Pharmaceutical composition for improving bioavailability of pranlukast and preparation method thereof

Abstract

The present invention relates to a pharmaceutical composition for improving the bioavailability of pranlukast and a method for preparing the same, and more particularly, to a pharmaceutical composition comprising 0.1 to 10 parts by weight of a water-soluble polymer and 0.1 to 5 parts by weight of a silica-based flow aid relative to 15 to 25 parts by weight of pranlukast, thus, even if the pranlukast content is reduced to 50 mg / tablet or less (one tablet each time, twice a day), the composition of the present invention can exhibit bioequivalent or even better pharmacokinetic characteristics than commercially available preparations in the human body, thereby improving the medication compliance of patients and improving the compliance of the patients. The side effect caused by excessive taking of pranlukast is reduced. The invention also discloses a preparation method of the pharmaceutical composition.

Description

Technical Field

[0001] This invention relates to pharmaceutical compositions and methods for preparing prunoxetine, a poorly soluble drug, and to pharmaceutical compositions thereof. Background Technology

[0002] Prunlast is only slightly soluble in water and has strong hydrophobic aggregation properties, resulting in extremely low bioavailability when administered orally. This leads to the problem that the clinical dosage needs to be higher than the actual amount required by the patient.

[0003] In response, Korean Patent No. 10-0389606 proposed a method of dissolving sugars, water-soluble polymers and surfactants in pure water, suspending prenstar in the solution and then spray-drying it. This method improved the adhesion and coagulation properties of prenstar, but failed to improve its solubility.

[0004] Korean Patent No. 10-0381834 describes the preparation of a solid dispersion by dissolving prenstar in a mixed solution of dichloromethane and methanol and then spray drying it. However, in order to improve solubility and make tablets, a large amount of disintegrant is used, which leads to the disadvantage of requiring separate moisture-proof coating and moisture-proof packaging.

[0005] Korean Patent No. 10-1332223 discloses a method for preparing nano-solid dispersions to improve the solubility of pranlast using a hot-melt method and a solvent evaporation method. However, the hot-melt method faces difficulties in commercialization due to its high manufacturing cost. To address this issue, Korean Patent Nos. 10-1086254 and 10-1233235 describe methods for improving pranlast solubility by using a hot-melt method and adding an anti-aggregating agent (HLB within a certain range), thereby preparing a pranlast solid dispersion. This product is currently commercially available as Pranair capsules (pranlast 112.5 mg / capsule, 1 capsule per dose, SK Chemicals). Although this product features a dosage reduction of 1 / 2 compared to Onon capsules, the hot-melt method requires specialized manufacturing equipment and has high production costs, thus potentially limiting its industrial value.

[0006] Furthermore, Korean Patent Nos. 10-0715355 and 10-0981751 are pharmaceutical compositions in tablet form that comprise spray-dried particles composed of water-soluble polymers and surfactants to improve the adhesion, cohesion, and solubility of pramux. These compositions are currently commercially available as Prakanon tablets (pramux 75mg / tablet, one tablet per dose, Yuhan Yanghang). However, spray-driing equipment has disadvantages such as complex and bulky equipment, high initial investment costs, low thermal efficiency, and high energy consumption. In addition, the high amount of surfactant used may lead to problems during the manufacturing process.

[0007] Korean Patent No. 10-2363727 is characterized by containing prenroximate prepared using an alcohol with 1 to 6 carbon atoms via wet granulation as a pharmaceutical carrier, and the single dose of prenroximate is less than 70 mg. However, the amount of alcohol used in the patent is approximately 1 to 1.7 times that of prenroximate, which raises the possibility of environmental pollution due to organic solvents. Furthermore, the use of a paste-like surfactant causes variations in surfactant viscosity with storage temperature, which may lead to problems in the manufacturing process and ultimately affect the density and particle size distribution of the particles.

[0008] As mentioned above, although existing patents employ various methods to reduce the single dose of pransildenafil, further improvements in bioavailability are needed to reduce the dosage. Furthermore, patient adherence needs to be improved by reducing the dosage and frequency of administration, and side effects from high-dose administration should be minimized. In addition, a novel preparation method suitable for industrial applications needs to be developed. Summary of the Invention

[0009] Technical issues

[0010] The purpose of this invention is to provide a pharmaceutical composition for improving the bioavailability of prunoxetine and a method for preparing the same.

[0011] The purpose of this invention is to provide a pharmaceutical composition for improving the solubility of prenstard and a method for preparing the same.

[0012] Technical solutions

[0013] 1. A pharmaceutical composition comprising: 15 to 25 parts by weight of pransiloxane, 0.1 to 10 parts by weight of a water-soluble polymer, and 0.1 to 5 parts by weight of a silica-based glidant.

[0014] 2. The pharmaceutical composition according to 1 above, wherein prunlast has 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.

[0015] 3. The pharmaceutical composition according to 1 above, wherein the water-soluble polymer is selected from one or more of the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinylpyrrolidone vinyl acetate and polyvinyl alcohol.

[0016] 4. The pharmaceutical composition according to 1 above, wherein the silica-based gliding agent is selected from one or more of the group consisting of silica, hard anhydrous silica, colloidal silica, hydrated silica, silicates, magnesium silicate, magnesium trisilicate, and magnesium aluminum silicate.

[0017] 5. The pharmaceutical composition according to claim 1 above, wherein the pharmaceutical composition further comprises 1 to 30 parts by weight of a solubilizer, the solubilizer being one or more selected from the group consisting of sodium dodecyl sulfate, polyethylene glycol-15-hydroxystearate, polyoxyethylene castor oil (Cremophor), poloxamer, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohol, lecithin and glycerol fatty acid esters.

[0018] 6. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises 1 to 20 parts by weight of a disintegrant, the disintegrant being one or more selected from the group consisting of sodium carboxymethyl starch, croscarmellose, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose and alginate.

[0019] 7. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises 40 to 80 parts by weight of a diluent, the diluent being one or more selected from the group consisting of microcrystalline cellulose, crystalline cellulose, mannitol, lactose hydrate, starch and pregelatinized starch.

[0020] 8. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition contains 50 mg or less of pramux.

[0021] 9. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is formulated as a powder, granule, pellet, capsule, tablet or dry syrup.

[0022] 10. A method for preparing a pharmaceutical composition, comprising: mixing pranoxetine, a diluent, a silica-based glidant and a disintegrant in a mixer; performing an initial kneading while dissolving a water-soluble polymer in water and adding it to the mixer; and performing a secondary kneading while suspending or dissolving a solubilizer in ethanol and adding it to the mixer.

[0023] 11. The method for preparing the pharmaceutical composition according to 10 above, wherein the method for preparing the pharmaceutical composition further includes the step of drying and granulating the secondary kneaded compound.

[0024] 12. The method for preparing the pharmaceutical composition according to 10 above, wherein prunustraz has 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.

[0025] 13. The method for preparing the pharmaceutical composition according to claim 10, wherein 40 to 80 parts by weight of a diluent, 0.1 to 5 parts by weight of a silica-based glidant and 1 to 20 parts by weight of a disintegrant are mixed relative to 15 to 25 parts by weight of pranoxetine.

[0026] 14. The method for preparing the pharmaceutical composition according to claim 10, wherein 0.1 to 10 parts by weight of a water-soluble polymer are added to a mixer relative to 15 to 25 parts by weight of pransil.

[0027] 15. The method for preparing the pharmaceutical composition according to claim 10, wherein 1 to 30 parts by weight of solubilizer are added to the mixer relative to 15 to 25 parts by weight of prenstar.

[0028] 16. The method for preparing the pharmaceutical composition according to claim 10, wherein the water-soluble polymer is selected from one or more of the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinylpyrrolidone vinyl acetate, and polyvinyl alcohol.

[0029] 17. The method for preparing the pharmaceutical composition according to the above 10, wherein the silica-based gliding agent is selected from one or more of the group consisting of silica, hard anhydrous silica, colloidal silica, hydrated silica, silicates, magnesium silicate, magnesium trisilicate, and magnesium aluminum silicate.

[0030] 18. The method for preparing the pharmaceutical composition according to claim 10 above, wherein the solubilizer is selected from one or more of the group consisting of sodium dodecyl sulfate, polyethylene glycol-15-hydroxystearate, polyoxyethylene castor oil (Cremophor), poloxamer, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohol, lecithin and glycerol fatty acid esters.

[0031] 19. The method for preparing the pharmaceutical composition according to 10 above, wherein the disintegrant is one or more selected from the group consisting of sodium carboxymethyl starch, croscarmellose, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose and alginate.

[0032] 20. The method for preparing the pharmaceutical composition according to claim 10, wherein the diluent is one or more selected from the group consisting of microcrystalline cellulose, crystalline cellulose, mannitol, lactose hydrate, starch, and pregelatinized starch.

[0033] 21. The method for preparing the pharmaceutical composition according to 10 above, wherein it contains 50 mg or less of pramux.

[0034] Invention Effects

[0035] The pharmaceutical composition of the present invention improves the dissolution rate and bioavailability of pransildenafil, thereby demonstrating clinical efficacy equivalent to or better than that of a single dose of 225 mg of the commercially available Onon capsules (112.5 mg / capsule of pransildenafil, 2 capsules twice daily), even when the pransildenafil content is reduced to below 50 mg / capsule (1 capsule twice daily).

[0036] The pharmaceutical composition of the present invention can improve patient medication adherence and reduce side effects caused by excessive use of pramuxart. Attached Figure Description

[0037] Figure 1 The results are a comparison of the dissolution of Examples 1 to 5 with that of Onon capsules.

[0038] Figure 2 The results are a comparison of the dissolution of Examples 11 to 15 with Onon capsules.

[0039] Figure 3 Example 21 and Onon capsules (112.5mg) * The results of the human pharmacokinetic (PK) evaluation of 2 caps. Detailed Implementation

[0040] This invention provides a pharmaceutical composition for improving the bioavailability of prunoxetine and a method for preparing the same.

[0041] This invention provides a pharmaceutical composition and its preparation method, wherein the pharmaceutical composition comprises 0.1 to 10 parts by weight of a water-soluble polymer and 0.1 to 5 parts by weight of a silica-based glidant relative to 15 to 25 parts by weight of pranlast, thereby demonstrating clinical efficacy equivalent to or better than commercially available formulations even when the pranlast content is reduced to below 50 mg / tablet (1 tablet twice daily), thereby improving patient adherence and reducing side effects caused by overdose of pranlast.

[0042] Pransil is a poorly soluble drug. To improve solubility, pransil is preferably micronized. In one embodiment, pransil may have a particle size distribution with D(0,50) of 0.1 to 2.0 μm and D(0,90) of 1.6 to 7.0 μm.

[0043] While using micronized pranoxetine can increase the particle surface area, which helps improve solubility and dissolution rate, the increased adhesion and cohesion between particles as the particle size decreases can also lead to a decrease in dissolution rate. This invention employs a method of uniformly mixing micronized pranoxetine with a diluent, a silica-based flow aid, and a disintegrant. The water-soluble polymer is dissolved in water and added to the mixture during the initial kneading process. A secondary kneading process is then performed, with the solubilizer suspended or dissolved in ethanol and added to the initially kneaded mixture. Therefore, even when using micronized pranoxetine, the problem of reduced solubility and dissolution rate due to interparticle adhesion and cohesion does not occur.

[0044] In one embodiment, the present invention can granulate the micronized pranoxetine drug, which is a poorly soluble drug, using water-soluble polymers, solubilizers, and pharmaceutically acceptable additives, thereby improving dissolution rate and bioavailability.

[0045] Water-soluble polymers are used as plasticizers or adhesives.

[0046] The water-soluble polymer can be any water-soluble polymer commonly used in the pharmaceutical field. In one embodiment, the water-soluble polymer is one or more selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinylpyrrolidone vinyl acetate, and polyvinyl alcohol.

[0047] Polyethylene glycol, as a nonionic substance, has the simplest structure among water-soluble polymers and is effective in improving the solubility of prenstar. The preferred molecular weight of polyethylene glycol is in the range of 3000 to 8000.

[0048] The water-soluble polymer contains 0.1 to 10 parts by weight relative to 15 to 25 parts by weight of prenstar. For example, the water-soluble polymer may contain 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.

[0049] Silica-based flow aids can reduce the electrostatic attraction between prancelast particles, thereby improving adhesion, cohesion, and flowability.

[0050] Silica-based flow aids are selected from one or more of the group consisting of silica, hard anhydrous silica, colloidal silica, hydrated silica, silicates, magnesium silicate, magnesium trisilicate, and magnesium aluminum silicate.

[0051] The silica-based flow aid contains 0.1 to 5 parts by weight relative to 15 to 25 parts by weight of pranstrex. For example, the silica-based flow aid may contain 0.1 to 4 parts by weight, 0.1 to 3 parts by weight, or 0.1 to 2 parts by weight, or 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.

[0052] The pharmaceutical compositions of the present invention may contain a solubilizer.

[0053] As a solubilizer, surfactants commonly used in the pharmaceutical field can be used. Surfactants include water-soluble and oil-soluble surfactants. In one embodiment, the solubilizer can be one or more selected from the group consisting of sodium dodecyl sulfate, polyethylene glycol-15-hydroxystearate, polyoxyethylene castor oil (Cremophor), poloxamer, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohols, lecithin, and glycerol fatty acid esters.

[0054] The solubilizer may contain 1 to 30 parts by weight relative to 15 to 25 parts by weight of prancexa. For example, the solubilizer may contain 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.

[0055] The pharmaceutical compositions of the present invention may contain disintegrants.

[0056] The inclusion of disintegrants is intended to cause the drug composition containing pransil to disintegrate rapidly in the body, thereby allowing for large-scale absorption in the upper small intestine.

[0057] The disintegrant may be a disintegrant conventionally used in the field of pharmaceuticals. In one embodiment, the disintegrant is one or more selected from the group consisting of sodium carboxymethyl starch, croscarmellose, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, and alginate.

[0058] The disintegrant may contain 1 to 20 parts by weight relative to 15 to 25 parts by weight of prenstar. In one embodiment, the disintegrant may contain 1 to 20 parts by weight or 1 to 10 parts by weight.

[0059] The pharmaceutical compositions of the present invention may contain a diluent.

[0060] The diluent may be any diluent conventionally used in the pharmaceutical field. In one embodiment, the diluent is one or more selected from the group consisting of microcrystalline cellulose, crystalline cellulose, mannitol, lactose hydrate, starch, and pregelatinized starch.

[0061] The diluent may contain 40 to 80 parts by weight relative to 15 to 25 parts by weight of prenstar. In one embodiment, the diluent may contain 40 to 70 parts by weight or 50 to 80 parts by weight.

[0062] The pharmaceutical composition of the present invention is prepared by comprising the following steps: (i) mixing pranoxetine, a diluent, a silica-based glidant and a disintegrant in a mixer; (ii) performing an initial kneading while dissolving a water-soluble polymer in water and adding it to the mixer; and (iii) performing a secondary kneading while suspending or dissolving a solubilizer in ethanol and adding it to the mixer.

[0063] The water-soluble polymer dissolves in water, and the solubilizer (surfactant) is suspended or dissolved in ethanol. The preparation method of the pharmaceutical composition of the present invention does not use organic solvents other than ethanol, and uses a small amount of ethanol, significantly reducing the amount of organic solvent used, which is superior to existing spray drying / hot-melt processes. In one embodiment, less than 25 parts by weight of ethanol are used relative to 15 to 25 parts by weight of prenstar.

[0064] The solubilizers used in the pharmaceutical compositions of the present invention are preferably solid. Paste-like solubilizers may undergo physicochemical changes depending on storage conditions, thereby potentially affecting the physical properties of the pharmaceutical composition (especially dissolution rate). Liquid solubilizers weaken the cohesiveness of particulate matter during tableting, which may cause tableting difficulties.

[0065] The mixer is not limited to a specific type. In one embodiment, the mixer can be a high-shear granulator commonly used in the pharmaceutical industry.

[0066] The method for preparing the pharmaceutical composition of the present invention may further include: (iv) granulation, drying, and sizing of the secondary kneaded compound. The pharmaceutical composition of the present invention manufactured in the above manner is in the form of granules containing prenroxith.

[0067] The method for preparing the pharmaceutical composition of the present invention uses less solvent compared to other spray drying and granulation methods, making it environmentally friendly. Furthermore, it eliminates the need for equipment such as high-speed stirrers and spray dryers, thus making it economical. For example, methods that involve vigorously stirring a solution composed of water-soluble polymers or surfactants (e.g., using a stirrer equipped with a propeller or a homogenizer) while adding prenroximate to prepare a suspension (spray solution), or preparing a spray solution using a high-pressure homogenizer, and then spraying it into granules in a fluidized bed granulator or spray dryer, have the disadvantages of high solvent usage and the need for additional equipment compared to the method for preparing the pharmaceutical composition of the present invention.

[0068] In one embodiment, to improve the adhesion and aggregation properties of prencalactone, a pharmaceutical composition consisting of prencalactone, a diluent, a silica-based flow aid, and a disintegrant is uniformly mixed in a high-shear mixer to reduce the attractive force between prencalactone particles and improve aggregation. Polyethylene glycol, a water-soluble polymer, is dissolved in purified water and slowly added to the high-shear mixer for initial kneading. The purified water reduces the attractive force between prencalactone particles while allowing the water-soluble polymer to adhere to the surface of the prencalactone particles, increasing the solubility of prencalactone. A solubilizer (surfactant) with a low critical micelle concentration (CMC) is suspended or dissolved in ethanol and slowly added to the initial kneaded mixture for secondary kneading. This involves the process of attaching the solubilizer to the initial kneaded mixture. The kneaded mixture is then granulated as needed and dried in a fluidized bed dryer to form pharmaceutical granules containing prencalactone.

[0069] The pharmaceutical composition of the present invention may be particulate matter containing prenroximate, and the pharmaceutical composition of the present invention may be prepared by wet granulation.

[0070] The pharmaceutical compositions of the present invention can be formulated into powders, granules, pellets, capsules, tablets, dry syrups, etc. The pharmaceutical compositions of the present invention can be formulated by comprising particles containing pranoxetine and acceptable pharmaceutical additives.

[0071] Acceptable pharmaceutical additives can include excipients, disintegrants, lubricants, coating agents, etc.

[0072] Excipients include mannitol, sorbitol, refined white sugar, lactose, lactose hydrate, microcrystalline cellulose, starch, pregelatinized starch, silicified microcrystalline cellulose, corn starch, crystalline cellulose, etc. Disintegrants include sodium carboxymethyl starch, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, etc. Lubricants include magnesium stearate, stearic acid, sodium stearate fumarate, colloidal silica, silica, etc.

[0073] For tablets, the process may include coating with a film using a coating agent. The Opadry series can be used as a coating agent.

[0074] The types and amounts of pharmaceutical additives can be selected based on the physical properties of the composition and can be appropriately selected based on the dosage form.

[0075] In one embodiment, relative to 15 to 25 parts by weight of prunustrol, the excipient may contain 1 to 80 parts by weight, the disintegrant may contain 1 to 20 parts by weight, the lubricant may contain 0.1 to 10 parts by weight, and the coating agent may contain 1 to 5 parts by weight.

[0076] The present invention will be described in more detail below through embodiments.

[0077] Example

[0078] Examples 1 to 5. Evaluation of the effect of solubilization

[0079] Micronized pranoxetine with D(0,50) of 0.1 to 2.0 μm and D(0,90) of 1.6 to 7.0 μm, along with diluents, glidants, and disintegrants, were mixed in a high-shear mixer. A water-soluble polymer (hydroxypropyl cellulose) was dissolved in water and slowly added to the high-shear mixer for initial kneading. The various solubilizers were then suspended or dissolved in ethanol for secondary kneading. Granulation was subsequently performed, and the solvents were evaporated using a fluidized bed dryer. The dried material was granulated to obtain pranoxetine-containing particles. The components of each embodiment are shown in Table 1 below.

[0080] Table 1

[0081]

[0082] Examples 6 to 10: Setting the diluent content

[0083] Using the same method as in Examples 1 to 5, particulate matter containing prannister was obtained. The components of each example are shown in Table 2 below.

[0084] Table 2

[0085]

[0086] Examples 11 to 15: Setting the content of water-soluble polymer and solubilizer

[0087] Using the same method as in Examples 1 to 5, particulate matter containing prannister was obtained. The components of each example are shown in Table 3 below.

[0088] Table 3

[0089]

[0090] Examples 16 to 21. Preparation of tablets containing pranoxetine granules

[0091] Tablets were prepared using the granules prepared in Examples 2, 6, 7, 8, 10, and 15, according to the components and contents listed in Table 4. Granules containing prenstar, excipients, disintegrants, lubricants, and coating agents were mixed and lubricated in a mixer, followed by tableting and coating processes to prepare Examples 16 to 21.

[0092] Table 4

[0093]

[0094] Experimental Example 1. Comparative test of solubilizer dissolution

[0095] According to the Korean Pharmacopoeia Dissolution Test Method II (Paddle Method), a dissolution comparison test was conducted on one coated tablet and two Onon capsules (Pronlast 112.5 mg / capsule, 2 capsules per dose, Dong-A Pharmaceutical) obtained by compressing the granules prepared in Examples 1 to 5. The test method is as follows.

[0096] Considering the solubility of prencalex as a poorly soluble drug, 900 mL of pH 6.8 + 0.2% PSB80 (polysorbate 80) dissolution solution was added. While maintaining the temperature at 37 ± 0.5 °C, the solution was stirred at 50 rpm. 5 mL samples were taken at 10, 15, 30, 45, 60, 90, and 120 minutes, filtered through a 0.45 μm filter, and analyzed by high-performance liquid chromatography (HPLC). The results are as follows: Figure 1 As shown, it can be confirmed that the pharmaceutical composition of this application has a significantly increased dissolution rate compared to commercially available Onon capsules.

[0097] Experimental Example 2. Comparative Test on the Dissolution of Water-Soluble Polymers and Solubilizers at Various Contents

[0098] A coated tablet obtained by compressing the granules prepared in Examples 11 to 15 was subjected to a dissolution comparison test with two Onon capsules using the same method as in Experimental Example 1. The results are as follows: Figure 2 As shown, it can be confirmed that the dissolution rate of the pharmaceutical composition of this application is significantly increased compared with that of commercially available Onon capsules.

[0099] Example 3. Human Pharmacokinetic (PK) Evaluation

[0100] In vivo dynamics were evaluated using tablets of Example 21 (formed from Example 15 into coated tablets) and the commercially available formulation Onon capsules (112.5 mg × 2 caps).

[0101] Twelve healthy adults aged 18 to 55 years were randomly divided into two groups (n=6). On an empty stomach, they were alternately administered the tablets prepared in Example 21 (Example 21, pramexate 50 mg / tablet, 1 tablet) (Group 1) and a commercially available formulation (Onon capsules, 112.5 mg / capsule, 2 capsules, total pramexate content 225 mg) (Group 2) with 200 mL of water. A washout period of 2 weeks was set. 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. Blood samples were placed in vacuum polyethylene tubes containing K3EDTA and centrifuged at 1538±10g for 15 minutes. Plasma was collected, transferred to polyethylene tubes, and frozen at 120℃±5℃ until analysis. The concentration of prenroximate in the plasma was analyzed using UPLC-MS / MS. The results are shown in Table 5. Figure 3 .

[0102] The tablets of Example 21 prepared according to the method of the present invention were confirmed to have a low AUC, even when administered at a lower dose (50 mg) than 2 capsules (premnaste 225 mg) of the commercially available formulation Onon capsules. 0-t and C max The T / R ratio indicates the equivalence level, demonstrating efficacy comparable to commercially available formulations. Furthermore, compared to existing commercially available formulations, this invention shortens the time to peak concentration (Tmax), achieving faster drug release and making it more suitable for the clinical treatment of acute conditions such as bronchial asthma and allergic rhinitis. Therefore, it is also a therapeutic improvement over existing commercially available formulations.

[0103] Table 5

[0104]

Claims

1. A pharmaceutical composition comprising: 15 to 25 parts by weight of praseodymium, 0.1 to 10 parts by weight of a water-soluble polymer, and 0.1 to 5 parts by weight of a silica-based flow aid.

2. The pharmaceutical composition according to claim 1, wherein, The prencetal has a particle size distribution with D(0,50) ranging from 0.1 to 2.0 μm and D(0,90) ranging from 1.6 to 7.0 μm.

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

4. The pharmaceutical composition according to claim 1, wherein, The silica-based flow aid is selected from one or more of the group consisting of silica, hard anhydrous silica, colloidal silica, hydrated silica, silicates, magnesium silicate, magnesium trisilicate, and magnesium aluminum silicate.

5. The pharmaceutical composition according to claim 1, wherein, The pharmaceutical composition further includes 1 to 30 parts by weight of a solubilizer, said solubilizer being one or more selected from the group consisting of sodium dodecyl sulfate, polyethylene glycol-15-hydroxystearate, polyoxyethylene castor oil (Cremophor), poloxamer, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohol, lecithin, and glycerol fatty acid esters.

6. The pharmaceutical composition according to claim 1, wherein, The pharmaceutical composition further includes 1 to 20 parts by weight of a disintegrant, said disintegrant being one or more selected from the group consisting of sodium carboxymethyl starch, croscarmellose, croscarmellose sodium, croscarmellose, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose and alginate.

7. The pharmaceutical composition according to claim 1, wherein, The pharmaceutical composition contains 50 mg or less of pramux.

8. A method for preparing a pharmaceutical composition, comprising: The step of mixing praseodymite, diluent, silica-based flow aid and disintegrant in a mixer; The initial kneading step involves dissolving the water-soluble polymer in water and adding it to the mixer; and The process involves suspending or dissolving the solubilizer in ethanol and adding it to the mixer while simultaneously performing a secondary kneading step.

9. The method for preparing the pharmaceutical composition according to claim 8, wherein, 0.1 to 10 parts by weight of the water-soluble polymer are added to the mixer relative to 15 to 25 parts by weight of the prencetal.

10. The method for preparing the pharmaceutical composition according to claim 8, wherein, 1 to 30 parts by weight of the solubilizer are added to the mixer relative to 15 to 25 parts by weight of the prencetal.

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