TWI878494B - Novel granules and method for producing the same - Google Patents

Abstract

The present invention provides a granule containing melatonin as an active ingredient. A method for producing a granule containing melatonin and a granule produced by the method, wherein the method comprises: a granulation step of mixing orally soluble core particles and melatonin in the presence of a binder to obtain naked melatonin particles; and a drying step of drying the naked melatonin particles obtained by the granulation step.

Description

Novel granules and method for producing the same

The present invention relates to a novel granule containing melatonin and a method for producing the same. More specifically, the present invention relates to a novel granule containing melatonin, which is easy to take and has immediate release, and a method for producing the granule.

Melatonin (N-acetyl-5-methoxytryptamine), an endogenous hormone secreted from the pineal gland of vertebrates, is known to be involved in sleep and regulation of body rhythms and has been used to treat sleep disorders. On the other hand, according to a survey on the use of melatonin in the treatment of sleep disorders in patients with neurodevelopmental disorders, melatonin is used in a wide range of age groups and in a variety of dosages (Non-patent Documents 1 and 2).

[Prior art literature] [Non-patent literature] Non-patent literature 1: Nakagawa Eiji, "Effects of drug treatment for autism disorders in children", "New Neuromedicine", Vol. 18, No. 1, 2013, p. 13-21. Non-patent literature 2: Fukunaga Michiro et al., "National survey on the use of melatonin and ramelteon in children", "Brain and Development", Vol. 47, 2015, p. 23-27.

[Problem the invention is intended to solve]

Although melatonin is widely used for the treatment and relief of sleep disorders, only tablets or orally disintegrating preparations have been used as melatonin preparations so far. However, considering that melatonin is used by a wide range of subjects of different ages and symptoms, a granule preparation that is easier to take is desired for subjects who have difficulty swallowing tablets, the elderly, and infants. [Means for solving the problem]

That is, the present invention is the following (1) to (4). (1) A method for producing a granule containing melatonin, characterized in that it includes: a granulation step, in which core particles having oral solubility and melatonin are mixed in the presence of a binder to obtain naked melatonin particles; and a drying step, in which the naked melatonin particles obtained by the granulation step are dried. (2) A method for producing a granule containing melatonin, characterized in that it includes a granulation and drying step, in which core particles having oral solubility and melatonin are mixed in the presence of a binder, and the prepared product is dried. (3) A granule containing melatonin, produced by the method of (1) or (2). (4) A granule containing melatonin, comprising particles in which melatonin is bound to an orally soluble core particle, wherein the 15-minute dissolution value of melatonin in the second method of the Japanese Pharmacopoeia dissolution test (slurry method, solvent: water, volume: 900 mL, rotation speed: 50 rpm) is 80% or more.

In the manufacturing methods and granule preparations of the present invention (1) to (4), the core particles having oral solubility can use particles containing water-soluble sugar or sugar alcohol as the main component, preferably, mannitol, trehalose, erythritol, sucrose or powdered sugar can be used. [Effect of the invention]

According to the present invention, a granule containing melatonin as an active ingredient can be provided. In addition, according to the present invention, a granule containing melatonin having excellent fluidity and dissolution can be provided.

Hereinafter, the present invention will be described in detail.

One aspect of the present invention is a granule containing melatonin, comprising particles in which core particles having oral solubility are bound to melatonin, wherein the 15-minute dissolution value of melatonin in the second method of the Japanese Pharmacopoeia dissolution test (slurry method, solvent: water, volume: 900 mL, rotation speed: 50 rpm) is 80% or more.

Due to such a form, the granules containing melatonin can be quickly dissolved in the mouth when orally taken, so that the granules containing melatonin can be used as an effective sleep disorder improving agent.

In a preferred embodiment, the Hausner Ratio of the granules of the present invention is 1.00 to 1.25. The "Hausner Ratio" is an index of the flowability of a powder specified in the Japanese Pharmacopoeia. When the Hausner Ratio is 1.00 to 1.11, the degree of flowability is very good, when the Hausner Ratio is 1.12 to 1.18, it is good, and when the Hausner Ratio is 1.19 to 1.25, it is slightly good. Therefore, by setting the Hausner Ratio to 1.00 to 1.25, good flowability can be obtained, and thus, the following effect can be achieved, that is, the operation of small package packaging or administration at the manufacturing site or pharmacy becomes easy.

In the present invention, the term "core particle" refers to a particle that is located approximately in the center of each particle constituting the granule preparation of the present invention and constitutes the core. In the present invention, the core particle uses a particle that is orally soluble. "Particles that are orally soluble" refer to particles that are dissolved by saliva in the mouth and contribute to the normal release of the granule preparation, especially the 15-minute dissolution value of melatonin reaching 80% or more.

In a preferred form, as core particles with oral solubility, particles with water-soluble sugar or sugar alcohol as the main component can be used, preferably particles with at least one substance selected from mannitol, trehalose, erythritol, sucrose, and powdered sugar as the main component (including monomers of these substances). Among them, it is particularly preferred to use one selected from mannitol, trehalose or erythritol, and mannitol is particularly preferred. By using water-soluble sugar or sugar alcohol as the core particles, the obtained granules dissolve quickly in the mouth and have appropriate sweetness and/or refreshing feeling, so the following excellent effect can be obtained, that is, it is easy to take, especially for the elderly and infants.

In addition, the shape of the core particles is not particularly limited, and it is preferable to use roughly spherical particles. The closer the shape of the particles is to a spherical shape, the more evenly melatonin can be bound, which helps stabilize the quality.

As the binder, various substances commonly used in the production of granules such as hydroxypropyl cellulose or hydroxypropyl methyl cellulose can be used. Preferably, a substance having a viscosity of 60 to 400 mPa·s (Japanese Pharmacopoeia Viscosity Determination Method 2, 20°C) can be used during granulation, and more preferably, a substance having a viscosity of 150 to 400 mPa·s (Japanese Pharmacopoeia Viscosity Determination Method 2, 20°C) can be used. By using a binder under such conditions, the generation of fine powder (powder passing through a sieve of No. 200 mesh (75μm)) can be suppressed, and granules with good fluidity can be obtained.

Specifically, hydroxypropyl cellulose having an average molecular weight of 140,000 to 700,000 or a weight average molecular weight of 30,000 to 60,000 obtained by GPC (Gel Permeation Chromatography) can be preferably used, and hydroxypropyl cellulose having an average molecular weight of 500,000 to 700,000 obtained by GPC can be more preferably used.

The amount of melatonin contained in the granules of the present invention does not need to be particularly limited as long as it is a concentration that is easy to handle when administering the necessary amount. Preferably, the melatonin content can be 0.05 to 1.0% by weight.

The granules of the present invention can be orally administered as a safe and effective agent for improving sleep difficulty by the same method as conventional granules or dry syrups, and can be produced, for example, by the production method shown below as another aspect or still another aspect of the present invention.

Another aspect of the method for producing melatonin-containing granules of the present invention is characterized in that it includes: a granulation step of mixing orally soluble core particles with melatonin in the presence of a binder to obtain naked melatonin particles; and a drying step of drying the naked melatonin particles obtained by the granulation step.

The granulation step can be performed by adding melatonin to the core particles and mixing them in the presence of a binder added simultaneously with the melatonin or a binder added separately. In addition, the granulation step can be performed by adding a suspension or solution of melatonin to the core particles having oral solubility and mixing them under the condition that the core particles are not completely dissolved.

Alternatively, the drying step may be performed by heating the obtained bare particles while stirring them and applying negative pressure as desired to dry the sample.

Another aspect of the method for producing melatonin-containing granules of the present invention is characterized in that it includes a granulation and drying step, in which orally soluble core particles are mixed with melatonin in the presence of a binder, and then dried.

Here, the granulation and drying step can be performed by a method in which melatonin is added to the core particles, and in the presence of a binder added simultaneously with the melatonin or a binder added separately, negative pressure is applied as desired, and the sample is dried while being mixed using warm air, etc. Furthermore, the granulation and drying step can be a step in which a suspension or solution of melatonin and a binder are added to the core particles having oral solubility under the condition that the core particles are not completely dissolved, and the obtained preparation is mixed and dried.

In the granulation step, the drying step, and the granulation drying step, the temperature of the sample can be the conditions usually used in the same step, but preferably the conditions that do not cause deterioration (decomposition, etc.) of each raw material. In addition, the air volume can be adjusted by controlling the pressure difference of the fluidized bed so that the powder and granules are in a better fluid state.

In the granulation step and the granulation drying step, melatonin can be added to the core particles by various methods. For example, a method of adding melatonin to the core particles in a solid state, or a method of adding a suspension or solution of melatonin to the core particles can be used. Among these methods, the method of adding a suspension or solution of melatonin to the core particles is more preferable because it is easier to mix melatonin and the core particles uniformly. Here, the suspension of melatonin does not need to be particularly limited as long as the melatonin can be dispersed, but it is preferably used that the melatonin is suspended in water or a liquid in which the melatonin is suspended in a mixture of water and alcohol (alcohol/water = 0.5/1 to 2/1, preferably 1/1). The melatonin solution is not particularly limited as long as it can dissolve melatonin, but an ethanol solution of melatonin or a liquid obtained by dissolving melatonin in a mixed solution of ethanol and water is preferably used.

In the granulation step and the granulation drying step, the addition of the binder to the core particles can be performed by various methods, similar to the addition of melatonin. For example, the binder can be added to the particles in a solid state, or in a solution or suspension state. In the case of a solution, an aqueous solution can be preferably used.

In the granulation step and the granulation drying step, as long as the timing of adding the binder can make the binder exist in the system at the same time when the core particles and melatonin are mixed, there is no need to limit it, that is, as long as it is "in the presence of the binder", it can be added to the core particles at the same time as melatonin, or it can be added to the core particles at a different time from the time of adding melatonin. For example, it can be added to the core particles before adding melatonin, or it can be added to the core particles after adding melatonin. Alternatively, it can be done by adding a liquid in which melatonin and the binder are dissolved in a mixture of ethanol and water to the core particles. In addition, the following method can also be used, that is, melatonin and the binder are added to the core particles together in a solid state and mixed, and a solvent is added thereto and transferred to the granulation step or the granulation drying step.

As described above, various substances commonly used in the production of granules such as hydroxypropyl cellulose and hydroxypropyl methyl cellulose can be used as the binder. Preferably, a substance having a viscosity of 60 to 400 mPa·s (Japanese Pharmacopoeia Viscosity Determination Method Second Method, 20°C) during granulation is used, and more preferably a substance having a viscosity of 150 to 400 mPa·s (Japanese Pharmacopoeia Viscosity Determination Method Second Method, 20°C) is used. By using a binder under such conditions, the generation of fines can be suppressed, and granules with good fluidity can be obtained.

Specifically, hydroxypropyl cellulose having an average molecular weight of 140,000 to 700,000 as measured by GPC (Gel Permeation Chromatography) or hydroxypropyl cellulose having a weight average molecular weight of 30,000 to 60,000 can be preferably used, and hydroxypropyl cellulose having an average molecular weight of 500,000 to 700,000 as measured by GPC can be more preferably used.

In the granulation step and the granulation drying step, the amount of liquid in the case of using a suspension or solution of melatonin is the amount of liquid in which the core particles cannot be completely dissolved. The amount of liquid in this case can be appropriately adjusted based on data related to the solubility of the core particles relative to the solvent used. In a preferred form, the amount of liquid in the suspension or solution can also be adjusted so that the viscosity of the binder is 60 to 400 mPa·s to meet the conditions in the preferred form related to the binder described above. By setting such conditions, granules with less fine particles and good fluidity can be obtained.

The production method of the present invention may further include the steps of screening the obtained particles, mixing a fluidizing agent such as light anhydrous silicic acid into the obtained particles, etc.

The manufacturing method of the present invention can be implemented by using various devices for manufacturing granules. For example, it can be implemented by a method commonly used in the manufacture of granules, such as a fluidized bed granulation method and a stirring granulation method. When a fluidized bed granulation method is used, melatonin can be added by spraying a suspension or solution of melatonin onto the core particles in the fluidized bed during the granulation drying step. [Example]

The present invention is illustrated by the following specific implementations, but the present invention is not limited to these implementations. Without departing from the scope or purpose of the present invention as defined by the attached patent application, technical personnel in this field can make various changes and modifications to these implementations.

[Reference Examples 1, 2] Research on manufacturing using different binders (1) Manufacturing of granule samples The basic research on the manufacturing of granules with mannitol as the core particle was conducted using binders of different viscosities. Experiments were conducted using hydroxypropyl methylcellulose (TC-5E manufactured by Shin-Etsu Chemical Co., Ltd., Reference Example 1) and hydroxypropyl cellulose (HPC-L manufactured by Nippon Soda Co., Ltd., Reference Example 2) as binders. The purpose of this experiment was to confirm whether fine particles were generated in granules manufactured using binders of different viscosities, so melatonin was not used in the experiment.

Hydroxypropyl methylcellulose (TC-5E manufactured by Shin-Etsu Chemical Co., Ltd., Reference Example 1) or hydroxypropyl cellulose (HPC-L manufactured by Nippon Soda Co., Ltd., Reference Example 2) was dissolved in 4.04 kg of pure water to prepare a hydroxypropyl methylcellulose bound liquid and a hydroxypropyl cellulose bound liquid. 19.4 kg of D-mannitol was added to a vertical granulator, and the entire amount of the prepared hydroxypropyl methylcellulose bound liquid was added, and granulation was performed for 5 minutes. The obtained granulated product was sized by a powder screening machine (filter mesh: 2575 μm) to prepare wet granules. The obtained wet granules were dried at 60°C for 60 minutes, crushed using a granulator, and then 0.2 kg of light anhydrous silicic acid was added and mixed to obtain a granule sample (Reference Example 1). In addition, a granule sample was prepared using the same method as Reference Example 1, except that hydroxypropyl cellulose was used as a binding liquid, as Reference Example 2.

(2) Determination of fine powder amount Approximately 50 g of each of the obtained granule samples were weighed and sieved with a No. 200 sieve (75 μm) according to the method described in the Japanese Pharmacopoeia Fineness Determination Method, Method 2 Sieving Method (Mechanical Oscillation Method), and the amount of powder (amount of fine powder) that passed through the No. 200 sieve was measured. As a result, the amount of fine powder was 33.9% in the case of granules produced using hydroxypropyl methyl cellulose (Reference Example 1) and 13.9% in the case of granules produced using hydroxypropyl cellulose (Reference Example 2). From this result, it was confirmed that no matter which binder was used, a granular preparation with suppressed fines generation could be produced, and in particular, when hydroxypropyl cellulose was used, the generation of fines was further suppressed.

[Examples 1 to 4] Research on the production of various core particles (1) Production of granules 0.202 kg of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-L) was dissolved in a mixture of 2.02 kg of ethanol and 2.02 kg of purified water to prepare a binding solution. 19.4 kg of the core particles listed in Table 1 and 0.2 kg of melatonin were placed in a vertical granulator, and the entire amount of binding solution was added, and granulation was performed for 5 minutes. The obtained granules were sized by a powder screening machine (filter mesh: 2575 μm) to prepare wet granules. The obtained wet granules were dried at 60° C. for 60 minutes, crushed using a granulator, and then 0.2 kg of light anhydrous silicic acid was added and mixed to obtain various granule samples.

(2) Determination of fines Approximately 50 g of each granular sample was weighed and sieved with a No. 200 sieve (75 μm) according to the method described in the Japanese Pharmacopoeia Fineness Determination Method, Method 2 Sieving Method (Mechanical Oscillation Method), and the amount of powder (amount of fines) that passed through the No. 200 sieve was measured. The results are shown in Table 1. It was confirmed that all core particles suppressed the generation of fines.

[Table 1] Amount of core particles and fine powder used in each granule sample Embodiment Core particles Amount of fines (%) (Amount of fines passing through 75μm) Embodiment 1 D-Mannitol 11.6 Embodiment 2 Powdered sugar 2.0 Embodiment 3 Trehalose 3.4 Embodiment 4 Erythritol 0.0

[Example 5] Evaluation of the flowability of granules prepared using hydroxypropyl cellulose as a binder (1) Preparation of granules To a solution prepared by dissolving 0.08 kg of melatonin in 9.8 kg of anhydrous ethanol, 9.8 kg of purified water and 0.4 kg of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-M) were added and dissolved to prepare a melatonin solution. 39.12 kg of D-mannitol was placed in a fluidized bed granulation dryer, and the entire amount of the prepared melatonin solution was sprayed thereon at a spray rate of 250 mL/min. Furthermore, under the same conditions, 1 kg of 50% ethanol was sprayed, and the fluidized bed was operated to perform granulation (intake temperature: 80°C), and the mixture was dried until a constant amount was reached (drying end point: exhaust temperature 50°C). The obtained particles were sieved with a 30-mesh sieve, and 0.4 kg of light anhydrous silicic acid was added and mixed to obtain 0.2% melatonin granules.

(2) Determination of the amount of fine powders Approximately 50 g of the obtained granules were weighed and sieved with a No. 200 sieve (75 μm) according to the method described in the second method of the Japanese Pharmacopoeia Fineness Determination Method Sieving Method (Mechanical Oscillation Method), and the amount of powder (amount of fine powders) passing through the No. 200 sieve was measured. As a result, the amount of fine powders was 3.76%. From this result, it can be confirmed that the granules in which the generation of fine powders is sufficiently suppressed can be produced by the production method of the present invention.

(3) Determination of Hausner ratio 100 g of the obtained granules were weighed and placed in a 250 mL measuring cylinder. The bulk specific volume (bulk density: mL/g) and the dense specific volume (tapped density: mL/g) were calculated according to the method described in the Japanese Pharmacopoeia. The Hausner ratio was calculated based on the obtained bulk specific volume and dense specific volume. The obtained Hausner ratio was 1.06, which was judged to have extremely good fluidity.

[Example 6] Evaluation of flowability and dissolution properties in a 40 kg scale (1) Preparation of granules 9.8 kg of pure water and 0.4 kg of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-M) were added to a solution prepared by dissolving 0.08 kg of melatonin in 9.8 kg of anhydrous ethanol to prepare a melatonin solution. 39.12 kg of D-mannitol was placed in a fluidized bed granulation dryer, and the entire amount of the prepared melatonin solution was sprayed thereon at a spray rate of 250 mL/min. Furthermore, under the same conditions, 1 kg of 50% ethanol was sprayed, and the fluidized bed was operated to granulate (intake temperature: 80°C), and dried to a constant amount (drying end point: exhaust temperature 50°C). The obtained particles were sieved with a 30-mesh sieve, and 0.4 kg of light anhydrous silicic acid was added and mixed to obtain 0.2% melatonin granules. A total of 3 batches were manufactured.

(2) Determination of the amount of fine powders Approximately 50 g of the obtained granules were weighed, and the amount of fine powders was determined in the same manner as in Example 5. The amounts of fine powders in each batch produced were 5.64%, 5.80%, and 4.68%. From this result, it can be confirmed that granules with sufficiently suppressed generation of fine powders can be produced in the same manner as in Example 5.

(3) Measurement of Hausner ratio The Hausner ratio of the obtained granules was measured in the same manner as in Example 5. The Hausner ratio values of the produced batches were 1.24, 1.11, and 1.11, which were judged to have slightly good or very good flowability.

(4) Determination of dissolution properties The granules obtained were subjected to the 15-minute dissolution value of melatonin using the second method of the Japanese Pharmacopoeia dissolution test method (test solution: water, test solution volume: 900 mL, rotation speed: 50 rpm). The amount of melatonin dissolved was determined by reversed phase liquid chromatography under the following conditions and by comparison with the measured value in a melatonin standard substance solution.

Liquid chromatography test conditions Measurement wavelength: 223nm Column: Fill octadecylsilane bonded silica gel with a diameter of 3μm into a stainless steel tube with an inner diameter of 4.6mm and a length of 75mm. Column temperature: 25℃ Mobile phase: 18mmol/L phosphate buffer at pH 3.0/acetonitrile mixture for liquid chromatography (4:1) Flow rate: 1.5mL per minute

The 15-minute dissolution values (average values) of each batch were 101%, 102%, and 103%, respectively, confirming that the drug had sufficient normal release.

(5) Confirmation of melatonin content in granules 3 g of each granule was dissolved in a mixture of methanol/water (7:3) to prepare 500 mL of liquid as a sample, and analyzed by high-performance liquid chromatography under the same conditions as the dissolution test. The melatonin content in the granule sample was calculated based on comparison with the analytical value of the melatonin standard substance. As a result, the melatonin content in all batches was 0.2%.

[Example 7] Evaluation of flowability and dissolution properties in the case of 120 kg scale production (1) Production of granules 29.4 kg of pure water and 1.2 kg of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-M) were added to a solution prepared by dissolving 0.24 kg of melatonin in 29.4 kg of anhydrous ethanol to prepare a melatonin solution. 117.36 kg of D-mannitol was placed in a fluidized bed granulation dryer, and the entire amount of the melatonin solution prepared above was sprayed thereon at a spray rate of 250 mL/min. Furthermore, under the same conditions, 3 kg of 50% ethanol was sprayed, and the fluidized bed was operated to perform granulation (intake temperature: 80°C), and the mixture was dried until a constant amount was reached (drying end point: exhaust temperature 50°C). The obtained particles were sieved with a 30-mesh sieve, and 1.2 kg of light anhydrous silicic acid was added and mixed to obtain 0.2% melatonin-containing granules.

(2) Determination of the amount of fine powders Weigh about 50 g of the obtained granules and determine the amount of fine powders in the same manner as in Example 5. The amount of fine powders was 1.82%.

(3) Measurement of Hausner ratio The Hausner ratio of the obtained granules was measured in the same manner as in Example 5. The Hausner ratio was 1.10, indicating that the granules had extremely good fluidity.

(4) Determination of dissolution properties For the obtained granules, the 15-minute dissolution value was determined using the same method as in Example 6. The 15-minute dissolution value (average value) was 99.8%, confirming that the granules had sufficient normal release properties.

(5) Confirmation of melatonin content in granules The melatonin content of the obtained granules was determined using the same method as in Example 6. As a result, the melatonin content in the granules was 0.2%.

[Example 8] Study on the influence of the difference in the spraying amount of melatonin solution in a fluidized bed granulation dryer (1) Preparation of granules Granules containing 0.2% melatonin were prepared under the same conditions as in Example 6, except that the spraying amount of the D-mannitol melatonin solution in the fluidized bed granulation dryer was set to 200 mL/min.

(2) Determination of the amount of fine powders Weigh about 50 g of the obtained granules and determine the amount of fine powders in the same manner as in Example 5. The amount of fine powders was 4.00%.

(3) Measurement of Hausner ratio The Hausner ratio of the obtained granules was measured in the same manner as in Example 5. The Hausner ratio was 1.07, indicating that the granules had extremely good fluidity.

(4) Determination of dissolution properties For the obtained granules, the 15-minute dissolution value was determined using the same method as in Example 6. The 15-minute dissolution value (average value) was 98.2%, confirming that the granules had sufficient normal release. Based on the above results, even if the spray volume of the melatonin solution was reduced to 200 mL/min, the amount of fine particles, fluidity, and dissolution properties were almost unaffected, confirming that good granules could be produced.

(Example 9) Study on the influence of the difference in the spraying amount of melatonin solution in the fluidized bed granulation dryer (1) Preparation of granules Granules containing 0.2% melatonin were prepared under the same conditions as in Example 6, except that the spraying amount of the melatonin solution sprayed with D-mannitol into the fluidized bed granulation dryer was set to 300 mL/min.

(2) Determination of the amount of fine powders Weigh about 50 g of the obtained granules and determine the amount of fine powders in the same manner as in Example 5. The amount of fine powders was 5.52%.

(3) Measurement of Hausner ratio The Hausner ratio of the obtained granules was measured in the same manner as in Example 5. The Hausner ratio was 1.15, indicating good fluidity.

(4) Determination of dissolution properties For the obtained granules, the 15-minute dissolution value was determined using the same method as in Example 6. The 15-minute dissolution value (average value) was 98.1%, confirming that it had sufficient normal release. Based on the above results, even if the spray volume of the melatonin solution was increased to 300 mL/min, the amount of fine particles, fluidity, and dissolution properties were almost unaffected, confirming that good granules can be produced. [Industrial Applicability]

According to the present invention, a granule containing melatonin can be provided, which has excellent fluidity and dissolution properties, and is easy to take even for subjects who have difficulty swallowing tablets, the elderly or infants, and can exert a sleep-inducing effect in a timely manner.

without.

without.

without.

Claims (8)

A method for producing a granule containing melatonin comprises the following steps: A granulation step, in the presence of a binder of a hydroxypropyl cellulose solution with a viscosity of 150-400 mPa·s, adding a suspension or solution of melatonin to core particles for mixing to obtain naked melatonin particles; and A drying step, drying the naked melatonin particles obtained by the granulation step, wherein the suspension or solution of melatonin is a suspension of melatonin or a liquid in which melatonin is dissolved in ethanol or a mixture of ethanol and water, and the core particles are particles having at least one selected from mannitol, trehalose, erythritol, sucrose or powdered sugar as a main component, The content of melatonin in the obtained granules is 0.05 to 1.0% by weight. A method for producing a granule containing melatonin as described in claim 1, wherein the granulation step is a step of adding a suspension or solution of melatonin to the core particles having oral solubility and mixing the mixture under the condition that the core particles are not completely dissolved. A method for producing a granule containing melatonin, comprising a granulation and drying step, wherein a suspension or solution of melatonin is added to core particles in the presence of a binder of a hydroxypropyl cellulose solution having a viscosity of 150 to 400 mPa·s, the mixture is mixed, and the preparation is dried, wherein the suspension or solution of melatonin is a suspension of melatonin or a liquid in which melatonin is dissolved in ethanol or a mixture of ethanol and water, and the core particles are particles containing at least one selected from mannitol, trehalose, erythritol, sucrose or powdered sugar as a main component, and the content of melatonin in the obtained granules is 0.05 to 1.0% by weight. A method for producing a granule containing melatonin as described in claim 3, wherein the granulation drying step is a step of adding a suspension or solution of melatonin and the binder to the core particles having oral solubility under the condition that the core particles are not completely dissolved, and mixing and drying the obtained preparation. The method for producing granules containing melatonin as described in claim 3, wherein the granulation drying step is carried out using a fluidized bed granulation method. A method for producing a melatonin-containing granule as described in claim 5, wherein melatonin is added in the granulation drying step by spraying a suspension or solution of melatonin onto the core particles in a fluidized bed. A granule containing melatonin, which is produced by the production method as described in claim 1 or 3, and is characterized in that it contains particles in which core particles having oral solubility are combined with melatonin, and the 15-minute dissolution value of melatonin in the second method of the Japanese Pharmacopoeia dissolution test is above 80%, and the conditions of the second method of the Japanese Pharmacopoeia dissolution test are a slurry method, a solvent is water, a volume is 900 mL, and a rotation speed is 50 rpm. The melatonin-containing granules as described in claim 7, wherein the Hausner ratio is 1.00 to 1.25.