Tivozanib drug substance and method for producing same

Abstract

The present invention relates to a method for producing tivozanib hydrochloride crystalline form I and the like, the method comprising: a step A for obtaining tivozanib crystalline form II by solvent-mediated transformation of tivozanib hydrochloride crystalline form I; and a step B for obtaining tivozanib hydrochloride crystalline form I by solvent-mediated transformation of the tivozanib hydrochloride crystalline form II obtained in the step A.

Description

TITLE OF INVENTION: TIVOZANIB DRUG SUBSTANCE AND METHOD FOR PRODUCING SAME TECHNICAL FIELD

[0001] The present invention relates to a high-purity tivozanib drug substance and a method for producing the tivozanib drug substance. BACKGROUND ART

[0002] Tivozanib, which is an active ingredient of FOTIVDA (registered trademark), is known as one of VEGF receptor inhibitors. The chemical name of tivozanib is N-[2-chloro-4-(6,7-dimethoxyquinoline-4-yloxy)phenyl]-N'-(5-methyisoxazol-3-yl)urea, and the chemical structure thereof is as follows.

[0003] [Chem. 1]

[0004] 2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (hereinafter, also referred to as "DPQ"), which is a decomposition impurity of tivozanib, is positive in the Ames test (Non Patent Literature 1). Therefore, it is important to provide a high-purity tivozanib drug substance with a reduced DPQ content, from the viewpoint of safety. In addition, since tivozanib has been currently developed as an eye drop for ophthalmic diseases, it is necessary to manage DPQ, which is positive in the Ames test, as a mutagenic impurity, based on the guideline of ICH-M7. For example, the daily intake of DPQ, which is allowed in the case where the eye drop is administered for more than 10 years to a lifetime, is 1.5 ug / day.

[0005] Heretofore, tivozanib and a method for producing tivozanib have been known. (Patent Literatures 1 to 11, Non Patent Literatures 2 and 3) CITATION LIST PATENT LITERATURE

[0006] Patent Literature 1: WO2002 / 088110 Patent Literature 2: WO2004 / 035572 Patent Literature 3: WO2018 / 052053 Patent Literature 4: Chinese Patent Application Publication No. 117417336 Patent Literature 5: Chinese Patent Application Publication No. 117327061 Patent Literature 6: Chinese Patent Application Publication No. 114213404 Patent Literature 7: Chinese Patent Application Publication No. 114213405 Patent Literature 8: Chinese Patent Application Publication No. 106967058 Patent Literature 9: Chinese Patent Application Publication No. 102408418 Patent Literature 10: Chinese Patent Application Publication No. 102532116 Patent Literature 11: WO2024 / 110606 NON-PATENT LITERATURE

[0007] Non Patent Literature 1: FOTIVDA EMA Assessment report, 2017 Non Patent Literature 2: Chinese Journal of New Drugs, 2013, 22(1), pp. 26-29 Non Patent Literature 3: Chinese Journal of Pharmaceuticals, 2013, 44(6), pp. 541543 SUMMARY OF INVENTION TECHNICAL PROBLEM

[0008] However, Patent Literatures 1 to 11 and Non Patent Literatures 2 and 3 do not disclose or suggest a method for reducing a content of DPQ or the management of DPQ during production of Form I crystal of tivozanib hydrochloride.

[0009] Therefore, an object of the present invention is to provide a high-purity tivozanib drug substance containing a small amount of impurities, particularly DPQ. Another object of the present invention is to provide a novel method for producing Form I crystal of tivozanib hydrochloride. Another object of the present invention is to provide a production method for obtaining a tivozanib drug substance containing Form I crystal of tivozanib hydrochloride at a high purity. In the novel method for producing Form I crystal of tivozanib hydrochloride, it is preferable that the content of impurities such as DPQ is small when the crystal is produced as a tivozanib drug substance. SOLUTION TO PROBLEM

[0010] The present invention is as follows. [1] A method for producing Form I crystal of tivozanib hydrochloride, the method comprising: a step A of obtaining Form II crystal of tivozanib hydrochloride by subjecting Form I crystal of tivozanib hydrochloride to solvent-mediated transformation; and a step B of obtaining Form I crystal of tivozanib hydrochloride by subjecting the Form II crystal of tivozanib hydrochloride obtained in the above step A to solvent-mediated transformation. [2] A method for reducing a content of 2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (DPQ) in a tivozanib drug substance, the method comprising: a step A of obtaining Form II crystal of tivozanib hydrochloride by subjecting Form I crystal of tivozanib hydrochloride to solvent-mediated transformation; and a step B of obtaining Form I crystal of tivozanib hydrochloride by subjecting the Form II crystal of tivozanib hydrochloride obtained in the above step A to solvent-mediated transformation. [3] The method according to [1] or [2] above, in which, in the step A of obtaining Form II crystal of tivozanib hydrochloride by subjecting Form I crystal of tivozanib hydrochloride to solvent-mediated transformation, the solvent is ethanol. [4] The method according to any one of [1] to [3] above, in which, in the step A of obtaining Form II crystal of tivozanib hydrochloride by subjecting Form I crystal of tivozanib hydrochloride to solvent-mediated transformation, the Form I crystal of tivozanib hydrochloride is contained in a mixed solution, and the mixed solution has a temperature of 40°C to 60°C. [5] The method according to any one of [1] to [4] above, in which, in the step B of obtaining Form I crystal of tivozanib hydrochloride by subjecting the Form II crystal of tivozanib hydrochloride obtained in the above step A to solvent-mediated transformation, the Form II crystal of tivozanib hydrochloride is contained in the mixed solution, the step B comprises a step of adding water to the mixed solution, a content of water with respect to a mixed solvent containing water is 5 volume% or more, and the mixed solution has a temperature of 40°C to 60°C. [6] The method according to [1] or [2] above, in which, in the step A of obtaining Form II crystal of tivozanib hydrochloride by subjecting Form I crystal of tivozanib hydrochloride to solvent-mediated transformation, the solvent is ethanol, the Form I crystal of tivozanib hydrochloride is contained in a mixed solution, and the mixed solution has a temperature of 40°C to 60°C; and the step B of obtaining Form I crystal of tivozanib hydrochloride by subjecting the Form II crystal of tivozanib hydrochloride obtained in the above step A to solvent-mediated transformation comprises a step of adding water to the mixed solution, a content of water with respect to a mixed solvent containing water is 5 volume% or more, and the mixed solution has a temperature of 40°C to 60°C. [7] A tivozanib drug substance comprising a crystal of tivozanib hydrochloride or a crystal of a hydrate of tivozanib hydrochloride as an active ingredient in a content of 99.5 mass% or more. [8] A tivozanib drug substance comprising a crystal of tivozanib hydrochloride or a crystal of a hydrate of tivozanib hydrochloride as an active ingredient in a content of 99.8 mass% or more. [9] A tivozanib drug substance comprising: a crystal of tivozanib hydrochloride or a crystal of a hydrate of tivozanib hydrochloride as an active ingredient; and 2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (DPQ), in which a mass of the DPQ is 0.04% or less with respect to a mass of the tivozanib drug substance.

[10] A tivozanib drug substance comprising: a crystal of tivozanib hydrochloride or a crystal of a hydrate of tivozanib hydrochloride as an active ingredient; and 2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (DPQ), in which a mass of the DPQ is 0.167% or less with respect to a mass of the tivozanib drug substance.

[11] A tivozanib drug substance comprising: a crystal of tivozanib hydrochloride or a crystal of a hydrate of tivozanib hydrochloride as an active ingredient; and 2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (DPQ), in which a content of the crystal of tivozanib hydrochloride or the crystal of a hydrate of tivozanib hydrochloride as the active ingredient is 99.5 mass% or more, and a mass of DPQ is 0.167% or less with respect to a mass of the tivozanib drug substance.

[12] A tivozanib drug substance comprising: a crystal of tivozanib hydrochloride or a crystal of a hydrate of tivozanib hydrochloride as an active ingredient; and 2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (DPQ), in which a content of the crystal of tivozanib hydrochloride or the crystal of a hydrate of tivozanib hydrochloride as the active ingredient is 99.8 wt% or more, and a mass of DPQ is 0.167% or less with respect to a mass of the tivozanib drug substance.

[13] The tivozanib drug substance according to any one of

[10] to

[12] above, in which the mass of DPQ is 0.125% or less, 0.100% or less, or 0.083% or less with respect to the mass of the tivozanib drug substance.

[14] The tivozanib drug substance according to any one of

[10] to

[13] above, in which the mass of DPQ is 0.04% or less with respect to the mass of the tivozanib drug substance.

[15] The tivozanib drug substance according to any one of [7] to

[14] above, in which the crystal of tivozanib hydrochloride or the crystal of a hydrate of tivozanib hydrochloride is Form I crystal or Form II crystal of tivozanib hydrochloride.

[16] The tivozanib drug substance according to any one of [7] to

[15] above, in which the crystal of tivozanib hydrochloride or the crystal of a hydrate of tivozanib hydrochloride is Form I crystal of tivozanib hydrochloride.

[17] The tivozanib drug substance according to any one of [7] to

[16] above, in which the content of the crystal of tivozanib hydrochloride or the crystal of a hydrate of tivozanib hydrochloride or the content of DPQ is determined by LC.

[18] A therapeutic agent for an ophthalmic disease, which is an eye drop comprising a dispersion medium and a tivozanib drug substance comprising a crystal of tivozanib hydrochloride or a crystal of a hydrate of tivozanib hydrochloride as an active ingredient in a content of 99.5 mass% or more.

[19] A therapeutic agent for an ophthalmic disease, which is an eye drop comprising a dispersion medium and a tivozanib drug substance comprising a crystal of tivozanib hydrochloride or a crystal of a hydrate of tivozanib hydrochloride as an active ingredient in a content of 99.8 mass% or more.

[20] A therapeutic agent for an ophthalmic disease, which is an eye drop comprising a dispersion medium and a tivozanib drug substance comprising a crystal of tivozanib hydrochloride or a crystal of a hydrate of tivozanib hydrochloride as an active ingredient, wherein a total content of impurities derived from the tivozanib drug substance is 0.2 mass% or less in the tivozanib drug substance.

[21] A therapeutic agent for an ophthalmic disease, which is an eye drop comprising a dispersion medium and a tivozanib drug substance comprising a crystal of tivozanib hydrochloride or a crystal of a hydrate of tivozanib hydrochloride as an active ingredient and 2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (DPQ), wherein a mass of DPQ is 0.167% or less with respect to a mass of the tivozanib drug substance.

[22] The therapeutic agent for an ophthalmic disease according to

[21] above, wherein the mass of DPQ is 0.125% or less, 0.100% or less, or 0.083% or less with respect to the mass of the tivozanib drug substance.

[23] The therapeutic agent for an ophthalmic disease according to

[21] or

[22] above, wherein the mass of DPQ is 0.04% or less with respect to the mass of the tivozanib drug substance.

[24] The therapeutic agent for an ophthalmic disease according to any one of

[18] to

[23] above, wherein the crystal of tivozanib hydrochloride or the crystal of a hydrate of tivozanib hydrochloride is Form I crystal or Form II crystal of tivozanib hydrochloride.

[25] The therapeutic agent for an ophthalmic disease according to any one of

[18] to

[24] above, wherein the crystal of tivozanib hydrochloride or the crystal of a hydrate of tivozanib hydrochloride is Form I crystal of tivozanib hydrochloride.

[26] The therapeutic agent for an ophthalmic disease according to any one of

[18] to

[25] above, wherein the content of the crystal of tivozanib hydrochloride or the crystal of a hydrate of tivozanib hydrochloride or a content of DPQ is determined by LC.

[27] A therapeutic agent for an ophthalmic disease, which is an eye drop comprising the tivozanib drug substance according to any one of [7] to

[15] above and a dispersion medium.

[28] The therapeutic agent for an ophthalmic disease according to any one of

[18] to

[27] above, wherein the ophthalmic disease is neovascular age-related macular degeneration, atrophic age-related macular degeneration, choroidal neovascularization, choroidal neovascularization in pathological myopia, macular edema, macular edema associated with retinal central vein occlusion, diabetic macular edema, diabetic retinopathy, proliferative diabetic retinopathy, neovascular glaucoma, angioid streaks, retinopathy of prematurity, Coats disease, retinal vein occlusion, branch retinal vein occlusion, retinal central vein occlusion, cystic macular edema, vitreous hemorrhage due to diabetic retinopathy, Eales disease, central serous chorioretinopathy, epiretinal membrane, uveitis, multifocal choroiditis, anterior ischemic optic neuropathy, corneal neovascularization, pterygium, intraocular melanoma, vasoproliferative tumor of retina, radiation retinopathy, tuberous sclerosis, conjunctival squamous cell carcinoma, and ocular hypertension.

[29] The therapeutic agent for an ophthalmic disease according to any one of

[18] to

[28] above, wherein the ophthalmic disease is neovascular age-related macular degeneration, choroidal neovascularization in pathological myopia, retinal vein occlusion, branch retinal vein occlusion, retinal central vein occlusion, macular edema associated with retinal central vein 7 occlusion, diabetic macular edema, diabetic retinopathy, proliferative diabetic retinopathy, retinopathy of prematurity, and neovascular glaucoma.

[30] The therapeutic agent for an ophthalmic disease according to any one of

[18] to

[29] above, which is an eye drop in which the crystal of tivozanib hydrochloride or the crystal of a hydrate of tivozanib hydrochloride is suspended in a form of nanoparticles.

[31] The therapeutic agent for an ophthalmic disease according to any one of

[18] to

[30] above, wherein the dispersion medium is water, alcohol, or liquid paraffin.

[32] The therapeutic agent for an ophthalmic disease according to any one of

[18] to

[31] above, wherein the dispersion medium comprises a solute.

[33] The therapeutic agent for an ophthalmic disease according to

[32] above, wherein the solute is one or more substances selected from sodium chloride, glucose, glycerol, mannitol, sodium dihydrogen phosphate, sodium hydrogen phosphate hydrate, sodium hydrogen carbonate, trishydroxymethylaminomethane, citric acid hydrate, boric acid, and borax.

[34] The therapeutic agent for an ophthalmic disease according to any one of

[18] to

[33] above, further comprising one or more components selected from a thickening agent and a surfactant.

[35] The therapeutic agent for an ophthalmic disease according to any one of

[18] to

[33] above, further comprising a thickening agent.

[36] The therapeutic agent for an ophthalmic disease according to

[34] or

[35] above, wherein the thickening agent is one or more substances selected from a carboxyvinyl polymer, calcium carboxymethylcellulose, sodium carboxymethylcellulose, povidone, partially saponified polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxyethyl cellulose, amorphous cellulose, methylcellulose, magnesium aluminum silicate, and triethanolamine.

[37] The therapeutic agent for an ophthalmic disease according to any one of

[34] to

[36] above, wherein the surfactant is one or more substances selected from polyoxyethylene castor oil, polyoxyl 40 stearate, sucrose stearate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan trioleate, sorbitan monolaurate, sodium lauryl sulfate, L-a-phosphatidylcholine (PC), 1,2-dipalmitoylphosphatidylcholine (DPPC), oleic acid, natural lecithin, synthetic lecithin, oleyl polyoxyethylene ether, lauryl polyoxyethylene ether, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, polyethylene glycol, tyloxapol, octylphenol ethoxylate, alkyl glucoside, and poloxamer.

[38] The therapeutic agent for an ophthalmic disease according to any one of

[18] to

[37] above, further comprising one or more components selected from a preservative and an inclusion substance.

[39] The therapeutic agent for an ophthalmic disease according to

[38] above, wherein the preservative is one or more substances selected from benzalkonium chloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, sodium edetate hydrate, chlorhexidine gluconate, and sorbic acid.

[40] The therapeutic agent for an ophthalmic disease according to

[38] or

[39] above, wherein the inclusion substance is one or more substances selected from a-cyclodextrin, 0-cyclodextrin, 2-hydroxypropyl-0-cyclodextrin, and Y—cyclodextrin.

[41] A method for treating an ophthalmic disease, wherein the method comprising administering an effective amount of the therapeutic agent for an ophthalmic disease according to any one of

[18] to

[40] above to a mammal (preferably, a patient in need thereof).

[42] Use of a tivozanib drug substance for manufacturing the therapeutic agent for an ophthalmic disease according to any one of

[18] to

[40] above.

[43] The tivozanib drug substance according to any one of [1] to

[17] above for treating a VEGF-related disease.

[44] A pharmaceutical composition comprising the tivozanib drug substance according to any one of [7] to

[15] above and a dispersion medium.

[45] A nanoparticle composition comprising the tivozanib drug substance according to any one of [7] to

[15] above and a dispersion medium.

[46] A tivozanib drug substance produced by solvent-mediated transformation.

[47] A therapeutic agent for an ophthalmic disease, which is an eye drop comprising the tivozanib drug substance according to

[46] above and a dispersion medium.

[48] A tivozanib drug substance produced by a method comprising a step A of obtaining Form II crystal of tivozanib hydrochloride by subjecting Form I crystal of tivozanib hydrochloride to solvent-mediated transformation, and a step B of obtaining Form I crystal of tivozanib hydrochloride by subjecting the Form II crystal of tivozanib hydrochloride obtained in the above step A to solvent-mediated transformation.

[49] The tivozanib drug substance according to any one of [7] to

[17] above, which is produced by a method comprising a step A of obtaining Form II crystal of tivozanib hydrochloride by subjecting Form I crystal of tivozanib hydrochloride to solvent-mediated transformation, and a step B of obtaining Form I crystal of tivozanib hydrochloride by subjecting the Form II crystal of tivozanib hydrochloride obtained in the above step A to solvent-mediated transformation.

[50] A therapeutic agent for an ophthalmic disease, which is an eye drop comprising the tivozanib drug substance according to

[48] or

[49] above and a dispersion medium. ADVANTAGEOUS EFFECTS OF INVENTION

[0011] According to the present invention, a high-purity tivozanib drug substance having a reduced content of impurities, particularly DPQ, can be provided. BRIEF DESCRIPTION OF DRAWINGS

[0012] [FIG. 1] FIG. 1 is a diagram showing an outline of steps 1 to 8 of Example 1. [FIG. 2] FIG. 2 shows data of ReactRaman in Example 1. [FIG. 3] FIG. 3 shows data of Easy Viewer in Example 1. DESCRIPTION OF EMBODIMENTS

[0013] A tivozanib drug substance of the present embodiment comprises, as an active ingredient, a crystal of tivozanib hydrochloride or a crystal of a hydrate of tivozanib hydrochloride, and may contain, as an impurity, a starting material or a by-product that may be generated in a production process thereof. Therefore, the tivozanib drug substance may be a composition comprising a crystal of tivozanib hydrochloride or a crystal of a hydrate of tivozanib hydrochloride and optionally comprising a by-product or the like as an impurity. Here, a total mass of the tivozanib drug substance is used as a reference in the case where a content of an impurity in the tivozanib drug substance is represented.

[0014] In the present description, tivozanib hydrochloride or a hydrate thereof may be collectively referred to as tivozanib.

[0015] As the hydrate of tivozanib hydrochloride, the number of water molecules used for hydration is not particularly limited, and a monohydrate, a dihydrate, or a trihydrate of tivozanib hydrochloride may be used.

[0016] The tivozanib drug substance of the present embodiment preferably comprises at least one of a crystal of tivozanib hydrochloride and a crystal of a hydrate of tivozanib hydrochloride, more preferably comprises Form I crystal or Form II crystal of tivozanib hydrochloride, and still more preferably comprises Form I crystal of tivozanib hydrochloride. Here, Form I crystal 10 of tivozanib hydrochloride is a crystal of a tivozanib hydrochloride monoadduct and monohydrate (monohydrochloride monohydrate), and Form II crystal of tivozanib hydrochloride is a crystal of a tivozanib hydrochloride monoadduct (monohydrochloride) (WO2004 / 035572). In the present description, Form I crystal and Form II crystal of tivozanib hydrochloride are also simply referred to as “Form I crystal” and “Form II crystal”, respectively.

[0017] Form I crystal of tivozanib hydrochloride is a crystal having a peak showing a relative intensity of 10% or more at least at a diffraction angle (20) described in Table 1 below in powder X-ray diffraction.

[0018] [Table 1] Table 1 ____________Diffraction angle (20)____________ 11.47 ± X 22.59 ± X 23.02 ± X 26.27 ± X _______________26.63 ± X_______________ [In the table, X represents a value of 0 to 0.20.]

[0019] In Form I crystal of tivozanib hydrochloride, the relative intensity shown at the diffraction angle (20) described in Table 1 above is preferably 15% or more, more preferably 20% or more, still more preferably 25% or more, and particularly preferably 30% or more. An error in a value of the diffraction angle (20) may occur due to the purity of crystals in a powder, a particle size of the powder, a water content of the powder, an error caused by a measurement limit of a powder X-ray diffractometer, and the like when performing the powder X-ray diffraction analysis. In the present description, in the case where the crystal is defined using the diffraction angle 20, the value of the diffraction angle 20 can include, as the diffraction angle 20 value of the crystal of the present invention, a range in which an error may occur. Typically, a range in which such an error occurs is a range of ±0 to 0.02 of a predetermined value. Therefore, in the case where the diffraction angle 20 of the crystal is represented by X as shown in Table 1, X is typically 0 to 0.20, preferably 0 to 0.15, more preferably 0 to 0.10, and still more preferably 0 to 0.05.

[0020] Form I crystal of tivozanib hydrochloride is more preferably a crystal having a peak showing a relative intensity of 10% or more at least at a diffraction angle (20) described in Table 2 below in powder X-ray diffraction.

[0021] [Table 2] Table 2 ____________Diffraction angle (20)____________ 8.76 ± X 11.47 ± X 15.28 ± X 17.16 ± X 17.53 ± X 18.80 ± X 20.02 ± X 22.59 ± X 23.02 ± X 25.32 ± X 25.43 ± X 26.27 ± X 26.63 ± X 27.00 ± X _______________28.57 ± X_______________ [In the table, X represents 0 to 0.20, preferably 0 to 0.15, more preferably 0 to 0.10, and still more preferably 0 to 0.05.] 5

[0022] In Form I crystal of tivozanib hydrochloride, the relative intensity shown at the diffraction angle (20) described in Table 2 above is preferably 15% or more, and more preferably 20% or more.

[0023] Form II crystal of tivozanib hydrochloride is a crystal having a peak showing a relative intensity of 10% or more at least at a diffraction angle (20) described in Table 3 below 10 in powder X-ray diffraction.

[0024] [Table 3] Table 3 __________Diffraction angle (20)__________ 12.15 ± X 12.54 ± X 21.32 ± X 21.48 ± X 22.13 ± X 24.12 ± X 25.22 ± X _____________25.95 ± X_____________ [In the table, X represents 0 to 0.20, preferably 0 to 0.15, more preferably 0 to 0.10, and still more preferably 0 to 0.05.] 15

[0025] In Form II crystal of tivozanib hydrochloride, the relative intensity shown at the diffraction angle (20) described in Table 3 above is preferably 15% or more, and more preferably 20% or more.

[0026] Form II crystal of tivozanib hydrochloride is more preferably a crystal having a peak showing a relative intensity of 10% or more at least at a diffraction angle (20) described in Table 4 below in powder X-ray diffraction.

[0027] [Table 4] Table 4 _________Diffraction Angle (20)_________ 9.37 ± X 12.15 ± X 12.54 ± X 12.88 ± X 21.32 ± X 21.48 ± X 21.82 ± X 22.13 ± X 23.16 ± X 24.12 ± X 25.22 ± X _____________25.95 ± X_____________ [In the table, X represents 0 to 0.20, preferably 0 to 0.15, more preferably 0 to 0.10, and still more preferably 0 to 0.05.]

[0028] In Form II crystal of tivozanib hydrochloride, the relative intensity shown at the diffraction angle (20) described in Table 4 above is preferably 15% or more, and more preferably 20% or more.

[0029] Tivozanib and Form I crystal and Form II crystal of tivozanib hydrochloride used in the method of the present embodiment can be produced by a method disclosed in WO2002 / 088110 or WO2004 / 035572, or a method conforming thereto.

[0030] 2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (also referred to as DPQ) is an intermediate during the production of tivozanib, a decomposition impurity of tivozanib, and is one of impurities generated during the production of tivozanib.

[0031] When tivozanib and Form I crystal and Form II crystal of tivozanib hydrochloride are produced by the method disclosed in WO2002 / 088110 and WO2004 / 035572, or a method conforming thereto, DPQ may be generated as an impurity.

[0032] The present inventors have found that, in the present embodiment, the content of impurities, particularly DPQ, contained in the tivozanib drug substance can be reduced by performing solvent-mediated transformation between Form I crystal of tivozanib hydrochloride and Form II crystal of tivozanib hydrochloride. More specifically, the present inventors have found that the solvent-mediated transformation from Form I crystal to Form II crystal and the solvent-mediated transformation from Form II crystal to Form I crystal can be controlled by controlling the content of water in a solvent during the solvent-mediated transformation, and have found that the content of impurities, particularly DPQ, can be reduced in this process. The present inventors have found that a solubility difference between Form I crystal of tivozanib hydrochloride and Form II crystal of tivozanib hydrochloride varies depending on the content (proportion) of water in the solvent, the most stable crystal forms of tivozanib hydrochloride varies depending on the content (proportion) of water in the solvent, and the proportion of water serving as a transition point between the most stable crystal forms varies with the temperature. In the case where ethanol is used as the solvent, for example, in the case of 45°C, Form II crystal is stable when the content of water in the solvent is less than 3 volume%, but Form I crystal is stable when the content of water in the solvent is 3 volume% or more.

[0033] A method for producing a Form I crystal of tivozanib hydrochloride of the present embodiment comprises a step A of obtaining Form II crystal of tivozanib hydrochloride by subjecting a Form I crystal of tivozanib hydrochloride to solvent-mediated transformation, and a step B of obtaining Form I crystal of tivozanib hydrochloride by subjecting the Form II crystal of tivozanib hydrochloride obtained in the above step to solvent-mediated transformation. The method including the above two steps is also a method for producing a tivozanib drug substance. In addition, the method comprising the above two steps is also a method for reducing the content of DPQ in the tivozanib drug substance. The content of DPQ in the tivozanib drug substance which is produced by the method comprising the two steps is reduced as compared with a tivozanib drug substance produced by a method not comprising the two steps. In the present description, the "method of the present embodiment" means at least one of the method for producing a Form I crystal of tivozanib hydrochloride, a method for producing a tivozanib drug substance, and a method for reducing the content of DPQ in the tivozanib drug substance.

[0034] The method of the present embodiment preferably comprises the following steps 1 to 8. Step 1 is a step of adding a solvent to a reaction vessel. Step 2 is a step of obtaining a mixed solution by adding a tivozanib drug substance comprising Form I crystal of tivozanib hydrochloride to the reaction vessel. Step 3 is a step of causing solvent-mediated transformation of the Form I crystal of tivozanib hydrochloride to Form II crystal of tivozanib hydrochloride in the mixed solution. Step 4 is a step of adding water to the mixed solution. Step 5 is a step of causing solvent-mediated transformation of Form II crystal of tivozanib hydrochloride to Form I crystal of tivozanib hydrochloride in the mixed solution. Step 6 is a step of aging the crystal by lowering temperature of the mixed solution. Step 7 is a step of filtering and collecting the tivozanib drug substance comprising the Form I crystal of tivozanib hydrochloride from the mixed solution. Step 8 is a step of drying the tivozanib drug substance comprising Form I crystal 5 of tivozanib hydrochloride. Here, the Form II crystal of tivozanib hydrochloride obtained in step 3 can be directly subjected to step 4 and subsequent steps without isolation. Note that the order of step 1 and step 2 may be reversed. The above-described step A comprises steps 1 to 3, and the above-described step B comprises steps 4 and 5. 10

[0035] In the method of the present embodiment, the solvent used in step 1 is preferably ethanol. In addition, it is preferable that, as step 1 and step 2, ethanol is added to the reaction vessel, for example, at room temperature, and then, the tivozanib drug substance comprising Form I crystal of tivozanib hydrochloride is added to the reaction vessel, that is, the tivozanib drug substance comprising Form I crystal of tivozanib hydrochloride is added to ethanol. An 15 amount of ethanol used is not particularly limited, and is, for example, 15 v / w to 22 v / w with respect to the mass of the tivozanib drug substance comprising Form I crystal of tivozanib hydrochloride. Here, regarding v / w, the expression that the amount of ethanol used is a v / w with respect to the mass of the tivozanib drug substance means that the amount of ethanol used is a 20 mL when the mass of the tivozanib drug substance is, for example, 1.0 g. In the present description, the numerical values described using the unit of v / w similarly represent the volume (mL) of the liquid with respect to the mass (g) of a reference substance.

[0036] In the method of the present embodiment, in step 3, as a method of performing the solvent-mediated transformation, for example, an appropriate stirring time may be set according 25 to a reaction scale, at a temperature within a range of 30°C to 65°C, and the mixed solution is heated and stirred, for example, for 3 hours or shorter, 1 hour or shorter, or 10 minutes or shorter. In order to promote the transformation of a crystal form, the heating temperature may be, for example, 30°C or higher, 35°C or higher, 40°C or higher, 45°C or higher, or 50°C or higher, and is preferably 45°C or higher. On the other hand, in order to prevent the generation of DPQ, 30 the heating temperature may be, for example, 65°C or lower, 60°C or lower, 55°C or lower, 50°C or lower, or 45°C or lower, and is preferably 60°C or lower. In a preferred embodiment, as step 3, the mixed solution is heated and stirred at a temperature within a range of 40°C to 60°C for 1 hour.

[0037] In the method of the present embodiment, in step 4, water is added to the mixed solution obtained in step 3. The volume of water in the mixed solution after adding water in step 4 is set to, for example, a range of 0.7 v / w to 4.0 v / w with respect to the mass of the tivozanib drug substance comprising Form I crystal of tivozanib hydrochloride added in step 2, thereby facilitating the transformation of Form II crystal to Form I crystal in the next step 5. Although the preferable water content varies depending on the temperature, for example, at a temperature of 40°C to 60°C, a total volume of water in the mixed solution after adding water in step 4 is, for example, in a range of 0.7 v / w to 4.0 v / w, preferably 1.7 v / w to 2.4 v / w, and more preferably 2 v / w with respect to the mass of the tivozanib drug substance comprising Form I crystal of tivozanib hydrochloride which was added in step 2, thereby facilitating the transformation of Form II crystal to Form I crystal. In another embodiment, for example, at a temperature of 40°C to 60°C, a proportion of water to the mixed solvent of ethanol and water after adding water in step 4 is set to, for example, 5 volume% to 15 volume%, preferably 7 volume% to 15 volume%, thereby facilitating Form II crystal to Form I crystal in step 5.

[0038] In the method of the present embodiment, it is preferable to add, together with the addition of water, the tivozanib drug substance comprising Form I crystal of tivozanib hydrochloride as a seed crystal in step 4. The tivozanib drug substance comprising Form I crystal of tivozanib hydrochloride used as the seed crystal is not particularly limited as long as it comprises Form I crystal. In one embodiment, the tivozanib drug substance which is used as a seed crystal is a substance comprising 98 mass% or more of Form I crystal of tivozanib hydrochloride in the drug substance. In step 4, a tivozanib drug substance used as a seed crystal, which is separately prepared according to the method disclosed in WO 2004 / 035572, is added in an amount of, for example, 0.01 mass% to 0.2 mass% with respect to the tivozanib drug substance comprising Form I crystals of tivozanib hydrochloride which is added in step 2.

[0039] In the method of the present embodiment, in step 5, as a method of performing solvent-mediated transformation, the mixed solution is heated and stirred, for example, at a temperature in a range of 30°C to 65°C, for example, for 10 hours or longer to slowly transform Form II crystal in the mixed solution to Form I crystal. In order to promote the transformation of a crystal form, the heating temperature may be, for example, 30°C or higher, 35°C or higher, 40°C or higher, 45°C or higher, or 50°C or higher, and is preferably 45°C or higher. On the other hand, in order to prevent the generation of DPQ, the heating temperature may be, for example, 65°C or lower, 60°C or lower, 55°C or lower, 50°C or lower, or 45°C or lower, and is preferably 60°C or lower. In a preferred embodiment, as step 5, the mixed solution is heated and stirred at a temperature in a range of 40°C to 60°C for 10 hours or longer.

[0040] In the method of the present embodiment, in step 6, the generated Form I crystals can be efficiently collected, for example, by cooling the mixed solution to 25°C or lower.

[0041] In the method of the present embodiment, in step 7, a suspension comprising the Form I crystal of tivozanib hydrochloride precipitated in step 6 is filtered, and the obtained crystal is washed with a mixed solvent of water and ethanol. The solvent used for washing may be a mixed solvent of water and ethanol in any ratio, and is preferably a mixed solvent in which a proportion of water to the mixed solvent of water and ethanol is 3 volume% to 15 volume%, more preferably 7 volume% to 12 volume%. In the method of the present embodiment, in step 8, the tivozanib drug substance comprising Form I crystal of tivozanib hydrochloride obtained in step 7 is dried under reduced pressure at 60°C or lower, for example, at 45°C.

[0042] The content of tivozanib in the tivozanib drug substance of the present embodiment is, for example, 98.0 mass% or more, 98.1 mass% or more, 98.2 mass% or more, 98.3 mass% or more, 98.4 mass% or more, 98.5 mass% or more, 98.6 mass% or more, 98.7 mass% or more, 98.8 mass% or more, 98.9 mass% or more, 99.0 mass% or more, 99.1 mass% or more, 99.2 mass% or more, 99.3 mass% or more, 99.4 mass% or more, 99.5 mass% or more, 99.6 mass% or more, 99.7 mass% or more, or 99.8 mass% or more. The content of tivozanib in the tivozanib drug substance can be measured and calculated using liquid chromatography (LC). More specifically, the content of tivozanib in the tivozanib drug substance can be measured and calculated by a method described in Examples.

[0043] In a drug substance quantification method using liquid chromatography (LC), as described in the Japanese Pharmacopoeia 18th edition, an upper limit of a content standard is often set to exceed 100%, such as 98.0% to 102.0%. An upper limit of the content of tivozanib in the tivozanib drug substance of the present embodiment is 102.0 mass% when the content of tivozanib is quantified using liquid chromatography (LC).

[0044] In other words, the content of impurities in the tivozanib drug substance of the present embodiment is, for example, 2.0 mass% or less, 1.9 mass% or less, 1.8 mass% or less, 1.7 mass% or less, 1.6 mass% or less, 1.5 mass% or less, 1.4 mass% or less, 1.3 mass% or less, 1.2 mass% or less, 1.1 mass% or less, 1.0 mass% or less, 0.9 mass% or less, 0.8 mass% or less, 0.7 mass% or less, 0.6 mass% or less, 0.5 mass% or less, 0.4 mass% or less, 0.3 mass% or less, or 0.2 mass% or less.

[0045] The content of DPQ in the tivozanib drug substance of the present embodiment is, for example, 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less with respect to the mass of the tivozanib drug substance. The content of DPQ in the tivozanib drug substance can be measured and calculated using liquid chromatography (LC). More specifically, the content of DPQ in the tivozanib drug substance can be measured and calculated by the method described in Examples.

[0046] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 98.0 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0047] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 98.1 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0048] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 98.2 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0049] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 98.3 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0050] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 98.4 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0051] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 98.5 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0052] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 98.6 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0053] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 98.7 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0054] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 98.8 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0055] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 98.9 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0056] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 99.0 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0057] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 99.1 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0058] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 99.2 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0059] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 99.3 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0060] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 99.4 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0061] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 99.5 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0062] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 99.6 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0063] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 99.7 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0064] When the content of tivozanib in the tivozanib drug substance of the present embodiment is 99.8 mass% or more, the content of DPQ is preferably 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.100 mass% or less, 0.09 mass% or less, 0.083 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less.

[0065] When an acceptable daily intake of DPQ is set to 1.5 pg in compliance with the guideline of ICH-M7, the acceptable DPQ content in the tivozanib drug substance of the present embodiment varies depending on the total daily dose of the tivozanib drug substance. For example, in the case of eye drops, the total daily dose is determined by a product of 1. "drug concentration", 2. "volume per instillation", and 3. "number of instillations per day". For example, in Ph1 test (NCT04594681) of a tivozanib eye drop, when a repetitive administration group is classified using the total daily dose as an index, the dose of the tivozanib drug substance can be roughly classified into three groups, i.e., 0.45 mg / day, 0.9 mg / day, and 1.8 mg / day. In consideration of the acceptable intake of DPQ (1.5 gg / day) for each of these three doses, when the eye drop contains a tivozanib drug substance, the mass% of DPQ accepted in the tivozanib drug substance is 0.333 mass% or less, 0.167 mass% or less, and 0.083 mass% or less, respectively. No serious side effects were confirmed at 1.8 mg / day, which is the maximum dose of the tivozanib drug substance in the Ph1 test, and therefore, the total daily dose of a clinically used tivozanib drug substance can be selected from doses of 1.8 mg / day or less. For example, 0.3 mg / day, 0.6 mg / day, 1.2 mg / day, and 1.5 mg / day can be selected as the total daily dose of the tivozanib drug substance, and in this case, the mass% of DPQ accepted in the tivozanib drug substance is 0.500 mass% or less, 0.250 mass% or less, 0.125 mass% or less, and 0.100 mass% or less, respectively.

[0066] Since DPQ is a decomposition product of tivozanib, there is a possibility that tivozanib is decomposed to generate DPQ even after the production of the tivozanib drug substance. Therefore, it is important to reduce the content of DPQ as much as possible at a time point when the tivozanib drug substance is produced, from the viewpoint of stable supply.

[0067] A therapeutic agent for an ophthalmic disease of the present embodiment is an eye drop comprising a tivozanib drug substance and a dispersion medium.

[0068] In the therapeutic agent for an ophthalmic disease of the present embodiment, crystals of tivozanib are preferably suspended in the form of nanoparticles. In other words, it is preferable that the crystals of tivozanib are dispersed in the form of solid nanoparticles in the eye drop so as to form a suspended state. At this time, some of the crystals of tivozanib may be dissolved in the eye drop.

[0069] The therapeutic agent for an ophthalmic disease of the present embodiment preferably comprises crystals of tivozanib in the form of nanoparticles, and may comprise crystals of tivozanib in a form other than the form of nanoparticles. Examples of the form other than the form of the nanoparticles include a form of microparticles. In the therapeutic agent for an ophthalmic disease of the present embodiment, the content of crystals of tivozanib in a form other than the form of nanoparticles may be 20 mass% or less of the content of crystals of tivozanib in the form of nanoparticles. In therapeutic agent for an ophthalmic disease, 60 mass% to 100 mass% of the total amount of crystals of tivozanib is preferably in the form of nanoparticles, 70 mass% to 100 mass% thereof is more preferably in the form of nanoparticles, and 80 mass% to 100 mass% thereof is still more preferably in the form of nanoparticles.

[0070] In the present description, the form of nanoparticles means that a substance is in the form of particles on a nanometer order, and generally means a form of particles having an average particle diameter of 10 nm to 1000 nm. In addition, in the present description, the form of the microparticles means that a substance is in the form of particles on a micrometer order, and generally means a form of particles having an average particle diameter of more than 1 pm and 1000 pm or less. The crystals of tivozanib in the form of nanoparticles, which are comprised in the therapeutic agent for an ophthalmic disease of the present embodiment, are preferably prepared by milling or crystallizing the tivozanib drug substance.

[0071] An average particle diameter of the crystals of tivozanib in the form of nanoparticles, which are comprised in the therapeutic agent for an ophthalmic disease of the present embodiment, is preferably 10 nm to 400 nm, more preferably 10 nm to 300 nm, still more preferably 50 to 300 nm, and still more preferably 100 nm to 300 nm.

[0072] A method for measuring the average particle diameter of the crystals of tivozanib in the present description is not particularly limited. The measurement of the average particle diameter can be performed using, for example, a dynamic light scattering method under measurement conditions of a scattering angle of 173° and a wavelength of 633 nm.

[0073] The content of tivozanib with respect to the mass of the tivozanib drug substance in the therapeutic agent for an ophthalmic disease of the present embodiment is, for example, 98.0 mass% or more, 98.1 mass% or more, 98.2 mass% or more, 98.3 mass% or more, 98.4 mass% or more, 98.5 mass% or more, 98.6 mass% or more, 98.7 mass% or more, 98.8 mass% or more, 98.9 mass% or more, 99.0 mass% or more, 99.1 mass% or more, 99.2 mass% or more, 99.3 mass% or more, 99.4 mass% or more, 99.5 mass% or more, 99.6 mass% or more, 99.7 mass% or more, or 99.8 mass% or more.

[0074] In other words, the content of impurities derived from tivozanib with respect to the mass of the tivozanib drug substance in the therapeutic agent for an ophthalmic disease of the present embodiment is, for example, 2.0 mass% or less, 1.9 mass% or less, 1.8 mass% or less, 1.7 mass% or less, 1.6 mass% or less, 1.5 mass% or less, 1.4 mass% or less, 1.3 mass% or less, 1.2 mass% or less, 1.1 mass% or less, 1.0 mass% or less, 0.9 mass% or less, 0.8 mass% or less, 0.7 mass% or less, 0.6 mass% or less, 0.5 mass% or less, 0.4 mass% or less, 0.3 mass% or less, or 0.2 mass% or less.

[0075] The content of DPQ with respect to the mass of the tivozanib drug substance in the therapeutic agent for an ophthalmic disease of the present embodiment is, for example, 0.167 mass% or less, 0.160 mass% or less, 0.155 mass% or less, 0.150 mass% or less, 0.145 mass% or less, 0.140 mass% or less, 0.135 mass% or less, 0.130 mass% or less, 0.125 mass% or less, 0.120 mass% or less, 0.115 mass% or less, 0.110 mass% or less, 0.105 mass% or less, 0.10 mass% or less, 0.09 mass% or less, 0.08 mass% or less, 0.07 mass% or less, 0.06 mass% or less, 0.05 mass% or less, 0.04 mass% or less, 0.03 mass% or less, 0.02 mass% or less, or 0.01 mass% or less with respect to the mass of the tivozanib drug substance.

[0076] The content of the tivozanib drug substance in the therapeutic agent for an ophthalmic disease is not particularly limited, and is, for example, preferably 0.01 parts by mass to 20 parts by mass, more preferably 0.01 parts by mass to 15 parts by mass, still more preferably 0.01 parts by mass to 10 parts by mass, still more preferably 0.01 parts by mass to 5 parts by mass, and still more preferably 0.01 parts by mass to 3 parts by mass with respect to 100 parts by mass of the therapeutic agent for an ophthalmic disease.

[0077] The mass (%) of tivozanib or the mass (%) of DPQ in the tivozanib drug substance of the present embodiment, in other words, the purity of the tivozanib drug substance can be measured and calculated using liquid chromatography (including various types of LC such as HPLC, UHPLC, and UPLC). For example, tivozanib and DPQ are separated by HPLC, and an HPLC area (%) of each substance can be calculated using an appropriate detection method (for example, an ultraviolet absorbance detector (UVD: measurement wavelength 240 nm to 250 nm (for example, 242 nm or 243 nm))).

[0078] In the case where the ultraviolet absorbance detector (UVD) is used, the HPLC Area (%) can be calculated as follows. Peak areas of sample-derived peaks on a chromatogram are calculated, a peak area of each peak is divided by the sum of all peak areas, the total of numerical values of peak area(s) corresponding to tivozanib is defined as the HPLC Area (%) of tivozanib, and the total of numerical values of peak area(s) corresponding to DPQ is defined as the HPLC Area (%) of DPQ.

[0079] Using a standard product in which the content of tivozanib is known, the mass (%) of tivozanib is calculated using a peak area ratio of each peak corresponding to tivozanib in a measurement sample to a peak corresponding to tivozanib in the standard product in HPLC, a ratio of a weighed amount of a measurement sample to a weighed amount of the standard product, and the content (mass%) of tivozanib in the standard product. 5            The conversion from HPLC Area (%) of DPQ to mass (%) thereof can be calculated by multiplying a relative response factor determined from the ratio of HPLC Area (%) obtained by analyzing the same amount of tivozanib and DPQ.

[0080] The content of tivozanib and the content of DPQ in the tivozanib drug substance contained in the therapeutic agent for an ophthalmic disease are measured in the same manner 10 as in the tivozanib drug substance.

[0081] Examples of the dispersion medium used in the therapeutic agent for an ophthalmic disease of the present embodiment include water, alcohol, and liquid paraffin. The dispersion medium is preferably water or liquid paraffin, and more preferably water. 15            The dispersion medium may be used alone or in combination of two or more kinds thereof.

[0082] In therapeutic agent for an ophthalmic disease of the present embodiment, the content of the dispersion medium is not particularly limited. In the therapeutic agent for an ophthalmic disease, the content of components other than the dispersion medium contained in the 20 therapeutic agent for an ophthalmic disease is adjusted as the content per 100 parts by mass of the therapeutic agent for an ophthalmic disease, and the dispersion medium may be contained so as to have the remaining content. Specifically, the dispersion medium may be contained in the therapeutic agent for an ophthalmic disease such that the total of the sum of the contents of the components other than the dispersion medium contained in the therapeutic agent for an 25 ophthalmic disease and the content of the dispersion medium is 100 parts by mass, that is, the amount of the therapeutic agent for an ophthalmic disease is 100 parts by mass. The content of the dispersion medium is, for example, preferably 68 parts by mass to 99.9 parts by mass, more preferably 78 parts by mass to 99.9 parts by mass, and still more preferably 85 parts by mass to 99.9 parts by mass with respect to 100 parts by mass of the therapeutic agent for an ophthalmic 30 disease.

[0083] The dispersion medium preferably comprises a solute. The solute contained in the dispersion medium is not particularly limited, and, for example, a solute used as an isotonic agent in the field of medicine is preferred. Examples of the solute contained in the dispersion medium include sodium chloride, glucose, glycerol, mannitol, sodium dihydrogen phosphate, sodium hydrogen phosphate hydrate, sodium hydrogen carbonate, trishydroxymethylaminomethane, citric acid hydrate, boric acid, borax, and phosphoric acid. The solute is preferably sodium chloride, glucose, glycerol, or mannitol. The solute may be used alone or in combination of two or more kinds thereof.

[0084] In the therapeutic agent for an ophthalmic disease of the present embodiment, the content of the solute is not particularly limited, and is preferably 0 part by mass to 50 parts by mass, and more preferably 0 part by mass to 25 parts by mass with respect to 100 parts by mass of water, alcohol, or liquid paraffin.

[0085] The therapeutic agent for an ophthalmic disease of the present embodiment may further contain one or more components selected from thickening agents and surfactants, or one or more components selected from preservatives and inclusion substances, in addition to the tivozanib drug substance and the dispersion medium of the present embodiment. The therapeutic agent for an ophthalmic disease of the present embodiment preferably further comprises one or more components selected from thickening agents and surfactants and one or more components selected from preservatives and inclusion substances, in addition to the tivozanib drug substance and the dispersion medium of the present embodiment. As the thickening agents, the surfactants, the preservatives, and the inclusion substances, one kind of component among the candidate components described below may be used, or two or more kinds of components may be used.

[0086] Examples of the thickening agents used for the therapeutic agent for an ophthalmic disease of the present embodiment include a carboxyvinyl polymer, calcium carboxymethylcellulose, sodium carboxymethylcellulose, povidone (polyvinylpyrrolidone), partially saponified polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxyethyl cellulose, amorphous cellulose, methylcellulose, magnesium aluminum silicate, and triethanolamine. As the thickening agent, polyvinyl alcohol, povidone (polyvinylpyrrolidone), hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxymethyl cellulose, and the like are preferred. The thickening agent may be used alone or in combination of two or more kinds thereof.

[0087] The content of the thickening agents in therapeutic agent for an ophthalmic disease of the present embodiment is not particularly limited, and is, for example, preferably 0.01 parts by mass to 5 parts by mass, more preferably 0.05 parts by mass to 3 parts by mass, and still more preferably 0.1 parts by mass to 2.5 parts by mass with respect to 100 parts by mass of the therapeutic agent for an ophthalmic disease.

[0088] Examples of the surfactants used for the therapeutic agent for an ophthalmic disease of the present embodiment include polyoxyethylene castor oil, polyoxyl 40 stearate, sucrose stearate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monooleate (polysorbate 80, Tween (registered trademark) 80), polyoxyethylene sorbitan trioleate, sorbitan monolaurate, sodium lauryl sulfate, L-a-phosphatidylcholine (PC), 1,2-dipalmitoylphosphatidylcholine (DPPC), oleic acid, natural lecithin, synthetic lecithin, oleyl polyoxyethylene ether, lauryl polyoxyethylene ether, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, polyethylene glycol, tyloxapol, octylphenol ethoxylate, alkyl glucoside, and poloxamer. As the surfactants, polyoxyethylene sorbitan monooleate and poloxamer are preferred, and among them, polyoxyethylene sorbitan monooleate (polysorbate 80) and poloxamer (Pluronic (registered trademark) F-127) are more preferred. The surfactant may be used alone or in combination of two or more kinds thereof.

[0089] The content of the surfactants in the therapeutic agent for an ophthalmic disease of the present embodiment is not particularly limited, and is, for example, preferably 0 part by mass to 5 parts by mass, more preferably 0 part by mass to 3 parts by mass, and still more preferably 0 part by mass to 1.0 part by mass with respect to 100 parts by mass of the therapeutic agent for an ophthalmic disease.

[0090] In one preferred aspect, the therapeutic agent for an ophthalmic disease of the present embodiment comprises a thickening agent and does not contain a surfactant.

[0091] In the case where a thickening agent and a surfactant are used in combination, the combination of the thickening agent and the surfactant is not particularly limited, and examples thereof include a combination of hydroxypropyl methylcellulose and polyoxyethylene sorbitan monooleate, a combination of hydroxypropyl cellulose and polyoxyethylene sorbitan monooleate, a combination of hydroxypropyl cellulose and tyloxapol, a combination of povidone and polyoxyethylene sorbitan monooleate, a combination of polyvinyl alcohol and polyoxyethylene sorbitan monooleate, and a combination of poloxamer and polyoxyethylene sorbitan monooleate. The combination of the thickening agent and the surfactant is preferably a combination of hydroxypropyl cellulose and polyoxyethylene sorbitan monooleate, a combination of povidone and polyoxyethylene sorbitan monooleate, a combination of polyvinyl alcohol and polyoxyethylene sorbitan monooleate, or a combination of poloxamer and polyoxyethylene sorbitan monooleate, and more preferably a combination of hydroxypropyl cellulose and polyoxyethylene sorbitan monooleate, a combination of povidone and polyoxyethylene sorbitan monooleate, or a combination of poloxamer and polyoxyethylene sorbitan monooleate. When the thickening agent and the surfactant are used in combination, the mass ratio of the surfactant to the thickening agent is not particularly limited, and a ratio of the surfactant to the thickening agent on a mass basis (surfactant / thickening agent) is, for example, 0 to 500, preferably 0 to 60, and more preferably 0 to 10.

[0092] Examples of the preservatives used for the therapeutic agent for an ophthalmic disease of the present embodiment include benzalkonium chloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, sodium edetate hydrate, chlorhexidine gluconate, and sorbic acid. The preservative is preferably benzalkonium chloride. The preservative may be used alone or in combination of two or more kinds thereof.

[0093] The content of the preservative in the therapeutic agent for an ophthalmic disease of the present embodiment is not particularly limited, and is, for example, preferably 0 part by mass to 1 part by mass, more preferably 0 part by mass to 0.75 parts by mass, and still more preferably 0 part by mass to 0.5 parts by mass with respect to 100 parts by mass of the therapeutic agent for an ophthalmic disease.

[0094] The inclusion substance used for the therapeutic agent for an ophthalmic disease of the present embodiment is not particularly limited as long as it has a property of incorporating a molecule, and examples thereof include a-cyclodextrin, P—cyclodextrin, 2-hydroxypropyl—P— cyclodextrin (HP—P—CD), and Y—cyclodextrin. The inclusion substance is preferably P-cyclodextrin or 2-hydroxypropyl-P-cyclodextrin, and more preferably 2-hydroxypropyl-P-cyclodextrin (HP-P-CD). The inclusion substance may be used alone or in combination of two or more kinds thereof.

[0095] The content of the inclusion substance in the therapeutic agent for an ophthalmic disease of the present embodiment is not particularly limited, and is, for example, preferably 0 part by mass to 1 part by mass, more preferably 0 part by mass to 0.75 parts by mass, and still more preferably 0 part by mass to 0.5 parts by mass with respect to 100 parts by mass of the therapeutic agent for an ophthalmic disease.

[0096] The therapeutic agent for an ophthalmic disease of the present embodiment can be administered topically to an eye. Examples of topical ocular administration include ophthalmic instillation, subconjunctival injection, sub-tenon injection, intravitreal administration, suprachoroidal injection, periocular injection, and administration using an intraocular implant or administration using other drug delivery devices, and eye drop administration is preferred.

[0097] The therapeutic agent for an ophthalmic disease of the present embodiment can be used for preventing or treating vascular endothelial growth factor (VEGF) related diseases, preferably ophthalmic diseases, by being administered to mammals or the like.

[0098] Examples of vascular endothelial growth factor (VEGF) related diseases include ophthalmic diseases.

[0099] Examples of the vascular endothelial growth factor (VEGF) related ophthalmic diseases include neovascular age-related macular degeneration, atrophic age-related macular degeneration, choroidal neovascularization, choroidal neovascularization in pathological myopia, macular edema, macular edema associated with retinal central vein occlusion, diabetic macular edema, diabetic retinopathy, proliferative diabetic retinopathy, neovascular glaucoma, angioid streaks, retinopathy of prematurity, Coats disease, retinal vein occlusion, branch retinal vein occlusion, retinal central vein occlusion, cystic macular edema, vitreous hemorrhage due to diabetic retinopathy, Eales disease, central serous chorioretinopathy, epiretinal membrane, uveitis, multifocal choroiditis, anterior ischemic optic neuropathy, corneal neovascularization, pterygium, intraocular melanoma, vasoproliferative tumor of retina, radiation retinopathy, tuberous sclerosis, conjunctival squamous cell carcinoma, and ocular hypertension. Preferable examples of the vascular endothelial growth factor (VEGF) related ophthalmic diseases include neovascular age-related macular degeneration, choroidal neovascularization in pathological myopia, retinal vein occlusion, branch retinal vein occlusion, retinal central vein occlusion, macular edema associated with retinal central vein occlusion, diabetic macular edema, diabetic retinopathy, proliferative diabetic retinopathy, retinopathy of prematurity, and neovascular glaucoma.

[0100] The therapeutic agent for an ophthalmic disease can be used for treatment, prevention, and the like of vascular endothelial growth factor (VEGF) related ophthalmic diseases, and among them, the therapeutic agent for an ophthalmic disease is preferably used for prevention, treatment, and the like of neovascular age-related macular degeneration, macular edema associated with retinal central vein occlusion, choroidal neovascularization, diabetic macular edema in pathological myopia, neovascular glaucoma, and retinopathy of prematurity, which are indications of existing anti-VEGF inhibitors (intravitreal injection agents), and ophthalmic diseases such as proliferative diabetic retinopathy and uveitis, for which therapeutic effects of anti-VEGF inhibitors (intravitreal injection agents) is reported in clinical practice even if the use is off-label.

[0101] In ophthalmic diseases as described above, for example, good therapeutic effects (recovery of maximum corrective eyesight, histological improvements such as thinning of the retina thickened due to pathological conditions, and the like) are recognized by intravitreally injecting anti-VEGF inhibitors in clinical practice. However, for example, an existing anti-VEGF inhibitor (intravitreal injection) has a high therapeutic effect, but the administration route is intravitreal injection, and a continuous treatment is required due to a high recurrence rate, and the like. Therefore, the burden on a patient himself / herself, a family, and a healthcare worker is extremely large, which is a social problem. In view of such circumstances, in the ophthalmic disease as described above, it is desired to develop a drug (for example, an eye drop) that can be administered through a non-invasive and simple route other than intravitreal injection from the viewpoint of reducing the burden on a patient himself / herself, a family, a healthcare worker, and the like, and the therapeutic agent for an ophthalmic disease of the present embodiment is useful in that an active ingredient can be administered to a patient through a route such as instillation.

[0102] The form of the therapeutic agent for an ophthalmic disease of the present embodiment is not particularly limited, and is preferably a liquid agent (liquid preparation). The liquid agent is more preferably a suspension preparation or a solution preparation. Some or all of the components of the therapeutic agent for an ophthalmic disease of the present embodiment, or a powder obtained by freeze-drying the components may be dissolved or dispersed in a dispersion medium such as water to obtain the therapeutic agent for an ophthalmic disease of the present embodiment.

[0103] A method for producing a tivozanib drug substance in the therapeutic agent for an ophthalmic disease of the present embodiment, which comprises Form I crystal of tivozanib hydrochloride in the form of nanoparticles, is not particularly limited. However, the tivozanib drug substance can be produced by a nanoparticle formation method generally used in the technical field of formulation such as milling. As a nanoparticle formation method, for example, a commercially available instrument (a zirconia container, a zirconia ball, or the like), a commercially available nanomill, or the like is used to mill the tivozanib drug substance of the present embodiment, and then purification or the like is performed using a commercially available centrifuge or the like to produce the tivozanib drug substance comprising Form I crystal of tivozanib hydrochloride in the form of nanoparticles. In addition, from a solution of tivozanib, stimulation is applied in a liquid phase or a gas phase to cause crystallization, thereby producing the tivozanib drug substance comprising Form I crystal of tivozanib hydrochloride in the form of nanoparticles.

[0104] In a milling step, one or more components selected from a thickening agent, a surfactant, a dispersion medium, a preservative, and an inclusion substance may be added to the tivozanib drug substance of the present embodiment, and then milling is performed. In the milling step, one or more components selected from a thickening agent, a surfactant, and a dispersion medium may be added, and one or more components selected from a preservative and an inclusion substance may be further added, and then, milling is performed.

[0105] The milling method is not particularly limited, and examples thereof include dry milling and wet milling, and wet milling is preferred. Wet milling, in which a dispersion medium is added to the tivozanib drug substance and then milling is performed, is more preferred.

[0106] The purification method is not particularly limited, and examples thereof include purification using a commercially available centrifuge or the like.

[0107] A nanoparticle composition obtained by formulating a tivozanib drug substance comprising Form I crystal of tivozanib hydrochloride in the form of nanoparticles obtained by the nanoparticle formation method described in the present description can be used as a pharmaceutical composition, and is preferably used as a therapeutic agent for an ophthalmic disease, and more preferably used as an eye drop.

[0108] The content of tivozanib and the content of DPQ in the tivozanib drug substance contained in the nanoparticle composition are measured in the same manner as in the case of the tivozanib drug substance or the therapeutic agent for an ophthalmic disease.

[0109] The description of the therapeutic agent for an ophthalmic disease in the present description is also applied to the nanoparticle composition. [Examples]

[0110] Hereinafter, the present invention will be described in more detail based on reference examples and examples, but the present invention is not limited to these examples.

[0111] Reference Example 1 Form I crystal of tivozanib hydrochloride was prepared according to a method disclosed in WO2004 / 035572. The tivozanib drug substance used in step 2 of Example 1 comprises Form I crystal of tivozanib hydrochloride obtained by the method of WO2004 / 035572 and at least DPQ as an impurity.

[0112] Example 1: In a tivozanib drug substance containing Form I crystal of tivozanib hydrochloride, Form I crystal of tivozanib hydrochloride was subjected to solvent-mediated transformation to form Form II crystal, and then the Form II crystal was further subjected to solvent-mediated transformation to form Form I crystal, thereby examining whether there was an effect of reducing the content of DPQ in the tivozanib drug substance. Specifically, the experiment was performed according to the following procedure. Ethanol (36.1 mL) was added to a reaction vessel (step 1), and the tivozanib drug substance (2.0 g) containing Form I crystal of tivozanib hydrochloride prepared in Reference Example 1 was added to the reaction vessel at room temperature (step 2), followed by stirring under suspension at 45°C for 10 minutes, and then, solvent-mediated transformation of the crystal form from Form I crystal to Form II crystal was confirmed (step 3). Water (4.0 mL) and a tivozanib drug substance (2.0 mg) containing Form I crystal of tivozanib hydrochloride were added as seed crystals to the mixed solution (step 4), followed by stirring at 45°C for 19 hours, and then the solvent-mediated transformation of the crystal form from Form II crystal to Form I crystal was checked (step 5). The mixed solution was cooled to 25°C and stirred for 1 hour (step 6). After a precipitate is filtered, the filtrate was washed with a 10% ethanol aqueous solution (2.0 mL) (step 7). The filtrate was dried under reduced pressure at 45°C to obtain a tivozanib drug substance (1.692 g) containing Form I crystal of tivozanib hydrochloride (yield of tivozanib drug substance = 86%) (step 8). An outline of a working process is shown in FIG. 1. In FIG. 1, FORM I means Form I crystal, and FORM II means Form II crystal.

[0113] A time course of the crystal form transition during the solvent-mediated transformation was confirmed using Raman spectrometry (ReactRaman (ReactRaman 785, manufactured by METTLER TOLEDO)) and particle image analysis (Easy Viewer (Easy Viewer 100, manufactured by METTLER TOLEDO)). In Raman spectrometry, a crystal form having a peak at 1442 cm-1 is Form I crystal. FIG. 2 shows data of ReactRaman, and FIG. 3 shows data of Easy Viewer. In FIG. 2, the horizontal axis represents Time, and the vertical axis represents Height. The numerical values on the horizontal axis are 00:00:00, 00:59:59, 01:59:59, 02:59:59, 03:59:59, 04:59:59, 05:59:59, 06:59:59, 07:59:59, 08:59:59, 09:59:59, 10:59:59, 11:59:59, 12:59:59, 13:59:59, 14:59:59, 15:59:59, 16:59:59, 17:59:59, 18:59:59, 19:59:59, 20:59:59, 21:59:59 and 22:59:59 from the left to the right. For example, 01:59:59 indicates 1 hour, 59 minutes, and 59 seconds. Numerical values on the vertical axis are 100, 200, 300, and 400 from bottom to top. The upper left number of each image in FIG. 3 corresponds to the step number described in FIG. 1. Step 5 was performed for a long period of time, and therefore, a plurality of types of data 5-1 to 5-6 corresponding to step 5 are shown in FIG. 3.

[0114] As shown in FIG. 2, it was confirmed in real time by Raman spectrometry that Form I crystal was transferred to Form II crystal by heating and stirring corresponding to step 3, and then the Form II crystal was gradually transferred to Form I crystal by heating and stirring after the addition of water (step 5).

[0115] As shown in FIG. 3, it was confirmed that the crystal state started to change by the heating and stirring (step 3) from Form I crystal (No. 2 in FIG. 3), which had a needle-shaped crystal form before the heating and stirring (step 2), and a fine Form II crystal (No. 3 in FIG. 3) was generated. Thereafter, it was confirmed that the fine Form II crystal started to be transformed to Form I crystal of the needle-like crystal by the heating and stirring after the addition of water (step 5) (Nos. 5-1 to 5-3 in FIG. 3), and the heating and stirring were continued overnight (step 5), thereby obtaining Form I crystal (Nos. 5-4 to 5-6 in FIG. 3).

[0116] Table 5 shows the results of analysis of the transition of tivozanib and DPQ contained before and after the execution of the solvent-mediated transformation described in Example 1, that is, contained in the tivozanib drug substance before the addition to the reaction vessel in the step 2 (before the step in Table 5) and the tivozanib drug substance obtained in step 8 (after the step in Table 5), with an ultraviolet absorbance detector (UVD) using HPLC. Here, the conversion of DPQ from HPLC Area (%) to weight (%) was calculated by multiplying a relative response factor of DPQ to tivozanib. Table 5 Tivozanib DPQ HPLC Area% Weight% in drug substance Relative retention time 1.00 0.85 Before step 99.484% 0.263% 0.184% After step 99.833% 0.014% 0.010%

[0118] The calculation of the content ( weight%) of tivozanib in the tivozanib drug substance in Table 6 was analyzed by an ultraviolet absorbance detector (UVD) using HPLC. Specifically, the measurement was performed as follows. First, a standard product having a known content of tivozanib was used as an external control, and a ratio of a peak area of a peak corresponding to tivozanib in the measurement sample to a peak area of a peak corresponding to tivozanib in the standard product was multiplied by a ratio of a weighed amount of the measurement sample to a weighed amount of the standard product and a content (weight%) of tivozanib in the standard product to calculate the content (weight%) of tivozanib in the measurement sample.

[0119] [Table 6] Table 6 Content of tivozanib (weight%) Before step 99.08 After step 100.08

[0120] From the results of Tables 5 and 6, it was found that by using the present production method utilizing the solvent-mediated transformation, the content of DPQ contained in the tivozanib drug substance can be significantly reduced, and a tivozanib drug substance containing tivozanib at a high content can be obtained.

[0121] Example 2: A nanoparticle composition formulated as an eye drop according to the following formulation was prepared using the tivozanib drug substance containing Form I crystal of tivozanib hydrochloride obtained according to the method of Example 1, and the purity of tivozanib in the nanoparticle composition was measured. Zirconia balls (diameter: 0.1 mm) were placed in a zirconia container, the tivozanib drug substance prepared according to the method of Example 1 was weighed, and then an aqueous hydroxypropyl cellulose solution was added thereto, followed by wet milling (Mill / Mix, 1500 rpm, 1 minute, Mill / Mix, 400 rpm, 1 minute, 10 times) using a 35 rotation / revolution nano pulverizer (NP-100 (manufactured by Thinky Corporation)). Thereafter, an aqueous solution containing hydroxypropyl cellulose and mannitol was added, followed by dispersion (Mill / Mix, 400 rpm, 5 minutes) using a rotation / revolution nano pulverizer, zirconia balls were removed (Clean Media, 2000 rpm, 1 minute, Mill / Mix, 400 rpm, 1 minute), and a nanoparticle composition formulated as an eye drop was obtained. The composition of the nanoparticle composition was as follows: tivozanib drug substance / hydroxypropyl cellulose / mannitol = 1 part by weight / 0.6 parts by weight / 2.25 parts by weight. When the average particle diameter of Form I crystals of tivozanib hydrochloride in the nanoparticle composition was measured using Zetasizer Nano (ZS (manufactured by Malvern Panalytical)), the average particle diameter was 212.5 nm. Table 7 shows the results of analysis of the transition of tivozanib and DPQ contained before and after the wet milling described in Example 2, that is, contained in the tivozanib drug substance obtained according to the method of Example 1 (before the step in Table 7) and the nanoparticle composition obtained in Example 2 (after the step in Table 7), with an ultraviolet absorbance detector (UVD) using HPLC. Here, the conversion of DPQ from HPLC Area (%) to weight (%) was calculated by correcting with a sensitivity coefficient.

[0122] The content of DPQ in the nanoparticle composition was measured by HPLC (quantitative limit (lower limit value) was 0.05 Area%), and the detection limit (lower limit value) was 0.02 Area%. The content of DPQ after forming the nanoparticle composition was smaller than a significant figure of the quantitative limit, and was specifically 0.0346 Area%. From the results shown in Table 7, it was found that, also in the nanoparticle composition formulated as an eye drop in the present Example using the tivozanib drug substance containing Form I crystal of the tivozanib hydrochloride obtained according to Example 1, the DPQ content was less than 0.05 weight% in the tivozanib drug substance. That is, the content of Form I crystals was maintained at a high value even after the tivozanib drug substance containing Form I crystals of the tivozanib hydrochloride obtained according to Example 1 was formulated as an eye drop. Table 7 Tivozanib DPQ HPLC Area% Weight% in drug substance Relative retention time 1.00 0.87 Before step 99.906% Less than 0.05% Less than 0.05% After step 99.858% Less than 0.05% Less than 0.05%

[0124] Example 3: A nanoparticle composition formulated as an eye drop according to the following formulation was prepared using the tivozanib drug substance containing Form I crystal of tivozanib hydrochloride obtained according to the method of Example 1, and the purity of tivozanib in the nanoparticle composition was measured. Zirconia balls (diameter: 0.1 mm) were placed in a zirconia container, the tivozanib drug substance prepared according to the method of Example 1 was weighed, and then an aqueous hydroxypropyl methyl cellulose solution was added thereto, followed by wet milling (Mill / Mix, 1500 rpm, 1 minute, Mill / Mix, 400 rpm, 1 minute, 10 times) using a rotation / revolution nano pulverizer (NP-100 (manufactured by Thinky Corporation)). Thereafter, an aqueous solution containing hydroxypropyl methyl cellulose and mannitol was added, followed by dispersion (Mill / Mix, 400 rpm, 5 minutes) using a rotation / revolution nano pulverizer, zirconia balls were removed (Clean Media, 2000 rpm, 1 minute, Mill / Mix, 400 rpm, 1 minute), and a nanoparticle composition formulated as an eye drop was obtained. The composition of the nanoparticle composition was as follows: tivozanib drug substance / hydroxypropyl methyl cellulose / mannitol = 1 part by weight / 0.6 parts by weight / 2.25 parts by weight. When the average particle diameter of Form I crystals of tivozanib hydrochloride in the nanoparticle composition was measured using Zetasizer Nano (ZS (manufactured by Malvern Panalytical)), the average particle diameter was 218.5 nm. Table 8 shows the results of analysis of the transition of tivozanib and DPQ contained before and after the wet milling described in Example 3, that is, contained in the tivozanib drug substance obtained according to the method of Example 1 (before the step in Table 8) and the nanoparticle composition obtained in Example 3 (after the step in Table 8), with an ultraviolet absorbance detector (UVD) using HPLC. Here, the conversion of DPQ from HPLC Area (%) to weight (%) was calculated by correcting with a sensitivity coefficient.

[0125] The content of DPQ in the nanoparticle composition was measured by HPLC 37 (quantitative limit (lower limit value) was 0.05 Area%), and the detection limit (lower limit value) was 0.02 Area%. The content of DPQ after forming the nanoparticle composition was smaller than a significant figure of the quantitative limit, and was specifically 0.0290 Area%. From the results shown in Table 8, it was found that, also in the nanoparticle composition formulated as an eye drop in the present Example using the tivozanib drug substance containing Form I crystal of the tivozanib hydrochloride obtained according to Example 1, the DPQ content was less than 0.05 weight% in the tivozanib drug substance. That is, the content of Form I crystals was maintained at a high value even after the tivozanib drug substance containing Form I crystals of the tivozanib hydrochloride obtained according to Example 1 was formulated as an eye drop.

[0126] [Table 8] Table 8 Tivozanib DPQ HPLC Area% Weight% in drug substance Relative retention time 1.00 0.87 Before step 99.906% Less than 0.05% Less than 0.05% After step 99.873% Less than 0.05% Less than 0.05%

[0127] Example 4: A nanoparticle composition formulated as an eye drop according to the following formulation was prepared using the tivozanib drug substance containing Form I crystal of tivozanib hydrochloride obtained according to the method of Example 1, and the purity of tivozanib in the nanoparticle composition was measured. Zirconia balls (diameter: 0.1 mm) were placed in a zirconia container, the tivozanib drug substance prepared according to the method of Example 1 was weighed, and then an aqueous polyvinylpyrrolidone solution was added thereto, followed by wet milling (Mill / Mix, 1500 rpm, 1 minute, Mill / Mix, 400 rpm, 1 minute, 10 times) using a rotation / revolution nano pulverizer (NP-100 (manufactured by Thinky Corporation)). Thereafter, an aqueous solution containing polyvinylpyrrolidone and mannitol was added, followed by dispersion (Mill / Mix, 400 rpm, 5 minutes) using a rotation / revolution nano pulverizer, zirconia balls were removed (Clean Media, 2000 rpm, 1 minute, Mill / Mix, 400 rpm, 1 minute), and a nanoparticle composition formulated as an eye drop was obtained. The composition of the nanoparticle composition was as follows: tivozanib drug substance / polyvinylpyrrolidone / mannitol = 1 part by weight / 0.6 parts by weight / 2.25 parts by weight. When the average particle diameter of Form I crystals of tivozanib hydrochloride in the nanoparticle composition was measured using Zetasizer Nano (ZS (manufactured by Malvern Panalytical)), the average particle diameter was 187.6 nm. Table 9 shows the results of analysis of the transition of tivozanib and DPQ contained before and after the wet milling described in Example 4, that is, contained in the tivozanib drug substance obtained according to the method of Example 1 (before the step in Table 9) and the nanoparticle composition obtained in Example 4 (after the step in Table 9), with an ultraviolet absorbance detector (UVD) using HPLC. Here, the conversion of DPQ from HPLC Area (%) to weight (%) was calculated by correcting with a sensitivity coefficient.

[0128] The content of DPQ in the nanoparticle composition was measured by HPLC (quantitative limit (lower limit value) was 0.05 Area%), and the detection limit (lower limit value) was 0.02 Area%. The content of DPQ after forming the nanoparticle composition was smaller than a significant figure of the quantitative limit, and was specifically 0.0298 Area%. From the results shown in Table 9, it was found that, also in the formation of the nanoparticle composition formulated as an eye drop in the present Example using the tivozanib drug substance containing Form I crystal of the tivozanib hydrochloride obtained according to Example 1, the DPQ content was less than 0.05 weight% in the tivozanib drug substance. That is, the content of Form I crystals was maintained at a high value even after the tivozanib drug substance containing Form I crystals of the tivozanib hydrochloride obtained according to Example 1 was formulated as an eye drop.

[0129] [Table 9] Table 9 Tivozanib DPQ HPLC Area% Weight% in drug substance Relative retention time 1.00 0.87 Before step 99.906% Less than 0.05% Less than 0.05% After step 99.868% Less than 0.05% Less than 0.05%

[0130] It is clear to those skilled in the art that various modifications or alterations can be conceived within the scope of the claims, and it should be understood that the modifications or alterations naturally fall within the technical scope of the present invention. In addition, the components in the above-described embodiments may be freely combined without departing from the gist of the invention.

[0131] The present application is based on a U.S. Provisional Application (application number: 63 / 633,996) filed on April 15, 2024, the contents of which are incorporated herein by reference.

Claims

1. A method for producing Form I crystal of tivozanib hydrochloride, the method comprising:a step A of obtaining Form II crystal of tivozanib hydrochloride by subjecting Form I crystal of tivozanib hydrochloride to solvent-mediated transformation; anda step B of obtaining Form I crystal of tivozanib hydrochloride by subjecting the Form II crystal of tivozanib hydrochloride obtained in the above step A to solvent-mediated transformation.

2. A method for reducing a content of 2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (DPQ) in a tivozanib drug substance, the method comprising:a step A of obtaining Form II crystal of tivozanib hydrochloride by subjecting Form I crystal of tivozanib hydrochloride to solvent-mediated transformation; anda step B of obtaining Form I crystal of tivozanib hydrochloride by subjecting the Form II crystal of tivozanib hydrochloride obtained in the above step A to solvent-mediated transformation.

3. A tivozanib drug substance comprising a crystal of tivozanib hydrochloride or a crystal of a hydrate of tivozanib hydrochloride as an active ingredient in a content of 99.8 mass% or more.

4. A tivozanib drug substance comprising:a crystal of tivozanib hydrochloride or a crystal of a hydrate of tivozanib hydrochloride as an active ingredient; and2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (DPQ),wherein a mass of the DPQ is 0.04% or less with respect to a mass of the tivozanib drug substance.

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