Abiraterone acetate-containing preparations

Abstract

To provide an abiraterone acetate-containing preparation having quick collapsibility and excellent elution properties.SOLUTION: According to one embodiment, an abiraterone acetate-containing preparation contains abiraterone acetate, and sodium starch glycolate of 2 wt.% or more relative to the total weight of the preparation. According to another embodiment, it may contain sodium starch glycolate of 5 wt.% or more relative to the total weight of the preparation. According to another embodiment, it may further contain croscarmellose sodium.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a formulation containing abiraterone acetate. [Background technology]

[0002] Abiraterone ((3β)-17-(pyridin-3-yl)androsta-5,16-dien-3-ol) is an irreversible and selective inhibitor of 17α-hydroxylase / C17,20-lyase (CYP17), inhibiting the synthesis of androgens in the testes, adrenal glands, and prostate tumor tissues. Abiraterone prodrug 17-(pyridin-3-yl)androsta-5,16-dien-3β-yl acetate is used as a treatment for castration-resistant prostate cancer and high-risk prostate cancer untreated with endocrine therapy.

[0003] Abiraterone acetate is a poorly water-soluble drug, and is known to have a slow oral absorption rate. In order to increase the dissolution rate of abiraterone acetate, a method has been proposed in which the particle size is reduced to increase the surface area (Patent Document 1).

[0004] Furthermore, Patent Document 2 proposes a method for dispersing abiraterone acetate by wet grinding using hydroxypropyl cellulose (HPC).

[0005] Another method for improving the dissolution rate of abiraterone acetate is, for example, increasing the amount of disintegrant added. However, increasing the amount of disintegrant added increases the size (weight) of the abiraterone acetate-containing formulation, making it difficult for patients to take it. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Special Publication No. 2016-514707 [Patent Document 2] International Publication No. 2019 / 208725 Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide an abiraterone acetate-containing formulation that has rapid disintegration and excellent dissolution properties. [Means for solving the problem]

[0008] According to one embodiment of the present invention, there is provided an abiraterone acetate-containing formulation comprising abiraterone acetate and sodium starch glycolate in an amount of 2% by weight or more based on the total weight of the formulation.

[0009] The preparation may contain 5% by weight or more of sodium starch glycolate based on the total weight of the preparation.

[0010] It may further comprise croscarmellose sodium.

[0011] The formulation may contain 50% by weight or more of abiraterone acetate based on the total weight of the formulation. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 shows the results of evaluation of dissolution properties of abiraterone acetate-containing formulations of Example 1 and Comparative Examples 1 to 3. [Diagram 2] FIG. 1 shows the results of evaluation of disintegration properties of the abiraterone acetate-containing formulation of Example 1 and a placebo tablet. [Diagram 3] FIG. 2 shows the results of evaluation of disintegration properties of the abiraterone acetate-containing formulation of Comparative Example 1 and a placebo tablet. [Figure 4] FIG. 1 shows the results of evaluation of disintegration properties of an abiraterone acetate-containing formulation and a placebo tablet in Comparative Example 2. [Diagram 5]FIG. 1 shows the results of evaluation of disintegration properties of the abiraterone acetate-containing formulation of Comparative Example 3 and the placebo tablet. [Figure 6] FIG. 1 shows the results of evaluation of dissolution properties of abiraterone acetate-containing formulations of Examples 2 to 6 and Comparative Example 4. [Figure 7] FIG. 1 shows the results of evaluation of dissolution properties of abiraterone acetate-containing formulations of Examples 3 to 6. [Figure 8] FIG. 1 shows the results of evaluation of dissolution properties of the abiraterone acetate-containing formulations of Examples 5 and 7. [Figure 9] FIG. 1 shows the results of evaluation of dissolution properties of abiraterone acetate-containing formulations of Examples 8 to 10. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The abiraterone acetate-containing formulation of the present invention will be described below with reference to the drawings. The abiraterone acetate-containing formulation of the present invention is not to be construed as being limited to the description of the following embodiments and examples. In the drawings referred to in the embodiments and examples described below, the same parts or parts having similar functions are given the same reference numerals, and repeated explanations thereof will be omitted.

[0014] As a result of the studies conducted by the present inventors, it was found that the combination of abiraterone acetate and a specific disintegrant significantly improves the dissolution rate of abiraterone acetate. Therefore, it was found that it is possible to significantly reduce the amount of disintegrant added compared to abiraterone acetate-containing preparations commercially available in Japan at the time of filing this application, and to reduce the size (weight) of the abiraterone acetate-containing preparation.

[0015] [Abiraterone acetate-containing preparations] The abiraterone acetate-containing formulation according to one embodiment of the present invention contains sodium starch glycolate in an amount of 2% by weight or more based on the total weight of the formulation. Alternatively, the sodium starch glycolate may be contained in an amount of 5% by weight or more based on the total weight of the formulation. In one embodiment, the abiraterone acetate-containing formulation contains 250 mg of abiraterone acetate per tablet, but is not limited thereto and may be arbitrarily changed within a range in which a pharmaceutical effect is obtained. In one embodiment, the abiraterone acetate-containing formulation may be a film-coated tablet having a coating layer on the surface of a plain tablet containing abiraterone acetate. The abiraterone acetate-containing formulation according to one embodiment of the present invention contains abiraterone acetate-containing particles and one or more pharma-ceutically acceptable additives on the outside of the particles.

[0016] In one embodiment, the abiraterone acetate-containing formulation contains 50% by weight or more, preferably 60% by weight or more, of abiraterone acetate based on the total weight of the formulation, and therefore the abiraterone acetate-containing formulation of the present invention has significantly improved intake properties compared to conventional formulations.

[0017] [Abiraterone acetate-containing particles] The abiraterone acetate-containing particle according to one embodiment of the present invention contains abiraterone acetate, sodium starch glycolate, an excipient, a binder, a surfactant, and a lubricant. In one embodiment, it is preferable that the particle further contains croscarmellose sodium. In one embodiment, the particle may be composed of abiraterone acetate, sodium starch glycolate, croscarmellose sodium, an excipient, a binder, a surfactant, and a lubricant.

[0018] Examples of excipients contained in the abiraterone acetate-containing particles include, but are not limited to, one or more excipients selected from glucose, lactose, sucrose, maltose, trehalose, dextrin, cyclodextrin, mannitol, erythritol, isomalt, lactitol, maltitol, sorbitol, xylitol, inositol, corn starch, crystalline cellulose, hydroxypropyl cellulose, hypromellose, light anhydrous silicic acid / crystalline cellulose, anhydrous calcium phosphate, light anhydrous calcium silicate, calcium silicate, calcium sulfate, calcium carbonate, calcium lactate, light anhydrous silicic acid, hydrated silicon dioxide, magnesium aluminometasilicate, anhydrous silicic acid, etc. In one embodiment, lactose hydrate, crystalline cellulose, and light anhydrous silicic acid can be preferably used.

[0019] Examples of the binder contained in the abiraterone acetate-containing particles include, but are not limited to, one or more binders selected from polyvinylpyrrolidone, hydroxypropylcellulose, light anhydrous silicic acid-containing hydroxypropylcellulose, hypromellose, polyvinyl alcohol, etc. In one embodiment, polyvinylpyrrolidone can be preferably used.

[0020] Examples of surfactants contained in the abiraterone acetate-containing particles include, but are not limited to, one or more surfactants selected from polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polysorbate 80, polysorbate 65, polysorbate 40, polysorbate 20, polyoxyethylene sorbitan monolaurate, polyethylene glycol monostearate, lauromacrogol BL-9, lauromacrogol BL-25, poloxamer 188, poloxamer 407, polyoxyethylene hydroxystearate, sodium lauryl sulfate, and sodium deoxycholate. In one embodiment, sodium lauryl sulfate can be preferably used.

[0021] Examples of lubricants contained in the abiraterone acetate-containing particles include, but are not limited to, magnesium stearate, calcium stearate, talc, macrogol, sucrose fatty acid ester, etc. In one embodiment, magnesium stearate is preferably used.

[0022] [Pharmaceutically acceptable additives] Examples of pharma- ceutically acceptable additives that can be contained outside the abiraterone acetate-containing particles include excipients, lubricants, colorants, etc. The abiraterone acetate-containing formulation of the present invention can be produced by compressing one or more of these additives together with the abiraterone acetate-containing particles.

[0023] The excipient may be one or more of the excipients described above. In one embodiment, hypromellose may be preferably used.

[0024] The lubricant may be one or more selected from the lubricants described above. In one embodiment, talc and macrogol may be preferably used.

[0025] Examples of coloring agents include edible coloring agents such as Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, Food Lake Color, Yellow Ferric Oxide, and Titanium Oxide, but are not limited to these.

[0026] In one embodiment, the abiraterone acetate-containing formulation may contain 2% by weight or more of sodium starch glycolate based on the total weight of the formulation, and preferably contains 5% by weight or more of sodium starch glycolate based on the total weight of the formulation.

[0027] In one embodiment, the abiraterone acetate-containing formulation may contain croscarmellose sodium in an amount of 1% by weight or more and 20% by weight or less based on the total weight of the formulation.

[0028] In one embodiment, the excipient may be contained in an amount of 1% by weight or more and 80% by weight or less based on the total weight of the abiraterone acetate-containing formulation.

[0029] In one embodiment, the binder may be contained in an amount of 0.1% by weight or more and 20% by weight or less based on the total weight of the abiraterone acetate-containing formulation.

[0030] In one embodiment, the surfactant may be present in an amount of 1% by weight to 20% by weight based on the total weight of the abiraterone acetate-containing formulation. When sodium lauryl sulfate is selected as the surfactant, it is preferably present in an amount of 5% by weight or more based on the total weight of the formulation.

[0031] In one embodiment, the disintegrant may be contained in an amount of 1% by weight or more and 40% by weight or less based on the total weight of the abiraterone acetate-containing formulation.

[0032] In one embodiment, the abiraterone acetate-containing formulation may contain 0.1% by weight or more and 5% by weight or less of a lubricant based on the total weight of the formulation.

[0033] In one embodiment, the colorant may be contained in an amount of 0.01% by weight or more and 5% by weight or less based on the total weight of the abiraterone acetate-containing formulation.

[0034] In one embodiment, the abiraterone acetate particles according to the present invention may be micrometer-scale particles. In Patent Documents 1 and 2, the particle size of abiraterone acetate is nanometer-sized in order to increase the dissolution rate of abiraterone acetate, but in the abiraterone acetate-containing formulation according to the present invention, even with abiraterone acetate of micrometer size, it is possible to improve the dissolution property of abiraterone acetate. Abiraterone acetate of micrometer size can improve the handling property during production compared to abiraterone acetate of nanometer size.

[0035] [Manufacturing method of abiraterone acetate-containing preparations] In one embodiment, the abiraterone acetate-containing formulation of the present invention can be produced by a known production method. In one embodiment, abiraterone acetate, sodium starch glycolate, an excipient, a binder, and a surfactant are granulated by a wet granulation method using a granulation liquid. As the granulation liquid, for example, purified water can be used, but granulation may be performed using a granulation liquid in which a binder is dissolved in purified water. The obtained granules can be sized to obtain the abiraterone acetate-containing particles of the present invention. The obtained abiraterone acetate-containing particles may be mixed with one or more pharma- ceutically acceptable additives such as a lubricant, and then compressed into tablets. The obtained tablets may also be film-coated to produce film-coated tablets. In one embodiment, the wet granulation method may be, for example, agitation granulation method to obtain a granule. EXAMPLES

[0036] The combination of abiraterone acetate and a disintegrant was investigated.

[0037] [Example 1] In Example 1, sodium starch glycolate (DEF Pharma, Primojel®) was selected as the disintegrant. Abiraterone acetate, lactose hydrate (DEF Pharma, Pharmatose® 200M), sodium starch glycolate, polyvinylpyrrolidone (Daiichi Kogyo Seiyaku Co., Ltd., Eiftact K30PH), and sodium lauryl sulfate (Kao Corporation, Emeral OS) were mixed and granulated in a mortar using purified water as a granulation solvent. The granulated material was dried in a dryer and then sieved. The sieved powder was mixed with crystalline cellulose (Asahi Kasei Corporation, CEOLUS® PH-102), light anhydrous silicic acid (Freund Corporation, Adsolider 101), and magnesium stearate (Taihei Chemical Industry Co., Ltd.), and tableted with a tablet press. The content of each additive in the tablet is shown in Table 1.

[0038] [Comparative Example 1] In Comparative Example 1, tablets were obtained by the same manufacturing method as in Example 1, except that croscarmellose sodium (FMC Health and Nutrition, Ac-Di-Sol (registered trademark)) was selected as the disintegrant. The contents of each additive in the tablets are shown in Table 1.

[0039] [Comparative Example 2] In Comparative Example 2, tablets were obtained by the same manufacturing method as in Example 1, except that low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd., L-HPC (registered trademark) LH-21) was selected as the disintegrant. The contents of each additive in the tablets are shown in Table 1.

[0040] [Comparative Example 3] In Comparative Example 3, except that crospovidone (BASF Japan, Kollidon (registered trademark) CL-F) was selected as the disintegrant, tablets were obtained by the same manufacturing method as in Example 1. The contents of each additive in the tablets are shown in Table 1.

[0041] [Table 1]

[0042] [Evaluation of dissolution] The dissolution properties of the abiraterone acetate-containing formulations of Example 1 and Comparative Examples 1 to 3 were evaluated according to the paddle method for dissolution testing in the 17th Edition of the Japanese Pharmacopoeia. The test fluid used was the first dissolution test fluid (pH 1.2) containing 0.5% polysorbate 80. The paddle rotation speed was 50 rpm.

[0043] The evaluation results of the dissolution properties of the abiraterone acetate-containing formulations of Example 1 and Comparative Examples 1 to 3 are shown in Figure 1. The results in Figure 1 demonstrate that the abiraterone acetate-containing formulation of Example 1, which contains sodium starch glycolate, exhibits excellent dissolution properties.

[0044] [Evaluation of disintegration] The disintegration properties of the abiraterone acetate-containing formulations of Example 1 and Comparative Examples 1 to 3 were evaluated according to the disintegration test method of the 17th Edition of the Japanese Pharmacopoeia. 900 mL of disintegration test first fluid (pH 1.2) containing 0.5% polysorbate 80 was used as the disintegration test fluid. In addition, for the abiraterone acetate-containing formulations of Example 1 and Comparative Examples 1 to 3, placebo tablets were produced in which all of the abiraterone acetate was replaced with lactose hydrate (total amount of lactose hydrate: 284.0 g), and disintegration properties were evaluated in the same manner.

[0045] FIG. 2 shows the evaluation results of the abiraterone acetate-containing formulation and placebo tablet of Example 1. FIG. 3 shows the evaluation results of the abiraterone acetate-containing formulation and placebo tablet of Comparative Example 1. FIG. 4 shows the evaluation results of the abiraterone acetate-containing formulation and placebo tablet of Comparative Example 2. FIG. 5 shows the evaluation results of the abiraterone acetate-containing formulation and placebo tablet of Comparative Example 3. From the results of FIG. 2 to FIG. 5, the abiraterone acetate-containing formulation of Example 1 completely disintegrated 10 minutes after the start of the disintegration test, but the abiraterone acetate-containing formulations of Comparative Examples 1 to 3 did not completely disintegrate at the time point 10 minutes after the start of the disintegration test. Therefore, it was revealed that sodium starch glycolate specifically imparts rapid disintegration to the abiraterone acetate-containing formulation.

[0046] [Study on sodium starch glycolate content] Abiraterone acetate-containing film-coated tablets of Examples 2 to 6 and Comparative Example 4 were produced using uncoated tablets with different contents of sodium starch glycolate and lactose hydrate from the abiraterone acetate-containing formulation of Example 1. Specifically, the uncoated tablets of Examples 2 to 6 and Comparative Example 4 were produced by the manufacturing method described in Test Example 1, and a film-coating solution was prepared by dissolving or dispersing hypromellose (Shin-Etsu Chemical Co., Ltd., TC-5 (registered trademark) M), macrogol 6000, titanium oxide (Toho Titanium Co., Ltd., NA-61), talc (Fuji Talc Co., Ltd.), ferric oxide, and yellow ferric oxide in a solvent, and the uncoated tablets of Examples 2 to 7 were coated with the film-coating solution. The contents of each additive in the tablets are shown in Table 2.

[0047] [Table 2]

[0048] [Evaluation of dissolution] Based on the above-mentioned dissolution test method, the dissolution properties of the film-coated tablets containing abiraterone acetate of Examples 2 to 6 and Comparative Example 4 were evaluated. The evaluation results are shown in Figure 6. It was revealed that the film-coated tablets containing abiraterone acetate of Examples 2 to 6 containing 2% by weight or more of sodium starch glycolate exhibited more rapid dissolution properties than the film-coated tablets containing abiraterone acetate of Comparative Example 4 containing 1.2% by weight of sodium starch glycolate. In addition, the results of the film-coated tablets containing abiraterone acetate of Examples 2 to 4 demonstrated that excellent dissolution properties were obtained by containing 5% by weight or more of sodium starch glycolate.

[0049] [Study of dissolution during storage] The film-coated tablets containing abiraterone acetate of Examples 3 to 6 were stored for 2 weeks at 60° C. and 60% RH. The dissolution properties of the film-coated tablets containing abiraterone acetate of Examples 3 to 6 after storage were evaluated using the same method as that for evaluating the dissolution properties of the film-coated tablets containing abiraterone acetate of Examples 3 to 6 described above.

[0050] The dissolution evaluation results are shown in Figure 7. The dissolution evaluation results of the abiraterone acetate-containing film-coated tablets of Examples 3 to 6 immediately after production (Initial) shown in Figure 6 are also shown again. The results in Figure 7 reveal that in all Examples, delayed dissolution of abiraterone acetate occurs in the abiraterone acetate-containing film-coated tablets after storage.

[0051] [Example 7] In Example 7, tablets were obtained by the same manufacturing method as in Example 5, except that croscarmellose sodium (DuPont Nutrition & Biosciences, Ac-Di-Sol (registered trademark)) was further added and the contents of lactose and crystalline cellulose were changed as shown in Table 3. The contents of each additive in the tablet are shown in Table 3.

[0052] [Table 3]

[0053] The film-coated tablets containing abiraterone acetate of Examples 5 and 7 were stored for 3 months at 40° C. and 75% RH. The dissolution properties of the film-coated tablets containing abiraterone acetate of Example 7 immediately after production and the film-coated tablets containing abiraterone acetate of Examples 5 and 7 after storage were evaluated using a method similar to that for evaluating the dissolution properties of the film-coated tablets containing abiraterone acetate of Example 5 described above.

[0054] The results of the dissolution evaluation are shown in Figure 8. The results of the evaluation of the dissolution of the film-coated tablets containing abiraterone acetate of Example 5 immediately after production shown in Figure 6 are also shown here. The results in Figure 8 demonstrate that the delayed dissolution of abiraterone acetate after storage is improved in the film-coated tablets containing abiraterone acetate of Example 7, which used sodium starch glycolate and croscarmellose sodium in combination.

[0055] The dissolution rate was evaluated for film-coated tablets containing abiraterone acetate with different ratios of sodium starch glycolate and croscarmellose sodium, but no significant difference was observed in the improvement of dissolution delay when the weight ratio of sodium starch glycolate:croscarmellose sodium was in the range of 1:1.35 to 1:3.6.

[0056] [Study of sodium lauryl sulfate content] In Example 8, abiraterone acetate, lactose hydrate (DEF Pharma, Pharmatose® 200M), sodium starch glycolate (DEF Pharma, Primojel®), croscarmellose sodium (DuPont Nutrition & Biosciences, Ac-Di-Sol®), polyvinylpyrrolidone (Daiichi Kogyo Seiyaku Co., Ltd., Eiftact K30PH), and sodium lauryl sulfate (Kao Corporation, Emeral OS) were mixed and granulated in a mortar using purified water as a granulation solvent. The granulated product was dried in a dryer and then sieved using a sieve. The sieved powder was mixed with crystalline cellulose (Asahi Kasei Corporation, CEOLUS® PH-102), light anhydrous silicic acid (Freund Corporation, Adsolider 101), and magnesium stearate (Taihei Chemical Industry Co., Ltd.), and tableted with a tablet press. The content of each additive in the tablet is shown in Table 4. In addition, the contents of sodium lauryl sulfate and lactose hydrate were changed as shown in Table 4, and the abiraterone acetate-containing formulations of Examples 9 and 10 were produced by the same production method as in Example 8.

[0057] [Table 4]

[0058] [Evaluation of dissolution] The dissolution properties of the abiraterone acetate-containing formulations of Examples 8 to 10 were evaluated according to the paddle method for dissolution testing in the 17th edition of the Japanese Pharmacopoeia. 200 ml of the first dissolution test fluid (pH 1.2) was used as the test fluid. The rotation speed of the paddle was 150 rpm.

[0059] The evaluation results of the dissolution property of the abiraterone acetate-containing formulations of Examples 8 to 10 are shown in Figure 9. The results in Figure 9 reveal that in the abiraterone acetate-containing formulation, the dissolution property improves depending on the content of sodium lauryl sulfate. The results in Example 9 reveal that the dissolution property improves by including 5 wt% or more of sodium lauryl sulfate based on the total weight of the formulation.

[0060] The particle size of the abiraterone acetate used in each Example and Comparative Example was measured using a Mastersizer 3000 (Malvern). The particle size of the abiraterone acetate used in Examples 1 to 6 and Comparative Examples 1 to 4 was measured using a D 50 = 2.2 μm, D 90 The particle size of the abiraterone acetate used in Example 7 was D 50 = 3.9 μm, D 90 The particle size of the abiraterone acetate used in Examples 8 to 10 was D 50 = 3.5 μm, D 90 = 8.0 μm. In Patent Documents 1 and 2, the particle size of abiraterone acetate is set to nanometer order in order to increase the dissolution rate of abiraterone acetate, but it has been shown that the abiraterone acetate-containing formulation according to the present invention can improve the dissolution property of abiraterone acetate even when the particle size of abiraterone acetate is micrometer order.

[0061] As is clear from the above examples, the abiraterone acetate-containing formulation according to the present invention can contain abiraterone acetate in an amount of 60% by weight or more based on the total weight of the formulation. This allows the formulation to be made smaller and improves ease of administration. It has been revealed that the abiraterone acetate-containing formulation according to the present invention can simultaneously improve the dissolution properties of abiraterone acetate and ease of administration.

Claims

1. An abiraterone acetate-containing formulation comprising particles containing abiraterone acetate of micrometer size having a particle size (D50) of 2.2 μm or more, lactose hydrate, crystalline cellulose, polyvinylpyrrolidone, sodium lauryl sulfate, and sodium starch glycolate, An abiraterone acetate-containing formulation comprising 50% by weight or more of abiraterone acetate based on the total weight of the abiraterone acetate-containing formulation, and 2% by weight or more of sodium starch glycolate based on the total weight of the abiraterone acetate-containing formulation.

2. An abiraterone acetate-containing formulation as described in claim 1, which contains light anhydrous silicic acid on the outside of the particles.

3. The abiraterone acetate-containing formulation according to claim 1, comprising 5% by weight or more of sodium starch glycolate based on the total weight of the formulation.

4. Further comprising croscarmellose sodium, The abiraterone acetate-containing formulation according to any one of claims 1 to 3, wherein the weight ratio of sodium starch glycolate:sodium croscarmellose is in the range of 1:1.35 to 1:3.

6.

5. 4. The abiraterone acetate-containing formulation according to claim 1, comprising 5% by weight or more of sodium lauryl sulfate based on the total weight of the abiraterone acetate-containing formulation.

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