Aqueous liquid preparations and light-stabilized aqueous liquid preparations

Abstract

An aqueous liquid preparation containing (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid or a pharmacologically acceptable acid addition salt thereof, which is stabilized with a water-soluble metal chloride, is provided.

Claims

1. An aqueous liquid preparation consisting essentially of (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid or a pharmacologically acceptable acid addition salt thereof as a sole therapeutic agent, and a water-soluble metal chloride in an amount sufficient to prevent precipitation of the sole therapeutic agent in the aqueous liquid preparation upon exposure to light, wherein the metal chloride has a concentration selected from the range of a lower limit concentration of 0.15 w/v % and an upper limit concentration of 1.5 w/v %, and wherein the aqueous liquid preparation has a pH in the range of 8.1-8.5.

2. The aqueous liquid preparation of claim 1, wherein the metal chloride is at least one kind selected from sodium chloride, potassium chloride and calcium chloride.

3. The aqueous liquid preparation of claim 1, wherein the (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid or the pharmacologically acceptable acid addition salt thereof as the sole therapeutic agent has a concentration selected from the range of a lower limit concentration of 0.1 w/v % and an upper limit concentration of 2.0 w/v %.

4. The aqueous liquid preparation of claim 1, wherein the sole therapeutic agent is an acid addition salt of (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid.

5. The aqueous liquid preparation of claim 4, wherein the acid addition salt is monobenzenesulfonate.

6. The aqueous liquid preparation of claim 1, which is an eye drop.

7. The aqueous liquid preparation of claim 1, which is a nasal drop.

8. An aqueous eye drop consisting essentially of (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid monobenzenesulfonate as a sole therapeutic agent, and sodium chloride at not less than 0.2 w/v % and not more than 0.8 w/v %, wherein the sodium chloride prevents precipitation of the sole therapeutic agent in the eye drop upon exposure to light, and wherein the eye drop has a pH in the range of 8.1-8.5.

9. A method of light-stabilizing (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid or a pharmacologically acceptable acid addition salt thereof as a sole therapeutic agent in an aqueous solution, the method comprising: adding a water-soluble metal chloride to an aqueous solution consisting essentially of the (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid or the pharmacologically acceptable acid addition salt thereof as the sole therapeutic agent in an amount sufficient to prevent precipitation of the sole therapeutic agent upon exposure to light, wherein the metal chloride has a concentration selected from the range of a lower limit concentration of 0.15 w/v % and an upper limit concentration of 1.5 w/v %, and wherein the aqueous solution has a pH in the range of 8.1-8.5.

10. The method of claim 9, wherein the (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid or the pharmacologically acceptable acid addition salt thereof as the sole active ingredient has a concentration selected from the range of a lower limit concentration of 0.1 w/v % and an upper limit concentration of 2.0 w/v %.

11. An aqueous eye drop consisting essentially of: a therapeutic agent consisting of (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid monobenzenesulfonate, and sodium chloride at not less than 0.2 w/v % and not more than 0.8 w/v %, wherein the sodium chloride prevents precipitation of the therapeutic agent in the eye drop upon exposure to light, and wherein the eye drop has a pH in the range of 8.1-8.5.

Description

BEST MODE FOR EMBODYING THE INVENTION

(1) The present invention is explained in more detail by referring to Experimental Examples and Examples, which are not to be construed as limitative.

Experimental Example 1 Effect of Water-Soluble Metal Chloride on Light-Stability of Bepotastine Besilate

(2) Test Method

(3) The aqueous liquid preparations (Formulations 1-6) shown in the following [Table 1], which contained bepotastine besilate, were prepared according to conventional methods and filled in glass ampoules by 5 mL each. Using a xenon long-life fade meter (FAL-25AX-Ec manufactured by SUGA TEST INSTRUMENTS Co., Ltd.), a light corresponding to not less than 200 W.Math.h/m.sup.2 in a total near-ultraviolet radiation energy was irradiated (irradiation time: 23-34 hr), and appearance of each formulated liquid preparation was observed. The amount of light exposure was measured by a quinine chemical actinometry system described in the Drug Approval and Licensing Procedures in Japan 2001.

(4) TABLE-US-00001 TABLE 1 Formulation 1 2 3 4 5 6 bepotastine 1.5 g 1.5 g 1.5 g 1.5 g  1.5 g  1.5 g besilate sodium — 0.1 g 0.2 g 0.3 g — — chloride potassium — — — — 0.79 g — chloride calcium — — — — — 1.18 g chloride 2H.sub.2O sodium suitable suitable suitable suitable suitable suitable hydroxide amount amount amount amount amount amount total 100 mL 100 mL 100 mL 100 mL 100 mL 100 mL amount PH 7.0 7.0 6.7 6.9 6.7 6.8
Test Results

(5) The appearance after light irradiation was black green in Formulation 1, and a precipitate was observed. It was slightly dark green-pale yellow in Formulation 2, and a precipitate was slightly observed. The appearance of Formulations 3-6 did not change from that immediately after preparation and were pale yellow and clear. The results indicate that addition of a water-soluble metal chloride in not less than 0.2 w/v % improves stability of bepotastine besilate under light irradiation conditions.

Experimental Example 2 Effect of Boric Acid and Glycerin on Light-Stability of Bepotastine Besilate

(6) Test Method

(7) The aqueous liquid preparations (Formulations 7-9) shown in the following [Table 2], which contained bepotastine besilate, were prepared according to conventional methods and processed in the same manner as in Experimental Example 1, and appearance of each formulated liquid preparation was observed.

(8) TABLE-US-00002 TABLE 2 Formulation 7 8 9 bepotastine besilate 1.5 g 1.5 g 1.5 g sodium dihydrogen 0.1 g — — phosphate dihydrate boric acid — 1.0 g 0.5 g sodium chloride 0.6 g — — glycerin — 0.5 g 2.0 g benzalkonium chloride 0.005 g 0.005 g 0.005 g sodium hydroxide suitable suitable suitable amount amount amount total amount 100 mL 100 mL 100 mL pH 6.8 6.8 6.8
Test Results

(9) The appearance after light irradiation did not change from that immediately after preparation and was pale yellow and clear for Formulation 7 comprising sodium chloride, but black green for Formulations 8 and 9 comprising boric acid and glycerin and a precipitate was observed. The results indicate that addition of boric acid and glycerin fails to improve stability of bepotastine besilate under light irradiation conditions.

Experimental Example 3 Effect of pH and Bepotastine Besilate Concentration on Light-Stability of Bepotastine Besilate

(10) Test Method

(11) The aqueous liquid preparations (Formulations 10-12) shown in the following [Table 3], which contained bepotastine besilate, were prepared according to conventional methods and processed in the same manner as in Experimental Example 1, and appearance of each formulated liquid preparation was observed.

(12) TABLE-US-00003 TABLE 3 Formulation 10 11 12 bepotastine besilate 1.5 g 1.5 g 0.1 g sodium dihydrogen 0.1 g 0.1 g 0.1 g phosphate dihydrate sodium chloride 0.6 g 0.6 g 0.82 g benzalkonium 0.005 g 0.005 g 0.005 g chloride sodium hydroxide suitable suitable suitable amount amount amount total amount 100 mL 100 mL 100 mL pH 4.0 8.5 6.8
Test Results

(13) The appearance after light irradiation did not change from that immediately after preparation and was pale yellow and clear for Formulation 10 (pH 4) and Formulation 11 (pH 8.5) comprising sodium chloride. In addition, the appearance did not change from that immediately after preparation and was colorless and clear for Formulation 12 having a bepotastine besilate concentration of 0.1 w/v %. These results and the results of Formulation 7 (pH 6.8) in Experimental Example 2 indicate that addition of sodium chloride, which is a water-soluble metal chloride, improves light stability of bepotastine besilate at pH 4-8.5. In addition, they indicate that the light-stability of bepotastine besilate is improved in the concentration range of 0.1 w/v %-1.5 w/v %.

Experimental Example 4 Effect of Bepotastine Besilate Concentration and pH on Light-Stability of Bepotastine Besilate in Aqueous Preparation Comprising Glycerin

(14) Test Method

(15) The aqueous liquid preparations (Formulations 13-17) shown in the following [Table 4], which contained bepotastine besilate, were prepared according to conventional methods and processed in the same manner as in Experimental Example 1, and appearance of each formulated liquid preparation was observed.

(16) TABLE-US-00004 TABLE 4 Formulation 13 14 15 16 17 bepotastine 0.5 g 1.0 g 1.5 g 1.5 g 1.5 g besilate sodium 0.1 g 0.1 g 0.1 g 0.1 g 0.1 g dihydrogen phosphate dihydrate glycerin 2.2 g 2.0 g 1.7 g 1.7 g 1.7 g benzalkonium 0.005 g 0.005 g 0.005 g 0.005 g 0.005 g chloride sodium suitable suitable suitable suitable suitable hydroxide amount amount amount amount amount total amount 100 mL 100 mL 100 mL 100 mL 100 mL pH 6.8 6.8 4.0 6.8 8.5
Test Results

(17) The appearance after light irradiation was pale black green for Formulation 13 and black green for Formulation 14, and a precipitate was observed in both Formulations. The results indicate that addition of glycerin results in coloration of bepotastine besilate into black green even at a low concentration.

(18) Formulation 15 (pH 4) turned blue and a precipitate was observed. Formulation 16 (pH 6.8) turned black green and a precipitate was observed. Formulation 17 (pH 8.5) turned yellow brown but no precipitation was observed. The results indicate that bepotastine besilate is extremely unstable at a pH near neutral. The results also indicate that glycerin does not improve light-stability of bepotastine besilate in the range of pH 4-8.5. When 3.3 w/v % of glucose or mannitol was added instead of glycerin of Formulation 16, black green was developed and a precipitate was observed. These results indicate that a water-soluble metal chloride improves light-stability of bepotastine besilate, and isotonic agents such as glycerin, saccharides and the like do not improve light-stability of bepotastine besilate.

Example 1: Eye Drop

(19) TABLE-US-00005 bepotastine besilate 0.3 g Sodium dihydrogenphosphate dihydrate 0.1 g sodium chloride 0.79 g benzalkonium chloride 0.005 g sodium hydroxide suitable amount sterile purified water total amount 100 mL pH 6.8

(20) Using the above-mentioned ingredients, an eye drop is prepared by a conventional method.

Example 2 Eye Drop

(21) TABLE-US-00006 bepotastine besilate 0.5 g Sodium dihydrogenphosphate dihydrate 0.1 g sodium chloride 0.76 g benzalkonium chloride 0.005 g sodium hydroxide suitable amount sterile purified water total amount 100 mL pH 6.8

(22) Using the above-mentioned ingredients, an eye drop is prepared by a conventional method

Example 3 Eye Drop

(23) TABLE-US-00007 bepotastine besilate 1.0 g Sodium dihydrogenphosphate dihydrate 0.1 g sodium chloride 0.68 g benzalkonium chloride 0.005 g sodium hydroxide suitable amount sterile purified water total amount 100 mL pH 6.8

(24) Using the above-mentioned ingredients, an eye drop is prepared by a conventional method

Example 4 Eye Drop

(25) TABLE-US-00008 bepotastine besilate 1.5 g Sodium acetate trihydrate 0.1 g sodium chloride 0.6 g benzalkonium chloride 0.005 g sodium hydroxide suitable amount sterile purified water total amount 100 mL pH 4.0

(26) Using the above-mentioned ingredients, an eye drop is prepared by a conventional method.

Example 5 Eye Drop

(27) TABLE-US-00009 bepotastine besilate 1.5 g epsilon-aminocaproic acid 0.1 g sodium chloride 0.6 g benzalkonium chloride 0.005 g sodium hydroxide suitable amount sterile purified water total amount 100 mL pH 4.0

(28) Using the above-mentioned ingredients, an eye drop is prepared by a conventional method.

Example 6 Eye Drop

(29) TABLE-US-00010 bepotastine besilate 1.5 g citric acid 0.1 g sodium chloride 0.6 g benzalkonium chloride 0.005 g sodium hydroxide suitable amount sterile purified water total amount 100 mL pH 6.8

(30) Using the above-mentioned ingredients, an eye drop is prepared by a conventional method.

Example 7 Eye Drop

(31) TABLE-US-00011 bepotastine besilate 1.5 g taurine 0.1 g sodium chloride 0.6 g benzalkonium chloride 0.005 g sodium hydroxide suitable amount sterile purified water total amount 100 mL pH 8.5

(32) Using the above-mentioned ingredients, an eye drop is prepared by a conventional method.

Example 8 Eye Drop

(33) TABLE-US-00012 bepotastine besilate 1.5 g sodium dihydrogenphosphate dihydrate 0.1 g sodium chloride 0.6 g methyl parahydroxybenzoate 0.026 g propyl parahydroxybenzoate 0.014 g sodium hydroxide suitable amount sterile purified water total amount 100 mL pH 6.8

(34) Using the above-mentioned ingredients, an eye drop is prepared by a conventional method.

Example 9 Eye Drop

(35) TABLE-US-00013 bepotastine besilate 1.5 g sodium dihydrogenphosphate dihydrate 0.1 g sodium chloride 0.6 g potassium sorbate 0.27 g sodium hydroxide suitable amount sterile purified water total amount 100 mL pH 6.8

(36) Using the above-mentioned ingredients, an eye drop is prepared by a conventional method.

Example 10 Eye Drop

(37) TABLE-US-00014 bepotastine besilate 1.5 g sodium dihydrogenphosphate dihydrate 0.1 g sodium chloride 0.6 g chlorhexidine gluconate 0.005 g sodium hydroxide suitable amount sterile purified water total amount 100 mL pH 6.8

(38) Using the above-mentioned ingredients, an eye drop is prepared by a conventional method.

Example 11 Eye Drop

(39) TABLE-US-00015 bepotastine besilate 1.5 g sodium dihydrogenphosphate dihydrate 0.1 g sodium chloride 0.6 g benzalkonium chloride 0.005 g sodium hydroxide suitable amount sterile purified water total amount 100 mL pH 6.8

(40) Using the above-mentioned ingredients, an eye drop is prepared by a conventional method.

Example 12 Nasal Drop

(41) TABLE-US-00016 bepotastine besilate 1.0 g sodium dihydrogenphosphate dihydrate 0.1 g sodium chloride 0.68 g benzalkonium chloride 0.005 g sodium hydroxide suitable amount sterile purified water total amount 100 mL pH 6.8

(42) Using the above-mentioned ingredients, a nasal drop is prepared by a conventional method.

INDUSTRIAL APPLICABILITY

(43) In the present invention, the light-stability of (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid or a pharmacologically acceptable acid addition salt thereof, particularly bepotastine besilate, which is monobenzenesulfonate, can be improved by adding a water-soluble metal chloride to an aqueous liquid preparation comprising (+)-(S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid or a pharmacologically acceptable acid addition salt thereof, and a stable aqueous liquid preparation can be produced. Since an aqueous liquid preparation stable to light can be obtained by the light-stabilizing method of the present invention, the aqueous liquid preparation of the present invention is advantageously used for the treatment of allergic conjunctivitis, spring catarrh, pollinosis, allergic rhinitis and the like.

(44) While some of the embodiments of this invention have been described in detail in the foregoing, it will be possible for those of ordinary skill in the art to variously modify and change the embodiments specifically shown herein, within the scope not substantially deviating from the novel teaching and benefit of the invention. Accordingly, this invention encompasses all such modifications and changes within the spirit and scope of the invention as defined by the following claims.

(45) This application is based on a patent application No. 223804/2002 filed in Japan, the contents of which are hereby incorporated by reference.