WO2015129893A1 - Pharmaceutical composition for oral administration - Google Patents

Abstract

Provided is a single pharmaceutical preparation consisting of a controlled release portion comprising mirabegron or a pharmaceutically acceptable salt thereof and a rapid release portion comprising solifenacin or a pharmaceutically acceptable salt thereof. The production of analogs of each drug during storage is controlled for the single pharmaceutical preparation, and changes in the mirabegron elution rate during storage are controlled for the single pharmaceutical preparation such that the single pharmaceutical composition can be used in a clinical setting. This pharmaceutical composition for oral administration contains: (1) a controlled release portion which comprises mirabegron or a pharmaceutically acceptable salt thereof; and (2) a rapid release portion which comprises solifenacin or a pharmaceutically acceptable salt thereof, and a pharmaceutical additive for improving the stability of the mirabegron or a pharmaceutically acceptable salt thereof.

Description

Pharmaceutical composition for oral administration

The present invention includes mirabegron or a pharmaceutically acceptable salt thereof, a release controlling part for controlling this release, and solifenacin or a pharmaceutically acceptable salt thereof for immediate release for prompt release. The present invention relates to a pharmaceutical composition for oral administration.
Specifically, the present invention relates to 1) a controlled release portion comprising 1) mirabegron or a pharmaceutically acceptable salt thereof, a macromolecular substance forming a hydrogel, and a hydrophilic base, and 2) a) solifenacin or a thereof. Oral administration comprising a pharmaceutically acceptable salt and b) an immediate release part containing mirabegron or a pharmaceutical additive that improves the stability of the pharmaceutically acceptable salt in a single preparation. The present invention relates to a pharmaceutical composition for use.

Mirabegron is a compound represented by the following chemical structural formula, and mirabegron or a pharmaceutically acceptable salt thereof has a β3 adrenergic receptor agonistic action and is useful as a therapeutic agent for overactive bladder. Known (Patent Document 1, Patent Document 2, Patent Document 3).

In addition, tablets containing mirabegron are sold as therapeutic agents for overactive bladder.

It has been reported that the pharmacokinetics fluctuates depending on the presence or absence of food intake in clinical trials conducted at the development stage of mirabegron (Patent Document 4). If the pharmacokinetics fluctuates depending on the presence or absence of food intake, it naturally affects its action and effect. In particular, in the case of pharmaceuticals, if an effect that is different from the prediction is generated, an unexpected situation may be caused, so that it is necessary to be able to predict a certain effect. Therefore, there is a strong demand for the development of drugs that minimize the fluctuations in pharmacokinetics with and without food intake. The changes in pharmacokinetics with and without food intake in mirabegron are related to drug release using various additives. It is known that it can be reduced by control (Patent Document 4).

Solifenacin is a compound represented by the following chemical structural formulas, solifenacin or a pharmaceutically acceptable salt thereof has a selective antagonistic action against muscarine M ₃ receptors, various disease prevention and / or It is known to be useful as a therapeutic agent (Patent Document 5).

Tablets containing solifenacin succinate as solifenacin or a pharmaceutically acceptable salt thereof are sold as a therapeutic agent for overactive bladder.

Pharmaceutical composition containing mirabegron or a pharmaceutically acceptable salt thereof for improving urinary urgency, frequent urination and / or urinary incontinence associated with overactive bladder, and solifenacin or a pharmaceutically acceptable salt thereof An invention relating to a pharmaceutical composition containing a salt and a combination thereof is disclosed (Patent Document 6).

In addition, tamsulosin or a pharmaceutically acceptable salt thereof, a release control part containing a hydrophilic substance and a polymer material forming a hydrogel, solifenacin or a pharmaceutically acceptable salt thereof and a hydrophilic substance A pharmaceutical composition for oral administration is known that contains a rapid-release part in a single preparation (Patent Document 7).

In addition, a stable particulate pharmaceutical composition using solifenacin or a salt thereof and a specific binder, a method for producing the same, an orally disintegrating tablet containing the particulate pharmaceutical composition, and the stability of the particulate pharmaceutical composition A technique related to the conversion method is known (Patent Document 8). This technique is an invention relating to a stable particulate pharmaceutical composition of solifenacin or a salt thereof.

International Publication No. 2004/041276 International Publication No. 99/20607 International Publication No. 03/037881 International Publication No. 2010/038690 International Publication No. 96/20194 International Publication No. 2009/057685 International Publication No. 2010/090172 International Publication No. 2006/070735

An object of the present invention is to provide a single preparation comprising a controlled-release part containing mirabegron or a pharmaceutically acceptable salt thereof and an immediate-release part containing solifenacin or a pharmaceutically acceptable salt thereof ( Providing a single formulation (mixture) that suppresses the generation of related substances during storage of each drug, and suppresses changes in the dissolution rate of mirabegron during storage. Is to provide a single preparation (mixture).

The inventors first described the controlled release pharmaceutical composition comprising mirabegron described in Example 10 of Patent Document 4 and (2) immediate release part of Example 1 of Patent Document 7, A single preparation (bilayer tablet) was prepared using the same component as the immediate-release part containing solifenacin succinate (Comparative Example 1 described later).
When the dissolution test was performed on the obtained bilayer tablet, [1] the dissolution rate of solifenacin was unexpectedly less than 85% in 15 minutes, and [2] the maximum dissolution rate of solifenacin was less than 90%. I knew. If the elution rate or maximum elution rate of solifenacin is reduced, the in vivo utilization rate (bioavailability) will be reduced, and as a result, the same pharmacology as when each current formulation (single agent) is used in combination. There is a concern that the effective effect cannot be obtained. In providing a single preparation (mixture), tableting troubles such as lamination and sticking, and coloring of the immediate release part during storage were also observed. The inventors have intensively studied and found that the above-mentioned problems can be solved by blending calcium stearate into the immediate-release part containing solifenacin succinate (Reference Example 1 described later), and filed a patent application. (PCT / JP2013 / 077351, International Publication No. 2014/034860). The solubility of solifenacin succinate in water is 610 mg / mL, the solubility in the second solution of the Japanese Pharmacopoeia Dissolution Test (pH 6.8) is 430 mg / mL, and the solubility expression of the Japanese Pharmacopoeia is expressed as succinic acid. Solifenacin is classified as a substance that is easily soluble in neutral solvents such as water.

Further, when the stability test was performed on the obtained bilayer tablet under open conditions, [3] the formation of solifenacin succinate and mirabegron related substances, [4] the dissolution rate of mirabegron changed during storage I found out.
With respect to the finding [3], it is more preferable to suppress the generation of related substances during storage under open conditions.
Regarding the finding [4], when the elution rate of mirabegron is changed, there is a possibility that the utilization rate in the living body (bioavailability) may be changed.

Therefore, the present inventors surprisingly conducted a further diligent study focusing on the suppression of mirabegron and solifenacin succinate related substance generation, and the suppression of the change in the dissolution rate of mirabegron from the release control part during storage. (A) Preventing the generation of mirabegron-related substances contained in the release control part by increasing the crystallinity of the pharmaceutical additive contained in the immediate-release part (including the seed crystal (seed crystal) formulation) What can be done, (b) prevent changes in the dissolution rate of mirabegron contained in the release control part by increasing the crystallinity of the pharmaceutical additive contained in the immediate release part (including the seed crystal (seed crystal) formulation) Knowing that it is possible, the present invention has been completed. It has also been found that the same effect can be obtained by adding a water-soluble polymer to the immediate release part.

That is, the present invention
[1] (1) A controlled release part containing mirabegron or a pharmaceutically acceptable salt thereof, (2) solifenacin or a pharmaceutically acceptable salt thereof, and mirabegron or a pharmaceutically acceptable salt thereof A pharmaceutical composition for oral administration, comprising an immediate release part containing a pharmaceutical additive that improves the stability of the salt,
[2] The pharmaceutical composition for oral administration according to [1], wherein the pharmaceutical additive that improves the stability of mirabegron or a pharmaceutically acceptable salt thereof is a crystalline saccharide and / or a water-soluble polymer.
[3] The pharmaceutical composition for oral administration according to [1] or [2], wherein the pharmaceutical additive that improves the stability of mirabegron or a pharmaceutically acceptable salt thereof is a crystalline saccharide,
[4] The blending ratio of the pharmaceutical additive that improves the stability of mirabegron or a pharmaceutically acceptable salt thereof is about 0.3% by weight or more and about 99% by weight or less with respect to the weight of the immediate release part. , A pharmaceutical composition for oral administration of any one of [1] to [3],
[5] The pharmaceutical composition for oral administration according to any one of [1] to [4], wherein the pharmaceutical additive that improves the stability of mirabegron or a pharmaceutically acceptable salt thereof is a crystalline reducing sugar,
[6] The pharmaceutical composition for oral administration according to any one of [1] to [5], wherein the pharmaceutical additive that improves the stability of mirabegron or a pharmaceutically acceptable salt thereof is crystalline maltose,
[7] The pharmaceutical composition for oral administration according to any one of [1] to [6], further comprising calcium stearate in the immediate release part,
[8] The pharmaceutical composition for oral administration according to any one of [1] to [7], wherein the release control part comprises a polymer substance that forms a hydrogel,
[9] The pharmaceutical composition for oral administration according to [8], wherein the polymer substance forming the hydrogel has an average molecular weight of about 100,000 or more, or a 5% aqueous solution at 25 ° C. having a viscosity of 12 mPa · s or more,
[10] One or more polymers selected from the group consisting of polyethylene oxide, hypromellose, hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, and carboxyvinyl polymer as the polymer material forming the hydrogel A pharmaceutical composition for oral administration of [9], which is a substance,
[11] The pharmaceutical composition for oral administration according to [10], wherein the polymer substance forming the hydrogel is polyethylene oxide,
[12] The oral administration according to any one of [8] to [11], wherein the blending ratio of the polymer substance forming the hydrogel is about 1 wt% or more and about 70 wt% or less with respect to the weight of the release controlling part. Pharmaceutical composition for
[13] The pharmaceutical composition for oral administration according to any one of [1] to [12], wherein the release control part further comprises an additive for allowing water to enter the inside of the release control part,
[14] The pharmaceutical composition for oral administration according to [13], wherein the additive for allowing water to enter the inside of the release control part has a solubility in which the amount of water dissolving 1 g is 10 mL or less,
[15] The ratio of the additive for causing water to enter the inside of the release control unit is about 5% by weight or more and about 75% by weight or less based on the weight of the release control unit. A pharmaceutical composition for oral administration;
[16] The pharmaceutical composition for oral administration according to any of [1] to [15], wherein the pharmaceutical composition is a pharmaceutical composition for improving urgency, frequent urination and / or urinary incontinence associated with overactive bladder ,
[17] The pharmaceutical composition for oral administration according to any one of [1] to [16], wherein the pharmaceutical composition is a tablet,
[18] The pharmaceutical composition for oral administration according to any one of [1] to [17], wherein the tablet is a multilayer tablet,
[19] The pharmaceutical composition for oral administration according to any one of [1] to [18], wherein the tablet is a bilayer tablet,
[20] (1) A layer containing mirabegron or a pharmaceutically acceptable salt thereof, and (2) a layer containing solifenacin or a pharmaceutically acceptable salt thereof, and a crystalline saccharide and / or a water-soluble polymer. A pharmaceutical composition for oral administration comprising
[21] (1) A layer containing mirabegron or a pharmaceutically acceptable salt thereof, and (2) a layer containing solifenacin or a pharmaceutically acceptable salt thereof, and a crystalline sugar and / or a water-soluble polymer. Or a pharmaceutical composition for oral administration, comprising mirabegron or a water-soluble polymer thereof according to (2) solifenacin or a pharmaceutically acceptable salt thereof. A method of stabilizing a pharmaceutically acceptable salt,
Is to provide.

According to the present invention, a single preparation comprising a controlled release part containing mirabegron or a pharmaceutically acceptable salt thereof and an immediate release part containing solifenacin or a pharmaceutically acceptable salt thereof ( (Combinations) can be provided to clinical sites, and a single formulation (combination) that suppresses the formation of related substances during storage of each drug can be provided, and changes in the dissolution rate of mirabegron during storage It is possible to provide a single preparation (mixture) that suppresses the above. Furthermore, by blending calcium stearate in the immediate-release part containing solifenacin or a pharmaceutically acceptable salt thereof, a single formulation (similar formulation having a rapid release of solifenacin compared to the current formulation (single agent)) A mixture) can be provided.

In order to examine the crystallization state of maltose contained in the solifenacin succinate layer of the pharmaceutical composition for oral administration (bilayer tablet) prepared in Example 1 and Reference Example 1, the solifenacin succinate layer was subjected to differential scanning calorimetry analysis. It is a DSC curve which shows the result of (DSC analysis). The mirabegron-related substance relative to the total amount of mirabegron-related substance in the 0% crystalline maltose preparation after storing the oral pharmaceutical composition (bilayer tablet) prepared in Test Example 7 at 40 ° C. and 75% relative humidity for 2 weeks. It is a figure which shows the relationship between the ratio of a total amount, and the content rate of a crystalline maltose among the maltose contained in a quick release part. The mirabegron-related substance relative to the total amount of mirabegron-related substance in the 0% crystalline maltose preparation after the oral pharmaceutical preparation (bilayer tablet) prepared in Test Example 7 was stored at 40 ° C. and 75% relative humidity for 1 month. It is a figure which shows the relationship between the ratio of a total amount, and the content rate of a crystalline maltose among the maltose contained in a quick release part.

Hereinafter, embodiments of the present invention will be described in detail.
In the present specification, “single agent” means an embodiment of a preparation containing one kind of drug.

In this specification, “single preparation” is also called “mixture” and means an embodiment of a preparation containing two or more kinds of drugs in the same preparation. The case where preparations having different functions relating to release characteristics are included in the same preparation, such as the release control section and the rapid release section in the present invention, also corresponds to a single preparation. As an embodiment of the “single preparation”, for example, a two-layer tablet in which a release control part and an immediate release part are laminated, a multilayer tablet in which a plurality of quick release parts and release control parts are laminated, a release control part and an immediate release Multi-layer tablets such as a three-layer tablet with a drug-free layer added between them, a dry-coated tablet with a release control part in the inner core and an immediate release part in the outer layer, and a quick release to the core tablet of the release control part Examples thereof include a film-coated tablet having a free part film-coated. Another embodiment includes a bilayer tablet.

In the present specification, the “release control part” means a part that controls the release of a drug contained in a single preparation.

In this specification, the “rapid release part” means a part contained in a single preparation that releases drug from a pharmaceutical composition quickly (in the case of a substance that is easily soluble, almost coincides with elution). . Rapid release (elution) means that drug release is not controlled.

In the present specification, “to improve the stability of mirabegron or a pharmaceutically acceptable salt thereof” refers to preservation of a pharmaceutical composition for oral administration containing mirabegron or a pharmaceutically acceptable salt thereof. In other cases, it means "suppressing the production of a related substance of mirabegron or a pharmaceutically acceptable salt thereof during storage", and in another aspect, "change in the dissolution rate of mirabegron from the release control part" Means to suppress.

In the present specification, “suppressing the production of mirabegron or a pharmaceutically acceptable salt related substance thereof during storage” means that the amount of the related substance of the drug is the amount indicated in the guidelines on the impurities of the preparation. It means that the amount does not exceed. Specifically, based on the concept regarding related substances (impurities) in pharmaceutical preparations described in Pharmaceutical Examination No. 0624001 published by the Ministry of Health, Labor and Welfare, “Revision of Guidelines on Impurities of Pharmaceuticals Containing New Active Ingredients” Among the related substances contained in mirabegron or its pharmaceutically acceptable salts, the one with the highest percentage (peak area) (maximum related substance) is 0.5% or less, solifenacin or its pharmaceutically acceptable It means that the percentage (peak area) of the maximum related substance of the salt to be produced is 1.0% or less. For example, after storing the pharmaceutical composition for oral administration under the following conditions, the related substances contained in the pharmaceutical composition for oral administration are defined as an embodiment having a specific percentage or less.

For the percentage of the maximum related substance of mirabegron or a pharmaceutically acceptable salt thereof (for example, mirabegron), for example, a pharmaceutical composition for oral administration is abbreviated to 40 ° C. and 75% relative humidity (hereinafter referred to as% RH). In some cases, the sample is stored for one month under open conditions, and then measured by a high performance liquid chromatography method (hereinafter sometimes abbreviated as HPLC method). The percentage of the maximal analog of mirabegron or a pharmaceutically acceptable salt thereof in the pharmaceutical composition for oral administration is, for example, 0.5% or less, in some embodiments 0.3% or less, and in other embodiments 0. It is defined as 18% or less. Specifically, the maximum related substance of mirabegron or a pharmaceutically acceptable salt thereof is specifically determined by measuring the peak area of each related substance contained in the pharmaceutical composition for oral administration by the HPLC method. Is defined as the substance having the highest percentage of the salt and its related substances to the total peak area.

In addition, regarding the total amount of mirabegron or a pharmaceutically acceptable salt thereof (for example, mirabegron), for example, after storing the pharmaceutical composition for oral administration for 1 month under 40 ° C. and 75% RH release condition, Measured by HPLC method. It is defined that the total amount of related substances of mirabegron or a pharmaceutically acceptable salt thereof in a pharmaceutical composition for oral administration is, for example, 1.5% or less, and in one embodiment, 1% or less.

Regarding stability test conditions, in addition to the above 40 ° C./75% RH open condition for 1 month, the conditions of 2 months, 3 months, or 6 months under the same conditions can also be adopted. Moreover, it can select and set suitably from the conditions from 1 month to 24 months or 36 months on 25 degreeC and 60% RH open | release conditions. Further, for example, the evaluation can be performed at 70 ° C. for 9 days (open condition or bottle-sealed condition) so that the evaluation can be performed in a short time. In this case, the evaluation of “stable” in this specification is judged to be scientifically valid, for example, so that the conditions correspond thermodynamically to the results of 40 ° C., 6 months, and storage conditions. For example, an extrapolation method may be used.

Specifically, the maximum related substance of solifenacin or a pharmaceutically acceptable salt thereof (for example, solifenacin succinate) is specifically determined by measuring the peak area of each related substance contained in a pharmaceutical composition for oral administration by HPLC. , Solifenacin or a pharmaceutically acceptable salt thereof and related substances are defined as substances having the highest ratio to the total peak area.
Regarding the total amount of solifenacin or a pharmaceutically acceptable salt thereof (for example, solifenacin succinate), for example, a pharmaceutical composition for oral administration was stored for 1 month under 40 ° C. and 75% RH open conditions. Thereafter, it is measured by the HPLC method.

In the present specification, “inhibiting the change in the dissolution rate of mirabegron from the release control unit during storage” means to reduce the change in the dissolution rate of mirabegron from the release control unit, more specifically, It means to reduce the difference between the dissolution rate after storage and the dissolution rate before storage. For example, a pharmaceutical composition for oral administration is stored at 40 ° C. and 75% RH for 1 month, and then the second method of Japanese Pharmacopoeia dissolution test (paddle method, 50 to 200 rpm, test solution is USP pH 6.8 phosphate) This means that the change in elution rate after 1.5 hours (difference between elution rate after storage and elution rate before storage) is 6% or less before and after storage when the elution test is carried out according to buffer 900mL) To do. As another aspect, it means that the change in dissolution rate after 2.5 hours is 11% or less before and after storage. As another aspect, it means that the change in elution rate after 4.5 hours is 9% or less before and after storage. In one embodiment, the pharmaceutical composition for oral administration is stored at 40 ° C. and 75% RH for one month, then the second method of Japanese Pharmacopoeia dissolution test (paddle method, 200 rpm, test solution is USP pH 6.8 phosphorus) The change in elution rate after 1.5 hours (difference between the elution rate after storage and the elution rate before storage) when the elution test is carried out according to the acid buffer (900 mL) is 6% or less before and after storage. means. As another aspect, it means that the change in dissolution rate after 2.5 hours is 11% or less before and after storage. As another aspect, it means that the change in elution rate after 4.5 hours is 9% or less before and after storage.

In the present specification, the “crystalline saccharide” means a crystalline saccharide in a final preparation produced through a preparation process.
The term “crystal” saccharide means a saccharide having a crystallographic crystal structure. The embodiment includes an amorphous saccharide together with a crystalline saccharide within a range that does not affect the stability of mirabegron or a pharmaceutically acceptable salt thereof. The term “amorphous” saccharide means a saccharide that does not have a crystallographic structure (a saccharide having an amorphous structure).

The crystal state can be measured by, for example, a differential scanning calorimeter analysis (DSC analysis) method, a powder X-ray diffraction method, a solid-state NMR method, a near infrared spectroscopy (NIR) method, and the like.
For example, in the case of crystalline maltose, it can be measured by the differential scanning calorimeter analysis (DSC analysis) method as follows. Differential scanning calorimetry analysis (DSC analysis) is performed using, for example, an EXSTAR6000 series DSC6220 manufactured by Seiko Instruments Inc. Approximately 5 mg of the sample is filled in a dedicated aluminum sample pan, and the measurement range is set to room temperature to 160 ° C under a nitrogen atmosphere (20 mL / min), and the sample and reference (empty aluminum sample are set at a heating rate of 10 ° C / min. Continuously measure and record the change in heat generated between Note that handling of devices including data processing follows the method and procedure instructed by each device. A crystal maltose having an endothermic peak in the range of about 125 ° C. ± 5 ° C. when measured under the above conditions is defined. The crystallinity of maltose is calculated from the peak area ratio with 20 mJ / mg as 100%.

Similarly, for crystallization detection methods other than the DSC analysis method, for example, solid NMR method or near infrared spectroscopy (NIR) method, for solid NMR method, for example, AVANCE 400 Bruker, for near infrared spectroscopy (NIR) method, For example, MPA Bruker can be used for each.

The pharmaceutical composition for oral administration of the present invention is described in detail below.
Solifenacin or a pharmaceutically acceptable salt thereof used in the present invention can be easily obtained, for example, by the method described in Patent Document 5 or by production according thereto.

Solifenacin can form a pharmaceutically acceptable salt with an acid in addition to a free form that does not form a salt. Examples of such salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid And acid addition salts with organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, and glutamic acid. As one embodiment, succinate can be mentioned. These salts can be produced by conventional methods.

Solifenacin or salts thereof pharmaceutically acceptable, have selective antagonistic action against muscarine M ₃ receptors are useful as therapeutic agents for overactive bladder.

The dose of solifenacin in administration of a single preparation (mixture) is appropriately determined according to individual cases in consideration of symptoms, age of administration, sex and the like. In the case of solifenacin succinate, it is usually about 0.01 mg or more and 100 mg or less per day in the case of oral administration, and this is administered once a day or divided into 2 to 4 times.

The blending ratio of solifenacin or a pharmaceutically acceptable salt thereof is not particularly limited as long as it is a therapeutically or prophylactically effective amount. As such a blending ratio, for example, it is 0.5% by weight or more and 85% by weight or less with respect to the weight of the quick release part. As a further embodiment, it is 0.5 wt% or more and 10 wt% or less. The amount of solifenacin or a pharmaceutically acceptable salt thereof is 0.01 mg or more and 100 mg or less in the whole preparation, and in another embodiment, 0.5 mg or more and 50 mg or less. 5 mg or more and 20 mg or less, yet another embodiment is 0.5 mg or more and 10 mg or less, and yet another embodiment is 2.5 mg, 5 mg or 10 mg.

The “rapid release part” in the present invention indicates the elution rate and / or maximum elution rate of solifenacin from the immediate release part as described below.
In the present specification, the “maximum dissolution rate” refers to, as one aspect, a dissolution test under certain conditions, and the dissolution rate when the drug dissolution rate from the pharmaceutical composition has leveled off. It means the dissolution rate after a certain period of time (for example, after 60 minutes).

The elution rate of solifenacin from the immediate-release part of the present invention is not particularly limited as long as it shows an in vivo utilization rate equivalent to that of the current formulation (single agent) of solifenacin. For example, Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method, 50 rpm to 200 rpm), Japanese Pharmacopoeia Dissolution Test Method 1 (Rotating Basket Method, 50 rpm to 200 rpm), US Pharmacopoeia Dissolution Test (Paddle Method), US Pharmacopoeia When testing by dissolution test (rotating basket method), etc. (1) After 15 minutes, the drug elutes 85% or more, as another aspect, 90% or more elutes, (2) After 30 minutes Elution of 90% or more of the drug, 95% or more of the elution as another embodiment, (3) elution of 90% or more of the drug after 60 minutes, or 95% or more of the elution as another embodiment In yet another embodiment, it is specified that 97% or more is eluted. Another aspect of the test method is the Japanese Pharmacopoeia dissolution test method 1 (rotating basket method, 100 rpm, test solution is water or USP pH 6.8 phosphate buffer, 900 mL).
The elution rate of solifenacin from the immediate release part is defined by combining one or more kinds of regulations from the provisions of (1), (2) and (3).

The maximum elution rate of solifenacin from the immediate-release part of the present invention is not particularly limited as long as it shows an in vivo use rate equivalent to that of the current formulation (single agent) of solifenacin. For example, Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method, 50 rpm to 200 rpm), Japanese Pharmacopoeia Dissolution Test Method 1 (Rotating Basket Method, 50 rpm to 200 rpm), US Pharmacopoeia Dissolution Test (Paddle Method), US Pharmacopoeia When the test is performed by a dissolution test (rotating basket method) or the like, the drug dissolution rate after 60 minutes is specified. As another embodiment, the dissolution rate of the drug after 60 minutes when the test is performed by the Japanese Pharmacopoeia First Method (Rotating Basket Method, 100 rpm, test solution is water or USP pH 6.8 phosphate buffer, 900 mL) It is prescribed by. As the maximum elution rate in the rapid release part, for example, the drug elution rate after 60 minutes is 90% or more, and in another aspect, the drug elution rate is defined as 92% or more. In another embodiment, the drug dissolution rate is 95% or more, and in another embodiment, the drug dissolution rate is defined as 97% or more.

Examples of pharmaceutical additives that improve the stability of mirabegron or a pharmaceutically acceptable salt thereof used in the immediate release part of the present invention include crystalline saccharides and / or water-soluble polymers.

Crystalline saccharide means a crystalline saccharide in the final preparation produced through the formulation process. The formulation process includes grinding, mixing, granulation, molding, and film coating as described later, but even if crystalline saccharide is used as a raw material, it may be included in the final formulation as amorphous saccharide. .

The crystalline saccharide is not particularly limited as long as the crystalline saccharide is measured in the final preparation and improves the stability of mirabegron or a pharmaceutically acceptable salt thereof. Specific examples include crystalline maltitol, crystalline erythritol, crystalline xylitol, crystalline maltose, crystalline lactose, crystalline sucrose, crystalline glucose, crystalline sorbitol, crystalline trehalose, crystalline lactitol, crystalline fructose, crystalline arabinose, and the like. . As one embodiment, crystalline maltitol, crystalline erythritol, crystalline xylitol, etc., which are saccharides having strong crystallinity can be mentioned. Other embodiments include saccharides that crystallize by making it dry after humidification, etc., such as crystalline maltose, crystalline lactose, crystalline sucrose, crystalline glucose, crystalline sorbitol, crystalline trehalose, crystalline lactitol, crystalline fructose, etc. Can be mentioned. Another embodiment includes crystalline maltose, crystalline glucose, crystalline fructose, crystalline arabinose and the like, which are crystalline reducing sugars. Moreover, crystal maltose is mentioned as another aspect.

The water-soluble polymer is not particularly limited as long as it improves the stability of mirabegron or a pharmaceutically acceptable salt thereof. For example, polyethylene glycol, hydroxypropyl cellulose, and polyvinyl pyrrolidone can be given as certain embodiments. As another embodiment, hydroxypropyl cellulose can be mentioned.

The water-soluble polymer is not particularly limited as long as it has a viscosity and molecular weight that can be used as a binder and can provide a single preparation in which the dissolution profile of solifenacin is not different from that of a single agent.

As the viscosity of the water-soluble polymer, for example, the viscosity of a 2% aqueous solution (20 ° C.) is 1 mPa · s or more and 20 mPa · s or less, and in one embodiment, the viscosity of a 2% aqueous solution (20 ° C.) is 2 mPa · s. It is 10 mPa · s or less.

The molecular weight of the water-soluble polymer is, for example, not less than 4000 and not more than 100,000.

Examples of the polyethylene glycol include PEG 4000, PEG 6000, PEG 20000 (trade name, manufactured by NOF Corporation), and Polyglycol 8000PF (trade name, manufactured by Clariant).
Examples of hydroxypropyl cellulose include HPC-SSL (trade name, manufactured by Nippon Soda Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: 2.0-2.9 mPa · s), HPC-SL (trade name, Nippon Soda Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: 3.0-5.9 mPa · s), HPC-L (trade name, manufactured by Nippon Soda Co., Ltd.) (2% aqueous solution at 20 ° C. Viscosity: 6.0 to 10.0 mPa · s).
Examples of polyvinylpyrrolidone include PVP K30 (trade name, manufactured by BASF).

These pharmaceutical additives can be contained, for example, as excipients and / or binders in the immediate release part. These pharmaceutical additives can be used alone or in combination of two or more.

The blending ratio of the pharmaceutical additive for improving the stability of mirabegron or a pharmaceutically acceptable salt thereof contained in the immediate release part is, for example, 0.3% by weight or more and 99% by weight with respect to the weight of the immediate release part. It is 1 weight% or more and 99 weight% or less as another embodiment. Or, for example, 0.01 wt% or more and 99 wt% or less, 0.1 to 50 wt% or less as another embodiment, and 0.5 to 50 wt% as a further embodiment with respect to the total weight of the preparation. % Or less. In still another embodiment, it is 1% by weight to 50% by weight. Or, for example, 1% by weight or more and 100% by weight or less, 3% by weight or more and 100% by weight or less, and 5% by weight as a further aspect with respect to the weight of mirabegron or a pharmaceutically acceptable salt thereof. It is 100 wt% or less, in another embodiment, 10 wt% or more and 100 wt% or less, and in still another embodiment, 20 wt% or more and 100 wt% or less.

When a pharmaceutical additive that improves the stability of mirabegron or a pharmaceutically acceptable salt thereof contained in the immediate-release part is used as an excipient, the blending ratio is, for example, relative to the weight of the immediate-release part 50 wt% or more and 99 wt% or less, in another embodiment, 70 wt% or more and 95 wt% or less, and in another embodiment, 80 wt% or more and 95 wt% or less.
The blending ratio when a pharmaceutical additive that improves the stability of mirabegron or a pharmaceutically acceptable salt thereof contained in the immediate release part is used as a binder is, for example, relative to the weight of the immediate release part 1 wt% or more and 30 wt% or less, in another embodiment, 1 wt% or more and 20 wt% or less, and in another embodiment, 1 wt% or more and 15 wt% or less.
When the pharmaceutical additive that improves the stability of mirabegron or a pharmaceutically acceptable salt thereof contained in the immediate release part is a crystalline saccharide, the blending ratio of the crystalline saccharide is mirabegron or a pharmaceutically acceptable salt thereof. There is no particular limitation as long as it does not affect the stability of the salt. For example, among the saccharides contained in the pharmaceutical composition of the present invention, the proportion of crystalline saccharide is 5% by weight or more and 100% by weight or less, in one embodiment, 10% by weight or more and 100% by weight or less, and in another embodiment, 20% by weight or more and 100% by weight or less. It is 30 weight% or less and 100 weight% or less as a further aspect.

In the present invention, calcium stearate can be blended in the quick release part. The calcium stearate contained in the quick release part in the present invention is not particularly limited as long as it conforms to the standards of Japanese Pharmacopoeia, US Pharmacopoeia or European Pharmacopoeia. An example is Parteck (registered trademark) LUB CST (trade name, manufactured by MERCK).

The blending ratio of calcium stearate is, for example, from 0.1% by weight to 10% by weight with respect to the weight of the immediate release part, and as another aspect, from 0.5% by weight to 3.0% by weight. In another embodiment, it is 0.5 wt% or more and 2.0 wt% or less, and in another embodiment, it is 0.5 wt% or more and 1.5 wt% or less. Or it is 0.05 weight% or more and 6 weight% or less with respect to the weight of the whole preparation, and is 0.2 weight% or more and 1 weight% or less as another aspect.

Mirabegron or a pharmaceutically acceptable salt thereof used in the release control unit of the present invention can be easily obtained by, for example, the method described in Patent Document 2 or a method similar thereto.

Mirabegron can form pharmaceutically acceptable salts with acids in addition to the free form that does not form salts. Examples of such salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid And acid addition salts with organic acids such as fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, and glutamic acid. As a certain aspect, the free body which does not form a salt can be mentioned. These salts can be produced by conventional methods.

Mirabegron or a pharmaceutically acceptable salt thereof has a β3 adrenergic receptor agonistic action and is useful as a therapeutic agent for overactive bladder.

The dosage of mirabegron or a pharmaceutically acceptable salt thereof in a single preparation (mixture) is appropriately determined according to individual cases in consideration of symptoms, age of the subject, sex, etc. In general, in the case of oral administration, it is about 0.01 mg or more and 100 mg or less per day for an adult, and this is administered once or divided into 2 to 4 times.

The blending ratio of mirabegron or a pharmaceutically acceptable salt thereof is, for example, 1% by weight or more and 70% by weight or less with respect to the weight of the controlled release part, and in another embodiment, 5% by weight or more and 70% by weight or less. As an aspect of this, it is 5 to 50 weight%. The blending amount of mirabegron or a pharmaceutically acceptable salt thereof is 1 mg to 500 mg in the whole preparation, 10 mg to 200 mg as another aspect, and 25 mg or 50 mg as another aspect.

As the “release control unit” in the present invention, for example, according to the United States Pharmacopoeia dissolution test method (paddle method), an appropriate test solution 900 mL (for example, USP pH 6.8 phosphate buffer solution) is used, and the paddle rotation speed is 100 rotations. Rotate the paddle using 900 mL of an appropriate test solution (eg USP pH 6.8 phosphate buffer solution or pH 6.8 Mc.Ilvain buffer solution) under the conditions of / min (rpm) or Japanese Pharmacopoeia Dissolution Test Method 2. In a dissolution test carried out under conditions of several 50 rpm to 200 rpm, the drug dissolution rate from the drug product was less than 85% 30 minutes after the start of the test, and the drug release was controlled to such an extent that the effect of food intake was reduced. It is a formulation. More specifically, in a dissolution test conducted using 900 mL of USP pH 6.8 phosphate buffer solution under the condition of a paddle rotation speed of 200 rpm, from the preparation 30 minutes after the start of the test or 1.5 hours after the start of the test. The drug dissolution rate is less than 85%.

Specifically, for example, as one embodiment, a preparation comprising a combination of a drug (mirabegron or a pharmaceutically acceptable salt thereof) and a polymer substance that forms a hydrogel, or a drug (mirabegron or a pharmaceutically acceptable salt thereof) An acceptable salt), an additive (hydrophilic base) for allowing water to penetrate into the preparation, and a polymer substance that forms a hydrogel. In another aspect, the drug (mirabegron or The pharmaceutically acceptable salt), an additive (hydrophilic base) for allowing water to enter the inside of the preparation, and a polymer substance that forms a hydrogel.

The polymer substance forming the hydrogel used in the present invention is not particularly limited as long as it can control the drug release rate to such an extent that the blood concentration profile of the drug is not affected by the presence or absence of food intake. Not.
The molecular weight of the polymer material forming the hydrogel is, for example, 100,000 or more, 100,000 to 8 million as another embodiment, 100,000 to 5 million as another embodiment, and 100,000 as another embodiment. More than 2 million. Alternatively, the viscosity of the polymer material forming the hydrogel is, for example, a 5% aqueous solution (25 ° C.) having a viscosity of 12 mPa · s or higher, and in another aspect, a 5% aqueous solution (25 ° C.) having a viscosity of 12 mPa · s or higher. % Aqueous solution (25 ° C.) has a viscosity of 40,000 mPa · s or less, and in another embodiment, a 2% aqueous solution (25 ° C.) has a viscosity of 400 mPa · s or more and a 1% aqueous solution (25 ° C.) has a viscosity of 7500 mPa · s or less. As a mode, the viscosity of a 2% aqueous solution (25 ° C.) is 400 mPa · s or more and the viscosity of a 1% aqueous solution (25 ° C.) is 5500 mPa · s or less.

Examples of the polymer substance forming the hydrogel used in the present invention include polyethylene oxide, hypromellose, hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, and carboxyvinyl polymer. Other embodiments include polyethylene oxide, hypromellose, and hydroxypropyl cellulose. Another embodiment includes polyethylene oxide.

Examples of the polyethylene oxide (hereinafter sometimes abbreviated as PEO) include, for example, trade name Polyox WSR-308 [average molecular weight: 8 million, viscosity: 10,000-15000 mPa · s (1% aqueous solution 25 ° C.)], Polyox WSR- 303 [average molecular weight: 7 million, viscosity: 7500-10000 mPa · s (1% aqueous solution 25 ° C.)], Polyox WSR Coagulant [average molecular weight: 5 million, viscosity: 5500-7500 mPa · s (1% aqueous solution 25 ° C.)], Polyox WSR-301 [average molecular weight: 4 million, viscosity: 1650-5500 mPa · s (1% aqueous solution 25 ° C.)], Polyox WSR-N-60K [average molecular weight: 2 million, viscosity: 2000-4000 mPa · s (2%) Aqueous solution 25 ° C)], Polyo WSR-N-12K [average molecular weight: 1 million, viscosity: 400-800 mPa · s (2% aqueous solution 25 ° C.)], Polyox WSR-1105 [average molecular weight: 900,000, viscosity: 8800-17600 mPa · s (5% aqueous solution) 25 ° C)], Polyox WSR-205 [average molecular weight: 600,000, viscosity: 4500-8800 mPa · s (5% aqueous solution 25 ° C)], Polyox WSR-N-750 [average molecular weight: 300,000, viscosity: 600-1200 mPa S (5% aqueous solution 25 ° C.)], Polyox WSR-N-80 [average molecular weight: 200,000, viscosity: 55-90 mPa · s (5% aqueous solution 25 ° C.)], Polyox WSR-N-10 [average molecular weight: 100,000, viscosity: 12-50 mPa · s (5% aqueous solution 25 ° C.)] (manufactured by DOW).

Examples of hypromellose (hereinafter sometimes abbreviated as HPMC) include, for example, trade name Metroze 90SH50000 [viscosity of 2% aqueous solution at 20 ° C .: 2900-3900 mPa · s], Metrose SB-4 (trade name, Shin-Etsu Chemical Co., Ltd.) Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: about 4 mPa · s), TC-5RW (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: about 6 mPa · s) TC-5S (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: about 15 mPa · s), TC-5R (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (20 ° C. TC-5M (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: about 4.5 mPa · s), TC-5 (Trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: about 3 mPa · s), Metrose 60SH-50 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (2% at 20 ° C. Viscosity of aqueous solution: about 50 mPa · s), Metroze 65SH-50 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: about 50 mPa · s), Metroze 90SH-100 (trade name, (Manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: about 100 mPa · s), Metrows 90SH-100SR (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: About 100 mPa · s), Metroze 65 SH-400 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: about 400 mPa · s), Metroze 90 H-400 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: about 400 mPa · s), Metrose 65SH-1500 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (20 ° C. Viscosity of 2% aqueous solution at about 1500 mPa · s), Metrows 60SH-4000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: about 4000 mPa · s), Metrows 65SH-4000 ( (Trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: about 4000 mPa · s), Metroles 90SH-4000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (2% aqueous solution at 20 ° C. Viscosity of about 4000 mPa · s), Metrolose 90SH-4000SR (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C. : Metrology 90SH-15000SR (trade name, Shin-Etsu Chemical Co., Ltd.) (Viscosity of 2% aqueous solution at 20 ° C .: about 15000 mPa · s), Metrows 90SH-15000SR (trade name, Shin-Etsu Chemical Co., Ltd.) (Made by Co., Ltd.) (Viscosity of 2% aqueous solution at 20 ° C .: about 15000 mPa · s), Metrows 90SH-30000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (Viscosity of 2% aqueous solution at 20 ° C .: about 30000 mPa · s) s).

Examples of hydroxypropylcellulose (hereinafter sometimes abbreviated as HPC) include, for example, HPC-SSL (trade name, manufactured by Nippon Soda Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: 2.0-2.9 mPas). S), HPC-SL (trade name, manufactured by Nippon Soda Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: 3.0-5.9 mPa · s), HPC-L (trade name, Nippon Soda Co., Ltd.) (Viscosity of 2% aqueous solution at 20 ° C .: 6.0-10.0 mPa · s), HPC-M (trade name, manufactured by Nippon Soda Co., Ltd.) (Viscosity of 2% aqueous solution at 20 ° C .: 150- 400 mPa · s), HPC-H (trade name, manufactured by Nippon Soda Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: 1000-4000 mPa · s).

Examples of methylcellulose (hereinafter, sometimes abbreviated as MC) include Metroze SM15 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: about 15 mPa · s), Metrouse SM25 ( Trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: about 25 mPa · s), Metrows SM100 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C. : About 100 mPa · s), Metrows SM400 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20 ° C .: about 400 mPa · s), Metrows SM 1500 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (Viscosity of 2% aqueous solution at 20 ° C .: about 1500 mPa · s), Metrows SM4000 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (20 2% viscosity of aqueous solution at: about 4000 mPa · s) and the like.

Examples of sodium carboxymethyl cellulose (hereinafter sometimes abbreviated as CMCNa) include, for example, trade name Sunrose F-30MC [viscosity: 250-350 mPa · s (1% aqueous solution 25 ° C.)], Sunrose F-150MC [average Molecular weight: 200,000, viscosity: 1200-1800 mPa · s (1% aqueous solution 25 ° C)], Sunrose F-600MC [viscosity: 6000-8000 mPa · s (1% aqueous solution 25 ° C)], Sunrose F-1000MC [average Molecular weight: 420,000, Viscosity: 8000-12000 mPa · s (1% aqueous solution 25 ° C.)], Sunrose F-1400MC [Viscosity: 12000-15000 mPa · s (1% aqueous solution 25 ° C.)], Sunrose F-300MC [Average Molecular weight: 300,000, Viscosity: 2500-3000 mPa · s (1% aqueous solution at 25 ° C.) (Manufactured by Nippon Paper Industries) and the like.

Examples of hydroxyethyl cellulose (hereinafter sometimes abbreviated as HEC) include, for example, trade name HEC Daicel SE850 [average molecular weight: 1,480,000, viscosity: 2400-3000 mPa · s (1% aqueous solution 25 ° C.)], HEC Daicel SE900 [ Average molecular weight: 1,560,000, viscosity: 4000-5000 mPa · s (1% aqueous solution 25 ° C.)] (manufactured by Daicel Chemical Industries).

Examples of the carboxyvinyl polymer include Carbopol 940 (average molecular weight of about 2.5 million, manufactured by BF Goodrich Chemical).

These polymer substances forming the hydrogel can be used alone or in combination of two or more. Further, different lots may be used in combination.
The mixing ratio of the polymer substance that forms the hydrogel is not particularly limited as long as the blood concentration profile of the drug is not affected by the presence or absence of food intake, but for example, relative to the weight of the release control unit 1% by weight or more and 70% by weight or less, in another aspect, 3% by weight or more and 70% by weight or less, and in another aspect, 5% by weight or more and 70% by weight or less, and in another aspect, 10% by weight or more and 60% by weight or less. It is 10 wt% or more and 40 wt% or less. Or 1% by weight to 45% by weight relative to the total weight of the preparation, in another aspect, 2% by weight or more and 45% by weight or less, and in another aspect, 3% by weight or more and 45% by weight or less, As an aspect, it is 5 to 35 weight%, and as another aspect, it is 5 to 25 weight%. The blending ratio of the polymer substance forming the hydrogel is 0.1% by weight or more and 1000% by weight or less with respect to the weight of the drug, as another embodiment, 1% by weight or more and 500% by weight or less, and as another embodiment 5 % By weight or more and 300% by weight or less.
In addition, even if the viscosity before mixing deviates from the predetermined viscosity range in the present invention, by mixing in combination, when measuring the viscosity before use to show the viscosity within the viscosity range, You may use it combining suitably.

As an additive (hydrophilic base) for allowing water to enter the inside of the release control unit used in the present invention, the amount of water required for dissolving 1 g of the hydrophilic base is 20 ± 5 ° C. 10 mL or less, another embodiment is 6 mL or less, another embodiment is 5 mL or less, and yet another embodiment is 4 mL or less. The higher the solubility in water, the higher the effect of entering water into the preparation.

Examples of such a hydrophilic base include polyethylene glycol [PEG; for example, trade names PEG400, PEG1500, PEG4000, PEG6000, PEG20000 (manufactured by NOF Corporation), Polyglycol 8000PF (manufactured by Clariant)], polyvinylpyrrolidone [PVP; , Trade name PVP K30 (manufactured by BASF)], sugar alcohols such as D-mannitol, D-sorbitol, xylitol; lactose, sucrose, anhydrous maltose, D-fructose, dextran (eg, dextran 40), Sugars such as glucose; polyoxyethylene hydrogenated castor oil [HCO; for example, Cremophor RH40 (manufactured by BASF), HCO-40, HCO-60 (manufactured by Nikko Chemicals)], polyoxyethylene polyoxy Surfactants such as propylene glycol [eg Pluronic F68 (Asahi Denka Co., Ltd.)], polyoxyethylene sorbitan higher fatty acid ester [Tween; eg Tween 80 (Kanto Chemical)]; salts such as sodium chloride and magnesium chloride; citric acid, Examples include organic acids such as tartaric acid; amino acids such as glycine, β-alanine, and lysine hydrochloride; and amino sugars such as meglumine.
As other embodiments, PEG, PVP, D-mannitol, D-sorbitol, xylitol, lactose, sucrose, anhydrous maltose, D-fructose, dextran, glucose, polyoxyethylene polyoxypropylene glycol, sodium chloride, magnesium chloride, citric acid , Tartaric acid, glycine, β-alanine, lysine hydrochloride, meglumine. Another embodiment includes PEG, PVP, D-mannitol, lactose, sucrose, sodium chloride, polyoxyethylene polyoxypropylene glycol. Yet another embodiment includes PEG.

These hydrophilic bases can be used alone or in combination of two or more.
The blending ratio of the hydrophilic base is not particularly limited as long as the drug release can be controlled to such an extent that it is not affected by food intake. For example, it is 5% by weight or more and 75% by weight or less with respect to the weight of the release control part. Or it is 3 weight% or more and 44 weight% or less with respect to the weight of the whole preparation, as another aspect, it is 3 weight% or more and 40 weight% or less, and as another aspect, it is 12 weight% or more and 35 weight% or less.

In the release control part of the present invention, an antioxidant may be blended. The antioxidant is not particularly limited as long as the influence of elution behavior can be avoided. For example, dibutylhydroxytoluene (BHT), propyl gallate (PG), butylhydroxyanisole (BHA), ascorbic acid, sodium ascorbate, erythorbic acid, sodium nitrite, sodium bisulfite, sodium pyrosulfite, citric acid, edetic acid Sodium is mentioned, BHT, PG, sodium ascorbate is mentioned as another aspect, and BHT is mentioned as another aspect.

These antioxidants can be appropriately added in an appropriate amount, alone or in combination of two or more.
The blending ratio of the antioxidant is, for example, 0.025 wt% or more and 0.25 wt% or less with respect to the weight of the release control unit. Or as another aspect, it is 0.015 weight% or more and 0.15 weight% or less with respect to the weight of the whole formulation.

The stabilizer in the present invention may contain a stabilizer. The stabilizer is not particularly limited as long as it does not change the drug release characteristics over time when polyethylene oxide is used as the polymer substance forming the hydrogel. For example, yellow iron sesquioxide, red iron sesquioxide, black iron oxide and the like can be mentioned.

These stabilizers can be appropriately added in an appropriate amount, alone or in combination. The blending ratio of the stabilizer is 0.05% by weight or more and 1% by weight or less with respect to the weight of the release control part. Or as another aspect, it is 0.03 weight% or more and 0.6 weight% or less with respect to the weight of the whole formulation.

In the pharmaceutical composition for oral administration of the present invention, various pharmaceutical additives are appropriately used and formulated as long as the desired effect of the invention is achieved. Such a pharmaceutical additive is not particularly limited as long as it is pharmaceutically acceptable and pharmacologically acceptable. For example, an excipient, a binder, a disintegrant, a sour agent, a foaming agent, a sweetener, a fragrance, a colorant, a buffer, an antioxidant, a surfactant and the like are used.

Examples of excipients include starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and metasilicate aluminum. Examples include magnesium acid.
Examples of the binder include gum arabic, hypromellose, hydroxyethyl cellulose and the like.

Examples of the disintegrant include corn starch, potato starch, carmellose calcium, carmellose sodium, and low-substituted hydroxypropylcellulose.
Examples of the sour agent include citric acid, tartaric acid, malic acid and the like.
Examples of the foaming agent include sodium bicarbonate.
Examples of the sweetener include saccharin sodium, glycyrrhizic acid, aspartame, stevia, thaumatin and the like.
Examples of the fragrances include lemon, lemon lime, orange, menthol and the like.

Examples of the colorant include food yellow No. 4, No. 5, food red No. 3, No. 102, food blue No. 3, and the like.
Buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid , Boric acid or a salt thereof.
Examples of the surfactant include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.

These pharmaceutical additives can be appropriately added in an appropriate amount by combining one or more kinds.
Regarding the blending ratio, any pharmaceutical additive is used in an amount within the range in which the desired effect of the present invention is achieved.

As the pharmaceutical composition (formulation) for oral administration of the present invention, a single preparation (mixture) produced by a method known per se, for example, a layer containing mirabegron or a pharmaceutically acceptable salt thereof and solifenacin or a combination thereof And a pharmaceutical composition for oral administration comprising a layer containing a pharmaceutically acceptable salt. In another embodiment, a bilayer tablet in which a layer containing mirabegron or a pharmaceutically acceptable salt thereof and a layer containing solifenacin or a pharmaceutically acceptable salt thereof are laminated, mirabegron or a pharmaceutically acceptable salt thereof A multi-layered tablet comprising a plurality of layers containing a salt that is allowed to be adsorbed and a layer containing solifenacin or a pharmaceutically acceptable salt thereof, a layer containing mirabegron or a pharmaceutically acceptable salt thereof, and solifenacin or a combination thereof A multilayer tablet such as a three-layer tablet in which a layer not containing a drug is added between a layer containing a pharmaceutically acceptable salt and a release control unit containing mirabegron or a pharmaceutically acceptable salt thereof in the inner core And having a rapid release part containing solifenacin or a pharmaceutically acceptable salt thereof in the outer layer, or solifenacin or a core tablet of a controlled release part containing mirabegron or a pharmaceutically acceptable salt thereof. A pharmaceutically acceptable coating the immediate release portion containing salts were film-coated tablets, and the like. Another embodiment includes a bilayer tablet in which a layer containing mirabegron or a pharmaceutically acceptable salt thereof and a layer containing solifenacin or a pharmaceutically acceptable salt thereof are laminated.

The layer containing mirabegron or a pharmaceutically acceptable salt thereof is selected from the group consisting of a polymer substance forming a hydrogel, a hydrophilic base, an antioxidant, a stabilizer and a pharmaceutical additive. A seed or two or more substances may be contained. As said substance, the above-mentioned substance can be used, respectively.

The layer containing solifenacin or a pharmaceutically acceptable salt thereof may contain one or more substances selected from the group consisting of excipients, binders, calcium stearate and pharmaceutical additives. As said substance, the above-mentioned substance can be used, respectively.

Below, the manufacturing method of the pharmaceutical composition for oral administration of this invention is described in detail.
The pharmaceutical composition for oral administration of the present invention can be produced by appropriately combining methods known per se.
(1) Pulverization / mixing step The pulverization step is not particularly limited as long as it is a method that can pharmaceutically pulverize drugs and appropriate pharmaceutical additives. Examples of the pulverizer include a hammer mill, a ball mill, a jet pulverizer, and a colloid mill. The grinding conditions are not particularly limited as long as they are appropriately selected.
The mixing step of each component continuous with the pulverization is not particularly limited to any device or means as long as it is a method that can generally uniformly mix each component pharmaceutically.

(2) Release control unit: granulation step There are no particular limitations on the apparatus and means of the step as long as it is a method capable of granulating a polymer substance or the like that forms a hydrogel.
Examples of the granulation method and apparatus include high-speed stirring granulation method, pulverization (pulverization) granulation method, fluidized bed granulation method, extrusion granulation method, rolling granulation method, spray granulation method, or those granulation methods Examples include an apparatus used by the method. Another aspect is a fluidized bed granulation method / apparatus, and another aspect is a rolling fluidized bed granulation method / apparatus. It can also be dried after granulation. The drying method is not particularly limited as long as it is a method that can be usually pharmaceutically dried.

(3) Rapid release part: granulation step There are no particular limitations on the apparatus and means of the step as long as it is a method capable of granulating drugs and the like.
As a production method and apparatus, for example, fluidized bed granulation method, melt granulation method, high speed stirring granulation method, crushing (pulverization) granulation method, extrusion granulation method, rolling granulation method, spray granulation method, Examples thereof include dry granulation methods and apparatuses used by these methods. Another embodiment is a fluidized bed granulation method / apparatus.

As the binder used in the wet granulation method, one kind or two or more kinds can be used in appropriate combination.
In the case of the spray granulation method, it can be dried after granulation. The drying method is not particularly limited as long as it is a pharmaceutically drying method.
Specifically, for example, water is used as a binder solution for solifenacin or a pharmaceutically acceptable salt thereof, or for a mixture of solifenacin or a pharmaceutically acceptable salt thereof and a pharmaceutical additive. Or when the crystal saccharide is dissolved in water and the solution is sprayed as a binder solution, all or part of the saccharide may exist in an amorphous state after drying. When all or part of the saccharide in the preparation is present in an amorphous state after drying, the saccharide in the amorphous state in the preparation is crystallized by a crystallization step of saccharide such as humidification drying described later. Can be

When the crystalline saccharide is dissolved in water and the solution is sprayed as a binder solution, the crystalline saccharide is seeded by adding solifenacin or a pharmaceutically acceptable salt thereof and the crystalline saccharide. As a result, crystallization of saccharides in an amorphous state can be promoted. When blending seed crystals (seed crystals), the product temperature of the granulated product during granulation is not particularly limited.

On the other hand, when a seed crystal (seed crystal) is not blended, sugars can be crystallized by controlling the product temperature of the granulated product during granulation described later to a specific temperature range. At this time, the product temperature of the granulated product during granulation is not particularly limited as long as it is a product temperature at which sugars crystallize. Specifically, for example, it is 30 ° C. or lower, as one embodiment, 20 ° C. or higher and 30 ° C. or lower, and as another embodiment, 25 ° C. or higher and 30 ° C. or lower. As the product temperature is lower, the saccharide is more easily crystallized, and therefore the crystallization of the saccharide in the granulated product can be adjusted by adjusting the temperature.

Other conditions such as the spray rate of the binding liquid can be adjusted as appropriate as long as the product temperature of the granulated product during granulation can be maintained.
Even when granulation exceeds the above-mentioned product temperature during granulation, crystallization of sugar proceeds by spraying water so that the above-mentioned product temperature is maintained after spraying of the binding liquid is completed. It can also be made.
Examples of the apparatus used in the granulation method for maintaining a specific product temperature of the granulated product in the granulation process include a fluidized bed granulator, a spray granulator, and a rolling fluidized bed granulator. Etc. Specific examples include a multiplex manufactured by Paulek, a GPCG manufactured by Glatt, and a flow coater manufactured by Freund Corporation.

(4) Molding step There are no particular limitations on the device and means of the step as long as it is a method for molding the pharmaceutical composition for oral administration of the present invention. For example, a method of directly compressing and molding a tablet after mixing a drug and appropriate pharmaceutical additives without granulation / drying process, a method of granulating and mixing a lubricant and then compressing and manufacturing a tablet , A method of stacking a release control part and a quick release part to make a two-layer tablet, a method of stacking a plurality of release control parts and a quick release part to make a multilayer tablet, and between a release control part and a quick release part And a method for producing a multi-layered tablet having a drug-free layer added thereto, a method for producing a dry-coated tablet having a release control part in the inner core and an immediate release part in the outer layer. As another embodiment, a method for producing a bilayer tablet can be mentioned.

Examples of the tableting device include a rotary stacked tableting machine and an oil press.
The tableting conditions such as tableting pressure are not particularly limited as long as the tableting pressure can produce a bilayer tablet and / or a multilayer tablet. For example, when preparing a two-layer tablet, the first-layer granulated product and the second-layer granulated product are laminated and compressed at about 2 to about 20 kN. In another embodiment, the first-layer granulated product is about 0. It is prepared by compressing at 1 to about 10 kN, then laminating the second granulation and compressing at about 2 to about 20 kN. In the case of a multi-layered tablet, the tableting pressure can be appropriately adjusted and compressed.
The hardness of the tableted product is not particularly limited as long as it does not break during the manufacturing process or the distribution process. An example is 40 to 200N.

(5) Film coating process You may film-coat on the tablet surface after tableting.
The method is not particularly limited as long as it is usually a pharmaceutically coating method. Examples thereof include pan coating and dip coating.
The film coating agent can be appropriately added in an appropriate amount by combining one kind or two or more kinds. The coating rate is not particularly limited as long as it is a rate for forming a film. For example, it is 1 to 10% by weight relative to the weight of the whole preparation.

When a core tablet containing a release control part is coated with a rapid release part to produce a film-coated tablet, a spray solution in which the components of the rapid release part are dissolved and / or dispersed in a solvent such as water is used. Can be produced by spraying. A film coating rate will not be restrict | limited especially if it is a rate which forms the film formed normally containing a quick release part. For example, it is 1 to 20% by weight relative to the weight of the whole preparation.

It may be dried after film coating. The method is not particularly limited as long as it can be usually pharmaceutically dried. The drying conditions are not particularly limited as long as they are appropriately set in consideration of, for example, the stability of the preparation. The initial moisture value after film coating is preferably 0.1 to 2% in consideration of stability, for example.

(6) Saccharide crystallization step As this step, for example, when the saccharide remains in the granulated product in an amorphous state in the (3) quick release part: granulation step, etc., solifenacin or its There are no particular limitations on the apparatus and means as long as they can crystallize the saccharide in the layer containing a pharmaceutically acceptable salt. For example, a method of humidifying and drying the obtained granulated product, tablet or the like can be mentioned.

In the humidification drying method, “humidification” is determined by the apparent critical relative humidity of the mixture containing sugars, but usually humidifies above the critical relative humidity of the mixture. For example, the humidity is 30 to 100% RH, and in some embodiments, 50 to 90% RH. The temperature at this time is 15 to 50 ° C. in one embodiment, and 20 to 40 ° C. in another embodiment. The humidification time is, for example, 1 to 36 hours, and in one embodiment, 12 to 24 hours.

“Drying” is not particularly limited as long as it is a step of removing moisture absorbed by humidification. Such “drying” is, for example, 1% RH to 40% RH as humidity, and as one embodiment, 20 to 40% RH. The temperature at this time is 10 to 100 ° C. in one embodiment, 20 to 60 ° C. in another embodiment, and 25 to 40 ° C. in another embodiment. The drying time is 0.5 to 5 hours in one embodiment, and 1 to 3 hours in another embodiment.

As an apparatus used in the humidification drying step, for example, a humidification dryer (a constant temperature and humidity machine) manufactured by Espec Corp. may be mentioned.
For example, the obtained granules, tablets, etc. are put into a humidifying dryer (constant temperature and humidity controller), humidified at 20 to 40 ° C. and 50 to 90% RH for 12 to 24 hours, and then 25 to 40 ° C., 20 to 20 ° C. By drying at 40% RH for 1 to 3 hours, saccharides that have become amorphous during granulation can be crystallized.

The pharmaceutical composition for oral administration of the present invention is used, for example, as a pharmaceutical composition for treating urgency, frequent urination and / or urinary incontinence associated with overactive bladder.
The method for producing the pharmaceutical composition for oral administration of the present invention includes a method for producing the pharmaceutical composition by appropriately combining methods known per se in addition to the method described above.

The present invention includes a method for stabilizing mirabegron or a pharmaceutically acceptable salt thereof with crystalline saccharide and / or water-soluble polymer.
For “crystalline saccharide”, “water-soluble polymer”, “mirabegron or a pharmaceutically acceptable salt thereof” used in the stabilization method of the present invention, the description in the pharmaceutical composition for oral administration of the present invention is not changed. Can be applied.

In the stabilization method of the present invention, oral administration comprising a controlled release part containing mirabegron or a pharmaceutically acceptable salt thereof and an immediate release part containing solifenacin or a pharmaceutically acceptable salt thereof. In providing a pharmaceutical composition for use, the stability of mirabegron or a pharmaceutically acceptable salt thereof can be improved by blending a crystalline saccharide and / or a water-soluble polymer with the immediate-release part.
About the compounding quantity of each component, the compounding method, etc. in the stabilization method of this invention, the said description in the pharmaceutical composition for oral administration of this invention and its manufacturing method is applicable as it is.

The present invention comprises (1) a controlled release part containing mirabegron or a pharmaceutically acceptable salt thereof, and (2) an immediate release part containing solifenacin or a pharmaceutically acceptable salt thereof. Such a pharmaceutical composition for oral administration includes the use of crystalline saccharides and / or water-soluble polymers for a stable pharmaceutical composition for oral administration.
For the “crystalline saccharide”, “water-soluble polymer”, “mirabegron or a pharmaceutically acceptable salt thereof” used in the present invention, the description in the pharmaceutical composition for oral administration of the present invention is applied as it is. be able to.

In the use of the crystalline saccharide and / or water-soluble polymer of the present invention, a controlled release part containing mirabegron or a pharmaceutically acceptable salt thereof, and an immediate release part containing solifenacin or a pharmaceutically acceptable salt thereof In providing a pharmaceutical composition for oral administration comprising, the stability of mirabegron or a pharmaceutically acceptable salt thereof can be improved by blending in the immediate release part.
About the compounding quantity of each component in the use of this invention, a compounding method, the said description in the pharmaceutical composition for oral administration of this invention and its manufacturing method is applicable as it is.

Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples, Reference Examples, and Test Examples, but the present invention is not construed as being limited thereto.

Example 1
(1) Preparation of Release Control Part Mixed Powder 24 kg of mirabegron was replaced with 33.6 kg of polyethylene oxide (POLYOX (registered trademark) N-60K, manufactured by Dow, hereinafter the same), polyethylene glycol 8000 (produced by Polyglycol 8000 PF, manufactured by Clariant, the same applies hereinafter) 57 .4 kg, and hydroxypropylcellulose (HPC-SL, manufactured by Nippon Soda Co., Ltd., the same shall apply hereinafter) 3.6 kg together with a screen mill (Comil, manufactured by QUADRO), and then the pulverized powder is fluidized bed granulator ( (GPCG-120, manufactured by Glatt) and granulated by spraying water. 118.6 kg of the dried granulated product, 0.192 kg of butylhydroxytoluene (dibutylhydroxytoluene, manufactured by MERCK / EMD, the same below) and magnesium stearate (Parteck (registered trademark) LUB MST, manufactured by MERCK, same below) 1.2 kg Were mixed to obtain a release control part mixed powder.

(2) Preparation of quick-release part mixed powder Maltose (San Malto S, manufactured by Sanwa Starch Co., Ltd., the same shall apply hereinafter) 235.2 g was stirred and dissolved in 940.8 g of water to obtain a spray solution. 140 g of solifenacin succinate was charged into a fluidized bed granulator (GPCG-5 / 15, manufactured by Glatt) together with 4012.4 g of mannitol (Pearitol 50C, manufactured by Rocket, the same shall apply hereinafter) and 232.4 g of maltose as a seed crystal. The product was granulated by spraying and then dried. The obtained granulated material is stored for 18 hours at 20 ° C. and 65% relative humidity in a humidifying dryer (constant temperature and humidity machine, manufactured by ESPEC), and then stored for 3 hours at 30 ° C. and 30% relative humidity, and humidified. Dried. 47.6 g of calcium stearate (Parteck (registered trademark) LUB CST, manufactured by MERCK, the same shall apply hereinafter) was mixed with 4620 g of the granulated product after humidification drying to obtain a quick-release part mixed powder. The product temperature of the granulated product during granulation was 40 ° C.

(3) Tableting Two-layer tableting using an oil press tableting machine (Autograph AGS-20KNG, manufactured by Shimadzu Corporation) so that the release control mixed powder 250 mg and the quick-release part mixed powder 166.7 mg per tablet. Thus, a pharmaceutical composition for oral administration (bilayer tablet) of the present invention containing mirabegron 50 mg and solifenacin succinate 5 mg was obtained.

Example 2
(1) Preparation of Release Control Part Mixed Powder A release control part mixed powder was obtained under the same formulation and production conditions as described in Example 1.

(2) Preparation of immediate-release part mixed powder 297.0 g of hydroxypropylcellulose (HPC-SL, manufactured by Nippon Soda) was stirred and dissolved in 3942.0 g of water to obtain a spray solution. 450 g of solifenacin succinate was charged into a fluid bed granulator (GPCG-5 / 15, manufactured by Glatt) together with 14103.0 g of mannitol, and granulated by spraying the spray solution. 153 g of calcium stearate was mixed with 14850 g of the dried granulated material to obtain a quick-release part mixed powder. The product temperature of the granulated product during granulation was 33 ° C.

(3) Tableting Using a two-layer tableting machine (HT-X65-LD-UW / 2L, manufactured by Elizabeth Hatta), the release-controlled mixed powder 250 mg and the quick-release part mixed powder 166.7 mg were tableted into two layers. A pharmaceutical composition for oral administration (bilayer tablet) of the present invention containing 50 mg of mirabegron and 5 mg of solifenacin succinate was obtained.

(4) Film coating Using a film coating machine (Labcoat III tablet coating system, manufactured by O'Hara), the concentration of OPADRY (registered trademark) 03F43159 (manufactured by Colorcon Co., Ltd.) is 10%. Was coated with a solution dissolved and dispersed in purified water to obtain a pharmaceutical composition for oral administration (bilayer tablet) of the present invention.

Reference example 1
(1) Preparation of Release Control Part Mixed Powder A release control part mixed powder was obtained under the same formulation and production conditions as described in Example 1.

(2) Preparation of quick-release part mixed powder 467.6 g of maltose was stirred and dissolved in 1870.4 g of water to obtain a spray solution. 140 g of solifenacin succinate was charged into a fluidized bed granulator (GPCG-5 / 15, manufactured by Glatt) together with 4012.4 g of mannitol, and granulated by spraying the spray solution. 47.6 g of calcium stearate was mixed with 4620 g of the dried granulated product to obtain a quick release part mixed powder. The product temperature of the granulated product during granulation was 40 ° C.

(3) Tableting Under the same production conditions as described in Example 1, a pharmaceutical composition for oral administration (bilayer tablet) containing 50 mg of mirabegron and 5 mg of solifenacin succinate was obtained.

Reference example 2
(1) Preparation of Release Control Part Mixed Powder A release control part mixed powder was obtained in accordance with the formulation described in Table 1 under the same production conditions as described in Example 1.

(2) Preparation of quick release part mixed powder 40.08 g of maltose was stirred and dissolved in 160.32 g of water to obtain a spray solution. Granulation was performed by charging 6.00 g of solifenacin succinate together with 349.92 g of mannitol into a fluid bed granulator (GPCG-01, manufactured by Glatt) and spraying the spray solution. According to the recipe of Table 1, the dried granulated product and calcium stearate were mixed with a pestle and mortar to obtain a quick-release part mixed powder. The product temperature during granulation was 33 ° C.

(3) Tableting Under the same production conditions as described in Example 1, a pharmaceutical composition for oral administration (bilayer tablet) containing 25 mg of mirabegron and 2.5 mg of solifenacin succinate was obtained.

Comparative Example 1
(1) Preparation of Release Control Part Mixed Powder A release control part mixed powder was obtained in accordance with the formulation described in Table 1 under the same production conditions as described in Example 1.

(2) Preparation of quick-release part mixed powder Maltose (41.75 g) was stirred and dissolved in 167 g of water to obtain a spray solution. 12.5 g of solifenacin succinate was charged into a fluidized bed granulator (FLO-01, manufactured by Freund Corporation) together with 358.25 g of mannitol, and granulated by spraying the spray solution. According to the recipe of Table 1, the dried granulated material and magnesium stearate were mixed with a pestle and mortar to obtain a quick-release part mixed powder. The product temperature during granulation was 33 ° C.

(3) Tableting Under the same production conditions as described in Example 1, a pharmaceutical composition for oral administration (bilayer tablet) containing 25 mg of mirabegron and 5 mg of solifenacin succinate was obtained.

Comparative Example 2
(1) Preparation of Release Control Part Mixed Powder A release control part mixed powder was obtained in accordance with the formulation described in Table 1 under the same production conditions as described in Example 1.

(2) Preparation of quick release part mixed powder 40.08 g of maltose was stirred and dissolved in 160.32 g of water to obtain a spray solution. Granulation was performed by charging 6.00 g of solifenacin succinate together with 349.92 g of mannitol into a fluid bed granulator (GPCG-01, manufactured by Glatt) and spraying the spray solution. According to the recipe of Table 1, the dried granulated material and magnesium stearate were mixed with a pestle and mortar to obtain a quick-release part mixed powder. The product temperature during granulation was 33 ° C.

(3) Tableting Under the same production conditions as described in Example 1, a pharmaceutical composition for oral administration (bilayer tablet) containing 25 mg of mirabegron and 2.5 mg of solifenacin succinate was obtained.

Example 3
(1) Preparation of Release Control Part Mixed Powder A release control part mixed powder was obtained according to the formulation described in Table 2 under the same production conditions as described in Example 1.

(2) Preparation of quick-release part mixed powder Maltose (327.6 g) was stirred and dissolved in 1310.4 g of water to obtain a spray solution. 140.0 g of solifenacin succinate was charged into a fluidized bed granulator (GPCG-5, manufactured by Glatt) together with 4012.4 g of mannitol and 140.0 g of maltose as a seed crystal, and granulated by spraying the spray solution. According to the recipe of Table 2, the dried granulated product and calcium stearate were mixed to obtain a quick-release part mixed powder. The product temperature during granulation was 33 ° C.

(3) Tableting Using a two-layer tableting machine (HT-CVX45LS-UW / 3L, manufactured by Hata Iron Works), the release controlled mixed powder 250 mg and the quick-release part mixed powder 166.7 mg were tableted into two layers, and mirabegron A pharmaceutical composition for oral administration (bilayer tablet) of the present invention containing 25 mg and 5 mg of solifenacin succinate was obtained.

(4) Film coating 10 kg of the obtained double-layer tablet was purified using a film coating machine (HiCoater HCT30, Freund Sangyo) so that the concentration of OPADRY (registered trademark) 03F43159 (Colorcon) was 10%. Film coating was performed with a solution dissolved and dispersed in water to obtain a pharmaceutical composition for oral administration (bilayer tablet) of the present invention.

Comparative Example 3
(1) Preparation of Release Control Part Mixed Powder A release control part mixed powder was obtained according to the formulation described in Table 2 under the same production conditions as described in Example 1.

(2) Preparation of quick release part mixed powder 1503 g of maltose was stirred and dissolved in 6012 g of water to obtain a spray solution. 450 g of solifenacin succinate was charged into a fluidized bed granulator (GPCG-15, manufactured by Glatt) together with 12897 g of mannitol, and granulated by spraying the spray solution. According to the recipe of Table 2, the dried granulated product and calcium stearate were mixed to obtain a quick-release part mixed powder. The product temperature during granulation was 33 ° C.

(3) Tableting Under the same production conditions as described in Example 3, a pharmaceutical composition for oral administration (bilayer tablet) containing 25 mg of mirabegron and 5 mg of solifenacin succinate was obtained.

(4) Film coating Film coating was carried out under the same production conditions as described in Example 3 to obtain a pharmaceutical composition for oral administration (bilayer tablet).

<Test Example 1> DSC Measurement After exfoliating only the immediate release part (solifenacin succinate layer) of the pharmaceutical composition for oral administration (bilayer tablet) of Example 1 and Reference Example 1, the solifenacin succinate layer was removed with a pestle mortar. Crushed. Differential scanning calorimetry analysis (DSC analysis) was performed using an EXSTAR6000 series DSC6220 manufactured by Seiko Instruments Inc. Approximately 5 mg of the sample is filled in a dedicated aluminum sample pan, and the measurement range is set to room temperature to 160 ° C under a nitrogen atmosphere (20 mL / min), and the sample and reference (empty aluminum sample are set at a heating rate of 10 ° C / min. The change in the amount of heat generated between the time and the time was measured and recorded continuously. In addition, the handling of the apparatus including data processing followed the method and procedure instructed by each apparatus. The results are shown in FIG.
Since the solifenacin succinate layer of Example 1 had an endothermic peak at about 125 ° C., it was confirmed that maltose was crystalline maltose. On the other hand, the solifenacin succinate layer of Reference Example 1 does not have an endothermic peak at about 125 ° C., suggesting that maltose is amorphous maltose.

<Test Example 2> Related Substances The pharmaceutical compositions for oral administration (double-layer tablets) of Example 1, Example 2, Reference Example 1, Example 3, and Comparative Example 3 were put in an aluminum pouch and opened, 40 It was stored for one month under open conditions at 75 ° C. and 75% relative humidity. Related substances before and after storage were measured by HPLC. Tables 3 and 4 show the results of measurement of related substances of mirabegron, and Table 5 shows the results of measurement of related substances of solifenacin succinate.
The pharmaceutical composition for oral administration of Example 1 and Example 2 (bilayer tablet) containing crystalline maltose is more than the pharmaceutical composition for oral administration (bilayer tablet) of Reference Example 1 containing amorphous maltose, In addition, the percentage of related substances decreased. Note that the pharmaceutical composition for oral administration of Reference Example 1 (bilayer tablet) containing amorphous maltose can also be provided to the medical site by applying moisture-proof packaging or the like.
In addition, since the percentage of the related substance of Example 3 manufactured on a large scale, or Comparative Example 3 and the percentage of the maximum related substance are higher than those of Example 1 or Reference Example 1 manufactured with an oil press tableting machine. It is appropriate to evaluate examples and comparative examples produced under the same scale.

In addition, the related substances of mirabegron were measured under the following conditions. As an HPLC column, XBridge C18, particle size 3.5 μm, 4.6 mm (inner diameter) × 15 cm (manufactured by Waters) or an equivalent thereof was used and maintained at 40 ° C. As mobile phase A, 50 mmol / L phosphate buffer (pH 7.2) was used, and as mobile phase B, acetonitrile was used. The sample solution used was diluted with methanol and 30% acetonitrile so that the concentration of the compound was 500 μg / mL. Using the gradient program shown in Table 6 below, adjusting the flow rate so that the retention time of mirabegron is about 10 minutes, and measuring the related substance with an ultraviolet absorptiometer (wavelength: 250 nm), mirabegron and its related substances The percentage of the peak area of the related substance was calculated as a percentage of the total peak area.

In addition, measurement of the related substance of solifenacin succinate was performed under the following conditions by peeling only the immediate-release part (solifenacin succinate layer) from the obtained bilayer tablet. As an HPLC column, XBridge C18, particle size 3.5 μm, 4.6 mm (inner diameter) × 15 cm (manufactured by Waters) or an equivalent thereof was used and maintained at 40 ° C. As mobile phase A, 50 mmol / L phosphate buffer (pH 7.2) was used, and as mobile phase B, acetonitrile was used. The sample solution used was diluted with methanol and 30% acetonitrile so that the concentration of the compound was 250 μg / mL. In the gradient program shown in Table 7 below, the flow rate was adjusted so that the retention time of solifenacin succinate was about 29 minutes, and a related substance was measured with an ultraviolet absorptiometer (wavelength: 210 nm), solifenacin succinate And the percentage of the peak area of the related substance as a percentage of the total peak area of the related substance.

<Test Example 3> Mirabegron Dissolution Test The pharmaceutical composition for oral administration (double-layer tablet) of Example 1 and Reference Example 1 was placed in an aluminum pouch and left open at 40 ° C. and a relative humidity of 75%. Saved months. About the pharmaceutical composition for oral administration (bilayer tablet) of Example 1 and Reference Example 1 before and after storage, a dissolution test was performed according to the Japanese Pharmacopoeia dissolution test method 2 (paddle method, 200 rpm). The test solution was 900 mL of USP pH 6.8 phosphate buffer, and the elution rate of mirabegron after 1.5 hours, 2.5 hours, and 4.5 hours after the start of the test was measured by ultraviolet spectroscopy (UV method (measurement wavelength: 247 nm / 450 nm)). In addition, the difference between the dissolution rate of mirabegron after storage and the dissolution rate of mirabegron before storage at each time point before and after storage was calculated. The results are shown in Table 8.
In the pharmaceutical composition for oral administration of Example 1 (bilayer tablet) containing crystalline maltose, the change in dissolution rate is more than that of the pharmaceutical composition for oral administration of Reference Example 1 (bilayer tablet) containing amorphous maltose. It was even smaller.
Note that the pharmaceutical composition for oral administration of Reference Example 1 (bilayer tablet) containing amorphous maltose can also be provided to the medical site by applying moisture-proof packaging or the like.

<Test Example 4> Solifenacin Dissolution Test Regarding the pharmaceutical composition for oral administration (double-layer tablet) of Example 1, Reference Example 1, Comparative Example 1 and Comparative Example 2, Japanese Pharmacopoeia Dissolution Test Method 1 (Rotating Basket Method) , 100 rpm). USP pH 6.8 phosphate buffer 900 mL (only Comparative Example 2; test solution is 900 mL water) was used as the test solution, and the elution rate of solifenacin was evaluated by HPLC method at 15 minutes, 30 minutes and 60 minutes after the start of the test. . The results of the solifenacin dissolution test are shown in Table 9. The dissolution rate and maximum dissolution rate of solifenacin in the pharmaceutical composition for oral administration of Example 1 and Reference Example 1 (bilayer tablet) are the pharmaceutical compositions for oral administration of Comparative Example 1 and Comparative Example 2 (bilayer tablet). It was a high value compared with.

<Test Example 5> Sticking and lamination incidence For the pharmaceutical compositions for oral administration (double-layer tablets) of Example 1, Reference Example 1 and Comparative Example 2, the manufacturability at the time of tableting (presence or absence of sticking) and the characteristics of laminated tablets The lamination, which is the problem of No. 1, was evaluated by visual observation. Table 10 shows the evaluation results. In the pharmaceutical composition for oral administration of Example 1 and Reference Example 1 (bilayer tablet), no sticking was observed, but in the pharmaceutical composition for oral administration of Comparative Example 2 (bilayer tablet), sticking was not observed. Admitted.
In the pharmaceutical composition for oral administration (bilayer tablet) of Example 1 and Reference Example 1, no lamination was observed under storage at 40 ° C. and 75% RH. On the other hand, in the pharmaceutical composition for oral administration (bilayer tablet) of Comparative Example 2, lamination was observed even under the milder conditions of 25 ° C. and 60% RH storage.

<Test Example 6> Coloring of quick-release part About the pharmaceutical composition for oral administration (bilayer tablet) of Reference Example 2 and Comparative Example 2, appearance change during storage (coloring of quick-release part) was evaluated by visual observation. . The evaluation results are shown in Table 11. In the pharmaceutical composition for oral administration of Reference Example 2 (double-layer tablet), coloring of the immediate-release part was not observed.

<Test example 7> Relationship between the amount of crystalline maltose and stability In order to examine the effect of the amount of crystalline maltose contained in the immediate release part on the stability, an immediate release part containing amorphous maltose and crystalline maltose in a specific ratio Prepared and evaluated the stability of mirabegron contained in other layers.
Amorphous maltose obtained by heat treatment at 150 ° C. for 30 minutes is weighed with crystalline maltose so that the total amount of maltose is 334 mg, and further mixed with solifenacin succinate 50 mg, mannitol 2916 mg, and calcium stearate 34 mg. A mixed powder was obtained. At this time, it mix | blended so that the amount of crystalline maltose with respect to the total amount of maltose might be 0, 5, 10, 20, 30, 50, or 100%. The release control part mixed powder was obtained under the same formulation and production conditions as described in Reference Example 2. Tableting was performed under the same conditions as described in Example 1 to obtain a pharmaceutical composition for oral administration (bilayer tablet) containing 25 mg of mirabegron and 2.5 mg of solifenacin succinate. Put the obtained pharmaceutical composition for oral administration (double-layer tablet) in an aluminum pouch and store it for 2 weeks or 40 months under open conditions at 40 ° C and 75% relative humidity, and then measure the total amount of mirabegron related substances. It was measured. FIG. 2 and FIG. 3 show the relationship between the ratio of the total amount of mirabegron-related substances to the total amount of mirabegron-related substances in the preparation with 0% crystalline maltose content after storage and the content of crystalline maltose in the maltose contained in the immediate-release part.
From FIG. 2, the addition of 5% or more of crystalline maltose to the rapid release part could suppress the increase in the maximum related substance of mirabegron and the total amount of related substances.

The present invention relates to a pharmaceutical composition for oral administration comprising a controlled release part containing mirabegron or a pharmaceutically acceptable salt thereof and an immediate release part containing solifenacin or a pharmaceutically acceptable salt thereof. Is to provide. According to the pharmaceutical composition for oral administration of the present invention, it can be used as a preparation technique for providing a single preparation that suppresses the generation of related substances during storage of each drug and the change in the dissolution rate of mirabegron during storage.

As mentioned above, although this invention was demonstrated along the specific aspect, the deformation | transformation and improvement obvious to those skilled in the art are included in the scope of the present invention.

Claims (21)

1. (1) a controlled release portion comprising mirabegron or a pharmaceutically acceptable salt thereof; (2) solifenacin or a pharmaceutically acceptable salt thereof; and stability of mirabegron or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for oral administration comprising an immediate release part containing a pharmaceutical additive for improving the properties.
2. The pharmaceutical composition for oral administration according to claim 1, wherein the pharmaceutical additive for improving the stability of mirabegron or a pharmaceutically acceptable salt thereof is a crystalline saccharide and / or a water-soluble polymer.
3. The pharmaceutical composition for oral administration according to claim 1 or 2, wherein the pharmaceutical additive that improves the stability of mirabegron or a pharmaceutically acceptable salt thereof is a crystalline saccharide.
4. The blending ratio of the pharmaceutical additive that improves the stability of mirabegron or a pharmaceutically acceptable salt thereof is about 0.3 wt% or more and about 99 wt% or less with respect to the weight of the immediate release part. The pharmaceutical composition for oral administration according to any one of 1 to 3.
5. The pharmaceutical composition for oral administration according to any one of claims 1 to 4, wherein the pharmaceutical additive that improves the stability of mirabegron or a pharmaceutically acceptable salt thereof is a crystalline reducing saccharide.
6. The pharmaceutical composition for oral administration according to any one of claims 1 to 5, wherein the pharmaceutical additive that improves the stability of mirabegron or a pharmaceutically acceptable salt thereof is crystalline maltose.
7. Furthermore, the pharmaceutical composition for oral administration as described in any one of Claims 1 thru | or 6 which contains a calcium stearate in an immediate release part.
8. The pharmaceutical composition for oral administration according to any one of claims 1 to 7, wherein the release control part comprises a polymer substance that forms a hydrogel.
9. The pharmaceutical composition for oral administration according to claim 8, wherein the polymer substance forming the hydrogel has an average molecular weight of about 100,000 or more or a viscosity of 5% aqueous solution at 25 ° C of 12 mPa · s or more.
10. The polymer material forming the hydrogel is one or more polymer materials selected from the group consisting of polyethylene oxide, hypromellose, hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, and carboxyvinyl polymer. The pharmaceutical composition for oral administration according to claim 9.
11. The pharmaceutical composition for oral administration according to claim 10, wherein the polymer substance forming the hydrogel is polyethylene oxide.
12. 12. The composition for oral administration according to claim 8, wherein the blending ratio of the polymer substance forming the hydrogel is about 1 wt% or more and about 70 wt% or less with respect to the weight of the release control part. Pharmaceutical composition.
13. The pharmaceutical composition for oral administration according to any one of claims 1 to 12, wherein the release control part further comprises an additive for allowing water to enter the release control part.
14. The pharmaceutical composition for oral administration according to claim 13, wherein the additive for allowing water to enter the inside of the release control part has a solubility in which the amount of water dissolving 1 g is 10 mL or less.
15. 15. The composition for oral administration according to claim 13 or 14, wherein a mixing ratio of an additive for allowing water to enter the inside of the release control part is about 5% by weight or more and about 75% by weight or less with respect to the weight of the release control part. Pharmaceutical composition.
16. The pharmaceutical composition for oral administration according to any one of claims 1 to 15, wherein the pharmaceutical composition is a pharmaceutical composition for improving urinary urgency, frequent urination and / or urinary incontinence associated with overactive bladder.
17. The pharmaceutical composition for oral administration according to any one of claims 1 to 16, wherein the pharmaceutical composition is a tablet.
18. The pharmaceutical composition for oral administration according to any one of claims 1 to 17, wherein the tablet is a multilayer tablet.
19. The pharmaceutical composition for oral administration according to any one of claims 1 to 18, wherein the tablet is a bilayer tablet.
20. (1) Contains a layer containing mirabegron or a pharmaceutically acceptable salt thereof, and (2) a layer containing solifenacin or a pharmaceutically acceptable salt thereof, and a crystalline saccharide and / or a water-soluble polymer. A pharmaceutical composition for oral administration.
21. (1) Contains a layer containing mirabegron or a pharmaceutically acceptable salt thereof, and (2) a layer containing solifenacin or a pharmaceutically acceptable salt thereof, and a crystalline saccharide and / or a water-soluble polymer. In the pharmaceutical composition for oral administration, mirabegron or a pharmaceutical product thereof, comprising a crystalline saccharide and / or a water-soluble polymer contained in the layer containing the solifenacin or the pharmaceutically acceptable salt of (2) Acceptable salt stabilization methods.

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