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.

Investigational Committee on Relief Services for Adverse Health Events in Pharmaceutical and Medical Devices Agency (PMDA) was herein introduced and the attempts for operational improvements of this committee were shown. Questionnaires were newly performed among patients and their family members who received payment decision notices for the last three years from PMDA. Their results were summarized and critically analyzed here. The committee has also been performed the hearing from one of the top investigators in this field. Based on the discussion among the committee members, we therefore created a new report of this committee to improve Relief Services for Adverse Health Events in PMDA. The summary of this report was demonstrated and potential problems were also discussed.

The Pharmaceuticals and Medical Devices Agency (PMDA) is responsible for the services regarding the operation of the Relief System for Adverse Health Effects to provide swift relief to sufferers from adverse health effects caused by adverse drug reactions by paying out benefits to them. This service is one of the three pillars of the PMDA’s activities, along with reviews, including related services, and safety measure services. In FY 2021, a total benefit of 2,376 million yen was provided for about 1,400 claims. The historical background to the establishment of the system is a bitter experience of large-scale drug-induced cases such as thalidomide and subacute myelo-optico-neuropathy (SMON). In addition to strengthening safety measures in pharmaceutical regulatory affairs, a unique scheme separate from the conventional legal liability theory was required to provide swift relief to sufferers from adverse health effects in a realistic manner. Under these circumstances, the Relief System for Sufferers from Adverse Drug Reactions was launched in 1980 after deliberation in the Diet. In 2004, the Relief System for Infections Acquired through Biological Products was added to the system. This relief system is currently being implemented after improvements in the organizational structure and other modifications. Of the issues to be addressed, “the operational issues of the system” will be improved in response to the recommendations of the “Study Group on the Operational Improvement of the Relief System for Adverse Health Effects.” Improvement measures have been included in the PMDA annual plan. For “the organizational management issues for the service operator” from the perspective of organizational and human resource management, the PMDA is seeking better management strategies, including how to motivate staff with responsibilities for services to achieve results.

Since the outbreak of the COVID-19, emergency pharmaceutical review systems have been utilized in countries around the world for the early application of therapeutic drugs and vaccines. In Japan as well, multiple therapeutic drugs and vaccines have been rapidly approved by utilizing the special approval system, but in order to address the issue that it cannot be applied to drugs developed in Japan, May 20, 2022, an emergency approval system was created due to the revision of the Pharmaceuticals and Medical Devices Act. In the future, it will be important to utilize this system in emergencies and quickly commercialize medicines.