Topical ophthalmic compositions and methods of treating abnormal vascularization

Abstract

A topical ophthalmic composition comprising a multi-kinase inhibitor as an active pharmaceutical ingredient and perfluorohexyloctane (F6H8) as a liquid vehicle. The multi-kinase inhibitor inhibits vascular endothelial growth factor receptor (VEGFR). A method of treating an ophthalmic condition comprising: providing a topical ophthalmic composition containing a multi-kinase inhibitor at a concentration of about 0.01-10% (w / v); and treating a patient with the topical ophthalmic composition to treat the ophthalmic condition.

Description

[0001] This application claims priority to US Provisional Application No. 63 / 032,920, filed June 1, 2020, which is incorporated herein by reference for all purposes as fully set forth herein. Technical Field

[0002] This invention relates to topical ophthalmic compositions and methods for treating abnormal angiogenesis and fibrosis. More specifically, the topical ophthalmic compositions include a multi-kinase inhibitor as an active pharmaceutical ingredient and perfluorohexyloctane (F6H8 or CF3(CF2)5(CH2)7CH3) as a liquid carrier, and methods for treating ophthalmic conditions with abnormal angiogenesis. Background Technology

[0003] Multi-kinase inhibitors are molecules that inhibit multiple kinases. They are often used in cancer treatment. Many of these inhibitors target tyrosine kinase receptors, such as vascular endothelial growth factor receptor (VEGFR). Inhibitors targeting VEGFR inhibit the formation of new or abnormal blood vessels in disease-related conditions. These inhibitors also inhibit platelet-derived growth factor receptor (PDGFR) with varying degrees of potency, which plays a role in vascular maintenance. Another family of kinases targeted by these inhibitors is fibroblast growth factor receptor (FGFR), which plays a role in fibroblast growth and fibrosis. Inhibitors with this type of targeting property can be used to treat diseases with abnormal angiogenesis or multiple vessels, including many eye diseases. They can also be used to treat diseases with abnormal fibrosis.

[0004] Multi-kinase inhibitors are known to be highly hydrophobic small molecules with very low solubility in water or water-based carriers. Therefore, there is a need to develop formulations to deliver sufficient concentrations of multi-kinase inhibitors to the target site to achieve the desired pharmacological effects. Summary of the Invention

[0005] In one embodiment, the topical ophthalmic composition includes a multi-kinase inhibitor as the active pharmaceutical ingredient and perfluorohexyloctane (F6H8) as a liquid carrier. The multi-kinase inhibitor inhibits vascular endothelial growth factor receptor (VEGFR).

[0006] In another implementation, a multi-kinase inhibitor inhibits VEGFR and fibroblast growth factor receptor (FGFR).

[0007] In another embodiment, the multi-kinase inhibitor is selected from the group consisting of axitinib, regorafenib, pazopanib, nintedanib, and pharmaceutically acceptable salts thereof.

[0008] In another embodiment, the multi-kinase inhibitor has a concentration of about 0.01-0.1% (w / v), about 0.1-1% (w / v), about 1-10% (w / v), about 1.5%-5% (w / v), about 1.5% (w / v), about 2% (w / v), about 2.5% (w / v), about 3% (w / v), about 3.5% (w / v), about 4% (w / v), about 4.5% (w / v), about 5% (w / v), about 6% (w / v), about 7% (w / v), about 8% (w / v), about 9% (w / v), or about 9% (w / v).

[0009] In another embodiment, the topical ophthalmic composition is a non-aqueous preparation of a suspension, solution, or emulsion.

[0010] In another implementation, the liquid carrier is water-free.

[0011] In another embodiment, the topical ophthalmic composition further includes an organic latent solvent selected from the group consisting of ethanol, isopropanol, glycerin, propylene glycol, and polyethylene glycol.

[0012] In another embodiment, the topical ophthalmic composition comprises a multi-kinase inhibitor as the active pharmaceutical ingredient and perfluorohexyloctane (F6H8) as a liquid carrier. The multi-kinase inhibitor inhibits the vascular endothelial growth factor receptor (VEGFR).

[0013] In another implementation, a multi-kinase inhibitor inhibits VEGFR and fibroblast growth factor receptor (FGFR).

[0014] In another embodiment, the multi-kinase inhibitor is selected from the group consisting of axitinib, regorafenib, pazopanib, nintedanib, and pharmaceutically acceptable salts thereof.

[0015] In another embodiment, the multi-kinase inhibitor has a concentration of about 0.01-0.1% (w / v), about 0.1-1% (w / v), about 1-10% (w / v), about 1.5%-5% (w / v), about 1.5% (w / v), about 2% (w / v), about 2.5% (w / v), about 3% (w / v), about 3.5% (w / v), about 4% (w / v), about 4.5% (w / v), about 5% (w / v), about 6% (w / v), about 7% (w / v), about 8% (w / v), about 9% (w / v), or about 9% (w / v).

[0016] In another embodiment, a method of treating an ophthalmic condition includes: providing a topical ophthalmic composition containing a concentration of about 1-10% (w / v) of a multi-kinase inhibitor; and treating a patient with the topical ophthalmic composition to treat the ophthalmic condition. The multi-kinase inhibitor inhibits the vascular endothelial growth factor receptor (VEGFR).

[0017] In another implementation, a multi-kinase inhibitor inhibits VEGFR and fibroblast growth factor receptor (FGFR).

[0018] In another embodiment, the multi-kinase inhibitor is selected from the group consisting of axitinib, regorafenib, pazopanib, nintedanib, and pharmaceutically acceptable salts thereof.

[0019] In another embodiment, the multi-kinase inhibitor has a concentration of about 0.01-0.1% (w / v), about 0.1-1% (w / v), about 1-10% (w / v), about 1.5%-5% (w / v), about 1.5% (w / v), about 2% (w / v), about 2.5% (w / v), about 3% (w / v), about 3.5% (w / v), about 4% (w / v), about 4.5% (w / v), about 5% (w / v), about 6% (w / v), about 7% (w / v), about 8% (w / v), about 9% (w / v), or about 9% (w / v).

[0020] In another embodiment, the topical ophthalmic composition is a non-aqueous formulation of a suspension, solution, or emulsion, and includes perfluorohexyloctane (F6H8) as a liquid carrier. Preferably, F6H8 is the only liquid carrier, and the liquid carrier is water-free.

[0021] In another implementation, the ophthalmic condition is selected from the group consisting of: failed glaucoma surgery, failed minimally invasive glaucoma surgery, neovascular glaucoma, meibomian gland dysfunction, dry eye disease, Sjogren's syndrome, alkali burns, ulcers, graft-versus-host disease, atopic conjunctivitis, ocular erythema, cicatricial pemphigoid, stem cell deficiency, Lyell's syndrome, Steven Johnson's syndrome, viruses, bacteria, fungi, pterygium, macular degeneration, corneal transplant infection, corneal parasitic infection, and contact lens-induced angiogenesis.

[0022] In another implementation, glaucoma surgery failure is caused by classic trabeculectomy, trabeculoablation, gonioscopy-assisted transcavitary trabeculotomy, excimer laser trabeculostomy, and endoscopic ciliary body photocoagulation; minimally invasive glaucoma surgery failure is caused by implantation of ocular filtering devices.

[0023] In another implementation, the ocular filtration device used in minimally invasive glaucoma surgery is selected from the group consisting of a subconjunctival stent, a scleral sinus stent, and a suprachoroidal stent.

[0024] It should be understood that the foregoing overview and the following embodiments are merely exemplary and illustrative, and are intended to provide further explanation of the claimed invention.

[0025] Brief description of the attached figures

[0026] The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and form part of this specification, illustrate embodiments of the invention and, together with the description, serve to explain the principles of the invention.

[0027] In the attached diagram:

[0028] Figure 1 shows the fibroblast density scores of groups 1-4. Group 1: Loading agent control; Group 2: MMC positive control; Group 3: 0.3% nintedanib treatment from day 7 to day 30; Group 4: 0.3% nintedanib treatment from day 1 to day 30. Detailed Implementation

[0029] The embodiments of the present invention will now be described in detail, examples of which are shown in the accompanying drawings.

[0030] Multi-kinase inhibitors (MKIs) refer to pharmaceutical compounds (e.g., small molecules) that inhibit the activity of two or more kinases, including, for example, intracellular and / or cell surface tyrosine protein kinases. "Small molecule" is understood to refer to compounds having a molecular weight of less than 2,000 Daltons. These small molecules are preferably organic molecules. In some embodiments, "small molecule" does not include peptides or nucleic acid molecules.

[0031] Exemplary multi-kinase inhibitors used in the methods described herein exhibit certain kinase inhibitory properties, such as multi-kinase inhibitors targeting VEGFR(1, 2, 3)(IC). 50 <100nM), PDGFRα (IC 50 <1000nM) and FGFR1 (IC 50 <500nM) in vitro IC 50The kinase inhibitory properties. Exemplary multi-kinase inhibitors used in the methods described herein include, for example, afatinib, amuvatinib, axitinib, cabozantinib, canertinib, cediranib, ceritinib, crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golvatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib. The preferred molecule is axitinib, lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tandutinib, tivantinib, tivozanib, trametinib, vandetanib, vatalanib, and vemurafenib; preferably axitinib, nintedanib, pazopanib, sildenafil, regorafenib, ponatinib, and lenvatinib; and more preferably axitinib, nintedanib, pazopanib, and regorafenib. The structures and in vitro efficacies of preferred kinase inhibitors are shown below and in Table 1.

[0032]

[0033] Table 1. In vitro potency of selected kinase inhibitors against key receptors

[0034]

[0035]

[0036] MKIs are commonly used to treat cancer. The mechanism is to inhibit angiogenesis / vascularization at the cancer site and to deprive cancer tissue of nutrients, causing its growth to regress. This mechanism can also be applied to other diseases with abnormally high vascularity. Some MKIs, as exemplified herein, can also inhibit FGFR and have the potential to treat diseases with abnormal fibrosis. The compositions and methods described herein can be used to treat patients with ocular diseases in the anterior part of the eye involving abnormal angiogenesis / hypervascularity or fibrosis, or both.

[0037] For example, the present invention provides compositions and treatment methods using one of the listed examples of MKIs such as regorafenib, which improve the success rate of glaucoma surgery (e.g., glaucoma filtration surgery) by administration to the eye of a subject requiring such treatment. One aspect is characterized by a method of adjunctive treatment in a subject associated with glaucoma surgery, comprising administering to the subject in need an effective amount of a composition containing regorafenib or a pharmaceutically acceptable salt thereof. This method improves the success rate of glaucoma surgery. Glaucoma surgery includes, for example, classic trabeculectomy, or methods selected from the group consisting of trabeculoablation, gonioscopy-assisted transluminal trabeculectomy, excimer laser trabeculostomy, and endoscopic cyclophotocoagulation. Glaucoma surgery performed can also be used for implantation of an ocular filtration device, wherein the ocular filtration device is an ocular stent. For example, the ocular filtration device may be selected from the group consisting of iStent, Xen gel stents, Hydrus, and CyPass microstents.

[0038] In another aspect, the disclosed method reduces scar formation during glaucoma surgery by reducing abnormal polyvascularity and fibrosis at the surgical site. In some aspects, the disclosed method is performed before, in conjunction with, or after surgery to reduce glaucoma surgical failure. In some aspects, the amount of regorafenib administered effectively prolongs the duration of intraocular pressure (IOP) reduction by at least 10 days, at least 365 days, or at least 3650 days postoperatively. In some aspects, the amount of regorafenib administered effectively prolongs filtering bleb survival.

[0039] The materials, methods, and examples are illustrative only and not intended to be limiting.

[0040] In summary, excessive angiogenesis and fibrosis are key risk factors leading to excessive scarring and failure in glaucoma surgery. This invention provides compositions and methods utilizing anti-angiogenesis and anti-fibrosis mechanisms to improve the success rate of glaucoma surgery.

[0041] MKIs are known to be highly hydrophobic small molecules with very low solubility in water or water-based carriers. For example, axitinib has a solubility of only 0.2 mg / ml in water at neutral pH. Therefore, they are difficult to formulate into stable eye drop compositions for ocular use. This invention provides compositions and treatment methods using MKIs in stable formulations comprising perfluorohexyloctane (F6H8) as a liquid carrier for the treatment of ocular diseases with abnormal polyvascularity and / or fibrosis. Perfluorohexyloctane (F6H8) is an amphiphilic liquid having two covalently bonded, immiscible portions (a hydrocarbon segment and a perfluorinated segment). Other related analogues used in the compositions of the present invention may be perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10), preferably perfluorobutylpentane (F4H5), perfluorohexylhexane (F6H6), and perfluorohexyloctane (F6H8), and more preferably perfluorohexyloctane (F6H8).

[0042] The structure of F6H8 is shown below.

[0043]

[0044] In some embodiments, the invention is based on studies described in the examples, which demonstrate that the use of regorafenib formulated in F6H8 is a preferred choice for treating the ocular indications listed in the invention. More specifically, this combination is chosen to reduce the failure rate of glaucoma surgery.

[0045] Example 1 describes the efforts made to develop an aqueous formulation of nintedanib. Nintedanib is highly insoluble in water, with reported solubility below 0.01 mg / mL (i.e., 0.001%). Various aqueous formulation carriers and combinations thereof were tested to attempt to formulate nintedanib at reasonably high concentrations. Thus, an aqueous emulsion formulation was found that maintains good long-term stability at 0.3% nintedanib. Example 2 describes the testing of 0.3% nintedanib in an emulsion formulation in a rabbit glaucoma filtration surgery model. However, in this example, it was found that the formulation could not deliver sufficient drug to the surgical site to achieve the expected effect of preventing filtration bleb failure. Simultaneously, therapeutic signals were detected, showing that the formulation reduced fibroblast density. Since fibrosis is a key step in surgical failure, this example indicates that the desired therapeutic effect could be achieved if more effective carriers could be used to deliver more nintedanib to the surgical site.

[0046] Because higher concentrations of nintedanib can lead to harmful side effects, such as yellow conjunctival discoloration observed clinically due to the yellow color of the nintedanib molecule, regorafenib, a colorless compound with similar pharmacological properties to nintedanib, was chosen for further formulation development and in vivo animal model testing. Further experiments were conducted to evaluate various solvents to determine which solvent would be best for forming a much higher concentration of regorafenib for topical ophthalmic application. In Example 3, among all the solvents tested, F6H8 was the preferred non-aqueous carrier for formulating regorafenib at concentrations such as about 0.01-0.1% (w / v) or about 0.1-1% (w / v), preferably about 1-10% (w / v), about 1.5%-5% (w / v), or about 1.5% (w / v), more preferably about 2% (w / v), about 2.5% (w / v), about 3% (w / v), about 3.5% (w / v), about 4% (w / v), about 4.5% (w / v), about 5% (w / v), about 6% (w / v), about 7% (w / v), about 8% (w / v), about 9% (w / v), or about 9% (w / v). In Example 4, a thought experiment using a 2% regorafenib formulation in F6H8 will improve the success rate of glaucoma surgery in a canine model. The present disclosure of compositions of MKIs formulated with F6H8 is a novel use of delivering sufficient concentrations of multi-kinase inhibitors to the target site to achieve the desired pharmacological effect.

[0047] Example

[0048] Example 1: Emulsion Formulation of Multi-Kinetic Kinase Inhibitors

[0049] The formulation of nintedanib was studied according to the following procedure:

[0050] 1. Subtract the tare weight of the 1.5mL Eppendorf tube.

[0051] 2. Add Nydanibue and record the weight.

[0052] 3. Add solubilizer and record the weight.

[0053] 4. Add water with pH 5 (except for F3 and F4) and record the weight.

[0054] 5. Mix in a bead mill for 120 seconds.

[0055] 6. Place on a rotating stirrer and incubate overnight at ambient temperature.

[0056] 7. Filtered through a 0.2μm SPIN-X centrifugal filter.

[0057] 8. Measure the pH of the filtrate.

[0058] 9. Analyze the filtrate using CBT-001 standard solution.

[0059] Although many of the solubilizers studied have similar structural properties, drastically different results were obtained for each solubilizer studied (see, for example, Tables 2 and 3). Solubilizers such as castor oil and polysorbate 80 were found to have high solubility for nintedanib.

[0060] Table 2. Screened Compositions (wt%)

[0061] Nidanip 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 benzyl alcohol 1 ethanol 1 castor oil 99.5 mineral oil 99.5 BZK 1 Polysorbate 20 1 Polysorbate 80 1 Polosham 188 1 Polosham 407 1 PEG400 5 PEG8000 2 Propylene glycol 1 WFI 98.5 98.5 98.5 98.5 98.5 98.5 98.5 94.5 97.5 98.5

[0062] Table 3. Solubility of Nydananib in various solubilizers

[0063]

[0064]

[0065] Based on the solubilization results, various aqueous emulsion systems were identified for use in the study. An aqueous emulsion system combining castor oil, polysorbate 80, and polyoxyethylene 35 castor oil was found to be suitable for dissolving nintedanib. As shown in Table 4, one of the emulsion systems dissolved nintedanib at approximately 3-5 mg / ml, i.e., a concentration of 0.3%-0.5% in an ophthalmic emulsion.

[0066] Table 4. Solubility of Nydanaibu in Representative Emulsion Systems

[0067] castor oil 1 1 Polysorbate 80 1 1 Polyoxyethylene 35 castor oil 2 2 water 95 95 Nydanib solubility (mg / ml) 5 3.4

[0068] Example 2: Study on the rabbit glaucoma filtration surgical model of nintedanib

[0069] In this embodiment, a 0.3% nintedanib emulsion was tested in a rabbit glaucoma filtration surgery model. Nintedanib is one of four MKIs that inhibit angiogenesis and fibrosis. The study showed a positive therapeutic signal on fibroblast density rather than bleb survival, suggesting a need for higher drug concentrations for potential use in actual glaucoma surgery.

[0070] method

[0071] Model establishment: A glaucoma filtration surgery model was established as previously described (Cordeiro et al., 1997; Zhong et al., 2011).

[0072] Negative control: BID administration of the load from day 7 to day 30 (group 1).

[0073] Positive control: Mitomycin C (MMC) was administered for 5 minutes during the operation (Group 2).

[0074] Test product: 0.3% CBT-001 (nintedanib) administered by BID from day 7 to day 30 (group 3) and from day 1 to day 30 (group 4).

[0075] Measurement methods: IOP, filtration follicle score, fibroblast density histology, fibrosis staining and inflammation level.

[0076] Time points: Days 2, 4, 7, 10, 14, 21, and 30 post-surgery.

[0077] Animals: 24 female New Zealand white rabbits (6 per group).

[0078] The study design is shown in Table 5 below.

[0079] Table 5: Research Design

[0080]

[0081] OU = both eyes, OD = right eye, OS = left eye, IOP = intraocular pressure, OE = ocular examination, H&E = hematoxylin and eosin staining, PK = pharmacokinetics

[0082] Results and Conclusions

[0083] Of all the measurements, only fibroblast density showed a therapeutic signal. The results are shown in Figure 3. A significant decrease in fibroblast density was observed in group 4 (treated with nintedanib for 30 days). A non-statistically significant decreasing trend was also seen in group 3 (treated with nintedanib from day 7 to day 30). No differences were observed in the primary therapeutic endpoint, blebular survival, or load-controlled fibroblasts between the two treatment groups.

[0084] The results suggest that the 0.3% nintedanib emulsion was ineffective in improving bleb survival. However, a therapeutic signal was detected in fibroblast density. Further, it is inferred that the current 0.3% formulation does not deliver sufficient drug to the surgical site, but the mechanism by which multi-kinase inhibitors reduce glaucoma surgery failure is well-founded. These results indicate that if adequate amounts could be delivered to the surgical site, MKIs with targeted pharmacological properties, such as nintedanib, would be effective.

[0085] Example 3: Regorafenib was formulated into a non-aqueous eye drop solution with a concentration of 2%.

[0086] In this embodiment, experiments were conducted to formulate regorafenib at, for example, a high concentration of 2% for topical ophthalmic use. F6H8 was identified as the most suitable non-aqueous carrier for this purpose.

[0087] 400 mg of micronized regorafenib monohydrate was suspended in 20 mL of perfluorohexyloctane (F6H8). The suspension was homogenized by stirring at room temperature for 15 minutes. The measured concentration of regorafenib was 95.4-99.1% of the theoretical concentration. The observed fluctuations were most likely due to sample inhomogeneity after hand-shaking the suspension. No unidentified degradation products were observed in the chromatogram using the HPLC method described below.

[0088] The HPLC method for determining the concentration of regorafenib is as follows: Samples were prepared by diluting the aliquots of the injected formulation to a final concentration of 100 μg / mL using a water:acetonitrile (25 / 75) solution. 100 μL of each sample was injected into an Agilent 1100 HPLC system (Agilent, Waldbron, Germany) and run at a flow rate of 1 mL / min on a heated (40 °C) Symmetry C18 column (150 × 4.6 mm - 3.5 μm particle size, Waters, Eschborn, Germany). The mobile phase consisted of a mixture of potassium phosphate buffer pH 2.4 (A) and acetonitrile / ethanol (6 / 4) (B). The following gradients were applied: 0 min: 60% A / 40% B, 12 min: 20% A / 80% B, 16 min: 20% A / 80% B, 16.5 min: 60% A / 40% B, 20 min: 60% A / 40% B. The Regfini peak was quantified at 265 nm using a DAD detector. The Regfini peak appeared at 12.5 minutes.

[0089] Example 4: Study of the Canine Glaucoma Filtering Surgical Model by Regfini

[0090] In this thought experiment, a 2% regorafenib formulation prepared in a perfluorohexyloctane (F6H8) carrier was tested in a canine model of glaucoma filtration surgery. Regorafenib is another example of an MKI in this invention that inhibits angiogenesis and fibrosis. Its in vitro potency against VEGFR and FGFR is more than twice that of nintedanib. Studies have shown that this formulation improves the success rate of glaucoma surgery in canine models and suggests its potential use in human glaucoma surgery to reduce failure rates.

[0091] method

[0092] Model establishment: A glaucoma filtration surgery model was established as previously described (Kojima et al., 2015). Ofloxacin ointment was applied to the eyes after surgery.

[0093] Test sample: 2% regorafenib in perfluorohexyloctane, with a postoperative BID lasting 4 weeks.

[0094] Control: Perfluorohexyloctane, BID lasted for 4 weeks postoperatively.

[0095] Measurement methods: IOP, filtration bubble score, collagen content.

[0096] Time points: Day 14 and Day 28 post-surgery.

[0097] The study design is shown in Table 6 below.

[0098] Table 6: Research Design

[0099]

[0100]

[0101] OU = both eyes, OD = right eye, OS = left eye, IOP = intraocular pressure, OE = ocular examination, H&E = hematoxylin and eosin staining, PK = pharmacokinetics

[0102] Results and Conclusions

[0103] As shown in Table 7, the regorafenib treatment group showed significant differences from the load group. Lower IOP was observed on days 14 and 28, while no significant changes were observed in the load group. The filtration bubble score was higher in the regorafenib group than in the load group, and the collagen content was lower in the regorafenib group.

[0104] Table 7: Results of Example 3 on IOP, filtration bubble score, and collagen density

[0105]

[0106] a There is a significant difference from the baseline. b : There was a significant difference compared to the carrier group.

[0107] Results showed that a 2% regorafenib formulation in perfluorohexyloctane (F6H8) improved the success rate of glaucoma filtration surgery in a canine model. This or a regorafenib-like formulation has the potential for use in human glaucoma surgery to reduce failure rates over time. It may also be used to treat other ocular diseases in the anterior segment of the eye involving abnormally high vascularity and / or fibrosis.

[0108] Those skilled in the art will understand that various modifications and variations can be made to this invention without departing from the spirit or scope thereof. Therefore, this invention is intended to cover modifications and variations thereof, provided they fall within the scope of the appended claims and their equivalents.

Claims

1. A topical ophthalmic composition comprising: As an active pharmaceutical ingredient, the multi-kinase inhibitor is selected from the group consisting of regorafenib and its pharmaceutically acceptable salts; and Perfluorohexyl octane (F6H8) as a liquid carrier, and The topical ophthalmic composition is a non-aqueous preparation of suspension or emulsion, and the multi-kinase inhibitor has a concentration of 2-10% (w / v).

2. The topical ophthalmic composition according to claim 1, wherein the multi-kinase inhibitor is regorafenib.

3. The topical ophthalmic composition according to claim 1 or 2, wherein the multi-kinase inhibitor has a concentration of 2% (w / v), 2.5% (w / v), 3% (w / v), 3.5% (w / v), 4% (w / v), 4.5% (w / v), 5% (w / v), 6% (w / v), 7% (w / v), 8% (w / v), 9% (w / v), or 10% (w / v).

4. The topical ophthalmic composition according to claim 1 or 2, wherein the topical ophthalmic composition is a non-aqueous suspension.

5. The topical ophthalmic composition according to claim 1 or 2, further comprising an organic latent solvent selected from the group consisting of ethanol, isopropanol, glycerin, propylene glycol and polyethylene glycol.

6. A topical ophthalmic composition comprising: As an active pharmaceutical ingredient, the multi-kinase inhibitor is selected from the group consisting of regorafenib and its pharmaceutically acceptable salts; and Perfluorohexyl octane (F6H8) as a liquid carrier, and The topical ophthalmic composition is a non-aqueous preparation of suspension or emulsion, and the multi-kinase inhibitor has a concentration of 2-10% (w / v).

7. The topical ophthalmic composition according to claim 6, wherein the multi-kinase inhibitor is regorafenib.

8. The topical ophthalmic composition according to claim 6 or 7, wherein the multi-kinase inhibitor has a concentration of 2% (w / v), 2.5% (w / v), 3% (w / v), 3.5% (w / v), 4% (w / v), 4.5% (w / v), 5% (w / v), 6% (w / v), 7% (w / v), 8% (w / v), 9% (w / v), or 10% (w / v).

9. Use of a topical ophthalmic composition comprising a multi-kinase inhibitor as an active pharmaceutical ingredient at a concentration of 2-10% (w / v) and perfluorohexyloctane (F6H8) as a liquid carrier in the preparation of a medicament for improving the success rate of glaucoma surgery or minimally invasive glaucoma surgery by means of: said multi-kinase inhibitor being selected from the group consisting of regorafenib and pharmaceutically acceptable salts thereof, said means comprising: Provide the aforementioned topical ophthalmic composition; and The topical ophthalmic composition is used to treat patients to improve the success rate of glaucoma surgery or minimally invasive glaucoma surgery, wherein the multi-kinase inhibitor inhibits vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), and The topical ophthalmic composition is a non-aqueous preparation of a suspension or emulsion.

10. The use according to claim 9, wherein the multi-kinase inhibitor is regorafenib.

11. The use according to claim 9 or 10, wherein the multi-kinase inhibitor has a concentration of 2% (w / v), 2.5% (w / v), 3% (w / v), 3.5% (w / v), 4% (w / v), 4.5% (w / v), 5% (w / v), 6% (w / v), 7% (w / v), 8% (w / v), 9% (w / v), or 10% (w / v).

12. The use according to claim 9 or 10, wherein the glaucoma surgery is selected from classic trabeculectomy, trabeculoablation, gonioscopy-assisted transcavitary trabeculotomy, excimer laser trabeculostomy, and endoscopic ciliary body photocoagulation; and the minimally invasive glaucoma surgery is the implantation of an ocular filter device.

13. The use according to claim 12, wherein the ocular filtering device is selected from the group consisting of a subconjunctival stent, a scleral sinus stent, and a suprachoroidal stent.

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