JP3435664B2 - Oral fast disintegrating tablet and method for producing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical preparation characterized by a specific physical form, and more specifically, an orally rapidly disintegrating tablet in which a substrate is formed from crushed and uncrushed products, and a tablet thereof. It relates to a manufacturing method.

[0002]

2. Description of the Related Art With the rapid progress of an aging society, conventional pharmaceutical solid oral preparations such as tablets, capsules, granules and powders may be difficult to take. In the case of elderly people, the swallowing ability deteriorates, and therefore tablets and capsules depend on their size, and granules and powders cause discomfort when they remain in the oral cavity. Further, since the above oral solid preparation requires water at the time of taking, it is often the case that a large amount of water is required due to the difficulty of taking. Since elderly people have a higher morbidity rate of chronic diseases, in recent years, development of a practical formulation suitable for long-term administration, easy to drink and easy to handle is desired. For example,
Intraoral rapid disintegrating tablets, pasty preparations, and jelly-like preparations are mentioned, and in particular, oral disintegrating rapidly disintegrating tablets rapidly disintegrate or dissolve in the oral cavity after taking, so any place or time is possible without water. Without taking it, it is a formulation suitable not only for the elderly but also for children.

Generally, the disintegration property and the hardness of a tablet are in a mutually contradictory relationship, and the hardness must be decreased to enhance the disintegration property. However, tablet hardness is an important factor in manufacturing, packaging and distribution processes, and also in taking out from the package at the time of taking. A tablet with insufficient hardness cannot maintain its shape in each of the above steps, and also causes difficulty in accurate administration of the dose. Therefore, development of a technique for producing an orally rapidly disintegrating tablet having appropriate hardness and rapid disintegration is desired, and various means as described below have been proposed.

For example, as an orally rapidly disintegrating type tablet, a tablet produced by dissolving a medicinal component in a carrier matrix and freeze-drying it is known (Manufacturing Ring Chemist, Manuf. Chemist. Feb. 36-37). (199
0)). However, this manufacturing method requires a freeze-drying manufacturing facility and requires a long time for manufacturing, so that the manufacturing cost tends to increase. In addition, the obtained tablets have such a low hardness that they cannot be extruded from PTP (Press Through Package) packaging, which is a general-purpose packaging material, and thus a special packaging material for removing the tablets by peeling off the seal on the back surface of the container is required. The tablets are likely to break or crack during the manufacturing process or when the tablets are taken out from the packaging material, and the handleability is not satisfactory for the elderly.

On the other hand, an orally rapidly disintegrating type tablet produced by compression-molding a wet granulated product is disclosed in, for example, JP-A-5-271.
Japanese Patent No. 054 describes a tablet produced by tableting a granulated product containing a medicinal component, a saccharide, and a water content that moistens the surface of the particle. In addition, international publication WO95 / 2038
No. 0 discloses a tablet produced by compression molding a granulated product containing a saccharide having low moldability and a saccharide having high moldability. A wet granulation process in which a physiologically acceptable organic solvent or water is sprayed and dried is used in the method for producing these tablets. Furthermore, JP-A-8-291051
The publication describes a production method that requires a humidification and drying step using a special device as an additional step after compression molding of a granulated product containing a medicinal component, a water-soluble binder and a water-soluble excipient. Has been done. In addition, international publication WO97 / 4728
No. 7 discloses a method for producing an orally rapidly disintegrating tablet in which a mixture containing a medicinal component, a saccharide having an average particle size of 30 μm or less, and a disintegrating agent is granulated and compression-molded. This manufacturing method is characterized in that saccharides are pulverized before the granulation step and the particle diameter of the saccharides to be blended is adjusted to 30 μm or less as described above. It should be noted that such a wet granulation step is necessary to improve the compressibility of each component during tableting and to increase the tablet hardness, but it is accompanied by humidification and drying, so that it has an unstable drug effect against water and heat. The problem remains that the ingredients cannot be adapted.

Further, when the rapidly disintegrating buccal tablets disclosed in the above publications contain a poorly water-soluble medicinal ingredient, the medicinal ingredient is used in order to improve the absorption rate of the medicinal ingredient into the living body. It is necessary to include some process in the manufacturing process to improve the dissolution property of Examples of such steps include formation of a complex of a medicinal component and a formulation additive, miniaturization of a medicinal component particle by a solid dispersion or a mixing and pulverizing method. However, whichever method is used, the manufacturing process becomes more complicated because a new process is added.

[0007]

Therefore, an object of the present invention is to provide a rapid disintegration in the oral cavity, which has an appropriate hardness and a rapid disintegration property in the oral cavity, and which can be easily obtained without complicated steps. A mold tablet and a method for producing the same.

[0008]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors obtained a mixture of sugars and disintegrants commonly used as additives for tablets, and co-pulverizing them. When a finely divided particle mixture (or co-ground material) is used in combination with untreated sugars, it can be used directly without the steps of dissolution, freezing, granulation, humidification and drying, which were necessary for conventional tableting. It was found that the desired rapid disintegrating tablet in the oral cavity can be obtained by the tableting method.

Thus, according to the present invention, a compression-molded product for tableting powder comprising a co-ground product of a mixture containing a saccharide and a disintegrating agent and an unground product of the saccharide, and having an appropriate hardness. An orally rapidly disintegrating type tablet having a rapid disintegrating property is provided.

Further, according to the present invention, there is provided a method for efficiently producing the rapidly disintegrating tablet in the oral cavity, which comprises the step of co-milling a mixture containing (A) a saccharide and a disintegrant with a milling mill. , (B) a step of physically mixing the co-ground product thus obtained with an unground product of a saccharide or an unground product of a saccharide and a disintegrant to form a tableting powder, (C) then the tableting powder There is provided a production method comprising a step of compression molding by a direct compression method.

The present invention will be described in detail below. In the rapidly disintegrating buccal tablet of the present invention, "moderate hardness" means 3 kg or more, preferably 5 kg or more in a usual hardness test described later, which is caused by abrasion of the tablet in a normal manufacturing process and distribution process. It means the hardness with almost no weight loss or chipping. Further, the tablet hardness of the present invention of 3 kg or more is applicable not only to PTP packaging but also to bottle containers in which tablets are enclosed in containers such as glass and plastic, that is, between tablets or tablets produced in the distribution process. It is thought that it can sufficiently withstand the contact between the container walls. "Promptly disintegrating" means 1 minute 3 in the oral cavity by saliva without taking water when orally administered to healthy adults.
It means disintegrating property such that the whole tablet disintegrates and disperses within 0 seconds, preferably within 1 minute, and more preferably within 40 seconds. In addition, this tablet can be applied to a person who has a dry or little saliva in the oral cavity by using water that wets the oral cavity. Further, the present tablet may be taken with water as it is like a normal tablet without any problem.

In the present invention, the saccharide used as a main excipient means monosaccharides and disaccharides which can be used in the technical field of pharmaceutical preparations, and sugar alcohols thereof. Specific examples thereof include mannitol, erythritol, xylitol, lactose and glucose, maltose, sorbitol, trehalose, sucrose and fructose. These can be used alone or in combination of two or more. The former mannitol, erythritol, xylitol, lactose and the like are preferable, but especially mannitol has a moderate sweetness and a cool sensation, has a low hygroscopic property, and is easy to obtain moderate hardness and rapid disintegrating property, and therefore, it has a palatability. It is advantageous in terms of stability and manufacturability. In the rapidly disintegrating buccal tablets disclosed in the above publications, when using a low moldability saccharide such as mannitol, for example, a high moldability saccharide is added to a low moldability saccharide to granulate (international Published WO95 / 203
80) or, after crushing the total amount of sugars having low moldability contained in the tablet and then adding a disintegrant and granulating (see International Publication WO97 / 47287), a tableting process is performed. Techniques for increasing compression moldability are described. However, the present invention is characterized in that even a sugar having low moldability can be contained in a tablet in an amount of about 80% by weight in an unmilled state, and a wet granulation step involving humidification and drying is not required. ing.

Generally, in order to increase tablet hardness, for example, polyvinylpyrrolidone, hydroxypropylmethylcellulose, methylcellulose, polyvinylalcohol, etc. are used as a water-soluble binder. It does not show strong disintegration.
In the present invention, without using such a water-soluble binder, an appropriate amount of a co-ground product of a saccharide and a disintegrant is added, so that a suitable hardness can be obtained by a simple direct compression method that does not require a granulation step. Tablets can be formed that have and that disintegrate rapidly in the oral cavity. Without being bound by theory, according to the tablet of the present invention, particles or powders of saccharides and disintegrants finely pulverized by a specific pulverizing method are used, and uncompressed saccharide particles which are considerably larger than these particles are used. By using by adding to, etc., the contact area between each particle or powder increases significantly,
Therefore, it is considered that the mixture has a certain hardness only by compression-molding a mixture of these particles, but on the other hand, since a binder such as a water-soluble polymer is not substantially used, it exhibits rapid disintegration.

As the disintegrant which can be used in combination with the above-mentioned saccharides in order to exert such an action, for example,
Examples include crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and partially pregelatinized starch. These can be used alone or in combination of two or more. Among such disintegrants, crospovidone and low-substituted hydroxypropylcellulose are preferred for achieving the desired tablet hardness and disintegration properties.

One of the main characteristics of the present invention is to use a co-ground product of a mixture containing a sugar and a disintegrant. By co-milled is meant that the sugar and disintegrant are milled together as a mixture. Therefore, as will be described later in detail, in the co-ground product according to the present invention from the mixture obtained by separately grinding the saccharide and the disintegrant, one is expected to act as a grinding aid for the other, so that it becomes finer. Is believed to be further promoted.

The ratio of the sugar and the disintegrant used for providing such a co-ground product may be any ratio as long as it is in accordance with the object of the present invention. Generally, the saccharide and the disintegrant are:
The weight ratio is preferably set in the range of 3: 1 to 19: 1.

The tablet according to the present invention comprises, as a material other than the above co-ground material, an unground material of the above-mentioned saccharide or an unground material of a saccharide and an unground material of a disintegrant, and these materials are used for tableting. The end is formed and compression molded. Further, the tablet of the present invention is also required to be a compression molded product having the above-mentioned appropriate hardness and rapid disintegration property. To meet the above requirements, the co-ground product should be 20 to
It preferably accounts for 50% by weight. If it is less than 20% by weight, it is often difficult to achieve an appropriate hardness, and if it exceeds 50% by weight, rapid disintegration may be impaired.

Usually, 200 mg of the above powder for tableting is pressed with a single-shot tableting machine at a tableting pressure of 100 using a punch having a diameter (φ) of 8 mm.
When tabletted at 0 kg, a tablet having a hardness of 3 kg or more and disintegrating within 1 minute and 30 seconds in the oral cavity can be obtained. In addition to the use of co-milling as described above, the disintegrant is
Generally, it has an effect of promoting the bonding between particles to some extent, and therefore the compounding amount thereof may contribute to increasing the tablet hardness while maintaining the rapid disintegrating property of the tablet. However, when a part of a sugar having low moldability such as mannitol is not used in the form of a co-ground product, it is necessary to include a large amount of the above-mentioned disintegrant in order to maintain an appropriate hardness in the compression molded product. However, the tablets produced in this manner are likely to cause discomfort due to the residual disintegrant in the oral cavity during administration, and cannot provide an orally rapidly disintegrating tablet that can be easily taken without water. Incidentally, instead of using the co-ground product of mannitol and the disintegrating agent, each plain ground product of mannitol and the disintegrating agent may be mixed and then added to the unground product of mannitol or the unground product of mannitol and the disintegrating agent. ,
It was extremely difficult to obtain a compression molded product having an appropriate hardness.

The medicinal ingredient used in the present invention may include any medicinal ingredient that can be taken orally, and not only water-soluble but also poorly water-soluble medicinal ingredients can be used. Further, those having no or little bitterness are preferable, but those having bitterness can also be used. As such medicinal ingredients, sleep sedatives, for example, estazolam, nitrazepam, phenobarbital sodium and the like, anxiolytics, for example, diazepam, chlordiazepoxide and the like, antipsychotics, for example, risperidone, pimozide, chlorpromazine and the like, antiparkinson drug, For example, levodopa, amantadine hydrochloride, etc., antipyretic analgesic and anti-inflammatory drug, for example, acetaminophen, ibuprofen, indomethacin, etc., antihistamines, for example, diphenhydramine hydrochloride, chlorpheniramine maleate, homochlorcyclidine hydrochloride, etc., antihypertensive drug, For example, nifedipine, amlodipine besylate, delapril hydrochloride and the like, hyperlipidemic agents, for example, clinofibrate, nicomol, and the like, diabetes drugs, for example, tolbutamide, glyclopyrazide, etc., Bronchodilators, such as theophylline, pirbuterol hydrochloride, skeletal muscle relaxants, such as metocarbamol, chlorzoxazone, antifungal agents, such as itraconazole, fluconazole, antibiotics, such as cephalexin, erythromycin, digestive Examples include ulcer drugs such as cimetidine and famotidine, gastrointestinal motility enhancers such as cisapride and itopride hydrochloride, and vitamins such as ascorbic acid and pyridoxine hydrochloride. These medicinal components may be contained alone or in combination of two or more.

The above-mentioned medicinal components can be added during the step of co-milling the mixture of the sugar and the disintegrator or in the tableting powder such as the non-milled product of the co-milled product and the sugar. If the medicinal ingredient is poorly water-soluble, after the medicinal ingredient is included in the mixture of the sugar and the disintegrant in order to enhance the dissolution rate of the medicinal ingredient from the tablet and improve the bioavailability after administration. It is preferable that the medicinal component particles are finely divided through a pulverizing step. In the present invention, the “poorly water-soluble drug component” means a drug component having a solubility in water of about 0.1 mg / ml or less and relatively stable crystallinity. In the tablet of the present invention,
The content of the medicinal component in the final product tablet is usually 0.05 to 60% by weight, preferably 0.5 to 30% by weight, although it varies depending on the kind of the medicinal component. However, when the medicinal component is water-soluble and the compounding ratio is 10% by weight or more in the tablet, it is added to a physical mixture such as a co-ground product and a non-ground product of sugars to prepare a powder for tableting. preferable.

The tableting powder can contain various additives generally used in the production of tablets, as long as the effects of the present invention are not adversely affected. However, in the present invention, it is considered that the tablet hardness is increased by the use of the co-ground product described above, and therefore it is not always necessary to use a generally known binder. As additives other than the binder, acidulants, for example, citric acid, tartaric acid, malic acid, etc., foaming agents, for example, baking soda, sodium carbonate, artificial sweeteners,
For example, aspartame, sodium saccharin, stevia and the like, fragrances such as lemon, orange and menthol, lubricants such as magnesium stearate,
Colorants such as sucrose fatty acid ester, talc, for example,
Examples thereof include food colors such as food yellow No. 5, food red No. 2 and food blue No. 2, food lake dyes, and iron oxide. These additives can be used singly or in combination of two or more. During the co-milling step of mixing the saccharide and the disintegrant, or during the physical mixing step of the co-milled product and the unmilled material of the saccharide, etc. Thus, an appropriate amount can be added.

Next, the manufacturing method of the present invention will be described in detail.
It In the production method of the present invention, first, the main excipient
After adding the above disintegrant to a part of the sugar,
Thus, a co-ground product of a mixture of sugar and disintegrant is prepared. So
At the same time, if necessary, the medicinal properties and other additives may be added simultaneously.
May be added to prepare a co-ground product. Especially poorly water-soluble
If it is a medicinal ingredient, add it to the co-milling process of this mixture.
By doing so, it is possible to miniaturize the particles of the medicinal component, and
Dissolution of poorly water-soluble medicinal ingredients without changing or adding
The fertility can be easily improved. This is
For example, a poorly water-soluble medicinal ingredient can be used as a low molecular weight water-soluble excipient such as sugar.
The physicochemical properties of medicinal ingredients, such as
For example, 1 to several μm easily without changing the crystal form,
It is known that in some cases, it is possible to reduce the size to 1 μm or less.
It can be understood from that (powder and industry,2
Four, 53-59 (1992)). In addition, it contains a poorly water-soluble medicinal ingredient.
When crushed with crospovidone, which is a disintegrant,
It is also known that the elution properties of
The^R, Kollidon^R, 2nd edition, BASF, pp.171-173 (199
3)). From these facts, the presence in the co-ground product of the present invention
Possible sugars, disintegrants and medicinal ingredients are efficiently miniaturized
You can understand that

The pulverizing step of the above mixture is a dry pulverizing method which does not use water which has been conventionally used, but a pulverizer which can be preferably used is a grinding type, for example, a mortar, a ball mill, a rod mill, a vibrating ball mill, For example, a vibrating rod mill. Specifically, for example, the saccharide and the disintegrant are charged into the vibrating rod mill so that the weight ratio of the saccharide and the disintegrant is 3: 1 to 19: 1, and it depends on the model to be used, the amount charged, the amount ratio, and the like. 5 minutes or more, preferably 5 to 2
Grind for 0 minutes. The same applies when a necessary amount of the medicinal component and other additives are added and the mixture is pulverized at the same time. However, when adding a poorly water-soluble medicinal ingredient, it is necessary to set the charged amount and the crushing time so that the desired dissolution of the medicinal ingredient from the tablet is achieved. Manufacturing temperature is generally room temperature (2
About 0 to 30 ° C.), which does not need to be adjusted,
Regarding the humidity, it is preferable from the viewpoint of production that the relative humidity be 60% or less in consideration of moisture absorption such as the type during the crushing process. Further, in a collision type pulverizer, for example, a hammer mill, a jet mill, etc., it is generally not possible to sufficiently pulverize, and in many cases only a tablet having an inferior hardness can be obtained,
For the purpose of improving the elution of poorly water-soluble medicinal components, it is better to avoid using such a crusher.

Next, the co-ground product obtained in the crushing step is physically mixed with the unground product of sugar or the unground product of sugar and the unground product of disintegrant to obtain a tableting powder. At that time, if necessary, the medicinal component and other additives can be simultaneously added to prepare a tableting powder. In this mixing step, a vinyl bag, a V-type mixer, and the like used for ordinary physical mixing are used, but the means is not limited to these means. However, the number of times of mixing or the time of mixing the lubricant, which is blended as necessary in order to maintain the uniformity of the medicinal components in the powder for tableting and prevent tableting failure (for example, sticking) during compression molding. Account for effects and set. When the powder for tableting has low fluidity, the sugar as the main excipient used in this mixing step is used unless it adversely affects the hardness and disintegration of the tablet obtained in the tableting step. Part of the above may be granulated in advance by an appropriate method.

In the tableting step, a tableting machine generally used for compression molding of powder, for example, a single shot tableting machine or a rotary tableting machine can be used. When the tableting pressure is, for example, 200 mg of the powder for tableting is tableted using a punch having a diameter (φ) of 8 mm and a single-shot tableting machine, it is usually 200 to 15
It is set to 00 kg, preferably about 500 to 1000 kg. The temperature during tableting is usually room temperature (about 20 to 30 ° C)
It does not need to be adjusted. Since the orally rapidly disintegrating tablet of the present invention has an appropriate hardness, it can be processed into a desired shape such as a circle, an ellipse, or a capsule. The diameter or major axis of such tablets is usually 6 to
15 mm, the weight is usually from 80 mg to 10
However, the amount is not limited to this. It is also possible to make a split tablet with a score line for dividing into tablets, which is particularly useful in medical care for the elderly, where half-tablet administration is often desired. Further, these tablets may be coated by a coating method generally used in the production of coated preparations to such an extent that the hardness and disintegration thereof are not adversely affected.

The orally rapidly disintegrating tablet of the present invention has appropriate hardness and rapid disintegration in the oral cavity, and is easy to drink and easy to handle. Therefore, it is suitable for long-term administration to patients, particularly elderly patients, who are applied according to the contained medicinal components, and can also be used for prevention and treatment of pediatric patients.

According to the manufacturing method of the present invention, since a general-purpose crusher, mixer, and tableting machine can be used, the conventional manufacturing apparatus can be used as it is. Furthermore, there is no need to change or add a manufacturing process depending on the dissolution characteristics of the medicinal component. Therefore, the production method of the present invention is extremely simple in the production process without going through complicated steps, and in terms of production cost, production time, etc., it is advantageous as compared with the conventional production method of rapidly disintegrating tablets in the oral cavity. Is.

[0028]

EXAMPLES The present invention will be described in detail below with reference to Examples, Comparative Examples and evaluation tests, but these are not intended to limit the present invention.

The evaluation test was carried out by the following method. (1) Hardness measurement The breaking strength of the tablet in the diameter direction was measured by a tablet hardness meter (TBH28,
(Made by Elweka). The measurement was performed 3 times, and the result represents the average value of 3 times. (2) Thickness measurement The thickness of the tablet was measured with a micrometer (SM-528, manufactured by Techlock). The measurement was performed 3 times, and the result represents the average value of 3 times. (3) Oral disintegration test The oral rapid disintegration type tablet of the present invention is included in the oral cavity of a healthy adult male without water, and the time until the tablet is completely disintegrated and dispersed only by saliva in the oral cavity is measured. did. The test is carried out by 3 persons and the results represent the average value of 3 persons. (4) Dissolution test Using a dissolution tester (NTR-VS3, manufactured by Toyama Sangyo Co., Ltd.), 5 mg of the medicinal component or a tablet containing the medicinal component was added to water 900 at 37 ° C.
Put it in ml and rotate the paddle at 50 rpm,
The eluate was collected over time. By filtering the collected eluate with a filter having a pore size of 0.2 μm, appropriately diluting the filtrate, and then measuring the absorbance at 236 nm using a spectrophotometer (UV-2200A, manufactured by Shimadzu Corporation). The dissolution rate of the medicinal component was determined. The test was performed 3 times and the results represent the average of 3 times.

Hereinafter, examples of tablets and results of comparative tests will be shown.

Examples 1 to 3 A two-component powder containing 3.6 g of mannitol (manufactured by Towa Kasei Co., Ltd.) and 0.4 g of crospovidone (manufactured by ISP Technology Co., Ltd.) was shaken with a vibrating rod mill (TI-100, manufactured by CMT).
Was pulverized for 20 minutes to obtain a co-pulverized product. 6.95 g of mannitol and 0.05 g of magnesium stearate (manufactured by Sakai Chemical Industry Co., Ltd.) were added to 3 g of this co-ground product, and mixed well in a vinyl bag 100 times to prepare a tableting powder. Then, using a single-punch tableting machine (J4, Inei Seieido), a flat corner punch having a diameter (φ) of 8 mm was used, and tableting was performed at a tablet weight of 200 mg and a tableting pressure of 1000 kg. To obtain tablets. In addition, 6.75 g of mannitol, 0.2 g of crospovidone and 0.05 g of magnesium stearate were added to 3 g of the co-ground product, and the mixture was tabletted in the same manner to obtain a tablet of Example 2. Furthermore, 3g of co-ground product
After the addition of 6.55 g of mannitol, 0.4 g of crospovidone and 0.05 g of magnesium stearate, the tablet was similarly tableted to give a tablet of Example 3.

Table 1 shows the component compositions of Examples 1 to 3 and the evaluation test results of the tablets.

[0033]

[Table 1] From Table 1, even in a tablet containing about 70% by weight of unmilled mannitol having a low compression moldability, when containing 30% by weight of the co-ground product of the mixture containing mannitol and crospovidone, the oral disintegration time is 5 kg or more with a hardness of 5 kg or more. It can be seen that tablets within minutes can be easily produced by the direct compression method. Furthermore,
When crushed crospovidone was added, the tablet hardness decreased depending on the amount added, but Example 3 in which 4% by weight was added
According to the data, the oral disintegration time is about 30 seconds while maintaining the hardness of about 5 kg, which shows that the tablet has excellent properties as an orally rapidly disintegrating tablet.

Comparative Examples 1 to 3 9.65 g of unmilled mannitol, 0.3 g of crospovidone and 0.05 g of magnesium stearate,
Mixing and tableting were carried out in the same manner as in Example 1 to obtain tablets of Comparative Example 1. Further, 4 g of mannitol and 4 g of crospovidone were each pulverized with a vibrating rod mill for 20 minutes to obtain a plain pulverized product. Mannitol of this plain ground product 2.
7 g and crospovidone 0.3 g, unground mannitol 6.95 g and magnesium stearate 0.0
After adding 5 g, mixing and tabletting were carried out in the same manner as in Example 1 to obtain tablets of Comparative Example 2. Furthermore, to 2.7 g of mannitol and 0.3 g of crospovidone, which were ground powders, 6.55 g of mannitol and 0.
After adding 4 g and 0.05 g of magnesium stearate, mixing and tableting were carried out in the same manner as in Example 1 to obtain tablets of Comparative Example 3.

Table 2 shows the component compositions of Comparative Examples 1 to 3 and the evaluation test results of the tablets.

[0036]

[Table 2] From Table 2, it can be seen that the tablet hardness is 1 kg or less even if uncrushed crospovidone is added to uncrushed mannitol. Furthermore, the hardness of the tablets of Comparative Example 2 and Comparative Example 3 in which the plain pulverized product of mannitol and crospovidone was added so as to have the same component composition as in Example 1 and Example 3,
It is less than 3 kg, indicating that a tablet having an appropriate hardness that does not collapse during the manufacturing process and distribution process cannot be obtained.

Examples 4 to 6 Tablets were obtained by the composition and manufacturing method of Example 3. However, 3.6 g mannitol and 0.4 g crospovidone
The co-grinding time of the two-component powder containing was changed to 5, 10, and 30 minutes, and respectively set to Example 4, Example 5, and Example 6.

Table 3 shows the evaluation test results of the tablets of Examples 4 to 6.
Shown in.

[0039]

[Table 3] From Table 3, in the crushing step of preparing a co-ground product of mannitol and crospovidone, if the crushing time is increased,
It can be seen that the tablet hardness increases and the oral disintegration time increases. However, in the component composition of Example 3, it is shown that if the co-milling time is 5 to 30 minutes, a tablet having a tablet hardness of 3 kg or more and an oral disintegration time of 1 minute or less can be obtained. In Example 4, the disintegration time in the oral cavity was as short as about 20 seconds, and the tablet had particularly excellent properties as an orally rapidly disintegrating tablet.

Examples 7 to 10 The production method is the same as in Example 3, but the mannitol in the component composition is erythritol (manufactured by Nikken Kagaku), xylitol (manufactured by Towa Kasei), and lactose (manufactured by DMV). ) And glucose (manufactured by Matsutani Chemical Industry Co., Ltd.) were used to obtain tablets of Example 7, Example 8, Example 9 and Example 10, respectively. However, only Example 7 containing erythritol,
The co-milling time was 60 minutes, and the tableting pressure was 1400 kg.

Table 4 shows the evaluation test results of the tablets of Examples 7 to 10.

[0042]

[Table 4] From Table 4, it can be seen that even when a saccharide other than mannitol is blended as the main excipient, tablets having a tablet hardness of 3 kg or more and an oral disintegration time of 1 minute 30 seconds or less are obtained.

Examples 11 to 14 The production method is the same as in Example 3, except that crospovidone in the component composition is croscarmellose sodium (manufactured by Asahi Kasei Kogyo KK), low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd.). Manufactured by Asahi Kasei Kogyo Co., Ltd., and sodium carboxymethyl starch (manufactured by Matsutani Chemical Co., Ltd.) and partially pregelatinized starch (manufactured by Asahi Kasei Kogyo Co., Ltd.), respectively.
The tablets of Example 13 and Example 14 were obtained.

Table 5 shows the evaluation test results of the tablets of Examples 11 to 14.

[0045]

[Table 5] From Table 5, even in the tablets of Examples 11 to 14 in which a disintegrating agent other than crospovidone was blended, similarly to Example 3, the tablet hardness was 3 kg or more and the oral disintegration time was within 1 minute. It had excellent characteristics as.

Next, examples and comparative examples containing a medicinal component in the present invention will be shown.

Examples 15 to 16 3 g of the co-ground product of Example 3 was added to 3 g of the unground product of mannitol.
After adding 55 g, crospovidone 0.4 g, ascorbic acid 3.0 g (manufactured by Wako Pure Chemical Industries, Ltd.), which is a water-soluble medicinal ingredient, and magnesium stearate 0.05 g, they were mixed and compressed in the same manner as in Example 3. The tablet of Example 15 was obtained.
In addition, 3 g of the above co-ground product contained 0.
55 g, crospovidone 0.4 g, ascorbic acid 6.
After adding 0 g and 0.05 g of magnesium stearate, they were mixed and tableted in the same manner to obtain tablets of Example 16.

Table 6 shows the component compositions of Examples 15 to 16 and the evaluation test results of the tablets.

[0049]

[Table 6] It can be seen from Table 6 that the tablet of the present invention has excellent properties as an orally rapidly disintegrating tablet even when it contains about 60% by weight of ascorbic acid. In the production method of the present invention, it can be understood that a large amount of water-soluble medicinal components having low compression moldability can be contained in the same manner as the unmilled mannitol. Examples 17 to 18 Mannitol 3.6 g, crospovidone 0.4 g and A three-component powder containing 0.34 g of nifedipine (manufactured by Wako Pure Chemical Industries, Ltd.), which is a poorly water-soluble drug, was co-ground for 20 minutes using a vibrating rod mill. To 3.25 g of this co-ground product, 6.3 g of mannitol, 0.4 g of crospovidone
g and 0.05 g of magnesium stearate were added, and then mixed and compressed in the same manner as in Example 3 to obtain tablets of Example 17. On the other hand, to 3 g of the co-ground product of Example 3, 6.3 g of mannitol, 0.4 g of crospovidone, 0.25 g of nifedipine and 0.0 g of magnesium stearate were added to the unground product.
After adding 5 g, the mixture was mixed and compressed in the same manner to obtain a tablet of Example 18. However, the tableting pressures of Examples 17 to 18 were both set to 800 kg.

Table 7 shows the component compositions of Examples 17 to 18 and the evaluation test results of the tablets.

[0051]

[Table 7] From Table 7, Example 17 in which nifedipine was added during the co-milling step of mannitol and the disintegrant, and Example 18 in which it was added during the physical mixing step of the co-milled product and the mannitol unmilled product
It can be seen that both of these tablets have excellent properties as an orally rapidly disintegrating tablet.

The results of the dissolution test of the tablets produced in Examples 17 to 18 are shown in FIG.

From FIG. 1, since nifedipine is a poorly water-soluble active ingredient, in Example 18 added in the physical mixing step, the dissolution of the active ingredient from the tablets was slow. On the other hand, in Example 17 in which nifedipine was added during the co-milling step to make it finer, it is shown that the dissolution of the medicinal component can be remarkably improved. In the production method of the present invention, by adding a poorly water-soluble medicinal ingredient during the mixing and pulverizing step, without adding or changing the production step, a rapidly disintegrating tablet in the oral cavity having rapid dissolution of the medicinal ingredient is obtained. It is clear that it is possible to obtain.

[Brief description of drawings]

FIG. 1 is a graph showing the time-dependent dissolution behavior of a medicinal ingredient from tablets produced according to Examples 17 to 18 and a medicinal ingredient alone (control). The black circles show only the medicinal ingredients, the black triangles show the elution of the medicinal ingredients from the tablets of Example 17, and the black squares show the dissolution of the tablets from Example 18.

Continued front page       (56) References JP-A-11-310539 (JP, A)                 Japanese Patent Laid-Open No. 11-12161 (JP, A)                 JP-A-9-71523 (JP, A)                 JP-A-8-175997 (JP, A)                 JP-A-2-184621 (JP, A)

Claims (12)

(57) [Claims] 1. A compression-molded product for tableting, comprising a co-ground product of a mixture containing a saccharide and a disintegrating agent, and a non-ground product of the saccharide, and having an appropriate hardness and a rapid disintegrating property. An orally rapidly disintegrating tablet having. 2. The tablet according to claim 1, wherein the tableting powder further contains an unpulverized disintegrant. 3. The tableting powder further contains a medicinal component.
Or the tablet according to 2. 4. The tablet according to claim 3, wherein the poorly water-soluble active ingredient is contained in a mixture containing a sugar and a disintegrant. 5. The tablet according to claim 1, wherein the saccharide is at least one selected from the group consisting of monosaccharides, disaccharides and sugar alcohols thereof. 6. The disintegrating agent is at least one selected from the group consisting of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and partially pregelatinized starch. Tablets. 7. The active ingredient is a sleep sedative, an anxiolytic, a psychotropic drug, an anti-Parkinson's drug, an antipyretic analgesic / anti-inflammatory drug, an antihistamine drug, an antihypertensive drug, a hyperlipidemic drug, a diabetic drug, a bronchial drug. The tablet according to any one of claims 3 to 6, which is selected from the group consisting of a dilator, a skeletal muscle relaxant, an antifungal drug, an antibiotic, a drug for peptic ulcer, a gastrointestinal motility enhancer, and a vitamin. 8. A co-ground product of a mixture containing a sugar and a disintegrant in a weight ratio of 3: 1 to 19: 1, respectively, in an amount of 20 to 50% by weight based on the total weight of the tablet. The tablet according to any one. 9. The tablet according to claim 1, further comprising at least one selected from the group consisting of an acidulant, a foaming agent, an artificial sweetener, a flavor, a lubricant and a coloring agent. 10. A mixture containing a saccharide and a disintegrant is co-pulverized with a grinding mill, and the co-pulverized product thus obtained is physically mixed with an unpulverized saccharide or an unpulverized saccharide and a disintegrant. 3. The method for producing a tablet according to claim 1 or 2, comprising the steps of forming a tableting powder by means of a direct compression method and then compression-molding the tableting powder by a direct tableting method. 11. The production method according to claim 10, which is included in the step of co-milling the medicinal component or the step of forming a tableting powder. 12. The production method according to claim 11, wherein the poorly water-soluble medicinal component is included in the co-grinding step.