Pharmaceutical composition comprising bepotastine and pranlukast

Abstract

Disclosed is a pharmaceutical composition comprising bepotastine or a pharmaceutically acceptable salt thereof, pranlukast or a pharmaceutically acceptable salt thereof, or a hydrate thereof as a main ingredient, and capable of inhibiting the generation of related substances by using an antioxidant.

Description

Pharmaceutical composition containing bepotastine and pranlukast

[0001] The present invention relates to a pharmaceutical composition containing bepotastine and pranlukast, and more particularly, to a pharmaceutical composition comprising bepotastine or a pharmaceutically acceptable salt thereof and pranlukast or a pharmaceutically acceptable salt thereof, or a hydrate thereof, as main components, and capable of suppressing the level of generation of related substances using an antioxidant.

[0002] While allergic rhinitis and asthma can occur independently, research suggests that 58% of rhinitis patients also have asthma, and 85-95% of asthma patients also have rhinitis, suggesting a high prevalence of both conditions. Therefore, the development of a combination drug with superior safety and efficacy that can simultaneously treat both conditions is essential.

[0003] Bepotastine is an antihistamine used for the treatment of perennial allergic rhinitis, chronic urticaria, and pruritus associated with skin diseases (eczema, dermatitis, prurigo, and prurigo). Currently, Turion Tablets (Dong-A Pharmaceutical) and Bepostavi Tablets (Daewon Pharmaceutical) are approved for the treatment of allergic rhinitis and are commercially available.

[0004] Pranlukast is an antileukotriene agent used for the treatment of bronchial asthma and allergic rhinitis. Currently, Onon Capsules (Dong-A ST), Pranair Capsules (SK Chemical), Prakanon Tablets (Yuhan Corporation), and Citus Tablets (Sam-A Pharmaceutical) are approved for the treatment of allergic rhinitis and bronchial asthma and are commercially available.

[0005] Therefore, a combination formulation containing both bepotastine and pranlukast may be considered for patients with allergic rhinitis and asthma, and a combination formulation containing both drugs in one unit dosage form is advantageous in terms of patient compliance.

[0006] Pranlukast has strong adhesion and cohesion and very low solubility (1.2 μg / ml), resulting in lower bioavailability when administered orally compared to other drugs. Therefore, to improve bioavailability, various solubilizers (surfactants) are used together. However, these solubilizers contain large amounts of peroxide, which can react with other drugs susceptible to oxidation to produce oxidizing compounds.

[0007] Bepotastine is not physicochemically stable, making it difficult to ensure its stability. In particular, it has the problem of reacting with peroxides to form volatile compounds.

[0008] The aforementioned characteristics of pranlukast and bepotastine pose significant obstacles to the development of combination formulations. Even if the stability of pranlukast and bepotastine as single agents is ensured, their stability may not be guaranteed in combination formulations.

[0009] Therefore, there is still a need for a combination drug composition with excellent safety and efficacy that includes two drugs, bepotastine and pranlukast, in a single unit dosage form, but has no stability issues and exhibits the same pharmacological effects, enabling simultaneous treatment of allergic rhinitis and asthma, thereby improving patient compliance.

[0010] [Prior Art Literature]

[0011] [Patent Document]

[0012] (Patent Document 1) Korean Patent No. 10-2046395

[0013] (Patent Document 2) Korean Patent No. 10-2363727

[0014] The inventors of the present invention have identified a problem in which the production of volatile compounds significantly increases when bepotastine and pranlukast are used together. To address this issue, the inventors of the present invention aim to provide a combination formulation that suppresses the production of volatile compounds by using an antioxidant.

[0015] The purpose of the present invention is to provide a pharmaceutical composition that uses bepotastine and pranlukast as active ingredients, while suppressing the production of active ingredient-related substances, thereby enabling long-term storage.

[0016] In order to achieve the above purpose, the present invention discloses the following means.

[0017] In one aspect, the present invention discloses a pharmaceutical composition comprising bepotastine or a pharmaceutically acceptable salt thereof; pranlukast or a pharmaceutically acceptable salt thereof, or a hydrate thereof; and an antioxidant.

[0018] The pharmaceutical composition containing bepotastine and pranlukast according to the present invention has the advantage of being able to suppress the level of generation of flexible substances.

[0019] The pharmaceutical composition containing bepotastine and pranlukast according to the present invention has the advantage of being able to be stored for a long period of time while using bepotastine and pranlukast as active ingredients, and suppressing the production of active ingredient-related substances.

[0020] The effects of the present invention are not limited to the effects mentioned above, and various effects may be included within a range apparent to those skilled in the art from the contents described below.

[0021] Hereinafter, the present specification will be described in more detail.

[0022] To explain this more specifically, the terms used in this specification are selected from widely used, general terms, taking into account the functions of the present invention. However, these terms may vary depending on the intentions of engineers working in the field, precedents, the emergence of new technologies, etc. Furthermore, in certain cases, terms may be arbitrarily selected by the applicant, and in such cases, their meanings will be described in detail in the description of the relevant invention. Therefore, the terms used in the present invention should not be defined simply as names of terms, but rather based on the meanings of the terms and the overall content of the present invention.

[0023] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and shall not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0024] Numerical ranges are inclusive of the numbers defined in the ranges above. Every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if that lower numerical limitation were explicitly stated. Every minimum numerical limitation given throughout this specification includes every higher numerical limitation, as if that higher numerical limitation were explicitly stated. Every numerical limitation given throughout this specification will include every better numerical range within that broader numerical range, as if that narrower numerical limitation were explicitly stated.

[0025] The following descriptions and embodiments disclosed in the present invention may also be applied to other descriptions and embodiments. In other words, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention should not be considered limited by the specific descriptions described below.

[0026] Expressions such as “comprising” as used herein should be understood as open-ended terms implying the possibility of including other embodiments, unless specifically stated otherwise in the phrase or sentence in which the expression is included.

[0027] Unless otherwise specified herein, the term weight percent refers to the mass ratio of a particular ingredient to the total pharmaceutical composition into which it is incorporated.

[0028] In this specification, even if it is described as bepotastine or pranlukast, it should be understood that it refers to all salts, hydrates, solvates and isomers mentioned below.

[0029] Hereinafter, the present invention will be described in detail.

[0030] Pharmaceutical composition containing bepotastine and pranlukast

[0031] The present invention discloses a pharmaceutical composition containing bepotastine and pranlukast as follows.

[0032] Specifically, the present invention provides a pharmaceutical composition comprising bepotastine or a pharmaceutically acceptable salt thereof, pranlukast or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and an antioxidant.

[0033] In the present invention, the term "pharmaceutically acceptable salt" includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases. The term "hydrate" refers to a compound of the present invention or a pharmaceutically acceptable salt thereof that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0034] In the present invention, the pharmaceutically acceptable salt of bepotastine may be bepotastine besilate, but is not limited thereto.

[0035] In the present invention, the pharmaceutically acceptable salt of pranlukast or a hydrate thereof may be pranlukast hydrate, but is not limited thereto.

[0036] In the present invention, the amount of bepotastine or a pharmaceutically acceptable salt thereof may be 5 to 15 milligrams, and the amount of pranlukast or a pharmaceutically acceptable salt thereof, or a hydrate thereof may be 30 to 70 milligrams, but is not limited thereto.

[0037] In the present invention, the antioxidant may be at least one selected from the group consisting of propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, sodium bisulfite, sodium metabisulfite, sodium edetate, and citric acid, but is not limited thereto.

[0038] In the present invention, the content of the antioxidant may be 0.2 to 5 wt%, based on the total weight of the entire pharmaceutical composition, and specifically, 0.5 to 2.5 wt%, but is not limited thereto. While the use of more antioxidants stabilizes the main ingredient, the problem of increased volatile substances due to antioxidant decomposition products arises.

[0039] In the present invention, the pharmaceutical composition may additionally include one or more of a diluent, a binder, a disintegrant, a lubricant, and a solubilizer.

[0040] In the present invention, the diluent may be at least one selected from the group consisting of microcrystalline cellulose, lactose, mannitol, corn starch, pregelatinized starch, dicalcium phosphate, and calcium phosphate, and the content of the diluent may be 40 to 80 wt% based on the total weight of the entire pharmaceutical composition, but is not limited thereto.

[0041] In the present invention, the binder may be at least one selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydroxyethyl cellulose, and the content of the binder may be within 10 wt%, specifically 1 to 7 wt%, based on the total weight of the entire pharmaceutical composition, but is not limited thereto.

[0042] In the present invention, the disintegrant may be at least one selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, and alginic acid, and the content of the disintegrant may be 5 to 20 wt%, specifically 7 to 15 wt%, based on the total weight of the entire pharmaceutical composition, but is not limited thereto.

[0043] In the present invention, the lubricant may be at least one selected from the group consisting of colloidal silicon dioxide, stearic acid, magnesium stearate, sodium stearyl fumarate, and talc, and the content of the lubricant may be 2 to 10 wt%, specifically 3 to 6 wt%, based on the total weight of the entire pharmaceutical composition, but is not limited thereto.

[0044] In the present invention, the solubilizer may be at least one selected from the group consisting of polyethylene glycol-15-hydroxystearate (macrogol 15 hydroxystearate), polyoxyethylene-polyoxypropylene copolymer (poloxamer), polyoxyethylene sorbitan fatty acid ester, and sodium lauryl sulfate, and the content of the solubilizer may be 5 to 20 wt%, specifically 5 to 10 wt%, based on the total weight of the entire pharmaceutical composition, but is not limited thereto.

[0045] The pharmaceutical composition of the present invention may be a solid oral preparation, specifically a tablet, granule, fine granule, capsule, or film-coated tablet, and preferably a tablet.

[0046] If the pharmaceutical composition according to the present invention is a tablet, it may be a single tablet or a bilayer tablet (double tablet), and if it is a film-coated tablet, a coating agent widely known in the art may be used, but is not limited thereto.

[0047] Hereinafter, the present invention will be described in more detail using examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples.

[0048] Examples and Comparative Examples

[0049] Examples 1-7. Preparation of granules containing bepotastine

[0050] Bepotastine-containing granules of Examples 1 to 7 were manufactured according to the following manufacturing method with the same ingredients and contents as in Table 1 below.

[0051] Specifically, the main ingredient and diluent were passed through a sieve, placed in a high-speed mixer, and uniformly mixed. A binder and antioxidant were dissolved in a solvent to form a binder solution, which was then used to mix the mixture of the main ingredient and the diluent to form granules. The granules were taken out, placed in a fluidized bed dryer, dried, and then granulated. The granules were sieved, and a disintegrant and a lubricant were mixed to prepare granules containing bepotastine according to Examples 1 to 7.

[0052] Unit (mg) Ingredient name Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Bepotastine besilate 10101010101010 D-mannitol 86.58 7.38 2.8 ---- Microcrystalline cellulose 12 10.7 10.79 3.59 587.59 3.0 Propyl gallate--3.0 ---- Butylated hydroxytoluene ---- 3.0 - 2.0 Butylated hydroxyanisole--- 3.0 - 0.5- polyvinyl alcohol 0.76 ------ Povidone K30-9.59.59.59.518.09.5Crospovidone-1.02.52.51.02.52.5Colloidal silicon dioxide------1.5Magnesium stearate1.51.51.51.51.51.51.51.5WaterQuantityQuantity---QuantityQuantityQuantityEthanol--QuantityQuantityQuantityQuantityQuantity

[0053] Examples 8-15. Preparation of granules containing pranlukast

[0054] Granules containing pranlukast of Examples 8 to 15 were manufactured according to the following manufacturing method with the ingredients and contents as shown in Table 2 below.

[0055] Specifically, the main ingredient, diluent, and part of the lubricant were passed through a sieve, placed in a high-speed mixer, and mixed uniformly. A binder, an antioxidant, and a solubilizer were dissolved in a solvent to form a binder solution, and the mixture of the main ingredient, the diluent, and part of the lubricant was combined to form a granule. The granule was taken out, placed in a fluidized bed dryer, dried, and then granulated. The granules were sieved, and the disintegrant and lubricant were mixed to prepare granules containing pranlukast according to Examples 8 to 15.

[0056] Unit (mg) Ingredient Name Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 Pranlukast Hydrate 50.050.050.050.050.050.050.050.050.0 D-Mannitol 61.060.060.060.060.071.060.060.0 Microcrystalline Cellulose 41.041.041.041.090.041.090.090.0 Dicalcium Phosphate-----80.0--Povidone K304.04.04.04.011.04.011.011.0Propyl gallate----3.0--3.0Butylated hydroxytoluene-5.6-5.6-1.0Butylated hydroxyanisole--3.03.0--2.5Macrogol 15hydroxystearate12.012.012.012.012.012.012.012.0Poloxamer 40721.021.021.021.021.021.021.021.021.0Crospovidone30.050.050.050.050.040.050.050.0Colloidal silicon dioxide5.012.012.012.012.010.012.012.0Sodium stearyl fumarate----9.0---Magnesium stearate3.59.09.09.0-9.09.09.0EthanolQuantityQuantityQuantityQuantityQuantityQuantityQuantity

[0057] Comparative Example 1 and Examples 16 to 23. Preparation of tablets containing bepotastine and pranlukast.

[0058] According to the composition in Table 3 below, tablets containing bepotastine and pranlukast in the form of single or double-layer tablets were manufactured using a tablet press.

[0059] Unit (mg) Classification Comparative Example 1 Example 16 Example 17 Example 18 Example 19-1 Example 19-2 Example 20 Example 21 Example 22 Example 23 Two-layer tablet Two-layer tablet Two-layer tablet Two-layer tablet Single tablet Two-layer tablet Two-layer tablet Two-layer tablet Two-layer tablet Bepotastine granules Example 1110.76---------Example 2-120.0120.0120.0------Example 3----120.0120.0----Example 4------120.0---Example 5-------120.0--Example 6--------120.0-Example 7---------120.0 Pranlukast granules Example 8227.5---------Example 9-264.6--------Example 10--262.0-------Example 11---267.6-------Example 12----318.0318.0318.0---Example 13-------339.0--Example 14--------317.5-Example 15---------318.0

[0060] Experimental example

[0061] Experimental Example 1: Stability Test of Commercially Available Formulations

[0062] Test method

[0063] Commercially available formulations, Turion Tablets (Bepotastine Besilate) and Citus Tablets 50 mg (Pranlukast Hydrate), and the crushed mixtures of each tablet crushed in a blender were placed in petri dishes and exposed to 60°C and 90°C for 2 weeks and 5 hours, respectively. The stability was confirmed by evaluating the total amount of flexible substances generated in each sample, and the results are shown in Table 4.

[0064] test

[0065] Referring to Table 4, the total amount of flexible substances for Turion tablets and Citus tablets 50 mg was confirmed to significantly increase when the two products were combined.

[0066] Total flexible substance (%) Test group Turion Jeong C-Tooth Tablet 50mg crushed mixture Before exposure (start) 0.000.000.0460℃, 2 weeks 3.697.2332.5190℃, 5 hours 17.192.4733.22

[0067] Experimental Example 2: Testing of Bepotastine-derived flexible substances

[0068] Test method

[0069] The formulations of Comparative Example 1 and Examples 16 to 23 were placed in glass vials and exposed to 90°C for 24 hours, and then the bepotastine-derived flexible substances of each sample were evaluated, and the results are shown in Table 5.

[0070] test

[0071] Referring to Table 5, it was confirmed that Comparative Example 1, which did not use an antioxidant, showed a significant increase in flexible substances compared to Examples 16 to 23.

[0072] Total flexible material (%) Comparative example 17.68 Example 19-23.50 Example 162.26 Example 201.15 Example 171.97 Example 210.48 Example 181.88 Example 221.33 Example 19-13.75 Example 230.43

[0073] Experimental Example 3: Testing of flexible substances derived from pranlukast

[0074] Test method

[0075] The formulations of Comparative Example 1 and Examples 16 to 23 were placed in glass vials and exposed to 90°C for 24 hours, and then the pranlukast-derived flexible substances of each sample were evaluated, and the results are shown in Table 6.

[0076] test

[0077] Referring to Table 6, it was confirmed that Comparative Example 1, which did not use an antioxidant, showed a significant increase in flexible substances compared to Examples 16 to 23.

[0078] Pranlukast Total Flexible Material (%) Comparative Example 10.8 Example 19-20.16 Example 160.18 Example 200.25 Example 170.26 Example 210.17 Example 180.24 Example 220.27 Example 19-10.15 Example 230.17

[0079] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the relevant technical field that these specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims

1. A pharmaceutical composition comprising bepotastine or a pharmaceutically acceptable salt thereof; pranlukast or a pharmaceutically acceptable salt thereof; and an antioxidant.

2. A pharmaceutical composition in claim 1, wherein the antioxidant is at least one selected from the group consisting of propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, sodium bisulfite, sodium metabisulfite, sodium edetate, and citric acid.

3. A pharmaceutical composition according to claim 1, wherein the content of the antioxidant is 0.2 to 5 wt% based on the total weight of the entire pharmaceutical composition.