Pharmaceutical composition containing a hydrophilic active compo

Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes

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424427, 264 41, 514912, 514 39, A61K 9127

Patent

active

052119556

DESCRIPTION:

BRIEF SUMMARY
SUBJECT OF THE INVENTION

The present invention relates to a pharmaceutical composition containing a hydrophilic active compound treated with an organic acid so as to achieve the formation of a complex between the two molecules, and encapsulated in a liposome.


SUMMARY OF THE STATE OF THE ART

Numerous substances exhibit pharmacological properties but are not used to their optimum efficiency because they do not possess all the properties of a good pharmaceutical compound. To remedy the insufficently potent action of these medicaments by increasing the doses would lead to an undoubted toxicity. Thus, if in order to remedy an excessively weak or excessively short-lasting action, a higher dose of active compound is injected, this runs the risk of causing high toxicity or secondary effects (which may be allergic, digestive, renal, nervous, hematological or the like). Specifically, the nephrotoxicity, ototoxicity and neurotoxicity of gentamycin and of the other aminoglucoside antibiotics have been extensively described.
Furthermore, publications on the encapsulation of antibiotics such as gentamycin (Morgan, J. R. and Williams, K. E., 1980, Antimicrob. Agents Chemother. 17: 544-548; Barza, M., Baum, J. and Szoka, F., 1984, Invest. Ophtalmol. Vis. Sci. 25:486-490) show that the authors only achieved degrees of encapsulation of between 5% and 25%.
Other publications (WO-Al-88/04573, The Liposome Company; WO-Al-87/00043, The Liposome Company; Schreier, H. and coll., 1987, J. Controlled Release 5: 187-192) refer only to the use of inorganic molecules in techniques for the encapsulation of antibiotics.
A use of organic acids for the preparation of a gel consisting of dehydrated liposomes is known from a European patent (EP-Al-0211647), but without coupling to the pharmaceutical molecules, and at much higher pH values than those of the encapsulated molecules. The organic acid is only used for the rehydration of the liposomes.


OBJECTS OF THE INVENTION

The present invention proposes to provide a product which, after encapsulation, :as the valuable property of being self-regulating, in &he sense that it liberates the active compound in inverse proportion to the concentration of this compound in the external medium. This has the advantage of guaranteeing a sustained action of the administered antibiotics, whilst avoiding giving rise to toxic doses or ineffective doses.
These properties are particularly valuable for certain applications, especially ophthalmological applications, which will be described below and for which the presence of an active compound in excessively high concentration can cause irreversible lesions. Additionally, the product of the invention also exhibits high degrees of encapsulation which can reach 50%.


CHARACTERISTIC ASPECTS OF THE INVENTION

In order to achieve the objects thus sought, the invention proposes a pharmaceutical composition containing a hydrophilic active compound treated with an organic acid so as to bring about the coupling of the two molecules, and encapsulated in a liposome. This composition may be characterized by a maximum intraliposomial volume when the hydrophilic active compound is linked to the carboxyl group or groups of the acid. Among the hydrophilic active compounds, the aminoglucoside antibiotics are preferred.
By an aminoglucoside antibiotic there is understood a molecule which comprises glycidyl residues which comprise NH.sub.2 groups in a side chain. The term thus encompasses other molecules than those which correspond to the conventional pharmacological definition of so-called aminoglucoside antibiotics.
In particular, gentamycin is treated with an organic acid at a pH of the order of 4.5.
Among the organic acids, preference is given to the amino acids, in particular glutamic acid, or to polycarboxylic acids such as succinic acid or citric acid.
However, monocarboxylic or simple acids such as acetic acid or formic acid may also be suitable.
Preferably, the liposomes employed are of the so-called "multilamellar" (MLV) type with cholesterol.
According to the in

REFERENCES:
patent: 3959255 (1976-05-01), Chazan et al.
patent: 3981861 (1976-09-01), Chazan et al.
patent: 4242331 (1980-12-01), Gasc et al.
patent: 4424344 (1984-01-01), Kirst et al.
patent: 4424345 (1984-01-01), Kirst et al.
patent: 4468512 (1984-08-01), Kirst et al.
patent: 4708861 (1987-11-01), Popescu et al.
Journal of Controlled Release; vol. 5, No. 2, Sep. 1987 pp. 187-192.
Chemical Abstracts, 101:43477g 1984.

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