Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-04-23
1998-04-28
Spivack, Phyllis G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 31445
Patent
active
057444846
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is the national stage of application No. PCT/EP 95/04520, filed on Nov. 16, 1995, which application claims priority from EP 94.203.422.4, filed on Nov. 24, 1994.
In U.S. Pat. No. 4,861,785 there are described benzoxazol- and benzothiazolamine derivatives having anti-anoxic activity. In WO-92/14,731 some of these benzothiazolamine derivatives were disclosed having useful anti-stroke activity. The subject invention furnishes injectable (generically known as lubeluzole) having excellent physical stability.
The most appropriate route of administration for the treatment of patients suffering from acute stroke probably is the direct infusion of the drug in the veins. A pharmaceutical formulation for intravenous administration has to comply with strict requirements regarding physical, chemical and biological stability. For example, problems may arise due to adsorption of the active ingredient to the walls of the i.v. administration equipment. In particular, substances tend to adsorb to the walls of the infusion bag and the PVC tubes in such equipment.
WO-92/14,731 discloses an injectable solution having pH 4 and containing a benzothiazolylamine derivative, glucose, hydrochloric acid, sodium hydroxide, hydroxypropyl-.beta.-cyclodextrin and water. The latter solution comprising lubeluzole shows significant problems regarding adsorption to the walls of the i.v. equipment. It was found that the adsorption of lubeluzole to the walls of the i.v. administration equipment could be significantly reduced by maintaining the pH of the formulation below 3.6. In this way, an intravenous solution was prepared having superior physical stability when compared to the art formulation.
Hence, the present invention is concerned with a solution for intravenous administration containing water, lubeluzole or a pharmaceutically acceptable addition salt thereof, an isotonizing agent, and acid and base substances to adjust the pH of the solution in the range from 2.5 to 3.6.
The present invention also relates to the use of acid and base substances in a solution according to the invention for preventing adsorption of lubeluzole or a pharmaceutically acceptable addition salt thereof to the walls of the i.v. administration equipment. Its preparation and properties are described in WO-92/14,731.
The addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic addition salt forms which lubeluzole is able to form. The latter can conveniently be obtained by treating the base form with appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methane-sulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely the salt form can be converted into the free base form by treatment with alkali.
The term addition salt as used hereinabove also comprises the solvates which lubeluzole is able to form and said solvates are meant to be included within the scope of the present invention. Examples of such solvates are, e.g. the hydrates, alcoholates and the like.
The term "physically stable" as used herein refers to a solution for which less than 10% by weight of active ingredient is adsorbed after passing through an infusion device. Preferably less than 5% by weight of active ingredient is adsorbed.
Hereinafter, the amounts of each of the ingredients in the compositions are expressed as percentages by weight based on the total volume of the formulation, unless otherwise indicated.
In one particular aspect of the invention, the concentration of lubeluzole or a pharmaceutically acceptable addition salt thereof in the present solutions may range from 0.005% to 5%, preferably from 0.01% to 1%, more preferably from 0.02% to 0.
REFERENCES:
patent: 5010198 (1991-04-01), Stokbroekx et al.
patent: 5434168 (1995-07-01), Stokbroekx et al.
Fran.cedilla.ois Marc Karel Jozef
Heyns Christiane Grabriella Gerardus Maria
Peeters Jozef
Ciambrone Coletti Ellen
Janssen Pharmaceutica N.V.
Spivack Phyllis G.
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