JP2006176496A - Solid agent and process for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a solid agent having practical hardness and decay time and also having temporal stability. <P>SOLUTION: 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. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  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.
Among these methods, the wet granulation method is a method in which a liquid binder is added to the raw material powder and granulated. From the granulation mechanism, extrusion, flow, rolling, crushing, spraying, stirring, etc. There is a way.
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, then coarsely crushed with various crushers and further sieved to obtain the desired particle size. It is a method of obtaining a granulated product having a granule, ie, a granule. The dry granulation method does not require the use of a liquid wetting agent such as water or an organic solvent as described above, and does not require a heat drying step. Therefore, there is a possibility of alteration by the wetting agent or decomposition by the heat drying step. It is suitable for the production of granules containing active ingredients such as certain pharmaceutical active 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 step, and therefore does not require a drying facility, and has a merit that the production cost of granules is low because the amount of energy consumption is small.

In the production of granules by these methods, the raw material powder containing the active ingredient is commonly used as it is, or an excipient, a binder, a disintegrant, and other appropriate additives are added to this. The mixture is made into a granule by an appropriate method, and a granule having the same size as possible is obtained.
Regardless of whether the granules obtained in this way are produced by wet granulation or dry granulation, they can be used as granules or powders as pharmaceutical preparations or as granular foods. Or used for the production of tablets by a compression molding method using a tableting machine.

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.
Among these methods, the direct compression method is basically compression molding a raw material containing an active ingredient or the like as it is, or a raw material, an excipient, a powdery binder generally called a dry binder, a disintegrant, This is a method of compression-molding a mixture in which other appropriate additives are added and mixed uniformly. This method is a method of directly compressing powder without pretreatment, and is adopted when the powder has good compression moldability. Among these, a powder containing an active ingredient as a raw material for direct compression is used. A product obtained by processing a filler or an excipient in advance for improving moldability is also commercially available.
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 granule is produced by a wet granulation method, it is called a wet granule compression method, and when it is produced by a dry granulation method, it is called a dry granule compression method.

The direct tableting method is generally applied when the tablet to be produced contains an active ingredient that is unstable to water or heat, as in the dry granulation method described above, but the number of manufacturing steps is the smallest. There are economic advantages.
The dry granule compression method is a method in which the granules obtained by the dry granulation method as described above are used for tableting. Usually, there are problems in the fluidity and compression moldability of the powder to be molded, and direct compression is performed. 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 compression molding is easy, mass deviation of the resulting tablet is small, and content uniformity is good.

  Various additives are used in the production of these granules and tablets. Among them, the binder is an additive used to give a binding force to the raw material powder or a mixed powder containing the same and facilitate compression molding. In many cases, liquid binders such as starch paste, hydroxypropyl cellulose liquid, and polyvinylpyrrolidone liquid are used, but powdered ones are also used. Cellulose is widely used.

  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 explanation on granulation of the dry granule compression method on page A-65 of the same book, "Add excipients, powdered binder, ... as necessary to the medicine to make a mixture, and ..." 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, Two types of particles having an average particle size of 40 μm and 120 μm are commercially available ”. 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.

  As described above, there are binders that are used in a liquid state and those that are used in a powder form. As described in the literatures exemplified, the latter binder is used as “powder. Sometimes referred to as “binder” or “powdered binder”. In the present specification, binders used in powder form are collectively referred to as “powder binder”. That is, the “powder binder” is generally called “dry binder”, and is used in an operation without using a solvent such as a direct tableting method or a dry granulation method, or in a liquid state in a wet granulation method. Also included are binders that are added in powder form.

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 granule or tablet, or the mass of the finished granule or tablet is increased to some extent to handle or take it. It is an additive for facilitating the process. As the excipient, lactose is most commonly used, but starch, D-mannitol, sucrose and the like are also used. The excipient used in the direct tableting method is desired to be excellent in fluidity and compression moldability. For example, in the case of lactose listed in the Japanese Pharmacopoeia, general lactose is a manufacturing method. Those produced by different spray drying methods and those obtained by granulating lactose obtained by a general production method are used for this purpose (flowability, compression moldability).
Lactose products as excipients for direct compression 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 additive standards, there are “lactose granulated products” and “synthetic aluminum silicate / hydroxypropyl starch / crystalline cellulose” as component names. The former consists of hydroxypropylcellulose and lactose. In the direct tableting method, if the properties of the tablet such as hardness do not reach the target level even when excipients for direct tableting are used, a powdery binder is further used.

Patent Documents 1 to 3 use starch such as corn starch as an additive for tableting by a direct compression method or the like to improve disintegration, swallowability, compression characteristics, and the like. Is disclosed.
JP-A-8-208523 International Publication No. 00/47233 Pamphlet JP 2002-12559 A

As described above, the powdered binder is used when producing tablets and granules, and powdered crystalline cellulose that is not soluble in water or an organic solvent is generally used.
However, crystalline cellulose is excellent in terms of binding properties, but has a property of gradually coloring to a tan color during storage. Therefore, a coloring change may be recognized with the naked eye on tablets containing a large amount of crystalline cellulose. Further, due to the interaction, the decomposition of the active ingredient is promoted and the coloring of the preparation is promoted.
For example, by Yoshioka Sumie: Stability of Pharmaceuticals, page 62, Nankodo (1995), compared the hydrolysis of flomoxef in the presence of cellulose and corn starch. While corn starch is faster, the relationship between the increase in moisture and the rate of degradation is slower, and data shows that corn starch degrades slower at the same moisture. Also, on page 120 of the same book, the description “The interaction between many drugs and additives such as the interaction with crystalline cellulose, which is the cause of the decrease in the stability of enalapril maleate, has been studied by thermal analysis.” Is seen. Thus, crystalline cellulose has a problem in terms of stability.

  In general, 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 the drug additive and the drug, etc., substitute for the additive. Another additive that can be selected is selected. However, there has been no other powdery binder having a binding property comparable to that of crystalline cellulose.

Furthermore, the conventional methods for producing granules and tablets have the following problems.
(1) When a tablet is formed by a compression molding method using a tableting machine, etc., when crystalline cellulose is used as a powdery binder and hardened oil is used as a lubricant, it is affected by the crystalline cellulose. Tablet disintegration is significantly slowed down. In other cases, tablets with practical disintegration time and tablet hardness may not be obtained.

(2) The dry granulation method is easy and simple as described above, and the production cost is low. However, fine particles are easily generated in the crushing process using a crusher or the like, and granules having a uniform particle size are obtained in a high yield. There was a problem that it was not possible. Moreover, in order to tablet the obtained granule and to obtain a tablet with good tablet physical properties, the physical properties of the granule are greatly involved. Generally, 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 dry granulation, a large amount of fine particles are generated at that time, so that granules with uniform particle sizes can be obtained in high yield. it has been very difficult to use the granules were stably obtain tablets sufficient hardness degree. In addition, when hydroxypropylcellulose, which is widely used as a binder in the wet granulation method, is used as a powdery binder in the dry granulation method, there has been a problem that the disintegration time of the tablet becomes remarkably long.
On the other hand, lactose widely used as an excipient may cause a Maillard reaction with a compound having an amino group. Maillard reaction is defined as a reaction that occurs between amino groups of amino acids, peptides, and proteins and hydroxyl groups having the ability to form glycosides of sugars, and is an excipient containing a compound having amino groups and lactose In the case of granules and tablets containing both of them, there is a problem that they are colored brown over time due to the Maillard reaction. Therefore, D-mannitol known as an excipient that does not cause such a Maillard reaction may be used. However, because D-mannitol has low moldability, when D-mannitol is used as an excipient, the yield of granules tends to decrease and it is difficult to obtain tablets with practical hardness. There was a problem. Thus, it has been difficult to achieve both moldability and color stability over time in the production of granules and tablets containing an active ingredient having an amino group by applying a dry granulation method. Met.

(3) The wet granulation method in which powder is granulated by a wet granulation method, the resulting granule is compression-molded with a tableting machine, etc., and the tablet is molded is insufficient in hardness and disintegration time of the resulting tablet There was a case. In addition, it is conceivable to use crystalline cellulose in order to develop sufficient hardness, but in that case, there is a problem regarding the stability of crystalline cellulose as described above.

(4) When a tablet is formed by a compression molding method using a tableting machine or the like, an excipient is often used, and as described above, many products are commercially available. Yes. However, when they are used, when the amount of the active ingredient in the tablet is high, the hardness of the resulting tablet is insufficient, and it is often necessary to use a powdery binder. In this case as well, it is conceivable to use crystalline cellulose as a powdery binder, but crystalline cellulose has the above-mentioned problems relating to stability.

This invention is made | formed in view of the said situation, and makes it a subject to improve the above-mentioned problem at the time of manufacturing a tablet and a granule. More specifically, it is as follows.
(1) When a tablet is formed by a compression molding method using a tableting machine or the like, the coloration with time is small, the stability with time is excellent, and even when a hardened oil is used as a lubricant, disintegration is slow. In addition, the present invention provides a tablet production method having practical tablet hardness and disintegration speed.
(2) In the dry granulation method, a granule having a small number of fine particles and the like and having a uniform particle size can be obtained in a high yield, and the obtained granule has little coloration with time and has excellent temporal stability. And a method for producing granules capable of producing tablets having practical tablet hardness and disintegration time and excellent in stability over time.
(3) To provide a method capable of producing a tablet having practical tablet hardness and disintegration time and excellent in temporal stability in the wet granule compression method.
(4) When a tablet is formed by a compression molding method using a tableting machine or the like, it has excellent temporal stability and has a tablet hardness and a disintegration rate that can be practically used without adding a powdery binder. A method for producing a tablet is provided.

As a result of intensive studies to solve such problems, the present inventors have found that it is useful to use rice starch and / or rice starch derivatives as powder binders in the production of tablets and granules. I found it. That is,
(1) The tablet production method of the present invention is characterized in that a tablet is formed by a compression molding method using rice starch and / or rice starch derivatives having a water content of 6 to 14% by mass as a powdery binder. .
The water content of the rice starch and / or rice starch derivative is preferably 9 to 14% by mass.
The tablet preferably contains an active pharmaceutical ingredient and / or a food health functional ingredient.
The content of rice starch and / or rice starch derivative in the tablet is preferably 5% by mass or more.
It is preferable that the rice starch and / or rice starch derivative is adjusted to the water content after being heat-treated.

(2) The granule production method of the present invention comprises granulating a powder by a dry granulation method using rice starch and / or rice starch derivatives having a water content of 6 to 14% by mass as a powdery binder. Features.
The water content of the rice starch and / or rice starch derivative is preferably 9 to 14% by mass.
The granule preferably contains an active pharmaceutical ingredient and / or a health functional ingredient for food.
The content of rice starch and / or rice starch derivative in the granules is preferably 10% by mass or more.
It is preferable to further use at least one cellulose-based powdery binder selected from the group consisting of crystalline cellulose, powdered cellulose or low-substituted hydroxypropylcellulose powder.
The content of the cellulose powder binder in the granules is preferably 10 to 30% by mass.
It is preferred to use D-mannitol as an excipient.
It is preferable that the rice starch and / or rice starch derivative is adjusted to the water content after being heat-treated.
The granule of the present invention is produced by the production method.
Moreover, the tablet of this invention contains the said granule, It is characterized by the above-mentioned.

(3) The method for producing a tablet of the present invention comprises granulating a powder by a wet granulation method using rice starch and / or rice starch derivatives as a powdery binder, and then obtaining the granule obtained by the granulation. It is characterized by compressing after adjusting the moisture activity (aw) to 0.4 to 0.8.
The tablet preferably contains an active pharmaceutical ingredient and / or a food health functional ingredient.

(4) The tablet production method of the present invention is obtained by granulating a powdery excipient by a wet granulation method using rice starch and / or rice starch derivatives as a powdery binder, and obtained by the granulation. The granular excipient is conditioned so that its water activity (aw) is 0.4 to 0.8, and then mixed with other powders, followed by compression molding.
The tablet preferably contains an active pharmaceutical ingredient and / or a food health functional ingredient.

  The tablet of the present invention is manufactured by any one of the tablet manufacturing methods.

According to the present invention, the characteristics of rice starch and / or rice starch derivatives (excellent binding properties and low interaction with active ingredients) are exhibited to the fullest. Specifically, the following effects are obtained. It is done.
(1) When a tablet is formed by a compression molding method using a tableting machine or the like, when it is desired to increase tablet hardness, there is little coloring over time and excellent stability over time, and lubrication. Even when hardened oil is used as the agent, disintegration does not slow, and tablets with practical tablet hardness and disintegration speed can be produced.
(2) In the dry granulation method, granules having a small number of fine particles and a uniform particle size can be obtained in a high yield. Moreover, the resulting granules are excellent in temporal stability, such as little coloring over time. In addition, by using the obtained granules, it is possible to produce tablets having practical tablet hardness and disintegration time and excellent in stability over time.
(3) In the wet granule compression method, a tablet having a practical tablet hardness and disintegration time and excellent in temporal stability can be produced.
(4) When a tablet is formed by a compression molding method using a tableting machine or the like, it has excellent temporal stability and has a tablet hardness and disintegration rate that can be practically used without adding a powdery binder. Tablets can be manufactured.

Hereinafter, the present invention will be described in detail.
The present invention is characterized in that rice starch and / or rice starch derivatives are used as a powdery binder in the production of tablets and granules which are solid agents. Specifically, the following method is used. It is composed. That is,
(1) A method for producing a tablet in which a tablet is formed by using rice starch and / or rice starch derivatives as a powder binder during compression molding using a tableting machine, etc. Rice starch and / or rice starch derivatives having a water content of 6 to 14% by weight, preferably 9 to 14% by weight, are used as the binder. Hereinafter, this manufacturing method may be referred to as a manufacturing method (1).
(2) A method for producing granules in which a powder is granulated by a dry granulation method, in which a rice starch having a water content of 6 to 14% by mass, preferably 9 to 14% by mass, is used as a powdery binder. And / or rice starch derivatives are used. Hereinafter, this manufacturing method may be referred to as a manufacturing method (2).
(3) A tablet manufacturing method in which a powder is compressed by a wet granule compression method, wherein the powder is granulated by a wet granulation method using rice starch and / or rice starch derivatives as a powdery binder. Granules are obtained, the granules are conditioned so that their water activity (aw) is 0.4 to 0.8, and then compressed. Hereinafter, this manufacturing method may be referred to as a manufacturing method (3).
(4) When producing a tablet by compression molding using a tableting machine, the following are used as excipients. That is, rice starch and / or rice starch derivatives are added to a powdery excipient as a powdery binder, granulated by a wet granulation method, and the water activity (aw) is 0.4 to 0. 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).

In the production method (1) and the production method (2) of the present invention, rice starch and / or rice starch having a water content of 6 to 14% by mass, preferably 9 to 14% by mass, as a powdery binder at that time Derivatives are used.
The water content of rice starch and / or rice starch derivatives is determined by the compression moldability when powder is compressed, the compression moldability when granules and tablets are produced from the powder, and also when tablets are formed from granules. If the moisture content is less than 6% by mass, sufficient moldability will not be exhibited, and in the case of producing granules, a granule with few fine particles and a uniform particle size is used. In addition to being difficult to obtain in a high yield, when a tablet is formed from the obtained granule, it tends to be difficult to obtain a product with sufficient hardness. On the other hand, when the content exceeds 14% by mass, the flowability of rice starch and / or rice starch derivatives is reduced, and this impairs operability in compression molding methods and dry granulation methods using a tableting machine (rice starch). And / or when the mixed powder mixed with rice starch derivative does not flow out of the hopper, causes tableting troubles such as sticking during tableting, adheres to the walls of various devices, etc.) and the growth of microorganisms There may be concerns.

On the other hand, in the case of the wet granulation method of the production method (3), rice starch and / or rice starch derivatives are added to the powder as a powder binder, granulated, and the water content of the resulting granule is determined as its water activity. Compression molding is performed after adjusting the humidity so that (aw) is 0.4 to 0.8.
That is, in a conventional general wet granule compression method, granulated granules are dried in a drying step and then granulated using rice starch and / or rice starch derivatives as a powder binder for compression molding. However, it is considered that the moisture content of the rice starch and / or rice starch derivative in the granule decreases in the drying step, and as a result, the compression moldability of the resulting granule decreases. Thus, even if a granule with low compression moldability is used, it is difficult to obtain a tablet with sufficient hardness. 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.

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 the container that has reached an equilibrium state by 100 when the sample is sealed in the container. For example, the product name “EZ-100” manufactured by Freund Sangyo Co., Ltd. It is measured by using a commercially available water activity measuring apparatus such as “
When the powder is compression-molded by the production method (3), the granule is preferably conditioned so that its water activity (aw) is 0.4 to 0.8. If the water activity (aw) is less than 0.4, sufficient moldability is not expressed, while if it exceeds 0.8, the fluidity of the granules decreases, and the powder does not flow out of the hopper during tableting. There are concerns such as causing tableting problems such as sticking during tableting.
From the same viewpoint, also in the case of the production method (4), the excipient formed into a granular shape is conditioned so that its water activity (aw) is 0.4 to 0.8. Good.

The Japanese Pharmacopoeia includes four items related to starch: wheat starch, rice starch, corn starch, and potato starch. is there. However, in the case of products distributed in the market, due to differences in drying and heat treatment conditions during production, actual numerical values vary greatly even within these standard ranges. For example, when heat treatment is performed to reduce miscellaneous bacteria in starch, the water content may be reduced to 1% by mass or less.
Therefore, in the present invention, in the production methods (1) and (2), commercially available rice starch and / or rice starch derivatives are appropriately selected as necessary so that the water content is in the range of 6 to 14% by mass. Use with moisture adjusted.

  In this case, it is preferable to adjust the water content of the rice starch and / or rice starch derivative after performing a heat treatment at a temperature of 75 ° C. or higher for at least 30 minutes. 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 present inventors have found that the moldability of the resulting rice starch and / or 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 considered that such treatment changes the particle structure of at least some of rice starch and / or rice starch derivatives, and as a result, the binding force is improved.

  When reducing the water content of rice starch and / or rice starch derivatives, it may be dried by a conventional method. When increasing the water content, water is added to the rice starch while stirring in a mixing / stirring device. The target moisture range may be reached by a method of spraying water, a method of supplying conditioned air to rice starch and / or rice starch derivatives, and the like.

  In the production methods (3) and (4), commercially available rice starch and / or rice starch derivatives may be used as they are, and there is no need to adjust moisture in advance. The water content of rice starch and / or rice starch derivatives is determined by weight loss when dried at a temperature of 105 ° C. for 6 hours in accordance with the Japanese Pharmacopoeia (14th revision) “Dehydration Loss Test Method”.

The rice starch used here is manufactured from uruchi rice and mochigome, and various manufacturing methods are known, but it is compatible with each article of rice starch such as Japanese Pharmacopoeia or European Pharmacopoeia. Any manufacturing method may be used as long as it is.
Examples of the rice starch derivative include derivatives such as esterified starch, etherified starch, and oxidized starch. Specific examples of esterified starch and etherified starch include rice starch acetate, phosphate monoester, phosphate crosslink (phosphate diester), octenyl succinate, acetic acid adipate crosslink, hydroxyethyl ether, hydroxypropyl ether, Examples thereof include carboxymethyl ether. 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.

  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 Manual, page 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. The difference between rice starch and other starches is that the 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, and 4 for rice starch, corn starch, wheat starch and potato starch, respectively. There are descriptions of 8 μm, 12.2 μm, 16.9 μm, and 32.2 μm. Rice starch and / or rice starch derivatives thus have a very small particle size compared to other starches, so that the contact area between the particles is large. Such an increase in the contact area contributes to the improvement of the binding property as a powdery binder, so that rice starch and / or rice starch derivatives are suitably used in the production methods (1) to (4). I can guess.

In said manufacturing method (1)-(4), what contains a pharmaceutical active ingredient and / or a food health functional ingredient can be used suitably as a raw material, As a result, the granule and tablet containing this ingredient are obtained. .
There are no particular restrictions on active pharmaceutical ingredients, but hypnosis / analgesics, antipyretic analgesics, antipsychotics, autonomic agents, antiparkinsonians, antihistamines, cardiotonic, diuretics, antihypertensives, vasoconstrictors, Arteriosclerotic agents, antitussive expectorants, vitamins, nourishing tonics, antibiotics, gastrointestinal drugs and the like.
Health functional ingredients for food that affect the physiological functions of the body and are used in foods, for example, nutrients such as vitamins, minerals, herbs, proteins, fatty acids, dietary fiber, etc. , Plant foods such as Korean carrots, animal foods such as propolis, fungi such as bifidobacteria, and coenzyme Q10, etc. Listed substances are listed.

  In the production methods (1) to (4), various other additives can be used, and powdery binders (generally called dry binders) other than rice starch and / or rice starch derivatives, excipients , Disintegrating agents, 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.

  Lubricants work to prevent uniform powder form and additives from containing active ingredients during compression molding with a tableting machine, etc., and to obtain uniform compression moldability. is there. Moreover, in the dry granulation method, it functions 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 is the property of the lubricant, the raw material powder, and the mixed powder obtained by adding various additives to the lubricant in any of the production methods (1) to (4). Although it is different and not uniform, the range of 0.1 to 10% by mass in tablets and granules is common.

  Disintegrants work to disintegrate granules and tablets in water or gastrointestinal fluids, and are common disintegrations such as carmellose calcium, croscarmellose sodium, sodium carboxymethyl starch, hydroxypropyl starch, etc. In addition to the agent, excipients such as lactose, D-mannitol and sucrose can be used.

  Furthermore, the tablets obtained by 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 a food health function. Film coating may be further performed for the purpose of masking unpleasant taste derived from the components, improving stability, and making the appearance beautiful.

Next, about each manufacturing method (1)-(4), the method is explained in full detail separately.
[Production Method (1)]
The production method (1) belongs to a method generally referred to as a direct tableting method, and rice starch and / or rice starch is used as a powdery binder when compression-molding by tableting or the like to form a tablet. Derivatives are used. In this production method (1), first, raw materials containing active ingredients such as active pharmaceutical ingredients and / or health functional ingredients for food, rice starch and / or rice starch derivatives as a powdered binder, A mixed powder is prepared by mixing various additives added accordingly. Here, the raw material may be in the form of powder, or may be subjected to preliminary processing such as a granular material generally marketed as a direct tableting raw material.
Since the formability of the raw material varies depending on the type and amount of the active ingredient contained in the raw material, the amount of rice starch and / or rice starch derivative to be used may be appropriately adjusted according to these, but it functions as a binder. From the viewpoint of ensuring, 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. If it exceeds 30% by mass, rice starch and / or rice starch derivatives have low fluidity, so that the fluidity of the mixed powder is also insufficient. 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 needed include powdery binders other than rice starch and / or rice starch derivatives, excipients for direct compression, disintegrants, lubricants, and the like.

Subsequently, the obtained mixed powder is compression-molded using a tableting machine having a mortar and a punch, such as a single-punch tableting machine or a rotary tableting machine, to obtain tablets.
When rice starch and / or rice starch derivatives are mixed with raw materials and additives, they may be mixed in advance with some of the raw materials and additives in order to make the resulting mixed powder uniform. Alternatively, sieving may be performed using a sieve having an appropriate opening. Moreover, there is no restriction | limiting in the shape of the tablet obtained, but if a cross section is circular, a diameter is 6-10 mm and the mass per tablet is about 100-500 mg is practical. In addition, the pressure (compression pressure) suitable for tableting in this case is preferably about 15 kN or less. By setting the amount of rice starch and / or rice starch derivative in the mixed powder as described above, the amount of rice starch and / or rice starch derivative in the obtained tablet is also 5% by mass or more, 5 to 30%, respectively. It becomes mass%.

  According to such production method (1), since tablets are produced by a compression molding method using rice starch and / or rice starch derivatives having a specific water content as a powdery binder, there are sufficient practical tablets. A tablet with good disintegration time is obtained that has hardness and does not slow down disintegration even when hardened oil is used as the lubricant. Moreover, the obtained tablet is excellent in the temporal stability in terms of color.

[Production method (2)]
As a specific method for granulating powder by dry granulation using rice starch and / or rice starch derivative as a powder binder, first, for example, active pharmaceutical ingredients and / or food Powder mixture of raw material containing active ingredients such as health functional ingredients, rice starch and / or rice starch derivatives as powder binder, and various additives added as necessary To prepare.
Since the formability of the raw material powder varies depending on the type and amount of the active ingredient contained in the raw material powder, the amount of rice starch and / or rice starch derivative to be used may be adjusted as appropriate according to these. From the viewpoint of ensuring the function as a binder, the content in the mixed powder is preferably 10% by mass or more, more preferably 10 to 90% by mass, and still more preferably 15 to 50% by mass. By setting the amount of rice starch and / or rice starch derivative in the mixed powder in this way, the amount of rice starch and / or rice starch derivative in the resulting granule is also 10% by mass or more and 10 to 90% by mass, respectively. %, 15 to 50% by mass.

  Next, 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 (roll compression molding conditions) are such that the compression molding rate is 60 to 95%. Next, by carrying out a crushing step of passing this plate-shaped molded product through a multi-stage roll crusher or various granulators so as to obtain the desired particle size, for example, the particle size is finer than 1700 μm and the bulk density is 0. .4 to 0.8 g / mL of granules are obtained.

  The obtained granule can be used as it is as a granule or can be used for compression molding using a tableting machine. If necessary, it can be sieved to have an appropriate particle size distribution. Moreover, when it is desired to reduce the amount of water contained in the obtained granule, it may be subsequently dried by a known method.

The compression molding rate is also called flake rate and is determined by the following measurement method.
<Method for measuring compression molding ratio>
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 a processing amount (Ag) for 1 minute.
2. The plate-like molded product and fine powder (Ag) obtained in 1 above are put in a sieve having an opening of 1000 μm, and a 1000 μm pass product is removed. The mass of the plate-like molded product remaining on the sieve having an opening of 1000 μm is defined as Bg.
3. The compression molding rate (flake rate) is calculated by the following formula.
Flakes rate (%) = (B / A) × 100

  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. The resulting mixture is compressed using a tableting machine having a mortar and a punch, such as a single tableting machine or a rotary tableting machine, at a pressure suitable for the tableting machine to be used and the size of the tablet. Molding may be performed. At this time, the shape of the tablet is not limited, but if the cross section is circular, the diameter is 6 to 10 mm, and the mass per tablet is about 100 to 500 mg. In addition, the pressure (compression pressure) suitable for tableting in this case is preferably about 15 kN or less.

The use of rice starch and / or rice starch derivatives with a specific water content as a powdery binder in this way greatly increases the compression moldability of the powder during granulation. And a granule having a uniform particle size can be obtained in a high yield. Furthermore, the tablet obtained by molding the granule thus produced has a practical tablet hardness, disintegration time, and temporal stability in terms of color.
In addition, granules containing rice starch and / or rice starch derivatives as a powder binder and tablets obtained from the granules may be combined with powder even when the content of rice starch and / or rice starch derivatives is high. Since there is little change in characteristics as in the case of using a large amount of crystalline cellulose as an agent, it is excellent in stability over time without being colored during storage.

  Furthermore, when producing granules containing an active ingredient having an amino group, even when D-mannitol having insufficient moldability is used as an excipient to avoid the Maillard reaction accompanied by brown coloring, a powdered binder By using rice starch and / or rice starch derivatives as moldability, the moldability is improved and granules with uniform particle size can be obtained in high yield, and the effect of improving moldability and avoiding Maillard reaction to suppress discoloration It is possible to achieve a balance with the effect.

  In addition, when tablets are produced from the granules obtained by using rice starch and / or rice starch derivatives having a specific water content in this way, the tablets are increased as the content of rice starch and / or rice starch derivatives increases. Hardness increases, but at the same time the disintegration time tends to be longer. In that case, together with rice starch and / or rice starch derivative as powder binder, one or more cellulose-based powder binder selected from crystalline cellulose, powdered cellulose or low substituted hydroxypropyl cellulose powder is used in combination By doing so, the disintegration time can be shortened. Further, 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, a tablet having high tablet hardness and moderately improved disintegration time can be obtained by using a cellulose-based powder binder together with rice starch and / or rice starch derivatives as a powder binder.

Further, when producing granules containing an active ingredient having an amino group, when D-mannitol is used as an excipient in order to avoid Maillard reaction, as described above, rice starch and / or rice starch as a powdery binder By using a derivative, moldability is improved. At that time, in addition to rice starch and / or rice starch derivative powder, a cellulose-based powder binder is used as a powdery binder. Can be obtained in a high yield. Moreover, the tablet of the outstanding tablet hardness and disintegration time can be obtained by shape | molding the obtained granule.
In addition, such a cellulose powder binder is 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-based powder binder used is preferably in the range of 10 to 30% by mass in the granule. When the amount exceeds 30% by mass, a change with time such as a change in the color of the resulting granule may occur.

According to such production method (2), by using rice starch and / or rice starch derivatives having a specific water content as a powdery binder, it is usually easy to produce fine particles, and granules having a uniform particle size are increased. In the dry granulation method, which is difficult to obtain in a yield, granules having a small number of fine particles and a uniform particle size can be obtained in a high yield. Furthermore, by using the obtained granule as a tableting granule, it is possible to obtain a tablet that exhibits practically sufficient tablet hardness, which has been difficult to obtain in the past, and has good temporal stability such as disintegration time and color. be able to. 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 both moldability and color stability over time are compatible. it can.
Conventionally, corn starch is widely used as an additive component as starch, but corn starch is not used as a binder because of its insufficient binding properties, and it is used as an excipient by mixing with lactose etc. It was always done. And when manufacturing a granule by a dry granulation method, it was forced to add another powdery binder. However, unlike corn starch, rice starch and / or rice starch derivatives are remarkably excellent in binding properties by controlling the water content within a specific range and can be used alone as a powdery binder.

[Production method (3)]
In the production method (3), first, a raw material powder containing an active ingredient such as a pharmaceutical active ingredient and / or a food health functional ingredient, rice starch and / or rice starch derivative, and if necessary, lactose Additive ingredients such as sucrose, D-mannitol, rice starch and / or starches such as corn starch other than rice starch derivatives, excipients such as starch derivatives such as hydroxypropyl starch, and disintegrants such as carmellose calcium To make a mixed powder.

Next, granulation is performed by a known wet granulation method. Examples of the wet granulation method include a crushing granulation method, an agitation granulation method, a fluidized bed granulation method, a centrifugal tumbling granulation method, and a centrifugal tumbling fluidized bed granulation method.
For example, in the case of the crushing type granulation method, a liquid binder is added to the mixed powder, a soft lump having an appropriate size is made with a granulator, and dried with a dryer to obtain granules. At this time, large granules are crushed. In addition, known wet granulation methods such as agitation granulation method, fluidized bed granulation method, centrifugal tumbling granulation method, and centrifugal tumbling fluidized bed granulation method may be applied.
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 solution in which a binder component such as hydroxypropylcellulose or polyvinylpyrrolidone is dissolved in these solvents. Is used.

  Subsequently, the obtained granules are conditioned so that their water activity (aw) is 0.4 to 0.8. That is, as described above, in the conventional general wet granule compression method, granulated granules are dried in the drying step, so even if rice starch and / or rice starch derivatives are used as a powder binder, It is considered that the water content of rice starch and / or rice starch derivatives in the granules decreases, and as a result, the compression moldability and binding properties of the granules decrease. Therefore, in order to ensure these performances, it is considered important to adjust the moisture content of the granules by humidity conditioning before compression molding.

As a 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, and is mixed in a mixing / stirring device or a fluidized bed and stirred or fluidized while being mixed with water. There are methods of spraying or supplying conditioned air. In order to obtain a desirable moisture through conditioning, the water activity (aw) is preferably controlled to be 0.4 to 0.8. The water activity is measured by a commercially available water activity measuring device such as a product name “EZ-100” manufactured by Freund Sangyo Co., Ltd.
If the water activity is less than 0.4, the tablet obtained by compression molding does not have sufficient hardness, and if it exceeds 0.8, the fluidity of the granules decreases, and tableting troubles such as sticking during tableting occur. There are problems such as waking up.
In order to increase the hardness of the resulting tablet to a practical level, to control the mass deviation of the tablet within a desired range, and to increase the uniformity of the tablet content, It is preferable to adjust the particle size to a specific range, and for that purpose, it is preferable to carry out a sieving step of sieving the granules before and after humidity control to make the average particle size 50 to 300 μm.

As in the case of production method (1), additives generally used in tablet production, such as lubricants and disintegrants added as necessary, are added to the granules thus conditioned. After that, it is compression-molded 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. A preferable tablet size and a preferable compression pressure are the same as those in the production method (1).
The appropriate addition amount of rice starch and / or rice starch derivative is preferably 5% by mass or more of the tablet. Although there is no restriction | limiting in particular in an upper limit, In the case of a common tablet, Preferably it is 50 mass% or less. If it is less than 5 mass%, the effect as a powdery binder tends to be insufficient. Moreover, when it exceeds 50 mass%, there exists a tendency for disintegration time to become long, and in the case of a common tablet, it becomes disadvantageous. However, this property is particularly suitable for the purpose of obtaining a sustained-release preparation, and it may be added in an amount exceeding 50% by mass. Further, a sustained-release base such as hydroxypropylmethylcellulose or hydroxypropylcellulose may be used. It can also be used in combination.

  According to such a production method (3), the water activity of the granules obtained by the wet granulation method is appropriately controlled and then compression molded. Therefore, high compression moldability is expressed, and a tablet having a practical tablet hardness and disintegration time can be produced without causing any tableting trouble. Moreover, the obtained tablet is excellent also in temporal stability, such as a color point.

[Production Method (4)]
This production method (4) is a method in which an excipient that has been molded in advance into granules is used as an excipient when a tablet is formed by a compression molding method. That is, a mixed powder containing known powdery excipients such as lactose, D-mannitol, sucrose and rice starch and / or rice starch derivatives is granulated by a wet granulation method, and the obtained granular form is obtained. A mixture of this material and an other powder containing the active ingredient is compression molded.
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 polyvinylpyrrolidone is used, the analysis of the composition will be difficult when analyzing the composition of the granules for quality control reasons. 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-mannitol, or sucrose is used as a powdery excipient, a method of using a solution obtained by dissolving the same in water as a binder is also preferable.

  For example, when a fluidized bed granulation method is employed as a wet granulation method, lactose or D-mannitol powder is added to a fluidized bed granulation coating apparatus (for example, Freund Sangyo Co., Ltd., trade name: Flow Coater). A mixed powder of rice starch and / or rice starch derivative is supplied, and fluid air is supplied in a container to float and flow the mixed powder, and the same substance as the charged lactose or D-mannitol powder is prepared as an aqueous solution. It can be granulated by spraying to obtain a granular excipient.

  The mixing ratio of the powdery excipient and rice starch and / or rice starch derivative in the wet granulation method is preferably 3 to 60 for rice starch and / or rice starch derivative in the obtained granular excipient. The ratio is mass%, more preferably 5 to 50 mass%. If the amount of rice starch and / or rice starch derivative is less than 3% by mass, the effect of improving moldability is insufficient, and if it exceeds 60% by mass, the resulting tablet may be slowly disintegrated.

Next, the obtained granules are conditioned by the same method as in the production method (3) so that the water activity (aw) is 0.4 to 0.8.
In order to increase the hardness of the resulting tablet to a practical level, to control the mass deviation of the tablet within a desired range, and to increase the uniformity of the tablet content, It is preferable to adjust the particle size to a specific range, and for that purpose, it is preferable to carry out a sieving step of sieving the granules before and after humidity control to make the average particle size 50 to 300 μm.

  Next, a granular excipient with a water activity (aw) of 0.4 to 0.8, another powder (raw material powder containing active ingredients), a lubricant, and as necessary The disintegrant added according to the manufacturing method (1) is mixed with additives generally used for the production of tablets similar to the production method (1), and the resulting mixture is compressed into a single tableting machine, rotary tableting machine, etc. Compress with a tablet to make tablets. A preferable tablet size and a preferable compression pressure are the same as those in the production method (1).

  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 is possible to use a tablet having a practical tablet hardness and disintegration time without adding a powdery binder. It can be manufactured without causing tableting problems. Moreover, the obtained tablet is excellent also in temporal stability, such as a color point.

Hereinafter, the present invention will be specifically described with reference to examples.
In addition, it shows below about a response | compatibility with the following Example and manufacturing method (1)-(4) mentioned above.
Examples 1 to 7, Examples 34 to 36: Production method (1)
Examples 8 to 24: Production method (2)
Examples 25 and 28 to 33: Production method (3)
Examples 26 and 27: Production method (4)

The physical properties of the granules and tablets were evaluated by the following methods.
Granule hardness: Using a hardness measuring instrument GRANO (manufactured by Okada Seiko Co., Ltd.), the load when the granule breaks under the measurement conditions of tip tip diameter 3 mmφ (tip tip shape: flat circle), load 200 g, measurement speed 100 μm / sec. Was measured with a load cell.
Tablet hardness: It was measured using a tablet hardness meter SCHLEUNIGER 6D (manufactured by Freund Corporation).
Tablet disintegration time: Measured according to the disintegration test method (test solution, water) of the Japanese Pharmacopoeia (14th revision).
Tablet whiteness and yellowness: A color difference meter SZ-Σ90 (manufactured by Nippon Denshoku Industries Co., Ltd.) was used, and the method for measuring the solid surface color was followed.
Color difference: Using a color difference meter SZ-Σ90 (manufactured by Nippon Denshoku Industries Co., Ltd.), the color difference ΔE ^* ab was measured based on L ^* a ^* b ^* color system in accordance with JIS Z-8729 and Z-8730. . In the measurement 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.
Water 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 water content.

[Example 1 and Comparative Examples 1 to 3]
Vitamin C is an active ingredient used as a health functional ingredient for foods in pharmaceuticals and health foods. A tablet containing 97% by mass of vitamin C, “BASF Takeda Co., Ltd., trade name: Vitamin C granule-97” sold as a direct tableting product and tableting test according to the formulation shown in Table 1 Went.
Rice starch having a water content of 12.2% by mass and corn starch having a water content of 12.4% by mass were used. As the crystalline cellulose, “Asahi Kasei Chemicals Co., Ltd., trade name: Theolas PH-101” was used. As the hardened oil, “Freund Sangyo Co., Ltd., trade name: Lovely Wax-101” was used.
Both Example 1 and Comparative Examples 1 to 3 were carried out for the purpose of comparing the performance of rice starch, which is a powdery binder, and crystalline cellulose, and comparing the performance of rice starch, which is a starch, and corn starch.
Specifically, out of 1 kg of the mixed powder having the composition shown in Table 1, components other than the hardened oil, which is a lubricant, are rotated 40 times per minute by a V-shaped mixer V-10 (Tokuju Seisakusho Co., Ltd.). 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. The measurement results are shown in Table 2.

The tableting conditions are as follows.
Tableting machine: Rotary tableting machine, HT-P15A-III type (manufactured by Hata Iron Works)
Tableting pressure: 10 kN, using an open feed shoe Tablet: Round tablet with a diameter of 8 mm and a curvature radius of 6.5 mm, the weight is 180 mg per tablet

Example 1 is based on the production method (1) and is an example of producing a tablet using rice starch and / or rice starch derivatives as a powder 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 in which crystalline cellulose was used as a powdery binder, but the tablet hardness was almost the same as Example 1, but the disintegration time was remarkably long, requiring 52 minutes. This is considered to be a result of the crystalline cellulose being specifically affected by the hardened oil used as a lubricant.
Comparative Example 3 is an example using corn starch as a powder binder, but the tablet hardness was remarkably inferior compared to the case of using rice starch.
Thus, the tablets according to Example 1 using rice starch and / or rice starch derivatives as powder binders showed the best overall properties. Comparative Example 2 was an example of tableting without adding a powdery binder, but the tablet hardness was as low as 53N, and the disintegration time was longer than that of the tablet of Example 1.

  Each tablet was placed in a glass bottle, placed in a constant temperature and humidity chamber at 40 ° C. and 75% relative humidity without a lid, and left for 4 weeks, and the whiteness of the mirror surface of the tablet before and after being left was measured. As a result, the whiteness before and after standing was compared with Examples 1: 98.4 and 90.8, Comparative Example 1: 97.9 and 84.3, Comparative Example 2: 96.6 and 89.3, respectively. Example 3: 98.1 and 90.1. The color change in the tablet of Comparative Example 1 containing crystalline cellulose as a component was the largest.

[Examples 2-7 and Comparative Examples 4-6]
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% to obtain rice starches having various water contents shown in Table 3. .
A mixed powder of 50 g 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, the mixed powder to which no hardened oil was added was mixed in a polyethylene bag so as to be sufficiently uniform, and then hardened oil was added and shaken for 30 seconds.
As a tableting test (model experiment) using these mixed powders, a flat tablet with a diameter of 20 mm and a weight of 2.0 g per tablet is molded using a hydraulic press molding machine under a compression pressure of 20 kN. Then, the hardness of the obtained tablets was measured. The test results are shown in Table 3.

In Comparative Example 4 using rice starch with a moisture content of 14.4% by mass, powder adhesion was observed on the mortar and punch of the tableting machine after molding, and it was necessary to remove it when molding next time. It was.
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, rice starch was not added, and a mixture of vitamin C granule-97: 100.0 parts by mass and hydrogenated oil: 3.0 parts by mass was similarly compression molded, and the hardness was 56 N. . When this result was collated, in Comparative Examples 5 and 6 using rice starch having a water content of 6% by mass, the tablet hardness was remarkably low, suggesting that rice starch did not act as a binder.

[Example 8 and Comparative Example 7]
In 2 kg of the mixed powder having the composition shown in Table 4, ingredients other than magnesium stearate are mixed for 20 minutes in accordance with the conditions of Example 1, then magnesium stearate is added and mixed for 5 minutes, and the mixed powder for granulation Got the body.
This mixed powder is compression molded at a pressure of 4 MPa (pressure cylinder / gauge pressure) by roll compression molding using a roller compactor TF-mini (manufactured by Freund Sangyo Co., Ltd.), and the obtained flake portion is sized with a screen. The mixture was coarsely crushed by a machine and further sized by a roll granulator to obtain granules for tableting.
Furthermore, using the obtained granules, tablets were molded under the same tableting conditions as in Example 1.

In accordance with the Japanese Pharmacopoeia (14th revision), the powder particle size measurement method, and the second method sieving method, the granules obtained by such dry granulation method are sieved using a sieve with a mesh size of 200 (75 μm). The fine particles that were separated and passed through the sieve were made into a 75 μm pass product. The content of the granulated sieve 75 μm pass product was 30% by mass in Comparative Example 7, whereas it was 25% by mass in Example 8.
Moreover, as a result of measuring the hardness of the obtained granules, the average value was 25 g in Comparative Example 7, whereas it was 45 g in Example 8.
Furthermore, as a result of testing the hardness of the obtained tablet 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, while 52 N in Example 8 And 185 seconds.
The composition of Comparative Example 7 consists 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.
From the above results, in Example 8, heavy granules having a low ratio of fine powder and high hardness could be obtained in high yield. Further, 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 9 and Comparative Example 8]
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 for the obtained granules. Furthermore, using these granules, tablets were formed under the same tableting conditions as in Example 8.

The content of the sieved 75 μm pass product of the granules obtained by such dry granulation method was 21% by mass in Comparative Example 8, whereas it was 17% by mass in Example 9. The granule hardness was 28 g in Comparative Example 8, whereas it was 44 g in Example 9. Regarding the hardness and disintegration time of the tablets, the average values were 42 N and 49 seconds in Comparative Example 8, while 77 N and 177 seconds in Example 9.
In Example 9, the corn starch of Comparative Example 8 was replaced with rice starch. From the above results, in Example 9, the content of fine particles at the time of 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 was improved in tablet hardness as compared with Comparative Example 8, and was a value that could be used practically.

[Examples 10 to 15 and Comparative Examples 9 to 11]
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 samples having various moisture contents shown in Table 6. Obtained. 200 g of mixed powder 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, a mixed powder without adding magnesium stearate in a polyethylene bag was mixed so as to be sufficiently uniform, and then magnesium stearate was added and shaken for 30 seconds.
These mixed powders are compression-molded at a pressure of 4 MPa (pressure cylinder / gauge pressure) by roll compression molding using a roller compactor TF-LABO (manufactured by Freund Sangyo Co., Ltd.), and the obtained flake portion is adjusted with a screen. The particles were sized using a granulator to obtain granules.
As a tableting test (model experiment) using these granules, a flat tablet having a diameter of 20 mm and a mass of 2.0 g per tablet was molded using a hydraulic press type molding machine under a compression pressure of 20 kN. The hardness of the tablets obtained was measured. The test results are shown in Table 6.

  In Comparative Example 9 using rice starch having a moisture content of 14.2% by mass, the fluidity of the mixed powder was poor, and the supply from the hopper was not smooth during dry granulation. Further, as shown in the above results, the water content of rice starch affects the hardness of the tablet. The hardness decreases as the water content decreases, and in Comparative Examples 10 and 11 where the water content is less than 6% by mass, the tablet hardness is It became extremely low, suggesting that it cannot be put to practical use.

[Example 16 and Comparative Examples 12-14]
Dry granulation was performed under the conditions shown in Table 7 and Example 10. As a tableting test (model experiment) using the obtained granules, a flat tablet having a diameter of 10 mm and a mass of 300 mg per tablet was molded using a hydraulic press molding machine under a compression pressure of 20 kN. Furthermore, the obtained tablet was filled in a glass bottle and sealed, and left in a thermostat at 50 ° C. for 1 week. Various physical property tests were performed on the tablets before and after the acceleration test. The results are shown in Table 8.

From the results in Table 8, the tablet of Comparative Example 13 has improved tablet hardness compared to the tablet of Comparative Example 12 that does not use crystalline cellulose. However, the tablet of Comparative Example 13 is delayed in disintegration time after the acceleration 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 temporal stability. Moreover, since the disintegration time of the tablet of Comparative Example 14 is significantly longer than that of the tablet of Comparative Example 12, improvement in disintegration is required.
The sample of Example 16 showed the same tablet hardness as that of Comparative Example 13 using crystalline cellulose as the binder, and no change in physical properties was observed before and after the accelerated test at 50 ° C. . From these results, it can be said that the tablet of Example 16 is excellent in stability over time as compared with tablets using other binders and is suitable for practical use.

[Example 17 and Comparative Example 15]
Dry granulation of tablets for tableting and molding of tablets were carried out under the conditions shown in Table 9 and Example 10. The obtained tablets were left 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 left were measured.

  As a result of the hardness measurement, Comparative Example 15 was 11.5 N before being left and 4.1 N after being left, whereas Example 17 was 18.6 N before being left and 11.2 N after being left. Further, 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. However, the change over time in tablet hardness and coloration on the tablet is large, and it is difficult to put to practical use. It was suggested that there is. On the other hand, the composition of Example 17 was obtained by replacing a part of crystalline cellulose used as the powdery binder of Comparative Example 15 with rice starch, although a slight decrease in tablet hardness was observed. The change in color tone is extremely small, stable over time, and suitable for practical use.

[Example 18 and Comparative Example 16]
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.

The hardness and disintegration time of the tablets obtained were 48 N and 2 minutes and 20 seconds in Comparative Example 16, whereas 121 N and 2 minutes and 30 seconds in Example 18, and those according to Example 18 were Comparative Example 16 On the other hand, a significant improvement in tablet hardness was observed. Further, the composition of Example 18 containing mannitol, which is generally considered to have low moldability, also showed a disintegration time equivalent to that of Comparative Example 16 containing no mannitol and using lactose and corn starch.
Each tablet was filled in a 50 mL glass bottle, placed in a thermostat at 50 ° C., and left for 24 hours. As a result of measuring the color of the tablets before and after the heating of these tablets, the color difference before and after the heating was +12.3 in Comparative Example 16 and +4.1 in Example 18. Compared to Example 18, Comparative Example 16 had a greater degree of change in color tone, and was clearly colored by the Maillard reaction. Therefore, in Example 16, the change in the acceleration test was small and the stability over time was excellent.

[Examples 19 to 22]
50% by weight of vitamin C powder, 29.5% by weight of the same rice starch powder as in Example 8, 0.5% by weight of magnesium stearate and the remaining 20% by weight are the components shown in Table 10, and are shown in Example 10. Dry granulation and tablet formation were performed according to the conditions. Table 11 shows the tablet hardness and disintegration time in each example.

  From the above results, the hardness of the tablet is increased by replacing part of it with crystalline cellulose, powdered cellulose or low-substituted hydroxypropylcellulose, compared to when rice starch is used alone as a powdery binder. Became shorter.

[Example 23 and Comparative Example 17]
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.

  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. The composition according to Example 23 had a composition in which the corn starch of Comparative Example 17 was replaced with rice starch, but a significant improvement in tablet hardness was observed with respect to Comparative Example 17.

[Example 24]
According to the conditions shown in Table 13 and the conditions of Example 8, dry granulation of the granules for tableting was performed, 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. According to the above, tablets were formed. As silicon dioxide, product name: Adsolider 101 manufactured by Freund Sangyo Co., Ltd. was used.

  The tablets obtained had a hardness and disintegration time of 103 N and 19 minutes, which were practical.

[Example 25 and Comparative Examples 18 to 19]
Aminophylline was used as an active pharmaceutical ingredient, D-mannitol was used as an excipient, and Rocket (Pearlitol) 35 was used as a product. . The crushing type granulation method was applied as the granulation method. And the case where rice starch or crystalline cellulose was used as a powdery binder and the case where these were not used were compared. Aminophylline is a cardiotonic drug, and is a substance known to have many substances and compound changes.
Specifically, ingredients other than magnesium stearate, which is a lubricant, were mixed, 2 kg of them were charged into a 5 L kneader, and water was added to each to knead. The kneaded product was taken out, and a screen type crushing granulator (manufactured by Okada Seiko Co., Ltd., trade name: New Speed Mill) was fitted with a screen having a diameter of 1.2 mm and crushed. It dried in the drier and sieved with the 500 micrometer sieve, and the granule was obtained.
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), Freund Sangyo Co., Ltd. product name: EZ-100 was used.
Magnesium stearate was mixed with the obtained granules, and tableting was performed under the following conditions.

The tableting conditions are as follows.
Tableting machine: Single tableting machine, FY-SS-7 (Fuji Pharmaceutical Machinery Co., Ltd.)
Tableting pressure: 10kN
Tablet: Flat tablet with a diameter of 10 mm, weight is 350 mg per tablet

In Comparative Example 19 in which no powdered binder was used, in the tableting test, a sticking tableting failure was observed shortly after the start of tableting, and it was difficult to continue tableting. Moreover, the hardness of the tablet obtained at the initial stage was remarkably low, which was not a practical level.
The tablet obtained in Comparative Example 18 was not inferior to Example 25 in terms of hardness and disintegration, but had a slightly yellowish coloration, and was further left at 40 ° C. and a relative humidity of 75% RH. As a result, the coloration increased significantly. This phenomenon is thought to result from the interaction between aminophylline and crystalline cellulose.

[Example 26 and Comparative Example 20]
The following Example 26 and Comparative Example 20 were carried out in order to show the usefulness of the excipient that was formed into granules and whose water activity (aw) was adjusted.
1 kg of lactose of grade 200M manufactured by DMV was dissolved in 3 kg of warm water (70 ° C.) to obtain a 25% strength by weight solution. By charging 3.5 kg of the same lactose and 0.5 kg of the rice starch of Example 1 into a fluidized bed granulation coating apparatus (trade name: Flow Coater FLO-5, manufactured by Freund Sangyo Co., Ltd.), and spraying the solution in its entirety. Granulation was carried out, and sieved with a sieve having an opening of 500 μm to obtain granules having an average particle diameter of 98 μm.
The obtained granule is put in a stainless steel vat, placed in a constant temperature and humidity chamber at 30 ° C. and a relative humidity of 60% for 24 hours, and the water activity (aw) becomes 0.58 with a tableting machine. Tablets were obtained by compression molding. 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.
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), direct compression tableting lactose DCL-11 produced by the spray drying method manufactured by DMV was tableted under the same conditions. The tablet hardness was 82 N and the disintegration time was 12 minutes and 40 seconds. It was.
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.

[Example 27 and Comparative Example 21]
The following Example 27 and Comparative Example 21 were carried out in order to show the usefulness of the excipient that was formed into granules and whose water activity (aw) was adjusted.
2 kg of the mixed powder in which the same D-mannitol and rice starch as used in Example 25 were mixed at a mass ratio of 8: 2 was granulated by the same crushing type granulation method as in Example 25, dried, and sieved The separation was performed in the same manner to obtain granules (average particle size: 143 μm).
This granule is placed in a vat, placed in a constant temperature and humidity chamber at 40 ° C. and a relative humidity of 70% for 6 hours, and the water activity (aw) of 0.55 is compressed by a tableting machine. To obtain tablets. Specifically, 1.0 part by mass of magnesium stearate was mixed with 99.0 parts by mass of this granular excipient, and tableting was performed under the same conditions as in Example 25.
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), D-mannitol 200SDD for direct compression, which is said to be produced by a spray drying method manufactured by ROQUETE, was tableted under the same conditions. The tablet hardness was 76 N and the disintegration time was 198. Second.
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.

[Examples 28 to 33 and Comparative Examples 22 to 24]
As an active pharmaceutical ingredient, 30 parts by mass of powder of acetaminophen, which is an antipyretic analgesic, previously sieved with a sieve having an opening of 75 μm, 20 parts by mass of the same rice starch used in Example 1, and lactose 50 parts by mass was mixed to obtain a mixed powder.
200 g of the mixed powder was put in a mortar, kneaded with water added to obtain a kneaded product. The kneaded product was sieved with a 500 μm sieve, dried at 50 ° C. for 5 hours, and passed through a sieve with an opening of 250 μm to obtain granules having an average particle diameter of 138 μm. The obtained granule is put into a constant temperature and humidity machine of 40 ° C. and relative humidity 75% RH or 40 ° C. and relative humidity 90% RH, taken out after an appropriate time, and samples having various water activities (aw) are taken. Obtained.
A direct compression method in which 99.5 parts by mass of the sample thus conditioned and 0.5 parts by mass of magnesium stearate are mixed and compression-molded using a hydraulic press-type molding machine under a compression pressure of 10 kN. As a result, tablets having a diameter of 10 mm and 400 mg per tablet were obtained. Table 16 shows the water activity of the obtained tablets and the hardness of the tablets.

As apparent from Table 16, when the water activity (aw) is less than 0.4, the hardness of the obtained tablet is remarkably low, and it is considered that practical use is difficult. Moreover, the sample of water activity (aw) 0.83 obtained in Comparative Example 22 had a moist feeling and lacked fluidity.
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).

[Example 34]
20 parts by mass of lactoferrin used in health foods, 20 parts by mass of acetylated rice cake rice starch described in Example 24 and Table 13 as powdered binder, and granulated lactose (trade name, manufactured by Freund Sangyo Co., Ltd.) 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 with a tableting pressure of 75 kN using the rotary tableting machine of Example 1. Thus, tablets with a diameter of 8 mm and 200 mg per tablet were obtained.
The tablet had a hardness of 115 N and a disintegration time of 6 minutes and 20 seconds, and had practical properties.

[Examples 35 to 36 and Comparative Example 25]
Tablets were produced by a direct tableting method in which a mixed powder having the composition shown in Table 17 was compression-molded by a tableting machine.
In Example 35, the same rice starch (water content 12.2% by mass) as that used in Example 1 without heat treatment was used as a powdery binder.
In Example 36, the same rice starch as used in Example 1 was heat-treated, 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 apparatus (Freund Sangyo Co., Ltd., trade name: Flow Coater FLO-5), fluidized at an intake air temperature of 140 ° C. for 60 minutes, and subjected to heat treatment. It was. Subsequently, the moisture content was adjusted by flowing water for 60 minutes while spraying water at an intake air temperature of 30 ° C. to adjust the water content. In the heat treatment, the temperature of the fluidized bed portion corresponding to the heating temperature was 67 ° C. at the start of flow, but after 12 minutes became 80 ° C., and then gradually increased to 107 ° C. after 60 minutes. Reached. Therefore, in the heat treatment, the temperature is 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 humidity-controlled was 12.4% by mass.
In Comparative Example 25, the same crystalline cellulose used in Comparative Example 1 was used.
In addition, as D-mannitol granulated material, the rocket (ROQUETTE) company make and the brand name: PEARLITOL 200SD which are excipient | fillers for direct compression were used.
As an active ingredient, chlorpheniramine maleate, which is an antihistamine, was used.

The tableting conditions are as follows.
Tableting machine: Rotary tableting machine Tableting pressure: 7kN
Tablet: Mass is 200mg per tablet

From Table 18, it was suggested that the hardness of the tablet of Example 36 was slightly higher than that of the tablet of Example 35, and that the moldability of rice starch was improved by heat treatment. The hardness of the tablet of Comparative Example 25 was comparable to that of Example 35.
The disintegration time of the tablets did not differ greatly between the cases. This indicates that the use of heat-treated rice starch can increase tablet hardness without affecting the disintegration time.
In addition, each tablet obtained in each example was put in a glass bottle, put in a thermostatic chamber at 50 ° C. in a sealed state, allowed to stand for 4 weeks, and compared for yellowness of the tablet surface before and after being left. However, the change of the tablet of Comparative Example 25 was large. This is considered to be derived from the color change of crystalline cellulose.

Claims (20)

  A method for producing a tablet, wherein the tablet is formed by a compression molding method using rice starch and / or rice starch derivative having a water content of 6 to 14% by mass as a powdery binder.   The method for producing a tablet according to claim 1, wherein the rice starch and / or rice starch derivative has a water content of 9 to 14% by mass.   The said tablet contains a pharmaceutical active ingredient and / or the component which has a health function for foodstuffs, The manufacturing method of the tablet described in Claim 1 or 2 characterized by the above-mentioned.   The method for producing a tablet according to any one of claims 1 to 3, wherein the content of rice starch and / or rice starch derivative in the tablet is 5% by mass or more.   The method for producing a tablet according to any one of claims 1 to 4, wherein the rice starch and / or rice starch derivative is adjusted to the water content after being heat-treated.   A method for producing granules comprising granulating powder by a dry granulation method using rice starch and / or rice starch derivatives having a water content of 6 to 14% by mass as a powdery binder.   The method for producing granules according to claim 6, wherein the rice starch and / or rice starch derivative has a water content of 9 to 14% by mass.   The method for producing a granule according to claim 6 or 7, wherein the granule contains an active pharmaceutical ingredient and / or a component having a health function for food.   The method for producing a granule according to any one of claims 6 to 8, wherein the content of rice starch and / or rice starch derivative in the granule is 10% by mass or more.   10. At least one cellulose-based powdery binder selected from the group consisting of crystalline cellulose, powdered cellulose, or low-substituted hydroxypropylcellulose powder is further used. The manufacturing method of the granule described in claim | item.   The method for producing a granule according to claim 10, wherein the content of the cellulose-based powder binder in the granule is 10 to 30% by mass.   The method for producing a granule according to any one of claims 6 to 11, wherein D-mannitol is used as an excipient.   The method for producing granules according to any one of claims 6 to 12, wherein the rice starch and / or rice starch derivative is heat-treated and then adjusted to the water content.   A granule produced by the method for producing a granule according to any one of claims 6 to 13.   A tablet comprising the granule according to claim 14.   Powders are granulated by a wet granulation method using rice starch and / or rice starch derivatives as a powdery binder, and the water activity (aw) of the granules obtained by the granulation is 0.4-0. 8. A method for producing a tablet, comprising adjusting the humidity to 8 and then compression molding.   The method for producing a tablet according to claim 16, wherein the tablet contains a pharmaceutical active ingredient and / or a component having a health function for food.   A powdery excipient is granulated by a wet granulation method using rice starch and / or rice starch derivatives as a powdery binder, and the granular excipient obtained by the granulation is treated with its water activity ( A method for producing a tablet comprising adjusting the humidity so that aw) is 0.4 to 0.8, mixing with other powders, and then compression-molding.   The method for producing a tablet according to claim 18, wherein the tablet contains a pharmaceutical active ingredient and / or a component having a food health function. A tablet produced by the method for producing a tablet according to any one of claims 1 to 5 and claims 16 to 19.