KR102481517B1 - Pharmaceutical Formulation - Google Patents

Abstract

A pharmaceutical formulation of the present invention contains levocetirizine or a pharmaceutically acceptable salt thereof, montelukast sodium, and an organic acid salt. The pharmaceutical formulation of the present invention has excellent dissolution properties, secures stability, and has excellent productivity. In addition, a method for preparing a pharmaceutical formulation of the present invention comprises: a step (A) of forming a mixture containing montelukast sodium and an organic acid salt into granules; and a step (B) of mixing the granules formed in step (A) with levocetirizine or a pharmaceutically acceptable salt thereof. The preparation method of the present invention has the effect of producing a pharmaceutical formulation which has excellent dissolution properties, secures stability, and has excellent productivity.

Description

Pharmaceutical formulation {Pharmaceutical Formulation}

The present invention relates to a pharmaceutical preparation containing levocetirizine or a pharmaceutically acceptable salt thereof, and montelukast sodium, and a method for preparing the same, and more particularly, to a pharmaceutical preparation capable of ensuring stability and having excellent productivity, and a pharmaceutical preparation thereof It's about manufacturing methods.

"Rhinitis" is defined as an inflammatory disease of the nasal mucosa accompanied by symptoms such as rhinorrhea, sneezing, itching, and nasal congestion. , and is observed in 10-50% of the total population, especially in Asia, where it is known to occur in 10-46% of adults.

In addition, "asthma" refers to a disease in which the bronchial mucosa is swollen due to inflammation of the bronchial tubes, and the bronchial muscles are spasmodic, causing bronchial obstruction, resulting in shortness of breath and severe coughing. even threaten

Although allergic rhinitis and asthma may occur alone, the two diseases share a high proportion of patients in the same patient group, with a study showing that 58% of rhinitis patients share asthma and 85-95% of asthma patients share rhinitis. Therefore, it is necessary to develop medicines for appropriate treatment of patients with both diseases at the same time.

Montelukast is an antagonist that inhibits the cysteinyl leukotriene type 1 (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, and viral bronchiolitis. Singulair (MSD), a salt, is approved and marketed for the treatment of asthma in adults and pediatric patients 2 years of age and older. This is because the solubility and stability of montelukast sodium salt are superior to that of montelukast free base. In fact, montelukast sodium salt is known to be soluble in water (0.1 to 1 g/mL). However, even if the montelukast salt is used, it shows significantly lower solubility than purified water in an aqueous solution with high ionic strength, and after it is dissolved, it is observed to precipitate by rapid reprecipitation. Research for this is ongoing.

On the other hand, Cetirizine is (2-(4-((4-chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy)acetic acid, its levorotatory and dextrorotatory enantiomers. are known as Levocetirizine and Dextrocetirizine, respectively. Levocetirizine known to have medicinal properties can be obtained by isolation or asymmetric synthesis from a racemic mixture of cetirizine. Levocetirizine has antihistamine properties, making it useful as an antiallergic, antihistamine, bronchodilator, and antispasmodic. In addition, Xyzal (Yuhan Corporation) using levocetirizine dihydrochloride has been approved for the treatment of allergic rhinitis and is currently on the market.

When montelukast, a leukotriene antagonist, and levocetirizine, an antihistamine, are applied as active ingredients, it not only effectively blocks the initial allergic reaction, but also has the advantage of long-term use for allergic diseases such as rhinitis and asthma. is in dire need of development. However, when the two components are simply mixed, there is a problem due to the physicochemical interaction between the two components, such as the color of the two main components having a white or almost white color changing to yellow. In order to minimize this problem, the two components are separated from each other and developed as a capsule formulation filled with two types of tablets (Refer to Korean Patent Registration Publication No. 10-2006000), or in the form of a double-layered tablet (Korean Patent See Registration Publication No. 10-2110304). However, these formulations can be manufactured only by using a tablet capsule machine or a multi-layer tablet press, which is a special manufacturing facility, and there are problems such as a complicated production process and a low production yield during actual manufacturing, so there is a need for additional research. is desperately needed.

Republic of Korea Patent Registration No. 10-2006000, 2019.8.1, specification Republic of Korea Patent Registration No. 10-2110304, 2020.5.14, specification

An object to be solved by the present invention is to provide a pharmaceutical preparation having excellent productivity as well as securing stability.

In addition, the problem to be solved by the present invention is to provide a pharmaceutical preparation method that can easily prepare the pharmaceutical preparation of the present invention.

The object of the present invention is not limited to the above-mentioned tasks, and other tasks not mentioned will be clearly understood by those skilled in the art from the following description.

A pharmaceutical preparation according to an embodiment of the present invention includes levocetirizine or a pharmaceutically acceptable salt thereof, montelukast sodium, and an organic acid salt.

The organic acid salt may be 10 to 500 parts by weight based on 100 parts by weight of montelukast sodium.

The organic acid salt is an alkali metal salt of an organic acid, and the organic acid may be at least one selected from the group consisting of citric acid, lactic acid, succinic acid, oxalic acid, malic acid, acetic acid, ascorbic acid, fumaric acid, and tartaric acid.

The alkali metal may be sodium.

The organic acid salt may be sodium citrate.

The montelukast sodium may be formed into granules together with the organic acid salt.

The levocetirizine or a pharmaceutically acceptable salt thereof may be mixed with the granules.

The levocetirizine or a pharmaceutically acceptable salt thereof, the montelukast sodium, and the organic acid salt may be included together in one layer or one compartment.

The pharmaceutical formulation may be a solid formulation for oral use selected from the group consisting of tablets or capsules.

The tablet contains the granules containing montelukast sodium and the organic acid salt and the levocetirizine or a pharmaceutically acceptable salt thereof mixed together in one layer, and the capsule contains the granules containing montelukast sodium and the organic acid salt The levocetirizine or a pharmaceutically acceptable salt thereof may be mixed together and filled into one empty capsule.

The tablet may be a monolayer tablet.

A pharmaceutical preparation method according to an embodiment of the present invention includes the steps of (A) molding a mixture containing montelukast sodium and an organic acid salt into granules; and (B) mixing the granules formed in step (A) with levocetirizine or a pharmaceutically acceptable salt thereof.

The manufacturing method may further include (C) molding the mixture mixed in step (B).

The pharmaceutical preparation of the present invention has the effect of excellent dissolution of active ingredients, stability and excellent productivity. In addition, the production method of the present invention has an effect that it is possible to easily prepare a pharmaceutical preparation having excellent dissolution of active ingredients and securing stability as well as excellent productivity.

1 is a flowchart for explaining a manufacturing method according to an embodiment of the present invention.
2 is a photograph showing an embodiment of the present invention and a comparative example.
Figure 3 is a graph showing the montelukast dissolution test results for Examples and Comparative Examples of the present invention.
Figure 4 is a graph showing the results of levocetirizine dissolution test for Examples and Comparative Examples of the present invention.
5 is a graph showing the test results of related substances derived from montelukast for Examples and Comparative Examples of the present invention.
Figure 6 is a graph showing the test results of related substances derived from levocetirizine for Examples and Comparative Examples of the present invention.

Advantages and features of the present invention and methods of achieving them will become clear with reference to the detailed description of the following embodiments taken in conjunction with the accompanying drawings. However, the present invention is not limited to the embodiments disclosed below and may be implemented in various different forms, only the present embodiments make the disclosure of the present invention complete, and common knowledge in the art to which the present invention belongs. It is provided to fully inform the person who has the scope of the invention, the invention is only defined by the claims.

A pharmaceutical preparation according to an embodiment of the present invention includes levocetirizine or a pharmaceutically acceptable salt thereof, montelukast sodium, and an organic acid salt.

As confirmed in the experimental examples described later, when levocetirizine and montelukast are applied together, problems may occur in the stability and dissolution rate of the formulation due to the interaction between the two components. By including the organic acid salt together, it seems that the stability and dissolution of the formulation can be secured. Such stability and dissolution are achieved even when montelukast and levocetirizine are not separated into separate layers or tablets, which is very desirable in terms of productivity of the formulation. This effect seems to be due to the buffering effect of the organic acid salt on levocetirizine reacting with montelukast sodium, which attenuates the physicochemical change, thereby delaying the change in the properties of the preparation, improving the dissolution rate and securing stability. . This can also be seen through the experimental examples described below.

At this time, the organic acid salt is not limited thereto as long as formulation stability can be secured, but is, for example, an alkali metal salt of an organic acid, and the organic acid is citric acid, lactic acid, succinic acid, oxalic acid, malic acid, acetic acid, ascorbic acid, fumaric acid and tartaric acid. It may be one or more selected from the group consisting of. The alkali metal may preferably be sodium. The organic acid salt may preferably be sodium citrate. Such organic acid salts may exhibit neutral to basic properties in a solvent such as water.

In addition, the organic acid salt is not limited thereto as long as formulation stability can be secured, but may be preferably 10 to 500 parts by weight, more preferably 20 to 200 parts by weight, based on 100 parts by weight of montelukast sodium. Within this range, formulation stability can be more secured. In particular, below this range, there is a concern that formulation stability may be insufficient, and above this range, there is a concern that moldability of a solid dosage form may be difficult, such as difficulty in forming granules. In addition, the organic acid salt may be 50 to 500 parts by weight based on 100 parts by weight of levocetirizine or a pharmaceutically acceptable salt thereof. In Examples 1 to 3 and Examples 5 to 9, the organic acid salt was sodium citrate, and as montelukast, the organic acid salt was 50 to 100 parts by weight based on 100 parts by weight of the montelukast sodium.

Levocetirizine or a pharmaceutically acceptable salt thereof, and montelukast sodium may be included as active ingredients or main ingredients in the pharmaceutical preparation, respectively.

Based on 100 parts by weight of montelukast sodium, levocetirizine or a pharmaceutically acceptable salt thereof may be 2 parts by weight to 5000 parts by weight.

The daily dose of montelukast sodium for an adult (60 kg) may be 1 to 50 mg, preferably 2.5 to 20 mg as montelukast. Levocetirizine or its pharmaceutically acceptable salts can be obtained by forming addition salts with pharmaceutically acceptable non-toxic organic and inorganic acids such as acetic acid, citric acid, maleic acid, succinic acid, ascorbic acid, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. can include A preferred example of levocetirizine or a pharmaceutically acceptable salt thereof is levocetirizine dihydrochloride. The daily dose of levocetirizine or a pharmaceutically acceptable salt thereof may be 1 to 50 mg, preferably 2.5 to 20 mg, based on levocetirizine dihydrochloride for an adult (60 kg).

The pharmaceutical preparation may be used for oral administration for preventing or treating allergic rhinitis or asthma. At this time, the prevention or treatment of allergic rhinitis or asthma includes alleviating symptoms of allergic rhinitis in patients with asthma and perennial allergic rhinitis. Allergic rhinitis may include symptoms of rhinorrhea, nasal obstruction, rhinopruritus, sneezing and ocular itching.

In the pharmaceutical preparation, montelukast sodium, an organic acid salt, and levocetirizine or a pharmaceutically acceptable salt thereof may be present in a mixed state. At this time, at least one of montelukast sodium, an organic acid salt, and levocetirizine or a pharmaceutically acceptable salt thereof may be formed into granules and mixed with other ingredients. For example, montelukast sodium may be formed into granules together with an organic acid salt, and levocetirizine or a pharmaceutically acceptable salt thereof may be mixed with the granules and included in a pharmaceutical preparation. That is, montelukast sodium may be included in the granules together with the organic acid salt, and levocetirizine or a pharmaceutically acceptable salt thereof may be included outside the granules. At this time, organic acid salts may not be included on the outside of the granules.

Preferably, levocetirizine or a pharmaceutically acceptable salt thereof, montelukast sodium, and an organic acid salt may be included together in one layer or one compartment. More specifically, the pharmaceutical formulation of one embodiment includes a tablet comprising montelukast sodium and organic acid salt-containing granules and levocetirizine or a pharmaceutically acceptable salt thereof mixed together in one layer; Alternatively, it may be a capsule containing montelukast sodium and organic acid salt-containing granules and levocetirizine or a pharmaceutically acceptable salt thereof mixed together and filled into one empty capsule.

As such, by including the organic acid salt, montelukast sodium, and levocetirizine or a pharmaceutically acceptable salt thereof in the pharmaceutical preparation, the organic acid salt more effectively attenuates the physicochemical changes of montelukast sodium and levocetirizine, thereby improving the quality of the preparation. It seems to be able to delay the change in appearance, improve the dissolution rate and secure stability. In addition, such pharmaceutical preparations can be formulated without using special manufacturing equipment, such as a tablet capsule machine or a multi-layer tablet press, and have the advantage that the manufacturing process is simple and uncomplicated. In addition, in the case of a simple process, it is natural that it is preferable in terms of defect rate compared to a complicated process.

Such a pharmaceutical preparation can be easily prepared by the pharmaceutical preparation manufacturing method according to an embodiment of the present invention.

Hereinafter, a manufacturing method according to an embodiment of the present invention will be described in detail with reference to FIG. 1 . 1 is a flowchart for explaining a manufacturing method according to an embodiment of the present invention.

As shown in Figure 1, one embodiment of the pharmaceutical formulation manufacturing method of the present invention, (A) granule molding step; and (B) a mixing step. (A) The step of shaping granules is a step of shaping a mixture containing montelukast sodium and an organic acid salt into granules, and a general method applied to shaping granules can be used. (B) The mixing step is a step of mixing the granules formed in step (A) with levocetirizine or a pharmaceutically acceptable salt thereof, and a general method applied to mixing may be used. More specifically, in step (A), montelukast sodium and an organic acid salt may be mixed, optionally with the addition of pharmaceutically acceptable additives, and the mixed mixture may be granulated and molded into granules. In this case, the additive may be one or more selected from a diluent, a disintegrant, a binder, and a colorant.

In step (B), the granules formed in step (A) and levocetirizine or a pharmaceutically acceptable salt thereof are mixed, but mixing is performed either directly using a mixer or indirectly in the process of filling capsules. It may also be by way of mixing. Additives may be added to and mixed with the molded granules and levocetirizine or a pharmaceutically acceptable salt thereof, or additives may be added after mixing. Additives can be diluents, disintegrants, binders, colorants and/or glidants.

In addition, the manufacturing method according to an embodiment of the present invention may further include (C) molding the mixture mixed in step (B). Forming in step (C) may be by tableting or filling into empty capsules. That is, the mixture may be tableted with a tablet press and molded into a tablet form, or the mixture may be filled into an empty capsule and molded into a capsule form. At this time, additives may be added to the mixture. Additives can be diluents, disintegrants, binders, colorants and/or glidants. That is, after adding additives to the mixture, it may be tableted or filled.

At this time, the moisture content of the granules is preferably 4% or less, and the moisture content of parts other than the granules (eg, the part containing levocetirizine or a pharmaceutically acceptable salt thereof) is preferably 2% or less, more preferably It may be less than 1%. In addition, the water content of the pharmaceutical preparation may be preferably 3% or less, more preferably 2% or less. At this moisture content, the formulation may be more stable. This is because excessive moisture contained in the formulation continuously induces the production of degradation products, and thus the stability of the formulation may be deteriorated.

As described above, the manufacturing method according to an embodiment of the present invention can be achieved by a simple process of molding a mixture containing montelukast sodium and an organic acid salt into granules, mixing montelukast sodium and an organic acid salt with the granules, and then selectively tableting or filling the mixture. , stability and dissolution properties can be prepared.

The pharmaceutical preparation according to an embodiment of the present invention is not limited thereto, but may preferably be in the form of a solid preparation for oral use such as a tablet or capsule, and more preferably in the form of a tablet. The tablet may preferably be a monolayer tablet. A single-layered tablet may be a round tablet with the same ratio of the major axis to the minor axis, or an oval or rectangular tablet with different ratios of the major axis and the minor axis. In the case of circular tablets, the ratio of diameter (major axis or minor axis) to thickness is preferably 1:0.2 to 1:0.8 in the form of a cylinder. If the diameter-to-thickness ratio is less than 1:0.2, the thickness of the tablet is too thin and it may be difficult to secure sufficient hardness. If the diameter-to-thickness ratio exceeds 1:0.8, the tablet will roll in a shape close to a sphere when manufacturing and dispensing. There is a concern that it is difficult to handle due to the thinning phenomenon. A tablet made of such a single layer is more preferable because it can simplify the manufacturing process. It is preferable to form a film coating layer on the prepared tablet. The polymer used herein may be a conventional polymer capable of forming a film coating layer, and the amount is preferably kept to a minimum to provide an optimal formulation size and to effectively manufacture, based on the total weight of the formulation. It may be about 1 to 20% by weight, preferably about 1 to 10% by weight, more preferably about 2 to 5% by weight. Coating may be carried out according to a conventional coating method, and it is preferable to apply the coating using a general method used for tablet coating. That is, the tablets may be manufactured in the form of uncoated tablets without a coating layer or in the form of coated tablets with a coating layer formed on the surface. The coating layer may include a coating material, and the coating material may include, for example, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or a mixture thereof. can be The coating agent may be used in an amount of 1 to 20% by weight based on the total weight of the tablet.

In addition, the pharmaceutical formulation according to one embodiment of the present invention may include a colorant as a pharmaceutically acceptable additive. The colorant is an additive for displaying colors such as white, yellow, pink, and red, and may be added when forming granules, added when mixing with levocetirizine or a pharmaceutically possible salt thereof, and/or added when forming a coating layer. can be added to tablets. Examples of the colorant include, but are not limited to, titanium dioxide or iron oxide-based pigments such as red iron oxide, yellow iron oxide, and black iron oxide, or lake-based pigments such as blue aluminum lake, yellow aluminum lake, and red aluminum lake, or mixtures thereof, All colorants that can be used as pharmaceutical additives can be used. The colorant may play a role in increasing the value of the final product by controlling the properties in various ways. The colorant may be from about 0.01 to about 10 weight percent, preferably from about 0.05 to about 1 weight percent, based on the total weight of the formulation.

A pharmaceutical formulation according to an embodiment of the present invention may include a diluent as a pharmaceutically acceptable additive. Examples of suitable diluents include mannitol, microcrystalline cellulose, lactose (including hydrated form), calcium dihydrogen phosphate, starch, low-substituted hydroxypropylcellulose, or mixtures thereof. The diluent may be in an amount of about 1 to about 99% by weight, preferably about 5 to about 95% by weight, based on the total weight of the formulation.

In addition, the pharmaceutical formulation may further include, for example, a disintegrant, a binder, and/or a lubricant as pharmaceutically acceptable additives.

The disintegrant may be specifically sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, starch, alginic acid or a sodium salt thereof, or a mixture thereof. The disintegrant may preferably be sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, or a mixture thereof. The disintegrant may be in an amount of 0.5 to 30% by weight, preferably 1 to 20% by weight, based on the total weight of the formulation.

The binder may be specifically hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone, copovidone, macrogol, or a mixture thereof. The binder may be in an amount of 0.5 to 30% by weight, preferably 0.9 to 20% by weight, based on the total weight of the formulation.

The lubricant is specifically stearic acid, stearic acid metal salts such as calcium stearate or magnesium stearate, talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable oil, high melting point wax, glyceryl fatty acid esters, glycerol di behenate, or mixtures thereof. The glidant may be in an amount of 0.3 to 5% by weight, preferably 0.5 to 3% by weight, based on the total weight of the formulation.

The pharmaceutical preparation, which is an embodiment of the present invention, has easy dissolution. For example, in an in vitro dissolution test, the dissolution rate is 80% or more within 20 minutes based on montelukast in 0.5% SLS eluate, and 30 minutes based on levocetirizine in purified water eluate. It may be more than 80% within.

In order to avoid repetition, overlapping contents are not described, but the matters mentioned in each of the manufacturing method and pharmaceutical preparation, which are an embodiment of the present invention, are applied to each of the contents of the same scope unless they contradict each other.

Hereinafter, the present invention will be described in more detail through Examples, Comparative Examples, and Experimental Examples. The materials used in the following Examples, Comparative Examples, and Experimental Examples were of the highest quality available on the market.

<Examples 1 to 9> Tablet preparation

<Example 1> Tablet

Montelukast Sodium 10.4 mg (10 mg as Montelukast)

D-Mannitol 200.0 mg

Croscarmellose Sodium 5.0 mg

Sodium Citrate 5.0 mg

Hydroxypropylcellulose 4.0 mg

Levocetirizine Dihydrochloride 5.0 mg

Magnesium Stearate 2.0 mg

Purified water (30.0 mg)

Montelukast sodium, D-mannitol, croscarmellose sodium and sodium citrate were put in a high shear mixer (High Shear Mixer), mixed well, and hydroxypropyl cellulose dissolved in purified water was used as a binding solution and kneaded for 5 minutes. After drying, the obtained granules are sized through a 16 mesh sieve. After adding levocetirizine dihydrochloride to the obtained sized product and mixing in a V-Mixer for 15 minutes, magnesium stearate was added and final mixing was further conducted for 5 minutes. The obtained final mixture was compressed into tablets using a circular punch having a diameter of 7.5 mm. The appearance of the tablet thus prepared was white.

<Example 2> Tablet

Tablets were prepared in the same manner as in Example 1, except that the amount of sodium citrate used was 10 mg. The appearance of the tablet thus prepared was white.

<Example 3> Tablet

Tablets were prepared in the same manner as in Example 1, except that sodium starch glycolate was used instead of croscarmellose sodium. The appearance of the tablet thus prepared was white.

<Example 4> Tablet

Tablets were prepared in the same manner as in Example 1, except that sodium lactate was used instead of sodium citrate. The appearance of the tablet thus prepared was white.

<Example 5> Tablet

Montelukast Sodium 5.2 mg (5 mg as Montelukast)

Lactose monohydrate 200.0 mg

Sodium Citrate 5.0 mg

Hydroxypropylcellulose 4.0 mg

Levocetirizine Dihydrochloride 5.0 mg

Magnesium Stearate 2.0 mg

Purified water (30.0 mg)

Put montelukast sodium, lactose hydrate and sodium citrate in a high shear mixer and mix them well. After mixing hydroxypropyl cellulose in purified water as a binding solution, combine them for 5 minutes and dry them to obtain granules. 16 Establish with a mesh sieve. After adding levocetirizine dihydrochloride to the obtained sized product and mixing in a V-Mixer for 15 minutes, magnesium stearate was added and final mixing was further conducted for 5 minutes. The obtained final mixture was compressed into tablets using a circular punch having a diameter of 7.5 mm. The appearance of the tablet thus prepared was white.

<Example 6> Tablet

Montelukast Sodium 10.4 mg (10 mg as Montelukast)

D-Mannitol 400.0 mg

Croscarmellose Sodium 5.0 mg

Sodium Citrate 5.0 mg

Hydroxypropylcellulose 4.0 mg

Levocetirizine Dihydrochloride 5.0 mg

Magnesium Stearate 4.0 mg

Purified water (30.0 mg)

Montelukast sodium, D-mannitol, croscarmellose sodium and sodium citrate were put in a high shear mixer (High Shear Mixer), mixed well, and hydroxypropyl cellulose dissolved in purified water was used as a binding solution and kneaded for 5 minutes. After drying, the obtained granules are sized through a 16 mesh sieve. After adding levocetirizine dihydrochloride to the obtained sized product and mixing in a V-Mixer for 15 minutes, magnesium stearate was added and final mixing was further conducted for 5 minutes. Tablets were prepared by tableting the obtained final mixture using a circular punch having a diameter of 9 mm. The appearance of the tablet thus prepared was white.

<Example 7> Tablet

Montelukast Sodium 10.4 mg (10 mg as Montelukast)

D-Mannitol 200.0 mg

Croscarmellose Sodium 5.0 mg

Sodium Citrate 3.0 mg

Hydroxypropylcellulose 4.0 mg

Sodium Citrate 2.0 mg

Red iron oxide 1.0 mg

Purified water (30.0 mg)

Levocetirizine Dihydrochloride 5.0 mg

D-Mannitol 20.0 mg

Magnesium Stearate 2.0 mg

After putting montelukast sodium, D-mannitol (200.0 mg), croscarmellose sodium, sodium citrate (3.0 mg), hydroxypropyl cellulose and red iron oxide in a high shear mixer and mixing well, sodium citrate (2.0 mg) in purified water is used as a binding solution, kneaded for 5 minutes, dried, and the obtained granules are sized through a 16 mesh sieve. Levocetirizine dihydrochloride and D-mannitol (20.0 mg) were added to the obtained sized product, mixed in a V-Mixer for 15 minutes, and then magnesium stearate was added and final mixing was further conducted for 5 minutes. The obtained final mixture was compressed into tablets using a circular punch having a diameter of 7.5 mm. The tablet thus prepared exhibited a pink color.

<Example 8> Tablet

Tablets were prepared in the same manner as in Example 7, except that the amount of red iron oxide used was 3.0 mg. The properties of the tablet thus prepared exhibited a red color.

<Example 9> Tablet

Montelukast Sodium 10.4 mg (10 mg as Montelukast)

D-Mannitol 200.0 mg

Croscarmellose Sodium 5.0 mg

Sodium Citrate 5.0 mg

Hydroxypropylcellulose 4.0 mg

Levocetirizine Dihydrochloride 5.0 mg

Magnesium Stearate 2.0 mg

Purified water (30.0 mg)

Hypromellose 3.0 mg

Hydroxypropylcellulose 2.0 mg

Titanium dioxide 1.5 mg

Red iron oxide 0.1 mg

Purified water (60.0 mg)

After producing white tablets in the same manner as in Example 1, hypromellose and hydroxypropyl cellulose (2.0 mg) were dissolved in purified water (60.0 mg), and titanium dioxide and red iron oxide were added to disperse the solution. The coating solution was film-coated using a tablet coater to prepare pink film-coated tablets.

<Comparative Examples 1 to 3> Tablet manufacture

Formulations without applying organic acid salts (Comparative Example 1, Comparative Example 3) and formulations using organic acids instead of organic acid salts (Comparative Example 2) were prepared as follows.

<Comparative Example 1> Tablet

Montelukast Sodium 10.4 mg (10 mg as Montelukast)

Levocetirizine Dihydrochloride 5.0 mg

D-Mannitol 100.0 mg

Lactose monohydrate 100.0 mg

Hydroxypropylcellulose 4.0 mg

Magnesium Stearate 2.0 mg

Purified water (30.0 mg)

Montelukast sodium, levocetirizine dihydrochloride, D-mannitol, and lactose hydrate were put into a high shear mixer (High Shear Mixer), mixed well, and hydroxypropyl cellulose dissolved in purified water was used as a binding solution and kneaded for 5 minutes. After drying, the obtained granules are sized through a 16 mesh sieve. Magnesium stearate was added to the obtained sized product, and final mixing was further performed for 5 minutes. The obtained final mixture was compressed into tablets using a circular punch having a diameter of 7.5 mm. The properties of the tablets thus prepared were found to be yellow.

<Comparative Example 2> Tablet

Montelukast Sodium 10.4 mg (10 mg as Montelukast)

Levocetirizine Dihydrochloride 5.0 mg

Lactose monohydrate 200.0 mg

Croscarmellose Sodium 5.0 mg

Citric acid 5.0 mg

Hydroxypropylcellulose 4.0 mg

Magnesium Stearate 2.0 mg

Purified water (30.0 mg)

After putting montelukast sodium, levocetirizine dihydrochloride, lactose hydrate and citric acid in a high shear mixer and mixing well, use a solution of hydroxypropyl cellulose dissolved in purified water as a binding solution, mix for 5 minutes and dry The resulting granules are sized through a 16 mesh sieve. After adding croscarmellose sodium to the obtained sized product and mixing in a V-Mixer for 15 minutes, magnesium stearate is added and final mixing is further performed for 5 minutes. The obtained final mixture was compressed into tablets using a circular punch having a diameter of 7.5 mm. The appearance of the tablet thus prepared was a fluorescent yellow color.

<Comparative Example 3> Tablet

Montelukast Sodium 10.4 mg (10 mg as Montelukast)

Levocetirizine Dihydrochloride 5.0 mg

D-Mannitol 100.0 mg

Lactose monohydrate 100.0 mg

Microcrystalline Cellulose 100.0 mg

Croscarmellose Sodium 5.0 mg

Hydroxypropylcellulose 4.0 mg

Magnesium Stearate 3.0 mg

After mixing montelukast sodium, levocetirizine dihydrochloride, D-mannitol, lactose hydrate, microcrystalline cellulose, croscarmellose sodium and hydroxypropyl cellulose in a V-Mixer for 15 minutes, add magnesium stearate and further mix for 5 minutes. do. The obtained final mixture was compressed into tablets using a circular punch having a diameter of 7.5 mm.

<Experiment 1> Appearance confirmation test

The tablets of Examples 1 to 3 and Comparative Examples 1 to 2 were photographed with a camera. The results are shown in FIG. 2 . 2 is a photograph showing an embodiment of the present invention and a comparative example. As shown in Figure 2, it can be seen that the tablets of Examples exhibit a white color, but the tablets of Comparative Examples exhibit a yellow to fluorescent yellow color. From these results, it can be seen that the tablets of Comparative Example show a change in properties, but the Examples show no change in appearance. Therefore, it can be seen that the formulation of the present invention shows little change in properties, and such a formulation can be easily prepared by the preparation method of the present invention.

<Experiment 2> Dissolution test

Dissolution tests were performed on the tablets obtained in Examples 1 to 2 and Comparative Examples 1 to 3 according to the FDA-recommended dissolution test method.

The dissolution test of montelukast was performed by the paddle method (stirring speed: 50 rpm) using 900 mL of a 0.5% sodium lauryl sulfate solution as an eluent. Levocetirizine was carried out by the paddle method (stirring speed 50 rpm) using 900 mL of purified water as an eluent. At 5, 10, 15, 20, 30 and 45 minutes after the dissolution test, 3 mL of the sample was taken and supplemented by adding the same amount of the elution solution. Subsequently, the solution obtained from the eluate was filtered through a 0.45 μm membrane filter, and the dissolution rates of montelukast and levocetirizine were analyzed using liquid chromatography under the following conditions.

<Liquid chromatography analysis conditions (Montelukast and Levocetirizine dissolution rate)>

Column: A column filled with 5 μm phenylsilylated silica gel for liquid chromatography in a stainless steel tube with an inside diameter of about 3.0 mm and a length of about 100 mm.

Mobile phase: 0.2% trifluoroacetic acid solution: 0.2% trifluoroacetic acid solution in acetonitrile (55 : 45, v/v)

Detector: Ultraviolet absorbance photometer (measurement wavelength 225 nm)

Flow rate: 1.0 mL/min

Temperature: normal temperature

Injection volume: 10 uL

The dissolution test results are shown in Figures 3 and 4. 3 is a graph showing montelukast dissolution test results for Examples and Comparative Examples of the present invention, and FIG. 4 is a graph showing levocetirizine dissolution test results for Examples and Comparative Examples of the present invention. In FIGS. 3 and 4, the x-axis represents time, and the y-axis represents montelukast dissolution rate (%) and levocetirizine dissolution rate (%), respectively. As shown in Figures 3 and 4, the tablets of Examples 1 and 2 reached a dissolution rate of 80% or more after 10 minutes in the case of montelukast, and a dissolution rate of 80% or more within 5 minutes in the case of levocetirizine. has been shown to have reached On the other hand, the tablets of Comparative Examples 1 to 3 did not reach the dissolution rate of 80% or more, which is the dissolution test standard of the US Pharmacopoeia for general tablets of montelukast, at 20 minutes, and the dissolution rate of montelukast was as low as less than 80% even at 30 minutes. From these results, it can be seen that the formulation of the present invention is easy to dissolve and has excellent dissolution properties.

<Experiment 3> Stability test

The tablets obtained in Examples 1 to 2 and Comparative Examples 2 to 3 were subjected to an accelerated storage test according to the following conditions, and the degree of generation of related substances of montelukast and levocetirizine was evaluated to compare stability. The results are shown in Figures 5 and 6. 5 is a graph showing the test results for related substances derived from montelukast in Examples and Comparative Examples of the present invention, and FIG. 6 is a graph showing the test results for related substances derived from levocetirizine for Examples and Comparative Examples of the present invention. 5 and 6, the x-axis represents the sample, and the y-axis represents the related material content (Impurity%). As shown in FIGS. 5 and 6 , it can be seen that the stability is excellent from the fact that the content of related substances in Examples is very low compared to that of Comparative Examples. Considering that the total amount of related substances in the general tablet of montelukast of the US Pharmacopoeia is 3.0% or less and the total amount of related substances in the general tablet of levocetirizine is 1.0% or less, Examples 1 and 2 are all within the standard for related substances for each single tablet. Although the degree of generation of substances was very low, Comparative Examples 2 to 3 showed a high degree of generation of related substances, exceeding the limit of related substances for each single tablet at the time of acceleration of 2 months. From these results, it can be seen that the formulation of the present invention has excellent stability.

<Accelerated Storage Test Conditions>

Storage conditions: Packed in HDPE bottles at 40℃ and 75% relative humidity

Test time: initial, 2 months

Analysis target: montelukast and related substances derived from montelukast,

Levocetirizine and related substances derived from levocetirizine

<Analysis Conditions for Montelukast and Related Substances Originating from Montelukast>

Column: A column filled with phenylsilylated silica gel for liquid chromatography with a particle size of 5 μm in a stainless steel tube with an inside diameter of about 4.6 mm and a length of 10 cm.

Mobile phase: A - 0.2% (v/v) trifluoroacetic acid solution

B - 3 : 2 (v/v) mixture of methanol and acetonitrile

Mobile phase elution conditions time (minutes) A(%) B(%) 0 48 52 5 45 55 12 45 55 22 25 75 23 25 75 25 48 52 30 48 52

Detector: UV absorbance photometer (measurement wavelength 255 nm)

Flow rate: 1.5 mL/min

Column temperature: 50℃

<Analysis Conditions for Levocetirizine and Related Substances Originating from Levocetirizine>

Column: A stainless steel tube with an inside diameter of about 4.6 mm and a length of 25 cm filled with high-purity silica gel for liquid chromatography with a particle size of 5 μm.

Mobile phase: Acetonitrile: Purified water: 1M sulfuric acid = 93: 6.6: 0.4 (v/v/v) mixture

Detector: UV absorbance photometer (measurement wavelength 230 nm)

Flow rate: 1.0 mL/min

Column temperature: 30℃

Analysis time: 30 minutes

From the above experimental results, it can be seen that the pharmaceutical preparation of the present invention has an effect of excellent dissolution of the active ingredient, securing stability, and excellent productivity. In addition, it can be seen that the production method of the present invention can easily prepare a pharmaceutical preparation having excellent dissolution of active ingredients, securing stability, and excellent productivity.

Claims (12)

It is an oral solid dosage form consisting of a tablet containing levocetirizine or a pharmaceutically acceptable salt thereof, montelukast sodium, and an organic acid salt,
Based on 100 parts by weight of montelukast sodium as montelukast, the organic acid salt is 50 to 100 parts by weight,
The montelukast sodium is formed into granules together with the organic acid salt,
The granules are molded by adding pharmaceutically acceptable additives,
The additives include diluents, disintegrants, and binders,
The granules containing montelukast sodium and the organic acid salt and the levocetirizine or a pharmaceutically acceptable salt thereof are mixed together and included in one layer,
The tablet is a single-layer tablet,
The organic acid salt is a pharmaceutical preparation of sodium citrate. delete delete delete delete delete delete delete delete delete The pharmaceutical formulation of claim 1, wherein the tablet comprises 5 to 95% by weight of the diluent, 1 to 20% by weight of the disintegrant, and 0.9 to 20% by weight of the binder, based on the total weight. The method of claim 1, wherein the diluent included in the additive is mannitol, microcrystalline cellulose, lactose, calcium dihydrogen phosphate, starch, low-substituted hydroxypropyl cellulose, or a mixture thereof, and the disintegrant included in the additive is sodium starch glycolate, croscarmellose sodium, alginic acid or a sodium salt thereof, or a mixture thereof, and the binder included in the additive is hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, copovidone , macrogol, or a pharmaceutical agent that is a mixture thereof.

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