JP2018070541A - Solifenacin-containing pharmaceutical composition and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a solifenacin-containing pharmaceutical composition that can facilitate the physical masking of a discomfort taste, or in which a discomfort taste is physically masked, and a method of producing the same.SOLUTION: The pharmaceutical composition contains solifenacin and/or salt thereof, and talc. The solifenacin and/or salt thereof is an amorphous body, and the content of talc is at least 150 mass% of the content of solifenacin and/or salt thereof.SELECTED DRAWING: None

Description

  The present invention relates to a pharmaceutical composition containing solifenacin and / or a salt thereof and a method for producing the same.

  Solifenacin or a salt thereof (hereinafter, solifenacin and / or a salt thereof may be referred to as “solifenacin”) is one of drugs having extremely strong bitterness and astringency. In order to make solifenacin or a salt thereof into an orally disintegrating tablet, it is necessary to mask (mask) the bitter taste.

  In general, in order to mask the bitter taste of drugs, artificial sweeteners are used to make other tastes feel harder (sensory masking), water-insoluble films on bitter drugs, etc. By controlling the release of drugs in the mouth (physical masking), changing the property of having a bitter taste by chemical interaction, ion exchange bonding, inclusion of compounds, etc. (chemical Masking) and combinations thereof.

  Since solifenacin or a salt thereof has not only a bitter taste but also strong astringency (numbness), it is indispensable to perform physical masking among the above methods. In order to perform physical masking, specifically, solifenacin or a salt thereof may be coated on core particles such as crystalline cellulose particles, and a water-insoluble film may be coated thereon.

  For example, in Japanese Patent No. 4277904 (Patent Document 1), in an oral particulate pharmaceutical composition containing a drug having a bitter taste such as solifenacin, in order to suppress drug release in the oral cavity for a certain period of time, The core particle containing the drug at the center of the pharmaceutical composition, the layer containing two types of water-soluble components, the insolubilization accelerator and the insolubilizing substance, in the middle layer, and the water penetration rate into the inside of the outermost layer are controlled. A time-release particulate pharmaceutical composition for oral administration containing a water infiltration amount control layer is described. As the drug, for example, solifenacin succinate is used, and crystalline cellulose is sprayed using a fluidized bed granulator to obtain core particles containing the drug. It is described that these core particles are coated with a liquid containing hydroxypropylmethylcellulose, a small amount of talc, and the like in a predetermined order.

  In addition, in Patent No. 5168711 (Patent Document 2), in order to stabilize solifenacin, the ratio of the solifenacin crystal body and the amorphous body to the amorphous body is less than a certain amount. A solid formulation of certain solifenacin or a salt thereof has been described.

Japanese Patent No. 4277904 Japanese Patent No. 5168711

  However, it is very difficult to coat solifenacin and / or a salt thereof in an amorphous state on core particles such as crystalline cellulose particles as they are. Solifenacin or a salt thereof in an amorphous state has a very high viscosity. Therefore, when the core particles are to be coated, the core particles are granulated, and it becomes difficult to coat the core particles with amorphous solifenacin or a salt thereof. If solifenacin or a salt thereof in an amorphous state cannot be coated on the core particles and granulation occurs between the core particles, it becomes difficult to physically mask the core particles, and it may become rough in the oral cavity. I feel it.

  Accordingly, an object of the present invention is to provide a solifenacin-containing pharmaceutical composition capable of facilitating physical masking of an unpleasant taste or having an unpleasant taste physical masking and a method for producing the same. It is.

  The pharmaceutical composition according to the present invention includes solifenacin and / or a salt thereof and talc, and the solifenacin and / or the salt thereof is an amorphous form, and the content of talc is that of solifenacin and / or the salt thereof. It is 150 mass% or more of content.

  In the pharmaceutical composition according to the present invention, the content of talc is preferably 200% by mass or more of the content of solifenacin and / or a salt thereof.

  The pharmaceutical composition according to the present invention comprises a core particle and a core particle coating layer that coats the outside of the core particle, and solifenacin and / or a salt thereof and talc are preferably contained in the core particle coating layer.

  The pharmaceutical composition according to the present invention preferably further comprises an outer layer covering the outer side of the core particle coating layer.

  In any of the above-described methods for producing a pharmaceutical composition according to the present invention, the core particles are sprayed with a suspension containing amorphous solifenacin and / or a salt thereof and talc. Including a step of coating the outside, and the content of talc is 150% by mass or more of the content of solifenacin and / or a salt thereof.

  Embodiments of the present invention will be described below.

  The pharmaceutical composition according to the present invention includes solifenacin and / or a salt thereof and talc, and the solifenacin and / or the salt thereof is an amorphous form, and the content of talc is that of solifenacin and / or the salt thereof. It is 150 mass% or more of content.

  The “pharmaceutical composition” in the present invention means a composition containing solifenacin and / or a salt thereof that can be used in various oral dosage forms.

  In the pharmaceutical composition of the present invention, the salt of solifenacin is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, etc. Salt with inorganic acid, succinate, citrate, oxalate, acetate, malate, tartrate, maleate, fumarate, salt with organic acid such as benzenesulfonate, calcium Salts, salts with alkaline earth metals such as magnesium salts, salts with alkali metals such as lithium salts, potassium salts, sodium salts, salts with organic bases such as ethylenediamine salts, diethanolamine salts, N-methylglucamine salts, etc. Is mentioned. These may be used alone or in combination of two or more. The pharmaceutically acceptable salt is preferably a salt with an organic acid, and more preferably succinic acid is used among the salts with an organic acid. Further, solifenacin and / or a salt thereof may be an anhydride thereof. It may be a solvate such as a hydrate.

  Whether solifenacin and / or a salt thereof in the present invention is “amorphous” can be evaluated by X-ray diffraction. When a peak specific to solifenacin is confirmed, it can be evaluated that it has partially changed to a crystalline form, and in the case of a halo peak, it can be evaluated that the amorphous state has been maintained.

  The “unpleasant taste” in the present invention specifically means bitterness, astringency, gummy taste, sour taste, astringent taste, pungent taste, and the like.

  In the pharmaceutical composition according to the present invention, the content of talc is preferably 200% by mass or more of the content of solifenacin and / or a salt thereof.

  The pharmaceutical composition according to the present invention comprises a core particle and a core particle coating layer that coats the outside of the core particle, and solifenacin and / or a salt thereof and talc are preferably contained in the core particle coating layer.

  The “nuclear particle coating layer” in the present invention is a layer that coats the outside of the core particle, and is formed as a coating layer comprising solifenacin and / or a salt thereof and one or more additives. The additive is typically a binder that is blended to enhance the binding properties of the drug particles, and can contain a dissolution rate improving agent such as a saccharide or a disintegrant as needed. is there. Examples of the binder include, but are not limited to, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, copolyvidone, and ethylcellulose.

  The pharmaceutical composition according to the present invention preferably further comprises an outer layer covering the outer side of the core particle coating layer.

  The “outer layer” in the present invention is a layer covering the outside of the core particle coating layer. An outer layer is a coating layer which consists of 1 type, or 2 or more types of water-insoluble substances, for example, and may contain 1 type or 2 or more types of water-conductivity adjusting substances.

  The water-insoluble substance used for forming the outer layer is, for example, one of the components arranged in the outer layer in order to control the infiltration rate of water, and is hardly soluble in water, extremely insoluble, or hardly soluble. It preferably has solubility. Specifically, ethyl cellulose, acetyl cellulose, cellulose acetate phthalate, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, dimethylaminoethyl methacrylate / methyl methacrylate copolymer, methyl acrylate / methacrylic acid copolymer, acrylic acid Ethyl / methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer RS, dry methacrylic acid copolymer LD, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer LD (aqueous dispersion), methacrylic acid copolymer S, polyvinyl acetal diethylamino Acetate, dry milky white rack, cell Higher fatty acids such as lacquer, zein, stearic acid, higher alcohols such as cetanol and stearyl alcohol, low melting point substances such as carnauba wax, beeswax and paraffin, low melting point materials of 30-120 ° C, higher fatty acids such as sucrose fatty acid esters Examples include, but are not limited to, fats obtained by adding hydrogen to oils such as alcohol esters and castor wax, lubricants such as synthetic wax, talc, and magnesium stearate. One or more water-insoluble substances can be used in appropriate combination. Moreover, it is also free to use a plasticizer such as castor oil, dibutyl phthalate, triethyl citrate and the like.

  Moreover, when forming an outer layer, a water-soluble substance, a hydrophilic substance, etc. can be mix | blended with a water-insoluble substance as a water-conductivity adjusting substance. The water permeability adjusting substance here is a component blended in the outer layer together with a water-insoluble substance in order to adjust the water infiltration rate and the amount of infiltration, and is a water-soluble component or a hydrophilic water such as a disintegrant. It is a component that makes it easy to pass through. Specific examples of the water conductivity adjusting substance in the outer layer of the present invention include pregelatinized starch, sodium caseinate, carboxyvinyl polymer, sodium carboxymethyl starch, sucrose fatty acid ester, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, Pullulan, polyvinylpyrrolidone, copolyvidone, polyoxyethylene-polyoxypropylene glycol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, macrogol, polyethylene oxide, amino acids such as glycine and alanine, sweeteners such as glycyrrhizic acid, dextrin and Sugars such as lactose, sugar alcohols such as mannitol and xylitol, crystal cellulose , Crospovidone, but citric acid triethyl, but are not limited to, addition, water conveying adjustment agent may also be used in combination of one or two or more appropriately.

  As the composition ratio of the water-insoluble substance and the water-conductivity adjusting substance in the outer layer of the present invention, a ratio suitable for achieving the purpose is selected according to the purpose such as the physical properties of the drug, the absorption site and the type of the preparation.

  Also for the coating amount of the outer layer in the present invention, an amount suitable for achieving the object of the present invention is selected. Specifically, it is preferably 5% by weight or more, particularly preferably 7% by weight or more, more preferably 50% by weight or less, particularly preferably 30% by weight or less, based on the particles in which the core particles are coated with the core particle coating layer. It is preferable that When the coating amount is lower than 5% by weight, the surface of the pharmaceutical composition may not be uniformly coated, and the outer layer is extremely thin, so that the water penetration rate into the pharmaceutical composition is sufficiently controlled. In some cases, it may not be possible to form a sufficiently long lag time, and there may be a phenomenon in which particles adhere to the oral cavity. Moreover, when there is too much coating amount, the rapid drug release after lag time may not be achieved.

  The blending amount of solifenacin and / or a salt thereof in the pharmaceutical composition is not particularly limited, but is preferably 0.5% by weight or more based on the whole pharmaceutical composition particle. However, the amount of solifenacin and / or a salt thereof shown here is an example that can be applied to the present invention, and should not be interpreted in a limited manner.

  As for the particle size of the pharmaceutical composition according to the present invention, the longest diameter is preferably 2 mm or less. When the shape of the pharmaceutical composition particles can approximate a sphere, the average particle diameter is preferably 2 mm or less. In addition, when the pharmaceutical composition particles have a shape other than a sphere, the average longest diameter is preferably 2 mm or less.

  The pharmaceutical composition masking the unpleasant taste according to the present invention is particularly useful as a fine particle for an orally disintegrating tablet that is retained in the oral cavity for a relatively long time. When the pharmaceutical composition particles according to the present invention are contained in an orally disintegrating tablet, the average particle size is preferably adjusted to 350 μm or less in order to reduce the roughness in the oral cavity. The more preferable average particle diameter of the pharmaceutical composition particles is 50 to 350 μm, and more preferably 70 to 300 μm.

  It goes without saying that the pharmaceutical composition of the present invention can be produced using various pharmaceutical additives used as commonly used additives. Examples of the pharmaceutical additive include a corrigent, sweetener, flavor, colorant, stabilizer (antioxidant), antioxidant, pH adjuster, solubilizer, solubilizer, fluidizer, and buffer. However, it is not limited to these.

  The pharmaceutical composition of the present invention can be prepared in the form of various pharmaceutical compositions for oral administration by mixing the required amount as it is. The preparations mentioned here include powders, granules, tablets, troches, dry syrups and the like. In some cases, powders and granules can be formulated by simply mixing and mixing the fine particles for formulation. In order to obtain an orally disintegrating tablet that has recently attracted attention, it is necessary to devise a formulation method by blending the fine particles for formulation.

  Next, the manufacturing method of the pharmaceutical composition particle | grains of this invention is demonstrated.

  In any of the above-described methods for producing a pharmaceutical composition according to the present invention, the core particles are sprayed with a suspension containing amorphous solifenacin and / or a salt thereof and talc. Including a step of coating the outside, and the content of talc is 150% by mass or more of the content of solifenacin and / or a salt thereof.

  The core particles are prepared by dissolving or dispersing a binder or the like in additive particles (for example, crystalline cellulose (particles), purified sucrose spherical particles, mannitol spherical particles, etc.) that are suitable nuclei using a fluidized bed coating apparatus. It may be made by spraying.

  As a method of coating the core particle coating layer on the core particle, a method of coating with a machine generally used for coating a particulate composition, such as a fluidized bed coating device, a rolling coating device, or a centrifugal rolling coating device is adopted. It is preferable to do. For example, a required amount of a liquid containing a coating component may be sprayed with a spray gun while fluidizing core particles containing a drug in a rolling fluidized bed coating apparatus. The liquid containing the coating component is prepared by dissolving or dispersing essential components or the like in a solvent such as water, ethanol, methanol, or the like, and these solvents can be used by appropriately mixing them. Needless to say, the coating method of these layers is not limited to the wet method.

  When using a pharmaceutical composition for manufacture of an orally disintegrating tablet, it is desirable that the average particle diameter of a pharmaceutical composition is about 100-200 micrometers normally. In order for the core particle coating layer and the outer layer to be coated with the substantially spherical core particles while maintaining the spherical shape to be about 100 to 200 μm, the average particle diameter of the substance used suspended in the solution used for coating Needs to have a particle size of 1/10 or less of the coated particles.

  As a method of coating the outer layer onto the particles coated with the core particle coating layer, the coating is performed by a machine generally used for coating a particulate composition, such as a fluidized bed coating apparatus, a rolling coating apparatus, or a centrifugal rolling coating apparatus. It is preferable to adopt the method to do. For example, a required amount of liquid containing a coating component may be sprayed with a spray gun while flowing the core particles in a rolling fluidized bed coating apparatus. The liquid containing the coating component is prepared by dissolving or dispersing essential components or the like in a solvent such as water, ethanol, methanol, or the like. These solvents can be used by appropriately mixing them. You may use only water. Needless to say, the coating method of these layers is not limited to the wet method.

  The orally disintegrating tablet containing the pharmaceutical composition particles of the present invention will be described below.

  The orally disintegrating tablet referred to in the present invention means a preparation similar to a tablet that disintegrates in the oral cavity within a certain time, preferably within 1 minute, more preferably within 45 seconds. For example, an orally disintegrating tablet containing pharmaceutical composition particles disclosed in Japanese Patent Application Laid-Open No. 2012-240917, Japanese Patent No. 4019374, Japanese Patent No. 3746167, and the like can be given. Similarly, the pharmaceutical composition particles of the present invention can be made into orally disintegrating tablets together with suitable excipients, disintegrants, binders, lubricants and the like.

  Specific examples of the production method are as follows: (1) A method in which the pharmaceutical composition particles are directly mixed with sugar or sugar alcohols or a selected disintegrant and compressed into a tablet by compression, (2) Pharmaceutical composition Tablets are prepared by mixing the product particles with sugar or sugar alcohols, selected disintegrants, etc. and granulating them with a binder solution, mixing with other suitable additives for tablets, and compressing them under pressure. (3) After mixing low-pressure compression molding of a mixture of the pharmaceutical composition particles with a low moldability saccharide, spraying the mixture with a high moldability saccharide as a binder and / or granulating the mixture, There are various production methods such as humidification and drying to make tablets. In the case of orally disintegrating tablets formulated with pharmaceutical composition particles, special consideration is required for particle destruction, tablet hardness, disintegration, content uniformity, etc. The method should not be limited to the method described here, and any method may be employed for tableting, such as a mold method and a wet molding / drying method.

  The blending amount of the fine particles for formulation, that is, the pharmaceutical composition particles in the tablet is preferably 5% by weight or more and 85% by weight or less, more preferably 5% by weight or more and 70% by weight or less, and still more preferably. Although it is 10 weight% or more and 70 weight% or less, it should not be limited to this. When the blending amount of the pharmaceutical composition particles is more than 85% by weight, there is a concern that strength and dissolution characteristics as a tablet, particularly an orally disintegrating tablet, may not be achieved.

  The orally disintegrating tablet according to the present invention can be produced by blending the pharmaceutical composition particles of the present invention and blending general additives usually used for the production of tablets. As the excipient, sugar such as mannitol, erythritol, maltitol, lactose or sugar alcohol, crystalline cellulose, calcium hydrogen phosphate and the like can be used. The binder is not limited as long as it is a normal binder such as corn starch, polyvinyl pyrrolidone, copolyvidone, hydroxypropyl cellulose, polyvinyl alcohol and the like. As the disintegrating agent, for example, carmellose, crospovidone, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose, etc. can be used. In addition, sweetening agents, flavoring agents and the like can be added to the preparation to improve the feeling of taking.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited by these Examples.

<Example 1>
In a mixed solution of 3000.0 g of water and 3000.0 g of ethanol, 200 g of hydroxypropyl cellulose (TC-5E), 80.0 g of amorphous solifenacin succinate and 56.0 g of tartaric acid are dissolved to prepare a drug substance solution. did. Next, 160.0 g of talc was dispersed in a mixed solution of 200.0 g of water and 200.0 g of ethanol and mixed with the drug substance solution.
200.0 g of crystalline cellulose (grain) (Selfia CP102) is put into a rolling fluid type coating granulator (manufactured by POWREC Co., Ltd .: MP-01 type), and the prepared liquid is sprayed, coated and dried while stirring and flowing. Thus, a pharmaceutical composition according to Example 1 was prepared.

<Example 2>
A pharmaceutical composition according to Example 2 was prepared in the same manner as in Example 1 except that the amount of talc was changed to 120.0 g.

<Comparative Examples 1-3>
The pharmaceutical compositions of Comparative Examples 1 to 3 were prepared in the same manner as in Example 1 except that the amount of talc was changed. The amount of talc was 80.0 g in Comparative Example 1, 40.0 g in Comparative Example 2, and 24.0 g in Comparative Example 3.

<Aggregation rate% (355 μm on / total)>
The aggregation rate of the pharmaceutical composition of each Example and Comparative Example was measured and calculated by the following method. The particles obtained in each Example and Comparative Example were sieved using a sieve having an opening of 355 μm, and the weight of what remained on the sieve was divided by the total weight to obtain the aggregation rate.

<Comparative Examples 4 and 5>
A pharmaceutical composition of Comparative Examples 4 and 5 was prepared using triacetin instead of talc. The amount of triacetin was 160.0 g in Comparative Example 4 and 24.0 g in Comparative Example 5. Specifically, in Comparative Example 4, in a mixed solution of 3000.0 g of water and 3000.0 g of ethanol, 200 g of hydroxypropyl cellulose (TC-5E), 80.0 g of solifenacin succinate which is amorphous, and 56.0 g of tartaric acid Was dissolved to prepare a drug substance solution. Next, 160.0 g of triacetin was dispersed in a mixed solution of 200.0 g of water and 200.0 g of ethanol and mixed with the drug substance solution. 200.0 g of crystalline cellulose (granule) (Selfia CP102) was put into a rolling fluid type coating granulator (manufactured by POWREC Co., Ltd .: MP-01 type), and the prepared liquid was sprayed and coated while stirring and flowing. In about 30 minutes from the start of coating, a lump was formed in the granulator, and the operation was stopped because the rolling flow became impossible. In Comparative Example 5, a pharmaceutical composition was prepared in the same manner as Comparative Example 4 except that triacetin was changed to 24.0 g. However, a lump was formed in the granulator in about 30 minutes from the start of coating, and the rolling flow was disabled. Operation was stopped.

<Comparative Examples 6 and 7>
A pharmaceutical composition of Comparative Examples 6 and 7 was prepared using stearic acid instead of talc. The amount of stearic acid was 160.0 g in Comparative Example 6 and 24.0 g in Comparative Example 7. Specifically, in Comparative Example 6, in a mixed solution of 3000.0 g of water and 3000.0 g of ethanol, 200 g of hydroxypropylcellulose (TC-5E), 80.0 g of solifenacin succinate which is amorphous, and 56.0 g of tartaric acid Was dissolved to prepare a drug substance solution. Next, 160.0 g of stearic acid was dispersed in a mixed solution of 200.0 g of water and 200.0 g of ethanol and mixed with the drug substance solution. 200.0 g of crystalline cellulose (granule) (Selfia CP102) was put into a rolling fluid type coating granulator (manufactured by POWREC Co., Ltd .: MP-01 type), and the prepared liquid was sprayed and coated while stirring and flowing. In about 30 minutes from the start of coating, a lump was formed in the granulator, and the operation was stopped because the rolling flow became impossible. In Comparative Example 7, a pharmaceutical composition was prepared in the same manner as in Comparative Example 6 except that stearic acid was changed to 24.0 g. However, a lump was formed in the granulator in about 30 minutes from the start of coating, and the rolling flow was impossible. The operation was stopped.

  As other additives, instead of talc, castor oil and dimethylpolysiloxane were added in an amount of 30% by mass with respect to the drug substance, and the same evaluation was performed. Was not obtained.

  As described above, the pharmaceutical composition particles include amorphous solifenacin and / or a salt thereof and talc, and the talc content is 150% by mass or more of the solifenacin and / or salt content thereof. As a result, it was found that granulation of particles can be remarkably prevented. By preventing granulation of the particles, it becomes easier to physically mask the unpleasant taste on it.

  It should be considered that the embodiments and examples disclosed above are illustrative and non-restrictive in every respect. The scope of the present invention is defined by the terms of the claims, rather than the description above, and includes all modifications within the scope and meaning equivalent to the terms of the claims.

Claims (5)

Solifenacin and / or a salt thereof,
Including talc,
The solifenacin and / or salt thereof is amorphous.
The pharmaceutical composition wherein the content of the talc is 150% by mass or more of the content of the solifenacin and / or a salt thereof.   The pharmaceutical composition according to claim 1, wherein a content of the talc is 200% by mass or more of a content of the solifenacin and / or a salt thereof. Nuclear particles,
A core particle coating layer covering the outside of the core particles;
The pharmaceutical composition according to claim 1 or 2, wherein the solifenacin and / or salt thereof and the talc are contained in the core particle coating layer.   The pharmaceutical composition according to claim 3, further comprising an outer layer covering an outer side of the core particle coating layer. Spraying a suspension containing amorphous solifenacin and / or a salt thereof and talc on the core particles to coat the outside of the core particles,
The method for producing a pharmaceutical composition according to any one of claims 1 to 4, wherein a content of the talc is 150% by mass or more of a content of the solifenacin and / or a salt thereof.