JP2011093882A - Unpleasant taste-masking particle and oral preparation containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide particles excellent in the masking effect of unpleasant taste of a medicine having the unpleasant taste in an oral cavity and also having the high dissolution property of the medicine in stomach, and an oral preparation containing the same. <P>SOLUTION: The unpleasant taste-masking particles are provided with that (A) core particles containing the medicine having an unpleasant taste are coated with a coating agent containing (B) one or more kinds selected from among ethyl cellulose, an aminoalkyl methacrylate copolymer E, an aminoalkyl methacrylate copolymer RS, cellulose acetate phthalate and an ethyl acrylate/methyl methacrylate copolymer and (C) a hydroxide which is easily water soluble at pH 1.2 but hardly water soluble at pH 6.8. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to an unpleasant taste masking particle which is excellent in the masking effect of a drug having an unpleasant taste in the oral cavity and has a high drug dissolution property in the stomach, and an oral preparation containing the same.

  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.

  Japanese Patent No. 3415835 (Patent Document 1) describes drug-containing particles for an orally rapidly disintegrating tablet having an average particle size of about 50 μm to about 250 μm. In the examples, bitterness masking of famotidine prepared by spray drying is described. Although there is a description of the particles, it is difficult to mask the unpleasant taste of a drug having a very strong unpleasant taste with this method. Further, as a coating method, a method using a film containing a gastric polymer is known, but this method has a problem that the drug elution is affected by the pH change of gastric juice or intestinal fluid.

  Therefore, a coating method using a water-insoluble polymer has been studied as a masking method for unpleasant taste that does not depend on pH. Here, the water-insoluble polymer means a polymer that does not dissolve at normal pH in the digestive tract. There are many reports on the unpleasant taste masking method using a water-insoluble polymer, but there are few reports on preparations that satisfy both unpleasant taste masking and immediate release simultaneously.

  Japanese Patent Application Laid-Open No. 2000-53563 (Patent Document 2) and Japanese Translation of PCT International Publication No. 2004-532257 (Patent Document 3) have a core comprising an active ingredient having a bitter taste and a film comprising ethyl cellulose and a water-soluble substance as a bitterness suppressing layer. Particles are disclosed. Japanese Patent No. 3317444 (Patent Document 4) discloses particles in which a core containing an unpleasant bitter drug and a water-swellable substance is coated with a film containing ethylcellulose and a water-soluble substance. All of these particles aim to satisfy unpleasant taste masking and quick release simultaneously. However, there is a problem that the amount of the coating increases as the unpleasant taste masking property is increased, and the dissolution rate decreases accordingly, so that both the masking property and the dissolution property are not satisfied.

  In addition to the above, various coating compositions have been proposed, but none of them can simultaneously achieve masking properties and gastric elution properties. For example, JP-A-9-2976 (Patent Document 5) prevents contamination of tablets and granule tablets in which polyvinylpyrrolidone (PVP) and / or polyvinyl alcohol (PVA) is blended with an inorganic substance and a coating agent. Coating compositions for this have been proposed. However, since it contains PVP and PVA, which are water-soluble polymers, as a coating composition component, it has solubility in the mouth and the masking effect is not sufficient. In particular, when a chewable tablet or an orally disintegrating tablet that is chewed and disintegrated in the mouth without being swallowed immediately with water, there is a problem in that the coating composition dissolves and unpleasant taste cannot be suppressed.

Japanese Patent No. 3415835 JP 2000-53563 A JP-T-2004-532257 Japanese Patent No. 3317444 JP-A-9-2976

  The present invention has been made in view of the above circumstances, has an unpleasant taste masking effect of a drug having an unpleasant taste in the oral cavity, and has a high dissolution property of the drug in the stomach and an oral containing the same The purpose is to provide a formulation.

  As a result of intensive investigations to achieve the above-mentioned object, the present inventors have dissolved a hydroxide having an unpleasant taste in the oral cavity at a pH in the stomach and hardly soluble in the oral pH. An unpleasant taste masking particle that can mask an unpleasant taste in the oral cavity and has a high dissolution property in the stomach by coating with a specific gastric poorly water-soluble polymer compound formulated as a regulator, and an oral preparation containing this particle As a result, the inventors have found that the present invention can be obtained and have made the present invention.

That is, the present invention provides the following unpleasant taste masking particles and oral preparations.
Claim 1:
(A) Core particles containing a drug having an unpleasant taste are selected from (B) ethyl cellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, cellulose acetate phthalate, and ethyl acrylate / methyl methacrylate copolymer. An unpleasant taste masking particle characterized by being coated with a coating agent comprising one or more kinds, and (C) a water-soluble hydroxide at pH 1.2 and a water-insoluble hydroxide at pH 6.8. .
Claim 2:
Represented by {(B) + (C)} / (A), the content ratio of the total solid content of components (B) and (C) to component (A) is 0.03 to 0.6 in terms of mass ratio. The unpleasant taste masking particle according to claim 1.
Claim 3:
The content ratio of the component (C) to the total solid content of the components (B) and (C) represented by (C) / {(B) + (C)} is 0.05 to 0.8 by mass ratio. The unpleasant taste masking particles according to claim 1 or 2.
Claim 4:
The unpleasant taste masking particle according to any one of claims 1 to 3, wherein (A) the core particle is acetaminophen or caffeine.
Claim 5:
(A) The average particle diameter of a core particle is 30-1000 micrometers, The unpleasant taste masking particle of any one of Claims 1 thru | or 4.
Claim 6:
The unpleasant taste masking particle according to any one of claims 1 to 5, wherein the hydroxide (C) is one or more selected from synthetic hydrotalcite and magnesium hydroxide.
Claim 7:
The unpleasant taste masking particle according to any one of claims 1 to 6, which is a masking immediate release particle.
Claim 8:
An oral preparation comprising the unpleasant taste masking particles according to any one of claims 1 to 7.
Claim 9:
The oral preparation according to claim 8, which is a granule tablet, a chewable tablet or an orally disintegrating tablet.

  According to the present invention, it is possible to provide an unpleasant taste masking particle capable of masking a drug having an unpleasant taste in the oral cavity and exhibiting a high drug dissolution property in the stomach and an oral preparation containing the particle.

  In the unpleasant taste masking particle of the present invention, (A) the core particle containing a drug having an unpleasant taste is easily soluble in water at the above component (B) and (C) pH 1.2, and hardly soluble in water at pH 6.8. It is characterized by being coated with a coating agent containing a hydroxide.

<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. Among these, acetaminophen and caffeine are preferable.

The average particle diameter of the drug core particles is preferably in the range of 30 to 1000 μm, more preferably in the range of 30 to 800 μm, still more preferably in the range of 50 to 600 μm, and particularly preferably in the range of 100 to 400 μm. If it is less than 30 μm, since the particles are fine, agglomeration of the particles easily occurs, and thus granulation is likely to proceed, the coating becomes uneven, and the masking property may be inferior. On the other hand, if it exceeds 1000 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.

<Coating agent>
The coating agent of the present invention comprises the following (B) component and (C) a coating composition which is easily soluble in water at pH 1.2 and contains a hardly water-soluble hydroxide at pH 6.8 as an essential component.

(B) component (B) component is a component used as the film base of a coating agent. In the present invention, official document listed products such as standard specifications for pharmaceutical additives such as ethyl cellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, cellulose acetate phthalate, 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 coating agent is preferably 11 to 80% by mass, more preferably 18 to 80%, based on the total solid content of the coating agent, in consideration of ease of coating, plasticity, elution and the like. It is mass%, More preferably, it is 20-73 mass%, Most preferably, it is 32-67 mass%. If the amount of the component (B) in the coating agent is too small, the film forming property and masking property may be inferior, and if too large, the dissolution property and quick 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 unpleasant taste masking effect in the oral cavity is impaired. , (B) component is 5% by mass or less, more preferably 1% by mass or less, and particularly preferably 0.5% by mass or less.

(C) The hydroxide (C) component that is easily water-soluble at pH 1.2 and hardly water-soluble at pH 6.8 is a component that controls the solubility of the coating agent. It is a hydroxide that is readily soluble in water and hardly soluble at pH 6.8. By combining this with the component (B), which is a film component, and blending it into the coating agent, the coating agent does not dissolve in the oral cavity (about pH 6.8) after taking, and the masking effect is high. At (pH of about 1.2), the component (C) in the coating agent dissolves and the film is broken, so that the drug as the core particles can be quickly released, and the coating agent can be made excellent in dissolution and rapid efficacy. 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 synthetic hydrotalcite, magnesium hydroxide, dry aluminum hydroxide gel, aluminum hydroxide gel, alumina magnesium hydroxide, aluminum hydroxide / sodium bicarbonate coprecipitation product, water Examples thereof include aluminum oxide / magnesium carbonate mixed dry gel and aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product. These can be used individually by 1 type or in combination of 2 or more types. Among these, synthetic hydrotalcite and magnesium hydroxide are preferable, and synthetic hydrotalcite is more preferable. 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 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 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 coating agent can further contain optional components such as pigments such as titanium oxide and iron oxide, coating composition cetanol, and sodium lauryl sulfate.

  The ratio of the total solid content of the components (B) and (C) to the component (A) represented by {(B) + (C)} / (A) in the coating agent is a mass ratio, preferably 0. 0.03 to 0.6, more preferably 0.04 to 0.6, still more preferably 0.08 to 0.55, and particularly preferably 0.08 to 0.35. If it is less than 0.03, the masking film may become thin and sufficient masking properties may not be obtained. If it exceeds 0.6, the coating film becomes thick and it may be difficult to ensure quick release.

  The component (C) is represented by (C) / {(B) + (C)} in the coating agent, and the ratio of the component (C) to the total amount of the components (B) and (C) is The mass ratio is preferably 0.05 to 0.8, more preferably 0.05 to 0.7, still more preferably 0.09 to 0.7, and particularly preferably 0.1 to 0.65. Blend. If it is less than 0.05, sufficient elution in the stomach may not be obtained, and if it exceeds 0.8, the blending amount in the coating film becomes excessive and the film formability of the coating film decreases. In addition, masking properties in the oral cavity may be deteriorated.

  Furthermore, the coating rate of the masking particle | grains of this invention is shown by the ratio of the coating agent solid content with respect to (A) component, 2-70 mass% is preferable, More preferably, it is 5-40 mass%.

The production method of the oral preparation of the present invention is not particularly limited, and (A) core particles containing a drug having an unpleasant taste are readily soluble in water at (B) component and (C) pH 1.2, and pH 6. No. 8 can be obtained by coating with a coating agent containing an elution regulator that is sparingly soluble in water.
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.

Device name Type Charge (Example) Manufacturer 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.

  The average particle size of the masking particles of the present invention obtained as described above is not particularly limited, and is preferably adjusted as appropriate depending on the target dosage form. For example, when blended in a dosage form such as an orally disintegrating tablet or chewable tablet that is dissolved in the mouth and taken, it is preferably 50 to 600 μm in order to prevent roughness during taking. Moreover, it is not restrict | limited especially in a tablet, It is preferable to adjust a granule and a powder to the particle size within the prescribed | regulated range. The method for measuring the average particle diameter is as described above.

  The structure of the masking particles of the present invention comprises (A) core particles and a coating formed so as to cover the (A) core particles with the polymer compound of component (B). Preferably, (A) hydroxide fine particles (C) having a particle size of 1/10 or less of the average particle size of the core particles are dispersed.

  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.

  The masking particles of the present invention can be used as oral preparations, and the types of preparations are tablets, pills, solutions, extracts, capsules, granules, powders, syrups, dip / decoction, troches, chewables. Agents, jelly preparations and the like. However, the dosage form that dissolves the coating film is excluded. Among these, it is particularly preferable to use them as tablets, particularly orally disintegrating tablets (including chewable tablets, the same applies hereinafter), granules, and powders. In addition, since bitterness is suppressed, it is useful as an orally disintegrating tablet, jelly preparation, etc. to be taken without water. The production method of these preparations is not particularly limited, and can be produced according to a conventional method under ordinary conditions.

  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 1 to 22]
<Manufacture of nuclear particles>
When using a granulated product for the core particles (Examples 14 and 17 to 22), 400 g of a 20% by mass aqueous solution of dextrin (paindex # 100) is added to 3000 g of acetaminophen (POWDER), and high speed Using a mixer (FS-25 type, manufactured by Fukae Pautech Co., Ltd.), the mixture was granulated with stirring at 400 rpm for 5 to 7 minutes. After the obtained granulated product was shelf-dried at 80 ° C. for 5 hours, a fraction having a target average particle size of ± 200 μm was sieved to obtain core particles used for coating.

  When acetaminophen drug substance is used for the core particles, it is prepared by sieving acetaminophen drug substance (POWDER) for Examples 13 and 15 and acetaminophen drug substance (DENSE POWDER) for Example 16; For the Examples and Comparative Examples, acetaminophen drug substance (SPECIAL GRANULAR) was used as it was.

<Manufacture of masking particles>
First, an ethyl cellulose aqueous dispersion, triacetin, and an elution regulator of component (C) as components (B) in purified water in an amount that adjusts the total solid content concentration of the coating solution to 20% by mass are shown in Tables 1 to 3, respectively. The coating liquid was obtained by stirring well and stirring well.
Next, 800 g of acetaminophen particles prepared as described above were added as component (A) using a fluidized bed granulator multiplex MP-01 (manufactured by POWREC Co., Ltd.). The coating liquid prepared above was sprayed at a rate of 14 g / min with the air volume at a temperature of 25 to 40 ° C. so that the total solid content of (B) + (C) shown in Tables 1 to 3 was obtained. This was dried at an air supply temperature of 80 ° C. for 30 minutes to obtain masking particles. 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).

[Comparative Example 1]
<Manufacture of nuclear particles>
The acetaminophen drug substance (SPECIAL GRANULAR) was used as the core particle.
<Manufacture of masking particles>
In the same manner as in Example 13, except that hypromellose 2910 (manufactured by Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (manufactured by Sanyo Chemical Industries, Ltd.) are used instead of the ethylcellulose aqueous dispersion and triacetin, A coating solution was prepared to obtain masking particles.

[Comparative Example 2]
<Manufacture of nuclear particles>
Granulated in the same manner as in Example 14.
<Manufacture of masking particles>
A coating solution was prepared at the ratio shown in Table 4 in the same manner as in Example 13 except that D-mannitol (manufactured by Rocket Japan Co., Ltd., water-soluble at any pH) was used as an elution regulator. Obtained.

[Comparative Example 3]
<Manufacture of nuclear particles>
The acetaminophen drug substance (SPECIAL GRANULAR) was used as the core particle.
<Manufacture of masking particles>
A coating solution was prepared at the ratio shown in Table 4 in the same manner as in Example 13 except that calcium carbonate was used as an elution adjusting agent to obtain masking particles.

[Comparative Example 4]
<Manufacture of nuclear particles>
The acetaminophen drug substance (SPECIAL GRANULAR) was used as the core particle.
<Manufacture of masking particles>
A coating solution was prepared at the ratio shown in Table 4 in the same manner as in Example 13 except that no elution modifier was used, and masking particles were obtained.

The masking particles obtained in Examples 1 to 22 and Comparative Examples 1 to 4 were evaluated for bitterness masking property, quick release property and roughness. The results are also shown in Tables 1-4.
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.

<Masking of bitterness>
The bitterness masking property was evaluated using a buffer solution of 37 ° C. and pH 6.8 assuming the pH of saliva as an alternative to the elution properties of saliva in the oral cavity.
[Dissolution test method]
The dissolution was carried out in accordance with the 15th revised Japanese Pharmacopoeia / dissolution test method. As a test solution, the 15th revised Japanese Pharmacopoeia, Dissolution Test Method, Dissolution Test Second Solution (pH about 6.8) was prepared and used at 900 mL per vessel. In the test, granulated particles or tablets (samples) are put into the test solution, the paddle rotation speed is set to 50 rpm, 10 mL of the test solution is sampled over a predetermined time while stirring, and the dissolution rate (initial value of the drug) (Elution amount with respect to the set amount of drug contained in the granulated particles) was measured by an absorbance measurement method (device name: spectrophotometer U-3310 type, manufactured by Hitachi High-Technologies Corporation, wavelength 243 nm). In the case of granulated particles and tablets, the amount of sample input was 100 mg of acetamine phene (when 100 mg in the tablet was exceeded, 1 tablet was input).

[Evaluation criteria (pH 6.8)]
If the elution rate of acetaminophen after 5 minutes was less than 25% by mass, it was judged to be effective. This is because when the amount is less than 25% by mass, the bitterness is at an acceptable level.
As a result of sensory evaluation as a preliminary test, when the acetaminophen elution rate was less than 25% by mass, the bitterness was acceptable, and when it was less than 10% by mass, the bitterness was further improved. On the other hand, in the case of 25 mass% or more, the bitterness was an unacceptable level. Therefore, in this evaluation, the elution rate of acetaminophen after 5 minutes was used as an evaluation index of bitterness masking property.
A: Less than 10% by mass B: 10% by mass or more and less than 25% by mass X: 25% by mass or more

<Quick release>
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).
[Dissolution test method]
The dissolution was carried out in accordance with the 15th revised Japanese Pharmacopoeia / dissolution test method. As a test solution, the 15th revised Japanese Pharmacopoeia, dissolution test method, dissolution test first solution (pH about 1.2) was prepared and used at 900 mL per vessel. In the test, granulated particles or tablets (samples) are put into the test solution, the paddle rotation speed is set to 50 rpm, 10 mL of the test solution is sampled over a predetermined time while stirring, and the dissolution rate (initial value of the drug) (Elution amount with respect to the set amount of drug contained in the granulated particles) was measured by an absorbance measurement method (device name: spectrophotometer U-3310 type, manufactured by Hitachi High-Technologies Corporation, wavelength 243 nm). In the case of granulated particles and tablets, the amount of sample input was 100 mg of acetamine phene (when 100 mg in the tablet was exceeded, 1 tablet was input).
The same evaluation was performed for the caffeine of Example 26.

[Evaluation criteria (pH 1.2)]
If the elution rate of acetaminophen after 30 minutes was 60% by mass or more, the effect of the present invention was considered.
A: 80% by mass or more O: 60% by mass or more and less than 80% by mass X: Less than 60% by mass

<Roughness>
Four panelists included 0.3 g of the masking particles in a drug equivalent amount in the mouth, evaluated the roughness of the feeling felt when dissolved in the oral cavity in five stages, and calculated the average score.
[Evaluation criteria]
An average score of less than 3 is acceptable.
This is because the texture becomes worse and the ingestibility worsens as the texture becomes stronger.
[Evaluation points]
0: Does not feel rough 1: Feels rough slightly 2: Feels a little rough 3: Feels rough considerably 4: Feels very rough [Average]
◎: Less than 1 ○: 1 or more and less than 2 △: 2 or more and less than 3 ×: 3 or more

<Raw materials>
Dextrin (Matsutani Chemical Industry Co., Ltd., Paindex # 100)
Acetaminophen (Tyco Healthcare Japan Co., Ltd., SPECIAL GRANULAR)
Acetaminophen (Tyco Healthcare Japan Co., Ltd., DENSE POWDER)
Acetaminophen (Tyco Healthcare Japan Co., Ltd., POWDER)
Ethylcellulose aqueous dispersion (FMC, Aquacoat ECD-30)
Triacetin (Daihachi Chemical Industry Co., Ltd., Triacetin)
Synthetic hydrotalcite (Kyowa Chemical Industry Co., Ltd., Alkamak VF)
Magnesium hydroxide (Kyowa Chemical Industry Co., Ltd., Kyowa Suimag Kisuma 200)
Calcium carbonate aqueous dispersion (Shiraishi Kogyo Co., Ltd., Cal Essen-P2)
Hypromellose 2910 (Shin-Etsu Chemical Co., Ltd., TC-5E)
Macrogol 6000 (Sanyo Chemical Industry Co., Ltd.)
D-mannitol (Rocket Japan, PEARLITOL 50C)

[Example 23] Orally disintegrating tablet As masking particles, acetaminophen coated particles produced in the same manner as in Example 5 were used. Next, an erythritol / starch granulated product was prepared by the following procedure. Erythritol (Erythritol, Saneigen FFI Co., Ltd.) 3200g and starch (Purified and Dry Sterilized Corn Starch, Matsutani Chemical Industry Co., Ltd.) 600g are mixed, and Spirer Flow SFC-5 (Freund Sangyo Co., Ltd.) is mixed. 2400 g of a 6% by mass aqueous solution of hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.) was sprayed and granulated at an air supply temperature of 90 ° C. and an exhaust temperature of 35 to 45 ° C.
Next, using the obtained granules, tablets having the composition shown in Table 5 were tableted (tablet pressure 1200 kgf) with a clean press (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain a circular tablet having a mass of 410 mg and 12 mm. .

[Example 24] Chewable tablets As masking particles, acetaminophen-coated particles produced in the same manner as in Example 5 were used. Next, a mannitol granulated product was prepared by the following procedure. 900 g of D-mannitol (manufactured by Rocket Japan Co., Ltd.) was placed in a fluidized bed granulator multiplex MP-01 (manufactured by Paulek Co., Ltd.), and the supply temperature was 80 ° C., the exhaust temperature was 40-50 ° C., and hydroxypropylcellulose 600 g of 12% by mass aqueous solution was sprayed and granulated.
Next, using the obtained granules, tablets having the composition shown in Table 6 were tableted (tablet pressure 1200 kgf) with a clean press (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain a circular tablet having a mass of 280 mg and 9 mm. .

[Example 25] Jelly preparation As masking particles, acetaminophen-coated particles produced in the same manner as in Example 16 were used. Next, a jelly-form preparation having the composition shown in Table 7 was prepared by the following procedure.
(1) 0.5 g of xanthan gum (xanthan gum, manufactured by San-Ei Gen FFI Co., Ltd.) was dispersed in 0.1 g of glycerin (Japanese glycerin, manufactured by Yuka Sangyo Co., Ltd.) to obtain a dispersion A.
(2) 0.15 g of locust bean gum (Locust bean gum, manufactured by Sanki Co., Ltd.) was dispersed in 0.05 g of glycerin to prepare dispersion B.
(3) Dispersion A, dispersion B, and 1.1 g of acetaminophen coating particles were added to 4.81 g of water, stirred for 30 minutes at room temperature, and then heated to 60 ° C. to obtain liquid C.
(4) The liquid C was stirred for 20 minutes under reduced pressure to remove bubbles while maintaining the temperature at 60 ° C. This was poured into an aluminum container (single dose 5 g) and cooled to 30 ° C. or lower to obtain a jelly preparation.

Example 26 Granules Acetaminophen coated particles produced in the same manner as in Example 16 were used as acetaminophen masking particles. Next, caffeine coating particles were prepared as caffeine masking particles by the following procedure.
(1) 6.7 g of an ethylcellulose aqueous dispersion (manufactured by FMC) in purified water in terms of solid content, 1.7 g of triacetin (manufactured by Daihachi Chemical Industry Co., Ltd.), and synthetic hydrotalcite (Kyowa Chemical Industry) 6.7g) was added and stirred well to obtain a coating solution.
(2) 1000 g of caffeine particles having an average particle size of 380 μm (anhydrous caffeine, manufactured by Shizuoka Caffeine Industry Co., Ltd.) are put into a fluidized bed granulator multiplex MP-01 (manufactured by Paulec Co., Ltd.) and supplied with air. Coating was performed by spraying 300 g of the coating agent solution prepared in (1) at a rate of 20 g / min with an air flow of 80 ° C. and an exhaust temperature of 35 to 45 ° C. This was dried at an air supply temperature of 80 ° C. for 30 minutes to obtain caffeine-coated particles. The total amount of ethyl cellulose and synthetic hydrotalcite in the coating agent for caffeine coating particles was 13.5 g, and the ratio of caffeine coating particles to caffeine particles was 0.27 in terms of mass ratio. Moreover, the ratio of the synthetic hydrotalcite to the total amount of ethyl cellulose and synthetic hydrotalcite was 0.56 in mass ratio.
Subsequently, the composition shown in Table 8 was mixed using the V type mixer V-5 type (made by Tokuju Seisakusho Co., Ltd.), and the granule was obtained.

  The preparations obtained in Examples 23 to 26 were evaluated in the same manner as described above. The results are also shown in Tables 5-8.

<Raw materials>
Erythritol (Saneigen FFI Co., Ltd., Erythritol)
Starch (Matsutani Chemical Industry Co., Ltd., refined dry sterilized corn starch)
Hydroxypropyl cellulose (Nippon Soda Co., Ltd., HPC-L)
Crospovidone (ISP Japan, Polyplusdon XL-10)
Crystalline cellulose (Asahi Kasei Chemicals Corporation, Theolas PH-102)
Croscarmellose sodium (San-Eigen FFI Co., Ltd., Kikkolate)
Magnesium stearate (Mallinckrodt Inc., magnesium stearate)
Xanthan gum (San-Eigen FFI Co., Ltd., xanthan gum)
Locust bean gum (Sanki Co., Ltd., Locust bean gum)
Glycerin (Oka Chemical Industry Co., Ltd., JP glycerin)
Caffeine (Shizuoka Caffeine Industrial Co., Ltd., anhydrous caffeine)
Potato starch (Nissho Chemical Co., Ltd., potato starch)

Claims (9)

  (A) Core particles containing a drug having an unpleasant taste are selected from (B) ethyl cellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, cellulose acetate phthalate, and ethyl acrylate / methyl methacrylate copolymer. An unpleasant taste masking particle characterized by being coated with a coating agent comprising one or more kinds, and (C) a water-soluble hydroxide at pH 1.2 and a water-insoluble hydroxide at pH 6.8. .   Represented by {(B) + (C)} / (A), the content ratio of the total solid content of components (B) and (C) to component (A) is 0.03 to 0.6 in terms of mass ratio. The unpleasant taste masking particle according to claim 1.   The content ratio of the component (C) to the total solid content of the components (B) and (C) represented by (C) / {(B) + (C)} is 0.05 to 0.8 by mass ratio. The unpleasant taste masking particles according to claim 1 or 2.   The unpleasant taste masking particle according to any one of claims 1 to 3, wherein (A) the core particle is acetaminophen or caffeine.   (A) The average particle diameter of a core particle is 30-1000 micrometers, The unpleasant taste masking particle of any one of Claims 1 thru | or 4.   The unpleasant taste masking particle according to any one of claims 1 to 5, wherein the hydroxide (C) is one or more selected from synthetic hydrotalcite and magnesium hydroxide.   The unpleasant taste masking particle according to any one of claims 1 to 6, which is a masking immediate release particle.   An oral preparation comprising the unpleasant taste masking particles according to any one of claims 1 to 7.   The oral preparation according to claim 8, which is a granule tablet, a chewable tablet or an orally disintegrating tablet.