JP2016006025A - Pharmaceutical composition and production method thereof as well as orally disintegrating tablet and production method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition which can mask bitterness of telmisartan and can suppress lowering of dissolution property of telmisartan in the pH of around 3.5, and to provide a production method thereof as well as an orally disintegrating tablet and a production method thereof.SOLUTION: The invention relates to a pharmaceutical composition which has a bulk drug-containing particle and a coating layer which coats the bulk drug-containing particle, contains telmisartan, aminoalkyl methacrylate copolymer E, and a nonionic surfactant, wherein the telmisartan is contained in the bulk drug-containing particle, and the aminoalkyl methacrylate copolymer E is contained in the coating layer; and to an application thereof.

Description

  The present invention relates to a pharmaceutical composition and a production method thereof, and an orally disintegrating tablet and a production method thereof.

  In recent years, development of orally disintegrating tablets that can be taken without water has been demanded as an easier-to-take formulation to improve compliance in elderly patients, patients who have difficulty swallowing, and patients whose water intake is restricted. .

  Telmisartan is an angiotensin II receptor antagonist developed for the treatment of hypertension and its indications. Since hypertension is a chronic disease and it is necessary to continue to take therapeutic drugs throughout life, the demand for orally disintegrating tablets containing telmisartan is expected to be high.

Orally disintegrating tablets differ from ordinary tablets in that the tablets are rapidly disintegrated in the oral cavity, so that they are easy to feel the bitter taste of drugs. Telmisartan is a drug having a bitter taste, and in the case of a dosage form of an orally disintegrating tablet, a technique for masking the bitter taste of telmisartan is required.
As a method for masking bitterness in an orally disintegrating tablet, a physical masking method for coating a drug with a polymer or the like is known.

  For example, Patent Document 1 discloses particles in which acetaminophen, which is a bitter component having a carboxyl group, is coated with a coating layer containing a poorly water-soluble polymer compound and an additive such as an elution regulator. In the particles disclosed in Patent Document 1, the solubility of the coating layer is controlled and the elution of acetaminophen is controlled by including components such as an elution regulator together with the poorly water-soluble polymer compound in the coating layer. .

  Patent Document 2 discloses a drug-containing granule in which olobatadine, which is a bitter component having a dimethylamino group and a carboxyl group, is coated with a masking film containing a polymer such as a methacrylic acid copolymer. In the drug-containing granules disclosed in Patent Document 2, the solubility of the masking film is controlled and the elution of olobatadine is controlled by allowing the masking film to contain components such as excipients together with the polymer.

JP 2012-140335 A International Publication 2012/029348 Pamphlet

  The inventors have found that aminoalkyl methacrylate copolymer E is effective as a polymer for coating telmisartan. However, when telmisartan is coated with a layer containing aminoalkyl methacrylate copolymer E, the carboxyl group possessed by telmisartan and the amino group possessed by aminoalkyl methacrylate copolymer E act around pH 3.5, and the elution property of telmisartan decreases. It became clear to do. In such a preparation, even though the bitter taste of telmisartan can be masked, it is expected that the dissolution of telmisartan from the drug and the absorption into the body will be hindered.

  The present invention has been made in view of the circumstances as described above, and can be used to mask the bitter taste of telmisartan and to suppress a decrease in the dissolution property of telmisartan near pH 3.5. It is an object to provide a product and a method for producing the same, an orally disintegrating tablet, and a method for producing the same.

  Specific means for solving the above problems are as follows.

[1] A drug substance-containing particle and a coating layer that coats the drug substance-containing particle, and includes telmisartan, an aminoalkyl methacrylate copolymer E, and a nonionic surfactant, and telmisartan is contained in the drug substance-containing particle. And an aminoalkyl methacrylate copolymer E in the coating layer.
[2] The pharmaceutical composition according to [1], wherein the nonionic surfactant is at least one selected from the group consisting of polysorbate, poloxamer, and polyethylene glycol.
[3] The pharmaceutical composition according to [1] or [2], wherein the nonionic surfactant is polysorbate.
[4] The medicine according to any one of [1] to [3], wherein the content of the nonionic surfactant is 1 part by mass to 40 parts by mass with respect to 100 parts by mass of the aminoalkyl methacrylate copolymer E. Composition.

[5] The pharmaceutical composition according to any one of [1] to [4], wherein the content of the aminoalkyl methacrylate copolymer E is 2% by mass or more based on the total mass of the pharmaceutical composition.
[6] The method according to any one of [1] to [5], further including light anhydrous silicic acid in at least one selected from the group consisting of the drug substance-containing particles and the coating layer that coats the drug substance-containing particles. Pharmaceutical composition.
[7] The pharmaceutical composition according to any one of [1] to [6], wherein the drug substance-containing particles further include at least one selected from the group consisting of hydroxypropylcellulose and hydroxypropylmethylcellulose.

[8] The pharmaceutical composition according to any one of [1] to [7], which is a granular material having an average particle diameter of 50 μm to 1000 μm.
[9] The pharmaceutical composition according to any one of [1] to [8], wherein the content of telmisartan is 10% by mass to 50% by mass with respect to the total mass of the pharmaceutical composition.

  [10] A method for producing a pharmaceutical composition according to any one of [1] to [9], wherein a drug substance layer containing at least telmisartan as a drug substance-containing particle using a granulator The spray liquid is sprayed onto the core particles that are the core of the drug substance-containing particles, and the manufacture of the drug substance-containing particles has a relative humidity of 20 at the supply temperature of the gas supplied to the granulator. % Or less, and a method for producing a pharmaceutical composition comprising at least one selected from intermittent spraying of a spray solution for a drug substance layer on core particles.

[11] An orally disintegrating tablet comprising the pharmaceutical composition according to any one of [1] to [9].
[12] A method for producing the orally disintegrating tablet according to [11], wherein the pharmaceutical composition according to any one of [1] to [9] and an excipient containing light anhydrous silicic acid To obtain a mixed powder, and tableting the obtained mixed powder to obtain a tableted product.

In the present specification, a numerical range indicated using “to” means a range including the numerical values described before and after “to” as a minimum value and a maximum value, respectively.
In this specification, the amount of each component in the composition is the total amount of the plurality of substances present in the composition unless there is a specific indication when there are a plurality of substances corresponding to each component in the composition. Means.

  In this specification, the “average particle diameter” means a volume average particle diameter (Mv), and is a value measured using a laser diffraction / scattering particle size distribution measuring device (product name: LS 13 320, manufactured by Beckman Coulter, Inc.). It is.

  In the present specification, the “layer” is not limited to a layer or a layered shape, and may be a shape in which a target substance covers a part or the whole of an object to be coated.

  In this specification, the term “process” is not limited to an independent process, and is included in this term if the intended purpose of the process is achieved even when it cannot be clearly distinguished from other processes. It is.

  ADVANTAGE OF THE INVENTION According to this invention, the pharmaceutical composition which can mask the bitter taste which telmisartan has, and can suppress the fall of the dissolution property of telmisartan in pH 3.5 vicinity, its manufacturing method, an orally disintegrating tablet, and A manufacturing method thereof can be provided.

It is a graph which shows the result of the elution test implemented about the fine granule of Example 2-7 and the comparative example 6 (medicine composition).

[Pharmaceutical composition]
The pharmaceutical composition of the present invention has drug substance-containing particles and a coating layer (hereinafter also referred to as “coating layer”) that coats the drug substance-containing particles, and telmisartan, aminoalkyl methacrylate copolymer E, A nonionic surfactant, telmisartan in the drug substance-containing particles, and an aminoalkyl methacrylate copolymer E in the coating layer.
The pharmaceutical composition of the present invention may contain other components other than telmisartan, aminoalkyl methacrylate copolymer E, and nonionic surfactant, if necessary, as long as the effects of the present invention are not impaired. You may have other layers other than a layer.

  The bitter taste of telmisartan can be markedly masked by coating drug substance-containing particles containing telmisartan with a coating layer containing aminoalkyl methacrylate copolymer E. However, when telmisartan and aminoalkyl methacrylate copolymer E are used in combination, telmisartan and aminoalkyl methacrylate copolymer E act and insolubilize in the vicinity of pH 3.5, and the elution property of telmisartan decreases.

In the present invention, the pharmaceutical composition having a drug substance-containing particle containing telmisartan and a layer containing the drug substance-containing particle and the aminoalkyl methacrylate copolymer E further contains a nonionic surfactant. Thus, both the bitterness masking of telmisartan and the suppression of the decrease in elution of telmisartan near pH 3.5 can be achieved.
The effect of achieving both the masking of bitterness of telmisartan in the present invention and the suppression of the decrease in elution of telmisartan near pH 3.5 is obtained by combining telmisartan, aminoalkyl methacrylate copolymer E, and nonionic surfactant. When combined, the aminoalkyl methacrylate copolymer E can be obtained by masking the bitter taste of telmisartan, and the nonionic surfactant can improve the solubility of telmisartan and improve the decrease in dissolution of telmisartan. Guessed.

<Drug containing particles>
The pharmaceutical composition of the present invention contains telmisartan in the drug substance-containing particles. The pharmaceutical composition of the present invention may contain components other than telmisartan in the drug substance-containing particles as necessary, as long as the effects of the present invention are not impaired.

(Telmisartan)
Telmisartan (chemical name: 4 ′-[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-ylmethyl] biphenyl-2-carboxylic acid) is used for hypertension. And an angiotensin II receptor antagonist developed for the treatment of and other medical indications, drugs with a bitter taste.

  The content of telmisartan is preferably 10% by mass to 50% by mass, more preferably 15% by mass to 40% by mass, and still more preferably, with respect to the total mass of the pharmaceutical composition, from the viewpoint of ingestion. Is 20% by mass to 30% by mass.

(Basic substance)
The pharmaceutical composition of the present invention can contain a basic substance in the drug substance-containing particles.
By including a basic substance in drug substance-containing particles containing telmisartan, the basic substance contributes to the stability, solubility, amorphization, etc. of telmisartan.
The basic substance is not particularly limited as long as it is a pharmacologically acceptable basic substance, and a known basic substance can be used. Examples of the basic substance include inorganic or organic basic substances and basic amino acids.

  Examples of the inorganic basic substance include metal oxides such as magnesium oxide, calcium oxide and aluminum oxide, metal hydroxides such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and aluminum hydroxide, Metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, metal hydrogen carbonates such as sodium bicarbonate, potassium bicarbonate, trisodium phosphate, tripotassium phosphate, tricalcium phosphate, trimagnesium phosphate Metal phosphates such as sodium pyrophosphate, potassium pyrophosphate, sodium polyphosphate, potassium polyphosphate, metal hydrogen phosphates such as sodium monohydrogen phosphate, potassium monohydrogen phosphate, sodium silicate, magnesium silicate, Calcium silicate, synthetic aluminum silicate Synthetic magnesium silicate, metal silicates such as talc, magnesium silicate aluminate, magnesium aluminum silicate, composite silicate-aluminum compound such as magnesium metasilicate aluminate, composite aluminum magnesium compound such as synthetic hydrotalcite Inorganic ammonium salts such as ammonium hydroxide, ammonium carbonate, ammonium hydrogen carbonate, and ammonium monohydrogen phosphate.

Examples of organic basic substances include metal salts of organic acids and organic amines.
Examples of metal salts of organic acids include sodium salts, potassium salts, magnesium salts, calcium salts, and the like of organic acids such as citric acid, succinic acid, tartaric acid, fumaric acid, maleic acid, malonic acid, malic acid and the like.
Examples of organic amines include meglumine, monoethanolamine, diisopropanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine, triisopropanolamine, 2-amino-2-methyl-1-propanol, 2-amino- Examples include 2-methyl-1,3-propanediol and polyoxyethylene alkylamine.

  Examples of basic amino acids include lysine, arginine, phenylalanine, tyrosine, histidine, proline, oxyproline, ornithine, hydroxylysine, and derivatives thereof.

  Among these, the basic substance is preferably at least one selected from the group consisting of meglumine, arginine, sodium hydroxide, potassium hydroxide, and lysine from the viewpoint of solubility of telmisartan. In particular, meglumine is preferable as the basic substance from the viewpoint of excellent telmisartan amorphization effect.

  When the pharmaceutical composition of the present invention contains a basic substance in the drug substance-containing particles, the pharmaceutical composition may contain one kind of basic substance or two or more kinds. The content of the basic substance is not particularly limited, and can be appropriately set according to the content of telmisartan.

  When the basic substance is meglumine, from the viewpoint of solubility of telmisartan, the meglumine content in the drug substance-containing particles is preferably 0. 0 relative to the mass of telmisartan contained in the drug substance-containing particles. The amount is 1 to 5 times, more preferably 0.5 to 3 times, and still more preferably 1 to 2 times.

(Light anhydrous silicic acid)
The pharmaceutical composition of the present invention may further contain light anhydrous silicic acid in at least one selected from the group consisting of drug substance-containing particles and a coating layer that coats the drug substance-containing particles.
The pharmaceutical composition of the present invention may contain light anhydrous silicic acid in both the drug substance-containing particles and the coating layer, or in either one of the drug substance-containing particles and the coating layer, Preferably, at least the drug substance-containing particles contain light anhydrous silicic acid, and more preferably, both the drug substance-containing particles and the coating layer contain light anhydrous silicic acid.
Normally, when granulating an active ingredient (drug substance) having adhesive properties, a spray solution in which a lubricant such as talc and stearate is dispersed together with the active ingredient to suppress aggregation of the active ingredient is used. The grain method is adopted. However, when granulating telmisartan, it is difficult to obtain an effect of suppressing aggregation of telmisartan with a normal lubricant.
In addition, when the drug substance-containing particles containing telmisartan are coated with a coating layer containing aminoalkyl methacrylate copolymer E, when a lubricant having a carboxyl group such as stearate is used, the carboxyl group possessed by the lubricant and Since there is a concern that the amino group of the aminoalkyl methacrylate copolymer E may act, the use of a lubricant having a carboxyl group is not preferable from the viewpoint of manufacturability.
In the pharmaceutical composition of the present invention, from the viewpoint of suppressing aggregation during granulation of particles containing telmisartan, it is unexpectedly preferable that the drug substance-containing particles contain light anhydrous silicic acid as a lubricant. In the pharmaceutical composition of the present invention, it is also preferable that light anhydrous silicic acid is contained as a lubricant in the coating layer from the viewpoint of suppressing aggregation during coating of the coating layer covering the drug substance-containing particles.

  When the drug substance-containing particles contain light anhydrous silicic acid, the content of the light anhydrous silicic acid in the drug substance-containing particles is determined in the drug substance-containing particles from the viewpoint of suppressing aggregation during granulation of the particles containing telmisartan. Preferably it is 5 mass parts-100 mass parts with respect to 100 mass parts of telmisartan contained, More preferably, they are 7.5 mass parts-50 mass parts, More preferably, they are 10 mass parts-25 mass parts.

The concentration of light silicic acid anhydride in the spray liquid used when granulating the drug substance-containing particles is preferably 0.05 w / v% to 10 w / v%, more preferably 0.1 w / v%. It is -5 w / v%, More preferably, it is 0.15 w / v%-2.5 w / v%.
When the concentration of the light anhydrous silicic acid in the spray liquid is 0.05 w / v% or more, the lubrication effect is sufficiently generated, and when it is 10 w / v% or less, the enlargement of the spray droplets due to an increase in the viscosity of the spray liquid. , Generation of aggregates and the like can be sufficiently suppressed.

(Nonionic surfactant)
The pharmaceutical composition of the present invention contains a nonionic surfactant, and the nonionic surfactant can be contained in the drug substance-containing particles. In addition, the pharmaceutical composition of the present invention can also contain a nonionic surfactant in the coating layer described later.
The pharmaceutical composition of the present invention may contain a nonionic surfactant in both the drug substance-containing particle and the coating layer, or in either one of the drug substance-containing particle and the coating layer. Preferably, it is preferably contained in at least the coating layer described later.

Since telmisartan is a compound having a carboxyl group, the carboxyl group possessed by telmisartan and the amino group possessed by the aminoalkyl methacrylate copolymer E may act and insolubilize in a weakly acidic region around pH 3.5. Telmisartan is known to have lower solubility near pH 3-6, and it is considered that telmisartan is more susceptible to a decrease in elution due to the action with aminoalkyl methacrylate copolymer E near pH 3.5.
In contrast to such properties, the pharmaceutical composition of the present invention unexpectedly improves the solubility of telmisartan by including a nonionic surfactant in at least one of the drug substance-containing particles and the coating layer. It is possible to improve the decrease in dissolution property of telmisartan around pH 3.5.

It does not specifically limit as a nonionic surfactant, A well-known nonionic surfactant can be used. As the nonionic surfactant, at least one selected from the group consisting of polysorbate, poloxamer, and polyethylene glycol is preferable, and it has high hydrophilicity and remarkably improves the decrease in elution of telmisartan near pH 3.5. Polysorbate is more preferable from the viewpoint that it can be used.
Polysorbate is a sorbitan fatty acid ester obtained by condensation of about 20 molecules of ethylene oxide. Examples of the polysorbate include polysorbate 20 (polyoxyethylene sorbitan monolaurate), polysorbate 60 (polyoxyethylene sorbitan monostearate), polysorbate 65 (polyoxyethylene sorbitan tristearate), and polysorbate 80 (polyoxyethylene sorbitan oleate). ) And the like. Among these, polysorbate 80 is preferable as the polysorbate.

When the pharmaceutical composition of the present invention contains a nonionic surfactant in the drug substance-containing particles, the drug substance-containing particles may contain one kind of nonionic surfactant or two or more kinds. Good.
The content of the nonionic surfactant in the pharmaceutical composition of the present invention (the total content of the nonionic surfactant contained in the drug substance-containing particles and the coating layer) is telmisartan around pH 3.5. From the viewpoint of improving the decrease in elution, it is preferably 1 part by weight to 40 parts by weight, more preferably 2 parts by weight to 35 parts by weight, even more preferably 100 parts by weight of aminoalkyl methacrylate copolymer E. 10 parts by mass to 35 parts by mass.

When the nonionic surfactant is polysorbate 80, the content of polysorbate 80 in the pharmaceutical composition of the present invention (the total content of polysorbate 80 contained in the drug substance-containing particles and the coating layer) is: Preferably it is 1 mass part-40 mass parts with respect to 100 mass parts of aminoalkyl methacrylate copolymer E, More preferably, they are 2 mass parts-35 mass parts, More preferably, they are 10 mass parts-35 mass parts.
When the content of polysorbate 80 in the pharmaceutical composition of the present invention is 1 part by mass or more with respect to 100 parts by mass of the aminoalkyl methacrylate copolymer E, the decrease in dissolution of telmisartan near pH 3.5 is sufficiently improved. can do.
On the other hand, since the polysorbate 80 can reduce the glass transition temperature of the aminoalkyl methacrylate copolymer E to cause fine particle aggregation and reduce the manufacturability of the pharmaceutical composition, the content of the polysorbate 80 is limited to the aminoalkyl methacrylate. It is desirable to make it 40 parts by mass or less with respect to 100 parts by mass of the copolymer E.

(Other ingredients)
The pharmaceutical composition of the present invention includes, in addition to telmisartan, optional basic substances, light silicic anhydride, and nonionic surfactants in the drug substance-containing particles, in a range that does not impair the effects of the present invention. In the above, other components may be included as required.
Examples of other components include excipients, disintegrants, binders, lubricants, and the like. These other components can be appropriately selected according to the purpose.

The excipient contributes to improving the moldability of the drug substance-containing particles.
The excipient is not particularly limited as long as it is a component that can function as an excipient and is pharmacologically acceptable, and a known one can be used.
Examples of the excipient include sugar, sugar alcohol, starch, crystalline cellulose, ethyl cellulose, anhydrous calcium phosphate, magnesium aluminate metasilicate, and the like.
Examples of the sugar include lactose, sucrose, maltose, trehalose, dextrin and the like. Examples of the sugar alcohol include mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol and the like. Examples of the starch include corn starch, potato starch, rice starch, wheat starch and the like.

The disintegrant can contribute to the promotion of the disintegration of the drug substance-containing particles.
The disintegrant is not particularly limited as long as it is a component that can function as a disintegrant and is pharmacologically acceptable, and known ones can be used.
Examples of the disintegrant include starch such as corn starch and potato starch, partially pregelatinized starch, sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, crystalline cellulose, Examples thereof include hydroxypropyl starch and sodium starch glycolate.

The binder can contribute to the improvement of the moldability of the drug substance-containing particles.
The binder is not particularly limited as long as it is a component that can function as a binder and is a pharmacologically acceptable component, and known ones can be used.
Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, carmellose sodium, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, gum arabic, gelatin, pregelatinized starch, pullulan and the like.
Among these, as the binder, at least one selected from the group consisting of hydroxypropylcellulose and hydroxypropylmethylcellulose is preferable, and hydroxypropylmethylcellulose is more preferable.

Lubricants can contribute to improving the productivity of drug substance-containing particles.
The lubricant is not particularly limited as long as it is a component that can function as a lubricant and is pharmacologically acceptable, and a known one can be used.
Examples of the lubricant include, in addition to the above-mentioned light anhydrous silicic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, glyceryl monostearate, talc and the like.
As described above, when the drug substance-containing particles containing telmisartan are coated with the coating layer containing the aminoalkyl methacrylate copolymer E, if a lubricant having a carboxyl group such as stearate is used, in some cases, The carboxyl group possessed by the bulking agent and the amino group possessed by the aminoalkyl methacrylate copolymer E act to insolubilize. Therefore, light anhydrous silicic acid is preferable as the lubricant from the viewpoint of suppressing aggregation during granulation of telmisartan.

When the pharmaceutical composition of the present invention contains other components in the drug substance-containing particles, the other components may be included, or two or more types may be included.
The content of other components in the drug substance-containing particles is not particularly limited, and can be appropriately set according to the contents of telmisartan and optional components.

(Average particle size of drug substance-containing particles)
The average particle size of the drug substance-containing particles is preferably 10 μm to 700 μm, more preferably 50 μm to 600 μm, and still more preferably 100 μm to 500 μm.
When the average particle diameter of the drug substance-containing particles is within the above range, roughness during taking can be suppressed, and a decrease in feeling of taking can be avoided.

(Form of drug substance-containing particles)
The drug substance-containing particle may be a granulated product containing telmisartan. For example, telmisartan and other components other than telmisartan may be mixed, and the surface of the core particle containing other components may be treated with telmisartan. It may be coated with a layer containing (hereinafter referred to as “the drug substance layer”). The drug substance layer may contain only telmisartan, or may contain telmisartan and other components.

-Nuclear particles-
The core particle is a particle that can serve as a base material when producing the drug substance-containing particle.
The component that forms the core particle is not particularly limited as long as it is a pharmacologically acceptable component.
The core particles contain at least one selected from the group consisting of excipients such as mannitol, lactose, crystalline cellulose, magnesium aluminate metasilicate, anhydrous calcium hydrogen phosphate, and calcium silicate, magnesium oxide, and magnesium carbonate. It is preferable.
The core powder itself may be used as the core particle, a granulated product of the above-described component powder may be used, or commercially available core particles may be used.
Examples of commercially available core particles include florite (manufactured by Eisai Food Chemical Co., Ltd.), nonpareil (manufactured by Freund Sangyo Co., Ltd.), and Selfia (manufactured by Asahi Kasei Chemicals Corporation). Among these, the commercially available core particles are preferably at least one selected from the group consisting of non-parrel (Freund Sangyo Co., Ltd.) and SELPHY (Asahi Kasei Chemicals Co., Ltd.).

  The drug substance-containing particles are prepared, for example, by spraying a spray liquid containing telmisartan in the core particles (hereinafter referred to as “spray liquid for drug substance layer”). From the viewpoint of facilitating spraying to the core particles, the core particles having a smooth surface are preferable, and from the viewpoint of uniforming the particle size distribution of the drug substance-containing particles, the core particles having a uniform particle size distribution are preferable.

<Coating layer covering drug substance-containing particles>
The pharmaceutical composition of the present invention has a coating layer that coats the drug substance-containing particles.
The pharmaceutical composition of the present invention may have one coating layer or two or more coating layers.
The coating layer preferably covers the entire drug substance-containing particle. The pharmaceutical composition of the present invention may have a portion where the drug substance-containing particles are not coated with the coating layer as long as the effects of the present invention are not impaired.

  The pharmaceutical composition of the present invention comprises aminoalkyl methacrylate copolymer E in the coating layer. The pharmaceutical composition of the present invention may contain components other than the aminoalkyl methacrylate copolymer E in the coating layer as necessary, as long as the effects of the present invention are not impaired.

(Aminoalkyl methacrylate copolymer E)
The aminoalkyl methacrylate copolymer E is a copolymer of methyl methacrylate and dimethylaminoethyl methacrylate, and has a property of dissolving at pH 5.0 or less and swelling when the pH exceeds 5.0. Since the pH in the oral cavity is neutral and the aminoalkyl methacrylate copolymer E does not dissolve in the oral cavity, elution of telmisartan having a bitter taste is suppressed. On the other hand, the pH in the stomach is acidic, and the aminoalkyl methacrylate copolymer E dissolves in the stomach and telmisartan dissolves quickly. Therefore, absorption of telmisartan into the body is not suppressed.

  As aminoalkyl methacrylate copolymer E, a well-known thing can be used as aminoalkyl methacrylate copolymer E, and a commercial item can also be used. Examples of commercially available aminoalkyl methacrylate copolymers E include Eudragit EPO (trade name, manufactured by Evonik).

The content of the aminoalkyl methacrylate copolymer E in the pharmaceutical composition of the present invention is preferably 2% by mass or more, more preferably 4% by mass or more, based on the total mass of the pharmaceutical composition. More preferably, it is 8 mass% or more.
In order to achieve the effect of the present invention of masking the bitter taste of telmisartan, the higher the content of aminoalkyl methacrylate copolymer E, the better. However, as the content of aminoalkyl methacrylate copolymer E increases, the size of the pharmaceutical composition increases and the feeling of dosing decreases. Therefore, the content of aminoalkyl methacrylate copolymer E preferably does not exceed 50% by mass with respect to the pharmaceutical composition.

(Light anhydrous silicic acid)
The pharmaceutical composition of the present invention can contain light anhydrous silicic acid in the coating layer.
The pharmaceutical composition of the present invention preferably contains light anhydrous silicic acid in at least the drug substance-containing particles described above, and more preferably in both the drug substance-containing particles and the coating layer.
As described above, when the drug substance-containing particles containing telmisartan are coated with the coating layer containing the aminoalkyl methacrylate copolymer E, if a lubricant having a carboxyl group such as stearate is used, the lubricant has Since there is a concern that the carboxyl group and the amino group of the aminoalkyl methacrylate copolymer E act, the use of a lubricant having a carboxyl group is not preferable from the viewpoint of manufacturability.
The pharmaceutical composition of the present invention is a light anhydrous silica as a lubricant not only in the drug substance-containing particles but also in the coating layer from the viewpoint of suppressing aggregation during coating of the coating layer covering the drug substance-containing particles. It is preferable that an acid is included.

  In the case where light anhydrous silicic acid is contained in the coating layer covering the drug substance-containing particles, the content of light anhydrous silicic acid in the coating layer is from the viewpoint of suppressing aggregation during the coating of the coating layer covering the drug substance-containing particles. The aminoalkyl methacrylate copolymer E contained in the coating layer is preferably 1 part by mass to 100 parts by mass, more preferably 5 parts by mass to 50 parts by mass, and still more preferably 10 parts by mass with respect to 100 parts by mass of the aminoalkyl methacrylate copolymer E. -40 mass parts.

(Nonionic surfactant)
The pharmaceutical composition of the present invention can contain a nonionic surfactant in the coating layer.
As described above, the pharmaceutical composition of the present invention may contain a nonionic surfactant in both the drug substance-containing particle and the coating layer, and preferably at least in the coating layer.

The nonionic surfactant is synonymous with the nonionic surfactant described in the section of drug substance-containing particles, and preferred examples thereof are also the same, and thus description thereof is omitted here.
When the nonionic surfactant is contained in the coating layer, the pharmaceutical composition of the present invention may contain one nonionic surfactant or two or more nonionic surfactants in the coating layer.
The content of the nonionic surfactant in the pharmaceutical composition of the present invention is synonymous with the content described in the section of drug substance-containing particles, and the preferred examples are also the same, so the description thereof is omitted here.

(Other ingredients)
The pharmaceutical composition of the present invention contains, as necessary, other than the aminoalkyl methacrylate copolymer E and the optional nonionic surfactant in the coating layer as long as the effects of the present invention are not impaired. Can be included.
Examples of other components include excipients, binders, plasticizers, lubricants, and dispersants. These other components can be appropriately selected according to the purpose.

Examples of the plasticizer include stearic acid, triethyl citrate, polyethylene glycol, polyoxyethylene sorbitan monooleate, acetyl triethyl citrate, tributyl citrate, and tributyl acetyl citrate.
Examples of the lubricant include, in addition to the above light anhydrous silicic acid, sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, glyceryl monostearate, talc and the like. Among these, light silicic acid anhydride is preferable as the lubricant from the viewpoint of suppressing aggregation during coating of the coating layer covering the drug substance-containing particles.
Dispersants include sodium lauryl sulfate, carboxyvinyl polymer, glycerin, glycerin fatty acid ester, sucrose fatty acid ester, dioctyl sodium sulfosuccinate, cetanol, sorbitan sesquioleate, sorbitan fatty acid ester, medium chain fatty acid triglyceride, trioleic acid Sorbitan, hydroxypropyl cellulose, propylene glycol, propylene glycolate, polyoxyethylene nonylphenyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, macrogol 300, macrogol 400, sorbitan monooleate, glyceryl monostearate , Sorbitan monolaurate, polyoxyethylene polyoxypropylene acceptable for oral administration Recall (e.g., polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol and the like) and the like.
The excipient and binder that can be included in the coating layer are synonymous with the excipient and binder described in the section of drug substance-containing particles, and preferred examples are also the same. Omitted.

When the coating composition contains other components, the pharmaceutical composition of the present invention may contain one or more of the other components.
The content of other components in the coating layer is not particularly limited, and is appropriately set according to the content of aminoalkyl methacrylate copolymer E and the type and content of the nonionic surfactant that is an optional component. be able to.

(Other layers)
The pharmaceutical composition of the present invention may contain, in addition to the coating layer, another layer that does not contain the aminoalkyl methacrylate copolymer E in a mode of coating the coating layer.
Examples of the other layer include an overcoat layer containing mannitol.

[Method for producing pharmaceutical composition]
The pharmaceutical composition of the present invention can be obtained by coating drug substance-containing particles containing telmisartan with a coating layer containing aminoalkyl methacrylate copolymer E.
The drug substance-containing particles can be obtained by a general granulation method. Examples of the granulation method include a fluidized bed granulation method, a stirring granulation method, and a spray drying method.

The drug substance-containing particles are sprayed with a spray liquid containing telmisartan (spray liquid for drug substance layer) on the core particles using a granulator, and then water contained in the spray liquid for drug substance layer on the sprayed core particles, etc. The solvent can be evaporated and the solvent can be removed from the core particles.
The details of the core particle are the same as the contents described in the section of the core particle, and thus description thereof is omitted here.

In addition to telmisartan, the active ingredient layer spray liquid contains optional components such as basic substances, light anhydrous silicic acid, nonionic surfactants, and the like, as long as the effects of the present invention are not impaired. Other components such as an agent, a disintegrant, a binder, and a lubricant can be included.
The drug substance spray solution preferably contains a lubricant along with telmisartan from the viewpoint of improving the productivity of the drug substance-containing particles. As the lubricant, as described above, it is preferable to use light anhydrous silicic acid from the viewpoint of suppressing aggregation during granulation of telmisartan.
Optional components such as basic substances, light anhydrous silicic acid, nonionic surfactants, excipients, disintegrants, binders, lubricants and other other components that can be included in the drug substance layer spray Is synonymous with the component described in the section of drug substance-containing particles, and preferred examples are also the same, and thus the description thereof is omitted here.

  In the preparation of a drug substance spray solution, pharmacologically acceptable water and alcohol miscible with water, for example, methanol, ethanol, propanol, isopropanol, acetone, acetonitrile, etc., within the range not impairing the effects of the present invention. A mixed solvent with a possible solvent may be used.

Conditions, such as temperature at the time of preparing the drug substance layer spray, are not particularly limited. The drug substance spray solution contains, for example, telmisartan, an optional basic substance, light anhydrous silicic acid, nonionic surfactant, other ingredients, etc. in water set at a temperature of 20 ° C. to 80 ° C. It can be prepared by adding.
The viscosity, temperature, etc. of the drug substance layer spray liquid can be appropriately set according to the type and amount of each component contained in the drug substance layer spray liquid.

The method of spraying the drug substance layer spray liquid onto the core particles using a granulator is not particularly limited, and the amount of the core particles to be sprayed with the drug substance layer spray liquid, It can be set as appropriate according to the physical strength and the like.
Examples of the granulator used when spraying the drug substance spray liquid onto the core particles include, for example, a fluidized bed granulator, a rolling fluidized bed granulator, a jet fluidized bed granulator, and a mechanical stirring composite type. Examples thereof include a granulator such as a fluidized bed granulator.
Examples of the fluidized bed granulator include, for example, a fluidized bed granulator (product name: FD-MP-01, manufactured by POWREC Co., Ltd.), a flow coater (product name: FL-1, manufactured by Freund Sangyo Co., Ltd.), and the like. Is mentioned.

  As a method for removing the solvent contained in the drug substance layer spray liquid sprayed on the core particles, there is a method in which only drying is performed independently of the above method using the fluidized bed granulator. Examples of the method of performing only drying independently include a method using a vacuum dryer and a method using a hot air dryer.

  The spray rate, spraying time, liquid temperature, drying conditions, etc. of the drug substance layer spray liquid when producing drug substance-containing particles are not particularly limited, and telmisartan is contained in the drug substance layer spray liquid. The amount can be appropriately set according to the viscosity of the drug substance spray liquid.

  One of the preferred embodiments for producing drug substance-containing particles is to control the relative humidity at the supply temperature of the gas supplied to the granulator to 20% or less, and to use the drug substance layer spray liquid as the core particle. In contrast, it includes at least one selected from intermittent spraying, preferably including at least controlling the relative humidity at the supply temperature of the gas supplied to the granulator to 20% or less, and more preferably granulation. This includes both controlling the relative humidity at the supply temperature of the gas supplied to the machine to 20% or less and intermittently spraying the drug substance layer spray liquid onto the core particles.

In the method for producing drug substance-containing particles using wet granulation, if the adhesion or aggregability of the components contained in the spray liquid is strong, the particles agglomerate with each other, and the size is larger than the target particle diameter. There is a problem that particles are formed and the yield decreases. Moreover, in order to suppress aggregation of particle | grains, the spraying speed of spray liquid must be made slow, and manufacturing time will be extended. Therefore, the granulation method using the spray liquid containing the adhesive or cohesive component also has a problem that the production efficiency is low.
In the method for producing the pharmaceutical composition of the present invention, when producing the drug substance-containing particles, the relative humidity at the supply temperature of the gas supplied to the granulator is controlled to 20% or less, so that adhesion or The fluidity of drug substance-containing particles containing telmisartan, which has cohesive properties, is more effectively suppressed, making it difficult for particles to agglomerate, eliminating the above-mentioned problems of yield reduction and production efficiency reduction. obtain.
Further, in the method for producing a pharmaceutical composition of the present invention, when producing drug substance-containing particles, the drug substance layer spray liquid containing at least telmisartan is intermittently sprayed onto the core particles, and the adherence is achieved. Alternatively, the fluidity of drug substance-containing particles containing telmisartan, which has cohesive properties, is more effectively suppressed, making it difficult for particles to agglomerate with each other, eliminating the above-described problems of yield reduction and production efficiency reduction. Can do.

The relative humidity at the supply temperature of the gas supplied to the granulator can be measured with a general hygrometer.
The humidity of the gas supplied to the granulator can be adjusted by heating and drying the gas before being supplied to the granulator using a drying means. A known dryer can be applied to the drying means. Examples of the dryer include a dry dehumidifier (trade name: Honey Dry, (Daikin Co., Ltd.)).

  As supply temperature of the gas supplied to a granulator, 25 to 100 degreeC is preferable, for example, 30 to 80 degreeC is more preferable, and 30 to 60 degreeC is still more preferable.

The method of intermittent spraying is not particularly limited as long as the spray liquid supply is stopped at regular intervals by an automatic or manual method to temporarily reduce the particle aggregation rate.
The fixed interval (stop interval) is not particularly limited, and is preferably once every 30 minutes to 3 hours, more preferably once every 30 minutes to 2 hours.
The stop time is not particularly limited, and is preferably 30 seconds to 15 minutes, and more preferably 1 minute to 10 minutes.
The number of stops is not particularly limited, and can be appropriately set according to the degree of decrease in the aggregation rate of the particles.

  The amount of water or other solvent remaining in the drug substance-containing particles is not particularly limited, and is preferably 5% by mass or less, for example, 4% by mass with respect to the total mass of the drug substance-containing particles. More preferably, it is more preferably 3% by mass or less.

The method for coating drug substance-containing particles containing telmisartan with a coating layer containing aminoalkyl methacrylate copolymer E is not particularly limited, and examples thereof include a method using a granulator.
In the case of using a granulator, a solution containing aminoalkyl methacrylate copolymer E (hereinafter referred to as “spray liquid for coating layer”) is sprayed onto drug substance-containing particles containing telmisartan, whereby the raw material containing telmisartan is sprayed. The drug-containing particles can be coated with a coating layer comprising aminoalkyl methacrylate copolymer E.

In addition to the aminoalkyl methacrylate copolymer E, the coating layer spray liquid contains optional components such as nonionic surfactants and light anhydrous silicic acid, excipients, as long as the effects of the present invention are not impaired. , Other components such as binders, plasticizers, lubricants, and the like.
Optional components such as nonionic surfactants and light anhydrous silicic acid that can be included in the coating layer spray solution, other components such as excipients, binders, plasticizers, lubricants, etc. Since it is synonymous with the component demonstrated in the term, and a preferable example is also the same, description is abbreviate | omitted here.

  In the preparation of the spray solution for the coating layer, pharmacologically acceptable water and alcohol miscible with water, for example, methanol, ethanol, propanol, isopropanol, acetone, acetonitrile, etc. are allowed within the range not impairing the effects of the present invention. A mixed solvent with the obtained solvent may be used.

Conditions, such as temperature at the time of preparing the coating layer spray, are not particularly limited.
In addition, the viscosity, temperature, and the like of the coating layer spray liquid can be appropriately set according to the type and amount of each component contained in the coating layer spray liquid.

The method of spraying the coating layer spray liquid onto the drug substance-containing particles using a granulator is not particularly limited. The amount of drug substance-containing particles to be sprayed with the coating layer spray liquid, the drug substance It can be set as appropriate according to the physical strength of the contained particles.
The granulator used when spraying the coating layer spray liquid onto the drug substance-containing particles should be the same as the granulator used when spraying the drug substance layer spray liquid onto the core particles. it can.

  The removal of the solvent in the coating layer spray solution sprayed onto the drug substance-containing particles can be performed by the same method as the removal of the solvent from the drug substance layer spray solution sprayed onto the core particles.

  The spray rate, spraying time, solution temperature, drying conditions, etc. of the coating layer spray liquid when the drug substance-containing particles are coated with the coating layer are not particularly limited, and aminoalkyl in the coating layer spray liquid is not limited. It can be appropriately set according to the content of the methacrylate copolymer E, the viscosity of the coating layer spray liquid, and the like.

(Form of pharmaceutical composition)
The pharmaceutical composition of the present invention has a granular form.
Examples of the form of the granular material include forms such as granules and fine granules.

(Average particle size of the pharmaceutical composition)
The average particle size of the pharmaceutical composition of the present invention is preferably 50 μm to 1000 μm, more preferably 100 μm to 750 μm, and still more preferably 150 μm to 500 μm.
When the average particle size of the pharmaceutical composition of the present invention is within the above range, roughness during taking can be suppressed, and a decrease in feeling of taking can be avoided.

[Orally disintegrating tablets]
The orally disintegrating tablet of the present invention contains the pharmaceutical composition of the present invention.
In addition to the pharmaceutical composition of the present invention, the orally disintegrating tablet of the present invention can contain excipients and other pharmacologically acceptable pharmaceutical additives.
The pharmaceutical composition of the present invention can mask the bitter taste of telmisartan and can suppress a decrease in dissolution of telmisartan at around pH 3.5. Therefore, an orally disintegrating tablet containing telmisartan as an active ingredient The fine particles can be suitably used.

The coating layer in the pharmaceutical composition of the present invention can also function as a film having elution control ability.
When the pharmaceutical composition of the present invention is used as fine granules of an orally disintegrating tablet, the pharmaceutical composition of the present invention may be further coated with a film having a dissolution control ability (dissolution control layer).
Specifically, the elution control layer is a water-soluble film that dissolves in water for a certain period of time, while the drug is prevented from being released, and the solubility in water is low or insoluble in water. And water-insoluble membranes that can only be gradually released.

  The orally disintegrating tablet containing the pharmaceutical composition of the present invention preferably contains 20 mg to 80 mg of telmisartan per one orally disintegrating tablet.

The shape of the orally disintegrating tablet of the present invention is not particularly limited as long as it is pharmaceutically acceptable. The shape of the orally disintegrating tablet of the present invention may be, for example, a round tablet or a deformed tablet, and may be appropriately set in consideration of medication compliance.
In addition, the size of the orally disintegrating tablet of the present invention is not particularly limited as long as it is pharmaceutically acceptable, but in view of the fact that orally disintegrating tablets are often used for patients who have difficulty swallowing, In consideration of the medicinal effect, it is preferable to be as small as possible.

The orally disintegrating tablet of the present invention preferably has an oral disintegration time of less than 60 seconds and more preferably less than 30 seconds from the viewpoint of medication compliance.
In the present specification, “orally disintegrating time” refers to an orally disintegrating tablet measuring device (product name: Tricorp Tester, manufactured by Okada Seiko Co., Ltd.), and purified water at 37 ° C. with respect to the orally disintegrating tablet. The tablet disintegration time measured when dropped at 6 ml / min.

[Method for producing orally disintegrating tablets]
The manufacturing method of the orally disintegrating tablet of this invention is not specifically limited, A well-known method can be used. The orally disintegrating tablet of the present invention can be obtained, for example, by mixing fine granules which are the pharmaceutical composition of the present invention and an excipient, tableting the obtained mixed powder, and drying.
When the fine particles and the excipient are mixed, in addition to the excipient, other pharmacologically acceptable additives for pharmaceutical preparation can be blended.

Excipients for mixing with the fine granules which are the pharmaceutical composition of the present invention include, for example, sugar, sugar alcohol, starch, crystalline cellulose, ethyl cellulose, anhydrous calcium phosphate, magnesium aluminate metasilicate, light anhydrous silicic acid, Lactose, sucrose, maltose, trehalose, dextrin, partially pregelatinized starch, sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, low substituted hydroxypropylcellulose, hydroxypropyl starch, sodium starch glycolate, Hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, carmellose sodium, polyethylene glycol, polyvinylpyrrolidone, poly Alkenyl alcohols, gum arabic, gelatin, pregelatinized starch, pullulan, sodium stearyl fumarate, magnesium stearate, calcium stearate, glyceryl monostearate, and talc. Examples of the sugar alcohol include mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol and the like. Examples of the starch include corn starch, potato starch, rice starch, wheat starch and the like.
One of the preferred embodiments of the method for producing an orally disintegrating tablet of the present invention is to obtain a mixed powder by mixing fine granules which are the pharmaceutical composition of the present invention and an excipient containing light anhydrous silicic acid. And tableting the obtained mixed powder to obtain a tableted product.
When a tablet is formed, by incorporating light anhydrous silicic acid as an excipient component, it is possible to produce an orally disintegrating tablet that can further suppress the decrease in dissolution of telmisartan at around pH 3.5. .

The method for mixing the fine particles and the excipient is not particularly limited. As a method of mixing the fine granules and the excipient, for example, a known mixer such as a V-type mixer (manufactured by Tsutsui Riken Kikai Co., Ltd.), a fluidized bed granulator (manufactured by Paulek Co., Ltd.) or the like is used. And mixing them.
Conditions such as time required for mixing can be appropriately adjusted depending on the types of the prepared fine granules and excipients.

The method for tableting the mixed powder of fine granules and excipient is not particularly limited. The temperature at the time of tableting is not particularly limited, and can be set as appropriate.
Examples of the method for tableting the mixed powder of fine granules and excipient include, for example, a rotary tableting machine (product name: HT-P18A, manufactured by Hata Seiko Co., Ltd.), a high-speed rotary tableting machine (product). Name: A method of tableting using a tableting machine such as AQUARIUS G, manufactured by Kikusui Seisakusho Co., Ltd.

  The method for drying the tableted product obtained by tableting the mixed powder is not particularly limited. Examples of the method for drying the tableted product obtained by tableting the mixed powder include a method of drying by vacuum drying, fluidized bed drying or the like.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples unless it exceeds the gist thereof.

[Preparation of pharmaceutical composition]
<Example 1>
As a core particle, 500 g of D-mannitol (trade name: Nonparel (registered trademark) -108, spherical granules having a size of 150 μm to 250 μm, manufactured by Freund Sangyo Co., Ltd.) is used. 01, manufactured by POWREC Co., Ltd. (hereinafter referred to as “fluidized bed granulator (1)”). Adjusting the supply temperature of the fluidized bed granulator (1) to 60 ° C to 80 ° C and the exhaust temperature to about 30 ° C to 50 ° C, flowing the spray liquid for the drug substance layer (1) having the following composition prepared beforehand It sprayed in the layer granulator (1). In addition, spraying of the spray liquid for the drug substance layer (1) is performed by operating a dryer (trade name: Honey Dry, manufactured by Daikin Co., Ltd.) after starting spraying to prevent particle aggregation. In an intermittent operation (stop interval: once every hour, stop time: 5 minutes) while supplying the air (25 ° C., about 1% RH to 5% RH) to the fluidized bed granulator (1) went. Spraying of the spray solution for the drug substance layer (1) was carried out until an equal amount of telmisartan was coated on the spherical granules of D-mannitol. After spraying a prescribed amount of the spray liquid for the drug substance layer (1), it was dried for 15 minutes while maintaining the supply air temperature. The resulting granulated product is passed through a No. 40 round sieve (425 μm) and a No. 60 round sieve (250 μm), so that the surface of the core particles is coated with the drug substance layer (1). Particles (1) were obtained.

[Spray liquid for drug substance layer (1)]
-Telmisartan 140 parts by mass-Meglumine 140 parts by mass-Hydroxypropyl cellulose 14 parts by mass-Sodium stearyl fumarate 140 parts by mass-Purified water 566 parts by mass

  12 g of the obtained drug substance-containing particles (1) were spouted fluidized bed granulator (product name: micro fluidized bed granulator, manufactured by Dalton Co.) (hereinafter referred to as “fluidized bed granulator (2)”) ). The feed temperature of the fluidized bed granulator (2) is adjusted to 30 ° C., the exhaust temperature is adjusted to about 20 ° C., and 14.16 g of the spray liquid for coating layer (1) having the following composition prepared in advance and 3.90 g of mannitol liquid Were sequentially sprayed into the fluidized bed granulator (2), and then dried for 30 minutes at a supply air temperature of 60 ° C. By sieving the resulting granulated product with a No. 40 round sieve (425 μm) and a No. 60 round sieve (250 μm), the surface of the drug substance-containing particles (1) containing telmisartan becomes the aminoalkyl methacrylate copolymer E. A fine granule (pharmaceutical composition) coated with a coating layer (1) containing

[Spray liquid for coating layer (1)]
Aminoalkyl methacrylate copolymer E 100 parts by mass (trade name: Eudragit (registered trademark) EPO, gastric polymer, manufactured by Evonik)
-Sodium lauryl sulfate 10 mass parts-Glycerol monostearate 5 mass parts-Polysorbate 80 2 mass parts-Stearic acid 15 mass parts-Purified water 778 mass parts

[Mannitol solution]
・ 140 parts by mass of mannitol ・ 860 parts by mass of purified water

<Comparative Example 1>
Drug substance-containing particles (1) were obtained by the same production method as in Example 1.
12 g of the obtained drug substance-containing particles (1) were charged into a fluidized bed granulator (2). The feed temperature of the fluidized bed granulator (2) is adjusted to 80 ° C., the exhaust temperature is adjusted to about 40 ° C., and 20.12 g of the spray liquid for the coating layer (2) having the following composition prepared in advance and 3.90 g of mannitol liquid are prepared. Were sequentially sprayed into the fluidized bed granulator (2), and then dried for 30 minutes at a supply air temperature of 60 ° C. The resulting granulated product is passed through a No. 40 round sieve (425 μm) and a No. 60 round sieve (250 μm), so that the surface of the drug substance-containing particles (1) containing telmisartan becomes hydroxypropyl methylcellulose acetate. Fine granules (pharmaceutical composition) coated with the coating layer (2) containing succinate were obtained.

[Spray liquid for coating layer (2)]
・ Hydroxypropyl methylcellulose ・ Acetate succinate (Product name: AQOAT AS-LF, enteric polymer, manufactured by Shin-Etsu Chemical Co., Ltd.)
70 parts by mass-triethyl citrate 14 parts by mass-talc 21 parts by mass-sodium lauryl sulfate 2.1 parts by mass-purified water 887.3 parts by mass

<Comparative Example 2>
Drug substance-containing particles (1) were obtained by the same production method as in Example 1.
12 g of the obtained drug substance-containing particles (1) were charged into a fluidized bed granulator (2). The feed temperature of the fluidized bed granulator (2) is adjusted to 80 ° C., the exhaust temperature is adjusted to about 40 ° C., and 7.98 g of the spray liquid for the coating layer (3) having the following composition prepared in advance and 3.90 g of mannitol liquid are prepared. Were sequentially sprayed into the fluidized bed granulator (2), and then dried for 30 minutes at a supply air temperature of 60 ° C. The resulting granulated product is passed through a No. 40 round sieve (425 μm) and a No. 60 round sieve (250 μm), so that the surface of the drug substance-containing particles (1) containing telmisartan is coated with ethyl cellulose. Fine granules (pharmaceutical composition) coated with (3) were obtained.

[Spray liquid for coating layer (3)]
-600 parts by mass of ethyl cellulose (trade name: Aquacoat (registered trademark) ECD30, insoluble polymer, manufactured by FMC)
・ 23 parts by mass of triethyl citrate ・ 392 parts by mass of purified water

<Comparative Example 3>
Drug substance-containing particles (1) were obtained by the same production method as in Example 1.
40 g of the obtained drug substance-containing particles (1) was transferred to a jet fluidized bed granulator (product name: FD-mini, manufactured by Paulek Co., Ltd.) (hereinafter referred to as “fluidized bed granulator (3)”). Prepared. Adjusting the supply temperature of the fluidized bed granulator (3) to 30 to 40 ° C. and the exhaust temperature to about 25 ° C. It sprayed in the granulator (3). 30 g of the obtained granulated material was again charged into the fluidized bed granulator (3), and 13.57 g of the coating layer (4) spray liquid and 3.90 g of mannitol liquid were sequentially added to the fluidized bed granulator (3). After spraying, the air supply temperature was 60 ° C. and drying was performed for 60 minutes. The resulting granulated product is passed through a No. 40 round sieve (425 μm) and a No. 60 round sieve (250 μm), so that the surface of the drug substance-containing particles (1) containing telmisartan becomes ethyl acrylate / methacrylic Fine granules (pharmaceutical composition) coated with a coating layer (4) containing an acid methyl copolymer were obtained.

[Spray liquid for coating layer (4)]
・ 125 parts by mass of ethyl acrylate / methyl methacrylate copolymer (trade name: Eudragit (registered trademark) NE30D, sustained-release polymer, manufactured by Evonik)
-Glyceryl monostearate 6.3 mass parts-polysorbate 80 3.1 mass parts-purified water 870.6 mass parts

<Comparative Example 4>
Drug substance-containing particles (1) were obtained by the same production method as in Example 1.
12 g of the obtained drug substance-containing particles (1) were charged into a fluidized bed granulator (2). The feed temperature of the fluidized bed granulator (2) is adjusted to 30 ° C., the exhaust temperature is adjusted to about 25 ° C., and 18.88 g of the spray solution for the coating layer (5) having the following composition prepared in advance and 3.83 g of mannitol solution are prepared. Were sequentially sprayed into the fluidized bed granulator (2), and then dried for 30 minutes at a supply air temperature of 60 ° C. By sieving the resulting granulated product with a No. 40 round sieve (425 μm) and a No. 60 round sieve (250 μm), the surface of the drug substance-containing particles (1) containing telmisartan becomes an aminoalkyl methacrylate copolymer RS. Fine particles (pharmaceutical composition) coated with a coating layer (5) containing (trade name: Eudragit (registered trademark) RL30D) were obtained.

[Spray liquid for coating layer (5)]
Aminoalkyl methacrylate copolymer RS 75 parts by mass (trade name: Eudragit (registered trademark) RL30D, sustained-release polymer, manufactured by Evonik)
-Polysorbate 80 16.7 parts by mass-Light anhydrous silicic acid 16.7 parts by mass-Purified water 891.6 parts by mass

<Comparative Example 5>
Drug substance-containing particles (1) were obtained by the same production method as in Example 1.
12 g of the obtained drug substance-containing particles (1) were charged into a fluidized bed granulator (2). Adjusting the supply temperature of the fluidized bed granulator (2) to 30 ° C. and the exhaust temperature to about 25 ° C., 18.88 g of the spray liquid for the coating layer (6) having the following composition prepared in advance and 3.83 g of mannitol liquid Were sequentially sprayed into the fluidized bed granulator (2), and then dried for 30 minutes at a supply air temperature of 60 ° C. By sieving the resulting granulated product with a No. 40 round sieve (425 μm) and a No. 60 round sieve (250 μm), the surface of the drug substance-containing particles (1) containing telmisartan becomes an aminoalkyl methacrylate copolymer RS. Fine particles (pharmaceutical composition) coated with a coating layer (6) containing (trade name: Eudragit (registered trademark) RS30D) were obtained.

[Spray liquid for coating layer (6)]
Aminoalkyl methacrylate copolymer RS 75 parts by mass (trade name: Eudragit (registered trademark) RS30D, sustained-release polymer, manufactured by Evonik)
-Polysorbate 80 16.7 parts by mass-Light anhydrous silicic acid 16.7 parts by mass-Purified water 891.6 parts by mass

[Evaluation of bitterness masking]
The fine granules obtained in Example 1 and Comparative Examples 1 to 5 were weighed so as to contain 40 mg of telmisartan, respectively, and placed in the oral cavity of the subject. The time during which bitterness was masked (hereinafter referred to as “bitterness masking time”) was measured and evaluated according to the following evaluation criteria. The results are shown in Table 1. In Table 1, the unit of the numerical value indicating the content of each component is part by mass.

-Evaluation criteria-
A: The bitterness masking time is 60 seconds or more.
B: The bitterness masking time is 30 seconds or more and less than 60 seconds.
C: The bitterness masking time is less than 30 seconds.

Comparison of Drug Substance-Containing Particles Containing Telmisartan Coated with the Pharmaceutical Composition of Comparative Example 1 Coated with a Coating Layer Containing Enteric Polymer Hydroxypropyl Methylcellulose Acetate Succinate and Coated Layer Containing Ethylcellulose as an Insoluble Polymer In the pharmaceutical composition of Example 2, the bitterness could not be masked for 30 seconds, which is preferable as the masking time for the orally disintegrating tablet.
In addition, the pharmaceutical composition of Comparative Example 3, aminoalkyl methacrylate copolymer RS (trade name: trade name: coated drug substance-containing particles containing telmisartan with a coating layer containing ethyl acrylate / methyl methacrylate copolymer which is a sustained release polymer. Comparative Example 5 coated with a pharmaceutical composition of Comparative Example 4 coated with a coating layer comprising Eudragit® RL30D) and a coating layer comprising aminoalkyl methacrylate copolymer RS (trade name: Eudragit® RS30D) Although the pharmaceutical composition of No. 1 maintained the bitter taste masking effect for 30 seconds or more, it did not satisfy the more preferable 60 seconds as the masking time of the orally disintegrating tablet.
In contrast to these pharmaceutical compositions, the pharmaceutical composition of Example 1 in which drug substance-containing particles containing telmisartan were coated with a coating layer containing aminoalkyl methacrylate copolymer E, which is a gastric soluble polymer, had a bitter taste masking effect. Lasted for more than 60 seconds.
From these results, it was found that the aminoalkyl methacrylate copolymer E is remarkably excellent as a polymer that masks the bitter taste of telmisartan.

[Preparation of pharmaceutical composition]
<Comparative Example 6>
As a core particle, 500 g of D-mannitol (trade name: Nonparel (registered trademark) -108, spherical granules of 150 μm to 250 μm, manufactured by Freund Sangyo Co., Ltd.) was charged into a fluidized bed granulator (1). Adjusting the supply temperature of the fluidized bed granulator (1) to 60 ° C. to 70 ° C. and the exhaust temperature to about 35 ° C. to 45 ° C. It sprayed in the granulator (1). In addition, spraying of the spray liquid for the drug substance layer (2) is performed by operating a dryer (trade name: Honey Dry, manufactured by Daikin Co., Ltd.) after the start of spraying in order to prevent particle aggregation. In an intermittent operation (stop interval: once every hour, stop time: 5 minutes) while supplying the air (25 ° C., about 1% RH to 5% RH) to the fluidized bed granulator (1) went. Moreover, spraying of the spray solution for the drug substance layer (2) was carried out until 3.5 times the solid content was coated on the spherical granules of D-mannitol. After spraying a prescribed amount of the spray liquid for the drug substance layer (2), it was dried for 15 minutes while maintaining the supply air temperature. The resulting granulated product is sieved with No. 40 round sieve (425 μm) and No. 60 round sieve (250 μm), so that the surface of the core particle is coated with the drug substance layer (2). Particles (2) were obtained.

[Spray solution for drug substance layer (2)]
-Telmisartan 70 parts by mass-Meglumine 70 parts by mass-Hydroxypropyl cellulose 14 parts by mass-Light anhydrous silicic acid 17.5 parts by mass-Purified water 828.5 parts by mass

200 parts by mass of the fine drug substance-containing particles (2) containing telmisartan obtained and excipients suitable for orally disintegrating tablets (165 parts by mass of mannitol / corn starch granulated product, 20 parts by mass of ethyl cellulose, crospovidone 12 parts by mass and 3 parts by mass of sodium stearyl fumarate) were mixed to obtain a tableting powder (mixed powder).
Using the tableting machine (HT-AP18SS-U, manufactured by Hata Kogyo Co., Ltd.), the tableting powder obtained (mixed powder) was 9 mmφ sumi angle so that 40 mg of telmisartan was contained per tablet. Tableting was carried out with a tableting pressure of 11 kN using an R-side scissors to obtain an orally disintegrating tablet.

<Example 2>
Drug substance-containing particles (2) were obtained by the same production method as in Comparative Example 6.
450 g of the obtained drug substance-containing particles (2) were charged into a fluidized bed granulator (1). Adjusting the supply temperature of the fluidized bed granulator (1) to 30 ° C. to 45 ° C. and the exhaust temperature to about 25 ° C. to 35 ° C., 491.8 g of the coating layer (1) spray liquid prepared in advance, and the mannitol liquid After spraying 318.8 g in the fluidized bed granulator (1) in order, drying was performed for 30 minutes at an air supply temperature of 80 ° C. By sieving the finished granulated product with a No. 40 round sieve (425 μm) and a No. 60 round sieve (250 μm), the surface of the drug substance-containing particles (2) containing telmisartan becomes the aminoalkyl methacrylate copolymer E. A fine granule (pharmaceutical composition) coated with a coating layer (1) containing

200 parts by mass of fine granules in which the surface of drug substance-containing particles (2) containing telmisartan is coated with a coating layer (1) containing aminoalkyl methacrylate copolymer E, and an excipient suitable for orally disintegrating tablets (mannitol Corn starch granule 165 parts by mass, ethyl cellulose 20 parts by mass, crospovidone 12 parts by mass, and sodium stearyl fumarate 3 parts by mass) were mixed to obtain a tableting powder (mixed powder).
Using the tableting machine (HT-AP18SS-U, manufactured by Hata Kogyo Co., Ltd.), the tableting powder obtained (mixed powder) was 9 mmφ sumi angle so that 40 mg of telmisartan was contained per tablet. Tableting was carried out with a tableting pressure of 11 kN using an R-side scissors to obtain an orally disintegrating tablet.

<Example 3>
Drug substance-containing particles (2) were obtained by the same production method as in Comparative Example 6.
500 g of the obtained drug substance-containing particles (2) were charged into a fluidized bed granulator (1). Adjusting the supply temperature of the fluidized bed granulator (1) to 30 ° C. to 45 ° C. and the exhaust temperature to about 25 ° C. to 35 ° C. Then, 356.1 g of mannitol liquid was sprayed in order into the fluidized bed granulator (1), and then the air supply temperature was set to 80 ° C. and drying was performed for 30 minutes. By sieving the finished granulated product with a No. 40 round sieve (425 μm) and a No. 60 round sieve (250 μm), the surface of the drug substance-containing particles (2) containing telmisartan becomes the aminoalkyl methacrylate copolymer E. A fine granule (pharmaceutical composition) coated with a coating layer (7) containing

[Spray liquid for coating layer (7)]
Aminoalkyl methacrylate copolymer E 100 parts by mass (trade name: Eudragit (registered trademark) EPO, gastric polymer, manufactured by Evonik)
-Sodium lauryl sulfate 10 mass parts-Glycerol monostearate 5 mass parts-Polysorbate 80 10 mass parts-Stearic acid 15 mass parts-Purified water 770 mass parts

200 parts by mass of fine granules in which the surface of drug substance-containing particles (2) containing telmisartan is coated with a coating layer (7) containing aminoalkyl methacrylate copolymer E, and excipients suitable for orally disintegrating tablets (mannitol Corn starch granule 165 parts by mass, ethyl cellulose 20 parts by mass, crospovidone 12 parts by mass, and sodium stearyl fumarate 3 parts by mass) were mixed to obtain a tableting powder (mixed powder).
Using the tableting machine (HT-AP18SS-U, manufactured by Hata Kogyo Co., Ltd.), the tableting powder obtained (mixed powder) was 9 mmφ sumi angle so that 40 mg of telmisartan was contained per tablet. Tableting was carried out with a tableting pressure of 11 kN using an R-side scissors to obtain an orally disintegrating tablet.

<Example 4>
Drug substance-containing particles (2) were obtained by the same production method as in Comparative Example 6.
12 g of the obtained drug substance-containing particles (2) were charged into a fluidized bed granulator (2). The feed temperature of the fluidized bed granulator (2) is adjusted to 30 ° C. to 45 ° C. and the exhaust temperature is adjusted to about 25 ° C. to 35 ° C. Then, 8.09 g of mannitol liquid was sprayed in order into the fluidized bed granulator (2), and then the air supply temperature was set to 80 ° C. and drying was performed for 30 minutes. By sieving the finished granulated product with a No. 40 round sieve (425 μm) and a No. 60 round sieve (250 μm), the surface of the drug substance-containing particles (2) containing telmisartan becomes the aminoalkyl methacrylate copolymer E. Fine particles (medicinal composition) coated with a coating layer (8) containing

[Spray liquid for coating layer (8)]
Aminoalkyl methacrylate copolymer E 100 parts by mass (trade name: Eudragit (registered trademark) EPO, gastric polymer, manufactured by Evonik)
-Sodium lauryl sulfate 10 mass parts-Glycerol monostearate 5 mass parts-Polysorbate 80 20 mass parts-Stearic acid 15 mass parts-Purified water 760 mass parts

200 parts by mass of fine granules in which the surface of drug substance-containing particles (2) containing telmisartan is coated with a coating layer (8) containing aminoalkyl methacrylate copolymer E, and excipients suitable for orally disintegrating tablets (mannitol Corn starch granule 165 parts by mass, ethyl cellulose 20 parts by mass, crospovidone 12 parts by mass, and sodium stearyl fumarate 3 parts by mass) were mixed to obtain a tableting powder (mixed powder).
Using the tableting machine (HT-AP18SS-U, manufactured by Hata Kogyo Co., Ltd.), the tableting powder obtained (mixed powder) was 9 mmφ sumi angle so that 40 mg of telmisartan was contained per tablet. Tableting was carried out with a tableting pressure of 11 kN using an R-side scissors to obtain an orally disintegrating tablet.

<Example 5>
As core particles, 12 g of D-mannitol (trade name: Nonparel (registered trademark) -108, spherical granules of 150 μm to 250 μm, manufactured by Freund Sangyo Co., Ltd.) was charged into a fluidized bed granulator (2). Adjust the feed temperature of the fluidized bed granulator (2) to 60 ° C to 70 ° C, the exhaust temperature to about 35 ° C to 45 ° C, and apply the pre-prepared spray liquid for the drug substance layer (3) as follows It sprayed in the granulator (2). In addition, spraying of the spray liquid for the drug substance layer (3) is performed by operating a dryer (trade name: Honey Dry, manufactured by Daikin Co., Ltd.) after starting spraying in order to prevent aggregation of particles. In an intermittent operation (stop interval: once every hour, stop time: 5 minutes) while supplying the air (25 ° C., about 1% RH to 5% RH) to the fluidized bed granulator (2) went. Moreover, spraying of the spray solution for the drug substance layer (3) was carried out until 3.5 times the solid content was coated on the spherical granules of D-mannitol. After spraying a prescribed amount of spray liquid for the drug substance layer (3), it was dried for 15 minutes while maintaining the supply air temperature. The resulting granulated product is passed through a No. 40 round sieve (425 μm) and a No. 60 round sieve (250 μm), so that the surface of the core particles is coated with the drug substance layer (3). Particles (3) were obtained.

[Spray solution for drug substance layer (3)]
-Telmisartan 70 parts by mass-Meglumine 70 parts by mass-Hydroxypropyl cellulose 14 parts by mass-Stearic acid 17.5 parts by mass-Purified water 828.5 parts by mass

  12 g of the obtained drug substance-containing particles (3) were charged into a fluidized bed granulator (2). Adjusting the supply temperature of the fluidized bed granulator (2) to 30 ° C. to 45 ° C. and the exhaust temperature to about 25 ° C. to 35 ° C., 13.74 g of the spray liquid for the coating layer (1) prepared in advance, and the mannitol liquid After spraying 8.93 g in the fluidized bed granulator (2) in order, drying was performed for 30 minutes at an air supply temperature of 80 ° C. By sieving the resulting granulated product with a No. 40 round sieve (425 μm) and a No. 60 round sieve (250 μm), the surface of the drug substance-containing particles (3) containing telmisartan becomes the aminoalkyl methacrylate copolymer E. A fine granule (pharmaceutical composition) coated with a coating layer (1) containing

200 parts by mass of fine granules in which the surface of drug substance-containing particles (3) containing telmisartan is coated with a coating layer (1) containing aminoalkyl methacrylate copolymer E, and an excipient suitable for orally disintegrating tablets (mannitol Corn starch granule 165 parts by mass, ethyl cellulose 20 parts by mass, crospovidone 12 parts by mass, and sodium stearyl fumarate 3 parts by mass) were mixed to obtain a tableting powder (mixed powder).
Using the tableting machine (HT-AP18SS-U, manufactured by Hata Kogyo Co., Ltd.), the tableting powder obtained (mixed powder) was 9 mmφ sumi angle so that 40 mg of telmisartan was contained per tablet. Tableting was carried out with a tableting pressure of 11 kN using an R-side scissors to obtain an orally disintegrating tablet.

<Example 6>
In the same manner as in Example 1, a spray liquid for drug substance layer (4) having the following composition prepared in advance was sprayed on spherical granules of D-mannitol. In addition, spraying of the spray solution for the drug substance layer (4) is performed by operating a dryer (trade name: Honey Dry, manufactured by Daikin Co., Ltd.) after starting spraying in order to prevent aggregation of particles. In an intermittent operation (stop interval: once every hour, stop time: 5 minutes) while supplying the air (25 ° C., about 1% RH to 5% RH) to the fluidized bed granulator (2) went. In addition, spraying of the spray liquid for the drug substance layer (4) was sprayed until a solid content of 3.8 times the solid content was coated on the spherical granules of D-mannitol. After spraying a prescribed amount of spray liquid for the drug substance layer (4), it was dried for 40 minutes while maintaining the supply air temperature. The resulting granulated product is sieved with No. 30 round sieve (500 μm) and No. 60 round sieve (250 μm), so that the surface of the core particles is coated with the drug substance layer (4). Particles (4) were obtained.

[Spray solution for drug substance layer (4)]
-Telmisartan 64.7 parts by mass-Meglumine 64.7 parts by mass-Hydroxypropyl methylcellulose 25.9 parts by mass-Light anhydrous silicic acid 16.2 parts by mass-Purified water 828.5 parts by mass

  12 g of the obtained drug substance-containing particles (4) were charged into a fluidized bed granulator (2). The feed temperature of the fluidized bed granulator (2) is adjusted to 30 ° C., the exhaust temperature is adjusted to about 30 ° C., and 14.08 g of the coating layer (9) spray liquid having the following composition prepared in advance and 8.35 g of mannitol liquid are prepared. Were sequentially sprayed into the fluidized bed granulator (2), and then dried for 30 minutes at a supply air temperature of 60 ° C. The resulting granulated product is passed through a No. 30 round sieve (500 μm) and a No. 60 round sieve (250 μm), so that the surface of the drug substance-containing particles (4) containing telmisartan becomes an aminoalkyl methacrylate copolymer E. Fine particles (medicine composition) coated with a coating layer (9) containing

[Spray liquid for coating layer (9)]
Aminoalkyl methacrylate copolymer E 94.9 parts by mass (trade name: Eudragit (registered trademark) EPO, gastric polymer, manufactured by Evonik)
-Sodium lauryl sulfate 9.5 mass parts-Glycerol monostearate 4.7 mass parts-Polysorbate 80 29.8 mass parts-Stearic acid 14.2 mass parts-Light anhydrous silicic acid 30.5 mass parts-Purified water 816. 4 parts by mass

[Mannitol solution]
・ 140 parts by mass of mannitol ・ 860 parts by mass of purified water

200 parts by mass of fine granules in which the surface of drug substance-containing particles (4) containing telmisartan is coated with a coating layer (9) containing aminoalkyl methacrylate copolymer E, and an excipient (mannitol Corn starch granule 165 parts by mass, ethyl cellulose 20 parts by mass, crospovidone 12 parts by mass, and sodium stearyl fumarate 3 parts by mass) were mixed to obtain a tableting powder (mixed powder).
Using the tableting machine (HT-AP18SS-U, manufactured by Hata Kogyo Co., Ltd.), the tableting powder obtained (mixed powder) was 9 mmφ sumi angle so that 40 mg of telmisartan was contained per tablet. Using an R-side punch, tableting was performed at a tableting pressure of 12 kN to obtain an orally disintegrating tablet.

<Example 7>
200 parts by mass of fine particles obtained by the same production method as in Example 6 and having the surface of drug substance-containing particles (4) containing telmisartan coated with a coating layer (9) containing aminoalkyl methacrylate copolymer E; Excipients suitable for orally disintegrating tablets (153 parts by weight of mannitol / corn starch granule, 20 parts by weight of ethyl cellulose, 12 parts by weight of crospovidone, 12 parts by weight of light anhydrous silicic acid, and 3 parts by weight of sodium stearyl fumarate) Were mixed to obtain a tableting powder (mixed powder).
Using the tableting machine (HT-AP18SS-U, manufactured by Hata Kogyo Co., Ltd.), the tableting powder obtained (mixed powder) was 9 mmφ sumi angle so that 40 mg of telmisartan was contained per tablet. Using an R-side punch, tableting was performed at a tableting pressure of 12 kN to obtain an orally disintegrating tablet.

[Evaluation of dissolution]
The fine granules obtained in Comparative Example 6 and Examples 2 to 7 were weighed so as to contain 40 mg of telmisartan, respectively, and in accordance with the dissolution test method method 2 (paddle method) shown in the Japanese Pharmacopoeia, pH 3. The dissolution rate in the 5 dissolution test solution was measured. The evaluation criteria are as shown below. The measurement results of the dissolution rate are shown in FIG. 1, and the evaluation results are shown in Table 2. In Table 2, the unit of numerical values indicating the content of each component is part by mass.

-Evaluation criteria-
AA: Very suitable range (30 minutes elution rate is 80% or more)
A: More appropriate range (30 minutes elution rate is 70% or more and less than 80%)
B: Appropriate range (30 minutes elution rate is 60% or more and less than 70%)
C: Tolerable range (30 minutes elution rate is 50% or more and less than 60%)
D: Insufficient (30 minutes elution rate is less than 50%)

[Evaluation of bitterness masking]
The fine granules obtained in Comparative Example 6 and Examples 2 to 7 were weighed so that 40 mg of telmisartan was contained, and placed in the oral cavity of the subject. The time during which bitterness was masked (hereinafter referred to as “bitterness masking time”) was measured and evaluated according to the following evaluation criteria. The results are shown in Table 2.

-Evaluation criteria-
A: The bitterness masking time is 60 seconds or more B: The bitterness masking time is 30 seconds or more and less than 60 seconds C: The bitterness masking time is less than 30 seconds

In the pharmaceutical compositions of Examples 2 to 7, although there was a difference in elution time, telmisartan was well eluted at pH 3.5.
In the pharmaceutical composition of Example 2, the telmisartan was compared with the pharmaceutical composition of Comparative Example 6 even though the pH at which the dissolution test was performed was pH 3.5 at which the aminoalkyl methacrylate copolymer E was dissolved. Delayed elution was observed.
On the other hand, in the pharmaceutical compositions of Examples 3, 4 and 6 in which the amount of polysorbate 80 was increased as compared with the pharmaceutical composition of Example 2, the dissolution property of telmisartan was improved, and the pharmaceutical composition of Example 4 was improved. Then, the dissolution property equivalent to that of the pharmaceutical composition of Comparative Example 6 was exhibited.
From these results, it was found that the delay in dissolution of telmisartan due to the use of aminoalkyl methacrylate copolymer E as the polymer for coating telmisartan can be eliminated by increasing the amount of polysorbate 80.

In addition, the pharmaceutical composition of Example 7 was superior to the pharmaceutical composition of Example 6 in terms of telmisartan elution at pH 3.5.
From this result, it was found that the dissolution property of telmisartan was improved by adding light anhydrous silicic acid as a component of the excipient during tablet molding.

  In the pharmaceutical composition of Example 5, a delay in elution of telmisartan was observed when compared with the pharmaceutical composition of Example 2, even though the composition of the coating layer was almost the same. For this reason, it is thought that light anhydrous silicic acid is preferable as a lubricant used for the production of telmisartan-containing fine granules.

The pharmaceutical composition of Comparative Example 6 in which the drug substance-containing particles containing telmisartan were not coated with the coating layer exhibited a strong bitter taste.
On the other hand, in the pharmaceutical compositions of Examples 2 to 7 in which the drug substance-containing particles containing telmisartan were coated with a coating layer containing aminoalkyl methacrylate copolymer E, which is a gastric polymer, all maintained the bitter taste masking effect for 60 seconds or more. did.
From the above results, it was found that by increasing the amount of polysorbate 80, which is a nonionic surfactant, the delay in dissolution of telmisartan was improved and a high masking effect on the bitter taste of telmisartan was also obtained.

Claims (12)

It has drug substance-containing particles, and a coating layer that coats the drug substance-containing particles,
Telmisartan, aminoalkyl methacrylate copolymer E, and nonionic surfactant,
A pharmaceutical composition comprising telmisartan in a drug substance-containing particle and an aminoalkyl methacrylate copolymer E in a coating layer.   The pharmaceutical composition according to claim 1, wherein the nonionic surfactant is at least one selected from the group consisting of polysorbate, poloxamer, and polyethylene glycol.   The pharmaceutical composition according to claim 1 or 2, wherein the nonionic surfactant is polysorbate.   The content of the nonionic surfactant is 1 part by mass to 40 parts by mass with respect to 100 parts by mass of the aminoalkyl methacrylate copolymer E. The pharmaceutical composition according to any one of claims 1 to 3. .   The pharmaceutical composition according to any one of claims 1 to 4, wherein the content of the aminoalkyl methacrylate copolymer E is 2% by mass or more based on the total mass of the pharmaceutical composition.   The pharmaceutical agent according to any one of claims 1 to 5, further comprising light anhydrous silicic acid in at least one selected from the group consisting of the drug substance-containing particles and the coating layer that coats the drug substance-containing particles. Composition.   The pharmaceutical composition according to any one of claims 1 to 6, further comprising at least one selected from the group consisting of hydroxypropylcellulose and hydroxypropylmethylcellulose in the drug substance-containing particles.   The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition is a granule having an average particle size of 50 µm to 1000 µm.   The pharmaceutical composition according to any one of claims 1 to 8, wherein the content of telmisartan is 10% by mass to 50% by mass with respect to the total mass of the pharmaceutical composition.   A method for producing the pharmaceutical composition according to any one of claims 1 to 9, wherein the drug substance-containing spray liquid containing at least telmisartan by using a granulator for the drug substance-containing particles. Is sprayed on the core particles that are the core of the drug substance-containing particles, and the manufacture of the drug substance-containing particles reduces the relative humidity at the air supply temperature of the gas supplied to the granulator to 20% or less. A method for producing a pharmaceutical composition comprising at least one selected from controlling and intermittent spraying of a spray liquid for drug substance layer on core particles.   An orally disintegrating tablet comprising the pharmaceutical composition according to any one of claims 1 to 9.   A method for producing an orally disintegrating tablet according to claim 11, wherein the pharmaceutical composition according to any one of claims 1 to 9 and an excipient containing light silicic anhydride are mixed. To obtain a mixed powder, and tableting the obtained mixed powder to obtain a tableted product.