Regulatory Status of Cyclodextrin

Cyclodextrins (CDs) are primarily used in the food industry, which serves as food additives to stabilize flavors and eliminate undesirable taste and odor in food. With the research and development of CDs, they are gradually becoming useful in the pharmaceutical field. In the Handbook of Pharmaceutical Excipients, CDs are classified as solubilizing and stabilizing agents ^[1]. As a suitable pharmaceutical excipient, CDs can be present in formulations to increase the solubility of poorly soluble drugs, as well as to improve the bioavailability and stability of drugs. Due to the food and pharmaceutical applications of CDs, the regulatory status of CDs is described from two aspects: regulatory status of CDs on GRAS substances and regulatory status of CDs as excipients in pharmaceutical formulations.

Regulatory Status of CDs on GRAS Substances▼

Some food additives need to be evaluated by the United States Food and Drug Administration (FDA) before they are included in the category Generally Recognized As Safe (GRAS). The α-, β- and γ-CDs are generally recognized as safe food additives or soluble fibers that were included on the FDA's GRAS list in 2000, 2001, and 2004, respectively. The GRAS determinations for CD are based on quantity and scope of use, physicochemical and characteristic properties, impurities, biological study results, toxicological study results, embryotoxicity/teratogenicity, etc ^{[2], [3]}.

Regulatory Status of CDs as Excipients in Pharmaceutical Formulations▼

The addition of excipients to drug formulations must be evaluated by regulatory organs during new drug applications. When CDs are considered excipients for use in pharmaceutical formulations, the regulatory status of general or new excipients also applies to CDs. The regulatory status of excipients in the International Pharmaceutical Excipients Council (IPEC), the United States (U.S.), European Union (EU), and Japan is described below, respectively ^[3].

IPEC was established in 1991 to address issues related to excipients used in pharmaceutical formulations and to assist regulatory authorities. The organization pioneered a new excipient evaluation procedure for evaluating the safety and chemistry of new excipient candidates, which has contributed to the harmonization of excipient standards worldwide.

Drug formulations and excipients are considered as a whole by U.S. regulatory authorities, and an excipient's approval is based on its specific application in formulations. As long as the levels and durations of exposure specified in the approved drug preparation are not exceeded, the use of new excipients in the formulation of other pharmaceutical preparations is permitted. In 2005, the FDA issued Guidance for Industry: Guidance for Nonclinical Studies to Evaluate the Safety of Pharmaceutical Excipients, which not only provides a definition of a new excipient, but also suggests strategies for excipients used for the first time in drug formulations.

The European Medicines Agency, as an agency of the EU in charge of the evaluation and supervision of pharmaceutical products, issued the Guideline on Excipients in the Dossier for Application for Marketing Authorisation of a Medicinal Product, which provides a definition of excipients as well as provides guidance on applications for drug product registration/licensing and marketing authorization or variations relating to an excipient in registered medicinal products. As in the U.S., approval in the EU is also based on excipients in drug products and not on the excipients themselves.

In Japan, a new excipient is an excipient that is being used for the first time, with a route of administration that is different from the previous route of administration or with an exposure level that is above the previous level used. Japan's management of excipients is also concerned about the use of excipients in drug products. Drugs containing previously used excipients are evaluated by the Pharmaceuticals and Medical Devices Evaluation Center (PMDE), and drugs containing new excipients used for the first time are evaluated by the Subcommittee on Pharmaceutical Excipients of the Central Pharmaceutical Affairs Council (CPAC).

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