Composition containing montelukast and rupatadine, having improved stability, and preparation method therefor

Abstract

The present invention relates to a composition containing montelukast and rupatadine, having improved stability, and, more specifically, to: a composition containing montelukast or a pharmaceutically acceptable salt, and rupatadine or a pharmaceutically acceptable salt thereof, the composition having a pH of 4 to 5.5 by an added pH regulator; and a preparation method therefor. The composition according to the present invention has a pH of 4 to 5.5 due to a pH regulator, thereby having reduced generation of related substances and having excellent stability.

Description

Composition containing montelukast and rupatadine with improved stability and method for preparing the same

[0001] This application claims the benefit of Republic of Korea Patent Application No. 10-2023-0169174, filed on November 29, 2023, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to a composition containing montelukast and rupatadine with improved stability, and more particularly, to a composition comprising montelukast or a pharmaceutically acceptable salt thereof; and rupatadine or a pharmaceutically acceptable salt thereof, wherein the composition has a pH of 4 to 5.5 due to an added pH adjusting agent, and a method for preparing the same.

[0003]

[0004] When foreign substances enter our body from the outside, an immune hypersensitivity reaction occurs, causing asthma or allergic rhinitis. Asthma is a disease caused by allergens such as pollen and house dust mites. The bronchial mucosa swells and becomes inflamed, and the muscles surrounding the bronchial tubes spasm (contract), narrowing the bronchial tubes and causing shortness of breath (shortness of breath). Allergic rhinitis can be divided into seasonal allergic rhinitis, which occurs only in certain seasons, such as spring pollen and fall ragweed pollen, and perennial allergic rhinitis, which occurs year-round, such as house dust, mites, mold, and animal dander. An allergic reaction occurs in the nasal mucosa, resulting in symptoms such as sneezing, clear runny nose, and nasal congestion.

[0005] Commonly used medications for asthma and allergic rhinitis include montelukast and rupatadine.

[0006] Montelukast is a leukotriene antagonist and leukotriene biosynthesis inhibitor, and is known in the art to be effective in the treatment of pulmonary diseases including asthma, bronchitis, and related obstructive airway diseases; allergic reactions such as allergic rhinitis, contact dermatitis, and allergic conjunctivitis; inflammation and pain such as arthritis or inflammatory bowel disease; skin diseases such as psoriasis and atopic eczema; and cardiovascular diseases such as angina pectoris, myocardial ischemia, hypertension, and platelet aggregation.

[0007] Meanwhile, Rupatadine is a second-generation antihistamine and a platelet-activating factor binding inhibitor. It has the characteristic of being effective not only for early allergic reactions but also for late allergic reactions due to this dual action, and is effective in improving itching associated with allergic rhinitis including hay fever, hives, and skin diseases (eczema, dermatitis, and itchy skin), and is sold under various names including Rupafin.

[0008] For the treatment of allergic rhinitis symptoms, the combination of montelukast and rupatadine has been shown to be more effective than rupatadine alone. However, capsule formulations containing montelukast or rupatadine alone are less effective than tablet combinations and may have compatibility and stability issues.

[0009] Furthermore, when manufacturing a combination formulation of montelukast and rupatadine, montelukast interacts with rupatadine, generating a volatile compound and reducing stability. Therefore, there is a need to develop a formulation containing montelukast and rupatadine with improved storage stability under harsh conditions, as well as a manufacturing method for producing such a formulation.

[0010]

[0011] Accordingly, the inventor of the present invention completed the present invention by confirming that when a pH adjusting agent is added to manufacture montelukast sodium and rupatadine fumarate together as a matrix tablet and an appropriate pH condition is met, the generation of flexible substances is reduced and stability is improved.

[0012]

[0013] Accordingly, an object of the present invention is to provide a composition comprising montelukast or a pharmaceutically acceptable salt thereof; and rupatadine or a pharmaceutically acceptable salt thereof; wherein the composition has a pH of 4 to 5.5 due to an added pH adjusting agent.

[0014]

[0015] Another object of the present invention is to provide a method for manufacturing a combination tablet of montelukast and rupatadine comprising the following steps:

[0016] 1) Step of preparing a binding solution;

[0017] 2) A step of mixing montelukast or a pharmaceutically acceptable salt thereof; lupatadine or a pharmaceutically acceptable salt thereof; excipients and a pH regulator into the above combination solution;

[0018] 3) A step of drying and sizing the above mixture to produce granules;

[0019] 4) A step of adding a disintegrant to the above granules;

[0020] 5) Step of manufacturing a mixture of the above 4) into a tablet.

[0021]

[0022] Another object of the present invention is to provide a method for manufacturing a combination tablet of montelukast and rupatadine comprising the following steps:

[0023] 1) Step of preparing a binding solution;

[0024] 2) A step of mixing montelukast or a pharmaceutically acceptable salt thereof, and an excipient and a pH regulator into the above-mentioned combination solution;

[0025] 3) A step of drying and sizing the above mixture to produce granules;

[0026] 4) A step of adding lupatadine or a pharmaceutically acceptable salt thereof and a disintegrant to the granules;

[0027] 5) Step of manufacturing the mixture of the above 4 into a tablet.

[0028]

[0029] In order to achieve the above purpose, the present invention provides a composition comprising montelukast or a pharmaceutically acceptable salt thereof; and rupatadine or a pharmaceutically acceptable salt thereof; wherein the composition has a pH of 4 to 5.5 due to an added pH adjusting agent.

[0030]

[0031] In order to achieve another object of the present invention, the present invention provides a method for manufacturing a combination tablet of montelukast and rupatadine comprising the following steps:

[0032] 1) Step of preparing a binding solution;

[0033] 2) A step of mixing montelukast or a pharmaceutically acceptable salt thereof; lupatadine or a pharmaceutically acceptable salt thereof; excipients and a pH regulator into the above combination solution;

[0034] 3) A step of drying and sizing the above mixture to produce granules;

[0035] 4) A step of adding a disintegrant to the above granules;

[0036] 5) Step of manufacturing a mixture of the above 4) into a tablet.

[0037]

[0038] In order to achieve another object of the present invention, the present invention provides a method for manufacturing a combination tablet of montelukast and rupatadine comprising the following steps:

[0039] 1) Step of preparing a binding solution;

[0040] 2) A step of mixing montelukast or a pharmaceutically acceptable salt thereof, and an excipient and a pH regulator into the above-mentioned combination solution;

[0041] 3) A step of drying and sizing the above mixture to produce granules;

[0042] 4) A step of adding lupatadine or a pharmaceutically acceptable salt thereof and a disintegrant to the granules;

[0043] 5) Step of manufacturing the mixture of the above 4 into a tablet.

[0044]

[0045] The present invention is described in detail below.

[0046]

[0047] The present invention provides a composition comprising montelukast or a pharmaceutically acceptable salt thereof; and rupatadine or a pharmaceutically acceptable salt thereof, wherein the composition has a pH of 4 to 5.5 due to an added pH adjusting agent.

[0048]

[0049] In the present invention, the 'montelukast' is C 35 H 35 It refers to a compound having the chemical formula of ClNNaO3S and the following [chemical formula 1].

[0050] [Chemical Formula 1]

[0051]

[0052]

[0053] The above-mentioned montelukast is disclosed for use in pulmonary diseases including diseases such as asthma, bronchitis and related obstructive airway diseases, allergic reactions such as allergic rhinitis, contact dermatitis and allergic conjunctivitis, inflammation such as arthritis or inflammatory bowel disease, pain, skin diseases such as psoriasis and atopic eczema, and cardiovascular diseases such as angina pectoris, myocardial ischemia, hypertension and platelet aggregation, as described above, but is mainly used for asthma, exercise-induced bronchospasm, allergic rhinitis and urticaria.

[0054] In the composition according to the present invention, the montelukast may be a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable salts of the montelukast may include, but are not limited to, montelukast sodium, montelukast potassium, montelukast magnesium, and montelukast ammonium.

[0055] Meanwhile, the composition according to the present invention preferably contains 1 to 10 wt%, preferably 2 to 8 wt%, more preferably 3 to 7 wt%, more preferably 4 to 6 wt%, and most preferably 4.5 to 5.5 wt% of montelukast or a pharmaceutically acceptable salt thereof, but is not limited thereto.

[0056]

[0057] In the present invention, the 'rupatadine' is C 26 H 26 It refers to a compound having the chemical formula of ClN3 and the following [chemical formula 2].

[0058] [Chemical Formula 2]

[0059]

[0060]

[0061] As described above, the above-mentioned rupatadine is a second-generation antihistamine that also has the effect of inhibiting inflammatory cell activation factors, thereby exhibiting an antiallergic effect by inhibiting degranulation of mast cells induced by immunological and non-immunological stimuli and inhibiting the release of cytokines, especially tumor necrosis factor, from human mast cells and monocytes. It is sold under various brand names such as Rupafin, Alergoliber, Rinialer, Pafinur, Rupax, and Ralif.

[0062] In the composition according to the present invention, the rupatadine may be a pharmaceutically acceptable salt thereof, and examples of the pharmaceutically acceptable salt of the rupatadine include, but are not limited to, rupatadine fumarate, rupatadine dihydrogenchoride, rupatadine trihydrogenchloride, rupatadine hydrogenbromide, rupatadine disulfate, and rupatadine hemisulfate.

[0063] Meanwhile, the composition according to the present invention preferably contains 1 to 10 wt%, preferably 2 to 8 wt%, more preferably 3 to 7 wt%, more preferably 4 to 6 wt%, and most preferably 4.5 to 5.5 wt% of the lupatadine or a pharmaceutically acceptable salt thereof, but is not limited thereto.

[0064]

[0065] In the present invention, the composition is characterized by having an appropriate amount of a pH regulator added thereto. Due to the 'pH regulator', the composition according to the present invention preferably has a pH of 6 or lower, more preferably a pH of 2 to 6 or lower, and most preferably a pH of 4 to 5.5 or lower. As a result of experiments conducted by the inventors of the present invention, compared to a composition without a pH regulator, which generated about 1.2% to 1.4% of reactive substances, the composition according to the present invention generated only about 0.5% to 0.6% of reactive substances within the above pH range, thereby exhibiting excellent stability.

[0066] The above "flexible substances" refer to impurities that remain or decompose during the manufacturing and storage of pharmaceuticals, resulting from exposure to light, temperature, additives, and direct reactions with containers / packaging. These substances, also known as "decomposition products," can reduce the effectiveness of the original pharmaceutical, and furthermore, the resulting flexible substances themselves can have adverse effects, including causing side effects.

[0067] In the present invention, the 'pH adjusting agent' may be any one selected from the group consisting of acetic acid, lactic acid, citric acid, phosphoric acid, succinic acid, tartaric acid, glutamic acid, aspartic acid, oxalic acid, malic acid, sorbic acid, ascorbic acid, alginic acid, fumaric acid, propionic acid, valeric acid, levulinic acid, and hexanoic acid, and is preferably citric acid, but is not limited thereto.

[0068] Meanwhile, the composition according to the present invention preferably contains 0.0001 to 2 wt%, preferably 0.001 to 1.5 wt%, most preferably 0.01 to 1 wt%, and more preferably 0.1 to 0.5 wt% of the pH regulator, but is not limited thereto.

[0069]

[0070] In the present invention, the composition may further comprise one or more pharmaceutically acceptable excipients. The term "pharmaceutically acceptable" refers to a non-toxic composition that is physiologically acceptable, does not inhibit the action of the active ingredient when administered to humans, and typically does not cause allergic reactions such as gastrointestinal upset or dizziness, or similar reactions. Pharmaceutically acceptable excipients included in the above composition include, but are not limited to, those commonly used in formulations, such as lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, silicon dioxide, magnesium stearate, and Opadry, as well as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, red iron oxide, yellow iron oxide, and mineral oil.

[0071] In addition to the above ingredients, the composition may further include a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, etc. Specifically, in the case of oral administration, a binder, a lubricant, a disintegrating agent, an excipient, a solubilizer, a dispersing agent, a stabilizer, a suspending agent, a coloring agent, or a flavoring agent, etc. may be used, and in the case of injections, a buffer, a preservative, an analgesic, a solubilizer, an isotonic agent, a stabilizer, etc. may be mixed and used, and in the case of topical administration, a base, an excipient, a lubricant, a preservative, etc. may be used.

[0072] In addition, the composition according to the present invention can be used in the form of general pharmaceutical preparations. Parenteral preparations may be prepared in the form of sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions or lyophilized preparations, injections, transdermal preparations, nasal inhalers, etc., and for oral administration, they may be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups or wafers. Injections may be prepared in the form of unit dose ampoules or multiple doses. Injections must be sterilized and protected from contamination by microorganisms such as bacteria and fungi. Examples of suitable carriers for injections include, but are not limited to, solvents or dispersion media including water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycol), mixtures thereof and / or vegetable oils. More preferably, suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) containing triethanolamine, or isotonic solutions such as sterile water for injection, 10% ethanol, 40% propylene glycol, and 5% dextrose. In order to protect the injection from microbial contamination, various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal may be additionally included. In addition, the injection may in most cases additionally contain isotonic agents such as sugars or sodium chloride.

[0073] In addition, the composition according to the present invention can be administered by any device that allows the active ingredient to move to the target site. Preferred administration methods and formulations include intravenous injection, subcutaneous injection, intradermal injection, intramuscular injection, or drip injection. The injection can be prepared using an aqueous solvent such as saline solution or Ringer's solution, a non-aqueous solvent such as vegetable oil, higher fatty acid ester (e.g., ethyl oleate, etc.), alcohol (e.g., ethanol, benzyl alcohol, propylene glycol, or glycerin, etc.), and may include a pharmaceutical carrier such as a stabilizer to prevent deterioration (e.g., ascorbic acid, sodium bisulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), an emulsifier, a buffer to adjust pH, a preservative to inhibit microbial growth (e.g., phenylmercuric nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.). A method for treating or preventing a neurodegenerative disease using the composition of the present invention comprises administering an effective amount (pharmaceutically effective amount) of the therapeutic composition of the present invention to a subject in need thereof. The pharmaceutically effective amount can be readily determined by those skilled in the art based on factors well known in the medical field, such as the type of disease, the patient's age, weight, health, sex, the patient's sensitivity to drugs, the route of administration, the method of administration, the number of administrations, the duration of treatment, and drugs used in combination or concurrently.

[0074] Additionally, the composition according to the present invention can be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.

[0075] Meanwhile, the composition according to the present invention preferably contains 78 to 98.9999 wt%, preferably 80 to 97.5 wt%, most preferably 82 to 95 wt%, and more preferably 85 to 90 wt% of an additive selected from the group consisting of a binder, a lubricant, a disintegrant, an excipient, a dispersant, a stabilizer, a suspending agent, a pigment, a fragrance, a buffer, a preservative, an analgesic, a solubilizer, an isotonic agent, a base, a lubricant, a wetting agent, and combinations thereof, but is not limited thereto.

[0076]

[0077] The total effective amount of the composition of the present invention can be administered to a patient as a single dose, or can be administered by a fractionated treatment protocol in which multiple doses are administered over a long period of time. The pharmaceutical composition of the present invention may vary the content of the active ingredient depending on the severity of the disease. Preferably, the preferred total dosage of the pharmaceutical composition of the present invention may be about 0.01 μg to 10,000 mg per 1 kg of patient body weight per day, and most preferably 0.1 μg to 500 mg. However, since the dosage of the pharmaceutical composition is determined by taking into consideration various factors such as the formulation method, administration route, and number of treatments, as well as the patient's age, weight, health status, sex, severity of the disease, diet, and excretion rate, a person having ordinary skill in the art will be able to determine an appropriate effective dosage of the composition of the present invention considering these points. The pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route, and administration method as long as it exhibits the effects of the present invention.

[0078]

[0079] The composition according to the present invention can be used for the prevention or treatment of any one or more diseases selected from the group consisting of, but not limited to, allergic rhinitis, asthma, urticaria, and itching associated with skin diseases (eczema, dermatitis, and itchy skin).

[0080] In the present invention, "prevention" refers to any action that reduces the frequency or severity of a pathological phenomenon. Prevention may be complete or partial. In this case, it may refer to a reduction in carcinogenic symptoms within an individual compared to when the composition is not used.

[0081] In addition, in the present invention, the term 'treatment' means any act of clinical intervention to change the natural process of a subject or cell to be treated, and may be performed during the progression of a clinical pathological condition or to prevent it.

[0082] The desired therapeutic effect may include preventing the occurrence or recurrence of a disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, slowing the progression of the disease, alleviating or temporarily alleviating the disease state, or improving the prognosis.

[0083]

[0084] The present invention also provides a method for preparing a combination tablet of montelukast and rupatadine, comprising the following steps:

[0085] 1) A step of preparing a binding solution containing a pH regulator;

[0086] 2) A step of mixing montelukast or a pharmaceutically acceptable salt thereof; lupatadine or a pharmaceutically acceptable salt thereof; and an excipient into the above combination solution;

[0087] 3) A step of drying and sizing the above mixture to produce granules;

[0088] 4) A step of adding a disintegrant to the above granules;

[0089] 5) Step of manufacturing a mixture of the above 4) into a tablet.

[0090]

[0091] The present invention also provides a method for preparing a combination tablet of montelukast and rupatadine, comprising the following steps:

[0092] 1) A step of preparing a binding solution containing a pH regulator;

[0093] 2) A step of mixing montelukast or a pharmaceutically acceptable salt thereof and an excipient into the above-mentioned combination solution;

[0094] 3) A step of drying and sizing the above mixture to produce granules;

[0095] 4) A step of adding lupatadine or a pharmaceutically acceptable salt thereof and a disintegrant to the granules;

[0096] 5) Step of manufacturing the mixture of the above 4 into a tablet.

[0097]

[0098] In the manufacturing method according to the present invention, terms that overlap with the terms described above are as described above, and therefore, below, terms unique to the manufacturing method are specifically described according to the manufacturing method step.

[0099]

[0100] 1) A step of preparing a binding solution containing a pH regulator;

[0101]

[0102] In the manufacturing method according to the present invention, the 'step of preparing a binding solution' is a step in which the active ingredient and additives are evenly and physically connected together to provide the mixed powder with appropriate binding force and flowability, and is typically a step in which the solvent and binding agent are stirred together to dissolve or swell the binding agent.

[0103] The type of solvent used in this step is not particularly limited, but purified water, ethanol, isopropyl alcohol, and methylene chloride can be used, and purified water is preferably used. The amount of solvent used can be 1 to 10 parts by weight per 1 part by weight of montelukast or lupatadine, but is not limited thereto. The binder can be selected from the group consisting of povidone, hypromellose, hydroxypropylcellulose, copovidone, and any combination thereof, and is preferably hydroxypropylcellulose, but is not limited thereto.

[0104] The manufacturing method according to the present invention relates to a method for manufacturing a composite formulation having improved stability by significantly reducing the generation of flexible substances by adjusting the pH to preferably 6 or lower, more preferably 2 to 6 or lower, and most preferably 4 to 5.5 or lower by a pH adjusting agent added in an appropriate amount as described above. Accordingly, for this purpose, the pH adjusting agent may be added in an appropriate amount in the step of manufacturing the binding solution, but is not limited thereto.

[0105]

[0106] 2) A step of mixing montelukast or a pharmaceutically acceptable salt thereof; lupatadine or a pharmaceutically acceptable salt thereof; excipients and a pH regulator into the above combination solution;

[0107] or,

[0108] 2) A step of mixing montelukast or a pharmaceutically acceptable salt thereof, and an excipient and a pH regulator into the above-mentioned combination solution;

[0109]

[0110] In the manufacturing method according to the present invention, montelukast or a pharmaceutically acceptable salt thereof and rupatadine or a pharmaceutically acceptable salt thereof may be mixed simultaneously in a binding solution, and then dried, sieved, and granulated. It is also possible that montelukast or a pharmaceutically acceptable salt thereof is first mixed in a binding solution, and then dried, sieved, and granulated, and then rupatadine or a pharmaceutically acceptable salt thereof is added together with a disintegrant to manufacture a tablet.

[0111] According to one embodiment of the present invention, it was confirmed that the montelukast and rupatadine-containing composition according to the present invention has a significantly reduced generation of related substances regardless of which of the two methods is used for manufacturing, and therefore, in the process of carrying out the present invention, either of the two methods may be selected depending on the convenience of carrying out the manufacturing method.

[0112]

[0113] 3) A step of drying and sizing the above mixture to produce granules;

[0114]

[0115] In the manufacturing method according to the present invention, the 'drying' is a process of evaporating moisture from a wet mass, which is generally made by evenly mixing a binder and a mixed powder, by applying an appropriate temperature to the wet mass to make it into a powder having an appropriate hardness. In the technical field to which the present invention pertains, including one embodiment of the present invention, a method of evenly spreading the wet mass on a plate and placing it in a drying oven and a method of drying the powder while fluidizing it using air at a constant temperature are widely used, but are not particularly limited thereto, and any method widely known to those skilled in the art as a tablet manufacturing method in the pharmaceutical industry can be used without limitation.

[0116] In the manufacturing method according to the present invention, the 'establishment' is a method of applying a physical force to an appropriately dried solid to pass through a mesh of a certain size to have a certain particle size distribution, and the mesh size is selected within the range of 0.5 mm to 2.0 mm, but may suitably be a mesh of 0.8 mm to 1.5 mm in size.

[0117]

[0118] 4) A step of adding a disintegrant to the above granules;

[0119] or

[0120] 4) A step of adding lupatadine or a pharmaceutically acceptable salt thereof and a disintegrant to the granules;

[0121]

[0122] In the manufacturing method according to the present invention, the 'disintegrant' is an additive used to accelerate the phenomenon of dissolving in water so that the solid pharmaceutical composition is appropriately disintegrated and the active ingredient can exhibit the expected pharmacological effect, and examples thereof include, but are not limited to, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, pregelatinized starch, and carboxymethyl cellulose calcium.

[0123] Additionally, as described above, when montelukast and rupatadine are separated and granulated, rupatadine or a pharmaceutically acceptable salt thereof may be added together with a disintegrant at this step.

[0124]

[0125] 5) Step of manufacturing a mixture of the above 4) into a tablet.

[0126]

[0127] In the manufacturing method according to the present invention, the "step of manufacturing into a tablet" is a step of tableting widely known in the pharmaceutical industry, and refers to a method of compressing a mixed powder into a tablet of a certain shape. This is not limited to a manufacturing method of simply compressing a single mixed powder, and may be a multilayer tablet in which powders of different compositions are layered and compression-molded multiple times by an appropriate method, or a cored tablet in which an inner core is coated with an outer layer of a different composition, and preferably, it may include a core and a coating layer.

[0128] Therefore, in the manufacturing method according to the present invention, the 'step of manufacturing into a tablet' may additionally include the 'step of coating the tablet to manufacture into a coated tablet'.

[0129]

[0130] Accordingly, the present invention provides a composition comprising montelukast or a pharmaceutically acceptable salt thereof and rupatadine or a pharmaceutically acceptable salt thereof, and to which a pH adjusting agent is added, and a method for preparing the same. The composition according to the present invention has a pH of 4 to 5.5 due to the pH adjusting agent, thereby reducing the generation of volatile substances and exhibiting excellent stability.

[0131]

[0132] Figure 1 is a diagram illustrating the montelukast-derived flexible substances of montelukast and lupatadine compositions with added pH adjusters (Examples 1 and 2) and compositions without added pH adjusters (Comparative Examples 1 and 2).

[0133]

[0134] The present invention is described in detail below.

[0135] However, the following examples are only illustrative of the present invention, and the content of the present invention is not limited to the following examples.

[0136]

[0137] Preparation of Examples and Comparative Examples

[0138] For the stability test of montelukast and lupatadine, two types of composite matrix tablets containing montelukast and lupatadine (Examples 1 and 2), a tablet containing only montelukast (Comparative Example 1), and a bilayer tablet containing montelukast and lupatadine (Comparative Example 2) were manufactured, respectively.

[0139]

[0140] Example 1: Preparation of composite matrix tablet 1 containing montelukast and rupatadine (simultaneous granulation of both components)

[0141] A binding solution was prepared by dissolving hydroxypropyl cellulose and a pH adjuster in purified water. The binding solution was combined with montelukast sodium, rupatadine fumarate, lactose hydrate, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose, and then dried and refined to prepare granules.

[0142] The final mixture was completed by mixing silicon dioxide, croscarmellose sodium, and magnesium stearate with the above granules. The mixture was compressed into tablets using a round punch. Opadry (20A630011) was mixed with ethanol and purified water to create a coating solution, and the tablets thus manufactured were coated.

[0143]

[0144] Example 2: Preparation of composite matrix tablet 2 containing montelukast and rupatadine (two-component separated granules)

[0145] Hydroxypropyl cellulose and a pH adjuster were dissolved in purified water to prepare a binding solution. The binding solution was combined with montelukast sodium, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and hydroxypropyl cellulose, and then dried and granulated to prepare granules.

[0146] The final mixture was prepared by mixing the above granules with rupatadine fumarate, lactose monohydrate, silicon dioxide, croscarmellose sodium, and magnesium stearate. The mixture was compressed into tablets using a round punch. Opadry (20A630011) was mixed with ethanol and purified water to prepare a coating solution, and the tablets thus prepared were coated.

[0147]

[0148] Comparative Example 1: Preparation of a single tablet of montelukast

[0149] Tablets were manufactured in the same manner as in Example 1, except that rupatadine fumarate and pH adjuster were not added during granule manufacturing.

[0150]

[0151] The specific components and compositions of Examples 1, 2 and Comparative Example 1 are as shown in Table 1 below.

[0152]

[0153] Raw material name Amount (mg) Example 1 Example 2 Comparative Example 1 Montelukast sodium 10.4 10.4 10.4 Lupatadine fumarate 12.8 12.8-Lactose hydrate 103.0 124.8 103.0 Microcrystalline cellulose 92.8 65.6 65.6 Croscarmellose sodium 10.0 12.0 10.0 pH regulator Amount Amount -Hydroxypropylcellulose 6.0 6.0 6.0 Silicon dioxide 3.0 3.6 3.0 Magnesium stearate 2.0 4.8 2.0 Opadry (20A630011) 9.0 9.0 5.0

[0154]

[0155] Comparative Example 2: Preparation of a composite bilayer tablet containing montelukast and rupatadine

[0156] Montelukast sodium, MicroceLac® 100, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, and magnesium stearate were sieved and mixed to prepare a mixed powder containing montelukast.

[0157] Meanwhile, when manufacturing the rupatadine-containing layer, rupatadine fumarate, pregelatinized starch, microcrystalline cellulose, lactose monohydrate, red iron oxide, and yellow iron oxide were sieved and mixed, then combined using purified water, dried, and granulated to manufacture the granular portion of the rupatadine-containing layer. Magnesium stearate was also mixed into the granular portion to manufacture the mixed portion of the rupatadine-containing layer.

[0158] A bilayer tablet was manufactured by pressing the mixed portion containing muntelukast as the first layer and the mixed portion containing rupatadine as the second layer using a circular punch. Opadry (20A630011) was mixed with ethanol and purified water to make a coating solution, and the manufactured tablets were coated.

[0159]

[0160] The specific components and composition of the above comparative example 2 are as shown in Table 2 below.

[0161]

[0162] Ingredients, name, amount (mg), comparative example 2, Montelukast sodium 10.4, Microcell 100, 119.6, Microcrystalline cellulose 60.0, Croscarmellose sodium 5.0, Silicon dioxide 3.0, Magnesium stearate 2.0, Montelukast mixed part total 200.0, Lupatadine fumarate 12.8, Pregelatinized starch 20.0, Microcrystalline cellulose 15.0, Lactose monohydrate 50.1, Red iron oxide 0.025, Yellow iron oxide 0.075, Magnesium stearate 2.0, Lupatadine mixed part total 100.0, Opadry (20A630011) 9.0

[0163]

[0164] Comparative tests for examples and comparative examples

[0165] Test Example 1: Stability Test under Harsh Storage Conditions

[0166] For the tablets manufactured in Examples 1 and 2 and Comparative Examples 1 and 2, the stability was compared by measuring the amount of generated flexible substances of montelukast and rupatadine under various analysis conditions after storage under the conditions below.

[0167]

[0168] Harsh storage conditions

[0169] Storage conditions: Stored in Alu-Alu packaging at 60±2℃ and 80±5% relative humidity.

[0170] Test time: 2 weeks of storage under initial and harsh conditions

[0171] Analytical substances: Montelukast, related substances from lupatadine

[0172]

[0173] <Montelukast flexible substance analysis conditions>

[0174] Detector: UV spectrophotometer (measurement wavelength: 255 nm)

[0175] Column: A column filled with 3.0 ㎛ pegylated silica gel for liquid chromatography in a stainless steel tube with an inner diameter of approximately 3.0 mm and a length of approximately 100 mm.

[0176] Column temperature: around 50℃

[0177] Mobile phase A - water: trifluoroacetic acid = 1000 : 2 (v / v)

[0178] Mobile phase B - methanol: acetonitrile = 3:2 (v / v)

[0179] Detailed moving conditions are as described in [Table 3] below.

[0180]

[0181] Time (min)Mobile Phase A (%)Mobile Phase B (%)0485254555124555222575232575254852304852

[0182]

[0183] <Analysis conditions for rupatadine-related substances>

[0184] Detector: UV spectrophotometer (measurement wavelength: 210 nm)

[0185] Column: A column filled with 5 μm octadecylsilyl silica gel for liquid chromatography in a stainless steel tube with an inner diameter of approximately 3.9 mm and a length of approximately 150 mm.

[0186] Mobile phase A - phosphate buffer (pH 4.4, 50 mM NaH2PO4 * H2O)

[0187] Mobile phase B - acetonitrile

[0188] Detailed moving phase conditions are as described in [Table 4] below.

[0189]

[0190] Time (minutes)Movement phase A (%)Movement phase B (%)08020255050308020358020

[0191]

[0192] The results of measuring flexible substances derived from montelukast under the harsh conditions described above were as shown in [Table 5] below.

[0193]

[0194] Sample Sulfoxide (%) Ketone (%) Cis-Isomers (%) Total Related Materials (%) Example 1 ▲0.44 ▲0.10 ▲0.01 ▲0.53 Example 2 ▲0.45 ▲0.08-▲0.58 Comparative Example 1 ▲1.11 ▲0.06-▲1.22 Comparative Example 2 ▲1.19 ▲0.06 ▲0.05 ▲1.34

[0195]

[0196] Additionally, the results of measurement of flexible substances derived from lupatadine were as shown in [Table 6] below.

[0197]

[0198] Total sample flexible material (%) Example 1 ▲0.19 Example 2 ▲0.15 Comparative example 2 ▲0.13

[0199]

[0200] Test Example 2: pH measurement of a mixed portion containing montelukast

[0201] In order to evaluate the stability of Examples 1 and 2 and Comparative Examples 1 and 2, the pH of the mixture containing montelukast was measured in each. The mixture containing montelukast of Examples 1 and 2 and Comparative Examples 1 and 2 was dispersed in purified water at a ratio of 1:10 (w / w), and then the pH was measured. The results were as described in [Table 7] below.

[0202]

[0203] Classification Example 1 Example 2 Comparative Example 1 Comparative Example 2 pH 5.175.389.239.25

[0204]

[0205] As can be seen in Tables 5 and 6 above, the results of the measurement of flexible substances and pH showed that all the tablets of the examples and comparative examples showed an increase in the amount of flexible substances generated under harsh storage conditions, but there was a difference in the amount of increase or decrease.

[0206] As a result of comparing the increase in the amount of rupatadine-derived flexible substances in Examples 1 and 2 and Comparative Example 2, the degree of physical separation from the montelukast component did not significantly affect the stability of rupatadine (see Table 6 above).

[0207] On the other hand, when examining the results of Example 1 and Comparative Examples 1 and 2, the stability of montelukast in the matrix formulation containing rupatadine fumarate and a pH regulator was improved compared to the stability of montelukast contained in the bilayer tablet of montelukast and rupatadine complex, and this was also greatly improved compared to the montelukast single formulation (Comparative Example 1) (see Table 5 above).

[0208] As can be seen in Table 7 above, the difference in stability of montelukast was found to be greatly affected by the pH of the mixed dispersion containing the component.

[0209] These results show that the stability of montelukast can be improved by creating an appropriate pH environment by adding a pH regulator during the manufacture of montelukast and lupatadine combination tablets.

[0210]

[0211] As described above, the composition comprising montelukast or a pharmaceutically acceptable salt thereof according to the present invention and rupatadine or a pharmaceutically acceptable salt thereof and to which a pH adjusting agent is added has a reduced amount of flexible substances and excellent stability, and thus has high industrial applicability.

Claims

1. A composition comprising montelukast or a pharmaceutically acceptable salt thereof; and rupatadine or a pharmaceutically acceptable salt thereof; wherein the composition has a pH of 4.0 to 5.5 due to an added pH adjusting agent.

2. A composition according to claim 1, characterized in that the montelukast or a pharmaceutically acceptable salt thereof is any one selected from the group consisting of montelukast sodium, montelukast potassium, montelukast magnesium, and montelukast ammonium.

3. A composition according to claim 1, characterized in that the rupatadine or a pharmaceutically acceptable salt thereof is any one selected from the group consisting of rupatadine fumarate, rupatadine dihydrogenchoride, rupatadine trihydrogenchloride, rupatadine hydrogenbromide, rupatadine disulfate, and rupatadine hemisulfate.

4. A composition according to claim 1, characterized in that it contains 1 to 10 wt% of montelukast or a pharmaceutically acceptable salt thereof.

5. A composition according to claim 1, characterized in that the pH adjusting agent is at least one selected from the group consisting of acetic acid, lactic acid, citric acid, phosphoric acid, succinic acid, tartaric acid, glutamic acid, aspartic acid, oxalic acid, malic acid, sorbic acid, ascorbic acid, alginic acid, fumaric acid, propionic acid, valeric acid, levulinic acid, and hexanoic acid.

6. A composition according to claim 1, characterized in that it contains 1 to 10 wt% of the lupatadine or a pharmaceutically acceptable salt thereof.

7. A composition according to claim 1, characterized in that the composition further comprises one or more excipients.

8. A pharmaceutical composition for preventing or treating itching associated with allergic rhinitis, asthma, urticaria, and skin diseases (eczema, dermatitis, and itchy skin), comprising a composition according to claims 1 to 7.

9. A method for manufacturing a combination tablet of montelukast and rupatadine comprising the following steps: 1) Step of preparing a binding solution; 2) A step of mixing montelukast or a pharmaceutically acceptable salt thereof; lupatadine or a pharmaceutically acceptable salt thereof; excipients and a pH regulator into the above combination solution; 3) A step of drying and sizing the above mixture to produce granules; 4) A step of adding a disintegrant to the above granules; 5) A step of manufacturing a mixture of the above 4) into a tablet.

10. A method for manufacturing a combination tablet of montelukast and rupatadine comprising the following steps: 1) Step of preparing a binding solution; 2) A step of mixing montelukast or a pharmaceutically acceptable salt thereof; and an excipient and a pH regulator into the above combination solution; 3) A step of drying and sizing the above mixture to produce granules; 4) A step of adding lupatadine or a pharmaceutically acceptable salt thereof and a disintegrant to the granule; 5) Step of manufacturing the mixture of the above 4 into a tablet.

11. A method for producing a combination tablet of montelukast and lupatadine, characterized in that in claim 9 or 10, the montelukast or a pharmaceutically acceptable salt thereof is any one selected from the group consisting of montelukast sodium, montelukast potassium, montelukast magnesium, and montelukast ammonium.

12. A method for producing a combination tablet of montelukast and rupatadine, characterized in that in claim 9 or 10, the rupatadine or a pharmaceutically acceptable salt thereof is any one selected from the group consisting of rupatadine fumarate, rupatadine dihydrogenchoride, rupatadine trihydrogenchloride, rupatadine hydrogenbromide, rupatadine disulfate, and rupatadine hemisulfate.

13. A method for producing a combination tablet of montelukast and lupatadine, characterized in that in claim 9 or 10, the pH adjusting agent is at least one selected from the group consisting of acetic acid, lactic acid, citric acid, phosphoric acid, succinic acid, tartaric acid, glutamic acid, aspartic acid, oxalic acid, malic acid, sorbic acid, ascorbic acid, alginic acid, fumaric acid, propionic acid, valeric acid, levulinic acid, and hexanoic acid.

14. A method for manufacturing a composite tablet according to claim 9 or 10, characterized in that step 5) further includes a step of manufacturing a coated tablet by coating the tablet.

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