WO2025018777A1 - Method for preparing pharmaceutical composition containing pranlukast and pharmaceutical composition prepared thereby - Google Patents

Abstract

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

Description

Method for producing a pharmaceutical composition containing pranlukast and a pharmaceutical composition produced by the method

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 composition is left overnight (12 to 16 hours), and the evaporated solvent is weighed and corrected before use the next day, and then a process of kneading in a high-speed mixer is performed. However, during the process described above, a problem occurs in which the solubilizer precipitates, and also a phenomenon occurs in which the kneaded product becomes sticky in a short period of time, preventing the mixture from being mixed and kneaded homogeneously, and a phenomenon in which sticking and chipping occur when the manufactured kneaded product is dried, ground, 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 following problems:

[Franlukast]

The present invention uses franlukast as an active ingredient.

Pranlukast, represented by the following chemical formula 1 and whose chemical name is 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.

[Chemical Formula 1]

Pranlukast is a drug used to treat asthma and allergic rhinitis. It has the effect of suppressing allergic reactions by blocking leukotrienes, inflammatory mediators that cause asthma and rhinitis.

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.

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

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 or fall ragweed pollen; and perennial allergic rhinitis, which occurs due to substances such as house dust, mites, mold, and animal hair; and symptoms such as sneezing, clear runny nose, and nasal congestion appear due to an allergic reaction in the nasal mucosa.

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

[Conventional formulation]

Pranlukast has been tried in various dosage forms, including tablets, suspensions, dry syrup, or capsules.

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

It has been revealed that the site of maximum absorption of pranlukast when administered orally is the upper small intestine, and as a drug belonging to the Biopharmaceutics Classification System (BCS) 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.

In this regard, in the case of Onon capsules, the problem of pranlukast could not be improved at the formulation stage, so a method of increasing the content of pranlukast was adopted, and when calculated, it was reported that only when 225 mg of pranlukast is administered per adult is there significant treatment for the intended disease. However, this is uneconomical because the single dose is large, and it can reduce patient compliance, and can cause side effects due to high-dose administration of the drug.

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 the adhesion and cohesion, a saccharide, 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 the adhesion and cohesion of pranlukast but has not improved the solubility of pranlukast. Therefore, the dissolution is delayed, and the dissolution rate is very low, so there is a limitation that the bioavailability is ultimately still low.

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

However, in order to manufacture the nano solid dispersion of the Korean Patent Publication No. 10-1332223, a mixing process, a thermal melting process, and a solvent evaporation process must be performed, so there are disadvantages such as high manufacturing costs and the need for performing a complex manufacturing process. In addition, since methanol/dichloromethanol is used as a cosolvent, the organic solvent may remain in the solid dispersion, and there is also the problem of environmental pollution due to the use of the organic solvent.

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

Korean Patent Publication No. 10-1086254 discloses a pranlukast solid dispersion composition characterized in that a polyvinylpyrrolidone vinyl acetate copolymer to pranlukast is melted by heat at a weight ratio of 0.2:1 to 10:1. This is a patent regarding Pranair Capsule (pranlukast 112.5 mg/capsule, 1 capsule per dose, SK Chemical).

However, although the solid dispersion disclosed in Korean Patent Publication No. 10-1086254 can be seen to have increased the bioavailability of pranlukast by twice that of 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 a burden in equipment investment and a 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 revert back to a stable crystalline form within the shelf life of the product, which may change the solubility and bioavailability of the drug.

Korean Patent Publication No. 10-0981751 discloses granules containing pranlukast including 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 on a granule core, and then tableting them. This patent relates to Prakanone tablets (pranlukast 75 mg/tablet, 1 tablet at a time, Yuhan Corporation).

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 and reduced the single-administered drug dosage by 1/3 compared to the existing control drug, Onon Capsule, the single-administered dosage is still 75 mg of pranlukast, so there is a need to improve patient compliance by further improving the bioavailability and reducing the dosage of the drug and the side effects of high-dose administration of the drug.

Korean Patent Publication No. 10-2363727 is a prior invention of the present inventor, which discloses a wet granulation of pranlukast. This invention is characterized by dramatically improving the bioavailability of pranlukast through a combination of a specific diluent, binder, and surfactant, despite adopting a general wet granulation process rather than a hot melt method, and successfully reducing the single administration dose to 50 mg. This is a patent regarding Citous tablets (pranlukast 50 mg/tablet, 1 tablet at a time, Sam-A Pharmaceutical), and is a patent listed on the pharmaceutical patent list of the Ministry of Food and Drug Safety.

However, the above patent documents do not recognize at all the problems that occur during the manufacture of a pranlukast-containing preparation (the problem of precipitation of the solubilizing agent, 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 tasks to be solved.

Accordingly, there is an urgent need for research and development of a method for manufacturing a novel pranlukast-containing formulation that solves the above-mentioned problems.

[Prior art literature]

[Patent Document]

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

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

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

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

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

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

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 improves 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.

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.

In addition, the optimal process results can be secured by adjusting the union/titration conditions, thereby improving the solubility of pranlukast.

When referring to pranlukast in this specification, it may refer to pranlukast, a hydrate thereof, a solvate thereof, or a salt thereof. Accordingly, a pharmaceutical composition comprising pranlukast in this specification may mean a pharmaceutical composition comprising pranlukast, a hydrate thereof, a solvate thereof, or a salt thereof.

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

The present invention is described in detail below.

The present invention solved the above-mentioned problems by the following means.

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 including 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 a dried granule; (S5) a step of sieving the dried granule of (S4) and then mixing it with a pharmaceutical additive to prepare a final mixture; and (S6) a step of compressing the final mixture of (S5).

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

3. A method for manufacturing 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 used within 5 hours.

4. A method for manufacturing 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 containing a solubilizing agent to a solution containing a binder and dissolving the solution for 15 to 45 minutes.

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.

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, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, and polyvinyl alcohol.

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.

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.

9. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the above 8, the diluent in the step (S2) is at least one of xylitol, mannitol, isomalt, sorbitol, maltitol, refined 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, and crystalline cellulose, and the sweetener is anti-caking sugar.

10. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the above 1, the mixing in the 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.

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, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, and polyvinyl alcohol.

12. A method for manufacturing a pharmaceutical composition containing pranlukast, characterized in that in the above 1, 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 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.

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 sugar, lactose, inositol, erythritol, crystalline fructose, trehalose, ribitol, arabitol, galactitol, lactitol, and maltotritol, microcrystalline cellulose, sodium croscarboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, carboxymethylcellulose, gelatinized starch, glucose, pregelatinized starch, starch, corn starch, light anhydrous silicic acid, and crystalline cellulose.

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.

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.

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 sucrose, glucose, mannitol, sorbitol, aspartame, acesulfame, and sucralose.

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

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

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

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

22. In the above 21, the oral solid preparation is a pharmaceutical composition characterized in that the dosage form is any 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. In the above 20, the pharmaceutical composition is characterized in that the pranlukast content per unit preparation is 26-74.2 mg.

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 2nd 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. In the above 20, the pharmaceutical composition is characterized in that the time required to reach the maximum blood concentration of pranlukast when administered to a human body is within 3 hours.

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, pulverized, and then compressed into a tablet after going through a post-mixing process.

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 that of the existing commercially available dry syrup formulation, so that clinical efficacy equivalent to or greater than that of the existing syrup formulation (pranlukast 50, 75, 100, 140 mg/package, 1 pack at a time, taken twice a day, Sam-A Pharmaceutical) can be exhibited with only a total of 53.0-148.4 pranlukast administered per day.

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

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

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.

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.

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.

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

This is explained specifically as follows. The terms used in this specification are selected from the most widely used general terms possible while considering the functions in the present invention, but this may vary depending on the intention of engineers engaged in the relevant field, precedents, the emergence of new technologies, etc. In addition, in certain cases, there are terms arbitrarily selected by the applicant, and in this case, the meanings thereof will be described in detail in the description of the relevant invention. Therefore, the terms used in the present invention should be defined based on the meanings of the terms and the overall contents of the present invention, rather than simply the names of the terms.

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 belongs. Terms defined in commonly used dictionaries, such as those defined in common usage, should be interpreted as having a meaning consistent with the meaning they have in the context of the relevant art, and will not be interpreted in an idealized or overly formal sense unless expressly defined in this application.

The numerical ranges are inclusive of the numbers defined in the above ranges. Every maximum numerical limitation given throughout this specification will include every lower numerical limitation, as if that lower numerical limitation were expressly written out. Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if that higher numerical limitation were expressly written out. 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 expressly written out.

Hereinafter, each description and embodiment disclosed in the present invention can be applied to other descriptions and embodiments for each. That is, all combinations of various elements disclosed in the present invention fall within the scope of the present invention. In addition, the scope of the present invention cannot be considered limited by the specific description described below.

Expressions such as “comprising” as used herein should be understood as open-ended terms implying the possibility of including other embodiments.

The inventors of the present invention, while researching and developing a method for manufacturing a pharmaceutical composition containing pranlukast, have found that, when manufacturing a pharmaceutical composition containing pranlukast in the past, a binder and a solubilizer are added to a solvent that dissolves the binder, the composition is left overnight (12 to 16 hours), the evaporated solvent is weighed and corrected before use the next day, and then the composition is kneaded in a high-speed mixer at the time of use. However, during the process described above, a problem occurs in which the solubilizer is precipitated, and further, the kneaded product becomes sticky in a short period of time, preventing the mixture from being mixed and kneaded homogeneously. In addition, when the manufactured kneaded product is dried, ground, and subjected to a post-mixing process and then compressed into a tablet, sticking and chipping phenomena occur.

Accordingly, the inventors of the present invention have carefully studied 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.

And, it was confirmed that by controlling the granule size in the process of establishing after mixing, a suitable process result can be secured, the 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 mixing/tableting conditions, an optimal process result can be secured, and thus the solubility of pranlukast can be improved, thereby completing the present invention.

Hereinafter, the present invention will be described in detail.

Method for preparing a pharmaceutical composition containing pranlukast

[definition]

The present invention uses pranlukast as an active ingredient, and the main ingredient is not particularly limited. For example, the commercially available main ingredient of pranlukast 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 main ingredient, the equivalent intended effect is exhibited. Therefore, it is disclosed that the term pranlukast in this specification can be used to mean pranlukast, a hydrate thereof, a solvate thereof, or a salt thereof.

[Method for manufacturing chewable tablets]

In the present invention, the inventor's prior invention, Korean Patent Publication No. 10-2363727, which improves the bioavailability of pranlukast and reduces the dosage, discloses an oral solid preparation manufactured by mixing a disintegrant with a wet granule containing pranlukast, a surfactant, a binder, and a diluent. Specifically, referring to an 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. Subsequently, the granule is mixed with a disintegrant and a lubricant, and then tableted and coated to manufacture a tablet.

This is a formulation design optimized for improving bioavailability, as the dosage of pranlukast can be reduced to 50 mg per tablet.

The inventor first attempted to formulate a pharmaceutical composition as a chewable tablet using the above formulation design. Generally, when manufacturing a chewable tablet, a binder, excipient, and sweetener are mixed in consideration of the physicochemical properties of the main ingredient and the taste or flavor, etc. Therefore, various sweeteners and flavoring agents were mixed in the above formulation by changing the type.

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 solubilizer and mixing amount most suitable for solubilization have already been discovered in the prior invention, the type and content of the solubilizer were used according to the method in the prior invention.

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

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

The dissolution method of the solubilizer and the type of the binder are the same as in the prior invention, and the dissolution temperature and dissolution time of the solubilizer among the manufacturing methods are 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 heating 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℃.

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

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

The exact cause of this phenomenon is unknown, but it is thought to be due to the subsequent process being performed without the solubilizer and binder being homogeneously mixed with the mixture.

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 using the binder after mixing.

As a result, it was found that the conditions for the solubilizer were suitable for dissolving in accordance with the conditions mentioned above, and the time for dissolving the binder and mixing the binder and solubilizer was within 35 to 95 minutes. In addition, the time for using the dissolved binder was also within 5 hours so as not to cause any problems in the kneading process and tableting process.

In addition, it was found that when manufactured in this way, the unique bitter taste of franlukast was strongly expressed, and as a result, it was found that the bitter taste remained in the mouth for a long time.

Even when manufactured by accurately specifying the dissolution method and usage time of the solubilizer and binder, there was a slight bitter taste. This was due to the bitter taste of 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 sucrose, glucose, mannitol, sorbitol, aspartame, acesulfame, and sucralose can be adopted and used.

In addition, it is necessary to control the content of the solubilizer and the content of the binder. Specifically, the solubilizer may 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 may be added in an amount of 1 to 5 wt%, preferably 1 to 3 wt%, relative to the weight of the entire pharmaceutical composition.

In the present invention, it was also found that, in addition to the conditions for manufacturing the solubilizing agent and binder, the conditions of manufacturing equipment such as a high-speed mixer and a tableting machine have a very important influence on the obstacles to the combination and tableting processes that were not resolved in the prior invention.

The mixture containing the main ingredient is put into a high-speed mixer and the agitator and chopper are started to mix. At this time, it is desirable to proceed under the conditions of the rotation speed of the agitator and chopper being 120±10 RPM and the time being 3±1 minutes. If the speed of the agitator or chopper is made slower, the degree of mixing of the mixture is poor, and if it is made faster, the mixture may be re-separated, which may result in the product being manufactured with a poor degree of mixing. When sufficiently mixed, the binder should be slowly added to ensure a good degree of mixing of the solubilizer and the main ingredient. It is most desirable to have the same rotation speed of the agitator and chopper as during mixing, and the mixing time of 5±1 minute showed the best result. When the mixing time was short, there was a problem that the binder was not mixed homogeneously in the mixture, and when the time was long, the mixture became sticky in an instant, which caused the problem of sticking or chipping occurring during tableting.

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 manufactured, the quality cannot be guaranteed.

As in the present invention, pranlukast is a very poorly soluble and poorly absorbed drug, 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.

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

The bitter taste can generally be reduced by mixing in sugar, but franlukast and the solubilizer polyoxyl 15 hydroxystearate have the characteristic of releasing the bitter taste later than at the beginning when taking and chewing, so the choice of sweetener is very important.

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

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.

The present invention may include lactose monohydrate and microcrystalline cellulose as diluents. This is a combination of additives of the prior invention of the present inventors, 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 the same effect as the amount of dry syrup, 50 mg, 70 mg, 100 mg, and 140 mg, so it is a convenient chewable tablet formulation that can be taken without water, and it is a diluent combination optimized for improving bioavailability.

[General method of manufacturing tablets]

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

At this time, Pranlukast is first wet granulated with a diluent and surfactant to improve bioavailability.

When manufacturing the granules according to the present invention, diluents commonly used in the pharmaceutical field can be used. For example, 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, and 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. In terms of the expression of the effect desired 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.

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, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, 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 hydroxypropyl methyl cellulose is preferable in terms of expression of the effect targeted by the present invention, and among these, polyvinylpyrrolidone is most preferable. It is preferable that the binder be contained in an amount of 2-10% relative to the weight of the entire pharmaceutical composition in terms of expression of the effect targeted by the present invention.

When manufacturing the granules according to the present invention, a surfactant (solubilizer) may be selected from one or more selected 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, and glyceryl fatty acid esters (e.g., glyceryl monostearate), and in particular, 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 in terms of expression of the effect aimed at by the present invention. In terms of expression of the effect desired by the present invention, it is preferable to contain 5-20% of the surfactant (solubilizer) based on the weight of the entire pharmaceutical composition.

When manufacturing the granules according to the present invention, it is preferable to use an alcohol solvent rather than purified water as a solvent. At this time, an alcohol having 1 to 6 carbon atoms is preferable as an alcohol solvent in terms of the expression of the effect aimed at by the present invention. For example, lower alcohols such as methanol, ethanol, propanol, isopropanol, and butanol may be used. In particular, when ethanol was used, the bioavailability of pranlukast was surprisingly improved.

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

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 sugar, lactose, inositol, erythritol, crystalline fructose, trehalose, ribitol, arabitol, galactitol, lactitol and maltotritol, microcrystalline cellulose, croscarboxymethylcellulose sodium, carboxymethylcellulose calcium, hydroxypropylcellulose, sodium carboxymethylcellulose, 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.

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.

[Dissolution and PK conditions]

The purpose of the present invention is to solubilize and chew a pranlukast preparation taken at a dose of 50 to 140 mg twice a day, so that it can be taken at a dose of 26.5 to 74.2 mg twice a day, for example, 26.5 mg, 37.1 mg, 53.0 mg or 74.2 mg, thereby achieving the same effect.

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 showing the same effect as the conventional commercially available preparation by only taking 26.5 to 74.2 mg per dose 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.

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 30 to 45 minutes.

In addition, the pharmaceutical composition of the present invention is characterized in that the time to reach the maximum blood concentration of pranlukast is within 3 hours when administered to a beagle dog. When the pranlukast preparation satisfies the above nonclinical test PK conditions, it is possible to have equivalent efficacy to the existing syrup preparation.

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

Hereinafter, examples of the present invention will be described. However, it is declared that the scope of the present invention should not be limited to the examples below.

[Manufacturing of chewable tablets]

[Examples 1-3 and Comparative Example 1]

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).

Manufacturing method

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

In order to solubilize very poorly soluble pranlukast, solubilizers, polyoxyl 15 hydroxystearate and poloxamer, are used and dissolved at 55±5°C, more preferably 60°C, for 30 to 60 minutes. Next, povidone (PVP K-30), a binder, is slowly added to ethanol, a binder solvent, 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.

Process 2. Mixing of franlukast hydrate, lactose hydrate and anti-caking powder

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.

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

Process 2 Slowly add the process 1 binding solution (dissolved solubilizer and binding solution) to the semi-finished product. The speed of the agitator and chopper is the same as that of the mixing step. The mixing time affects the properties of the mixture, so it is performed for 5 minutes.

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

After the coalescence is complete, the coalescence is granulated using a Cone-Mill at 300 to 900 rpm.

Process 5. Process 4 Drying of semi-finished products

Drying is done using a preheated flat plate dryer, and the granules are spread thinly to a thickness of about 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, about 0.8% is the most suitable.

Process 6. Process 5 semi-finished product was established using an Oscillator (18-piece, 850 μm)

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

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

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 for another 5 minutes at 10 rpm.

Process 8. Process 7 semi-finished product is pressed in a rotary press.

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/ ^cm2 and a main pressure of 35±5 kgf/ ^cm2 .

[Example 4-5]

For the chewable tablets according to Examples 4 and 5, 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.

Manufacturing method

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

In order to solubilize very poorly soluble pranlukast, solubilizers, polyoxyl 15 hydroxystearate and poloxamer, are used and dissolved at 55±5°C, more preferably 60°C, for 30 to 60 minutes. Next, povidone (PVP K-30), a binder, is slowly added to ethanol, a binder solvent, 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.

Process 2. Mixing of franlukast hydrate, lactose hydrate, isomalt, anti-caking powder and hydroxypropyl cellulose

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.

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

Process 2 Slowly add the process 1 binding solution (dissolved solubilizer and binding solution) to the semi-finished product. The speed of the agitator and chopper is the same as that of the mixing step. The mixing time affects the properties of the mixture, so it is performed for 5 minutes.

Process 4. Drying of semi-finished products of Process 3

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

Process 5. Process 4 semi-finished product was established using an Oscillator (No. 18 screen, 850 μm)

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

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

Next, D-mannitol, crospovidone, citric acid hydrate, 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.

Process 7. Process 6 Semi-finished product is pressed in a rotary press.

Process 6 The final mixture, which is a semi-finished product, 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/ ^cm2 and a main pressure of 35±5 kgf/ ^cm2 .

Mixing purpose ingredient Content (mg) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 chief ingredient franlukast hydrate 74.2 74.2 74.2 74.2 74.2 74.2 diluent Lactose hydrate (200mesh) 123.7 147.9 97.4 108.8 108.8 130 Sweetener Anti-corrosion powder per minute 74.2 50.0 100.5 14.5 14.5 67.9 diluent Isomalt - - - 94.0 94.0 - binder Hydroxypropyl cellulose - - - 4.6 4.6 - binder Povidone (PVP K-30) 13.6 13.6 13.6 13.6 13.6 13.6 Availability agent Polyoxyl 15 hydroxy
Stearate 17.8 17.8 17.8 17.8 17.8 17.8 Availability agent Poloxamer 407 31.2 31.2 31.2 31.2 31.2 31.2 binding solvent Ethanol 44.5 44.5 44.5 46.7 46.7 44.5 diluent D-Mannitol 101.5 120.7 109.5 46.6 46.6 81.2 Disintegrant Crospovidone 14.8 14.8 14.8 40.6 40.6 14.8 pH regulator Citric acid hydrate 18.6 15.6 18.6 18.6 18.6 15.0 Disintegrant Low-substituted hydroxypropyl
cellulose - - - 5.0 5.0 - Sweetener Aspartame 4.3 2.3 5.3 4.3 4.3 0 Sweetener Sucralose 3.5 1.8 4.5 3.5 3.5 0 Flavoring agent Strawberry flavor powder 49.5 40.0 49.5 49.5 49.5 49.5 Active agent Colloidal silicon dioxide 4.9 4.9 2.9 4.9 4.9 4.9 Active agent Sodium stearyl fumarate 24.7 26.7 26.7 18.6 24.8 26.7 Active agent Magnesium stearate - - - 6.2 - - total 556.5 561.5 566.5 556.5 556.5 526.8

[Manufacture of general tablets]

[Example 6]

For the purification according to Example 6, the composition described in Table 2 below is used to manufacture the product using the following manufacturing method.

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

To solubilize very poorly soluble pranlukast, solubilizers polyoxyl 15 hydroxystearate and poloxamer are dissolved in a constant temperature water bath at 60°C for 10 to 30 minutes. Then, povidone (PVP K-30), a binder, is slowly added to ethanol, a binder solvent, 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.

Process 2. Mixing of franlukast hydrate, lactose hydrate and microcrystalline cellulose

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.

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

Process 2 Slowly add the process 1 binding solution (dissolved solubilizer and binding solution) to the semi-finished product. The speed of the agitator and chopper is the same as that of the mixing step. The mixing time affects the properties of the mixture, so it is performed for 5 minutes.

Process 4. Granulate the semi-finished product of Process 3 using Corn-Mill.

Once the coalescence is complete, the coalescence is granulated using an Oscillator or a Cone-Mill at 300 to 900 rpm.

Process 5. Process 4 Drying of semi-finished products

Drying is done using a preheated flat plate dryer, and the granules are spread thinly to a thickness of about 1 cm and then dried at 50°C until the LOD becomes 2.0%. Preferably, 0.8 to 1.2% is suitable, and more preferably, about 1% is the most suitable.

Process 6. Process 5 semi-finished product was established using an Oscillator (18-piece, 850 μm)

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

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 the final step.

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

Process 8. Process 7 semi-finished product is pressed in a rotary press.

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 and a main pressure of 30 to 45 kgf/cm ² .

The tablet hardness should be 5 to 12 kp, preferably 5 to 10 kp, and more preferably 6 to 8 kp.

Process 9. Coating of Process 8 Semi-finished product

The semi-finished product of process 8, the tablet, is coated with a coating solution.

Mixing purpose Ingredient name Content (mg) chief ingredient franlukast hydrate 50.0 diluent Lactose hydrate (200mesh) 61.0 binder Povidone (PVP K-30) 11.0 Availability agent Polyoxyl 15 hydroxystearate 12.0 Availability agent Poloxamer 407 21.0 Binder solvent Ethanol 38.0 diluent Microcrystalline Cellulose PH101 61.0 Disintegrant Crospovidone 16.0 Disintegrant Crocarmellose sodium 16.0 Active agent Colloidal silicon dioxide 5.0 Active agent Magnesium stearate 7.0 Coating agent Opadry II White (85G68914) 10.0 Coating solvent Purified water 40.0 total 270.0

Experimental example

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

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. Accordingly, the inventors of the present invention were unable to determine the exact cause, but expected that the solubilizer would have an effect, so they conducted research on the dissolution method, dissolution time, and shelf life after dissolution, thereby establishing the optimal conditions for the kneading and tableting processes and completing the present invention.

The solubilizer was dissolved at dissolution temperatures of 50℃, 55℃, 60℃, 65℃, and 70℃, and the dissolution time was set to 30 minutes and 60 minutes, respectively.

When dissolved under each condition, the phenomenon of obstacles in the combining process and the tableting process according to the dissolution temperature and dissolution time of the solubilizer, taking Example 1 as a representative example, is shown in Table 3, and the phenomenon of process obstacles according to the dissolution time and shelf life of the binder is shown in Table 4.

Temperature (℃) Time (minutes) Union Process The process of tableting Elution rate (30 minutes) 50 30 Increased union time Poor compression 75% or less 60 Increased union time Poor compression 75% or less 55 30 Increased union time Poor compression 75% or less 60 Good Good 80% or more 60 30 Good Good 80% or more 60 Good Good 80% or more 65 30 I'm tired Sticking 80% or more 60 I'm tired Sticking 80% or more 70 30 I'm tired Severe stickiness 80% or more 60 I'm tired Severe stickiness 80% or more

Time (minutes) Expiration date (hours) Union Process The process of tableting Elution rate (30 minutes) 30 5 Good Good 80% or more 15 Good Good 80% or more 60 5 Good Good 80% or more 15 Good Good 80% or more 90 5 Good Good 80% or more 15 Good Good 80% or more 15 hours - I'm tired Very sticky 70% or less

The dissolution time and shelf life of the binder were first discovered in the present invention, and although the mechanism is not known exactly, 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 clarify this phenomenon, the inventors of the present invention are trying to discover 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. It was confirmed that more preferably, 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 combining during the production process or severe sticking occurring during the tableting process, which lowers the production efficiency.

Experimental Example 2. Test of formulation suitability according to the size of the established network

Evaluation method

It is manufactured according to the size of the net and evaluated after completion of the pressing.

<Test Results>

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.

Evaluation criteria

Hardness: 4~8KP

Wear resistance: 20 tablets 100 rotations 0.5% or less

Fluidity: Resting angle 43℃ or less

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

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

Establishment network size Hardness test Masonry test Liquidity test disintegration test Eruption 850 μm fitness fitness fitness fitness fitness 710 μm fitness fitness fitness fitness fitness 600 μm fitness fitness Inappropriate fitness Inappropriate 500 μm fitness fitness Inappropriate Inappropriate Inappropriate

Evaluation Results

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 the smaller the mesh size, the longer the time required and the more fine particles were generated, which affected the fluidity.

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.

Experimental Example 3. Evaluation of taste masking of chewable tablets

Evaluation method

In the present invention, a chewable tablet containing pranlukast hydrate was developed. In the case of a preparation to be chewed and taken in the mouth, the taste or smell should not be unpleasant to patients. Therefore, the inventors of the present invention mixed various sweeteners and flavoring agents and then conducted a sensory test on the taste and chewing sensation.

Specifically, a 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.

Bitterness level +++ It's a little bitter, but I can't help but like it ++ It has a bit of a bitter taste. + It has a bitter taste - It has a strong bitter taste. - - Very bitter taste

Sweetness level +++ Very sweet (very good) ++ Sweet (good) + Slightly sweet (moderate) - A little sweet but not noticeable (bad) - - No sweetness at all (very bad)

Degree of authorship +++ Very good ++ Good + commonly - Bad (tough and strong) - - Very bad (very tough and strong)

item Example 1 Example 2 Example 3 Example 4 Comparative Example 1 acerbity +++ ++ +++ +++ - - sweetness ++ + +++ ++ - - Copyright +++ +++ ++ +++ +

Evaluation Results

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

Experimental Example 4. Evaluation of Chewable Tablet Dissolution

Evaluation method

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

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 solution was stirred at a rotation speed of 50 rpm while maintaining the temperature at 37±0.5℃ to measure the dissolution rate. 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.

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

Evaluation Results

FIG. 1 shows the results of a dissolution test confirmed for a chewable tablet (test material, Citrus chewable tablet, pranlukast hydrate 74.2 mg) according to Example 1 of the present invention compared to a control dry syrup (Sam-A Pharmaceutical, Citrus dry syrup 140 mg). As can be confirmed in FIG. 1, in the case of the chewable tablet (test material) 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 Citrus dry syrup 50-140 mg once a day twice a day with only 26.5-74.2 mg administered once a day, twice.

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

FIG. 2 shows whether the chewable tablets (test substance, Citrus chewable tablet, pranlukast hydrate 74.2 mg) according to Examples 4 and 5 show 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 a time point of 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 administering 50-140 mg of Citrus dry syrup twice a day, with only 26.5-74.2 mg administered once a day, twice.

Experimental Example 5. Chewable Tablet Bioequivalence Test

Evaluation method

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, Citrus dry syrup (Sam-A Pharmaceutical, 140 mg).

Evaluation Results

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 Citrus dry syrup, an existing commercial product.

While the specific parts of the present invention have been described in detail above, it is obvious to those skilled in the art that these specific descriptions are merely preferred embodiments and that the scope of the present invention is not limited thereto. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (25)

(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 then stirring to prepare a mixed solution including the solubilizing agent 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 mixture of (S1) to the mixture of (S2) and then mixing them to produce granules; (S4) A step of drying the granules of (S3) to produce a dried granule; (S5) a step of preparing a final mixture by refining the dried granule of (S4) and mixing it with a pharmaceutical additive; and (S6) Step of pressing the final mixture of (S5) above A method for preparing a pharmaceutical composition containing pranlukast. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in claim 1, the solution containing the solubilizing agent is used within 1 hour after dissolving the solubilizing agent at 50 to 60°C for 30 to 60 minutes. 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 used within 5 hours. 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 containing a solubilizing agent to a solution containing a binder and dissolving the solution for 15 to 45 minutes. 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. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in claim 1, the binder in step (S1) is at least one selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, and polyvinyl alcohol. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in claim 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. 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. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the 8th paragraph, the diluent in the step (S2) is at least one of xylitol, mannitol, isomalt, sorbitol, maltitol, refined 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, and crystalline cellulose, and the sweetener is anti-caking sugar. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the first paragraph, the mixing in the 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. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in claim 8, the binder in the step (S2) is at least one selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, and polyvinyl alcohol. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in the first paragraph, the formulation in (S5) is formulated by using a sizing mesh of 710 to 850 μm to form a dried granule. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in claim 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. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in claim 13, the diluent is at least one of xylitol, mannitol, isomalt, sorbitol, maltitol, refined sugar, lactose, inositol, erythritol, crystalline fructose, trehalose, ribitol, arabitol, galactitol, lactitol, and maltotritol, microcrystalline cellulose, sodium croscarboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, carboxymethylcellulose, gelatinized starch, glucose, pregelatinized starch, starch, corn starch, light anhydrous silicic acid, and crystalline cellulose. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in claim 13, the disintegrant is any one of crospovidone, low-substituted hydroxypropyl cellulose, or a mixture thereof. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in claim 13, the pH adjusting agent is citric acid hydrate. 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 sucrose, glucose, mannitol, sorbitol, aspartame, acesulfame, and sucralose. A method for producing a pharmaceutical composition containing pranlukast, characterized in that in claim 13, the lubricant is any one of colloidal silicon dioxide, sodium stearyl fumarate, magnesium stearate, or a mixture thereof. A method for manufacturing a pharmaceutical composition containing pranlukast, characterized in that in the first paragraph, the tableting step in the step (S6) is performed by tableting at a turret speed of 20 to 30 rpm, a tableting position of 16.5 to 18 mm, a tableting pressure of 25 to 35 kgf/cm ² as a preload, and 30 to 40 kgf/cm ² as a main pressure to adjust the hardness to 5 to 12 kp. A pharmaceutical composition containing pranlukast, manufactured by a manufacturing method according to any one of claims 1 to 19. A pharmaceutical composition according to claim 20, characterized in that the pharmaceutical composition is an oral solid preparation. A pharmaceutical composition according to claim 21, characterized in that the oral solid preparation has a dosage form of any one of pellets, capsules, chewable tablets, single-layer tablets, multi-layer tablets, core tablets, granules or mini-tablets. In claim 20, the pharmaceutical composition is characterized in that the pranlukast content per unit preparation is 26-74.2 mg. In claim 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. In claim 20, the pharmaceutical composition is characterized in that the time required to reach the maximum blood concentration of pranlukast when administered to a human body is within 3 hours.

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