JP2018123115A - Oral solid preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an oral solid preparation that inhibits the decomposition of silodosin as an active ingredient, for a long time from just after its production, and can stably hold the quality of the preparation.SOLUTION: An oral solid preparation contains silodosin or its pharmaceutically acceptable salt and an alkalization agent, where, the content of the silodosin or its pharmaceutically acceptable salt is 0.5 wt.% to 5 wt.% based on the weight of the preparation, and the content of the alkalization agent is 0.1 wt.% to 20 wt.% based on the weight of the preparation.SELECTED DRAWING: None

Description

  The present invention relates to an oral solid preparation, and more particularly to an oral solid preparation stably containing silodosin.

Silodosin is an α ₁ adrenergic receptor blocker. For example, when used as a remedy for dysuria due to prostatic hypertrophy, it selectively binds to the α1A receptor subtype in the lower urinary tract tissues such as prostate, urethra, and bladder triangle, bladder neck, urethra, prostate, etc. By relaxing the smooth muscles of the body, it acts to suppress urinary pressure increase and facilitate urination.

  However, the production of silodosin has heretofore required a multi-step synthesis process. For this reason, for example, in Patent Documents 1 to 3, proposals have been made for improving the production efficiency of silodosin through a new synthetic intermediate.

  On the other hand, with respect to silodosin, it has also been pointed out that the compound itself has insufficient stability to light and high temperature.

  Thus, several proposals have been made to improve the stability of sidrosine in the preparation. For example, Patent Document 4 describes preparing an inclusion compound of silodosin and cyclodextrin and formulating it. Further, Patent Document 5 describes mixing and granulating silodosin together with a binder other than hydroxypropylcellulose (for example, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer).

  However, even with these techniques, it is difficult to say that the stability of silodosin is sufficiently maintained in each preparation. In particular, there is a demand for technical development that can suppress the degradation of silodosin in the preparation from immediately after production to a predetermined storage period and can stably maintain the quality of the preparation.

Special table 2013-504563 JP2015-151395A Japanese Unexamined Patent Publication No. 2016-23186 JP 2013-529663 A JP-A-2006-138073

  An object of the present invention is to solve the above-mentioned problems. The object of the present invention is to suppress the degradation of silodosin, which is an active ingredient, over a long period of time immediately after production, and stably maintain the quality of the preparation. It is to provide an oral solid preparation that can be obtained.

The present invention is an oral solid preparation containing silodosin or a pharmaceutically acceptable salt thereof and an alkalizing agent,
The content of silodosin or a pharmaceutically acceptable salt thereof is 0.5% to 5% by weight, based on the weight of the formulation, and the content of the alkalizing agent accounts for the weight of the formulation. It is an oral solid preparation which is 0.1 to 20% by weight as a reference.

  In one embodiment, the silodosin or a pharmaceutically acceptable salt thereof is contained in a non-inclusion form.

  In one embodiment, the alkalizing agent is an alkali metal carbonate, alkaline earth metal carbonate, alkali metal citrate, alkaline earth citrate, alkali metal malate, alkaline earth metal malate. Salt, alkali metal succinate, alkaline earth metal succinate, alkali metal acetate, alkaline earth metal acetate, alkali metal pyrophosphate, alkaline earth metal pyrophosphate, alkali metal benzoate, benzoic acid Alkaline earth metal salt, alkali metal ascorbate, alkaline earth metal ascorbate, alkali metal tartrate, alkaline earth metal tartrate, alkali metal dehydroacetate, alkaline earth metal dehydroacetate, alkali metal glutamate , Alkaline earth metal glutamate, basic amino acids, basic amino sugars, and Is at least one compound selected from the group consisting of hydrates.

  In one embodiment, the oral solid formulation of the present invention further comprises a binder that has a viscosity of 1 mPa · s to 10 mPa · s in a 2% aqueous solution at 20 ° C.

  In one embodiment, the oral solid formulation of the present invention further comprises a binder, wherein the binder is at least one compound selected from the group consisting of hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, hypromellose, and agar. It is.

  In one embodiment, the oral solid formulation of the present invention further contains an excipient.

In one embodiment, comprising a plurality of laminated particles comprising a core particle, an intermediate layer surrounding the core particle, and a coating layer surrounding the intermediate layer,
The laminated particles contain the silodosin or a pharmaceutically acceptable salt thereof and the alkalizing agent in the intermediate layer.

The present invention is also a method for producing an oral solid preparation,
Adding and mixing silodosin or a pharmaceutically acceptable salt thereof with an alkalizing agent;
The content of silodosin or a pharmaceutically acceptable salt thereof is 0.5% to 5% by weight, based on the weight of the formulation, and the content of the alkalizing agent accounts for the weight of the formulation. This is a method of 0.1 to 20% by weight as a reference.

  In one embodiment, the adding and mixing step is performed by adding and mixing excipients with the alkalizing agent and silodosin or a pharmaceutically acceptable salt thereof.

  In a further embodiment, the adding and mixing step is performed by adding and mixing the silodosin or a pharmaceutically acceptable salt thereof to a premix of the alkalizing agent and the excipient.

  According to the present invention, since the generation of related substances is suppressed, the quality of the oral solid preparation itself can be maintained over a long period of time. Moreover, such an oral solid preparation can be produced through a relatively simple process. This makes it possible to achieve both long-term storage and mass production.

  Hereinafter, the present invention will be described in detail.

(Oral solid preparation)
The oral solid preparation of the present invention contains silodosin or a pharmaceutically acceptable salt thereof and an alkalizing agent.

  As used herein, the term “oral solid formulation” encompasses a solid pharmaceutical formulation that is administered through the oral cavity without water or with a small amount of water. Examples of oral solid preparations include tablets that are solid preparations formed into a certain shape by a method such as compression molding, and orally disintegrating tablets that are tablets prepared so as to disintegrate in the oral cavity. OD tablets).

  Cidrosine constituting the oral solid preparation of the present invention is 1- (3-hydroxypropyl) -5-[(2R) -2-({2- [2- (2,2,2-trifluoroethoxy) phenoxy]]. Ethyl} amino) propyl] -2,3-dihydro-1H-indole-7-carboxamide, which has the general chemical formula:

It is an indoline derivative represented by. As an α ₁ adrenergic receptor blocker, sidrosine is known to have a function of blocking the receptor localized in the prostate, relaxing the bladders, urethra and prostate smooth muscle to facilitate urination. Thereby, for example, it can be used as a therapeutic agent for dysuria associated with enlarged prostate. Silodosin has also been proposed for use as a male contraceptive. In the present invention, silodosin may be a solvate with other pharmaceutically acceptable solvents such as hydrates and ethanol solvates.

  Furthermore, the pharmaceutically acceptable salt of sidrosine constituting the oral solid preparation of the present invention is any form of pharmaceutically acceptable salt for the above-mentioned sidrosine, such as acid addition salts and base addition salts. Is mentioned. Examples of acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, or phosphate; and citrate, oxalate, acetate, And organic acid salts such as formate, propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, or paratoluenesulfonate. Examples of base addition salts include inorganic base salts such as sodium, potassium, calcium, magnesium, or ammonium salts; and organic base salts such as triethylammonium, triethanolammonium, pyridinium, and diisopropylammonium salts; Is mentioned.

  In the oral solid preparation of the present invention, the content of the above-mentioned sidrosine or a pharmaceutically acceptable salt thereof is 0.5% to 5% by weight, preferably 0.6% by weight, based on the weight of the oral solid preparation. -4% by weight, more preferably 0.8% -3% by weight.

  In the present invention, sidrosine or a pharmaceutically acceptable salt thereof may be contained in a form (that is, a non-inclusion form) that is not included by an excipient or the like described later. preferable.

  The alkalizing agent constituting the oral solid preparation of the present invention includes any pharmaceutically acceptable inorganic and / or organic alkalizing agent. Examples of the alkalizing agent include carbonates, bicarbonates, ammonia salts, basic amino acids, and hydrates thereof, and combinations thereof. Alternatively, when the alkalizing agent is composed of an inorganic alkalizing agent, examples of the inorganic alkalizing agent include alkali metal salts such as sodium salt or potassium salt; magnesium salt, calcium salt, or barium. And alkaline earth metal salts such as salts; and their hydrates: and combinations thereof.

  Specific examples of the alkalizing agent in the present invention are not necessarily limited, but include alkali metal carbonates, alkaline earth metal carbonates, alkaline metal citrates, alkaline earth metal citrates, and alkaline metal malates. , Alkaline earth metal malate, alkali metal succinate, alkaline earth metal succinate, alkali metal acetate, alkaline earth metal acetate, alkali metal pyrophosphate, alkaline earth metal pyrophosphate, benzoic acid Alkali metal salt, alkaline earth metal benzoate, alkali metal ascorbate, alkaline earth metal ascorbate, alkali metal tartrate, alkaline earth metal tartrate, alkali metal dehydroacetate, alkaline earth dehydroacetate Metal salt, alkali metal glutamate, alkaline earth metal glutamate, basic amino acid Acid, basic amino sugars, and their hydrates, and combinations thereof. Specific examples of the alkalizing agent in the present invention include potassium carbonate, magnesium carbonate, calcium carbonate, meglumine, L-arginine, L-lysine, sodium citrate, sodium malate, sodium succinate, sodium acetate, pyrroline. And sodium benzoate, sodium ascorbate, sodium glutamate, sodium tartrate, sodium dehydroacetate, and hydrates thereof, and combinations thereof.

  In the oral solid preparation of the present invention, the content of the alkalizing agent is, for example, 0.1% by weight to 20% by weight based on the weight of the oral solid preparation. When the content of the alkalizing agent contained in the preparation is less than 0.1% by weight, the stability of the drug component (ie, sidrosine or a pharmaceutically acceptable salt thereof) contained in the preparation is maintained over a long period of time. It becomes difficult. When the content of the alkalizing agent contained in the preparation exceeds 20% by weight, the stability of the drug component contained in the preparation is not changed, but rather only a large number of alkalizing agents are used and produced. It will lack sex. The preferred content of the alkalizing agent is not necessarily limited, since it may vary depending on the content of sidrosine, the type of alkalizing agent, the type and content of excipients, etc. in the oral solid preparation of the present invention, It can be arbitrarily selected from various ranges resulting from combinations of the lower limit and the upper limit of the amounts. Examples of the lower limit of the content of the alkalizing agent that can constitute the range of the content of the alkalizing agent include 0.1% by weight or more and 0.2% by weight or more based on the weight of the oral solid preparation. 0.5% by weight or more, and 1% by weight or more. And as an example of the upper limit of the content of the alkalizing agent that can constitute the range of the content of the alkalizing agent, it is 20% by weight or less, 10% by weight or less, 6% by weight or less based on the weight of the oral solid preparation. 5 wt% or less, and 4 wt% or less.

  The excipient in the present invention exists in an oral solid preparation, for example, in a mixed state with the above-mentioned sidrosine or a pharmaceutically acceptable salt thereof and an alkalizing agent. In the oral solid preparation of the present invention, the above-mentioned sidrosine or a pharmaceutically acceptable salt thereof and an alkalinizing agent may constitute an uncoated tablet, or these form a dry tablet and are further described below. The coating layer may be formed by the coating agent.

  The oral solid preparation of the present invention may also contain an excipient.

  The excipient that can constitute the present invention is not particularly limited. For example, starch (corn starch (corn starch), potato starch, wheat starch, rice starch, partially pregelatinized starch, hydroxypropyl starch, etc.) and derivatives thereof, Sugar (glucose, lactose, sucrose (including refined sucrose), powdered sugar, trehalose, dextran, dextrin, etc.), sugar alcohol (D-mannitol, xylitol, sorbitol, erythritol, etc.), glycerin fatty acid ester, inorganic powder (aluminum metasilicate) Magnesium hydroxide, synthetic hydrotalcite), light anhydrous silicic acid, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium hydrogen phosphate hydrate, sodium hydrogen carbonate and other inorganic salts, and combinations thereof . Examples of preferred excipients include D-mannitol, lactose, and starch, and combinations thereof.

The content of the excipient in the present invention is not necessarily limited, but is preferably 0.1% by weight to 99.4% by weight, more preferably 1% by weight to 90% by weight, based on the weight of the oral solid preparation. It is. In the present invention, when the content of the excipient satisfies the above range, the pharmaceutical effect and function (eg, α ₁ adrenergic receptor blocking) of the drug component, sidrosine, or a pharmaceutically acceptable salt thereof itself. (Function as a medicine) can be appropriately maintained, and the stability of the drug component in the preparation can be enhanced.

  The oral solid preparation of the present invention may also contain a binder.

  In one embodiment, the binder capable of constituting the oral solid preparation of the present invention has a viscosity of 2 m aqueous solution at 20 ° C., preferably 1 mPa · s to 10 mPa, more preferably 1 mPa · s to 6 mPa · s. . The viscosity in a 2% aqueous solution at 20 ° C. can be measured, for example, according to the Japanese Pharmacopoeia. By containing a binder satisfying such a viscosity range, the dissolution property of the drug component (that is, sidrosine or a pharmaceutically acceptable salt thereof) contained in the formulation is improved, and the drug is present in the presence of water. The components can be eluted earlier.

  In the present invention, the binder is preferably a pharmaceutically acceptable polysaccharide compound (for example, a cellulose compound, an agarose compound, and an agaropectin compound). In one embodiment, the polysaccharide-based compound is preferably 10,000 to 620,000, more preferably 10,000 to 140,000, even more preferably 10,000 to 100,000, or about 40. Those having an average weight molecular weight (Mw) of 1,000 can be selected. Specific examples of binders include, but are not necessarily limited to, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, hypromellose, and agar, and combinations thereof. In the present invention, hydroxypropylcellulose can be suitably selected because the dissolution property of the oral solid preparation can be enhanced and it is easily available.

  Furthermore, when hydroxypropylcellulose is selected as the binder, the viscosity of the hydroxypropylcellulose in a 2% aqueous solution at 20 ° C. is, for example, 2 mPa · s to 6 mPa, 2 mPa · s to 2.9 mPa, 3 mPa · s to Those satisfying any range of 5.9 mPa can be selected. Hydroxypropyl cellulose satisfying such a viscosity range is commercially available from Nippon Soda Co., Ltd. under trade names such as HPC-SSL and HPC-SL.

  The preferred content of the binder in the present invention may vary depending on the content of sidrosine in the oral solid preparation of the present invention and the type of alkalizing agent, and so is not necessarily limited. It can be arbitrarily selected from various ranges resulting from the combination of examples. Examples of the lower limit of the content of the binder that can constitute the range of the content of the binder include 0.1% by weight or more, 0.2% by weight or more based on the weight of the oral solid preparation, 0 .3% by weight or more, 1.5% by weight or more, and 2.5% by weight or more. And as an example of the upper limit of the content of the binder that can constitute the range of the content of the binder, it is 20% by weight or less, 10% by weight or less, 7% by weight or less, based on the weight of the oral solid preparation. Weight percent or less, 2.5 weight percent or less, and 1.5 weight percent or less. In the present invention, by satisfying the range in which the binder content can be composed of the combination of the above lower limit and upper limit, the dissolution property of the drug component sidrosine or a pharmaceutically acceptable salt thereof is further enhanced. Can do.

  The oral solid preparation of the present invention may further contain any other pharmaceutically acceptable additive. Examples of such other additives include disintegrants, fluidizers, colorants, flavoring agents, lubricants, and perfumes, and combinations thereof.

  The disintegrant is not particularly limited, but for example, crospovidone, crystalline cellulose, carboxymethylcellulose (carmellose), croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, starch, partially pregelatinized starch, starch glycolic acid Examples include sodium, hydroxypropyl starch, calcium carbonate, precipitated calcium carbonate, calcium citrate, light anhydrous silicic acid, synthetic aluminum silicate, and combinations thereof.

  The fluidizing agent is not particularly limited, and examples thereof include hydrous silicon dioxide, light anhydrous silicic acid, talc, synthetic aluminum silicate, titanium oxide, stearic acid, magnesium stearate, calcium stearate, magnesium aluminate metasilicate, and the like. The combination of these is mentioned.

  The colorant is not particularly limited, and examples thereof include titanium oxide, iron sesquioxide, yellow sesquioxide, edible red No. 2, edible red No. 3, edible yellow No. 4, and edible yellow No. 5, and combinations thereof. Can be mentioned.

  The corrigent is not particularly limited, and examples thereof include aspartame, stevia, sugar alcohol, saccharin sodium, dipotassium glycyrrhizin, thaumatin, acesulfame potassium, and sucralose, and combinations thereof.

  The lubricant is not particularly limited. For example, stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, light anhydrous silicic acid, hydrogenated oil, glycerin fatty acid ester, and talc. And combinations thereof.

  The fragrance is not particularly limited, and examples thereof include mint, lemon fragrance, orange corton, pineapple flavor, and l-menthol, and combinations thereof.

  The content of other additives in the oral solid preparation of the present invention is not particularly limited and can be appropriately selected by those skilled in the art.

  Further, the oral solid preparation of the present invention comprises the above-described components (ie, sidrosine or a pharmaceutically acceptable salt thereof, and an alkalinizing agent, and excipients, binders and other additives that can be added as necessary. You may have the dosage form of the uncoated tablet (bare tablet) which compressed the agent directly.

  Alternatively, the oral solid preparation of the present invention comprises the above-described components (ie, sidrosine or a pharmaceutically acceptable salt thereof, and an alkalizing agent, and excipients, binders and other additives that can be added as necessary. Agent) constitutes a dry-coated tablet, the dry-coated tablet may be coated with a coating agent, and may have a dosage form of a coated tablet in which a coating layer is formed.

  An example of the coated tablet in the present invention will be described.

  Such an oral solid preparation in the form of a coated tablet contains, for example, a plurality of laminated particles comprising a core particle, an intermediate layer surrounding the core particle, and a coating layer surrounding the intermediate layer. It may be a thing. Here, the core particles contain the above-mentioned excipients, other additives, and the like. The intermediate layer contains the sidrosine or a pharmaceutically acceptable salt thereof, and an alkalizing agent, and may contain the binder and / or other additives as necessary. The coating layer contains a coating agent, and may contain other additives as necessary.

  The coating agent constituting the coating layer is not particularly limited, and examples thereof include aminoalkyl methacrylate copolymer E, sugar (for example, glucose, fructose, lactose, sucrose, reduced maltose, trehalose and combinations thereof), sugar alcohol ( For example, polyethylene glycols such as mannitol, erythritol, sorbitol, xylitol, maltitol, and lactitol, and combinations thereof), methylcellulose, ethylcellulose, hydroxypropylcellulose, hypromellose, polyvinyl acetal diethylaminoacetate, triethyl citrate, triacetin, macrogol, etc. PEG), polysorbates, talc, yellow ferric oxide and titanium oxide, and combinations thereof . Aminoalkyl methacrylate copolymer E, ethylcellulose, and polyvinyl acetal diethylaminoacetate, and combinations thereof are preferred. The content of the coating agent in the present invention is not particularly limited and can be appropriately selected by those skilled in the art.

  When the oral solid preparation of the present invention has the dosage form of the coated tablet, the coating layer constituting the coated tablet is the entire surface of the dry-coated tablet constituting the content component (for example, the intermediate layer surrounding the core particles). It is preferable to cover. Moreover, it is preferable that the thickness of a coating layer is substantially uniform over the whole surface of the oral solid formulation of this invention. The thickness of the coating layer that can constitute the present invention is not particularly limited, and an appropriate thickness can be set by those skilled in the art.

  The oral solid preparation of the present invention may have any shape. For example, when the oral solid preparation of the present invention is an orally disintegrating tablet, examples of the shape of the orally disintegrating tablet include a disc shape, a donut shape, a polygonal plate shape, a spherical shape, an oval shape, and a caplet shape. Can be mentioned. The size of the oral solid preparation of the present invention is preferably small, the diameter is, for example, about 5 mm to 12 mm, and the thickness is, for example, about 2 mm to 5 mm. The mass is, for example, about 50 mg to 500 mg. Although hardness is not specifically limited, For example, it may be set to about 40N-100N. When the oral solid preparation of the present invention is an orally disintegrating tablet, the time required for disintegration is not particularly limited. For example, when taken without water, the disintegration time is set to about 10 to 60 seconds in the oral cavity. The ones made are preferred.

(Method for producing oral solid preparation)
First, an example of a method for producing an uncoated tablet containing silodosin or a pharmaceutically acceptable salt thereof will be described as a method for producing an oral solid preparation of the present invention.

  In the production method of the present invention, silodosin or a pharmaceutically acceptable salt thereof is added to and mixed with the alkalizing agent.

  In addition and mixing of the above silodosin or a pharmaceutically acceptable salt thereof, in one embodiment, in one embodiment, an alkalizing agent, an excipient, and silodosin or a pharmaceutical thereof, each weighed to have a predetermined content Are added together or in any order and then mixed by mixing means well known to those skilled in the art, for example until substantially uniform. During the mixing, the binder and other additives may be added to the mixture.

  In one embodiment, the addition and mixing of silodosin or a pharmaceutically acceptable salt thereof involves adding alkalinizing agents and excipients, and optionally binders and other additives to those skilled in the art. A premix obtained by mixing in advance by a known mixing means (for example, so as to be substantially uniform) may be used. In this case, the silodosin or a pharmaceutically acceptable salt thereof is added to the premix and can be mixed by mixing means well known to those skilled in the art, for example, until substantially uniform.

  Silodosin or a pharmaceutically acceptable salt thereof used in the present invention, when mixed with an alkalinizing agent, for example, in the presence of the above-mentioned binder or the like, may be decomposed by itself to generate a related substance. There is. Therefore, as described above, silodosin or a pharmaceutically acceptable salt thereof and an alkalizing agent are added and mixed at the same timing as much as possible, or the alkalizing agent and other components (excipient, binder) And other additives) as a premix, and then adding and mixing silodosin or a pharmaceutically acceptable salt thereof to the premix to produce related substances in such a mixing stage. Is preferably suppressed.

Subsequently, the mixture obtained as described above is compressed by a hydraulic hand press machine, a single-shot tablet machine, a rotary tablet machine, etc., using, for example, a tableting mortar, a tableting upper punch and a lower punch. Is done. Tableting is preferably performed by adjusting so that the resulting tablet has an appropriate hardness. The tableting pressure can be appropriately adjusted according to the tableting method, the equipment used for tableting, the size of the tablet, and the like. Tableting pressure is preferably ^{20kg / cm 2 ~2000kg / cm 2} , more preferably ^{100kg / cm 2 ~1000kg / cm 2} . Thereby, an uncoated tablet can be manufactured.

  Next, an example of a method for producing a coated tablet containing silodosin or a pharmaceutically acceptable salt thereof will be described as a method for producing the oral solid preparation of the present invention.

  When the oral solid preparation of the present invention is produced in the form of a coated tablet, the above-mentioned coating agent is applied (for example, sprayed or dispersed) to the plain tablet obtained above by means known to those skilled in the art. Thereby, the uncoated tablet becomes a dry-coated tablet, and a coated tablet having a coating layer formed around it is manufactured.

  Furthermore, another example of the method for producing a coated tablet containing silodosin or a pharmaceutically acceptable salt thereof will be described as a method for producing the oral solid preparation of the present invention.

  In adding and mixing the alkalizing agent with silodosin or a pharmaceutically acceptable salt thereof, first, the silodosin or a pharmaceutically acceptable salt thereof and the alkalizing agent are added to and mixed with water, and further required. Depending on the addition and mixing of other additives, one suspension (laying solution is prepared. This is applied to core particles having a predetermined particle size (for example, spraying, coating, or By impregnating, an intermediate layer is formed on the outer periphery of the core particle, and then a coating liquid containing the coating agent is applied to the intermediate layer (for example, spraying, applying, or impregnating). Laminated particles are formed.

  In the present invention, water, alcohol or a mixture of alcohol and water is used as the solvent for the coating liquid. As a solvent constituting the coating liquid, the inherent unpleasant taste (bitterness) caused by silodosin or a pharmaceutically acceptable salt thereof in the coated tablet (orally disintegrating tablet) can be effectively reduced. Preference is given to using alcohol or a mixture of alcohol and water. Examples of alcohols constituting such a solvent include ethanol and methanol, and combinations thereof. Furthermore, the alcohol concentration in the solvent is preferably 30% (w / w) or more, more preferably 50% (w / w) or more. When the solvent constituting the coating liquid has such an alcohol concentration, the solubility of the coating agent in the coating liquid is further improved, and the coating liquid is applied to the intermediate layer surrounding the core particles. In addition, a more uniform coating is possible. Thereby, while suppressing the unpleasant taste resulting from the sidrosine contained in an intermediate | middle layer, or its pharmaceutically acceptable salt, decomposition | disassembly of the silodosin in a formulation over a storage period can be suppressed further.

  The obtained laminated particles are mixed and tableted so as to have a predetermined size together with the other additives as necessary. Thereby, a coated tablet (orally disintegrating tablet) is produced.

  In this way, the oral solid preparation of the present invention can be produced.

  The obtained oral solid preparation is sealed in a container using a means known in the art. After enclosing in a container, the oral solid preparation of the present invention is stored under appropriate storage conditions until use.

  According to the oral solid preparation of the present invention, the stability over time is excellent, and the generation of related substances due to decomposition during storage can be suppressed. For this reason, even if a part of the product obtained through mass production is stored in stock, the quality can be maintained for a long time.

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

Example 1
2 parts by weight of shidrosin, 16 parts by weight of corn starch, 2.5 parts by weight of hydroxypropyl cellulose (HPC-SSL manufactured by Nippon Soda Co., Ltd .; viscosity in 2% aqueous solution at 20 ° C. is 2 mPa · s to 2.9 mPa) After 1 part by weight of calcium carbonate and 1 part by weight of magnesium stearate are sufficiently kneaded in a mortar, 77.5 parts by weight of D-mannitol (PEARLITOL (registered trademark) 100SD manufactured by Ferromet) is added and kneaded further sufficiently. A mixture for tablets was obtained. The obtained mixture was put into a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd .: VGRGO) and tableted. Uncoated tablet (E1) with a tablet diameter of 6.5 mm, a tablet mass of 100 mg, and a hardness of 40 N or more (Sidrosine 2 mg tablet ) The formulation in this example is shown in Table 1.

(Comparative Example 1)
A tableting mixture was obtained in the same manner as in Example 1 except that it did not contain precipitated calcium carbonate and the amount of D-mannitol was changed to 78.5 parts by weight. An uncoated tablet (C1) having a mass of 100 mg and a hardness of 40 N or more (Sidrosine 2 mg tablet) was obtained. Table 1 shows the formulation in this comparative example.

(Test Example 1: Measurement of increase in related substances)
With respect to the sidrosine uncoated tablets (E1) and (C1) obtained in Example 1 and Comparative Example 1, the rate of increase of sidrosine-derived related substances under the following conditions A and B was measured.

(Condition A)
About the sidrosine uncoated tablets (E1) and (C1) obtained in Example 1 and Comparative Example 1, the content of all related substances (total related substances) derived from sidrosine contained in the tablets immediately after production ( %) Was calculated as a ratio (%) of the peak area of each related substance to the peak area of sidrosine from the detection result of liquid chromatography of each uncoated tablet. The obtained results are shown in Table 2.

(Condition B)
About the sidrosine uncoated tablets (E1) and (C1) obtained in Example 1 and Comparative Example 1, each was individually wrapped with aluminum foil to completely shield from light, and the resulting package was 40 ° C. and 75% RH. And stored for 2 weeks. Immediately after storage, the content (%) of all related substances (total related substances) derived from sidrosine contained in the tablets was measured in the same manner as in Condition A above. Furthermore, the increase amount (increase amount) of the related substance was calculated in comparison with the result of Condition A. The obtained results are shown in Table 2.

  As shown in Table 2, the uncoated tablet (E1) obtained in Example 1 was compared with the uncoated tablet (C1) obtained in Comparative Example 1 from the stage immediately after production, and the similar line derived from sidrosine. The substance content was kept low. Further, the uncoated tablet (E1) of Example 1 was suppressed to about 1/4 of the increase in related substances compared to the uncoated tablet (C1) of Comparative Example 1 even after a storage period of 2 weeks. From this, it can be seen that the precipitated calcium carbonate used as the alkalinizing agent suppresses the generation of sidrosine-related substances in the preparation and improves the storage stability of the preparation itself.

(Example 2)
2 parts by weight of shidrosin, 16 parts by weight of corn starch, 2.5 parts by weight of hydroxypropyl cellulose (HPC-SL manufactured by Nippon Soda Co., Ltd .; viscosity in a 2% aqueous solution at 20 ° C. is 3 mPa · s to 5.9 mPa) After 1 part by weight of potassium and 1 part by weight of magnesium stearate are sufficiently kneaded in a mortar, 77.5 parts by weight of D-mannitol (Merck Partech 100M) is added and further kneaded to obtain a mixture for tableting. Obtained. The obtained mixture was put into a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd .: VGRGO) and tableted. Uncoated tablet (E2) with a tablet diameter of 6.5 mm, a tablet mass of 100 mg, and a hardness of 40 N or more (Sidrosine 2 mg tablet ) Table 3 shows the formulation in this example.

(Example 3)
A mixture for tableting was obtained in the same manner as in Example 2 except that 0.2 parts by weight of magnesium carbonate was used instead of potassium carbonate and the amount of D-mannitol was changed to 78.3 parts by weight. An uncoated tablet (E3) (Sidrosine 2 mg tablet) having a tablet diameter of 6.5 mm, a tablet mass of 100 mg, and a hardness of 40 N or more was obtained. Table 3 shows the formulation in this example.

Example 4
A tableting mixture was obtained in the same manner as in Example 2 except that 1 part by weight of magnesium carbonate was used instead of potassium carbonate and the amount of D-mannitol was changed to 77.5 parts by weight. An uncoated tablet (E4) (Sidrosine 2 mg tablet) of 6.5 mm, a tablet mass of 100 mg, and a hardness of 40 N or more was obtained. Table 3 shows the formulation in this example.

(Example 5)
A tableting mixture was obtained in the same manner as in Example 2 except that 4 parts by weight of magnesium carbonate was used instead of potassium carbonate and the amount of D-mannitol was changed to 74.5 parts by weight. An uncoated tablet (E5) (Sidrosine 2 mg tablet) having a thickness of 0.5 mm, a tablet mass of 100 mg, and a hardness of 40 N or more was obtained. Table 3 shows the formulation in this example.

(Example 6)
A mixture for tableting was obtained in the same manner as in Example 2 except that 1 part by weight of calcium carbonate was used instead of potassium carbonate, and an uncoated tablet having a tablet diameter of 6.5 mm, a tablet mass of 100 mg, and a hardness of 40 N or more ( E6) (Sidrosine 2 mg tablet) was obtained. Table 3 shows the formulation in this example.

(Example 7)
A mixture for tableting was obtained in the same manner as in Example 2 except that 1 part by weight of meglumine was used instead of potassium carbonate, and a tablet with a tablet diameter of 6.5 mm, a tablet mass of 100 mg, and a hardness of 40 N or more (E6 ) (Sidrosine 2 mg tablet). Table 3 shows the formulation in this example.

(Comparative Example 2)
It does not contain potassium carbonate, and instead of HPC-SL manufactured by Nippon Soda Co., Ltd. as hydroxypropylcellulose, HPC-SSL manufactured by Nippon Soda Co., Ltd. (viscosity in 2% aqueous solution at 20 ° C. is 2 mPa · s˜2. 9 mPa), and a mixture for tableting was obtained in the same manner as in Example 2 except that the amount of D-mannitol used was changed to 78.5 parts by weight, and a tablet diameter of 6.5 mm and a tablet mass of 100 mg were obtained. And an uncoated tablet (C2) having a hardness of 40 N or more (Sidrosine 2 mg tablet). Table 3 shows the formulation in this comparative example.

(Comparative Example 3)
A mixture for tableting was obtained in the same manner as in Example 2 except that it did not contain potassium carbonate and the amount of D-mannitol was changed to 78.5 parts by weight, and the tablet diameter was 6.5 mm and the tablet mass. An uncoated tablet (C3) (Sidrosine 2 mg tablet) having a hardness of 100 mg and a hardness of 40 N or more was obtained. Table 3 shows the formulation in this comparative example.

(Test Example 2: Measurement of increase in related substances)
With respect to uncoated tablets (E2) to (E7) and (C2) and (C3) of sidrosine obtained in Examples 2 to 7 and Comparative Examples 2 and 3, similarities derived from sidrosine under the following conditions CE The increase rate of the substance was measured.

(Condition C)
About the sidrosine uncoated tablets (E2) to (E7) and (C2) and (C3) obtained in Examples 2 to 7 and Comparative Examples 2 and 3, derived from the sidrosine contained in the tablets immediately after production The content (%) of all related substances (total related substances) was calculated as the ratio (%) of the peak area of each related substance to the peak area of sidrosine from the detection result of liquid chromatography of each uncoated tablet. Table 4 shows the obtained results.

(Condition D)
The sidrosine uncoated tablets (E2) to (E7) and (C2) and (C3) obtained in Examples 2 to 7 and Comparative Examples 2 and 3 were individually wrapped with aluminum foil and completely shielded from light. The obtained package was stored at 60 ° C. and 75% RH for 1 week. Immediately after storage, the content (%) of all related substances (total related substances) derived from sidrosine contained in the tablets was measured in the same manner as in Condition C above. Furthermore, the amount of increase (increase) of the related substance was calculated in comparison with the result of Condition C. Table 4 shows the obtained results.

(Condition E)
The sidrosine uncoated tablets (E2) to (E7) and (C2) and (C3) obtained in Examples 2 to 7 and Comparative Examples 2 and 3 were individually wrapped with aluminum foil and completely shielded from light. The obtained package was stored at 60 ° C. and 75% RH for 2 weeks. Immediately after storage, the content (%) of all related substances (total related substances) derived from sidrosine contained in the tablets was measured in the same manner as in Condition C above. Furthermore, the amount of increase (increase) of the related substance was calculated in comparison with the result of Condition C. Table 4 shows the obtained results.

  As shown in Table 4, the uncoated tablets (C2) and (C3) obtained in Comparative Examples 2 and 3 are approximately proportional to the content of related substances when stored for 1 week and 2 weeks immediately after production. Increased. In contrast, the sidrosine uncoated tablets (E2) to (E7) obtained in Examples 2 to 7 were stored for 1 week in comparison with the uncoated tablets (C2) and (C3) of Comparative Examples 2 and 3. The content of the related substance showed a low value both after storage and after 2 weeks storage, and it can be seen that the increase in the related substance was suppressed during storage during these periods.

  In addition, although the uncoated tablets (E2) to (E7) of Examples 2 to 7 and the uncoated tablets (C2) of Comparative Example 2 were different in product type of the binder (hydroxypropylcellulose) used, these This difference does not affect the content and increase of related substances after storage for the predetermined period. About this point, it is clear by comparison with the uncoated tablet (C3) which made the product type of binder (hydroxypropylcellulose) the same as that of Examples 2-7 about the uncoated tablet (C2) of the said comparative example 2. is there.

  Thus, in the comparison of the uncoated tablets (E2) to (E7) of Examples 2 to 7 and the uncoated tablets (C2) of Comparative Example 2, the product type of the binder (hydroxypropylcellulose) used temporarily is different. Even if it is, these differences do not affect the content and increase of related substances after storage for the predetermined period. Rather, it can be seen that such an effect varies depending on whether or not an alkalinizing agent as shown in Table 4 was contained in the uncoated tablet.

(Example 8)
148 parts by weight of partially pregelatinized starch (PCS (registered trademark) manufactured by Asahi Kasei Co., Ltd.) and 10 parts by weight of talc are mixed using a fluidized bed granulator / dryer (MP-01 manufactured by Paulec Co., Ltd.) to produce core particles. did. Next, a suspension (1) (laying solution) in which 20 parts by weight of silodosin and 1.4 parts by weight of hydroxypropylcellulose (HPC-SSL manufactured by Nippon Soda Co., Ltd.) was added to purified water was prepared. An intermediate layer was formed around the core particles by coating while spraying with a spray nozzle.

  Next, 1.4 parts by weight of sodium lauryl sulfate, 14 parts by weight of aminoalkyl methacrylate copolymer E (Eudragit EPO), 7 parts by weight of talc, 0.03 part by weight of iron sesquioxide, and 0.15 part by weight of yellow ferric oxide A solution (2) (coating solution) was prepared by adding to purified water, and this was coated on the core particles surrounded by the intermediate layer while spraying with a spray nozzle, thereby masking particles (enclosed by the coating layer). Particles).

  20.2 parts by weight of the masking particles, 39.82 parts by weight of D-mannitol, 22 parts by weight of crystalline cellulose (CEOLUS (registered trademark) KG-802 manufactured by Asahi Kasei Corporation), 5 parts by weight of corn starch, 5 parts by weight of crospovidone, For tableting, mix to 0.017 parts iron sesquioxide, 0.085 parts by weight yellow iron sesquioxide, 5 parts by weight sucralose, 2 parts by weight sodium citrate hydrate, and 1 part by weight magnesium stearate. A mixture was obtained. This tableting mixture was tableted using a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to a mortar of 8 mm and a tablet thickness of 3.9 mm, and a tablet with a mass of 200 mg containing 4 mg of silodosin per tablet. (E8) was obtained. Table 5 shows the composition of the obtained tablet (E8).

Example 9
Instead of the solution (2) prepared in Example 8, 1.4 parts by weight of sodium lauryl sulfate, 14 parts by weight of aminoalkyl methacrylate copolymer E (Eudragit EPO), 7 parts by weight of talc, 0.03 part by weight of iron sesquioxide, A solution (2) was prepared by adding 0.15 parts by weight of yellow ferric oxide and 2.5 parts by weight of sodium citrate hydrate to purified water, and this was surrounded by the intermediate layer prepared in Example 8. Masking particles were obtained by coating the core particles while spraying them with a spray nozzle.

  20.45 parts by weight of the masking particles, 39.82 parts by weight of D-mannitol, 22 parts by weight of crystalline cellulose (CEOLUS (registered trademark) KG-802 manufactured by Asahi Kasei Corporation), 5 parts by weight of corn starch, 5 parts by weight of crospovidone, Mix to make 0.017 parts of iron sesquioxide, 0.085 parts by weight of yellow iron sesquioxide, 5 parts by weight of sucralose, 1.75 parts by weight of sodium citrate hydrate, and 1 part by weight of magnesium stearate. A mixture for tablets was obtained. This tableting mixture was tableted using a rotary tableting machine so that the mortar was 8 mm and the tablet thickness was 3.9 mm, and 200 mg tablets (E9) containing 4 mg silodosin per tablet were obtained. Table 5 shows the composition of the obtained tablet (E9).

(Example 10)
Instead of the suspension (1) prepared in Example 8, silodosin 20 parts by weight, hydroxypropylcellulose (Nippon Soda Co., Ltd. HPC-SSL) 1.4 parts by weight, and sodium citrate aqueous solution 0.25 parts by weight Suspension (1) was prepared by adding to the purified water, and this was coated on the core particles produced in Example 8 while spraying with a spray nozzle, thereby forming an intermediate layer around the core particles. Masking particles were obtained in the same manner as in Example 8 except that the core particles surrounded by this intermediate layer were used.

  20.45 parts by weight of the masking particles, 39.82 parts by weight of D-mannitol, 22 parts by weight of crystalline cellulose (CEOLUS (registered trademark) KG-802 manufactured by Asahi Kasei Corporation), 5 parts by weight of corn starch, 5 parts by weight of crospovidone, Mix to make 0.017 parts of iron sesquioxide, 0.085 parts by weight of yellow iron sesquioxide, 5 parts by weight of sucralose, 1.75 parts by weight of sodium citrate hydrate, and 1 part by weight of magnesium stearate. A mixture for tablets was obtained. This tableting mixture was tableted using a rotary tableting machine so that the mortar was 8 mm and the tablet thickness was 3.9 mm, and 200 mg tablets (E10) containing 4 mg silodosin per tablet were obtained. Table 5 shows the composition of the obtained tablet (E10).

(Test Example 3: Measurement of related substances)
For the tablets (E8) to (E10) obtained in Examples 8 to 10, a package body packaged with aluminum foil was prepared in the same manner as in Condition D of Test Example 2, and the conditions were 60 ° C. and 75% RH. Stored for 1 week. Immediately after the storage, the content (%) of all related substances (total related substances) derived from sidrosine contained in the tablets was measured in the same manner as in Condition C of Test Example 2 above. The results obtained are shown in Table 6.

  As shown in Table 6, all of the tablets (E8) to (E10) obtained in Examples 8 to 10 showed a low content of related substances after storage for 1 week, and storage during the period It can be seen that the increase in related substances was suppressed. In addition, a part of sodium citrate hydrate was suspended in the layering solution (suspension) from the tablet (E8) of Example 8 in which the total amount of sodium citrate hydrate as an alkalizing agent was added as a late additive. The tablets (E9) and (E10) of Examples 9 and 10 to which the liquid (1)) or the coating liquid (solution (2)) was added and applied, and the remainder was added as a late powder additive It can be seen that it has excellent thermal stability under such severe heat conditions.

(Example 11)
148 parts by weight of D-mannitol and 10 parts by weight of talc were mixed using a fluidized bed granulator / dryer (MP-01 manufactured by POWREC Co., Ltd.) to prepare core particles. Next, suspension (1) (Leiah) in which 20 parts by weight of silodosin, 1.4 parts by weight of hydroxypropylcellulose (HPC-SSL manufactured by Nippon Soda Co., Ltd.) and 5 parts by weight of sodium citrate hydrate were added to purified water. An intermediate layer was formed around the core particles by preparing a ring liquid) and coating the core particles while spraying with a spray nozzle.

  Next, 2.8 parts by weight of sodium lauryl sulfate, 14 parts by weight of aminoalkyl methacrylate copolymer E (Eudragit EPO), 7 parts by weight of talc, 0.03 part by weight of iron sesquioxide, and 0.15 part by weight of yellow ferric oxide A solution (2) (coating solution) was prepared by adding to purified water, and this was coated on the core particles surrounded by the intermediate layer while spraying with a spray nozzle, thereby masking particles (enclosed by the coating layer). Particles).

  20.84 parts by weight of the masking particles, 40.18 parts by weight of D-mannitol, 24 parts by weight of crystalline cellulose (CEOLUS (registered trademark) KG-802 manufactured by Asahi Kasei Corporation), 5 parts by weight of corn starch, 5 parts by weight of crospovidone, A mixture for tableting was obtained by mixing 0.017 weight iron sesquioxide, 0.085 weight parts yellow iron sesquioxide, 4 weight parts sucralose, and 1 weight part magnesium stearate. This tableting mixture was tableted using a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to a mortar of 8 mm and a tablet thickness of 3.9 mm, and a tablet with a mass of 200 mg containing 4 mg of silodosin per tablet. (E11) was obtained. Table 7 shows the composition of the obtained tablet (E11).

(Example 12)
Example 11 except that the content of D-mannitol in the core particles was changed to 143 parts by weight and the content of sodium citrate hydrate contained in the suspension (1) was changed to 10 parts by weight. In the same manner as in Example 11, an intermediate layer was formed around the core particles. Further, in the same manner as in Example 11, a masking particle and a tableting mixture were obtained, and this tableting mixture was used with a rotary tableting machine. Tableting was performed so that the tablet thickness was 8 mm and 3.9 mm, and a tablet (E12) having a mass of 200 mg containing 4 mg of silodosin per tablet was obtained. Table 7 shows the composition of the obtained tablet (E12).

(Example 13)
The content of D-mannitol in the core particles was changed to 143 parts by weight, and the content of sodium citrate hydrate contained in the suspension (1) was changed to 10 parts by weight and the suspension (1) An intermediate layer was formed around the core particles in the same manner as in Example 11 except that the solvent was changed to a mixture of ethanol and purified water having an ethanol concentration of 50% (w / w) instead of purified water. Then, in the same manner as in Example 11, a masking particle and a tableting mixture were obtained, and this tableting mixture was punched using a rotary tableting machine so that the pestle was 8 mm and the tablet thickness was 3.9 mm. Tablets (E13) having a mass of 200 mg containing 4 mg of silodosin per tablet were obtained. Table 7 shows the composition of the obtained tablet (E13).

(Test Example 4: Determination of unpleasant taste)
When the tablets (E11) to (E13) obtained in Examples 11 to 13 were held by each of four experts in the technical field until they completely disintegrated in the oral cavity (about 15 to 20 seconds), The presence / absence of bitterness (unpleasant taste) due to sidrosine was evaluated based on the following six criteria, and the evaluation by majority vote was used as the result of this determination.

  Table 9 shows the determination results of unpleasant taste for the tablets (E11) to (E13) obtained in Examples 11 to 13.

  As shown in Table 7 and Table 9, among the tablets (E11) to (E13) obtained in Examples 11 to 13, the tablet (E12) of Example 12 was compared with the tablet (E11) of Example 11. ) Increases the content of the alkalizing agent (sodium citrate hydrate) contained in the layering solution (suspension (1)) twice, thereby reducing the unpleasant taste caused by sidrosine. I understand that it was. Moreover, compared with each of the tablet (E11) of Example 11 and the tablet (E12) of Example 12, the tablet (E13) of Example 13 is contained in the layering solution (suspension (1)). Double the content of alkalinizing agent (sodium citrate hydrate) and change the solvent of the coating solution (solution (2)) from purified water to a mixture of ethanol and purified water Thus, it can be seen that the unpleasant taste caused by sidrosine was further reduced.

(Test Example 5: Dissolution test)
The tablets (E11) to (E13) obtained in Examples 11 to 13 were subjected to a silodosin dissolution test by the Japanese Pharmacopoeia dissolution test method 2 (paddle method). Using 900 mL of water and 900 mL of the second dissolution test solution (pH 6.8) as test solutions, the change over time in the dissolution rate (%) for 30 minutes was measured every 5 minutes at a paddle rotation number of 50 rpm. The results obtained are shown in Tables 10 and 11.

  As shown in Table 10, the tablets (E11) to (E13) obtained in Examples 11 to 13 showed only about 82% dissolution in water even after 5 minutes from the start of the test. It can be seen that, when these tablets are administered into the oral cavity, the immediate dissolution of sidrosine can be suppressed. In the tablet (E13) of Example 13 using a mixture of ethanol and purified water as the solvent of the coating liquid (solution (2)), the tablets (E11) and (E12) obtained in Examples 11 and 12 were used. ), The elution of silodosin in water was remarkably suppressed even after 5 minutes from the start of the test.

  On the other hand, as shown in Table 11, the tablets (E11) to (E13) obtained in Examples 11 to 13 have a dissolution property of 90% or more even in 15 minutes after the start of the test in an aqueous solution of pH 6.8. It can be seen that all of these tablets were good in terms of enteric properties.

  According to the present invention, it is possible to obtain a solid preparation that is excellent in stability over time and suppresses the generation of related substances even for long-term storage. For this reason, even if mass production is carried out at one time, silodosin or a pharmaceutically acceptable salt thereof contained as a medicinal component can be stored for a long period of time while sufficiently retained. Therefore, it is useful as a preparation that can be stably supplied to a patient.

Claims (10)

An oral solid preparation containing silodosin or a pharmaceutically acceptable salt thereof and an alkalizing agent,
The content of silodosin or a pharmaceutically acceptable salt thereof is 0.5% to 5% by weight, based on the weight of the formulation, and the content of the alkalizing agent accounts for the weight of the formulation. An oral solid formulation that is 0.1% to 20% by weight as a reference.   The oral solid preparation according to claim 1, wherein the silodosin or a pharmaceutically acceptable salt thereof is contained in a non-inclusion form.   The alkalizing agent is an alkali metal carbonate, alkaline earth metal carbonate, alkali metal citrate, alkaline earth metal citrate, alkali metal malate, alkaline earth metal malate, alkali metal succinate Salt, alkaline earth metal succinate, alkali metal acetate, alkaline earth metal acetate, alkali metal pyrophosphate, alkaline earth metal pyrophosphate, alkali metal benzoate, alkaline earth metal benzoate, Ascorbic acid alkali metal salt, ascorbic acid alkaline earth metal salt, tartaric acid alkali metal salt, tartaric acid alkaline earth metal salt, dehydroacetic acid alkali metal salt, dehydroacetic acid alkaline earth metal salt, glutamic acid alkali metal salt, glutamic acid alkaline earth metal The group consisting of salts, basic amino acids, basic amino sugars, and hydrates thereof Is at least one compound al selected, the oral solid preparation according to claim 1 or 2.   The oral solid preparation according to any one of claims 1 to 3, further comprising a binder, wherein the binder has a viscosity of 1 mPa · s to 10 mPa · s in a 2% aqueous solution at 20 ° C.   The binder according to any one of claims 1 to 3, further comprising a binder, wherein the binder is at least one compound selected from the group consisting of hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, hypromellose, and agar. Oral solid formulation.   Furthermore, the oral solid formulation in any one of Claim 1 to 5 containing an excipient | filler. Containing a plurality of laminated particles comprising a core particle, an intermediate layer surrounding the core particle, and a coating layer surrounding the intermediate layer;
The oral solid preparation according to any one of claims 1 to 6, wherein the laminated particle contains the silodosin or a pharmaceutically acceptable salt thereof and the alkalizing agent in the intermediate layer. A method for producing an oral solid preparation,
Adding and mixing silodosin or a pharmaceutically acceptable salt thereof with an alkalizing agent;
The content of silodosin or a pharmaceutically acceptable salt thereof is 0.5% to 5% by weight, based on the weight of the formulation, and the content of the alkalizing agent accounts for the weight of the formulation. A method that is 0.1% to 20% by weight as a reference.   9. The method of claim 8, wherein the adding and mixing step is performed by adding and mixing an excipient with the alkalinizing agent and the silodosin or a pharmaceutically acceptable salt thereof.   10. The adding and mixing step is performed by adding and mixing the silodosin or a pharmaceutically acceptable salt thereof to a premix of the alkalizing agent and the excipient. the method of.