JP3232503B2 - Light stable aqueous solution containing benzyl alcohol derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a benzyl alcohol compound having an excellent adrenergic β ₂ -receptor stimulating action, useful as a uterine relaxant and a bladder relaxant, etc., as an active ingredient. And a pharmaceutical composition in the form of an aqueous solution.

[0002]

2. Description of the Related Art The following formula (I) having a uterine relaxing action, a bladder relaxing action, etc .:

Embedded image The optically active (-)-(R) -α-[(tert-
Butylamino) methyl] -2-chloro-4-hydroxybenzyl alcohol (hereinafter referred to as the present compound) or a pharmacologically acceptable salt thereof is used as a therapeutic agent for imminent preterm birth or urinary incontinence, nocturnal enuresis, etc. Its usefulness as a therapeutic agent and the like has been clarified (JP-A-4-178356).

[0003] For emergency treatment of imminent premature birth, it is desired to apply an injection which can be expected to rapidly exert its effects.
For the treatment of dysuria such as urinary incontinence and nocturnal enuresis, which are common diseases in children, liquid preparations that can be applied orally are clinically very important because of the reduced swallowing ability of the elderly and ease of medication for children. Useful for

The present inventors have intensively studied to provide a pharmaceutical composition in the form of an aqueous solution containing the present compound as an active ingredient, but the present compound is unstable in an aqueous solution and is easily decomposed by light irradiation. Product and the amount of photodegradation product can be adjusted by adding buffers such as citric acid, acetic acid, L-tartaric acid, D-tartaric acid, and DL-tartaric acid necessary to adjust and maintain the pH of the solution. It has been found that it tends to be further accelerated. Such findings have not been reported at all.

In general, in order to provide an aqueous solution containing a photolabile drug as an active ingredient as a pharmaceutical composition, a brown container is used to shield light. By filling an aqueous solution containing the present compound as an active ingredient into a brown container, the photodecomposition of the present compound could be partially prevented, but it was not completely satisfactory from the viewpoint of formulation stability. The cause of this is that short wavelength light of about 400 nm or less is often involved in photodecomposition for ordinary organic compounds, and brown vessels are mainly designed to block short wavelength light of about 400 nm or less. However, it is considered that long-wavelength light exceeding 400 nm is involved in the photodecomposition of the present compound, and sufficient light shielding cannot be achieved in a brown container. Therefore, in order to provide a stable aqueous solution containing the present compound as an active ingredient as a pharmaceutical composition, it is necessary to further stabilize against light.

[0006]

One object of the present invention is to provide a pharmaceutical composition in the form of an aqueous solution containing the present compound or a pharmaceutically acceptable salt thereof as an active ingredient and having improved photostability. Is to provide. In particular, it is an object of the present invention to provide a pharmaceutical composition having suitable photostability even for long-wavelength light that cannot be sufficiently shielded even in a brown container. Another object of the present invention is to provide a highly safe light stabilizer which has an action of suppressing the photodecomposition of the present compound or a pharmacologically acceptable salt thereof and can be incorporated into a pharmaceutical composition. It is in.

[0007]

Means for Solving the Problems The present inventors have made intensive efforts to solve the above-mentioned problems, and as a result, have found that an aqueous solution containing the present compound contains a substance selected from the group consisting of saccharides, sugar alcohols, and polyhydric alcohols. It has been found that the addition of the compound significantly suppresses the photodecomposition of the present compound and that the photodecomposition of the present compound caused by light transmitted through the brown container can be completely prevented. The present invention has been completed based on the above findings. In addition, saccharides, sugar alcohols, or polyhydric alcohols are used as isotonic agents and excipients in pharmaceutical preparation compositions, respectively.
No photostabilizing effect on this compound is known.

That is, the present invention provides the following formula (I):

Embedded image The optically active (-)-(R) -α-[(tert-
Butylamino) methyl] -2-chloro-4-hydroxybenzyl alcohol or a pharmacologically acceptable salt thereof, and at least one photostable selected from the group consisting of saccharides, sugar alcohols, and polyhydric alcohols. And an aqueous solution containing an agent.

According to a preferred embodiment of the present invention, the aqueous solution wherein the saccharide is selected from the group consisting of glucose, sucrose, fructose and maltose; the aqueous solution wherein the sugar alcohol is selected from the group consisting of xylitol, sorbitol and mannitol; The above aqueous solution, wherein the polyhydric alcohol is glycerin or propylene glycol; p
The above aqueous solution having an H of 6.5 or less; an optically active (-)-
(R) -α-[(tert-butylamino) methyl] -2-
The above aqueous solution in which the content of chloro-4-hydroxybenzyl alcohol or a pharmaceutically acceptable salt thereof is 0.01 to 10 w / v% based on the volume of the aqueous solution; sugars, sugar alcohols, and polyhydric alcohols The content of the light stabilizer selected from the group consisting of 1 to 50 w /
v% of the above aqueous solution; and optically active (−) −
(R) -α-[(tert-butylamino) methyl] -2-
The above aqueous solution is provided which contains 10% w / w or more of a light stabilizer based on the total weight of chloro-4-hydroxybenzyl alcohol or a pharmaceutically acceptable salt thereof.

According to another aspect of the present invention, a saccharide,
Selected from the group consisting of sugar alcohols and polyhydric alcohols, and containing the above-mentioned optically active (-)-
(R) -α-[(tert-butylamino) methyl] -2-
A stabilizer that inhibits the photolysis of chloro-4-hydroxybenzyl alcohol or a pharmaceutically acceptable salt thereof;
And the optically active (-)-(R) -α-[(te
rt-butylamino) methyl] -2-chloro-4-hydroxybenzyl alcohol or a pharmaceutically acceptable salt thereof, and a substance selected from the group consisting of saccharides, sugar alcohols, and polyhydric alcohols. A light-stabilized aqueous solution is provided.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The aqueous solution of the present invention is orally or
A pharmaceutical composition that can be used as a parenteral drug such as, for example, intravenous injection, and is optically active (-)-(R) -α
-[(Tert-butylamino) methyl] -2-chloro-4
-Hydroxybenzyl alcohol or a pharmacologically acceptable salt thereof, and a substance selected from the group consisting of sugars, sugar alcohols, and polyhydric alcohols used as a light stabilizer for those compounds. It is characterized by including.

The present compound represented by the formula (I) is, for example,
It can be produced by the method described in JP-A-4-178356. Pharmaceutically acceptable salts of the present compound include:
For example, mineral salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid, or acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, malic acid, methanesulfonic acid, p- Toluenesulfonic acid, mandelic acid, D-10-camphorsulfonic acid, L-10-camphorsulfonic acid, DL-1
Organic acid salts such as 0-camphorsulfonic acid, L-tartaric acid, D-tartaric acid, DL-tartaric acid, succinic acid and the like can be mentioned.

The content of the present compound or a pharmaceutically acceptable salt thereof in the aqueous solution of the present invention is 0.01 to 10 w / v%, preferably 0.02 to 5 w / v%, based on the total volume of the solution.
More preferably, it is 0.05 to 0.5 w / v%. The aqueous solution of the present invention may contain one or two or more active ingredients selected from the present compound and a pharmaceutically acceptable salt thereof.

The light stabilizer has an action of reducing or preventing the photodecomposition of the present compound or a pharmacologically acceptable salt thereof in an aqueous solution. Examples of the saccharides include glucose, sucrose, fructose, maltose, and the like.
For example, xylitol, sorbitol, mannitol and the like can be mentioned, and as polyhydric alcohols, for example, glycerin, propylene glycol and the like can be mentioned. One or more of these light stabilizers can be blended with the aqueous solution of the present invention.

The kind and amount of the light stabilizer used in the present invention are appropriately selected depending on the kind of the present compound or a pharmaceutically acceptable salt thereof so that desired light stability can be achieved. Can be. For such a light stability test, the method described in the examples of the present specification may be employed. For example, 1 to 50 w / v% based on the total volume of the aqueous solution,
Preferably, 2 to 10 w / v% of a light stabilizer can be incorporated. Further, it can be compounded in an amount of 10 w / w% or more based on the 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 is 6.5 or less, especially pH
It is preferable to adjust to H3 to 6.5. The acid or alkali used for adjusting the pH is not particularly limited as long as it can be added to a drug, and for example, hydrochloric acid or sodium hydroxide can be used. If necessary, a buffer (citric acid, acetic acid, L-tartaric acid, D-tartaric acid, DL-tartaric acid, etc.) may be added. The content of the buffer is not particularly limited, but it is preferable to add a minimum amount that can adjust or maintain the pH. In the aqueous solution of the present invention, even when a buffer such as citric acid, acetic acid, L-tartaric acid, D-tartaric acid, or DL-tartaric acid is added, the photodecomposition of the present compound or a pharmacologically acceptable salt thereof is prevented. There is a feature that does not occur.

When the aqueous solution of the present invention is used as an injection, an isotonic agent is preferably added, but isotonicity is partially or completely achieved by the light stabilizer contained in the aqueous solution of the present invention. In such a case, it is generally not necessary to add the entire required amount of the tonicity agent. For example, when glucose and mannitol, which are light stabilizers, are used at about 5 w / v% and propylene glycol at about 2 w / v% based on the total volume of the aqueous solution, the aqueous solution is sufficiently isotonic. It is not necessary to add a tonicity agent.

The method for producing the aqueous solution of the present invention is not particularly limited, and the present compound or its pharmacologically acceptable salt as an active ingredient, a light stabilizer, and if necessary, other pharmaceutical additives (buffer). , PH adjusters, isotonic agents, preservatives, soothing agents) at the same time or in an appropriate order in purified water or water for injection. It can be produced by sterilizing. As the active compound of the present compound or a pharmacologically acceptable salt thereof, any known or unknown crystal form, or any known or unknown hydrate may be used. it can.

[0019]

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited by these specific examples.

Embodiment 1

The L-tartrate, propylene glycol, and citric acid of the present compound are weighed in the prescribed ratio, dissolved in water, adjusted to pH 5 with sodium hydroxide or hydrochloric acid, and added with water to adjust the above concentration. And filled in a brown container and sealed.

Examples 2 to 20 Examples 2 to 20 were obtained according to the method of Example 1. The formulations of each example are shown in Tables 1 to 3.

[0023]

[Table 1]

[0024]

[Table 2]

[0025]

[Table 3]

Comparative Example 1

The L-tartrate salt of the present compound and citric acid are weighed in the prescribed ratio, dissolved in water, adjusted to pH 5 with sodium hydroxide or hydrochloric acid, and added with water to adjust the total amount to the above concentration. And filled in a brown container and sealed.

Comparative Examples 2 to 7 Comparative Examples 2 to 7 were obtained according to the method of Comparative Example 1. Table 4 shows the formulation of each comparative example.

[0029]

[Table 4]

Test Example: Light Stability Test In order to examine the light stability, each sample sealed in a brown container was irradiated with a fluorescent lamp at 25 ° C. (3500 lux, wavelength width: 300 to 70).
(0 nm) for 15 days, and the amount of the decomposed product was measured by HPLC. Table 5 shows the results. In the comparative example
While 0.08 to 0.44% of decomposition products were observed, the aqueous solution of the present invention did not show decomposition products, and it was confirmed that the aqueous solution was excellent in light stability.

[0031]

[Table 5]

[0032]

The aqueous solution of the present invention containing the present compound or a pharmacologically acceptable salt thereof as an active ingredient is light-stable and has suitable stability as a pharmaceutical. In addition, since the light stabilizer incorporated in the aqueous solution of the present invention has high safety, the aqueous solution of the present invention has suitable safety as a pharmaceutical, and is used parenterally as a uterine relaxant or a bladder relaxant. Or it can be applied orally.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁷ Identification symbol FI // C07M 7:00 C07M 7:00 (56) References JP-A-4-178356 (JP, A) JP-A-7-126017 (JP, A) JP-A-62-277323 (JP, A) JP-A-8-73348 (JP, A) JP-B-55-43446 (JP, B2) International publication 91/1718 (WO, A1) International publication 94/25032 (WO, A1) European Patent Application Publication 420120 (EP, A2) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 215/60 A61K 31/135 A61P 13/02 A61P 43 / 00 111 C07C 213/10 C07M 7:00 CA (STN) REGISTRY (STN)

Claims (10)

(57) [Claims] (1) The following formula: The optically active (-)-(R) -α-[(tert-
Butylamino) methyl] -2-chloro-4-hydroxybenzyl alcohol or a pharmacologically acceptable salt thereof, and at least one photostable selected from the group consisting of sugars, sugar alcohols, and polyhydric alcohols. And an aqueous solution. 2. The aqueous solution according to claim 1, wherein the saccharide is selected from the group consisting of glucose, sucrose, fructose and maltose. 3. The aqueous solution according to claim 1, wherein the sugar alcohol is selected from the group consisting of xylitol, sorbitol and mannitol. 4. The aqueous solution according to claim 1, wherein the polyhydric alcohol is glycerin or propylene glycol. 5. The aqueous solution according to claim 1, which has a pH of 6.5 or less. 6. An optically active (-)-(R) -α-[(te
rt-butylamino) methyl] -2-chloro-4-hydroxybenzyl alcohol or a pharmaceutically acceptable salt thereof is 0.01 to 10 w / v% based on the volume of the aqueous solution.
The aqueous solution according to any one of claims 1 to 5, wherein 7. The content of a light stabilizer selected from the group consisting of sugars, sugar alcohols, and polyhydric alcohols,
The amount is 1 to 50 w / v% based on the volume of the aqueous solution.
The aqueous solution according to any one of the above. 8. An optically active (-)-(R) -α-[(te
rt-butylamino) methyl] -2-chloro-4-hydroxybenzyl alcohol or a pharmaceutically acceptable salt thereof, containing at least 10% w / w of a light stabilizer based on the total weight of the salt. 8. The aqueous solution according to any one of 7 above. 9. A compound selected from the group consisting of sugars, sugar alcohols, and polyhydric alcohols and contained in an aqueous solution represented by the following formula: The optically active (-)-(R) -α-[(tert-
[Butylamino) methyl] -2-chloro-4-hydroxybenzyl alcohol or a pharmacologically acceptable salt thereof. 10. The following formula: The optically active (-)-(R) -α-[(tert-
Butylamino) methyl] -2-chloro-4-hydroxybenzyl alcohol or a pharmacologically acceptable salt thereof, and a substance selected from the group consisting of sugars, sugar alcohols, and polyhydric alcohols. Aqueous solution stabilized against