JP7633786B2 - Pharmaceutical tablets containing sunitinib malate as the active ingredient - Google Patents

Description

The present invention relates to a pharmaceutical tablet containing sunitinib malate as an active ingredient and exhibiting a dissolution behavior similar to that of Sutent (registered trademark) capsules.

Sunitinib malate is a compound with the chemical name N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide mono[(2S)-2-hydroxysuccinate] and the structure shown in formula (1).

Sunitinib is a novel kinase inhibitor that targets multiple receptor tyrosine kinases (RTKs). In vitro studies have shown that sunitinib inhibits the RTK activity of platelet-derived growth factor receptors (PDGFR-α and PDGFR-β), vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, and VEGFR-3), stem cell factor receptor (KIT), fms-like tyrosine kinase 3 (FLT3), colony-stimulating factor-1 receptor, and glial cell line-derived neurotrophic factor receptor, and also inhibits phosphorylation of PDGFR-β, VEGFR-2, KIT, and FLT3 in tumors in vivo. Furthermore, non-clinical pharmacological studies have suggested that sunitinib has direct antitumor activity against various solid cancers and tumor angiogenesis inhibitory activity. Sunitinib is available as a capsule formulation under the trade name Sutent (registered trademark) (Non-Patent Publication 1).

Sunitinib formulations have been reported as hard capsules. Patent Document 1 describes a hard capsule obtained by stirring and granulating a mixture of sunitinib malate, mannitol, croscarmellose sodium, and povidone (K-25), adding croscarmellose sodium and magnesium stearate to the mixture, and filling the mixture into a capsule. Patent Document 2 describes a hard capsule obtained by stirring and granulating a mixture of sunitinib malate, mannitol, croscarmellose sodium, povidone (K-25), and hydroxypropyl methylcellulose, adding magnesium stearate to the mixture, and filling the mixture into a gelatin capsule.

Sutent (registered trademark) Capsule 12.5 mg Package Insert (Revised October 2019, 1st edition)

Special table number 2006-503032 European Patent Application No. 3539536

Capsules are generally considered to be a dosage form that tends to be difficult to swallow. For this reason, the development of a tablet of sunitinib that is also easy to swallow is desirable. However, when making the tablet, it is required that the tablet exhibits dissolution properties equivalent to those of existing sunitinib formulations. The object of the present invention is to provide a pharmaceutical tablet containing sunitinib malate as an active ingredient, and to provide a pharmaceutical tablet that exhibits dissolution behavior similar to that of Sutent (registered trademark) capsules.

The present inventors have discovered that by forming sunitinib malate into a pharmaceutical tablet with a sunitinib malate content of 4% by mass or more and 15% by mass or less, it is possible to provide a pharmaceutical tablet that exhibits a dissolution behavior similar to that of Sutent (registered trademark) capsules, and have completed the present invention. That is, the gist of the present invention is as follows: [1] to [5].

[1] A pharmaceutical tablet comprising sunitinib malate and an excipient, wherein the content of sunitinib malate in the pharmaceutical tablet mass is 4% by mass or more and 15% by mass or less.
By making the sunitinib malate content in the pharmaceutical tablet 4% by mass or more and 15% by mass or less, the dissolution of the active ingredient can be effectively controlled, and it is possible to provide a pharmaceutical tablet that exhibits dissolution behavior similar to that of Sutent (registered trademark) capsules.
[2] The pharmaceutical tablet according to [1], wherein the content of the excipient is 73% by mass or more and 93% by mass or less of the pharmaceutical tablet mass.
In the present invention, by preparing a pharmaceutical tablet containing an appropriately large amount of excipient, it becomes possible to more preferably control the dissolution properties.
[3] The pharmaceutical tablet according to [1] or [2], wherein the content of the disintegrant is 2% by mass or more and 9% by mass or less based on the mass of the pharmaceutical tablet.
[4] The pharmaceutical tablet according to any one of [1] to [3], wherein the content of the binder is 1% by mass or more and 8% by mass or less based on the mass of the pharmaceutical tablet.
[5] The pharmaceutical tablet according to any one of [1] to [4], which is film-coated.

The pharmaceutical tablet of the present invention can provide a pharmaceutical tablet that exhibits a dissolution behavior similar to that of Sutent (registered trademark) capsules.

The present invention is a pharmaceutical tablet containing sunitinib as an active ingredient, and the content of sunitinib malate is 4% by mass or more and 15% by mass or less. The details are described below.

The pharmaceutical tablet of the present invention uses sunitinib malate as an active ingredient. Sunitinib malate is a compound with the chemical name N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide mono[(2S)-2-hydroxysuccinate]. This compound is disclosed in Japanese Patent No. 3663382 and can be synthesized by the method described therein.

Sunitinib malate has multiple crystal polymorphs. Representative examples include I-type and II-type crystal polymorphs, which are disclosed in Japanese Patent Publication No. 4159988. I-type crystal polymorphs are characterized by peaks at 2θ (°) of approximately 11.39, 11.90, 13.16, 15.92, 16.79, 17.18, 19.40, 20.30, 21.26, 21.68, 22.13, 22.91, 24.17, 25.46, 26.06, 26.96, 27.56, 32.27, 32.93, and 34.43 in powder X-ray crystal diffraction (XRD). The Form II polymorph is characterized by powder X-ray diffraction (XRD) peaks at approximately 3.02, 5.93, 7.61, 9.26, 12.08, 14.54, 17.54, 19.46, 23.36, 24.77, and 27.71 degrees 2θ.
In the present invention, the active ingredient sunitinib malate can be used without any problem as long as it has the quality required for use as a pharmaceutical drug. The crystal polymorphism is not particularly limited and can be applied. Preferably, the I-type crystal polymorphism is applied.
The active ingredient, sunitinib malate, is preferably used in an amount of 4% by mass to 15% by mass, more preferably 6% by mass to 15% by mass, based on the total weight of the pharmaceutical tablet.
In this application, the pharmaceutical tablet refers to a formulation type distributed on the market, and may be a plain tablet or a film-coated tablet. Film-coated tablets are preferable. In the case of film-coated tablets, the content of each component is set based on the total mass including the coating layer.

The pharmaceutical tablet of the present invention contains an excipient. Examples of the excipient include sugars such as mannitol, lactose, maltose, sucrose, sorbitol, xylitol, and inositol, starches such as corn starch, and crystalline cellulose, and it is preferable to use these alone or in combination of two or more. It is preferable to use sugars, and it is preferable to not contain starches and crystalline cellulose. As the sugar, mannitol and/or lactose are preferable.
When an excipient is used, it is preferably used in an amount of 73% by mass or more and 93% by mass or less, more preferably 75% by mass or more and 90% by mass or less, and even more preferably 75% by mass or more and 85% by mass or less, based on the total weight of the pharmaceutical tablet.
The excipient is preferably used in an amount of 5 parts by mass or more and 20 parts by mass or less, more preferably 5 parts by mass or more and 15 parts by mass or less, and even more preferably 5 parts by mass or more and 10 parts by mass or less, relative to 1 part by mass of sunitinib malate.

To prepare the tablet, conventional pharmaceutical additives for preparing pharmaceutical preparations, such as disintegrants, binders, lubricants, colorants, solubilizers, flow agents, stabilizers, preservatives, etc., may be used.
Examples of disintegrants include croscarmellose sodium, carboxymethyl starch sodium, crospovidone, carmellose, carmellose sodium, carmellose calcium, low-substituted carboxymethyl starch sodium, etc., and it is preferable to use these alone or in combination of two or more. Preferably, it is one or more selected from the group consisting of croscarmellose sodium, carboxymethyl starch sodium, and crospovidone. More preferably, it is croscarmellose sodium and/or carboxymethyl starch sodium.
When a disintegrant is used, it is preferably used in an amount of 1% by mass to 10% by mass, more preferably 2% by mass to 9% by mass, and even more preferably 3% by mass to 8% by mass, based on the total weight of the pharmaceutical tablet.
The disintegrant is preferably used in an amount of 0.30 to 1.00 parts by mass relative to 1 part by mass of sunitinib malate. More preferably, the amount is 0.30 to 0.70 parts by mass. More preferably, in relation to the excipient content, the disintegrant is used in an amount of 0.30 to 0.70 parts by mass relative to 1 part by mass of sunitinib malate, and the excipient is used in an amount of 5 to 10 parts by mass relative to 1 part by mass of sunitinib malate.

Examples of the binder include povidone, hydroxypropyl cellulose, copolyvidone, hydroxypropyl methylcellulose, partially pregelatinized starch, polyvinyl alcohol, etc., and these are preferably used alone or in combination of two or more. Preferably, one or more selected from the group consisting of povidone and hydroxypropyl cellulose are used.
The standard of povidone is generally defined by the K value, which is a viscosity characteristic value that correlates with the molecular weight. It is preferable to use K-25 and/or K-30. Examples of the povidone include Kollidon (BASF Corporation), which is available in grades 25 and 30, and it is preferable to use these.
When a binder is used, it is preferably used in an amount of 1% by mass to 10% by mass, more preferably 1% by mass to 8% by mass, and even more preferably 1% by mass to 7% by mass, based on the total weight of the pharmaceutical tablet.
The binder is preferably used in an amount of 0.10 to 0.80 parts by mass relative to 1 part by mass of sunitinib malate. More preferably, the binder is used in an amount of 0.20 to 0.70 parts by mass relative to 1 part by mass of sunitinib malate. More preferably, in relation to the excipient content, the binder is used in an amount of 0.20 to 0.70 parts by mass relative to 1 part by mass of sunitinib malate, and the excipient is used in an amount of 5 to 10 parts by mass relative to 1 part by mass of sunitinib malate.

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 10% by mass, more preferably 0.2% by mass to 5% by mass, based on the total weight of the pharmaceutical tablet.

The formulation additives may also include colorants, solubilizers, fluidizing agents, stabilizers, preservatives, and the like.
Examples of coloring agents include titanium oxide, ferric oxide, talc, yellow ferric oxide, yellow ferric oxide, black ferric oxide, brown ferric oxide, zinc oxide, edible yellow dyes, edible blue dyes, edible red dyes, and the like.
Examples of solubilizers include sodium lauryl sulfate, soybean lecithin, refined soybean lecithin, sorbitan fatty acid ester, soybean oil, lauromacrogol, and the like.
The fluidizing agent includes light anhydrous silicic acid, talc, hydrous silicon dioxide, and the like.
The stabilizer may include dibutylhydroxytoluene, tocopherol, sulfite, and the like.
Examples of preservatives include paraoxybenzoic acid esters.

These additives can be used without any particular restrictions as long as they have a purity acceptable for use in pharmaceutical formulations. These additives may be used alone or as a mixture.

The pharmaceutical tablet of the present invention can be obtained by mixing sunitinib malate with additives such as excipients and directly compressing the mixture, but can also be obtained by compressing granules prepared by stirring granulation, fluidized bed granulation, extrusion granulation, dry granulation, or the like.
The method for preparing the granulated product includes agitation granulation, or fluidized bed granulation, in which sunitinib malate and excipients, and any of the additives are mixed, water and/or an organic solvent are added thereto, granulated, dried, sized if necessary, and then appropriately sieved if necessary to obtain a granulated product. Alternatively, an extrusion granulation method includes mixing sunitinib malate and any of the additives, adding water and/or an organic solvent thereto, kneading, granulating, drying, sized if necessary, or sized if necessary, dried, and then appropriately sieved if necessary to obtain a granulated product. The agitation granulation method, fluidized bed granulation method, and extrusion granulation method are generally called wet granulation methods because they are granulated by adding water and/or an organic solvent. In the wet granulation method, a solution containing a binder may be used as the water and/or organic solvent.
Alternatively, a dry granulation method can be used in which sunitinib malate and any of the above-mentioned additives are mixed, compressed, sized if necessary, and then appropriately sieved to obtain a granule.
The pharmaceutical tablet of the present invention is preferably a tablet obtained by preparing a granulation product and molding the granulation product, more preferably a pharmaceutical tablet obtained by preparing a granulation product by wet granulation of a mixture containing sunitinib malate, an excipient, a disintegrant, and a binder, and molding the granulation product.

The pharmaceutical tablet of the present invention is prepared by mixing sunitinib malate as an active ingredient and an excipient together with other additives such as disintegrants, binders, lubricants, and other formulation additives, and molding the mixture. Examples of molding methods include rotary tableting and single shot tableting. The formulation may be in any form, such as bare tablets, film-coated tablets, dispersible tablets, orally disintegrating tablets, chewable tablets, and effervescent tablets.

Film-coated tablets can be prepared by dissolving or suspending a coating agent containing additives such as titanium oxide, ferric oxide, and optional additives such as plasticizers in water or an aqueous solvent containing an organic solvent that can be mixed with water in any ratio, on a plain tablet that is not coated with the film, preparing an aqueous solution of the coating agent, applying the solution to the tablet surface by a spray or the like, and blowing hot air to remove the solvent from the tablet surface and dry it.

Examples of coating agents include hydroxypropylmethylcellulose, polyvinyl alcohol, hydroxypropylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, hydroxypropylmethylcellulose phthalate, ethylcellulose, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, 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 kinds. Hydroxypropylcellulose and polyvinyl alcohol are preferred.
When a coating agent is used, it 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.

Examples of colorants include titanium oxide, ferric oxide, talc, yellow ferric oxide, yellow ferric oxide, black ferric oxide, brown ferric oxide, zinc oxide, edible yellow dyes, edible blue dyes, edible red dyes, etc., and these are preferably used alone or in combination of two or more kinds. Titanium oxide and ferric oxide are preferred.
When a colorant is used, it is preferably used in an amount of 0.01% by mass to 4% by mass, more preferably 0.02% by mass to 2% by mass, based on the total weight of the pharmaceutical tablet.

Examples of plasticizers include triacetin, triethyl citrate, glycerin, propylene glycol, polyethylene glycol, polysorbate, D-sorbitol, liquid paraffin, etc., and it is preferable to use these alone or in combination of two or more. When using a plasticizer, it is preferable to use it in an amount of 0.01% by mass to 4% by mass of the total weight of the pharmaceutical tablet. It is preferably 0.02% by mass to 2% by mass.

The pharmaceutical formulation of the present invention is in the form of a tablet, typically a tablet or an orally disintegrating tablet. That is, the pharmaceutical tablet of the present invention is a tablet prepared by mixing sunitinib malate and an excipient as the active ingredient together with any other additives such as disintegrants, binders, lubricants, and other formulation additives, and molding the mixture.

The pharmaceutical tablet of the present invention exhibits dissolution properties similar to those of existing sunitinib malate preparations, i.e., it is characterized in that it is a pharmaceutical tablet exhibiting a dissolution behavior similar to that of Sutent (registered trademark) capsules.
The dissolution similarity of the pharmaceutical tablet of the present invention with the existing capsule formulation can be confirmed by a normal dissolution test method. As an example of the dissolution test method, the aqueous solution of pH 6.8 in the dissolution test is preferably prepared by the method described in the Japanese Pharmacopoeia. Then, using 900 mL of the test solution, the active ingredient is dissolved from the pharmaceutical tablet of the present invention and the existing capsule formulation into the test solution by the Japanese Pharmacopoeia dissolution test method 2 (paddle method), and the dissolution rate into the test solution is evaluated using an ultraviolet-visible spectrophotometer or liquid chromatography, thereby confirming the dissolution similarity with the existing capsule formulation, which is a feature of the present invention.

The present invention will be further explained below with reference to examples. However, the present invention is not limited to these examples.

[Example 1]
The contents per tablet were 16.7 mg of sunitinib malate, 143.4 mg of mannitol, 8.7 mg of croscarmellose sodium, and 5.2 mg of povidone (K-25), and 40 μL of purified water was added to the mixture, followed by stirring and granulation. The resulting granules were dried at 60° C. for 1 hour. The tablets according to Example 1 were prepared by mixing and tableting 1.8 mg of magnesium stearate per 174 mg of the granules.

[Example 2]
The contents per tablet were mixed at a ratio of 16.7 mg sunitinib malate, 123.3 mg mannitol, 7.6 mg croscarmellose sodium, and 4.7 mg povidone (K-25), and 30 μL of purified water was added to the mixture, followed by stirring and granulation. The resulting granules were dried at 60° C. for 1 hour. The tablets according to Example 2 were prepared by mixing and tableting 1.5 mg magnesium stearate per 152.3 mg of the granules.

[Example 3]
The contents per tablet were mixed at a ratio of 16.7 mg sunitinib malate, 103.5 mg mannitol, 6.5 mg croscarmellose sodium, and 3.9 mg povidone (K-25), and 25 μL of purified water was added to the mixture, followed by stirring and granulation. The resulting granules were dried at 60° C. for 1 hour. The tablets according to Example 3 were prepared by mixing and tableting 1.3 mg magnesium stearate per 130.6 mg of the granules.

[Example 4]
The contents per tablet were mixed at a ratio of 16.7 mg sunitinib malate, 93.4 mg mannitol, 6.0 mg croscarmellose sodium, and 3.6 mg povidone (K-25), and 10 μL of purified water was added to the mixture, followed by stirring and granulation. The resulting granules were dried at 60° C. for 1 hour. The tablets according to Example 4 were prepared by mixing and tableting 1.2 mg magnesium stearate per 119.7 mg of the granules.

[Example 5]
Tablets of Example 5 were prepared in the same manner as in Example 1, except that 5.2 mg of povidone (K-25) was changed to 5.2 mg of povidone (K-30).

[Example 6]
The contents per tablet were mixed at a ratio of 16.7 mg sunitinib malate, 138.0 mg mannitol, 10.5 mg croscarmellose sodium, and 8.8 mg povidone (K-25), and 40 μL of purified water was added to the mixture, followed by stirring and granulation. The resulting granules were dried at 60° C. for 1 hour. The tablets according to Example 6 were prepared by mixing and tableting 1.8 mg magnesium stearate per 174 mg of the granules.

[Example 7]
The tablets obtained in Example 1 were film-coated with 2.5 mg of hydroxypropylmethylcellulose, 0.3 mg of titanium oxide, and 0.2 mg of ferric oxide per tablet to prepare film-coated tablets according to Example 7.

[Example 8]
The tablets obtained in Example 1 were film-coated with 5.1 mg of hydroxypropylmethylcellulose, 0.7 mg of titanium oxide, and 0.5 mg of ferric oxide per tablet to prepare film-coated tablets according to Example 8.

[Example 9]
The tablets obtained in Example 1 were film-coated with 2.5 mg of polyvinyl alcohol, 0.3 mg of titanium oxide, and 0.2 mg of ferric oxide per tablet to prepare film-coated tablets according to Example 9.

[Example 10]
The tablets obtained in Example 1 were film-coated with 5.1 mg of polyvinyl alcohol, 0.7 mg of titanium oxide, and 0.5 mg of ferric oxide per tablet to prepare film-coated tablets according to Example 10.

As comparative examples to demonstrate the characteristics of the present invention, tablets according to the formulation in Example 4 and tablets according to the formulation in Example 3 were set as Comparative Examples 1 and 2, with reference to the formulation examples described in JP-T 2006-503032.

[Comparative Example 1]
The contents per tablet were 16.7 mg of sunitinib malate, 80 mg of mannitol, 6.6 mg of croscarmellose sodium, and 5.6 mg of povidone (K-25), and 30 μL of purified water was added to the mixture and stirred for granulation. The resulting granules were dried at 60° C. for 1 hour. The tablets according to Comparative Example 1 were prepared by mixing 1.1 mg of magnesium stearate per 108.9 mg of the granules and compressing the mixture.

[Comparative Example 2]
The contents per tablet were 16.7 mg sunitinib malate, 19.3 mg mannitol, 2.5 mg croscarmellose sodium, and 2.1 mg povidone (K-25), mixed in a ratio of 10 μL purified water per tablet, and stirred and granulated. The resulting granules were dried at 60° C. for 1 hour. The tablets according to Comparative Example 2 were prepared by mixing 0.6 mg magnesium stearate per 40.6 mg of the granules and compressing the mixture.

[Test Example 1]
The dissolution rates of the tablets of Examples 1 to 10 and Comparative Examples 1 and 2, and the Sutent (registered trademark) capsule were evaluated by the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle method) using a test solution of pH 6.8 prepared by the method described in the Japanese Pharmacopoeia.
The dissolution rate was evaluated using a dissolution tester (NTR-6200A, manufactured by Toyama Sangyo Co., Ltd.) and an ultraviolet-visible spectrophotometer (UV-1700, manufactured by Shimadzu Corporation) 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 time points and dissolution rates used to judge the similarity of dissolution to Sutent capsules and their judgments are summarized in Table 1.

The pharmaceutical tablets of Examples 1 to 10 had dissolution rates within the range of ±15% at 15 minutes and 90 minutes compared to the existing formulation, Sutent (registered trademark) capsule, and were judged to be similar. On the other hand, the comparative example was judged to be dissimilar, as it was not possible to suppressively control the dissolution, especially at the initial stage. In other words, the present invention is a pharmaceutical tablet that shows a dissolution behavior similar to that of the existing capsule formulation, and the present invention can provide a pharmaceutical formulation that is excellent in swallowability and makes it easy to take medicine.

Claims (2)

A pharmaceutical tablet comprising sunitinib malate, excipients, a disintegrant and a binder,
The content of sunitinib malate in the pharmaceutical tablet mass is 4% by mass or more and 15% by mass or less;
The content of the excipient is 75% by weight or more and 90% by weight or less in the pharmaceutical tablet mass;
The content of the disintegrant is 2% by mass or more and 9% by mass or less based on the mass of the pharmaceutical tablet;
The content of the binder is 1% by weight or more and 8% by weight or less based on the weight of the pharmaceutical tablet;
The excipient is 5 parts by mass or more and 20 parts by mass or less relative to 1 part by mass of sunitinib malate;
Pharmaceutical tablets. 2. The pharmaceutical tablet of claim 1, which is film-coated.