JP5201837B2 - Orally disintegrating tablets - Google Patents

Description

  The present invention relates to an intraorally rapidly disintegrating tablet that suppresses bitterness, has a good texture, and has a good flavor with respect to a drug having a bitter taste.

In order to make it possible for patients with weak swallowing power, such as elderly people and children, to take a bitter-tasting drug easily without water, intraoral rapidly disintegrating tablets masking bitterness have been developed and studied.
For example, for the purpose of suppressing the unpleasant taste of acetaminophen blended in solid preparations for internal use, technology has been developed to blend aspartame or a combination of aspartame and a sour substance. Yes.
However, the unpleasant taste of acetaminophen is not sufficiently suppressed by the method of simply aspartame (Patent Document 1), and also by the method of combining other sweeteners with glycyrrhizic acid (Patent Document 2). The effect was not sufficient.

  Further, in the method of using a combination of aspartame and a sour substance (Patent Document 3), acetaminophen, aspartame, and a sour substance are merely mixed together, and this results from the blending of acetaminophen over time. Discoloration of the preparation occurred, and there was a problem in terms of stability.

Furthermore, granules containing acetaminophen and granules containing aspartame and sour-tasting substances are separately granulated, and by mixing both, the unpleasant taste of acetaminophen is suppressed, and the formulation A solid preparation containing acetaminophen that prevents discoloration over time (Patent Document 4) has been reported.
However, a practical acetaminophen-containing intraoral rapidly disintegrating tablet that has a good flavor and stability over time, has a good texture and low friability has not yet been developed.

The tablet physical properties required for an intraoral quick disintegrating tablet include hardness for ensuring product strength and disintegration property in the oral cavity. However, it is generally difficult to satisfy all these physical properties at the same time.
For example, if the hardness of the tablet is increased, the chewability and disintegration property are impaired, and conversely, if the hardness is adjusted to be low in order to improve the chewability and disintegration property, the tablet becomes brittle and easily broken during production or storage.

Accordingly, various techniques for improving these points have been proposed. For example, as one of them, a rapidly disintegrating tablet in the oral cavity is prepared by mixing a tablet with wetted sugar, drug and water, and then drying. A method has been proposed (Patent Document 5). However, in the above method, there is a problem in manufacturing such that a drying process must be performed and special equipment is required.
In addition, various methods have been proposed (Patent Documents 6 to 9), but the present situation is that satisfactory oral disintegrating tablets have not yet been obtained.

JP-A-2-56416 JP-A-6-298668 JP 2000-290199 A JP 2001-294524 A Japanese Patent Laid-Open No. 5-271054 Japanese Patent Laid-Open No. 10-182436 JP-A-10-298062 JP 2000-273039 A Republished 97-47287

  In view of the current situation, the present invention suppresses the bitterness of a drug having a bitter taste, has a good flavor and touch, has a practical hardness with low friability as a tablet, and is stable over time. An object of the present invention is to provide an intraoral quick disintegrating tablet which is easy to handle and has characteristics such as that the preparation does not discolor, and a method for producing the same.

  As a result of diligent investigations by the present inventors in order to solve such a problem, particles obtained by coating a mixture containing a drug having a bitter taste and light anhydrous silicic acid with a coating agent and a granulated product having a sweetener are separately produced. However, it was found that a tablet obtained by adding another excipient or the like to the tablet to achieve the above-mentioned purpose was completed, and the present invention was completed.

Therefore, the invention according to claim 1, which is a basic aspect of the present invention for solving the above-mentioned problems, has the following configuration.
An intraoral quick disintegrating tablet obtained by tableting a mixture of the following (a) to (c).
(A) A water-insoluble polymeric substance, gastric soluble polymeric substance, enteric polymeric substance, or wax obtained by dissolving a mixture containing only two kinds of a bitter drug and light anhydrous silicic acid in water or an organic solvent Particles (coated particles) coated with a coating agent selected from a particulate material ,
(B) Particles (granulated product) obtained by spraying an aqueous solution of hydroxypropylcellulose onto a mixture containing erythritol, crystalline cellulose, low-substituted hydroxypropylcellulose, and sweetener,
(C) Crystalline cellulose.

As yet another aspect, the invention described in claim 2 of the present invention has the following configuration.
An intraoral quick disintegrating tablet obtained by tableting a mixture of the following (a) to (e).
(A) A water-insoluble polymeric substance, gastric soluble polymeric substance, enteric polymeric substance, or wax obtained by dissolving a mixture containing only two kinds of a bitter drug and light anhydrous silicic acid in water or an organic solvent Particles (coated particles) coated with a coating agent selected from a particulate material ,
(B) Particles (granulated product) obtained by spraying an aqueous solution of hydroxypropylcellulose onto a mixture containing erythritol, crystalline cellulose, low-substituted hydroxypropylcellulose, and sweetener,
(C) crystalline cellulose,
(D) a mixed pulverized product comprising at least one selected from the group consisting of a refreshing agent, starches, and celluloses;
(E) A dye-doubled powder comprising at least one selected from the group consisting of a colorant, starches and celluloses.

  The most specific present invention is an orally rapidly disintegrating tablet in which the sweetener is one or more selected from the group consisting of aspartame and acesulfame potassium, and an orally rapidly disintegrating tablet in which the drug having a bitter taste is acetaminophen. is there.

INDUSTRIAL APPLICABILITY According to the present invention, there is provided an intraorally rapidly disintegrating tablet having a practical tablet hardness with a good taste, a good touch and a low friability, with reduced drug bitterness. Such intraoral quick disintegrating tablets are stable over time, easy to handle, and have the characteristics that the preparation does not change color.
Therefore, it is particularly excellent in that an intraoral rapidly disintegrating tablet with reduced bitterness of a drug that can be easily taken without water by patients with weak swallowing power, such as elderly people and children, can be provided.

  In particular, an orally rapidly disintegrating tablet that suppresses the bitterness of the drug is provided by mixing a drug having bitterness with light anhydrous silicic acid, forming this into coated particles coated with a coating agent, and compressing it into a tablet. There is a feature in the point, and it has an advantage of being an intraorally rapidly disintegrating tablet which is excellent in stability over time and has good in vivo absorbability.

As described above, the intraoral rapidly disintegrating tablet provided by the present invention basically compresses a mixture of the following components (a) to (c) or a mixture of the following components (a) to (e). It is obtained by this.
(A) A water-insoluble polymeric substance, gastric soluble polymeric substance, enteric polymeric substance, or wax obtained by dissolving a mixture containing only two kinds of a bitter drug and light anhydrous silicic acid in water or an organic solvent Particles (coated particles) coated with a coating agent selected from a particulate material ,
(B) Particles (granulated product) obtained by spraying an aqueous solution of hydroxypropylcellulose onto a mixture containing erythritol, crystalline cellulose, low-substituted hydroxypropylcellulose, and sweetener,
(C) crystalline cellulose,
(D) a mixed pulverized product comprising at least one selected from the group consisting of a refreshing agent, starches, and celluloses;
(E) A dye-doubled powder comprising at least one selected from the group consisting of a colorant, starches and celluloses.

The component (a) to be coated particles is a particle in which a bitter drug is mixed with light anhydrous silicic acid and coated with a coating agent. By coating the coating agent together with light anhydrous silicic acid, the particle disintegration is excellent, while it is characterized in that the bitter taste of the drug is coated.
That is, even if the intraoral quick disintegrating tablet of the present invention disintegrates immediately in the oral cavity after taking, the coated particles are transported to the stomach or intestinal tissue which is the absorption site while covering the bitter taste, where good in vivo absorption is achieved. It is prepared to show sex.

  The light silicic acid used for the preparation of the coated particles is not particularly limited, and light silicic acid generally used in the pharmaceutical field can be used, for example, Aerosil.

As the coating agent, various polymer substances can be used depending on the drug to be contained, and examples thereof include water-insoluble polymer substances, gastric polymer substances, enteric polymer substances, and wax-like substances. .
Examples of the water-insoluble polymer substance include water-insoluble cellulose ethers such as ethyl cellulose and Aquacoat (trade name, manufactured by Asahi Kasei Co., Ltd.); ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl copolymer (for example, Product name: Eudragit RS, manufactured by Rohm Co., Ltd.), water-insoluble acrylic copolymers such as ethyl acrylate / methyl methacrylate copolymer dispersion (for example, product name: Eudragit NE30D, manufactured by Rohm Co., Ltd.), and the like. .

  Examples of the gastric soluble polymer substance include gastric soluble polyvinyl derivatives such as polyvinyl acetal diethylaminoacetate; methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer (for example, trade name: Eudragit E, Rohm Co., Ltd.) Gastric soluble acrylic acid copolymers and the like.

  Examples of the enteric polymer substance include enteric cellulose derivatives such as hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose phthalate, and carboxymethylethylcellulose; methacrylic acid / methyl methacrylate copolymer ( For example, enteric properties such as trade names: Eudragit L100, Eudragit S, both manufactured by Laem Co., Ltd., methacrylic acid / ethyl acrylate copolymer (for example, trade names: Eudragit L100-55, Eudragit L30D55, Laem Co., Ltd.), etc. Examples thereof include acrylic acid copolymers.

Examples of the wax-like substance include solid fats such as hardened castor oil, hardened coconut oil, and beef tallow; higher fatty acids such as stearic acid, lauric acid, myristic acid, and palmitic acid; higher alcohols such as cetyl alcohol and stearyl alcohol.
These polymer substances can be used alone or in combination of two or more.

  In the present invention, a water-insoluble polymer substance ethyl acrylate / methyl methacrylate copolymer dispersion (for example, trade name: Eudragit NE30D, manufactured by Rohm Co., Ltd.) is particularly preferable.

These polymer substances are coated in a mixture of a bitter drug and light anhydrous silicic acid to prepare coated particles. The solution used for coating is water and / or an organic solvent, such as methanol, Alcohol solvents such as ethanol, propanol and isopropanol; Halogenated hydrocarbon solvents such as dichloromethane, chloroform, chloroethane, trichloroethane and carbon tetrachloride; Ketones such as acetone and methyl ethyl ketone; Nitriles such as acetonitrile; n-hexane and cyclohexane And the like.
These media may be used singly or in combination of two or more at an appropriate ratio.

  The coated particles can be obtained by coating a mixture of a drug and light silicic anhydride with a coating agent by a method known per se. The particle diameter of the coated particles is not particularly limited as long as it does not feel a rough feeling in the oral cavity. For example, the average particle diameter is usually preferably about 0.1 to about 350 μm, more preferably about 5 to about 250 μm, and further preferably about 50 to about 250 μm. When the particle diameter is larger than 350 μm, a sense of discomfort such as a rough feeling in the oral cavity is strongly recognized.

In the present invention, a commonly used plasticizer can be added as long as the properties of the coated particles are not impaired. In addition, in order to facilitate drug elution from the coated particles, in addition to the aforementioned water-insoluble polymeric substances, gastric soluble polymeric substances, enteric polymeric substances such as enteric polymeric substances, waxy substances, etc., which are coating agents. In addition, water-soluble polymer substances, sugars, salts and the like can be blended.
Examples of such water-soluble polymer substances include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and the like. These water-soluble polymer substances and saccharides may be used alone or in combination of two or more. it can.
The blending amounts of the water-soluble polymer substance and saccharide can be adjusted as appropriate so as to control the dissolution rate of the drug from the coated particles.

The coated particles of the present invention can be prepared by a general stirring granulation method or a rolling fluid granulation method. The prepared particles are further ventilated in a fluidized bed granulator until the particles are smoothly flowed.After ventilating, the particles are crushed and sized by a pulverizer, dried by a fluidized bed granulator, Coated particles can be produced by sieving.
The temperature range of the fluidized bed granulator is not particularly limited, but the temperature of the product is about 40 ° C. to about 60 ° C. when coating with water, and about 30 ° C. to about 60 ° C. when using an organic solvent. The set temperature, the amount of spray liquid, the amount of spray air, and the like are set so that The concentration of the drug to be coated, the ratio of the polymer substance, the amount and the like can be appropriately adjusted according to the target elution rate.

On the other hand, the granulated product as the component (b) is a granulated product obtained by spraying a hydroxypropyl cellulose aqueous solution onto a mixture containing erythritol, crystalline cellulose, low-substituted hydroxypropyl cellulose and a sweetener.
Ingredients to be blended as a granulated product reduce discomfort at the time of taking the erythritol and sweetener when the tablet rapidly disintegrating in the oral cavity of the present invention disintegrates in the oral cavity after taking, The low-substituted hydroxypropylcellulose exhibits the property of improving the feel of the tongue.

As a sweetening agent to be used, aspartame and acesulfame potassium can be mentioned, and commercially available products can be appropriately used, and one or both of them can be used in combination.
In addition, commercially available products can be used as appropriate even in erythritol, crystalline cellulose, and low-substituted hydroxypropylcellulose.

Specifically, the granulated product can be prepared as follows.
That is, erythritol, crystalline cellulose, low-substituted hydroxypropyl cellulose, and further aspartame and acesulfame potassium as a sweetening agent are charged into a fluid bed granulator and mixed. Next, an aqueous solution of hydroxypropylcellulose is sprayed by, for example, a top spray method, granulated, dried after completion of spraying, and sieved to prepare a granulated product.

  The intraoral rapidly disintegrating tablet provided by the present invention comprises (a) the coated particles prepared as described above, and (b) the granulated product as the component with crystalline cellulose as an excipient. Mixed and tableted, or in addition to this, a mixed pulverized product composed of a cooling agent such as menthol and starches and / or celluloses, a colorant and starches and / or pigments composed of celluloses It is manufactured by mixing and tableting.

  In the present invention, the mixed pulverized product composed of a refreshing agent and starches and celluloses is added as a refreshing agent, and is added to give a refreshing feeling when it is disintegrated in the oral cavity after taking. The Examples of the refreshing agent include l-menthol, 2- or 3-substituted-p-menthanediol, N-substituted-p-menthane-3-carboxamide, 3-substituted-p-menthane, trialkyl-substituted cyclohexanecarboxyamide, and the like. These can be used alone or in combination of two or more. Preferably, it is 1-menthol which makes a refreshing feeling strong. Specifically, after l-menthol and corn starch are mixed, a mixed pulverized product as a refreshing agent can be obtained by passing through a pulverizer and sieving.

In addition, the pigment double powder can be prepared by mixing a pigment and starches, celluloses and the like in a mortar.
Examples of the dye include food dyes such as food yellow No. 5, food red No. 2 and food blue No. 2; food lake dyes such as red No. 3 aluminum lake; Bengala and the like.
The above starches include corn starch, wheat starch, rice starch, potato starch, tapioca starch, pregelatinized starch, partially pregelatinized starch, high amylose starch, hydroxypropyl starch, starch hydrolysate, starch acetate, phosphate starch Octenyl succinate starch, carboxymethyl starch, phosphate cross-linked starch, oxidized starch, dialdehyde starch, acid-treated starch, sodium hypochlorite-treated starch and the like.
Examples of celluloses include crystalline cellulose, powdered cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, and the like.
These excipients can be used alone or in combination of two or more.

  The amount of crystalline cellulose to be used varies depending on the amount of coated particles to be mixed, the amount of granulated product used, etc., and cannot be unconditionally limited. 80% by weight.

  It should be noted that various other additives can also be added at the stage of tableting as a tablet. Examples of such additives include further excipients, disintegrants, binders, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, colorants, stabilizers, and the like. Such additives can be used alone or in combination of two or more.

  Other excipients can also include pharmaceutically acceptable sugars or sugar alcohols. Specific examples of the sugar or sugar alcohol include xylitol, erythritol, glucose, mannitol, sucrose, or lactose. Of these, erythritol is particularly preferred. Such saccharides can be used alone or in combination of two or more. Examples of the lubricant include stearic acid and magnesium stearate.

When such a excipient is used, the amount of the excipient is increased when the dose of the drug is small, and the amount of the excipient is decreased when the dose of the drug is large. It can adjust suitably so that it may become a tablet of a desired magnitude | size. The blending amount is, for example, 10 to 80% by weight per tablet together with crystalline cellulose.
Examples of the disintegrant include starches such as corn starch, carmellose calcium, partially pregelatinized starch, crospovidone, and low-substituted hydroxypropylcellulose.

Examples of acidulants include citric acid, tartaric acid, malic acid and the like.
Examples of the foaming agent include baking soda. Examples of sweeteners include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia, thaumatin and the like. Examples of the fragrances include lemon, lemon lime, orange, menthol and the like. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like. Examples of the colorant include edible pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2; edible lake pigments; These additives can be appropriately added in an appropriate amount by combining one kind or two or more kinds.

  The drug contained in the intraoral quick disintegrating tablet of the present invention is not particularly limited as long as it is a therapeutically or prophylactically effective active ingredient having a bitter taste. For example, hypnotic sedative, sleep inducer, anti-anxiety agent, antiepileptic agent, antidepressant, anti-parkinsonian agent, neuropsychiatric agent, central nervous system agent, local anesthetic, skeletal muscle relaxant, autonomic nerve agent, antipyretic Analgesic / anti-inflammatory agent, antispasmodic agent, supressive agent, cardiotonic agent, arrhythmic agent, diuretic, antihypertensive agent, vasoconstrictor, vasodilator, cardiovascular agent, hyperlipidemic agent, respiratory accelerator, antitussive agent, Stagnation, antitussives, bronchodilators, antiseptics, intestinal, peptic ulcers, stomach digesters, antacids, laxatives, antibacterials, gastrointestinal drugs, adrenal hormones, hormones Urinary organs, vitamins, hemostatics, liver diseases, ventilation treatments, diabetes, antihistamines, antineoplastics, chemotherapeutics, antibiotics, antibacterials, general colds, nourishing tonics And osteoporosis drugs.

  The particle size of the drug is not particularly limited, but is preferably a high density powder. The amount of the drug is not particularly limited as long as it is usually a therapeutically effective amount, but it is usually preferably 50 w / w% or less based on the total weight of the tablet.

  The intraoral rapidly disintegrating tablet provided by the present invention has an oral disintegration time of less than 30-60 seconds, and the friability is 0.4% or less at 100 rotations of the tablet friability test (Japanese Pharmacopoeia). Moreover, even after the end of the severe test, the preparation has practical tablet hardness and does not discolor while maintaining disintegration.

The present invention provides an intraoral quick disintegrating tablet in which the bitter taste of acetaminophenone as a drug is coated with a coating agent.
That is, the rapidly disintegrating tablet in the oral cavity provided by the present invention is a drug in which acetamine phene, which is a drug, is coated with a coating agent, so that the bitter taste of acetaminophen is suppressed, and erythritol, crystalline cellulose, low It is an orally disintegrating tablet that can suppress bitterness and adjust sweetness by adjusting the amount of substitution hydroxypropylcellulose and a sweetener (for example, aspartame, acesulfame potassium).

  Hereinafter, the present invention will be described in detail by way of specific examples, but the present invention is not limited to these examples.

Example 1:
(Process 1)
300 g of acetaminophen high-density powder [trade name, manufactured by Tyco Healthcare Japan Co., Ltd.] and 10 g of light anhydrous silicic acid [Aerosil 200, trade name, manufactured by Nippon Aerosil Co., Ltd.] are stirred and granulated [VG-01, Co., Ltd.] and mixed (blade 350 rpm, cross screw 1500 rpm). Next, 88 g of Eudragit NE30D [trade name, manufactured by Degussa Japan Co., Ltd.] was injected while mixing and coated with acetaminophen high-density powder. Next, the resulting coated particles were ventilated with a fluidized bed granulator [MP-01, manufactured by POWREC Co., Ltd.] until the coated particles flowed smoothly (supply temperature 35 ° C., supply air volume 70 m). ³ / hr). After ventilating, the coated particles were pulverized and sized with a pulverizer [TC-150, manufactured by Fukae Powtech Co., Ltd.] (screen φ1 mm, rotor rotation speed 3000 rpm), and fluidized bed granulator [MP-01, KK] Coated particles were dried by a powder manufactured by POWREC (supply temperature 70 ° C., supply air volume 40 m ³ / hr, drying end point / product temperature 50 ° C.), and sieved with a sieve (aperture 500 μm).

(Process 2)
Erythritol [manufactured by Nikken Kasei Co., Ltd.] 200 g, crystalline cellulose [Theolas PH-101, trade name, Asahi Kasei Chemicals Co., Ltd.] 50 g, low-substituted hydroxypropyl cellulose [L-HPC (LH-21), trade name , Shin-Etsu Chemical Co., Ltd.] 70 g, Aspartame [Ajinomoto Co., Ltd.] 10 g, Acesulfame Potassium (Neutrinova Co., Ltd.) 15 g are charged into a fluidized bed granulator [MP-01, manufactured by Powrec Co., Ltd.] Further, 10.8 g of hydroxypropylcellulose [HPC-SSL, trade name, Nippon Soda Co., Ltd.] was dissolved in 49.2 g of purified water, and 38.89 g of the solution was sprayed by the top spray method (amount of sprayed liquid 10 g / min). Spray air pressure 1.2 MPa, supply air volume 40 m ³ / hr, supply air temperature 55 ° C., and after spraying, dry (supply air volume 30 m ³ / sieving with a sieve (opening temperature: 850 μm), and a granulated product was obtained.

(Process 3)
1-Menthol [manufactured by Kobayashi Katsura Co., Ltd.] 50 g and corn starch 50 g were mixed in a plastic bag, and then passed through a crusher (P-14 Frichche) (no screen, rotor speed 2000 rpm), sieve ( The mixture was sieved with an opening of 1180 μm to obtain a menthol mixed and pulverized product.

(Process 4)
2 g of red No. 3 aluminum lake (manufactured by Saneihara F.F.I.) and 18 g of crystalline cellulose (Ceolus PH-101, trade name, manufactured by Asahi Kasei Chemicals) were mixed in a mortar to obtain a dyed powder powder.

(Process 5)
336.4 g of coated particles obtained in each of the above steps, 352.0 g of granulated product, 2.24 g of menthol mixed and pulverized product, 0.45 g of powdered powder powder, crystalline cellulose (Theorus PH-302, trade name, Asahi Kasei Chemicals) 189.04 g and magnesium stearate (Tahei Kasei Kogyo) 4.47 g were mixed, and 894. containing 300 mg of acetaminophen per tablet using a rotary tableting machine (HATA RT3A, manufactured by Hata Iron Works). 6 mg tablets were made. The specific volume of the tableting powder at this time was 2.34 (mL / g).

(Tablet hardness, friability, oral disintegration time)
The tablet hardness, friability, and oral disintegration time were measured according to conventional methods.
The obtained tablet had a hardness of 7.0 kp (n = 10), a friability of 0.35% (100 rotations), and an oral disintegration time of 52 seconds (n = 3). Moreover, the moldability of the tablet was good, and the result of the severe test was better than the comparative example described later.

Example 2:
(Steps 1-4)
Prepared according to Example 1 above.

(Process 5)
336.4 g of coated particles obtained in each of the above steps, 352.0 g of granulated product, 2.12 g of menthol mixed pulverized product, 0.42 g of dyed powder powder, crystalline cellulose (Theorus PH-302, trade name, Asahi Kasei Chemicals) 155.40 g and 4.25 g of magnesium stearate (produced by Taihei Kasei Kogyo Co., Ltd.), and then mixed with 850. containing 300 mg of acetaminophen per tablet using a rotary tableting machine (HATA RT3A, manufactured by Hata Iron Works). 6 mg tablets were made.
(Tablet hardness, friability, oral disintegration time)
The hardness, friability, and disintegration time in the oral cavity were obtained in the same manner as in Example 1.

Example 3:
(Process 1)
Prepared according to Example 1 above.

(Process 2)
Erythritol [manufactured by Nikken Kasei Co., Ltd.] 200 g, crystalline cellulose [Theoras PH-101, trade name, manufactured by Asahi Kasei Chemicals Co., Ltd.] 57.5 g, low-substituted hydroxypropyl cellulose [L-HPC (LH-21), Product name, Shin-Etsu Chemical Co., Ltd.] 70 g, Aspartame [Ajinomoto Co., Ltd.] 2.5 g, Acesulfame Potassium (Nutrinova) 15 g was fluidized bed granulator [MP-01, Powrec Co., Ltd.] In addition, 10.8 g of hydroxypropylcellulose [HPC-SSL, trade name, Nippon Soda Co., Ltd.] is dissolved in 49.2 g of purified water, and 38.89 g of the solution is sprayed by a top spray method (a spray solution) The amount 10 g / min, spraying air pressure 1.2 MPa, supply air volume ^{40 m} 3 / hr, inlet air temperature 55 ° C.), after the completion of spraying, dried (supply air flow rate 30 ³ / hr, inlet air temperature 75 ° C., the end point of drying, product temperature 50 ° C.), sieved with a sieve (mesh 850 .mu.m), to obtain a granulated product.

(Process 3-5)
Based on Example 1, 894.6 mg tablets containing 300 mg acetaminophen per tablet were produced. The specific volume of the tableting powder at this time was 2.34 (mL / g).

(Tablet hardness, friability, oral disintegration time)
In the same manner as in Example 1, it became a preparation capable of practical production, hardness, friability, disintegration time in the oral cavity, and bitterness was suppressed.

Comparative Example 1:
In Step 1 of Example 1, in addition to light anhydrous silicic acid, 106 g of D-mannitol was further added, and the coated particles obtained by processing in the same manner as in Example 1 below, and in Step 2 of Example 1 above Using the obtained granulated product, the ratio of one menthol mixed pulverized product in Step 3 to the powdered powder powder in Step 4 and magnesium stearate in Step 5 in one tablet was determined in accordance with Example 1. 198.20 g of PH-302 was used to obtain 1000.60 mg tablets containing 300 mg of acetaminophen.
The obtained tablet is larger in weight than one tablet obtained in Example 1 and is slightly disintegrating because the tablet is slightly thicker. Also, since D-mannitol is blended in the coated particles, the moldability is improved. It was inferior to. The specific volume of the tableting powder at this time was 2.07 (mL / g).

Comparative Examples 2-8:
Acetaminophen-containing tablets of Comparative Examples 2 to 8 were prepared in accordance with the formulation described in Table 1 to be described later in accordance with Comparative Example 1 above.
In addition, Comparative Examples 2 to 7 are those in which D-mannitol is further added as a coated particle component to light anhydrous silicic acid, and Comparative Example 8 is added to light anhydrous silicic acid as a coated particle component. Furthermore, sodium lauryl sulfate and lactose are added.

  Compared with the tablet obtained in Example 1, the tablet obtained in Comparative Example 2 is larger in weight and slightly disintegrated because the tablet is slightly thick, and D-mannitol is blended in the coated particles. Therefore, the formability was inferior. Moreover, compared with Comparative Example 1, since Ceolus PH-101 was used in the blending process, it was bulkier than Comparative Example 1, and the filling amount into the die became close to the upper limit at the time of tableting.

  The specific volume of the tableting powder of Comparative Example 3 was 2.43 (mL / g). In this formulation, when the granulated product was prepared, the HPC solution was sprayed so that the compounding amount of hydroxypropyl cellulose (HPC) was 10 mg per tablet, and thus the bulk was bulky. Along with this, the specific volume of the tableting powder also increased, and it was not possible to enter the die during tableting.

  The specific volume of the tableting powder of Comparative Example 4 was 2.65 (mL / g). In this formulation, since the blending amount of crystalline cellulose was small, the moldability was slightly worse and the tablet was scratched.

  In Comparative Example 5, sodium starch glycolate [Expprotab, Kimura Sangyo Co., Ltd.] is used instead of hydroxypropylcellulose (HPC) in the preparation of Step 2, but this formulation does not adhere to the mortar. It was seen. The exprotab used was hygroscopic, and when water was added, it swelled and became a viscous paste-like liquid, which was expected to cause adhesion to the mortar.

  In Comparative Example 6, in the preparation of Step 2, mannitol [Partec M200: registered trademark, manufactured by Merck & Co., Ltd.] was used instead of crystalline cellulose, and carmellose [trade name NS-300, Gotoku Pharmaceutical Co., Ltd.], HPC-SSL is not used, and granulated products are not used. In step 3, D-mannitol is used instead of corn starch, and crystalline cellulose in step 5 is used. Other than not, it was a tablet processed according to Example 1, but the moldability of this tablet was inferior. This is probably because the particles other than the coated particles were hit directly.

  In Comparative Example 7, in the preparation of Step 2, the crystalline cellulose was replaced with D-mannitol, and further, instead of L-HPC, carmellose [trade name NS-300, manufactured by Gotoku Pharmaceutical Co., Ltd.] was used for granulation. In Step 5, crystalline cellulose was replaced with carmellose, but the obtained tablet had scratches. It is considered that the moldability of D-mannitol is inferior to that of crystalline cellulose.

  In Comparative Example 8, in the preparation of Step 2, the crystalline cellulose is replaced with lactose, and further, carmellose [trade name NS-300, manufactured by Gotoku Pharmaceutical Co., Ltd.] is used in place of L-HPC and granulated. In Example 5, crystalline cellulose was replaced with carmellose, but discoloration of the obtained tablets was observed by a severe test. The cause is presumed to be due to the Maillard reaction between aspartame and lactose.

  Table 1 shows the compounding component names, blending amounts, weight per tablet, and specific volume (mL / g) of the tableting powder obtained in Examples 1 to 3 and Comparative Examples 1 to 8 of the present invention.

In the oral disintegration test, the tablets obtained in Examples 1 to 3 and Comparative Examples 1 to 8 were included in the oral cavity of 5 healthy adult males without water, and the tablets were completely composed of only saliva in the oral cavity. The time until disintegration and dispersion was measured.
The tablet of Example 1 disintegrates and disperses within the range of 50-55 seconds, the tablet of Example 2 within the range of 45-55 seconds, and the tablet of Example 3 disperses within the range of 40-50 seconds. Good disintegration in the oral cavity was exhibited.

In the oral taste (bitter taste) test, the tablets obtained in Examples 1 to 3 and Comparative Examples 2 to 8 were included in the oral cavity of five healthy adult males without water, and the tablets were only saliva in the oral cavity. At the time of complete disintegration and dispersion, the presence or absence of bitterness was tested.
The bitterness of the tablets of Examples 1 to 3 was suppressed.

The intraoral quick disintegrating tablet of the present invention is an intraoral quick disintegrating tablet having a practical tablet hardness with good bitterness, good touch and low friability, with reduced drug bitterness.
Such intraoral quick disintegrating tablets are stable over time, easy to handle, and have the characteristics that the preparation does not change color.
Therefore, it is particularly excellent in that an intraoral rapidly disintegrating tablet with reduced bitterness of a drug that can be easily taken without water by patients with weak swallowing power, such as elderly people and children, can be provided.

  In addition, the present invention suppresses the bitter taste of acetaminophen, which is an active ingredient, by coating with acetamine phen, and further, erythritol, crystalline cellulose, low-substituted hydroxypropyl cellulose, sweetener (for example, aspartame, acesulfame) Practical acetaminophen-containing oral cavity that suppresses bitterness, has good flavor and stability over time, has a good texture, and has a low friability. It is an internal fast disintegrating tablet and is industrially useful.

Claims (4)

An intraoral quick disintegrating tablet obtained by tableting a mixture of the following (a) to (c).
(A) A water-insoluble polymeric substance, gastric soluble polymeric substance, enteric polymeric substance, or wax obtained by dissolving a mixture containing only two kinds of a bitter drug and light anhydrous silicic acid in water or an organic solvent Particles (coated particles) coated with a coating agent selected from a particulate material ,
(B) Particles (granulated product) obtained by spraying an aqueous solution of hydroxypropylcellulose onto a mixture containing erythritol, crystalline cellulose, low-substituted hydroxypropylcellulose, and sweetener,
(C) Crystalline cellulose. An intraoral quick disintegrating tablet obtained by tableting a mixture of the following (a) to (e).
(A) A water-insoluble polymeric substance, gastric soluble polymeric substance, enteric polymeric substance, or wax obtained by dissolving a mixture containing only two kinds of a bitter drug and light anhydrous silicic acid in water or an organic solvent Particles (coated particles) coated with a coating agent selected from a particulate material ,
(B) Particles (granulated product) obtained by spraying an aqueous solution of hydroxypropylcellulose onto a mixture containing erythritol, crystalline cellulose, low-substituted hydroxypropylcellulose, and sweetener,
(C) crystalline cellulose,
(D) a mixed pulverized product comprising at least one selected from the group consisting of a refreshing agent, starches, and celluloses;
(E) A dye-doubled powder comprising at least one selected from the group consisting of a colorant, starches and celluloses.   The intraoral quick disintegrating tablet according to claim 1 or 2, wherein the sweetening agent is at least one selected from the group consisting of aspartame and acesulfame potassium.   The oral disintegrating tablet according to claim 1, 2 or 3, wherein the drug having a bitter taste is acetaminophen.