Pharmaceutical Applications of Cyclodextrins. III. Toxicological Issues and Safety Evaluation

Abstract

The objective of this review is to summarize recent findings on the safety profiles of three natural cyclodextrins (alpha-, beta- and gamma-CDs) and several chemically modified CDs. To demonstrate the potential of CDs in pharmaceutical formulations, their stability against non-enzymatic and enzymatic degradations in various body fluids and tissue homogenates and their pharmacokinetics via parenteral, oral, transmucosal, and dermal routes of administration are outlined. Furthermore, the bioadaptabilities of CDs, including in vitro cellular interactions and in vivo safety profiles, via a variety of administration routes are addressed. Finally, the therapeutic potentials of CDs are discussed on the basis of their ability to interact with various endogenous and exogenous lipophiles or, especially for sulfated CDs, their effects on cellular processes mediated by heparin binding growth factors.

Pharmacokinetic study of a new synthetic MMP inhibitor (Ro 28-2653) after IV and oral administration of cyclodextrin solutions

“…Among these cyclodextrins, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) appears to be especially useful, based on its safety for intravenous administration and on its complexation potential (Bertholet et al, 2005;Brewster and Loftsson, 2002;Irie and Uekama, 1997;Ma et al, 1999;Mosher and Thompson, 2000).…”

Apolipoprotein A-I, Phospholipid Vesicles, and Cyclodextrins as Potential Anti-Atherosclerotic Drugs: Delivery, Pharmacokinetics, and Efficacy

“…We speculated that the removal of UC (and possibly PLs) from the PM causes a relaxing of the membrane structure, thus stimulating pseudopodial development. In fact, Irie and Uekama (1997) state that both PC and SPM are removed by CDs from the outer half of the plasma membrane bilayer, leading to the formation of stomatocytes caused by the inward "bending" of the PMs. The authors also claim that proteins are removed from the membranes, probably as an aftereffect of the gradual loss of lipids that normally anchor membrane-bound proteins in place.…”

“…Since the interaction of CDs with the plasma membranes may be the initial site of cellular damage, the incubation of erythrocytes with these agents may be useful as bioindicator. It is believed that PL association occurs best with the small cavities of a -CDs, while b -CDs are ideal for binding cholesterol (Irie and Uekama 1997).…”

“…Also, when the cavity of a CD molecule is occupied, it is not cytotoxic (Irie and Uekama 1997). The best approach would be to rst expose the CD, judged by in vitro tests to be ideal for a certain task, to a variety of mammalian cells in culture.…”

“…Humans have been noted to tolerate high doses of hpb -CD as long as the daily dose is < 16 g orally (reviewed in Irie and Uekama 1997). Above this dose, diarrhea and soft stools are noted.…”