WO2017038732A1

WO2017038732A1 - Water-containing pharmaceutical formulation of montelukast

Info

Publication number: WO2017038732A1
Application number: PCT/JP2016/075118
Authority: WO
Inventors: 慶裕菱川; 由佳理垣野; 中村　淳子
Original assignee: 大蔵製薬株式会社
Priority date: 2015-08-31
Filing date: 2016-08-29
Publication date: 2017-03-09
Also published as: JPWO2017038732A1

Abstract

The main problem of the invention is to provide a stable water-containing pharmaceutical formulation of montelukast that can be taken easily even by young or elderly patients. A water-containing pharmaceutical formulation (for example, a jelly) containing, as an active ingredient, montelukast or a pharmaceutically acceptable salt thereof, in which the pH is in the range of 4-10 can be given as an example of the invention. The dissolved oxygen concentration in the formulation of the invention is preferably 5 mg/L or less. The water-containing pharmaceutical formulation according to the invention is especially useful for young or elderly patients who are generally less able to swallow solid formulations.

Description

Montelukast hydrous pharmaceutical formulation

The present invention belongs to the technical field of hydrous pharmaceutical preparations such as jelly. The present invention relates to a water-containing pharmaceutical preparation containing montelukast or a pharmaceutically acceptable salt thereof (hereinafter also referred to simply as “montelukast”) as an active ingredient. Specifically, the present invention relates to a water-containing pharmaceutical preparation that is stable and suitable for use by children and the elderly, including montelukast effective for the treatment of bronchial asthma and the like.

Montelukast is derived from (+)-1-[[[(R) -3-[(E) -2- (7-chloro-2-quinolyl) vinyl] -α- [2- (1-hydroxy-1-methyl Ethyl) phenethyl] benzyl] thio] methyl] cyclopropaneacetic acid. This is a leukotriene receptor antagonist developed by Merck & Co., USA, and is widely used as a therapeutic agent for bronchial asthma and allergic rhinitis in the form of sodium salt.

In Japan, the drug containing montelukast is the product name of Singrea (registered trademark) from MSD Co., Ltd., and the product name of Kipress (registered trademark) from Kyorin Pharmaceutical Co., Ltd., coated tablets, oral fine granules, And are sold as chewable tablets.

On the other hand, montelukast is a drug that is unstable to moisture, light and heat. For this reason, various studies have been conducted on stable montelukast-containing preparations.
For example, Patent Document 1 discloses a stable non-hygroscopic amorphous montelukast. Patent Document 2 discloses a coated solid preparation of montelukast stabilized for a long period of time by coating with a coating agent containing PVA and swellable clay. Patent Document 3 discloses a pharmaceutical composition of montelukast stabilized by various additives. The montelukast formulation described in Patent Document 3 shows high stability for 3 months under conditions of 40 ° C. and 75% humidity. In Patent Document 4, stabilization is achieved by using a montelukast orally disintegrating film having a loss on drying of 1 to 8% by weight.
The above all relate to solid preparations that are relatively easy to stabilize montelukast.

Patent Document 5 realizes an oily and stable liquid oral pharmaceutical composition of montelukast by including montelukast, mineral oil, desiccant, and additives. This is a method of protecting and stabilizing montelukast by suspending it in mineral oil. However, since it contains mineral oil, it is not desirable in terms of ease of drinking.

By the way, it is difficult for children or elderly people to take tablets due to underdeveloped or weak swallowing function, and it is also difficult to swallow fine granules in children under 2 years old. Therefore, a water-containing preparation such as a jelly or syrup that can be easily taken is preferred for children or the elderly.
However, since montelukast has an unstable physical property of easily decomposing into water, it is not easy to realize a preparation such as a jelly agent having a high water content.
In addition, conventional montelukast fine granules can be taken and mixed with water-containing foods such as baby food (ice cream, rice, carrot, applesauce), and adjusted milk at the time of taking. Yes. However, because of the unstable physical properties of montelukast with respect to water and light, it is inconvenient that it is necessary to take it within a short time (for example, within 15 minutes) after opening the package and mixing it with the water-containing food.

Special table 2007-520546 gazette International Publication No. 2011/105539 JP 2013-049709 A JP-T-2015-503549 Special table 2013-545743 gazette

Conventionally, regarding montelukast, studies have been made mainly on solid preparations that are relatively easy to stabilize. However, even if montelukast can be stabilized with respect to such a solid preparation, it is usually difficult to say that the solid preparation is always easy to take for children and the elderly. On the other hand, there have been few studies on preparations such as montelukast jelly that are easy to take for children and the elderly and stable, and such preparations have not been found so far.

The main object of the present invention is to provide a stable and novel water-containing pharmaceutical preparation containing montelukast which is effective for bronchial asthma and the like, which is suitable for taking by children and the elderly.
Here, the “hydrated pharmaceutical preparation” refers to a pharmaceutical preparation in which an active ingredient is dissolved, dispersed or suspended in water, or a pharmaceutical preparation comprising a step of dissolving, dispersing or suspending an active ingredient in water in the production thereof. Basically, oily raw materials such as oil, fats and oils, and fats are not included, but may be included within a range not impairing the effects of the present invention. Specific dosage forms include, for example, jelly, syrup, liquid, injection, dry syrup containing water during the production process, orally disintegrating tablet, and the like.

As a result of intensive studies, the present inventors have found that the above problem can be solved by at least adjusting the pH in the preparation to a certain range, and have completed the present invention.

Examples of the present invention include the following.
[1] A water-containing pharmaceutical preparation comprising montelukast or a pharmaceutically acceptable salt thereof as an active ingredient and having a pH in the range of 4 to 10.
[2] The water-containing pharmaceutical preparation according to [1], wherein the dissolved oxygen concentration in the preparation is 5 mg / L or less.
[3] The water-containing pharmaceutical preparation according to [1] or [2], further containing a gelling agent.
[4] The hydrous pharmaceutical preparation according to [3], wherein the gelling agent is a high molecular polysaccharide.
[5] The water-containing pharmaceutical preparation according to any one of [1] to [4], which is enclosed in a storage container having an oxygen scavenger.
[6] The water-containing pharmaceutical preparation according to [5], wherein the oxygen scavenger is iron or an oxide thereof, titanium or an oxide thereof, or an organic oxygen-absorbing resin.

[7] The water-containing pharmaceutical preparation according to any one of [1] to [6], wherein an antioxidant is blended.
[8] The hydrous pharmaceutical preparation according to [7], wherein the antioxidant is ascorbic acid or a salt thereof, erythorbic acid or a salt thereof, or sulfite.
[9] The hydrous pharmaceutical preparation according to any one of [1] to [8] above, wherein the pharmaceutically acceptable salt of montelukast is a sodium salt of montelukast.
[10] The water-containing pharmaceutical preparation according to any one of [1] to [9], wherein the pH is in the range of 9.0 to 9.5.
[11] The water-containing pharmaceutical preparation according to any one of the above [1] to [10], wherein the water-containing pharmaceutical preparation is a jelly agent.

According to the present invention, it is possible to keep montelukast stable for a long period of time, there is no need to adjust the mixing to foods etc. at the time of taking, and the convenience of patients such as being able to be taken easily even by children and elderly people. High montelukast water-containing pharmaceutical preparations can be provided.

It represents the time course of montelukast at each pH. The vertical axis indicates the relative content (%) of each initial content of montelukast, and the horizontal axis indicates the storage period (weeks). -○-indicates the result at pH 2.6,-×-indicates the result at pH 3,-△-indicates the result at pH 4,-□-indicates the result at pH 5, and-◇-indicates the result at pH 6. ,-*-Indicate the results at pH 7, respectively. It represents the time course of montelukast at each storage temperature. The vertical axis indicates the relative content (%) of each initial content of montelukast, and the horizontal axis indicates the storage period (weeks). -○-indicates the result when the storage temperature is 25 ° C, -X- indicates the result when the storage temperature is 40 ° C,-△-indicates the result when the storage temperature is 50 ° C,-□-indicates the result when the storage temperature is The results at 60 ° C. are shown respectively. It represents the change over time in the total content of related substances at each storage temperature. The vertical axis represents the total content (%) of related substances in the preparation, and the horizontal axis represents the storage period (days). -○-indicates the result when the storage temperature is 25 ° C, -X- indicates the result when the storage temperature is 40 ° C,-△-indicates the result when the storage temperature is 50 ° C,-□-indicates the result when the storage temperature is The results at 60 ° C. are shown respectively. It represents the time course of the total content of related substances by exposure to each sample. The vertical axis represents the total content (%) of related substances in the preparation, and the horizontal axis represents the exposure time (minutes). − ○ − indicates the result of the preparation of the present invention, − × − indicates the result of Singlea, and −Δ− indicates the result of the wet Singrea.

1. Water-containing pharmaceutical preparation according to the present invention The water-containing pharmaceutical preparation according to the present invention (hereinafter referred to as "the present invention") contains montelukast or a pharmaceutically acceptable salt thereof as an active ingredient, and has a pH of 4-10. It is in the range of.

1.1 Pharmaceutically acceptable salt of montelukast The pharmaceutically acceptable salt of montelukast is not particularly limited as long as it can form a salt with montelukast and is pharmaceutically acceptable. Examples thereof include alkali metal salts such as potassium, alkaline earth metal salts such as calcium and magnesium, inorganic salts such as aluminum salts, and organic amines such as dicyclohexylamine, amantadine and cyclopropylamine. Of these, sodium salts are preferred.

1.2 State and content of montelukast Montelukast is in a state of being dissolved, dispersed or suspended in the preparation of the present invention or when water is included in the production process. Among these, it is particularly preferable that montelukast is dissolved in the preparation of the present invention. When dissolved, when the patient takes the preparation of the present invention, it is easy to confirm that there is no foreign body feeling and that it is easy to swallow, and that there is no foreign substance in the preparation. This is because it can give a good impression over the throat. The main medium of the preparation of the present invention is water, and examples of such water include normal water, purified water, and water for injection, and are not particularly limited as long as they are pharmaceutically acceptable. It is preferable to use deoxygenated water.

In order to enhance the solubility of montelukast in water, for example, a solubilizer can be added, and it is preferable to add it. Examples of the solubilizer include a surfactant and an alcohol solvent.

As the surfactant, those having an HLB value (hydrophilic / lipophilic balance value) of 14 or more are suitable, and those having 16 or more are preferable. Specifically, for example, sodium lauryl sulfate, glycerin fatty acid ester (caprylic acid) , Myristic acid, lauric acid, etc.), polysorbate 80, and poloxamer. Of these, sodium lauryl sulfate, glycerin fatty acid ester (myristic acid), poloxamer (polyoxyethylene (105) polyoxypropyl (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol) are preferred, and lauryl sulfate. Sodium is more preferred.
Examples of the alcohol solvent include ethanol, propylene glycol, glycerin, and macrogol. Of these, ethanol and propylene glycol are preferred. One or more of these can be used in combination as appropriate.
When the preparation of the present invention is orally administered, a solubilizer is usually selected in consideration of taste factors.

The content of montelukast in the preparation of the present invention is not particularly limited as long as it is an effective dose of montelukast or less, but it is suitably within the range of 0.04 to 100 mg / g, and 0.1 to 10 mg. / G is preferable, and the range of 1 to 2 mg / g is more preferable. If it is less than 0.04 mg / g, the dosage of the preparation of the present invention may be increased, and if it is more than 100 mg / g, there may be a problem in the solubility, dispersibility or suspension of montelukast.
The total weight of the preparation of the present invention varies depending on the form of the preparation of the present invention, but in the case of a jelly agent, for example, a range of about 0.1 to 100 g is appropriate, and a range of about 0.5 to 30 g. The inside is preferable.

1.3 Liquidity The preparation of the present invention is adjusted within the range of pH 4-10. As a result, the stability of montelukast can be improved, and the formation of montelukast crystals and decomposition products (mainly sulfoxides, which are related substances of montelukast) can be suppressed. The pH is preferably in the range of 7.8 to 9.5, more preferably in the range of pH 9.0 to 9.5.

For adjusting the liquidity, a pH adjuster can be used and is not particularly limited as long as it is pharmaceutically acceptable. Specifically, examples of the pH adjuster include phosphoric acid or a salt thereof, citric acid or a salt thereof, carbonic acid or a salt thereof, maleic acid, glycine, hydrochloric acid, sodium hydroxide and the like. Of these, carbonic acid or a salt thereof is preferred. One or more of these can be used in combination as appropriate. Moreover, buffer solutions, such as a phosphate buffer, a citrate buffer, a citrate phosphate buffer, and a carbonate buffer, can also be used.

1.4 Dissolved oxygen concentration in the preparation In the preparation of the present invention, the dissolved oxygen concentration in the preparation is suitably 5 mg / L or less. As a result, the stability of montelukast in the preparation of the present invention can be improved, and the production of decomposition products (mainly sulfoxides that are analogs of montelukast) can be suppressed.
The smaller the dissolved oxygen concentration in the preparation, the better. Therefore, the dissolved oxygen concentration in the preparation is preferably 4 mg / L or less, more preferably 2 mg / L or less.

It is preferable to enclose the preparation of the present invention in a suitable packaging material (container) having a sealing property and a light shielding property in order to avoid the transpiration of moisture and the influence of light.

In order to keep the oxygen concentration in the preparation low, an oxygen scavenger can be used. As the oxygen scavenger, those generally used can be used, and specific examples include iron or an oxide thereof, titanium or an oxide thereof, and an organic oxygen-absorbing resin. Among these, iron or its oxide, titanium or its oxide is preferable. One or more of these can be used in combination as appropriate. Further, an oxygen scavenger is affixed inside the packaging material (for example, AGELESS (registered trademark), manufactured by Mitsubishi Gas Chemical Company), or an oxygen scavenger is kneaded into the packaging material (for example, Oxyguard (registered trademark)). ), Manufactured by Toyo Seikan Co., Ltd.), the oxygen in the preparation may be actively reduced by forcibly removing oxygen.

In addition, an antioxidant can be added to the preparation of the present invention in order to keep the oxygen concentration in the preparation low. Antioxidants include, for example, ascorbic acid or its salt, nitrite, sulfite, erythorbic acid or its salt, dibutylhydroxytoluene, thioglycolic acid or its salt, hydroquinone, edetic acid or its salt, methionine, tocopherol, butyl Mention may be made of hydroxyanisole. Among these, sodium ascorbate is preferable. One or more of these can be used in combination as appropriate.

1.5 Forms of the preparation of the present invention, other additives, packaging materials Specific forms of the preparation of the present invention include, for example, jelly, syrup, liquid, injection, dry syrup containing water during the production process, and oral cavity Examples include internally disintegrating tablets. Among these, a jelly agent is preferable.

Among the above forms, a gelling agent is usually used in order to obtain a jelly-like form (jelly agent). Such a gelling agent is not particularly limited as long as it can be pharmaceutically acceptable and can gel a liquid (water) into a viscous semi-solid, for example, high molecular polysaccharides, gelatin, Mention may be made of sodium polyacrylate. Of these, polymeric polysaccharides are preferred.
Specific examples of the polymer polysaccharide include pectin, agar, carrageenan, gellan gum, xanthan gum, locust bean gum, guar gum, tara gum, alginic acid or a salt thereof, and mannanoic acid. One or more of these can be used in combination as appropriate. The polymer polysaccharide has an appropriate pH for forming a gel state, and is appropriately selected according to the liquidity (pH) of the preparation of the present invention. For example, in the preparation of the present invention having a pH of 7.0 to 9.5, it is preferable to use locust bean gum and xanthan gum, or carrageenan or agar, in order to maintain the gel state stably under these conditions. It is more preferable to use agarene having a low conversion temperature.

The content of the gelling agent (eg, polymeric polysaccharide) in the preparation of the present invention varies depending on the gelling agent used, the pH of the preparation of the present invention, etc., but is usually in the range of 0.01 to 10%. It is preferably in the range of 0.03% to 5%, and more preferably in the range of 0.05% to 3%. If it is less than 0.01%, gelation may be insufficient, and if it is more than 10%, it may become too hard to cause trouble in swallowing.

Additives other than those described above can be added as long as the effects of the present invention are not impaired. Examples of such additives include sweeteners, flavoring agents, fragrances, thickeners, preservatives, and excipients. These can be added at a concentration of 80% or less in the preparation of the present invention.

The shape of the packaging material (container) for enclosing the preparation of the present invention is not particularly limited, and for example, an ampoule shape, a vial shape, a cup shape, an envelope shape, a stick shape, a blister pack, and the like are appropriately selected. Moreover, what can interrupt | block oxygen and can be commercialized in the airtight state is preferable. In particular, in consideration of portability and convenience during administration or administration, a stick-like one is usually preferable although it depends on the final form of the preparation of the present invention.

Further, since montelukast is unstable to light, it is appropriate to enclose it in a light-shielding packaging material (container) such as a light-shielding bottle or aluminum. In order to ensure the stability of montelukast, the material is preferably a material that does not transmit oxygen and light, such as glass having a light shielding property, plastic having a light shielding property and oxygen shielding ability, aluminum, or aluminum laminate. When the preparation of the present invention is particularly a jelly agent, for example, it is preferable to enclose it with an aluminum wrapping material laminated with a film having an oxygen scavenger.

2. Preparation method and use of the preparation of the present invention The preparation of the present invention is a conventional method for producing jelly preparations, syrup preparations, liquid preparations, injections, dry syrup preparations containing water during the manufacturing process, orally disintegrating tablets, etc. Can be manufactured according to.

In addition, since montelukast is also weak against light, it is preferable to manufacture it under light-shielding conditions as much as possible during the manufacturing process. Moreover, in order to suppress that montelukast decomposes | disassembles with water by the heating process in a manufacturing process, adding montelukast to a preparation liquid just before performing a disinfection process (generally 85 degreeC, about 30 minutes). preferable. The water used in the preparation liquid is more preferably deoxygenated as necessary. In addition, the filling process after the end of the sterilization process may be a manufacturing process in which measures for preventing decomposition of montelukast due to heat load are taken as much as possible, such as keeping the temperature of the preparation liquid to a temperature close to the gelation temperature. More preferred.

The pharmaceutical preparation of the present invention can be used in a pharmaceutically appropriate amount for the indication disease observed in montelukast. Examples of such indications include bronchial asthma and allergic rhinitis. The dosage of the preparation of the present invention varies depending on the type of disease to be applied, the age of the patient, the patient's condition, etc., but the amount of montelukast is, for example, within the range of 1-50 mg / day, and 3-20 mg / day. Is preferably within the range of 4 to 10 mg / day. It is preferable to divide this dose once or several times a day (preferably once a day) and administer it orally before going to bed. The age of the indication patient is not particularly limited, but the preparation of the present invention is particularly excellent for taking children and the elderly who are generally poor in swallowing a solid preparation.

Hereinafter, the present invention will be described in more detail with reference to examples and test examples, but the present invention is not limited to these examples. “Montelukast” described below is “Montelukast sodium”.

<Content measuring method>
The high performance liquid chromatography (HPLC) conditions for measuring the content of montelukast and the content of related substances such as sulfoxide compounds in the following test examples are as follows.

(Measurement of montelukast content)
Mobile phase: Water: acetonitrile = 1: 1 (volume ratio, containing 1.5 v / v% trifluoroacetic acid)
Flow rate: about 1.0 mL / min. (Adjusted so that montelukast appears in 5 min.)
Measurement wavelength: 389 nm
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 10 cm filled with 3.5 μm of phenylsilylated silica gel for liquid chromatography The analysis conditions were appropriately changed depending on the sample.

(Measurement of content of related substances such as sulfoxide)
Mobile phase: A = water: trifluoroacetic acid = 2000: 3 (volume ratio)
B = acetonitrile: trifluoroacetic acid = 2000: 3 (volume ratio)
A and B gradient. B maximum density 50%
Flow rate: about 1 mL / min. (Adjusted so that montelukast appears in about 20 min.)
Measurement wavelength: 238nm
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 10 cm packed with 3.5 μm of phenylsilylated silica gel for liquid chromatography

[Test Example 1] Examination of pH A pH suitable for montelukast hydrous pharmaceutical preparation was examined. Prepare a solution (pH 2.6, 3, 4, 5) or suspension (pH 6, 7) sample having the target pH according to the formulation shown in Table 1 below. The change with time was observed. The result is shown in FIG.

As shown in FIG. 1, in the samples of pH 2.6 and pH 3, a significant decrease in the content of montelukast was observed with time. The remaining samples with a pH of 4 or higher had almost constant contents and no decrease was observed. Therefore, it is clear that the water-containing pharmaceutical preparation of montelukast is stable at pH 4 or higher.

[Test Example 2] Examination of pH A montelukast jelly solution (gelling agent: agar) was prepared according to the formulation shown in Table 2 below, and the pH was raised by gradually adding 0.1 N sodium hydroxide to increase the pH of montelukast. When the dissolution state was confirmed, it was a jelly solution that did not dissolve and became cloudy at pH 7.5, 8, and 8.5. On the other hand, pH 9, 9.5 and 10 were not cloudy at the time of the jelly solution. About pH 9, 9.5, 10 in which white turbidity is not recognized, it cooled to room temperature and gelatinized, and the pH of the next day and the dissolution state of montelukast were confirmed. The results are shown in Table 3.

As shown in Table 3, crystal precipitation was observed in the samples having a pH of 7.5 to 8.5. Therefore, in order to obtain a jelly agent in which montelukast is dissolved, it has been shown that the pH needs to be higher than 8.5, more preferably the pH needs to be around 9 or higher.

[Test Example 3] Examination of surfactants Surfactants in the Montelukast jelly were examined by screening 21 surfactants having an HLB value of 3 to 57. Regarding the concentration of the surfactant, only sodium lauryl sulfate was 0.3% by weight and 2% by weight, and the remaining 20 kinds were all performed at 2% by weight. After preparing samples of the formulation shown in Table 4 below, the visual solubility, the content of montelukast, and the production of related substances (sulfoxides, etc.) were tested on the next day of preparation. The results are shown in Table 5.

As shown in Table 5, for the surfactant having an HLB value of less than 14, the solubility of montelukast was inferior in the jelly solution on the day after preparation, and white turbidity was observed. In terms of content, formation of related substances, and taste, sodium lauryl sulfate, glycerin fatty acid ester (myristic acid) and poloxamer (polyoxyethylene (105) polyoxypropyl (5) glycol and polyoxyethylene (160) poly Oxypropylene (30) glycol) was good. Furthermore, sodium lauryl sulfate (0.3%) was the best when taking into account the presence or absence of montelukast after storage for 3 weeks under conditions of 60 ° C. and 75% humidity.

[Example 1]
The preparation of the present invention (jelly agent) having the formulation shown in Table 6 below was prepared by a conventional method. This jelly agent was clear.

[Test Example 4] Influence of oxygen In order to examine the influence of oxygen in the preparation, the preparation of the present invention (jelly agent) of Example 1 was kneaded with an aluminum packaging material containing oxygen scavenger (titanium oxide was incorporated into the oxygen absorbing layer). Stuff) (Montelukast 4mg / 1 formulation 2g) and examined the effect when stored at 60 ° C for 30 days. As test items, related substances and pH were measured.

In addition, in order to estimate the dissolved oxygen concentration in the preparation, water in place of the preparation was put into a deoxygenated packaging and stored at 4 ° C., room temperature, and 40 ° C. as follows. The reason for measuring with water instead of the preparation in this test is that accurate dissolved oxygen cannot be measured due to the components in the preparation.

(Measurement of dissolved oxygen concentration in the preparation)
Using an oxygen concentration measuring device (type: Packmaster RO-103, manufactured by Iijima Electronics Co., Ltd.), the operation was performed according to the operation procedure manual. In the measurement, a stirrer and a wagnit were set inside the measuring device, the inside of the measuring device was filled with the measurement sample and washed together, and then the sample was injected into the measuring device. Thereafter, the bubbles around the wagnet were removed by the rotation of the stirring bar, and when the bubbles disappeared completely, the measurement was started and the results were recorded.

As a result, during the storage period, the generation of individual related substances was suppressed to 1% or less, the generation of total related substances was suppressed to 3% or less, and the change in pH was also suppressed and stable. From the second day of storage, the dissolved oxygen concentration in the preparation was 5 mg / L or less.

[Test Example 5] Stability of Packaged Invention Formulation The formulation of the present invention (jelly agent) of Example 1 was packaged in a package containing a deoxygenation packaging material (Montelukast 4 mg / 1 formulation 2 g). Thereafter, the change with time of 30 days was observed under various conditions of temperature and humidity of 75%. The temperature conditions were four conditions of 25 ° C, 40 ° C, 50 ° C and 60 ° C. As the measurement items, the content of montelukast and the generation of related substances were used. The results are shown in FIG. 2 and FIG.

As shown in FIGS. 2 and 3, there was no change in the content in the preparation during the test period of 30 days at 25 ° C. to 60 ° C. Moreover, the total production | generation content of related substances, such as a sulfoxide body in a formulation, was 1% or less. Under temperature conditions other than 60 ° C., the amount of related substances and the like increased at the beginning of storage, but became constant after a certain period of time. Even at 60 ° C., an initial rapid increase in the amount of related substances was observed after a certain period of time. This result is thought to be due to the fact that the oxygen present in the packaging material in the early stage was absorbed by the deoxidation packaging material. As a result, it is clear that during the test period, less than 1% of the related substance was produced at all temperature conditions and was stable.

[Test Example 6] Exposure test An exposure test was performed on the preparation of the present invention (opened product) of Example 1 and a Singlea fine granule (manufactured by MSD) which is a conventional montelukast preparation. For the Single fine granule, the fine granule itself (single rare) and the fine granule kneaded with water (wet single rare) were used. Wet single rare was prepared by adding approximately 350 μL of water to 0.5 g single rare. The exposure test was performed for 60 minutes using a white fluorescent lamp as a light source, and data obtained after 15 minutes, 30 minutes, and 60 minutes were obtained. The result is shown in FIG.

As shown in FIG. 4, despite the fact that montelukast is dissolved in water, it is confirmed that the total amount of related substances produced is significantly lower in the present preparation than in single rare and wet single rare. It was done. In addition, regarding the relative content of montelukast, the preparation of the present invention remained almost unchanged during the test time.

Since the preparation of the present invention is excellent in stability and easy to take, it is particularly useful for patients such as children and the elderly who are generally poor in swallowing solid preparations.

Claims

A water-containing pharmaceutical preparation comprising montelukast or a pharmaceutically acceptable salt thereof as an active ingredient and having a pH in the range of 4 to 10.
The water-containing pharmaceutical preparation according to claim 1, wherein the dissolved oxygen concentration in the preparation is 5 mg / L or less.
The water-containing pharmaceutical preparation according to claim 1 or 2, further comprising a gelling agent.
The hydrous pharmaceutical preparation according to claim 3, wherein the gelling agent is a high molecular polysaccharide.
The water-containing pharmaceutical preparation according to any one of claims 1 to 4, which is enclosed in a storage container having an oxygen scavenger.
The hydrous pharmaceutical preparation according to claim 5, wherein the oxygen scavenger is iron or an oxide thereof, titanium or an oxide thereof, or an organic oxygen-absorbing resin.
The hydrous pharmaceutical preparation according to any one of claims 1 to 6, wherein an antioxidant is blended.
The hydrous pharmaceutical preparation according to claim 7, wherein the antioxidant is ascorbic acid or a salt thereof, erythorbic acid or a salt thereof, or sulfite.
The hydrous pharmaceutical preparation according to any one of claims 1 to 8, wherein the pharmaceutically acceptable salt of montelukast is the sodium salt of montelukast.
The hydrous pharmaceutical preparation according to any one of claims 1 to 9, wherein the pH is in the range of 9.0 to 9.5.
The water-containing pharmaceutical preparation according to any one of claims 1 to 10, wherein the water-containing pharmaceutical preparation is a jelly agent.