Bosutinib pharmaceutical preparation

Abstract

To provide a pharmaceutical product containing bosutinib as an active ingredient, which minimizes change in dissolution of the active ingredient with the passage of storage time, ensuring excellent storage stability.SOLUTION: Provided is a pharmaceutical product wherein a pharmaceutical preparation containing bosutinib as an active ingredient is packaged in a packaging material having a water vapor transmission rate of 1.00 g / m2 24hr or less. A preferred embodiment of the present invention has a change rate of 5% or less in a dissolution test at pH 5.0 after storage at 40°C and 75% RH for 3 months, thereby preventing deterioration in quality even after storage.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a medicine including 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 Publication No. 2015-12063 Summary of the Invention [Problem to be solved by the invention]

[0005] As a result of investigations conducted by the present inventors, it was found that bosutinib tablets have physical properties such that the dissolution property of the active ingredient is significantly reduced by moisture absorption. An object of the present invention is to provide a pharmaceutical product containing bosutinib as an active ingredient, which has excellent storage stability and in which the dissolution properties of the active ingredient change little even over the course of storage. [Means for solving the problem]

[0006] The present application discloses an invention the gist of which is to package bosutinib in a moisture-proof packaging material in order to suppress a decrease in dissolution property of bosutinib after storage. [1] A pharmaceutical formulation containing bosutinib as an active ingredient was tested in a container with a moisture permeability of 1.00 g / m 2 Medicines packaged in packaging materials lasting less than 24 hours. [2] The pharmaceutical composition according to [1], wherein the packaging is a PTP package. [3] The pharmaceutical described in [1] or [2], wherein the packaging is a combination of PTP packaging and aluminum pillow. [4] The pharmaceutical preparation according to any one of [1] to [3], wherein the pharmaceutical preparation containing bosutinib as an active ingredient is a film-coated tablet containing polyvinyl alcohol (partially saponified) and macrogol 6000. [5] The pharmaceutical preparation according to any one of [1] to [4], wherein the pharmaceutical preparation containing bosutinib as an active ingredient is a tablet containing crystalline cellulose and the crystalline cellulose is contained in an amount of 20 mass% or less in the pharmaceutical tablet. [6] The pharmaceutical preparation according to any one of [1] to [5], wherein the pharmaceutical preparation containing bosutinib as an active ingredient is a tablet containing bosutinib monohydrate as an active ingredient, and the bosutinib monohydrate is contained in an amount of 65% by mass or more in the pharmaceutical tablet. Effect of the Invention

[0007] The pharmaceutical of the present invention exhibits little change in dissolution properties of bosutinib even after storage, and can provide a pharmaceutical product with excellent storage stability. 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 based on the total amount of the pharmaceutical preparation. Preferably, it is 65% by mass or more and 75% by mass or less. Preferably, it contains bosutinib monohydrate as an active ingredient, and the bosutinib monohydrate content is preferably 60% by mass or more and 80% by mass or less based on the total amount of the pharmaceutical preparation. Preferably, it is 65% by mass or more and 75% by mass or less.

[0009] The pharmaceutical preparation containing bosutinib as an active ingredient is a preparation that can be orally administered, and examples of such preparations include tablets, capsules, granules, powders, etc., and it is preferable to apply tablets. It is preferable to apply film-coated tablets with a coating film containing a suitable coating agent and any plasticizer, light-shielding agent, colorant, etc.

[0010] 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.

[0011] Examples of the plasticizer include triacetin, triethyl citrate, glycerin, propylene glycol, macrogol, polysorbate, D-sorbitol, liquid paraffin, etc., and it is preferable to use these alone or in combination of two or more. Macrogol is preferable, and examples of such are 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.

[0012] 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.

[0013] The bosutinib tablet is preferably a film-coated tablet containing polyvinyl alcohol (partially saponified) and macrogol 6000. The manufacturing process for film-coated tablets involves dissolving or suspending the coating agent and any plasticizers, light-blocking agents, colorants, etc. in an aqueous solvent to prepare an aqueous solution of the coating agent, which is then applied to the tablet surface by spraying or the like, and hot air is then blown in to remove the solvent from the tablet surface, followed by drying. 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, such as ethanol or acetone.

[0014] Preferably, the bosutinib tablet contains an excipient, a disintegrant, a binder, a solubilizer, and a lubricant.

[0015] 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.

[0016] 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.

[0017] 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 in an amount of 0.5% by mass to 10% by mass, more preferably 1% by mass to 5% by mass, based on the total weight of the pharmaceutical tablet.

[0018] Solubilizers include sodium lauryl sulfate, soybean lecithin, refined soybean lecithin, sorbitan fatty acid esters, soybean oil, lauromacrogol, polyoxyethylene-polyoxypropylene-polyoxyethylene block copolymers, etc. Polyoxyethylene-polyoxypropylene-polyoxyethylene block copolymers (poloxamer 188) are 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.

[0019] 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.

[0020] 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.

[0021] Bosutinib tablets can be prepared in the following manner. (1) adding and mixing bosutinib (hydrate), excipients, disintegrants, and other optional ingredients; (2) adding a granulation liquid to wet-granulate the mixture of (1) to prepare a granule; (3) A process of mixing the granules of (2) with a lubricant and compressing the mixture to prepare tablets. (4) A step of applying a coating solution containing a coating agent, a plasticizer, and a light-shielding agent to the tablet of (3) and drying the solution to prepare a film coating agent; In the above-mentioned manufacturing method, a binder and / or a solubilizer may be included in step (1). The granulation liquid in step (2) may be a liquid containing a binder and / or a solubilizer. The granulation liquid may be a volatile solvent, such as water, methanol, ethanol, acetone, etc. An aqueous solvent containing water is preferred, and an aqueous solution containing a binder and / or a solubilizer is preferred. In step (3), the excipient and disintegrant may be divided into two in step (1), and the remainder from step (1) may be added in step (3) as a final powder.

[0022] The present invention provides a pharmaceutical formulation containing bosutinib as an active ingredient, with a moisture permeability of 1.00 g / m 2 - Pharmaceuticals packaged in packaging materials lasting less than 24 hours Moisture permeability 1.00g / m 2 Packaging materials for 24 hours or less include packaging materials made of resin materials and / or packaging materials made of aluminum sheets. The moisture permeability is a value measured according to JIS K7129-2. Examples of the resin material include polyolefin resins such as polyethylene (PE), polypropylene (PP), and cyclic polyolefin (COC), chlorine resins such as polyvinyl chloride (PVC) and polyvinylidene chloride (PVDC), and fluorine resins such as polychlorotrifluoroethylene (PCTFE) and chlorotrifluoroethylene-ethylene copolymer (ECTFE). The resin materials may be used alone or in combination of two or more. Cyclic polyolefin (COC), polyvinylidene chloride (PVDC), and polychlorotrifluoroethylene (PCTFE) are preferred, and it is also preferred to use laminates of these with other materials such as polyvinyl chloride (PVC). Laminates of chlorine resins and fluorine resins are more preferred. Laminates containing polyvinylidene chloride (PVDC) and polyvinyl chloride (PVC), and laminates containing polychlorotrifluoroethylene (PCTFE) and polyvinyl chloride (PVC) are particularly preferred. Examples of packaging using a resin material include a film package in which the resin material sheet is shaped into a bag and sealed by heat sealing or the like, and a PTP package made by combining the resin with an aluminum sheet. A PTP package is a package in which the resin material is used as a base sheet having recessed pockets for storing pharmaceutical preparations one by one, and is sealed with an aluminum sheet. A preferred package using the resin material of the present invention is a PTP package.

[0023] The aluminum sheet packaging material may be aluminum foil, a laminate of aluminum foil and a resin layer, or an aluminum vapor deposition film. The aluminum sheet may be used to directly package pharmaceuticals, or may be used as a secondary package in which a primary package such as a PTP package is further packaged. A laminate film of a resin film and an aluminum layer is preferably used as aluminum pillow packaging. For aluminum pillow packaging, a laminate film is used in which aluminum foil is laminated or aluminum is vapor deposited on a resin film such as polyethylene, polypropylene, polyethylene terephthalate, or polyamide. Packaging with an aluminum sheet is a preferred packaging form in the present invention because the moisture permeability is extremely low, usually below the lower limit of measurement. A preferred embodiment is to package a pharmaceutical preparation in a PTP package in an aluminum pillow case. In addition, a desiccant or an oxygen scavenger may be enclosed in the aluminum pillow together with the PTP-packaged pharmaceutical preparation.

[0024] The packaging material for the bosutinib formulation has a moisture permeability of 0.50 g / m 2 -24hr or less is preferable, and 0.20g / m 2 · Packaging materials lasting 24 hours or less are preferred.

[0025] The present invention is based on the discovery of a phenomenon in which the dissolution performance of bosutinib formulations significantly decreases over the course of storage, and the clarification that this is caused by moisture absorption during storage. The present invention makes it possible to suppress changes in the dissolution performance of the active ingredient even over the course of storage, and to provide a pharmaceutical product whose efficacy is guaranteed even after storage. In a preferred embodiment of the present invention, in a dissolution test at pH 5.0 after storage at 40° C. and 75% RH for 3 months, the rate of change is 5% or less, indicating that deterioration in quality can be suppressed even after storage. 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] [Packaging materials] PVC sheet: Sumitomo Bakelite Co., Ltd., thickness 0.25 mm, moisture permeability 3.20 g / m 2 24hr PVC / PE / PVDC / PVC sheet: Sumitomo Bakelite Co., Ltd., thickness 0.25 mm, moisture permeability 0.90 g / m 2 24hr PVC / PCTFE (51 μm) sheet: Sumitomo Bakelite Co., Ltd., PVC layer 0.2 mm, PCTFE layer 0.051 mm, moisture permeability 0.15 g / m 2 24hr PVC / PCTFE (101μm) sheet (high moisture-proof): Sumitomo Bakelite Co., Ltd., PVC layer 0.15mm, PCTFE layer 0.101mm, moisture permeability 0.07g / m 2 24hr Aluminum foil for PVC: Toyo Aluminum, 0.02 mm, Aluminum gusset bag for PTP: Hosokawa Yoko, 100 x 180 mm

[0028] [Production Example 1] Preparation of uncoated tablets A polyoxyethylene (160) polyoxypropylene (30) glycol solution was prepared by dissolving 3.5 mg of polyoxyethylene (160) polyoxypropylene (30) glycol in 71 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 74.5 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 (screen diameter 4 mm) and then dried at 50°C. The dried granules were dry-sized using a granulator (screen diameter 1 mm), 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 tablets according to Production Example 1.

[0029] [Production Example 2] Preparation of coated tablets A coating liquid was prepared by adding 160 g of polyvinyl alcohol (partially saponified), 130 g of talc, 110 g of titanium oxide, 30 mg of macrogol 6000, and 5 g of yellow ferric oxide to 2500 g of purified water. The tablets obtained in Production Example 1 were coated with the coating liquid so that 5.7 mg of coating was applied per 143.3 mg of tablet to prepare coated tablets according to Production Example 2.

[0030] [Example 1] Preparation of PVC / PE / PVDC / PVC sheet packaging medicine The coated tablets obtained in Production Example 1 were packed in a PTP packaging machine using a PVC / PE / PVDC / PVC sheet (moisture permeability 0.90 g / m 2 The packaged drug of Example 1 was prepared by covering the contents filled with the drug for 10 minutes at 30° C. (100 ml) with aluminum foil for PVC.

[0031] [Example 2] Preparation of PVC / PCTFE (51μm) sheet packaging medicines In Example 1, the PVC / PE / PVDC / PVC sheet was replaced with a PVC / PCTFE (51 μm) sheet (moisture permeability 0.15 g / m 2 The packaged drug of Example 2 was prepared in the same manner except for changing the time period from 0.1 min to 24 hr.

[0032] [Example 3] Preparation of PVC / PCTFE (101μm) sheet packaging medicines In Example 1, the PVC / PE / PVDC / PVC sheet was replaced with a PVC / PCTFE (101 μm) sheet (moisture permeability 0.07 g / m 2 The packaged drug of Example 3 was prepared in the same manner except for changing the temperature of the reaction vessel to 24 hours.

[0033] [Example 4] Preparation of aluminum pillow stable packaging The coated tablets obtained in Production Example 2 were packed in a PTP packaging machine using a PVC sheet (moisture permeability 3.20 g / m 2 The contents were filled for 10 minutes (24 hours) and then wrapped in aluminum foil for PVC to prepare a PTP package. This PTP package was placed in an aluminum flared bag for PTP and then sealed to prepare the packaged drug of Example 3.

[0034] [Comparative Example 1] Preparation of PVC sheet stable packages The coated tablets obtained in Production Example 2 were packed in a PTP packaging machine using a PVC sheet (moisture permeability 3.20 g / m 2 The packaged drug of Comparative Example 1 was prepared by covering the contents filled with the drug for 10 minutes (100 ml) with aluminum foil for PVC.

[0035] [Test Example 1] Storage stability evaluation by dissolution test at pH 5.0, paddle method, 50 rpm The packaged pharmaceuticals of the coated tablets of Examples 1 to 4 and Comparative Example 1 were stored under conditions of 40° C. and 75% RH for 3 months and used as evaluation samples. The coated tablets of Production Example 2 were used as a control sample of the drug before storage (initial value). The storage stability of the examples was evaluated by evaluating the dissolution rate of the evaluation sample and the control sample using a McIlvaine buffer solution of pH 5.0 according to the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method). The test was performed using 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 30 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 of the dissolution evaluation are summarized in Table 1.

[0036] [Table 1] TIFF2025073688000001.tif21127

[0037] The dissolution rates of the Examples were within a change of -5% compared to the dissolution rate of the control coated tablets before storage (Production Example 2; initial value). On the other hand, in Comparative Example 1, the dissolution rate was reduced by 6.3% compared to the initial value of the preparation before storage. These results demonstrate that the packaged pharmaceutical product of the present invention has little reduction in dissolution rate over the course of storage and can ensure the expression of appropriate pharmacological effects over a long period of time.

Claims

1. A pharmaceutical preparation containing bosutinib as an active ingredient was placed in a container with a moisture permeability of 1.00 g / m ２ - Medicines packaged in packaging materials lasting less than 24 hours.

2. The pharmaceutical composition according to claim 1, wherein the packaging is a PTP packaging.

3. The pharmaceutical composition according to claim 1, wherein the packaging is a combination of a PTP package and an aluminum pillow.

4. The pharmaceutical preparation according to claim 1, wherein the pharmaceutical preparation containing bosutinib as an active ingredient is a film-coated tablet containing polyvinyl alcohol (partially saponified) and macrogol 6000.

5. The pharmaceutical preparation according to claim 1, which contains bosutinib as an active ingredient, is a tablet containing crystalline cellulose, and the crystalline cellulose is contained in an amount of 20 mass% or less in the pharmaceutical tablet.

6. The pharmaceutical preparation according to claim 1, wherein the pharmaceutical preparation containing bosutinib as an active ingredient is a tablet containing bosutinib monohydrate as an active ingredient, and the bosutinib monohydrate is contained in an amount of 65% by mass or more in the pharmaceutical tablet.

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