JP5664225B2 - Unpleasant taste masking particles and oral preparations containing the same - Google Patents

Description

  Disclosed is an unpleasant taste masking particle which has an excellent masking effect for a drug having an unpleasant taste in the oral cavity, has a high dissolution property of the drug in the stomach, and is inhibited from being broken during tableting, and an oral preparation containing the same About.

  The most commonly used dosage form for oral solid preparations is tablets, but normal tablets disintegrate for more than 2 minutes, so swallow them immediately with water after taking them, and disintegrate in the digestive tract such as the stomach To do. On the other hand, in recent years, orally disintegrating tablets and chewable tablets that are attracting attention as dosage forms that are easy to drink for the elderly or children, that is, dosage forms that improve the quality of life (QOL) of patients, It can be taken without water because it disintegrates in the body, but in the case of an active ingredient having an unpleasant taste, the feeling of taking may be worsened and it is necessary to mask it.

  As a masking method for unpleasant taste, a method of adding a sweetener or a corrigent, a matrix method of dispersing a drug in a carrier by spray-drying a liquid in which a gastric or water-insoluble polymer is suspended or dissolved, A coating method in which a nucleus containing a drug is coated with a film containing a gastric polymer or a water-insoluble polymer is mainly known. In general, the method of adding sweeteners and flavoring agents has insufficient masking of unpleasant taste, and the matrix method can be used for drugs having a strong unpleasant taste because part of the drug is exposed on the surface of the preparation. difficult.

  For example, Japanese Patent Application Laid-Open No. 2000-7556 (Patent Document 1) proposes a chewable tablet obtained by granulating a component having an unpleasant taste such as acetaminophen using a poorly water-soluble polymer substance such as ethyl cellulose. JP 2005-343800 A (Patent Document 2) proposes coated caffeine particles in which caffeine particles are coated with a coating agent containing a poorly water-soluble polymer such as ethyl cellulose and a plasticizer. JP 2008-37863 A (Patent Document 3) covers core particles containing a drug exhibiting an unpleasant taste such as ibuprofen with an undercoat layer containing a water-soluble polymer and an elution accelerator, From the top, pharmaceutical particles coated with an overcoat layer containing a water-soluble polymer, a water-insoluble polymer and an elution accelerator have been proposed. However, there has been a demand for particles that suppress bitterness in the mouth and that are superior in rapid release in the stomach.

  In addition, even when particles with suppressed bitterness are used, the coating film of the particles is broken at the time of tableting, and the drug elutes in the mouth at the time of tablet administration, so that the desired bitterness masking effect cannot be achieved. This is because the mechanical strength of the coating film is weak. If the coating rate of the coating film is increased, breakage at the time of tableting can be suppressed, but elution in the stomach is delayed, and a desired medicinal effect (rapid release) cannot be achieved. With the current composition, a coating film that achieves both the effect of suppressing the bitter taste in the mouth after tableting and the rapid dissolution effect in the stomach and masking particles having this coating film have not been obtained.

JP 2000-7556 A JP-A-2005-343800 JP 2008-37863 A

  The present invention has been made in view of the above circumstances, and is excellent in the unpleasant taste masking effect of a drug having an unpleasant taste in the oral cavity, has high drug elution in the stomach, and suppresses breakage during tableting. An object of the present invention is to provide an unpleasant taste masking particle and an oral preparation containing the same.

  As a result of intensive studies to achieve the above-mentioned object, the present inventors have formulated an elution regulator that is hardly soluble at the pH in the oral cavity but soluble at the pH in the stomach into a drug having an unpleasant taste in the oral cavity. By coating the poorly water-soluble polymer compound (first layer) and further coating the poorly water-soluble polymer compound containing the disintegrant (second layer), the second layer coating film Because of its high mechanical strength, it prevents masking particles from breaking during tableting even at low coverage, and dissolves quickly in the low pH range, so it does not delay elution in the stomach and bitter taste in the mouth after tableting. It has been found that an unpleasant taste masking particle having both a masking effect and rapid dissolution in the stomach and an oral preparation containing the particle are obtained, and the present invention has been made.

That is, the present invention provides the following unpleasant taste masking particles and oral preparations.
Claim 1:
(A) an unpleasant taste masking particle having a core particle containing a drug having an unpleasant taste, a first coating layer covering the core particle, and a second coating layer covering the first coating layer,
The first coating layer contains (B) a poorly water-soluble polymer compound and (C) a synthetic hydrotalcite ,
The second coating layer, see contains the (B) sparingly water-soluble polymeric compound and (D) disintegrants,
The component (B) is one or more selected from ethyl cellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, cellulose acetate phthalate, and ethyl acrylate / methyl methacrylate copolymer. Unpleasant taste masking particles.
Claim 2:
2. The unpleasant taste masking particles according to claim 1, wherein the disintegrant is one or more selected from crospovidone, low-substituted hydroxypropylcellulose and polyvinylpyrrolidone.
Claim 3 :
(A) The core particle is acetaminophen, caffeine or ibuprofen, The unpleasant taste masking particle according to claim 1 or 2 .
Claim 4 :
The unpleasant taste masking particle according to any one of claims 1 to 3 , wherein in the first coating layer, the ratio of the total amount of the components (B) and (C) to 100 parts by mass of the component (A) is 5 parts by mass or more. .
Claim 5 :
In the first coating layer, the ratio of the component (C) to the total amount of the components (B) and (C) represented by (C) / {(B) + (C)} is 0.11 to 0.11 by mass ratio. The unpleasant taste masking particle according to any one of claims 1 to 4 , which is 0.8.
Claim 6 :
The unpleasant taste masking particle according to any one of claims 1 to 5 , wherein in the second coating layer, the ratio of the total amount of the components (B) and (D) to 100 parts by mass of the component (A) is 5 parts by mass or more. .
Claim 7 :
In the second coating layer, the ratio of the (D) component to the total amount of the (B) and (D) components represented by (D) / {(B) + (D)} is 0.11 to 0.11 by mass ratio. The unpleasant taste masking particle according to any one of claims 1 to 6 , which is 0.8.
Claim 8:
The content of (B) poorly water-soluble polymer compound in the first coating agent is 11 to 80% by mass with respect to the total solid content of the first coating agent. Unpleasant taste masking particles.
Claim 9:
The content of (B) poorly water-soluble polymer compound in the second coating agent is 30 to 90% by mass with respect to the total solid content of the second coating agent. Unpleasant taste masking particles.
Claim 10:
The unpleasant taste masking particle according to any one of claims 1 to 9, which is a masking immediate release particle.
Claim 11:
An oral preparation comprising the unpleasant taste masking particles according to any one of claims 1 to 10.
Claim 12:
The oral preparation according to claim 11, which is a tablet or granule.

  According to the present invention, an unpleasant taste masking particle capable of masking a drug having an unpleasant taste in the oral cavity, exhibiting a high drug elution property in the stomach and suppressing breakage during tableting, and an oral containing the particle A formulation can be provided.

  The unpleasant taste masking particle of the present invention has (A) a core particle containing a drug having an unpleasant taste, a first coating layer covering the core particle, and a second coating layer covering the first coating layer. The first coating layer contains (B) a poorly water-soluble polymer compound and (C) an elution regulator, and the second coating layer contains (B) a poorly water-soluble polymer compound and (D) a disintegrant.

<Nuclear particles>
(A) Core particle containing a drug having an unpleasant taste As a drug having an unpleasant taste, acetaminophen, aspirin, ibuprofen, ethenamide, phenacetin, mefenamic acid, antipyrine, phenylbutazone, sulpyrine, diclofenate sodium, ketoprofen, Naproxen, loxoprofen sodium, etodolac, epilysole, thiaramide hydrochloride, indomethacin, pentazocine, acetylcholine chloride, alimemazine tartrate, cyproheptazine hydrochloride, diphenhydramine hydrochloride, chlorpheniramine maleate, codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, Pentoxyberine citrate, theophylline, aminophylline, ephedrine hydrochloride, epinephrine hydrochloride, salbutamol sulfate, trimerme hydrochloride Examples include quinol, procaterol hydrochloride, methylephedrine hydrochloride, phenylpropanolamine hydrochloride, guaifenesin, tranexamic acid, anhydrous caffeine, caffeine, choline salicylate, sodium salicylate, etc., and the core particles can be used alone or in combination of two or more. In combination, the granulated particles may be used as the drug substance or in combination with an appropriate binder or excipient. Of these, acetaminophen, caffeine and ibuprofen are preferred.

  The average particle diameter of the drug core particles is preferably in the range of 50 to 600 μm, more preferably in the range of 100 to 400 μm. If it is less than 50 μm, since the particles are fine, agglomeration of the particles easily occurs, so that granulation proceeds easily, the coating becomes uneven, and the masking property may be inferior. On the other hand, if it exceeds 600 μm, there is no problem in the masking property, but the roughness becomes strong and the dosing property may deteriorate. It is 100 μm or more that the performance of the apparatus can be most utilized in producing the present coated particles, and it is 600 μm or less that the coating particles can be less rough in the mouth.

  In the present invention, the average particle size means a sieve of 1000 μm, 850 μm, 500 μm, 355 μm, 250 μm, 150 μm, 75 μm, 45 μm, 20 μm with an inner diameter of 75 mm and a sample amount of 10 g. The particle diameter is 50% of the cumulative mass when the test is performed based on the second method and measured. For those having an average particle diameter of 100 μm or less by the above measurement method, the average particle diameter of 50% of the cumulative mass when measured using a laser-type scattering diffraction particle size distribution analyzer (manufactured by BECKMAN COULTER) The particle size was taken.

  As the core particles, raw materials can be used as they are, or granulated products or those adjusted to a target particle size can be appropriately used. When granulating, other ingredients such as dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol partial saponified product, binders such as gelatin, pullulan, carboxyvinyl polymer, starches such as corn starch and rice starch , Starch derivatives such as sodium carboxymethyl starch and hydroxypropyl starch, celluloses such as crystalline cellulose and powdered cellulose, cellulose derivatives such as low-substituted hydroxypropylcellulose, sugars such as lactose and mannitol, and sugar alcohols as appropriate can do. Although content (mass ratio) of these binders etc. with respect to the drug which has an unpleasant taste is not specifically limited, The drug which has an unpleasant taste: Other component = 1: 0.01-1: 1 grade is preferable.

  (A) The content of the drug or the core particle containing the drug may be a ratio of 0.25 to 0.98 in terms of mass ratio with respect to the entire particle of the present invention from the viewpoint of masking property and formulation. Preferably, it is 0.33-0.96.

<First coating agent>
The 1st coating agent which forms the 1st coating layer of this invention consists of a 1st coating composition which contains the following (B) and (C) component as an essential component.

(B) The poorly water-soluble polymer compound (B) The poorly water-soluble polymer compound is a component that serves as a film base of the coating agent. In the present invention, ethyl cellulose, aminoalkyl methacrylate copolymer E (methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer), aminoalkyl methacrylate copolymer RS (ethyl acrylate / methyl methacrylate / methacrylated trimethylammonium ethyl copolymer) ), Officially listed products such as pharmaceutical additive standards such as cellulose acetate phthalate and ethyl acrylate / methyl methacrylate copolymer can be used. These are gastric soluble poorly water-soluble polymer compounds whose amount dissolved in 10,000 mL of water is 1 g or less than 1 mL. These can be used singly or in appropriate combination of two or more. Among these, ethyl cellulose is particularly preferred from the viewpoint of usability and odor, and commercially available ethyl cellulose aqueous dispersions (standards for pharmaceutical additives, FMC) For example, Aqua Coat ECD-30) manufactured by the company can be used.

  The content of the component (B) in the first coating agent is 11 to 80 mass with respect to the total solid content of the first coating agent in consideration of ease of coating, plasticity, elution property, etc. in the first coating layer. % Is preferable, and more preferably 40 to 60% by mass. If the amount of the component (B) in the first coating agent is too small, the film-forming property and unpleasant taste masking property may be inferior, and if it is too much, the gastric dissolution property and the rapid release property may be deteriorated.

  In addition, when a water-soluble polymer compound such as polyvinyl pyrrolidone, polyvinyl alcohol, or hydroxypropyl cellulose is contained as a coating base, it is preferable not to use it because the masking effect of unpleasant taste in the oral cavity is impaired. , (B) 5 mass% or less, more preferably 1 mass% or less, particularly preferably 0.5 mass% or less.

(C) The elution regulator (C) component is a component that controls the solubility of the coating agent. Examples include pH sensitivity, temperature sensitivity, substance-specific sensitivity, etc., and any factor governing solubility may be used. Examples of pH sensitive examples are as follows. That is, it is a component that controls the solubility of the coating agent, and includes a component that is easily soluble in water at pH 1.2 and hardly soluble in water at pH 6.8 at a temperature of 37 ° C. By combining this with the component (B), which is a film component, in the coating agent, after taking, the coating agent does not dissolve in the oral cavity (about pH 6.8) and the masking effect is high. At about pH 1.2), the component (C) in the coating agent dissolves and the coating is broken, so that the drug as the core particles can be quickly released, and particles with excellent dissolution and rapid efficacy can be obtained. In the present invention, “easily water-soluble” in “a component that is readily water-soluble at pH 1.2 and hardly water-soluble at pH 6.8” means that the amount of solvent required to dissolve 1 g of solute is less than 30 mL. In some cases, “poorly water-soluble” refers to the case where the amount of solvent required to dissolve 1 g of solute is 100 mL or more.

  Examples of such component (C) include magnesium antacids such as magnesium hydroxide, magnesium oxide, magnesium carbonate and magnesium silicate, sodium antacids such as sodium hydrogen carbonate, calcium carbonate and calcium hydroxide. Aluminum antacids such as calcium antacid, hydrotalcite, dihydroxyaluminum aminoacetate, aluminum hydroxide gel, aluminum hydroxide, aluminum silicate, magnesium metasilicate magnesium aluminate, magnesium aluminate, aluminum sulfate Can be mentioned. These can be used individually by 1 type or in combination of 2 or more types. Of these, hydrotalcite is preferable, and either natural or synthetic hydrotalcite may be used. Preferred hydrotalcite includes synthetic hydrotalcite (trade name: Alkamak (Kyowa Chemical Co., Ltd.)) and the like. Commercial products can be used. In addition, it is preferable to use the particle diameter of (C) component mix | blended in a coating liquid with 1/10 or less of a core particle.

  The content of the component (C) is (C) / {(B) + as a mass ratio with respect to the total solid content of the components (B) and (C) of the first coating agent in consideration of elution and the like. (C)} = 0.11 to 0.8 is preferable, and 0.4 to 0.6 is more preferable. If the amount of the component (C) in the first coating agent is too small, gastric elution and rapid release may be reduced, and if too large, the film formability may be reduced.

  Moreover, it is preferable that the ratio of the solid content total amount of (B) and (C) component with respect to 100 mass parts of (A) component is 5 mass parts or more from the point of a masking effect. The upper limit is not particularly limited, but is preferably 30 parts by mass or less, more preferably 20 parts by mass or less, and further preferably 18 parts by mass or less from the viewpoint of rapid dissolution in the stomach.

Other Components The first coating agent of the present invention preferably contains a plasticizer. The plasticizer is presumed to have a function of imparting appropriate spreadability to the solution containing the coating composition and facilitating film formation. Examples of the plasticizer include those described in official documents such as standards for pharmaceutical additives such as triacetin and triethyl citrate (Pharmaceutical Daily Inc.). These can be used individually by 1 type or in combination of 2 or more types. Considering film formability, triacetin and triethyl citrate are preferable, and triacetin is more preferable from the viewpoint of taste. The content of the plasticizer is preferably 7 to 50% by mass and more preferably 8 to 47% by mass with respect to the total solid content of the first coating agent. The total solid content (mass ratio) of the plasticizer: component (B) is preferably 1: 1 to 1: 8, more preferably 1: 3 to 1: 5.

  The first coating agent may further contain optional components such as pigments such as titanium oxide and iron oxide, cetanol, and sodium lauryl sulfate, as long as the effects of the present invention are not hindered.

  In the present invention, the coating rate of the first coating layer means the coating rate (mass / weight) of the solid content of the coating film containing the components (B) and (C) with respect to the core particles containing the drug (A) having an unpleasant taste. Mass (%)). As a coating rate of a 1st coating layer, 5 to 30% is preferable, More preferably, it is 10 to 20%. If the coating rate is too low, the protection of the component (A) may be insufficient and the bitterness suppressing effect may not be sufficiently expected. If the coating rate is too high, the protection of the component (A) is sufficient, but (A) in the stomach In some cases, elution of components is suppressed, and immediate release cannot be secured.

<Second coating agent>
The 2nd coating agent which forms the 2nd coating layer of this invention consists of a 2nd coating composition which contains the following (B) and (D) component as an essential component.
(B) The component similar to what was demonstrated about the 1st coating agent as (B) component used with a poorly water soluble high molecular compound 2nd coating agent is mentioned. 30-90 mass% is preferable with respect to the total solid of a 2nd coating agent, and, as for content of (B) component in a 2nd coating agent, More preferably, it is 35-60 mass%. If the amount of the component (B) in the second coating agent is too small, the film-forming property may be inferior, and if it is too large, the gastric dissolution property and the rapid release property may be deteriorated.

(D) The disintegrant (D) component is a component that increases the physical strength of the coating agent, and examples thereof include crospovidone, low-substituted hydroxypropylcellulose (HPC), polyvinylpyrrolidone, and hydroxypropylcellulose. Commercially available products can be used. For example, as crospovidone, Kollidon series (trade names: Kollidon CL, Kollidon CL-F, Kollidon CL-SF, Kollidon CL-M, manufactured by BASF) can be mentioned. In addition, hydroxypropylcellulose (trade name: HPC-L, manufactured by Nippon Soda Co., Ltd.) and the like can also be used. These can be used individually by 1 type or in combination of 2 or more types.

  In addition, the content of the component (D) is a mass ratio with respect to the total solid content of the components (B) and (D) in the second coating agent, considering the prevention of breakage during tableting. /{(B)+(D)}=0.11 to 0.8 is preferable, and 0.3 to 0.62 is more preferable. If the amount of component (D) in the second coating agent is too small, gastric dissolution and rapid release may be reduced, and if it is too much, the physical strength of the coating film will be reduced and the effect of the present invention will be reduced. There is a case.

  The ratio of the total solid content of the components (B) and (D) to 100 parts by mass of the component (A) is preferably 5 parts by mass or more, more preferably 8 parts by mass or more, still more preferably from the viewpoint of masking effect. It is 20 parts by mass or more. The upper limit is not particularly limited, but is preferably 30 parts by mass or less from the viewpoint of rapid gastric dissolution.

Other Components It is preferable that the second coating agent of the present invention contains a plasticizer as well as the first coating agent. As a plasticizer, the same thing as what was demonstrated in the 1st coating agent can be used in the same ratio.
Further, the second coating agent can also contain optional components similar to those of the first coating agent as long as the effects of the present invention are not hindered.

  In the present invention, the coating rate of the second coating agent refers to the coating rate (mass / weight) of the solid content of the coating film containing the components (B) and (D) with respect to the (A) core particles containing a drug having an unpleasant taste. Mass (%)). The coating rate of the second coating agent is preferably 5 to 40%, more preferably 10 to 35%, and particularly preferably 15 to 35%. If this coating rate is too low, the protection may be insufficient, and granule breakage during tableting may not be sufficiently suppressed. If the coating rate is too high, elution of the component (A) in the stomach may be suppressed and immediate release cannot be ensured. There is.

<Method for producing particles>
The method for producing the unpleasant taste masking particles of the present invention is not particularly limited, and (A) a core particle containing a drug having an unpleasant taste includes (B) a poorly water-soluble polymer compound and (C) an elution regulator. It can be obtained by coating with a coating agent and further coating with a second coating agent containing (B) a poorly water-soluble polymer compound and (D) a disintegrant.

  The coating with the coating agent is generally wet coating, but is not limited thereto. In the case of wet coating, for example, a dispersion liquid in which a coating agent composition is dispersed in an arbitrary dispersion medium (hereinafter also referred to as a coating agent solution) is sprayed onto the core particles. Preferred examples of the dispersion medium for the coating agent solution include hydrophilic solvents such as water and ethanol.

  The method for spraying the coating agent solution is not particularly limited, but it is preferable to use a coating apparatus having a fluidized bed because the coating agent can be uniformly attached to the surface of the core particles. Thereby, it is possible to perform an excellent coating that is uniform and has less unevenness in elution. Moreover, the strength of the coating film to be formed is high, and the possibility of breaking by tableting or chewing is reduced.

  An apparatus as shown below can be used for coating fine particles. There are multiplex capable of stirring rolling fluidized bed coating, CF granulator capable of centrifugal rolling bed coating, flow coater capable of fluidized bed coating, GPCG, and Spirer flow. In particular, in an apparatus capable of the Wurster method (for example, a GPCG Wurster specification machine), efficient fine particle coating is possible. The Wurster method is a system in which a spray liquid is sprayed onto the core particle powder from the bottom of the fluidized bed toward the top.

Equipment name Type Charge (Example) Manufacturer Multiplex MP-01 20kg POWREC Multiplex MP-25 20kg POWREC CF Granulator CF-360 3kg Freund Sangyo Co., Ltd.
Flow coater FLO-5 1.8kg Freund Sangyo Co., Ltd.
GPCG GPCG-15 15 kg POWREC Spiral Flow SFC-5 3 kg Freund Sangyo Co., Ltd.

Conditions for coating are not particularly limited, and commonly used conditions can be used. For example, the spray rate of the coating agent solution is preferably adjusted as appropriate depending on the charged amount and the scale of the apparatus to be used. For example, when the charged amount is 1 kg, it can be 5 to 30 g / min. The exhaust temperature of the coating apparatus is preferably 20 to 70 ° C, and the supply air temperature is preferably 60 to 90 ° C. When the exhaust temperature and the supply air temperature are within this range, uniform coating can be achieved.
After the coating of the first layer, the obtained particles can be coated with the second layer to obtain the masking particles of the present invention.

  The average particle size of the masking particles of the present invention obtained as described above is not particularly limited for tablets, and it is preferable to adjust the granule and powder to a particle size within a specified range. The method for measuring the average particle diameter is as described above.

  Further, the structure of the masking particle of the present invention is such that (A) the core particle is uniformly coated with the polymer compound of the component (B), and this coating preferably has a 1 / (1) average particle diameter of the core particle (A). The (C) elution regulator having a particle size of 10 or less is dispersed, and the coated particles are uniformly coated with the (B) component, and the (D) disintegrant is dispersed in the (B) component. is there.

  The masking particles of the present invention are masking fast-release particles having excellent masking properties that shield the unpleasant taste of the core particles in the oral cavity and having high dissolution properties (rapid release) in the stomach. In the present invention, the rapid release means a substance exhibiting an elution property of 60% by mass or more of the saturated solubility of the drug (A) within 30 minutes at 37 ° C. in a pH 1.2 solution.

<Oral preparation>
The masking particles of the present invention can be used as an oral preparation, and examples of the preparation include tablets and granules. The production method of these preparations is not particularly limited, and can be produced according to a conventional method under ordinary conditions.

  The content of the masking particles in the oral preparation is preferably 20 to 50% by mass, more preferably 25 to 40% by mass. If the masking particle content is too low, the tablet may be too large to contain the effective amount, or the number of tablets must be increased to take the effective amount. The ratio may be low and molding may be difficult.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.

[Examples 1a to 35a, Comparative Examples 1a to 6a]
<Nuclear particles>
Commercially available acetaminophen (Tyco Healthcare Japan Co., Ltd., SPECIAL GRANULAR, average particle size 295.0 μm) was used for the core particles.

<Manufacture of masking particle (1)>
First, an ethylcellulose aqueous dispersion, triacetin, and an elution regulator of component (C) as components (B) are added to purified water in an amount to adjust the total solid content concentration of the coating solution to 20% by mass, respectively. , 8, 10 and the mixture was stirred well to obtain a coating solution.
Next, using a fluidized bed granulator multiplex MP-01 (manufactured by POWREC Co., Ltd.), 800 g of the acetaminophen particles are added as the component (A), and the supply temperature is 65 ° C. and the exhaust temperature is 25 to 40 ° C. The coating liquid prepared above was sprayed at a rate of 14 g / min so that the total amount of solid content (B) + (C) shown in Tables 2, 4, 6, 8, and 10 was reached. This was dried at an air supply temperature of 80 ° C. for 30 minutes to obtain acetaminophen masking particles (1). The average particle size of the obtained particles was almost the same as the average particle size of the particles used as the core particles, or even a little. The structure of the masking particles was such that (A) the core particles were uniformly coated with the component (B), and the component (C) was uniformly dispersed in the component (B).

<Manufacture of masking particle (2)>
Next, ethyl cellulose aqueous dispersion, triacetin, and disintegrant of component (D) are added to purified water in an amount to adjust the total solid content concentration of the coating solution to 20% by mass as components (B), respectively. , 8, 10 and the mixture was stirred well to obtain a coating solution.
Next, 800 g of acetaminophen masking particles (1) prepared in <Manufacture of masking particles (1)> were added using a fluidized bed granulator multiplex MP-01 (manufactured by POWREC Co., Ltd.) and supplied to this. Tables 2, 4, 6, 8, and 10 (B) + (D) shown in Tables 2, 4, 6, 8, and 10 at a speed of 17 g / min with an airflow of 65 ° C. and an exhaust temperature of 25 to 40 ° C. It sprayed so that it might become the total amount of solid content. This was dried at an air supply temperature of 80 ° C. for 30 minutes to obtain acetaminophen masking particles (2). The average particle size of the obtained particles (2) was almost the same as the average particle size of the acetaminophen masking particles (1) prepared in <Manufacturing of the masking particles (1)>, or even a little. . The structure of the masking particle (2) was such that the component (B) was uniformly coated with the acetaminophen masking particle (1), and the component (D) was uniformly dispersed in the component (B).

[Examples 1b to 35b, Comparative Examples 1b to 6b]
<Manufacture of tablets>
As the masking particles, acetaminophen coated particles (2) obtained in <Production of masking particles (2)> were used.
Next, a mannitol granulated product was prepared by the following procedure. 3600 g of D-mannitol (Rocket Japan Co., Ltd., PEARLITOL 50C) is put into Spiral Flow SFC-5 type (manufactured by Freund Sangyo Co., Ltd.). 2400 g of a mass% aqueous solution (HPC-L, manufactured by Nippon Soda Co., Ltd.) was sprayed and granulated to obtain a mannitol granulated product.
Next, using the obtained particles, tablets having the compositions shown in Tables 3, 5, 7, 9, and 11 were tableted (tablet pressure 1000 kgf) with a clean press (manufactured by Kikusui Seisakusho), mass 453 mg, 12 mm A round tablet was obtained.
The tablets of the present invention of Examples 1b to 35b could be tableted without breaking. On the other hand, the tablets of Comparative Examples 1b to 6b were sometimes broken during tableting.

About the tablet containing the masking particle | grains obtained in the said Example and comparative example, the bitterness masking property and quick release property were evaluated. The results are also shown in Tables 3, 5, 7, 9, and 11.
In addition, the bitterness masking property and quick release property were evaluated by dissolution property. The dissolution test based on the Japanese Pharmacopoeia paddle method was conducted.

［評価基準（ｐＨ６．８）］
◎：４点以上
○：３点以上４点未満
×：３点未満 <Bitter taste masking evaluation>
About bitterness masking property, 7 panelists included one tablet in their mouths, and evaluated the bitterness intensity felt when it was dissolved by applying shear with the tongue and upper jaw in the following five levels, and the average value was calculated. An evaluation score of 3 or more is acceptable.

[Evaluation criteria (pH 6.8)]
◎: 4 points or more ○: 3 points or more and less than 4 points ×: Less than 3 points

<Rapid release evaluation>
The rapid release was evaluated using a buffer solution at 37 ° C. and pH 1.2 assuming the pH of the gastric juice as an alternative to the dissolution property in the gastric juice in the stomach. At that time, when the content of acetaminophen contained in one sample was 100% by mass, the ratio of eluted acetaminophen to that was shown as the dissolution rate (% by mass).
[Evaluation criteria (pH 1.2)]
If the elution of acetaminophen after 30 minutes was 60% by mass or more, it was judged to be effective. This is because if it is 60% by mass or more, it is possible to ensure elution at the level of a commercial product.
A: 80% by mass or more O: 60% by mass or more and less than 80% by mass X: Less than 60% by mass

<Raw materials>
Acetaminophen (Tyco Healthcare Japan Co., Ltd., SPECIAL GRANULAR)
Ethylcellulose aqueous dispersion (FMC, Aquacoat ECD-30)
Triacetin (Daihachi Chemical Industry Co., Ltd., Triacetin)
Synthetic hydrotalcite (Kyowa Chemical Industry Co., Ltd., Alkamak VF)
D-mannitol (Rocket Japan, PEARLITOL 50C)
Kollidon CL-SF (Crosspovidone, manufactured by BASF)
Kollidon CL-M (Crospovidone, manufactured by BASF)
Cornstarch (Matsuya Chemical Co., Ltd.)
Low-substituted hydroxypropyl cellulose (Nippon Soda Co., Ltd., HPC-L)
Magnesium stearate (Mallinckrodt Inc)

Claims (12)

(A) an unpleasant taste masking particle having a core particle containing a drug having an unpleasant taste, a first coating layer covering the core particle, and a second coating layer covering the first coating layer,
The first coating layer contains (B) a poorly water-soluble polymer compound and (C) a synthetic hydrotalcite ,
The second coating layer, see contains the (B) sparingly water-soluble polymeric compound and (D) disintegrants,
The component (B) is one or more selected from ethyl cellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, cellulose acetate phthalate, and ethyl acrylate / methyl methacrylate copolymer. Unpleasant taste masking particles.   2. The unpleasant taste masking particles according to claim 1, wherein the disintegrant is one or more selected from crospovidone, low-substituted hydroxypropylcellulose and polyvinylpyrrolidone. (A) The core particle is acetaminophen, caffeine or ibuprofen, The unpleasant taste masking particle according to claim 1 or 2 . The unpleasant taste masking particle according to any one of claims 1 to 3 , wherein in the first coating layer, the ratio of the total amount of the components (B) and (C) to 100 parts by mass of the component (A) is 5 parts by mass or more. . In the first coating layer, the ratio of the component (C) to the total amount of the components (B) and (C) represented by (C) / {(B) + (C)} is 0.11 to 0.11 by mass ratio. The unpleasant taste masking particle according to any one of claims 1 to 4 , which is 0.8. The unpleasant taste masking particle according to any one of claims 1 to 5 , wherein in the second coating layer, the ratio of the total amount of the components (B) and (D) to 100 parts by mass of the component (A) is 5 parts by mass or more. . In the second coating layer, the ratio of the (D) component to the total amount of the (B) and (D) components represented by (D) / {(B) + (D)} is 0.11 to 0.11 by mass ratio. The unpleasant taste masking particle according to any one of claims 1 to 6 , which is 0.8. The content of (B) poorly water-soluble polymer compound in the first coating agent is 11 to 80% by mass with respect to the total solid content of the first coating agent. Unpleasant taste masking particles. The content of (B) poorly water-soluble polymer compound in the second coating agent is 30 to 90% by mass with respect to the total solid content of the second coating agent. Unpleasant taste masking particles.   The unpleasant taste masking particle according to any one of claims 1 to 9, which is a masking immediate release particle.   An oral preparation comprising the unpleasant taste masking particles according to any one of claims 1 to 10.   The oral preparation according to claim 11, which is a tablet or granule.