Method for preparing pharmaceutical composition containing pranlukast and pharmaceutical composition prepared thereby

Abstract

Disclosed are a method for preparing a pharmaceutical composition containing pranlukast, and a pharmaceutical composition prepared by the preparation method.

Description

Method for preparing a pharmaceutical composition containing pranlukast and a pharmaceutical composition prepared by the method

[0001] The present invention relates to a method for manufacturing a pharmaceutical composition containing pranlukast and a pharmaceutical composition manufactured by the method. More specifically, when manufacturing a pharmaceutical composition containing pranlukast, a binder and a solubilizer are added to a solvent that dissolves the binder, the mixture is left overnight (12 to 16 hours), and the volatilized solvent is weighed and corrected before use the next day. Then, the composition is kneaded in a high-speed mixer. However, during the process described above, a problem occurs in which the solubilizer precipitates, and the mixture becomes sticky in a short period of time, preventing the mixture from being homogeneously mixed and kneaded. In addition, when the manufactured mixture is dried, pulverized, and subjected to a post-mixing process and then compressed into a tablet, the present invention relates to a method for manufacturing a pharmaceutical composition containing pranlukast and a pharmaceutical composition manufactured by the method, which can solve the problems in which the binder precipitates and the mixture becomes sticky in a short period of time, preventing the mixture from being homogeneously mixed and kneaded.

[0002] [Franlukast]

[0003] The present invention uses pranlukast as an active ingredient.

[0004] Pranlukast, represented by the following chemical formula 1 and having the chemical name 4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran hemihydrate, is a new drug developed by Ono Pharmaceutical Co., Ltd. of Japan.

[0005] [Chemical Formula 1]

[0006]

[0007] Pranlukast is a drug used to treat asthma and allergic rhinitis. It suppresses allergic reactions by blocking leukotrienes, inflammatory mediators that cause asthma and rhinitis.

[0008] For example, if a foreign substance enters the human body, it can cause an immune hypersensitivity reaction, which can lead to asthma or allergic rhinitis.

[0009] Asthma is a disease caused by substances such as pollen and dust mites, which causes the bronchial mucosa to swell and become inflamed, and the muscles surrounding the bronchial tubes contract, narrowing the bronchial tubes and causing breathing difficulties.

[0010] Allergic rhinitis can be divided into seasonal allergic rhinitis, which occurs only in certain seasons depending on the timing of exposure to the antigen, such as spring pollen and fall ragweed pollen; and perennial allergic rhinitis, which occurs due to substances such as house dust, mites, mold, and animal dander; and symptoms such as sneezing, clear runny nose, and nasal congestion appear due to an allergic reaction in the nasal mucosa.

[0011] Pranlukast is a drug used to treat asthma and allergic rhinitis, and helps improve symptoms.

[0012] [Conventional formulation]

[0013] Pranlukast has been tried in various dosage forms, including tablets, suspensions, dry syrups, and capsules.

[0014] Among them, the early solid oral preparations of pranlukast include Onon Capsule (pranlukast 112.5 mg / capsule, 2 capsules taken at a time, Dong-A ST), Pranair Capsule (pranlukast 112.5 mg / capsule, 1 capsule taken at a time, SK Chemical), Prakanon Tablet (pranlukast 75 mg / tablet, 1 tablet taken at a time, Yuhan Corporation), and Citus Tablet (pranlukast 50 mg / tablet, 1 tablet taken at a time, Sam-A Pharmaceutical).

[0015] It has been revealed that the site of maximum absorption of pranlukast when administered orally is the upper small intestine. As a drug belonging to BCS (Biopharmaceutics Classification System) Class II, it has strong adhesion and cohesion and very low solubility (1.2 μg / ml), so it has the problem of low bioavailability when administered orally compared to other drugs.

[0016] In this regard, in the case of Onon Capsule, these pranlukast problems could not be improved during the formulation stage, so a method of increasing the pranlukast content was adopted. Calculation showed that only when adults take a single dose of 225 mg of pranlukast was there a significant effect in treating the target disease. However, this is uneconomical due to the large single dose, can reduce patient compliance, and can cause side effects due to high-dose administration.

[0017] In order to improve the shortcomings of the above Onon capsule, Korean Patent Publication No. 10-0389606 discloses a spray-dried granule with improved adhesion and cohesion of pranlukast. In the patent, in order to improve adhesion and cohesion, a sugar, a binder, and a surfactant are dissolved in purified water and pranlukast is suspended to prepare a spray-dried granule. However, the spray-dried granule disclosed in Korean Patent Publication No. 10-0389606 has improved adhesion and cohesion of pranlukast, but has not improved the solubility of pranlukast, so dissolution is delayed and the dissolution rate is very low, and ultimately, there are limitations in that bioavailability is still low.

[0018] Korean Patent Publication No. 10-1332223 discloses a nano-solid dispersion of pranlukast that can improve the low solubility of pranlukast and thereby increase bioavailability. The pranlukast nano-solid dispersion in the patent has a structure in which pranlukast exists in a carrier composed of polyethylene glycol and poloxamer, and exhibits improved bioavailability while stably maintaining the drug at the nano-level particle size.

[0019] However, the manufacturing of the nano-solid dispersion of Korean Patent No. 10-1332223 requires a mixing process, a thermal melting process, and a solvent evaporation process, resulting in high manufacturing costs and a complex manufacturing process. Furthermore, the use of methanol / dichloromethanol as a cosolvent can result in residual organic solvents within the solid dispersion, and the use of organic solvents also poses the problem of environmental pollution.

[0020] Korean Patent Publication No. 10-1446129 discloses a mixture comprising pranlukast and polyvinylpyrrolidone or a copolymer of polyvinylpyrrolidone and vinyl acetate. The patent improves solubility and dissolution rate through simple mixing of pranlukast and a hydrophilic polymer, but the ratio of hydrophilic polymer to the main ingredient is high, and there is a lack of experimental data on in vivo and no data is presented to prove whether actual bioavailability has been improved.

[0021] Korean Patent Publication No. 10-1086254 discloses a pranlukast solid dispersion composition characterized by being formed by melting a polyvinylpyrrolidone vinyl acetate copolymer to pranlukast at a weight ratio of 0.2:1 to 10:1 by heat. This patent relates to Pranair Capsule (pranlukast 112.5 mg / capsule, 1 capsule per dose, SK Chemical).

[0022] However, although the solid dispersion disclosed in Korean Patent Publication No. 10-1086254 can be seen to have doubled the bioavailability of pranlukast compared to the existing reference drug, Onon Capsule, it cannot be manufactured using the manufacturing equipment generally used in the pharmaceutical industry, such as the method of melting with heat (hot melt), and thus has the disadvantages of burden in terms of equipment investment and complicated manufacturing process. In addition, since the change of the drug to an amorphous form by hot melt can be seen as a thermodynamically unstable state, there is a limitation that it can return to a stable crystalline form within the product's shelf life, which may change the solubility and bioavailability of the drug.

[0023] Korean Patent Publication No. 10-0981751 discloses pranlukast-containing granules comprising a drug coating layer coated on a granule core. The patent is characterized by manufacturing granules by coating a suspension of pranlukast, a binder, and a surfactant onto the granule core, which are then tableted. This patent pertains to Prakanone tablets (pranlukast 75 mg / tablet, one tablet per dose, Yuhan Corporation).

[0024] However, the spray-dried granules disclosed in Korean Patent Publication No. 10-0981751 require a suspension process that vigorously suspends pranlukast in a solvent, and there are various manufacturing process variables according to the spray-drying process, which may lead to an increase in manufacturing costs due to the complex manufacturing process. In addition, although the patent improved the bioavailability of pranlukast, reducing the single-administered drug dosage by 1 / 3 compared to the existing reference drug, Onon Capsule, the single-administered dosage is still 75 mg of pranlukast, so there is a need to improve patient compliance and reduce side effects of high-dose administration of the drug by further improving the bioavailability and reducing the dosage of the drug.

[0025] Korean Patent Publication No. 10-2363727, a prior invention of the present inventor, discloses a wet granulation of pranlukast. Despite employing a conventional wet granulation process rather than a hot melt process, this invention is characterized by dramatically improving the bioavailability of pranlukast through a combination of specific diluents, binders, and surfactants, and successfully reducing the single-administration dose to 50 mg. This patent pertains to Citus Tablets (pranlukast 50 mg / tablet, one tablet per dose, Sam-A Pharmaceutical) and is also listed on the Ministry of Food and Drug Safety's Pharmaceutical Patent List.

[0026] However, the above patent documents do not recognize the problems that occur during the manufacture of pranlukast-containing preparations (the problem of solubilizing agent precipitation, the phenomenon of the mixture not being homogeneously mixed and combined due to the phenomenon of the mixture being hardened in a short period of time, and the phenomenon of sticking and chipping when pressed) and do not present any problems to be solved.

[0027] Accordingly, there is an urgent need to research and develop a method for manufacturing a novel pranlukast-containing formulation that solves the above-mentioned problems.

[0028] [Prior Art Literature]

[0029] [Patent Document]

[0030] (Patent Document 1) Republic of Korea Patent Publication No. 10-0389606

[0031] (Patent Document 2) Republic of Korea Patent Publication No. 10-1332223

[0032] (Patent Document 3) Republic of Korea Patent Publication No. 10-1446129

[0033] (Patent Document 4) Republic of Korea Patent Publication No. 10-1086254

[0034] (Patent Document 5) Republic of Korea Patent Publication No. 10-0981751

[0035] (Patent Document 6) Republic of Korea Patent Publication No. 10-2363727

[0036] The purpose of the present invention is to solve the above problems, and the method for manufacturing a pharmaceutical composition containing pranlukast of the present invention can improve the problems of the conventional overnight preparation by controlling the dissolution temperature and dissolution time of the solubilizer, the dissolution time of the binder, and the use time of the binder after mixing, so that the mixture is mixed and combined homogeneously and the tableting problem can be solved.

[0037] In addition, by adjusting the granule size during the process of establishing after union, it is possible to secure suitable process results, improve mixing unevenness in the post-mixing stage, and secure a suitable dissolution rate.

[0038] In addition, the optimal process results can be secured by adjusting the combination / coating conditions, thereby improving the solubility of pranlukast.

[0039] In this specification, the term "pranlukast" may refer to pranlukast, a hydrate thereof, a solvate thereof, or a salt thereof. Accordingly, in this specification, a pharmaceutical composition comprising pranlukast may refer to a pharmaceutical composition comprising pranlukast, a hydrate thereof, a solvate thereof, or a salt thereof.

[0040] 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.

[0041] The present invention is described in detail below.

[0042] The present invention solves the above-mentioned problem by the following means.

[0043] 1. A method for producing a pharmaceutical composition containing pranlukast, comprising: (S1) a step of dissolving a solubilizer at 50 to 60°C for 30 to 60 minutes, adding the solution to a solution in which a binder is dissolved, and stirring to prepare a mixed solution containing the solubilizer and the binder; (S2) a step of mixing pranlukast, a hydrate thereof, a solvate thereof, or a salt thereof, and a pharmaceutical additive; (S3) a step of adding the mixed solution of (S1) to the mixture of (S2) and kneading them to prepare granules; (S4) a step of drying the granules of (S3) to prepare dried granules; (S5) a step of sizing the dried granules of (S4) and then mixing them with a pharmaceutical additive to prepare a final mixture; and (S6) a step of compressing the final mixture of (S5).

[0044] 2. A method for manufacturing a pharmaceutical composition containing pranlukast, characterized in that in the above 1, the solution in which the solubilizer is dissolved is used within 1 hour after dissolving the solubilizer at 50 to 60°C for 30 to 60 minutes.

[0045] 3. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the above 1, the solution in which the binder is dissolved in the step (S1) is obtained by adding the binder to the binding solvent and stirring for 20 to 50 minutes, and then using the obtained solution within 5 hours.

[0046] 4. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the above 1, the mixed solution in the step (S1) is obtained by adding a solution in which a solubilizing agent is dissolved to a solution in which a binder is dissolved and then dissolving for 15 to 45 minutes.

[0047] 5. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the above 1, the solubilizing agent in the step (S1) is any one of polyoxyl 15 hydroxystearate, poloxamer 407, or a mixture thereof.

[0048] 6. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the above 1, the binder in the step (S1) is at least one selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene glycol, and polyvinyl alcohol.

[0049] 7. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the above 1, the content of the solubilizer is 1 to 20 wt% and the content of the binder is 1 to 5 wt% relative to the weight of the entire pharmaceutical composition.

[0050] 8. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the above 1, the pharmaceutical additive in the step (S2) is at least one selected from the group consisting of a diluent, a sweetener, and a binder.

[0051] 9. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the above 8, the diluent in the above (S2) step is at least one of xylitol, mannitol, isomalt, sorbitol, maltitol, refined white sugar, lactose, lactose monohydrate, inositol, erythritol, crystalline fructose, trehalose, ribitol, arabitol, galactitol, lactitol, and maltotritol, microcrystalline cellulose, sodium croscarboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose, gelatinized starch, glucose, pregelatinized starch, starch, corn starch, light anhydrous silicic acid, or crystalline cellulose, and the sweetener is anti-caking sugar.

[0052] 10. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the above 1, the mixing in the above step (S2) is performed at an agitator speed of 110 to 130 rpm and a chopper speed of 1800 to 2200 rpm for 1 to 5 minutes.

[0053] 11. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the above 8, the binder in the step (S2) is at least one selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene glycol, and polyvinyl alcohol.

[0054] 12. A method for manufacturing a pharmaceutical composition containing pranlukast, characterized in that in the above 1, the formulation in the above (S5) is formulated by using a formulating mesh of 710 to 850 μm to form a dried granule.

[0055] 13. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the above 1, the pharmaceutical additive in the above (S5) is at least one selected from the group consisting of a diluent, a disintegrant, a pH regulator, a sweetener, a flavoring agent, and a lubricant.

[0056] 14. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the above 13, the diluent is at least one of xylitol, mannitol, isomalt, sorbitol, maltitol, refined white sugar, lactose, inositol, erythritol, crystalline fructose, trehalose, ribitol, arabitol, galactitol, lactitol, and maltotritol, microcrystalline cellulose, sodium croscarboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose, gelatinized starch, glucose, pregelatinized starch, starch, corn starch, light anhydrous silicic acid, or crystalline cellulose.

[0057] 15. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the above 13, the disintegrant is any one of crospovidone, low-substituted hydroxypropyl cellulose, or a mixture thereof.

[0058] 16. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the above 13, the pH adjusting agent is citric acid hydrate.

[0059] 17. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the above 13, the sweetener is any one selected from the group consisting of white sugar, glucose, mannitol, sorbitol, aspartame, acesulfame, and sucralose.

[0060] 18. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the above 13, the lubricant is any one of colloidal silicon dioxide, sodium stearyl fumarate, magnesium stearate, or a mixture thereof.

[0061] 19. In the above 1, the step of pressing in the step (S6) is a turret speed of 20 to 30 rpm, a pressing position of 16.5 to 18 mm, and a pressing pressure of 25 to 35 kgf / cm preload. 2 , the main pressure is 30 to 40 kgf / cm 2 A method for manufacturing a pharmaceutical composition containing pranlukast, characterized in that the hardness is adjusted to 5 to 12 kp by pressing.

[0062] 20. A pharmaceutical composition containing pranlukast manufactured by any one of the manufacturing methods 1 to 19 above.

[0063] 21. A pharmaceutical composition according to the above 20, characterized in that the pharmaceutical composition is an oral solid preparation.

[0064] 22. In the above 21, the oral solid dosage form is a pharmaceutical composition characterized in that the dosage form is any one of pellets, capsules, chewable tablets, single-layer tablets, multi-layer tablets, core tablets, granules, or mini-tablets.

[0065] 23. In the above 20, the pharmaceutical composition is characterized in that the pranlukast content per unit formulation is 26-74.2 mg.

[0066] 24. In the above 20, the pharmaceutical composition is characterized in that when the pharmaceutical composition is dissolved in a pH 6.8 solution by the second dissolution method (paddle method) of the Korean Pharmacopoeia, the concentration of pranlukast is 80% or more at a time point of 30 to 45 minutes.

[0067] 25. In the above 20, the pharmaceutical composition is characterized in that the time taken to reach the maximum blood concentration of pranlukast when administered to a human body is within 3 hours.

[0068] In the manufacturing method according to the present invention, when manufacturing a pharmaceutical composition containing pranlukast, the phenomenon of not being homogeneously mixed and combined can be solved by controlling the process of adding a binder and a solubilizer to a solvent that dissolves the binder, and the phenomenon of sticking and chipping occurring when the manufactured combination is dried, crushed, and then subjected to a post-mixing process and then compressed into a tablet.

[0069] In the pharmaceutical composition manufactured according to the present invention, the dissolution rate of pranlukast is improved, and the bioavailability is significantly improved compared to the existing commercially available dry syrup formulation, so that it can exhibit clinically equivalent or higher efficacy than the existing syrup formulation (pranlukast 50, 75, 100, 140 mg / package, 1 pack at a time, taken twice a day, Sam-A Pharmaceutical) with only a total of 53.0-148.4 pranlukast administered per day.

[0070] In the case of the pharmaceutical composition manufactured according to the present invention, it is possible to exhibit the same efficacy as administering 50-140 mg of Citrus dry syrup twice a day by administering 26.5-74.2 mg once a day, twice a day.

[0071] 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.

[0072] Figure 1 shows the results of a dissolution test of a chewable tablet (test material, Citrus chewable tablet, pranlukast hydrate 74.2 mg) and a dry syrup (Sam-A Pharmaceutical, Citrus dry syrup 140 mg, control material) according to Example 1 in a dissolution solution containing a mixture of a pH 6.8 solution and a 0.2% PSB solution.

[0073] Figure 2 shows the results of a dissolution test of chewable tablets (test substance, Citrus chewable tablet, pranlukast hydrate 74.2 mg) according to Examples 1, 4 and 5 in a dissolution solution containing a mixture of a pH 6.8 solution and a 0.2% PSB solution.

[0074] Figure 3 shows the results of a human in vivo kinetic test (human bioequivalence test results) of a chewable tablet (test material, Citrus chewable tablet, pranlukast hydrate 74.2 mg) and a dry syrup (Sam-A Pharmaceutical, Citrus dry syrup 140 mg, control material) according to Example 1 of the present invention.

[0075] Hereinafter, the present specification will be described in more detail.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] Expressions such as “comprising” as used herein should be understood as open-ended terms that imply the possibility of including other embodiments.

[0081] The inventors of the present invention, while researching and developing a method for manufacturing a pharmaceutical composition containing pranlukast, confirmed that in the conventional process of manufacturing a pharmaceutical composition containing pranlukast, a binder and a solubilizer are added to a solvent that dissolves the binder, the mixture is left overnight (12 to 16 hours), and the volatilized solvent is weighed and corrected before use the next day, and then the composition is kneaded in a high-speed mixer. However, during the process described above, a problem occurs in which the solubilizer precipitates, and also, the mixture becomes sticky in a short period of time, so that the mixture is not mixed and kneaded homogeneously. In addition, when the manufactured mixture is dried, ground, and subjected to a post-mixing process and then compressed into a tablet, sticking and chipping phenomena occur.

[0082] Accordingly, the inventors of the present invention have carefully observed the above problems to solve them, and as a result, confirmed that by controlling the dissolution temperature and dissolution time of the solubilizer, the dissolution time of the binder, and the use time of the binder after mixing, the mixture can be mixed and combined homogeneously, and the tableting problem can be solved.

[0083] In addition, it was confirmed that by controlling the granule size during the process of establishing after combining, a suitable process result can be secured, mixing unevenness in the post-mixing step can be improved, and a suitable dissolution rate can be secured. In addition, it was confirmed that by controlling the combining / compression conditions, an optimal process result can be secured, and thus the solubility of pranlukast can be improved, thereby completing the present invention.

[0084] Hereinafter, the present invention will be described in detail.

[0085] Method for preparing a pharmaceutical composition containing pranlukast

[0086] [definition]

[0087] The present invention uses pranlukast as an active ingredient, and the active ingredient is not particularly limited. For example, the active ingredient of pranlukast currently on the market is pranlukast hydrate, but the present invention is characterized by overcoming the physicochemical limitations of pranlukast itself through a novel formulation design, so even if a salt compound in which a pharmaceutically acceptable salt other than the hydrate is combined is used as the active ingredient, the equivalent intended effect is exhibited. Therefore, it is disclosed that the term "pranlukast" in this specification can be used to mean pranlukast, its hydrate, its solvate, or its salt.

[0088] [Chewable tablet manufacturing method]

[0089] In the present invention, the inventor's prior invention, Republic of Korea Patent Publication No. 10-2363727, which improves the bioavailability of pranlukast and reduces the dosage, discloses a solid formulation for oral administration prepared by mixing a disintegrant with a wet granule containing pranlukast, a surfactant, a binder, and a diluent. Specifically, in the example, pranlukast, lactose, and microcrystalline cellulose are mixed in a high-speed rotary mixer, and then a binder solution obtained by stirring a solvent, a binder, and a surfactant is added, and after kneading, granulation and sizing are performed to obtain a wet granule. Next, the granule is mixed with a disintegrant and a lubricant, and then tableted and coated to prepare a tablet.

[0090] This is a formulation design optimized for improving bioavailability, as it can reduce the dosage of pranlukast to 50 mg per tablet.

[0091] The inventors first attempted to formulate the above formulation into a chewable tablet, an example of a pharmaceutical composition, using the above formulation design. Typically, when manufacturing chewable tablets, binders, excipients, and sweeteners are combined based on the physicochemical properties of the main ingredient, as well as its taste and aroma. Therefore, the inventors attempted to incorporate various sweeteners and flavoring agents into the above formulation, varying their types.

[0092] In the present invention, the most important thing in manufacturing a preparation containing pranlukast is the process of solubilizing the poorly soluble pranlukast. Since the most suitable solubilizing agent and mixing amount for solubilization have already been discovered in the prior invention, the type and content of the solubilizing agent were used according to the method in the prior invention.

[0093] However, in the case of the prior art, it was found that many problems occurred during mass production because there was no research on the method of dissolving and mixing the solubilizer. The biggest problem among them was that when the solubilizer and binder were manufactured and used by dissolving them in an appropriate solvent and using them overnight, which is a commonly used binder dissolution method, sticking and chipping frequently occurred during the kneading and tableting processes. Accordingly, the inventors of the present invention conducted a detailed investigation on the order of adding the binder and solubilizer, the dissolution time, and the use time after dissolution, among the manufacturing methods, and invented the optimal dissolution method.

[0094] When the solubilizer and binder were weighed and added in the following order, no problems were found in the mixing process and drying and tableting process.

[0095] The dissolution method of the solubilizer and the type of binder are the same as in the prior art, and the dissolution temperature and dissolution time of the solubilizer in the manufacturing method are among the very important factors, and it was found that the most suitable dissolution temperature and dissolution time were 55±5 ℃ and 45±15 minutes, respectively. When the dissolution temperature was less than 50 ℃, not only did the dissolution time of the solubilizer become longer, but it also affected the solubilization of the main ingredient, and when the temperature exceeded 60 ℃, the dissolution time could be shortened, but it caused sticking or chipping during tableting. In addition, when the dissolution time was less than 30 minutes, the solubilization of the main ingredient was not sufficiently induced, and when it exceeded 60 minutes, it caused tableting problems, just like when the temperature exceeded 60 ℃.

[0096] In addition, the process of manufacturing the binder after dissolving the solubilizer also affected the successful completion of the formulation, causing problems in the combination process and the tableting process.

[0097] When the binder and solubilizer were added to the solvent that dissolves the binder and left overnight (12-16 hours), and the evaporated solvent was weighed and corrected before use the next day, the problem of the solubilizer precipitating during the mixing process in the high-speed mixer occurred, and also the mixture became sticky in a short period of time, so that the mixture could not be mixed and mixed homogeneously. When the manufactured binder was dried, ground, and subjected to a post-mixing process and then pressed into a tablet, it was found that sticking and chipping occurred.

[0098] Although the exact cause of this phenomenon is unknown, it is presumed that it occurs because the subsequent process is carried out without the solubilizer and binder being homogeneously mixed with the mixture.

[0099] To solve this phenomenon, the inventors of the present invention closely investigated not only the dissolution time of the solubilizer but also the dissolution time of the binder, the time for mixing the solubilizer and the binder, and the time for which the binder should be used after mixing.

[0100] As a result, it was found that the conditions for solubilizing the solubilizer were suitable for dissolving the binder and mixing the binder and solubilizing agent within 35 to 95 minutes to meet the above-mentioned conditions. In addition, the time for using the dissolved binder was also suitable for within 5 hours to avoid causing problems in the kneading and tableting processes.

[0101] In addition, it was found that when manufactured in this way, the unique bitter taste (bitterness) of franlukast was strongly expressed, and as a result, the bitter taste was found to remain in the mouth for a long time.

[0102] Even when manufacturing by accurately specifying the dissolution method and use time of the solubilizer and binder, there was a slight bitter taste. This bitter taste was caused by the main ingredient and the solubilizer, so in order to overcome this, various sweeteners and flavoring agents were mixed to reduce the bitter taste. As such sweeteners, one or more selected from the group consisting of white sugar, glucose, mannitol, sorbitol, aspartame, acesulfame, and sucralose can be adopted and used.

[0103] In addition, the content of the solubilizer and the content of the binder also need to be controlled. Specifically, the solubilizer can be added in an amount of 1 to 20 wt%, preferably 1 to 10 wt%, relative to the weight of the entire pharmaceutical composition, and the binder can be added in an amount of 1 to 5 wt%, preferably 1 to 3 wt%, relative to the weight of the entire pharmaceutical composition.

[0104] In the present invention, it was also discovered that, in addition to the conditions for manufacturing the solubilizer and binder, the conditions of manufacturing equipment such as a high-speed mixer and a tablet press have a very important influence on the obstacles to the combination and tableting process that were not resolved in the prior invention.

[0105] The mixture containing the main ingredient is put into a high-speed mixer and the agitator and chopper are started to mix. It is desirable that the agitator and chopper rotate at 120±10 RPM for 3±1 minutes. If the agitator or chopper speed is slower, the mixture will not be mixed well, and if it is faster, the mixture may separate again, resulting in a poor mixing quality. When sufficiently mixed, the binder should be slowly added to ensure good mixing of the solubilizer and the main ingredient. It is most desirable that the rotation speed of the agitator and chopper be the same as that during mixing, and the mixing time of 5±1 minutes gave the best results. If the mixing time is short, the binder is not mixed homogeneously in the mixture, and if the mixing time is long, the mixture becomes sticky in an instant, causing sticking or chipping during tableting.

[0106] These problems are not common phenomena when manufacturing tablets using a general wet granulation method, but when manufacturing a poorly soluble drug by solubilizing it as in the present invention, there are many cases where it is impossible to manufacture using a general formulation manufacturing method, or even if it is manufactured, the quality cannot be guaranteed.

[0107] Pranlukast, as in the present invention, is a drug that is very poorly soluble and poorly absorbed, so it can be said that not only the composition but also the manufacturing process is one of the most important factors in the performance of the drug.

[0108] In the present invention, the main ingredient and the ingredient for solubilization act alone or in combination to produce a very bitter taste. When developing a chewable tablet as in the present invention, it is very important to mask the bitter taste.

[0109] The bitter taste can generally be reduced by mixing in sugars, but pranlukast and the solubilizer polyoxyl 15 hydroxystearate have the characteristic of releasing the bitter taste later than at the beginning when chewing, so the selection of sweetener is very important.

[0110] In the present invention, when masking bitterness with sweetness, a weakly acidic organic acid (pH adjuster) was added to more effectively mask the bitterness, and by appropriately mixing sucralose and aspartame as sugars, the bitterness of the main ingredient pranlukast and the solubilizer polyoxyl 15 hydroxystearate could be completely masked.

[0111] Specifically, in the case of aspartame and sucralose, they can be added in a weight ratio of 1 to 2:1, preferably 1.1 to 1.3:1.

[0112] The present invention may include lactose monohydrate and microcrystalline cellulose as diluents. This is a combination of additives of the inventor's prior invention, Korean Patent Publication No. 10-2363727, which dramatically improves the bioavailability of pranlukast and reduces the dosage, and reduces the daily dosage of pranlukast by a total of 26.5-74.2 mg, for example, 26.5 mg, 37.1 mg, 53 mg, and 74.2 mg, while exhibiting an effect equivalent to that of dry syrup of 50 mg, 70 mg, 100 mg, and 140 mg, making it a convenient chewable tablet that can be taken without water, while being a diluent combination optimized for improving bioavailability.

[0113] [General method of manufacturing tablets]

[0114] The present invention can be manufactured by mixing the chewable drug delivery system described above with pranlukast that has undergone a solubilization process.

[0115] At this time, pranlukast is first wet-granulated with a diluent and surfactant to improve bioavailability.

[0116] When manufacturing the granules according to the present invention, diluents commonly used in the pharmaceutical field can be used. For example, one or more of xylitol, mannitol, isomalt, sorbitol, maltitol, refined white sugar, lactose, inositol, erythritol, crystalline fructose, trehalose, ribitol, arabitol, galactitol, lactitol, and maltotritol, microcrystalline cellulose, sodium croscarboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose, gelatinized starch, glucose, pregelatinized starch, starch, corn starch, light anhydrous silicic acid, or crystalline cellulose can be selected and used. In particular, microcrystalline cellulose, lactose, or a mixture thereof is preferable in terms of expression of the effect aimed at by the present invention. It is preferable to contain the diluent in an amount of 20 to 60% by weight of the total pharmaceutical composition in order to achieve the desired effect of the present invention.

[0117] When manufacturing the granules according to the present invention, a binder commonly used in the pharmaceutical field can be used. For example, one or more selected from polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene glycol, polyvinyl alcohol, etc. can be used. In particular, at least one selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, and hydroxypropylmethylcellulose is preferable in terms of expression of the effect aimed at by the present invention, and among these, polyvinylpyrrolidone is most preferable. In terms of expression of the effect aimed at by the present invention, it is preferable to contain the binder in an amount of 2-10% relative to the weight of the entire pharmaceutical composition.

[0118] When manufacturing the granules according to the present invention, one or more surfactants (solubilizers) may be selected and used from the group consisting of polyethylene glycol-15-hydroxystearate (e.g., Kolliphor® HS 15), polyoxyethylene glycol-hydrated natural or hydrogenated castor oil (e.g., Kolliphor® RH 40), polyoxyethylene-polyoxypropylene copolymers (e.g., poloxamers), polyoxyethylene sorbitan fatty acid esters (e.g., polysorbates), sodium lauryl sulfate, glyceryl fatty acid esters (e.g., glyceryl monostearate), etc., and in particular, from the viewpoint of expression of the effects aimed at by the present invention, at least one selected from the group consisting of polyethylene glycol-15-hydroxystearate, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylene sorbitan fatty acid esters, and sodium lauryl sulfate is preferable. It is preferable to contain 5-20% of the surfactant (solubilizer) based on the weight of the entire pharmaceutical composition in terms of the expression of the effect desired by the present invention.

[0119] When manufacturing the granules according to the present invention, it is preferable to use an alcoholic solvent rather than purified water. In this case, an alcohol having 1 to 6 carbon atoms is preferable in terms of achieving the desired effects of the present invention. For example, lower alcohols such as methanol, ethanol, propanol, isopropanol, and butanol can be used. In particular, the use of ethanol resulted in a remarkable improvement in the bioavailability of pranlukast.

[0120] The pharmaceutical composition according to the present invention may contain solid granules of the above pranlukast and a pharmaceutically acceptable carrier.

[0121] Pharmaceutically acceptable carriers include diluents, disintegrants, lubricants, etc., which are already known and used. In the present invention, diluents usable as carriers include xylitol, mannitol, isomalt, sorbitol, maltitol, refined white sugar, lactose, inositol, erythritol, crystalline fructose, trehalose, ribitol, arabitol, galactitol, lactitol and maltotritol, microcrystalline cellulose, croscarboxymethylcellulose sodium, carboxymethylcellulose calcium, hydroxypropylcellulose, carboxymethylcellulose sodium, carboxymethylcellulose, gelatinized starch, glucose, pregelatinized starch, starch, corn starch, light anhydrous silicic acid or crystalline cellulose and mixtures thereof, and disintegrants include sodium starch glycolate, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and the like, and lubricants include sodium stearyl fumarate, Contains magnesium stearate, stearic acid, colloidal silicon dioxide, etc.

[0122] The above pharmaceutically acceptable carrier can be flexibly adjusted with respect to the total weight of the composition, and can be appropriately selected and used depending on the final formulation obtained.

[0123] [Dissolution and PK conditions]

[0124] The purpose of the present invention is to solubilize and chew a pranlukast preparation that is administered at a dose of 50 to 140 mg twice a day, so that the same effect can be achieved by administering only 26.5 to 74.2 mg twice a day, for example, 26.5 mg, 37.1 mg, 53.0 mg or 74.2 mg at a time.

[0125] In the present invention, while manufacturing a chewable tablet containing pranlukast, the inventors have first disclosed the conditions for dissolution and clinical trial PK to achieve the purpose of being able to exhibit the same effect as the conventional commercially available formulation by taking only 26.5 to 74.2 mg twice a day in the corresponding amount instead of the conventional dry syrup dosage form of 50 to 140 mg twice a day, for example, 50 mg, 70 mg, 100 mg or 140 mg.

[0126] The pharmaceutical composition of the present invention is characterized in that, when dissolved in a pH 6.8 + 0.2% PSB solution using the second dissolution method paddle method, the pranlukast concentration is 80% or more at a time point of 30 to 45 minutes.

[0127] In addition, the pharmaceutical composition of the present invention is characterized in that the time to reach the peak blood concentration of pranlukast is within 3 hours when administered to a beagle dog. When the pranlukast formulation satisfies the above nonclinical trial PK conditions, it is possible to achieve equivalence with the existing syrup formulation.

[0128] The formulation design of the present invention satisfies both the above dissolution and PK conditions, and ultimately succeeds in securing equivalence with a syrup formulation.

[0129] The following examples illustrate the present invention. However, it is to be understood that the scope of the present invention is not limited to the following examples.

[0130] [Manufacturing of Chewable Tablets]

[0131] [Examples 1-3 and Comparative Example 1]

[0132] In the case of chewable tablets according to Examples 1-3 and Comparative Example 1, the manufacturing method and process variables, except for the compositions described in Table 1 below, were all carried out in the same manner and are described in detail below (in the case of a composition containing lactose monohydrate or microcrystalline cellulose as a diluent, a solubilizer, a sweetener, and a flavoring agent are mixed).

[0133] Manufacturing method

[0134] Process 1. Preparation of binding solution (dissolution and dispersion of ethanol, polyoxyl 15 hydroxystearate, povidone, and poloxamer)

[0135] To solubilize the very poorly soluble pranlukast, the solubilizers polyoxyl 15 hydroxystearate and poloxamer are used and dissolved at 55±5℃, more preferably 60℃, for 30 to 60 minutes. Next, the binder povidone (PVP K-30) is slowly added to the binder solvent ethanol and stirred with a stirrer for 35±15 minutes to completely dissolve. Check that there are no lumps or undissolved residues and slowly add the previously dissolved solubilizers polyoxyl 15 hydroxystearate and poloxamer while stirring, homogenizing, and dispersing for 30±15 minutes.

[0136] Process 2. Mixing of pranlukast hydrate, lactose hydrate, and anti-caking powder

[0137] Add pranlukast hydrate, lactose hydrate, and anti-caking powder to a high-speed mixer and mix for 3 minutes at an agitator speed of 120±10 rpm and a chopper speed of 2000±200 rpm.

[0138] Process 3. Granulate the semi-finished product of Process 2 with the binder of Process 1.

[0139] Slowly add the Process 1 binding solution (dissolved solubilizer and binding solution) to the Process 2 semi-finished product. The agitator and chopper speeds are the same as in the mixing step. The mixing time affects the properties of the mixture, so perform the mixing for 5 minutes.

[0140] Process 4. Granulate the semi-finished product (combined product) of Process 3 using Corn-Mill.

[0141] After the coalescence is complete, the coalescence is granulated using a cone mill at 300 to 900 rpm.

[0142] Process 5. Drying of semi-finished products from Process 4

[0143] Drying is performed using a preheated flat-plate dryer, and the granules are thinly spread to a thickness of approximately 1 cm and then dried at 50°C until the LOD becomes 2.0% or less. Preferably, 0.4 to 1.0% is suitable, and more preferably, approximately 0.8% is most suitable.

[0144] Process 6. Process 5 semi-finished product was established using an oscillator (No. 18 sieve, 850 μm).

[0145] The dried granules are sieved using an oscillator (No. 18 sieve, sieving mesh size: 850 μm) and transferred to a bin blender.

[0146] Process 7. Add D-mannitol, crospovidone, citrate monohydrate, aspartame, sucralose, strawberry flavoring powder, and colloidal silicon dioxide to the semi-finished product of Process 6, mix, then add sodium stearyl fumarate and mix for the final step.

[0147] Next, add D-mannitol, crospovidone, citrate monohydrate, aspartame, sucralose, strawberry flavoring powder, and colloidal silicon dioxide to the empty blender and mix at 10 rpm for 10 minutes. Finally, add sodium stearyl fumarate and mix at 10 rpm for another 5 minutes.

[0148] Process 8. Process 7 semi-finished products are pressed in a rotary press.

[0149] The final mixture, which is a semi-finished product of Process 7, is pressed using a rotary press, with the turret speed set to 20 to 30 rpm, preferably 23 to 27 rpm, the pressing position set to 16.5 to 18 mm, and the pressing pressure set to a preload of 30±5 kgf / cm. 2 , the main pressure is 35±5 kgf / cm 2 Set it to .

[0150] [Example 4-5]

[0151] For the chewable tablets according to Examples 4 and 5, the manufacturing method and process variables, except for the composition described in Table 1 below, were all carried out in the same manner and are described in detail below.

[0152] Manufacturing method

[0153] Process 1. Preparation of binding solution (dissolution and dispersion of ethanol, polyoxyl 15 hydroxystearate, povidone, and poloxamer)

[0154] To solubilize the very poorly soluble pranlukast, the solubilizers polyoxyl 15 hydroxystearate and poloxamer are used and dissolved at 55±5℃, more preferably 60℃, for 30 to 60 minutes. Next, the binder povidone (PVP K-30) is slowly added to the binder solvent ethanol and stirred with a stirrer for 35±15 minutes to completely dissolve. Check that there are no lumps or undissolved residues and slowly add the previously dissolved solubilizers polyoxyl 15 hydroxystearate and poloxamer while stirring, homogenizing, and dispersing for 30±15 minutes.

[0155] Process 2. Mixing of pranlukast hydrate, lactose hydrate, isomalt, anti-caking powder, and hydroxypropyl cellulose.

[0156] Add pranlukast hydrate, lactose hydrate, isomalt, anti-caking powder, and hydroxypropyl cellulose to a high-speed mixer and mix for 3 minutes at an agitator speed of 120±10 rpm and a chopper speed of 2000±200 rpm.

[0157] Process 3. Granulate the semi-finished product of Process 2 with the binder of Process 1.

[0158] Slowly add the Process 1 binding solution (dissolved solubilizer and binding solution) to the Process 2 semi-finished product. The agitator and chopper speeds are the same as in the mixing step. The mixing time affects the properties of the mixture, so perform the mixing for 5 minutes.

[0159] Process 4. Drying of semi-finished products from Process 3

[0160] Drying is performed using a preheated fluidized bed dryer, and the granules, which are semi-finished products of process 3, are dried at 50-55℃ until the LOD becomes 2.0% or less. Preferably, 0.4-1.0% is suitable, and more preferably, approximately 0.8% is the most suitable.

[0161] Process 5. Process 4 semi-finished product is established using an oscillator (No. 18 sieve, 850 μm).

[0162] The dried granules are sieved using an oscillator (No. 18 sieve, sieving mesh size: 850 μm) and transferred to a bin blender.

[0163] Process 6. Add D-mannitol, crospovidone, citric acid monohydrate, low-substituted hydroxypropyl cellulose, aspartame, sucralose, strawberry flavoring powder, and colloidal silicon dioxide to the semi-finished product of Process 5, mix, then add stearic acid and sodium stearyl fumarate (Example 4) or sodium stearyl fumarate (Example 5), and mix finally.

[0164] Next, D-mannitol, crospovidone, citric acid monohydrate, low-substituted hydroxypropyl cellulose, aspartame, sucralose, strawberry flavoring powder, and colloidal silicon dioxide are added to an empty blender and mixed at 10 rpm for 10 minutes. Finally, stearic acid and sodium stearyl fumarate (Example 4) or sodium stearyl fumarate (Example 5) are added and mixed at 10 rpm for another 5 minutes.

[0165] Process 7. Process 6 semi-finished products are pressed in a rotary press.

[0166] Process 6 The final mixture, which is a semi-finished product, is pressed into tablets using a rotary press. The turret speed is set to 20 to 30 rpm, preferably 23 to 27 rpm, the pressing position is set to 16.5 to 18 mm, and the pressing pressure is a preload of 30±5 kgf / cm. 2 , the main pressure is 35±5 kgf / cm 2 Set it to .

[0167] Mixing purpose Ingredient content (mg) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative example 1 Main ingredient Pranlukast hydrate 74.2 74.2 74.2 74.2 74.2 74.2 74.2 Diluent Lactose hydrate (200 mesh) 123.7 147.9 97.4 108.8 108.8 130 Sweetener Anti-caking agent Powdered sugar 74.2 50.0 100.5 14.5 14.5 6 7.9 Diluent Isomalt--- 4.0 94.0 - Binder Hydroxypropyl cellulose--- 4.6 4.6 - Binder Povidone (PVP) K-30)13.613.613.613.613.613.6SolubilizerPolyoxyl 15-hydroxystearate17.817.817.817.817.817.8SolubilizerPoloxamer40731.231.231.231.231.231.231.2Binding solventEthanol44.544.544.546.746.744.5DiluentD-mannitol101.5120.7109.546.646.681.2DisintegrantCrospovidone14.814.814.840.640.614.8pH Modifier: Citric acid hydrate 18.615.618.618.618.615.0 Disintegrant: Low-substituted hydroxypropyl cellulose --- 5.05.0 Sweetener: Aspartame 4.32.35.34.34.30 Sweetener: Sucralose 3.51.84.53.53.50 Flavoring agent: Strawberry flavored powder 49.540.049.549.549.549.5 Lubricant: Colloidal silicon dioxide 4.94.92.94.94.94.9 Lubricant: Sodium stearyl fumarate 24.726.726.718.624.826.7 Lubricant: Magnesium stearate --- 6.2-- Total 556.5561.5566.5556.5556.5526.8

[0168] [Manufacturing of general tablets]

[0169] [Example 6]

[0170] In the case of the tablet according to Example 6, the composition described in Table 2 below is used to manufacture the tablet according to the following manufacturing method.

[0171] Process 1. Preparation of binding solution (dissolution and dispersion of ethanol, polyoxyl 15 hydroxystearate, povidone, and poloxamer)

[0172] To solubilize the very poorly soluble pranlukast, the solubilizers polyoxyl 15 hydroxystearate and poloxamer are dissolved in a constant temperature water bath at 60°C for 10 to 30 minutes. Next, the binder povidone (PVP K-30) is slowly added to the binder solvent ethanol and stirred with a stirrer for 60±30 minutes to completely dissolve. Check that there are no lumps or undissolved residues, and slowly add the previously dissolved solubilizers polyoxyl 15 hydroxystearate and poloxamer while stirring, homogenizing, and dispersing for 120±30 minutes.

[0173] Process 2. Mixing of pranlukast hydrate, lactose hydrate, and microcrystalline cellulose

[0174] Add pranlukast hydrate, lactose hydrate, and microcrystalline cellulose to a high-speed mixer and mix for 3 minutes at an agitator speed of 120±10 rpm and a chopper speed of 1800±200 rpm.

[0175] Process 3. Granulate the semi-finished product of Process 2 with the binder of Process 1.

[0176] Slowly add the Process 1 binding solution (dissolved solubilizer and binding solution) to the Process 2 semi-finished product. The agitator and chopper speeds are the same as in the mixing step. The mixing time affects the properties of the mixture, so perform the mixing for 5 minutes.

[0177] Process 4. Process 3 semi-finished product is granulated using Corn-Mill.

[0178] Once the coalescence is complete, the coalescence is granulated using an oscillator or a cone-mill at 300 to 900 rpm.

[0179] Process 5. Drying of semi-finished products from Process 4

[0180] Drying is done using a preheated flat-plate dryer, and the granules are spread thinly to a thickness of approximately 1 cm and then dried at 50°C until the LOD becomes 2.0%. 0.8 to 1.2% is preferable, and approximately 1% is most preferable.

[0181] Process 6. Process 5 semi-finished product was established using an oscillator (No. 18 sieve, 850 μm).

[0182] The dried granules are sieved using an oscillator (No. 18 sieve, 850 μm) and transferred to a bin blender.

[0183] Process 7. Add crospovidone, croscarmellose sodium, and colloidal silicon dioxide to the semi-finished product of Process 6, mix, then add magnesium stearate and mix for final mixing.

[0184] Next, add crospovidone, croscarmellose sodium, and colloidal silicon dioxide to the empty blender and mix at 10 rpm for 10 to 15 minutes, then finally add magnesium stearate and mix at 10 rpm for another 5 minutes.

[0185] Process 8. Process 7 semi-finished products are pressed in a rotary press.

[0186] The final mixture, which is a semi-finished product of process 7, is pressed into tablets using a rotary press, with the turret speed set to 20 to 30 rpm, preferably 23 to 27 rpm, the pressing position set to 14.0 to 17.5 mm, and the pressing pressure set to a preload of 25 to 40 kgf / cm. 2 , the main pressure is 30~45 kgf / cm 2 Set it to .

[0187] It is recommended that the tablet hardness be 5 to 12 kp, preferably 5 to 10 kp, and more preferably 6 to 8 kp.

[0188] Process 9. Coating of semi-finished products from Process 8

[0189] The semi-finished product of process 8 is coated with a coating solution.

[0190] Ingredient name Content (mg) Main ingredient Pranlukast hydrate 50.0 Diluent Lactose hydrate (200 mesh) 61.0 Binder Povidone (PVP K-30) 11.0 Solubilizer Polyoxyl 15 hydroxystearate 12.0 Solubilizer Poloxamer 4072 1.0 Binder Solvent Ethanol 38.0 Diluent Microcrystalline cellulose PH 1016 1.0 Disintegrant Crospovidone 16.0 Disintegrant Crocarmellose sodium 16.0 Lubricant Colloidal silicon dioxide 5.0 Lubricant Magnesium stearate 7.0 Coating agent Opadry II White (85G68914) 10.0 Coating solvent Purified water 40.0 Total 270.0

[0191] Experimental example

[0192] Experimental Example 1. Confirmation of the occurrence of obstacles during the mixing process / compression process according to the dissolution method and time of the solubilizer and binder.

[0193] In the present invention, it was found that obstacles occurred during the kneading process or tableting process depending on the dissolution method and time of the solubilizer and binder. Therefore, although it was difficult to determine the exact cause, the inventors of the present invention anticipated that the solubilizer would have an effect, so they conducted research on the dissolution method, dissolution time, and shelf life after dissolution, and established the optimal conditions for the kneading and tableting process, thereby completing the present invention.

[0194] The solubilizer was dissolved by setting the dissolution temperature to 50℃, 55℃, 60℃, 65℃, and 70℃, and the dissolution time was set to 30 minutes and 60 minutes, respectively.

[0195] When dissolved under each condition, the obstacles in the combination process and the tableting process according to the dissolution temperature and dissolution time of the solubilizer are shown in Table 3, with Example 1 as a representative example, and the obstacles in the process according to the dissolution time and shelf life of the binder are shown in Table 4.

[0196] Temperature (℃) Time (min) Combination process Tableting process Dissolution rate (30 min) 50 30 Increase in combination time Compression failure 75% or less 60 Increase in combination time Compression failure 75% or less 55 30 Increase in combination time Compression failure 75% or less 60 Good Good 80% or more 60 30 Good Good 80% or more 60 Good Good 80% or more 65 30 Toughened sticky 80% or more 60 Toughened sticky 80% or more 70 30 Toughened sticky severe 80% or more 60 Toughened sticky severe 80% or more

[0197] Time (minutes) Expiration date (hours) Combined process Tableting process Dissolution rate (30 minutes) 305 Good Good 80% or more 15 Good Good 80% or more 605 Good Good 80% or more 15 Good Good 80% or more 905 Good Good 80% or more 15 Good Good 80% or more 15 hours - Toughness Sticking Very severe 70% or less

[0198] The dissolution time and shelf life of the binder were first discovered in the present invention, and although the mechanism is not precisely known, it is presumed to be due to the influence of polyoxyl 14 hydroxystearate and poloxamer 407, which are solubilizers used to solubilize pranlukast in the present invention. In order to elucidate this phenomenon, the inventors of the present invention are trying to elucidate the mechanism by diversifying other poorly soluble drugs and binders. In the present invention, as shown in Tables 3 and 4, the manufacturing time is preferably 30 minutes to 90 minutes, and the shelf life is preferably no longer than 5 hours. More preferably, it was confirmed that the binder and solubilizer should be used in production immediately after complete dissolution and swelling to prevent the mixture from becoming sticky in a short period of time when combined during the production process or severe sticking occurring during the tableting process, which lowers production efficiency.

[0199] Experimental Example 2. Testing formulation suitability according to the size of the established network.

[0200] Evaluation method

[0201] It is manufactured according to the size of the net and evaluated after completion of the stamping.

[0202] Test Results

[0203] If the following criteria are met in terms of hardness, wear, fluidity, disintegration, and dissolution, it is evaluated as suitable, and the results for each mesh size are shown in Table 5 below.

[0204] Evaluation criteria

[0205] Hardness: 4~8KP

[0206] Wear: 20 tablets, 100 rotations, 0.5% or less

[0207] Fluidity: Angle of repose 43℃ or less

[0208] Disintegration: within 15 minutes (visually confirmed), 6 specimens each

[0209] Elution: 30% or more within 10 minutes, 70% or more in 30 minutes

[0210] Established mesh size Hardness test Friction test Flowability test Disintegration test Dissolution 850 μm Suitable Suitable Suitable Suitable Suitable 710 μm Suitable Suitable Suitable Suitable Suitable 600 μm Suitable Suitable Inappropriate Suitable Inappropriate 500 μm Suitable Suitable Inappropriate Inappropriate Inappropriate

[0211] Evaluation Results

[0212] As shown in Table 5, when granules containing pranlukast were manufactured using a mesh size of 700 μm or less, specifically 500 to 600 μm, inadequate results were confirmed in the fluidity test and disintegration test. Through this, it was confirmed that as the mesh size became smaller, the time increased and fine particles were generated more, which affected the fluidity.

[0213] However, when granules containing pranlukast were manufactured using a sizing mesh of 710 to 850 μm according to the present invention (in the case of Example 1, a sizing mesh of 850 μm was used), it was confirmed that the sizing time was short and a formulation (chewable tablet, tablet) suitable for hardness, friability, fluidity, disintegration test, dissolution rate, etc. could be manufactured.

[0214] Experimental Example 3. Evaluation of Taste Masking in Chewable Tablets

[0215] Evaluation method

[0216] In the present invention, a chewable tablet containing pranlukast hydrate was developed. Since the preparation is chewed and taken orally, the taste and odor must not be unpleasant for patients. Therefore, the inventors of the present invention mixed various sweeteners and flavoring agents and conducted sensory tests to assess the taste and chewability.

[0217] Specifically, sensory evaluation (simple) was conducted on the bitterness, sweetness, and chewiness of the chewable tablets manufactured in Examples 1 to 4 and Comparative Example 1, and the results are shown in Tables 6 to 9.

[0218] Bitterness level+++ There is a little bitterness, but it is not overpowering++ There is a little bitterness+ There is a bitterness- The bitterness is strong- The bitterness is very strong

[0219] Sweetness level +++ Very strong sweetness (very good) ++ Strong sweetness (good) + A little sweetness (average) - A little sweetness but can't feel it (bad) - - No sweetness at all (very bad)

[0220] Quality of workmanship +++ Very good ++ Good + Average - Poor (tough and strong) - - Very poor (very tough and strong)

[0221] Item Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Bitterness+++++++++++- -Sweetness++++++++- -Mastication++++++++++++

[0222] Evaluation Results

[0223] Referring to Table 9, the chewable tablets according to Examples 1 to 4 were evaluated as good / very good for bitterness, sweetness, and chewiness, but the chewable tablet according to Comparative Example 1 was found to have a problem in that the bitterness was not masked and the sweetness was hardly felt, resulting in poor convenience of taking.

[0224] Experimental Example 4. Dissolution Evaluation of Chewable Tablets

[0225] Evaluation method

[0226] Comparative dissolution was performed on one chewable tablet manufactured in Example 1 (test material, Citus chewable tablet, pranlukast hydrate 74.2 mg) and dry syrup (Sam-A Pharmaceutical, Citus dry syrup, control material) according to the second method of dissolution test of the Korean Pharmacopoeia.

[0227] Specifically, 900 mL of each solution containing a pH 6.8 solution and a 0.2% PSB solution was added to the elution device, and the elution rate was measured while stirring at a rotation speed of 50 rpm while maintaining the temperature at 37±0.5℃. Approximately 5 mL of the elution solution was taken at each time point (0 min, 10 min, 15 min, 30 min, and 45 min), filtered through a 0.45 μm filter, and analyzed by HPLC. The results are shown in Fig. 1.

[0228] And, comparative dissolution was performed on one chewable tablet (test substance, Citrus chewable tablet, pranlukast hydrate 74.2 mg) manufactured in Examples 1, 4, and 5 according to the second dissolution test method of the Korean Pharmacopoeia. The comparative dissolution method was the same as the method described above, and the results are shown in Fig. 2.

[0229] Evaluation Results

[0230] FIG. 1 shows the results of a dissolution test performed on a chewable tablet (test substance, Citrus chewable tablet, pranlukast hydrate 74.2 mg) according to Example 1 of the present invention compared to a control drug, dry syrup (Sam-A Pharmaceutical, Citrus dry syrup 140 mg). As can be seen in FIG. 1, in the case of the chewable tablet (test substance) according to Example 1 of the present invention, it was confirmed that the pranlukast concentration was dissolved by 75% or more at a time point of 30 to 45 minutes. Through this, it was confirmed that the chewable tablet according to Example 1 of the present invention can exhibit the same efficacy as that of Citrus dry syrup 50-140 mg once a day twice a day with only 26.5-74.2 mg administered once a day, twice.

[0231] And, the chewable tablet (test substance, Citrus chewable tablet) according to Example 1 of the present invention was crushed (74.2 mg crushed in Figure 1), and it was confirmed that the crushed tablet showed a dissolution result at the same level as the control drug.

[0232] FIG. 2 shows whether the chewable tablets (test substance, Citrus chewable tablet, pranlukast hydrate 74.2 mg) according to Examples 4 and 5 exhibit dissolution behaviors equivalent to or similar to those of the chewable tablets (test substance, Citrus chewable tablet, pranlukast hydrate 74.2 mg) according to Example 1. As can be confirmed in FIG. 2, in the case of the chewable tablets (test substance) according to Examples 4 and 5, it was confirmed that, like the chewable tablet (test substance) according to Example 1, the pranlukast concentration was dissolved by 75% or more at 30 to 45 minutes. Through this, it was confirmed that not only the chewable tablet according to Example 1 of the present invention, but also the chewable tablet according to Examples 4 and 5 can exhibit the same efficacy as that of administering 50-140 mg of Citrus dry syrup twice a day, with only 26.5-74.2 mg administered once a day, twice a day.

[0233] Experimental Example 5. Bioequivalence Test of Chewable Tablets

[0234] Evaluation method

[0235] The in vivo kinetics in humans were evaluated using the chewable tablet manufactured according to the present invention (Example 1) and the commercially available formulation, Citus dry syrup (Sam-A Pharmaceutical, 140 mg).

[0236] Evaluation Results

[0237] Referring to FIG. 3, it was confirmed that the chewable tablet of Example 1 manufactured by the manufacturing method according to the present invention can exhibit the same level of clinical efficacy even when administered at a much lower dose (74.2 mg / tablet) than the total 140 mg of pranlukast in one packet of Citus dry syrup, an existing commercial product.

[0238] 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. (S1) A step of dissolving a solubilizing agent at 50 to 60°C for 30 to 60 minutes, adding the solution to a solution in which a binder is dissolved, and stirring to prepare a mixed solution containing a solubilizing agent and a binder; (S2) A step of mixing pranlukast, its hydrate, its solvate or its salt and a pharmaceutical additive; (S3) A step of adding the mixture of (S1) to the mixture of (S2) and then mixing them to prepare granules; (S4) A step of drying the granules of (S3) to produce a dried granule; (S5) A step of preparing a final mixture by sizing the dried granules of (S4) and mixing them with pharmaceutical additives; and (S6) Step of pressing the final mixture of (S5) above A method for preparing a pharmaceutical composition containing pranlukast.

2. A method for producing a pharmaceutical composition containing pranlukast, characterized in that, in the first paragraph, the solution in which the solubilizing agent is dissolved is used within 1 hour after dissolving the solubilizing agent at 50 to 60°C for 30 to 60 minutes.

3. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the first paragraph, the solution in which the binder is dissolved in the step (S1) is obtained by adding the binder to the binding solvent and stirring for 20 to 50 minutes, and then using the obtained solution within 5 hours.

4. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the first paragraph, the mixed solution in the step (S1) is obtained by adding a solution in which a solubilizing agent is dissolved to a solution in which a binder is dissolved and then dissolving for 15 to 45 minutes.

5. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the first paragraph, the solubilizing agent in the step (S1) is any one of polyoxyl 15 hydroxystearate, poloxamer 407, or a mixture thereof.

6. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the first paragraph, the binder in the step (S1) is at least one selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene glycol, and polyvinyl alcohol.

7. A method for producing a pharmaceutical composition containing pranlukast, characterized in that, in paragraph 1, the content of the solubilizer is 1 to 20 wt% and the content of the binder is 1 to 5 wt% relative to the weight of the entire pharmaceutical composition.

8. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the first paragraph, the pharmaceutical additive in the step (S2) is at least one selected from the group consisting of a diluent, a sweetener, and a binder.

9. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the step (S2), the diluent is at least one of xylitol, mannitol, isomalt, sorbitol, maltitol, refined white sugar, lactose, inositol, erythritol, crystalline fructose, trehalose, ribitol, arabitol, galactitol, lactitol, and maltotritol, microcrystalline cellulose, sodium croscarboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose, gelatinized starch, glucose, pregelatinized starch, starch, corn starch, light anhydrous silicic acid, or crystalline cellulose, and the sweetener is anti-caking sugar.

10. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the step (S2), mixing is performed for 1 to 5 minutes at an agitator speed of 110 to 130 rpm and a chopper speed of 1800 to 2200 rpm.

11. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the 8th paragraph, the binder in the step (S2) is at least one selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyethylene glycol, and polyvinyl alcohol.

12. A method for manufacturing a pharmaceutical composition containing pranlukast, characterized in that in the first paragraph, the formulation in (S5) is formulated by using a sizing net of 710 to 850 μm to form a dried granule.

13. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in paragraph 1, the pharmaceutical additive in (S5) is at least one selected from the group consisting of a diluent, a disintegrant, a pH regulator, a sweetener, a flavoring agent, and a lubricant.

14. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in paragraph 13, the diluent is at least one of xylitol, mannitol, isomalt, sorbitol, maltitol, refined white sugar, lactose, inositol, erythritol, crystalline fructose, trehalose, ribitol, arabitol, galactitol, lactitol, and maltotritol, microcrystalline cellulose, sodium croscarboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose, gelatinized starch, glucose, pregelatinized starch, starch, corn starch, light anhydrous silicic acid, or crystalline cellulose.

15. A method for producing a pharmaceutical composition containing pranlukast, characterized in that the disintegrant in claim 13 is any one of crospovidone, low-substituted hydroxypropyl cellulose, or a mixture thereof.

16. A method for producing a pharmaceutical composition containing pranlukast, characterized in that the pH adjusting agent in claim 13 is citric acid hydrate.

17. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in claim 13, the sweetener is any one selected from the group consisting of white sugar, glucose, mannitol, sorbitol, aspartame, acesulfame, and sucralose.

18. A method for producing a pharmaceutical composition containing pranlukast, characterized in that the lubricant in claim 13 is any one of colloidal silicon dioxide, sodium stearyl fumarate, magnesium stearate, or a mixture thereof.

19. In the first paragraph, the step of pressing in the step (S6) is performed at a turret speed of 20 to 30 rpm, a pressing position of 16.5 to 18 mm, and a pressing pressure of 25 to 35 kgf / cm preload. 2 , the main pressure is 30 to 40 kgf / cm 2 A method for manufacturing a pharmaceutical composition containing pranlukast, characterized in that the hardness is adjusted to 5 to 12 kp by pressing.

20. A pharmaceutical composition containing pranlukast manufactured by a manufacturing method according to any one of claims 1 to 19.

21. A pharmaceutical composition according to claim 20, characterized in that the pharmaceutical composition is an oral solid dosage form.

22. A pharmaceutical composition according to claim 21, wherein the oral solid dosage form is one of a pellet, a capsule, a chewable tablet, a single-layer tablet, a multi-layer tablet, a core tablet, a granule, or a mini-tablet.

23. A pharmaceutical composition according to claim 20, characterized in that the pharmaceutical composition has a pranlukast content of 26-74.2 mg per unit dosage form.

24. In paragraph 20, the pharmaceutical composition is characterized in that when the pharmaceutical composition is dissolved in a pH 6.8 solution by the second dissolution method (paddle method) of the Korean Pharmacopoeia, the concentration of pranlukast is 80% or more at a time point of 30 to 45 minutes.

25. A pharmaceutical composition according to claim 20, characterized in that the time taken for the highest blood concentration of pranlukast to be reached is within 3 hours when administered to a human body.

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