Solid pharmaceutical composition for vagina

Abstract

To provide a solid pharmaceutical composition for vagina in which solubility of (A) isoconazole and / or salt thereof, to water is improved.SOLUTION: The inventors have found that, as results of the earnest research, when (A) isoconazole and / or salt thereof, and (B) one kind or more kinds selected from carmellose, hydroxypropylcellulose and salts thereof, coexist, solubility of the (A) isoconazole and / or salt thereof to water is efficiently improved, thereby completing the invention. The invention provides, namely, a solid pharmaceutical composition for vagina comprising: (A) isoconazole and / or salt thereof; (B) one kind or more kinds selected from carmellose, hydroxypropylcellulose, and salts thereof.SELECTED DRAWING: None

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, candidal onychomycosis, and esophageal and intestinal candidiasis.

[0003] Preparations containing isoconazole, 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] JP 2007-182385 A Summary of the Invention [Problem to be solved by the invention]

[0005] However, isoconazole and / or its salts are very poorly soluble in water.

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

[0007] As a result of extensive research, the present inventors have found that the solubility of isoconazole and / or a salt thereof in water is effectively improved when isoconazole and / or a salt thereof is coexisted with one or more selected from the group consisting of carmellose, low-substituted hydroxypropylcellulose, and salts thereof, and have thus completed the present invention.

[0008] That is, the present invention provides [1] (A) isoconazole and / or a salt thereof, and (B) one or more selected from the group consisting of carmellose, low-substituted hydroxypropyl cellulose, and salts thereof a solid pharmaceutical composition for vaginal application comprising: [2] The solid pharmaceutical composition for vaginal application according to the above [1], wherein the component (B) is carmellose and / or a salt thereof; [3] The solid pharmaceutical composition for vaginal application according to the above [1] or [2], wherein the content of the component (A) per unit of the composition is 600 mg; [4] The solid pharmaceutical composition for vaginal application according to any one of the above [1] to [3], wherein the content of the component (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], comprising 0.15 to 40 parts by mass of the component (B) per 100 parts by mass of the isoconazole and / or a salt thereof (A); [6] The solid pharmaceutical composition for vaginal application according to any one of the above [1] to [5], further comprising at least one selected from the group consisting of crystalline cellulose, lactose, stearic acid and a salt thereof; [7] The solid pharmaceutical composition for vaginal application according to any one of [1] to [6] above, which is a tablet; [8] The present invention provides a solid pharmaceutical composition for vaginal application according to any one of [1] to [7], which is for treating vaginal candidiasis. In another embodiment, the present invention relates to a composition comprising: (A) isoconazole and / or a salt thereof; (B) It is also possible to provide a method for imparting an effect of improving the solubility in water to a solid pharmaceutical composition for vaginal application, which comprises allowing one or more selected from the group consisting of carmellose, low-substituted hydroxypropyl cellulose, and salts thereof to coexist in the solid pharmaceutical composition for vaginal application. The present invention also provides a method for producing a solid pharmaceutical composition for vaginal application, which comprises combining (A) isoconazole and / or a salt thereof, and (B) one or more members selected from the group consisting of carmellose, low-substituted hydroxypropylcellulose, and salts thereof. Effect of the Invention

[0009] The solid pharmaceutical composition for vaginal application of the present invention improves the solubility of isoconazole and / or a salt thereof in water by allowing isoconazole and / or a salt thereof to coexist with one or more selected from the group consisting of carmellose, low-substituted hydroxypropylcellulose, and salts thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] [Solid pharmaceutical composition for vaginal application] The solid pharmaceutical composition for vaginal application of the present invention contains (A) isoconazole and / or a salt thereof, and (B) one or more members selected from the group consisting of carmellose, low-substituted hydroxypropylcellulose, and salts thereof.

[0011] [(A) Isoconazole and / or its salt] Isoconazole is an imidazole antifungal agent that exerts its antifungal effect by rapidly and potently altering the permeability of fungal cell membranes. Its chemical name (IUPAC name) is 1-{2-[(2,6-dichlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl}imidazole.

[0012] The salt of isoconazole is not particularly limited as long as it is pharmacologically or physiologically acceptable. Examples of the salt of isoconazole include various salts such as organic acid salts, inorganic acid salts, and metal salts. The salt of isoconazole may be used alone or in any combination of two or more.

[0013] (A) A preferred example of isoconazole and / or a salt thereof is isoconazole nitrate.

[0014] The dose (administration) of (A) isoconazole 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 isoconazole nitrate per unit (i.e., one solid), and particularly preferably, it can be provided in the form of a tablet containing 600 mg of isoconazole nitrate.

[0015] That is, the content of (A) isoconazole 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.

[0016] [(B) Carmellose, low-substituted hydroxypropyl cellulose, and salts thereof] The carmellose, low-substituted hydroxypropyl cellulose, and salts thereof used in the present invention can be used in ordinary pharmaceuticals, and are preferably one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, carmellose (carboxymethyl cellulose), carmellose sodium (sodium carboxymethyl cellulose), carmellose calcium (calcium carboxymethyl cellulose), and carmellose potassium (potassium carboxymethyl cellulose). Particularly preferred is carmellose. These (B) components are not limited by particle shape, and may be granular or powdery. In addition, the particle size (average particle size) may be any. Low-substituted hydroxypropyl cellulose is a low-substituted hydroxypropyl ether of cellulose, and contains 5.0 to 16.0% hydroxypropoxy groups.

[0017] The content of one or more selected from the group consisting of (B) carmellose, low-substituted hydroxypropylcellulose, and salts thereof per unit of 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.

[0018] The total content of one or more selected from the group consisting of (B) carmellose, low-substituted hydroxypropyl cellulose, and salts thereof is the amount of (A) isoconazole and / or a salt thereof, Although this may vary depending on the type of component (B) and the types and amounts of other components, it can usually be 0.1 to 40 mass%, preferably 0.3 to 30 mass%, more preferably 0.4 to 20 mass%, and most preferably 0.5 to 15 mass%, based on the total amount of the solid pharmaceutical composition for vaginal application.

[0019] In addition, (A) isoconazole and / or a salt thereof in the solid pharmaceutical composition for vaginal application of the present invention The content ratio of (B) one or more selected from the group consisting of carmellose, low-substituted hydroxypropylcellulose, and salts thereof can be appropriately set depending on the types and amounts of other components, and is not limited, but from the viewpoint of more significantly exerting the effects of the present invention, the content of (B) one or more selected from the group consisting of carmellose, low-substituted hydroxypropylcellulose, and salts thereof can usually be 0.15 to 40 parts by mass, preferably 0.20 to 35 parts by mass, more preferably 0.25 to 30 parts by mass, particularly preferably 0.30 to 25 parts by mass, and most preferably 0.35 to 20 parts by mass, per 100 parts by mass of (A) isoconazole and / or a salt thereof.

[0020] In addition, 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., within the scope that does not impair the effects of the invention. More specifically, examples of the monomer include polyvinylpyrrolidone, polyvinyl alcohol, sucrose, lactose, lactose hydrate, starch, corn starch, crystalline cellulose, 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. In addition, dispersants, emulsifiers, stabilizers, buffers, solubilizers, pH regulators, preservatives (preservatives), antioxidants, colorants, fragrances, and the like may be added as appropriate.

[0021] 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 hydrate, crystalline cellulose, and magnesium stearate, and more preferably to use all of lactose hydrate, crystalline cellulose, and magnesium stearate.

[0022] [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.

[0023] The solid pharmaceutical composition for vaginal application of the present invention can be manufactured by adopting a conventional preparation method according to the formulation form. For example, the above-mentioned components can be granulated (e.g., extrusion granulation, fluidized bed granulation, spray drying granulation, etc.), dried, and sieved to produce granules. These can be used to manufacture tablets by a conventional method. Here, it is preferable to adopt a method in which (A) isoconazole and / or a salt thereof and (B) one or more selected from the group consisting of carmellose, low-substituted hydroxypropylcellulose, and salts thereof, and other components are thoroughly mixed.

[0024] Alternatively, the solid pharmaceutical composition for vaginal application of the present invention can be prepared by thoroughly mixing (A) isoconazole and / or a salt thereof, (B) one or more selected from the group consisting of carmellose, low-substituted hydroxypropylcellulose and salts thereof, and other ingredients, and then directly compressing the mixture into tablets.

[0025] The solid pharmaceutical composition for vaginal use of the present invention can be prepared in the form of a solid preparation according to a method known to those skilled in the art. There is no particular limitation on the shape or size of the solid preparation, and it may be, for example, a vaginal suppository, particularly a vaginal tablet. The vaginal suppository is solid when inserted into the vagina using a hand or an applicator, and it is desirable that it melts, softens, or disintegrates in the vagina due to body temperature or secretions. There is no particular limitation on the shape, and it may be arrow-shaped, cone-shaped, spindle-shaped, spherical, or ovoid. Among these, particularly preferred is an arrow-shaped vaginal suppository 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. There is no particular limitation on the size of the tablet, but an arrow-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. There is no particular limitation on the hardness of the tablet, and it may be 30 N or more. The solid pharmaceutical composition for vaginal use of the present invention may be coated.

[0026] The composition may be packaged as a vaginal suppository in a PTP package. Furthermore, the composition may be in the form of a kit together with a vaginal applicator formed of a material that can be inserted into the vagina.

[0027] [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.

[0028] So far, semi-solid and liquid forms have been widely used as forms that can be administered transmucosally through the vaginal mucosa, but solids, particularly tablets, that allow for fewer administrations are preferred. Such solids can be administered to the vagina once a day or in the form of multiple tablets. However, administration of solids can be a burden in some cases, and in such cases, the present invention can provide a vaginal suppository that contains a large amount of (A) isoconazole and / or a salt thereof per unit. Such vaginal suppositories can maintain the effect by administering only one tablet once a week, which also contributes to improving the patient's QOL.

[0029] 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 suppository) containing 600 mg of active ingredient, which allows administration once a week.

[0030] [Method of imparting water-solubility improving effect to a solid pharmaceutical composition for vaginal application] The solid pharmaceutical composition for vaginal application of the present invention can improve its solubility in water by the coexistence of (A) isoconazole and / or a salt thereof and (B) one or more selected from the group consisting of carmellose, low-substituted hydroxypropylcellulose and salts thereof in the solid pharmaceutical composition for vaginal application. By improving the solubility in water according to the present invention, the separation ability is improved in reverse phase chromatography and the like, and quality control is facilitated by increasing test accuracy. Therefore, it is possible to provide a high-quality solid pharmaceutical composition for vaginal application containing (A) isoconazole and / or a salt thereof.

[0031] That is, the present invention can provide a method for imparting a solubility improving effect to a solid pharmaceutical composition for vaginal application, comprising allowing (A) isoconazole and / or a salt thereof and (B) one or more selected from the group consisting of carmellose, low-substituted hydroxypropylcellulose and salts thereof to coexist in the solid pharmaceutical composition for vaginal application. The amount of (A) isoconazole and / or a salt thereof, the type and amount of (B) one or more selected from the group consisting of carmellose, low-substituted hydroxypropylcellulose and salts thereof, and the type and amount of other components can be determined in accordance with the above. The same applies as in the case of [Solid pharmaceutical composition for vaginal application]. EXAMPLES

[0032] Next, the present invention will be specifically described with reference to examples, but the present invention is not limited to the following examples.

[0033] [Test Example 1: Solubility Evaluation] The components shown in Table 1 were mixed according to the recipe, and purified water was added to make 1000 mL of test solution. After stirring the test solution at 800 rpm for 30 minutes, 1 μL was accurately weighed out and the isoconazole nitrate content was measured by high performance liquid chromatography according to the analytical conditions below. As a control solution, a solution in which isoconazole nitrate was dissolved in methanol was measured in the same manner. (B) One or more components selected from the group consisting of carmellose, low-substituted hydroxypropylcellulose, and salts thereof, and other components that satisfy the requirements listed in the 17th Edition of the Japanese Pharmacopoeia (hereinafter the same).

[0034] Analysis conditions Detector: UV spectrophotometry (wavelength 220 nm), Column: Stainless steel tube (inner diameter 4.6 mm, length 100 mm) packed with 5 μm octadecylsilylated silica gel for liquid chromatography Column temperature: constant temperature around 45℃ Mobile phase: A 1:1 mixture of phosphate buffer and acetonitrile (phosphate buffer is 1.1 g NaH 2 PO 4 2H 2 O, 0.57g NaClO 4 H 2 O and 0.3 mL H 3 PO 4 (Prepared by dissolving Flow rate: Adjusted so that the retention time of isoconazole nitrate is approximately 6 minutes (0.95 ml / min).

[0035] The isoconazole nitrate content (mass ratio) of the test solution relative to the control solution was calculated to determine the quantitative value of isoconazole nitrate in each test solution. The dissolution improvement rate was then calculated using the following formula 1. [Formula 1] Dissolution improvement rate (%) = {(quantitative value of isoconazole nitrate in the example) / (quantitative value of isoconazole nitrate in Comparative Example 1) - 1} x 100 The results are also shown in Table 1.

[0036] [Table 1]

[0037] As shown in Table 1, the following became clear: It was found that, compared to Comparative Example 1 which contained only (A) isoconazole and / or a salt thereof, Examples 1 to 3 which contained (A) isoconazole and / or a salt thereof together with (B) one or more selected from the group consisting of carmellose, low-substituted hydroxypropylcellulose, and salts thereof, exhibited a significant improvement in the solubility of (A) isoconazole and / or a salt thereof.

[0038] [Production Example] Tablets were prepared according to the usual method for the formulation examples shown in Table 2. The weights in the table are the contents per tablet.

[0039] [Table 2]

Claims

[Claim 1] (A) isoconazole and / or a salt thereof, and (B) one or more selected from the group consisting of carmellose, low-substituted hydroxypropyl cellulose, and salts thereof A solid pharmaceutical composition for vaginal application comprising:

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