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

Tivozanib drug substance and its manufacturing method

[0001] The present invention relates to a highly pure tivozanib drug substance and a method for producing the same.

[0002] Tivozanib, the active ingredient in FOTIVDA (registered trademark), is known as a VEGF receptor inhibitor. The chemical name of tivozanib is N-[2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-N'-(5-methylisoxazol-3-yl)urea, and its chemical structure is as follows:

[0003]

[0004] 2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (hereinafter also referred to as "DPQ"), a degradation impurity of tivozanib, tested positive in the Ames test (Non-Patent Document 1). Therefore, from a safety perspective, it is important to provide a high-purity tivozanib drug substance with a reduced DPQ content. In addition, since tivozanib is currently being developed as an eye drop formulation for ophthalmic diseases, DPQ that tested positive in the Ames test must be managed as a mutagenic impurity based on the ICH-M7 guidelines. For example, the acceptable daily intake of DPQ when administering eye drops for more than 10 years to a lifetime is 1.5 μg / day.

[0005] Tivozanib and its manufacturing method have been known so far (Patent Documents 1 to 11, Non-Patent Documents 2 and 3).

[0006] International Publication No. 2002 / 088110 International Publication No. 2004 / 035572 International Publication No. 2018 / 052053 Chinese Patent Application Publication No. 117417336 Chinese Patent Application Publication No. 117327061 Chinese Patent Application Publication No. 114213404 Chinese Patent Application Publication No. 114213405 Chinese Patent Application Publication No. 106967058 Chinese Patent Application Publication No. 102408418 Chinese Patent Application Publication No. 102532116 International Publication No. 2024 / 110606

[0007] FOTIVDA EMA Assessment report, 2017 Chinese Journal of New Drugs, 2013, 22(1), pp. 26-29)Chinese Journal of Pharmaceuticals, 2013, 44(6), pp. 541-543)

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

[0009] Therefore, an object of the present invention is to provide a high-purity tivozanib drug substance with a low content of impurities, particularly DPQ. Another object of the present invention is to provide a novel method for producing tivozanib hydrochloride type I crystals. Another object of the present invention is to provide a method for producing a tivozanib drug substance containing tivozanib hydrochloride type I crystals at a high purity. In the novel method for producing tivozanib hydrochloride type I crystals, it is preferable that the content of impurities such as DPQ is low when produced as a tivozanib drug substance.

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

[10] A tivozanib drug substance comprising tivozanib hydrochloride or a crystalline form of a hydrate thereof as active ingredients, and 2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (DPQ), wherein the mass of the DPQ is 0.167% or less relative to the mass of the tivozanib drug substance.

[11] A tivozanib drug substance comprising tivozanib hydrochloride or a crystalline form of a hydrate thereof as active ingredients, and 2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (DPQ), wherein the content of tivozanib hydrochloride or a crystalline form of a hydrate thereof as the active ingredients is 99.5% by mass or more, and the mass of the DPQ is 0.167% or less relative to the mass of the tivozanib drug substance.

[12] A tivozanib drug substance comprising tivozanib hydrochloride or a crystalline form of a hydrate thereof as active ingredients, and 2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (DPQ), wherein the content of tivozanib hydrochloride or a crystalline form of a hydrate thereof as the active ingredients is 99.8% by mass or more, and the mass of the DPQ is 0.167% or less, relative to the mass of the tivozanib drug substance.

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

[10] to

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

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

[10] to

[13] above, wherein the mass of DPQ is 0.04% or less, relative to the mass of the tivozanib drug substance.

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

[14] above, wherein the crystal of tivozanib hydrochloride or a hydrate thereof is a type I crystal or a type II crystal of tivozanib hydrochloride.

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

[15] above, wherein the crystals of tivozanib hydrochloride or a hydrate thereof are Type I crystals of tivozanib hydrochloride.

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

[16] above, wherein the content of crystals of tivozanib hydrochloride or a hydrate thereof or the content of DPQ is determined by LC.

[18] A therapeutic agent for ophthalmic diseases, which is an eye drop preparation comprising a tivozanib drug substance having a content of crystals of tivozanib hydrochloride or a hydrate thereof as an active ingredient of 99.5% by mass or more and a dispersion medium.

[19] A therapeutic agent for ophthalmic diseases, which is an eye drop preparation comprising a tivozanib drug substance having a content of crystals of tivozanib hydrochloride or a hydrate thereof as an active ingredient of 99.8% by mass or more and a dispersion medium.

[20] A therapeutic agent for ophthalmic diseases, comprising a tivozanib drug substance containing tivozanib hydrochloride or a hydrate thereof as an active ingredient, and a dispersant, wherein the total content of impurities derived from the tivozanib drug substance is 0.2% by mass or less in the tivozanib drug substance.

[21] A therapeutic agent for ophthalmic diseases, comprising tivozanib hydrochloride or a hydrate thereof as an active ingredient, a tivozanib drug substance containing 2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (DPQ), and a dispersant, wherein the mass of the DPQ is 0.167% or less relative to the mass of the tivozanib drug substance.

[22] The therapeutic agent for ophthalmic diseases according to

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

[23] The therapeutic agent for ophthalmological diseases according to

[21] or

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

[24] The therapeutic agent for ophthalmological diseases according to any one of

[18] to

[23] above, wherein the crystals of tivozanib hydrochloride or a hydrate thereof are Form I crystals or Form II crystals of tivozanib hydrochloride.

[25] The therapeutic agent for ophthalmological diseases according to any one of

[18] to

[24] above, wherein the crystals of tivozanib hydrochloride or a hydrate thereof are Form I crystals of tivozanib hydrochloride.

[26] The therapeutic agent for ophthalmological diseases according to any one of

[18] to

[25] above, wherein the content of tivozanib hydrochloride or a hydrate thereof or the 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 ophthalmic disease is age-related macular degeneration accompanied by choroidal neovascularization (age-related macular degeneration).

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

[18] to

[27] above, wherein the ophthalmic disease is selected from the group consisting of atrophic age-related macular degeneration, choroidal neovascularization, choroidal neovascularization in pathological myopia, macular edema, macular edema associated with central retinal 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, central retinal vein occlusion, cystoid macular edema, intravitreal hemorrhage associated with diabetic retinopathy, Eales' disease, central serous chorioretinopathy, epiretinal membrane, uveitis, multifocal choroiditis, anterior ischemic optic neuropathy, corneal neovascularization, pterygium, intraocular melanoma, glioma, acquired retinal angioma, radiation retinopathy, tuberous sclerosis, conjunctival squamous cell carcinoma, and ocular hypertension.

[29] The therapeutic agent for ophthalmological diseases according to any one of

[18] to

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

[30] The therapeutic agent for ophthalmological diseases according to any one of

[18] to

[29] above, wherein the tivozanib hydrochloride or hydrate thereof crystals are suspended in the form of nanoparticles.

[31] The therapeutic agent for ophthalmological diseases according to any one of

[18] to

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

[32] The therapeutic agent for ophthalmological diseases according to any one of

[18] to

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

[33] The therapeutic agent for an ophthalmic disease according to the above-mentioned

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

[34] The therapeutic agent for ophthalmologic diseases according to any one of

[18] to

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

[35] The therapeutic agent for ophthalmologic diseases according to any one of

[18] to

[33] above, further comprising a thickener.

[36] The therapeutic agent for ophthalmologic diseases according to

[34] or

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

[37] The surfactant is selected from the group consisting of 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-α-phosphatidylcholine (PC), 1,2-dipalmitoylphosphatidylcholine (DPPC), oleic acid, natural lecithin, synthetic lecithin The therapeutic agent for ophthalmic diseases according to any one of the above

[34] to

[36] , wherein the active ingredient is one or more substances selected from the group consisting of glycerin, 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 ophthalmic diseases according to any one of the above

[18] to

[37] , further comprising one or more components selected from the group consisting of preservatives and inclusion materials.

[39] The therapeutic agent for ophthalmological diseases 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 ophthalmological diseases according to

[38] or

[39] above, wherein the inclusion substance is one or more substances selected from α-cyclodextrin, β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, and γ-cyclodextrin.

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

[18] to

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

[42] Use of tivozanib drug substance for producing the therapeutic agent for ophthalmological diseases according to any one of

[18] to

[40] above.

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

[17] above for use in 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 ophthalmic diseases, 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: Step A of subjecting tivozanib hydrochloride Type I crystals to solvent-mediated transformation to obtain tivozanib hydrochloride Type II crystals; and Step B of subjecting the tivozanib hydrochloride Type II crystals obtained in Step A to solvent-mediated transformation to obtain tivozanib hydrochloride Type I crystals.

[49] The tivozanib drug substance according to any one of the above-mentioned [7] to

[17] , which is produced by a method comprising: Step A, in which tivozanib hydrochloride type I crystals are subjected to solvent-mediated rearrangement to obtain tivozanib hydrochloride type II crystals; and Step B, in which tivozanib hydrochloride type II crystals obtained in Step A are subjected to solvent-mediated rearrangement to obtain tivozanib hydrochloride type I crystals.

[50] A therapeutic agent for ophthalmic diseases, which is an eye drop preparation comprising the tivozanib drug substance according to the above-mentioned

[48] or

[49] and a dispersion medium.

[0011] According to the present invention, it is possible to provide a high-purity tivozanib drug substance with a reduced content of impurities, particularly DPQ.

[0012] Fig. 1 is a diagram showing an overview of steps 1 to 8 in Example 1. Fig. 2 shows ReactRaman data in Example 1. Fig. 3 shows Easy Viewer data in Example 1.

[0013] The tivozanib drug substance of this embodiment contains tivozanib hydrochloride or a hydrate thereof as an active ingredient, and may contain starting materials or by-products that may be produced in the manufacturing process as impurities. Thus, the tivozanib drug substance may be a composition that contains tivozanib hydrochloride or a hydrate thereof and, in some cases, by-products or the like as impurities. Here, when expressing the content of impurities in the tivozanib drug substance, the total mass of the tivozanib drug substance is used as the basis.

[0014] In this specification, tivozanib hydrochloride or a hydrate thereof may be collectively referred to as tivozanib.

[0015] The hydrate of tivozanib hydrochloride is not particularly limited in the number of waters of hydration, and may be a monohydrate, dihydrate, or trihydrate.

[0016] The tivozanib drug substance of this embodiment preferably contains at least one of tivozanib hydrochloride crystals and tivozanib hydrochloride hydrate crystals, more preferably tivozanib hydrochloride Type I crystals or Type II crystals, and even more preferably tivozanib hydrochloride Type I crystals. Here, Type I crystals of tivozanib hydrochloride are crystals of tivozanib hydrochloride monoadduct and monohydrate (monohydrochloride monohydrate), and Type II crystals of tivozanib hydrochloride are crystals of tivozanib hydrochloride monoadduct (monohydrochloride) (WO 2004 / 035572). In this specification, Type I crystals and Type II crystals of tivozanib hydrochloride are also simply referred to as "Type I crystals" and "Type II crystals," respectively.

[0017] The type I crystal of tivozanib hydrochloride is a crystal that has, in powder X-ray diffraction, peaks showing relative intensities of 10% or more at at least the diffraction angles (2θ) shown in Table 1 below.

[0018]

[0019] In the Type I crystals of tivozanib hydrochloride, the relative intensity shown at the diffraction angle (2θ) shown in Table 1 above is preferably 15% or more, more preferably 20% or more, even more preferably 25% or more, and particularly preferably 30% or more. The diffraction angle (2θ) value may contain errors due to factors such as the purity of the crystals in the powder, the particle size of the powder, the water content in the powder, and errors due to the measurement limits of the powder X-ray diffractometer when performing powder X-ray diffraction analysis. When a crystal is defined herein using the diffraction angle 2θ, the range of possible errors in the diffraction angle 2θ value of the crystal of the present invention can also be included. Typically, the range of such errors is within ±0 to ±0.02 of the specified value. Therefore, when the diffraction angle 2θ value of a crystal is represented by X as shown in Table 1 above, X is typically 0 to 0.20, preferably 0 to 0.15, more preferably 0 to 0.10, and even more preferably 0 to 0.05.

[0020] More preferred type I crystals of tivozanib hydrochloride are crystals that, in powder X-ray diffraction, have peaks showing relative intensities of 10% or more at at least the diffraction angles (2θ) shown in Table 2 below.

[0021]

[0022] In the Type I crystals of tivozanib hydrochloride, the relative intensity shown at the diffraction angles (2θ) shown in Table 2 above is preferably 15% or more, more preferably 20% or more.

[0023] The type II crystal of tivozanib hydrochloride is a crystal that has, in powder X-ray diffraction, peaks showing relative intensities of 10% or more at at least the diffraction angles (2θ) shown in Table 3 below.

[0024]

[0025] In the Type II crystal of tivozanib hydrochloride, the relative intensity shown at the diffraction angles (2θ) shown in Table 3 above is preferably 15% or more, more preferably 20% or more.

[0026] More preferred type II crystals of tivozanib hydrochloride are crystals that have, in powder X-ray diffraction, peaks showing relative intensities of 10% or more at at least the diffraction angles (2θ) shown in Table 4 below.

[0027]

[0028] In the Type II crystal of tivozanib hydrochloride, the relative intensity shown at the diffraction angles (2θ) shown in Table 4 above is preferably 15% or more, more preferably 20% or more.

[0029] The type I crystals and type II crystals of tivozanib and tivozanib hydrochloride used in the method of this embodiment can be produced by the methods disclosed in WO 2002 / 088110 and WO 2004 / 035572, or methods similar thereto.

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

[0031] When tivozanib and Form I and II crystals of tivozanib hydrochloride are produced by the methods disclosed in WO 2002 / 088110 and WO 2004 / 035572, or methods similar thereto, DPQ may be generated as an impurity.

[0032] The present inventors have found that, in this embodiment, solvent-mediated transition between Form I crystals and Form II crystals of tivozanib hydrochloride can reduce the content of impurities, particularly DPQ, contained in the tivozanib drug substance. More specifically, they have found that controlling the water content in the solvent during solvent-mediated transition can control the solvent-mediated transition from Form I crystals to Form II crystals and from Form II crystals to Form I crystals, and that this process can reduce the content of impurities, particularly DPQ. They have also found that the solubility difference between Form I crystals and Form II crystals of tivozanib hydrochloride varies depending on the water content (proportion) in the solvent, that the most stable form of tivozanib hydrochloride varies depending on the water content (proportion) in the solvent, and that the water proportion at which the most stable form develops varies with temperature. When ethanol is used as the solvent, for example, at 45°C, Form II crystals are stable when the water content in the solvent is less than 3% by volume, but Form I crystals are stable when the water content in the solvent is 3% by volume or more.

[0033] The method for producing tivozanib hydrochloride Type I crystals of this embodiment includes Step A, in which tivozanib hydrochloride Type I crystals are subjected to solvent-mediated rearrangement to obtain tivozanib hydrochloride Type II crystals, and Step B, in which tivozanib hydrochloride Type II crystals obtained in the previous step are subjected to solvent-mediated rearrangement to obtain tivozanib hydrochloride Type I crystals. The method including these two steps is also a method for producing a tivozanib drug substance. Furthermore, the method including these two steps is also a method for reducing the DPQ content in a tivozanib drug substance. Compared to a tivozanib drug substance produced by a method not including the above two steps, the DPQ content of the tivozanib drug substance produced by the method including these two steps is reduced. As used herein, the term "method of this embodiment" refers to at least one of a method for producing tivozanib hydrochloride Type I crystals, a method for producing a tivozanib drug substance, and a method for reducing the DPQ content in a tivozanib drug substance.

[0034] The method of this embodiment preferably includes 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 adding tivozanib drug substance containing tivozanib hydrochloride Form I crystals to a reaction vessel to obtain a mixture, step 3 is a step of solvent-mediated transformation of tivozanib hydrochloride Form I crystals to tivozanib hydrochloride Form II crystals in the mixture, step 4 is a step of adding water to the mixture, step 5 is a step of solvent-mediated transformation of tivozanib hydrochloride Form II crystals to tivozanib hydrochloride Form I crystals in the mixture, step 6 is a step of lowering the temperature of the mixture and aging the crystals, step 7 is a step of filtering the tivozanib drug substance containing tivozanib hydrochloride Form I crystals from the mixture, and step 8 is a step of drying the tivozanib drug substance containing tivozanib hydrochloride Form I crystals. Here, the tivozanib hydrochloride Form II crystals obtained in step 3 can be directly used in steps 4 and beyond without isolation. The order of steps 1 and 2 may be reversed. The above-mentioned step A includes steps 1 to 3, and step B includes steps 4 and 5.

[0035] In the method of this embodiment, the solvent used in step 1 is preferably ethanol. Furthermore, in steps 1 and 2, for example, at room temperature, ethanol is added to a reaction vessel, and a tivozanib drug substance containing tivozanib hydrochloride Form I crystals is added to the reaction vessel, i.e., the tivozanib drug substance containing tivozanib hydrochloride Form I crystals is preferably added to ethanol. The amount of ethanol used is not particularly limited, but is, for example, 15 v / w to 22 v / w relative to the mass of the tivozanib drug substance containing tivozanib hydrochloride Form I crystals. Here, with respect to v / w, the amount of ethanol used relative to the mass of the tivozanib drug substance is α v / w, meaning that when the mass of the tivozanib drug substance is, for example, 1.0 g, the amount of ethanol used is α mL. Throughout this specification, numerical values ​​described using the unit v / w similarly represent the volume (mL) of liquid relative to the mass (g) of the reference substance.

[0036] In the method of this embodiment, in step 3, the solvent-mediated transformation is carried out by heating and stirring the mixture at a temperature in the range of 30°C to 65°C for an appropriate stirring time depending on the reaction scale, for example, for 3 hours or less, 1 hour or less, 10 minutes or less, etc. To promote the transformation of the 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, but is preferably 45°C or higher. On the other hand, to suppress the formation 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, but is preferably 60°C or lower. In a preferred embodiment, in step 3, the mixture is heated and stirred at a temperature in the range of 40°C to 60°C for 1 hour.

[0037] In the method of this embodiment, in step 4, water is added to the mixed solution obtained in step 3. By adjusting the volume of water in the mixed solution after the addition of water in step 4 to, for example, 0.7 v / w to 4.0 v / w relative to the mass of the tivozanib drug substance containing the Type I crystals of tivozanib hydrochloride added in step 2, the transformation of Type II crystals to Type I crystals in the subsequent step 5 is facilitated. The preferred water content varies depending on the temperature, but at a temperature of, for example, 40 to 60°C, the total volume of water in the mixed solution after the addition of water in step 4 to, for example, 0.7 v / w to 4.0 v / w, preferably 1.7 v / w to 2.4 v / w, more preferably 2 v / w relative to the mass of the tivozanib drug substance containing the Type I crystals of tivozanib hydrochloride added in step 2, facilitates the transformation of Type II crystals to Type I crystals. In another embodiment, for example, at a temperature of 40 to 60°C, the ratio of water to the mixed solvent of ethanol and water after adding water in step 4 is, for example, 5% by volume to 15% by volume, preferably 7% by volume to 15% by volume, which makes it easier to transform the type II crystal into the type I crystal in step 5.

[0038] In the method of this embodiment, it is preferable to add a tivozanib drug substance containing Type I crystals of tivozanib hydrochloride as seed crystals together with the addition of water in Step 4. The tivozanib drug substance containing Type I crystals of tivozanib hydrochloride used as seed crystals is not particularly limited as long as it contains Type I crystals. In one embodiment, the tivozanib drug substance used as seed crystals contains 98% by mass or more of Type I crystals of tivozanib hydrochloride. In Step 4, for example, 0.01 to 0.2% by mass of a tivozanib drug substance used as seed crystals, which has been separately produced in accordance with the method disclosed in WO 2004 / 035572, is added to the tivozanib drug substance containing Type I crystals of tivozanib hydrochloride added in Step 2.

[0039] In the method of this embodiment, in step 5, the solvent-mediated transition is carried out by heating and stirring the mixture for, for example, 10 hours or more at a temperature in the range of 30°C to 65°C, thereby slowly transitioning the Type II crystals in the mixture to Type I crystals. To promote the crystal form transition, 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, but is preferably 45°C or higher. On the other hand, to suppress the production 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, but is preferably 60°C or lower. In a preferred embodiment, in step 5, the mixture is heated and stirred for 10 hours or more at a temperature in the range of 40°C to 60°C.

[0040] In the method of this embodiment, the resulting type I crystals can be efficiently recovered in step 6 by, for example, cooling the mixture to 25°C or lower.

[0041] In step 7 of the method of this embodiment, the suspension containing the Form I crystals of tivozanib hydrochloride precipitated in step 6 is filtered, and the obtained crystals are washed with a mixed solvent of water and ethanol. The solvent used for washing can be a mixed solvent of water and ethanol in any ratio, but is preferably a mixed solvent in which the ratio of water to the mixed solvent of water and ethanol is 3 to 15% by volume, more preferably 7 to 12% by volume. In step 8 of the method of this embodiment, the tivozanib drug substance containing the Form I crystals 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 this embodiment can be, for example, 98.0% by mass or more, 98.1% by mass or more, 98.2% by mass or more, 98.3% by mass or more, 98.4% by mass or more, 98.5% by mass or more, 98.6% by mass or more, 98.7% by mass or more, 98.8% by mass or more, 98.9% by mass or more, 99.0% by mass or more, 99.1% by mass or more, 99.2% by mass or more, 99.3% by mass or more, 99.4% by mass or more, 99.5% by mass or more, 99.6% by mass or more, 99.7% by mass or more, or 99.8% by mass or more. The content of tivozanib in the tivozanib drug substance can be measured and calculated using liquid chromatography (LC). More specifically, it can be measured and calculated using the methods described in the Examples.

[0043] In a method for quantifying a drug substance using liquid chromatography (LC), the upper limit of the content specification is often set to more than 100%, such as 98.0 to 102.0%, as described in the 18th Edition of the Japanese Pharmacopoeia. When the content of tivozanib in the tivozanib drug substance of this embodiment is quantified using liquid chromatography (LC), the upper limit is 102.0% by mass.

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

[0045] The content of DPQ in the tivozanib drug substance of this embodiment, relative to the mass of the tivozanib drug substance, is, for example, 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0. Examples of the DPQ content include 115% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, 0.07% by mass or less, 0.06% by mass or less, 0.05% by mass or less, 0.04% by mass or less, 0.03% by mass or less, 0.02% by mass or less, and 0.01% by mass or less. The DPQ content in the tivozanib drug substance can be measured and calculated using liquid chromatography (LC). More specifically, it can be measured and calculated using the methods described in the Examples.

[0046] When the content of tivozanib in the tivozanib drug substance of this embodiment is 98.0% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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 this embodiment is 98.1% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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 this embodiment is 98.2% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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 this embodiment is 98.3% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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 this embodiment is 98.4% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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 this embodiment is 98.5% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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 this embodiment is 98.6% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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 this embodiment is 98.7% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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 this embodiment is 98.8% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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 this embodiment is 98.9% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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 this embodiment is 99.0% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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 this embodiment is 99.1% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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 this embodiment is 99.2% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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 this embodiment is 99.3% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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 this embodiment is 99.4% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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 this embodiment is 99.5% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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 this embodiment is 99.6% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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 this embodiment is 99.7% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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 this embodiment is 99.8% by mass or more, the content of DPQ is 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.11 5% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.100% by mass or less, 0.09% by mass or less, 0.083% by mass or less, 0.08% by mass or less, It is preferably 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] According to the ICH-M7 guidelines, assuming that the acceptable daily intake of DPQ is 1.5 μg, the acceptable DPQ content in the tivozanib drug substance of this 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 the product of 1. "drug concentration," 2. "amount administered per administration," and 3. "number of administrations per day." For example, in the Ph1 study of tivozanib ophthalmic solution (NCT04594681), when the repeated administration groups were categorized based on the total daily dose, the doses of the tivozanib drug substance could be roughly divided into three groups: 0.45 mg / day, 0.9 mg / day, and 1.8 mg / day. Considering the tolerable intake of DPQ (1.5 μg / day) at each of these three doses, when an eye drop contains tivozanib drug substance, the allowable mass percentages of DPQ in the tivozanib drug substance are 0.333 mass% or less, 0.167 mass% or less, and 0.083 mass% or less, respectively. Since no serious side effects were observed at the maximum dose of 1.8 mg / day of tivozanib drug substance in the Ph1 study, the total daily dose of tivozanib drug substance for clinical use can be selected from doses of 1.8 mg / day or less. For example, the total daily dose of tivozanib drug substance can be selected from 0.3 mg / day, 0.6 mg / day, 1.2 mg / day, and 1.5 mg / day, and in these cases, the mass percentages of DPQ allowable in the tivozanib drug substance are 0.500 mass% or less, 0.250 mass% or less, 0.125 mass% or less, and 0.100 mass% or less, respectively.

[0066] Because DPQ is a degradation product of tivozanib, there is a possibility that tivozanib may decompose and produce DPQ even after the production of the tivozanib drug substance. Therefore, from the perspective of stable supply, it is important to reduce the DPQ content as much as possible at the time the tivozanib drug substance is produced.

[0067] The therapeutic agent for an ophthalmic disease of this embodiment is an eye drop containing tivozanib active ingredient and a dispersion medium.

[0068] In the therapeutic agent for ophthalmic diseases of this embodiment, tivozanib crystals are preferably suspended in the form of nanoparticles. In other words, tivozanib crystals are preferably dispersed in the eye drops in the form of solid nanoparticles so as to form a suspension. In this case, some of the tivozanib crystals may be dissolved in the eye drops.

[0069] The ophthalmic disease therapeutic agent of this embodiment preferably contains tivozanib crystals in the form of nanoparticles, but may also contain tivozanib crystals in a form other than nanoparticles. Examples of forms other than nanoparticles include microparticles. In the ophthalmic disease therapeutic agent of this embodiment, the content of tivozanib crystals in a form other than nanoparticles may be 20% by mass or less of the content of tivozanib crystals in the form of nanoparticles. In the ophthalmic disease therapeutic agent, preferably 60% by mass to 100% by mass of the total amount of tivozanib crystals is in the form of nanoparticles, more preferably 70% by mass to 100% by mass is in the form of nanoparticles, and even more preferably 80% by mass to 100% by mass is in the form of nanoparticles.

[0070] As used herein, "nanoparticle form" means that a substance is in the form of particles on the order of nanometers, generally meaning a particle form having an average particle size of 10 to 1000 nm. Furthermore, as used herein, "microparticle form" means that a substance is in the form of particles on the order of micrometers, generally meaning a particle form having an average particle size of more than 1 μm and not more than 1000 μm. The nanoparticle form of tivozanib crystals contained in the therapeutic agent for ophthalmic diseases of this embodiment are preferably prepared by pulverizing or crystallizing the tivozanib drug substance.

[0071] The nanoparticle-form tivozanib crystals contained in the therapeutic agent for an ophthalmic disease of this embodiment preferably have an average particle size of 10 to 400 nm, more preferably 10 to 300 nm, even more preferably 50 to 300 nm, and even more preferably 100 to 300 nm.

[0072] The method for measuring the average particle size of tivozanib crystals herein is not particularly limited. The average particle size can be measured, for example, by dynamic light scattering under measurement conditions of a scattering angle of 173° and a wavelength of 633 nm.

[0073] In the ophthalmic disease therapeutic agent of this embodiment, the content of tivozanib relative to the mass of the tivozanib drug substance may be, for example, 98.0% by mass or more, 98.1% by mass or more, 98.2% by mass or more, 98.3% by mass or more, 98.4% by mass or more, 98.5% by mass or more, 98.6% by mass or more, 98.7% by mass or more, 98.8% by mass or more, 98.9% by mass or more, 99.0% by mass or more, 99.1% by mass or more, 99.2% by mass or more, 99.3% by mass or more, 99.4% by mass or more, 99.5% by mass or more, 99.6% by mass or more, 99.7% by mass or more, or 99.8% by mass or more.

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

[0075] In the ophthalmic disease therapeutic agent of this embodiment, the content of DPQ relative to the mass of the tivozanib drug substance includes, for example, 0.167% by mass or less, 0.160% by mass or less, 0.155% by mass or less, 0.150% by mass or less, 0.145% by mass or less, 0.140% by mass or less, 0.135% by mass or less, 0.130% by mass or less, 0.125% by mass or less, 0.120% by mass or less, 0.115% by mass or less, 0.110% by mass or less, 0.105% by mass or less, 0.10% by mass or less, 0.09% by mass or less, 0.08% by mass or less, 0.07% by mass or less, 0.06% by mass or less, 0.05% by mass or less, 0.04% by mass or less, 0.03% by mass or less, 0.02% by mass or less, and 0.01% by mass or less, relative to the mass of the tivozanib drug substance.

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

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

[0078] When an ultraviolet absorbance detector (UVD) is used, the HPLC area (%) can be calculated as follows: the peak areas of the peaks derived from the sample on the chromatogram are calculated, and the peak area of ​​each peak is divided by the sum of the calculated peak areas. The sum of the numerical values ​​of the peaks corresponding to tivozanib is defined as the HPLC area (%) of tivozanib, and the sum of the numerical values ​​of the peaks corresponding to DPQ is defined as the HPLC area (%) of DPQ.

[0079] The mass (%) of tivozanib is calculated using a standard with a known tivozanib content, the peak area ratio of each peak corresponding to tivozanib in the standard and the measurement sample in HPLC, the ratio of the weighed amounts of the standard and the measurement sample, and the content (% by mass) of tivozanib in the standard. The HPLC area (%) of DPQ can be converted to mass (%) by multiplying it by the relative response factor determined from the ratio of the HPLC area (%) obtained by analyzing equal amounts 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 ophthalmic diseases are each measured in the same manner as the tivozanib drug substance.

[0081] Examples of the dispersion medium used in the therapeutic agent for ophthalmic diseases of the present embodiment include water, alcohol, and liquid paraffin. As the dispersion medium, water and liquid paraffin are preferred, and water is more preferred. One type of dispersion medium may be used, or two or more types may be used in combination.

[0082] In the ophthalmic disease therapeutic agent of this embodiment, the content of the dispersion medium is not particularly limited, and the content of the dispersion medium in the ophthalmic disease therapeutic agent may be adjusted to the content of other components other than the dispersion medium contained in the ophthalmic disease therapeutic agent per 100 parts by mass of the ophthalmic disease therapeutic agent, and the dispersion medium may be contained in an amount that is the remainder. Specifically, the dispersion medium may be contained in the ophthalmic disease therapeutic agent such that the sum of the contents of other components other than the dispersion medium contained in the ophthalmic disease therapeutic agent and the content of the dispersion medium totals 100 parts by mass, i.e., the ophthalmic disease therapeutic agent is 100 parts by mass. The content of the dispersion medium is, for example, preferably 68 to 99.9 parts by mass, more preferably 78 to 99.9 parts by mass, and even more preferably 85 to 99.9 parts by mass, relative to 100 parts by mass of the ophthalmic disease therapeutic agent.

[0083] The dispersion medium preferably contains a solute. The solute contained in the dispersion medium is not particularly limited, but is preferably one used as an isotonic agent in the pharmaceutical field. Examples of solutes contained in the dispersion medium include sodium chloride, glucose (dextrose), glycerol, mannitol, sodium dihydrogen phosphate, sodium hydrogen phosphate hydrate, sodium bicarbonate, trishydroxymethylaminomethane, citric acid hydrate, boric acid, borax, phosphoric acid, etc. The solute is preferably sodium chloride, glucose (dextrose), glycerol, or mannitol. One type of solute may be used, or two or more types may be used in combination.

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

[0085] The therapeutic agent for ophthalmological disease of this embodiment may further contain, in addition to the tivozanib drug substance and dispersion medium of this embodiment, one or more components selected from a thickener and a surfactant, or one or more components selected from a preservative and an inclusion material. The therapeutic agent for ophthalmological disease of this embodiment preferably further contains, in addition to the tivozanib drug substance and dispersion medium of this embodiment, one or more components selected from a thickener and a surfactant, as well as one or more components selected from a preservative and an inclusion material. The thickener, surfactant, preservative, and inclusion material may be one or more of the candidate components listed below, or two or more of these may be used.

[0086] Examples of thickeners used in the ophthalmic disease therapeutic agent of this embodiment include carboxyvinyl polymer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, povidone (polyvinylpyrrolidone), partially saponified polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxyethyl cellulose, amorphous cellulose, methylcellulose, magnesium aluminum silicate, and triethanolamine. Preferred thickeners are polyvinyl alcohol, povidone (polyvinylpyrrolidone), hydroxypropyl cellulose, hydroxypropyl methylcellulose, and hydroxymethylcellulose. One type of thickener may be used, or two or more types may be used in combination.

[0087] In the ophthalmic disease therapeutic agent of the present embodiment, the content of the thickener is not particularly limited, but is, for example, preferably 0.01 to 5 parts by mass, more preferably 0.05 to 3 parts by mass, and even more preferably 0.1 to 2.5 parts by mass, relative to 100 parts by mass of the ophthalmic disease therapeutic agent.

[0088] Examples of surfactants used in the ophthalmic disease therapeutic agent of this 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-α-phosphatidylcholine (PC), 1,2- Examples of surfactants include 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. Preferred surfactants include polyoxyethylene sorbitan monooleate and poloxamer, with polyoxyethylene sorbitan monooleate (Polysorbate 80) and poloxamer (Pluronic (registered trademark) F-127) being more preferred. One surfactant may be used, or two or more surfactants may be used in combination.

[0089] In the ophthalmic disease therapeutic agent of the present embodiment, the content of the surfactant is not particularly limited, but is, for example, preferably 0 to 5 parts by mass, more preferably 0 to 3 parts by mass, and even more preferably 0 to 1.0 part by mass, relative to 100 parts by mass of the ophthalmic disease therapeutic agent.

[0090] In one preferred embodiment of the therapeutic agent for ophthalmic diseases of this embodiment, it contains a thickener but does not contain a surfactant.

[0091] When a thickener and a surfactant are used in combination, the combination of the thickener and the surfactant is not particularly limited, and examples thereof include combinations of hydroxypropyl methylcellulose and polyoxyethylene sorbitan monooleate, hydroxypropyl cellulose and polyoxyethylene sorbitan monooleate, hydroxypropyl cellulose and tyloxapol, povidone and polyoxyethylene sorbitan monooleate, polyvinyl alcohol and polyoxyethylene sorbitan monooleate, and poloxamer and polyoxyethylene sorbitan monooleate. Preferred combinations of thickeners and surfactants are those of hydroxypropyl cellulose and polyoxyethylene sorbitan monooleate, povidone and polyoxyethylene sorbitan monooleate, polyvinyl alcohol and polyoxyethylene sorbitan monooleate, and poloxamer and polyoxyethylene sorbitan monooleate, and more preferred are those of hydroxypropyl cellulose and polyoxyethylene sorbitan monooleate, povidone and polyoxyethylene sorbitan monooleate, and poloxamer and polyoxyethylene sorbitan monooleate. When a thickener and a surfactant are used in combination, the mass ratio of the thickener and the surfactant is not particularly limited, but is, for example, 0 to 500, preferably 0 to 60, and more preferably 0 to 10, as the mass ratio of the surfactant to the thickener (surfactant / thickener).

[0092] Examples of preservatives used in the ophthalmic disease therapeutic agent of this embodiment include benzalkonium chloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, sodium edetate hydrate, chlorhexidine gluconate, and sorbic acid. Benzalkonium chloride is preferred as the preservative. One type of preservative may be used, or two or more types may be used in combination.

[0093] In the ophthalmic disease therapeutic agent of the present embodiment, the content of the preservative is not particularly limited, but is, for example, preferably 0 to 1 part by mass, more preferably 0 to 0.75 parts by mass, and even more preferably 0 to 0.5 parts by mass, relative to 100 parts by mass of the ophthalmic disease therapeutic agent.

[0094] The inclusion substance used in the ophthalmic disease therapeutic agent of this embodiment is not particularly limited as long as it has the property of incorporating molecules, and examples thereof include α-cyclodextrin, β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), γ-cyclodextrin, etc. As the inclusion substance, β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin are preferred, and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) is more preferred. One type of inclusion substance may be used, or two or more types may be used in combination.

[0095] In the ophthalmic disease therapeutic agent of the present embodiment, the content of the inclusion material is not particularly limited, but is, for example, preferably 0 to 1 part by mass, more preferably 0 to 0.75 parts by mass, and even more preferably 0 to 0.5 parts by mass, relative to 100 parts by mass of the ophthalmic disease therapeutic agent.

[0096] The therapeutic agent for ophthalmic diseases of this embodiment can be administered locally to the eye. Examples of local administration to the eye include eye drops, subconjunctival administration, sub-Tenon administration, intravitreal administration, suprachoroidal injection, periocular injection, administration via an intraocular implant, or administration via other drug delivery devices, with eye drops being preferred.

[0097] The therapeutic agent for ophthalmic diseases of this embodiment can be used for the prevention and treatment of vascular endothelial growth factor (VEGF)-related diseases, preferably ophthalmic diseases, by administering it to mammals or the like.

[0098] Vascular endothelial growth factor (VEGF)-associated diseases include, for example, ophthalmological diseases.

[0099] Examples of ophthalmic diseases related to vascular endothelial growth factor (VEGF) include neovascular age-related macular degeneration (AMD) associated with choroidal neovascularization. degeneration), atrophic age-related macular degeneration, choroidal neovascularization, choroidal neovascularization in pathological myopia, macular edema, macular edema associated with central retinal 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, central retinal vein occlusion, cystoid macular edema, intravitreal hemorrhage due to diabetic retinopathy, Eales' disease, central serous chorioretinopathy, epiretinal membrane, uveitis, multifocal choroiditis, anterior ischemic optic neuropathy, corneal neovascularization, pterygium, intraocular melanoma, glioma, acquired retinal hemangioma, radiation retinopathy, tuberous sclerosis, conjunctival squamous cell carcinoma, and ocular hypertension. The vascular endothelial growth factor (VEGF)-associated ophthalmic disease is preferably neovascular age-related macular degeneration accompanied by choroidal neovascularization, choroidal neovascularization in pathological myopia, retinal vein occlusion, branch retinal vein occlusion, central retinal vein occlusion, macular edema associated with central retinal vein occlusion, diabetic macular edema, diabetic retinopathy, proliferative diabetic retinopathy, retinopathy of prematurity, or neovascular glaucoma.

[0100] The above-mentioned therapeutic agent for ophthalmological diseases can be used for the treatment, prevention, etc. of vascular endothelial growth factor (VEGF)-related ophthalmological diseases. Among these, it is preferable to use it for the prevention, treatment, etc. of ophthalmological diseases such as neovascular age-related macular degeneration accompanied by choroidal neovascularization, macular edema associated with central retinal vein occlusion, choroidal neovascularization in pathological myopia, diabetic macular edema, neovascular glaucoma, and retinopathy of prematurity, for which existing anti-VEGF inhibitors (intravitreal injections) have been approved for use, as well as proliferative diabetic retinopathy and uveitis, for which the therapeutic effects of anti-VEGF inhibitors (intravitreal injections) have been reported in clinical trials, even though they are not approved for use.

[0101] In the above-mentioned ophthalmic diseases, for example, intravitreal injection of anti-VEGF inhibitors has been shown to have good therapeutic effects (such as recovery of best corrected visual acuity, histological improvement such as thinning of retina thickened by pathological conditions, etc.) in clinical practice. However, for example, existing anti-VEGF inhibitors (intravitreal injections), although highly effective, require continuous treatment due to the intravitreal injection route and high recurrence rate, which places a significant burden on patients, their families, and medical professionals, and has become a social problem. For these reasons, in the above-mentioned ophthalmic diseases, the development of drugs (e.g., eye drops, etc.) that can be administered by a non-invasive and simple route other than intravitreal injection is desired in order to reduce the burden on patients, their families, and medical professionals, etc. The ophthalmic disease treatment agent of this embodiment is useful in that the active ingredient can be administered to patients by a route such as eye drops.

[0102] The form of the therapeutic agent for ophthalmologic diseases of this embodiment is not particularly limited, but is preferably a liquid (liquid preparation), and as a liquid preparation, a suspension preparation or a solution preparation is more preferable. The therapeutic agent for ophthalmologic diseases of this embodiment may be prepared by dissolving or dispersing some or all of the components of the therapeutic agent for ophthalmologic diseases of this embodiment, or a powder obtained by lyophilizing them, in a dispersion medium such as water.

[0103] The method for producing the tivozanib drug substance containing Type I crystals of tivozanib hydrochloride in the form of nanoparticles in the ophthalmic disease therapeutic agent of this embodiment is not particularly limited, and can be produced by a nanoparticle formation method commonly used in the technical field of pharmaceuticals, such as pulverization. For example, the nanoparticle formation method can be such that the tivozanib drug substance of this embodiment containing Type I crystals of tivozanib hydrochloride in the form of nanoparticles is pulverized using commercially available equipment (such as zirconia containers and zirconia balls) or a commercially available nano-pulverizer, followed by purification using a commercially available centrifuge. Alternatively, the tivozanib drug substance containing Type I crystals of tivozanib hydrochloride in the form of nanoparticles can be produced by crystallizing the tivozanib drug substance from a solution of tivozanib by applying a stimulus in the liquid or gas phase.

[0104] In the pulverization step, one or more components selected from a thickener, a surfactant, a dispersion medium, a preservative, and an inclusion material may be added to the tivozanib drug substance of this embodiment, and then pulverized. In the pulverization step, one or more components selected from a thickener, a surfactant, and a dispersion medium may be added, and one or more components selected from a preservative and an inclusion material may also be added, and then pulverized.

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

[0106] The purification method is not particularly limited, but may be performed using a commercially available centrifuge or the like.

[0107] A nanoparticle composition formulated from tivozanib drug substance containing Type I crystals of tivozanib hydrochloride in the form of nanoparticles obtained by the nanoparticle formation method described herein can be used as a pharmaceutical composition, preferably as a therapeutic agent for ophthalmic diseases, and more preferably 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 for the tivozanib drug substance or the therapeutic agent for ophthalmic diseases, respectively.

[0109] The descriptions in this specification regarding the therapeutic agent for ophthalmic diseases also apply to the nanoparticle composition.

[0110] The present invention will be explained in more detail below based on Reference Examples and Examples, but the present invention is not limited to these Examples.

[0111] Reference Example 1 Type I crystals of tivozanib hydrochloride were prepared according to the method disclosed in WO 2004 / 035572. The tivozanib drug substance used in step 2 of Example 1 contained Type I crystals of tivozanib hydrochloride obtained by the method of WO 2004 / 035572 and at least DPQ as an impurity.

[0112] Example 1: In a tivozanib drug substance containing tivozanib hydrochloride type I crystals, whether or not solvent-mediated transformation of tivozanib hydrochloride type I crystals to type II crystals, followed by further solvent-mediated transformation to type I crystals, would have an effect of reducing the DPQ content in the tivozanib drug substance was investigated. Specifically, the experiment was carried out as follows: Ethanol (36.1 mL) was added to a reaction vessel (Step 1), and tivozanib drug substance (2.0 g) containing tivozanib hydrochloride type I crystals prepared in Reference Example 1 was added to the reaction vessel at room temperature (Step 2). The mixture was then stirred in suspension at 45°C for 10 minutes, and the solvent-mediated transformation of the crystal form from type I crystals to type II crystals was confirmed (Step 3). Water (4.0 mL) and tivozanib drug substance (2.0 mg) containing tivozanib hydrochloride type I crystals were added to the mixture as seed crystals (Step 4). After stirring in suspension at 45°C for 19 hours, solvent-mediated crystal transformation from type II crystals to type I crystals was confirmed (Step 5). The mixture was cooled to 25°C and stirred for 1 hour (Step 6). The precipitate was filtered, and the filtrate was washed with 10% aqueous ethanol (2.0 mL) (Step 7). The filtrate was dried under reduced pressure at 45°C to obtain tivozanib drug substance (1.692 g) containing tivozanib hydrochloride type I crystals (yield of tivozanib drug substance = 86%) (Step 8). The work process is outlined in Figure 1. In Figure 1, Form I refers to type I crystals, and Form II refers to type II crystals.

[0113] The time-dependent change in the crystal form transition due to the solvent-mediated transition was confirmed using Raman spectroscopy (ReactRaman (METTLER TOLEDO: ReactRaman 785)) and particle image analysis (EasyViewer (METTLER TOLEDO: EasyViewer 100)). In the Raman spectroscopy, －１The crystal form having a peak at is crystal form I. ReactRaman data is shown in Figure 2, and EasyViewer data is shown in Figure 3. In Figure 2, the horizontal axis represents time, and the vertical axis represents height. The numbers on the horizontal axis are, from left to right, 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. For example, 01:59:59 indicates 1 hour, 59 minutes, and 59 seconds. The numbers on the vertical axis are 100, 200, 300, and 400 from the bottom. The numbers in the upper left corner of each image in Figure 3 correspond to the process numbers shown in Figure 1. Because process 5 took a long time, Figure 3 lists multiple types of data corresponding to process 5, labeled 5-1 to 5-6.

[0114] As shown in FIG. 2, the transformation of the type I crystals into type II crystals by heating and stirring corresponding to step 3, and the subsequent heating and stirring after the addition of water (step 5) gradually transformed the type II crystals into type I crystals, as confirmed in real time by Raman spectroscopy.

[0115] As shown in Figure 3, it was confirmed that the type I crystals (No. 2 in Figure 3) were needle-like before heating and stirring (Step 2), but the crystalline state began to change upon heating and stirring (Step 3), and fine type II crystals were produced (No. 3 in Figure 3). Thereafter, upon heating and stirring after the addition of water (Step 5), the fine type II crystals began to transform into needle-like type I crystals (Nos. 5-1 to 5-3 in Figure 3), and by continuing heating and stirring overnight (Step 5), type I crystals were obtained (Nos. 5-4 to 5-6 in Figure 3).

[0116] The changes in tivozanib and DPQ contained in the tivozanib drug substance before and after the dissolution-mediated transfer described in Example 1, i.e., the tivozanib drug substance before addition to the reaction vessel in step 2 (before step in Table 5) and the tivozanib drug substance obtained in step 8 (after step in Table 5), were analyzed using HPLC with an ultraviolet absorbance detector (UVD), and the results are shown in Table 5. Here, the HPLC area (%) of DPQ was converted to weight (%) by multiplying by the relative response factor of DPQ to tivozanib.

[0117]

[0118] The content (wt%) of tivozanib in the tivozanib drug substance in Table 6 was calculated by analysis using HPLC with an ultraviolet absorbance detector (UVD). Specifically, the calculation was carried out as follows. First, a standard with a known tivozanib content was used as an external control, and the content (wt%) of tivozanib in the measurement sample was calculated by multiplying the ratio of the peak area of ​​the peak corresponding to tivozanib in the standard to the peak area of ​​the peak corresponding to tivozanib in the measurement sample by the ratio of the weighed amount of the measurement sample to the weighed amount of the standard, and the content (wt%) of tivozanib in the standard.

[0119]

[0120] The results in Tables 5 and 6 demonstrate that the use of this manufacturing method utilizing dissolution-mediated transition makes it possible to significantly reduce the DPQ content contained in the tivozanib drug substance, thereby producing a tivozanib drug substance containing a high content of tivozanib.

[0121] Example 2: A nanoparticle composition formulated as an eye drop according to the following formulation was obtained using the tivozanib drug substance containing Type I crystals 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) and the tivozanib drug substance produced according to the method of Example 1 were weighed and placed in a zirconia container, followed by the addition of an aqueous hydroxypropyl cellulose solution. The mixture was wet-pulverized (Mill / Mix, 1500 rpm, 1 minute; Mill / Mix, 400 rpm, 1 minute, 10 times) using a rotation / revolution nano-pulverizer (NP-100 (Thinky Corporation)). An aqueous solution of hydroxypropyl cellulose and mannitol was then added, and the mixture was dispersed using a rotation / revolution nanomill (Mill / Mix, 400 rpm, 5 minutes). The zirconia balls were removed (Clean Media, 2000 rpm, 1 minute; Mill / Mix, 400 rpm, 1 minute), yielding a nanoparticle composition formulated as an eye drop. The nanoparticle composition had a composition of tivozanib drug substance / hydroxypropyl cellulose / mannitol = 1 part by weight / 0.6 parts by weight / 2.25 parts by weight. The mean particle size of the Type I crystals of tivozanib hydrochloride in the nanoparticle composition was measured using a Zetasizer Nano (ZS, manufactured by Malvern Panalytical) and found to be 212.5 nm. The changes in the amounts of tivozanib and DPQ contained in the tivozanib drug substance obtained according to the method of Example 1 (before the process in Table 7) and the nanoparticle composition obtained in Example 2 (after the process in Table 7) before and after the wet milling described in Example 2 were analyzed using HPLC with an ultraviolet absorbance detector (UVD), and the results are shown in Table 7. Here, the HPLC area (%) of DPQ was converted to weight (%) by correction using a sensitivity coefficient.

[0122] The DPQ content in the nanoparticle composition was measured by HPLC (quantitation limit (lower limit) was 0.05 Area%), and the detection limit (lower limit) was 0.02 Area%. The DPQ content after nanoparticle composition was smaller than the significant digit of the quantitation limit, specifically 0.0346 Area%. The results in Table 7 show that even in the nanoparticle composition prepared in this Example from tivozanib drug substance containing Type I crystals of tivozanib hydrochloride obtained according to Example 1, the DPQ content was less than 0.05 wt% of the tivozanib drug substance. In other words, even after the tivozanib drug substance containing Type I crystals of tivozanib hydrochloride obtained according to Example 1 was formulated into eye drops, the content of Type I crystals was maintained at a high value.

[0123]

[0124] Example 3: A nanoparticle composition formulated as eye drops according to the following formulation was obtained using the tivozanib drug substance containing Type I crystals 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) and the tivozanib drug substance produced according to the method of Example 1 were weighed and placed in a zirconia container. An aqueous hydroxypropyl methylcellulose solution was then added, and the mixture was wet-pulverized (Mill / Mix, 1500 rpm, 1 minute, Mill / Mix, 400 rpm, 1 minute, 10 times) using a rotation / revolution nano-pulverizer (NP-100 (Thinky Corporation)). Subsequently, an aqueous solution of hydroxypropyl methylcellulose and mannitol was added, and the mixture was dispersed using a rotation / revolution nanomill (Mill / Mix, 400 rpm, 5 minutes). The zirconia balls were removed (Clean Media, 2000 rpm, 1 minute; Mill / Mix, 400 rpm, 1 minute), yielding a nanoparticle composition formulated as an eye drop. The nanoparticle composition had a composition of tivozanib drug substance / hydroxypropyl methylcellulose / mannitol = 1 part by weight / 0.6 parts by weight / 2.25 parts by weight. The mean particle size of the Type I crystals of tivozanib hydrochloride in the nanoparticle composition was measured using a Zetasizer Nano (ZS, manufactured by Malvern Panalytical) and found to be 218.5 nm. The changes in the amounts of tivozanib and DPQ contained in the tivozanib drug substance obtained according to the method of Example 1 (before the process in Table 8) and the nanoparticle composition obtained in Example 3 (after the process in Table 8) before and after the wet milling described in Example 3 were analyzed using HPLC with an ultraviolet absorbance detector (UVD), and the results are shown in Table 8. Here, the HPLC area (%) of DPQ was converted to weight (%) by correction using a sensitivity coefficient.

[0125] The DPQ content in the nanoparticle composition was measured by HPLC (quantitation limit (lower limit) was 0.05 Area%), and the detection limit (lower limit) was 0.02 Area%. The DPQ content after nanoparticle composition was smaller than the significant digit of the quantitation limit, specifically 0.0290 Area%. The results in Table 8 show that even in the nanoparticle composition prepared in this Example from tivozanib drug substance containing Type I crystals of tivozanib hydrochloride obtained according to Example 1, the DPQ content was less than 0.05 wt% of the tivozanib drug substance. In other words, even after the tivozanib drug substance containing Type I crystals of tivozanib hydrochloride obtained according to Example 1 was formulated into eye drops, the content of Type I crystals was maintained at a high value.

[0126]

[0127] Example 4: A nanoparticle composition formulated as eye drops according to the following formulation was obtained using tivozanib drug substance containing Type I crystals 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) and the tivozanib drug substance produced according to the method of Example 1 were weighed and placed in a zirconia container. An aqueous polyvinylpyrrolidone solution was then added, and the mixture was wet-pulverized (Mill / Mix, 1500 rpm, 1 minute; Mill / Mix, 400 rpm, 1 minute, 10 times) using a rotation / revolution nano-pulverizer (NP-100 (Thinky Corporation)). An aqueous solution of polyvinylpyrrolidone and mannitol was then added, and the mixture was dispersed using a rotation / revolution nanomill (Mill / Mix, 400 rpm, 5 minutes). The zirconia balls were removed (Clean Media, 2000 rpm, 1 minute; Mill / Mix, 400 rpm, 1 minute), yielding a nanoparticle composition formulated as an eye drop. The nanoparticle composition had a composition of tivozanib drug substance / polyvinylpyrrolidone / mannitol = 1 part by weight / 0.6 parts by weight / 2.25 parts by weight. The mean particle size of the Type I crystals of tivozanib hydrochloride in the nanoparticle composition was measured using a Zetasizer Nano (ZS, manufactured by Malvern Panalytical). The mean particle size was 187.6 nm. The changes in the concentrations of tivozanib and DPQ contained in the tivozanib drug substance obtained according to the method of Example 1 (before the process in Table 9) and the nanoparticle composition obtained in Example 4 (after the process in Table 9) before and after the wet milling described in Example 4 were analyzed using HPLC with an ultraviolet absorbance detector (UVD), and the results are shown in Table 9. Here, the HPLC area (%) of DPQ was converted to weight (%) by correction using a sensitivity coefficient.

[0128] The DPQ content in the nanoparticle composition was measured by HPLC (quantitation limit (lower limit) was 0.05 Area%), and the detection limit (lower limit) was 0.02 Area%. The DPQ content after nanoparticle composition was smaller than the significant digit of the quantitation limit, specifically 0.0298 Area%. The results in Table 9 show that even in the nanoparticle composition prepared in this Example, in which the tivozanib drug substance containing Type I crystals of tivozanib hydrochloride obtained according to Example 1 was formulated into an eye drop, the DPQ content was less than 0.05 wt% in the tivozanib drug substance. In other words, even after the tivozanib drug substance containing Type I crystals of tivozanib hydrochloride obtained according to Example 1 was formulated into an eye drop, the content of Type I crystals was maintained at a high value.

[0129]

[0130] It is clear that a person skilled in the art can conceive of various modifications and alterations within the scope of the claims, and it is understood that these also naturally fall within the technical scope of the present invention. Furthermore, the components in the above-described embodiments may be combined in any manner without departing from the spirit of the invention.

[0131] This 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 tivozanib hydrochloride Form I crystals, comprising: Step A: subjecting tivozanib hydrochloride Form I crystals to solvent-mediated rearrangement to obtain tivozanib hydrochloride Form II crystals; and Step B: subjecting the tivozanib hydrochloride Form II crystals obtained in Step A to solvent-mediated rearrangement to obtain tivozanib hydrochloride Form I crystals.

2. A method for reducing the content of 2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (DPQ) in a tivozanib drug substance, comprising: Step A: subjecting tivozanib hydrochloride Type I crystals to solvent-mediated rearrangement to obtain tivozanib hydrochloride Type II crystals; and Step B: subjecting the tivozanib hydrochloride Type II crystals obtained in Step A to solvent-mediated rearrangement to obtain tivozanib hydrochloride Type I crystals.

3. Tivozanib drug substance containing tivozanib hydrochloride or its hydrate crystals as the active ingredient at a content of 99.8% by mass or more.

4. A tivozanib drug substance comprising tivozanib hydrochloride or a crystalline hydrate thereof as active ingredients, and 2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]aniline (DPQ), wherein the mass of the DPQ is 0.04% or less of the mass of the tivozanib drug substance.

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