JP2018065776A - Pharmaceutical composition particle and orally disintegrable preparation containing the same, and method for producing pharmaceutical composition particle - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition particle that can mask a discomfort taste and improve its elution properties, an orally disintegrable tablet containing the same, and a method for producing a pharmaceutical composition particle.SOLUTION: A pharmaceutical composition particle has a medicine layer containing solifenacin and/or a salt thereof, a gelatinized swelling material layer containing a water-soluble gelatinized swelling material, and an outer layer that contains a water-insoluble material to coat the medicine layer and the gelatinized swelling material layer.SELECTED DRAWING: None

Description

  The present invention relates generally to pharmaceutical composition particles for oral administration, orally disintegrating tablets containing the same, and methods for producing the pharmaceutical composition particles, and in particular to masking unpleasant taste and improving dissolution. The present invention relates to a pharmaceutical composition particle for oral administration which can be controlled for release, an orally disintegrating tablet containing the same, and a method for producing the pharmaceutical composition particle.

  Oral pharmaceutical composition particles such as granules, fine granules, and powders are smaller in size than tablets and capsules, and thus are easy to take even for patients who have difficulty swallowing tablets and capsules. In recent years, dosage forms with increased convenience for patients and hospitals have attracted attention. In particular, orally disintegrating tablets can be taken without water, are easy to swallow, and have high convenience such as preparations suitable for tube administration. Various innovations are being made in the manufacturing method.

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

  In order to prevent these problems from occurring, 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 solifenacin succinate-containing composition particles are present in the oral cavity, it is possible to mask unpleasant taste and to develop side effects and differences in efficacy between individuals Etc. can be avoided.

  On the other hand, in order for solifenacin succinate to exhibit a sufficient medicinal effect, it is necessary that solifenacin succinate is released from the oral pharmaceutical composition particles and a sufficient amount is absorbed into the body. The internal preparations move through the digestive tract over time, but in general, drugs are often absorbed in the upper digestive tract.

Considering these, after suppressing the drug release from the oral pharmaceutical composition particles for a certain period of time,
It is desirable to disintegrate the pharmaceutical composition particles as quickly as possible to release solifenacin succinate as soon as possible and absorb it in the upper digestive tract.

  Therefore, in order to achieve the objectives of masking 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, while at the same time in the digestive tract It is important that solifenacin succinate is rapidly released from the oral pharmaceutical composition particles. In addition, it is very important to design pharmaceutical composition particles in consideration of the optimal combination of the time when the release of solifenacin succinate 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 to suppress 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, Thereafter, there is a need for a pharmaceutical composition particle design that releases solifenacin succinate at a target rate after a certain period of time. That is, there is a need for a technique that freely controls the combination of the solifenacin succinate release time in the oral cavity and the solifenacin succinate release speed in vivo.

  Further, in orally disintegrating tablets, which have been attracting attention in terms of convenience, there has been devised to contain pharmaceutical composition particles with controlled drug release for the purpose of shielding unpleasant tastes and the like. However, the pharmaceutical composition particles contained in this orally disintegrating tablet are further reduced in size than oral pharmaceutical composition particles such as granules, fine granules, powders, etc., in order to reduce the rough feeling 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 is reduced, the tendency for the drug to be released more rapidly than necessary becomes stronger. 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 is required. In fact, in such a fine oral pharmaceutical composition particle, satisfying both “suppression of initial drug release (control of lag time)” and “subsequent rapid drug release” is a common formulation method. It was very difficult.

  Usually, as a method for shielding an unpleasant taste by controlling the drug release from the particles, a method of coating various coatings on the particles 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 intrusion of water into the particle. Taste masking is achieved.

  However, with this technique, even when water enters the particles, the film composed of the water-insoluble polymer is not broken, and the drug release rate remains suppressed. Therefore, rapid drug release after the lag time cannot be achieved. Therefore, if the amount of the film is reduced to achieve rapid drug release, the initial drug release cannot be suppressed and the unpleasant taste cannot be masked. In other words, “inhibition of initial drug release” and “subsequent rapid drug release” cannot be satisfied simultaneously by simply coating the drug-containing particles with a water-insoluble polymer.

  Therefore, as described in, for example, International Publication No. WO02 / 96392 (Patent Document 1), as a method of simultaneously satisfying the initial drug release suppression and the subsequent rapid drug release, a water-insoluble polymer and a water-soluble polymer can be used. There is a method of coating a mixed film. The drug described in Patent Document 1 is expected to suppress the penetration of water into the particles until the water-soluble polymer in the film is dissolved, thereby suppressing drug release and shielding an unpleasant taste. The

  For the purpose of more reliably releasing the drug in the gastrointestinal tract, as described in, for example, JP-A-2007-63263 (Patent Document 2), a gastric polymer or an enteric polymer is used as a water-insoluble polymer. There is a method of coating the particles.

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

  Japanese Laid-Open Patent Publication No. 2000-191519 (Patent Document 6) discloses an immediate-release granular material in which a core layer containing a drug is coated with two coating layers. It is disclosed that 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.

  In addition, JP 2011-225468 A (Patent Document 7) uses a carrier prepared by blending a water-swellable substance widely used as a disintegrant as a core particle, and a drug formed around the carrier. An active ingredient layer to be contained and a particulate pharmaceutical composition in which a coating layer containing a gastric polymer is formed around the active ingredient layer are described. Japanese Patent Laid-Open No. 3-130214 (Patent Document 8) discloses an immediate-release preparation in which a core composed of an unpleasant-tasting drug and a water-swellable substance and its periphery are coated with a mixture of ethyl cellulose and a water-soluble substance. Yes.

International Publication WO02 / 96392 JP 2007-63263 A JP 2008-214334 A JP 2008-260712 A JP 2011-063627 A JP 2000-191519 A JP 2011-225468 A Japanese Patent Laid-Open 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, and a water channel for allowing the drug to pass therethrough is formed. In a film with a proper formulation or thickness, it is not possible to form a sufficient water channel to achieve rapid drug release. Therefore, for example, in order to solve “suppression of initial drug release”, when the coating amount is increased to extend the lag time, it is not possible to achieve rapid drug release after the lag time. Also, if the amount of water-soluble polymer in the mixed film is increased in order to achieve rapid drug release, it becomes difficult to control the initial drug release rate, so the coating amount is reduced until lag time is formed. Again, rapid drug release cannot be achieved. In other words, even in the case of coating with a mixed film of a water-insoluble substance and a water-soluble substance, it is practically impossible to achieve lag time control and rapid elution rate at the same time.

  In addition, even by the methods described in Patent Documents 2 to 5, if the lag time is sufficient, the intended rapid drug release cannot be obtained, and unpleasant taste shielding cannot be achieved. Thus, it is difficult to solve the two problems at the same time only by coating one layer.

  Moreover, it is difficult to realize a long lag time only with a water-soluble substance as described in Patent Document 6. In Patent Document 6, there is no description regarding control of lag time.

  In Patent Documents 7 and 8, there is a problem in the yield of particles having a uniform particle diameter due to the manufacturing method, and the drug elution amount after 15 minutes is about 55%, which is not necessarily a rapid drug release, and an unpleasant taste. The shielding time of about 30 seconds is not sufficient. In addition, there is no mention of lag time during which the drug does not elute relatively.

  In this way, the conventional bitterness masking method using the inner core with a water-swellable substance that simply swells with water, such as a disintegrant, and the bitterness masking method with a film agent using a mixture of a water-insoluble substance and a water-soluble substance, Formation and rapid release of solifenacin and / or its salt after a desired lag time cannot be achieved at the same time.

  Therefore, an object of the present invention is to provide a pharmaceutical composition particle capable of both unpleasant taste shielding and improved dissolution, that is, a sufficiently long lag time that does not dissolve solifenacin and / or a salt thereof in the oral cavity. For oral administration that can quickly release solifenacin and / or a salt thereof after the lag time and can control the length of the lag time according to the purpose Pharmaceutical composition particles of the present invention, an orally disintegrating preparation containing the same, and a method for producing the pharmaceutical composition particles.

  The present inventors have intensively studied to solve this problem. As a result, the pharmaceutical composition particles have a multilayer structure, the core of the particulate composition is a core particle containing solifenacin and / or a salt thereof, and a coating layer made of a gelled swellable substance is provided in the intermediate layer, or Core particles containing a water-soluble gelling swelling substance are provided, a coating layer containing solifenacin and / or a salt thereof is provided on the intermediate layer, and an outer layer containing a water-insoluble component is coated on the outermost layer as a water infiltration control layer The pharmaceutical composition particles having a multilayer structure have a sufficient lag time that does not cause an unpleasant taste in the mouth, can realize a rapid drug release after the lag time, and each coating layer can be coated. It was found that the length of the lag time can be controlled to about 2 to 10 minutes by changing the amount and components.

  A notable feature of the present invention resides in an intermediate layer or core particle that absorbs water and gels and swells. As described above, satisfactory masking of unpleasant taste has not been achieved by a known method for formulating bitterness-masking fine particles using a water-swellable substance that swells by simply sucking water, such as a disintegrant. Therefore, the present inventors include a water-soluble gelling / swelling substance that absorbs water, gels and swells and denatures into a paste to enlarge the volume as an intermediate layer or core particles, and further contains a water-insoluble polymer. A method for coating the outer layer was found.

  Based on the above knowledge, this invention is comprised as follows. That is, the pharmaceutical composition particles according to the present invention contain a drug layer containing solifenacin and / or a salt thereof, a gelled swelling substance layer containing a water-soluble gelling swelling substance, and a water-insoluble substance. An outer layer covering 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 core particle containing solifenacin and / or a salt thereof, and the gelled swelling substance layer contains a water-soluble gelling swelling substance and contains a core particle. The outer layer is preferably an outer layer that covers the outer side of the intermediate layer by containing a water-insoluble substance.

  When this invention is comprised in this way, the detail of the drug elution from pharmaceutical composition particle | grains is as follows. The water in the oral cavity gradually enters the inside of the particles through the outer layer containing the water-insoluble substance. The water that has entered the inside causes the gelled swelling substance in the intermediate layer to gelate and swell in a paste form. The time required for this gelation swelling is the lag time. The gelled swelling substance that has absorbed water becomes a highly viscous gel and the volume increases. As a result, the gelled swelling substance spreads the outer layer, causes the outer layer to become thin, causes film deformation such as causing cracks and breakage in the outer layer, and diffuses into water. Although the gelled swelling substance is temporarily gelled, it is quickly dissolved in water and dispersed in water, so that the surface of the core particle containing solifenacin and / or a salt thereof is easily exposed, solifenacin And / or rapid release of its salts is achieved.

  When this invention is comprised in this way, lag time can be controlled by adjusting the component and coating amount of an outer layer, and / or the component of an intermediate | middle layer so that it may explain in full detail later.

  As a result of intensive studies by the present inventors, it has been found that the amount of the intermediate layer does not significantly affect the release rate of the internal solifenacin and / or its salt. It was found that a lag time can be set. On the other hand, it was found that even when the amount and thickness of the outer layer were increased, the water absorption swelling and enlargement of the intermediate layer caused the outer layer to become thinner, cracked, and ruptured, so that the drug release rate after the lag time did not decrease.

  Therefore, for example, if an outer layer capable of maintaining the shape in the oral cavity for 1 to 2 minutes or more is formed, the pharmaceutical composition particles do not disintegrate in the oral cavity for at least 1 to 2 minutes. Unpleasant taste can be shielded for 2 minutes. During the lag time of 1 to 2 minutes, water penetrates into the particles through the outer layer, and the thinning, cracking, and destruction of the outer layer occur due to swelling of the above-mentioned intermediate layer within a few minutes to 10 minutes after moving into the stomach. Thus, both control of lag time and rapid drug release can be achieved.

  In this way, the pharmaceutical composition particles capable of coexisting masking of unpleasant taste and improving dissolution, that is, having a sufficiently long lag time not to dissolve solifenacin and / or a salt thereof in the oral cavity, Furthermore, it is possible to provide pharmaceutical composition particles for oral administration that can cause a rapid drug release after lag time and that can control the length of lag time according to the purpose. Can do.

  Further, in the pharmaceutical composition particles according to the present invention, the gelled swelling substance layer is a core particle containing a water-soluble gelling swelling substance, and the drug layer contains solifenacin and / or a salt thereof and is a core particle. The outer layer is preferably an outer layer that covers the outer side of the intermediate layer by containing a water-insoluble substance.

  When this invention is comprised in this way, the detail of the drug elution from pharmaceutical composition particle | grains is as follows. The water in the oral cavity gradually enters the inside of the particles through the outer layer containing the water-insoluble substance. Water that has entered the interior passes through an intermediate layer containing solifenacin and / or a salt thereof, penetrates into the core particles containing a water-soluble gelled swelling substance having higher water absorption than the intermediate layer, and the core particles are paste-like. Gelled and swollen. While the core particles are gelled and swollen in a paste form, the transfer of water from the inside to the outside of the pharmaceutical composition particles is limited, so 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 the volume increases. As a result, the gelled swelling substance spreads the intermediate layer and the outer layer, causes film deformation such as thinning of the outer layer and generation of cracks and fractures in the outer layer, and solifenacin and / or its salt in the intermediate layer is submerged in water. To achieve rapid release of solifenacin and / or its salts.

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

  As a result of intensive studies by the present inventors, it has been found that the amount of the gelled swelling substance in the core particle does not significantly affect the release rate of solifenacin and / or its salt in the intermediate layer. It was found that a certain 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 drug release rate after the lag time did not decrease because the water absorption swelling and enlargement of the core particles caused the outer layer to become thinner, cracked, and ruptured.

  Therefore, for example, if an outer layer capable of maintaining the shape in the oral cavity for 1 to 2 minutes or more is formed, the pharmaceutical composition particles do not disintegrate in the oral cavity for at least 1 to 2 minutes. Unpleasant taste can be shielded for 2 minutes. During the lag time of 1 to 2 minutes, water penetrates into the particles through the outer layer, and the thinning, cracking, and destruction of the outer layer occur due to swelling of the above-mentioned intermediate layer within a few minutes to 10 minutes after moving into the stomach. Thus, both control of lag time and rapid drug release can be achieved.

  In this way, the pharmaceutical composition particles capable of coexisting masking of unpleasant taste and improving dissolution, that is, having a sufficiently long lag time not to dissolve solifenacin and / or a salt thereof in the oral cavity, Furthermore, it is possible to provide pharmaceutical composition particles for oral administration that can cause a rapid drug release after lag time and that can control the length of lag time according to the purpose. Can do.

  In addition, the outer layer of the pharmaceutical composition particles according to the present invention preferably contains 30% by weight or more of the water-insoluble substance of the total weight of the outer layer, and more preferably contains 50% by weight or more.

  In the present application, the swelling force of the gelled swelling substance is defined as follows. That is, the blending amount of water with respect to 100 (parts by weight) of the gelled swelling substance when the gelled swelling substance and water are mixed to form a water tank-like highly viscous solution having a viscosity at 25 ° C. of 1900 to 2100 mPa · s. (Parts by weight) is defined as the swelling force (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, 1000 or more. It is more preferable that

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

  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 layer is coated with the intermediate layer.

  Moreover, in the pharmaceutical composition particles according to the present invention, it is preferable that solifenacin and / or a salt thereof is amorphous.

  The orally disintegrating tablet according to the present invention contains any of the pharmaceutical composition particles described above.

  The method for producing pharmaceutical composition particles according to the present invention includes, for example, a pulverization step of pulverizing a gelled swelling substance to an average particle diameter of 15 μm or less, and suspending the gelled swelling substance pulverized in the pulverization step in an organic solvent. A suspension step for obtaining a suspension; an intermediate layer forming step for spraying the suspension obtained in the suspension step onto the drug-containing core particles to form an intermediate layer outside the core particles; and And an outer layer forming step of forming an outer layer by coating a water-insoluble substance on the outside.

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

  A gel-swelling substance becomes a paste when dissolved in water, so it binds to solifenacin and / or its salt and inhibits the rapid release of solifenacin and / or its salt. In some cases, it cannot be easily pulverized due to its quality and is not suitable as a particle coating material. In addition, if the gelled swelling substance is dissolved in water at a low concentration, the coating may take a long time. For this reason, it has been considered difficult to produce a substantially spherical fine particle nucleus mainly composed of a gelled swelling substance and to coat the fine particles. The present inventors use the gelled swelling substance for the intermediate layer by pulverizing the gelled swelling substance to an average particle size of 15 μm or less and using a solution obtained by suspending the gelled swelling substance in an organic solvent such as ethanol. I found out that I can. In particular, by pulverizing the gelled swollen material to an average particle size of 15 μm or less, it is coated in a homogeneous film, so that after the lag time, the gelled swollen material is quickly dispersed in water, and the core particles are promptly dispersed. It is considered to be exposed to water.

  In this way, the pharmaceutical composition particles capable of coexisting masking of unpleasant taste and improving dissolution, that is, having a sufficiently long lag time not to dissolve solifenacin and / or a salt thereof in the oral cavity, In addition, a method for producing pharmaceutical composition particles for oral administration capable of prompt drug release after lag time, and further capable of controlling the length of lag time according to the purpose. Can be provided.

  Embodiments of the present invention will be described below.

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

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

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

  When the particles of the present invention are kept 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. In 900 mL of dissolution test solution, gelled swelling substance softens in 2 minutes and dissolves little by little, and even if it is particles in which the internal drug elutes 0-15%, gelation will occur in a small amount of saliva present in the oral cavity. The swelling substance gels inside the outer layer and does not become a clay state and does not diffuse into the oral cavity. Naturally, the drug inside the particles does not diffuse into the oral cavity, and the bitter taste in the oral cavity is shielded.

  According to the knowledge of the present inventors, a lag time of about 2 minutes is required in order to shield the unpleasant taste of the drug for 1-2 minutes when taking the pharmaceutical composition particles. Also 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 masked. 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, making it difficult to release the drug. Therefore, the sample in which the event appeared was tested at 100 rpm in order to prevent aggregation and accumulation.

  In addition, the expression “release drug (solifenacin and / or salt thereof) rapidly” or “rapid drug release” in the present invention means a drug release condition that is expected to exhibit a sufficient drug effect. That is, in a dissolution test using a test solution assuming a gastrointestinal fluid, the drug dissolution rate 60 minutes after the start of the test is required to be at least 90%, and when more rapid release is required, the test is started. 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 in this dissolution test, it means that the absorption of the drug in the upper gastrointestinal tract is reduced and sufficient drug efficacy cannot be expected.

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

  In the present invention, as the “test solution assuming the oral cavity”, Japanese Pharmacopoeia dissolution test second liquid (pH 6.8 phosphate buffer) was used based on the knowledge that the pH in the oral cavity is weakly acidic. As the “test solution assuming a gastrointestinal tract solution”, Japanese Pharmacopoeia disintegration test first solution (pH 1.2 hydrochloric acid buffer solution) or dissolution test second solution in consideration of changes 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 sometimes refers to particles serving as 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 sometimes refers to particles serving as the core of the pharmaceutical composition particles.

  The “nuclear particle containing solifenacin and / or a salt thereof” in the present invention is a particle composed solely of solifenacin and / or a salt thereof, or a particle composed of solifenacin and / or a salt thereof and one or more additives. And also includes a core not containing solifenacin and its salt coated with solifenacin and / or its salt.

  In the present invention, the “intermediate layer containing a water-soluble gelling swelling substance and covering the outside of the core particle” is present between the core particle containing the drug and the outer layer, and one or more kinds of the core layer. It means a coating layer containing a gelled swelling substance. The intermediate layer can be directly coated on core particles containing solifenacin and / or a salt thereof. In addition, a component that does not prevent lagtime formation and subsequent rapid drug release is coated as one or more coating layers on core particles containing solifenacin and / or a salt thereof in advance, and then an intermediate layer is coated. May be. The intermediate layer is formed using a gelled swelling substance as an essential component, but two or more gelled swelling substances may be mixed and used. Moreover, it is also free to cover the intermediate layer in two layers.

  The “core particle containing a gelled swelling substance” in the present invention means a particle consisting only of a gelled swelling substance, or a particle consisting of a gelled swelling substance and one or more additives, and gelled. Also included are nuclei that do not contain a swelling substance coated with a gelled swelling substance. Two or more kinds of gelled swelling substances may be mixed and used for the core particles, or the gelled swelling substances may be formed as a plurality of layers to constitute the core particles.

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

  Since these gelled swelling substances dissolve in water to form a paste and become a highly viscous solution, it is basically impossible to coat particles individually 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 with core particles. At this time, water is added to the organic solvent as long as suspension is not inhibited, and hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, which is widely used as a coating binder for the purpose of improving the adhesion of the gelled swelling substance. , Copolyvidone, macrogol, ethyl cellulose, polyvinyl acetal diethylaminoacetate, hydroxypropylmethylcellulose, hypromellose phthalate, and the like can be 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, saccharides such as mannitol, erythritol, and xylitol, sugar alcohols, organic acids such as citric acid, tartaric acid, malic acid, etc. are added to the intermediate layer for the purpose of adjusting the dissolution rate of the gelled swelling substance used in the intermediate layer. The coating is free.

  Regarding the above-mentioned gelled swelling substance, the difference between items and grades are very large in the viscosity and swelling power. Therefore, the amount of gelled swelling substance in the intermediate layer and the intermediate layer to the drug-containing core particles The covering amount cannot be generally mentioned. However, if it dares to say, it is preferable that the compounding quantity of the gelatinization swelling substance in an intermediate | middle layer is 20% or more, Preferably it is 40% or more. Further, the coating amount of the intermediate layer is preferably 5% by weight or more, particularly preferably 10% by weight or more, more preferably 75% by weight or less, particularly preferably 60% by weight or less based on the core particles containing the drug. . When the coating amount is lower than 5% by weight, there is a concern that a sufficiently long lag time cannot be formed.

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

  The “outer layer” in the present invention is a coating layer composed of one or more kinds of water-insoluble substances, and may contain one or more kinds of water conductivity adjusting substances, and is a gelled swelling substance. Further coating is performed on the coated intermediate layer. The outer layer controls the rate of water penetration into the pharmaceutical composition particles, thereby adjusting the water-absorbing gelation swelling rate of the intermediate layer to form lag time.

  The outer layer may be coated directly on the intermediate layer, or a component that does not prevent lag time formation and subsequent rapid drug release is coated on the intermediate layer as one or more coating layers. Later, it may be coated. On the outer layer, a component that does not prevent lag time formation and subsequent rapid drug release may be coated as one or more coating layers. Further, since the outer layer is intended to control the water intrusion rate, it may be one layer or a plurality of two or more layers 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 in order to control the infiltration rate of water, and it is difficult to dissolve in water. Have sex. Specifically, ethyl cellulose, acetyl cellulose, cellulose acetate phthalate, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, dimethylaminoethyl methacrylate / methyl methacrylate copolymer, methyl acrylate / methacrylic acid copolymer, acrylic acid Ethyl / methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer RS, dry methacrylic acid copolymer LD, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, methacrylic acid copolymer LD (aqueous dispersion), methacrylic acid copolymer S, polyvinyl acetal diethylamino Acetate, dry milky white rack, cell Higher fatty acids such as lacquer, zein, stearic acid, higher alcohols such as cetanol and stearyl alcohol, low melting point substances such as carnauba wax, beeswax and paraffin, low melting point materials of 30-120 ° C, higher fatty acids such as sucrose fatty acid esters Examples include, but are not limited to, fats obtained by adding hydrogen to oils such as alcohol esters and castor wax, lubricants such as synthetic wax, talc, and magnesium stearate. One or more water-insoluble substances can be used in appropriate combination. Moreover, it is also free to use a plasticizer such as castor oil, dibutyl phthalate, triethyl citrate and the like.

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

  As the composition ratio of the water-insoluble substance and the water-conductivity adjusting substance in the outer layer of the present invention, a ratio suitable for achieving the purpose is selected according to the purpose such as the physical properties of the drug, the absorption site and the type of the preparation. In the pharmaceutical composition particles of the present invention, when the water permeability of the outer layer is high (when the amount of the water-conducting substance to be blended with the water-insoluble substance is large), the gelled swelling substance coated on the intermediate layer is the outer layer. May be rapidly exposed to the oral cavity through the pores, and the viscosity may cause the particles to harden in the oral cavity and stick to the oral mucosa. Accordingly, 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 an amount exceeding 50% by weight. In addition, when the ratio of the water-insoluble substance is lower than 30% by weight, the rate of water intrusion into the pharmaceutical composition particles cannot be sufficiently controlled, and a sufficiently long lag time cannot be formed. There is concern.

  Also for the coating amount of the outer layer in the present invention, an amount suitable for achieving the object of the present invention is selected. Specifically, it is preferably 5% by weight or more, particularly 7% by weight or more, more preferably 50% by weight or less, particularly preferably 30% by weight, based on the intermediate layer-coated particles obtained by coating the core particles 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. In some cases, it cannot be controlled, and a sufficiently long lag time may not be formed. In addition, there is a possibility that a phenomenon of adhesion of particles to the oral cavity may occur. Moreover, when there is too much coating amount, the rapid drug release after lag time may not be achieved.

  The blending amount of solifenacin and / or a salt thereof in the pharmaceutical composition particles is not particularly limited. Preferably, it is 0.5% by weight or more of the whole pharmaceutical composition particle, and is preferably 80% by weight or less, particularly preferably 70% by weight or less, and further preferably 60% by weight or less. However, the amount of solifenacin and / or a salt thereof shown here is an example that can be applied to the present invention, and should not be interpreted in a limited manner.

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

  The pharmaceutical composition particles with masked unpleasant taste according to the present invention are particularly useful as microparticles 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 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 particles of the present invention can be produced using various pharmaceutical additives used as commonly used additives. Examples of the pharmaceutical additive include a corrigent, a sweetener, a fragrance, a colorant, a stabilizing agent, an antioxidant, a pH adjuster, a solubilizer, a solubilizer, a fluidizer, and a buffer. However, it is not limited to these.

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

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

  In the first method for producing the pharmaceutical composition particles of the present invention, the core layer containing solifenacin and / or a salt thereof is coated with the intermediate layer and the outer layer. As the core particle containing solifenacin and / or a salt thereof, a particle consisting only of solifenacin and / or a salt thereof can be used, or one or two of solifenacin and / or a salt thereof can be used using a known technique. You may manufacture the particle | grains which consist of the above additive, and may use the particle | grains. The particles comprising solifenacin and / or a salt thereof and an additive may be mixed with, for example, solifenacin and / or a salt thereof and an appropriate excipient (for example, crystalline cellulose, lactose, corn starch, etc.), and a binder may be added as necessary. The dissolved solution may be added, granulated, sized and dried. In addition, with a fluidized bed coating device, etc., a solution in which a drug and a binder are dissolved or dispersed in an additive particle (for example, crystalline cellulose (particle), purified sucrose spherical particle, mannitol spherical particle, etc.) serving as an appropriate core is sprayed. And may be manufactured.

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

  When using pharmaceutical composition particles for the production of orally disintegrating tablets, the average particle size of the pharmaceutical composition particles is usually desired to be about 100 to 200 μm. In order to coat the intermediate layer and the outer layer to about 100 to 200 μm while the substantially spherical core particles remain in a spherical shape, the average particle diameter of the substance used suspended in the solution used for coating is It is necessary to have a particle size of 1/10 or less 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 grind and cannot be easily miniaturized. Then, the present inventors diligently studied about the pulverization method, and found that pulverization with a jet mill can efficiently pulverize to a target particle size. Moreover, it discovered that it could grind | pulverize efficiently also by the wet crushing method.

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

  As described above, the first method for producing pharmaceutical composition particles according to the present invention includes a pulverization step of pulverizing a gelled swelling substance to an average particle size of 15 μm or less, and a gelled swelling substance pulverized in the pulverization step. A suspension step in which the suspension is obtained by suspending in an organic solvent, and the suspension obtained in the suspension step is sprayed onto the core particles containing solifenacin and / or a salt thereof to form an intermediate layer outside the core particles. It is preferable to include an intermediate layer forming step for forming and an outer layer forming step for forming an outer layer by coating a water-insoluble substance on the outer side of the intermediate layer.

  The organic solvent is preferably ethanol.

  In the second method for producing pharmaceutical composition particles of the present invention, core particles containing a gelled swelling substance are coated with an intermediate layer and an outer layer containing a drug.

  When only the gelled swelling substance is used as the core particle, the simple particles of the gelled swelling substance can be procured from the market. It is preferable to use the particles having a diameter of about 50 to 300 μm as the core particles as they are. However, it goes without saying that the gelled swelling substance alone or particles comprising the gelled swelling substance and one or more additives can be produced and used as core particles.

  When using a particle (core) that does not contain a gelled swelling substance as a core particle, the average particle diameter of the gelled swelling substance on the core particle is preferably 15 μm or less, More preferably, it is 10 μm or less. An example of a method for producing core particles is a pulverization step of pulverizing a gelled swelling substance to an average particle size of 15 μm or less, and a suspension obtained by suspending the gelled swelling substance pulverized in the pulverization step in an organic solvent. And a step of spraying the suspension obtained in the suspending step onto a nucleus that does not contain the gelled swelling substance to form a layer of the gelled swelling substance on the outside of the nucleus. The organic solvent used in the suspending step is preferably ethanol, and water may be added as long as the suspension is not inhibited. Hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and copolyvidone that are widely used as binders , Macrogol, ethylcellulose, polyvinyl acetal diethylaminoacetate, hydroxypropylmethylcellulose, hypromellose phthalate, etc. can be formulated and dissolved at the same time. Of course, it goes without saying that the formulation method can be devised using only water as a solvent.

  As a method of coating an intermediate layer containing solifenacin and / or a salt thereof on a core particle, or a method of coating an outer layer containing a water-insoluble polymer on an intermediate layer, a fluidized bed coating device, a rolling coating device, a centrifugal It is preferable to employ a method of coating with a machine that is widely used for coating the particulate composition, such as a rolling coating device. For example, a necessary amount of a liquid containing a coating component may be sprayed with a spray gun while flowing the core particles or intermediate layer coated particles to be coated in a rolling fluidized bed coating apparatus. The liquid containing the coating component is prepared by dissolving or dispersing essential components or the like in a solvent such as water, ethanol, methanol, or the like, and these solvents can be used by appropriately mixing them. Needless to say, the coating method of these layers is not limited to the wet method.

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

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

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

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

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

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

The drug substance used in the experiment is as follows. Hydroxypropylmethylcellulose 2910 (TC-5E, viscosity: 3 mPa · s, S value: 434, Shin-Etsu Chemical), carmellose sodium (cellogen PR-S, viscosity: 28 mPa · s, S value: 1101.11, Daiichi Kogyo) Pharmaceutical), carmellose sodium (cellogen F-SC, viscosity: 400 mPa · s, S value: 2073.91, Daiichi Kogyo Seiyaku), carmellose sodium (Branose 7M1F-PH, average particle size 245 μm, viscosity: 100 mPa · s) , S value: 1624.14, Ashland), sodium alginate (Kimika argin IL-6, viscosity: 67 mPa · s ^*) , S value: 2225.58, Kimika), hydroxypropyl cellulose (HPC-L, viscosity: 6- 10 mPa · s, S value: 589.67, Nippon Soda), ethyl cellulose (Etocel STD7, Dow Chemical), talc (FL108, Fuji talc), crystalline cellulose (grain) (Selfia CP102, Asahi Kasei Chemicals), crystalline cellulose (grain) (Selfia CP203, Asahi Kasei Chemicals), D-mannitol (160C, rocket) Japan), D-mannitol (Mannit Q, Mitsubishi Foodtech), crystalline cellulose (KG-802, Asahi Kasei Chemicals), crospovidone (Polyplastdone XL-10, Ashland), magnesium stearate (Taihei Chemical Industry), tartaric acid ( Wako Pure Chemical Industries). The viscosity indicated by ^*) is the viscosity of the 1% liquid, and the other is the viscosity of the 2% liquid.

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

  Serogen F-5A having an S value of 613 will be described. Since the volume of an aqueous solution in which 10 g of serogen F-5A is mixed and dissolved in 100 g of water is 106 mL, the volume of the aqueous solution of serogen F-5A is 106 mL. The volume corresponds to 6 mL. Therefore, an aqueous solution in which 100 g of Serogen F-5A and 613 g of water are added has a volume of 673 mL, a viscosity of 1900 to 2100 mPa · s, and a water absorption swelling ratio of 11.2 times. Moreover, when the same experiment was conducted for TC-5E, 1 g of TC-5E corresponds to a volume of 0.9 mL in an aqueous solution. Therefore, TC-5E aqueous solution of 434 g of water in TC-5E100 g has a volume of 524 mL. Thus, the viscosity is 1900-2100 mPa · s, and the water absorption swelling ratio is 5.8 times.

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

[Example 1]
A waterproofing membrane solution is prepared by suspending 6.25g of talc in a solution obtained by dissolving 6.25g of etosel STD-7 in 237.5g 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 etosel STD-7 and 4 g of TC-5E are taken and dissolved in a mixture of 608 g of ethanol and 152 g of purified water to prepare an outer layer solution.
Carmellose sodium (Branose 7M1F-PH, average particle size: 245 μm, viscosity: 100 mPa · s, S value: 1624.14, Ashland) on a tumbling fluid type coating granulator (manufactured by Paulec Co., Ltd .: MP-01 type) ) Was sprayed and coated with 250 g of the waterproof membrane solution while stirring and flowing, and dried to produce waterproof membrane-coated particles. 200 g of the waterproof membrane-coated particles were put into a rolling fluid type coating granulator (MP-01 type), and 500 g of the drug coating solution was sprayed, coated and dried while stirring and flowing to produce drug-coated particles.
Next, 200 g of the drug-coated particles were put into a rolling fluid type coating granulator (MP-01 type), and 800 g of the outer layer solution was spray-coated while being stirred and flowed, and dried to obtain outer layer-coated particles.

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

  Next, the drug layer is a core particle containing solifenacin and / or a salt thereof, and the gelled swelling substance layer is an intermediate layer containing a water-soluble gelling swelling substance and covering the outside of the core particle, 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 outer side of the intermediate layer.

[Example 3]
A drug coating solution is prepared by suspending 20 g of talc in a solution of 10 g of solifenacin succinate, 25 g of TC-5E, and 7 g of tartaric acid and dissolved in a mixture of 375 g of ethanol and 375 g of purified water. Refinement of carmellose sodium (cellogen PR-S, viscosity: 28 mPa · s, S value: 1101.11, Daiichi Kogyo Seiyaku) in a solution of 20 g of HPC-L dissolved in a mixture of 630 g of ethanol and 70 g of purified water An intermediate layer solution is prepared by suspending 60 g of powder (having been pulverized with jet mill and sieved with a mesh to obtain an average particle diameter of 5 μm). Etocel STD-7 39.6 g and TC-5E 4.4 g are taken and dissolved in a mixed solution of ethanol 704 g and purified water 176 g to prepare an outer layer solution.
200 g of crystalline cellulose (Selfia CP102) was added to a tumbling fluid type coating granulator (MP-01 type), and 812 g of the drug coating solution was sprayed, coated and dried while stirring and flowing to produce drug coated particles. 200 g of the drug-coated particles were put into a rolling fluid coating granulator (MP-01 type), and 780 g of the intermediate layer solution was sprayed, coated and dried while stirring and flowing to produce intermediate layer coated particles.
Next, 220 g of the intermediate layer coated particles were put into a tumbling fluid type coating granulator (MP-01 type), and 924 g of the outer layer solution was spray-coated while being stirred and flowed, and dried to obtain outer layer coated particles.

[Example 4]
A drug coating solution is prepared by suspending 160 g of talc in a solution of 80 g of solifenacin succinate, 200 g of TC-5E, 56 g of tartaric acid, and dissolved in a mixture of 3000 g of ethanol and 3000 g of purified water. Refinement of carmellose sodium (cellogen F-SC, viscosity: 400 mPa · s, S value: 2073.91, Daiichi Kogyo Seiyaku Co., Ltd.) in a solution of 20 g of HPC-L dissolved in a mixture of 630 g of ethanol and 70 g of purified water An intermediate layer solution is prepared by suspending 60 g of powder (having been pulverized with jet mill and sieved with a mesh to obtain an average particle diameter of 5 μm). Etocel STD-7 39.6 g and TC-5E 4.4 g are taken and dissolved in a mixed solution of ethanol 704 g and purified water 176 g to prepare an outer layer solution.
200 g of crystalline cellulose (Selfia CP102) was put into a tumbling fluid type coating granulator (MP-01 type), 6496 g of drug coating solution was sprayed, coated and dried while being stirred and flowed to produce drug coated particles. 200 g of the drug-coated particles were put into a rolling fluid coating granulator (MP-01 type), and 780 g of the intermediate layer solution was sprayed, coated and dried while stirring and flowing to produce intermediate layer coated particles.
Next, 220 g of the intermediate layer coated particles were put into a tumbling fluid type coating granulator (MP-01 type), and 924 g of the outer layer solution was spray-coated while being stirred and flowed, and dried to obtain outer layer coated particles.

[Comparative Example 1]
In place of carmellose sodium used in Example 1, crystalline cellulose (CP203: average particle size 230 μm) of approximately the same size was used, and a waterproof membrane solution, a drug coating solution and an outer layer solution were obtained in the same manner as in Example 1. The outer layer coated particles of Comparative Example 1 were obtained by spray coating and drying.

[Comparative Example 2]
In the formulation and production method shown in Example 3, the drug-coated particles were produced by not coating the gelled swelling substance layer (intermediate layer), that is, by spraying, coating and drying crystalline cellulose (Selfia CP102) with a drug coating solution. 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 gelled swelling material (Serogen PR-S) used in Example 3, hydroxypropylmethylcellulose 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 to obtain outer layer coated particles of Comparative Example 3.

[Test example]
For the particles obtained in Examples 1 to 4 and Comparative Examples 1 to 3, the following dissolution test and evaluation of unpleasant taste shielding were performed.

[Test Example 1: Dissolution test]
An outer layer-coated fine particle containing 5 mg of solifenacin succinate was taken, and an elution test was conducted according to the second method of the Japanese Pharmacopoeia using an automatic 6-ellution tester (manufactured by Toyama Sangyo Co., Ltd.). As a test solution, 900 mL of Japanese Pharmacopoeia dissolution test second solution was used. Note that the rotational speed of the paddle is 50 rpm or 100 rpm. For samples with a particularly strong tendency to aggregate in the test solution, 100 rpm was employed. The results of the dissolution test are shown in Table 1.

[Test Example 2: Evaluation of unpleasant taste shielding properties]
The taste of the outer layer coated particles containing solifenacin succinate was evaluated according to the following evaluation method and evaluation criteria. The results are shown in Table 2.
<Evaluation method>
Four healthy adult males (Panels 1 to 4) contained outer-layer coated particles containing 5 mg of solifenacin succinate in an amount equivalent to 2 minutes, then spit it out and evaluated the unpleasant taste after 1 and 2 minutes did. Solifenacin succinate is a drug with a strong bitter as well as astringent taste.
<Evaluation criteria for unpleasant taste>
-: Does not feel unpleasant taste ±: Slightly tastes but is acceptable +: Feels unpleasant taste ++: Feels unpleasant taste strongly

  Regarding all the samples of Examples 1 to 4, no unpleasant taste that causes problems such as bitterness and astringent taste is felt even 2 minutes after being put in the mouth, and a clear unpleasant taste suppressing effect is obtained. It was. Further, in the dissolution test, the dissolution rate was 80% or more after 15 to 30 minutes, and it had drug release characteristics that expected rapid and sufficient expression of efficacy.

  On the other hand, the outer layer coated particles of Comparative Example 1 produced by the same method as Example 1 using core particles having the same size as carmellose sodium used in Example 1 and not corresponding to the gelled swelling substance Although an unpleasant taste was not felt after 2 minutes, in the dissolution test, it was found that even after 60 minutes, the drug release was about 50% and sufficient drug efficacy could not be expected. The same core particles as in Example 3 were used, the drug was coated in the same manner as in Example 3, and the particles in Comparative Example 2 in which the intermediate layer was not coated and the outer layer was directly coated with a water penetration amount control layer In addition, a plurality of panelists felt an unpleasant taste, and even in a dissolution test, it was not possible to expect sufficient drug efficacy. Moreover, although the particle | grains of the comparative example 3 which used TC-5E with a weak water absorption swelling power as a gelatinization swelling substance are masked unpleasant taste, since the gelation swelling power is weak, the ability to denature an outer layer However, 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 that it partially changed to a crystalline body, and when it was a halo peak, it was evaluated that the amorphous state was maintained. 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 crystalline.

[Example 5]
43.85 g of the outer layer-coated particles produced in Example 4, 30.2 g of D-mannitol (160C), 3.36 g of mannit Q, 9 g of crystalline cellulose (KG-802), crospovidone (Polyplastdone XL-10) ) And 2.7 g of magnesium stearate, and using tableting particles that had been sufficiently mixed, tablets with a tableting pressure of 5 kN and a diameter of 7.5 mm (corner plane) and a weight of 150 mg were produced. When this tablet was contained in the oral cavity, it disintegrated within 30 seconds and did not feel an unpleasant taste that was problematic for about 2 minutes.

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

Claims (11)

A drug layer containing solifenacin and / or a salt thereof;
A gelled swelling substance layer containing a water-soluble gelling swelling substance;
Pharmaceutical composition particles comprising an outer layer containing a water-insoluble substance and covering the drug layer and the gelled swelling substance layer. The drug layer is a core particle containing solifenacin and / or a salt thereof,
The gelled swelling substance layer is an intermediate layer that contains a water-soluble gelling swelling substance and covers the outside of the core particles,
The pharmaceutical composition particle according to claim 1, wherein the outer layer is an outer layer containing a water-insoluble substance and covering the outer side of the intermediate layer. The gelled swelling substance layer is a core particle containing a water-soluble gelling swelling substance,
The drug layer is an intermediate layer that contains solifenacin and / or a salt thereof and covers the outside of the core particle,
The pharmaceutical composition particle according to claim 1, wherein the outer layer is an outer layer containing a water-insoluble substance and covering the outer side of the intermediate layer.   The pharmaceutical composition particle 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 of the total weight of the outer layer.   The pharmaceutical composition particle according to any one of claims 1 to 4, wherein the gelled swelling substance has a swelling power (S) value of 500 or more.   The pharmaceutical composition particle according to any one of claims 1 to 5, wherein the gelled swelling substance has a viscosity at 25 ° C of a 2% aqueous solution of 4 mPa · s or more.     The coating amount of the outer layer is 5 wt% or more and 50 wt% or less with respect to the intermediate layer coated particles in which the core particles are coated with the intermediate layer. Pharmaceutical composition particles.   The pharmaceutical composition particle according to any one of claims 1 to 7, wherein the solifenacin and / or a salt thereof is in an amorphous form.   An orally disintegrating tablet comprising the pharmaceutical composition particle according to any one of claims 1 to 8. A pulverizing step of pulverizing the gelled swelling substance to an average particle size of 15 μm or less;
A suspension step of suspending the gelled swelling substance pulverized in the pulverization step in an organic solvent to obtain a suspension;
An intermediate layer forming step of spraying the suspension obtained in the suspension step onto the drug-containing core particles to form an intermediate layer outside the core particles;
An outer layer forming step of forming an outer layer by coating a water-insoluble substance on the outer side of the intermediate layer.   The method for producing pharmaceutical composition particles according to claim 10, wherein the organic solvent is ethanol.