CN101495101B - Sugar-coated preparation and its manufacturing method - Google Patents

Abstract

The present invention provides a technique for producing sugar-coated preparations having sufficient hardness in a short time and easily, and having excellent low hygroscopicity, deodorant properties, and disintegration properties. Specifically, the present invention provides a sugar-coating solution that can be preferably used in the production of a sugar-coated preparation using a continuous coating method that simultaneously performs a spraying step and a drying step of the sugar-coating solution, a sugar-coated preparation having a sugar-coated layer formed of the sugar-coating solution, and its method of manufacture. The present invention uses the following sugar-coating solution to manufacture sugar-coated preparations, the sugar-coating solution is a sugar-coating solution containing ethyl acrylate/methyl methacrylate copolymer and a solvent, and the concentration of ethyl acrylate/methyl methacrylate copolymer is relative to the total The solid content is 0.01 to 10% by weight.

Description

Sugar-coated preparation and its manufacturing method

technical field

The present invention relates to a sugar-coated preparation and a method for its manufacture.

Background technique

Sugar-coated preparations have low oxygen permeability, low hygroscopicity, and excellent deodorant properties because the sugar-coated layer has the function of preventing the permeation of oxygen, water, and unpleasant ingredients. It is a dosage form suitable for stabilizing ingredients mixed in plain tablets.

For example, in addition to fatigue recovery and nourishing and strengthening effects, garlic processed products also have the effects of enhancing gastric contractility, promoting metabolism, promoting blood circulation, and protecting the liver. They are widely used as medicines, but they are affected by heat or moisture. Since it produces an unpleasant smell, it is made into a sugar-coated formulation in many cases.

In addition, methylmethioninesulfonium chloride (Methylmethioninesulfonium chloride is also referred to as "MMSC" hereafter.) can improve the subjective symptoms and other symptoms such as gastric ulcer, duodenal ulcer, gastritis, and improve the liver function of chronic liver disease. It is widely used as a medicine for the relief of many symptoms. However, since MMSC has the property of decomposing by absorbing moisture in the air, preparations containing MMSC have problems such as generation of unpleasant odor, discoloration, and decrease in the content of active ingredients. Therefore, in order to prevent moisture absorption, many MMSC preparations are sugar-coated (Patent Documents 1 and 2).

In addition, sodium valproate is used as a treatment for various types of epilepsy such as petit mal seizures, partial seizures, psychomotor seizures, and mixed seizures, as well as personality and behavioral disorders (dissatisfaction, irritability, etc.) Drugs for the treatment of madness are widely used. However, sodium valproate has hygroscopicity and deliquescent properties, and sugar-coated formulations were performed in order to prevent quality deterioration after opening (patent documents 3 and 4).

A sugar-coated preparation is generally manufactured by repeating [1] spraying of a sugar-coating solution, [2] evaporation, and [3] drying several times (for example, Patent Document 5). Among them, [2] Evaporation is the process of completely covering the side of the sugar-coated preparation and spreading the sprayed sugar-coated liquid evenly on the plain tablet. When using a sugar-coated liquid that usually has a high viscosity, it is an indispensable process. . On the other hand, the production method of the sugar-coated preparation including this step requires a very long operation time, and has disadvantages such as requiring a large amount of sugar-coated liquid for plain tablets.

As a production method to overcome the disadvantages described above, as in the production of film-coated tablets, a method of forming a coating layer by drying while spraying a coating solution (hereinafter also referred to as a continuous coating method) has been studied to form a sugar coating. The method of layer.In the continuous coating method, since the sugar-coated liquid of spraying must be expanded rapidly and evenly on the core materials such as plain tablets, it is necessary to dilute the sugar-coated liquid to reduce the viscosity.Therefore, for example, the use of suspended sugar and talc has been developed. The technology etc. (patent document 6) that the sugar-coating liquid of powder forms thin-layer sugar-coating layer.But, this thin-layer sugar-coating layer has the problem that strength is poor compared with existing product.In addition, as the method for improving the intensity of thin-layer sugar-coating layer , have also developed such as the technology of setting an intermediate layer between a film-coated tablet and a sugar-coated layer (Patent Document 7). However, this method is very difficult because it includes preparation and spraying of a coating solution having a composition different from that of the sugar-coated layer. It is hard to say that it is simple enough. In addition, instead of gum arabic or gelatin, which are usually used as binders, a technology has been developed to reduce the viscosity of the sugar coating solution by using hydroxypropylmethylcellulose or hydroxypropylcellulose (Patent Document 8). However, the sugar-coated layer obtained by this method has problems of insufficient compactness, low oxygen permeability, low hygroscopicity, and poor deodorization properties characteristic of sugar-coated preparations.

Thus, although various researches have been conducted on the production method of sugar-coated preparations and sugar-coated liquids in terms of both operability and improvement of preparation properties, no technology has been developed to jointly improve both.

[Patent Document 1] JP-A-2003-63953

[Patent Document 2] JP-A-2003-95928

[Patent Document 3] JP-A-2006-256961

[Patent Document 4] Japanese Patent Laid-Open Publication No. 04-235914

[Patent Document 5] Japanese Patent Laid-Open Publication No. 06-292511

[Patent Document 6] JP-A-56-87518

[Patent Document 7] JP-A-2004-155656

[Patent Document 8] JP-A-49-133515

Contents of the invention

An object of the present invention is to provide a technique for easily producing a sugar-coated preparation having sufficient hardness, low hygroscopicity, deodorization, and disintegration in a short period of time. Specifically, an object of the present invention is to provide a sugar-coating solution that can be preferably used in the production of a sugar-coating preparation using a continuous coating method that simultaneously performs a spraying process and a drying process of the sugar-coating solution, and a sugar-coating solution having a sugar-coating layer formed of the sugar-coating solution. Formulations and methods for their manufacture.

The inventors of the present invention conducted various studies on the composition of the sugar coating solution suitable for the continuous coating method. Furthermore, it has been found that a sugar-coating liquid in which ethyl acrylate/methyl methacrylate copolymer is blended in a specific ratio in a sugar-containing solvent has physical properties suitable for a continuous coating method, and that a sugar-coating liquid formed by a continuous coating method using a sugar-coating liquid The sugar-coated preparation of the first layer has low hygroscopicity, deodorization and good disintegration properties, and further completes the present invention. The continuous coating method uses a coating solution having the above-mentioned composition.

That is, the present invention provides a sugar coating solution containing sugar, ethyl acrylate/methyl methacrylate copolymer and solvent, wherein the concentration of ethyl acrylate/methyl methacrylate copolymer is 0.01 to 10% by weight, a method for producing a sugar-coated preparation using the sugar-coating liquid, and a sugar-coated preparation obtained by the production method.

Description of drawings

[ Fig. 1 ] A graph showing changes in moisture absorption rate of sugar-coated preparations over time.

[ Fig. 2 ] A graph showing changes in time and moisture absorption rate of sugar-coated preparations containing processed garlic products.

[ Fig. 3] Fig. 3 is a graph showing changes in moisture absorption rate of sugar-coated preparations containing MMSC over time.

[ Fig. 4] Fig. 4 is a graph showing changes in moisture absorption rate of sugar-coated formulations containing sodium valproate over time.

[ Fig. 5 ] A graph showing changes in the dissolution rate of sodium valproate over time.

Detailed ways

The sugar coating liquid of the present invention contains sugar, ethyl acrylate/methyl methacrylate copolymer and solvent.

The sugar used in the present invention is not particularly limited as long as it is generally used for forming a sugar coating layer of sugar coating preparations, and examples thereof include granulated sugar, refined white sugar, white sugar, glucose, trehalose, and the like. Among them, granulated sugar, refined white sugar, and white sugar can be preferably used.

In the sugar-coating solution of the present invention, the compounding amount of sugar is not particularly limited, but may be usually 10 to 85% by weight, preferably 10 to 70% by weight, more preferably 15 to 60% by weight.

The ethyl acrylate/methyl methacrylate copolymer used in the present invention refers to a polymer in which ethyl acrylate and methyl methacrylate are copolymerized. The number average molecular weight of the copolymer may be within a range that can impart appropriate hardness and disintegratability to the sugar-coated preparation, and is usually 10,000 to 1,500,000, preferably 400,000 to 1,200,000, more preferably 500,000 to 1,100,000. In addition, the molar ratio of ethyl acrylate and methyl methacrylate constituting the copolymer is usually 10:1 to 1:10, preferably 4:1 to 1:4, more preferably 3:1 to 1:3. Moreover, the glass transition temperature of a copolymer is -40-30 degreeC normally, Preferably it is -30-20 degreeC, More preferably, it is the range of -20-10 degreeC.

The ethyl acrylate/methyl methacrylate copolymer can be obtained by copolymerizing ethyl acrylate and methyl methacrylate according to a conventional method. In addition, a commercial item can be used for an ethyl acrylate/methyl methacrylate copolymer. Commercially available products include, for example, Oidragit NE30D (Hiro Shokai) and Koricott EMM30D (BASF Japan) using an emulsion obtained by dispersing an ethyl acrylate/methyl methacrylate copolymer in water as a surfactant.

In the sugar-coating liquid of the present invention, the blending amount of the ethyl acrylate/methyl methacrylate copolymer is 0.01 to 10% by weight relative to the total solid content contained in the sugar-coating liquid. Among them, 0.1 to 8% by weight is preferable. When the compounding amount exceeds 10% by weight, aggregation of solid components suspended in the sugar-coating liquid occurs, which is not preferable.

In the sugar coating solution of the present invention, the mass ratio of ethyl acrylate/methyl methacrylate copolymer to sugar is usually 1:1 to 1:10,000, preferably 1:3 to 1:1,000, more preferably 1:5 to 1:500.

The solvent of the sugar-coating solution of the present invention is not particularly limited as long as it is a solvent generally used for a sugar-coating solution. Examples thereof include water, lower alcohols such as ethanol and isopropanol, acetone, or mixtures thereof. Among these solvents, purified water is usually preferably used.

The compounding quantity of the solvent in a sugar-coating liquid is not specifically limited, Usually, it is 15-90 weight%, Preferably it is 15-85 weight%, More preferably, it is 20-80 weight%. When the compounding amount of the solvent exceeds 90% by weight, the operation time for forming the sugar-coat layer is prolonged, and it is difficult to form a dense sugar-coat layer, which affects the stability of the drug contained in the core material. In addition, when it is less than 15% by weight, the viscosity of the sugar-coating solution will increase, and there will be operational problems such as the tablet will adhere to the pan of the tablet coating device. In addition, when the sugar-coated preparation is produced by the continuous coating method, it cannot Spread the icing liquid evenly on the top, and it is impossible to form a icing layer of uniform thickness. In addition, the viscosity of the sugar-coating solution should be within the range that can be sprayed by the equipment used to manufacture the sugar-coating preparation, and the compounding amount of the solvent can be adjusted so that the viscosity is usually 3 to 1,000 cp, preferably 5 to 700 cp, more preferably 10 to 700 cp. 400cp.

In addition to the above-mentioned components, the sugar-coated solution of the present invention may also contain various optional components that are permitted as pharmaceutical additives and that can be taken orally as needed. Examples of such additives include coating agents, colorants, and gloss agents.

Examples of coating agents include hydroxypropylcellulose, hydroxypropylmethylcellulose 2910, hydroxypropylmethylcellulose 2208, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, crystalline cellulose, Gum Arabic Powder, Refined Shellac, Pullulan, Precipitated Calcium Carbonate, Talc, Dicalcium Phosphate, Light Silicic Anhydride, Hydrous Silica, Titanium Oxide, Sodium Dihydrogen Phosphate, Hydrogenated Oil, Glyceryl Monostearate and polyethylene glycol monostearate, etc., the compounding amount thereof is preferably 0 to 80% by weight relative to the sugar-coating solution.

Examples of coloring agents include various food colorings, tar colorings, ferric oxide, and the like, and the compounding amount thereof is preferably 0.1% by weight or less with respect to the sugar-coated preparation.

Examples of gloss agents include carnauba wax, beeswax, and the like, and the compounding amount thereof is preferably 0.1% by weight or less with respect to the sugar-coating preparation.

Moreover, the viscosity of the sugar-coating liquid of this invention is 3-1,000 cp normally, Preferably it is 5-700 cp, More preferably, it is 10-400 cp. When using a sugar-coating liquid having a viscosity in this range, it is easy to form a uniform sugar-coating layer even when a sugar-coated preparation is produced by a continuous coating method.

The sugar coating solution of the present invention can be produced by suspending sugar, ethyl acrylate/methyl methacrylate copolymer, and necessary optional components described above in a solvent. At this time, it is also preferable to add a surfactant in order to sufficiently disperse the ethyl acrylate/methyl methacrylate copolymer in the solvent.

The sugar-coated preparation of the present invention has at least one sugar-coated layer formed using the sugar-coating solution of the present invention around a drug-containing core material.

The drug-containing core material contained in the sugar-coated preparation of the present invention includes plain tablets or core granules. That is, the sugar-coated preparation of the present invention can be prepared, for example, in the form of sugar-coated tablets or sugar-coated granules.

In the present invention, the drug contained in the core material is a drug whose safety for oral administration has been confirmed, and is not particularly limited as long as it is suitable for sugar-coated preparations. Whisker drugs, etc. For example, drugs having an unpleasant smell include herbal medicines (okisoamina powder, hops, barley, herbal medicines, ginseng, astragalus, fennel, cloves, ginger, and belladonna extracts, etc.), garlic processed products, methyl sulfide chloride, etc. Aminosulfonium sulfonium, L-cysteine, vitamin B _1, etc., various vitamins (vitamin A, vitamin B ₁ , vitamin B ₂ , vitamin B 6, vitamin B ₆ , etc.) Vitamin B ₁₂ , vitamin C, vitamin D, vitamin E, biotin, calcium pantothenate, nicotinamide, vitamin P and its derivatives, etc.), sulfonium chloride methylmethionine, amino acids (ascorbic acid and L-cysteine, etc.), adenosine triphosphate·2 sodium salt, enzymes (starch-digesting enzyme, protein-digesting enzyme, fat-digesting enzyme, cellulose-digesting enzyme, etc.), sodium valproate, ibuprofen, guaiac Examples of whisker-generating drugs include glyceryl ether (Gaifinesin) and scopolamine bromide, ibuprofen, anhydrous caffeine, ethyl salicylamide, iprofen, and L-menthol. The compounding quantity of these drugs can be adjusted suitably according to the use of a drug, Preferably it is 0.1-99 weight% with respect to a core material, More preferably, it is 1-85 weight%.

In the present invention, examples of the drug contained in the core material preferably include the following drugs.

〔Garlic processed product〕

Garlic processed products are obtained by processing the bulbs of Allium sativum l. in the family Liliaceae. The method of processing is not particularly limited, and examples include drying raw garlic and then pulverizing it; extracting raw garlic with steam distillation, oil, water, hot water, or a water-soluble organic solvent; And so on to get raw garlic. The oil used for extraction includes edible vegetable oils such as rapeseed oil, olive oil, and soybean oil, and the water-soluble organic solvent includes lower alcohols such as ethanol and isopropanol; glycols such as propylene glycol and diethylene glycol; and the like. The garlic processed product is particularly preferably dried, powdered, extracted with a lower alcohol, or processed with heat. In addition, a processed garlic product may be a commercially available product. For example, processed garlic, garlic extract, garlic extract, dried garlic, etc. are preferable, and processed garlic is particularly preferable. Here, processed garlic is garlic powder obtained by drying an extract obtained by heat-treating garlic by extraction with a lower alcohol. (strain) system). Garlic extracts are commercially available, for example, garlic extracts (Alps Pharmaceutical Co., Ltd.), garlic liquid extracts (Nippon Powder Pharmaceutical Co., Ltd.), and the like. Dried garlic is commercially available, for example, Garlic Pounder and Rosette Garlic Pounder EX (manufactured by Riken Chemical Industry Co., Ltd.). Among these commercially available garlic processed products, Okisoramin (registered trademark) (manufactured by Riken Chemical Industry Co., Ltd.), Okisoramin (registered trademark) (manufactured by Riken Chemical Industry Co., Ltd.), garlic extract (Alps Pharmaceutical Industry Co., Ltd.) are preferable. ), garlic liquid extract (Japan Powder Pharmaceutical Co., Ltd.). The compounding quantity of the garlic processed product can be adjusted suitably according to the use of a sugar-coated preparation, Preferably it is 2-30 weight% with respect to a core material, More preferably, it is 5-15 weight%.

〔Sulfonium methylmethionine chloride〕

Methylmethioninesulfonium chloride (MMSC) can be obtained by a known production method. In addition, commercially available products include, for example, methyl methionine sulfonium chloride (manufactured by Yonezawahama Riyaku Co., Ltd., manufactured by Alps Pharmaceutical Co., Ltd.). The blending amount of MMSC is preferably 1 to 80% by weight, more preferably 10 to 40% by weight, based on the core material.

In addition, the core material containing MMSC also preferably contains ingredients that neutralize gastric acid or inhibit gastric acid secretion (antacid ingredients), ingredients that improve gastric motility (stomach-enhancing ingredients), ingredients that aid digestion (digestive enzymes), repair stomach Components of mucous membranes (mucosal repair components), etc.

The acid-making components can include synthetic aluminum magnesium carbonate, sodium bicarbonate, aluminum magnesium silicate, aluminum hydroxide, sodium bicarbonate coprecipitate, belladonna extract, aluminum hydroxide, sodium bicarbonate, magnesium carbonate, sedimentation carbonic acid Calcium, Precipitated Magnesium Carbonate, Aluminum Dihydroxy Glycinate, Magnesium Hydroxide, Magnesium Oxide, Dry Aluminum Hydroxide Gel, Magnesium Bismuth Aluminosilicate, Magnesium Silicate, Synthetic Calcium Silicate, Ranitidine Hydrochloride, Cimet Tidine, famotidine, nizatidine, lafutidine, omeprazole, lansoprazole, pantoprazole, rabeprazole sodium, leminoprazole, esomeprazole, Pirenzepine hydrochloride, proglumide, etc.

Stomach invigorating ingredients include powdered medicine, hops extract, gentian (Gentiana) extract, fennel powder, ginger powder, clove powder, wild tung (Akamegashiwa) powder, catechu powder , ebony powder, black medicine powder, scutellaria baicalensis powder, phellodendron powder, coptis powder, zedoary powder, rhododendron (カツコウ) powder, licorice powder, husk (キコク) powder, cinchona powder, flavescens powder, cinnamon powder, cassia seed powder, Geranium (ゲンノショウウコ) powder, red ginseng powder, Magnolia officinalis powder, Evodia fruit powder, Chinese gallnut powder, Coronbo powder, tangerine peel powder, hawthorn powder powder, Sanjiao powder, herbal medicine (Sanna) powder, perilla seed powder, ginger flower (シュクシヤ) powder, cardamom powder, seihi powder powder, stone calamus powder powder, atractylodes powder powder, perilla powder powder, rhubarb powder powder, bamboo ginseng powder powder, juniper tree powder (ヒウヒ) powder, bitter tree (Nigaki) powder, nutmeg (Nikuzuku) powder, ginseng powder, hairy leaf fragrant tea (ヒキオコシ) powder, Piper dial (Hヒハツ) powder, Atractylodes macrocephala (Biyaku ジュツ) powder, woody powder, benefit Chi powder, bayberry peel powder, peppermint oil, gentian powder, galangal powder, fennel seed, aloe vera, suisai leaf, aniseed fennel, milk vine, Processed Garlic, Calamus Root (Karamus Root), Centauria (Centauria), Nuxychia (Homika) Extract, Dried Yeast, Carnitine Chloride, Glutamic Acid, Bectoline (塩化ベタネコル), trimebutine maleate (trimebutine maleate) and the like.

Examples of digestive enzymes include Aspergillus oryzae, lipase, ursodeoxycholic acid, sugar-containing human pepsin, jasmen, cellulase, celrosin, Takasa amylase, bile powder, dehidroko Il, new lipase (Niyu-la-ze), pancreatin, proteolytic enzyme (Biotamira-ze), proteolytic enzyme (Prozaim), Polyperase, etc.

The mucosal repairing components include sucralfate (scrallfate), aluminum allantoin (Algiokisa), L-glutamine, sofalcone (Sofarcon), sodium copper chlorophyllin (copper chlorophyllinatrium), potassium copper chlorophyllin ( Copper Chrolfinkarium), Cetraxate Hydrochloride (Setrakisate Hydrochloride), Gefarate (Gefalnat), Trimebutine Maleate Tablets, Sodium Azulene Sulfonate .

〔Sodium valproate〕

Sodium valproate can be obtained by known production methods (for example, refer to JP-A-60-156638, JP-A-62-106041, JP-A-63-122646, JP-10-130197). Moreover, as a commercial item, sodium valproate (manufactured by Nippon Synthetic Chemical Industry Co., Ltd., manufactured by Alibaba) etc. are commercially available, for example. The compounding quantity of sodium valproate is preferably 1-80 weight% with respect to a core material, More preferably, it is 30-60 weight%.

In addition, in addition to the above-mentioned drugs, various optional components that can be administered orally can be added to the core material as needed. Examples of various optional additives that can be administered orally include excipients, binders, disintegrants, lubricants and the like.

Examples of excipients include lactose, crystalline cellulose, sucrose, mannitol, light anhydride silicic acid, calcium hydrogen phosphate, and corn starch.

Examples of the binder include methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, and pullulan.

Examples of the disintegrant include carmellose calcium, low-substituted hydroxypropyl cellulose, crospovidone, and croscarmellose sodium.

Examples of lubricants include magnesium stearate, calcium stearate, and talc.

The core material used in the sugar-coated preparation of the present invention can be produced by a conventional method using drugs and other optional ingredients.

For example, when it is a plain tablet, the method of compressing the granulated product after granulating the compounded drug and other optional additives; or using a granulator to granulate the compounded drug and other optional additives They are granulated to make powder, and then according to the need, add other arbitrary additives to the powder to make a mixed powder, and then compress these powders; or mix directly compounded drugs and other arbitrary additives A method for compressing a substance into tablets using a tablet press, etc.

Here, granulation can include dry granulation method and wet granulation method, and dry granulation method means that powder is granulated by dry granulator without using liquids such as water, ethanol, isopropanol, and their mixtures. The body is compressed and formed, and then the plate-shaped solids are crushed to produce granular objects.

In addition, the wet granulation method refers to the process of adding a binding liquid to the powder by using a high-speed stirring granulator, a mixing granulator, a fluidized bed granulator, a rotary flow granulator, etc., forming particles and then drying them. As a method, the type of adhesive liquid is not particularly limited, and water, ethanol, isopropanol, and a mixture thereof can be used.

Next, in the case of core granules, a method of granulating the compounded drug and other optional additives using a dry granulation method, a method of granulating a wet granulation method or a combination of a wet granulation method and an extrusion granulation method method etc.

At least one layer of the sugar coating layer covering the core material contained in the sugar coating preparation of the present invention contains 0.01 to 10% by weight of sugar and ethyl acrylate/methyl methacrylate copolymer.

In addition, the sugar-coated preparation of the present invention may have one or more coating layers formed of other coating liquids in addition to the one or more sugar-coating layers formed using the sugar-coating liquid of the present invention. Note that, in this specification, the layer formed using the sugar-coating solution of the present invention is described as a "sugar-coating layer", and the sugar-coating layer and layers formed using a coating solution other than the sugar-coating solution of the present invention are collectively described as a "coating layer". ".

The cladding layer can be divided into multiple layers such as waterproof layer (protective coating), subcoating, smoothing, coloring and polishing according to its function. . The ratio of these layers to the overall coating layer is usually 0-20% for the waterproof layer, 15-100% for the primer layer, 0-50% for the middle coat layer, 0-50% for the top coat layer, and 0-50% for the polishing layer. 0-10%. The waterproof layer is implemented to prevent migration of moisture to the core material during the sugar coating process. In addition, the undercoat is applied to regulate the shape of the sugar-coated tablet, and the quality of the undercoat affects the appearance and strength of the sugar-coated tablet. In addition, the middle coat is applied to smooth the surface of sugar-coated tablets, the top coat is applied to color the sugar-coated tablets to improve the visibility and commercial value, and the polishing layer is applied to impart luster to the sugar-coated tablets. The sugar-coated preparation of the present invention does not necessarily have all the coating layers with the above-mentioned functions, and preferably contains a coating layer with a primer function. The sugar-coat layer formed by using the sugar-coating liquid of the present invention can be used as a coating layer with a primer function. use.

Furthermore, the sugar-coated preparation of the present invention may be coated with a controlled-release layer differently from the above-mentioned coating layer according to the purpose. The controlled-release layer is implemented to impart a function of controlling the dissolution of the drug contained in the core material, and may be one or more layers. The controlled-release layer can be directly coated on the core material, or can also be implemented between any of the above-mentioned waterproof layer, primer coat, middle coat, top coat and polishing layer, and is usually preferably coated on the core material. When coating the controlled-release layer, it is preferably 1 to 10% by weight, more preferably 2 to 8% by weight, based on 1 weight part of the sugar-coated preparation. In addition, conventional methods and components can be used for the method of implementing the controlled release layer or the components used.

In the sugar-coated preparation of the present invention, the weight of the sugar-coated layer formed using the sugar-coated solution of the present invention is preferably 5 to 60% by weight, more preferably 10 to 50% by weight, based on the weight of the core material. When the weight of the sugar-coat layer exceeds 60% by weight, the time of the coating process will be prolonged, and the mass of the obtained sugar-coated preparation will increase relative to the mass of the core material to be charged, thus causing a problem that a coating device is required separately. In addition, if it is less than 5% by weight, sufficient hardness of the coating layer cannot be obtained, and since the coating layer is thin, there is a problem that it is difficult to protect the contents such as the plain sheet and core particles from the ambient humidity.

The moisture absorption rate of the sugar-coated preparation of the present invention is preferably 1.0% or less, more preferably 0.5% or less under the condition of temperature and humidity of 25°C-85% after 24 hours, and preferably under the condition of temperature and humidity of 40°C-75% after 30 days. 4.0% or less, more preferably 3.0% or less. In addition, hardness and disintegration can be appropriately adjusted according to the purpose of use of the sugar-coated preparation of the present invention or the drug contained in the core material.

When the core material of the sugar-coated preparation of the present invention contains processed garlic, the hardness of the sugar-coated preparation is preferably 100N or higher, more preferably 110N or higher. In addition, the disintegration degree is preferably within 25 minutes.

When the core material of the sugar-coated preparation of the present invention contains MMSC, the hardness of the sugar-coated preparation is preferably 65N or higher, more preferably 70N or higher. In addition, the disintegration degree is preferably within 15 minutes.

When the core material of the sugar-coated preparation of the present invention contains sodium valproate, the hardness of the sugar-coated preparation is preferably 65N or higher, more preferably 70N or higher.

The sugar-coated preparation of the present invention can be produced by forming a sugar-coated layer by a continuous coating method in which a spraying step and a drying step of the sugar-coating solution of the present invention are performed simultaneously. That is, by drying the drug-containing core material while spraying the sugar-coating solution of the present invention, the solvent in the sugar-coating solution covering the core material can be volatilized to form a sugar-coated layer. In addition, the dosage form of sugar-coated tablets or sugar-coated granules can also be made by using the core material (plain tablet or core granule).

When producing sugar-coated tablets, the plain tablet containing the drug or the protective sheet with a waterproof layer or the like can be put into the continuously rotating coating device, and the sugar-coating liquid can be sprayed and sprayed on the plain tablet or protective tablet rotating in the device at the same time. Dries to form a sugar coating that coats the core material. As an apparatus used in the continuous coating method, for example, Hicoater (Floint Industry), Aquacoater (Floint Industry), Powreck Cotter (Pauretsuku), Doriacoater (Powreku) and the like can be mentioned.

The droplet diameter of the sprayed sugar-coating liquid is preferably 0.1-1000 μm, and the spray amount can be adjusted according to the size or amount of the core material so as to cover the entire surface of the core material. In addition, the temperature of the sugar coating solution is preferably 10 to 80°C. The air supply temperature and air volume are preferably adjusted according to the product temperature reaching 10-60°C.

When producing sugar-coated granules, it is preferable to use a fluidized bed coater, and it is particularly preferable to use a rotating fluidized bed coater with a rotating disk at the bottom. For example, Maltipurex (Powrec), Granyurex (Floint Industry), Spiraflow (Floint Industry), Agromaster (Hosokawa Micron), Niyuyi Malmelaser (Fuji Poutal) and the like can be mentioned.

Continuously inject drug-containing granules or protected granules with a water-repellent layer into the coating device that rotates on the bottom of the main body, and simultaneously spray and dry the sugar-coated granules or protected granules that flow and rotate in the device , can form a sugar coating layer covering the core material.

The droplet diameter of the sprayed sugar coating solution is preferably 0.1 to 100 μm, and the spray amount can be adjusted according to the size or amount of the core material so as to cover the entire surface of the core material. In addition, the temperature of the sugar coating solution is preferably 10 to 80°C. The air supply temperature and air volume are preferably adjusted according to the product temperature reaching 10-50°C.

In addition, the formation of the coating layer using a coating solution other than the sugar-coating solution of the present invention can be performed by a method generally used in the production of sugar-coated preparations. The coating device used at this time can also be appropriately selected according to the type of coating liquid, etc., and is not particularly limited. In addition, the liquid droplets or the amount of spray when spraying the coating liquid can also be adjusted in the same manner as the spraying of the sugar-coating liquid.

The sugar-coated preparation of the present invention thus obtained has a thinner sugar-coated layer, sufficient hardness, low hygroscopicity, deodorant property, and disintegration property compared with conventional preparations.

Example

The present invention will be specifically described below using examples.

<Manufacturing example 1>

Put 3,000 g of lactose, 150 g of hydroxypropyl cellulose (HPC-L: Nippon Soda), 1,200 g of corn starch, and 1,000 g of crystalline cellulose (Seolas PH-101: Asahi Kasei) into a high-speed stirring granulator (VG-25: Powrec) , adding purified water to prepare granules. This was dried using a fluidized bed dryer (FLO-5B: FLOINT INDUSTRY), and then the dried product was sized using a granulator (Power Mill, Showa Chemical Machinery).

鐵工所)将其制成每1片为270mg的素片。50 g of magnesium stearate was mixed with 5350 g of the obtained granules, and a rotary tablet machine (HP-AP18-SS:

Iron Works) made it into plain tablets of 270 mg per tablet.

To 5400 g of the obtained plain tablets, a coating solution containing 100 g of hydroxypropylmethylcellulose 2910 (TC-5R: Shin-Etsu Chemical Industry) and 900 g of purified water was used, and a coating machine (Driacoater DRC-650, Powrec) was used. A water-repellent layer was applied to the plain sheet to produce a protective sheet of 275 mg per tablet.

<Example 1>

For 5500 g of the protective sheet obtained in Production Example 1, 66.7 g and The sugar-coated liquid suspended in 2000 g of purified water was sprayed with a coating machine (Driacoat DRC-650, Powrec) while drying the sugar-coated liquid to obtain 375 mg sugar-coated tablets per tablet. It should be noted that the time taken for the coating work was 2 hours.

<Example 2>

For 5500 g of the protective sheet obtained in Production Example 1, 133.3 g and The sugar-coated solution suspended in 2,000 g of purified water was sprayed with a coating machine (Driacoat DRC-650, Pautsuku) while drying the sugar-coated solution to obtain 375 mg sugar-coated tablets per tablet. The time taken for the coating work was 2 hours.

<Example 3>

For 5500 g of the protective sheet obtained in Production Example 1, 266.7 g and The sugar-coated liquid suspended in 2000 g of purified water was sprayed with a coating machine (Driacoat DRC-650, Powrec) while drying the sugar-coated liquid to obtain 375 mg sugar-coated tablets per tablet. The time taken for the coating work was 2 hours.

<Comparative example 1>

For 5500 g of the protective sheet obtained in Production Example 1, a suspension containing 1160 g of granulated sugar, 400 g of talc powder, 400 g of precipitated calcium carbonate, 40 g of hydroxypropylmethylcellulose 2910 (TC-5R: Shin-Etsu Chemical Industry) and 2000 g of purified water was used. The sugar-coated solution was sprayed with a coating machine (Driacoater DRC-650, Powrec) while drying, to obtain 375 mg sugar-coated tablets per tablet. The time taken for the coating work was 2 hours.

<Comparative example 2>

For 5500 g of the protective sheet obtained in Manufacturing Example 1, use was made of 1924 g of granulated sugar, 542 g of talc, 818 g of precipitated calcium carbonate, 64 g of gum arabic, 30 g of gelatin, polyoxyethylene (105) polyoxypropylene (5) diol (PEP-101: FLOINT INDUSTRIAL) 22g and purified water 1200g of the suspension sugar-coating liquid, utilize the existing sugar-coating coating method of spraying, evaporating, and drying the sugar-coating liquid using a coating machine (Driacota-DRC-650, Powrec), respectively, to obtain each 1 sugar-coated tablet of 445 mg. The time taken for the coating operation was 6.5 hours.

<Manufacturing example 2>

Garlic processed product 500g (Okiso Amino, manufactured by Riken Chemical Industry Co., Ltd.), lactose 2500g, hydroxypropyl cellulose (HPC-L: Nippon Soda) 150g, cornstarch 1200g, crystalline cellulose (Seoras PH-101: Asahi Kasei ) 1000 g was put into a high-speed stirring granulator (VG-25: Powrec), and purified water was added to prepare a granulated product. This was dried using a fluidized bed dryer (FLO-5B: FLOINT INDUSTRY), and then the dried product was sized using a granulator (Powa Mill, Showa Chemical Machinery).

鐵工所)将其制造每1片为270mg的素片。50 g of magnesium stearate was mixed with 5350 g of the obtained granules, and a rotary tablet machine (HP-AP18-SS:

Iron Works) to manufacture plain tablets of 270 mg per tablet.

5400 g of the obtained plain tablets were coated with a coating solution containing 100 g of hydroxypropylmethylcellulose 2910 (TC-5R: Shin-Etsu Chemical Industry) and 900 g of purified water, and a coating machine (Driacoater DRC-650, Powrec) was used. A water-repellent layer was applied to the plain sheet to produce a protective sheet of 275 mg per tablet.

<Example 4>

For 5500 g of the protective sheet obtained in Production Example 2, 66.7 g and The sugar-coated liquid suspended in 2000 g of purified water was sprayed with a coating machine (Driacoat DRC-650, Powrec) while drying the sugar-coated liquid to obtain 375 mg sugar-coated tablets per tablet. It should be noted that the time taken for the coating work was 2 hours.

<Example 5>

For 5500 g of the protective sheet obtained in Production Example 2, 133.3 g and The sugar-coated liquid suspended in 2000 g of purified water was sprayed with a coating machine (Driacoat DRC-650, Powrec) while drying the sugar-coated liquid to obtain 375 mg sugar-coated tablets per tablet. It should be noted that the time taken for the coating work was 2 hours.

<Example 6>

For 5500 g of the protective sheet obtained in Production Example 2, 266.7 g and The sugar-coated liquid suspended in 2000 g of purified water was sprayed with a coating machine (Driacoat DRC-650, Powrec) while drying the sugar-coated liquid to obtain 375 mg sugar-coated tablets per tablet. It should be noted that the time taken for the coating work was 2 hours.

<Comparative example 3>

For 5500 g of the protective sheet obtained in Production Example 2, a suspension containing 1160 g of granulated sugar, 400 g of talc powder, 400 g of precipitated calcium carbonate, 40 g of hydroxypropylmethylcellulose 2910 (TC-5R: Shin-Etsu Chemical Industry) and 2000 g of purified water was used. The sugar-coated solution was sprayed with a coating machine (Driacoater DRC-650, Powrec) while drying, to obtain 375 mg sugar-coated tablets per tablet. It should be noted that the time taken for the coating work was 2 hours.

<Comparative example 4>

For 5500 g of the protective sheet obtained in Manufacturing Example 2, use 1924 g of granulated sugar, 542 g of talc, 818 g of precipitated calcium carbonate, 64 g of gum arabic, 30 g of gelatin, polyoxyethylene (105) polyoxypropylene (5) diol (PEP-101: FLOINT INDUSTRIAL) 22g and purified water 1200g of the suspension sugar-coating liquid, utilize the existing sugar-coating coating method of spraying, evaporating, and drying the sugar-coating liquid using a coating machine (Driacota-DRC-650, Powrec), respectively, to obtain each 1 sugar-coated tablet of 445 mg. It should be noted that the time taken for the coating work was 6.5 hours.

<Manufacturing example 3>

Mix 1000 g of sulfonium chloride methylmethionine (sulfonium chloride methylmethionine, Yonezawa Hamari Pharmaceutical Co., Ltd.), 600 g of lactose, 300 g of polyvinylpyrrolidone (Coridon 30: BASF Japanpan), 1550 g of cornstarch, carboxymethyl 500 g of cellulose calcium (ECG-505: Gotoku Pharmaceutical) was put into a high-speed stirring granulator (VG-25: Powrec), and ethanol was added to prepare a granulated product. This was dried with a fluidized bed dryer (FLO-5B: FLOINT INDUSTRY), and then the dried product was sized with a granulator (Power Mill, Showa Chemical Machinery).

鐵工所)将其制造为每1片为100mg的素片。50 g of magnesium stearate was mixed with 3950 g of the obtained granules, and a rotary tablet press (HP-AP18-SS:

Iron Works) manufactures it as a plain tablet of 100 mg per tablet.

For 4000 g of the obtained plain tablet, 400 g of hydrogenated oil, 100 g of glyceryl monostearate (Nichiko MGS-B: Nikko Chemical) and polyethylene glycol monostearate (40EO) (Nichiko Il MYS-40: Nikko Chemical) 100 g of liquid and talc powder 200 g, and a coating machine (Driacoat DRC-650, Powrec) was used to apply a water-repellent layer to the plain tablet to produce a protective sheet of 120 mg per tablet.

<Example 7>

For 4800 g of the protective sheet obtained in Production Example 3, 66.7 g and The sugar-coated liquid suspended in 2000 g of purified water was sprayed with a coating machine (Driacoater DRC-650, Powrec) while drying the sugar-coated liquid to obtain 170 mg sugar-coated tablets per tablet. It should be noted that the time taken for the coating work was 1 hour.

<Embodiment 8>

For 4800 g of the protective sheet obtained in Production Example 3, 133.3 g of a dispersion containing 1160 g of granulated sugar, 400 g of talc, 400 g of precipitated calcium carbonate, and a 30% dispersion of ethyl acrylate/methyl methacrylate copolymer (オイドラギツト NE30D: Hiro Shokai) and The sugar-coated liquid suspended in 2000 g of purified water was sprayed with a coating machine (Driacoater DRC-650, Powrec) while drying the sugar-coated liquid to obtain 170 mg sugar-coated tablets per tablet. It should be noted that the time taken for the coating work was 1 hour.

<Example 9>

For 4800 g of the protective sheet obtained in Production Example 3, 266.7 g and The sugar-coated liquid suspended in 2000 g of purified water was sprayed with a coating machine (Driacoater DRC-650, Powrec) while drying the sugar-coated liquid to obtain 170 mg sugar-coated tablets per tablet. It should be noted that the time taken for the coating work was 1 hour.

<Comparative example 5>

For 4800 g of the protective sheet obtained in Production Example 3, a suspension containing 1160 g of granulated sugar, 400 g of talc powder, 400 g of precipitated calcium carbonate, 40 g of hydroxypropylmethylcellulose 2910 (TC-5R: Shin-Etsu Chemical Industry) and 2000 g of purified water was used. The sugar-coated solution was sprayed with a coating machine (Driacoater DRC-650, Powrec) while drying to obtain 170 mg sugar-coated tablets per tablet. It should be noted that the time taken for the coating work was 1 hour.

<Comparative example 6>

For 4800 g of the protective sheet obtained in Manufacturing Example 3, using a suspension sugar-coating solution containing 660 g of granulated sugar, 1100 g of talcum powder, 1100 g of precipitated calcium carbonate, 280 g of gum arabic, 60 g of gelatin, and 600 g of purified water, a coating machine (Dria Coater) was used. DRC-650, パュレツク) was sprayed with a sugar-coated solution while drying to obtain 200 mg sugar-coated tablets per tablet. It should be noted that the time taken for the coating work was 3.5 hours.

<Manufacturing example 4>

3300 g of sodium valproate, 165 g of light silicic anhydride, and 303.6 g of ethyl cellulose were put into a high-speed stirring granulator (VG-25: Powrec), and ethanol was added to prepare a granulated product. This was dried with a fluidized bed dryer (FLO-5B: FLOINT INDUSTRY), and then the dried product was sized with a granulator (Power Mill, Showa Chemical Machinery).

鐵工所)将其制造为每1片为230mg的素片。24 g of calcium stearate was mixed with 3426 g of the obtained granules, and a rotary tablet press (HP-AP18-SS:

Iron Works) manufactures it as plain tablets of 230 mg per tablet.

To 3220 g of the obtained plain sheet, 60 g of ethyl cellulose, 30 g of methacrylic acid copolymer L (Eudragit L100: Hikou Shokai), 22.5 g of triethyl citrate and 22.5 g of light silicic anhydride were used in 1365 g of ethanol and dispersed therein. For the liquid, after applying a controlled-release layer to the plain tablet using a coating machine (Driacoater-DRC-650, Powrec), a liquid in which 60 g of ethyl cellulose and 30 g of light silicic anhydride were dissolved and decomposed in 1410 g of ethanol was used, A controlled-release layer was applied using a coating machine (Driacoater DRC-650, Powrec) to produce controlled-release tablets of 245 mg per tablet.

<Example 10>

For 686 g of the controlled-release tablets obtained in Production Example 4, 9.9 g of a dispersion containing 93 g of granulated sugar, 3 g of talc, 51 g of precipitated calcium carbonate, and a 30% dispersion of ethyl acrylate/methyl methacrylate copolymer (オイドラギツト NE30D: Hikou Shokai) was used. and purified water 135.6g of the suspended sugar-coating solution, utilize a coating machine (Hicota-HCT-30N, FLOINT INDUSTRY) to spray the sugar-coating solution, and dry simultaneously to obtain 295 mg per tablet (wherein the quality of the sugar-coating layer is 50 mg) ) sugar-coated tablets. It should be noted that the time taken for the coating operation was 40 minutes.

<Example 11>

For 686 g of the controlled-release tablets obtained in Production Example 4, 20.1 g of a dispersion containing 186 g of granulated sugar, 6 g of talc, 102 g of precipitated calcium carbonate, and a 30% dispersion of ethyl acrylate/methyl methacrylate copolymer (オイドラギツト NE30D: Hikou Shokai) was used. and purified water 270.9g of the suspended sugar-coated liquid, utilize a coating machine (Hicota-HCT-30N, FLOINT industry)) to spray the sugar-coated liquid, and dry simultaneously to obtain 345 mg per tablet (wherein the quality of the sugar-coated layer is 100mg) sustained-release sugar-coated tablets. It should be noted that the time taken for the coating operation was 75 minutes.

<Comparative example 7>

686 g of controlled-release tablets obtained in Manufacturing Example 4 were prepared by using 288.6 g of granulated sugar, 81.3 g of talcum powder, 122.7 g of precipitated calcium carbonate, 9.6 g of gum arabic, 4.5 g of gelatin, polyoxyethylene (105) polyoxypropylene (5) two Suspended sugar-coating solution of 3.3 g of alcohol and 180 g of purified water was obtained by using the existing sugar-coating method of spraying, evaporating, and drying the sugar-coating solution using a small sugar-coating machine (manufactured by Kikusui Seisakusho) to obtain 415 mg per tablet. Base smear. In addition, the time consumed for this coating operation was 300 minutes. Furthermore, using a suspension sugar coating solution containing 114 g of granulated sugar, 6 g of titanium oxide, and 72 g of purified water, the existing sugar coating method of spraying, evaporating, and drying the sugar coating solution using a small sugar coating machine (manufactured by Kikusui Seisakusho), respectively, Colored tablets of 455 mg per 1 tablet were obtained. In addition, the time consumed for this coating operation was 240 minutes. Finally, using a sugar-coating solution containing 15 g of sugar and 9 g of purified water, the conventional sugar-coating method of spraying, evaporating, and drying the sugar-coating solution using a small sugar-coating machine (manufactured by Kikusui Seisakusho) was used to obtain 460 mg per tablet ( Wherein the quality of sugar-coated layer is the sugar-coated tablet of 215mg). In addition, the time consumed for this coating operation was 30 minutes, and the total time consumed for all coating operations was 570 minutes.

From the above results, it can be seen that when using the production method of the present invention in which the sugar-coating liquid is sprayed and dried, the working time can be shortened to less than 1/3 compared with the conventional coating method. In addition, the weight of the sugar-coated layer of the sugar-coated tablet can also reach about 1/2 to 1/4.

<Evaluation of Hygroscopicity>

Measure the quality of 10 sugar-coated tablets obtained in Examples 1 to 9 and Comparative Examples 1 to 6 at 25° C.-84.3% for 1 hour, 2 hours, 3 hours and 24 hours. Ratio, measure the amount of moisture absorption, and calculate the moisture absorption rate (%). In addition, it was measured that 10 sugar-coated tablets obtained in Examples 10 to 11 and Comparative Example 7 were left to stand at 40°C-75% for 3 hours, 1 day, 2 days, 3 days, 7 days, 10 days, 14 days, For the mass after 21 days, 28 days and 30 days, the moisture absorption rate (%) was calculated in the same manner as above. The results are shown in Figs. 1 to 4 .

Moisture absorption rate (%)=(mass of 10 tablets after storage for each hour-mass of 10 tablets at the beginning)/mass of 10 tablets at the beginning×100

As can be seen from FIG. 1 , even if the sugar-coated preparations of Examples 1 to 3 were left to stand for 24 hours under the above-mentioned conditions, the moisture absorption rate was as low as 0.1%. The sugar-coated preparation of Comparative Example 1 had a moisture absorption rate of 0.2% when left standing for 3 hours, and increased to nearly 1.2% when left standing for 24 hours. In addition, when the sugar-coated preparation of Comparative Example 2 was left to stand for 24 hours, the moisture absorption rate increased to about 0.5%.

As can be seen from FIG. 2 , even if the sugar-coated preparations of Examples 4 to 6 were left to stand for 24 hours under the above-mentioned conditions, the moisture absorption rate was as low as 0.1%. The sugar-coated preparation of Comparative Example 3 had a moisture absorption rate of 0.4% when left standing for 3 hours, and increased to nearly 2.1% when left standing for 24 hours. In addition, when the sugar-coated preparation of Comparative Example 4 was left to stand for 24 hours, the moisture absorption rate increased to about 0.5%.

As can be seen from FIG. 3 , even if the sugar-coated preparations of Examples 7 to 9 and Comparative Example 6 were left to stand for 24 hours under the above conditions, the moisture absorption rate was as low as 0.5% or less. In the sugar-coated preparation of Comparative Example 5, the moisture absorption rate increased to approximately 1.3% when left to stand for 3 hours, and increased to approximately 5.6% when left to stand for 24 hours.

It can be seen from FIG. 4 that even though the sugar-coated layer masses of the sugar-coated preparations of Examples 10 and 11 were about 1/4 and 1/2 compared with Comparative Example 7, the moisture absorption rates after 30 days were 2.0% and 1.0%, respectively. extremely low. On the other hand, the sugar-coated preparation of Comparative Example 7 had a moisture absorption rate close to 4.0% after 7 days, and the tablet ruptured after 10 days. Tablet rupture may be due to the hygroscopic nature of sodium valproate.

From the above, it can be seen that when the sugar-coating liquid of the present invention is used, even when the sugar-coating preparation is produced by a coating method of drying while spraying the sugar-coating liquid, a sugar-coated preparation having excellent low hygroscopicity compared to conventional sugar-coating preparations can be obtained.

<Evaluation of Physical Properties>

The hardness and disintegration degree of the sugar-coated tablets obtained in Examples 1-9 and Comparative Examples 1-6 were measured. For the hardness, 20 tablets were taken and the tablet hardness was measured for each tablet with a tablet hardness tester (PTB-311E manufactured by Pharmatest Co., Ltd.), and the average value was calculated. The disintegration degree was measured in accordance with the disintegration test method described in the 15th revision of the Japanese Pharmacopoeia using an auxiliary plate (disintegration tester manufactured by Toyama Sangyo Co., Ltd.). The test was carried out on 6 pieces, and the average value was calculated. The results are shown in Tables 1-3.

【Table 1】

The sugar-coated preparations of Examples 1 to 3 had sufficient hardness and were also excellent in disintegration properties. On the other hand, the sugar-coated preparation of Comparative Example 1 had insufficient hardness and disintegration properties. Although the sugar-coated preparation of Comparative Example 2 had high hardness, its disintegration property was insufficient.

【Table 2】

The sugar-coated preparations of Examples 4 to 6 had sufficient hardness and were also excellent in disintegration properties. On the other hand, the sugar-coated preparation of Comparative Example 3 had insufficient hardness and disintegration properties. Although the sugar-coated preparation of Comparative Example 4 had high hardness, disintegration was insufficient.

【table 3】

The sugar-coated preparations of Examples 7 to 9 had sufficient hardness and were also excellent in disintegration properties. On the other hand, the sugar-coated preparations of Comparative Examples 5 and 6 had insufficient hardness and disintegration properties.

From the above, it can be seen that the sugar-coated preparation of the present invention has sufficient hardness and is also excellent in disintegration properties.

<Evaluation of smell>

The odor of the sugar-coated tablets obtained in Examples 4-9 and Comparative Examples 3-6 was evaluated. After putting the obtained preparation into a transparent glass bottle and sealing it, the occurrence of odor when stored at 60°C for 3 days, 1 week, and 2 weeks was evaluated according to the following 4 levels, 0: No odor from the drug was felt at all. Unpleasant smell, 1: The unpleasant smell derived from the drug is hardly felt, 2: The unpleasant smell derived from the drug is sensed, 3: The unpleasant smell derived from the drug is strongly felt. The evaluation was performed by 5 persons, and the average value was calculated. The results are shown in Tables 4-5.

【Table 4】

In the sugar-coated preparations of Examples 4 to 6 and Comparative Example 4, the unpleasant smell derived from okisoamina was not sensed at all even after a 2-week storage period. On the other hand, the sugar-coated preparation of Comparative Example 3 had a strong unpleasant smell derived from okisoamina. Especially with prolonged storage, the unpleasant smell intensifies.

【table 5】

In the sugar-coated preparations of Examples 7 to 9 and Comparative Example 6, even after a 2-week storage period, the unpleasant smell derived from MMSC was hardly felt. On the other hand, in the sugar-coated preparation of Comparative Example 5, the unpleasant smell derived from MMSC was felt after 3 days, and the unpleasant smell was strongly felt after 1 week.

From the above, it can be seen that the sugar-coated preparation of the present invention is more excellent in deodorant property than the conventional sugar-coated preparation.

<Moisture value evaluation immediately after manufacture>

The sugar-coated tablets of Examples 7 to 9 and Comparative Examples 5 to 6 immediately after manufacture were pulverized, about 5 g was weighed, calcium hydroxide was used as a reaction reagent, and the water content (%) was calculated by measuring with a barometric moisture meter for 10 minutes. The results are shown in Table 6.

【Table 6】

The water content (%) of the sugar-coated preparations of Examples 7-9 and Comparative Example 5 was lower than that of the sugar-coated preparation of Comparative Example 6. Therefore, when using the continuous coating method, the moisture value in the tablet can be reduced compared to the existing coating method.

<Dissolution test>

The dissolution test of the sugar-coated tablet of Example 11 was carried out. The test was carried out by using Japanese Pharmacopoeia Prescription Dissolution Test Method 2 (paddle method) and using 500 mL of Japanese Pharmacopoeia General Test Method Disintegration Test Method 2 Liquid as the test solution at 100 rpm per minute. Sampling was carried out every hour, and sodium valproate in the quantitative sampling solution was utilized by HPLC to calculate the dissolution rate (%) of sodium valproate. The results are shown in Figure 5.

As can be seen from FIG. 5 , the sugar-coated formulation of the present invention is also excellent in sustained release. From the above, it can be seen that the sugar-coated solution of the present invention is also useful for sugar-coated formulations of drugs requiring sustained release.

As can be seen from the above, the sugar-coated preparation of the present invention has sufficient hardness, low hygroscopicity, and excellent deodorization compared with the conventional sugar-coated preparation produced by the continuous coating method. Compared with sugar-coated preparations, it can be produced in a short coating operation, and it is a preparation with a low moisture content immediately after production and excellent disintegration properties.

That is, according to the production method of the present invention, a sugar-coated preparation that has a thin sugar-coated layer but has sufficient hardness and is excellent in low water content, low hygroscopicity, disintegration property, and deodorant property immediately after production can be easily produced in a short time.

Industrial applicability

Sugar-coated preparations can be produced by using the sugar-coated solution of the present invention by a continuous coating method in which a spraying step and a drying step of the sugar-coated solution are performed simultaneously. That is, a sugar-coated preparation excellent in low oxygen permeability, low hygroscopicity, deodorant property, and disintegration property can be produced in a short time without requiring complicated steps. In addition, since the production method of the present invention can form a thin sugar-coated layer, it greatly contributes to the reduction of the amount of sugar-coated solution used and the miniaturization of the formulation.

Claims (5)

1. A sugar-coating liquid, which is a sugar-coating liquid containing sugar, ethyl acrylate/methyl methacrylate copolymer and solvent, the concentration of ethyl acrylate/methyl methacrylate copolymer is 0.01～ 10% by weight, the mass ratio of ethyl acrylate/methyl methacrylate copolymer to sugar is 1:5~1:500, the number average molecular weight of ethyl acrylate/methyl methacrylate copolymer is 500,000~1,100,000, acrylic acid In the ethyl ester/methyl methacrylate copolymer, the molar ratio of ethyl acrylate to methyl methacrylate is 3:1-1:3. 2. A sugar-coated preparation comprising a drug-containing core material and a sugar-coated layer covering the core material, wherein at least one of the sugar-coated layers contains sugar and 0.01 to 10% by weight of ethyl acrylate /methyl methacrylate copolymer, the mass ratio of ethyl acrylate/methyl methacrylate copolymer to sugar is 1:5～1:500, and the number average molecular weight of ethyl acrylate/methyl methacrylate copolymer is 500,000～1,100,000, in ethyl acrylate/methyl methacrylate copolymer, the molar ratio of ethyl acrylate to methyl methacrylate is 3:1～1:3. 3. The sugar-coated preparation according to claim 2, further comprising a release-controlling layer. 4. The sugar-coated preparation according to claim 2 or 3, wherein the medicine is a medicine having an unpleasant smell, a medicine unstable to moisture, or a medicine producing whiskers. 5. A method for producing a sugar-coated preparation, wherein the spraying step and the drying step of the sugar-coating liquid according to claim 1 are performed simultaneously.

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