A pharmaceutical composition in the form of a double-layer tablet comprising levocetirizine and montelukast

Abstract

The present invention relates to a pharmaceutical composition in the form of a bilayer tablet comprising levocetirizine and montelukast. The pharmaceutical composition in the form of a bilayer tablet according to the present invention offers not only significantly superior patient convenience compared to existing commercially available levocetirizine and montelukast combination preparations, but also has the advantages of requiring no special manufacturing process and having a low manufacturing cost. Furthermore, it provides excellent stability over time without using separate physical separation means, such as mini-tablets or coatings, to avoid mutual contact between the two drugs, levocetirizine and montelukast.

Description

Technology Field

[0001] The present invention relates to a pharmaceutical composition in the form of a bilayer tablet comprising levocetirizine and montelukast. Background Technology

[0002] Levocetirizine is a third-generation non-sedating antihistamine that works by blocking histamine H1 receptors and is used to treat allergic diseases such as allergic rhinitis or urticaria.

[0003] Montecarust is a drug of the leukotriene receptor antagonist class used to treat asthma. In addition, Montecarust is also used as a second-line treatment for allergic diseases such as allergic rhinitis or urticaria.

[0004] Since a pharmaceutical composition containing levocetirizine and montelukast can provide convenience of administration to patients requiring simultaneous administration of levocetirizine and montelukast, a conventional pharmaceutical composition containing levocetirizine and montelukast, as a montelirizine TMA product called a capsule is currently on the market. Montelizin capsules are in the form of containing a mini-tablet containing 5 mg of levocetirizine hydrochloride and a mini-tablet containing 10.4 mg of montelukast sodium together within a single capsule. In this regard, according to Korean Registered Patent No. 10-1843086 (Patent Document 1), montelukast exhibits unstable stability against light, humidity, and heat, and levocetirizine also has poor physicochemical stability; thus, it is reported that ensuring stability over time is very difficult for both drugs. Accordingly, Patent Document 1 attempted to ensure the stability of the two drugs by including an organic acid as a stabilizer in the levocetirizine portion, while manufacturing the levocetirizine tablet and montelukast tablet separately and enclosing them inside a hard capsule, thereby achieving complete separation between the active ingredients. However, since Montelizin capsules require containing two mini-tablets within a single capsule, the manufacturing process is complex and production costs are high. In addition, although it was manufactured as a single capsule to improve patient convenience, the long axis of the capsule reaches 16.7 mm, which actually reduces patient convenience.

[0005] Other literature regarding combination formulations containing levocityrizine and montelukast can be found in Korean Patent Publication No. 10-2021-0152280 (Patent Document 2) and Korean Patent Publication No. 10-2023-0057974 (Patent Document 3).

[0006] Patent Document 2 relates to a single tablet in the form of a mixture of a pellet containing montelukast and a granule containing levocetirizine, describing that the formation of impurities due to long-term storage can be suppressed by blocking contact between the two drugs through an external coating layer on the montelukast pellet. However, the tablet according to Patent Document 2 is manufactured by requiring a secondary coating of the montelukast pellet, followed by the separate preparation of levocetirizine granules, and then mixing the pellet and granules to form a tablet. Therefore, the manufacturing process is not only very complex, but there has also been no verification of whether the stability of the tablet over time is ensured through this technology.

[0007] Meanwhile, Patent Document 3 discloses a technology for manufacturing a montelukast core tablet, applying an endothelial coating, coating it with a drug of levocetirizine hydrochloride, and then applying an outer coating. This technology suppresses the generation of impurities resulting from drug interactions by blocking direct contact between the two drugs between the montelukast core tablet and the levocetirizine drug layer. Patent Document 3 discloses that while the stability under harsh storage or accelerated storage is poor in the case of a single-matrix tablet containing montelukast sodium and levocetirizine hydrochloride, or in the case of a double tablet with a drug coating of levocetirizine hydrochloride applied to a montelukast core tablet without an endothelial coating, the stability is improved in the case of a double tablet in which direct contact between the two drugs is blocked by the endothelial coating of the montelukast core tablet. However, manufacturing a double tablet through a multi-step process of core tablet manufacturing, endothelial coating, drug coating, and outer coating is not only very complex but also inefficient in terms of cost. Prior art literature

[0008] 1. Korean Registered Patent No. 10-1843086 2. Korean Patent Publication No. 10-2021-0152280 3. Korean Patent Publication No. 10-2023-0057974 The problem to be solved

[0009] The present invention aims to provide a new type of pharmaceutical composition suitable for the purpose of simultaneous administration of levocetirizine and Montecarust, which can achieve patient convenience, simplification of the manufacturing process, and cost reduction. means of solving the problem

[0010] As a result of research on the formulation of a pharmaceutical composition containing levocetirizine and montelukast, the inventors confirmed that when levocetirizine and montelukast come into direct contact, the amount of impurities increases significantly, leading to a decrease in the stability of both drugs. Furthermore, they confirmed that merely separating the levocetirizine part and the montelukast part into two layers does not improve the stability of levocetirizine and montelukast, and that even if a bilayer tablet is adopted, the selection of a stabilizer is important to ensure the stability of each of levocetirizine and montelukast.

[0011] According to Patent Document 1, it is disclosed that the stability of levocetirizine and montelukast can be improved by using an organic acid as a stabilizer in the levocetirizine portion, and examples of organic acids include citric acid, tartaric acid, succinic acid, etc.

[0012] However, as can be seen in the following examples, Patent Document 1 is a capsule formulation containing levocetirizine mini-tablets and montelukast mini-tablets, whereas the present invention is intended for a bilayer tablet, so it was confirmed that the suitable stabilizer varies depending on the form of the formulation.

[0013] As can be specifically confirmed in the following examples, citric acid was used as a stabilizer in the levocetirizine layer of the bilayer tablet according to the present invention and its content was varied; however, the tablet of Example 5, in which the amount of citric acid was doubled compared to Example 1, showed a tendency for the level of levocetirizine impurities to actually increase under harsh storage conditions. Even in the case of Example 7, in which the amount of citric acid was quadrupled compared to Example 1, although there was a difference in that lactose monohydrate was additionally used as an excipient, it showed a similar level of impurities to Example 1. On the other hand, in the case of Example 8, in which anhydrous calcium hydrogen phosphate was used as a stabilizer for the levocetirizine layer, it was confirmed that the level of levocetirizine impurities could be significantly lowered compared to the examples in which citric acid was used as a stabilizer.

[0014] Meanwhile, during the screening process of the stabilizer for the montelukast portion, the inventors confirmed that the level of impurities in the levocetirizine portion varied depending on the change in the stabilizer for the montelukast portion. In the case of Examples 1 to 4, the composition and content of the levocetirizine portion were all the same, but in the case of Examples 3 to 4, in which magnesium aluminum silicate or sodium bicarbonate was used as the stabilizer for the montelukast portion, it was experimentally confirmed that not only the level of increase in impurities of montelukast but also the level of increase in impurities of levocetirizine was poor compared to Examples 1 to 2.

[0015] In other words, in the manufacture of bilayer tablets containing levocetirizine and montelukast, the stabilizer of the levocetirizine layer and the stabilizer of the montelukast layer can affect the stability of the other drug layer, which means that selecting a stabilizer for each drug layer is by no means easy.

[0016] The inventors selected anhydrous calcium hydrogen phosphate during the screening process for the stabilizer of montelukast and intended to control the level of increase in impurities of montelukast by changing its content. In Example 5, the content of citric acid as the stabilizer for levocetirizine and anhydrous calcium hydrogen phosphate as the stabilizer for montelukast were increased by 2 times and 10 times, respectively, compared to Example 1; however, contrary to expectations, the level of impurities of levocetirizine under harsh storage conditions increased, while the level of impurities of montelukast decreased only slightly. However, in Example 8, when the stabilizer of the levocetirizine portion was changed to anhydrous calcium hydrogen phosphate, it was confirmed that, despite no change in the composition of the montelukast portion, the level of increase in impurities of both levocetirizine and montelukast under harsh storage conditions was significantly lower.

[0017] This ultimately implies that including anhydrous calcium hydrogen phosphate as a stabilizer for montelukast and simultaneously including anhydrous calcium hydrogen phosphate as a stabilizer for levocetirizine plays a crucial role in ensuring the long-term stability of the bilayer tablet by controlling the formation of impurities from both drugs.

[0018] Accordingly, the present invention provides a pharmaceutical composition in the form of a bilayer tablet comprising a layer comprising levocetirizine or its pharmaceutically acceptable salt and calcium anhydrous hydrogen phosphate as a stabilizer, and a layer comprising montelukast or its pharmaceutically acceptable salt and calcium anhydrous hydrogen phosphate as a stabilizer.

[0019] In one embodiment of the present invention, the stabilizer content of the levocetirizine layer may be 300 to 500 parts by weight, for example, 350 to 450 parts by weight, based on 100 parts by weight of levocetirizine or its pharmaceutically acceptable salt. The stabilizer content of the levocetirizine layer may be 5 to 20 parts by weight, for example, 5 to 15 parts by weight, 10 to 20 parts by weight, or 10 to 15 parts by weight, based on 100 parts by weight of the total composition of the levocetirizine layer.

[0020] In addition, in one embodiment of the present invention, the stabilizer content of the montelukast layer may be 350 to 600 parts by weight, for example, 400 to 600 parts by weight, or 400 to 550 parts by weight, based on 100 parts by weight of montelukast or its pharmaceutically acceptable salt. The stabilizer content of the montelukast layer may be 15 to 40 parts by weight, for example, 15 to 35 parts by weight, or 20 to 30 parts by weight, based on 100 parts by weight of the total composition of the montelukast layer.

[0021] In the present invention, the pharmaceutically acceptable salt of levocetirizine may include known salts of levocetirizine, for example, acid addition salts such as hydrochloric acid, acetic acid, citric acid, maleic acid, succinic acid, ascorbic acid, hydrobromide, sulfuric acid, and phosphoric acid, or metal salts such as sodium or potassium salts, ammonium salts, amine salts, and amino acid salts. In a specific embodiment of the present invention, the pharmaceutically acceptable salt of levocetirizine may be levocetirizine hydrochloride.

[0022] In the present invention, a preferred example of a pharmaceutically acceptable salt of montelukast may be montelukast sodium salt.

[0023] The pharmaceutical composition of the present invention includes excipients, disintegrants, and binders as additives.

[0024] Examples of excipients include lactose (including hydrates), mannitol, microcrystalline cellulose [e.g., Celphere™], silicified microcrystalline cellulose [e.g., Prosolv™], dextrin, sorbitol, starch, calcium phosphate hydrate, anhydrous calcium phosphate, calcium carbonate, sugars, or mixtures thereof.

[0025] In a specific embodiment of the present invention, the levocetirizine layer may include microcrystalline cellulose, mannitol, lactose monohydrate, or a mixture thereof as an excipient. In a preferred embodiment, the levocetirizine layer may include a mixture of microcrystalline cellulose and lactose monohydrate. The excipient content of the levocetirizine layer may be 70 to 90 parts by weight, for example, 75 to 85 parts by weight, based on 100 parts by weight of the total composition of the levocetirizine layer. In a preferred embodiment, the microcrystalline cellulose content of the levocetirizine layer may be 50 to 65 parts by weight based on 100 parts by weight of the total composition of the levocetirizine layer, and the lactose monohydrate content of the levocetirizine layer may be 15 to 25 parts by weight based on 100 parts by weight of the total composition of the levocetirizine layer.

[0026] In a specific embodiment of the present invention, the montelukast layer may include microcrystalline cellulose, mannitol, lactose monohydrate, or a mixture thereof as an excipient. In a preferred embodiment, the montelukast layer may include a mixture of microcrystalline cellulose and mannitol. The excipient content of the montelukast layer may be 40 to 60 parts by weight, for example, 45 to 55 parts by weight, based on 100 parts by weight of the total composition of the montelukast layer. In a preferred embodiment, the microcrystalline cellulose content of the montelukast layer is 15 to 30 parts by weight, for example, 15 to 25 parts by weight, 20 to 30 parts by weight, or 20 to 25 parts by weight, based on 100 parts by weight of the total composition of the montelukast layer, and the mannitol content of the montelukast layer is 20 to 35 parts by weight, for example, 20 to 30 parts by weight, or 25 to 30 parts by weight, based on 100 parts by weight of the total composition of the montelukast layer.

[0027] The levocetirizine layer and the montelukast layer may additionally include a disintegrant. Examples of disintegrants include sodium starch glycolate, crospovidone, sodium croscarmellose, and low-substituted hydroxypropylcellulose. In a specific embodiment of the present invention, the disintegrant included in the levocetirizine layer and the montelukast layer may be sodium starch glycolate. Although not limited thereto, in a specific embodiment of the present invention, the content of the disintegrant included in the levocetirizine layer may be 1 to 10 parts by weight, for example, 1 to 5 parts by weight, based on 100 parts by weight of the total composition of the levocetirizine layer. In a specific embodiment of the present invention, the content of the disintegrant included in the montelukast layer may be 5 to 20 parts by weight, for example, 13 to 17 parts by weight, based on 100 parts by weight of the total composition of the montelukast layer.

[0028] Examples of binders include methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylalkylcellulose (e.g., hydroxypropylmethylcellulose), polyvinylpyrrolidone, povidone, gelatin, starch, sucrose, and mixtures thereof. In a specific embodiment of the present invention, the montelukast layer may include a binder, for example, hydroxypropylcellulose. The content of the binder may be 0.5 to 5 parts by weight based on 100 parts by weight of the entire levocetirizine layer or montelukast layer.

[0029] Examples of other additives include lubricants and coloring agents.

[0030] The above lubricant comprises stearic acid, stearate (e.g., magnesium stearate), colloidal silicon dioxide, talc, corn starch, carnauba wax, magnesium silicate, synthetic aluminum silicate, hardened oil, white wax, titanium oxide, microcrystalline cellulose, macrogol 4000 and 6000, isopropyl myristate, calcium hydrogen phosphate, and mixtures thereof. The content of the lubricant may be 0.5 to 5 parts by weight based on 100 parts by weight of the total levocetirizine layer or montelukast layer.

[0031] In one embodiment, the pharmaceutical composition of the present invention in the form of a bilayer tablet may be manufactured by preparing a levocetirizine part comprising levocetirizine or a pharmaceutically acceptable salt thereof and an additive, and a montelukast part comprising montelukast or a pharmaceutically acceptable salt thereof and an additive, respectively according to a conventional method, and then compressing them using a bilayer tablet press. In one embodiment of the present invention, the bilayer tablet according to the present invention may be manufactured by a direct compression method. That is, the pharmaceutical composition according to the present invention can be manufactured directly into a bilayer tablet by a direct compression method after mixing the active ingredient and the additive, without a process of manufacturing the levocetirizine part and the montelukast part into granules or pellets.

[0032] If necessary, the pharmaceutical composition of the present invention may be coated with a coating agent. In one embodiment, the pharmaceutical composition of the present invention may be a bilayer tablet coated with a coating agent. The coating agent, for example, the film coating agent, may include a conventional polymer such as Opadry™. Specifically, the film coating agent may be polyvinyl alcohol (PVA), polyvinyl alcohol copolymer, hydroxypropyl methylcellulose (HPMC), etc. Examples of polyvinyl alcohol copolymers may be PVA / macrogol grafted polymers, though not limited thereto. In one embodiment, the pharmaceutical composition of the present invention may be a bilayer tablet coated with Opadry. It is preferable to use the minimum amount of the film coating agent that can provide an optimal formulation size, but it is not particularly limited.

[0033] The pharmaceutical composition according to the present invention may be administered to patients requiring simultaneous administration of levocetirizine and Montecarust. For example, the pharmaceutical composition according to the present invention may be administered orally to patients with asthma and allergic rhinitis. In one embodiment, the pharmaceutical composition according to the present invention may be used for the treatment or prevention of allergic rhinitis in patients with asthma and allergic rhinitis (e.g., perennial allergic rhinitis).

[0034] In a specific embodiment of the present invention, the pharmaceutical composition according to the present invention is Montelizin TM It demonstrates bioequivalence with the capsule.

[0035] The pharmaceutical composition according to the present invention may be administered orally 1 to 3 times a day, but is not limited thereto. In a specific embodiment of the present invention, one tablet of the pharmaceutical composition according to the present invention may be administered once a day. Preferably, one tablet is administered orally once a day in the evening.

[0036] In the pharmaceutical composition of the present invention, the active ingredients levocetirizine or its salt and Monte Carust or its salt may be used in a therapeutically effective amount. The therapeutically effective amount may vary depending on the patient's symptoms, age, weight, severity of the disease, etc.

[0037] In a pharmaceutical composition according to the present invention, based on a unit formulation (i.e., unit dosage form), levocetirizine or a pharmaceutically acceptable salt thereof may be included in an amount of 0.1 to 50 mg, e.g., 0.2 to 30 mg, 0.5 to 15 mg, 0.5 to 10 mg, 1 to 10 mg, or 2 to 10 mg. Montelukast or a pharmaceutically acceptable salt thereof may be included in an amount of 1 to 50 mg, e.g., 2.5 to 30 mg or 5 to 15 mg. In one embodiment, in a pharmaceutical composition according to the present invention, levocetirizine or a pharmaceutically acceptable salt thereof may be included in an amount of about 0.5 to 5 mg, and montelukast or a pharmaceutically acceptable salt thereof may be included in an amount of about 4.16 to 10.4 mg, but is not limited thereto. Preferably, in the pharmaceutical composition according to the present invention, levocetirizine or a pharmaceutically acceptable salt thereof may be contained in an amount of about 5 mg, and montelukast or a pharmaceutically acceptable salt thereof may be contained in an amount of about 10.4 mg. For example, the pharmaceutical composition according to the present invention may contain 5 mg of levocetirizine hydrochloride and 10.4 mg of montelukast sodium salt. Effects of the invention

[0038] The pharmaceutical composition in the form of a bilayer tablet according to the present invention offers not only significantly superior patient convenience compared to existing commercially available levocetirizine and montelukast combination preparations, but also has the advantages of requiring no special manufacturing process and having a low manufacturing cost. Furthermore, it provides excellent stability over time without using separate physical separation means, such as mini-tablets or coatings, to avoid mutual contact between the two drugs, levocetirizine and montelukast. Brief explanation of the drawing

[0040] Figure 1 shows the results of evaluating the bioequivalence between formulations by statistically analyzing the AUC and Cmax of levocetirizine and montelukast when administered with the control drug and the test drug. Specific details for implementing the invention

[0041] [Example]

[0042] Hereinafter, preferred embodiments are presented to aid in understanding the present invention; however, the following embodiments are merely illustrative of the invention and the scope of the invention is not limited to the following embodiments.

[0044] Examples 1 to 4: Preparation of bilayer tablets containing levocetirizine and montelukast (preparation of simple mixed bilayer tablets)

[0045] Citric acid was selected as a stabilizer for levocetirizine, and a stabilizer screening study was conducted using anhydrous calcium hydrogen phosphate, meglumine, magnesium aluminum silicate, and sodium bicarbonate as stabilizers for montelukast.

[0046] To this end, a bilayer tablet containing levocetirizine and montelukast was prepared according to the composition of Table 1 using the following method.

[0047] Revocetirizine

[0048] Levocetirizine hydrochloride, D-mannitol, microcrystalline cellulose, sodium starch glycolate, and citric acid as a stabilizer were mixed, and then colloidal silicon dioxide and magnesium stearate were added and mixed to prepare the levocetirizine part.

[0049] Montelukast Department

[0050] Montelukast sodium, mannitol, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose, and one of anhydrous calcium hydrogen phosphate, meglumine, magnesium aluminum silicate, or sodium bicarbonate as a stabilizer were mixed, and then colloidal silicon dioxide and magnesium stearate were added and mixed to prepare the montelukast part.

[0051] manufacturing of bilayer tablets

[0052] A bilayer tablet was formed using the above-mentioned revocetirizine and montelukast parts, and film-coated using Opadry 20A680000 White (Colorcon's product name) as a coating agent in a conventional manner.

[0054] division classification ingredient Example 1 Example 2 Example 3 Example 4 Revocetirizine chief ingredient Levocetirizine hydrochloride 5.00 5.00 5.00 5.00 Brothers Mannitol 30.00 30.00 30.00 30.00 Brothers Microcrystalline cellulose 100.00 100.00 100.00 100.00 disintegrant Sodium starch glycolate 15.00 15.00 15.00 15.00 stabilizer citric acid 5.00 5.00 5.00 5.00 Hwaltaekje Colloidal silicon dioxide 2.00 2.00 2.00 2.00 Hwaltaekje Magnesium stearate 3.00 3.00 3.00 3.00 Montelukast Department chief ingredient Montelukast sodium 10.40 10.40 10.40 10.40 Brothers Mannitol 50.60 50.60 50.60 50.60 Brothers Microcrystalline cellulose 88.00 88.00 88.00 88.00 disintegrant Sodium starch glycolate 20.00 20.00 20.00 20.00 stabilizer Anhydrous calcium hydrogen phosphate 10.00 - - - stabilizer Meglumine - 10.00 - - stabilizer magnesium aluminum silicate - - 10.00 - stabilizer sodium bicarbonate - - - 10.00 binder hydroxypropyl cellulose 5.00 5.00 5.00 5.00 Hwaltaekje Colloidal silicon dioxide 3.00 3.00 3.00 3.00 Hwaltaekje Magnesium stearate 5.00 5.00 5.00 5.00 Coating agent Opadry 20A680000 White 18.00 18.00 18.00 18.00 Total (mg / tablet) 370.00 370.00 370.00 370.00

[0056] Experimental Example 1: Stability analysis of bilayer tablets of Examples 1 to 4

[0057] The stability of the bilayer tablets of Examples 1 to 4 was tested for 2 weeks under harsh test conditions at a temperature of 60℃.

[0059] 1.1 Test Method for Impurities

[0060] Impurities were measured using the liquid chromatography method according to the general test methods of the Korean Pharmacopoeia. For the test solution, approximately 20 tablets of each prepared in the Examples and Preparation Examples were taken, ground into powder, and an amount equivalent to 2 tablets was accurately weighed and placed in a 20 mL light-shielding volumetric flask. A diluent (Note 1) was added, the mixture was ultrasonically shaken, and filtered through a 0.45 μm membrane filter for use. For the standard solution, approximately 10.4 mg of montelukast sodium standard and approximately 5.0 mg of levocetirizine hydrochloride standard were accurately weighed, placed in a 50 mL light-shielding volumetric flask, and ultrasonically extracted for at least 10 minutes. After cooling to room temperature, the solution was adjusted to the mark. 1 mL of this solution was accurately taken and placed in a 100 mL light-shielding volumetric flask. The solution was adjusted to the mark with the diluent and filtered through a 0.45 μm membrane filter; the first 2 mL or more was discarded, and the remaining filtrate was used as the standard solution.

[0061] 20 µl each of the test solution and standard solution were used to measure the relative retention time (RRT) of the impurities under the following liquid chromatography conditions.

[0063] [Liquid Chromatography Conditions]

[0064] - Column: Symmetry C8 (3.9 × 150 mm, 5 μm)

[0065] - Column temperature: 40 ℃

[0066] - Sample temperature: 5 ℃

[0067] - Detector: Ultraviolet absorption spectrophotometer (Measurement wavelength: 230 nm)

[0068] - Injection volume: 20 μL

[0069] - Flow rate: 1.0 mL / min

[0070] - Analysis time: 30 minutes

[0071] - Mobile phase: Mobile phase A and mobile phase B are controlled by the concentration gradient as follows.

[0072] Solution A: A solution prepared by accurately weighing 2.8 g of disodium hydrogen phosphate anhydrous, dissolving it in 1000 mL of water, and adjusting the pH to 7.0 with phosphoric acid.

[0073] Solution B: Acetonitrile

[0074]

[0076] 1.2 Harshness Stability Test Method

[0077] The harsh stability test was performed for 2 weeks under temperature conditions of 60°C.

[0078] division period Example 1 Example 2 Example 3 Example 4 Saint Early white, round tablet white, round tablet white, round tablet white, round tablet 2 weeks white, round tablet white, round tablet white, round tablet white, round tablet Levocetirizine unknown flexible substances (total flexible substances) Early 0.15(0.24) 0.36(0.43) 0.47(0.55) 0.40(0.52) 2 weeks 0.30(1.44) 0.34(1.27) 0.65(2.71) 0.33(2.06) Montelukast unknown flexible material (total flexible material) Early 0.05(0.10) 0.03(0.08) 0.05(0.15) 0.05(0.10) 2 weeks 1.19(1.69) 1.00(1.38) 2.19(3.20) 1.30(1.78)

[0080] As can be seen in Table 2, regarding the trend of increase in impurities of montelukast, the bilayer tablets using anhydrous calcium hydrogen phosphate (Example 1), meglumine (Example 2), and sodium bicarbonate (Example 4) as stabilizers showed superior results compared to the bilayer tablet using magnesium aluminum silicate (Example 3) as a stabilizer. Regarding the trend of increase in impurities of levocetirizine, the rate of increase in impurities was somewhat lower in the bilayer tablets using anhydrous calcium hydrogen phosphate (Example 1) and meglumine (Example 2) as stabilizers. Overall, it was decided to consider using anhydrous calcium hydrogen phosphate or meglumine as stabilizers for montelukast and subsequent formulation studies were conducted.

[0082] Comparative Examples 1, 2 and Example 5: Preparation of a single tablet containing levocetirizine, a single tablet containing montelukast, and a simple mixed bilayer tablet containing levocetirizine and montelukast

[0083] Based on the stability test results of the bilayer tablets of Examples 1 to 4, we intended to investigate whether the stability of the tablets is further improved when the content of the stabilizer for montelukast is increased.

[0084] To this end, a single tablet containing levocetirizine (Comparative Example 1), a single tablet containing montelukast (Comparative Example 2), and a bilayer tablet containing levocetirizine and montelukast (Example 5) were prepared according to the composition of Table 3 in the following manner.

[0085] Revocetirizine

[0086] Levocetirizine hydrochloride, D-mannitol, microcrystalline cellulose, sodium starch glycolate, and citric acid as a stabilizer were mixed, and then colloidal silicon dioxide and magnesium stearate were added and mixed to prepare the levocetirizine part.

[0087] Montelukast Department

[0088] Montelukast sodium, mannitol, microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose, and anhydrous calcium hydrogen phosphate as a stabilizer were mixed, and then colloidal silicon dioxide and magnesium stearate were added and mixed to prepare the montelukast part.

[0089] Single tablet manufacturing

[0090] Using the levocetirizine part and the montelukast part prepared above, a single tablet containing levocetirizine (Comparative Example 1) and a single tablet containing montelukast (Comparative Example 2) were compressed, and a film-coated tablet was prepared by a conventional method using Opadry 20A680000 White (product name of Colorcon) as a coating agent.

[0091] manufacturing of bilayer tablets

[0092] Using the levocetirizine and montelukast parts prepared above, a bilayer tablet was compressed according to a conventional method, and a film-coated bilayer tablet containing levocetirizine and montelukast was prepared by film-coating using Opadry 20A680000 White (Colorcon's product name) as a coating agent according to a conventional method.

[0094] division classification ingredient Comparative Example 1 Comparative Example 2 Example 5 Revocetirizine chief ingredient Levocetirizine hydrochloride 5.00 5.00 Brothers Mannitol 35.00 30.00 Brothers Microcrystalline cellulose 100.00 100.00 disintegrant Sodium starch glycolate 15.00 15.00 stabilizer citric acid 10.00 10.00 Hwaltaekje Colloidal silicon dioxide 2.00 2.00 Hwaltaekje Magnesium stearate 3.00 3.00 Montelukast Department chief ingredient Montelukast sodium 10.40 10.40 Brothers Mannitol 50.60 50.60 Brothers Microcrystalline cellulose 88.00 80.00 disintegrant Sodium starch glycolate 20.00 20.00 stabilizer Anhydrous calcium hydrogen phosphate 100.00 100.00 binder hydroxypropyl cellulose 5.00 5.00 Hwaltaekje Colloidal silicon dioxide 3.00 3.00 Hwaltaekje Magnesium stearate 5.00 5.00 Coating agent Opadry 20A680000 White 10.00 10.00 18.00 Total (mg / tablet) 180.00 292.00 377.00

[0096] Experimental Example 2: Analysis of severe stability of the tablets of Comparative Examples 1 and 2 and Example 5

[0097] The stability of the tablets of Comparative Examples 1 and 2 and Example 5 was tested for 2 weeks under harsh test conditions at a temperature of 60°C.

[0098] division period Comparative Example 1 Comparative Example 2 Example 5 Saint Early white, round tablet white, round tablet white, round tablet 2 weeks white, round tablet white, round tablet white, round tablet Levocetirizine unknown flexible substances (total flexible substances) Early 0.34(1.27) - 0.66(0.66) 2 weeks 1.47(5.98) - 0.75(3.11) Montelukast unknown flexible material (total flexible material) Early - 0.15(0.19) 0.05(0.07) 2 weeks - 1.06(1.54) 0.85(1.29)

[0099] The bilayer tablet of Example 5 was prepared by setting the content of anhydrous calcium hydrogen phosphate, used as a stabilizer for montelukast, higher than the stabilizer content of Examples 1 to 4. Looking at the results of the severe stability test, while the impurities of montelukast showed somewhat more stable results compared to Example 1, the increasing trend of specific impurities of levocetirizine was observed, so additional screening studies for the stabilizer of levocetirizine were conducted as follows.

[0101] Examples 6 to 8: Preparation of a bilayer tablet containing levocetirizine and montelukast

[0102] Based on the stability test results of the bilayer tablets of Examples 1 to 5, we intended to test the stability of bilayer tablets prepared by using citric acid or anhydrous calcium hydrogen phosphate as a stabilizer for levocetirizine, while changing the content of anhydrous calcium hydrogen phosphate in the montelukast part, and simultaneously using mannitol or lactose monohydrate together with microcrystalline cellulose as an excipient.

[0103] To this end, bilayer tablets (Examples 6 to 8) containing levocetirizine and montelukast were prepared according to the composition of Table 5 in the following manner.

[0104] Revocetirizine

[0105] Levocetirizine hydrochloride, D-mannitol, microcrystalline cellulose, sodium starch glycolate, and anhydrous calcium hydrogen phosphate or citric acid as a stabilizer were mixed, and then colloidal silicon dioxide and magnesium stearate were added and mixed to prepare the levocetirizine part.

[0106] Montelukast Department

[0107] Montelukast sodium, mannitol or lactose monohydrate as an excipient, and microcrystalline cellulose, sodium starch glycolate as a disintegrant, hydroxypropyl cellulose as a binder, and anhydrous calcium hydrogen phosphate as a stabilizer were mixed, and then colloidal silicon dioxide and magnesium stearate were added and mixed to prepare the montelukast part.

[0108] manufacturing of bilayer tablets

[0109] Using the levocetirizine and montelukast parts prepared above, a bilayer tablet was compressed according to a conventional method, and a film-coated bilayer tablet containing levocetirizine and montelukast was prepared by using Opadry 20A680000 White (product name of Colorcon) as a coating agent and film-coating it according to a conventional method.

[0110] division classification ingredient Example 6 Example 7 Example 8 Revocetirizine chief ingredient Levocetirizine hydrochloride 5.00 5.00 5.00 Brothers Mannitol 40.00 - - Brothers lactose monohydrate - 40.00 30.00 Brothers Microcrystalline cellulose 80.00 80.00 87.00 disintegrant Sodium starch glycolate 5.00 5.00 3.00 stabilizer Anhydrous calcium hydrogen phosphate 10.00 - 20.00 stabilizer citric acid - 20.00 - Hwaltaekje Colloidal silicon dioxide 2.00 2.00 2.00 Hwaltaekje Magnesium stearate 3.00 3.00 3.00 Montelukast Department chief ingredient Montelukast sodium 10.40 10.40 10.40 Brothers Mannitol 30.60 - 56.60 Brothers lactose monohydrate - 30.60 - Brothers Microcrystalline cellulose 63.00 68.00 45.00 disintegrant Sodium starch glycolate 10.00 10.00 30.00 stabilizer Anhydrous calcium hydrogen phosphate 90.00 90.00 50.00 binder hydroxypropyl cellulose 5.00 5.00 2.00 Hwaltaekje Colloidal silicon dioxide 3.00 3.00 3.00 Hwaltaekje Magnesium stearate 5.00 5.00 4.00 Coating agent Opadry 20A680000 White 13.00 13.00 19.00 Total (mg / tablet) 375.00 390.00 370.00

[0112] Experimental Example 3: Stability analysis of bilayer tablets in Examples 6 to 8

[0113] The stability of the bilayer tablets of Examples 6 to 8 was tested for 2 weeks under harsh test conditions at a temperature of 60°C.

[0114] division period Example 6 Example 7 Example 8 Saint Early white, round tablet white, round tablet white, round tablet 2 weeks white, round tablet white, round tablet white, round tablet Levocetirizine unknown flexible substances (total flexible substances) Early 0.07(0.28) 0.09(0.31) 0.07(0.22) 2 weeks 0.94(1.91) 0.31(1.21) 0.06(0.32) Montelukast unknown flexible material (total flexible material) Early 0.10(0.16) 0.10(0.16) 0.10(0.24) 2 weeks 1.45(2.36) 1.87(2.98) 0.12(0.37)

[0115] As can be seen in Table 6, it was confirmed that the rate of increase in impurities was lower when lactose monohydrate was used instead of mannitol in the levocetirizine portion (Examples 7 and 8). In addition, it was confirmed that when lactose monohydrate was used as an excipient in the levocetirizine portion, the rate of increase in impurities was lowered further when anhydrous calcium hydrogen phosphate was used as a stabilizer instead of citric acid.

[0116] In addition, it was confirmed that when anhydrous calcium hydrogen phosphate was used as a stabilizer in the montelukast part and mannitol was used as an excipient instead of lactose monohydrate (Examples 6 and 8), the rate of increase in impurities was low.

[0118] Experimental Example 4: Severe Stability Analysis of the Bilayer Tablet of Example 8

[0119] The harsh stability of the bilayer tablet of Example 8 was tested for 5 weeks under harsh test conditions of a temperature of 50°C and a humidity of 80%.

[0120] As shown in Table 7, the stability of Example 8 was confirmed to be within the standard for 5 weeks under harsh conditions (temperature 50°C, humidity 80%), thus confirming the stability of the bilayer tablet of Example 8 through this test (Reference drug: Montelizin capsule).

[0121] Impurities Monte Imp B Monte Imp C Levo Imp A Levo Imp G ant-like material Total unknown flexible material Total flexible material Criteria ≤ 0.3% ≤ 2.0% ≤ 0.30% ≤ 0.30% ≤ 0.2% ≤ 0.6% ≤ 3.0% Sample Weeks 　 　 　 　 　 　 　 Control 1W ND 1.35% ND 0.17% 0.37% 0.94% 2.46% 3W ND 3.16% ND 0.31% 1.29% 2.36% 5.83% 5W ND 4.48% ND 0.35% 1.83% 3.01% 7.85% The bilayer tablet of Example 8 1W ND 0.20% ND 0.09% 0.06% 0.25% 0.54% 3W ND 0.26% ND 0.09% 0.12% 0.22% 0.57% 5W ND 0.38% ND 0.10% 0.16% 0.25% 0.73%

[0123] Experimental Example 5: Bioequivalence Test

[0124] Using the bilayer tablet of Example 8 as the test drug, a pharmacokinetic study (PK study) was performed on the test drug formulation to evaluate bioequivalence with the reference drug (Montelizin capsule). Thirty-six subjects were divided into two groups; Group 1 received oral administration of the test drug tablet, and Group 2 received oral administration of the Montelizin capsule. Blood samples were collected at 0, 0.08, 0.17, 0.33, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, and 36 hours after administration, and the blood concentrations of levocetirizine and montelukast were quantified. After quantification, the AUC and Cmax of levocetirizine and montelukast administered with the reference drug (co-administration) and the test drug were statistically analyzed to evaluate the bioequivalence between the formulations.

[0125] The test results were shown in Figure 1.

[0126] When comprehensively assessing the bioequivalence between the test drug and the reference drug, Montelizin capsules, the AUCt and Cmax, which are comparative evaluation items between the reference drug and the test drug, were log-transformed and statistically processed, the 90% confidence interval of the log-transformed mean difference for levocetirizine's AUCt was log 0.9910 to log 1.0490, and the 90% confidence interval of the log-transformed mean difference for Cmax was log 1.0159 to log 1.1923.

[0127] The 90% confidence interval of the log-transformed mean difference for Montelukast's AUCt was log 0.9750 to log 1.0742, and the 90% confidence interval of the log-transformed mean difference for Cmax was log 0.9529 to log 1.0569. Based on these results, both Levoxetirizine and Montelukast satisfied the bioequivalence test criteria for the test drug and the reference drug Montelukast capsules, which require that the 90% confidence interval of the log-transformed mean difference for the comparative evaluation items AUCt and Cmax be within log 0.8 to log 1.25.

Claims

Claim 1 A pharmaceutical composition in the form of a bilayer tablet comprising a layer containing levocetirizine or its pharmaceutically acceptable salt and anhydrous calcium hydrogen phosphate as a stabilizer, and a layer containing montelukast or its pharmaceutically acceptable salt and anhydrous calcium hydrogen phosphate as a stabilizer. Claim 2 A pharmaceutical composition according to claim 1, wherein the stabilizer of the levocetirizine layer comprises 300 to 500 parts by weight based on 100 parts by weight of levocetirizine or a pharmaceutically acceptable salt thereof. Claim 3 A pharmaceutical composition according to claim 1, wherein the stabilizer of the montelukast layer comprises 350 to 600 parts by weight based on 100 parts by weight of montelukast or its pharmaceutically acceptable salt. Claim 4 A pharmaceutical composition according to claim 1, wherein the levocetirizine layer comprises levocetirizine hydrochloride. Claim 5 A pharmaceutical composition according to claim 1, wherein the montelukast layer comprises montelukast sodium salt. Claim 6 A pharmaceutical composition according to claim 1, wherein the levocetirizine layer comprises microcrystalline cellulose, mannitol, lactose monohydrate, or a mixture thereof as an excipient. Claim 7 A pharmaceutical composition according to claim 6, wherein the levocetirizine layer comprises 70 to 90 parts by weight of an excipient based on 100 parts by weight of the total composition of the levocetirizine layer. Claim 8 A pharmaceutical composition according to claim 1, wherein the montelukast layer comprises microcrystalline cellulose, mannitol, lactose monohydrate, or a mixture thereof as an excipient. Claim 9 A pharmaceutical composition according to claim 8, wherein the montelukast layer comprises 40 to 60 parts by weight of an excipient based on 100 parts by weight of the total composition of the montelukast layer. Claim 10 A pharmaceutical composition according to claim 1, wherein the levocetirizine layer and the montelukast layer additionally comprise a disintegrant. Claim 11 A pharmaceutical composition according to claim 1, wherein the bilayer tablet is manufactured by the direct compression method. Claim 12 A pharmaceutical composition in which the bilayer tablet is coated with a coating agent, as described in claim 1. Claim 13 A pharmaceutical composition according to claim 1, administered orally to a patient with asthma and allergic rhinitis. Claim 14 A pharmaceutical composition according to claim 1, administered orally once a day. Claim 15 A pharmaceutical composition according to claim 1, comprising 5 mg of levocetirizine hydrochloride and 10.4 mg of montelukast sodium salt.

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