JP2007332074A - Tablet quickly disintegrable in oral cavity and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide tablets quickly disintegrable in the oral cavity, producible relatively easily without using any special equipment and/or technology, and also having such hardness as to be resistant to breakage under production, transportation, storage, etc. <P>SOLUTION: The tablets each comprise starch, crystalline cellulose and/or powdery cellulose and an active ingredient in the mass ratio of the starch to the crystalline cellulose and/or powdery cellulose of (90:10) to (50:50), wherein the total content of the starch and the crystalline cellulose and/or powdery cellulose is 60 mass% or greater. In producing the tablets, it is preferable that compression molding be carried out after granulating at least the starch to obtain the final tablets. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a tablet for pharmaceuticals and the like, and more particularly to an intraorally rapidly disintegrating tablet that rapidly disintegrates in the oral cavity and a method for producing the same.

As humans age, swallowing power decreases, and regular tablets often make it difficult to take. For this reason, in recent years, researches on rapidly disintegrating tablets in the oral cavity that disintegrate rapidly in the oral cavity (rapid disintegration) and are easy to take have been actively conducted, and many products have actually been marketed.
For example, Patent Document 1 describes an orally disintegrating solid preparation obtained by suspending a saccharide composed of an active ingredient, lactose and mannitol in an agar aqueous solution, filling a mold, solidifying in a jelly form, and drying. Has been. R. P. An orally disintegrating tablet developed by Scherer (UK) and marketed mainly in the United States and Europe is "Zydis (trade name)", which contains the main drug, gelatin, mannitol, sweeteners, flavors, etc. It is said that it can be obtained by vacuum lyophilization after injection into a PTP blister mold.
However, these molded products are rich in porosity and can be rapidly disintegrated, but their strength (hardness) is insufficient, and they are prone to cracking, chipping, etc. during production, transportation, storage, etc. However, there are problems such as requiring special formulation technology and equipment.

  Patent Document 2 describes a method in which a mixture containing saccharides is compressed by adding water and then dried. However, although this method may improve the strength, special formulation technology is used to uniformly contain moisture in a mixture containing saccharides and to perform tableting without any obstacles. There is a problem you need.

Patent Document 3 discloses an orally rapidly disintegrating tablet by combining a sugar alcohol or saccharide having an average particle size of 30 μm or less, an active ingredient, and a disintegrant, granulating the mixture, and then compression-molding the mixture. . As a result of comparison using D-mannitol having an average particle diameter of about 60 μm and those obtained by pulverizing the D-mannitol to an average particle diameter of about 20 μm, the former is remarkably low in terms of tablet hardness, whereas the latter Is described as sufficient.
However, D-mannitol has a problem in handling in that it is powdered by fine pulverization and fluidity is lowered.

Patent Document 4 describes a rapidly disintegrating solid preparation containing an active ingredient, a sugar or sugar alcohol having an average particle size of 30 μm to 300 μm, a disintegrant and celluloses. In this method, since the number of components required is large, there is a problem that complexity is increased in terms of management and handling of each component in production.
Japanese Patent No. 2807346 Japanese Patent Laid-Open No. 5-271054 International Publication No. 97/47287 Pamphlet JP 2001-58944 A

  The purpose of the present invention is to produce relatively easily without using special equipment or technology, has a fast disintegrating property that quickly disintegrates in the oral cavity, and is not easily damaged during manufacturing, transportation, storage, etc. An object of the present invention is to provide an intraoral quick disintegrating tablet having hardness.

As a result of intensive studies to solve the above problems, the present inventors have used starch and crystalline cellulose and / or powdered cellulose having a specific ratio as an additive component of the tablet, and the total of these tablets. It has been found that by controlling the content within a specific range, an intraorally rapidly disintegrating tablet having fast disintegrating properties and sufficient tablet hardness can be obtained.
Further, among these additive components, at least starch is granulated in advance and then compression-molded to find that such excellent hardness can be obtained more easily, and the present invention has been completed. It was.

The intraoral quick disintegrating tablet of the present invention contains starch, crystalline cellulose and / or powdered cellulose, and an active ingredient, and the mass ratio of the starch to the crystalline cellulose and / or the powdered cellulose is 90:10. 50:50, and the total content of the starch and the crystalline cellulose and / or the powdered cellulose is 60% by mass or more.
The starch is preferably rice starch.
The method for producing an orally rapidly disintegrating tablet of the present invention contains starch, crystalline cellulose and / or powdered cellulose, and an active ingredient, and the mass ratio of the starch to the crystalline cellulose and / or the powdered cellulose is 90. : 10 to 50:50, and a method for producing an orally rapidly disintegrating tablet comprising compression-molding a mixture in which the total content of the starch and the crystalline cellulose and / or the powdered cellulose is 60% by mass or more. , At least the starch is granulated, and then the compression molding is performed.
Specifically, after granulating the starch into granules, it is preferable to perform the compression molding by mixing the granules, the crystalline cellulose and / or the powdered cellulose, and the active ingredient.
Alternatively, it is preferable to perform the compression molding by mixing the starch with the crystalline cellulose and / or the powdered cellulose and granulating it, and then mixing the active ingredient with the granule.
Alternatively, the compression molding is preferably performed after the starch and the crystalline cellulose and / or the powdered cellulose and the active ingredient are mixed and granulated.
The starch is preferably rice starch.
The granulation may be performed by a dry granulation method or a wet granulation method. When the wet granulation method is employed, the water activity (aw) of the obtained granule is converted into the water activity (aw). ) Is preferably adjusted to 0.4 to 0.8 before the compression molding is performed.

  According to the present invention, it can be produced relatively easily without using special equipment or technology, has a rapid disintegration property that rapidly disintegrates in the oral cavity, and is not easily damaged during production, transportation, storage, etc. An intraoral quick disintegrating tablet having hardness can be provided.

Hereinafter, the present invention will be described in detail.
[Intraoral rapidly disintegrating tablets]
The rapidly disintegrating tablet in the oral cavity of the present invention contains starch, crystalline cellulose and / or powdered cellulose, and an active ingredient, and among these, starch, crystalline cellulose and / or powdered cellulose are additive components. Is included.
There is no restriction | limiting in particular as starch, One or more types of well-known starch and its derivative (s) can be used, For example, wheat starch, rice starch, corn starch, potato starch etc. which are generally used as an additive of a tablet can be used. Various methods are known as a method for producing these starches, but any method can be used as long as it conforms to each article of the Japanese Pharmacopoeia.
In addition, as starch, sweet potato starch, tapioca starch, kudzu starch and the like can be used.
Derivatives of starch include esterified starch such as acetate ester and phosphate monoester, and etherified starch such as hydroxyethyl ether, hydroxypropyl ether, carboxymethyl ether, and the like.

  Among these starches, there is no sense of incongruity in the taste when the oral rapidly disintegrating tablet is included in the mouth, the touch feeling is good, and the highly rapidly disintegrating oral disintegrating tablet is easily obtained by molding, etc. It is desirable to use rice starch or derivatives thereof. Rice starch is said to be the smallest among commercially available starches with a particle size of 2 to 5 μm, and this is a factor that develops a good texture with no rough feeling. It is considered that the effect of increasing the binding property is also achieved.

Crystalline cellulose is obtained by partially depolymerizing α-cellulose with an acid and purifying it. For example, Asahi Kasei Chemicals Co., Ltd., trade names, Theolas PH-101, PH-102, PH-301, PH-302, PH-F20, etc. are mentioned.
On the other hand, powdered cellulose is a product obtained by partially subjecting α-cellulose to hydrolysis and the like, then purifying and mechanically pulverizing. For example, Nippon Paper Chemicals Co., Ltd., trade name, KC Flock W-100, W-200, W-300, W-400, and the like.
At least one of crystalline cellulose and powdered cellulose may be contained in the intraoral quick disintegrating tablet, and may be contained together.

  The mass ratio of starch to crystalline cellulose and / or powdered cellulose in the intraorally rapidly disintegrating tablet, that is, starch: crystalline cellulose and / or powdered cellulose = 90: 10 to 50:50, preferably 85:15 to 60 : 40 (provided that the total of starch and crystalline cellulose and / or powdered cellulose is 100). When the mass ratio is out of such a range, a sufficiently fast oral disintegrating tablet cannot be obtained. That is, when the ratio of starch exceeds 90% by mass in the total amount of starch and crystalline cellulose and / or powdered cellulose, the disintegration time of the rapidly disintegrating tablet in the oral cavity becomes long, and the rapid disintegration property cannot be obtained. On the other hand, if the ratio of crystalline cellulose and / or powdered cellulose exceeds 50% by mass, the paper-like taste when contained in a specific mouth becomes remarkable, causing troubles during taking.

  The total content of starch, crystalline cellulose and / or powdered cellulose in the intraoral quick disintegrating tablet is 60% by mass or more, preferably 65% by mass or more. If it is less than 60% by mass, the disintegration time becomes long and the rapid disintegration property cannot be obtained, or the necessary tablet hardness cannot be ensured.

The active ingredient is not particularly limited as long as it is an orally administrable active ingredient, and granulated in advance for the purpose of concealing an unpleasant taste such as bitterness of the active ingredient, or for enteric and sustained release. After being made fine by the above method, a material coated by a known method may be used.
Specifically, hypnosis / sedation, antipyretic analgesic / anti-inflammatory agent, neuropsychiatric agent, autonomic nerve agent, anti-parkinsonian agent, antihistamine, cardiotonic agent, diuretic, antihypertensive agent, vasoconstrictor, arteriosclerotic agent, antitussive Expectorants, vitamins, nourishing tonics, antibiotics, gastrointestinals, etc.
The content of these active ingredients in the intraoral quick disintegrating tablet varies depending on the type of active ingredient, but is usually 30% by mass or less, preferably 20% by mass or less.

[Method for producing intraorally rapidly disintegrating tablets]
Such an orally rapidly disintegrating tablet contains the above-mentioned starch, crystalline cellulose and / or powdered cellulose, and an active ingredient, and the mass ratio of starch to crystalline cellulose and / or powdered cellulose is 90:10 to 50: 50, and a mixture in which the total content of starch and crystalline cellulose and / or powdered cellulose is 60% by mass or more can be produced by a compression molding method. As a general method (compression method) for producing tablets by compression molding, there are so-called direct powder compression methods (hereinafter sometimes referred to as direct tableting methods) and granule compression methods. Fast disintegrating tablets can be produced by any of these methods.

The direct tableting method is basically a mixture of raw materials containing essential ingredients such as active ingredients plus additives such as powdered binders and disintegrants as required in addition to excipients. In addition, a lubricant is further added at the time of compression, and compression molding is directly performed by a tableting machine. This method is basically a method in which the powder is directly compressed without pretreatment, and is employed when the powder has good compression moldability. However, for the purpose of improving moldability and fluidity, powders and excipients containing the active ingredient may be granulated in advance and marketed directly as raw materials for tableting.
On the other hand, in the granule compression method, first, using an excipient or the like, a raw material containing all essential components such as active ingredients (excluding lubricant) is made into granules, and then the obtained granules are lubricated. This is a method in which an agent or the like is added and compression molded by a tableting machine. Here, the granule compression method in which the granules are produced by the dry granulation method is called a dry granule compression method, and the granule compression method produced by the wet granulation method is called a wet granule compression method.

As a more preferable method for producing an orally rapidly disintegrating tablet, at least for starch having low fluidity, it is granulated in advance to form granules, and a mixture containing the granules is compression-molded with a tableting machine or the like. . When this method is adopted, an intraoral quick disintegrating tablet that is excellent in content uniformity, has a fast disintegrating property, and has a sufficient tablet hardness can be obtained more easily. When starch is not granulated in advance, the fluidity of the tableting powder is insufficient, and the tableting operation tends to be difficult.
Specifically, the following methods (1) to (3) are suitable.
(1) A method of granulating starch into granules, mixing the granules, crystalline cellulose and / or powdered cellulose, and an active ingredient, and compressing the resulting mixture into tablets.
(2) A method in which starch and crystalline cellulose and / or powdered cellulose are mixed to form granules, and then the granules and the active ingredient are mixed, and the resulting mixture is compression-molded to form tablets.
(3) A method in which starch and crystalline cellulose and / or powdered cellulose and an active ingredient are mixed and granulated into granules, and then the granules are compression molded into tablets.
Among the methods (1) to (3) described above, the methods (1) and (2) are generally in the category of direct compression methods, and (3) is in the category of granule compression methods. .

In the case of the method (1), the crystalline cellulose and / or powdered cellulose may be granulated in advance and granulated as necessary. Also, the active ingredient may be in powder form, or may be in the form of granules that are generally commercially available as direct tableting raw materials. Furthermore, the active ingredient and crystalline cellulose and / or powdered cellulose may be mixed and granulated in advance.
Also in the case of the method (2), as the active ingredient, a powdery one may be used, or a granular one that is generally commercially available as a direct tableting raw material may be used.

<Granulation method>
In the production methods (1) to (3) described above, a dry granulation method or a wet granulation method can be employed as a granulation method for producing granules.
(Dry granulation method)
When adopting the dry granulation method, first, additives are mixed with the powder to be granulated (hereinafter referred to as granulated powder) as necessary, and the resulting mixture is rolled by high pressure compression molding. Roll compression molding is performed with a machine or the like to obtain a high-density plate-like molded product (hereinafter sometimes referred to as flake). As conditions for roll compression molding at this time, flakes of 60 to 95% by mass are obtained when the supply amount of the granulated powder is 100% by mass. Next, the flakes are passed through a multi-stage roll crusher or various granulators to obtain the desired particle size, and if necessary, sieving is performed so as to obtain a more appropriate particle size distribution.

Here, in the direct compression method such as the above-described methods (1) and (2), when granules are granulated by a dry granulation method, as additives, usually sweeteners, lubricants, etc. Is used.
As sweeteners, D-mannitol, D-sorbitol, sucrose, aspartame, xylitol, fructose, glucose, etc. are used for the purpose of improving the feeling of tongue when taking a rapidly disintegrating tablet in the oral cavity. It is about 5% by mass or less in the granular powder. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, hydrogenated oil and the like, and are usually used in an amount of 5% by mass or less in the granulated powder.

  In addition, when the obtained granules are subjected to compression molding, the hardness of the intraoral quick disintegrating tablet is further increased, the mass deviation of the intraoral quick disintegrating tablet is controlled within a desirable range, For the purpose of increasing the uniformity of the tablet content, it is preferable to adjust the particle size of the granules beforehand by sieving so that the average particle size is in the range of 50 to 300 μm.

  In the granule compression method such as the method (3) described above, when granulation is performed by a dry granulation method, as an additive, a general excipient or a disintegration for promoting disintegration is usually used. An agent (such as crospovidone) is used. In addition, the above-mentioned sweeteners and lubricants, as well as fragrances, colorants and the like are used as necessary.

(Wet granulation method)
When the wet granulation method is employed in the production methods (1) to (3) described above, a liquid binder is used, and the pulverization granulation method, the agitation granulation method, the fluidized bed granulation method, the centrifugation What is necessary is just to granulate by well-known granulation methods, such as a rolling granulation method, a centrifugal rolling fluidized bed granulation method, and a spray granulation method.
For example, in the case of the crushing granulation method, a liquid binder is added to the granulated powder, a soft lump of an appropriate size is made with a granulator, crushed with a crushing granulator, and then with a dryer. Granules are obtained by drying. Large granules are pulverized.

  In these wet granulation methods, 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. There is a case. However, when it is necessary to analyze the composition of the obtained granules for quality control (for example, in the case of direct tableting), an aqueous starch solution of the same type as the starch contained in the granulated powder, water, It is preferable to use only an organic solvent as a binder because it does not hinder composition analysis.

  In addition, when the granules are produced by the wet granulation method, it is preferable that the moisture content of the granules is adjusted before being subjected to compression molding. The moisture content affects the compression moldability and bondability when the powder containing it is compression molded, and if it is too low, sufficient moldability tends not to be exhibited. On the other hand, if the moisture is too high, problems such as a decrease in the fluidity of the powder tend to occur. In addition, the water content of commercially available starch generally exceeds 10% by mass.

  The water activity (aw) suitable as an indicator of water content 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, usually at a room temperature of about 25 ° C. And the water activity (aw) of a granule is 0.4-0.8, The moldability, fluidity | liquidity, etc. become favorable. If the water activity is less than 0.4, the moldability of the granule is insufficient, so the intraoral quick disintegrating tablet obtained by compression molding tends not to have sufficient hardness. Problems such as a decrease in fluidity of the granules and a tableting failure such as sticking during tableting are likely to occur.

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.
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.

  In the conventional general wet granule compression method, the moisture content of starch is reduced in the drying process when producing granules by wet granulation method, and as a result, the compression moldability and binding properties of the granules are reduced. It is thought. Therefore, in order to ensure these performances, it is considered important to control the water activity of the granules before subjecting the granules to compression molding. In addition, when the water activity of the granule obtained by the wet granulation method is in the range of 0.4 to 0.8, it is not necessary to adjust the humidity. Moreover, the water activity of the obtained granule is 0.4-0.0.0 by controlling the conditions of the normal drying process at the time of manufacturing a granule by a wet granulation method, without providing the process for conditioning humidity separately. It may be within the range of 8.

In addition, in the direct tableting method such as the above methods (1) and (2), when the granules are granulated by the wet granulation method, the above-mentioned sweet taste is used as in the case of employing the dry granulation method. The material can be used in the granulated powder in the range of about 5% by mass or less. In addition, when the granules obtained by the wet granulation method are subjected to compression molding, the average particle size of the granule is in the range of 50 to 300 μm in advance, as in the case of employing the dry granulation method. Furthermore, it is preferable to adjust by sieving.
In addition, in the granule compression method such as the method (3) described above, in the case of granulating the granule by the wet granulation method, generally, as in the case where the dry granulation method is adopted, a general excipient is used. Alternatively, a disintegrant (for example, crospovidone) for promoting disintegration is used. In addition, the above-mentioned sweeteners and lubricants, as well as fragrances, colorants and the like are used as necessary.

<Compression molding method>
As the compression molding method, a method using a tableting machine having a mortar and a punch, such as a single tableting machine or a rotary tableting machine, is preferred. At that time, in the case of the direct tableting method such as the method of (1) or (2), excipients for direct tableting generally used for tablet production, disintegrating agents (for example, crospovidone, etc.), A tableting agent (for example, magnesium stearate, calcium stearate, sucrose fatty acid ester, hydrogenated oil, etc.), a fluidizing agent, a fragrance, a sweetening agent, a coloring agent, and the like may be added as necessary and tableted. The lubricant is usually used in an amount of 5% by mass or less in the intraoral quick disintegrating tablet. Further, it is preferable to add the lubricant at the time of tableting by a method of independently mixing lightly separately from other additives. As the fluidizing agent, light anhydrous silicic acid or the like is used for the purpose of improving the fluidity of the tableting powder and increasing the hardness of the resulting tablet. The amount used is usually 0% in the mixture to be tableted. .1 to 0.5% by mass.

  In the case of the granule compression method such as the method (3) described above, a lubricant is usually added as an additive, and further additives such as excipients, disintegrants, fragrances, sweeteners, and colorants are added. Of these, an additive suitable to be added at this timing may be added as appropriate, and tableting may be performed with the tableting machine described above.

Although there is no restriction | limiting in the shape of the intraoral quick disintegrating tablet obtained by compression molding, if a cross section is circular, the 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.
Moreover, about the intraoral quick disintegrating tablet obtained in this way, you may perform the drying by the well-known method for reducing a water content, and the coating by a well-known method irrespective of the manufacturing method.

[Action / Effect]
Such an orally rapidly disintegrating tablet contains starch, crystalline cellulose and / or powdered cellulose, and an active ingredient, and the mass ratio of starch to crystalline cellulose and / or powdered cellulose is 90:10 to 50:50. And the total content of starch and crystalline cellulose and / or powdered cellulose is 60% by mass or more. Therefore, even when taken without using water, it is not accompanied by a sense of discomfort such as a feeling of touching the tongue, quickly softens and disintegrates in the oral cavity, and the disintegration time when contained in the mouth is 30 seconds or less, Preferably it is 20 seconds or less. Further, this intraoral quick disintegrating tablet has such a rapid disintegrating property and has a sufficient hardness that is difficult to break during its production, transportation, storage and the like. The tablet hardness depends on the size of the rapidly disintegrating tablet in the oral cavity and cannot be generally stated, but is generally in the range of 30 to 150 N as measured by a tablet hardness meter.
In addition, such an orally rapidly disintegrating tablet is a preparation with an excellent effect, but it is based on inexpensive starch and does not require special equipment or technology. This is advantageous in terms of cost. Moreover, since there are few essential additive components, the number of steps in production and the labor required for management of raw materials can be reduced, which is also preferable in terms of cost.

The reason why the intraoral rapidly disintegrating tablet of the present invention exhibits particularly excellent rapid disintegration is not necessarily clear, but is considered as follows.
In other words, general tablet additives include excipients, binders, disintegrants, lubricants, etc., and usually starch is used as an excipient or disintegrant, and crystalline cellulose is used as a powder. It is classified as a binder. Starch as a disintegrant is generally used for the purpose of giving mild disintegration, and it is known that fast disintegration cannot be expected. In fact, when starch is used alone as an additive, Does not provide tablets with the desired rapid disintegration. However, according to the present invention, fast disintegration is manifested by combining starch and crystalline cellulose and / or powdered cellulose in a specific mass ratio and setting the total content of these in a specific range. Found.
From this point of view, in the present invention, starch has a function as an excipient, and crystalline cellulose and powdered cellulose act as a binder used as a powder and simultaneously act as a disintegrant. Can be guessed.

Although crystalline cellulose and powdered cellulose are widely used as binders used as powders, they are generally not used in the expectation of a function as a disintegrant.
For example, “14th revised Japanese Pharmacopoeia Description” Yodogawa Shoten (2001) has the following description: Crystalline cellulose is widely used as a binder used as a powder (page A-64). The agent is an additive that imparts disintegration to the tablet in water or gastrointestinal fluid. Starch (5% of drug, add about 10-20% as needed) is most widely used. Recently, carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like having excellent disintegration ability have also been used (pages A-64 to A-65).
In addition, Tsusuke Keisuke, Nogami Kotobuki: Drug Development Basic Course XI, Drug Manufacturing Method (above) page 135 has a description of binders in the direct powder compression method, and there are many examples of substances used as binders. Crystalline cellulose and powdered cellulose (here described as α-cellulose but synonymous with powdered cellulose) are also included. Also, on page 146 of the same book, there is an explanation about crystalline cellulose, and there is the following description: ... On the other hand, this substance has high water absorption and quick introduction of water into the tablet. The swelling as a result is small, and the action as a disintegrant is weak.
From such description, it can be presumed that crystalline cellulose exhibits binding and exerts an effect of increasing tablet hardness. However, surprisingly, in the intraoral quick disintegrating tablet of the present invention, crystalline cellulose functions as a binder, while at the same time contributing to fast disintegration. The reason for this is not clear, but it can be inferred that, as described above, the rapid introduction of water into the tablet is combined with some properties of starch, so to speak to act as a disintegration aid.

Hereinafter, the present invention will be specifically described with reference to examples.
[Example 1]
Rice starch granules were prepared by applying the crushing granulation method. Specifically, water was added to 500 g of rice starch, kneaded in a mortar, passed through a sieve having an opening of 500 μm, dried in a dryer at 50 ° C., and further sieved using the same sieve. The resulting granulated product was further conditioned by leaving it in a constant temperature and humidity chamber at 30 ° C. and a relative humidity of 60% for 16 hours to obtain rice starch granules having a water activity (aw) of 0.64. For measurement of water activity (aw), Freund Sangyo Co., Ltd., trade name: EZ-100 was used. About the obtained granules, a laser diffraction type particle size distribution measuring device (Nikkiso Co., Ltd., trade name) The average particle diameter was measured using a Microtrac particle size analyzer) and found to be 163 μm.
The resulting rice starch granules, chlorpheniramine maleate (antihistamine) as an active ingredient, and crystalline cellulose were mixed at a mass ratio shown in Table 1, and 99.5 parts by mass of this mixture was mixed with a lubricant. A tableting test was conducted in which 0.5 part by mass of certain magnesium stearate was mixed and tableted. In addition, "Asahi Kasei Chemicals Co., Ltd. make, brand name: Theolas PH-101" was used for the crystalline cellulose.
The weight ratio of starch to crystalline cellulose is 70.6: 29.4 and their total content in the tablet is 96.5% by weight.

The tableting conditions are as follows.
Tableting machine: Single tableting machine, FY-SS-7 (Fuji Pharmaceutical Machinery Co., Ltd.)
Tableting pressure: 4kN
Tablet: Flat tablet with a diameter of 10mm, mass is 330mg per tablet

The tablet hardness and oral disintegration time of the obtained tablets (oral rapidly disintegrating tablets) were measured as follows. As a result, the tablet hardness of the obtained tablet was 76 N, and the oral disintegration time was 14 seconds.
Tablet hardness: It was measured using a tablet hardness meter SCHLEUNIGER 6D (manufactured by Freund Sangyo Co., Ltd.).
Oral disintegration time: After rinsing the mouth with water, the time from putting one tablet into the mouth and moving the tongue lightly until there was no foreign object feeling due to solid matter was measured.

[Comparative Examples 1-3]
A tableting test was conducted in the same manner as in Example 1 except that the mass ratio of rice starch granules, active ingredient chlorpheniramine maleate (antihistamine) and crystalline cellulose was as shown in Table 1. The obtained tablets were measured in the same manner as in Example 1. The results are shown in Table 1.
In addition, in the thing of the comparative example 1 with excess crystalline cellulose, the characteristic paper-like taste was remarkable when the tablet was included in the mouth.

[Example 2]
Corn starch and the same crystalline cellulose used in Example 1 were mixed at a mass ratio of 7: 3, and 5.0 kg of this mixture was mixed with a fluidized bed granulation coating apparatus (Freund Sangyo Co., Ltd., trade name, flow). Coater FLO-5) was charged. Then, 2500 g of a separately prepared corn starch solution (a solution having a corn starch concentration of 3% by mass which is heated and dissolved by adding corn starch to water) is cooled to room temperature, and then the whole amount is sprayed into the coating apparatus. And granulated. In this granulation, after spraying was completed, the conditions were controlled so that drying did not proceed excessively, and granules having a water activity (aw) of 0.69 were obtained. The average particle size of the granules was 123 μm.
To 96.5 parts by mass of the granules, 3.0 parts by mass of chlorpheniramine maleate as an active ingredient and 0.5 parts by mass of magnesium stearate as a lubricant are added to obtain 200 g of a mixture. Was tableted under the same conditions as in Example 1. However, only the tableting pressure was 6 kN.
The obtained tablet was measured in the same manner as in Example 1. As a result, the tablet hardness was 65 N and the oral disintegration time was 11 seconds.
The mass ratio of starch to crystalline cellulose is about 70.4: 29.6, and the total content of these in the tablet is about 96.5% by mass.

[Example 3]
Rice starch granules were prepared by applying dry granulation to rice starch. Specifically, 300 g of a mixture obtained by adding 0.5 parts by mass of magnesium stearate to 99.5 parts by mass of rice starch was mixed for 5 minutes using an 800 mL V-type mixer having a charging capacity. Subsequently, this mixture was compression-molded at a pressure of 4 MPa (pressure cylinder / gauge pressure) by a roll compression molding method using a roller compactor TF-LABO (Freund Sangyo Co., Ltd.), and the obtained flake portion was adjusted with a screen. The particles were sized using a granulator to obtain granules having an average particle size of 155 μm.
In 55.4 parts by mass of the granules, 23.8 parts by mass of crystalline cellulose same as that used in Example 1, 20.0 parts by mass of ethenzamide (antipyretic analgesic / anti-inflammatory agent) as an active ingredient, and light anhydrous as a fluidizing agent Silica (product of Freund Sangyo Co., Ltd., trade name: Adsolider-101) 0.5 part by mass and magnesium stearate 0.3 part by mass as a lubricant were added to obtain 200 g of a mixture. Tableting was performed under the same conditions as in 1. However, only the tableting pressure was 7 kN.
The obtained tablet was measured in the same manner as in Example 1. As a result, the tablet hardness was 72 N and the oral disintegration time was 13 seconds.
Moreover, the mass ratio of starch to crystalline cellulose is about 69.8: 30.2, and the total content of these in the tablet is about 78.9% by mass.

[Example 4]
An intraoral rapidly disintegrating tablet was prepared by applying the wet granulation method by the crushing granulation method. Specifically, 500 g of a mixture of 30 parts by mass of active ingredient etenzaamide (an antipyretic analgesic / anti-inflammatory agent), 49 parts by mass of rice starch, and 21 parts by mass of crystalline cellulose used in Example 1 was placed in a mortar. Granules for tableting having a water activity (aw) of 0.62 were obtained by the crushing granulation method under the same conditions as in Example 1. To 99.5 parts by mass of the obtained granules, 0.5 part by mass of magnesium stearate as a lubricant was added to obtain 200 g of a mixture, and this mixture was tableted under the same conditions as in Example 1. However, only the tableting pressure was 7 kN.
The obtained tablets were measured in the same manner as in Example 1. As a result, the tablet hardness was 75 N and the oral disintegration time was 15 seconds.
The mass ratio of starch to crystalline cellulose is 70:30, and the total content of these in the tablet is about 69.7% by mass.

[Example 5]
An intraoral rapidly disintegrating tablet was prepared using the dry granule compression method. Specifically, 20 parts by mass of active ingredient ethenzamide (antipyretic analgesic / anti-inflammatory agent), 51.7 parts by mass of rice starch, powdered cellulose (manufactured by Nippon Paper Chemicals Co., Ltd., trade name, KC Flock W-300) 300 g of a mixture of 8 parts by mass and 0.5 parts by mass of magnesium stearate as a lubricant was dry granulated in the same manner as in Example 3 to obtain granules having an average particle size of 125 μm.
To 99.5 parts by mass of the granules, 0.5 part by mass of magnesium stearate as a lubricant was added to obtain 200 g of a mixture, and this mixture was tableted under the same conditions as in Example 1. However, only the tableting pressure was 7 kN.
The obtained tablet was measured in the same manner as in Example 1. As a result, the tablet hardness was 62 N and the oral disintegration time was 16 seconds.
Moreover, the mass ratio of rice starch and powdered cellulose is 65:35, and the total content of these in the tablet is 79.1% by mass.

[Example 6]
An intraoral rapidly disintegrating tablet was prepared by applying the wet granulation method by fluidized bed granulation. Specifically, 3 parts by weight of thiamine hydrochloride (vitamin preparation) as active ingredients, 63 parts by weight of rice starch, and 3 kg of a mixture of 34 parts by weight of crystalline cellulose used in Example 1 were used in Example 2. The same fluidized bed granulation coating equipment was charged. Then, after separately cooling 1000 g of a separately prepared rice starch solution (a solution having a rice starch concentration of 3% by mass by adding rice starch to water and heating and dissolving it), the whole amount is sprayed into the coating apparatus. And granulated. In this granulation, after spraying was completed, the conditions were controlled so that drying did not proceed excessively, and granules having a water activity (aw) of 0.64 were obtained. The average particle size of the granules was 108 μm.
To 99.5 parts by mass of the granules, 0.5 part by mass of magnesium stearate as a lubricant was added to obtain 200 g of a mixture, and this mixture was tableted under the same conditions as in Example 1. However, only the tableting pressure was 7 kN.
The obtained tablets were measured in the same manner as in Example 1. As a result, the tablet hardness was 65 N and the oral disintegration time was 15 seconds.
Moreover, the mass ratio of rice starch and crystalline cellulose is 65.3: 34.7, and the total content of these in the tablet is 96.5% by mass.

[Example 7]
Potato starch granules were prepared by applying the crushing granulation method. Specifically, 2 kg of potato starch and 6 g of aspartame as a sweetener were charged in a 5 L kneader, and a separately prepared potato starch solution (a solution having a potato starch concentration of 5% by mass by adding potato starch to water and dissolving) 800 g was added as a kneaded solution and kneaded. The kneaded product is taken out from the kneader, left to dry in a dryer at 40 ° C., taken out when the loss on drying is 30%, and screen-type crushing granulator (Okada Seiko Co., Ltd., trade name: New) The mixture was crushed by a speed mill and further dried by standing at 40 ° C. for 16 hours, and sieved using a sieve having an opening of 500 μm. The obtained granulated material was conditioned in the same manner as in Example 1 to obtain granules having a water activity (aw) of 0.67 and an average particle size of 147 μm.
A product containing 97% by mass of active ingredient (vitamin) vitamin C in 62.7 parts by mass of the obtained potato starch granules, sold as a direct tableting product “BASF Takeda Co., Ltd.” , Trade name: Vitamin C granule-97 "10 parts by mass, 26.8 parts by mass of the same crystalline cellulose used in Example 1, 0.5 parts by mass of magnesium stearate as a lubricant, and 500 g of the mixture And the mixture was tableted under the same conditions as in Example 1. However, only the tableting pressure was 6 kN.
The obtained tablets were measured in the same manner as in Example 1. As a result, the tablet hardness was 71 N and the oral disintegration time was 12 seconds.
Moreover, the mass ratio of potato starch and crystalline cellulose is 70:30, and these total content in a tablet is 89.3% by mass.

[Reference Experimental Examples 1-1 to 6]
A plurality of samples having different water activities (aw) were obtained by conditioning the granules of rice starch obtained by the wet granulation method, and the influence of the water activity (aw) on tableting properties was examined.
Specifically, a portion of the rice starch granules granulated in Example 1 and not conditioned is left in a constant temperature and humidity chamber at 30 ° C./60% relative humidity, and the other 30 portions. It was left in a constant temperature and humidity chamber at 0 ° C./85% relative humidity. At this time, various water activity samples as shown in Table 2 were obtained by variously changing the standing time.
70 parts by mass of each sample and 30 g of a mixture of 30 parts by mass of the same crystalline cellulose used in Example 1 were sufficiently mixed so as to be uniform in a polyethylene bag, and the resulting mixture was obtained by a hydraulic press molding machine. Tableting test (model experiment) was conducted. At this time, a lubricant was not added to the mixture, and a flat tablet having a compression pressure of 7 kN and a diameter of 10 mm and a mass of 300 mg per tablet was formed.
Table 2 shows the tablet hardness and oral disintegration time measured for the obtained tablets in the same manner as in Example 1. In Reference Experimental Example 1-6, the mixture used for tableting was moist and tended to have low fluidity.

[Reference Experimental Examples 2-1 to 5]
The effect of the mass ratio of rice starch and crystalline cellulose and / or powdered cellulose in tablets on tablet properties was investigated.
Specifically, the rice starch granules after humidity control obtained in Example 1 and the same crystalline cellulose used in Example 1 were mixed at various ratios, and this was performed in the same manner as in Reference Experimental Example 1. The mixture was mixed in a polyethylene bag and tableted in the same manner.
Table 3 shows the tablet hardness and oral disintegration time measured for the obtained tablets in the same manner as in Example 1.

As is apparent from Table 3, in the mass ratio of starch: crystalline cellulose, when the mass ratio of starch is more than 90:10, the disintegration time in the oral cavity becomes longer, while when it is less than 50:50, The paper-like taste became remarkable and resulted in discomfort when taking.

Claims (9)

Contains starch, crystalline cellulose and / or powdered cellulose, and active ingredients;
The mass ratio of the starch to the crystalline cellulose and / or the powdered cellulose is 90:10 to 50:50, and the total content of the starch and the crystalline cellulose and / or the powdered cellulose is 60% by mass or more. Orally rapidly disintegrating tablet characterized by being.   2. The intraoral quick disintegrating tablet according to claim 1, wherein the starch is rice starch. Starch, crystalline cellulose and / or powdered cellulose, and an active ingredient, wherein the weight ratio of the starch to the crystalline cellulose and / or the powdered cellulose is 90:10 to 50:50, and the starch A method for producing an orally rapidly disintegrating tablet, comprising compression-molding a mixture having a total content of the crystalline cellulose and / or the powdered cellulose of 60% by mass or more,
A method for producing an intraorally rapidly disintegrating tablet, comprising granulating at least the starch into granules and then performing the compression molding.   The intraoral speed according to claim 3, wherein the starch is granulated, the granule is mixed with the crystalline cellulose and / or the powdered cellulose and the active ingredient, and the compression molding is performed. A method for producing a disintegrating tablet.   The said starch and the said crystalline cellulose and / or the said powdered cellulose are mixed and granulated, The said active ingredient is mixed with this granule, The said compression molding is performed, The said compression molding is performed. A method for producing an intraoral rapidly disintegrating tablet.   The intraoral quick disintegrating tablet according to claim 3, wherein the compression molding is performed after the starch and the crystalline cellulose and / or the powdered cellulose and the active ingredient are mixed and granulated. Production method.   The method for producing an intraoral quick disintegrating tablet according to any one of claims 3 to 6, wherein the starch is rice starch.   The method for producing an intraoral quick disintegrating tablet according to any one of claims 3 to 7, wherein the granulation is performed by a dry granulation method. The granulation is performed by a wet granulation method, the moisture activity (aw) of the obtained granules is adjusted so that the moisture activity (aw) is 0.4 to 0.8, and then the compression molding is performed. The method for producing an orally rapidly disintegrating tablet according to any one of claims 3 to 7, wherein: