HK1016072B - Photostable aqueous solution containing benzyl alcohol derivatives - Google Patents
Photostable aqueous solution containing benzyl alcohol derivatives Download PDFInfo
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- HK1016072B HK1016072B HK99101120.3A HK99101120A HK1016072B HK 1016072 B HK1016072 B HK 1016072B HK 99101120 A HK99101120 A HK 99101120A HK 1016072 B HK1016072 B HK 1016072B
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Description
Technical Field
The present invention relates to a pharmaceutical composition in an aqueous solution state having improved photostability, which comprises a benzyl alcohol compound as an active ingredient, said benzyl alcohol compound having an excellent adrenergic β 2-receptor agonistic action and being useful as a uterine relaxant, a bladder relaxant, or the like.
Technical Field
It has been known that optically active (-) - (R) - α - [ (tert-butylamino) methyl ] -2-chloro-4-hydroxybenzyl alcohol (hereinafter, referred to as the present compound) or a pharmaceutically acceptable salt thereof, which has uterine relaxation and bladder relaxation effects and is represented by the following formula (I), is useful as a therapeutic agent for prematurity or a therapeutic agent for urination disorders such as bedwetting and nocturnal enuresis (Japanese patent application laid-open No. 4-178356).
In order to treat urination disorders such as bedwetting and nocturnal enuresis, which are frequently encountered in old people and children, a liquid medicine suitable for oral administration is very useful clinically from the viewpoint of swallowing decline in old people and convenience in administration to children.
The present inventors have conducted intensive studies to provide a pharmaceutical composition in the form of an aqueous solution containing the compound of the present invention as an active ingredient, and have found that the compound of the present invention is unstable in an aqueous solution and easily generates a decomposition product upon irradiation with light, and that the amount of the decomposition product generated by light tends to be further accelerated by adding a buffer such as citric acid, acetic acid, L-tartaric acid, D-tartaric acid, or DL-tartaric acid as necessary for adjusting and maintaining the pH of the solution. The above findings have not been reported in the past.
In general, in order to provide an aqueous solution containing a photo-labile drug as an active ingredient as a pharmaceutical composition, a brown container is used so as to be protected from light. Although the photodecomposition of the compound of the present invention can be partially prevented by charging an aqueous solution containing the compound of the present invention as an active ingredient into a brown container, it is not satisfactory in any way from the viewpoint of the stability of the preparation. This is because, in many cases, light having a short wavelength of about 400nm or less is involved in photodecomposition of general organic compounds, and the use of a brown container is designed mainly to block light having a short wavelength of about 400nm or less, while light having a long wavelength exceeding 400nm is also involved in photodecomposition of the compound of the present invention, and therefore, it is considered that the object of sufficient light blocking cannot be achieved even with the use of a brown container. Therefore, in order to provide a stable aqueous solution containing the compound of the present invention as an active ingredient as a pharmaceutical composition, it is necessary to further stabilize the solution against light.
An object of the present invention is to provide a pharmaceutical composition in an aqueous solution state with improved photostability, which contains the compound of the present invention or a pharmacologically acceptable salt thereof as an active ingredient. In particular, it is an object of the present invention to provide a pharmaceutical composition having suitable light stability even when long-wavelength light which cannot be completely shielded even with a brown container is used.
It is another object of the present invention to provide a photostabilizer which has an inhibitory effect on photodecomposition of the compound of the present invention or a pharmacologically acceptable salt thereof and is highly safe to be incorporated into a pharmaceutical composition.
Disclosure of the invention
As a result of intensive efforts made by the present inventors to solve the above-mentioned problems, it has been found that when a substance selected from the group consisting of saccharides, sugar alcohols and polyhydric alcohols is added to an aqueous solution containing the compound of the present invention, photodegradation of the compound of the present invention can be significantly suppressed and photodegradation of the compound of the present invention due to transmitted light in a brown container can be completely prevented. The present invention has been completed based on the above findings. Although saccharides, sterols, or polyols may be used as isotonic agents and excipients in pharmaceutical compositions, the photostabilizing effect of the compounds of the present invention is not completely clear.
That is, the present invention provides an aqueous solution characterized by containing optically active (-) - (R) - α - [ (tert-butylamino) methyl ] -2-chloro-4-hydroxybenzyl alcohol represented by the following formula (I) or a pharmacologically acceptable salt thereof and at least one light stabilizer selected from saccharides, sugar alcohols and polyhydric alcohols.
According to a preferred aspect, the present invention provides an aqueous solution containing the above saccharide selected from glucose, sucrose, fructose and maltose; an aqueous solution containing the above sugar alcohol selected from xylitol, sorbitol and mannitol; an aqueous solution of the above polyol containing glycerin or propylene glycol; the aqueous solution having a pH of 6.5 or less; an optically active (-) - (R) - α - [ (tert-butylamino) methyl ] -2-chloro-4-hydroxybenzyl alcohol or a pharmacologically acceptable salt thereof, wherein the volume of the aqueous solution is 0.01 to 10W/V%; a light stabilizer selected from saccharides, sugar alcohols and polyols, the content of which is 1-50W/V% of the volume of the aqueous solution; and an aqueous solution containing 10W/W% or more of a light stabilizer relative to the total weight of the photo-active (-) - (R) - α - [ (tert-butylamino) methyl ] -2-chloro-4-hydroxybenzyl alcohol or a pharmacologically acceptable salt thereof.
According to another aspect of the present invention, there is also provided a stabilizer selected from the group consisting of sugars, sugar alcohols and polyhydric alcohols, which is capable of inhibiting photodegradation of the above optically active (-) - (R) - α - [ (tert-butylamino) methyl ] -2-chloro-4-hydroxybenzyl alcohol or a pharmacologically acceptable salt thereof contained in an aqueous solution; and a photostable aqueous solution containing the above-mentioned (-) - (R) - α - [ (tert-butylamino) methyl ] -2-chloro-4-hydroxybenzyl alcohol which is optically active or a pharmacologically acceptable salt thereof and a substance selected from the group consisting of saccharides, sugar alcohols and polyhydric alcohols.
According to still another aspect of the present invention, there is also provided a pre-term labor therapeutic agent or a urination disorder therapeutic agent comprising the above aqueous solution stabilized against light.
Best mode for carrying out the invention
The aqueous solution of the present invention is characterized by containing a photoactive (-) - (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 saccharides, sugar alcohols and polyhydric alcohols as a photostabilizer for these compounds, which can be used as a pharmaceutical composition for oral administration or non-oral administration such as intravenous injection.
The compound of the present invention represented by the formula (I) can be produced by a method described in Japanese patent laid-open No. Hei 4-178356. Examples of the pharmacologically acceptable salts of the compounds of the present invention include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid, and salts of organic acids such as 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-10-camphorsulfonic acid, L-tartaric acid, D-tartaric acid, DL-tartaric acid and succinic acid.
The content of the compound of the present invention or a pharmacologically acceptable salt thereof in the aqueous solution of the present invention is 0.01 to 10W/V%, preferably 0.02 to 5W/V%, more preferably 0.05 to 0.5W/V%, based on the total volume of the solution. The aqueous solution of the present invention may contain one or more active ingredients selected from the compounds of the present invention and pharmacologically acceptable salts thereof.
Light stabilizers have the effect of reducing or preventing photodecomposition of the compounds of the present invention or pharmacologically acceptable salts thereof in an aqueous solution state. Examples of the saccharide include glucose, sucrose, fructose, maltose, etc., examples of the sugar alcohol include xylitol, sorbitol, mannitol, etc., and examples of the polyol include glycerol, propylene glycol, etc. One or more of these light stabilizers may be incorporated into the aqueous solutions of the present invention.
The type and amount of the light stabilizer usable in the present invention may be appropriately selected depending on the type of the compound of the present invention or a pharmacologically acceptable salt thereof and the desired light stability. The light stability test may be performed by the method described in examples of the present specification. For example, the light stabilizer may be added in an amount of 1 to 50W/V%, preferably 2 to 10W/V%, based on the total volume of the aqueous solution. The content of the compound of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is 10W/W% or more.
The pH of the aqueous solution of the present invention is 6.5 or less, and it is particularly preferable to adjust the pH to 3 to 6.5. The acid or base used for adjusting pH is not particularly limited as long as it can be added to the drug, and for example, hydrochloric acid or sodium hydroxide can be used. Further, a buffer (e.g., citric acid, acetic acid, L-tartaric acid, D-tartaric acid, DL-tartaric acid, etc.) may be added as necessary. The content of the buffer is not particularly limited, and a minimum amount capable of adjusting or maintaining the pH is preferably added. The present invention is also characterized in that the photodecomposition of the compound of the present invention or a pharmacologically acceptable salt thereof is not caused even when a buffer such as citric acid, acetic acid, L-tartaric acid, D-tartaric acid, or DL-tartaric acid is added to the aqueous solution.
When the aqueous solution of the present invention is used as an injection preparation, although an isotonic agent may be added, the light stabilizer contained in the aqueous solution of the present invention may partially or entirely satisfy the requirement of the isotonic pressure, and in this case, it is generally not necessary to add the total amount of the isotonic agent. For example, when glucose, mannitol, or propylene glycol is used at a concentration of about 5W/V% relative to the total volume of the aqueous solution as a light stabilizer, the aqueous solution can be brought into an isotonic state sufficiently, and generally, it is not necessary to add an isotonic agent.
The method for producing the aqueous solution of the present invention is not particularly limited, and the compound of the present invention or a pharmacologically acceptable salt thereof, a photostabilizer and other agents (a buffer, a pH adjuster, an isotonic agent, a preservative, a painless agent and the like) to be added as necessary as active ingredients may be dissolved in purified water or water for injection simultaneously or in an appropriate order, and subjected to sterilization treatment such as heat sterilization and filter sterilization as necessary. The compound of the present invention or a pharmacologically acceptable salt thereof as an active ingredient may be used in any known or unknown crystalline form or in any known or unknown hydrate.
Examples
The present invention will be described in further detail with reference to examples. However, the scope of the present invention is not limited to these specific examples.
Example 1
L-tartrate salt of Compound of the present invention 0.2mg
Propylene glycol 20mg
Citric acid 0.3mg
Proper amount of sodium hydroxide
Appropriate amount of hydrochloric acid
Proper amount of water
Total volume of 1ml
pH 5.0
Weighing the L-tartrate, the propylene glycol and the citric acid of the compound according to the proportion of the formula, dissolving in water, adjusting the pH value to 5 by using sodium hydroxide or hydrochloric acid, adding water to prepare a solution with the concentration to the total amount, and filling the solution into a brown container to seal.
Examples 2 to 20
Examples 2 to 20 were prepared according to the method of example 1. The formulations of the examples are shown in tables 1 to 3.
| Example No. | Example 1 | Example 2 | Example 3 | Example 4 |
| L-tartaric acid salts of the compounds of the present invention | 0.2mg | 1mg | 5mg | 50mg |
| Light stabilizers | Propylene glycol 20mg | Propylene glycol 20mg | Propylene glycol 20mg | Propylene glycol 20mg |
| Acid (citric acid) | 0.3mg | 0.3mg | 0.3mg | 0.3mg |
| Sodium hydroxide | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Hydrochloric acid | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Water (W) | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Total up to | 1ml | 1ml | 1ml | 1ml |
| 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-tartaric acid salts of the compounds of the present invention | 1mg | 1mg | 1mg | 1mg |
| Light stabilizers | Propylene glycol 20mg | Propylene glycol 20mg | Propylene glycol 10mg | Propylene glycol 100mg |
| Acid (citric acid) | 0.3mg | 0.3mg | 0.3mg | 0.3mg |
| Sodium hydroxide | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Hydrochloric acid | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Water (W) | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Total up to | 1ml | 1ml | 1ml | 1ml |
| 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-tartaric acid salts of the compounds of the present invention | 1mg | 1mg | 1mg | 1mg |
| Light stabilizers | Glucose 47mg | Sucrose 89mg | Fructose 47mg | Maltose 95mg |
| Acid (citric acid) | 0.3mg | 0.3mg | 0.3mg | 0.3mg |
| Sodium hydroxide | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Hydrochloric acid | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Water (W) | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Total up to | 1ml | 1ml | 1ml | 1ml |
| 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-tartaric acid salts of the compounds of the present invention | 1mg | 1mg | 1mg | 1mg |
| Light stabilizers | Xylitol 40mg | Sorbitol 47mg | Mannitol 47mg | Glycerol 25mg |
| Acid (citric acid) | 0.3mg | 0.3mg | 0.3mg | 0.3mg |
| Sodium hydroxide | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Hydrochloric acid | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Water (W) | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Total up to | 1ml | 1ml | 1ml | 1ml |
| 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 |
| Compounds of the invention | L-tartrate 1mg | L-tartrate 1mg | 0.6mg | Hydrochloride salt 0.7mg |
| Light stabilizers | Propylene glycol 20mg | Propylene glycol 20mg | Propylene glycol 20mg | Propylene glycol 20mg |
| Acid(s) | Acetic acid 0.3mg | L-tartaric acid 1.0mg | Citric acid 0.3mg | Citric acid 0.3mg |
| Sodium hydroxide | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Hydrochloric acid | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Water (W) | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Total up to | 1ml | 1ml | 1ml | 1ml |
| pH | 5.0 | 5.0 | 5.0 | 5.0 |
| Osmotic pressure ratio | 1.0 | 1.0 | 1.0 | 1.0 |
Comparative example 1
1mg of L-tartrate salt of the Compound of the present invention
Citric acid 0.3mg
Proper amount of sodium hydroxide
Appropriate amount of hydrochloric acid
Proper amount of water
Total volume of 1ml
pH 5.0
Weighing the L-tartrate and the citric acid of the compound according to the formula proportion, dissolving in water, adjusting the pH value to 5 by using sodium hydroxide or hydrochloric acid, adding water to prepare a solution with the concentration to the total amount, filling the solution into a brown container, and sealing the brown container.
Comparative examples 2 to 7
Comparative examples 2 to 7 were prepared according to the method of comparative example 1. The formulation of each comparative example is shown in table 4.
| Comparative example No. | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 |
| L-tartaric acid salts of the compounds of the present invention | 1mg | 1mg | 1mg | 1mg |
| Additive agent | -- | Sodium chloride 8mg | Boric acid 19mg | Sodium bicarbonate 13mg |
| Acid (citric acid) | 0.3mg | 0.3mg | 0.3mg | 0.3mg |
| Sodium hydroxide | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Hydrochloric acid | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Water (W) | Proper amount of | Proper amount of | Proper amount of | Proper amount of |
| Total up to | 1ml | 1ml | 1ml | 1ml |
| 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-tartaric acid salts of the compounds of the present invention | 1mg | 1mg | 1mg |
| Additive agent | Sodium acetate 20mg | Magnesium chloride 21mg | Potassium chloride 11mg |
| Acid (citric acid) | 0.3mg | 0.3mg | 0.3mg |
| Sodium hydroxide | Proper amount of | Proper amount of | Is suitable forMeasurement of |
| Hydrochloric acid | Proper amount of | Proper amount of | Proper amount of |
| Water (W) | Proper amount of | Proper amount of | Proper amount of |
| Total up to | 1ml | 1ml | 1ml |
| pH | 5.0 | 5.0 | 5.0 |
| Osmotic pressure ratio | 1.1 | 1.0 | 1.0 |
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 (3500 lux, wavelength range: 300 to 700nm) at 25 ℃ for 15 days, and then the amount of the decomposition product produced was measured by HPLC. The results are shown in Table 5. In comparison with the comparative examples in which 0.08 to 0.44% of the decomposition product was detected, no decomposition product was detected in the aqueous solution of the present invention, and it was confirmed that the photostability was excellent.
| Example No. comparative example No. | Decomposition amount (%) of 3500 lux light for 15 days |
| Examples 1 to 20 | N.D |
| Comparative example 1 | 0.44 |
| 2 | 0.22 |
| 3 | 0.13 |
| 4 | 0.09 |
| 5 | 0.10 |
| 6 | 0.08 |
| 7 | 0.18 |
N.D.: less than 0.05%
Possibility of industrial utilization
The aqueous solution of the present invention containing the compound of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is stable to light and has suitable stability as a pharmaceutical. Further, since the photostabilizer which can be incorporated into the aqueous solution of the present invention is highly safe, the aqueous solution of the present invention has suitable safety as a pharmaceutical product, and can be suitably used as a non-oral or oral uterine relaxant, bladder relaxant or the like.
Claims (7)
1. Use of at least one light stabilizer selected from the group consisting of saccharides, sugar alcohols and polyols as a light stabilizer in an aqueous solution containing optically active (-) - (R) - α - [ (tert-butylamino) methyl ] -2-chloro-4-hydroxybenzyl alcohol represented by the following formula or a pharmacologically acceptable salt thereof, wherein the aqueous solution contains 10W/W% or more of the light stabilizer relative to the total weight of the optically active (-) - (R) - α - [ (tert-butylamino) methyl ] -2-chloro-4-hydroxybenzyl alcohol or the pharmacologically acceptable salt thereof.
2. Use according to claim 1, characterized in that the sugar is selected from glucose, sucrose, fructose and maltose.
3. Use according to claim 1, characterized in that the sugar alcohols are selected from xylitol, sorbitol and mannitol.
4. Use according to claim 1, characterized in that the polyol is glycerol or propylene glycol.
5. Use according to any one of claims 1 to 4, characterized in that the pH is 6.5 or less.
6. Use according to any one of claims 1 to 4, characterized in that the content of photoactive (-) - (R) - α - [ (tert-butylamino) methyl ] -2-chloro-4-hydroxybenzyl alcohol or of a pharmacologically acceptable salt thereof is 0.01 to 10W/V% relative to the volume of the aqueous solution.
7. The use according to any one of claims 1 to 4, wherein the content of the light stabilizer selected from the group consisting of saccharides, sugar alcohols and polyols is 1 to 50W/V% based on the volume of the aqueous solution.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21972995 | 1995-08-04 | ||
| JP219729/95 | 1995-08-04 | ||
| PCT/JP1996/001950 WO1997005860A1 (en) | 1995-08-04 | 1996-07-12 | Photostable aqueous solution containing benzyl alcohol derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1016072A1 HK1016072A1 (en) | 1999-10-29 |
| HK1016072B true HK1016072B (en) | 2005-01-07 |
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