Compositions and methods for using nintedanib to treat eye diseases involving abnormal neovascularization.

Abstract

This invention provides a method for treating ocular indications involving abnormal neovascularization. [Solution] The present invention provides a method comprising the step of administering an effective amount of nintedanib or a pharmaceutically acceptable salt thereof in the form of a topical eye drop or implant to the eye of a subject.

Description

Technical Field

[0001] Priority Claim This application claims the benefit of U.S. Provisional Patent Application No. 62 / 344,878, filed on June 2, 2016, and U.S. Provisional Patent Application No. 62 / 344,870, filed on June 2, 2016, the entire contents of each of which are incorporated herein by reference.

[0002] Technical Field The present disclosure relates to ophthalmic compositions and methods using nintedanib for the treatment and prevention of graft rejection in high-risk corneal transplant patients and for the treatment of eye diseases associated with abnormal neovascularization in the anterior segment of the eye.

Background Art

[0003] Background Abnormal neovascularization is involved in many diseases in the anterior segment of the eye. Abnormal neovascularization is involved in graft rejection in high-risk corneal transplant patients. Current treatment methods for many of these indications need improvement. The methods disclosed herein address the problems of current treatment methods and provide improved treatment for these diseases.

Summary of the Invention

[0004] Summary In certain aspects, the present disclosure provides a method for treating an eye disease associated with abnormal neovascularization in the anterior segment of the eye, the method comprising administering to the eye of a subject needing such treatment an effective amount of nintedanib or a pharmaceutically acceptable salt thereof. In certain aspects, the disclosed method treats, prevents, or delays the onset of graft rejection in a corneal transplant patient. For example, the disclosed method treats, prevents, or delays the onset of graft rejection in a corneal transplant patient at high risk of graft rejection. In certain aspects, the disclosed method is performed before, simultaneously with, or after surgery to prevent graft rejection in a high-risk corneal transplant.

[0005] In certain situations, nintedanib is administered in the form of a topical ophthalmic formulation that is administered topically to the affected eye. In certain situations, the concentration of nintedanib in the formulation is 0.001% to 10% of the total weight or total volume of the composition. For example, aqueous compositions contain 0.001%, 0.01%, 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 5.0%, or up to 10% nintedanib. In certain situations, the topical ophthalmic formulation is a solution, suspension, gel, or emulsion. In other situations, nintedanib is administered in the form of an implant inserted into the affected eye or in the form of a semi-solid sustained-release formulation. In certain situations, the amount of nintedanib in the implant is 1 μg to 100 mg.

[0006] The term "subject" refers to an animal or human, or one or more cells derived from an animal or human. Preferably, the subject is human. The subject may also include non-human primates. A human subject may be publicly known as a patient.

[0007] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by a person of ordinary skill in the art to which this invention pertains. While the methods and materials used in this invention are described herein, other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative and not intended to limit the invention. All publications, patent applications, patients, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of any conflict, including definitions, this specification shall prevail.

[0008] [Invention 1001] A method for treating an indication of the eye with abnormal neovascularization, comprising the step of administering an effective amount of nintedanib or a pharmaceutically acceptable salt thereof in the form of a topical eye drop or an implant to the eye of a subject. [Invention 1002] The method of the present invention 1001, wherein the indication accompanied by the aforementioned abnormal neovascularization is corneal graft rejection after a corneal transplant in a high-risk patient. [Invention 1003] The method of the present invention 1001, wherein nintedanib is administered in an amount effective in preventing graft rejection by inhibiting abnormal neovascularization and inflammation in the eye of the subject. [Invention 1004] The method of the present invention 1001, wherein the indication accompanied by the aforementioned abnormal neovascularization is graft-versus-host disease. [Invention 1005] The method of the present invention 1001, wherein the indication accompanied by the aforementioned abnormal neovascularization is atopic conjunctivitis. [Invention 1006] The method of the present invention 1001, wherein the indication accompanied by the aforementioned abnormal neovascularization is ocular rosacea. [Invention 1007] The method of the present invention 1001, wherein the indication accompanied by the aforementioned abnormal neovascularization is ocular pemphigoid. [Invention 1008] The method of the present invention 1001, wherein the indication accompanied by the aforementioned abnormal neovascularization is Lyell's syndrome. [Invention 1009] The method of the present invention 1001, wherein the indication accompanied by the abnormal neovascularization is neovascularization induced by a viral infection, bacterial infection, fungal infection, or parasitic infection. [Invention 1010] The method of the present invention 1001, wherein the indication accompanied by the aforementioned abnormal neovascularization is contact lens-induced neovascularization. [Invention 1011] The method of the present invention 1001, wherein the indication accompanied by the aforementioned abnormal neovascularization is an ulcer. [Invention 1012] The method of the present invention 1001, wherein the indication accompanied by the aforementioned abnormal neovascularization is burns caused by alkali. [Invention 1013] The method of the present invention 1001, wherein the indication accompanied by the aforementioned abnormal neovascularization is stem cell deficiency. [Invention 1014] The method of the present invention 1001, wherein the indication accompanied by the aforementioned abnormal neovascularization is pinguecula. [Invention 1015] The method of the present invention 1001, wherein the indication accompanied by the aforementioned abnormal neovascularization is neovascular glaucoma. [Invention 1016] The method of the present invention 1001, wherein the indication accompanied by the aforementioned abnormal neovascularization is dry eye disease. [Invention 1017] The method of the present invention 1001, wherein the indication accompanied by the aforementioned abnormal neovascularization is Sjögren's syndrome. [Invention 1018] The method of the present invention 1001, wherein the indication accompanied by the aforementioned abnormal neovascularization is meibomian gland dysfunction. [Invention 1019] The method of the present invention 1001, wherein the indication accompanied by the aforementioned abnormal neovascularization is Stevens-Johnson syndrome. [Invention 1020] The method of the present invention 1001, wherein the indication accompanied by the aforementioned abnormal neovascularization is a tumor of the eye. [Invention 1021] The method of the present invention 1001, wherein nintedanib is administered in the form of a topical ophthalmic formulation or an ophthalmic implant. [Invention 1022] The method of the present invention 1021, wherein the ophthalmic implant is in the form of a semi-solid or solid sustained-release implant. [Invention 1023] The method of the present invention 1022, wherein the implant is inserted into the target eye. [Invention 1024] The method of the present invention 1021, wherein the topical ophthalmic preparation is a topical eye drop solution. [Invention 1025] The method of the present invention 1021, wherein the topical ophthalmic preparation is a solution, suspension, cream, ointment, gel, gel-forming solution, suspension containing liposomes or micelles, spray preparation, or emulsion. Other features and advantages of the present invention will become apparent from the following detailed description and drawings, as well as from the claims.

Brief Description of the Drawings

[0009] [Figure 1] This is a schematic diagram showing an exemplary mechanism for preventing graft rejection in high-risk corneal transplant patients in accordance with the present disclosure. [Figure 2] Figures 2A and 2B are graphs showing that corneal neovascularization was reduced in the presence of nintedanib in a rabbit corneal suture model. Figure 2A provides the results on day 12, and Figure 2B provides the results on day 14. The area of corneal neovascularization in each treatment group is shown (CBT-1 = nintedanib ophthalmic formulation: 0.2% CBT-1 BID, 0.2% CBT-1 TID; 0.05% CBT-1 BID, 0.05% CBT-1 TID; vehicle control TID). The T-test significance levels comparing each group to the vehicle are indicated by asterisks.

Modes for Carrying Out the Invention

[0010] Detailed Description Corneal transplantation is a common surgical procedure. Although the overall success rate of corneal transplantation is good, graft failure remains a problem in some high-risk patients. These patients have strong inflammation and neovascularization at the host graft site, which enhance the immune response and rejection of allogeneic grafts (Yu et al. World J Transplant. 2016; 6(1): 10-27). Oral immunosuppressive drugs may be used to reduce the risk of graft failure, but these have systemic side effects. The disclosed method prevents graft rejection in high-risk patients by inhibiting excessive neovascularization via vascular endothelial growth factor (「VEGF」) and platelet-derived growth factor receptor (「PDGFR」), and by weakening the immune response associated with VEGF and fibroblast growth factor (「FGF」). This mechanism is shown in Figure 1.

[0011] In addition to corneal graft rejection, the disclosed method can be used to treat any ocular indications involving abnormal neovascularization in the anterior portion of the eye. These indications include graft-versus-host disease, atopic conjunctivitis, ocular rosacea, ocular pemphigoid, Lyell's syndrome, neovascularization induced by viral, bacterial, fungal, or parasitic infections, contact lens-induced neovascularization, ulcers, alkali burns, stem cell deficiency, pinguecula, neovascular glaucoma, dry eye disease, Sjögren's syndrome, meibomian gland dysfunction, Stevens-Johnson syndrome, and tumors in the eye.

[0012] The terms “treatment,” “treating,” and “treat” are used herein to generally describe obtaining a desired pharmacological and / or physiological effect. This effect may be preventive in that it completely or partially prevents the disease or its symptoms, and / or therapeutic in that it partially or completely stabilizes or cures the disease and / or any side effects caused by it. The term “treatment” encompasses any treatment of a disease in mammals, particularly humans, and includes (a) preventing the disease and / or symptoms from developing in a subject who may be predisposed to developing the disease or symptoms but has not yet been diagnosed with the disease; (b) suppressing the disease and / or symptoms, i.e., halting their progression; or (c) reducing the symptoms of the disease, i.e., regressing the disease and / or symptoms. Persons requiring treatment include those who have already developed the disease (e.g., those with increased corneal neovascularization) and those for whom prevention is desired.

[0013] Nintedanib {methyl(3Z)-3-{[(4-{methyl[(4-methylpiperazine-1-yl)acetyl]amino}phenyl)amino](phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate} is a kinase inhibitor as described herein. Nintedanib primarily inhibits receptor tyrosine kinases, including, for example, vascular endothelial growth factor receptors (VEGFR1-3), platelet-derived growth factor receptors (PDGFRα and β), and fibroblast growth factor receptors (FGFR1-4).

[0014] Formulations and drug regimens The methods described herein include the preparation and use of a pharmaceutical composition comprising a compound identified by the methods described herein as an active ingredient. The pharmaceutical composition itself is also included.

[0015] Pharmaceutical compositions typically contain pharmaceutically acceptable excipients. As used herein, the terms “pharmaceutically acceptable excipients” or “pharmaceutically acceptable carriers” include physiological salines, solvents, dispersions, coatings, antimicrobial and antifungal agents, isotonic agents and absorption retarders, etc., that are suitable for pharmaceutical administration.

[0016] As used herein, the term “pharmaceutically acceptable salt” means a salt of a compound of interest that is safe and effective for administration to mammals and possesses the desired biological activity. Pharmacologically acceptable acidic salts include, but are not limited to, hydrochlorides, hydrobroms, hydroiodides, nitrates, sulfates, bisulfates, phosphates, superphosphates, I₂O isonicotinates, carbonates, bicarbonates, acetates, lactates, salicylates, citrates, tartrates, propionates, butyrates, pyruvates, oxalates, malons, pantothenates, tartrates, ascorbicates, succinates, maleates, gentisinates, fumarates, glucons, glucurons, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoic acid (i.e., I,I'methylene-bis-(2-hydroxy-3-naphthoate)) salts. Suitable basic salts include, but are not limited to, aluminum-15, calcium, lithium, magnesium, potassium, sodium, zinc, bismuth, and diethanolamine salts.

[0017] Methods for formulating appropriate pharmaceutical compositions are known in the art; see, for example, Remington: The Science and Practice of Pharmacy, 21st ed., 2005 and the series of literature Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, solutions, suspensions, creams, ointments, gels, gel-forming solutions, suspensions containing liposomes or micelles, spray formulations, or emulsions used in ophthalmic applications may contain the following components: sterile diluents, e.g., water for injection, saline solution, fixative oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents; antioxidants; chelating agents; buffers, e.g., acetic acid, citric acid, or phosphoric acid; and isotonic modifiers, e.g., sodium chloride or dextrose. The pH may be adjusted using an acid or base, e.g., hydrochloric acid or sodium hydroxide.

[0018] The pharmaceutical compositions disclosed herein may contain a “therapeutic effective dose” of the active substances described herein. Such an effective dose may be determined based on the effect of the administered active substance, or, if two or more active substances are used, on the combined effect of the active substances. The therapeutic effective dose of an active substance may also vary depending on factors such as the individual’s disease state, age, sex, and weight, as well as the compound’s ability to induce a desired response in that individual, such as improvement in at least one disorder parameter or improvement in at least one symptom of that disorder. The therapeutic effective dose is also the amount in which the therapeutically beneficial effect of the composition outweighs any toxic or adverse effects of the composition.

[0019] The effective dose of the compositions of this disclosure for treating a condition varies depending on many different factors, including the means of administration, the target site, whether human or animal, the physiological condition of the subject, other pharmaceuticals administered, and whether the treatment is prophylactic or therapeutic. The treatment dose may be titrated using conventional methods known to those skilled in the art for optimizing safety and efficacy.

[0020] Pharmaceutical compositions suitable for injection may include sterile aqueous solutions (if water-soluble) or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. They should be stable under manufacturing and storage conditions and protected against contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium, including, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Adequate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many examples, it is preferable to include isotonic agents, such as sugars, polyhydric alcohols, such as mannitol, sorbitol, and sodium chloride, in the composition. Long-term absorption of the injectable composition can be achieved by including absorption-delaying agents, such as aluminum monostearate and gelatin, in the composition.

[0021] Sterile injectable solutions can be prepared by adding the required amount of the active compound to a suitable solvent, along with one or a combination of the components listed above as needed, and then sterilizing and filtering. Generally, dispersions are prepared by adding the active compound to a sterile vehicle containing a basic dispersion medium and other required components from those listed above. For sterile powders for the preparation of sterile injectable solutions, preferred preparation methods are vacuum drying and lyophilization, which produce powders of the active ingredient and any additional desired components from a pre-sterilizing and filtered solution.

[0022] In one embodiment, the therapeutic compound is prepared using a carrier that protects the therapeutic compound from rapid elimination from the body, such as a controlled-release formulation including implants and microencapsulation delivery systems. Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, may be used. Such formulations can be prepared using standard techniques and are also commercially available.

[0023] The pharmaceutical composition may be contained in a container, pack, or dispenser, along with instructions for administration.

[0024] Compositions and formulations of nintedanib may be administered topically, by insertion of a semi-solid formulation or solid implant, or by any other suitable method known in the art. While the active substances disclosed herein may be used directly for therapeutic purposes, it may be preferable to administer the active substances as pharmaceutical formulations mixed with appropriate pharmaceutical excipients, diluents, or carriers selected, for example, in relation to the intended route of administration and standard pharmacokinetics. Pharmaceutical formulations comprise at least one active compound together with pharmaceutically acceptable excipients, diluents, and / or carriers.

[0025] The composition or formulation may be administered once, twice, three times, four times, or more times daily. The frequency may be reduced during the maintenance phase of the treatment, for example, from once every two or three days instead of daily or twice daily. The dosage and frequency of administration may be adjusted at the discretion of the treating physician, taking into account, for example, the clinical signs, pathological signs, and clinical and subclinical symptoms of the condition treated by the method of the present invention, as well as the patient's medical history.

[0026] It will be understood that the amount of the active ingredient disclosed herein required for use in treatment will vary depending on the route of administration, the nature of the condition requiring treatment, and the patient's age, weight, and condition, and ultimately it is at the discretion of the attending physician. The composition typically contains an effective amount of nintedanib. A preliminary dose may be determined according to animal studies, and dose scaling for human administration may be carried out according to methods accepted in the art.

[0027] The length of the procedure, i.e., the number of days, is readily determined by the physician performing the procedure, but the duration of the procedure can range from approximately 1 day to approximately 365 days. When provided by the method of the present invention, the effectiveness of the procedure can be monitored during the procedure to determine whether the procedure was successful or whether additional (or modified) procedures are necessary.

[0028] The dose, toxicity, and therapeutic effect of the therapeutic compound can be determined by standard pharmaceutical methods in cell cultures or experimental animals, for example, to determine the LD50 (lethal dose for 50% of the population) and ED50 (therapeutic dose for 50% of the population). The dosage form of nintedanib can be readily determined by those skilled in the art and can be obtained, for example, in animal models and clinical studies reported in the literature regarding dose, safety, and efficacy determination according to standard methods known in the art. Specific formulations, routes of administration, and doses can be selected by individual physicians in light of the patient's condition.

[0029] The compositions for use in the method of the present invention may contain nintedanib at a concentration of 0.001% to 10% of the total weight or total volume of the composition. For example, an aqueous composition may contain 0.001%, 0.01%, 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 5.0%, or up to 10% of nintedanib.

[0030] As is well known to those skilled in the art, administration of an aqueous solution to the eye may take the form of "eye drops" or multiple eye drops from a dropper or pipette or other dedicated sterile device (e.g., nintedanib solution). Such eye drops may typically be up to 50 microliters in volume, but may be less, for example, less than 10 microliters. [Examples]

[0031] The present invention is further illustrated by the following embodiments, but these embodiments are not intended to limit the scope of the invention as described in the claims.

[0032] Example 1: Rabbit corneal suture model The rabbit corneal suture model for neovascularization demonstrates the ability of this method to reduce abnormal corneal neovascularization.

[0033] Topical ophthalmic preparations Topical compositions were prepared containing 0.2% or 0.05% nintedanib in 10% 2-hydroxypropyl β-cyclodextrin in a phosphate buffer solution, pH 7.4.

[0034] Animals and treatment methods This study was conducted using 13 female New Zealand White rabbits. Briefly, on day 1, five sutures were placed in the upper cornea of ​​the right eye of each animal to induce neovascularization. Both eyes of these animals were treated with either drugs, vehicles, or saline solution, as described in Table 1.

[0035] (Table 1) TIFF2026110820000001.tif73138BID: Twice a day (approximately every 10-12 hours). TID: Three times a day (approximately every 6-8 hours). OD = Right eye. OS = Left eye. The medication was administered to both eyes, with a dosage of approximately 40 μL per eye. Note: The first administration of saline solution on day 1 was given 4 hours after the sutures were placed.

[0036] During the study, the animals were carefully observed for various ocular indications and their overall physical condition, including body weight. Eye images were taken on days 7, 10, 12, 14, 21, and 28 for the analysis of conjunctivitis.

[0037] Data Analysis Eye images were analyzed using NIH ImageJ® software. Each image was opened in ImageJ®, scales were added to the image using the ruler, and the neovascularization area on the cornea near the sutures was selected using the selection tool. 2 The area of ​​each unit was calculated using a measurement tool within the software, recorded in Excel, and images were captured and saved. A two-tailed t-test was used to determine whether there were significant differences between the groups. The results were plotted as a histogram of the means, along with the standard deviation, to facilitate comparison.

[0038] Results and Discussion As shown in Figures 2A and 2B, nintedanib showed a significant inhibitory effect on suture-induced neovascularization in rabbit corneas 12 and 14 days after suture induction. Higher doses of 0.2% nintedanib showed better efficacy than 0.05% nintedanib, and higher-frequency dosing regimens of TID showed better efficacy compared to BID dosing.

[0039] In summary, nintedanib strongly inhibited suture-induced corneal neovascularization. This strong activity is thought to be due to nintedanib's specific target profile, which exhibits potent activity against VEGFR1-3 and FGFR1-2. These results support the methods disclosed herein.

[0040] Example 2: Mouse corneal graft rejection model In this example, the corneas of C57BL / 6 mice were transplanted into BALB / c mouse corneas as described (Sonoda et al. Invest Ophthalmol Vis Sci. 1995 Feb; 36(2): 427-34; Invest Ophthalmol Vis Sci. 2000 Mar; 41(3): 790-8; Yamagami et al. Invest Ophthalmol Vis Sci. 2001 May; 42(6): 1293-8). The sutures were removed on day 7 post-transplant. The mice were divided into two groups. Group 1 was treated with a 0.2% nintedanib solution, and Group 2 was treated with a vehicle solution. Treatment was started immediately after transplantation and carried out over 8 weeks in a TID. Corneal opacity and graft rejection were evaluated weekly for 8 weeks as described.

[0041] The nintedanib-treated group showed a significantly higher graft survival rate (lower rejection rate) during the 8-week experiment. This result indicates that a 0.2% nintedanib solution can prevent corneal graft rejection.

[0042] Example 3: Formulation Nintedanib ophthalmic solution This drug formulation is an isotonic ophthalmic solution prepared with 2-hydroxypropyl β-cyclodextrin or other similar cyclodextrins and a buffer solution in the pH range of 5.5 to 8.0. Other viscous agents, lubricants, and preservatives may be added to enhance the functionality of this formulation. The composition of this ophthalmic solution is shown in Table 2.

[0043] (Table 2) Nintedanib Ophthalmic Solution TIFF2026110820000002.tif37156TIFF2026110820000003.tif219156

[0044] Nintedanib ophthalmic suspension This drug formulation is an isotonic ophthalmic suspension prepared with carboxymethylcellulose sodium and a buffer solution in the pH range of 5.5 to 8.0. The drug particle size is less than 40 micrometers. Other viscous agents, lubricants, solubilizers, and preservatives may be added to enhance the functionality of this formulation suspension. Its composition is shown in Table 3.

[0045] (Table 3) Nintedanib ophthalmic suspension TIFF2026110820000004.tif162156TIFF2026110820000005.tif98156

[0046] Nintedanib Ophthalmic Emulsion This drug formulation is an isotonic ophthalmic emulsion. The drug is dissolved in a mixed oil phase and an emulsifying excipient, then emulsified and mixed with an aqueous phase in the pH range of 5.5 to 8.0. Other viscous agents, lubricants, solubilizers, and preservatives may be added to enhance the functionality of this emulsion formulation. Its composition is shown in Table 4.

[0047] (Table 4) Nintedanib Ophthalmic Emulsion TIFF2026110820000006.tif226156TIFF2026110820000007.tif36156

[0048] Nintedanib sustained-release semi-solid formulation This drug formulation is an isotonic, sustained-release semi-solid formulation. The drug is dissolved and / or suspended in a semi-solid medium with a pH range of 5.5 to 8.0. Other viscous agents, lubricants, solubilizers, and preservatives may be added to enhance the functionality of this sustained-release semi-solid formulation. Its composition is shown in Table 5.

[0049] (Table 5) Sustained-release semi-solid formulations TIFF2026110820000008.tif131156

[0050] Nintedanib sustained-release implant This drug formulation is a solid implant. The drug is mixed and blended with one or more polymers. This drug-polymer mixture is melted at a predetermined temperature and extruded to form a filament of a predetermined diameter size. This filament formulation is cut into predetermined-sized segments that can be implanted into ocular tissue. Its composition is shown in Table 6.

[0051] (Table 6) Persistent-release implants TIFF2026110820000009.tif81156

[0052] Non-limitingly, the example compositions used in the methods according to the present invention may be modified from the ophthalmologically acceptable compositions shown.

[0053] Other embodiments While the present invention is described in connection with its detailed description, it should be understood that the above description is intended to be illustrative and not to limit the scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are also included in the scope of the appended claims.

Claims

1. A method for treating an indication of the eye with abnormal neovascularization, comprising the step of administering an effective amount of nintedanib or a pharmaceutically acceptable salt thereof in the form of a topical eye drop or an implant to the eye of a subject.

2. The method according to claim 1, wherein the indication accompanied by abnormal neovascularization is corneal graft rejection after a corneal transplant in a high-risk patient.

3. The method according to claim 1, wherein nintedanib is administered in an amount effective in preventing graft rejection by inhibiting abnormal neovascularization and inflammation in the eye of the subject.

4. The method according to claim 1, wherein the indication accompanied by abnormal neovascularization is graft-versus-host disease.

5. The method according to claim 1, wherein the indication accompanied by the abnormal neovascularization is atopic conjunctivitis.

6. The method according to claim 1, wherein the indication accompanied by the abnormal neovascularization is ocular rosacea.

7. The method according to claim 1, wherein the indication accompanied by the abnormal neovascularization is ocular pemphigoid.

8. The method according to claim 1, wherein the indication accompanied by the abnormal neovascularization is Lyell's syndrome.

9. The method according to claim 1, wherein the indication involving abnormal neovascularization is neovascularization induced by a viral infection, bacterial infection, fungal infection, or parasitic infection.

10. The method according to claim 1, wherein the indication accompanied by the abnormal neovascularization is contact lens-induced neovascularization.

11. The method according to claim 1, wherein the indication accompanied by the abnormal neovascularization is an ulcer.

12. The method according to claim 1, wherein the indication accompanied by the abnormal neovascularization is burns caused by alkali.

13. The method according to claim 1, wherein the indication accompanied by the abnormal neovascularization is stem cell deficiency.

14. The method according to claim 1, wherein the indication accompanied by the abnormal neovascularization is pinguecula.

15. The method according to claim 1, wherein the indication accompanied by the abnormal neovascularization is neovascular glaucoma.

16. The method according to claim 1, wherein the indication accompanied by the abnormal neovascularization is dry eye disease.

17. The method according to claim 1, wherein the indication accompanied by the abnormal neovascularization is Sjögren's syndrome.

18. The method according to claim 1, wherein the indication accompanied by the abnormal neovascularization is meibomian gland dysfunction.

19. The method according to claim 1, wherein the indication accompanied by abnormal neovascularization is Stevens-Johnson syndrome.

20. The method according to claim 1, wherein the indication accompanied by abnormal neovascularization is a tumor of the eye.

21. The method according to claim 1, wherein nintedanib is administered in the form of a topical ophthalmic formulation or an ophthalmic implant.

22. The method according to claim 21, wherein the ophthalmic implant is in the form of a semi-solid or solid sustained-release implant.

23. The method according to claim 22, wherein the implant is inserted into the target eye.

24. The method according to claim 21, wherein the topical ophthalmic preparation is a topical eye drop solution.

25. The method according to claim 21, wherein the topical ophthalmic preparation is a solution, suspension, cream, ointment, gel, gel-forming solution, suspension containing liposomes or micelles, spray preparation, or emulsion.

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