A tyrosine kinase inhibitor ophthalmic preparation and its preparation method and use

Abstract

The present invention provides a tyrosine kinase inhibitor ophthalmic preparation suitable for eye drop administration, which is made of the following raw materials and excipients by weight: active ingredient: 0.5 to 1.5 parts of tyrosine kinase inhibitor; the content of the active ingredient in the ophthalmic preparation is 0.05 to 1 mg / mL; pharmaceutically acceptable excipients: 20 to 300 parts of surfactant, 0.5 to 70 parts of viscosity enhancer, 10 to 800 parts of solubilizer, and the balance is solvent. The ophthalmic preparation of the present invention can effectively deliver the active ingredient to the fundus to treat fundus angiogenesis diseases. The ophthalmic preparation of the present invention has a high absorption utilization rate, a small particle size, and good stability. It is suitable for preparing a sterile preparation by microporous membrane sterilization and / or high temperature sterilization, and has a very good clinical application prospect.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and in particular relates to a tyrosine kinase inhibitor ophthalmic preparation and a preparation method and application thereof. Background Art

[0002] Due to the aging of the population, the incidence of fundus angiogenesis diseases such as cataract, glaucoma, age-related macular degeneration (AMD), and diabetic macular edema (DME) has increased significantly. Currently, the use of drugs that antagonize vascular endothelial growth factor (VEGF) to inhibit fundus angiogenesis is one of the main means of treating related fundus angiogenesis diseases.

[0003] However, due to the complex physiological structure and barriers in the eye, it is difficult for drugs to penetrate the barriers and reach the vitreous body at the posterior segment of the eye through the administration of eye drops, which makes it difficult to effectively treat fundus diseases through ocular surface administration in clinical practice. For a long time, fundus diseases have been treated by local injection in the eye. In order to overcome the ocular barrier, the clinical practice is to administer anti-vascular endothelial growth factor macromolecular biological drugs such as Bevacizumab, Ranibizumab, Aflibercept, Conbercept and Brolucizumab through vitreous injection to treat fundus diseases such as age-related macular degeneration (AMD) and diabetic macular edema (DME) caused by fundus neovascularization. In addition to the above-mentioned anti-VEGF monoclonal antibodies, fusion proteins and other macromolecular biological drugs, small molecule chemical drugs such as tyrosine kinase inhibitors (TKIs) have an antagonistic effect on the tyrosine kinase of vascular endothelial growth factor receptor (VEGFR) and can inhibit blood vessel growth. TKIs including axitinib, regorafenib, sunitinib and nintedanib also have an antagonistic effect on platelet derived growth factor receptor (PDGFR), inhibiting angiogenesis and treating AMD, DME and other angiogenesis-related eye diseases (Samanta, et al., Emerging Therapies in Neovascular Age-Related Macular Degeneration in 2020, Asia Pac J Ophthalmol (Phila) 2020; 9: 250–259). A small preclinical study injected a suspension of TKI axitinib into the suprachoroidal space at the posterior fundus for the treatment of wAMD, and clinical research has been initiated in the United States (Kansara VS, Muya LW, Ciulla TA. Evaluation of long-lasting potential of suprachoroidal axitinib suspension via ocular and systemic disposition in rabbits. Transl Vis Sci Technol. 2021; 10(7): 19).

[0004] However, intravitreal injection or fundus injection is invasive, and long-term repeated injections increase the risk of complications. Furthermore, although small molecule chemical drugs such as tyrosine kinase inhibitors are more stable than large molecule biological drugs, they are metabolized and distributed faster in the eyeball. To maintain effective drug concentrations in fundus lesions, more frequent injections are required, which increases the risk of complications and is therefore not suitable for intravitreal injection.

[0005] In addition to the above-mentioned local injection administration method, the commonly used administration methods, such as oral administration, injection (non-ocular injection) and other systemic administration methods, will increase systemic toxic side effects, and due to the obstruction of the blood-eye barrier, only a very small amount of drug molecules may reach the posterior segment of the eye, and the purpose of treating fundus diseases cannot be achieved (Chen Zuji, ed., "Practical Ophthalmic Pharmacology", China Science and Technology Press, p27, 1993). Most oral TKIs anti-tumor drugs will have systemic adverse reactions, such as oral axitinib tablets and sorafenib tablets, whose main adverse reactions include diarrhea (incidence: 55% and 53%, respectively), hypertension (40%, 29%), fatigue (39%, 32%), loss of appetite (34%, 29%), nausea (32%, 22%), etc. (drug instructions, Reference ID: 3078397). In a phase II clinical study of an oral tinib drug (X-82) for the treatment of age-related macular degeneration, subjects were given different doses of X-82 tablets (50 mg, 100 mg, and 200 mg / day) orally. After 6 months, the visual acuity improvement was non-inferior, but the clinical study was suspended due to its toxicity (Cohen et al., APEX: a phase II randomised clinical trial evaluating the safety and preliminary efficacy of oral X-82 to treat exudative age-related macular degeneration, Br J Ophthalmol, 2021 May; 105(5): 716-722).

[0006] Given that oral, injection, and local ocular injection methods all have safety and efficacy deficiencies, there is an urgent need to study new methods of administration of tyrosine kinase inhibitors (such as tinib drugs) to treat retinal neovascularization diseases.

[0007] Eye drops (conjunctival sac administration) are the most convenient and safest way of eye administration. They belong to local administration, with a small dosage and little toxic and side effects. However, the cornea has a multi-layer structure, which is roughly divided from the outside to the inside into: a lipid-rich epithelial layer, a matrix layer rich in aqueous components, and a lipid-rich endothelial layer. After the eye drops are instilled, they first contact the tear layer on the ocular surface, and then they need to cross the epithelial layer, matrix layer, and endothelial layer of the cornea to reach the posterior segment of the eye. In this process, due to the dilution of tears, the ocular surface barriers of the cornea and conjunctiva, and the anatomical position of the lens and vitreous body, the eye drops often have high concentrations in the tissues of the anterior segment of the eye and produce toxic and side effects, but it is still difficult to enter the posterior segment of the eye and reach an effective therapeutic concentration. Therefore, although the method of eye drops is safe, it is difficult for existing drug preparations to deliver drugs to the posterior segment of the eye to achieve the purpose of effectively treating fundus diseases.

[0008] In previous studies, the inventors developed a nanocrystalline eye drop, which successfully achieved the effect of delivering tyrosine kinase inhibitor drugs to the fundus by using dual-soluble macromolecules and single-soluble macromolecule excipients (patent application CN110664757A). However, this solution still has the following problems:

[0009] Eye drops are solutions that are directly used for eye treatment and must be sterile preparations. To achieve the sterility of liquid pharmaceutical preparations, two methods are often used in production and preparation: terminal high-temperature sterilization or process sterilization (using a 0.22μm microporous filter membrane for filtration and sterilization) to achieve the sterility of the final product (Chinese Pharmacopoeia 2020 Edition Part 4, edited by the National Pharmacopoeia Committee, China Medical Science and Technology Press, Beijing, 2020; Ophthalmic Drugs and Preparations, edited by Ling Peixue, China Light Industry Press, Beijing, 2010). The temperature change during the sterilization process of nanocrystalline solutions has a direct impact on the structure and properties of the nanocrystals. Terminal high-temperature sterilization of nanocrystalline solutions will cause the nanocrystals to dissolve, or the important physical and chemical properties of the nanocrystals such as crystal form and particle size will change, and even cause the nanocrystals to disappear, and a colloid will appear in the solution. Therefore, similar methods cannot be used for sterilization.

[0010] However, the sterilization process using a membrane material with a pore size of 0.22 μm for filtration and sterilization, due to the particle size of the nanocrystalline preparation being as high as 300 to 800 nm, results in a very high loss of the raw material drug after filtration, seriously affecting the content of the product's active ingredients. Therefore, there are difficulties in sterilization and disinfection during the industrial production process of the product.

[0011] In addition, the absorption and utilization rate of the raw materials of the nanocrystalline eye drops is also low, and its stability and other properties need to be improved.

[0012] Therefore, it is of great significance to provide a tyrosine kinase inhibitor eye drop with low loss of active ingredient content after sterilization and high absorption and utilization rate of raw materials, so as to treat fundus neovascularization diseases by eye drop administration. Summary of the invention

[0013] The object of the present invention is to provide a more stable eye drop that can reduce the loss of active ingredients during filtration sterilization or high-temperature sterilization, and has a high fundus absorption utilization rate and excellent stability (more stable than nanocrystals) for eye drop administration.

[0014] The present invention provides an ophthalmic preparation for eye drop administration, which is composed of an active substance for treating eye diseases and a pharmaceutically acceptable carrier or excipient. The active substance for treating eye diseases is a small molecule compound drug, such as a tyrosine kinase inhibitor (TKIs), which has an antagonistic effect on the tyrosine kinase of vascular endothelial growth factor receptor (VEGFR) and / or platelet growth factor receptor (PDGFR). Tyrosine kinase compounds are TKI drug molecules, and most of their free bases are difficult to dissolve in water. To prepare them into eye drops with water as the matrix that can penetrate into the posterior segment of the eye, the tyrosine kinase drugs must be dispersed in an aqueous solution and stabilized. The pharmaceutically acceptable carrier or excipient contains the following ingredients: a surfactant, a solubilizer, a viscosity enhancer and a solvent. Specifically, the present invention provides a tyrosine kinase inhibitor ophthalmic preparation, which is made of the following raw and auxiliary materials in parts by weight:

[0015] Active ingredient: 0.5 to 1.5 parts of tyrosine kinase inhibitor; the content of the active ingredient in the ophthalmic preparation is 0.05 to 1 mg / mL, preferably 0.1 to 1 mg / mL;

[0016] Pharmaceutically acceptable excipients: 20 to 300 parts of surfactant, 0.5 to 70 parts of viscosity enhancer, 10 to 800 parts of solubilizer, and the balance is solvent.

[0017] Furthermore, the above-mentioned ophthalmic preparation is made of the following raw materials and auxiliary materials in parts by weight:

[0018] Active ingredients: 1 part of tyrosine kinase inhibitor;

[0019] Pharmaceutically acceptable excipients: 25 to 200 parts of surfactant, 1 to 60 parts of viscosity enhancer, 27.5 to 500 parts of solubilizer, and the balance is solvent.

[0020] Preferably, the content of the active ingredient in the ophthalmic preparation is 0.05 to 0.5 mg / mL, preferably 0.1 to 0.5 mg / mL.

[0021] Furthermore, the above-mentioned tyrosine kinase inhibitor is a tinib-type active pharmaceutical ingredient or a pharmaceutically acceptable salt thereof, and the tinib-type active pharmaceutical ingredient (API) is at least one of axitinib, sorafenib, regorafenib, pazopanib, nintedanib, carbozantinib, lenvatinib, and sunitinib.

[0022] Furthermore, the HLB value (Hydrophile Lipophilic Balance value, HLB value) of the above-mentioned surfactant is greater than 10, preferably 13-29.

[0023] Furthermore, the above-mentioned non-ionic surfactant is at least one of polysorbate (Tween), sorbitan fatty acid ester (Span), polyoxyethylene fatty acid ester (Myrij), polyoxyethylene fatty alcohol ether (Brij), and poloxamer.

[0024] Furthermore, the above-mentioned surfactant is polysorbate and / or poloxamer.

[0025] Furthermore, the above-mentioned surfactant is polysorbate and poloxamer, and the weight ratio of polysorbate to poloxamer is (1-5):1.

[0026] Furthermore, the polysorbate is polysorbate 80.

[0027] Furthermore, the above-mentioned viscosity increasing agent is at least one of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose or its salt, hyaluronic acid or its salt, xanthan gum, carbomer or solid polyethylene glycol.

[0028] The solid polyethylene glycol is polyethylene glycol with a molecular weight of not less than 1000, preferably polyethylene glycol 4000 (PEG4K), polyethylene glycol 5000 (PEG 5K) or polyethylene glycol 6000 (PEG 6K), more preferably PEG 6K.

[0029] Furthermore, the above-mentioned viscosity enhancer is at least one of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hyaluronic acid or its salt, carboxymethyl cellulose or its salt or solid polyethylene glycol.

[0030] Furthermore, the solubilizing agent is at least one of liquid polyethylene glycol, cyclodextrin, hydroxypropyl cyclodextrin, tyloxapol, castor oil polyoxyethylene ether, and polyoxyethylene hydrogenated castor oil.

[0031] Furthermore, the solubilizer is liquid polyethylene glycol, castor oil polyoxyethylene ether and / or polyoxyethylene hydrogenated castor oil.

[0032] Furthermore, the solubilizer is any one of polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG400), castor oil polyoxyethylene ether EL-40, and polyoxyethylene hydrogenated castor oil PEG-60, and the HLB value of the castor oil polyoxyethylene ether EL-40 is 13-14.

[0033] Furthermore, the above-mentioned solvent is a polar solvent, preferably water.

[0034] Furthermore, the above-mentioned ophthalmic preparation also contains the following parts by weight of pharmaceutically acceptable excipients: 5 to 60 parts of an emulsion stabilizer.

[0035] Furthermore, it also contains the following pharmaceutically acceptable excipients in parts by weight: 6 to 50 parts of an emulsion stabilizer.

[0036] Furthermore, the emulsion stabilizer is povidone, hydroxyethyl cellulose and / or polyvinyl alcohol.

[0037] Furthermore, the emulsion stabilizer is povidone.

[0038] Furthermore, the above-mentioned polyvidone is a polyvidone with a weight average molecular weight of 10,000 to 50,000 Dalton.

[0039] Furthermore, the above-mentioned ophthalmic preparation also contains one or more of the following pharmaceutically acceptable excipients: an osmotic pressure regulator, a pH regulator, a preservative;

[0040] The osmotic pressure regulator is any one or more of glucose, sodium chloride, potassium chloride, mannitol, sorbitol, sodium citrate, potassium citrate and glycerol;

[0041] The pH adjuster is any one or more of hydrochloric acid, sodium hydroxide, acetic acid or its salt, citric acid or its salt, fumaric acid, succinic acid, sorbic acid, phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, boric acid, borax, tartaric acid or its salt;

[0042] The preservative is any one or more of sorbic acid, chlorobutanol, sodium chlorite, sodium perborate, quaternary ammonium salts, hydroxyphenyl esters, and phenylmercuric nitrate; preferably, the quaternary ammonium salts include benzalkonium chloride, benzalkonium bromide, polyquaternium-1 and / or cetyltrimethylammonium bromide, and the hydroxyphenyl esters include methylparaben, ethylparaben and / or propylparaben.

[0043] Furthermore, the pH value of the above preparation is 5-8.

[0044] Furthermore, the pH value of the above preparation is 6-8.

[0045] Furthermore, the pH value of the above preparation is 6-7.

[0046] Furthermore, the above-mentioned ophthalmic preparation is eye drops.

[0047] The present invention also provides a method for preparing the above-mentioned ophthalmic preparation, which comprises mixing and dispersing the active ingredient and the pharmaceutically acceptable auxiliary materials uniformly, and then performing stirring dispersion and / or homogenous dispersion.

[0048] Furthermore, the above preparation method comprises the following steps:

[0049] (1) dispersing a surfactant in a solvent to obtain a solution A, and dispersing an emulsion stabilizer and a viscosity enhancer in a solvent to obtain a solution B;

[0050] (2) dispersing the active ingredient in a solubilizer, and then adding the solution to the solution B obtained in step (1) to disperse the solution uniformly, thereby obtaining a solution C;

[0051] (3) Add solution C into solution A and disperse evenly, then disperse by high pressure homogenization to obtain the product.

[0052] Furthermore, the dispersion in the above step (2) and / or step (3) is selected from at least one of mechanical stirring dispersion, magnetic stirring dispersion, vortex shaking dispersion, shearing dispersion, grinding dispersion, and ultrasonic dispersion.

[0053] Furthermore, the high-pressure homogenization dispersion described in the above step (3) is first homogenized at a pressure not higher than 1000 Bar for 1 to 5 cycles, then the pressure is increased to above 1300 Bar for 10 to 20 cycles, and then the pressure is reduced to below 1000 Bar for 1 to 5 cycles.

[0054] (4) adding or not adding an osmotic pressure regulator and / or a pH regulator to adjust the osmotic pressure of the solution obtained in step (3) to isotonicity and the pH value to 5 to 8, and then adding or not adding a preservative; thus obtaining the product.

[0055] The present invention also provides the use of the above-mentioned ophthalmic preparation in preparing medicines for treating eye diseases.

[0056] Furthermore, the above-mentioned drug for treating eye diseases is a drug for treating ocular surface diseases and / or fundus diseases.

[0057] Furthermore, the above-mentioned drug for treating fundus diseases is a drug that inhibits the formation of new blood vessels.

[0058] Furthermore, the above-mentioned drug for treating fundus diseases is a drug for treating any one of age-related maculopathy, macular edema due to retinal vein occlusion, retinal vein occlusion, diabetic retinopathy, diabetic macular edema, vision loss caused by choroidal neovascularization secondary to pathological myopia, and neovascular glaucoma.

[0059] Furthermore, the above-mentioned drug for treating ocular surface diseases is a drug for treating ocular surface neovascularization diseases.

[0060] Furthermore, the above-mentioned drug for treating ocular surface diseases is a drug for treating any one of keratitis, corneal neovascularization caused by mechanical damage, chemical damage and / or biological damage, corneal neovascularization complicated by pterygium, corneal neovascularization caused by corneal transplant rejection, and corneal stem cell deficiency.

[0061] Beneficial effects of the present invention:

[0062] 1. The eye drops of the present invention are clear liquids with good stability and significantly reduced particle size (can be as low as 0.1 μm and smaller), and are suitable for preparing sterile preparations by filtration sterilization through a 0.22 μm microporous filter membrane or / and high-temperature sterilization (121°C). The loss of active ingredients after sterilization is small, and sterilization does not affect the delivery of the raw materials and the absorption of the raw materials by the posterior segment of the eye.

[0063] 2. On the basis of reducing the amount of raw materials by 90%, the absorption amount of raw materials in the vitreous body is equivalent to or even higher than that recorded in patent application CN110664757A (the concentration of raw materials in the eye drops of the present invention is 0.1-0.5 mg / mL, while the concentration of raw materials in the embodiment of patent application CN110664757A reaches 1 mg / mL), indicating that the absorption utilization rate of the eye drops of the present invention is improved;

[0064] At the same time, since in most cases 80-90% of the drug solution is discharged from the lacrimal canaliculus with tears or absorbed into the blood system through the eyelids and conjunctival blood vessels after eye drops are administered, systemic toxic and side effects may occur. Under the condition of ensuring that the therapeutic amount of the drug is delivered to the fundus, reducing the total dosage is conducive to reducing systemic toxic and side effects, so the eye drops of the present invention have less toxic and side effects.

[0065] The HLB value described in the present invention is the hydrophile-lipophile balance constant.

[0066] The polyethylene glycol 4000 (PEG 4K) described in the present invention refers to polyethylene glycol with a weight average molecular weight of 4000. Similarly, the numerical values ​​after other polyethylene glycols represent their weight average molecular weights.

[0067] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0068] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1 This is a transmission electron microscopy image of the sample prepared in Example 2 (scale bar = 200 nm).

[0070] Figure 2 This is a transmission electron microscopy image of the sample prepared in Example 3 (scale bar = 100 nm). DETAILED DESCRIPTION

[0071] The reagents or instruments used in the present invention can be purchased from the market. If no specific conditions are specified, they are used according to conventional conditions or conditions recommended by the manufacturer.

[0072] Some of the equipment are as follows:

[0073] ES225SM-DR(E) electronic analytical balance, Precisa (Switzerland);

[0074] DF-101S collector-type constant temperature heating magnetic stirrer, Gongyi Yingyu High-Tech Instrument Factory (Henan, China);

[0075] WH-2 micro vortex mixer, Shanghai Huxi Analytical Instrument Factory Co., Ltd. (Shanghai, China);

[0076] Disperser: T25 easy clean digital, IKA (Germany);

[0077] KQ-500 ultrasonic cleaner, Kunshan Ultrasonic Instrument Co., Ltd. (Kunshan, China);

[0078] AH-NANO Plus high pressure homogenizer, Antos Nanotechnology (Suzhou) Co., Ltd. (China);

[0079] PM-DK2 planetary ball mill, Zhuodi Instrument Equipment (Shanghai) Co., Ltd. (Shanghai, China);

[0080] Mettler Toledo FE20 pH meter, Mettler-Toledo (Switzerland);

[0081] NS-90 nanoparticle size analyzer, Zhuhai OMEC Instrument Co., Ltd. (Zhuhai, China);

[0082] Agilent 1100HPLC high performance liquid chromatograph, Agilent Technologies, Inc. (USA);

[0083] API 4000 triple quadrupole mass spectrometer (Applied Biosystems, USA);

[0084] STY-1A osmometer, Tianjin Tianda Tianfa Technology Co., Ltd. (Tianjin, China).

[0085] The property detection method of the preparation of the present invention is as follows:

[0086] Particle size detection method:

[0087] 1 mL of the sample prepared in the embodiment or comparative example was transferred to the sample pool, the detection temperature was set to 40°C, the sample pool was placed in the NS-90 nanoparticle size analyzer, and the detection was started. Each sample was tested 3 times, and the average of the 3 test results was taken as the particle size (in terms of the main particle size distribution and its proportion) and the polydispersity index (PdI) of the sample.

[0088] Osmolality test method:

[0089] Measure the freezing point depression of the solution to determine its osmotic pressure molar concentration. Operation: Clean the STY-1A osmotic pressure meter probe: Take three 100μL distilled water into three sample tubes. After the instrument is preheated, screw the sample tubes containing 100μL distilled water onto the instrument probe, select to clean 3 times, click "clean", and repeat three times. Detection: After filling in the sample information in the instrument information table, click "test"; use a pipette to transfer 100μL of sample to the sample tube, gently screw it onto the instrument, and click "start" to test. Repeat the test three times, and take the average of the three test results as the test result.

[0090] pH value detection method:

[0091] The FE20 acidity meter was calibrated with pH buffer solutions (pH 4.00, 6.86 and 9.18, respectively). After the electrode was rinsed with pure water, excess water was absorbed with fiber-free paper, immersed in the liquid sample to be tested, and the reading key was pressed to start measurement. The data obtained after the reading stabilized was the pH value of the sample.

[0092] Unless otherwise stated, the efficacy of drug delivery to the posterior segment of the eye was demonstrated as follows:

[0093] Experimental instruments and equipment: High performance liquid chromatograph, model: LC-20AD (Shimadzu, Japan); mass spectrometer: model: API4000 triple quadrupole mass spectrometer (Applied Biosystems, USA); chromatographic column: Fortis Pace C18 5μm, 2.1X30mm (Fortis, UK).

[0094] Rat eye test method: Healthy adult Sprague Dawley (SD) rats were selected and divided into a test group and a control group, with 4 eyes in each group. The test group was dripped with the ophthalmic preparation prepared in the embodiment of the present invention, 20 μL per eye. After administration, the animals were euthanized at a predetermined time point, and the vitreous and / or aqueous humor were quickly collected. The vitreous samples were homogenized and stored at -80°C.

[0095] Sample processing and detection method: After homogenizing the rat vitreous sample, take 5 μL, add 45 μL 70% methanol-water, ultrasonicate for 2 minutes, vortex for 1 minute, add 25 μL internal standard and 150 μL methanol, vortex mix for 2 minutes, centrifuge at 12000 rpm at 4°C for 10 minutes, and take the supernatant for LC-MS / MS analysis (positive ion mode, MRM SCAN). The aqueous humor sample does not need to be homogenized, and is processed in the same way and then analyzed by LC-MS / MS.

[0096] Rabbit eye test method: Healthy adult New Zealand rabbits were selected and divided into a test group and a control group, with 4 eyes in each group. The test group was dripped with the ophthalmic preparation prepared in the embodiment of the present invention, 50 μL per eye. After administration, the animals were euthanized at a predetermined time point, and eye tissues (retina, choroid, sclera) were quickly collected. After the samples were homogenized, they were stored at -80°C.

[0097] Sample processing and detection methods: refer to the rat eye tissue sample processing and detection methods.

[0098] Example 1. Preparation of the ophthalmic preparation of the present invention

[0099] Preparation method: Weigh 75 mg of polysorbate 80 (TW-80) and add it to a glass conical flask containing 10 mL of purified water, and start magnetic stirring for 0.5 h to obtain solution 1; weigh 18 mg of povidone K12 (PVP K12) and 18 mg hydroxypropyl methylcellulose (HPMC) were added to a glass conical flask containing 10 mL of purified water and magnetically stirred for 60 min to obtain solution 2; 2.5 mg of axitinib was weighed and put into a 50 mL polypropylene tube containing 1.2 g of castor oil polyoxyethylene ether EL-40, solution 2 was added, stirred for 30 min, solution 1 was added, water was added to 25 mL, and stirred for 30 min to obtain a mixed solution; the mixed solution was dispersed at 10000 rpm for 3 min using a disperser, the machine was stopped and after the foam disappeared, the dispersion was transferred to a high-pressure homogenizer, the temperature was controlled at 15±5°C, the pressure was increased to 1300 Bar and the homogenization cycle was repeated 3 times, and then the pressure was increased to 1300 Bar and the homogenization cycle was repeated 15 times, and the pressure was reduced to 300 Bar and the homogenization cycle was repeated 2 times, and then discharged to obtain a homogenized solution, the pH value and osmotic pressure were tested, and the pH was adjusted to 7.0 with sodium citrate or / and dilute hydrochloric acid solution; sodium chloride was added to adjust the osmotic pressure to: 272 mOsmol / kg. After adding the preservative, the mixture was stirred and dispersed, and the solution was filtered under reduced pressure through a 0.45 μm filter membrane to obtain the product as a solution.

[0100] HPLC detection: Agilent HPLC1100 system equipped with DAD detection unit, chromatographic conditions: chromatographic column: WatersXBridge C18, 5μm, 4.6x250mm;

[0101] Mobile phase A: 0.1% H 3 PO 4 Solution, mobile phase B: ACN (acetonitrile). Temp.: 35°C, detection wavelength: 360nm, flow rate: 0.8mL / min; gradient elution program: 0': 85% A-15% B, 15': 50% A-50% B, 20-21': 30% A-70% B, 25': 85% A-15% B. HPLC content detection result: 0.078mg / mL.

[0102] Particle size test results (main particle size distribution and its proportion), particle size: 13.0nm (92.1%), PdI: 0.227;

[0103] After the solution was sterilized by filtration through a 0.22 μm pore size membrane, the particle size detection results were: particle size 14.4 nm (100.0%), PdI: 0.080; HPLC content detection results: 0.077 mg / mL.

[0104] Results of the rat eye absorption experiment: 20 μL of 0.5hAPI was dropped into the rat's eye, and the concentration in the vitreous body of the animal was 19.9±3.2 ng / g, and the concentration in the aqueous humor was 237.5±47.6 ng / g.

[0105] Rabbit eye tissue absorption test results: 50 μL was dripped into New Zealand rabbits, and the concentration of API in the retina was 0.92±0.64 ng / g, the concentration in the choroid was 1.22±0.60 ng / g, and the concentration in the sclera was 10.3±5.61 ng / g, all of which were significantly higher than the in vitro inhibition of VEGFR-1 by API (IC 50 =0.03-0.05ng / g) and VEGFR-2 (IC 50 =0.08ng / g) concentration.

[0106] Example 2: Preparation of the ophthalmic preparation of the present invention

[0107] The materials and proportions used are shown in Table 1. The preparation process (pH adjusted to 6.5) and content detection are the same as in Example 1 to obtain a solution; the osmotic pressure is adjusted to: 332mOsmol / kg;

[0108] Particle size detection results: particle size: 12.8 nm (76.0%), PdI: 0.283; HPLC content detection results: 0.181 mg / mL.

[0109] After the solution was sterilized by filtration through a 0.22 μm pore size membrane, the particle size test results were: particle size: 15.2 nm (93.5%), PdI: 0.234; HPLC content test results: 0.178 mg / mL.

[0110] Results of the rat eye absorption experiment: After 20 μL of 0.5hAPI was dripped into the rat's eye, the concentration of 17.3±9.0 ng / g in the rat's vitreous body was 0.5hAPI.

[0111] Transmission electron microscopy analysis showed that the particle size was spherical ( Figure 1 )

[0112] Example 3: Preparation of the ophthalmic preparation of the present invention

[0113] The materials and proportions used are shown in Table 1. The preparation process (pH adjusted to 5.7) and content detection are the same as in Example 1 to obtain a solution; the osmotic pressure is adjusted to: 338mOsmol / kg;

[0114] Particle size detection results: particle size: 13.8nm (67.2%), 72.6nm (21.5%), PdI: 0.249; HPLC detection results content: 0.391mg / mL.

[0115] After the solution was sterilized at 121° C. for 20 min, the particle size test results were: particle size: 12.7 nm (68.6%), 76.7 nm (31.4%), PdI: 0.286; HPLC content test results: 0.387 mg / mL.

[0116] The solution was sterilized by filtration through a 0.22 μm membrane. The particle size test results showed: 16.2 nm (70.0%), 126.5 nm (23.7%), PdI: 0.513; HPLC content test results: 0.389 mg / mL.

[0117] Results of the rat vitreous absorption experiment: When 20 μL of 0.5hAPI was dropped into the rat's eye, the concentration of 0.5hAPI in the rat's vitreous was 37.2±25.1 ng / g, and the concentration in the aqueous humor was 370±92.4 ng / g.

[0118] Results of the rabbit eye tissue absorption experiment: When 50 μL of 0.5hAPI was dropped into the eyes of New Zealand rabbits, the concentration of retina was 1.66±2.08 ng / g, the concentration of choroid was 0.98±0.76 ng / g, and the concentration of sclera was 9.40±6.41 ng / g.

[0119] Transmission electron microscopy analysis showed that the particle size was snowflake-shaped ( Figure 2 )

[0120] Example 4. Preparation of the ophthalmic preparation of the present invention

[0121] The materials and proportions used are shown in Table 1. The preparation process (pH adjusted to 6.1) and content detection are the same as in Example 1 to obtain a solution; the osmotic pressure is adjusted to: 288mOsmol / kg;

[0122] Particle size detection results: particle size: 284.6nm (53.5%), 15.2nm (46.5%) PdI: 0.500; HPLC content detection results: 0.077mg / mL.

[0123] After the solution was sterilized by filtration through a 0.22 μm pore size membrane, the particle size test results were: particle size: 12.3 nm (89.8%), PdI: 0.179; HPLC content test results: 0.076 mg / mL.

[0124] Results of the rat eye absorption experiment: After 20 μL of eye drops were administered to rats, the concentration of API in the rat vitreous was 46.8±36.1 ng / g at 0.5 h.

[0125] Example 5. Preparation of the ophthalmic preparation of the present invention

[0126] The materials and proportions used are shown in Table 1. The preparation process (pH adjusted to 6.7) and content detection are the same as in Example 1 to obtain a solution;

[0127] Particle size detection results: particle size: 106.0 nm (91.2%), PdI: 0.288; HPLC content detection results: 0.081 mg / mL.

[0128] After the solution was sterilized by filtration through a 0.22 μm pore size membrane, the particle size test results were: 97.8 nm (98.9%), PdI: 0.247; HPLC content test results: 0.078 mg / mL.

[0129] The solution was placed at 40° C. for 1 month. There was no significant change in the appearance and content of the solution, particle size detection: 93.1 nm (99.6%), PdI: 0.255, HPLC content detection result: 0.076 mg / mL.

[0130] Example 6. Preparation of the ophthalmic preparation of the present invention

[0131] The materials and proportions used are shown in Table 1. The preparation process (pH adjusted to 6.1) and content detection are the same as in Example 1 to obtain a solution;

[0132] Particle size detection results: particle size: 19.8nm (99.3%), PdI: 0.186; HPLC content detection results: 0.082mg / mL.

[0133] After the solution was sterilized by filtration through a 0.22 μm pore size membrane, the particle size test results were: 20.0 nm (98.6%), PdI: 0.218; HPLC content test results: 0.081 mg / mL.

[0134] The solution was placed at 40° C. for 1 month. There was no significant change in the appearance and content of the solution, the particle size test result was: 19.6 nm (99.2%), PdI: 0.236, and the HPLC content test result was: 0.080 mg / mL.

[0135] Example 7. Preparation of the ophthalmic preparation of the present invention

[0136] The materials and proportions used are shown in Table 1. The preparation process (pH adjusted to 6.3) and content detection are the same as in Example 1 to obtain a solution;

[0137] Particle size detection results: particle size: 20.3nm (95.2%), PdI: 0.246; HPLC content detection results: 0.082mg / mL.

[0138] After the solution was sterilized by filtration through a 0.22 μm pore size membrane, the particle size test results were: particle size: 19.2 nm (98.3%), PdI: 0.198; HPLC content test results: 0.081 mg / mL.

[0139] The solution was placed at 40° C. for 1 month. There was no significant change in the appearance and content of the solution, the particle size test result was: 18.6 nm (98.8%), PdI: 0.210, and the HPLC content test result was: 0.081 mg / mL.

[0140] Example 8. Preparation of the ophthalmic preparation of the present invention

[0141] The materials and proportions used are shown in Table 1. The preparation process (pH adjusted to 6.1) and content detection are the same as in Example 1 to obtain a solution;

[0142] Particle size detection results: particle size: 13.3nm (99.4%), PdI: 0.305; HPLC content detection results: 0.083mg / mL.

[0143] After the solution was sterilized by filtration through a 0.22 μm pore size membrane, the particle size test results were: particle size: 12.7 nm (99.3%), PdI: 0.237; HPLC content test results: 0.082 mg / mL.

[0144] Example 9: Preparation of the ophthalmic preparation of the present invention

[0145] The materials and proportions used are shown in Table 1. The preparation process (pH adjusted to 6.1) and content detection are the same as in Example 1. Sodium chloride and sorbitol are added to adjust the osmotic pressure to 284 mOsmol / kg to obtain a solution;

[0146] Particle size detection results: particle size: 15.6nm (78.2%), PdI: 0.454; HPLC content detection results: 0.084mg / mL.

[0147] After the solution was sterilized by filtration through a 0.22 μm pore size membrane, the particle size test results were: particle size: 14.3 nm (89.6%), PdI: 0.317; HPLC content test results: 0.082 mg / mL.

[0148] Results of the rat eye absorption experiment: After 20 μL of drug was dropped into the rat's eye, the concentration of API in the rat's vitreous was 39.5±26.3 ng / g at 0.5 h.

[0149] Example 10: Preparation of the ophthalmic preparation of the present invention

[0150] The materials and proportions used are shown in Table 1. The API is regorafenib. The preparation process and content detection are the same as in Example 1 (HPLC detection wavelength: 265 nm) to obtain a solution; the content detection result is: 0.048 mg / mL.

[0151] Particle size detection results: particle size: 17.4nm (81.2%), PdI: 0.387;

[0152] After the solution was sterilized by filtration through a 0.22 μm pore size membrane, the particle size test results were: 16.3 nm (91.2%), PdI: 0.342; HPLC content test results: 0.046 mg / mL.

[0153] Example 11. Preparation of the ophthalmic preparation of the present invention

[0154] The materials and proportions used are shown in Table 1. The API is sorafenib p-toluenesulfonate. The preparation process and content detection are the same as in Example 1 (HPLC detection wavelength: 255 nm) to obtain a solution; the content detection result is: 0.089 mg / mL.

[0155] Particle size detection results: particle size: 19.6nm (88.2%), PdI: 0.406;

[0156] After the solution was sterilized by filtration through a 0.22 μm pore size membrane, the particle size test results were: particle size: 17.9 nm (92.6%), PdI: 0.265; HPLC content test results: 0.087 mg / mL.

[0157] Example 12: Preparation of the ophthalmic preparation of the present invention

[0158] The materials and proportions used are shown in Table 1. The preparation process (pH adjusted to 6.3) and content detection are the same as in Example 1 to obtain a solution;

[0159] Particle size detection results: particle size: 17.2nm (93.4%), PdI: 0.294; HPLC content detection results: 0.189mg / mL.

[0160] After the solution was sterilized by filtration through a 0.22 μm pore size membrane, the particle size test results were: particle size: 16.7 nm (95.8%), PdI: 0.243; HPLC content test results: 0.186 mg / mL.

[0161] Results of the New Zealand rabbit ocular absorption experiment: 50 μL was dropped into the eyes of New Zealand rabbits, and the concentration of API in the sclera of New Zealand rabbits was 5.3±1.5 ng / g after 0.5 h.

[0162] Example 13. Preparation of the ophthalmic preparation of the present invention

[0163] The materials and proportions used are shown in Table 1. The preparation process (pH adjusted to 6.3) and content detection are the same as in Example 1 to obtain a solution;

[0164] Particle size detection results: particle size: 16.1 nm (91.3%), PdI: 0.276; HPLC content detection results: 0.185 mg / mL.

[0165] After the solution was sterilized by filtration through a 0.22 μm pore size membrane, the particle size test results were: particle size: 15.1 nm (95.9%), PdI: 0.278; HPLC content test results: 0.182 mg / mL.

[0166] Results of the New Zealand rabbit ocular absorption experiment: 50 μL was dropped into the eyes of New Zealand rabbits, and the concentration of API in the choroid of the New Zealand rabbits was 1.4±0.7 ng / g after 0.5h.

[0167] Example 14. Preparation of the ophthalmic preparation of the present invention

[0168] The materials and proportions used are shown in Table 1. The preparation process (pH adjusted to 6.5) and content detection are the same as in Example 1 to obtain a solution;

[0169] Particle size detection results: particle size: 14.5nm (92.5%), PdI: 0.258; HPLC content detection results: 0.193mg / mL.

[0170] After the solution was sterilized by filtration through a 0.22 μm pore size membrane, the particle size test results were: particle size: 14.4 nm (98.4%), PdI: 0.182; HPLC content test results: 0.191 mg / mL.

[0171] Results of the New Zealand rabbit ocular absorption experiment: 50 μL was dropped into the eyes of New Zealand rabbits, and the concentration of API in the sclera of New Zealand rabbits was 10.3±5.6 ng / g after 0.5 h.

[0172] Example 15. Preparation of the ophthalmic preparation of the present invention

[0173] The materials and proportions used are shown in Table 1. The preparation process (pH adjusted to 6.6) and content detection are the same as in Example 1 to obtain a solution;

[0174] Particle size detection results: particle size: 13.6nm (97.3%), PdI: 0.172; HPLC content detection results: 0.182mg / mL.

[0175] After the solution was sterilized by filtration through a 0.22 μm pore size membrane, the particle size test results were: particle size: 12.5 nm (100.0%), PdI: 0.163; HPLC content test results: 0.180 mg / mL.

[0176] Results of the New Zealand rabbit ocular absorption experiment: 50 μL of API was dropped into the eye of the New Zealand rabbit, and the concentration of API in the vitreous of the New Zealand rabbit was 0.244 ng / g after 0.5 h.

[0177] Example 16. Preparation of the ophthalmic preparation of the present invention

[0178] The materials and proportions used are shown in Table 1. The preparation process (pH adjusted to 6.6) and content detection are the same as in Example 1 to obtain a solution;

[0179] Particle size detection results: particle size: 14.5nm (94.2%), PdI: 0.223; HPLC content detection results: 0.186mg / mL.

[0180] After the solution was sterilized by filtration through a 0.22 μm pore size membrane, the particle size test results were: particle size: 13.0 nm (100.0%), PdI: 0.163; HPLC content test results: 0.181 mg / mL.

[0181] Results of the New Zealand rabbit ocular absorption experiment: 50 μL of the drug was dropped into the eyes of New Zealand rabbits, and the concentration of API in the New Zealand rabbit brain membrane was 3.85±5.00 ng / g after 0.5h.

[0182] Comparative Example 1

[0183] The materials and proportions used are shown in Table 1. The preparation process and content detection are the same as in Example 1 to obtain a solution;

[0184] Particle size detection results: particle size: 2105nm (100.0%), PdI: 0.645;

[0185] After standing at room temperature overnight, the substances in the preparation condensed into agglomerates and water-oil separation occurred, indicating that the stability of this preparation was poor.

[0186] Results of the rat eye absorption experiment: After 20 μL of eye drops were administered to rats, the concentration of API in the rat vitreous was 7.87±2.83 ng / g at 0.5 h, indicating that the concentration of this preparation in the fundus was low.

[0187] Comparative Example 2

[0188] The materials and proportions used are shown in Table 1. Preparation method: Weigh 500 mg TW-80 and 500 mg hydroxypropyl cellulose (HPC) and add them to a conical flask containing 40 mL purified water, stir for 30 minutes to obtain solution 1. Weigh 50 mg axitinib and add it to 100 mL polypropylene plastic. Add solution 1 and stir for 10 minutes. Then add purified water to 50 ml and stir for 30 minutes to obtain a mixed solution. Use a disperser to disperse the mixed solution at 10000 rpm for 3 minutes. (1) Use ball milling method: transfer the dispersion into a ball mill and add 80 g wet zirconium beads (particle size of 0.3-0.4 mm). Then add 1 mL purified water to rinse the polypropylene plastic tube and then merge it into the ball mill. Then cover the ball mill tightly and grind at 0°C at a speed of 300 rpm for 2 hours. After grinding, filter using a G2 glass sand core funnel to obtain a milky white suspension.

[0189] Particle size detection results: particle size: 280.9 nm (100.0%), PdI: 0.274; HPLC content detection results: 0.879 mg / mL.

[0190] After the solution was sterilized by pressure filtration through a 0.22 μm microporous filter membrane, the particle size test results were: 310.0 nm (100.0%), PdI: 0.248; HPLC content test results: 0.736 mg / mL.

[0191] The solution was sterilized at 121°C; after 20 minutes, the solution separated into layers, indicating that the preparation was unstable when heated at high temperature.

[0192] Or, (2) using a high-pressure homogenization method, the mixed liquid is dispersed at 10000 rpm for 3 minutes using a disperser, the machine is stopped and after the foam disappears, the dispersed liquid is transferred to a high-pressure homogenizer, the temperature is controlled at 15±5°C, the homogenization cycle is performed at a pressure of about 400 Bar for 3 times, and then the pressure is increased to >1300 Bar and homogenized for 15 times, and the pressure is reduced to 300 Bar and homogenized for 2 times before being discharged to obtain a homogenized liquid, which is a white suspension.

[0193] Particle size detection results: particle size: 295.0 nm (100.0%), PdI: 0.443; HPLC content detection results: 0.830 mg / mL.

[0194] After the solution was sterilized by pressure filtration through a 0.22 μm microporous filter membrane, the particle size test results were: 815.7 nm (80.7%), PdI: 0.736; HPLC content test results: 0.025 mg / mL.

[0195] Comparative Example 3

[0196] The materials and proportions used are shown in Table 1. The preparation process (pH adjusted to 7.0) was the same as that of Comparative Example 1 to obtain a solution. After being placed at room temperature for 3 days, precipitation occurred, indicating that the prepared solution was unstable.

[0197] Comparative Example 4

[0198] The eye drops prepared according to the record of No. 12 in Table 8 of patent application CN110664757A: 5 mg axitinib; 2 mg Tween 80; 2 mg HPMC E5, add water to 50 mL, and use high pressure homogenization method. The obtained eye drops are subjected to rat vitreous eye drop absorption test. The API content in rat vitreous 0.5 h after eye drops is 1.7 ng / mL.

[0199] Comparative Example 5

[0200] The eye drops prepared according to the record of No. 13 in Table 8 of patent application CN110664757A: 10 mg axitinib; 2 mg Tween 80; 2 mg HPMC E5, add water to 50 mL, and use high pressure homogenization method. The obtained eye drops are subjected to rat vitreous eye drop absorption test. The content of 0.5 hAPI in rat vitreous is 6.3 ng / mL.

[0201] Table 1

[0202]

[0203]

[0204] Note: The weight average molecular weight of PVP K12 is 2500 Dalton, and the weight average molecular weight of PVP K15 is 8000 Dalton.

[0205] The weight average molecular weight of PVP K17 is 10,000 Dalton, and the weight average molecular weight of PVP K30 is 50,000 Dalton.

[0206] It can be seen from the above results that the eye drops of the embodiment of the present invention are significantly more stable than the eye drops prepared by using a weakly hydrophilic solubilizer (HLB value is not greater than 10) (Comparative Example 1); and, at an API dosage equivalent to that of Comparative Example 1, the absorption amount in the rat vitreous body after eye drop administration of the embodiment is higher, that is, the drug utilization rate of the eye drops of the present invention is significantly higher;

[0207] The eye drops of the present invention are also significantly more stable than the preparation lacking a surfactant (Comparative Example 3);

[0208] Compared with the comparative example 2, the eye drops of the embodiment of the present invention are solutions, and the preparation properties and stability are better, and the API content loss after sterilization is lower; while the preparation of the comparative example 2 is a nanocrystalline suspension, and there is a risk of crystal transformation during the production process, which affects the absorption and distribution of the drug in the body; there is a risk of aggregation during storage, which affects the product quality; and the suspension of the comparative example 2 has a high API content loss after filtration sterilization, and is unstable and stratified after high-temperature sterilization, making it difficult to prepare a sterile preparation.

[0209] Furthermore, by comparing the eye drops of the embodiment of the present invention with comparative examples 4 and 5, it can be seen that at an API dosage equivalent to that of the comparative examples (axitinib concentration of 0.1 mg / mL), the absorption of axitinib in the vitreous body of the present invention is significantly improved compared with that of comparative examples 4 and 5, indicating that the drug utilization rate of the eye drops of the present invention is significantly improved.

[0210] The preparation of the present invention contains non-ionic surfactants, which have fixed hydrophilic and lipophilic groups in their chemical structure, and the ratio of their hydrophilic and lipophilic groups determines their HLB values. The lipophilicity or hydrophilicity of the surfactant can be judged by the size of the HLB value (Pan Weisan, ed., "Pharmaceutics", Chapter 3, Chemical Industry Press, Beijing, 2017; MR Shah et al., original work, Liu Ying, translator, "Application of Lipid-based Nanocarriers in Drug Delivery and Diagnosis", Chapter 4, Science Press, Beijing, 2019; SSS mail et al., Studies on Surfactants, Cosurfactants, and Oils for Prospective Use in Formulation of Ketorolac Tromethamine Ophthalmic Nanoemulsions, Pharmaceutics 2021, 13, 467). The inventors found in the study that when the surfactant HLB value is >10, the eye drops containing API prepared under the same or similar conditions have better stability. The surfactants include polysorbate 80 (molecular weight 1130 Dalton), poloxamer 407 (molecular weight 11.5 KDalton), PEG-40 hydrogenated castor oil (molecular weight 2500 Dalton) and solubilizer polyoxyethylene hydrogenated castor oil EL-40 (molecular weight 2500 Dalton), etc., and their HLB values ​​are 13 to 29. The inventors have found through many experiments that the use of more than one surfactant with similar HLB values ​​but significantly different molecular weights can produce an eye drop that is more stable than using only one surfactant.

[0211] Therefore, only on the basis of the specific combination of excipient types and dosages of the present invention can the eye drops of the present invention be obtained, which have excellent stability, are suitable for filtration through a 0.22 μm microporous filter membrane and / or high temperature (121° C.) aseptic treatment, and have a high utilization rate of the raw material drug.

[0212] In summary, the present invention provides a tyrosine kinase inhibitor ophthalmic preparation suitable for eye drop administration, which can effectively deliver active ingredients to the fundus to treat fundus angiogenesis diseases. The ophthalmic preparation of the present invention has high absorption utilization rate, small particle size, good stability, is suitable for preparing sterile preparations by microporous membrane sterilization method and / or high temperature sterilization method, and has very good clinical application prospects.

Claims

1. A tyrosine kinase inhibitor ophthalmic preparation, characterized in that: The ophthalmic preparation is an eye drop, which is made of the following raw materials and auxiliary materials in parts by weight: Active ingredient: 0.5-1.5 parts of tyrosine kinase inhibitor; the content of the active ingredient in the ophthalmic preparation is 0.05-1 mg / mL; Pharmaceutically acceptable excipients: 25-200 parts of surfactant, 0 part or 6-50 parts of emulsion stabilizer, 1-60 parts of viscosity enhancer, 27.5-500 parts of solubilizer, at least one of optional osmotic pressure regulator, pH regulator or preservative, and the balance is solvent; The tyrosine kinase inhibitor is selected from at least one of axitinib, regorafenib, and sorafenib p-toluenesulfonate; The surfactant is polysorbate and / or poloxamer; the HLB value of the surfactant is 13-29; The viscosity enhancer is at least one of methylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose or its salt, hyaluronic acid or its salt or solid polyethylene glycol; The solubilizing agent is liquid polyethylene glycol, castor oil polyoxyethylene ether and / or polyoxyethylene hydrogenated castor oil; the HLB value of the castor oil polyoxyethylene ether is 13-14; The solvent is water; The emulsion stabilizer is polyvidone with a weight average molecular weight of 10,000 to 50,000 Dalton.

2. The ophthalmic preparation according to claim 1, characterized in that It is made of the following raw materials by weight: Active ingredient: 0.5-1.5 parts of tyrosine kinase inhibitor; the content of the active ingredient in the ophthalmic preparation is 0.1-1 mg / mL; Pharmaceutically acceptable excipients: 25-200 parts of surfactant, 0 part or 6-50 parts of emulsion stabilizer, 1-60 parts of viscosity enhancer, 27.5-500 parts of solubilizer, at least one of optional osmotic pressure regulator, pH regulator or preservative, and the balance is solvent.

3. The ophthalmic preparation according to claim 1 or 2, characterized in that It is made of the following raw materials by weight: Active ingredients: 1 part of tyrosine kinase inhibitor; Pharmaceutically acceptable excipients: 25-200 parts of surfactant, 0 part or 6-50 parts of emulsion stabilizer, 1-60 parts of viscosity enhancer, 27.5-500 parts of solubilizer, at least one of optional osmotic pressure regulator, pH regulator or preservative, and the balance is solvent.

4. The ophthalmic preparation according to claim 3, characterized in that The content of the active ingredient in the ophthalmic preparation is 0.05-0.5 mg / mL.

5. The ophthalmic preparation according to claim 4, characterized in that The content of the active ingredient in the ophthalmic preparation is 0.1-0.5 mg / mL.

6. The ophthalmic preparation according to claim 1, wherein The surfactants are polysorbate and poloxamer, and the weight ratio of the polysorbate to poloxamer is (1-5):

1.

7. The ophthalmic preparation according to claim 1 or 6, characterized in that The polysorbate is polysorbate-80.

8. The ophthalmic preparation according to claim 1 or 2, characterized in that The solid polyethylene glycol is polyethylene glycol with a molecular weight of not less than 1000.

9. The ophthalmic preparation according to claim 8, characterized in that The solid polyethylene glycol is polyethylene glycol 4000, polyethylene glycol 5000 or polyethylene glycol 6000.

10. The ophthalmic preparation according to claim 9, wherein The solid polyethylene glycol is polyethylene glycol 6000.

11. The ophthalmic preparation according to claim 1 or 2, characterized in that: The solubilizer is any one of polyethylene glycol 300, polyethylene glycol 400, castor oil polyoxyethylene ether EL-40, and polyoxyethylene hydrogenated castor oil PEG-60, and the HLB value of the castor oil polyoxyethylene ether EL-40 is 13-14.

12. The ophthalmic preparation according to claim 1 or 2, characterized in that The pH value of the preparation is 5-8.

13. The ophthalmic preparation according to claim 12, wherein The pH value of the preparation is 6-8.

14. The ophthalmic preparation according to claim 13, wherein The pH value of the preparation is 6-7.

15. The method for preparing the ophthalmic preparation according to any one of claims 1 to 14, characterized in that: The active ingredient and the pharmaceutically acceptable excipients are mixed and dispersed uniformly, and then stirred and / or homogenized; The steps include: (1) Dispersing a surfactant in a solvent to obtain a solution A, and dispersing an emulsion stabilizer and a thickener in a solvent to obtain a solution B; (2) dispersing the active ingredient in a solubilizer, and then adding the solution to the solution B obtained in step (1) and dispersing the solution evenly to obtain a solution C; (3) Add solution C to solution A and disperse evenly, then disperse by high pressure homogenization; (4) adding or not adding an osmotic pressure regulator and / or a pH regulator to adjust the osmotic pressure of the solution obtained in step (3) to isotonicity and the pH value to 5-8, and then adding or not adding a preservative; the product is obtained.

16. The preparation method according to claim 15, characterized in that: The dispersion in step (2) and / or step (3) is selected from at least one of mechanical stirring dispersion, magnetic stirring dispersion, vortex shaking dispersion, shearing dispersion, grinding dispersion, and ultrasonic dispersion.

17. The preparation method according to claim 15, characterized in that: The high-pressure homogenization dispersion in step (3) is to first homogenize at a pressure not higher than 800 Bar for 1 to 5 cycles, then increase the pressure to not higher than 1300 Bar for 5 to 20 cycles, and then reduce the pressure to below 800 Bar for 1 to 5 cycles.

18. Use of the ophthalmic preparation according to any one of claims 1 to 14 in the preparation of a medicament for treating fundus neovascularization diseases.

19. The use according to claim 18, characterized in that The drug for treating fundus neovascularization disease is a drug for treating any one of age-related fundus maculopathy, macular edema due to retinal vein occlusion, retinal vein occlusion, diabetic retinopathy, diabetic macular edema, vision loss caused by choroidal neovascularization secondary to pathological myopia, and neovascular glaucoma.

20. Use of the ophthalmic preparation according to any one of claims 1 to 14 in the preparation of a medicament for treating corneal neovascularization complicated by pterygium.

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