Route of Administration

Cyclodextrins are able to be used via every route of administration possible. Clearly, one must test the particular Cyclodextrin used for the specific route used to ensure safety.

The main causes of toxicity caused by Cyclodextrins are related to effects on sensitive cell membranes and bulk effects (such as precipitation). Almost all Cyclodextrins are safe for topical use when there is no danger of the Cyclodextrin getting past the outer skin barrier. Topical uses such as eye drops, suppositories (vaginal and rectal), and any others that have the possibility of getting beyond the dermal barrier, require attention to possibilities of irritation and systemic residuals.

There are general rules about the suitability of certain Cyclodextrins for various routes of administration that early tox/safety studies have established. The generalizations made below are not intended to replace careful testing, but rather to provide a rational point to start safety testing protocols for obtaining regulatory approval.

The natural Cyclodextrin's (ACD, BCD, GCD) can be used orally, buccally, nasally and in suppositories.
BCD should not be used parenterally because of its propensity to produce precipitable complexes of cholesterol. The other natural Cyclodextrins do not show this propensity for their complexes to precipitate.
The chemically modified Cyclodextrins (methyl-, hydroxypropyl-, sulfobutyl-) are equally as safe for topical use as the natural Cyclodextrins, but are more suitable for parenteral use because of their greatly enhanced water solubility.

Any materials that are given in such a way as to bypass the body's natural protective barriers and systems must be studied carefully, and derivatized Cyclodextrins are no exceptions. Usually these materials may be used safely below certain concentrations and the safety studies are designed to determine those levels. Sometimes, acute but reversible adverse effects are observed and the studies must address acute vs. chronic use as well as maximum safe concentrations.

In this section more detail is given for the major categories of oral and parenteral administration. CTD makes available as a report for purchase, information on tox/safety studies done with all the Cyclodextrins. Contact CTD for more information about that report.

Oral Administration

ORAL DOSING: Cyclodextrin/drug complexes offer two important product advantages for oral preparations – improved bioavailability and reduced irritation. Improved bioavailability is observed for certain drugs which are not fully absorbed or are absorbed in a variable manner due to incomplete dissolution of the drug in the gastrointestinal tract.

Reduced irritation of the stomach mucosa is claimed by the Chiesi Group in a B-Cyclodextrin/Piroxicam formulation launched in October 1989 in Italy (Brexin^TM for dysmenorrhea). Presumably, the claimed reduction in side effects results from the prevention of physical/chemical interaction of undissolved piroxicam with the lining of the stomach. The product is claimed to have a faster onset of action as well.

Cyclodextrins offer the potential for improving the reliability of oral dosing by permitting the use of true solutions of the drug rather than suspensions during manufacture of the tablets or as the final formulation available to the patient.

Patient dosing compliance can be improved by using Cyclodextrins to mask objectionable odor and/or taste.

Insoluble compounds, which previously could only be given by injection, may now be given sublingually when formulated with Cyclodextrins. Pitha [16] has reported excellent absorption into blood of an HPB/testosterone tablet given sublingually.

Parenteral Administration

INJECTABLE FORMULATIONS: For parenteral products, chemically modified Cyclodextrins, especially HPB, are preferred to natural Cyclodextrins because of their greater inherent solubility and superior safety profile. The use of Cyclodextrins can reduce both dosing volume and in situ irritation resulting from high or low pH's, organic solvents or the direct chemical irritancy of the drug. The latter is especially important for anticancer agents which are highly reactive and are widely recognized for their propensity to cause phlebitis and pain at the site of injection.

From the pharmacist's perspective, Cyclodextrin/drug complexes are easily reconstituted (or can be provided in liquid form), eliminating the need for elaborate mixing procedures.

Osmolarity

Since 10 years of accumulated toxicity and safety data for the parenteral use of HPBCyclodextrin have shown no adverse effects at all above 400 mg/kg in humans and animals, more clinical studies are being done using HPBCyclodextrin as a parenteral excipient. One product, Sporanox®, by Janssen Pharmaceutica, was approved in 2000 for use as an injectable; Sporanox® contains 40% w/v HPBCyclodextrin.

Since potential parenteral products have to be compatible with human blood in terms of pH and osmolarity, it is important that the effect on these parameters of the ingredients in a formulation be readily characterized and controllable.

In the matter of osmolarity, it was necessary to use an osmometric device to determine osmolarity of aqueous HPBCyclodextrin solutions - not very convenient.

The very amorphousness that makes HPB so useful caused it to have, until now, no validated method of computing the osmolarity of its aqueous solutions.

Thanks to some thorough experimental work by Dr. Erika Zannou, of Novartis Pharmaceutical Corp. in E. Hanover, N.J. and able consultation from Dr. Valentino Stella of the University of Kansas, Lawrence, KS, a reliable osmolarity of aqueous solutions of HPB, HPG, and six different SBE Cyclodextrins may now be computed. The work is reported in Pharmaceutical Research (2001), volume 18, number 8, page 1226. Thank you Dr. Zannou and Dr. Stella (William H. Streng is also one of the authors of the paper).

CTD wishes to make the above osmotic information readily usable for Cyclodextrin formulators. Therefore we respectfully submit the following graphical aid for determining the concentration (w/v %) of THPB-P (CTD's catalog number for hydroxypropyl BCD needed to make up a 286 mOsm aqueous solution when the degree of substitution of the HPB is known.

The following equation reported by Dr. Zannou provides computed results within 3% of the experimentally determined values in her study with the HPBCD used -

Osmolality = 1.154 times (molality) **1.043

Simply use the graph below for aqueous solutions of hydroxypropyl BCD by finding the degree of substitution on the Y-axis and move laterally from there to an intersection with the 286 mOsm line; drop vertically to the X-axis and read off the concentration (w/v %) that the final THPB-P solution should be.