Nilotinib-containing capsule formulation

Abstract

To provide a nilotinib-containing capsule formulation that enables suppressive control of a dissolution rate.SOLUTION: According to one embodiment of the present invention, a nilotinib-containing capsule formulation is provided that comprises a composition containing nilotinib or a salt thereof and sodium lauryl sulfate. A content of sodium lauryl sulfate may be 0.5 mass% or more and 12.0 mass% or less relative to a mass of nilotinib. When the dissolution profile of the capsule formulation is evaluated under conditions of solvent: McIlvaine buffer solution (pH 3.0), volume: 900 mL, and rotation speed: 50 rpm in accordance with the Japanese Pharmacopoeia 18th edition, Dissolution Test, Method 2 (Paddle Method), a dissolution rate of nilotinib upon 60 minutes from dissolution initiation may be 35% or less.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a nilotinib-containing capsule.

Background Art

[0002] Nilotinib (4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide) is an anti-tumor agent effective against chronic or transitional chronic myeloid leukemia. In Japan, Tasigna (registered trademark) capsules containing nilotinib hydrochloride monohydrate as an active ingredient are on the market. In oral preparations such as capsules and tablets, in formulating the preparation, it is necessary to devise a means for controlling the elution property of the active ingredient. For example, in Patent Document 1, a capsule agent is disclosed which contains a polyoxyethylene-polyoxypropylene block copolymer, lactose monohydrate, and polyvinylpyrrolidone in the inner phase of granules containing nilotinib or a pharmaceutically acceptable salt thereof, and contains lactose monohydrate, colloidal silicon dioxide, and magnesium stearate in the outer phase of the granules. Patent Document 2 discloses a film-coated tablet containing a tablet containing nilotinib or a pharmaceutically acceptable salt thereof and an additive, and at least one polymer for coating the tablet. Further, Patent Document 3 discloses a tablet containing nilotinib or a pharmaceutically acceptable salt thereof and an amino group-modified polymer additive.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0004] Although Patent Document 1 discloses a nilotinib-containing capsule preparation having a certain elution property, it does not disclose how to control the elution. Patent Document 2 suppressively controls the disintegration of tablets by applying a film coating to the tablet surface. Further, Patent Document 3 suppressively controls the disintegration of tablets by adding an amino group-modified polymer additive. However, although Patent Documents 2 and 3 disclose an elution control method for nilotinib-containing tablets, they do not disclose anything about capsule preparations.

[0005] The present invention solves the above problems and aims to provide a nilotinib-containing capsule agent capable of suppressively controlling the elution rate.

Means for Solving the Problems

[0006] According to one embodiment of the present invention, there is provided a nilotinib-containing capsule agent comprising a composition containing nilotinib or a salt thereof and sodium lauryl sulfate.

[0007] The content of sodium lauryl sulfate may be 0.5% by mass or more and 12.0% by mass or less based on the mass of nilotinib.

[0008] When the dissolution property of the capsule agent was evaluated according to the second dissolution test method (paddle method) of the 18th revised Japanese Pharmacopoeia, with the test drug: McIlvaine buffer solution (pH 3.0), volume: 900 mL, and rotation speed: 50 rpm, the dissolution rate of nilotinib at a dissolution time of 60 minutes may be 35% or less.

Effects of the Invention

[0009] According to one embodiment of the present invention, there is provided a nilotinib-containing capsule agent capable of suppressively controlling the elution rate.

Brief Description of the Drawings

[0010]

Figure 1

Figure 2

Mode for Carrying Out the Invention

[0011] Hereinafter, the nilotinib-containing capsule agent according to the present invention will be described in detail. However, the nilotinib-containing capsule agent of the present invention is not construed as being limited to the contents described in the following embodiments and examples.

[0012] As a result of intensive studies by the present inventors to provide a nilotinib-containing capsule agent capable of suppressingly controlling the dissolution rate, as will also be described in the examples below, by including sodium lauryl sulfate in a composition containing nilotinib or a salt thereof, it has become clear that the dissolution rate can be suppressingly controlled. Sodium lauryl sulfate is known as a surfactant and solubilizing agent, and is known to increase the dissolution rate of the active ingredient or accelerate the dissolution rate of the active ingredient. However, in the present invention, a new action of suppressingly controlling the dissolution rate of nilotinib by including sodium lauryl sulfate, which is contrary to the generally known action of sodium lauryl sulfate, has been found.

[0013] [Composition] The nilotinib-containing capsule agent according to an embodiment of the present invention includes a composition containing nilotinib or a salt thereof, and sodium lauryl sulfate. As described above, the nilotinib-containing capsule agent can suppressingly control the dissolution rate of nilotinib by including nilotinib or a salt thereof, and sodium lauryl sulfate in the composition.

[0014] In this embodiment, a hydrate of nilotinib hydrochloride can be used as nilotinib or a salt thereof. For example, nilotinib hydrochloride monohydrate or nilotinib hydrochloride dihydrate can be used. The content of nilotinib or a salt thereof can be appropriately selected according to the expected therapeutic effect. For example, each capsule of a nilotinib-containing capsule agent may contain 50 mg, 150 mg, or 200 mg of nilotinib.

[0015] In one embodiment, the content of sodium lauryl sulfate is preferably 0.5% by mass or more and 12.0% by mass or less based on the mass of nilotinib. For example, it is preferable that the composition contains 1 to 24 mg of sodium lauryl sulfate per capsule of a nilotinib-containing capsule agent relative to nilotinib hydrochloride dihydrate (200 mg as nilotinib). By including sodium lauryl sulfate in the composition containing nilotinib or a salt thereof, the dissolution rate of nilotinib decreases.

[0016] In one embodiment, when the dissolution property of the capsule agent was evaluated according to the second dissolution test method (paddle method) of the 18th revised Japanese Pharmacopoeia, with the test drug: McIlvaine buffer solution (pH 3.0), volume: 900 mL, and rotation speed: 50 rpm, the dissolution rate of nilotinib at a dissolution time of 60 minutes was preferably 35% or less, and more preferably 4% or more and 35% or less. By controlling the rapid dissolution at the initial stage of dissolution, an unnecessary increase in the maximum blood concentration can be suppressed, and the occurrence of unexpected side effects can be suppressed. When the content of sodium lauryl sulfate is increased, the dissolution rate of nilotinib until a dissolution time of 60 minutes decreases depending on the content of sodium lauryl sulfate. The dissolution rate until a dissolution time of 60 minutes shows a negative correlation with the content of sodium lauryl sulfate. From this, by adjusting the content of sodium lauryl sulfate, the dissolution rate of nilotinib can be controllably suppressed.

[0017] The composition contained in the nilotinib-containing capsule may further contain nilotinib or its salt, sodium lauryl sulfate, and pharmaceutically acceptable additives. As pharmaceutically acceptable additives, for example, excipients can be included.

[0018] As excipients, for example, they can be selected from the group consisting of binders, disintegrants, lubricants, glidants, fillers and diluents, and combinations thereof, but are not limited thereto.

[0019] Binders can be selected from, for example, the group consisting of starch, cellulose and its derivatives, sucrose, dextrose, corn syrup, polysaccharides, povidone, and gelatin, but are not limited thereto.

[0020] Disintegrants can be selected from, for example, the group consisting of starch, clay, cellulose, alginate, rubber, polyvinylpyrrolidone, crospovidone, sodium carboxymethylcellulose, croscarmellose sodium, calcium carboxymethylcellulose, soybean polysaccharides, and guar gum, but are not limited thereto.

[0021] Lubricants can be selected from, for example, the group consisting of talc, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, polyethylene glycol, glyceryl behenate, stearic acid, hydrogenated castor oil, glycerol monostearate, and sodium stearyl fumarate, but are not limited thereto.

[0022] Glidants can be selected from the group consisting of colloidal silica, magnesium trisilicate, starch, talc, tricalcium phosphate, aluminum stearate, magnesium carbonate, magnesium oxide, powdered cellulose, and light anhydrous silicic acid, but are not limited thereto.

[0023] As the filler and diluent, for example, it can be selected from the group consisting of powdered sugar, compressed sugar, dextrate, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose, and lactose hydrate, but is not limited thereto.

[0024] [Nilotinib-containing Capsules] The nilotinib-containing capsules can contain one or more pharmaceutically acceptable additives in addition to the composition containing nilotinib or its salt and sodium lauryl sulfate. As the one or more pharmaceutically acceptable additives, the excipients described above can be included. For example, it can contain a diluent and a glidant.

[0025] In this embodiment, the capsules used for the nilotinib-containing capsules are not particularly limited, and known pharmaceutically acceptable capsules can be used. For example, gelatin capsules manufactured with a gelatin base or the like can be used.

[0026] [Method for Producing Nilotinib-containing Capsules] For the method for producing the nilotinib-containing capsules according to the present invention, a known production method can be used. For example, in one embodiment, a composition containing nilotinib or its salt and sodium lauryl sulfate is produced by a dry granulation method, and the nilotinib-containing capsules are produced by filling the composition into capsules.

[0027] [Dissolution] In this specification, the dissolution of nilotinib in the nilotinib-containing capsules is evaluated according to the second dissolution test method (paddle method) of the Japanese Pharmacopoeia, eighteenth revision. Stir with 900 ml of the test solution at 50 rpm. Note that a diluted McIlvaine buffer solution (pH 3.0) is used as the test solution. The dissolution rate of nilotinib is measured by high performance liquid chromatography (HPLC).

Examples

[0028] The specific examples and comparative examples of the nilotinib-containing capsule agent according to the present invention described above and their test results will be described in more detail.

[0029] [Comparative Example 1] The compounding amounts per capsule were mixed so that they were 227.4 mg of nilotinib hydrochloride dihydrate (200.0 mg as nilotinib), 72.6 mg of lactose hydrate (DFE Pharma, Pharmatose (registered trademark), 200M), 16.0 mg of crospovidone (BASF Japan Ltd., Kollidon (registered trademark), CL), and 2.0 mg of magnesium stearate (Taihei Chemical Industry Co., Ltd., plant), and the composition was produced by a dry granulation method. The obtained composition and light anhydrous silicic acid (Freund Industry Co., Ltd., Adsolider (registered trademark), 101) were mixed so that the compounding amounts per capsule were 318.0 mg of the composition and 2.0 mg of light anhydrous silicic acid. 320.0 mg of the obtained mixture was filled into No. 1 gelatin capsules to produce a capsule agent. The details of the above capsule agent are shown in Table 1.

[0030] [Example 1] In Example 1, sodium lauryl sulfate was added in an amount of 0.5% by mass based on 100% by mass of nilotinib, and the addition amount of lactose hydrate was decreased. Specifically, the compounding amounts per capsule were added so that they were 1.0 mg of sodium lauryl sulfate (Kao Corporation, Emal OS) and 71.6 mg of lactose hydrate. Except for the above, the capsule agent of Example 1 was produced in the same manner as the production method of Comparative Example 1. The details of the above capsule agent are shown in Table 1.

[0031] [Example 2] In Example 2, sodium lauryl sulfate was added in an amount of 2.0% by mass based on 100% by mass of nilotinib, and the addition amount of lactose hydrate was decreased. Specifically, the compounding amounts per capsule were added so that they were 4.0 mg of sodium lauryl sulfate (Kao Corporation, Emal OS) and 68.6 mg of lactose hydrate. Except for the above, the capsule agent of Example 1 was produced in the same manner as the production method of Example 1. The details of the above capsule agent are shown in Table 1.

[0032] [Example 3] In Example 3, sodium lauryl sulfate was added to 100% by mass of nilotinib so as to be 4.0% by mass, and the addition amount of lactose hydrate was decreased. Specifically, the compounding amounts per capsule were added so as to be 8.0 mg of sodium lauryl sulfate (Kao Corporation, Emal OS) and 64.6 mg of lactose hydrate. Except for the above, the capsule agent of Example 1 was produced in the same manner as the production method of Example 1. The details of the above capsule agent are shown in Table 1.

[0033] [Example 4] In Example 4, sodium lauryl sulfate was added to 100% by mass of nilotinib so as to be 12.0% by mass, and the addition amount of lactose hydrate was increased. Specifically, the compounding amounts per capsule were added so as to be 24.0 mg of sodium lauryl sulfate (Kao Corporation, Emal OS) and 128.6 mg of lactose hydrate. Capsules made of size 0 gelatin capsules were used. Except for the above, the capsule agent of Example 1 was produced in the same manner as the production method of Example 1. The details of the above capsule agent are shown in Table 1.

[0034]

Table 1

[0035] [Evaluation 1 of Dissolution] The dissolution properties of the nilotinib-containing capsule agents of Comparative Example 1 and Examples 1 to 4 were evaluated. The dissolution rates of nilotinib in Comparative Example 1 and Examples 1 to 4 were measured by HPLC. The measurement results are shown in Figure 1. The measurement conditions of HPLC are shown below.

[0036] HPLC measurement conditions: Detector: Ultraviolet absorptiometer (measurement wavelength: 268 nm) Column: Octadecylsilylated silica gel, 4.6 × 150 mm, 5 μm Column temperature: Constant temperature around 40°C Mobile phase: Acetonitrile / 0.02 mol / L potassium dihydrogen phosphate solution (pH 3.0) (11:9) Flow rate: Adjust so that the retention time of nilotinib is about 3 minutes.

[0037] From the results of Figure 1, it was revealed that by including sodium lauryl sulfate in the composition, the solubility of nilotinib or its salt decreased, and the elution rate of nilotinib could be controlled.

[0038] Next, the elution rate of nilotinib with a conventional surfactant or solubilizer was evaluated.

[0039] [Comparative Example 2] In Comparative Example 2, polyoxyethylene (160) polyoxypropylene (30) glycol was added in an amount of 1.6% by mass based on 100% by mass of nilotinib, and the addition amount of lactose hydrate was decreased to produce a composition. The obtained composition was further mixed with lactose hydrate. Specifically, the blending amount per capsule was adjusted so that it contained 3.2 mg of polyoxyethylene (160) polyoxypropylene (30) glycol (manufactured by BASF, Kolliphor P188 (registered trademark)) and 71.4 mg of lactose hydrate. Further, lactose hydrate was added to the composition so that the blending amount per capsule was 78.0 mg. Except for the above, a capsule preparation of Comparative Example 2 was produced in the same manner as the production method of Comparative Example 1. The details of the above capsule preparation are shown in Table 2.

[0040] [Comparative Example 3] In Comparative Example 3, polyoxyethylene (160) polyoxypropylene (30) glycol was added in an amount of 6.0% by mass based on 100% by mass of nilotinib, and the addition amount of lactose hydrate in the composition was decreased. Specifically, the blending amount per capsule was adjusted so that it contained 3.2 mg of polyoxyethylene (160) polyoxypropylene (30) glycol (manufactured by BASF, Kolliphor P188 (registered trademark)) and 71.4 mg of lactose hydrate. Except for the above, a capsule preparation of Comparative Example 3 was produced in the same manner as the production method of Comparative Example 2. The details of the above capsule preparation are shown in Table 2.

[0041]

Table 2

[0042] [Evaluation of Dissolution 2] The dissolution properties of the nilotinib-containing capsules of Comparative Examples 1 to 3 were evaluated. The dissolution rates of nilotinib in Comparative Examples 1 to 3 were measured by HPLC. The measurement results are shown in Figure 2. The measurements were carried out under the measurement conditions used in Comparative Example 1 and Examples 1 to 4.

[0043] From the results in Figure 2, an increase in the amount of poloxamer was found to increase the dissolution rate up to 60 minutes of dissolution time. This increase in the dissolution rate is the effect of commonly used surfactants. From the results in Figures 1 and 2, it became clear that sodium lauryl sulfate can suppressively control the dissolution rate of nilotinib by adjusting its content in the composition. Sodium lauryl sulfate is generally used as a surfactant or solubilizer, and is known to increase the dissolution rate or accelerate the dissolution rate of the active ingredient. However, in the present invention, it was revealed that it exhibits an effect opposite to this conventionally known effect.

[0044] Even other operational effects different from the operational effects brought about by the aspects of each of the above-described embodiments, those that are obvious from the description in this specification or can be easily predicted by those skilled in the art are of course understood to be brought about by the present invention.

Claims

Claim 1 A nilotinib-containing capsule agent comprising a composition containing nilotinib or a salt thereof and sodium lauryl sulfate. Claim 2 The content of the sodium lauryl sulfate is 0.5% by mass or more and 12.0% by mass or less based on the mass of the nilotinib, The nilotinib-containing capsule agent according to claim 1. Claim 3 When the dissolution property of the capsule agent was evaluated according to the second dissolution test method (paddle method) of the Japanese Pharmacopoeia, eighteenth revision, with the test drug: McIlvaine buffer solution (pH 3.0), volume: 900 mL, and rotation speed: 50 rpm, the dissolution rate of the nilotinib at a dissolution time of 60 minutes is 35% or less. The nilotinib-containing capsule agent according to claim 1.

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