. Notably, the effect of Capryol 90 was greater at pH 3.0 than at pH 7.0. Additionally, almost no mucosal damage was observed in the presence of these formulations, as these formulations did not affect the activity of lactate dehydrogenase (LDH) and the amount of protein released from the small intestine. In mechanistic studies, Capryol 90 improved the stability of insulin and suppressed the association with insulin under acidic conditions. The loosening of the tight junctions (TJs) could be the underlying mechanism by which Capryol 90 improved intestinal insulin absorption via a paracellular route. These findings suggest that Capryol 90 is an effective absorption enhancer for improving the intestinal absorption of insulin, without inducing serious damage to the intestinal epithelium.

Propylene Glycol Caprylate as a Novel Potential Absorption Enhancer for Improving the Intestinal Absorption of Insulin: Efficacy, Safety, and Absorption-Enhancing Mechanisms.

Sodium caprate (C10) acts as an absorption enhancer. However, the absorption-enhancing effects of compounds with structures similar to C10 have not been characterized. In the present study, insulin was used as a model drug. We examined the effects of C10 and its related compounds on intestinal absorption of insulin using an in situ closed loop in rats. Insulin absorption was significantly enhanced by propylene glycol caprylate (Sefsol-218), a C10-related compound, after large intestinal administration. In addition, activity of lactate dehydrogenase did not increase in the intestinal epithelium in the presence of Sefsol-218 at concentrations equivalent to or lower than 1% (v/v). However, a significant increase in lactate dehydrogenase activity was observed in response to C10. These findings suggested that Sefsol-218 was safer than C10. Furthermore, mechanistic studies showed that increased membrane fluidity and loosening of tight junctions (TJs) might be underlying mechanisms by which this compound improved intestinal absorption of insulin. Furthermore, Sefsol-218 opened TJs by reducing the expression of claudin-4, which is a major TJ protein. These findings suggested that Sefsol-218 effectively enhanced intestinal insulin absorption without causing serious damage to the intestinal epithelium.