Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1998-06-23
1999-09-21
Reamer, James H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
A61K 31575
Patent
active
059554568
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a novel pharmaceutical composition based on ursodeoxycholic acid, either as such or conjugated with taurine.
In particular, the invention relates to an injectable formulation of ursodeoxycholic acid or tauroursodeoxycholic acid for intravenous administration, especially by slow perfusion.
Ursodeoxycholic acid and tauroursodeoxycholic acid are drugs which are widely used in therapy as litholytics and in the treatment of various pathological conditions of the liver, such as hepatic cholestasis and primary biliary cirrhosis. It has now been found that the action of these drugs is also particularly useful in the treatment of pathological conditions of the liver in patients for whom oral administration is impossible or difficult.
No injectable pharmaceutical formulations based on ursodeoxycholic acid or tauroursodeoxycholic acid are currently available on the market because their preparation presents problems due to the physicochemical properties of these active principles.
Ursodeoxycholic acid is a weak acid which is practically insoluble in water; its solubility increases greatly in the presence of strong bases such as sodium hydroxide and potassium hydroxide. However, aqueous solutions consisting solely of ursodeoxycholic acid and a strong base are not suitable for intravenous administration because even a small variation in the amount of strong base in the preparation leads to a consequent variation in the pH of the injectable solution which is often incompatible with intravenous administration.
In contrast to ursodeoxycholic acid, tauroursodeoxycholic acid is a strong acid which is soluble in water, its pKa being about 1.4. This strong acidity is incompatible with intravenous administration; in this case too, it is possible to resort to the addition of bases to the solution, although the above-mentioned problems of pH variation still remain unsolved.
Also, ursodeoxycholic and tauroursodeoxycholic acids are detergent compounds and, for this reason, cause foaming when added to an aqueous solution such as the solution for intravenous perfusion.
It has now been found that the addition of trometamol ((trishydroxymethyl)aminomethane) to an aqueous solution containing ursodeoxycholic acid or tauroursodeoxycholic acid and strong bases produces stable, well-buffered solutions suitable for intravenous administration.
It has moreover been observed that the addition of trometamol surprisingly reduces foaming and the persistence of the foam which forms in the solution for intravenous perfusion following the addition of the above preparation.
The present invention therefore relates to an injectable aqueous composition which comprises ursodeoxycholic acid or tauroursodeoxycholic acid, a strong base compatible with intravenous administration, and trometamol.
According to the present invention, the water used is suitable for injectable preparations.
The formulation according to the invention comprises an amount of active principle--ursodeoxycholic acid or tauroursodeoxycholic acid--of between 1 and 30% (w/v) and preferably of between 5 and 20% (w/v), for example 10% (w/v).
The strong base compatible with intravenous administration is preferably sodium or potassium hydroxide; such bases are used in a stoichiometrically equivalent amount relative to the acid employed.
The trometamol is added at a rate of 0.01-2% (w/v), preferably at a rate of about 0.1% (w/v).
The formulation according to the invention advantageously consists of an aqueous solution which comprises from 5 to 15% (w/v) of active principle (ursodeoxycholic acid or tauroursodeoxycholic acid), a stoichiometrically equivalent amount of strong base (sodium or potassium hydroxide) and from 0.05 to 0.2% (w/v) of trometamol, ursodeoxycholic acid being the preferred active principle.
The injectable aqueous formulation forming the subject of the present invention preferably contains about 10% (w/v) of ursodeoxycholic acid, about 1% (w/v) of sodium hydroxide and about 0.1% (w/v) of trometamol.
The formulation of the present invention is p
REFERENCES:
patent: 4649155 (1987-03-01), Steffen et al.
Prato Tiziano
Rusticali Anna Giulia
Alexander Michael D.
DuPont Paul E.
Reamer James H.
Sanofi
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