KR20120084296A - Unpleasant taste-masking particles and an oral preparation containing same - Google Patents

Abstract

Provided are particles which are excellent in the unpleasant masking effect of a drug having an unpleasant taste in the oral cavity, and which have a high dissolution of the drug in the stomach, and an oral preparation containing the same. (A) Nuclear particles containing a drug having discomfort include (B) ethyl cellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, cellulose acetate cellulose and ethyl methacrylate methacrylate. 1 or 2 or more types chosen from a copolymer, and (C) Unpleasant masking particle | grains which are water-soluble at pH 1.2 and coat | covered with the coating agent containing a poorly water-soluble hydroxide at pH 6.8.

Description

Unpleasant masking particles and oral preparations containing the same {UNPLEASANT TASTE-MASKING PARTICLES AND AN ORAL PREPARATION CONTAINING SAME}

The present invention is excellent in the masking effect of a drug having an unpleasant taste in the oral cavity, and high dissolution of the drug in the stomach, and an oral preparation containing the same. It is about.

The most widely used formulations for oral solid preparations are tablets, and since conventional tablets have a disintegration of 2 minutes or more, they are swallowed immediately with water or the like after ingestion, To collapse. On the other hand, in recent years, oral disintegrating tablets and chemo tablets, which are attracting attention as an easy-to-drink formulation, that is, a formulation that improves the quality of life (QOL) of the patient, have to be disintegrated in the oral cavity after taking. Therefore, although it can take without water, in the case of the main medicine which has unpleasant taste, it may worsen a feeling of taking, and it is necessary to mask.

As a masking method of unpleasant taste, the method of adding a sweetening agent and a copper, the matrix method which disperse | distributes a drug in a carrier by spray-drying the liquid which suspended or dissolved the gas-soluble polymer or the water-insoluble polymer, and a drug The coating method which coat | covers the nucleus containing with the film containing a gasosoluble polymer or a water insoluble polymer is mainly known. In general, a method of adding a sweetener or a copper is insufficient for masking unpleasant tastes, and it is difficult to use a drug having strong unpleasant taste because a part of the drug is exposed to the surface of the preparation by the matrix method.

Japanese Patent No. 3515835 (Patent Document 1) has a description of drug-containing particles for fast disintegrating tablets in the oral cavity having an average particle diameter of about 50 µm to about 250 µm, and in the examples, pamoti prepared by the spray drying method. There is a description regarding Dean's highly masked particles, and it is difficult to mask the discomfort of a drug having a very strong discomfort by this method. In addition, as a coating method, a method using a coating containing gastric soluble polymer is known, but this method has a problem in that the elution property of the drug is affected by the pH variation of gastric juice or intestinal fluid.

Therefore, the coating method using a water-insoluble polymer is examined as an unpleasant masking method without pH dependence. Here, the water-insoluble polymer means a polymer that does not dissolve at a pH in a normal digestive tract. Although there are many reports on the unpleasant masking method using a water-insoluble polymer, there are few reports about the agent which simultaneously satisfies unpleasant masking and immediate release.

Japanese Patent Application Laid-Open No. 2000-53563 (Patent Document 2) and Japanese Patent Application Laid-Open No. 2004-532257 (Patent Document 3) include a film made of ethyl cellulose and a water-soluble substance as a bite suppression layer in a nucleus containing an active ingredient having bitumen. Disclosed is a particle coated with. In addition, Japanese Patent No. 3317444 (Patent Document 4) discloses a particle coated with a coating containing ethylcellulose and a water-soluble substance in a nucleus containing an unpleasant drug and water-swellable substance. All of these particles aim to satisfy both unpleasant masking and immediate release. However, since there is a problem that the amount of the film increases as the unpleasant masking property is increased, and the dissolution rate decreases with it, the problem of both masking and dissolution properties is not reached.

In addition, various coating compositions have been proposed in addition to the above, but none of them can achieve masking properties and gastric elution resistance at the same time. For example, Japanese Patent Application Laid-Open No. 9-2976 (Patent Document 5) discloses tablets and granules in which polyvinylpyrrolidone (PVP) and / or polyvinyl alcohol (PVA) are blended with an inorganic substance and a coating agent. Coating compositions for preventing contamination of tablets have been proposed. However, since the coating composition component contains PVP and PVA which are water-soluble polymers, it has solubility in the mouth and the masking effect was not enough. In particular, in the case of cold indetermination and intraoral disintegrating tablets that are chewed and collapsed in the mouth without being swallowed with water immediately, there is a problem that the coating composition melts and the unpleasant taste cannot be suppressed.

Patent Document 1: Japanese Patent No. 3415835 Patent Document 2: Japanese Patent Application Laid-Open No. 2000-53563 Patent Document 3: Japanese Patent Application Laid-Open No. 2004-532257 Patent Document 4: Japanese Patent No. 3317444 Patent Document 5: Japanese Patent Application Laid-Open No. 9-2976

This invention is made | formed in view of the said situation, and is an unpleasant masking particle which is excellent in the unpleasant masking effect of the drug which has an unpleasant taste in the oral cavity, and has high elution property of the drug in the stomach, and oral containing this It is an object to provide a formulation.

The present inventors earnestly examined in order to achieve the above object, and as a result, a specific gas solubility in which a drug having an unpleasant taste in the oral cavity is hardly dissolved at pH in the oral cavity, and a hydroxide soluble at pH in the stomach as a dissolution regulator. By coating a poorly water-soluble high molecular compound, it is possible to mask an unpleasant taste in the oral cavity, and discover that unpleasant masking particles exhibiting high dissolution in the stomach and oral preparations containing the particles can be obtained. It has come true.

That is, the present invention provides the following unpleasant masking particles and oral preparations.

Claim 1:

(A) Nuclear particles containing a drug having discomfort include (B) ethyl cellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, cellulose acetate cellulose and ethyl methacrylate methacrylate. (C) is coated with a coating agent containing one or two or more selected from copolymers and (C) a water-soluble at pH 1.2 and a poorly water-soluble hydroxide at pH 6.8. Nasty masking particles.

Claim 2:

The content ratio of solid content total amount of (B) and (C) component with respect to (A) component represented by {(B) + (C)} / (A) is 0.03 to 0.6 by mass ratio in Claim 1 Described unpleasant masking particles.

Claim 3:

Claim 1 whose content ratio of (C) component with respect to solid content total amount of (B) and (C) component represented by (C) / {(B) + (C)} is 0.05-0.8 by mass ratio, or Unpleasant masking particle | grains of Claim 2.

Claim 4:

(A) Unpleasant masking particle | grains in any one of Claims 1-3 whose nucleus particle is acetaminophen or caffeine.

Claim 5:

(A) Unpleasant masking particle | grains in any one of Claims 1-4 whose average particle diameter of a nuclear particle is 30-1000 micrometers.

Claim 6:

(C) Unpleasant masking particle | grains in any one of Claims 1-5 whose hydroxide is 1 type, or 2 or more types chosen from synthetic hydrotalcite and magnesium hydroxide.

Claim 7:

The unpleasant masking particle | grains in any one of Claims 1-6 which are masking immediate release particle | grains.

Claim 8:

The oral preparation containing the unpleasant masking particle of any one of Claims 1-7.

Claim 9:

The oral preparation according to claim 8, which is a granular tablet, indeterminate or orally disintegrating tablet.

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

The unpleasant masking particle of this invention is a nucleus particle containing the drug which has (A) unpleasant taste is water-soluble at the said (B) component and (C) pH 1.2, and poorly water-soluble hydroxide at pH 6.8. It is characterized by consisting of a coating material comprising a).

<Nuclear particle>

(A) Discomfort  Containing drug Nuclear particle

Examples of drugs with discomfort include acetaminophen, aspirin, ibuprofen, methenamide, phenacetin, mefenamic acid, anchiphyrin, phenylbutazone, sulfirin, diclofenac sodium, ketoprofen, naproxen, sodium roxofene and eto Dolac, Epirisol, Tiaramid Hydrochloride, Indomethacin, Pentazosin, Acetylcholine Chloride, Alimethazine Chloride, Ciproheptadine Hydrochloride, Diphenhydramine Hydrochloride, Chlorpheniramine Hydrochloride, Codeine Phosphate, Dihydrocodene Phosphate Dextromethorphan, Citrate Pentoberine, Theophylline, Aminopyrine, Ephedrine Hydrochloride, Epinephrine Hydrochloride, Salbutamol Sulfate, Trimethoquinol Sulfate, Procaterol Hydrochloride, Methyl Ephedrine Hydrochloride, Phenylpropanolamine Hydrochloride, Guapenesine, Tranexamic acid, caffeine anhydride, caffeine, choline salicylate, sodium salicylate, and the like. Examples of the nucleus particles include one kind alone or two or more kinds. In combination, it may be used in combination and the stay wonyak (原 藥), or an appropriate coupling agent or excipient using assembly (造粒) particles. Among these, acetaminophen and caffeine are preferable.

The mean particle size of the drug nuclear 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, particularly preferably in the range of 100 to 400 µm. to be. If it is less than 30 micrometers, since granules generate | occur | produce a particle | grains because a particle | grain is fine, coating may become uneven and coating may be inferior and maskability may be inferior. On the other hand, when it exceeds 1000 micrometers, there is no problem in masking property, but tingling becomes strong and taking property may worsen. The most capable of utilizing the performance of the apparatus in producing the present coated particles is 100 μm or more, and the coated particles are less than 600 μm capable of making the fuzziness less than in the mouth.

In addition, in this invention, an average particle diameter uses the sieve of inner diameter 75mm of 1000 micrometers, 850 micrometers, 500 micrometers, 355 micrometers, 250 micrometers, 150 micrometers, 75 micrometers, 45 micrometers, and 20 micrometers, The particle size shall be 50% of the cumulative mass at the time of performing a test based on the 2nd method of "powder particle size measuring method" of Japan. In addition, about the thing whose average particle diameter was 100 micrometers or less by the said measuring method, 50% particle diameter of the cumulative mass at the time of measuring using the laser type scattering lime method particle size distribution measuring apparatus (made by Beckman Coulter) was made into the average particle diameter.

As the nucleus particles, raw materials may be used as they are, or granulated products or those adjusted to a desired particle size. When granulated, other components such as dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol partial saponified, gelatin, pullulan, carboxyvinyl polymer and the like binders, corn starch , Starches such as rice starch, starch derivatives such as sodium carboxymethyl starch, hydroxypropyl starch, celluloses such as crystalline cellulose and powdered cellulose, cellulose derivatives such as low-substituted hydroxypropyl cellulose, lactose, mannitol Sugars, sugar alcohols, etc. can be added suitably. Although content (mass ratio) of these binders with respect to the drug which has unpleasant taste is not specifically limited, The drug which has unpleasant taste: another component = 1: 0.01-1: 1 is preferable.

(A) From the viewpoint of masking properties and formulation, the content of the nucleus particles containing the drug or drug is preferably in a ratio of 0.25 to 0.98 in mass ratio, more preferably 0.33 to 0.96, based on the entire particle of the present invention. to be.

<Coating agent>

The coating agent of this invention consists of a coating composition which is water-soluble at the following (B) component and (C) pH 1.2, and contains a poorly water-soluble hydroxide at pH 6.8 as an essential component.

(B) ingredient

(B) component is a component used as the coating base of a coating agent. In the present invention, the procedure such as the pharmaceutical additive specification such as ethyl cellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, cellulose acetate cellulose acetate, ethyl acrylate-methyl methacrylate copolymer, etc. ) Handicrafts can be used. These are gastric poorly water-soluble high molecular compounds whose amount melt | dissolves in 10,000 ml of water is less than 1 g or 1 ml. These can be used individually by 1 type or in combination of 2 or more types, Among these, ethyl cellulose is especially preferable at the point of usability and odor, A commercial ethyl cellulose aqueous dispersion (pharmaceutical additive specification, FMC) Company, Aquacoat ECD-30) etc. 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% by mass, and more preferably 18% to 80% by mass based on the total solid content of the coating agent, in view of ease of coating, plasticity, elution, and the like. Preferably it is 20-73 mass%, Especially preferably, it is 32-67 mass%. When the amount of (B) component in a coating agent is too small, it may be inferior to film-forming property and masking property, and when too much, elution property and immediate release property may fall.

In addition, when water-soluble high molecular compounds, such as polyvinylpyrrolidone, polyvinyl alcohol, and hydroxypropyl cellulose, are contained as a coating base, the unpleasant masking effect in an oral cavity is impaired, It is preferable not to use it, and to use it. Even if it does, 5 mass% or less with respect to (B) component, More preferably, it is 1 mass% or less, Especially preferably, it is restrict | limited to 0.5 mass% or less.

(C) pH  From 1.2 It's water soluble , pH  From 6.8 Water-soluble  hydroxide

(C) component is a component which controls the solubility of a coating agent, and is a hydroxide which is water-soluble at pH 1.2, and poorly water-soluble at pH 6.8 at temperature 37 degreeC. It is combined with (B) component which is a coating component, and it mix | blends in coating agent, and after taking it, the coating agent does not melt | dissolve in oral cavity (pH 6.8 grade), and the masking effect is high, and in a stomach (pH 1.2 grade), it is a coating agent. Since component (C) melt | dissolves and a film is broken, the drug which is a nuclear particle can be discharged quickly, and it can be set as the coating agent excellent in the elution property and fast-acting property. In addition, in this invention, "water solubility" of "a component which is water-soluble at pH 1.2 and poorly water-soluble at pH 6.8" means the case where the amount of solvent required to melt | dissolve 1 g of solutes is less than 30 ml, and "water-soluble", Refers to the case where the amount of solvent required to dissolve 1 g of the solute is 100 ml or more.

As such (C) component, synthetic hydrotalcite, magnesium hydroxide, dry aluminum hydroxide gel, aluminum hydroxide gel, alumina magnesium hydroxide, aluminum hydroxide, sodium hydrogen carbonate coprecipitation product, aluminum hydroxide, carbonate, for example Magnesium mixed dry gel, aluminum hydroxide, magnesium carbonate, calcium carbonate coprecipitation product, and the like. These can be used individually by 1 type or in combination of 2 or more types. Among them, synthetic hydrotalcite and magnesium hydroxide are preferred, and more preferably synthetic hydrotalcite. In addition, it is preferable that the particle diameter of (C) component mix | blended in a coating liquid uses the thing of 1/10 or less of a nuclear particle.

It is preferable that the coating agent of this invention contains a plasticizer. It is presumed that the plasticizer has a function of giving a suitable malleability to the solution containing the coating composition and making it easy to form a film. As a plasticizer, what was described in process documentation, such as a pharmaceutical additive standard (pharmaceutical company Ilbo), such as triacetin and triethyl citrate, is mentioned. These can be used individually by 1 type or in combination of 2 or more types. In consideration of the film formability, triacetin and triethyl citrate are preferred, and triacetin is more preferable in terms of taste. 7-50 mass% is preferable with respect to the total solid of a coating agent, and, as for content of a plasticizer, 8-47 mass% is more preferable. Moreover, plasticizer: total solid content (mass ratio) of the (B) component = 1: 1-1: 8 is preferable, and 1: 3-1: 1 are more preferable.

The coating agent may also contain optional components such as pigments such as titanium oxide and iron oxide, coating composition cetanol, sodium lauryl sulfate and the like.

The ratio of the total amount of solid content of (B) and (C) component with respect to (A) component represented by {(B) + (C)} / (A) in a coating agent is mass ratio, Preferably it is 0.03-0.6, More preferably, it is 0.04 to 0.6, More preferably, it is 0.08 to 0.55, Especially preferably, it is 0.08 to 0.35. When the thickness is less than 0.03, the coating film may become thin, so that sufficient masking properties may not be obtained. When the coating film is larger than 0.6, the coating film may be thick, and it may be difficult to secure rapid release properties.

In addition, as for (C) component, the ratio of (C) component with respect to the total amount of (B) and (C) component represented by (C) / {(B) + (C)} in a coating agent is mass ratio. Preferably, it is 0.05-0.8, More preferably, it is 0.05-0.7, More preferably, it is 0.09-0.7, Especially preferably, it is 0.1-0.65, and mix | blending. If less than 0.05, sufficient elution in the stomach may not be obtained. If it exceeds 0.8, the compounding amount in the coating film becomes excessive, the film forming property of the coating film is deteriorated, and the masking property in the oral cavity is deteriorated. There is.

Moreover, the coating rate of the masking particle of this invention is represented by the ratio of the total amount of coating agent solid content with respect to (A) component, 2-40 mass% is preferable, More preferably, it is 5-40 mass%.

The method for producing the oral preparation of the present invention is not particularly limited, and (A) nucleus particles containing a drug having an unpleasant taste are water-soluble at component (B) and (C) pH 1.2 and poorly watered at pH 6.8. It can obtain by coating with the coating agent containing a soluble dissolution regulator.

Coating with a coating agent is generally a wet coating, but is not limited thereto. In the case of wet coating, for example, a dispersion liquid (hereinafter sometimes referred to as a coating solution) in which the coating composition is dispersed in an arbitrary dispersion medium is sprayed onto the nuclear particles. As a dispersion medium of a coating agent solution, hydrophilic solvents, such as water and ethanol, are mentioned preferably.

Although it does not specifically limit as a spraying method of a coating solution, Since it is possible to make a coating agent adhere uniformly to the surface of a nuclear particle, it is preferable to use the coating apparatus which has a fluidized bed. As a result, excellent coating can be performed that is uniform and has low staining properties. Moreover, the strength of the formed coating film is also high, and the possibility of breaking by tableting or chewing becomes low.

The apparatus as shown below can be used for coating of microparticles | fine-particles. There are multiplexes capable of stirring electric fluidized bed coating, CF granulators capable of centrifugal electric fluidized bed coating, flow coaters capable of fluidized bed coating, GPCG, and spyflow. Among them, in a device capable of a washer method (for example, a washer specification machine of GPCG), highly efficient fine particle coating is possible. The wasa method is a structure which sprays a spray liquid to nuclear particle powder from a fluidized bed bottom part to an upper part.

Device Name Type Introduction (Example) Maker

Multiplex MP-25 20㎏

CF Granulator CF-360 3㎏ Furo Into Industry Co., Ltd.

Flow Coater FLO-5 1.8㎏ Furo Into Industry Co., Ltd.

GPCG GPCG-15 15㎏

Spiral Flow SFC-5 3㎏ Furo Into Industry Co., Ltd.

As conditions at the time of coating, it does not specifically limit but the conditions normally used can be used. For example, although the spray rate of a coating agent solution is suitable to be prepared suitably by the introduction amount and the scale of the apparatus to be used, For example, when an introduction amount is 1 kg, it can be 5-30 g / min. As for the exhaust temperature of a coating apparatus, 20-70 degreeC is preferable, and air supply temperature has preferable 60-90 degreeC. If the exhaust temperature and the air supply temperature are within this range, uniform coating can be achieved.

The average particle diameter of the masking particle of this invention obtained as mentioned above is not restrict | limited, It is preferable to adjust suitably with the target formulation. For example, when it mix | blends with the formulation which melt | dissolves in a mouth, such as an intraoral disintegrating tablet and an indefinite tablet, it is preferable that it is 50-600 micrometers in order to prevent the tingling at the time of taking. Moreover, it does not restrict | limit especially in tablet, It is preferable to adjust granules and powder to the particle size within a prescribed range. In addition, the measuring method of an average particle diameter is as above-mentioned.

Moreover, the structure of the masking particle of this invention consists of (A) nuclear particle and the film formed so that this (A) nuclear particle may be coat | covered with the high molecular compound of (B) component, In this film, Preferably, (A (C) hydroxide microparticles | fine-particles which have a particle diameter of 1/10 or less of the average particle diameter of a nuclear particle are disperse | distributed.

The masking particle of this invention is a masking immediate release particle which is excellent in the masking property which shields the nuisance of a nuclear particle in oral cavity, and has high dissolution property (fast release property) in the stomach. And in this invention, immediate release means what shows the elution property of 60 mass% or more of the saturated solubility of the drug of (A) component within 37 degreeC and 30 minutes in pH 1.2 liquid.

The masking particle of this invention can be used as an oral preparation, As a kind of preparation, it is a tablet, a pill, a liquid, an extract, a capsule, a granule, a powder, a syrup, a disinfecting agent Viii), a troche, a chewable agent, a jelly agent, etc. are mentioned. However, the formulation dissolving the coating film is excluded. Among these, it is especially preferable to use it as a tablet, especially an orally disintegrating tablet (including indeterminate, below), granules, and powder. Moreover, since bitterness is suppressed, it is useful as an oral disintegrating tablet, a jelly preparation, etc. which are taken without water. The manufacturing method of these preparations is not specifically limited, either, According to a daily method, it can manufacture on normal conditions.

Example

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

[Examples 1 to 22]

<Production of Nuclear Particles>

As a manufacturing method in the case of using a granulated material for nuclear particles (Examples 14 and 17 to 22), 400 g of 20 mass% aqueous solution of dextrin (finedex # 100) was added to 3000 g of acetaminophen (POWDER), and a high speed mixer ( It stirred and granulated at 400 rpm for 5 to 7 minutes using FS-25 type | mold and the product made by Fukae Powder. After drying the obtained granulated product at 80 degreeC for 5 hours, the thing of the fraction of a target average particle diameter of +/- 200 micrometers was sifted, and it was set as the nuclear particle used for coating.

When the acetaminophen medicinal product is used for the nucleus particles, the acetaminophen medicinal product (POWDER) for Examples 13 and 15 and the acetaminophen medicinal agent (DENSE POWDER) for Example 16 are prepared by sieving. As for the examples and the comparative examples, acetaminophen original drug (SPECIAL GRANULAR) was used as it is.

<Production of Masking Particles>

First, in the purified water of the amount which adjusts the total solid content concentration of a coating liquid to 20 mass%, the elution regulator of ethylcellulose aqueous dispersion, a triacetin, and (C) component as (B) component was the ratio shown to Tables 1-3, respectively. It put and stirred well, and obtained the coating liquid.

Subsequently, 800 g of acetaminophen particles prepared as described above were used as (A) component by using a fluidized bed granulated gas multiplex MP-01 (manufactured by Powder Co., Ltd.), and the air supply temperature was 65 ° C and the exhaust temperature was 25 to 40. The coating solution prepared above was sprayed at a rate of 14 ° C./min so as to obtain a solids total amount of (B) + (C) shown in Tables 1 to 3 at the airflow rate of ℃. This was dried for 30 minutes at the air supply temperature of 80 degreeC, and masking particle | grains were obtained. The average particle diameter of the obtained particles was almost equal to or larger than the average particle diameter of the particles used as the nuclear particles. In the structure of the masking particles, the component (B) was uniformly coated with the (A) nucleus particle, and the component (C) was uniformly dispersed in the component (B).

Comparative Example 1

<Production of Nuclear Particles>

Acetaminophen original drug (SPECIAL GRANULAR) was used as it was for nuclear particles.

<Production of Masking Particles>

Instead of using an ethyl cellulose aqueous dispersion and triacetin, Table 4 is used in the same manner as in Example 13 except that Hypurromes 2910 (manufactured by Shin-Etsu Chemical Co., Ltd.) and Macrogol 6000 (manufactured by Sanyokasei Co., Ltd.) are used. Coating liquid was prepared at the ratio to display, and masking particle | grains were obtained.

Comparative Example 2

<Production of Nuclear Particles>

It was assembled in the same manner as in Example 14.

<Production of Masking Particles>

Coating liquid was prepared by the ratio shown in Table 4 similarly to Example 13 except having used D-mannitol (made by Rocket Japan Co., Ltd., water solubility in any pH) as an elution regulator, and the masking particle was obtained.

[Comparative Example 3]

<Production of Nuclear Particles>

Acetaminophen original drug (SPECIAL GRANULAR) was used as it was for nuclear particles.

<Production of Masking Particles>

Except using calcium carbonate as an elution regulator, the coating liquid was prepared at the ratio shown in Table 4 like Example 13, and masking particle was obtained.

[Comparative Example 4]

<Production of Nuclear Particles>

Acetaminophen original drug (SPECIAL GRANULAR) was used as it was for nuclear particles.

<Production of Masking Particles>

Except not using an elution regulator, the coating liquid was prepared at the ratio shown in Table 4 like Example 13, and masking particle was obtained.

About masking particle | grains obtained by Examples 1-22 and Comparative Examples 1-4, the masking property, fast release property, and stifferness of high rice were evaluated. The results are written together in Tables 1-4.

Masking properties and fast release properties of bitter rice were evaluated by dissolution property. A dissolution test in accordance with the Japanese Pharmacy Defense Paddle Method was conducted.

<Masking property of Gomi>

The masking property of bitter rice was evaluated using the buffer of 37 degreeC and pH 6.8 which assumed pH of saliva as a substitute for the elution to saliva in oral cavity.

[Dissolution test method]

Elution was performed in accordance with the 15th Amendment of Japanese Pharmacy and Dissolution Testing. As the test solution, the 15th revised Japanese Pharmacopoeia, Elution Test Method, and Elution Test 2nd solution (pH approximately 6.8) were prepared, and 900 ml per vessel was used. In the test, granulated particles or tablets (samples) were added to the test solution, the paddle rotation speed was set to 50 rpm, and 10 ml of the test solution was collected at predetermined time with stirring, and the dissolution rate (initial value of the drug ( Elution amount) of the drug contained in the granulated particles) was measured by an absorbance measurement method (device name: Spectrophotometer U-3310, Hitachi Hi-Technologies Co., Ltd., wavelength 243 nm). In the case of granulated particles and tablets, the amount of the sample injected was 100 mg of acetaminophen (in case of exceeding 100 mg in tablets, 1 tablet was added).

[Evaluation Criteria (pH 6.8)]

It was judged that it was effective if the elution rate of acetaminophen after 5 minutes was less than 25 mass%. This is because when the amount is less than 25% by mass, the level is acceptable.

As a result of performing a sensory evaluation as a preliminary test, when the elution rate of acetaminophen is less than 25 mass%, it is a level which can accept bitterness, and when it is less than 10 mass%, taste is improved more. On the other hand, in the case of 25 mass% or more, the level was unacceptable. Therefore, in this evaluation, the dissolution rate of acetaminophen after 5 minutes was used as an evaluation index of high masking property.

◎: less than 10 mass%

(Circle): 10 mass% or more and less than 25 mass%

X: 25 mass% or more

Rapid release

The immediate release was evaluated using a buffer of pH 1.2 at 37 ° C, assuming the pH of the gastric juice as an alternative to elution in gastric juice in the stomach. In that case, when the acetaminophen content contained in one sample was 100 mass%, the ratio of the acetaminophen eluted to it was shown as an elution rate (mass%).

[Dissolution test method]

Elution was performed in accordance with the 15th Amendment of Japanese Pharmacy and Dissolution Testing. As the test solution, the 15th revised Japanese Pharmacopoeia, Elution Test Method, and Elution Test first solution (pH about 1.2) was prepared, and 900 ml per vessel was used. In the test, granulated particles or tablets (samples) were added to the test solution, the paddle rotation speed was set to 50 rpm, and 10 ml of the test solution was collected at a predetermined time with stirring, and the dissolution rate (initial value of the drug (containing in the granulated particles). The amount eluted with respect to the set amount of the drug) was measured by an absorbance measurement method (device name: Spectrophotometer U-3310, Hitachi Hi-Technologies Co., Ltd., wavelength 243 nm). In the case of granulated particles and tablets, the amount of acetaminophen that was 100 mg was added (in case of exceeding 100 mg in tablets, 1 tablet was added).

The same evaluation was performed about the caffeine of Example 26.

[Evaluation Criteria (pH 1.2)]

If the elution rate of acetaminophen after 30 minutes is 60 mass% or more, it is said that there exists an effect of this invention.

◎: 80% by mass or more

(Circle): 60 mass% or more and less than 80 mass%

X: less than 60 mass%

<Squeak>

Four panelists put the masking particle in 0.3 g of the drug equivalent amount in the mouth, and evaluated the intensity of the tingling which was felt when it melt | dissolved in the oral cavity in 5 steps, and computed the average score.

[Evaluation standard]

If the average is less than 3, it is acceptable.

The stronger the feeling of wheezing, the worse the texture (食 感), because the dose is worse.

[Rating]

0: do not feel sick

1: feel a little tingling

2: feel a little tingling

3: I feel a lot of tingling

4: I feel very sick

[Average point]

◎: less than 1

○: 1 or more but less than 2

△: 2 or more and less than 3

×: 3 or more

[Table 1]

[Table 2]

[Table 3]

[Table 4]

<Used raw material>

Dextrin (Shokuku Chemical Co., Ltd., Finedex # 100)

Acetaminophen (TAICO Healthcare Japan, SPECIAL GRANULAR)

Acetaminophen (TAICO Healthcare Japan, DENSE POWDER)

Acetaminophen (TAICO Healthcare Japan, POWDER)

Ethyl cellulose aqueous dispersion (FMC, Aquakoto ECD-30)

Triacetin (Daihachi Chemical Co., Ltd., Triacetin)

Synthetic hydrotalcite (Kyowa Chemical Industries, Alkamak VF)

Magnesium Hydroxide (Kyowa Chemical Industry Co., Ltd.

Calcium carbonate aqueous dispersion (Shiraishi Kogyo Co., Calesen-P2)

Hypuromeros 2910 (Shin-Etsu Chemical Co., Ltd., TC-5E)

Macrogol 6000 (Sanyo Kasei Co., Ltd.)

D-Mannitol (Rocket Japan, PEARLITOL 50C)

Example 23 Intraoral Disintegrating Tablets

As the masking particles, acetaminophen coated particles prepared in the same manner as in Example 5 were used. Next, the erythritol / starch granulated product was prepared in the following procedure. 3200 g of erythritol (erythritol, made by Samyoungwon F.F.) and 600 g of starch (tablet dried sterilized corn starch, manufactured by Shokoku Chemical Co., Ltd.) are mixed, and Spiral SFC-5 type (Huroin) It was put into the earth industry, and 2400 g of hydroxypropyl cellulose 6 mass% aqueous solution (HPC-L, Nippon Soda Co., Ltd.) was sprayed and granulated at the air supply temperature of 90 degreeC, and exhaust temperature of 35-45 degreeC.

Subsequently, the tablet of the composition shown in Table 5 was tableted (tableting pressure 1200 kgf) through the obtained granules, and the circular tablet of mass 410 mg and 12 mm was obtained. .

Example 24 Indeterminate

As the masking particles, acetaminophen coated particles prepared in the same manner as in Example 5 were used. Next, the mannitol granulated product was prepared in the following procedure. 900 g of D-mannitol (manufactured by Rocket Japan Co., Ltd.) is placed in a fluidized bed granulator multiplex MP-01 (manufactured by Powder Co., Ltd.), and 12% by mass of hydroxypropyl cellulose at an air supply temperature of 80 ° C and an exhaust temperature of 40 to 50 ° C. 600 g of aqueous solution was sprayed and assembled.

Subsequently, tablets of the compositions shown in Table 6 were compressed using clean granules (manufactured by Kikusui Co., Ltd.) (compressive pressure 1200 kgf) using the obtained granules, thereby obtaining a circular tablet having a mass of 280 mg and 9 mm. Got it.

Example 25 Jelly Preparation

As the masking particles, acetaminophen coated particles prepared in the same manner as in Example 16 were used. Next, the jelly state preparation of the composition shown in Table 7 was prepared in the following procedures.

(1) Disperse 0.5 g of xanthan gum (xanthan gum, Samyoungwon F.I. Co., Ltd.) in 0.1 g of glycerin (Japanese glycerin, emulsification industry). A) was set.

(2) 0.15 g of locust bean gum (Locust bean gum, manufactured by Samjung Co., Ltd.) was dispersed in 0.05 g of glycerin to obtain a dispersion (B).

(3) To 4.81 g of water, 1.1 g of a dispersion liquid (A), a dispersion liquid (B), and acetaminophen coated particles were added, stirred at room temperature for 30 minutes, and then heated to 60 ° C to obtain a C liquid.

(4) The C solution was stirred for 20 minutes under reduced pressure to remove bubbles while maintaining the liquid at 60 ° C. This was inject | poured into the aluminum container (5 g of single dose), and it cooled to 30 degrees C or less, and obtained the jelly formulation.

Example 26 Granules

As masking particles of acetaminophen, acetaminophen coated particles prepared in the same manner as in Example 16 were used. Next, caffeine coated particles were prepared in the following order as masking particles of caffeine.

(1) 6.7 g of ethyl cellulose aqueous dispersion (manufactured by FMC Corporation) in terms of solids content in purified water, 1.7 g of triacetin (manufactured by Daihachi Chemical Co., Ltd.), and synthetic hydrotalcite (Kyowa Chemical Co., Ltd.) 6.7g of agents) were put and stirred well to obtain a coating solution.

(2) 1000 g of caffeine particles (anhydrous caffeine, manufactured by Shizuoka Caffeine Industrial Co., Ltd.) having an average particle diameter of 380 µm were placed in a fluidized bed granulator multiplex MP-01 (manufactured by Faurek Co., Ltd.), and the air supply temperature was 80 ° C and the exhaust temperature was 35 to The coating was prepared by spraying 300 g of the coating solution prepared in (1) at a rate of 20 g / min, at an air flow rate of 45 ° C. This was dried for 30 minutes at an air supply temperature of 80 ° C to obtain caffeine coated particles. The total amount of ethylcellulose and synthetic hydrotalcite in the coating agent of the caffeine coated particles was 13.5 g, and the ratio to the caffeine particles was 0.27 by mass ratio. In addition, the ratio of the synthetic hydrotalcite with respect to the total amount of ethyl cellulose and synthetic hydrotalcite was 0.56 by mass ratio.

Subsequently, the composition shown in Table 8 was mixed using V type | mold mixer V-5 type (made by Tokuju Corporation make), and granules were obtained.

Evaluation similar to the above was performed about the formulation obtained in Examples 23-26. The results are written together in Tables 5-8.

[Table 5]

TABLE 6

[Table 7]

[Table 8]

<Used raw material>

Erythritol (Samyoungwon F.F.I., erythritol)

Starch (Shokoku Chemical Co., Ltd., tablet drying sterilization cornstarch)

Hydroxypropyl cellulose (Nihon Soda Co., Ltd., HPC-L)

Crospovidone (ISP Japan, Polyplusdon XL-10)

Crystalline cellulose (Asahi Kasei Chemicals Co., Ltd., seolasu pH -102)

Croscarmellose Sodium (Samyoungone F.F.I., Kichorate)

Magnesium Stearate (Mallinckrodt Inc., Magnesium Stearate)

Xanthan gum (Samyoungwon F.F.I Co., Xanthan gum)

Locust bean gum (samjung, locust bean gum)

Glycerin (Emulsification Industry Co., Ltd. glycerin)

Caffeine (Shizuoka caffeine industry place, anhydrous caffeine)

Maryeongseo Starch (Iljeon Chemical Co., Ltd.

Claims (9)

(A) Nuclear particles containing a drug having discomfort include (B) ethyl cellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, cellulose acetate cellulose and ethyl methacrylate methacrylate. The unpleasant masking particle | grains characterized by coat | covering with 1 type (s) or 2 or more types chosen from a copolymer, and (C) water-soluble at pH 1.2, and coating agent containing a poorly water-soluble hydroxide at pH 6.8. The method of claim 1,
The content ratio of solid content total amount of (B) and (C) component with respect to (A) component represented by {(B) + (C)} / (A) is 0.03-0.6 by mass ratio, The unpleasant thing characterized by the above-mentioned Mi masking particles. 3. The method according to claim 1 or 2,
The content ratio of (C) component with respect to solid content total amount of (B) and (C) component represented by (C) / {(B) + (C)} is 0.05-0.8 by mass ratio, The unpleasant thing characterized by the above-mentioned Mi masking particles. 4. The method according to any one of claims 1 to 3,
(A) Unpleasant masking particle | grains characterized by the nuclear particle being acetaminophen or caffeine. 5. The method according to any one of claims 1 to 4,
(A) The unpleasant masking particle | grains whose average particle diameter of a nuclear particle is 30-1000 micrometers. The method according to any one of claims 1 to 5,
(C) Unpleasant masking particle | grains characterized by the hydroxide being 1 type (s) or 2 or more types chosen from synthetic hydrotalcite and magnesium hydroxide. The method according to any one of claims 1 to 6,
Unpleasant masking particles, characterized in that the masking immediate release particles. An oral preparation containing the unpleasant masking particles according to any one of claims 1 to 7. The method of claim 8,
Oral preparations characterized in that they are granules, indeterminate or orally disintegrating tablets.