HK40100310A - Film-coated tablet with improved stability containing montelukast or pharmaceutically acceptable salt thereof and levocetirizine or pharmaceutically acceptable salt thereof - Google Patents

Description

Film-coated tablets with improved stability containing montelukast or a pharmaceutically acceptable salt thereof and levocetirizine or a pharmaceutically acceptable salt thereof.

Technical Field

This invention relates to a combination formulation comprising montelukast and levocetirizine, and more particularly to a tablet comprising montelukast and levocetirizine in a non-contact state.

Technical Background

Montelukast is a leukotriene antagonist and an inhibitor of leukotriene biosynthesis. US5565473 discloses the use of montelukast in the following diseases: lung diseases such as asthma, bronchitis and related obstructive airway diseases; allergic reactions such as allergic rhinitis, contact dermatitis, allergic conjunctivitis, etc.; inflammation such as arthritis or inflammatory bowel disease, etc.; pain; skin diseases such as psoriasis, atopic dermatitis, etc.; and cardiovascular diseases such as angina pectoris, myocardial ischemia, hypertension, platelet aggregation, etc.

Cetirizine is a second-generation _H1 histamine receptor antagonist that offers advantages over first-generation antihistamines in its racemic state. US 5698558 discloses that administration of pure optically active (-) cetirizine, namely levocetirizine, can reduce or avoid side effects associated with the use of racemic cetirizine, including sedation, drowsiness, headache, gastrointestinal disturbances, dizziness, nausea, arrhythmias, and other cardiovascular effects.

Numerous studies have reported that when these leukotriene inhibitors are used in combination with cetirizine, they provide a synergistic effect for the treatment or prevention of inflammatory, asthmatic, or allergic conditions. Furthermore, there are reports that this combination therapy can reduce the side effects associated with _H1 histamine receptor antagonists.

Therefore, although combination formulations containing montelukast sodium and levocetirizine hydrochloride are being developed, drug interactions between montelukast sodium and levocetirizine hydrochloride have been reported, and various dosage forms are being investigated to address this issue.

As an example, there are reports of capsule formulations prepared by separately tableting montelukast sodium and levocetirizine hydrochloride and then filling them into capsules, which are currently in clinical use. However, these formulations involve complex manufacturing processes, requiring tableting followed by capsule filling. Therefore, there is a need to develop combination formulations that minimize drug interactions between montelukast sodium and levocetirizine hydrochloride and can be prepared using more efficient methods.

Content of the invention

The technical problem that the invention aims to solve

The problem to be solved by the present invention is to provide a combination formulation that minimizes the drug interaction between montelukast and levocetirizine and is prepared in a more efficient manner.

Furthermore, the problem to be solved by the present invention is to provide a method for preparing the compound preparation.

The problems to be solved by the present invention are not limited to those mentioned above. Those skilled in the art can clearly understand other unmentioned technical problems through the following description.

Technical solutions for solving the problem

To address the aforementioned technical problem, according to one aspect of the present invention, a tablet is provided, comprising: a first drug layer containing montelukast or a pharmaceutically acceptable salt thereof; a second drug layer containing levocetirizine or a pharmaceutically acceptable salt thereof; an inner layer contacting the first drug layer on one side and the second drug layer on the other side, such that the first drug layer and the second drug layer do not contact each other; and an outer layer comprising the first drug layer, the inner layer, and the second drug layer.

In one embodiment, a triple-coated tablet is provided, comprising: a core containing montelukast sodium; a drug coating layer containing levocetirizine hydrochloride; an endothelial coating layer that contacts the core on one side and the drug coating layer on the other side, such that the core and the drug coating layer do not contact each other; and an outer coating layer that includes the core, the endothelial coating layer, and the drug coating layer.

According to another aspect of the present invention, a method for preparing a tablet is provided, comprising: step (a) preparing a first drug layer comprising montelukast or a pharmaceutically acceptable salt thereof; step (b) preparing an inner layer surrounding the first drug layer; step (c) preparing a second drug layer comprising levocetirizine or a pharmaceutically acceptable salt thereof and surrounding the inner layer; and step (d) preparing an outer layer surrounding the second drug layer.

The effects of the invention

According to the present invention, the two drugs, montelukast and levocetirizine, are contained in a single tablet and do not come into contact through the boundary layer of the endothelial layer (e.g., the coating layer). In this case, it has been confirmed that both drugs remain stable under harsh and accelerated storage conditions, and the formation of related substances does not change significantly, regardless of whether the drug coating layer contains organic acids as acidifying agents. Even with changes in the coating matrix, the formation of related substances does not change significantly. Furthermore, dissolution tests confirm that the main components (montelukast and levocetirizine) contained in the coated tablets of the prepared two-drug combination tablets are within suitable ranges.

Therefore, the montelukast and levocetirizine of the present invention, which are present in a single tablet and do not come into contact through the boundary layer, can minimize drug interactions in the pharmaceutical field and can be prepared in an efficient manner, and can be usefully used as a combination formulation.

It should be understood that the effects of the present invention are not limited to those described herein, but include all effects that can be inferred from the composition of the present invention as set forth in the specification or claims of the present invention.

Attached Figure Description

Figure 1 is a schematic diagram showing the structure of the tablet of the present invention.

Figures 2a to 2d are graphs showing the dissolution test results of levocetirizine hydrochloride in water (Figure 2a), a first solution (pH 1.2) (Figure 2b), a pH 4.0 solution (Figure 2c), and a second solution (pH 6.8) (Figure 2d).

Figures 3a to 3d are graphs showing the dissolution test results of sodium montelukast in water (Figure 3a), a first solution (pH 1.2) (Figure 3b), a pH 4.0 solution (Figure 3c), and a second solution (pH 6.8) (Figure 3d) [each containing 0.5% sodium lauryl sulfate (SLS)].

Detailed Implementation

The present invention provides a tablet and a method for preparing the same, the tablet comprising: a first drug layer containing montelukast or a pharmaceutically acceptable salt thereof; a second drug layer containing levocetirizine or a pharmaceutically acceptable salt thereof; an inner layer in contact with the first drug layer on one side and with the second drug layer on the other side, such that the first drug layer and the second drug layer do not contact each other; and an outer layer comprising the first drug layer, the inner layer, and the second drug layer.

In one embodiment of the present invention, the montelukast or a pharmaceutically acceptable salt thereof may be montelukast sodium, and the levocetirizine or a pharmaceutically acceptable salt thereof may be levocetirizine hydrochloride.

Preferably, as shown in FIG1, the tablet of the present invention has a coated tablet structure comprising a core and three coating layers, wherein the three coating layers are a first endothelial coating (sub-coating), a second drug coating (coating with levocetirizine hydrochloride), and a third outer coating (final coating).

In one embodiment of the present invention, as shown in FIG1, the first drug layer containing the montelukast (first drug) may be a tablet core containing montelukast sodium.

In one embodiment, the core may further comprise at least one additive selected from excipients, disintegrants, and lubricants. The excipients may comprise at least one selected from lactose, microcrystalline cellulose, and mannitol; the disintegrants may comprise at least one selected from croscarmellose sodium and croscarmellose; and the lubricant may comprise at least one selected from colloidal silica, talc, and magnesium stearate, but is not limited thereto.

In one embodiment, the tablet may contain 2 to 10 weight percent of the first drug, 40 to 70 weight percent of the excipient, 5 to 20 weight percent of the disintegrant, and 1 to 5 weight percent of the lubricant, relative to the total weight of the tablet.

In one embodiment, as shown in FIG1, the second drug layer containing the levocetirizine (second drug) may be a drug coating layer containing levocetirizine hydrochloride.

In one embodiment, the drug coating layer may comprise a coating agent. The coating agent may be a coating agent comprising a polyvinyl alcohol (PVA)-polyethylene glycol (PEG) copolymer or a coating agent comprising hydroxypropyl methylcellulose (HPMC), but is not limited thereto.

The coating agent comprising polyvinyl alcohol (PVA)-polyethylene glycol (PEG) copolymer may further comprise at least one component selected from talc, glyceryl monocapryloyl caprate, and polyvinyl alcohol. The coating agent may be commercially available, such as Opadry QX, but is not limited thereto.

The coating agent containing hydroxypropyl methylcellulose (HPMC) may use, but is not limited to, commercially available hydroxypropyl methylcellulose (HPMC)-based coating matrices.

In one embodiment, the second drug may be contained in a weight percentage of 1 to 5 weight percentage relative to the total weight of the tablet.

In one embodiment, the inner layer may be a coating layer. The coating layer serving as the inner layer may contain at least one coating agent selected from, but is not limited to, a coating agent comprising a polyvinyl alcohol (PVA)-polyethylene glycol (PEG) copolymer, a coating agent comprising hydroxypropyl methylcellulose (HPMC), and a coating agent comprising polyvinyl alcohol (PVA).

The descriptions of the coating agents containing polyvinyl alcohol (PVA)-polyethylene glycol (PEG) copolymers and the coating agents containing hydroxypropyl methylcellulose (HPMC) are the same as those described above.

The coating agent containing polyvinyl alcohol (PVA) can use commercially available Opadry AMB II coating matrix, but is not limited to it.

In one embodiment, the outer layer may be a coating layer. The coating layer, as the outer layer, may contain a coating agent comprising a polyvinyl alcohol (PVA)-polyethylene glycol (PEG) copolymer or a coating agent comprising hydroxypropyl methylcellulose (HPMC), but is not limited thereto.

The description of the coating agent containing polyvinyl alcohol (PVA)-polyethylene glycol (PEG) copolymer is the same as described above.

The coating agent containing hydroxypropyl methylcellulose (HPMC) may also contain at least one component selected from titanium dioxide, talc, and polyethylene glycol 400, and may also contain a pigment component such as iron oxide yellow. The coating agent may use commercially available coating matrices based on Opadry hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose (HPMC) based materials such as Tabshield Yellow, but is not limited thereto.

Regarding the coating agents used in each layer, relative to the total weight of the tablet, the total amount of the coating agent contained in the inner coating layer, the drug coating layer contained in the second drug layer, and the coating agent contained in the outer coating layer can be from 10% to 30% by weight, and can be appropriately distributed in the inner coating layer (first coating), the drug coating layer (second coating) of the second drug layer, and the outer coating layer (third coating).

In addition to excipients, disintegrants, lubricants and coating agents, the tablets may contain other additives as needed, with the content of other additives being no more than 20% by weight relative to the total weight of the tablets.

According to a preferred embodiment, the present invention provides a triple-coated tablet, comprising: a tablet core containing montelukast sodium; a drug coating layer containing levocetirizine hydrochloride; an endothelial coating layer that contacts the tablet core on one side and the drug coating layer on the other side, such that the tablet core and the drug coating layer do not contact each other; and an outer coating layer that comprises the tablet core, the endothelial coating layer, and the drug coating layer.

Furthermore, the present invention also provides a method for preparing the tablet of the present invention. The method for preparing the tablet includes: step (a), preparing a first drug layer comprising montelukast or a pharmaceutically acceptable salt thereof; step (b), preparing an inner layer surrounding the first drug layer; step (c), preparing a second drug layer comprising levocetirizine or a pharmaceutically acceptable salt thereof and surrounding the inner layer; and step (d), preparing an outer layer surrounding the second drug layer.

Step (a) is the preparation of a first drug layer comprising montelukast or a pharmaceutically acceptable salt thereof, which may be achieved using a combination of a first drug (preferably montelukast sodium) and appropriate additives, employing wet granulation or direct compression. The prepared first drug layer may be referred to as the tablet core or core.

Step (b) is the step of preparing the inner layer surrounding the first drug layer. After preparing a coating solution by mixing a suitable coating agent and purified water, the first drug layer (tablet core) containing the first drug (preferably montelukast sodium) is coated, thereby preparing the first coating layer (inner layer) to isolate the tablet core from the outside. The intermediate product prepared can be called an endothelial coated tablet.

Step (c) is the step of preparing a second drug layer containing levocetirizine or a pharmaceutically acceptable salt thereof and surrounding the inner layer. After preparing a coating solution by mixing the second drug (preferably levocetirizine hydrochloride), a suitable coating agent and purified water, the endothelial-coated tablet after the first coating is coated, thereby preparing a double-coated tablet (endothelial + drug coating) in which the first drug (preferably montelukast sodium) as the main component in the core and the second drug (preferably levocetirizine hydrochloride) as the drug coating layer (second drug layer) are separated.

Step (d) is the step of preparing an outer layer surrounding the second drug layer. After preparing a coating solution using a suitable coating agent and purified water, the double-coated tablet is coated, thereby preparing a third coating layer (outer layer) to isolate the second drug (preferably levocetirizine hydrochloride) of the drug coating layer from the outside.

The present invention will now be described in more detail through examples and test cases. However, the following examples and test cases are intended to illustrate the invention, and the scope of the invention is not limited thereto.

<Example>

Examples 1 and 2: Preparation of compound tablets with isolated main components I

Table 1

For the montelukast-containing layers shown in Table 1, wet granules were prepared using the ingredients other than the disintegrant (crosslinked sodium carboxymethyl cellulose) and lubricant (colloidal silica and magnesium stearate). The remaining ingredients were then mixed, passed through a 25-mesh sieve, and then the prepared granules were processed into tablets (cores) containing only montelukast using a circular punch with a diameter of Φ7.5.

To prepare a compound tablet containing the main ingredient montelukast mentioned above, as well as levocetirizine hydrochloride, the following coating process was performed, and the specific details of the preparation are as follows.

In Example 1, all coating layers used a coating agent based on a polyvinyl alcohol (PVA)-polyethylene glycol (PEG) copolymer. A coating solution was prepared using Opadry QX clearing and purified water as described in the endothelial coating layer to endothelially coat montelukast tablets (core), thus preparing a single-use coated tablet (endothelial coating) with the main ingredient montelukast separated from the external barrier.

To enable a continuous process, a coating solution is prepared during the endothelial coating process using levocetirizine hydrochloride, Opadry QX clearing agent, and purified water as described in the drug coating layer. The prepared drug coating solution is then used to coat the endothelial-coated tablets, thereby preparing a double-coated tablet (endothelial + drug coating) in which the main component montelukast in the core and levocetirizine hydrochloride in the drug coating layer are separated.

An outer coating is performed to isolate the outermost drug coating layer of the double-coated tablet from the outside. Similarly, for continuous processing, an outer coating solution is prepared using Opadry QX Yellow and purified water as described in the outer coating layer of Example 1, and then the outer coating is performed, thereby preparing a triple-coated tablet (endothelium + drug + outer coating) in which the two main components exist independently within a single tablet. In the case of Example 2, all coating layers use an Opadry hydroxypropyl methylcellulose (HPMC)-based coating agent, prepared in the same manner as in Example 1.

Examples 3 to 5: Preparation of compound tablets with isolated main components II

Table 2

For the montelukast-containing layers shown in Table 2, wet granules were prepared using the same method as in Table 1, and tablets (cores) containing only montelukast were prepared using a circular punch with a diameter of Φ7.5.

To prepare a compound tablet containing levocetirizine hydrochloride alone, the following coating process was performed, and the preparation details are as follows.

For the endothelial coating layer, a coating solution was prepared using Opadry AMBII white based on polyvinyl alcohol (PVA) and purified water to endothelially coat montelukast tablets (core) to prepare single-use coated tablets (endothelial coating).

For the drug coating layer, a coating solution was prepared using levocetirizine hydrochloride, hydroxypropyl methylcellulose (HPMC)-based Opadryl clearing agent, and purified water. Examples 4 and 5 additionally used 1.0 mg and 3.0 mg of citric acid, respectively, as acidifying agents. The prepared drug coating solution was used for drug coating to prepare double-coated tablets (endothelium + drug coating) in which the main component montelukast in the core and levocetirizine hydrochloride in the drug coating layer were separated.

An outer coating is performed to isolate the outermost drug coating layer of the double-coated tablet from the outside. The coating solution is prepared using Tabshield Yellow based on hydroxypropyl methylcellulose (HPMC) and 70% ethanol, as described in the outer coating layers of each embodiment, and the outer coating is then performed.

Examples 6 and 7: Preparation of compound tablets with isolated main components III

Table 3

The components and amounts of the montelukast-containing layer and outer coating layer in Examples 6 and 7 shown in Table 3 are almost the same or similar to those in Examples 3 to 5 shown in Table 2, and the preparation methods are also almost the same.

In Example 6, the coating matrix of the endothelial coating layer in Example 5 was changed to Opadry QX White based on polyvinyl alcohol (PVA)-polyethylene glycol (PEG) copolymer. In Example 7, the acidifier of the drug coating layer in Example 6 was changed to acetic acid.

Examples 8 to 11: Preparation of compound tablets with isolated main components IV

Table 4

The montelukast-containing layers and endothelial coatings of Examples 8 to 11 shown in Table 4 have almost identical compositions and were prepared by almost the same preparation method as Examples 3 to 7 shown in Tables 2 and 3.

In Example 8, the main components of the drug coating layer were levocetirizine hydrochloride, Opadry QX clearing agent, and purified water. The outer coating layer used Opadry QX whitening agent and purified water. All coating layers used Opadry QX based on polyvinyl alcohol (PVA)-polyethylene glycol (PEG) copolymer as the coating matrix.

In Example 9, acetic acid was further added to the drug coating layer of Example 8 to increase the amount of Opadry QX white in the outer coating layer.

In Example 10, the drug coating layer of Example 8 was prepared in the same manner, with a reduced amount of Opadry QX white in the outer coating layer, including a final coating layer containing Tabshield Yellow based on hydroxypropyl methylcellulose (HPMC) and 70% ethanol.

In Example 11, the drug coating layer of Example 8 was prepared in the same way, except that the outer coating layer was changed to Tabshield Yellow and 70% ethanol.

Examples 12-13: Preparation of compound tablets with isolated main components V

Table 5

Compared with the examples in Tables 1 to 4, Examples 12 and 13 shown in Table 5 contain different components and preparation methods for the montelukast layer. First, the components other than the lubricant (talc and magnesium stearate) are mixed, and then the remaining components are mixed. The mixture is passed through a 25-mesh sieve, and then the prepared granules are made into tablets (cores) containing only montelukast by direct compression using a circular punch with a diameter of Φ7.5.

Subsequently, a coating process similar to that in Example 11 was performed to prepare a combination tablet containing montelukast and levocetirizine hydrochloride. Both the endothelial coating and the drug coating layer used Opadry QX clear water and purified water as the coating matrix, based on a polyvinyl alcohol (PVA)-polyethylene glycol (PEG) copolymer, while the outer coating layer used Tabshield Yellow and 70% ethanol as the coating matrix.

Comparative Example 1: Preparation of compound tablets in which the main components are not separated I

Table 6

In Comparative Example 1 shown in Table 6, one of the main components, montelukast and levocetirizine hydrochloride, was first mixed with all components except for the lubricants (talc and magnesium stearate), and then the remaining components were mixed. The mixture was passed through a 25-mesh sieve, and then the prepared granules were processed into compound tablets (core) containing montelukast and levocetirizine hydrochloride using a circular punch with a diameter of Φ7.5. Subsequently, Tabshield Yellow based on hydroxypropyl methylcellulose (HPMC) was used as the coating matrix, and a coating solution was prepared using 70% ethanol. Coating was performed only once (outer coating).

Comparative Example 2: Preparation of Compound Tablets Where the Main Components Are Not Separated II

Table 7

In Comparative Example 2 shown in Table 7, montelukast, one of the main components, was first mixed with all components except lubricants (talc and magnesium stearate), followed by the remaining components. The mixture was then passed through a 25-mesh sieve and prepared into tablets (core) containing only montelukast using a Φ7.5 diameter circular press via direct compression. Subsequently, without physical separation of the inner lining, a drug coating containing levocetirizine hydrochloride was performed to prepare a compound tablet in which the two main components are present in each layer but at their boundaries. Afterward, a coating solution was prepared using TabshieldYellow based on hydroxypropyl methylcellulose (HPMC) and 70% ethanol as the coating matrix, and the outer lining was coated.

Test Example 1: Severe Storage Stability Test

Severe storage stability tests were conducted on the montelukast sodium and levocetirizine hydrochloride combination tablets obtained in Examples 1 to 13 and Comparative Examples 1 to 2 under the following conditions, and the stability was evaluated by comparing the related substances levels of montelukast sodium and levocetirizine hydrochloride. The results are shown in Tables 11 to 12 below.

[Severe storage stability test conditions]

- Trial period: Initial and severe 1 month

Storage conditions: 60℃

-Analysis subject: Related substances caused by montelukast sodium and levocetirizine hydrochloride

[Analytical conditions for related substances of montelukast sodium]

(1) Preparation of test solution

Take 20 or more tablets of this product, cut off 5 tablets, place them in a 100ml brown volumetric flask, add 75% methanol, sonicate for 30 minutes, and stir for 30 minutes to dissolve completely. Label with 75% methanol, centrifuge at 3000rpm for 10 minutes, and filter through a 0.45μm RC filter. Use the resulting solution as the test solution (as montelukast 0.5mg/ml).

(2) Preparation of standard solutions

-Standard solution (1): Accurately weigh 13 mg of montelukast dicyclohexylamine standard, place it in a 100 ml brown volumetric flask, add 75% methanol, sonicate, and label. Accurately take 1 ml of this solution, place it in a 100 ml brown volumetric flask, add 75% methanol, label, centrifuge at 3000 rpm for 10 minutes, and filter through a 0.45 μm RC filter. The resulting solution is used as standard solution (1) (as montelukast 0.001 mg/ml, 0.2% of the test solution).

-Standard solution (2): Accurately weigh 20 mg of sulfoxide impurity standard, place it in a 20 ml brown volumetric flask, add 75% methanol, sonicate, and label (①). Separately, accurately weigh 10 mg of montelukast ketone impurity standard, place it in a 100 ml brown volumetric flask, add 75% methanol, sonicate, and label (②). Accurately take 1 ml of each of solutions ① and ②, place them in a 100 ml brown volumetric flask, add 75% methanol, label, centrifuge at 3000 rpm for 10 minutes, and filter through a 0.45 μm RC filter. The resulting solution is used as standard solution (2) (sulfoxide: 2% of the test solution, ketone: 0.2% of the test solution).

Montelukast Methylstyrene Impurity Standard Solution: Accurately weigh 10 mg of montelukast methylstyrene impurity standard into a 100 mL amber volumetric flask, add 10 mL of DMSO and 75% methanol, sonicate, and label. Accurately transfer 1 mL of this solution into a 100 mL amber volumetric flask, add 75% methanol, and label. Verify the RT (retention time) and calculate from related substances.

(3) Dissolution conditions

Using test solutions and standard solutions, conduct the test according to the following test method, and calculate the content of the relevant substances according to the formula.

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

Mobile phase B: Methanol: Acetonitrile = 3:2

Table 8

Time (minutes) Mobile phase A Mobile phase B 0 48 52 5 45 55 12 45 55 twenty two 25 75 twenty three 25 75 25 48 52 30 48 52

- Column: Luna phenyl-hexyl 4.6 x 100 mm, 3 μm or equivalent column

- Detector: Ultraviolet absorption spectrometer (measurement wavelength: 255nm)

- Flow rate: 1.5 ml/min

- Column temperature: 50℃

-Injection volume: 20 μl

<Calculation Formula 1> [Unknown related substances]

*I_{_t} = Peak area of each relevant substance detected in the test solution

*I_{_s} = Peak area of montelukast detected in the standard solution

*C _{_s} = Concentration of montelukast-dicyclohexylamine standard solution (mg/ml)

* _Cu = Concentration of montelukast in the test solution (mg/ml)

* _Mr1 = Molecular weight of montelukast (586.18)

* _Mr2 = Molecular weight of montelukast dicyclohexylamine (767.50)

*P = Purity (%) of montelukast dicyclohexylamine standard

<Calculation Formula 2> [Known Relevant Substances]

*S _{_t} = Peak area of each known relevant substance detected in the test solution

*S_{_s} = Peak area of each known related substance (sulfoxide impurity, montelukastone impurity, cis-isomer impurity) detected in the standard solutions of each known related substance.

*C _{_s} = Concentration (mg/ml) of each known relevant standard solution.

* _Cu = Concentration of the test solution (mg/ml)

*P = Purity (%) of each known relevant substance standard.

[System Compatibility]

*System compatibility solution: Accurately weigh 13 mg of montelukast dicyclohexylamine standard into a 25 ml amber volumetric flask, add 75% methanol, sonicate, and then label. Accurately transfer 10 ml of this solution into a transparent 10 ml volumetric flask, add 4 μl of hydrogen peroxide, mix thoroughly, and expose to light for at least 4 hours. Under these conditions, some montelukast is converted to the cis-isomer.

*The separation degree between the cis-isomer and montelukast detected in the system compatibility solution should be greater than 1.5.

*When the standard solution is injected repeatedly 6 times, the relative standard deviation should be below 2%.

(4) Information about the substance

Table 9

[Analytical conditions for related substances in levocetirizine hydrochloride]

(1) Preparation of test solution

Place two tablets of this product in a 100ml volumetric flask and add 10% methanol. Sonicate for at least 2 hours, then stir for at least 5 hours and label. Centrifuge the labeled solution at 3000rpm for 20 minutes, filter through a 0.45μm PVDF (PALL) filter, and use the resulting solution as the test solution (0.1mg/ml).

(2) Preparation of standard solutions

- Levocetirizine hydrochloride standard solution

Accurately weigh 12 mg of levocetirizine hydrochloride standard into a 200 mL volumetric flask, add 10% methanol, shake for 5 minutes to dissolve, sonicate for 20 minutes, and label. Accurately transfer 1 mL of this solution into a 200 mL volumetric flask and label with 10% methanol. Filter through a 0.45 μm PVDF (PALL) filter to obtain the levocetirizine hydrochloride standard solution (0.0003 mg/mL).

1-Chlorobenzhydryl piperazine standard solution

Accurately weigh 12 mg of chlorodiphenylmethylpiperazine standard into a 200 mL volumetric flask, add 10% methanol, shake for 5 minutes to dissolve, sonicate for 20 minutes, and label. Accurately transfer 1 mL of this solution into a 20 mL volumetric flask and label with 10% methanol. Filter through a 0.45 μm PVDF (PALL) filter. Use the resulting solution as the chlorodiphenylmethylpiperazine standard solution, confirm the RT (retention time), and exclude it from the relevant substances calculation formula.

Levocetirizine amide standard solution

Accurately weigh 12 mg of levocetirizine amide standard and place it in a 200 mL volumetric flask. Add 10% methanol, shake for 5 minutes to dissolve, sonicate for 20 minutes, and label. Accurately transfer 1 mL of this solution to a 20 mL volumetric flask and label it with 10% methanol. Filter the solution through a 0.45 μm PVDF (PALL) filter. Use the resulting solution as the levocetirizine amide standard solution, confirm the RT (retention time), and exclude it from the relevant substances calculation formula.

(3) Dissolution conditions

Using test solutions and standard solutions, conduct the tests according to the following method, and calculate the content of related substances according to the formula. Related substances whose calculated values are less than 0.1% should be excluded from the calculation, as should the peaks of dichloromethylpiperazine and levocetirizine amide.

Mobile phase: Acetonitrile: Purified water: 1M sulfuric acid = 930:65:5

-Analysis time: 20 minutes

- Column: Supelcosil LC-SI 4.6 x 150 mm, 5 μm or equivalent column

- Detector: Ultraviolet absorption spectrometer (measurement wavelength: 230nm)

- Flow rate: 1.0 ml/min

- Column temperature: 30℃

-Injection volume: 30 μl

<Formula 3> [Impurity]

* _RU = Peak area of each relevant substance detected in the test solution

* _RS = Peak area of levocetirizine hydrochloride detected in the standard solution

*C_{_S} = Concentration of levocetirizine hydrochloride standard solution (mg/ml)

* _CU = Concentration of levocetirizine hydrochloride in the test solution (mg/ml)

*P = Purity (%) of levocetirizine hydrochloride standard

[System Compatibility]

*System compatibility solution:

Accurately weigh 12 mg of levocetirizine hydrochloride standard and 12 mg of dichlorodiphenylmethylpiperazine standard, place them in a 200 ml volumetric flask, label with 10% methanol, and sonicate. Accurately transfer 1 ml of this solution to a transparent 20 ml volumetric flask, label with 10% methanol, and filter through a 0.45 μm PVDF (PALL) filter. Use the resulting solution as the system compatibility solution (3 μg/ml each).

*The separation degree between levocetirizine and dichlorodiphenylmethylpiperazine should be above 3.0.

*The tailing factor of levocetirizine should be below 2.0.

*When the levocetirizine hydrochloride standard solution is injected repeatedly 6 times, the relative standard deviation should be below 2.0%.

(4) Information about the substance

Table 10

The related substances of montelukast sodium under harsh storage conditions are shown in Table 11 below, and the related substances of levocetirizine hydrochloride are shown in Table 12 below.

Table 11

*M.S.: Montelukast Sulfoxide

*M.K.: Montelukast Ketone

*M.C.I: Montelukast Cis-Isomer

*U.I.: Unspecified Impurity

Table 12

*U.I.: Unspecified Impurity

Tables 11 and 12 show the substances generated under harsh conditions when the two drugs, montelukast sodium and levocetirizine hydrochloride, from Examples 1 to 13 are present in a tablet and a boundary layer is formed by endothelial coating.

It can be confirmed that there are no significant changes in the formation of related substances in Examples 4, 5, 6, 7 and 9 using organic acids and Examples 1, 2, 3, 8, 10, 11, 12 and 13 not using organic acids.

Furthermore, it can be confirmed that even when the coating matrix is changed, the formation of the relevant substances does not change significantly.

Tables 11 and 12 show the related substances generated under harsh conditions when the two drugs, montelukast sodium and levocetirizine hydrochloride, from Comparative Examples 1 and 2 are present in a single tablet without a boundary layer. In Comparative Example 1, the main components are mixed and in contact within the tablet, and it was confirmed that montelukast sulfoxide and unknown related substances were significantly increased in the related substances of montelukast sodium, and unknown related substances were also significantly increased in the related substances of levocetirizine hydrochloride. In Comparative Example 2, the montelukast sodium tablet and the levocetirizine hydrochloride drug coating layer are in contact without a boundary, and it was confirmed that montelukast sulfoxide was significantly increased in the related substances of montelukast sodium, and the increase in related substances of levocetirizine hydrochloride was greater than in Comparative Example 1.

In Comparative Example 1, it was confirmed that the amount of unknown related substances also increased. Furthermore, the total amount of all related substances increased significantly. It was confirmed that the amount of related substances of levocetirizine hydrochloride also increased significantly. In Comparative Example 2, it was confirmed that the amount of unknown related substances increased significantly.

Test Example 2: Accelerated Storage Stability Test

Accelerated storage stability tests were conducted on the montelukast sodium and levocetirizine hydrochloride combination tablets obtained in Examples 1 to 13 and Comparative Examples 1 to 2 under the following conditions, and the stability was evaluated by comparing the related substances levels of montelukast sodium and levocetirizine hydrochloride. The results are shown in Tables 13 to 14 below.

[Accelerated Storage Stability Test Conditions]

- Trial period: Initial and accelerated 6 months

Storage conditions: 40℃/RH 75%

-Analysis subject: Related substances caused by montelukast sodium and levocetirizine hydrochloride

Related substances of montelukast sodium under accelerated storage conditions are shown in Table 13 below, and related substances of levocetirizine hydrochloride are shown in Table 14 below.

[Analytical conditions for related substances of montelukast sodium]

The conditions are the same as in Test Example 1.

[Analytical conditions for related substances in levocetirizine hydrochloride]

The conditions are the same as in Test Example 1.

Related substances of montelukast sodium under accelerated storage conditions are shown in Table 13 below, and related substances of levocetirizine hydrochloride are shown in Table 14 below.

Table 13

*M.S.: Montelukast Sulfoxide

*M.K.: Montelukast Ketone

*M.C.I: Montelukast Cis-Isomer*U.I: Unspecified Impurity

Table 14

*U.I.: Unspecified Impurity

Tables 13 and 14 show the substances generated under accelerated conditions when the two drugs, montelukast sodium and levocetirizine hydrochloride, from Examples 1 to 13 are present in a tablet and a boundary layer is formed through endothelial coating.

It can be confirmed that there are no significant changes in the formation of related substances in Examples 4, 5, 6, 7 and 9 using organic acids and Examples 1, 2, 3, 8, 10, 11, 12 and 13 not using organic acids.

Furthermore, it can be confirmed that even when the coating matrix is changed, the formation of the relevant substances does not change significantly.

Tables 13 and 14 show the related substances generated under accelerated conditions when the two drugs, montelukast sodium and levocetirizine hydrochloride, from Comparative Examples 1 and 2 are present in a single tablet without a boundary layer. In Comparative Example 1, the main components are mixed and in contact within the tablet, and it was confirmed that the related substances of montelukast sodium increased, as did montelukast sulfoxide, montelukastone, and unknown related substances, and the related substances of levocetirizine hydrochloride also increased significantly. In Comparative Example 2, the montelukast sodium tablet and the levocetirizine hydrochloride drug coating layer were in contact without a boundary, and it was confirmed that the related substances of montelukast sodium increased significantly, as did montelukast sulfoxide and unknown related substances, and the increase in related substances of levocetirizine hydrochloride was greater than in Comparative Example 1.

Test Example 3: Dissolution Test

Dissolution tests were conducted on the coated tablets of Example 13 under the following conditions, and the results are shown in Figures 2a to 2d (dissolution rate of levocetirizine) and Figures 3a to 3d (dissolution rate of montelukast).

<Experimental Conditions>

- Dissolution test solutions: Korean Pharmacopoeia Dissolution Test Method, Solution 1 (pH 1.2), Solution 2 (pH 6.8), water, pH 4.0 solution (but in the case of montelukast sodium, add all test solutions + solubilizer sodium lauryl sulfate (SLS) 0.5%), 37±0.5℃

-Test Method: Dissolution Test Method 2 of the Korean Pharmacopoeia

- Test subjects: Control drug (Monterizine Cap), test drug (coated tablets of Example 13)

As shown in Figures 2a to 2d (dissolution rate of levocetirizine) and Figures 3a to 3d (dissolution rate of montelukast), the dissolution rate of the coated tablets of Example 13 was measured based on the main components (montelukast and levocetirizine) of the control drugs. The results confirmed that the main components (montelukast and levocetirizine) contained in the coated tablets of Example 13 were within the appropriate range.

The above description of the present invention is illustrative, and those skilled in the art will understand that it can be easily modified into other specific forms without changing the technical spirit or essential characteristics of the invention. Therefore, it should be understood that the above embodiments are exemplary in all respects and not restrictive. For example, components described as a single type can be implemented in a distributed manner, and similarly, components described as distributed can be implemented in a combined manner.

The scope of this invention is defined by the appended claims, and all changes or modifications derived from the meaning and scope of the claims and their equivalents are considered to be included within the scope of this invention.

Claims (10)

1. A tablet comprising: The first drug layer contains montelukast or a pharmaceutically acceptable salt thereof; The second drug layer contains levocetirizine or a pharmaceutically acceptable salt thereof; An inner layer, which contacts the first drug layer on one side and the second drug layer on the other side, such that the first drug layer and the second drug layer do not contact each other; and The outer layer comprises the first drug layer, the inner layer, and the second drug layer. 2. The tablet of claim 1, wherein the montelukast or a pharmaceutically acceptable salt thereof is montelukast sodium, and the levocetirizine or a pharmaceutically acceptable salt thereof is levocetirizine hydrochloride. 3. The tablet according to claim 1, wherein the first drug layer is a tablet core containing sodium montelukast. 4. The tablet of claim 3, wherein the tablet core further comprises one or more additives selected from excipients, disintegrants and lubricants. 5. The tablet of claim 1, wherein the second drug layer is a drug coating layer comprising levocetirizine hydrochloride. 6. The tablet according to claim 1, wherein the inner layer is a coating layer. 7. The tablet of claim 6, wherein the coating layer comprises one or more coating agents selected from those comprising a polyvinyl alcohol (PVA)-polyethylene glycol (PEG) copolymer, a coating agent comprising hydroxypropyl methylcellulose (HPMC), and a coating agent comprising polyvinyl alcohol (PVA). 8. The tablet according to claim 1, wherein the outer layer is a coating layer. 9. A triple-coated tablet comprising: The tablet core contains sodium montelukast; The drug coating layer contains levocetirizine hydrochloride; An inner coating layer, which contacts the tablet core on one side and the drug coating layer on the other side, such that the tablet core does not contact the drug coating layer; and The outer coating layer includes the tablet core, the inner coating layer, and the drug coating layer. 10. A method for preparing a tablet, comprising: (a) Preparation of a first drug layer comprising montelukast or a pharmaceutically acceptable salt thereof; (b) Prepare an inner layer surrounding the first drug layer; (c) Preparing a second drug layer comprising levocetirizine or a pharmaceutically acceptable salt thereof and surrounding the inner layer; and (d) Prepare an outer layer surrounding the second drug layer.