Lupatadine solid preparation

Abstract

To provide a lupatadine solid preparation having favorable dissolution characteristics even when provided with a coating layer.SOLUTION: The foregoing problem is solved by a lupatadine solid preparation comprising granules in which core particles containing lupatadine or a salt thereof are provided with a coating layer containing an aminoalkyl methacrylate copolymer and methylcellulose. It is preferable that, within the coating layer, the mass ratio of methylcellulose to the aminoalkyl methacrylate copolymer [methylcellulose / aminoalkyl methacrylate copolymer] is from 0.1 to 2.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Rupatadine is an oral drug for the treatment of allergic diseases, and ordinary tablets containing rupatadine fumarate, i.e., 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 "Rupafin (registered trademark) tablets" (see Non-Patent Document 1). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Rupafin® Tablets 10 mg Package Insert (Revised June 2022 (2nd Edition), Revised December 2020 (1st Edition)) Summary of the Invention [Problem to be solved by the invention]

[0004] As described above, ordinary tablets are commercially available as solid preparations containing rupatadine fumarate. However, the present inventors have conducted extensive research to provide a novel solid preparation, and have found that rupatadine or its salts have a strong bitter taste, and therefore, it is desirable to mask the bitterness. One method for masking the bitterness is to provide a coating layer on the surface of core particles containing the active ingredient. However, depending on the type of coating base and additives that form the coating layer, even if the bitterness can be masked, other properties required for pharmaceuticals may be affected. The present inventors have found that, particularly in the case of solid preparations containing rupatadine or a salt thereof as an active ingredient, the formation of a coating layer is likely to cause problems in dissolution behavior.

[0005] The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a rupatadine solid preparation that exhibits good dissolution behavior even when a coating layer is provided. [Means for solving the problem]

[0006] As a result of extensive research, the present inventors have found that the above problems can be solved by using an aminoalkyl methacrylate copolymer and methyl cellulose as a coating base for the coating layer, and have thus completed the present invention.

[0007] The present invention has the following aspects. [1] A rupatadine solid formulation, characterized by containing granules in which core particles containing rupatadine or a salt thereof are provided with a coating layer containing an aminoalkyl methacrylate copolymer and methylcellulose. [2] The rupatadine solid formulation according to [1], wherein the mass ratio of the aminoalkyl methacrylate copolymer to the methylcellulose in the coating layer [methylcellulose / aminoalkyl methacrylate copolymer] is 0.1 to 2. [3] The rupatadine solid formulation according to [1], which contains the granules and crospovidone. [4] The rupatadine solid formulation according to any one of [1] to [3], which is a tablet. [5] The rupatadine solid formulation according to [4], which is an orally disintegrating tablet. [Effects of the Invention]

[0008] According to the present invention, a rupatadine solid preparation having a good dissolution behavior can be provided even when a coating layer is provided. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present invention will be described in detail below. The rupatadine solid formulation of the present invention (hereinafter sometimes simply referred to as a solid formulation) comprises granules having core particles containing rupatadine or a salt thereof, and a coating layer containing an aminoalkyl methacrylate copolymer and methylcellulose. Such a coating layer can improve the dissolution behavior of the solid formulation while masking the bitterness of rupatadine or a salt thereof.

[0010] The type of rupatadine salt is not limited as long as it is usable as a pharmaceutical, but rupatadine fumarate is preferred. Rupatadine or its salts can be commercially available and may be in either crystalline or amorphous form.

[0011] The particle size of rupatadine or its salt is set to 90% particle size (D 90 ) is preferably 60 μm or less, more preferably 20 μm or less, and even more preferably 10 μm or less. 90 The lower limit of the thickness is preferably 3 μm. 50% particle size (D 50 ) is preferably 10 μm or less, more preferably 3 μm or less. 50 The lower limit of the thickness is preferably 1 μm. 10% particle size (D 10 ) is preferably 5 μm or less, more preferably 1 μm or less. 10 The lower limit of the thickness is preferably 0.5 μm.

[0012] Here, the 90% particle size is the particle size at which the cumulative frequency in the volume-based particle size distribution is 90%. 90 Particles with a particle size equal to or smaller than this value account for 90% of the total volume. Similarly, the 50% particle size is the particle size at which the cumulative frequency in the volume-based particle size distribution is 50%, and is also called the median size. The 10% particle size is the particle size at which the cumulative frequency in the volume-based particle size distribution is 10%. In this specification, the particle size refers to a value measured by a dry laser diffraction method using a particle size distribution measuring device (Mastersizer 3000, manufactured by Malvern Instruments).

[0013] The aminoalkyl methacrylate copolymer may be commercially available aminoalkyl methacrylate copolymer type E for pharmaceutical applications, such as commercially available Eudragit (registered trademark) E100, Eudragit (registered trademark) EPO, Kollicoat (registered trademark) Smartseal 30D, or Kollicoat (registered trademark) Smartseal 100P, which are copolymers of methyl methacrylate, butyl methacrylate, and dimethylaminoethyl methacrylate. Methylcellulose that can be used is commercially available for pharmaceutical use, such as METOLOSE (registered trademark) manufactured by Shin-Etsu Chemical Co., Ltd. Preferably, the viscosity of a 2% aqueous solution at 20°C (Japanese Pharmacopoeia) is in the range of 2 to 10 mPa·s and the proportion of methoxy groups is 26.0 to 33.0%, and more preferably, the viscosity of a 2% aqueous solution at 20°C is 4 mPa·s and the proportion of methoxy groups is 26.0 to 33.0%. An example of such methylcellulose is the SM type of METOLOSE (registered trademark) mentioned above.

[0014] Examples of the form of core particles containing rupatadine or a salt thereof include granules containing rupatadine or a salt thereof and an additive, and layered particles in which an active ingredient layer containing rupatadine or a salt thereof is formed on the surface of additive particles. There are no restrictions on the specific form of the particulate material as long as it contains rupatadine or a salt thereof, but a granule containing rupatadine or a salt thereof and an additive is preferred. The coating layer may contain additives such as coating bases other than aminoalkyl methacrylate copolymer and methylcellulose, plasticizers, disintegrants, lubricants, etc. as needed. An overcoat layer may be provided on the outside of the coating layer depending on the purpose to form granules. The provision of an overcoat layer can impart specific functions, such as preventing adhesion between granules. An example of an overcoat layer is a layer formed by containing 3% by mass or less of D-mannitol based on 100% by mass of the solid preparation.

[0015] The form of the solid preparation is not limited to a specific embodiment as long as it contains granules in which a coating layer containing an aminoalkyl methacrylate copolymer and methylcellulose is provided on the surface of core particles containing rupatadine or a salt thereof, and examples thereof include granular preparations (granules, dry syrups, fine granules, etc.) in which additives are added to granules as needed, and tablets (immediate-release tablets, orally disintegrating tablets, etc.) obtained by mixing additives with granules as needed and compressing the resulting tableting composition. The surface of the tablet can also be coated with any material to provide an outermost coating layer.

[0016] As additives, any of additives usable in the pharmaceutical field, such as excipients, binders, disintegrants, surfactants, colorants, sweeteners, and flavors, may be contained as needed.

[0017] Examples of excipients include D-mannitol, crystalline cellulose, lactose hydrate, anhydrous lactose, refined sucrose, potato starch, pregelatinized starch, etc., and one or more of these can be used as needed, but it is preferable to use D-mannitol because it has low reactivity with drugs, is suitable as an excipient, is easy to granulate, and tends to produce solid preparations with a good taste. It is also preferable to use crystalline cellulose in combination because it has low reactivity with other ingredients, is excellent in moldability, tends to produce solid preparations with excellent disintegration properties, and is expected to have a segregation-preventing effect.

[0018] 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 as needed, but it is preferable to use hypromellose, as this inhibits the production of related substances and makes it easier to obtain a solid formulation with excellent stability.

[0019] 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. One or more of these can be used as needed, but it is preferable to use partially pregelatinized starch because it provides excellent dissolution behavior of the solid preparation. From the viewpoint of disintegration property, it is also preferable to use crospovidone together with partially pregelatinized starch, and it is also preferable to further use corn starch in combination as needed. Low-substituted hydroxypropyl cellulose can be used as needed from the viewpoint of disintegration property, etc., but from the viewpoint of the dissolution behavior of the solid preparation, it is preferable to use it in an amount of 5% by mass or less based on 100% by mass of the solid preparation, or not to use it at all.

[0020] Examples of surfactants 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, and Food Red No. 102, and one or more of these can be used.

[0021] Examples of sweeteners include acesulfame potassium, aspartame, sucralose, thaumatin, sucrose, saccharin or a salt thereof, glycyrrhizic acid or a salt thereof, and stevia or a salt thereof, and one or more of these can be used. Flavoring agents 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, and rose oil, and one or more of these can be used.

[0022] Other additives include lubricants (metal stearates such as magnesium stearate and calcium stearate, fatty acid esters such as glycerin fatty acid esters and sucrose fatty acid esters, sodium stearyl fumarate, talc, etc.), light anhydrous silicic acid, titanium oxide, carnauba wax, etc., and one or more of these can be used. In addition, other coating bases (hydroxypropyl cellulose, hypromellose, carmellose sodium, etc.), coating plasticizers (triethyl citrate, etc.), lubricants such as talc, etc. may be used in the coating layer as needed.

[0023] 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, manufactured by Shin-Etsu Chemical Co., Ltd.)) in which D-mannitol (excipient), low-substituted hydroxypropyl cellulose (disintegrant), and fully saponified polyvinyl alcohol (binder) have been granulated may be used. SmartEx (registered trademark) is a granulated product consisting 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 fully saponified polyvinyl alcohol, and either "QD-50" or "QD-100" with different particle sizes can be used.

[0024] The above-mentioned additives may be used in any manner in the production of a solid preparation, but when the solid preparation comprises granules in which core particles made of a granulation containing rupatadine or a salt thereof are provided with a coating layer containing an aminoalkyl methacrylate copolymer and methylcellulose, the core particles preferably contain at least D-mannitol as an excipient and partially pregelatinized starch as a disintegrant. This allows the use of D-mannitol as an excipient, which has low reactivity with drugs, is easy to granulate, and tends to produce a solid preparation with a good taste, while the addition of partially pregelatinized starch can solve the problem of dissolution behavior that arises from the use of D-mannitol.

[0025] The mass ratio of D-mannitol to partially pregelatinized starch in the core particles [D-mannitol / partially pregelatinized starch] is preferably 0.5-2, more preferably 1-2.

[0026] When the solid preparation is a tablet formed (compressed) containing granules and post-additives, D-mannitol is preferably also contained in the post-additives, and the mass ratio of D-mannitol to partially pregelatinized starch in the entire tablet [D-mannitol / partially pregelatinized starch] is preferably 1 to 7, and more preferably 3 to 6.

[0027] Furthermore, when the solid preparation is a tablet formed (compressed) containing granules and post-additives, it is preferable that the core particles further contain a binder, and hypromellose is particularly preferred.

[0028] When the solid preparation is a tablet formed (compressed) containing granules and post-additives, the post-additives preferably contain excipients, disintegrants, lubricants, sweeteners, etc., and as described above, D-mannitol is preferably used as the excipient. Furthermore, to prevent segregation between the granules and post-additives, it is also preferable to incorporate crystalline cellulose into the post-additives in an amount of 7% by mass or less based on 100% by mass of the solid preparation. Crospovidone, and optionally corn starch, are preferably used as disintegrants, as they have excellent disintegration properties and dissolution behavior. When a colorant is added, it is also preferable to disperse the colorant in the corn starch beforehand.

[0029] The content of rupatadine or a salt thereof in the solid preparation of the present invention can be appropriately set, for example, 3 to 20% by mass, preferably 3 to 10% by mass, and more preferably 3 to 8% by mass, based on 100% by mass of the solid preparation. When the granules are taken as 100% by mass, the content of rupatadine or a salt thereof in the granules can be, for example, 1 to 25% by mass, preferably 5 to 20% by mass, and more preferably 10 to 15% by mass. When the core particles are taken as 100% by mass, the content of rupatadine or a salt thereof in the core particles can be, for example, 1 to 30% by mass, preferably 7 to 25% by mass, and more preferably 12 to 18% by mass.

[0030] The content of the excipient can be set appropriately, and can be 50 to 80% by mass, preferably 55 to 75% by mass, and more preferably 60 to 75% by mass, based on 100% by mass of the solid preparation. When the granules are taken as 100% by mass, the content of the excipient in the granules can be, for example, 20 to 50% by mass, preferably 25 to 45% by mass, and more preferably 30 to 40% 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, 20 to 60% by mass, preferably 30 to 50% by mass, and more preferably 35 to 45% by mass. As for the excipients used in the post-additives, as described above, it is preferable to use D-mannitol and, if necessary, crystalline cellulose for the purpose of preventing segregation, etc., and the excipients are preferably contained in the post-additives so that their total amount is preferably 35 to 70% by mass, more preferably 40 to 65% by mass, and even more preferably 45 to 60% by mass, based on 100% by mass of the solid preparation.

[0031] The content of the disintegrant can also be set appropriately, and can be 1 to 35% by mass, preferably 5 to 30% by mass, and more preferably 10 to 25% by mass, based on 100% by mass of the solid preparation. When the granules are taken as 100% by mass, the content of the disintegrant in the granules can be, for example, 15 to 45% by mass, preferably 20 to 40% by mass, and more preferably 25 to 35% 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, 20 to 50% by mass, preferably 25 to 45% by mass, and more preferably 30 to 40% by mass. As for the disintegrants used in post-additives, as mentioned above, crospovidone and, if necessary, cornstarch are preferably used, and it is preferable to use crospovidone in an amount of 1 to 5% by mass based on 100% by mass of the solid preparation, and cornstarch in an amount of 2 to 8% by mass based on 100% by mass of the solid preparation. Low-substituted hydroxypropyl cellulose may be contained in the post-additive in an amount of 5% by mass or less based on 100% by mass of the solid preparation.

[0032] The content of the aminoalkyl methacrylate copolymer in the coating layer can be set as appropriate, but when the solid preparation is taken as 100% by mass, it can be 1 to 15% by mass, preferably 1 to 10% by mass, and more preferably 1 to 5% 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, 1 to 25% by mass, preferably 5 to 20% by mass, and more preferably 5 to 10% 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 45 to 85% by mass, more preferably 50 to 80% by mass, and even more preferably 50 to 75% by mass.

[0033] The content of methylcellulose in the coating layer can be set appropriately, but when the solid preparation is taken as 100% by mass, it can be 0.5 to 10% by mass, preferably 0.5 to 5% by mass, and more preferably 0.5 to 3% by mass. When the granules are taken as 100% by mass, the content of methylcellulose 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 coating layer is taken as 100% by mass, the content of methyl cellulose in the coating layer is preferably 10 to 35% by mass, more preferably 15 to 30% by mass, and even more preferably 15 to 25% by mass.

[0034] The mass ratio of the aminoalkyl methacrylate copolymer to the methyl cellulose in the coating layer [methyl cellulose / aminoalkyl methacrylate copolymer] is preferably from 0.1 to 2, more preferably from 0.1 to 1, and even more preferably from 0.1 to 0.5.

[0035] The mass ratio of the core particles to the coating layer in the granules is preferably 1 to 30 parts by mass, more preferably 5 to 25 parts by mass, and even more preferably 10 to 20 parts by mass, of the coating layer when the core particles are taken as 100 parts by mass.

[0036] 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 0.5 to 4% by mass, and more preferably 1 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 2 to 8% by mass, and more preferably 3 to 7% 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 15% by mass, and preferably 3 to 12% by mass, or 5 to 10% by mass.

[0037] The sweetener is preferably contained in an amount of 0.1 to 1% by mass when the solid preparation is taken as 100% by mass, and the lubricant is preferably contained in an amount of 0.1 to 3% by mass when the solid preparation is taken as 100% by mass. When the solid preparation is a tablet formed (compressed) containing granules and post-additives, the sweetener and lubricant are preferably contained in the post-additives.

[0038] When the solid preparation is a tablet formed (compressed) containing granules and post-additives, the mass ratio of the granules constituting the tablet to the post-additives [post-additives / granules] is preferably 0.5 to 3, more preferably 1 to 2, and even more preferably 1.3 to 1.7.

[0039] The solid preparation of the present invention can be produced by any known method as long as it contains granules in which core particles containing rupatadine or a salt thereof are provided with a coating layer containing an aminoalkyl methacrylate copolymer and methylcellulose. However, it is preferable to produce the granules by the following method. Rupatadine or a salt thereof is mixed with optional 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, tumbling fluidized bed granulation, or agitation granulation. In this process, a binder or other additives may be dissolved in the solvent. The resulting granules (core particles) are then sprayed with a solution of aminoalkyl methacrylate copolymer, methylcellulose, and optional additives dissolved in a solvent such as ethanol, followed by drying to form a coating layer on the outside of the granules. An overcoat layer containing D-mannitol or the like is then formed on the outside of the coating layer, as needed. Granules can be produced in this manner. Alternatively, particles made of an excipient such as D-mannitol may be prepared, and a liquid containing rupatadine or a salt thereof, D-mannitol, partially pregelatinized starch, etc. may be sprayed onto the surface of the particles to form a drug substance layer to prepare layering particles, which may then be used as core particles on the surface of which a coating layer, etc., is formed.

[0040] The granules thus obtained may be blended with additives as needed to form granular preparations (granules, dry syrups, fine granules, etc.), or additives may be added to the granules obtained as needed to form a composition for tableting, which may then be compressed to form tablets (immediate-release tablets, orally disintegrating tablets, etc.). An outermost coating layer may be formed on the resulting tablets as needed.

[0041] As described above, the present invention comprises granules in which core particles containing rupatadine or a salt thereof are provided with a coating layer containing an aminoalkyl methacrylate copolymer and methylcellulose. Therefore, even when a coating layer that masks the bitterness of rupatadine or a salt thereof is provided, a rupatadine solid preparation having good dissolution behavior can be provided. [Example]

[0042] The present invention will now be described in more detail with reference to examples. [Examples 1-5] Orally disintegrating tablets were prepared as follows. The components listed in the "Granulation" column of Table 1, except for hypromellose, were mixed to form a granulation composition, and a solution of hypromellose dissolved in water was sprayed onto the granulation composition while fluidized-bed granulation was performed to obtain granules (core particles). Next, a solution of each component listed in the "Coating Layer" column of Table 1 dissolved in a solvent (ethanol) was sprayed onto the obtained granules, followed by drying to form a coating layer. Next, a solution of D-mannitol dissolved in water listed in the "Overcoat Layer" column of Table 1 was sprayed onto the obtained granules, followed by drying to form an overcoat layer, to obtain granules. The ingredients listed in the column for post-additives in Table 1 were then added to the sized granules to prepare a tableting composition, which was then tableted to obtain orally disintegrating tablets of Examples 1 to 5 (mass 250 mg, diameter 8.5 mm). The orally disintegrating tablets obtained were subjected to a dissolution test by the following method. The results of the dissolution test are shown in Table 1.

[0043] The particle sizes of rupatadine fumarate in Table 1 are as follows: Rupatadine fumarate D 90 :8.07μm D 50 :2.78μm D 10 :0.907μm Furthermore, Eudragit (registered trademark) E100 was used as the aminoalkyl methacrylate copolymer E, and METOLOSE (registered trademark) SM-4 type, which has a 2% aqueous solution viscosity of 4 mPa·s at 20°C and a methoxy group ratio of 26.0 to 33.0%, was used as the methylcellulose.

[0044] <Dissolution test> Using one orally disintegrating tablet obtained from each example and 900 mL of test solution (pH 6.8), a dissolution test was carried out at 50 revolutions per minute by the paddle method. Specifically, 10 mL of the eluate was taken at predetermined times (5, 15, 30, and 60 minutes) after the start of the dissolution test, and 10 mL of test solution preheated to 37±0.5°C was immediately added. This solution was quickly centrifuged at 3,000 rpm for 5 minutes, and 1 mL of the supernatant was measured. 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 assay was weighed out and dissolved in dissolution test fluid 1 to make 100 mL. 4 mL of this solution was measured out and added with dissolution test fluid 1 to make 100 mL. 1 mL of this solution was measured out and added with 1 mL of test solution 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. After the start of the dissolution test for each sample solution, the dissolution rate (%) at a predetermined time was calculated based on the peak area of ​​the standard solution. The above test was carried out on two orally disintegrating tablets (n=2) of each example, and the average of the two tablets (average dissolution rate) was calculated and shown in Table 1. The mobile phase was prepared by adding 350 mL of acetonitrile and 100 mL of methanol to 550 mL of a solution prepared by dissolving 6.8 g of potassium dihydrogen phosphate in water to make 1000 mL.

[0045] [Table 1]

[0046] As shown in Table 1, orally disintegrating tablets obtained by forming granules with a coating layer formed using aminoalkyl methacrylate copolymer and methylcellulose as coating bases on the surface of core particles (granules) and then adding post-additives to these granules and compressing them showed excellent dissolution behavior. Furthermore, the dissolution behavior was particularly good when crospovidone was used as a disintegrant added as a post-additive.

Claims

1. A rupatadine solid preparation comprising granules in which core particles containing rupatadine or a salt thereof are provided with a coating layer containing an aminoalkyl methacrylate copolymer and methylcellulose.

2. The rupatadine solid formulation according to claim 1, wherein the mass ratio of the aminoalkyl methacrylate copolymer to the methylcellulose in the coating layer [methylcellulose / aminoalkyl methacrylate copolymer] is 0.1 to 2.

3. The rupatadine solid formulation according to claim 1, comprising the granules and crospovidone.

4. The rupatadine solid formulation according to any one of claims 1 to 3, which is in the form of a tablet.

5. The rupatadine solid formulation according to claim 4, which is an orally disintegrating tablet.

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