Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Patent
1995-03-06
1996-11-12
Azpuru, Carlos
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
424427, 424428, 514 58, 514777, 514912, 536120, A61F 202, A61K 31715, A61K 4740, C07H 1504
Patent
active
055737730
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to stable highly concentrated formulations, in particular solutions, of specific fluorescein derivatives, to the preparation of said formulations and the use thereof, especially for photodynamic therapy, preferably for the treatment or prevention of secondary cataract. The formulations of the present invention include a fluorescein diester and a partially etherified .beta.-cyclodextrin, the ether substituents of which are hydroxyethyl, hydroxypropyl or dihydroxypropyl groups, some of which ether substituents may be methyl or ethyl groups.
The fluorescein derivatives are special diesters of fluorescein, preferably fluorescein diacetate. The novel formulations contain as component that makes possible the preparation of stable and highly concentrated solutions of these fluorescein derivatives special cyclodextrin derivatives, in particular hydroxypropyl-.beta.-cyclodextrin.
Pharmaceutical compositions of sparingly water-soluble or unstable medicaments and the preparation thereof are taught in EP-A-149 197. This patent specification also postulates, inter alia, hydroxypropyl-.beta.-cyclodextrin for use with drugs such as indomethacin or dexamethason.
It has already been proposed in EP-A-447 351 to complex fluorescein with a cyclodextrin sulfate and to make it available in this form as an ophthalmological agent.
In contradistinction to this prior art, formulations comprising fluorescein diacetate and a compound of the hydroxypropyl-.beta.-cyclodextrin type have hitherto not been disclosed. Surprisingly, however, it has been found that such formulations afford unexpected advantages over the closest prior art, especially in view of the use of such formulations in the field of the photodynamic therapy of secondary cataract. The novel formulations have been found to be, inter alia, unexpectedly stable, and it is also possible with these formulations to dissolve fluorescein diacetate in the sufficiently high concentrations necessary for photodynamic therapy, typically for the treatment or prevention of secondary cataract, in order to make this therapy practicable.
The present invention therefore relates primarily to a formulation, conveniently an aqueous solution, comprising a fluorescein diester, preferably a fluorescein di-lower alkyl ester, and a partially etherified .beta.-cyclodextrin the ether substituents of which are hydroxyethyl, hydroxypropyl or dihydroxypropyl groups, some of which ether substituents may be methyl or ethyl groups. Preferably the .beta.-cyclodextrin ether has a water-solubility of more than 1.8 g in 100 ml of water. The present invention also relates to dry formulations comprising a fluorescein diester, preferably a fluorescein di-lower alkyl ester, and a partially etherified .beta.-cyclodextrin the ether substituents of which are hydroxyethyl, hydroxypropyl or dihydroxypropyl groups, some of which ether substituents may be methyl or ethyl groups, from which the above described solutions can be reconstituted. The .beta.-cyclodextrin ether preferably has a water-solubility of more than 1.8 g in 100 ml of water.
The term "lower" used in the context of this invention denotes radicals or groups containing up to 7, preferably up to 4, carbon atoms.
Lower alkyl is alkyl of up to 7, preferably of up to 4, carbon atoms, and is typically methyl, ethyl, propyl, 2-propyl, butyl, tert-butyl, pentyl or 2,2-dimethylpropyl.
The fluorescein diester is conveniently an ophthalmogically acceptable diester of fluorescein. Suitable diesters are typically fluorescein diphosphate or fluorescein di-lower alkyl esters such as fluorescein diacetate, fluorescein dibutyrate or fluorescein dipivalate. The fluorescein diester may also be a mixed diester, conveniently a fluorescein monophosphate-monoacetate, or a mixed fluorescein monoacetate-monobutyrate. Fluorescein diacetate is particularly preferred.
The novel solutions typically contain the fluorescein diester in a concentration of up to about 200 micromol/l (200 .mu.mol/l), preferably in a concentration of about 40 to about 200 microm
REFERENCES:
patent: 5227372 (1993-07-01), Folkman
Diabetic Cataract: Prevention by Photo affinity Drug, Sihn Van Chow, Chem. Abstracts, vol. 105, No. 19, 1984.
EP Search Report.
Kis Gyoergy L.
Wachsmuth Ernst D.
Azpuru Carlos
Ciba Geigy Corporation
Lee Michael U.
McC. Roberts Edward
Meece R. Scott
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