Pharmaceutical composition having improved bioavailability of pranlukast, and preparation method therefor

Abstract

The present invention relates to a pharmaceutical composition having improved bioavailability of pranlukast, and a preparation method therefor, and, more specifically, to a pharmaceutical composition and a preparation method therefor, the composition comprising, on the basis of 15-25 parts by weight of pranlukast, 0.1 to 10 parts by weight of a water-soluble polymer and 0.1 to 5 parts by weight of a silica-based superplasticizer, thereby exhibiting drug efficacy that is at least clinically equal to that of commercially available formulations even if the amount of pranlukast is reduced to 50 mg / tablet or less (1 tablet taken twice per day), and thus improves patient drug compliance and reduces side effects caused by taking an excessive amount of pranlukast.

Description

Pharmaceutical composition with improved bioavailability of pranlukast and method for preparing the same

[0001] The present invention relates to a pharmaceutical composition having improved bioavailability of pranlukast, a poorly soluble drug, and a method for producing the same.

[0002]

[0003] Pranlukast has a problem in that it is practically insoluble in water and has strong adhesive properties, so it has low bioavailability when administered orally, requiring a larger dose than the patient needs.

[0004] In this regard, Korean Patent Registration No. 10-0389606 proposed a method of dissolving sugars, water-soluble polymers, and surfactants in purified water, suspending pranlukast, and spray drying, thereby improving the adhesion and cohesion of pranlukast, but not its solubility.

[0005] Korean Patent Registration No. 10-0381834 prepares a solid dispersion by dissolving pranlukast in a mixed solution of dichloromethane and methanol and spray drying it. However, it has the disadvantage of requiring a separate moisture-proof coating and moisture-proof packaging because it uses a large amount of disintegrant to increase solubility and formulate it into tablets.

[0006] Korean Patent No. 10-1332223 discloses a method for producing a nano-solid dispersion using a hot-melt method and a solvent evaporation method to increase the solubility of pranlukast. However, the hot-melt method has difficulties in commercialization due to the high manufacturing cost. To solve this problem, Korean Patent No. 10-1086254 and 10-1233235 used the hot-melt method to increase the solubility of pranlukast and added an anti-caking agent with a certain HLB range to produce a pranlukast solid dispersion. This is currently commercialized as Pranair Capsule (pranlukast 112.5 mg / capsule, 1 capsule per dose, SK Chemical). This product has the characteristic of reducing the dosage by half compared to Onon Capsule, but the hot-melt method requires special manufacturing equipment and has high manufacturing cost, so it can be seen as having low industrial value.

[0007] In addition, Korean Patent Registration Nos. 10-0715355 and 10-0981751 disclose a pharmaceutical composition in tablet form comprising spray-dried granules composed of a water-soluble polymer and a surfactant to improve the adhesion, cohesion, and solubility of pranlukast. This composition is currently commercially available as Prakanone Tablets (pranlukast 75 mg / tablet, 1 tablet per dose, Yuhan Corporation). However, the spray-dried device has the disadvantages of being complex and bulky, requiring high one-time investment costs, and having low thermal efficiency, resulting in high energy consumption. In addition, the high amount of surfactant used may cause problems during the manufacturing process.

[0008] In the case of Korean Patent Registration No. 10-2363727, a pharmaceutical carrier containing pranlukast manufactured using an alcohol having 1 to 6 carbon atoms by a wet granulation method is characterized by a single pranlukast dosage of 70 mg or less. However, since the amount of alcohol used is 1 to 1.7 times that of pranlukast, there is a possibility of environmental pollution by organic solvents. In addition, when using a paste-type surfactant, the viscosity of the surfactant may vary depending on the storage temperature, which may cause problems in the manufacturing process and may ultimately affect the density and particle size distribution of the granules.

[0009] As described above, prior patents have applied various methods to reduce the single dose of pranlukast. However, there is still a need to further improve bioavailability to reduce the dosage. Furthermore, reducing the dosage and frequency of administration can improve patient compliance and reduce the side effects associated with high-dose administration. Furthermore, the development of new manufacturing methods that are advantageous for industrial applications is necessary.

[0010]

[0011] The purpose of the present invention is to provide a pharmaceutical composition having improved dissolution rate and bioavailability of pranlukast and a method for producing the same.

[0012] The purpose of the present invention is to provide a pharmaceutical composition having improved solubility of pranlukast and a method for producing the same.

[0013]

[0014] 1. A pharmaceutical composition comprising 15 to 25 parts by weight of pranlukast; 0.1 to 10 parts by weight of a water-soluble polymer; and 0.1 to 5 parts by weight of a silica-based fluidizing agent.

[0015] 2. In the above 1, pranlukast is a pharmaceutical composition having a particle size distribution of D(0.50) of 0.1 to 2.0 μm and D(0.90) of 1.6 to 7.0 μm.

[0016] 3. A pharmaceutical composition in the above 1, wherein the water-soluble polymer is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinylpyrrolidone vinyl acetate, and polyvinyl alcohol.

[0017] 4. A pharmaceutical composition in which the silica-based fluidizing agent in the above 1 is at least one selected from the group consisting of silica, light anhydrous silica, colloidal silica, hydrous silica, silicate, magnesium silicate, magnesium trisilicate, and magnesium aluminum silicate.

[0018] 5. A pharmaceutical composition further comprising 1 to 30 parts by weight of at least one solubilizing agent selected from the group consisting of sodium lauryl sulfate, polyethylene glycol-15 hydroxystearate, cremophor, poloxamer, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohol, lecithin, and glyceryl fatty acid ester in the above 1.

[0019] 6. A pharmaceutical composition further comprising 1 to 20 parts by weight of at least one disintegrant selected from the group consisting of sodium starch glycolate, croscarmellose, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, and alginic acid in the above 1.

[0020] 7. A pharmaceutical composition further comprising 40 to 80 parts by weight of at least one diluent selected from the group consisting of microcrystalline cellulose, crystalline cellulose, mannitol, lactose monohydrate, starch, and pregelatinized starch in the above 1.

[0021] 8. A pharmaceutical composition comprising pranlukast in an amount of 50 mg or less in the above 1.

[0022] 9. A pharmaceutical composition formulated as a powder, granule, capsule, tablet or dry syrup in the above 1.

[0023] 10. A method for manufacturing a pharmaceutical composition, comprising the steps of mixing pranlukast, a diluent, a silica-based fluidizing agent, and a disintegrant in a mixer; performing a first association while dissolving a water-soluble polymer in water and introducing it into the mixer; and performing a second association while suspending or dissolving a solubilizing agent in ethanol and introducing it into the mixer.

[0024] 11. A method for manufacturing a pharmaceutical composition, further comprising the step of drying and establishing a secondary compound in the above 10.

[0025] 12. In the above 10, a method for producing a pharmaceutical composition having a particle size distribution of D(0.50) of 0.1 to 2.0 μm and D(0.90) of 1.6 to 7.0 μm.

[0026] 13. A method for producing a pharmaceutical composition, comprising mixing 40 to 80 parts by weight of a diluent, 0.1 to 5 parts by weight of a silica-based fluidizing agent, and 1 to 20 parts by weight of a disintegrant with respect to 15 to 25 parts by weight of pranlukast in the above 10.

[0027] 14. A method for manufacturing a pharmaceutical composition in the above 10, wherein 0.1 to 10 parts by weight of a water-soluble polymer is added to a mixer for 15 to 25 parts by weight of pranlukast.

[0028] 15. A method for manufacturing a pharmaceutical composition in the above 10, wherein 1 to 30 parts by weight of a solubilizer are added to a mixer for 15 to 25 parts by weight of pranlukast.

[0029] 16. A method for producing a pharmaceutical composition, wherein in the above 10, the water-soluble polymer is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl pyrrolidone vinyl acetate, and polyvinyl alcohol.

[0030] 17. A method for producing a pharmaceutical composition in the above 10, wherein the silica-based fluidizing agent is at least one selected from the group consisting of silica, light anhydrous silica, colloidal silica, hydrous silica, silicate, magnesium silicate, magnesium trisilicate, and magnesium aluminum silicate.

[0031] 18. A method for producing a pharmaceutical composition, wherein in the above 10, the solubilizing agent is at least one selected from the group consisting of sodium lauryl sulfate, polyethylene glycol-15 hydroxystearate, cremophor, poloxamer, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohol, lecithin, and glyceryl fatty acid ester.

[0032] 19. A method for producing a pharmaceutical composition in the above 10, wherein the disintegrant is at least one selected from the group consisting of sodium starch glycolate, croscarmellose, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, and alginic acid.

[0033] 20. A method for manufacturing a pharmaceutical composition, wherein in the above 10, the diluent is at least one selected from the group consisting of microcrystalline cellulose, crystalline cellulose, mannitol, lactose monohydrate, starch, and pregelatinized starch.

[0034] 21. A method for manufacturing a pharmaceutical composition comprising pranlukast in an amount of 50 mg or less in the above 10.

[0035]

[0036] The pharmaceutical composition of the present invention has improved dissolution rate and bioavailability of pranlukast, so that even when the content of pranlukast is reduced to 50 mg / tablet or less (1 tablet at a time, taken twice a day), it shows clinically equivalent or higher efficacy than a single dose of 225 mg of Onon Capsule, a commercially available formulation (112.5 mg of pranlukast / capsule, 2 capsules at a time, taken twice a day).

[0037] The pharmaceutical composition of the present invention can improve patient compliance with medication and reduce side effects caused by excessive intake of pranlukast.

[0038]

[0039] Figure 1 shows comparative dissolution results of Examples 1 to 5 and Onon capsules.

[0040] Figure 2 shows the comparative dissolution results of Examples 11 to 15 and Onon capsules.

[0041] Figure 3 shows the results of the in vivo kinetic evaluation of Example 21 and Onon capsules (112.5 mg*2 caps).

[0042]

[0043] The present invention provides a pharmaceutical composition having improved bioavailability of pranlukast and a method for preparing the same.

[0044] The present invention provides a pharmaceutical composition and a method for preparing the same, which can improve patient compliance and reduce side effects caused by taking excessive amounts of pranlukast by showing clinically equivalent or higher efficacy than a commercially available formulation even when the content of pranlukast is reduced to 50 mg / tablet or less (1 tablet at a time, taken twice a day) by including 0.1 to 10 parts by weight of a water-soluble polymer and 0.1 to 5 parts by weight of a silica-based fluidizing agent relative to 15 to 25 parts by weight of pranlukast.

[0045] Pranlukast is a poorly soluble drug. Pranlukast is preferably micronized to improve solubility. In one embodiment, pranlukast may have a particle size distribution with a D(0,50) of 0.1 to 2.0 μm and a D(0,90) of 1.6 to 7.0 μm.

[0046] Using pranlukast with a fine particle size can help improve solubility and dissolution rate in that the particle surface area increases, but as the particle size decreases, the adhesion and cohesion between particles becomes stronger, which may lower the dissolution rate. In the present invention, the fine particle size pranlukast is uniformly mixed with a diluent, a silica-based fluidizing agent, and a disintegrant, a water-soluble polymer is dissolved in water and added to the mixture to perform the first association, and a solubilizing agent is suspended or dissolved in ethanol and added to the first association to perform the second association. Thus, even if the fine particle size pranlukast is used, the problem of a decrease in solubility and dissolution rate due to the adhesion and cohesion between particles does not occur.

[0047] In one embodiment, the present invention can improve the dissolution rate and bioavailability by granulating the micronized pranlukast drug, which is a poorly soluble drug, using a water-soluble polymer, a solubilizer, and pharmaceutically acceptable additives.

[0048] Water-soluble polymers are used as plasticizers or binders.

[0049] The water-soluble polymer may be any water-soluble polymer commonly used in the pharmaceutical field. In one embodiment, the water-soluble polymer is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinylpyrrolidone vinyl acetate, and polyvinyl alcohol.

[0050] Polyethylene glycol is a nonionic substance with the simplest structure among water-soluble polymers and is effective in improving the solubility of pranlukast. It is preferable to use polyethylene glycol with a molecular weight in the range of 3,000 to 8,000.

[0051] The water-soluble polymer is included in an amount of 0.1 to 10 parts by weight based on 15 to 25 parts by weight of pranlukast. For example, the water-soluble polymer may be included in an amount of 1 to 8 parts by weight, 1 to 6 parts by weight, 1 to 4 parts by weight, or 1 to 3 parts by weight.

[0052] Silica-based fluidizing agents reduce the electrostatic attraction between particles of pranlukast, thereby improving adhesion cohesion and fluidity.

[0053] The silica-based fluidizing agent is at least one selected from the group consisting of silica, light anhydrous silica, colloidal silica, hydrous silica, silicate, magnesium silicate, magnesium trisilicate, and magnesium aluminum silicate.

[0054] The silica-based fluidizing agent is included in an amount of 0.1 to 5 parts by weight based on 15 to 25 parts by weight of pranlukast. For example, the silica-based fluidizing agent may be included in an amount of 0.1 to 4 parts by weight, 0.1 to 3 parts by weight, or 0.1 to 2 parts by weight, and may be included in an amount of 0.5 to 5 parts by weight, 0.5 to 4 parts by weight, 0.5 to 3 parts by weight, or 0.5 to 2 parts by weight.

[0055] The pharmaceutical composition of the present invention may include a solubilizer.

[0056] Surfactants commonly used in the pharmaceutical field can be used as solubilizers. Surfactants include water-soluble and oil-soluble surfactants. In one embodiment, the solubilizer may be at least one selected from the group consisting of sodium lauryl sulfate, polyethylene glycol-15 hydroxystearate, cremophor, poloxamer, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohols, lecithin, and glyceryl fatty acid esters.

[0057] The solubilizer may be included in an amount of 1 to 30 parts by weight based on 15 to 25 parts by weight of pranlukast. For example, the solubilizer may be included in an amount of 5 to 30 parts by weight, 5 to 20 parts by weight, 5 to 10 parts by weight, 10 to 30 parts by weight, or 10 to 20 parts by weight.

[0058] The pharmaceutical composition of the present invention may include a disintegrant.

[0059] A disintegrant is included to ensure that the pharmaceutical composition containing pranlukast disintegrates rapidly in the body and is largely absorbed in the upper part of the small intestine.

[0060] The disintegrant may be any disintegrant commonly used in the pharmaceutical field. In one embodiment, the disintegrant is at least one selected from the group consisting of sodium starch glycolate, croscarmellose, sodium croscarmellose, crospovidone, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, and alginic acid.

[0061] The disintegrant may be included in an amount of 1 to 20 parts by weight based on 15 to 25 parts by weight of pranlukast. In one embodiment, the disintegrant may be included in an amount of 1 to 20 parts by weight or 1 to 10 parts by weight.

[0062] The pharmaceutical composition of the present invention may include a diluent.

[0063] The diluent may be any diluent commonly used in the pharmaceutical field. In one embodiment, the diluent is at least one selected from the group consisting of microcrystalline cellulose, crystalline cellulose, mannitol, lactose monohydrate, starch, and pregelatinized starch.

[0064] The diluent may be included in an amount of 40 to 80 parts by weight based on 15 to 25 parts by weight of pranlukast. In one embodiment, the diluent may be included in an amount of 40 to 70 parts by weight or 50 to 80 parts by weight.

[0065] The pharmaceutical composition of the present invention is manufactured by including the steps of (i) placing pranlukast, a diluent, a silica-based fluidizing agent, and a disintegrant in a mixer and mixing them; (ii) dissolving a water-soluble polymer in water and slowly adding it to the mixer while performing a first association; and (iii) suspending or dissolving a solubilizing agent in ethanol and slowly adding it to the mixer while performing a second association.

[0066] The water-soluble polymer is dissolved in water, and the solubilizing agent (surfactant) is suspended or dissolved in ethanol. The method for preparing the pharmaceutical composition of the present invention does not use organic solvents other than ethanol and uses a small amount of ethanol. In one embodiment, ethanol is used in an amount of less than 25 parts by weight relative to 15 to 25 parts by weight of pranlukast.

[0067] The solubilizer used in the pharmaceutical composition of the present invention is preferably a solid. Paste-type solubilizers may exhibit changes in physicochemical properties depending on storage conditions, which may affect the physical properties (particularly, dissolution rate) of the pharmaceutical composition. Liquid-type solubilizers may weaken the cohesiveness of granules during the tableting process, thereby causing tableting failure.

[0068] The mixer is not limited to a specific one. In one embodiment, the mixer may be a high shear granulator commonly used in the pharmaceutical industry.

[0069] The method for manufacturing the pharmaceutical composition of the present invention may further include (iv) a process of granulating, drying, and sizing the secondary compound. When manufactured in this manner, the pharmaceutical composition of the present invention takes the form of a granule containing pranlukast.

[0070] The method for manufacturing the pharmaceutical composition of the present invention is environmentally friendly because it uses less solvent than other spray drying and granulating methods, and is economical because it does not require equipment such as a high-speed stirrer or spray dryer. For example, a method for manufacturing a suspension (spray) by adding pranlukast while vigorously stirring a solution composed of a water-soluble polymer or a surfactant (e.g., a propeller-equipped stirrer or a homomixer), or a method for manufacturing a spray using a high-pressure homogenizer, etc. and spraying the resulting solution in a fluidized bed granulator or spray dryer of a spray drying method, has the disadvantages of using a large amount of solvent and requiring additional equipment compared to the method for manufacturing the pharmaceutical composition of the present invention.

[0071] In one embodiment, in order to improve the adhesion and cohesion of pranlukast, a pharmaceutical composition comprising pranlukast, a diluent, a silica-based fluidizing agent, and a disintegrant is uniformly mixed in a high-shear mixer to reduce the interparticle attraction of pranlukast and improve the cohesion, and a water-soluble polymer, polyethylene glycol, is dissolved in purified water and slowly added to the high-shear mixer to perform a first association. The purified water reduces the interparticle attraction of pranlukast and at the same time increases the solubility of pranlukast by allowing the water-soluble polymer to attach to the surface of the pranlukast particles. A solubilizing agent (surfactant) with a low critical micelle concentration (CMC) is suspended or dissolved in ethanol and slowly added to the first association to perform a second association. This is a process for attaching the solubilizing agent to the first association. The association is granulated as needed, dried in a fluidized bed dryer, and the dried material is granulated to produce pharmaceutical granules containing pranlukast.

[0072] The pharmaceutical composition of the present invention may be a granule containing pranlukast, and the method for producing the pharmaceutical composition of the present invention may be a wet granulation method.

[0073] The pharmaceutical composition of the present invention may be formulated as a powder, granule, granule, capsule, tablet, dry syrup, etc. The pharmaceutical composition of the present invention may be formulated by including a granule containing pranlukast and an acceptable pharmaceutical additive.

[0074] Acceptable pharmaceutical excipients may include excipients, disintegrants, lubricants, coating agents, etc.

[0075] Excipients include mannitol, sorbitol, refined white sugar, lactose, lactose monohydrate, microcrystalline cellulose, starch, pregelatinized starch, silicified microcrystalline cellulose, corn starch, crystalline cellulose, etc.; disintegrants include sodium starch glycolate, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, etc.; and lubricants include magnesium stearate, stearic acid, sodium stearyl fumarate, colloidal silicon dioxide, silicon dioxide, etc.

[0076] In the case of purification, a process of film coating using a coating agent may be included. The coating agent may be of the Opadry series.

[0077] The type and content of pharmaceutical additives can be selected according to the properties of the composition and can be appropriately selected according to the formulation.

[0078] In one embodiment, the excipient may be included in an amount of 1 to 80 parts by weight, the disintegrant in an amount of 1 to 20 parts by weight, the lubricant in an amount of 0.1 to 10 parts by weight, and the coating agent in an amount of 1 to 5 parts by weight, based on 15 to 25 parts by weight of pranlukast.

[0079] The present invention is described in more detail with the following examples.

[0080]

[0081] Example

[0082] Examples 1 to 5. Evaluation of the effect of solubilizing agents

[0083] Pranlukast, diluent, fluidizing agent, and disintegrant, which were micronized to D(0.50) of 0.1 to 2.0 μm and D(0.90) of 1.6 to 7.0 μm, were placed in a high-shear mixer and mixed. A water-soluble polymer (hydroxypropyl cellulose) was dissolved in water and slowly introduced into the high-shear mixer to perform the first kneading, and each solubilizing agent was suspended or dissolved in ethanol to perform the second kneading. Thereafter, granulation was performed, and the solvent was evaporated using a fluidized bed dryer. The dried product was granulated to obtain a granule containing pranlukast. The compositions of each example are shown in Table 1 below.

[0084]

[0085]

[0086] Examples 6 to 10. Setting the content of the diluent

[0087] Granules containing pranlukast were obtained in the same manner as in Examples 1 to 5. The compositions of each example are shown in Table 2 below.

[0088]

[0089]

[0090] Examples 11 to 15: Setting the content of water-soluble polymer and solubilizer

[0091] Granules containing pranlukast were obtained in the same manner as in Examples 1 to 5. The compositions of each example are shown in Table 3 below.

[0092]

[0093]

[0094] Examples 16 to 21. Preparation of tablets containing pranlukast granules

[0095] Tablets were manufactured using the granules manufactured in Examples 2, 6, 7, 8, 10, and 15 with the ingredients and contents of Table 4. The granules containing pranlukast, excipients, disintegrants, lubricants, and coating agents were placed in a mixer, mixed and lubricated, and tableted and coated to manufacture Examples 16 to 21.

[0096]

[0097] Test Example 1. Comparative dissolution test according to solubilizing agent

[0098] A comparative dissolution test was conducted on one coated tablet obtained by pressing the granules manufactured in Examples 1 to 5 and two Onon capsules (pranlukast 112.5 mg / capsule, 2 capsules taken at a time, Dong-A ST) according to the paddle method of the second dissolution test method of the Korean Pharmacopoeia. The test method is as follows.

[0099] Considering the solubility of pranlukast, a poorly soluble drug, 900 mL of pH 6.8 + 0.2% PSB80 (polysorbate 80) dissolution solution was added and maintained at 37 ± 0.5℃ and stirred at a rotation speed of 50 rpm. 5 mL of the dissolution solution was taken at time points of 10, 15, 30, 45, 60, 90, and 120 minutes, filtered through a 0.45 μm filter, and then analyzed by HPLC. The results are shown in Fig. 1. It was confirmed that the dissolution rate of the pharmaceutical composition of the present invention was significantly increased compared to that of the commercially available formulation, Onon capsule.

[0100]

[0101] Test Example 2. Comparative dissolution test by water-soluble polymer and solubilizer content

[0102] A comparative dissolution test was conducted on one coated tablet obtained by pressing the granules manufactured in Examples 11 to 15 with two Onon capsules using the same method as Test Example 1. The results are shown in Fig. 2. It was confirmed that the pharmaceutical composition of the present invention had a significantly increased dissolution rate compared to the commercially available Onon capsule.

[0103]

[0104] Test Example 3. Evaluation of dynamics in the human body

[0105] The tablets of Example 21, manufactured as coated tablets of Example 15, and commercially available Onon capsules (112.5 mg*2 caps) were used to evaluate the kinetics in the human body.

[0106] Twelve healthy adults aged 18 to 55 years were divided into two groups (n=6). The tablets manufactured in Example 21 (Example 21, pranlukast 50 mg / tablet, 1 tablet) (Group 1) and the commercially available formulation (Onon Capsule 112.5 mg / cap., 2 capsules, total pranlukast 225 mg) (Group 2) were administered crosswise with 200 mL of water on an empty stomach. The washout period was set to 2 weeks. Approximately 5.0 mL of blood was collected immediately before administration and at 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 7.00, 8.00, 10.00, 12.00, and 24.00 hours after administration. The collected blood was placed in a vacuum polyethylene tube containing K3EDTA and centrifuged at 1538±10g for 15 minutes. The plasma was collected and transferred to a polyethylene tube and stored frozen at 120°C±5°C until analysis. The concentration of pranlukast in the plasma was analyzed using UPLC-MS / MS. The results of the analysis are shown in Table 5 and Fig. 3.

[0107] Example 21 tablets manufactured by the manufacturing method according to the present invention had an AUC of 50 mg even when administered at a much lower dose (50 mg) than the existing commercially available Onon Capsule 2 capsules (pranlukast 225 mg). 0-t Wow C maxIt was confirmed that the T / R Ratio of the drug showed the same level of results, and it was confirmed that it could show the same level of efficacy as the commercially available drug. In addition, compared to the existing commercially available drug, T max Since it appears quickly, patients with bronchial asthma and allergic rhinitis, which are indicated for pranlukast, can expect a faster onset of drug effect when taking it, and it was found to be an improvement in therapeutic aspects compared to existing commercially available preparations.

[0108]

Claims

1. A pharmaceutical composition comprising 15 to 25 parts by weight of pranlukast, 0.1 to 10 parts by weight of a water-soluble polymer, and 0.1 to 5 parts by weight of a silica-based fluidizing agent.

2. In claim 1, the pharmaceutical composition has a particle size distribution in which D(0.50) is 0.1 to 2.0 μm and D(0.90) is 1.6 to 7.0 μm.

3. A pharmaceutical composition according to claim 1, wherein the water-soluble polymer is at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinylpyrrolidone vinyl acetate, and polyvinyl alcohol.

4. A pharmaceutical composition according to claim 1, wherein the silica-based fluidizing agent is at least one selected from the group consisting of silica, light anhydrous silica, colloidal silica, hydrous silica, silicate, magnesium silicate, magnesium trisilicate, and magnesium aluminum silicate.

5. A pharmaceutical composition according to claim 1, further comprising 1 to 30 parts by weight of at least one solubilizing agent selected from the group consisting of sodium lauryl sulfate, polyethylene glycol-15 hydroxystearate, cremophor, poloxamer, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohol, lecithin, and glyceryl fatty acid ester.

6. A pharmaceutical composition according to claim 1, further comprising 1 to 20 parts by weight of at least one disintegrant selected from the group consisting of sodium starch glycolate, croscarmellose, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, and alginic acid.

7. A pharmaceutical composition according to claim 1, wherein the pranlukast is contained in an amount of 50 mg or less.

8. A method for producing a pharmaceutical composition, comprising the steps of mixing pranlukast, a diluent, a silica-based fluidizing agent, and a disintegrant in a mixer; performing a first association by dissolving a water-soluble polymer in water and introducing it into the mixer; and performing a second association by suspending or dissolving a solubilizing agent in ethanol and introducing it into the mixer.

9. A method for producing a pharmaceutical composition according to claim 8, wherein 0.1 to 10 parts by weight of the water-soluble polymer is added to the mixer with respect to 15 to 25 parts by weight of the pranlukast.

10. A method for producing a pharmaceutical composition according to claim 8, wherein 1 to 30 parts by weight of the solubilizer is added to the mixer relative to 15 to 25 parts by weight of the pranlukast.

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