JP6915258B2 - Pharmaceutical composition particles, orally disintegrating preparation containing them, method for producing pharmaceutical composition particles - Google Patents

Description

The present invention relates generally to pharmaceutical composition particles for oral administration, orally disintegrating tablets containing the same, and a method for producing the pharmaceutical composition particles, specifically, masking an unpleasant taste and improving elution. The present invention relates to pharmaceutical composition particles for oral administration whose release can be controlled, an orally disintegrating tablet containing the same, and a method for producing the pharmaceutical composition particles.

Oral pharmaceutical composition particles such as granules, fine granules, and powders are smaller in size than tablets and capsules, and therefore are easy to take even for patients who have difficulty swallowing tablets and capsules. In recent years, a dosage form that is more convenient for patients and hospitals has been attracting attention. Among them, the orally disintegrating tablet can be taken without water, is easy to swallow, and has high convenience such as a preparation suitable for tube administration. Various ideas are being made for the manufacturing method.

The pharmaceutical composition particles, particularly the fine particles having an average particle diameter of 400 μm or less, have a larger surface area per weight than the larger fine particles. Therefore, since the area of contact with water in the oral cavity is large and the rate of water infiltration into the particles is high, there is a strong tendency for the drug to be rapidly released in the oral cavity after administration. This can cause various problems. For example, when a drug is absorbed in the oral cavity, it is considered that the drug released rapidly in the oral cavity may cause problems such as side effects and individual differences in drug efficacy. In addition, when the drug has an unpleasant taste, it is considered that the drug released rapidly in the oral cavity causes strong discomfort to the patient and significantly reduces the administration compliance. Solifenacin succinate is one of the drugs having extremely strong bitterness and astringency, and there are these problems in order to make it an orally disintegrating tablet.

In order not to cause these problems, it is necessary to suppress the release of solifenacin succinate in the oral cavity for a certain period of time in the oral pharmaceutical composition particles containing solifenacin succinate. By suppressing the release of solifenacin succinate for a certain period of time when the composition particles containing solifenacin succinate are present in the oral cavity, the unpleasant taste can be shielded, and side effects and individual differences in drug efficacy are manifested. Etc. can be avoided.

On the other hand, in order for solifenacin succinate to exhibit a sufficient medicinal effect, solifenacin succinate must be released from the oral pharmaceutical composition particles and a sufficient amount must be absorbed into the body. The orally taken preparation moves through the gastrointestinal tract over time, but in general, the drug is often absorbed in the upper part of the gastrointestinal tract.

Considering these, after suppressing the release of the drug from the oral pharmaceutical composition particles for a certain period of time,
It is hoped that the pharmaceutical composition particles will disintegrate as quickly as possible and solifenacin succinate will be rapidly released and absorbed in the upper gastrointestinal tract.

Therefore, in order to achieve the objectives of shielding the unpleasant taste of solifenacin succinate and avoiding absorption in the oral cavity, it is necessary to suppress the release of solifenacin succinate for a certain period of time in the oral cavity, and at the same time, in the digestive tract. It is imperative that solifenacin succinate be rapidly released from the oral pharmaceutical composition particles. In addition, it is very important to design the pharmaceutical composition particles in consideration of the optimum combination of the time when the release of solifenacin succinate starts in the oral cavity and the release time of solifenacin succinate after oral administration according to the characteristics of solifenacin succinate. is important.

In order to realize the optimum combination, the time for suppressing the initial release of solifenacin succinate (hereinafter, also referred to as “lag time”) can be arbitrarily controlled according to the characteristics of the solifenacin succinate preparation, and is taken orally. After that, a pharmaceutical composition particle design is required in which solifenacin succinate is released at a desired rate after a lapse of a certain period of time. That is, there is a need for a technique for freely controlling the combination of the suppression of the solifenacin succinate release time in the oral cavity and the release speed of the solifenacin succinate in the living body.

In addition, in orally disintegrating tablets, which are gaining increasing attention in terms of convenience, a device is devised to contain pharmaceutical composition particles in which drug release is controlled for the purpose of shielding an unpleasant taste. However, the pharmaceutical composition particles contained in the orally disintegrating tablets are made smaller in size than the oral pharmaceutical composition particles such as granules, fine granules, and powders in order to reduce the feeling of roughness in the oral cavity. The average particle size needs to be 400 μm or less, preferably 300 μm or less. However, as the size of the pharmaceutical composition particles decreases, the tendency for the drug to be released more rapidly than necessary increases. Therefore, in order to freely control the combination of the suppression of the drug release time in the oral cavity and the drug release speed in the living body, a very advanced formulation device is required. In fact, in such a minute oral pharmaceutical composition particle, simultaneously satisfying "suppression of initial drug release (control of lag time)" and "subsequent rapid drug release" is a general formulation method. It was very difficult.

Usually, as a method of shielding an unpleasant taste by controlling the release of a drug from the particles, a method of coating the particles with various films is used. For example, when a water-insoluble polymer is coated on a particle containing a drug having an unpleasant taste, the release of the drug inside the particle is restricted by suppressing the infiltration of water into the particle, which is unpleasant. Taste shielding is achieved.

However, in this method, even if water infiltrates into the particles, the film composed of the water-insoluble polymer is not broken, and the release rate of the drug remains suppressed. Therefore, rapid drug release after lag time cannot be achieved. Therefore, if the amount of the film is reduced in order to achieve rapid drug release, the initial drug release cannot be suppressed and the unpleasant taste cannot be shielded. That is, simply coating the drug-containing particles with a water-insoluble polymer cannot simultaneously satisfy "suppression of initial drug release" and "subsequent rapid drug release".

Therefore, for example, as described in International Publication WO02 / 96392 (Patent Document 1), as a method for simultaneously satisfying the initial suppression of drug release and the subsequent rapid drug release, a water-insoluble polymer and a water-soluble polymer are used. There is a method of coating a mixed film. The drug described in Patent Document 1 is expected to suppress the invasion of water into the particles until the water-soluble polymer in the film is dissolved, suppress the release of the drug, and shield the unpleasant taste. NS.

For the purpose of ensuring the release of the drug in the gastrointestinal tract, for example, as described in JP-A-2007-63263 (Patent Document 2), gastric-soluble polymers and enteric-soluble polymers are used as water-insoluble polymers. There is a method of coating the particles.

Further, Japanese Patent Application Laid-Open No. 2008-214334 (Patent Document 3) describes a method in which a disintegrant and an anti-aggregation agent are used in combination with a water-insoluble polymer for the purpose of improving the degree of film disintegration. Japanese Patent Application Laid-Open No. 2008-260712 (Patent Document 4) describes a method of using an acidic substance or a basic substance in combination, and Japanese Patent Application Laid-Open No. 2011-063627 (Patent Document 5) describes a method of using a saccharide in combination. There is.

Japanese Unexamined Patent Publication No. 2000-191519 (Patent Document 6) discloses a fast-release granular material in which two coating layers are coated on nuclear particles containing a drug. It is disclosed that the initial drug elution is suppressed by coating a water-soluble substance as a second layer on a mixed film of a water-insoluble substance and a water-soluble substance.

Further, in Japanese Patent Application Laid-Open No. 2011-225468 (Patent Document 7), a carrier prepared by blending a water-swellable substance commonly used as a disintegrant is used as nuclear particles, and a drug formed around the carrier is used. Described is a particulate pharmaceutical composition in which an active ingredient layer containing the active ingredient layer and a coating layer containing a gastrosoluble polymer are formed around the active ingredient layer. Japanese Unexamined Patent Publication No. 3-130214 (Patent Document 8) discloses a quick-release preparation in which a nucleus composed of an unpleasant-tasting drug and a water-swelling substance and its surroundings are coated with a mixture of ethyl cellulose and a water-soluble substance. There is.

International release WO02 / 96392 JP-A-2007-63263 Japanese Unexamined Patent Publication No. 2008-214334 Japanese Unexamined Patent Publication No. 2008-260712 Japanese Unexamined Patent Publication No. 2011-063627 Japanese Unexamined Patent Publication No. 2000-191519 Japanese Unexamined Patent Publication No. 2011-225468 Japanese Unexamined Patent Publication No. 3-130214

However, in the drug described in Patent Document 1, after the water-soluble polymer in the film is dissolved, pores are formed in the film to form a water channel through which the drug passes, but the unpleasant taste is sufficiently shielded. With a well-formulated or thick film, it is not possible to form sufficient channels to achieve rapid drug release. Therefore, for example, when the coating amount is increased to extend the lag time in order to solve "suppression of initial drug release", rapid drug release after the lag time cannot be achieved. In addition, if the amount of the water-soluble polymer in the mixed film is increased in order to achieve rapid drug release, it becomes difficult to suppress the initial drug release rate, so the coating amount is increased until a lag time is formed. It will increase, and it will not be possible to achieve rapid drug release. That is, even in the case of coating a mixed film of a water-insoluble substance and a water-soluble substance, it is practically impossible in most cases to achieve control of lag time and rapid elution rate at the same time.

Further, even by the methods described in Patent Documents 2 to 5, if the lag time is sufficiently set, the desired rapid drug release cannot be obtained, and the unpleasant taste cannot be shielded. As described above, it is difficult to solve two problems at the same time only by coating one layer.

Further, it is difficult to realize a long lag time only with a water-soluble substance as described in Patent Document 6. Note that Patent Document 6 does not describe anything regarding control of lag time.

Patent Documents 7 and 8 have unpleasant tastes in which there is a problem in the yield of particles having the same particle size due to the manufacturing method, the drug elution amount after 15 minutes is about 55%, and the drug release is not necessarily rapid. There is a problem that the shielding time of about 30 seconds is not sufficient. Also, there is no mention of lag time when the drug is relatively non-eluting.

In this way, the conventional bitterness shielding method using the inner core of a water-swelling substance that simply swells with water such as a disintegrant, and the bitterness shielding method using a film agent using a mixture of a water-insoluble substance and a water-soluble substance have lag times. The formation is incompatible with the rapid release of solifenacin and / or its salt after the lapse of the desired lag time.

Therefore, an object of the present invention is to provide a sufficiently long lag time that does not elute solifenacin and / or a salt thereof in the oral cavity, that is, pharmaceutical composition particles capable of both shielding an unpleasant taste and improving elution. For oral administration, which has and can cause the release of solifenacin and / or a salt thereof promptly after the lag time, and further, the length of the lag time can be controlled according to the purpose. The present invention provides a method for producing pharmaceutical composition particles, an orally disintegrating preparation containing the same, and pharmaceutical composition particles.

The present inventors have conducted diligent studies to solve this problem. As a result, the pharmaceutical composition particles have a multi-layer structure, the central portion of the particulate composition is formed as nuclei particles containing soriphenacin and / or a salt thereof, and a coating layer made of a gelled swelling substance is provided in the intermediate layer, or Nuclear particles containing a water-soluble gelled swelling substance were used, a coating layer containing soliphenacin and / or a salt thereof was provided in the intermediate layer, and an outer layer containing a water-insoluble component was coated as a water infiltration amount control layer on the outermost layer. The multi-layered pharmaceutical composition particles have a sufficient lag time that does not cause any unpleasant taste in the mouth, can realize rapid drug release after the lag time, and coat each coating layer. It was found that the length of the lag time can be controlled to about 2 to 10 minutes by changing the amount and the components.

A notable feature of the present invention is the intermediate layer or nuclear particles that absorb water and gel and swell. As described above, satisfactory shielding of an unpleasant taste has not been achieved by a known method for formulating bitterness-shielding fine particles using a water-swelling substance that simply absorbs water and swells, such as a disintegrant. Therefore, the present inventors include a water-soluble gelled swelling substance that absorbs water, gels and swells, denatures into a paste, and enlarges the volume as an intermediate layer or nuclear particles, and further contains a water-insoluble polymer. We have found a way to coat the outer layer.

Based on the above findings, the present invention is configured as follows. That is, the pharmaceutical composition particles according to the present invention contain a drug layer containing soriphenacin and / or a salt thereof, a gelled swelling substance layer containing a water-soluble gelled swelling substance, and a water-insoluble substance. It includes an outer layer that covers the drug layer and the gelled swelling substance layer.

Further, in the pharmaceutical composition particles according to the present invention, the drug layer is a nuclear particle containing soriphenacin and / or a salt thereof, and the gelled swelling substance layer is a nuclear particle containing a water-soluble gelled swelling substance. It is preferable that the outer layer is an intermediate layer that covers the outside of the intermediate layer, and the outer layer is an outer layer that contains a water-insoluble substance and covers the outside of the intermediate layer.

When the present invention is constructed in this way, the details of drug elution from the pharmaceutical composition particles are as follows. Water in the oral cavity gradually infiltrates into the particles through the outer layer containing the water-insoluble substance. The water that has entered the inside gels and swells the gelled and swelling substance in the intermediate layer in a paste-like manner. The time required for this gelation and swelling is the lag time. The gelled swelling substance that has absorbed water becomes a highly viscous gel and its volume increases. As a result, the gelled swelling substance causes film deformation such as spreading the outer layer, thinning the outer layer, causing cracks and breakage in the outer layer, and diffuses into water. The gelled swelling substance temporarily gels, but then rapidly dissolves in water and disperses in water, so that the surface of the nuclear particles containing solifenacin and / or a salt thereof is easily exposed, and solifenacin. And / or rapid release of its salt is achieved.

When the present invention is configured in this way, the lag time can be controlled by adjusting the components of the outer layer and the coating amount, and / or the components of the intermediate layer, as will be described in detail later.

As a result of diligent studies by the present inventors, it was found that the amount of the intermediate layer does not significantly affect the release rate of solifenacin and / or a salt thereof. It turned out that it is possible to set a lag time. On the other hand, it was found that even if the amount and thickness of the outer layer were increased, the water absorption swelling and enlargement of the intermediate layer caused thinning, cracking, and rupture of the outer layer, so that the drug release rate after the lag time did not decrease.

Therefore, for example, if an outer layer capable of retaining the shape in the oral cavity is formed for 1 to 2 minutes or more, the pharmaceutical composition particles do not disintegrate in the oral cavity for at least 1 to 2 minutes, and as a result, at least 1 to 1 The unpleasant taste can be shielded for 2 minutes. During this 1-2 minute lag time, water infiltrates into the particles through the outer layer, and within a few minutes to 10 minutes after the transfer into the stomach, the outer layer is thinned, cracked, or destroyed due to the above-mentioned swelling of the intermediate layer. In this way, it is possible to achieve both control of lag time and rapid drug release.

In this way, the pharmaceutical composition particles capable of both masking the unpleasant taste and improving the elution property, that is, solifenacin and / or a salt thereof, have a sufficient length of lag time to prevent elution in the oral cavity. Moreover, it is possible to provide pharmaceutical composition particles for oral administration which can cause rapid drug release after lag time and can control the length of lag time according to a purpose. Can be done.

Further, in the pharmaceutical composition particles according to the present invention, the gelled swelling substance layer is a nuclear particle containing a water-soluble gelled swelling substance, and the drug layer is a nuclear particle containing soriphenacin and / or a salt thereof. It is preferable that the outer layer is an intermediate layer that covers the outside of the intermediate layer, and the outer layer is an outer layer that contains a water-insoluble substance and covers the outside of the intermediate layer.

When the present invention is constructed in this way, the details of drug elution from the pharmaceutical composition particles are as follows. Water in the oral cavity gradually infiltrates into the particles through the outer layer containing the water-insoluble substance. The water that has entered the inside passes through the intermediate layer containing soriphenacin and / or a salt thereof, and infiltrates into the nuclear particles containing a water-soluble gelled swelling substance having higher water absorption than the intermediate layer, and the nuclear particles are paste-like. Gelled and swollen. While the nuclei particles gel and swell in a paste-like manner, the transfer of water from the inside to the outside of the pharmaceutical composition particles is restricted, so that the time required for this gelation and swelling becomes a lag time. The gelled swelling substance that has absorbed water becomes a highly viscous gel and its volume increases. As a result, the gelled swelling substance causes film deformation such as spreading the intermediate layer and the outer layer, thinning the outer layer, causing cracks and breakage in the outer layer, and solifenacin and / or a salt thereof in the intermediate layer in water. Diffuse into to achieve rapid release of solifenacin and / or its salt.

When the present invention is configured in this way, the lag time can be controlled by adjusting the components and coating amount of the outer layer and / or the components and amount of the nuclear particles, as will be described in detail later.

As a result of diligent studies by the present inventors, it was found that the amount of the gelled swelling substance in the nuclear particles does not significantly affect the release rate of solifenacin and / or its salt in the intermediate layer. It was found that a reliable lag time can be set by increasing the content to some extent. On the other hand, it was found that even if the amount and thickness of the outer layer were increased, the outer layer was thinned, cracked, and ruptured due to water absorption swelling and enlargement of the nuclear particles, so that the drug release rate after the lag time did not decrease.

Therefore, for example, if an outer layer capable of retaining the shape in the oral cavity is formed for 1 to 2 minutes or more, the pharmaceutical composition particles do not disintegrate in the oral cavity for at least 1 to 2 minutes, and as a result, at least 1 to 1 The unpleasant taste can be shielded for 2 minutes. During this 1-2 minute lag time, water infiltrates into the particles through the outer layer, and within a few minutes to 10 minutes after the transfer into the stomach, the outer layer is thinned, cracked, or destroyed due to the above-mentioned swelling of the intermediate layer. In this way, it is possible to achieve both control of lag time and rapid drug release.

In this way, the pharmaceutical composition particles capable of both masking the unpleasant taste and improving the elution property, that is, solifenacin and / or a salt thereof, have a sufficient length of lag time to prevent elution in the oral cavity. Moreover, it is possible to provide pharmaceutical composition particles for oral administration which can cause rapid drug release after lag time and can control the length of lag time according to a purpose. Can be done.

Further, the outer layer of the pharmaceutical composition particles according to the present invention preferably contains 30% by weight or more of a water-insoluble substance, more preferably 50% by weight or more, based on the total weight of the outer layer.

In the present application, the swelling power of the gelled swelling substance is defined as follows. That is, the amount of water to be mixed with the gelled swelling substance 100 (part by weight) when the gelled swelling substance and water are mixed to form a candy-like highly viscous solution having a viscosity at 25 ° C. of 1900 to 2100 mPa · s. (Part by weight) is defined as the swelling power (S) of the gelled swelling substance. The gelled swelling substance contained in the intermediate layer in the pharmaceutical composition particles according to the present invention is preferably a gelled swelling substance having a swelling power value (S value) of 500 or more, preferably 1000 or more. Is more preferable.

Further, in the pharmaceutical composition particles according to the present invention, the gelled swelling substance preferably has a viscosity of a 2% aqueous solution at 25 ° C. of 4 mPa · s or more.

Further, in the pharmaceutical composition particles according to the present invention, the coating amount of the outer layer is preferably 5% by weight or more and 50% by weight or less with respect to the intermediate layer-coated particles in which the core particles are coated with the intermediate layer.

Further, in the pharmaceutical composition particles according to the present invention, solifenacin and / or a salt thereof is preferably amorphous.

Orally disintegrating tablets according to the present invention contain any of the above pharmaceutical composition particles.

The method for producing the pharmaceutical composition particles according to the present invention is, for example, a crushing step of crushing the gelled swelling substance to an average particle diameter of 15 μm or less, and a suspension of the gelled swelling substance crushed in the crushing step in an organic solvent. A suspension step of obtaining a suspension, an intermediate layer forming step of spraying the suspension obtained in the suspension step onto nuclear particles containing a drug to form an intermediate layer on the outside of the nuclear particles, and an intermediate layer. It is preferable to include an outer layer forming step of coating the outside with a water-insoluble substance to form an outer layer.

Further, in the method for producing pharmaceutical composition particles according to the present invention, the organic solvent is preferably ethanol.

Fibers that cling to solifenacin and / or its salts and impede the rapid release of solifenacin and / or its salts, which cannot be used for granulation or coating operations, because the gelled swelling material becomes pasty when dissolved in water. Due to its quality, it cannot be easily pulverized and may not be suitable as a material for coating particles. Further, when the gelled swelling substance is dissolved in water at a low concentration, it may take a long time for coating. Therefore, it has been considered that it is pharmaceutical to produce substantially spherical fine particle nuclei mainly containing a gelled swelling substance and to coat the fine particles. The present inventors use the gelled swelling substance in the intermediate layer by finely pulverizing the gelled swelling substance to an average particle size of 15 μm or less and using a solution in which the gelled swelling substance is suspended in an organic solvent such as ethanol. I found that I could do it. In particular, since the gelled swelling substance is finely pulverized to an average particle size of 15 μm or less to form a homogeneous film, the gelled swelling substance is rapidly dispersed in water after a lag time, and the nuclear particles are rapidly dispersed. It is thought that it will be exposed to water.

In this way, the pharmaceutical composition particles capable of both masking the unpleasant taste and improving the elution property, that is, solifenacin and / or a salt thereof, have a sufficient length of lag time to prevent elution in the oral cavity. In addition, a method for producing pharmaceutical composition particles for oral administration, which can cause rapid drug release after the lag time and can control the length of the lag time according to the purpose. Can be provided.

Hereinafter, embodiments of the present invention will be described.

The "pharmaceutical composition particles" in the present invention mean a particulate composition containing solifenacin and / or a salt thereof that can be used in various oral dosage forms.

In the present invention, "suppressing drug release" or "suppressing initial drug elution" means that the dissolution rate of a drug (solifenacin and / or a salt thereof) is 0 in an dissolution test using a test solution assuming the oral cavity. It means to suppress to ~ 15%, and hereinafter, the time during which the drug elution rate is within that range is referred to as "lag time".

The pharmaceutical composition particles of the present invention may contain solifenacin and / or a salt thereof in either a crystalline or / or amorphous form. The salt of soriphenacin is not particularly limited as long as it is a pharmaceutically acceptable salt, and for example, a salt with an inorganic acid such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, etc. Salts with organic acids such as acid salts, citrates, oxalates, acetates, malates, tartrates, maleates, fumarates, benzenesulfonates, alkaline soils such as calcium salts and magnesium salts. Examples thereof include salts with similar metals, salts with alkali metals such as lithium salt, potassium salt and sodium salt, salts with organic bases such as ethylenediamine salt, diethanolamine salt and N-methylglucamine salt. 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 among the salts with an organic acid, it is more preferable to use succinic acid. In addition, solifenacin and / or a salt thereof may be an anhydride thereof. It may be a solvate such as a hydrate.

When the particles of the present invention are retained in the oral cavity for a certain period of time, saliva moves into the particles through the outer layer and the gelled swelling substance swells. Gelation in 900 mL of dissolution test solution Gelation in 2 minutes Even if the swelling substance is softened and gradually dissolves and the internal drug is eluted by 0 to 15%, it gelles with a small amount of saliva present in the oral cavity. The swelling substance gels inside the outer layer and becomes clay-like, and does not diffuse into the oral cavity. Naturally, the drug inside the particles does not diffuse into the oral cavity, and the bitterness in the oral cavity is shielded.

According to the findings of the present inventors, when taking the pharmaceutical composition particles, a lag time of about 2 minutes is required to shield the unpleasant taste of the drug for 1 to 2 minutes. Even in the case of the pharmaceutical composition particles according to the present invention, if the dissolution rate in the above dissolution test is satisfied, the unpleasant taste of the drug can be shielded. When the gelled swelling substance is exposed to the outer layer of the particles during the test at 50 rpm, the particles are aggregated and deposited on the round bottom portion of the dissolution test container due to its viscosity, and the drug is difficult to be released. Therefore, the sample in which the event appears was tested at 100 rpm in order to prevent aggregation and deposition.

In addition, the expression "prompt release of drug (solifenacin and / or salt thereof)" or "prompt drug release" in the present invention means a drug release condition in which sufficient drug efficacy is expected to be exhibited. That is, in the dissolution test using a test solution assuming gastrointestinal fluid, it is necessary that the drug dissolution rate 60 minutes after the start of the test is at least 90% or more, and the test is started when faster release is required. It is desirable that the drug dissolution rate after 30 minutes is 80% or more. If the drug dissolution rate does not reach the above level in this dissolution test, it means that the absorption of the drug in the upper part of the gastrointestinal tract is reduced and sufficient drug efficacy cannot be expected.

The "unpleasant taste" in the present invention specifically means bitter taste, astringent taste, harsh taste, acid taste, astringent taste, pungent taste and the like.

In the present invention, as the "test solution assuming the oral cavity", the second solution of the Japanese Pharmacopoeia dissolution test (pH 6.8 phosphate buffer solution) was used based on the finding that the pH in the oral cavity was weakly acidic. As the "test solution assuming gastrointestinal fluid", the first solution of the Japanese Pharmacopoeia disintegration test (pH 1.2 hydrochloric acid buffer solution) or the second solution of the dissolution test in consideration of fluctuations in gastric pH was used.

The composition of the pharmaceutical composition particles of the present invention will be described below.

The "drug layer" in the present invention refers to a layer containing solifenacin and / or a salt thereof, and may also refer to particles that are the core of the pharmaceutical composition particles.

The "gelled swelling substance layer" in the present invention refers to a layer containing a gelled swelling substance, and may also refer to particles that are the core of the pharmaceutical composition particles.

The "nuclear particles containing solifenacin and / or a salt thereof" in the present invention are particles consisting only of solifenacin and / or a salt thereof, or particles consisting of solifenacin and / or a salt thereof and one or more additives. Means that, solifenacin and / or a salt thereof coated on a nucleus containing no solifenacin and its salt is also included.

The "intermediate layer containing a water-soluble gelled swelling substance and coating the outside of the nuclear particles" in the present invention exists between the nuclear particles containing a drug and the outer layer, and is present in one or more types. It means a coating layer containing a gelled swelling substance. The intermediate layer can be directly coated with nuclear particles containing solifenacin and / or salts thereof. Further, a component that does not hinder the formation of lag time and the subsequent rapid release of the drug is previously coated with nuclear particles containing solifenacin and / or a salt thereof as one or more coating layers, and then the intermediate layer is coated. You may. The intermediate layer is formed with a gelled swelling substance as an essential component, but two or more kinds of gelled swelling substances may be mixed and used. It is also free to cover the intermediate layer in two layers.

The "nuclear particles containing a gelled swelling substance" in the present invention mean particles composed of only a gelled swelling substance or particles composed of a gelled swelling substance and one or more kinds of additives, and gelling. Includes nuclei that do not contain swelling substances and are coated with gelled swelling substances. Two or more kinds of gelled swelling substances may be mixed and used for the nuclear particles, or the gelled swelling substances may be formed as a plurality of layers to form the nuclear particles.

It is important that the gelled swelling substance used in the present invention is a substance that absorbs water and gels and swells like a paste. Sodium carboxymethyl cellulose (carmellose), polyethylene oxide, sodium polyacrylate, sodium alginate, propylene glycol alginate , Xanthan gum, carrageenan, guar gum, tara gum, pectin, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxyvinyl polymer, locust bean gum, tamarind seed gum, arabic gum, karaya gum, agar, gelatin, polyvinyl alcohol, or polyvinyl alcohol There are some copolymers and the like. One or more of these gelled swelling substances are used to coat as an intermediate layer.

Since these gelled and swelling substances dissolve in water to form a paste-like and highly viscous solution, it is basically impossible to coat individual particles using water as a solvent. Therefore, for example, a gelled swelling substance pulverized to an average particle size of 15 μm or less, preferably 10 μm or less is suspended in an organic solvent such as ethanol and coated on the nuclear particles. At this time, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone, which are widely used as binders for coating, are mixed with water in an organic solvent within a range that does not inhibit suspension, and for the purpose of improving adhesion of gelled swelling substances. , Copolyvidone, Macrogol, Ethylcellulose, Polyvinylacetal diethylaminoacetate, Hydroxypropylmethylcellulose, Hypromellose phthalate and other binders can be freely formulated and dissolved at the same time. The production method is not limited as long as the gelled swelling substance can be coated.

In addition, sugars such as mannitol, erythritol, and xylitol, sugar alcohols, and organic acids such as citric acid, tartaric acid, and malic acid are added to the intermediate layer for the purpose of adjusting the dissolution rate of the gelled swelling substance used in the intermediate layer. It is free to cover.

Regarding the above-mentioned gelled swelling substance, since the difference between items and grades is very large in its viscosity and swelling power, the amount of the gelled swelling substance blended in the intermediate layer and the intermediate layer to the drug-containing nuclear particles The coating amount cannot be unequivocally mentioned. However, if it is dared to say, the blending amount of the gelled swelling substance in the intermediate layer is preferably 20% or more, preferably 40% or more. The coating amount of the intermediate layer is preferably 5% by weight or more, particularly preferably 10% by weight or more, and preferably 75% by weight or less, particularly 60% by weight or less, based on the nuclear particles containing the drug. .. If the coating amount is lower than 5% by weight, there is a concern that a sufficient length of lag time cannot be formed.

In the present invention, the "intermediate layer containing solifenacin and / or a salt thereof and coating the outside of the nuclear particles" is present between the nuclear particles containing the gelled swelling substance and the outer layer, and is present as a drug and one kind or one. It is formed as a coating layer composed of two or more kinds of additives. The additive is typically a binder that is added to enhance the binding of the drug particles, and is free to contain a dissolution rate improving agent such as a saccharide or a disintegrant, if necessary. be. Examples of the binder include, but are not limited to, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, copolyvidone, ethyl cellulose and the like.

The "outer layer" in the present invention is a coating layer composed of one or more water-insoluble substances, which may contain one or more water-conducting substances, and is a gelled swelling substance. The intermediate layer is further coated with respect to the one coated with. By controlling the infiltration rate of water into the particles of the pharmaceutical composition, the outer layer adjusts the water absorption gelation and swelling rate of the intermediate layer to form a lag time.

The outer layer may be coated directly on the intermediate layer, or a component that does not interfere with lag time formation and subsequent rapid drug release is coated on the intermediate layer as one or more coating layers. After that, it may be coated. The outer layer may be coated with a component that does not interfere with lag time formation and subsequent rapid drug release as one or more coating layers. Further, since the purpose of the outer layer is to control the infiltration rate of water, it may be one layer or a plurality of layers of two or more depending on the control purpose.

The water-insoluble substance used to form the outer layer is one of the essential components arranged in the outer layer to control the infiltration rate of water. Has sex. 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 / methacrylate copolymer, acrylic acid. Ethyl / methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer RS, dry methacrylate copolymer LD, aminoalkyl methacrylate copolymer E, methacrylate copolymer L, methacrylate copolymer LD (aqueous dispersion), methacrylate copolymer S, polyvinyl acetal diethylamino Higher fatty acids such as acetate, dried milky white rack, cellac, zein, stearic acid, higher alcohols such as cetanol and stearyl alcohol, low melting point substances such as carnauba wax, honeydew and paraffin with a melting point of 30 to 120 ° C, sucrose fatty acid esters, etc. Higher fatty acids and polyhydric alcohol esters, fats obtained by adding hydrogen to oils such as castor wax, synthetic waxes, talc, lubricants such as magnesium stearate, etc., but are limited to these. is not it. As the water-insoluble substance, one kind or a combination of two or more kinds thereof can be used as appropriate. It is also free to mix and use plasticizers 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 blended with the water-insoluble substance as a water-conducting adjusting substance. The water-conducting substance referred to here is a component to be blended in the outer layer together with a water-insoluble substance in order to adjust the infiltration rate and the amount of infiltration of water. It is a component that easily passes through. Specific examples of the water-conducting substance in the outer layer of the present invention include pregelatinized starch, sodium caseinate, carboxyvinyl polymer, sodium carboxymethyl starch, sucrose fatty acid ester, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose, and the like. Purulan, polyvinylpyrrolidone, copolyvidone, polyoxyethylene-polyoxypropylene glycol, polyvinyl alcohol-polyethylene glycol implant copolymer, polyvinyl alcohol, macrogol, polyethylene oxide, amino acids such as glycine and alanine, sweeteners such as glycyrrhizic acid, dextrin and Examples include, but are not limited to, sugars such as lactose, sugar alcohols such as mannitol and xylitol, crystalline cellulose, crospovidone, and triethyl citrate, and one or two water-conducting regulators thereof. The above can be used in combination as appropriate.

As for the composition ratio of the water-insoluble substance and the water-conducting substance in the outer layer of the present invention, a ratio suitable for achieving the object is selected according to the purpose such as the physical properties of the drug, the absorption site, and the type of the pharmaceutical product. In the pharmaceutical composition particles of the present invention, when the outer layer has high water permeability (when the amount of the water-conducting substance mixed with the water-insoluble substance is large), the gelled swelling substance covering the intermediate layer is the outer layer. It is rapidly exposed into the oral cavity through the pores of the particle, and due to its viscosity, the particles may solidify in the oral cavity and stick to the oral mucosa. Therefore, the content of the water-insoluble substance in the outer layer is preferably 30% by weight or more, more preferably 50% by weight or more, and particularly preferably more than 50% by weight. Further, when the proportion of the water-insoluble substance is lower than 30% by weight, the rate of water infiltration into the particles of the pharmaceutical composition cannot be sufficiently controlled, and a lag time of a sufficient length cannot be formed. Is a concern.

As for the coating amount of the outer layer in the present invention, an amount suitable for achieving the object of the present invention is also 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, based on the intermediate layer-coated particles in which the core particles are coated with the intermediate layer. The following is preferable. When the coating amount is lower than 5% by weight, the surface of the pharmaceutical composition particles may not be uniformly coated, and the outer layer is extremely thin, so that the rate of water penetration into the pharmaceutical composition particles is sufficient. It may not be possible to control it, it may not be possible to form a lag time of a sufficient length, and the phenomenon of particles adhering to the oral cavity may occur. Further, if the coating amount is too large, rapid drug release after the lag time may not be achieved.

The blending amount of solifenacin and / or a salt thereof in the pharmaceutical composition particles is not particularly limited. It is preferably 0.5% by weight or more of the total particles of the pharmaceutical composition, and more preferably 80% by weight or less, particularly 70% by weight or less, and further preferably 60% by weight or less. However, the blending amount of solifenacin and / or a salt thereof shown here is an example applicable to the present invention and should not be construed in a limited manner.

The particle size of the pharmaceutical composition particles 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 size 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 pharmaceutical composition particles that shield the unpleasant taste according to the present invention are 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 average particle size of the pharmaceutical composition particles is more preferably 50 to 350 μm, still more preferably 70 to 300 μm.

It goes without saying that the pharmaceutical composition particles 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 fragrance, 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, it is not limited to these.

The pharmaceutical composition particles of the present invention can be produced in various forms of orally administered pharmaceutical compositions by blending the required amounts as they are. The pharmaceutical product referred to here is a powder, a granule, a tablet, a troche, a dry syrup, or the like. In some cases, powders and granules can be formulated by simply blending and mixing the fine particles for formulation as they are. In the case of an orally disintegrating tablet, which has been attracting attention recently, it is necessary to devise a formulation method by blending the formulation fine particles.

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

The first method for producing the pharmaceutical composition particles of the present invention is produced by coating core particles containing solifenacin and / or a salt thereof with an intermediate layer and an outer layer. As the nuclear particles containing solifenacin and / or a salt thereof, particles consisting only of solifenacin and / or a salt thereof may be used, or one or two kinds of solifenacin and / or a salt thereof and one or two kinds may be used by using a known technique. Particles composed of the above additives may be produced and the particles may be used. Particles consisting of soriphenacin and / or a salt thereof and an additive are prepared by mixing, for example, soriphenacin and / or a salt thereof with an appropriate excipient (for example, crystalline cellulose, lactose, corn starch, etc.) and adding a binder as necessary. The dissolved solution may be added, granulated, sized, and dried for production. In addition, a liquid in which a drug and a binder are dissolved or dispersed is sprayed on appropriate core additive particles (for example, crystalline cellulose (grains), purified sucrose spherical particles, mannitol spherical particles, etc.) using a fluidized bed coating device or the like. You may make it.

As a method of coating an intermediate layer on nuclear particles containing solifenacin and / or a salt thereof, it is widely used for coating operations of particulate compositions such as a fluidized layer coating device, a rolling coating device, and a centrifugal rolling coating device. It is preferable to adopt a method of coating by a machine. For example, a required amount of a liquid containing a coating component may be sprayed with a spray gun while flowing nuclear particles containing a drug in a rolling fluidized bed coating device. The liquid containing this coating component is prepared by dissolving or dispersing essential components and the like in a solvent such as water, ethanol, and methanol, and these solvents can be appropriately mixed and used. Needless to say, the coating method for these layers is not limited to the wet method.

When the pharmaceutical composition particles are used for producing an orally disintegrating tablet, it is desirable that the average particle size of the pharmaceutical composition particles is usually about 100 to 200 μm. In order for the intermediate layer and the outer layer to be covered with the substantially spherical nuclear particles while maintaining the spherical shape to be about 100 to 200 μm, the average particle size of the substance used by suspending in the solution used for the coating is covered. It is necessary that the particle size is 1/10 or less of that of the coated particles. Therefore, the average particle size of the gelled swelling substance contained in the intermediate layer is preferably 15 μm or less, more preferably 10 μm or less, and most preferably 7 μm or less.

However, since the gelled swelling substance is fibrous, it is difficult to crush it and cannot be easily refined. Therefore, as a result of diligent studies on the pulverization method, the present inventors have found that pulverization by a jet mill can efficiently pulverize to a target particle size. It was also found that the wet crushing method can also be used for efficient crushing.

As a method of coating the outer layer on the intermediate layer coating particles coated with the intermediate layer, a machine widely used for coating operation of a particulate composition such as a fluidized layer coating device, a rolling coating device, and a centrifugal rolling coating device is used. It is preferable to adopt a coating method. For example, a required amount of a liquid containing a coating component may be sprayed with a spray gun while flowing nuclear particles containing a drug in a rolling fluidized bed coating device. The liquid containing this coating component is prepared by dissolving or dispersing essential components in a solvent such as water, ethanol, methanol, etc., but these solvents can be appropriately mixed and used, for example, as a solvent. Only water may be used. Needless to say, the coating method for these layers is not limited to the wet method.

As described above, in the first method for producing pharmaceutical composition particles according to the present invention, a crushing step of crushing a gelled swelling substance to an average particle diameter of 15 μm or less and a gelled swelling substance crushed in the crushing step are combined. A suspension step of suspending in an organic solvent to obtain a suspension, and spraying the suspension obtained in the suspension step onto the nuclear particles containing soriphenacin and / or a salt thereof to form an intermediate layer on the outside of the nuclear particles. It is preferable to include an intermediate layer forming step of forming and an outer layer forming step of coating the outside of the intermediate layer with a water-insoluble substance to form an outer layer.

The organic solvent is preferably ethanol.

The second method for producing the pharmaceutical composition particles of the present invention is produced by coating nuclear particles containing a gelled swelling substance with an intermediate layer and an outer layer containing a drug.

When only the gelled swelling substance is used as the nuclear particles, the particles of the gelled swelling substance can be procured from the market. Therefore, the particle size is made uniform by sieving the particles, for example, the average particle size. It is preferable to use the particles having a size of about 50 to 300 μm as they are as nuclear particles. However, it goes without saying that it is also free to produce particles composed of the gelled swelling substance alone or the gelled swelling substance and one or more kinds of additives and use them as nuclear particles.

When a particle (nucleus) containing no gelled swelling substance is coated with the gelled swelling substance as the nuclear particle, the average particle size of the gelled swelling substance is preferably 15 μm or less. More preferably, it is 10 μm or less. Examples of the method for producing nuclear particles include a crushing step of crushing a gelled swelling substance to an average particle diameter of 15 μm or less, and a suspension in which the gelled swelling substance crushed in the crushing step is suspended in an organic solvent to obtain a suspension. The step includes a step of spraying the suspension obtained in the suspension step onto a nucleus containing no gelled swelling substance to form a layer of the gelled swelling substance on the outside of the nucleus. The organic solvent used in the suspension step is preferably ethanol, water may be blended as long as it does not inhibit suspension, and hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, and copolyvidone, which are widely used as binders. , Macrogol, ethyl cellulose, polyvinyl acetal diethylaminoacetate, hydroxypropyl methyl cellulose, hypromellose phthalate and other binders can be freely formulated and dissolved at the same time. Of course, it goes without saying that the formulation method can be devised by using only water as a solvent.

As a method of coating the core particles with an intermediate layer containing soriphenacin and / or a salt thereof, or a method of coating the intermediate layer with an outer layer containing a water-insoluble polymer, a fluidized layer coating device, a rolling coating device, or a centrifugation device is used. It is preferable to adopt a method of coating with a machine commonly used for coating operations of particulate composition such as a rolling coating device. For example, in a rolling fluidized bed coating apparatus, a required amount of a liquid containing a coating component may be sprayed with a spray gun while flowing the nuclear particles or intermediate layer coating particles to be coated. The liquid containing this coating component is prepared by dissolving or dispersing essential components and the like in a solvent such as water, ethanol, and methanol, and these solvents can be appropriately mixed and used. Needless to say, the coating method for 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 in which the tablet disintegrates within a certain period of time, preferably within 1 minute, more preferably within 45 seconds. Examples thereof include orally disintegrating tablets 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. Similarly, the pharmaceutical composition particles of the present invention can be made into orally disintegrating tablets with suitable excipients, disintegrants, binders, lubricants and the like.

Specific examples of the production method include (1) a method of mixing pharmaceutical composition particles as they are with sugars or sugar alcohols or a selected disintegrant and pressurizing and compressing them to form tablets, and (2) pharmaceutical composition. Tablets are made by mixing physical particles with sugar or sugar alcohols, selected disintegrants, etc. and granulating with a binder solution, and then mixing appropriate other tablet additives and compressing under pressure. Method for producing, (3) Pharmaceutical composition A saccharide having low moldability is mixed with particles, and the mixture is sprayed with a saccharide having high moldability as a binder, coated and / or granulated, and then subjected to low-pressure compression molding. There are various manufacturing methods such as humidification and drying to make tablets. In the case of an orally disintegrating tablet containing pharmaceutical composition particles, special consideration must be given to particle destruction, tablet hardness, disintegration, content uniformity, etc., and the method for producing an orally disintegrating tablet is described. The method should not be limited to the method described here, and any method may be adopted for tableting, such as a molding method and a wet molding / drying method.

The 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, still more preferably. It is 10% by weight or more and 70% by weight or less, but is not limited to this. If the blending amount of the pharmaceutical composition particles is more than 85% by weight, there may be a concern that the strength and dissolving characteristics of tablets, particularly orally disintegrating tablets, 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 also blending a general additive usually used in the manufacture of tablets. As the excipient, sugars such as mannitol, erythritol, maltitol, 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, and polyvinyl alcohol. As the disintegrant, commonly used, for example, carmellose, crospovidone, cornstarch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, low degree of substitution hydroxypropyl cellulose and the like can be used. In addition, it is also free to add a sweetening agent, a flavoring agent, or the like to the formulation 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.

The pharmaceutical material used in the experiment is as follows. Hydroxypropyl Methyl Cellulose 2910 (TC-5E, Viscosity: 3 mPa · s, S Value: 434, Shin-Etsu Chemical Industry), Carmellose Sodium (Cerogen PR-S, Viscosity: 28 mPa · s, S Value: 1101.11, Daiichi Kogyo (Pharmaceutical), Carmellose Sodium (Cellulose F-SC, Viscosity: 400 mPa · s, S Value: 2073.91, Daiichi Kogyo Seiyaku), Carmellose Sodium (Branose 7M1F-PH, Average Particle Diameter 245 μm, Viscosity: 100 mPa · s , S value: 1624.14, Ashland), sodium alginate (Kimika algin IL-6, viscosity: 67 mPa · s ^*) , S value: 2225.58, Kimika), hydroxypropyl cellulose (HPC-L, viscosity: 6 ~ 10 mPa · s, S value: 589.67, Nihon Soda), ethyl cellulose (Etocell STD7, Dow Chemical), talc (FL108, Fuji talc), crystalline cellulose (grains) (Selfia CP102, Asahi Kasei Chemicals), crystalline cellulose (grains) ) (Selfia CP203, Asahi Kasei Chemicals), D-Mannitol (160C, Rocket Japan), D-Mannitol (Mannit Q, Mitsubishi Shoji Food Tech), Crystalline Cellulose (KG-802, Asahi Kasei Chemicals), Viscosdone XL- 10, Ashland), magnesium stearate (Taipei Chemical Industry), tartrate acid (Wako Pure Chemical Industries). The ^{viscosity indicated by *)} is the viscosity of the 1% liquid, and the others are the viscosities of the 2% liquid.

[Reference example 1]
Water with respect to 100 (parts by weight) of gelled swelling substance when a gelled swelling substance and water are mixed using various gelled swelling substances to obtain a viscous solution having a viscosity at 25 ° C. of 1900 to 2100 mPa · s. The blending amount (part by weight) of the gelled swelling substance was determined and used as the swelling power (S) of the gelled swelling substance. The obtained S value was as follows.
TC-5E: 434, Cellogen F-5A: 613

Regarding the cellogen F-5A having an S value of 613, since the volume of the aqueous solution obtained by mixing 10 g of the cellogen F-5A and 100 g of water is 106 mL, the volume of the aqueous solution is 106 mL. The volume of is equivalent to 6 mL. Therefore, the aqueous solution containing 100 g of cellogen F-5A and 613 g of water has a volume of 673 mL, a viscosity of 1900 to 2100 mPa · s, and a water absorption swelling rate of 11.2 times. Further, when a similar experiment was conducted on TC-5E, 1 g of TC-5E corresponds to a volume of 0.9 mL in an aqueous solution, so 100 g of TC-5E and 434 g of water in a TC-5E aqueous solution have a volume of 524 mL. The viscosity is 1900 to 2100 mPa · s, and the water absorption swelling ratio is 5.8 times.

First, the gelled swelling substance layer is a nuclear particle containing a water-soluble gelled swelling substance, the drug layer is an intermediate layer containing solifenacin and / or a salt thereof and covering the outside of the nuclear particle, and the outer layer is. Examples of solifenacin and / or a salt-containing pharmaceutical composition thereof, which is an outer layer containing a water-insoluble substance and covering the outside of the intermediate layer, will be described.

[Example 1]
A waterproof membrane solution is prepared by suspending 6.25 g of talc in a solution prepared by taking 6.25 g of etocell STD-7 and dissolving it in 237.5 g of ethanol. 10 g of solifenacin succinate, 20 g of TC-5E, and 5 g of tartaric acid are taken and dissolved in a mixed solution of 325.5 g of ethanol and 139.5 g of purified water to prepare a drug coating solution. 36 g of Etocell STD-7 and 4 g of TC-5E are taken and dissolved in a mixed solution of 608 g of ethanol and 152 g of purified water to prepare an outer layer solution.
Rolling flow type coating granulator (manufactured by Paulek Co., Ltd .: MP-01 type) with carmellose sodium (Brannose 7M1F-PH, average particle size: 245 μm, viscosity: 100 mPa · s, S value: 1624.14, Ashland ) Was added, and 250 g of the waterproof film solution was sprayed and coated while being stirred and flowed, and dried to produce waterproof film-coated particles. 200 g of the waterproof film-coated particles were put into a rolling flow type coating granulator (MP-01 type), and 500 g of the drug coating liquid was sprayed and coated while being stirred and flowed, and dried to produce drug-coated particles.
Next, 200 g of the drug-coated particles were put into a rolling flow-type coating granulator (MP-01 type), and 800 g of the outer layer solution was spray-coated and dried while stirring and flowing to obtain outer layer-coated particles.

[Example 2]
A waterproof membrane solution is prepared by suspending 6.25 g of talc in a solution prepared by taking 6.25 g of etocell STD-7 and dissolving it in 237.5 g of ethanol. 40 g of solifenacin succinate, 100 g of TC-5E, and 30 g of tartaric acid are taken and dissolved in a mixed solution of 1627.5 g of ethanol and 697.5 g of purified water to prepare a drug coating solution. 36 g of Etocell STD-7 and 4 g of TC-5E are taken and dissolved in a mixed solution of 608 g of ethanol and 152 g of purified water to prepare an outer layer solution.
Sodium alginate (Kimika algin IL-6 (sieved to make the average particle size 160 μm), viscosity: 67 mPa · s (2) on a rolling flow type coating granulator (manufactured by Paulek Co., Ltd .: MP-01 type) % Liquid viscosity), S value: 2225.58, Kimika) was added, and 250 g of the waterproof film solution was sprayed and coated while being stirred and flowed, and dried to produce waterproof film-coated particles. 200 g of the waterproof film-coated particles were put into a rolling flow type coating granulator (MP-01 type), and 2495 g of the drug coating liquid was sprayed and coated while being stirred and flowed, and dried to produce drug-coated particles.
Next, 200 g of the drug-coated particles were put into a rolling flow-type coating granulator (MP-01 type), and 800 g of the outer layer solution was spray-coated and dried while stirring and flowing to obtain outer layer-coated particles.

Next, the drug layer is a nuclear particle containing solifenacin and / or a salt thereof, and the gelled swelling substance layer is an intermediate layer containing a water-soluble gelled swelling substance and covering the outside of the nuclear particle, and is an outer layer. Describes an example of a pharmaceutical composition containing solifenacin and / or a salt thereof, which is an outer layer containing a water-insoluble substance and covering the outside of the intermediate layer.

[Example 3]
A drug coating solution is prepared by suspending 20 g of talc in a solution prepared by taking 10 g of solifenacin succinate, 25 g of TC-5E, and 7 g of tartaric acid and dissolving them in a mixed solution of 375 g of ethanol and 375 g of purified water. 20 g of HPC-L was taken and dissolved in a mixed solution of 630 g of ethanol and 70 g of purified water. An intermediate layer solution is prepared by suspending 60 g of a powder (ground with a jet mill, sieved with a mesh to have an average particle size of 5 μm). 39.6 g of Etocell STD-7 and 4.4 g of TC-5E are taken and dissolved in a mixed solution of 704 g of ethanol and 176 g of purified water to prepare an outer layer solution.
200 g of crystalline cellulose (Selfia CP102) was put into a rolling flow type coating granulator (MP-01 type), and 812 g of a drug coating liquid was sprayed and coated while being stirred and flowed, and dried to produce drug-coated particles. 200 g of the drug-coated particles were put into a rolling flow type coating granulator (MP-01 type), and 780 g of the intermediate layer solution was sprayed and coated while being stirred and flowed, and dried to produce intermediate layer coated particles.
Next, 220 g of the intermediate layer coating particles were put into a rolling flow type coating granulator (MP-01 type), and 924 g of the outer layer solution was spray-coated and dried while stirring and flowing to obtain outer layer coating particles.

[Example 4]
A drug coating solution is prepared by suspending 160 g of talc in a solution prepared by taking 80 g of solifenacin succinate, 200 g of TC-5E, and 56 g of tartaric acid and dissolving them in a mixed solution of 3000 g of ethanol and 3000 g of purified water. Fine particles of carmellose sodium (cellogen F-SC, viscosity: 400 mPa · s, S value: 20739.91, Daiichi Kogyo Seiyaku) in a solution of 20 g of HPC-L dissolved in a mixed solution of 630 g of ethanol and 70 g of purified water. An intermediate layer solution is prepared by suspending 60 g of a powder (ground with a jet mill, sieved with a mesh to have an average particle size of 5 μm). 39.6 g of Etocell STD-7 and 4.4 g of TC-5E are taken and dissolved in a mixed solution of 704 g of ethanol and 176 g of purified water to prepare an outer layer solution.
200 g of crystalline cellulose (Selfia CP102) was put into a rolling flow type coating granulator (MP-01 type), and 6496 g of a drug coating liquid was sprayed and coated while being stirred and flowed, and dried to produce drug-coated particles. 200 g of the drug-coated particles were put into a rolling flow type coating granulator (MP-01 type), and 780 g of the intermediate layer solution was sprayed and coated while being stirred and flowed, and dried to produce intermediate layer coated particles.
Next, 220 g of the intermediate layer coating particles were put into a rolling flow type coating granulator (MP-01 type), and 924 g of the outer layer solution was spray-coated and dried while stirring and flowing to obtain outer layer coating particles.

[Comparative Example 1]
Instead of the carmellose sodium used in Example 1, crystalline cellulose (CP203: average particle size 230 μm) having almost the same size was used, and the waterproof membrane solution, drug coating solution and outer layer solution were used in the same manner as in Example 1. Was spray-coated and dried to obtain outer layer-coated particles of Comparative Example 1.

[Comparative Example 2]
In the formulation / manufacturing method shown in Example 3, the gelled swelling substance layer (intermediate layer) is not coated, that is, the drug-coated particles produced by spraying / coating a drug-coating solution on crystalline cellulose (Selfia CP102) and drying the particles. On the other hand, the outer layer solution was directly spray-coated and dried to obtain outer layer-coated particles of Comparative Example 2.

[Comparative Example 3]
In place of the intermediate layer gelling and swelling substance (cellogen PR-S) used in Example 3, hydroxypropyl methylcellulose 2910 (TC-5E, viscosity: 3 mPa · s, S value: 434, Shin-Etsu Chemical Co., Ltd.) was used. Particles were produced in the same manner as in Example 3 and used as outer layer coated particles of Comparative Example 3.

[Test example]
The following dissolution test and evaluation of the unpleasant taste shielding property were carried out on the particles obtained in Examples 1 to 4 and Comparative Examples 1 to 3.

[Test Example 1: Dissolution test]
The outer layer coating fine particles containing 5 mg of solifenacin succinate were taken, and the dissolution test was performed according to the second method of the Japanese Pharmacopoeia using an automatic 6-series dissolution tester (manufactured by Toyama Sangyo Co., Ltd.). As the test solution, 900 mL of the second solution of the Japanese Pharmacopoeia dissolution test was used. The rotation speed of the paddle is 50 rpm or 100 rpm. For a sample having a particularly strong tendency to agglutinate in the test solution, 100 rpm was adopted. The results of the dissolution test are shown in Table 1.

[Test Example 2: Evaluation of unpleasant taste shielding property]
The taste of the outer layer coating particles containing solifenacin succinate was evaluated according to the following evaluation methods and evaluation criteria. The results are shown in Table 2.
<Evaluation method>
Four healthy adult males (Panels 1 to 4) contained outer layer coating particles containing an amount equivalent to 5 mg of solifenacin succinate for 2 minutes, then spit it out, and evaluated the unpleasant taste after 1 minute and 2 minutes. did. Solifenacin succinate is a drug with a strong bitterness and astringent taste.
<Evaluation criteria for unpleasant taste>
-: No unpleasant taste ±: Slight taste but acceptable +: Unpleasant taste ++: Strongly unpleasant taste

For all the samples of Examples 1 to 4, no unpleasant taste such as bitterness and astringent taste was felt even 2 minutes after being put in the mouth, and a clear unpleasant taste suppressing effect was obtained. Was there. Further, in the dissolution test, the dissolution rate was 80% or more after 15 to 30 minutes, and the drug release characteristic was expected to rapidly and sufficiently develop the drug effect.

On the other hand, the outer layer coating particles of Comparative Example 1 produced by the same method as in Example 1 using nuclear particles having almost the same size as the carmellose sodium used in Example 1, which does not correspond to the gelled swelling substance, Although no unpleasant taste was felt after 2 minutes, in the dissolution test, it was found that the drug release was about 50% even after 60 minutes, and sufficient drug efficacy could not be expected. The particles of Comparative Example 2 in which the same nuclear particles as in Example 3 were used, the drug was coated in the same manner as in Example 3, and the outer layer was directly coated with the water infiltration amount control layer without coating the intermediate layer, were obtained after 2 minutes. In the above, a plurality of panelists felt an unpleasant taste, and even in the dissolution test, sufficient drug efficacy could not be expected. Further, the particles of Comparative Example 3 using TC-5E having a weak water-absorbing swelling power as the gelling swelling substance have an ability to denature the outer layer because the gelling swelling power is weak although the unpleasant taste is shielded. In the dissolution test, it did not reach 90% after 60 minutes, and it was found that sufficient drug efficacy could not be expected.

[Test Example 3: Evaluation of crystal state by X-ray diffraction]
The crystal states of solifenacin succinate of Examples 1 to 4 and Comparative Examples 1 to 3 were evaluated by X-ray diffraction. When a peak specific to solifenacin was confirmed, it was evaluated as having partially changed to a crystal, and when it was a halo peak, it was evaluated as having maintained an amorphous state. As a result, all of the solifenacin succinates of Examples 1 to 4 were amorphous, and all of the solifenacin succinates of Comparative Examples 1 to 3 were partially changed to crystals.

[Example 5]
43.85 g of outer layer coating particles produced in Example 4, 30.2 g of D-mannitol (160C), 3.36 g of mannitol Q, 9 g of crystalline cellulose (KG-802), and crospovidone (Polyplasmdone XL-10). ) And 1 g of magnesium stearate were taken and sufficiently mixed particles for tableting were used to prepare a tablet having a diameter of 7.5 mm (corner plane) and a weight of 150 mg at a tableting pressure of 5 kN. This tablet was a tablet that disintegrated within 30 seconds when contained in the oral cavity and did not feel the unpleasant taste that became a problem for about 2 minutes.

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

Claims (10)

A drug layer containing solifenacin and / or a salt thereof,
A gelled swelling material layer containing a water-soluble gelled swelling material and
An outer layer containing a water-insoluble substance and covering the drug layer and the gelled swelling substance layer is provided.
The gelled swelling substance has a swelling power (S) value of 500 or more, and contains sodium carboxymethyl cellulose, polyethylene oxide, sodium polyacrylate, sodium alginate, propylene glycol alginate, xanthan gum, carrageenan, guar gum, tara gum, and pectin . carboxymethyl polymer, locust bean gum, tamarind seed gum, gum arabic, karaya gum, agar, gelatin, polyvinyl alcohol, and, is one or more selected from the group consisting of a copolymer obtained by a part of polyvinyl alcohol , Pharmaceutical composition particles. The drug layer is a nuclear particle containing solifenacin and / or a salt thereof.
The gelled swelling substance layer is an intermediate layer containing a water-soluble gelled swelling substance and covering the outside of the nuclear particles.
The pharmaceutical composition particles according to claim 1, wherein the outer layer is an outer layer that contains a water-insoluble substance and covers the outside of the intermediate layer. The gelled swelling material layer is a nuclear particle containing a water-soluble gelled swelling material.
The drug layer is an intermediate layer containing solifenacin and / or a salt thereof and coating the outside of the nuclear particles.
The pharmaceutical composition particles according to claim 1, wherein the outer layer is an outer layer that contains a water-insoluble substance and covers the outside of the intermediate layer. The pharmaceutical composition particles according to any one of claims 1 to 3, wherein the outer layer contains the water-insoluble substance in an amount of 50% by weight or more based on the total weight of the outer layer. The pharmaceutical composition particles according to any one of claims 1 to 4, wherein the gelled swelling substance has a viscosity of a 2% aqueous solution at 25 ° C. of 4 mPa · s or more. The pharmaceutical composition particles according to claim 2 or 3 , wherein the coating amount of the outer layer is 5% by weight or more and 50% by weight or less with respect to the intermediate layer-coated particles in which the core particles are coated with the intermediate layer. The pharmaceutical composition particle according to any one of claims 1 to 6 , wherein the solifenacin and / or a salt thereof is an amorphous substance. An orally disintegrating tablet containing the pharmaceutical composition particles according to any one of claims 1 to 7. A pulverization step of pulverizing a gelled swelling substance to an average particle size of 15 μm or less, and
A suspension step of suspending the gelled swelling substance crushed in the pulverization step in an organic solvent to obtain a suspension, and a suspension step.
An intermediate layer forming step of spraying the suspension obtained in the suspension step onto the nuclear particles containing a drug to form an intermediate layer on the outside of the nuclear particles.
The outer layer forming step of coating the outside of the intermediate layer with a water-insoluble substance to form an outer layer is included.
The gelled swelling substance has a swelling power (S) value of 500 or more, and contains sodium carboxymethyl cellulose, polyethylene oxide, sodium polyacrylate, sodium alginate, propylene glycol alginate, xanthan gum, carrageenan, guar gum, tara gum, and pectin . carboxymethyl polymer, locust bean gum, tamarind seed gum, gum arabic, karaya gum, agar, gelatin, polyvinyl alcohol, and, is one or more selected from the group consisting of a copolymer obtained by a part of polyvinyl alcohol , A method for producing pharmaceutical composition particles. The method for producing pharmaceutical composition particles according to claim 9 , wherein the organic solvent is ethanol.