Method for manufacturing bosutinib pharmaceutical tablet

Abstract

To provide a method for manufacturing a bosutinib tablet for controlling elution property of bosutinib to a proper degree.SOLUTION: A method for manufacturing a pharmaceutical tablet having bosutinib as an active ingredient includes the steps of: (A) preparing a composition containing bosutinib, an excipient, a binder and a disintegrator; (B) adding a granulation-liquid to the composition to prepare a wet composition and preparing a granulated material by wet-granulating the composition, wherein a solvent in the granulation-liquid is added in an amount of 30 pts.mass or more and 40 pts.mass or less against 100 pts.mass of the wet composition; and (C) compression-molding the granulated material to prepare a pharmaceutical tablet.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a pharmaceutical formulation containing bosutinib as an active ingredient. [Background technology]

[0002] Bosutinib is a selective inhibitor of Bcr-Abl tyrosine kinase and Src family kinases involved in the onset and progression of chronic myeloid leukemia, and tablets containing bosutinib hydrate as an active ingredient are provided as therapeutic agents for chronic myeloid leukemia (Non-Patent Document 1). Regarding bosutinib tablets, Patent Document 1 describes a tablet containing bosutinib (SKI-606) hydrate, microcrystalline cellulose, croscarmellose sodium, poloxamer 188, povidone, and magnesium stearate. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Pharmaceutical Interview Form Bosulif(R) Tablets 100mg

[0004] [Patent Document 1] Special table 2015-12063 publication Summary of the Invention [Problem to be solved by the invention]

[0005] As a result of the study by the present inventors, it was found that the dissolution property of the active ingredient bosutinib in bosutinib tablets is significantly affected by the formulation preparation conditions. In other words, the present invention aims to provide a method for producing bosutinib tablets that exhibit suitable dissolution property so that the pharmacological activity of bosutinib can be appropriately exerted. [Means for solving the problem]

[0006] [1] A method for producing a pharmaceutical tablet containing bosutinib as an active ingredient, comprising: (A) preparing a composition comprising bosutinib, an excipient, and a disintegrant; (B) adding a granulation liquid to the composition to prepare a wet composition, and wet granulating the wet composition to prepare a granulated product, A step in which the solvent in the granulation liquid is added in an amount of 30 parts by mass or more to 40 parts by mass or less relative to 100 parts by mass of the wet composition; (C) compressing the granules to prepare a pharmaceutical tablet; A method for producing a pharmaceutical tablet comprising the steps of: [2] The method for producing a pharmaceutical tablet according to [1], wherein in step (B), granulation is performed after wet granulation and before drying. [3] The method for producing a pharmaceutical tablet according to [1] or [2], wherein in step (B), the granulated product has a 30 mesh sieve passing rate of 25% or less and a 200 mesh sieve passing rate of 20% or less. [4] The method for producing a pharmaceutical tablet according to any one of [1] to [3], wherein in step (C), a lubricant is added but no disintegrant is added. [5] The method for producing a pharmaceutical tablet according to any one of [1] to [4], wherein in step (A), bosutinib is applied in an amount such that the content in the pharmaceutical tablet is 65% by mass or more. Effect of the Invention

[0007] In order for bosutinib to exhibit its appropriate efficacy, it is necessary for the active ingredient to be dissolved at an appropriate rate from the pharmaceutical formulation. The manufacturing method of the present invention provides a manufacturing method for bosutinib tablets that can exhibit appropriate dissolution properties by discovering a control factor for the dissolution properties of bosutinib. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The medicine of the present invention uses a pharmaceutical preparation containing bosutinib as an active ingredient. The chemical name of bosutinib is 4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinoline-3-carbonitrile. This compound can be synthesized, for example, according to the description in Japanese Patent No. 4537582. Bosutinib may be used in the form of a pharmacologically acceptable acid addition salt or solvate. Bosutinib is well known as a monohydrate, and it is preferable to use bosutinib monohydrate. In addition, it is preferable to use a compound of a quality level that can be used as an active ingredient of pharmaceuticals. The bosutinib content is preferably 60% by mass or more and 80% by mass or less, more preferably 65% ​​by mass or more and 75% by mass or less, based on the total amount of the pharmaceutical preparation. Preferably, the pharmaceutical preparation contains bosutinib monohydrate as an active ingredient, and the bosutinib monohydrate content is 60% by mass or more and 80% by mass or less, more preferably 65% ​​by mass or more and 75% by mass or less, based on the total amount of the pharmaceutical preparation.

[0009] The bosutinib tablet of the present invention contains an excipient and a disintegrant. Examples of the excipient include celluloses such as crystalline cellulose, sugars such as lactose, mannitol, maltose, sucrose, sorbitol, xylitol, inositol, starches such as corn starch, and inorganic salts such as magnesium aluminometasilicate and anhydrous calcium phosphate, and these are preferably used alone or in combination of two or more. Preferred are crystalline cellulose, lactose, and mannitol, and excipients containing one or more of these. It is preferable to use crystalline cellulose. The excipient is preferably contained in an amount of 5% by mass or more and 30% by mass or less, more preferably 10% by mass or more and 20% by mass or less, based on the total weight of the pharmaceutical tablet.

[0010] Examples of disintegrants include croscarmellose sodium, carboxymethyl starch sodium, crospovidone, carmellose, carmellose calcium, low-substituted carboxymethyl starch sodium, etc., and these are preferably used alone or in combination of two or more. Preferred are croscarmellose sodium, carboxymethyl starch sodium, and crospovidone. More preferred is croscarmellose sodium. When a disintegrant is used, it is preferably used in an amount of 2% by mass to 10% by mass, more preferably 3% by mass to 8% by mass, based on the total weight of the pharmaceutical tablet.

[0011] The bosutinib tablet of the present invention preferably comprises a binder, a solubilizer and a lubricant. Examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copolyvidone, carmellose sodium, methylcellulose, partially pregelatinized starch, polyvinyl alcohol, etc., and these are preferably used alone or in combination of two or more. Preferred are hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, copolyvidone, carmellose sodium, and methylcellulose. When a binder is used, it is preferably used at 0.5% by mass or more and 10% by mass or less based on the total weight of the pharmaceutical tablet. Preferably, it is 1% by mass or more and 5% by mass or less. Examples of solubilizers include sodium lauryl sulfate, soybean lecithin, refined soybean lecithin, sorbitan fatty acid ester, soybean oil, lauromacrogol, polyoxyethylene-polyoxypropylene-polyoxyethylene block copolymer, etc. Polyoxyethylene-polyoxypropylene-polyoxyethylene block copolymer (poloxamer 188) is preferred. The solubilizer is preferably used in an amount of 0.5% by mass to 5% by mass, more preferably 1.0% by mass to 5% by mass, and even more preferably 2.0% by mass to 5% by mass, based on the total weight of the pharmaceutical tablet.

[0012] Examples of lubricants include magnesium stearate, stearic acid, zinc stearate, aluminum stearate, glycerin monostearate, sodium stearyl fumarate, calcium stearate, talc, carnauba wax, and the like. These are preferably used alone or in combination of two or more kinds. When a lubricant is used, it is preferably used in an amount of 0.1% by mass to 5% by mass, more preferably 0.2% by mass to 5% by mass, based on the total weight of the pharmaceutical tablet.

[0013] In addition to the above ingredients, the bosutinib tablet may contain other additives such as coloring agents, fluidizing agents, stabilizers, preservatives, and flavoring agents. Examples of colorants include titanium oxide, ferric oxide, talc, yellow ferric oxide, yellow ferric oxide, black ferric oxide, zinc oxide, brown ferric oxide, edible yellow dyes, edible blue dyes, edible red dyes, etc. Preferred are titanium oxide and ferric oxide. When a colorant is used, it is preferably used in an amount of 0.001% by mass to 5% by mass, more preferably 0.002% by mass to 5% by mass, based on the total weight of the pharmaceutical tablet. The fluidizing agent includes light anhydrous silicic acid, talc, hydrous silicon dioxide, and the like. The stabilizers include dibutylhydroxytoluene, tocopherol, ascorbic acid, sulfites, and the like. Examples of preservatives include paraoxybenzoic acid esters. Examples of flavoring agents include sucrose, D-sorbitol, and xylitol. These additives can be used without any particular limitation as long as they have a purity acceptable for use in pharmaceutical preparations. These additives may be used alone or in combination. They are optionally used when preparing the pharmaceutical composition or pharmaceutical preparation.

[0014] The bosutinib tablet of the present invention is in the form of a regular tablet, an orally disintegrating tablet, etc. It may be a film-coated tablet with a coating film containing a suitable coating agent and an optional plasticizer, light-shielding agent, colorant, etc.

[0015] Examples of coating agents include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol (partially saponified), polyvinyl alcohol-polyethylene glycol-graft copolymer, ethyl acrylate-methyl methacrylate copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, etc., and it is preferable to use these alone or in combination of two or more. Hydroxypropylmethylcellulose, hydroxypropylcellulose, or polyvinyl alcohol (partially saponified) is preferred, and polyvinyl alcohol (partially saponified) is more preferred. The coating agent is preferably used in an amount of 0.1% by mass to 10% by mass, more preferably 0.2% by mass to 5% by mass, based on the total weight of the pharmaceutical tablet.

[0016] Examples of the plasticizer include triacetin, triethyl citrate, glycerin, propylene glycol, macrogol, polysorbate, D-sorbitol, and liquid paraffin, and it is preferable to use these alone or in combination of two or more. Macrogol is preferable, and examples of the plasticizer include Macrogol 4000 and Macrogol 6000. From the viewpoint of moisture absorption resistance, it is preferable to use Macrogol 6000. When a plasticizer is used, it is preferably used in an amount of 0.01% by mass to 2% by mass, more preferably 0.02% by mass to 2% by mass, based on the total weight of the pharmaceutical tablet.

[0017] Examples of light-shielding agents and colorants include titanium oxide, ferric oxide, talc, yellow ferric oxide, yellow ferric oxide, black ferric oxide, zinc oxide, brown ferric oxide, edible yellow dyes, edible blue dyes, edible red dyes, etc. Titanium oxide and ferric oxide are preferred. When a light-shielding agent or coloring agent is used, it is preferable to use it in an amount of 0.001% by mass or more and 2% by mass or less, and more preferably 0.002% by mass or more and 2% by mass or less, based on the total amount of the pharmaceutical tablet.

[0018] The method for producing bosutinib tablets of the present invention comprises the following steps: (Step A) Preparing a composition comprising bosutinib, an excipient, and a disintegrant. (Step B) A step of preparing a granulated product by wet granulation of a wet composition prepared by adding a granulation liquid to the composition prepared by Step A. The solvent in the granulation liquid is added in an amount of 30 to 40 parts by mass per 100 parts by mass of the wet composition. (Step C) A step of compressing and molding the granulated product from Step B to prepare pharmaceutical tablets. Optionally, (Step D) the pharmaceutical tablet obtained in Step C is subjected to a coating treatment to prepare a film-coated tablet. Each step will be described below.

[0019] (Step A) is a step of preparing a composition containing the active ingredient bosutinib (hydrate), an excipient, and a disintegrant, in which each component is added in a predetermined amount to prepare a uniform mixture. The mixing may be performed using a stirring granulator, a fluidized bed granulator, a V-type mixer, or the like. Here, a binder, a colorant, a fluidizing agent, a stabilizer, a preservative, or a flavoring agent may be added. The mixing may be performed as long as it is visually confirmed that each component is a uniform mixed composition.

[0020] (Step B) is a step of preparing a granulated product by adding a granulation liquid to the composition of step A to prepare a wet composition, and wet granulating the composition. The granulation liquid may be a solution containing a solubilizer and / or a binder. The granulation liquid may be a volatile solvent, such as water, methanol, ethanol, or acetone. An aqueous solvent containing water is preferred, and the granulation liquid is preferably an aqueous solution containing a binder and / or a solubilizer. In this step, the amount of the solvent in the granulation liquid is 30 parts by mass or more and 40 parts by mass or less relative to 100 parts by mass of the wet composition obtained by adding the granulation liquid to the composition in step A. If the amount of the solvent added in the granulation liquid is less than 30 parts by mass, the active ingredient dissolution of the tablet prepared will be low. On the other hand, if the amount of the solvent added in the granulation liquid is more than 40 parts by mass, granulation with an appropriate particle distribution will not be achieved, and the operability of the subsequent formulation process will be reduced. The amount of the solvent in the granulation liquid is preferably 30 parts by mass or more and 38 parts by mass or less relative to 100 parts by mass of the wet composition.

[0021] The granules are prepared by wet granulation, in which a granulation liquid is added to a mixture of formulation ingredients and mechanical granulation is performed. Granulation causes each ingredient, such as bosutinib, excipients, binders, and disintegrants, to adhere to each other, producing granules with a certain particle size distribution. Examples of the granulation procedure include rolling granulation, fluidized bed granulation, stirring granulation, extrusion granulation, etc. In the present invention, the stirring granulation method is preferred. After the wet granulation operation, the prepared granules are dried. Drying is performed at 40 to 80°C, and the drying is terminated when the mass loss of the granules is 1 to 10%. The mass loss of the granules is preferably 1 to 4%. The drying operation can be performed using a permeation dryer, a fluidized bed dryer, or the like.

[0022] After the granulation operation, it is preferable to carry out a sieving operation to adjust the particle size of the obtained granulated product. The sieving operation is preferably a method of passing through a screen. In the present invention, it is preferable to carry out sieving by passing through a 1 to 5 mm screen. The granules used in the present invention preferably have a 30 mesh sieve passing rate of 25% or less and a 200 mesh sieve passing rate of 20% or less, and more preferably have a 30 mesh sieve passing rate of 20% or less and a 200 mesh sieve passing rate of 15% or less.

[0023] (Step C) is a step of compressing and molding the granulated product from step B to prepare a pharmaceutical tablet. It is preferable to add a lubricant to the granulated product as a post-added component. Also, an excipient or a disintegrant may be added as a post-added component. Alternatively, any component such as a colorant, a flow agent, a stabilizer, a preservative, or a flavoring agent may be added. The granulated product, the lubricant, and any post-added components are mixed, and the mixture is molded into a tablet shape by tableting or the like to prepare a pharmaceutical tablet.

[0024] (Step D) is a step of preparing a film-coated tablet by applying a coating treatment to the pharmaceutical tablet obtained by step C. The film-coated tablet can be prepared by dissolving or suspending a coating agent and an optional plasticizer, light-shielding agent, colorant, etc. in an aqueous solvent to prepare an aqueous solution of the coating agent, attaching it to the tablet surface by spraying, etc., and drying the tablet surface by blowing hot air to remove the solvent. The solvent may be removed under reduced pressure to volatilize the aqueous solvent and dry the tablet. The aqueous solvent is a solvent containing water, and may be water alone or a mixed solvent of water and a water-miscible organic solvent. Examples of the water-miscible organic solvent include ethanol and acetone.

[0025] The present invention is a method for producing a pharmaceutical tablet that ensures proper dissolution of bosutinib. After oral ingestion, bosutinib is a drug in which the active ingredient is dissolved and absorbed, and a predetermined amount is delivered to the diseased site to exert its medicinal effect. In a dissolution test using a pH 5.0 solution, bosutinib desirably has a dissolution rate of 55 to 85% in 15 minutes, and more preferably a dissolution rate of 65 to 75%. The bosutinib tablet produced by the production method of the present invention exhibits proper dissolution, and can be a pharmaceutical preparation that ensures the desired medicinal effect. EXAMPLES

[0026] The present invention will be further described below with reference to examples, although the present invention is not limited to these examples.

[0027] [Example 1] Preparation of tablets with a solvent addition rate of 31% A polyoxyethylene (160) polyoxypropylene (30) glycol solution was prepared by dissolving 3.5 mg of polyoxyethylene (160) polyoxypropylene (30) glycol in 64.4 mg of purified water per tablet. The contents per tablet were 103.4 mg of bosutinib hydrate, 24.8 mg of crystalline cellulose, 7.2 mg of croscarmellose sodium, and 4.3 mg of povidone, and 67.9 mg of polyoxyethylene (160) polyoxypropylene (30) glycol solution was added per 139.7 mg of the mixture, followed by stirring and granulation. The resulting granules were wet-sized using a granulator, and then dried at 50°C. The dried granules were dry-sized using a granulator, and then mixed in a ratio of 1.4 mg of magnesium stearate per 143.2 mg of the sized granules, followed by tableting to prepare the tablets according to Example 1.

[0028] [Example 2] Preparation of tablets with a solvent addition rate of 33% A polyoxyethylene (160) polyoxypropylene (30) glycol solution was prepared by dissolving 3.5 mg of polyoxyethylene (160) polyoxypropylene (30) glycol in 71.6 mg of purified water per tablet. The contents per tablet were 103.4 mg of bosutinib hydrate, 24.8 mg of crystalline cellulose, 7.2 mg of croscarmellose sodium, and 4.3 mg of povidone, and 75.1 mg of polyoxyethylene (160) polyoxypropylene (30) glycol solution was added per 139.7 mg of the mixture, followed by stirring and granulation. The resulting granules were wet-sized using a granulator, and then dried at 50°C. The dried granules were dry-sized using a granulator, and then mixed in a ratio of 1.4 mg of magnesium stearate per 143.2 mg of the sized granules, followed by tableting to prepare the tablets according to Example 2.

[0029] [Example 3] Preparation of tablets with a solvent addition rate of 35.5% A polyoxyethylene (160) polyoxypropylene (30) glycol solution was prepared by dissolving 3.5 mg of polyoxyethylene (160) polyoxypropylene (30) glycol in 78.8 mg of purified water per tablet. The contents per tablet were 103.4 mg of bosutinib hydrate, 24.8 mg of crystalline cellulose, 7.2 mg of croscarmellose sodium, and 4.3 mg of povidone, and 82.3 mg of polyoxyethylene (160) polyoxypropylene (30) glycol solution was added per 139.7 mg of the mixture, followed by stirring and granulation. The resulting granules were wet-sized using a granulator, and then dried at 50°C. The dried granules were dry-sized using a granulator, and then mixed in a ratio of 1.4 mg of magnesium stearate per 143.2 mg of the sized granules, followed by tableting to prepare the tablets according to Example 3.

[0030] [Comparative Example 1] Preparation of tablets Preparation of tablets with a solvent addition rate of 16.7% A polyoxyethylene (160) polyoxypropylene (30) glycol solution was prepared by dissolving 3.5 mg of polyoxyethylene (160) polyoxypropylene (30) glycol in 28.5 mg of purified water per tablet. The contents per tablet were 103.4 mg of bosutinib hydrate, 27.1 mg of crystalline cellulose, 3.6 mg of croscarmellose sodium, and 4.3 mg of povidone, and 32.0 mg of polyoxyethylene (160) polyoxypropylene (30) glycol solution was added per 138.4 mg of the mixture, followed by stirring and granulation. The resulting granules were wet-sized using a granulator, and then dried at 50°C. The dried granules were dry-sized using a granulator, and then mixed in a ratio of 1.4 mg of magnesium stearate per 141.9 mg of the sized granules, followed by tableting to prepare the tablets according to Comparative Example 1.

[0031] [Comparative Example 2] Preparation of tablets with a solvent addition rate of 28.7% A polyoxyethylene (160) polyoxypropylene (30) glycol solution was prepared by dissolving 3.5 mg of polyoxyethylene (160) polyoxypropylene (30) glycol in 57.0 mg of purified water per tablet. The contents per tablet were 103.4 mg of bosutinib hydrate, 23.5 mg of crystalline cellulose, 7.2 mg of croscarmellose sodium, and 4.3 mg of povidone, and 60.5 mg of polyoxyethylene (160) polyoxypropylene (30) glycol solution was added per 138.4 mg of the mixture, followed by stirring and granulation. The resulting granules were wet-sized using a granulator, and then dried at 50°C. The dried granules were dry-sized using a granulator, and then mixed in a ratio of 1.4 mg of magnesium stearate per 141.9 mg of the sized granules, followed by tableting to prepare the tablets according to Comparative Example 2.

[0032] [Test Example 1] Dissolution test at pH 5.0, paddle method, 50 rpm The dissolution rates of the tablets of Examples 1 to 3 and Comparative Examples 1 and 2, and a commercially available bosutinib tablet (Bosulif (registered trademark) tablet 100 mg) as a control formulation were evaluated by the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method) using a McIlvaine buffer solution of pH 5.0. The test method used a dissolution tester (NTR-6600A, Toyama Sangyo Co., Ltd.) and an ultraviolet-visible spectrophotometer (UV-1900, Shimadzu Corporation, measurement wavelength 267 nm) to evaluate the dissolution rate at 15 minutes with a test liquid volume of 900 mL, a test liquid temperature of 37±0.5°C, and a paddle rotation speed of 50 rpm. The results are shown in Table 1.

[0033] TIFF2025075898000001.tif15151

[0034] From the results of Test Example 1, the dissolution rates in 15 minutes were 65-75% in Examples 1 to 3, which were equivalent to the performance of existing bosutinib tablets. In contrast, the tablets in Comparative Examples 1 and 2 had physical properties that did not achieve the appropriate dissolution property of bosutinib.

[0035] [Test Example 2] Japanese Pharmacopoeia Disintegration Test The tablets of Examples 1 to 3 and Comparative Examples 1 and 2, and a commercially available bosutinib tablet (Bosulif (registered trademark) tablet 100 mg) as a control formulation were evaluated for disintegration time by the Japanese Pharmacopoeia disintegration test. The disintegration time was evaluated using a disintegration tester (NT-20HS model, manufactured by Toyama Sangyo Co., Ltd.) The results are shown in Table 2.

[0036] [Table 2] TIFF2025075898000002.tif15151

[0037] As a result of the tablet disintegration time in Test Example 2, Examples 1 to 3 showed rapid disintegration within 7 minutes. In contrast, the tablets in the Comparative Example disintegrated slowly, which was disadvantageous for proper dissolution of the active ingredient.

Claims

1. A method for producing a pharmaceutical tablet containing bosutinib as an active ingredient, comprising the steps of: (A) preparing a composition comprising bosutinib, an excipient, and a disintegrant; (B) adding a granulation liquid to the composition to prepare a wet composition, and wet granulating the wet composition to prepare a granulated product, A step in which the solvent in the granulation liquid is added in an amount of 30 parts by mass or more to 40 parts by mass or less based on 100 parts by mass of the wet composition; (C) compressing the granules to prepare a pharmaceutical tablet; A method for producing a pharmaceutical tablet comprising the steps of:

2. The method for producing pharmaceutical tablets according to claim 1, wherein in step (B), granulation is carried out after wet granulation and before drying.

3. The method for producing pharmaceutical tablets according to claim 1, wherein in step (B), the granulated product has a 30 mesh sieve passing rate of 25% or less and a 200 mesh sieve passing rate of 20% or less.

4. The method for producing a pharmaceutical tablet according to claim 1, wherein in step (C), a lubricant is added but no disintegrant is added.

5. The method for producing a pharmaceutical tablet according to claim 1, wherein in step (A), bosutinib is applied in an amount such that the content of the bosutinib in the pharmaceutical tablet is 65% by mass or more.

Images