Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-07-25
1999-03-23
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 31405
Patent
active
058860185
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP96/00515 filed Feb. 8, 1996.
This invention relates to pharmaceutical composition for parenteral administration. More particularly it relates to aqueous formulations of a glycine antagonist for parenteral administration.
UK Patent Application GB 2266091A describes physiologically acceptable salts or metabolically labile esters thereof which exhibit antagonist activity at the strychnine insensitive glycine binding site associated with the NMDA receptor complex. Further the specification teaches that the compound may be formulated for parenteral administration and in particular an aqueous solution for injection consisting of the active ingredient, sodium phosphate, water for injection and sufficient sodium hydroxide to adjust to the pH or the solution to within the range 3-10.
We have now surprisingly found that an improved formulation for parenteral administration may be obtained if the glycine antagonist is formulated in an isotonic sugar solution suitable for injection containing a water miscible organic solvent for the compound and the pH of the solution is adjusted to be within the range 7 to 9.
Thus the present invention provides a pharmaceutical composition in a form suitable for parenteral administration comprising a solution of a physiologically acceptable salt thereof, in an isotonic sugar solution containing a water miscible organic solvent for the compound, said composition having a pH within the range 7 to 9.
The isotonic sugar solution for use in the composition is conveniently an aqueous dextrose solution such as 2 to 5% dextrose solution. Examples of suitable alternative isotonic sugar solutions include those containing mannitol or sorbitol.
Conveniently, the composition according to the invention is prepared from etheny!-4,6-dichloroindole-2-carboxylic acid in the form of the free acid or more particularly in the form of the sodium salt thereof.
The amount of the glycine antagonist (expressed in terms of the free acid) in the formulation is preferably within the range 0.1 to 80 mg/ml.
If necessary, the pH of the solution may be adjusted by the addition of a suitable base such as aqueous sodium hydroxide. More conveniently however the pH of the solution may be adjusted to and/or maintained within the range 7 to 9 e.g 8.0 to 9.0 by the use of a suitable buffer salt. Examples of suitable buffer salts include tris(hydroxymethyl)aminomethane or alkali metal salts of citric acid and or phosphoric add e.g. disodium phosphate. A particularly convenient buffer salt for use in the invention is tris(hydroxymethyl)aminomethane.
Suitable water miscible organic solvents for use in the formulation include propylene glycol, glycofurol, ethanol, benzyl alcohol, glycerol, polyethylene glycols, N-methyl pyrrolidone or dimethylacetamide. The amount of water miscible organic solvent present is conveniently within the range of 0.1 to 40% by weight of the total formulation.
The formulation according to the invention may be administered in the form of a bolus injection or intravenous infusion. For the bolus injection the amount of water miscible organic solvent present is conveniently within the range 5 to 40% and the concentration of the glycine antagonist is conveniently within the range of 10 to 80 mg/ml e.g. 20-70 mg/ml. A particularly convenient water miscible organic solvent for use in the bolus injection is glycofurol. The isotonic sugar solution for use in the bolus injection is conveniently an aqueous mannitol solution.
For the intravenous infusion the amount of water miscible organic solvent is conveniently within the range 1 to 4% and the concentration of the glycine antagonist is conveniently in the range of 0.1 to 5 mg/ml e.g. 0.5 to 2 mg/ml. A particularly convenient water miscible organic solvent for use in intravenous infusion is propylene glycol. A particularly useful sugar for use in the intravenous infusion formulation is dextrose.
For the intravenous infusion formulation and more particularly those wherein the concentration of glycine antagonists (expressed as
REFERENCES:
patent: 5106847 (1992-04-01), Salituro et al.
Remington's Pharmaceutical Sciences (15th ed.) 1975, p. 759.
Lodi Andrea
Rossato Maria Teresa
Glaxo Wellcome SpA
Spivack Phyllis G.
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