KR102391494B1 - Liquid formulation with enhanced stability comprising montelukast or pharmaceutically acceptable salt thereof and method for preparing same - Google Patents

Abstract

The present invention relates to a liquid formulation comprising montelukast or a pharmaceutically acceptable salt thereof as an electrolyte compound and an active ingredient, and a method for preparing the same. According to the present invention, montelukast or a pharmaceutically acceptable salt thereof is substantially dissolved therein. Because it exists in a solution state, there is no degradation of stability and dissolution with time, and bioavailability can be increased. In addition, the liquid formulation of the present invention has excellent stability, taste and aroma, and thus can improve patients' medication compliance, and thus can be usefully used in the treatment of patients such as asthma and allergic rhinitis.

Description

Liquid formulation with improved stability comprising montelukast or a pharmaceutically acceptable salt thereof, and a method for preparing the same

The present invention relates to a liquid formulation comprising montelukast or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient and a method for preparing the same, and more particularly, to a liquid formulation comprising montelukast or a pharmaceutically acceptable salt thereof in a solution state It relates to a syrup formulation with improved stability for the prevention or treatment of asthma, and a method for preparing the same.

Asthma is an inflammatory airway obstruction disease in which the bronchial mucosa swells due to inflammation of the bronchial tubes, and the bronchial muscles spasm and block the bronchi, causing shortness of breath and severe coughing. Asthma patients complain of symptoms such as wheezing, shortness of breath, and cough due to airway obstruction, and the symptoms tend to be worse at night than during the day. Also, due to excessive sputum formation, breathing is difficult, and in severe cases, life-threatening asthma attacks.

Asthma is a worldwide problem, and it is estimated that there are about 300 million asthmatics. Half of childhood asthma continues into adulthood and persists as adult asthma. The prevalence of asthma in children and adults confirmed by standard survey methods varies from country to country, but ranges from 1% to 18%.

Asthma treatment agents are broadly divided into disease control agents and symptom relievers. Among them, disease control agents are drugs mainly used to control asthma symptoms through an anti-inflammatory effect, and symptom relievers are agents that rapidly expand the airways to improve symptoms within a short period of time. It is a drug that is used when necessary.

As a disease modulator, montelukast is an antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor, and is used for the prevention and treatment of leukotriene-mediated diseases and disorders. In particular, montelukast is known to be effective in allergic rhinitis, atopic dermatitis, chronic urticaria, sinusitis, nasal polyps, chronic obstructive pulmonary disease, conjunctivitis including rhinoconjunctivitis, migraine, cystic fibrosis, viral bronchiolitis, etc. (SE Dahlen, Eur. J. Pharmacol. , 533(1-3), 40-56 (2006)), and is also effective for patients with aspirin-sensitive asthma, and has few side effects. Currently, Singulair ^TM , MSD, which uses montelukast sodium as a pharmacologically active ingredient, has been approved for the treatment of asthma in adults and children over 6 months of age and is on the market.

The usage, dosage and formulation of Singulair are as follows: 10 mg tablets for adults 15 years of age or older to take once a day, 4-5 mg chewable tablets for children aged 2 to 14 years to chew once a day, children 6 months to 2 years old It is marketed as a 4 mg fine-grained formulation taken once a day. Among them, the fine-grained formulation has the inconvenience of taking it directly orally, or mixing it with a small amount of 5 mL or less of room temperature baby food, breast milk or soft food such as porridge and taking it immediately (within 15 minutes).

Moreover, montelukast is unstable to light, humidity, and heat, and when decomposed, it generates decomposition products such as montelukast sulfoxide of the following Chemical Formula 1 and montelukast cis-isomer of the following Chemical Formula 2. In addition, when Singulare Chew Tablet, a commercial product containing montelukast sodium as its main ingredient, was exposed to sunlight, the montelukast sulfoxide content increased to 2.4% in 3 weeks, and montelukast cis-isomer was 14.6 when montelukast was placed in 0.1 M hydrochloric acid solution and exposed to sodium for 6 hours. % has been reported (see MM Al Omari et al., J. Pharm. and Biomed. Anal. , 45, 465-471 (2007)). Through this, it can be seen that it is not easy to secure stability over time for products containing montelukast.

[Formula 1]

[Formula 2]

On the other hand, oral liquid preparations such as syrups, suspensions, elixirs, and spirits among the dosage forms of drugs are easy to adjust the dosage. In addition, it is convenient to take for infants and children and elderly patients, and can increase bioavailability and reduce individual variation compared to oral solid preparations such as tablets, chewable tablets, and granules. Moreover, there is an advantage in that it is possible to improve medication compliance by adding a sweetener and a flavoring agent to improve taste and aroma.

However, montelukast has good solubility in water, but when dissolved in water, decomposition of pharmacologically active ingredients in aqueous solution occurs rapidly, increasing related substances, and there is difficulty in maintaining properties. Therefore, it has not been easy to develop a liquid formulation containing montelukast or a pharmaceutically acceptable salt thereof to date. For this reason, a liquid formulation containing montelukast or a pharmaceutically acceptable salt thereof has not yet been marketed or developed.

Accordingly, the present inventors completed the present invention as a result of research to develop a liquid formulation of montelukast with improved medication compliance, maintaining properties over time, preventing dissolution degradation, increasing stability and bioavailability by adding a stabilizing agent.

S. E. Dahlen, Eur. J. Pharmacol., 533 (1-3), 40-56 (2006) M. M. Al Omari et al., J. Pharm. and Biomed. Anal., 45, 465-471 (2007).

An object of the present invention is to provide a liquid formulation containing montelukast or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient in a solution state, and having improved stability and medication compliance with time, and a method for preparing the same.

According to the above object, the present invention provides a liquid formulation comprising an electrolyte compound and montelukast or a pharmaceutically acceptable salt thereof as an active ingredient.

According to another object, the present invention adds one or more pharmaceutically acceptable additives selected from the group consisting of (1) a sweetener, a flavoring agent, a preservative, a solubilizer, an emulsifier, a pH adjuster, an antioxidant and a colorant to purified water and then stirring to prepare solution 1; (2) adding and stirring at least one electrolyte compound to purified water, adding montelukast or a pharmaceutically acceptable salt thereof thereto and stirring to prepare a solution 2; and (3) mixing the solution 2 with the solution 1 and adding purified water to adjust the concentration.

The liquid formulation containing montelukast or a pharmaceutically acceptable salt thereof according to the present invention has excellent bioavailability because the pharmacologically active ingredient exists in a solution state, there is no deterioration in dissolution over time, and excellent taste and flavor. It is easy to take, and the dosage adjustment is convenient, so that patients' adherence to the medication can be improved. In addition, the addition of electrolyte compounds prevents recrystallization, precipitation, layer separation and generation of related substances even during long-term storage, improves stability and improves homogeneity of drug efficacy, so it can be usefully used for patients with asthma and allergic rhinitis there is.

1 shows the amount of montelukast sulfoxide produced when liquid formulations according to Examples 1 to 3 and Comparative Examples 1 to 8 are stored under accelerated conditions.
2 shows the total amount of montelukast related substances produced when the liquid formulations according to Examples 1 to 3 and Comparative Examples 1 to 8 are stored under accelerated conditions.

The liquid formulation according to the present invention comprises an electrolyte compound and montelukast or a pharmaceutically acceptable salt thereof as an active ingredient.

The active ingredient may be an ingredient selected from the group consisting of montelukast, montelukast sodium, montelukast potassium, montelukast strontium, montelukast calcium, montelukast magnesium, montelukast ammonium and mixtures thereof. An example of the active ingredient is montelukast sodium.

The active ingredient is present in an amount of 0.005 to 10% by weight, preferably 0.008 to 5% by weight, more preferably 0.01 to 2% by weight, based on the weight of montelukast, based on the total weight of the liquid formulation (that is, montelukast contained in the active ingredient is a liquid so as to be included in the desired amount in the formulation) may be included in the liquid formulation. When the amount of montelukast is within the above preferred range, it is possible to solve the inconvenience of the patient having to take too much or too little amount of the liquid formulation thereof in order to ingest the required amount of montelukast, and also the quality test analysis of the prepared liquid formulation It may be easier.

The liquid formulation contains montelukast or a pharmaceutically acceptable salt thereof as an active ingredient, so that asthma, allergic rhinitis, atopic dermatitis, chronic urticaria, sinusitis, nasal polyps, chronic obstructive pulmonary disease, conjunctivitis including rhinoconjunctivitis; It can be used for prevention or treatment of migraine, cystic fibrosis, viral bronchiolitis, and the like.

One or more kinds of the electrolyte compound may be included in the liquid formulation to act as a stabilizer.

Specifically, the stabilizer may be a property stabilizer.

As used herein, the term “appearance” refers to physical properties or properties of a liquid formulation or a pharmacologically active ingredient contained therein. In addition, "property stability" refers to maintaining a stable solution state over time while preventing deterioration or changes in the physical properties and properties of the liquid formulation or the pharmacologically active ingredient contained therein. In addition, the term "property stabilizer" refers to an agent that improves the property stability as described above.

In addition, as used herein, the term "solution state" means that the solubility measured at room temperature for montelukast or a pharmaceutically acceptable salt thereof dissolved in a liquid formulation is 70% to 100%, specifically 80% to 100%, more Specifically, it means 90% to 100%, more specifically 95% to 100%.

In addition, in this specification, "room temperature" means a range of about 15 ℃ to 25 ℃.

The electrolyte compound may be an electrolyte compound that is dissociated in a solvent and exhibits neutral to weak basic properties. Specifically, the electrolyte compound may have a pKa of 6.0 to 12.0, specifically a pKa of 6.5 to 11.0, and more specifically a pKa of 7.0 to 10.0. When the pKa of the electrolyte compound is within the preferred range, the degree to which the electrolyte compound exerts stimulation on the active ingredient is minimized, which may be advantageous in preventing deterioration of properties of the active ingredient.

In addition, the electrolyte compound may have a solubility of 100 to 900 g/L at room temperature (for example, 20° C.), specifically, a solubility of 200 to 750 g/L at room temperature in the solvent of the liquid formulation, More specifically, it may be 300 to 600 g/L.

As a specific example, the electrolyte compound may be at least one selected from chlorides of alkali metals and chlorides of alkaline earth metals.

As a more specific example, the electrolyte compound may be selected from the group consisting of potassium chloride, sodium chloride, calcium chloride, and mixtures thereof.

The electrolyte compound may be included in the liquid formulation in an amount of 0.5 to 20 parts by weight, preferably 1 to 15 parts by weight, more preferably 2 to 10 parts by weight, based on 1 part by weight of montelukast included in the active ingredient. When the content of the electrolyte compound is within the above preferred range, solubilization to effectively maintain the dissolved state of the pharmacologically active ingredient in the liquid formulation and preventing the increase of related substances in the liquid formulation may further improve stability.

Such an electrolyte compound allows montelukast or a pharmaceutically acceptable salt thereof to maintain a stable phase in solution without recrystallization and precipitation over time in the formulation. In addition, the electrolyte compound also serves to maintain proper pH, water balance, osmotic pressure control, acid-base balance, and the like.

The liquid formulation of the present invention may further include a pharmaceutically acceptable additive. The pharmaceutically acceptable additive may be, for example, at least one selected from the group consisting of a sweetener, a flavoring agent, a preservative, a solubilizing agent, an emulsifier, a pH adjusting agent, an antioxidant, and a colorant. By including the pharmaceutically acceptable additive, the liquid formulation of the present invention can maintain the solution state of the liquid formulation well even when stored for a long period of time or improve the taste and aroma to improve medication compliance.

The sweetener improves the taste of the liquid formulation, for example, at least one selected from the group consisting of sucrose, high fructose, sorbitol, mannitol, xylitol, aspartame, steviol glycoside, sucralose, acesulfame potassium and glycerin. material can be used. The sweetener may be added in an amount of 0.001 to 50% by weight, preferably 0.005 to 30% by weight, based on the total weight of the liquid formulation.

The flavoring agent improves medication compliance by allowing the user to feel the scent when taking the liquid formulation, for example, apple flavor, cherry flavor, orange flavor, strawberry flavor, banana flavor, grape flavor, mango flavor, peach flavor, etc. fruity or overall fruity flavor; vanilla flavor; mint flavor; And one or more substances selected from the group consisting of honey flavor may be used. The flavoring agent may be added in an amount of 0.1 to 5% by weight, preferably 0.2 to 3% by weight, based on the total weight of the liquid formulation.

The preservative inhibits the growth of microorganisms during storage of the liquid formulation, and includes, for example, paraoxybenzoic acids such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate; benzoic acids such as benzoic acid and sodium benzoate; And one or more substances selected from the group consisting of sorbic acids such as sorbic acid and potassium sorbate may be used. The preservative may be added in an amount of 0.01 to 2% by weight, preferably 0.02 to 1% by weight, based on the total weight of the liquid formulation.

The solubilizing agent improves the solubility of the active substance in the liquid formulation, and for example, one or more substances selected from the group consisting of meglumine, arginine and lysine may be used. The solubilizing agent may be added in an amount of 0.001 to 1.0 wt%, preferably 0.005 to 0.5 wt%, based on the total amount of the liquid formulation.

In addition, an emulsifier for improving the properties of the liquid formulation, a pH adjusting agent for adjusting the acidity of the liquid formulation to an appropriate level, and the like may be added.

The liquid formulation contains a solvent for dissolving the active ingredient and the like. The solvent is not particularly limited, but may be, for example, a polar solvent, preferably a polar aqueous solvent. As a specific example, the solvent may be water (purified water).

The liquid formulation may exhibit basicity, for example, may exhibit neutral to weak basicity. Specifically, the liquid formulation may have a pH of 6.0 to 12.0, and more specifically, a pH of 8.0 to 12.0. When the pH of the liquid formulation is within the above preferred range, there is an advantage in property stability, that is, improvement in properties of the liquid formulation through prevention of precipitation of montelukast and pharmaceutically acceptable salts thereof.

In addition, the active ingredient dissolved in the liquid formulation is 70% to 100%, specifically 80% to 100%, more specifically 90% to 100% under 40°C, 75% relative humidity, and accelerated conditions of 3 months. , more specifically, it may exhibit a solubility of 95% to 100%.

In addition, in the liquid formulation, the production amount of montelukast sulfoxide is 0.9% or less, specifically 0.7% or less, more specifically 0.5% or less, even more specifically 0.4 % or less, and the total amount of related substances produced may be 1% or less, specifically 0.8% or less, more specifically 0.6% or less, and even more specifically 0.5% or less.

The liquid formulation may be a liquid formulation for oral use such as syrup, suspension, elixirs, and alcohol, and as a preferred example, may be syrup.

The liquid formulation has excellent bioavailability because the pharmacologically active ingredient is present in a solution state, does not decrease dissolution over time, is easy to take because of its excellent taste and fragrance, and is convenient to control the dosage, thereby improving the compliance of patients with medication. can be improved In addition, the addition of electrolyte compounds prevents recrystallization, precipitation, layer separation and generation of related substances even during long-term storage, improves stability and improves homogeneity of drug efficacy, so it can be usefully used for patients with asthma and allergic rhinitis there is.

The liquid formulation of the present invention comprises the steps of (1) adding one or more pharmaceutically acceptable additives to purified water and stirring to prepare solution 1; (2) adding one or more electrolyte compounds to purified water and stirring, adding a pharmacologically active ingredient thereto and stirring to prepare a solution 2; and (3) mixing the prepared solution 1 and solution 2 and adding purified water to adjust the concentration.

In the step (1), the one or more pharmaceutically acceptable additives may be the additives exemplified above. As an example, after a solubilizing agent is added to purified water and stirred, a sweetener and an antioxidant are sequentially added and stirred to prepare solution 1. As a specific example, step (1) comprises the steps of: i) adding a dissolution aid (eg, meglumine) to sterile purified water at 30° C. or less, preferably 15° C. to 30° C. in a preparation tank and stirring; ii) adding a sweetener to the solution obtained in step i) and stirring; and iii) adding an antioxidant to the solution obtained through step ii) and stirring to prepare solution 1.

In step (2), the pharmacologically active ingredient is montelukast or a pharmaceutically acceptable salt thereof, and specific examples thereof are as described above. As a specific example, step (2) may include: a) stirring at least one electrolyte compound into purified water at 30° C. or less, preferably 15° C. to 30° C.; and b) adding montelukast sodium to the solution obtained in step a) and stirring to prepare solution 2.

In step (3), a liquid formulation can be prepared by mixing solution 1 and solution 2 prepared above and adding purified water to adjust the concentration. As an example, after adding the solution 2 to the solution 1, sterile purified water cooled to room temperature may be added to adjust the volume to a desired volume and agitation. The liquid formulation prepared in this way is preferably further filtered through a 1 μm filter or the like. The final prepared liquid formulation may be stored in a storage tank or may be stored in an appropriate container.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1: Preparation of liquid formulation containing montelukast

50 mL of sterile purified water was added to the preparation tank, and 0.20 g of meglumine was added and dissolved while stirring. After cooling the temperature of the preparation tank to 30° C. or less, 0.50 g of sucralose was added thereto and stirred, and then 0.01 g of sodium edetate was added to prepare solution 1. Separately, 0.5 g of potassium chloride was added to purified water at 25° C. to prepare a solution, and then 0.104 g of montelukast sodium (amount of montelukast: 0.100 g) was added and stirred to prepare a solution 2. The solution 2 was put into solution 1 and mixed, and then sterile purified water was added to prepare a solution with a final volume of 100 mL. The resulting final mixture was filtered through a 1 μm filter to complete a liquid formulation in a solution state. In the liquid formulation thus prepared, the solubility of montelukast was measured to be 100%, and it was confirmed that montelukast sodium was present in a solution state.

Example 2 and 3: monterukast Preparation of liquid formulations containing

A liquid formulation was prepared in the same manner as in Example 1, except that potassium chloride or sodium chloride was added as a stabilizer in the amounts shown in Table 1 below.

additive Example 1 Example 2 Example 3 montelukast sodium (g)
(Based on Montelukast) 0.104
(0.100) 0.104
(0.100) 0.104
(0.100) Meglumine (g) 0.20 0.20 0.20 Sucralose (g) 0.50 0.50 0.50 Sodium edetate (g) 0.01 0.01 0.01 Potassium Chloride (g) 0.20 1.00 - Sodium Chloride (g) - - 0.20 Purified water appropriate amount appropriate amount appropriate amount Total volume (mL) 100 100 100 Stabilizer addition amount (parts by weight)
(based on 1 part by weight of montelukast) 2 10 2

comparative example 1 to 8: monterukast Preparation of liquid formulations containing

A liquid formulation was prepared in the same manner as in Example 1, except that no stabilizer was added or potassium chloride, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, or glucose was added in the amounts shown in Table 2 below as stabilizers. did

additive Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 montelukast sodium (g)
(Based on Montelukast) 0.104
(0.100) 0.104
(0.100) 0.104
(0.100) 0.104
(0.100) 0.104
(0.100) 0.104
(0.100) 0.104
(0.100) 0.104
(0.100) meglumine 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 sucralose 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 sodium edetate 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 potassium chloride - 0.04 2.10 - - - - - potassium hydroxide - - - 0.01 0.20 - - - sodium hydroxide - - - - - 0.01 - - sodium bicarbonate - - - - - - 1.00 - glucose - - - - - - - 10.0 Purified water appropriate amount appropriate amount appropriate amount appropriate amount appropriate amount appropriate amount appropriate amount appropriate amount Total volume (mL) 100 100 100 100 100 100 100 100 Stabilizer addition amount (parts by weight)
(based on 1 part by weight of montelukast) 0 0.4 21 0.1 2 0.1 10 100

Experimental Example 1: Measurement of pH of montelukast liquid formulation

The pH of the liquid formulations prepared in Examples 1 to 3 and Comparative Examples 1 to 8 was measured with a pH meter. The results are shown in Table 3.

Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 pH 10.1 10.2 10.6 10.0 10.1 10.8 10.4 13.5 10.8 9.8 9.0

As shown in Table 3, the liquid formulation samples of Comparative Examples except for Comparative Example 5 exhibited a pH in the range of pH 9 to 11. However, in Comparative Example 5, although in the same amount as the potassium chloride of Example 1, the pH was out of the proper pH due to the characteristic showing a strong base.

Experimental Example 2: Observation of stability of montelukast liquid formulation

The liquid formulations prepared in Examples 1 to 3 and Comparative Examples 1 to 8 were placed in a transparent glass bottle and stored under accelerated conditions (40° C., 75% relative humidity) for 7 days and 3 months to visually observe precipitation and properties. The results are shown in Table 4.

division Precipitation and property evaluation Accelerated 7-day storage Accelerated 3 months storage precipitation Transparency precipitation Transparency Example 1 - - - - Example 2 - - - - Example 3 - - - - Comparative Example 1 + + + + Comparative Example 2 - - + + Comparative Example 3 - - - - Comparative Example 4 - + + + Comparative Example 5 - - + + (browning) Comparative Example 6 - + + + Comparative Example 7 - + + + Comparative Example 8 + + + + - : No precipitation, transparency,
+ : Precipitation, opacity, discoloration

As shown in Table 4, the liquid formulations of Examples 1 to 3 according to the present invention did not form precipitation for 3 months under accelerated conditions and showed transparent properties.

However, Comparative Example 1 to which the electrolyte compound was not added showed an opaque appearance due to precipitation at the time of acceleration 7 days. In addition, as in Comparative Example 2, when the amount of the electrolyte compound was insufficient, the degree of ionization of the active ingredient was lowered, showing an opaque property, and at the same time, precipitation occurred. In Comparative Examples 4 to 6, although the liquid formulations were in the pH range of 8.0 to 12.0, strong stimulation was applied to the main component due to the addition of a strong basic electrolyte compound, so that precipitation and browning occurred at 3 months of acceleration. In the case of Comparative Example 7, the electrolyte compound showed a low degree of ionization, showing a precipitation pattern. In Comparative Example 8, precipitation occurred at the time of acceleration 7 days due to the addition of the non-electrolyte material.

Experimental Example 3: Evaluation of solubility of montelukast liquid formulation

The liquid formulations prepared in Examples 1 to 3 and Comparative Examples 1 to 8 were stored under accelerated conditions (40° C., 75% relative humidity) for 3 months. After centrifuging the sample at 16,000 rpm for 20 minutes, the supernatant was filtered through a 0.45 μm filter, diluted by 1/4 with methanol, and then solubility was analyzed according to the following analysis conditions.

<Montelukast solubility analysis conditions>

Equipment used: HPLC (Hitachi 2000 series, Japan)

Detector: Ultraviolet absorptiometry (measurement wavelength: 225 nm)

Column: A column filled with octylsilylated silica gel for liquid chromatography with a particle diameter of 5 μm in a stainless steel tube with an inner diameter of about 4.6 mm and a length of about 15 cm (Inertsil C8, GL Science)

Mobile phase: 0.025 mol/L potassium dihydrogen phosphate solution (pH 6.6 adjusted with 10 mol/L sodium hydroxide solution)/acetonitrile = 4:6 (v/v)

Flow rate: 1.0 mL/min

Column temperature: 45°C

Tables 5 and 6 show the solubility test results of the liquid formulation containing montelukast measured under the above analysis conditions.

Example 1 Example 2 Example 3 Dosage of montelukast (㎍/mL) 1,000 1,000 1,000 Solubility of montelukast (μg/mL) 999.5 998.1 997.3 Solubility to Input (w/w%) 99.9% 99.8% 99.7%

Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Dosage of montelukast (㎍/mL) 1,000 1,000 1,000 1,000 1,000 1,000 1,000 1,000 Montelukast solubility (μg/mL) 541.1 789.4 997.9 496.1 674.1 501.6 582.2 234.7 Solubility to Input (w/w%) 54.1% 79.0% 99.8% 50.0% 67.4% 50.1% 58.2% 23.5%

In the liquid formulations of Examples 1 to 3 and Comparative Examples 1 to 8, montelukast sodium was added at a concentration of 1,040 μg/mL, and when converted into the amount of montelukast, the concentration when all of the input amount is dissolved is 1,000 μg/mL am.

As a result of the solubility measurement, the liquid formulations prepared in Examples 1 to 3 and Comparative Example 3, which had good properties, all showed a solubility of 98-100 w/w% relative to the input amount, so that all montelukast showed a solution state, but the rest of Comparative Examples prepared In the liquid formulation, montelukast was precipitated and the content decreased.

Experimental Example 4: Analysis of montelukast liquid formulation related substances

After the liquid formulations of Examples 1 to 3 and Comparative Examples 1 to 8 were put in a light-shielding airtight glass container and stored under accelerated conditions, the generation of montelukast sulfoxide and montelukast total related substances was analyzed under the conditions for analyzing related substances described below.

<Accelerated storage conditions>

Storage conditions: 40℃ and 75% relative humidity, light-shielded glass container

Test time points: Initial, 1 month and 3 months

Analytical subject: montelukast analogs

<Montelukast Related Substance Analysis Conditions>

Equipment used: HPLC (Hitachi 2000 series, Japan)

Detector: UV absorbance spectrometer (measurement wavelength: 238 nm)

Column: A column filled with diisopropylphenethyl silica gel for liquid chromatography with a particle diameter of 5 μm in a stainless tube with an inner diameter of about 4.6 mm and a length of 25 cm (Zorbax SB-Phenyl, Agilent)

Mobile phase: A - purified aqueous solution containing 0.1% (v/v) trifluoroacetic acid

B - Acetonitrile solution containing 0.1% (v/v) trifluoroacetic acid

Mobile phase elution conditions

Flow rate: 1.5 mL/min

Column temperature: 25°C

The amounts of montelukast sulfoxide and total related substances measured under the analysis conditions are shown in Table 7 and FIGS. 1 and 2 .

sample Early 1 month 3 months sulfoxide Total Flexible Substances sulfoxide Total Flexible Substances sulfoxide Total Flexible Substances Example 1 0.07% 0.18% 0.16% 0.27% 0.23% 0.38% Example 2 0.09% 0.17% 0.18% 0.29% 0.26% 0.40% Example 3 0.06% 0.15% 0.20% 0.33% 0.30% 0.44% Comparative Example 1 0.10% 0.21% 0.23% 0.40% 0.31% 0.49% Comparative Example 2 0.06% 0.15% 0.15% 0.22% 0.29% 0.42% Comparative Example 3 0.15% 0.29% 0.34% 0.52% 0.50% 0.78% Comparative Example 4 0.11% 0.18% 0.49% 0.56% 0.79% 1.17% Comparative Example 5 0.12% 0.19% 0.71% 0.90% 0.98% 1.89% Comparative Example 6 0.11% 0.18% 0.52% 0.69% 0.82% 1.28% Comparative Example 7 0.08% 0.19% 0.27% 0.42% 0.53% 0.77% Comparative Example 8 0.12% 0.19% 0.32% 0.51% 0.62% 0.87%

As shown in Table 7 and FIGS. 1 and 2, it was confirmed that the stability was improved due to the addition of the electrolyte compound. In addition, as in Comparative Example 3, when the amount of the electrolyte compound added was too excessive, the property stability was improved, but the amount of related substances was slightly increased. As in Comparative Examples 4 to 6, when an electrolyte compound having a high ionization degree and a strong basic property was added, decomposition of the main component occurred rapidly, and it was confirmed that the increase in the amount of related substances was large. In addition, in the case of Comparative Example 7 to which an electrolyte compound having a low ionization degree was added, the property stability was poor, and related substances were slightly increased, and Comparative Example 8 to which non-electrolyte glucose was added showed poor stability similar to Comparative Example 7 it was

Claims (10)

an electrolyte compound as a stabilizer, and montelukast or a pharmaceutically acceptable salt thereof as an active ingredient;
The electrolyte compound is included in an amount of 2 to 10 parts by weight based on 1 part by weight of montelukast included in the active ingredient,
The electrolyte compound is potassium chloride or sodium chloride,
The liquid formulation for oral use, wherein the pH of the liquid formulation for oral use is in the range of 8.0 to 12.0.
delete delete The method of claim 1,
The liquid formulation for oral use, characterized in that the active ingredient is included in an amount of 0.005 to 10% by weight based on the total weight of the oral liquid formulation based on the weight of montelukast.
The method of claim 1,
An oral liquid formulation, characterized in that the active ingredient exhibits a solubility of 95% to 100% at 40°C, 75% relative humidity, and accelerated conditions of 3 months.
The method of claim 1,
The liquid formulation for oral use, characterized in that the electrolyte compound has a pKa of 6.0 to 12.0.
The method of claim 1,
The liquid formulation for oral use, characterized in that the electrolyte compound has a solubility of 100 to 900 g/L at 20°C.
delete The method of claim 1,
The oral liquid formulation further comprises one or more pharmaceutically acceptable additives selected from the group consisting of a sweetening agent, a flavoring agent, a preservative, a solubilizing agent, an emulsifying agent, a pH adjusting agent, an antioxidant and a coloring agent. For liquid formulations.
(1) After adding at least one pharmaceutically acceptable additive selected from the group consisting of a sweetener, a flavoring agent, a preservative, a solubilizer, an emulsifier, a pH adjuster, an antioxidant and a colorant to purified water, stirring to prepare solution 1 step;
(2) adding and stirring at least one electrolyte compound as a stabilizer to purified water, adding montelukast or a pharmaceutically acceptable salt thereof thereto, followed by stirring to prepare a solution 2; and
(3) mixing the solution 2 with the solution 1 and adding purified water to adjust the concentration,
The electrolyte compound is included in an amount of 2 to 10 parts by weight based on 1 part by weight of montelukast included in the active ingredient,
The electrolyte compound is potassium chloride or sodium chloride,
The method of claim 1, wherein the pH of the liquid formulation for oral use is in the range of 8.0 to 12.0.

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