Safe and effective methods for improving the oral delivery of macromolecules.

摘要

Oral delivery is a convenient and patient-friendly route of drug administration compared to injections. Unfortunately, the oral route cannot be utilized for macromolecules due to their low oral bioavailability. This limitation is particularly aggravated for proteins and peptides because of their susceptibility to enzymatic degradation in the gastrointestinal tract and low permeability across the intestinal epithelium. In order to overcome such challenges, a novel method has been developed that utilizes mucoadhesive intestinal patches to deliver therapeutic doses of drug into systemic circulation. Intestinal patches were capable of securely adhering to the intestinal epithelium, localizing a drug near the mucosa, protecting it from proteolytic degradation, and releasing drug in a unidirectional manner. In vivo experiments performed via jejunal administration demonstrated that intestinal patches loaded with insulin were able to achieve therapeutic results comparable to those obtained by subcutaneous injection.; The effectiveness of any oral drug delivery system potentially can be increased through the use of chemical permeation enhancers (CPEs). Such chemicals offer a plausible solution to the issue of low epithelial permeability to therapeutic agents. However, the use of CPEs to alleviate such problems has been hampered by the notion that enhancer efficacy is directly linked to toxicity. Given the issues at hand, this study set out to understand enhancer behavior and the relationships between potency and toxicity. Through the study of over 50 CPEs at concentrations spanning three orders of magnitude, it was established that no relationship existed between toxicity and efficacy, and that numerous formulations could provide safe and effective behavior. Additionally, a simple method was developed through a combination of theory and experiments that was able to uncover the mechanistic details of epithelial permeability enhancement for a broad set of enhancers. Finally, binary and ternary enhancer formulations were analyzed for their ability to provide improved performance over single enhancer formulations. The results presented here underscore the potential of chemical permeation enhancers while significantly increasing the repertoire of safe and effective epithelial enhancers for oral drug delivery applications.