Safety and Regulatory Status

It has taken many years to dispel the notion of ß-Cyclodextrin toxicity created by some earlier work (1956) using adulterated material. However, that has long since been accomplished and major pharmaceutical companies are routinely approaching the FDA to get approval for the use of derivatives of ß-Cyclodextrin and food companies have confirmed the GRAS status of the natural CD's as food additives.

The new opinion about the oral safety of the natural Cyclodextrins and the early work showing the safety of THPB in animals and humans has created a favorable environment for expeditious approval of THPB containing formulations. Additional clinical studies using heretofore intractable, but potent drugs, have been completed using THPB as the drug delivery vehicle in phase I studies, IND Applications , and in completed NDA's.

From the pharmaceutical standpoint in the USA and Europe, no Cyclodextrins have GRAS status for any route of dosing and no lifetime carcinogenicity studies conducted in a GLP fashion for any Cyclodextrin have been reported. Even so, drugs containing Cyclodextrins have reached the marketplace. For a more complete list of available pharmaceutical products formulated with Cyclodextrins see the table below.

TABLE 4 : Approved & Marketed Drugs Formulated with Cyclodextrins

Since available data suggest that Cyclodextrins given orally are not absorbed intact and the products of whatever limited digestion that may take place are probably single and multiple units of glucose, all Cyclodextrins are likely to be safe when taken orally; however, only THPB has substantial clinical data to support parenteral safety. Additional studies will be required, but a solid foundation for human safety has been established.

In summary, before 1997 no Cyclodextrin had been approved in the USA for human use by any route of administration. Outside the USA natural Cyclodextrins are used in commercial pharmaceutical and food products. Some CMCD's were judged safe enough in the US in the 80's for compassionate use in humans and for IND studies. Additional formal toxicology studies are undertaken on a case by case basis by pharmaceutical companies to develop data suitable for approval as acute and short term parenteral formulations.

Pharmaceutical products containing THPB/drug complexes are likely to be marketed first where no other method of drug delivery has been possible. As human experience with the HPB formulations grow and longer term toxicology studies are completed, first THPB and then other CMCD's will become staples in drug formulators' armamentaria.