Pharmaceutical composition and packaged pharmaceutical product

Abstract

To provide a pharmaceutical composition which inhibits the transition of vortioxetine hydrobromide into a β-form crystal.SOLUTION: A pharmaceutical composition according to one embodiment of the present invention is a pharmaceutical composition comprising vortioxetine hydrobromide as an active ingredient, wherein the vortioxetine hydrobromide substantially does not contain a β-form crystal, and the pharmaceutical composition has a moisture value of 2.5 wt.% or less.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to pharmaceutical compositions and packaged pharmaceutical products. [Background technology]

[0002] Vortioxetine is a compound whose chemical name is 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine. Vortioxetine has been shown to be effective in treating depression, and depression treatment drugs containing vortioxetine hydrobromide as an active ingredient are on the market. Vortioxetine hydrobromide is known to have crystalline polymorphisms such as α-, β-, and γ-types (see Patent Document 1, etc.). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Special Publication No. 2009-541216 Summary of the Invention [Problem to be solved by the invention]

[0004] The present inventors have investigated the transition of crystal forms in order to develop a pharmaceutical composition containing vortioxetine hydrobromide, which is a crystal form other than the β form, as an active ingredient.The new findings obtained through this study showed that crystals of vortioxetine hydrobromide other than the β form (such as the α form) transition to the β form when in contact with water.

[0005] In general, pharmaceuticals are required to have high quality stability, so pharmaceutical compositions containing vortioxetine hydrobromide, which is a crystalline form other than β-form, as an active ingredient must be formulated to prevent the transition of the crystalline form.

[0006] One aspect of the present invention aims to provide a pharmaceutical composition in which the transformation of vortioxetine hydrobromide to β-crystalline form is inhibited. [Means for solving the problem]

[0007] The present invention includes the following aspects. <1> A pharmaceutical composition comprising vortioxetine hydrobromide as an active ingredient, The water content of the pharmaceutical composition is 2.5% by weight or less. Pharmaceutical compositions. <2> A pharmaceutical composition comprising vortioxetine hydrobromide as an active ingredient, The vortioxetine hydrobromide salt contains alpha crystals. Pharmaceutical compositions. <3> A pharmaceutical composition comprising vortioxetine hydrobromide as an active ingredient, The vortioxetine hydrobromide is substantially free of β-crystals; Pharmaceutical compositions. <4> A pharmaceutical composition comprising vortioxetine hydrobromide as an active ingredient, The pharmaceutical composition is a direct compression tablet. Pharmaceutical compositions. <5> A pharmaceutical composition comprising vortioxetine hydrobromide as an active ingredient, The pharmaceutical composition contains a granule obtained by dry granulation. Pharmaceutical compositions. <6> The water content of the pharmaceutical composition is 2.5% by weight or less. <1> ~ <5> 2. The pharmaceutical composition according to claim 1 , <7> The vortioxetine hydrobromide salt contains alpha crystals. <1> ~ <6> 2. The pharmaceutical composition according to claim 1 , <8> The vortioxetine hydrobromide salt contains alpha crystals, The water content of the pharmaceutical composition is 2.5% by weight or less. <1> ~ <7> 2. The pharmaceutical composition according to claim 1 , <9> When the total content of vortioxetine hydrobromide in the pharmaceutical composition is taken as 100% by weight, the content of α-crystals of vortioxetine hydrobromide is 50% by weight or more. <1> ~ <8> Any of the pharmaceutical compositions described above. <10> When the total content of vortioxetine hydrobromide in the pharmaceutical composition is taken as 100% by weight, the content of α-crystals of vortioxetine hydrobromide is more than 90% by weight. <1> ~ <9> 2. The pharmaceutical composition according to claim 1 , <11> A pharmaceutical composition comprising vortioxetine hydrobromide as an active ingredient; A desiccant; and Packaged medicines. <12> A pharmaceutical composition comprising vortioxetine hydrobromide as an active ingredient, A packaged pharmaceutical product contained in an airtight packaging material, Packaged medicines. <13> The moisture permeability of the above airtight packaging material is 5.4 g / m 2 / 24hr or less, <12> A packaged pharmaceutical product as described in. <14> The moisture permeability of the above airtight packaging material is 1.0 g / m 2 / 24hr or less, <12> A packaged pharmaceutical product as described in. <15> Further comprising a desiccant. <12> ~ <14> 2. A packaged pharmaceutical product according to any one of the preceding claims. <16> When the total content of vortioxetine hydrobromide in the pharmaceutical composition is taken as 100% by weight, the content of α-crystals of vortioxetine hydrobromide is 50% by weight or more. <12> ~ <15> 2. A packaged pharmaceutical product according to any one of the preceding claims. <17> When the total content of vortioxetine hydrobromide in the pharmaceutical composition is taken as 100% by weight, the content of α-crystals of vortioxetine hydrobromide is more than 90% by weight. <12> ~ <17> 2. A packaged pharmaceutical product according to any one of the preceding claims. <18> and <19> <1> ~ <10> A pharmaceutical composition according to any one of the preceding claims, A desiccant; and Packaged medicines. <20> 1. A packaged pharmaceutical comprising a pharmaceutical composition comprising vortioxetine hydrobromide as an active ingredient, The pharmaceutical composition is contained in an airtight packaging material, The pharmaceutical composition is a packaged pharmaceutical product that satisfies one or more of the following (i) to (v): (i) a moisture content of 2.5% by weight or less; (ii) contains α-crystals; (iii) substantially free of β crystals; (iv) are direct compression tablets; (v) Contains a granulated material obtained by dry granulation. <21> The moisture permeability of the above airtight packaging material is 5.4 g / m 2 / 24hr or less, <20> A packaged pharmaceutical product as described in. <22> The moisture permeability of the above airtight packaging material is 1.0 g / m 2 / 24hr or less, <20> A packaged pharmaceutical product as described in. <23> A method for preparing a pharmaceutical composition containing vortioxetine hydrobromide as an active ingredient, comprising the steps of: The water content of the pharmaceutical composition is adjusted to 2.5% by weight or less. Manufacturing method. <24> A method for preparing a pharmaceutical composition containing vortioxetine hydrobromide as an active ingredient, comprising the steps of: The pharmaceutical composition is formed by direct compression. Manufacturing method. <25> 1. A method for producing a packaged pharmaceutical product, the method comprising: The pharmaceutical composition is contained in an airtight packaging material. Manufacturing method. <26> A method for producing a packaged pharmaceutical product in which a pharmaceutical composition containing vortioxetine hydrobromide as an active ingredient is contained in a packaging material, comprising: combining the pharmaceutical composition with a desiccant. Manufacturing method. <27> The vortioxetine hydrobromide salt contains alpha crystals. <23> ~ <26> 13. The method for producing a semiconductor device according to any one of the preceding claims. <28> A method for inhibiting the transition to β-type crystals in a pharmaceutical composition containing vortioxetine hydrobromide in a crystal form other than β-type as an active ingredient, comprising: The water content of the pharmaceutical composition is adjusted to 2.5% by weight or less. method. <29> A method for inhibiting the transition to β-type crystals in a pharmaceutical composition containing vortioxetine hydrobromide in a crystal form other than β-type as an active ingredient, comprising: The pharmaceutical composition is formed by direct compression. method. <30> A method for inhibiting the transition to β-type crystals in a pharmaceutical composition containing vortioxetine hydrobromide in a crystal form other than β-type as an active ingredient, comprising: The pharmaceutical composition is contained in an airtight packaging material. method. <31> A method for inhibiting the transition to β-type crystals in a pharmaceutical composition containing vortioxetine hydrobromide in a crystal form other than β-type as an active ingredient, comprising: combining the pharmaceutical composition with a desiccant. method. <32> The vortioxetine hydrobromide salt contains alpha crystals. <28> ~ <31> A method comprising the steps of any one of the following: Effect of the Invention

[0008] According to one aspect of the present invention, there is provided a pharmaceutical composition in which the transformation of vortioxetine hydrobromide to β-crystalline form is inhibited. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] An embodiment of the present invention will be described below. However, the present invention is not limited to each of the configurations described below. The present invention can be modified in various ways within the scope of the claims. The technical scope of the present invention also extends to embodiments or examples obtained by appropriately combining multiple technical means disclosed in this specification. In this case, multiple technical means may be disclosed across multiple embodiments or examples.

[0010] Unless otherwise specified in this specification, "A to B" expressing a numerical range means "A or more, and B or less."

[0011] 1. Pharmaceutical Compositions As described above, the inventors have found that contact with water induces a transition in the crystal form of vortioxetine hydrobromide. Based on this finding, a means for achieving a highly stable pharmaceutical composition containing a crystal form of vortioxetine hydrobromide other than β (such as α crystals) is, for example, to reduce the water content of the pharmaceutical composition. Another means is to avoid contact with water during the manufacturing process of the pharmaceutical composition.

[0012] The crystal form of vortioxetine hydrobromide is determined by XRPD according to the description in Patent Document 1. Patent Document 1 discloses the XRPD spectrum and peak positions of α- and β-crystals of vortioxetine hydrobromide (paragraphs 0030-0032 and Figures 2 and 3). In this specification, if a peak at 2θ=12.82° is detected, it is determined that α-crystals are present (see paragraph 0006 of Chinese Patent Application Publication No. 107954947, claim 3 of Chinese Patent Application Publication No. 110372635, etc.). In order to detect α-crystals more accurately, it is preferable to set the condition that α-crystals are present as the detection of one or more peaks selected from 2θ=5.85°, 9.30°, 17.49°, and 18.58° in addition to the peak at 2θ=12.82°. Here, an error of ±0.2° is allowed for each of the above peaks.

[0013] In one embodiment, the moisture content of the pharmaceutical composition is 2.5% by weight or less. The moisture content of the pharmaceutical composition is preferably 2.0% by weight or less, more preferably 1.5% by weight or less. The lower the moisture content of the pharmaceutical composition, the more preferable it is, but it may be, for example, 0.2% by weight or more or 0.4% by weight or more. In this specification, the moisture content is measured by the Karl Fischer method.

[0014] In one embodiment, the pharmaceutical composition is substantially free of β-crystals of vortioxetine hydrobromide. As used herein, "substantially free of β-crystals of vortioxetine hydrobromide" means that the content of β-crystals is preferably less than 10% by weight, more preferably less than 7% by weight, even more preferably less than 5% by weight, even more preferably less than 2.5% by weight, and particularly preferably less than 1% by weight, relative to the total content of vortioxetine hydrobromide contained in the pharmaceutical composition being 100% by weight. In one embodiment, the content of β-crystals is 0% by weight.

[0015] In one embodiment, the vortioxetine hydrobromide contained in the pharmaceutical composition comprises α-type crystals. In one embodiment, the vortioxetine hydrobromide contained in the pharmaceutical composition is substantially composed of α-type crystals. For example, when the total content of vortioxetine hydrobromide contained in the pharmaceutical composition is taken as 100% by weight, the content of α-type crystals may be 50% by weight or more, 60% by weight or more, 70% by weight or more, 80% by weight or more, or 90% by weight or more. More than 90% by weight is preferred, more preferably more than 93% by weight, even more preferably more than 95% by weight, and particularly preferably more than 99% by weight. In one embodiment, the content of α-type crystals is 100% by weight.

[0016] In one embodiment, the pharmaceutical composition is a direct compression tablet. In this specification, a direct compression tablet refers to a tablet obtained by a direct compression method. The direct compression method is a manufacturing method in which raw material powder (vortioxetine hydrobromide powder) is compressed into a tablet without granulation. A manufacturing method in which ungranulated raw material powder and granulated additives are mixed and compressed together is also included in the category of direct compression. Whether a pharmaceutical composition is a direct compression tablet can be determined by checking whether it contains granules containing raw material powder.

[0017] In one embodiment, the pharmaceutical composition contains a granule obtained by dry granulation, which is a granulation method in which flakes of a raw material compressed with a roller are sized to obtain a granule.

[0018] The pharmaceutical composition which is a direct compression tablet or which contains a granulated product obtained by dry granulation can avoid contact with water during the manufacturing process. Therefore, the moisture content of the pharmaceutical composition can be reduced. In one embodiment, the moisture value of the pharmaceutical composition which contains a granulated product which is a direct compression tablet or a granulated product obtained by dry granulation may be in the above-mentioned range.

[0019] The dosage form of the pharmaceutical composition is not particularly limited. In one embodiment, the pharmaceutical composition is a tablet. In one embodiment, the tablet is a film-coated tablet.

[0020] The above-mentioned pharmaceutical composition may contain other ingredients in addition to the active ingredient, such as excipients, disintegrants, binders, lubricants, flow agents, surfactants, acidulants, foaming agents, sweeteners, flavors, colorants, buffers, and coating agents.

[0021] Examples of excipients include D-mannitol, crystalline cellulose, anhydrous calcium hydrogen phosphate, D-sorbitol, lactose, sucrose, starch, low-substituted hydroxypropyl cellulose, carmellose sodium, gum arabic, dextrin, pullulan, synthetic aluminum silicate, and magnesium aluminometasilicate.

[0022] Examples of the disintegrant include potato starch, corn starch, partially pregelatinized starch, sodium starch glycolate, carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and crospovidone.

[0023] An example of a flow agent is light anhydrous silicic acid.

[0024] Examples of surfactants include polyvinyl alcohol, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polysorbate 80, sodium lauryl sulfate, and polyoxyethylene hydrogenated castor oil.

[0025] Examples of binders include hypromellose, gum arabic, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone.

[0026] Examples of acidulants include citric acid, tartaric acid, and malic acid.

[0027] An example of a foaming agent is baking soda.

[0028] Examples of sweeteners include sucralose, sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, and thaumatin.

[0029] Examples of flavors include lemon, lemon-lime, orange, and menthol.

[0030] Examples of coloring agents include ferric oxide, yellow ferric oxide, black ferric oxide, titanium oxide, Food Yellow No. 4, Food Yellow No. 5, Food Red No. 3, Food Red No. 102, and Food Blue No. 3.

[0031] Examples of buffering agents include citric acid, succinic acid, fumaric acid, tartaric acid, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine, phosphoric acid, boric acid or salts thereof. Further examples of buffering agents include magnesium oxide, zinc oxide, magnesium hydroxide.

[0032] Examples of lubricants include sodium stearyl fumarate, stearic acid, sodium stearate, talc, calcium stearate, hardened oil, sucrose fatty acid ester, and magnesium stearate.

[0033] Examples of coating agents include hydroxypropyl cellulose, hypromellose, ethyl cellulose, methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, macrogol (such as macrogol 6000), polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl alcohol-polyethylene glycol graft copolymer, talc, and titanium oxide.

[0034] [2. Packaged Pharmaceuticals] Another possible means of achieving a highly stable pharmaceutical composition containing vortioxetine hydrobromide in a crystalline form other than β (such as α crystals) is to avoid contact with water during storage of the pharmaceutical composition. This can be achieved by packaging the pharmaceutical composition in an airtight packaging material. As used herein, "airtight packaging material" refers to a packaging material that can prevent the inclusion of solid or liquid foreign matter during normal handling, transportation or storage conditions.

[0035] The moisture permeability of the airtight packaging material is 6.0 g / m 2 / 24hr or less is preferable, 5.4g / m 2 / 24hr or less is more preferable, 5.0g / m 2 / 24hr or less is more preferable, and 4.7g / m 2 / 24hr or less is even more preferable, 4.0g / m 2 / 24hr or less is even more preferable, 3.0g / m 2 / 24hr or less is even more preferable. The moisture permeability of the airtight packaging material is measured according to Method 2 of the Water Vapor Permeability Test of the Japanese Pharmacopoeia, 18th Edition. When the packaged pharmaceutical product has a primary packaging material and a secondary packaging material, the moisture permeability is measured in the state packaged in the primary packaging material and the secondary packaging material. If the moisture permeability is within the above range, the transition of vortioxetine hydrobromide to β-crystals can be suppressed over a long period of time during storage of the pharmaceutical composition.

[0036] The airtight packaging material may be a primary packaging material that directly packages the pharmaceutical composition, or a secondary packaging material that further packages the pharmaceutical composition from the outside of the primary packaging material. The specific form of the airtight packaging material is not particularly limited. Examples of the primary packaging include PTP packaging, strip packaging, bottle filling, and aluminum packaging. Examples of the secondary packaging include pillow packaging. From the viewpoint of moisture resistance, it is preferable that the packaged pharmaceutical product has a combination of a primary packaging material and an aluminum pillow.

[0037] Examples of materials for PTP packaging include resins (polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, polycarbonate, etc.) and metals (aluminum, etc.). These materials may be used alone or in combination. Examples of combinations of materials include a laminate of polyvinyl chloride and polyvinylidene chloride, and a laminate of polyvinyl chloride and polychlorotrifluoroethylene. A resin sheet with pockets is formed by a known method, tablets are placed in the pockets, and the tablet is then covered with aluminum foil to be packaged in a PTP.

[0038] In one embodiment, the packaged pharmaceutical further comprises a desiccant. A desiccant is a member that captures moisture in the space in which the pharmaceutical composition or packaged pharmaceutical is contained. The desiccant may be a member separate from the airtight packaging material, or may be incorporated into a part of the airtight packaging material. For example, the container in which the desiccant is contained may be separate from the airtight packaging material, may be integrated with the airtight packaging material, or the material constituting the airtight packaging material may contain the desiccant. Examples of components constituting the desiccant include zeolite, silica gel, calcium oxide, calcium chloride, and magnesium oxide. Only one type of these components may be used, or multiple types may be used in combination.

[0039] In one embodiment, the pharmaceutical composition and the desiccant are contained together in an airtight packaging material, and the moisture permeability of the airtight packaging material is 1.0 g / m 2 / 24hr or less (preferably 0.5g / m 2 / 24 hr or less). Examples of such packaged pharmaceuticals include packaged pharmaceuticals in which a pharmaceutical composition is primarily packaged in a PTP package or the like and then secondarily packaged in an aluminum pillow together with a desiccant.

[0040] In one embodiment, the packaged pharmaceutical further comprises an oxygen scavenger. Examples of the oxygen scavenger include iron-based oxygen scavengers (iron powder, etc.) and organic oxygen scavengers (ascorbic acid, isoascorbic acid, hydroquinone, catechol, etc.). Only one type of oxygen scavenger may be used, or multiple types may be used in combination. Also, a desiccant and an oxygen scavenger may be used in combination. An example of a product that combines a desiccant and an oxygen scavenger is PharmaKeep (registered trademark) (Mitsubishi Gas Chemical Company, Inc.).

[0041] In one embodiment, the pharmaceutical composition is filled in a glass or plastic bottle. Examples of materials for the plastic bottle include those resins exemplified above for PTP packaging. In one embodiment, the pharmaceutical composition may be packaged in aluminum packaging for each dose. The aluminum packaging may be secondary packaged in an aluminum pillow. The aluminum pillow may further contain the above-mentioned desiccant and / or oxygen scavenger.

[0042] In one embodiment, the pharmaceutical composition contained in the packaged pharmaceutical product may satisfy one or more of the characteristics described in Section [1].

[0043] 3. Manufacturing Methods of Pharmaceutical Compositions and Packaged Pharmaceuticals In one aspect, the present invention provides a pharmaceutical composition and a method for producing a packaged pharmaceutical product comprising an active ingredient vortioxetine hydrobromide in a crystal form other than β (such as α crystals), which can inhibit the transition to β crystals in a pharmaceutical composition comprising vortioxetine hydrobromide as an active ingredient.

[0044] In one embodiment, the method for producing the pharmaceutical composition includes adjusting the moisture content of the pharmaceutical composition to 2.5% by weight or less. This is typically achieved by avoiding contact of the raw materials with moisture during the production process. Specific examples include using a formulation method that does not use water and maintaining a low humidity level in the production environment.

[0045] In one embodiment, the method for producing the pharmaceutical composition includes a step of molding the pharmaceutical composition by direct compression. By molding the pharmaceutical composition by direct compression, the pharmaceutical composition can be produced without a granulation step that may cause moisture contamination. The pharmaceutical composition is described in Section [1].

[0046] In one embodiment, the method for producing the pharmaceutical composition includes a step of producing the pharmaceutical composition by dry granulation. Since the dry granulation method does not use moisture in the production process, the pharmaceutical composition can be produced without mixing moisture.

[0047] In one embodiment, the molded pharmaceutical composition is film-coated, for example by spraying a solution containing a coating agent onto the plain tablet and then drying.

[0048] In the step of molding the pharmaceutical composition by direct compression, the compression pressure can be appropriately adjusted as necessary and is, for example, 3 to 16 kN.

[0049] In one embodiment, the method of manufacturing a packaged pharmaceutical product comprises the step of packaging a pharmaceutical composition in an airtight packaging material. The airtight packaging material preferably has a moisture permeability of 5.4 g / m 2 / 24hr or less, and more preferably 1.0g / m 2 / 24hr or less, and more preferably 0.5g / m 2 / 24hr or less. The explanation of airtight packaging materials is as described in Section [2].

[0050] In one embodiment, the method of manufacturing the packaged pharmaceutical product includes combining the packaged pharmaceutical product with a desiccant. The description of the airtight packaging material and the desiccant is as described in Section [2].

[0051] 4. Method for inhibiting the transition of vortioxetine hydrobromide to β-crystals In one aspect, the present invention provides a method for inhibiting the transition to β-crystals in a pharmaceutical composition comprising a crystalline form of vortioxetine hydrobromide other than β (such as α-crystals) as an active ingredient.

[0052] In one embodiment, the method includes adjusting the moisture content of the pharmaceutical composition to 2.5% by weight or less. This step is typically performed by avoiding contact of raw materials with moisture during the manufacturing process. The pharmaceutical composition is described in Section [1].

[0053] In one embodiment, the method includes a step of forming the pharmaceutical composition by direct compression. By forming the pharmaceutical composition by direct compression, the pharmaceutical composition can be produced without a granulation step that may introduce moisture. The pharmaceutical composition is described in Section [1].

[0054] In one embodiment, the method includes a step of preparing the pharmaceutical composition by dry granulation. By preparing the pharmaceutical composition by dry granulation, the pharmaceutical composition can be prepared without being contaminated with water. The pharmaceutical composition is described in Section [1].

[0055] In one embodiment, the method comprises the step of housing the pharmaceutical composition in an airtight packaging material, the moisture permeability of which is preferably 5.4 g / m 2 / 24hr or less, and more preferably 1.0g / m 2 / 24hr or less, and more preferably 0.5g / m 2 / 24hr or less. The explanation of airtight packaging materials is as described in Section [2].

[0056] In one embodiment, the method includes combining the packaged pharmaceutical with a desiccant, the description of which is given in Section [2] regarding the airtight packaging material and the desiccant. EXAMPLES

[0057] Example 1-1 [Preparation of film-coated tablets] Film-coated tablets containing α-crystals of vortioxetine hydrobromide were prepared and the stability of the crystal form was examined. The film-coated tablets were prepared by direct compression (specifically as described below). Then, the stability test described below was performed. 1. Of the ingredients listed in the uncoated tablet column in Table 1, all ingredients except magnesium stearate were mixed. 2. Magnesium stearate was added to the resulting mixture and further mixed. 3. The mixture obtained was compressed into tablets, and formed into cylindrical tablets with a diameter of 7.5 mm and a height of 3.3 mm. In this way, uncoated tablets were obtained. 4. Each component shown in the film coating column in Table 1 was dissolved or dispersed in purified water. In this manner, a coating liquid was obtained. 5. The coating solution was sprayed onto the plain tablets and then dried. Thus, film-coated tablets were obtained. The tablet hardness of the obtained film-coated tablets was 171N.

[0058] Details of the ingredients used in preparing the film-coated tablets are as follows: D-mannitol: Parteck M100 (Merck) Crystalline cellulose: Ceolas UF-702 (Asahi Kasei Corporation) Sodium starch glycolate: Primogel (DFE Pharma Co., Ltd.) Light anhydrous silicic acid: Adsolider-101 (Freund Corporation) Magnesium stearate (Taipei Chemical Industry) Hypromellose: TC-5 (Shin-Etsu Chemical Co., Ltd.) Talc: Talcan Hayashi (Hayashi Kasei Co., Ltd.)

[0059] [Table 1]

[0060] [Stability test] The obtained film-coated tablets were subjected to a stability test, the procedure of which is as follows: 1. The obtained film-coated tablets were stored for one month under different packaging methods and storage conditions. 2. After one month of storage, XRPD was used to confirm whether the crystal form of vortioxetine hydrobromide had transitioned to β-form crystals. The criteria for judgment were as follows. The results are shown in Table 2. -: No β-type crystals were detected at the detection limit. +: β-type crystals were detected at least in some parts.

[0061] The storage conditions for the film-coated tablets examined were as follows: Open conditions: Stored on an open petri dish. Packaged medicine 1: Stored in a PTP sheet made of polyvinyl chloride film (thickness: 0.2 mm) and aluminum foil. The moisture permeability of polyvinyl chloride film is 4.7 g / m 2 / 24hr. Packaged medicine 2: The medicine was stored in a PTP sheet made of polychlorotetrafluoroethylene-polyvinyl chloride laminated film (thickness: 0.223 mm) and aluminum foil. The moisture permeability of the laminated film is 0.26 g / m 2 / 24hr. Packaged medicine 3: Stored in a PTP sheet made of polychlorotetrafluoroethylene-polyvinyl chloride laminated film (thickness: 0.251 mm) and aluminum foil. The moisture permeability of the laminated film is 0.13 g / m 2 / 24hr. Packaged medicine 4: Packaged in a PTP sheet made of polyvinyl chloride film (thickness: 0.2 mm) and aluminum foil, which was then stored in an aluminum pillow. The moisture permeability of the polyvinyl chloride film is 4.7 g / m 2 / 24hr. The moisture permeability of the aluminum pillow was 1.0g / m 2 / 24hr. Packaged medicine 5: Packaged in a PTP sheet made of polyvinyl chloride film (thickness: 0.2 mm) and aluminum foil, which was then stored in an aluminum pillow. The aluminum pillow contained a desiccant (zeolite) along with the PTP sheet. The moisture permeability of the polyvinyl chloride film is 4.7 g / m 2 / 24hr. The moisture permeability of the aluminum pillow was 1.0g / m 2 / 24hr. Packaged medicine 6: Packaged in a PTP sheet made of polychlorotetrafluoroethylene-polyvinyl chloride laminated film (thickness: 0.223 mm) and aluminum foil, which was then stored in an aluminum pillow. The aluminum pillow contained a desiccant (zeolite) along with the PTP sheet. The moisture permeability of the laminated film was 0.26 g / m 2 / 24hr. The moisture permeability of the aluminum pillow was 1.0g / m 2 / 24hr.

[0062] [Moisture content measurement] The moisture content of the film-coated tablets was measured before and after one month of storage. The Karl Fischer method was used. The difference between the moisture content (weight %) after one month and the moisture content (weight %) before storage was taken as the increase in moisture content. The results are shown in Table 2.

[0063] [result] [Table 2]

[0064] As shown in Table 2, no transition from α-type crystals to β-type crystals was observed under any of the storage conditions. In particular, no transition was observed even under open conditions in an environment of 25°C and 60% RH. This is thought to be because the moisture content of the film-coated tablets was kept low because the plain tablets were prepared by direct compression. In addition, storing the tablets in airtight packaging material with low moisture permeability and combining them with a desiccant are also thought to contribute to suppressing the transition to β-type crystals.

[0065] [Example 1-2] The same film-coated tablets as in Example 1-1 were stored for 3 months to examine their stability. The results are shown in Table 3.

[0066] [Table 3]

[0067] As shown in Table 3, no transition from α-type crystals to β-type crystals was observed under any of the storage conditions. In particular, no transition was observed even under open conditions in an environment of 25°C and 60% RH. This is thought to be because the moisture content of the film-coated tablets was kept low because the plain tablets were prepared by direct compression. In addition, storing the tablets in airtight packaging material with low moisture permeability and combining them with a desiccant are also thought to contribute to suppressing the transition to β-type crystals.

[0068] Example 2-1 The drug substance (vortioxetine hydrobromide) used in the manufacture of uncoated tablets was changed from unground to ground. A pin mill was used to grind the drug substance. The rotation speed of the pin mill was 18,000 rpm. The particle size distribution of the drug substance after grinding was D10: 0.637 μm, D50: 5.08 μm, and D90: 13.2 μm. The particle size distribution was measured in a dry state using a laser diffraction particle size distribution analyzer (Mastersizer3000, Malvern Panalytical).

[0069] Film-coated tablets were prepared in the same manner as in Example 1, except that the drug substance was pulverized. The hardness of the obtained film-coated tablets was 173 N. The obtained film-coated tablets were subjected to the same stability test as in Example 1. The storage period was one month. The results are shown in Table 4.

[0070] [Table 4]

[0071] [result] As shown in Table 4, no transition from α-type crystals to β-type crystals was observed under any of the storage conditions. In particular, no transition was observed even under open conditions under an environment of 25°C and 60% RH. This is thought to be because the moisture value of the film-coated tablets was kept low because the plain tablets were prepared by direct compression. In addition, it is thought that storing the tablets in airtight packaging material with low moisture permeability and combining them with a desiccant also contribute to suppressing the transition to β-type crystals. The film-coated tablets subjected to the stability test in Example 2-1 were prepared by a manufacturing method similar to that of the actual product, and high stability was also confirmed for these tablets.

[0072] Example 2-2 The same film-coated tablets as in Example 1-1 were stored for two months to examine their stability. The results are shown in Table 5.

[0073] [Table 5]

[0074] As shown in Table 5, no transition from α-type crystals to β-type crystals was observed under any of the storage conditions. In particular, no transition was observed even under open conditions under an environment of 25°C and 60% RH. This is thought to be because the moisture value of the film-coated tablets was kept low because the plain tablets were prepared by direct tableting. In addition, it is thought that storing the tablets in airtight packaging material with low moisture permeability and combining them with a desiccant also contribute to suppressing the transition to β-type crystals. The film-coated tablets subjected to the stability test in Example 2-2 were prepared by a manufacturing method similar to that of the actual product, and high stability was also confirmed. [Industrial Applicability]

[0075] The present invention can be used with pharmaceutical compositions containing vortioxetine hydrobromide in a crystalline form other than the beta form (such as the alpha form).

Claims

1. A pharmaceutical composition comprising vortioxetine hydrobromide as an active ingredient, The water content of the pharmaceutical composition is 2.5% by weight or less. Pharmaceutical compositions.

2. A pharmaceutical composition comprising vortioxetine hydrobromide as an active ingredient, The vortioxetine hydrobromide salt contains alpha crystals. Pharmaceutical compositions.

3. A pharmaceutical composition comprising vortioxetine hydrobromide as an active ingredient, The vortioxetine hydrobromide is substantially free of β-crystals; Pharmaceutical compositions.

4. A pharmaceutical composition comprising vortioxetine hydrobromide as an active ingredient, The pharmaceutical composition is a direct compression tablet. Pharmaceutical compositions.

5. A pharmaceutical composition comprising vortioxetine hydrobromide as an active ingredient, The pharmaceutical composition contains a granule obtained by dry granulation. Pharmaceutical compositions.

6. The water content of the pharmaceutical composition is 2.5% by weight or less. The pharmaceutical composition according to any one of claims 2 to 5.

7. The vortioxetine hydrobromide salt contains alpha crystals. The pharmaceutical composition according to any one of claims 3 to 5.

8. The vortioxetine hydrobromide salt contains alpha crystals, The water content of the pharmaceutical composition is 2.5% by weight or less. The pharmaceutical composition according to any one of claims 3 to 5.

9. When the total content of vortioxetine hydrobromide in the pharmaceutical composition is taken as 100% by weight, the content of α-type crystals of vortioxetine hydrobromide is 50% by weight or more. The pharmaceutical composition according to any one of claims 1 to 5.

10. When the total content of vortioxetine hydrobromide in the pharmaceutical composition is taken as 100% by weight, the content of α-crystals of vortioxetine hydrobromide is more than 90% by weight. The pharmaceutical composition according to any one of claims 1 to 5.

11. A pharmaceutical composition comprising vortioxetine hydrobromide as an active ingredient; A desiccant; and Packaged medicines.

12. A pharmaceutical composition comprising vortioxetine hydrobromide as an active ingredient, A packaged pharmaceutical product contained in an airtight packaging material, Packaged medicines.

13. The moisture permeability of the airtight packaging material is 5.4 g / m ２ / 24hr or less, The packaged pharmaceutical product of claim 12.

14. The moisture permeability of the airtight packaging material is 1.0 g / m ２ / 24hr or less, The packaged pharmaceutical product of claim 12.

15. Further comprising a desiccant. The packaged pharmaceutical product according to any one of claims 12 to 14.

16. When the total content of vortioxetine hydrobromide in the pharmaceutical composition is taken as 100% by weight, the content of α-type crystals of vortioxetine hydrobromide is 50% by weight or more. The packaged pharmaceutical product according to any one of claims 12 to 14.

17. When the total content of vortioxetine hydrobromide in the pharmaceutical composition is taken as 100% by weight, the content of α-crystals of vortioxetine hydrobromide is more than 90% by weight. The packaged pharmaceutical product according to any one of claims 12 to 14.

18. A pharmaceutical composition according to any one of claims 1 to 5, A desiccant; and Packaged medicines.

19. A pharmaceutical composition according to claim 6 ; A desiccant; and Packaged medicines.

20. 1. A packaged pharmaceutical comprising a pharmaceutical composition comprising vortioxetine hydrobromide as an active ingredient, The pharmaceutical composition is contained in an airtight packaging material, The pharmaceutical composition is a packaged pharmaceutical product that satisfies one or more of the following (i) to (v): (i) the moisture content is less than or equal to 2.5% by weight; (ii) contains alpha crystals; (iii) substantially free of β-type crystals; (iv) Directly compressed tablets; (v) Contains a granulated material obtained by dry granulation.

21. The moisture permeability of the airtight packaging material is 5.4 g / m ２ / 24hr or less, 21. The packaged pharmaceutical product of claim 20.

22. The moisture permeability of the airtight packaging material is 1.0 g / m ２ / 24hr or less, 21. The packaged pharmaceutical product of claim 20.

23. A method for preparing a pharmaceutical composition containing vortioxetine hydrobromide as an active ingredient, comprising the steps of: A step of adjusting the moisture content of the pharmaceutical composition to 2.5% by weight or less. Manufacturing method.

24. A method for preparing a pharmaceutical composition containing vortioxetine hydrobromide as an active ingredient, comprising the steps of: The pharmaceutical composition is formed by direct compression. Manufacturing method.

25. 1. A method for producing a packaged pharmaceutical product, the method comprising: The pharmaceutical composition is contained in an airtight packaging material. Manufacturing method.

26. A method for producing a packaged pharmaceutical product in which a pharmaceutical composition containing vortioxetine hydrobromide as an active ingredient is contained in a packaging material, comprising: combining the pharmaceutical composition with a desiccant. Manufacturing method.

27. The vortioxetine hydrobromide salt contains alpha crystals. The method according to any one of claims 23 to 26.

28. A method for inhibiting the transition to β-type crystals in a pharmaceutical composition containing vortioxetine hydrobromide in a crystal form other than β-type as an active ingredient, comprising: A step of adjusting the moisture content of the pharmaceutical composition to 2.5% by weight or less. method.

29. A method for inhibiting the transition to β-type crystals in a pharmaceutical composition containing vortioxetine hydrobromide in a crystal form other than β-type as an active ingredient, comprising: The pharmaceutical composition is formed by direct compression. method.

30. A method for inhibiting the transition to β-type crystals in a pharmaceutical composition containing vortioxetine hydrobromide in a crystal form other than β-type as an active ingredient, comprising: The pharmaceutical composition is contained in an airtight packaging material. method.

31. A method for inhibiting the transition to β-type crystals in a pharmaceutical composition containing vortioxetine hydrobromide in a crystal form other than β-type as an active ingredient, comprising: combining the pharmaceutical composition with a desiccant. method.

32. The vortioxetine hydrobromide salt contains alpha crystals. A method comprising the steps of any one of claims 28 to 31.

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