Novel granular formulation and method for producing the same

Abstract

The present invention provides a granular preparation containing melatonin as an active ingredient. [Solution] A granular preparation for improving difficulty falling asleep, containing orally soluble core particles, melatonin, and a binder, wherein the binder is hydroxypropylcellulose with an average molecular weight of 140,000 to 700,000 as determined by GPS (Gel Permeation Chromatography).

Description

Technical Field

[0003] , , , , , , , ,

[0004] ,

[0001] The present invention relates to a novel granule containing melatonin and a method for producing the same. Specifically, a novel granule containing melatonin, which is easy to take and has immediate-release properties, and the production method thereof.

Background Art

[0002] Melatonin (N-acetyl-5 -methoxytryptamine), a hormone secreted from the pineal gland of vertebrates, is known to be involved in the regulation of sleep and the body's internal rhythm, and has been used for the treatment of sleep disorders. On the other hand, according to a survey on the actual use of melatonin in the treatment of sleep disorders in patients with neurodevelopmental disorders, it has been reported that melatonin is used in a wide range of age groups and that its dosage varies widely (Non-Patent Document 1, Non-Patent Document 2).

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0004] Although melatonin is widely used for the treatment and alleviation of sleep disorders, melatonin has not been Only tablets or orally disintegrating agents were used as formulations. However, melatonin has a wide range of uses. It is intended for use in individuals of a certain age and with specific symptoms, particularly those who have difficulty swallowing tablets. Furthermore, for the elderly and infants, a granular formulation that is easier to take is desirable. [Means for solving the problem]

[0005] In other words, the present invention is as follows [1] to [4]. [1] Orally soluble core particles and melatonin are mixed in the presence of a binder to produce melatonin A granulation process to obtain melatonin granules, and a drying process to dry the melatonin granules obtained in the granulation process. A method for producing a melatonin-containing granule preparation, characterized by including the following: [2] A preparation made by mixing orally soluble core particles and melatonin in the presence of a binder. A method for producing melatonin-containing granules, characterized by including a granulation drying step for drying. Melatonin-containing granules manufactured by the method of [3][1] or [2]. [4] Contains particles in which melatonin is bound to an orally soluble core particle, and is Japanese Pharmacopoeia soluble In the second test method (paddle method, solvent: water, volume: 900 mL, rotation speed: 50 rpm) A melatonin-containing granule preparation in which the melatonin dissolution value at 15 minutes is 80% or higher.

[0006] In the above-mentioned manufacturing methods and granular formulations [1] to [4] according to the present invention, the granular formulation has orally soluble properties. The core particles can be made of water-soluble sugars or sugar alcohols, and Alternatively, mannitol, trehalose, erythritol, sucrose, or powdered sugar can be used. It is possible. [Effects of the Invention]

[0007] The present invention makes it possible to provide a granule containing melatonin as an active ingredient. Further, the present invention makes it possible to provide a melatonin-containing granule excellent in fluidity and elution property.

Mode for Carrying Out the Invention

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

[0009] One aspect of the present invention includes particles in which melatonin is bound to core particles having intraoral solubility, and the elution 15-minute value of melatonin in the Japanese Pharmacopoeia dissolution test method 2 (paddle method, solvent: water, volume: 90 0 mL, rotation speed: 50 rpm) is 80% or more, which is a melatonin-containing granule.

[0010] With such an aspect, it can be quickly dissolved in the mouth when administered orally, so that the melatonin-containing granule can be used as an effective sleep disorder improver.

[0011] In a preferred aspect, the granule according to the present invention has a Hausner ratio of 1.00 to 1.2 5. The "Hausner ratio" is an index of the fluidity of powders defined in the Japanese Pharmacopoeia, and when it is 1.00 to 1.11, the degree of fluidity is extremely good, and when it is 1.12 to 1.18, it is good, and when it is 1.19 to 1.25, it is somewhat good. Therefore, by setting the Hausner ratio to 1.00 to 1.25, good fluidity can be obtained, and thus effects such as easy handling during sub-packaging at the manufacturing site, pharmacy, etc. and during administration are achieved.

[0012] In the present invention, the term "core particles" refers to each particle constituting the granule preparation according to the present invention. ​​Refers to the core particle located approximately at the center of the sub. In the present invention, the core particle has an oral solubility Particles having it are used. "Particles having oral solubility" are particles that dissolve in saliva in the mouth ]Particles, which can contribute to the immediate release of the granule, particularly the elution value of melatonin at 15 minutes being 80% or more Means particles that can contribute to such.

[0013] In a preferred embodiment, as the core particles having oral solubility, particles mainly composed of water-soluble sugars or sugar alcohols can be used, and particles mainly composed of at least one substance selected from mannitol, trehalose, erythritol, sucrose, and powdered sugar (including these substances alone) can be preferably used. Among these, particularly, one selected from mannitol, trehalose, or erythritol is preferably used, and mannitol is particularly preferably used. By using water-soluble sugars or sugar alcohols as the core particles, the obtained granule dissolves quickly in the mouth and has a moderate sweetness and / or a refreshing feeling, so that particularly excellent effects such as easy administration can be obtained even in the elderly and infants. Particles mainly composed of water-soluble sugars or sugar alcohols can be used, and particles mainly composed of at least one substance selected from mannitol, trehalose, erythritol, sucrose, and powdered sugar (including these substances alone) can be preferably used. Among these, particularly, one selected from mannitol, trehalose, or erythritol is preferably used, and mannitol is particularly preferably used. By using water-soluble sugars or sugar alcohols as the core particles, the obtained granule dissolves quickly in the mouth and has a moderate sweetness and / or a refreshing feeling, so that particularly excellent effects such as easy administration can be obtained even in the elderly and infants. Particles mainly composed of water-soluble sugars or sugar alcohols can be used, and particles mainly composed of at least one substance selected from mannitol, trehalose, erythritol, sucrose, and powdered sugar (including these substances alone) can be preferably used. Among these, particularly, one selected from mannitol, trehalose, or erythritol is preferably used, and mannitol is particularly preferably used. By using water-soluble sugars or sugar alcohols as the core particles, the obtained granule dissolves quickly in the mouth and has a moderate sweetness and / or a refreshing feeling, so that particularly excellent effects such as easy administration can be obtained even in the elderly and infants. Particles mainly composed of water-soluble sugars or sugar alcohols can be used, and particles mainly composed of at least one substance selected from mannitol, trehalose, erythritol, sucrose, and powdered sugar (including these substances alone) can be preferably used. Among these, particularly, one selected from mannitol, trehalose, or erythritol is preferably used, and mannitol is particularly preferably used. By using water-soluble sugars or sugar alcohols as the core particles, the obtained granule dissolves quickly in the mouth and has a moderate sweetness and / or a refreshing feeling, so that particularly excellent effects such as easy administration can be obtained even in the elderly and infants. Particles mainly composed of water-soluble sugars or sugar alcohols can be used, and particles mainly composed of at least one substance selected from mannitol, trehalose, erythritol, sucrose, and powdered sugar (including these substances alone) can be preferably used. Among these, particularly, one selected from mannitol, trehalose, or erythritol is preferably used, and mannitol is particularly preferably used. By using water-soluble sugars or sugar alcohols as the core particles, the obtained granule dissolves quickly in the mouth and has a moderate sweetness and / or a refreshing feeling, so that particularly excellent effects such as easy administration can be obtained even in the elderly and infants. Particles mainly composed of water-soluble sugars or sugar alcohols can be used, and particles mainly composed of at least one substance selected from mannitol, trehalose, erythritol, sucrose, and powdered sugar (including these substances alone) can be preferably used. Among these, particularly, one selected from mannitol, trehalose, or erythritol is preferably used, and mannitol is particularly preferably used. By using water-soluble sugars or sugar alcohols as the core particles, the obtained granule dissolves quickly in the mouth and has a moderate sweetness and / or a refreshing feeling, so that particularly excellent effects such as easy administration can be obtained even in the elderly and infants. Particles mainly composed of water-soluble sugars or sugar alcohols can be used, and particles mainly composed of at least one substance selected from mannitol, trehalose, erythritol, sucrose, and powdered sugar (including these substances alone) can be preferably used. Among these, particularly, one selected from mannitol, trehalose, or erythritol is preferably used, and mannitol is particularly preferably used. By using water-soluble sugars or sugar alcohols as the core particles, the obtained granule dissolves quickly in the mouth and has a moderate sweetness and / or a refreshing feeling, so that particularly excellent effects such as easy administration can be obtained even in the elderly and infants. Particles mainly composed of water-soluble sugars or sugar alcohols can be used, and particles mainly composed of at least one substance selected from mannitol, trehalose, erythritol, sucrose, and powdered sugar (including these substances alone) can be preferably used. Among these, particularly, one selected from mannitol, trehalose, or erythritol is preferably used, and mannitol is particularly preferably used. By using water-soluble sugars or sugar alcohols as the core particles, the obtained granule dissolves quickly in the mouth and has a moderate sweetness and / or a refreshing feeling, so that particularly excellent effects such as easy administration can be obtained even in the elderly and infants. Particles mainly composed of water-soluble sugars or sugar alcohols can be used, and particles mainly composed of at least one substance selected from mannitol, trehalose, erythritol, sucrose, and powdered sugar (including these substances alone) can be preferably used. Among these, particularly, one selected from mannitol, trehalose, or erythritol is preferably used, and mannitol is particularly preferably used. By using water-soluble sugars or sugar alcohols as the core particles, the obtained granule dissolves quickly in the mouth and has a moderate sweetness and / or a refreshing feeling, so that particularly excellent effects such as easy administration can be obtained even in the elderly and infants.

[0014] Also, the shape of the core particles is not particularly limited, but substantially spherical particles can be preferably used. The closer the shape of the particles is to a sphere, the easier it is to uniformly bind melatonin, contributing to the stability of the quality. Also, the shape of the core particles is not particularly limited, but substantially spherical particles can be preferably used. The closer the shape of the particles is to a sphere, the easier it is to uniformly bind melatonin, contributing to the stability of the quality. Also, the shape of the core particles is not particularly limited, but substantially spherical particles can be preferably used. The closer the shape of the particles is to a sphere, the easier it is to uniformly bind melatonin, contributing to the stability of the quality.

[0015] Binders can be various substances commonly used in the production of granules, such as hydroxypropyl cellulose and hypromellose. Preferably, during granulation, the viscosity is 60 - 400 mPa·s (Japanese Pharmacopoeia Viscosity Measurement Method No. 2, 20 °C). Binders can be various substances commonly used in the production of granules, such as hydroxypropyl cellulose and hypromellose. Preferably, during granulation, the viscosity is 60 - 400 mPa·s (Japanese Pharmacopoeia Viscosity Measurement Method No. 2, 20 °C). Binders can be various substances commonly used in the production of granules, such as hydroxypropyl cellulose and hypromellose. Preferably, during granulation, the viscosity is 60 - 400 mPa·s (Japanese Pharmacopoeia Viscosity Measurement Method No. 2, 20 °C). Such substances can be used, and more preferably have a viscosity of 150-400 mPa·s (Japan Substances that meet the viscosity measurement method (2nd method, 20°C) of the Pharmacopoeia can be used. By using the binder in question, the fine powder (powder that passes through a No. 200 sieve (75 μm)) This method allows for the suppression of generation and the acquisition of granular formulations with good fluidity.

[0016] Specifically, the GPS method (Gel Permeation Chromatography) y; Gel permeation chromatography) The average molecular weight is 140,000 to 700,000 Hydroxypropylcellulose with a molecular weight of 0, or a weight-average molecular weight of 30,000 to 60,0 Hydroxypropylcellulose of 00 can be preferably used, and the average by GPS method Hydroxypropylcellulose with a molecular weight of 500,000 to 700,000 is preferred. It can be used in various ways.

[0017] In the granular formulation according to the present invention, the melatonin content is such that when administering the required amount, handling and As long as the concentration is such that it is a sufficient amount, there is no particular need to limit it. Preferably, The melatonin content can be set to 0.05 to 1.0% by weight.

[0018] The granular formulation according to the present invention is a safe and effective agent for improving difficulty falling asleep, and is similar to conventional granular formulations and dry formulations. It can be administered orally in the same manner as the syrup, for example, as shown in the present invention below. It can be manufactured by a manufacturing method shown as another embodiment, or yet another embodiment. Cut.

[0019] Another aspect of the present invention involves orally soluble core particles and melatonin in the presence of a binder. A granulation step in which the mixture is used to obtain melatonin granules, and the melatonin granules obtained in the granulation step This is a method for producing melatonin-containing granules, characterized by including a drying step.

[0020] In the granulation process, melatonin is added to the core particles, either simultaneously with or separately from the melatonin. This can be done by mixing in the presence of a binder. Furthermore, granulation The process involves applying melatonin to orally soluble core particles under conditions where the core particles do not completely dissolve. This step may involve adding and mixing a turbid liquid or solution.

[0021] Furthermore, the drying process involves heating the obtained granules while stirring, and applying negative pressure as desired. This can be done by drying the material.

[0022] Another aspect of the present invention involves orally soluble core particles and melatonin in the presence of a binder. Melatonin-containing granules characterized by including a granulation and drying process in which the mixture is dried while being mixed underwater. This is a method for manufacturing the agent.

[0023] In the granulation and drying process, melatonin is added to the core particles, either simultaneously or separately. The sample is mixed using warm air or the like, while optionally applying negative pressure, in the presence of the added binder. This can be done by drying while rinsing. Furthermore, the granulation drying process is performed inside the mouth. A suspension of melatonin or a soluble core particle is placed in the core particle under conditions where the core particle does not completely dissolve. The process can involve adding a liquid and a binder, and then drying the resulting preparation while mixing it. .

[0024] In the granulation process, drying process, and granulation-drying process, the temperature of the sample is controlled in the same way throughout the process. These can be commonly used conditions, but they must be conditions that prevent deterioration (decomposition, etc.) of each raw material. It is preferable to do so. Furthermore, the airflow rate should be adjusted to the differential pressure in the fluidized bed so that the powder and granules are in a desirable flow state. It can be adjusted by controlling it.

[0025] The addition of melatonin to core particles during the granulation and granulation drying processes is performed in various ways. Methods can be used. For example, a method of adding melatonin to core particles in solid form, A method can be used in which a suspension or solution of melatonin is added to the core particles. Among the methods, the method of adding a melatonin suspension or solution to the core particles involves melatonin and co This is preferable because it allows for more uniform mixing of the particles. Here, the melatonin suspension There is no particular need to limit it as long as melatonin can be dispersed, but melatonin Aqueous suspension or melatonin in a mixture of water and alcohol (alcohol / water = 0.5 / 1~2 / 1 A solution in which melatonin is suspended (preferably 1 / 1) can be used. The solution does not need to be particularly limited as long as it can dissolve melatonin, but Preferably, an ethanol solution of melatonin or a solution of melatonin dissolved in a mixture of ethanol and water is used. It is possible to be there.

[0026] The addition of a binder to the core particles during the granulation and granulation drying processes also contributes to the production of melatonin. Similar to addition, various methods can be used. For example, the binder can be attached to the particles in solid form. It can be added by adding it by hand, or in the form of a solution or suspension. In the case of a solution, it is preferable. An aqueous solution can be used.

[0027] In the granulation process and the granulation drying process, the timing of adding the binder is determined by the relationship between the core particles and the medium. The limit is to the extent that latonin can be present in the system at the same time when mixed. It is not necessary; in other words, it is sufficient to have a binder in the presence of the core particle simultaneously with melatonin. It can be added, or added to the core particles at a different time than the melatonin. For example... Alternatively, melatonin may be added to the core particles before it is added to the core particles. It may be added to the child. Alternatively, melatonin and a binder may be dissolved in a mixture of ethanol and water. This can also be done by adding the prepared liquid to the core particles. Alternatively, melatonin and a binder can be used together. The solid is added to the core particles and mixed, and then a solvent is added to the mixture for a granulation process or granulation drying process. You could also use a method such as attaching it to the appropriate amount.

[0028] The binder is, for example, hydroxypropylcellulose or hypromellose, which are used in granular formulations. Various substances commonly used in manufacturing can be used. Preferably, during granulation... The viscosity is 60-400 mPa·s (Japanese Pharmacopoeia Viscosity Measurement Method 2, 20°C). Such substances can be used, and more preferably have a viscosity of 150-400 mPa·s (Japan Substances that meet the viscosity measurement method (2nd method, 20°C) of the Pharmacopoeia can be used. By using the binder in question, the generation of fine particles is suppressed, and a granular formulation with good fluidity is produced. It is possible to obtain it.

[0029] Specifically, the GPS method (Gel Permeation Chromatography) y; Gel permeation chromatography) for an average molecular weight of 140,000 to 700,000 Hydroxypropyl cellulose or a weight-average molecular weight of 30,000 to 60,000 Hydroxypropyl cellulose can be preferably used, and the average molecule can be measured by GPS method. Hydroxypropylcellulose in an amount of 500,000 to 700,000 is more preferable. It can be used.

[0030] When using a melatonin suspension or solution in the granulation process and the granulation drying process: The volume of liquid should be such that the core particles are not completely dissolved. In this case, the volume of liquid should be relative to the solvent used. Based on data regarding the solubility of the core particles, adjustments can be made as appropriate. In a preferred embodiment, In this case, the volume of the suspension or solution is determined according to the conditions in the preferred embodiment relating to the binder described above. To satisfy this requirement, the viscosity of the binder may be adjusted to 60-400 mPa·s. By setting such conditions, it is possible to obtain a granular preparation with less fine powder and good fluidity. It is possible.

[0031] The manufacturing method according to the present invention includes a step of sieving the obtained granules and a step of applying light anhydrous keratin to the obtained granules. The process may further include steps such as mixing in a fluidizing agent like yic acid.

[0032] The manufacturing method according to the present invention is carried out using various apparatus used for the manufacture of granular formulations. This is possible. For example, in the production of granules, it is common to use methods such as fluidized bed granulation and agitated granulation. This can be carried out using the method used in the following: When using the fluid bed granulation method, the granulation drying process The addition of melatonin in this process involves adding a suspension or solution of melatonin to the core particles in a fluidized bed. This can be done by spraying. [Examples]

[0033] The present invention will be described below with reference to specific embodiments, but the present invention is not limited to these embodiments. These are not intended to be modified, and various changes and modifications therein may be made by those skilled in the art, as per the attached patent application. It may be carried out without departing from the scope or spirit of the present invention as defined in the scope of the request. It will be understood.

[0034] (Reference Examples 1 and 2) Manufacturing studies using different binders (1) Preparation of granular samples Granule production when using binders of different viscosities and mannitol as the core particle. Basic studies were conducted. As a binder, hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd., TC-5) was used. E. Reference Example 1) and hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-L, Each experiment was conducted using Reference Example 2). This experiment aims to confirm the presence or absence of fine particle generation in granules produced using binders with different viscosities. Since the purpose was recognition, the procedure was performed without the use of melatonin.

[0035] Hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd., TC-5E, Reference Example 1) or hydroxyp Ropil cellulose (manufactured by Nippon Soda Co., Ltd., HPC-L, Reference Example 2) in 4.04 kg of purified water. Prepare the solutions by dissolving the substances in each of the following: hypromellose bound solution and hydroxypropylcellulose It was used as a binding solution. 19.4 kg of D-mannitol was placed in a vertical granulator, and the adjusted hypnotherapy was performed. The entire amount of romerose binding solution was added and granulation was carried out for 5 minutes. The resulting granules were then subjected to a double-spread sieve (screen). The granules were sized to a mesh size of 2575 μm and processed into wet granules. The resulting wet granules were dried at 60°C for 60 minutes, then ground using a Comill, and finally light anhydrous silica. 0.2 kg of acid was added and mixed to obtain a granular sample (Reference Example 1). Furthermore, the method is the same as in Reference Example 1, except that hydroxypropyl cellulose was used as the binding agent. A granular sample was prepared using the method and designated as Reference Example 2.

[0036] (2) Measurement of trace amounts Approximately 50g of each granular sample obtained was weighed and subjected to the sieving method according to the Japanese Pharmacopoeia Particle Size Measurement Method No. 2 ( The sample was passed through a No. 200 sieve (75 μm) using the method described (mechanical shaking method), and passed through the No. 200 sieve. The amount of powder (amount of fine powder) was measured. As a result, the amount of fine powder was obtained using hypromellose. The granules produced (Reference Example 1) were manufactured using 33.9% hydroxypropyl cellulose. In the case of the granules (Reference Example 2), the figure was 13.9%. From this result, it can be concluded that in any case when using a binder... In this case, granular formulations with suppressed generation of fine particles can be manufactured, particularly hydroxypropyl cellulose It was confirmed that using [the specified method] further suppressed the generation of fine particles.

[0037] (Examples 1-4) Manufacturing studies using various core particles (1) Manufacturing of granules A mixture of 2.02 kg of ethanol and 2.02 kg of purified water, to which hydroxypropylcellulose is added. 0.202 kg of HPC-L (manufactured by Nippon Soda Co., Ltd.) was dissolved and used as the binding solution. Table 1 lists 19.4 kg of core particles and 0.2 kg of melatonin, which are then vertically granulated. The material was placed in a granulator, the entire amount of binding solution was added, and granulation was carried out for 5 minutes. The resulting granules were then subjected to a double-spread sieve (screw). The granules were sized using a lean mesh opening of 2575 μm and processed into wet granules. The resulting wet granules were dried at 60°C for 60 minutes, then ground using a Comill, and finally light anhydrous silica. 0.2 kg of acid was added and mixed to obtain each granular sample.

[0038] (2) Measurement of trace amounts Approximately 50g of each granular sample obtained was weighed and analyzed using the sieving method according to the Japanese Pharmacopoeia's Particle Size Measurement Method No. 2. (Mechanical shaking method) The material is passed through a No. 200 sieve (75 μm) using the method described, and then through the No. 200 sieve. The amount of powder (amount of fine powder) that passed through was measured. The results are shown in Table 1. For all core particles, the generation of fine particles was suppressed. Confirmed.

[0039] [Table 1]

[0040] (Example 5) Flow of granules prepared using hydroxypropylcellulose as a binder Sexual evaluation (1) Manufacturing of granules A solution of 0.08 kg of melatonin dissolved in 9.8 kg of anhydrous ethanol was mixed with 9.8 kg of purified water. g and 0.4 kg of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-M) It was then dissolved to obtain a melatonin solution. 39.12 kg of D-mannitol was granulated in a fluid bed. Place in a dryer and add the entire amount of the melatonin solution prepared above, spraying it at a volume of 250 mL / ml. The spray was performed under condition n. Furthermore, 1 kg of 50% ethanol was sprayed under the same conditions, and the fluidized bed was The granulation process was carried out while the machine was running (intake temperature: 80°C), and it was dried until a constant weight was reached (end of drying period). (Exhaust temperature 50℃). The obtained particles are sieved through a 30-mesh sieve, and light anhydrous silicic acid 0 By adding 0.4 kg and mixing, a 0.2% melatonin granule preparation was obtained.

[0041] (2) Measurement of trace amounts Approximately 50 g of the obtained granules were weighed and subjected to sieving according to the Japanese Pharmacopoeia's Particle Size Analysis Method No. 2 (mechanical). The material is passed through a 200-size sieve (75 μm) using the method described (shaking method), and the material that passes through the 200-size sieve... The amount of powder (amount of fine powder) was measured. The result showed that the amount of fine powder was 3.76%. Therefore, the manufacturing method according to the present invention can produce granular formulations in which the generation of fine particles is sufficiently suppressed. This was confirmed.

[0042] (3) Measurement of the Hausner ratio Weigh 100g of the obtained granules, place them in a 250mL graduated cylinder, and put them into the Japanese Pharmacopoeia. According to the method described, the crude specific volume (bulk density: mL / g) and the dense specific volume (tap density: m) are determined. The specific volume (L / g) was determined. Based on the obtained values ​​of crude and dense specific volumes, the Hausner ratio was calculated. The calculated Hausner ratio was 1.06, indicating extremely good liquidity. It was decided.

[0043] (Example 6) Evaluation of fluidity and elution when manufactured on a 40kg scale (1) Manufacturing of granules A solution of 0.08 kg of melatonin dissolved in 9.8 kg of anhydrous ethanol was mixed with 9.8 kg of purified water. g and 0.4 kg of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-M) It was then dissolved to obtain a melatonin solution. 39.12 kg of D-mannitol was granulated in a fluid bed. Place in a dryer and add the entire amount of the melatonin solution prepared above, spraying it at a volume of 250 mL / ml. The spray was performed under condition n. Furthermore, 1 kg of 50% ethanol was sprayed under the same conditions, and the fluidized bed was The granulation process was carried out while the machine was running (intake temperature: 80°C), and it was dried until a constant weight was reached (end of drying period). (Exhaust temperature 50℃). The obtained particles are sieved through a 30-mesh sieve, and light anhydrous silicic acid 0 By adding 0.4 kg and mixing, a 0.2% melatonin granule preparation was obtained. A total of three production batches were manufactured.

[0044] (2) Measurement of trace 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 amount of fine particles in each lot was 5.64%, 5.80%, and 4.68%. From the results, it was confirmed that, similar to Example 5, granular formulations with sufficiently suppressed generation of fine particles can be produced. It was acknowledged.

[0045] (3) Measurement of the Hausner ratio The Hausner ratio of the obtained granules was measured in the same manner as in Example 5. The Hausner ratio values ​​for each lot produced were 1.24, 1.11, and 1.11. It was determined to have moderately good or very good fluidity.

[0046] (4) Measurement of elution For the obtained granules, the Japanese Pharmacopoeia Dissolution Test Method 2, Paddle Method (Test solution: water, test Using a solution volume of 900 mL and a rotation speed of 50 rpm, the 15-minute elution value of melatonin was determined. The amount of melatonin eluted was measured using reversed-phase liquid chromatography under the following conditions. This was performed based on comparison with measurements in a nin standard solution.

[0047] Liquid chromatography test conditions Measurement wavelength: 223nm Column: Octadecylsilylated silica gel with a diameter of 3 μm, with an inner diameter of 4.6 mm and a length of 75 m. This is a product filled into a stainless steel pipe (m). Column temperature: 25℃ Mobile phase: pH 3.0 18 mmol / L phosphate buffer / acetate for liquid chromatography Tonitrile mixture (4:1) Flow rate: 1.5 mL per minute

[0048] The 15-minute elution values ​​(average) for each lot were 101%, 102%, and 103%, respectively. It was confirmed that it possesses sufficient immediate-release properties.

[0049] (5) Confirmation of melatonin content in granules Dissolve 3 g of each granule obtained in a methanol / water (7:3) mixture to make 500 mL of solution. The sample was used and analyzed by high-performance liquid chromatography under the same conditions as the elution test. Based on comparison with analytical values ​​in melatonin standard substances, the melatonin content in the granular sample was determined. The quantity was determined. As a result, the melatonin content was 0.2% in all lots.

[0050] (Example 7) Evaluation of fluidity and elution properties when manufactured on a 120 kg scale (1) Manufacturing of granules Dissolve 0.24 kg of melatonin in 29.4 kg of anhydrous ethanol, then add 29g of purified water. 4 kg and 1.2 kg of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HPC-M) g was added and dissolved to obtain a melatonin solution. 117.36 kg of D-mannitol was added in liquid form. Place the mixture in a layer granulation dryer, and spray the entire amount of the melatonin solution prepared above into it, in a volume of 250 mL. The spray was performed under the condition of / min. Furthermore, 3 kg of 50% ethanol was sprayed under the same conditions. The fluidized bed was operated to granulate the material (intake temperature: 80°C) and dried until a constant weight was reached. Drying endpoint: exhaust temperature 50°C). The obtained particles are sieved through a 30-mesh sieve to obtain light, anhydrous particles. By adding 1.2 kg of silica and mixing, a 0.2% melatonin granule preparation was obtained.

[0051] (2) Measurement of trace 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 amount was 1.82%.

[0052] (3) Measurement of the Hausner ratio The Hausner ratio of the obtained granules was measured in the same manner as in Example 5. The Ausner ratio was 1.10, indicating extremely good liquidity. .

[0053] (4) Measurement of elution The elution value at 15 minutes was determined for the obtained granules using the same method as in Example 6. The average value was 99.8%, confirming that it possesses 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 0.2%.

[0055] (Example 8) Investigation of the effect of differences in the amount of melatonin solution sprayed in a fluidized bed granulator. discussion (1) Manufacturing of granules The amount of melatonin solution sprayed onto D-mannitol in the fluidized bed granulator is 200. Except for the concentration being mL / min, the same conditions as in Example 6 were used to prepare 0.2% melatonin granules. It was made.

[0056] (2) Measurement of trace 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 amount was 4.00%.

[0057] (3) Measurement of the Hausner ratio The Hausner ratio of the obtained granules was measured in the same manner as in Example 5. The Ausner ratio was 1.07, indicating extremely good liquidity. .

[0058] (4) Measurement of elution The elution value at 15 minutes was determined for the obtained granules using the same method as in Example 6. The average value was 98.2%, confirming that it possesses sufficient immediate release properties. Based on the above results, in terms of fine powder volume, fluidity, and dissolution, the amount of melatonin solution sprayed was 200 ml. Even when reduced to L / min, it is possible to produce good quality granules with almost no impact. This was confirmed.

[0059] (Example 9) Investigation of the effect of differences in the amount of melatonin solution sprayed in a fluidized bed granulator. discussion (1) Manufacturing of granules The amount of melatonin solution sprayed onto D-mannitol in the fluid bed granulator is 300. Except for the concentration being mL / min, the same conditions as in Example 6 were used to prepare 0.2% melatonin granules. It was made.

[0060] (2) Measurement of trace 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 amount was 5.52%.

[0061] (3) Measurement of the Hausner ratio The Hausner ratio of the obtained granules was measured in the same manner as in Example 5. The Ausner ratio was 1.15, indicating good liquidity.

[0062] (4) Measurement of elution The elution value at 15 minutes was determined for the obtained granules using the same method as in Example 6. The average value was 98.1%, confirming that it possesses sufficient immediate release properties. Based on the above results, in terms of fine powder volume, fluidity, and dissolution, the amount of melatonin solution sprayed was 300 ml. Even when increased to L / min, it is possible to produce good quality granules with almost no effect. This was confirmed. [Industrial applicability]

[0063] This invention provides excellent fluidity and dissolution properties, making it suitable for individuals who have difficulty swallowing tablets, and for the elderly. This melatonin-containing medication is easy to take, even for adults and infants, and provides a timely sleep-inducing effect. This makes it possible to provide granular formulations.

Claims

1. Granules for improving difficulty falling asleep, containing orally soluble core particles, melatonin, and a binder. Granular formulation, the binder is GPS method (Gel Permeation Chromato Graph (gel permeation chromatography) shows an average molecular weight of 140,000 to 7 A granular preparation containing 00,000 hydroxypropyl cellulose.

2. The claim 1 includes particles in which melatonin is bound to an orally soluble core particle. Granules.

3. The orally soluble core particles are particles whose main component is water-soluble sugar or sugar alcohol. The granular preparation according to claim 1 or 2.

4. The orally soluble core particles are mannitol, trehalose, erythritol, and sodium. The particle is mainly composed of at least one selected from sugar or powdered sugar, as described in claim 3. A granular formulation.

5. The present invention relates to any one of claims 1 to 4, which contains 0.05 to 1.0% by weight of melatonin. A granular formulation.

6. The binder is hydroxyl with an average molecular weight of 500,000 to 700,000 as determined by GPS. A granular preparation according to any one of claims 1 to 5, wherein the granular preparation is propylcellulose.

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