Apremilast solid preparation and preparation method therefor

Abstract

To provide an apremilast solid preparation suppressed in increase of related substances with time and excellent in stability.SOLUTION: The apremilast solid preparation contains apremilast and an additive, wherein the additive contains at least one selected from the group consisting of low-substituted hydroxypropyl cellulose, crospovidone, glycerin fatty acid ester, hydrous silicon dioxide, and light anhydrous silicic acid. It is preferable that the additive does not contain at least one selected from the group consisting of a sodium salt, a calcium salt, and a magnesium salt.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a solid formulation of apremilast and a method for producing the same. [Background technology]

[0002] Apremilast, i.e., N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide, is a therapeutic agent for psoriasis vulgaris, psoriatic arthritis, and the like, and tablets containing it are sold under the name "Otezla (registered trademark) tablets" (Non-Patent Document 1). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Otezla® Tablets 10 mg, 20 mg, 30 mg Package Insert (Revised January 2024 (3rd Edition)) Summary of the Invention [Problem to be solved by the invention]

[0004] However, when the present inventors investigated solid preparations containing apremilast, they found that solid preparations containing apremilast tend to have an increased amount of related substances over time, depending on the types of additives incorporated. The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a solid preparation of apremilast that 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 investigated the stability of apremilast solid formulations and found that when sodium salts, calcium salts, and magnesium salts are used as additives, the amount of related substances in the apremilast solid formulation tends to increase over time, and that when certain specific additives are used, the increase in the amount of related substances tends to be suppressed, leading to the completion of the present invention.

[0006] The present invention has the following aspects. [1] An apremilast solid formulation comprising apremilast and an additive, wherein the additive comprises at least one selected from the group consisting of low-substituted hydroxypropylcellulose, crospovidone, glycerin fatty acid ester, hydrous silicon dioxide, and light anhydrous silicic acid. [2] The apremilast solid formulation according to [1], wherein the additive comprises low-substituted hydroxypropyl cellulose and a glycerin fatty acid ester. [3] The apremilast solid formulation according to [1], wherein the additive contains crospovidone and a glycerin fatty acid ester. [4] The apremilast solid formulation according to [1], wherein the additive does not contain at least one selected from the group consisting of sodium salts, calcium salts, and magnesium salts. [5] A method for producing a solid formulation of apremilast, comprising a tableting step of tableting a composition containing apremilast and an additive, wherein the additive contains at least one selected from the group consisting of low-substituted hydroxypropylcellulose, crospovidone, glycerin fatty acid ester, hydrous silicon dioxide, and light anhydrous silicic acid. [6] The method for producing an apremilast solid formulation according to [5], wherein the tableting step is carried out by direct tableting. [7] An apremilast solid formulation comprising apremilast and an additive, wherein the additive does not contain at least one of a sodium salt, a calcium salt, and a magnesium salt. [Effects of the Invention]

[0007] According to the present invention, it is possible to provide a solid formulation of apremilast that is excellent in stability and in which the increase of related substances over time is suppressed. DETAILED DESCRIPTION OF THE INVENTION

[0008] The present invention will be described in detail below. The apremilast solid formulation of the present invention (hereinafter sometimes simply referred to as a solid formulation) is a solid formulation containing apremilast and pharmaceutical additives, including at least one additive selected from the group consisting of low-substituted hydroxypropylcellulose, crospovidone, glycerin fatty acid esters, hydrous silicon dioxide, and light anhydrous silicic acid.

[0009] Apremilast is not particularly limited, and commercially available apremilast may be used, and may be in crystalline or amorphous form. Furthermore, either anhydrous or hydrated apremilast may be used. Among these, crystalline anhydrous apremilast is preferred.

[0010] The additives used are one or more of low-substituted hydroxypropyl cellulose, crospovidone, glycerin fatty acid ester, hydrous silicon dioxide, and light anhydrous silicic acid. Solid preparations containing these additives have excellent stability, suppressing the increase in total related substances over time. Low-substituted hydroxypropyl cellulose and crospovidone are commonly used as disintegrants, glycerin fatty acid esters are commonly used as lubricants, and hydrated silicon dioxide and light anhydrous silicic acid are commonly used as flow agents. In a more preferred solid formulation, the excipients contain low-substituted hydroxypropyl cellulose and a glycerin fatty acid ester, or contain crospovidone and a glycerin fatty acid ester. Specifically, a solid formulation containing apremilast and further containing, as additives, an excipient, a disintegrant containing one or more of low-substituted hydroxypropyl cellulose and crospovidone, and a lubricant containing a glycerin fatty acid ester is preferred.

[0011] The additives may be one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, crospovidone, glycerin fatty acid ester, hydrous silicon dioxide, and light anhydrous silicic acid, as well as any additives commercially available for pharmaceutical use (such as excipients, binders, disintegrants, surfactants, colorants, sweeteners, and flavorings), if necessary. However, in order to suppress an increase in the total amount of related substances in the solid formulation over time, it is preferable not to use additives consisting of sodium salts, calcium salts, and magnesium salts. Specifically, it is preferable that the additive does not contain at least one selected from the group consisting of sodium salts, calcium salts, and magnesium salts, i.e., it does not contain one or more of these salts, and more preferably it does not contain any of sodium salts, calcium salts, and magnesium salts.

[0012] Examples of sodium salts include croscarmellose sodium and sodium starch glycolate, which are generally used as disintegrants, and sodium stearyl fumarate, which is often used as a lubricant.

[0013] Examples of calcium salts include calcium hydrogen phosphate hydrate, which is generally used as an excipient. Examples of magnesium salts include magnesium aluminometasilicate, which is generally used as a fluidizing agent, and magnesium stearate, which is generally used as a lubricant.

[0014] Examples of additives that may be preferably used as needed are given below. 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 needed.

[0015] Examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), polyvinyl alcohol, polyvinylpyrrolidone, stearyl alcohol, ammonio methacrylate copolymer, polyvinyl acetal diethylaminoacetate, dextrin, and starch syrup, and one or more of these can be used.

[0016] Examples of disintegrants include carmellose, corn starch, partially pregelatinized starch, hydroxypropyl starch, etc., and one or more of these can be used.

[0017] Examples of surfactants include polysorbate 80, and one or more of these can be used. Examples of coloring agents include titanium oxide, yellow ferric oxide, ferric oxide, Food Yellow No. 4, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, and Food Red No. 102, and one or more of these can be used.

[0018] 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.

[0019] Examples of lubricants include fatty acid esters such as sucrose fatty acid esters, and talc. Other waxes that can be used include carnauba wax.

[0020] When the solid preparation is a tablet having a coating layer on the surface, examples of the coating base include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc., and examples of the coating plasticizer include triethyl citrate, etc.

[0021] The solid preparation of the present invention is not limited in its form, so long as it contains apremilast and one or more additives selected from the group consisting of low-substituted hydroxypropylcellulose, crospovidone, glycerin fatty acid esters, hydrous silicon dioxide, and light anhydrous silicic acid, and examples thereof include granular preparations (granules, dry syrups, fine granules, etc.) and tablets (immediate-release tablets, orally disintegrating tablets, etc.).

[0022] The method for producing a solid formulation of the present invention is a method for producing a solid formulation of apremilast, which comprises a tableting step of tableting a composition containing apremilast and an additive, and the additive is at least one selected from the group consisting of the above-mentioned low-substituted hydroxypropylcellulose, crospovidone, glycerin fatty acid ester, hydrous silicon dioxide, and light anhydrous silicic acid. The tableting step of tableting the composition can be carried out by a known method, but is preferably carried out by direct tableting. The direct tableting method in this specification refers to a method in which apremilast is subjected to the tableting step without being granulated together with at least some of the additives. At least some of the additives contained in the composition may be granulated. By undergoing the tableting step, tablets are obtained as solid preparations. A coating layer may be formed on the surface of the tablets obtained in the tableting step. When producing a granular preparation, a granulated product obtained by a known granulation method can be used to form the granular preparation.

[0023] As explained above, the solid preparation of the present invention and the method for producing the same contain apremilast and specific additives, and therefore the increase in the total amount of related substances over time is suppressed, resulting in excellent stability. [Example]

[0024] [Examples 1-12] Apremilast (Example 1) and compositions (Examples 2 to 12) in which apremilast was mixed with various additives at the mixing ratios (compounding ratios) shown in Tables 1 to 3 were used as samples, and purity tests were carried out using the following method. Specifically, the total amount of related substances in each sample was measured after storage at 40°C and 75% RH for 2 and 4 weeks, and before storage. In Examples 2 to 6, an additive used mainly as a disintegrant was used, in Examples 7 to 9 an additive used mainly as a fluidizing agent was used, and in Examples 10 to 12 an additive used mainly as a lubricant was used. The results are shown in Tables 1 to 3.

[0025] <Purity test (total amount of related substances)> A sample was added to a 7:3 mixture of water and acetonitrile in an amount equivalent to 15 mg of apremilast to obtain 50 mL of solution, which was then centrifuged to obtain the supernatant, which was used as the sample solution and analyzed by automated analysis using high performance liquid chromatography. The values ​​for the total amount of related substances listed in Table 1 are expressed as a percentage of the sum of the peak areas of the observed related substances relative to the peak area derived from apremilast.

[0026] [Table 1]

[0027] Among the additives mainly used as disintegrants, when low-substituted hydroxypropyl cellulose and crospovidone were added (Examples 2 and 4), the increase in the amount of total related substances was suppressed. On the other hand, when carmellose calcium, croscarmellose sodium, and sodium starch glycolate were added (Examples 3, 5, and 6), an increase in the amount of total related substances was observed.

[0028] [Table 2]

[0029] Among the additives mainly used as fluidizing agents, when hydrous silicon dioxide and light anhydrous silicic acid were added (Examples 7 and 9), the increase in the amount of total related substances was kept low compared to when magnesium aluminometasilicate was added (Example 8).

[0030] [Table 3]

[0031] Among additives mainly used as lubricants, when glycerin fatty acid ester was added (Example 12), the increase in the amount of total related substances was suppressed. When magnesium stearate was added (Example 10), the increase in the amount of total related substances was observed, and when sodium stearyl fumarate was added (Example 11), the increase in the amount of total related substances was remarkable.

[0032] The results of Examples 1 to 12 revealed that the use of low-substituted hydroxypropyl cellulose, crospovidone, glycerin fatty acid ester, hydrous silicon dioxide, and light anhydrous silicic acid as additives suppresses the increase in the total amount of related substances in apremilast solid formulations.

[0033] [Prescription example] Based on the findings obtained from the results of Examples 1 to 12 above, tablets containing low-substituted hydroxypropyl cellulose and glycerin fatty acid ester as additives and having the formulation shown in Table 4 were produced by direct compression. Specifically, first, the components shown in Table 4 except for the glycerin fatty acid ester were mixed, and then the glycerin fatty acid ester was added and mixed to obtain a composition for tableting. Next, this composition was compressed into tablets (direct compression) using a rotary tableting machine without granulation to obtain oval tablets weighing 300 mg, with a major axis of 12.5 mm and a minor axis of 5.8 mm. To confirm the pharmaceutical properties of the obtained tablets, the tablet hardness was measured by the following method, and the average dissolution rate was also calculated.

[0034] <Tablet hardness> The hardness of five tablets was measured using a tablet hardness tester (PC-30, manufactured by Okada Seiko Co., Ltd.), and the average value was calculated and used as the tablet hardness.

[0035] <Average dissolution rate> A dissolution test was conducted using one tablet and 900 mL of test solution (pH 4.0) containing 0.5% polysorbate by the paddle method at 50 revolutions per minute. Sixty minutes after the start of the test, 10 mL of the dissolution solution was collected and filtered through a membrane filter with a pore size of 0.45 μm. The first 5 mL of filtrate was removed and immediately replaced with 10 mL of test solution. Then, 1 mL of the filtrate was accurately measured and 1 mL of a 7:3 acetonitrile / water mixture was added to prepare the sample solution. Separately, accurately weigh 33 mg of apremilast for assay and dissolve in a 7:3 mixture of acetonitrile and water to make exactly 100 mL. Measure 5 mL of this solution accurately and add a 7:3 mixture of acetonitrile and water to make exactly 50 mL. Measure 1 mL of this solution accurately and add 1 mL of the 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 230 nm was measured to obtain a chromatogram. The dissolution rate (%) of each sample solution 60 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 on three tablets (n=3), and the average (average dissolution rate) was calculated and shown in Table 4. The mobile phases used were a solution of 1 mL of trifluoroacetic acid with water to make 10,000 mL, and a solution of acetonitrile mixed in a ratio of 6:4.

[0036] [Table 4]

[0037] As shown in Table 4, it was confirmed that the solid preparations of the formulation examples containing low-substituted hydroxypropyl cellulose and glycerin fatty acid esters had sufficient tablet hardness and also exhibited good average dissolution rates.

Claims

1. An apremilast solid formulation comprising apremilast and an additive, An apremilast solid formulation, wherein the additive comprises at least one selected from the group consisting of low-substituted hydroxypropyl cellulose, crospovidone, glycerin fatty acid ester, hydrous silicon dioxide, and light anhydrous silicic acid.

2. The apremilast solid formulation according to claim 1, wherein the additive comprises low-substituted hydroxypropyl cellulose and a glycerin fatty acid ester.

3. The apremilast solid formulation according to claim 1, wherein the additive comprises crospovidone and a glycerin fatty acid ester.

4. The apremilast solid formulation according to claim 1, wherein the additive does not contain at least one selected from the group consisting of sodium salts, calcium salts, and magnesium salts.

5. A method for producing a solid formulation of apremilast, comprising a tableting step of tableting a composition containing apremilast and an additive, A method for producing a solid formulation of apremilast, wherein the additive comprises at least one selected from the group consisting of low-substituted hydroxypropyl cellulose, crospovidone, glycerin fatty acid ester, hydrous silicon dioxide, and light anhydrous silicic acid.

6. The method for producing an apremilast solid formulation according to claim 5 , wherein the tableting step is carried out by direct compression.

7. An apremilast solid formulation comprising apremilast and an additive, The solid formulation of apremilast, wherein the additive does not contain at least one of a sodium salt, a calcium salt, and a magnesium salt.

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