Coated particles containing solifenacin succinate and orally disintegrating tablets containing the same

Abstract

To provide a solifenacin succinate-containing coated particle that can inhibit the formation of analogs of solifenacin succinate during its production and can also sufficiently mask the bitterness, or provide a solifenacin succinate-containing orally disintegrating tablet that can inhibit the formation of analogs of solifenacin succinate during its production and can also sufficiently mask the bitterness.SOLUTION: One embodiment of the solifenacin succinate-containing coated particle has spherical silica that carries solifenacin succinate and has an average particle size of 100 μm or more and a coating layer that coats the spherical silica.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to coated particles containing solifenacin succinate and orally disintegrating tablets containing the same. [Background technology]

[0002] Solifenacin succinate ((3R)-1-Azabicyclo[2,2,2]oct-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate monosuccinate) is a drug that has selective antagonistic effects on muscarinic M3 receptors and is used as a treatment for urgency, frequent urination, and urge urinary incontinence associated with overactive bladder.

[0003] In the treatment of these diseases, it is desired to make the solifenacin succinate-containing preparation into an orally disintegrating tablet, which is an easy-to-take dosage form for elderly people and patients with difficulty in swallowing, in order to improve the ease of administration. In particular, in the case of the treatment of overactive bladder, it is necessary to take the medicine for a long period of time, so it is expected that an orally disintegrating tablet that is easy to take will lead to active participation in the treatment of patients and improvement of their drug-taking behavior. In addition to the appropriate hardness and rapid disintegration as a tablet, an orally disintegrating tablet is required to have a good feeling of taking it, such as a good taste, and if the drug substance has a bitter taste, it is required to mask the bitter taste. When making a solifenacin succinate-containing preparation into an orally disintegrating tablet, solifenacin succinate has a strong bitter taste, so it is necessary to devise a way to mask the bitter taste of solifenacin succinate (Patent Document 1). For this reason, Patent Document 1 describes that the bitter taste is suppressed by adding a metal chloride. However, as described above, solifenacin succinate is known to have stability problems, and therefore it is necessary to mask the bitterness while maintaining the stability of solifenacin succinate during production.

[0004] For example, Patent Document 2 describes a solid preparation and an orally disintegrating tablet containing a core particle of hydrated silicon dioxide covered with a coating layer containing a binder and solifenacin succinate. Patent Document 2 also describes secondary coated granules in which the coating layer is covered with a layer containing a coating agent.

[0005] The method of covering core particles with a coating layer containing solifenacin succinate as in Patent Document 2 is also described in, for example, Patent Documents 3 and 4. Patent Document 3 describes a pharmaceutical composition in which solifenacin succinate is dissolved in water in which silicon dioxide (Adsolider (registered trademark) 101) is dispersed, and the solution is sprayed and dried. Patent Document 4 describes granules in which solifenacin succinate and hypromellose 2910 are dissolved in purified water, light anhydrous silicic acid and malic acid are mixed in a mortar, and the previously dissolved solifenacin succinate solution is added to the mixture and kneaded. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] JP 2016-79102 A [Patent Document 2] JP 2017-190325 A [Patent Document 3] JP 2017-210422 A [Patent Document 4] JP 2015-189677 A Summary of the Invention [Problem to be solved by the invention]

[0007] Patent Document 1 focuses only on suppressing bitterness, and does not consider maintaining the stability of solifenacin succinate. In Patent Documents 2 to 4, solifenacin succinate is made amorphous during the preparation manufacturing process, and only the stability of the amorphous form of solifenacin succinate in the obtained preparation is considered, and the masking of bitterness required for the above-mentioned orally disintegrating tablet is not considered.

[0008] An object of the present invention is to provide a coated particle containing solifenacin succinate that can suppress and stabilize the production of related substances of solifenacin succinate during production, and can also sufficiently mask the bitterness. Alternatively, an object of one embodiment of the present invention is to provide an orally disintegrating tablet containing solifenacin succinate that can suppress the production of related substances of solifenacin succinate during production, and can also sufficiently mask the bitterness. [Means for solving the problem]

[0009] According to one embodiment of the present invention, there is provided a coated particle containing solifenacin succinate, characterized in that it comprises spherical silica having an average particle diameter of 100 μm or more carrying solifenacin succinate, and a coating layer covering the spherical silica.

[0010] In the solifenacin succinate-containing coated particles, the spherical silica may be hydrous silicon dioxide.

[0011] In the solifenacin succinate-containing coated particles, the spherical silica may be porous spherical silica having an average pore size of less than 50 nm.

[0012] In the solifenacin succinate-containing coated particles, the spherical silica may be porous spherical silica having an average pore size of 30 nm or less.

[0013] In the solifenacin succinate-containing coated particles, solifenacin succinate may be present in an amorphous form.

[0014] In the solifenacin succinate-containing coated particles, the spherical silica may further carry a binder.

[0015] According to one embodiment of the present invention, there is provided an orally disintegrating tablet comprising any one of the above-mentioned solifenacin succinate-containing coated particles and a disintegrant. Effect of the Invention

[0016] According to one embodiment of the present invention, there is provided a solifenacin succinate-containing coated particle capable of suppressing and stabilizing the production of solifenacin succinate analogues during production, as well as sufficiently masking the bitterness. Alternatively, according to one embodiment of the present invention, there is provided a solifenacin succinate-containing orally disintegrating tablet capable of suppressing and stabilizing the production of solifenacin succinate analogues during production, as well as sufficiently masking the bitterness. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The solifenacin succinate-containing coated particles and the solifenacin succinate-containing orally disintegrating tablet according to the present invention will be described in detail below. However, the solifenacin succinate-containing coated particles and the solifenacin succinate-containing orally disintegrating tablet according to the present invention should not be construed as being limited to the description of the following embodiments and examples.

[0018] [Solifenacin succinate-containing coated particles] In one embodiment of the present invention, the solifenacin succinate-containing coated particles include spherical silica carrying solifenacin succinate and a coating layer disposed on the spherical silica.

[0019] As used herein, the term "spherical silica supporting" solifenacin succinate means that solifenacin succinate is held within the pores of the spherical silica and / or that solifenacin succinate is disposed on the spherical silica.

[0020] The spherical silica is a carrier for carrying solifenacin succinate. The spherical silica is preferably hydrated silicon dioxide. The spherical silica has an average particle size of more than 40 μm, preferably 100 μm or more. The spherical silica having an average particle size of 40 μm or less cannot suppress the bitterness of solifenacin succinate. In this specification, the average particle size is calculated by the amount of classification by sieve.

[0021] In one embodiment, the spherical silica is porous spherical silica having pores. The pores of the porous spherical silica have an average pore size of less than 50 nm, preferably 30 nm or less. Spherical silica having an average pore size of 50 nm or more is not preferred because related substances increase during production. The main related substances of solifenacin succinate are N-oxides, which are generated by oxidation of solifenacin succinate. For this reason, it is presumed that in spherical silica having an average pore size of 50 nm or more, the fluidity of solifenacin succinate in the pores is increased and there is a place for reaction with oxygen, so that related substances including N-oxides are generated. In this specification, the average pore size is calculated by nitrogen gas adsorption method (BJH method analysis).

[0022] Solifenacin succinate supported on spherical silica exists in an amorphous form. In this specification, "solifenacin succinate exists in an amorphous form" means that no peak derived from solifenacin succinate crystals is observed by X-ray diffraction (XRD).

[0023] In one embodiment, the spherical silica may further carry a pharma- ceutically acceptable binder together with solifenacin succinate, such as, but not limited to, one or more selected from the group consisting of hypromellose, hydroxypropyl cellulose, methyl cellulose, povidone, ethyl cellulose, polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and polyethylene glycol.

[0024] In one embodiment, the spherical silica can support 0% to 20.0% by weight of the binder relative to 100.0 parts by weight of solifenacin succinate, and the spherical silica can support 100.0% to 1000.0% by weight relative to 100.0 parts by weight of solifenacin succinate.

[0025] The coating layer covers the spherical silica carrying solifenacin succinate. In one embodiment, the coating layer may be one layer or may be composed of multiple layers. The coating layer is, for example, a film containing one or more coating agents selected from the group consisting of ammonioalkyl methacrylate copolymer, hypromellose, ethyl cellulose, ethyl cellulose dispersion, ethyl acrylate-methyl methacrylate copolymer dispersion, and dimethylamino methacrylate-methyl methacrylate copolymer, but is not limited thereto. The coating agent is preferably contained in the range of 5.0% by weight or more and 100.0% by weight or less based on the total weight of the solifenacin succinate-containing coated particle.

[0026] The solifenacin succinate-containing coated particles have the above structure, and thus can suppress the bitterness derived from solifenacin succinate. Also, the solifenacin succinate-containing coated particles have the above structure, and thus can maintain the amorphous state of solifenacin succinate during production and storage, and can suppress the generation of related substances.

[0027] [Orally disintegrating tablet containing solifenacin succinate] The solifenacin succinate-containing coated particles according to the above-mentioned embodiment can be used to form a solifenacin succinate-containing orally disintegrating tablet. In one embodiment, the solifenacin succinate-containing orally disintegrating tablet contains solifenacin succinate-containing coated particles and one or more pharma-ceutically acceptable additives. The one or more pharma-ceutically acceptable additives may contain a disintegrant. The solifenacin succinate-containing orally disintegrating tablet may be in the form of a coated tablet that is further coated. The solifenacin succinate-containing orally disintegrating tablet contains 2.5 mg or 5.0 mg of solifenacin succinate per tablet, but is not limited thereto, and the formulation may be changed as necessary.

[0028] The disintegrant contained in the solifenacin succinate-containing orally disintegrating tablet can be selected from known disintegrants. For example, one or more disintegrants selected from the group consisting of low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, crystalline cellulose, sodium starch glycolate, and light anhydrous silicic acid can be used, but are not limited thereto. The disintegrant may be contained in the range of 1.0% by weight to 20.0% by weight, preferably 5.0% by weight to 15.0% by weight, based on the total weight of the solifenacin succinate-containing orally disintegrating tablet. The disintegrant may be contained in the coating particles containing solifenacin succinate, outside the coating particles containing solifenacin succinate, or both.

[0029] The pharma- ceutically acceptable additives contained in the solifenacin succinate-containing orally disintegrating tablet include, in addition to the disintegrants described above, excipients, binders, stabilizers, flavoring agents, and lubricants. One or more of these additives may be selected to constitute the solifenacin succinate-containing orally disintegrating tablet. The solifenacin succinate-containing orally disintegrating tablet may also contain a premix additive that combines these disintegrants and one or more additives. These additives may be contained in the solifenacin succinate-containing coating particles, outside the solifenacin succinate-containing coating particles, or both.

[0030] Examples of the excipient include D-mannitol, lactose hydrate, anhydrous lactose, isomalt, trehalose, crystalline cellulose, corn starch, etc. The orally disintegrating tablet containing solifenacin succinate may contain the excipient in an amount of 10.0% by weight to 97.0% by weight, preferably 70.0% by weight to 92.0% by weight, based on the total weight of the tablet.

[0031] Examples of the binder include hydroxypropyl cellulose, hypromellose, methyl cellulose, povidone, ethyl cellulose, polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyethylene glycol, etc. The binder may be contained in an amount of 0% by weight or more and 20.0% by weight or less, preferably 0% by weight or more and 10.0% by weight or less, based on the total weight of the orally disintegrating tablet containing solifenacin succinate.

[0032] Examples of lubricants include magnesium stearate, calcium stearate, sodium stearyl fumarate, etc. The lubricant may be contained in an amount of 0.1% by weight to 3.0% by weight based on the total weight of the orally disintegrating tablet containing solifenacin succinate.

[0033] The orally disintegrating tablet containing solifenacin succinate can suppress the bitterness derived from solifenacin succinate by containing the coating particles containing solifenacin succinate having the above structure. Also, the orally disintegrating tablet containing solifenacin succinate can maintain the amorphous state of solifenacin succinate during production and storage and suppress the generation of related substances by containing the coating particles containing solifenacin succinate having the above structure.

[0034] <Method for producing coated particles containing solifenacin succinate> The solifenacin succinate-containing coated particles according to the present invention can be prepared by, for example, carrying solifenacin succinate on spherical silica using a known silica adsorption method.

[0035] In addition, in the solifenacin succinate-containing coated particles according to the present invention, a coating layer that covers the spherical silica can be formed, for example, by a known coating method.

[0036] [Method of manufacturing orally disintegrating tablets containing solifenacin succinate] Orally disintegrating tablets containing solifenacin succinate can be produced by mixing solifenacin succinate-containing coated particles with one or more pharma- ceutically acceptable additives using a commonly used mixer and compressing (tabletting) using a commonly used tablet press.

[0037] [bitter taste] In the present specification, the bitterness of the solifenacin succinate-containing coated particles is evaluated by a sensory test.

[0038] [Related substances] In the present specification, the purity of solifenacin succinate is evaluated by liquid chromatography to evaluate the stability of solifenacin succinate-containing orally disintegrating tablets. By the area percentage method, the sum of the peak areas of solifenacin succinate and related substances derived from solifenacin succinate obtained on a chromatogram is set to 100, and the total amount of related substances derived from solifenacin succinate (%) and the amount of N-oxide (%) are calculated from the ratio of the peak areas.

[0039] [Amorphous] In the present specification, a substance is considered to be amorphous when no peak derived from solifenacin succinate crystals is detected by X-ray diffraction (XRD) method. EXAMPLES

[0040] The above-mentioned embodiment of the present invention will be described in detail with reference to specific examples and test results.

[0041] [Example 1] 25 g of solifenacin succinate and 10 g of hypromellose (Shin-Etsu Chemical Co., Ltd., TC-5E) were dissolved in 100 g of purified water to obtain a drug substance solution. Next, 100 g of spherical hydrated silicon dioxide (Fuji Silysia Chemical Co., Ltd., SYLOPURE P100) with an average particle size of 100 μm as spherical silica was mixed in a mortar while adding the drug substance solution, and then dried in a fluidized bed granulator. The obtained coarse particles were classified using a No. 42 sieve to obtain particles in which solifenacin succinate and hypromellose were supported on spherical silica.

[0042] 125 g of the obtained particles were placed in a fluidized bed granulator and coated by spraying with an aqueous ethanol solution containing 42.5 g of ammonioalkyl methacrylate copolymer (EVONIK, Eudragit (registered trademark) RSPO) and 7.5 g of hypromellose (Shin-Etsu Chemical Co., Ltd., TC-5E). After drying, the obtained coarse particles were classified using a No. 42 sieve to obtain the solifenacin succinate-containing coated particles of Example 1.

[0043] [Example 2] The solifenacin succinate-containing coated particles of Example 2 were obtained by the same production method as in Example 1, except that spherical hydrous silicon dioxide having an average particle diameter of 200 μm (SYLOPURE 65, Fuji Silysia Chemical Ltd.) was used instead of spherical hydrous silicon dioxide having an average particle diameter of 100 μm (SYLOPURE P100, Fuji Silysia Chemical Ltd.).

[0044] [Comparative Example 1] The solifenacin succinate-containing coated particles of Comparative Example 1 were obtained by the same manufacturing method as in Example 1, except that spherical hydrous silicon dioxide having an average particle diameter of 40 μm (Fuji Silysia Chemical Ltd., SYLOPURE P100) was used instead of spherical hydrous silicon dioxide having an average particle diameter of 100 μm.

[0045] [Comparative Example 2] An attempt was made to produce coated particles containing solifenacin succinate in Comparative Example 2 by the same production method as in Example 1, except that light anhydrous silicic acid (Adsolider (registered trademark) 101, Freund Corporation) with an average particle size of 3 μm was used instead of spherical hydrated silicon dioxide (SYLOPURE P100, Fuji Silysia Chemical Ltd.) with an average particle size of 100 μm. However, in Comparative Example 2, the solifenacin succinate-containing particles using Adsolider as a carrier were very fine, making it difficult to maintain an appropriate fluid state for coating, and coated particles containing solifenacin succinate could not be obtained.

[0046] [Sensory test] The bitterness of the coated particles containing solifenacin succinate of Examples 1-2 and Comparative Example 1 was evaluated by a sensory test by three testers. The coated particles containing solifenacin succinate of Examples 1-2 and Comparative Example 1 were weighed so that the amount of solifenacin succinate was 5 mg. The coated particles containing solifenacin succinate of Examples 1-2 or Comparative Example 1 were held in the mouth for 30 seconds to determine the presence or absence of bitterness. The evaluation results of the bitterness of the coated particles containing solifenacin succinate of Examples 1-2 and Comparative Example 1 are shown in Table 1. [Table 1]

[0047] The bitterness was suppressed in the solifenacin succinate-containing coated particles of Examples 1 and 2, in which spherical hydrous silicon dioxide having an average particle size of 100 μm or more was used as a carrier, but the bitterness could not be suppressed in the solifenacin succinate-containing coated particles of Comparative Example 1, in which spherical hydrous silicon dioxide having an average particle size of 40 μm was used as a carrier. As described above, in Comparative Example 2, in which light anhydrous silicic acid having an average particle size of 3 μm was used as a carrier, no solifenacin succinate-containing coated particles were obtained, and the sensory test could not be performed.

[0048] [Example 3] 25g of solifenacin succinate was dissolved in 100g of purified water to obtain a drug substance solution. Next, 100g of spherical hydrated silicon dioxide (Fuji Silysia Chemical Co., Ltd., CHROMATOREX MB3A 100-200) with an average particle size of 100μm and an average pore size of 2.5nm was mixed in a mortar, and the drug substance solution was added, followed by drying in a fluidized bed granulator. The obtained coarse particles were classified using a sieve No. 42 to obtain the particles of Example 3 in which solifenacin succinate was supported on the spherical silica.

[0049] [Example 4] The particles of Example 4 were obtained by the same production method as in Example 2, except that spherical hydrous silicon dioxide having an average particle size of 100 μm and an average pore size of 7 nm (Fuji Silysia Chemical Ltd., CHROMATOREX MB4B 100-200) was used as the spherical silica.

[0050] [Example 5] Particles of Example 5 were obtained by the same production method as in Example 2, except that spherical hydrous silicon dioxide having an average particle size of 100 μm and an average pore size of 30 nm (Fuji Silysia Chemical Ltd., CHROMATOREX MB300 100-200) was used as the spherical silica.

[0051] [Comparative Example 3] Particles of Comparative Example 3 were obtained by the same manufacturing method as in Example 3, except that spherical hydrous silicon dioxide having an average particle size of 100 μm and an average pore size of 50 nm (Fuji Silysia Chemical Ltd., CHROMATOREX MB500-75 / 200) was used as the spherical silica.

[0052] [Purity evaluation] For each of the particles of Examples 1, 3 to 5 and Comparative Examples 2 to 3, the total amount (%) of related substances and the amount (%) of N-oxide bodies were measured by high performance liquid chromatography (HPLC). (HPLC conditions) Detector: Ultraviolet spectrophotometer (measurement wavelength: 210 nm) Column: Phenylbutylsilylated silica gel Column temperature: 40℃ Mobile phase A: A mixture of ammonium dihydrogen phosphate buffer at pH 3.0 and acetonitrile / water = 19 / 1, v / v Mobile phase B: Acetonitrile The elution conditions were as shown in Table 2. [Table 2]

[0053] Table 3 shows the evaluation of the purity of each particle of Examples 1, 3 to 5 and Comparative Examples 2 to 3. [Table 3]

[0054] In the particles of Comparative Example 3 having an average pore size of 50 nm, N-oxides and total related substances derived from solifenacin succinate were generated during production. On the other hand, in the particles of Examples 1, 3 to 5 and Comparative Example 2 having an average pore size smaller than 50 nm, it was revealed that the generation of N-oxides and total related substances was significantly suppressed.

[0055] [Evaluation of amorphous materials] Each of the particles of Examples 3 to 5 was stored for one week at 60° C. or for one week at 60° C. and 60% RH. The crystal form of solifenacin succinate was evaluated by XRD for each of the particles of Examples 3 to 5 immediately after production and after storage. (XRD conditions) X-ray diffraction equipment: D8 ADVANCE (Bruker) Measurement conditions: Tube: Cu, Tube voltage: 40kV, Tube current: 40mA, Divergence slit: 0.3°, Antiscattering slit: 0.5°, Scanning range: 2°~40° Judgment criteria: When no peaks derived from solifenacin succinate crystals were observed, it was judged that the amorphous state was maintained.

[0056] The evaluation results of the amorphous nature of each of the particles in Examples 3 to 5 are shown in Table 4. [Table 4]

[0057] The results in Table 4 reveal that the particles of Examples 3 to 5 maintained their amorphous state.

[0058] Even if there are other effects and advantages different from those brought about by the aspects of each of the above-mentioned embodiments, those that are clear from the description in this specification or that can be easily predicted by a person skilled in the art are naturally understood to be brought about by the present invention.

Claims

1. Spherical silica having an average particle size of 100 μm or more carrying solifenacin succinate and a binder; A coating layer that covers the spherical silica; Including, The spherical silica is a porous hydrous silicon dioxide having an average pore size of 30 nm or less, The binder is one or more selected from the group consisting of hypromellose, hydroxypropyl cellulose, methyl cellulose, povidone, ethyl cellulose, polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, and polyethylene glycol; The coating layer comprises one or more coating agents selected from the group consisting of ammonioalkyl methacrylate copolymer, hypromellose, ethyl cellulose, ethyl cellulose dispersion, ethyl acrylate-methyl methacrylate copolymer dispersion, and dimethylamino methacrylate-methyl methacrylate copolymer; 2. A coated particle containing solifenacin succinate, wherein the solifenacin succinate is present in an amorphous form.

2. The binder is hypromellose, 2. The solifenacin succinate-containing coated particle according to claim 1, characterized in that the coating agent is an ammonioalkyl methacrylate copolymer and hypromellose.

3. A coating particle containing solifenacin succinate according to claim 1 or 2, and a disintegrant, An orally disintegrating tablet comprising:

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