New granules and their manufacturing method

Abstract

To provide methods for producing granules having melatonin as an active ingredient and such granules.SOLUTION: A production method for melatonin-containing granules includes a granulation step for mixing melatonin and core particles having oral solubility in the presence of a binding agent to obtain melatonin granules, and a drying step for drying the melatonin granules obtained by the granulation step. There are also provided granules produced by the method.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a novel granule containing melatonin and a method for producing the same, and more particularly to a novel granule containing melatonin, which is easy to take and has immediate release properties, and a method for producing the granule. [Background technology]

[0002] Melatonin (N-acetyl-5-methoxytryptamine), a biological hormone secreted by the pineal gland of vertebrates, is known to be involved in regulating sleep and biological rhythms, and has been used to treat sleep disorders. On the other hand, a survey of melatonin use in the treatment of sleep disorders in patients with neurodevelopmental disorders has reported that melatonin is used in a wide range of age groups and at a wide variety of dosages (Non-patent Document 1, Non-patent Document 2). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Eiji Nakagawa, "Effects of Drug Treatment for Childhood Autistic Disorder," Latest Psychiatry, Vol. 18, No. 1, 2013, pp. 13-21 [Non-patent document 2] Michio Fukunaga et al., "National Survey on Pediatric Use of Melatonin and Remelteon," Brain and Development, Vol. 47, 2015, pp. 23-27 Summary of the Invention [Problem to be solved by the invention]

[0004] Although melatonin is widely used to treat and alleviate sleep disorders, melatonin formulations have only been available in tablet or orally disintegrating form until now. However, melatonin is expected to be used in a wide range of ages and symptoms, and a granular formulation that is easier to take is desired for patients who have difficulty swallowing tablets, as well as the elderly and infants. [Means for solving the problem]

[0005] That is, the present invention includes the following [1] to [4]. [1] A method for producing melatonin-containing granules, comprising a granulation step in which orally soluble core particles and melatonin are mixed in the presence of a binder to obtain melatonin granules, and a drying step in which the melatonin granules obtained in the granulation step are dried. [2] A method for producing melatonin-containing granules, characterized by including a granulation and drying step in which orally soluble core particles and melatonin are mixed in the presence of a binder while the preparation is dried. [3] Melatonin-containing granules manufactured by the method of [1] or [2]. [4] Melatonin-containing granules containing particles in which melatonin is bound to core particles that are orally soluble, and in which the melatonin dissolution value after 15 minutes is 80% or more according to the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method, solvent: water, volume: 900 mL, rotation speed: 50 rpm).

[0006] In the manufacturing methods and granule preparations of the present invention described above in [1] to [4], the orally soluble core particles may be particles whose main component is a water-soluble sugar or sugar alcohol, and preferably, mannitol, trehalose, erythritol, sucrose, or powdered sugar. [Effects of the Invention]

[0007] The present invention makes it possible to provide granules containing melatonin as an active ingredient, and melatonin-containing granules with excellent flowability and dissolution properties. DETAILED DESCRIPTION OF THE INVENTION

[0008] The present invention will be specifically described below.

[0009] One aspect of the present invention is a melatonin-containing granule comprising particles in which melatonin is bound to orally soluble core particles, and in which the 15-minute melatonin dissolution value measured in Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method, solvent: water, volume: 900 mL, rotation speed: 50 rpm) is 80% or more.

[0010] In this embodiment, the melatonin-containing granules can be quickly dissolved in the mouth when orally administered, and can therefore be used as an effective agent for improving sleep disorders.

[0011] In a preferred embodiment, the granules of the present invention have a Hausner ratio of 1.00 to 1.25. The "Hausner ratio" is an index of powder fluidity specified in the Japanese Pharmacopoeia, with a value of 1.00 to 1.11 indicating extremely good fluidity, a value of 1.12 to 1.18 indicating good fluidity, and a value of 1.19 to 1.25 indicating somewhat good fluidity. Therefore, by setting the Hausner ratio to 1.00 to 1.25, good fluidity can be achieved, which has the effect of making the granules easier to handle when dividing into smaller portions at manufacturing sites, pharmacies, etc., and when taking the granules.

[0012] In the present invention, the term "core particle" refers to a particle located approximately at the center of each particle constituting the granule formulation of the present invention, which serves as a core. In the present invention, particles having oral solubility are used as the core particle. "Orosoluble particle" refers to a particle that dissolves in saliva in the mouth, thereby contributing to the immediate release of the granule, particularly to a 15-minute melatonin dissolution value of 80% or more.

[0013] In a preferred embodiment, particles primarily composed of a water-soluble sugar or sugar alcohol can be used as the orally soluble core particles, and particles primarily composed of at least one substance selected from mannitol, trehalose, erythritol, sucrose, and powdered sugar (including these substances alone) are preferred. Among these, one selected from mannitol, trehalose, and erythritol is particularly preferred, with mannitol being particularly preferred. By using a water-soluble sugar or sugar alcohol as the core particles, the resulting granules dissolve quickly in the mouth and have a moderate sweetness and / or a refreshing sensation, providing excellent effects such as ease of administration, particularly for the elderly and infants.

[0014] The shape of the core particles is not particularly limited, but approximately spherical particles are preferred. The closer the particle shape is to a sphere, the more uniformly melatonin can be bound, contributing to stable quality.

[0015] The binder may be any of a variety of substances commonly used in the production of granules, such as hydroxypropyl cellulose or hypromellose. Preferably, a substance with a viscosity of 60 to 400 mPa·s (Viscosity Measurement Method 2 of the Japanese Pharmacopoeia, 20°C) during granulation is used, and more preferably a substance with a viscosity of 150 to 400 mPa·s (Viscosity Measurement Method 2 of the Japanese Pharmacopoeia, 20°C) is used. By using a binder with such properties, the generation of fine powder (powders that pass through a No. 200 sieve (75 μm)) is suppressed, and granules with good flowability can be obtained.

[0016] Specifically, hydroxypropyl cellulose having an average molecular weight of 140,000 to 700,000 as measured by GPS (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 GPS can be more preferably used.

[0017] The melatonin content of the granules according to the present invention is not particularly limited as long as it is a concentration that allows for easy administration of the required amount, and is preferably 0.05 to 1.0 wt %.

[0018] The granules of the present invention can be used orally as a safe and effective agent for improving difficulty in falling asleep in the same manner as ordinary granules or dry syrups, and can be manufactured, for example, by the manufacturing method shown below as another embodiment of the present invention, or as yet another embodiment.

[0019] Another aspect of the present invention is a method for producing melatonin-containing granules, comprising a granulation step of mixing orally soluble core particles and melatonin in the presence of a binder to obtain melatonin element granules, and a drying step of drying the melatonin element granules obtained in the granulation step.

[0020] The granulation step can be carried out by adding melatonin to core particles and mixing them in the presence of a binder added simultaneously with or separately from the melatonin. Furthermore, the granulation step can be a step of adding a suspension or solution of melatonin to orally soluble core particles and mixing them under conditions in which the core particles do not completely dissolve.

[0021] The drying step can be carried out by heating the obtained elementary granules while stirring, and optionally applying negative pressure to dry the sample.

[0022] Yet another aspect of the present invention is a method for producing melatonin-containing granules, which comprises a granulation and drying step in which orally soluble core particles and melatonin are mixed in the presence of a binder and dried.

[0023] The granulation and drying step can be carried out by adding melatonin to core particles, and then drying the sample while mixing it with warm air or the like, in the presence of a binder added simultaneously with or separately from the melatonin, optionally under negative pressure.Furthermore, the granulation and drying step can be a step of adding a melatonin suspension or solution and a binder to orally soluble core particles under conditions in which the core particles do not completely dissolve, and then drying the resulting preparation while mixing.

[0024] In the granulation, drying, and granulation / drying processes, the sample temperature can be set to the conditions normally used in the same processes, but it is preferable to set the conditions so that the raw materials do not change in quality (decomposition, etc.). The air volume can be adjusted by controlling the differential pressure of the fluidized bed so that the powder and granules are in a suitable fluidized state.

[0025] Various methods can be used to add melatonin to core particles during the granulation process and the granulation and drying process. For example, a method in which melatonin is added as a solid to core particles or a method in which a suspension or solution of melatonin is added to core particles can be used. Of these methods, the method in which a suspension or solution of melatonin is added to core particles is more preferred because it facilitates more uniform mixing of melatonin and core particles. Here, the melatonin suspension need not be particularly limited as long as it can disperse melatonin, but a water suspension of melatonin or a suspension of melatonin in a mixture of water and alcohol (alcohol / water = 0.5 / 1 to 2 / 1, preferably 1 / 1) can be preferably used. Furthermore, the melatonin solution need not be particularly limited as long as it can dissolve melatonin, but an ethanol solution of melatonin or a solution of melatonin dissolved in a mixture of ethanol and water can be preferably used.

[0026] In the granulation and granulation drying processes, the binder can be added to the core particles in the same manner as the addition of melatonin, using various methods. For example, the binder can be added to the particles as a solid, or in the form of a solution or suspension. In the case of a solution, an aqueous solution is preferably used.

[0027] In the granulation step and the granulation drying step, the timing of adding the binder is not limited as long as it can be present in the system simultaneously when the core particles and melatonin are mixed; that is, "in the presence of the binder." The binder may be added to the core particles simultaneously with melatonin or at a different time from the addition of melatonin. For example, the binder may be added to the core particles prior to the addition of melatonin, or may be added to the core particles after the addition of melatonin. Alternatively, the binder may be added to the core particles by dissolving melatonin and the binder in a mixture of ethanol and water. Alternatively, the binder may be added to the core particles as solids, mixed, and then a solvent may be added to the mixture, followed by the granulation step or the granulation drying step.

[0028] The binder may be any of various substances commonly used in the production of granules, such as hydroxypropyl cellulose or hypromellose. Preferably, a substance with a viscosity of 60 to 400 mPa·s (Viscosity Measurement Method 2 of the Japanese Pharmacopoeia, 20°C) during granulation is used, and more preferably a substance with a viscosity of 150 to 400 mPa·s (Viscosity Measurement Method 2 of the Japanese Pharmacopoeia, 20°C) is used. By using a binder with such properties, the generation of fine powder can be suppressed, and granules with good flowability can be obtained.

[0029] Specifically, hydroxypropyl cellulose having an average molecular weight of 140,000 to 700,000 as determined by GPS (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 determined by GPS can be more preferably used.

[0030] When using a melatonin suspension or solution in the granulation and granulation drying processes, the amount of liquid is determined so that the core particles do not completely dissolve. The amount of liquid can be adjusted appropriately based on data regarding the solubility of the core particles in the solvent used. In a preferred embodiment, the amount of the suspension or solution may be adjusted so that the viscosity of the binder is 60 to 400 mPa·s, satisfying the conditions of the preferred embodiment regarding the binder described above. By using such conditions, granules with fewer fine particles and good flowability can be obtained.

[0031] The production method according to the present invention may further include a step of sieving the obtained granules, a step of mixing the obtained granules with a fluidizing agent such as light anhydrous silicic acid, and the like.

[0032] The manufacturing method of the present invention can be carried out using various apparatuses used in the manufacture of granules. For example, it can be carried out by methods commonly used in the manufacture of granules, such as fluidized bed granulation and agitation granulation. When using fluidized bed granulation, melatonin can be added in the granulation drying step by spraying a suspension or solution of melatonin onto the core particles in the fluidized bed. [Example]

[0033] The present invention will be described below with reference to specific embodiments, but it will be understood that the present invention is not limited to these embodiments, and that various changes and modifications therein can be made by those skilled in the art without departing from the scope or spirit of the present invention as defined in the appended claims.

[0034] (Reference Examples 1 and 2) Examination of manufacturing using different binders (1) Preparation of granule samples A basic study was conducted on the production of granules using binders of different viscosities and mannitol as the core particles. Experiments were conducted using hypromellose (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. This experiment was conducted without using melatonin, as the purpose was to confirm whether or not fine particles were generated in granules manufactured using binders with different viscosities.

[0035] Hypromellose (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 purified water to prepare a hypromellose-bound solution and a hydroxypropyl cellulose-bound solution, respectively. 19.4 kg of D-mannitol was placed in a vertical granulator, and the entire amount of the prepared hypromellose binding solution was added and granulated for 5 minutes. The resulting granules were sized using a double-sieving machine (screen opening: 2575 μm) to produce wet granules. The obtained wet granules were dried at 60°C for 60 minutes and pulverized using a Comil, after which 0.2 kg of light anhydrous silicic acid was added and mixed to obtain a granule sample (Reference Example 1). A granule sample was prepared as Reference Example 2 in the same manner as in Reference Example 1, except that hydroxypropyl cellulose was used as the binding liquid.

[0036] (2) Measurement of minute amounts Approximately 50 g of each granule sample was weighed and passed through a No. 200 sieve (75 μm) according to the method described in the Japanese Pharmacopoeia's Particle Size Measurement Method, Method 2, Sieving Method (Mechanical Shaking Method), and the amount of powder passing through the No. 200 sieve (amount of fine powder) was measured. As a result, the amount of fine powder was 33.9% for the granules produced using hypromellose (Reference Example 1) and 13.9% for the granules produced using hydroxypropyl cellulose (Reference Example 2). These results confirmed that granules with reduced fine powder generation could be produced regardless of the binder used, and that the use of hydroxypropyl cellulose significantly reduced the amount of fine powder generation.

[0037] (Examples 1 to 4) Production studies using various core particles (1) Manufacturing of granules A binding solution was prepared by dissolving 0.202 kg of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) in a mixture of 2.02 kg of ethanol and 2.02 kg of purified water. 19.4 kg of the core particles shown in Table 1 and 0.2 kg of melatonin were placed in a vertical granulator, the entire amount of binding liquid was added, and the mixture was granulated for 5 minutes. The resulting granules were sized using a double-sieving machine (screen opening: 2575 μm) to produce wet granules. The obtained wet granules were dried at 60°C for 60 minutes, pulverized using a Comil, and then 0.2 kg of light anhydrous silicic acid was added and mixed to obtain each granule sample.

[0038] (2) Measurement of minute amounts Approximately 50 g of each granule sample obtained was weighed and passed through a No. 200 sieve (75 μm) according to the method described in the Japanese Pharmacopoeia, Particle Size Measurement Method, Method 2, Sieving Method (Mechanical Shaking Method), and the amount of powder passing through the No. 200 sieve (amount of fine powder) was measured. The results are shown in Table 1. It was confirmed that the generation of fine particles was suppressed for all core particles.

[0039] [Table 1]

[0040] (Example 5) Evaluation of flowability of granules prepared using hydroxypropyl cellulose as a binder (1) Manufacturing of granules A melatonin solution was prepared by dissolving 0.08 kg of melatonin in 9.8 kg of absolute ethanol, adding 9.8 kg of purified water and 0.4 kg of hydroxypropyl cellulose (HPC-M, Nippon Soda Co., Ltd.). 39.12 kg of D-mannitol was placed in a fluidized-bed granulator and sprayed at a spray rate of 250 mL / min. 1 kg of 50% ethanol was then sprayed under the same conditions. The fluidized bed was operated to granulate the mixture (inlet air temperature: 80°C) and dry it to a constant weight (drying endpoint: exhaust air temperature: 50°C). The resulting particles were sieved through a 30-mesh sieve, and 0.4 kg of light anhydrous silicic acid was added and mixed to obtain 0.2% melatonin granules.

[0041] (2) Measurement of minute amounts Approximately 50 g of the resulting granules were weighed and passed through a No. 200 sieve (75 μm) according to the method described in the Japanese Pharmacopoeia's Particle Size Measurement Method, Method 2, Sieving Method (Mechanical Shaking Method), and the amount of powder passing through the No. 200 sieve (amount of fine powder) was measured. As a result, the amount of fine powder was found to be 3.76%. This result confirmed that the production method of the present invention can produce granules in which the generation of fine powder is sufficiently suppressed.

[0042] (3) Measurement of Hausner ratio 100 g of the resulting granules were weighed and placed in a 250 mL measuring cylinder. The crude specific volume (bulk density: mL / g) and dense specific volume (tapped density: mL / g) were determined according to the method described in the Japanese Pharmacopoeia. The Hausner ratio was calculated based on the obtained crude specific volume and dense specific volume values. The calculated Hausner ratio was 1.06, indicating that the granules had extremely good fluidity.

[0043] (Example 6) Evaluation of fluidity and dissolution properties when produced on a 40 kg scale (1) Manufacturing of granules A melatonin solution was prepared by dissolving 0.08 kg of melatonin in 9.8 kg of absolute ethanol, adding 9.8 kg of purified water and 0.4 kg of hydroxypropyl cellulose (HPC-M, Nippon Soda Co., Ltd.). 39.12 kg of D-mannitol was placed in a fluidized-bed granulator and sprayed at a spray rate of 250 mL / min. 1 kg of 50% ethanol was then sprayed under the same conditions. The fluidized bed was operated to granulate the mixture (inlet air temperature: 80°C) and dry it to a constant weight (drying endpoint: exhaust air temperature: 50°C). The resulting particles were sieved through 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 three batches were produced.

[0044] (2) Measurement of minute amounts Approximately 50 g of the obtained granules was weighed, and the amount of fine powder was determined in the same manner as in Example 5. The amounts of fine powder in each produced batch were 5.64%, 5.80%, and 4.68%. From these results, it was confirmed that, as in Example 5, granules in which the generation of fine powder was sufficiently suppressed could be produced.

[0045] (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 ​​for the produced lots were 1.24, 1.11, and 1.11, and the granules were judged to have fairly good or extremely good fluidity.

[0046] (4) Measurement of dissolution The melatonin dissolution value after 15 minutes was determined for the obtained granules using the paddle method (test solution: water, test solution volume: 900 mL, rotation speed: 50 rpm) in accordance with the Japanese Pharmacopoeia Dissolution Test Method 2. The amount of melatonin dissolved was measured using reversed-phase liquid chromatography under the following conditions, based on a comparison with the measured value for a melatonin standard solution.

[0047] Liquid chromatography test conditions Measurement wavelength: 223nm Column: Octadecylsilanized silica gel with a diameter of 3 μm packed in a stainless steel tube with an inner diameter of 4.6 mm and a length of 75 mm. Column temperature: 25℃ Mobile phase: 18 mmol / L phosphate buffer solution (pH 3.0) / acetonitrile for liquid chromatography (4:1) Flow rate: 1.5 mL per minute

[0048] The dissolution values ​​(average values) at 15 minutes for each batch were 101%, 102%, and 103%, respectively, confirming sufficient immediate release properties.

[0049] (5) Confirmation of melatonin content in granules 3 g of each granule was dissolved in a 7:3 mixture of methanol and water to make 500 mL of the solution, which was then analyzed by high-performance liquid chromatography under the same conditions as in the dissolution test. The melatonin content in the granule samples was determined by comparison with the analytical value of a melatonin standard substance. The melatonin content was found to be 0.2% in all lots.

[0050] (Example 7) Evaluation of fluidity and dissolution properties when produced on a 120 kg scale (1) Manufacturing of granules A melatonin solution was prepared by dissolving 0.24 kg of melatonin in 29.4 kg of absolute ethanol, adding 29.4 kg of purified water and 1.2 kg of hydroxypropyl cellulose (HPC-M, Nippon Soda Co., Ltd.). 117.36 kg of D-mannitol was placed in a fluidized-bed granulator and sprayed at a spray rate of 250 mL / min. Under the same conditions, 3 kg of 50% ethanol was sprayed, and the fluidized bed was operated to granulate (inlet air temperature: 80°C) until a constant weight was reached (drying endpoint: exhaust air temperature: 50°C). The resulting particles were sieved through a 30-mesh sieve, and 1.2 kg of light anhydrous silicic acid was added and mixed to obtain 0.2% melatonin granules.

[0051] (2) Measurement of minute amounts Approximately 50 g of the resulting granules was weighed, and the amount of fine powder was determined in the same manner as in Example 5. The amount of fine powder was 1.82%.

[0052] (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 value was 1.10, and it was determined that the granules had extremely good flowability.

[0053] (4) Measurement of dissolution The dissolution value at 15 minutes of the obtained granules was determined in the same manner as in Example 6. The dissolution value at 15 minutes (average value) was 99.8%, confirming that the granules had sufficient immediate release properties.

[0054] (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 found to be 0.2%.

[0055] (Example 8) Examination of the effect of different spray volumes of melatonin solution in a fluidized bed granulation dryer (1) Manufacturing of granules 0.2% melatonin granules were produced under the same conditions as in Example 6, except that the spray rate of the melatonin solution onto the D-mannitol in the fluidized bed granulation dryer was set to 200 mL / min.

[0056] (2) Measurement of minute amounts Approximately 50 g of the resulting granules was weighed, and the amount of fine powder was determined in the same manner as in Example 5. The amount of fine powder was 4.00%.

[0057] (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 value was 1.07, and it was determined that the granules had extremely good flowability.

[0058] (4) Measurement of dissolution The dissolution value at 15 minutes of the obtained granules was determined in the same manner as in Example 6. The dissolution value at 15 minutes (average value) was 98.2%, confirming that the granules had sufficient immediate release properties. From the above results, it was confirmed that the amount of melatonin solution sprayed was reduced to 200 mL / min, and that the amount, fluidity, and dissolution properties were hardly affected, and that good granules could be produced.

[0059] (Example 9) Examination of the effect of different spray volumes of melatonin solution in a fluidized bed granulation dryer (1) Manufacturing of granules 0.2% melatonin granules were produced under the same conditions as in Example 6, except that the spray rate of the melatonin solution onto the D-mannitol in the fluidized bed granulation dryer was set to 300 mL / min.

[0060] (2) Measurement of minute amounts Approximately 50 g of the resulting granules was weighed, and the amount of fine powder was determined in the same manner as in Example 5. The amount of fine powder was 5.52%.

[0061] (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 value was 1.15, and it was determined that the granules had good flowability.

[0062] (4) Measurement of dissolution The dissolution value at 15 minutes of the obtained granules was determined in the same manner as in Example 6. The dissolution value at 15 minutes (average value) was 98.1%, confirming that the granules had sufficient immediate release properties. From the above results, it was confirmed that the amount of melatonin solution sprayed was increased to 300 mL / min, and that the amount of fine powder, fluidity, and dissolution properties were hardly affected, and that good granules could be produced. [Industrial Applicability]

[0063] The present invention makes it possible to provide melatonin-containing granules that have excellent fluidity and dissolution properties, are easy to take even for subjects who have difficulty swallowing tablets, the elderly, or infants, and have the effect of inducing sleep at the appropriate time.

Claims

1. The orally dissolvable core particles and melatonin are mixed in the presence of a binder to form a melatonin complex. a granulation step to obtain granules; The method comprises a drying step of drying the melatonin granules obtained in the granulation step. A method for producing melatonin-containing granules, comprising: The orally soluble core particles are made of mannitol, trehalose, erythritol, and sucrose. or powdered sugar, and the binder has a viscosity of 6. Hydroxypropyl cellulose of 0 to 10.0 mPa·s or 150 to 400 mPa·s cellulose solution or hydroxypropyl methylcellulose solution, and melatonin-containing granules The Hausner ratio of the agent is 1.00 to 1.

25.

2. A melatonin component obtained by mixing orally soluble core particles and melatonin in the presence of a binder. a granulation step to obtain granules; The method comprises a drying step of drying the melatonin granules obtained in the granulation step. A method for producing melatonin-containing granules, comprising: The orally soluble core particles are made of mannitol, trehalose, erythritol, and sucrose. or powdered sugar, and the binder has a viscosity of 6. Hydroxypropyl cellulose of 0 to 10.0 mPa·s or 150 to 400 mPa·s cellulose solution or hydroxypropyl methylcellulose solution, and melatonin-containing granules When the agent is passed through a No. 200 sieve according to the method described in the Japanese Pharmacopoeia Particle Size Measurement Method, Method 2, Sieving Method, The amount of powder passing through the sieve is 11.6% or less.

3. The granulation step is a step of adding melat to core particles having oral solubility under conditions in which the core particles do not completely dissolve.

3. The method according to claim 1 or 2, wherein the step of adding a suspension or solution of ginseng to the mixture and mixing the mixture. Law.

4. The suspension or solution of melatonin used in the granulation process is a suspension or solution of melatonin. The preparation according to claim 3, wherein tonin is dissolved in ethanol or a mixture of ethanol and water. Construction method.

5. A method of drying a preparation by mixing orally soluble core particles and melatonin in the presence of a binder. The method for producing melatonin-containing granules is characterized by including a granulation drying step. hand, The orally soluble core particles are made of mannitol, trehalose, erythritol, and sucrose. or powdered sugar, and the binder has a viscosity of 6. Hydroxypropyl cellulose of 0 to 10.0 mPa·s or 150 to 400 mPa·s cellulose solution or hydroxypropyl methylcellulose solution, and melatonin-containing granules The Hausner ratio of the agent is 1.00 to 1.

25.

6. A method of drying a preparation by mixing orally soluble core particles and melatonin in the presence of a binder. The method for producing melatonin-containing granules is characterized by including a granulation drying step. hand, The orally soluble core particles are made of mannitol, trehalose, erythritol, and sucrose. or powdered sugar, and the binder has a viscosity of 6. Hydroxypropyl cellulose of 0 to 10.0 mPa·s or 150 to 400 mPa·s cellulose solution or hydroxypropyl methylcellulose solution, and melatonin-containing granules When the agent is passed through a No. 200 sieve according to the method described in the Japanese Pharmacopoeia Particle Size Measurement Method, Method 2, Sieving Method, The amount of powder passing through the sieve is 11.6% or less.

7. The granulation and drying step is carried out under conditions in which the core particles are not completely dissolved in the mouth. A suspension or solution of Latonin and a binder are added, and the resulting preparation is dried while being mixed. The method according to claim 5 or 6,

8. The melatonin suspension or solution used in the granulation and drying process is a melatonin suspension or 8. The melatonin according to claim 7, which is a solution obtained by dissolving melatonin in ethanol or a mixture of ethanol and water. Manufacturing method.

9. The method according to any one of claims 5 to 8, wherein the granulation and drying step is carried out using a fluidized bed granulation method. method.

10. The addition of melatonin in the granulation and drying step is carried out by adding melatonin to the core particles in a fluidized bed.

10. The method of claim 9, wherein the method is carried out by spraying a suspension or solution of the compound. Construction method.

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