WO2006057194A1 - Solid agent and process for producing the same - Google Patents

Solid agent and process for producing the same Download PDF

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Publication number
WO2006057194A1
WO2006057194A1 PCT/JP2005/021143 JP2005021143W WO2006057194A1 WO 2006057194 A1 WO2006057194 A1 WO 2006057194A1 JP 2005021143 W JP2005021143 W JP 2005021143W WO 2006057194 A1 WO2006057194 A1 WO 2006057194A1
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WIPO (PCT)
Prior art keywords
rice starch
tablet
producing
mass
granule
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PCT/JP2005/021143
Other languages
French (fr)
Japanese (ja)
Inventor
Takeshi Honma
Ikuo Tanai
Terumi Takahashi
Fujio Sekigawa
Masayuki Arakawa
Kenji Furukawa
Hidemi Ohno
Hajime Fukuda
Nobumasa Tanaka
Original Assignee
Freund Corporation
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Publication of WO2006057194A1 publication Critical patent/WO2006057194A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • the present invention relates to a method for producing a solid preparation (granule, tablet) suitably used in the fields of pharmaceuticals, health foods, and the like, and a solid preparation produced by the method.
  • Drugs and health foods are often molded into solid dosage forms such as granules and tablets.
  • Common granule production methods include a wet granulation method and a dry granulation method.
  • the wet granulation method is a method of granulating by adding a liquid binder to the raw material powder. From the granulation mechanism, extrusion, flow, rolling, crushing, spraying, stirring, etc. There is a method.
  • the raw material powder is compression-molded (hereinafter sometimes referred to as roll compression molding) with a roller or the like, and then coarsely crushed with various crushers and further sieved to obtain the desired product.
  • This is a method for obtaining a granulated product having a particle size, that is, a granule.
  • the dry granulation method does not require a heat drying step that does not require the use of a liquid wetting agent such as water or organic solvent, there is a possibility of alteration by the wetting agent or decomposition by the heating drying step. It is suitable for the production of granules containing active ingredients such as active pharmaceutical ingredients and ingredients having food health functions (hereinafter referred to as “food health functional ingredients”).
  • the dry granulation method does not require a heating and drying process, so that the amount of energy consumption required for the drying equipment is small, so that the granule production cost is low.
  • Common tablet production methods include a direct powder compression method (hereinafter sometimes referred to as a direct tableting method) and a granule compression method.
  • the granule compression method includes a wet granule compression method and a dry granule compression method based on the difference in the granule production method.
  • the direct tableting method is basically compression molding of raw materials containing active ingredients or the like as they are, or the raw materials are mixed with excipients, generally called powdery binders, disintegrants, also called dry binders, This is a method of compression-molding a mixture in which other suitable additives are added and mixed uniformly. This method directly compresses the powder without pre-treatment, and is used when the powder has good compression moldability. In some cases, the powder contains an active ingredient as a raw material for direct compression. Some products that have been processed in advance to improve moldability are sold on the market.
  • the granule compression method is a method in which granules containing raw material powder are first produced using excipients, and then a lubricant is added to the obtained granules, followed by compression molding.
  • a lubricant is added to the obtained granules, followed by compression molding.
  • the direct tableting method is generally applied when the tablet to be produced contains an active ingredient unstable to water or heat. Has the least economic advantage.
  • the dry granule compression method uses the granules obtained by the dry granulation method as described above for tableting, and usually has problems in the fluidity and compression moldability of the powder to be molded. Used when it is difficult to apply the lock method.
  • the wet granule compression method is the most commonly used tablet manufacturing method, and is advantageous in that it is easy to compress and has a small mass deviation and good content uniformity.
  • the binder gives a binding force to the raw material powder and mixed powders containing it, facilitating compression molding. It is an additive used for In many cases, liquid binders such as starch paste liquid, hydroxypropyl cellulose liquid, polybutylpyrrolidone liquid are used, but powdered ones are also used. For example, crystalline cellulose is commonly used.
  • Yusuke Tsuda Basic Course on Drug Development, XI, Pharmaceutical Manufacturing Method, page 136, Jinjinshokan (Tokyo), (1971) states, “The use of crystalline cellulose as a binder for direct powder compression is common, There are two types of particle sizes with an average particle size of 40 m and 120 m on the market. " As described above, a powdery binder is used in the direct tableting method and the dry granulation method. As an example, water-insoluble crystalline cellulose is widely used.
  • binder binder As described above, there are binders used in a liquid state and those used in a powder form, and the latter binder is referred to as “powder” as described in the exemplified literature. May be referred to as “binder used as” or “powdered binder”. In this specification, binders used in powder form are collectively referred to as “powder binder”. In other words, “powder-like binders” are generally called “dry binders”, and are used in binders used in a punching operation without using a solvent, such as direct tableting and dry granulation methods, and wet granulation methods. Oh! It also includes binders that are added in powder form rather than liquid form.
  • the excipient When the amount of the raw material powder containing the active ingredient is small, the excipient is used to give a certain size and mass to the granules and tablets, or to increase the mass of the finished granules and tablets to some extent, It is an additive to facilitate handling and taking.
  • the excipient lactose is most commonly used, but starch, D-manntol, sucrose, etc. are also used.
  • the excipient used in the direct compression method is expected to be excellent in fluidity and compression moldability.
  • Lactose products as excipients for direct tableting are generally composed of a single component of lactose, but there are also examples of excipients composed of multiple components.
  • lactose granulated products there are “lactose granulated products” and “synthetic carboxylic acid hydroxypropyl starch. The former consists of hydroxypropylcellulose and lactose.
  • a powdery binder is further used.
  • Patent Documents 1 to 3 starch such as corn starch is used as an additive when tablets are formed by a direct tableting method, etc. to improve disintegration, swallowability, compression characteristics, and the like. A technique to be obtained is disclosed.
  • Patent Document 1 JP-A-8-208523
  • Patent Document 2 Pamphlet of International Publication No. 00Z47233
  • Patent Document 3 Japanese Patent Laid-Open No. 2002-12559
  • the powdered binder is used when producing tablets and granules, and powdered crystalline cellulose that is insoluble in water or an organic solvent is generally used.
  • crystalline cellulose has excellent properties in terms of binding properties, and has the property of gradually coloring yellowish brown during storage. For this reason, color changes may be observed with the naked eye on tablets containing a large amount of crystalline cellulose. Also, due to the interaction, it may promote the degradation of the active ingredient and promote the coloring of the preparation.
  • lactose widely used as an excipient may cause a Maillard reaction with a compound having an amino group.
  • the Maillard reaction is defined as a reaction that occurs between amino groups of amino acids, peptides, and proteins and hydroxyl groups that have the ability to form glycosides of sugars, and is an excipient that contains amino group-containing compounds and lactose.
  • D-mann-toll which is known as an excipient that does not cause such Maillard reaction, may be used.
  • the strength of D-mann-toll is low as moldability, so D-mann-toll is used as an excipient In this case, the yield of the granules tends to decrease, and there is a problem that it is difficult to obtain a tablet having a practical hardness.
  • a granulation method or tablet containing an active ingredient having an amino group is conventionally applied by applying a dry granulation method, the moldability and temporal color stability are improved. It was difficult to achieve both.
  • the present invention has been made in view of the above circumstances, and an object thereof is to improve the above-mentioned problems and the like when manufacturing tablets and granules. More specifically, it is as follows.
  • the present invention provides a method for producing tablets having practical tablet hardness and disintegration speed.
  • the tablet production method of the present invention is a compression molding using at least one of rice denpene having a water content of 6 to 14% by mass and rice starch derivative having a water content of 6 to 14% by mass as a powdery binder. By shaping the tablet by the method.
  • the water content of at least one of the rice starch and the rice starch derivative is preferably 9 to 14% by mass! /.
  • the tablet preferably contains at least one of an active pharmaceutical ingredient and a food health functional ingredient.
  • the content of at least one of rice starch and rice starch derivative in the tablet is preferably 5% by mass or more.
  • At least one of the rice starch and the rice starch derivative is adjusted to the water content after being heat-treated.
  • the granule production method of the present invention is a dry process using at least one of a rice starch having a water content of 6 to 14% by mass and a rice starch derivative having a water content of 6 to 14% by mass as a powdery binder. It includes granulating the powder by a granulation method.
  • the water content of at least one of the rice starch and the rice starch derivative is preferably 9 to 14% by mass! /.
  • the granule preferably contains at least one of an active pharmaceutical ingredient and a health functional ingredient for food.
  • the content of at least one of rice starch and rice starch derivatives in the granules is preferably 10% by mass or more.
  • At least one cellulosic powder binder selected from the group consisting of crystalline cellulose, powdered cellulose or low substituted hydroxypropylcellulose powder. Furthermore, it is preferable to use it.
  • the content of the cellulose-based powder binder in the granules is preferably 10 to 30% by mass.
  • D-mannitol is preferred to use as an excipient.
  • At least one of the rice starch and the rice starch derivative is adjusted to the water content after being heat-treated.
  • the granule of the present invention is produced by the above production method.
  • the tablet of this invention contains the said granule.
  • the tablet production method of the present invention is obtained by granulating a powder by a wet granulation method using at least one of rice starch and rice starch derivative as a powdery binder, and obtaining the granulated product. This includes conditioning the resulting granule so that its water activity (aw) is 0.4 to 0.8, and then compression molding.
  • the tablet preferably contains at least one of an active pharmaceutical ingredient and a food health functional ingredient.
  • the method for producing a tablet of the present invention comprises granulating a powdery excipient by a wet granulation method using at least one of rice starch and a rice starch derivative as a powder binder, It includes conditioning the granular excipient obtained by granulation so that its water activity (aw) is 0.4 to 0.8, mixing with other powders, and compression molding. .
  • the tablet preferably contains at least one of an active pharmaceutical ingredient and a food health functional ingredient.
  • the tablet of the present invention is manufactured by any one of the manufacturing methods of the tablets.
  • a tablet When a tablet is formed by a compression molding method using a tableting machine, etc., it has excellent stability over time and has a tablet hardness and disintegration rate that can be used without adding a powdery binder. A tablet can be produced.
  • the present invention includes the use of at least one of rice starch and rice starch derivatives as a powder binder in the manufacture of tablets and granules as solid preparations, and specifically comprises the following method. It is a thing.
  • a method for producing a tablet in which a tablet is formed by using at least one of rice starch and a rice starch derivative as a powder binder during compression molding using a tableting machine In this case, rice starch having a water content of 6 to 14% by weight, preferably 9 to 14% by weight and rice starch having a water content of 6 to 14% by weight, preferably 9 to 14% by weight, are used as a powdery binder. At least one of the derivatives is used.
  • this manufacturing method may be referred to as manufacturing method (1).
  • this manufacturing method may be referred to as a manufacturing method (2).
  • a tablet manufacturing method in which a powder is compressed by a wet granule compression method, which uses at least one of rice starch and rice starch derivatives as a powder binder.
  • Granules are used to granulate the powder to obtain granules.
  • the granules are conditioned to a water activity (aw) of 0.4 to 0.8 and then compression molded.
  • this production method may be referred to as production method (3).
  • rice starch and water having a water content of 6 to 14% by mass, preferably 9 to 14% by mass, are used as a powdery binder. At least one of rice starch derivatives having a content of 6 to 14% by mass, preferably 9 to 14% by mass, is used.
  • the water content of at least one of rice starch and rice starch derivatives is determined by the compression moldability when the powder is compressed, the compression moldability when producing granules and tablets from the powder, and the granule strength. This will affect the compression moldability during molding, and if the water content is less than 6% by mass, sufficient moldability will not be exhibited. There is a tendency that it is difficult to obtain a uniform granule in a high yield and that it is difficult to obtain a tablet having sufficient hardness even when a tablet is formed from the obtained granule.
  • the wet granulation method of production method (3) at least one of rice starch and rice starch derivative is added to the powder as a powder binder, granulated, and the granules obtained Adjust the moisture value so that the water activity (aw) is between 0.4 and 0.8 and force compression mold. That is, in the conventional general wet granule compression method, granulated granules are dried in a drying process and then compression-molded, so at least one of rice starch and rice starch derivatives is used as a powder binder.
  • the water activity (aw) is a value obtained by dividing the relative humidity in a container that has reached an equilibrium state by 100 when the sample is sealed in a container.
  • the granules are preferably conditioned so that the water activity (aw) thereof is 0.4 to 0.8. If the water activity (aw) is less than 0.4, sufficient formability will not be exhibited, while if it exceeds 0.8, the fluidity of the granules will decrease, and the powder will flow out of the hopper during tableting. There are concerns that tableting troubles such as stateking will occur during tableting.
  • the excipient formed in the granular form is conditioned so that its water activity (aw) is 0.4 to 0.8. Is good.
  • the Japanese Pharmacopoeia includes four items related to starch: wheat starch, rice starch, corn starch, and potato starch. 0% or less.
  • actual values vary widely even within these standards due to differences in drying and heat treatment conditions in production. For example, when heat treatment is performed to reduce germs in starch, the water content may be reduced to 1% by mass or less.
  • At least one of commercially available rice starch and rice starch derivative is required so that its water content is in the range of 6 to 14% by mass.
  • the water content is appropriately adjusted accordingly.
  • it is preferable that at least one of the rice starch and the rice starch derivative is subjected to a heat treatment at a temperature of 75 ° C or higher for at least 30 minutes, and then its water content is adjusted.
  • a heat treatment at a temperature of 75 ° C or higher for at least 30 minutes, and then its water content is adjusted.
  • the inventors of the present invention have found that the moldability of at least one of the obtained rice starch and the rice starch derivative is further improved by adjusting the water content after performing such heat treatment. The reason for this is not clear, but it is thought that such treatment changes the particle structure of at least one of rice starch and rice starch derivatives, and as a result, improves the binding force.
  • At least one of the commercially available rice starch and the rice starch derivative may be used as it is, and it is not necessary to adjust the moisture in advance.
  • the water content of at least one of rice starch and rice starch derivatives is the mass when dried at a temperature of 105 ° C for 6 hours in accordance with the Japanese Pharmacopoeia (14th revision) “Loss on drying test method”. Required by weight loss.
  • the rice starch used here is produced from uruchime and mochigome as raw materials, and is known for various production methods.
  • Each item of rice starch such as the Japanese Pharmacopoeia or European Pharmacopoeia It may be manufactured by any manufacturing method as long as it conforms to the requirements.
  • rice starch derivatives include derivatives such as ester starch, ether starch, oxidized starch and the like.
  • esterified starch and etherified starch include rice starch acetate, phosphate monoester, phosphate bridge (phosphate diester), otatur succinate, adipic acetate bridge, hydroxy ether, hydroxy Propyl ether, carboxymethyl ether, etc. I can get lost.
  • acid-treated starch, bleach-treated starch, and physically-treated starch (such as wet heat-treated starch) can also be used. These may be used alone or in combination of two or more.
  • Starches are used as excipients, disintegrants and binders in the field of pharmaceutical additives.
  • the description that it is usually used in the form of 5-10% starch paste is found in the 14th revised Japanese Pharmacopoeia, A-64, Yodogawa Shoten (2001). It is done.
  • the description that starches are used as a binder in powder form has not been found so far.
  • Rice starch differs from other starches in that its particle size is very small.
  • At least one of rice starch and rice starch derivatives has a very small particle size as compared with other starches, so that the contact area between the particles is increased. Since the increase in the contact area contributes to the improvement of the binding property as a powdery binder, at least one of rice starch and rice starch derivatives is produced in the production methods (1) to (4). It can be inferred that it is suitably used.
  • analgesics There are no particular restrictions on active pharmaceutical ingredients, but hypnotic analgesics, antipyretic analgesics, antipsychotic agents, autonomic agents, antiparkinson agents, antihistamines, cardiotonics, diuretics, antihypertensive agents, vasoconstrictors , Arteriosclerotic agents, antitussive expectorants, vitamins, nourishing tonics, antibiotics, gastrointestinal drugs and the like.
  • Food health functional ingredients affect the body's physiological functions and are used in foods, such as vitamins, minerals, herbs, proteins, fatty acids, dietary fiber, etc. Notification from the Ministry of Health, Labor and Welfare such as nutritional ingredients, plant foods such as ginseng carrots, animal foods such as propolis, fungi such as bifidobacteria, and coenzyme Q10 Substances listed in the list of “essences of ingredients that are recognized as food unless they are targeted for pharmaceutical efficacy” are listed.
  • a powdery binder other than at least one of rice starch and rice starch derivatives (generally called a dry binder).
  • Excipients Excipients, disintegrants, lubricants and the like.
  • fluidizing agents, fragrances, sweeteners, coloring agents and the like generally used for the production of tablets and granules may be added.
  • Lubricants prevent the powder of raw materials and additive containing active ingredients from adhering to the die during compression molding using a tableting machine, etc., and provide uniform compression moldability. It works as you can. Further, in the dry granulation method, it acts to prevent the molded product from adhering to the roll during roll compression molding. Specifically, magnesium stearate, sodium stearyl fumarate, hydrogenated oil, sucrose fatty acid ester, glycerin fatty acid ester, talc and the like can be used. The amount of lubricant added depends on the type of lubricant, the raw material powder, and the mixed powder with various additives added to it, in any of the above production methods (1) to (4). Although it is not uniform and is not uniform, a range of 0.1 to 10% by mass in tablets and granules is common.
  • the disintegrant acts to disintegrate granules and tablets in water or in the gastrointestinal fluid, and includes carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium, hydroxypropyl starch, and the like.
  • excipients such as lactose, D-mannitol and sucrose can be used.
  • the tablets obtained by each of the production methods (1), (3) and (4), and the tablets containing the granules obtained by the production method (2) have an active pharmaceutical ingredient or Film coating may be used for masking of unpleasant tastes derived from health functional ingredients for food, improving stability, and making the appearance beautiful.
  • the production method (1) belongs to a method generally referred to as a direct tableting method.
  • a tablet is formed by compression molding with a tableting or the like, rice starch and rice are used as a powdery binder.
  • At least one of starch derivatives is used.
  • a mixed powder is prepared by mixing at least one of the derivatives and various additives added as necessary.
  • the raw material may be in the form of a powder, or may have been subjected to a preliminary force such as a granular material that is generally commercially available as a raw material for direct compression. .
  • the formability of the raw material varies depending on the type and amount of the active ingredient contained in the raw material, at least one of the rice starch and the rice starch derivative to be used may be appropriately adjusted accordingly. From the viewpoint of ensuring the function as, it is preferably 5% by mass or more, more preferably 5 to 30% by mass in the mixed powder. If it is less than 5% by mass, the effect as a binder becomes insufficient, and if it exceeds 30% by mass, at least one of rice starch and rice medendun derivatives has low fluidity, so the fluidity of the mixed powder is also insufficient. The As a result, the filling amount of the mixed powder into the die may vary, and the mass deviation of the tablet may increase.
  • Additives used as necessary include powdery binders other than at least one of rice starch and rice starch derivatives, excipients for direct compression, disintegrants, lubricants, and the like. Can be mentioned.
  • the obtained mixed powder is compression-molded using a tableting machine having a mortar and a punch, such as a single tableting machine or a rotary tableting machine, to obtain tablets.
  • the resulting mixed powder When at least one of rice starch and rice starch derivatives is mixed with raw materials and additives, in order to make the resulting mixed powder uniform, it is mixed with some of the raw materials and additives. Alternatively, it may be sieved using a sieve having an appropriate opening.
  • the shape of the tablet to be obtained is not limited, but if the cross section is circular, the diameter is 6 to 1 Omm, and the mass per tablet is about 100 to 500 mg.
  • the pressure (compression pressure) suitable for tableting is preferably about 15 kN or less.
  • the tablet is produced by a compression molding method using at least one of rice starch having a specific water content and a rice starch derivative as a powdery binder, A tablet with sufficient disintegration time that has practically sufficient tablet hardness and does not slow down disintegration even when hardened oil is used as a lubricant is obtained.
  • the obtained tablets are also excellent in the temporal stability in terms of color.
  • the amount of at least one of the rice starch and the rice starch derivative to be used may be adjusted accordingly.
  • the content in the mixed powder is preferably 10% by mass or more, more preferably 10 to 90% by mass, and further preferably 15 to 50% by mass.
  • this mixed powder is roll compression molded with a roll-type high-pressure compression molding machine or the like to obtain a high-density plate-like molded product (hereinafter sometimes referred to as flake).
  • the granulation conditions are such that the compression molding rate is 60 to 95%.
  • a crushing process in which this plate-shaped product is passed through a multi-stage roll crusher or various granulators so as to achieve the desired particle size, for example, a force that makes the particle size finer than 1700 / zm.
  • Granules with a cocoon density of 0.4 to 0.8 gZmL are obtained.
  • the obtained granule is used as it is as a granule or for compression molding using a tableting machine. If necessary, it may be sieved to obtain an appropriate particle size distribution. Further, when it is desired to reduce the amount of water contained in the obtained granule, it may be continuously dried by a known method.
  • the compression molding rate is also called flake rate, and is determined by the following measurement method.
  • a tablet is produced by further shaping the obtained granule, first, the granule is mixed with additives such as a lubricant and a disintegrant added as necessary, and other components. To do. The resulting mixture is compressed with a pressure suitable for the tableting machine to be used and the size of the tablet using a tableting machine having a mortar and a punch, such as a single tableting machine or a rotary tableting machine. What is necessary is just to perform compression molding.
  • the shape of the tablet is not limited, but if the cross section is circular, the diameter is 6 to: LOmm, and the mass per tablet is about 100 to 500 mg.
  • the pressure (compression pressure) suitable for tableting is preferably about 15 kN or less.
  • the compression moldability of the powder during granulation is very high. Since it becomes higher, the fine powder content in the coarse crushing process is reduced, and granules with uniform particle size can be obtained in high yield. Furthermore, the tablets obtained by molding the granules produced in this way have practical tablet hardness, disintegration time, and temporal stability in terms of color.
  • granules containing at least one of rice starch and rice starch derivatives as a powder binder and tablets obtained from the granules have a high content of at least one of rice starch and rice starch derivatives.
  • crystalline cellulose as a powdery binder Since there is little change in properties, such as when a large amount of is used, there is no coloration during storage and the stability over time is excellent.
  • the present inventors have found that by using the cellulose-based powder binder in this way, even if the disintegration time is shortened, the tablet hardness does not decrease but rather improves. Therefore, by using a cellulosic powder binder together with at least one of rice starch and rice starch derivatives as a powder binder, tablets with high tablet hardness and moderately improved disintegration time can be obtained. Obtainable.
  • Such cellulosic powder binders are used when the content of active pharmaceutical ingredients or food health functional ingredients in granules is as high as 30% by mass or more, or when the moldability of these active ingredients is poor. Also, the effect of improving moldability is exhibited.
  • the amount of the cellulose powder binder used is preferably in the range of 10 to 30% by mass in the granule. If it exceeds 30% by mass, it may cause changes over time such as the color of the resulting granules. If it is less than 10% by mass, sufficient addition effect may not be exhibited.
  • At least one of rice starch and rice starch derivative having a specific water content is usually used as a powdery binder, so that fine particles are usually generated immediately.
  • a dry granulation method in which it is difficult to obtain a granule having a uniform particle size in a high yield, a granule having a small particle size and a uniform particle size can be obtained in a high yield.
  • the obtained condylar granules as tableting granules, it is possible to develop tablets that exhibit practically sufficient tablet hardness, which has been difficult to obtain in the past, and that have good temporal stability such as disintegration time and color. Obtainable.
  • sufficient moldability can be secured, so that moldability and color stability over time can be maintained. Can be compatible.
  • corn starch is widely used as an additive component for starch.
  • Maize starch is used as an excipient by mixing with lactose that cannot be used as a binder because of its insufficient binding properties. It was always. Then, when producing granules by the dry granulation method, another powdery binder must be added.
  • rice starch and rice starch derivatives unlike corn starch, is remarkably excellent in binding by controlling the water content within a specific range, and can be used alone as a powder binder. It is.
  • active ingredients selected from, for example, active pharmaceutical ingredients and food health functional ingredients, and at least of rice starch and rice starch derivatives
  • lactose, sucrose, D mantle Additive ingredients such as starch, corn starch, starch derivatives such as hydroxypropyl starch, and disintegrants such as carmellose calcium other than at least one of rice starch, rice starch and rice starch derivatives It is a mixed powder.
  • granulation is performed by a known wet granulation method.
  • the wet granulation method include a crushing granulation method, a stirring granulation method, a fluidized bed granulation method, a centrifugal tumbling granulation method, and a centrifugal tumbling fluidized bed granulation method.
  • a liquid binder is added to the mixed powder, a soft lump having an appropriate size is formed with a granulator, and the granule is obtained by drying with a dryer. At this time, large granules are crushed.
  • a known wet granulation method such as agitation granulation method, fluidized bed granulation method, centrifugal rolling granulation method, centrifugal rolling fluidized bed granulation method may be applied.
  • a solvent such as water or an organic solvent is used as it is as a liquid binder, or a binder component such as hydroxypropylcellulose or polyvinylpyrrolidone is dissolved in these solvents. A solution is used.
  • the obtained granule is conditioned so that its water activity (aw) is 0.4 to 0.8.
  • granulated granules are dried in the drying step, so that at least one of rice starch and rice starch derivatives may be used as a powder binder.
  • the water content of at least one of the rice starch and the rice denpene derivative in the granule is decreased, and as a result, the compression molding property and binding property of the granule are considered to be decreased. Therefore, in order to ensure these performances, it is considered important to adjust the moisture content of the granules by conditioning before compression molding.
  • the granule is allowed to stand in a constant temperature and humidity atmosphere controlled at a constant temperature and humidity, or is mixed in a mixing / stirring device or a fluidized bed and stirred or fluidized.
  • a mixing / stirring device or a fluidized bed and stirred or fluidized.
  • the water activity (aw) should be controlled to be 0.4 to 0.8.
  • the water activity is measured by a commercially available water activity measuring device such as “EZ 100” manufactured by Freund Sangyo Co., Ltd.
  • the tablet obtained by compression molding does not have sufficient hardness, and 0.8 Exceeding this causes problems such as decreased fluidity of the granules and problems with tableting such as sticking during tableting.
  • a granular excipient is used.
  • the granules thus conditioned are additives commonly used in the manufacture of tablets, as in the case of production method (1), such as lubricants and disintegrants added as necessary. Is added to the tablet by a tableting machine having a mortar and a punch, such as a single tableting machine or a rotary tableting machine, to obtain a tablet.
  • the preferred tablet size and preferred compression pressure are the same as in production method (1).
  • an appropriate amount of at least one of rice starch and rice starch derivative is 5% by mass or more of the tablet.
  • the upper limit is not particularly limited, but in the case of a general tablet, it is preferably 50% by mass or less. If it is less than 5% by mass, the effect as a powder binder tends to be insufficient. If it exceeds 50% by mass, the disintegration time tends to be longer, which is disadvantageous for general tablets.
  • this property is particularly suitable for the purpose of obtaining a sustained-release preparation, and may be added in excess of 50% by mass, and a sustained-release product such as hydroxypropylmethylcellulose or hydroxypropylcellulose may be used. It can also be used in combination with a base.
  • the water activity of the granules obtained by the wet granulation method is appropriately controlled and then compression molded. Therefore, it is possible to produce a tablet having high compression moldability and having a practical tablet hardness and disintegration time without causing any tableting trouble. In addition, the obtained tablets have excellent temporal stability such as color points.
  • This production method (4) is a method in which an excipient formed in a granular shape is used as an excipient when a tablet is formed by a compression molding method. That is, known powdery excipients such as lactose, D-mannitol and sucrose, and rice starch and rice starch derivatives. Then, the mixed powder containing at least one of them is granulated by the wet granulation method, and the resulting granular product is used as an excipient, and this is mixed with other powders containing the active ingredient and compression molded. To do. As the specific method of the wet granulation method and the liquid binder used at that time, the same ones exemplified in the production method (3) can be applied.
  • lactose or D —Mandol powder and at least one of rice starch and rice starch derivatives are mixed, and air is supplied in the container to float and flow the mixed powder, while the charged lactose or D— It can be granulated by spraying the same substance as the powder of mannitol as an aqueous solution to obtain a granular excipient.
  • the mixing ratio of the powdery excipient in the wet granulation method and at least one of the rice starch and the rice starch derivative is selected from among the rice starch and the rice starch derivative in the obtained granular excipient. At least one of the ratios is preferably 3 to 60% by mass, more preferably 5 to 50% by mass. If at least one of rice starch and rice starch derivative is less than 3% by mass, the effect of improving moldability is insufficient, and if it exceeds 60% by mass, disintegration of the resulting tablet may be delayed.
  • the obtained granule is conditioned by the same method as in production method (3) so that its water activity (aw) force becomes O. 4 to 0.8.
  • a granular excipient is used.
  • a granular excipient having a water activity (aw) of 0.4 to 0.8, another powder (a raw material powder containing an active ingredient), a lubricant, Additives and disintegrants added as necessary, such as those used in the manufacturing method (1), are mixed with general additives for tablet production, and the resulting mixture is mixed into a single-punch tablet machine, It is compressed into a tablet by a tableting machine such as a rotary tableting machine.
  • a tableting machine such as a rotary tableting machine.
  • the size of the tablet and the compression pressure are the same as in the production method (1).
  • a granular excipient is obtained by a wet granulation method, and the water activity is appropriately controlled before use. Since such a granular excipient is very excellent in compression moldability, it can be used to produce a tablet having a practical tablet hardness and disintegration time without adding a powdery binder. Can be manufactured without causing tableting problems. Moreover, the obtained tablet is excellent also in temporal stability, such as a color point.
  • Granule hardness When a condylar particle breaks using a hardness measuring instrument GRANO (Okada Seisen-made) with a tip diameter of 3mm ⁇ (tip tip shape: flat circle), a load of 200g, and a measurement speed of 100mZ seconds. The load of was measured with a load cell.
  • GRANO Alkada Seisen-made
  • Tablet hardness Measured with a tablet hardness meter SCHLEUNIGER 6D (Freund Sangyo Co., Ltd.).
  • Tablet disintegration time Measured according to the disintegration test method (test solution, water) of the Japanese Pharmacopoeia (14th revision)
  • Whiteness and yellowness of tablets Solid color using a color difference meter SZ— ⁇ 90 (manufactured by Nippon Denshoku Industries Co., Ltd.) The method for measuring the surface color was followed.
  • Color difference Use color difference meter SZ- ⁇ 90 (Nippon Denshoku Industries Co., Ltd.) and color difference ⁇ E * ab based on L * a * b * color system according to JIS Z-8729 and Z-8730. It was measured.
  • Moisture content according to the Japanese Pharmacopoeia (14th revision) “loss on drying test method”, the weight loss after drying at 105 ° C for 6 hours was measured to obtain the moisture content.
  • Vitamin C is an active ingredient used as a food health functional ingredient in pharmaceuticals and health foods.
  • As the crystalline cellulose “Asahi Kasei Chemicals Co., Ltd., trade name: Serus PH-101” was used.
  • As the hardened oil “Freund Industrial Co., Ltd., trade name: Lapriwax-101” was used.
  • Example 1 and Comparative Examples 1 to 3 were carried out for the purpose of comparing the performance of rice powder, which is a powdery binder, and crystalline cellulose, and comparing the performance of rice starch, which is a starch, and corn starch.
  • components other than hardened oil, which is a lubricant, of lkg of the mixed powder composition shown in Table 1 are rotated 40 times per minute using a V-shaped mixer V-10 (Tokuju Seisakusho Co., Ltd.). And mixed for 20 minutes. Subsequently, hydrogenated oil was added thereto and mixed for 5 minutes to obtain a mixed powder for tableting. And the tablet was obtained on the following tableting conditions, and various measurements were implemented about it. Table 2 shows the measurement results.
  • Rice starch 20.0 R parts ⁇ One ⁇ Crystalline cellulose One 20.0 parts by mass ⁇ ⁇ Corn starch One ⁇ ⁇ 20.0 parts by weight Hardened oil 3.0 parts by weight 3.0 parts by weight 3, 0 parts by weight 3 .0 parts by mass
  • Tableting machine Rotary tableting machine, HT-P15A-III type (manufactured by Hata Iron Works)
  • Example 1 is based on the production method (1), and is an example of producing a tablet using at least one of rice starch and rice starch derivatives as a powdery binder. As shown in Table 2, the tablet hardness and disintegration time (within 10 minutes) of the tablet of Example 1 were both satisfactory.
  • Comparative Example 1 is an example using crystalline cellulose as a powdery binder, but the tablet hardness was almost the same as in Example 1, but the disintegration time was remarkably long 52 minutes. This is considered to be the result of specific effects of crystalline cellulose strength S and hydrogenated oil used as a lubricant.
  • Comparative Example 3 is an example in which corn starch was used as a powder binder. The tablet strength was remarkably inferior to that using rice starch.
  • Example 1 using at least one of rice starch and rice starch derivative as a powder binder showed the most excellent properties overall.
  • Comparative Example 2 was an example in which tableting was performed without adding a powdery binder, but the tablet hardness was 53 N and the disintegration time was lower than that of the tablet of Example 1.
  • put each tablet in a glass bottle put it in a constant temperature and humidity chamber at 40 ° C and 75% relative humidity without a lid, and leave it for 4 weeks to measure the whiteness of the tablet surface before and after leaving it. did.
  • Example 1 98.4 and 90.8
  • Comparative Example 1 99.9 and 84.3
  • Comparative Example 2 96.6 and 89.3, respectively.
  • Example 3 98.1 and 90.1, and the color change in the tablet of Comparative Example 1 containing crystalline cellulose as a component was the strongest.
  • Example 1 The rice starch used in Example 1 was dried at 80 ° C for a predetermined time or left in a constant temperature and humidity chamber at 40 ° C and a relative humidity of 80%, so that the rice starches with various water contents shown in Table 3 were used. Got.
  • Example 1 50 g of mixed powder having the same composition as in Example 1 was obtained except that rice starch having each water content was used. However, mixing was performed as follows. First, hardened oil was not added in a polyethylene bag. The mixed powder was mixed so as to be sufficiently uniform, and then hardened oil was added in and shaken for 30 seconds.
  • Example 1 When a mixture of 97 parts by mass of vitamin C granules and 3.0 parts by mass of hardened oil without compression of rice starch was compression-molded, the hardness was 56N.
  • This mixed powder is compression-molded at a pressure of 4 MPa (pressure cylinder 'gauge pressure) using a roller compactor TF-mini (Freund Sangyo Co., Ltd.) and the resulting flakes are screened.
  • the mixture was coarsely pulverized with a particle sizer and further sized with a roll duller-yuretor to obtain granules for tableting.
  • tablets were formed under the same tableting conditions as in Example 1.
  • Granules obtained by this dry granulation method are sieved with a mesh size of 200 (75 m) according to the Japanese Pharmacopoeia (14th revision), the powder particle size measurement method, and the second screening method.
  • the fine particles that passed through the sieve were made into a 75 ⁇ m pass product.
  • the content of the granule sieving 75 ⁇ m pass product was 30% by mass in Comparative Example 7 whereas it was 25% by mass in Example 8.
  • the average value was 25 g in Comparative Example 7 and 45 g in Example 8.
  • the average value was 31 N and 65 seconds in Comparative Example 7, whereas Example 8 Then it was 52N and 185 seconds.
  • the composition of Comparative Example 7 is composed of a 7: 3 mixture of lactose and corn starch excluding the lubricant. On the other hand, in the composition of Example 8, 20% by mass of the mixture of lactose and corn starch was replaced with rice starch powder.
  • Example 8 heavy granules with high hardness and low ratio of fine powder could be obtained in high yield.
  • the tablet according to Example 8 had a slightly longer disintegration time, but the tablet hardness was greatly improved as compared with Comparative Example 7.
  • Example 8 dry granulation of the granules for tableting was performed using the mixed powder having the composition shown in Table 5, and the hardness of the granules was measured. Using these granules, tablets were molded under the same tableting conditions as in Example 8.
  • the content of the granulated sieving 75 ⁇ m pass product obtained by such a dry granulation method is 21% by mass in Comparative Example 8, compared with 17% by mass in Example 9. became.
  • the granule hardness was 28 g in Comparative Example 8, compared with 44 g in Example 9.
  • the hardness and disintegration time of the tablets were 77N and 177 seconds in Example 9, compared to 42N and 49 seconds in Comparative Example 8 on average.
  • Example 9 the corn starch of Comparative Example 8 was replaced with rice starch. From the above results, however, in Example 9, the content of fine particles during granule production decreased, and compared with Comparative Example 8 An improvement was observed in terms of granule hardness. Furthermore, the tablet according to Example 9 is improved in tablet hardness as compared with Comparative Example 8, and is a value that can be used practically. [0083] [Examples 10 to 15 and Comparative Examples 9 to 11]
  • Example 8 The rice starch used in Example 8 was dried at 80 ° C for a predetermined time, or left in a constant temperature and humidity chamber at 40 ° C and a relative humidity of 80% to obtain various moisture contents shown in Table 6. A sample was obtained. A mixed powder of 200 g having the same composition as in Example 8 was obtained except that rice starch having each water content was used. However, mixing was performed as follows. First, without adding magnesium stearate in a polyethylene bag, the mixed powder was mixed so that it was sufficiently uniform, and then magnesium stearate was added and shaken for 30 seconds.
  • Dry granulation was performed under the composition of Table 7 and the conditions of Example 10.
  • a tableting test model experiment
  • a flat tablet with a diameter of 1 Omm and a mass of 300 mg per tablet was molded using a hydraulic press molding machine under a compression pressure of 20 kN. did.
  • the resulting tablets were filled in a glass bottle, sealed, and left in a 50 ° C incubator for 1 week.
  • Various physical property tests were conducted on the tablets before and after the acceleration test. The results are shown in Table 8.
  • the tablet of Comparative Example 13 has improved tablet hardness as compared with the tablet of Comparative Example 12 that does not use crystalline cellulose.
  • the tablet of Comparative Example 13 has a delayed disintegration time after the accelerated test at 50 ° C., and the color is greatly changed in the yellow direction. From this, it can be expected that Comparative Example 13 has low stability over time.
  • the tablet of Comparative Example 14 has a significantly longer disintegration time than the tablet of Comparative Example 12, it is necessary to improve disintegration and the like.
  • Example 16 shows the same tablet hardness as that of Comparative Example 13 using crystalline cellulose as the binder, and further, no change in physical properties was observed before and after the accelerated test at 50 ° C. Katsutsu. From these results, it can be said that the tablet of Example 16 is suitable for practical use because it is superior in stability over time as compared with tablets using other binders. [Example 17 and Comparative Example 15]
  • Comparative Example 15 had 11.5N before being left and 4.1N after being left, whereas Example 17 had 18.6N before being left and 11.2N after being left.
  • the color difference of the tablet before and after being left was +11.4 in Comparative Example 15, whereas it was +0.7 in Example 17.
  • the composition of Comparative Example 15 is one in which the content of crystalline cellulose is remarkably increased for the purpose of increasing tablet hardness, but the change over time in tablet hardness and coloration on the tablet is large, and it is difficult to provide practical use. It was suggested that there is.
  • the composition of Example 17 was obtained by replacing a part of the crystalline cellulose with rice starch as the powdery binder of Comparative Example 15, although a slight decrease in tablet hardness was observed. It can be said that the color tone of the tablet is extremely small and stable over time and suitable for practical use.
  • Example 18 The hardness and disintegration time of the tablets obtained were 48N and 2 minutes and 20 seconds in Comparative Example 16, while 121N and 2 minutes and 30 seconds in Example 18, and those according to Example 18 were A marked improvement in tablet hardness was observed with respect to Comparative Example 16. In general, formability is low!
  • the composition of Example 18 containing mannitol was shown to have a disintegration time equivalent to that of Comparative Example 16 using lactose and corn starch without mannitol. .
  • Example 16 Each tablet was filled into a 50 mL glass bottle, placed in a 50 ° C incubator and left for 24 hours. As a result of measuring the color of the tablets before and after heating, the color difference before and after heating was +12.3 in Comparative Example 16 and +4.1 in Example 18. Compared to Example 18, it was clear that Comparative Example 16 was colored by the Maillard reaction with a greater degree of change in color tone. Therefore, the sample according to Example 16 was excellent in stability over time with little change in the acceleration test.
  • Example 19 Rice starch (same as Example 8) 13. 1 23:30
  • Example 20 Crystalline cellulose (same as Example 9) 21.9 7:45
  • the hardness of the tablet is higher by replacing part of it with crystalline cellulose, powdered cellulose or low-substituted hydroxypropyl cellulose than when using rice starch alone as the powder binder. It became clear that the decay time was shortened.
  • Example 23 The hardness and disintegration time of the tablets obtained were 74N and 70 seconds for Comparative Example 17, while 139N and 4 minutes and 10 seconds for Example 23. According to Example 23, a force that is a composition in which the corn starch of Comparative Example 17 was replaced with rice starch was greatly improved in terms of tablet hardness as compared with Comparative Example 17.
  • the granulation for tableting was dry granulated according to the composition shown in Table 13 and the conditions of Example 8, and 6 parts by mass of hardened oil and 1 part by mass of silicon dioxide were added to 93 parts by mass of the obtained granules.
  • Article Tablets were formed according to the conditions.
  • Adsolida 101 was used as the nitric acid silicate.
  • Aminophylline was used as the active pharmaceutical ingredient, and D-mann-tol was used as the excipient, manufactured by ROQUETTE. Tablets were prepared. The crushing granulation method was applied as the granulation method. The case where rice starch or crystalline cellulose was used as the powder binder was compared with the case where these were not used. Aminophylline is a cardiotonic drug, and is known to have many substances and mixed changes.
  • ingredients other than magnesium stearate which is a lubricant, were mixed, 2 kg of the mixture was charged into a 5 L-line, and water was added to each to knead.
  • the kneaded product is taken out, and a screen-type crushing granulator (manufactured by Seida Okada Co., Ltd., product name: U-speed mill) is equipped with a screen with a diameter of 1.2 mm and further crushed. It was dried in a dryer at ° C and sieved with a 500 m sieve to obtain granules.
  • Example 25 the obtained granule was placed in a thermo-hygrostat at 30 ° C. and a relative humidity of 60% for 16 hours to adjust the moisture activity (aw) to 0.63.
  • moisture activity (aw) For measurement of water activity (aw), product name: EZ-100 manufactured by Freund Sangyo Co., Ltd. was used.
  • Magnesium stearate was mixed with the obtained granules, and tableting was performed under the following conditions.
  • Table 15 shows the tablet hardness, disintegration time, and tablet yellowness in each example. [0106]
  • the tableting conditions are as follows.
  • Tablet press Single-type tablet press, FY—SS—7 (Fuji Pharmaceutical Machinery Co., Ltd.)
  • Tablet Flat tablet with a diameter of 10mm, the weight is 350mg per tablet
  • the tablet obtained in Comparative Example 18 was not inferior to Example 25 in terms of hardness and disintegration, but it had a slightly yellowish coloration, and further under 40 ° C and relative humidity of 75% RH. As a result of standing, the coloration increased significantly. This phenomenon is thought to be due to the interaction between aminophylline and crystalline cellulose.
  • Example 26 and Comparative Example 20 were carried out in order to demonstrate the usefulness of an excipient that was formed into granules and adjusted for water activity (aw).
  • the obtained granules are put in a stainless steel vat, placed in a constant temperature and humidity chamber at 30 ° C and 60% relative humidity for 24 hours to adjust the moisture activity (aw) to 0.58. Compressed to obtain tablets. Specifically, 0.73 parts by mass of magnesium stearate was mixed with 99.3 parts by mass of this granular excipient, and tableting was performed under the same conditions as in Example 1.
  • Example 26 had a higher hardness and a shorter disintegration time. Therefore, it was shown that the granular excipient of Example 26 is excellent as an excipient for so-called direct compression.
  • Example 27 The following Example 27 and Comparative Example 21 were carried out in order to demonstrate the usefulness of an excipient that was formed into granules and whose water activity (aw) was adjusted.
  • Example 25 2 kg of the same mixed powder in which D-mannitol and rice starch were mixed at a mass ratio of 8: 2 as used in Example 25 was granulated by the same crushing-type granulation method as in Example 25. Drying and sieving were performed in the same manner to obtain granules (average particle size: 143 ⁇ m).
  • This granule is placed in a vat, placed in a constant temperature and humidity chamber at 40 ° C and 70% relative humidity for 6 hours to adjust the humidity, and the water activity (aw) is 0.55.
  • To obtain tablets. 99.0 parts by mass of the granular excipient was mixed with 1.0 part by mass of magnesium stearate, and tableting was performed under the same conditions as in Example 25.
  • the tablet hardness was 93 N and the disintegration time was 108 seconds.
  • a control (Comparative Example 21), manufactured by the spray drying method of Rocket (ROQUETTE) Co., Ltd.
  • the tablet hardness was 76 N and the disintegration time was 198 seconds.
  • Example 27 had a higher hardness and a shorter disintegration time. Therefore, it was shown that the granular excipient of Example 27 is excellent as an excipient for so-called direct compression.
  • an active pharmaceutical ingredient 30 parts by mass of powder of acetaminophen, an antipyretic analgesic, sieved with a 75 ⁇ m sieve in advance, and the same rice starch as used in Example 1 was used. Part by mass and 50 parts by mass of lactose were mixed to obtain a mixed powder.
  • Tablets were produced by the direct tableting method in which the mixed powder having the composition shown in Table 17 was compression-molded by a tableting machine.
  • Example 35 the same rice starch (water content 12.2% by mass) as that used in Example 1 was used as a powdery binder after heat treatment.
  • Example 36 the same rice starch as used in Example 1 was heat-treated, and the water content was adjusted and used as a powder binder. Specifically, 4 kg of rice starch is charged into a fluidized bed granulation coating device (Freund Sangyo Co., Ltd., product name: Flow Coater FLO-5), fluidized for 60 minutes at an inlet temperature of 140 ° C, and heat-treated. Went. Next, the moisture content was adjusted by allowing the fluid to flow for 60 minutes while spraying water at the suction part temperature of 30 ° C.
  • a fluidized bed granulation coating device Red Sangyo Co., Ltd., product name: Flow Coater FLO-5
  • the temperature of the fluidized bed portion corresponding to the heating temperature becomes 80 ° C after 12 minutes of force, which was 67 ° C at the start of flow, and then gradually increases to 107 ° C after 60 minutes. ° C reached. Therefore, the heat treatment was maintained at a temperature of 80 ° C or higher for 48 minutes. In the humidity control operation, a total of 830 ml of water was sprayed. Thus, the moisture content of the rice starch that had been heat-treated and then conditioned was 12.4% by mass.
  • Comparative Example 25 the same crystalline cellulose as used in Comparative Example 1 was used.
  • chlorfelamamine maleate an antihistamine, is used as an active ingredient. It was.
  • Table 18 shows the tablet hardness, disintegration time, and tablet yellowness in each example.
  • Tablet press Rotary tablet press
  • the disintegration time of the tablets was not very different between the cases. This indicates that the use of heat-treated rice starch can increase tablet hardness without affecting disintegration time.
  • each tablet obtained in each example was put in a glass bottle, sealed in a thermostat at 50 ° C, left for 4 weeks, and the yellowness of the tablet surface before and after being left was compared.
  • the change was significant in the tablet of Comparative Example 25 containing This is a crystal cell It is thought to be derived from a change in the color of roulose.
  • a tablet When a tablet is formed by a compression molding method using a tableting machine, etc., it has excellent stability over time and has a tablet hardness and disintegration rate that can be used without adding a powdery binder. A tablet can be produced.

Abstract

At least either of rice starch and a rice starch derivative each having a specific water content is used as a powdery binder. Alternatively, at least either of rice starch and a rice starch derivative is used as a powdery binder to form a powder into granules, which are compression-molded after moisture conditioning. Alternatively, at least either of rice starch and a rice starch derivative is used as a powdery binder to form a granular excipient, which is used in compression molding after moisture conditioning.

Description

明 細 書  Specification
固形剤およびその製造方法  Solid agent and method for producing the same
技術分野  Technical field
[0001] 本発明は医薬品、健康食品などの分野で好適に使用される固形剤 (顆粒、錠剤） の製造方法と、該方法により製造された固形剤に関する。  The present invention relates to a method for producing a solid preparation (granule, tablet) suitably used in the fields of pharmaceuticals, health foods, and the like, and a solid preparation produced by the method.
本願は、 2004年 11月 24日に日本国特許庁に出願された特願 2004— 338817 号、 2005年 10月 21曰に曰本国特許庁に出願された特願 2005— 306978号に基 づく優先権を主張し、その内容をここに援用する。  This application is priority based on Japanese Patent Application No. 2004-338817 filed with the Japan Patent Office on November 24, 2004, and Japanese Patent Application No. 2005-306978 filed with the Japan Patent Office on October 21, 2005. Claim the right and use it here.
背景技術  Background art
[0002] 医薬品、健康食品は、顆粒や錠剤などの固形剤の形態に成形されていることが多 い。一般的な顆粒の製造方法としては、湿式造粒法と乾式造粒法とがある。  [0002] Drugs and health foods are often molded into solid dosage forms such as granules and tablets. Common granule production methods include a wet granulation method and a dry granulation method.
これら方法のうち湿式造粒法は、原料の粉体に、液状の結合剤を加えて造粒する 方法であり、その造粒機構から、押出し、流動、転動、解砕、噴霧、撹拌などの方法 がある。  Among these methods, the wet granulation method is a method of granulating by adding a liquid binder to the raw material powder. From the granulation mechanism, extrusion, flow, rolling, crushing, spraying, stirring, etc. There is a method.
乾式造粒法は、ローラーなどで原料の粉体を圧縮成形 (以下、ロール圧縮成形とい う場合もある。）した後、各種の破砕機などで粗砕を行い、さらに篩い分けして目的の 粒度を持つ造粒物、すなわち顆粒を得る方法である。乾式造粒法は、このように水や 有機溶媒などの液状の湿潤剤を使用する必要がなぐ加熱乾燥工程も不要であるこ とから、湿潤剤による変質や加熱乾燥工程による分解の可能性のある医薬品有効成 分や食品用保健機能を有する成分 (以下、「食品用保健機能成分」という。）などの有 効成分を含有する顆粒の製造に好適である。また、乾式造粒法は加熱乾燥工程が 不要であるため乾燥設備が必要なぐ消費エネルギー量も少ないことから、顆粒の製 造コストが低 、と 、う長所を持つ。  In the dry granulation method, the raw material powder is compression-molded (hereinafter sometimes referred to as roll compression molding) with a roller or the like, and then coarsely crushed with various crushers and further sieved to obtain the desired product. This is a method for obtaining a granulated product having a particle size, that is, a granule. Since the dry granulation method does not require a heat drying step that does not require the use of a liquid wetting agent such as water or organic solvent, there is a possibility of alteration by the wetting agent or decomposition by the heating drying step. It is suitable for the production of granules containing active ingredients such as active pharmaceutical ingredients and ingredients having food health functions (hereinafter referred to as “food health functional ingredients”). In addition, the dry granulation method does not require a heating and drying process, so that the amount of energy consumption required for the drying equipment is small, so that the granule production cost is low.
[0003] これらの方法による顆粒の製造にお!、ては、共通して、有効成分などを含む原料の 粉体をそのままで、または、これに賦形剤、結合剤、崩壊剤、他の適当な添加剤など を加えて混合したものを、適当な方法で粒状とし、できるだけ大きさの揃った顆粒とし ている。 このようにして得られた顆粒は、湿式造粒法または乾式造粒法のどちらで製造され たものであっても、顆粒剤または散剤として医薬品などの製剤とされたり、顆粒状の 食品として用いられたり、打錠機を用いた圧縮成形法による錠剤の製造に用いられ たりする。 [0003] For the production of granules by these methods, it is common to use raw powders containing active ingredients as they are, or to this as excipients, binders, disintegrants, other A mixture obtained by adding an appropriate additive or the like is granulated by an appropriate method to obtain a granule having the same size as possible. Regardless of whether the granule obtained in this way is produced by either wet granulation or dry granulation, it can be used as a granule or powder as a pharmaceutical preparation or used as a granular food. Or used in the manufacture of tablets by compression molding using a tableting machine.
[0004] 一般的な錠剤の製造法には、直接粉末圧縮法 (以下、直接打錠法と言う場合もあ る。）と、顆粒圧縮法とがある。そして、顆粒圧縮法には、顆粒の製造方法の違いに基 づき、湿式顆粒圧縮法と乾式顆粒圧縮法とがある。  [0004] Common tablet production methods include a direct powder compression method (hereinafter sometimes referred to as a direct tableting method) and a granule compression method. The granule compression method includes a wet granule compression method and a dry granule compression method based on the difference in the granule production method.
これら方法のうち直接打錠法は、基本的には、有効成分などを含む原料をそのまま 圧縮成形するか、原料に、賦形剤、一般には乾式結合剤とも呼ばれる粉末状結合剤 、崩壊剤、他の適当な添加剤などを加えて均一に混合したものを圧縮成形する方法 である。この方法は、粉体を前処理しないで直接打錠する方法であり、粉体の圧縮成 形性が良好な場合に採用されるが、なかには、直接打錠用原料として、有効成分を 含む粉体ゃ賦形剤などがあらかじめ成形性の改良のために加工されたものも巿販さ れている。  Among these methods, the direct tableting method is basically compression molding of raw materials containing active ingredients or the like as they are, or the raw materials are mixed with excipients, generally called powdery binders, disintegrants, also called dry binders, This is a method of compression-molding a mixture in which other suitable additives are added and mixed uniformly. This method directly compresses the powder without pre-treatment, and is used when the powder has good compression moldability. In some cases, the powder contains an active ingredient as a raw material for direct compression. Some products that have been processed in advance to improve moldability are sold on the market.
一方、顆粒圧縮法は、まず、賦形剤などを用いて原料の粉体を含む顆粒を製造し 、ついで、得られた顆粒に滑沢剤などを加えて、これを圧縮成形する方法である。顆 粒を湿式造粒法で製造した場合には湿式顆粒圧縮法と呼ばれ、乾式造粒法で製造 した場合には乾式顆粒圧縮法と呼ばれる。  On the other hand, the granule compression method is a method in which granules containing raw material powder are first produced using excipients, and then a lubricant is added to the obtained granules, followed by compression molding. . When the condyles are produced by wet granulation, they are called wet granule compression, and when they are produced by dry granulation, they are called dry granule compression.
[0005] 直接打錠法は、上述した乾式造粒法における場合と同様に、製造される錠剤が水 や熱に不安定な有効成分を含む場合に一般的に適用されるが、製造工程数は最も 少なぐ経済的な利点がある。  [0005] Similar to the dry granulation method described above, the direct tableting method is generally applied when the tablet to be produced contains an active ingredient unstable to water or heat. Has the least economic advantage.
乾式顆粒圧縮法は、上述したように乾式造粒法により得られた顆粒を打錠に用いる 方法であって、通常、成形する粉体の流動性や圧縮成形性などに問題があり、直接 打錠法の適用が難しい場合に採用される。湿式顆粒圧縮法は最も一般的に用いら れている錠剤の製法であって、圧縮成形が容易であり、得られる錠剤の質量偏差が 小さぐ含量均一性も良好であるという長所がある。  The dry granule compression method uses the granules obtained by the dry granulation method as described above for tableting, and usually has problems in the fluidity and compression moldability of the powder to be molded. Used when it is difficult to apply the lock method. The wet granule compression method is the most commonly used tablet manufacturing method, and is advantageous in that it is easy to compress and has a small mass deviation and good content uniformity.
[0006] これら顆粒や錠剤の製造においては、各種の添加剤が使用される。そのなかで結 合剤は、原料の粉体や、これを含む混合粉体に結合力を与え、圧縮成形を容易に するために用いられる添加剤である。結合剤には、デンプンのり液、ヒドロキシプロピ ルセルロース液、ポリビュルピロリドン液など液状のものが使用される場合が多 、が、 粉末状のものが使用される場合もあり、粉末状の結合剤としては結晶セルロースが汎 用されている。 [0006] Various additives are used in the production of these granules and tablets. Among them, the binder gives a binding force to the raw material powder and mixed powders containing it, facilitating compression molding. It is an additive used for In many cases, liquid binders such as starch paste liquid, hydroxypropyl cellulose liquid, polybutylpyrrolidone liquid are used, but powdered ones are also used. For example, crystalline cellulose is commonly used.
[0007] 例えば、第十四改正日本薬局方解説書、 A— 64ページ、廣川書店（2001)には、 「粉末として用いられる結合剤としては結晶セルロースが汎用される」との記載がある 。同書 A— 65ページの乾式顆粒圧縮法の造粒に関する解説の中に「薬品に必要に 応じて賦形剤、粉末状の結合剤、 · · ·を加えて混合物とし、 · · ·」との記載がある。また 津田恭介:医薬品開発基礎講座、 XI、薬剤製造法、 136ページ、地人書館 (東京） 、（1971)には、「直接粉末圧縮法の結合剤として、結晶セルロースの使用が一般的 で、平均粒子径 40 m、 120 mの 2種の粒度のものが市販されている。」との記載 がある。このように直接打錠法や乾式造粒法における結合剤には粉末状のものが使 用され、その例としては、水不溶性の結晶セルロースが汎用されている。  [0007] For example, the 14th revised Japanese Pharmacopoeia Manual, page A-64, Yodogawa Shoten (2001) states that "crystalline cellulose is widely used as a binder used as a powder". In the commentary on the granulation of the dry granule compression method on page 65 of the same book A--In the explanation about the granulation of the dry granule compression method, “add excipients, powdery binder, ... There is a description. In addition, Yusuke Tsuda: Basic Course on Drug Development, XI, Pharmaceutical Manufacturing Method, page 136, Jinjinshokan (Tokyo), (1971) states, “The use of crystalline cellulose as a binder for direct powder compression is common, There are two types of particle sizes with an average particle size of 40 m and 120 m on the market. " As described above, a powdery binder is used in the direct tableting method and the dry granulation method. As an example, water-insoluble crystalline cellulose is widely used.
[0008] このように結合剤には、液状で使用されるものと粉末状で使用されるものとがあり、 例示した文献などに記載されているように、後者の結合剤のことを「粉末として用いら れる結合剤」または「粉末状の結合剤」と言う場合がある。本明細書においては、粉 末状で使用される結合剤のことをまとめて「粉末状結合剤」と呼ぶ。すなわち、「粉末 状結合剤」には、一般に「乾式結合剤」と呼ばれ、直接打錠法や乾式造粒法など溶 媒を使わな ヽ操作で用いられる結合剤や、湿式造粒法にお！ヽて液状ではなく粉末 状で加えられる結合剤も含まれる。  [0008] As described above, there are binders used in a liquid state and those used in a powder form, and the latter binder is referred to as "powder" as described in the exemplified literature. May be referred to as "binder used as" or "powdered binder". In this specification, binders used in powder form are collectively referred to as “powder binder”. In other words, “powder-like binders” are generally called “dry binders”, and are used in binders used in a punching operation without using a solvent, such as direct tableting and dry granulation methods, and wet granulation methods. Oh! It also includes binders that are added in powder form rather than liquid form.
[0009] 賦形剤は、有効成分を含む原料の粉体の量が少ない場合、顆粒や錠剤に一定の 大きさと質量を与えるため、または、でき上がった顆粒や錠剤の質量をある程度大き くして、取り扱いや服用を容易にするための添加剤である。賦形剤としては、乳糖が 最も汎用されるが、その他にデンプン、 D—マン-トール、白糖などが用いられる。直 接打錠法において使用される賦形剤は、流動性と圧縮成形性に優れていることが望 まれ、例えば日本薬局方に収載されている乳糖の場合には、一般的な乳糖とは製法 が異なる噴霧乾燥によるものや、一般的な製法により得られた乳糖を造粒したものが 、この目的 (流動性、圧縮成形性）に使用されて!ヽる。 直接打錠用の賦形剤としての乳糖の製品は、乳糖単一成分で構成されるものが一 般的であるが、このほかに複数成分から構成される賦形剤の例もあり、例えば医薬品 添加物規格に収載されているものに、成分名として「乳糖造粒物」や、「合成ケィ酸ァ ルミ-ゥム ·ヒドロキシプロピルスターチ ·結晶セルロース」などがある。前者はヒドロキ シプロピルセルロースと乳糖から成るものである。直接打錠法においては、直接打錠 用の賦形剤を使用しても、硬度などの錠剤の性質が目的のレベルに達しない場合、 粉末状結合剤がさらに使用される。 [0009] When the amount of the raw material powder containing the active ingredient is small, the excipient is used to give a certain size and mass to the granules and tablets, or to increase the mass of the finished granules and tablets to some extent, It is an additive to facilitate handling and taking. As the excipient, lactose is most commonly used, but starch, D-manntol, sucrose, etc. are also used. The excipient used in the direct compression method is expected to be excellent in fluidity and compression moldability. For example, in the case of lactose listed in the Japanese Pharmacopoeia, A spray-dried one with a different production method or one obtained by granulating lactose obtained by a general production method is used for this purpose (fluidity, compression moldability). Lactose products as excipients for direct tableting are generally composed of a single component of lactose, but there are also examples of excipients composed of multiple components. Among those listed in the Pharmaceutical Additives Standard, there are “lactose granulated products” and “synthetic carboxylic acid hydroxypropyl starch. The former consists of hydroxypropylcellulose and lactose. In the direct tableting method, if the tablet properties such as hardness do not reach the target level even if the excipient for direct tableting is used, a powdery binder is further used.
[0010] また、特許文献 1〜3には、トウモロコシデンプンなどのデンプンを、直接打錠法な どで錠剤成形する際の添加剤として使用して、崩壊性、嚥下性、圧縮特性などを高 めようとする技術が開示されている。  [0010] In Patent Documents 1 to 3, starch such as corn starch is used as an additive when tablets are formed by a direct tableting method, etc. to improve disintegration, swallowability, compression characteristics, and the like. A technique to be obtained is disclosed.
特許文献 1：特開平 8 - 208523号公報  Patent Document 1: JP-A-8-208523
特許文献 2：国際公開第 00Z47233号パンフレット  Patent Document 2: Pamphlet of International Publication No. 00Z47233
特許文献 3 :特開 2002— 12559号公報  Patent Document 3: Japanese Patent Laid-Open No. 2002-12559
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0011] 上記のように、粉末状結合剤は、錠剤や顆粒を製造する際に使用されるものであり 、水や有機溶媒には溶けない粉末状の結晶セルロースが一般的に使用されている。 しかし、結晶セルロースは、結合性の点では優れている力 保存中に徐々に黄褐 色系に着色する性質がある。そのため、結晶セルロースを多く含む錠剤などには、着 色変化が肉眼でも認められることがある。また、相互作用を起因として、有効成分の 分解を促進することや、製剤の着色を促進することなどがある。 [0011] As described above, the powdered binder is used when producing tablets and granules, and powdered crystalline cellulose that is insoluble in water or an organic solvent is generally used. . However, crystalline cellulose has excellent properties in terms of binding properties, and has the property of gradually coloring yellowish brown during storage. For this reason, color changes may be observed with the naked eye on tablets containing a large amount of crystalline cellulose. Also, due to the interaction, it may promote the degradation of the active ingredient and promote the coloring of the preparation.
例えば、吉岡澄江著：医薬品の安定性、 62ページ、南江堂（1995)には、セルロー スおよびトウモロコシデンプンの存在下におけるフロモキセフの加水分解を比較した 結果、セルロースの場合、水分の増加と共に急激に分解が速くなるのに対し、トウモ ロコシデンプンでは水分の増加と分解の速さの関係は緩慢であり、同一水分ではトウ モロコシデンプンの方が分解が遅いデータが示されている。また、同書 120ページに は、「マレイン酸ェナラプリルの安定性低下の原因である結晶セルロースとの相互作 用など多くの薬物と添加剤との相互作用が熱分析によって検討されている。」との記 載が見られる。このように結晶セルロースには、安定性の点で問題があった。 For example, Yoshie Sumie: Stability of pharmaceuticals, page 62, Nanedo (1995), compared the hydrolysis of flomoxef in the presence of cellulose and corn starch. On the other hand, the relationship between the increase in moisture and the rate of degradation is slow in corn starch, and the degradation of corn starch is slower at the same moisture. In addition, page 120 of the same book states, “The interaction between many drugs and additives, such as the interaction with crystalline cellulose, which is the cause of reduced stability of enalapril maleate, has been studied by thermal analysis.” Record You can see the story. Thus, crystalline cellulose has a problem in terms of stability.
[0012] 通常、製剤の処方設計において、医薬品添加物と薬物との相互作用などが原因で 、得られる製剤が不安定になったり、その性質が不十分になったりする場合には、そ の添加剤の代替えとなり得る別の添加剤が選択される。しかし、結晶セルロースと同 程度の結合性を持つ他の粉末状結合剤は、従来、存在しなカゝつた。  [0012] Normally, in the formulation design of a drug product, if the resulting drug product becomes unstable or its properties become insufficient due to the interaction between pharmaceutical additives and the drug, etc. Another additive is selected that can replace the additive. However, other powdery binders having the same degree of binding as crystalline cellulose have not existed in the past.
[0013] さらに、従来の顆粒や錠剤の製造方法においては、以下の問題もある。  Furthermore, the conventional methods for producing granules and tablets have the following problems.
( 1)打錠機などを使用した圧縮成形法により錠剤を成形する際に、粉末状結合剤と して結晶セルロースを使用するとともに滑沢剤として硬化油を使用した場合、結晶セ ルロースの影響を受けて錠剤の崩壊が著しく遅くなる。また、それ以外の場合でも、 実用可能な崩壊時間や錠剤硬度を備えた錠剤が得られない場合があった。  (1) When tablets are formed by compression molding using a tableting machine, etc., if crystalline cellulose is used as a powder binder and hardened oil is used as a lubricant, the effect of crystalline cellulose In response to this, the disintegration of the tablets is significantly slowed down. In other cases, tablets with practical disintegration time and tablet hardness may not be obtained.
[0014] (2)乾式造粒法は、上述のとおり容易かつ簡便であり、製造コストは低いものである 力 破砕機などによる破砕工程において微粒子が生じやすぐ粒度が揃った顆粒を 高収率で得られないという問題があった。また、得られた顆粒を打錠して良好な錠剤 物性の錠剤を得るためには、顆粒の物性が大きく関与する。一般には、不定形で硬 度が低い顆粒は打錠時の圧縮成形性を高めるため、高い硬度の錠剤を成形でき、 好ましいとされている。ところが、乾式造粒法でこのような特性の打錠用顆粒を得よう とすると、その際に多量の微粒子を発生してしまうため、粒度が揃った顆粒を高収率 で得て、し力も得られた顆粒を使用して十分な硬度の錠剤を安定して得ることは非常 に困難であった。また、湿式造粒法において結合剤として汎用されているヒドロキシ プロピルセルロースを粉末状結合剤として、乾式造粒法に用いた場合、錠剤の崩壊 時間が著しく長くなるという問題があった。 [2] (2) The dry granulation method is easy and simple as described above, and the production cost is low. A high yield is obtained in the form of fine particles in the crushing process using a force crusher or the like, and a granule with a uniform particle size. There was a problem that could not be obtained. In addition, in order to tablet the obtained granule to obtain a tablet having good physical properties, the physical property of the granule is greatly involved. In general, granules having an irregular shape and low hardness are considered preferable because they can form tablets with high hardness in order to improve compression moldability during tableting. However, when trying to obtain tableting granules with such characteristics by the dry granulation method, a large amount of fine particles are generated at that time. It was very difficult to stably obtain tablets with sufficient hardness using the obtained granules. In addition, when hydroxypropylcellulose, which is widely used as a binder in wet granulation methods, is used as a powdery binder in dry granulation methods, there has been a problem that the disintegration time of the tablet becomes extremely long.
一方、賦形剤に汎用される乳糖は、アミノ基を持つ化合物とメイラード反応を起こす ことがある。メイラード反応は、アミノ酸、ペプチド、たんぱく質のアミノ基と糖の配糖体 形成能を有する水酸基との間に起こる反応と定義されるものであって、アミノ基を持 つ化合物と乳糖を含む賦形剤とを共に含有する顆粒や錠剤では、メイラード反応に より経時的に褐色に着色するという問題があった。そのため、このようなメイラード反 応を起こさない賦形剤として知られている D—マン-トールを使用することがある。とこ ろ力 D—マン-トールは成形性が低いため、 D—マン-トールを賦形剤として使用 した場合には、顆粒の収率が低下する傾向があるとともに、実用可能な硬度を持つ 錠剤が得られにくいという問題があった。このように、従来、乾式造粒法を適用して、 アミノ基を持つ活性成分を含有する顆粒や錠剤を製造する際にお!/ヽて、成形性と経 時的な色の安定性とを両立することは困難であった。 On the other hand, lactose widely used as an excipient may cause a Maillard reaction with a compound having an amino group. The Maillard reaction is defined as a reaction that occurs between amino groups of amino acids, peptides, and proteins and hydroxyl groups that have the ability to form glycosides of sugars, and is an excipient that contains amino group-containing compounds and lactose. In the case of granules and tablets containing the agent together, there is a problem that the color becomes brown over time due to the Maillard reaction. Therefore, D-mann-toll, which is known as an excipient that does not cause such Maillard reaction, may be used. The strength of D-mann-toll is low as moldability, so D-mann-toll is used as an excipient In this case, the yield of the granules tends to decrease, and there is a problem that it is difficult to obtain a tablet having a practical hardness. As described above, when a granulation method or tablet containing an active ingredient having an amino group is conventionally applied by applying a dry granulation method, the moldability and temporal color stability are improved. It was difficult to achieve both.
[0015] (3)湿式造粒法で粉体を造粒し、得られた顆粒を打錠機などで圧縮成形し、錠剤を 成形する湿式顆粒圧縮法では、得られる錠剤の硬度や崩壊時間が不十分となる場 合があった。また、十分な硬度を発現させるために結晶セルロースを使用することも 考えられるが、その場合には上述したような結晶セルロースの安定性に関する問題 かあつた。  [0015] (3) In the wet granulation method in which a powder is granulated by a wet granulation method, the resulting granule is compression-molded with a tableting machine, and the tablet is molded, the hardness and disintegration time of the resulting tablet May be insufficient. It is also conceivable to use crystalline cellulose in order to develop sufficient hardness, but in that case, there was a problem related to the stability of crystalline cellulose as described above.
[0016] (4)打錠機などを使用した圧縮成形法により錠剤を成形する際には、賦形剤が使用 されることが多ぐ賦形剤としては、上述したように多くの製品が市販されている。しか しながら、それらを用いた場合、錠剤中の有効成分量が高い場合などには得られる 錠剤の硬度が不足し、粉末状結合剤の併用が必要となる場合も多い。この場合にも 、結晶セルロースを粉末状結合剤として利用することが考えられる力 結晶セルロー スには上述したような安定'性に関する問題があった。  [4] (4) When a tablet is formed by a compression molding method using a tableting machine or the like, an excipient is often used as an excipient. It is commercially available. However, when they are used, when the amount of the active ingredient in the tablet is high, the hardness of the obtained tablet is insufficient, and it is often necessary to use a powdery binder. In this case as well, the force crystalline cellulose, which can be considered to use crystalline cellulose as a powdery binder, has the above-mentioned problems relating to stability.
[0017] 本発明は上記事情に鑑みてなされたもので、錠剤や顆粒を製造する際の上述の問 題点などを改善することを課題とする。より具体的には、以下の通りである。  [0017] The present invention has been made in view of the above circumstances, and an object thereof is to improve the above-mentioned problems and the like when manufacturing tablets and granules. More specifically, it is as follows.
( 1)打錠機などを使用した圧縮成形法により錠剤を成形する場合において、経時的 な着色が少なく経時的安定性に優れ、かつ滑沢剤に硬化油を使用した場合でも崩 壊が遅くならず、実用可能な錠剤硬度と崩壊速度とを備えた錠剤の製造方法を提供 する。  (1) When tablets are formed by compression molding using a tableting machine, etc., there is little coloration over time, excellent stability over time, and even when hardened oil is used as a lubricant, collapse is slow. In addition, the present invention provides a method for producing tablets having practical tablet hardness and disintegration speed.
(2)乾式造粒法にぉ 、て、微粒子などが少なく粒度が揃った顆粒を高収率で得るこ とができ、し力も得られる顆粒は経時的な着色が少な 、経時的安定性に優れたもの となる顆粒の製造方法、さらには、実用可能な錠剤硬度と崩壊時間とを備え、経時的 安定性にも優れた錠剤を製造可能な顆粒の製造方法を提供する。  (2) By using the dry granulation method, it is possible to obtain a granule with a small particle size and a uniform particle size in a high yield. An excellent granule production method, and further a granule production method capable of producing a tablet having practical tablet hardness and disintegration time and excellent in temporal stability.
(3)湿式顆粒圧縮法において、実用可能な錠剤硬度と崩壊時間とを備え、経時的安 定性にも優れた錠剤を製造可能な方法を提供する。  (3) To provide a method capable of producing a tablet having practical tablet hardness and disintegration time and excellent in stability over time in the wet granule compression method.
(4)打錠機などを使用した圧縮成形法により錠剤を成形する場合において、経時的 安定性に優れ、粉末状結合剤を追加添加しなくても実用可能な錠剤硬度と崩壊速 度とを備える錠剤の製造方法を提供する。 (4) When tablets are formed by compression molding using a tableting machine, etc. Provided is a method for producing a tablet having excellent stability and a practical tablet hardness and disintegration speed without adding a powdery binder.
課題を解決するための手段  Means for solving the problem
[0018] 本発明者らはカゝかる課題を解決するために鋭意検討した結果、錠剤や顆粒を製造 する際に、粉末状結合剤として、コメデンプンとコメデンプン誘導体のうち少なくとも一 方を使用することが有用であることを見出した。  [0018] As a result of intensive studies to solve the problem, the present inventors use at least one of rice starch and rice starch derivatives as a powdery binder when producing tablets and granules. I found it useful.
すなわち、（1)本発明の錠剤の製造方法は、水分含量 6〜14質量％のコメデンプ ンと水分含量 6〜14質量％のコメデンプン誘導体のうち少なくとも一方を粉末状結合 剤として使用した圧縮成形法により、錠剤を成形することを含む。  That is, (1) the tablet production method of the present invention is a compression molding using at least one of rice denpene having a water content of 6 to 14% by mass and rice starch derivative having a water content of 6 to 14% by mass as a powdery binder. By shaping the tablet by the method.
前記コメデンプンとコメデンプン誘導体のうち少なくとも一方の水分含量は、 9〜14 質量％であることが好まし!/、。  The water content of at least one of the rice starch and the rice starch derivative is preferably 9 to 14% by mass! /.
前記錠剤は、医薬品有効成分と食品用保健機能成分のうち少なくとも一方を含有 することが好ましい。  The tablet preferably contains at least one of an active pharmaceutical ingredient and a food health functional ingredient.
前記錠剤中のコメデンプンとコメデンプン誘導体のうち少なくとも一方の含有量は、 5質量％以上であることが好まし 、。  The content of at least one of rice starch and rice starch derivative in the tablet is preferably 5% by mass or more.
前記コメデンプンとコメデンプン誘導体のうち少なくとも一方は、加熱処理されてか ら前記水分含量に調整されたものであることが好ましい。  It is preferable that at least one of the rice starch and the rice starch derivative is adjusted to the water content after being heat-treated.
[0019] (2)本発明の顆粒の製造方法は、水分含量 6〜14質量％のコメデンプンと水分含量 6〜 14質量％のコメデンプン誘導体のうち少なくとも一方を粉末状結合剤として使用 した乾式造粒法により、粉体を造粒することを含む。 [0019] (2) The granule production method of the present invention is a dry process using at least one of a rice starch having a water content of 6 to 14% by mass and a rice starch derivative having a water content of 6 to 14% by mass as a powdery binder. It includes granulating the powder by a granulation method.
前記コメデンプンとコメデンプン誘導体のうち少なくとも一方の水分含量は、 9〜14 質量％であることが好まし!/、。  The water content of at least one of the rice starch and the rice starch derivative is preferably 9 to 14% by mass! /.
前記顆粒は、医薬品有効成分と食品用保健機能成分のうち少なくとも一方を含有 することが好ましい。  The granule preferably contains at least one of an active pharmaceutical ingredient and a health functional ingredient for food.
前記顆粒中のコメデンプンとコメデンプン誘導体のうち少なくとも一方の含有量は、 10質量％以上であることが好まし 、。  The content of at least one of rice starch and rice starch derivatives in the granules is preferably 10% by mass or more.
結晶セルロース、粉末セルロースまたは低置換度ヒドロキシプロピルセルロースの 粉末からなる群から選択される少なくとも 1種以上のセルロース系粉末状結合剤をさ らに使用することが好ましい。 At least one cellulosic powder binder selected from the group consisting of crystalline cellulose, powdered cellulose or low substituted hydroxypropylcellulose powder. Furthermore, it is preferable to use it.
前記顆粒中の前記セルロース系粉末状結合剤の含有量は、 10〜30質量％である ことが好ましい。  The content of the cellulose-based powder binder in the granules is preferably 10 to 30% by mass.
D—マン-トールを賦形剤として使用することが好ましい。  It is preferred to use D-mannitol as an excipient.
前記コメデンプンとコメデンプン誘導体のうち少なくとも一方は、加熱処理されてか ら前記水分含量に調整されたものであることが好ましい。  It is preferable that at least one of the rice starch and the rice starch derivative is adjusted to the water content after being heat-treated.
本発明の顆粒は、前記製造方法により製造されてなるものである。  The granule of the present invention is produced by the above production method.
また、本発明の錠剤は、前記顆粒を含有する。  Moreover, the tablet of this invention contains the said granule.
[0020] (3)本発明の錠剤の製造方法は、コメデンプンとコメデンプン誘導体のうち少なくとも 一方を粉末状結合剤として使用した湿式造粒法により粉体を造粒し、該造粒で得ら れた顆粒をその水分活性 (aw)が 0. 4〜0. 8になるように調湿してから、圧縮成形す ることを含む。 [0020] (3) The tablet production method of the present invention is obtained by granulating a powder by a wet granulation method using at least one of rice starch and rice starch derivative as a powdery binder, and obtaining the granulated product. This includes conditioning the resulting granule so that its water activity (aw) is 0.4 to 0.8, and then compression molding.
前記錠剤は、医薬品有効成分と食品用保健機能成分のうち少なくとも一方を含有 することが好ましい。  The tablet preferably contains at least one of an active pharmaceutical ingredient and a food health functional ingredient.
[0021] (4)本発明の錠剤の製造方法は、コメデンプンとコメデンプン誘導体のうち少なくとも 一方を粉末状結合剤として使用した湿式造粒法により粉末状の賦形剤を造粒し、該 造粒で得られた顆粒状の賦形剤をその水分活性 (aw)が 0. 4〜0. 8になるように調 湿してから他の粉体と混合し、圧縮成形することを含む。  [0021] (4) The method for producing a tablet of the present invention comprises granulating a powdery excipient by a wet granulation method using at least one of rice starch and a rice starch derivative as a powder binder, It includes conditioning the granular excipient obtained by granulation so that its water activity (aw) is 0.4 to 0.8, mixing with other powders, and compression molding. .
前記錠剤は、医薬品有効成分と食品用保健機能成分のうち少なくとも一方を含有 することが好ましい。  The tablet preferably contains at least one of an active pharmaceutical ingredient and a food health functional ingredient.
[0022] 本発明の錠剤は、前記錠剤の製造方法のうち、いずれかの製造方法により製造さ れる。  [0022] The tablet of the present invention is manufactured by any one of the manufacturing methods of the tablets.
発明の効果  The invention's effect
[0023] 本発明によれば、コメデンプンとコメデンプン誘導体のうち少なくとも一方の特性 (優 れた結合性、有効成分との相互作用の低さ）が最大限に発揮され、具体的には次の ような効果が得られる。  [0023] According to the present invention, at least one of the characteristics of rice starch and rice starch derivatives (excellent binding, low interaction with active ingredients) is exhibited to the maximum. The following effects can be obtained.
(1)打錠機などを使用した圧縮成形法により錠剤を成形する場合において、錠剤硬 度を高くすることが望まれる場合などに、経時的な着色が少なく経時的安定性に優 れ、かつ滑沢剤に硬化油を使用した場合でも崩壊が遅くならず、実用可能な錠剤硬 度と崩壊速度を備えた錠剤を製造できる。 (1) When a tablet is formed by a compression molding method using a tableting machine, etc., when it is desired to increase the tablet hardness, there is little coloration over time and excellent stability over time. In addition, even when a hardened oil is used as a lubricant, disintegration does not slow, and tablets with practical tablet hardness and disintegration speed can be produced.
(2)乾式造粒法にぉ 、て、微粒子が少なく粒度が揃った顆粒を高収率で得ることが できる。し力も、得られる顆粒は経時的な着色が少ないなど経時的安定性にも優れて いる。また、得られる顆粒を用いることによって、実用可能な錠剤硬度と崩壊時間を 備え、経時的安定性に優れた錠剤を製造できる。  (2) By the dry granulation method, granules with few fine particles and uniform particle size can be obtained in high yield. In addition, the resulting granules are excellent in stability over time, such as little coloring over time. Further, by using the obtained granules, it is possible to produce tablets having practical tablet hardness and disintegration time and excellent in temporal stability.
(3)湿式顆粒圧縮法において、実用可能な錠剤硬度と崩壊時間を備え、経時的安 定性にも優れた錠剤を製造できる。  (3) In the wet granule compression method, a tablet having practical tablet hardness and disintegration time and excellent in stability over time can be produced.
(4)打錠機などを使用した圧縮成形法により錠剤を成形する場合において、経時的 安定性に優れ、粉末状結合剤を追加添加しなくても実用可能な錠剤硬度と崩壊速 度とを備える錠剤を製造できる。  (4) When a tablet is formed by a compression molding method using a tableting machine, etc., it has excellent stability over time and has a tablet hardness and disintegration rate that can be used without adding a powdery binder. A tablet can be produced.
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
以下、本発明を詳細に説明する。  The present invention will be described in detail below.
本発明は、固形剤である錠剤や顆粒の製造において、コメデンプンとコメデンプン 誘導体のうち少なくとも一方を粉末状結合剤として使用すること含むものであり、具体 的には次のような方法より構成されものである。  The present invention includes the use of at least one of rice starch and rice starch derivatives as a powder binder in the manufacture of tablets and granules as solid preparations, and specifically comprises the following method. It is a thing.
すなわち、（1)打錠機などを使用した圧縮成形の際に、コメデンプンとコメデンプン 誘導体のうち少なくとも一方を粉末状結合剤として使用して、錠剤を成形する錠剤の 製造方法であって、その際に粉末状結合剤として、水分含量が 6〜14質量％、好ま しくは 9〜14質量％のコメデンプンと水分含量が 6〜14質量％、好ましくは 9〜14質 量％のコメデンプン誘導体のうち少なくとも一方を使用する。以下、この製造方法を 製造方法 (1)という場合がある。  That is, (1) a method for producing a tablet in which a tablet is formed by using at least one of rice starch and a rice starch derivative as a powder binder during compression molding using a tableting machine, In this case, rice starch having a water content of 6 to 14% by weight, preferably 9 to 14% by weight and rice starch having a water content of 6 to 14% by weight, preferably 9 to 14% by weight, are used as a powdery binder. At least one of the derivatives is used. Hereinafter, this manufacturing method may be referred to as manufacturing method (1).
(2)乾式造粒法により粉体を造粒する顆粒の製造方法であって、その際に粉末状結 合剤として、水分含量が 6〜14質量％、好ましくは 9〜14質量％のコメデンプンと水 分含量が 6〜14質量％、好ましくは 9〜14質量％のコメデンプン誘導体のうち少なく とも一方を使用する。以下、この製造方法を製造方法 (2)という場合がある。  (2) A method for producing granules in which powder is granulated by a dry granulation method, in which a rice powder having a moisture content of 6 to 14% by mass, preferably 9 to 14% by mass, is used as a powdery binder. At least one of the starch and starch derivatives having a water content of 6-14% by weight, preferably 9-14% by weight, is used. Hereinafter, this manufacturing method may be referred to as a manufacturing method (2).
(3)湿式顆粒圧縮法により粉体を圧縮成形する錠剤の製造方法であって、粉末状結 合剤としてコメデンプンとコメデンプン誘導体のうち少なくとも一方を使用した湿式造 粒法により粉体を造粒して顆粒を得て、この顆粒をその水分活性 (aw)が 0. 4〜0. 8 になるように調湿した後、圧縮成形する。以下、この製造方法を製造方法 (3)という場 合がある。 (3) A tablet manufacturing method in which a powder is compressed by a wet granule compression method, which uses at least one of rice starch and rice starch derivatives as a powder binder. Granules are used to granulate the powder to obtain granules. The granules are conditioned to a water activity (aw) of 0.4 to 0.8 and then compression molded. Hereinafter, this production method may be referred to as production method (3).
(4)打錠機などを使用した圧縮成形により錠剤を製造する際に、賦形剤として以下の ものを使用する。すなわち、粉末状の賦形剤にコメデンプンとコメデンプン誘導体のう ち少なくとも一方を粉末状結合剤として加え、これを湿式造粒法により造粒し、さらに その水分活性 (aw)が 0. 4〜0. 8になるように調湿したものを顆粒状の賦形剤とし、 これを他の粉体と混合して圧縮成形する。以下、この製造方法を製造方法 (4)という 場合がある。  (4) When manufacturing tablets by compression molding using a tableting machine, etc., the following are used as excipients. That is, at least one of rice starch and rice starch derivative is added as a powdery binder to a powdery excipient, granulated by wet granulation method, and further its water activity (aw) is 0.4. The powder adjusted to a humidity of ˜0.8 is used as a granular excipient, and this is mixed with other powders and compression molded. Hereinafter, this manufacturing method may be referred to as a manufacturing method (4).
[0025] 本発明の製造方法（1)と製造方法 (2)においては、その際に粉末状結合剤として、 水分含量が 6〜14質量％、好ましくは 9〜14質量％のコメデンプンと水分含量が 6〜 14質量％、好ましくは 9〜14質量％のコメデンプン誘導体のうち少なくとも一方を使 用する。  [0025] In the production method (1) and production method (2) of the present invention, rice starch and water having a water content of 6 to 14% by mass, preferably 9 to 14% by mass, are used as a powdery binder. At least one of rice starch derivatives having a content of 6 to 14% by mass, preferably 9 to 14% by mass, is used.
コメデンプンとコメデンプン誘導体のうち少なくとも一方の水分含量は、粉体を圧縮 成形する際の圧縮成形性や、粉体から顆粒や錠剤を製造する際の圧縮成形性、さら には顆粒力も錠剤を成形する際の圧縮成形性などに影響を与えるものであって、水 分含量が 6質量％未満では十分な成形性が発現せず、顆粒を製造する場合にあつ ては、微粒子が少なく粒度の揃った顆粒を高収率で得られにくいうえ、得られた顆粒 から錠剤を成形する場合にも、十分な硬度のものが得られにくい傾向がある。一方、 14質量％を超えると、コメデンプンとコメデンプン誘導体のうち少なくとも一方の流動 性が低下して、打錠機などでの圧縮成形法や乾式造粒法にお！ヽて操作性に支障を 来たす場合 (コメデンプンとコメデンプン誘導体のうち少なくとも一方が混合された混 合粉体がホッパー力 流出しな 、場合、打錠時にステイツキングなどの打錠障害を起 こす場合、各種装置類の壁に付着する場合など)や、微生物の増殖が懸念される場 合がある。  The water content of at least one of rice starch and rice starch derivatives is determined by the compression moldability when the powder is compressed, the compression moldability when producing granules and tablets from the powder, and the granule strength. This will affect the compression moldability during molding, and if the water content is less than 6% by mass, sufficient moldability will not be exhibited. There is a tendency that it is difficult to obtain a uniform granule in a high yield and that it is difficult to obtain a tablet having sufficient hardness even when a tablet is formed from the obtained granule. On the other hand, if it exceeds 14% by mass, the fluidity of at least one of rice starch and rice starch derivatives will be reduced, so that it can be used in compression molding methods such as tableting machines and dry granulation methods! When operability is hindered (If mixed powder in which at least one of rice starch and rice starch derivatives is mixed does not flow out of hopper, it may cause tableting problems such as sticking during tableting. In some cases, it may adhere to the walls of various devices, etc.) and there may be concerns about the growth of microorganisms.
[0026] 一方、製造方法（3)の湿式顆粒圧縮法の場合には、コメデンプンとコメデンプン誘 導体のうち少なくとも一方を粉末結合剤として粉体に加え、造粒し、得られた顆粒の 水分値をその水分活性 (aw)が 0. 4〜0. 8になるように調湿して力 圧縮成形する。 すなわち、従来の一般の湿式顆粒圧縮法では、造粒された顆粒を乾燥工程で乾 燥してから、圧縮成形するため、コメデンプンとコメデンプン誘導体のうち少なくとも一 方を粉末結合剤として使用して造粒したとしても、乾燥工程にぉ ヽて顆粒中のコメデ ンプンとコメデンプン誘導体のうち少なくとも一方の水分含量が低下し、その結果、得 られる顆粒の圧縮成形性などが低下してしまうと考えられる。このように圧縮成形性の 低い顆粒を使用しても、十分な硬度の錠剤は得られにくい。よって、圧縮成形性を確 保するためには、圧縮成形の前に調湿して、顆粒の水分含量を調整することが重要 であると考えられる。 [0026] On the other hand, in the case of the wet granulation method of production method (3), at least one of rice starch and rice starch derivative is added to the powder as a powder binder, granulated, and the granules obtained Adjust the moisture value so that the water activity (aw) is between 0.4 and 0.8 and force compression mold. That is, in the conventional general wet granule compression method, granulated granules are dried in a drying process and then compression-molded, so at least one of rice starch and rice starch derivatives is used as a powder binder. Even if granulated, the water content of at least one of rice starch and rice starch derivative in the granule decreases during the drying process, and as a result, the compression moldability of the resulting granule decreases. Conceivable. Thus, it is difficult to obtain tablets with sufficient hardness even if granules with low compression moldability are used. Therefore, in order to ensure compression moldability, it is considered important to adjust the moisture content of the granules by adjusting the humidity before compression molding.
[0027] 水分含量の指標としては、水分活性 (aw)を用いるのがよい。水分活性 (aw)は、試 料を容器に密封したとき、平衡状態に達した容器内の相対湿度を 100で除して得ら れる値で、例えばフロイント産業 (株)製の商品名「EZ— 100」などの市販されている 水分活性測定装置を用いることにより測定される。  [0027] As an indicator of the water content, it is preferable to use water activity (aw). The water activity (aw) is a value obtained by dividing the relative humidity in a container that has reached an equilibrium state by 100 when the sample is sealed in a container.For example, the product name `` EZ '' manufactured by Freund Sangyo Co., Ltd. It is measured by using a commercially available water activity measuring device such as “100”.
製造方法 (3)により粉体を圧縮成形する場合には、顆粒をその水分活性 (aw)が 0 . 4〜0. 8になるように調湿するのがよい。水分活性 (aw)が 0. 4未満では十分な成 形性が発現せず、一方 0. 8を超えると、顆粒の流動性が低下して、打錠の際にホッ パーから粉体が流出しない、打錠時にステイツキングなどの打錠障害を起こす、など の懸念がある。  When the powder is compression-molded by the production method (3), the granules are preferably conditioned so that the water activity (aw) thereof is 0.4 to 0.8. If the water activity (aw) is less than 0.4, sufficient formability will not be exhibited, while if it exceeds 0.8, the fluidity of the granules will decrease, and the powder will flow out of the hopper during tableting. There are concerns that tableting troubles such as stateking will occur during tableting.
また、同様の観点から、製造方法 (4)の場合にも、顆粒状に成形された賦形剤をそ の水分活性（aw)が 0. 4〜0. 8になるように調湿するのがよい。  From the same point of view, in the case of the production method (4), the excipient formed in the granular form is conditioned so that its water activity (aw) is 0.4 to 0.8. Is good.
[0028] 日本薬局方には、デンプンに関する品目としてはコムギデンプン、コメデンプン、ト ゥモロコシデンプンおよびバレイショデンプンの 4品目が収載されており、コメデンプ ンの乾燥減量 (水分含量)の規格は、 15. 0%以下である。しかしながら、巿場に流通 する製品の場合、製造における乾燥や熱処理条件の違いから、これら規格範囲であ つても実際の数値には大きくバラツキがある。例えば、デンプン中の雑菌を減らすた めに熱処理を行うと水分が 1質量％以下にまで減少することがある。 [0028] The Japanese Pharmacopoeia includes four items related to starch: wheat starch, rice starch, corn starch, and potato starch. 0% or less. However, in the case of products distributed in the factory, actual values vary widely even within these standards due to differences in drying and heat treatment conditions in production. For example, when heat treatment is performed to reduce germs in starch, the water content may be reduced to 1% by mass or less.
そのため本発明においては、製造方法（1)および（2)においては、特に市販のコメ デンプンとコメデンプン誘導体のうち少なくとも一方を、その水分含量が 6〜14質量 %の範囲となるように必要に応じて適宜水分調整して使用する。 [0029] この場合、コメデンプンとコメデンプン誘導体のうち少なくとも一方には、 75°C以上 の温度で少なくとも 30分間加熱する加熱処理を行ってから、その水分含量を調整す ることが好ましい。なお、殺菌などを目的として、すでにこのような条件の加熱処理が 行われている市販品などについては、再度加熱処理をしなくてもよい。本発明者らは 、このような加熱処理を行ってから水分含量を調整することにより、得られるコメデンプ ンとコメデンプン誘導体のうち少なくとも一方の成形性がより向上することを見出した。 その理由は明らかではないが、このような処理により、コメデンプンとコメデンプン誘導 体のうち少なくとも一方の、少なくとも一部の粒子構造が変化し、その結果、結合力が 向上すると考えられる。 Therefore, in the present invention, in the production methods (1) and (2), at least one of commercially available rice starch and rice starch derivative is required so that its water content is in the range of 6 to 14% by mass. The water content is appropriately adjusted accordingly. [0029] In this case, it is preferable that at least one of the rice starch and the rice starch derivative is subjected to a heat treatment at a temperature of 75 ° C or higher for at least 30 minutes, and then its water content is adjusted. For the purpose of sterilization and the like, commercial products that have already been subjected to heat treatment under such conditions need not be heat-treated again. The inventors of the present invention have found that the moldability of at least one of the obtained rice starch and the rice starch derivative is further improved by adjusting the water content after performing such heat treatment. The reason for this is not clear, but it is thought that such treatment changes the particle structure of at least one of rice starch and rice starch derivatives, and as a result, improves the binding force.
[0030] コメデンプンとコメデンプン誘導体のうち少なくとも一方の水分含量を低くする場合 には、通常の方法でこれを乾燥すればよぐ水分含量を高くする場合には、混合'撹 拌装置内で撹拌しながらこれに水を噴霧する方法、調湿した空気をコメデンプンとコ メデンプン誘導体のうち少なくとも一方に供給する方法などにより目標の水分範囲に 到達させればよい。  [0030] When reducing the water content of at least one of rice starch and rice starch derivatives, it should be dried by a conventional method. What is necessary is just to reach the target moisture range by, for example, spraying water on this while stirring, or supplying conditioned air to at least one of rice starch and rice starch derivatives.
[0031] また、製造方法（3)および (4)にお 、ては、市販のコメデンプンとコメデンプン誘導 体のうち少なくとも一方は、そのまま用いればよぐ事前に水分調整の必要はない。な お、コメデンプンとコメデンプン誘導体のうち少なくとも一方の水分含量は、 日本薬局 方 (第 14改正）「乾燥減量試験法」に準じて、 105°Cの温度で 6時間乾燥した際の質 量減量により求められる。  [0031] In the production methods (3) and (4), at least one of the commercially available rice starch and the rice starch derivative may be used as it is, and it is not necessary to adjust the moisture in advance. The water content of at least one of rice starch and rice starch derivatives is the mass when dried at a temperature of 105 ° C for 6 hours in accordance with the Japanese Pharmacopoeia (14th revision) “Loss on drying test method”. Required by weight loss.
[0032] ここで使用されるコメデンプンは、ウルチコメ、モチゴメを原料に製造されるものであ つて、各種の製造方法が知られている力 日本薬局方またはヨーロッパ薬局方などの コメデンプンの各条に適合するものであればどのような製造方法により製造されたも のでもよい。  [0032] The rice starch used here is produced from uruchime and mochigome as raw materials, and is known for various production methods. Each item of rice starch such as the Japanese Pharmacopoeia or European Pharmacopoeia It may be manufactured by any manufacturing method as long as it conforms to the requirements.
また、コメデンプン誘導体としては、例えばエステルイ匕デンプン、エーテルィ匕デンプ ン、酸化デンプンなどの誘導体が挙げられる。エステル化デンプン、エーテル化デン プンとして具体的には、コメデンプンの酢酸エステル、リン酸モノエステル、リン酸架 橋（リン酸ジエステル）、オタテュルコハク酸エステル、酢酸アジピン酸架橋、ヒドロキ シェチルエーテル、ヒドロキシプロピルエーテル、カルボキシメチルエーテルなどが挙 げられる。さらには、酸処理デンプン、漂白処理デンプン、物理処理デンプン (湿熱 処理デンプンなど)も使用できる。これらは 1種を単独で使用しても、 2種以上を併用 してちよい。 Examples of the rice starch derivatives include derivatives such as ester starch, ether starch, oxidized starch and the like. Specific examples of esterified starch and etherified starch include rice starch acetate, phosphate monoester, phosphate bridge (phosphate diester), otatur succinate, adipic acetate bridge, hydroxy ether, hydroxy Propyl ether, carboxymethyl ether, etc. I can get lost. Furthermore, acid-treated starch, bleach-treated starch, and physically-treated starch (such as wet heat-treated starch) can also be used. These may be used alone or in combination of two or more.
[0033] デンプン類は、医薬品添加剤の分野では賦形剤、崩壊剤および結合剤として使用 される。結合剤として使用される場合は、通常、 5〜 10%デンプンのり液の形で使用 されるとの記載が第十四改正日本薬局方解説書、 A— 64ページ、廣川書店（2001) に見られる。しかし、デンプン類が粉末状で結合剤として使用されるとの記載は、従 来、見られない。コメデンプンが他のデンプン類に比べて異なる点はその粒子径が 微小であることである。不破英次他編:澱粉科学の事典、 373ページ、朝倉書店 (東 京）（2003)には、各種デンプンの粒径が示されており、米澱粉、コーンスターチ、小 麦 粉、 '焉鈴薯滅粉ではそれぞれ 4. 8 m、 12. 2 m、 16. 9 m、 32. 2 mと の記載がある。  [0033] Starches are used as excipients, disintegrants and binders in the field of pharmaceutical additives. When used as a binder, the description that it is usually used in the form of 5-10% starch paste is found in the 14th revised Japanese Pharmacopoeia, A-64, Yodogawa Shoten (2001). It is done. However, the description that starches are used as a binder in powder form has not been found so far. Rice starch differs from other starches in that its particle size is very small. Eiji Fuwa et al .: Encyclopedia of Starch Science, page 373, Asakura Shoten (Tokyo) (2003) shows the particle sizes of various starches, rice starch, corn starch, barley flour, For dusting, there are 4.8 m, 12.2 m, 16.9 m, and 32.2 m, respectively.
コメデンプンとコメデンプン誘導体のうち少なくとも一方は、このように、その粒子径 が他のデンプン類と比較して著しく微小であるため、粒子間の接触面積が大きくなる 。このような接触面積の増カロが、粉末状結合剤としての結合性の向上に寄与するた め、コメデンプンとコメデンプン誘導体のうち少なくとも一方は、製造方法（1)〜(4)に おいて好適に使用されると推察できる。  As described above, at least one of rice starch and rice starch derivatives has a very small particle size as compared with other starches, so that the contact area between the particles is increased. Since the increase in the contact area contributes to the improvement of the binding property as a powdery binder, at least one of rice starch and rice starch derivatives is produced in the production methods (1) to (4). It can be inferred that it is suitably used.
[0034] 上記製造方法 (1)〜(4)では、原料として、医薬品有効成分と食品用保健機能成 分のうち少なくとも一方を含有するものが好適に使用でき、その結果、該成分を含有 する顆粒や錠剤が得られる。 [0034] In the above production methods (1) to (4), as the raw material, those containing at least one of an active pharmaceutical ingredient and a food health functional ingredient can be suitably used, and as a result, contain the ingredient. Granules and tablets are obtained.
医薬品有効成分としては特に制限はないが、催眠'鎮痛剤、解熱鎮痛消炎剤、精 神神経用剤、自律神経用剤、抗パーキンソン剤、抗ヒスタミン剤、強心剤、利尿剤、 血圧降下剤、血管収縮剤、動脈硬化用剤、鎮咳去痰剤、ビタミン剤、滋養強壮薬、 抗生物質、胃腸薬などが挙げられる。  There are no particular restrictions on active pharmaceutical ingredients, but hypnotic analgesics, antipyretic analgesics, antipsychotic agents, autonomic agents, antiparkinson agents, antihistamines, cardiotonics, diuretics, antihypertensive agents, vasoconstrictors , Arteriosclerotic agents, antitussive expectorants, vitamins, nourishing tonics, antibiotics, gastrointestinal drugs and the like.
食品用保健機能成分としては、身体の生理学的機能などに影響を与え、食品に使 用されるものであって、例えば、ビタミン類、ミネラル類、ハーブ類、たんぱく質、脂肪 酸、食物繊維などの栄養成分、高麗にんじんなどの植物性食品、プロポリスなどの動 物性食品、ビフィズス菌などの菌類、及びコェンザィム Q10など厚生労働省より通知 された「医薬品的効能効果を標ぼうしない限り食品と認められる成分本質リスト」に収 載されて!ヽる物質が挙げられる。 Food health functional ingredients affect the body's physiological functions and are used in foods, such as vitamins, minerals, herbs, proteins, fatty acids, dietary fiber, etc. Notification from the Ministry of Health, Labor and Welfare such as nutritional ingredients, plant foods such as ginseng carrots, animal foods such as propolis, fungi such as bifidobacteria, and coenzyme Q10 Substances listed in the list of “essences of ingredients that are recognized as food unless they are targeted for pharmaceutical efficacy” are listed.
[0035] また、上記製造方法（1)〜 (4)では、他の各種添加剤が使用でき、コメデンプンとコ メデンプン誘導体のうち少なくとも一方以外の粉末状結合剤（一般に乾式結合剤と呼 ばれるもの）、賦形剤、崩壊剤、滑沢剤などが挙げられる。また、必要があれば、錠剤 や顆粒の製造に一般に用いられる流動化剤、香料、甘味料、着色料などを加えても よい。 [0035] In addition, in the production methods (1) to (4), various other additives can be used, and a powdery binder other than at least one of rice starch and rice starch derivatives (generally called a dry binder). ), Excipients, disintegrants, lubricants and the like. If necessary, fluidizing agents, fragrances, sweeteners, coloring agents and the like generally used for the production of tablets and granules may be added.
[0036] 滑沢剤は、打錠機などによる圧縮成形時に、有効成分を含む原料の粉体や添カロ 剤が杵ゃ臼に付着しな ヽようにするとともに、均一な圧縮成形性が得られるように働く ものである。また、乾式造粒法においては、ロール圧縮成形の際に、成形物がロール に付着するのを防止するように働くものである。具体的には、ステアリン酸マグネシゥ ム、フマル酸ステアリルナトリウム、硬化油、ショ糖脂肪酸エステル、グリセリン脂肪酸 エステル、タルクなどが使用できる。滑沢剤の添加量は、上記製造方法（1)〜(4)の いずれの場合でも、滑沢剤の種類や、原料の粉体やこれに各種添加剤が添加され た混合粉体の性質などにより異なり、一様ではないが、錠剤や顆粒中 0. 1〜10質量 %となる範囲が一般的である。  [0036] Lubricants prevent the powder of raw materials and additive containing active ingredients from adhering to the die during compression molding using a tableting machine, etc., and provide uniform compression moldability. It works as you can. Further, in the dry granulation method, it acts to prevent the molded product from adhering to the roll during roll compression molding. Specifically, magnesium stearate, sodium stearyl fumarate, hydrogenated oil, sucrose fatty acid ester, glycerin fatty acid ester, talc and the like can be used. The amount of lubricant added depends on the type of lubricant, the raw material powder, and the mixed powder with various additives added to it, in any of the above production methods (1) to (4). Although it is not uniform and is not uniform, a range of 0.1 to 10% by mass in tablets and granules is common.
[0037] 崩壊剤は、水中または消化管液中で顆粒や錠剤に崩壊性を与える働きをするもの であって、カルメロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルス ターチナトリウム、ヒドロキシプロピルスターチなどの一般的な崩壊剤の他、乳糖、 D —マン-トール、ショ糖などの賦形剤を使用することができる。  [0037] The disintegrant acts to disintegrate granules and tablets in water or in the gastrointestinal fluid, and includes carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium, hydroxypropyl starch, and the like. In addition to common disintegrants, excipients such as lactose, D-mannitol and sucrose can be used.
[0038] さらに、製造方法 (1)、（3)、（4)の各方法で得られた錠剤や、製造方法 (2)で得ら れた顆粒を含有する錠剤には、医薬品有効成分または食品用保健機能成分に由来 する不快な味のマスキング、安定性の改善、外観を美しくするなどの目的で、さらに フィルムコーティングを行ってもよ 、。  [0038] Furthermore, the tablets obtained by each of the production methods (1), (3) and (4), and the tablets containing the granules obtained by the production method (2) have an active pharmaceutical ingredient or Film coating may be used for masking of unpleasant tastes derived from health functional ingredients for food, improving stability, and making the appearance beautiful.
[0039] 次に各製造方法（1)〜(4)について、個別にその方法を詳述する。  [0039] Next, each of the production methods (1) to (4) will be described in detail.
[製造方法 (1) ]  [Production method (1)]
製造方法（1)は、一般に直接打錠法と呼ばれる方法に属するものであって、打錠な どにより圧縮成形して錠剤を成形する際に、粉末状結合剤として、コメデンプンとコメ デンプン誘導体のうち少なくとも一方を使用するものである。この製造方法（1)では、 まず、例えば医薬品有効成分、食品用保健機能成分などのうちから選択される 1種 以上の有効成分を含有する原料と、粉末状結合剤としてのコメデンプンとコメデンプ ン誘導体のうち少なくとも一方と、必要に応じて添加される各種添加剤などとを混合し て混合粉体を調製する。ここで、原料は粉体状であってもよいし、直接打錠用原料と して一般に市販されて ヽる顆粒状のものなど、予備的な力卩ェが施されたものであって ちょい。 The production method (1) belongs to a method generally referred to as a direct tableting method. When a tablet is formed by compression molding with a tableting or the like, rice starch and rice are used as a powdery binder. At least one of starch derivatives is used. In this production method (1), first, a raw material containing one or more active ingredients selected from, for example, an active pharmaceutical ingredient, a health function ingredient for food, etc., rice starch as a powdery binder, and rice starch. A mixed powder is prepared by mixing at least one of the derivatives and various additives added as necessary. Here, the raw material may be in the form of a powder, or may have been subjected to a preliminary force such as a granular material that is generally commercially available as a raw material for direct compression. .
原料の成形性は、それに含まれる有効成分の種類、量などにより異なるため、これ らに応じて、使用するコメデンプンとコメデンプン誘導体のうち少なくとも一方の量を 適宜調整すればよいが、結合剤としての機能を確保する観点から、混合粉体中、好 ましくは 5質量％以上であり、より好ましくは 5〜30質量％である。 5質量％未満では、 結合剤としての効果が不十分になり、 30質量％を超えると、コメデンプンとコメデンプ ン誘導体のうち少なくとも一方は流動性が低いことから、混合粉体の流動性も不足す る。その結果、混合粉体の臼への充填量にばらつきが生じ、錠剤の質量偏差が大き くなることがある。  Since the formability of the raw material varies depending on the type and amount of the active ingredient contained in the raw material, at least one of the rice starch and the rice starch derivative to be used may be appropriately adjusted accordingly. From the viewpoint of ensuring the function as, it is preferably 5% by mass or more, more preferably 5 to 30% by mass in the mixed powder. If it is less than 5% by mass, the effect as a binder becomes insufficient, and if it exceeds 30% by mass, at least one of rice starch and rice medendun derivatives has low fluidity, so the fluidity of the mixed powder is also insufficient. The As a result, the filling amount of the mixed powder into the die may vary, and the mass deviation of the tablet may increase.
[0040] 必要に応じて使用される添加剤としては、コメデンプンとコメデンプン誘導体のうち の少なくとも一方以外の粉末状結合剤、直接打錠用の賦形剤、崩壊剤、滑沢剤など が挙げられる。  [0040] Additives used as necessary include powdery binders other than at least one of rice starch and rice starch derivatives, excipients for direct compression, disintegrants, lubricants, and the like. Can be mentioned.
[0041] ついで、得られた混合粉体を、単発打錠機、ロータリー打錠機など、臼と杵とを有す る打錠機を用いて圧縮成形することにより、錠剤が得られる。  [0041] Next, the obtained mixed powder is compression-molded using a tableting machine having a mortar and a punch, such as a single tableting machine or a rotary tableting machine, to obtain tablets.
なお、コメデンプンとコメデンプン誘導体のうち少なくとも一方を原料や添加剤と混 合する場合には、得られる混合粉体を均一にするため、あらカゝじめ原料や添加剤の 一部と混合しておいてもよいし、適当な目開きの篩いを用いて篩い分けしてもよい。 また、得られる錠剤の形状には制限はないが、断面が円形状のものならば直径 6〜1 Ommで、 1錠あたりの質量は 100〜500mg程度が実用的である。また、この場合の 打錠に適した圧力（圧縮圧）としては、おおむね 15kN以下が望ましい。コメデンプン とコメデンプン誘導体のうち少なくとも一方の混合粉体中における量を上記のように 設定することにより、得られる錠剤中のコメデンプンとコメデンプン誘導体のうち少なく とも一方の量もそれぞれ 5質量％以上、 5〜30質量％となる。 When at least one of rice starch and rice starch derivatives is mixed with raw materials and additives, in order to make the resulting mixed powder uniform, it is mixed with some of the raw materials and additives. Alternatively, it may be sieved using a sieve having an appropriate opening. The shape of the tablet to be obtained is not limited, but if the cross section is circular, the diameter is 6 to 1 Omm, and the mass per tablet is about 100 to 500 mg. In this case, the pressure (compression pressure) suitable for tableting is preferably about 15 kN or less. By setting the amount in the mixed powder of at least one of rice starch and rice starch derivative as described above, it is possible to reduce the amount of rice starch and rice starch derivative in the resulting tablet. In either case, the amount is 5 mass% or more and 5 to 30 mass%, respectively.
[0042] このような製造方法（1)によれば、特定の水分含量のコメデンプンとコメデンプン誘 導体のうち少なくとも一方を粉末状結合剤として使用した圧縮成形法により錠剤を製 造するので、実用性のある十分な錠剤硬度を有し、たとえ滑沢剤に硬化油を用いた 場合でも崩壊が遅くならない良好な崩壊時間の錠剤が得られる。また、得られた錠剤 は、色の点における経時的安定性にも優れる。  [0042] According to such a production method (1), since the tablet is produced by a compression molding method using at least one of rice starch having a specific water content and a rice starch derivative as a powdery binder, A tablet with sufficient disintegration time that has practically sufficient tablet hardness and does not slow down disintegration even when hardened oil is used as a lubricant is obtained. The obtained tablets are also excellent in the temporal stability in terms of color.
[0043] [製造方法 (2) ]  [0043] [Production method (2)]
コメデンプンとコメデンプン誘導体のうち少なくとも一方を粉末状結合剤として使用 した乾式造粒法により、粉体を造粒して顆粒を製造する具体的方法としては、まず、 例えば医薬品有効成分、食品用保健機能成分などのうちから選択される 1種以上の 有効成分を含有する原料の粉体と、粉末状結合剤としてのコメデンプンとコメデンプ ン誘導体のうち少なくとも一方と、必要に応じて添加される各種添加剤などを混合し て混合粉体を調製する。  As a specific method for granulating powder by dry granulation using at least one of rice starch and rice starch derivative as a powder binder, first, for example, active pharmaceutical ingredients, food Raw material powder containing one or more active ingredients selected from health functional ingredients, etc., and at least one of rice starch and rice medpun derivatives as powder binders are added as necessary Various powders are mixed to prepare a mixed powder.
原料の粉体の成形性は、それに含まれる有効成分の種類、量などにより異なるため 、これらに応じて、使用するコメデンプンとコメデンプン誘導体のうち少なくとも一方の 量を適宜調整すればよいが、粉末状結合剤としての機能を確保する観点から、混合 粉体中、好ましくは 10質量％以上であり、より好ましくは 10〜90質量％、さらに好ま しくは 15〜50質量％である。コメデンプンとコメデンプン誘導体のうち少なくとも一方 の混合粉体中における量をこのように設定することにより、得られる顆粒中のコメデン プンとコメデンプン誘導体のうち少なくとも一方の量もそれぞれ 10質量％以上、 10〜 90質量％、 15〜50質量％となる。  Since the formability of the raw material powder varies depending on the type and amount of the active ingredient contained therein, the amount of at least one of the rice starch and the rice starch derivative to be used may be adjusted accordingly. From the viewpoint of ensuring the function as a powdery binder, the content in the mixed powder is preferably 10% by mass or more, more preferably 10 to 90% by mass, and further preferably 15 to 50% by mass. By setting the amount in the mixed powder of at least one of rice starch and rice starch derivative in this way, the amount of at least one of rice starch and rice starch derivative in the resulting granule is also 10% by mass or more, 10 to 90% by mass, 15 to 50% by mass.
[0044] っ ヽで、この混合粉体をロール式高圧圧縮成形機などによりロール圧縮成形し、高 密度の板状成形物（以下、フレークということもある。）とする。このとき、造粒条件（口 ール圧縮成形の条件）としては、圧縮成形率が 60〜95%となるような条件とする。つ いで、目的の粒度となるように、この板状成形物を多段式ロール解砕機や各種の製 粒機に通す粗砕工程を行うことにより、例えば粒径が 1700 /z mよりも細かぐ力ゝさ密 度が 0. 4〜0. 8gZmLの顆粒が得られる。  [0044] Then, this mixed powder is roll compression molded with a roll-type high-pressure compression molding machine or the like to obtain a high-density plate-like molded product (hereinafter sometimes referred to as flake). At this time, the granulation conditions (the conditions for the mold compression molding) are such that the compression molding rate is 60 to 95%. Next, by carrying out a crushing process in which this plate-shaped product is passed through a multi-stage roll crusher or various granulators so as to achieve the desired particle size, for example, a force that makes the particle size finer than 1700 / zm. Granules with a cocoon density of 0.4 to 0.8 gZmL are obtained.
[0045] 得られた顆粒は、そのまま顆粒剤として用いたり、打錠機を用いた圧縮成形に用い たりすることも可能であり、必要があれば適当な粒度分布になるように篩い分けしても よい。また、得られた顆粒には、その含有する水分量の低減が望まれる場合、引き続 き公知の方法により乾燥を行ってもよい。 [0045] The obtained granule is used as it is as a granule or for compression molding using a tableting machine. If necessary, it may be sieved to obtain an appropriate particle size distribution. Further, when it is desired to reduce the amount of water contained in the obtained granule, it may be continuously dried by a known method.
[0046] なお、圧縮成形率は、フレーク率とも呼ばれ、下記の測定法により求められる。  [0046] The compression molding rate is also called flake rate, and is determined by the following measurement method.
《圧縮成形率の測定法》  <Method for measuring compression molding ratio>
1.ロール圧縮成形を 1分間行い、ロールを通過した板状成形物および微粉を、粗砕 せずに直接容器等で受け取る。この質量を 1分間の処理量 (Ag)とする。  1. Roll compression molding is performed for 1 minute, and the plate-like molded product and fine powder that have passed through the roll are directly received in a container or the like without being crushed. This mass is defined as 1 minute throughput (Ag).
2.上記 1で得られた板状成形物および微粉 (Ag)を目開き 1000 μ mの篩いに入れ 、 1000 pass品（通過したもの）を除去する。この目開き 1000 mの篩い上に 残った板状成形物の質量を Bgとする。  2. Put the plate-shaped product and fine powder (Ag) obtained in 1 above into a sieve with a mesh size of 1000 μm, and remove the 1000-pass product (passed product). Let Bg be the mass of the plate-shaped product remaining on the sieve with an opening of 1000 m.
3.次式により圧縮成形率 (フレーク率)を算出する。  3. Calculate compression molding rate (flake rate) by the following formula.
フレーク率（0/0) = (B/A) X 100 Flake ratio (0/0) = (B / A) X 100
[0047] 得られた顆粒をさらに成形して錠剤を製造する場合には、まず、顆粒と、必要に応 じて添加される滑沢剤、崩壊剤などの添加剤や他の成分とを混合する。そして、得ら れた混合物を単発打錠機、ロータリー打錠機など、臼と杵とを有する打錠機を用いて 、使用する打錠機や錠剤の大きさに適した圧力で打錠する圧縮成形を行えばよい。 この際、錠剤の形状には制限はないが、断面が円形状のものならば直径 6〜： LOmm で、 1錠あたりの質量は 100〜500mg程度が実用的である。また、この場合の打錠に 適した圧力（圧縮圧）としては、おおむね 15kN以下が望ましい。  [0047] When a tablet is produced by further shaping the obtained granule, first, the granule is mixed with additives such as a lubricant and a disintegrant added as necessary, and other components. To do. The resulting mixture is compressed with a pressure suitable for the tableting machine to be used and the size of the tablet using a tableting machine having a mortar and a punch, such as a single tableting machine or a rotary tableting machine. What is necessary is just to perform compression molding. At this time, the shape of the tablet is not limited, but if the cross section is circular, the diameter is 6 to: LOmm, and the mass per tablet is about 100 to 500 mg. In this case, the pressure (compression pressure) suitable for tableting is preferably about 15 kN or less.
[0048] このように特定の水分含量のコメデンプンと特定の水分含量のコメデンプン誘導体 のうち少なくとも一方を粉末状結合剤として使用することによって、造粒時における粉 体の圧縮成形性が非常に高くなるため、粗砕工程における微粉含量が少なくなり、 粒度が揃った顆粒を高収率で得ることができる。さら〖ここのようにして製造された顆粒 を成形して得られた錠剤は、実用可能な錠剤硬度、崩壊時間を備え、色の点におけ る経時的安定性を備えたものとなる。  [0048] Thus, by using at least one of rice starch having a specific water content and rice starch derivatives having a specific water content as a powdery binder, the compression moldability of the powder during granulation is very high. Since it becomes higher, the fine powder content in the coarse crushing process is reduced, and granules with uniform particle size can be obtained in high yield. Furthermore, the tablets obtained by molding the granules produced in this way have practical tablet hardness, disintegration time, and temporal stability in terms of color.
また、粉末状結合剤としてコメデンプンとコメデンプン誘導体のうち少なくとも一方を 含む顆粒やその顆粒から得られた錠剤は、コメデンプンとコメデンプン誘導体のうち 少なくとも一方の含有量が多 、場合であっても、粉末状結合剤として結晶セルロース を多量に使用した場合のような特性変化が少ないため、保存中などに着色することが なく経時的安定性に優れて 、る。 In addition, granules containing at least one of rice starch and rice starch derivatives as a powder binder and tablets obtained from the granules have a high content of at least one of rice starch and rice starch derivatives. Also crystalline cellulose as a powdery binder Since there is little change in properties, such as when a large amount of is used, there is no coloration during storage and the stability over time is excellent.
[0049] さらに、アミノ基を有する有効成分を含む顆粒を製造するに際して、褐色の着色が 伴うメイラード反応を避けるために成形性が不十分な D—マン-トールを賦形剤に使 用した場合でも、粉末状結合剤としてコメデンプンとコメデンプン誘導体のうち少なく とも一方を使用することによって成形性が向上し、粒度が揃った顆粒を高収率で得る ことができ、成形性の向上効果と、メイラード反応を回避し変色を抑制する効果との 両立が可能になる。  [0049] Further, when producing granules containing an active ingredient having an amino group, when D-mannitol having insufficient moldability is used as an excipient in order to avoid the Maillard reaction accompanied by brown coloring However, by using at least one of rice starch and rice starch derivatives as a powdery binder, the moldability is improved and granules having a uniform particle size can be obtained in a high yield. It is possible to achieve both the effect of suppressing the discoloration by avoiding the Maillard reaction.
[0050] また、このように特定の水分含量のコメデンプンとコメデンプン誘導体のうち少なくと も一方を使用して得られた顆粒カゝら錠剤を製造した場合、コメデンプンとコメデンプン 誘導体のうち少なくとも一方の含有量の増加に伴って錠剤硬度が高まるが、同時に 崩壊時間が長くなる傾向がある。その場合には、粉末状結合剤としてのコメデンプン とコメデンプン誘導体のうち少なくとも一方とともに、結晶セルロース、粉末セルロース または低置換度ヒドロキシプロピルセルロースの粉末力 選択される一種以上のセル ロース系粉末状結合剤を併用することにより、崩壊時間を短縮することができる。 また、このようにセルロース系粉末状結合剤を併用することによって、崩壊時間は短 縮しても、錠剤硬度は低下せず、むしろ向上することを本発明者らは見出した。よつ て、粉末状結合剤としてコメデンプンとコメデンプン誘導体のうち少なくとも一方ととも にセルロース系粉末状結合剤を併用することによって、錠剤硬度が高ぐしかも崩壊 時間が適度に改善された錠剤を得ることができる。  [0050] In addition, in the case where a granule powder tablet obtained by using at least one of rice starch and rice starch derivatives having a specific water content is produced, of rice starch and rice starch derivatives As the content of at least one increases, the tablet hardness increases, but at the same time, the disintegration time tends to increase. In that case, the powder power of crystalline cellulose, powdered cellulose or low-substituted hydroxypropylcellulose, together with at least one of rice starch and rice starch derivatives as powder binders, one or more cellulose-based powder binders selected By using the agent in combination, the disintegration time can be shortened. In addition, the present inventors have found that by using the cellulose-based powder binder in this way, even if the disintegration time is shortened, the tablet hardness does not decrease but rather improves. Therefore, by using a cellulosic powder binder together with at least one of rice starch and rice starch derivatives as a powder binder, tablets with high tablet hardness and moderately improved disintegration time can be obtained. Obtainable.
[0051] さらに、アミノ基を有する有効成分を含む顆粒を製造するに際して、メイラード反応 を避けるために D—マン-トールを賦形剤に使用した場合、上述したように粉末状結 合剤としてコメデンプンとコメデンプン誘導体のうち少なくとも一方を使用することによ つて成形性が向上する力 その際、粉末状結合剤として、コメデンプンとコメデンプン 誘導体のうちの少なくとも一方の粉末に加えてセルロース系粉末結合剤を併用する ことによって、より一層成形性が向上して粒径の揃った顆粒を高収率で得ることがで きる。また、得られた顆粒を成形することによって、優れた錠剤硬度、崩壊時間の錠 剤を得ることができる。 [0051] Further, in the production of granules containing an active ingredient having an amino group, when D-manntol is used as an excipient in order to avoid the Maillard reaction, as described above, rice is used as a powdery binder. The ability to improve moldability by using at least one of starch and rice starch derivatives. At this time, in addition to at least one of rice starch and rice starch derivatives, cellulosic powder By using a binder in combination, it is possible to obtain a granule having a uniform particle size with a high yield by further improving the moldability. In addition, by molding the obtained granules, tablets with excellent tablet hardness and disintegration time An agent can be obtained.
また、このようなセルロース系粉末結合剤は、顆粒における医薬品有効成分または 食品用保健機能成分の含量が 30質量％以上と高くなる場合や、それら有効成分の 成形性が劣る場合に使用することによって、成形性を高める効果も発揮する。  Such cellulosic powder binders are used when the content of active pharmaceutical ingredients or food health functional ingredients in granules is as high as 30% by mass or more, or when the moldability of these active ingredients is poor. Also, the effect of improving moldability is exhibited.
[0052] セルロース系粉末状結合剤の使用量は、顆粒中 10〜30質量％となる範囲が好ま しい。 30質量％を超えて使用すると、得られる顆粒の色の変化など経時的変化が生 じる可能性があり、 10質量％未満では、十分な添加効果を発現しない可能性がある [0052] The amount of the cellulose powder binder used is preferably in the range of 10 to 30% by mass in the granule. If it exceeds 30% by mass, it may cause changes over time such as the color of the resulting granules. If it is less than 10% by mass, sufficient addition effect may not be exhibited.
[0053] このような製造方法（2)によれば、特定の水分含量のコメデンプンとコメデンプン誘 導体のうち少なくとも一方を粉末状結合剤として使用することによって、通常は微粒 子を生じやすぐ粒度が揃った顆粒を高収率で得られにくい乾式造粒法において、 微粒子が少なく粒度が揃った顆粒を高収率で得ることができる。さらに、得られた顆 粒を打錠用顆粒として用いることにより、従来得ることが困難であった実用上十分な 錠剤硬度を発現し、崩壊時間、色などの経時的安定性も良好な錠剤を得ることがで きる。また、アミノ基を有する有効成分を含む顆粒を製造する場合に賦形剤として D マン-トールを使用しても、十分な成形性を確保できるため、成形性と色の経時的 安定性とを両立できる。 [0053] According to the production method (2), at least one of rice starch and rice starch derivative having a specific water content is usually used as a powdery binder, so that fine particles are usually generated immediately. In a dry granulation method in which it is difficult to obtain a granule having a uniform particle size in a high yield, a granule having a small particle size and a uniform particle size can be obtained in a high yield. Furthermore, by using the obtained condylar granules as tableting granules, it is possible to develop tablets that exhibit practically sufficient tablet hardness, which has been difficult to obtain in the past, and that have good temporal stability such as disintegration time and color. Obtainable. In addition, when manufacturing granules containing an active ingredient having an amino group, even if D-mannitol is used as an excipient, sufficient moldability can be secured, so that moldability and color stability over time can be maintained. Can be compatible.
従来、デンプンとしてはトウモロコシデンプンが添加剤成分として広く利用されてい る力 トウモロコシデンプンは結合性が十分ではないため結合剤として使用されること がなぐ乳糖などと混合して賦形剤として使用されるのが常であった。そして、乾式造 粒法で顆粒を製造する際には、別の粉末状結合剤を添加することを余儀なくされるも のであった。しかしながら、コメデンプンとコメデンプン誘導体のうち少なくとも一方は 、トウモロコシデンプンとは異なり、水分含量を特定の範囲にコントロールして用いるこ とで著しく結合性に優れ、単独でも粉末状結合剤として使用できるものである。  Conventionally, corn starch is widely used as an additive component for starch. Maize starch is used as an excipient by mixing with lactose that cannot be used as a binder because of its insufficient binding properties. It was always. Then, when producing granules by the dry granulation method, another powdery binder must be added. However, at least one of rice starch and rice starch derivatives, unlike corn starch, is remarkably excellent in binding by controlling the water content within a specific range, and can be used alone as a powder binder. It is.
[0054] [製造方法 (3) ]  [0054] [Production method (3)]
製造方法 (3)においては、まず、例えば医薬品有効成分、食品用保健機能成分な どのうちから選択される一種以上の有効成分を含有する原料の粉体と、コメデンプン とコメデンプン誘導体のうち少なくとも一方と、必要に応じて乳糖、白糖、 D マン-ト ール、コメデンプンとコメデンプン誘導体のうち少なくとも一方以外のトウモロコシデン プンなどのデンプン、ヒドロキシプロピルスターチなどのデンプン誘導体などの賦形剤 、カルメロースカルシウムなどの崩壊剤などの添加剤成分をカ卩えて混合粉体とする。 In the production method (3), first, a raw material powder containing one or more active ingredients selected from, for example, active pharmaceutical ingredients and food health functional ingredients, and at least of rice starch and rice starch derivatives On the other hand, if necessary, lactose, sucrose, D mantle Additive ingredients such as starch, corn starch, starch derivatives such as hydroxypropyl starch, and disintegrants such as carmellose calcium other than at least one of rice starch, rice starch and rice starch derivatives It is a mixed powder.
[0055] っ 、で、公知の湿式造粒法により造粒する。湿式造粒法としては、破砕型造粒法、 撹拌造粒法、流動層造粒法、遠心転動造粒法、遠心転動流動層造粒法などが例示 できる。  [0055] Then, granulation is performed by a known wet granulation method. Examples of the wet granulation method include a crushing granulation method, a stirring granulation method, a fluidized bed granulation method, a centrifugal tumbling granulation method, and a centrifugal tumbling fluidized bed granulation method.
例えば破砕型造粒法の場合、混合粉体に液状の結合剤を添加して造粒機で適当 な大きさの軟塊を作り、乾燥機で乾燥することで顆粒が得られる。また、この際、大き な顆粒は砕かれる。他に撹拌造粒法、流動層造粒法、遠心転動造粒法、遠心転動 流動層造粒法など、公知の湿式造粒法を適用してもよ ヽ。  For example, in the case of the pulverized granulation method, a liquid binder is added to the mixed powder, a soft lump having an appropriate size is formed with a granulator, and the granule is obtained by drying with a dryer. At this time, large granules are crushed. In addition, a known wet granulation method such as agitation granulation method, fluidized bed granulation method, centrifugal rolling granulation method, centrifugal rolling fluidized bed granulation method may be applied.
これらいずれの造粒法においても、液状の結合剤として、水や有機溶媒などの溶 媒がそのままで使用される場合や、これら溶媒に例えばヒドロキシプロピルセルロース やポリビニルピロリドンなどの結合剤成分を溶解した溶液が使用される。  In any of these granulation methods, when a solvent such as water or an organic solvent is used as it is as a liquid binder, or a binder component such as hydroxypropylcellulose or polyvinylpyrrolidone is dissolved in these solvents. A solution is used.
[0056] つ!、で、得られた顆粒をその水分活性 (aw)が 0. 4〜0. 8になるように調湿する。 [0056] Then, the obtained granule is conditioned so that its water activity (aw) is 0.4 to 0.8.
すなわち、上述したように従来の一般の湿式顆粒圧縮法では、造粒された顆粒を乾 燥工程で乾燥するため、コメデンプンとコメデンプン誘導体のうち少なくとも一方を粉 末結合剤として使用したとしても、乾燥工程において顆粒中のコメデンプンとコメデン プン誘導体のうち少なくとも一方の水分含量が低下し、その結果、顆粒の圧縮成形 性や結合性が低下してしまうと考えられる。よって、これらの性能を確保するためには 、圧縮成形の前に、調湿により顆粒の水分含量を調整することが重要であると考えら れる。  That is, as described above, in the conventional general wet granule compression method, granulated granules are dried in the drying step, so that at least one of rice starch and rice starch derivatives may be used as a powder binder. In the drying process, the water content of at least one of the rice starch and the rice denpene derivative in the granule is decreased, and as a result, the compression molding property and binding property of the granule are considered to be decreased. Therefore, in order to ensure these performances, it is considered important to adjust the moisture content of the granules by conditioning before compression molding.
[0057] 調湿方法としては、例えば、顆粒を一定の温度と湿度にコントロールされた恒温恒 湿の雰囲気下に放置する方法、混合 ·撹拌装置または流動層に充填し、撹拌または 流動させながら、これに水を噴霧したり、調湿した空気を供給したりする方法がある。 調湿により望ましい水分にするためには、水分活性 (aw)が 0. 4〜0. 8になるように コントロールするのがよい。水分活性は、例えばフロイント産業 (株)製の商品名「EZ 100」など、市販されている水分活性測定装置により測定される。  [0057] As the humidity control method, for example, the granule is allowed to stand in a constant temperature and humidity atmosphere controlled at a constant temperature and humidity, or is mixed in a mixing / stirring device or a fluidized bed and stirred or fluidized. There are methods for spraying water and supplying conditioned air. In order to obtain the desired moisture by conditioning, the water activity (aw) should be controlled to be 0.4 to 0.8. The water activity is measured by a commercially available water activity measuring device such as “EZ 100” manufactured by Freund Sangyo Co., Ltd.
水分活性が 0. 4未満では、圧縮成形で得られた錠剤が十分な硬度を有さず、 0. 8 を超えると、顆粒の流動性が低下する、打錠時にステイツキングなどの打錠障害を起 こすなどの問題がある。 If the water activity is less than 0.4, the tablet obtained by compression molding does not have sufficient hardness, and 0.8 Exceeding this causes problems such as decreased fluidity of the granules and problems with tableting such as sticking during tableting.
なお、得られる錠剤の硬度を実用可能な程度に高くしたり、錠剤の質量偏差を望ま しい範囲内にコントロールしたり、錠剤の含量均一性を高めたりするためには、顆粒 状の賦形剤の粒度を特定の範囲に調整することが好ましぐそのためには、調湿の 前後に顆粒を篩分けする篩い工程を実施し、平均粒子径で 50〜300 mとすること が好ましい。  In order to increase the hardness of the resulting tablet to a practical level, control the tablet mass deviation within a desired range, and increase the uniformity of tablet content, a granular excipient is used. For this purpose, it is preferable to adjust the particle size to a specific range by carrying out a sieving step of sieving the granules before and after humidity control to obtain an average particle size of 50 to 300 m.
[0058] こうして調湿された顆粒は、滑沢剤や、必要に応じて添加される崩壊剤など、製造 方法（1)の場合と同様に、錠剤の製造に一般的に使用される添加剤が加えられた後 、単発打錠機、ロータリー打錠機など、臼と杵とを有する打錠機により圧縮成形され、 錠剤とされる。好ましい錠剤の大きさや、好ましい圧縮圧は製造方法（1)の場合と同 様である。  [0058] The granules thus conditioned are additives commonly used in the manufacture of tablets, as in the case of production method (1), such as lubricants and disintegrants added as necessary. Is added to the tablet by a tableting machine having a mortar and a punch, such as a single tableting machine or a rotary tableting machine, to obtain a tablet. The preferred tablet size and preferred compression pressure are the same as in production method (1).
コメデンプンとコメデンプン誘導体のうち少なくとも一方の適切な添カ卩量は、錠剤の 5質量％以上であることが好ましい。上限には特に制限はないが、一般的な錠剤の 場合は好ましくは 50質量％以下である。 5質量％未満では、粉末状結合剤としての 効果が不十分になる傾向がある。また、 50質量％を超えると崩壊時間が長くなる傾 向があり、一般的な錠剤の場合は不利になる。しかし、特に、徐放性製剤を得る目的 にはこの性質は好適であり、 50質量％を超えて添カロしてもよいし、さらにヒドロキシプ 口ピルメチルセルロースゃヒドロキシプロピルセルロースなどの徐放性の基剤と組み 合わせて用いることも出来る。  It is preferable that an appropriate amount of at least one of rice starch and rice starch derivative is 5% by mass or more of the tablet. The upper limit is not particularly limited, but in the case of a general tablet, it is preferably 50% by mass or less. If it is less than 5% by mass, the effect as a powder binder tends to be insufficient. If it exceeds 50% by mass, the disintegration time tends to be longer, which is disadvantageous for general tablets. However, this property is particularly suitable for the purpose of obtaining a sustained-release preparation, and may be added in excess of 50% by mass, and a sustained-release product such as hydroxypropylmethylcellulose or hydroxypropylcellulose may be used. It can also be used in combination with a base.
[0059] このような製造方法（3)によれば、湿式造粒法で得られた顆粒の水分活性を適切 に制御してから、これを圧縮成形する。よって、高い圧縮成形性が発現され、実用可 能な錠剤硬度、崩壊時間を有する錠剤を打錠障害など起こさずに製造できる。また、 得られた錠剤は、色の点などの経時的安定性にも優れて ヽる。  [0059] According to the production method (3), the water activity of the granules obtained by the wet granulation method is appropriately controlled and then compression molded. Therefore, it is possible to produce a tablet having high compression moldability and having a practical tablet hardness and disintegration time without causing any tableting trouble. In addition, the obtained tablets have excellent temporal stability such as color points.
[0060] [製造方法 (4) ]  [0060] [Production method (4)]
この製造方法 (4)は、圧縮成形法により錠剤を成形する際に、賦形剤として、あらか じめ顆粒状に成形された賦形剤を使用する方法である。すなわち、乳糖、 D—マン- トール、白糖などの公知の粉末状の賦形剤と、コメデンプンとコメデンプン誘導体のう ち少なくとも一方とを含む混合粉体を湿式造粒法で造粒し、得られた顆粒状のものを 賦形剤とし、これと有効成分を含む他の粉体とを混合したものを圧縮成形する。 湿式造粒法の具体的方法や、その際に使用される液状の結合剤としては、製造方 法（3)で例示したものと同様のものを適用できる。しかしながら、賦形剤を造粒するに あたって、ヒドロキシプロピルセルロースやポリビュルピロリドンなどの結合剤成分を含 有する液状の結合剤を使用すると、品質管理上の理由から顆粒を組成分析する際 に、その分析が困難となる場合が多い。よって、分析に影響を与えないように、液状 の結合剤として、水や有機溶媒などの溶媒のみを用いる方法が好ましい。また、特に 、粉末状の賦形剤として乳糖、 D—マン-トール、白糖を用いた場合には、同じもの を水に溶力した液を結合剤として用いる方法も好ま 、。 This production method (4) is a method in which an excipient formed in a granular shape is used as an excipient when a tablet is formed by a compression molding method. That is, known powdery excipients such as lactose, D-mannitol and sucrose, and rice starch and rice starch derivatives. Then, the mixed powder containing at least one of them is granulated by the wet granulation method, and the resulting granular product is used as an excipient, and this is mixed with other powders containing the active ingredient and compression molded. To do. As the specific method of the wet granulation method and the liquid binder used at that time, the same ones exemplified in the production method (3) can be applied. However, when granulating excipients, if a liquid binder containing a binder component such as hydroxypropylcellulose or polybulurpyrrolidone is used, the composition of the granule is analyzed for quality control reasons. The analysis is often difficult. Therefore, a method using only a solvent such as water or an organic solvent as the liquid binder is preferable so as not to affect the analysis. In particular, when lactose, D-manntol or sucrose is used as a powdery excipient, a method using a solution obtained by dissolving the same in water as a binder is also preferred.
[0061] 例えば、湿式造粒法として、流動層造粒法を採用する場合には、流動層造粒コー ティング装置 (例えばフロイント産業 (株)製、商品名：フローコーター）に、乳糖または D—マン-トールの粉末と、コメデンプンとコメデンプン誘導体のうち少なくとも一方と の混合粉体を仕込み、容器内で流動空気を供給し、混合粉体を浮遊流動させながら 、仕込んだ乳糖または D—マン-トールの粉末と同じ物質を水溶液としてスプレーす ることにより造粒でき、顆粒状の賦形剤が得られる。  [0061] For example, when the fluidized bed granulation method is adopted as the wet granulation method, lactose or D —Mandol powder and at least one of rice starch and rice starch derivatives are mixed, and air is supplied in the container to float and flow the mixed powder, while the charged lactose or D— It can be granulated by spraying the same substance as the powder of mannitol as an aqueous solution to obtain a granular excipient.
[0062] 湿式造粒法における粉末状の賦形剤と、コメデンプンとコメデンプン誘導体のうち 少なくとも一方との混合比率は、得られる顆粒状の賦形剤中、コメデンプンとコメデン プン誘導体のうち少なくとも一方が好ましくは 3〜60質量％、より好ましくは 5〜50質 量％となる比率である。コメデンプンとコメデンプン誘導体のうち少なくとも一方が 3質 量％未満では、成形性の改善効果が不十分であり、 60質量％を超えると、得られる 錠剤の崩壊が遅くなることがある。  [0062] The mixing ratio of the powdery excipient in the wet granulation method and at least one of the rice starch and the rice starch derivative is selected from among the rice starch and the rice starch derivative in the obtained granular excipient. At least one of the ratios is preferably 3 to 60% by mass, more preferably 5 to 50% by mass. If at least one of rice starch and rice starch derivative is less than 3% by mass, the effect of improving moldability is insufficient, and if it exceeds 60% by mass, disintegration of the resulting tablet may be delayed.
[0063] つ ヽで、得られた顆粒を製造方法 (3)と同様の方法で調湿し、その水分活性 (aw) 力 O. 4〜0. 8となるようにする。  [0063] On the other hand, the obtained granule is conditioned by the same method as in production method (3) so that its water activity (aw) force becomes O. 4 to 0.8.
なお、得られる錠剤の硬度を実用可能な程度に高くしたり、錠剤の質量偏差を望ま しい範囲内にコントロールしたり、錠剤の含量均一性を高めたりするためには、顆粒 状の賦形剤の粒度を特定の範囲に調整することが好ましぐそのためには、調湿の 前後に顆粒を篩分けする篩い工程を実施し、平均粒子径で 50〜300 mとすること が好ましい。 In order to increase the hardness of the resulting tablet to a practical level, control the tablet mass deviation within a desired range, and increase the uniformity of tablet content, a granular excipient is used. For this purpose, it is preferable to adjust the particle size of the product to a specific range. Is preferred.
[0064] っ 、で、水分活性 (aw)が 0. 4〜0. 8とされた顆粒状の賦形剤と、他の粉体 (有効 成分を含有する原料の粉体)と、滑沢剤や、必要に応じて添加される崩壊剤など、製 造方法（1)の場合と同様の錠剤の製造に一般的な添加剤とを混合し、得られた混合 物を単発打錠機、ロータリー打錠機などの打錠機により圧縮成形し、錠剤とする。好 ま 、錠剤の大きさや、好ま 、圧縮圧は製造方法（1)の場合と同様である。  [0064] A granular excipient having a water activity (aw) of 0.4 to 0.8, another powder (a raw material powder containing an active ingredient), a lubricant, Additives and disintegrants added as necessary, such as those used in the manufacturing method (1), are mixed with general additives for tablet production, and the resulting mixture is mixed into a single-punch tablet machine, It is compressed into a tablet by a tableting machine such as a rotary tableting machine. Preferably, the size of the tablet and the compression pressure are the same as in the production method (1).
[0065] このような製造方法 (4)では、湿式造粒法で顆粒状の賦形剤を得て、さらにその水 分活性を適切に制御してから使用する。このような顆粒状の賦形剤は圧縮成形性に 非常に優れるため、これを使用することによって、粉末状結合剤を追加添加しなくて も、実用可能な錠剤硬度、崩壊時間を有する錠剤を打錠障害など起こさずに製造で きる。また、得られた錠剤は、色の点などの経時的安定性にも優れている。  [0065] In such a production method (4), a granular excipient is obtained by a wet granulation method, and the water activity is appropriately controlled before use. Since such a granular excipient is very excellent in compression moldability, it can be used to produce a tablet having a practical tablet hardness and disintegration time without adding a powdery binder. Can be manufactured without causing tableting problems. Moreover, the obtained tablet is excellent also in temporal stability, such as a color point.
実施例  Example
[0066] 以下本発明につ 、て実施例を示して具体的に説明する。  Hereinafter, the present invention will be specifically described with reference to examples.
なお、下記実施例と、上述した製造方法（1)〜(4)との対応について、以下に示す 実施例 1〜7、実施例 34〜36：製造方法（1)  In addition, about the response | compatibility with the following Example and manufacturing method (1)-(4) mentioned above, the following Example 1-7, Example 34-36: Manufacturing method (1)
実施例 8〜24：製造方法 (2)  Examples 8 to 24: Manufacturing method (2)
実施例 25、 28〜33：製造方法（3)  Examples 25 and 28 to 33: Production method (3)
実施例 26および 27：製造方法 (4)  Examples 26 and 27: Manufacturing method (4)
[0067] なお、顆粒および錠剤の物性評価は下記の方法にて行った。 [0067] The physical properties of the granules and tablets were evaluated by the following methods.
顆粒硬度：硬度測定器 GRANO (岡田精エネ土製)を使用して、先端チップ径 3mm Φ (先端チップ形状:平円形)、荷重 200g、測定速度 100 mZ秒の測定条件で顆 粒が破壊するときの荷重をロードセルで測定した。  Granule hardness: When a condylar particle breaks using a hardness measuring instrument GRANO (Okada Seisen-made) with a tip diameter of 3mm Φ (tip tip shape: flat circle), a load of 200g, and a measurement speed of 100mZ seconds. The load of was measured with a load cell.
錠剤硬度：錠剤硬度計 SCHLEUNIGER 6D (フロイント産業社製)を用いて測定 した。  Tablet hardness: Measured with a tablet hardness meter SCHLEUNIGER 6D (Freund Sangyo Co., Ltd.).
錠剤崩壊時間：日本薬局方 (第 14改正)の崩壊試験法 (試験液、水）に準拠して測 Tablet disintegration time: Measured according to the disintegration test method (test solution, water) of the Japanese Pharmacopoeia (14th revision)
¾し 7こ。 ¾ 7
錠剤の白色度および黄色度:色差計 SZ—∑90 (日本電色工業社製)を用い、固体 表面色を測定する方法に従った。 Whiteness and yellowness of tablets: Solid color using a color difference meter SZ—∑90 (manufactured by Nippon Denshoku Industries Co., Ltd.) The method for measuring the surface color was followed.
色差:色差計 SZ—∑90 (日本電色工業社製)を使用して、 JIS Z —8729および Z— 8730に準拠して L * a*b *表色系に基づき色差 Δ E * abを測定した。  Color difference: Use color difference meter SZ-∑90 (Nippon Denshoku Industries Co., Ltd.) and color difference Δ E * ab based on L * a * b * color system according to JIS Z-8729 and Z-8730. It was measured.
なお測定値には、黄色系へ変色した場合、色差の値に「 +」を表記し、青色系へ変 色した場合、色差の値に「 」を表記することとした。  In the measured values, “+” is written as the color difference value when the color is changed to yellow, and “” is written as the color difference value when the color is changed to blue.
水分含量：日本薬局方 (第 14改正）「乾燥減量試験法」に準じて、 105°Cで 6時間 乾燥した後の乾燥減量を測定し、水分含量とした。  Moisture content: according to the Japanese Pharmacopoeia (14th revision) “loss on drying test method”, the weight loss after drying at 105 ° C for 6 hours was measured to obtain the moisture content.
[0068] [実施例 1および比較例 1〜3] [Example 1 and Comparative Examples 1 to 3]
ビタミン Cは、医薬品や健康食品における食品用保健機能成分として使用されてい る有効成分である。ビタミン Cを 97質量％含有する顆粒で、直接打錠用の製品として 販売されている「BASF武田株式会社製、商品名：ビタミン C顆粒 97」を用い、表 1 に示す処方に従って打錠試験を行った。  Vitamin C is an active ingredient used as a food health functional ingredient in pharmaceuticals and health foods. A tablet containing 97% by mass of vitamin C and sold as a direct tableting product, “BASF Takeda Co., Ltd., trade name: Vitamin C granule 97”, was subjected to a tableting test according to the formulation shown in Table 1. went.
コメデンプンとしては、水分含量： 12. 2質量0 /0のもの、トウモロコシデンプンとして は水分含量： 12. 4質量％のものを用いた。結晶セルロースは、「旭化成ケミカルズ（ 株)製、商品名：セォラス PH— 101」を用いた。硬化油としては、「フロイント産業株式 会社製、商品名：ラプリワックス— 101」を用いた。 The rice starch, water content: 12. a two mass 0/0, the water content as corn starch: used was a 12.4% by weight. As the crystalline cellulose, “Asahi Kasei Chemicals Co., Ltd., trade name: Serus PH-101” was used. As the hardened oil, “Freund Industrial Co., Ltd., trade name: Lapriwax-101” was used.
実施例 1および比較例 1〜3は、ともに粉末状結合剤であるコメデンプンと結晶セル ロースの性能比較、ともにデンプンであるコメデンプンとトウモロコシデンプンとの性能 比較を目的として実施した。  Example 1 and Comparative Examples 1 to 3 were carried out for the purpose of comparing the performance of rice powder, which is a powdery binder, and crystalline cellulose, and comparing the performance of rice starch, which is a starch, and corn starch.
具体的には、表 1に示す組成の混合粉体 lkgのうち、滑沢剤である硬化油以外の 成分を、 V字型混合機 V— 10 ( (株)徳寿製作所）により毎分 40回転で 20分間混合を 行った。ついで、これに硬化油を加えて 5分間混合を行い、打錠用混合粉体を得た。 そして、以下のような打錠条件で錠剤を得て、それについて、各種測定を実施した 。測定結果を表 2に示す。  Specifically, components other than hardened oil, which is a lubricant, of lkg of the mixed powder composition shown in Table 1 are rotated 40 times per minute using a V-shaped mixer V-10 (Tokuju Seisakusho Co., Ltd.). And mixed for 20 minutes. Subsequently, hydrogenated oil was added thereto and mixed for 5 minutes to obtain a mixed powder for tableting. And the tablet was obtained on the following tableting conditions, and various measurements were implemented about it. Table 2 shows the measurement results.
[0069] [表 1] 成分 実施例 1 比較例 1 比較例 2 比較例 3 ビタミン c 80. 0質量部 80. 0質量部 1 00. 0質量部 80. 0質量部 [0069] [Table 1] Ingredient Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Vitamin c 80.0 parts by mass 80.0 parts by mass 1 00.0 parts by mass 80.0 parts by mass
顆粒一 97  Granule 1 97
コメデンプン 20. 0 R量部 ― 一 ― 結晶セルロース 一 20. 0質量部 ― ― トウモロコシデンプン 一 ― ― 20. 0質量部 硬化油 3. 0質量部 3. 0竄量部 3, 0質量部 3. 0質量部  Rice starch 20.0 R parts ― One ― Crystalline cellulose One 20.0 parts by mass ― ― Corn starch One ― ― 20.0 parts by weight Hardened oil 3.0 parts by weight 3.0 parts by weight 3, 0 parts by weight 3 .0 parts by mass
[0070] 打錠条件は以下の通りである。 [0070] Tableting conditions are as follows.
打錠機:ロータリー打錠機、 HT— P15A— III型 (畑鉄工所社製）  Tableting machine: Rotary tableting machine, HT-P15A-III type (manufactured by Hata Iron Works)
打錠圧： 10kN、オープンフィードシユー使用  Tableting pressure: 10kN, using open feed shout
錠剤：径 8mm、曲率半径 6. 5mmの円形錠、質量は 1錠当たり 180mg [0071] [表 2]
Figure imgf000026_0001
Tablet: Round tablet with a diameter of 8 mm and a radius of curvature of 6.5 mm, and the weight is 180 mg per tablet [0071] [Table 2]
Figure imgf000026_0001
[0072] 実施例 1は製造方法（1)に基づくもので、コメデンプンとコメデンプン誘導体のうち 少なくとも一方を粉末状結合剤として使用した錠剤の製造例である。表 2に示すよう に、実施例 1の錠剤の錠剤硬度と崩壊時間（10分以内）は、いずれも満足できるもの であった。 [0072] Example 1 is based on the production method (1), and is an example of producing a tablet using at least one of rice starch and rice starch derivatives as a powdery binder. As shown in Table 2, the tablet hardness and disintegration time (within 10 minutes) of the tablet of Example 1 were both satisfactory.
比較例 1は粉末状結合剤として結晶セルロースを用いた例であるが、錠剤硬度は 実施例 1とほぼ同一であるものの、崩壊時間は著しく長ぐ 52分を要した。これは、結 晶セルロース力 S、滑沢剤として使用された硬化油の影響を特異的に受けた結果であ ると考免られる。  Comparative Example 1 is an example using crystalline cellulose as a powdery binder, but the tablet hardness was almost the same as in Example 1, but the disintegration time was remarkably long 52 minutes. This is considered to be the result of specific effects of crystalline cellulose strength S and hydrogenated oil used as a lubricant.
比較例 3は粉末結合剤としてトウモロコシデンプンを用いた例である力 錠剤硬度 はコメデンプン使用の場合に比べ著しく劣るものであった。  Comparative Example 3 is an example in which corn starch was used as a powder binder. The tablet strength was remarkably inferior to that using rice starch.
このように、コメデンプンとコメデンプン誘導体のうち少なくとも一方を粉末状結合剤 として使用した実施例 1による錠剤が、総合的に最も優れた性質を示した。なお、比 較例 2は粉末状結合剤を加えずに打錠した例であるが、錠剤硬度は 53Nと低ぐ崩 壊時間も実施例 1の錠剤よりも長いものであった。 [0073] また、それぞれの錠剤をガラス瓶に入れ、ふたをしない状態で 40°Cおよび相対湿 度 75%の恒温恒湿器に入れ、 4週間放置し、放置前後における錠剤表面の白色度 を測定した。その結果、放置前と後の白色度はそれぞれ、実施例 1 : 98. 4および 90 . 8、比較例 1 : 97. 9および 84. 3、比較例 2: 96. 6および 89. 3、比較例 3 : 98. 1お よび 90. 1であり、結晶セルロースを成分に含んだ比較例 1の錠剤における着色変化 が最も大き力つた。 Thus, the tablet according to Example 1 using at least one of rice starch and rice starch derivative as a powder binder showed the most excellent properties overall. Comparative Example 2 was an example in which tableting was performed without adding a powdery binder, but the tablet hardness was 53 N and the disintegration time was lower than that of the tablet of Example 1. [0073] Also, put each tablet in a glass bottle, put it in a constant temperature and humidity chamber at 40 ° C and 75% relative humidity without a lid, and leave it for 4 weeks to measure the whiteness of the tablet surface before and after leaving it. did. As a result, the whiteness before and after standing was compared with Example 1: 98.4 and 90.8, Comparative Example 1: 99.9 and 84.3, Comparative Example 2: 96.6 and 89.3, respectively. Example 3: 98.1 and 90.1, and the color change in the tablet of Comparative Example 1 containing crystalline cellulose as a component was the strongest.
[0074] [実施例 2〜7および比較例 4〜6]  [0074] [Examples 2 to 7 and Comparative Examples 4 to 6]
実施例 1で使用したコメデンプンを所定時間 80°Cで乾燥、または、 40°Cおよび相 対湿度 80%の恒温恒湿器中に放置することにより、表 3に示す各種水分含量のコメ デンプンを得た。  The rice starch used in Example 1 was dried at 80 ° C for a predetermined time or left in a constant temperature and humidity chamber at 40 ° C and a relative humidity of 80%, so that the rice starches with various water contents shown in Table 3 were used. Got.
各水分含量のコメデンプンを用いた以外は、実施例 1と同じ組成の 50gの混合粉体 を得た。ただし、混合は次のように行った。始めに、ポリエチレン袋中で硬化油を加え な ヽ混合粉体を十分に均一になるように混合し、次 、で硬化油を加えて 30秒間振り 混ぜた。  50 g of mixed powder having the same composition as in Example 1 was obtained except that rice starch having each water content was used. However, mixing was performed as follows. First, hardened oil was not added in a polyethylene bag. The mixed powder was mixed so as to be sufficiently uniform, and then hardened oil was added in and shaken for 30 seconds.
これら混合粉体を用いた打錠試験 (モデル実験)として、油圧プレス式成形機を用 いて、圧縮圧 20kNの条件下、直径 20mm、 1錠当たり質量が 2. Ogの平型の錠剤を 成形し、得られた錠剤の硬度を測定した。試験結果を表 3に示す。  As a tableting test (model experiment) using these mixed powders, a flat tablet with a diameter of 20 mm and a mass of 2. Og is formed using a hydraulic press molding machine under a compression pressure of 20 kN. Then, the hardness of the obtained tablets was measured. Table 3 shows the test results.
[0075] [表 3] [0075] [Table 3]
Figure imgf000027_0001
Figure imgf000027_0001
[0076] 水分含量が 14. 4質量％のコメデンプンを用いた比較例 4では、成形後に打錠機 の臼ゃ杵に粉末の付着が認められ、次に成形するときにそれを取り除くことが必要で めつに。 [0076] In Comparative Example 4 using a rice starch having a moisture content of 14.4% by mass, powder adhesion was observed on the mortar of the tableting machine after molding, and this could be removed at the next molding. Necessary.
また、上記結果に示されるように、コメデンプンの水分含量は錠剤の硬度に影響し、 水分含量が低くなるに従って硬度は低くなる傾向があった。実施例 1の処方において コメデンプンをカ卩えず、ビタミン C顆粒 97 : 100. 0質量部と硬化油： 3. 0質量部か らなる混合物を同様に圧縮成形したものでは、硬度が 56Nであった。この結果を照 合すると、水分含量が 6質量％未満のコメデンプンを使用した比較例 5および 6では、 錠剤硬度は著しく低ぐコメデンプンが結合剤として作用して 、な 、ことが示唆された Further, as shown in the above results, the water content of rice starch affected the hardness of the tablet, and the hardness tended to decrease as the water content decreased. In the formulation of Example 1 When a mixture of 97 parts by mass of vitamin C granules and 3.0 parts by mass of hardened oil without compression of rice starch was compression-molded, the hardness was 56N. These results suggest that in Comparative Examples 5 and 6 using rice starch having a water content of less than 6% by mass, rice starch having a significantly low tablet hardness acts as a binder.
[0077] [実施例 8および比較例 7] [Example 8 and Comparative Example 7]
表 4に示す組成の混合粉体 2kgのうち、ステアリン酸マグネシウム以外の成分を実 施例 1の条件に準じて 20分間混合し、次いでステアリン酸マグネシウムを加えて 5分 間混合し、造粒用混合粉体を得た。  In 2 kg of the mixed powder with the composition shown in Table 4, ingredients other than magnesium stearate were mixed for 20 minutes according to the conditions of Example 1, then magnesium stearate was added and mixed for 5 minutes for granulation. A mixed powder was obtained.
この混合粉体をローラーコンパクタ一 TF— mini (フロイント産業 (株)製)を用いた口 ール圧縮成形により 4MPa (圧力シリンダー 'ゲージ圧）の圧力で圧縮成形し、得られ たフレーク部分をスクリーン付き整粒機で粗砕し、さらにロールダラ-ユレ一ターで整 粒して打錠用顆粒を得た。  This mixed powder is compression-molded at a pressure of 4 MPa (pressure cylinder 'gauge pressure) using a roller compactor TF-mini (Freund Sangyo Co., Ltd.) and the resulting flakes are screened. The mixture was coarsely pulverized with a particle sizer and further sized with a roll duller-yuretor to obtain granules for tableting.
さらに得られた顆粒を用いて、実施例 1と同じ打錠条件により錠剤を成形した。  Further, using the obtained granules, tablets were formed under the same tableting conditions as in Example 1.
[0078] [表 4] [0078] [Table 4]
Figure imgf000028_0001
Figure imgf000028_0001
注" 水分含量 1 1. 8質量％のコメデンプン粉末  Note "Rice starch powder with a moisture content of 1 1. 8% by weight
[0079] このような乾式造粒法により得られた顆粒を日本薬局方 (第 14改正)、粉体粒度測 定法、第 2法ふるい分け法に準拠し、目開き 200号 (75 m)の篩いを用いて篩分け し、篩いを通過した微粒子を 75 μ m pass品とした。顆粒の篩分 75 μ m pass品の含 有率は、比較例 7で 30質量％であるのに対して、実施例 8では 25質量％となった。 また、得られた顆粒の硬度測定を行った結果、平均値で比較例 7では 25gであるの に対して、実施例 8では 45gとなった。 [0079] Granules obtained by this dry granulation method are sieved with a mesh size of 200 (75 m) according to the Japanese Pharmacopoeia (14th revision), the powder particle size measurement method, and the second screening method. The fine particles that passed through the sieve were made into a 75 μm pass product. The content of the granule sieving 75 μm pass product was 30% by mass in Comparative Example 7 whereas it was 25% by mass in Example 8. In addition, as a result of measuring the hardness of the obtained granule, the average value was 25 g in Comparative Example 7 and 45 g in Example 8.
さらに、得られた錠剤の硬度と、日本薬局方に従った崩壊試験法による崩壊時間を 試験した結果、平均値で比較例 7では 31Nおよび 65秒であるのに対して、実施例 8 では 52Nおよび 185秒であつた。 Furthermore, as a result of testing the hardness of the obtained tablets and the disintegration time by the disintegration test method according to the Japanese Pharmacopoeia, the average value was 31 N and 65 seconds in Comparative Example 7, whereas Example 8 Then it was 52N and 185 seconds.
比較例 7の組成は、滑沢剤を除!、て乳糖とトウモロコシデンプンが 7： 3の混合物か ら成るものである。これに対して、実施例 8の組成は乳糖とトウモロコシデンプンの混 合物のうち 20質量％をコメデンプンの粉末で置き換えたものである。  The composition of Comparative Example 7 is composed of a 7: 3 mixture of lactose and corn starch excluding the lubricant. On the other hand, in the composition of Example 8, 20% by mass of the mixture of lactose and corn starch was replaced with rice starch powder.
以上の結果から、実施例 8では、微粉の比率が低ぐ硬度の高い重質な顆粒を高 収率で得ることができた。また、実施例 8による錠剤はやや崩壊時間は長くなつたが、 錠剤硬度は比較例 7に対して大きく改善されていた。  From the above results, in Example 8, heavy granules with high hardness and low ratio of fine powder could be obtained in high yield. In addition, the tablet according to Example 8 had a slightly longer disintegration time, but the tablet hardness was greatly improved as compared with Comparative Example 7.
[0080] [実施例 9および比較例 8] [0080] [Example 9 and Comparative Example 8]
実施例 8に示した条件に準じ、表 5に示す組成の混合粉体を用いて打錠用顆粒の 乾式造粒を行い、得られた顆粒について顆粒の硬度測定を行った。さら〖ここれらの 顆粒を用いて、実施例 8と同じ打錠条件により錠剤を成形した。  According to the conditions shown in Example 8, dry granulation of the granules for tableting was performed using the mixed powder having the composition shown in Table 5, and the hardness of the granules was measured. Using these granules, tablets were molded under the same tableting conditions as in Example 8.
[0081] [表 5] [0081] [Table 5]
Figure imgf000029_0001
Figure imgf000029_0001
注 旭化成ケミカルズ （株） 製 （商品名セォラス P H— 1 0 1 )  Note: Asahi Kasei Chemicals Co., Ltd. (Brand name Ceras PH-1 0 1)
[0082] このような乾式造粒法により得られた顆粒の篩分 75 μ m pass品の含有率は、比較 例 8では 21質量％であるのに対して、実施例 9では 17質量％となった。また顆粒硬 度は、比較例 8では 28gであるのに対して、実施例 9では 44gとなった。錠剤の硬度 および崩壊時間につ 、ては、平均値で比較例 8では 42Nおよび 49秒であるのに対 して、実施例 9では 77Nおよび 177秒であった。 [0082] The content of the granulated sieving 75 μm pass product obtained by such a dry granulation method is 21% by mass in Comparative Example 8, compared with 17% by mass in Example 9. became. The granule hardness was 28 g in Comparative Example 8, compared with 44 g in Example 9. The hardness and disintegration time of the tablets were 77N and 177 seconds in Example 9, compared to 42N and 49 seconds in Comparative Example 8 on average.
実施例 9によるものは比較例 8のトウモロコシデンプンをコメデンプンに置き換えたも のであるが、以上の結果から、実施例 9では、顆粒製造時の微粒子の含有率が低下 し、比較例 8に対して顆粒硬度の点で改善が認められた。さらに実施例 9による錠剤 は、比較例 8に対して錠剤硬度についても改善され、実用上、十分に使用できる値で めつに。 [0083] [実施例 10〜 15および比較例 9〜 11 ] In Example 9, the corn starch of Comparative Example 8 was replaced with rice starch. From the above results, however, in Example 9, the content of fine particles during granule production decreased, and compared with Comparative Example 8 An improvement was observed in terms of granule hardness. Furthermore, the tablet according to Example 9 is improved in tablet hardness as compared with Comparative Example 8, and is a value that can be used practically. [0083] [Examples 10 to 15 and Comparative Examples 9 to 11]
実施例 8に使用したコメデンプンを、所定時間 80°Cで乾燥、または、 40°Cおよび相 対湿度 80%の恒温恒湿器中に放置することにより、表 6に示す各種の水分含量を有 する試料を得た。各水分含量のコメデンプンを用いた以外は、実施例 8と同じ組成の 200gの混合粉体を得た。ただし、混合は、次のように行った。始めに、ポリエチレン 袋中でステアリン酸マグネシウムを加えな 、混合粉体を十分に均一になるように混合 し、次 、でステアリン酸マグネシウムを加えて 30秒間振り混ぜた。  The rice starch used in Example 8 was dried at 80 ° C for a predetermined time, or left in a constant temperature and humidity chamber at 40 ° C and a relative humidity of 80% to obtain various moisture contents shown in Table 6. A sample was obtained. A mixed powder of 200 g having the same composition as in Example 8 was obtained except that rice starch having each water content was used. However, mixing was performed as follows. First, without adding magnesium stearate in a polyethylene bag, the mixed powder was mixed so that it was sufficiently uniform, and then magnesium stearate was added and shaken for 30 seconds.
これら混合粉体を、ローラーコンパクタ一 TF—LABO (フロイント産業 (株)製)を用 いたロール圧縮成形により 4MPa (圧力シリンダー 'ゲージ圧）の圧力で圧縮成形し、 得られたフレーク部分をスクリーン付き整粒機で整粒し、顆粒を得た。  These mixed powders are compression-molded at a pressure of 4MPa (pressure cylinder 'gauge pressure) by roll compression molding using a roller compactor TF-LABO (manufactured by Freund Sangyo Co., Ltd.), and the resulting flakes are screened. Granules were obtained by sizing with a sizing machine.
これら顆粒を用いた打錠試験 (モデル実験)として、油圧プレス式成形機を用いて 圧縮圧 20kNの条件下、直径 20mm、 1錠当たり質量が 2. Ogの平型の錠剤を成形 し、得られた錠剤の硬度を測定した。試験結果を表 6に示す。  As a tableting test (model experiment) using these granules, a flat tablet with a diameter of 20 mm and a weight of 2. Og per tablet was molded using a hydraulic press molding machine under a compression pressure of 20 kN. The hardness of the tablets obtained was measured. Table 6 shows the test results.
[0084] [表 6] [0084] [Table 6]
Figure imgf000030_0001
Figure imgf000030_0001
[0085] 水分含量が 14. 2質量％のコメデンプンを用いた比較例 9では、混合粉体の流動 性が悪ぐ乾式造粒の際にホッパー力もの供給がスムースではな力つた。また上記結 果に示されるように、コメデンプンの水分含量は錠剤の硬度に影響し、水分含量が低 くなるに従って硬度は低くなり、水分含量が 6質量％を下回る比較例 10および 11で は錠剤硬度は著しく低くなり、実用に供することはできないことが示唆された。 [0085] In Comparative Example 9 using rice starch with a moisture content of 14.2% by mass, the supply of hopper force was not smooth during dry granulation, where the fluidity of the mixed powder was poor. In addition, as shown in the above results, the moisture content of rice starch affects the hardness of the tablet. The hardness decreases as the moisture content decreases, and in Comparative Examples 10 and 11 where the moisture content is less than 6% by mass. The tablet hardness was remarkably lowered, suggesting that it could not be put to practical use.
[0086] [実施例 16および比較例 12〜14]  [0086] [Example 16 and Comparative Examples 12-14]
表 7の組成、実施例 10の条件で乾式造粒を行った。得られた顆粒を用いた打錠試 験 (モデル実験）として、油圧プレス式成形機を用い、圧縮圧 20kNの条件下、直径 1 Omm, 1錠当たりの質量が 300mgの平型の錠剤を成形した。さらに、得られた錠剤 をガラス瓶に充填して密栓し、 50°Cの恒温器内に 1週間放置した。この加速試験前 後の錠剤にっ ヽて各種物性試験を行った。結果を表 8に示す。 Dry granulation was performed under the composition of Table 7 and the conditions of Example 10. As a tableting test (model experiment) using the obtained granules, a flat tablet with a diameter of 1 Omm and a mass of 300 mg per tablet was molded using a hydraulic press molding machine under a compression pressure of 20 kN. did. In addition, the resulting tablets Was filled in a glass bottle, sealed, and left in a 50 ° C incubator for 1 week. Various physical property tests were conducted on the tablets before and after the acceleration test. The results are shown in Table 8.
[表 7]  [Table 7]
Figure imgf000031_0001
Figure imgf000031_0001
注" 日本曹達 （株） 製 （商品名： HPG-し)  Note "Made by Nippon Soda Co., Ltd. (Product name: HPG-shi)
[0088] [表 8] [0088] [Table 8]
Figure imgf000031_0002
Figure imgf000031_0002
注 *1 L ' a ' b *値を、 加速試験前後の錠剤について測定して色差厶 E ' a b 算出。 +は黄色系への変化、 -は青色系への変化を示す。 Note * 1 L 'a' b * value is measured for tablets before and after the acceleration test, and color difference 厶 E 'ab is calculated. + Indicates a change to yellow,-indicates a change to blue.
[0089] 表 8の結果より、比較例 13の錠剤は、結晶セルロースを使用していない比較例 12 の錠剤と比較して錠剤硬度が向上している。ところが、比較例 13の錠剤は、 50°Cに おける加速試験後には崩壊時間が遅延し、さらに色も黄色方向への変化が大きい。 このことから、比較例 13は経時的安定性が低いと予想できる。また、比較例 14の錠 剤は、比較例 12の錠剤に比較して崩壊時間が顕著に長くなつているため、崩壊性の 改善等が必要である。 [0089] From the results shown in Table 8, the tablet of Comparative Example 13 has improved tablet hardness as compared with the tablet of Comparative Example 12 that does not use crystalline cellulose. However, the tablet of Comparative Example 13 has a delayed disintegration time after the accelerated test at 50 ° C., and the color is greatly changed in the yellow direction. From this, it can be expected that Comparative Example 13 has low stability over time. In addition, since the tablet of Comparative Example 14 has a significantly longer disintegration time than the tablet of Comparative Example 12, it is necessary to improve disintegration and the like.
実施例 16のものは、結晶セルロースを結合剤に用いた比較例 13のものと比較して 同等の錠剤硬度を示し、さらに、 50°Cにおける加速試験の前後でも、物性の変化は 認められなカゝつた。これらの結果から、実施例 16の錠剤は、他の結合剤を用いた錠 剤と比較して経時的安定性に優れており、実用に適していると言える。 [0090] [実施例 17および比較例 15] The product of Example 16 shows the same tablet hardness as that of Comparative Example 13 using crystalline cellulose as the binder, and further, no change in physical properties was observed before and after the accelerated test at 50 ° C. Katsutsu. From these results, it can be said that the tablet of Example 16 is suitable for practical use because it is superior in stability over time as compared with tablets using other binders. [Example 17 and Comparative Example 15]
表 9に示す組成、実施例 10の条件で打錠用顆粒の乾式造粒および錠剤の成形を 行った。そして、得られた錠剤を 40°Cおよび 75%RHの雰囲気で 4週間放置し、放 置前後における錠剤の硬度および色差の測定を行った。  Dry granulation of tablets for tableting and tablet formation were carried out under the conditions shown in Table 9 and Example 10. The obtained tablets were allowed to stand in an atmosphere of 40 ° C. and 75% RH for 4 weeks, and the hardness and color difference of the tablets before and after being released were measured.
[0091] [表 9] [0091] [Table 9]
Figure imgf000032_0001
Figure imgf000032_0001
[0092] 硬度測定の結果、比較例 15は放置前 11. 5N、放置後 4. 1Nであるのに対して、 実施例 17では放置前 18. 6N、放置後 11. 2Nとなった。また放置前後における錠剤 の色差は、比較例 15で + 11. 4であるのに対して、実施例 17では + 0. 7となった。 比較例 15の組成は、錠剤硬度を高くする目的で結晶セルロースの含有量を著しく上 げたものであるが、錠剤硬度および錠剤への着色の経時的な変化は大きぐ実用に 供するのは困難であることが示唆された。一方、実施例 17の組成は、比較例 15の粉 末状結合剤として用いて 、る結晶セルロースの一部をコメデンプンで置き換えたもの であるが、多少の錠剤硬度の低下が認められたものの、錠剤の色調の変化は極めて 小さぐ経時的に安定で実用に適して 、ると言える。 As a result of the hardness measurement, Comparative Example 15 had 11.5N before being left and 4.1N after being left, whereas Example 17 had 18.6N before being left and 11.2N after being left. The color difference of the tablet before and after being left was +11.4 in Comparative Example 15, whereas it was +0.7 in Example 17. The composition of Comparative Example 15 is one in which the content of crystalline cellulose is remarkably increased for the purpose of increasing tablet hardness, but the change over time in tablet hardness and coloration on the tablet is large, and it is difficult to provide practical use. It was suggested that there is. On the other hand, the composition of Example 17 was obtained by replacing a part of the crystalline cellulose with rice starch as the powdery binder of Comparative Example 15, although a slight decrease in tablet hardness was observed. It can be said that the color tone of the tablet is extremely small and stable over time and suitable for practical use.
[0093] [実施例 18および比較例 16]  [0093] [Example 18 and Comparative Example 16]
表 10に示す組成、実施例 8の条件に従って打錠用顆粒の乾式造粒および錠剤の 成形を行った。  According to the composition shown in Table 10 and the conditions of Example 8, dry granulation of tablets for tableting and molding of tablets were performed.
[0094] [表 10] 配合組成 [0094] [Table 10] Composition
成分 比較例 16 実施例 18  Ingredients Comparative Example 16 Example 18
アミノフィリン 5. 00質量％ 5. 00置量％  Aminophylline 5.00% by mass 5.00%
乳糖 （200メッシュタイプ） 52. 15質量％  Lactose (200 mesh type) 52. 15% by mass
トウモロコシデンプン 22. 35質量％  Corn starch 22. 35% by mass
コメデンプン 37. 25質置％  Rice starch 37. 25%
(実施例 8と同じもの）  (Same as Example 8)
結晶セル D—ス 20. 00質量％ 20.00質虽％  Crystal cell D-cell 20.00 mass% 20.00 mass%
(荬施例 9と罔じもの）  (Same as Ninth Example 9)
D—マンニ t -ール粉末 37. 25質暈％ ス亍アリン酸マグネシウム 0. 50質量％ 0, 50： 9量％  D—Manni-tall powder 37. 25% by weight Magnesium sulphate 0.5% by weight 0, 50: 9% by weight
[0095] 得られた錠剤の硬度および崩壊時間は、比較例 16は 48Nおよび 2分 20秒である のに対して、実施例 18では 121Nおよび 2分 30秒であり、実施例 18によるものは比 較例 16に対して錠剤硬度の点で著しい改善が認められた。また、一般に成形性が 低！、とされて 、るマン-トールを含有した実施例 18の組成につ!、ても、マン-トール を含まず乳糖およびトウモロコシデンプンを使用した比較例 16の組成と同等の崩壊 時間を示した。 [0095] The hardness and disintegration time of the tablets obtained were 48N and 2 minutes and 20 seconds in Comparative Example 16, while 121N and 2 minutes and 30 seconds in Example 18, and those according to Example 18 were A marked improvement in tablet hardness was observed with respect to Comparative Example 16. In general, formability is low! The composition of Example 18 containing mannitol was shown to have a disintegration time equivalent to that of Comparative Example 16 using lactose and corn starch without mannitol. .
また、それぞれの錠剤を 50mLのガラス瓶に充填し、 50°Cの恒温器に入れて 24時 間放置した。これらの錠剤について加熱前後での錠剤の色を測定した結果、加熱前 後における色差は比較例 16で + 12. 3、実施例 18で +4. 1となった。実施例 18と 比較して比較例 16の方が色調の変化度が大きぐメイラード反応により着色している ことが明らかであった。よって、実施例 16によるものは、加速試験における変化が少 なぐ経時的安定性に優れていた。  Each tablet was filled into a 50 mL glass bottle, placed in a 50 ° C incubator and left for 24 hours. As a result of measuring the color of the tablets before and after heating, the color difference before and after heating was +12.3 in Comparative Example 16 and +4.1 in Example 18. Compared to Example 18, it was clear that Comparative Example 16 was colored by the Maillard reaction with a greater degree of change in color tone. Therefore, the sample according to Example 16 was excellent in stability over time with little change in the acceleration test.
[0096] [実施例 19〜22]  [Examples 19 to 22]
ビタミン Cの粉末 50質量0 /0、実施例 8と同じコメデンプンの粉末 29. 5質量0 /0、ステ アリン酸マグネシウム 0. 5質量％ぉよび残り 20質量％を表 11に示す成分とし、実施 例 10に示される条件に従って乾式造粒および錠剤の成形を行った。各例での錠剤 硬度および崩壊時間を表 11に示す。 Vitamin C powder 50 mass 0/0, the same rice starch as in Example 8 powder 29.5 mass 0/0, 20 mass% magnesium 0.5 wt% Oyobi remainder stearyl stearic acid and ingredients shown in Table 11, Dry granulation and tablet molding were performed according to the conditions shown in Example 10. Table 11 shows the tablet hardness and disintegration time for each example.
[0097] [表 11] 添加した成分 硬度 崩壊時間 [0097] [Table 11] Added ingredients Hardness Disintegration time
[ N ] [分：秒]  [N] [minute: second]
実施例 19 コメデンプン （実施例 8と同じもの） 13. 1 23 : 30  Example 19 Rice starch (same as Example 8) 13. 1 23:30
実施例 20 結晶セルロース （実施例 9と同じもの） 21 . 9 7：45  Example 20 Crystalline cellulose (same as Example 9) 21.9 7:45
実施例 21 粉末セルロース 23. 5 6：50  Example 21 Powdered cellulose 23.5 5:50
実施例 低置換度ヒドロキシプロピルセルロース'2 16, 8 9：00 Examples Low-substituted hydroxypropylcellulose ' 2 16, 8 9:00
注'' 日本製紙 （株） 製 商品名： K C一フロック、 W— 2 0 O G  Note '' Made by Nippon Paper Industries Co., Ltd.
注'2 信越化学工業 (株)製 商品名： L— H P C、 L H - 2 1 Note ' 2 Shin-Etsu Chemical Co., Ltd. Product Name: L—HPC, LH-2 1
[0098] 上記結果より、粉末状結合剤としてコメデンプンを単独で使用した場合よりも、その 一部を結晶セルロース、粉末セルロースまたは低置換度ヒドロキシプロピルセルロー スで置き換えることにより、錠剤の硬度は高くなり、崩壊時間は短くなることが明らかに なった。 [0098] From the above results, the hardness of the tablet is higher by replacing part of it with crystalline cellulose, powdered cellulose or low-substituted hydroxypropyl cellulose than when using rice starch alone as the powder binder. It became clear that the decay time was shortened.
[0099] [実施例 23および比較例 17]  [Example 23 and Comparative Example 17]
表 12に示す組成、実施例 8の条件に従って打錠用顆粒の乾式造粒および錠剤の 成形を行った。  According to the composition shown in Table 12 and the conditions of Example 8, dry granulation of tablets for tableting and molding of tablets were performed.
[0100] [表 12] [0100] [Table 12]
Figure imgf000034_0001
Figure imgf000034_0001
[0101] 得られた錠剤の硬度および崩壊時間は、比較例 17は 74Nおよび 70秒であるのに 対して、実施例 23が 139Nおよび 4分 10秒となった。実施例 23によるものは、比較 例 17のトウモロコシデンプンをコメデンプンに置き換えた組成である力 比較例 17に 対して錠剤硬度の点で大きな改善が認められた。 [0101] The hardness and disintegration time of the tablets obtained were 74N and 70 seconds for Comparative Example 17, while 139N and 4 minutes and 10 seconds for Example 23. According to Example 23, a force that is a composition in which the corn starch of Comparative Example 17 was replaced with rice starch was greatly improved in terms of tablet hardness as compared with Comparative Example 17.
[0102] [実施例 24]  [0102] [Example 24]
表 13に示す組成、実施例 8の条件に従って打錠用顆粒の乾式造粒を行い、得ら れた顆粒 93質量部に硬化油 6質量部と二酸化ケイ素 1質量部を加え、実施例 8の条 件に従って錠剤の成形を行った。なお、ニ酸ィ匕ケィ素としては、フロイント産業 (株) 製 商品名：アドソリダ一 101を使用した。 The granulation for tableting was dry granulated according to the composition shown in Table 13 and the conditions of Example 8, and 6 parts by mass of hardened oil and 1 part by mass of silicon dioxide were added to 93 parts by mass of the obtained granules. Article Tablets were formed according to the conditions. In addition, as Freund Sangyo Co., Ltd. trade name: Adsolida 101 was used as the nitric acid silicate.
[表 13]  [Table 13]
Figure imgf000035_0001
Figure imgf000035_0001
注" ァセチル化モチゴメデンプン （水分含量 11. 2質量％) 注 *2 フロイント産業 （株） 製 商品名：ラブリワックス 1 0 1 Note "Acetylated mochigome starch (moisture content: 11.2% by mass) Note * 2 manufactured by Freund Sangyo Co., Ltd.
[0104] 得られた錠剤の硬度および崩壊時間は 103Nおよび 19分であり、実用可能なもの であった。 [0104] The hardness and disintegration time of the obtained tablets were 103 N and 19 minutes, which were practical.
[0105] [実施例 25および比較例 18〜19]  [Example 25 and Comparative Examples 18 to 19]
医薬品有効成分としてアミノフイリンを、賦形剤に D—マン-トールとしてロケット (R OQUETTE)社製、商品名：パーリトール（PEARLITOL) 35を用い、表 14の処方 に従い、湿式顆粒圧縮法を適用した錠剤を調製した。造粒法としては破砕型造粒法 を適用した。そして、粉末状結合剤としてコメデンプンまたは結晶セルロースを用いた 場合と、これらを用いない場合とを比較した。なお、アミノフィリンは強心薬であり、多く の物質と配合変化があることが知られている物質である。  Aminophylline was used as the active pharmaceutical ingredient, and D-mann-tol was used as the excipient, manufactured by ROQUETTE. Tablets were prepared. The crushing granulation method was applied as the granulation method. The case where rice starch or crystalline cellulose was used as the powder binder was compared with the case where these were not used. Aminophylline is a cardiotonic drug, and is known to have many substances and mixed changes.
具体的には、滑沢剤であるステアリン酸マグネシウム以外の成分を混合し、その 2k gを 5Lの-一ダ一に仕込み、それぞれに水を加えて混練した。混練したものを取り出 し、スクリーン型破砕型造粒機（岡田精ェ (株)社製、商品名 ユースピードミル）に 口径が 1. 2mmのスクリーンを装着してこれを破砕し、さらに 50°Cの乾燥機中で乾燥 し、 500 mの篩いで篩い分け、顆粒を得た。  Specifically, ingredients other than magnesium stearate, which is a lubricant, were mixed, 2 kg of the mixture was charged into a 5 L-line, and water was added to each to knead. The kneaded product is taken out, and a screen-type crushing granulator (manufactured by Seida Okada Co., Ltd., product name: U-speed mill) is equipped with a screen with a diameter of 1.2 mm and further crushed. It was dried in a dryer at ° C and sieved with a 500 m sieve to obtain granules.
実施例 25の場合は、得られた顆粒を 30°C、相対湿度 60%の恒温恒湿器に 16時 間入れ調湿し、水分活性 (aw)を 0. 63にした。水分活性 (aw)の測定には、フロイン ト産業 (株)製、商品名： EZ- 100を用いた。  In the case of Example 25, the obtained granule was placed in a thermo-hygrostat at 30 ° C. and a relative humidity of 60% for 16 hours to adjust the moisture activity (aw) to 0.63. For measurement of water activity (aw), product name: EZ-100 manufactured by Freund Sangyo Co., Ltd. was used.
得られた顆粒にステアリン酸マグネシウムを混合し、下記条件にて打錠を行った。 各例での錠剤硬度、崩壊時間、錠剤の黄色度を表 15に示す。 [0106] 打錠条件は以下の通りである。 Magnesium stearate was mixed with the obtained granules, and tableting was performed under the following conditions. Table 15 shows the tablet hardness, disintegration time, and tablet yellowness in each example. [0106] The tableting conditions are as follows.
打錠機:単式打錠機、 FY— SS— 7 (富士薬品機械 (株) )  Tablet press: Single-type tablet press, FY—SS—7 (Fuji Pharmaceutical Machinery Co., Ltd.)
打錠圧： 10kN  Tableting pressure: 10kN
錠剤:径 10mmの平形錠、質量は 1錠当たり 350mg  Tablet: Flat tablet with a diameter of 10mm, the weight is 350mg per tablet
[0107] [表 14] [0107] [Table 14]
Figure imgf000036_0001
Figure imgf000036_0001
[0108] [表 15] [0108] [Table 15]
Figure imgf000036_0002
Figure imgf000036_0002
[0109] 粉末状結合剤が使用されな力つた比較例 19では、打錠試験において、打錠開始 力もまもなくステイツキングの打錠障害が見られ、打錠の継続は困難であった。また、 初期に得られた錠剤の硬度は著しく低ぐ実用的なレベルではな力つた。 [0109] In Comparative Example 19, where no powdered binder was used, in the tableting test, the tableting start force was soon observed and the tableting failure of the sticking was seen, and it was difficult to continue the tableting. In addition, the hardness of the tablets obtained in the early stage was extremely low, so it was not practical at a practical level.
比較例 18で得られた錠剤は、硬度および崩壊性に関しては実施例 25に劣らない ものであつたが、わずかに黄色が力つた着色があり、さらに 40°C、相対湿度 75%RH 下に放置した結果、その着色は著しく増大した。この現象はアミノフィリンと結晶セル ロースの相互作用に起因すると考えられる。  The tablet obtained in Comparative Example 18 was not inferior to Example 25 in terms of hardness and disintegration, but it had a slightly yellowish coloration, and further under 40 ° C and relative humidity of 75% RH. As a result of standing, the coloration increased significantly. This phenomenon is thought to be due to the interaction between aminophylline and crystalline cellulose.
[0110] [実施例 26および比較例 20] [0110] [Example 26 and Comparative Example 20]
顆粒状に成形され、水分活性 (aw)が調整された賦形剤の有用性を示すために、 次のような実施例 26と比較例 20を実施した。  The following Example 26 and Comparative Example 20 were carried out in order to demonstrate the usefulness of an excipient that was formed into granules and adjusted for water activity (aw).
グレード 200Mの DMV社製乳糖 lkgを 3kgの温水（70°C)に溶力し、 25質量0 /0濃 度の溶液を得た。同じ乳糖 3. 5kgと実施例 1のコメデンプン 0. 5kgを流動層造粒コ 一ティング装置 (フロイント産業 (株)製、商品名：フローコーター FLO— 5)に仕込み 、前記溶液を全量スプレーすることにより造粒を行い、さらに目開き 500 mの篩い で篩い分け、平均粒子径 98 mの顆粒を得た。 And溶力the DMV Co. lactose lkg grade 200M in warm water (70 ° C) of 3 kg, 25 mass 0/0 concentrated Degree solution was obtained. Charge 3.5 kg of the same lactose and 0.5 kg of the rice starch of Example 1 into a fluidized bed granulating coating device (Freund Sangyo Co., Ltd., trade name: Flow Coater FLO-5) and spray the solution in its entirety. The resulting mixture was granulated and sieved with a sieve having an opening of 500 m to obtain granules having an average particle diameter of 98 m.
得られた顆粒をステンレス製バットに入れ、 30°C、相対湿度 60%の恒温恒湿器に 24時間入れ調湿し、水分活性 (aw)が 0. 58になったものを、打錠機で圧縮成形して 錠剤を得た。具体的には、この顆粒状の賦形剤 99. 3質量部にステアリン酸マグネシ ゥム 0. 7質量部を混合し、実施例 1と同じ条件で打錠を行った。  The obtained granules are put in a stainless steel vat, placed in a constant temperature and humidity chamber at 30 ° C and 60% relative humidity for 24 hours to adjust the moisture activity (aw) to 0.58. Compressed to obtain tablets. Specifically, 0.73 parts by mass of magnesium stearate was mixed with 99.3 parts by mass of this granular excipient, and tableting was performed under the same conditions as in Example 1.
得られた錠剤の物性を試験したところ、錠剤硬度は 125Nであり、崩壊時間は 57秒 であった。対照として (比較例 20) DMV社製の噴霧乾燥法により製造されて ヽる直 接打錠用乳糖 DCL— 11を同じ条件で打錠したところ、錠剤硬度は 82N、崩壊時間 は 12分 40秒であった。  When the physical properties of the obtained tablets were tested, the tablet hardness was 125 N and the disintegration time was 57 seconds. As a control (Comparative Example 20) Directly tableted lactose DCL-11 manufactured by the DMV spray drying method was tableted under the same conditions. The tablet hardness was 82 N and the disintegration time was 12 minutes 40 seconds. Met.
このように実施例 26で得られた錠剤の方が硬度は高ぐ崩壊時間は短力つた。よつ て、実施例 26の顆粒状の賦形剤は、いわゆる直接打錠用の賦形剤として優れている ことが示された。  Thus, the tablet obtained in Example 26 had a higher hardness and a shorter disintegration time. Therefore, it was shown that the granular excipient of Example 26 is excellent as an excipient for so-called direct compression.
[実施例 27および比較例 21] [Example 27 and Comparative Example 21]
顆粒状に成形され、水分活性 (aw)が調整された賦形剤の有用性を示すために、 次のような実施例 27と比較例 21を実施した。  The following Example 27 and Comparative Example 21 were carried out in order to demonstrate the usefulness of an excipient that was formed into granules and whose water activity (aw) was adjusted.
実施例 25で使用したものと同じ D—マン-トールとコメデンプンが質量比 8： 2で混 合された混合粉体 2kgを、実施例 25と同様の破砕型造粒法により造粒し、乾燥、篩 Vヽ分けも同様に行って顆粒 (平均粒子径 143 μ m)を得た。  2 kg of the same mixed powder in which D-mannitol and rice starch were mixed at a mass ratio of 8: 2 as used in Example 25 was granulated by the same crushing-type granulation method as in Example 25. Drying and sieving were performed in the same manner to obtain granules (average particle size: 143 μm).
この顆粒をバットに入れ、 40°C、相対湿度 70%の恒温恒湿器に 6時間入れて調湿 し、水分活性 (aw)が 0. 55になったものを、打錠機で圧縮成形して錠剤を得た。具 体的には、この顆粒状の賦形剤 99. 0質量部にステアリン酸マグネシウム 1. 0質量 部を混合し、実施例 25と同じ条件で打錠を行った。  This granule is placed in a vat, placed in a constant temperature and humidity chamber at 40 ° C and 70% relative humidity for 6 hours to adjust the humidity, and the water activity (aw) is 0.55. To obtain tablets. Specifically, 99.0 parts by mass of the granular excipient was mixed with 1.0 part by mass of magnesium stearate, and tableting was performed under the same conditions as in Example 25.
得られた錠剤の物性を試験したところ、錠剤硬度は 93Nであり、崩壊時間は 108秒 であった。対照（比較例 21)としてロケット (ROQUETTE)社製の噴霧乾燥法により 製造されて 、ると 、われる直接打錠用 D-マン-トール 200SDDを同じ条件で打錠し たところ、錠剤硬度は 76N、崩壊時間は 198秒であった。 When the physical properties of the obtained tablets were tested, the tablet hardness was 93 N and the disintegration time was 108 seconds. As a control (Comparative Example 21), manufactured by the spray drying method of Rocket (ROQUETTE) Co., Ltd. As a result, the tablet hardness was 76 N and the disintegration time was 198 seconds.
このように実施例 27で得られた錠剤の方が硬度は高ぐ崩壊時間は短力つた。よつ て、実施例 27の顆粒状の賦形剤は、いわゆる直接打錠用の賦形剤として優れている ことが示された。  Thus, the tablet obtained in Example 27 had a higher hardness and a shorter disintegration time. Therefore, it was shown that the granular excipient of Example 27 is excellent as an excipient for so-called direct compression.
[0112] [実施例 28〜33および比較例 22〜24] [0112] [Examples 28 to 33 and Comparative Examples 22 to 24]
医薬品有効成分として、あらかじめ目開き 75 μ mの篩 、で篩 、分けした解熱鎮痛 剤であるァセトァミノフェンの粉末 30質量部を用い、これに実施例 1で使用したものと 同じコメデンプン 20質量部と、乳糖 50質量部とを混合し、混合粉体を得た。  As an active pharmaceutical ingredient, 30 parts by mass of powder of acetaminophen, an antipyretic analgesic, sieved with a 75 μm sieve in advance, and the same rice starch as used in Example 1 was used. Part by mass and 50 parts by mass of lactose were mixed to obtain a mixed powder.
混合粉体 200gを乳鉢に入れ、水を加えて混練し、混練物を得た。この混練物を 50 0 mの篩いで篩い分け、 50°Cで 5時間乾燥し、さらに目開き 250 mの篩いを通し 、平均粒径が 138 mの顆粒を得た。得られた顆粒を 40°C、相対湿度 75%RHまた は 40°C、相対湿度 90%RHの恒温恒湿機に入れ、適当な時間が経過した後に取り 出し、各種の水分活性 (aw)を持つ試料を得た。  200 g of the mixed powder was put in a mortar, kneaded with water added to obtain a kneaded product. This kneaded product was sieved with a sieve of 500 m, dried at 50 ° C. for 5 hours, and passed through a sieve with an opening of 250 m to obtain granules having an average particle diameter of 138 m. The obtained granules are placed in a thermo-hygrostat at 40 ° C, relative humidity 75% RH or 40 ° C, relative humidity 90% RH, and taken out after an appropriate time. Various water activities (aw) A sample with was obtained.
このように調湿された試料 99. 5質量部とステアリン酸マグネシウム 0. 5質量部を混 合し、これを、油圧プレス式成形器を用い、圧縮圧 10kNの条件で圧縮成形する直 接打錠法により、直径 10mm、 1錠剤当たり 400mgの錠剤を得た。得られた錠剤の 水分活性および錠剤の硬度を表 16に示した。  Mixing 99.5 parts by mass of the sample thus conditioned with 0.5 part by mass of magnesium stearate, and then directly compressing it using a hydraulic press molding machine under a compression pressure of 10 kN. Tablets with a diameter of 10 mm and 400 mg per tablet were obtained by the tablet method. Table 16 shows the water activity and hardness of the obtained tablets.
[0113] [表 16] [0113] [Table 16]
Figure imgf000038_0001
表 16から明らかなように、水分活性 (aw)が 0. 4未満では、得られる錠剤の硬度が 著しく低ぐ実用は困難と考えられた。また、比較例 22で得られた水分活性 (aw) 0. 83の試料はしつとり感があり、流動性を欠くものであった。
Figure imgf000038_0001
As is clear from Table 16, it was considered difficult to use practically when the water activity (aw) was less than 0.4, the hardness of the resulting tablet was extremely low. Further, the sample of water activity (aw) 0.83 obtained in Comparative Example 22 had a feeling of stickiness and lacked fluidity.
これらの結果から、製造方法 (3)において顆粒を調湿する際には、水分活性 (aw) が 0. 4〜0. 8の範囲とすることが適切であると示唆された。 [0115] [実施例 34] From these results, it was suggested that the water activity (aw) should be in the range of 0.4 to 0.8 when conditioning the granules in the production method (3). [0115] [Example 34]
健康食品に用いられるラタトフエリン 20質量部と、粉末状結合剤として、実施例 24と 表 13に記載されたァセチル化モチゴメコメデンプン 20質量部と、造粒乳糖 (フロイン ト産業 (株)製、商品名 ダイラクトーズ -S) 55質量部と、カルメロースカルシウム 2質 量部と、ショ糖脂肪酸エステル 3質量部との混合粉体を、実施例 1のロータリー打錠 機を用いて 75kNの打錠圧で打錠し、径 8mm、 1錠当たり 200mgの錠剤を得た。 この錠剤の硬度は 115Nであり、崩壊時間は 6分 20秒であり、実用可能な性質を備 えていた。  20 parts by weight of ratatoferrin used in health foods, 20 parts by weight of acetylated rice cake rice starch described in Example 24 and Table 13 as a powdered binder, and granulated lactose (produced by Freund Sangyo Co., Ltd. Name Dilactos -S) A mixed powder of 55 parts by mass, 2 parts by mass of carmellose calcium, and 3 parts by mass of sucrose fatty acid ester was compressed at a tableting pressure of 75 kN using the rotary tableting machine of Example 1. Tableting was performed to obtain tablets with a diameter of 8 mm and 200 mg per tablet. The tablet had a hardness of 115 N and a disintegration time of 6 minutes and 20 seconds.
[0116] [実施例 35〜36および比較例 25]  [0116] [Examples 35 to 36 and Comparative Example 25]
表 17に示す組成の混合粉体を打錠機で圧縮成形する直接打錠法で錠剤を製造 した。  Tablets were produced by the direct tableting method in which the mixed powder having the composition shown in Table 17 was compression-molded by a tableting machine.
実施例 35では、加熱処理をして ヽな 、実施例 1で使用したものと同じコメデンプン（ 水分含量 12. 2質量％)を粉末状結合剤として使用した。  In Example 35, the same rice starch (water content 12.2% by mass) as that used in Example 1 was used as a powdery binder after heat treatment.
実施例 36では、実施例 1で使用したものと同じコメデンプンを加熱処理した後、水 分含量を調整し、粉末状結合剤として使用した。具体的には、コメデンプン 4kgを流 動層造粒コーティング装置 (フロイント産業 (株)製、商品名：フローコーター FLO— 5 )に仕込み、吸気部温度 140°Cで 60分間流動させ、加熱処理を行った。ついで、吸 気部温度 30°Cで水をスプレーしながら、 60分間流動させる調湿操作を行い、水分含 量を調整した。なお、加熱処理においては、加熱温度に相当する流動層部分の温度 は、流動開始時には 67°Cであった力 12分後には 80°Cとなり、その後、徐々に上昇 して 60分後には 107°Cに達した。よって、加熱処理においては、 80°C以上の温度で 48分間維持されたこととなる。また、調湿操作では、合計 830mlの水をスプレーした 。こうして、加熱処理された後に調湿操作されたコメデンプンの水分含量は、 12. 4質 量％であった。  In Example 36, the same rice starch as used in Example 1 was heat-treated, and the water content was adjusted and used as a powder binder. Specifically, 4 kg of rice starch is charged into a fluidized bed granulation coating device (Freund Sangyo Co., Ltd., product name: Flow Coater FLO-5), fluidized for 60 minutes at an inlet temperature of 140 ° C, and heat-treated. Went. Next, the moisture content was adjusted by allowing the fluid to flow for 60 minutes while spraying water at the suction part temperature of 30 ° C. In the heat treatment, the temperature of the fluidized bed portion corresponding to the heating temperature becomes 80 ° C after 12 minutes of force, which was 67 ° C at the start of flow, and then gradually increases to 107 ° C after 60 minutes. ° C reached. Therefore, the heat treatment was maintained at a temperature of 80 ° C or higher for 48 minutes. In the humidity control operation, a total of 830 ml of water was sprayed. Thus, the moisture content of the rice starch that had been heat-treated and then conditioned was 12.4% by mass.
比較例 25では、比較例 1で使用したものと同じ結晶セルロースを用いた。 なお、 D—マン-トール造粒物としては、直接打錠用の賦形剤であるロケット (ROQ UETTE)社製、商品名： PEARLITOL 200SDを使用した。  In Comparative Example 25, the same crystalline cellulose as used in Comparative Example 1 was used. In addition, as D-Mann-Toll granulated product, the product name: PEARLITOL 200SD manufactured by Rocket (ROQ UETTE), which is an excipient for direct tableting, was used.
また、有効成分としては、抗ヒスタミン剤であるマレイン酸クロルフエ-ラミンを使用し た。 In addition, chlorfelamamine maleate, an antihistamine, is used as an active ingredient. It was.
各例での錠剤硬度、崩壊時間、錠剤の黄色度を表 18に示す。  Table 18 shows the tablet hardness, disintegration time, and tablet yellowness in each example.
[0117] [表 17] [0117] [Table 17]
Figure imgf000040_0001
Figure imgf000040_0001
[0118] 打錠条件は以下の通りである。 [0118] Tableting conditions are as follows.
打錠機:ロータリー打錠機  Tablet press: Rotary tablet press
打錠圧： 7kN  Tableting pressure: 7kN
錠剤：質量は 1錠当たり 200mg  Tablet: Mass is 200mg per tablet
[0119] [表 18] [0119] [Table 18]
Figure imgf000040_0002
Figure imgf000040_0002
[0120] 表 18から、実施例 36の錠剤の硬度が実施例 35の錠剤よりもやや高ぐ加熱処理 によりコメデンプンの成形性が向上することが示唆された。比較例 25の錠剤の硬度 は、実施例 35の錠剤と同程度であった。 [0120] From Table 18, it was suggested that the moldability of rice starch was improved by heat treatment in which the hardness of the tablet of Example 36 was slightly higher than that of the tablet of Example 35. The hardness of the tablet of Comparative Example 25 was almost the same as that of the tablet of Example 35.
錠剤の崩壊時間は、各例間であまり差がな力つた。これは、加熱処理したコメデン プンを使用すると、崩壊時間に影響を与えることなぐ錠剤硬度を高められることを示 している。  The disintegration time of the tablets was not very different between the cases. This indicates that the use of heat-treated rice starch can increase tablet hardness without affecting disintegration time.
また、各例で得られた錠剤をそれぞれガラス瓶に入れ、密栓をした状態で 50°Cの 恒温器に入れ、 4週間放置し、放置前後における錠剤表面の黄色度を比較したとこ ろ、結晶セルロースを含んだ比較例 25の錠剤で変化が大き力つた。これは、結晶セ ルロースの着色変化に由来すると考えられる。 In addition, each tablet obtained in each example was put in a glass bottle, sealed in a thermostat at 50 ° C, left for 4 weeks, and the yellowness of the tablet surface before and after being left was compared. The change was significant in the tablet of Comparative Example 25 containing This is a crystal cell It is thought to be derived from a change in the color of roulose.
産業上の利用可能性 Industrial applicability
(1)打錠機などを使用した圧縮成形法により錠剤を成形する場合において、錠剤硬 度を高くすることが望まれる場合などに、経時的な着色が少なく経時的安定性に優 れ、かつ滑沢剤に硬化油を使用した場合でも崩壊が遅くならず、実用可能な錠剤硬 度と崩壊速度を備えた錠剤を製造できる。 (1) When a tablet is formed by a compression molding method using a tableting machine, etc., when it is desired to increase the tablet hardness, the coloration with time is small and the stability over time is excellent. Even when hardened oil is used as a lubricant, disintegration is not slow, and tablets with practical tablet hardness and disintegration speed can be produced.
(2)乾式造粒法にぉ 、て、微粒子が少なく粒度が揃った顆粒を高収率で得ることが できる。し力も、得られる顆粒は経時的な着色が少ないなど経時的安定性にも優れて いる。また、得られる顆粒を用いることによって、実用可能な錠剤硬度と崩壊時間を 備え、経時的安定性に優れた錠剤を製造できる。  (2) By the dry granulation method, granules with few fine particles and uniform particle size can be obtained in high yield. In addition, the resulting granules are excellent in stability over time, such as little coloring over time. Further, by using the obtained granules, it is possible to produce tablets having practical tablet hardness and disintegration time and excellent in temporal stability.
(3)湿式顆粒圧縮法において、実用可能な錠剤硬度と崩壊時間を備え、経時的安 定性にも優れた錠剤を製造できる。  (3) In the wet granule compression method, a tablet having practical tablet hardness and disintegration time and excellent in stability over time can be produced.
(4)打錠機などを使用した圧縮成形法により錠剤を成形する場合において、経時的 安定性に優れ、粉末状結合剤を追加添加しなくても実用可能な錠剤硬度と崩壊速 度とを備える錠剤を製造できる。  (4) When a tablet is formed by a compression molding method using a tableting machine, etc., it has excellent stability over time and has a tablet hardness and disintegration rate that can be used without adding a powdery binder. A tablet can be produced.

Claims

請求の範囲 The scope of the claims
[I] 水分含量 6〜 14質量％のコメデンプンと水分含量 6〜 14質量％のコメデンプン誘 導体のうち少なくとも一方を粉末状結合剤として使用した圧縮成形法により、錠剤を 成形することを含む錠剤の製造方法。  [I] including tableting by a compression molding method using at least one of rice starch having a moisture content of 6 to 14% by mass and a rice starch derivative having a moisture content of 6 to 14% by mass as a powdery binder Tablet manufacturing method.
[2] 前記コメデンプンとコメデンプン誘導体のうち少なくとも一方の水分含量力 9〜14 質量％である請求項 1に記載された錠剤の製造方法。  [2] The method for producing a tablet according to claim 1, wherein the water content of at least one of the rice starch and the rice starch derivative is 9 to 14% by mass.
[3] 前記錠剤が、医薬品有効成分と食品用保健機能を有する成分のうち少なくとも一 方を含有する請求項 1に記載された錠剤の製造方法。 [3] The method for producing a tablet according to claim 1, wherein the tablet contains at least one of an active pharmaceutical ingredient and a component having a food health function.
[4] 前記錠剤中のコメデンプンとコメデンプン誘導体のうち少なくとも一方の含有量力[4] Content power of at least one of rice starch and rice starch derivative in the tablet
5質量％以上である請求項 1に記載された錠剤の製造方法。 The method for producing a tablet according to claim 1, which is 5% by mass or more.
[5] 前記コメデンプンとコメデンプン誘導体のうち少なくとも一方は、加熱処理されてか ら前記水分含量に調整されたものである請求項 1に記載された錠剤の製造方法。 5. The method for producing a tablet according to claim 1, wherein at least one of the rice starch and the rice starch derivative is adjusted to the water content after being heat-treated.
[6] 水分含量 6〜 14質量0 /0のコメデンプンと水分含量 6〜 14質量0 /0のコメデンプン誘 導体のうち少なくとも一方を粉末状結合剤として使用した乾式造粒法により、粉体を 造粒することを含む顆粒の製造方法。 [6] The dry granulation method using at least one as a powdery binding agent of rice starch derivative conductor rice starch and water content of the water content from 6 to 14 weight 0/0 6-14 mass 0/0, powder A method for producing granules, comprising granulating.
[7] 前記コメデンプンとコメデンプン誘導体のうち少なくとも一方の水分含量力 9〜14 質量％である請求項 6に記載された顆粒の製造方法。 [7] The method for producing granules according to [6], wherein the water content of at least one of the rice starch and the rice starch derivative is 9 to 14% by mass.
[8] 前記顆粒が、医薬品有効成分と食品用保健機能を有する成分のうち少なくとも一 方を含有する請求項 6に記載された顆粒の製造方法。 8. The method for producing a granule according to claim 6, wherein the granule contains at least one of an active pharmaceutical ingredient and a component having a food health function.
[9] 前記顆粒中のコメデンプンとコメデンプン誘導体のうち少なくとも一方の含有量力[9] Content power of at least one of rice starch and rice starch derivative in the granule
10質量％以上である請求項 6に記載された顆粒の製造方法。 The method for producing a granule according to claim 6, wherein the content is 10% by mass or more.
[10] 結晶セルロース、粉末セルロースまたは低置換度ヒドロキシプロピルセルロースの 粉末からなる群から選択される少なくとも 1種以上のセルロース系粉末状結合剤をさ らに使用する請求項 6に記載された顆粒の製造方法。 [10] The granule according to claim 6, wherein at least one cellulosic powdery binder selected from the group consisting of crystalline cellulose, powdered cellulose or low-substituted hydroxypropylcellulose powder is further used. Production method.
[II] 前記顆粒中の前記セルロース系粉末状結合剤の含有量が、 10〜30質量％である 請求項 10に記載の顆粒の製法。  [II] The method for producing a granule according to claim 10, wherein the content of the cellulosic powder binder in the granule is 10 to 30% by mass.
[12] D—マン-トールを賦形剤として使用する請求項 6に記載された顆粒の製造方法。  12. The method for producing a granule according to claim 6, wherein D-manntol is used as an excipient.
[13] 前記コメデンプンとコメデンプン誘導体のうち少なくとも一方は、加熱処理されてか ら前記水分含量に調整されたものである請求項 6に記載された顆粒の製造方法。 [13] Is at least one of the rice starch and the rice starch derivative heat-treated? 7. The method for producing granules according to claim 6, wherein the water content is adjusted.
[14] 請求項 6乃至 13のいずれか 1項に記載された顆粒の製造方法により製造された顆 粒。 [14] A condyle produced by the method for producing a granule according to any one of claims 6 to 13.
[15] 請求項 14に記載の顆粒を含有する錠剤。  [15] A tablet containing the granule according to claim 14.
[16] コメデンプンとコメデンプン誘導体のうち少なくとも一方を粉末状結合剤として使用 した湿式造粒法により粉体を造粒し、該造粒で得られた顆粒をその水分活性 (aw)が 0. 4〜0. 8になるように調湿してから、圧縮成形することを含む錠剤の製造方法。  [16] Powders are granulated by a wet granulation method using at least one of rice starch and rice starch derivatives as a powdery binder, and the granules obtained by the granulation have a water activity (aw) of 0. A method for producing a tablet comprising adjusting the humidity to 4 to 0.8 and then compression-molding.
[17] 前記錠剤が、医薬品有効成分と食品用保健機能を有する成分のうち少なくとも一 方を含有する請求項 16に記載された錠剤の製造方法。  17. The method for producing a tablet according to claim 16, wherein the tablet contains at least one of an active pharmaceutical ingredient and a component having a food health function.
[18] コメデンプンとコメデンプン誘導体のうち少なくとも一方を粉末状結合剤として使用 した湿式造粒法により粉末状の賦形剤を造粒し、該造粒で得られた顆粒状の賦形剤 をその水分活性 (aw)が 0. 4〜0. 8になるように調湿して力 他の粉体と混合し、圧 縮成形することを含む錠剤の製造方法。  [18] A granular excipient obtained by granulating a powdery excipient by a wet granulation method using at least one of rice starch and a rice starch derivative as a powdery binder. A method for producing a tablet, comprising adjusting the water activity (aw) of water to 0.4 to 0.8 and mixing the mixture with other powders and compression molding.
[19] 前記錠剤が、医薬品有効成分と食品用保健機能を有する成分のうち少なくとも一 方を含有する請求項 18に記載された錠剤の製造方法。  19. The method for producing a tablet according to claim 18, wherein the tablet contains at least one of an active pharmaceutical ingredient and a component having a food health function.
[20] 請求項 1乃至 5のいずれか 1項に記載された錠剤の製造方法により製造された錠剤  [20] A tablet produced by the method for producing a tablet according to any one of claims 1 to 5.
[21] 請求項 16又は 17に記載された錠剤の製造方法により製造された錠剤。 [21] A tablet produced by the method for producing a tablet according to claim 16 or 17.
[22] 請求項 18又は 19に記載された錠剤の製造方法により製造された錠剤。 [22] A tablet produced by the method for producing a tablet according to claim 18 or 19.
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