Rupatadine orally disintegrating tablets

Abstract

To provide an orally disintegrating tablet that exhibits good dissolution behavior even when a coating layer is applied to mask the bitter taste, and is of a size that is easy to pick up with your fingers. [Solution] The problem is solved by an orally disintegrating tablet containing granules in which a coating layer is provided on a core particle comprising rupatadine or a salt thereof and at least one additive selected from the group consisting of excipients, disintegrants, and binders, characterized in that the mass is 180 to 300 mg.

Description

Technical Field

[0001] The present invention relates to rupatadine orally disintegrating tablets.

Background Art

[0002] Rupatadine is a therapeutic agent for oral allergic diseases, and tablets containing rupatadine fumarate, that is, 8-Chloro-6,11-dihydro-11-{1-[(5-methylpyridin-3-yl)methyl]piperidin-4-ylidene}-5H-benzo [5,6]cyclohepta[1,2-b]pyridine monofumarate, are sold under the name of "Rupafin (registered trademark) tablets" (see Non-Patent Document 1). Rupafin (registered trademark) tablets are ordinary tablets, which are circular tablets with a mass of 100 mg and a diameter of 6.3 mm. Thus, as a solid preparation containing rupatadine fumarate, ordinary tablets are sold, but orally disintegrating tablets are not sold. Therefore, the development of orally disintegrating tablets that are easy to swallow for children, the elderly, etc. is desired.

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] However, when the present inventors proceeded with studies to provide an orally disintegrating tablet containing rupatadine or its salt, it was found that rupatadine or its salt has a strong bitter taste, so it is necessary to mask the bitter taste felt by the user when it disintegrates in the mouth. Therefore, the inventors prepared granules in which a coating layer that masks bitterness is provided on core particles containing rupatadine or a salt thereof and an additive, and manufactured orally disintegrating tablets by compressing these granules together with an additive (post-additive). The mass and diameter of the orally disintegrating tablets were the same as the commercially available "Rupafin® Tablets," being round tablets with a mass of 100 mg and a diameter of 6.3 mm. However, an evaluation of the performance of this orally disintegrating tablet revealed that while the bitterness was masked, there were issues with its dissolution behavior. Furthermore, the size of this orally disintegrating tablet made it difficult to pick up with fingers. [Means for solving the problem]

[0005] The present invention has been made in view of the above circumstances, and aims to provide an orally disintegrating tablet that exhibits good dissolution behavior even when a coating layer is provided to mask the bitter taste, and is of a size that is easy to pick up with your fingers.

[0006] As a result of diligent research, the inventors of the present invention have found that an orally disintegrating tablet, in which granules containing rupatadine or a salt thereof and an additive are provided with a coating layer, and with a mass of 180 to 300 mg, is a formulation in which bitterness is masked, yet dissolution behavior is excellent, the tablet size is appropriate, and the problem of being difficult to pick up with fingers is also solved, thus completing the present invention.

[0007] The present invention has the following aspects. [1] A rupatadine orally disintegrating tablet comprising granules having a coating layer on a core particle containing rupatadine or a salt thereof and at least one additive selected from the group consisting of excipients, disintegrants, and binders, characterized in that the mass is 180 to 300 mg. [2] A rupatadine orally disintegrating tablet as described in [1], containing 5 to 30 mg of rupatadine or a salt thereof. [3] The rupatadine orally disintegrating tablet according to [1], comprising the granules and a post-additive separately formulated with the granules, wherein the mass ratio [granules / post-additive] is 0.55 to 1.2. [4] The rupatadine orally disintegrating tablet according to [1], wherein the additive contains at least a disintegrant, and the disintegrant contains partially pregelatinized starch. [5] The rupatadine orally disintegrating tablet according to [1], wherein the coating layer contains an aminoalkyl methacrylate copolymer. [Effects of the Invention]

[0008] According to the present invention, even when a coating layer is provided to mask the bitter taste, it is possible to provide an orally disintegrating tablet that exhibits good dissolution behavior and is of a size that is easy to pick up with your fingers. [Brief explanation of the drawing]

[0009] [Figure 1] This graph plots the average dissolution rate (%) at 30 minutes and 60 minutes after the start of the test against the tablet mass (mg) for the orally disintegrating tablets used in the examples. [Modes for carrying out the invention]

[0010] The present invention will be described in detail below. The rupatadine orally disintegrating tablets of the present invention (hereinafter sometimes simply referred to as "orally disintegrating tablets") contain granules in which a coating layer is provided on a core particle containing rupatadine or a salt thereof and at least one additive selected from the group consisting of excipients, disintegrants, and binders, and the mass is in the range of 180 to 300 mg. By setting the mass of the orally disintegrating tablets in the range of 180 to 300 mg, good dissolution behavior can be achieved even when a coating layer is provided on the core particle. Furthermore, the orally disintegrating tablets can be made to a size that is easy to pick up with the fingers.

[0011] There are no restrictions on the type of rupatadine salt that is available for use as a pharmaceutical, but rupatadine fumarate is preferred. Rupatadine or its salts can be those available on the market and may be in crystalline or amorphous form.

[0012] Excipients, disintegrants, and binders can be those available on the market for pharmaceutical applications. As excipients, one or more of the following can be used in combination as needed: D-mannitol, crystalline cellulose, lactose monohydrate, anhydrous lactose, refined sucrose, potato starch, pregelatinized starch, etc. Among these, D-mannitol is preferred because of its low reactivity with other components, excellent moldability, and ease with which a solid formulation with good disintegration properties can be obtained.

[0013] Examples of disintegrants include partially pregelatinized starch, croscarmellose sodium, carmellose calcium, carmellose sodium, carmellose, low-substituted hydroxypropyl cellulose, crospovidone, corn starch, sodium starch glycolate, and hydroxypropyl starch. However, using at least one of partially pregelatinized starch and crospovidone is preferable in that it yields orally disintegrating tablets with excellent disintegration properties. Low-substituted hydroxypropyl cellulose can be used as needed in terms of disintegration properties, but from the viewpoint of the dissolution behavior of the orally disintegrating tablets, it is preferable to use it in an amount of 5% by mass or less per 100% by mass of the orally disintegrating tablet, or not to use it at all.

[0014] Examples of binders include hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), polyvinyl alcohol, polyvinylpyrrolidone, stearyl alcohol, ammonia methacrylate copolymer, polyvinyl acetal diethylaminoacetate, dextrin, and corn syrup. One or more of these can be used as needed, but hypromellose is preferred because it suppresses the formation of related substances and makes it easier to obtain orally disintegrating tablets with excellent stability.

[0015] Examples of surfactants include sodium lauryl sulfate and polysorbate 80, and one or more of these can be used. Examples of colorants include yellow iron oxide, iron oxide, Food Yellow No. 4, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Red No. 102, etc., and one or more of these can be used.

[0016] Examples of sweeteners include acesulfame potassium, aspartame, sucralose, thaumatin, sucrose, saccharin or its salts, glycyrrhizic acid or its salts, stevia, etc., and one or more of these can be used. Examples of flavors include orange essence, orange oil, caramel, camphor, cinnamon oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, cedarwood oil, pine oil, peppermint oil, vanilla flavor, bitter essence, fruit flavor, peppermint essence, mixed flavor, mint flavor, l-menthol, lemon powder, lemon oil, rose oil, etc., and one or more of these can be used.

[0017] Examples of other additives include lubricants (metal stearates such as magnesium stearate and calcium stearate, fatty acid esters such as glycerin fatty acid ester and sucrose fatty acid ester, sodium stearyl fumarate, talc, etc.), light anhydrous silicic acid, titanium oxide, carnauba wax, etc., and one or more of these can be used.

[0018] Note that as additives, a granulated product in which a plurality of additives are granulated in advance may be used. For example, a commercially available granulated product (SmartEx (registered trademark, manufactured by Shin-Etsu Chemical Co., Ltd.)) in which D-mannitol (excipient), low-substituted hydroxypropyl cellulose (disintegrant), and completely saponified polyvinyl alcohol (binder) are granulated may be used. SmartEx (registered trademark) is a granulated product composed of 90.0 to 95.0% by mass of D-mannitol, 5.0 to 7.0% by mass of low-substituted hydroxypropyl cellulose, and 0.1 to 0.3% by mass of completely saponified polyvinyl alcohol, and either "QD-50" or "QD-100" with different particle diameters can be used.

[0019] The orally disintegrating tablets of the present invention contain granules provided with a coating layer on nuclear particles containing rupatadine or a salt thereof and at least one additive selected from the group consisting of excipients, disintegrants, and binders as described above. As the form of the nuclear particles, a form of granules containing rupatadine or a salt thereof and an additive, a form of layered particles in which a drug layer containing rupatadine or a salt thereof, a disintegrant, and a binder is formed on the surface of particles composed of an excipient, etc. are preferable.

[0020] The coating layer provided on the nuclear particles contains at least a coating base, and is formed by including, if necessary, a coating plasticizer, a lubricant such as talc, etc. Examples of the coating base include aminoalkyl methacrylate copolymer, hydroxypropyl cellulose, hypromellose, methyl cellulose, ethyl cellulose, hypromellose acetate succinate, sodium carboxymethyl cellulose, etc., and one or more kinds can be used. Examples of the coating plasticizer include triethyl citrate, etc., and one or more kinds can be used. An overcoat layer according to the purpose may be provided outside the coating layer. By providing the overcoat layer, specific functions such as preventing adhesion between granules can be imparted. Examples of the overcoat layer include a layer formed by containing D-mannitol in the range of 3% by mass or less in 100% by mass of the orally disintegrating tablets.

[0021] It is preferable to use an aminoalkyl methacrylate copolymer as the coating base. Thereby, it is possible to obtain an orally disintegrating tablet that effectively masks bitterness while maintaining good dissolution behavior. More preferably, methyl cellulose is used together with an aminoalkyl methacrylate copolymer as the coating base.

[0022] As the aminoalkyl methacrylate copolymer, E-type aminoalkyl methacrylate copolymers available on the market for pharmaceutical applications can be used. As E-type aminoalkyl methacrylate copolymers, commercially available Eudragit® E100, Eudragit® EPO, Coricoat® Smart Seal 30D, Coricoat® Smart Seal 100P, etc., which are copolymers of methyl methacrylate, butyl methacrylate, and dimethylaminoethyl methacrylate, can be used. As the methylcellulose, one available from the market for pharmaceutical use, such as METOLOSE® manufactured by Shin-Etsu Chemical Co., Ltd., can be used. Preferably, a methylcellulose with a viscosity of 2 to 10 mPa·s in a 2% aqueous solution at 20°C (Japanese Pharmacopoeia) and a methoxy group content of 26.0 to 33.0% is preferred, and among these, a methylcellulose with a viscosity of 4 mPa·s in a 2% aqueous solution at 20°C and a methoxy group content of 26.0 to 33.0% is more preferred. As such a methoxycellulose, the SM type of METOLOSE® mentioned above is preferred.

[0023] The orally disintegrating tablets of the present invention preferably contain the granules described above and a post-additive added in addition to the granules. As the post-additive, various additives already exemplified can be used as needed, but it is preferable to use at least a disintegrant as the post-additive, as this improves the disintegration of the orally disintegrating tablets and also improves the dissolution behavior. Crospovidone is preferred as the disintegrant used as the post-additive. Furthermore, when orally disintegrating tablets contain granules and post-additives, the mass ratio [granules / post-additives] is preferably 0.55 to 1.2, and more preferably 0.6 to 1.1. Such a mass ratio results in superior dissolution behavior of the orally disintegrating tablets.

[0024] The orally disintegrating tablets of the present invention have a mass in the range of 180 to 300 mg. By having a mass in this range, good dissolution behavior can be achieved even when a coating layer is provided on the core particles to mask bitterness. Furthermore, within this mass range, the tablets can be formed into a size that is easy for elderly people and others to pick up with their fingers. A more preferable mass is 230 to 280 mg. There are no particular restrictions on the shape of the orally disintegrating tablets; examples include circular tablets with a circular shape in plan view, and irregularly shaped tablets such as oval tablets in plan view. However, circular tablets with a diameter in the range of 7.0 mm to 9.0 mm, and more specifically, in the range of 7.5 to 9.0 mm, are preferred.

[0025] There are no particular restrictions on the content of each component in orally disintegrating tablets, but the preferred content of rupatadine or its salts, excipients, disintegrants, and binders is as follows: The content of rupatadine or its salt per orally disintegrating tablet is preferably in the range of 5 to 30 mg, more preferably 5 to 15 mg, and most preferably 10 mg. The excipient content is preferably 50-80% by mass, more preferably 55-75% by mass, and even more preferably 60-70% by mass, of 100% by mass of the orally disintegrating tablet. If the orally disintegrating tablet contains post-additives, the excipient is preferably contained in both the granules and the post-additives, and it is preferable that the amount of excipient contained in the post-additives is greater than the amount of excipient contained in the granules. The disintegrant content is preferably 5 to 40% by mass, more preferably 10 to 30% by mass, and most preferably 10 to 20% by mass, per 100% by mass of the orally disintegrating tablet. If the orally disintegrating tablet contains post-additives, the disintegrant is preferably contained in both the granules and the post-additives, and the amount of disintegrant contained in the post-additives is preferably less than the amount of disintegrant contained in the granules. The binder content is preferably 0.5 to 5% by mass, and more preferably 1 to 3% by mass, per 100% by mass of the orally disintegrating tablet. If the orally disintegrating tablet contains post-additives, it is preferable that the binder is contained only in the granules and not in the post-additives.

[0026] As described above, the coating layer preferably contains an aminoalkyl methacrylate copolymer as a coating base. The content of the aminoalkyl methacrylate copolymer can be set as appropriate, but when the orally disintegrating tablet is considered to be 100% by mass, the content of the aminoalkyl methacrylate copolymer in the coating layer can be, for example, 1 to 15% by mass, preferably 1 to 10% by mass, and more preferably 1 to 5% by mass. When the granules are considered to be 100% by mass, the content of aminoalkyl methacrylate copolymer in the coating layer can be, for example, 1 to 20% by mass, preferably 3 to 15% by mass, and more preferably 5 to 10% by mass. When the coating layer is considered to be 100% by mass, the content of aminoalkyl methacrylate copolymer in the coating layer is preferably 45% by mass or more, more preferably 50% by mass or more, and even more preferably 55% by mass or more. There is no particular upper limit, but when the coating layer contains other coating bases, coating plasticizers, lubricants, etc., 70% by mass is preferred, 65% by mass is more preferred, and 60% by mass is even more preferred.

[0027] As described above, it is preferable to use methylcellulose in combination with aminoalkyl methacrylate copolymer as the coating base. The methylcellulose content in this case can be set as appropriate, but when the orally disintegrating tablet is considered to be 100% by mass, the methylcellulose content in the coating layer can be, for example, 0.1 to 10% by mass, preferably 0.5 to 5% by mass, and more preferably 0.5 to 3% by mass. When the granules are considered to be 100% by mass, the methylcellulose content in the coating layer can be, for example, 0.5 to 10% by mass, preferably 1 to 8% by mass, and more preferably 1 to 5% by mass. When the coating layer is considered to be 100% by mass, the methylcellulose content in the coating layer is preferably 5% by mass or more, more preferably 10% by mass or more, and even more preferably 15% by mass or more. There is no particular upper limit, but 35% by mass is preferred, 30% by mass is more preferred, and 25% by mass is even more preferred. When aminoalkyl methacrylate copolymer and methylcellulose are used in combination as a coating base, the mass ratio of these [methylcellulose / aminoalkyl methacrylate copolymer] is preferably 0.1 to 2, more preferably 0.1 to 1, and even more preferably 0.1 to 0.5.

[0028] In granules, the mass ratio of core particles to the coating layer can be 1 to 30 parts by mass of the coating layer when the core particles are 100 parts by mass, preferably 5 to 25 parts by mass, and more preferably 10 to 20 parts by mass.

[0029] The orally disintegrating tablets of the present invention can be manufactured by methods known to the public. Specifically, a granulation composition is prepared by mixing rupatadine or a salt thereof with at least one additive selected from the group consisting of excipients, disintegrants, and binders. A solvent such as purified water is added to the granulation composition, and granulation is carried out by known methods such as fluidized bed granulation, rolling fluidized bed granulation, and agitated granulation. In this case, the binder and other additives may be dissolved in the solvent. Next, the obtained granules (core particles) are sprayed with a solution in which a coating base (preferably aminoalkyl methacrylate copolymer, and more preferably methylcellulose in combination) and additives such as coating plasticizers used as needed are dissolved in a solvent such as ethanol, and the mixture is dried to form a coating layer on the outside of the granules. An overcoat layer containing D-mannitol or the like is optionally formed on the outside of the coating layer. Granules can be produced in this way. Alternatively, particles consisting of excipients such as D-mannitol may be prepared, and a liquid containing rupatadine or a salt thereof, along with a disintegrant, a binder, etc., may be sprayed onto their surface to form a raw material layer, thereby creating layered particles. These layered particles may then be used as core particles, and a coating layer or the like may be formed on their surface to produce granules.

[0030] The granules obtained in this way are preferably combined with post-additives to form a tableting composition, and by compressing this composition, orally disintegrating tablets can be produced. An outermost coating layer may be formed on the obtained orally disintegrating tablets as needed.

[0031] As described above, the orally disintegrating tablets of the present invention exhibit good dissolution behavior even when a coating layer is provided on the core particles containing rupatadine or a salt thereof to mask the bitter taste. Furthermore, they are sized to be easily picked up with fingers, even by the elderly, thus facilitating medication adherence. [Examples]

[0032] [Examples 1-7] Orally disintegrating tablets were manufactured as follows, according to the formulations in Tables 1 and 2. From the components listed in the "Granulated Material" column of the table, all components except hypromellose were mixed to form a granulation composition. A solution of hypromellose dissolved in water was sprayed onto the granulation composition while fluid bed granulation was performed to obtain granules (core particles). Next, a solution of each component listed in the "Coating Layer" column of the table dissolved in a solvent (ethanol) was sprayed onto the obtained granules and dried to form a coating layer. Then, a solution of D-mannitol dissolved in water, as listed in the "Overcoat (OC) Layer" column of the table, was sprayed and dried to form an overcoat layer, thereby obtaining granules. Subsequently, the granulated granules were mixed with the ingredients listed in the "Post-Additives" column of the table to create a tableting composition, which was then compressed to obtain orally disintegrating tablets (round tablets) of various masses and diameters as shown in the table. Furthermore, Eudragit® E100 was used as the aminoalkyl methacrylate copolymer E, and METOLOSE® SM-4 type, which has a viscosity of 4 mPa·s in a 2% aqueous solution at 20°C and a methoxy group content of 26.0-33.0%, was used as the methylcellulose. Dissolution tests were performed on each of the orally disintegrating tablets obtained as described above using the following method. The results of the dissolution test are shown in each table. Figure 1 also shows a graph plotting the average dissolution rate 30 minutes and 60 minutes after the start of the dissolution test against the tablet mass (mg) of the orally disintegrating tablet.

[0033] <Dissolution Test> Dissolution tests were performed using one orally disintegrating tablet obtained in each case and 900 mL of test solution (pH 6.8) at a paddle rate of 50 revolutions per minute. Specifically, at predetermined intervals after the start of the dissolution test (5 minutes, 15 minutes, 30 minutes, and 60 minutes), 5 mL of the eluate was taken and immediately 5 mL of the test solution, which had been warmed to 37 ± 0.5°C, was added. This solution was quickly centrifuged at 3000 rpm for 5 minutes, and 1 mL of the supernatant was measured out. 1 mL of the first dissolution test solution was added to this supernatant to prepare the sample solution. Separately, approximately 36 mg of rupatadine fumarate for quantification was weighed out and dissolved in dissolution test solution 1 to make 100 mL. 4 mL of this solution was weighed out and dissolution test solution 1 was added to make 100 mL. 1 mL of this solution was weighed out and 1 mL of test solution was added to prepare the standard solution. Sample solutions and standard solutions were tested by HPLC, and ultraviolet absorption at a wavelength of 258 nm was measured to obtain chromatograms. After the start of the elution test for each sample solution, the elution rate (%) at a predetermined time was determined based on the peak area of ​​the standard solution. The above tests were performed on two orally disintegrating tablets (n=2) for each case, and the average of the two tablets (average dissolution rate) was calculated and is shown in Tables 1 and 2 and Figure 1. The mobile phase was prepared by dissolving 6.8 g of potassium dihydrogen phosphate in water to make 1000 mL of solution, to which 350 mL of acetonitrile and 100 mL of methanol were added.

[0034] [Table 1]

[0035] Example 1 is an orally disintegrating tablet with the same mass and diameter (100 mg mass, 6.3 mm diameter) as the already marketed "Rupafin® Tablets," but as shown in Table 1, the average dissolution rate (%) was low and the dissolution performance was insufficient.

[0036] Orally disintegrating tablets are meant to be taken by disintegrating them in the mouth, not swallowed whole. Therefore, even if their diameter is somewhat large, swallowing is less likely to be a problem. In fact, from the perspective of ease of picking them up with your fingers, a somewhat larger diameter is preferable. Therefore, taking ease of handling into consideration, we manufactured an orally disintegrating tablet with a larger mass of 150 mg and a diameter of 7.0 mm than in Example 1 (Example 2), and conducted a dissolution test. In this case, the mass and diameter of the tablet were increased by increasing the amount of post-additives. However, as shown in Table 1, the orally disintegrating tablet of Example 2 showed even lower dissolution than that of Example 1.

[0037] Therefore, we increased the size of the orally disintegrating tablets by increasing not only the post-additives but also the additives in the granules, and manufactured orally disintegrating tablets with a mass of 300 mg and a diameter of 9.0 mm (Examples 3 and 4). As a result, as shown in Table 1, the orally disintegrating tablets of Examples 3 and 4 showed improved dissolution compared to the orally disintegrating tablets of Examples 1 and 2. Although the formulations of post-additives differed between Examples 3 and 4, they showed almost the same level of dissolution.

[0038] Based on the above results, orally disintegrating tablets with masses and diameters between Example 2 and Examples 3 and 4 were manufactured (Examples 5-7), and dissolution tests were performed. The results are shown in Table 2 below.

[0039] [Table 2]

[0040] As shown in Table 2, the orally disintegrating tablets of Examples 5 and 6, with a tablet mass of 200 mg, had a higher average dissolution rate than the orally disintegrating tablets of Examples 1 and 2. The orally disintegrating tablet of Example 7, with a tablet mass of 250 mg, had an even higher average dissolution rate. The above results are plotted in the graph in Figure 1. As is clear from the graph in Figure 1, when the mass of the tablets was varied, it was found that the average dissolution rate of orally disintegrating tablets was high and the dissolution behavior was excellent in the mass range of 180 to 300 mg. Such tablets have a large diameter, making them easy to pick up even for the elderly, and are preferable from the standpoint of medication adherence.

Claims

1. An orally disintegrating tablet comprising granules having a coating layer on a core particle containing rupatadine or a salt thereof and at least one additive selected from the group consisting of excipients, disintegrants, and binders, characterized in that the mass is 180 to 300 mg.

2. The rupatadine orally disintegrating tablet according to claim 1, comprising 5 to 30 mg of rupatadine or a salt thereof as rupatadine.

3. The rupatadine orally disintegrating tablet according to claim 1, comprising the granules and a post-additive separately formulated with the granules, wherein the mass ratio [granules / post-additive] is 0.55 to 1.

2.

4. The rupatadine orally disintegrating tablet according to claim 1, wherein the additive contains at least a disintegrant, and the disintegrant contains partially pregelatinized starch.

5. The rupatadine orally disintegrating tablet according to claim 1, wherein the coating layer contains an aminoalkyl methacrylate copolymer.

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