JP6733499B2 - Solifenacin-containing pharmaceutical composition and method for producing the same - Google Patents

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 the drugs having extremely strong bitterness and astringency. In order to make solifenacin or its salt into an orally disintegrating tablet, it is necessary to mask the bitterness.

Generally, in order to mask the bitterness of a drug, a method of making other tastes less sensitive by using an artificial sweetener (sensory masking), a water-insoluble film on the drug having a bitterness, etc. To suppress drug release in the oral cavity (physical masking), electrical interaction, ion exchange bond, inclusion of compounds, etc. to change the property of bitterness (chemical Masking) and combinations thereof.

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

For example, Japanese Patent No. 4277904 (Patent Document 1) discloses 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 A core particle containing a drug in the center of the pharmaceutical composition, a layer containing two types of water-soluble components, an insolubilizing agent and an insolubilizing substance in the intermediate layer, and the outermost layer controlling the rate of water penetration into the interior. A time-release type particulate pharmaceutical composition for oral administration, each of which contains a water intrusion control layer. As the drug, for example, solifenacin succinate is used, and crystalline cellulose is sprayed by using a fluidized bed granulator to obtain core particles containing the drug. It is described that the core particles are coated with a liquid containing hydroxypropylmethyl cellulose, a small amount of talc, or the like in a predetermined order.

It should be noted that, in Japanese Patent No. 5168711 (Patent Document 2), in order to stabilize solifenacin, the ratio of the amorphous body to the crystalline body and the amorphous body of solifenacin is not more than a certain amount. Solid formulations of certain solifenacin or salts thereof have been described.

Japanese Patent No. 4277904 Japanese Patent No. 5168711

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

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

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

The pharmaceutical composition according to the present invention comprises a core particle and a core particle coating layer coating the outside of the core particle, and solifenacin and/or its salt 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 coating the outside of the core particle coating layer.

The method for producing any of the above pharmaceutical compositions according to the present invention comprises the steps of spraying a suspension containing amorphous solifenacin and/or a salt thereof and talc on the core particles to give the core particles. The step of coating the outside is included, and the content of talc is 150% by mass or more of the content of solifenacin and/or its salt.

Hereinafter, embodiments of the present invention will be described.

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

The “pharmaceutical composition” in the present invention means a composition containing solifenacin and/or a salt thereof, which can be provided 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, and examples thereof include hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate and the like. Salts with inorganic acids, succinates, citrates, oxalates, acetates, malates, tartrates, maleates, fumarates, salts with organic acids 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. Are listed. 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 of the salts with an organic acid, succinic acid is more preferably used. Further, solifenacin and/or its salt may be an anhydride thereof. It may be a solvate such as a hydrate.

Whether or not solifenacin and/or its salt in the present invention is an "amorphous substance" can be evaluated by X-ray diffraction. When a peak specific to solifenacin is confirmed, it can be evaluated that a part thereof has been changed to a crystalline body, and when it is a halo peak, it can be evaluated that the amorphous state is maintained.

The “unpleasant taste” in the present invention specifically means bitterness, astringency, astringent taste, sourness, astringent taste, spiciness 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 its salt.

The pharmaceutical composition according to the present invention comprises a core particle and a core particle coating layer coating the outside of the core particle, and solifenacin and/or its salt 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 nuclear particles, and is formed as a coating layer comprising solifenacin and/or its salt and one or more additives. The additive is typically a binder that is blended in order to enhance the binding properties of drug particles, and it is free to include a dissolution rate improver such as a saccharide or a disintegrant, if necessary. is there. Examples of the binder include, but are not limited to, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, copolyvidone, ethyl cellulose and the like.

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

The “outer layer” in the present invention is a layer that covers the outside of the core particle coating layer. The outer layer is, for example, a coating layer made of one or more kinds of water-insoluble substances, and may contain one or more kinds 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 for controlling the infiltration rate of water, and is considered to be insoluble, extremely insoluble, or almost insoluble in water. It is preferably soluble. Specifically, ethyl cellulose, acetyl cellulose, cellulose acetate phthalate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, dimethylaminoethyl methacrylate/methyl methacrylate copolymer, methyl acrylate/methacrylic acid copolymer, acrylic acid. Ethyl/methyl methacrylate copolymer dispersion, aminoalkylmethacrylate copolymer RS, dry methacrylic acid copolymer LD, aminoalkylmethacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer LD (water dispersion), methacrylic acid copolymer S, polyvinyl acetal diethylamino Higher fatty acids such as acetate, dried milky white lac, shellac, zein, stearic acid, higher alcohols such as cetanol and stearyl alcohol, low melting point substances such as carnauba wax, beeswax and paraffin with a low melting point of 30 to 120°C, sucrose fatty acid ester, etc. Examples thereof include esters of higher fatty acids and polyhydric alcohols, fats obtained by adding hydrogen to oils such as castor wax, synthetic waxes, talc, lubricants such as magnesium stearate, but are not limited to these. is not. The water-insoluble substance may be used alone or in combination of two or more kinds. It is also free to mix and use a plasticizer such as castor oil, dibutyl phthalate and triethyl citrate.

Further, when forming the outer layer, a water-soluble substance, a hydrophilic substance or the like can be added to the water-insoluble substance as a water-conductivity adjusting substance. The water-conductivity adjusting substance here is a component to be mixed in the outer layer together with the water-insoluble substance in order to adjust the infiltration rate and the amount of infiltration of water, a component which is easily soluble in water, and a hydrophilic water such as a disintegrant. It is a component that is easy to pass through. Specifically exemplifying the water-conductivity adjusting substance in the outer layer of the present invention, 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 glycyrrhizinic acid, dextrin and Examples thereof include sugars such as lactose, sugar alcohols such as mannitol and xylitol, crystalline cellulose, crospovidone, triethyl citrate, and the like, but are not limited thereto, and the water-conductivity adjusting substance is one or two kinds thereof. It is also possible to use a combination of the above as appropriate.

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

Regarding 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 7% by weight or more, and 50% by weight or less, particularly preferably 30% by weight or less, with respect to the particles obtained by coating the core particles with the core particle coating layer. Is preferred. If the coating amount is less 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 rate of water infiltration into the interior of the pharmaceutical composition is sufficiently controlled. In some cases, it may not be possible to form a lag time of sufficient length, and there is a possibility that particles may adhere to the oral cavity. If the coating amount is too large, rapid drug release after lag time may not be achieved.

The compounding amount of solifenacin and/or its salt in the pharmaceutical composition is not particularly limited, but is preferably 0.5% by weight or more based on the whole particles of the pharmaceutical composition. However, the compounding amount of solifenacin and/or its salt shown here is an example applicable to the present invention, and should not be limitedly interpreted.

The particle size of the pharmaceutical composition according to the present invention preferably has a maximum diameter of 2 mm or less. When the shape of the pharmaceutical composition particles can be approximated to a sphere, the average particle diameter is preferably 2 mm or less. When the pharmaceutical composition particles have a shape other than a sphere, the average longest diameter is preferably 2 mm or less.

The unpleasant taste-masked pharmaceutical composition according to the present invention is particularly useful as fine particles for orally disintegrating tablets that are 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 feeling of 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 flavoring agent, a sweetening agent, a flavoring agent, a coloring agent, a stabilizing agent, an antioxidant, a pH adjusting agent, a solubilizing agent, a solubilizing agent, a fluidizing agent, a buffering agent and the like. However, the present invention is not limited to these.

The pharmaceutical composition of the present invention can be formulated into various orally administrable pharmaceutical compositions by mixing the required amount as it is. The formulation as used herein includes powders, granules, tablets, troches, dry syrups and the like. In some cases, powders and granules can be prepared by simply blending and mixing the fine particles for formulation. In the case of an orally disintegrating tablet, which has recently received attention, it is necessary to incorporate the fine particles for formulation to devise a formulation method.

Next, a method for producing the pharmaceutical composition particles of the present invention will be described.

The method for producing any of the above pharmaceutical compositions according to the present invention comprises the steps of spraying a suspension containing amorphous solifenacin and/or a salt thereof and talc on the core particles to give the core particles. The step of coating the outside is included, and the content of talc is 150% by mass or more of the content of solifenacin and/or its salt.

The core particles are prepared by, for example, using a fluidized bed coating device, a solution in which a binder or the like is dissolved or dispersed in additive particles (for example, crystalline cellulose (particles), purified sucrose spherical particles, mannitol spherical particles, etc.) that become appropriate nuclei. It may be produced by spraying.

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

When the pharmaceutical composition is used for producing an orally disintegrating tablet, the average particle size of the pharmaceutical composition is usually desired to be about 100 to 200 μm. The average particle diameter of the substance suspended in the solution used for coating is used in order that the coating layer and the outer layer of the substantially spherical spherical particles are coated with the core particle coating layer and the outer layer while maintaining the spherical shape. Needs to have a particle size that is not more than one-tenth that of the coated particles.

As a method of coating the outer layer on the particles coated with the core particle coating layer, coating is performed by a machine generally used for coating operation of the particulate composition, such as a fluidized bed coating device, a tumbling coating device, or a centrifugal tumbling coating device. It is preferable to adopt the method described above. For example, in a tumbling fluidized bed coating device, a required amount of a liquid containing a coating component may be sprayed with a spray gun while flowing the core particles. A liquid containing this coating component is prepared by dissolving or dispersing essential components and the like in a solvent such as water, ethanol or methanol, but these solvents can also be appropriately mixed and used, for example, as a solvent. You may use only water. Needless to say, the method for coating these layers is not limited to the wet method.

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

The term “orally disintegrating tablet” as used in the present invention means a preparation similar to a tablet that disintegrates in the oral cavity within a certain period of time, preferably within 1 minute, more preferably within 45 seconds. Examples thereof include orally disintegrating tablets containing the pharmaceutical composition particles disclosed in JP 2012-240917 A, JP 4019374 A, JP 3746167 A, and the like. 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.

As a specific example of the production method, (1) a method for producing a tablet by mixing particles of the pharmaceutical composition as they are with sugar or sugar alcohols and a selected disintegrant and compressing under pressure, (2) pharmaceutical composition Particles made by mixing the product particles with sugar or sugar alcohols, selected disintegrants, etc. and granulating with a binder solution, and mixing with other suitable tablet additives, and compressing into tablets Method for producing, (3) after mixing a saccharide having low moldability to the particles of the pharmaceutical composition, spraying the mixture with a saccharide having high moldability as a binder and coating and/or granulating the mixture, low-pressure compression molding, There are various manufacturing methods such as moistening and drying to make tablets. In the case of orally disintegrating tablets containing pharmaceutical composition particles, it is necessary to pay particular attention to particle destruction, tablet hardness, disintegrating property, content uniformity, and the like. It should not be limited to the method described here, and any method may be adopted for tableting, such as a molding method, a wet molding drying method, and the like.

The compounding amount of the fine particles for formulation, that is, the particles of the pharmaceutical composition 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 further preferably It is not less than 10% by weight and not more than 70% by weight, but not limited thereto. When the content of the pharmaceutical composition particles is more than 85% by weight, it may be feared that the strength and dissolution characteristics of tablets, particularly orally disintegrating tablets, may not be achieved.

The orally disintegrating tablet according to the present invention can be produced by incorporating the particles of the pharmaceutical composition of the present invention, and also by incorporating general additives usually used for producing tablets. As the excipient, mannitol, erythritol, maltitol, sugars such as lactose or sugar alcohols, crystalline cellulose, calcium hydrogen phosphate and the like can be used. The binder is not limited as long as it is an ordinary binder such as corn starch, polyvinylpyrrolidone, copolyvidone, hydroxypropyl cellulose, polyvinyl alcohol. As the disintegrant, it is possible to use commonly used disintegrants such as carmellose, crospovidone, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, and low-substituted hydroxypropylcellulose. It is also free to add a sweetener, a corrigent and the like to the preparation to improve the feeling of ingestion.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

<Example 1>
To a mixture 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 were 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 (particles) (Celphia CP102) was put into a rolling fluid type coating granulator (manufactured by Paulec Co., Ltd.: MP-01 type), and the prepared liquid was sprayed/coated and dried while stirring and flowing. Thus, the 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 to 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 of the examples and comparative examples were sieved with a sieve having a mesh size 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>
The pharmaceutical compositions of Comparative Examples 4 and 5 were prepared by 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, 2000.0 g of hydroxypropyl cellulose (TC-5E), 80.0 g of amorphous solifenacin succinate, and 56.0 g of tartaric acid were added to a mixed liquid of 3000.0 g of water and 3000.0 g of ethanol. 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 (granules) (Celphia CP102) was put into a tumbling fluidized coating granulator (manufactured by Paulec Co., Ltd.: MP-01 type), and the prepared liquid was sprayed and coated while stirring and flowing. About 30 minutes after the start of coating, lumps were formed in the granulator and the rolling flow became impossible, so the operation was stopped. In Comparative Example 5, a pharmaceutical composition was prepared in the same manner as in Comparative Example 4 except that triacetin was changed to 24.0 g, but lumps were formed in the granulator within about 30 minutes from the start of coating, and tumbling flow became impossible. The operation was stopped.

<Comparative Examples 6 and 7>
The pharmaceutical compositions of Comparative Examples 6 and 7 were 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, 200 g of hydroxypropylcellulose (TC-5E), 80.0 g of amorphous solifenacin succinate, and 56.0 g of tartaric acid were added to a mixed liquid of 3000.0 g of water and 3000.0 g of ethanol. 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 (particles) (Celphia CP102) was put into a tumbling fluidized coating granulator (manufactured by Paulec Co., Ltd.: MP-01 type), and the prepared liquid was sprayed and coated while stirring and flowing. About 30 minutes after the start of coating, lumps were formed in the granulator and the rolling flow became impossible, so the operation was stopped. In Comparative Example 7, a pharmaceutical composition was prepared in the same manner as in Comparative Example 6 except that the amount of stearic acid was changed to 24.0 g. However, about 30 minutes after the start of coating, lumps were formed in the granulator, and the rolling flow was impossible. The operation was stopped because it became.

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

As described above, the pharmaceutical composition particles contain amorphous solifenacin and/or a salt thereof and talc, and the content of talc is set to 150% by mass or more of the content of solifenacin and/or a salt thereof. By doing so, it was found that granulation between the particles can be significantly prevented. Preventing granulation of the particles facilitates physical masking of unpleasant tastes thereon.

It should be considered that the embodiments and examples disclosed above are illustrative and non-restrictive in all respects. The scope of the present invention is shown not by the above description but by the scope of the claims, and includes meaning equivalent to the scope of the claims and all modifications within the scope.

Claims (5)

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