Current Regulatory Considerations for Mucosal Permeation Enhancers

Abstract

Biopharmaceuticals such as peptides, proteins, and nucleic acids generally have such poor mucous membrane permeability that the majority have been put into practical use as invasive injections. Over the past 60 years, research into mucosal permeation enhancement technologies has led to the development of chelate agents, detergents, medium-chain fatty acids, toxin fragments, and other molecules that promote mucosal absorption of drugs. Some of these absorption enhancers are in clinical use. In Japan, capric acid is used in a rectal formulation of ceftizoxime sodium, dodecylphosphocholine is used in a nasal formulation of glucagon, and salcaprozate sodium is used in an oral formulation of semaglutide. In the United States, an oral formulation of octreotide has been approved that contains sodium caprylate as an absorption enhancer. It is expected that non-invasive administration of biopharmaceuticals and other drugs will accelerate in the future. Whereas almost all excipients are inactive ingredients, absorption enhancers are active ingredients that enhance mucosal permeation of an active pharmaceutical ingredient by acting on the mucosal epithelium. Unlike most general inactive ingredients, the development of drugs that contain absorption enhancers as active ingredients requires a safety evaluation based on the underlying mechanism of the mucosal permeation-enhancing activity. In this review, we provide overviews of the biochemical structures of mucosal barriers and current absorption-enhancing technologies, and summarize the regulatory considerations for active ingredients that are used to enhance the permeation of active pharmaceutical ingredients, focusing on approved drugs.