N-MORPHOLINO-N-NITROSAMINOACETONITRIL CYCLODEXTRIN INCLUSION COMPLEXES

摘要

PCT No. PCT/HU95/00011 Sec. 371 Date Apr. 16, 1996 Sec. 102(e) Date Apr. 16, 1996 PCT Filed Apr. 25, 1995 PCT Pub. No. WO95/29172 PCT Pub. Date Nov. 2, 1995New inclusion complexes which are stable in their so-lid state formed of SIN-1A and cyclodextrins or cyclodextrin derivatives and optionally also containing ions as catalyst or stabilizer. The complexes release nitric oxide at room temperature upon dissolving in water or aqueous systems. The ions are preferably carboxylic acid anions such as acetate, formiate, propionate, ascorbinate, tartarate and/or lactate and/or inorganic acid anions such as phosphate, phosphite, borate, carbonate, hydrocarbonate, sulfate, sulfite and/or cations such as alkali and/or ammonium. Pharmaceutical compositions as well as kits containing the complexes. The kits are to be used as NO-liberating standards to release NO in a predictable amount and rate on dissolving in aqueous media. Processes for the preparation of the complexes by subjecting at a suitable pH SIN-1 to the catalytic action of ions to shift the equilibrium towards formation of SIN-1A in the presence of cyclodextrins or cyclodextrin derivatives capable to form inclusion complexes, whereby the SIN-1A formed is immediately complexed and stabilized and isolating in the solid state the obtained new complexes optionally containing ions. A preferred process includes reacting SIN-1 and a cyclodextrin or cyclodextrin derivative in the solid state in the presence of a salt as a catalyst by thoroughly admixing or milling the components together or by freeze drying an aqueous, oxygen-free solution containing the components, followed preferably by "second drying" in vacuo.