Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1996-12-09
1998-06-02
Peselev, Elli
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536103, A61K 3170, C08B 3116
Patent
active
057600163
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the use of derivatives of cyclodextrins for solubilizing in an aqueous medium hydrophobic chemical compounds, in particular pharmaceutically active molecules, by the inclusion of these molecules in the cyclodextrin derivative.
Cyclodextrins or cyclomaltooligosaccharides are compounds having a natural origin forming by a linking of 6, 7 or 8 glucose units bonded in .chi.-1,4. Numerous works have shown that these cyclodextrins could form inclusion complexes with hydrophobic molecules and thus permit the solubilization of these molecules in aqueous media. Numerous applications have been proposed for taking advantage of this phenomenon, particularly in the pharmaceutical field, as is described by D. Duchene in the work entitled "Cyclodextrins and their industrial uses", chapter 6, pp 213 to 257, Editions de Sante, 1987. Pharmaceutical compositions using these cyclodextrins have also been marketed in Japan and Italy and more recently in France, e.g. by Pierre Fabre Medicament for Brexin.sup.(R), which is an inclusion complex of Piroxicam in .beta.-cyclodextrin.
Among the usable cyclodextrins, .beta.-cyclodextrin, which has 7 glucose units, is the most appropriate with regards to the size of its cavity and is the least expensive of the three, but its use causes certain problems, because it is less soluble than other cyclodextrins and has a hemolytic character.
Consideration has also been given to the improvement of the properties of .beta.-cyclodextrin by chemically modifying to make it more suitable. Several solutions have been envisaged and have led to the use of methyl derivatives or hydroxyalkyl derivatives.
Methyl derivatives are much more soluble than the original cyclodextrin and they have good properties of solubilizing hydrophobic, organic compounds, particularly in the case of 2,6-dimethyl-.beta.-cyclodextrin. However, these methyl derivatives, apart from the fact that they are difficult to obtain in the pure state, are unusable for pharmaceutical applications, particularly for injectable forms, due to their very pronounced hemolytic character.
The hydroxyalkyl derivatives more particularly developed by Janssen, e.g. hydroxypropyl-cyclodextrins have a very high solubility in water and are only slightly hemolytic. However, their use remains difficult due to their extreme chemical heterogeneity. In addition, substitutions can limit the formation of inclusion complexes by steric hindrance and as yet no pharmaceutical application has been developed with these derivatives.
The present invention specifically relates to the use of other derivatives of cyclodextrins for the solubilization of hydrophobic chemical compounds making it possible to obviate these disadvantages. It also relates to a novel process for the preparation of the cyclodextrin derivatives leading to very pure products without requiring laborious purification stages.
According to the invention, the process for solubilizing a hydrophobic chemical compound in an aqueous medium consists of combining the hydrophobic chemical compound with a mono-3,6-anhydrocyclodextrin of formula: ##STR2## in which n is equal to 5, 6 or 7, to for therewith a water-soluble inclusion complex.
The use in this process of the monoanhydrocyclodextrin derivative complying with the aforementioned formula has the advantage of improving the solubility, stability and bioavailability, in various administration forms of the hydrophobic compound, particularly in the case of pharmaceutically active molecules.
In particular, the solubility in water of these derivatives is considerable and greatly superior to that of the parent cyclodextrin, particularly with respect to .beta.-cyclodextrin. Moreover, these cyclodextrin derivatives have a much weaker hemolytic character than the parent cyclodextrin. These cyclodextrin derivatives also have the property of different affinities for the isomers of a mixture of isomers and can be consequently used in chromatography-based isomer separation processes. They also make it possible to easily carry out a puri
REFERENCES:
patent: 4983586 (1991-01-01), Bodor
Gadelle et al, Angew. Chem. Int. Ed. Engl. 30 (1991, No. 1 pp. 78-80.
Fujita et al, Chemistry Letters, pp. 593-596, 1988.
Ashton et al, Angewandte Chemie, International Edition, vol. 30, No. 1, 1991, pp. 80-81.
Ashton et al, Journal of Organic Chemistry, vol. 56, 1991, pp. 7279-7280.
Djedaini-Pilard Florence
Perly Bruno
Commissariat a l''Energie Atomique
Peselev Elli
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