JP2024141310A - Method for producing granules and film-coated tablets, and granules and film-coated tablets - Google Patents

Abstract

[Problem] To provide a method for producing granules capable of forming granulated powder (granules) with excellent fluidity, a method for producing film-coated tablets using the same, and granules and film-coated tablets obtained by these production methods.
[Solution] A method for producing granules includes a mixing step (A) of mixing a drug and hydroxypropyl cellulose powder to form a mixture, a granulation step (B) of adding water to the mixture to form a granule, and a drying step (C) of drying the granule.
[Selected Figure] Figure 1

Description

The present invention relates to a method for producing granules and a method for producing film-coated tablets, as well as granules and film-coated tablets. The method for producing granules and film-coated tablets, as well as the granules and film-coated tablets of the present invention, can be used in the field of pharmaceutical production.

An important characteristic in manufacturing tablet-type pharmaceuticals is the fluidity of each component powder and additive powder, more specifically, the fluidity of granulated powder (granules) and/or tablet powder containing active ingredients.

Fluidity is an index that indicates how free-flowing a powder is. If fluidity is poor, the powders containing active ingredients will not flow smoothly through the equipment during the filling process into capsule filling machines or tablet presses in the pharmaceutical manufacturing process for capsules and tablets, resulting in problems such as weight variations during filling and clogging during production, preventing smooth production.

Conventionally, it has been known that fluidity can be increased by making the particle sizes of the additives in the powder formulation or the granulated powder uniform, but this knowledge alone is not enough to increase the fluidity of the granulated powder itself. In the first place, if the fluidity of the granulated powder (granules) containing the active ingredient itself can be increased, it is relatively easy to increase the fluidity of the tableting powder, but there is a problem in that, for example, the fluidity of the granulated powder (granules) itself cannot be increased simply by making the particle sizes of the core particles used uniform.

Regarding this problem, for example, the following invention regarding a method for producing a controlled release lacosamide formulation has been disclosed (Patent Document 1).
Patent Document 1 discloses that a binder solution is prepared by dissolving hydroxypropyl cellulose as a binder in purified water, and the binder solution is added to a dry mixture containing a drug to produce granules by a wet method (granulation).

Patent No. 6027539

However, the granulated powder (granules) produced by the method of Patent Document 1 has poor fluidity. In addition, the tableting powder obtained by adding the latter powder to the granulated powder (granules) also has poor fluidity. Therefore, when the tableting powder is inserted into a tableting dies, there are problems such as the inability to insert the tableting powder in a fixed time and the weighing stability of the tableting powder being impaired.
In order to increase the fluidity of the granulated powder (granules), for example, it is not possible to increase the fluidity of the granulated powder (granules) itself simply by making the particle size of the core particles used uniform.
An object of the present invention is to provide a method for producing granules capable of forming a granulated powder (granules) with excellent fluidity, a method for producing film-coated tablets using the same, and the granules and film-coated tablets obtained by these production methods.

In order to solve the problems related to fluidity, the inventors focused on the excipients and binders used in granulated powders (granules) containing active ingredients, as well as the preparation of the binders. As a result of extensive investigation, it was found that by making the granulated powders (granules) contain specific excipients and binders in addition to the active ingredients, and further by producing the granulated powders (granules) using a specific method, it was possible to increase the fluidity of the granulated powders (granules) when they are mixed with the latter powder. Thus, the present invention provides the following various aspects.

[1] A mixing step (A) of mixing a drug and a powder containing hydroxypropyl cellulose powder to form a mixture;
A granulation step (B) of adding a granulation liquid to the mixture to form a granule;
A drying step (C) of drying the granulated product.
[2] The method for producing granules described in [1], wherein the mixing step (A) is a step of mixing a drug, hydroxypropyl cellulose powder, and crystalline cellulose powder to form a mixture, and the angle of repose of the crystalline cellulose powder is 40° or less.
[3] A mixing step (D) of adding a powder containing an excipient and a disintegrant to the granules obtained by the method for producing granules according to [1] or [2] and mixing to form a tablet powder;
A tableting step (E) of compressing the tablet powder to form a plain tablet;
A method for producing a film-coated tablet, comprising: a coating step (F) of coating the uncoated tablet with a coating liquid.
[4] The method for producing a film-coated tablet according to [3], wherein the granulation liquid is water.
[5] The method for producing a film-coated tablet according to [4], wherein the coating solution contains hypromellose.
[6] The method for producing a film-coated tablet according to [5], wherein the drug is lacosamide.

[7] A granule containing a drug, hydroxypropyl cellulose and microcrystalline cellulose,
The angle of repose of the granules is 45° or less;
Granules, the particle size distribution of which, when measured under dry conditions using a laser diffraction/scattering method, is such that the value calculated using the following formula (1) is 3.0 or less.
(D ₉₀ - _{D 10} )/D ₅₀ ...(1)
[8] Add an excipient and a disintegrant to the granules according to [7] and mix to form a tablet powder;
A film-coated tablet is obtained by compressing the tablet powder into a plain tablet and forming a coating layer on the outside of the plain tablet.
[9] The film-coated tablet according to [8], wherein the drug is lacosamide.

The present invention provides a method for producing granules that can form granulated powder (granules) with excellent fluidity, a method for producing film-coated tablets using the same, and granules and film-coated tablets obtained by these production methods.

1 is a graph showing the particle size distribution of the sized granules of Example 1. 1 is a graph showing the particle size distribution of sized granules of Comparative Example 1. 1 is a graph comparing the dissolution rates of test samples of the film-coated tablets of Example 2 and Comparative Example 2 stored for one month.

<Method of producing granules>
The method for producing granules of this embodiment includes a mixing step (A) of mixing a powder containing a drug and a hydroxypropyl cellulose powder to form a mixture;
A granulation step (B) of further adding water to the mixture to form a granule;
and a drying step (C) of drying the granulated product.
A preferred embodiment of the method for producing granules according to the present embodiment will be described below, but it is merely an example and is not limited to the following.

In the mixing step (A), the drug and at least hydroxypropyl cellulose powder as a binder are mixed to form a mixture. In the granulation step (B), water is further added to the mixture to form a granule in a wet state. Thereafter, in the drying step (C), the granule is dried. Although the granulation step (B) is a wet granulation step, hydroxypropyl cellulose as a binder is added not in the form of a binder solution but in the form of hydroxypropyl cellulose powder, mixed, and then granulated by adding water, thereby making it possible to obtain granules with excellent fluidity. The granules may be sized and then dried. After drying, they may be further sized. These sizing steps are aimed at removing large granules and do not affect the fluidity of the final granules.

The drug may be a single type or two or more types. The drug may have an unpleasant taste, such as a bitter taste, or may not have an unpleasant taste.

In this embodiment, the granules may be those obtained by a known formulation process, for example, those obtained by mixing with other additives, or granulated products obtained by granulation. Examples of the granulation method include conventional granulation methods such as agitation granulation and fluidized bed granulation.

Additives that can be mixed into the granules include hydroxypropylcellulose powder as a binder, as well as excipients, disintegrants, flow agents, lubricants, flavorings, sweeteners, fragrances, stabilizers, plasticizers, colorants, etc. These additives are added in appropriate amounts, either alone or in combination of two or more.

Examples of excipients that can be mixed into the granules include crystalline cellulose powder, and sugar alcohols such as D-mannitol, erythritol, D-sorbitol, xylitol, and maltitol.
The excipient is preferably crystalline cellulose powder. The angle of repose of the crystalline cellulose powder is preferably 40° or less, more preferably 38° or less, and even more preferably 36° or less. Furthermore, examples of the crystalline cellulose used in this embodiment include Ceolus (registered trademark) UF-702, Ceolus (registered trademark) UF-711, Ceolus (registered trademark) PH-101, Ceolus (registered trademark) PH-102, Ceolus (registered trademark) PH-200, Ceolus (registered trademark) PH-301, and Ceolus (registered trademark) PH-302 (all manufactured by Asahi Kasei Corporation), and are preferably Ceolus UF-702, Ceolus PH-200, or Ceolus PH-302, and more preferably Ceolus UF-702.
One type selected from the above may be used alone, or two or more types may be used in combination.

The content of the excipient in the granules is preferably 1 to 70% by weight, more preferably 5 to 60% by weight, and even more preferably 10 to 50% by weight.

Disintegrants that can be mixed with the granules include, in addition to crospovidone, celluloses such as croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, low-substituted hydroxypropyl cellulose, and the like, starches such as sodium carboxymethyl starch, hydroxypropyl starch, rice starch, wheat starch, corn starch, potato starch, partially pregelatinized starch, and the like, and crospovidone copolymers.
The disintegrant is preferably low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, or crospovidone, and more preferably low-substituted hydroxypropyl cellulose.
One type selected from the above may be used alone, or two or more types may be used in combination.
The amount of the disintegrant in the granules is preferably 1 to 15% by weight, more preferably 4 to 12% by weight.

Examples of fluidizing agents that can be mixed with the granules include stearic acid, metal salts of stearic acid such as magnesium stearate and calcium stearate, sodium stearyl fumarate, talc, sucrose fatty acid esters, light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminometasilicate, fumed silica, etc. One type selected from the above may be used alone, or two or more types may be used in combination.
The fluidizing agent is preferably magnesium aluminometasilicate, fumed silica, light anhydrous silicic acid, and talc, more preferably magnesium aluminometasilicate and light anhydrous silicic acid, and further preferably light anhydrous silicic acid.
The blending amount of the fluidizing agent in the powder is preferably 0.1 to 10.0% by weight, more preferably 0.1 to 5.0% by weight, and further preferably 0.5 to 2.0%.

Lubricants that can be mixed into the granules include stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid esters, polyethylene glycol, light anhydrous silicic acid, hardened oils, glycerin fatty acid esters, talc, etc. One type selected from the above may be used alone, or two or more types may be used in combination.

Flavoring agents that can be mixed into the granules include glutamic acid, fumaric acid, succinic acid, citric acid, sodium citrate, tartaric acid, malic acid, ascorbic acid, sodium chloride, 1-menthol, etc. One type selected from the above may be used alone, or two or more types may be used in combination.

Sweeteners that can be mixed into the granules include sugar alcohols, aspartame, saccharin, dipotassium glycyrrhizinate, stevia, maltose, maltitol, starch syrup, and amacha powder. One of the above can be used alone, or two or more can be used in combination.

Flavors that can be mixed into the granules include oils such as orange, vanilla, strawberry, yogurt, menthol, fennel oil, cinnamon oil, spruce oil, and peppermint oil, and green tea powder. One of the above may be used alone, or two or more may be used in combination.

Examples of plasticizers that can be mixed into the granules include those listed in official compendia such as the Japanese Pharmacopoeia and Pharmaceutical Additives Standards, such as triethyl citrate, triacetin, dibutyl sebacate, acetylated monoglyceride, propylene glycol, polysorbate 80, polyethylene glycol, and sodium lauryl sulfate.

<Granules>
The granule manufacturing method of the above embodiment can produce granules containing a drug, hydroxypropyl cellulose and crystalline cellulose, the granules having an angle of repose of 45° or less, and when the particle size distribution of the granules is measured by a laser diffraction/scattering method under dry conditions, the value calculated by the following formula (1) is 3.0 or less.
(D ₉₀ - _{D 10} )/D ₅₀ ...(1)

The angle of repose is a physical property for evaluating the fluidity of a powder. It can be measured according to the Angle of Repose Measurement Method in the Reference Information of the Japanese Pharmacopoeia (18th revision), for example, using a commercially available electromagnetic vibration type angle of repose measuring device.
The angle of repose of the granules is 45° or less, preferably 44° or less.

In formula (1), _D50 is the median diameter, which is the diameter below which half of the powder population is. _D90 is the diameter below which 90% of the powder population is. _D10 is the diameter below which 10% of the powder population is. When the particle size distribution of the granules is measured, the value calculated by formula (1) is 3.0 or less, preferably 2.5 or less, more preferably 2.3 or less, and even more preferably 2.1 or less.

<Method of manufacturing film-coated tablets>
The method for producing a film-coated tablet of this embodiment includes a mixing step (D) of adding an additive (herein referred to as "final powder") containing an excipient and a disintegrant to the granules obtained by the method for producing granules of the above embodiment and mixing them to form a mixed powder (herein referred to as "tablet powder");
A tableting step (E) of compressing the tablet powder to form a plain tablet;
and a coating step (F) of coating the uncoated tablet with a coating liquid.

In the mixing step (D), additives contained in the tablet powder as the final powder include excipients, disintegrants, as well as flow agents, lubricants, sweeteners, flavorings, stabilizers, plasticizers, colorants, and flavoring agents. These additives are added in appropriate amounts, either alone or in combination of two or more.

Examples of excipients used in the final preparation include crystalline cellulose and sugar alcohols such as D-mannitol, erythritol, D-sorbitol, xylitol, and maltitol.
A preferred example of the excipient is crystalline cellulose.
One type selected from the above may be used alone, or two or more types may be used in combination.
The content of the excipient in the uncoated tablet is preferably 1 to 70% by weight, more preferably 5 to 60% by weight, and even more preferably 10 to 50% by weight.

Disintegrants used in the latter portion include, in addition to crospovidone, celluloses such as croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, low-substituted hydroxypropyl cellulose, etc., starches such as sodium carboxymethyl starch, hydroxypropyl starch, rice starch, wheat starch, corn starch, potato starch, partially pregelatinized starch, etc., and crospovidone copolymers.
The disintegrant is preferably low-substituted hydroxypropylcellulose, croscarmellose sodium, sodium starch glycolate, or crospovidone, and more preferably crospovidone.
One type selected from the above may be used alone, or two or more types may be used in combination.
The amount of the disintegrant in the powder is preferably 1 to 15% by weight, more preferably 4 to 12% by weight.

Examples of fluidizing agents that can be mixed into the powder include stearic acid, metal salts of stearic acid such as magnesium stearate and calcium stearate, sodium stearyl fumarate, talc, sucrose fatty acid esters, light anhydrous silicic acid, hydrous silicon dioxide, magnesium aluminometasilicate, fumed silica, etc. One type selected from the above may be used alone, or two or more types may be used in combination.
The fluidizing agent is preferably magnesium aluminometasilicate, fumed silica, light anhydrous silicic acid, and talc, more preferably magnesium aluminometasilicate and light anhydrous silicic acid, and further preferably light anhydrous silicic acid.
The blending amount of the fluidizing agent in the powder is preferably 0.1 to 10.0% by weight, more preferably 0.1 to 5.0% by weight, and further preferably 0.3 to 2.0%.

Examples of lubricants that can be mixed into the powder include stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid esters, polyethylene glycol, light anhydrous silicic acid, hardened oils, glycerin fatty acid esters, and talc.
The lubricant is preferably sodium stearyl fumarate, magnesium stearate or calcium stearate, more preferably magnesium stearate.
One type selected from the above may be used alone, or two or more types may be used in combination.

The flow agents, lubricants, flavorings, sweeteners, fragrances, stabilizers, plasticizers, and colorants used in the final powder can be any of those listed as being suitable for mixing with granules.

In the tableting step (E), the powder is compressed to form plain tablets. For example, plain tablets can be formed by compressing the powder using a rotary tablet press.

In this embodiment, the plain tablet may be formed into, for example, a round, elliptical, spherical, polygonal plate, rod, or doughnut shape, as well as a layered tablet, a dry-coated tablet, or the like. If necessary, the tablet may be coated with a coating agent. Marks, letters, or other marks may be printed on the tablet to improve its identifiability, and a dividing line may be added.

The size of the uncoated tablet is preferably small, with a diameter of about 5 to 12 mm and a thickness of about 2 to 7 mm.

The weight of the uncoated tablet is preferably about 50 to 600 mg.

The hardness of the uncoated tablet is not particularly limited, but a certain degree of hardness is necessary to prevent breakage of the tablet during transportation, etc. In this embodiment, the hardness is preferably 30 to 150 N, more preferably 40 to 130 N, even more preferably 50 to 120 N, and most preferably 50 to 100 N.

In the coating step (F), the plain tablets are coated with a coating liquid to obtain film-coated tablets.

The "coating agent" contained in the coating liquid includes a coating base, a plasticizer, a lubricant, a colorant, etc. These coating agents are added in appropriate amounts, either alone or in combination of two or more. Here, the coating agent refers to the solid component contained in the coating liquid, and is the same as the component of the coating layer formed on film-coated tablets.

The coating base used in the coating agent is not particularly limited, and examples thereof include enteric cellulose derivatives such as hypromellose (i.e., hydroxypropyl methylcellulose), cellulose acetate propionate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxymethylethylcellulose phthalate, carboxymethylethylcellulose, and cellulose acetate phthalate, methacrylic acid copolymer LD (e.g., trade name: Eudragit L30D-55, manufactured by Evonik Degussa Japan Co., Ltd.; trade names: Polyquid PA-30 and Polyquid PA-30S, manufactured by Sanyo Chemical Industries, Ltd.; trade name: Kollicoat MAE30DP, manufactured by BASF Corporation), methacrylic acid copolymer L (e.g., trade name: Eudragit L, manufactured by Evonik Degussa Japan Co., Ltd.), methacrylic acid copolymer S (e.g., trade names: Eudragit S, Eudragit S100, and Eudragit FS30D, manufactured by Evonik Degussa Japan Co., Ltd.), and methacrylic acid copolymer S (e.g., trade names: Eudragit S, Eudragit S100, and Eudragit FS30D, manufactured by Evonik Degussa Japan Co., Ltd.). Examples of such enteric acrylic copolymers include those manufactured by Eppendorf Pharmaceuticals Co., Ltd.
As the coating base, preferred are hypromellose, methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, etc., and more preferred is hypromellose. These coating bases may be used alone or in combination of two or more.

In the manufacturing method of this embodiment, the coating solution contains hypromellose, making it possible to produce a film-coated tablet with excellent dissolution properties.

Here, dissolution is an index that indicates how orally administered tablets, capsules, etc. dissolve in the body. For a film-coated tablet to exert its drug effect, it must dissolve in the digestive tract and then be absorbed from the intestine. Dissolution indicates how the drug dissolves.
Furthermore, for example, a tablet-type drug undergoes several processes in the body before it exerts its medicinal effects, and dissolution is an important characteristic of this process.
The higher each of these performances is, the better the film-coated tablet is judged to be.

In order to improve dissolution, for example, when an active ingredient is poorly soluble, the active ingredient compound may be converted into a salt or hydrate, the active ingredient may be finely ground to reduce its size as much as possible, or a disintegrant may be appropriately combined, but this alone may not improve dissolution. In particular, pharmaceuticals generally have a shelf life of 2 to 3 years from the date of manufacture, and they must maintain stable dissolution performance during the shelf life.
In order to solve the problem regarding dissolution, the present inventors focused on coating bases.
The use of a specific coating base has enabled the production of granules or formulations such as tablets and orally disintegrating tablets whose dissolution performance does not decrease even when stored under harsh conditions or for long periods of time, thereby solving the above-mentioned problems.
In addition, even if the granules or preparations have high dissolution properties, there is a problem of maintaining high dissolution properties during the effective period of the pharmaceutical product. Furthermore, there is a demand for granules or preparations that combine both properties. In the manufacturing method of this embodiment, the coating liquid contains hypromellose, so that a film-coated tablet having excellent dissolution properties can be obtained even after storage at 60°C for one month.

The weight ratio of the coating base in the coating agent is 10 to 100% by weight, preferably 25 to 90% by weight, and more preferably about 35 to 85% by weight, relative to 100% by weight of the coating agent.

Examples of plasticizers used in the coating agent include those listed in official compendia such as the Japanese Pharmacopoeia and Pharmaceutical Additives Standards, such as polyethylene glycol, triethyl citrate, triacetin, dibutyl sebacate, acetylated monoglyceride, propylene glycol, polysorbate 80, and sodium lauryl sulfate.
The plasticizer is preferably polyethylene glycol.
The amount of the plasticizer is about 5 to 40 parts by weight, preferably about 5 to 20 parts by weight, based on 100 parts by weight of the coating base (meaning the weight of the solid content). The weight ratio of the plasticizer in the coating agent is about 4 to 200% by weight, preferably about 6 to 10% by weight, more preferably about 7 to 9% by weight, based on 100% by weight of the coating agent.

Examples of lubricants used in the coating agent include stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid esters, polyethylene glycol, light anhydrous silicic acid, hardened oils, glycerin fatty acid esters, talc, etc. One type selected from the above may be used alone, or two or more types may be used in combination.
The lubricant is preferably magnesium stearate.
The amount of the lubricant is about 5 to 40 parts by weight, preferably about 5 to 20 parts by weight, based on 100 parts by weight of the coating base (meaning the weight of solid content). The weight ratio of the lubricant in the coating agent is about 4 to 200% by weight, preferably 6 to 10% by weight, more preferably 7 to 9% by weight, based on 100% by weight of the coating agent.

Colorants used in the coating agent include food dyes such as yellow ferric oxide, food red No. 3, food yellow No. 5, food blue No. 1, etc., as well as colorants such as copper chlorophyll sodium, titanium oxide, and riboflavin. One of the above may be used alone, or two or more may be used in combination.

Furthermore, the coating agent may contain pH adjusters, colorants, flavorings, fragrances, etc.

In addition, one or more other polymers may be mixed into the coating agent as long as the effect of this embodiment is not impaired. Examples include water-soluble polymers, water-insoluble polymers, gastrosoluble polymers, and thermoplastic substances (wax-like substances).

<Film-coated tablets>
According to the method for producing a film-coated tablet of the above embodiment, a film-coated tablet can be produced by adding a powder such as an excipient and a disintegrant to the granule of the above embodiment, mixing them to form a powder for tableting, and compressing the powder for tableting to obtain a plain tablet on the outside of which a coating layer is formed.

The dissolution rate (after 5 minutes) of the film-coated tablet thus obtained is preferably 80% or more, more preferably 85% or more, even more preferably 90% or more, and most preferably 91% or more.
The dissolution rate (after 15 minutes) of the film-coated tablet is preferably 90% or more, more preferably 95% or more, even more preferably 99% or more, and most preferably 100%.
The dissolution time is not particularly limited, but is preferably within 15 minutes, more preferably within 10 minutes, and even more preferably within 5 minutes in a dissolution test (apparatus: paddle method, test fluid: second fluid for dissolution test in the Japanese Pharmacopoeia), for example.

The above-mentioned film-coated tablets can preferably have a dissolution rate (after 5 minutes) of 80% or more, more preferably 85% or more, even more preferably 90% or more, and most preferably 91% or more, even in the case of test samples stored under normal conditions for one month.
Even in the case of a test sample of a film-coated tablet stored under normal conditions for one month, the dissolution rate (after 15 minutes) can be preferably 90% or more, more preferably 95% or more, even more preferably 99% or more, and most preferably 100%.
In this specification, "normal state" refers to an environment of about 1 atmosphere (i.e., 86 kPa or more and 106 kPa or less), "normal temperature" and "normal humidity", and "normal temperature" refers to 5 to 35°C (sometimes referred to as room temperature), and "normal humidity" refers to an environment with a relative humidity of 45 to 85% RH.

Furthermore, the above-mentioned film-coated tablet can preferably have a dissolution rate (after 5 minutes) of 80% or more, more preferably 85% or more, even more preferably 90% or more, and most preferably 91% or more, even in the case of a test sample stored at 60°C and normal humidity for one month.
Even in the case of a test sample of a film-coated tablet stored under normal conditions for one month, the dissolution rate (after 15 minutes) can be preferably 90% or more, more preferably 95% or more, even more preferably 99% or more, and most preferably 100%.

The present invention will be described in more detail below with reference to examples. However, these examples are merely examples of the present invention and the present invention is not limited to the following examples.

[Example 1]: Sized granules (drug)
The drug used in the Examples and Comparative Examples was lacosamide (D ₁₀ : 5.0 μm, D ₅₀ : 10.8 μm, D ₉₀ : 29.7 μm).

(crystalline cellulose)
As the crystalline cellulose, "CEOLUS UF-702" manufactured by Asahi Kasei Corporation (average particle size: 90 μm, bulk density: 0.29 g/cm ³ , loss on drying: 2.0 to 6.0%, angle of repose: 34°) was used.

(Mixing step (A))
The lacosamide (350 g), the crystalline cellulose (98 g), low-substituted hydroxypropyl cellulose (87.5 g (manufactured by Shin-Etsu Chemical Co., Ltd., "L-HPC (registered trademark) LH-21")), hydroxypropyl cellulose (21 g (manufactured by Nippon Soda Co., Ltd., "NISSO (registered trademark) HPC SL")), and light anhydrous silicic acid (4.9 g (manufactured by Freund Corporation, "Adsolider (registered trademark) 101")) were placed in a wet high-shear granulator (manufactured by Powrex Corporation, "VG-5") and mixed to obtain a mixture.

(Granulation process (B))
To this mixture was added a granulation liquid (purified water, weight (g) equivalent to 55% of the powder (the mixture obtained in the mixing step (A))) and the mixture was granulated.
The granulated product was placed in a granulator (Powrex Corporation, "QC-197S") and sized to produce a sized product.

(Drying process (C))
The sized product was placed in a dryer (Powrex Corporation, "MP-01") and dried at an intake air temperature of 80°C until the exhaust air temperature reached 45°C, obtaining a dried product.
The dried product was placed in a granulator (manufactured by Powrex Corporation, "QC-197S") and sized to obtain sized granules of Example 1.
The formulation of Example 1 is shown in Table 1.

[Comparative Example 1]: Sized granules (preparation of binder solution)
The hydroxypropyl cellulose (21 g) was not added to the mixing step (A) of Example 1, but instead, the granulation liquid of Example 1 (purified water, weight (g) equivalent to 40% of the powder (mixture obtained in the mixing step (A))) in which the hydroxypropyl cellulose (21 g) had been dissolved in advance was used, and the granulation liquid of Example 1 (purified water, weight (g) equivalent to 30% of the powder (mixture obtained in the mixing step (A))) was additionally used for granulation. The sized granules of Comparative Example 1 were obtained in the same manner as in Example 1 except for the above.

[Test Example 1]: Measurement of Angle of Repose The angle of repose of the granules obtained in Example 1 and Comparative Example 1 was measured by the Japanese Pharmacopoeia (18th edition) Reference Information Angle of Repose Measurement Method. The measurement device used was an electromagnetic vibration type angle of repose measurement device AOR-57 (Tsutsui Rikagaku Kikai Co., Ltd.), and the sample was poured on top of a 10 mesh sieve (sample pouring height: about 2-4 cm), and the sample was piled up until it spilled over the entire stainless steel measuring disk with a diameter of 6 cm, and the discharge of the sample was stopped when the sample was piled up to the highest point. Then, the angle of repose was measured using a measuring protractor.

(Test Results)
The average results of five measurements are shown in Table 2.

The granules of Example 1 have a small angle of repose and excellent flowability.

[Test Example 2]: Measurement of particle size (particle size distribution) For the granules obtained in Example 1 and Comparative Example 1, the particle size distribution was measured in a dry state using a laser diffraction/scattering particle size distribution measuring device ("MT3200II" manufactured by Microtrac-Bell Co., Ltd.) The measurement conditions were measurement time: 10 s, dispersion pressure: 0 MPa.

(Test Results)
The results are shown in Table 3 and in FIG. 1 (Example 1) and FIG. 2 (Comparative Example 1).

The value calculated by the following formula (1) was 2.13 for the sized granules of Example 1 and 3.66 for the sized granules of Comparative Example 1. It was shown that the sized granules of Example 1 had a sharper particle size distribution than the sized granules of Comparative Example 1.
(D ₉₀ - _{D 10} )/D ₅₀ ...(1)

[Example 2]: Film-coated tablets (mixing step (D))
The sized granules of Example 1 (320.8 g), microcrystalline cellulose (13.2 g (Asahi Kasei Corporation, CEOLUS UF-702)), crospovidone (40 g (Ashland Corporation, Polyplasdone (registered trademark) XL-10)) and light anhydrous silicic acid (1.2 g (Freund Corporation, Adsolider (registered trademark) 101)) were placed in a plastic bag, and the plastic bag was taken up and down by hand and mixed until homogenous (at least 30 times). 4.8 g of magnesium stearate was added to this, and the mixture was similarly mixed by shaking up and down 15 times to obtain a tablet powder.

(Tableting process (E))
The tableting powder was compressed using a rotary tablet press (Kikusui Seisakusho Co., Ltd., "VELA5") to obtain plain tablets with an average tablet weight (240 mg), tablet thickness (3.8 to 4.2 mm), and hardness (30 N or more). The tableting powder made from the sized granules of Example 1 had excellent fluidity, and could be inserted into a tableting mortar in a constant time.

(Adjustment of coating liquid)
Next, hypromellose (80 g (manufactured by Shin-Etsu Chemical Co., Ltd., "TC-5 (registered trademark) R")) and macrogol 6000 (12 g (manufactured by Sanyo Chemical Industries, Ltd., "PEG6000SP"))) were added to purified water (800 g) and stirred until dissolved. Separately, talc (8 g (manufactured by Matsumura Sangyo Co., Ltd., "Crown Talc Official PP")) and yellow ferric oxide (1.4 g) were added to purified water (200 g) and ultrasonically dispersed. These liquids were mixed and stirred, washed together with purified water (120 g), mixed and stirred, and sieved to prepare a coating liquid with a solid concentration of 8 wt%.

(Coating step (F))
The uncoated tablets obtained in the tableting step (E) were placed in a coating machine (Freund Corporation, "HiCoater MINI") and coated with the coating solution so that the average tablet weight became 250 mg. The uncoated tablets were then dried to obtain the film-coated tablets of Example 2.

The formulation for Example 2 is shown in Table 4.

Comparative Example 2: Film-coated tablets Film-coated tablets of Comparative Example 2 were obtained in the same manner as in Example 2, except that the hypromellose (80 g) in Example 2 was changed to polyvinyl alcohol (PVA, 80 g (manufactured by Mitsubishi Chemical Corporation, "GOHSENOL (registered trademark) EG-05PW")).

[Test Example 3]: Dissolution test For the tablets obtained in Example 2 and Comparative Example 2, test samples were prepared by storing them under normal conditions for one month and storing them under normal humidity at 60°C for one month. A dissolution test was carried out for each tablet (total of four types) using purified water as the test liquid according to the Japanese Pharmacopoeia General Test Method Dissolution Test Method 2 (paddle method) at 50 rpm. The HPLC conditions were as follows:

(HPLC measurement conditions)
The HPLC measurement conditions were as follows.
Apparatus: High performance liquid chromatography apparatus: ACQUITY UPLC H-Class system (Nihon Waters).
Column: A stainless steel tube having an inner diameter of 2.1 mm and a length of 5 cm is packed with 1.7 μm octadecylsilylated silica gel for liquid chromatography.

(Test Results)
The results are shown in Table 5 and FIG.

In the film-coated tablets of Example 2, which used hypromellose (HPMC) as the coating agent, the test samples stored for 1 month under normal conditions and those stored for 1 month at 60° C. quickly dissolved. In contrast, in the film-coated tablets of Comparative Example 2, which used polyvinyl alcohol (PVA) as the coating agent, the test samples stored for 1 month under normal conditions quickly dissolved, but the test samples stored for 1 month at 60° C. slowly dissolved.

Claims (9)

A mixing step (A) of mixing a drug and a powder containing hydroxypropyl cellulose powder to form a mixture;
A granulation step (B) of adding a granulation liquid to the mixture to form a granule;
A drying step (C) of drying the granulated product. The method for producing granules according to claim 1, wherein the mixing step (A) is a step of mixing a drug, hydroxypropyl cellulose powder, and crystalline cellulose powder to form a mixture, and the angle of repose of the crystalline cellulose powder is 40° or less. A mixing step (D) of adding a powder containing an excipient and a disintegrant to the granules obtained by the method for producing granules according to claim 1 or 2 and mixing them to form a tablet powder;
A tableting step (E) of compressing the tablet powder to form a plain tablet;
A method for producing a film-coated tablet, comprising: a coating step (F) of coating the uncoated tablet with a coating liquid. The method for producing film-coated tablets according to claim 3, wherein the granulation liquid is water. The method for producing a film-coated tablet according to claim 4, wherein the coating solution contains hypromellose. The method for producing a film-coated tablet according to claim 5, wherein the drug is lacosamide. A granule containing a drug, hydroxypropyl cellulose and microcrystalline cellulose,
The angle of repose of the granules is 45° or less;
Granules, the particle size distribution of which, when measured under dry conditions using a laser diffraction/scattering method, is such that the value calculated using the following formula (1) is 3.0 or less.
(D ₉₀ - _{D 10} )/D ₅₀ ...(1) Adding an excipient and a disintegrant to the granules according to claim 7 and mixing them to form a tablet powder;
A film-coated tablet is obtained by compressing the tablet powder into a plain tablet and forming a coating layer on the outside of the plain tablet. The film-coated tablet according to claim 8, wherein the drug is lacosamide.