Solid preparation of sustained-release pharmaceutical composition

Abstract

To provide a solid preparation of a sustained-release pharmaceutical composition in which even a solid preparation has excellent structural stability while maintaining an effect of sustained-release of a pharmaceutical composition.SOLUTION: A solid preparation of a sustained-release pharmaceutical composition contains: (1) (R)-2-(2-aminothiazole-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl] acetic acid anilide or a pharmaceutically acceptable salt thereof; (2) one or more kinds of polymeric substances which form hydrogel having the average molecular weight of 100,000 or more or in which 5% aqueous solution has viscosity of 25°C 12 mPa s or more; and (3) one or more kinds of non-hydrophilic additives showing dissolubility that [amount of water for dissolving 1 g at 20±5°C exceeds 10 mL], where the solid preparation without considering coating does not contain a hydrophilic component showing dissolubility that [amount of water for dissolving 1 g at 20±5°C is 10 mL or less] other than a polymeric substance forming hydrogel of the component (2).SELECTED DRAWING: Figure 2

Description

Technical Field

[0001] The present invention relates to a solid preparation of a sustained-release pharmaceutical composition.

Background Art

[0002] Those skilled in the art know that, as related art, (R)-2-(2-aminothiazol-4-yl)-4’-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide has a medical function.

[0003] For example, Patent Document 1 shows that the compound has an effect of promoting insulin secretion and enhancing insulin sensitivity.

[0004] Therefore, this compound has anti-obesity and anti-hyperlipidemic effects based on selective β3 receptor stimulating action and is valuable for the treatment of diabetes.

[0005] Patent Document 2 and others also show other related art known to those skilled in the art. This compound may be used as a drug for overactive bladder. For example, in addition to the treatment of overactive bladder associated with benign prostatic hyperplasia, it can also be used as a treatment for overactive bladder accompanied by urinary urgency, urinary incontinence, and frequent urination.

[0006] Therefore, pharmaceutical compositions containing (R)-2-(2-aminothiazol-4-yl)-4’-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide are under research.

[0007] For the purpose of improving patient compliance and / or treatment efficacy, there is a need for a dosage form that can be released slowly within a predetermined time or at a predetermined rate. There is a demand for research and development products of sustained-release or release-controlled pharmaceutical compositions of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide. Furthermore, in a release-controlled dosage form, it is still necessary to avoid rapid release of the active ingredient. For the sake of simplicity, in this application, "sustained-release pharmaceutical composition or release-controlled pharmaceutical composition" will be hereinafter referred to as "sustained-release pharmaceutical composition".

[0008] In addition, the inventor of this application discovered that a sustained-release pharmaceutical composition of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide is disclosed in Patent Document 3.

Prior Art Documents

Patent Documents

[0009]

Patent Document 1

Patent Document 1

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0010] However, the composition of the sustained-release pharmaceutical composition described in the content of this application does not have good structural stability in solid preparations (such as tablets).

[0011] Under the storage conditions required for the accelerated testing in the stability test of the sustained-release pharmaceutical composition, the external form (hereinafter also referred to as "external structure") or internal form (hereinafter also referred to as "internal structure") of the solid preparation of the sustained-release pharmaceutical composition changes in a relatively short period after the packaging outside the preparation is damaged (for details, refer to the results of Comparative Example 1 in each of the following tests).

[0012] If the structural stability is low, problems are likely to occur in the appearance of the solid preparation, which not only affects the user's sense of use, but also increases the possibility that the active ingredient in the pharmaceutical composition reacts with substances in the environment and decomposes. As a result, the proportion of the active ingredient in the composition decreases, or the proportion of impurities increases. In serious cases, it may even fail to meet the relevant pharmaceutical regulations or affect the expected effectiveness of the preparation.

[0013] That is, if the structural stability of the preparation itself is not good, it will have an even worse impact on the stability of the active ingredient in the preparation.

[0014] Therefore, the purpose of the present application is to provide a sustained-release pharmaceutical composition with excellent structural stability for solid preparations while maintaining the sustained-release effect of the pharmaceutical composition.

Means for Solving the Problems

[0015] In view of the above problems, the present invention has the following configuration. That is, a solid preparation of a sustained-release pharmaceutical composition containing the components of: (1) (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide or a pharmaceutically acceptable salt thereof; (2) one or more polymer substances that form a hydrogel having an average molecular weight of 100,000 or more or a viscosity of 12 mPa·s or more at 25 °C for a 5% aqueous solution; and (3) one or more non-hydrophilic additives showing solubility of "the amount of water for dissolving 1 g exceeds 10 mL at 20 ± 5 °C". When the solid preparation has a coating, regardless of the coating, except for the polymer substance that forms the hydrogel of component (2), the solid preparation does not contain a hydrophilic component showing solubility of "the amount of water for dissolving 1 g is 10 mL or less at 20 ± 5 °C". When the solid preparation does not have a coating, except for the polymer substance that forms the hydrogel of component (2), it does not contain a hydrophilic component showing solubility of "the amount of water for dissolving 1 g is 10 mL or less at 20 ± 5 °C".

[0016] Using the above composition, the inventor has discovered that the solid preparation of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide is excellent in structural stability while maintaining the sustained-release effect.

[0017] For example, compared with other compositions, this composition can enable the solid preparation to function better under the storage conditions required for the accelerated test, and the outer shape or internal structure of the solid preparation can maintain the original state at the time of preparation completion for a longer period.

[0018] Furthermore, in multiple embodiments, when the solid preparation is subjected to the dissolution test method of the United States Pharmacopeia, and a dissolution test is carried out at a rotation speed of 100 rpm by the rotating basket method in 900 mL of USP phosphate buffer at 37 °C and pH 6.8, the dissolution rate of component (1) of the solid preparation after 1 hour is 25% or less, and the dissolution rate of component (1) of the solid preparation after 12 hours is 75% or more.

[0019] Furthermore, the present application also provides a method for manufacturing a solid preparation of a sustained-release pharmaceutical composition that can obtain the above solid preparation with excellent structural stability while maintaining the sustained-release effect. Specifically, this method includes the step of mixing the following components. (1) (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide or a pharmaceutically acceptable salt thereof; (2) One or more polymer substances that form a hydrogel having an average molecular weight of about 100,000 or more or a viscosity of 12 mPa·s or more at 25°C for a 5% aqueous solution; and (3) One or more non-hydrophilic additives showing solubility of "the amount of water for dissolving 1 g exceeds 10 mL at 20 ± 5°C"; Here, when the solid preparation formed through this mixing step does not have a coating, the solid preparation does not contain a hydrophilic component showing solubility of "the amount of water for dissolving 1 g is 10 mL or less at 20 ± 5°C", except for the polymer substance that forms the hydrogel of the component (2), and when the solid preparation formed through this mixing step has a coating, the solid preparation does not contain a hydrophilic component showing solubility of "the amount of water for dissolving 1 g is 10 mL or less at 20 ± 5°C", except for the polymer substance that forms the hydrogel of the component (2), without considering the coating.

Advantages of the Invention

[0020] It is possible to provide a sustained-release pharmaceutical composition in which the solid preparation also has excellent structural stability while maintaining the sustained-release effect of the pharmaceutical composition.

Brief Description of the Drawings

[0021]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Mode for Carrying Out the Invention

[0022] Hereinafter, an explanation related to the sustained-release pharmaceutical composition of the present application will be given. The "sustained-release pharmaceutical composition" of the present application refers to a formulation in which, when a dissolution test is performed at a rotation speed of 100 rpm in 900 mL of USP phosphate buffer solution at 37 °C and pH 6.8 using the Rotating Basket Method in the dissolution test method of the United States Pharmacopeia, the drug elution rate from the formulation 30 minutes after the start of the test is less than 85%.

[0023] According to an embodiment of the present application, the present case provides a solid formulation of a sustained-release pharmaceutical composition containing the following components. (1) (R)-2-(2-Aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide or a pharmaceutically acceptable salt thereof; (2) One or more polymer substances that form a hydrogel having an average molecular weight of about 100,000 or more or a viscosity of 12 mPa·s or more at 25 °C for a 5% aqueous solution; and (3) One or more non-hydrophilic additives showing solubility of "the amount of water for dissolving 1 g exceeds 10 mL". When the solid preparation has a coating, without considering the coating, the solid preparation does not contain a hydrophilic component having a solubility of "the amount of water for dissolving 1 g is 10 mL or less at 20 ± 5°C", except for the polymer substance that forms the hydrogel of the component (2). When the solid preparation does not have the coating, it does not contain a hydrophilic component having a solubility of "the amount of water for dissolving 1 g is 10 mL or less at 20 ± 5°C", except for the polymer substance that forms the hydrogel of the component (2).

[0024] The "solid preparation" in the present application refers to a preparation having a certain shape that is not paste-like or liquid-like, and examples include oral preparations such as tablets, capsules (including microcapsules), granules, and powders, or parenteral drugs such as suppositories (for example, rectal suppositories, vaginal suppositories, etc.). Each of these can be safely administered orally or parenterally to the target.

[0025] The present application can use the structure of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide as the component (1), and this structure is shown in the following [Formula 1] (for convenience, hereinafter, this compound is referred to as the "compound of Formula 1").

[0026]

Chemical formula

[0027] In addition to the non-salt state of the compound of Formula 1, the component (1) may be a pharmaceutically acceptable salt formed by the compound of Formula 1 and an acid.

[0028] Examples of the salt include mineral acids such as sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid, and salts formed from organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, and acid containing lemon.

[0029] The dosage of component (1) is determined according to the individual conditions of the subject, such as symptoms, age, gender, etc. Usually, in the case of oral administration, for adults, it is administered at 0.01 mg / kg or more and 100 mg / kg or less per day, once a day or divided into 2 to 4 times a day.

[0030] The content of component (1) in the solid preparation (without considering the coating if there is a coating) can be, for example, 1% by weight or more and 35% by weight or less in each preparation, or, for example, 3% by weight or more and 30% by weight or less, 5% by weight or more and 25% by weight or less.

[0031] The polymer substance that forms the hydrogel used in component (2) of the present application can be used to control the drug release rate. The average molecular weight (viscosity average molecular weight) of the polymer substance that forms the hydrogel is, for example, 100,000 or more, 100,000 or more and 8,000,000 or less, 100,000 or more and 5,000,000 or less, or 100,000 or more and 2,000,000 or less, etc.

[0032] Alternatively, the viscosity of the polymer substance that forms the hydrogel is, for example, the viscosity of a 5% aqueous solution at 25°C is 12 mPa·s or more, the viscosity of a 5% aqueous solution at 25°C is 12 mPa·s or more and the viscosity of a 1% aqueous solution at 25°C is 40,000 mPa·s or less, the viscosity of a 2% aqueous solution at 25°C is 400 mPa·s or more and the viscosity of a 1% aqueous solution at 25°C is 7,500 mPa·s or less, or the viscosity of a 2% aqueous solution at 25°C is 400 mPa·s or more and the viscosity of a 1% aqueous solution at 25°C is 5,500 mPa·s or less.

[0033] The solid preparation of the sustained-release pharmaceutical composition of the present application can adjust the release period and / or release mode of component (1) from the preparation by adjusting the viscosity of the polymer substance that forms the hydrogel of component (2).

[0034] As the polymer substance that forms the hydrogel used in the solid preparation of the present application, as long as it can control the release of component (1), there are no particular limitations other than the above molecular weight or viscosity conditions.

[0035] For example, polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, carboxyvinyl polymer, etc. can be used. Preferably, they are polyethylene oxide, hydroxypropyl methylcellulose, and hydroxypropyl cellulose.

[0036] The above polyethylene oxide (hereinafter referred to as PEO) is, for example, the trade name Polyox WSR-308 [average molecular weight: 8 million, viscosity: 10,000 - 15,000 mPa·s (1% aqueous solution at 25°C)], Polyox WSR-303 [average molecular weight: 7 million, viscosity: 7,500 - 10,000 mPa·s (1% aqueous solution at 25°C)], Polyox WSR Coagulant [average molecular weight: 5 million, viscosity: 5,500 - 7,500 mPa·s (1% aqueous solution at 25°C)], Polyox WSR-301 [average molecular weight: 4 million, viscosity: 1,650 - 5,500 mPa·s (1% aqueous solution at 25°C)], Polyox WSR-N-60K [average molecular weight: 2 million, viscosity: 2,000 - 4,000 mPa·s (2% aqueous solution at 25°C)], Polyox WSR-N-12K [average molecular weight: 1 million, viscosity: 400 - 800 mPa·s (2% aqueous solution, 25°C)] (manufactured by DOW).

[0037] Hydroxypropyl methylcellulose (hereinafter referred to as HPMC) includes, for example, the product name Metolose 90SH-50000 [viscosity of 2% aqueous solution at 20°C: 2,900 to 3,900 mPa·s], TC-5S (product name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20°C: about 15 mPa·s), Metolose 60SH-50 (product name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20°C: about 50 mPa·s), Metolose 65SH-50 (product name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20°C: about 50 mPa·s), Metolose 90SH-100 (product name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20°C: about 100 mPa·s), Metolose 90SH-100SR (product name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20°C: about 100 mPa·s), Metolose 65SH-400 (product name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20°C: about 400 mPa·s), Metolose 90SH-400 (product name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20°C: about 400 mPa·s), Metolose 65SH-1500 (product name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20°C: about 1500 mPa·s), Metolose 60SH-4000 (product name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20°C: about 4000 mPa·s), Metolose 65SH-4000 (product name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20°C: about 4000 mPa·s), Metolose 90SH-4000 (product name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20°C: about 4000 mPa·s).

[0038] Hydroxypropyl cellulose (hereinafter referred to as HPC) includes, for example, HPC-SL (trade name, manufactured by Nippon Soda Co., Ltd.) (average molecular weight: 100,000, viscosity of 2% aqueous solution at 20°C: 3.0 to 5.9 mPa·s), HPC-L (trade name, manufactured by Nippon Soda Co., Ltd.) (average molecular weight: 140,000, viscosity of 2% aqueous solution at 20°C: 6.0 to 10.0 mPa·s), HPC-M (trade name, manufactured by Nippon Soda Co., Ltd.) (viscosity of 2% aqueous solution at 20°C: 150 to 400 mPa·s), HPC-H (trade name, manufactured by Nippon Soda Co., Ltd.) (viscosity of 2% aqueous solution at 20°C: 1000 to 4000 mPa·s), and other hydroxypropyl celluloses.

[0039] Examples of methyl cellulose (hereinafter referred to as MC) include Metolose SM15 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20°C: about 15 mPa·s), Metolose SM25 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20°C: about 25 mPa·s), and Metolose SM100 (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) (viscosity of 2% aqueous solution at 20°C: about 100 mPa·s).

[0040] Sodium carboxymethyl cellulose (hereinafter referred to as CMC-Na) includes, for example, the product named Sunrose F-30MC [viscosity: 250 to 350 mPa·s (1% aqueous solution, 25°C)], the product named Sunrose F-150MC [average molecular weight: 200,000, viscosity: 1200 to 1800 mPa·s (1% aqueous solution at 25°C)], the product named Sunrose F-600MC [viscosity: 6000 to 8000 mPa·s (1% aqueous solution at 25°C)], and the product named Sunrose F-1000MC [average molecular weight: 420,000, viscosity: 8000 to 12000 mPa·s (1% aqueous solution, 25°C)] (manufactured by Nippon Paper Industries Co., Ltd.).

[0041] Hydroxyethylcellulose (hereinafter referred to as HEC) includes product names such as HEC Daicel SE850 (average molecular weight: 1.48 million, viscosity: 2400 - 3000 mPa·s (1% aqueous solution at 25°C)), and HEC Daicel SE900 (average molecular weight: 1.56 million, viscosity: 4000 - 5000 mPa·s (1% aqueous solution, 25°C)) (manufactured by Daicel Chemical Industries, Ltd.).

[0042] Carboxyvinyl polymer includes, for example, Carbopol 71G (viscosity: 4000 - 11000 mPa·s), Carbopol 971P (viscosity: 4000 - 11000 mPa·s), Carbopol 981 (viscosity: 4000 - 10000 mPa·s), Carbopol 941 (viscosity: 4000 - 10000 mPa·s), Carbopol 934 (viscosity: 30500 - 39400 mPa·s), Carbopol 934P (viscosity: 29400 - 39400 mPa·s) (manufactured by B.F. Goodrich Chemical Company).

[0043] As described above, in a plurality of embodiments, the polymer substances forming these hydrogels can be used singly or in combination of two or more as component (2).

[0044] In a plurality of embodiments, when component (1) in the solid preparation (when there is a coating, the coating is not considered) is 1 part by weight, the polymer substance forming the hydrogel of component (2) is 0.6 part by weight or more and 5 parts by weight or less, 0.8 part by weight or more and 4 parts by weight or less, or 0.88 part by weight or more and 3.79 parts by weight or less. By controlling the ratio of component (2) to component (1), the solid preparation can obtain a desired sustained-release effect and / or better structural stability.

[0045] The solid preparation of the sustained-release pharmaceutical composition of the present application further contains, as component (3), a non-hydrophilic additive exhibiting solubility of "the amount of water required to dissolve 1 g at 20 ± 5°C exceeds 10 mL". In other words, more than 10 mL of water is required to dissolve 1 g of the non-hydrophilic additive at 20 ± 5°C.

[0046] In a plurality of embodiments, component (3) may be a non-hydrophilic additive exhibiting solubility of "the amount of water required to dissolve 1 g at 20 ± 5°C exceeds 15 mL", or "the amount of water required to dissolve 1 g at 20 ± 5°C exceeds 20 mL".

[0047] As an example, the non-hydrophilic additive of component (3) exhibiting solubility of "the amount of water required to dissolve 1 g at 20 ± 5°C exceeds 10 mL" can be calcium gluconate, microcrystalline cellulose, or a combination thereof.

[0048] In a plurality of embodiments, by controlling the ratio between component (3) and component (1), the solid preparation can obtain a desired sustained-release effect and / or better structural stability.

[0049] In a plurality of embodiments, when component (1) in the solid preparation (when a coating is present, the coating is not considered) is 1 part by weight, the non-hydrophilic additive of component (3) is 0.05 part by weight or more and 10 parts by weight or less, 0.1 part by weight or more and 8 parts by weight or less, or 0.15 part by weight or more and 7 parts by weight or less.

[0050] When the solid preparation of the present application does not have a coating, except for the polymer substance forming the hydrogel of component (2) in the solid preparation, it does not contain a hydrophilic component exhibiting solubility of "the amount of water required to dissolve 1 g at 20 ± 5°C is 10 mL or less".

[0051] When the solid preparation of the present application is coated, in a situation where the coating is not considered, except for the polymer substance forming the hydrogel of component (2) in the solid preparation, it does not contain a hydrophilic component exhibiting solubility of "the amount of water required to dissolve 1 g at 20 ± 5°C is 10 mL or less".

[0052] In multiple embodiments, when the solid preparation is in a capsule dosage form, when determining whether it has the "coating" described in this application, it is judged by each particle in the capsule.

[0053] The inventor has found that by making the composition the above composition, the solid preparation containing component (1) has better structural stability while maintaining the sustained-release effect.

[0054] Furthermore, in the solid preparation (without considering the coating), by not containing a hydrophilic component showing a solubility of "the amount of water for dissolving 1 g at 20 ± 5°C is 10 mL or less" other than the polymer substance forming the hydrogel, while maintaining the sustained-release effect in the solid preparation, the influence of moisture in the environment is reduced, and the probability of the components inside the preparation reacting with moisture is reduced.

[0055] Examples of the above "hydrophilic component showing a solubility of 'the amount of water for dissolving 1 g at 20 ± 5°C is 10 mL or less'" include the following (1) to (8). For example, (1) is a water-soluble polymer: polyethylene glycol [Polyethylene glycol, abbreviated as PEG], and PEG is an ethylene glycol polymer with an average molecular weight of 20,000 or less.

[0056] PEG includes, for example, trade names PEG400, PEG1500, PEG4000, PEG6000, PEG20000 (manufactured by NOF Corporation), polyvinylpyrrolidone [PVP; for example, trade name PVP K30 (manufactured by BASF)] and the like.

[0057] Also, (2) includes sugar alcohols: D-mannitol, D-sorbitol, xylitol, and the like.

[0058] Also, (3) includes saccharides: lactose, sucrose, anhydrous maltose, D-fructose, dextran (such as dextran 40), glucose, and the like.

[0059] Further, (4) is a surfactant: polyoxyethylene hydrogenated castor oil [HCO; for example, Cremophor RH40 (manufactured by BASF), HCO-40, HCO-60 (manufactured by Nikko Chemicals)], polyoxyethylene polyoxypropylene glycol [for example, Pluronic F68 (manufactured by Asahi Denka Co., Ltd.), etc.], polyoxyethylene sorbitan higher fatty acid ester [for example, Tween80 (manufactured by Kanto Chemical Co., Inc.)], and the like.

[0060] Examples of (5) to (8) include (5) amino acids: glycine, β-alanine, lysine hydrochloride, etc., (6) salts: salts such as sodium chloride and magnesium chloride, (7) organic acids: citric acid, tartaric acid, etc., and (8) amino sugars: meglumine, etc.

[0061] In a plurality of embodiments, the sustained-release pharmaceutical composition of the present invention can use additional additives according to actual needs.

[0062] The additional additive is pharmaceutically acceptable and is sufficient as long as it does not exhibit the solubility of "the amount of water required to dissolve 1 g at 20 ± 5°C is 10 mL or less" except when used for forming a coating or when it is a component belonging to the above-mentioned component (2), and there are no other special restrictions.

[0063] Examples of various organic or inorganic carrier substances generally used in formulations include formulation additives such as binders, disintegrants, excipients, lubricants, antioxidants, and coating materials.

[0064] Binders include, but are not limited to, polyethylene oxide, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, povidone, and the like.

[0065] Examples of disintegrants include, but are not limited to, starch, calcium carboxymethylcellulose, sodium croscarmellose, sodium carboxymethyl starch, light anhydrous silicic acid, low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, calcium carboxymethylcellulose, potato starch, etc.

[0066] Excipients include, but are not limited to, starch, α-starch, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminum metasilicate acid, etc.

[0067] Examples of lubricants include, but are not limited to, talc, kaolin, titanium dioxide, magnesium stearate, calcium stearate, stearic acid, light anhydrous silicic acid, micronized silica, etc.

[0068] Antioxidants include, but are not limited to, butylated hydroxytoluene (BHT), propyl gallate (PG), butylated hydroxyanisole (BHA), etc.

[0069] The coating material only needs to be able to form a coating for the solid preparation, and its components are not particularly limited.

[0070] In the present application, the coating material may contain a hydrophilic substance showing a solubility of "the amount of water for dissolving 1 g at 20 ± 5°C is 10 mL or less".

[0071] Coating materials include commonly used water-soluble polymer substances (such as HPMC, HPC, MC, etc.), plasticizers (such as glycerin, phthalate ester, etc.), colorants, or mixtures thereof.

[0072] Examples of the coloring agent include water-soluble edible tar dyes (edible colorants such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, Food Blue No. 1 and No. 2, etc.), water-insoluble lake pigments (for example, aluminum salts of the above water-soluble edible tar dyes), natural pigments (for example, β-carotene, chlorophyll, ferric oxide), and the like.

[0073] These other additives can be used alone or in combination of two or more as needed.

[0074] The amounts of these additional additives in the solid preparation can be adjusted according to actual needs. For example, the antioxidant should not exceed 1% by weight based on the total weight of the solid preparation. For example, its content may be not less than 0.025% by weight and not more than 0.25% by weight.

[0075] The pharmaceutical composition of the present invention can be produced by mixing and molding the above components. For example, the solid preparation of the present application can be obtained by granulating, sizing, mixing, tableting, compressing, and coating the necessary components. In the present application, each step can be carried out based on conventional methods and apparatuses in the pharmaceutical technology field.

[0076] For example, to granulate each component or a mixture containing each component, a general granulation method can be used. For example, any granulation method such as fluidized bed granulation, batch granulation, stirring granulation, high-speed stirring granulation, dry granulation, wet granulation, etc. can be used as long as it is a granulation method.

[0077] Examples of the granulation apparatus include a fluidized bed granulator. In some cases, the granulated product can also be dried and heat-treated. Further, in order to make the particle size of the granulated product uniform, the granulated product can also be subjected to a granulation step.

[0078] In the method for manufacturing the pharmaceutical composition of the present application, the order of mixing each component is not limited. For example, component (1), component (2), and component (3) can be mixed together at once as needed, simultaneously with other additional additives (if any). For example, component (3) can be first mixed with the additional additives and then mixed with the other components.

[0079] As the tableting method, there are a direct tableting method in which component (1), component (2), and component (3) are mixed with appropriate additives and compression molded to obtain tablets, or a method in which component (1), component (2), and component (3) are mixed with appropriate additives, granulated by spraying an adhesive solution (wet granulation), and then tableted. Examples of tableting devices include rotary tablet presses and single-shot tablet presses.

[0080] Coating can be formed on the formed tablets as needed. For example, using a pan coating device after tableting, a coating film is formed on the tablets before coating (hereinafter referred to as core tablets) at a ratio of 1% to 10% by weight (e.g., 2% to 8% by weight) per core tablet.

[0081] Also, as described above, the solid preparation formed from the composition of the present application has a sustained-release effect.

[0082] In multiple embodiments, when the solid preparation is subjected to an elution test by the rotating basket method in the dissolution test method of the United States Pharmacopeia at 37°C, with 900 mL of USP phosphate buffer at pH 6.8 and a rotation speed of 100 rpm, the elution rate of component (1) of the solid preparation in 1 hour is 10% or less, and the elution rate of component (1) of the solid preparation in 12 hours is 80% or more.

[0083] In other embodiments, when the solid preparation of the present application is subjected to an elution test using the rotating basket method in the dissolution test method of the United States Pharmacopeia, in a 900 mL USP phosphate buffer at 37°C and pH 6.8 with a rotation speed of 100 rpm, the elution rate of component (1) of the solid preparation in 1 hour is 25% or less, and the elution rate of component (1) of the solid preparation in 12 hours is 75% or more.

[0084] Hereinafter, the present invention will be described in more detail with reference to Examples, but these Examples do not limit the scope of the present invention.

[0085] [Example 1] 1.00 part by weight of the compound of Formula 1 as component (1), 2.00 parts by weight of polyethylene oxide as component (2), and 1.94 parts by weight of calcium gluconate as component (3) are uniformly mixed in a mortar, and a tableting machine is used for tableting.

[0086] Next, a coating solution is sprayed onto the tablets using a coating machine to form a coating film on the tablets, thereby obtaining the sustained-release pharmaceutical composition of the present application. In the following Examples / Comparative Examples, unless otherwise specified, the coating solution is mainly prepared from hydroxypropyl methylcellulose and water.

[0087] [Example 2] 1.00 part by weight of the compound of Formula 1 as component (1), 0.88 part by weight of polyethylene oxide as component (2), and 7.00 parts by weight of calcium gluconate as component (3) are uniformly mixed in a mortar, and a tableting machine is used for tableting.

[0088] Next, a coating solution is sprayed onto the tablets using a coating machine to form a coating film on the tablets, thereby obtaining the sustained-release pharmaceutical composition of the present application.

[0089] [Example 3] 1.00 part by weight of the compound of Formula 1 as component (1), 3.79 parts by weight of polyethylene oxide as component (2), and 0.15 part by weight of calcium gluconate as component (3) are uniformly mixed in a mortar, and a tableting machine is used for tableting.

[0090] Next, a coating solution is sprayed onto the tablets using a coating machine to form a coating film on the tablets, thereby obtaining the sustained-release pharmaceutical composition of the present application.

[0091] [Example 4] 100.00 parts by weight of the compound of Formula 1 as component (1), 3.75 parts by weight of polyethylene oxide as component (2), and 0.19 parts by weight of microcrystalline cellulose as component (3) are uniformly mixed in a mortar, and a tableting machine is used for tableting.

[0092] Next, a coating solution is sprayed onto the tablets using a coating machine to form a coating film on the tablets, thereby obtaining the sustained-release pharmaceutical composition of the present application.

[0093] [Comparative Example 1, High-dose Commercial Product] The trade name is Betmiga, and the manufacturer is Avara Pharmaceutical Technologies, Inc. in the United States. The coated tablets contain 50 mg of the compound of Formula 1 (corresponding to component (1) of the present application) and the following components: polyethylene glycol (a hydrophilic component showing solubility of "1 g dissolves in 10 mL or less of water at 20 ± 5°C"), polyethylene oxide (corresponding to component (2) of the present application), hydroxypropylcellulose (corresponding to component (2) of the present application), 2,6-dibutyl-p-cresol, magnesium stearate, and yellow ferric oxide.

[0094] [Comparative Example 2] 1.00 part by weight of the compound of Formula 1 (corresponding to component (1) of the present application), 2.00 parts by weight of polyethylene oxide (corresponding to component (2) of the present application), and 1.94 parts by weight of polyethylene glycol (a hydrophilic component showing solubility of "1 g dissolves in 10 mL or less of water at 20 ± 5°C") are uniformly mixed in a mortar, and a tableting machine is used for tableting.

[0095] Next, a coating solution is sprayed onto the tablets using a coating machine to form a coating film on the tablets, thereby obtaining the composition of the comparative example.

[0096] [Comparative Example 3, Low-dose Commercial Product] The trade name is Betmiga, and the manufacturer is Avara Pharmaceutical Technologies, Inc. of the United States. The coated tablets contain 25 mg of the compound of Formula 1 (corresponding to Component (1) of the present application), and the following components: polyethylene glycol (a hydrophilic component showing solubility of "1 g dissolves in 10 mL or less of water at 20 ± 5 °C"), polyethylene oxide (corresponding to Component (2) of the present application), hydroxypropyl cellulose (corresponding to Component (2) of the present application), 2,6-dibutyl-p-cresol, magnesium stearate, and yellow iron oxide.

[0097] The components included in Comparative Example 2 and Examples 1 to 4 (the coating part is not included in Table 1) are summarized in Table 1 as follows.

[0098]

Table 1

[0099] [Stability Test 1] The formulations of Comparative Example 1 (i.e., high-dose commercial product), Comparative Example 2, and Examples 1 to 4 were each placed in a brown glass bottle, the mouth of the bottle was sealed with aluminum foil, then holes were made in the aluminum foil paper, and they were left in an environment of 60 °C and 80% RH for 1 day to conduct a stability test (in Examples 1 to 4, the content of Component (1) is the same as the content of Component (1) in Comparative Example 1).

[0100] The initial appearance (appearance on the 0th day) of each formulation is shown in Figure 1, and the appearance of each formulation after the test is shown in Figure 2. Also, the weight change of each formulation after the test (hereinafter, may also be referred to as "weight difference". Calculation method: ((weight of the formulation after the test - weight of the formulation before the test) / weight of the formulation before the test) × 100%) was recorded in Table 2 below.

[0101]

Table 2

[0102] Comparing Figure 1 and Figure 2, the following can be understood. That is, Comparative Example 1 and Comparative Example 2, which contain a hydrophilic component showing solubility of "the amount of water dissolving 1 g at 20 ± 5°C is 10 mL or less" and do not contain the non-hydrophilic additive of component (3) of the present application, had a large change in the appearance of the preparation after the test.

[0103] Specifically, the preparation of Comparative Example 1 collapsed after the test, and the preparation of Comparative Example 2 had its appearance damaged after the test, and the components inside the preparation leaked to the outside of the preparation.

[0104] In comparison with these, Examples 1 to 4 do not contain the above hydrophilic component and have the non-hydrophilic additive of component (3) described in the present application, but the appearance of each preparation is intact and almost maintains the original appearance even after the test.

[0105] In the comparison of weight difference, as can be seen from Table 2, compared with Examples 1 to 4, the weight increase of Comparative Example 1 and Comparative Example 2 is more obvious, which is considered to be caused by the relatively large amount of moisture in the air being absorbed. That is, when there is a lot of moisture in the preparation, it affects the appearance and internal form of the preparation and also affects the stability of the components inside the preparation.

[0106] Notably, Comparative Example 2 and Example 1 are similar in that both preparations have three components and the weight ratios of the three components in each preparation are the same. The only difference in their preparations is that the PEG in Comparative Example 2 is replaced by calcium gluconate.

[0107] However, it can be seen that the above adjustment significantly improves the stability of the external structure and the weight stability of the preparation. On the other hand, according to the results of Example 2, it can be seen that increasing the content of component (3) relative to component (1) significantly improves the weight stability.

[0108] Based on this, it can be seen that the composition of the present application is indeed excellent in structural stability.

[0109] [Stability Test 2] The formulations of Comparative Example 1 (i.e., high-dose commercial product), Comparative Example 2, and Examples 1 to 4 were each placed in a brown glass bottle, and after closing the bottle mouth with aluminum foil, holes were made in the aluminum foil paper, and then left in an environment of 50°C and 80% RH for 1 day to test the stability. The appearance of each formulation after the test is shown in Figure 3. Also, the internal state of the formulations of Comparative Example 1 and Example 1 after the test is shown in Figure 4.

[0110] Comparing Figure 1 and Figure 2, the following can be found. That is, even at a temperature lower than that of the stability test 1, Comparative Example 1 and Comparative Example 2, which contain a hydrophilic component showing solubility of "the amount of water to dissolve 1 g is 10 mL or less" and do not contain the non-hydrophilic additive of component (3) of the present application, still showed a remarkable change in the appearance of their formulations after the test.

[0111] Specifically, the formulation of Comparative Example 1 remained collapsed after the test, but the formulation of Comparative Example 2 was damaged in appearance after the test, and the components inside the formulation could be directly observed.

[0112] In comparison, Examples 1 to 4, which do not contain the above hydrophilic component and have the non-hydrophilic additive of component (3) described in the present application, maintained almost the original appearance of their respective formulations even after the test was completed (the initial appearance of each formulation is shown in Figure 1).

[0113] To confirm the internal state of the formulation, the formulations of Comparative Example 1 (commercial product) and Example 1 after the test were cut open.

[0114] It was found that the internal form of the formulation of Comparative Example 1 had changed after the test, and the substances inside were stuck together to form a block shape (it can be seen that the cut surface of the formulation is flat), but the inside of the formulation of Example 1 remained powdery (the cut surface of the formulation showed a pulverized shape).

[0115] From this, it is presumed that Comparative Example 1 absorbed relatively more moisture in the air.

[0116] From this, it can be seen that the composition of the present application can not only improve the stability of the external structure of the preparation, but also maintain the stability of the internal structure of the preparation.

[0117] [Stability Test 3] Each preparation of Comparative Example 1 (i.e., high-dose commercial product), Comparative Example 2, and Examples 1 to 4 was placed in its respective brown glass bottle, the mouth of the bottle was sealed with aluminum foil, and then holes were made in the aluminum foil paper, and it was left in an environment of 40 °C and 75% RH for 2 days for a stability test.

[0118] After the test is completed, the weight change of each preparation (calculation method: ((weight of the preparation after the test - weight of the preparation before the test) / weight of the preparation before the test)) × 100%) is recorded in Table 3 below.

[0119] Furthermore, the moisture content of each preparation after the test was measured with a KF micro moisture meter using Karl Fisher Coulometric Titration, and the results were recorded in Table 4 below.

[0120]

Table 3

[0121]

Table 4

[0122] As shown in Table 3, even in a test environment with lower temperature and humidity than Stability Test 1, compared with Examples 1 to 4, the weight increase of Comparative Example 1 and Comparative Example 2 is relatively obvious, which is considered to be due to the relatively large amount of moisture in the air being absorbed.

[0123] The inventor of the present invention further measured the moisture content of each preparation in order to confirm the moisture contained in each preparation.

[0124] According to the moisture detection test results shown in Table 4, it can be seen that the preparations of Comparative Example 1 and Comparative Example 2 contain significantly more moisture after the test than the preparations of Examples 1 to 4.

[0125] From the above test results, it can be seen that the preparations of the comparative examples are more likely to absorb water than the preparations of the composition of the present application. As a result, it affects the appearance and internal form of the preparation, and it can be seen that the stability of the components inside the preparation is reduced.

[0126] From this, it can be seen that the composition of the present application can not only improve the stability of the external structure of the preparation, but also maintain the stability of the internal structure of the preparation.

[0127] [Stability Test 4] The tablets of Comparative Example 3 (low-dose commercial product) and the sustained-release pharmaceutical composition of Example 1 were each packaged in an aluminum foil blister (AL-AL Blister) pack and left in an environment of 40 °C and 75% RH for 3 months and 6 months for a stability test.

[0128] When each test was completed, the samples were analyzed using high performance liquid chromatography (HPLC), and the amount of impurities in each sample (each impurity is directly shown in the following table by the relative retention time (RRT) of HPLC) was evaluated. The conditions of the HPLC used are as follows.

[0129] System / Column: Waters Alliance 2690 series HPLC system, Symmetry Shield RP18 column, 5 microns, 4.6×250 mm Mobile phase A (MP A): Buffer / methanol = 70 / 30 (v / v) Mobile phase B (MP B): Acetonitrile / buffer = 70 / 30 (v / v) (Preparation of buffer: 1.74 grams of dipotassium hydrogen phosphate anhydrous (K2HPO4) and sodium octanesulfonate anhydrous (C8H 17Dissolve 3 grams of (NaO3S)3 in 1000 mL of pure water, and use phosphoric acid (H3PO4) to adjust the pH of the solution to pH 5.0. After uniformly mixing this solution, filter the solution through a filter equipped with a 0.2 μm GHP (GH Polypro) membrane and degas it.) Flow rate: 1.0 mL / min Column temperature: 45 °C Detection method: Ultraviolet (UV) 210 nm Analysis time: 55 minutes

[0130] Gradient conditions:

Table 5

[0131] Preparation of stock solution: Crush the total amount of 5 tablets of the preparation in a mortar, transfer it to a 100 mL brown volumetric flask, add methanol up to the calibration line of the volumetric flask, and stir for 4 hours. Before proceeding to the next step, confirm that the volume has been restored to the marked position. Centrifuge a part of the stock solution at 4000 rpm for 10 minutes.)

[0132] Preparation of sample solution: After centrifuging 8 mL, transfer the aforementioned stock solution to a 20 mL brown volumetric flask, add Diluent 1 up to the calibration line of the volumetric flask, and mix uniformly. Filter this solution through a filter with a 0.45 μm polyvinylidene difluoride (PVDF) membrane, and discard the first 8 mL. (Preparation of Diluent 1: Water / acetonitrile = 1 / 1 (v / v)).

[0133] Sample injection volume: 5 μL The analysis results of the tablets of Comparative Example 3 (i.e., low-dose commercial product) are shown in Table 6 below. The analysis results of the sustained-release pharmaceutical composition of Example 1 are as shown in Table 7 below.)

[0134]

Table 6

[0135]

Table 7

[0136] As can be seen from Table 6, when the low-dose commercial tablets of Comparative Example 3 were stored for 6 months, the tablets contained impurities exceeding 0.2% of the reference value (see RTT 0.84), did not comply with the relevant regulations regarding the inspection and registration of pharmaceuticals, indicating that the internal components of this formulation were not stable.

[0137] Relatively speaking, as shown in Table 7, Example 1, which has a non-hydrophilic additive of component (3) and does not contain a hydrophilic component showing a solubility of "the amount of water to dissolve 1 g is 10 mL or less" at "20 ± 5°C", still had the proportion of each impurity lower than 0.2% even after being stored for 6 months and complied with the regulations.

[0138] It is worth mentioning that it is generally known that the higher the proportion of the active ingredient in the tablet, the higher the possibility that the active ingredient will cause subsequent reactions and become unstable.

[0139] However, although the comparison target is a low-dose commercial product (the commercial tablets of Comparative Example 3 are about 256 mg, so the dosage of the active ingredient is about 9.8%), the component (1) of Example 1 is at a more stringent high dosage (that is, the proportion of component (1) exceeds 10%, for example, in the example, component (1) accounts for about 20.2% of the whole formulation), yet the formulation comprising the composition of the present application still has even better component stability.

[0140] [Dissolution Test] The formulation of Example 1 was subjected to the rotating basket method in the dissolution test method of the United States Pharmacopeia. At 37°C, in 900 mL of USP phosphate buffer, pH 6.8, the dissolution rate test of component (1) was carried out at a rotation speed of 100 rpm and repeated 8 times, and the results of each time were shown in Table 8 below. Also, the average value of the dissolution rate at each time point of each test was drawn as a dissolution curve as shown in Figure 5.

[0141]

Table 8

[0142] As can be seen from Table 8 and Figure 5, the elution rate of component (1) of the formulation of Example 1 at 1 hour was 25% or less (average about 8.7%), and the elution rate of component (1) of the solid formulation at 12 hours was 75% or more (average about 88.8%). This indicates that the formulation of Example 1 can actually release the drug slowly and achieve a sustained-release effect.

[0143] From this, it can be understood that the formulation formed by the composition of the present application not only has the structural stability and component stability shown in the above tests, but also has a sustained-release effect.

[0144] Based on the above description, those skilled in the art will understand the following. That is, those skilled in the art can make various modifications and changes to the present invention without departing from the spirit and scope of the present invention. Therefore, the technical scope of the present invention should be construed to include all equivalents thereof in addition to the scope of the claims.

Claims

1. (1) (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid anilide or a pharma- ceutically acceptable salt thereof; (2) one or more polymeric substances that form a hydrogel having an average molecular weight of 100,000 or more or a viscosity of a 5% aqueous solution of 12 mPa·s or more at 25° C.; and (3) One or more non-hydrophilic additives that exhibit a solubility of "more than 10 mL of water to dissolve 1 g at 20±5°C"; A solid formulation of a sustained release pharmaceutical composition comprising the components: When the solid preparation has a coating, the solid preparation does not contain a hydrophilic component that exhibits a solubility of "the amount of water that dissolves 1 g at 20±5° C. is 10 mL or less" except for the hydrogel-forming polymeric substance of component (2), regardless of the coating, When the solid preparation does not have the coating, it does not contain a hydrophilic component that exhibits a solubility of "1 g of water dissolving in 10 mL or less at 20±5° C.", except for the polymeric substance that forms a hydrogel of the component (2). A solid formulation of a sustained release pharmaceutical composition.

2. The solid formulation of the sustained release pharmaceutical composition according to claim 1, characterized in that the one or more non-hydrophilic additives of component (3) include microcrystalline cellulose, calcium gluconate, or a combination thereof.

3. The solid formulation of the sustained release pharmaceutical composition according to claim 1 or 2, characterized in that the component (1) is 1 part by weight, and the non-hydrophilic additive of the component (3) is 0.05 to 10 parts by weight or less.

4. The solid formulation of the sustained release pharmaceutical composition according to claim 1, characterized in that the polymeric substance forming one or more hydrogels of component (2) comprises at least one selected from the group consisting of polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, and carboxyethylene polymer.

5. The solid formulation of the sustained release pharmaceutical composition according to claim 1, characterized in that the component (1) is 1 part by weight, and the hydrogel-forming polymeric substance of the component (2) is 0.6 parts by weight or more and 5 parts by weight or less.

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