Apremilast Solid Formulation and Method for Producing the Same

Abstract

This invention provides an apremilast solid dosage form that exhibits excellent dissolution properties even when using lactose monohydrate. [Solution] The problem is solved by an apremilast solid formulation containing apremilast and lactose monohydrate, further containing low-substituted hydroxypropyl cellulose. More preferably, the solid formulation further contains stearate. When lactose monohydrate is used as an excipient, a solid formulation with excellent dissolution properties can be provided by using low-substituted hydroxypropyl cellulose in combination.

Description

Technical Field

[0001] The present invention relates to an apremilast solid preparation and a method for producing the same.

Background Art

[0002] Apremilast, namely N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H isoindole-4-yl}acetamide, is a therapeutic agent for psoriasis vulgaris, psoriatic arthritis and the like, and tablets containing the same are sold under the name "Otezla (registered trademark) Tablets". For example, Patent Documents 1 to 3 describe tablets and capsules as pharmaceutical compositions containing apremilast.

[0003] Generally, in the production of tablets, an active ingredient is mixed with an excipient and other additives to obtain a composition, which is granulated as necessary and then tabletted. As excipients, for example, D-mannitol, lactose hydrate and the like are widely used. Among them, D-mannitol has low hygroscopicity, so it has advantages such as being suitable for formulation of active ingredients that are easily affected by moisture. However, it tends to have poor binding force between particles and inferior moldability (see, for example, "Background Art" in Patent Document 2), and there have been cases where it is not suitable for use in tablets. Accordingly, from the viewpoint of moldability, it is conceivable not to select D-mannitol but to use other excipients. Lactose hydrate is particularly preferable because it has the advantage of being excellent in moldability. However, it has been pointed out that when lactose hydrate is used in a solid preparation containing apremilast, problems occur in the dissolution property and the like of the solid preparation (see Patent Document 3).

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

[0005] This invention has been made in view of the above circumstances, and aims to provide an apremilast solid formulation that has sufficient dissolution properties even when lactose monohydrate is included. [Means for solving the problem]

[0006] As a result of diligent research, the inventors discovered that when lactose monohydrate is used as an excipient in the production of a solid dosage form containing apremilast, a solid dosage form with excellent dissolution properties can be provided by using low-substituted hydroxypropyl cellulose in combination, leading to the present invention. Furthermore, the use of lactose monohydrate improves the moldability of compositions containing apremilast. Therefore, even when employing a direct compression method that compresses the composition without granulation, for example, stable tablet compression can be achieved without problems in terms of moldability or tablet hardness.

[0007] The present invention has the following aspects. [1] An apremilast solid preparation comprising apremilast and lactose monohydrate, wherein the apremilast solid preparation contains low-substituted hydroxypropyl cellulose. [2] The apremilast solid preparation according to [1], further containing stearate. [3] A method for producing an apremilast solid preparation, comprising a tableting step of compressing a composition containing apremilast and lactose monohydrate, wherein the composition further contains low-substituted hydroxypropyl cellulose. [4] The method for producing an apremilast solid dosage form according to [3], wherein the tableting step is performed by a direct tableting method. [Effects of the Invention]

[0008] According to the present invention, it is possible to provide an apremilast solid formulation that has sufficient dissolution properties even when lactose monohydrate is included. [Modes for carrying out the invention]

[0009] The present invention will be described in detail below. The apremilast solid formulation of the present invention is a solid formulation containing apremilast and an additive. There are no particular restrictions on the apremilast; any apremilast available on the market can be used, and it may be in crystalline or amorphous form, and either anhydrous or hydrated form can be used, but known type A crystalline apremilast (anhydrous) is preferred. Type A crystalline apremilast is disclosed as form A in, for example, Patent Document 1. The apremilast may also be in the form of a salt that can be used as a pharmaceutical. The apremilast content in 100% by mass of the solid formulation is, for example, 1 to 20% by mass, preferably 5 to 15% by mass.

[0010] There are no particular restrictions on the particle size of apremilast, however, the 50% particle size of apremilast (D 50 The particle size is preferably 10 to 40 μm in terms of the dissolution properties of the solid dosage form.

[0011] Here, the 50% particle size is the particle size at which the cumulative frequency in the volume-based particle size distribution reaches 50%, and is also called the median diameter. 50 Particles with a particle size less than or equal to the value of account for 50% of the total volume. In this specification, particle size refers to the value measured by dry laser diffraction using a particle size distribution analyzer (Mastersizer3000, manufactured by Malvern Instruments).

[0012] Apremilast solid dosage form contains lactose monohydrate as an additive and also contains low-substituted hydroxypropyl cellulose (hereinafter sometimes referred to as L-HPC). By using lactose monohydrate, there are no problems with moldability when manufacturing solid dosage forms. Even if tablets are manufactured using the direct compression method, stable and continuous compression is possible without any problems with moldability. Furthermore, by using L-HPC together with lactose monohydrate, the dissolution issues that may occur when using lactose monohydrate can be resolved, and an apremilast solid dosage form with sufficient dissolution properties can be provided. As for lactose monohydrate (L-HPC), any product available on the market for pharmaceutical use can be used without restriction. To fully utilize the combined effects of lactose monohydrate and L-HPC, the mass ratio [lactose monohydrate / L-HPC] is preferably 8 or higher, more preferably 10 or higher. It is also preferably 15 or lower, and more preferably 12 or lower.

[0013] In this specification, the direct tableting method refers to a method in which apremilast is subjected to the tableting process without being granulated along with at least some of the additives. At least some of the additives contained in the composition may be granulated beforehand.

[0014] Other additives that may be contained in apremilast solid dosage forms include any additives available on the market for pharmaceutical use (excipients, binders, disintegrants, surfactants, fluidizers, colorants, sweeteners, flavorings, etc.) as needed. For example, a solid dosage form may be a tablet supplied by a direct tableting process and may not contain a binder; the use of additives is optional in such cases.

[0015] As an excipient, in addition to lactose hydrate, one or more selected from, for example, crystalline cellulose, anhydrous lactose, refined sucrose, potato starch, pregelatinized starch, β-cyclodextrin and the like can be used in combination as necessary. Among these, crystalline cellulose is preferable from the viewpoint of moldability, and for example, the CEOLUS® series available from Asahi Kasei Corporation can be suitably used, specifically, "CEOLUS® PH-102", "CEOLUS® UF-711" and the like can be used. It is preferable not to use D-mannitol from the viewpoint of moldability. The content of the excipient in 100% by mass of the solid preparation can be, for example, in the range of 70 to 95% by mass. More preferably, in 100% by mass of the solid preparation, the content of lactose hydrate can be 40 to 70% by mass, more preferably 50 to 65% by mass, and the content of crystalline cellulose can be 10 to 40% by mass, more preferably 20 to 30% by mass.

[0016] Examples of the binder include hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), polyvinyl alcohol, polyvinylpyrrolidone, stearyl alcohol, ammonio methacrylate copolymer, polyvinyl acetal diethylaminoacetate, dextrin, glucose syrup and the like, and one or more of these can be used.

[0017] As the disintegrant, in addition to the above-mentioned L-HPC, one or more other disintegrants may be used as necessary, but it is preferable to use only L-HPC from the viewpoint that the dissolution property of the solid preparation can be more favorably controlled. The content of the disintegrant in 100% by mass of the solid preparation can be, for example, 1 to 6% by mass, and the range of 3 to 6% by mass is preferable.

[0018] Examples of the surfactant include polysorbate 80 and the like, and one or more of these can be used. Examples of the glidant include hydrated silicon dioxide, light anhydrous silicic acid and the like, and one or more of these can be used. Examples of coloring agents include titanium dioxide, yellow iron(III) oxide, iron(III) oxide, black 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.

[0019] 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 may 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, l-menthol, lemon powder, lemon oil, rose oil, etc., and one or more of these may be used.

[0020] Examples of lubricants include stearates, glycerin fatty acid esters, sucrose fatty acid esters and other fatty acid esters, and talc, and one or more of these can be used. Among these, stearates (magnesium stearate, calcium stearate, etc.) tend to have excellent dissolution properties in the initial stages of solid formulations and are therefore preferred. The lubricant content can be appropriately set depending on the type of lubricant, but is usually about 0.3 to 5% by mass per 100g of solid formulation, with 0.3 to 3% by mass being preferred. In the case of stearates, 0.3 to 1% by mass is more preferred. Other additives that can be used include carnauba wax.

[0021] When the solid dosage form is a tablet with a coating layer on its surface, examples of coating bases include partially saponified polyvinyl alcohol, polyethylene glycol, hydroxypropyl cellulose, and hydroxypropyl methylcellulose, while examples of coating plasticizers include triethyl citrate. In addition, any additives such as colorants and talc may be added to the coating layer as needed. In tablets, the ratio of the coating layer to the remaining portion (uncoated portion) is preferably 0.01 to 0.1 by mass, and more preferably 0.02 to 0.07 by mass [coating layer / uncoated portion].

[0022] The solid dosage form of the present invention is not limited in its form and can be a granular preparation (granules, dry syrup, fine granules, etc.), a tablet (immediate-release tablet, orally disintegrating tablet, etc.), etc., but a tablet is preferred.

[0023] The solid dosage form of the present invention contains apremilast, lactose monohydrate, and L-HPC, and can be manufactured by conventionally known methods. If the solid dosage form is a granular dosage form, it can be manufactured, for example, by the following method. First, apremilast, lactose monohydrate, L-HPC, and other additives as needed are mixed to form a granulation composition. A solvent such as purified water is then added to the granulation composition as a granulation solution, and granulation is carried out using known methods such as fluidized bed granulation, tumbling fluidized bed granulation, or agitated granulation. In this process, some of the additives may be dissolved in the solvent that forms the granulation solution. Next, by adding additives such as fluidizing agents as needed to the obtained granules, a granular formulation, which is one embodiment of the solid formulation of the present invention, can be obtained.

[0024] When the solid dosage form of the present invention is a tablet, a tableting step is performed in which a composition obtained by mixing apremilast, lactose monohydrate, L-HPC, and other additives as needed is compressed into tablets. The tableting step can be carried out by known methods, and granules may be obtained first in the same manner as the method for producing granular formulations described above, and then the composition to which additives (post-additives) as needed may be added to the granules may be compressed into tablets, but it is preferable to carry out the tableting by direct tableting. Through a tableting process, tablets are obtained as solid dosage forms. A coating layer may be formed on the surface of the tablets obtained in the tableting process.

[0025] As described above, the solid formulation of the present invention contains apremilast and lactose monohydrate, and further contains L-HPC, thus providing an apremilast solid formulation with sufficient dissolution properties. Furthermore, the apremilast solid formulation also has excellent moldability, so even when tablets are formed by direct compression, tablets with sufficient hardness can be stably and continuously compressed without any problems during compression. [Examples]

[0026] [Examples 1-3] Tablets (immediate-release tablets) were manufactured according to the formulation in Table 1 as follows. The components listed in Table 1 were mixed to form a tableting composition, which was then compressed using a rotary tablet press to obtain elliptical tablets with a major axis of 12.5 mm, a minor axis of 5.8 mm, and a mass of 300 mg, by direct compression. As for apremilast, anhydrous type A crystal (D 50 A 12.5 μm (=12.5 μm) was used. Dissolution tests were performed on each of the obtained tablets using the following method. The results of the dissolution test are shown in Table 1.

[0027] <Dissolution Test> Dissolution tests were performed using one tablet and 900 mL of a pH 4.0 test solution containing 0.5 w / v% polysorbate, at a paddle rate of 50 revolutions per minute. At three points (15 minutes, 120 minutes, and 180 minutes after the start of the test), 10 mL of the eluate was collected and filtered through a 0.45 μm pore size membrane filter. After removing the initial 5 mL of filtrate, 10 mL of the test solution was immediately added, and 1 mL of the filtrate was accurately measured and 1 mL of acetonitrile / water mixture (7:3) was accurately added to prepare the sample solution. Separately, 33 mg of apremilast for quantitative analysis was accurately weighed and dissolved in acetonitrile / water mixture (7:3) to make exactly 100 mL. 5 mL of this solution was accurately weighed and acetonitrile / water mixture (7:3) was added to make exactly 50 mL. 1 mL of this solution was accurately weighed and 1 mL of the test solution was accurately added to prepare the standard solution. The sample solution and standard solution were tested by HPLC, and the ultraviolet absorption at a wavelength of 230 nm was measured to obtain chromatograms. The elution rate (%) of each sample solution was determined at 15 minutes, 120 minutes, and 180 minutes after the start of the elution test, using the peak area of ​​the standard solution as a reference. The above tests were performed on three tablets (n=3), and the average (average dissolution rate) was calculated and recorded in Table 1. For the mobile phase, a solution of 1 mL of trifluoroacetic acid mixed with water to make 10,000 mL of liquid was used, and acetonitrile was mixed in a 6:4 ratio.

[0028] [Table 1] In the table, the following ingredients were used: Lactose monohydrate: "Florac 90" (Maigre Japan), Crystalline cellulose: "Ceolus® PH-102" (Asahi Kasei), L-HPC: "LH-21" (Shin-Etsu Chemical), Crospovidone: "CL-F" (BASF).

[0029] As shown in Table 1, when comparing Example 1 and Example 3 in the tablets containing lactose monohydrate, Example 1, which contained L-HPC, showed superior dissolution, whereas Example 3, which contained crospovidone instead of L-HPC, did not reach a sufficient average dissolution rate even after 180 minutes from the start of the test. Furthermore, while glycerin fatty acid ester was used as a lubricant, as in Example 2, and showed excellent dissolution properties, the dissolution properties in the initial stage (after 15 minutes) were superior in Example 1, which used magnesium stearate. In all three examples (1-3), tablets were formed using the direct compression method. We were able to stably and continuously compress tablets with a hardness of approximately 10 kgf without any problems during compression.

[0030] [FC tablet example] Tablets were manufactured in the same manner as in Example 1, and a coating layer according to the formulation shown in Table 2 was formed on the surface of these tablets to obtain 312 mg film-coated tablets (FC tablets). Specifically, the coating layer was formed by coating the surface of the tablets with a solution of the additives shown in Table 2 added to water and then drying it. Dissolution tests were also conducted on these FC tablets, and the results showed excellent dissolution properties, comparable to those of Example 1.

[0031] [Table 2]

Claims

1. an apremilast solid dosage form containing apremilast and lactose monohydrate, Apremilast solid formulation containing low-substituted hydroxypropylcellulose.

2. The apremilast solid preparation according to claim 1, further containing stearate.

3. A method for producing apremilast solid dosage form, comprising a tableting step of compressing a composition containing apremilast and lactose monohydrate, The method for producing an apremilast solid formulation, wherein the composition further contains low-substituted hydroxypropylcellulose.

4. The method for producing an apremilast solid dosage form according to claim 3, wherein the tableting step is performed by a direct tableting method.

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