JP2020075921A - Vaginal solid pharmaceutical composition - Google Patents

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

  The present invention relates to vaginal solid pharmaceutical compositions.

  Fungi belonging to the genus Candida such as Candida albicans are non-pathogenic fungi which are present in the skin, mucous membranes, intestinal tract and the like together with other indigenous bacteria. However, due to factors such as excessive administration of drugs such as steroids, antibiotics, and immunosuppressive agents, diminished immunity due to diabetes and immunodeficiency, deterioration of hygiene, etc., the balance of indigenous bacteria is lost and Local spread causes candidiasis such as cutaneous candidiasis, vaginal candidiasis, vulvar candidiasis, oral candidiasis, candida interdigital erosion, candida paronychia, esophageal / intestinal candidiasis, etc. ..

  A preparation containing oxiconazole, which is an imidazole antifungal agent, or a salt thereof is used for the treatment of such candidiasis (see, for example, Patent Document 1).

Japanese Patent Publication No. 2018-501277

  However, when oxiconazole and / or its salt is made into a solid preparation, it may be difficult to administer it particularly to the vagina.

  Therefore, an object of the present invention is to provide a vaginal solid pharmaceutical composition containing oxyconazole and / or a salt thereof and contained in an applicator.

  As a result of intensive studies, the present inventors have completed the present invention by making a solid vaginal agent containing oxyconazole and / or a salt thereof into a mode suitable for use in an applicator.

That is, the present invention includes the following aspects.
[1] A solid vaginal solid pharmaceutical composition containing (A) oxyconazole and / or a salt thereof and (B) cellulose, wherein the composition is contained in an applicator. A pharmaceutical composition;
[2] The vaginal solid pharmaceutical composition according to [1] above, wherein the content of the (A) oxyconazole and / or its salt per unit of the composition is 100 to 600 mg;
[3] The (B) cellulose is
At least one type of cellulose selected from the group consisting of crystalline cellulose and powdered cellulose, and / or a derivative obtained by substituting a part of hydroxyl groups of cellulose with another substituent,
(1) A cellulose derivative whose substituent is a hydroxypropoxy group,
(2) A cellulose derivative whose substituent is a carboxyl group,
(3) a cellulose derivative having a methyl group as a substituent, and (4) a cellulose derivative having at least two types of substituents selected from the group consisting of a hydroxypropoxy group, a carboxyl group, and a methyl group,
The solid pharmaceutical composition for vagina according to [1] or [2], containing at least one cellulose derivative selected from the group consisting of:
[4] The vaginal solid pharmaceutical composition according to any one of [1] to [3] above, wherein the content of the (B) cellulose per unit of the composition is 0.05 to 640 mg;
[5] The above [1] to [4], wherein the (B) cellulose is contained in a proportion of 0.001 to 1,000 parts by weight relative to 100 parts by weight of the (A) oxyconazole and / or its salt. Vaginal solid pharmaceutical composition according to any of the above;
[6] The vaginal solid pharmaceutical composition according to any one of [1] to [5], further containing at least one selected from the group consisting of lactose, lactose hydrate, stearic acid and salts thereof. ;
[7] The vaginal solid pharmaceutical composition according to any of [1] to [6], which is a tablet;
[8] A solid vaginal solid pharmaceutical composition, which comprises a step of preparing a solid agent containing (A) oxyconazole and / or a salt thereof, and (B) celluloses; and a step of housing the solid agent in an applicator. Method of manufacturing things.

The present invention also includes the following aspects.
[9] A solid vaginal pharmaceutical composition containing (A) oxyconazole and / or a salt thereof, and (C) starch, wherein the composition is contained in an applicator. A pharmaceutical composition;
[10] The vaginal solid pharmaceutical composition according to the above [9], wherein the content of the component (A) per unit of the composition is 600 mg;
[11] The [9] or [9] above, wherein the (C) starch contains at least one selected from the group consisting of sodium starch glycolate, starch acrylate 1000, pregelatinized starch, corn starch and potato starch. [10] The solid pharmaceutical composition for vagina according to [10].
[12] The solid vaginal pharmaceutical composition according to any of [9] to [11], wherein the content of the component (C) per unit of the composition is 0.05 to 640 mg;
[13] The above [9] to [12], wherein the (C) starch is contained in a proportion of 0.005 to 640 parts by weight relative to 100 parts by weight of the (A) oxyconazole and / or its salt. Vaginal solid pharmaceutical composition according to any of the above;
[14] The solid vaginal solid pharmaceutical composition according to any one of [9] to [13], further containing at least one selected from the group consisting of lactose, lactose hydrate, stearic acid and salts thereof. ;
[15] The solid vaginal pharmaceutical composition according to any of [9] to [14], which is a tablet;
[16] A solid vaginal solid pharmaceutical composition, which comprises a step of preparing a solid agent containing (A) oxyconazole and / or a salt thereof, and (C) starch, and a step of housing the solid agent in an applicator. Method of manufacturing things.

Moreover, in another embodiment, the present invention includes the following aspects.
[17] A kit comprising a solid vaginal pharmaceutical composition containing (A) oxyconazole and / or a salt thereof, and (B) celluloses, and an applicator;
[18] A kit comprising a solid vaginal pharmaceutical composition containing (A) oxyconazole and / or a salt thereof, and (C) starch, and an applicator.

  The vaginal solid pharmaceutical composition of the present invention is contained in an applicator, which contributes to convenience and safety of administration.

FIG. 3 is a perspective view of an applicator shown as an embodiment of the present invention.

  A vaginal administration can be performed hygienically and easily by the method of inserting the applicator in which the solid agent is placed into the vagina, and pushing the solid agent out of the applicator with an extruding member provided in the applicator. However, when the user places the solid agent in the applicator, or when the solid agent is produced, distributed, or stored in the state where the solid agent is placed in the applicator, the solid agent collides with the applicator or causes friction, and The agent may be damaged. This is particularly remarkable when the solid agent is a tablet. Damage to the solid agent not only makes it difficult for an effective amount of the drug to reach the affected area, but also broken pieces and particles of the solid agent enter the gap between the outer cylinder of the applicator and the push rod, making it difficult for the solid agent to extrude. In addition, it may be attached to the inner wall of the applicator and physically impede the extrusion of the solid agent, leading to inconvenience in application. Furthermore, the convex shape of the broken portion of the solid agent may cause irritation or damage to the vaginal mucosa. In the present invention, damage to the solid agent containing oxyconazole and / or its salt in the applicator can be suppressed. The solid agent capable of suppressing breakage has a manufacturing advantage that it is not necessary to change the shape and size of the applicator for each shape of the solid agent.

[Vaginal solid pharmaceutical composition]
The vaginal solid pharmaceutical composition of the present invention contains (A) oxyconazole and / or a salt thereof, and a polymer in which glucose molecules are polymerized by glycoside bonds, and the composition is contained in an applicator. , Vaginal solid pharmaceutical composition.

  Here, the polymer in which the glucose molecule is polymerized by the glycoside bond is (B) cellulose or (C) starch.

((A) Oxyconazole and / or its salt)
Oxyconazole is an imidazole antifungal agent which has a fungal cell membrane-damaging effect and exerts an antifungal effect.

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

  The dose (dose) of (A) oxyconazole and / or its salt is 600 mg / week, from the viewpoint of significantly exerting the effect of the present invention. Typically provided in the form of tablets containing 100-600 mg of oxyconazole nitrate per unit (ie one solid), particularly preferably in the form of tablets containing 600 mg of oxyconazole nitrate. Can be provided.

  That is, the content of (A) oxyconazole and / or its salt may vary depending on the type and amount of other components, the condition of the recipient (weight, age, symptoms, physical condition, etc.), dosage form, and the like. Although good, it is usually 8 to 95% by mass, preferably 12 to 90% by mass, more preferably 15 to 85% by mass, and most preferably 18 to 80% by mass, based on the total amount of the vaginal solid pharmaceutical composition.

((B) Cellulose)
The cellulose used in the present invention is not particularly limited as long as it can be usually used in pharmaceuticals, and is cellulose or a cellulose derivative. Here, the cellulose derivative refers to a derivative obtained by substituting a part of the hydroxyl groups of cellulose with another substituent. As such a cellulose derivative, (1) a cellulose derivative whose substituent is a hydroxypropoxy group, (2) a cellulose derivative whose substituent is a carboxyl group, (3) a cellulose derivative whose substituent is a methyl group, or ( 4) There is a cellulose derivative having two or more substituents selected from the group consisting of a hydroxypropoxy group, a carboxyl group, and a methyl group. Cellulose includes non-derivatives of cellulose such as crystalline cellulose or powdered cellulose.

  Here, (1) a hydroxypropyl cellulose is illustrated as a cellulose derivative whose substituent is a hydroxypropoxy group. (2) Examples of the cellulose derivative whose substituent is a carboxyl group include carmellose (carboxymethyl cellulose), carmellose sodium (carboxymethyl cellulose sodium), carmellose calcium (carboxymethyl cellulose calcium), and carmellose potassium (carboxymethyl cellulose potassium). To be done. (3) Methyl cellulose is illustrated as a cellulose derivative whose substituent is a methyl group. (4) Examples of the cellulose derivative having two or more substituents selected from the group consisting of a hydroxypropoxy group, a carboxyl group, and a methyl group include hydroxypropylmethylcellulose. As hydroxypropyl cellulose whose substituent is a hydroxypropoxy group, the ratio of the substituted hydroxypropoxy group is 3.0% or more, 5.0% or more, 8.0% or more, 10.0% or more, 14.0. % Or more, and there is no limitation. As the hydroxypropyl cellulose whose substituent is a hydroxypropoxy group, the ratio of the substituted hydroxypropoxy group is 85.0% or less, 82.0% or less, 78.0% or less, 70.0 %% or less, 60. It may be 0% or less, 55.0% or less, 50.0% or less, 40.0% or less, 30.0% or less, or 20.0% or less, and is not limited. Furthermore, for example, as the case may be, hydroxypropyl cellulose having a hydroxypropoxy group as a substituent may have a substituted hydroxypropoxy group ratio of 5 to 20%, 20% to 90%, or 50%. It may be about 85% or less. The celluloses used in the present invention are preferably one or more selected from the group consisting of hydroxypropyl cellulose, crystalline cellulose, powdered cellulose, carmellose (carboxymethyl cellulose), sodium carmellose (carboxymethyl cellulose sodium), and methyl cellulose. It is a cellulose derivative. The component (B) is not limited to the shape of particles, but may be granular or powder. Further, the particle size (average particle diameter) may be any value.

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

  The total content of (B) celluloses may vary depending on the amount of (A) oxyconazole and / or its salt, the type of component (B), the type and amount of other components, and the like, but a solid vaginal pharmaceutical composition It can be usually 0.001 to 80% by mass, preferably 0.005 to 70% by mass, more preferably 0.01 to 55% by mass, and most preferably 0.05 to 45% by mass based on the total amount of the products. It is% by mass.

  In addition, the content ratio of (A) oxyconazole and / or its salt and (B) cellulose in the vaginal solid pharmaceutical composition of the present invention can be appropriately set according to the types and amounts of other components. From the viewpoint of more remarkably exerting the effect of the present invention, although not limited, 0.001 to 1000 parts by weight of (B) cellulose is usually added to 100 parts by weight of (A) oxyconazole and / or a salt thereof. %, 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, most preferably 0.35 to 20 parts by weight. Can be

  The reason why damage to the solid composition containing oxyconazole and / or its salt and celluloses is suppressed in the present invention is not necessarily clear, but it can be inferred as follows. When the solid composition containing oxyconazole and / or its salt and celluloses is placed in the applicator, or when the solid composition placed in the applicator is manufactured, distributed, or stored, the applicator A force such as collision or friction occurs when the placed solid composition is extruded to the affected area, and when a force is applied to the solid composition from the outside, a crystal structure that is a higher-order structure of cellulose, an amorphous structure, or the like It is considered that one of the factors is that the damage is suppressed because the external force transmitted to the inside of the solid composition is dispersed due to the distribution of the above. In particular, when the cellulose is a cellulose derivative in which some of the hydroxyl groups are substituted, the cellulose derivative and oxyconazole and / or its salt may be more uniformly arranged due to the higher-order structure of the cellulose derivative in the solid composition. It is considered to be one of the factors that suppress damage. In a cellulose derivative in which a part of the hydroxyl groups is substituted with a polar functional group, the placement of oxiconazole and / or its salt is more likely to occur due to some interaction with oxiconazole and / or its salt when preparing a solid composition. There is a possibility that it becomes uniform and damage is suppressed.

((C) Starch)
The starch used in the present invention is not particularly limited as long as it is a starch that can be usually used in pharmaceuticals, but sodium starch glycolate, starch acrylate 1000, pregelatinized starch, corn starch, potato demp, or Examples include rice starch. It is preferably one or more selected from the group consisting of sodium starch glycolate, starch acrylate 1000, pregelatinized starch, corn starch, and potato demp. The component (C) is not limited to the shape of particles, but may be granular or powder. Further, the particle size (average particle diameter) may be any value.

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

  The total content of (C) starches may vary depending on the amount of (A) oxyconazole and / or its salt, the type of component (C), the type and amount of other components, etc., but a solid vaginal pharmaceutical composition It can be usually 0.001 to 55% by mass, preferably 0.01 to 45% by mass, more preferably 0.035 to 30% by mass, and most preferably 0.05 to 10% by mass based on the total amount of the products. It is% by mass.

  Further, the content ratio of (A) oxyconazole and / or a salt thereof and (C) starch in the vaginal solid pharmaceutical composition of the present invention can be appropriately set according to the types and amounts of other components. Although not limited, from the viewpoint of more significantly exhibiting the effect of the present invention, 0.005 to 640 parts by weight of (C) starch is usually added to 100 parts by weight of (A) oxyconazole and / or a salt thereof. %, 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, most preferably 0.15 to 160 parts by weight. Can be

(Other ingredients)
In the vaginal solid pharmaceutical composition of the present invention, as long as the effect of the invention is not impaired, a binder, an excipient, a lubricant, a fluidizing agent and the like are appropriately selected according to the form thereof, One type or two or more types can be used in combination.

  More specifically, for example, polyvinylpyrrolidone, polyvinyl alcohol, sucrose, lactose, lactose hydrate, light anhydrous silicic acid, mannitol, sorbitol, sucrose fatty acid ester, stearic acid such as magnesium stearate and salts thereof, talc. Examples thereof include sodium aluminometasilicate, and light anhydrous silicic acid.

  In addition to these, dispersants, emulsifiers, stabilizers, buffers, solubilizers, pH adjusters, preservatives (preservatives), antioxidants, colorants, and fragrances may be appropriately added.

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

(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, an outer cylinder that holds a solid agent that is an insert and that can be discharged from the distal end portion, and an movably arranged inside the outer cylinder, and press the base end portion of the outer cylinder to insert it into the outer cylinder. And an extruding member for ejecting the inserted insert from the distal end portion.

  Such an applicator is not limited, but an engaged portion is optionally formed on the inner peripheral surface of the outer cylinder, and the extruded member is provided with the insert by the extruded member. There may be formed an engaging portion that engages with the engaged portion when reaching a predetermined position therein, and that senses the position of the insert.

  The engaging portion and the engaged portion are engaged with each other when the insert is arbitrarily placed in the discharge standby region of the outer cylinder by the pushing member and the discharge of the insert can be started. It may be formed to have a positional relationship.

  Alternatively, optionally, the engaging portion and the engaged portion have a positional relationship in which they engage with each other when the distal end portion of the insert projects from the distal end portion of the outer cylinder by the pushing member. It may be formed.

  Optionally, the engaging portion and the engaged portion have a positional relationship in which they engage with each other when the insert is pushed out by the pushing member and completely discharged from the distal end portion of the outer cylinder. It may be formed as follows.

  The engaging portion has at least a first engaging portion that makes it possible to perceive that the insert is placed in the discharge standby region when engaged with the engaged portion, and the engaged portion. It may be configured with a second engaging portion that makes it possible to perceive that the insert has been completely discharged when they are fitted together.

  The engaged portion includes one convex portion that makes it possible to perceive that the insert has been placed in the discharge standby region, and another convex portion that makes it possible to perceive that the insert has protruded from the distal end portion. The one convex portion and the other convex portion may be adjacently arranged in this order toward the tip portion.

  When the first engaging portion is engaged with the convex portion, the outer cylinder is engaged with the second engaging portion so that the pushing member moves toward the base end portion of the outer cylinder. An auxiliary convex portion that restricts movement may be formed.

  When the first engaging portion is engaged with the convex portion, the outer cylinder is engaged with the second engaging portion so that the pushing member moves toward the base end portion of the outer cylinder. An auxiliary convex portion that restricts movement may be formed.

  The outer diameter of the outer cylinder of the applicator can be 8 to 20 mm, preferably 9 to 19 mm, and more preferably 10 to 18 mm for containing the vaginal solid pharmaceutical composition. The length of the outer cylinder can be set to 60 to 150 mm, preferably 70 to 140 mm, and more preferably 80 to 130 mm for containing the vaginal solid pharmaceutical composition. The outer diameter of the extruded member of the applicator can be 9 to 16 mm at the end, preferably 10 to 15 mm, and more preferably 11 to 14 mm. The tubular portion may be 9 to 18 mm, preferably 10 to 17 mm, and more preferably 11 to 16 mm.

  Hereinafter, one mode of the applicator will be described with reference to the drawings.

  As shown in FIG. 1, the applicator 1 of the present embodiment has an outer cylinder 3 that can hold a solid agent 2 that is an insert therein and discharge it from the tip, and is movably inserted into the outer cylinder 3. An extrusion member 4 for pressing and moving the solid agent 2 from its base end is provided.

  The outer cylinder 3 is formed in a bottomed cylinder shape, the tip end portion is formed to be recessed into a semi-spherical shape, and the base end portion is opened on a surface substantially perpendicular to the axis of the outer cylinder 3, It is formed so that the solid agent 2 and the extruding member 4 can be inserted.

As shown in FIG. 1, a discharge hole 5 capable of discharging the solid agent 2 and a plurality of cuts communicating with the discharge hole 5 are formed at the tip of the outer cylinder 3, and the plurality of cuts are formed. A plurality of tongue pieces are formed between them.
The tongue pieces are elastically deformed when the pushing member 4 is inserted into the outer cylinder 3 and the solid agent 2 is sent outward, and spread to each other, and elastically return when the solid agent 2 is discharged to the outside. It is formed so as to return to its original shape.

  The plurality of cuts are radial from the discharge hole 5 when viewed from the tip 3a side of the outer cylinder 3 in the direction of arrow P so that the tongues can be evenly spread, and the tip is divided equally in the circumferential direction ( It is normally formed so as to be divided into 6 to 10 equal parts. Inside the outer cylinder 3, a certain region on the front side of the discharge hole 5 is set as a discharge standby region in which discharge of the solid agent 2 can be started.

  The push-out member 4 has a sliding portion which is inserted into the outer cylinder 3 and slides in the outer cylinder 3 when the solid agent 2 is set in the discharge standby region W of the outer cylinder 3, and the sliding portion. The solid agent 2 is provided at the base end portion and projects outward from the base end portion of the outer cylinder 3 in a state where the solid agent 2 is arranged in the discharge standby region W, and when the solid agent 2 is discharged, the solid agent 2 further enters the outer cylinder 3 and slides. And a pressing portion that advances the moving portion.

  Further, in order to protect the tip of the outer cylinder 3, a cap or the like to be capped on the tip 3a of the outer cylinder 3 may be used.

  The material for molding the outer cylinder and the extruded member of the applicator is not particularly limited, but polyethylene (high density polyethylene (HDPE), low density polyethylene (LDPE), Synthesis containing 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. A resin may be used. Preferred are polyethylene and polypropylene, more preferred is polyethylene, and particularly preferred is linear low-density polyethylene.

[Formulation and manufacturing method]
The vaginal solid pharmaceutical composition 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 a pharmaceutical is particularly preferred.

  The vaginal solid pharmaceutical composition of the present invention can be manufactured in the form of a solid agent by adopting an ordinary method of formulation depending on the formulation form. The shape and size of the solid preparation are not particularly limited and may be, for example, vaginal tablets, particularly vaginal tablets.

  For example, (A) oxyconazole and / or its salt and (B) cellulose, which is a polymer in which glucose molecules are polymerized by a glycoside bond, and / or (C) starch, and other components are granulated ( For example, extrusion granulation, fluidized bed granulation or spray drying granulation), drying, and sieving can be performed to produce granules. The granulated product may be further coated with a coating agent. Preferably, such a granulated product can be further subjected to a tableting step to produce a tablet. Here, (A) oxyconazole and / or a salt thereof, and (B) a cellulose derivative, which is a polymer obtained by polymerizing glucose molecules by glycoside bonds, and / or (C) starches, and other components are sufficiently mixed. It is preferable to adopt the method described above.

  The vaginal solid pharmaceutical composition of the present invention can be more easily prepared into a dosage form as a solid preparation such as a tablet according to a method known to those skilled in the art. When preparing a tablet, the above compound (A) oxyconazole and / or its salt and (B) celluloses, and / or (C) starches, and other components are thoroughly mixed, and the mixture is directly compressed into tablets. It can also be subjected to a process.

  In the tableting step, typically, pressure can be applied to perform compression molding, and an ordinary tableting machine 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. It can also be a multi-layered tablet.

  The shape and size of the solid preparation are not particularly limited and may be, for example, vaginal tablets, particularly vaginal tablets. The vaginal tablet is solid when inserted into the vagina, and it is desirable that the vaginal tablet disintegrate in the vagina due to body temperature or secretory fluid. The shape may be, but is not limited to, an arrowhead shape, a caplet shape, a cone shape, a spindle shape, an almond shape, a spherical shape, an oval shape, or the like. Of these, a vaginal tablet having an arrowhead shape, tapering toward one end in the major axis direction and having a recess at the end opposite to the one side is particularly preferable. The size of the tablet is not limited, but an arrowhead shape having a longitudinal diameter (major diameter) of 10 to 30 mm, a lateral diameter (minor diameter) of 5 to 15 mm, and a thickness of 1 to 15 mm is particularly preferable. Tablet hardness may be, but is not limited to, 30 N or more. The vaginal solid pharmaceutical composition of the present invention may be coated.

[kit]
The vaginal solid pharmaceutical composition 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 with a vaginal applicator, molded of a vaginal insertable material. The kit may be in a form in which the vaginal tablet is contained in the applicator. In another aspect, the vaginal tablet and applicator can be provided separately in a kit so that the user can place the solid dosage form in the applicator. Conditions for the vaginal tablet and applicator included in the kit, that is, (A) amount of oxyconazole and / or its salt, (B) cellulose and / or (, which is a polymer in which glucose molecules are polymerized by glycoside bonds. The type and amount of C) starches and the types and amounts of other components are the same as those in the above-mentioned [Vaginal solid pharmaceutical composition].

[Application]
The vaginal solid pharmaceutical composition of the present invention is mainly applied for candidiasis. For example, it can be applied for treatment or prevention of vaginal candidiasis. It may be used for the purpose of treating vaginal candidiasis, or for the purpose of preventing vaginal candidiasis or preventing recurrence. Although not limited, recurrent treatment of vaginal candida is a particularly preferable target.

  Heretofore, the form which can be transmucosally administered through the vaginal mucosa is preferably a solid substance, particularly a tablet, which allows a small number of administrations. Vaginal administration of such solids can also be carried out once a day or in the form of multiple tablets once a day. However, in the case of a solid form, administration may be a burden, and in such a case, the present invention provides a vaginal tablet containing a large amount of (A) oxyconazole and / or a salt thereof. You can also Such a vaginal tablet allows once-weekly administration of only one tablet at a time to maintain the effect, which also contributes to improvement of the patient's QOL.

  That is, with regard to the dose and administration frequency of the vaginal solid pharmaceutical composition of the present invention, it depends on the purpose of use of the composition, the type of candidiasis and the degree of symptoms, the type of other components used, the age of the user, etc. Although it can be appropriately set depending on the case, typically, it is preferable to administer 1 unit (1 tablet) tablet (vaginal tablet) containing 600 mg of the active ingredient, which enables administration once a week.

[Method of giving breakage suppressing ability to vaginal solid pharmaceutical composition]
The vaginal solid pharmaceutical composition of the present invention comprises (A) oxyconazole and / or a salt thereof and (B) cellulose and / or (C) starch, which are polymers obtained by polymerizing glucose molecules through glycoside bonds. By coexisting in the vaginal solid pharmaceutical composition, the ability to suppress damage when stored in an applicator can be imparted.

  That is, according to the present invention, (A) oxyconazole and / or a salt thereof and (B) celluloses and / or (C) starches, which are polymers obtained by polymerizing glucose molecules through glycoside bonds, are used as a vaginal solid medicine. It is possible to provide a method for imparting breakage suppressing ability to the vaginal solid pharmaceutical composition, which method comprises coexisting with the composition. (A) The amount of oxyconazole and / or its salt, (B) the type and amount of celluloses and / or starches, and the type and amount of other components are the above-mentioned [solid pharmaceutical composition for vagina]. Is the same as.

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

[Test Example 1: Damage evaluation (1)]
The tablets shown in Table 1 were prepared by the same conventional method. The tablets had the same shape, and had 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 of them were placed in the discharge standby area of the applicator. Here, as the applicator, an outer cylinder having an outer diameter of 15 mm, an outer cylinder having a length of 105 mm, an end portion outer diameter of 11 mm of the extruding member, and a discharge standby region having a length of 23 mm is used. I was there. The outer cylinder and the extruded member were molded from a resin containing PE.

The ingredients used were those satisfying the items listed in the 17th revised Japanese Pharmacopoeia. Fix the applicator to a shaker (KM Shaker V-DX, manufactured by Iwaki Co., Ltd.) so that the solid agent discharge hole faces the ground, and the longitudinal axis of the applicator is in a direction perpendicular to the ground. Shake at 350 spm for 10 minutes. Since the discharge hole of the applicator is facing downward, if broken pieces or broken particles occur, they will fall out of the applicator. The weight before and after shaking (total weight of the applicator and tablets in the applicator) was measured, and the weight change rate was calculated by the following formula 1.
[Formula 1] Weight change rate (%) = {1- (weight after shaking) / (weight before shaking)} × 100

  This operation was performed 3 times using different applicators, and the average of the 3 times the weight change rate was calculated and used as the weight change rate of the test example. The results are also shown in Table 1.

[Test Example 2: Damage evaluation (2)]
Next, the shape of the broken tablet in the applicator was evaluated.
The tablets after carrying out Test Example 1 were in the same situation with the same formulation. Then, among the tablets after carrying out Test Example 1, the fingertips were slid on the boundaries between the surfaces of three arbitrary tablets of the same formulation and the recesses caused by breakage, and evaluation was performed according to the evaluation criteria. The results are also shown in Table 1.
⊚: All three samples do not feel fingertips and feel good for application to the vagina.
◯: Two fingers do not feel caught on the fingertips. One feels a slight fingertip catch, but feels that the boundary between the tablet surface and the breakage is smooth and there is no problem for vaginal application.
Δ: Two fingers do not feel caught on the fingertips. I feel a snag on the fingertip about one, but I feel that there is no problem because it is applied to the vagina.
X: A fingertip is caught on 3 or 2 fingers.

As shown in Table 1, the following things became clear.
It was found that Formulations 1 to 4 in which oxyconazole and / or a salt thereof and hydroxypropyl cellulose coexist were good in that the weight change was small and the smoothness of the solid agent surface was also good. 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 tablet with a total of 1138 mg containing oxyconazole nitrate 600 mg, hydroxypropyl cellulose 60 mg, crystalline cellulose 80 mg, lactic acid hydrate 368 mg, and magnesium stearate 30 mg in the shape of an arrowhead (length 21 mm, width 11 mm, thickness 9 mm). Was placed in the same applicator as in Test Example 1 and Test Example 1 was carried out.

  When 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, the same test as in Formulations 1 and 2 was performed. The change in weight was suppressed, and the smoothness of the surface of the solid agent was such that it could be used.

[Production example]
With respect to the formulation examples shown in Table 2, tablets were prepared and housed in an applicator according to a conventional method. The weight in the table is the content of one tablet.

1 Applicator 2 Tablet (insert)
3 Outer cylinder 4 Push-out member 5 Discharge hole

Claims (9)

A vaginal solid pharmaceutical composition containing (A) oxyconazole and / or a salt thereof, and (B) celluloses, wherein the composition is contained in an applicator. ..   The solid pharmaceutical composition for vagina according to claim 1, wherein the content of the (A) oxyconazole and / or a salt thereof per unit of the composition is 100 to 600 mg. The (B) celluloses are
At least one type of cellulose selected from the group consisting of crystalline cellulose and powdered cellulose, and / or a derivative obtained by substituting a part of hydroxyl groups of cellulose with another substituent,
(1) A cellulose derivative whose substituent is a hydroxypropoxy group,
(2) A cellulose derivative whose substituent is a carboxyl group,
(3) a cellulose derivative having a methyl group as a substituent, and (4) a cellulose derivative having at least two substituents selected from the group consisting of a hydroxypropoxy group, a carboxyl group, and a methyl group,
The vaginal solid pharmaceutical composition according to claim 1 or 2, containing at least one cellulose derivative selected from the group consisting of:   The solid pharmaceutical composition for vagina according to any one of claims 1 to 3, wherein the content of the (B) celluloses per unit of the composition is 0.05 to 640 mg.   The (A) oxyconazole and / or the salt thereof is contained in a proportion of 0.001 to 1000 parts by weight with respect to 100 parts by weight of the (B) cellulose. The vaginal solid pharmaceutical composition described.   Furthermore, the vaginal solid pharmaceutical composition according to any one of claims 1 to 5, further comprising at least one selected from the group consisting of lactose, lactose hydrate, stearic acid and salts thereof.   The vaginal solid pharmaceutical composition according to any one of claims 1 to 6, which is a tablet.   A method for producing a solid vaginal solid pharmaceutical composition for containing an applicator, comprising the step of preparing a solid agent containing (A) oxyconazole and / or a salt thereof and (B) celluloses. A kit comprising a solid vaginal pharmaceutical composition containing (A) oxyconazole and / or a salt thereof, and (B) celluloses, and an applicator.

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