Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-23
2001-12-11
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06329410
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an aqueous liquid preparation suitable for intravenous injection, comprising (R)-(−)-3-methyl-3-methylsulfonyl-1-(1H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]butan-2-ol having an excellent antifungal effect, or a pharmaceutically acceptable salt thereof.
BACKGROUND ART
Mycoses involve skin diseases typified by various trichophytoses, leprid, psoriasis, cutaneous candidiasis, and the like, and deep mycoses typified by mycotic meningitis, mycotic respiratory infection, hematomycosis, mycosis of urinary tract, and the like.
Among these, deep mycoses cannot be treated by using a usual antibiotic or chemotherapeutic agent, and thus the number of patients suffering therefrom shows a tendency to rise. Accordingly, there have been required drugs efficacious in treating them.
At present, only four drugs are clinically usable in treating deep mycoses, namely, amphotericin B which is a peptide antibiotic, flucytosine which is a growth inhibitor for fungal cells, and fluconazole and itraconazole which are azole antifungal agents. However, these agents are not satisfactory yet. Moreover, it is said that deep mycoses would frequently cause multiple fungal infection. Thus, it has been required to develop a drug having a broader antifungal spectrum. Under these circumstances, a triazole derivative, (R)-(−)-3-methyl-3-methylsulfonyl-1-(1H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]butan-2-ol, and pharmaceutically acceptable salts thereof have been found (JP-A-3-223266 and JP-A-7-2802). This compound will be sometimes referred to as “the present compound” in this description.
The present compound has excellent characteristics of: (1) showing an antifungal effect on the genus Aspergillus in addition to the genera Candida and Cryptococcus; (2) showing an antifungal effect even on the genus Candida which is fluconazole-resistant; (3) showing an excellent therapeutic effect on a neutropenia systemic fungal infection model (in vivo); (4) causing a more remarkable decrease in the viable count in the lung in a local infection model (in vivo) than existing drugs; (5) having a higher selectivity of P450 derived from fungi and animals than existing drugs; (6) having a water solubility which is usable as injections; and (7) having a safety margin comparable to existing drugs. Thus, it is expected that it is useful as a remedy for deep mycoses.
The present compound has a water solubility which is usable as injections. Therefore, it is preferred that the present compound is used as injections from the viewpoint of providing dosage forms over a wide range, in particular, those for intravenous administration.
Although the antifungal effect of the present compound was proved by orally administering it to mice in JP-A-3-223226, it is disclosed that the compound can be formulated by conventional methods into antifungal agents in various dosage forms, such as tablets, granules, powders, capsules, suspensions, injections, suppositories, external preparations, and the like. When injections are prepared, it is also disclosed that the present compound may be preliminarily dissolved, dispersed, emulsified, etc. in an aqueous carrier, such as distilled water for injection or the like, or formulated into powders for injection which are to be dissolved when they are used, namely, the present compound is usable as injections by conventional methods.
In order to prepare an injection for intravenous administration, it is necessary to add an isotonizing agent (an osmotic regulator) to regulate the osmotic pressure of the aqueous solution. Thus, the present inventors prepared an injection by using sodium chloride (0.9 W/V %) commonly used as an isotonizing agent. As a result, they have found that the present compound is decomposed at a considerably high ratio by heat sterilization and that its decomposition product is increased when stored over a long time. To develop an injection, it is necessary to minimize the decomposition during heating and enhance the stability. However, no such injection has been obtained so far.
DISCLOSURE OF THE INVENTION
Accordingly, an object of the present invention is to provide an aqueous liquid preparation of the present compound keeping an osmotic pressure suitable for intravenous administration, being prevented from thermal decomposition during sterilization as far as possible, having a high storage stability and thus being suitable for intravenous injection, and to injections for intravenous administration using the same.
As a result of intensive studies, the present inventors have found that when an aqueous solution of the present compound is adjusted to a specific pH value, the decomposition product formed by heat sterilization can be reduced, no decomposition product is formed after the sterilization and it is stable with the passage of time. Thus, the present invention has been completed.
Accordingly, the present invention provides an aqueous liquid preparation, which has a pH of from 3 to 5 and comprises (R)-(−)-3-methyl-3-methylsulfonyl-1-(1H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]butan-2-ol having a broad antifungal spectrum, or a pharmaceutically acceptable salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
(R)-(−)-3-Methyl-3-methylsulfonyl-1-(1H-1,2,4-triazol-1-yl)-2-[4-(trifluoromethyl)phenyl]butan-2-ol or a pharmaceutically acceptable salt thereof, which is an active ingredient of the aqueous liquid preparation of the present invention, can be produced by, for example, the methods described in JP-A-3-223266 and JP-A-7-2802.
Examples of the pharmaceutically acceptable salt include hydrochloride, nitrate, hydrobromide, sulfate, p-toluenesulfonate, methanesulfonate, fumarate, maleate, succinate, lactate, bromocamphorsulfonate, and the like.
The aqueous liquid preparation of the present invention can be stabilized by regulating the pH to 3 to 5. Examples of a pH regulator for adjusting the pH to 3 to 5 include anhydrous sodium monohydrogenphosphate, citric acid, sodium citrate, hydrochloric acid, lactic acid, sodium hydroxide, dry sodium carbonate, dilute hydrochloric acid, crystalline sodium dihydrogenphosphate, succinic acid, acetic acid, sodium acetate, tartaric acid, sodium hydrogencarbonate, sodium carbonate, triethanolamine, sodium lactate solution, glacial acetic acid, citric anhydride, anhydrous sodium dihydrogenphosphate, meglumine, monoethanolamine, phosphoric acid, trisodium phosphate, sodium hydrogenphosphate, dipotassium phosphate, potassium dihydrogenphosphate, sodium dihydrogenphosphate, and the like. They may be used alone or a combination thereof to adjust the pH to 3 to 5.
These pH regulators may be used in an effective and pharmaceutically acceptable amount. For example, anhydrous sodium monohydrogenphosphate is used at an amount of from 0.1 to 8.0 parts by weight per part by weight of the present compound.
The aqueous liquid preparation of the present invention has preferably a pH of form 3 to 5, more preferably form 3 to 4.5. The stabilizing effect according to the present invention can be effectively achieved within this range. A preparation having a pH value less than 3 is not favorable as an injection due to that it shows a tendency to give a strengthened local stimulus (rash pain) when an injection needle sticks in the body.
In order to prepare an injection for intravenous administration, it is also necessary to add an isotonizing agent (an osmotic regulator). Examples of the isotonizing agent appropriate for the aqueous liquid preparation of the present invention include one or at least two of substances selected from phosphates (phosphoric acid, sodium hydrogenphosphate, disodium hydrogenphosphate, potassium dihydrogenphosphate, anhydrous sodium pyrophosphate, crystalline sodium dihydrogenphosphate, calcium hydrogenphosphate, etc.), saccharides (glucose, D-mannitol, D-sorbitol, lactose, fructose, sucrose, etc.), polyols (glycerol, xylitol, MACROGOL 4000™, etc.), sulfates (sodium hydrogensulfite, etc.), chlorides (potas
Baba Toshihiro
Fujii Tsuneo
Criares Theodore J.
Kim Jennifer
Sughrue Mion Zinn Macpeak & Seas, PLLC
Welfide Corporation
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