JP2011057655A - Orally disintegrable tablet - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an orally disintegrable tablet which contains a drug having unpleasant taste, in which the unpleasant taste in an oral cavity is reduced, and which has an outstanding elution property in the gut. <P>SOLUTION: The orally disintegrable tablet contains a drug having unpleasant taste as a core substance, and uses a multi-core type microcapsule in which a film-forming substance is a hydrophilic polymer gelling agent (for example agar or the like) is used, wherein an average particle size of the multi-core type microcapsule is 100-300 μm. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to an orally disintegrating tablet.

  An orally disintegrating tablet is an oral preparation that rapidly disintegrates in the oral cavity when swallowed in the mouth and is swallowed with saliva, and has the advantage that it can be easily taken without water. However, when the drug contained in the orally disintegrating preparation has an unpleasant taste such as a bitter taste or astringency, there has been a problem that it is accompanied by an unpleasant feeling when taken. In order to solve this problem, various methods have been proposed so far.

  For example, an intraoral rapidly disintegrating tablet in which a granulated product containing a pharmaceutical ingredient having an odd taste is coated with a coating agent, crospopidone and sugar alcohol are blended as a powder, and compression-molded. Intraoral rapidly disintegrating tablet which is an alkyl methacrylate copolymer (see Patent Document 1), (a) Particles (coat particles) obtained by coating a mixture containing a bitter drug and light anhydrous silicic acid with a coating agent (b) By tableting particles (granulated product) obtained by spraying an aqueous solution of hydroxypropyl cellulose onto a mixture containing erythritol, crystalline cellulose, low-substituted hydroxypropyl cellulose, sweetener, and (c) a mixture of crystalline cellulose Oral rapidly disintegrating tablet obtained (see Patent Document 2), (a) unpleasant mixed with excipient And a drug-containing granule formed by granulating or coating a drug having ethyl acetate with ethyl cellulose, and (b) a drug-free granule formed by granulating or coating a sugar or sugar alcohol in water but with a hydrophilic granulating component. , And orally disintegrating tablets with reduced unpleasant taste (see Patent Document 3) have been proposed.

  However, in the above method, if the coating amount is increased in order to suppress the taste of a drug having an unpleasant taste, elution of the drug in the digestive tract is significantly delayed at the time of taking, and there is a problem that sufficient medicinal effect cannot be obtained. . Therefore, an orally disintegrating tablet containing a drug having an unpleasant taste is required to simultaneously satisfy the condition of reducing the unpleasant taste in the oral cavity and the excellent dissolution property in the digestive tract. .

JP 2009-179604 A JP 2008-162989 A Japanese Patent Laid-Open No. 2005-060309

  An object of the present invention is to provide an orally disintegrating tablet containing a drug having an unpleasant taste, in which the unpleasant taste in the oral cavity is reduced and having an excellent dissolution property in the digestive tract. And

As a result of intensive studies to solve the above-mentioned problems, the present inventor, in a multi-core type microcapsule containing a drug having an unpleasant taste, (i) making the film-forming substance agar, and (ii) ) By adjusting the average particle size to a specific range, the orally disintegrating tablet using the microcapsule has a reduced drug unpleasant taste (masking) and is excellent in drug dissolution. The present invention has been completed.
That is, the present invention
(1) An orally disintegrating tablet comprising a multi-core microcapsule containing a drug having an unpleasant taste as a core substance and a film-forming substance being a hydrophilic polymer gelling agent, Orally disintegrating tablets, wherein the average particle size of the microcapsules is 100 to 300 μm,
(2) The orally disintegrating tablet according to (1), wherein the hydrophilic polymer gelling agent is agar,
Is to provide.

  In the orally disintegrating tablet of the present invention, the unpleasant taste of the drug is sufficiently reduced, and the drug dissolution property is excellent.

The figure which shows the structure of the multi-core type microcapsule which concerns on this invention.

  As used herein, an orally disintegrating tablet refers to a preparation that disintegrates in the mouth in the presence of saliva without chewing for about 90 seconds, preferably about 60 seconds, more preferably less than 40 seconds.

  The multicore type microcapsule used for the orally disintegrating tablet of the present invention contains a drug having an unpleasant taste as a core substance, and the film forming substance is a hydrophilic polymer gelling agent. That is, the multi-core microcapsule according to the present invention has a structure in which the core substance 2 is uniformly dispersed in the film-forming substance 1 (FIG. 1). The particle diameter of the core substance is 50 μm or less, preferably 20 μm or less, more preferably 10 μm or less.

  The drug having an unpleasant taste used in the present invention is not particularly limited as long as it is an orally administered drug and has an unpleasant taste such as a bitter taste or astringent taste. For example, an antipyretic analgesic, an antihistamine, Allergic agents, sympathomimetic agents, parasympathetic blockers, central stimulants, H2 blockers, antacids, anti-inflammatory agents, anti-inflammatory agents, bronchodilators, antibacterial agents, antitussives, expectorants, anticholinergics, antitussives Hypnotic sedatives, antibacterials, antihypertensives, skeletal muscle relaxants, preventive and therapeutic drugs for motion sickness, vitamins, herbal medicines and the like.

  Examples of the hydrophilic polymer gelling agent used in the present invention include agar, carrageenan, gellan gum, and preferably agar.

  The multi-core microcapsules used in the present invention are prepared so that the average particle size is preferably 100 to 300 μm, more preferably 100 to 250 μm. Multi-core type microcapsules having an average particle diameter of less than 100 μm are prepared in the manufacturing method using a rotating disk described later, because the solution sprayed from the rotating disk floats in the tower or adheres to the inner wall of the tower. It is difficult in itself. In addition, multi-core microcapsules having an average particle diameter of more than 300 μm are not preferable because the dissolution property of the drug in the digestive tract is reduced when an orally disintegrating tablet using the microcapsules is taken.

  The average particle size of the multi-core microcapsules used in the present invention is measured according to the 15th revised Japanese Pharmacopoeia particle size measurement method (second method: sieving method). Then, the 50% cumulative average particle size is calculated.

  Although the manufacturing method in particular of the multi-core type microcapsule which concerns on this invention is not restrict | limited, For example, it can manufacture by implementing the following processes (1)-(4).

Step (1): A hydrophilic polymer gelling agent and an emulsifier are added to water, and this is dissolved by heating to about 40 to 90 ° C.
Step (2): A drug having an unpleasant taste is added to the solution prepared in (1), and the mixture is stirred and dispersed uniformly.
Step (3): The dispersion prepared in (2) is sprayed into a column filled with liquid nitrogen. The sprayed dispersion is cooled and dropped and becomes frozen fine particles at the bottom of the tower.
Step (4): The fine particles prepared in (3) are collected and dried to a target moisture content by, for example, a shelf-type ventilation dryer, fluidized bed dryer, vacuum freeze dryer, etc., and according to the present invention. A multi-core microcapsule is obtained.

  Examples of the emulsifier in the above step (1) include glycerin fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester, polyoxyethylene sorbitan fatty acid ester and the like. In the present invention, these emulsifiers may be used alone or in combination of two or more. Examples of the glycerin fatty acid ester include glycerin and fatty acid esters, glycerin acetic acid ester, glycerin acetic acid fatty acid ester, glycerin lactic acid fatty acid ester, glycerin succinic acid fatty acid ester, glycerin diacetyl tartaric acid fatty acid ester and polyglycerin fatty acid ester. Esters are included.

  For the stirring in the above step (2), a high-speed rotary dispersing / emulsifying machine such as TK homomixer (manufactured by Primix) or Claremix (manufactured by MTechnic) is used. As stirring conditions, it is preferable to set the rotation speed to about 3000 to 10,000 rpm and the stirring time to about 5 to 60 minutes.

  The content of the hydrophilic polymer gelling agent, the emulsifier, water and the drug having an unpleasant taste in 100% by mass of the dispersion prepared in the above step (2) is not particularly limited. For example, the hydrophilic polymer The gelling agent is usually about 5 to 25% by mass, the emulsifier is usually about 0.01 to 2% by mass, the water is usually about 50 to 75% by mass, and the drug having an unpleasant taste is usually about 1 to 30% by mass. It is preferable to prepare as follows.

  For spraying in the above step (3), for example, a pressurized spray nozzle, a rotary spray nozzle, a rotating disk or the like is used, and a rotating disk is preferable. When a rotating disk is used for spraying, about 4000 to 8000 rpm can be exemplified as a preferable number of rotations of the rotating disk.

  When using a fluidized bed dryer for drying in the above step (4), add about 0.1 to 4% by weight of talc and about 0.1 to 4% by weight of glycerin fatty acid ester to 100% by weight of fine particles in advance before drying. Mixing is preferably performed.

  The content of a drug having an unpleasant taste in 100% by mass of the multi-core microcapsules according to the present invention is about 0.1 to 80% by mass, preferably about 1 to 70% by mass. The characteristic value of the multi-core type microcapsule according to the present invention is that the loss on drying is 10.0% by mass or less, preferably 7.0% by mass or less (1 g, 105 ° C., 2 hours). The loss on drying is measured according to “Japanese Pharmacopoeia General Test Method 10. Drying Loss Test Method”.

  The orally disintegrating tablet of the present invention can be produced by a per se known pharmaceutical method. For example, the multi-core type microcapsule according to the present invention, an excipient (for example, D-mannitol, etc.) and a disintegrant (for example, croscarmellose sodium, etc.) are mixed and tableted to form an oral disintegration of the present invention. Get a lock.

  If necessary, the orally disintegrating tablet of the present invention can be blended with additives that can be used in the production of pharmaceutical preparations. Specifically, for example, stearic acid and its metal salts as lubricants, and talc, light anhydrous silicic acid, hydrous silicon dioxide, sucrose fatty acid esters, etc., and sweeteners such as sugars, sugar alcohols, aspartame, saccharin and the like Salts, glycyrrhizic acid and its salts, stevia, acesulfame potassium, etc., citric acid, sodium citrate, succinic acid, tartaric acid, fumaric acid, etc. as flavoring agents, iron sesquioxide, yellow iron sesquioxide, caramel, riboflavin as coloring agents And menthol and orange oil as perfumes such as aluminum lake.

  Hereinafter, the present invention will be described more specifically based on examples, but the present invention is not limited thereto.

[Example 1]
(1) Preparation of famotidine-containing multi-core microcapsules 100 g of agar (product name: Ultra Agar RB; manufactured by Ina Food Industry Co., Ltd.) and 0.5 g of sorbitan fatty acid ester (product name: L-300; manufactured by Riken Vitamin Company) are purified. In addition to 1250 g of water, it was dissolved by heating to 80 ° C. The obtained solution is kept at 80 ° C., and 350 g of famotidine (manufactured by Yoshindo Co., Ltd.) is added as a drug having an unpleasant taste to the solution, and is uniformly dispersed at 10,000 rpm with a TK homomixer (manufactured by Primix). Stir. The obtained dispersion was deaerated under a reduced pressure of −60 kPa (gauge pressure) to obtain a famotidine-containing dispersion.
Next, the famotidine-containing dispersion was fed to a spray cooling device (tester) in which the lower part of the tower was cooled with liquid nitrogen, and the rotating disk was rotated at a rotational speed of 7000 rpm and sprayed in the form of a mist. The sprayed solution was cooled to become fine particles, dropped to the bottom of the tower, and collected as frozen particles. To 1000 g of the collected fine particles, 8.3 g of talc (product name: Microace P-3; manufactured by Nippon Talc Co., Ltd.) and 20.8 g of glycerin fatty acid ester (product name: Poem HB; manufactured by Riken Vitamin Co., Ltd.) are added. After mixing, using a fluidized bed dryer (model: LAB-1; manufactured by POWREC), drying was performed in the order of 1 hour at 20 ° C, 30 minutes at 30 ° C, and 30 minutes at 50 ° C. The obtained dried product was sieved with a No. 60 sieve (aperture 250 μm) to obtain a famotidine-containing multi-core microcapsule as a passing product. The average particle diameter of the obtained multi-core type microcapsule was 123 μm.
(2) Preparation of orally disintegrating tablets 3 g of the above multi-core microcapsules, 14 g of D-mannitol (Niken Chemical Co., Ltd.) and 3 g of croscarmellose sodium (Product name: Akzizol; Dainippon Sumitomo Pharma Co., Ltd.) were mixed. Thereafter, 200 mg of the obtained mixture was filled in a circular mortar having a diameter of 10 mm, and this was compression-molded with a hand pressing machine with a flat punch from the top and bottom at a tableting pressure of 1 t to obtain an orally disintegrating tablet (Example product 1). Obtained.

[Example 2]
The same procedure as in Example 1 was conducted except that the rotational speed of the rotating disk was 6000 rpm, to prepare a famotidine-containing multi-core microcapsule. The average particle diameter of the obtained microcapsules was 153 μm.
Subsequently, the preparation of an orally disintegrating tablet was carried out in the same manner as in Example 1 to obtain an orally disintegrating tablet (Example product 2).

[Example 3]
The same procedure as in Example 1 was conducted except that the rotational speed of the rotating disk was set to 5000 rpm, to prepare a famotidine-containing multi-core microcapsule. The average particle size of the obtained microcapsules was 177 μm.
Subsequently, the preparation of an orally disintegrating tablet was carried out in the same manner as in Example 1 to obtain an orally disintegrating tablet (Example product 3).

[Example 4]
The same procedure as in Example 1 was performed except that a rotary spray nozzle was used instead of the rotary disk of Example 1 and the rotational speed of the rotary spray nozzle was set to 1000 rpm, to prepare a famotidine-containing multi-core microcapsule. . The average particle diameter of the obtained microcapsules was 221 μm.
Subsequently, preparation of an orally disintegrating tablet was carried out in the same manner as in Example 1 to obtain an orally disintegrating tablet (Example product 4).

[Comparative Example 1]
The same procedure as in Example 1 was performed except that a rotary spray nozzle was used instead of the rotary disk of Example 1, and the rotational speed of the rotary spray nozzle was 500 rpm, to prepare a famotidine-containing multi-core microcapsule. . The average particle diameter of the obtained microcapsules was 360 μm.
Subsequently, the preparation of an orally disintegrating tablet was carried out in the same manner as in Example 1 to obtain an orally disintegrating tablet (Comparative Example product 1).

[Reference Example 1]
(1) Preparation of Famotidine-containing chip (granulated product) 100 g of agar (product name: Ultra Agar RB; manufactured by Ina Food Industry Co., Ltd.), 0.5 g of sorbitan fatty acid ester (product name: L-300; manufactured by Riken Vitamin Co., Ltd.) In addition to 1250 g of purified water, it was dissolved by heating to 80 ° C. The obtained solution was kept at 80 ° C., and 350 g of famotidine (manufactured by Yoshindo Co., Ltd.) was added to the solution, followed by stirring with TK homomixer (manufactured by Primix Co.) at 10,000 rpm. The obtained dispersion was deaerated under a reduced pressure of −60 kPa (gauge pressure) to obtain a famotidine-containing dispersion.
Next, the famotidine-containing dispersion was cooled with stirring and gelled. The gelled famotidine-containing dispersion was dried with a vacuum dryer for 16 hours to obtain a dried product. The obtained dried product was pulverized with a food mixer (manufactured by Zojirushi Co., Ltd.), 5.6 g of talc (product name: Microace P-3; manufactured by Nippon Talc Co., Ltd.), glycerin fatty acid ester ( Product name: Poem HB; Riken Vitamin Co., Ltd. (14.2 g) was added and mixed, and then sieved with No. 50 sieve (aperture 300 μm) to obtain a famotidine-containing chip as a passing product. The average particle diameter of the obtained chip was 168 μm.
(2) Preparation of orally disintegrating tablet 3 g of the above-mentioned chip containing famotidine, 14 g of D-mannitol (manufactured by Nikken Chemical Co., Ltd.) and 3 g of croscarmellose sodium (product name: Akzizol; Sumitomo Dainippon Pharma) are obtained. 200 mg of the obtained mixture was filled into a circular mortar having a diameter of 10 mm, and this was compression molded from above and below with a flat punch at a tableting pressure of 1 t to obtain an orally disintegrating tablet (Reference Example Product 1).

[Reference Example 2]
It was obtained after mixing 2.1 g of famotidine (manufactured by Yoshindo Co., Ltd.), 14.9 g of D-mannitol (manufactured by Nikken Chemical Co., Ltd.) and 3 g of croscarmellose sodium (product name: Akzizol; Sumitomo Dainippon Pharma). 200 mg of the mixture was filled into a circular mortar having a diameter of 10 mm, and this was compression molded from above and below with a flat punch from the top with a tableting pressure of 1 t to obtain an orally disintegrating tablet (Reference Example Product 2).

[Sensory evaluation test]
Table 1 shows the degree of bitterness felt after disintegration in the state where the orally disintegrating tablets (Example products 1 to 4, Comparative Example product 1 or Reference Example product 1 or 2) are placed on the tongue and not chewed in the closed state. Evaluation tests were conducted according to the evaluation criteria shown. The test was conducted with 5 panelists, and the result was obtained as an average value of the scores of 5 people and was symbolized according to the following criteria. The results are shown in Table 2.
○: Average score is less than 0.7 Δ: Average score is 0.7 or more, less than 1.5 ×: Average score is 1.5 or more

[Evaluation of drug dissolution by simple initial dissolution test]
In order to evaluate the dissolution amount of the drug in a state imitating the oral environment having physical action by mastication for the orally disintegrating tablets (Example products 1 to 4, Comparative product 1 and Reference product 1 and 2), An evaluation test by the simple initial dissolution test method shown below was performed. The results are shown in Table 2.
<Test method>
The tip of a 10 ml plastic syringe (made by Terumo) is closed with a rubber stopper, and one orally disintegrating tablet is placed from the rear end of the syringe, and further 10 ml of purified water at 37 ± 1 ° C. is placed. A piston is attached to the rear end of the syringe, and after gently shaking for 30 seconds, a syringe filter (manufactured by WHATMAN) having a pore diameter of 0.45 μm is attached to the tip of the syringe, and the liquid in the syringe is filtered and collected. The collected filtrate is measured for the maximum absorption wavelength near 279 nm by visible ultraviolet spectroscopy to determine the famotidine concentration. Based on the determined famotidine concentration, the dissolution amount relative to the amount of famotidine blended in the orally disintegrating tablet is evaluated as a percentage.

[Evaluation of drug dissolution by paddle method]
The paddle method shown below is used to simulate the dissolution of the drug in the digestive tract when taking orally disintegrating tablets (Examples 1 to 4, Comparative Example 1 and Reference Examples 1 and 2). An evaluation test was conducted. The results are shown in Table 2.
<Test method>
According to the 15th revised Japanese Pharmacopoeia dissolution test (second method: paddle method), 37 ° C. purified water is used as a test solution, and the test is performed at a paddle rotation speed of 50 rotations per minute. At this time, sampling is performed over time, and the famotidine concentration is determined by measuring the maximum absorption wavelength near 279 nm by visible ultraviolet spectroscopy for the sampled test solution. Based on the determined famotidine concentration, the dissolution amount relative to the amount of famotidine blended in the orally disintegrating tablet is evaluated as a percentage. The evaluation results are symbolized according to the following evaluation criteria.
○: Elution rate after 15 minutes is 85% or more ×: Elution rate after 15 minutes is less than 85%

  As is clear from the results of Table 2, the orally disintegrating tablets of the present invention (Example products 1 to 4) were those in which the bitterness of the drug (famotidine) was sufficiently reduced and the drug dissolution was excellent. It was.

1 Film-forming material 2 Core material

Claims (2)

  An orally disintegrating tablet comprising a multi-core microcapsule containing a drug having an unpleasant taste as a core substance and a film-forming substance being a hydrophilic polymer gelling agent, wherein the multi-core microcapsule is used The orally disintegrating tablet is characterized by having an average particle size of 100 to 300 μm.   The orally disintegrating tablet according to claim 1, wherein the hydrophilic polymer gelling agent is agar.

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