PHOTOSTABLE AQUEOUS SOLUTION CONTAINING BENZYL ALCOHOL DERIVATIVES

Abstract: A photostabilized aqueous solution characterized in that the solution comprises optically active ( - )-(R)-α-[(tert-butylamino)methyl]-2-chloro-4-hydroxybenzyl alcohol represented by the following formula: or a pharmacologically acceptable salt thereof, together with at least one photostabilizer selected from the group consisting of saccharides, sugar alcohols, and polyalcohols.

Description: The present invention relates to a pharmaceutical composition in the form of an aqueous solution with improved photostability which comprises as an active ingredient a benzyl alcohol compound having excellent stimulating activity on an adrenergic β 2 -receptor and useful as a uterine relaxing agent, bladder relaxing agent and the like. Background Art Optically active ( - )-(R)- α -[(tert-butylamino)methyl]-2-chloro-4-hydroxybenzyl alcohol (hereinafter referred to as "the present compound") represented by the following formula (I): and pharmacologically acceptable salts thereof, which have uterine relaxing activity, bladder relaxing activity and other, have been revealed useful as a therapeutic medicament for threatened premature delivery or a therapeutic medicament for urination disorders such as urinary incontinence, nocturnal enuresis or the like (Japanese Patent Unexamined Publication No. (Hei) 178356/1992). For emergent therapy of threatened premature delivery, it is desirable to use an injection by which rapid manifestation of efficacy can be expected. For therapeutic treatment of urination disorder such as urinary incontinence, nocturnal enuresis or the like, which are frequent in the elderly or children, orally applicable liquid formulations are clinically very useful in view of lowered deglutition ability of the elderly and convenient administration to children. The inventors of the present invention conducted various studies to provide a pharmaceutical composition in the form of an aqueous solution comprising the present compound as an active ingredient. In the course of the studies, they found that the present compound was unstable in an aqueous solution and easily formed decomposed products under irradiation with light, and that an amount of the photodecomposition products tended to be further increased by the addition of a buffering agent required to maintain pH of the solution, e,g., citric acid, acetic acid, L-tartaric acid, D-tartaric acid, or DL-tartaric acid. These findings have not yet been reported so far. Generally, brown containers for protection from light are used to distribute an aqueous solution for a use as a pharmaceutical composition which contains a photo-unstable drug as an active ingredient. It was found that the photodecomposition of the present compound was partly prevented by filling an aqueous solution comprising the present compound as an active ingredient in brown containers. However, the results were far from satisfactory from a viewpoint of stability essential to pharmaceutical formulations. The results can be elucidated that light with a relatively short wavelength, i.e., 400 nm or less, is primarily involved in photodecomposition of an ordinary organic compound, and for this reason, brown containers are designed to mainly achieve protection from light having a short wavelength of 400 nm or less, whereas light having a longer wavelength above 400 nm is also involved in the photodecomposition of the present compound, and accordingly, sufficient protection from light cannot be achieved by the brown containers. Therefore, in order to distribute a stable aqueous solution for a use as a pharmaceutical composition which comprises the present compound as an active ingredient, it is necessary to develop a means to achieve higher photostability. An object of the present invention is to provide a pharmaceutical composition in the form of an aqueous solution having improved photostability which comprises the present compound or a pharmacologically acceptable salt thereof as an active ingredient. In particular, the object of the present invention is to provide a pharmaceutical composition having satisfactory photostability against light with a long wavelength which cannot be sufficiently protected even by a brown container. Another object of the present invention is to provide a highly safe photostabilizer which suppresses the photodecomposition of the present compound or a pharmacologically acceptable salt thereof, and can be formulated in a pharmaceutical composition. Disclosure of the Invention The inventors of the present invention made eager efforts to achieve the foregoing objects, and as a result, they found that the photodecomposition of the present compound was remarkably suppressed by the addition of a substance selected from saccharides, sugar alcohols, and polyalcohols to an aqueous solution containing the present compound, and that the photodecomposition of the present compound caused by the light transmitted by a brown container was completely prevented. The present invention was achieved on the basis of these findings. Saccharides, sugar alcohols, and polyalcohols are used as isotonicities or excipients in formulations as pharmaceutical compositions. However, their photostabilizing functions for the present compound has not yet been known. The present invention thus provides an aqueous solution characterized in that said solution comprises optically active ( - )-(R)-α-[(tert-butylamino)methyl]-2-chloro-4-hydroxybenzyl alcohol represented by the following formula (I): or a pharmacologically acceptable salt thereof, together with at least one photostabilizer selected from the group consisting of saccharides, sugar alcohols, and polyalcohols, the solution containing 10% (w/w) or more of the photostabilizer based on the total weight of the optical active (-)-(R)-α-[(tert-butylamino)methyl]-2-chloro-4-hydroxybenzyl alcohol or a pharmacologically acceptable salt thereof. According to preferred embodiments of the present invention, there are provided the aforementioned solution wherein the saccharide is selected from the group consisting of glucose, sucrose, fructose, and maltose; the aforementioned solution wherein the sugar alcohol is selected from the group consisting of xylitol, sorbitol, and mannitol; the aforementioned solution wherein the polyalcohol is selected from the group consisting of glycerin and propylene glycol; the aforementioned solution wherein a pH is 6.5 or less; the aforementioned solution wherein a content of the optical active ( - )-(R)- α -[(tert-butylamino)methyl]-2-chloro-4-hydroxybenzyl alcohol or a pharmacologically acceptable salt thereof is 0.01-10% (w/v) based on a volume of the aqueous solution; and the aforementioned solution wherein a content of the photostabilizer selected from the group consisting of saccharides, sugar alcohols, and polyalcohols is 1-50% (w/v) based on a volume of the aqueous solution. According to another aspect of the present invention, there is provided a method of suppressing the photodecomposition of the optical active ( - )-(R)-α-[(tert-butylamino)methyl]-2-chloro-4-hydroxybenzyl alcohol or a pharmacologically acceptable salt thereof contained in an aqueous solution, by adding a photostabilizer selected from the group consisting of saccharides, sugar alcohols, and polyalcohols. There is also provided herein a therapeutic medicament for threatened premature delivery or urination disorders which comprises the aforementioned photostabilized solution. Best Mode for Carrying Out the Invention The aqueous solution of the present invention is a pharmaceutical composition which can be used as a medicament for oral administration or parenteral administration such as by intravenous injection. The solution is characterized to contain the optical active ( - )-(R)- α -[(tert-butylamino)methyl]-2-chloro-4-hydroxybenzyl alcohol or a pharmacologically acceptable salt thereof, together with a substance selected from the group consisting of saccharides, sugar alcohols, and polyalcohols as a photostabilizer for said compound. The present compound represented by the formula (I) can be prepared by, for example, the method described in the Japanese Patent Unexamined Publication No. (Hei) 178356/1992. The pharmacologically acceptable salts of the present compound include, for example, mineral acid salts such as hydrochloride, hydrobromide, hydriodide, nitrate, sulfate, or phosphate, and organic acid salts such as acetate, maleate, fumarate, citrate, oxalate, malate, methanesulfonate, p-toluenesulfonate, mandelate, D-10-camphorsulfonate, L-10-camphorsulfonate, DL-10-camphorsulfonate, L-tartrate, D-tartrate, DL-tartrate, succinate and the like. A content of the present compound or a pharmacologically acceptable salt thereof in the aqueous solution of the present invention may be 0.01-10% (w/v), preferably 0.02-5% (w/v), and more preferably 0.05-0.5% (w/v) based on the total volume of the solution. The aqueous solution of the present invention may contain one or more of the active ingredients selected from the present compound and pharmacologically acceptable salts thereof. The photostabilizer has a function to reduce or prevent the photodecomposition of the present compound or a pharmacologically acceptable salt thereof in an aqueous solution. Examples of the saccharides include, for example, glucose, sucrose, fructose, maltose and the like; examples of the sugar alcohols include, for example, xylitol, sorbitol, mannitol and the like; and examples of the polyalcohols include, for example, glycerin, propylene glycol and the like. The aqueous solution of the present invention may contain one or more of these photostabilizers. The type and amount of the photostabilizer used according to the present invention may be appropriately chosen so as to achieve a desired photostability depending on the type of the active ingredient selected from the present compound or pharmacologically acceptable salts thereof. As a test for the photostability, the method described in Examples of the specification may be employed. For example, 1-50% (w/v), preferably 2-10% (w/v) of the photostabilizer based on the total volume of the aqueous solution may be formulated. The photostabilizer may also be formulated in an amount of 10% (w/w) or more based on a weight of the present compound or a pharmacologically acceptable salt thereof as an active ingredient. The pH of the aqueous solution of the present invention may preferably be adjusted to 6.5 or lower, most preferably 3-6.5. Acids or bases used for adjusting the pH are not particularly limited so long as they can be added in pharmaceuticals. For example, hydrochloric acid, sodium hydroxide or other may be used. If necessary, a buffering agent such as citric acid, acetic acid, L-tartaric acid, D-tartaric acid, or DL-tartaric acid may be added. Amounts of the buffering agent are not particularly limited, however, it is preferable to add a minimum amount of the buffering agent that is capable of adjusting or maintaining a desired pH. The aqueous solutions of the present invention has a characteristic feature in that the solution is free from photodecomposition of the present compound or a pharmacologically acceptable salt thereof even when the solution is added with a buffering agent such as citric acid, acetic acid, L-tartaric acid, D-tartaric acid, or DL-tartaric acid. When the aqueous solution of the present invention is used as an injection, the addition of an isotonicity is preferred. However, partial or complete isotonization is sometimes achieved by the photostabilizer contained in the aqueous solution of the present invention, and in that case, it is generally unnecessary to use an entire amount of theoretically-required isotonicity. For example, when glucose or mannitol is used as the photostabilizer in an amount of about 5% (w/v) based on the total volume of the aqueous solution, or when propylene glycol is used in an amount of about 2% (w/v), the aqueous solution is sufficiently isotonized, and therefore, it is generally unnecessary to add an isotonicity. Methods for preparing the aqueous solution of the present invention are not particularly limited. For example, the solution can be prepared by dissolving, simultaneously or in an appropriate order in purified water or water for injection, respective required amounts of the present compound or a pharmacologically acceptable salt thereof as an active ingredient, the photostabilizer, and other pharmaceutical additives, e.g., a buffering agent, a pH modifier, an isotonicity, an antiseptic, and a soothing agent, if necessary, and then optionally subjecting the resulting solution to a sterilization process such as heat sterilization and sterilization of filtration. As the present compound or a pharmacologically acceptable salt thereof as an active ingredient, any type of known or unknown crystals, or any type of known or unknown hydrates may be used. Examples The present invention will be further detailed by referring to the following examples. However, the scope of the present invention is not limited to these specific examples. Example 1 L-Tartrate of the present compound 0.2 mg Propylene glycol 20 mg Citric acid 0.3 mg Sodium hydroxide Sufficient quantity Hydrochloric acid Sufficient quantity Water Sufficient quantity Total 1 ml pH 5.0 L-Tartrate of the present compound, propylene glycol, and citric acid were weighed in the ratio according to the aforementioned prescription, and then dissolved in water. The solution was adjusted to pH 5 with sodium hydroxide or hydrochloric acid, and then added with water up to the total volume so as to obtain the prescribed concentrations. The solution was then filled in a brown container and sealed. Examples 2-20 According to the method of Example 1, solutions of Examples 2-20 were obtained. Prescriptions for these examples are shown in Tables 1-3. Example No. Example 1 Example 2 Example 3 Example 4 L-Tartrate of the present compound 0.2 mg 1 mg 5 mg 50 mg Photostabilizer Propylene glycol 20 mg Propylene glycol 20 mg Propylene glycol 20 mg Propylene glycol 20 mg Acid (citric acid) 0.3 mg 0.3 mg 0.3 mg 0.3 mg Sodium hydroxide Sufficient quantity Sufficient quantity Sufficient quantity Sufficient quantity Hydrochloric acid Sufficient quantity Sufficient quantity Sufficient quantity Sufficient quantity Water Sufficient quantity Sufficient quantity Sufficient quantity Sufficient quantity Total volume 1 ml 1 ml 1 ml 1 ml pH 5.0 5.0 5.0 5.0 Osmotic pressure ratio 1.0 1.0 1.1 2.2 Example No. Example 5 Example 6 Example 7 Example 8 L-Tartrate of the present compound 1 mg 1 mg 1 mg 1 mg Photostabilizer Propylene glycol 20 mg Propylene glycol 20 mg Propylene glycol 10 mg Propylene glycol 100 mg Acid (citric acid) 0.3 mg 0.3 mg 0.3 mg 0.3 mg Sodium hydroxide Sufficient quantity Sufficient quantity Sufficient quantity Sufficient quantity Hydrochloric acid Sufficient quantity Sufficient quantity Sufficient quantity Sufficient quantity Water Sufficient quantity Sufficient quantity Sufficient quantity Sufficient quantity Total volume 1 ml 1 ml 1 ml 1 ml pH 3.0 6.5 5.0 5.0 Osmotic pressure ratio 1.0 1.0 0.5 5.3 Example No. Example 9 Example 10 Example 11 Example 12 L-Tartrate of the present compound 1 mg 1 mg 1 mg 1 mg Photostabilizer Glucose 47 mg Sucrose 89 mg Fructose 47 mg Maltose 95 mg Acid (citric acid) 0.3 mg 0.3 mg 0.3 mg 0.3 mg Sodium hydroxide Sufficient quantity Sufficient quantity Sufficient quantity Sufficient quantity Hydrochloric acid Sufficient quantity Sufficient quantity Sufficient quantity Sufficient quantity Water Sufficient quantity Sufficient quantity Sufficient quantity Sufficient quantity Total volume 1 ml 1 ml 1 ml 1 ml pH 5.0 5.0 5.0 5.0 Osmotic pressure ratio 1.0 1.0 1.0 1.0 Example No. Example 13 Example 14 Example 15 Example 16 L-Tartrate of the present compound 1 mg 1 mg 1 mg 1 mg Photostabilizer Xylitol 40 mg Sorbitol 47 mg Mannitol 47 mg Glycerin 25 mg Acid (citric acid) 0.3 mg 0.3 mg 0.3 mg 0.3 mg Sodium hydroxide Sufficient quantity Sufficient quantity Sufficient quantity Sufficient quantity Hydrochloric acid Sufficient quantity Sufficient quantity Sufficient quantity Sufficient quantity Water Sufficient quantity Sufficient quantity Sufficient quantity Sufficient quantity Total volume 1 ml 1 ml 1 ml 1 ml pH 5.0 5.0 5.0 5.0 Osmotic pressure ratio 1.0 1.0 1.0 1.0 Example No. Example 17 Example 18 Example 19 Example 20 The present compound L-Tartrate 1 mg L-Tartrate 1 mg 0.6 mg Hydrochloride 0.7 mg Photostabilizer Propylene glycol 20 mg Propylene glycol 20 mg Propylene glycol 20 mg Propylene glycol 20 mg Acid Acetic acid 0.3 mg L-Tartaric acid 1.0 mg Citric acid 0.3 mg Citric acid 0.3 mg Sodium hydroxide Sufficient quantity Sufficient quantity Sufficient quantity Sufficient quantity Hydrochloric acid Sufficient quantity Sufficient quantity Sufficient quantity Sufficient quantity Water Sufficient quantity Sufficient quantity Sufficient quantity Sufficient quantity Total volume 1 ml 1 ml 1 ml 1 ml pH 5.0 5.0 5.0 5.0 Osmotic pressure ratio 1.0 1.0 1.0 1.0 Comparative Example 1 L-Tartrate of the present compound 1 mg Citric acid 0.3 mg Sodium hydroxide Sufficient quantity Hydrochloric acid Sufficient quantity Water Sufficient quantity Total 1 ml pH 5.0 L-Tartrate of the present compound and citric acid were weighed in the ratio according to the aforementioned prescription, and then dissolved in water. The solution was adjusted to pH 5 with sodium hydroxide or hydrochloric acid, and then added with water up to the total volume so as to obtain the above concentrations. The solution was then filled in a brown container and sealed. Comparative Examples 2-7 According to the method of Comparative Example 1, solutions of Comparative Examples 2-7 were obtained. Prescriptions for these comparative examples are shown in Table 4. Comparative Example No. Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 L-Tartrate of the present compound 1 mg 1 mg 1 mg 1 mg Additive - Sodium chloride 8 mg Boric acid 19 mg Sodium hydrogen carbonate 13 mg Acid (citric acid) 0.3 mg 0.3 mg 0.3 mg 0.3 mg Sodium hydroxide Sufficient quantity Sufficient quantity Sufficient quantity Sufficient quantity Hydrochloric acid Sufficient quantity Sufficient quantity Sufficient quantity Sufficient quantity Water Sufficient quantity Sufficient quantity Sufficient quantity Sufficient quantity Total volume 1 ml 1 ml 1 ml 1 ml pH 5.0 5.0 5.0 5.0 Osmotic pressure ratio 0.03 0.9 1.1 1.1 Comparative Example No. Comparative Example 5 Comparative Example 6 Comparative Example 7 L-Tartrate of the present compound 1 mg 1 mg 1 mg Additive Sodium acetate 20 mg Magnesium chloride 21 mg Potassium chloride 11 mg Acid (citric acid) 0.3 mg 0.3 mg 0.3 mg Sodium hydroxide Sufficient quantity Sufficient quantity Sufficient quantity Hydrochloric acid Sufficient quantity Sufficient quantity Sufficient quantity Water Sufficient quantity Sufficient quantity Sufficient quantity Total volume 1 ml 1 ml 1 ml pH 5.0 5.0 5.0 Osmotic pressure ratio 1.1 1.0 1.0 Test Example: Photostability test To examine photostability, each sample sealed in a brown container was stored under irradiation with a fluorescent lamp (3500 luxes, wavelength range: 300-700 nm) at 25°C for 15 days, and then amounts of decomposed products produced were measured by HPLC. The results are shown in Table 5. From 0.08 to 0.44% of decomposed products were observed in the comparative examples, whereas no decomposition product was observed in the aqueous solutions of the present invention, which verified their excellent photostability. Example No. and Comparative Example No. Decomposed amount under irradiation at 3500 luxes for 15 days (%) Examples 1-20 N.D. Comparative Example 1 0.44 Comparative Example 2 0.22 Comparative Example 3 0.13 Comparative Example 4 0.09 Comparative Example 5 0.10 Comparative Example 6 0.08 Comparative Example 7 0.18 N.D. : 0.05% or less Industrial Applicability The aqueous solution of the present invention comprising the present compound or a pharmacologically acceptable salt thereof as an active ingredient is stable to light, and has desirable stability as a pharmaceutical preparation. In addition, the photostabilizer added to the aqueous solutions of the present invention is highly safe, and the aqueous solution of the present invention has satisfactory safety as a medicament. Therefore, the aqueous solution is parenterally or orally applicable as a therapeutic medicament for uterine relaxation, bladder relaxation or other.

Claims: An aqueous solution characterized in that the solution comprises optically active (-)-(R)-α -[(tert-butyl-amino)methyl]-2-chloro-4-hydroxybenzyl alcohol represented by the following formula: or a pharmacologically acceptable salt thereof, together with at least one photostabilizer selected from the group consisting of saccharides, sugar alcohols, and polyalcohols, the aqueous solution containing 10 % (w/w) or more of the photostabilizer based on the total weight of the optical active (-)-(R)- α -[(tert-butylamino)methyl]-2-chloro-4-hydroxybenzyl alcohol or a pharmacologically acceptable salt thereof. The aqueous solution according to claim 1, wherein the saccharide is selected from the group consisting of glucose, sucrose, fructose and maltose. The aqueous solution according to claim 1, wherein the sugar alcohol is selected from the group consisting of xylitol, sorbitol and mannitol. The aqueous solution according to claim 1, wherein polyalcohol is selected from the group consisting of glycerin and propylene glycol The aqueous solution according to any one of claims 1 to 4 having a pH 25 of 6.5 or less. The aqueous solution according to any one of clams 1 to 5 wherein a content of the optical active (-)-(R)- α -[(tert-butyl-amino)methyl]-2-chloro-4-hydroxybenzyl alcohol or a pharmacologically acceptable salt thereof is 0.01 - 10 % (w/v) based on the volume of the aqueous solution The aqueous solution according to any one of claims 1 - 6, wherein a content of the photostabilizer selected from the group consisting of saccharides, sugar alcolhols, and polyalcohols is 1-50 % (w/v) based on the volume of the aqueous solution. Method of suppressing the photodecomposition of optical active (-)-(R)- α -[(tert-butyl-amino)methyl]-2-chloro-4-hydroxybenzyl alcohol represented by the following formula: or a pharmacologically acceptable salt thereof contained in an aqueous solution by adding a photostabilizer which is selected from the group consisting of saccharides, sugar alcohols and polyalcohols.

Inventors: ITO YASUO, KATO HIDEO, KOSHINAKA EIICHI, MATSUO KAZUYA, YAMAZAKI MASAHIRO, ITO, YASUO, KATO, HIDEO, KOSHINAKA, EIICHI, MATSUO, KAZUYA, YAMAZAKI, MASAHIRO
Applicants: HOKURIKU PHARMACEUTICAL, HOKURIKU SEIYAKU CO., LTD.
Application year: 1996
Main classification: A61K31
IPC codes: A61K31, A61K47, C07C215