WO2024039213A1 - Amorphous sunitinib, method for producing same, and pharmaceutical composition comprising same - Google Patents

Abstract

The present invention relates to amorphous sunitinib, to a method for producing same, and to a pharmaceutical composition comprising amorphous sunitinib.

Description

Amorphous sunitinib, manufacturing method thereof, and pharmaceutical composition containing the same

The present invention relates to amorphous sunitinib, a method for producing the same, and a pharmaceutical composition containing amorphous sunitinib.

Sunitinib is a drug that inhibits tyrosine kinases (RTK, Receptor Tyrosine Kinase) such as VEGFR (VEGF receptor), and is used for age-related macular degeneration (AMD) disease.

Sunitinib has a low solubility in water, about 0.364 mg/ml (pH 6; J. Med. Chem., 2003, 46, 1116-1119). Accordingly, to improve solubility, commercially available sunitinib products were released in the form of malate, which overcomes the poor solubility and low bioavailability of the drug. However, Sunitinib malate is not only not completely improved in solubility in a wide range of pH aqueous solutions, but also has poor bioavailability.

Amorphous refers to a solid state in which molecular interaction exists but does not form a crystal arrangement. It has a higher energy level than the crystalline form and has the advantage of high solubility.

However, due to the high energy level, there is a problem of low thermodynamic stability and a very rapid phase transition to the crystalline form, making it very difficult to obtain the amorphous form normally. This is because the method of producing the amorphous form is to extremely increase the degree of supersaturation and precipitate the solid without properly forming a crystal structure, making it difficult to properly manufacture and obtain the amorphous form.

A general manufacturing method for amorphous materials requires the use of a crystallization method that quickly achieves a high degree of supersaturation by controlling the crystallization rate very quickly. However, manufacturing amorphous forms using this method is less efficient because special equipment must be used, and in the general raw drug manufacturing process, the above manufacturing method is not easy to produce amorphous forms.

And even if this extreme crystallization method is used to manufacture amorphous form, it is difficult to produce 100% amorphous form because the amorphous form transfers to crystalline form during the production process. The use of the amorphous form in pharmaceutical substances is mainly used when the bioavailability is low due to the low solubility of the crystalline form, which affects the absorption rate in the body, and when it is desired to increase the absorption rate in the body by using higher solubility.

Therefore, the present invention provides amorphous sunitinib with higher solubility than the crystalline form, adopts an efficient manufacturing method using shear stress, and ultimately provides a pharmaceutical composition containing amorphous sunitinib.

[Patent Document]

(Patent Document 1) US 2003-0069298 A1

(Patent Document 2) US 2010-0256392 A1

(Patent Document 3) US 9012665 B2

The object of the present invention is to provide amorphous sunitinib and a manufacturing method related thereto. Additionally, the invention ultimately relates to a pharmaceutical composition containing amorphous sunitinib.

The present invention provides amorphous sunitinib.

Additionally, according to one embodiment of the present invention, a composition comprising the amorphous sunitinib is provided.

In addition, according to one embodiment of the present invention, an ophthalmic composition containing the amorphous sunitinib is provided.

In addition, according to one embodiment of the present invention, a pharmaceutical kit comprising a container containing a pharmaceutical composition containing the amorphous sunitinib, wherein the container has a dispensing means adapted to topically administer the pharmaceutical composition to the eyes of a patient. , provides medication kits.

In addition, according to one embodiment of the present invention, a method for producing amorphous sunitinib is provided, comprising the step of applying shear stress to a solution containing sunitinib or a salt of sunitinib.

Sunitinib prepared by the present invention has an amorphous form, unlike the conventional crystalline sunitinib, and thus has the advantage of having a higher solubility than the crystalline form. Additionally, according to the present invention, amorphous sunitinib can be efficiently produced through a production method using shear stress.

In addition, the pharmaceutical composition containing amorphous sunitinib of the present invention has the advantage of being relatively easily dissolved and absorbed because it does not need to overcome lattice energy, unlike crystalline sunitinib, and has excellent bioavailability.

Figure 1 shows the DSC analysis results of a sunitinib precursor (Comparative Example 2) according to an embodiment of the present invention.

Figure 2 shows the DSC analysis results of amorphous sunitinib (Example 2) according to an embodiment of the present invention.

Figure 3 is a diagram comparing the XRD spectra of sunitinib malate crystal form according to an embodiment of the present invention, sunitinib malate of Comparative Example 1, and amorphous sunitinib obtained in Example 1.

Figure 4 is a diagram comparing the XRD spectrum of the sunitinib precursor (Comparative Example 2) according to an embodiment of the present invention with the XRD spectrum of amorphous sunitinib obtained in Example 2.

Terms

In the present invention, the term "amorphous" refers to the material molecules being arranged in a completely disordered manner, and refers to belonging to a thermodynamic instability structure.

As used herein, the term “precursor” refers to a precursor or precursor used to produce amorphous sunitinib according to the present invention. That is, the precursor of amorphous sunitinib according to the present invention refers to sunitinib or a salt of sunitinib to which no shear stress is applied.

In the present invention, the term “composition” or “pharmaceutical composition” refers to at least one compound of the present invention and a carrier, stabilizer, diluent, dispersant, suspending agent, or thickening agent. means a mixture of other chemical components such as agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism.

As used herein, the terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” are non-toxic but effective in providing the desired biological result. It represents a sufficient amount. The result may be reduction and/or alleviation of the signs, symptoms, or cause of the disease, or any other desired alteration of the biological system. The appropriate therapeutic amount in any individual case can be determined by the skilled artisan using routine experimentation.

In the present invention, the term “efficacy” refers to the maximum effect (Emax) achieved within the assay method.

As used herein, “treatment” or “treating” refers to treating a condition contemplated herein, symptoms of a condition contemplated herein, or the potential to develop a condition contemplated herein ( To cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect, a therapeutic agent, that is, the present invention. defined as the application or administration of a compound (alone or in combination with other pharmaceutical agents) to a patient, or the application of a therapeutic agent to tissues or cell lines isolated from a patient (e.g., for diagnostic or ex vivo applications). is defined as applying or administering (e.g., for diagnostic or ex vivo applications) a condition contemplated herein, symptoms of a condition contemplated herein, or progression to a condition contemplated herein. It has the potential to become The treatment can be specifically tailored or modified based on knowledge gained from the field of pharmacology.

In the present invention, a “therapeutically effective amount” is the amount of a compound of the present invention that improves the symptoms of a disease when administered to a patient. The amount of a compound of the present invention that constitutes a “therapeutically effective amount” may vary depending on the compound, the disease state and its severity, the age of the patient being treated, etc. A therapeutically effective amount can be routinely determined by a person of ordinary skill in the art in light of his/her knowledge and this disclosure.

Amorphous sunitinib of the present invention

The present invention provides amorphous sunitinib. The amorphous sunitinib may mean that there is no sharp diffraction peak in the X-ray powder diffraction spectrum of sunitinib.

Amorphous belongs to a thermodynamically high energy state, is a thermodynamically metastable structure, the basic particles constituting the compound are randomly arranged in three-dimensional space, and the X-ray powder diffraction spectrum is used to determine the amorphous form. This is known to those skilled in the art in the most intuitive manner. Specifically, when a compound exists in amorphous form, its X-ray powder diffraction spectrum generally does not show sharp diffraction peaks. That is, the XRPD spectrum may not show a diffraction peak or may show one or a plurality of wide and mild diffraction peaks. The XRD spectrum of this amorphous form has broad and mild diffraction peaks, which can be compared to the narrow and sharp diffraction peaks of the XRPD spectrum of the crystalline form.

The X-ray powder diffraction spectrum of amorphous sunitinib of the present invention is characterized by the presence of two broad and mild diffraction peaks when the diffraction angle 2θ is between 0 ^o - and 30 ^o , and more specifically, at 11.9 o. It may have an X-ray diffraction peak at a diffraction angle 2θ of ±0.2° and 26.2°±0.2°.

Additionally, amorphous sunitinib of the present invention may have a glass transition temperature of 100°C to 120°C as measured by differential scanning calorimetry (DSC). More specifically, the amorphous sunitinib undergoes a glass transition at an exothermic temperature of 100 to 120°C when measured under differential scanning thermal analysis (DSC) conditions at a temperature increase rate of 10°C/min, 99.999% N2, and 30-210°C. It may have a DSC profile characterized by .

Method for producing amorphous sunitinib of the present invention

Amorphous sunitinib according to an embodiment of the present invention can be prepared by applying shear stress to a solution containing sunitinib or a salt of sunitinib, which is a precursor of the structure.

The shear stress applied to the solution containing sunitinib, which is the precursor of the structure, and the salt may be either mechanical shear stress or ultrasound.

The mechanical shear stress may be applied by passing the solution through a column or filter paper filled with silica. Below, mechanical shear stress is explained in detail.

According to one embodiment of the present invention, the mechanical shear stress may be applied by passing a solution containing sunitinib and a salt through a column filled with silica. When the solution containing sunitinib and the salt passes through a column filled with silica, etc., the sunitinib and the salt undergo very high shear stress as they pass through a physically narrow area.

The silica may be spherical or prismatic, but its shape is not limited.

The size of the silica may be 0.01 to 100 μm, preferably 0.1 to 10 μm, and more preferably 2.5 to 3.7 μm. When the size of the silica is less than 0.01 μm or more than 100 μm, even if the solution containing sunitinib passes through a column filled with silica, shear stress is not applied and there may be no change in the structure.

A negative pressure of 0.1 bar to 1.0 bar or 0.2 bar to 0.9 bar can be applied to the bottom of the column filled with silica. When the negative pressure applied to the bottom of the silica-filled column is less than 0.1 bar, the time required for the solution containing sunitinib and the salt to pass through the column increases, thereby producing amorphous sunitinib according to the present invention. There may be a delay. In addition, when the negative pressure applied to the lower part of the column filled with silica is more than 1.0 bar, the time required for the solution containing sunitinib and the salt to pass through the column is reduced, and the amorphous suniti according to the present invention is reduced. The manufacturing time of the nip may be shortened, but manufacturing costs may increase because additional pump equipment is required.

According to another embodiment of the present invention, the mechanical shear stress may be applied by passing the solution containing sunitinib and the salt through one or more filter papers. When passing through the one or more filter papers, the sunitinib and salt are subjected to very high shear stress by passing through a physically narrow area.

The filter paper may be one filter paper or two or more filter papers. When the filter paper consists of two or more filter papers, the filter papers may be stacked and arranged. When the filter paper is a plurality of two or more filter papers, a higher shear stress can be provided than a single filter paper.

The pore size of the filter paper may be 0.1 to 5.0 microns or 0.3 to 4.5 microns. When the pore size of the filter paper is less than 0.1 micron, the amount of the solution containing sunitinib and the salt passed through or filtered through the filter paper is too small, so the production speed of amorphous sunitinib according to the present invention is reduced. Alternatively, if the pore size of the filter paper is greater than 5.0 microns, the solution containing sunitinib and the salt may simply pass through the filter paper and shear stress may not be effectively applied.

The shear stress may be applied using ultrasonic waves. The application of ultrasonic waves will be described in detail below.

According to one embodiment of the present invention, the shear stress may be applied by applying ultrasound to the solution containing sunitinib and the salt.

When the ultrasound is applied to the solution containing sunitinib and the salt, a pressure wave is generated, and shear stress may be applied to the sunitinib and the salt by the pressure wave.

The intensity of the applied ultrasound may be 200 J/sec to 800 J/sec or 400 J/sec to 600 J/sec.

The energy applied per volume of the applied ultrasound can be calculated as the intensity of the ultrasound (J/sec) x the applied time (sec)/measured volume (ml).

According to one embodiment of the present invention, the energy applied per volume of ultrasound applied to the solution containing sunitinib and the salt may be 100 J/ml to 90 kJ/ml. If the energy of the ultrasound is less than 100 J/ml, sufficient shear stress is not applied to the solution containing sunitinib and the salt, making it difficult to form the structure. Additionally, when the energy of the ultrasound is greater than 90 kJ/ml, excessive heat may be applied to the solution containing sunitinib and the salt, making it difficult to form the structure.

The ultrasound may be applied at 10°C to 80°C for 10 seconds to 60 minutes. When the ultrasound is applied at a temperature below 10°C, there is no change in the solution containing sunitinib and the salt, and when the ultrasound is applied at a temperature above 80°C, there is a phase change in the solution containing the sunitinib and the salt. may occur, making it difficult to form amorphous sunitinib according to the present invention. In addition, when the ultrasound is applied for less than 10 seconds, there is no change in the solution containing sunitinib and the salt, and when the ultrasound is applied for a time exceeding 60 minutes, there is no change in the solution containing the sunitinib and the salt. is modified, and cannot form the amorphous structure of sunitinib according to the present invention.

According to another embodiment of the present invention, a column filled with silica can be combined with an ultrasonic generator by applying the shear stress. The silica-filled column may be placed inside an ultrasonic generator, or the silica-filled column and the ultrasonic generator may be separated and placed continuously.

For example, after pouring a solution containing sunitinib and a salt into the silica-filled column, the column may be placed in an ultrasonic generator to apply ultrasound. Additionally, after applying ultrasound to a solution containing sunitinib and a salt, the solution may be passed through a column filled with silica.

Additionally, if necessary, a step of reacting sunitinib in an organic solvent may be performed prior to applying the shear stress. As the organic solvent, any polar solvent can be used without particular limitation. Specifically, a solvent containing an OH group can be used, and alcohols such as ethanol can be preferably used.

In addition, after applying shear stress to the sunitinib solution and the solution containing the salt to prepare the amorphous sunitinib of the present invention, filtering and drying steps can be further performed to remove the remaining solvent. At this time, filtration and drying methods used in the industry can be used without particular restrictions as long as they do not affect the amorphous sunitinib.

medicinal composition

The present invention provides a pharmaceutical composition containing the amorphous sunitinib.

In the present invention, the pharmaceutical composition is used to treat age-related macular degeneration (AMD), choroidal neovascularization (CNV), chorionic neovascular membrane (CNVM), retinal macular hole (ERM), retinal macular hole, and myopia-associated choroid. Neovascular proliferation, retinal detachment, diabetic retinopathy, diabetic macular edema (DME), atrophic changes in the reticular pigment epithelium (RPE), hypertrophic changes in the reticular pigment epithelium (RPE), retinal vein occlusion, chorionic retina Venous occlusion, retinitis pigmentosa, Stargardt's disease, glaucoma, inflammatory diseases, cataracts, refractory anomalies, keratoconus, retinopathy of prematurity, polykeratitis, corneal vascularization, corneal migration or corneal molding, hypoxia. It is characterized by treating or preventing one or more ophthalmological disorders selected from the group consisting of corneal vascularization, pterygium conjunctiva, fundus edema, and intraretinal edema caused by (wearing wide-area contact lenses).

Additionally, the present invention provides a method of treating or preventing ophthalmological disorders by administering a composition containing the amorphous sunitinib to the eye.

The above ophthalmological disorders include age-related macular degeneration (AMD), choroidal neovascularization (CNV), chorionic neovascular membrane (CNVM), retinal retina (ERM), retinal macular hole, myopia-associated neovascularization of the choroid, Retinal detachment, diabetic retinopathy, diabetic macular edema (DME), atrophic changes of the reticular pigment epithelium (RPE), hypertrophic changes of the reticular pigment epithelium (RPE), retinal vein occlusion, chorionic retinal vein occlusion, pigment Retinitis, Stargardt's disease, glaucoma, inflammatory diseases, cataracts, refractory anomalies, keratoconus, retinopathy of prematurity, polykeratitis, corneal angiogenesis, corneal migration or corneal molding, hypoxemia (wide-contact lenses) It may be any one or more selected from the group consisting of corneal vascularization, pterygium conjunctiva, fundus edema, and intraretinal edema due to wear.

In the present invention, in addition to the amorphous sunitinib, the pharmaceutical composition may further include general components used in the field of pharmaceutical compositions without particular limitation, and may include, for example, a surfactant, etc.

In the present invention, the pharmaceutical composition may contain the amorphous sunitinib in an amount of 0.01% by weight to 10.0% by weight, specifically, 0.02% by weight or more, 0.03% by weight or more, or 0.05% by weight or more, It may be 5.0 weight% or less, 2.0 weight% or less, 1.0 weight% or less, and 0.5 weight% or less.

Additionally, the present invention provides an eye drop composition containing the amorphous sunitinib.

Additionally, the eye drop composition according to the present invention may contain other conventional ingredients, such as one or more pharmaceutically acceptable buffering agents, preservatives, tonicity adjusting agents, pH adjusting agents, etc.

The pH of the eye drop composition according to the present invention is preferably 5.5, more preferably 6, more preferably greater than 6 as the lower limit, and preferably 8, more preferably 7.5, and even more preferably 7 as the upper limit. . Within this pH range, not only can sunitinib and its salt in the eye drop composition be stabilized, but also the eye drop can be suitably used as a hypoallergenic agent.

The eye drop composition according to the present invention may further include a buffering agent suitable for maintaining the above-mentioned preferred pH range. Examples of the buffering agent include bicarbonate buffer, acetate buffer, citrate buffer, phosphate buffer, borate buffer, or tromethamine (TRIS, 2-amino2-hydroxymethyl-1,3-propanediol) buffer and these. Including but not limited to combinations. The amount (concentration) of the buffering agent added is not particularly limited as long as the pH of the ophthalmic composition according to one embodiment of the present invention can be maintained in the above-mentioned preferable range.

The eye drop composition according to the present invention may further include a preservative suitable for preventing microbial contamination. The preservative may include any compound or substance. Examples of the preservative include persalts such as perborate, percarbonate, etc.; Alcohols such as benzyl alcohol, chlorobutanol, etc.; Preservatives containing quaternary ammonium salts such as benzalkonium chloride, benzalkonium bromide, and polyquaternium; Guanidine-based preservatives including polyhexamethylene biguanidine (PHMB), chlorhexidine, etc.; mercury preservatives such as thimerosal, phenylmercuric acetate, and phenylmercuric nitrate; metal chlorides such as alkali metal and alkaline earth metal chlorites; Ophthalmologically acceptable salts such as sorbic acid and potassium sorbic acid and mixtures; and stabilized oxychloro complexes (e.g., Purite® (registered trademark of Allergan, Inc.)). The amount of preservative varies over a relatively wide range depending on the specific preservative used. If no preservatives are added to the eye drop composition, it can be used as a disposable eye drop, and the eye drop composition is consumed in one administration. Alternatively, the eye drop composition may be used as a multiple-use eye drop, for example, contained in a container with a filter attached to the nozzle of the container for dispensing the eye drop, or contained in an airless application system device.

The eye drop composition according to the present invention may further include a tonicity regulator that adjusts the osmotic pressure of the eye drop to be similar to the osmotic pressure in the eye to eliminate irritation and pain caused by the difference in osmotic pressure when instilling the eye. Examples of the tonicity regulators may be in ionic and/or nonionic form. Ionic tonicity regulators are, for example, alkali or earth metal halides, one or more of the following: calcium chloride, potassium chloride, sodium chloride, lithium chloride, potassium bromide, sodium bromide, sodium iodide, sodium phosphate, potassium phosphate, sodium and potassium sulfate, bicarbonate. Sodium and potassium and boric acid. Nonionic tonicity regulators are, for example, urea, glycerol, sorbitol, mannitol, propylene glycol, dextrose, or combinations thereof. Glycerin, sodium chloride and mannitol are the most preferred tonicity regulators. The amount of tonicity adjusting agent may vary depending on whether isotonic, hypertonic, or hypotonic liquid is desired. The compositions of the invention generally have an osmotic pressure in the range of 150-1500 mOsm/kg, preferably 150-500 mOsm/kg, and most preferably 180-250 mOsm/kg.

The eye drop composition according to the present invention may further contain a pH adjuster in order to adjust the pH to the above-mentioned preferable range. The pH adjuster is not particularly limited as long as it can adjust the pH of the eye drop composition according to one embodiment of the present invention, and specific examples include dilute hydrochloric acid, sodium hydroxide, and the like. The amount (concentration) of the pH adjuster added is not particularly limited as long as the pH of the eye drop composition according to one embodiment of the present invention can be adjusted to the above-mentioned preferable range.

The eye drop composition according to the present invention can be prepared by dissolving the components in an aqueous medium. Deionized water is a preferred aqueous medium that may contain small amounts of other hydrophilic solvents such as glycols and/or polyols. The composition may be prepared by preparing a solution of one or more ingredients and then adding the remaining one or more ingredients, or by preparing two or more separate solutions, each containing one or more ingredients, and then mixing these solutions together.

The eye drop composition according to an embodiment of the present invention may be an eye drop composition for preventing or treating dry eye syndrome.

The present invention provides a pharmaceutical kit including a container containing a composition containing the amorphous sunitinib. The container containing the composition comprising the topical sunitinib includes dispensing means adapted to topically administer the pharmaceutical composition to the eye of a patient. The dispensing means can provide the ophthalmic composition dropwise with a volume of 0.01 to 0.10 ml, but is not limited to the volume and includes the volume per drop typically applied to the eye. can do.

Hereinafter, the present invention will be described in more detail through examples of the present invention. It will be natural that the present invention is not limited to these examples.

[Example]

Example 1. Manufacturing method of amorphous sunini tip

Approximately 0.25% sunitinib malate solution was prepared by dissolving 0.332 g of sunitinib malate (Nanjing furuisi Pharma, China) in 100 g of purified water.

After wetting 20 g of SYLOID 244FP (GRACE, USA) with 200 g of 94.5% ethanol, place a 0.45 μm PVDF membrane filter on a Buchner funnel with a diameter of 90 mm, and prepare it as a vacuum filtration type. The SYLOID 244FP solution soaked in ethanol was poured into a Buchner funnel and packed to prepare a SYLOID 244FP column about 1 cm high.

The sunitinib malate solution prepared on the column was added using a vacuum pump, and 400 g of 94.5% ethanol solution containing 0.1 mL of 1M HCl and 0.2 mL of 1M NaCl was passed through the column to recover the sunitinib remaining in SYLOID 244 FP. . At this time, the outflow flow rate was about 2.25 g/min and the outflow liquid was 506.83 g.

The concentration of sunitinib present in the effluent was analyzed using HPLC (Waters, e2695), and the amount of sunitinib obtained was 0.206 g. At this time, the recovery rate is about 82%.

An equal amount of deionized water was added to 506.83 g of this effluent, and ethanol was removed using a rotary vacuum dryer. It was operated for 3 hours at 25°C and 20 mbar pressure while maintaining the rotation speed at 50 to 150 rpm, and when the concentration of sunitinib in the concentrate reached about 0.3%, concentration was stopped and filtered through a 0.22μm PVDF syringe filter. The amorphous sunitinib obtained by concentration was confirmed to be 0.225 g as a result of HPLC analysis.

45 g of filtered amorphous sunitinib was prefrozen for 3 hours in a prefreezer (Ilshin biobase, DF8502S) and then dried in a freeze dryer (Ilshin biobase, FD8508) for 48 hours.

Finally, amorphous sunitinib in the form of orange powder was obtained. Of the dried powder weight of 0.2324 g, 35% (813.4 mg) was excipient [salt] and 65% (1510 mg) was sunitinib.

Example 2. Manufacturing method of amorphous sunini tip

About 0.20% sunitinib solution was prepared by dissolving 0.5055 g of sunitinib (Teva, Mexico) in 250 g of EtOH.

After wetting 15 g of SYLOID 244FP (GRACE, USA) with 150 g of 94.5% ethanol, place a 0.45 μm PVDF membrane filter on a Buchner funnel with a diameter of 90 mm, and prepare it as a vacuum filtration type. The SYLOID 244FP solution soaked in ethanol was poured into a Buchner funnel to prepare a SYLOID 244FP column with a height of approximately 1 cm.

The sunitinib solution prepared on the column was added using a vacuum pump, and 200 g of 94.5% ethanol solution containing 0.2 mL of 1M NaCl was passed through the column to recover the sunitinib remaining in SYLOID 244 FP. At this time, the outflow flow rate was about 4.10 g/min and the outflow liquid was 492.59 g.

The concentration of sunitinib present in the effluent was analyzed using HPLC (Waters, e2695), and the amount of sunitinib obtained was 494 mg. At this time, the recovery rate is about 98%.

Divide the effluent into small portions and concentrate using a reduced pressure dryer. The solubility of the solid produced after completion of concentration was measured using 20mM PBS and is shown in Table 1 below.

Concentration of the remaining effluent was stopped when the concentration of sunitinib reached about 0.2% using a rotary vacuum dryer. The pH of the concentrate was adjusted to 5.0-5.5 using 100mM HCl. Ethanol was removed by adding 3 times the amount of deionized water of the concentrate to adjust the pH. It was operated at 40°C and 20 mbar pressure at a rotation speed of 50 rpm to 150 rpm for about 2 hours, and when the concentration of sunitinib in the concentrate reached about 0.20%, concentration was stopped and filtered through a 0.22 μm PVDF syringe filter. The amorphous sunitinib obtained by concentration was confirmed to be 0.412 g as a result of HPLC analysis.

204.39 g of filtered amorphous sunitinib was prefrozen for 3 hours in a prefreezer (Ilshin biobase, DF8502S) and then dried in a freeze dryer (Ilshin biobase, FD8508) for 48 hours.

Finally, amorphous sunitinib in the form of orange powder was obtained. Of the dried powder weight of 0.426 g, 25% (106 mg) was excipient [salt] and 75% (320 mg) was sunitinib.

Comparative Example 1. Sunitinib precursor (Sunitinib API)

Approximately 0.25% sunitinib malate solution was prepared by dissolving 0.332 g of sunitinib malate (Nanjing furuisi Pharma, China) in 100 g of purified water.

A 0.45 μm PVDF membrane filter was placed on a Buchner funnel with a diameter of 90 mm, and then the sunitinib malate solution prepared using a vacuum pump was added, and 405 g of 94.5% ethanol solution was passed through to recover sunitinib. . The effluent was 498 g. An equal amount of deionized water was added to 498 g of this effluent, and ethanol was removed using a rotary vacuum dryer. It was operated at 25°C and 20 mbar pressure at a rotation speed of 50 rpm to 150 rpm for about 3 hours, and when the concentration of sunitinib in the concentrate reached about 0.3%, concentration was stopped and filtered through a 0.22 μm PVDF syringe filter.

The filtered sunitinib was prefrozen for 3 hours in a prefreezer (Ilshin biobase, DF8502S) and then dried in a freeze dryer (Ilshin biobase, FD8508) for 48 hours. Finally, sunitinib in the form of orange powder was obtained.

That is, sunitinib malate itself prepared in the same manner as Example 1 was used, except that the process of passing the sunitinib malate solution through silica was not performed.

Comparative Example 2. Sunitinib precursor (Sunitinib API)

Sunitinib itself, prepared in the same manner as in Example 2, except that the process of passing through silica was not performed, was used.

[Experimental example]

Amorphous sunitinib prepared in the present invention can be characterized through the following analysis method.

Differential scanning calorimetry (DSC)

It is an analysis method that can measure heat flow and temperature related to the heat transfer of materials. Place the sample and control on separate pans and raise the temperature according to a preset level. Then, when heat is used or released from the pan with the sample, the DSC applies more or less heat to maintain the same temperature as the control. This change in heat quantity can be obtained as a graph, and the change in heat quantity of the sample according to temperature change through DSC can be seen. In general, endothermic processes that occur in DSC include solvent removal, melting, etc., and in rare cases, decomposition processes are also included. Additionally, exothermic reactions that generally occur in DSC include molecular structural transformations such as decomposition and crystallization. Since endotherm appears when a substance melts, the temperature at which the onset point of the endothermic peak of DSC appears is the melting point of the substance. As such, it is a widely used analysis method to measure the identity or purity of substances, and since polymorphs, salt forms, and co-crystals generally have different melting points (Tm), they can be confirmed through DSC. On the other hand, in the case of amorphous materials, the glass transition can generally be confirmed in DSC, and the glass transition temperature (Tg) is observed.

X-ray powder diffraction analysis (XRD)

X-ray diffraction analysis (X-ray diffraction analysis) is mainly used to reveal the structure of complex materials. Even if it is not possible to know what components a sample is made of, the diffraction pattern that appears by irradiating X-rays to the sample being measured The characteristics can be confirmed by comparing the diffraction pattern obtained from a sample whose diffraction pattern is already known.

Typically, an amorphous X-ray powder diffraction (XRD) spectrum means that no sharp specific diffraction peaks appear, and it can be confirmed that it is amorphous through this spectrum.

Experimental Example 1. Solubility measurement results

After taking 4 mg of each of the amorphous sunitinib prepared in Example 2 and Comparative Example 2, 10 mL of 20mM PBS was placed in a 5 mL vial and stirred for 30 minutes. After filtering using a 0.22㎛ PVDF syringe filter, the concentration of the filter filtrate was measured by HPLC. The HPLC used was Water's Separations Module Liquid Chromatograph (Waters, e2695), and the mobile phase used as measurement conditions was Acetonitrile:Water (20mM Ammonium acetate)=60:40, and the measured solubility is shown in Table 1 below.

	Comparative Example 2 (sunitinib (API) precursor)	Example 2 (Amorphous Sunitinib)
Solubility in 20mM PBS (mg/mL)	0.0331	0.532

Experimental Example 2. DSC measurement DSC analysis was performed on the amorphous sunitinib prepared in Example 2 and the sunitinib precursor prepared in Comparative Example 2. At this time, the DSC analysis conditions were measurement temperature 30-210 ℃, temperature increase rate 10 ℃/min, and 99.999% N2.

DSC analysis was performed on the amorphous sunitinib prepared in Example 2, and the DSC analysis results are shown in Figure 2. Looking at Figure 2, it was found that the exothermic temperature of amorphous sunitinib showed a glass transition around 110°C.

In addition, DSC analysis was performed on the sunitinib precursor prepared in Comparative Example 2, and the DSC analysis results are shown in Figure 1. Looking at Figure 1, it was seen that a peak appeared around the endothermic temperature of 180°C.

Experimental Example 3. XRD measurement

XRD analysis of amorphous sunitinib prepared in Examples 1 and 2 was performed. At this time, the XRD analysis conditions were 40kV and 15 mA for the X-ray generator, 2.00 degree/min scan speed, 0.02 degree step width, 10-30 degree scan range, and Cu-K-alpha x-ray source. .

Under the above conditions, 30 mg of amorphous sunitinib of Example 1 and Example 2 was placed on a silicon holder, respectively, and measurement was performed.

As a result of the measurement, the You can check the spectrum. Therefore, it can be seen from the XRD measurement results that Example 1 is in an amorphous state.

In addition, the X-ray powder diffraction spectrum of amorphous sunitinib of Example 2 is broad, except for the area where the diffraction angle 2θ is 11.9°±0.2° and 26.2°±0.2°, as shown at the bottom of FIG. 4. You can check the spectrum. Therefore, it can be seen from the XRD measurement results that Example 2 is in an amorphous state.

Likewise, 30 mg of the sunitinib precursor of Comparative Example 1 and Comparative Example 2 was placed on a silicon holder and measured.

As shown in the middle part of Figure 3, the The main peak was found in the vicinity of °, and it was possible to confirm the spectrum of the crystal form showing a distinct peak in the vicinity similar to the crystal form of sunitinib malate at the top of Figure 3.

In addition, the X-ray powder diffraction spectrum of the sunitinib precursor of Comparative Example 2 showed a crystalline spectrum showing several distinct peaks at a diffraction angle 2θ of around 10 to 30°, as shown at the top of FIG. 4.

Through the above XRD measurement results, it was found that Examples 1 and 2 according to the present invention were in an amorphous state, and Comparative Examples 1 and 2 were in a crystalline state.

Claims (14)

1. Amorphous sunitinib.
2. According to paragraph 1,

   The amorphous sunitinib is characterized by a glass transition at an exothermic temperature of 100 to 120°C when measured under differential scanning thermal analysis (DSC) conditions at a temperature increase rate of 10°C/min, 99.999% N2, and 30-210°C. Amorphous sunitinib with DSC profile.
3. According to paragraph 1,

   Amorphous sunitinib, characterized in that there are no sharp diffraction peaks in the X-ray powder diffraction spectrum of the amorphous sunitinib.
4. According to paragraph 1,

   The X-ray powder diffraction spectrum of the amorphous sunitinib is characterized by two broad and mild diffraction peaks when the diffraction angle 2θ is between 0 ^o -30 ^o .
5. According to paragraph 1,

   The X-ray powder diffraction spectrum of the amorphous sunitinib has X-ray diffraction peaks at a diffraction angle of 2θ of 11.9°±0.2° and 26.2°±0.2°.
6. A composition comprising the amorphous sunitinib of claim 1.
7. According to clause 6,

   The composition containing the amorphous sunitinib is suitable for treating age-related macular degeneration (AMD), choroidal neovascularization (CNV), chorionic neovascular membrane (CNVM), retinal retina (ERM), retinal macular hole, myopia-associated choroid Neovascular proliferation, retinal detachment, diabetic retinopathy, diabetic macular edema (DME), atrophic changes in the reticular pigment epithelium (RPE), hypertrophic changes in the reticular pigment epithelium (RPE), retinal vein occlusion, chorionic Retinal vein occlusion, retinitis pigmentosa, Stargardt's disease, glaucoma, inflammatory diseases, cataracts, refractory anomalies, keratoconus, retinopathy of prematurity, polykeratitis, corneal angiogenesis, corneal migration or corneal molding, hypoxia. A composition for treating or preventing one or more ophthalmological disorders selected from the group consisting of corneal vascularization, pterygium conjunctiva, fundus edema, and intraretinal edema caused by blood (wearing wide-area contact lenses).
8. An ophthalmic composition comprising the amorphous sunitinib of claim 1.
9. A pharmaceutical kit comprising a container containing a pharmaceutical composition containing the amorphous sunitinib of claim 1,

   A pharmaceutical kit, wherein the container has dispensing means adapted for topical administration of the pharmaceutical composition to the patient's eyes.
10. A method for producing amorphous sunitinib, comprising: applying shear stress to a solution containing sunitinib or a salt of sunitinib.
11. According to clause 10,

    A method for producing amorphous sunitinib, further comprising reacting sunitinib with a pharmaceutically acceptable salt in an organic solvent prior to applying the shear stress.
12. According to clause 10,

    The shear stress is applied by passing a solution containing sunitinib or a salt of sunitinib through a column filled with silica.
13. According to clause 10,

    The shear stress is applied by passing a solution containing sunitinib or a salt of sunitinib through one or more filter papers.
14. According to clause 10,

    A method for producing amorphous sunitinib, characterized in that the shear stress is applied by applying ultrasound to a solution containing sunitinib or a salt of sunitinib.

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