Vaginal solid pharmaceutical composition

Abstract

To provide a vaginal solid pharmaceutical composition that contains (A) oxiconazole and / or a salt thereof and is stored in an applicator.SOLUTION: (A) Oxiconazole and / or a salt thereof, and a polymer with glucose molecules polymerized by glycosidic linkage are made to coexist and stored in an applicator. Even when a solid pharmaceutical composition containing (A) oxiconazole and / or a salt thereof is stored in an applicator, the solid pharmaceutical composition can be protected from breakage.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a solid pharmaceutical composition for vaginal application. [Background technology]

[0002] Fungi of the Candida genus, such as Candida albicans, are non-pathogenic fungi that exist together with other normal flora on the skin, mucous membranes, intestinal tract, etc. However, when the balance of normal flora is disrupted and Candida spreads locally due to factors such as overadministration of drugs such as steroids, antibiotics, and immunosuppressants, weakened immunity due to diabetes or immunodeficiency, or poor hygiene, it causes candidiasis such as cutaneous candidiasis, vaginal candidiasis, vulvar candidiasis, oral candidiasis, candidal interdigital erosion, candidal paronychia, and esophageal and intestinal candidiasis.

[0003] Preparations containing oxiconazole, an imidazole antifungal agent, or a salt thereof are used to treat such candidiasis (see, for example, Patent Document 1). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Special Publication No. 2018-501277 Summary of the Invention [Problem to be solved by the invention]

[0005] However, when oxiconazole and / or a salt thereof is made into a solid formulation, administration, particularly to the vagina, may be difficult.

[0006] Therefore, an object of the present invention is to provide a solid pharmaceutical composition for vaginal application which contains oxiconazole and / or a salt thereof and is housed in an applicator. [Means for solving the problem]

[0007] As a result of extensive research, the inventors have developed a vaginal solid preparation containing oxiconazole and / or a salt thereof into an embodiment suitable for use with an applicator, thereby completing the present invention.

[0008] That is, the present invention includes the following aspects. [1] (A) oxiconazole and / or a salt thereof, and (B) Cellulose a solid pharmaceutical composition for vaginal application comprising: [2] The solid pharmaceutical composition for vaginal application according to the above [1], wherein the content of the (A) oxiconazole and / or a salt thereof per unit of the composition is 100 to 600 mg; [3] The (B) cellulose, At least one cellulose selected from the group consisting of crystalline cellulose and powdered cellulose, and / or A derivative of cellulose in which some of the hydroxyl groups are replaced with other substituents, (1) A cellulose derivative having a hydroxypropoxy group as a substituent. (2) A cellulose derivative having a carboxyl group as a substituent. (3) Cellulose derivatives in which the substituent is a methyl group, and (4) The solid pharmaceutical composition for vaginal application according to [1] or [2], which contains at least one cellulose derivative selected from the group consisting of cellulose derivatives in which the substituents are two or more selected from the group consisting of a hydroxypropoxy group, a carboxyl group, and a methyl group; [4] The solid pharmaceutical composition for vaginal application according to any one of the above [1] to [3], wherein the content of the cellulose (B) per unit of the composition is 0.05 to 640 mg; [5] The solid pharmaceutical composition for vaginal application according to any one of the above [1] to [4], which contains the above (B) cellulose in a ratio of 0.001 to 1000 parts by weight per 100 parts by weight of the above (A) oxiconazole and / or a salt thereof; [6] The solid pharmaceutical composition for vaginal application according to any one of the above [1] to [5], further comprising at least one member selected from the group consisting of lactose, lactose hydrate, stearic acid and salts thereof; [7] The solid pharmaceutical composition for vaginal application according to any one of [1] to [6] above, which is a tablet; [8] A process for preparing a solid formulation containing (A) oxiconazole and / or a salt thereof, and (B) a cellulose compound; and A method for producing a solid pharmaceutical composition for vaginal application, comprising the step of placing the solid formulation in an applicator.

[0009] The present invention also includes the following aspects. [9] (A) oxiconazole and / or a salt thereof, and (C) Starches a solid pharmaceutical composition for vaginal application comprising:

[10] The solid pharmaceutical composition for vaginal application according to the above [9], wherein the content of component (A) per unit of the composition is 600 mg;

[11] The solid pharmaceutical composition for vaginal application according to [9] or

[10] above, wherein the starches (C) contain at least one selected from the group consisting of sodium starch glycolate, starch acrylate 1000, pregelatinized starch, corn starch, and potato starch;

[12] The solid pharmaceutical composition for vaginal application according to any one of the above [9] to

[11] , wherein the content of the component (C) per unit of the composition is 0.05 to 640 mg;

[13] The solid pharmaceutical composition for vaginal application according to any one of the above [9] to

[12] , comprising the above (C) starches in a ratio of 0.005 to 640 parts by weight per 100 parts by weight of the above (A) oxiconazole and / or a salt thereof;

[14] The solid pharmaceutical composition for vaginal application according to any one of the above [9] to

[13] , further comprising at least one member selected from the group consisting of lactose, lactose hydrate, stearic acid and salts thereof;

[15] The solid pharmaceutical composition for vaginal application according to any one of [9] to

[14] above, which is a tablet;

[16] A process for preparing a solid formulation containing (A) oxiconazole and / or a salt thereof, and (C) starches; and A method for producing a solid pharmaceutical composition for vaginal application, comprising the step of placing the solid formulation in an applicator.

[0010] In another embodiment, the present invention includes the following aspects.

[17] A kit comprising: (A) oxiconazole and / or a salt thereof; and (B) a solid pharmaceutical composition for vaginal application containing a cellulose compound; and an applicator;

[18] A kit comprising: (A) oxiconazole and / or a salt thereof; and (C) a solid pharmaceutical composition for vaginal application containing starches; and an applicator. Effect of the Invention

[0011] The solid pharmaceutical composition for vaginal application of the present invention is contained in an applicator, which contributes to the convenience and safety of administration. [Brief description of the drawings]

[0012] [Figure 1] 1 is a perspective view of an applicator according to an embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] By inserting an applicator with a solid agent placed thereon into the vagina and pushing the solid agent out of the applicator with a pusher member provided on the applicator, administration to the vagina can be performed hygienically and simply. However, when a user places a solid agent in the applicator, or when the applicator is manufactured, distributed, or stored with the solid agent placed therein, the solid agent may collide with the applicator or friction may occur, causing the solid agent to be damaged. This is particularly noticeable when the solid agent is a tablet. Breakage of the solid agent not only makes it difficult for an effective amount of the drug to reach the affected area, but also leads to inconveniences in application, such as broken pieces or broken grains of the solid agent getting into the gap between the outer cylinder and the push rod of the applicator, making it difficult to push out the solid agent, or adhering to the inner wall of the applicator and physically hindering the pushing out of the solid agent. Furthermore, the convex shape of the broken part of the solid agent may irritate or damage the vaginal mucosa. In the present invention, breakage of the solid agent containing oxiconazole and / or a salt thereof in the applicator can be suppressed. Solid preparations that can be prevented from breaking have the advantage in terms of production that there is no need to change the shape or size of the applicator for each shape of the solid preparation.

[0014] [Solid pharmaceutical composition for vaginal application] The solid pharmaceutical composition for vaginal application of the present invention relates to a solid pharmaceutical composition for vaginal application comprising (A) oxiconazole and / or a salt thereof, and a polymer in which glucose molecules are polymerized through glycosidic bonds, the composition being contained in an applicator.

[0015] Here, the polymers in which glucose molecules are polymerized through glycosidic bonds are (B) celluloses or (C) starches.

[0016] ((A) Oxiconazole and / or its salt) Oxiconazole is an imidazole antifungal agent that exhibits antifungal activity by damaging the cell membranes of fungi.

[0017] The salt of oxiconazole is not particularly limited as long as it is pharmacologically or physiologically acceptable. Examples of the salt of oxiconazole include various salts such as organic acid salts, inorganic acid salts, and metal salts. The salt of oxiconazole may be used alone or in any combination of two or more. (A) A preferred example of oxiconazole and / or its salt is oxiconazole nitrate.

[0018] The dose (administration) of (A) oxiconazole and / or a salt thereof is 600 mg / week from the viewpoint of significantly exhibiting the effects of the present invention. Typically, it is provided in the form of a tablet containing 100 to 600 mg of oxiconazole nitrate per unit (i.e., one solid), and particularly preferably, it can be provided in the form of a tablet containing 600 mg of oxiconazole nitrate.

[0019] That is, the content of (A) oxiconazole and / or a salt thereof may vary depending on the types and amounts of other ingredients, the condition of the recipient (body weight, age, symptoms, physical condition, etc.), and the dosage form, but is usually 8 to 95 mass%, preferably 12 to 90 mass%, more preferably 15 to 85 mass%, and most preferably 18 to 80 mass%, based on the total amount of the solid pharmaceutical composition for vaginal application.

[0020] ((B) Cellulose) The cellulose used in the present invention is not particularly limited as long as it is a cellulose that can be used in ordinary pharmaceuticals, and is cellulose or a cellulose derivative. Here, the cellulose derivative refers to a derivative in which a part of the hydroxyl group of cellulose is replaced with another substituent. Such cellulose derivatives include (1) cellulose derivatives in which the substituent is a hydroxypropoxy group, (2) cellulose derivatives in which the substituent is a carboxyl group, (3) cellulose derivatives in which the substituent is a methyl group, or (4) cellulose derivatives in which the substituent is two or more selected from the group consisting of a hydroxypropoxy group, a carboxyl group, and a methyl group. The cellulose includes non-cellulose derivatives such as crystalline cellulose or powdered cellulose.

[0021] Here, (1) an example of a cellulose derivative having a hydroxypropoxy group as a substituent is hydroxypropyl cellulose. (2) an example of a cellulose derivative having a carboxyl group as a substituent is carmellose (carboxymethyl cellulose), carmellose sodium (sodium carboxymethyl cellulose), carmellose calcium (calcium carboxymethyl cellulose), or carmellose potassium (potassium carboxymethyl cellulose). (3) an example of a cellulose derivative having a methyl group as a substituent is methylcellulose. (4) an example of a cellulose derivative having two or more substituents selected from the group consisting of a hydroxypropoxy group, a carboxyl group, and a methyl group is hydroxypropyl methylcellulose. As for the hydroxypropyl cellulose having a hydroxypropoxy group as a substituent, the ratio of the substituted hydroxypropoxy group may be any of 3.0% or more, 5.0% or more, 8.0% or more, 10.0% or more, and 14.0% or more, and is not limited thereto. For the hydroxypropyl cellulose having a hydroxypropoxy group as a substituent, the ratio of the substituted hydroxypropoxy group may be any of 85.0% or less, 82.0% or less, 78.0% or less, 70.0% or less, 60.0% or less, 55.0% or less, 50.0% or less, 40.0% or less, 30.0% or less, and 20.0% or less, and is not limited thereto. Furthermore, for example, depending on the case, for the hydroxypropyl cellulose having a hydroxypropoxy group as a substituent, the ratio of the substituted hydroxypropoxy group may be about 5% or more and 20% or less, about 20% or more and 90% or less, or about 50% or more and 85% or less. The cellulose used in the present invention is preferably one or more cellulose derivatives selected from the group consisting of hydroxypropyl cellulose, crystalline cellulose, powdered cellulose, carmellose (carboxymethyl cellulose), carmellose sodium (sodium carboxymethyl cellulose), and methyl cellulose. These (B) components are not limited to the particle shape, and may be granular or powdery. Furthermore, the size of the particles (average particle size) may be any size.

[0022] The content of the (B) cellulose per unit in the solid pharmaceutical composition for vaginal application of the present invention is not limited, but from the viewpoint of more significantly exerting the effects of the present invention, it can be usually 0.05 to 950 mg, preferably 0.1 to 800 mg, more preferably 0.5 to 650 mg, and most preferably 1 to 500 mg.

[0023] The total content of (B) celluloses may vary depending on the amount of (A) oxiconazole and / or a salt thereof, the type of (B) component, the types and amounts of other components, etc., but can usually be 0.001 to 80 mass%, preferably 0.005 to 70 mass%, more preferably 0.01 to 55 mass%, and most preferably 0.05 to 45 mass%, based on the total amount of the solid pharmaceutical composition for vaginal application.

[0024] The content ratio of (A) oxiconazole and / or a salt thereof to (B) cellulose in the solid pharmaceutical composition for vaginal application of the present invention can be appropriately set depending on the types and amounts of other components, and is not limited. From the viewpoint of more significantly exerting the effects of the present invention, the content of (B) cellulose can usually be 0.001 to 1000 parts by weight, preferably 0.03 to 900 parts by weight, more preferably 0.1 to 650 parts by weight, particularly preferably 0.15 to 500 parts by weight, and most preferably 0.35 to 20 parts by weight, per 100 parts by weight of (A) oxiconazole and / or a salt thereof.

[0025] The reason why the breakage of the solid composition containing oxiconazole and / or a salt thereof and celluloses in the present invention is suppressed is not necessarily clear, but can be presumed as follows. When the solid composition containing oxiconazole and / or a salt thereof and celluloses is placed in an applicator, when the solid composition placed in the applicator is manufactured, distributed, stored, or when the solid composition placed in the applicator is pushed out to the affected area, a force such as a collision or friction occurs, and when a force is applied to the solid composition from the outside, the crystal structure, amorphous structure, and their distribution, which are the higher-order structures of the celluloses, are related to each other, and the external force transmitted to the inside of the solid composition is dispersed, thereby suppressing breakage. In particular, when the celluloses are cellulose derivatives in which a part of the hydroxyl groups is substituted, the higher-order structure of the cellulose derivative in the solid composition allows the cellulose derivative and oxiconazole and / or a salt thereof to be more uniformly arranged, which is considered to be one of the factors for suppressing breakage. In cellulose derivatives in which some of the hydroxyl groups are replaced with polar functional groups, some interaction with oxiconazole and / or its salt may result in more uniform distribution of oxiconazole and / or its salt when preparing a solid composition, thereby suppressing breakage.

[0026] ((C) Starches) The starches used in the present invention are not particularly limited as long as they are starches that can be used in general pharmaceuticals, and examples thereof include sodium starch glycolate, starch acrylate 1000, pregelatinized starch, corn starch, potato starch, and rice starch. Preferably, the starch is one or more selected from the group consisting of sodium starch glycolate, starch acrylate 1000, pregelatinized starch, corn starch, and potato starch. These component (C) are not limited by particle shape, and may be granular or powdery. In addition, the particle size may be The (average particle size) may be any value.

[0027] The content of (C) starches per unit in the solid pharmaceutical composition for vaginal application of the present invention is not limited, but from the viewpoint of more significantly exerting the effects of the present invention, it can be usually 0.05 to 640 mg, preferably 0.1 to 480 mg, more preferably 0.5 to 320 mg, and most preferably 1 to 160 mg.

[0028] The total content of (C) starches may vary depending on the amount of (A) oxiconazole and / or a salt thereof, the type of component (C), the types and amounts of other components, etc., but can usually be 0.001 to 55 mass%, preferably 0.01 to 45 mass%, more preferably 0.035 to 30 mass%, and most preferably 0.05 to 10 mass%, based on the total amount of the solid pharmaceutical composition for vaginal application.

[0029] Furthermore, the content ratio of (A) oxiconazole and / or a salt thereof to (C) starches in the solid pharmaceutical composition for vaginal application of the present invention can be appropriately set depending on the types and amounts of other ingredients, and is not limited. From the viewpoint of more significantly exerting the effects of the present invention, the content of (C) starches can usually be 0.005 to 640 parts by weight, preferably 0.01 to 480 parts by weight, more preferably 0.03 to 390 parts by weight, particularly preferably 0.05 to 320 parts by weight, and most preferably 0.15 to 160 parts by weight, per 100 parts by weight of (A) oxiconazole and / or a salt thereof.

[0030] (Other Ingredients) The solid pharmaceutical composition for vaginal application of the present invention may contain one or more of a binder, excipient, lubricant, flow agent, etc., selected appropriately depending on the form, etc., as long as the effects of the invention are not impaired.

[0031] More specifically, examples of the additives include polyvinylpyrrolidone, polyvinyl alcohol, sucrose, lactose, lactose hydrate, light anhydrous silicic acid, mannitol, sorbitol, sucrose fatty acid esters, stearic acid and its salts such as magnesium stearate, talc, sodium aluminometasilicate, and light anhydrous silicic acid.

[0032] In addition, dispersants, emulsifiers, stabilizers, buffers, solubilizers, pH regulators, preservatives (preservatives), antioxidants, colorants, fragrances, and the like may be added as appropriate.

[0033] Among these additives, from the viewpoint of stably exerting the effects of the present invention, it is preferable to use at least one selected from the group consisting of lactose, lactose hydrate, and stearates, and more preferably to use a combination of lactose hydrate and magnesium stearate.

[0034] (Applicator) The applicator that can be used in the present invention is not particularly limited as long as it has a shape suitable for insertion into the vagina. Specifically, the applicator is provided with an outer cylinder that holds a solid agent as an insert and is ejectable from a tip end thereof, and a pusher that is movably disposed within the outer cylinder and that pushes the base end thereof to eject the insert inserted into the outer cylinder from the tip end thereof.

[0035] Although not limited to this type of applicator, optionally, an engaged portion may be formed on the inner surface of the outer tube, and the pusher member may be formed with an engaging portion that engages with the engaged portion when the pusher member brings the insert to a predetermined position within the outer tube, thereby allowing the position of the insert to be perceived.

[0036] The engaging portion and the engaged portion may be optionally configured to be in a positional relationship in which they engage with each other when the insert is placed in the discharge waiting area of ​​the outer tube by the pushing member and discharge of the insert can begin.

[0037] Alternatively, optionally, the engaging portion and the engaged portion may be formed in a positional relationship such that they engage with each other when the tip of the insert is protruded from the tip of the outer tube by the extrusion member.

[0038] Optionally, the engaging portion and the engaged portion may be configured to be in a positional relationship in which they engage with each other when the insert is pushed out by the pushing member and completely ejected from the tip end of the outer tube.

[0039] The engagement portion may be composed of at least a first engagement portion that, when engaged with the engaged portion, causes the user to perceive that the insertion item has been placed in the ejection waiting area, and a second engagement portion that, when engaged with the engaged portion, causes the user to perceive that the insertion item has been completely ejected.

[0040] The engaged portion may comprise one convex portion that causes the user to sense that the insertion object has been placed in the discharge waiting area, and another convex portion that causes the user to sense that the insertion object has protruded from the tip portion, and the one convex portion and the other convex portion may be arranged adjacent to each other in this order toward the tip portion.

[0041] The outer tube may be formed with an auxiliary convex portion that engages with the second engaging portion to limit movement of the pusher member toward the base end of the outer tube when the first engaging portion engages with the convex portion.

[0042] The outer tube may be formed with an auxiliary convex portion that engages with the second engaging portion to limit movement of the pusher member toward the base end of the outer tube when the first engaging portion engages with the convex portion.

[0043] The outer diameter of the outer cylinder of the applicator may be 8 to 20 mm, preferably 9 to 19 mm, and more preferably 10 to 18 mm, in order to accommodate the solid pharmaceutical composition for vaginal application. The length of the outer cylinder may be 60 to 150 mm, preferably 70 to 140 mm, and more preferably 80 to 130 mm, in order to accommodate the solid pharmaceutical composition for vaginal application. The outer diameter of the extrusion member of the applicator may be 9 to 16 mm at the end, preferably 10 to 15 mm, and more preferably 11 to 14 mm. The cylindrical portion may be 9 to 18 mm, preferably 10 to 17 mm, and more preferably 11 to 16 mm.

[0044] One embodiment of the applicator will now be described with reference to the drawings.

[0045] As shown in FIG. 1, the applicator 1 of this embodiment is configured to include an outer cylinder 3 that holds an inserted solid agent 2 inside and can eject it from the tip, and a pusher member 4 that is movably inserted into the outer cylinder 3 and pushes and moves the solid agent 2 from its base end.

[0046] The outer cylinder 3 is formed into a cylindrical shape with a bottom, the tip portion is formed to be tapered into a semispherical shape, and the base portion is opened on a plane approximately perpendicular to the axis of the outer cylinder 3, and is formed so that the solid agent 2 and the extrusion member 4 can be inserted.

[0047] As shown in FIG. 1, the tip of the outer cylinder 3 is formed with a discharge hole 5 through which the solid agent 2 can be discharged, and a number of slits communicating with the discharge hole 5, and a number of tongues are formed between the slits. These tongue pieces are formed so as to elastically deform and spread apart when the extrusion member 4 is inserted into the outer cylinder 3 to push the solid agent 2 outward, and to elastically return to their original shape when the solid agent 2 is expelled to the outside.

[0048] The plurality of slits are formed evenly so that each tongue can be uniformly expanded radially from the discharge hole 5 and so as to divide the tip into appropriate equal parts (usually 6 to 10 parts) in the circumferential direction when viewed from the tip 3a side of the outer cylinder 3 in the direction of the arrow P. Inside the outer cylinder 3, a certain area on the front side of the discharge hole 5 is set as a discharge standby area where the solid dosage form 2 can start to be discharged.

[0049] The extrusion member 4 is configured to include a sliding part that is inserted into the outer cylinder 3 and slides within the outer cylinder 3 when the solid agent 2 is set in the discharge waiting area W of the outer cylinder 3, and a pressing part that is provided at the base end of the sliding part, protrudes outward from the base end of the outer cylinder 3 when the solid agent 2 is placed in the discharge waiting area W, and further advances into the outer cylinder 3 when the solid agent 2 is discharged, thereby advancing the sliding part.

[0050] In order to protect the tip of the outer cylinder 3, a cap or the like that is placed on the tip 3a of the outer cylinder 3 may be used.

[0051] The material for molding the outer cylinder and extrusion member of the applicator is not particularly limited, but from the viewpoint of moldability and significantly achieving the effects of the present invention, examples of suitable materials include synthetic resins containing polyethylene (high density polyethylene (HDPE), low density polyethylene (LDPE), linear low density polyethylene (LLDPE)), polypropylene (PP), polystyrene, acrylonitrile butadiene styrene, polycarbonate, polyethylene terephthalate, polymethyl methacrylate, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, etc. Preferred are polyethylene and polypropylene, more preferred is polyethylene, and particularly preferred is linear low density polyethylene.

[0052] [Formulation and manufacturing method] The solid pharmaceutical composition for vaginal application of the present invention can be, for example, a drug, a quasi-drug, or a raw material thereof (for example, a pharmaceutical preparation, a quasi-drug preparation), and is particularly preferably a drug.

[0053] The solid pharmaceutical composition for vaginal application of the present invention can be prepared in the form of a solid preparation by adopting a conventional preparation method according to the preparation form. The shape and size of the solid preparation are not particularly limited, and it can be, for example, a vaginal tablet, particularly a vaginal tablet.

[0054] For example, granules can be produced by granulating (e.g., extrusion granulation, fluidized bed granulation, spray drying granulation, etc.) (A) oxiconazole and / or a salt thereof, (B) cellulose derivatives which are polymers in which glucose molecules are polymerized through glycosidic bonds, and / or (C) starches, and other components, drying, and sieving. The granules may be further coated with a coating agent. Preferably, such granules can be further subjected to a tableting step to produce tablets. Here, it is preferable to adopt a method in which (A) oxiconazole and / or a salt thereof, (B) cellulose derivatives which are polymers in which glucose molecules are polymerized through glycosidic bonds, and / or (C) starches, and other components are thoroughly mixed.

[0055] The solid pharmaceutical composition for vaginal application of the present invention can be more easily prepared into a solid preparation such as a tablet according to a method known to those skilled in the art. When preparing a tablet, the compound (A) oxiconazole and / or its salt, (B) celluloses, and / or (C) starches, and other ingredients can be thoroughly mixed, and the mixture can be subjected to a tableting step as it is.

[0056] The tableting process can typically be performed by compression molding using pressure, and a conventional tablet press or the like can be preferably used. A coating layer can be provided on the surface of the tablet, and a conventionally known coating method can be used. A multi-layer tablet can also be used.

[0057] The shape and size of the solid preparation are not particularly limited, and may be, for example, a vaginal tablet, particularly a vaginal tablet. It is desirable that the vaginal tablet is solid when inserted into the vagina, and disintegrates in the vagina by body temperature or secretions. The shape is not limited, and may be arrowhead-shaped, caplet-shaped, cone-shaped, spindle-shaped, almond-shaped, spherical, or ovoid. Of these, particularly preferred is an arrowhead-shaped vaginal tablet that is gradually tapered toward the tip of one side in the major axis direction and has a depression at the end opposite to the one side. The size of the tablet is not limited, but an arrowhead-shaped tablet with a vertical diameter (major axis) of 10 to 30 mm, a horizontal diameter (minor axis) of 5 to 15 mm, and a thickness of 1 to 15 mm is particularly preferred. The hardness of the tablet is not limited, and may be 30 N or more. The solid pharmaceutical composition for vagina of the present invention may be coated.

[0058] [kit] The solid pharmaceutical composition for vaginal application of the present invention is typically contained in an applicator as a vaginal tablet. Most preferably, it is provided in the form of a kit together with a vaginal applicator molded from a material that can be inserted into the vagina. The kit may be an embodiment in which the vaginal tablet is contained in the applicator. In another embodiment, the vaginal tablet and the applicator may be provided separately in one kit so that the user can place the solid agent in the applicator. The conditions of the vaginal tablet and the applicator included in the kit, i.e., the amount of (A) oxiconazole and / or its salt, the type and amount of (B) celluloses and / or (C) starches, which are polymers in which glucose molecules are polymerized by glycosidic bonds, and the type and amount of other components, are the same as those of the above-mentioned [Solid pharmaceutical composition for vaginal application].

[0059] [Apply] The solid pharmaceutical composition for vaginal application of the present invention is applicable to candidiasis, which is the main symptom. For example, it can be applied for treating or preventing vaginal candidiasis. It may be used for the purpose of treating vaginal candidiasis, or for the purpose of preventing or preventing recurrence of vaginal candidiasis. In addition, although not limited thereto, the treatment of recurrence of vaginal candidiasis is a particularly preferred application.

[0060] So far, the form that can be administered transmucosally through the vaginal mucosa is preferably a solid, particularly a tablet, which allows for a small number of administrations. Such solids can be administered to the vagina once a day or in the form of multiple tablets. However, the administration of solids can be burdensome in some cases, and in such cases, the present invention can provide a vaginal tablet containing a large amount of (A) oxiconazole and / or a salt thereof. Such vaginal tablets can maintain the effect by administering only one tablet once a week, which also contributes to improving the patient's QOL.

[0061] That is, the dosage and frequency of administration of the solid pharmaceutical composition for vaginal application of the present invention can be appropriately determined depending on the purpose of the composition, the type and severity of symptoms of candidiasis, the types of other ingredients used, the age of the user, etc., but typically, it is preferable to administer one unit (one tablet) of tablet (vaginal tablet) containing 600 mg of active ingredient, which allows administration once a week.

[0062] [Method for imparting breakage prevention ability to a solid pharmaceutical composition for vaginal application] The solid pharmaceutical composition for vaginal application of the present invention can be endowed with the ability to suppress breakage when placed in an applicator by the coexistence in the solid pharmaceutical composition for vaginal application of (A) oxiconazole and / or a salt thereof with (B) celluloses and / or (C) starches, which are polymers formed by the polymerization of glucose molecules through glycosidic bonds.

[0063] That is, the present invention can provide a method for imparting breakage suppression ability to a solid pharmaceutical composition for vaginal application, comprising causing (A) oxiconazole and / or a salt thereof and (B) celluloses and / or (C) starches, which are polymers formed by polymerization of glucose molecules through glycosidic bonds, to coexist in the solid pharmaceutical composition for vaginal application. The amount of (A) oxiconazole and / or a salt thereof, the type and amount of (B) celluloses and / or starches, and the type and amount of other components are the same as those in the above-mentioned [Solid pharmaceutical composition for vaginal application]. EXAMPLES

[0064] Next, the present invention will be specifically described with reference to examples, but the present invention is not limited to the following examples.

[0065] [Test Example 1: Damage Assessment (1)] The tablets shown in Table 1 were prepared by the same conventional method. The shape of the tablets was the same, a caplet shape with a vertical diameter of 13 mm, a horizontal diameter of 6.5 mm, and a thickness of 5.9 mm. Two tablets were placed in the discharge standby area of ​​the applicator. The applicator used here had an outer cylinder with an outer diameter of 15 mm, an outer cylinder with a length of 105 mm, an end outer diameter of the extrusion member of 11 mm, and a discharge standby area in the outer cylinder with a length of 23 mm. The outer cylinder and the extrusion member were molded from a resin containing PE.

[0066] Each component used was one that satisfied the requirements listed in the 17th revised Japanese Pharmacopoeia. The applicator was fixed to a shaker (KM Shaker V-DX, Iwaki Co., Ltd.) so that the discharge hole of the solid agent faced the ground and the long axis of the applicator was perpendicular to the ground, and was shaken at 350 spm for 10 minutes. Since the discharge hole of the applicator faced downward, any broken pieces or broken grains would fall out of the applicator. The weight (total weight of the applicator and the tablets in the applicator) was measured before and after shaking, and the weight change rate was calculated using the following formula 1. [Formula 1] Weight change rate (%) = {1-(weight after shaking) / (weight before shaking)} x 100

[0067] This operation was carried out three times using different applicators, and the average of the three weight change rates was calculated to be the weight change rate of the test example. The results are also shown in Table 1.

[0068] [Test Example 2: Damage Evaluation (2)] The shape of the tablets broken within the applicator was then evaluated. The tablets after Test Example 1 were in the same condition for the same formulation. Therefore, among the tablets after Test Example 1, the fingertips were slid along the boundary between the surface of three random tablets of the same formulation and the recessed portion caused by the breakage, and the tablets were evaluated according to the evaluation criteria. The results are also shown in Table 1. ◎: No fingertips were felt to catch on any of the three tablets, and it was felt that the tablets were suitable for application to the vagina. ○: No fingertips were felt to catch on two tablets. One tablet was slightly felt to catch on the fingertips, but the boundary between the tablet surface and the breakage was smooth, and it was felt that there was no problem at all in applying to the vagina. △: No fingertips were felt to catch on two tablets. One tablet was felt to catch on the fingertips, but it was felt that there was no problem in applying to the vagina. ×: Fingertips were felt to catch on three or two tablets.

[0069] As shown in Table 1, the following became clear: It was found that formulations 1 to 4, in which oxiconazole and / or its salt coexist with hydroxypropylcellulose, showed little weight change and good smoothness on the solid surface. If the boundary between the tablet surface and the breakage is sharp, there is a risk of damaging the mucous membrane during use, which is dangerous, but it was confirmed that such a risk is low in the embodiment of this example. One arrowhead-shaped tablet (vertical diameter 21 mm, horizontal diameter 11 mm, thickness 9 mm) containing 600 mg of oxiconazole nitrate, 60 mg of hydroxypropyl cellulose, 80 mg of crystalline cellulose, 368 mg of lactose hydrate, and 30 mg of magnesium stearate was placed in the same applicator as in Test Example 1, and Test Example 1 was performed.The weight change rate was lower than that of Formulation 1, and the results were favorable.

[0070] When the hydroxypropyl cellulose was replaced with carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, sodium starch glycolate, starch acrylate 1000, pregelatinized starch, corn starch, and potato starch, respectively, and tests similar to those of formulations 1 and 2 were conducted, the weight change was suppressed, and the surface of the solid preparation was smooth enough for use.

[0071] [Table 1]

[0072] [Production Example] Tablets were prepared according to the usual method for the formulation examples shown in Table 2 and placed in an applicator. The weights in the table indicate the content of one tablet.

[0073] [Table 2] [Explanation of symbols]

[0074] 1 Applicator 2 tablets (insert) 3. Outer cylinder 4 Extrusion members 5 Discharge hole

Claims

1. (A) Oxiconazole and / or salts thereof (B) Celluloses An applicator containing a vaginal tablet containing, The tablets are arrowhead-shaped, caplet-shaped, conical, spindle-shaped, almond-shaped, spherical, or oval-shaped. The applicator is, The device comprises an outer cylinder that holds the tablet, which is an insert, and is capable of discharging it from its tip, and an extrusion member that is movably disposed inside the outer cylinder and presses its base end to discharge the insert inserted inside the outer cylinder from its tip, Molded from a synthetic resin containing polyethylene, polypropylene, polystyrene, acrylonitrile butadiene styrene, polycarbonate, polyethylene terephthalate, polymethyl methacrylate, ethylene vinyl acetate copolymer and / or ethylene vinyl alcohol copolymer, The outer diameter of the applicator's outer cylinder is 8 to 20 mm, the length of the outer cylinder is 60 to 150 mm, and the outer diameter of the extruder is 9 to 16 mm at the end and 9 to 18 mm in the cylindrical section. Applicator.

2. The applicator according to claim 1, wherein the content of (A) oxiconazole and / or a salt thereof per unit of the tablet is 100 to 600 mg.

3. In the tablet, (B) Celluloses At least one type of cellulose selected from the group consisting of crystalline cellulose and powdered cellulose, and / or A derivative of cellulose in which some of the hydroxyl groups are replaced with other substituents, (1) Cellulose derivatives having a hydroxypropoxy group as a substituent, (2) Cellulose derivatives in which the substituent is a carboxyl group, (3) Cellulose derivatives having a methyl group as a substituent, and (4) The applicator according to claim 1 or 2, comprising at least one cellulose derivative selected from the group consisting of two or more cellulose derivatives having substituents selected from the group consisting of a hydroxypropoxy group, a carboxyl group, and a methyl group.

4. The applicator according to any one of claims 1 to 3, wherein the content of (B) cellulose per unit in the tablet is 0.05 to 640 mg.

5. In the tablet, The applicator according to any one of claims 1 to 4, comprising (B) cellulose in a ratio of 0.001 to 1000 parts by weight per 100 parts by weight of (A) oxiconazole and / or a salt thereof.

6. The applicator according to any one of claims 1 to 5, wherein the tablet further contains at least one selected from the group consisting of lactose, lactose monohydrate, stearic acid, and salts thereof.

7. The applicator according to any one of claims 1 to 6, wherein the tablet is arrowhead-shaped with a vertical diameter (long axis) of 10 to 30 mm, a horizontal diameter (short axis) of 5 to 15 mm, and a thickness of 1 to 15 mm.

8. The applicator according to any one of claims 1 to 6, wherein the shape of the tablet is a caplet with a vertical diameter of 13 mm, a horizontal diameter of 6.5 mm, and a thickness of 5.9 mm.

9. The applicator according to any one of claims 1 to 8, wherein the outer diameter of the outer cylinder of the applicator is 15 mm, the length of the outer cylinder is 105 mm, the outer diameter of the end of the extrusion member is 11 mm, and the length of the discharge waiting area in the outer cylinder is 23 mm.

10. A kit comprising (A) oxiconazole and / or a salt thereof, and (B) cellulose-containing vaginal tablets, and an applicator, The tablets are arrowhead-shaped, caplet-shaped, conical, spindle-shaped, almond-shaped, spherical, or oval-shaped. The applicator is, The device comprises an outer cylinder that holds the tablet, which is an insert, and is capable of discharging it from its tip, and an extrusion member that is movably disposed inside the outer cylinder and presses its base end to discharge the insert inserted inside the outer cylinder from its tip, Molded from a synthetic resin containing polyethylene, polypropylene, polystyrene, acrylonitrile butadiene styrene, polycarbonate, polyethylene terephthalate, polymethyl methacrylate, ethylene vinyl acetate copolymer and / or ethylene vinyl alcohol copolymer, The outer diameter of the applicator's outer cylinder is 8 to 20 mm, and the length of the outer cylinder is 60 to 150 mm. The outer diameter of the extruder is 9 to 16 mm at the ends and 9 to 18 mm in the cylindrical section. kit.

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