Drug manufacturing methods

Abstract

To provide methods for manufacturing drugs by which drug components can be coated easily and the elution of drug components can be sufficiently suppressed.SOLUTION: The present invention provides a method for manufacturing a drug, and the like, which comprises: a suspension preparation step of mixing a water-insoluble polymer, a polymeric dispersant, an active ingredient, and a dispersion medium to obtain a suspension; an electrolytic solution preparation step of mixing an electrolyte and a solvent to obtain an electrolytic solution; a mixing step of mixing the suspension and the electrolytic solution to obtain a mixed solution; a granulation step of mixing a liquid adsorbent with the mixed solution to obtain granules; and a drug manufacturing step of obtaining a drug containing the granules.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for producing a drug.

Background Art

[0002] In recent years, for the elderly, children, and others who have difficulty ingesting drugs with unpleasant tastes such as bitterness, technologies for facilitating absorption in the stomach or intestine and technologies for masking bitterness felt in the oral cavity have been actively developed. Among these technologies, as the simplest method, a technology of adding sweeteners such as aspartame, stevia, and sugar alcohol to conceal bitterness and the like has been proposed. However, since these technologies conceal bitterness with other tastes, it is difficult to completely eliminate the bitterness of the drug.

[0003] Therefore, it is conceivable to coat components presenting an unpleasant taste with a coating agent. As such coating technology, a spray coating method of spraying a polymer solution onto a particulate active ingredient and a coacervation method of dispersing an active ingredient in a medium, suspending this in a solution of a film-forming component such as a polymer, and depositing a film on the surface to encapsulate it have been studied. The spray coating method is known as a general method, but there is a problem that the spraying process takes time and the apparatus is large-scale.

[0004] Regarding the coacervation method that can coat relatively simply and efficiently, for example, Patent Documents 1 and 2 can be cited. Patent Document 1 discloses dissolving a coating polymer in an aqueous solvent or an organic solvent, suspending a core or an active ingredient therein, and then causing phase separation to cause coacervation to coat the active ingredient with the polymer. Patent Document 2 discloses causing coacervation by mixing a substrate to be microencapsulated with an aqueous buffer solution containing an ionic polymer and an organic solvent and adding a phase separation component to coat the substrate with the ionic polymer.

[0005] However, in the manufacturing process of pharmaceuticals such as tablets containing drugs coated by these coacervation methods, a filtration step is required after phase separation to separate the liquid component, such as the dispersion medium, from the particles, making the manufacturing process complex. Furthermore, in drugs with a coating of active ingredients, if the coating dissolves relatively quickly, it may not be possible to sufficiently suppress the dissolution of components that are not intended to dissolve in the oral cavity, such as bitter components. Therefore, there is a need for drugs that can sufficiently suppress dissolution. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] Patent No. 4968829 [Patent Document 2] Patent No. 4978917 [Overview of the project] [Problems that the invention aims to solve]

[0007] This invention has been made in view of the problems of the prior art described above, and aims to provide a method for producing a drug that can be easily coated with a drug component and can sufficiently suppress the dissolution of the drug component. [Means for solving the problem]

[0008] The present invention relates to a suspension preparation step of mixing a water-insoluble polymer, a polymer dispersant, an active ingredient, and a dispersion medium to obtain a suspension. The electrolyte preparation process involves mixing an electrolyte and a solvent to obtain an electrolyte solution, A mixing step of mixing the suspension and the electrolyte to obtain a mixture, A granulation step is performed by mixing a liquid adsorbent into the aforementioned mixture to obtain granules, The process includes a drug manufacturing step of obtaining a drug containing the aforementioned granules.

[0009] In the present invention, the electrolyte may be at least one selected from the group consisting of sodium bicarbonate, sodium acetate, disodium hydrogen phosphate, sodium tartrate, potassium tartrate, sodium potassium tartrate, and magnesium chloride.

[0010] In the present invention, the mixing step may be performed at a temperature of 35°C to 65°C.

[0011] In the present invention, a water-soluble polymer may be further mixed in the electrolyte preparation step.

[0012] Another aspect of the present invention is a suspension preparation step of mixing a water-insoluble polymer, a polymer dispersant, an active ingredient, and a dispersion medium to obtain a suspension. A mixing step in which the suspension and a water-soluble polymer are mixed at a temperature of 35°C to 65°C to obtain a mixed solution, A granulation step is performed by mixing a liquid adsorbent into the aforementioned mixture to obtain granules, The process includes a drug manufacturing step of obtaining a drug containing the aforementioned granules.

[0013] In the present invention, the water-insoluble polymer may be an aminoalkyl methacrylate copolymer.

[0014] In the present invention, the polymer dispersant may be at least one selected from the group consisting of lauryl sulfate, stearic acid, and salts thereof.

[0015] In the present invention, the water-soluble polymer may be at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, and polyvinylpyrrolidone.

[0016] In the present invention, the liquid adsorbent may be silicon dioxide.

[0017] In the present invention, the active ingredient may be a component suspended in the dispersion medium.

[0018] In the present invention, in the drug manufacturing process, the granulated product may be molded into tablets.

Advantages of the Invention

[0019] According to the present invention, it is possible to provide a method for manufacturing a drug that can easily coat a drug component and sufficiently suppress the elution of the drug component.

Brief Description of the Drawings

[0020] [Figure 1] FIG. 1 is a graph showing the results of a sensory test using examples and comparative examples. [Figure 2] FIG. 2 is a graph showing the results of a sensory test using examples and comparative examples.

Modes for Carrying Out the Invention

[0021] Hereinafter, embodiments of a method for manufacturing a drug according to the present invention (hereinafter also simply referred to as a manufacturing method) will be described.

[0022] The manufacturing method according to the first embodiment is a suspension preparation step of mixing a water-insoluble polymer, a polymer dispersant, an active ingredient, and a dispersion medium to obtain a suspension; an electrolyte preparation step of mixing an electrolyte and a solvent to obtain an electrolytic solution; a mixing step of mixing the suspension and the electrolytic solution to obtain a mixed solution; a granulation step of mixing a liquid adsorbent into the mixed solution to obtain a granulated product; a drug manufacturing step of obtaining a drug containing the granulated product, and is a method for manufacturing a drug including these steps.

[0023] [Suspension Preparation Step] The manufacturing method of the present embodiment includes a suspension preparation step of mixing a water-insoluble polymer, a polymer dispersant, an active ingredient, and a dispersion medium to obtain a suspension.

[0024] (Active Ingredient) The active ingredient can be appropriately selected according to the purpose, and examples include medicinal ingredients, food ingredients, and the like. Examples of the aforementioned active ingredients include drugs such as antitumor drugs, antibiotics, anti-inflammatory drugs, analgesics, osteoporosis drugs, antihyperlipidemic drugs, antibacterial drugs, sedatives, tranquilizers, antiepileptic drugs, antidepressants, drugs for treating digestive system diseases, drugs for treating allergic diseases, drugs for treating hypertension, drugs for treating arteriosclerosis, drugs for treating diabetes, hormone drugs, and fat-soluble vitamin drugs; vitamins; minerals such as calcium, zinc, and iron; quasi-drugs other than drugs such as amino acids such as aspartic acid and arginine; foods for specified health uses; and foods with nutritional function claims.

[0025] The active ingredient is not particularly limited, but for example, it may be a component that is suspended in the dispersion medium. When the active ingredient is suspended in the dispersion medium together with a water-insoluble polymer and a polymer dispersant during the suspension preparation process, the active ingredient can obtain a sufficient masking effect. Furthermore, from the viewpoint of ease of suspension, it is preferable that the active ingredient is not a salt and has low solubility in water. More specifically, the active ingredient is selected from the group consisting of acetaminophen, diclofenac, loxoprofen, felbinac, flurbiprofen, propranolol, quinine, azithromycin, clarithromycin, silodosin, prednisolone, telmisartan, valsartan, caffeine, catechin, and turmeric. These active ingredients are components that exhibit unpleasant tastes such as bitterness in the oral cavity, but when used as active ingredients in the drug manufactured by the manufacturing method of this embodiment, these unpleasant tastes are masked. The amount of the aforementioned active ingredient is not particularly limited and can be appropriately selected within a range that produces the desired effect.

[0026] (Water-insoluble polymer) The water-insoluble polymer is one of the components that coat the active ingredient, and is not particularly limited as long as it is a water-insoluble polymer that can be used as a component of a drug. For example, an aminoalkyl methacrylate copolymer can be used. In the manufacturing method of this embodiment, the content of the water-insoluble polymer is not particularly limited and can be arbitrarily selected from a range in which the effect of coating the active ingredient can be obtained. For example, the concentration in the suspension may be 7% to 15% by mass, or 9% to 13% by mass, from the viewpoint of the miscibility of the suspension and miniaturization of the formulation. Furthermore, the ratio of water-insoluble polymer to the active ingredient is typically 10% to 30% by mass, or 15% to 25% by mass, from the viewpoint of achieving a sufficient masking effect and miniaturizing the formulation.

[0027] (Polymer dispersant) The polymer dispersant is not particularly limited as long as it is a polymer that promotes the dispersion of the water-insoluble polymer in the dispersion medium. For example, it may be at least one selected from the group consisting of lauryl sulfate, stearic acid, and salts thereof. More specifically, examples include sodium lauryl sulfate, magnesium lauryl sulfate, potassium lauryl sulfate, magnesium, stearic acid, calcium stearate, and sodium stearate. Polymeric dispersants can be used alone or in combination of multiple types.

[0028] In the manufacturing method of this embodiment, the content of the polymer dispersant is not particularly limited and can be arbitrarily selected from a range in which the effect of dispersing the water-insoluble polymer in the dispersion medium can be obtained. For example, the amount may be 1.75% by mass or more and 3.75% by mass or less, or 2.5% by mass or more and 3.0% by mass or less.

[0029] (dispersion medium) The dispersion medium is not particularly limited as long as it can disperse the aforementioned components, and water such as purified water, deionized water, or ion-exchanged water, or an organic dispersion medium can be used as appropriate. Water is preferred when considering safety and other factors. In the manufacturing method of this embodiment, the amount of dispersion medium used is not particularly limited and can be arbitrarily selected from a range that can appropriately disperse each of the components. For example, the amount may be 30% to 110% by mass or 34% to 50% by mass relative to the solid component.

[0030] In the suspension preparation step of this embodiment, a suspension in which a water-insoluble polymer is dispersed in a dispersion medium is obtained by mixing each component by known means. The means for mixing each component may involve mixing all components with the dispersion medium simultaneously, or some components may be mixed with the dispersion medium first, and then the remaining components may be added and mixed. For example, a suspension may be obtained by first adding a water-insoluble polymer and a polymer dispersant to a dispersion medium, stirring, then adding the active ingredient and stirring further. The stirring time, stirring temperature, etc., are not particularly limited and can be set so that each component is sufficiently dispersed.

[0031] [Electrolyte preparation process] The manufacturing method of this embodiment includes an electrolyte preparation step of mixing an electrolyte and a solvent to obtain an electrolyte solution.

[0032] (electrolyte) The electrolyte is a component that acts as a precipitation accelerator, causing the water-insoluble polymer to precipitate so as to surround the active ingredient, and is not particularly limited as long as it is usable as a component of the drug. For example, at least one selected from the group consisting of sodium bicarbonate, sodium acetate, disodium hydrogen phosphate, sodium tartrate, potassium tartrate, sodium potassium tartrate, and magnesium chloride may be used. In the manufacturing method of this embodiment, the content of the electrolyte is not particularly limited and can be arbitrarily selected from a range in which the effect of precipitating water-insoluble polymers can be obtained. For example, the ratio to the water-insoluble polymer can be 4% by mass or more and 15% by mass or 6% by mass or more and 9% by mass or less, from the viewpoint of coating by the insoluble polymer. Electrolytes can be used individually or in combination of multiple types.

[0033] (solvent) The solvent is not particularly limited as long as it can dissolve the electrolyte and form an electrolyte solution; purified water, deionized water, or other types of water, organic solvents, etc., can be used as appropriate. Water is preferred when considering safety and other factors. In the manufacturing method of this embodiment, the content of the solvent is not particularly limited and can be arbitrarily selected from a range that provides an effect of appropriately dissolving each of the components. For example, the amount may be 15% to 65% by mass, or 20% to 50% by mass, relative to the solid component.

[0034] (Water-soluble polymer) In the electrolyte preparation process of this embodiment, a water-soluble polymer may be further mixed in. The water-soluble polymer is one of the components that coat the active ingredient together with the water-insoluble polymer, and is not particularly limited as long as it is a water-soluble polymer that can be used as a component of a drug. For example, at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and polyvinylpyrrolidone can be used. In the manufacturing method of this embodiment, the content of the water-soluble polymer is not particularly limited and can be arbitrarily selected from a range in which the effect of coating the active ingredient can be obtained. For example, the amount added to the electrolyte may be 0.5% by mass or more and 2.5% by mass or 1% by mass or more and 2% by mass or less. Water-soluble polymers can be used individually or in combination of multiple types.

[0035] In the electrolyte preparation process of this embodiment, a solution is obtained in which each component is dissolved in a solvent by mixing each component by known means. The components may be mixed by mixing all components with the solvent simultaneously, or by mixing some components with the solvent first, and then adding and mixing the remaining components. The means for mixing the components can be known, such as a stirring device. Furthermore, the stirring time, stirring temperature, etc., are not particularly limited and can be set so that each component is sufficiently dissolved.

[0036] [Mixing process] The manufacturing method of this embodiment includes a mixing step of mixing the suspension and the electrolyte to obtain a mixture. A known stirring device or the like can be used to mix the liquids. Furthermore, the stirring time, stirring temperature, etc., are not particularly limited, but it is preferable to stir until each liquid is thoroughly mixed, that is, until the volume stabilizes.

[0037] In the mixing process, mixing may be done at a temperature of 35°C to 65°C, or 38°C to 50°C. Mixing at this temperature ensures that the active ingredients are coated more reliably.

[0038] Furthermore, the ratio of liquid components (including solvent and dispersion medium) to solid components in the mixture obtained in the mixing process can be 50% to 150% by mass or 55% to 140% by mass, etc., from the viewpoint of suspension miscibility and miniaturization of the formulation.

[0039] In this mixing process, particles coated with the active ingredient are formed.

[0040] [Granulation process] The manufacturing method of this embodiment includes a granulation step in which a liquid adsorbent is mixed into the mixture and then granulated.

[0041] (Liquid adsorbent) The liquid adsorbent is not particularly limited as long as it can adsorb liquid components such as solvents and dispersion media from the mixture and can be used as a component of a pharmaceutical agent. For example, silicon dioxide can be cited, and among these, hydrated silicon dioxide is a preferred example. In the manufacturing method of this embodiment, the content of the liquid adsorbent is not particularly limited and can be arbitrarily selected from a range that provides the effect of sufficiently adsorbing liquid components such as solvents and granulating them. For example, the amount may be 10% by mass or more and 50% by mass or 12% by mass or more and 40% by mass.

[0042] In the granulation process, known methods can be used for granulation. For example, granules can be obtained by stirring the mixture to which the liquid adsorbent has been added using a known stirring granulation apparatus. The granulated material may be sized using a sieve or similar method and then dried. Furthermore, any liquid components that could not be absorbed by the liquid adsorbent may be removed by filtration or other means. In the granulation process of this embodiment, since granulation is performed using a liquid adsorbent, there is little or no liquid component to be removed by filtration or the like, which has the advantage that filtrate treatment is unnecessary or only requires simple treatment.

[0043] [Pharmaceutical Manufacturing Process] The manufacturing method of this embodiment includes a drug manufacturing step to obtain a drug containing the granules. The method for obtaining a drug containing the aforementioned granules is not particularly limited. The granules may be used as is or mixed with other components to obtain a granular drug. The granular components may be further enclosed in capsules to obtain a capsule-shaped drug. Furthermore, the granules may be molded to obtain tablets. In this embodiment, the granules are molded into tablets during the drug manufacturing process. The means for forming the granules can be any known method for forming tablets. For example, they may be formed by tableting methods such as wet tableting or dry tableting. For example, the granules obtained in this embodiment may be mixed with known components such as disintegrants, binders, excipients, and lubricants, and then molded into tablets using a tablet press.

[0044] In this embodiment, the suspension preparation step and the electrolyte preparation step may be performed sequentially or in parallel, and the order is not particularly limited.

[0045] The manufacturing method according to the second embodiment is: A suspension preparation step involves mixing a water-insoluble polymer, a polymer dispersant, an active ingredient, and a dispersion medium to obtain a suspension. A mixing step in which the suspension and a water-soluble polymer are mixed at a temperature of 35°C to 65°C to obtain a mixed solution, A granulation step is performed by mixing a liquid adsorbent into the aforementioned mixture to obtain granules, A method for manufacturing a drug, comprising a drug manufacturing process for obtaining a drug containing the aforementioned granules, and a method for manufacturing a drug.

[0046] The manufacturing method of this embodiment includes the suspension preparation step, granulation step, and drug manufacturing step of the manufacturing method of the first embodiment described above, as well as the following mixing step.

[0047] [Mixing process] The manufacturing method of this embodiment includes a mixing step of mixing the suspension and a water-soluble polymer at a temperature of 35°C to 65°C to obtain a mixed solution. In the mixing step of this embodiment, by mixing the water-soluble polymer at a temperature of 35°C to 65°C, the water-soluble polymer can act as a nucleus for sufficiently precipitating the water-insoluble polymer, even without using the electrolyte used in the first embodiment described above.

[0048] A known stirring device or the like can be used to mix the liquids. Furthermore, the stirring time, stirring temperature, etc., are not particularly limited, but it is preferable to stir until each liquid is thoroughly mixed, that is, until the volume stabilizes.

[0049] Other points common to the first embodiment described above will be explained in the same manner as above.

[0050] The tablets (drugs) obtained by the manufacturing method of this embodiment are sufficiently coated with the active ingredient and have a dissolution rate such that the active ingredient does not dissolve in the oral cavity or elsewhere. For example, the elution rates measured in the examples described later may be low, such as 33% or less, 30% or less, 25% or less, or 20% or less.

[0051] In this embodiment, all components can be selected to be usable as pharmaceuticals. This allows for safe removal of components during the manufacturing process and treatment of washing solutions and filtrates. Alternatively, removal and washing may become unnecessary, resulting in a simpler manufacturing process. Or, it may become unnecessary to evaluate and control the residual amount of components whose residue in the final formulation is restricted.

[0052] The method for producing the drug according to this embodiment is as described above, but the embodiments disclosed herein should be considered in all respects to be illustrative and not restrictive. The scope of the present invention is indicated by the claims rather than the foregoing description, and all modifications within the meaning and scope of the claims are intended to be included. [Examples]

[0053] Next, embodiments of the present invention will be described together with comparative examples. However, the present invention is not limited to the embodiments described below.

[0054] [Measurement of dissolution rate, hardness, and decay time] The dissolution rate was measured for Examples 1-23 and Comparative Examples 1-2. Hardness and disintegration time were also measured for Examples 23 and 24. (Example 1) A premixed powder was prepared by adding 780g of D-mannitol, 120g of crospovidone, and 180g of hydrated silicon dioxide to a vertical granulator (device name: FM-VG-10, manufactured by Powrec Co., Ltd.) and mixing them. Separately, 9 g of sodium lauryl sulfate, 6 g of stearic acid, and 60 g of Eudragit EPO were sequentially added to 500 mL of purified water to prepare a slightly turbid solution 1. Separately, 3 g of hydroxypropyl cellulose and 3.6 g of sodium bicarbonate were dissolved in 300 mL of purified water to prepare solution 2 (electrolyte). Next, 300 g of acetaminophen was suspended in solution 1 to obtain a suspension, and then solution 2 was added and the mixture was stirred until the volume stabilized. After that, the mixture was heated to approximately 40°C while stirring. The above liquid was added to the pre-mixed powder prepared earlier, and granulation was performed by stirring. After that, the granules were sorted using a No. 12 sieve, and then dried using a flow coater (device name: FLO-5B, manufactured by Freund Industrial Co., Ltd.) to obtain granulated powder.

[0055] (Example 2) Solution 1, a slightly turbid solution, was prepared by sequentially adding 0.15 g of sodium lauryl sulfate, 0.1 g of stearic acid, and 1 g of Eudragit EPO to 9 mL of purified water. Separately, Solution 2 (electrolyte) was prepared by dissolving 0.06 g of sodium bicarbonate in 5 mL of purified water. Next, a suspension was prepared by suspending 5g of acetaminophen in solution 1. Solution 2 was then added to this suspension, and the mixture was stirred until the volume stabilized. After that, the mixture was heated to approximately 40°C while stirring. The above liquid was added to 3.64 g of hydrated silicon dioxide, which had been pre-loaded into a mixer (device name: Analytical Grinding Machine R-8, manufactured by Nippon Rikagaku Kikai Co., Ltd.), and granulation was performed by stirring. After drying in a shelf-type dryer, the granulated powder was obtained by sieving through a No. 18 sieve.

[0056] (Example 3) Solution 1, a slightly turbid solution, was prepared by sequentially adding 0.15 g of sodium lauryl sulfate, 0.1 g of stearic acid, and 1 g of Eudragit EPO to 9.1 mL of purified water. Separately, Solution 2 (electrolyte) was prepared by dissolving 0.06 g of sodium bicarbonate in 5 mL of purified water. Next, 5 g of acetaminophen was suspended in solution 1 to obtain a suspension, and then solution 2 was added and the mixture was stirred until the volume stabilized. The above liquid was added to 3.64 g of hydrated silicon dioxide, which had been pre-loaded into a mixer (device name: Analytical Grinding Machine R-8, manufactured by Nippon Rikagaku Kikai Co., Ltd.), and granulation was performed by stirring. After drying in a shelf-type dryer, the granulated powder was obtained by sieving through a No. 18 sieve.

[0057] (Example 4) Granulated powder was obtained in the same manner as in Example 2, except that 0.05 g of hydroxypropyl cellulose was used instead of sodium bicarbonate when preparing Solution 2 (electrolyte) of Example 2.

[0058] (Example 5) Granulated powder was obtained in the same manner as in Example 2, except that 0.05 g of hydroxypropyl cellulose was further dissolved when preparing Solution 2 (electrolyte) of Example 2, and heating was not performed when stirring the mixture.

[0059] (Example 6) Solution 1, a slightly turbid solution, was prepared by sequentially adding 0.15 g of sodium lauryl sulfate, 0.1 g of stearic acid, and 1 g of Eudragit EPO to 9.1 mL of purified water. Separately, Solution 2 (electrolyte) was prepared by dissolving 0.06 g of sodium bicarbonate and 0.025 g of hydroxypropyl cellulose in 5 mL of purified water. Next, 5 g of acetaminophen was suspended in solution 1 to obtain a suspension, and then solution 2 was added. The mixture was stirred until the volume stabilized. After that, the suspension was heated to approximately 40°C while stirring. The above liquid was added to 3.64 g of hydrated silicon dioxide, which had been pre-loaded into a mixer (device name: Analytical Grinding Machine R-8, manufactured by Nippon Rikagaku Kikai Co., Ltd.), and granulation was performed by stirring. After drying in a shelf-type dryer, the granulated powder was obtained by sieving through a No. 18 sieve.

[0060] (Example 7) Granulated powder was obtained in the same manner as in Example 5, except that the amount of hydroxypropyl cellulose added during the preparation of Solution 2 (electrolyte) in Example 6 was 0.125 g.

[0061] (Example 8) Granulated powder was obtained in the same manner as in Example 7, except that hydroxypropyl methylcellulose was used instead of hydroxypropyl cellulose when preparing Solution 2 (electrolyte) of Example 7, and the heating temperature was set to approximately 45°C.

[0062] (Example 9) Granulated powder was obtained in the same manner as in Example 7, except that polybinolpyrrolidone was used instead of hydroxypropylcellulose when preparing Solution 2 (electrolyte) of Example 7, and the heating temperature was set to approximately 50°C.

[0063] (Example 10) Solution 1, a slightly turbid solution, was prepared by sequentially adding 0.15 g of sodium lauryl sulfate, 0.1 g of stearic acid, and 1 g of Eudragit EPO to 9.1 mL of purified water. Separately, Solution 2 (electrolyte) was prepared by dissolving 0.09 g of sodium bicarbonate and 0.05 g of hydroxypropyl cellulose in 5 mL of purified water. Next, 5 g of acetaminophen was suspended in solution 1 to obtain a suspension, and then solution 2 was added and the mixture was stirred until the volume stabilized. After that, the mixture was heated to approximately 40°C while stirring. The above liquid was added to 3.64 g of hydrated silicon dioxide, which had been pre-loaded into a mixer (device name: Analytical Grinding Machine R-8, manufactured by Nippon Rikagaku Kikai Co., Ltd.), and granulation was performed by stirring. After drying in a shelf-type dryer, the granulated powder was obtained by sieving through a No. 18 sieve.

[0064] (Example 11) Solution 1, a slightly turbid solution, was prepared by sequentially adding 0.075 g of sodium lauryl sulfate, 0.05 g of stearic acid, and 0.5 g of Eudragit EPO to 4.5 mL of purified water. Separately, Solution 2 (electrolyte) was prepared by dissolving 0.03 g of sodium bicarbonate and 0.05 g of hydroxypropyl cellulose in 5 mL of purified water. Next, 5 g of acetaminophen was suspended in solution 1 to obtain a suspension, and then solution 2 was added and the mixture was stirred until the volume stabilized. After that, the mixture was heated to approximately 40°C while stirring. The above liquid was added to 2.3 g of hydrated silicon dioxide, which had been pre-loaded into a mixer (device name: Analytical Grinding Machine R-8, manufactured by Nippon Rikagaku Kikai Co., Ltd.), and granulation was performed by stirring. After drying in a shelf-type dryer, the granulated powder was obtained by sieving through a No. 18 sieve.

[0065] (Example 12) Solution 1, a slightly turbid solution, was prepared by sequentially adding 0.225 g of sodium lauryl sulfate, 0.15 g of stearic acid, and 1.5 g of Eudragit EPO to 13.6 mL of purified water. Separately, Solution 2 (electrolyte) was prepared by dissolving 0.09 g of sodium bicarbonate and 0.05 g of hydroxypropyl cellulose in 5 mL of purified water. Next, 5 g of acetaminophen was suspended in solution 1 to obtain a suspension, and then solution 2 was added and the mixture was stirred until the volume stabilized. After that, the mixture was heated to approximately 40°C while stirring. The above liquid was added to 6g of hydrated silicon dioxide that had been pre-loaded into a mixer (device name: Analytical Grinding Machine R-8, manufactured by Nippon Rikagaku Kikai Co., Ltd.), and granulation was performed by stirring. After drying in a shelf-type dryer, the granulated powder was obtained by sieving through a No. 18 sieve.

[0066] (Example 13) Solution 1, a slightly turbid solution, was prepared by sequentially adding 0.15 g of sodium lauryl sulfate, 0.1 g of stearic acid, and 1 g of Eudragit EPO to 14.3 mL of purified water. Separately, Solution 2 (electrolyte) was prepared by dissolving 0.06 g of sodium bicarbonate and 0.05 g of hydroxypropyl cellulose in 5 mL of purified water. Next, 5 g of acetaminophen was suspended in solution 1 to obtain a suspension, and then solution 2 was added and the mixture was stirred until the volume stabilized. After that, the mixture was heated to approximately 40°C while stirring. The above liquid was added to 6.64 g of hydrated silicon dioxide, which had been pre-loaded into a mixer (device name: Analytical Grinding Machine R-8, manufactured by Nippon Rikagaku Kikai Co., Ltd.), and granulation was performed by stirring. After drying in a shelf-type dryer, the granulated powder was obtained by sieving through a No. 18 sieve.

[0067] (Example 14) Solution 1, a slightly turbid solution, was prepared by sequentially adding 0.15 g of sodium lauryl sulfate, 0.1 g of stearic acid, and 1 g of Eudragit EPO to 6.7 mL of purified water. Separately, Solution 2 (electrolyte) was prepared by dissolving 0.06 g of sodium bicarbonate and 0.05 g of hydroxypropyl cellulose in 5 mL of purified water. Next, 5 g of acetaminophen was suspended in solution 1 to obtain a suspension, and then solution 2 was added and the mixture was stirred until the volume stabilized. After that, the mixture was heated to approximately 40°C while stirring. The above liquid was added to 3.19 g of hydrated silicon dioxide, which had been pre-loaded into a mixer (device name: Analytical Grinding Machine R-8, manufactured by Nippon Rikagaku Kikai Co., Ltd.), and granulation was performed by stirring. After drying in a shelf-type dryer, the granulated powder was obtained by sieving through a No. 18 sieve.

[0068] (Example 15) Solution 1, a slightly turbid solution, was prepared by sequentially adding 0.15 g of sodium lauryl sulfate, 0.1 g of stearic acid, and 1 g of Eudragit EPO to 9.1 mL of purified water. Separately, Solution 2 (electrolyte) was prepared by dissolving 0.06 g of sodium acetate and 0.05 g of hydroxypropyl cellulose in 5 mL of purified water. Next, 5 g of acetaminophen was suspended in solution 1 to obtain a suspension, and then solution 2 was added and the mixture was stirred until the volume stabilized. After that, the mixture was heated to approximately 40°C while stirring. The above liquid was added to 3.64 g of hydrated silicon dioxide, which had been pre-loaded into a mixer (device name: Analytical Grinding Machine R-8, manufactured by Nippon Rikagaku Kikai Co., Ltd.), and granulation was performed by stirring. After drying in a shelf-type dryer, the granulated powder was obtained by sieving through a No. 18 sieve.

[0069] (Example 16) Granulated powder was obtained in the same manner as in Example 15, except that sodium carbonate was used instead of sodium acetate when preparing Solution 2 (electrolyte) of Example 15.

[0070] (Example 17) Granulated powder was obtained in the same manner as in Example 15, except that disodium hydrogen phosphate was used instead of sodium acetate when preparing Solution 2 (electrolyte) of Example 15.

[0071] (Example 18) Granulated powder was obtained in the same manner as in Example 15, except that 0.13 g of magnesium chloride hexahydrate was used instead of 0.06 g of sodium acetate when preparing Solution 2 (electrolyte) of Example 15, and the suspension was not heated.

[0072] (Example 19) Granulated powder was obtained in the same manner as in Example 15, except that 0.08 g of sodium potassium tartrate tetrahydrate was used instead of 0.06 g of sodium acetate when preparing Solution 2 (electrolyte) of Example 15.

[0073] (Example 20) Solution 1, a slightly turbid solution, was prepared by sequentially adding 0.15 g of sodium lauryl sulfate, 0.1 g of stearic acid, and 1 g of Eudragit EPO to 9.1 mL of purified water. Separately, Solution 2 (electrolyte) was prepared by dissolving 0.06 g of sodium bicarbonate and 0.05 g of hydroxypropyl cellulose in 5 mL of purified water. Next, 5 g of acetaminophen was suspended in solution 1 to obtain a suspension, and then solution 2 was added and the mixture was stirred until the volume stabilized. After that, the mixture was heated to approximately 50°C while stirring. The above liquid was added to 3.64 g of hydrated silicon dioxide, which had been pre-loaded into a mixer (device name: Analytical Grinding Machine R-8, manufactured by Nippon Rikagaku Kikai Co., Ltd.), and granulation was performed by stirring. After drying in a shelf-type dryer, the granulated powder was obtained by sieving through a No. 18 sieve.

[0074] (Example 21) Granulated powder was obtained in the same manner as in Example 20, except that the mixture from Example 20 was heated to 60°C.

[0075] (Example 22) Solution 1, a slightly turbid solution, was prepared by sequentially adding 0.15 g of sodium lauryl sulfate, 0.1 g of stearic acid, and 1 g of Eudragit EPO to 9.1 mL of purified water. Separately, Solution 2 (electrolyte) was prepared by dissolving 0.06 g of sodium bicarbonate and 0.05 g of hydroxypropyl cellulose in 5 mL of purified water. Next, 5 g of meloxicam was suspended in solution 1 to obtain a suspension, which was then added to solution 2 and stirred until the volume stabilized. After that, the mixture was heated to approximately 40°C while stirring. The above liquid was added to 3.64 g of hydrated silicon dioxide, which had been pre-loaded into a mixer (device name: Analytical Grinding Machine R-8, manufactured by Nippon Rikagaku Kikai Co., Ltd.), and granulation was performed by stirring. After drying in a shelf-type dryer, the granulated powder was obtained by sieving through a No. 18 sieve.

[0076] (Comparative Example 1) To 10 mL of stirred purified water, 0.15 g of sodium lauryl sulfate, 0.1 g of stearic acid, and 1 g of Eudragit EPO were sequentially added to prepare a slightly cloudy solution 1. Separately, 0.05 g of hydroxypropyl cellulose was dissolved in 5 mL of purified water to prepare solution 2. Then, solution 2 was mixed with solution 1 to prepare a mixed solution. Next, 5g of acetaminophen, 13.45g of D-mannitol, 2g of crospovidone, and 3g of hydrated silicon dioxide were added and granulated by stirring with the previously prepared mixture. After drying in a shelf-type dryer, the granules were sieved through a No. 18 sieve to obtain the granulated powder.

[0077] (Comparative Example 2) Solution 1 was prepared by sequentially adding 0.15 g of sodium lauryl sulfate, 0.1 g of stearic acid, and 1 g of Eudragit EPO to 9.1 mL of purified water. Separately, Solution 2 was prepared by dissolving 0.06 g of sodium bicarbonate and 0.05 g of hydroxypropyl cellulose in 5 mL of purified water. Next, 5 g of acetaminophen was suspended in solution 2, and this solution was added to solution 1. The mixture was then stirred until the volume stabilized. After that, the mixture was heated to approximately 40°C while stirring. The above liquid was added to 3.64 g of hydrated silicon dioxide, which had been pre-loaded into a mixer (device name: Analytical Grinding Machine R-8, manufactured by Nippon Rikagaku Kikai Co., Ltd.), and granulation was performed by stirring. After drying in a shelf-type dryer, the granulated powder was obtained by sieving through a No. 18 sieve.

[0078] (Example 23) 365.4 g of the granulated powder prepared in Example 1, 10 g of low-substituted hydroxypropyl cellulose, 10 g of crystalline cellulose, and 112.1 g of D-mannitol were placed in a plastic bag and mixed for 1 minute. Then, 2.5 g of magnesium stearate was added and mixed for a further 30 seconds to obtain compressed tablet powder. Tablets with a diameter of 8.5 mm and a tablet mass of 250 mg were prepared using this compressed tablet powder. An orally disintegrating tablet with a hardness of 73N and a disintegration time of 27 seconds was obtained. The hardness and disintegration time were measured using the following method. Hardness: Measured using a Kiya-type digital hardness tester (KHT-20N, manufactured by Fujiwara Seisakusho) (N=10). Disintegration time: The time it took for the tablet to disintegrate and dissolve in the oral cavity using only saliva without water was measured (N=3).

[0079] (Example 24) 487.2 g of the granulated powder prepared in Example 1, 5.2 g of low-substituted hydroxypropyl cellulose, and 5.1 g of crystalline cellulose were placed in a plastic bag and mixed for 1 minute. Then, 2.5 g of magnesium stearate was added and mixed for a further 30 seconds to obtain compressed tablet powder. Tablets with a diameter of 8.5 mm and a tablet mass of 250 mg were prepared using this compressed tablet powder. We obtained an orally disintegrating tablet with a hardness of 58N and a disintegration time of 29 seconds.

[0080] The following components were used in each example and comparative example. Active ingredients Acetaminophen: Manufactured by HEBI JIHENG PHARMACEUTICAL Meloxicam: Manufactured by Tokyo Chemical Industry Co., Ltd. Polymer dispersant Sodium lauryl sulfate: Kolliphor SLS Fine, manufactured by BASF. Stearic acid: NF-GenAR, manufactured by Avator. Water-insoluble polymer Aminoalkyl methacrylate copolymer: Eudragit EPO, manufactured by Evonik. Water-soluble polymer Hydroxypropylcellulose: HPC SSL, manufactured by Nippon Soda Co., Ltd. Hydroxypropyl methylcellulose: TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd. Polyvinylpyrrolidone: Coridon K-30, manufactured by BASF. electrolyte components Sodium bicarbonate: Manufactured by Merck. Sodium acetate trihydrate: Manufactured by Kanto Chemical Co., Ltd. Disodium hydrogen phosphate: Manufactured by Merck. Sodium potassium tartrate tetrahydrate: Manufactured by Kanto Chemical Co., Ltd. Liquid adsorbent Hydrated silicon dioxide: Fujisil, manufactured by Fuji Chemical Industry Co., Ltd. Other additive components Crospovidone: Coridon CL-SF, manufactured by BASF. Low-substituted hydroxypropyl cellulose: NBD-022, manufactured by Shin-Etsu Chemical Co., Ltd. Crystalline cellulose: Ceolus OD-20P, manufactured by Asahi Kasei Corporation. D-Mannitol: Pairitol 25C (manufactured by Rocket Co., Ltd.), Pairitol Flash (manufactured by Rocket Co., Ltd.), Mannit P (manufactured by Mitsubishi Corporation Life Sciences Co., Ltd.) Magnesium stearate: Magnesium stearate (plant-derived), manufactured by Taihei Chemical Co., Ltd.

[0081] (elution rate) The elution rate of the granulated powder obtained in each of the above examples and comparative examples was measured by the following method. This shows the drug dissolution rate at 1 minute after the start of the dissolution test, conducted in accordance with the paddle method of the 17th revised Japanese Pharmacopoeia. The acetaminophen test solution was purified water, and the meloxicam test solution was pH 6.8.

[0082] The results are shown in Table 1. The table also shows the addition rate (mass%) of electrolyte components to Eudragit EPO (EPO), the EPO concentration (mass%) in Solution 1, the EPO ratio (mass%) to acetaminophen or meloxicam (API), and the amount of liquid components (mass%) relative to solid components.

[0083] [Table 1]

[0084] The granulated powders obtained in the above examples all showed a suppressed elution rate compared to the granulated powders obtained in the comparative examples. Furthermore, the tablets obtained in the above examples possessed appropriate hardness and disintegration properties in the oral cavity.

[0085] [Elution Sensory Test] Sensory evaluation was conducted to measure the elution properties of the following Examples 25-26 and Comparative Examples 3-4. Furthermore, the same materials as those used in the above examples and comparative examples were used, except for the following active ingredients. All of these active ingredients are components that produce a strong bitter taste. Clarithromycin: Manufactured by Tokyo Chemical Industry Co., Ltd. Prednisolone: ​​Manufactured by Tokyo Chemical Industry Co., Ltd.

[0086] (Example 25) A premixed powder was prepared by adding 13.21 g of D-mannitol, 2 g of crospovidone, and 3 g of hydrated silicon dioxide to a mixer (device name: Analytical Grinding Machine R-8, manufactured by Nippon Rikagaku Kikai Co., Ltd.) and mixing them. Separately, 0.15 g of sodium lauryl sulfate, 0.1 g of stearic acid, and 1 g of Eudragit EPO were sequentially added to 8.3 mL of purified water to prepare a slightly turbid solution 1. Separately, 0.05 g of hydroxypropyl cellulose and 0.24 g of sodium bicarbonate were dissolved in 5 mL of purified water to prepare solution 2 (electrolyte). Next, 5 g of clarithromycin was suspended in solution 1 to obtain a suspension, and then solution 2 was added. The mixture was stirred until the volume stabilized to obtain a mixed solution. After that, the solution was heated to approximately 40°C while stirring. The above mixture was added to the pre-mixed powder prepared earlier, and granulation was carried out by stirring. After drying in a shelf-type dryer, the granulated powder was obtained by sieving through a No. 18 sieve.

[0087] (Example 26) A premixed powder was prepared by adding 13.21 g of D-mannitol, 2 g of crospovidone, and 3 g of hydrated silicon dioxide to a mixer (device name: Analytical Grinding Machine R-8, manufactured by Nippon Rikagaku Kikai Co., Ltd.) and mixing them. Separately, 0.15 g of sodium lauryl sulfate, 0.1 g of stearic acid, and 1 g of Eudragit EPO were sequentially added to 8.3 mL of purified water to prepare a slightly turbid solution 1. Separately, 0.06 g of hydroxypropyl cellulose and 0.24 g of sodium bicarbonate were dissolved in 5 mL of purified water to prepare solution 2 (electrolyte). Next, 5 g of prednisolone was suspended in solution 1 to obtain a suspension, and then solution 2 was added, and the mixture was stirred until the volume stabilized. After that, the mixture was heated to approximately 40°C while stirring. The above suspension was added to the pre-mixed powder prepared earlier, and granulation was carried out by stirring. After drying in a shelf-type dryer, the granulated powder was obtained by sieving through a No. 18 sieve.

[0088] (Comparative Example 3) Solution 1 was prepared by sequentially adding 0.15 g of sodium lauryl sulfate, 0.1 g of stearic acid, and 1 g of Eudragit EPO to 8.3 mL of purified water. Separately, Solution 2 was prepared by dissolving 0.05 g of hydroxypropyl cellulose in 5 mL of purified water. Then, Solution 2 was mixed with Solution 1 to prepare a mixed solution. Next, 5g of clarithromycin, 13.45g of D-mannitol, 2g of crospovidone, and 3g of hydrated silicon dioxide were added to a mixer (device name: Analytical Grinding Machine R-8, manufactured by Nippon Rikagaku Kikai Co., Ltd.), and granulation was carried out by stirring with the previously prepared mixed solution. After drying in a shelf-type dryer, the granulated powder was obtained by sieving through a No. 18 sieve.

[0089] (Comparative Example 4) Solution 1 was prepared by sequentially adding 0.15 g of sodium lauryl sulfate, 0.1 g of stearic acid, and 1 g of Eudragit EPO to 8.3 mL of purified water. Separately, Solution 2 was prepared by dissolving 0.05 g of hydroxypropyl cellulose in 5 mL of purified water. Then, Solution 2 was mixed with Solution 1 to prepare a mixed solution. Next, 5g of prednisolone, 13.45g of D-mannitol, 2g of crospovidone, and 3g of hydrated silicon dioxide were added to a mixer (device name: Analytical Grinding Machine R-8, manufactured by Nippon Rikagaku Kikai Co., Ltd.), and granulation was carried out by stirring with the previously prepared mixed solution. After that, the mixture was dried in a shelf-type dryer and then sieved through a No. 18 sieve to obtain granulated powder.

[0090] (Sensory testing) The following sensory tests were conducted using the granulated powders from the above examples and comparative examples. Two test subjects were instructed to hold 0.2g of the drug in their mouths and score the bitterness they felt within 10 seconds as score A, and the bitterness they felt after rinsing their mouths after 10 seconds as score B, according to the following criteria. 0 points: No bitterness detected 1 point: Can perceive bitterness. 2 points: Slightly bitter taste 3 points: I can taste the bitterness. 4 points: I feel a strong bitterness. Table 2 shows the scores for scores A and B, and the average scores for each score of the two testers. Figures 1 and 2 show the average scores for each active ingredient (clarithromycin and prednisolone) for the two testers.

[0091] [Table 2]

[0092] The granulated powder obtained in the above example did not produce a bitter taste at either the time within 10 seconds or after 10 seconds, compared to the granulated powder obtained in the comparative example. In particular, even after 10 seconds, when bitterness is usually strongly perceived, the perception of bitterness was suppressed. From this, it is clear that the granulated powder of the example does not easily dissolve the active ingredient in water (saliva) and does not produce a bitter taste in the oral cavity. In other words, the granulated powder obtained in the examples is thought to suppress the dissolution of the active ingredient that causes bitterness in the oral cavity, and also suppress the retention of the active ingredient in the oral cavity.

Claims

1. A suspension preparation step involves mixing a water-insoluble polymer, a polymer dispersant, an active ingredient, and a dispersion medium to obtain a suspension. The electrolyte preparation process involves mixing an electrolyte and a solvent to obtain an electrolyte solution, A mixing step of mixing the suspension and the electrolyte to obtain a mixture, A granulation step is performed by mixing a liquid adsorbent into the aforementioned mixture to obtain granules, A pharmaceutical manufacturing process for obtaining a pharmaceutical product containing the aforementioned granules, The liquid adsorbent is silicon dioxide. A method for manufacturing pharmaceuticals.

2. The method for producing a drug according to claim 1, wherein the electrolyte is at least one selected from the group consisting of sodium bicarbonate, sodium acetate, disodium hydrogen phosphate, sodium tartrate, potassium tartrate, sodium potassium tartrate, and magnesium chloride.

3. The method for producing a pharmaceutical agent according to claim 1 or 2, wherein the mixing step is performed at a temperature of 35°C or higher and 65°C or lower.

4. A method for producing a drug according to any one of claims 1 to 3, wherein a water-soluble polymer is further mixed in the electrolyte preparation step.

5. The method for producing a drug according to claim 4, wherein the water-soluble polymer is at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and polyvinylpyrrolidone.

6. A suspension preparation step involves mixing a water-insoluble polymer, a polymer dispersant, an active ingredient, and a dispersion medium to obtain a suspension. A mixing step in which the suspension and a water-soluble polymer are mixed at a temperature of 35°C to 65°C to obtain a mixed solution, A granulation step is performed by mixing a liquid adsorbent into the aforementioned mixture to obtain granules, A pharmaceutical manufacturing process for obtaining a pharmaceutical product containing the aforementioned granules, A method for producing a drug, wherein the liquid adsorbent is silicon dioxide.

7. A method for producing a drug according to any one of claims 1 to 6, wherein the water-insoluble polymer is an aminoalkyl methacrylate copolymer.

8. A method for producing a drug according to any one of claims 1 to 7, wherein the polymer dispersant is at least one selected from the group consisting of lauryl sulfate, stearic acid, and salts thereof.

9. The method for producing a drug according to claim 6, wherein the water-soluble polymer is at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and polyvinylpyrrolidone.

10. A method for producing a drug according to any one of claims 1 to 9, wherein the active ingredient is a component suspended in the dispersion medium.

11. A method for producing a pharmaceutical product according to any one of claims 1 to 10, wherein the granules are molded into tablets in the pharmaceutical product manufacturing process.

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