JP5502358B2 - Oral rapidly disintegrating tablet and method for producing the same - Google Patents

Description

  The present invention relates to a rapidly disintegrating tablet in the oral cavity that is rapidly and satisfactorily disintegrated in the presence of saliva or a small amount of water in the oral cavity, and a method for producing the same.

  Tablets, capsules, granules, powders and the like are generally known as dosage forms for oral solid preparations in the fields of pharmaceuticals, foods and the like. However, few of these dosage forms are easy to handle and easy to take. For example, tablets and capsules have a problem that it becomes difficult to swallow as the shape increases, and granules and powders have a problem that they are peeled off when taken and a problem that they enter between teeth. Further, all of these dosage forms require water at the time of taking, and there is a problem that it is difficult to take while sleeping in an emergency or a serious patient.

  In addition, chewable tablets are known as dosage forms that can be taken without water, but those currently available are low in disintegration and suitable for the elderly and children with weak chewing ability. It's hard to say. That is, in order to increase disintegration, it is conceivable to reduce the hardness of the tablet, but in order to prevent breakage during tablet manufacturing operations or transportation, a certain degree of hardness is required. It was difficult to provide chewable tablets with high disintegration.

  Therefore, in view of the above, there has been a demand for the development of an orally rapidly disintegrating tablet that can be easily taken by patients without water, and can be taken easily at any time and anywhere. Several techniques for achieving the objective are also known.

  As a technique for producing such an intraoral rapidly disintegrating tablet, a suspension of an active ingredient and a saccharide in an agar aqueous solution is filled in a mold of a resin film sheet for PTP packaging, and then solidified into a jelly shape. After pressure-drying the tablet material in a dry state containing a method (see Patent Document 1), a drug, a water-soluble binder, and a water-soluble excipient by vacuum drying or ventilation drying, There is known a method (Patent Document 2) in which a molded tablet is humidified and then the humidified tablet is dried. However, these methods have a problem that a special manufacturing facility is required, and the manufacturing process related to it is complicated.

  Therefore, it has been desired to develop a preparation that can be produced by ordinary production equipment, has excellent disintegration properties in the oral cavity, and has an appropriate hardness with no practical problems.

Japanese Patent No. 2807346 Japanese Patent No. 29197771

  Therefore, the present invention can be manufactured without using a complicated manufacturing process or a special device, and has a rapid disintegration property in the oral cavity at the time of use, and an excellent intraoral rapid disintegration as a pharmaceutical having a tablet hardness that does not cause a practical problem. It is an object of the present invention to provide a functional tablet and a method for producing the same.

  As a result of intensive studies to solve the above problems, the present inventors have found that the active pharmaceutical ingredient, D-mannitol and / or lactose hydrate, povidone, magnesium aluminate metasilicate, synthetic aluminum silicate, light By producing a granulated product or a mixture of one or more selected from silicic acid anhydride and crystalline cellulose and a pharmaceutical carrier containing crospovidone, and then compression molding this, a complicated production process or It was found that an intraorally rapidly disintegrating tablet having the same or better performance than a preparation produced by a known method in terms of hardness and disintegration time can be produced without using a special device. Completed the invention.

That is, the present invention provides an oral cavity characterized by producing a granulated product or a mixed product of a pharmaceutical active ingredient and a pharmaceutical carrier containing the following components (a) to (d), and then compression-molding the product. The present invention provides a method for producing an internally disintegrating tablet.
(A) D-mannitol and / or lactose hydrate (b) povidone (c) one or more selected from magnesium aluminate metasilicate, synthetic aluminum silicate, light anhydrous silicic acid and crystalline cellulose (d) Crospovidone

  The intraoral rapidly disintegrating tablet of the present invention is a preparation that exhibits excellent disintegration properties in the oral cavity and has an appropriate hardness with no practical problems, and therefore has excellent dosing properties.

  The intraoral rapidly disintegrating tablet (hereinafter referred to as “the present tablet”) of the present invention is composed of a pharmaceutical active ingredient and a pharmaceutical carrier.

  The pharmaceutical active ingredient of this tablet can be used without particular limitation as long as it is a drug that can be administered orally without causing discomfort such as bitterness and astringency to the extent that it is not difficult to swallow in the oral cavity. In addition, these drugs can be blended within a range that does not hinder the effects of the present invention, and the blendable range varies depending on the properties of the drug.

  Among the pharmaceutical carriers of this tablet, D-mannitol which is component (a) is well known as a sugar alcohol, and lactose hydrate is well known as a saccharide. Any of these can be used as long as it can be generally used in the field of pharmaceutical preparations. The amount of component (a) is about 10 to 90% by mass (hereinafter simply referred to as “%”), preferably 20 to 80%, based on the entire pharmaceutical carrier.

  Of the pharmaceutical carriers of the tablet, povidone as component (b) is a polymer compound also called polyvinylpyrrolidone. Any povidone can be used as long as it can be generally used in the pharmaceutical field. As this povidone, for example, Plusdon K-25 (K value: 25), Plusdon K-29 / 32 (K value: 29 to 32), Plusdon K-90 (K value: 90), Plusdon K-90D (K value) : 90), Plusdon K-90M (K value: 90) (all trade names, ISP Japan), Kollidon 25 (K value: 25), Kollidon 30 (K value: 30), Kollidon 90F (K value: 90) (Both are trade names, BASF Japan). The amount of component (b) is about 0.1 to 20%, preferably 1 to 10%, based on the entire pharmaceutical carrier.

  Furthermore, among the pharmaceutical carriers of the present tablet, component (c) is selected from magnesium metasilicate aluminate, synthetic aluminum silicate, light anhydrous silicic acid and crystalline cellulose. Of these, magnesium metasilicate aluminate is Neusilin, Neusilin UFL2 (both trade names, Fuji Chemical Industry), and synthetic aluminum silicate is heavy, light and extraordinary synthetic aluminum silicate (Kyowa Chemical). Industrial), etc., as light anhydrous silicic acid, AdSolider 101 (trade name, Freund Industries), and as crystalline cellulose, Theolas UF-702, Theolas UF-711, Theolas KG-802, Theolas KG-1000, Theolas PH -101, Theolas PH-101D, Theolas PH-102, Theolas PH-301, Theolas PH-301D, Theolas PH-301Z, Theolas PH-302, Theolas PH-F20JP (all are trade names, Asahi Kasei Chemicals) . These components are not limited to those listed here, and any of those that can be generally used in the pharmaceutical field can be used. The amount of component (c) is about 0.1 to 20%, preferably 1 to 10%, based on the entire pharmaceutical carrier.

  Furthermore, crospovidone which is the component (d) of the pharmaceutical carrier of the tablet is a cross-linked polyvinyl pyrrolidone, and any can be used as long as it can be generally used in the pharmaceutical field. The amount of component (d) is about 0.1 to 20%, preferably 1 to 10%, based on the entire pharmaceutical carrier.

  In order to produce the tablet using each of the above-described components, first, a granulated product or a mixed product of the pharmaceutically active ingredient and a pharmaceutical carrier is produced, and then this is compression molded.

  Examples of the granulation treatment in the production include wet granulation treatment, dry granulation treatment and fluidized bed granulation treatment, and wet granulation treatment is particularly preferable.

  The wet granulation treatment is a treatment in which a pharmaceutically active ingredient and a pharmaceutical carrier are mixed, kneaded with a solvent, and then granulated. In this treatment, methods and apparatuses used for production of general preparations such as crushing granulation method, extrusion granulation method, stirring granulation method, and rolling granulation method can be used. In addition, as a solvent used in this treatment, alcohols such as ethanol and isopropanol used for production of general preparations and water can be used as a solvent.

  The dry granulation treatment is a treatment in which a pharmaceutically active ingredient and a pharmaceutical carrier are mixed, sieved, and then granulated. In this treatment, a method or apparatus used for production of general preparations such as compression granulation can be used.

  The fluidized bed granulation process is a process in which a pharmaceutically active ingredient and a pharmaceutical carrier are mixed and then granulated while spraying a mixed solution of the solvent and a solvent and a binder or the like. In this treatment, a method or apparatus used for production of a general preparation such as a fluidized bed granulation method can be used.

For compression molding of the granulated product obtained by the above granulation treatment, for example, a method or an apparatus generally used for molding a tablet of a rotary tableting machine or a single tableting machine can be used. As the compression pressure in the compression ^{molding, 100kgf / cm 2 ~2000kgf / cm} 2 is preferred.

  Prior to the compression molding, the granulated product was dried using, for example, a fluidized bed dryer or a shelf dryer, a screen mill, a jet mill, a hammer mill, a pin mill using a pin mill, or a vibrating screen. You may attach to operation required for manufacture of preparations, such as sieving.

  Furthermore, as long as there is no hindrance to the effect of the invention, the tablet may be blended with additives that can be generally used in the pharmaceutical field. These additives are mainly blended in a pharmaceutical carrier. Examples thereof include excipients, binders, flavoring agents, fluidizing agents, lubricants, coloring agents, flavoring agents, sweetening agents, and the like. Can be mentioned. Among these, excipients include, for example, sugars such as fructose, sucrose, glucose and trehalose, starches such as corn starch, potato starch, wheat starch and rice starch, and sugar alcohols such as xylitol, erythritol, sorbitol and maltitol As cellulose, powdered cellulose and other binders, for example, carmellose sodium, ethyl cellulose, gum arabic, sodium alginate, dextrin, gelatin, pullulan, hypromellose, polyvinyl alcohol, methylcellulose, carboxyvinyl polymer, etc. Examples thereof include citric acid, tartaric acid, malic acid, ascorbic acid, sodium chloride and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, and sucrose fatty acid ester. Examples of the colorant include edible dyes, edible lake dyes, iron sesquioxide, and yellow iron sesquioxide. . Furthermore, examples of the fragrances include fennel oil, orange oil, chamomile oil, spearmint oil, cinnamon oil, clove oil, mint oil, bergamot oil, eucalyptus oil, lavender oil, lemon oil, rose oil, roman chamomile oil, menthol and the like. Examples of the sweetening agent include aspartame, acesulfame potassium, saccharin, saccharin sodium, dipotassium glycyrrhizinate, stevia, thaumatin, sucralose and the like. These additives can be used alone or in combination.

  The tablet thus obtained has an appropriate hardness with no practical problem, preferably a hardness of 5 kgf or more, and has excellent disintegration properties in the oral cavity, preferably the disintegration time according to the disintegration test of the Japanese Pharmacopoeia. It has a disintegration property within 30 seconds.

  EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated in more detail, these do not limit this invention at all.

Example 1
According to the formulation shown in the following Table 1 and the following production method, the present tablets 1 to 5 and the comparative tablets 1 to 5 were produced. The obtained product of the present invention and comparative product were measured for hardness and disintegration time by the following test methods. The results are also shown in Table 1.

  The product names or grades used, and the manufacturers or dealers are as follows. D-mannitol (Mannit-S, Mitsubishi Corporation Foodtech), lactose hydrate (200M, DMV), trehalose (Trehalose P, Asahi Kasei Chemicals), erythritol (fine powder, Mitsubishi Chemical Foods) xylitol (Xylit P, Towa Kasei Kogyo) ), Sorbitol (Sorbit DP-50M, product food science), glycine (fine powder, organic synthetic chemical industry), magnesium metasilicate aluminate (Neusilin UFL2, Fuji Chemical Industry), light anhydrous silicic acid (Adsolider 101, Freund Industries) Aluminum silicate (light, Kyowa Chemical Industry), crystalline cellulose (Theolas PH-101, Asahi Kasei Chemicals), povidone (Prasdon K-29 / 30, ISP Japan), hydroxypropyl cellulose (HPC-L, Nippon Soda), crospovid (Kollidon CL-F, BASF Japan), croscarmellose sodium (Kickolate ND-200, Nichirin Chemical Industry), carmellose (NS-300, Nichirin Chemical Industry), low-substituted hydroxypropylcellulose (LH-11, Shin-Etsu Chemical Industry) ), Carmellose calcium (ECG-505, Nichirin Chemical Industries), citric acid hydrate (100M, Komatsuya Chemical)

<Production method>
After mixing the active ingredient and the component (a) in the table with a stirring granulator, 250 g of ethanol as a granulating solvent was gradually added and kneaded. Next, after drying this kneaded product with a shelf dryer, the dried product was sized. Furthermore, after adding ingredients other than the above to this sized product and mixing, using a tableting machine, the tablet diameter is 8.5 mm and the mass is 240 mg at a tableting pressure of 1000 kgf / cm ² . Tablets were obtained.

<Test method>
Hardness test:
The test was carried out using a tablet hardness tester (manufactured by Toyama Sangyo Co., Ltd.), the number of tests was 10 tablets, and the average value of the hardness was evaluated.

Disintegration test:
The test was conducted using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd.) with reference to the disintegration test method by the Japanese Pharmacopoeia, and the number of tests was 6 tablets, and the average value of disintegration time was evaluated.

  As is clear from the results in Table 1, the products 1 to 5 of the present invention are excellent in hardness that is practically no problem of about 5 to 6 kgf and a disintegration time of about 11 to 16 seconds according to the disintegration test of the Japanese Pharmacopoeia. It was disintegrating. On the other hand, in comparative products, those with high tablet hardness have poor disintegration properties (Comparative products 1, 3, 4), and conversely those with good disintegration properties have extremely low tablet hardness (Comparative products 2, 5). It was not practical.

  From this result, it was shown that (a) D-mannitol and / or lactose hydrate are extremely important for the intraoral rapidly disintegrating tablet of the present invention.

Comparative Example 1
In order to confirm the action of each carrier component of the present invention, comparative tablets 6 to 11 were produced according to the formulation shown in Table 2 and the production method of Example 1. About each obtained comparative tablet, the hardness and disintegration time were measured similarly to Example 1. The results are also shown in Table 2.

  As is apparent from the results in Table 2, the comparative products 6 to 11 have a certain level of disintegration, but the hardness of the tablet is as low as 5 kgf or less. It was not possible to achieve both.

  From this result, in the intraoral quick disintegrating tablet of the present invention, one or two selected from (b) povidone, (c) magnesium aluminate metasilicate, synthetic aluminum silicate, light anhydrous silicic acid and crystalline cellulose. It was found that blending of more than seeds and (d) crospovidone was essential.

Example 2
The active ingredient and the amount of component (a) were changed as shown in Table 3, and the tablets of the present invention products 6 to 8 were prepared by the production method shown in Example 1. About the obtained tablet, it carried out similarly to Example 1, and measured the hardness and disintegration time. The results are also shown in Table 3.

  As is clear from this result, even if the active pharmaceutical ingredient is replaced, (a) D-mannitol and / or lactose hydrate, (b) povidone, (c) magnesium aluminate metasilicate, synthetic aluminum silicate, It is shown that by incorporating one or more selected from light silicic anhydride and crystalline cellulose and (d) crospovidone, an intraoral rapidly disintegrating tablet having both disintegration property and tablet hardness can be obtained. It was done.

  The intraoral quick disintegrating tablet of the present invention can be manufactured without using a complicated manufacturing process or a special apparatus, and has both excellent moldability and disintegrating property.

  Therefore, this product is suitable for industrial large-scale production, and at the same time exhibits excellent disintegration properties in the oral cavity and has a suitable hardness with no practical problems. It can be widely used as an orally disintegrating agent.

Claims (2)

It is obtained by producing a granulated product or mixed product of an active pharmaceutical ingredient and a pharmaceutical carrier containing the following components (a) to (d), and then compressing only this, and the hardness is 5 kgf or more. In addition, rapidly disintegrating tablets in the oral cavity whose disintegration time is 30 seconds or less in the disintegration test by the Japanese Pharmacopoeia (except for those containing crystalline cellulose).
(A) D-mannitol and / or lactose hydrate (b) povidone (c) one or more selected from magnesium metasilicate aluminate, synthetic aluminum silicate and light anhydrous silicic acid (d) crospovidone A hardness characterized by producing a granulated product or a mixture of a pharmaceutical active ingredient and a pharmaceutical carrier containing the following components (a) to (d), and then only compression molding this: A method for producing an orally rapidly disintegrating tablet (excluding those containing crystalline cellulose) whose disintegration time in a disintegration test by the Japanese Pharmacopoeia is within 30 seconds.
(A) D-mannitol and / or lactose hydrate (b) povidone (c) one or more selected from magnesium metasilicate aluminate, synthetic aluminum silicate and light anhydrous silicic acid (d) crospovidone