Voriconazole granules

Abstract

To provide voriconazole granules that are suitably usable for administration through a simple suspension technique.SOLUTION: The problem can be solved by voriconazole granules containing voriconazole and a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910. A preferable embodiment includes a coating layer containing the mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910 on the exterior of a core particle containing voriconazole.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to voriconazole granules. [Background technology]

[0002] Voriconazole, known as an antifungal drug, i.e., (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, is commercially available in the form of tablets and the like, and for example, Patent Document 1 studies the miniaturization of voriconazole tablets. It is believed that miniaturization of tablets improves swallowability and makes them easier to take.

[0003] There is also a simple suspension method for administering pharmaceuticals, in which solid preparations such as tablets and granules are disintegrated and suspended in warm water at the medical site and administered to patients through a feeding tube, and is applicable to patients who have difficulty swallowing. In this way, solid preparations such as tablets and granules may be administered by the simple suspension method depending on the patient's condition, and therefore, for tablets and granules for which there is such a possibility, it is considered preferable that they are suitable for simple suspension. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] JP 2016-037463 A Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention has been made in view of the above circumstances, and an object of the present invention is to provide voriconazole granules that can be suitably used for administration by a simple suspension method. [Means for solving the problem]

[0006] The present inventors have discovered that by combining a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, it is possible to provide voriconazole granules that are also suitable for simple suspension, and have thus completed the present invention.

[0007] The present invention has the following aspects. [1] Voriconazole granules, characterized by containing voriconazole and a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910. [2] Voriconazole granules as described in [1], characterized in that the outside of the core particle containing voriconazole has a coating layer containing the fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910 mixture. Effect of the Invention

[0008] According to the present invention, it is possible to provide voriconazole granules that can be suitably used for administration by a simple suspension method. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The present invention will be described in detail below. The voriconazole granules (hereinafter simply referred to as granules) of the present invention contain voriconazole and a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate and hydroxypropyl methylcellulose 2910.

[0010] There are no particular limitations on the voriconazole, and commercially available voriconazole can be used, and it may be in a crystalline or amorphous form. The mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910 is a mixture whose main component is hydroxypropyl methylcellulose. Specifically, it contains 1.5-2.3% by mass of fumaric acid, 12-17% by mass of stearic acid, 16-26% by mass of polyvinyl acetal diethylaminoacetate, and 50-75% by mass of hydroxypropyl methylcellulose 2910. It is obtained by dispersing fumaric acid, stearic acid (JP), and polyvinyl acetal diethylaminoacetate in water, mixing with hydroxypropyl methylcellulose 2910 (JP), granulating, and drying (based on the Pharmaceutical Excipients Standards 2018).

[0011] The granules of the present invention may contain, in addition to the mixture of voriconazole and fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, any of additives usable in the pharmaceutical field, such as excipients, binders, disintegrants, surfactants, colorants, sweeteners, and flavors, as necessary.

[0012] Examples of excipients include D-mannitol, crystalline cellulose, lactose hydrate, anhydrous lactose, refined sucrose, potato starch, pregelatinized starch, β-cyclodextrin, etc., and one or more of these can be used as necessary.

[0013] Examples of binders include polyvinylpyrrolidone (povidone), hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, stearyl alcohol, ammonio methacrylate copolymer, polyvinyl acetal diethylamino acetate, dextrin, and starch syrup, and one or more of these can be used.

[0014] Examples of disintegrants include croscarmellose sodium, carmellose calcium, carmellose, low-substituted hydroxypropyl cellulose, crospovidone, corn starch, sodium starch glycolate, partially pregelatinized starch, hydroxypropyl starch, and the like, and one or more of these can be used.

[0015] Examples of the surfactant include sodium lauryl sulfate and polysorbate 80, and one or more of these can be used. Examples of coloring agents include titanium oxide, yellow ferric oxide, ferric oxide, Food Yellow No. 4, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Red No. 102, and the like, and one or more of these can be used.

[0016] Examples of sweeteners include acesulfame potassium, aspartame, sucralose, thaumatin, sucrose, saccharin or a salt thereof, glycyrrhizic acid or a salt thereof, stevia such as purified stevia extract or a salt thereof, and the like, and one or more of these can be used. Examples of flavoring agents include erythritol, ascorbic acid, xylitol, citric acid hydrate, sodium citrate hydrate, succinic acid, tartaric acid, D-sorbitol, and the like, and one or more of these can be used. Examples of flavorings include orange essence, orange oil, caramel, camphor, cinnamon oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, spruce oil, pine oil, peppermint oil, vanilla flavor, bitter essence, fruit flavor, peppermint essence, mixed flavor, mint flavor, 1-menthol, lemon powder, lemon oil, rose oil, and the like, and one or more of these can be used.

[0017] Other additives include light anhydrous silicic acid, carnauba wax, hydrated silicon dioxide, magnesium aluminometasilicate, magnesium stearate, sodium stearyl fumarate, glycerin fatty acid esters, sodium chloride, sodium hydroxide, etc., and one or more of these can be used.

[0018] The granule of the present invention preferably has a coating layer containing a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylamino acetate, and hydroxypropyl methylcellulose 2910 on the outside of the core particle containing voriconazole. At least one of the inner and outer coating layers may have another coating layer depending on the purpose, and the provision of such another layer can impart a specific function, for example, preventing adhesion between granules. When multiple coating layers are formed, it is preferable that the coating layer containing the mixture of fumaric acid, stearic acid, polyvinyl acetal diethylamino acetate, and hydroxypropyl methylcellulose 2910 is the outermost layer, in order to obtain a granule more suitable for administration by the simple suspension method. The form of the core particle may be a granulated material containing voriconazole and an additive, or a layered particle in which a layer of active pharmaceutical ingredient containing voriconazole is formed on the surface of an additive particle, and the like, as long as it is a particulate material containing voriconazole.

[0019] The voriconazole content in the voriconazole granules of the present invention can be set as appropriate, but when the granules are taken as 100% by mass, it can be, for example, 10 to 30% by mass, preferably 15 to 25% by mass, and more preferably 18 to 23% by mass. Furthermore, when the core particles are taken as 100% by mass, the content of voriconazole in the core particles can be, for example, 15 to 35% by mass, and preferably 18 to 30% by mass, or 20 to 28% by mass.

[0020] The core particles may contain, as necessary, additives such as those exemplified above in addition to voriconazole, and preferably contain at least a binder such as povidone, a flavoring agent such as erythritol, and a sweetener such as aspartame, thaumatin, stevia, etc. When the granules are taken as 100% by mass, the content of the binder may be, for example, 1 to 25% by mass, preferably 1 to 20% by mass, and more preferably 2 to 15% by mass. When the core particles are taken as 100% by mass, the content of the binder in the core particles can be, for example, 2 to 26% by mass, preferably 2 to 22% by mass, and more preferably 3 to 16% by mass.

[0021] When the granules are taken as 100% by mass, the content of the flavoring agent can be, for example, 25 to 65% by mass, preferably 30 to 60% by mass, and more preferably 35 to 55% by mass. When the core particles are taken as 100% by mass, the content of the flavoring agent in the core particles can be, for example, 35 to 75% by mass, preferably 40 to 70% by mass, and more preferably 45 to 65% by mass.

[0022] When the granules are taken as 100% by mass, the content of the sweetener can be, for example, 0.5 to 10% by mass, preferably 0.5 to 8% by mass, and more preferably 0.5 to 5% by mass. When the core particles are taken as 100% by mass, the content of the sweetener in the core particles can be, for example, 0.6 to 12% by mass, preferably 0.6 to 10% by mass, and more preferably 0.6 to 7% by mass.

[0023] The content of the fumaric acid-stearic acid-polyvinyl acetal diethylaminoacetate-hydroxypropyl methylcellulose 2910 mixture in the granules of the present invention can be appropriately set, but when the granules are taken as 100% by mass, it can be, for example, 0.1 to 8% by mass, preferably 0.1 to 5% by mass, and more preferably 0.1 to 3% by mass. In addition, when providing a coating layer containing a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylamino acetate, and hydroxypropyl methylcellulose 2910, the content of the mixture of fumaric acid, stearic acid, polyvinyl acetal diethylamino acetate, and hydroxypropyl methylcellulose 2910 in the coating layer is preferably at least 20% by mass, more preferably 30% by mass or more, and even more preferably 40% by mass or more, when the coating layer is taken as 100% by mass. The coating layer containing the mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910 may contain, in addition to the mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, additives such as sweeteners and colorants, as exemplified above, as necessary.

[0024] The mass ratio of the coating layer containing the mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910 to the core particles is, for example, 0.5 to 10 parts by mass, preferably 0.5 to 5 parts by mass, and more preferably 1 to 5 parts by mass, based on 100 parts by mass of the core particles. The mass ratio of the mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910 contained in the coating layer to the core particles is, for example, 0.5 to 5 parts by mass, preferably 0.5 to 3 parts by mass, and more preferably 1 to 2 parts by mass, based on 100 parts by mass of the core particles.

[0025] The granules can be produced, for example, by the following method. First, voriconazole is mixed with additives to be used as necessary to prepare a composition for granulation, and a solvent such as water is added to the composition for granulation, followed by granulation by a known method such as fluidized bed granulation, stirring granulation, rolling granulation, etc. At this time, a part of the additives to be used may be added to the solvent. Next, a liquid obtained by dissolving a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropylmethylcellulose 2910 and additives to be used as necessary in a solvent such as water is sprayed onto the obtained granules (core particles), and then dried to form a coating layer on the outside of the granules. If necessary, a liquid obtained by dissolving D-mannitol or the like in water may be sprayed onto at least one of the inside and outside of this coating layer, and another coating layer may be formed by drying. In this way, granules are obtained. A small amount of other additives may be added to the granules to form a granule, and in that case, the proportion of the granules in the granules is preferably 90% by mass or more.

[0026] The granules of the present invention described above contain a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylamino acetate, and hydroxypropyl methylcellulose 2910, and therefore have good dispersibility and excellent easy suspension properties when prepared for administration by the simple suspension method. In particular, when a coating layer containing a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylamino acetate, and hydroxypropyl methylcellulose 2910 is formed, more preferably when it is formed as the outermost layer, the easy suspension properties are further improved. EXAMPLES

[0027] The present invention will now be described in more detail with reference to examples. [Examples 1-3] Voriconazole granules were prepared according to the formulation in Table 1 below. Specifically, first, voriconazole, β-cyclodextrin, erythritol, and aspartame were mixed among the components listed in the granulated product column of Table 1, and the remaining components (povidone and thaumatin) were added to purified water and dissolved in a solution, which was sprayed onto the resulting mixture and subjected to tumbling fluid granulation to obtain granulated products (core particles). Next, a solution in which the components listed in the coating layer (I) column of Table 1 were added to purified water and dissolved was sprayed onto the resulting granulated product, and the product was dried to form a coating layer (I). Furthermore, a solution in which the components listed in the coating layer (II) column of Table 1 were added to purified water and dissolved in a solution was sprayed onto the resulting granulated product, and the product was dried to form a coating layer (II), which was then used as a granule. Thereafter, the components shown in the final mixture column were mixed and sized by passing through an 18 mesh screen to obtain granules of Examples 1 to 3 containing the components in the ratios shown in Table 1. In order to confirm the simple suspension property of each of the obtained granules, a passability test was carried out by the following method. The results are shown in Table 1.

[0028] <Passivity test> Approximately 20 mL of purified water at approximately 55°C was placed in a glass beaker, and the granules (1.0 g) were added. After 5 minutes, the mixture was stirred four times with a spatula, and after another 5 minutes, the mixture was stirred four times with a spatula. The resulting suspension was placed in a syringe and injected at a constant rate from the injection end of a feeding tube (8Fr. x 120cm). Assuming administration to a patient lying in bed, the feeding tube was horizontal for two-thirds of the way from the end inserted into the body to the injection end, and the injection end was set at a height of 30cm. After the injection, 10 mL of water was injected into the syringe to wash the inside of the feeding tube, and then the syringe and feeding tube were visually inspected to see whether any residue remained.

[0029] [Table 1]

[0030] The granules of Example 1, which are mainly composed of granules with a coating layer containing a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910, had excellent dispersibility in the suspension prepared in the passability test, and as shown in Table 1, no residue was found in the syringe or tube as a result of the passability test. On the other hand, the granules of Example 2, which contained granules without a coating layer, and the granules of Example 3, which contained granules with a coating layer containing hydroxypropylmethylcellulose, had poor dispersibility in the suspensions prepared in the passability test, and as shown in Table 1, residues were found in the syringe in both cases. From the above results, it was revealed that the granules of Example 1 have excellent easy suspension properties and are suitable for administration by the easy suspension method.

Claims

1. 1. A voriconazole granule comprising voriconazole and a mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate, and hydroxypropyl methylcellulose 2910.

2. 2. The voriconazole granule according to claim 1, characterized in that the voriconazole-containing core particle has a coating layer on the outside thereof, the coating layer containing the mixture of fumaric acid, stearic acid, polyvinyl acetal diethylaminoacetate and hydroxypropyl methylcellulose 2910.

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