Solid dispersion, pharmaceutical composition using the same, method for producing the same, and method for improving the dissolution rate of suvorexant.

Abstract

To provide a solid dispersion containing suvorexant or a salt thereof with a high dissolution rate, a pharmaceutical composition using the same, a method for producing the same, and a method for improving the dissolution rate of suvorexant or a salt thereof. [Solution] A pharmaceutical composition comprising an amorphous form of suvorexant or a salt thereof and a water-soluble polymer, characterized in that, when tested at 50 revolutions per minute according to the dissolution test method (paddle method) of the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of suvorexant or a salt thereof into the second dissolution test solution is 25% or more in 360 minutes.

Description

Technical Field

[0006]

[0001] The present invention relates to a solid dispersion, a pharmaceutical composition using the same, a method for producing the same, and a method for improving the dissolution rate of suvorexant.

Background Art

[0002] Suvorexant is known as an orexin receptor antagonist and has attracted attention as a therapeutic agent for insomnia and the like. However, it is known that suvorexant hardly dissolves in water (for example, Non-Patent Document 1, etc.).

[0003] Therefore, a solid dispersion containing suvorexant, having a high dissolution rate, a pharmaceutical composition using the same, a method for producing the same, and a method for improving the dissolution rate of suvorexant have not yet been provided, and there is a strong demand for their prompt provision.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] An object of the present invention is to solve the above-described conventional problems and achieve the following objects. That is, an object of the present invention is to provide a solid dispersion containing suvorexant or a salt thereof, having a high dissolution rate, a pharmaceutical composition using the same, a method for producing the same, and a method for improving the dissolution rate of suvorexant or a salt thereof.

Means for Solving the Problems

[0006] As a result of diligent research conducted by the present inventors to achieve the above objective, they have found that it is possible to provide a solid dispersion containing suvorexant or a salt thereof with a high dissolution rate, a pharmaceutical composition using the same, a method for producing the same, and a method for improving the dissolution rate of suvorexant or a salt thereof.

[0007] The present invention is based on the aforementioned findings by the inventors, and the means for solving the aforementioned problems are as follows: <1> It comprises an amorphous form of suborexant or a salt thereof, and a water-soluble polymer. This pharmaceutical composition is characterized by the fact that, according to the dissolution test method (paddle method) of the 18th edition of the Japanese Pharmacopoeia, when the test is performed at 50 revolutions per minute, the dissolution rate of suvorexant or its salt into the second dissolution test solution is 25% or more after 360 minutes. <2> It comprises an amorphous form of suborexant or a salt thereof, and a water-soluble polymer. This solid dispersion is characterized by the fact that, according to the dissolution test method (paddle method) of the 18th edition of the Japanese Pharmacopoeia, when the test is performed at 50 revolutions per minute, the dissolution rate of suvorexant or its salt into the second dissolution test solution is 25% or more after 360 minutes. <3> A method for producing a pharmaceutical composition, comprising the step of mixing suvorexant or a salt thereof with a water-soluble polymer to form a solid dispersion, The present invention relates to a method for producing a pharmaceutical composition characterized in that, when the pharmaceutical composition is tested at 50 revolutions per minute according to the dissolution test method (paddle method) of the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of suvorexant or its salt into the second dissolution test solution is 25% or more in 360 minutes. <4> This method for improving the elution rate of suvorexant or its salt is characterized by including a step of mixing suvorexant or its salt with a water-soluble polymer to form a solid dispersion. [Effects of the Invention]

[0008] According to the present invention, it is possible to provide a solid dispersion containing suvorexant or a salt thereof with a high dissolution rate, a pharmaceutical composition using the same, a method for producing the same, and a method for improving the dissolution rate of suvorexant or a salt thereof. [Brief explanation of the drawing]

[0009] [Figure 1] Figure 1 shows the results of the dissolution behavior evaluation for solid dispersion powders 1 to 7 and the active pharmaceutical ingredient. [Figure 2] Figure 2 shows the results of the dissolution behavior evaluation for solid dispersion powders 1 and 8 to 10. [Figure 3] Figure 3 shows the results of the dissolution behavior evaluation for solid dispersion powders 2 and 11 to 13. [Figure 4] Figure 4 shows the results of the dissolution behavior evaluation for solid dispersion powders 14 to 17. [Figure 5] Figure 5 shows the results of the dissolution behavior evaluation of solid dispersion powders 18 to 20. [Modes for carrying out the invention]

[0010] (Pharmaceutical composition) The pharmaceutical composition comprises an amorphous form of suvorexant or a salt thereof, a water-soluble polymer, and may further contain other components. The aforementioned pharmaceutical composition has an elution rate within a specific range.

[0011] <Amorphous form of suvorexant or its salt> -Amorphous form of suborexant- Examples of the amorphous form of suvorexant ([(7R)-4-(5-chloro-1,3-benzoxazole-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazole-2-yl)phenyl]methanone) include a subvorexant in an amorphous state in which atoms are irregularly arranged and which does not have a crystalline structure (a subvorexant without long-range order).

[0012] Whether or not the aforementioned suborexant is in an amorphous state can be confirmed by X-ray diffraction (XRD).

[0013] The method for producing the amorphous form of the subolexant is not particularly limited and can be appropriately selected according to the purpose. For example, it can be obtained by melting the subolexant at 180 °C and then naturally cooling it to room temperature for solidification.

[0014] - Salt of subolexant - The salt of the subolexant is not particularly limited as long as it is a pharmaceutically acceptable salt and can be appropriately selected according to the purpose. For example, hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, hydrofluoric acid salt, phosphate, formate, acetate, propionate, 2-hydroxyacetate, trifluoroacetate, malate, butyrate, benzoate, dihydroxybenzoate, trihydroxybenzoate, 4-hydroxy-3-methoxybenzoate, oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, dodecylsulfonate, benzenesulfonate, p-toluenesulfonate, etc. can be mentioned.

[0015] The average particle diameter (D50) of the subolexant is not particularly limited and can be appropriately selected according to the purpose. The average particle diameter (D50) of the Form I crystal of the subolexant is preferably 50 μm or more and 150 μm or less, and more preferably 70 μm or more and 130 μm or less. The average particle diameter (D50) of the Form II crystal of the subolexant is preferably 60 μm or more and 170 μm or less, and more preferably 80 μm or more and 150 μm or less. The average particle diameter (D50) is a value obtained by a particle size distribution measuring device and is the particle diameter of the particles that reach 50% cumulative from the small particle side of the particle size distribution based on volume.

[0016] The Form I crystal of the subolexant and the Form II crystal of the subolexant are those described in International Publication No. 2012 / 148553.

[0017] <Water-soluble polymer> The water-soluble polymer is not particularly limited and can be appropriately selected depending on the purpose. Examples include hypromellose (hydroxypropyl methylcellulose), hydroxypropylcellulose, polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer, methylcellulose, carboxymethyl ethylcellulose, hypromellose acetate succinate, methacrylic acid copolymer L, aminoalkyl methacrylate copolymer E, and polyvinyl alcohol. Among these, cellulose derivatives such as hypromellose (hydroxypropyl methylcellulose), hydroxypropyl cellulose, methylcellulose, carboxymethyl ethylcellulose, and hypromellose acetate succinate are preferred, alkylcellulose derivatives having 2 or more carbon atoms such as hypromellose (hydroxypropyl methylcellulose), hydroxypropyl cellulose, carboxymethyl ethylcellulose, and hypromellose acetate succinate are more preferred, and hydroxyalkylcellulose derivatives having 2 or more carbon atoms are even more preferred. Water-soluble polymers include enteric-coated polymers and gastric-soluble polymers.

[0018] There are no particular restrictions on the lower limit of the amount of the water-soluble polymer per 1 part by mass of the amorphous suvorexant or its salt, and it can be appropriately selected depending on the purpose. However, in terms of improving the elution rate, 0.5 parts by mass or more is preferred, 1 part by mass or more is more preferred, 1.1 parts by mass or more is even more preferred, 1.2 parts by mass or more is even more preferred, 1.5 parts by mass or more is particularly preferred, and 2.0 parts by mass or more is most preferred. There is no particular upper limit to the amount of the water-soluble polymer per 1 part by mass of the amorphous form of suvorexant or its salt, and it can be appropriately selected depending on the purpose. However, in terms of improving the elution rate, it is preferably 30 parts by mass or less, more preferably 20 parts by mass or less, even more preferably 15 parts by mass or less, even more preferably 10 parts by mass or less, particularly preferably 8 parts by mass or less, and most preferably 5 parts by mass or less. Furthermore, a range of values ​​where one of the values ​​indicated as the lower limit and one of the values ​​indicated as the upper limit are used as the preferred range. Among these, in terms of improving the dissolution rate, 0.5 parts by mass or more and 30 parts by mass or less is preferred, 0.5 parts by mass or more and 20 parts by mass or less is more preferred, 0.5 parts by mass or more and 10 parts by mass or less is even more preferred, 1 part by mass or more and 10 parts by mass or less is even more preferred, 1 part by mass or more and 5 parts by mass or less is particularly preferred, and 2 parts by mass or more and 5 parts by mass or less is most preferred.

[0019] <Other ingredients> The aforementioned other components are not particularly limited and can be appropriately selected depending on the purpose. Examples include excipients, disintegrants, lubricants, and coating agents.

[0020] There are no particular restrictions on the excipients, and they can be appropriately selected depending on the purpose. Examples include lactose monohydrate, crystalline cellulose, silica-treated crystalline cellulose, calcium hydrogen phosphate monohydrate, and mannitol. These may be used individually or in combination of two or more. Among these, lactose monohydrate or crystalline cellulose is preferred, and lactose monohydrate and crystalline cellulose are more preferred. Furthermore, it is preferable that mannitol is not included.

[0021] The disintegrant is not particularly limited and can be appropriately selected depending on the purpose. Examples include partially pregelatinized starch, pregelatinized starch, sodium starch glycolate, croscarmellose sodium, crospovidone, corn starch, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose. These may be used individually or in combination of two or more. Among these, croscarmellose sodium or light anhydrous silicic acid is preferred, and the combination of croscarmellose sodium and light anhydrous silicic acid is more preferred.

[0022] There are no particular restrictions on the lubricant, and it can be appropriately selected depending on the purpose. Examples include talc, magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, sucrose fatty acid ester, stearyl alcohol, and sodium lauryl sulfate. These may be used individually or in combination of two or more. Among these, magnesium stearate is preferred. Furthermore, it is preferable that it does not contain sodium lauryl sulfate.

[0023] The coating agent is not particularly limited and can be appropriately selected depending on the purpose. Examples include hydroxypropyl methylcellulose, hydroxypropyl cellulose, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, macrogol 20000, titanium dioxide, talc, and silicic acid. These may be used individually or in combination of two or more.

[0024] <Elution rate> When the aforementioned pharmaceutical composition is tested using the dissolution test method (paddle method) of the 18th edition of the Japanese Pharmacopoeia at 50 revolutions per minute, the dissolution rate of suvorexant or its salt into the second dissolution test solution over 360 minutes is not particularly limited as long as it is 25% or more, and can be appropriately selected depending on the purpose. However, 30% or more is preferred, 40% or more is more preferred, 50% or more is even more preferred, 60% or more is particularly preferred, and 70% or more is most preferred.

[0025] The dissolution rate of suvorexant or its salt into the second dissolution test solution over 1000 minutes, when the pharmaceutical composition is tested at 50 revolutions per minute according to the dissolution test method (paddle method) of the 18th edition of the Japanese Pharmacopoeia, is not particularly limited and can be appropriately selected depending on the purpose, but is preferably 25% or more, more preferably 30% or more, even more preferably 40% or more, even more preferably 50% or more, particularly preferably 60% or more, and most preferably 70% or more.

[0026] There are no particular restrictions on the dosage form of the pharmaceutical composition, and it can be appropriately selected depending on the purpose. Examples include capsules and tablets. Among these, tablets are preferred.

[0027] The surface of the tablets in this invention may be engraved or printed with the product number, active ingredient name, active ingredient content, dosage form, product number, QR code (registered trademark), barcode, etc., in order to improve identifiability. The aforementioned markings or printing may be done directly on the surface of the uncoated or film-coated tablet. There are no particular restrictions on the printing method, and it can be appropriately selected according to the purpose. Examples include ink-based printing methods using plate transfer printing, gravure printing, offset printing, and inkjet printing, as well as laser printing. The ink used for the printing can be selected from edible inks containing dyes and / or pigments, and the ink may be one color or two or more colors from the viewpoint of identification, etc.

[0028] The moisture content of the pharmaceutical composition may be in the range of 0 to 5%, for example, 1%, 2%, 3%, 3.5%, or 4%.

[0029] (solid dispersion) The solid dispersion comprises an amorphous form of suvorexant or a salt thereof, a water-soluble polymer, and may further contain other components. The solid dispersion has an elution rate within a specific range.

[0030] The amorphous form of suvorexant or its salt, the water-soluble polymer, the other components, and the elution rate are as described in the above-mentioned (pharmaceutical composition). The pharmaceutical composition may be the solid dispersion. The water-soluble polymer can function as a carrier for the solid dispersion.

[0031] In this invention, "dispersion" refers to a dispersion system in which one substance, which is the dispersed phase, is dispersed as distinct units in a second substance (continuous phase or medium). The size of the dispersed phase can vary considerably (for example, from colloidal particles with a volume of nanometers to several microns in size). Generally, the dispersed phase can be a solid, liquid, or gas. In the case of a solid dispersion, both the dispersed phase and the continuous phase are solids. The moisture content of the solid dispersion powder obtained in this invention may be in the range of 0 to 5%, for example, 1%, 2%, or 3%.

[0032] In pharmaceutical applications, the solid dispersion may include a crystalline drug (dispersed phase) in a polymer (continuous phase), or an amorphous drug (dispersed phase) in a polymer (continuous phase). In one embodiment, the solid dispersion includes a polymer constituting the dispersed phase and a drug constituting the continuous layer. In another embodiment, the solid dispersion includes an amorphous compound or a substantially amorphous compound.

[0033] In this invention, "amorphous" is used in a general sense and refers to a state in which atoms in a solid are arranged irregularly. It may also contain some crystals.

[0034] As used herein, the term "amorphous" refers to a solid material that lacks long-range order in the position of its molecules. Amorphous solids are generally supercooled liquids that lack long-range order, such as a clear arrangement of molecules, including molecular packing, because the molecules are arranged randomly. Amorphous solids are generally isotropic, meaning they exhibit similar properties in all directions and do not have a distinct melting point. For example, an amorphous material is a solid material that does not have sharp, characteristic crystalline peaks (or more) in its X-ray powder diffraction (XRPD) pattern (i.e., it is not crystalline as measured by XRPD). Instead, one or more broad peaks (e.g., halos) appear in its XRPD pattern.

[0035] The solid dispersion is in the form of a powder or particles, and there are no particular restrictions on the average particle size (D50) of the solid dispersion; it can be appropriately selected depending on the purpose, but it is preferably 100 μm or more and 200 μm or less. The aforementioned average particle diameter (D50) is a value obtained by a particle diameter distribution analyzer, and is the particle size of the particle that accounts for 50% of the cumulative particle diameter distribution from the smallest particle side, based on volume.

[0036] (Method of manufacturing a pharmaceutical composition) The method for producing the pharmaceutical composition includes a solid dispersion formation step, and may further include other steps. The aforementioned pharmaceutical composition has an elution rate within a specific range. The aforementioned dissolution rate is as described above in (Pharmaceutical Composition).

[0037] <Solid dispersion formation process> The solid dispersion formation step involves mixing a suvorexant or a salt thereof with a water-soluble polymer to form a solid dispersion. In the solid dispersion formation step, a solid dispersion is obtained that contains an amorphous form of suvorexant or a salt thereof and a water-soluble polymer. The amorphous form of suvorexant or its salt, and the water-soluble polymer are as described in the above-mentioned (pharmaceutical composition).

[0038] There are no particular restrictions on the mixing method, and it can be selected as appropriate.

[0039] There are no particular limitations on the method for forming the solid dispersion, and any method can be appropriately selected. For example, a method may be used in which a mixture obtained by mixing a suvorexant or a salt thereof with a water-soluble polymer is melted and kneaded.

[0040] The aforementioned melting and mixing method is not particularly limited and can be selected as appropriate. Examples include methods using equipment such as a screw compounder. There are no particular restrictions on the screw compounder, and it can be selected as appropriate. For example, a microconical twin-screw compounder is a suitable choice. The melting and mixing temperatures are not particularly limited and can be selected as appropriate, but are preferably 100°C to 250°C, more preferably 150°C to 220°C, and even more preferably 160°C to 200°C.

[0041] <Other processes> The aforementioned other processes are not particularly limited and can be appropriately selected depending on the purpose. Examples include tableting processes and coating processes.

[0042] (Method for manufacturing solid dispersions) The method for producing the solid dispersion includes a solid dispersion formation step, and may further include other steps. The solid dispersion has an elution rate within a specific range. The solid dispersion formation step and the other steps are as described above (method for producing a pharmaceutical composition). The aforementioned dissolution rate is as described above in (Pharmaceutical Composition).

[0043] (Method for improving the elution rate of suvorexant or its salts) The method for improving the elution rate of the suvorexant or its salt includes a solid dispersion formation step and may further include other steps. The solid dispersion formation step and the other steps are as described above (method for producing a pharmaceutical composition). [Examples]

[0044] The following describes embodiments of the present invention, but the present invention is not limited in any way to these embodiments.

[0045] <Preparation of Solid Dispersion> (Example 1) 10 g of suvorexant and 40 g of hydroxypropyl methylcellulose (TC-5(registered trademark)E: manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed and placed in a microconical twin-screw compounder (HAAKE MiniCTW: manufactured by Thermo Fisher Scientific). The mixture was melted and kneaded at 180°C, and then allowed to solidify by natural cooling to room temperature. The resulting solidified mixture was pulverized using an impact pulverizer to obtain a solid dispersion powder 1 containing 20% ​​by mass of suvorexant.

[0046] (Example 2) A solid dispersion powder 2 containing 20% ​​by mass of suvorexant was obtained in the same manner as in Example 1, except that hydroxypropyl methylcellulose was replaced with hydroxypropyl cellulose (HPC-SL (viscosity of a 2% aqueous solution at 20°C: 3.0-5.9 mPa·s): manufactured by Nippon Soda Co., Ltd.).

[0047] (Example 3) A solid dispersion powder 3 containing 20% ​​by mass of suvorexant was obtained in the same manner as in Example 1, except that hydroxypropyl methylcellulose was replaced with polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer (Soluplus: manufactured by BASF).

[0048] (Example 4) A solid dispersion powder 4 containing 20% ​​by mass of suvorexant was obtained in the same manner as in Example 1, except that hydroxypropyl methylcellulose was replaced with methylcellulose (SM-4: manufactured by Shin-Etsu Chemical Co., Ltd.).

[0049] (Example 5) A solid dispersion powder 5 containing 20% ​​by mass of suvorexant was obtained in the same manner as in Example 1, except that hydroxypropyl methylcellulose was replaced with carboxymethyl ethylcellulose (CMEC: manufactured by Freund Industrial Co., Ltd.).

[0050] (Example 6) A solid dispersion powder 6 containing 20% ​​by mass of suvorexant was obtained in the same manner as in Example 1, except that hydroxypropyl methylcellulose was replaced with hypromellose acetate succinate (Shin-Etsu AQOAT AS-LF: manufactured by Shin-Etsu Chemical Co., Ltd.).

[0051] (Comparative Example 1) A solid dispersion powder 7 containing 20% ​​by mass of suvorexant was obtained in the same manner as in Example 1, except that hydroxypropyl methylcellulose was replaced with a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (POVACOAT: manufactured by Daido Chemical Industries, Ltd.).

[0052] (Evaluation of dissolution behavior of solid dispersion powder and active pharmaceutical ingredient 1) For the solid dispersion powders 1 to 7 and the active pharmaceutical ingredient (suvorexant) obtained in Examples 1 to 6 and Comparative Example 1, the dissolution rate of suvorexant into the second dissolution test solution was measured as follows, using a small-volume dissolution test system (μDISS: manufactured by Pion) and the dissolution test method (paddle method) of the 18th edition of the Japanese Pharmacopoeia, at 50 revolutions per minute.

[0053] A container containing 900 mL of Japanese Pharmacopoeia Dissolution Test Solution 2 (pH 6.8), warmed to 37 ± 0.5°C, was placed in a small-volume dissolution test system (μDISS: manufactured by Pion). Then, the solid dispersion powders 1 to 7 obtained in Examples 1 to 6 and Comparative Example 1, or the active pharmaceutical ingredient (suvorexant) as Reference Example 1, were added. The amount added was 20 mg in terms of the active pharmaceutical ingredient (suvorexant). The device was operated at a rotation speed of 50 rpm, and solubility was measured periodically for up to 6 hours. The results are shown in Figure 1.

[0054] (Example 7) A solid dispersion powder 8 containing 25% by mass of suvorexant was obtained in the same manner as in Example 1, except that 10 g of suvorexant and 30 g of hydroxypropyl methylcellulose were mixed.

[0055] (Example 8) A solid dispersion powder 9 containing 33% by mass of suvorexant was obtained in the same manner as in Example 1, except that 10 g of suvorexant and 20 g of hydroxypropyl methylcellulose were mixed.

[0056] (Example 9) A solid dispersion powder 10 containing 50% by mass of suvorexant was obtained in the same manner as in Example 1, except that 10 g of suvorexant and 10 g of hydroxypropyl methylcellulose were mixed.

[0057] (Evaluation of dissolution behavior of solid dispersion powder and active pharmaceutical ingredient 2) For the solid dispersion powders 1 and 8 to 10 obtained in Examples 1 and 7 to 9, the dissolution rate of suvorexant into the second dissolution solution was measured using a small-volume dissolution test system (μDISS: Pion Corporation) in the same manner as in "(Evaluation of Dissolution Behavior of Solid Dispersion Powder and Active Pharmaceutical Ingredient 1)" when the test was performed at 50 revolutions per minute according to the dissolution test method (paddle method) of the 18th edition of the Japanese Pharmacopoeia. The results are shown in Figure 2.

[0058] (Example 10) A solid dispersion powder 11 containing 25% by mass of suvorexant was obtained in the same manner as in Example 1, except that 10 g of suvorexant and 30 g of hydroxypropyl cellulose were mixed.

[0059] (Example 11) A solid dispersion powder 12 containing 33% by mass of suvorexant was obtained in the same manner as in Example 1, except that 10 g of suvorexant and 20 g of hydroxypropyl cellulose were mixed.

[0060] (Example 12) A solid dispersion powder 13 containing 50% by mass of suvorexant was obtained in the same manner as in Example 1, except that 10 g of suvorexant and 10 g of hydroxypropyl cellulose were mixed.

[0061] (Evaluation of dissolution behavior of solid dispersion powder and active pharmaceutical ingredient 3) For the solid dispersion powders 2 and 11 to 13 obtained in Examples 2 and 10 to 12, the dissolution rate of suvorexant into the second dissolution solution was measured using a small-volume dissolution test system (μDISS: Pion Corporation) in the same manner as in "(Evaluation of dissolution behavior of solid dispersion powder and active pharmaceutical ingredient 1)" when the test was performed at 50 revolutions per minute according to the dissolution test method (paddle method) of the 18th edition of the Japanese Pharmacopoeia. The results are shown in Figure 3.

[0062] (Example 13) A solid dispersion powder 14 containing 20% ​​by mass of suvorexant was obtained in the same manner as in Example 1, except that hydroxypropyl methylcellulose was replaced with methylcellulose (SM-4: manufactured by Shin-Etsu Chemical Co., Ltd.).

[0063] (Example 14) A solid dispersion powder 15 containing 25% by mass of suvorexant was obtained in the same manner as in Example 1, except that 10 g of suvorexant and 30 g of methylcellulose (SM-4: manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed.

[0064] (Example 15) A solid dispersion powder 16 containing 33% by mass of suvorexant was obtained in the same manner as in Example 1, except that 10 g of suvorexant and 20 g of methylcellulose (SM-4: manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed.

[0065] (Example 16) A solid dispersion powder 17 containing 50% by mass of suvorexant was obtained in the same manner as in Example 1, except that 10 g of suvorexant and 10 g of methylcellulose (SM-4: manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed.

[0066] (Evaluation of dissolution behavior of solid dispersion powder and active pharmaceutical ingredient 4) For the solid dispersion powders 14 to 17 obtained in Examples 13 to 16, the dissolution rate of suvorexant into the second dissolution test solution was measured using a small-volume dissolution test system (μDISS: Pion Corporation) in the same manner as in "(Evaluation of Dissolution Behavior of Solid Dispersion Powder and Active Pharmaceutical Ingredient 1)" when the test was performed at 50 revolutions per minute according to the dissolution test method (paddle method) of the 18th edition of the Japanese Pharmacopoeia. The results are shown in Figure 4.

[0067] (Example 17) A solid dispersion powder 18 containing 20% ​​by mass of suvorexant was obtained in the same manner as in Example 1, except that hydroxypropyl methylcellulose was replaced with hypromellose acetate succinate (HPMCAS LF: manufactured by Shin-Etsu Chemical Co., Ltd.).

[0068] (Example 18) A solid dispersion powder 19 containing 40% by mass of suvorexant was obtained in the same manner as in Example 1, except that 10 g of suvorexant and 15 g of hypromellose acetate succinate (HPMCAS-LF: manufactured by Shin-Etsu Chemical Co., Ltd.) were mixed.

[0069] (Example 19) A solid dispersion powder 20 containing 50% by mass of suvorexant was obtained in the same manner as in Example 1, except that 10 g of suvorexant and 10 g of hypromellose acetate succinate were mixed.

[0070] (Evaluation of dissolution behavior of solid dispersion powder and active pharmaceutical ingredient 5) For the solid dispersion powders 18 to 20 obtained in Examples 17 to 19, the dissolution rate of suvorexant into the second dissolution test solution was measured using a small-volume dissolution test system (μDISS: Pion Corporation) in the same manner as in "(Evaluation of Dissolution Behavior of Solid Dispersion Powder and Active Pharmaceutical Ingredient 1)" when the test was performed at 50 revolutions per minute according to the dissolution test method (paddle method) of the 18th edition of the Japanese Pharmacopoeia. The results are shown in Figure 5.

[0071] (Tablet manufacturing 1) Tablets were manufactured by compressing and coating them according to the formulation in Table 1, as follows.

[0072] To the solid dispersion powder 1 obtained in Example 1, lactose monohydrate (Dilactose S: ​​manufactured by Freund Industrial Co., Ltd.), crystalline cellulose (Ceolus UF-702: manufactured by Asahi Kasei Corporation), and croscarmellose sodium (Acdisol: International N&H Mfg. Ireland) were added and mixed. Then, magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed, and the resulting tableting mixture powder was compressed into tablets to obtain uncoated tablets.

[0073] Hydroxypropyl methylcellulose (TC-5®: manufactured by Shin-Etsu Chemical Co., Ltd.), macrogol 6000 (macrogol 6000(SP): manufactured by Sanyo Chemical Industries, Ltd.), titanium dioxide (titanium dioxide FG: manufactured by Freund Industrial Co., Ltd.), and talc (talcanhayashi: manufactured by Hayashi Chemical Co., Ltd.) were dispersed in purified water to obtain a coating solution. A film-coated tablet was obtained by coating the uncoated tablet with the coating liquid using a pan coating apparatus and drying the coated tablet.

[0074] [Table 1]

[0075] (Tablet manufacturing 2) Tablets were manufactured by compressing and coating them according to the formulation in Table 2, as follows.

[0076] To the solid dispersion powder 9 obtained in Example 8, lactose monohydrate (Dilactose S: ​​manufactured by Freund Industrial Co., Ltd.), crystalline cellulose (Ceolus UF-702: manufactured by Asahi Kasei Corporation), and croscarmellose sodium (Acdisol: International N&H Mfg. Ireland) were added and mixed. Then, magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed, and the resulting tableting mixture powder was compressed into tablets to obtain uncoated tablets. The tablet compression pressure was 9.5 kN.

[0077] The following two particle sizes were used for the solid dispersion powder. Sample (1) D50: 72 μm D90: 134 μm Sample (2) D50: 111 μm D90: 202 μm Here, D50 represents the particle size [median diameter] corresponding to 50% of the cumulative sieve distribution, and D90 represents the particle size [median diameter] corresponding to 90% of the cumulative sieve distribution. D50 and D90 were measured using a dry sieving method (robot sifter, manufactured by Seishin Corporation).

[0078] Hydroxypropyl methylcellulose (TC-5®: manufactured by Shin-Etsu Chemical Co., Ltd.), macrogol 6000 (macrogol 6000(SP): manufactured by Sanyo Chemical Industries, Ltd.), titanium dioxide (titanium dioxide FG: manufactured by Freund Industrial Co., Ltd.), and talc (talcanhayashi: manufactured by Hayashi Chemical Co., Ltd.) were dispersed in purified water to obtain a coating solution. A film-coated tablet was obtained by coating the uncoated tablet with the coating liquid using a pan coating apparatus and drying the coated tablet.

[0079] The uncoated tablet of sample (2) had a diameter of 6.3 mm, while the film-coated tablet had a diameter of 6.4 mm. The thickness of the uncoated tablet in sample (2) was 4.0 mm, and the thickness of the film-coated tablet was also 4.0 mm. The tablet hardness of sample (2) was 70N for the uncoated tablets and 105N for the film-coated tablets.

[0080] [Table 2]

[0081] (Tablet manufacturing 3) Tablets were manufactured by compressing and coating them according to the formulation in Table 3, as follows.

[0082] To the solid dispersion powder 9 obtained in Example 8, lactose monohydrate (Dilactose S: ​​manufactured by Freund Industrial Co., Ltd.), crystalline cellulose (Ceolus UF-702: manufactured by Asahi Kasei Corporation), and croscarmellose sodium (Acdisol: International N&H Mfg. Ireland) were added and mixed. Then, magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed, and the resulting tableting mixture powder was compressed into tablets to obtain uncoated tablets. The tablet compression pressure was 9.5 kN.

[0083] The following two particle sizes were used for the solid dispersion powder. Sample (3) D50: 72 μm D90: 134 μm Sample (4) D50: 111 μm D90: 202 μm Here, D50 represents the particle size [median diameter] corresponding to 50% of the cumulative sieve distribution, and D90 represents the particle size [median diameter] corresponding to 90% of the cumulative sieve distribution. D50 and D90 were measured using a dry sieving method (robot sifter, manufactured by Seishin Corporation).

[0084] Hydroxypropyl methylcellulose (TC-5®: manufactured by Shin-Etsu Chemical Co., Ltd.), macrogol 6000 (macrogol 6000(SP): manufactured by Sanyo Chemical Industries, Ltd.), titanium dioxide (titanium dioxide FG: manufactured by Freund Industrial Co., Ltd.), and talc (talcanhayashi: manufactured by Hayashi Chemical Co., Ltd.) were dispersed in purified water to obtain a coating solution. A film-coated tablet was obtained by coating the uncoated tablet with the coating liquid using a pan coating apparatus and drying the coated tablet.

[0085] The uncoated tablet of sample (4) had a diameter of 7.5 mm, while the film-coated tablet had a diameter of 7.8 mm. The thickness of the uncoated tablet in sample (4) was 3.9 mm, and the thickness of the film-coated tablet was 4.0 mm. The tablet hardness of the uncoated tablet of sample (4) was 75N, and the tablet hardness of the film-coated tablet was 107N.

[0086] [Table 3]

[0087] (Tablet manufacturing 4) Tablets were manufactured by compressing and coating them according to the formulation in Table 4, as follows.

[0088] To the solid dispersion powder 9 obtained in Example 8, lactose monohydrate (Dilactose S: ​​manufactured by Freund Industrial Co., Ltd.), crystalline cellulose (Ceolus UF-702: manufactured by Asahi Kasei Corporation), and croscarmellose sodium (Acdisol: International N&H Mfg. Ireland) were added and mixed. Then, magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed, and the resulting tableting mixture powder was compressed into tablets to obtain uncoated tablets. The tablet compression pressure was 11 kN.

[0089] The following two particle sizes were used for the solid dispersion powder. Sample (5) D50: 72 μm D90: 134 μm Sample (6) D50: 111 μm D90: 202 μm Here, D50 represents the particle size [median diameter] corresponding to 50% of the cumulative sieve distribution, and D90 represents the particle size [median diameter] corresponding to 90% of the cumulative sieve distribution. D50 and D90 were measured using a dry sieving method (robot sifter, manufactured by Seishin Corporation).

[0090] Hydroxypropyl methylcellulose (TC-5®: manufactured by Shin-Etsu Chemical Co., Ltd.), macrogol 6000 (macrogol 6000(SP): manufactured by Sanyo Chemical Industries, Ltd.), titanium dioxide (titanium dioxide FG: manufactured by Freund Industrial Co., Ltd.), and talc (talcanhayashi: manufactured by Hayashi Chemical Co., Ltd.) were dispersed in purified water to obtain a coating solution. A film-coated tablet was obtained by coating the uncoated tablet with the coating liquid using a pan coating apparatus and drying the coated tablet.

[0091] The uncoated tablet of sample (6) had a diameter of 7.8 mm, while the film-coated tablet had a diameter of 8.0 mm. The thickness of the uncoated tablet in sample (6) was 4.9 mm, and the thickness of the film-coated tablet was 5.0 mm. The tablet hardness of the uncoated tablets in sample (6) was 100N, and the tablet hardness of the film-coated tablets was 131N.

[0092] [Table 4]

[0093] (Evaluation of moisture content) For the film-coated tablets (samples (1) to (6)) obtained in manufacturing steps 2 to 4 of the tablet production process, the moisture content was measured using a Karl Fischer method with a moisture meter (MKV-710: manufactured by Kyoto Electronics Manufacturing Co., Ltd.), and the results showed that all samples had a moisture content of approximately 3.0 to 3.5%.

[0094] The solvent (Hayashi Solvent FM-II Dehydrating Solvent (for sugars): manufactured by Hayashi Pure Chemical Industries, Ltd.) was placed in a titration bottle and titrated with Karl Fischer reagent to anhydrous state. The lightly crushed sample was added to the titration bottle. The moisture content was measured using Karl Fischer reagent (Aquamicron (trademark registered) titrator SS-Z 3mg: manufactured by Mitsubishi Chemical Corporation), whose titer had been previously standardized with purified water.

[0095] Examples of embodiments of the present invention include the following: <1> It comprises an amorphous form of suborexant or a salt thereof, and a water-soluble polymer. This pharmaceutical composition is characterized by the fact that, according to the dissolution test method (paddle method) of the 18th edition of the Japanese Pharmacopoeia, when the test is performed at 50 revolutions per minute, the dissolution rate of suvorexant or its salt into the second dissolution test solution is 25% or more after 360 minutes. <2> The aforementioned dissolution rate is 60% or more in 360 minutes, <1> This is the pharmaceutical composition described in [the relevant document]. <3> The water-soluble polymer is contained in 0.5 to 10 parts by mass per 1 part by mass of the amorphous suborexant or its salt. <1> This is the pharmaceutical composition described in [the relevant document]. <4> The water-soluble polymer is contained in 1 to 5 parts by mass per 1 part by mass of the amorphous form of suborexant or its salt. <1> This is the pharmaceutical composition described in [the relevant document]. <5> The water-soluble polymer is a cellulose derivative, <1> This is the pharmaceutical composition described in [the relevant document]. <6> The water-soluble polymer is a hydroxyalkylcellulose derivative having 2 or more carbon atoms. <1> This is the pharmaceutical composition described in [the relevant document]. <7> The above, which does not contain sodium lauryl sulfate or mannitol. <1> This is the pharmaceutical composition described in [the relevant document]. <8> The pharmaceutical composition is a tablet. <1> This is the pharmaceutical composition described in [the relevant document]. <9> It comprises an amorphous form of suborexant or a salt thereof, and a water-soluble polymer. This solid dispersion is characterized by the fact that, according to the dissolution test method (paddle method) of the 18th edition of the Japanese Pharmacopoeia, when the test is performed at 50 revolutions per minute, the dissolution rate of suvorexant or its salt into the second dissolution test solution is 25% or more after 360 minutes. <10> A method for producing a pharmaceutical composition, comprising the step of mixing suvorexant or a salt thereof with a water-soluble polymer to form a solid dispersion, The present invention relates to a method for producing a pharmaceutical composition characterized in that, when the pharmaceutical composition is tested at 50 revolutions per minute according to the dissolution test method (paddle method) of the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of suvorexant or its salt into the second dissolution test solution is 25% or more in 360 minutes. <11> This method for improving the elution rate of suvorexant or its salt is characterized by including a step of mixing suvorexant or its salt with a water-soluble polymer to form a solid dispersion.

Claims

1. It comprises an amorphous form of suborexant or a salt thereof, and a water-soluble polymer. A pharmaceutical composition characterized in that, according to the dissolution test method (paddle method) of the 18th edition of the Japanese Pharmacopoeia, when the test is performed at 50 revolutions per minute, the dissolution rate of suvorexant or its salt into the second dissolution test solution is 25% or more after 360 minutes.

2. The pharmaceutical composition according to claim 1, wherein the dissolution rate is 60% or more in 360 minutes.

3. The pharmaceutical composition according to claim 1, comprising 0.5 to 10 parts by mass of the water-soluble polymer per 1 part by mass of the amorphous form of suvorexant or a salt thereof.

4. The pharmaceutical composition according to claim 1, comprising 1 to 5 parts by mass of the water-soluble polymer per 1 part by mass of the amorphous form of suvorexant or a salt thereof.

5. The pharmaceutical composition according to claim 1, wherein the water-soluble polymer is a cellulose derivative.

6. The pharmaceutical composition according to claim 1, wherein the water-soluble polymer is a hydroxyalkylcellulose derivative having 2 or more carbon atoms.

7. The pharmaceutical composition according to claim 1, which does not contain sodium lauryl sulfate or mannitol.

8. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a tablet.

9. It comprises an amorphous form of suborexant or a salt thereof, and a water-soluble polymer. A solid dispersion characterized in that, when tested at 50 revolutions per minute according to the dissolution test method (paddle method) of the 18th edition of the Japanese Pharmacopoeia, the dissolution rate of suvorexant or its salt into the second dissolution test solution is 25% or more after 360 minutes.

10. A method for producing a pharmaceutical composition, comprising the step of mixing suvorexant or a salt thereof with a water-soluble polymer to form a solid dispersion, A method for producing a pharmaceutical composition, characterized in that the pharmaceutical composition exhibits a dissolution rate of 25% or more of suvorexant or its salt into the second dissolution test solution in 360 minutes when tested at 50 revolutions per minute according to the dissolution test method (paddle method) of the 18th edition of the Japanese Pharmacopoeia.

11. A method for improving the elution rate of a suvorexant or a salt thereof, characterized by comprising the step of mixing a suvorexant or a salt thereof with a water-soluble polymer to form a solid dispersion.

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