Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1996-12-05
1998-06-02
Peselev, Elli
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
536 46, 536103, A01K 3170, C08B 3018
Patent
active
057600171
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel cyclodextrin derivatives more particularly usable for solubilizing in an aqueous medium hydrophobic chemical compounds, such as pharmaceutically active molecules, by inclusion in said derivatives.
Cyclodextrins or cyclomaltooligosaccharides are compounds having a natural origin forming by a linking of 6, 7 or 8 glucose units bonded in .alpha.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.RTM., 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 injection 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.
More recently consideration has been given to the use of other cyclodextrin derivatives, as is described in WO-A-91/13100. Among these derivatives there are those substituted by a diamine, but the results obtained with these diamino derivatives are not entirely satisfactory for pharmaceutical applications.
The present invention specifically relates to novel cyclodextrin derivatives usable for solubilizing hydrophobic chemical compounds and which obviate these disadvantages.
These novel cyclodextrin derivatives comply with the formula: ##STR2## in which R.sup.1 represent OH or NH(CH.sub.2).sub.p OH, n is equal to 5, 6 or 7 and p is an integer from 2 to 6, in which the p can differ when one or more of the R.sup.1 represent NH(CH.sub.2).sub.p OH.
According to a first embodiment of the invention, the cyclodextrin derivative is a monosubstituted derivative, i.e. in the aforementioned formula I, all the R.sup.1 represent OH.
Such a derivative can be prepared by reacting a tosyl derivative of formula: ##STR3## in which R.sup.4 represents the tosyl group and n is equal to 5, 6 or 7 with a compound of formula NH.sub.2 (CH.sub.2).sub.p OH with p having the meaning given hereinbefore.
The tosyl derivative of formula (II) can e.g. be obtained by the process described in J. Am. Chem. Soc., 112, 1990, pp 3860-3868.
The reaction of the tosyl derivative with the compound of formula NH.sub.2 (CH.sub.2).sub.p OH can be simply carried out by dissolving the tosyl derivative in said compound.
According to a second embodiment of the invention, the cyclod
REFERENCES:
Chemistry Letters vol. 10,1976, JP pp. 1037-1040 Y. Matsui et al. `Catalytic properties of a Cu (II) complex with a modified cyclodetrin` p. 1037, ligne 15-- p. 1038, ligne 2.
Azaroual-Bellanger Nathalie
Djedaini-Pilard Florence
Perly Bruno
Commissariat a l''Energie Atomique
Peselev Elli
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