Product - Excipients

Pharmacopoeial approval status:
Pharmeuropa Vol. 10. No. 2, p. 237-239 (1998) published the draft of αCD monograph. The final monograph was published in the Supplement 2001 of European Pharmacopoeia first.

Examples for αCD containing marketed drug formulations:
PGE1(Alprostadil)-αCD freeze-dried powder formulations under the trade names of Edex, Prostavasin, Caverject etc. are marketed in Europe, USA.

Food approval status:
The FAO/WHO status of αCD was disclosed by the 57th report of the Joint FAO/WHO Expert Committee on Food Additives.(WHO Techn. Rep. Series No. 909, p. 40-42,). The report summarized the submitted toxicological data and based on the expected consumption data classified the αCD as food additive. The Committee concluded that for αCD an ADI "not specified" is suitable.

ADI "not specified" is used to refer to a food substance of very low toxicity which, on the basis of the available data (chemical, biochemical, toxicological and other) and the total dietary intake of the substance arising from its use at the levels necessary to achieve the desired effect and from its acceptable background levels in food, does not, in the opinion of the Committee, represent a hazard to health.

Detailed and reassuring toxicity data of γCD have been published by the Regulatory Tox. & Pharmacol. Vol 27, 1998, on oral toxicity studies in dogs and rats, embriotoxicity/teratogenicity studies in rats and rabbits, and on absorption, disposition, metabolism and excretion of 14C labeled γCD. Earlier acute oral toxicity examinations of γCD showed no mortality or toxic effects at the highest dose tested, 16 g/kg bw./day in mice, and 8 g/kg bw./day in rats. Intravenously or subcutaneously administered γCD also was well tolerated. The iv injected γCD had a LD50 of approx. 10 g/kg bw. in mice and >3.75 g/kg bw. in rats.

The γCD was well tolerated up to 20% of the diet (corresponding to 11 to 12 g/kg bw), no any sign of toxicity has been observed. Its metabolism resembles closely to that of starch and linear dextrins.

γCD is available in the USA as a Generally Recognised as Safe (GRAS) dietary ingredient (GRAS Notice No. GRN 000046).

γCD is being considered for approval under EU Novel Food regulations.

It is considered to be food additive in Japan and hence explicit approval is not required. There are no Codex standards in relation to γCD.

The methylated CDs are the presently known most effective solubilizers for poorly soluble substances. Methylated CDs have two main types: the so-called RAMEB (randomly-methylated βCD, available with DS=1.8, i.e. 1.8 methyl groups are attached in average to one glucose unit). The RAMEB is an amorphous, infinitely soluble, hygroscopic substance.

The so called DIMEB is available in three different qualities, as DIMEB-50, DIMEB-80, and DIMEB-95. All three products are crystalline products, very well soluble in cold water, but crystallize very rapidly at elevated temperature which depends on the homogeneity of the product. The DIMEB-50 contains at least 50% heptakis (2,6-di-O-methyl)-βCD, the DIMEB-80 and DIMEB 95 contain at least 80%, and 95% of this isomer, respectively. In the latter product there is less than 5% hardly detectable traces of other isomers or homologues.

Because the methylated CDs have the highest affinity toward the most lipophylic components of the cell-membranes (cholesterol and phospholipids) they have the highest haemolysing capacity. The haemolysis is, however, a typically concentration dependent phenomenon, at appropriately low concentration no any traces of haemolysis can be observed. At very low concentration the CDs generally exert stabilizing effect on the cell-membranes, the disorganization of the membranes takes place only at higher concentration by sequestering the mentioned lipid components. Therefore, if a very poorly soluble, highly active drug has to be administered in extremely low doses – for example a radioactive marker - its solubilization can be performed with DIMEB. The DIMEB is not accumulated in the body, is excreted rather rapidly through the kidneys.