Ophthalmic tyrosine kinase inhibitor formulations, preparation method and use thereof

Abstract

The present invention provides an ophthalmic tyrosine kinase inhibitor formulation suitable for ophthalmic administration, which is made to contain the following parts by weight of raw materials and auxiliary materials: active ingredient: 0.5-1.5 parts of tyrosine kinase inhibitor, the content of the active ingredient in the ophthalmic formulation is 0.1-1 mg / mL, pharma- ceutically acceptable auxiliary materials: 20-300 parts of surfactant, 0.5-70 parts of thickener, 10-800 parts of solubilizer, and the remainder is solvent. The ophthalmic formulation of the present invention can effectively deliver the active ingredient to the fundus and treat fundus neovascular diseases, has a high absorption utilization rate, a small particle size, good stability, and is suitable for preparing a sterile formulation by a sterilization method using a microporous filter membrane and / or a high-temperature sterilization method.

Description

[Technical field]

[0001] The present invention is in the field of pharmaceutical formulations, in particular, ophthalmic tyrosine kinase inhibitor formulations, their preparation methods and uses. [Background technology]

[0002] The aging of the population has led to a significant increase in ocular neovascular diseases, including cataracts, glaucoma, age-related macular degeneration (AMD), and diabetic macular edema (DME). Currently, the use of drugs with antagonistic effects against vascular endothelial growth factor (VEGF) to inhibit the proliferation of ocular blood vessels is one of the main methods for treating related ocular neovascular diseases.

[0003] However, because of the complex physiological structures and barriers present in the eye, it is difficult for drugs to penetrate the barrier and reach the vitreous body in the posterior part of the eye when administered by eye drops. Therefore, in clinical practice, it is difficult to effectively treat fundus diseases by administering drugs to the ocular surface, and the method of administering drugs by local injection into the eye has long been used to treat fundus diseases. In order to overcome the ocular barrier, in clinical practice, polymeric biological preparations of anti-vascular endothelial growth factor drugs such as Bevacizumab, Ranibizumab, Aflibercept, Conbercept, and Brolucizumab are administered by 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 high molecular weight biological preparations such as anti-VEGF monoclonal antibodies and fusion proteins, small molecule chemical drugs such as tyrosine kinase inhibitors (TKIs) can also antagonize vascular endothelial growth factor receptor (VEGFR) tyrosine kinase and inhibit vascular proliferation. TKIs include axitinib, regorafenib, sunitinib, nintedanib, etc., which also antagonize platelet derived growth factor receptor (PDGFR), inhibiting the formation of new blood vessels and treating neovascular-related eye diseases such as AMD and DME (Samanta, et al., Emerging therapies in neovascular age-related macular degeneration in 2020, Asia Pac J Ophthalmol (Phila) 2020;9:250-259). In small preclinical studies, a suspension containing the TKI axitinib has been injected into the suprachoroidal space at the back of the eye to treat wAMD, and clinical trials have already begun 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 or fundus injections are invasive, and repeated injections over a long period of time increase the risk of complications. In addition, although small molecule chemical drugs such as tinib are more stable than polymeric biological preparations, they are not suitable for intravitreal injection because they have a fast metabolism and distribution rate in the eyeball, and therefore require more frequent injections to maintain an effective drug concentration in the fundus lesion, which further increases the risk of complications.

[0005] In addition to the above-mentioned administration method of local injection into the eye, other commonly used administration methods include systemic administration methods such as oral administration and injection (injection outside the eye), but these methods increase systemic toxic side effects and, due to the inhibition of the blood-ocular barrier, only a small amount of drug molecules can reach the posterior segment of the eye, which may prevent the treatment of ocular diseases from being achieved (Chen Zuji, editor, Practical Ophthalmic Pharmacology, China Science and Technology Press, p27, 1993). Many oral TKIs antitumor drugs, such as oral axitinib tablets and sorafenib tablets, have systemic side effects, the main side effects of which are diarrhea (incidence rates of 55% and 53%, respectively), hypertension (40% and 29%), fatigue (39% and 32%), loss of appetite (34% and 29%), and nausea (32% and 22%) (Drug Instructions, Reference ID: 3078397). In a phase II clinical trial to treat age-related macular degeneration with oral tinib (X-82), subjects were orally administered different doses of X-82 tablets (50 mg, 100 mg, and 200 mg / day), and vision improved to non-inferiority after six months, but the clinical trial was discontinued due to 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 all delivery methods, including oral, injection, and local injection into the eye, have safety and efficacy deficiencies, there is an urgent need to investigate new delivery methods of tyrosine kinase inhibitors (such as tinib-class drugs) for the treatment of ocular neovascular diseases.

[0007] Eye drop administration (conjunctival sac administration) is the most convenient and safest method of administration to the eye, belonging to topical administration, with a small dose and small toxic side effects. However, the cornea of ​​the eye has a multi-layer structure, which can be roughly divided into a lipid-rich epithelial layer, a water-rich stroma layer, and a lipid-rich endothelial layer from the outside to the inside. After being instilled into the eye, the eye drop first comes into contact with the tear film on the ocular surface, and then passes through the epithelial layer, stroma layer, and endothelial layer of the cornea before finally reaching the posterior segment. During this process, due to the dilution of the tear film, the ocular surface barrier of the cornea and conjunctiva, and the anatomical position of the lens and vitreous body, the concentration of the eye drop is often high in the tissues of the anterior segment, which often causes toxic side effects, but it is still difficult to reach an effective therapeutic concentration in the posterior segment. Therefore, although the eye drop administration method is safe, it is difficult for existing pharmaceutical preparations to achieve the purpose of delivering drugs to the posterior segment and effectively treating ocular fundus diseases.

[0008] In previous research, the inventors have developed nanocrystalline eye drops and successfully achieved the effect of delivering tyrosine kinase inhibitors to the fundus by using bisoluble and monosoluble polymer auxiliary materials (patent application CN110664757A), but this method still has the following problems:

[0009] Eye drops are solutions that are directly applied to the eye to exert a therapeutic effect, and must be sterile preparations. In order to achieve the goal of making liquid pharmaceutical preparations sterile, both terminal high-temperature sterilization and in-process sterilization (selection of filtration sterilization with 0.22 μm microporous filter membrane) are often adopted in production and manufacturing, thus achieving the goal of making the final product sterile (Chinese Pharmacopoeia, 2020 Edition, Part 4, edited by State Pharmacopoeia Commission, China Pharmaceutical Science and Technology Press, Beijing, 2020; Ophthalmic Drugs and Formulations, edited by Ling Pei Xue, China Light Industry Press, Beijing, 2010). The temperature change during the sterilization process of nanocrystal solutions directly affects the structure and properties of nanocrystals. Final high-temperature sterilization of nanocrystal solutions will cause the nanocrystals to dissolve, or important physical and chemical properties such as the crystal shape and particle size of the nanocrystals will change, or even cause the nanocrystals to disappear and a jelly-like substance to appear in the solution, so such a method cannot be used for sterilization.

[0010] On the other hand, in the sterilization process using a membrane material with a pore size of 0.22 μm, the particle size of nanocrystal preparations is large at 300 to 800 nm, so the loss of the active ingredient after filtration is very large, which has a significant impact on the content of the active ingredient in the product. Therefore, the industrialized production process of the product is difficult in terms of sterilization and sterilization.

[0011] Furthermore, the absorption and utilization rate of the active pharmaceutical ingredient in these nanocrystal eye drops is low, and improvements in performance such as stability are desired.

[0012] Therefore, it is of great significance to provide a tyrosine kinase inhibitor ophthalmic solution with little loss of active ingredient content after sterilization and high absorption and utilization rate of the active ingredient, thereby treating ocular fundus neovascularization diseases by ophthalmic administration. Summary of the Invention

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

[0014] The present invention provides an ophthalmic eye drop preparation, which comprises an active ingredient for treating an ophthalmic disease and a pharma- ceutical acceptable carrier or auxiliary material. The active ingredient for treating an ophthalmic disease is a low molecular weight drug such as a tyrosine kinase inhibitor (TKIs) having an antagonistic effect on the tyrosine kinase of vascular endothelial growth factor receptor (VEGFR) and / or platelet-derived growth factor receptor (PDGFR). Tinib-class compounds are TKI drug molecules, and many of their free bases are poorly soluble in water. In order to prepare a water-based eye drop solution that can penetrate to the posterior segment of the eye, the tinib-class drug must be dispersed in an aqueous solution and stabilized. The pharma-ceutical acceptable carrier or auxiliary material includes a surfactant, a solubilizer, a thickener, and a solvent. Specifically, the present invention provides an ophthalmic tyrosine kinase inhibitor preparation containing the following weight parts of raw materials and auxiliary materials:

[0015] Active ingredient: tyrosine kinase inhibitor 0.5 to 1.5 parts, the content of the active ingredient in the ophthalmic preparation is 0.05 to 1 mg / mL, preferably 0.1 to 1 mg / mL Pharmaceutically acceptable auxiliary materials: 20-300 parts surfactant, 0.5-70 parts thickener, 10-800 parts solubilizer, the remainder solvent Further, the above ophthalmic formulation is made to contain the following parts by weight of raw materials and auxiliary materials:

[0016] Active ingredient: tyrosine kinase inhibitor Pharmaceutically acceptable auxiliary materials: 25-200 parts surfactant, 1-60 parts thickener, 27.5-500 parts solubilizer, the remainder solvent 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.

[0017] Furthermore, the above-mentioned tyrosine kinase inhibitor is an active pharmaceutical ingredient (API) of the tinib family or a pharmaceutically acceptable salt thereof, and the active pharmaceutical ingredient (API) of the tinib family is at least one of axitinib, sorafenib, regorafenib, pazopanib, nintedanib, carbozantinib, lenvatinib, and sunitinib.

[0018] Furthermore, the HLB value (hydrophilic-lipophilic balance value) of the above surfactant is greater than 10, and preferably 13-29.

[0019] Furthermore, the nonionic surfactant is at least one of polysorbates (Tween series), dehydrated sorbitan fatty acid esters (Span series), polyoxyethylene fatty acid esters (Myrij series), polyoxyethylene fatty alcohol ethers (Brij series), and poloxamers.

[0020] Furthermore, the surfactant is a polysorbate and / or a poloxamer.

[0021] Furthermore, the surfactant is a polysorbate and a poloxamer, and the weight ratio of the polysorbate to the poloxamer is (1-5:1).

[0022] Furthermore, the polysorbate is polysorbate 80.

[0023] Further, the thickening agent is at least one of methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose or a salt thereof, hyaluronic acid or a salt thereof, xanthan gum, carbomer, and solid polyethylene glycol.

[0024] The solid polyethylene glycol is a polyethylene glycol having a molecular weight of 1000 or more, preferably polyethylene glycol 4000 (PEG 4K), polyethylene glycol 5000 (PEG 5K) or polyethylene glycol 6000 (PEG 6K), more preferably PEG 6K.

[0025] Furthermore, the viscosity increasing agent is at least one of methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hyaluronic acid or a salt thereof, carboxymethylcellulose or a salt thereof, and solid polyethylene glycol.

[0026] Further, the solubilizer is at least one of liquid polyethylene glycol, cyclodextrin, hydroxypropylcyclodextrin, tyloxapol, castor oil polyoxyethylene ether, polyoxyethylene hydrogenated castor oil.

[0027] Furthermore, the solubilizer is liquid polyethylene glycol, castor oil polyoxyethylene ether and / or polyoxyethylene hydrogenated castor oil.

[0028] Furthermore, the solubilizer is any one of polyethylene glycol 300 (PEG300), 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 to 14.

[0029] Furthermore, the solvent is a polar solvent, preferably water.

[0030] Furthermore, the above ophthalmic preparation contains 5 to 60 parts by weight of an emulsion stabilizer as a pharma-ceutically acceptable auxiliary material.

[0031] Furthermore, the above ophthalmic preparation contains 6 to 50 parts by weight of an emulsion stabilizer as a pharma-ceutically acceptable auxiliary material.

[0032] Furthermore, the emulsion stabilizer is povidone, hydroxyethyl cellulose and / or polyvinyl alcohol.

[0033] Furthermore, the emulsion stabilizer is povidone.

[0034] Furthermore, the povidone has a weight average molecular weight of 10,000 to 50,000 daltons.

[0035] Furthermore, the ophthalmic formulation may further comprise, as a pharma- ceutically acceptable auxiliary material, one or more of an osmolality adjusting agent, a pH adjusting agent, and a preservative; the osmolality adjusting agent is any one or more of glucose, sodium chloride, potassium chloride, mannitol, sorbitol, sodium citrate, potassium citrate, and glycerol; The pH adjuster is any one or more of hydrochloric acid, sodium hydroxide, acetic acid or a salt thereof, citric acid or a salt thereof, fumaric acid, succinic acid, sorbic acid, phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, boric acid, borax, and tartaric acid or a salt thereof; The preservative is any one or more of sorbic acid, chlorobutanol, sodium chlorite, sodium perborate, quaternary ammonium salts, parabens, phenylmercuric nitrate, preferably, the quaternary ammonium salts include benzalkonium chloride, benzalkonium bromide, polyquaternium-1 and / or hexadecyltrimethylammonium bromide, and the parabens include methylparaben, ethylparaben and / or propylparaben.

[0036] Furthermore, the pH value of the above formulation is 5-8.

[0037] Furthermore, the pH value of the above formulation is 6-8.

[0038] Furthermore, the pH value of the above formulation is 6-7.

[0039] Furthermore, the ophthalmic preparation is an eye drop.

[0040] The present invention further provides a method for preparing the above-mentioned ophthalmic formulation, which comprises uniformly mixing and dispersing the active ingredient and pharma- ceutically acceptable auxiliary materials, followed by stirring and / or homogeneous dispersion.

[0041] Furthermore, the above preparation method includes the following steps (1) to (4).

[0042] (1) A surfactant is dispersed in a solvent to obtain solution A, and an emulsion stabilizer and a viscosity enhancer are dispersed in the solvent to obtain solution B. (2) After dispersing the active ingredient in the solubilizer, add it to solution B obtained in step (1) and disperse it uniformly to obtain solution C. (3) Add solution C to solution A and disperse it uniformly, then disperse it homogeneously under high pressure to obtain Furthermore, the dispersion in the above-mentioned step (2) and / or step (3) is selected from at least one of mechanical stirring dispersion, magnetic stirring dispersion, vortex shaking dispersion, shear dispersion, pulverization dispersion, and ultrasonic dispersion.

[0043] Furthermore, the high pressure homogenization in the above step (3) is performed by first homogenizing at a pressure of 1000 bar or less for 1 to 5 cycles, then increasing the pressure to 1300 bar or more for 10 to 20 cycles, and then decreasing the pressure again to 1000 bar or less for 1 to 5 cycles.

[0044] (4) Adjusting the osmolarity of the solution obtained in step (3) to isotonicity and pH value to 5-8 with or without the addition of an osmolarity adjusting agent and / or a pH adjusting agent, and then adding or without the addition of a preservative to obtain The present invention further provides the use of the above ophthalmic formulation in the preparation of a medicament for treating an eye disease.

[0045] Furthermore, the above-mentioned drugs for treating eye diseases are drugs for treating ocular surface diseases and / or ocular fundus diseases.

[0046] Furthermore, the above-mentioned drug for treating ocular fundus diseases is a drug that inhibits the formation of new blood vessels.

[0047] Furthermore, the above-mentioned drug for treating an ocular fundus disease is a drug for treating any one of age-related macular degeneration, retinal vein occlusion macular edema, retinal vein occlusion, diabetic retinopathy, diabetic macular edema, decreased vision caused by choroidal neovascularization secondary to pathological myopia, and neovascular glaucoma.

[0048] Furthermore, the above-mentioned drug for treating an ocular surface disease is a drug for treating an ocular surface neovascular disease.

[0049] Furthermore, the above-mentioned drug for treating an ocular surface disease is a drug for treating any one of keratitis, corneal neovascularization due to mechanical injury, chemical injury and / or biological injury, corneal neovascularization associated with pterygium, corneal neovascularization in corneal transplant rejection, and corneal stem cell deficiency.

[0050] Beneficial Effects of the Invention: 1. The ophthalmic solution of the present invention is a transparent liquid with good stability and a significantly reduced particle size (can be reduced to 0.1 μm or less). It is suitable for preparing sterile formulations by filtration sterilization using a 0.22 μm microporous filter membrane and / or high-temperature sterilization (121°C). The loss of active ingredients after sterilization is small, and the delivery of the drug substance and the absorption of the drug substance in the posterior segment of the eye after sterilization are not affected.

[0051] 2. After reducing the dose of the drug substance by 90%, the amount of the drug substance absorbed in the vitreous body is equal to or greater than that described in patent application CN110664757A (the drug substance concentration in the ophthalmic solution of the present invention is 0.1-0.5 mg / mL, while the drug substance concentration in the examples of patent application CN110664757A reaches 1 mg / mL), which shows that the drug absorption utilization rate in the fundus of the ophthalmic solution of the present invention is high.

[0052] On the other hand, in many cases, 80-90% of the drug solution after ophthalmic administration is discharged from the lacrimal canaliculus with tears or absorbed into the blood system through the blood vessels of the eyelids or conjunctiva, which may cause systemic toxic side effects. If it is guaranteed that a therapeutic amount of the drug is delivered to the fundus, reducing the total dosage is advantageous for reducing systemic toxic side effects, and for this reason, the ophthalmic solution of the present invention has less toxic side effects.

[0053] The HLB value in the present invention means the hydrophilic-lipophilic balance value.

[0054] In the present invention, polyethylene glycol 4000 (PEG 4K) means that the weight average molecular weight of polyethylene glycol is 4000, and similarly, other numbers following polyethylene glycol also represent their weight average molecular weights.

[0055] Obviously, based on the above content of the present invention, various other improvements, substitutions or modifications can be made in accordance with ordinary technical knowledge and conventional means in this field, without departing from the above basic technical idea of ​​the present invention.

[0056] The above contents of the present invention will be described in more detail below in the form of specific implementations in the form of examples. However, the scope of the above subject matter of the present invention should not be construed as 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]

[0057] [Figure 1] Transmission electron microscope image of the sample prepared in Example 2 (scale bar = 200 nm). [Diagram 2] Transmission electron microscope image of the sample prepared in Example 3 (scale bar = 100 nm) DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0058] The reagents or equipment used in the present invention are commercially available and can be purchased. Unless otherwise specified, they are used according to the usual conditions or the conditions recommended by the manufacturer.

[0059] The following are some of the equipment and facilities:

[0060] ES225SM-DR(E) Electronic Analytical Balance, Precisa (Switzerland) DF-101S heat collecting type constant temperature heating magnetic stirrer, Yingyu High School of Gunyi City (Henan, China) WH-2 Micro Vortex Mixer, Shanghai HuXi Analytical Instrument Factory Co., Ltd. (Shanghai, China) Disperser: T25 easy clean digital, IKA (Germany) KQ-500 Ultrasonic Cleaning Machine, Kunshan Ultrasonic Instrument Co., Ltd. (Kunshan, China) AH-NANO Plus high pressure homogenizer, Antao Sina Rice Technology (Suzhou) Co., Ltd. (China) PM-DK2 Planetary Ball Mill, Zhongde Instrument Equipment (Shanghai) Co., Ltd. (Shanghai, China) Mettler Toledo FE20 pH meter, Mettler Toledo (Switzerland) NS-90 nanoparticle size analyzer, Zhuhai Omeike Equipment Co., Ltd. (Zhuhai, China) Agilent 1100 HPLC high performance liquid chromatograph, Agilent Technologies (USA) API4000 triple quadrupole mass spectrometer (Applied Biosystems, USA) STY-1A Osmometer, Tianjin Tianda Tianfa Science and Technology Co., Ltd. (Tianjin, China) The methods for measuring the properties of the formulation of the present invention are as follows.

[0061] How to measure particle size: 1 mL of the sample prepared in the Examples or Comparative Examples is transferred to a sample cell, the measurement temperature is set to 40°C, the sample cell is placed in an NS-90 nano particle size analyzer, and the measurement is started. The measurement is repeated three times for each sample, and the average of the three measurement results is taken as the measurement result for that sample, and is expressed as particle size (main particle size distribution and its ratio) and polydispersity index (PdI).

[0062] How to measure osmolality: Measure the freezing point depression of the solution to determine its osmolality. Operation: Wash the probe of the STY-1A osmometer. Take 100 μL of distilled water into three sample tubes for three times. After pre-heating the instrument, rotate the sample tube containing 100 μL of distilled water into the instrument probe and select wash three times. Click "Wash" and repeat three times. Measurement: After entering the sample information in the instrument information table, click "Measure". Use a pipette to transfer 100 μL of sample into the sample tube, gently rotate it into the instrument, click "Start" to measure. Repeat the measurement three times and use the average value of the three measurement results as the measurement result.

[0063] How to measure pH value: The FE20 pH meter is calibrated using pH buffer solutions (pH 4.00, 6.86, and 9.18, respectively), the electrode is rinsed with purified water, excess water is absorbed using fiberless paper, and then it is immersed in the liquid sample to be measured, the reading button is pressed to start the measurement, and the data obtained after the reading is stable is the pH value of the sample.

[0064] Unless otherwise specified, the method for verifying the efficacy of drug delivery to the posterior segment is as follows.

[0065] Test instruments and equipment: high-performance liquid chromatograph, model number: LC-20AD (Shimadzu Corporation, Japan), mass spectrometer, model number: API4000 triple quadrupole mass spectrometer (Applied Biosystems, USA), chromatography column: Fortis Pace C18 5 μm, 2.1 × 30 mm (Fortis, UK).

[0066] Rat eye test method: Healthy adult Sprague Dawley (SD) rats were selected and divided into a test group and a control group, each group having 4 eyes. In the test group, 20 μL of the ophthalmic preparation prepared in the examples of the present invention was dropped into each eye. At a predetermined time point after administration, the rats were euthanized and processed, and the vitreous and / or aqueous humor were promptly collected. The vitreous samples were homogenized and stored at -80°C.

[0067] Sample processing and measurement method: Rat vitreous samples were collected, homogenized, and then 5μL was taken and added to 45μL of 70% methanol-water, ultrasonicated for 2 minutes and vortexed for 1 minute, followed by addition of 25μL of internal standard and 150μL of methanol, vortexed for 2 minutes, centrifuged at 4℃ and 12000rpm for 10 minutes, and the supernatant was collected and analyzed by LC-MS / MS analysis (positive ion mode, MRM SCAN). Aqueous humor samples did not require homogenization and were treated in the same manner and then measured by LC-MS / MS analysis.

[0068] Rabbit Eye Test Method: Healthy adult New Zealand rabbits were selected and divided into a test group and a control group, each group having 4 eyes, and 50 μL of the ophthalmic formulation prepared in the Examples of the present invention was dropped into each eye of the test group. At a predetermined time point after administration, the rabbits were euthanized and processed, and ocular tissues (retina, choroid, sclera) were quickly collected, and the samples were homogenized and stored at -80°C.

[0069] Sample processing and measurement methods: See rat ocular tissue sample processing and measurement methods.

[0070] Example 1. Preparation of Ophthalmic Formulations of the Present Invention Preparation method: 75 mg of polysorbate 80 (TW-80) was weighed out and added to a glass Erlenmeyer flask containing 10 mL of purified water, and magnetically stirred for 0.5 hours to obtain solution 1. 18 mg of povidone K12 (PVP K12) and 18 mg of hydroxypropyl methylcellulose (HPMC) were weighed out and added to a glass Erlenmeyer flask containing 10 mL of purified water, and magnetically stirred for 60 minutes to obtain solution 2. 2.5 mg of axitinib was weighed out and placed in a 50 mL polypropylene tube containing 1.2 g of castor oil polyoxyethylene ether EL-40, and solution 2 was added and stirred for 30 minutes, solution 1 was added, 25 mL of water was added, and the mixture was stirred for 30 minutes to obtain a mixed solution. The mixture was dispersed at 10,000 rpm for 3 minutes using a disperser, the machine was stopped and the bubbles were waited for to disappear, then the dispersion was transferred to a high-pressure homogenizer, the temperature was controlled at 15±5°C, and homogenized for 3 cycles at a pressure of about 400 bar, then the pressure was increased to 1300 bar for 15 cycles, and the pressure was reduced to 300 bar for 2 cycles, after which it was discharged and a homogenized liquid was obtained. The pH value and osmotic pressure were measured, and the pH was adjusted to 7.0 using sodium citrate and / or dilute hydrochloric acid solution. The osmotic pressure was adjusted to 272 mOsmol / kg by adding sodium chloride. 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.

[0071] HPLC measurement: Agilent HPLC1100 system equipped with DAD detector, chromatographic conditions: chromatographic column was Waters XBridge C18, 5 μm, 4.6 × 250 mm.

[0072] Mobile phase A: 0.1% H3PO4 solution, Mobile phase B: ACN (acetonitrile). Temperature: 35°C, Measurement wavelength: 360 nm, Flow rate: 0.8 mL / min, Gradient elution order: 0': 85%A-15%B, 15': 50%A-50%B, 20-21': 30%A-70%B, 25': 85%A-15%B. HPLC content measurement result: 0.078 mg / mL.

[0073] Particle size measurement results (main particle size distribution and its ratio): Particle size: 13.0 nm (92.1%), PdI: 0.227.

[0074] After filtering the solution through a membrane with a pore size of 0.22 μm, the particle size was measured as 14.4 nm (100.0%), PdI was 0.080, and the HPLC content was measured as 0.077 mg / mL.

[0075] Absorption experiment results in rat eyes: 20 μL was instilled into rat eyes, and the API concentration in the rat vitreous at 0.5 hours was 19.9 ± 3.2 ng / g, and the concentration in the aqueous humor was 237.5 ± 47.6 ng / g.

[0076] Absorption test results in rabbit ocular tissue: 50 μL was dropped into the eyes of New Zealand rabbits, and at 0.5 hours the API concentration in the retina was 0.92 ± 0.64 ng / g, in the choroid 1.22 ± 0.60 ng / g, and in the sclera 10.3 ± 5.61 ng / g.

[0077] Example 2. Preparation of ophthalmic formulations of the present invention The materials and proportions used are as shown in Table 1, and the preparation process (pH was adjusted to 6.5) and content measurement were the same as in Example 1 to obtain a solution. The osmotic pressure was adjusted to 332 mOsmol / kg.

[0078] Particle size measurement results, particle size: 12.8nm (76.0%), PdI: 0.283, HPLC content measurement results: 0.181mg / mL.

[0079] After filtering the solution through a membrane with a pore size of 0.22 μm, the particle size was measured as follows: particle size: 15.2 nm (93.5%), PdI: 0.234, and HPLC content: 0.178 mg / mL.

[0080] Results of the absorption experiment in rat eyes: 20 μL was instilled into the rat eye, and the API concentration in the rat vitreous at 0.5 hours was 17.3 ± 9.0 ng / g.

[0081] Particle size analysis using a transmission electron microscope revealed that the particles were spherical (Figure 1). Example 3. Preparation of ophthalmic formulations of the present invention The materials and proportions used are as shown in Table 1, and the preparation process (pH was adjusted to 5.7) and content measurement were the same as in Example 1 to obtain a solution. The osmotic pressure was adjusted to 338 mOsmol / kg.

[0082] Particle size measurement results: Particle size: 13.8 nm (67.2%), 72.6 nm (21.5%), PdI: 0.249, HPLC content measurement results: 0.391 mg / mL.

[0083] After the solution was sterilized at 121°C for 20 min, the particle size was measured as follows: particle size: 12.7 nm (68.6%), 76.7 nm (31.4%), PdI: 0.286, HPLC content: 0.387 mg / mL.

[0084] After the solution was sterilized by filtration through a membrane with a pore size of 0.22 μm, the particle size was measured as follows: particle size: 16.2 nm (70.0%), 126.5 nm (23.7%), PdI: 0.513, and HPLC content: 0.389 mg / mL.

[0085] Absorption in the rat vitreous: 20 μL was instilled into the rat eye, and the API concentration in the rat vitreous at 0.5 hours was 37.2 ± 25.1 ng / g, and the concentration in the aqueous humor was 370 ± 92.4 ng / g.

[0086] Absorption test results in rabbit ocular tissue: 50 μL was instilled into the eyes of New Zealand rabbits, and at 0.5 hours the API concentration in the retina was 1.66 ± 2.08 ng / g, in the choroid 0.98 ± 0.76 ng / g, and in the sclera 9.40 ± 6.41 ng / g.

[0087] Particle size analysis using a transmission electron microscope reveals that the particles are snowflake-like (Figure 2). Example 4. Preparation of ophthalmic formulations of the present invention The materials and proportions used are as shown in Table 1, and the preparation process (pH was adjusted to 6.1) and content measurement were the same as in Example 1 to obtain a solution. The osmotic pressure was adjusted to 288 mOsmol / kg.

[0088] Particle size measurement results, particle size: 284.6nm (53.5%), 15.2nm (46.5%), PdI: 0.500, HPLC content measurement result: 0.077mg / mL.

[0089] After filtering the solution through a membrane with a pore size of 0.22 μm, the particle size was measured as follows: particle size: 12.3 nm (89.8%), PdI: 0.179, and HPLC content: 0.076 mg / mL.

[0090] Absorption experiment results in rat eyes: 20 μL was instilled into the rat eye, and the API concentration in the rat vitreous at 0.5 hours was 46.8 ± 36.1 ng / g.

[0091] Example 5. Preparation of Ophthalmic Formulations of the Present Invention The materials and proportions used are as shown in Table 1, and the preparation process (pH was adjusted to 6.7) and content measurement were the same as in Example 1 to obtain a solution.

[0092] Particle size measurement results: Particle size: 106.0nm (91.2%), PdI: 0.288, HPLC content measurement results: 0.081mg / mL.

[0093] After filtering the solution through a membrane with a pore size of 0.22 μm, the particle size was measured as follows: particle size: 97.8 nm (98.9%), PdI: 0.247, and HPLC content: 0.078 mg / mL.

[0094] The solution was left at 40°C for one month. There was no obvious change in the appearance or content of the solution. Particle size was measured: 93.1 nm (99.6%), PdI: 0.255, and HPLC content was measured: 0.076 mg / mL.

[0095] Example 6. Preparation of ophthalmic formulations of the present invention The materials and proportions used are as shown in Table 1, and the preparation process (pH was adjusted to 6.1) and content measurement were the same as in Example 1 to obtain a solution.

[0096] Particle size measurement results: Particle size: 19.8nm (99.3%), PdI: 0.186, HPLC content measurement results: 0.082mg / mL.

[0097] After the solution was sterilized by filtration through a membrane with a pore size of 0.22 μm, the particle size was measured as follows: particle size: 20.0 nm (98.6%), PdI: 0.218, and HPLC content: 0.081 mg / mL.

[0098] The solution was left at 40°C for one month. There was no obvious change in the appearance or content of the solution. The particle size was measured as 19.6nm (99.2%), PdI was 0.236, and the HPLC content was 0.080mg / mL.

[0099] Example 7. Preparation of ophthalmic formulations of the present invention The materials and proportions used are as shown in Table 1, and the preparation process (pH was adjusted to 6.3) and content measurement were the same as in Example 1 to obtain a solution.

[0100] Particle size measurement results: Particle size: 20.3 nm (95.2%), PdI: 0.246, HPLC content measurement results: 0.082 mg / mL.

[0101] After filtering the solution through a membrane with a pore size of 0.22 μm, the particle size was measured as follows: particle size: 19.2 nm (98.3%), PdI: 0.198, and HPLC content: 0.081 mg / mL.

[0102] The solution was left at 40°C for one month. There was no obvious change in the appearance or content of the solution. The particle size was measured as 18.6nm (98.8%), PdI was 0.210, and the HPLC content was 0.081mg / mL.

[0103] Example 8. Preparation of ophthalmic formulations of the present invention The materials and proportions used are as shown in Table 1, and the preparation process (pH was adjusted to 6.1) and content measurement were the same as in Example 1 to obtain a solution.

[0104] Particle size measurement results: Particle size: 13.3nm (99.4%), PdI: 0.305, HPLC content measurement results: 0.083mg / mL.

[0105] After filtering the solution through a membrane with a pore size of 0.22 μm, the particle size was measured as follows: particle size: 12.7 nm (99.3%), PdI: 0.237, and HPLC content: 0.082 mg / mL.

[0106] Example 9. Preparation of ophthalmic formulations of the present invention The materials and proportions used are as shown in Table 1. The preparation process (pH adjusted to 6.1) and content measurement were the same as in Example 1. Sodium chloride and sorbitol were added to adjust the osmotic pressure to 284 mOsmol / kg to obtain a solution.

[0107] Particle size measurement results: Particle size: 15.6 nm (78.2%), PdI: 0.454, HPLC content measurement results: 0.084 mg / mL.

[0108] After filtering the solution through a membrane with a pore size of 0.22 μm, the particle size was measured as follows: particle size: 14.3 nm (89.6%), PdI: 0.317, and HPLC content: 0.082 mg / mL.

[0109] Absorption experiment results in rat eyes: 20 μL was instilled into the rat eye, and the API concentration in the rat vitreous at 0.5 hours was 39.5 ± 26.3 ng / g.

[0110] Example 10. Preparation of ophthalmic formulations of the present invention The materials and proportions used are as shown in Table 1. The API is regorafenib. The preparation process and content measurement were the same as in Example 1 (HPLC measurement wavelength: 265 nm) to obtain a solution. The content measurement result was 0.048 mg / mL.

[0111] Particle size measurement results, particle size: 17.4 nm (81.2%), PdI: 0.387.

[0112] After filtering the solution through a membrane with a pore size of 0.22 μm, the particle size was measured as follows: particle size: 16.3 nm (91.2%), PdI: 0.342, and HPLC content: 0.046 mg / mL.

[0113] Example 11. Preparation of ophthalmic formulations of the present invention The materials and proportions used are as shown in Table 1. The API was sorafenib tosylate. The preparation process and content measurement were the same as in Example 1 (HPLC measurement wavelength: 255 nm) to obtain a solution. The content measurement result was 0.089 mg / mL.

[0114] Particle size measurement results, particle size: 19.6 nm (88.2%), PdI: 0.406.

[0115] After filtering the solution through a membrane with a pore size of 0.22 μm, the particle size was measured as follows: particle size: 17.9 nm (92.6%), PdI: 0.265, HPLC content: 0.087 mg / mL.

[0116] Contrast ratio 1. The materials and proportions used are as shown in Table 1, and the preparation process and content measurement were the same as in Example 1 to obtain a solution.

[0117] Particle size measurement results, particle size: 2105 nm (100.0%), PdI: 0.645.

[0118] When left standing overnight at room temperature, the substances in the formulation aggregated into clumps and the water and oil separated, indicating that the formulation was not very stable.

[0119] Results of the absorption experiment in rat eyes: 20 μL was instilled into the rat eye, and the API concentration in the rat vitreous at 0.5 hours was 7.87 ± 2.83 ng / g, indicating that the concentration of this formulation in the fundus was low.

[0120] Contrast ratio 2. The materials and proportions used are as shown in Table 1. Preparation method: 500 mg of TW-80 and 500 mg of hydroxypropyl cellulose (HPC) were weighed out and added to an Erlenmeyer flask containing 40 mL of purified water, and stirred for 30 minutes to obtain solution 1. 50 mg of axitinib was weighed out and added to 100 mL polypropylene plastic, solution 1 was added, and stirred for 10 minutes, and then purified water was added up to 50 mL and stirred for 30 minutes to obtain a mixed solution. The mixed solution was dispersed at 10,000 rpm for 3 minutes using a disperser. (1) When the ball milling method was adopted: The dispersion was transferred to a ball mill tank, 80 g of wet zirconium beads (particle size 0.3 to 0.4 mm) were added, and then 1 mL of purified water was added to wash the polypropylene plastic tube, and then poured into the ball mill tank, the ball mill tank was tightly covered, and milled at 0 ° C and 300 rpm for 2 hours. After milling was completed, it was filtered using a G2 glass sand core funnel to obtain a milky suspension.

[0121] Particle size measurement results, particle size: 280.9nm (100.0%), PdI: 0.274, HPLC content measurement results: 0.879mg / mL.

[0122] After the solution was sterilized by pressure filtration through a microporous filter membrane with a pore size of 0.22 μm, the particle size was measured as follows: particle size: 310.0 nm (100.0%), PdI: 0.248, and HPLC content: 0.736 mg / mL.

[0123] After the solution was sterilized at 121° C. for 20 minutes, the solution separated into layers, indicating that this formulation is unstable when heated at high temperatures.

[0124] Or, (2) when high pressure homogenization method is adopted: the mixture is dispersed by a disperser at 10,000 rpm for 3 minutes, the machine is stopped and the bubbles are waited until disappearance, then the dispersion is transferred to a high pressure homogenizer, the temperature is controlled at 15±5℃, and the pressure is homogenized at about 400 bar for 3 cycles, then the pressure is increased to >1,300 bar for 15 cycles, the pressure is reduced to 300 bar for 2 cycles, and then discharged to obtain a homogenized liquid. The homogenized liquid is a white suspension.

[0125] Particle size measurement results, particle size: 295.0nm (100.0%), PdI: 0.443, HPLC content measurement results: 0.830mg / mL.

[0126] After the solution was sterilized by pressure filtration through a microporous filter membrane with a pore size of 0.22 μm, the particle size was measured as follows: particle size: 815.7 nm (80.7%), PdI: 0.736, and HPLC content: 0.025 mg / mL.

[0127] Contrast ratio 3. The materials and their proportions used are as shown in Table 1, and the preparation process (pH was adjusted to 7.0) was the same as in Comparative Example 1 to obtain a solution. After leaving the solution at room temperature for 3 days, precipitation occurred, indicating that the prepared solution was unstable.

[0128] Contrast ratio 4. According to the description in No. 12 of Table 8 of patent application CN110664757A, an eye drop was prepared: axitinib 5mg, Tween80 2mg, HPMC E5 2mg, water was added to 50mL, and then high pressure homogenization method was used. The obtained eye drop was instilled into rat eyes to perform a vitreous absorption test, and the API content in the rat vitreous 0.5 hours after instillation was 1.7ng / mL.

[0129] Contrast ratio 5. According to the description in No. 13 of Table 8 of patent application CN110664757A, an eye drop was prepared: axitinib 10mg, Tween80 2mg, HPMC E5 2mg, water was added to 50mL, and then high pressure homogenization method was used. The obtained eye drop was instilled into rat eyes to perform a vitreous absorption test, and the API content in the rat vitreous 0.5 hours after instillation was 6.3ng / mL.

[0130] [Table 1]

[0131] As can be seen from the above results, the ophthalmic solutions of the Examples of the present invention are significantly more stable than the ophthalmic solution prepared using a weakly hydrophilic solubilizer (HLB value of 10 or less) (Comparative Example 1). Moreover, at an API dose equivalent to Comparative Example 1, the absorption amount in the rat vitreous body after instillation of the Examples is higher, that is, the drug availability of the ophthalmic solution of the present invention is significantly higher.

[0132] The ophthalmic solutions of the Examples of the present invention have significantly better stability than the preparation lacking a surfactant (Comparative Example 3).

[0133] Comparing the ophthalmic solutions of the examples of the present invention with Comparative Example 2, the ophthalmic solutions of the present invention are solutions, have excellent formulation properties and stability, and have little loss of API content after sterilization. On the other hand, the formulation of Comparative Example 2 is a nanocrystalline suspension, and there is a risk of the crystal form changing during the production process, which will affect the absorption and distribution of the drug in the body. There is also a risk of aggregation during the storage period, which will affect the quality of the product. In addition, the suspension of Comparative Example 2 has a large loss of API content after filtration sterilization, is unstable when sterilized at high temperature, and separates into layers, making it difficult to prepare a sterile formulation.

[0134] Furthermore, when the ophthalmic solutions of the examples of the present invention are compared with Comparative Examples 4 and 5, it can be seen that in the present invention, at an API dose equivalent to the comparative examples (axitinib concentration of 0.1 mg / mL), the amount of axitinib absorbed in the vitreous body is significantly greater than in Comparative Examples 4 and 5, and the drug availability of the ophthalmic solution of the present invention is significantly higher.

[0135] The formulation of the present invention includes a nonionic surfactant, whose chemical structure has a fixed hydrophilic / lipophilic group, and the HLB value is determined by the ratio of the new hydrophilic / lipophilic group. The degree of lipophilicity or hydrophilicity of the surfactant can be judged by the magnitude of the HLB value (Chapter 3 of Pharmaceutics, edited by Pan Weisan, Chemical Industry Press, Beijing, 2017; MR Shah et al., Original, Chapter 4 of Application of Lipid-Based Nanocarriers in Drug Delivery and Diagnostics, translated by Liu Ying, Science Press, Beijing, 2019; SS Smail et al., Studies on surfactants, cosurfactants, and oils for prospective use in formulation of ketorolac tromethamine ophthalmic nanoemulsions, Pharmaceutics 2021, 13, 467). The present inventors have found in their research that when the HLB value of the surfactant is >10, the stability of the ophthalmic solution containing the API prepared under the same or similar conditions is improved. The surfactants include polysorbate 80 (molecular weight 1130 daltons), poloxamer 407 (molecular weight 11500 daltons), PEG-40 hydrogenated castor oil (molecular weight 2500 daltons) and solubilizer polyoxyethylene hydrogenated castor oil EL-40 (molecular weight 2500 daltons), and their HLB values ​​are 13 to 29. The present inventors have found through numerous experiments that the use of multiple surfactants with similar HLB values ​​but clearly different molecular weights results in a more stable ophthalmic solution than the use of a single surfactant.

[0136] Therefore, only based on the combination of the types and dosages of the specific auxiliary materials of the present invention can the ophthalmic solution of the present invention, which has excellent stability, is suitable for filtration through a 0.22 μm microporous filter membrane and / or high-temperature (121° C.) sterilization, and has a high utilization rate of the active ingredient.

[0137] In summary, the present invention provides an ophthalmic tyrosine kinase inhibitor formulation suitable for ophthalmic administration, which can effectively deliver the active ingredient to the fundus and treat ocular fundus neovascular disease. The ophthalmic formulation of the present invention has a high absorption utilization rate, a small particle size, good stability, and is suitable for preparing a sterile formulation by sterilization using a microporous filter membrane and / or high-temperature sterilization, and is highly expected to be used in clinical applications.

Claims

1. An ophthalmic tyrosine kinase inhibitor formulation, comprising: Active ingredient: 0.5 to 1.5 parts of a tyrosine kinase inhibitor, and the content of the active ingredient in the ophthalmic preparation is 0.05 to 1 mg / mL; Pharmaceutically acceptable auxiliary materials: surfactant 20-300 parts, thickener 0.5-70 parts, solubilizer 10-800 parts, remainder solvent An ophthalmic preparation characterized by comprising the following parts by weight of raw materials and auxiliary materials:

2. Active ingredient: 0.5 to 1.5 parts of a tyrosine kinase inhibitor, and the content of the active ingredient in the ophthalmic preparation is 0.1 to 1 mg / mL; Pharmaceutically acceptable auxiliary materials: surfactant 20-300 parts, thickener 0.5-70 parts, solubilizer 10-800 parts, remainder solvent 2. The ophthalmic preparation of claim 1, wherein the preparation is made to contain the following parts by weight of raw materials and auxiliary materials:

3. Active ingredient: tyrosine kinase inhibitor, Pharmaceutically acceptable auxiliary materials: surfactant 25-200 parts, thickener 1-60 parts, solubilizer 27.5-500 parts, the rest is solvent. Preferably, the content of the active ingredient in the ophthalmic preparation is 0.05-0.5 mg / mL, more preferably 0.1-0.5 mg / mL.

2. The ophthalmic preparation of claim 1, wherein the preparation is made to contain the following parts by weight of raw materials and auxiliary materials:

4. 2. The ophthalmic formulation of claim 1, wherein the tyrosine kinase inhibitor is a tinib-class drug substance or a pharmaceutically acceptable salt thereof, and the tinib-class drug substance includes, but is not limited to, at least one of axitinib, sorafenib, regorafenib, pazopanib, nintedanib, carbozantinib, lenvatinib, and sunitinib.

5. 2. The ophthalmic preparation according to claim 1, characterized in that the surfactant has an HLB value greater than 10, preferably between 13 and 29.

6. 6. The ophthalmic preparation of claim 5, wherein the nonionic surfactant is at least one of polysorbate, dehydrated sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, and poloxamer.

7. 7. The ophthalmic preparation according to claim 6, wherein the surfactant is a polysorbate and / or a poloxamer.

8. 8. The ophthalmic preparation according to claim 7, wherein the surfactants are polysorbate and poloxamer, and the weight ratio of the polysorbate to the poloxamer is (1-5):

1.

9. 8. The ophthalmic preparation of claim 7, wherein the polysorbate is polysorbate 80.

10. the thickening agent is at least one of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose or a salt thereof, hyaluronic acid or a salt thereof, xanthan gum, carbomer, and solid polyethylene glycol; 2. The ophthalmic preparation according to claim 1, characterized in that the solid polyethylene glycol is polyethylene glycol having a molecular weight of 1000 or more, preferably polyethylene glycol 4000, polyethylene glycol 5000 or polyethylene glycol 6000, more preferably polyethylene glycol 6000.

11. 11. The ophthalmic formulation of claim 10, wherein the viscosity increasing agent is at least one of methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hyaluronic acid or a salt thereof, carboxymethylcellulose or a salt thereof, carbomer, and solid polyethylene glycol.

12. 2. The ophthalmic formulation of claim 1, wherein the solubilizing agent is at least one of liquid polyethylene glycol, cyclodextrin, hydroxypropyl cyclodextrin, tyloxapol, castor oil polyoxyethylene ether, and polyoxyethylene hydrogenated castor oil.

13. 13. The ophthalmic preparation according to claim 12, characterized in that the solubilizer is liquid polyethylene glycol, castor oil polyoxyethylene ether and / or polyoxyethylene hydrogenated castor oil.

14. 14. The ophthalmic preparation according to claim 13, wherein the solubilizing agent 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 to 14.

15. 2. The ophthalmic preparation according to claim 1, characterized in that the solvent is a polar solvent, preferably water.

16. 10. The ophthalmic preparation of claim 1, further comprising 5 to 60 parts by weight of an emulsion stabilizer as a pharmaceutically acceptable auxiliary material.

17. 17. The ophthalmic tyrosine kinase inhibitor formulation of claim 16, wherein the ophthalmic formulation comprises 6 to 50 parts by weight of an emulsion stabilizer as a pharmaceutically acceptable auxiliary material.

18. 18. The ophthalmic formulation of claim 17, wherein the emulsion stabilizer is at least one of povidone, hydroxyethyl cellulose, and polyvinyl alcohol.

19. 19. The ophthalmic formulation of claim 18, wherein the emulsion stabilizer is povidone.

20. 20. The ophthalmic preparation according to claim 19, wherein the povidone has a weight average molecular weight of 3,500 to 50,000 daltons, preferably 10,000 to 50,000 daltons.

21. the ophthalmic formulation further comprises one or more of a pharmaceutically acceptable auxiliary material, an osmolality adjusting agent, a pH adjusting agent, and a preservative; the osmolality adjuster is any one or more of glucose, sodium chloride, potassium chloride, mannitol, sorbitol, sodium citrate, potassium citrate, and glycerol; the pH adjuster is one or more of hydrochloric acid, sodium hydroxide, acetic acid or a salt thereof, citric acid or a salt thereof, fumaric acid, succinic acid, sorbic acid, phosphoric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, boric acid, borax, tartaric acid or a salt thereof, 21. The ophthalmic formulation according to any one of claims 1 to 20, wherein the preservative is any one or more of sorbic acid, chlorobutanol, sodium chlorite, sodium perborate, quaternary ammonium salts, parabens, and phenylmercuric nitrate, preferably, the quaternary ammonium salts include benzalkonium chloride, benzalkonium bromide, polyquaternium-1, and / or hexadecyltrimethylammonium bromide, and the parabens include methylparaben, ethylparaben, and / or propylparaben.

22. Ophthalmic preparation according to any one of claims 1 to 20, characterized in that the pH value of the preparation is between 5 and 8, preferably between 6 and 8, more preferably between 6 and 7.

23. The ophthalmic preparation according to any one of claims 1 to 20, wherein the ophthalmic preparation is an eye drop.

24. A method for preparing the ophthalmic formulation according to any one of claims 1 to 20, comprising uniformly mixing and dispersing the active ingredient and pharmaceutically acceptable auxiliary materials, followed by stirring and / or homogeneous dispersion.

25. (1) dispersing a surfactant in a solvent to obtain a solution A, and dispersing an emulsion stabilizer and a viscosity enhancer in the solvent to obtain a solution B; (2) dispersing the active ingredient in the solubilizer, and then adding and uniformly dispersing the dispersion in solution B obtained in step (1) to obtain solution C; (3) adding solution C to solution A and dispersing it uniformly, and then subjecting it to high-pressure homogeneous dispersion; (4) adjusting the osmotic pressure of the solution obtained in step (3) to isotonicity and pH value to 5-8 with or without adding an osmotic pressure adjusting agent and / or pH adjusting agent, and then obtaining a solution with or without adding a preservative.

25. A method for preparing the ophthalmic formulation of claim 24, comprising:

26. 26. The method according to claim 25, wherein 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, shear dispersion, grinding dispersion, and ultrasonic dispersion.

27. 26. The method of claim 25, wherein the high-pressure homogenizing in step (3) comprises first homogenizing at a pressure of 800 bar or less for 1 to 5 cycles, then increasing the pressure to 1300 bar or less for 5 to 20 cycles, and then decreasing the pressure to 800 bar or less for 1 to 5 cycles.

28. Use of an ophthalmic formulation according to any one of claims 1 to 20 in the preparation of a medicament for treating an eye disease.

29. 29. The use according to claim 28, wherein the drug for treating an ocular disease is a drug for treating an ocular surface disease and / or an ocular fundus disease.

30. The use according to claim 29, wherein the drug for treating an ocular fundus disease is a drug that inhibits the formation of neovascularization.

31. The use according to claim 30, characterized in that the drug for treating an ocular fundus disease is a drug for treating any one of age-related macular degeneration, retinal vein occlusion macular edema, retinal vein occlusion, diabetic retinopathy, diabetic macular edema, visual loss caused by choroidal neovascularization secondary to pathological myopia, and neovascular glaucoma.

32. 30. The use according to claim 29, wherein the drug for treating an ocular surface disease is a drug for treating an ocular surface neovascular disease.

33. The use of claim 32, characterized in that the drug for treating an ocular surface disease is a drug for treating any one of keratitis, corneal neovascularization due to mechanical, chemical and / or biological damage, corneal neovascularization associated with pterygium, corneal neovascularization in corneal transplant rejection, and corneal stem cell deficiency.

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