Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-18
2001-10-23
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S248000
Reexamination Certificate
active
06306856
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for solubilizing pyridonecarboxylic acid, which is an amphoteric compound and which has an antibacterial activity, and a pharmacologically acceptable salt thereof, a solubilizer therefor, an aqueous solution preparation containing solubilized pyridonecarboxylic acid, and a production method thereof.
BACKGROUND OF THE INVENTION
Pyridonecarboxylic acid and pharmacologically acceptable salts thereof are superior synthetic antibacterial agents. However, since pyridonecarboxylic acid has carboxylic acid and the dihydropyridine skeleton in a molecule, forming a zwitterion, it shows low solubility in water at a physiological pH, i.e., neutral range. This imposes a problem that an aqueous solution containing pyridonecarboxylic acid or a pharmacologically acceptable salt thereof cannot be formulated into a pharmaceutical preparation having a near neutral pH.
Hardly soluble pyridonecarboxylic acid and a pharmacologically acceptable salt thereof have been conventionally solubilized by, for example, adding an inorganic acid to pyridonecarboxylic lactate (JP-A-60-94910), or adding an excess base to pyridonecarboxylic acid (JP-A-61-180771), or adding a metal compound comprising aluminum, magnesium or zinc to pyridonecarboxylic acid or a salt thereof (JP-A-63-188626). The aqueous solutions thus obtained show changes in pH, which is caused by the solubilizer added, and the toxicity of the solubilizer itself which may cause a local irritation and the like. In addition, the absorption into the living body may decrease due to an interaction between the solubilizer and pyridonecarboxylic acid.
Thus, there has not been provided an aqueous solution containing solubilized pyridonecarboxylic acid, which is safe and useful at a physiological pH, i.e., about neutral pH (pH 6-8).
DISCLOSURE OF THE INVENTION
It is an object of the present invention to provide a method for solubilizing pyridonecarboxylic acid and a pharmacologically acceptable salt thereof.
Another object of the present invention is to provide a solubilizer for pyridonecarboxylic acid and a pharmacologically acceptable salt thereof.
A yet another object of the present invention is to provide an aqueous solution having an improved solubility of pyridonecarboxylic acid and a pharmacologically acceptable salt thereof.
A further object of the present invention is to provide a method for producing an aqueous solution comprising pyridonecarboxylic acid or a pharmacologically acceptable salt thereof.
The present inventor has conducted intensive studies in an attempt to achieve the above-mentioned objects, and found that glycyrrhizic acid and a salt thereof can solubilize pyridonecarboxylic acid and a pharmacologically acceptable salt thereof in water at a physiological pH, which resulted in the completion of the present invention.
Thus, the present invention provides the following.
(1) A method for solubilizing pyridonecarboxylic acid or a pharmacologically acceptable salt thereof, comprising incorporating glycyrrhizic acid or a salt thereof and pyridonecarboxylic acid or a pharmacologically acceptable salt thereof.
(2) The method for solubilizing pyridonecarboxylic acid or a pharmacologically acceptable salt thereof according to (1) above, which comprises adding pyridonecarboxylic acid or a pharmacologically acceptable salt thereof to water, adjusting pH to not more than 3, adding glycyrrhizic acid or a salt thereof and adjusting pH of this aqueous solution to 3.5-8.5.
(3) The method for solubilizing pyridonecarboxylic acid or a pharmacologically acceptable salt thereof according to (1) above, wherein the pyridonecarboxylic acid is a compound of the formula (I):
wherein X, Y and Z may be the same or different and each is nitrogen atom or optionally substituted CH, R
1
, R
2
, R
3
, R
4
and R
5
may be the same or different and each is hydrogen atom, halogen, carboxyl group, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted aryl or optionally substituted heterocyclic group, or at least two members selected from R
1
, R
2
, R
3
, R
4
and R
5
in combination form an optionally substituted 4- to 7-membered ring via or not via a hetero atom.
(4) The method for solubilizing pyridonecarboxylic acid or a pharmacologically acceptable salt thereof according to (1) above, wherein the pyridonecarboxylic acid is a member selected from the group consisting of lomefloxacin, norfloxacin, enoxacin, ofloxacin, ciprofloxacin, tosufloxacin, fleroxacin, cinoxacin, levofloxacin and sparfloxacin.
(5) A solubilizer for pyridonecarboxylic acid or a pharmacologically acceptable salt thereof, which comprises glycyrrhizic acid or a salt thereof as an active ingredient.
(6) An aqueous solution comprising pyridonecarboxylic acid or a pharmacologically acceptable salt thereof, and glycyrrhizic acid or a salt thereof.
(7) The aqueous solution of (6) above, which is in the form of an eye drop, nasal drop or ear drop.
(8) A method for producing an aqueous solution comprising pyridonecarboxylic acid or a pharmacologically acceptable salt thereof, which comprises incorporating glycyrrhizic acid or a salt thereof and pyridonecarboxylic acid or a pharmacologically acceptable salt thereof.
(9) The method for producing an aqueous solution comprising pyridonecarboxylic acid or a pharmacologically acceptable salt thereof according to (8) above, which comprises adding pyridonecarboxylic acid or a pharmacologically acceptable salt thereof to water, adjusting pH to not more than 3, adding glycyrrhizic acid or a salt thereof, and adjusting pH of this aqueous solution to 3.5-8.5.
DETAILED DESCRIPTION OF THE INVENTION
The pyridonecarboxylic acid and a pharmacologically acceptable salt thereof, which are amphoteric compounds and which have an antibacterial activity, are solubilized by incorporating these compounds and a solubilizing agent containing glycyrrhizic acid or a salt thereof as an active ingredient.
For example, pyridonecarboxylic acid or a pharmacologically acceptable salt thereof is added to water, the mixture is adjusted to pH 3 or below with an acid such as hydrochloric acid, phosphoric acid, acetic acid and the like, glycyrrhizic acid or a salt thereof is added thereto, and this aqueous solution is adjusted to pH 3.5-8.5, preferably 6-8, with an alkali such as sodium hydroxide, potassium hydroxide, monoethanolamine and tromethamine. The pyridonecarboxylic acid and a pharmacologically acceptable salt thereof are generally subjected to the above-mentioned solubilization in water at around room temperature.
The pyridonecarboxylic acid is free of any particular imitation as long as it is a compound having a carboxyl group at the 3-position of the pyridine skeleton or pyridazine skeleton and an oxo group at the 4-position thereof.
The pyridonecarboxylic acid capable of exerting a significant effect as a solubilization target in the present invention has a solubility in water, which corresponds to the solubility of from “somewhat insoluble” to “sparingly soluble” in the solubility test as defined in Japan Pharmacopoeia, 13th Edition, Explanation (1996), Hirokawashoten, Tokyo, p. A-51, General Notices 23, Description, or from “sparingly soluble” to “practically insoluble” as defined in International Pharmacopoeia III.
The pyridonecarboxylic acid to be preferably used has the following formula (I):
wherein X, Y and Z may be the same or different and each is nitrogen atom or optionally substituted CH, R
1
, R
2
, R
3
, R
4
and R
5
may be the same or different and each is hydrogen atom, halogen, carboxylic group, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted aryl or optionally substituted heterocyclic group, or at least two members selected from R
1
, R
2
, R
3
, R
4
and R
5
in combination form an optionally substituted 4- to 7-membered ring via or not via a hetero atom.
“Halogen” is exemplified by fluorine, chlorine, bromine, iodine and the like.
The
Fay Zohreh
Senju Pharmaceutical Co. Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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