Desloratadine solid preparation

Abstract

To provide a desloratadine solid preparation that suppresses the time-dependent increase in analogs and exhibits superior stability.SOLUTION: The present invention provides a desloratadine solid preparation containing desloratadine and arginine, thereby suppressing the time-dependent increase in analogs, particularly N-formyl desloratadine. The solid preparation is preferably an orally disintegrating tablet.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a solid formulation of desloratadine. [Background technology]

[0002] Desloratadine, i.e., 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, is an antihistamine, and tablets containing it are sold under the name "Desalex (registered trademark) tablets" (Non-Patent Document 1). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Desalex (registered trademark) Tablets 5 mg Package Insert (Revised January 2023 (3rd edition), revised June 2021 (2nd edition)) Summary of the Invention [Problem to be solved by the invention]

[0004] However, while the present inventors continued to study preparations containing desloratadine, it was found that the preparations were prone to increase in related substances over time, and had problems with stability. The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a desloratadine solid preparation which is excellent in stability and in which the increase of related substances over time is suppressed. [Means for solving the problem]

[0005] The present inventors have discovered that by incorporating arginine, the increase in related substances, particularly N-formyldesloratadine, can be suppressed, thereby solving the above-mentioned problems, and have thus completed the present invention.

[0006] The present invention has the following aspects. [1] A desloratadine solid formulation comprising desloratadine and arginine. [2] The desloratadine solid formulation according to [1], wherein the mass ratio of desloratadine to arginine [arginine / desloratadine] is 0.01 to 0.8. [3] The desloratadine solid formulation according to [1] or [2], further comprising hypromellose. [4] The desloratadine solid formulation according to [1], which is an orally disintegrating tablet. Effect of the Invention

[0007] According to the present invention, it is possible to provide a desloratadine solid preparation which is excellent in stability and in which an increase in related substances over time is suppressed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The present invention will be described in detail below. The desloratadine solid preparation of the present invention (hereinafter, sometimes simply referred to as a solid preparation) contains desloratadine and arginine. By adding arginine, the increase in total related substances over time, especially the increase in N-formyldesloratadine, can be suppressed, and the solid preparation can be made to have excellent stability. That is, in the present invention, arginine is added as a stabilizer for the preparation.

[0009] There are no particular limitations on the desloratadine, and any commercially available desloratadine can be used, and it may be in either crystalline or amorphous form. As the arginine, L-arginine available on the market for pharmaceutical use can be used.

[0010] The solid preparation of the present invention may further contain magnesium oxide in order to inhibit an increase in related substances. Magnesium oxide available on the market for pharmaceutical use (for example, magnesium oxide with brands such as "heavy" and "fine granule") can be used without any restrictions, but it is preferable that the magnesium oxide contains 70% by mass or more, and more preferably 70 to 80% by mass, of powder that passes through a sieve with sieve number 30 according to the Japanese Pharmacopoeia but does not pass through a sieve with sieve number 83 according to the Japanese Pharmacopoeia, in 100% by mass, in the method described in the sieve size measurement method, sieve analysis method (mechanical shaking method), of the Japanese Pharmacopoeia, 18th Edition. Here, the sieve with sieve number 30 has an opening size of 500 μm, and the sieve with sieve number 83 has an opening size of 180 μm. Moreover, the magnesium oxide preferably has a volume of 5 to 20 mL per 5 g, more preferably 6.5 to 19.0 mL, and even more preferably 6.5 mL. As a commercially available magnesium oxide, the Japanese Pharmacopoeia magnesium oxide sold by Kyowa Chemical Industry Co., Ltd. under the brand name "fine granules" satisfies the above conditions and can be suitably used.

[0011] The solid formulation of the present invention may contain, in addition to desloratadine, arginine, and optionally magnesium oxide, any of the 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, but it is preferable to use D-mannitol in terms of taste and ease of granulation, etc. It is also preferable to use crystalline cellulose in terms of low reactivity with other ingredients, excellent moldability, and ease of obtaining a solid preparation with excellent disintegration properties. More preferably, these are used in combination.

[0013] Examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), polyvinyl alcohol, polyvinylpyrrolidone, stearyl alcohol, ammonio methacrylate copolymer, polyvinyl acetal diethylaminoacetate, dextrin, and starch syrup. One or more of these can be used, but the use of hypromellose is preferred because it provides better stability to the desloratadine solid formulation and can better suppress the production of related substances.

[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. One or more of these can be used, but it is preferable to use at least low-substituted hydroxypropyl cellulose in terms of superior disintegration properties, and it is also preferable to use corn starch in combination.

[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 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] Sweetening agents include acesulfame potassium, aspartame, sucralose, thaumatin, sucrose, saccharin or a salt thereof, glycyrrhizic acid or a salt thereof, stevia or a salt thereof, etc., and one or more of these can be used. In the case of desloratadine solid formulations, however, it is preferable from the standpoint of taste to use sucralose in combination with stevia. 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 lubricants (metal stearates such as magnesium stearate, calcium stearate, etc., fatty acid esters such as glycerin fatty acid esters, sucrose fatty acid esters, sodium stearyl fumarate, talc, etc.), coating bases (hydroxypropyl cellulose, hydroxypropyl methylcellulose, carmellose sodium, etc.), coating plasticizers (triethyl citrate, etc.), light anhydrous silicic acid, titanium oxide, carnauba wax, etc., and one or more of these can be used.

[0018] As the additive, a granulated product in which multiple types of additives have been granulated in advance may be used. For example, a commercially available granulated product (SmartEx (registered trademark), Shin-Etsu Chemical Co., Ltd.) in which D-mannitol (excipient), low-substituted hydroxypropyl cellulose (disintegrant), and polyvinyl alcohol completely saponified product (binder) may be granulated may be used. SmartEx (registered trademark) is a granule consisting of 90.0 to 95.0% by mass of D-mannitol, 5.0 to 7.0% by mass of low-substituted hydroxypropylcellulose, and 0.1 to 0.3% by mass of fully saponified polyvinyl alcohol, and either "QD-50" or "QD-100", which have different particle sizes, can be used.

[0019] The solid formulation of the present invention is not limited in its form as long as it contains desloratadine and arginine, and examples of such formulations include granular formulations (granules, dry syrups, fine granules, etc.) and tablets (immediate-release tablets, orally disintegrating tablets, etc.). However, since desloratadine has a bitter taste, granular formulations and tablets containing granules having a coating layer on core particles containing desloratadine are preferred. Specifically, a granular preparation in which an additive is added to granules having a coating layer as required, or a tablet obtained by mixing an additive with granules having a coating layer as required and compressing the resulting composition for tableting is preferred. The surface of the tablet can also be coated with any material to provide an outermost coating layer.

[0020] In such an embodiment containing granules, arginine is preferably contained in the core particles together with desloratadine. Examples of the form of the core particle containing desloratadine include a granule containing desloratadine, arginine, and optionally added additives, and a layering particle in which a drug substance layer containing desloratadine and arginine is formed on the surface of an additive particle, but a granule containing desloratadine, arginine, and optionally added additives is preferred.

[0021] The coating layer provided on the core particles can be made of a known coating base, but it is preferable to use at least an aminoalkyl methacrylate copolymer. The use of an aminoalkyl methacrylate copolymer is preferable because it can effectively suppress the bitterness of desloratadine and is less likely to affect the stability, dissolution behavior, etc. of desloratadine. The coating layer can contain other coating bases and additives such as coating plasticizers as necessary. In addition, an overcoat layer may be provided on the outside of the coating layer according to the purpose. By providing an overcoat layer, a specific function can be imparted, such as preventing adhesion between granules.

[0022] As the aminoalkyl methacrylate copolymer, aminoalkyl methacrylate copolymer type E available on the market for pharmaceutical use can be used. As the aminoalkyl methacrylate copolymer type E, commercially available Eudragit (registered trademark) E100, Eudragit (registered trademark) EPO, Kollicoat (registered trademark) Smart Seal 30D, Kollicoat (registered trademark) Smart Seal 100P, etc., which are copolymers of methyl methacrylate, butyl methacrylate, and dimethylaminoethyl methacrylate, can be used.

[0023] The content of desloratadine in the solid preparation of the present invention can be appropriately set and can be, for example, 0.5 to 10% by mass, preferably 1 to 8% by mass, and more preferably 1 to 4% by mass, based on 100% by mass of the solid preparation. When the granules are taken as 100% by mass, the content of desloratadine in the granules can be, for example, 1 to 13% by mass, preferably 4 to 10% by mass, and more preferably 6 to 9% by mass. When the core particles are taken as 100% by mass, the content of desloratadine in the core particles can be, for example, 3 to 15% by mass, preferably 5 to 11% by mass, and more preferably 7 to 9% by mass.

[0024] The arginine content can also be appropriately set and can be, for example, 0.1 to 10 mass%, preferably 0.1 to 8 mass%, more preferably 0.1 to 3 mass%, and particularly preferably 0.1 to 2 mass%, based on 100 mass% of the solid preparation. When the granules are taken as 100% by mass, the arginine content in the granules can be, for example, 0.1 to 15% by mass, preferably 0.1 to 10% by mass, and more preferably 0.2 to 8% by mass. When the core particle is taken as 100% by mass, the content of arginine in the core particle can be, for example, 0.1 to 15% by mass, preferably 0.2 to 12% by mass, and more preferably 0.3 to 9% by mass. When the arginine content is within the above range, the increase in related substances over time, particularly the increase in N-formyldesloratadine, can be further suppressed, the dissolution behavior can be maintained within a good range, and a solid preparation with excellent disintegrability can be obtained.

[0025] The mass ratio of arginine to desloratadine, i.e., the mass ratio [arginine / desloratadine], is preferably 0.8 or less, more preferably 0.01 or more, more preferably 0.05 or more, and even more preferably 0.1 or more. When the mass ratio [arginine / desloratadine] is within the above range, the increase in related substances over time, particularly the increase in N-formyldesloratadine, can be further suppressed, the dissolution behavior can be maintained within a good range, and a solid preparation with excellent disintegrability can be obtained. In particular, in consideration of disintegrability, a mass ratio of 0.5 or less is preferable.

[0026] When the solid preparation contains magnesium oxide, the content thereof can be appropriately set. From the viewpoint of suppressing an increase in related substances, the content can be, for example, 1 to 20 mass%, preferably 3 to 20 mass%, more preferably 5 to 15 mass%, and particularly preferably 5 to 10 mass%, based on 100 mass% of the solid preparation. When the granules are taken as 100% by mass, the content of magnesium oxide in the granules can be, for example, 2 to 45% by mass, preferably 6 to 45% by mass, and more preferably 8 to 35% by mass. When the core particles are taken as 100% by mass, the content of magnesium oxide in the core particles can be, for example, 3 to 55% by mass, preferably 9 to 55% by mass, and more preferably 12 to 40% by mass. The mass ratio of magnesium oxide to desloratadine, ie, the mass ratio [magnesium oxide / desloratadine], is preferably 1-10, more preferably 2-5, and further preferably 2-3.

[0027] When the solid formulation of the present invention contains granules in which a coating layer containing an aminoalkyl methacrylate copolymer is provided on a core particle containing desloratadine, arginine, and optionally added additives, the content of the aminoalkyl methacrylate copolymer in the coating layer provided on the core particle can be appropriately set, but when the solid formulation is taken as 100% by mass, the content of the aminoalkyl methacrylate copolymer in the coating layer can be, for example, 1 to 12% by mass, preferably 1 to 10% by mass, and more preferably 2 to 8% by mass. When the granules are taken as 100% by mass, the content of the aminoalkyl methacrylate copolymer in the coating layer can be, for example, 6 to 20% by mass, preferably 8 to 18% by mass, and more preferably 10 to 16% by mass. When the coating layer is taken as 100% by mass, the content of the aminoalkyl methacrylate copolymer in the coating layer is preferably 80% by mass or more, more preferably 90% by mass or more, even more preferably 95% by mass or more, and particularly preferably 100% by mass.

[0028] The mass ratio of the core particles to the coating layer in the granules can be 5 to 25 parts by mass, preferably 10 to 20 parts by mass, and more preferably 12 to 18 parts by mass, of the coating layer when the core particles are taken as 100 parts by mass.

[0029] When the solid preparation is taken as 100% by mass, the content of the excipient in the solid preparation can be, for example, 35 to 75% by mass, preferably 40 to 70% by mass, and more preferably 45 to 65% by mass. When the granules are taken as 100% by mass, the content of the excipient in the granules can be, for example, 40 to 80% by mass, preferably 45 to 75% by mass, and more preferably 50 to 70% by mass. When the core particles are taken as 100% by mass, the content of the excipient in the core particles can be, for example, 50 to 90% by mass, preferably 55 to 85% by mass, and more preferably 60 to 80% by mass.

[0030] Here, when the solid preparation is a tablet, and the tablet is a tablet obtained by compressing a composition for tableting obtained by mixing an additive with a granule, the excipient is preferably contained in both the granule (preferably the core particle) and the additive added to the granule, and it is preferable from the viewpoint of taste and stability of the solid preparation that D-mannitol is contained in both. In this case, the content of the excipient in 100% by mass of the additive added to the granule is preferably 40 to 60% by mass, more preferably 45 to 55% by mass.

[0031] When the solid preparation is taken as 100% by mass, the content of the binder in the solid preparation can be, for example, 0.1 to 5% by mass, preferably 0.1 to 3% by mass, and more preferably 0.5 to 3% by mass. When the granules are taken as 100% by mass, the content of the binder in the granules can be, for example, 1 to 10% by mass, preferably 1 to 8% by mass, and more preferably 1 to 5% 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, 1 to 10% by mass, preferably 1 to 8% by mass, and more preferably 1 to 5% by mass. As for the binder, as described above, hypromellose is preferred in terms of the stability of the solid formulation, and when the solid formulation is a tablet and the tablet is produced by compressing a composition for tableting obtained by mixing granules with additives, it is preferable that the binder is contained at least in the core particles of the granules in terms of stability as well as molding.

[0032] When the solid preparation is taken as 100% by mass, the content of the disintegrant in the solid preparation can be, for example, 10 to 50% by mass, preferably 15 to 45% by mass, and more preferably 20 to 40% by mass. When the granules are taken as 100% by mass, the content of the disintegrant can be, for example, 1 to 20% by mass, preferably 5 to 20% by mass, and more preferably 7 to 15% by mass. When the core particles are taken as 100% by mass, the content of the disintegrant in the core particles can be, for example, 1 to 20% by mass, preferably 5 to 20% by mass, and more preferably 8 to 18% by mass.

[0033] Here, when the solid preparation is a tablet, and the tablet is a tablet obtained by tableting a composition for tableting obtained by mixing an additive with a granule, the disintegrant is preferably contained in both the granule and the additive added to the granule, and it is preferable that the core particles constituting the granule contain low-substituted hydroxypropyl cellulose, and the additive added to the granule contains at least one of low-substituted hydroxypropyl cellulose and corn starch. This can further increase the disintegration property of the solid preparation. In this case, the content of the disintegrant in 100% by mass of the additive added to the granule is preferably 35 to 55% by mass, more preferably 40 to 50% by mass.

[0034] The sweetener is preferably contained in an amount of 0.1 to 1% by mass, based on 100% by mass of the solid preparation, and the lubricant is preferably contained in an amount of 0.1 to 3% by mass, based on 100% by mass of the solid preparation.

[0035] The solid preparation of the present invention can be produced by known methods so long as it contains desloratadine and arginine. However, when the preparation contains granules, it is preferable to first produce the granules by the following method. Desloratadine and arginine are mixed with optional excipients, binders, disintegrants, and other additives to prepare a granulation composition, and a solvent such as purified water is added to the granulation composition, followed by granulation by a known method such as fluidized bed granulation, rolling fluidized bed granulation, or stirring granulation. At this time, a part of the additives such as the binder may be dissolved in the solvent. Next, a liquid in which an aminoalkyl methacrylate copolymer and additives used as necessary are dissolved in a solvent such as ethanol is sprayed onto the obtained granules (core particles), and then dried to form a coating layer on the outside of the granules. In this manner, granules can be produced. Alternatively, particles made of excipients such as D-mannitol, lactose hydrate, etc. may be prepared, and a liquid containing desloratadine, arginine, and optionally added magnesium oxide may be sprayed onto the surface to form a layer of active ingredients to produce layered particles, which are then used as core particles and a coating layer formed on the surface to produce granules.

[0036] The granules thus obtained may be mixed with additives as necessary to form a granular preparation (granules, dry syrups, fine granules, etc.), or the granules obtained may be added with additives as necessary and compressed to form tablets (immediate release tablets, orally disintegrating tablets, etc.). An outermost coating layer may be formed on the resulting tablets as necessary. When additives are added to the granules and compressed, the proportion of the granules in 100% by mass of the resulting tablet is preferably 25 to 55% by mass, more preferably 30 to 50% by mass, and even more preferably 35 to 45% by mass, from the viewpoint of disintegration property, etc.

[0037] As described above, since the solid preparation of the present invention contains desloratadine and arginine, the increase in total related substances (especially N-formyldesloratadine) over time is suppressed, and the solid preparation has excellent stability. In addition, the dissolution behavior can be maintained within a good range, and the disintegration property can be made good. EXAMPLES

[0038] [Test example] In considering the formulation of a solid preparation containing desloratadine, desloratadine was mixed with various binders and purity tests were performed by the following method. Specifically, desloratadine was mixed with the binders shown in Table 1 in a mass ratio of 1:2, and the total amount of related substances was measured when stored under the following conditions 1 to 4. The results are shown in Table 1. Condition 1: Stored at 40℃ and 75% RH for 4 weeks Condition 2: Stored at 25°C and 85% RH for 4 weeks Condition 3: Stored at 60℃ in an open environment for 4 weeks Condition 4: Storage under harsh light conditions (integral illuminance of 1.2 million lx h)

[0039] <Purity test (total amount of related substances)> A 43:57 mixture of acetonitrile and buffer solution (a solution of 0.865 g of sodium lauryl sulfate, 0.5 mL of trifluoroacetic acid, and water to make 1000 mL) was added with 24 mg of a mixture of desloratadine and a binder shown in Table 1 to obtain a dissolution solution of 100 mL. This was centrifuged and the supernatant was collected as a sample solution, which was then analyzed by an automatic analysis method using high performance liquid chromatography. The values ​​for the total amount of related substances shown in Table 1 are expressed as a percentage of the sum of the peak areas due to the observed related substances relative to the peak area due to desloratadine.

[0040] [Table 1]

[0041] As shown in Table 1, the mixture of desloratadine and hypromellose did not solidify under any of the conditions, had a small amount of total related substances, and was excellent in stability.

[0042] [Example 1 to Example 4] Based on the results of the above test examples, orally disintegrating tablets were produced using hypromellose as a binder and having the formulation shown in Table 2 below. Specifically, first, the components listed in the granulation column of Table 2 were mixed to prepare a granulation composition, and purified water was sprayed onto the granulation composition and stirred to granulate, thereby obtaining a granulation product (core particles (granules)). The granules were then passed through a screen to size them, and the ingredients listed in the column for post-additives in Table 2 were added to prepare a composition for tableting. This was then tableted to obtain the orally disintegrating tablets of Examples 1 to 4 (mass 180 mg, diameter 8 mm). The orally disintegrating tablets obtained were subjected to a purity test and a dissolution test by the following methods.

[0043] <Purity test> The orally disintegrating tablets obtained in each example were either unpackaged or packaged in a PTP sheet and stored at 60°C in an open environment. A purity test was performed by measuring the amount of N-formyldesloratadine after 2 weeks and 1 month. Specifically, a buffer solution (2.72 g of potassium dihydrogen phosphate was added to water to make 2000 mL, which was then filtered (cellulose acetate), and 10 mL of triethylamine was added to 1000 mL of the filtrate, and phosphoric acid was further added to adjust the pH to 2.0) and a 850:50:100 mixture of acetonitrile and methanol were added with 2 orally disintegrating tablets to make 50 mL. The solution was then centrifuged and the supernatant was collected as the sample solution, which was then analyzed using an automatic analysis method using high-performance liquid chromatography. The results are shown in Table 3. The amount of N-formyldesloratadine shown in Table 3 is expressed as a percentage of the peak area of ​​N-formyldesloratadine relative to the peak area derived from desloratadine.

[0044] <Dissolution test> Using the obtained orally disintegrating tablets and test liquid (pH 6.8), a dissolution test was performed at 75 revolutions per minute by the paddle method. After a specified time (30 minutes) from the start of the test, 10 mL or more of the dissolution liquid was collected and filtered through a membrane filter with a pore size of 0.45 μm or less. The first 5 mL of filtrate collected was removed, and the next 1 mL of filtrate was accurately measured and accurately added with 1 mL of the first dissolution test liquid to prepare a sample solution. Separately, accurately weigh out approximately 28 mg of desloratadine for quantitative measurement, and dissolve it in dissolution test fluid 1 to make exactly 50 mL. Accurately measure 5 mL of this solution, and add dissolution test fluid 1 to make exactly 50 mL. Further, accurately measure 5 mL of this solution, and add dissolution test fluid 1 to make exactly 50 mL. Accurately measure 1 mL of this solution, and add exactly 1 mL of test fluid to make the standard solution. The sample solution and the standard solution were tested by HPLC, and the ultraviolet absorption at a wavelength of 258 nm was measured to obtain a chromatogram. The dissolution rate (%) of the sample solution 30 minutes after the start of the dissolution test was calculated based on the peak area of ​​the standard solution. The above test was carried out twice (n=2) for each orally disintegrating tablet, and the average (average dissolution rate) was calculated. The mobile phase was prepared by adding 400 mL of a mixture of acetonitrile:methanol=4:1 for liquid chromatography to 600 mL of a solution prepared by dissolving 6.8 g of potassium dihydrogen phosphate in water to make 1000 mL.

[0045] [Table 2]

[0046] [Table 3] TIFF2024180244000004.tif64150

[0047] As shown in Table 3, the orally disintegrating tablet of Example 1 to which L-arginine was added suppressed the increase in N-formyldesloratadine, whether unpackaged or in a PTP package. The average dissolution rate of the orally disintegrating tablets of Example 1 after storage for 2 weeks at 40°C and 75% RH without packaging was 98.0%, which was almost the same as the average dissolution rate before storage (100.5%), and the delay in dissolution was suppressed.

[0048] [Prescription Examples A and B] Orally disintegrating tablets of Formulation Examples A and B were prepared as follows. Among the components listed in the granulation column of Table 4, the components other than hypromellose were mixed to prepare a granulation composition, and a liquid in which hypromellose was dissolved in water was sprayed onto the granulation composition and granulated in a tumbling fluidized bed to obtain a granulation product (core particles). Next, a liquid in which each component listed in the coating layer column of Table 4 was dissolved in a solvent (ethanol) was sprayed onto the obtained granulation product, and the mixture was dried to form a coating layer, thereby obtaining granules. Thereafter, a fluidizing agent was added, and the ingredients listed in the column for post-additives in Table 4 were added to the granules that had been passed through a screen to prepare a composition for tableting. This was then tableted to obtain orally disintegrating tablets of Formulation Examples A and B (mass 180 mg, diameter 8 mm). The orally disintegrating tablets obtained were subjected to the purity test and dissolution test by the methods described above. However, in the purity test, the amount of N-formyldesloratadine and the amount of total related substances were calculated separately. The value of the amount of total related substances is expressed as a percentage of the sum of the peak areas of the observed related substances to the peak area of ​​desloratadine.

[0049] [Table 4] TIFF2024180244000006.tif77144

[0050] [Table 5]

[0051] As shown in Table 5, the orally disintegrating tablet of Example A to which arginine was added suppressed the increase in N-formyldesloratadine and also suppressed the increase in the total amount of related substances, whether unpackaged or in a PTP package. Moreover, the average dissolution rate of the orally disintegrating tablets of Example A was 99.9%, and the dissolution behavior was good.

[0052] [Prescription Examples C~F] Orally disintegrating tablets of Formulation Examples C to F were produced in which the amount of L-arginine was changed as follows. Among the components listed in the granulation column of Table 6, the components other than hypromellose were mixed to prepare a granulation composition, and a liquid in which hypromellose was dissolved in water was sprayed onto the granulation composition and granulated in a tumbling fluidized bed to obtain a granulation product (core particles). Next, a liquid in which each component listed in the coating layer column of Table 6 was dissolved in a solvent (ethanol) was sprayed onto the obtained granulation product, and the product was dried to form a coating layer, thereby obtaining granules. Thereafter, a fluidizing agent was added, and the components listed in the column for post-additives in Table 6 were added to the granules that had been passed through a screen to prepare a composition for tableting. This was then tableted to obtain orally disintegrating tablets (mass 180 mg, diameter 8 mm) of Formulation Examples C to F. The orally disintegrating tablets obtained were subjected to the purity test by the method described above, and the disintegrability was evaluated by the method described below. However, in the purity test, the amount of N-formyldesloratadine and the amount of total related substances were calculated separately. The value of the amount of total related substances is expressed as a percentage of the sum of the peak areas of the observed related substances to the peak area of ​​desloratadine.

[0053] <Collapseability (collapse time)> Using a disintegration tester (NT-400, manufactured by Toyama Sangyo Co., Ltd.), the disintegration time of six tablets for each example (n=6) was measured in accordance with the disintegration test method of the Japanese Pharmacopoeia, and the average disintegration time of the six tablets was calculated.

[0054] [Table 6]

[0055] [Table 7]

[0056] [Table 8]

[0057] As shown in Table 7, the orally disintegrating tablets of Examples C to E containing L-arginine suppressed the increase in N-formyldesloratadine and also suppressed the increase in the total amount of related substances, whether unpackaged or packaged in a PTP. Furthermore, all of the orally disintegrating tablets of Examples C to E had good disintegrability, and the orally disintegrating tablets of Examples D and E in particular had excellent disintegrability.

Claims

1. A solid preparation of desloratadine, comprising desloratadine and arginine.

2. 2. The desloratadine solid formulation according to claim 1, wherein the mass ratio of desloratadine to arginine [arginine / desloratadine] is 0.01 to 0.

8.

3. 3. The desloratadine solid formulation according to claim 1, further comprising hypromellose.

4. 2. The desloratadine solid formulation of claim 1, which is an orally disintegrating tablet.

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