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WO2025018777A1 - Procédé de préparation d'une composition pharmaceutique contenant du pranlukast et composition pharmaceutique ainsi préparée - Google Patents

Procédé de préparation d'une composition pharmaceutique contenant du pranlukast et composition pharmaceutique ainsi préparée Download PDF

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Publication number
WO2025018777A1
WO2025018777A1 PCT/KR2024/010245 KR2024010245W WO2025018777A1 WO 2025018777 A1 WO2025018777 A1 WO 2025018777A1 KR 2024010245 W KR2024010245 W KR 2024010245W WO 2025018777 A1 WO2025018777 A1 WO 2025018777A1
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Prior art keywords
pharmaceutical composition
pranlukast
composition containing
producing
binder
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English (en)
Korean (ko)
Inventor
노현종
김경희
길영식
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Sama Pharm Co Ltd
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Sama Pharm Co Ltd
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Priority claimed from KR1020240091120A external-priority patent/KR102840220B1/ko
Application filed by Sama Pharm Co Ltd filed Critical Sama Pharm Co Ltd
Publication of WO2025018777A1 publication Critical patent/WO2025018777A1/fr
Pending legal-status Critical Current
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • 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.
  • 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:
  • 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.
  • 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.
  • 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.
  • Pranlukast has been tried in various dosage forms, including tablets, suspensions, dry syrup, or capsules.
  • 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).
  • 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
  • Citus Tablet pran
  • Korean Patent Publication No. 10-0389606 discloses a spray-dried granule with improved adhesion and cohesion of pranlukast.
  • a saccharide, a binder, and a surfactant are dissolved in purified water and pranlukast is suspended to prepare a spray-dried granule.
  • 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.
  • Korean Patent Publication No. 10-1446129 discloses a mixture comprising pranlukast and polyvinylpyrrolidone or a copolymer of polyvinylpyrrolidone and vinyl acetate.
  • 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.
  • Pranair Capsule pranlukast 112.5 mg/capsule, 1 capsule per dose, SK Chemical.
  • 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).
  • 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.
  • 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.
  • 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.
  • the optimal process results can be secured by adjusting the union/titration conditions, thereby improving the solubility of pranlukast.
  • 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.
  • weight % refers to the mass ratio of a particular ingredient to the total pharmaceutical composition into which it is incorporated.
  • the present invention solved the above-mentioned problems by the following means.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ m to form a dried granule.
  • 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.
  • 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.
  • 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.
  • a method for producing a pharmaceutical composition containing pranlukast characterized in that in the above 13, the pH adjusting agent is citric acid hydrate.
  • 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical composition is characterized in that the pranlukast content per unit preparation is 26-74.2 mg.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention uses pranlukast as an active ingredient, and the main ingredient is not particularly limited.
  • 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.
  • 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.
  • 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.
  • the inventor first attempted to formulate a pharmaceutical composition as a chewable tablet using the above formulation design.
  • 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.
  • 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.
  • 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°C and 45 ⁇ 15 minutes, respectively.
  • the dissolution temperature was less than 50°C, 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°C, the dissolution time could be shortened, but it caused sticking or chipping during tableting.
  • 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°C.
  • 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.
  • 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.
  • sweeteners and flavoring agents were mixed to reduce the bitter taste.
  • sweeteners one or more selected from the group consisting of sucrose, glucose, mannitol, sorbitol, aspartame, acesulfame, and sucralose can be adopted and used.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • aspartame and sucralose 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.
  • the present invention can be manufactured by mixing the chewable drug delivery system described above with pranlukast that has undergone a solubilization process.
  • Pranlukast is first wet granulated with a diluent and surfactant to improve bioavailability.
  • diluents commonly used in the pharmaceutical field can be used.
  • diluents commonly used in the pharmaceutical field.
  • microcrystalline cellulose, lactose, or a mixture thereof is preferable in terms of expression of the effect aimed at by the present invention.
  • a binder commonly used in the pharmaceutical field can be used.
  • one or more selected from polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate copolymer, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, polyvinyl alcohol, etc. can be used.
  • 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.
  • 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.
  • a surfactant 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
  • an alcohol solvent rather than purified water as a solvent.
  • 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.
  • lower alcohols such as methanol, ethanol, propanol, isopropanol, and butanol may be used.
  • 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.
  • 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 hydroxy
  • 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.
  • 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.
  • the inventors 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.
  • 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.
  • 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.
  • solubilizers 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.
  • povidone (PVP K-30) a binder
  • PVP K-30 povidone
  • 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 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.
  • coalescence is granulated using a Cone-Mill at 300 to 900 rpm.
  • Process 5 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.
  • 0.4 to 1.0% is suitable, and more preferably, about 0.8% is the most suitable.
  • Process 5 semi-finished product was established using an Oscillator (18-piece, 850 ⁇ m)
  • the dried granules are sieved using an oscillator (No. 18 sieve, sieving mesh size: 850 ⁇ m) 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.
  • 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 .
  • solubilizers 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.
  • povidone (PVP K-30) a binder
  • PVP K-30 povidone
  • 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 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.
  • 0.4 to 1.0% is suitable, and more preferably, approximately 0.8% is the most suitable.
  • Process 4 semi-finished product was established using an Oscillator (No. 18 screen, 850 ⁇ m)
  • the dried granules are sieved using an oscillator (No. 18 sieve, sieving mesh size: 850 ⁇ m) 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.
  • 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.
  • 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 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 .
  • 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 13.6 13.6 Availability agent Polyoxyl 15 hydroxy Stearate 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
  • 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.
  • povidone PVP K-30
  • 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.
  • coalescence is granulated using an Oscillator or a Cone-Mill at 300 to 900 rpm.
  • Process 5 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%.
  • Process 5 semi-finished product was established using an Oscillator (18-piece, 850 ⁇ m)
  • the dried granules are sieved using an oscillator (No. 18 sieve, 850 ⁇ m) 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.
  • 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 is coated with a coating solution.
  • the solubilizer was dissolved at dissolution temperatures of 50°C, 55°C, 60°C, 65°C, and 70°C, and the dissolution time was set to 30 minutes and 60 minutes, respectively.
  • the manufacturing time is preferably 30 minutes to 90 minutes, and the shelf life is preferably no longer than 5 hours.
  • 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.
  • a chewable tablet containing pranlukast hydrate was developed.
  • 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.
  • Sweetness level +++ Very sweet (very good) ++ Sweet (good) + Slightly sweet (moderate) - A little sweet but not noticeable (bad) - - No sweetness at all (very bad)
  • Example 1 Example 2
  • Example 3 Example 4 Comparative Example 1 acerbity +++ ++ +++ +++ - - sweetness ++ + +++ ++ - - Copyright +++ +++ ++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +++ +
  • 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.
  • 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.
  • 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°C 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 ⁇ m filter, and analyzed by HPLC. The results are shown in Fig. 1.
  • 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.
  • 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).
  • test material Citrus chewable tablet, pranlukast hydrate 74.2 mg
  • control dry syrup Sud-A Pharmaceutical, Citrus dry syrup 140 mg
  • 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.
  • the pranlukast concentration was dissolved by 75% or more at a time point of 30 to 45 minutes.
  • Example 1 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).
  • 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.

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Abstract

Sont divulgués un procédé de préparation d'une composition pharmaceutique contenant du pranlukast, et une composition pharmaceutique préparée par le procédé de préparation.
PCT/KR2024/010245 2023-07-18 2024-07-17 Procédé de préparation d'une composition pharmaceutique contenant du pranlukast et composition pharmaceutique ainsi préparée Pending WO2025018777A1 (fr)

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KR20230093065 2023-07-18
KR10-2023-0093065 2023-07-18
KR1020240091120A KR102840220B1 (ko) 2023-07-18 2024-07-10 프란루카스트 함유 약제학적 조성물의 제조방법 및 상기 제조방법에 의해 제조된 약제학적 조성물
KR10-2024-0091120 2024-07-10

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999004790A1 (fr) * 1997-07-23 1999-02-04 Ono Pharmaceutical Co., Ltd. Composition pharmaceutique liquide aqueuse contenant un derive de benzopyranne en tant que principal constituant
KR20040085193A (ko) * 2002-02-14 2004-10-07 솔베이 파마슈티칼스 비. 브이 수-난용성 활성 물질의 경구용 고용체 제형
WO2007024123A1 (fr) * 2005-08-26 2007-03-01 Sk Chemicals Co., Ltd. Composition pharmaceutique de dispersion solide de pranlukast a vitesse de dissolution initiale amelioree et procede de preparation de ladite composition
KR20070045798A (ko) * 2005-10-28 2007-05-02 주식회사유한양행 분무-건조 과립 및 그의 제조방법
KR20150127483A (ko) * 2014-05-07 2015-11-17 한미약품 주식회사 몬테루카스트 또는 이의 약제학적으로 허용가능한 염을 포함하는 안정성이 개선된 액상 제제 및 이의 제조방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999004790A1 (fr) * 1997-07-23 1999-02-04 Ono Pharmaceutical Co., Ltd. Composition pharmaceutique liquide aqueuse contenant un derive de benzopyranne en tant que principal constituant
KR20040085193A (ko) * 2002-02-14 2004-10-07 솔베이 파마슈티칼스 비. 브이 수-난용성 활성 물질의 경구용 고용체 제형
WO2007024123A1 (fr) * 2005-08-26 2007-03-01 Sk Chemicals Co., Ltd. Composition pharmaceutique de dispersion solide de pranlukast a vitesse de dissolution initiale amelioree et procede de preparation de ladite composition
KR20070045798A (ko) * 2005-10-28 2007-05-02 주식회사유한양행 분무-건조 과립 및 그의 제조방법
KR20150127483A (ko) * 2014-05-07 2015-11-17 한미약품 주식회사 몬테루카스트 또는 이의 약제학적으로 허용가능한 염을 포함하는 안정성이 개선된 액상 제제 및 이의 제조방법

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