Scientific bases of technologies for synthesis and safety of water-soluble nitrates of cyclodextrins for medicinal purposes

A set of studies of nitrates α -, β - and γ -cyclodextrins with an extremely low nitrogen content was carried out in order to establish optimal conditions for their production, as well as to systematically substantiate the possibility of their safe use in medicinal drugs. We consider that nitrates of cyclodextrines by analogy with native cyclodextrines and their other known derivatives, not only as carriers of pharmacological substances, but also as compounds which, due to the presence of nitrate groups, can exhibit properties of potential donors of exogenous nitric oxide with a probable additional therapeutic effect. To ensure mild and environmentally friendly nitration, the process was carried out in aqueous solutions of nitric acid. The optimal compositions of nitrating solutions, their mass ratios with nitrated objects, as well as the temperature and time of the process were determined, which allowed to obtain nitrates α-, β- and γ-cyclodextrins with a given degree of substitution of hydroxyl groups for nitrate groups. The acute toxicity of water-soluble cyclodextrines nitrates was determined by the Behrens method, which in accordance with GOST 12.1.007-76 were classified as moderately toxic substances. Taking this into account it was concluded that the prospect of their use in pharmaceutics will be determined by water solubility, and the joint consideration of information on toxicity and solubility determined the group of cyclodextrines nitrates possible for use, which should contain no more than 10-12.5% wt. of nitrate groups. It means that in pharmaceutics it is reasonable to use nitrates α-, β- and γ-cyclodextrines containing (on the average) 1-2, 2.5 and 3 nitrate groups, respectively.